Monday, July 14, 2008
Metalosis Maligna reference
Metalosis Maligna :is one of the most impressive and powerful diseases the human body has ever being capable of development, a virus called STREPTOCOCCCUS METALOMALIGNA is the responsible for this impressive disorder involving the human tissue and the metal implant.
Symtoms: you start feeling itchy and are forced to use a metal object to scratch your back.
Cure: Theres is no cure or treatment for this disease.
Saturday, July 12, 2008
AIDS reference
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome (AIDS or Aids) is a set of symptoms and infections resulting from the damage to the human immune system caused by the human immunodeficiency virus (HIV).[1] This condition progressively reduces the effectiveness of the immune system and leaves individuals susceptible to opportunistic infections and tumors. HIV is transmitted through direct contact of a mucous membrane or the bloodstream with a bodily fluid containing HIV, such as blood, semen, vaginal fluid, preseminal fluid, and breast milk.[2][3] This transmission can involve anal, vaginal or oral sex, blood transfusion, contaminated hypodermic needles, exchange between mother and baby during pregnancy, childbirth, or breastfeeding, or other exposure to one of the above bodily fluids.
AIDS is now a pandemic.[4] In 2007, an estimated 33.2 million people lived with the disease worldwide, and it killed an estimated 2.1 million people, including 330,000 children.[5] Over three-quarters of these deaths occurred in sub-Saharan Africa,[5] retarding economic growth and destroying human capital.[6] Most researchers believe that HIV originated in sub-Saharan Africa during the twentieth century.[7] The disease was first identified by the U.S. Centers for Disease Control and Prevention in 1981 and its cause identified by American and French scientists in the late 1980s.[8]
Although treatments for AIDS and HIV can slow the course of the disease, there is currently no vaccine or cure. Antiretroviral treatment reduces both the mortality and the morbidity of HIV infection, but these drugs are expensive and routine access to antiretroviral medication is not available in all countries.[9] Due to the difficulty in treating HIV infection, preventing infection is a key aim in controlling the AIDS epidemic, with health organizations promoting safe sex and needle-exchange programmes in attempts to slow the spread of the virus.
The symptoms of AIDS are primarily the result of conditions that do not normally develop in individuals with healthy immune systems. Most of these conditions are infections caused by bacteria, viruses, fungi and parasites that are normally controlled by the elements of the immune system that HIV damages. Opportunistic infections are common in people with AIDS.[10] HIV affects nearly every organ system. People with AIDS also have an increased risk of developing various cancers such as Kaposi's sarcoma, cervical cancer and cancers of the immune system known as lymphomas. Additionally, people with AIDS often have systemic symptoms of infection like fevers, sweats (particularly at night), swollen glands, chills, weakness, and weight loss.[11][12] The specific opportunistic infections that AIDS patients develop depend in part on the prevalence of these infections in the geographic area in which the patient lives.
Pulmonary infections
X-ray of Pneumocystis jirovecii caused pneumonia. There is increased white (opacity) in the lower lungs on both sides, characteristic of Pneumocystis pneumonia
X-ray of Pneumocystis jirovecii caused pneumonia. There is increased white (opacity) in the lower lungs on both sides, characteristic of Pneumocystis pneumonia
Pneumocystis pneumonia (originally known as Pneumocystis carinii pneumonia, and still abbreviated as PCP, which now stands for Pneumocystis pneumonia) is relatively rare in healthy, immunocompetent people, but common among HIV-infected individuals. It is caused by Pneumocystis jirovecii. Before the advent of effective diagnosis, treatment and routine prophylaxis in Western countries, it was a common immediate cause of death. In developing countries, it is still one of the first indications of AIDS in untested individuals, although it does not generally occur unless the CD4 count is less than 200 cells per µL of blood.[13]
Tuberculosis (TB) is unique among infections associated with HIV because it is transmissible to immunocompetent people via the respiratory route, is easily treatable once identified, may occur in early-stage HIV disease, and is preventable with drug therapy. However, multidrug resistance is a potentially serious problem. Even though its incidence has declined because of the use of directly observed therapy and other improved practices in Western countries, this is not the case in developing countries where HIV is most prevalent. In early-stage HIV infection (CD4 count >300 cells per µL), TB typically presents as a pulmonary disease. In advanced HIV infection, TB often presents atypically with extrapulmonary (systemic) disease a common feature. Symptoms are usually constitutional and are not localized to one particular site, often affecting bone marrow, bone, urinary and gastrointestinal tracts, liver, regional lymph nodes, and the central nervous system.[14]
Gastrointestinal infections
Esophagitis is an inflammation of the lining of the lower end of the esophagus (gullet or swallowing tube leading to the stomach). In HIV infected individuals, this is normally due to fungal (candidiasis) or viral (herpes simplex-1 or cytomegalovirus) infections. In rare cases, it could be due to mycobacteria.
Unexplained chronic diarrhea in HIV infection is due to many possible causes, including common bacterial (Salmonella, Shigella, Listeria or Campylobacter) and parasitic infections; and uncommon opportunistic infections such as cryptosporidiosis, microsporidiosis, Mycobacterium avium complex (MAC) and viruses,[16] astrovirus, adenovirus, rotavirus and cytomegalovirus, (the latter as a course of colitis). In some cases, diarrhea may be a side effect of several drugs used to treat HIV, or it may simply accompany HIV infection, particularly during primary HIV infection. It may also be a side effect of antibiotics used to treat bacterial causes of diarrhea (common for Clostridium difficile). In the later stages of HIV infection, diarrhea is thought to be a reflection of changes in the way the intestinal tract absorbs nutrients, and may be an important component of HIV-related wasting.[17]
Neurological and psychiatric involvement
HIV infection may lead to a variety of neuropsychiatric sequelae, either by infection of the now susceptible nervous system by organisms, or as a direct consequence of the illness itself.
Toxoplasmosis is a disease caused by the single-celled parasite called Toxoplasma gondii; it usually infects the brain causing toxoplasma encephalitis but it can infect and cause disease in the eyes and lungs.[18] Cryptococcal meningitis is an infection of the meninx (the membrane covering the brain and spinal cord) by the fungus Cryptococcus neoformans. It can cause fevers, headache, fatigue, nausea, and vomiting. Patients may also develop seizures and confusion; left untreated, it can be lethal.
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease, in which the gradual destruction of the myelin sheath covering the axons of nerve cells impairs the transmission of nerve impulses. It is caused by a virus called JC virus which occurs in 70% of the population in latent form, causing disease only when the immune system has been severely weakened, as is the case for AIDS patients. It progresses rapidly, usually causing death within months of diagnosis.[19]
AIDS dementia complex (ADC) is a metabolic encephalopathy induced by HIV infection and fueled by immune activation of HIV infected brain macrophages and microglia which secrete neurotoxins of both host and viral origin.[20] Specific neurological impairments are manifested by cognitive, behavioral, and motor abnormalities that occur after years of HIV infection and is associated with low CD4+ T cell levels and high plasma viral loads. Prevalence is 10–20% in Western countries[21] but only 1–2% of HIV infections in India.[22][23] This difference is possibly due to the HIV subtype in India. AIDS related mania is sometimes seen in patients with advanced HIV illness; it presents with more irritability and cognitive impairment and less euphoria than a manic episode associated with true bipolar disorder. Unlike the latter condition, it may have a more chronic course. This syndrome is less often seen with the advent of multi-drug therapy.
Tumors and malignancies
Kaposi's sarcoma
Patients with HIV infection have substantially increased incidence of several malignant cancers. This is primarily due to co-infection with an oncogenic DNA virus, especially Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and human papillomavirus (HPV).[24][25]
Kaposi's sarcoma (KS) is the most common tumor in HIV-infected patients. The appearance of this tumor in young homosexual men in 1981 was one of the first signals of the AIDS epidemic. Caused by a gammaherpes virus called Kaposi's sarcoma-associated herpes virus (KSHV), it often appears as purplish nodules on the skin, but can affect other organs, especially the mouth, gastrointestinal tract, and lungs.
High-grade B cell lymphomas such as Burkitt's lymphoma, Burkitt's-like lymphoma, diffuse large B-cell lymphoma (DLBCL), and primary central nervous system lymphoma present more often in HIV-infected patients. These particular cancers often foreshadow a poor prognosis. In some cases these lymphomas are AIDS-defining. Epstein-Barr virus (EBV) or KSHV cause many of these lymphomas.
Cervical cancer in HIV-infected women is considered AIDS-defining. It is caused by human papillomavirus (HPV).[26]
In addition to the AIDS-defining tumors listed above, HIV-infected patients are at increased risk of certain other tumors, such as Hodgkin's disease and anal and rectal carcinomas. However, the incidence of many common tumors, such as breast cancer or colon cancer, does not increase in HIV-infected patients. In areas where HAART is extensively used to treat AIDS, the incidence of many AIDS-related malignancies has decreased, but at the same time malignant cancers overall have become the most common cause of death of HIV-infected patients.[27]
Other opportunistic infections
AIDS patients often develop opportunistic infections that present with non-specific symptoms, especially low-grade fevers and weight loss. These include infection with Mycobacterium avium-intracellulare and cytomegalovirus (CMV). CMV can cause colitis, as described above, and CMV retinitis can cause blindness. Penicilliosis due to Penicillium marneffei is now the third most common opportunistic infection (after extrapulmonary tuberculosis and cryptococcosis) in HIV-positive individuals within the endemic area of Southeast Asia.[28]
AIDS is the most severe acceleration of infection with HIV. HIV is a retrovirus that primarily infects vital organs of the human immune system such as CD4+ T cells (a subset of T cells), macrophages and dendritic cells. It directly and indirectly destroys CD4+ T cells.[29] Once HIV has killed so many CD4+ T cells that there are fewer than 200 of these cells per microliter (µL) of blood, cellular immunity is lost. Acute HIV infection progresses over time to clinical latent HIV infection and then to early symptomatic HIV infection and later to AIDS, which is identified either on the basis of the amount of CD4+ T cells remaining in the blood, and/or the presence of certain infections, as noted above.[30]
In the absence of antiretroviral therapy, the median time of progression from HIV infection to AIDS is nine to ten years, and the median survival time after developing AIDS is only 9.2 months.[31] However, the rate of clinical disease progression varies widely between individuals, from two weeks up to 20 years. Many factors affect the rate of progression. These include factors that influence the body's ability to defend against HIV such as the infected person's general immune function.[32][33] Older people have weaker immune systems, and therefore have a greater risk of rapid disease progression than younger people. Poor access to health care and the existence of coexisting infections such as tuberculosis also may predispose people to faster disease progression.[31][34][35] The infected person's genetic inheritance plays an important role and some people are resistant to certain strains of HIV. An example of this is people with the homozygous CCR5-Δ32 variation are resistant to infection with certain strains of HIV.[36] HIV is genetically variable and exists as different strains, which cause different rates of clinical disease progression.[37][38][39]
Sexual transmission
Sexual transmission occurs with the contact between sexual secretions of one person with the rectal, genital or oral mucous membranes of another. Unprotected receptive sexual acts are riskier than unprotected insertive sexual acts, and the risk for transmitting HIV through unprotected anal intercourse is greater than the risk from vaginal intercourse or oral sex. However, oral sex is not entirely safe, as HIV can be transmitted through both insertive and receptive oral sex.[40] The risk of HIV transmission from exposure to saliva is considerably smaller than the risk from exposure to semen, one would have to swallow liters of saliva from a carrier to run a significant risk of becoming infected.[41] Sexual assault greatly increases the risk of HIV transmission as protection is rarely employed and physical trauma to the vagina frequently occurs, facilitating the transmission of HIV.[42]
Other sexually transmitted infections (STI) increase the risk of HIV transmission and infection, because they cause the disruption of the normal epithelial barrier by genital ulceration and/or microulceration; and by accumulation of pools of HIV-susceptible or HIV-infected cells (lymphocytes and macrophages) in semen and vaginal secretions. Epidemiological studies from sub-Saharan Africa, Europe and North America suggest that genital ulcers, such as those caused by syphilis and/or chancroid, increase the risk of becoming infected with HIV by about four-fold. There is also a significant although lesser increase in risk from STIs such as gonorrhea, Chlamydial infection and trichomoniasis, which all cause local accumulations of lymphocytes and macrophages.[43]
Transmission of HIV depends on the infectiousness of the index case and the susceptibility of the uninfected partner. Infectivity seems to vary during the course of illness and is not constant between individuals. An undetectable plasma viral load does not necessarily indicate a low viral load in the seminal liquid or genital secretions. However, each 10-fold increase in the level of HIV in the blood is associated with an 81% increased rate of HIV transmission.[43][44] Women are more susceptible to HIV-1 infection due to hormonal changes, vaginal microbial ecology and physiology, and a higher prevalence of sexually transmitted diseases.[45][46] People who have been infected with one strain of HIV can still be infected later on in their lives by other, more virulent strains.
Infection is unlikely in a single encounter. High rates of infection have been linked to a pattern of overlapping long-term romantic relationships. This allows the virus to quickly spread to multiple partners who in turn infect their partners. A pattern of serial monogamy or occasional casual encounters is associated with lower rates of infection.[47]
Exposure to blood-borne pathogens
CDC poster from 1989 highlighting the threat of AIDS associated with drug use
CDC poster from 1989 highlighting the threat of AIDS associated with drug use
This transmission route is particularly relevant to intravenous drug users, hemophiliacs and recipients of blood transfusions and blood products. Sharing and reusing syringes contaminated with HIV-infected blood represents a major risk for infection with HIV. Needle sharing is the cause of one third of all new HIV-infections in North America, China, and Eastern Europe. The risk of being infected with HIV from a single prick with a needle that has been used on an HIV-infected person is thought to be about 1 in 150 (see table above). Post-exposure prophylaxis with anti-HIV drugs can further reduce this risk.[48] This route can also affect people who give and receive tattoos and piercings. Universal precautions are frequently not followed in both sub-Saharan Africa and much of Asia because of both a shortage of supplies and inadequate training. The WHO estimates that approximately 2.5% of all HIV infections in sub-Saharan Africa are transmitted through unsafe healthcare injections.[49] Because of this, the United Nations General Assembly has urged the nations of the world to implement precautions to prevent HIV transmission by health workers.[50]
The risk of transmitting HIV to blood transfusion recipients is extremely low in developed countries where improved donor selection and HIV screening is performed. However, according to the WHO, the overwhelming majority of the world's population does not have access to safe blood and between 5% and 10% of the world's HIV infections come from transfusion of infected blood and blood products.[51]
Perinatal transmission
The transmission of the virus from the mother to the child can occur in utero during the last weeks of pregnancy and at childbirth. In the absence of treatment, the transmission rate between a mother and her child during pregnancy, labor and delivery is 25%. However, when the mother takes antiretroviral therapy and gives birth by caesarean section, the rate of transmission is just 1%.[52] The risk of infection is influenced by the viral load of the mother at birth, with the higher the viral load, the higher the risk. Breastfeeding also increases the risk of transmission by about 4 %.[53]
Misconceptions
A number of misconceptions have arisen surrounding HIV/AIDS. Three of the most common are that AIDS can spread through casual contact, that sexual intercourse with a virgin will cure AIDS, and that HIV can infect only homosexual men and drug users. Other misconceptions are that any act of anal intercourse between gay men can lead to AIDS infection, and that open discussion of homosexuality and HIV in schools will lead to increased rates of homosexuality and AIDS.
Cells affected
The virus, entering through which ever route, acts primarily on the following cells:[61]
1. Lymphoreticular system:
1. CD4+ T-Helper cells
2. CD4+ Macrophages
3. CD4+ Monocytes
4. B-lymphocytes
2. Certain endothelial cells
3. Central nervous system:
1. Microglia of the nervous system
2. Astrocytes
3. Oligodendrocytes
4. Neurones - indirectly by the action of cytokines and the gp-120
The effect
The virus has cytopathic effects but how it does it is still not quite clear. It can remain inactive in these cells for long periods, though. This effect is hypothesized to be due to the CD4-gp120 interaction.
* The most prominent effect of the HIV virus is its T-helper cell suppression and lysis. The cell is simply killed off or deranged to the point of being function-less (they do not respond to foreign antigens). The infected B-cells can not produce enough antibodies either. Thus the immune system collapses leading to the familiar AIDS complications, like infections and neoplasms (vide supra).
* Infection of the cells of the CNS cause acute aseptic meningitis, subacute encephalitis, vacuolar myelopathy and peripheral neuropathy. Later it leads to even AIDS dementia complex.
* The CD4-gp120 interaction (vide supra) is also permissive to other viruses like Cytomegalovirus, Hepatitis virus, Herpes simplex virus, etc. These viruses lead to further cell damage i.e. cytopathy.
Molecular basis
For details, see:
* Structure and genome of HIV,
* HIV replication cycle
* HIV tropism
Diagnosis
The diagnosis of AIDS in a person infected with HIV is based on the presence of certain signs or symptoms. Since June 5, 1981, many definitions have been developed for epidemiological surveillance such as the Bangui definition and the 1994 expanded World Health Organization AIDS case definition. However, clinical staging of patients was not an intended use for these systems as they are neither sensitive, nor specific. In developing countries, the World Health Organization staging system for HIV infection and disease, using clinical and laboratory data, is used and in developed countries, the Centers for Disease Control (CDC) Classification System is used.
In 1990, the World Health Organization (WHO) grouped these infections and conditions together by introducing a staging system for patients infected with HIV-1.[63] An update took place in September 2005. Most of these conditions are opportunistic infections that are easily treatable in healthy people.
* Stage I: HIV infection is asymptomatic and not categorized as AIDS
* Stage II: includes minor mucocutaneous manifestations and recurrent upper respiratory tract infections
* Stage III: includes unexplained chronic diarrhea for longer than a month, severe bacterial infections and pulmonary tuberculosis
* Stage IV: includes toxoplasmosis of the brain, candidiasis of the esophagus, trachea, bronchi or lungs and Kaposi's sarcoma; these diseases are indicators of AIDS.
CDC classification system
There are two main definitions for AIDS, both produced by the Centers for Disease Control and Prevention (CDC). The older definition is to referring to AIDS using the diseases that were associated with it, for example, lymphadenopathy, the disease after which the discoverers of HIV originally named the virus.[64][65] In 1993, the CDC expanded their definition of AIDS to include all HIV positive people with a CD4+ T cell count below 200 per µL of blood or 14% of all lymphocytes.[66] The majority of new AIDS cases in developed countries use either this definition or the pre-1993 CDC definition. The AIDS diagnosis still stands even if, after treatment, the CD4+ T cell count rises to above 200 per µL of blood or other AIDS-defining illnesses are cured.
HIV test
Many people are unaware that they are infected with HIV.[67] Less than 1% of the sexually active urban population in Africa has been tested, and this proportion is even lower in rural populations. Furthermore, only 0.5% of pregnant women attending urban health facilities are counseled, tested or receive their test results. Again, this proportion is even lower in rural health facilities.[67] Therefore, donor blood and blood products used in medicine and medical research are screened for HIV.
HIV tests are usually performed on venous blood. Many laboratories use fourth generation screening tests which detect anti-HIV antibody (IgG and IgM) and the HIV p24 antigen. The detection of HIV antibody or antigen in a patient previously known to be negative is evidence of HIV infection. Individuals whose first specimen indicates evidence of HIV infection will have a repeat test on a second blood sample to confirm the results. The window period (the time between initial infection and the development of detectable antibodies against the infection) can vary since it can take 3–6 months to seroconvert and to test positive. Detection of the virus using polymerase chain reaction (PCR) during the window period is possible, and evidence suggests that an infection may often be detected earlier than when using a fourth generation EIA screening test. Positive results obtained by PCR are confirmed by antibody tests.[68] Routinely used HIV tests for infection in neonates, born to HIV-positive mothers, have no value because of the presence of maternal antibody to HIV in the child's blood. HIV infection can only be diagnosed by PCR, testing for HIV pro-viral DNA in the children's lymphocytes
Sexual contact
The majority of HIV infections are acquired through unprotected sexual relations between partners, one of whom has HIV. The primary mode of HIV infection worldwide is through sexual contact between members of the opposite sex.[78][79][80] During a sexual act, only male or female condoms can reduce the chances of infection with HIV and other STDs and the chances of becoming pregnant. The best evidence to date indicates that typical condom use reduces the risk of heterosexual HIV transmission by approximately 80% over the long-term, though the benefit is likely to be higher if condoms are used correctly on every occasion.[81] The male latex condom, if used correctly without oil-based lubricants, is the single most effective available technology to reduce the sexual transmission of HIV and other sexually transmitted infections. Manufacturers recommend that oil-based lubricants such as petroleum jelly, butter, and lard not be used with latex condoms, because they dissolve the latex, making the condoms porous. If necessary, manufacturers recommend using water-based lubricants. Oil-based lubricants can however be used with polyurethane condoms.[82]
The female condom is an alternative to the male condom and is made from polyurethane, which allows it to be used in the presence of oil-based lubricants. They are larger than male condoms and have a stiffened ring-shaped opening, and are designed to be inserted into the vagina. The female condom contains an inner ring, which keeps the condom in place inside the vagina – inserting the female condom requires squeezing this ring. However, at present availability of female condoms is very low and the price remains prohibitive for many women. Preliminary studies suggest that, where female condoms are available, overall protected sexual acts increase relative to unprotected sexual acts, making them an important HIV prevention strategy.[83]
Studies on couples where one partner is infected show that with consistent condom use, HIV infection rates for the uninfected partner are below 1% per year.[84] Prevention strategies are well-known in developed countries, however, recent epidemiological and behavioral studies in Europe and North America have suggested that a substantial minority of young people continue to engage in high-risk practices and that despite HIV/AIDS knowledge, young people underestimate their own risk of becoming infected with HIV.[85]
Randomized controlled trials have shown that male circumcision lowers the risk of HIV infection among heterosexual men by up to 60%.[86] It is expected that this procedure will be actively promoted in many of the countries affected by HIV, although doing so will involve confronting a number of practical, cultural and attitudinal issues. Some experts fear that a lower perception of vulnerability among circumcised men may result in more sexual risk-taking behavior, thus negating its preventive effects.[87]
Exposure to infected body fluids
Health care workers can reduce exposure to HIV by employing precautions to reduce the risk of exposure to contaminated blood. These precautions include barriers such as gloves, masks, protective eyeware or shields, and gowns or aprons which prevent exposure of the skin or mucous membranes to blood borne pathogens. Frequent and thorough washing of the skin immediately after being contaminated with blood or other bodily fluids can reduce the chance of infection. Finally, sharp objects like needles, scalpels and glass, are carefully disposed of to prevent needlestick injuries with contaminated items.[88] Since intravenous drug use is an important factor in HIV transmission in developed countries, harm reduction strategies such as needle-exchange programmes are used in attempts to reduce the infections caused by drug abuse.
Mother-to-child transmission (MTCT)
Current recommendations state that when replacement feeding is acceptable, feasible, affordable, sustainable and safe, HIV-infected mothers should avoid breast-feeding their infant. However, if this is not the case, exclusive breast-feeding is recommended during the first months of life and discontinued as soon as possible.[91]
Treatment
Abacavir – a nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs)
Abacavir – a nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs)
The chemical structure of Abacavir
The chemical structure of Abacavir
There is currently no vaccine or cure for HIV or AIDS. The only known methods of prevention are based on avoiding exposure to the virus or, failing that, an antiretroviral treatment directly after a highly significant exposure, called post-exposure prophylaxis (PEP).[92] PEP has a very demanding four week schedule of dosage. It also has very unpleasant side effects including diarrhea, malaise, nausea and fatigue.[93]
Antiviral therapy
Current treatment for HIV infection consists of highly active antiretroviral therapy, or HAART.[94] This has been highly beneficial to many HIV-infected individuals since its introduction in 1996 when the protease inhibitor-based HAART initially became available.[9] Current optimal HAART options consist of combinations (or "cocktails") consisting of at least three drugs belonging to at least two types, or "classes," of antiretroviral agents. Typical regimens consist of two nucleoside analogue reverse transcriptase inhibitors (NARTIs or NRTIs) plus either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRTI). Because HIV disease progression in children is more rapid than in adults, and laboratory parameters are less predictive of risk for disease progression, particularly for young infants, treatment recommendations are more aggressive for children than for adults.[95] In developed countries where HAART is available, doctors assess the viral load, rapidity in CD4 decline, and patient readiness while deciding when to recommend initiating treatment.[96]
HAART allows the stabilization of the patient’s symptoms and viremia, but it neither cures the patient of HIV, nor alleviates the symptoms, and high levels of HIV-1, often HAART resistant, return once treatment is stopped.[97][98] Moreover, it would take more than the lifetime of an individual to be cleared of HIV infection using HAART.[99] Despite this, many HIV-infected individuals have experienced remarkable improvements in their general health and quality of life, which has led to the plummeting of HIV-associated morbidity and mortality. In the absence of HAART, progression from HIV infection to AIDS occurs at a median of between nine to ten years and the median survival time after developing AIDS is only 9.2 months. HAART is thought to increase survival time by between 4 and 12 years.
For some patients, which can be more than fifty percent of patients, HAART achieves far less than optimal results, due to medication intolerance/side effects, prior ineffective antiretroviral therapy and infection with a drug-resistant strain of HIV. Non-adherence and non-persistence with therapy are the major reasons why some people do not benefit from HAART.[105] The reasons for non-adherence and non-persistence are varied. Major psychosocial issues include poor access to medical care, inadequate social supports, psychiatric disease and drug abuse. HAART regimens can also be complex and thus hard to follow, with large numbers of pills taken frequently.[106][107][108] Side effects can also deter people from persisting with HAART, these include lipodystrophy, dyslipidaemia, diarrhoea, insulin resistance, an increase in cardiovascular risks and birth defects.[109] Anti-retroviral drugs are expensive, and the majority of the world's infected individuals do not have access to medications and treatments for HIV and AIDS.
Future research
It has been postulated that only a vaccine can halt the pandemic because a vaccine would possibly cost less, thus being affordable for developing countries, and would not require daily treatments. However, even after almost 30 years of research, HIV-1 remains a difficult target for a vaccine.
