The current study describes the epidemiology of bacterial, viral and fungal infection in a large cohort of patients with haematological malignancies receiving CAR T-cell therapy and focuses on their respective, possible causes. Half of the patients receiving CAR T-cell therapy will develop an infection. Understanding the factors related to these infections and their epidemiology is key to providing the best preventive and early treatment strategies for this population.
Our study describes a similar number of infections in patients receiving different CAR T-cells and/or having different baseline haematological diseases. Infections were frequent both in the neutropenic phase or in later stages of the therapy. However, the cause and, consequently, the epidemiology of these infections varied according to patients’ treatment stage. We documented a high percentage of nosocomial infections—mainly related to the use of vascular catheters and the need of mechanical ventilation devices—in the early phase following chemotherapy administration prior to CD19-targeted and BCMA-targeted CAR T-cell therapy and beyond the neutropenia period. Strict adherence to recommendations that aim to prevent nosocomial infections is essential to reduce the incidence of infections in this population 14–16. It is important to remember that antibiotic prophylaxis might have little impact within this specific context.
In neutropenic patients, bacterial, fungal and viral infections have been documented, as previously reported 5,7,17–19. A cause of bacterial infection in this period is the endogenous translocation of intestinal microorganisms into the bloodstream. In our study, this cause represented only 16% of infections in neutropenic patients. It is important to note that in our centre, all patients had received antibiotic prophylaxis during the neutropenic stage. However, the role of universal antibacterial prophylaxis in this scenario is controversial5,17. Our study provides additional data suggesting that patients with severe mucositis and concomitant corticosteroid use may be those who benefit most from antibacterial prophylaxis in the neutropenic phase. This results are comparable with those obtained by other authors5,17,19. Investigators Rejeski et al.20 stratified patients following five pre-lymphodepletion variables to identify patients in whom antibacterial prophylaxis significantly reduced the likelihood of severe bacterial infections.
Furthermore, Clostridiodes difficile has been described as a frequent infectious disease issue for these patients 17,21. In our cohort, this infection was documented relatively frequently in neutropenic patients. Lowering this figure poses a challenge for physicians, though. Patients receiving CAR T-cell therapy often have fever and elevated inflammatory biomarkers following the infusion. Thus, it is nowadays difficult to distinguish inflammatory reactions due to CRS from infections. Consequently, prolonged use of broad-spectrum antibiotics is common. Further studies to demonstrate the safety of early antibiotic de-escalation strategies in patients receiving CAR T-cell therapy and presenting fever but without evidence of infection are warranted.
Finally, respiratory infections are very common, especially in later treatment stages when the patient has normal neutrophil count but still presents B-cell aplasia and hypogammaglobulinemia. Although a conserved humoral immunity to some viruses after CD19-targeted CAR T-cell therapy has been reported 22, respiratory viral infections were frequent in our study. Vaccination strategies would, therefore, be extremely important to help reduce these infections. However, of note, many of these patients might have a poor response to vaccines. In such a scenario, it would be a suitable strategy to vaccinate those in close contact or quarters. Further studies on vaccination after CAR T-cells are necessary. Another strategy to prevent respiratory infections is the use of immunoglobulins. Although there is debate about the usefulness of IgG replacement in this population, the high rate of respiratory infections in our cohort suggests that this strategy might be needed. Hill et al 17 provided an algorithm based on data from other contexts for immunoglobulin replacement within the first three months after CD19-targeted CAR T-cell therapy. These authors recommend IgG replacement in those patients with serum IgG lower than 400 mg/dL, even before CAR-T infusion.
Our study has several limitations. It was a retrospective and descriptive study from one hospital with specific prophylaxis strategies. Frequency and epidemiology of infections may be different in other centres. Second, the relatively small number of patients included in the study precludes further risk factor analyses. Finally, this study was non-interventional; therefore, some infection diagnostic methods may have been underused by the attending physicians.
As a conclusion, a high number of patients have infections after treatment with CAR T-cells. The causes of these infections, and consequently their epidemiology, vary in relation to the different treatment periods. Clinicians should aim to prevent nosocomial infections. It is important to identify patients with a more elevated risk of infection during the neutropenic and hypogammaglobulinemia phases to implement prophylactic measures and limit the use of antibiotics to decrease Clostridioides difficile infections. Through these means, there may be a higher likelihood of clinical outcomes in this series of patients.
