Classes Of Sarcodosis

Types

Sarcoidosis may be divided into the following types:^[6]:708-11

• Annular sarcoidosis
• Erythrodermic sarcoidosis
• Ichthyosiform sarcoidosis
• Hypopigmented sarcoidosis
• Löfgren syndrome
• Lupus pernio
• Morpheaform sarcoidosis
• Mucosal sarcoidosis
• Neurosarcoidosis
• Papular sarcoid
• Scar sarcoid
• Subcutaneous sarcoidosis
• Systemic sarcoidosis
• Ulcerative sarcoidosis

Signs and symptoms

Signs and symptoms of sarcoidosis.^[7]

Sarcoidosis is a systemic disease that can affect any organ. Common symptoms are vague, such as fatigue unchanged by sleep, lack of energy, weight loss, aches and pains, arthralgia, dry eyes, blurry vision, shortness of breath, a dry hacking cough or skin lesions. The cutaneous symptoms vary, and range from rashes and noduli (small bumps) to erythema nodosum or lupus pernio. It is often asymptomatic.

The combination of erythema nodosum, bilateral hilar lymphadenopathy and arthralgia is called Löfgren syndrome. This syndrome has a relatively good prognosis.

Renal, liver (including portal hypertension), heart^[8] or brain involvement may cause further symptoms and altered functioning. Manifestations in the eye include uveitis, uveoparotitis, and retinal inflammation, which may result in loss of visual acuity or blindness. Sarcoidosis affecting the brain or nerves is known as neurosarcoidosis.

The combination of anterior uveitis, parotitis, VII cranial nerve paralysis and fever is called uveoparotid fever, and is associated with Heerfordt-Waldenstrom syndrome. (D86.8)

Sarcoidosis of the scalp presents with diffuse or patchy hair loss.^[6]:762

Investigations

Hypercalcemia (high calcium levels) and its symptoms may be the result of excessive conversion of vitamin D to its active form by epithelioid macrophages.

Sarcoidosis most often manifests as a restrictive disease of the lungs, causing a decrease in lung volume and decreased compliance (the ability to stretch). The disease typically limits the amount of air drawn into the lungs, but produces higher than normal expiratory flow ratios. The vital capacity (full breath in, to full breath out) is decreased, and most of this air can be blown out in the first second. This means the FEV₁/FVC ratio is increased from the normal of about 80%, to 90%. Obstructive lung changes, causing a decrease in the amount of air that can be exhaled, may occur when enlarged lymph nodes in the chest compress airways or when internal inflammation or nodules impede airflow.

CT scan of the chest showing lymphadenopathy in the mediastinum due to sarcoidosis.

Chest X-ray changes are divided into four stages

• Stage 1 bihilar lymphadenopathy
• Stage 2 bihilar lymphadenopathy and reticulonodular infiltrates
• Stage 3 bilateral pulmonary infiltrates
• Stage 4 fibrocystic sarcoidosis typically with upward hilar retraction, cystic & bullous changes

Because sarcoidosis can affect multiple organ systems, follow-up on a patient with sarcoidosis should always include an electrocardiogram, ocular examination by an ophthalmologist, liver function tests, serum calcium and 24-hour urine calcium. In female patients sarcoidosis is significantly associated with hypothyroidism, hyperthyroidism and other thyroid diseases, hence close surveillance of thyroid function is recommended ^[9]

Causes and pathophysiology

The exact cause of sarcoidosis is not known. The current working hypothesis is that in genetically susceptible individuals sarcoidosis is caused through alteration in immune response after exposure to an environmental, occupational, or infectious agent.^[10]

Anergy

Sarcoidosis has paradoxical effects on inflammatory processes; it is characterized by increased macrophage and CD4 helper T-cell activation resulting in accelerated inflammation, however, immune response to antigen challenges such as tuberculin is suppressed. This paradoxic state of simultaneous hyper- and hypo- activity is suggestive of a state of anergy. The anergy may also be responsible for the increased risk of infections and cancer. It appears that regulatory T-lymphocytes in the periphery of sarcoid granulomas suppress IL-2 secretion which is hypothesized to cause the state of anergy by preventing antigen-specific memory responses.^[11]

While it is widely believed that TNF-alpha plays an important role in the formation of granulomas it was observed that sarcoidosis can be triggered by treatment with the TNF-alpha antagonist etanercept.^[12][13]

