HYPERSENSITIVITY PNEUMONITIS

Hypersensitivity pneumonitis (HP) is a complex syndrome resulting from repeated exposure to a variety of organic particles.
The syndrome was first described in 1713 by the Italian scientist Bernardino Ramazzini in subjects belonging to 52 different professions.
It involves the lung parenchyma and specifically the alveoli, terminal bronchioli, and alveolar interstitium. Repeated exposure to particles sufficiently small (diameter < 5 μm) to reach the alveoli and to trigger an immune response is necessary. Primarily an occupation-linked disorder, the most at risk professional categories are workers in environments or settings contaminated by organic dust of various origin, mostly farmers or breeders. The syndrome is greatly variable in symptoms severity, clinical presentation, and prognosis, depending on the nature of causative agent, the duration of exposure, the host factors, and the characteristics of the antigen. In most cases, it can be reversed, in the early stages, by promptly identifying and removing the causative agent(s).

DISEASE DEFINITION

There is no universally agreed upon definition of hypersensitivity pneumonitis. However, there is consensus on the following key features of the disease:

  1. HP is a pulmonary disease which may or may not be accompanied by systemic manifestations (eg, fever and weight loss)
  2. It is caused by the inhalation of an antigen to which the individual is sensitized and hyperresponsive.
  3. It is defined by exposure to a given antigen, sensitization to this antigen, and the presence of clinical symptoms.

PATHOGENESIS

An intriguing question regarding hypersensitivity pneumonitis is why, given the universal and wide distribution of the offending antigens, only few individuals develop the disease.
A two-hit hypothesis has been suggested, wherein preexisting genetic susceptibility or environmental factors (i.e., the first hit) increases the risk for the development of HP after antigen exposure (the second hit). Antigen exposure acts as the inducing factor, and genetic or environmental factors act as promoting risk factors.
Most exposed individuals develop an immune tolerance, and the antigen inhalation may result at most in a mild increase of local lymphocytes, without clinical consequences.
The coexistence of genetic or environmental promoting factors provokes the development of an exaggerated immune reaction that results in marked lung inflammation.
Subsequently, in the presence of progressing factors (i.e., further exposure) or genetic predisposition, critical immunopathological changes occur in the lung microenvironment inducing the expansion and activation of the fibroblast population and the accumulation of extracellular matrix.

Proposed mechanisms in the pathogenesis of hypersensitivity pneumonitis.
Figure 1 – Proposed mechanisms in the pathogenesis of hypersensitivity pneumonitis. (Adapted from Am J Respir Crit Care Med. 2012 Aug 15;186(4):314–24)

DISEASE CLASSIFICATION

The clinical features of hypersensitivity pneumonitis depend upon several factors. Some of the significant factors include the nature of the inhaled dust, such as antigenicity, particle size, intensity and frequency of exposure to the antigens, the immunological response of the host and concomitant bacterial or viral infections.
Clinically hypersensitivity pneumonitis can be categorized into acute, subacute, and chronic forms (Table 1).

Table 1 – Comparison of features of acute, subacute and chronic hypersensitivity pneumonitis

ACUTESUBACUTECHRONIC
High-level exposure to antigen over a short period of time.Repeated low-level exposure.Repeated low-level exposure to antigen.
Symptoms develop within 4 – 8 hours & are similar to acute viral infection – high fever up to 40°C, chills, myalgia, fatigue, dyspnea, non-productive cough.Progressive respiratory symptoms over weeks-to-months (productive cough, dyspnea, fatigue, anorexia, weight loss, and pleurisy).Progressive dyspnoea, cough, malaise, weakness, anorexia, and weight loss are common. Fever is often not present.
Examination during an acute attack reveals an acutely ill, febrile and dyspneic individual. Bibasilar end-inspiratory rales are prominent and may persist for weeks after the fever subsides.Physical examination often reveals crepitant rales and hypoxemia especially with exertion.Lung examination may demonstrate dry crackles, but wheezing is uncommon.
The patient will usually recover in about 18 to 24 hours, once removed from the environment.Removal of the patient from the offending environment improves symptoms.Since the chronic form of HP is characterized by fibrosing interstitial lung disease, avoidance of the offending antigen will not result in complete resolution of symptoms.

DIAGNOSIS

Various diagnostic criteria have been proposed for hypersensitivity pneumonitis, but none of these have been validated. As such, diagnosis relies on the integration of a variety of factors, including history of antigen exposure, precipitating antibodies to the offending antigen, clinical features, BAL, and radiological and pathologic abnormalities.
A clinical prediction model for a diagnosis of HP has been developed (Figure 2). If all 6 predictors in the model are present, the probability of having HP is 98%.

Clinical predictors for the diagnosis of hypersensitivity pneumonitis
Figure 2 – Clinical predictors for the diagnosis of hypersensitivity pneumonitis

Physical Examination

The physical examination may be completely normal; however in the advanced, fibrotic phase coarse inspiratory rales are usually heard on auscultation and in some cases high-pitched mid–end inspiratory wheeze known as “chirping rales” or “inspiratory squeaks” may be present.

