ORIGINAL ARTICLE


https://doi.org/10.5005/jp-journals-11010-1077
Indian Journal of Respiratory Care
Volume 12 | Issue 4 | Year 2023

Hypersensitivity Pneumonitis with Environmental Exposure Manifesting as Fibrotic and Nonfibrotic Forms at a Tertiary Care Center in Western Maharashtra


Ajai Kumar Tentu1https://orcid.org/0000-0002-7244-1935, Samruddhi P Deshpande2https://orcid.org/0000-0002-9592-5297, Nilesh P Phole3https://orcid.org/0009-0005-9969-5117, Rongala Laxmivandana4https://orcid.org/0000-0002-0052-7596

1–3Department of Respiratory Medicine, Army Institute of Cardio-Thoracic Sciences (AICTS), Armed Forces Medical College, Pune, Maharashtra, India

4Department of Bioinfo and Data Management, ICMR-National Institute of Virology, Pune, Maharashtra, India

Corresponding Author: Ajai Kumar Tentu, Department of Respiratory Medicine, Army Institute of Cardio-Thoracic Sciences (AICTS), Armed Forces Medical College, Pune, Maharashtra, India, Phone: +91 95792 45417, e-mail: docajay@hotmail.com

Received: 09 October 2023; Accepted: 26 November 2023; Published on: 18 January 2024

ABSTRACT

Aims and background: Hypersensitivity pneumonitis (HP) is a complex immune-mediated disease affecting the lung, leading to fibrosis on recurrent exposure to organic/inorganic antigens. The sources of antigens include avian droppings, avian feathers, cotton fibers, metal particles, chemical fumes, etc.

Materials and methods: This study comprises 27 adult individuals presenting with HP symptoms like shortness of breath, cough, chest tightness, fatigue, and wheezing who were assessed for clinical, radiological, functional, and bronchoscopic alveolar lavage evaluation.

Results: The mean age of 27 patients diagnosed with HP in our study is 67.4 years which comprises 11 males and 16 females. Out of 27 (92.6%), 25 patients had prior comorbidities, of which hypertension (HTN) (44.4%) and type 2 diabetes mellitus (33.3%) were major contributors. Among 27 patients, 55.56% were diagnosed with fibrotic HP and 44.44% with nonfibrotic HP. The average percent predicted forced vital capacity (FVC) of patients was 61.9. The most common high-resolution computerized tomography (HRCT) chest abnormalities were ground glass opacities (GGOs) (27%). In this study, four out of 12 patients reported positive for the HP panel test. The p-value of 0.031 established a statistically significant association between type of HP and history of avian exposure in patients.

Conclusion: The prevalence of HP was found to be in patients of older age, and the association of avian exposure in patients has a statistical significance in determining the type of HP.

Clinical significance: This study emphasizes the importance of identifying antigen sources related to disease prognosis among HP patients.

How to cite this article: Tentu AK, Deshpande SP, Phole NP, et al. Hypersensitivity Pneumonitis with Environmental Exposure Manifesting as Fibrotic and Nonfibrotic Forms at a Tertiary Care Center in Western Maharashtra. Indian J Respir Care 2023;12(4):345–351.

Source of support: Nil

Conflict of interest: None

Keywords: Avian droppings, Bronchoalveolar lavage, Exposure history, Forced vital capacity, High-resolution computerized tomography

INTRODUCTION

Hypersensitivity pneumonitis (HP) is an immune-mediated lung disease that occurs due to prolonged or repeated exposure to a variety of identified or unidentified environmental exposures.1 HP is also known as extrinsic allergic alveolitis, which is characterized by inflammation in the lung parenchyma and manifests as a spectrum of clinical presentations ranging from acute to chronic forms.2 The disease results from repeated exposure to antigens including but not limited to organic antigens such as microbial agents, animal proteins, and plant materials.3

Hypersensitivity pneumonitis (HP) is observed globally and has no evidence of any gender preference; however, its prevalence increases with age.4 Certain occupations and hobbies are associated with a higher risk of exposure to potentially causative agents, such as farmers, bird keepers, and workers in environments with organic/inorganic exposure.5 The prevalence of HP varies globally based on environmental factors and occupational exposures. Agricultural settings, bird-related environments, and mold-contaminated areas are notable sources of exposure.6 The disease results from an exaggerated immune response to inhaled organic antigens.1,7,8 These antigens can originate from sources such as mold spores, bird droppings, animal proteins, and microbial contaminants in humidifiers.1,9 In a case report by Beniwal et al., eugenol, a phenolic compound, is shown to have caused type IV hypersensitivity reactions among a young patient.10 Also, the inhalation of chemical fumes like nitric acid can lead to severe lung injury confirmed by radiological evaluation and restrictive pattern revealed by pulmonary function test (PFT).11 Host factors, including genetic predisposition and immunological history, contribute to disease susceptibility.9

