Pneumocystis jirovecii pneumonia associated with immune checkpoint inhibitors: A systematic literature review of published case reports and disproportionality analysis based on the FAERS database

Abstract

Background: Pneumocystis jirovecii pneumonia (PJP) has been reported with ICIs but limited to case reports. The clinical features of PJP with ICIs remain mostly unknown. This study aims to investigate the association of PJP with ICIs and describe clinical features.Methods: Reports of PJP recorded in FAERS (January 2004–December 2022) were identified through the preferred term “Pneumocystis jirovecii pneumonia”. Demographic and clinical features were described, and disproportionality signals were assessed through the Reporting Odds Ratio (ROR) and Information Component (IC), using traditional chemotherapy and targeted therapy as comparators, and adjusting signals by excluding contaminant immunosuppressive drugs and pre-existing diseases. A systematic literature review was conducted to describe clinical features of published PJP reports with ICIs. Bradford Hill criteria was adopted for global assessment of the evidence.Results: We identified 677 reports of PJP associated with ICIs, in which 300 (44.3%) PJP cases with fatal outcome. Nivolumab (IC025 2.05), pembrolizumab (IC025 1.88), ipilimumab (IC025 1.43), atezolizumab (IC025 0.36), durvalumab (IC025 1.65), nivolumab plus ipilimumab (IC025 1.59) have significant signals compared to other drugs in FAERS database. After excluding pre-existing diseases and immunosuppressive agents which may increase susceptibility of PJP, the signals for PJP associated with nivolumab, pembrolizumab, durvalumab, nivolumab plus ipilimumab remained robust (IC025 > 0). When compared to other anticancer regimens, although all ICIs showed a lower disproportionate signal for PJP than chemotherapy, nivolumab (IC025 0.33, p < 0.001), pembrolizumab (IC025 0.16, p < 0.001), both PD-1 inhibitors, presented a higher signal for PJP than targeted therapy. Male gender (IC025 0.26, p < 0.001) and age >65 years (IC025 0.38, p < 0.001) were predominant in PJP cases associated with across all ICIs. In literature, 15 PJP cases associated with ICIs were reported in 10 published case reports. 12 of 15 (80.0%) of cases received PD-1 inhibitors before PJP was diagnosed.Conclusion: By the combined analysis of post-marketing data from FAERS and published case reports, we identified ICIs may be associated with PJP, especially in males aged >65years. After accounting for confounders, PD-1 inhibitors emerged with a robust disproportionality signal when compared to PD-L1/CTLA-4 inhibitors as well as targeted therapy. Further research is warranted to validate our findings.

Protocol for the systematic review of the Pneumocystis jirovecii-associated pneumonia in non-HIV immunocompromised patients

“…Moreover, more recent studies have demonstrated a high seroprevalence of P . jirovecii , in healthy individuals with HIV as well as elevated rates of clinical disease among patients with non-HIV immunosuppression, including those undergoing corticosteroid treatment, chemotherapy, organ transplants, or managing autoimmune diseases [ 4 – 7 ]. Apparently, from an epidemiologic viewpoint, the increase in prevalence among patients with non-HIV immunosuppression may be explained possibly as a result of improved access to diagnostics and treatment [ 8 ].…”

“…patients with non-HIV immunosuppression, including those undergoing corticosteroid treatment, chemotherapy, organ transplants, or managing autoimmune diseases [4][5][6][7]. Apparently, from an epidemiologic viewpoint, the increase in prevalence among patients with non-HIV immunosuppression may be explained possibly as a result of improved access to diagnostics and treatment [8].…”

“…In contrast, the prevalence of PJP has risen steadily and has emerged as a major cause of morbidity and mortality among patients with non-HIV immunosuppression [ 4 ]. These patients have different causes of immune system alterations that can increase the risk of developing PJP, such as hematological or solid malignancies [ 5 ], organ transplantation [ 2 ], inflammatory or autoimmune diseases [ 6 ], as well as immunosuppressive treatments [ 6 , 7 ].…”

Pneumocystis jirovecii Pneumonia (PCP) in a Non-HIV Lung Cancer Patient in the Absence of Common Risk Factors

“…Ray A et al reported a case of PCP infection in a metastatic breast cancer patient, though the patient was on biological therapy [ 11 ]. Additionally, there have been cases reported of PCP infections in malignancies but usually, patients are on chemotherapy or biological therapies [ 6 , 12 ]. PCP infection remains a rare occurrence either way, especially in patients suffering from lung cancer [ 6 ].…”

Model Driven Method for exploring Individual and Confounding Effects in Spontaneous Adverse Event Reporting Databases

“…These SAER databases accept the ADR reports in real-time, such as FDA Adverse Event Report System (FAERS), Korea Adverse Event Reporting System (KAERS), Canada Vigilance Adverse Reaction Online Database (CVARD), Europe's Eudravigilance (EV), etc. Data mining from these SAER databases involves identifying drug-AE combinations with high frequency [3]. To identify the signi cant signals of drug-AE combinations, disproportionality measures, such as Proportional Reporting Ratios (PRR) and Reported Odds Ratio (ROR), are developed [4].…”