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A 43-year-old Indian man presents to an emergency department in Doha, Qatar, with a fever and headache, low energy, and shortness of breath -- symptoms that he says he has had for about a week, but without cough or flu-like symptoms.

Physical examination shows he has a temperature of 39°C, basal crackles in both lungs, and an oxygen saturation level at room air of 91%; the rest of the physical exam is unremarkable.

The patient notes that he was diagnosed with tuberculosis (TB) meningitis about 2 months previously, and has been receiving treatment. About 2 weeks before this latest hospital visit, he developed drug-induced hepatitis and his first-line medications were switched to second-line anti-TB treatment with moxifloxacin 400 mg oral once daily, cycloserine 500 mg oral twice daily, rifampicin 600 mg oral once daily, ethionamide 500 mg oral once daily, and pyridoxine 50 mg oral once daily.

He is admitted to the hospital, and kept on droplet and airborne isolation, following COVID-19 protocols and the possibility of SARS-CoV-2 infection or pulmonary TB.

Laboratory test results are normal for white blood cell counts, eosinophils, procalcitonin, kidney and liver function tests, and electrolytes. His C reactive protein, however, is markedly elevated: 109.2 mg/L, compared with a normal range of 0-5 mg/L.

Chest x-ray reveals bilateral pulmonary infiltrates and patchy bilateral consolidation. The patient's files show that this was not observed in the previous chest x-ray taken when he was diagnosed with tuberculous meningitis.

Clinicians consider heart failure unlikely since the patient is not in clinical overload. The initial workup for infection is negative for any bacterial growth (including Mycoplasma pneumonia, Legionella pneumophila, and Chlamydia pneumonia). Nasopharyngeal polymerase chain reaction (PCR) tests eliminate possible infection with common respiratory viruses including influenza, parainfluenza, respiratory syncytial virus, and Middle East respiratory syndrome coronavirus.

In light of the patient's respiratory symptoms during the ongoing COVID-19 pandemic, clinicians perform two SARS-CoV-2 nasopharyngeal reverse transcription (RT)-PCR tests 24 hours apart, and both return negative results.

To rule out potential TB re-infection or drug resistance, an acid-fast bacilli (AFB) smear is tested by PCR, and culture from sputum is also tested, with negative results.

The team also considers the possibility of acute eosinophilic pneumonitis, but deems it unlikely since the patient is a non-smoker and his white cell differential count, including eosinophils, is normal. Hypersensitivity pneumonitis is similarly considered unlikely because the patient has not been exposed to animals or birds.

A combined HIV antibody/p24 antigen test is non-reactive.

Clinicians start the patient on empirical antibiotic treatment, and continue his ongoing treatment with 2 L supplemental oxygen through a nasal cannula.

Over the following several days, the patient continues to be feverish, and further investigation includes abdominal and thoracic computed tomography (CT) scans. His CT thorax shows perihilar and peribronchovascular ill-defined opacities with a patchy area of alveolar consolidation.

Scans also reveal ground-glass opacities at the base of the lungs, with small basal pleural thickening, and a few subcentimetric lymph nodes in the mediastinum. Patchy consolidation and air bronchograms, consistent with acute respiratory distress syndrome (ARDS), are also noted.

Five days after the patient's hospital admission, clinicians order a bronchoscopy and send bronchoalveolar lavage (BAL) and tissue samples for detailed analysis.

The results show predominant lymphocytes (63% lymphocytes, 20% neutrophils, and 16% macrophages), but negative for AFB and bacterial, viral, and fungal cultures. PCR for Pneumocystis jiroveci and SARS-CoV-2 are also negative, and BAL analysis rules out alveolar hemorrhage.

Histopathology identifies widened interstitial septae by loose connective tissue and few chronic inflammatory cells, including lymphocytes, histiocytes, and rare eosinophils, but there is no evidence of dense fibrosis.

In addition, the alveolar ducts and sacs are filled with organizing fibrinous material, and there is evidence of type II pneumocyte hyperplasia but no granulomas, vasculitis, viral inclusions, fungal elements, or malignancy.

Based on all the findings, clinicians suspect that the patient's pneumonitis is drug-induced, with the likely drug rifampicin, based on the patient's clinical presentation, tissue diagnosis, and available data. The team discontinues the patient's rifampicin on day 6 after admission, and start steroid therapy (prednisolone 40 mg orally once daily); the other anti-TB medications are continued.

