What is the infection risk and severity in Crohn disease patients on immunosuppressive agents (systemic corticosteroids, azathioprine, 6‑mercaptopurine, methotrexate, anti‑tumor necrosis factor antibodies such as infliximab (Remicade), adalimumab (Humira), certolizumab (Cimzia), vedolizumab (Entyvio), ustekinumab (Stelara)), and how should screening, vaccination, and treatment be managed?

Infection Risk and Management in Crohn's Disease Patients on Immunosuppressive Therapy

Infection Risk Stratification

Crohn's disease patients on immunosuppressive therapy face substantially elevated infection risks, with combination therapy (particularly thiopurines plus steroids or anti-TNF agents) increasing opportunistic infection odds ratios from 2.9 for single agents to 14.5 for dual/triple therapy—the highest risk scenario being patients over 65 years on anti-TNF agents, who face up to a 20-fold increased risk of severe infections (11% vs 0.5% in younger patients). 1

Agent-Specific Infection Profiles

Anti-TNF agents (infliximab, adalimumab, certolizumab):

• Carry the highest infection risk among IBD therapies, particularly for mycobacterial and fungal infections 1
• Opportunistic infections include tuberculosis (both reactivation and new infection), invasive fungal infections (aspergillosis, histoplasmosis, coccidioidomycosis, blastomycosis), and bacterial infections 2, 3
• Patients frequently present with disseminated rather than localized disease 2
• Each 100-point increase in CDAI score increases opportunistic infection risk by 30% in patients on adalimumab 1, 4

Systemic corticosteroids:

• Doses ≥20 mg for >2 weeks constitute moderate-severe immunosuppression 1
• Associated with 1.85-fold relative risk of infections at high doses, compared to 1.10-fold at <5 mg/day 1
• Specifically increase risk of fungal infections (Candida) and bacterial infections 1
• Concomitant corticosteroid use with adalimumab increases serious infection risk 2.4-fold by day 120 4

Thiopurines (azathioprine, 6-mercaptopurine):

• Doses >3 mg/kg/day (azathioprine) or >1.5 mg/kg/day (6-MP) constitute moderate-severe immunosuppression 1
• Primarily associated with viral infections, particularly herpes zoster (40% of opportunistic infections) 1, 4
• Lower doses can be considered low-degree immunosuppression 1

Methotrexate:

• Doses >20 mg/week (>0.4 mg/kg/week) constitute moderate-severe immunosuppression 1
• Lower doses represent low-degree immunosuppression 1

Vedolizumab:

• Gut-selective mechanism results in lower rates of non-gastrointestinal infections 1
• No increases in opportunistic infections reported due to gut selectivity 1
• Increased risk for enteric infections (Clostridioides difficile) 1

Ustekinumab:

• Likely lower immunosuppression compared to anti-TNF agents 1
• Classified as moderate-severe immunosuppression but with more favorable infection profile 1

Additional Risk Amplifiers

Patient-specific factors that compound infection risk:

• Age >65 years: up to 20-fold increased risk with anti-TNF therapy 1
• Malnutrition: OR 2.31 for opportunistic infections 1
• Obesity: OR 1.07 per kg/m² for opportunistic infections 1
• Active disease: each 100-point CDAI increase = 30% increased infection risk 1, 4
• Comorbidities (diabetes, chronic kidney/liver disease) 1

Pre-Treatment Screening Algorithm

Before initiating any immunosuppressive therapy, mandatory screening includes: 1

1. Tuberculosis assessment:

   • Tuberculin skin test (TST) or interferon-gamma release assay (IGRA) 2, 3
   • Consider induration ≥5 mm as positive, even in BCG-vaccinated patients 2, 3
   • Chest radiograph if latent TB suspected 2, 3
   • Initiate anti-tuberculosis therapy before starting anti-TNF agents in patients with latent TB or past inadequately treated TB 2, 3

