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Home , Eosinophilic pneumonia, Immunoglobulin E, Pulmonary edema

Focused review

Immunoglobulin E associated respiratory : Part 2

Amr Ismail MD, Kenneth C. Iwuji MD, James A. Tarbox MD

Abstract Multiple pulmonary pathologies have been associated with elevated levels of Immunoglobulin E (IgE). Since its discovery in 1966, its role in multiple diseases has become clearer. This has allowed for the emergence of new that target IgE. In this review, we will summarize some of the most common pulmonary pathologies in which IgE has a role in their etiology.

Keywords: Immunoglobulin E, , allergic , acute eosinophilic , chronic , parasitic , allergic bronchopulmonary aspergillosis

Introduction these effects by its dual interactions with specific anti- gens and two receptors, FcεRI and CD23, present Immunoglobulin E (IgE) is one of the five human on effector cells, most notably mast cells, , immunoglobulins: IgG, IgA, IgM, IgD, and IgE. It is pro- , and . duced by B-cells after they undergo switching In this review♦, we will summarize some of the to produce IgE instead of the default IgM. This is usu- most common pulmonary pathologies in which IgE ally achieved by DNA recombination events within the has a role in their etiology (Table 1). immunoglobulin heavy chain locus. B-cells produced in the bone marrow produce heavy chains for both IgM and IgD. Later in the B-cell life cycle, after stimu- Asthma lation by specific and T-cell interaction, the B-cell undergoes class-switch recombination and can Asthma, according to the National Asthma produce different immunoglobulin classes, including Education and Prevention Program, is defined as a IgE.1 chronic inflammatory disorder of the airways in which many cells and cellular elements have a role; these The role of IgE in humans is not fully understood. include mast cells, eosinophils, neutrophils (especially It is the least abundant isotype in the serum and has in sudden onset, fatal exacerbations, occupational the shortest serum half-life (~2 days) among human asthma, and patients who ), T , 2 immunoglobulin types. It has an obvious role in , and epithelial cells. In susceptible indi- defense against parasitic and inactivation viduals, this causes recurrent episodes of certain . It also has a major role in the pro- of wheezing, breathlessness, chest tightness, and cess of immune regulation and, therefore, is involved coughing, particularly at night or in the early morn- 1 in the pathogenesis of allergic . IgE exerts ing. These episodes are associated with widespread

Corresponding author: Amr Ismail Contact Information: [email protected] ♦ Part 1 of this review was published in July 2019 in DOI: 10.12746/swrccc.v7i31.593 The Southwest Respiratory and Critical Care Chronicles 2019;7(31):29–35.

34 The Southwest Respiratory and Critical Care Chronicles 2019;7(31):34–43 Immunoglobulin E Associated Respiratory Diseases: Part 2 Ismail et al.

Table 1. Summary of IgE related pulmonary conditions Disease Characteristics Diagnosis Treatment Asthma Chronic inflammatory Suggestive history and SABA are used for mild symptoms disorder of the airways symptoms Inhaled and LABA Episodic wheezing, chest Reduced FEV1 and are added for maintenance therapy tightness, SOB, and reduced FEV1/FVC Other medications: Airflow limitation is the Reversibility is positive receptor antagonists, long-acting hallmark of the disease when FEV1 (or FVC) muscarinic receptor antagonists, increase ≥12% or >200 ml and biologics (anti-IgE, anti-IL-5, after anti-IL-5Rα, and anti-IL-4α) is used when a strong association with exists Chronic inflammatory Chronicity, seasonality, Mild/episodic symptoms are disorder of the nasal mucosa and pattern of symptoms treated with second-generation suggest diagnosis Associated with rhinosinusitis, allergic Pale, boggy nasal Moderate/severe symptoms conjunctivitis, and asthma turbinates; nasal crease; are treated with intranasal allergic shiners corticosteroids Congestion, , sneezing, itching, upper Combination sprays (intranasal , and corticosteroids with nasal watery eyes are common antihistamines) and short courses of oral steroids for severe cases and/or nasal polyps is used when a strong association with allergens exists Acute eosinophilic Idiopathic, hypothesized Inspiratory and Responds well to corticosteroids pneumonia to be a possible IV 125 mg reaction Peripheral not every 6 hours for initial dose Temporal relation with common Switch to oral of exposure to different CXR: bilateral opacities 40–60 mg daily once symptoms allergens/irritants, especially of alveolar, interstitial, or improve tobacco smoke mixed pattern Taper over 2–6 weeks , dyspnea, and cough >25% eosinophils on BAL Respiratory distress can or eosinophilic pneumonia be present and progress to on lung Absence of other causes of pulmonary eosinophilia

