KEY POINTS
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Hypersensitivity pneumonitis is a type of interstitial lung disease that requires early diagnosis and treatment because it can lead to progressive pulmonary fibrosis.
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Occupational history is essential in the evaluation of patients with respiratory symptoms.
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Causes of hypersensitivity pneumonitis include infectious agents; enzymes; proteins from animals, insects and plants; low molecular weight chemicals and metals.
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Patients with respiratory symptoms who have had exposure to isocyanates should avoid exposure and be evaluated for asthma and hypersensitivity pneumonitis.
A 47-year-old woman was admitted to the hospital with a 3-month history of dry cough, wheezing, dyspnea, and intermittent fever. She was admitted briefly 2 months ago for treatment of a suspected lower respiratory tract infection or bronchitis; she was prescribed inhalers (salbutamol, ipratropium) and antibiotics (initially ceftriaxone and azithromycin and then amoxicillin-clavulanic acid).
The patient had smoked 7 cigarettes per day for 12 years, but had stopped smoking 3 months earlier. She took no regular medications and her medical history was notable only for obstructive sleep apnea, which was treated with continuous positive airway pressure. She has no asthma, no pets, and no exposure to hot tubs, birds, or mold at home. She had recently started working for a horticultural company, making plant plug kits in which soil, glues, oil and water were combined to create stable forms for seedlings.
The patient’s chest radiograph was normal at presentation and unchanged from her previous admission 2 months ago. She is directed to the respirology service. On evaluation, her respiratory rate is 22 breaths/min, oxygen saturation is 96% on room air, temperature is 35.9°C, heart rate is 104 beats/min, and blood pressure is 129/86 mm Hg. There were bilateral rales and normal heart sounds. On examination, she had no signs of toes, leg swelling, rashes, or features suggestive of a connective tissue disorder. The emergency room physician ordered a computed tomography (CT) scan of the chest with contrast (pulmonary embolism protocol) to rule out pulmonary embolism.
Figure 1 is a representative chest CT image from the time of hospital admission showing diffuse centrilobular ground-glass nodules in both lungs without any zonal predominance. There was no pulmonary embolism. The patient had significant leukocytosis with neutrophilia (leukocytes 15.6 [normal 4.0–11.0] × 109/L, neutrophils 12.0 [normal 2.0–7.5] × 109/L), normal eosinophil count (0.2 [normal 0.0–0.5] × 109/L) и повишен С-реактивен протеин (49[нормално<8mg/L)ТъйкатоимашеподозрениезаинтерстициалнабелодробнаболестниватанаревматоиденфакторантинуклеарноантитялоицитоплазменииперинуклеарниантинеутрофилницитоплазмениантителабяхаподредениивсичкибяхаотрицателниНиватанамозъчниянатриуретиченпептидитропонинпредписаниотлекаротспешнотоотделениебяхавнормалнигранициипридветепосещениявболницатаСпирометриятапоказвапропорционалнонамаляваненафорсиранияекспираторенобемза1секунда(FEV1)ифорсираниявиталенкапацитет(FVC)безданнизаобструкцияНейниятFVCбеше213L(59%прогнозиран)нейниятFEV1беше154L(53%прогнозиран)инейнотосъотношениеFEV1:FVCбеше723%[normal<8mg/L)BecauseinterstitiallungdiseasewassuspectedrheumatoidfactorantinuclearantibodyandcytoplasmicandperinuclearantineutrophilcytoplasmicantibodylevelswereorderedandwereallnegativeBrainnatriureticpeptideandtroponinlevelsorderedbyanemergencydepartmentphysicianwerewithinnormallimitsonbothvisitstohospitalSpirometryshowedproportionatereductioninforceexpiratoryvolumeat1second(FEV1)andforcedvitalcapacity(FVC)withnoevidenceofobstructionHerFVCwas213L(59%predicted)herFEV1was154L(53%predicted)andherFEV1:FVCratiowas723%[нормално<8mg/L)ТъйкатоимашеподозрениезаинтерстициалнабелодробнаболестниватанаревматоиденфакторантинуклеарноантитялоицитоплазменииперинуклеарниантинеутрофилницитоплазмениантителабяхаподредениивсичкибяхаотрицателниНиватанамозъчниянатриуретиченпептидитропонинпредписаниотлекаротспешнотоотделениебяхавнормалнигранициипридветепосещениявболницатаСпирометриятапоказвапропорционалнонамаляваненафорсиранияекспираторенобемза1секунда(FEV1)ифорсираниявиталенкапацитет(FVC)безданнизаобструкцияНейниятFVCбеше213L(59%прогнозиран)нейниятFEV1беше154L(53%прогнозиран)инейнотосъотношениеFEV1:FVCбеше723%[normal<8mg/L)BecauseinterstitiallungdiseasewassuspectedrheumatoidfactorantinuclearantibodyandcytoplasmicandperinuclearantineutrophilcytoplasmicantibodylevelswereorderedandwereallnegativeBrainnatriureticpeptideandtroponinlevelsorderedbyanemergencydepartmentphysicianwerewithinnormallimitsonbothvisitstohospitalSpirometryshowedproportionatereductioninforcedexpiratoryvolumeat1second(FEV1)andforcedvitalcapacity(FVC)withnoevidenceofobstructionHerFVCwas213L(59%predicted)herFEV1was154L(53%predicted)andherFEV1:FVCratiowas723%
Figure 1:
Computed tomography (with contrast) of the chest of a 47-year-old woman with hypersensitivity pneumonitis during hospital admission showing bilateral diffuse, centrilobular ground-glass opacities.
