Pneumocystis jirovecii pneumonia in liver transplant recipients in an era of routine prophylaxis.

BACKGROUND: Pneumocystis jirovecii pneumonia (PCP) is an opportunistic infection in organ transplant recipients that may be prevented by antibiotic prophylaxis. We aimed to investigate the incidence rate (IR) of PCP and the related hospitalization and mortality rates in liver transplant recipients in an era of routine prophylaxis. METHODS: We included all adult liver transplant recipients transplanted at Rigshospitalet between January 1, 2011 and October 1, 2019. Microbiology data were obtained from the Danish Microbiology Database (MiBa), a national database containing all data from all Departments of Clinical Microbiology in Denmark receiving samples from both hospitals and general practices. According to local guidelines, PCP prophylaxis was initiated 1 week posttransplantation and discontinued after 6 months or sooner in patients experiencing side effects. RESULTS: We included 343 liver transplant recipients with 1153 person-years of follow-up (PYFU), of which 269 (78%) received PCP prophylaxis during the first 6 months posttransplantation. Seven (2%) recipients were diagnosed with PCP during follow-up. In the first 6 months posttransplantation and in 269 transplant recipients who received prophylaxis there were zero PCP events while the IR was 32 (95% confidence interval [CI] 2.9-148) per 1000 PYFU in 74 recipient who did not receive prophylaxis. During 7th to 12th month posttransplantation the IR was 20 (95% CI: 5.5-53) per 1000 PYFU. All seven (100%) recipients diagnosed with PCP were hospitalized, however none died. CONCLUSIONS: PCP was not detected in liver transplant recipients while on prophylaxis. Though, it worth mentioning that two out of the seven PCP patients received high-dose prednisolone before the PCP event. All liver transplant recipients with PCP were hospitalized, but none died. Randomized clinical trials to determine the optimal duration of prophylaxis are warranted.

Quantitative analysis of the CD4+ T cell response to therapeutic antibodies in healthy donors using a novel T cell:PBMC assay.

Many biopharmaceuticals (BPs) are known to be immunogenic in the clinic, which can result in modified pharmacokinetics, reduced efficacy, allergic reactions and anaphylaxis. During recent years, several technologies to predict immunogenicity have been introduced, but the predictive value is still considered low. Thus, there is an unmet medical need for optimization of such technologies. The generation of T cell dependent high affinity anti-drug antibodies plays a key role in clinical immunogenicity. This study aimed at developing and evaluating a novel in vitro T cell:PBMC assay for prediction of the immunogenicity potential of BPs. To this end, we assessed the ability of infliximab (anti-TNF-α), rituximab (anti-CD20), adalimumab (anti-TNF-α) and natalizumab (anti-α4-integrin), all showing immunogenicity in the clinic, to induce a CD4+ T cells response. Keyhole limpet hemocyanin (KLH) and cytomegalovirus pp65 protein (CMV) were included as neo-antigen and recall antigen positive controls, respectively. By analyzing 26 healthy donors having HLA-DRB1 alleles matching the European population, we calculated the frequency of responding donors, the magnitude of the response, and the frequency of BP-specific T cells, as measured by 3[H]-thymidine incorporation and ELISpot IL-2 secretion. KLH and CMV demonstrated a strong T cell response in all the donors analyzed. The frequency of responding donors to the BPs was 4% for infliximab, 8% for adalimumab, 19% for rituximab and 27% for natalizumab, which is compared to and discussed with their respective observed clinical immunogenicity. This study further complements predictive immunogenicity testing by quantifying the in vitro CD4+ T cell responses to different BPs. Even though the data generated using this modified method does not directly translate to the clinical situation, a high sensitivity and immunogenic potential of most BPs is demonstrated.