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Table 1. Summary of IgE related pulmonary conditions (Continued) Disease Characteristics Diagnosis Treatment Chronic Insidious course Wheezes/crackles present High dose corticosteroids eosinophilic for more than 2 weeks 0.5 mg/kg/day continued for Eosinophilic infiltration pneumonia 2 weeks after resolution of leads to tissue damage Alveolar eosinophilia symptoms and radiologic findings 40% on BAL; blood Not associated with ≥ eosinophilia 1000/ l Taper steroids to the lowest effective environmental exposures ≥ µ dose to control the symptoms CXR: Predominantly Productive cough, weight peripheral pulmonary High rate of relapse loss, fever, , and infiltrates dyspnea Occasional need of long term Absence of other causes of steroids pulmonary eosinophilia Steroid-sparing drugs: anti-IgE and anti-IL-5 monoclonal Parasitic lung Hydatid cystic lung disease, Travel history and exam are Hydatid cysts may require surgical infections Amoebiasis, Ascariasis, paramount resection and albendazole and Schistosomiasis cause CXR and CT are helpful Amoebiasis is treated with parasitic lung infections tinidazole or metronidazole for Amoebiasis: stool positive Stimulate a TH2 response: trophozoites, then paromomycin for for trophozoites and eosinophilia, IL-4, IL-5, IL- intestinal cysts serum positive for parasite 13, and -specific IgE specific antibodies Surgical treatment may be needed in pleuropulmonary disease Allergic Hypersensitivity reaction to Supported by clinical Long-term corticosteroids: bronchopulmonary Aspergillus fumigatus picture, radiological prednisolone 0.5–1 mg/kg/day for aspergillosis findings, and immunologic 2 weeks, then 0.5 mg/kg every other Commonly seen in cystic findings day for 6–8 weeks, then a slow taper fibrosis and asthma over 3–5 months Peripheral eosinophilia, Recurrent cough, wheezing, elevated total IgE ( 1000 Itraconazole 200 mg twice daily for pleuritic , > IU/mL), and Aspergillus 16 weeks dyspnea, blood tinged specific IgE , and brown may be used as a plugs Positive Aspergillus steroid sparing drug or adjunct intradermal skin testing in patients who fail to respond to steroids CXR: parenchymal infiltrates and usually in upper lobes, better defined by HRCT

