Can Tacrolimus (TAC) cause intermittent fever?

Can Tacrolimus Cause Intermittent Fever?

Yes, tacrolimus can cause intermittent fever as a rare but documented adverse effect, typically presenting as drug-induced fever that resolves within 24 hours of discontinuation.

Evidence for Tacrolimus-Induced Fever

The most compelling evidence comes from a case series specifically documenting tacrolimus-induced drug fever in renal transplant recipients. Three patients developed drug-induced fever one to five months after renal transplantation while on tacrolimus, with extensive workup excluding infection, autoimmune disease, and malignancy 1. Critically, fever completely resolved within 24 hours after discontinuing tacrolimus and switching to cyclosporine A 1.

A similar pattern was observed with sirolimus (another immunosuppressant), where a patient on tacrolimus and mycophenolate developed intermittent high fever, fatigue, myalgias, and diarrhea after sirolimus was added 2. While this case primarily implicated sirolimus, it demonstrates that mTOR inhibitors and calcineurin inhibitors can cause drug fever in transplant patients on complex immunosuppressive regimens 2.

Distinguishing Drug Fever from Infection

The critical clinical challenge is that tacrolimus causes immunosuppression with increased susceptibility to infection, making fever far more likely to represent true infection than drug fever 3, 4. The FDA black box warning explicitly states that tacrolimus increases infection risk, and serious infections can cause death 4.

Key Diagnostic Features of Tacrolimus-Induced Drug Fever:

• Timing: Typically occurs 1-5 months post-transplant 1
• Pattern: Intermittent high fever without clear infectious source 2, 1
• Associated symptoms: May include fatigue, myalgias, and diarrhea 2
• Laboratory findings: Elevated inflammatory markers (LDH, CRP) but normal white blood cell count 2
• Negative workup: Extensive cultures, serologies, and imaging exclude infection, malignancy, and autoimmune disease 2, 1
• Rapid resolution: Fever resolves within 24 hours of stopping tacrolimus 1

Clinical Approach to Fever in Tacrolimus-Treated Patients

Always assume infection first in any patient on tacrolimus presenting with fever, given the life-threatening implications of untreated infection in immunosuppressed patients 3, 4.

Systematic Evaluation:

1. Immediate infectious workup: Blood cultures, urinalysis, chest imaging, and site-specific cultures based on symptoms 3
2. Monitor tacrolimus levels: Check trough levels, as toxicity can present with fever and other systemic symptoms 3
3. Review medication interactions: CYP3A4 inhibitors can increase tacrolimus levels and toxicity 3
4. Consider opportunistic infections: Pneumocystis jiroveci pneumonia (note: blood eosinophilia may be an early indicator in tacrolimus patients) 5, viral infections including EBV 6, and fungal infections 3

When to Consider Drug Fever:

Drug fever should only be considered after exhaustive exclusion of infection, malignancy, and rejection 2, 1. This diagnosis requires:

• Multiple negative cultures over several days 2, 1
• Failure to respond to broad-spectrum antibiotics 2
• Normal or non-diagnostic imaging 2, 1
• Stable graft function excluding rejection 2, 1
• No evidence of malignancy (particularly lymphoma, given tacrolimus's black box warning) 3, 4

Management Strategy

If drug fever is suspected after excluding other causes, switch tacrolimus to an alternative immunosuppressant (such as cyclosporine A) rather than simply stopping immunosuppression 1. Complete cessation risks organ rejection 3.

Monitoring Parameters:

• CBC with differential: Monitor for bone marrow suppression and leukopenia 3
• Renal and hepatic function: Check every 4-6 weeks minimum 3
• Electrolytes: Potassium and magnesium levels 3
• Glucose: Monitor for hyperglycemia and diabetes mellitus 3
• Blood pressure: Frequent monitoring for hypertension 3

Critical Pitfalls to Avoid

• Never attribute fever to drug effect without comprehensive infectious workup 3, 4
• Do not stop tacrolimus abruptly without alternative immunosuppression, as this risks acute rejection 3
• Remember that diarrhea with tacrolimus can paradoxically increase drug levels (due to intestinal epithelial damage affecting P-glycoprotein), potentially causing toxicity-related symptoms including fever 7
• Recognize that tacrolimus levels may be normal in drug fever cases, as this appears to be an idiosyncratic reaction rather than dose-dependent toxicity 2, 1