Research to improve current treatments includes decreasing side effects of current drugs, further simplifying drug regimens to improve adherence, and determining the best sequence of regimens to manage drug resistance. A number of studies have shown that measures to prevent opportunistic infections can be beneficial when treating patients with HIV infection or AIDS. Vaccination against hepatitis A and B is advised for patients who are not infected with these viruses and are at risk of becoming infected.[111] Patients with substantial immunosuppression are also advised to receive prophylactic therapy for Pneumocystis jiroveci pneumonia (PCP), and many patients may benefit from prophylactic therapy for toxoplasmosis and Cryptococcus meningitis as well.[93]
Alternative medicine
Various forms of alternative medicine have been used to treat symptoms or alter the course of the disease.[112] Acupuncture has been used to alleviate some symptoms, such peripheral neuropathy, but cannot cure the HIV infection.[113] Several randomized clinical trials testing the effect of herbal medicines have shown that there is no evidence that these herbs have any effect on the progression of the disease, but may instead produce serious side-effects.[114]
Some data suggest that multivitamin and mineral supplements might reduce HIV disease progression in adults, although there is no conclusive evidence on if they reduce mortality among people with good nutritional status.[115] Vitamin A supplementation in children probably has some benefit.[115] Daily doses of selenium can suppress HIV viral burden with an associated improvement of the CD4 count. Selenium can be used as an adjunct therapy to standard antiviral treatments, but cannot itself reduce mortality and morbidity.[116]
Current studies indicate that that alternative medicine therapies have little effect on the mortality or morbidity of the disease, but may improve the quality of life of individuals afflicted with AIDS. The psychological benefits of these therapies are the most important use.
Epidemiology
Estimated prevalence of HIV among young adults (15-49) per country at the end of 2005
The AIDS pandemic can also be seen as several epidemics of separate subtypes; the major factors in its spread are sexual transmission and vertical transmission from mother to child at birth and through breast milk.[4] Despite recent, improved access to antiretroviral treatment and care in many regions of the world, the AIDS pandemic claimed an estimated 2.1 million (range 1.9–2.4 million) lives in 2007 of which an estimated 330,000 were children under 15 years.[5] Globally, an estimated 33.2 million people lived with HIV in 2007, including 2.5 million children. An estimated 2.5 million (range 1.8–4.1 million) people were newly infected in 2007, including 420,000 children.[5]
Sub-Saharan Africa remains by far the worst affected region. In 2007 it contained an estimated 68% of all people living with AIDS and 76% of all AIDS deaths, with 1.7 million new infections bringing the number of people living with HIV to 22.5 million, and with 11.4 million AIDS orphans living in the region. Unlike other regions, most people living with HIV in sub-Saharan Africa in 2007 (61%) were women. Adult prevalence in 2007 was an estimated 5.0%, and AIDS continued to be the single largest cause of mortality in this region.[5] South Africa has the largest population of HIV patients in the world, followed by Nigeria and India.[117] South & South East Asia are second worst affected; in 2007 this region contained an estimated 18% of all people living with AIDS, and an estimated 300,000 deaths from AIDS.[5] India has an estimated 2.5 million infections and an estimated adult prevalence of 0.36%.[5] Life expectancy has fallen dramatically in the worst-affected countries; for example, in 2006 it was estimated that it had dropped from 65 to 35 years in Botswana.[4]
Prognosis
Without treatment, the net median survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype,[5] and the median survival rate after diagnosis of AIDS in resource-limited settings where treatment is not available ranges between 6 and 19 months, depending on the study.[118] In areas where it is widely available, the development of HAART as effective therapy for HIV infection and AIDS reduced the death rate from this disease by 80%, and raised the life expectancy for a newly-diagnosed HIV-infected person to about 20 years.
As new treatments continue to be developed and because HIV continues to evolve resistance to treatments, estimates of survival time are likely to continue to change. Without antiretroviral therapy, death normally occurs within a year. Most patients die from opportunistic infections or malignancies associated with the progressive failure of the immune system.[120] The rate of clinical disease progression varies widely between individuals and has been shown to be affected by many factors such as host susceptibility and immune function health care and co-infections,[ as well as which particular strain of the virus is involved.
History
AIDS was first reported June 5, 1981, when the U.S. Centers for Disease Control and Prevention recorded a cluster of Pneumocystis carinii pneumonia (now still classified as PCP but known to be caused by Pneumocystis jirovecii) in five homosexual men in Los Angeles.[123] In the beginning, the Centers for Disease Control and Prevention (CDC) did not have an official name for the disease, often referring to it by way of the diseases that were associated with it, for example, lymphadenopathy, the disease after which the discoverers of HIV originally named the virus.[64][65] They also used Kaposi's Sarcoma and Opportunistic Infections, the name by which a task force had been set up in 1981.[124] In the general press, the term GRID, which stood for Gay-related immune deficiency, had been coined.[125] The CDC, in search of a name, and looking at the infected communities coined “the 4H disease,” as it seemed to single out Haitians, homosexuals, hemophiliacs, and heroin users.[126] However, after determining that AIDS was not isolated to the homosexual community,[124] the term GRID became misleading and AIDS was introduced at a meeting in July 1982.[127] By September 1982 the CDC started using the name AIDS, and properly defined the illness.[128]
A more controversial theory known as the OPV AIDS hypothesis suggests that the AIDS epidemic was inadvertently started in the late 1950s in the Belgian Congo by Hilary Koprowski's research into a poliomyelitis vaccine.[129][130] According to scientific consensus, this scenario is not supported by the available evidence.[131][132][133]
A recent study states that HIV probably moved from Africa to Haiti and then entered the United States around 1969.
Society and culture
Stigma
Ryan White became a poster child for HIV after being expelled from school because of his infection.
Ryan White became a poster child for HIV after being expelled from school because of his infection.
AIDS stigma exists around the world in a variety of ways, including ostracism, rejection, discrimination and avoidance of HIV infected people; compulsory HIV testing without prior consent or protection of confidentiality; violence against HIV infected individuals or people who are perceived to be infected with HIV; and the quarantine of HIV infected individuals.[135] Stigma-related violence or the fear of violence prevents many people from seeking HIV testing, returning for their results, or securing treatment, possibly turning what could be a manageable chronic illness into a death sentence and perpetuating the spread of HIV.
AIDS stigma has been further divided into the following three categories:
* Instrumental AIDS stigma—a reflection of the fear and apprehension that are likely to be associated with any deadly and transmissible illness.[137]
* Symbolic AIDS stigma—the use of HIV/AIDS to express attitudes toward the social groups or lifestyles perceived to be associated with the disease.[137]
* Courtesy AIDS stigma—stigmatization of people connected to the issue of HIV/AIDS or HIV- positive people.[138]
Often, AIDS stigma is expressed in conjunction with one or more other stigmas, particularly those associated with homosexuality, bisexuality, promiscuity, and intravenous drug use.
In many developed countries, there is an association between AIDS and homosexuality or bisexuality, and this association is correlated with higher levels of sexual prejudice such as anti-homosexual attitudes.[139] There is also a perceived association between AIDS and all male-male sexual behavior, including sex between uninfected men.[137]
Economic impact
Changes in life expectancy in some hard-hit African countries. Botswana Zimbabwe Kenya South Africa Uganda
Changes in life expectancy in some hard-hit African countries. Botswana Zimbabwe Kenya South Africa Uganda
HIV and AIDS affects economic growth by reducing the availability of human capital.[6] Without proper nutrition, health care and medicine that is available in developed countries, large numbers of people are falling victim to AIDS. They will not only be unable to work, but will also require significant medical care. The forecast is that this will likely cause a collapse of economies and societies in countries with a significant AIDS populationi. In some heavily infected areas, the epidemic has left behind many orphans cared for by elderly grandparents.
The increased mortality in this region will result in a smaller skilled population and labor force. This smaller labor force will be predominantly young people, with reduced knowledge and work experience leading to reduced productivity. An increase in workers’ time off to look after sick family members or for sick leave will also lower productivity. Increased mortality will also weaken the mechanisms that generate human capital and investment in people, through loss of income and the death of parents. By killing off mainly young adults, AIDS seriously weakens the taxable population, reducing the resources available for public expenditures such as education and health services not related to AIDS resulting in increasing pressure for the state's finances and slower growth of the economy. This results in a slower growth of the tax base, an effect that will be reinforced if there are growing expenditures on treating the sick, training (to replace sick workers), sick pay and caring for AIDS orphans. This is especially true if the sharp increase in adult mortality shifts the responsibility and blame from the family to the government in caring for these orphans.[140]
On the level of the household, AIDS results in both the loss of income and increased spending on healthcare by the household. The income effects of this lead to spending reduction as well as a substitution effect away from education and towards healthcare and funeral spending. A study in Côte d'Ivoire showed that households with an HIV/AIDS patient spent twice as much on medical expenses as other households.[141]
AIDS denialism
A small group of activists, including several scientists who do not study HIV/AIDS, question the connection between HIV and AIDS,[142] the existence of HIV itself,[143] or the validity of current testing and treatment methods. Though these claims have been examined and thoroughly rejected by the scientific community,[144] they continue to be promulgated through the Internet[145] and have had a significant political impact, particularly in South Africa, where President Thabo Mbeki's embrace of AIDS denialism has been blamed for an ineffective response to that country's AIDS epidemic.
allergies reference
Allergy is a disorder of the immune system often also referred to as atopy. Allergic reactions occur to environmental substances known as allergens; these reactions are acquired, predictable and rapid. Strictly, allergy is one of four forms of hypersensitivity and is called type I (or immediate) hypersensitivity. It is characterized by excessive activation of certain white blood cells called mast cells and basophils by a type of antibody known as IgE, resulting in an extreme inflammatory response. Common allergic reactions include eczema, hives, hay fever, asthma, food allergies, and reactions to the venom of stinging insects such as wasps and bees.[1]
Mild allergies like hay fever are highly prevalent in the human population and cause symptoms such as allergic conjunctivitis, itchiness, and runny nose. Allergies can play a major role in conditions such as asthma. In some people, severe allergies to environmental or dietary allergens or to medication may result in life-threatening anaphylactic reactions and potentially death.
A variety of tests now exist to diagnose allergic conditions; these include testing the skin for responses to known allergens or analyzing the blood for the presence and levels of allergen-specific IgE. Treatments for allergies include allergen avoidance, use of anti-histamines, steroids or other oral medications, immunotherapy to desensitize the response to allergen, and targeted therapy.
Classification and history
The concept "allergy" was originally introduced in 1906 by the Viennese pediatrician Clemens von Pirquet, after he noted that some of his patients were hypersensitive to normally innocuous entities such as dust, pollen, or certain foods.[2] Pirquet called this phenomenon "allergy" from the Greek words allos meaning "other" and ergon meaning "work".[3] Historically, all forms of hypersensitivity were classified as allergies, and all were thought to be caused by an improper activation of the immune system. Later, it became clear that several different disease mechanisms were implicated, with the common link to a disordered activation of the immune system. In 1963, a new classification scheme was designed by Philip Gell and Robin Coombs that described four types of hypersensitivity reactions, known as Type I to Type IV hypersensitivity.[4] With this new classification, the word "allergy" was restricted to only type I hypersensitivities (also called immediate hypersensitivity), which are characterized as rapidly developing reactions.
A major breakthrough in understanding the mechanisms of allergy was the discovery of the antibody class labeled immunoglobulin E (IgE) - Kimishige Ishizaka and co-workers were the first to isolate and describe IgE in the 1960s.
Cause
Risk factors for allergy can be placed in two general categories, namely host and environmental factors. Host factors include heredity, sex, race, and age, with heredity being by far the most significant. There have been recent increases in the incidence of allergic disorders, however, that cannot be explained by genetic factors alone. The four main environmental candidates are alterations in exposure to infectious diseases during early childhood, environmental pollution, allergen levels, and dietary changes.[14]
Genetic basis
Allergic diseases are strongly familial: identical twins are likely to have the same allergic diseases about 70% of the time; the same allergy occurs about 40% of the time in non-identical twins.[15] Allergic parents are more likely to have allergic children,[16] and their allergies are likely to be more severe than those from non-allergic parents. Some allergies, however, are not consistent along genealogies; parents who are allergic to peanuts may have children who are allergic to ragweed. It seems that the likelihood of developing allergies is inherited and related to an irregularity in the immune system, but the specific allergen is not.[16]
The risk of allergic sensitization and the development of allergies varies with age, with young children most at risk.[17] Several studies have shown that IgE levels are highest in childhood and fall rapidly between the ages of 10 and 30 years.[17] The peak prevalence of hay fever is highest in children and young adults and the incidence of asthma is highest in children under 10.[18] Overall, boys have a higher risk of developing allergy than girls,[16] although for some diseases, namely asthma in young adults, females are more likely to be affected.[19] Sex differences tend to decrease in adulthood.[16] Ethnicity may play a role in some allergies, however racial factors have been difficult to separate from environmental influences and changes due to migration.[16] Interestingly, it has been suggested that different genetic loci are responsible for asthma, specifically, in people of Caucasian, Hispanic, Asian, and African origins.[20]
Environmental factors
International differences have been associated with the number of individuals within a population that suffer from allergy. Allergic diseases are more common in industrialized countries than in countries that are more traditional or agricultural, and there is a higher rate of allergic disease in urban populations versus rural populations, although these differences are becoming less defined.[21]
Exposure to allergens, especially in early life, is an important risk factor for allergy. Alterations in exposure to microorganisms is the most plausible explanation, at present, for the increase in atopic allergy.[14] Since children that live in large families or overcrowded households, or attend day care, have a reduced incidence of allergic disease, a relationship has been proposed between exposures to bacteria and viruses during childhood, and protection against the development of allergy, which has been called – the "hygiene hypothesis".[21] Exposure to endotoxin and other components of bacteria may reduce atopic diseases.[22] Endotoxin exposure reduces release of inflammatory cytokines such as TNF-α, IFNγ, interleukin-10, and interleukin-12 from white blood cells (leukocytes) that circulate in the blood.[23] Certain microbe-sensing proteins, known as Toll-like receptors, found on the surface of cells in the body are also thought to be involved in these processes.[24]
Gutworms and similar parasites are present in untreated drinking water in developing countries, and were present in the water of developed countries until the routine chlorination and purification of drinking water supplies.[25] Recent research has shown that some common parasites, such as intestinal worms (e.g. hookworms), secrete chemicals into the gut wall (and hence the bloodstream) that suppress the immune system and prevent the body from attacking the parasite.[26] This gives rise to a new slant on the hygiene hypothesis theory — that co-evolution of man and parasites has led to an immune system that only functions correctly in the presence of the parasites. Without them, the immune system becomes unbalanced and oversensitive.[27] In particular, research suggests that allergies may coincide with the delayed establishment of gut flora in infants.[28] However, the research to support this theory is conflicting, with some studies performed in China and Ethiopia showing an increase in allergy in people infected with intestinal worms.[21] Clinical trials have been initiated to test the effectiveness of certain worms in treating some allergies.[29] It may be that the term 'parasite' could turn out to be inappropriate, and in fact a hitherto unsuspected symbiosis is at work.[29] For more information on this topic, see Helminthic therapy.
Pathophysiology
The pathophysiology of allergic responses can be divided into two phases. The first is an acute response that occurs immediately after exposure to an allergen. This phase can either subside or progress into a "late phase reaction" which can substantially prolong the symptoms of a response, and result in tissue damage.
Acute response
Degranulation process in allergy.1 - antigen; 2 - IgE antibody; 3 - FcεRI receptor; 4 - preformed mediators (histamine, proteases, chemokines, heparine); 5 - granules; 6 - mast cell; 7 - newly formed mediators (prostaglandins, leukotrienes, thromboxanes, PAF)
Degranulation process in allergy.1 - antigen; 2 - IgE antibody; 3 - FcεRI receptor; 4 - preformed mediators (histamine, proteases, chemokines, heparine); 5 - granules; 6 - mast cell; 7 - newly formed mediators (prostaglandins, leukotrienes, thromboxanes, PAF)
In the early stages of allergy, a type I hypersensitivity reaction against an allergen, encountered for the first time, causes a response in a type of immune cell called a TH2 lymphocyte, which belongs to a subset of T cells that produce a cytokine called interleukin-4 (IL-4). These TH2 cells interact with other lymphocytes called B cells, whose role is production of antibodies. Coupled with signals provided by IL-4, this interaction stimulates the B cell to begin production of a large amount of a particular type of antibody known as IgE. Secreted IgE circulates in the blood and binds to an IgE-specific receptor (a kind of Fc receptor called FcεRI) on the surface of other kinds of immune cells called mast cells and basophils, which are both involved in the acute inflammatory response. The IgE-coated cells, at this stage are sensitized to the allergen.[14]
If later exposure to the same allergen occurs, the allergen can bind to the IgE molecules held on the surface of the mast cells or basophils. Cross-linking of the IgE and Fc receptors occurs when more than one IgE-receptor complex interacts with the same allergenic molecule, and activates the sensitized cell. Activated mast cells and basophils undergo a process called degranulation, during which they release histamine and other inflammatory chemical mediators (cytokines, interleukins, leukotrienes, and prostaglandins) from their granules into the surrounding tissue causing several systemic effects, such as vasodilation, mucous secretion, nerve stimulation and smooth muscle contraction. This results in rhinorrhea, itchiness, dyspnea, and anaphylaxis. Depending on the individual, allergen, and mode of introduction, the symptoms can be system-wide (classical anaphylaxis), or localized to particular body systems; asthma is localized to the respiratory system and eczema is localized to the dermis.[14]
Late-phase response
After the chemical mediators of the acute response subside, late phase responses can often occur. This is due to the migration of other leukocytes such as neutrophils, lymphocytes, eosinophils and macrophages to the initial site. The reaction is usually seen 2-24 hours after the original reaction.[30] Cytokines from mast cells may also play a role in the persistence of long-term effects. Late phase responses seen in asthma are slightly different from those seen in other allergic responses, although they are still caused by release of mediators from eosinophils, and are still dependent on activity of TH2 cells.[31]
Diagnosis
An allergy testing machine being operated in the diagnostic immunology lab at Lackland Air Force Base
An allergy testing machine being operated in the diagnostic immunology lab at Lackland Air Force Base
Before a diagnosis of allergic disease can be confirmed, the other possible causes of the presenting symptoms should be carefully considered.[32] Vasomotor rhinitis, for example, is one of many maladies that shares symptoms with allergic rhinitis, underscoring the need for professional differential diagnosis.[33] Once a diagnosis of asthma, rhinitis, anaphylaxis, or other allergic disease has been made, there are several methods for discovering the causative agent of that allergy.
Skin testing
Skin Testing
For assessing the presence of allergen-specific IgE antibodies, allergy skin testing is preferred over blood allergy tests because it is more sensitive and specific, simpler to use, and less expensive.[34] Skin testing is also known as "puncture testing" and "prick testing" due to the series of tiny puncture or pricks made into the patient's skin. Small amounts of suspected allergens and/or their extracts (pollen, grass, mite proteins, peanut extract, etc.) are introduced to sites on the skin marked with pen or dye (the ink/dye should be carefully selected, lest it cause an allergic response itself). A small plastic or metal device is used to puncture or prick the skin. Sometimes, the allergens are injected "intradermally" into the patient's skin, with a needle and syringe. Common areas for testing include the inside forearm and the back. If the patient is allergic to the substance, then a visible inflammatory reaction will usually occur within 30 minutes. This response will range from slight reddening of the skin to a full-blown hive (called "wheal and flare") in more sensitive patients. Interpretation of the results of the skin prick test is normally done by allergists on a scale of severity, with +/- meaning borderline reactivity, and 4+ being a large reaction. Increasingly, allergists are measuring and recording the diameter of the wheal and flare reaction. Interpretation by well-trained allergists is often guided by relevant literature.[35] Some patients may believe they have determined their own allergic sensitivity from observation, but a skin test has been shown to be much better than patient observation to detect allergy.[36]
If a serious life threatening anaphylactic reaction has brought a patient in for evaluation, some allergists will prefer an initial blood test prior to performing the skin prick test. Skin tests may not be an option if the patient has widespread skin disease or has taken antihistamines sometime the last several days.
Blood testing
Various blood allergy testing methods are also available for detecting allergy to specific substances. This kind of testing measures a "total IgE level" - an estimate of IgE contained within the patient's serum. This can be determined through the use of radiometric and colormetric immunoassays. Radiometric assays include the radioallergosorbent test (RAST) test method, which uses IgE-binding (anti-IgE) antibodies labeled with radioactive isotopes for quantifying the levels of IgE antibody in the blood.[34] Other newer methods use colorimetric or fluorometric technology in the place of radioactive isotopes. Some "screening" test methods are intended to provide qualitative test results, giving a "yes" or "no" answer in patients with suspected allergic sensitization. One such method has a sensitivity of about 70.8% and a positive predictive value of 72.6% according to a large study.[37]
A low total IgE level is not adequate to rule out sensitization to commonly inhaled allergens. Statistical methods, such as ROC curves, predictive value calculations, and likelihood ratios have been used to examine the relationship of various testing methods to each other. These methods have shown that patients with a high total IgE have a high probability of allergic sensitization, but further investigation with specific allergy tests for a carefully chosen allergens is often warranted.
Pharmacotherapy
Several antagonistic drugs are used to block the action of allergic mediators, or to prevent activation of cells and degranulation processes. These include antihistamines, cortisone, dexamethasone, hydrocortisone, epinephrine (adrenaline), theophylline and cromolyn sodium. Anti-leukotrienes, such as Montelukast (Singulair) or Zafirlukast (Accolate), are FDA approved for treatment of allergic diseases.[citation needed] Anti-cholinergics, decongestants, mast cell stabilizers, and other compounds thought to impair eosinophil chemotaxis, are also commonly used. These drugs help to alleviate the symptoms of allergy, and are imperative in the recovery of acute anaphylaxis, but play little role in chronic treatment of allergic disorders.
Immunotherapy
Desensitization or hyposensitization is a treatment in which the patient is gradually vaccinated with progressively larger doses of the allergen in question. This can either reduce the severity or eliminate hypersensitivity altogether. It relies on the progressive skewing of IgG antibody production, to block excessive IgE production seen in atopys. In a sense, the person builds up immunity to increasing amounts of the allergen in question. Studies have demonstrated the long-term efficacy and the preventive effect of immunotherapy in reducing the development of new allergy.[40] Meta-analyses have also confirmed efficacy of the treatment in allergic rhinitis in children and in asthma.[citation needed] A review by the Mayo Clinic in Rochester confirmed the safety and efficacy of allergen immunotherapy for allergic rhinitis and conjunctivitis, allergic forms of asthma, and stinging insect based on numerous well-designed scientific studies.[41] Additionally, national and international guidelines confirm the clinical efficacy of injection immunotherapy in rhinitis and asthma, as well as the safety, provided that recommendations are followed.[42]
A second form of immunotherapy involves the intravenous injection of monoclonal anti-IgE antibodies. These bind to free and B-cell associated IgE; signalling their destruction. They do not bind to IgE already bound to the Fc receptor on basophils and mast cells, as this would stimulate the allergic inflammatory response. The first agent of this class is Omalizumab. While this form of immunotherapy is very effective in treating several types of atopy, it should not be used in treating the majority of people with food allergies.[citation needed]
A third type, Sublingual immunotherapy, is an orally-administered therapy which takes advantage of oral immune tolerance to non-pathogenic antigens such as foods and resident bacteria. This therapy currently accounts for 40 percent of allergy treatment in Europe.[citation needed] In the United States, sublingual immunotherapy is gaining support among traditional allergists and is endorsed by doctors who treat allergy.[citation needed]
Unproven or ineffective treatments
An experimental treatment, enzyme potentiated desensitization (EPD), has been tried for decades but is not generally accepted as effective.[43] EPD uses dilutions of allergen and an enzyme, beta-glucuronidase, to which T-regulatory lymphocytes are supposed to respond by favouring desensitization, or down-regulation, rather than sensitization. EPD has also been tried for the treatment of autoimmune diseases but again is not FDA approved or of proven effectiveness.[43]
In alternative medicine, a number of allergy treatments are described by its practitioners, particularly naturopathic, herbal medicine, homeopathy, traditional Chinese medicine and kinesiology. Systematic literature searches conducted by the Mayo Clinic through 2006, involving hundreds of articles studying multiple conditions, including asthma and upper respiratory tract infection showed no effectiveness of any alternative treatments, and no difference compared with placebo. The authors concluded that, based on rigorous clinical trials of all types of homeopathy for childhood and adolescence ailments, there is no convincing evidence that supports the use of alternative treatments.[44]
Epidemiology
Many diseases related to inflammation such as type 1 diabetes, rheumatoid arthritis and allergic diseases—hay fever and asthma—have increased in the Western world over the past 2-3 decades.[45] Rapid increases in allergic asthma and other atopic disorders in industrialized nations probably began in the 1960s and 1970s, with further increases occurring during the 1980s and 1990s,[46] although some suggest that a steady rise in sensitization has been occurring since the 1920s.[47] The incidence of atopy in developing countries has generally remained much lower.
Mild allergies like hay fever are highly prevalent in the human population and cause symptoms such as allergic conjunctivitis, itchiness, and runny nose. Allergies can play a major role in conditions such as asthma. In some people, severe allergies to environmental or dietary allergens or to medication may result in life-threatening anaphylactic reactions and potentially death.
A variety of tests now exist to diagnose allergic conditions; these include testing the skin for responses to known allergens or analyzing the blood for the presence and levels of allergen-specific IgE. Treatments for allergies include allergen avoidance, use of anti-histamines, steroids or other oral medications, immunotherapy to desensitize the response to allergen, and targeted therapy.
Classification and history
The concept "allergy" was originally introduced in 1906 by the Viennese pediatrician Clemens von Pirquet, after he noted that some of his patients were hypersensitive to normally innocuous entities such as dust, pollen, or certain foods.[2] Pirquet called this phenomenon "allergy" from the Greek words allos meaning "other" and ergon meaning "work".[3] Historically, all forms of hypersensitivity were classified as allergies, and all were thought to be caused by an improper activation of the immune system. Later, it became clear that several different disease mechanisms were implicated, with the common link to a disordered activation of the immune system. In 1963, a new classification scheme was designed by Philip Gell and Robin Coombs that described four types of hypersensitivity reactions, known as Type I to Type IV hypersensitivity.[4] With this new classification, the word "allergy" was restricted to only type I hypersensitivities (also called immediate hypersensitivity), which are characterized as rapidly developing reactions.
A major breakthrough in understanding the mechanisms of allergy was the discovery of the antibody class labeled immunoglobulin E (IgE) - Kimishige Ishizaka and co-workers were the first to isolate and describe IgE in the 1960s.