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but variable airflow obstruction that is often reversible ordered. These tests should show a reduced FEV1 either spontaneously or with treatment. The inflam- and reduced FEV1/FVC in patients with asthma, mation also causes an increase in bronchial hyper- which suggests obstruction. Reversibility is present responsiveness to a variety of stimuli. Reversibility of when FEV1 (or FVC) increases by ≥12% or >200 ml airflow limitation may be incomplete in some patients. after bronchodilator administration. The presence of Asthma was reported to affect 22 million people in the a consistent history and symptoms, obstructive PFTs, US in 2007.3 and the exclusion of other possible diagnoses are generally adequate to make a diagnosis of asthma.3 Airflow limitation is the hallmark of asthma. Itis When patients present with symptoms strongly sug- usually caused by airway hyperresponsiveness, gesting asthma but have normal PFTs, provocation which is an exaggerated response to stimuli leading tests using methacholine, , or exercise can to bronchoconstriction. This can be allergen induced be done. Further workup could include skin testing to when antigen specific IgE crosslinks on the surface evaluate for environmental triggers of asthma.3 of mast cells and releases mediators (e.g., histamine, prostaglandins, , and tryptase) resulting After the diagnosis is made, asthma severity in airway smooth muscle contraction. Patients with should be assessed by checking symptom sever- high levels of IgE are more likely to have asthma ity, effect on daily activities, nighttime awakenings, than those with normal IgE levels; however, there impact on quality of life, and lung function with PFTs.3 is no absolute cutoff for IgE levels in patients with Treatment of asthma requires avoidance of triggers, asthma. Aspirin, NSAIDs, stress, exercise, irritants, control of symptoms with medications, and prompt and cold air can also stimulate bronchoconstriction recognition and treatment of complications. A step- but not through IgE mediated reactions. As the dis- wise approach to treatment is recommended. Short ease progresses, chronic inflammation develops, and acting beta agonists are used as needed initially. this leads to airway characterized by mucus Inhaled corticosteroids are the cornerstone for main- hypersecretion, inspissated mucus plugs, and hyper- tenance therapy, and long acting beta agonists are trophy of airway smooth muscles. Airway remodeling added later if control is inadequate. Leukotriene recep- occurs as a consequence of chronic inflammation tor antagonists can reduce symptoms in both upper leading to non-reversible structural changes and par- and lower airways. Specific allergen immunotherapy tially reversible airflow limitation. Examples of this can be used in cases in which a strong association include thickening of the basement membrane, sube- between the asthma syndrome and an allergen is pithelial fibrosis, mucus cell hyperplasia/hypertrophy, apparent.3 and blood vessel proliferation.3 Immunomodulators in asthma are a current In one study, the most common reported symp- area of clinical study. are glycopro- toms with asthma included chest tightness, wheezing, teins produced by lymphocytes to regulate immune coughing, and .4 These symp- responses and are targeted in asthma therapy. The toms are frequently episodic and related to expo- first approved modulator was omalizumab (anti-IgE) sure to triggers and typically resolve spontaneously for use in moderate to severe asthma. Mepolizumab or with medications. Symptoms can increase at night (anti-IL-5), (anti-IL-5), benralizumab (anti- causing nighttime awakenings. Physical examina- IL-5Rα), and dupilumab (anti-IL-4Rα) are all newer tion findings are not specific for asthma. Suggestive immunomodulators that have been approved for use findings include wheezing on normal or forced expi- in patients with moderate and/or severe asthma.5 ration, increased nasal secretions, nasal mucosal inflammation, nasal polyposis, and eczema.3 Allergic rhinitis After a diagnosis of asthma is considered, pul- monary function tests measuring FEV1, FVC, and Allergic rhinitis (AR) is a chronic inflammatory FEV1/FVC before and after bronchodilator should be disorder of the nasal mucosa that involves both early

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and late hypersensitivity reactions. It affects about Mild or episodic symptoms are managed on an as 400 million people worldwide yearly.6 Allergic rhinitis needed basis using oral second-generation antihista- is associated with other chronic inflammatory condi- mines or intranasal corticosteroids. For patients with tions, including asthma, rhinosinusitis, and allergic moderate to severe symptoms, regular use of intra- conjunctivitis. It has a major impact on quality of life, nasal corticosteroids effectively reduces symptoms. including sleep, productivity, and social life.7 Since AR Combination sprays (intranasal steroids with antihis- is a prevalent disease, it produces a significant finan- tamines) and leukotriene receptor antagonists may be cial burden, estimated at $11.2 billion in 2005.8 needed for better control. Short courses of oral corti- costeroids (5–7 days) are used in severe intractable IgE has a major role in the pathogenesis of cases or to treat nasal polyposis.9 Intranasal anticho- AR. However, in patients with perennial allergic rhi- linergic nasal sprays reduce rhinorrhea/postnasal nitis, total IgE levels do not correlate with skin test drip; while anti-leukotriene inhibitors provide sympto- reactivity. Within minutes of exposure to inhaled matic relief similar to antihistamines.11 Omalizumab allergens, like pollen, mold, mites, or animal has been proven effective in alleviating symptoms of dander, crosslinking of IgE on the surface of mast AR but is not approved for that use.9 Anti-IL-5 therapy cells occurs. This leads to the release of inflamma- is also being evaluated in patients with AR and nasal tory mediators, including histamine, prostaglandins, polyps.12 and leukotrienes, which are responsible for the early phase of the allergic reaction. The late phase is medi- Allergen immunotherapy was effective in the ated by other inflammatory cells, namely neutrophils, treatment of AR in several studies.9 Subcutaneous eosinophils, and T lymphocytes, that are activated by immunotherapy is widely used in severe, intractable the same mediators. This typically occurs hours after cases in which medical therapy and avoidance of the exposure to the allergen.7 allergens have not achieved adequate control and/or the patient wants to take less . Common symptoms of the early phase of AR include congestion, rhinorrhea, sneezing, itching, upper airway obstruction, and watery eyes. Late Acute eosinophilic pneumonia phase symptoms are related to chronic inflamma- tion, and is the most common com- Eosinophilic pneumonia was originally thought to plaint.7 Allergic rhinitis is usually seasonal but can be have a chronic course. Acute eosinophilic pneumonia persistent when caused by non-seasonal allergens, was first described in 1989 when a patient presented like dust mites, animal dander, or mold.9 with acute respiratory distress and bilateral pulmo- nary infiltrates.13 After ruling out an infectious etiology, A comprehensive history and physical examina- the bronchoalveolar lavage (BAL) and transbronchial tion are usually sufficient to make the diagnosis of AR biopsy confirmed the presence of an eosinophilic infil- and initiate therapy. Historical details should include trate. This patient responded well to chronicity, seasonality, and pattern of symptoms. therapy. A detailed environmental history and occupational exposure history are essential in identifying precip- Acute eosinophilic pneumonia (AEP) is thought itating factors. should include to have no single cause. Some authors hypothesized systems that could be affected in AR, such as skin, that it is a hypersensitivity reaction in the . This upper airways, lower airways, and gastrointestinal belief is due to the temporal relationship between the tract. Treatment can be started based on a supportive onset of AEP and recent exposure to different aller- history and examination. It is not always necessary gens. has been the most frequently to perform allergen specific IgE testing, but identify- identified exposure associated with AEP; other poten- ing culprit allergens is associated with better patient tial exposures associated with AEP are summarized outcomes, probably secondary to avoidance and tar- in Table 2.14 TH2 cells have a major role in the patho- geted immunotherapy.10 genesis of AEP; high levels of IL-5 and IL-18 are found

