Hypersensitivity pneumonitis (HP) classified as an interstitial lung disease is characterized by a complex immunological reaction of the lung parenchyma in response to repetitive inhalation of a sensitized allergen. The name HP defines the disease more appropriately than the previous term extrinsic allergic alveolitis, as the inflammation involves not only the alveoli but the bronchioles as well. The severity of the disease and clinical presentation varies depending on the inhaled antigen and quantity. The first detailed clinical descriptions of the disease came out in 1932 describing symptoms in workers exposed to a fungus on Maple bark at a Michigan company and agricultural workers exposed to moldy hay in England. Since these initial observations, numerous exposures have been described from all over the world that causes HP.
Traditionally it has been classified into acute, sub-acute and chronic forms based on the time course and the presentation. But more recently classifying it to Acute or Inflammatory HP (symptoms less than six months) and Chronic or fibrotic HP has been proposed based on clinical, radiologic and pathologic characteristics.
Numerous organic antigens can induce this immune response and cause a specific form of the disease in susceptible individuals. More than 300 antigens that span over a wide range of occupations have been described to cause HP. These antigens can be broadly classified into bacteria, fungi, animal proteins, plant proteins, low molecular weight chemicals, and metals. These exposures typically occur in specific occupations or hobbies but could also occur in the home and immediate environment. Interestingly only a small proportion of the people who are exposed to these antigens develop HP, which implies a complex interplay between host genetic factors and environmental agents. The genetic susceptibility is likely determined by polymorphisms of the major histocompatibility complex (MHC) Class II molecules. Cigarette smoking imparts decreased risk of developing clinically significant HP. However, smokers who develop HP have been shown to have a more severe course and higher mortality. The most commonly reported occupational exposures that can cause HP and their specific names are:
The incidence and prevalence are variable largely due to lack of internationally accepted diagnostic criteria, seasonal and geographical variability in antigen exposures and other host factors. Mild HP may also be misdiagnosed due to non-specific findings. The incidence of HP among Swedish farmers as reported in the Sweden population registry is approximately 20 per 100,000 person-years. Other European population registries report HP incidence at 1.5% to 12% of all interstitial lung diseases (ILD). Data from surveys of high-risk occupations report the prevalence of 1.3% to 12% and 8% to 10% for exposed farmers and pigeon-breeders respectively. Globally, bird-related HP is the most commonly reported form of HP. HP is reported more often in middle-aged men. HP occurs more frequently in certain occupational groups and hobbies due to the specific exposures.
Lung parenchymal inflammation in HP is a combination of type-III and type-IV hypersensitivity reactions. The offending antigen or chemical agent initially triggers an immune complex-mediated (type III) hypersensitivity reaction after initial sensitization. Hence, in acute HP, high titers of specific IgG antibodies (precipitins) can be detected in serum. Continued exposure to the antigen shifts it to a delayed (type IV) hypersensitivity reaction. This activates CD8 cytotoxic T cells releasing chemokines that result in macrophage activation and granuloma formation. As the disease progresses to subacute and chronic HP, an exaggerated T-cell-mediated immune response is noted. This results in increased T-cell migration and proliferation. The mechanism behind progression to fibrosis is not clearly understood. There is thought to be a shift to the increased TH2 response that promotes collagen deposition and fibrosis. The individual differences in susceptibility to HP suggests a genetic link likely through major histocompatibility complex (MHC) class II namely HLA-DR and DQ. Cigarette smoking seems to protect from developing clinically significant HP likely due to nicotine inhibiting macrophage activation and lymphocyte proliferation.
Acute and Sub-acute HP
The inflammation is centered around the airway due to the inhalational nature of the injury. The classic finding is bronchiolocentric, poorly-formed, non-caseating granulomas, and inflammatory cell infiltrates, typically lymphocytes. Findings of organizing pneumonia which are small airways filled with fibroblastic plugs (Masson bodies) may be seen.
The main differential diagnosis to consider is sarcoidosis where well-formed non-caseating granulomas are seen along the bronchovascular bundle, without evidence of inflammatory cell infiltrate. Findings of organizing pneumonia are not seen with sarcoidosis. Poorly formed granulomas, giant cells, and lymphocytic infiltration can be seen with lymphoid hyperplasia such as in lymphocytic interstitial pneumonia (LIP). Infections can also cause granuloma formation with cellular infiltration. Hence special stains for organisms are utilized.
As the disease progresses untreated (chronic HP), fibrosis occurs. Sparse poorly formed non-caseating granulomas and chronic inflammation are seen around the bronchioles with variable amounts of fibrosis. Pathologically this can appear similar to usual interstitial pneumonia (UIP) or fibrotic non-specific interstitial pneumonia (NSIP). Poorly formed granulomas and fibrosis centered around the small airways support HP over the alternate diagnosis. In advanced fibrosis, histologic changes become indistinguishable from UIP and may require clinical and radiographic correlation.
