Nitrofurantoin-induced Desquamative Interstitial Pneumonitis in a 7-year-old Child

To the Editors: We report the case of a 7-year-old girl referred by her family physician for severe uncontrolled asthma. Two years earlier, she had her first respiratory complaints (dry cough, wheezing) that were considered to be asthma and were treated with montelukast (4 mg) and salmeterol/fluticasone (25/250 μg), without further investigation. Six months earlier, her asthma became uncontrolled. Severe activity limitation, shortness of breath, and 2 kg of body-weight loss were reported during the last 3 weeks. Thirty months earlier, she was treated with amoxicillin for pyelonephritis and was given nitrofurantoin 4 mg/kg/d as prophylaxis until the present day. She had no surgical or familial history otherwise. On physical examination, she was alert, tachypneic (respiratory rate, 40/min), with a room-air oxygen saturation of 94%, with some fine crackles on lung auscultation. The rest of the examination was normal. The allergic investigation (skin prick test and blood analysis) was negative. Chest radiograph showed diffuse bilateral infiltrates. She was unable to undergo spirometry, due to shortness of breath. She was admitted for further investigation and treatment. Blood analysis revealed an elevated erythrocyte sedimentation rate, elevated immunoglobulin IgG, 12-fold increased SGOT, SGPT, and GGT, and positive auto-antibodies (p-ANCA, fluor ANA, anti-DNA double stranded, anti-mDNA, antinucleosomes). The work-up ruled out infectious and cardiac etiologies, immune deficiency, emphysema, gastroesophageal reflux disease, and cystic fibrosis. Chest computed tomography (CT) scan showed a ground-glass appearance with subpleural reaction, and a 7-mm left parenchymal nodule in the anterobasal left inferior lobe consistent with a nonspecific interstitial pneumonia. We performed a lung biopsy by a video-assisted thoracoscopy that showed a desquamative interstitial pneumonitis (DIP) with predominance of macrophages within the air-space without fibrosis. The percutaneous liver biopsy demonstrated severe hepatitis with portal fibrosis and presence of rare eosinophils and microgranules. All medications were stopped after suspicion of toxic cause and oral prednisolone (2 mg/kg/d) was started. She improved clinically and her liver tests returned to normal within 10 days. The lung function test showed a severe restrictive pattern with a total lung capacity of 1.19 L (52% of predicted value for age) and a vital capacity of 0.55 L (32% of predicted value for age); helium-diffusion study could not be obtained due to inability to perform a 10-second apnea necessary for the test. Chest CT scan improved within 4 weeks of treatment. Considering the marked clinical, radiologic, and biochemical improvement, prednisolone was tapered by 25% every 2 weeks and a weekly follow-up with a lung function testing was done. At 3 months follow-up, chest CT, lung function testing, and inflammatory profile were back to normal, with negative auto-antibodies. Prednisolone was stopped. After 9 months of follow-up, she did not show signs of recurrence. Weight loss in a child with uncontrolled asthma may not be explained solely by asthma, and other etiologies should be considered. We report the case of a patient with an erroneous diagnosis of severe uncontrolled asthma, where the investigations revealed a DIP with a severe hepatitis that resolved after withdrawal of the suspected drug, nitrofurantoin, and administration of corticosteroids. DIP is a rare form of interstitial lung disease of unknown etiology and is distinguished from other forms of interstitial lung disease by its pathology. Identification is important because of its poor prognosis. The etiology of DIP in infants and children previously considered uncertain seems to be in some cases related to genetic defects of surfactant function.1 Nitrofurantoin-induced DIP has been reported mainly in adults after 1 or more years of nitrofurantoin therapy with a mean dosage of 50 to 200 mg/d.2 Zimmerman and colleagues3 reported chronic active hepatitis induced by nitrofurantoin with elevated gammaglobulin and antinuclear antibody. Pulmonary toxicity has been described in acute, subacute, and chronic forms of lung disease.2 The usual presenting symptoms are progressive dyspnea and dry cough for weeks to years. The diagnosis of drug-induced lung disease can be difficult, particularly in chronic cases, and is usually based on the clinical context and radiologic features. The pathologic findings are not specific and the surgical lung biopsy specimens have shown various histopathologic patterns.2 In our patient, symptoms appeared 6 months after starting nitrofurantoin. Dry cough, wheezing, and chest tightness were considered to be an intrinsic asthma and treated as such. Worsening of symptoms and weight loss led us to investigate other possible etiologies. The work-up ruled out common and rare etiologies, so we considered that our patient had a DIP associated with severe hepatitis associated with chronic nitrofurantoin treatment. The clinical evolution and the absence of autoimmunity or inflammation 9 months after steroids were stopped, make the diagnosis of primary autoimmune disease unlikely. As most patients experience improvement of symptoms and radiologic abnormalities after cessation of nitrofurantoin, a definite diagnosis could be confirmed by recurrence following nitrofurantoin retreatment.