Genetic associations

Investigations of genetic susceptibility yielded many candidate genes but only few were confirmed by further investigations and no reliable genetic markers are known. Currently most interesting candidate gene is BTNL2, several HLA-DR risk alleles are also investigated.^[14] In persistent sarcoidosis the HLA haplotype HLA-B7-DR15 are either cooperating in disease or another gene between these two loci is associated. In non-persistent disease there is a strong genetic association with HLA DR3-DQ2.^[15] Siblings have only a modestly increased risk (hazard ratio 5-6) to develop the disease, indicating that genetic susceptibility plays only a small role. The alternate hypothesis that family members share similar exposures to environmental pathogens is quite plausible to explain the apparent hereditary factor.

[edit] Infectious agents

Several infectious agents appear to be significantly associated with sarcoidosis but none of the known associations is specific enough to suggest a direct causative role. Propionibacterium acnes can be found in bronchoalveolar lavage of approximately 70% patients and is associated with disease activity, however it can be also found in 23% of controls.^[16][17] A recent meta-analysis investigating the role of mycobacteria in sarcoidosis found it was present in 26.4% of cases, however the meta-analysis also detected a possible publication bias, so the results need further confirmation.^[18][19]

There have also been reports of transmission of sarcoidosis via organ transplants.^[20]

Vitamin D dysregulation

Sarcoidosis frequently causes a dysregulation of vitamin D production with an increase in extrarenal (outside the kidney) production.^[21] Specifically, macrophages inside the granulomas convert vitamin D to its active form, resulting in elevated levels of the hormone 1,25-dihydroxyvitamin D and symptoms of hypervitaminosis D that may include fatigue, lack of strength or energy, irritability, metallic taste, temporary memory loss or cognitive problems. Physiological compensatory responses (e.g., suppression of the parathyroid hormone levels) may mean the patient does not develop frank hypercalcemia. This condition may be aggravated by high levels of estradiol and prolactin such as in pregnancy, leading to hypercalciuria and/or compensatory hypoparathyroidism.^[22] High levels of Vitamin D are also implicated in immune-system dysfunctions which tie into the sarcoid condition.

The connection between Vitamin D dysregulation, its effects on immune function, and how the combined effect might mediate sarcoidosis, is currently being explored by Dr. Trevor Marshall. The theory which Dr. Marshall is currently researching via a protocol (the Marshall Protocol) under FDA oversight, asserts that L-form or cell wall deficient bacteria infect the body, and evade the immune system by inducing or enhancing this Vitamin D disregulation, which in turn suppresses the body's immune response to said bacterial infection. Dr. Marshall's research is highly controversial, and the Marshall Protocol's suggestion that people should avoid all sources of vitamin D contradicts a vast body of medical knowledge concerning the benefits of vitamin D. No research about the efficacy of the Marshall Protocol has been published in a medical journal. Marshall is not a medical doctor; his doctorate is in electrical engineering.^[23]

Hyperprolactinemia

Prolactin is frequently increased in sarcoidosis, between 3–32% cases have hyperprolactinemia ^[24], this frequently leads to amenorrhea, galactorrhea or nonpuerperal mastitis in women. Prolactin also has a broad spectrum of effects on the immune system and increased prolactin levels are associated with disease activity or may exacerbate symptoms in many autoimmune diseases and treatment with prolactin lowering medication has been shown effective in some cases. ^[25] However it is unknown if this relation holds in sarcoidosis and the gender predilection in sarcoidosis is less pronounced than in some other autoimmune diseases where such relation has been established. In pregnancy the effects of prolactin and estrogen counteract each other to some degree, with a slight trend to improve pulmonary manifestations of sarcoidosis while lupus, uveitis and arthralgia might slightly worsen^[22]. Lupus, uveitis and arthralgia are known to be in some cases associated with increased prolactin levels and respond to bromocriptin treatment but so far this has not been investigated specifically for sarcoidosis. The reasons for increased prolactin levels in sarcoidosis are hitherto uncertain. It has been observed that prolactin is produced by T-lymphocytes in some autoimmune disorders in amounts high enough to affect the feedback by the hypothalamic dopaminergic system ^[26] . The extrapituitary prolactin is believed to play a role as a cytokine like proinflammatory factor. Prolactin antibodies are believed to play a role in hyperprolactinemia in other autoimmune disorders and high prevalence endocrine autoimmunity has been observed in patients with sarcoidosis ^[27] . It may also be a consequence of renal disease or treatment with steroids. Neurosarcoidosis may occasionally cause hypopituiarism but has not been reported to cause hyperprolactinemia.

