Nitrofurantoin pulmonary reactions

Rosenow EC 3rd, DeRemee RA, Dines DE. Chronic nitrofurantoin pulmonary reaction. Report of 5 cases. N Engl J Med 1968 279(23) 1258-62. 

Nitrofurantoin administration may result in nausea, vomiting, anorexia, rash, peripheral neuropathy, headache, brown discoloration of the urine, and hypersensitivity reactions, which may range from mild to severe Acute and chronic pulmonary reactions also have been seen. 

Pulmonary reactions Acute, subacute, or chronic pulmonary reactions have been observed in patients treated with nitrofurantoin. 

Pleuropericardial reactions, with sterile effusions and eosinophilia, have also rarely been reported in patients taking 225-400 mg/day for 3 months to 4 years (5). There is no proof of a causal relation, but the chemically related nitrofurantoin has also been associated with pulmonary reactions. Patients taking dantrolene should be screened periodically. 

Larsson S, Cronberg S, Denneberg T, Ohlsson NM. Pulmonary reaction to nitrofurantoin. Scand J Respir Dis 1973 54(2) 103-10. 

Selroos O, Edgren J. Lupus-like syndrome associated with pulmonary reaction to nitrofurantoin. Report of three cases. Acta Med Scand 1975 197(l-2) 125-9. 

Nitrofurantoin This agent is effective as both a therapeutic and prophylactic agent in patients with recurrent UTIs. Main advantage is the lack of resistance even after long courses of therapy. Adverse effects may limit use (Gl intolerance, neuropathies, pulmonary reactions). 

Nitrofurantoin may cause pulmonary reactions manifested by sudden onset of dyspnea, chest pain, cough, fever, and chills. These reactions may occur rapidly (few hours) or slowly (few weeks). Chest X-rays show alveolar infiltrates or effusions an elevated sedimentation rate and eosinophilia are also present. Resolution of clinical and radiological abnormalities occurs within 24 to 48 hours after discontinuation. 

Gluck and Janower (1969) describe two cases of acute pulmonary syndrome with chill, fever, tussis, dyspnea, and thoracodynia after administration of nitrofurantoin. Allen et al. (1969) report further cases, and David et al. (1968) chronic fibrosing pulmonary degenerations. Other pulmonary reactions are reported by Leiber (1972), Teigelkotter (1972), and Ponte (1982). 

The increase in cases - in absolute terms and also in relation to the number of doses-sold - is explained by permanent sensitization. In the period 1966-1976,398 acute and 49 chronic pulmonary reactions to nitrofurantoin were registered in Sweden. Of these patients, 75% had to be admitted to hospital and 85% were female. The average age of those with acute reactions was about 59 years, of the chronic cases about 68 years. It is assumed that acute reactions are of allergic nature, chronic and hepatic reactions of toxic nature. Immediate discontinuation of the drug is necessary in either case. Chronic reactions do not follow the acute cases and acute cases do not tend to become chronic (Muller 1974 Holmberg and Roman 1981). 

Goldstein and Janicki (1974) have the opinion that after nitrofurantoin, acute pulmonary reactions can be connected with the presence of a specific cellular reaction to the drug even there is no specific antibody reaction. 

In acute eosinophilic pulmonary reactions after nitrofurantoin there is an interval between application of the drug and appearance of the reaction. A peripheral eosinophilia is shown. Histologically it is a matter of eosinophilic infiltration with edema and perivasculitis in the lungs. Observations supporting an allergic genesis are ... 

Because these phenomena are also observed in other acute pulmonary reactions caused by antigen-antibody complexes, it is supposed that nitrofurantoin acts similarly, although Goldstein and Janicki (1974) had no success in demonstrating the specific antibody. In contrast, Pearsell et al. (1974) assume that pathogenesis is based on hypersensitivity of the prolonged type (cell-bound immune response). 

Holmberg L, Boman G (1981) Pulmonary reactions to nitrofurantoin. Eur J Respir Dis 62 180... 

