Infection Risk Associated with Azathioprine Therapy
Azathioprine monotherapy does not appear to give rise to a marked increase in susceptibility to infections, but combination with other immunosuppressants significantly increases infection risk. 1
General Infection Risk
- Azathioprine is classified as causing moderate-severe immunosuppression at doses >3 mg/kg/day, which affects infection susceptibility 1
- The risk of infection with azathioprine varies depending on:
- Bone marrow suppression, particularly neutropenia, is a dose-dependent side effect occurring in 5-30% of patients that increases infection risk 1
- Mild lymphopenia is common with thiopurine therapy and may contribute to infection susceptibility 1
Specific Infection Risks
Viral Infections
- Varicella zoster virus (VZV) infections occur more commonly in patients receiving azathioprine 1
- Herpesvirus family infections (including cytomegalovirus) are the most frequent opportunistic infections in patients on azathioprine 2
- Azathioprine selectively induces NK cell depletion and IFN-γ deficiency, predisposing to herpesvirus reactivation 3
- Fatal cases of Epstein-Barr virus infection have been reported in patients on azathioprine 4
Bacterial and Other Infections
- Patients receiving immunosuppressants like azathioprine are at increased risk for bacterial, viral, fungal, protozoal, and opportunistic infections, including reactivation of latent infections 5
- Reactivation of latent tuberculosis has been reported, though routine TB screening is not required before starting azathioprine monotherapy 6
- Progressive multifocal leukoencephalopathy (PML) from JC virus has been reported in patients on azathioprine 5
Risk Factors for Infection
- Combination therapy with corticosteroids significantly increases infection risk compared to azathioprine monotherapy 1
- Elderly patients are at particularly high risk, with infection being a significant cause of mortality in elderly patients with bullous pemphigoid treated with azathioprine and prednisolone 1
- Patients with hepatic or renal impairment require more careful monitoring due to increased risk 1
- TPMT or NUDT15 deficiency increases risk of severe myelosuppression, which can lead to secondary infections 5
Monitoring and Prevention
- Weekly monitoring of full blood count (FBC) for the first 4 weeks of therapy, then monthly or every 2 months for the duration of treatment 1
- More frequent monitoring is required for patients with hepatic or renal impairment, the elderly, and those on higher doses 1
- Patients should be instructed to report immediately any evidence of infection, unexpected bruising or bleeding 1
- Patients who have not previously had chickenpox should be identified before starting azathioprine and advised to seek immediate attention if exposed to VZV 1
- Live vaccines are contraindicated in patients receiving azathioprine 1
- Killed vaccines may have diminished efficacy in patients on azathioprine 1
Management of Infections
- Consider temporary withdrawal of azathioprine if VZV infection occurs 1
- Prompt use of appropriate antivirals for herpesvirus infections 1, 2
- Consider reducing immunosuppression in patients who develop PML 5
- For serious infections, azathioprine should be discontinued and appropriate antimicrobial therapy initiated 5, 2
Common Pitfalls and Caveats
- Mild lymphopenia is common and not necessarily an indication to reduce dose unless levels fall below 0.5 × 10^9 L^-1 1
- Infection can occur even without neutropenia, so normal blood counts do not rule out infection risk 1
- TPMT activity measurement should not be performed just after bone marrow depression as it may be falsely elevated 7
- Hepatotoxicity may be confused with viral hepatitis (e.g., cytomegalovirus) in patients on azathioprine 8
- The risk of TB in patients on azathioprine depends on the local disease burden of TB 6