38 The Southwest Respiratory and Critical Care Chronicles 2019;7(31):34–43 Immunoglobulin E Associated Respiratory Diseases: Part 2 Ismail et al.

Table 2. Exposures reported to be associated with AEP with elevated IgE levels associated with AEP, and its role in the disease pathogenesis has not been well Drugs studied. • Minocycline • Fludarabine Diagnostic criteria were adopted to help diagnose • Sertraline AEP without the need for lung biopsy. The criteria 17 • Intramuscular progesterone require all the following: • BCG vaccine 1. Acute onset of respiratory symptoms with fever Inhalation exposure manifestations for less than 1 month in duration • Tobacco smoke • World Trade Center demolition dust 2. Bilateral diffuse infiltrates on • Firework smoke 3. defined as PaO <60 mm Hg or arterial • Tear gas bomb explosion 2 saturation <90% on room-air pulse oximetry • Cave exploration • Plant repotting 4. BAL >25% eosinophils or eosinophilic pneumonia on lung biopsy 5. Absence of known causes of pulmonary eosino- in the BAL fluid of patients with AEP. These cytokines philia, including drugs, toxins, and infections. recruit large numbers of eosinophils into the alveoli and interstitium and activate them to release their Corticosteroids are the main treatment, and granules leading to the lung damage seen in AEP.14 varying doses have been reported in the literature. Intravenous methylprednisolone (125 mg every Patients typically present with fever, dyspnea, and 6 hours) is often the initial dose. Rapid improvement cough. They have variable degrees of respiratory dis- generally occurs, and the patient can be switched to tress that can progress to respiratory failure requir- oral prednisone at 40–60 mg daily which can then be ing intubation, but this has been rarely reported.15 tapered over 2–6 weeks.18 A study comparing a 2 or Pulmonary examination reveals inspiratory crackles 4-week taper of corticosteroids reported no added and rarely wheezing.14 Complete blood counts, a benefit for the 4-week period.19 These patients typi- comprehensive metabolic panel, and liver function cally have complete recovery and no residual respira- testing should be done, but no laboratory tests are tory symptoms, and no relapses have been reported specific for AEP. Peripheral eosinophilia is not ordi- after corticosteroids are stopped. narily present.14 Arterial blood gas will reveal hypox- emia of variable degrees; the PaO2 is <60 mm Hg. The chest x-ray (CXR) shows bilateral opacities in an Chronic eosinophilic pneumonia alveolar, interstitial, or mixed pattern.15 Chronic eosinophilic pneumonia (CEP) was A case series of 5 patients presenting with AEP first described in 1969 by Charles Carrington when and transient wheezes reported levels of IgE rang- 9 women presented with high fever, night sweats, ing from 106-2,310 U/ml (normal: 0-300 U/ml). weight loss, and severe dyspnea.20 They were ini- Pulmonary function tests showed irreversible small tially treated for with no improvement. airway dysfunction, and showed eosinophilic Eventually, they had lung biopsies demonstrating infiltration into bronchial mucosa and the epithelium eosinophilic infiltration and responded dramatically to of the bronchioles. This demonstrates that eosino- corticosteroids. philic infiltration is not limited to the lung parenchyma as previously believed. Eosinophilic can be Chronic eosinophilic pneumonia, unlike AEP, present in AEP, and these patients commonly have is an insidious disease, and it often takes months wheezing on examination.16 These are the only cases before a clinical diagnosis is made. It is characterized