Cause
Risk factors for allergy can be placed in two general categories, namely host and environmental factors. Host factors include heredity, sex, race, and age, with heredity being by far the most significant. There have been recent increases in the incidence of allergic disorders, however, that cannot be explained by genetic factors alone. The four main environmental candidates are alterations in exposure to infectious diseases during early childhood, environmental pollution, allergen levels, and dietary changes.[14]
Genetic basis
Allergic diseases are strongly familial: identical twins are likely to have the same allergic diseases about 70% of the time; the same allergy occurs about 40% of the time in non-identical twins.[15] Allergic parents are more likely to have allergic children,[16] and their allergies are likely to be more severe than those from non-allergic parents. Some allergies, however, are not consistent along genealogies; parents who are allergic to peanuts may have children who are allergic to ragweed. It seems that the likelihood of developing allergies is inherited and related to an irregularity in the immune system, but the specific allergen is not.[16]
The risk of allergic sensitization and the development of allergies varies with age, with young children most at risk.[17] Several studies have shown that IgE levels are highest in childhood and fall rapidly between the ages of 10 and 30 years.[17] The peak prevalence of hay fever is highest in children and young adults and the incidence of asthma is highest in children under 10.[18] Overall, boys have a higher risk of developing allergy than girls,[16] although for some diseases, namely asthma in young adults, females are more likely to be affected.[19] Sex differences tend to decrease in adulthood.[16] Ethnicity may play a role in some allergies, however racial factors have been difficult to separate from environmental influences and changes due to migration.[16] Interestingly, it has been suggested that different genetic loci are responsible for asthma, specifically, in people of Caucasian, Hispanic, Asian, and African origins.[20]
Environmental factors
International differences have been associated with the number of individuals within a population that suffer from allergy. Allergic diseases are more common in industrialized countries than in countries that are more traditional or agricultural, and there is a higher rate of allergic disease in urban populations versus rural populations, although these differences are becoming less defined.[21]
Exposure to allergens, especially in early life, is an important risk factor for allergy. Alterations in exposure to microorganisms is the most plausible explanation, at present, for the increase in atopic allergy.[14] Since children that live in large families or overcrowded households, or attend day care, have a reduced incidence of allergic disease, a relationship has been proposed between exposures to bacteria and viruses during childhood, and protection against the development of allergy, which has been called – the "hygiene hypothesis".[21] Exposure to endotoxin and other components of bacteria may reduce atopic diseases.[22] Endotoxin exposure reduces release of inflammatory cytokines such as TNF-α, IFNγ, interleukin-10, and interleukin-12 from white blood cells (leukocytes) that circulate in the blood.[23] Certain microbe-sensing proteins, known as Toll-like receptors, found on the surface of cells in the body are also thought to be involved in these processes.[24]
Gutworms and similar parasites are present in untreated drinking water in developing countries, and were present in the water of developed countries until the routine chlorination and purification of drinking water supplies.[25] Recent research has shown that some common parasites, such as intestinal worms (e.g. hookworms), secrete chemicals into the gut wall (and hence the bloodstream) that suppress the immune system and prevent the body from attacking the parasite.[26] This gives rise to a new slant on the hygiene hypothesis theory — that co-evolution of man and parasites has led to an immune system that only functions correctly in the presence of the parasites. Without them, the immune system becomes unbalanced and oversensitive.[27] In particular, research suggests that allergies may coincide with the delayed establishment of gut flora in infants.[28] However, the research to support this theory is conflicting, with some studies performed in China and Ethiopia showing an increase in allergy in people infected with intestinal worms.[21] Clinical trials have been initiated to test the effectiveness of certain worms in treating some allergies.[29] It may be that the term 'parasite' could turn out to be inappropriate, and in fact a hitherto unsuspected symbiosis is at work.[29] For more information on this topic, see Helminthic therapy.
Pathophysiology
The pathophysiology of allergic responses can be divided into two phases. The first is an acute response that occurs immediately after exposure to an allergen. This phase can either subside or progress into a "late phase reaction" which can substantially prolong the symptoms of a response, and result in tissue damage.
Acute response
Degranulation process in allergy.1 - antigen; 2 - IgE antibody; 3 - FcεRI receptor; 4 - preformed mediators (histamine, proteases, chemokines, heparine); 5 - granules; 6 - mast cell; 7 - newly formed mediators (prostaglandins, leukotrienes, thromboxanes, PAF)
Degranulation process in allergy.1 - antigen; 2 - IgE antibody; 3 - FcεRI receptor; 4 - preformed mediators (histamine, proteases, chemokines, heparine); 5 - granules; 6 - mast cell; 7 - newly formed mediators (prostaglandins, leukotrienes, thromboxanes, PAF)
In the early stages of allergy, a type I hypersensitivity reaction against an allergen, encountered for the first time, causes a response in a type of immune cell called a TH2 lymphocyte, which belongs to a subset of T cells that produce a cytokine called interleukin-4 (IL-4). These TH2 cells interact with other lymphocytes called B cells, whose role is production of antibodies. Coupled with signals provided by IL-4, this interaction stimulates the B cell to begin production of a large amount of a particular type of antibody known as IgE. Secreted IgE circulates in the blood and binds to an IgE-specific receptor (a kind of Fc receptor called FcεRI) on the surface of other kinds of immune cells called mast cells and basophils, which are both involved in the acute inflammatory response. The IgE-coated cells, at this stage are sensitized to the allergen.[14]
If later exposure to the same allergen occurs, the allergen can bind to the IgE molecules held on the surface of the mast cells or basophils. Cross-linking of the IgE and Fc receptors occurs when more than one IgE-receptor complex interacts with the same allergenic molecule, and activates the sensitized cell. Activated mast cells and basophils undergo a process called degranulation, during which they release histamine and other inflammatory chemical mediators (cytokines, interleukins, leukotrienes, and prostaglandins) from their granules into the surrounding tissue causing several systemic effects, such as vasodilation, mucous secretion, nerve stimulation and smooth muscle contraction. This results in rhinorrhea, itchiness, dyspnea, and anaphylaxis. Depending on the individual, allergen, and mode of introduction, the symptoms can be system-wide (classical anaphylaxis), or localized to particular body systems; asthma is localized to the respiratory system and eczema is localized to the dermis.[14]
Late-phase response
After the chemical mediators of the acute response subside, late phase responses can often occur. This is due to the migration of other leukocytes such as neutrophils, lymphocytes, eosinophils and macrophages to the initial site. The reaction is usually seen 2-24 hours after the original reaction.[30] Cytokines from mast cells may also play a role in the persistence of long-term effects. Late phase responses seen in asthma are slightly different from those seen in other allergic responses, although they are still caused by release of mediators from eosinophils, and are still dependent on activity of TH2 cells.[31]
Diagnosis
An allergy testing machine being operated in the diagnostic immunology lab at Lackland Air Force Base
An allergy testing machine being operated in the diagnostic immunology lab at Lackland Air Force Base
Before a diagnosis of allergic disease can be confirmed, the other possible causes of the presenting symptoms should be carefully considered.[32] Vasomotor rhinitis, for example, is one of many maladies that shares symptoms with allergic rhinitis, underscoring the need for professional differential diagnosis.[33] Once a diagnosis of asthma, rhinitis, anaphylaxis, or other allergic disease has been made, there are several methods for discovering the causative agent of that allergy.
Skin testing
Skin Testing
For assessing the presence of allergen-specific IgE antibodies, allergy skin testing is preferred over blood allergy tests because it is more sensitive and specific, simpler to use, and less expensive.[34] Skin testing is also known as "puncture testing" and "prick testing" due to the series of tiny puncture or pricks made into the patient's skin. Small amounts of suspected allergens and/or their extracts (pollen, grass, mite proteins, peanut extract, etc.) are introduced to sites on the skin marked with pen or dye (the ink/dye should be carefully selected, lest it cause an allergic response itself). A small plastic or metal device is used to puncture or prick the skin. Sometimes, the allergens are injected "intradermally" into the patient's skin, with a needle and syringe. Common areas for testing include the inside forearm and the back. If the patient is allergic to the substance, then a visible inflammatory reaction will usually occur within 30 minutes. This response will range from slight reddening of the skin to a full-blown hive (called "wheal and flare") in more sensitive patients. Interpretation of the results of the skin prick test is normally done by allergists on a scale of severity, with +/- meaning borderline reactivity, and 4+ being a large reaction. Increasingly, allergists are measuring and recording the diameter of the wheal and flare reaction. Interpretation by well-trained allergists is often guided by relevant literature.[35] Some patients may believe they have determined their own allergic sensitivity from observation, but a skin test has been shown to be much better than patient observation to detect allergy.[36]
If a serious life threatening anaphylactic reaction has brought a patient in for evaluation, some allergists will prefer an initial blood test prior to performing the skin prick test. Skin tests may not be an option if the patient has widespread skin disease or has taken antihistamines sometime the last several days.
Blood testing
Various blood allergy testing methods are also available for detecting allergy to specific substances. This kind of testing measures a "total IgE level" - an estimate of IgE contained within the patient's serum. This can be determined through the use of radiometric and colormetric immunoassays. Radiometric assays include the radioallergosorbent test (RAST) test method, which uses IgE-binding (anti-IgE) antibodies labeled with radioactive isotopes for quantifying the levels of IgE antibody in the blood.[34] Other newer methods use colorimetric or fluorometric technology in the place of radioactive isotopes. Some "screening" test methods are intended to provide qualitative test results, giving a "yes" or "no" answer in patients with suspected allergic sensitization. One such method has a sensitivity of about 70.8% and a positive predictive value of 72.6% according to a large study.[37]
A low total IgE level is not adequate to rule out sensitization to commonly inhaled allergens. Statistical methods, such as ROC curves, predictive value calculations, and likelihood ratios have been used to examine the relationship of various testing methods to each other. These methods have shown that patients with a high total IgE have a high probability of allergic sensitization, but further investigation with specific allergy tests for a carefully chosen allergens is often warranted.
Pharmacotherapy
Several antagonistic drugs are used to block the action of allergic mediators, or to prevent activation of cells and degranulation processes. These include antihistamines, cortisone, dexamethasone, hydrocortisone, epinephrine (adrenaline), theophylline and cromolyn sodium. Anti-leukotrienes, such as Montelukast (Singulair) or Zafirlukast (Accolate), are FDA approved for treatment of allergic diseases.[citation needed] Anti-cholinergics, decongestants, mast cell stabilizers, and other compounds thought to impair eosinophil chemotaxis, are also commonly used. These drugs help to alleviate the symptoms of allergy, and are imperative in the recovery of acute anaphylaxis, but play little role in chronic treatment of allergic disorders.
Immunotherapy
Desensitization or hyposensitization is a treatment in which the patient is gradually vaccinated with progressively larger doses of the allergen in question. This can either reduce the severity or eliminate hypersensitivity altogether. It relies on the progressive skewing of IgG antibody production, to block excessive IgE production seen in atopys. In a sense, the person builds up immunity to increasing amounts of the allergen in question. Studies have demonstrated the long-term efficacy and the preventive effect of immunotherapy in reducing the development of new allergy.[40] Meta-analyses have also confirmed efficacy of the treatment in allergic rhinitis in children and in asthma.[citation needed] A review by the Mayo Clinic in Rochester confirmed the safety and efficacy of allergen immunotherapy for allergic rhinitis and conjunctivitis, allergic forms of asthma, and stinging insect based on numerous well-designed scientific studies.[41] Additionally, national and international guidelines confirm the clinical efficacy of injection immunotherapy in rhinitis and asthma, as well as the safety, provided that recommendations are followed.[42]
A second form of immunotherapy involves the intravenous injection of monoclonal anti-IgE antibodies. These bind to free and B-cell associated IgE; signalling their destruction. They do not bind to IgE already bound to the Fc receptor on basophils and mast cells, as this would stimulate the allergic inflammatory response. The first agent of this class is Omalizumab. While this form of immunotherapy is very effective in treating several types of atopy, it should not be used in treating the majority of people with food allergies.[citation needed]
A third type, Sublingual immunotherapy, is an orally-administered therapy which takes advantage of oral immune tolerance to non-pathogenic antigens such as foods and resident bacteria. This therapy currently accounts for 40 percent of allergy treatment in Europe.[citation needed] In the United States, sublingual immunotherapy is gaining support among traditional allergists and is endorsed by doctors who treat allergy.[citation needed]
Unproven or ineffective treatments
An experimental treatment, enzyme potentiated desensitization (EPD), has been tried for decades but is not generally accepted as effective.[43] EPD uses dilutions of allergen and an enzyme, beta-glucuronidase, to which T-regulatory lymphocytes are supposed to respond by favouring desensitization, or down-regulation, rather than sensitization. EPD has also been tried for the treatment of autoimmune diseases but again is not FDA approved or of proven effectiveness.[43]
In alternative medicine, a number of allergy treatments are described by its practitioners, particularly naturopathic, herbal medicine, homeopathy, traditional Chinese medicine and kinesiology. Systematic literature searches conducted by the Mayo Clinic through 2006, involving hundreds of articles studying multiple conditions, including asthma and upper respiratory tract infection showed no effectiveness of any alternative treatments, and no difference compared with placebo. The authors concluded that, based on rigorous clinical trials of all types of homeopathy for childhood and adolescence ailments, there is no convincing evidence that supports the use of alternative treatments.[44]
Epidemiology
Many diseases related to inflammation such as type 1 diabetes, rheumatoid arthritis and allergic diseases—hay fever and asthma—have increased in the Western world over the past 2-3 decades.[45] Rapid increases in allergic asthma and other atopic disorders in industrialized nations probably began in the 1960s and 1970s, with further increases occurring during the 1980s and 1990s,[46] although some suggest that a steady rise in sensitization has been occurring since the 1920s.[47] The incidence of atopy in developing countries has generally remained much lower.
Alzheimer's disease reference
Alzheimer's disease (AD), also called Alzheimer disease or simply Alzheimer's, is the most common cause of dementia. Alzheimer's is a degenerative and terminal disease for which there is no known cure. In its most common form, it afflicts individuals over 65 years old, although a less prevalent early-onset form also exists. It is estimated that 26.6 million people worldwide were afflicted by AD in 2006, which could quadruple by 2050,[1] although estimations vary greatly.[2]
Each individual experiences the symptoms of AD in unique ways.[3] The symptoms of Alzheimer's disease are generally reported to a physician when memory loss becomes apparent. If AD is suspected as the cause, the physician or healthcare specialist will confirm the diagnosis with behavioral assessments and cognitive tests, often followed by a brain scan, if available.[4] A prognosis for Alzheimer's is hard to make, as the duration of the disease varies per individual, and the disease can develop for an indeterminate time before becoming fully apparent, sometimes escaping diagnosis for years. Generally, life with Alzheimer's disease lasts between 5 and 20 years.[5][6] In the early stages, the most commonly recognised symptom is memory loss, such as the difficulty to remember recently learned facts. Earliest occurring symptoms are often mistaken as being noncritical age-related complaints, or forms of stress.[7] As the disease advances, progressive symptoms include confusion, anger, mood swings, language breakdown, long-term memory loss, and the general withdrawal of the sufferer as his or her senses decline.[7][8] Gradually, minor and major bodily functions are lost, leading ultimately to death.[9]
The cause and progression of Alzheimer's disease are not well understood. Research indicates that the disease is associated with plaques and tangles in the brain.[10] No treatment has been found to stop or reverse the disease, and it is not known whether current treatments slow the progression, or simply manage the symptoms. Many preventive measures have been suggested for Alzheimer's disease, but their value is unproven in reducing the course and severity of the disease. Mental stimulation, exercise and a balanced diet are often recommended, both as a possible prevention and as a sensible way of managing the disease
Characteristics
The disease course is divided into four stages, with a progressive pattern of cognitive and functional impairment expressed during each stage.
Predementia
Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria of diagnosis.[16] These early symptoms can have an effect on the most complex daily living activities.[17] The most noticeable deficit is memory loss , shown as a difficulty to remember recently learned facts and an inability to acquire new information.[18][19] In addition, subtle executive function problems (attention, planning, flexibility, abstraction...) or impairments in semantic memory (memory of meanings and concept relationships) can also occur.[20][21] Apathy can be observed at this stage, and is the most common and persistent neuropsychiatric symptom throughout the course of the disease.[22][23][24] This stage of the disease has also been termed mild cognitive impairment,[25] but there is still a debate on whether this term corresponds to a different diagnostic entity by itself or just a first step of the disease.[26]
Early dementia
In 1994 the former United States president R. Reagan informed the country of his AD diagnosis via a hand-written letter. Writing is usually affected in the first stages of the disease.
In 1994 the former United States president R. Reagan informed the country of his AD diagnosis via a hand-written letter. Writing is usually affected in the first stages of the disease.
In most people with the disease the increasing impairments in learning and memory will lead to diagnosis, while in a small proportion of them difficulties with language, executive functions, recognition of perceptions (agnosia) or execution of movements (apraxia) will be more salient.[27] Nevertheless, memory problems do not affect all memory subcapacities equally. Older memories of the patient's life (episodic memory), facts learned (semantic memory), and implicit memory (the memory of the body on how to do things, such as using a fork to eat) are affected to a much lesser degree than the capacities needed to learn new facts or make new memories.[28][29] Language problems are mainly characterised by a shrinking vocabulary and a decreased word fluency which leads to a general impoverishment of oral and written language. The Alzheimer's patient is usually capable of adequately communicating basic ideas.] While performing fine motor tasks such as writing, drawing or dressing, certain visoconstructional difficulties, or apraxia, may be present, which may appear as clumsiness. As the disease progresses to the middle stage, patients might still be able to live and perform tasks independently for most of the time, but may need assistance or supervision with the most complicated activities.[27]
Moderate dementia
In the early stage, people with Alzheimer's can usually care for themselves. At the moderate stage, progressive deterioration seriously hinders the possibility of independence.[27]
Speech difficulties become clearly noticeable: due to difficulties in finding words the person makes frequent incorrect substitutions (paraphasias) , and content is poor. Reading and writing are also progressively forgotten.[30][34] As time passes, complex motor sequences become less coordinated, costing the patient most of their daily-living abilities.[35] Memory problems worsen, and the person may not recognize close relatives.[36] Long-term memory, which was previously left intact, is now also impaired.[37] At this stage, behavior changes are the norm. Common neuropsychiatric manifestations in this stage are irritability and labile affect, leading to crying or outbursts of unpremeditated aggression and physical violence, even in patients whose life-long behavior has been peaceful. Approximately 30% of the patients also develop illusionary misidentifications and other delusional symptoms.[22][38] Often urinary incontinence develops.[39] Because of the communication deficit along with delusions, patients often resist when caregivers attempt to provide care.[40] It is important to prevent escalation of resistiveness to care into combativeness when patient might strike out. All these symptoms create stress for relatives and caretakers, increasing the likelihood of moving the patient from home care to other long-term care facilities.[27][41]
Advanced
In the last stage of Alzheimer's disease the subject with the disease is fully dependent. Language is reduced to simple phrases or even single words before being lost altogether.[30] Nevertheless many patients can receive and return emotional signals long after the loss of verbal language.[42] Although aggressiveness can still be present, extreme apathy and exhaustion are much more common.[27] Patients will ultimately not be able to perform even the most simple tasks independently. Finally, deterioration of muscle and mobility will develop, leading the patient to become bedridden,[43] and to lose the ability to feed oneself,[44] if death from some external cause, such as infection due to pressure ulcers or pneumonia, does not occur first.[45][46]
Causes
Three major competing hypotheses exist to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is known as the cholinergic hypothesis and suggests that AD is due to reduced biosynthesis of the neurotransmitter acetylcholine. However, the medications that treat acetylcholine deficiency only affect symptoms of the disease and neither halt nor reverse it.[47] The cholinergic hypothesis has not maintained widespread support in the face of this evidence, although cholinergic effects have been proposed to initiate large-scale aggregation,[48] leading to generalised neuroinflammation.[49]
In 1991 the amyloid hypothesis was proposed,[50] while research after 2000 is also centered on tau proteins. The two positions differ with one stating that the tau protein abnormalities initiate the disease cascade, while the other states that amyloid beta (Aβ) deposits are the causative factor in the disease.[51]
The tau hypothesis is supported by the long-standing observation that deposition of amyloid plaques does not correlate well with neuron loss.[52] In this model, hyperphosphorylated tau begins to pair with other threads of tau and they become tangled up together inside nerve cell bodies in masses known as neurofibrillary tangles.[53] When this happens, the microtubules disintegrate, collapsing the neuron's transport system. This may result first in malfunctions in communication between neurons and later in the death of the cells.[54]
A majority of researchers support the alternative hypothesis that Aβ is the primary causative agent.[51] The amyloid hypothesis is compelling because the gene for the amyloid beta precursor (APP) is located on chromosome 21, and patients with trisomy 21 (Down Syndrome) who thus have an extra gene copy almost universally exhibit AD-like disorders by 40 years of age. It should be noted further that APOE4, the major genetic risk factor for AD, leads to excess amyloid build-up in the brain before AD symptoms arise. Thus, Aβ deposition precedes clinical AD.[57] It is known that some types of inherited AD involve only mutations in the APP gene (although this is not the most common type—others involve genes for "pre-senilin" proteins which process APP and may also have still-unknown functions).[58] However, another strong support for the amyloid hypothesis, which looks at Aβ as the common initiating factor for Alzheimer's disease, is that transgenic mice solely expressing a mutant human APP gene develop fibrillar amyloid plaques.[59]
Pathophysiology
Main article: Biochemistry of Alzheimer's disease
Neuropathology
MRI images of a normal aged brain (right) and an Alzheimer's patient's brain (left). In the Alzheimer brain, atrophy is clearly seen.
MRI images of a normal aged brain (right) and an Alzheimer's patient's brain (left). In the Alzheimer brain, atrophy is clearly seen.
At a macroscopic level, AD is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.[49]
Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in AD brains.[10] Plaques are dense, mostly insoluble deposits of amyloid-beta protein and cellular material outside and around neurons. Tangles are insoluble twisted fibers that build up inside the nerve cell. Though many older people develop some plaques and tangles, the brains of AD patients have them to a much greater extent and in different brain locations.[60]
Biochemical characteristics
Alzheimer's disease has been identified as a protein misfolding disease, or proteopathy, due to the accumulation of abnormally folded A-beta and tau proteins in the brains of AD patients.[61] Plaques are made of a small peptide (39 to 43 amino acid residues) called beta-amyloid (also A-beta or Aβ), a protein fragment snipped from a larger protein called amyloid precursor protein (APP). APP is a transmembrane protein; which means that it sticks through the neuron's membrane; and is believed to help neurons grow, survive and repair themselves after injury.[62][63] In AD, something causes APP to be divided by enzymes through a mechanism called proteolysis.[64] One of these fragments is beta-amyloid. Beta-amyloid fragments (amyloid fibrils) outside the cell form clumps that deposit outside neurons in dense formations known as senile plaques.[65][10]
AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Healthy neurons have an internal support structure, or cytoskeleton, partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell down to the ends of the axon and back. A protein called tau makes the microtubules stable when phosphorylated, and is therefore called a microtubule-associated protein.[66] In AD, tau is changed chemically, becoming phosphate saturated (hyperphosphorylated).
Disease mechanism
If the production and aggregation of the amyloid beta peptide plays a key role in AD, the exact mechanism has not been elucidated.[67] The traditional formulation of the amyloid hypothesis points to the accumulation of beta-amyloid peptides as the central event triggering neurons degeneration. Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces apoptosis (programmed cell death).[68] It is also known that Aβ selectively builds up in the cells mitochondria of brains with AD and inhibits certain enzyme functions and the utilization of glucose by neurons. This process may also lead to the formation of damaging reactive oxygen species, calcium influx, and apoptosis.[69]
Various inflammatory processes and inflammatory cytokines may also have a role in the pathology of Alzheimer's disease. However, these are general markers of tissue damage in any disease, and may also be either secondary causes of tissue damage in AD, or else bystander "marker" effects.
Genetic
While earlier disease familial onset is mainly explained by three genes, later age of disease onset representing most cases of AD has yet to be explained by a purely genetic model. In the second case the APOE gene is the strongest genetic risk factor discovered but it is far from explaining all occurrences of the disease.[71]
Only 10% of AD cases occurring before 60 years of age are due to autosomal dominant (familial) mutations, which represents less than 0,01 of all patients.[71][72] These mutations have been discovered in three different genes: amyloid precursor protein or APP,[73] and presenilins 1,[74] and 2[75]. Most mutations in the APP and presenilin genes increase the production of a small protein called Abeta42, which is the main component of senile plaques in brains of AD patients.[76]
Most cases of Alzheimer's disease do not exhibit familial inheritance. In this case genes may act as risk factors. The best known genetic risk factor is the inheritance of the ε4 allele of the apolipoprotein E (APOE). This gene is regarded as a risk factor for development of up to 50% of late-onset sporadic Alzheimer's.[77] Genetic experts agree that there are other risk and protective factor genes that influence the development of late onset Alzheimer's disease.[71] Over 400 genes have been tested for association with late-onset sporadic AD.[78]
Diagnosis
Dementia is by definition a clinical condition but not an exact diagnosis. Alzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic neurological and neuropsychological features and the absence of alternative conditions.[79][80] Advanced medical imaging with CT or MRI, and with SPECT or PET are generally used to help to diagnose the subtype of dementia and exclude other cerebral pathology.[81] Neuropsychological evaluation including memory testing and assessment of intellectual functioning can further characterize the dementia.[82] Medical organizations have created diagnostic criteria to ease and standardize the process for practicing physicians. Sometimes the diagnosis can be confirmed or made at postmortem when brain material is available and can be examined histologically and histochemically.[83]
Diagnostic criteria
The diagnostic criteria for Alzheimer of the NINCDS-ADRDA (NINCDS and the ADRDA) are among the most used.[84] These criteria require that the presence of cognitive impairment and a suspected dementia syndrome be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable AD while they need histopathologic confirmation (microscopic examination of brain tissue) for the definitive diagnosis. They have shown good reliability and validity.[85] They specify as well eight cognitive domains that may be impaired in AD (i.e., memory, language, perceptual skills, attention, constructive abilities, orientation, problem solving and functional abilities). Similar to the NINCDS-ADRDA Alzheimer's Criteria are the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria published by the American Psychiatric Association.[86][87]
Diagnostic tools
Neuropsychological screening tests can help in the diagnosis of AD. In them patients have to copy drawings similar to the one shown in the picture, remember words, read or sum.
Neuropsychological screening tests can help in the diagnosis of AD. In them patients have to copy drawings similar to the one shown in the picture, remember words, read or sum.
Neuropsychological screening tests such as the Mini mental state examination (MMSE) are widely used to evaluate the cognitive impairments needed for diagnosis, but more comprehensive tests arrays are necessary for high reliability by this method, especially in the earliest stages of the disease.[88][89] Neurological examination in early AD will usually be normal, independent of cognitive impairment; but for many of the other dementing disorders is key for diagnosis. Therefore, neurological examination is crucial in the differential diagnosis of Alzheimer and other diseases.[82] In addition, interviews with family members are also utilized in the assessment of the disease. Caregivers can supply important information on the daily living abilities, as well as on the decrease over time of the patient's mental function.[90] This is especially important since a patient with AD is commonly unaware of his or her own deficits (anosognosia).[91] Many times families also have difficulties in the detection of initial dementia symptoms and in adequately communicating them to a physician.[92] Finally, supplemental testing provides extra information on some features of the disease or are used to rule out other diagnoses. Examples are blood tests, which can identify other causes for dementia different than AD,[82] which rarely may even be reversible;[93] or psychological tests for depression, as depression can both co-occur with AD or, on the contrary, be at the origin of the patient's cognitive impairment.[94][95]
Increasingly, the functional neuroimaging modalities of single photon emission computed tomography (SPECT) and positron emission tomography (PET) are being used to diagnose Alzheimer's, as they have shown similar ability to diagnose Alzheimer's disease as methods involving mental status examination.[96] Furthermore, the ability of SPECT to differentiate Alzheimer's disease from other possible causes, in a patient already known to be suffering from dementia, appears to be superior to attempts to differentiate the cause of dementia cause by mental testing and history.[97] A new technique known as "PiB PET" has been developed for directly and clearly imaging beta-amyloid deposits in vivo using a contrasting tracer that binds selectively to the Abeta deposits.[98][99][100] Another recent objective marker of the disease is the analysis of cerebrospinal fluid for amyloid beta or tau proteins.[101] Both advances (neuroimaging and cerebrospinal fluid analysis) have led to the proposal of new diagnostic criteria.[84][82]
Prevention
Intellectual activities such as playing chess or regular social interaction have been linked to a reduced risk of AD in epidemiological studies, although no causal relationship has been found.