Sarcoidosis Detail

Sarcoidosis (sarc = flesh, -oid = like, -osis = a process), also called sarcoid or Besnier-Boeck disease, is a multisystem disorder^[1] characterized by non-caseating granulomas (small inflammatory nodules). The cause of the disease is still unknown. Virtually any organ can be affected; however, granulomas most often appear in the lungs or the lymph nodes. Symptoms usually appear gradually but can occasionally appear suddenly. The clinical course generally varies and ranges from asymptomatic disease to a debilitating chronic condition that may lead to death.

Classes Of Bronchitis

Acute bronchitis

Main article: Acute bronchitis

Acute bronchitis is most often caused by viruses that infect the epithelium of the bronchi, resulting in inflammation and increased secretion of mucus. Cough, a common symptom of acute bronchitis, develops in an attempt to expel the excess mucus from the lungs. Other common symptoms include sore throat, runny nose, nasal congestion (coryza), low-grade fever, malaise, and the production of sputum.^[1]

Acute bronchitis often develops during the course of an upper respiratory infection (URI) such as the common cold or influenza.^[1] About 90% of cases of acute bronchitis are caused by viruses, including rhinoviruses, adenoviruses, and influenza. Bacteria, including Mycoplasma pneumoniae, Chlamydia pneumoniae, and Bordetella pertussis, account for about 10% of cases.^[1]

Treatment for acute bronchitis is primarily symptomatic. Non-steroidal anti-inflammatory drugs (NSAIDs) may be used to treat fever and sore throat. Decongestants can be useful in patients with nasal congestion, and expectorants may be used to loosen mucus and increase expulsion of sputum. Cough suppressants may be used if the cough interferes with sleep or is bothersome, although coughing may be useful in expelling sputum from the airways. Even with no treatment, most cases of acute bronchitis resolve quickly.^[1]

As most cases of acute bronchitis are caused by viruses, antibiotics should not be used since they are only effective against bacteria. Using antibiotics in patients who do not have bacterial infections promotes the development of antibiotic-resistant bacteria, which may lead to greater morbidity and mortality. Antibiotics should only be prescribed if microscopic examination of Gram stained sputum shows large numbers of bacteria present.^[1]

Chronic bronchitis

Main article: Chronic bronchitis

Chronic bronchitis, a type of chronic obstructive pulmonary disease, is defined by a productive cough that lasts for 3 months or more per year for at least 2 years. Other symptoms may include wheezing and shortness of breath, especially upon exertion. The cough is often worst soon after awakening, and the sputum produced may have a yellow or green color and may be streaked with blood.^[1]

Chronic bronchitis is caused by recurring injury or irritation to the respiratory epithelium of the bronchi, resulting in chronic inflammation, edema (swelling), and increased production of mucus by goblet cells.^[1] Airflow into and out of the lungs is partly blocked because of the swelling and extra mucus in the bronchi or due to reversible bronchospasm.^[2]

Most cases of chronic bronchitis are caused by smoking cigarettes or other forms of tobacco. Chronic inhalation of irritating fumes or dust from occupational exposure or air pollution may also be causative. About 5% of the population has chronic bronchitis, and it is two times more common in males than females.^[1]

Chronic bronchitis is treated symptomatically. Inflammation and edema of the respiratory epithelium may be reduced with inhaled corticosteroids. Wheezing and shortness of breath can be treated by reducing bronchospasm (reversible narrowing of smaller bronchi due to constriction of the smooth muscle) with bronchodilators such as inhaled β-Adrenergic agonists (e.g., albuterol) and inhaled anticholinergics (e.g., ipratropium bromide). Hypoxemia, too little oxygen in the blood, can be treated with supplemental oxygen.^[1] However, oxygen supplementation can result in decreased respiratory drive leading to increased blood levels of carbon dioxide and subsequent respiratory acidosis.

The most effective method of preventing chronic bronchitis and other forms of COPD is to avoid smoking cigarettes and other forms of tobacco.^[1]

Bronchitis Details

Bronchitis is inflammation of the mucous membranes of the bronchi, the airways that carry airflow from the trachea into the lungs. Bronchitis can be classified into two categories, acute and chronic, each of which has unique etiologies, pathologies, and therapies.