Role of Radiology

The high resolution computed tomography (HRCT) patterns typical for acute hypersensitivity pneumonitis include a centrilobular diffuse micronodular pattern, ground-glass opacification and mosaic attenuation predominantly in upper and middle lobes.
The findings in chronic hypersensitivity pneumonitis are fibrosis, architectural distortion, and traction bronchiectasis with or without honeycomb change. The fibrosis may be patchy, peribronchovascular, or subpleural, and may occur in any zonal distribution.
Although it is possible to make a high-confidence, HRCT-based diagnosis of hypersensitivity pneumonitis (88–92% accuracy and 44–61% sensitivity), the radiologic findings are often not specific, and other granulomatous and fibrosing interstitial lung diseases with a predominantly upper lobe distribution need to be considered.

Role of BAL fluid analysis

A predominantly lymphocytic pattern in BAL fluid raises the probability of hypersensitivity pneumonitis, as more than 80% of patients with chronic hypersensitivity pneumonitis have more than 20% lymphocytes.(5)
However, BAL fluid lymphocyte counts may be normal, or even lower than normal, in some patients with chronic hypersensitivity pneumonitis.

Role of Antigen Detection

Identifying the causative antigen is crucial for diagnosis, preventive measures, and prognosis of hypersensitivity pneumonitis. The relationship between the exposure and the disease may be obvious in cases of occupational hypersensitivity pneumonitis, but, in domestic cases, is often not immediately clear, making identification of the underlying trigger challenging:

  1. Meticulously collect a detailed patient history of exposure in their occupational and domestic environments, as well as any regularly visited places.
  2. The second step is laboratory investigation for confirmation of the suspect antigen by identification of serum specific IgGs.
  3. The third step to confirm the causality between a suspected antigen and the disease is the SIC (Specific Inhalation Challenge) test, which can be performed by natural exposure to the environment where the antigen is thought to be present, by direct challenge with inhalation of the alleged hypersensitivity pneumonitis inducer obtained from the patient’s environment, or by commercially available extracts. However, this test is neither standardized nor validated, and requires experienced personnel and laboratories. It should be performed only when histopathological diagnosis is not possible or available.

Role of Histopathology

Before considering a lung biopsy, careful physical examination, pulmonary function tests, interpretation of HRCT images by a chest radiologist, and BAL cellular analysis (if available) should be less than definitive for a confident diagnosis. A biopsy sample with histopathological features consistent with hypersensitivity pneumonitis can clinch the diagnosis in cases where there is some measure of doubt.
Considering all the above points, a diagnostic algorithm was put forward for chronic hypersensitivity pneumonitis by Vasakova et al in 2017 (Figure 3).

OFFENDING ANTIGENS

There are over 200 antigens known to be involved in various forms of hypersensitivity pneumonitis. The antigens can be proteins or glycoproteins from animals, plants, bacteria, protozoa, and viral origins or small molecular weight chemicals and drugs.
There are many named diseases caused by hypersensitivity pneumonitis, most named after the occupation at risk or the source of the antigen. These include farmer’s lung, pigeon breeder’s or pigeon fancier’s disease, baggassosis, mushroom worker’s lung, woodworker’s lung, summer-type pneumonitis, humidifier lung, furrier’s lung and many, many more.

TESTS AVAILABLE AT SUBURBAN DIAGNOSTICS

Suburban Diagnostics offers a hypersensitivity pneumonitis panel which detects 6 very common antigens implicated in hypersensitivity pneumonitis. The panel tests for the presence of serum specific IgG for the following antigens, by ImmunoCAP:

  1. Alternaria alternata
  2. Cladosporium herbarum
  3. Penicillium chrysogenum (P.notatum)
  4. Pigeon serum proteins, feathers & droppings
  5. Aspergillus fumigatus
  6. Mucor racemosus

Apart from this, routine analysis and cytology of BAL fluid and histopathological analysis of all types of lung biopsies can be performed at Suburban Diagnostics.

Diagnostic criteria/algorithm for hypersensitivity pneumonitis (HP)
Figure 3 – Diagnostic criteria/algorithm for hypersensitivity pneumonitis (HP) (Adapted from Am J Respir Crit Care Med. 2017 Sep 15;196(6):680–9)

References:

  1. Selman M, Pardo A, King TE. Hypersensitivity Pneumonitis: Insights in Diagnosis and Pathobiology. Am J Respir Crit Care Med. 2012 Aug 15;186(4):314–24.
  2. Riario Sforza GG, Marinou A. Hypersensitivity pneumonitis: a complex lung disease. Clin Mol Allergy. 2017 Dec;15(1):6.
  3. Spagnolo P, Rossi G, Cavazza A, Bonifazi M, Paladini I, Bonella F, et al. Hypersensitivity Pneumonitis: A Comprehensive Review. J Investig Allergol Clin Immunol. 2015;25(4):237–50; quiz follow 250.
  4. Kurup VP, Zacharisen MC, Fink JN. Hypersensitivity pneumonitis. Indian J Chest Dis Allied Sci. 2006 Jun;48(2):115–28.
  5. Vasakova M, Morell F, Walsh S, Leslie K, Raghu G. Hypersensitivity Pneumonitis: Perspectives in Diagnosis and Management. Am J Respir Crit Care Med. 2017 Sep 15;196(6):680–9.
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