Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis

INTRODUCTION — Hypersensitivity pneumonitis (HP), also called extrinsic allergic alveolitis, is a complex syndrome of varying intensity, clinical presentation, and natural history, rather than a single, uniform disease [1-8]. Numerous inciting agents have been described including, but not limited to, agricultural dusts, bioaerosols, microorganisms (fungal, bacterial, or protozoal), and certain reactive chemical species.

The clinical features and diagnostic evaluation of patients with suspected HP will be reviewed here. The epidemiology, causes, immunopathogenesis, treatment, and prognosis of HP are discussed separately. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Epidemiology, causes, and pathogenesis" and "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Treatment, prognosis, and prevention".)

CATEGORIZATION — For many years, the clinical presentations of HP have been categorized as acute, subacute, or chronic depending upon the frequency, duration, and intensity of exposure and upon the duration of illness [6]. Several other classification schemes have been proposed (table 1) [3,6,9-11], but none are completely satisfactory because of the great variability and overlap in the presentation and course of HP [6].

Recognizing the limitations of the previous classification system, the 2020 guidelines from the American Thoracic Society, Japanese Respiratory Society, and Asociación Latinoamericana de Tórax (ATS/JRS/ALAT) categorize HP into nonfibrotic (purely inflammatory) and fibrotic (mixed inflammatory plus fibrotic or purely fibrotic) phenotypes based on the predominant presence or absence of fibrosis on imaging or histopathologic examination [8]. The guidelines committee favored the nonfibrotic and fibrotic subtypes as being more objective and more likely to correlate with clinical course and other outcomes, than prior classifications [11,12].

Additionally, the traditional categories of acute, subacute, and chronic HP suggest a serial evolution that is not necessarily evident. For example, some patients present with fibrotic disease without prior symptoms or imaging of acute or subacute disease. Additionally, precise differentiation between the acute, subacute, and chronic is not always possible.

CLINICAL FEATURES — The 2020 guidelines from the American Thoracic Society, Japanese Respiratory Society, and Asociación Latinoamericana de Tórax (ATS/JRS/ALAT) categorize HP into fibrotic and nonfibrotic phenotypes based on the predominant presence or absence of fibrosis on imaging or histopathologic examination [8]. The guidelines do not separate the description of symptoms and signs based on these categories because of the overlap in symptom patterns between the traditionally described acute, subacute, and chronic presentations and also between nonfibrotic and fibrotic presentations.

Common symptoms of HP whether nonfibrotic or fibrotic include dyspnea and cough [3,8,13-17]. Chest tightness and constitutional symptoms, such as fever, chills, weight loss, and malaise, are less common [14,18]. Symptoms may present acutely (days to weeks), insidiously (months to years), or as recurrent episodes [8,14,19]. While an acute presentation with or without constitutional symptoms seems more consistent with nonfibrotic HP and the insidious presentation seems more consistent with fibrotic HP, the pattern of symptom onset has not been rigorously evaluated with respect to fibrosis status. (See 'Categorization' above.)

Physical examination in HP may reveal tachypnea, focal or diffuse crackles, midinspiratory squeaks (chirping or squawks) [8,16]. Wheezing is rarely present. Digital clubbing is generally associated with more advanced disease [20,21].

The chest radiograph may be normal or demonstrate micronodular or reticular opacities (image 1) [17,22,23]. The distribution of opacities varies. In a series of patients with bird fanciers’ lung, the upper lung zone was frequently affected, while in a series of patients with summer-type hypersensitivity pneumonitis, lower lung zone opacities predominated.

INITIAL EVALUATION — Hypersensitivity pneumonitis should be suspected in patients with known exposure to a causative agent of HP and in patients with clinical and imaging evidence of interstitial lung disease without specific features to suggest an alternate diagnosis (eg, sarcoid, rheumatic disease, drug exposure, cystic lung disease).

The main goals of the evaluation are to identify potential exposures, determine the severity of respiratory impairment, and identify characteristic imaging and bronchoalveolar lavage features. When the diagnosis remains uncertain, a multidisciplinary evaluation can help guide the decision to pursue tissue sampling to confirm the diagnosis [24,25].

Detailed exposure history — The first step in the evaluation of a patient with suspected HP is a detailed history of potential occupational, avocational, or domestic exposures (table 2). Sometimes it helps to use a standardized questionnaire, although available questionnaires have not been validated [8,11,26,27]. The antigen and source of exposure are not identified in up to 60 percent of patients with HP, despite a thorough history [8,11,15,28-30]. A discussion of potential causes of HP is provided separately. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Epidemiology, causes, and pathogenesis", section on 'Etiologic agents'.)

Laboratory tests — Laboratory testing for specific sensitivity to culprit antigens is limited by the high rate of positive tests among individuals who are exposed but well and a high rate of false negative serologic tests. General laboratory tests that should be obtained as part of the evaluation of diffuse parenchymal lung disease are discussed separately. (See "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Laboratory tests'.)