Withdrawal of rifampicin effectively relieves the patient's symptoms -- his fever resolves by day 2 of steroid treatment, and he maintains normal oxygen saturation on room air. He is discharged to home in an asymptomatic condition with a 3-week tapering dose regimen of steroids, and scheduled for follow-up appointments with medicine and infectious disease clinics.

Two weeks later, the patient presents to the TB clinic, still free of symptoms. An attempt to reintroduce rifampicin results in the return of his previous symptoms, confirming the diagnosis of rifampicin-induced pneumonitis.

One month after discharge, at follow-up in the medical clinic, the patient is afebrile and asymptomatic, maintaining oxygen saturation on room air, and chest x-ray shows his lungs to be completely clear of infiltrates.

Discussion

Clinicians reporting this of rifampicin-induced pneumonitis note that the clinical and radiological similarities to COVID-19 infection make differentiation challenging, and that one of the difficulties in treating TB involves the potential adverse effects of first-line drugs such as rifampicin. That DNA-dependent RNA polymerase inhibitor, which has been used to treat TB for over 4 decades, offers broad bactericidal activity against mycobacteria and many gram-positive organisms.

The case authors note that although rifampicin-induced pneumonitis is rare, the drug has been linked with numerous other adverse effects, ranging from skin reactions to fulminant liver or kidney failure, which have been extensively studied in the setting of combination therapy with isoniazid in the treatment of TB.

The prevalence of drug-induced pneumonitis varies depending on the medication used -- while it reportedly affects up to 50% of patients using methotrexate, the prevalence is about 5-10% for non-cytotoxic drugs.

Given the importance of ruling out other causes, antibiotic-induced pneumonitis is generally diagnosed after an extensive workup that includes radiological imaging, bronchoscopy with lavage analysis, and biopsy.

The clinical, radiological, and histological findings for drug-induced pneumonitis are comparable to those for ARDS -- such as ground-glass opacities with air bronchograms. Histological findings for early ARDS include diffuse alveolar damage with an initial exudative phase, followed by hyaline membrane formation.

The case authors note that because the features of drug-induced pneumonitis – such as fever, cough, dyspnea, desaturation, and ground-glass opacities on CT scans of the thorax – are so similar to those of COVID-19 pneumonia, it is crucial to maintain all recommended isolation precautions until COVID-19 can be ruled out with confidence.

Malignancies, allergic bronchopulmonary aspergillosis, autoimmune conditions (such as Churg-Strauss vasculitis, acute eosinophilic pneumonia, and systemic lupus erythematosus), and drug reaction with eosinophilia and systemic symptoms syndrome can all also present with features of pneumonitis, and thus should be considered in the differential diagnosis.

Risk factors associated with pneumonitis related to non-cytotoxic drugs include diabetes mellitus, low serum albumin level, involvement of the lungs and pleura by rheumatoid arthritis, female sex, older age, and history of use of disease-modifying agents.

As in this case, the symptoms of rifampicin-induced pneumonitis generally include persistent low-grade fever and shortness of breath with or without cough. Diagnostic workup should begin with a chest x-ray, which may reveal interstitial infiltrates. Patients receiving antibiotic/anti-TB treatment whose symptoms persist despite testing negative for viral, bacterial, and mycobacterial pathogens should be further assessed.

The authors point to a of 60 patients in which CT thorax findings for antibiotic-induced pneumonitis included patchy ground-glass opacities with central opacities.

Other diagnostic tools that help differentiate drug-induced pneumonitis from SARS-CoV-2 pneumonia include the following, the case authors note:

• Bronchoscopy, with results showing a lymphocytic predominance in the BAL analysis; SARS-CoV-2 RT-PCR should be sent from the BAL to , as it is highly sensitive (sensitivity of 93%)

• Tissue biopsy: Common findings include a homogenous interstitial proliferation secondary to inflammatory cell infiltration, mild fibrosis, and type II pneumocyte hyperplasia

• Drug lymphocyte stimulation test, although the diagnostic capability remains controversial, with sensitivity ranging from 33% to 92% and as low as 11.6% for rifampicin; a positive test suggests an immunological reaction, while a negative result may be related to a cytotoxic process or a false-negative result due to decreased immunity secondary to steroid therapy

In pulmonary toxicities due to drugs including rifampicin, the first step is to discontinue the offending drug, the case authors emphasize, adding that glucocorticoid treatment has demonstrated excellent results, and may be used if there are no contraindications.

Conclusions

The team concludes that this patient's case highlights the importance of early, rapid, and accurate testing for SARS-CoV-2 and that timely diagnosis of rifampicin-induced pneumonitis requires a high clinical suspicion, detailed workup, and histopathological analysis to avoid permanent lung damage.

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