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by eosinophilic infiltration leading to tissue dam- Diagnostic criteria proposed for the CEP include:25 age. It is a rare disease with a reported incidence of 0.23/100,000 population21 and occurs mostly in 1. Respiratory symptoms for more than 2 weeks females. Chronic eosinophilic pneumonia doesn’t 2. Alveolar and/or blood eosinophilia (alveolar eosin- spontaneously resolve and can cause irreversible ophilia ≥40% at BAL differential cell count; blood if untreated.22 eosinophilia ≥1000/µl) Like AEP, TH2 cells have an integral role in the 3. Pulmonary infiltrates with a peripheral predomi- pathogenesis of the CEP. These cells release IL-5, nance on chest imaging which recruits and activates eosinophils. The release of proteolytic material from eosinophilic granules leads 4. Exclusion of any known cause of eosinophilic lung to tissue damage. High levels of IL-5, IL-6, IL-10, and disease. eosinophils are found in the BAL of affected patients.23 The initiating stimulus is unknown, and smoking and A surgical lung biopsy is not always needed for the environmental factors are not associated with CEP. diagnosis. If the BAL fluid shows no eosinophilia, but IgE levels were elevated in approximately one half the suspicion for CEP is high, a surgical lung biopsy of the patients in a study involving 62 cases. Most could help confirm the diagnosis. Pathology shows of these patients had an atopic history, so it was not alveolar eosinophils and histiocytes; minimal fibrosis clear whether the elevated IgE was related to CEP or is seen early in the course of the disease.22 to coexisting atopic conditions.24 After the diagnosis is made, treatment should be These patients present with productive cough, fever, started immediately to reduce symptoms and prevent weight loss, night sweats, and dyspnea. irreversible fibrosis. The main treatment is high dose and chest pain can occur but are rare. Pulmonary corticosteroids. Oral prednisone at doses of 0.5 mg/ examination reveals wheezes and/or crackles. It is a kg/day is effective and is continued for 2 weeks after slowly progressive disease, and the patients do not resolution of symptoms and radiologic abnormalities. necessarily appear ill.22 No specific laboratory test- A small percent of patients may present with fulminant ing is available for CEP. Complete blood counts with rapidly progressive disease and should be started on differential counts, comprehensive metabolic panel, high dose IV methylprednisolone (250 mg every 6 hours) erythrocyte sedimentation rate (ESR), C-reactive pro- in the initial phase. The dose of corticosteroids should tein (CRP), and arterial blood gases should be done. be tapered to the lowest effective dose to control Blood eosinophils are typically elevated ( 1,000/ L). > µ the symptoms. Unlike AEP, CEP has a high rate of As mentioned previously, IgE is elevated in one half of relapse after discontinuation of steroids. The duration the cases. The other tests are non-specific and include of therapy isn’t well studied with some patients staying elevated ESR, CRP, and counts.22 on low dose prednisone (5–10 mg daily) indefinitely.22 Chest imaging is essential in the diagnosis of A study comparing initial treatment with pred- CEP. These patients frequently have bilateral periph- nisone (0.5mg/kg/day) for 3 months (taper by 20% eral parenchymal infiltrates which are described as every 2 weeks) vs 6 months (tapered by 20% every the photographic negative of . 2 weeks for 2 months followed by 20% every 3 weeks) However, this pattern is present in only 25% of cases was done comparing rates of relapse.26 These study and is not specific. The infiltrates commonly have an arms had similar outcomes with no added benefit with alveolar pattern ranging from ground glass to consoli- the prolonged treatment period. dation with air bronchograms and can be migratory.22 Since the patients do not respond to conventional Since long-term glucocorticoid therapy is associ- treatment, is done to rule out infec- ated with several side effects, corticosteroid sparing tion. The BAL has an elevated count that is medications may be needed. Inhaled glucocorticoid always higher than 25%.22 can reduce the dose of systemic corticosteroids