●Serologic assays for specific IgG antibodies – Serologic assays for specific immunoglobulin G (IgG) antibodies (eg, Ouchterlony precipitin test, enzyme-linked immunosorbent assay [ELISA], and automated detection by ImmunoCAP) are available for many potential antigens, but their diagnostic utility is controversial [11,31-35]. Sensitivity and specificity appear to vary with the particular antigen, duration and frequency of exposure, cigarette smoking, and stage of disease. We primarily view serologic tests as evidence of exposure, as positive results are seen in asymptomatic exposed individuals and negative results cannot be used to exclude HP.

As an example of the high false positive rate, 10 to 40 percent of farmers and pigeon breeders have positive serum precipitins to relevant antigens in the absence of clinical disease [19,32,36-38]. The higher incidence of positive precipitins in asymptomatic pigeon breeders is probably due to more intense and prolonged exposure to inciting antigens.

A high false negative rate is primarily attributable to commercial assays testing for only a small fraction of the potential causative antigens [31]. However, the test may be nonreactive even if the correct antigen is included in the setting of chronic/fibrotic HP with histopathology of usual interstitial pneumonia [32].

Research to develop a panel of recombinant antigens for serodiagnosis of farmer’s lung disease has identified immunoreactive proteins with high sensitivity and specificity (although not yet commercially available) [39]. This type of research may enable creation of standardized and validated panels for HP diagnosis in the future.

●Testing of environmental samples – If one's reference laboratory has the capability, it is sometimes helpful to obtain a sample of likely causative antigens from the original source and test it against the patient's serum [28,31,40,41]. A positive reaction is based upon the presence of a precipitin band against the antigen. In many cases, the main value of a positive result is to convince a patient that he or she is indeed sensitive to something in the environment, particularly when it implies that a valued and loved pet may require removal.

●Lymphocyte proliferation test – In vitro lymphocyte proliferation testing of a patient’s serum or bronchoalveolar lavage fluid to avian antigens has been described in patients with chronic bird fanciers’ HP, but is not standardized and remains a research tool in the evaluation of HP [35,42,43].

●Skin tests – Skin tests for immediate hypersensitivity to avian, animal, and fungal antigens are not helpful in the diagnosis of HP, as they test for IgE-mediated, rather than IgG-mediated hypersensitivity.

●Nonspecific tests of inflammation – Laboratory tests of inflammation, such as erythrocyte sedimentation rate, C-reactive protein, circulating immune complexes, and quantitative immunoglobulins, are elevated in many patients, although not of diagnostic help. Rheumatoid factor may be positive. The serum lactate dehydrogenase (LDH) may be high in acute phases of the disease and decline as clinical indices improve.

Pulmonary function tests — Pulmonary function tests (PFTs) are useful to assess the pattern and severity of respiratory impairment, but no pattern is diagnostic. PFTs are not able to differentiate nonfibrotic from fibrotic HP. Patients with nonfibrotic disease are more likely to demonstrate improvement after cessation of exposure [6,19].

Patients with HP usually have a restrictive ventilatory defect and may have reduced pulse oxygen saturation (SpO₂) during symptomatic episodes. However, an obstructive pattern or mixed obstructive and restrictive ventilatory abnormalities can be seen [44].

The diffusing capacity of carbon monoxide (DLCO) is invariably reduced, and resting or exertional reduction in SpO₂ is typical.

High resolution computed tomography — High resolution computed tomography (HRCT) with thin-section (≤1.5 mm) continuous or overlapping images is increasingly used in the diagnosis of HP [14,29,45]. HRCT is preferred to conventional chest radiography as HRCT is more sensitive for detecting abnormalities and offers greater definition of radiographic patterns and information on the presence or absence of features suggesting fibrosis. Two series of images should be obtained with the patient supine: one at deep inspiration and another at one second after prolonged exhalation [8]. Prone images are usually not necessary. Evidence of air trapping is best elicited by comparing HRCT images on inspiration and expiration.  

The HRCT pattern of HP varies depending on the subtype of disease, nonfibrotic or fibrotic (table 3) [8,11,12,46-49].

●Nonfibrotic HP – The typical findings of nonfibrotic HP is ground-glass opacification (image 2) [50]; however, the HRCT may be normal due to the fleeting nature of the radiographic opacities [14,19]. Other HRCT findings of nonfibrotic HP include small centrilobular nodules (<5 mm), ground-glass attenuation, and lobular areas of decreased attenuation and vascularity (image 3) [50]. The centrilobular nodules can be numerous or few and can be the predominant or only finding. Nodules >10 mm in diameter are unusual and usually represent areas of organizing pneumonia [50]. Air trapping (mosaic attenuation) can be demonstrated by comparison of inspiratory and expiratory images.

Cysts, usually few in number, range in diameter from 3 to 25 mm and are associated with areas of ground glass opacification.

