What is hypersensitivity pneumonitis?

Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) characterized by an immune reaction to an inhaled environmental antigen in a susceptible individual.^1-3 Hypersensitivity pneumonitis is also sometimes called by other names based on the type of antigen inhaled, such as farmer’s lung and bird fancier’s/bird breeder’s lung. There is no consensus definition for HP, and diagnostic guidelines vary between organizations. HP may often be mistaken for other ILDs, such as idiopathic pulmonary fibrosis. Additionally, no treatment clinical practice guidelines exist. 

Historically, HP has been divided into the following subgroups: acute, subacute, or chronic. However, the definition of these categories varies widely and has limited utility. The American Thoracic Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax (ATS/JRS/ALAT) clinical practice guidelines recommend instead categorizing by the presence or absence of fibrosis (fibrotic and nonfibrotic).¹ The American College of Chest Physicians (CHEST) guideline and expert panel report similarly recommends use of fibrotic and nonfibrotic categorizations.²

Common signs and symptoms of HP for both fibrotic and nonfibrotic HP include dyspnea, cough, and inspiratory squeaks.^1,3 Less common symptoms include weight loss, flu-like symptoms (e.g., chill, low-grade fever, malaise), chest tightness, wheezing, and cyanosis. One study of 199 patients with HP found that the 98% experienced dyspnea, 91% cough, 87% inspiratory squeaks or crackling, 42% weight loss, 35% chest tightness, 34% chills, 32% cyanosis, 31% wheezing, 24% body aches, and 19% fever.⁴ Onset may be acute, developing over days to weeks, or long-term, worsening over the course of months or even years.

Causes

There are many sources of the antigens that can cause HP, including bacteria, fungi, animal proteins, plant proteins, low molecular weight chemicals, and metals.^1-3 Research is always ongoing and leads to the discovery of new causes of HP, so the list of known inciting antigens is continually evolving.

A study of 199 patients with HP found that the most common causes were avian antigens (66%), farmer’s lung (19%), and fungi (10%).⁴ Another study of 85 patients with HP found that common causes were avian antigens (34%), a bacteria found in hot tub water (21%), farm-related mold (11%), and household mold (9%).⁵ Another study of 142 patients with HP found that common causes were avian antigens (17%), household mold (11%), farm or animal-related exposures (8%), and hot tub water (4%).⁶

In many cases of HP, the exposure factor cannot be determined.¹ Studies have reported varying percentages of antigen-indeterminate HP. One study of 85 patients with HP found that 25% had an unknown antigen cause.⁵ Another study of patients with ILD, 206 of which had a confirmed diagnosis of HP, found that 60% of patients had an unidentified antigen exposure.⁷ Another study of 142 patients with HP found that 53% of patients had an unidentified inciting antigen.⁶

Patients who contract HP have been previously sensitized to the offending antigen.^1-3 There is a need for more research to explain why only a fraction of people exposed to the harmful antigens develop HP.

Diagnosis

The diagnosis of HP is challenging; there is no one gold standard test. The diagnosis is made from a combination of the collection of personal information including potential exposure history, testing, imaging, and procedures. Current guidelines suggest a multidisciplinary approach involving a range of clinical tests and scans, including but not limited to the involvement of clinicians, radiologists, pathologists, occupational physicians.

Clinical practice guidelines suggest the following diagnostic workflow:^1,2

1. Exposure assessment and/or serum immunoglobulin G (IgG) testing
2. High-resolution CT (HRCT)
3. Bronchoalveolar lavage (BAL) with lymphocyte cellular analysis, with or without transbronchial lung biopsy
4. If previous diagnostic options are exhausted, consider transbronchial lung cryobiopsy or surgical lung biopsy

A comprehensive exposure history is important in the diagnosis and treatment of HP. Blood testing for IgG antibodies can help identify potential inciting agents of HP.^1-3 However, IgG testing only provides supporting evidence of HP and cannot be used to confirm or exclude a diagnosis of HP as often the tests are not sensitive or specific for an exposure. If exposure history is unclear or indeterminant, that does not exclude HP.