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during acute flares but should not be used alone. spread by the fecal-oral route. In most carriers the Anti-IgE, omalizumab, and new IL-5 inhibitors, such trophozoites do not invade the gut lining, but in some as benralizumab, mepolizumab, and reslizumab, pro- cases the trophozoite attaches to the gut mucosa vide some benefit in patients with CEP, especially in causing lysis of the epithelium. This leads to inva- patients with concomitant asthma and positive sive amoebiasis and colitis. Hematogenous spread tests.22 of trophozoites can cause the formation of amoe- bic liver abscesses. Amoebic pleuropulmonary dis- Parasitic lung infections ease occurs in about 15% of patients with amoebic liver abscess and develops by direct extension into The incidence of parasitic lung infections is the lung parenchyma causing pneumonia or lung increasing due to worldwide travel and migration. abscesses. Empyema can also occur after rupture These infections occur in both immunocompetent and of a hepatic abscess with direct extension into the immunocompromised hosts. Parasites stimulate a pleural space. Patients present with cough with fever, TH2 response involving IL-4, IL-5, IL-13, eosinophilia, sputum production, pleuritic pain, and dyspnea. Chest and eventually class switching to produce antigen x-rays typically show right lower lobe disease, includ- specific IgE. The cross-linking of IgE on the surface of ing and consolidation. Laboratory basophils, eosinophils, and mast cells by the parasitic testing includes stool studies for trophozoites which leads to release of preformed proteases and are not usually present in sputum or pleural fluid. toxic proteins that are necessary to control different Antibodies against the parasite can also be detected stages of the helminthic infections.27 in the serum. Treatment involve tinidazole or metro- nidazole to kill trophozoites followed by paromomy- Hydatid cystic lung disease is caused by the spe- cin to destroy intestinal cysts. Surgical treatment is cies Echinococcus granulosus. This parasite is pres- sometimes needed in pleuropulmonary disease.29 ent in dogs’ guts and is transferred to humans through feces contaminated food. The eggs hatch producing Other parasites are associated with lung disease. larvae that travel through the circulation to reach the These include , Toxocara canis, liver and the lungs where they develop slowly into , and others and are discussed in an hydatid cysts. The cysts can remain asymptomatic excellent review article by Kunst et al.29 for years before incidentally being found on imaging. Symptoms include cough, hemoptysis, or chest pain. Allergic bronchopulmonary aspergillosis The diagnosis is often made with examina- tion. On chest x-ray, cysts are well-defined lesions Allergic bronchopulmonary aspergillosis (ABPA) surrounded by normal lung parenchyma. Computed occurs when the airways are colonized by Aspergillus tomography of the chest shows more detailed fea- fumigatus. Hypersensitivity reactions to Aspergillus tures, including presence of daughter cysts or cyst antigens lead to the development of symptoms.30 This rupture.28 Laboratory testing is non-specific, and disease frequently occurs in patients with cystic fibro- serologic testing is not sensitive for lung disease. sis and severe asthma, and prevalences as high as Treatment usually requires surgical resection of the 9% and 13% have been reported in asthma and cystic cyst. Postoperative albendazole can be used, but fibrosis, respectively.31 In immunocompetent individu- treatment should be avoided preoperatively due to als, colonization of lower airways by Aspergillus spp. potential weakening of the cyst wall that can lead to is common but rarely has any clinical significance. rupture causing an anaphylactic reaction.29 However, in immunocompromised patients, coloniza- tion can lead to clinical symptoms and ABPA.32 Amoebiasis is caused by Entamoeba histolyt- ica. The trophozoite form of the parasite lives in the Helper T cells are the main cells associated with the intestinal lumen where they multiply and differentiate pathogenesis of this hypersensitivity response. They into cysts. These cysts are passed in feces and are are activated by the antigens of the fungus leading to