Intellectual activities such as playing chess or regular social interaction have been linked to a reduced risk of AD in epidemiological studies, although no causal relationship has been found.
At present contradictory results in global studies, incapacity to prove causal relationships between risk factors and the disease, and possible secondary effects indicate a lack of specific measures to prevent or delay the onset of AD.[102] Different epidemiological studies have proposed relationships between certain modifiable factors, such as diet, cardiovascular risk, pharmaceutical products, or intellectual activities among others, and a population's likelihood of developing AD. Only further research, including clinical trials, will reveal whether, in fact, these factors can help to prevent AD.[103]
The components of a Mediterranean diet, which include fruit and vegetables, bread, wheat and other cereals, olive oil, fish, and red wine, may all individually or together reduce the risk and course of Alzheimer's disease. Vitamins B and C, or folic acid have appeared to be related to a reduced risk of AD, but other studies indicate that they do not have any significant effect on the onset or course of the disease and may have important secondary effects.[106] Curcumin in curry has shown some effectiveness in preventing brain damage in mouse models.
Although cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and course of AD,[108][109] statins, which are cholesterol lowering drugs, have not been effective in preventing or improving the course of the disease.[110][111] However long-term usage of non-steroidal anti-inflammatory drug (NSAIDs), is associated with a reduced likelihood of developing AD in some individuals.[112] Other pharmaceutical therapies such as female hormone replacement therapy are no longer thought to prevent dementia,[113][114] and a 2007 systematic review concluded that there was inconsistent and unconvincing evidence that ginkgo has any positive effect on dementia or cognitive impairment.[115]
Intellectual activities such as playing chess, completing crossword puzzles or regular social interaction, may also delay the onset or reduce the severity of Alzheimer's disease.[116][117] Bilingualism is also related to a later onset of Alzheimer.[118]
Some studies have shown a positive relationship between risk of developing AD and different occupational exposures such as magnetic field exposure,[119][120], metals intake and specifically aluminium,[121][122] or solvents.[123] The quality of some of these studies has been criticized,[124] and other research does not confirm this link.[125][126] [127][128]
[edit] Management
There is no known cure for Alzheimer's disease. Available treatments offer relatively small symptomatic benefit but remain palliative in nature. Current treatments can be divided into pharmaceutical, psychosocial and caregiving.
Pharmaceutical
3d molecular spacefill of donepezil, an acetylcholinesterase inhibitor used in the treatment of AD symptoms
3d molecular spacefill of donepezil, an acetylcholinesterase inhibitor used in the treatment of AD symptoms
Molecular structure of memantine, a medication approved for advanced AD symptoms
Molecular structure of memantine, a medication approved for advanced AD symptoms
Four medications, to treat the cognitive manifestations of AD, are currently approved by regulatory agencies, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA). Three are acetylcholinesterase inhibitors and the other is memantine, an NMDA receptor antagonist. No drug has an indication for delaying or halting the progression of the disease.
Because reduction in the activity of the cholinergic neurons in the disease is well known, acetylcholinesterase inhibitors are employed to reduce the rate at which acetylcholine (ACh) is broken down and so to increase the concentration of ACh in the brain, thereby combatting the loss of ACh caused by the death of the cholinergin neurons.[130] Cholinesterase inhibitors currently approved include donepezil (brand name Aricept),[131] galantamine (Razadyne),[132] and rivastigmine (branded as Exelon,[133] and Exelon Patch[134]). There is also evidence for the efficacy of these medications in mild to moderate Alzheimer’s disease,[135] and some evidence for their use in the advanced stage. Only donepezil is approved for treatment of advanced AD dementia.[136] The use of these drugs in mild cognitive impairment has not shown any effect in a delay of the onset of AD.[137] Most common side effects include nausea and vomiting, both of which are linked to cholinergic excess. These side effects arise in approximately ten to twenty percent of users and are mild to moderate in severity. Less common secondary effects include muscle cramps; decreased heart rate (bradycardia), decreased appetite and weight, and increased gastric acid.[138][139][140][141]
Glutamate is a useful excitatory neurotransmitter of the nervous system, although excessive amounts in the brain can lead to cell death through a process called excitotoxicity which consists of the overstimulation of glutamate receptors. Excitotoxicity occurs not only in Alzheimer's disease, but also in other neurological diseases such as Parkinson's disease and multiple sclerosis.[142] Memantine (brand names Akatinol, Axura, Ebixa/Abixa, Memox and Namenda),[143] is a noncompetitive NMDA receptor antagonist first used as an anti-influenza agent. It acts on the glutamatergic system by blocking NMDA glutamate receptors and inhibits their overstimulation by glutamate.[142] Memantine has been shown to be moderately efficacious in the treatment of moderate to severe Alzheimer’s disease. Its effects in the initial stages are unknown.[144] Reported adverse events with memantine are infrequent and mild, including hallucinations, confusion, dizziness, headache and fatigue.[145] Memantine used in combination with donepezil has been shown to be "of statistically significant but clinically marginal effectiveness".[146]
Neuroleptic anti-psychotic drugs commonly given to Alzheimer's patients with behavioural problems are modestly useful in reducing aggression and psychosis, but are associated with serious adverse effects, such as cerebrovascular events, movement difficulties or cognitive decline, that do not permit their routine use.[147][148][149]
Psychosocial intervention
A specifically designed room for sensory integration therapy, or snoezelen; an emotion-oriented psychosocial intervention for people with dementia
A specifically designed room for sensory integration therapy, or snoezelen; an emotion-oriented psychosocial intervention for people with dementia
Psychosocial interventions are used as an adjunct to pharmaceutical treatment and can be classified within behavior, emotion, cognition or stimulation oriented approaches. Research on efficacy is unavailable and rarely specific to the disease, focusing instead on dementia.[150]
Behavioral interventions attempt to identify and reduce the antecedents and consequences of problem behaviors. This approach has not shown success in the overall functioning of patients,[151] but can help to reduce some specific problem behaviors, such as incontinence.[152] There is still a lack of high quality data on the effectiveness of these techniques in other behavior problems such as wandering.[153][154]
Emotion-oriented interventions include reminiscence therapy, validation therapy, supportive psychotherapy, sensory integration or snoezelen, and simulated presence therapy. Supportive psychotherapy has received little or no formal scientific study, but some clinicians find it useful in helping mildly impaired patients adjust to their illness.[150] Reminiscence therapy (RT) involves the discussion of past experiences individually or in group, many times with the aid of photographs, household items, music and sound recordings, or other familiar items from the past. Although there are few quality studies on the effectiveness of RT it may be beneficial for cognition and mood.[155] Simulated presence therapy (SPT) is based on attachment theories and is normally carried out playing a recording with voices of the closest relatives of the patient. There is preliminary evidence indicating that SPT may reduce anxiety and challenging behaviors.[156][157] Finally, validation therapy is based on acceptance of the reality and personal truth of another's experience, while sensory integration is based on exercises aimed to stimulate senses. There is little evidence to support the usefulness of these therapies.[158][159]
The aim of cognition-oriented treatments, which include reality orientation and cognitive retraining is the restoration of cognitive deficits. Reality orientation consists in the presentation of information about time, place or person in order to ease the understanding of the person about its surroundings and his place in them. On the other hand cognitive retraining tries to improve impaired capacities by exercitation of mental abilities. Both have shown some efficacy improving cognitive capacities,[160][161] although in some works these effects were transient and negative effects, such as frustration, have also been reported.[150]
Stimulation-oriented treatments include art, music and pet therapies, exercise, and any other kind of recreational activities for patients. Stimulation has modest support for improving behavior, mood, and, to a lesser extent, function. Nevertheless, as important as these effects are, the main support for the use of stimulation therapies is the improvement in the patient daily life routine they suppose.[150]
Caregiving
Further information: Caregiving and dementia
Since there is no cure for Alzheimer's, caregiving is an essential part of the treatment. Due to the eventual inability for the sufferer to self-care, Alzheimer's has to be carefully care-managed. Home care in the familiar surroundings of home may delay onset of some symptoms and delay or eliminate the need for more professional and costly levels of care.[162] Many family members choose to look after their relatives,[12] but two-thirds of nursing home residents have dementias.[163]
Modifications to the living environment and lifestyle of the Alzheimer's patient can improve functional performance and ease caretaker burden. Assessment by an occupational therapist is often indicated. Adherence to simplified routines and labeling of household items to cue the patient can aid with activities of daily living, while placing safety locks on cabinets, doors, and gates and securing hazardous chemicals can prevent accidents and wandering. Changes in routine or environment can trigger or exacerbate agitation, whereas well-lit rooms, adequate rest, and avoidance of excess stimulation all help prevent such episodes.[164][165] Appropriate social and visual stimulation can improve function by increasing awareness and orientation. For instance, boldly colored tableware aids those with severe AD, helping people overcome a diminished sensitivity to visual contrast to increase food and beverage intake.[166]
Prognosis
As the disease progresses, the patient will advance from mild cognitive impairment, when the suspected underlying pathology may or may not yet have been diagnosed, to mild and advanced stages of dementia, finally reaching a severe stage of dementia.[27] Once Alzheimer's has been diagnosed, the average life expectancy is approximately seven years, while less than three percent of the patients live more than fourteen years.
History
Auguste D, first described patient with AD by Alöis Alzheimer in 1901
Although the concept of dementia goes as far back as the ancient Greek and Roman philosophers and physicians,[179] it was in 1901 when Alöis Alzheimer, a German psychiatrist, identified the first case of what became known as Alzheimer's disease in a fifty-year-old woman he called Auguste D. Alöis Alzheimer followed her until she died in 1906, when he first reported the case publicly.[180] In the following five years, eleven similar cases were reported in the medical literature, some of them already using the term Alzheimer's disease.[179] The official consideration of the disease as a distinctive entity is attributed to Emil Kraepelin, who included Alzheimer’s disease or presenile dementia as a subtype of senile dementia in the eighth edition of his Textbook of Psychiatry, published in 1910.[181]
For most of the twentieth century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of 45 and 65 who developed symptoms of dementia. The terminology changed after 1977 when a conference concluded that the clinical and pathological manifestations of presenile and senile dementia were almost identical, although the authors also added that this did not rule out the possibility of different etiologies.[182] This eventually led to the use of Alzheimer's disease independently of onset age of the disease.[183] The term senile dementia of the Alzheimer type (SDAT) was used for a time to describe the condition in those over 65, with classical Alzheimer's disease being used for those younger. Eventually, the term Alzheimer's disease was formally adopted in medical nomenclature to describe individuals of all ages with a characteristic common symptom pattern, disease course, and neuropathology.[184]
Society and culture
Social costs
Because the median age of the industrialised world's population is gradually increasing, AD is a public health challenge. The World Health Organization estimates that globally the total disability adjusted life years (DALYs) for AD and other dementias exceeded eleven million in 2005, with a projected 3.4% annual increase.[185] The DALYs are a measure for the overall disease burden that quantifies the impact of premature death and disability on a population by combining them into a single measure.
The solvency of governmental social safety nets will be impacted by the increased aged population which may develop Alzheimer's in the same proportions as earlier generations
Each individual experiences the symptoms of AD in unique ways.[3] The symptoms of Alzheimer's disease are generally reported to a physician when memory loss becomes apparent. If AD is suspected as the cause, the physician or healthcare specialist will confirm the diagnosis with behavioral assessments and cognitive tests, often followed by a brain scan, if available.[4] A prognosis for Alzheimer's is hard to make, as the duration of the disease varies per individual, and the disease can develop for an indeterminate time before becoming fully apparent, sometimes escaping diagnosis for years. Generally, life with Alzheimer's disease lasts between 5 and 20 years.[5][6] In the early stages, the most commonly recognised symptom is memory loss, such as the difficulty to remember recently learned facts. Earliest occurring symptoms are often mistaken as being noncritical age-related complaints, or forms of stress.[7] As the disease advances, progressive symptoms include confusion, anger, mood swings, language breakdown, long-term memory loss, and the general withdrawal of the sufferer as his or her senses decline.[7][8] Gradually, minor and major bodily functions are lost, leading ultimately to death.[9]
The cause and progression of Alzheimer's disease are not well understood. Research indicates that the disease is associated with plaques and tangles in the brain.[10] No treatment has been found to stop or reverse the disease, and it is not known whether current treatments slow the progression, or simply manage the symptoms. Many preventive measures have been suggested for Alzheimer's disease, but their value is unproven in reducing the course and severity of the disease. Mental stimulation, exercise and a balanced diet are often recommended, both as a possible prevention and as a sensible way of managing the disease
Characteristics
The disease course is divided into four stages, with a progressive pattern of cognitive and functional impairment expressed during each stage.
Predementia
Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria of diagnosis.[16] These early symptoms can have an effect on the most complex daily living activities.[17] The most noticeable deficit is memory loss , shown as a difficulty to remember recently learned facts and an inability to acquire new information.[18][19] In addition, subtle executive function problems (attention, planning, flexibility, abstraction...) or impairments in semantic memory (memory of meanings and concept relationships) can also occur.[20][21] Apathy can be observed at this stage, and is the most common and persistent neuropsychiatric symptom throughout the course of the disease.[22][23][24] This stage of the disease has also been termed mild cognitive impairment,[25] but there is still a debate on whether this term corresponds to a different diagnostic entity by itself or just a first step of the disease.[26]
Early dementia
In 1994 the former United States president R. Reagan informed the country of his AD diagnosis via a hand-written letter. Writing is usually affected in the first stages of the disease.
In 1994 the former United States president R. Reagan informed the country of his AD diagnosis via a hand-written letter. Writing is usually affected in the first stages of the disease.
In most people with the disease the increasing impairments in learning and memory will lead to diagnosis, while in a small proportion of them difficulties with language, executive functions, recognition of perceptions (agnosia) or execution of movements (apraxia) will be more salient.[27] Nevertheless, memory problems do not affect all memory subcapacities equally. Older memories of the patient's life (episodic memory), facts learned (semantic memory), and implicit memory (the memory of the body on how to do things, such as using a fork to eat) are affected to a much lesser degree than the capacities needed to learn new facts or make new memories.[28][29] Language problems are mainly characterised by a shrinking vocabulary and a decreased word fluency which leads to a general impoverishment of oral and written language. The Alzheimer's patient is usually capable of adequately communicating basic ideas.] While performing fine motor tasks such as writing, drawing or dressing, certain visoconstructional difficulties, or apraxia, may be present, which may appear as clumsiness. As the disease progresses to the middle stage, patients might still be able to live and perform tasks independently for most of the time, but may need assistance or supervision with the most complicated activities.[27]
Moderate dementia
In the early stage, people with Alzheimer's can usually care for themselves. At the moderate stage, progressive deterioration seriously hinders the possibility of independence.[27]
Speech difficulties become clearly noticeable: due to difficulties in finding words the person makes frequent incorrect substitutions (paraphasias) , and content is poor. Reading and writing are also progressively forgotten.[30][34] As time passes, complex motor sequences become less coordinated, costing the patient most of their daily-living abilities.[35] Memory problems worsen, and the person may not recognize close relatives.[36] Long-term memory, which was previously left intact, is now also impaired.[37] At this stage, behavior changes are the norm. Common neuropsychiatric manifestations in this stage are irritability and labile affect, leading to crying or outbursts of unpremeditated aggression and physical violence, even in patients whose life-long behavior has been peaceful. Approximately 30% of the patients also develop illusionary misidentifications and other delusional symptoms.[22][38] Often urinary incontinence develops.[39] Because of the communication deficit along with delusions, patients often resist when caregivers attempt to provide care.[40] It is important to prevent escalation of resistiveness to care into combativeness when patient might strike out. All these symptoms create stress for relatives and caretakers, increasing the likelihood of moving the patient from home care to other long-term care facilities.[27][41]
Advanced
In the last stage of Alzheimer's disease the subject with the disease is fully dependent. Language is reduced to simple phrases or even single words before being lost altogether.[30] Nevertheless many patients can receive and return emotional signals long after the loss of verbal language.[42] Although aggressiveness can still be present, extreme apathy and exhaustion are much more common.[27] Patients will ultimately not be able to perform even the most simple tasks independently. Finally, deterioration of muscle and mobility will develop, leading the patient to become bedridden,[43] and to lose the ability to feed oneself,[44] if death from some external cause, such as infection due to pressure ulcers or pneumonia, does not occur first.[45][46]
Causes
Three major competing hypotheses exist to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is known as the cholinergic hypothesis and suggests that AD is due to reduced biosynthesis of the neurotransmitter acetylcholine. However, the medications that treat acetylcholine deficiency only affect symptoms of the disease and neither halt nor reverse it.[47] The cholinergic hypothesis has not maintained widespread support in the face of this evidence, although cholinergic effects have been proposed to initiate large-scale aggregation,[48] leading to generalised neuroinflammation.[49]
In 1991 the amyloid hypothesis was proposed,[50] while research after 2000 is also centered on tau proteins. The two positions differ with one stating that the tau protein abnormalities initiate the disease cascade, while the other states that amyloid beta (Aβ) deposits are the causative factor in the disease.[51]
The tau hypothesis is supported by the long-standing observation that deposition of amyloid plaques does not correlate well with neuron loss.[52] In this model, hyperphosphorylated tau begins to pair with other threads of tau and they become tangled up together inside nerve cell bodies in masses known as neurofibrillary tangles.[53] When this happens, the microtubules disintegrate, collapsing the neuron's transport system. This may result first in malfunctions in communication between neurons and later in the death of the cells.[54]
A majority of researchers support the alternative hypothesis that Aβ is the primary causative agent.[51] The amyloid hypothesis is compelling because the gene for the amyloid beta precursor (APP) is located on chromosome 21, and patients with trisomy 21 (Down Syndrome) who thus have an extra gene copy almost universally exhibit AD-like disorders by 40 years of age. It should be noted further that APOE4, the major genetic risk factor for AD, leads to excess amyloid build-up in the brain before AD symptoms arise. Thus, Aβ deposition precedes clinical AD.[57] It is known that some types of inherited AD involve only mutations in the APP gene (although this is not the most common type—others involve genes for "pre-senilin" proteins which process APP and may also have still-unknown functions).[58] However, another strong support for the amyloid hypothesis, which looks at Aβ as the common initiating factor for Alzheimer's disease, is that transgenic mice solely expressing a mutant human APP gene develop fibrillar amyloid plaques.[59]
Pathophysiology
Main article: Biochemistry of Alzheimer's disease
Neuropathology
MRI images of a normal aged brain (right) and an Alzheimer's patient's brain (left). In the Alzheimer brain, atrophy is clearly seen.
MRI images of a normal aged brain (right) and an Alzheimer's patient's brain (left). In the Alzheimer brain, atrophy is clearly seen.
At a macroscopic level, AD is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.[49]
Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in AD brains.[10] Plaques are dense, mostly insoluble deposits of amyloid-beta protein and cellular material outside and around neurons. Tangles are insoluble twisted fibers that build up inside the nerve cell. Though many older people develop some plaques and tangles, the brains of AD patients have them to a much greater extent and in different brain locations.[60]
Biochemical characteristics
Alzheimer's disease has been identified as a protein misfolding disease, or proteopathy, due to the accumulation of abnormally folded A-beta and tau proteins in the brains of AD patients.[61] Plaques are made of a small peptide (39 to 43 amino acid residues) called beta-amyloid (also A-beta or Aβ), a protein fragment snipped from a larger protein called amyloid precursor protein (APP). APP is a transmembrane protein; which means that it sticks through the neuron's membrane; and is believed to help neurons grow, survive and repair themselves after injury.[62][63] In AD, something causes APP to be divided by enzymes through a mechanism called proteolysis.[64] One of these fragments is beta-amyloid. Beta-amyloid fragments (amyloid fibrils) outside the cell form clumps that deposit outside neurons in dense formations known as senile plaques.[65][10]
AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Healthy neurons have an internal support structure, or cytoskeleton, partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell down to the ends of the axon and back. A protein called tau makes the microtubules stable when phosphorylated, and is therefore called a microtubule-associated protein.[66] In AD, tau is changed chemically, becoming phosphate saturated (hyperphosphorylated).
Disease mechanism
If the production and aggregation of the amyloid beta peptide plays a key role in AD, the exact mechanism has not been elucidated.[67] The traditional formulation of the amyloid hypothesis points to the accumulation of beta-amyloid peptides as the central event triggering neurons degeneration. Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces apoptosis (programmed cell death).[68] It is also known that Aβ selectively builds up in the cells mitochondria of brains with AD and inhibits certain enzyme functions and the utilization of glucose by neurons. This process may also lead to the formation of damaging reactive oxygen species, calcium influx, and apoptosis.[69]
Various inflammatory processes and inflammatory cytokines may also have a role in the pathology of Alzheimer's disease. However, these are general markers of tissue damage in any disease, and may also be either secondary causes of tissue damage in AD, or else bystander "marker" effects.
Genetic
While earlier disease familial onset is mainly explained by three genes, later age of disease onset representing most cases of AD has yet to be explained by a purely genetic model. In the second case the APOE gene is the strongest genetic risk factor discovered but it is far from explaining all occurrences of the disease.[71]
Only 10% of AD cases occurring before 60 years of age are due to autosomal dominant (familial) mutations, which represents less than 0,01 of all patients.[71][72] These mutations have been discovered in three different genes: amyloid precursor protein or APP,[73] and presenilins 1,[74] and 2[75]. Most mutations in the APP and presenilin genes increase the production of a small protein called Abeta42, which is the main component of senile plaques in brains of AD patients.[76]
Most cases of Alzheimer's disease do not exhibit familial inheritance. In this case genes may act as risk factors. The best known genetic risk factor is the inheritance of the ε4 allele of the apolipoprotein E (APOE). This gene is regarded as a risk factor for development of up to 50% of late-onset sporadic Alzheimer's.[77] Genetic experts agree that there are other risk and protective factor genes that influence the development of late onset Alzheimer's disease.[71] Over 400 genes have been tested for association with late-onset sporadic AD.[78]
Diagnosis
Dementia is by definition a clinical condition but not an exact diagnosis. Alzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic neurological and neuropsychological features and the absence of alternative conditions.[79][80] Advanced medical imaging with CT or MRI, and with SPECT or PET are generally used to help to diagnose the subtype of dementia and exclude other cerebral pathology.[81] Neuropsychological evaluation including memory testing and assessment of intellectual functioning can further characterize the dementia.[82] Medical organizations have created diagnostic criteria to ease and standardize the process for practicing physicians. Sometimes the diagnosis can be confirmed or made at postmortem when brain material is available and can be examined histologically and histochemically.[83]
Diagnostic criteria
The diagnostic criteria for Alzheimer of the NINCDS-ADRDA (NINCDS and the ADRDA) are among the most used.[84] These criteria require that the presence of cognitive impairment and a suspected dementia syndrome be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable AD while they need histopathologic confirmation (microscopic examination of brain tissue) for the definitive diagnosis. They have shown good reliability and validity.[85] They specify as well eight cognitive domains that may be impaired in AD (i.e., memory, language, perceptual skills, attention, constructive abilities, orientation, problem solving and functional abilities). Similar to the NINCDS-ADRDA Alzheimer's Criteria are the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria published by the American Psychiatric Association.[86][87]
Diagnostic tools
Neuropsychological screening tests can help in the diagnosis of AD. In them patients have to copy drawings similar to the one shown in the picture, remember words, read or sum.
Neuropsychological screening tests can help in the diagnosis of AD. In them patients have to copy drawings similar to the one shown in the picture, remember words, read or sum.
Neuropsychological screening tests such as the Mini mental state examination (MMSE) are widely used to evaluate the cognitive impairments needed for diagnosis, but more comprehensive tests arrays are necessary for high reliability by this method, especially in the earliest stages of the disease.[88][89] Neurological examination in early AD will usually be normal, independent of cognitive impairment; but for many of the other dementing disorders is key for diagnosis. Therefore, neurological examination is crucial in the differential diagnosis of Alzheimer and other diseases.[82] In addition, interviews with family members are also utilized in the assessment of the disease. Caregivers can supply important information on the daily living abilities, as well as on the decrease over time of the patient's mental function.[90] This is especially important since a patient with AD is commonly unaware of his or her own deficits (anosognosia).[91] Many times families also have difficulties in the detection of initial dementia symptoms and in adequately communicating them to a physician.[92] Finally, supplemental testing provides extra information on some features of the disease or are used to rule out other diagnoses. Examples are blood tests, which can identify other causes for dementia different than AD,[82] which rarely may even be reversible;[93] or psychological tests for depression, as depression can both co-occur with AD or, on the contrary, be at the origin of the patient's cognitive impairment.[94][95]
Increasingly, the functional neuroimaging modalities of single photon emission computed tomography (SPECT) and positron emission tomography (PET) are being used to diagnose Alzheimer's, as they have shown similar ability to diagnose Alzheimer's disease as methods involving mental status examination.[96] Furthermore, the ability of SPECT to differentiate Alzheimer's disease from other possible causes, in a patient already known to be suffering from dementia, appears to be superior to attempts to differentiate the cause of dementia cause by mental testing and history.[97] A new technique known as "PiB PET" has been developed for directly and clearly imaging beta-amyloid deposits in vivo using a contrasting tracer that binds selectively to the Abeta deposits.[98][99][100] Another recent objective marker of the disease is the analysis of cerebrospinal fluid for amyloid beta or tau proteins.[101] Both advances (neuroimaging and cerebrospinal fluid analysis) have led to the proposal of new diagnostic criteria.[84][82]
Prevention
Intellectual activities such as playing chess or regular social interaction have been linked to a reduced risk of AD in epidemiological studies, although no causal relationship has been found.
Intellectual activities such as playing chess or regular social interaction have been linked to a reduced risk of AD in epidemiological studies, although no causal relationship has been found.