HRCT is one of the key diagnostic tools for HP as it can help determine presence of fibrosis, which aids in determining treatment and prognosis.^1,2 A HRCT typical for HP includes irregular linear opacities and course reticulation with lung distortion, traction bronchiectasis, honeycombing, centrilobular nodules and/or ground-glass opacity (GGO), inspiratory mosaic attenuation, air-trapping, or the three-density pattern. The distribution of fibrosis is typically random both axially and craniocaudally, mid-lung predominant, or relatively spared in the lower lung zones. An HRCT compatible with HP exhibits variation from the typical presentation but can still be indicative of HP and includes basal and subpleural distribution of honeycombing with or without traction bronchiectasis, extensive GGOs with superimposed subtle features of lung fibrosis, variant distribution of lung fibrosis, ill-defined centrilobular nodules, three-density pattern, or air trapping. An HRCT indeterminate for HP is neither a strong indication nor a strong exclusion criterion for HP. They tend to have patterns in isolation, not accompanied by other findings suggestive of HP.

BAL with lymphocyte cellular analysis involves the use of a bronchoscope to insert and recollect a small amount of saline solution to assess the cell counts (i.e., neutrophils, eosinophils, lymphocytes) in a patient’s lungs.^1-3 Elevated lymphocyte counts are a characteristic of both types of HP, however lymphocytosis is not consistently present in patients with fibrotic HP. BAL analysis can narrow the differential diagnosis and can increase the diagnostic likelihood of HP, but it is not sufficiently sensitive or specific to either rule out or make a definitive diagnosis of HP.

Transbronchial lung biopsy is suggested for patients with potential nonfibrotic HP and transbronchial lung cryobiopsy is suggested for patients with potential fibrotic HP who don’t have a definitive diagnosis after exposure assessment, HRCT, and BAL.^1,2 These procedures can spare patients who are difficult to diagnose from the more invasive and costly surgical lung biopsy. Although surgical lung biopsy is the diagnostic method that brings the highest level of confidence for both fibrotic and nonfibrotic HP, it is only recommended once all other diagnostic options have been exhausted.

ATS/JRS/ALAT provides the following graphic on the confidence of a HP diagnosis based on results from the recommended diagnostic workflow outlined above:¹

Incidence

It is difficult to accurately report the incidence of HP for a number of reasons including the lack of a consensus definition, because it is often misdiagnosed or goes unrecognized, and because of high variation between populations depending on environment and occupation.¹ ATS/JRS/ALAT clinical practice guidelines state that available studies estimate an incidence between 0.3-0.9 per 100,000 people.

A Danish national population-based study found an average incidence of 1.16 per 100,000 people from 1998-2010.⁸ An insurance claims-based population analysis in the United States found that between 2004-2013, the 1-year incidence rates of HP ranged from 1.28-1.94 per 100,000 people per year.⁹ A Spanish study of a population with 9% (38,452) reporting >5 hours of contact with birds per week found that the incidence HP was 4.9 per 100,000 people and 54.6 per 100,000 people in frequent contact with birds.¹⁰

HP is most common among people 65 years of age and older.⁹ One population analysis found that incidence of HP among those 65 and older was about 5 cases per 100,000 people in 2013 compared to 3 cases per 100,000 for ages 55-64, 2 for ages 45-54, and between 0-1 for ages 35-44, 25-34, 18-24, 10-17, and 0-9. There is not enough data available to suggest a difference in incidence based on sex.

Prognosis

Prognosis for patients with HP varies depending on the patient’s overall health and the severity of their disease progression.¹ Patients with relatively mild HP can stabilize and even recover, while some with more severe HP progressively decline, ultimately leading to respiratory failure and death. Patients with nonfibrotic HP tend to have a more favorable prognosis than those with fibrotic HP, particularly those with an unusual interstitial pneumonia (UIP)-like pattern.