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production of IgE, eosinophilia, and degran- and improve symptoms. This is especially important ulation. Proinflammatory cytokines IL-4, IL-5, IL-8, and in patients with uncontrolled asthma.30 IL-13 are produced which damage the epithelial cells Eosinophilic granulomatosis with polyangiitis and increase blood and airway IgE.30 Chronic bron- is reviewed in Part 1 of the review Immunoglobulin chial inflammation, eosinophilia, airways remodeling, E associated systemic conditions.33 and bronchiectasis are seen in lung histology.30

The clinical presentation varies; these patients pres- Summary ent with non-specific symptoms, including low grade fever, weight loss, anorexia, malaise, and fatigue. Several pulmonary diseases have IgE as an Recurrent wheezing, cough, dyspnea, blood stained important factor in their etiology. More complete mucus, or brown mucus plugs are also common understanding of its function and structure has ena- presentations.30 bled clinicians to better manage these disorders. With The diagnosis of ABPA requires typical clinical the emergence of new medications designed to inhibit features, radiological signs, and immunologic find- the production or activity of IgE, better control of these ings. The CXR shows pulmonary infiltrates and bron- diseases has become possible. Additional advances chiectasis often in the upper lobes. These changes in treatment are expected as more targeted and less can be further characterized with high resolution com- toxic medications are being developed. puted tomography (HRCT). Patients with no abnor- 30 malities on HRCT have been reported. Aspergillus Article citation: Ismail A, Iwuji KC, Tarbox JA. skin testing is done to confirm immediate hypersen- Immunoglobulin E associated respiratory diseases: sitivity to Aspergillus. Positive tests signify the pres- Part 2. The Southwest Respiratory and Critical Care ence of Aspergillus fumigatus specific IgE. Peripheral Chronicles 2019;7(31):34–43 eosinophilia, Aspergillus specific IgE, and total serum From: Department of Internal Medicine, Texas Tech IgE are frequently elevated above 1,000 IU/mL (nor- University Health Sciences Center, Lubbock, Texas mal: 0-300 U/ml).30 Submitted: 9/24/2019 Accepted: 10/19/2019 Treatment goals include controlling inflammation Reviewer: John Pixley MD and maintaining normal lung function. Corticosteroids Conflicts of interest: none are the primary treatment during acute exacerbations. This work is licensed under a Creative Commons Prednisone is used (dose of 0.5-1 mg/kg/day) for Attribution-ShareAlike 4.0 International License. 2 weeks followed by 0.5mg/kg every other day for an additional 6–8 weeks. This is followed by a slow taper over 3–5 months. A low dose maintenance regimen References (5–10 mg daily) can be used long term to avoid exacer- bations and maintain remission. IgE levels are usually 1. Oettgen HC. Fifty years later: Emerging functions of IgE checked every 2 months after an acute exacerbation to antibodies in host defense, immune regulation, and allergic ensure response to treatment. Inhaled corticosteroids diseases. J Allergy Clin Immunol 2016;137(6):1631–1645. can decrease the dose of systemic corticosteroids.30 2. Ishizaka T, Ishizaka, K, Johansson, S, et al. Histamine release from human leukocytes by anti-e antibodies. Immunol 1969 Antifungals, mainly itraconazole, are used to 102(4):884–892. reduce the fungal load and associated inflammation. 3. National Asthma Education and Prevention Program: Expert The dose recommended is 200 mg twice daily for panel report III: Guidelines for the diagnosis and manage- 16 weeks; this often leads to significant reductions ment of asthma. Bethesda, MD: National , Lung, and in the corticosteroid dose needed to control the dis- Blood Institute, 2007. (NIH publication no. 08-4051) www. ease. Finally, omalizumab is used as steroid sparing nhlbi.nih.gov/guidelines/asthma/asthgdln.htm (Accessed on medication or alternative to decrease exacerbations June 03, 2018).

42 The Southwest Respiratory and Critical Care Chronicles 2019;7(31):34–43 Immunoglobulin E Associated Respiratory Diseases: Part 2 Ismail et al.

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