Ubiquitous Fungus Irking Inclined Wheezers – A succinct on Allergic Bronchopulmonary Aspergillosis

Amal Johnson¹, Vaseema Thabassum², Narasimhan R³

¹Post graduate –Department of Respiratory Medicine, Apollo Hospitals, Greams Road, Chennai, India
²Post graduate –Department of Respiratory Medicine, Apollo Hospitals, Greams Road, Chennai, India
³Senior Consultant Pulmonologist, Apollo Hospitals, Greams Road, Chennai, India

Corresponding Author: Dr.Amal Johnson, Post graduate, Department of Respiratory Medicine, Apollo Hospitals, Greams Road, Chennai,
India

Aspergillus mold cause respiratory disease depending upon the host immunity and organism virulence. The manifestations can be classified into 3 distinct clinical categories; allergic aspergillosis (Allergic Aspergillus sinusitis, ABPA), saprophytic colonization (Aspergilloma) and invasive aspergillosis (Airway invasive aspergillosis, chronic necrotizing aspergillosis and invasive aspergillosis)1. ABPA, the most significant manifestation of allergic aspergillosis is immunological pulmonary disease caused by hypersensitivity reaction (Type 1,3, 4) to the aspergillus fumigatus antigen(Af) in susceptible patients mostly commonly with asthma and cystic fibrosis2,3(Cf).

History of ABPA

ABPA was first described in 1952 by Hinson, Moon and Plummer described three patients with recurrent wheezing, pulmonary infiltrates, eosinophilia in blood and sputum, and brown plugs or flecks in expectorated mucus⁴.

Epidemiology of ABPA

The prevalence of ABPA in asthma varied between 2.5% and 22.3% according to the International Society for Human and Animal Mycology (ISHAM) working group. Most cases present in the 3^rd to 5^th decade⁵.

Genetic Factors Involved in ABPA

Genetic risk factors include expression of HLA-DR2 and HLA-DR5 genotypes, while HLADQ2 protected against ABPA^6,7. In subjects with CF, increased chances of Aspergillus colonization of the airways and subsequent development of ABPA were found in those with CF transmembrane conductance regulator gene mutations^8,9. Surfactant protein-A2 polymorphisms, elevated levels of mannan-binding lectin due to the 1011A allele, and toll-like receptor polymorphisms 43, IL -4,IL-10,1L13,1L-15 polymorphisms also play an important role in the development of ABPA^10,11,12.

Pathology of ABPA

Histologic examination reveals the presence of mucus, fibrin, Curschmann spirals, CharcotLeyden crystals, and inflammatory cells with scanty hyphae. The bronchial wall in ABPA is usually infiltrated by eosinophils and other inflammatory cells. Bronchocentric granulomatosis, the presence of noncaseating granulomas containing eosinophils and multinucleated giant cells centered on the airway is also a feature^{14, 15, 16}.

Pathogenesis of ABPA

Clinical Features of ABPA

The presentation can range from mild asthma, with very few symptoms, to extensive lung disease that may manifest as respiratory failure. Patients encounter frequent exacerbations and if left untreated, lead to chronic fibrotic lung disease. Respiratory symptoms included cough (99%), breathlessness (99%), expectoration (98%), wheezing (97%), and haemoptysis (41%). Nasal symptoms suggestive of upper airways allergy were present in 45%. Expectoration of sputum plugs was reported by 37% of the patients and nasal plugs by 6%. Approximately half of the patients had a personal/family history of atopy.

Physical examination in ABPA may reveal rhonchi and crepitations. These patients may also exhibit cyanosis, digital clubbing, and features of corpulmonale in end stage fibrotic stages(15%)¹⁷.

Diagnostic Criteria

Staging of ABPA:

Investigations

1) Serum Eosinophil Count

Absolute eosinophil count greater than 1000 cells/ul is one of the major criteria for ABPA diagnosis. However, low eosinophil counts does not rule out ABPA²⁴.
2) Skin Testing with Aspergillus Antigens

Aspergillus skin testing is done using commercial or locally prepared Aspergillus fumigatus antigen. The test is read every 15 minutes for 1 hour and then after 6-8 hours. The reactions are classified as Type 1: If wheal and erythema develops within 1 min, reaches maximum within 10-20 minutes and resolves within 1-2 hours and Type 3: Is read after 6 hours and if edema present, termed as positive¹⁷.

3) Sputum Cultures for A fumigatus

Culture of A. fumigatus in the sputum is supportive but not diagnostic of ABPA. The fungus can also be grown in patients with other pulmonary diseases due to the ubiquitous nature of the fungi¹⁷.