Hypersensitivity pneumonitis (HP) manifests in a diverse array of clinical presentations, making its diagnosis challenging. Acute HP often presents with flu-like symptoms, cough, fever, and dyspnea, typically within hours of antigen exposure. Subacute and chronic forms display insidious onset, with symptoms resembling other interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF).12 Physical examination findings may include inspiratory crackles and digital clubbing in chronic cases.13

Diagnosing HP can be challenging, as its symptoms mimic those of other respiratory illnesses and, therefore, lacks a definitive diagnostic tool.12,14 The diagnosis of HP requires a multifaceted approach: clinical evaluation, radiological findings (such as ground-glass opacities, nodular infiltrates, and honeycombing), PFTs, and serological markers.15 High-resolution computed tomography (HRCT) plays a pivotal role in identifying characteristic radiological patterns associated with HP.16 Bronchoalveolar lavage (BAL) fluid analysis reveals an elevated lymphocyte count (LC) and a CD (cluster of differentiation) 4+/CD8+ ratio greater than 1.17 Histopathological examination of lung biopsies can aid in differentiating HP from other lung diseases.18 However, a definitive diagnosis often necessitates BAL to check lymphocytosis.19 In addition, transbronchial lung biopsy is also suggested to show granulomatous inflammation in selected cases.20 The changes in forced vital capacity (FVC) parameters like decline ≥10% are linked with poor survival in chronic HP patients.21

The most crucial for HP management is antigen avoidance. Identifying and minimizing exposure to the offending antigens are pivotal steps in preventing disease progression. In cases where complete avoiding of the antigen is not feasible, pharmacological therapies are employed.22 Corticosteroids, deployed often as an initial therapy, can alleviate inflammation and symptoms, but their long-term use can lead to adverse effects.23 Prognosis varies based on disease severity, and the effectiveness of antigen avoidance and early diagnosis and management are critical for improving long-term outcomes.22,24 Acute forms tend to resolve with prompt intervention upon antigen removal, whereas chronic cases may lead to irreversible lung fibrosis.9,25 Advancements in understanding the immunological mechanisms of HP are paving the way for targeted therapies like regulatory T-cells to attenuate proinflammatory patterns and protect against HP. Biomarkers that aid in early diagnosis, disease monitoring, and predicting treatment response are actively being investigated.26 Additionally, public awareness campaigns and education among healthcare professionals are essential to enhance recognition and timely intervention. This study is crucial in understanding the relationship between environmental exposures and disease severity in HP.

MATERIALS AND METHODS

This study is a retrospective analysis of 27 adult patients out of 150, presenting with features consistent with HP. Inpatients, as well as outpatients, were included in this study to get adequate diversified HP presentations. The inclusion criteria to recruit patients in this study were:

Any patient presenting with the abovementioned symptoms and having an exposure history to environmental factors like avian feathers, avian droppings, indoor coolant, farming, biomass, and harsh chemical fumes were selected. The average age, age of diagnosis and age of onset of symptoms of patients were noted. The comorbidities like hypertension (HTN), type 2 diabetes mellitus (T2DM), coronavirus disease of 2019 infection history, hypothyroidism, chronic respiratory failure, Bronchial asthma, coronary artery disease, old tuberculosis infection, combined pulmonary fibrosis and emphysema, sleep apnea, benign prostatic hyperplasia, hypercholesterolemia, and chronic kidney disease were noted in all cases of HP. The patient’s history of tobacco exposure was also noted. The patients were advised to undergo an HRCT chest scan to evaluate HP-like characteristics like fibrotic bands, ground glass opacities (GGOs), mosaic attenuation, septal thickening, honeycombing, air trapping seen in expiratory scans, and triple density pattern; and PFTs (spirometry). After reviewing the above tests, if the diagnosis was of moderate confidence,3 the patient underwent BAL to evaluate for differential cytological analysis. To further assess the source of the agent causing hypersensitivity, the patients were advised an HP panel blood test against known agents causing HP like Alternaria alternata, Aspergillus fumigatus, Cladosporiumherbarum, Mucor racemosus, Penicillium chrysogenum, and pigeon serum protein. The autoimmune factor tests like rheumatoid factor and antinuclear antibody (ANA) were also advised to the patients.