●Fibrotic HP – Fibrotic HP has a variable appearance and the American Thoracic Society, Japanese Respiratory Society, and Asociación Latinoamericana de Tórax (ATS/JRS/ALAT) guidelines suggest characterizing findings as typical, compatible, or indeterminate for fibrotic HP [8]. The “typical” feature of fibrotic HP is the presence of irregular linear opacities/coarse reticulation with lung distortion in a random or mid-lung zone predominant location; traction bronchiectasis and honeycombing may be present but do not predominate (image 4) [8,11,12,19]. Evidence of small airways disease includes patchy ground-glass attenuation, centrilobular nodules, and mosaic attenuation (due to air trapping) [12,45,48]. The “three density pattern” (also known as “headcheese sign”) refers to a mixture of ground glass opacities, mosaic attenuation, and normal lung attenuation in a lobular distribution that is highly specific for chronic/fibrotic HP. Honeycombing, when present (16 to 69 percent), is less frequently basilar predominant compared with usual interstitial pneumonia in idiopathic pulmonary fibrosis (IPF) [11,51,52].

Other patterns compatible with fibrotic HP include a usual interstitial pneumonia (UIP) pattern, extensive ground glass opacities, and “typical” opacities in a variant distribution such as peribronchovascular or subpleural [8]. The variant pattern of fibrosis should be accompanied by abnormalities indicating small airways disease (ie, ill-defined centrilobular nodules, “three-density pattern,” air trapping).

Patterns considered indeterminate for HP include patterns seen in other idiopathic interstitial pneumonias, such as UIP pattern, probable UIP, indeterminate UIP, fibrotic nonspecific interstitial pneumonia, and organizing pneumonia, and truly indeterminate HRCT patterns [8].

Several studies in individuals with chronic/fibrotic HP suggest that emphysema (without a history of smoking or other occupational exposure) is found in up to 15 percent of persons on chest radiograph and 27 percent on HRCT [52-54]. Rarely, farmer’s lung presents as combined pulmonary fibrosis and emphysema [55-57]. The presence of emphysema is not related to smoking but appears to be related to longer duration and higher intensity exposure to organic dusts [57].

Clinical prediction models — Clinical prediction models are generally specific, but lacking in sensitivity for establishing the diagnosis of HP. Nonetheless, they provide insight into the features that are most indicative of HP.

●A panel of specific clinical parameters was evaluated in a cohort of 400 patients, of whom 116 were ultimately diagnosed with HP and subsequently validated using a second cohort of 261 patients, of whom 83 were eventually diagnosed with HP [14]. Logistic regression analysis identified six significant variables associated with HP: exposure to a known offending antigen, recurrent episodes of symptoms, symptoms occurring within 4 to 8 hours after exposure, weight loss, crackles on chest exam, and the presence of serum precipitins.

●Two multidimensional diagnostic models were shown to support the identification of patients with chronic HP with a high degree of specificity [58]. Model 1 included the following predictor variables: age, a history of down feather and/or bird exposure, the presence of diffuse craniocaudal ground-glass opacity on HRCT, and the presence of mosaic perfusion on HRCT. An "HP score" point value ≥63 (range 0 to 100) showed a specificity of 91 percent and sensitivity of 48 percent for the diagnosis of chronic HP. Model 2 included: age, history of down feather and/or bird exposure, and a moderate to high confidence in the radiographic diagnosis of HP. Using model 2, HP scores ≥57 demonstrated a specificity of 91 percent and sensitivity of 50 percent for the diagnosis of chronic HP.

●An international modified Delphi survey of experts identified 18 items that met the a priori definition of consensus as important for the diagnosis of chronic hypersensitivity pneumonitis. These experts gave the highest level of importance to the identification of a causative antigen, time relation between exposure and disease, mosaic attenuation on chest imaging, and poorly formed non-necrotizing granulomas on pathology [59].

Trial of antigen avoidance — Antigen avoidance, such as removal of feather bedding or birds, avoiding hot tubs, and work-place mitigation, is a form of environmental “dechallenge.” A trial of antigen avoidance that leads to resolution of symptoms and radiographic opacities lends supportive evidence to a diagnosis of HP, but is not standardized [60]. Patients with fibrotic disease may have only partial or no improvement following removal from exposure [60].

Specific antigen avoidance can also help determine whether a specific antigen is causative. In a case series, clinical improvement after antigen avoidance for two weeks had a sensitivity of 51 percent and a specificity of 81 percent among patients with chronic HP [60].

SUBSEQUENT EVALUATION — When the initial evaluation fails to yield a confident diagnosis of HP, additional studies may include bronchoalveolar lavage, lung biopsy, or inhalation challenge, depending on the specific features of each patient (table 4). (See 'Diagnosis' below.)

Bronchoalveolar lavage — Bronchoalveolar lavage (BAL) is the most sensitive tool to detect an alveolitis in patients suspected of having HP, but is not always necessary, particularly in patients with a convincing exposure history and typical high resolution computed tomography (HRCT) findings. (See 'Diagnosis based on clinical and HRCT features' below.).