Acute HP typically presents with fever, malaise, cough, and dyspnea within a few hours of heavy exposure to a specific antigen. Symptoms usually resolve within 1 to 2 days of avoiding exposure. Prolonged exposure to the sensitized antigen results in subacute and chronic forms. A cough is a predominant symptom due to airway-centered nature of inflammation. Patients also report shortness of breath, malaise, weight loss. A thorough history including hobbies and occupational should be obtained to identify specific exposures in the patient’s environment that could be causing disease. Reportedly in up to 60% of cases, a trigger is not identified. The physical examination is often normal, but inspiratory crackles or inspiratory squeaks that reflect small airway inflammation can be heard on pulmonary examination. In chronic HP, crackles may be more prominent, and clubbing may be seen.
Some patients with chronic HP may develop acute worsening of their respiratory condition which can appear similar to acute exacerbations of IPF.
Diagnosis of HP can be challenging and requires a combination of detailed history, HRCT findings, laboratory, and pathological examination. There is no single diagnostic test. Evaluation by an interprofessional team of pulmonologist, radiologist, pathologist, and social worker is recommended for making a prompt definitive diagnosis.
Blood counts and metabolic panels are usually normal. Inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are typically elevated.
Serum precipitins (IgG antibodies) against potential organic antigens- molds, fungi, grain dust can be assayed in patient’s serum. Identification of the offending agent is critical in diagnosing HP and advocating preventive measures. Unfortunately a positive IgG antibody only indicates exposure and does not confirm diagnosis. Moreover these tests have very high false-negative rates and the specific antigen may not be represented in the testing panel. Hence, a positive test does not confirm diagnosis and a negative test does not rule out a diagnosis of HP.
When the suspected inciting factor is not commercially available, a sampling of settled dust at home or workplace environment may be required. Dust extracts from these samples can be used in specific IgG-inhibition tests with the patient’s serum.
If the patient develops clinical symptoms on exposure to the suspected antigen associated with a drop in spirometry values and radiographic changes, this would help confirm the diagnosis. This can be only performed at specialized centers and often standardized antigen preparations are not available.
Pulmonary Function Testing (PFT)
Spirometry often reveal a restrictive pattern along with a significantly reduced FEF due to small airways involvement. Lung volume measurements reveal a restrictive ventilatory pattern. Marked impairment in diffusion capacity (DLCO) is also noted. An obstructive or a mixed pattern of PFTs has also been described. PFTs aid in defining disease severity, monitor progression of disease and predict prognosis.
Plain Chest Radiograph
Patients often have normal chest radiographs. Patchy or diffuse airspace opacities, rarely consolidations are seen typically sparing apices and bases. In the chronic stage when fibrosis develops, an upper zone predominant reticular interstitial pattern with volume loss may be seen.
High Resolution CT Scan (HRCT)
The classic HRCT finding is upper and middle lobe predominant patchy ground-glass or nodular opacities in a bronchovascular distribution, with evidence of air trapping. On expiratory images, mosaic attenuation indicative of air trapping is better appreciated. The heterogeneous appearance on CT scan of subacute HP with areas of ground glass or nodular opacities (high attenuation), air trapping (low attenuation) and normal parenchyma is referred to as the "head cheese sign." This appearance is compared to the cut surface of head cheese which is made from pieces of meat made from various parts of different animals. Accuracy of diagnosis based on HRCT can be as high as 92%.
As the disease progresses increased reticulation indicative of fibrosis and traction bronchiectasis are seen. Thin-walled cystic changes, parenchymal distortion and mediastinal lymphadenopathy can also be seen in chronic HP. The presence of reticulation and honeycombing can make it difficult to make a distinction from usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP). The relative sparing of bases and presence of air trapping favors HP over UIP or NSIP. Presence of honeycombing and traction bronchiectasis predicts higher mortality in chronic HP.
Flexible bronchoscopy with bronchoalveolar lavage (BAL) in HP typically reveals lymphocytosis (often greater than 50%) and low CD4:CD8 ratio. This is not diagnostic of HP but only provides supportive evidence. Sarcoidosis has normal cell counts, with neutrophilia and high CD4:CD8 ratio. Lymphocytosis may not be seen in chronic HP and but the presence of lymphocytosis helps to differentiate it from UIP.
If a definitive diagnosis cannot be reached after a comprehensive evaluation, then lung biopsy should be pursued. Transbronchial lung biopsy has a limited diagnostic role in HP as it does not yield enough tissue. In a small minority of patients with classic clinical and radiographic presentation, transbronchial lung biopsy should suffice to make the diagnosis. Surgical lung biopsies are often required in subacute and chronic HP to make a definitive diagnosis. Transbronchial cryobiopsy is a new tool utilized to obtain larger tissue samples.
The cornerstone of treatment is prompt diagnosis and eradication of the causative agent from the patient’s environment. The condition is typically reversible if diagnosed early in the course of the disease and complete antigen avoidance can be achieved. This is often very difficult due to social, economic or occupational reasons. Using respiratory protective equipment has been associated with a reduction of specific IgG antibodies but has not been shown to be an effective strategy in preventing chronic HP. Complete antigen avoidance should be advised by whatever means necessary to prevent progression of disease and fibrosis.