All the findings were analyzed, and through multidisciplinary discussions, the diagnosis of HP was confirmed. Statistical analysis was performed on the data collected from patients using Statistical Package for the Social Sciences software version 18. The mean and standard deviations were calculated based on the patient’s age at diagnosis, percentage FVC predicted, and BAL LC. A Chi-squared test was performed to evaluate the association between the two groups. The confidence level was set at 95% with a degree of freedom equal to 1. If the p-value was ≤0.05, the association between the two groups was considered statistically significant. The patients were informed about the study, informed consent was obtained, and ethical clearance was obtained from the institutional committee.

RESULTS

A total of 150 patients were identified with the above-mentioned symptoms, and upon evaluation, 27 cases of HP were confirmed. Among the 27 patients, 11 were male (40.74%) and 16 were female (59.25%). A total of 14 patients enrolled in this study were from the inpatient department, while 13 were from the outpatient department. The average age at which patients were diagnosed was 67.44 [standard deviation (SD) = ±13.39], and the age of diagnosis was 66.67 (SD = ±13.13). The onset age of symptoms in patients was 63.63 (SD = ±12.28). The number of years to reach a final definite diagnosis was 3.04 years, as demonstrated in Table 1.

Table 1: Patient demographic data (number of patients, age, tobacco exposure, FVC percentage, and BAL status)
Sr. no. Characteristics Entire cohort (N)
1 Number of total patients (N) 27
2 Males (n, %) 11 (40.74)
3 Females (n, %) 16 (59.25)
4 Mean age at diagnosis (n, SD) 67.4(13.38)
5 Smoking status
Never (n, %) 23 (85.18)
Former (n, %) 4 (14.81)
Current (n, %) 0 (0)
6 Tobacco exposure
Never (n, %) 22
Former (n, %) 5
Current (n, %) 0
7 FVC status
FVC percentage predicted in patients 21
Spirometry (patients unable to perform) 6
FVC percentage predicted mean (n, SD) 61.9 (18.79)
8 BAL lymphocytosis
BAL done (n) 19
BAL not done 8
BAL LC mean (n, SD) 28.26 (20.4)

All the patients enrolled in this study suffered from SOB; three, eight, 11, and three patients had SOB of mMRC grade I, II, III, and IV, respectively. The other symptoms exhibited were cough, chest tightness, wheezing, and fatigue. The distribution of symptoms can be seen in Figure 1.

Fig. 1: The pie chart indicates symptom history in HP patients

Among the 27 patients, 25 patients (92.6%) had prior comorbidities. Two patients (7.4%) did not have any prior known comorbidities. The patients were distributed based on the number of comorbidities, wherein eight patients (29.62%) had more than or equal to three comorbidities, six patients (22.22%) had two comorbidities, and nine patients (33.33%) had one comorbidity. The distribution pattern of comorbidities is shown in Figure 2. Nine out of 27 patients had a history of tobacco exposure in the past. Among those nine patients, five patients (55.56%) had a history of chewing tobacco, and four patients (44.44%) had a history of smoking (cigarettes and beedi) with an average smoking index (SI) of 168.

Fig. 2: Patients depicting various types of comorbidities (the x-axis indicates the type of comorbidity, and the y-axis indicates the number of patients)

A total of 15 (55.56%) patients were diagnosed as fibrotic type, while 12 (44.44%) were diagnosed as nonfibrotic type. Along with HRCT findings, the patients were categorized based on the exposure duration to antigens as acute and chronic HP. A total of 25 (92.59%) patients were grouped as chronic HP and two (7.4%) patients as acute HP, as shown in Figure 3.

Figs 3A and B: The pie chart indicates the number of patients diagnosed with different types of HP: (A) Fibrotic vs nonfibrotic HP; (B) Chronic vs acute HP

The patients enrolled in this study were exposed to environmental or occupational factors, which included avian, indoor coolant, farming, biomass, pet and cattle, etc. The varied exposure demographics can be seen in Figure 4.

Fig. 4: Distribution of environmental exposure among HP patients (the x-axis indicates the type of exposure, and y-axis indicates the number of patients)

A total of 21 out of 27 patients (77.78%) were able to perform spirometry, and the remaining six patients (22.22%) were unable to perform spirometry satisfactorily. The percentage FVC vs age of each patient is mentioned in Figure 5 of a scatter plot diagram. The percentage FVC of the study population was compared to the standardized percentage FVC (based on height and age).

Fig. 5: Scatter plot of percentage FVC value vs age of patients at diagnosis

Out of 27 patients, 19 (70.37 %) underwent bronchoscopy, and the average BAL LC was 28.26 (SD = ±20.24), while seven patients (25.93%) had a BAL LC of ≥30. The distribution of BAL vs age is shown in Figure 6.