At present contradictory results in global studies, incapacity to prove causal relationships between risk factors and the disease, and possible secondary effects indicate a lack of specific measures to prevent or delay the onset of AD.[102] Different epidemiological studies have proposed relationships between certain modifiable factors, such as diet, cardiovascular risk, pharmaceutical products, or intellectual activities among others, and a population's likelihood of developing AD. Only further research, including clinical trials, will reveal whether, in fact, these factors can help to prevent AD.[103]
The components of a Mediterranean diet, which include fruit and vegetables, bread, wheat and other cereals, olive oil, fish, and red wine, may all individually or together reduce the risk and course of Alzheimer's disease. Vitamins B and C, or folic acid have appeared to be related to a reduced risk of AD, but other studies indicate that they do not have any significant effect on the onset or course of the disease and may have important secondary effects.[106] Curcumin in curry has shown some effectiveness in preventing brain damage in mouse models.
Although cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and course of AD,[108][109] statins, which are cholesterol lowering drugs, have not been effective in preventing or improving the course of the disease.[110][111] However long-term usage of non-steroidal anti-inflammatory drug (NSAIDs), is associated with a reduced likelihood of developing AD in some individuals.[112] Other pharmaceutical therapies such as female hormone replacement therapy are no longer thought to prevent dementia,[113][114] and a 2007 systematic review concluded that there was inconsistent and unconvincing evidence that ginkgo has any positive effect on dementia or cognitive impairment.[115]
Intellectual activities such as playing chess, completing crossword puzzles or regular social interaction, may also delay the onset or reduce the severity of Alzheimer's disease.[116][117] Bilingualism is also related to a later onset of Alzheimer.[118]
Some studies have shown a positive relationship between risk of developing AD and different occupational exposures such as magnetic field exposure,[119][120], metals intake and specifically aluminium,[121][122] or solvents.[123] The quality of some of these studies has been criticized,[124] and other research does not confirm this link.[125][126] [127][128]
[edit] Management
There is no known cure for Alzheimer's disease. Available treatments offer relatively small symptomatic benefit but remain palliative in nature. Current treatments can be divided into pharmaceutical, psychosocial and caregiving.
Pharmaceutical
3d molecular spacefill of donepezil, an acetylcholinesterase inhibitor used in the treatment of AD symptoms
3d molecular spacefill of donepezil, an acetylcholinesterase inhibitor used in the treatment of AD symptoms
Molecular structure of memantine, a medication approved for advanced AD symptoms
Molecular structure of memantine, a medication approved for advanced AD symptoms
Four medications, to treat the cognitive manifestations of AD, are currently approved by regulatory agencies, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA). Three are acetylcholinesterase inhibitors and the other is memantine, an NMDA receptor antagonist. No drug has an indication for delaying or halting the progression of the disease.
Because reduction in the activity of the cholinergic neurons in the disease is well known, acetylcholinesterase inhibitors are employed to reduce the rate at which acetylcholine (ACh) is broken down and so to increase the concentration of ACh in the brain, thereby combatting the loss of ACh caused by the death of the cholinergin neurons.[130] Cholinesterase inhibitors currently approved include donepezil (brand name Aricept),[131] galantamine (Razadyne),[132] and rivastigmine (branded as Exelon,[133] and Exelon Patch[134]). There is also evidence for the efficacy of these medications in mild to moderate Alzheimer’s disease,[135] and some evidence for their use in the advanced stage. Only donepezil is approved for treatment of advanced AD dementia.[136] The use of these drugs in mild cognitive impairment has not shown any effect in a delay of the onset of AD.[137] Most common side effects include nausea and vomiting, both of which are linked to cholinergic excess. These side effects arise in approximately ten to twenty percent of users and are mild to moderate in severity. Less common secondary effects include muscle cramps; decreased heart rate (bradycardia), decreased appetite and weight, and increased gastric acid.[138][139][140][141]
Glutamate is a useful excitatory neurotransmitter of the nervous system, although excessive amounts in the brain can lead to cell death through a process called excitotoxicity which consists of the overstimulation of glutamate receptors. Excitotoxicity occurs not only in Alzheimer's disease, but also in other neurological diseases such as Parkinson's disease and multiple sclerosis.[142] Memantine (brand names Akatinol, Axura, Ebixa/Abixa, Memox and Namenda),[143] is a noncompetitive NMDA receptor antagonist first used as an anti-influenza agent. It acts on the glutamatergic system by blocking NMDA glutamate receptors and inhibits their overstimulation by glutamate.[142] Memantine has been shown to be moderately efficacious in the treatment of moderate to severe Alzheimer’s disease. Its effects in the initial stages are unknown.[144] Reported adverse events with memantine are infrequent and mild, including hallucinations, confusion, dizziness, headache and fatigue.[145] Memantine used in combination with donepezil has been shown to be "of statistically significant but clinically marginal effectiveness".[146]
Neuroleptic anti-psychotic drugs commonly given to Alzheimer's patients with behavioural problems are modestly useful in reducing aggression and psychosis, but are associated with serious adverse effects, such as cerebrovascular events, movement difficulties or cognitive decline, that do not permit their routine use.[147][148][149]
Psychosocial intervention
A specifically designed room for sensory integration therapy, or snoezelen; an emotion-oriented psychosocial intervention for people with dementia
A specifically designed room for sensory integration therapy, or snoezelen; an emotion-oriented psychosocial intervention for people with dementia
Psychosocial interventions are used as an adjunct to pharmaceutical treatment and can be classified within behavior, emotion, cognition or stimulation oriented approaches. Research on efficacy is unavailable and rarely specific to the disease, focusing instead on dementia.[150]
Behavioral interventions attempt to identify and reduce the antecedents and consequences of problem behaviors. This approach has not shown success in the overall functioning of patients,[151] but can help to reduce some specific problem behaviors, such as incontinence.[152] There is still a lack of high quality data on the effectiveness of these techniques in other behavior problems such as wandering.[153][154]
Emotion-oriented interventions include reminiscence therapy, validation therapy, supportive psychotherapy, sensory integration or snoezelen, and simulated presence therapy. Supportive psychotherapy has received little or no formal scientific study, but some clinicians find it useful in helping mildly impaired patients adjust to their illness.[150] Reminiscence therapy (RT) involves the discussion of past experiences individually or in group, many times with the aid of photographs, household items, music and sound recordings, or other familiar items from the past. Although there are few quality studies on the effectiveness of RT it may be beneficial for cognition and mood.[155] Simulated presence therapy (SPT) is based on attachment theories and is normally carried out playing a recording with voices of the closest relatives of the patient. There is preliminary evidence indicating that SPT may reduce anxiety and challenging behaviors.[156][157] Finally, validation therapy is based on acceptance of the reality and personal truth of another's experience, while sensory integration is based on exercises aimed to stimulate senses. There is little evidence to support the usefulness of these therapies.[158][159]
The aim of cognition-oriented treatments, which include reality orientation and cognitive retraining is the restoration of cognitive deficits. Reality orientation consists in the presentation of information about time, place or person in order to ease the understanding of the person about its surroundings and his place in them. On the other hand cognitive retraining tries to improve impaired capacities by exercitation of mental abilities. Both have shown some efficacy improving cognitive capacities,[160][161] although in some works these effects were transient and negative effects, such as frustration, have also been reported.[150]
Stimulation-oriented treatments include art, music and pet therapies, exercise, and any other kind of recreational activities for patients. Stimulation has modest support for improving behavior, mood, and, to a lesser extent, function. Nevertheless, as important as these effects are, the main support for the use of stimulation therapies is the improvement in the patient daily life routine they suppose.[150]
Caregiving
Further information: Caregiving and dementia
Since there is no cure for Alzheimer's, caregiving is an essential part of the treatment. Due to the eventual inability for the sufferer to self-care, Alzheimer's has to be carefully care-managed. Home care in the familiar surroundings of home may delay onset of some symptoms and delay or eliminate the need for more professional and costly levels of care.[162] Many family members choose to look after their relatives,[12] but two-thirds of nursing home residents have dementias.[163]
Modifications to the living environment and lifestyle of the Alzheimer's patient can improve functional performance and ease caretaker burden. Assessment by an occupational therapist is often indicated. Adherence to simplified routines and labeling of household items to cue the patient can aid with activities of daily living, while placing safety locks on cabinets, doors, and gates and securing hazardous chemicals can prevent accidents and wandering. Changes in routine or environment can trigger or exacerbate agitation, whereas well-lit rooms, adequate rest, and avoidance of excess stimulation all help prevent such episodes.[164][165] Appropriate social and visual stimulation can improve function by increasing awareness and orientation. For instance, boldly colored tableware aids those with severe AD, helping people overcome a diminished sensitivity to visual contrast to increase food and beverage intake.[166]
Prognosis
As the disease progresses, the patient will advance from mild cognitive impairment, when the suspected underlying pathology may or may not yet have been diagnosed, to mild and advanced stages of dementia, finally reaching a severe stage of dementia.[27] Once Alzheimer's has been diagnosed, the average life expectancy is approximately seven years, while less than three percent of the patients live more than fourteen years.
History
Auguste D, first described patient with AD by Alöis Alzheimer in 1901
Although the concept of dementia goes as far back as the ancient Greek and Roman philosophers and physicians,[179] it was in 1901 when Alöis Alzheimer, a German psychiatrist, identified the first case of what became known as Alzheimer's disease in a fifty-year-old woman he called Auguste D. Alöis Alzheimer followed her until she died in 1906, when he first reported the case publicly.[180] In the following five years, eleven similar cases were reported in the medical literature, some of them already using the term Alzheimer's disease.[179] The official consideration of the disease as a distinctive entity is attributed to Emil Kraepelin, who included Alzheimer’s disease or presenile dementia as a subtype of senile dementia in the eighth edition of his Textbook of Psychiatry, published in 1910.[181]
For most of the twentieth century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of 45 and 65 who developed symptoms of dementia. The terminology changed after 1977 when a conference concluded that the clinical and pathological manifestations of presenile and senile dementia were almost identical, although the authors also added that this did not rule out the possibility of different etiologies.[182] This eventually led to the use of Alzheimer's disease independently of onset age of the disease.[183] The term senile dementia of the Alzheimer type (SDAT) was used for a time to describe the condition in those over 65, with classical Alzheimer's disease being used for those younger. Eventually, the term Alzheimer's disease was formally adopted in medical nomenclature to describe individuals of all ages with a characteristic common symptom pattern, disease course, and neuropathology.[184]
Society and culture
Social costs
Because the median age of the industrialised world's population is gradually increasing, AD is a public health challenge. The World Health Organization estimates that globally the total disability adjusted life years (DALYs) for AD and other dementias exceeded eleven million in 2005, with a projected 3.4% annual increase.[185] The DALYs are a measure for the overall disease burden that quantifies the impact of premature death and disability on a population by combining them into a single measure.
The solvency of governmental social safety nets will be impacted by the increased aged population which may develop Alzheimer's in the same proportions as earlier generations
anxiety disorders reference
Anxiety disorder is a blanket term covering several different forms of abnormal, pathological anxiety, fears, and phobias.
Anxiety and fear are ubiquitous emotions. The terms anxiety and fear have specific scientific meanings, but common usage has made them interchangeable. For example, a phobia is a kind of anxiety that is also defined in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV-TR) as a "persistent or irrational fear." Fear is defined as an emotional and physiological response to a recognized external threat. Anxiety is an unpleasant emotional state, the sources of which are less readily identified. It is frequently accompanied by physiological symptoms that may lead to fatigue or even exhaustion. Because fear of recognized threats causes similar unpleasant mental and physical changes, patients sometimes use the terms fear and anxiety interchangeably. Distinguishing among different anxiety disorders is important, since accurate diagnosis is more likely to result in effective treatment and a better prognosis. Surveys have shown as many as 30% of Americans may be affected by anxiety disorders
Diagnosis
Anxiety disorders are often debilitating chronic conditions, which can be present from an early age or begin suddenly after a triggering event. They are prone to flare up at times of high stress.
A good assessment is essential for the initial diagnosis of an anxiety disorder, preferably using a standardized interview or questionnaire procedure alongside expert evaluation and the views of the affected person. There should be a medical examination in order to identify possible medical conditions that can cause the symptoms of anxiety. A family history of anxiety disorders is often suggestive of the possibility of an anxiety disorder.
Anxiety can be accompanied by headache, sweating, palpitations, and hypertension.
It is important to note that a patient with an anxiety disorder will often exhibit symptoms of Clinical Depression and vice-versa. Rarely does a patient exhibit symptoms of only one or the other.
Causes and contributing factors
Clinical and animal studies suggest a correlation between anxiety disorders and difficulty in maintaining balance.
A possible mechanism is malfunction in the parabrachial nucleus, a structure in the brain, that among other functions, coordinates signals from the amygdala with input concerning balance. The amygdala is involved in the emotion of fear. [6]
Biochemical factors come into play. Low levels of GABA, a neurotransmitter that reduces overactivity in the central nervous system, contributes to anxiety. A number of anxiolytics achieve their effect by modulating the GABA receptors.[7] [8] [9]
Types
Generalized anxiety disorder
Generalized anxiety disorder is a common chronic disorder that affects twice as many women as men and can lead to considerable impairment (Brawman-Mintzer & Lydiard, 1996, 1997). As the name implies, generalized anxiety disorder is characterized by long-lasting anxiety that is not focused on any particular object or situation. In other words it is unspecific or free-floating. People with this disorder feel afraid of something but are unable to articulate the specific fear. They fret constantly and have a hard time controlling their worries. Because of persistent muscle tension and autonomic fear reactions, they may develop headaches, heart palpitations, dizziness, insomnia and chest pain. These physical symptoms, combined with the intense, long-term anxiety, make it difficult to cope with normal daily activities.
Panic disorder
In panic disorder, a person suffers from brief attacks of intense terror and apprehension that cause trembling and shaking, confusion, dizziness, nausea, difficulty breathing, and feelings of impending doom or a situation that would be embarrassing. One who is often plagued by sudden bouts of intense anxiety might be said to be afflicted by this disorder. The American Psychiatric Association (2000) defines a panic attack as fear or discomfort that arises abruptly and peaks in 10 minutes or less, and can occasionally last hours.
Although panic attacks sometimes seem to occur out of nowhere, they generally happen after frightening experiences, prolonged stress, or even exercise. Many people who have panic attacks (especially their first one) think they are having a heart attack and often end up at the doctor or emergency room. Even if the tests all come back normal the person will still worry, with the physical manifestations of anxiety only reinforcing their fear that something is wrong with their body. Heightened awareness (hypervigilance) of any change in the normal function of the human body will be noticed and interpreted as a possible life threatening illness by an individual suffering from panic attacks.
Normal changes in heartbeat, such as when climbing a flight of stairs will be noticed by a panic sufferer and lead them to think something is wrong with their heart or they are about to have another panic attack. Some begin to worry excessively and even quit jobs or refuse to leave home to avoid future attacks. Panic disorder can be diagnosed when several apparently spontaneous attacks lead to a persistent concern about future attacks.
Agoraphobia
A common complication of panic disorder is agoraphobia, anxiety about being in a place or situation where escape is difficult or embarrassing (Craske, 2000; Gorman, 2000). It seems that the definition of the word has expanded to refer to avoidance behaviors that sufferers often develop. If a sufferer of panic attacks seems to have them while driving, for example, then he or she may avoid driving, which relieves the anxiety, and subsequently makes future driving more difficult, as a result of behavioral reinforcement.
Phobias
This category involves a strong, irrational fear and avoidance of an object or situation. The person knows the fear is irrational, yet the anxiety remains. Phobic disorders differ from generalized anxiety disorders and panic disorders because there is a specific stimulus or situation that elicits a strong fear response. A person suffering from a phobia of spiders might feel so frightened by a spider that he or she would try to jump out of a speeding car to get away from one.
People with phobias have especially powerful imaginations, so they vividly anticipate terrifying consequences from encountering such feared objects as knives, bridges, blood, enclosed places, certain animals or situations. These individuals generally recognize that their fears are excessive and unreasonable but are generally unable to control their anxiety.
Social anxiety disorder
Social anxiety disorder is also known as social phobia. Individuals with this disorder experience intense fear of being negatively evaluated by others or of being publicly embarrassed because of impulsive acts. Almost everyone experiences "stage fright" when speaking or performing in front of a group. Since occasionally there are artists or performers with social anxiety disorder who are able to perform publicly without significant anxiety, their love of performing and practicing their art may be diminishing their anxiety. Although some high-functioning phobics such as Glenn Gould are able to perform despite anxiety, most people with social phobias become so anxious that performance is out of the question. In fact, their fear of public scrutiny and potential humiliation becomes so pervasive that normal life can become impossible (den Boer 2000; Margolis & Swartz, 2001). Another social phobia is fear of intimacy, or "love-shyness", which most adversely affects certain men. Those afflicted find themselves unable to initiate intimate adult relationships (Gilmartin 1987).
Obsessive-compulsive disorder
Obsessive compulsive disorder is a type of anxiety disorder primarily characterized by obsessions and/or compulsions. Obsessions are distressing, repetitive, intrusive thoughts or images that the individual often realizes are senseless. Compulsions are repetitive behaviors that the person feels forced or compelled into doing, sometimes, in order to relieve anxiety. The OCD thought pattern may be likened to superstitions: if X is done, Y won't happen—in spite of how unlikely it may be that doing X will actually prevent Y, if Y is even a real threat to begin with. A common example of this behavior would be obsessing that one's door is unlocked, which may lead to compulsive constant checking and rechecking of doors. Another example is obsession with the state of one's personal items, such as eyeglasses, leading to their excessive cleaning or adjustment. Often the process seems much less logical. For example, the compulsion of walking in a certain pattern may be employed to alleviate the obsession that something bad is about to happen. More often, though, the compulsion is inexplicable, simply an urge to complete a ritual triggered by nervousness. Light switches and other household items are also common objects of obsession.
Post-traumatic stress disorder
Post-traumatic stress disorder is an anxiety disorder which results from a traumatic experience. Post-traumatic stress can result from an extreme situation, such as being involved in warfare, rape, hostage situations, or involvement in a serious accident. It can also result from long term (chronic) exposure to a severe stressor,[10] for example soldiers who endure individual battles but cannot cope with an unceasing sequence of battles. The sufferer may experience flashbacks, avoidant behavior, and other symptoms.
Separation anxiety
Separation anxiety disorder is the feeling of excessive and inappropriate levels of anxiety over being separated from an attachment figure or from a person or place that gives a feeling of safety. While it is seen mostly in children (for example on being left at school) it is also seen in adolescents and adults.
Separation anxiety itself is a normal part of development in babies or children.[11] It is only when this feeling is excessive or inappropriate that it can be considered a disorder.
Treatment
The choices of treatment include cognitive behavioral therapy, lifestyle changes, and/or pharmaceutical therapy (medications). Mainstream treatment for anxiety consists of the prescription of anxiolytic agents and/or antidepressants and/or referral to a Psychologist/cognitive-behavioral therapist. Treatment controversy arises because some studies indicate that a combination of the medications and behavioral therapy can be more effective than either one alone; however, others studies suggest pharmacological interventions are largely just pallative, and can actually interfere with the mechanisms of successful therapy
Anxiety and fear are ubiquitous emotions. The terms anxiety and fear have specific scientific meanings, but common usage has made them interchangeable. For example, a phobia is a kind of anxiety that is also defined in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV-TR) as a "persistent or irrational fear." Fear is defined as an emotional and physiological response to a recognized external threat. Anxiety is an unpleasant emotional state, the sources of which are less readily identified. It is frequently accompanied by physiological symptoms that may lead to fatigue or even exhaustion. Because fear of recognized threats causes similar unpleasant mental and physical changes, patients sometimes use the terms fear and anxiety interchangeably. Distinguishing among different anxiety disorders is important, since accurate diagnosis is more likely to result in effective treatment and a better prognosis. Surveys have shown as many as 30% of Americans may be affected by anxiety disorders
Diagnosis
Anxiety disorders are often debilitating chronic conditions, which can be present from an early age or begin suddenly after a triggering event. They are prone to flare up at times of high stress.
A good assessment is essential for the initial diagnosis of an anxiety disorder, preferably using a standardized interview or questionnaire procedure alongside expert evaluation and the views of the affected person. There should be a medical examination in order to identify possible medical conditions that can cause the symptoms of anxiety. A family history of anxiety disorders is often suggestive of the possibility of an anxiety disorder.
Anxiety can be accompanied by headache, sweating, palpitations, and hypertension.
It is important to note that a patient with an anxiety disorder will often exhibit symptoms of Clinical Depression and vice-versa. Rarely does a patient exhibit symptoms of only one or the other.
Causes and contributing factors
Clinical and animal studies suggest a correlation between anxiety disorders and difficulty in maintaining balance.
A possible mechanism is malfunction in the parabrachial nucleus, a structure in the brain, that among other functions, coordinates signals from the amygdala with input concerning balance. The amygdala is involved in the emotion of fear. [6]
Biochemical factors come into play. Low levels of GABA, a neurotransmitter that reduces overactivity in the central nervous system, contributes to anxiety. A number of anxiolytics achieve their effect by modulating the GABA receptors.[7] [8] [9]
Types
Generalized anxiety disorder
Generalized anxiety disorder is a common chronic disorder that affects twice as many women as men and can lead to considerable impairment (Brawman-Mintzer & Lydiard, 1996, 1997). As the name implies, generalized anxiety disorder is characterized by long-lasting anxiety that is not focused on any particular object or situation. In other words it is unspecific or free-floating. People with this disorder feel afraid of something but are unable to articulate the specific fear. They fret constantly and have a hard time controlling their worries. Because of persistent muscle tension and autonomic fear reactions, they may develop headaches, heart palpitations, dizziness, insomnia and chest pain. These physical symptoms, combined with the intense, long-term anxiety, make it difficult to cope with normal daily activities.
Panic disorder
In panic disorder, a person suffers from brief attacks of intense terror and apprehension that cause trembling and shaking, confusion, dizziness, nausea, difficulty breathing, and feelings of impending doom or a situation that would be embarrassing. One who is often plagued by sudden bouts of intense anxiety might be said to be afflicted by this disorder. The American Psychiatric Association (2000) defines a panic attack as fear or discomfort that arises abruptly and peaks in 10 minutes or less, and can occasionally last hours.
Although panic attacks sometimes seem to occur out of nowhere, they generally happen after frightening experiences, prolonged stress, or even exercise. Many people who have panic attacks (especially their first one) think they are having a heart attack and often end up at the doctor or emergency room. Even if the tests all come back normal the person will still worry, with the physical manifestations of anxiety only reinforcing their fear that something is wrong with their body. Heightened awareness (hypervigilance) of any change in the normal function of the human body will be noticed and interpreted as a possible life threatening illness by an individual suffering from panic attacks.
Normal changes in heartbeat, such as when climbing a flight of stairs will be noticed by a panic sufferer and lead them to think something is wrong with their heart or they are about to have another panic attack. Some begin to worry excessively and even quit jobs or refuse to leave home to avoid future attacks. Panic disorder can be diagnosed when several apparently spontaneous attacks lead to a persistent concern about future attacks.
Agoraphobia
A common complication of panic disorder is agoraphobia, anxiety about being in a place or situation where escape is difficult or embarrassing (Craske, 2000; Gorman, 2000). It seems that the definition of the word has expanded to refer to avoidance behaviors that sufferers often develop. If a sufferer of panic attacks seems to have them while driving, for example, then he or she may avoid driving, which relieves the anxiety, and subsequently makes future driving more difficult, as a result of behavioral reinforcement.
Phobias
This category involves a strong, irrational fear and avoidance of an object or situation. The person knows the fear is irrational, yet the anxiety remains. Phobic disorders differ from generalized anxiety disorders and panic disorders because there is a specific stimulus or situation that elicits a strong fear response. A person suffering from a phobia of spiders might feel so frightened by a spider that he or she would try to jump out of a speeding car to get away from one.
People with phobias have especially powerful imaginations, so they vividly anticipate terrifying consequences from encountering such feared objects as knives, bridges, blood, enclosed places, certain animals or situations. These individuals generally recognize that their fears are excessive and unreasonable but are generally unable to control their anxiety.
Social anxiety disorder
Social anxiety disorder is also known as social phobia. Individuals with this disorder experience intense fear of being negatively evaluated by others or of being publicly embarrassed because of impulsive acts. Almost everyone experiences "stage fright" when speaking or performing in front of a group. Since occasionally there are artists or performers with social anxiety disorder who are able to perform publicly without significant anxiety, their love of performing and practicing their art may be diminishing their anxiety. Although some high-functioning phobics such as Glenn Gould are able to perform despite anxiety, most people with social phobias become so anxious that performance is out of the question. In fact, their fear of public scrutiny and potential humiliation becomes so pervasive that normal life can become impossible (den Boer 2000; Margolis & Swartz, 2001). Another social phobia is fear of intimacy, or "love-shyness", which most adversely affects certain men. Those afflicted find themselves unable to initiate intimate adult relationships (Gilmartin 1987).
Obsessive-compulsive disorder
Obsessive compulsive disorder is a type of anxiety disorder primarily characterized by obsessions and/or compulsions. Obsessions are distressing, repetitive, intrusive thoughts or images that the individual often realizes are senseless. Compulsions are repetitive behaviors that the person feels forced or compelled into doing, sometimes, in order to relieve anxiety. The OCD thought pattern may be likened to superstitions: if X is done, Y won't happen—in spite of how unlikely it may be that doing X will actually prevent Y, if Y is even a real threat to begin with. A common example of this behavior would be obsessing that one's door is unlocked, which may lead to compulsive constant checking and rechecking of doors. Another example is obsession with the state of one's personal items, such as eyeglasses, leading to their excessive cleaning or adjustment. Often the process seems much less logical. For example, the compulsion of walking in a certain pattern may be employed to alleviate the obsession that something bad is about to happen. More often, though, the compulsion is inexplicable, simply an urge to complete a ritual triggered by nervousness. Light switches and other household items are also common objects of obsession.
Post-traumatic stress disorder
Post-traumatic stress disorder is an anxiety disorder which results from a traumatic experience. Post-traumatic stress can result from an extreme situation, such as being involved in warfare, rape, hostage situations, or involvement in a serious accident. It can also result from long term (chronic) exposure to a severe stressor,[10] for example soldiers who endure individual battles but cannot cope with an unceasing sequence of battles. The sufferer may experience flashbacks, avoidant behavior, and other symptoms.
Separation anxiety
Separation anxiety disorder is the feeling of excessive and inappropriate levels of anxiety over being separated from an attachment figure or from a person or place that gives a feeling of safety. While it is seen mostly in children (for example on being left at school) it is also seen in adolescents and adults.
Separation anxiety itself is a normal part of development in babies or children.[11] It is only when this feeling is excessive or inappropriate that it can be considered a disorder.