BAL findings are nonspecific and can be seen in asymptomatic individuals with exposure to antigens associated with HP [61]. BAL fluid is obtained from areas with radiographic disease and sent for cell counts, microbiologic studies (especially mycobacterial), and cytology. (See "Basic principles and technique of bronchoalveolar lavage" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)

The evolution of the alveolitis in HP remains ill-defined, but BAL findings tend to mirror the stage of disease and intensity of the exposure to the inciting antigen.

A marked BAL lymphocytosis (greater than 20 percent and often exceeding 50 percent of the white blood cells recovered) is a nonspecific, but helpful, finding when the clinical and radiographic findings suggest subacute HP [19,61]. Patients who smoke cigarettes tend to have a lower BAL lymphocyte count (>20 percent) compared with nonsmokers (>30 percent) [14]. BAL lymphocytosis can also be seen in organizing pneumonia and nonspecific interstitial pneumonia, but not usually at this high level. (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease", section on 'Lymphocytic BAL'.)

While the majority of patients with chronic HP have BAL lymphocyte counts >20 percent, some patients with chronic HP have normal or low lymphocyte numbers [11,19,62,63]. A longer duration of time since last exposure can cause a lower BAL lymphocyte count [5].

Transbronchial biopsy and cryobiopsy — The role of obtaining transbronchial biopsies during flexible bronchoscopy remains under discussion. The centrilobular distribution of HP (except in chronic fibrotic disease) can increase the yield relative to other interstitial diseases, although the small size of these biopsies may be insufficient to secure a definitive diagnosis. In contrast, video-assisted surgical biopsy yields larger samples and enables sampling from more than one lobe. Selecting among these options is done on a case-by-case basis; a multidisciplinary conference can help guide decision-making. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

●Transbronchial lung biopsy – Transbronchial lung biopsies (TBLB) can often be obtained during the same procedure as BAL, except in cases of advanced fibrotic disease when the yield is expected to be low [8]. Alternatively, a decision on performing TBLB can be made after review of BAL results, although this would require a separate procedure. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Transbronchial lung biopsy' and 'Diagnosis' below.)

To optimize the yield, multiple biopsies (five or more "good" samples of tissue) should be taken from areas of radiographic involvement. As with sarcoidosis, the biopsy of radiographically normal lung will sometimes show abnormal histology, but yield is not predictable. (See "Flexible bronchoscopy in adults: Associated diagnostic and therapeutic procedures", section on 'Transbronchial biopsy'.)

Most studies of TBLB in HP have reported yields of 11 to 40 percent [19,64-66]. In a series of 155 patients with HP, transbronchial lung biopsy was performed in 72 (47 percent) and was characteristic of HP in 29 (40 percent) [64]. In this study, TBLB increased the diagnostic yield over BAL alone. Using a threshold of BAL lymphocytosis >30 percent, the combination of BAL and transbronchial biopsy had a diagnostic yield of 53 percent compared with 27 percent for BAL alone.

A "negative" or "inadequate" transbronchial lung biopsy should not be used to rule out HP, unless a clear alternate histopathologic diagnosis can be made.

●Transbronchial cryobiopsy – Transbronchial cryobiopsy (TBCB) uses a cryoprobe to obtain a tissue sample that is larger than TBLB, but smaller than a surgical lung biopsy. The diagnostic accuracy in diffuse parenchymal lung disease approaches that of surgical lung biopsy, but data in HP are limited [67-72]. One concern is that multinucleated giant cells and granulomas are infrequent in HP and may be missed on tissue obtained by TBCB. Expertise with and availability of TBCB are limited; adverse events include bleeding and pneumothorax (approximately 4 and 27 percent, respectively) [8]. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Transbronchial cryobiopsy'.)

Surgical lung biopsy — A surgical lung biopsy is not necessary when a confident diagnosis can be made based on exposure history and HRCT features. In contrast, when the exposure history, serum specific immunoglobulin G (IgG), bronchoalveolar lavage findings, and HRCT pattern do not yield a confident diagnosis, a surgical lung biopsy is often necessary. Sometimes, presenting a patient at a multidisciplinary conference can help guide decision-making about whether to obtain TBLB prior to surgical lung biopsy (if not already obtained), proceed directly to surgical biopsy, or avoid invasive procedures due to patient frailty or unlikely benefit [8,11,12]. (see 'Transbronchial biopsy and cryobiopsy' above).

We obtain surgical lung biopsy most often when the HRCT features are more consistent with one of the other idiopathic interstitial pneumonias (eg, organizing pneumonia, nonspecific interstitial pneumonia) or when the clinical features are atypical for idiopathic pulmonary fibrosis (eg, age <60 years) in a patient with a usual interstitial pneumonia (UIP) pattern on HRCT [73]. (See "Role of lung biopsy in the diagnosis of interstitial lung disease" and "Overview of minimally invasive thoracic surgery".)