Fig. 6: Scatter plot of BAL LC value vs age of patients at diagnosis

All the patient’s HRCT scans showed features consistent with HP. Out of 27, fibrosis bands were seen in 15 patients (55.56%). The distribution of HRCT characteristics is shown in detail in the figure below (Fig. 7). The diagnosis of HP was confirmed by the HRCT patterns of patients. The most common chest abnormalities in patients in this study were GGOs (27%), septal thickening (23%), mosaic attenuation (22%), honeycombing (14%), air trapping (10%), and triple density pattern (4%) as demonstrated in Figure 7.

Fig. 7: Distribution of HRCT abnormalities among HP patients

A total of 12 patients (44.44%) underwent an HP panel test [immunoglobulin G (IgG) specific], of which four (33.33%) were positive and eight (66.67%) were negative for the test. The autoimmune features of patients were also tested, and 10 patients (37%) out of the total had autoimmune features.

Statistical analysis was carried out using a Chi-squared test (2 × 2) table to determine the association between groups. The confidence level was set at 95%, with the degree of freedom equal to 1, as explained in Table 2.

Table 2: Statistical analysis in relevance to various environmental exposures
Sr. no. Association studies Chi-square value p-value Statistical significance
1 Bird exposure vs fibrotic and nonfibrotic HP 4.363 0.0313 The association is statistically significant
2 Other environmental exposure vs fibrotic and nonfibrotic HP 0.767 0.381 The association is not statistically significant
3 Occupational exposure vs fibrotic and nonfibrotic HP 0.898 0.343 The association is not statistically significant
4 Autoimmune factor vs fibrotic and nonfibrotic HP 0.071 0.789 The association is not statistically significant
5 Tobacco exposure vs fibrotic and nonfibrotic HP 2.7 0.1 The association is not statistically significant

DISCUSSION

Hypersensitivity pneumonitis (HP) is a complicated immune-mediated lung disorder whose diverse sources of exposure, clinical presentation, challenges in diagnostics, and potential for irreversible lung damage emphasize the magnitude of early recognition and management.14,27 According to previous studies, the prevalence of this disease is not confined to a specific gender or ethnicity.4 On the contrary, some studies highlight the occurrence of HP is seen in older females.28 Similarly, in our study, the average age of patients at the time of diagnosis was 67.4 years, and among 27 patients, 59.26% of the population were females.

According to a retrospective study by Kumar et al., the patients presented with symptoms like cough (97%), dyspnea (91.2%), and fever (17.4%), and their median duration of symptoms was 14 months.28 However, in our study, the most common symptom was SOB (100%), followed by cough in 29% of patients, and the mean duration of symptoms was 3.04 years. The onset of symptoms was recorded to establish a time delay for disease diagnosis among HP patients. All patients suffered from SOB, and most patients suffered from grade 3, which is one of the major initial symptoms identified in HP cases. The disease prognosis of HP is severe, with prior comorbidities in patients with various numbers and types of comorbidities proportionally associated with a worse outcome of this disease.29 Our study also validates the occurrence of fibrotic HP is more than nonfibrotic HP, where the majority of patients have at least two comorbidities like HTN, DM-2 being the most common, and 92.6% of patients had prior comorbidity. Based on the duration of antigen exposure, HP can be classified into acute and chronic forms, whereas, based on HRCT patterns in patients, it can be divided into fibrotic and nonfibrotic HP.3 Our study comprised 92% chronic HP and 8% acute HP, which correlates with our higher duration of symptoms. The occurrence of fibrotic HP was seen in 56% of patients, and the remaining 44% were diagnosed as a nonfibrotic type of HP. This is in line with the severe comorbidities among our patients in this study and the association of worse disease prognosis with prior comorbidities. Interestingly, many studies validate the fact that there are fewer incidents of HP among smokers exposed to nicotine. Nicotine inhibits macrophage activation in individuals, thus reducing lung inflammation, which in turn leads to protection against antigen exposure.30 Likewise, among patients diagnosed with HP in our study, 33.33% of total patients had a history of tobacco exposure (five of these had chewing tobacco history, and four had a history of smoking). The most common form of HP is bird fancier’s lung, constituting 66–68% of total HP cases.31 There are other causative microbial agents, exposure through indoor humidifiers and farming, named summer type HP and farmer’s lung, respectively.3 Among all the patients analyzed, the majority of them had environmental exposure history either to bird feathers or droppings (14 patients), indoor humidifiers (seven), farming (six), and biomass exposure (four), which is also majorly associated with fibrotic HP.