Treatment
The choices of treatment include cognitive behavioral therapy, lifestyle changes, and/or pharmaceutical therapy (medications). Mainstream treatment for anxiety consists of the prescription of anxiolytic agents and/or antidepressants and/or referral to a Psychologist/cognitive-behavioral therapist. Treatment controversy arises because some studies indicate that a combination of the medications and behavioral therapy can be more effective than either one alone; however, others studies suggest pharmacological interventions are largely just pallative, and can actually interfere with the mechanisms of successful therapy
arthritis reference
Arthritis (from Greek arthro-, joint + -itis, inflammation; plural: arthritides) is a group of conditions involving damage to the joints of the body. Arthritis is the leading cause of disability in people older than fifty-five years.
There are different forms of arthritis; each has a different cause. The most common form of arthritis, osteoarthritis (degenerative joint disease) is a result of trauma to the joint, infection of the joint, or age. Emerging evidence suggests that abnormal anatomy might contribute to the early development of osteoarthritis. Other arthritis forms are rheumatoid arthritis and psoriatic arthritis, autoimmune diseases in which the body attacks itself. Septic arthritis is caused by joint infection. Gouty arthritis is caused by deposition of uric acid crystals in the joint, causing inflammation. There is also an uncommon form of gout caused by the formation of rhomboid crystals of calcium pyrophosphate. This gout is known as pseudogout
History and physical examination
All arthritides feature pain. Pain patterns may differ depending on the arthritides and the location. Rheumatoid arthritis is generally worse in the morning and associated with stiffness; in the early stages, patients often have no symptoms after a morning shower. In the aged and children, pain might not be the main feature; the aged patient simply moves less, the infantile patient refuses to use the affected limb.
Elements of the history of the disorder guide diagnosis. Important features are speed and time of onset, pattern of joint involvement, symmetry of symptoms, early morning stiffness, tenderness, gelling or locking with inactivity, aggravating and relieving factors, and other systemic symptoms. Physical examination may confirm the diagnosis, or may indicate systemic disease. Radiographs are often used to follow progression or assess severity in a more quantitative manner.
Types of arthritis
Primary forms of arthritis:
* Osteoarthritis
* Rheumatoid arthritis
* Septic arthritis
* Gout and pseudogout
* Juvenile idiopathic arthritis
* Still's disease
* Ankylosing spondylitis
Secondary to other diseases:
* Lupus erythematosus
* Henoch-Schönlein purpura
* Psoriatic arthritis
* Reactive arthritis
* Haemochromatosis
* Hepatitis
* Wegener's granulomatosis (and many other vasculitis syndromes)
* Lyme disease
* Familial Mediterranean fever
* Hyperimmunoglobulinemia D with recurrent fever
* TNF receptor associated periodic syndrome
* Inflammatory bowel disease (Including Crohn's Disease and Ulcerative Colitis)
Diseases that can mimic arthritis include:
* Hypertrophic osteoarthropathy
* Multiple myeloma
* Osteoporosis
* Fifth disease
Treatment
Treatment options vary depending on the type of arthritis and include physical and occupational therapy, lifestyle changes (including exercise and weight control), medications and dietary supplements (symptomatic or targeted at the disease process causing the arthritis). Arthroplasty (joint replacement surgery) may be required in eroding forms of arthritis.
In general, studies have shown that physical exercising of the affected joint can have noticeable improvement in terms of long-term pain relief. Furthermore, exercising of the arthritic joint is encouraged to maintain the health of the particular joint and the overall body of the person.
Another form of non-drug treatment that does have a body of proper research to support its efficacy is marine oil, from both fish and the New Zealand green-lipped mussel (Perna canaliculus). Diets high in marine oils from cold-water fish such as salmon, mackerel, and tuna have been shown to reduce the inflammation of joint conditions such as arthritis[citation needed]. Massage on joints with neem oil has reported improvement in chronic and acute cases[citation needed].
History
While evidence of primary ankle (kaki) osteoarthritis has been discovered in dinosaurs, the first known traces of human arthritis date back as far as 4500 BC. It was noted in skeletal remains of Native Americans found in Tennessee and parts of what is now Olathe, Kansas. Evidence of arthritis has been found throughout history, from Ötzi, a mummy (circa 3000 BC) found along the border of modern Italy and Austria, to the Egyptian mummies circa 2590 BC
There are different forms of arthritis; each has a different cause. The most common form of arthritis, osteoarthritis (degenerative joint disease) is a result of trauma to the joint, infection of the joint, or age. Emerging evidence suggests that abnormal anatomy might contribute to the early development of osteoarthritis. Other arthritis forms are rheumatoid arthritis and psoriatic arthritis, autoimmune diseases in which the body attacks itself. Septic arthritis is caused by joint infection. Gouty arthritis is caused by deposition of uric acid crystals in the joint, causing inflammation. There is also an uncommon form of gout caused by the formation of rhomboid crystals of calcium pyrophosphate. This gout is known as pseudogout
History and physical examination
All arthritides feature pain. Pain patterns may differ depending on the arthritides and the location. Rheumatoid arthritis is generally worse in the morning and associated with stiffness; in the early stages, patients often have no symptoms after a morning shower. In the aged and children, pain might not be the main feature; the aged patient simply moves less, the infantile patient refuses to use the affected limb.
Elements of the history of the disorder guide diagnosis. Important features are speed and time of onset, pattern of joint involvement, symmetry of symptoms, early morning stiffness, tenderness, gelling or locking with inactivity, aggravating and relieving factors, and other systemic symptoms. Physical examination may confirm the diagnosis, or may indicate systemic disease. Radiographs are often used to follow progression or assess severity in a more quantitative manner.
Types of arthritis
Primary forms of arthritis:
* Osteoarthritis
* Rheumatoid arthritis
* Septic arthritis
* Gout and pseudogout
* Juvenile idiopathic arthritis
* Still's disease
* Ankylosing spondylitis
Secondary to other diseases:
* Lupus erythematosus
* Henoch-Schönlein purpura
* Psoriatic arthritis
* Reactive arthritis
* Haemochromatosis
* Hepatitis
* Wegener's granulomatosis (and many other vasculitis syndromes)
* Lyme disease
* Familial Mediterranean fever
* Hyperimmunoglobulinemia D with recurrent fever
* TNF receptor associated periodic syndrome
* Inflammatory bowel disease (Including Crohn's Disease and Ulcerative Colitis)
Diseases that can mimic arthritis include:
* Hypertrophic osteoarthropathy
* Multiple myeloma
* Osteoporosis
* Fifth disease
Treatment
Treatment options vary depending on the type of arthritis and include physical and occupational therapy, lifestyle changes (including exercise and weight control), medications and dietary supplements (symptomatic or targeted at the disease process causing the arthritis). Arthroplasty (joint replacement surgery) may be required in eroding forms of arthritis.
In general, studies have shown that physical exercising of the affected joint can have noticeable improvement in terms of long-term pain relief. Furthermore, exercising of the arthritic joint is encouraged to maintain the health of the particular joint and the overall body of the person.
Another form of non-drug treatment that does have a body of proper research to support its efficacy is marine oil, from both fish and the New Zealand green-lipped mussel (Perna canaliculus). Diets high in marine oils from cold-water fish such as salmon, mackerel, and tuna have been shown to reduce the inflammation of joint conditions such as arthritis[citation needed]. Massage on joints with neem oil has reported improvement in chronic and acute cases[citation needed].
History
While evidence of primary ankle (kaki) osteoarthritis has been discovered in dinosaurs, the first known traces of human arthritis date back as far as 4500 BC. It was noted in skeletal remains of Native Americans found in Tennessee and parts of what is now Olathe, Kansas. Evidence of arthritis has been found throughout history, from Ötzi, a mummy (circa 3000 BC) found along the border of modern Italy and Austria, to the Egyptian mummies circa 2590 BC
asthma reference
Asthma is a chronic condition involving the respiratory system in which the airways occasionally constrict, become inflamed, and are lined with excessive amounts of mucus, often in response to one or more triggers.[1] These episodes may be triggered by such things as exposure to an environmental stimulant such as an allergen, environmental tobacco smoke, cold or warm air, perfume, pet dander, moist air, exercise or exertion, or emotional stress. In children, the most common triggers are viral illnesses such as those that cause the common cold.[2] This airway narrowing causes symptoms such as wheezing, shortness of breath, chest tightness, and coughing. The airway constriction responds to bronchodilators. Between episodes, most patients feel well but can have mild symptoms and they may remain short of breath after exercise for longer periods of time than the unaffected individual. The symptoms of asthma, which can range from mild to life threatening, can usually be controlled with a combination of drugs and environmental changes.
Public attention in the developed world has recently focused on asthma because of its rapidly increasing prevalence, affecting up to one in four urban children
Signs and symptoms
In some individuals asthma is characterized by chronic respiratory impairment. In others it is an intermittent illness marked by episodic symptoms that may result from a number of triggering events, including upper respiratory infection, stress, airborne allergens, air pollutants (such as smoke or traffic fumes), or exercise. Some or all of the following symptoms may be present in those with asthma: dyspnea, wheezing, stridor, coughing, an inability for physical exertion. Some asthmatics who have severe shortness of breath and tightening of the lungs never wheeze or have stridor and their symptoms may be confused with a COPD-type disease.
An acute exacerbation of asthma is commonly referred to as an asthma attack. The clinical hallmarks of an attack are shortness of breath (dyspnea) and either wheezing or stridor.[4] Although the former is "often regarded as the sine qua non of asthma",[4] some patients present primarily with coughing, and in the late stages of an attack, air motion may be so impaired that no wheezing may be heard. When present the cough may sometimes produce clear sputum. The onset may be sudden, with a sense of constriction in the chest, breathing becomes difficult, and wheezing occurs (primarily upon expiration, but can be in both respiratory phases).
Signs of an asthmatic episode include wheezing, prolonged expiration, a rapid heart rate (tachycardia), rhonchous lung sounds (audible through a stethoscope), the presence of a paradoxical pulse (a pulse that is weaker during inhalation and stronger during exhalation), and over-inflation of the chest. During a serious asthma attack, the accessory muscles of respiration (sternocleidomastoid and scalene muscles of the neck) may be used, shown as in-drawing of tissues between the ribs and above the sternum and clavicles.
During very severe attacks, an asthma sufferer can turn blue from lack of oxygen, and can experience chest pain or even loss of consciousness. Just before loss of consciousness, there is a chance that the patient will feel numbness in the limbs and palms may start to sweat. The person's feet may become icy cold. Severe asthma attacks, which may not be responsive to standard treatments (status asthmaticus), are life-threatening and may lead to respiratory arrest and death. Despite the severity of symptoms during an asthmatic episode, between attacks an asthmatic may show few or even no signs of the disease.[5]
Cause
Asthma is caused by a complex interaction of genetic and environmental factors that researchers do not fully understand yet.[6] These factors can also influence how severe a person’s asthma is and how well they respond to medication.[7] As with other complex diseases, many genetic and environmental factors have been suggested as causes of asthma, but not all of them have been replicated. In addition, as researchers detangle the complex causes of asthma, it is becoming more evident that certain environmental and genetic factors may only affect asthma when combined.
The hygiene hypothesis is a theory about the cause of asthma and other allergic disease, and is supported by epidemiologic data for asthma. For example, asthma prevalence has been increasing in developed countries along with increased use of antibiotics, c-sections, and cleaning products.[8][9][10] All of these things may negatively affect exposure to beneficial bacteria and other immune system modulators that are important during development, and thus may cause increased risk for asthma and allergy.
Environmental
Many environmental risk factors have been associated with asthma, but a few stand out as well-replicated or that have a meta-analysis of several studies to support their direct association:
* Poor air quality, from traffic pollution or high ozone levels, has been repeatedly associated with increased asthma morbidity and has a suggested association with asthma development that needs further research.[11][12]
* Environmental tobacco smoke, especially maternal cigarette smoking, is associated with high risk of asthma prevalence and asthma morbidity, wheeze, and respiratory infections.[11]
* Viral respiratory infections at an early age, along with siblings and day care exposure, may be protective against asthma, although there have been controversial results, and this protection may depend on genetic context.[11][13][14]
* Antibiotic use early in life has been linked to development of asthma in several examples; it is thought that antibiotics make one susceptible to development of asthma because they modify gut flora, and thus the immune system (as described by the hygiene hypothesis).[8]
* Caesarean sections have been associated with asthma when compared with vaginal birth; a meta-analysis found a 20% increase in asthma prevalence in children delivered by Caesarean section compared to those who were not. It was proposed that this is due to modified bacterial exposure during Caesarean section compared with vaginal birth, which modifies the immune system (as described by the hygiene hypothesis).[9]
* Psychological stress on the part of a child's caregiver has been associated with asthma, and is an area of active research. Stress can modify behaviors that affect asthma, like smoking, but research suggests that stress has other effects as well. There is growing evidence that stress may influence asthma and other diseases by influencing the immune system.[11]
Genetic
Over 100 genes have been associated with asthma in at least one genetic association study.[15] However, as with all association studies, replication is important before genetic variation (such as a single nucleotide polymorphism, or SNP) in a certain gene is thought to influence asthma
Bronchoconstriction
During an asthma episode, inflamed airways react to environmental triggers such as smoke, dust, or pollen. The airways narrow and produce excess mucus, making it difficult to breathe. In essence, asthma is the result of an immune response in the bronchial airways.[17]
The airways of asthmatics are "hypersensitive" to certain triggers, also known as stimuli (see below). In response to exposure to these triggers, the bronchi (large airways) contract into spasm (an "asthma attack"). Inflammation soon follows, leading to a further narrowing of the airways and excessive mucus production, which leads to coughing and other breathing difficulties.
The normal calibre of the bronchus is maintained by a balanced functioning of these systems, which both operate reflexively. The parasympathetic reflex loop consists of afferent nerve endings which originate under the inner lining of the bronchus. Whenever these afferent nerve endings are stimulated (for example, by dust, cold air or fumes) impulses travel to the brain-stem vagal centre, then down the vagal afferent pathway to again reach the bronchus. Acetylcholine is released from the afferent nerve endings. This acetylcholine results in the excessive formation of cyclic Guanine Mono phosphate (GMP). This initiates bronchoconstriction.
Bronchial inflammation
The mechanisms behind allergic asthma—i.e., asthma resulting from an immune response to inhaled allergens—are the best understood of the causal factors. In both asthmatics and non-asthmatics, inhaled allergens that find their way to the inner airways are ingested by a type of cell known as antigen presenting cells, or APCs. APCs then "present" pieces of the allergen to other immune system cells. In most people, these other immune cells (TH0 cells) "check" and usually ignore the allergen molecules. In asthmatics, however, these cells transform into a different type of cell (TH2), for reasons that are not well understood. The resultant TH2 cells activate an important arm of the immune system, known as the humoral immune system. The humoral immune system produces antibodies against the inhaled allergen. Later, when an asthmatic inhales the same allergen, these antibodies "recognize" it and activate a humoral response. Inflammation results: chemicals are produced that cause the airways to constrict and release more mucus, and the cell-mediated arm of the immune system is activated. The inflammatory response is responsible for the clinical manifestations of an asthma attack.
Stimuli
* Allergens from nature, typically inhaled, which include waste from common household pests, such as the house dust mite and cockroach, grass pollen, mould spores, and pet epithelial cells;[citation needed]
* Indoor air pollution from volatile organic compounds, including perfumes and perfumed products. Examples include soap, dishwashing liquid, laundry detergent, fabric softener, paper tissues, paper towels, toilet paper, shampoo, hairspray, hair gel, cosmetics, facial cream, sun cream, deodorant, cologne, shaving cream, aftershave lotion, air freshener and candles, and products such as oil-based paint.[citation needed]
* Medications, including aspirin,[18] β-adrenergic antagonists (beta blockers), and penicillin.[citation needed]
* Food allergies such as milk, peanuts, and eggs. However, asthma is rarely the only symptom, and not all people with food or other allergies have asthma.[citation needed]
* Use of fossil fuel related allergenic air pollution, such as ozone, smog, summer smog, nitrogen dioxide, and sulfur dioxide, which is thought to be one of the major reasons for the high prevalence of asthma in urban areas.[citation needed]
* Various industrial compounds and other chemicals, notably sulfites; chlorinated swimming pools generate chloramines—monochloramine (NH2Cl), dichloramine (NHCl2) and trichloramine (NCl3)—in the air around them, which are known to induce asthma.[19]
* Early childhood infections, especially viral respiratory infections. However, persons of any age can have asthma triggered by colds and other respiratory infections even though their normal stimuli might be from another category (e.g. pollen) and absent at the time of infection. In many cases, significant asthma may not even occur until the respiratory infection is in its waning stage, and the person is seemingly improving. Eighty percent of asthma attacks in adults and 60% in children are caused by respiratory viruses.[citation needed]
* Exercise or intense use of respiratory system. The effects of which differ somewhat from those of the other triggers, since they are brief. It is known that exercising regularly actually helps to cure asthma.[citation needed]
* Hormonal changes in adolescent girls and adult women associated with their menstrual cycle can lead to a worsening of asthma. Some women also experience a worsening of their asthma during pregnancy whereas others find no significant changes, and in other women their asthma improves during their pregnancy.[citation needed]
* Emotional stress which is poorly understood as a trigger.[citation needed] Emotional stress can affect breathing temporarily, however unlike something such as heart problems, it is unclear if it has any long-term effect.
* Cold weather can make it harder for asthmatics to breathe.[20] Whether high altitude helps or worsens asthma is debatable and may vary from person to person.[21]
Pathogenesis
The fundamental problem in asthma appears to be immunological: young children in the early stages of asthma show signs of excessive inflammation in their airways. Epidemiological findings give clues as to the pathogenesis: the incidence of asthma seems to be increasing worldwide, and asthma is now very much more common in affluent countries.
In 1968 Andor Szentivanyi first described The Beta Adrenergic Theory of Asthma; in which blockage of the Beta-2 receptors of pulmonary smooth muscle cells causes asthma.[22] Szentivanyi's Beta Adrenergic Theory is a citation classic[23] and has been cited more times than any other article in the history of the Journal of Allergy.
In 1995 Szentivanyi and colleagues demonstrated that IgE blocks beta-2 receptors.[24] Since overproduction of IgE is central to all atopic diseases, this was a watershed moment in the world of allergy.[25]
The Beta-Adrenergic Theory has been cited in the scholarship of such noted investigators as Richard F. Lockey (former President of the American Academy of Allergy, Asthma, and Immunology),[26] Charles Reed (Chief of Allergy at Mayo Medical School),[27] and Craig Venter (Human Genome Project).[28]
John P. McGovern, President of the American Association of Allergy nominated Szentivanyi for The 1968 Nobel Prize in Medicine in recognition of The Beta Adrenergic Theory.
In 2006, Researchers at Harvard Medical School found evidence that asthma is caused by over-proliferation of a special type of natural "killer" cell.[29]
Asthma and sleep apnea
It is recognized with increasing frequency, that patients who have both obstructive sleep apnea (OSA) and bronchial asthma, often improve tremendously when the sleep apnea is diagnosed and treated.[30] CPAP is not effective in patients with nocturnal asthma only.[31]
Asthma and gastro-esophageal reflux disease
Main article: gastro-esophageal reflux disease
If gastro-esophageal reflux disease is present, the patient may have repetitive episodes of acid aspiration, which results in airway inflammation and "irritant-induced" asthma.[citation needed] GERD may be common in difficult-to-control asthma, but according to one study, treating it does not seem to affect the asthma.[32]
Diagnosis
Asthma is defined simply as reversible airway obstruction. Reversibility occurs either spontaneously or with treatment. The basic measurement is peak flow rates and the following diagnostic criteria are used by the British Thoracic Society:[33]
* ≥20% difference on at least three days in a week for at least two weeks;
* ≥20% improvement of peak flow following treatment, for example:
o 10 minutes of inhaled β-agonist (e.g., salbutamol);
o six week of inhaled corticosteroid (e.g., beclometasone);
o 14 days of 30mg prednisolone.
* ≥20% decrease in peak flow following exposure to a trigger (e.g., exercise).
In many cases, a physician can diagnose asthma on the basis of typical findings in a patient's clinical history and examination. Asthma is strongly suspected if a patient suffers from eczema or other allergic conditions—suggesting a general atopic constitution—or has a family history of asthma. While measurement of airway function is possible for adults, most new cases are diagnosed in children who are unable to perform such tests. Diagnosis in children is based on a careful compilation and analysis of the patient's medical history and subsequent improvement with an inhaled bronchodilator medication. In adults, diagnosis can be made with a peak flow meter (which tests airway restriction), looking at both the diurnal variation and any reversibility following inhaled bronchodilator medication.
Testing peak flow at rest (or baseline) and after exercise can be helpful, especially in young asthmatics who may experience only exercise-induced asthma. If the diagnosis is in doubt, a more formal lung function test may be conducted. Once a diagnosis of asthma is made, a patient can use peak flow meter testing to monitor the severity of the disease.
Monitoring asthma with a peak flow meter on an ongoing basis assists with self monitoring of asthma. Peak flow readings can be charted on graph paper charts together with a record of symptoms or use peak flow charting software.[34] This allows patients to track their peak flow readings and pass information back to their doctor or nurse.[35]
In the Emergency Department doctors may use a capnography which measures the amount of exhaled carbon dioxide,[36] along with pulse oximetry which shows the amount of oxygen dissolved in the blood, to determine the severity of an asthma attack as well as the response to treatment.
Differential diagnosis
Before diagnosing someone as asthmatic, alternative possibilities should be considered. A clinician taking a history should check whether the patient is using any known bronchoconstrictors (substances that cause narrowing of the airways, e.g., certain anti-inflammatory agents or beta-blockers).
Chronic obstructive pulmonary disease, which closely resembles asthma, is correlated with more exposure to cigarette smoke, an older patient, less symptom reversibility after bronchodilator administration (as measured by spirometry), and decreased likelihood of family history of atopy.
Pulmonary aspiration, whether direct due to dysphagia (swallowing disorder) or indirect (due to acid reflux), can show similar symptoms to asthma. However, with aspiration, fevers might also indicate aspiration pneumonia. Direct aspiration (dysphagia) can be diagnosed by performing a Modified Barium Swallow test and treated with feeding therapy by a qualified speech therapist. If the aspiration is indirect (from acid reflux) then treatment directed at this is indicated.
A majority of children who are asthma sufferers have an identifiable allergy trigger. Specifically, in a 2004 study, 71% had positive test results for more than 1 allergen, and 42% had positive test results for more than 3 allergens.[37]
The majority of these triggers can often be identified from the history; for instance, asthmatics with hay fever or pollen allergy will have seasonal symptoms, those with allergies to pets may experience an abatement of symptoms when away from home, and those with occupational asthma may improve during leave from work. Allergy tests can help identify avoidable symptom triggers.
After a pulmonary function test has been carried out, radiological tests, such as a chest X-ray or CT scan, may be required to exclude the possibility of other lung diseases. In some people, asthma may be triggered by gastroesophageal reflux disease, which can be treated with suitable antacids. Very occasionally, specialized tests after inhalation of methacholine — or, even less commonly, histamine — may be performed.
Asthma is categorized by the United States National Heart, Lung and Blood Institute as falling into one of four categories: intermittent, mild persistent, moderate persistent and severe persistent. The diagnosis of "severe persistent asthma" occurs when symptoms are continual with frequent exacerbations and frequent night-time symptoms, result in limited physical activity and when lung function as measured by PEV or FEV1 tests is less than 60% predicted with PEF variability greater than 30%.
Prevention
Current treatment protocols recommend prevention medications such as an inhaled corticosteroid, which helps to suppress inflammation and reduces the swelling of the lining of the airways, in anyone who has frequent (greater than twice a week) need of relievers or who has severe symptoms. If symptoms persist, additional preventive drugs are added until the asthma is controlled. With the proper use of prevention drugs, asthmatics can avoid the complications that result from overuse of relief medications.
Asthmatics sometimes stop taking their preventive medication when they feel fine and have no problems breathing. This often results in further attacks, and no long-term improvement.
Preventive agents include the following.
* Inhaled glucocorticoids are the most widely used of the prevention medications and normally come as inhaler devices (ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometasone, and triamcinolone).
Long-term use of corticosteroids can have many side effects including a redistribution of fat, increased appetite, blood glucose problems and weight gain. In particular high doses of steroids may cause osteoporosis. For this reasons inhaled steroids are generally used for prevention, as their smaller doses are targeted to the lungs unlike the higher doses of oral preparations. Nevertheless, patients on high doses of inhaled steroids may still require prophylactic treatment to prevent osteoporosis.
Deposition of steroids in the mouth may cause a hoarse voice or oral thrush (due to decreased immunity). This may be minimised by rinsing the mouth with water after inhaler use, as well as by using a spacer which increases the amount of drug that reaches the lungs.
* Leukotriene modifiers (montelukast, zafirlukast, pranlukast, and zileuton).
* Mast cell stabilizers (cromoglicate (cromolyn), and nedocromil).
* Antimuscarinics/anticholinergics (ipratropium, oxitropium, and tiotropium), which have a mixed reliever and preventer effect. (These are rarely used in preventive treatment of asthma, except in patients who do not tolerate beta-2-agonists.)
* Methylxanthines (theophylline and aminophylline), which are sometimes considered if sufficient control cannot be achieved with inhaled glucocorticoids and long-acting β-agonists alone.
* Antihistamines, often used to treat allergic symptoms that may underlie the chronic inflammation.
* Hyposensitization, (also known as immunodesensitisation therapy) may be recommended in some cases where allergy is the suspected cause or trigger of asthma. Depending on the allergen, it can be given orally or by injection.
* Omalizumab, an IgE blocker; this can help patients with severe allergic asthma that does not respond to other drugs. However, it is expensive and must be injected.
* Methotrexate is occasionally used in some difficult-to-treat patients.
* If chronic acid indigestion (GERD) contributes to a patient's asthma, it should also be treated, because it may prolong the respiratory problem.
Trigger avoidance
As is common with respiratory disease, smoking is believed to adversely affect asthmatics in several ways, including an increased severity of symptoms, a more rapid decline of lung function, and decreased response to preventive medications.[38] Automobile emissions are considered an even more significant cause and aggravating factor. [1] Asthmatics who smoke or who live near traffic [2] typically require additional medications to help control their disease. Furthermore, exposure of both non-smokers and smokers to wood smoke, gas stove fumes and second-hand smoke is detrimental, resulting in more severe asthma, more emergency room visits, and more asthma-related hospital admissions.[39] Smoking cessation and avoidance of second-hand smoke is strongly encouraged in asthmatics.[40]
For those in whom exercise can trigger an asthma attack (exercise-induced asthma), higher levels of ventilation and cold, dry air tend to exacerbate attacks. For this reason, activities in which a patient breathes large amounts of cold air, such as skiing and running, tend to be worse for asthmatics, whereas swimming in an indoor, heated pool, with warm, humid air, is less likely to provoke a response.[4]
Air Filters
If an asthmatic lives with a smoker, use of air filter or room air cleaner is likely to be helpful. Secondhand smoke can worsen the symptoms. The same is true for those with hay fever (allergic rhino sinusitis) or COPD (emphysema or chronic bronchitis). Room air cleaners remove small particles that are in the air near the air cleaner. However, room air cleaners do not remove small allergen particles that are caused by local disturbances, such as the microscopic house dust mite feces that surround a pillow when your head hits it or you turn over in bed. There are several types of air filters available.[41]
* Mechanical air filters use a fan to force air through a special screen that traps particles such as smoke, pollens, and other airborne allergens. The high-efficiency particulate air (HEPA) filter is the best-known air filter. HEPA (which is a type of filter, not a brand name) was developed during World War II to prevent radioactive particles from escaping from laboratories.