Acute bronchitis is characterized by the development of a cough, with or without the production of sputum, mucus that is expectorated (coughed up) from the respiratory tract. Acute bronchitis often occurs during the course of an acute viral illness such as the common cold or influenza. Viruses cause about 90% of cases of acute bronchitis while bacteria account for less than 10%.^[1]

Chronic bronchitis, a type of chronic obstructive pulmonary disease, is characterized by the presence of a productive cough that lasts for 3 months or more per year for at least 2 years. Chronic bronchitis most often develops due to recurrent injury to the airways caused by inhaled irritants. Cigarette smoking is the most common cause, followed by air pollution and occupational exposure to irritants.^[1]

Treatment of Asthma

Perhaps the most important step in controlling asthma is establishing a partnership between doctor and patient (whether child or adult) to create a specific, customized plan for proactively monitoring and managing symptoms. It is essential to be certain that someone who has asthma understands (and takes an active part in deciding) what needs to be accomplished, including reducing exposure to allergens, taking medical tests to assess the severity of symptoms, and possibly using medications. The treatment plan should be written down, consulted at every visit, and adjusted according to changes in symptoms.^[108]

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 has been suggested as a possible cure.^[109] Additionally, some trial subjects were able to remove their symptoms by retraining their breathing habits with the Buteyko method.^[110]

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)^[101] of the U.S. National Asthma Education and Prevention Program, and the British Guideline on the Management of Asthma^[111] are broadly used and supported by many doctors.

The Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma of the U.S. National Asthma Education and Prevention Program, released in 2007, presented a focused 6-step approach to asthma management, based on four principles that act as a blueprint to guide individualized treatment:

• Frequent and regular assessment of symptoms
• Patient education
• Control of environmental triggers
• Systematic evaluation of the effectiveness and safety of medications.

The 2007 revised NAEPP guidelines differ from the earlier version in an increased focus on asthma control and individualized treatment, reorganizing the goals of treatment to differentiate risk from impairment. They specify defined measures that should prompt a decision to "step up" or "step down" the intensity of treatment, and they emphasize education and integrated decision-making to encourage patient self-management.^[112]

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 asthma, oral glucocorticoids may be added to these treatments during severe attacks.

Pharmaceutical agents

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. 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.^{[113] [114]} When used solely as a relief medication, inhaled epinephrine has been shown to be an effective agent to terminate an acute asthmatic exacerbation.^[113] 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 while oral glucocorticoids are often used to supplement treatment of a severe attack. They should be used twice daily in children with mild to moderate persistent asthma.^[115] 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.^[116]

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.^[117] In December 2008, members of the FDA's drug-safety office recommended withdrawing approval for these medications in children. Discussion is ongoing about their use in adults.^[118]

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.^[119] "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".^[120] This assertion is viewed by many asthma specialists as being inaccurate. Dr. Hal Nelson, in a recent letter to the Annals of Internal Medicine, points out the following:

"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, as follows:

"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 treatment options available for emergency management include:^[121]

• Oxygen to alleviate the hypoxia that results from extreme asthma attacks (but not the asthma attack itself).
• 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.^[122]
• Other bronchodilators that are occasionally effective when the usual drugs fail:
  • Intravenous salbutamol
  • Nonspecific beta-agonists, injected or inhaled (epinephrine, isoetharine, isoproterenol, metaproterenol)
  • Anticholinergics, IV or nebulized, with systemic effects (glycopyrrolate, atropine, ipratropium)
  • Methylxanthines (theophylline, aminophylline)
  • Inhalation anesthetics that have a bronchodilatory effect (isoflurane, halothane, enflurane)
  • The dissociative anaesthetic ketamine, often used in endotracheal tube induction
  • 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 asthma patients, 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.^[123][124] There is little data to support the effectiveness of most of these therapies. However, the Buteyko method of controlling hyperventilation hypocapnia has shown in five randomized controlled trials to result in a significant reduction in need for medications without an effect on bronchial hyperreactivity or lung function.^{[125][126][127][128][129]} In May 2008 the updated British Guidelines for the Management of Asthma endorsed Buteyko Technique.^[130] A Cochrane systematic review of acupuncture for asthma found no evidence of efficacy.^[131] 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.^[132] Another systematic study reviewed a range of dust mite control measures, including air filtration, chemicals to kill mites, vacuuming, mattress covers and others. Overall these methods had no effect on asthma symptoms.^[133] 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;^[134] 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.^[135] However, the number of patients involved in the analysis was small, and subsequent studies have not supported this finding.^[136] Several small trials have suggested some benefit from various yoga practices, ranging from integrated yoga programs,^[137] yogasanas, Pranayama, meditation, and kriyas, to Sahaja yoga,^[138] a form of 'new religious' meditation.^[139] A study, performed by scientists at Egypt's Tanta University, has found that a combination of omega-3, vitamin C and zinc may improve the symptoms of asthma.^{[citation needed]}

