Nitrofurantoin-induced pulmonary fibrosis - RACGP
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Clinical
Nitrofurantoin-induced
pulmonary fibrosis
John O’Bryen, Gwynne Hannay, QUESTION 2 a detailed past and present medication list,
Sarah Gleeson What medications are known to cause including chemotherapy, non-prescription
pulmonary fibrosis? medications and recreational drugs.
Resources such as the Pneumotox
CASE ANSWER 1 application (https://pneumotox.com) are
A woman aged 75 years presented to a Causes of pulmonary fibrosis include helpful in identifying culprit medications.2
general practitioner (GP) with a dry cough idiopathic pulmonary fibrosis,
and increasing exertional dyspnoea for autoimmune, environmental
the preceding three years. She was now (hypersensitivity pneumonitis), CASE CONTINUED
short of breath walking 50 metres. Her occupational (pneumoconiosis), Given the possibility of DIPF, the
cough was largely unproductive but could drug-induced pulmonary fibrosis (DIPF) nitrofurantoin was ceased, and the
produce a small amount of clear sputum and radiation. Given this patient’s history, patient felt an improvement of her
in the morning. She had experienced the lead differentials are idiopathic symptoms over the following weeks. She
episodes of atypical chest pain. There was pulmonary fibrosis and DIPF. was referred to a respiratory physician
no history of haemoptysis, orthopnoea, and cardiologist. The cardiologist
paroxysmal nocturnal dyspnoea or pedal ANSWER 2 arranged a myocardial perfusion scan
oedema. She had never smoked, received Many offending medications are cancer and echocardiography, which helped
chemotherapy or had occupational dust therapies, rheumatological therapies exclude ischaemic heart disease and
exposures or recurrent chest infections. and antibiotics.1 Those commonly seen heart failure. The echocardiogram did
Her medical history included use of in general practice include amiodarone, not show pulmonary hypertension. The
nitrofurantoin 50 mg daily for the nitrofurantoin and methotrexate. When respiratory physician arranged complex
preceding six years as prophylaxis for assessing for DIPF, it is important to obtain lung function tests, which showed a
urinary tract infections.
On examination, she had a blood
pressure of 120/80 mmHg and oxygen
saturation of 95% on room air. She did not
have digital clubbing, and heart sounds
were dual with no murmurs. There were
fine inspiratory crackles throughout the
lung fields, particularly at the bases, and
reduced breath sounds. The patient was
referred for computed tomography (CT)
of the chest, which showed advanced
pulmonary fibrosis (Figure 1).
Figure 1. Computed tomography images of the lungs demonstrating peripheral reticular
opacification, which involves the upper (image on left) and lower lobes (image on right) with a
QUESTION 1 slight basal predominance. There is honeycombing present and minimal ground glass changes.
What are the causes of pulmonary fibrosis?
© The Royal Australian College of General Practitioners 2022 Reprinted from AJGP Vol. 51, No. 3, March 2022 149
Clinical Nitrofurantoin-induced pulmonary fibrosis mild restrictive ventilatory deficit with 300 metres. She had received vaccination QUESTION 3 a moderate impairment in gas transfer for influenza and pneumococcus. She was What screening blood tests could be used to (after correction for volume restriction). encouraged to remain a non-smoker and investigate causes of pulmonary fibrosis? The results are shown in Figure 2. to engage in pulmonary rehabilitation. A pulmonary fibrosis association Given the improvement in her symptoms QUESTION 4 screening panel was negative. Repeat following the cessation of nitrofurantoin, What monitoring is required for patients CT of the chest three months later a diagnosis of DIPF was made. The receiving a medication known to cause DIPF? showed no radiological progression of medication adverse event was reported the pulmonary interstitial fibrosis. At this to the Therapeutic Goods Administration QUESTION 5 time, the patient reported her shortness (TGA). Which medication adverse events should of breath on exertion had improved to be reported to the TGA? Figure 2. Complex lung function test results CH4, methane; Chg, change; CO, carbon monoxide; DLCO_SB, single-breath diffusing lung capacity for carbon monoxide; DLCOcSB, single-breath diffusing lung capacity for carbon monoxide corrected for haemoglobin; ERV, expiratory reserve volume; F/V ex, expiratory flow/volume; FEV 1, forced expiratory volume in one second; FIF 50, 50% of forced vital capacity; FRCpleth, functional residual capacity; FVC, forced vital capacity; Hb, haemoglobin; KCO_SB, single-breath transfer coefficient of the lung for carbon monoxide; KCOc_SB, single-breath transfer coefficient of the lung for carbon monoxide corrected for haemoglobin; LL, lower limit; MEF 50, maximal expiratory flow at 50% of the forced vital capacity; MFEF 75/25, mid-forced expiratory flow rate of 25–75%; PEF, peak expiratory flow; PIF, peak inspiratory flow; Pred, predicted; RV, residual volume; T, time; TLC, total lung capacity; UL, upper limit; V, volume; VA_SB, single-breath alveolar volume; VC, vital capacity 150 Reprinted from AJGP Vol. 51, No. 3, March 2022 © The Royal Australian College of General Practitioners 2022
Nitrofurantoin-induced pulmonary fibrosis Clinical
ANSWER 3 pulmonary reactions have been observed
A screen could include the following with nitrofurantoin use. The estimated
depending on the situation: incidence of severe acute pulmonary
• autoimmune screen – antinuclear reactions is estimated at one in 5000
autoantibody, dsDNA, extractable short-term users, while chronic pulmonary
nuclear antigen, rheumatoid factor, reactions causing hospitalisation occur in
anti–cyclic citrullinated peptide approximately one in 750 long-term users.5
• if myositis-associated interstitial lung
disease is suspected – extended myositis
panel, creatine kinase Key points
• vasculitic screen – anti-neutrophil • Typical presenting symptoms of
cytoplasmic antibodies and perinuclear pulmonary fibrosis are dry cough and
anti-neutrophil cytoplasmic antibodies exertional dyspnoea.