There have been no controlled trials for the treatment of HP, but glucocorticoids have been shown to hasten initial recovery particularly in patients with severe symptoms, abnormal lung function tests or extensive radiographic involvement. Glucocorticoid treatment has not shown any benefit for long-term outcomes. Inhaled steroids have not shown to be effective as a replacement for systemic glucocorticoids. Patients are usually started on 0.5 to 1 mg/kg per day (up to a maximum of 60 mg per day). Usually treated with a high dose for 1 to 2 weeks and then tapered over 2 to 4 weeks with the goal of using the lowest dose and shortest duration of glucocorticoids.
Patients with chronic HP and in progressive cases, adjunctive agents are used. Azathioprine and mycophenolate mofetil have been used as steroid-sparing agents and also in resistant cases. They have been shown to improve pulmonary function testing when used in patients with chronic HP with persistent symptoms despite antigen avoidance and glucocorticoid therapy. Rituximab and leflunomide have also been reported in small studies to be of benefit. In cases of chronic HP with progressive fibrosis, antifibrotic agents have been suggested.
Lung transplantation has been shown to have excellent medium-term survival in patients with advanced lung disease due to HP when compared to patients with UIP/IPF. There is some evidence that patients with chronic HP are less susceptible to bronchiolitis obliterans syndrome (BOS).
Acute and Subacute HP
The primary differential for acute HP is infections of the respiratory tract. Conditions such as metal fume fever and organic dust toxic syndrome can also present similarly. Detailed history, physical examination and radiologic examination should help differentiate the conditions.
Sarcoidosis can have a similar clinical and radiologic picture to sub-acute HP. Exposure history, the presence of serum precipitins, lymphocytosis on BAL support a diagnosis of HP. Pathological examination in sarcoidosis typically reveals well-formed non-caseating granulomas along the bronchovascular bundle, without inflammatory cell infiltrate.
Organizing pneumonia and smoking-related ILDs should be considered in the differential, but history, HRCT findings, and pathological examination will help in differentiating the conditions.
Chronic HP can appear similar to UIP/IPF clinically, radiographically and pathologically. A detailed history may provide some insight into exposure history supporting HP. BAL lymphocytosis supports the diagnosis of HP. Radiographically the reticulation and honeycombing in chronic HP tend to be predominantly upper and mid zone as opposed to UIP. Additionally, patchy ground-glass opacities and areas of air trapping support chronic HP. Fibrosis predominantly involving the upper zone, peri-bronchiolar fibrosis, the presence of granulomas, and lymphocytic interstitial inflammation are pathological features that help differentiate chronic HP from UIP. UIP will have marked sub-pleural fibrosis and microscopic honeycombing with distortion of pulmonary parenchyma.
Fibrotic NSIP can have similar radiographic and pathologic appearance. Pathologically presence of granulomas and giant cells provide supportive evidence for chronic HP. HP/NSIP overlap syndromes have also been reported.
Early diagnosis and complete avoidance of inciting antigen results in total recovery of lung function in the majority of patients. Presence of pulmonary fibrosis portends a poor prognosis with a median survival of 3 to 5 years. Other factors such as older age, greater exposure, delayed diagnosis, cigarette smoking, the absence of lymphocytosis on BAL fluid, recurrent acute exacerbations, and pulmonary arterial hypertension have been associated with worse outcomes.
If not promptly diagnosed and treated as detailed above, HP can progress to pulmonary fibrosis and progressive respiratory failure. Presence of fibrosis and honeycombing have been associated with higher mortality.
Primary prevention at the workplace should aim to reduce exposure of agricultural workers to known organic antigens and provide safety education. This may involve better engineering techniques, maintenance, use of personal protective equipment, and health and safety education. Detection of a case of HP at the workplace should trigger a detailed review of the workplace and a survey of the other workers to diagnose additional cases early.
HP is characterized by bronchiolocentric lung inflammation in response to a repetitive insult by sensitized inhaled antigen. Diagnosis requires a high index of suspicion and clinical course is highly variable. Prompt diagnosis and antigen avoidance is key to management. Corticosteroids hasten recovery. Progression to fibrosis portends a poor prognosis.
The diagnosis and management of hypersensitivity pneumonitis is made by an interprofessional team. Once the diagnosis is made, the cornerstone of treatment is the eradication of the causative agent from the patient’s environment. The condition is typically reversible if diagnosed early in the course of the disease and complete antigen avoidance can be achieved. This is often very difficult due to social, economic or occupational reasons. Complete antigen avoidance should be advised by whatever means necessary to prevent progression of disease and fibrosis. Even though corticosteroids are widely prescribed, there are no clinical trials that have shown a reversal of the disease in severe cases. Plus, long term steroids also have serious adverse effects. Many other potent disease-modifying agents have been used but good data to support their use are also lacking. Lung transplantation has been shown to have excellent medium-term survival in patients with advanced lung disease due to HP when compared to patients with UIP/IPF. There is some evidence that patients with chronic HP are less susceptible to bronchiolitis obliterans syndrome (BOS). For patients with lung fibrosis, the life span is significantly reduced. (Level V)
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