* Electronic air filters use electrical charges to attract and deposit allergens and irritants. If the device contains collecting plates, the particles are captured within the system; otherwise, they stick to room surfaces and have to be cleared away.
* Hybrid air filters contain elements of both mechanical and electrostatic filters.
* Gas phase air filters use activated carbon granules to remove odors (volatile organic compounds or VOCs) and non-particulate pollution such as cooking gas, gases emitted from paint or building materials (such as formaldehyde), and perfume.
* Germicidal air cleaners use ultraviolet (UV) lights to kill bacteria, viruses, and molds that pass through the area with the UV light. Such UV lights can be included with other air cleaner devices, which use a fan.
* Ozone generators are devices that intentionally produce high concentrations of ozone to clean the air in a room. They are often used to decontaminate rooms after smoke exposure following a fire.
Treatment
The most effective treatment for asthma is identifying triggers, such as pets or aspirin, and limiting or eliminating exposure to them. If trigger avoidance is insufficient, medical treatment is available. Desensitization is currently the only known "cure" to the disease.[42] Other forms of treatment include relief medication, prevention medication, long-acting β2-agonists, and emergency treatment.
Medical
The specific medical treatment recommended to patients with asthma depends on the severity of their illness and the frequency of their symptoms. Specific treatments for asthma are broadly classified as relievers, preventers and emergency treatment. The Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma (EPR-2)[40] of the U.S. National Asthma Education and Prevention Program, and the British Guideline on the Management of Asthma[43] are broadly used and supported by many doctors. On August 29, 2007 the final Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma was officially released. Bronchodilators are recommended for short-term relief in all patients. For those who experience occasional attacks, no other medication is needed. For those with mild persistent disease (more than two attacks a week), low-dose inhaled glucocorticoids or alternatively, an oral leukotriene modifier, a mast-cell stabilizer, or theophylline may be administered. For those who suffer daily attacks, a higher dose of glucocorticoid in conjunction with a long-acting inhaled β-2 agonist may be prescribed; alternatively, a leukotriene modifier or theophylline may substitute for the β-2 agonist. In severe asthmatics, oral glucocorticoids may be added to these treatments during severe attacks.
The discovery in 2006 by researchers at Harvard Medical School that asthma may be caused by over-proliferation of a special type of natural "killer" cell may ultimately lead to the development of better and more targeted drugs. Natural killer T cells seem to be resistant to the corticosteroids, one of the mainstays of current treatment.[29] Other promising avenues of current research include using cholesterol-lowering drugs (statins) and fish oil supplementation to reduce airway inflammation [44].
Pharmaceutical
Symptomatic control of episodes of wheezing and shortness of breath is generally achieved with fast-acting bronchodilators. These are typically provided in pocket-sized, metered-dose inhalers (MDIs). In young sufferers, who may have difficulty with the coordination necessary to use inhalers, or those with a poor ability to hold their breath for 10 seconds after inhaler use (generally the elderly), an asthma spacer (see top image) is used. The spacer is a plastic cylinder that mixes the medication with air in a simple tube, making it easier for patients to receive a full dose of the drug and allows for the active agent to be dispersed into smaller, more fully inhaled bits.
A nebulizer which provides a larger, continuous dose can also be used. Nebulizers work by vaporizing a dose of medication in a saline solution into a steady stream of foggy vapour, which the patient inhales continuously until the full dosage is administered. There is no clear evidence, however, that they are more effective than inhalers used with a spacer. Nebulizers may be helpful to some patients experiencing a severe attack. Such patients may not be able to inhale deeply, so regular inhalers may not deliver medication deeply into the lungs, even on repeated attempts. Since a nebulizer delivers the medication continuously, it is thought that the first few inhalations may relax the airways enough to allow the following inhalations to draw in more medication.
Relievers include:
* Short-acting, selective beta2-adrenoceptor agonists, such as salbutamol (albuterol USAN), levalbuterol, terbutaline and bitolterol.
Tremors, the major side effect, have been greatly reduced by inhaled delivery, which allows the drug to target the lungs specifically; oral and injected medications are delivered throughout the body. There may also be cardiac side effects at higher doses (due to Beta-1 agonist activity), such as elevated heart rate or blood pressure; with the advent of selective agents, these side effects have become less common. Patients must be cautioned against using these medicines too frequently, as with such use their efficacy may decline, producing desensitization resulting in an exacerbation of symptoms which may lead to refractory asthma and death.
* Older, less selective adrenergic agonists, such as inhaled epinephrine and ephedrine tablets, have also been used. Cardiac side effects occur with these agents at either similar or lesser rates to albuterol.[45] [46] When used solely as a relief medication, inhaled epinephrine has been shown to be an effective agent to terminate an acute asthmatic exacerbation.[45] In emergencies, these drugs were sometimes administered by injection. Their use via injection has declined due to related adverse effects.
* Anticholinergic medications, such as ipratropium bromide may be used instead. They have no cardiac side effects and thus can be used in patients with heart disease; however, they take up to an hour to achieve their full effect and are not as powerful as the β2-adrenoreceptor agonists.
* Inhaled glucocorticoids are usually considered preventive medications; however, a randomized controlled trial has demonstrated the benefit of 250 microg beclomethasone when taken as an as-needed combination inhaler with 100 microg of albuterol.[47]
Long-acting β2-agonists
A typical inhaler, of Serevent (salmeterol), a long-acting bronchodilator.
Long-acting bronchodilators (LABD) are similar in structure to short-acting selective beta2-adrenoceptor agonists, but have much longer side chains resulting in a 12-hour effect, and are used to give a smoothed symptomatic relief (used morning and night). While patients report improved symptom control, these drugs do not replace the need for routine preventers, and their slow onset means the short-acting dilators may still be required. In November 2005, the American FDA released a health advisory alerting the public to findings that show the use of long-acting β2-agonists could lead to a worsening of symptoms, and in some cases death.[48]
Currently available long-acting beta2-adrenoceptor agonists include salmeterol, formoterol, bambuterol, and sustained-release oral albuterol. Combinations of inhaled steroids and long-acting bronchodilators are becoming more widespread; the most common combination currently in use is fluticasone/salmeterol (Advair in the United States, and Seretide in the United Kingdom). Another combination is budesonide/formoterol which is commercially known as Symbicort.
A recent meta-analysis of the roles of long-acting beta-agonists may indicate a danger to asthma patients. The study, published in the Annals of Internal Medicine in 2006, found that long-acting beta-agonists increased the risk for asthma hospitalizations and asthma deaths 2- to 4-fold, compared with placebo.[49] "These agents can improve symptoms through bronchodilation at the same time as increasing underlying inflammation and bronchial hyper-responsiveness, thus worsening asthma control without any warning of increased symptoms," said Shelley Salpeter in a press release after the publication of the study. The release goes on to say that "Three common asthma inhalers containing the drugs salmeterol or formoterol may be causing four out of five US asthma-related deaths per year and should be taken off the market".[50] This assertion has drawn criticism from many asthma specialists for being inaccurate. As Dr. Hal Nelson points out in a recent letter to the Annals of Internal Medicine, "Salpeter and colleagues also assert that salmeterol may be responsible for 4000 of the 5000 asthma-related deaths that occur in the United States annually. However, when salmeterol was introduced in 1994, more than 5000 asthma-related deaths occurred per year. Since the peak of asthma deaths in 1996, salmeterol sales have increased about 5-fold, while overall asthma mortality rates have decreased by about 25%, despite a continued increase in asthma diagnoses. In fact, according to the most recent data from the National Center for Health Statistics, U.S. asthma mortality rates peaked in 1996 (with 5667 deaths) and have decreased steadily since. The last available data, from 2004, indicate that 3780 deaths occurred. Thus, the suggestion that a vast majority of asthma deaths could be attributable to LABA use is inconsistent with the facts."
Dr. Shelley Salpeter, in a letter to the Annals of Internal Medicine, responds to the comments of Dr. Nelson, "It is true that the asthma death rate increased after salmeterol was introduced, then peaked and is now starting to decline despite continued use of the long-acting beta-agonists. This trend in death rates can best be explained by examining the ratio of beta-agonist use to inhaled corticosteroids... In the recent past, inhaled corticosteroid use has increased steadily while long-acting beta-agonist use has begun to stabilize and short-acting beta-agonist use has declined... Using this estimate, we can imagine that if long-acting beta-agonists were withdrawn from the market while maintaining high inhaled corticosteroid use, the death rate in the United States could be reduced significantly..."
Emergency
When an asthma attack is unresponsive to a patient's usual medication, other treatments are available to the physician or hospital:[51]
* Oxygen to alleviate the hypoxia (but not the asthma itself) that results from extreme asthma attacks.
* Nebulized salbutamol or terbutaline (short-acting beta-2-agonists), often combined with ipratropium (an anticholinergic).
* Systemic steroids, oral or intravenous (prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone). Some research has looked into an alternative inhaled route.[52]
* Other bronchodilators that are occasionally effective when the usual drugs fail:
o Intravenous salbutamol
o Nonspecific beta-agonists, injected or inhaled (epinephrine, isoetharine, isoproterenol, metaproterenol)
o Anticholinergics, IV or nebulized, with systemic effects (glycopyrrolate, atropine, ipratropium)
o Methylxanthines (theophylline, aminophylline)
o Inhalation anesthetics that have a bronchodilatory effect (isoflurane, halothane, enflurane)
o The dissociative anaesthetic ketamine, often used in endotracheal tube induction
o Magnesium sulfate, intravenous
* Intubation and mechanical ventilation, for patients in or approaching respiratory arrest.
* Heliox, a mixture of helium and oxygen, may be used in a hospital setting. It has a more laminar flow than ambient air and moves more easily through constricted airways.
Non-medical treatments
Many asthmatics, like those who suffer from other chronic disorders, use alternative treatments; surveys show that roughly 50% of asthma patients use some form of unconventional therapy.[53][54] There is little data to support the effectiveness of most of these therapies. A Cochrane systematic review of acupuncture for asthma found no evidence of efficacy.[55] A similar review of air ionisers found no evidence that they improve asthma symptoms or benefit lung function; this applied equally to positive and negative ion generators.[56] A study of "manual therapies" for asthma, including osteopathic, chiropractic, physiotherapeutic and respiratory therapeutic manoeuvres, found there is insufficient evidence to support or refute their use in treating asthma;[57] these manoeuvers include various osteopathic and chiropractic techniques to "increase movement in the rib cage and the spine to try and improve the working of the lungs and circulation"; chest tapping, shaking, vibration, and the use of "postures to help shift and cough up phlegm." One meta-analysis finds that homeopathy may have a potentially mild benefit in reducing the intensity of symptoms.[58] However, the number of patients involved in the analysis was small, and subsequent studies have not supported this finding.[59] Several small trials have suggested some benefit from various yoga practices, ranging from integrated yoga programs,[60] yogasanas, Pranayama, meditation, and kriyas, to sahaja yoga,[61] a form of 'new religious' meditation.
Treatment controversies
In November 2007 The New York Times reported a review of more than 500 studies finding that independently backed studies on inhaled corticosteroids are up to four times more likely to find adverse effects than studies paid for by drug companies.[62][63]
Prognosis
The prognosis for asthmatics is good; especially for children with mild disease. For asthmatics diagnosed during childhood, 54% will no longer carry the diagnosis after a decade. The extent of permanent lung damage in asthmatics is unclear. Airway remodelling is observed, but it is unknown whether these represent harmful or beneficial changes.[17] Although conclusions from studies are mixed, most studies show that early treatment with glucocorticoids prevents or ameliorates decline in lung function as measured by several parameters.[64] For those who continue to suffer from mild symptoms, corticosteroids can help most to live their lives with few disabilities. The mortality rate for asthma is low, with around 6000 deaths per year in a population of some 10 million patients in the United States.[4] Better control of the condition may help prevent some of these deaths.
The prevalence of childhood asthma has increased since 1980, especially in younger children.
The prevalence of childhood asthma has increased since 1980, especially in younger children.
Epidemiology
More than 6% of children in the United States have been diagnosed with asthma, a 75% increase in recent decades. The rate soars to 40% among some populations of urban children.[citation needed]
Asthma is usually diagnosed in childhood. The risk factors for asthma include:[citations needed]
* A personal or family history of asthma or atopy
* Triggers (see Pathophysiology above)
* Premature birth or low birth weight
* Viral respiratory infection in early childhood
* Maternal smoking
* Being male, for asthma in prepubertal children
* Being female, for persistence of asthma into adulthood
Current research suggests that the prevalence of childhood asthma has been increasing. According to the Centers for Disease Control and Prevention's National Health Interview Surveys, some 9% of US children below 18 years of age had asthma in 2001, compared with just 3.6% in 1980 (see figure). The World Health Organization (WHO) reports that some 8% of the Swiss population suffers from asthma today, compared with just 2% some 25–30 years ago.[65] Although asthma is more common in affluent countries, it is by no means a problem restricted to the affluent; the WHO estimate that there are between 15 and 20 million asthmatics in India. In the U.S., urban residents, Hispanics, and African Americans are affected more than the population as a whole. Globally, asthma is responsible for around 180,000 deaths annually.
Population disparities
Asthma prevalence, morbidity, mortality, and drug response vary greatly across populations. There is an almost 30-fold difference in asthma prevalence between some of the countries included in the International Study of Asthma and Allergy in Childhood[3], with a trend toward more developed and westernized countries having higher asthma prevalence. Westernization can’t explain the entire difference in asthma prevalence between countries, however, and the disparities may also be affected by differences in genetic, social and environmental risk factors.[11] There are also worldwide disparities in asthma mortality, which is most common in low to middle income countries.[66]
Asthma prevalence in the US is higher than in most other countries in the world, but varies drastically between diverse US populations.[11] In the US, asthma prevalence is highest in Puerto Ricans, African Americans, Filipinos and Native Hawaiians, and lowest in Mexicans and Koreans. Mortality rates follow similar trends, and response to albuterol is lower in Puerto Ricans than in African Americans or Mexicans.[70][71] As with worldwide asthma disparities, differences in asthma prevalence, mortality, and drug response in the US may be explained by differences in genetic, social and environmental risk factors.
Asthma prevalence also differs between populations of the same ethnicity who are born and live in different places.[72] US-born Mexican populations, for example, have higher asthma rates than non-US born Mexican populations that are living in the US.[73] This probably reflects differences in social and environmental risk factors associated with acculturation to the US.
Asthma prevalence and asthma deaths also differ by gender. Males are more likely to be diagnosed with asthma as children, but asthma is more likely to persist into adulthood in females. Sixty five percent more adult women than men will die from asthma. This difference may be attributable to hormonal differences, among other things. In support of this, girls who reach puberty before age 12 were found to have a later diagnosis of asthma more than twice as much as girls who reach puberty after age 12. Asthma is also the number one cause of children missing school.
Socioeconomic factors
The incidence of asthma is highest among low-income populations (asthma deaths are most common in low to middle income countries [4]), which in the western world are disproportionately ethnic minorities[74] and are more likely to live near industrial areas. Additionally, asthma has been strongly associated with the presence of cockroaches in living quarters, which is more likely in such neighborhoods.
Asthma incidence and quality of treatment varies among different racial groups, though this may be due to correlations with income (and thus affordability of health care) and geography. For example, Black Americans are less likely to receive outpatient treatment for asthma despite having a higher prevalence of the disease. They are much more likely to have emergency room visits or hospitalization for asthma, and are three times as likely to die from an asthma attack compared to whites. The prevalence of "severe persistent" asthma is also greater in low-income communities compared with communities with better access to treatment.[75][76]
Asthma and athletics
Asthma appears to be more prevalent in athletes than in the general population. One survey of participants in the 1996 Summer Olympic Games, in Atlanta, Georgia, U.S., showed that 15% had been diagnosed with asthma, and that 10% were on asthma medication.[77] These statistics have been questioned on at least two bases. Athletes with mild asthma may be more likely to be diagnosed with the condition than non-athletes, because even subtle symptoms may interfere with their performance and lead to pursuit of a diagnosis. It has also been suggested that some professional athletes who do not suffer from asthma claim to do so in order to obtain special permits to use certain performance-enhancing drugs.[citation needed]
There appears to be a relatively high incidence of asthma in sports such as cycling, mountain biking, and long-distance running, and a relatively lower incidence in weightlifting and diving. It is unclear how much of these disparities are from the effects of training in the sport, and from self-selection of sports that may appear to minimize the triggering of asthma.
In addition, there exists a variant of asthma called exercise-induced asthma that shares many features with allergic asthma. It may occur either independently, or concurrent with the latter. Exercise studies may be helpful in diagnosing and assessing this condition.
History
Asthma was long considered a psychosomatic disease, and
... during the 1930s–50s, was even known as one of the 'holy seven' psychosomatic illnesses. At that time, psychoanalytic theories described the aetiology of asthma as psychological, with treatment often primarily involving psychoanalysis and other 'talking cures'. As the asthmatic wheeze was interpreted as the child's suppressed cry for his or her mother, psychoanalysts viewed the treatment of depression as especially important for individuals with asthma
Public attention in the developed world has recently focused on asthma because of its rapidly increasing prevalence, affecting up to one in four urban children
Signs and symptoms
In some individuals asthma is characterized by chronic respiratory impairment. In others it is an intermittent illness marked by episodic symptoms that may result from a number of triggering events, including upper respiratory infection, stress, airborne allergens, air pollutants (such as smoke or traffic fumes), or exercise. Some or all of the following symptoms may be present in those with asthma: dyspnea, wheezing, stridor, coughing, an inability for physical exertion. Some asthmatics who have severe shortness of breath and tightening of the lungs never wheeze or have stridor and their symptoms may be confused with a COPD-type disease.
An acute exacerbation of asthma is commonly referred to as an asthma attack. The clinical hallmarks of an attack are shortness of breath (dyspnea) and either wheezing or stridor.[4] Although the former is "often regarded as the sine qua non of asthma",[4] some patients present primarily with coughing, and in the late stages of an attack, air motion may be so impaired that no wheezing may be heard. When present the cough may sometimes produce clear sputum. The onset may be sudden, with a sense of constriction in the chest, breathing becomes difficult, and wheezing occurs (primarily upon expiration, but can be in both respiratory phases).
Signs of an asthmatic episode include wheezing, prolonged expiration, a rapid heart rate (tachycardia), rhonchous lung sounds (audible through a stethoscope), the presence of a paradoxical pulse (a pulse that is weaker during inhalation and stronger during exhalation), and over-inflation of the chest. During a serious asthma attack, the accessory muscles of respiration (sternocleidomastoid and scalene muscles of the neck) may be used, shown as in-drawing of tissues between the ribs and above the sternum and clavicles.
During very severe attacks, an asthma sufferer can turn blue from lack of oxygen, and can experience chest pain or even loss of consciousness. Just before loss of consciousness, there is a chance that the patient will feel numbness in the limbs and palms may start to sweat. The person's feet may become icy cold. Severe asthma attacks, which may not be responsive to standard treatments (status asthmaticus), are life-threatening and may lead to respiratory arrest and death. Despite the severity of symptoms during an asthmatic episode, between attacks an asthmatic may show few or even no signs of the disease.[5]
Cause
Asthma is caused by a complex interaction of genetic and environmental factors that researchers do not fully understand yet.[6] These factors can also influence how severe a person’s asthma is and how well they respond to medication.[7] As with other complex diseases, many genetic and environmental factors have been suggested as causes of asthma, but not all of them have been replicated. In addition, as researchers detangle the complex causes of asthma, it is becoming more evident that certain environmental and genetic factors may only affect asthma when combined.
The hygiene hypothesis is a theory about the cause of asthma and other allergic disease, and is supported by epidemiologic data for asthma. For example, asthma prevalence has been increasing in developed countries along with increased use of antibiotics, c-sections, and cleaning products.[8][9][10] All of these things may negatively affect exposure to beneficial bacteria and other immune system modulators that are important during development, and thus may cause increased risk for asthma and allergy.
Environmental
Many environmental risk factors have been associated with asthma, but a few stand out as well-replicated or that have a meta-analysis of several studies to support their direct association:
* Poor air quality, from traffic pollution or high ozone levels, has been repeatedly associated with increased asthma morbidity and has a suggested association with asthma development that needs further research.[11][12]
* Environmental tobacco smoke, especially maternal cigarette smoking, is associated with high risk of asthma prevalence and asthma morbidity, wheeze, and respiratory infections.[11]
* Viral respiratory infections at an early age, along with siblings and day care exposure, may be protective against asthma, although there have been controversial results, and this protection may depend on genetic context.[11][13][14]
* Antibiotic use early in life has been linked to development of asthma in several examples; it is thought that antibiotics make one susceptible to development of asthma because they modify gut flora, and thus the immune system (as described by the hygiene hypothesis).[8]
* Caesarean sections have been associated with asthma when compared with vaginal birth; a meta-analysis found a 20% increase in asthma prevalence in children delivered by Caesarean section compared to those who were not. It was proposed that this is due to modified bacterial exposure during Caesarean section compared with vaginal birth, which modifies the immune system (as described by the hygiene hypothesis).[9]
* Psychological stress on the part of a child's caregiver has been associated with asthma, and is an area of active research. Stress can modify behaviors that affect asthma, like smoking, but research suggests that stress has other effects as well. There is growing evidence that stress may influence asthma and other diseases by influencing the immune system.[11]
Genetic
Over 100 genes have been associated with asthma in at least one genetic association study.[15] However, as with all association studies, replication is important before genetic variation (such as a single nucleotide polymorphism, or SNP) in a certain gene is thought to influence asthma
Bronchoconstriction
During an asthma episode, inflamed airways react to environmental triggers such as smoke, dust, or pollen. The airways narrow and produce excess mucus, making it difficult to breathe. In essence, asthma is the result of an immune response in the bronchial airways.[17]
The airways of asthmatics are "hypersensitive" to certain triggers, also known as stimuli (see below). In response to exposure to these triggers, the bronchi (large airways) contract into spasm (an "asthma attack"). Inflammation soon follows, leading to a further narrowing of the airways and excessive mucus production, which leads to coughing and other breathing difficulties.
The normal calibre of the bronchus is maintained by a balanced functioning of these systems, which both operate reflexively. The parasympathetic reflex loop consists of afferent nerve endings which originate under the inner lining of the bronchus. Whenever these afferent nerve endings are stimulated (for example, by dust, cold air or fumes) impulses travel to the brain-stem vagal centre, then down the vagal afferent pathway to again reach the bronchus. Acetylcholine is released from the afferent nerve endings. This acetylcholine results in the excessive formation of cyclic Guanine Mono phosphate (GMP). This initiates bronchoconstriction.
Bronchial inflammation
The mechanisms behind allergic asthma—i.e., asthma resulting from an immune response to inhaled allergens—are the best understood of the causal factors. In both asthmatics and non-asthmatics, inhaled allergens that find their way to the inner airways are ingested by a type of cell known as antigen presenting cells, or APCs. APCs then "present" pieces of the allergen to other immune system cells. In most people, these other immune cells (TH0 cells) "check" and usually ignore the allergen molecules. In asthmatics, however, these cells transform into a different type of cell (TH2), for reasons that are not well understood. The resultant TH2 cells activate an important arm of the immune system, known as the humoral immune system. The humoral immune system produces antibodies against the inhaled allergen. Later, when an asthmatic inhales the same allergen, these antibodies "recognize" it and activate a humoral response. Inflammation results: chemicals are produced that cause the airways to constrict and release more mucus, and the cell-mediated arm of the immune system is activated. The inflammatory response is responsible for the clinical manifestations of an asthma attack.
Stimuli
* Allergens from nature, typically inhaled, which include waste from common household pests, such as the house dust mite and cockroach, grass pollen, mould spores, and pet epithelial cells;[citation needed]
* Indoor air pollution from volatile organic compounds, including perfumes and perfumed products. Examples include soap, dishwashing liquid, laundry detergent, fabric softener, paper tissues, paper towels, toilet paper, shampoo, hairspray, hair gel, cosmetics, facial cream, sun cream, deodorant, cologne, shaving cream, aftershave lotion, air freshener and candles, and products such as oil-based paint.[citation needed]
* Medications, including aspirin,[18] β-adrenergic antagonists (beta blockers), and penicillin.[citation needed]
* Food allergies such as milk, peanuts, and eggs. However, asthma is rarely the only symptom, and not all people with food or other allergies have asthma.[citation needed]
* Use of fossil fuel related allergenic air pollution, such as ozone, smog, summer smog, nitrogen dioxide, and sulfur dioxide, which is thought to be one of the major reasons for the high prevalence of asthma in urban areas.[citation needed]
* Various industrial compounds and other chemicals, notably sulfites; chlorinated swimming pools generate chloramines—monochloramine (NH2Cl), dichloramine (NHCl2) and trichloramine (NCl3)—in the air around them, which are known to induce asthma.[19]
* Early childhood infections, especially viral respiratory infections. However, persons of any age can have asthma triggered by colds and other respiratory infections even though their normal stimuli might be from another category (e.g. pollen) and absent at the time of infection. In many cases, significant asthma may not even occur until the respiratory infection is in its waning stage, and the person is seemingly improving. Eighty percent of asthma attacks in adults and 60% in children are caused by respiratory viruses.[citation needed]
* Exercise or intense use of respiratory system. The effects of which differ somewhat from those of the other triggers, since they are brief. It is known that exercising regularly actually helps to cure asthma.[citation needed]
* Hormonal changes in adolescent girls and adult women associated with their menstrual cycle can lead to a worsening of asthma. Some women also experience a worsening of their asthma during pregnancy whereas others find no significant changes, and in other women their asthma improves during their pregnancy.[citation needed]
* Emotional stress which is poorly understood as a trigger.[citation needed] Emotional stress can affect breathing temporarily, however unlike something such as heart problems, it is unclear if it has any long-term effect.
* Cold weather can make it harder for asthmatics to breathe.[20] Whether high altitude helps or worsens asthma is debatable and may vary from person to person.[21]
Pathogenesis
The fundamental problem in asthma appears to be immunological: young children in the early stages of asthma show signs of excessive inflammation in their airways. Epidemiological findings give clues as to the pathogenesis: the incidence of asthma seems to be increasing worldwide, and asthma is now very much more common in affluent countries.