4) Total Serum IgE

The total IgE level is the most useful test for diagnosis and follow-up of ABPA. A normal serum IgE level excludes ABPA as the cause of the patient’s current symptoms. After treatment with glucocorticoids, the serum IgE levels decline, and a >35 % is taken as a criteria for remission. The serum IgE determination is also used for follow-up, and a doubling of the patient’s baseline IgE levels indicates relapse of ABPA²⁵

5) Pulmonary Function Tests

These tests help categorize the severity of the lung disease but have no diagnostic value in ABPA and need not constitute the basis for screening. The usual finding is an mixed obstructive with restrictive defect of varying severity^26-29. Normalisation of the parameters can be noticed after treatment.

6) Precipitating Antibodies against A. fumigatus 

By the double gel diffusion technique, precipitating antibodies against Af could be detected in the serum upto 92% of patients in concentrated serum^30,31.

7) Radiological manifestations

Differential Diagnosis¹³

1. Aspergillus hypersensitive bronchial asthma
2. Tuberculosis/CAP
3. Inflammatory pulmonary disorders – eosinophilic pneumonia, bronchocenteric

Complications¹³

1) Recurrent asthma exacerbations
2) Bronchiectasis
3) Pulmonary hypertension
4) Respiratory failure
5) End stage fibrotic lung disease

Treatment

The goals of treatment of ABPA according to the AAAAI Committee report on ABPA32 are

1) Control symptoms of asthma or CF2) Prevent or treat pulmonary exacerbations of ABPA
3) Reduce or remit pulmonary inflammation
4) Mitigate progression to end stage fibrotic
or cavitatory disease.

a) Oral Steroids

Oral corticosteroids is the treatment of choice for ABPA.

Steroid dosing in ABPA

Stage 1(Acute) and Stage 3(Exacerbation)₃₃

Prednisolone 0.5mg/kg/day for 2 weeks followed by alternate days for 6-8 weeks. Once Ig declines by 1/3rd and radiological opacities cleared, tapered 2.5 to 5mg every 2 weeks. After completion of therapy, patient monitored for 2 months to assure remission.

Stage 4 (steroid dependent asthma) –

Alternate therapy with prednisolone 10- 40mg/day to maintain symptom control34

Stage 5 (Fibrotic lung disease) – management of end stage lung disease

Pulse therapy with intravenous methylpred nisolone using 10 to 20 mg/kg/day for 3 consecutive days has been shown to be useful in managing severe and sometimes life-threatening exacerbations among children with ABPA and cystic fibrosis³⁵

b) Antifungals (azole)

Antifungals reduce the fungal load thereby decreasing the antigenic stimulus and inflammatory response and proven to have adjunctive role in steroid dependent or steroid unresponsive patients₃₆. They are also used in initial therapy of acute and exacerbation of ABPA₃₇. The mechanism of action is by blocking the CYP450 dependent demthylation of lanosterol, leading to the inhibition of ergosterol synthesis. Ergosterol depletion enchances fungal cell susceptibility to both oxidative and nonoxidative phagocytic damage. The most common used drug is itraconazole followed by newer azoles, voriconazole and posaconazole. Itraconazole has low oral bioavailability and high side effect profile. Dose adjustments are required for patients with mild to moderate hepatic dysfunction(Child class A and B). Monitoring of LFT is recommended at baseline, within the first 2 weeks of treatment initiation and periodically thereafter. The dosage of itraconazole recommended is 200 mg twice daily for 4 to 6 months, which is then tapered over the next 4 to 6 months. Oral itroconazole has side effect of nausea and diarrhea causes by the excipient hydroxypropyl B cyclodextrin which is used to increase the solubility of the drug. It is associated with a unique triad of hypertension, hypokalemia, and edema. Also causes negative inotropic effect avoiding administration in patients with a history of heart failure. By inhibiting steroid metabolism and thereby exacerbating adrenal suppression, itraconazole might lead to cushingoid features when used for very long durations.

Voriconazole is extended spectrum azole with good oral bioavailability and does not inhibit steroid metabolism. It is associated with visual disturbances and cutaneous phototoxicity in a minority of patients.

c) AntiIgE

Omalizumab, a monoclonal antibody against IgE has been tried and shown excellent results in patients with steroid dependent ABPA_38-39.

Conclusion

All patients with uncontrolled asthma should be evaluated for allergic bronchopulmonary aspergillosis. Diagnosis of ABPA is based on clinical, immunological and radiological criteria and the management is primarily steroids with antifungals having an adjunct role.

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