Histopathology — It is important that the pathologist be informed when HP is being considered; the findings are often subtle and must be interpreted with knowledge of the clinical setting, preferably in the context of a multidisciplinary conference [74-76]. When working with small tissue samples such as transbronchial or cryobiopsies, step sectioning of tissue specimens and examination of multiple levels is often necessary to identify key histopathologic features. (See "Interpretation of lung biopsy results in interstitial lung disease", section on 'Multidisciplinary discussion' and "Interpretation of lung biopsy results in interstitial lung disease", section on 'Hypersensitivity pneumonitis'.)

●Nonfibrotic HP – The classic triad of histopathologic findings in nonfibrotic HP, seen in approximately 70 percent of biopsies in a large series [77], includes the following features [8,12,78,79]:

•Chronic cellular bronchiolitis with a peribronchial infiltration of lymphocytes (picture 1 and picture 2). An organizing pneumonia pattern may be present with intraluminal “buds” or “whorls” of granulation tissue (Masson bodies), as are seen in cryptogenic organizing pneumonia (picture 3).

•Small, poorly-formed nonnecrotizing granulomas located near respiratory or terminal bronchioles (picture 4). These ill-defined aggregates of epithelioid macrophages may be associated with multinucleated giant cells (picture 5). Well-formed granulomas are not commonly seen, in contrast to their frequent identification in patients with sarcoidosis.

•Chronic cellular pneumonitis with a patchy mononuclear cell infiltration (predominantly lymphocytes and plasma cells) of the alveolar walls.

If granulomatous inflammation is absent, the appearance resembles cellular nonspecific pneumonia [79]. Foamy macrophages may be present in the alveoli and the interstitium, reflecting microscopic obstructive pneumonia due to small airways dysfunction [8].

●Fibrotic HP – The histopathology of fibrotic HP can include features of UIP and/or fibrotic nonspecific interstitial pneumonia (NSIP) [8]. Sometimes features such as lymphocytic infiltrates, organizing pneumonia, poorly-formed granulomas, and multinucleated giant cells (often isolated) are present in patients with chronic/fibrotic HP, although the predominant pattern is fibrosis (picture 6 and picture 7) [12,80,81]. Airway-centered fibrotic lesions (peribronchiolar metaplasia) may be present, but are nonspecific [12].

These patterns of injury can be seen in the absence of granulomas. Multinucleated giant cells with cholesterol clefts (picture 8) or Schaumann bodies (fragmented, irregular, calcified, basophilic refractile structures) support a diagnosis of chronic/fibrotic HP [42,82].

In addition, it is not uncommon to discover histopathologic findings consistent with HP at surgical lung biopsy when the diagnosis was not anticipated (usually inciting antigen was not suspected from the history) [15,30].

Inhalation challenge — Inhalation challenge using re-exposure to a suspected environment or by laboratory challenge can sometimes help in supporting a diagnosis of HP, although methods are not standardized.

●Environmental inhalation challenge – Re-exposure of the patient to the environment of the supposed agent is sometimes used to demonstrate a relationship between symptoms and a particular environment, and thus support the diagnosis of HP (figure 1) [83-87]. Two patterns of response are observed:

•Most commonly, fever, malaise, headache, crackles on chest exam, peripheral neutrophilia, and decreased forced vital capacity (FVC) occur 8 to 12 hours after exposure. Hypoxemia and radiologic abnormalities (increase in ground glass opacities or nodularity) may occur in severe reactions. Consequently, the patient should be monitored closely or have ready access to medical care for at least 24 hours (figure 1).

•Less commonly, a two stage reaction can occur in atopic individuals, with immediate, transient wheezing and a decrease in the forced expiratory volume in one second (FEV₁) but preservation of the diffusing capacity. This is followed in four to six hours by decreased FEV₁ and FVC, fever, and leukocytosis (figure 2).

●Specific inhalation challenge – Specific inhalation challenge (SIC) to a preparation of a suspected antigen in a hospital setting (figure 2) is not generally performed, because it may induce progressive disease and because the test has not been standardized or validated [12]. While we do not recommend such challenges at present, some studies suggest such testing may have utility in selected cases, such as when histopathology cannot be obtained or is inconclusive [11,19,86-89].

SICs have often been performed in asymptomatic but exposed persons, such as after a cluster of cases is identified [19]. A positive test in the absence of symptoms is thought to reflect the "healthy worker" effect: certain workers under even heavy exposure will, for unclear reasons, report less frequent symptoms as compared with those who are less heavily exposed to a particular respiratory irritant [90].

DIAGNOSIS — The diagnosis of HP requires a high index of suspicion and careful attention to exposure history. Diagnostic criteria for HP have evolved as our knowledge of high resolution computed tomography (HRCT) patterns of interstitial lung diseases has improved [14,22,35,40,51,91,92]. The exact criteria for diagnosis and the optimal selection of diagnostic tests remains under discussion, but in general depends on the constellation of findings in the individual patient (table 4 and figure 3) [5,8,11,12,38].

Our diagnostic approach is based on the degree of diagnostic certainty for HP (typical, compatible, or indeterminate) after the initial evaluation. When all the features are typical for HP, the diagnosis of HP can be based upon exposure history, clinical assessment, HRCT, and, if possible, the response to antigenic avoidance, without need for lung biopsy.

