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Malaise, weight loss, and respiratory symptoms

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Q1: What abnormalities are shown in the flow volume loops?

Restrictive lung defect with reduced lung volumes, plus minor airflow obstruction.

Q2: What abnormalities are shown in the chest radiograph and computed tomogram (see p 55)?

The chest radiograph shows bilateral interstitial infiltrate in the lower zones with loss of lung volume. HRCT shows ground glass opacification in the mid thoracic region with patchy fibrosis and traction bronchiectasis.

Q3: What is the differential diagnosis?

  • Drug induced alveolitis.

  • Cryptogenic fibrosing alveolitis.

  • Extrinsic allergic alveolitis.

  • Outcome

    The patient had been taking prophylactic nitrofurantoin 100 mg daily for the preceding 11 months because of recurrent urinary tract infections. This antibiotic was stopped two days after her presentation and the patient was then treated with oral steroids. Her condition improved significantly within one month, allowing a gradual reduction in steroid dosage thereafter. Three months later, by which time the steroids had been discontinued, a control chest radiograph (fig 1, above) showed complete resolution of the lower zone infiltrate.

    Figure 1

    Control chest radiograph.

    Discussion

    The combination of progressive dyspnoea and cough, with audible crackles on auscultation of the lungs, and the chest radiograph appearances of an interstitial infiltrate, should suggest a diagnosis of fibrosing alveolitis. Whereas the epithet “cryptogenic” can reasonably be applied to the majority of such cases where a specific causal factor cannot be identified, it is important to consider potential aetiological agents. Though uncommon, the recognition and removal of such agents can result in significant clinical improvement. Nitrofurantoin is one of many drugs that can be implicated (box 1). Extrinsic allergic alveolitis (for example, bird fancier's lung) can also present with a similar picture.

    Box 1: Drugs commonly associated with interstitial pulmonary disease

    Antibiotics

    • Sulfasalazine.

    • Nitrofurantoin.

    Antiarrythmics

    • Amiodarone.

    • Flecainide.

    Anti-inflammatory drugs

    • Gold.

    • Penicillamine.

    • Methotrexate.

    Chemotherapeutic agents

    • Mitomycin C.

    • Bleomycin.

    • Busulfan.

    • Cyclophosphamide.

    • Azathioprine

    Toxins

    • Paraquat.

    Nitrofurantoin is widely used in treating acute urinary tract infections and in suppression of chronic asymptomatic bacteruria. It was one of the first drugs to be implicated as a cause of pulmonary disease and is associated with various toxic pulmonary manifestations (box 2).1 Nitrofurantoin induced pulmonary disease is postulated to result from the generation of free radicals as a result of redox cycling of the drug in the lung causing direct tissue damage to the endothelium and the alveoli. Antioxidant depleted tissues are most vulnerable.2

    Box 2: Toxic pulmonary manifestation of nitrofurantoin

    • Hypersensensitivity pneumonitis.

    • Interstitial fibrosis.

    • Pulmonary eosinophilia.

    • Bronchiolitis obliterans organising pneumonia.

    • Pulmonary vasculitis.

    • Pleural disease.

    • Airway disease.

    • Desquamative interstitial pneumonia.

    • Adult respiratory distress syndrome.

    • Pulmonary haemorrhage.

    Classically, the pulmonary reaction to nitrofurantoin is divided into acute and chronic forms, though some authorities are suggesting a wider classification because of the heterogeneity of manifestations.3 The acute form begins hours to several days after the initiation of therapy. Symptoms include fever, dyspnoea, bronchospasm, rash, arthralgia, and cough. An eosinophilic leucocytosis, high ESR, pleural effusions, and an interstitial infiltrate on chest radiography are common findings. Management entails discontinuation of the medication and supportive measures. While the role of steroids is unclear, they are often prescribed.3–6

    The chronic form of reaction is less common, and fever and eosinophilia occur less frequently. It usually affects older females and occurs many months or years after initiation of treatment. The onset of cough and dyspnoea is usually insidious and is commonly accompanied by constitutional symptoms of fatigue and weight loss. Chest radiographs show a diffuse interstitial process. HRCT is particularly helpful in outlining the extent of pulmonary injury and evaluating disease activity. Desquamative pneumonitis and groundglass opacification is usually associated with a good prognosis and is radiologically reversible, while a reticular pattern implies irregular fibrosis and is usually irreversible.7 Pulmonary function tests demonstrate a restrictive pattern with a reduced diffusion capacity. A positive rheumatoid factor, antinuclear antibodies, and raised immunoglobulin levels may be associated features.

    Bronchoalveolar lavage shows a lymphocytic reaction while histology shows inflammation and interstitial fibrosis, though the appearances are somewhat non-specific. Immediate cessation of nitrofurantoin treatment is essential, but the role of steroid therapy is uncertain. While steroids might be justified in the presence of a pulmonary infiltrate, desquamative pneumonitis or bronchiolitis obliterans organising pneumonia, they are less likely to be effective for established fibrosis.3–6 The outcome tends to be less favourable in the chronic disease pattern, which has a mortality of 8%4 and in which 70% of cases fail to resolve fully.4

    The relevance and importance of this patient's medication history was not fully realised at the time of presentation. A detailed drug history should always be sought and the possibility of a drug induced illness considered in the differential diagnosis.

    Final diagnosis

    Drug induced alveolitis.

    References

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