Can tuberculosis (TB) medications, such as isoniazid, rifampicin, pyrazinamide, and ethambutol, cause fever?

Can TB Medications Cause Fever?

Yes, tuberculosis medications can cause fever as a documented adverse effect, with rifampicin being the most common culprit, followed by para-aminosalicylic acid and pyrazinamide, though isoniazid can also rarely cause isolated fever. 1, 2

Specific Medications That Cause Fever

Rifampicin (Most Common)

• Rifampicin causes a "flu-like" syndrome characterized by fever, chills, and headache, particularly with intermittent dosing regimens rather than daily administration 1
• This syndrome occurs more frequently when rifampicin is taken irregularly or when daily administration is resumed after a drug-free interval 3
• The fever typically presents as episodes accompanied by dizziness and bone pain 3
• Side effects are more common with intermittent regimens, especially when daily dosage exceeds 600 mg 1

Isoniazid (Rare but Documented)

• Isoniazid can cause isolated fever without other manifestations, which may be misdiagnosed as an infectious process 4
• The fever typically develops within the first week of treatment and presents as spiked afternoon fevers 4
• Isoniazid-induced flu-like syndrome is very rare but well-documented, with symptoms occurring within 1 hour of drug ingestion and subsiding within 12 hours 5
• This reaction can occur without evidence of hypersensitivity, normal liver function tests, and normal leukocyte counts 4

Pyrazinamide

• Pyrazinamide is the third most common cause of drug-induced fever among anti-TB medications 2
• Gastrointestinal symptoms and hepatic transaminase elevations may accompany the fever 1

Clinical Presentation and Timing

Onset Pattern

• Drug fever typically occurs within 2 months of starting treatment, most commonly between 1-3 weeks 2
• The main symptom is high fever with body temperature above 39°C 2

Accompanying Symptoms

• Rash, chills, headache, stuffy nose, runny nose, nausea, vomiting, and joint pain may occur 2
• Eosinophilia may be present (increased in some cases, decreased in others) 2
• Liver function abnormalities occur in approximately 16% of cases (10 of 63 patients tested), with frank liver damage in 6% 2

Diagnostic Approach

Confirming Drug-Induced Fever

• Rechallenge testing is the gold standard: fever recurs upon reintroduction of the offending drug and subsides with discontinuation 4, 5
• Rule out other causes: ensure no evidence of infection at other sites, normal routine biochemistry, and negative autoimmune markers 4
• Monitor for hypersensitivity syndrome features: cutaneous reaction, eosinophilia, and organ involvement (hepatitis, pneumonitis, nephritis) 6

Key Pitfall to Avoid

• Do not assume fever during TB treatment is always due to inadequate disease control or secondary infection—drug-induced fever must be in the differential diagnosis 4

Management Protocol

Immediate Management

• Stop all suspected medications when drug fever is identified 7, 2
• For patients with complications (liver damage, rash), treat the complication first before reintroducing any drugs 2
• For uncomplicated cases, wait until body temperature normalizes before sequential drug reintroduction 2

Sequential Reintroduction Protocol

When reintroducing drugs after fever resolution 7:

1. Isoniazid first: Start 50 mg/day, increase to 300 mg/day after 2-3 days if no reaction, continue 2-3 more days before adding next drug
2. Rifampicin second: Start 75 mg/day, increase to 300 mg after 2-3 days, then to weight-appropriate dose after 2-3 more days
3. Pyrazinamide third: Start 250 mg/day, increase to 1.0 g after 2-3 days, then to weight-appropriate dose

• Monitor daily during reintroduction for fever recurrence 7
• If fever recurs, the most recently added drug is the offending agent and should be permanently excluded 7

Alternative Regimens When a Drug Must Be Excluded

If isoniazid causes fever and must be excluded 7:

• Use rifampicin, ethambutol, and pyrazinamide for 2 months, then rifampicin and ethambutol for 10 additional months (total 12 months)

If rifampicin causes fever and must be excluded 8:

• Use pyrazinamide, ethambutol, and a fluoroquinolone (levofloxacin or moxifloxacin) for 9-12 months
• Alternative: isoniazid-based regimen for 9 months with ethambutol for initial 2 months 7

If pyrazinamide causes fever and must be excluded 7:

• Use rifampicin and isoniazid for 9 months, with ethambutol for the initial 2 months

Prognosis

• Drug fever resolves completely upon discontinuation of the offending medication 4, 2
• Patients can be successfully rechallenged with alternative regimens without the causative drug 4, 5
• No treatment failures were reported when appropriate alternative regimens were used 4