For patients with features that are considered to be compatible or indeterminate for HP, most often the next step is lung biopsy using a transbronchial or video-assisted surgical approach (table 4). These additional tests can be helpful in excluding other potential diagnoses and in lending further support to the diagnosis of HP, especially in the context of multidisciplinary assessment [8]. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

Prompt diagnosis of HP is important, as complete avoidance of the culprit antigen may lead to complete or partial resolution in early stages and disease stability in later stages.

Diagnosis based on clinical and HRCT features — In a patient with evidence of exposure to a provocative antigen based on history, examination of work or home environment, and/or serum specific immunoglobulin G (IgG), a confident diagnosis of HP can be made when the HRCT scan shows "classic" features (eg, small centrilobular nodules, ground-glass attenuation, and lobular areas of decreased attenuation and vascularity) (table 4 and table 3 and figure 3).  

Bronchoalveolar lavage (BAL) lymphocytosis (>20 percent) provides additional support but is not always necessary. (See 'High resolution computed tomography' above.)

While it is preferable to know the specific culprit antigen, a presumptive diagnosis of HP can be established even without the identification of the specific agent.

Diagnosis when clinical features or HRCT are not typical — For some patients, the diagnosis of HP remains inconclusive after review of clinical features, HRCT findings, and BAL results (table 4 and figure 3).

As examples, the first two scenarios are considered “probable” HP and the third is considered “possible” HP:

●The clinical history and serologic testing, if obtained, do not reveal evidence of exposure, although the HRCT appearance suggests HP and BAL is lymphocytic.

●The clinical history suggests a likely exposure to a known HP culprit, but HRCT features suggest an idiopathic interstitial pneumonia (IIP) rather than HP (eg, features of organizing pneumonia, nonspecific interstitial pneumonia, or usual interstitial pneumonia [UIP]) and the BAL is lymphocytic.

●The history suggests exposure and the HRCT is either consistent with HP or an IIP, but the BAL is nonlymphocytic.

Such patients are considered to have probable or possible HP and require histopathologic examination of a lung biopsy specimen for a confident diagnosis. Most often, we obtain a video-assisted surgical lung biopsy; transbronchial forceps biopsy or cryobiopsy are reasonable alternatives, although the small size may impede a definitive diagnosis. (See 'Surgical lung biopsy' above and 'Transbronchial biopsy and cryobiopsy' above.)  

The diagnosis of HP is based on the presence of typical histopathologic features of HP. (See 'Histopathology' above.)

Diagnosis when HRCT shows usual interstitial pneumonia — For patients with an HRCT pattern of UIP, but a clinical suspicion of HP, a lung biopsy is often warranted as the diagnosis of HP might lead to additional therapeutic options. The clinical suspicion could be based on one or more of the following: features that are atypical for idiopathic pulmonary fibrosis (eg, age <60 years), a history of exposure to a potential antigen, a positive serologic test for specific IgG, or lymphocytic BAL fluid (table 4 and figure 3).

The histopathologic features of chronic HP can be subtle (eg, infrequent and poorly formed granulomas, isolated multinucleated giant cells) and require a careful search by the pathologist in combination with multidisciplinary review. (See "Interpretation of lung biopsy results in interstitial lung disease", section on 'Multidisciplinary discussion'.)

DIFFERENTIAL DIAGNOSIS — There are several important clinical syndromes that occur as a result of inhalation of organic agents but are not true forms of HP. Nevertheless, they are important to recognize and manage. In particular, inhalation fever, organic dust toxic syndrome, chronic bronchitis, asthma, and chronic airflow limitation have been found in patients with exposure to agricultural products, wood dust, and to a lesser extent among persons with other exposures [93-95].

Hot tub lung — Hot tub lung reflects a hypersensitivity reaction to Mycobacterium avium complex (MAC) in response to recurring exposure to MAC during hot tub use. It shares some clinical features with HP, but has some important differentiating characteristics.

Clinical features include hot tub use, cough and dyspnea with variable fever, chest tightness, and weight loss, and isolation of MAC from respiratory secretions, hot tub water, or lung biopsy. High resolution computed tomography (RCT) findings include diffuse centrilobular micro-nodules, and/or ground glass opacities [96]. A prominent histopathologic finding is the presence of multiple, non-necrotizing, well-formed granulomas in a bronchiolocentric location and associated with airspace-filling fibroblastic plugs (organizing pneumonia) and alveolar septal thickening [96,97]. The observation that many patients improve with hot tub avoidance makes a hypersensitivity reaction more likely than true infection. On the other hand, the well-formed granulomas of hot tub lung are clearly different from the poorly-formed granulomas typical of HP.

A clinical presentation similar to hot tub lung has been reported with ongoing use of a shower with MAC contamination [98].

