Infection associated with immune checkpoint inhibitors

Immune Checkpoint Inhibitors (ICI) are used to treat malignancy (breast CA, bladder CA, cervical CA, lung CA, colon CA, Hodgkin lymphoma etc). There are three types of ICIs

Type of ICIs	Example
Programmed death 1(PD-1) inhibitors	Atezolizumab, Avelumab, Durvalumab
Programmed death 1 ligand (PD-L1) inhibitors	Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab
cytotoxic T lymphocyte-associated antigen 4 (CTLA4) inhibitors	Ipilimumab, Tremelimumab

How does the ICI work?

PD-1 and PD-L1 inhibitors

Activated CD4 and CD8 T-cells express PD-1 on their surface. On coming into contact with the malignant cells, T cells secrete pro-inflammatory cytokines (e.g. IFN‐γ). The IFN‐γ upregulate the expression of PD-L1 on tumour cells. PD-1 binds to the PD-L1 to downregulate the T-cell response. This is a natural brake (immune checkpoint) to limit the damage caused by the T cells.

PD1 and PD-L1 blockers remove this brake and increase the effectiveness of the T cell-mediated damage, leading to better clearance of the malignant cells.

Unfortunately, as a side effect of this action, the risk of damage to the non-tumour cells is also high. These side effects are called immune-related Adverse Effects (irAE). These irAEs are treated with steroids and infliximab.

On its own, the ICI usually does not increase the risk of infection significantly. However, the risk of infection increases due to frequent irAEs associated with ICI use. The management of irAEs requires steroids/infliximab, which causes immunosuppression, increasing the risk of infection.
ICI induced neutropenia has been reported in some patients – which may increase the risk of infection directly. [Abers, 2020]

CTLA4 inhibitors

Another type of checkpoint is CTLA4. When an antigen-presenting cell (APC) presents a foreign antigen (pathogen) to the T cells, it uses two types of signals.
Signal 1 – MHC on the APC present the foreign antigen to the T-cell receptor.
Signal 2 – A costimulation process where CD80/CD86 on the APC interact with the CD28 on the T-cell. This is blocked by CTLA4 (another immune checkpoint). CTLA4 tries to regulate the T cell response to limit the T cell-mediated damage.

CTLA4 can be blocked by ICIs like Ipilimumab.

Infections associated with ICIs

• The most common infection is bacterial (Pneumonia, Intra-abdominal infection, bacteremia) – 85%.
• C difficile-associated diarrhoea has been reported.
• ICI therapy with meningitis/encephalitis – consider Listeria (PD-L1 block may worsen the clinical outcome of Listeria infection).
• Reactivation of TB has been reported, mostly within 3 -6 months of exposure.

• Other infections – VZV, CMV, EBV and opportunistic fungal infection (Pneumocystis jiroveci, Aspergillus, and Candida).
• CMV infection has been seen in CPI-induced colitis – refractory to steroids.

• Time of exposure to infection – 1 week to >1 year (most infections occur within 6 months – 80%).
• Most cases are associated with steroid exposure.
• Diabetes is a risk factor.

Screening:

• Screening for Latent TB (IGRA) before ICI treatment.
• Screening for HCV, HBV and HIV – due to the possibility of reactivation if the patient receives treatment for irAEs in future.
• Chest CT scan if the patient is suspected of having chronic pulmonary Aspergillosis.

Monitoring and treatment

• Patients on steroid/ infliximab should be closely monitored for infection and reactivation of latent infection (HBV/HCV) for several months.
• Patients expected to receive prolonged high-dose steroid [prednisone (≥ 20 mg/day)] may need Pneumocystis (expected >4 weeks of steroid use) and antifungal (expected >6 weeks of steroid use) prophylaxis.
• Prophylaxis for herpes zoster reactivation.
• Strict diabetic control is required.
• Appropriate vaccination
• Anti-TB therapy if reactivation of TB occurs. Discontinuation of immunotherapy could be considered, but specialist opinion should be taken. [Lu 2020]