Prevalence of hypersensitive pneumonitis specific IgG antibodies in the Indian population: A retrospective study

Introduction

Hypersensitive pneumonitis (HP), also recognized as extrinsic allergic alveolitis, represents a lung condition arising from allergic reactions triggered by the inhalation of microorganisms, fungi/yeasts, plant or animal proteins, or chemical agents. This immune hypersensitivity response can induce inflammation within the lung's alveoli and airways, potentially leading to the development of Interstitial Lung Disease (ILD).1, 2

The incidence of HP varies significantly, influenced by factors such as geographical location, environmental shifts, and genetic predisposition. In the United States, HP accounts for less than 2% of ILD cases, with an annual occurrence of approximately 30 cases per 100,000 individuals.3 Notably, data from the interstitial lung disease-India registry indicates a substantial prevalence of 47.3% for HP within the spectrum of interstitial lung diseases. 4

Historically, HP classification comprised acute, subacute, or chronic forms. However, recent guidelines endorsed by a clinical committee comprising the American Thoracic Society (ATS), the Japanese Respiratory Society, and the Asociacion Latinoamericana del Torax have categorized HP as either fibrotic or nonfibrotic. This classification stems from the primary diagnostic reliance on radiological or histopathological evidence of fibrosis. Fibrotic HP is associated with elevated mortality and morbidity rates, while nonfibrotic variants exhibit more favourable prognoses and treatment responses. Consequently, serum IgG testing has been advocated by the committee to identify potential antigens linked to both fibrotic and nonfibrotic forms of HP. 5

Clinical presentations of both fibrotic and nonfibrotic HP commonly encompass symptoms like dyspnoea, cough, chest tightness, wheezing, and mid-inspiratory squeaks, with less frequent manifestations, including low-grade fever, weight loss, and malaise. These symptoms may manifest acutely, spanning weeks to months, or chronically, persisting over extended durations. Non-fibrotic HP may manifest acutely, with or without symptoms, whereas fibrotic HP typically unfolds insidiously and is often associated with specific exposure histories. 5

Should an individual experience acute symptoms following exposure to an antigen, symptom onset typically occurs 8-9 hours post-exposure and may subside within 24-48 hours of cessation. Accurate diagnosis necessitates a meticulous inquiry into the individual's occupational history and potential exposure to antigens. 2

However, HP is frequently underrecognized owing to its low incidence in the general population. It frequently masquerades as respiratory infections or idiopathic ILD, thereby contributing to potential underdiagnosis. Given its diverse clinical presentations, considering HP as a potential diagnosis across various clinical contexts is imperative. 6

Diagnosing HP proves intricate as no definitive test exists. Diagnosis relies on a composite evaluation encompassing clinical, radiological, and histopathological examinations. Early identification offers the potential for reversibility, while untreated cases can progress to irreversible pulmonary fibrosis. Consequently, identifying the underlying antigen is pivotal for both prevention and prognosis prediction. Quantitative serologic testing of serum-specific immunoglobulins IgG (sIgG) serves as a crucial component in determining the causative antigen, aligned with ATS guidelines that endorse serum IgG testing to distinguish HP from other ILDs. This test boasts a sensitivity of 83% and specificity of 68%. 7

Elevated sIgG antibody levels can indicate exposure to specific antigens within a medical context, facilitating the identification of the triggering antigen responsible for HP's onset and diagnosis. Nonetheless, the absence of elevated sIgG levels does not unequivocally exclude the possibility of HP, primarily due to the limited availability and variability of commercially accessible antigens for routine testing. Despite these constraints, the determination of sIgG antibodies remains an indispensable facet of HP diagnosis and prognosis forecasting, with quantitative antigen sIgG analysis constituting a pivotal criterion within HP's diagnostic algorithms. 8

At the Global Reference Lab, we conducted a retrospective study to assess the primary positive rate of Hypersensitive Pneumonitis antigens within the Indian population. This study encompassed an in-depth evaluation of prevalence, meticulously considering gender, age, and geographic factors.

Materials and Methods

A comprehensive retrospective study was conducted at, Global Reference Laboratory, Mumbai, Maharashtra, spanning 5 years (from January 2018 to June 2023). Data collection and meticulous examination transpired in July 2023, with the requisite prior authorization secured for utilizing Laboratory Information Management System (LIMS) data from the independent ethics committee.

Results

Discussion

Hypersensitive Pneumonitis presents a diagnostic challenge due to the often-unknown triggering substance. Currently, no definitive method exists for HP diagnosis. However, testing with a range of common antigens may offer valuable insights, particularly in cases lacking an exposure history. Despite being a prevalent form of ILD, limited research has focused on HP epidemiology. Discrepancies in ILD and its subtypes, including HP, have arisen from differences in study methodologies, definitions, and actual environmental or cultural factors impacting occurrence and frequency. 4

In our retrospective study at the Global Reference Laboratory, we observed a higher proportion of women (62.47%) undergoing HP testing compared to men (37.53%). A study conducted in North India, as reported in the European Respiratory Journal, found a similar trend with 73.3% of participants being female.9 Another study by Evans et al. in the United States also identified a higher prevalence of HP among women than men. Additionally, their study revealed an increase in cases with age, particularly among adults aged 65 years and older. 10 Conversely, a study conducted in Turkey by Adem et al. showed a different pattern, with 52.6% of cases being male. 11