Other processes caused by inhalation of organic agents

●Inhalation fever – Inhalation fevers (eg, "Monday morning miseries," "metal fume fever," "humidifier fever") are characterized by fevers, chills, malaise, headaches, and myalgias without prominent pulmonary findings [99]. Mild dyspnea, cough, and chest tightness may occur. The onset usually occurs 4 to 12 hours after exposure, and attack rates can be very high. There are no long-term sequelae.

●Organic dust toxic syndrome – Organic dust toxic syndrome (ODTS or pulmonary mycotoxicosis) results from the deleterious actions of mycotoxins or endotoxin [100-104]. The toxins enter the body after exposure to bioaerosols contaminated with toxin-producing fungi. The syndrome has been associated with exposure to grains, moldy hay, and textile materials contaminated with Fusarium, an aflatoxin-producing fungus [100].

Fever, chills, dyspnea, and myalgias occur four to six hours after exposure (often a first exposure) to contaminated dust [104]. Leukocytosis, diffuse opacities on chest radiograph, restrictive ventilatory defects, and reduced diffusing capacity of carbon monoxide (DLCO) are common laboratory abnormalities. Obliterative bronchiolitis without granulomas is usually present on lung biopsy; desquamative interstitial pneumonitis and diffuse alveolar damage may also be seen. These cases are thought not to represent true cases of HP because no prior sensitization is required and there is a lack of serologic response to common fungal antigens.

●Fire-eater's lung – A rare but well-described entity, fire-eater's lung, is caused by aspiration of flammable petrochemical derivatives used during "fire-eating" demonstrations [105,106]. Typically, a viscous organic solvent (kerdan) is accidentally aspirated, with immediate symptoms including choking, coughing, and respiratory distress. Pleuritic pain and fever are common, but hemoptysis is unusual. (See "Acute hydrocarbon exposure: Clinical toxicity, evaluation, and diagnosis".)

Chest radiographic findings include dense, dependent alveolar opacities with prominent cystic changes on computed tomographic scans. Bronchoalveolar lavage may reveal a predominance of macrophages with numerous lipoid inclusions [107]. Treatment is supportive, and respiratory symptoms generally resolve within 72 hours. Limited six month follow-up suggests that most patients recover completely [105,107].

Chronic bronchitis and asthma — Airway diseases such as chronic bronchitis and asthma are the most common cause of respiratory symptoms among agricultural workers and the most common cause of severe lung disease [108,109]. The prevalence of chronic bronchitis in farm workers approaches 10 percent (a large portion of whom are nonsmokers) versus a prevalence of HP of 1 to 2 percent. Chronic bronchitis is more common in men and increases in frequency with age and with altitude.

Findings in farmers and bird breeders suggest a common or related immunoallergic mechanism between the pathogenesis of HP and of chronic bronchitis in nonsmoking subjects. In such individuals who are also smokers, atopy and smoking appear to have additive effects on both the prevalence and incidence of chronic bronchitis [44,110]. Evidence for an association between chronic bronchitis and HP includes the following:

●There is a demonstrated relationship between exposure to thermophilic actinomycetes, the culprit antigen of farmer's lung, and chronic bronchitis.

●Chronic bronchitis occurs more frequently in agricultural workers with a prior history of farmer's lung, particularly HP with a subacute presentation.

●The frequency of serum precipitins is more likely to be elevated in farm workers with chronic bronchitis than in asymptomatic agricultural workers. There are no strong associations, however, between chronic bronchitis and the intensity of antigenic exposure.

●Nonsmokers without evidence of farmer's lung who suffer from chronic bronchitis have a pulmonary function pattern and a bronchoalveolar lavage (BAL) cellular profile characteristic of HP following provocation with moldy hay.

●The prevalence of chronic bronchitis correlates with the level of antibody to pigeon gamma-globulin in pigeon breeders.

●Obstructive airways disease is an important feature of the acute form of pigeon breeder's disease and consists of a hypersecretory state similar to chronic bronchitis.

Airway-centered interstitial fibrosis — Airway-centered interstitial fibrosis, also known as chronic bronchiolitis with fibrosis, represents a chronic airway-centered injury characterized by bronchiolitis and fibrosis and accompanied by prominent epithelial hyperplasia involving adjacent alveolar septa [111]. Many of the cases described were mistakenly thought to be HP on clinical grounds although specific antigens were not identified. (See "Overview of bronchiolar disorders in adults", section on 'Airway-centered interstitial fibrosis'.)

Idiopathic pulmonary fibrosis — Differentiation of chronic fibrotic HP from idiopathic pulmonary fibrosis (IPF) can be difficult, as poorly formed granulomas are often absent in chronic fibrotic HP and the fibroblast foci typical of IPF are common in HP [11,47,112,113]. (See "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis", section on 'Diagnosis'.)

HRCT features that favor IPF over HP include the lower zone predominance of abnormalities (image 2), compared with the more diffuse or upper lung zone predominance of HP, and the absence of small airways involvement (mosaic attenuation and centrilobular nodules) seen in HP. However, HRCT features allowed confident distinction of fibrotic HP from IPF and nonspecific interstitial pneumonia (NSIP) only about 50 percent of the time [51].