2. Viral serology:

   • Hepatitis A, B, C 1
   • HIV 1
   • Epstein-Barr virus 1
   • Cytomegalovirus 1
   • Varicella zoster virus (particularly important before thiopurines) 1

3. Endemic fungal infection risk assessment:

   • Travel/residence history in endemic regions (histoplasmosis, coccidioidomycosis, blastomycosis) 2, 3

Vaccination Strategy

Complete all vaccinations BEFORE initiating moderate-severe immunosuppression: 1

Contraindicated vaccines (live vaccines) during moderate-severe immunosuppression:

• Live vaccines are absolutely contraindicated in patients on systemic steroids ≥20 mg for >2 weeks, anti-TNF agents, calcineurin inhibitors, methotrexate >20 mg/week, or azathioprine >3 mg/kg/day 1

Recommended killed/inactivated vaccines:

• Pneumococcal (PCV13 followed by PPSV23) 1
• Annual influenza (inactivated) 1
• Hepatitis B (if non-immune) 1
• HPV 1
• Herpes zoster (recombinant, non-live vaccine preferred given high risk with thiopurines) 4

Critical caveat: Vaccine efficacy may be diminished in immunosuppressed patients; administer vaccines before starting therapy whenever possible 1

Monitoring During Therapy

Ongoing surveillance requirements:

• Clinical monitoring: Closely monitor for signs/symptoms of infection at every visit 2, 3
• Tuberculosis: Periodic TB testing during therapy, as tests may be falsely negative while on treatment 2, 3
• New infection threshold: Any new systemic illness warrants prompt diagnostic workup appropriate for immunocompromised patients 2, 3

Management of Active Infections

Immediate discontinuation of immunosuppressive therapy is mandatory if:

• Serious infection develops 2, 3
• Sepsis occurs 2, 3
• Opportunistic infection is diagnosed 2, 3

Diagnostic approach for new infections:

• Perform complete diagnostic workup appropriate for immunocompromised host 2, 3
• For systemic illness in patients residing/traveling in endemic fungal regions: empiric antifungal therapy while diagnostic workup proceeds (antigen/antibody testing may be falsely negative) 2, 3
• Consider tuberculosis in differential for any new infection, especially in patients with travel history or TB exposure 2, 3
• Consult infectious disease specialists for invasive fungal infections or complex opportunistic infections 2, 3

High-Risk Scenarios Requiring Intervention

Triple immunosuppression (anti-TNF + thiopurine + corticosteroid) represents the highest-risk scenario and should be avoided whenever possible. 1

Patients requiring continuous corticosteroids while on biologics:

• This indicates treatment failure 1
• Severe infection rate reaches 11% in patients >65 years on this regimen 1
• Alternative medical treatments or surgery should be explored rather than continuing triple therapy 1

Corticosteroid-sparing strategies are essential:

• Anti-TNF agents demonstrate superior corticosteroid-sparing compared to azathioprine (43% vs 27% at 12 months) 5
• Thiopurines and methotrexate facilitate corticosteroid withdrawal when used as maintenance therapy 6, 7

Common Pitfalls to Avoid

1. Failing to screen for latent TB before anti-TNF initiation: TB reactivation can occur despite prophylaxis, but screening and treatment reduce risk substantially 2, 3

2. Administering live vaccines to patients on moderate-severe immunosuppression: This creates risk of vaccine-strain infection 1

3. Continuing immunosuppression during active serious infection: Immediate discontinuation is required 2, 3

4. Underestimating infection risk in elderly patients: The 20-fold increased risk in patients >65 on anti-TNF therapy demands heightened vigilance 1

5. Ignoring endemic fungal infection risk: Travel/residence history is critical; empiric antifungal therapy may be needed before diagnostic confirmation 2, 3

6. Maintaining triple immunosuppression in corticosteroid-dependent patients: This represents treatment failure with unacceptable infection risk—switch therapy or consider surgery 1