Epidemiology

• One of the most common drug-induced pulmonary diseases
• Toxicity occurs in <1% of all users of drug

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Physiology

• Acute Nitrofurantoin Toxicity: unclear mechanism (studies have shown prolonged lymhocyte transformation factor and migration inhibition factor production)
• Chronic Nitrofurantoin Toxicity: induction of oxygen radicals by parenchymal cells

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Pathologic Patterns

• Acute Nitrofurantoin Toxicity: proliferation of fibroblasts/lymhoplasmocytic infiltrate (IgA-laden plasma cells)/DIP-like features
  • Importantly, absence of eosinophilia in lung tissue (despite peripheral eosinophilia)
• Chronic Nitrofurantoin Toxicity: mimics idiopathic pulmonary fibrosis

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Adverse Effects

Pulmonary Adverse Effects

Acute Nitrofurantoin Toxicity (see Drug-Induced Pulmonary Eosinophilia, Pneumonia, Interstitial Lung Disease-Etiology, and Pleural Effusion-Exudate)

• Epidemiology
  • Onset: few hrs to several days after initiation of nitrofurantoin
  • Incidence is 1 in 550-5400
  • More common in females (possibly due to increased use of drug in females for UTI’s)
  • Not dose-related (can occur after single dose)
• Diagnosis
  • CBC: peripheral leukocytosis and eosinophilia (33% of cases)
  • Elevated ESR (50% of cases)
  • CXR/Chest CT
    • Basilar-predominant alveolar and/or interstitial infiltrates: may be unilateral or asymmetric
    • Pleural Effusion: usually unilateral
      • 20% of acute cases have infiltrate with effusion
      • 3% of acute cases have isolated effusion
  • PFT’s: obstruction
  • Pleural Fluid: may demonstrate pleural eosinophilia in some cases
• Clinical
  • Fever (usually present)
  • Dyspnea (usually present)
  • Cough (66% of cases)
  • Bronchospasm (see Obstructive Lung Disease): may occur in the absence of parenchymal or pleural manifestations in some cases
  • Pleuritic Chest Pain (33% of cases)
  • Rales (most cases)
• Treatment
  • Supportive care
  • Not clear that corticosteroids are effective -> probably not indicated
  • Re-challenge is contraindicated

Chronic Nitrofurantoin Toxicity (see Pneumonia, Interstitial Lung Disease-Etiology, and Pleural Effusion-Exudate)

• Epidemiology
  • Chronic nitrofurantoin toxicity is less common than acute nitrofurantoin toxicity
  • Onset: 6 months-years after start of continuous or intermittent use of nitrofurantoin
  • More common in females
• Diagnosis
  • CXR/Chest CT
    • Diffuse interstitial infiltrates
    • Pleural Effusion: 10% of chronic cases have effusion (no chronic cases have effusion without infiltrates)
  • PFT’s: restriction without obstruction
  • FOB-BAL: lymphocytosis
  • OLB: inflammatory cells and fibrosis
• Clinical
  • Fever and eosinophilia are less common than in acute toxicity
  • Insidious onset of fever and cough
• Treatment
  • Withdraw Nitrofurantoin: wait 2-4 mo to see if resolves (by CT + PFT’s) without steroids -> if not, then initiate a trial of corticosteroids

Drug-Induced SLE (see Systemic Lupus Erythematosus)

• Few reported cases: present with pleuropulmonary disease with positive ANA

Cryptogenic Organizing Pneumonia (see Cryptogenic Organizing Pneumonia and Lung Nodule or Mass)

• May appear as nodular infiltrates

Acute Lung Injury-ARDS (see Acute Lung Injury-ARDS)

Other Adverse Effects

• Risk of Hemolysis in Patient with G6PD Deficiency (see Glucose-6-Phosphate Dehydrogenase Deficiency and Hemolytic Anemia)

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Prognosis

• 71% of all reactions are severe enough to require hospitalization
• 1% of all cases were fatal: 4/49 with chronic fibrosis toxicity and 2/398 with acute toxicity

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References

• Chronic nitrofurantoin-induced lung disease. Mayo Clin Proc 2005; 80:1298.
• Pulmonary reactions to nitrofurantoin. 447 cases reported to the Swedish Adverse Drug Reaction Committee 1966-1976. Eur J Respir Dis 1981; 62:180.
• Nitrofurantoin-induced acute, subacute and chronic pulmonary reactions. Scand J Respir Dis 1977; 58:41.
• Nitrofurantoin lung injury. Age Ageing 2004; 33:414.
• Nitrofurantoin-induced interstitial pulmonary fibrosis. Presentation and outcome. Med J Aust 1983; 1:72.
• Nitrofurantoin pulmonary toxicity. J Fam Pract 1981; 13:817.
• Bronchiolitis obliterans organising pneumonia associated with the use of nitrofurantoin. Thorax 2000; 55:249.
• Acute pulmonary injury in rats by nitrofurantoin and modification by vitamin E, dietary fat, and oxygen. Am Rev Respir Dis 1979; 120:93.
• Concomitant pulmonary and hepatic toxicity secondary to nitrofurantoin: a case report. J Med Case Reports 2007; 1:59.
• Nitrofurantoin-induced lung- and hepatotoxicity. Ann Hepatol 2007; 6:119.
• Recurrent acute nitrofurantoin-induced pulmonary toxicity. Pharmacotherapy 2006; 26:713.
• Chronic eosinophilic pneumonia secondary to long-term use of nitrofurantoin: high-resolution computed tomography findings. J Bras Pneumol 2008; 34:181.
• Severe nitrofurantoin lung disease resolving without the use of steroids. J Postgrad Med 2007; 53:111.
• Nitrofurantoin-induced lung disease: two cases demonstrating resolution of apparently irreversible CT abnormalities. J Comput Assist Tomogr 2000; 24:259
• Nitrofurantoin-induced pulmonary fibrosis: a case report. J Med Case Reports 2008; 2:169.