Bronchoscopy with bronchoalveolar lavage and transbronchial biopsy was performed. Right upper lobe bronchoalveolar lavage fluid was negative for malignant cells with few lymphocytes, eosinophils, and hemosiderin-laden macrophages. Insufficient leukocytes are available to allow an accurate cell count. Cultures of fluid specimens were negative for bacteria, fungi, and mycobacteria. A transbronchial biopsy of the right middle lobe showed chronic inflammation, diffuse fibrosis, and reactive epithelial proliferation.
Because of the clinical, radiographic, and bronchoscopic findings, the working diagnosis was hypersensitivity pneumonitis, most likely from the patient’s occupational exposure to adhesives. She was started on intravenous solumedrol, experienced immediate relief of dyspnea and cough, and was discharged on prednisone (30 mg/day) with a 2-month taper schedule. She was advised to avoid exposure to adhesives. She was followed up after several weeks in the outpatient clinic, with almost resolution of symptoms.
The patient was seen in our occupational pulmonary clinic 3 months after hospital discharge, and we confirmed the occupational history. The patient took photos with her cell phone of product labels she used at work, which confirmed she had been exposed to toluene diisocyanate (TDI), a compound found in polyurethane-based adhesives that can be highly immunogenic to the lungs . She said that when making plug kits, the heated polyurethane adhesive will often bubble and aerosolize as it is poured into the soil mix. Despite the use of surgical masks and high quality respirators, she continued to have respiratory symptoms.
Because the patient was advised to stop exposure to TDI, her employer found another job for her in a building without isocyanate exposure. Prednisone therapy for 1 month resulted in significant improvement in symptoms and physical examinations. Compared with values at the time of hospital admission, her pulmonary function test at week 4 after discharge showed a greater than 25% improvement in FVC and FEV1. Her FVC was 2.86 L (79% predicted) and FEV1 was 2.38 L (82% predicted). In addition, her total lung capacity was 4.61 L (89% predicted) and diffusing capacity was 16.6 mL/min/mm Hg (78% predicted). Follow-up computed tomography of her chest 1 month after starting prednisone showed complete clearance of ground nodules in the lungs (Figure 2). The outpatient allergy test was negative for mold and other common environmental allergens.
Figure 2:
High-resolution computed tomography scan of the chest of a 47-year-old woman with hypersensitivity pneumonitis after treatment and antigen avoidance showing complete resolution of centrilobular ground-glass opacities.
Discussion
Occupational lung diseases are a common group of respiratory diseases. Although some of these diseases, such as asbestosis and silicosis, are almost always caused by occupational exposure, conditions such as asthma, chronic obstructive pulmonary disease, and interstitial lung disease are caused or exacerbated by occupational exposure in about 25% of cases.1 Classification of interstitial lung disease is shown in Figure 3.
Figure 3:
Classification of selected types of interstitial lung disease (ILD). Note: IIP = idiopathic interstitial pneumonia. Adapted from Kotin and colleagues2 and published with permission from the European Respiratory Society.
Hypersensitivity pneumonitis, formerly known as extrinsic allergic alveolitis, is a type of interstitial lung disease caused by inhalation of antigens that induce non-immunoglobulin (Ig) E-mediated immune dysfunction in the lungs. If untreated, hypersensitivity pneumonitis can lead to progressive pulmonary fibrosis with associated morbidity and mortality.3 About 20% of cases of hypersensitivity pneumonitis are caused by occupational exposure. Therefore, any patient suspected of having hypersensitivity pneumonitis based on history or imaging should be asked for a detailed occupational history.4 More than 200 antigens have been reported to cause hypersensitivity pneumonitis. Although it is often associated with agriculture, exposure to birds, and mold, many cases of hypersensitivity pneumonitis do not have a clearly identified antigen.5 Exposure to the diisocyanate used in polyurethanes in our patient’s case is commonly associated with asthma, but it is also one of many agents known to cause occupational hypersensitivity pneumonitis (Table 1).5-7
Table 1:
Select list of important agents known to cause occupational hypersensitivity pneumonitis*
Isocyanates are low molecular weight compounds classified as mono-, di-, or polyisocyanates. Methylene diphenyl diisocyanate and TDI account for 95% of the diisocyanates used to create polyurethane polymers, with TDI being important in the production of paint, adhesives, and insulating foam.8 Given its association with lung disease, patients with respiratory symptoms and a history of exposure of diisocyanate-containing polyurethanes should be investigated with pulmonary function testing and chest imaging (preferably high-resolution CT) to rule out asthma and hypersensitivity pneumonitis when other diagnoses are less likely.
The diagnosis of hypersensitivity pneumonitis can be relatively challenging due to the lack of standardized and validated diagnostic criteria. Recent consensus guidelines emphasize important factors that support the diagnosis, including history of exposure, supportive computed tomography, bronchoalveolar lavage showing lymphocytosis, histopathologic findings (eg, poorly formed granulomas, cellular interstitial pneumonia, bronchiolitis), and specific serum IgG testing for exposed antigens. 9, 10 According to expert panels, when high-resolution CT findings suggest hypersensitivity pneumonitis and there is known antigen exposure (either by history or laboratory findings), bronchoalveolar lavage lymphocytosis is sufficient to be very confident in the diagnosis. However, in its absence, a lung biopsy should be performed to accurately diagnose hypersensitivity pneumonitis.9
In our patient, the combination of history, imaging, and biopsy findings supported the diagnosis of hypersensitivity pneumonitis. The absence of lymphocytosis on bronchoalveolar lavage may be due to the early fibrosis noted on biopsy as well as the patient’s smoking history. The onset of symptoms soon after starting work and the dramatic…
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