Nitrofurantoin-induced immune-mediated lung and liver disease Bolest plu a i jetre indukovana nitrofurantoinom i imunološki posredovana

Introduction. Nitrofurantoin, a furan derivative, introduced in the fifties has widely been used as an effective agent for the treatment and prevention of urinary tract infections (UTI). Spectrum of adverse reactions to nitrofurantoin is wide, ranging from eosinophilic interstitial lung disease, acute hepatitis and granulomatous reaction, to the chronic active hepatitis, a very rare adverse effect, that can lead to cirrhosis and death. Case report. We presented a 55-yearold female patient with eosinophilic interstitial lung disease, severe chronic active hepatitis and several other immunemediated multisystemic manifestations of prolonged exposure to nitrofurantoin because of the recurrent UTI caused by Escherichia coli. We estimated typical radiographic and laboratory disturbances, also restrictive ventilatory changes, severe reduction of carbon monoxide diffusion capacity and abnormal liver function tests. Lymphocytic-eosinophylic alveolitis was consistent with druginduced reaction. Hepatitis was confirmed by liver biopsy. After withdrawal of nitrofurantoin and application of high dose of glicocorticosteroids, prompt clinical and laboratory recovery was achieved. Conclusion. Adverse drug reactions should be considered in patients with concomitant lung and liver disease. The mainstay of treatment is drug withdrawal and the use of immunosuppressive drugs in severe cases. Consideration should be given to monitor lung and liver function tests during long term nitrofurantoin therapy.


Introduction
Nitrofurantoin, a furan derivative, was introduced in the fifties and has widely been used as an effective agent for the treatment and prevention of urinary tract infections (UTI).Nitrofurantoin-induced hepatic injury was first re-ported in 1961 1 .Since then a spectrum of adverse reactions to nitrofurantoin has been reported, ranging from eosinophilic interstitial lung disease, acute hepatitis, granulomatous reaction, to the very rare adverse effect of chronic active hepatitis that can lead to cirrhosis or death 2 .Autoimmune liver disease is not uncommon cause of chronic hepatitis in women.Although autoimmune destruction usually occurs without an identifiable trigger, some drugs such as methyldopa, minocycline and nitrofurantoin are associated with autoimmune liver disease 3 .Today, nitrofurantoin is well recognized as a cause of adverse drug reactions.Although the combination of lung and liver toxicity is rare, concomitant pulmonary and liver disease can occur together and it may well be that these share a common autoimmune mechanism [4][5][6][7][8] .Eighty five percent of patients having nitrofurantoin-associated pulmonary reactions are women.This observation may be related to the fact that women are more susceptible to recurrent UTI 9,10 .
We presented a middle age female patient with eosinophilic interstitial lung disease, severe chronic active hepatitis and several other immune-mediated multisystemic manifestations after prolonged exposure to nitrofurantoin.

Case report
A 55-year-old female was admited to hospital because of breathless, nonproductive cough and fever during six weeks.Few months prior admission the patient began to suffer from general weakness, nausea, weight lost and polyarthralgia without morning rigidity.Her past medical history included mesangioproliferative glomerulonephritis (diagnosed in 1985 and treated with systemic glicocorticosteroids), hypothyreosis (because of that she used levotiroxin substitution).The patient had been treated with nitrofurantoin 100 mg twice daily for the last six months because of the recurrent UTI caused by Escherichia coli.There was no history of liver disease; she denied consumption of any other medications, alcohol or tobacco.Physical examination on admission revealed profound jaundice, obesity, dark colour of skin with excoriated papulomatous rash on the face and arms (Figure 1).Auscultation of the lungs revealed normal breath sound with diffuse, bilateral, fine end-inspiratory crackles.Initial laboratory tests revealed an erythrocyte sedimentation rate (ESR) of 24 mm/h (normal range 0-12 mm/h), elevated C-reactive protein -9 mg/L (normal 0-4 mg/L), a normal blood count with eosinophilia (880/mL, normal 100-250/mL), deranged liver function with total serum bilirubin of 139 μmol/L (normal range 2-21 μmol/L) with a direct fraction of 37 μmol/L (normal range 0-5 μmol/L), aspartate aminotransferase (AST) -466 IU/L (normal range 0-34 IU/L), alanine aminotransferase (ALT) -430 IU/L (normal range 7-49 IU/L), lactate dehydrogenase (LDH) -535 IU/L (normal range 200-378 IU/L), alkaline phosphatase-1,111 IU/L (normal range 7-290 IU/L), gamaglutamyl-transpeptidase 1,590 IU/L (normal range 0-38 IU/L), normal total protein -69 g/L, low albumin -29 g/L (normal range 32-48 g/L).Other biochemical parameters and coagulation screen were normal.Antinuclear antibodies (ANA) were positive (++++ speckled pattern of fluorescence), also anti-smooth muscle antibodies -ASMA (++).Antibodies for extractable nuclear antigens, anticardiolipin, anti-mitochondrial, anti-CCP (cyclic citrullinated peptide), anti-neutrophil cytoplasmic (against myeloperoxidase and proteinase 3) were normal.Relative values of subpopulations of T lymphocytes in peripheral blood (CD4+ and CD8+) were normal, with normal CD4+/CD8+ ratio, so values of natural killer cells (CD16+, CD56+) were mildly elevated.There was an accompanying hyper-gammaglobulinemia with elevated IgG -22 g/L (normal range 7-16 g/L), IgA 4.41 g/L (normal range 0.7-4 g/L), IgE 902 IU/mL (normal range 0-100 IU/mL) and normal IgM level.Serological tests for intestinal parasites, hepatitis A, B, C, human immunodeficiency, Epstein Barr and cytomegaloviruses were negative.No eggs of parasites were found in feces.Chest radiography (X-Ray) showed bilateral ground-glass and micronodular opacities, predominantly in lower lung fields (Figure 2).and eosinophils 11% with decreased CD4/CD8 ratio.A liver biopsy was performed showing severe chronic active hepatitis, which was considered to be consistent with a drug induced hepatitis (Figure 4).Apperance of eyes and mouth dryness Shirmer`s test was performed which showed reduced secretion of tears (3 mm/5 min).Dermatological examination established Lichen simplex chronicus (Figure 1).After withdrawal of nitrofurantoin, high dose of glicocorticosteroids was applied -metylprednisolon in daily dose of 80 mg (60 mg in the morning and 20 mg in the evening).The result was a prompt clinical and laboratory recovery (symptoms and signs wanished, normalisation of acute phase reactants, liver and lung function parameters).The patient was discharged two weeks later and swiched to oral prednisone with taper to maintenance dose of 10 mg daily.Control examinations after three, six and twelve months showed normal physical findings, laboratory tests, chest X-ray and CT (Figure 5), abdominal ultrasonography, spirometry and carbon monoxide diffusion capacity.Follow-up was recommended.