The role of radiological findings is crucial to diagnose HP. The most common chest CT scan abnormalities are GGOs, mosaic attenuation, and honeycombing among fibrotic HP, while GGOs and air trapping are seen in nonfibrotic HP and acute forms of HP.3,32 The HRCT scans of patients diagnosed in our study comprised mostly having GGOs (27%), septal thickening (23%), mosaic attenuation (22%), and honeycombing (14%) and these patterns correlate with more progressive type, that is, fibrotic HP. 10% of the total patients had air trapping seen in expiratory scans; thus, a smaller number of patients were diagnosed as nonfibrotic HP. PFTs and measurement of FVC reveal functional impairment and can be used as a guide for HP disease management.18 A >10% decline in FVC value over one year is related to a worse disease prognosis.21 Though FVC reflects lung functional impairment, it still doesn’t differentiate between HP and other forms of lung disease at the time of diagnosis and should be used only for insight into disease management.19 The mean FVC value in our study was 61.9, a restrictive pattern that reveals low lung functionality in HP patients.

Bronchoalveolar lavage (BAL) studies and LC are sensitive tools to detect lung inflammation for HP. The higher levels of LC can be used in differential diagnosis of HP from IPF.9 The LC value set for the initial diagnosis of HP is >30%.3 On the contrary, according to a few studies, the levels of lymphocytes in BAL are higher (>30–40%), while in the chronic type, the levels can be > 20% but below 30%.33 Our study comprises a mean LC in BAL of 28.26% and correlates with more cases of chronic HP. According to a report by Adegunsoye et al., the incidence of autoimmune features in HP patients is 15%, and it signifies a poor prognosis. In contrast, in our study population, 10 patients (37%) of the total were autoimmune positive, and among them, the majority (60%) were diagnosed with chronic fibrotic HP.34 A noninvasive diagnostic tool such as the IgG marker test can also be used for HP. The problem with IgG testing against antigens is the fact that even healthy individuals can be sensitized toward the antigen and reveal a false positive result, making HP difficult to diagnose.35 The lack of inclusion of antigens for serological evaluation against HP is indicated by the patient’s negative results for specific IgG markers in our study. Around 44.44% of patients underwent an HP panel test against the standard six source pathogens, among which four patients tested positive and the remaining tested negative. This is indicative of the fact that the HP panel test does not include another pathogen to which patients might be exposed. The positive test results can be an indication of the patient’s sensitivity toward the pathogen but not necessarily be the causative agent for hypersensitivity reaction. Thus, it cannot be used as a strong diagnostic tool for HP diagnosis.

The statistical analysis reveals that only exposure to birds is correlated with the type of HP diagnosis, that is, fibrotic or nonfibrotic. Exposure to birds leads to a worse form of HP seen among patients at our respiratory centre. However, the association between other environmental exposures, occupational exposures, autoimmune features, and tobacco exposure vs the type of HP was not statistically significant in our population.

CONCLUSION

Hypersensitivity pneumonitis (HP) is a complex lung disorder arising from immune dysregulation triggered by exposure to various types of antigens. Its diverse clinical symptoms being similar to various other lung diseases make it challenging for an early diagnosis. Antigen identification and avoidance are the most important to curb the disease progression from acute to chronic form of HP and leading to fibrotic type. We diagnosed 27 patients with HP based on exposure history, FVC, HRCT abnormalities, and BAL LC. The mean age of patients in our study was 67.4, and the time taken to reach a final diagnosis was approximately 3 years. Avian exposure was the most common source of antigen, and the association of bird exposure with the type of HP is the only statistically significant association. Ongoing research endeavours hold the promise of improved diagnostic accuracy, tailored therapeutic approaches, and, ultimately, better outcomes for individuals affected by this complex disorder. To fasten the diagnostic time of disease, it is crucial to understand the agents that cause hypersensitivity reactions.

*Clinical Significance

This study emphasizes the importance of recognizing and avoidance of antigens in cases of HP. The patients exposed to avian feathers and droppings as an antigenic source have an association with the type of HP.

Limitations of the Study

The small sample size is one of the limitations of this study. The other limitation is that patients have been tested only against known and common environmental agents. Detailed exposure information should be obtained by accessing their home environment and recognizing those agents.

Ethics Committee

The study was approved by the Institutional Ethics Committee (number 138/2021 and dated 17th June 2021).

ORCID

Ajai Kumar Tentu https://orcid.org/0000-0002-7244-1935

Samruddhi P Deshpande https://orcid.org/0000-0002-9592-5297

Nilesh P Phole https://orcid.org/0009-0005-9969-5117

Rongala Laxmivandana https://orcid.org/0000-0002-0052-7596

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