In 1968 Andor Szentivanyi first described The Beta Adrenergic Theory of Asthma; in which blockage of the Beta-2 receptors of pulmonary smooth muscle cells causes asthma.[22] Szentivanyi's Beta Adrenergic Theory is a citation classic[23] and has been cited more times than any other article in the history of the Journal of Allergy.
In 1995 Szentivanyi and colleagues demonstrated that IgE blocks beta-2 receptors.[24] Since overproduction of IgE is central to all atopic diseases, this was a watershed moment in the world of allergy.[25]
The Beta-Adrenergic Theory has been cited in the scholarship of such noted investigators as Richard F. Lockey (former President of the American Academy of Allergy, Asthma, and Immunology),[26] Charles Reed (Chief of Allergy at Mayo Medical School),[27] and Craig Venter (Human Genome Project).[28]
John P. McGovern, President of the American Association of Allergy nominated Szentivanyi for The 1968 Nobel Prize in Medicine in recognition of The Beta Adrenergic Theory.
In 2006, Researchers at Harvard Medical School found evidence that asthma is caused by over-proliferation of a special type of natural "killer" cell.[29]
Asthma and sleep apnea
It is recognized with increasing frequency, that patients who have both obstructive sleep apnea (OSA) and bronchial asthma, often improve tremendously when the sleep apnea is diagnosed and treated.[30] CPAP is not effective in patients with nocturnal asthma only.[31]
Asthma and gastro-esophageal reflux disease
Main article: gastro-esophageal reflux disease
If gastro-esophageal reflux disease is present, the patient may have repetitive episodes of acid aspiration, which results in airway inflammation and "irritant-induced" asthma.[citation needed] GERD may be common in difficult-to-control asthma, but according to one study, treating it does not seem to affect the asthma.[32]
Diagnosis
Asthma is defined simply as reversible airway obstruction. Reversibility occurs either spontaneously or with treatment. The basic measurement is peak flow rates and the following diagnostic criteria are used by the British Thoracic Society:[33]
* ≥20% difference on at least three days in a week for at least two weeks;
* ≥20% improvement of peak flow following treatment, for example:
o 10 minutes of inhaled β-agonist (e.g., salbutamol);
o six week of inhaled corticosteroid (e.g., beclometasone);
o 14 days of 30mg prednisolone.
* ≥20% decrease in peak flow following exposure to a trigger (e.g., exercise).
In many cases, a physician can diagnose asthma on the basis of typical findings in a patient's clinical history and examination. Asthma is strongly suspected if a patient suffers from eczema or other allergic conditions—suggesting a general atopic constitution—or has a family history of asthma. While measurement of airway function is possible for adults, most new cases are diagnosed in children who are unable to perform such tests. Diagnosis in children is based on a careful compilation and analysis of the patient's medical history and subsequent improvement with an inhaled bronchodilator medication. In adults, diagnosis can be made with a peak flow meter (which tests airway restriction), looking at both the diurnal variation and any reversibility following inhaled bronchodilator medication.
Testing peak flow at rest (or baseline) and after exercise can be helpful, especially in young asthmatics who may experience only exercise-induced asthma. If the diagnosis is in doubt, a more formal lung function test may be conducted. Once a diagnosis of asthma is made, a patient can use peak flow meter testing to monitor the severity of the disease.
Monitoring asthma with a peak flow meter on an ongoing basis assists with self monitoring of asthma. Peak flow readings can be charted on graph paper charts together with a record of symptoms or use peak flow charting software.[34] This allows patients to track their peak flow readings and pass information back to their doctor or nurse.[35]
In the Emergency Department doctors may use a capnography which measures the amount of exhaled carbon dioxide,[36] along with pulse oximetry which shows the amount of oxygen dissolved in the blood, to determine the severity of an asthma attack as well as the response to treatment.
Differential diagnosis
Before diagnosing someone as asthmatic, alternative possibilities should be considered. A clinician taking a history should check whether the patient is using any known bronchoconstrictors (substances that cause narrowing of the airways, e.g., certain anti-inflammatory agents or beta-blockers).
Chronic obstructive pulmonary disease, which closely resembles asthma, is correlated with more exposure to cigarette smoke, an older patient, less symptom reversibility after bronchodilator administration (as measured by spirometry), and decreased likelihood of family history of atopy.
Pulmonary aspiration, whether direct due to dysphagia (swallowing disorder) or indirect (due to acid reflux), can show similar symptoms to asthma. However, with aspiration, fevers might also indicate aspiration pneumonia. Direct aspiration (dysphagia) can be diagnosed by performing a Modified Barium Swallow test and treated with feeding therapy by a qualified speech therapist. If the aspiration is indirect (from acid reflux) then treatment directed at this is indicated.
A majority of children who are asthma sufferers have an identifiable allergy trigger. Specifically, in a 2004 study, 71% had positive test results for more than 1 allergen, and 42% had positive test results for more than 3 allergens.[37]
The majority of these triggers can often be identified from the history; for instance, asthmatics with hay fever or pollen allergy will have seasonal symptoms, those with allergies to pets may experience an abatement of symptoms when away from home, and those with occupational asthma may improve during leave from work. Allergy tests can help identify avoidable symptom triggers.
After a pulmonary function test has been carried out, radiological tests, such as a chest X-ray or CT scan, may be required to exclude the possibility of other lung diseases. In some people, asthma may be triggered by gastroesophageal reflux disease, which can be treated with suitable antacids. Very occasionally, specialized tests after inhalation of methacholine — or, even less commonly, histamine — may be performed.
Asthma is categorized by the United States National Heart, Lung and Blood Institute as falling into one of four categories: intermittent, mild persistent, moderate persistent and severe persistent. The diagnosis of "severe persistent asthma" occurs when symptoms are continual with frequent exacerbations and frequent night-time symptoms, result in limited physical activity and when lung function as measured by PEV or FEV1 tests is less than 60% predicted with PEF variability greater than 30%.
Prevention
Current treatment protocols recommend prevention medications such as an inhaled corticosteroid, which helps to suppress inflammation and reduces the swelling of the lining of the airways, in anyone who has frequent (greater than twice a week) need of relievers or who has severe symptoms. If symptoms persist, additional preventive drugs are added until the asthma is controlled. With the proper use of prevention drugs, asthmatics can avoid the complications that result from overuse of relief medications.
Asthmatics sometimes stop taking their preventive medication when they feel fine and have no problems breathing. This often results in further attacks, and no long-term improvement.
Preventive agents include the following.
* Inhaled glucocorticoids are the most widely used of the prevention medications and normally come as inhaler devices (ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometasone, and triamcinolone).
Long-term use of corticosteroids can have many side effects including a redistribution of fat, increased appetite, blood glucose problems and weight gain. In particular high doses of steroids may cause osteoporosis. For this reasons inhaled steroids are generally used for prevention, as their smaller doses are targeted to the lungs unlike the higher doses of oral preparations. Nevertheless, patients on high doses of inhaled steroids may still require prophylactic treatment to prevent osteoporosis.
Deposition of steroids in the mouth may cause a hoarse voice or oral thrush (due to decreased immunity). This may be minimised by rinsing the mouth with water after inhaler use, as well as by using a spacer which increases the amount of drug that reaches the lungs.
* Leukotriene modifiers (montelukast, zafirlukast, pranlukast, and zileuton).
* Mast cell stabilizers (cromoglicate (cromolyn), and nedocromil).
* Antimuscarinics/anticholinergics (ipratropium, oxitropium, and tiotropium), which have a mixed reliever and preventer effect. (These are rarely used in preventive treatment of asthma, except in patients who do not tolerate beta-2-agonists.)
* Methylxanthines (theophylline and aminophylline), which are sometimes considered if sufficient control cannot be achieved with inhaled glucocorticoids and long-acting β-agonists alone.
* Antihistamines, often used to treat allergic symptoms that may underlie the chronic inflammation.
* Hyposensitization, (also known as immunodesensitisation therapy) may be recommended in some cases where allergy is the suspected cause or trigger of asthma. Depending on the allergen, it can be given orally or by injection.
* Omalizumab, an IgE blocker; this can help patients with severe allergic asthma that does not respond to other drugs. However, it is expensive and must be injected.
* Methotrexate is occasionally used in some difficult-to-treat patients.
* If chronic acid indigestion (GERD) contributes to a patient's asthma, it should also be treated, because it may prolong the respiratory problem.
Trigger avoidance
As is common with respiratory disease, smoking is believed to adversely affect asthmatics in several ways, including an increased severity of symptoms, a more rapid decline of lung function, and decreased response to preventive medications.[38] Automobile emissions are considered an even more significant cause and aggravating factor. [1] Asthmatics who smoke or who live near traffic [2] typically require additional medications to help control their disease. Furthermore, exposure of both non-smokers and smokers to wood smoke, gas stove fumes and second-hand smoke is detrimental, resulting in more severe asthma, more emergency room visits, and more asthma-related hospital admissions.[39] Smoking cessation and avoidance of second-hand smoke is strongly encouraged in asthmatics.[40]
For those in whom exercise can trigger an asthma attack (exercise-induced asthma), higher levels of ventilation and cold, dry air tend to exacerbate attacks. For this reason, activities in which a patient breathes large amounts of cold air, such as skiing and running, tend to be worse for asthmatics, whereas swimming in an indoor, heated pool, with warm, humid air, is less likely to provoke a response.[4]
Air Filters
If an asthmatic lives with a smoker, use of air filter or room air cleaner is likely to be helpful. Secondhand smoke can worsen the symptoms. The same is true for those with hay fever (allergic rhino sinusitis) or COPD (emphysema or chronic bronchitis). Room air cleaners remove small particles that are in the air near the air cleaner. However, room air cleaners do not remove small allergen particles that are caused by local disturbances, such as the microscopic house dust mite feces that surround a pillow when your head hits it or you turn over in bed. There are several types of air filters available.[41]
* Mechanical air filters use a fan to force air through a special screen that traps particles such as smoke, pollens, and other airborne allergens. The high-efficiency particulate air (HEPA) filter is the best-known air filter. HEPA (which is a type of filter, not a brand name) was developed during World War II to prevent radioactive particles from escaping from laboratories.
* Electronic air filters use electrical charges to attract and deposit allergens and irritants. If the device contains collecting plates, the particles are captured within the system; otherwise, they stick to room surfaces and have to be cleared away.
* Hybrid air filters contain elements of both mechanical and electrostatic filters.
* Gas phase air filters use activated carbon granules to remove odors (volatile organic compounds or VOCs) and non-particulate pollution such as cooking gas, gases emitted from paint or building materials (such as formaldehyde), and perfume.
* Germicidal air cleaners use ultraviolet (UV) lights to kill bacteria, viruses, and molds that pass through the area with the UV light. Such UV lights can be included with other air cleaner devices, which use a fan.
* Ozone generators are devices that intentionally produce high concentrations of ozone to clean the air in a room. They are often used to decontaminate rooms after smoke exposure following a fire.
Treatment
The most effective treatment for asthma is identifying triggers, such as pets or aspirin, and limiting or eliminating exposure to them. If trigger avoidance is insufficient, medical treatment is available. Desensitization is currently the only known "cure" to the disease.[42] Other forms of treatment include relief medication, prevention medication, long-acting β2-agonists, and emergency treatment.
Medical
The specific medical treatment recommended to patients with asthma depends on the severity of their illness and the frequency of their symptoms. Specific treatments for asthma are broadly classified as relievers, preventers and emergency treatment. The Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma (EPR-2)[40] of the U.S. National Asthma Education and Prevention Program, and the British Guideline on the Management of Asthma[43] are broadly used and supported by many doctors. On August 29, 2007 the final Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma was officially released. Bronchodilators are recommended for short-term relief in all patients. For those who experience occasional attacks, no other medication is needed. For those with mild persistent disease (more than two attacks a week), low-dose inhaled glucocorticoids or alternatively, an oral leukotriene modifier, a mast-cell stabilizer, or theophylline may be administered. For those who suffer daily attacks, a higher dose of glucocorticoid in conjunction with a long-acting inhaled β-2 agonist may be prescribed; alternatively, a leukotriene modifier or theophylline may substitute for the β-2 agonist. In severe asthmatics, oral glucocorticoids may be added to these treatments during severe attacks.
The discovery in 2006 by researchers at Harvard Medical School that asthma may be caused by over-proliferation of a special type of natural "killer" cell may ultimately lead to the development of better and more targeted drugs. Natural killer T cells seem to be resistant to the corticosteroids, one of the mainstays of current treatment.[29] Other promising avenues of current research include using cholesterol-lowering drugs (statins) and fish oil supplementation to reduce airway inflammation [44].
Pharmaceutical
Symptomatic control of episodes of wheezing and shortness of breath is generally achieved with fast-acting bronchodilators. These are typically provided in pocket-sized, metered-dose inhalers (MDIs). In young sufferers, who may have difficulty with the coordination necessary to use inhalers, or those with a poor ability to hold their breath for 10 seconds after inhaler use (generally the elderly), an asthma spacer (see top image) is used. The spacer is a plastic cylinder that mixes the medication with air in a simple tube, making it easier for patients to receive a full dose of the drug and allows for the active agent to be dispersed into smaller, more fully inhaled bits.
A nebulizer which provides a larger, continuous dose can also be used. Nebulizers work by vaporizing a dose of medication in a saline solution into a steady stream of foggy vapour, which the patient inhales continuously until the full dosage is administered. There is no clear evidence, however, that they are more effective than inhalers used with a spacer. Nebulizers may be helpful to some patients experiencing a severe attack. Such patients may not be able to inhale deeply, so regular inhalers may not deliver medication deeply into the lungs, even on repeated attempts. Since a nebulizer delivers the medication continuously, it is thought that the first few inhalations may relax the airways enough to allow the following inhalations to draw in more medication.
Relievers include:
* Short-acting, selective beta2-adrenoceptor agonists, such as salbutamol (albuterol USAN), levalbuterol, terbutaline and bitolterol.
Tremors, the major side effect, have been greatly reduced by inhaled delivery, which allows the drug to target the lungs specifically; oral and injected medications are delivered throughout the body. There may also be cardiac side effects at higher doses (due to Beta-1 agonist activity), such as elevated heart rate or blood pressure; with the advent of selective agents, these side effects have become less common. Patients must be cautioned against using these medicines too frequently, as with such use their efficacy may decline, producing desensitization resulting in an exacerbation of symptoms which may lead to refractory asthma and death.
* Older, less selective adrenergic agonists, such as inhaled epinephrine and ephedrine tablets, have also been used. Cardiac side effects occur with these agents at either similar or lesser rates to albuterol.[45] [46] When used solely as a relief medication, inhaled epinephrine has been shown to be an effective agent to terminate an acute asthmatic exacerbation.[45] In emergencies, these drugs were sometimes administered by injection. Their use via injection has declined due to related adverse effects.
* Anticholinergic medications, such as ipratropium bromide may be used instead. They have no cardiac side effects and thus can be used in patients with heart disease; however, they take up to an hour to achieve their full effect and are not as powerful as the β2-adrenoreceptor agonists.
* Inhaled glucocorticoids are usually considered preventive medications; however, a randomized controlled trial has demonstrated the benefit of 250 microg beclomethasone when taken as an as-needed combination inhaler with 100 microg of albuterol.[47]
Long-acting β2-agonists
A typical inhaler, of Serevent (salmeterol), a long-acting bronchodilator.
Long-acting bronchodilators (LABD) are similar in structure to short-acting selective beta2-adrenoceptor agonists, but have much longer side chains resulting in a 12-hour effect, and are used to give a smoothed symptomatic relief (used morning and night). While patients report improved symptom control, these drugs do not replace the need for routine preventers, and their slow onset means the short-acting dilators may still be required. In November 2005, the American FDA released a health advisory alerting the public to findings that show the use of long-acting β2-agonists could lead to a worsening of symptoms, and in some cases death.[48]
Currently available long-acting beta2-adrenoceptor agonists include salmeterol, formoterol, bambuterol, and sustained-release oral albuterol. Combinations of inhaled steroids and long-acting bronchodilators are becoming more widespread; the most common combination currently in use is fluticasone/salmeterol (Advair in the United States, and Seretide in the United Kingdom). Another combination is budesonide/formoterol which is commercially known as Symbicort.
A recent meta-analysis of the roles of long-acting beta-agonists may indicate a danger to asthma patients. The study, published in the Annals of Internal Medicine in 2006, found that long-acting beta-agonists increased the risk for asthma hospitalizations and asthma deaths 2- to 4-fold, compared with placebo.[49] "These agents can improve symptoms through bronchodilation at the same time as increasing underlying inflammation and bronchial hyper-responsiveness, thus worsening asthma control without any warning of increased symptoms," said Shelley Salpeter in a press release after the publication of the study. The release goes on to say that "Three common asthma inhalers containing the drugs salmeterol or formoterol may be causing four out of five US asthma-related deaths per year and should be taken off the market".[50] This assertion has drawn criticism from many asthma specialists for being inaccurate. As Dr. Hal Nelson points out in a recent letter to the Annals of Internal Medicine, "Salpeter and colleagues also assert that salmeterol may be responsible for 4000 of the 5000 asthma-related deaths that occur in the United States annually. However, when salmeterol was introduced in 1994, more than 5000 asthma-related deaths occurred per year. Since the peak of asthma deaths in 1996, salmeterol sales have increased about 5-fold, while overall asthma mortality rates have decreased by about 25%, despite a continued increase in asthma diagnoses. In fact, according to the most recent data from the National Center for Health Statistics, U.S. asthma mortality rates peaked in 1996 (with 5667 deaths) and have decreased steadily since. The last available data, from 2004, indicate that 3780 deaths occurred. Thus, the suggestion that a vast majority of asthma deaths could be attributable to LABA use is inconsistent with the facts."
Dr. Shelley Salpeter, in a letter to the Annals of Internal Medicine, responds to the comments of Dr. Nelson, "It is true that the asthma death rate increased after salmeterol was introduced, then peaked and is now starting to decline despite continued use of the long-acting beta-agonists. This trend in death rates can best be explained by examining the ratio of beta-agonist use to inhaled corticosteroids... In the recent past, inhaled corticosteroid use has increased steadily while long-acting beta-agonist use has begun to stabilize and short-acting beta-agonist use has declined... Using this estimate, we can imagine that if long-acting beta-agonists were withdrawn from the market while maintaining high inhaled corticosteroid use, the death rate in the United States could be reduced significantly..."
Emergency
When an asthma attack is unresponsive to a patient's usual medication, other treatments are available to the physician or hospital:[51]
* Oxygen to alleviate the hypoxia (but not the asthma itself) that results from extreme asthma attacks.
* Nebulized salbutamol or terbutaline (short-acting beta-2-agonists), often combined with ipratropium (an anticholinergic).
* Systemic steroids, oral or intravenous (prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone). Some research has looked into an alternative inhaled route.[52]
* Other bronchodilators that are occasionally effective when the usual drugs fail:
o Intravenous salbutamol
o Nonspecific beta-agonists, injected or inhaled (epinephrine, isoetharine, isoproterenol, metaproterenol)
o Anticholinergics, IV or nebulized, with systemic effects (glycopyrrolate, atropine, ipratropium)
o Methylxanthines (theophylline, aminophylline)
o Inhalation anesthetics that have a bronchodilatory effect (isoflurane, halothane, enflurane)
o The dissociative anaesthetic ketamine, often used in endotracheal tube induction
o Magnesium sulfate, intravenous
* Intubation and mechanical ventilation, for patients in or approaching respiratory arrest.
* Heliox, a mixture of helium and oxygen, may be used in a hospital setting. It has a more laminar flow than ambient air and moves more easily through constricted airways.
Non-medical treatments
Many asthmatics, like those who suffer from other chronic disorders, use alternative treatments; surveys show that roughly 50% of asthma patients use some form of unconventional therapy.[53][54] There is little data to support the effectiveness of most of these therapies. A Cochrane systematic review of acupuncture for asthma found no evidence of efficacy.[55] A similar review of air ionisers found no evidence that they improve asthma symptoms or benefit lung function; this applied equally to positive and negative ion generators.[56] A study of "manual therapies" for asthma, including osteopathic, chiropractic, physiotherapeutic and respiratory therapeutic manoeuvres, found there is insufficient evidence to support or refute their use in treating asthma;[57] these manoeuvers include various osteopathic and chiropractic techniques to "increase movement in the rib cage and the spine to try and improve the working of the lungs and circulation"; chest tapping, shaking, vibration, and the use of "postures to help shift and cough up phlegm." One meta-analysis finds that homeopathy may have a potentially mild benefit in reducing the intensity of symptoms.[58] However, the number of patients involved in the analysis was small, and subsequent studies have not supported this finding.[59] Several small trials have suggested some benefit from various yoga practices, ranging from integrated yoga programs,[60] yogasanas, Pranayama, meditation, and kriyas, to sahaja yoga,[61] a form of 'new religious' meditation.
Treatment controversies
In November 2007 The New York Times reported a review of more than 500 studies finding that independently backed studies on inhaled corticosteroids are up to four times more likely to find adverse effects than studies paid for by drug companies.[62][63]
Prognosis
The prognosis for asthmatics is good; especially for children with mild disease. For asthmatics diagnosed during childhood, 54% will no longer carry the diagnosis after a decade. The extent of permanent lung damage in asthmatics is unclear. Airway remodelling is observed, but it is unknown whether these represent harmful or beneficial changes.[17] Although conclusions from studies are mixed, most studies show that early treatment with glucocorticoids prevents or ameliorates decline in lung function as measured by several parameters.[64] For those who continue to suffer from mild symptoms, corticosteroids can help most to live their lives with few disabilities. The mortality rate for asthma is low, with around 6000 deaths per year in a population of some 10 million patients in the United States.[4] Better control of the condition may help prevent some of these deaths.
The prevalence of childhood asthma has increased since 1980, especially in younger children.
The prevalence of childhood asthma has increased since 1980, especially in younger children.
Epidemiology
More than 6% of children in the United States have been diagnosed with asthma, a 75% increase in recent decades. The rate soars to 40% among some populations of urban children.[citation needed]
Asthma is usually diagnosed in childhood. The risk factors for asthma include:[citations needed]
* A personal or family history of asthma or atopy
* Triggers (see Pathophysiology above)
* Premature birth or low birth weight
* Viral respiratory infection in early childhood
* Maternal smoking
* Being male, for asthma in prepubertal children
* Being female, for persistence of asthma into adulthood
Current research suggests that the prevalence of childhood asthma has been increasing. According to the Centers for Disease Control and Prevention's National Health Interview Surveys, some 9% of US children below 18 years of age had asthma in 2001, compared with just 3.6% in 1980 (see figure). The World Health Organization (WHO) reports that some 8% of the Swiss population suffers from asthma today, compared with just 2% some 25–30 years ago.[65] Although asthma is more common in affluent countries, it is by no means a problem restricted to the affluent; the WHO estimate that there are between 15 and 20 million asthmatics in India. In the U.S., urban residents, Hispanics, and African Americans are affected more than the population as a whole. Globally, asthma is responsible for around 180,000 deaths annually.
Population disparities
Asthma prevalence, morbidity, mortality, and drug response vary greatly across populations. There is an almost 30-fold difference in asthma prevalence between some of the countries included in the International Study of Asthma and Allergy in Childhood[3], with a trend toward more developed and westernized countries having higher asthma prevalence. Westernization can’t explain the entire difference in asthma prevalence between countries, however, and the disparities may also be affected by differences in genetic, social and environmental risk factors.[11] There are also worldwide disparities in asthma mortality, which is most common in low to middle income countries.[66]
Asthma prevalence in the US is higher than in most other countries in the world, but varies drastically between diverse US populations.[11] In the US, asthma prevalence is highest in Puerto Ricans, African Americans, Filipinos and Native Hawaiians, and lowest in Mexicans and Koreans. Mortality rates follow similar trends, and response to albuterol is lower in Puerto Ricans than in African Americans or Mexicans.[70][71] As with worldwide asthma disparities, differences in asthma prevalence, mortality, and drug response in the US may be explained by differences in genetic, social and environmental risk factors.
Asthma prevalence also differs between populations of the same ethnicity who are born and live in different places.[72] US-born Mexican populations, for example, have higher asthma rates than non-US born Mexican populations that are living in the US.[73] This probably reflects differences in social and environmental risk factors associated with acculturation to the US.
Asthma prevalence and asthma deaths also differ by gender. Males are more likely to be diagnosed with asthma as children, but asthma is more likely to persist into adulthood in females. Sixty five percent more adult women than men will die from asthma. This difference may be attributable to hormonal differences, among other things. In support of this, girls who reach puberty before age 12 were found to have a later diagnosis of asthma more than twice as much as girls who reach puberty after age 12. Asthma is also the number one cause of children missing school.
Socioeconomic factors
The incidence of asthma is highest among low-income populations (asthma deaths are most common in low to middle income countries [4]), which in the western world are disproportionately ethnic minorities[74] and are more likely to live near industrial areas. Additionally, asthma has been strongly associated with the presence of cockroaches in living quarters, which is more likely in such neighborhoods.
Asthma incidence and quality of treatment varies among different racial groups, though this may be due to correlations with income (and thus affordability of health care) and geography. For example, Black Americans are less likely to receive outpatient treatment for asthma despite having a higher prevalence of the disease. They are much more likely to have emergency room visits or hospitalization for asthma, and are three times as likely to die from an asthma attack compared to whites. The prevalence of "severe persistent" asthma is also greater in low-income communities compared with communities with better access to treatment.[75][76]
Asthma and athletics
Asthma appears to be more prevalent in athletes than in the general population. One survey of participants in the 1996 Summer Olympic Games, in Atlanta, Georgia, U.S., showed that 15% had been diagnosed with asthma, and that 10% were on asthma medication.[77] These statistics have been questioned on at least two bases. Athletes with mild asthma may be more likely to be diagnosed with the condition than non-athletes, because even subtle symptoms may interfere with their performance and lead to pursuit of a diagnosis. It has also been suggested that some professional athletes who do not suffer from asthma claim to do so in order to obtain special permits to use certain performance-enhancing drugs.[citation needed]
There appears to be a relatively high incidence of asthma in sports such as cycling, mountain biking, and long-distance running, and a relatively lower incidence in weightlifting and diving. It is unclear how much of these disparities are from the effects of training in the sport, and from self-selection of sports that may appear to minimize the triggering of asthma.
In addition, there exists a variant of asthma called exercise-induced asthma that shares many features with allergic asthma. It may occur either independently, or concurrent with the latter. Exercise studies may be helpful in diagnosing and assessing this condition.
History
Asthma was long considered a psychosomatic disease, and
... during the 1930s–50s, was even known as one of the 'holy seven' psychosomatic illnesses. At that time, psychoanalytic theories described the aetiology of asthma as psychological, with treatment often primarily involving psychoanalysis and other 'talking cures'. As the asthmatic wheeze was interpreted as the child's suppressed cry for his or her mother, psychoanalysts viewed the treatment of depression as especially important for individuals with asthma
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