Anorexia, nausea, and vomiting are the principal side effects of nitrofurantoin. Neuropathies and hemolytic anemia occur in glucose-6-phosphate dehydrogenase deficiency. Nitrofurantoin antagonizes the action of nalidixic acid. Rashes, pulmonary infiltration and fibrosis, and other hypersensitivity reactions have been reported. 

The incidence of gastrointestinal side-effects including nausea, vomiting and diarrhoea with nitrofurantoin is as high as 30% with standard microcrystalline formulations and patients should be advised to take the doses with food. Other important but less common adverse reactions include pulmonary fibrosis, peripheral neuropathy and hypersensitivity. Patients should also be warned that nitrofurantoin can colour the urine yellow or brown. 

Atypical courses have been rarely described (5). A mixed type of reaction can occur after an initial short fever peak, the patient becomes either afebrile or subfeb-rile, despite continuing to take nitrofurantoin and unabated activity of the lung process, or a typical chronic reaction converts to a typical acute reaction on re-expo-sure to nitrofurantoin after withdrawal. Acute reactions can occur without clinical symptoms, and can be recognized only on X-ray. Single cases of pulmonary hemorrhage, eosinophilic pneumonia, and interstitial giant cell pneumonia have also been reported (26,27). 

Basoglu T, Erkan L, Canbaz F, Bernay I, Onen T, Sahin M, Furtun F, Yalin T. Transient reverse ventilation-perfusion mismatch in acute pulmonary nitrofurantoin reaction. Ann Nucl Med 1997 ll(3) 271-4. 

Taskinen E, Tukiainen P, Sovijarvi AR. Nitrofurantoin-induced alterations in pulmonary tissue. A report on five patients with acute or subacute reactions. Acta Pathol Microbiol Scand [A] 1977 85(5) 713-20. 

However, there is no evidence for a specific humoral antibody reaction to nitrofurantoin in the acute pulmonary syndrome (Geller et al. 1976 Pearsall et al. 1974). Experienced antibody tests are not carried out with nitrofurantoin. Tep-PO et al. (1976), in immune electrophoresis of ten patients of whom eight had been treated with nitrofurantoin, observed an enlarged albumin fraction to the cathode which disappeared in five cases after cessation of treatment. Most of the patients had polyclonally increased IgG und IgA levels and decreased albumin values. IgM, C3, and C4 were normal. Antinucleic activity of the IgG type was seen in nine patients. The phenomenon was the consequence of immune complexes between IgG and albumins. The activity similar to that of antibodies of IgG was directed to autologous and isologous albumin. 

Heijer A (1970) Pleuro-pulmonary allergic reaction to nitrofurantoin. Acta Allerg (Kbh)... 

Lundgren R, Back O, Wiman LG (1975) Pulmonary lesions and autoimmune reactions after long-term nitrofurantoin treatment. Scand Respir Dis 56 208 Lynn KL, Little PJ (1976) Reaction to trimoxazole. NZ Med J 377 78 Mackie BS, Mackie LE (1979) Systemic lupus erythematosus-dermatomyositis induced by sulphacetamide eye drops. Aust J Dermatol 20 49 Maddrey W, Boitnott J (1977) Drug-induced chronic liver disease. Gastroenterology 72 1348... 

The time frame in which pulmonary drug-induced toxicity occurs is also highly variable, ranging from acute hypersensitivity reactions (e.g., methotrexate, nitrofurantoin toxicides) to delayed presentations (e.g., nitrosoureas, or radiation recall seen with bleomycin, as discussed below). This along with the fact that combination treatments have become commonplace, in particular in the context of chemotherapy protocols, may further hamper the clinician s ability to identify the culprit medication. In addition, several drugs may be implicated in an additive or synergistic fashion and further confuse the clinical picture. 

Lundgren, R., Back, O. and Wiman, L. G. (1975) Pulmonary lesions and autoimmune reactions after long-term nitrofurantoin treatment. Scand. J. resp. Dis., 56, 208. 

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