While many patients with chronic HP have a BAL lymphocytosis, patients with a radiographic pattern more like usual interstitial pneumonia are more likely to have a low level lymphocytosis, which overlaps that seen in IPF. Differentiating HP and IPF often requires multidisciplinary consultation. (See 'Bronchoalveolar lavage' above and "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis", section on 'Diagnosis'.)

Other causes of centrilobular nodules — Centrilobular nodules are found 5 to 10 mm from the pleural surfaces in a patchy or diffuse distribution, consistent with bronchiolar inflammation. In addition to HP, they are found in sarcoidosis, pulmonary Langerhans cell histiocytosis, and various types of bronchiolitis. (See "High resolution computed tomography of the lungs", section on 'Centrilobular nodules' and "Clinical manifestations and diagnosis of sarcoidosis" and "Pulmonary Langerhans cell histiocytosis" and "Overview of bronchiolar disorders in adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Interstitial lung disease".)

SUMMARY AND RECOMMENDATIONS

●The clinical presentations of hypersensitivity pneumonitis (HP) have traditionally been categorized as acute, subacute, or chronic. Guidelines from the American Thoracic Society, Japanese Respiratory Society, and Asociación Latinoamericana de Tórax (ATS/JRS/ALAT) categorize subtypes of HP as nonfibrotic or fibrotic, as these subtypes are easier to distinguish and correlate better with clinical outcomes. (See 'Categorization' above.)

●Common symptoms of HP, whether nonfibrotic or fibrotic, include dyspnea and cough. Chest tightness and constitutional symptoms, such as fever, chills, weight loss, and malaise, are less common. Symptoms may present acutely (days to weeks), insidiously (months to years), or as recurrent episodes. Crackles, midinspiratory squeaks, and rarely wheezes, may be heard on examination, and clubbing may be noted. (See 'Clinical features' above.)

●The initial evaluation includes a combination of exposure history, clinical assessment, directed laboratory testing (when available), radiographic and physiologic findings, and, when possible, the response to avoidance of the suspected etiologic agent (table 4). (See 'Initial evaluation' above.)

●Laboratory panels for measurement of specific serum immunoglobulin (Ig) G antibodies (eg, precipitins) have a high false negative rate, and positive results can be seen in exposed, but asymptomatic individuals. (See 'Laboratory tests' above.)

●The characteristic high resolution computed tomography (HRCT) features of nonfibrotic HP are mid-to-upper zone predominance of centrilobular ground-glass or nodular opacities with a mosaic attenuation pattern and signs of air-trapping. The “typical” feature of fibrotic HP is the presence of irregular linear opacities/coarse reticulation with lung distortion in a random or mid-lung zone predominant location; traction bronchiectasis and honeycombing may be present but do not predominate (table 3). (See 'High resolution computed tomography' above.)

●Bronchoalveolar lavage (BAL) may be helpful in supporting the diagnosis of hypersensitivity pneumonitis. A marked BAL lymphocytosis (greater than 20 percent and often exceeding 50 percent) is supportive, but not diagnostic. (See 'Bronchoalveolar lavage' above.)

●When the initial evaluation reveals exposure to an offending antigen (with or without positive serum specific immunoglobulin G [IgG]), clinical and HRCT findings compatible with HP, and improvement with antigen avoidance, a confident clinical diagnosis can be made. (See 'Diagnosis based on clinical and HRCT features' above.)

●When the initial evaluation reveals features that are not sufficiently convincing of HP, BAL lymphocytosis can help lend support to a diagnosis of HP or suggest the need for additional investigation. Most often, subsequent evaluation includes a lung biopsy or rarely inhalation challenge (table 4 and figure 3). (See 'Subsequent evaluation' above.)

●A lung biopsy can be obtained via transbronchial lung biopsy (TBLB), often at the time of a BAL, transbronchial cryobiopsy (TBCB), or video-assisted lung biopsy. A multidisciplinary discussion can help guide selection of a procedure or a decision to avoid invasive procedures due to patient frailty or unlikely benefit. (See 'Transbronchial biopsy and cryobiopsy' above and 'Surgical lung biopsy' above.)

●The histopathologic triad of HP includes: poorly formed granulomata or multinucleated giant cells located near respiratory or terminal bronchioles, chronic cellular bronchiolitis, and chronic cellular pneumonitis with patchy lymphoplasmacytic infiltration. Some patients have only one or two features of the triad. In chronic/fibrotic HP, the lung pathology may more closely resemble usual interstitial pneumonitis (UIP), or fibrotic non-specific interstitial pneumonia, but with occasional granulomas or multinucleated giant cells that suggest chronic/fibrotic HP rather than IPF or other fibrotic disorders. (See 'Histopathology' above.)

●Several diseases should be considered in the differential diagnosis of HP, including hot tub lung, inhalation "metal fume" fever, organic dust toxic syndrome, chronic bronchitis, asthma, airway-centered interstitial fibrosis, and other causes of centrilobular nodules on HRCT. (See 'Differential diagnosis' above.)