• if sarcoidosis is suspected – serum • Numerous medications can cause
angiotensin-converting enzyme pulmonary fibrosis, and patients require
• if hypersensitivity pneumonitis related monitoring for its occurrence.
to bird exposure is suspected – avian • Serious medication adverse events
precipitins. should be reported to the TGA.
ANSWER 4
Authors
The clinician should consult a reliable
John O’Bryen BSc, MBBS, FRACGP, FARGP,
source, such as product information or DipDerm, General Practitioner, Qld
local guideline, to determine baseline Gwynne Hannay BEng (Medical), PhD, MBBS,
FRACGP, General Practitioner, Qld
evaluation and monitoring. Typically,
Sarah Gleeson BMed, FRACP, Respiratory and
monitoring for DIPF involves a baseline Sleep Physician, Qld
chest X-ray and lung function test, with Competing interests: None.
periodic lung function tests thereafter. Funding: None.
Ideally the doctor initiating the medication Provenance and peer review: Not commissioned,
externally peer reviewed.
would perform the baseline evaluation.
Correspondence to:
It should be made explicit which doctor j.obryen@griffith.edu.au
is responsible for ongoing monitoring.
The patient should be educated about References
possible side effects and recommended 1. Skeoch S, Weatherley N, Swift AJ, et al. Drug-
induced interstitial lung disease: A systematic
monitoring. Use of a recall system would review. J Clin Med 2018;7(10):356. doi: 10.3390/
be ideal to ensure monitoring is not jcm7100356.
forgotten. A review article indicated that 2. Camus P. Pneumotox on line: The drug induced
respiratory disease website. Dijon, FR: Pneumotox,
approximately 50% of patients beginning 2021. Available at www.pneumotox.com [Accessed
amiodarone received minimum baseline 3 April 2021].
evaluation, and fewer than 25% received 3. Stelfox HT, Ahmed SB, Fiskio J, Bates DW.
Monitoring amiodarone’s toxicities:
the recommended ongoing surveillance.3 Recommendations, evidence, and clinical
In the case of long-term nitrofurantoin practice. Clin Pharmacol Ther 2004;75(1):110–22.
doi: 10.1016/j.clpt.2003.09.010.
use, there is no Australian authority
4. Therapeutic Goods Administration. Reporting
recommending routine screening with adverse events involving medicines, vaccines
chest X-rays and/or lung function tests. or medical devices. Canberra, ACT: TGA, 2021.
Available at www.tga.gov.au/reporting-adverse-
events [Accessed 26 January 2021].
ANSWER 5 5. Jick SS, Jick H, Walker AM, Hunter JR.
The TGA recommends a report be made Hospitalizations for pulmonary reactions following
nitrofurantoin use. Chest 1989;96(3):512–15.
for all suspected adverse events to new doi: 10.1378/chest.96.3.512.
therapeutic goods, all suspected medicine
and/or vaccine interactions, undocumented
adverse events and serious adverse events.4
In this case, the adverse event was reported
as the nitrofurantoin caused significant
harm to the patient. Clinicians should be
aware that acute, subacute and chronic correspondence ajgp@racgp.org.au
© The Royal Australian College of General Practitioners 2022 Reprinted from AJGP Vol. 51, No. 3, March 2022 151You can also read