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.^[140][141]

Asthma

Asthma
Classification and external resources
peak flow meter
ICD-10	J45.
ICD-9	493
OMIM	600807
DiseasesDB	1006
MedlinePlus	000141
eMedicine	med/177 emerg/43
MeSH	C08.127.108

Asthma is a chronic inflammation of the lungs in which the airways (bronchi) are reversibly narrowed. Asthma affects 7% of the population,^[1][2] and 300 million worldwide.^[3] During attacks (exacerbations), the smooth muscle cells in the bronchi constrict, and the airways become inflamed and swollen. Breathing becomes difficult, and asthma causes 4,000 deaths a year in the U.S. Attacks can be prevented by avoiding triggering factors and by drug treatment. Drugs are used for acute attacks, commonly inhaled β2-agonists. In more serious cases, drugs are used for long-term prevention, starting with inhaled corticosteroids, and then long-acting β2-agonists if necessary. Leukotriene antagonists are less effective than corticosteroids but have no side effects. Monoclonal antibodies such as mepolizumab and omalizumab are sometimes effective. Prognosis is good with treatment.

In contrast to chronic obstructive pulmonary disease and chronic bronchitis, the inflammation of asthma is reversible. In contrast to emphysema, asthma affects the bronchi, not the alveoli.

The National Heart, Lung and Blood Institute defines asthma as a common chronic disorder of the airways characterized by variable and recurring symptoms, airflow obstruction, bronchial hyperresponsiveness (bronchospasm), and an underlying inflammation.^[4]

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.^[5]

Contents 1 Classification 2 Signs and symptoms 3 Cause 3.1 Environmental 3.2 Genetic 3.3 Gene–environment interactions 4 Risk factors 4.1 Hygiene hypothesis 4.2 Population disparities 4.3 Socioeconomic factors 4.4 Asthma and athletics 4.5 Occupational asthma 5 Pathophysiology 5.1 Bronchoconstriction 5.2 Bronchial inflammation 5.3 Stimuli 5.4 Pathogenesis 5.5 Asthma and sleep apnea 5.6 Asthma and gastro-esophageal reflux disease 6 Diagnosis 6.1 Differential diagnosis 7 Prevention and Control 7.1 Trigger avoidance 7.2 Diet and Supplements 8 Treatment 8.1 Medical 8.1.1 Pharmaceutical agents 8.2 Emergency 8.3 Non-medical treatments 8.4 Treatment controversies 9 Prognosis 10 Epidemiology 11 History 12 References 13 External links

Classification

Asthma is classified according to the frequency of symptoms, FEV₁ and peak expiratory flow rate.^[6]

Classification of asthma severity^[6]

Severity	Symptom frequency	Nighttime symptoms	Peak expiratory flow rate or FEV1 of predicted	Variability of peak expiratory flow rate or FEV1
Intermittent	<>	≤ twice per month	≥ 80% predicted	<>
Mild persistent	> once per week but <>	> twice per month	≥ 80% predicted	20–30%
Moderate persistent	Daily	> once per week	60–80% predicted	> 30%
Severe persistent	Daily	Frequent	<>	> 30%

Signs and symptoms

Because of the spectrum of severity within asthma, some people with asthma only rarely experience symptoms, usually in response to triggers, where as other more severe cases may have marked airflow obstruction at all times.

Asthma exists in two states: the steady-state of chronic asthma, and the acute state of an acute asthma exacerbation. The symptoms are different depending on what state the patient is in.