One study following 142 patients with HP from 1982-2008 reported that the rate of mortality was significantly higher among those who were older (median age 61 vs 54), had lower total lung capacity (77% vs 89%), diffusing capacity of the lung for carbon monoxide (DLCO)(54% vs 58%), had worse dyspnea (American Thoracic Society [ATS] dyspnea score 10 vs 7, with a higher score meaning more severe dyspnea), and were more likely to have fibrosis (75% mortality of those with fibrotic HP, 45% for those with nonfibrotic HP).⁶ Mean survival was 4.9 years for those with fibrotic HP compared to 16.9 years for those with nonfibrotic HP. Identification of an inciting antigen also improved survivability, with 39% mortality among those with an identified inciting antigen compared to 72% for those without, and a median survival of 18.2 years vs 9.3 years.

A retrospective study of 101 patients with HP over a median of 4.6 years found that older age, lower lung function, and higher levels of fibrosis seen on HRCT were associated with an increased mortality rate.¹¹ Forced vital capacity was 66.6% in non-survivors vs 79.2% in survivors, DLCO was 55.4% vs 63.4%, and total lung capacity was 66.9% vs 76.1%. Higher levels of reticulation (16.2% in non-survivors vs 11.6% in survivors), honeycombing (1.7% vs 0.5%), fibrosis (20.9% vs 12.1%), mosaic attenuation (17.3% vs 9.4%), and presence of a UIP-like pattern (66.7% among non-survivors vs 47.5%) seen on HRCT imaging were also associated with higher mortality rates.

References

1. Raghu G, Remy-Jardin M, Ryerson CJ, et al. Diagnosis of Hypersensitivity Pneumonitis in Adults. An Official ATS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. Aug 1 2020;202(3):e36-e69. doi:10.1164/rccm.202005-2032ST
2. Fernández Pérez ER, Travis WD, Lynch DA, et al. Diagnosis and Evaluation of Hypersensitivity Pneumonitis: CHEST Guideline and Expert Panel Report. Chest. Aug 2021;160(2):e97-e156. doi:10.1016/j.chest.2021.03.066
3. Quirce S, Vandenplas O, Campo P, et al. Occupational hypersensitivity pneumonitis: an EAACI position paper. Allergy. Jun 2016;71(6):765-79. doi:10.1111/all.12866
4. Lacasse Y, Selman M, Costabel U, et al. Clinical diagnosis of hypersensitivity pneumonitis. Am J Respir Crit Care Med. Oct 15 2003;168(8):952-8. doi:10.1164/rccm.200301-137OC
5. Hanak V, Golbin JM, Ryu JH. Causes and presenting features in 85 consecutive patients with hypersensitivity pneumonitis. Mayo Clin Proc. Jul 2007;82(7):812-6. doi:10.4065/82.7.812
6. Fernández Pérez ER, Swigris JJ, Forssén AV, et al. Identifying an inciting antigen is associated with improved survival in patients with chronic hypersensitivity pneumonitis. Chest. Nov 2013;144(5):1644-1651. doi:10.1378/chest.12-2685
7. Ryerson CJ, Vittinghoff E, Ley B, et al. Predicting survival across chronic interstitial lung disease: the ILD-GAP model. Chest. Apr 2014;145(4):723-728. doi:10.1378/chest.13-1474
8. Rittig AH, Hilberg O, Ibsen R, Løkke A. Incidence, comorbidity and survival rate of hypersensitivity pneumonitis: a national population-based study. ERJ Open Res. Oct 2019;5(4)doi:10.1183/23120541.00259-2018
9. Fernández Pérez ER, Kong AM, Raimundo K, Koelsch TL, Kulkarni R, Cole AL. Epidemiology of Hypersensitivity Pneumonitis among an Insured Population in the United States: A Claims-based Cohort Analysis. Ann Am Thorac Soc. Apr 2018;15(4):460-469. doi:10.1513/AnnalsATS.201704-288OC
10. Morell F, Villar A, Ojanguren I, et al. Hypersensitivity Pneumonitis and (Idiopathic) Pulmonary Fibrosis Due to Feather Duvets and Pillows. Arch Bronconeumol (Engl Ed). Feb 2021;57(2):87-93. doi:10.1016/j.arbres.2019.12.003
11. Oh JH, Kang J, Song JW. Fibrosis score predicts mortality in patients with fibrotic hypersensitivity pneumonitis. Front Med (Lausanne). 2023;10:1131070. doi:10.3389/fmed.2023.1131070