Drug-Induced Interstitial Lung Disease from a Misdiagnosed Infection.

Dear Editor

A urinary tract infection (UTI) is defined as “dysuria, frequency, and/or urgency and the presence of bacteriuria.”[1] It is difficult to assess patients with a chronic indwelling urethral catheter, as a symptom like urgency may be misconstrued as discomfort from the catheter rather than a UTI. Cloudy, foul-smelling urine should not be interpreted as symptomatic infection.[1]

Asymptomatic bacteriuria is the absence of urinary symptoms in the presence of a positive urine culture.[1] Chronic indwelling catheters[1] are associated with bacteriuria 100% of the time. The only indications for screening asymptomatic patients are pregnancy or before urologic procedures. Research shows that treatment does not change infection rates, survival, or resolution of symptoms but increases rates of adverse drug events and bacterial resistance.[2]

Nitrofurantoin is commonly used to treat UTIs.[3-5] It is usually well tolerated and is the only safe antibiotic in pregnancy.[1] Nitrofurantoin-induced interstitial lung disease (NIILD) is seen in <1% of patients.[3] Most cases are reversible, and the overall mortality is 1.19%.[3]

A 69-year-old woman had multiple health care visits for various subjective complaints including urgency, hematuria, and cloudy urine. She had an indwelling urethral catheter in place for 2-years after a spinal cord injury. Medications include amlodipine, metformin, and escitalopram. Ten urinalysis and urine cultures had been performed since 2011 (Table 1), all of which had positive leukocytes and nitrites, but were otherwise unremarkable. She was given multiple courses of antibiotics, but given her “infection” recurrence, she was placed on chronic prophylaxis with nitrofurantoin 100 mg orally daily. A computed tomography (CT) chest 1 year prior to this was unremarkable.

Table 1.

Results of urinalysis and urine cultures from patient, demonstrating increasing prevalence of multiple drug-resistant organisms over time.

Date of test	Species	Susceptibilities(S = susceptible, I = intermediate, R = resistant)
October 2011	Urinalysis only	—
October 2013	Urinalysis only	—
October 2015	Candida species >100 000 CFU/mL	Pansensitive
October 2016	Urinalysis only
January 2017	Candida species 10 000 CFU/mL	Pansensitive
February 22, 2017	Enterococcus faecalis >100 000 CFU/mL	Ampicillin S; Ciprofloxacin R; Levofloxacin R; Nitrofurantoin S; Penicillin S; Tetracycline RVancomycin S
February 22, 2017	Citrobacter freundii, Klebsiella pneumoniae >100 000 CFU/mL	Amox/Clavulanate S; Ampicillin R; Cefazolin RCiprofloxacin S; Gentamicin S; Levofloxacin SNitrofurantoin I; Piperac/Tazobactam STetracycline S; Trimeth/Sulfa S
March 2017	Carbapenem-resistant Klebsiella pneumoniae >100 000 CFU/mL	Amikacin S; Amox/Clavulanate R; Ampicillin RAztreonam R; Cefazolin R; Cefepime R; Cefotaxime R; Ceftazidime R; Ceftriaxone RCefuroxime R; Ciprofloxacin R; Gentamicin IImipenem R; Levofloxacin R; Meropenem RNitrofurantoin R; Piperac/Tazobactam R; Tetracycline S; Trimeth/Sulfa R
August 2017	Polymicrobial >100 000 CFU/mL	—
August 2017	Enterobacter aerogenes >100 000 CFU/mL	Ampicillin R; Cefazolin R; Ciprofloxacin SNitrofurantoin I; Gentamicin SLevofloxacin SPiperac/Tazobactam STrimeth/Sulfa STetracycline S
December 2017	Polymicrobial >50 000 CFU/mL	—

She was admitted to the hospital with pneumonia 2.5 years into her prophylactic treatment course. A CT chest without contrast showed interval development of extensive interstitial lung disease with pulmonary fibrosis, traction bronchiectasis, and honeycombing. High-resolution CT chest after resolution of her pneumonia confirmed these findings (Figure 1).

Figure 1.

High-resolution computed tomography of the chest showing extensive interstitial lung disease with pulmonary fibrosis, traction bronchiectasis, architectural distortion, and honeycombing.

Pulmonary function testing confirmed severe restrictive lung disease (FEV1 [FEV in the first second of expiration] 39%, FVC [forced vital capacity] 33%, FEV1/FVC 120%) and decreased carbon monoxide diffusion capacity. Co-oximetry and hypersensitivity pneumonitis panels were negative. Testing for autoimmune (rheumatoid arthritis, lupus, scleroderma) or infectious causes of her symptoms was unremarkable. Lung biopsy was not performed. Nitrofurantoin was discontinued and 2 days later the patient reported improvement in her cough and dyspnea. The patient was lost to follow-up.

Nitrofurantoin-induced interstitial lung disease is often misdiagnosed given its lack of unique clinical/laboratory/imaging findings. As a result, patients may be treated for other more common conditions such as pneumonia or heart failure.

Our patient’s Naranjo score[6] was 8, indicating that the interstitial lung disease was likely caused by nitrofurantoin. She met the criteria for drug-induced pulmonary toxicity based on her clinical symptoms, imaging, documented exposure to drug, improvement after drug removal, and exclusion of other potential causes of her lung disease.[3]

With rising bacterial resistance, nitrofurantoin is increasingly used to treat UTIs.[4-5] Although NIILD is rare, nitrofurantoin should only be used in a proven UTI. To minimize the risk of NIILD and bacterial resistance, prophylactic treatment should not exceed 6 months.[7] If patients are on a prophylactic regimen, clinicians should strongly consider periodic monitoring for pulmonary toxicity. In addition, patients should be educated about the side effects of nitrofurantoin and to seek medical attention if respiratory symptoms develop.