Common symptoms of asthma in a steady-state include: nighttime coughing, shortness of breath with exertion but no dyspnea at rest, a chronic 'throat-clearing' type cough, and complaints of a tight feeling in the chest. Severity often correlates to an increase in symptoms. Symptoms can worsen gradually and rather insidiously, up to the point of an acute exacerbation of asthma. It is a common misconception that all people with asthma wheeze—some never wheeze, and their disease may be confused with another Chronic obstructive pulmonary disease such as emphysema or chronic bronchitis.

An acute exacerbation of asthma is commonly referred to as an asthma attack. The cardinal symptoms of an attack are shortness of breath (dyspnea), wheezing and chest tightness.^[7] Although the former is "often regarded as the sine qua non of asthma.^[8] 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.^[9] 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). It is important to note inspiratory stridor without expiratory wheeze however, as an upper airway obstruction may manifest with symptoms similar to an acute exacerbation of asthma, with stridor instead of wheezing, and will remain unresponsive to bronchodilators.

Severity of asthma attack ^[9]

Sign/Symptom	Mild	Moderate	Severe	Imminent respiratory arrest
Alertness	May show agitation	Agitated	Agitated	Confused/Drowsy
Breathlessness	On walking	On talking	Even at rest
Talks in	Sentences	Phrases	Words
Wheeze	Moderate	Loud	Loud	Absent
Accessory muscle	Usually,not used	Used	Used
Respiratory rate (/min)	Increased	Increased	Often >30
Pulse rate (/min)	100	100-120	>120	<60>
PaO2	Normal	>60	<60>
PaCO2	<45	<45	>45

Signs of an asthmatic episode include wheezing, prolonged expiration, a rapid heart rate (tachycardia), and rhonchous lung sounds (audible through a stethoscope). 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, and there may be the presence of a paradoxical pulse (a pulse that is weaker during inhalation and stronger during exhalation), and over-inflation of the chest.

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 cold. Severe asthma attacks which are not responsive to standard treatments, called status asthmaticus, are life-threatening and may lead to respiratory arrest and death.

Though symptoms may be very severe during an acute exacerbation, between attacks a patient may show few or even no signs of the disease.^[10]

Cause

Asthma is caused by environmental and genetic factors,^[11] which can influence how severe asthma is and how well it responds to medication.^[12] Some environmental and genetic factors have been confirmed by further research, while others have not been.

Environmental

Many environmental risk factors have been associated with asthma development and morbidity in children, but a few stand out as well-replicated or that have a meta-analysis of several studies to support their direct association.

Environmental tobacco smoke, especially maternal cigarette smoking, is associated with high risk of asthma prevalence and asthma morbidity, wheeze, and respiratory infections.^[13] 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.^[13][14]

Recent studies show a relationship between exposure to air pollutants (e.g. from traffic) and childhood asthma.^[15] This research finds that both the occurrence of the disease and exacerbation of childhood asthma are affected by outdoor air pollutants.

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).^[16]

Psychological stress has long been suspected of being an asthma trigger, but only in recent decades has convincing scientific evidence substantiated this hypothesis. Rather than stress directly causing the asthma symptoms, it is thought that stress modulates the immune system to increase the magnitude of the airway inflammatory response to allergens and irritants.^[13][17]

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.^[13][18][19]

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).^[20] The hygiene hypothesis is a hypothesis 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.^[16][20][21] 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.

Recently scientists connected the rise in prevalence of asthma, to the rise in use of paracetamol, suggesting the possibility that paracetamol can cause asthma.^[22]

Genetic

Over 100 genes have been associated with asthma in at least one genetic association study.^[23] However, such studies must be repeated to ensure the findings are not due to chance. Through the end of 2005, 25 genes had been associated with asthma in six or more separate populations:^[23]

GSTM1 IL10 CTLA-4 SPINK5 LTC4S

LTA GRPA NOD1 CC16 GSTP1

STAT6 NOS1 CCL5 TBXA2R TGFB1

IL4 IL13 CD14 ADRB2 (β-2 adrenergic receptor) HLA-DRB1

HLA-DQB1 TNF FCER1B IL4R ADAM33

Many of these genes are related to the immune system or to modulating inflammation. However, even among this list of highly replicated genes associated with asthma, the results have not been consistent among all of the populations that have been tested.^[23] This indicates that these genes are not associated with asthma under every condition, and that researchers need to do further investigation to figure out the complex interactions that cause asthma. One theory is that asthma is a collection of several diseases, and that genes might have a role in only subsets of asthma. For example, one group of genetic differences (single nucleotide polymorphisms in 17q21) was associated with asthma that develops in childhood.^[24]