In our research, slightly over half of the participants (50.78%) did not exhibit any antibodies in the HP panel, while the remaining 49.22% tested positive for HP panel antibodies. This aligns with a study by the National Data Coordinating Centre in India, which found a prevalence rate of 47.3% for HP in India. However, international studies have reported varying incidence rates, such as 6.4% in Saudi Arabia, 4% in Turkey, 2.6% in Greece, and 13.2% in Germany. These variations result from differences in antigens used in HP panels, as well as geographic, environmental, and cultural factors. Notably, the presence of Specific IgG implies exposure to the causative antigen but is not diagnostic of HP, and the absence of IgG to specific antigens does not exclude HP. 4

In our study, 16.01% tested positive for at least one antibody, and 33.21% were positive for two or more antibodies. A study conducted in Thailand reported that 64.7% of participants had only one antibody, while 19.9% had multiple antibodies. Importantly, the number of antigens did not impact survival, histopathologic results, or radiographic findings. The type of antigen also did not affect survival. However, those exposed to Mold were more likely to experience fibrotic HP compared to those exposed to avian antibodies. 12

The highest antibody positivity in our study was for Specific IgG Penicillium chrysogenum among both females (36.38%) and males (31.86%). Pigeon serum proteins and droppings followed at 29.08% for females. Specific IgG Aspergillus fumigatus showed positivity rates of 28.57% in females and 24.02% in males. Positivity for Specific IgG Penicillium chrysogenum was highest in the 18 to 30 years age group (48.28%), followed by Aspergillosis Fumigatus at 44.83%. Among the 31 to 45 years age group, the highest prevalence was of Pigeon serum proteins (39.69%).Prospective data from the ILD-India study by Collins et al. suggest that cooler pads may serve as a breeding ground for mold, reported by approximately 48% of individuals exposed to air coolers, potentially acting as the inciting antigen for HP. 4

The occurrence of Mold-induced HP (Aspergillus, Cladosporium, Penicillium, and Mucor species) has been on the rise due to factors such as humidifiers, heating, and ventilation systems. Nevertheless, molds can also be present in unexpected places in homes, such as fruits and vegetables, resulting in different types of HP. 13

However, another North Indian study reported that 31.7% of patients were exposed to pigeon droppings.9 Similarly, a German study by Sennekamp et al. found that most antibodies were against avian antigens (28%) and Aspergillus fumigatus (25%). Bird fancier's lung could be the cause of 40% of HP cases in Germany and the United States. 14

Many studies have also reported bird-related HP as the most common antibody in Europe and North America, while Japan has reported domestic antigen exposure (Mold) as the most common cause of HP, followed by avian and other occupational exposures. 1 Nogueira et al. have substantiated that Bird Fancier's Lung (BFL) is the most common type of Hypersensitivity Pneumonitis (HP) found worldwide, accounting for 66-68% of all HP cases. BFL is caused by inhaling bird droppings and secretions. 13

Our study findings indicate that the North region had the highest number of HP tests conducted (55.47%) and exhibited a positivity rate of 30.68% for Penicillium chrysogenum. On the other hand, the East region had high positivity rates for Aspergillus fumigatus (38.71%), Mucor racemosus (28.57%), and Penicillium chrysogenum (45.16%). In the West region, Penicillium Chrysogenum (42.0%) showed the highest positivity followed by Pigeon serum protein feathers and droppings (31.50%) and Aspergillus fumigatus (29.71%). Penicillium chrysogenum was found to have a high positivity rate in both the North (30.68%) and South (30.10%) regions. According to an Indian study, 45.8% of patients residing in urban areas across 11 cities were diagnosed with HP, with the highest number of cases (55%) coming from the North region, followed by East (43.4%), South (40.9%), and Western India (38.5%). It is possible that the decline in lung function in Indian urban cities compared to other countries could be linked to higher levels of ambient air pollution. The particulate matter in the air can reach the alveoli, contributing to this issue. 15

Limitations

The study was done using the Laboratory data of patient results and basic demographic details, however, it lacked the details of clinical condition and treatment history. This could have given more insights pertaining to the disease pattern and its outcome.

Conclusion

HP, a type of interstitial lung disease, results from repeated exposure to environmental and occupational antigens. Identifying specific antibodies and the source of exposure in suspected HP patients can be challenging. Our study, which included 1087 patients, revealed that nearly half of them tested positive for HP. We found that the most common antibody in the Indian population is Specific IgG Penicillium chrysogenum, followed by Aspergillus fumigatus and pigeon serum feathers. The onset of symptoms in suspected HP patients may be linked to certain environments and workplaces. Avoiding exposure to the triggering antigen is crucial for improving HP prognosis and outcomes. HP is a complex syndrome that urgently requires more stringent and selective diagnostic criteria and validation, including broader panels of IgG and collaboration with occupational physicians as part of multidisciplinary expertise.

Conflicts of Interests

None declared.

Source of Funding

None.

Acknowledgements

None.