Discussion
Nitrofurantoin is widely used for both acute and chronic management of UTI.It is cheap and effective, with a low incidence of resistance in common urinary pathogens; it is also safe in pregnancy 11 .Adverse drug reactions to nitrofurantoin include pulmonary reactions, hepatic toxicity, blood dyscrasias, peripheral neuropathy, etc 9 .Concomitant pulmonary and hepatic toxicity secondary to nitrofurantoin is rare with few reported cases [4][5][6][7][8] .The vast majority of pulmonary reactions to nitrofurantoin (90%) are acute and characterised by fever, cough, dyspnoea, and peripheral eosinophilia [9][10] .Nitrofurantoin also causes a range of subacute or chronic pulmonary disease, often presenting with insidious onset of increasing dyspnoea, dry cough and radiological evidence of fibrosis 10 .Because of that optimal duration of nitrofurantoin treatmen should not be over 14 days.Also, profilactic treatment of recurrent UTI should be discontinued, with switch by other effective antibacteriale medications.In patients who have some pulmonary, hepatic, alergic, neurologic disorder, anemia, diabetes or vitamin B deficiency special caution is necessery.Although severe adverse reactions caused by nitrofurantoin are rare, consideration should be given to monitoring lung and liver function tests during a long-term nitrofurantoin therapy.Pulmonary function tests (PFTs) may show a restrictive pattern with a reduced carbon monoxide diffusion capacity.Nitrofurantoin has been linked to autoimmune hepatitis, but in view of the rarity of the association, almost all reports of the association have been single case reports or small series [1][2][3] .Further information has been obtained from national adverse drug reaction monitoring agencies in the Netherlands 12 and Denmark 13 and it has been estimated that the incidence of nitrofurantoin-induced hepatic injury is low at about three cases in 1,000,000 14 .
The underlying mechanism behind nitrofurantoin toxicity remains uncertain; an immunological response is suggested by the presence of autoantibodies (ANA, ASMA).Direct cytotoxic mechanisms, for example by increased oxidative stress, have also been suggested 15 .Cytotoxic T-cells play a pivotal role in the pathogenesis of nitrofurantoininduced liver injury.It has been hypothesized that a breakdown product of the drug or the drug itself, bound to an endogenous peptide, is presented by the class 1 HLA antigen on the hepatocyte cell membrane; this induces cytotoxic Tcell activation and subsequent hepatocyte death 16 .Ethnicity or genetic background may be a risk factor because of the variability in detoxification mechanisms (acetylator phenotype, human leukocyte antigen group) 17 .Our patient had a clear autoimmune disposition (mesangioproliferative glomerulonephritis and hypothireosis), and according to anamnestic, clinical, laboratory, imaging and other findings we estimated the existence of nitrofurantoin-induced, immunemediated eosinophilic interstitial lung diseases, autoimmune hepatitis and several other multisystemic manifestations as lichen simplex chronicus and sicca syndrome, as well.There were no criterias for any diffuse connective tissue diseases, however it was possible that nitrofurantoin induced lupuslike syndrome associated with hepatitis 18 .Lung disease had subacute presentation with characteristic symptoms, clinical, X-ray, CT and PFTs findings.Lymphocytic-eosinophylic alveolitis was consistent with drug-induced reaction (DIR).Liver disease had chronic course.The positive ANA and ASMA results, hyper-gammaglobulinemia, histological features of liver biopsy and clinical response to immunosuppressive drugs were strongly suggestive of autoimmune hepatitis-type 1, triggered by nitrofurantoin.Definitive confirmation of DIR was positive rechallenge test according to WHO method 19 .Rechallenge, however, is not ethical due to severity of our patient`s clinical presentation.We applied the Naranjo algorithm for determination the likelihood of whether a DIR is actually due to the nitrofurantoin rather than the result of other factors and score was 6 -probable DIR.Initial treatment consists of drug withdrawal.In addition, we elected to use parenteral glucocorticosteroids because of the severe damage of lung and liver function.If glucocorticosteroid treatment fails, azathioprin may be introduced.

Conclusion
Adverse drug reactions should be considered in patients with concomitant lung and liver disease.The mainstay of treatment is drug withdrawal and the use of immunosuppressive drugs in severe cases.Consideration should be given to monitoring lung and liver function tests during a long term nitrofurantoin therapy.

Computed a b Fig. 1 -Fig. 2 -
Fig. 1 -A female patient, 55-year-old, with lichen simplex chronicus on the face (a) and the arm (b)