Gene–environment interactions

Research suggests that some genetic variants may only cause asthma when they are combined with specific environmental exposures, and otherwise may not be risk factors for asthma.^[11]

The genetic trait, CD14 single nucleotide polymorphism (SNP) C-159T and exposure to endotoxin (a bacterial product) are a well-replicated example of a gene-environment interaction that is associated with asthma. Endotoxin exposure varies from person to person and can come from several environmental sources, including environmental tobacco smoke, dogs, and farms. Researchers have found that risk for asthma changes based on a person’s genotype at CD14 C-159T and level of endotoxin exposure.^[25]

CD14-endotoxin interaction based on CD14 SNP C-159T^[25]

Endotoxin levels	CC genotype	TT genotype
High exposure	Low risk	High risk
Low exposure	High risk	Low risk

Risk factors

Studying the prevalence of asthma and related diseases such as eczema and hay fever have yielded important clues about some key risk factors. The strongest risk factor for developing asthma is a family history of atopic disease;^[26] this increases one's risk of hay fever by up to 5x and the risk of asthma by 3-4x.^[27] In children between the ages of 3-14, a positive skin test for allergies and an increase in immunoglobulin E increases the chance of having asthma.^[28] In adults, the more allergens one reacts positively to in a skin test, the higher the odds of having asthma.^[29]

Because much allergic asthma is associated with sensitivity to indoor allergens and because Western styles of housing favor greater exposure to indoor allergens, much attention has focused on increased exposure to these allergens in infancy and early childhood as a primary cause of the rise in asthma.^[30][31] Primary prevention studies aimed at the aggressive reduction of airborne allergens in a home with infants have shown mixed findings. Strict reduction of dust mite allergens, for example, reduces the risk of allergic sensitization to dust mites, and modestly reduces the risk of developing asthma up until the age of 8 years old.^{[32][33][34][35]} However, studies also showed that the effects of exposure to cat and dog allergens worked in the converse fashion; exposure during the first year of life was found to reduce the risk of allergic sensitization and of developing asthma later in life.^[36][37][38]

The inconsistency of this data has inspired research into other facets of Western society and their impact upon the prevalence of asthma. One subject that appears to show a strong correlation is the development of asthma and obesity. In the United Kingdom and United States, the rise in asthma prevalence has echoed an almost epidemic rise in the prevalence of obesity.^[39][40] In Taiwan, symptoms of allergies and airway hyperreactivity increased in correlation with each 20% increase in body-mass index.^[41]

Hygiene hypothesis

Main article: Hygiene hypothesis

One theory for the cause of the increase in asthma prevalence worldwide is the so-called "hygiene hypothesis" — that the rise in the prevalence of allergies and asthma is a direct and unintended result of the success of modern hygienic practices in preventing childhood infections. Studies have shown repeatedly that children coming from environments one would expect to be less hygienic (East Germany vs. West Germany,^[42] families with many children,^[43][44][45] day care environments,^[46][47]) tended to result in lower incidences of asthma and allergic diseases. This seems to run counter to the logic that viruses are often causative agents in exacerbation of asthma.^[48][49][50] Additionally, other studies have shown that viral infections of the lower airway may in some cases induce asthma, as a history of bronchiolitis or croup in early childhood is a predictor of asthma risk in later life.^[51] Studies which show that upper respiratory tract infections are protective against asthma risk also tend to show that lower respiratory tract infections conversely tend to increase the risk of asthma.^[52]

Population disparities

Asthma prevalence in the US is higher than in most other countries in the world, but varies drastically between diverse US populations.^[13] In the US, asthma prevalence is highest in Puerto Ricans, African Americans, Filipinos, Irish Americans, and Native Hawaiians, and lowest in Mexicans and Koreans.^[53][54][55] Mortality rates follow similar trends, and response to Ventolin is lower in Puerto Ricans than in African Americans or Mexicans.^[56][57] 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.^[58] US-born Mexican populations, for example, have higher asthma rates than non-US born Mexican populations that are living in the US.^[59] This probably reflects differences in social and environmental risk factors associated with acculturation to the US.^{[citation needed]}

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.^[60] Sixty five percent more adult women than men will die from asthma.^{[citation needed]} 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.^{[citation needed]} Asthma is also the number one cause of missed days from school.^{[citation needed]}