Maria Angeles Marcos

Human herpesvirus 6 (HHV-6) comprises two genetically and biologically distinct species, HHV-6A and HHV-6B, yet species-level differentiation is rarely performed in clinical practice. We conducted a retrospective study of 119 immunocompromised adults with detectable HHV-6 DNA between 2020 and 2025 to characterize species distribution, compare epidemiological, clinical, and virological features, and evaluate the diagnostic relevance of genotyping. Viral species were detected by real-time polymerase chain reaction (PCR) across multiple sample types, and suspected chromosomal integration was confirmed through detection of endogenous HHV-6 (eHHV-6) DNA in hair follicles by quantitative real-time PCR. HHV-6B accounted for ~96% of infections and was significantly associated with organ involvement, predominantly gastrointestinal disease, irrespective of plasma viral load. In contrast, HHV-6A was less frequently detected in tissues and was consistently associated with viremia and chromosomal integration, independent of viral load. Genotypic concordance across plasma, biopsy, cerebrospinal fluid, bronchoalveolar lavage, and hair follicle samples from the same patient was complete. Incorporating species-level genotyping and targeted testing for chromosomal integration (eHHV-6) into diagnostic workflows may improve interpretation of viral detection and help prevent unnecessary antiviral therapy. IMPORTANCE: Species-specific identification of human herpesvirus 6 (HHV-6A/B) has critical diagnostic implications in immunocompromised patients, although it is rarely performed in diagnostic laboratories. Our study showed that HHV-6A detection is associated with chromosomal integration, whereas HHV-6B is the main species linked to clinically relevant disease and invasive tissue infection. This study emphasizes that implementing species-specific PCR and testing for eHHV-6 in clinical microbiology laboratories may help interpret viral DNA detection, prevent misclassification of integrated virus as active infection, and avoid unnecessary antiviral therapy.

Background: Cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) are common toxicities after chimeric antigen receptor (CAR) T-cell therapy. We evaluated the incidence, timing, microbiology, and risk factors of microbiologically documented infections during the CRS and/or ICANS phase. Method: Consecutive adults receiving CAR T-cell therapy between 2020 and 2023 were retrospectively analyzed. Infections were classified by type and timing. The 60-day cumulative incidence of first infection and associated factors were assessed using Fine–Gray competing-risk models. Results: Among 152 CAR T-cell infusions, CRS and/or ICANS occurred in 117 (77.0%) episodes, and 70 (59.8%) required immunomodulatory therapy. An infectious etiology was documented in 30 (25.6%) episodes, yielding 45 documented infections (21 bacterial [46.7%], 17 viral [37.8%], and 7 fungal [15.6%]), more frequent in immunomodulatory-treated episodes (32.9% vs 14.9%; P = .033). At infection onset, median temperature, and C-reactive protein (CRP) levels were lower than at CRS/ICANS diagnosis (37.2°C vs 38.4°C; P < .001 and 3.9 vs 6.0 mg/L; P = .002). In immunomodulatory-treated episodes, median time to first infection was 15 (7–22) days from CRS and 9 (5–20) days from ICANS. The 60-day cumulative infection incidence was 60.0% with multimodal immunosuppression and 20.8% without; multimodal immunosuppression independently increased infection risk (subdistribution hazard ratio [sHR] 3.29; 95% CI 1.38–7.82; P = .007). Conclusions: The CRS/ICANS phase carries a high risk of bacterial, viral, and fungal infections, particularly under multimodal immunosuppression, while fever and CRP are unreliable indicators. Focused strategies for early detection, prevention, and prompt treatment of infections are urgently needed.

Background Eosinopenia has been reported as a marker of severity in infections, but its prognostic value in patients with severe community-acquired pneumonia (CAP) admitted to the intensive care unit (ICU) is unclear. Methods We retrospectively analyzed 496 patients with severe CAP admitted to the ICU, stratified by presence of eosinopenia at admission. Clinical characteristics, laboratory data, microbiological etiology, treatment, and outcomes were compared. Multivariable Cox regression identified independent predictors of 30-day mortality. Predictive performance of eosinophil counts, severity scores (CRB-65, CURB-65, PSI), and a modified CURB-65 incorporating eosinopenia (CURB-65Eos) were assessed. Results Eosinopenia was detected in 33% of patients. There were no differences in age and comorbidities between eosinopenic and non eosinopenic patients. Compared to non-eosinopenic patients, these patients had lower leukocyte, neutrophil, and lymphocyte counts and more frequent viral or polymicrobial infections. They more often required invasive mechanical ventilation (58% vs. 45%, p = 0.009) and developed pleural effusions (30% vs. 19%, p = 0.008). In-hospital and 30-day mortality were higher in the eosinopenia group (21% vs. 13%, p = 0.036; 20% vs. 12%, p = 0.022). Eosinopenia independently predicted 30-day mortality (HR 1.98; 95% CI 1.23–3.16; p = 0.005). Eosinophil counts alone had poor predictive accuracy (AUC 0.562), while established severity scores performed moderately. CURB-65Eos showed a numerical but nonsignificant improvement over CURB-65. Conclusions Eosinopenia is common in patients with severe CAP admitted to the ICU and is strongly associated with increased severity and mortality independent of age and comorbidities. It may serve as simple and inexpensive biomarker for the early identification of high-risk patients and could help guide more intensive therapeutic interventions.

Background: BK polyomavirus (BKPyV) reactivation is a common complication after kidney transplantation and may result in nephropathy and graft loss. As there is no effective antiviral therapy, management focuses on early detection and reduction of immunosuppression, which increases the risk of rejection. Identifying patients at higher risk remains challenging. Monitoring BKPyV-specific T-cell responses could aid in predicting reactivation. This study evaluated the usefulness of ELISpot to monitor BKPyV-specific cellular immunity before and after kidney transplantation. Methods: A prospective multicenter study was conducted between October 2020 and March 2022. ELISpot assays were performed prior to transplantation and two months afterward. Results: Seventy-two patients were included, with a median age of 56 years; 61% were men, and 24% had undergone previous transplantation. Nine patients developed presumptive BKPyV-nephropathy. No significant differences were found in donor type, induction therapy, or rejection rates between patients with or without nephropathy (p = 0.38). Based on ELISpot results, patients were classified into three groups according to their risk of BKPyV-nephropathy. The high-risk group included those who changed from positive to negative at 2 months post-transplant, representing 40% of presumptive BKPyV-nephropathy cases. Patients who remained negative at 2 months were classified as moderate risk (14.5%), while those with a positive ELISpot at 2 months comprised the low-risk group (0%). In the logistic regression analysis, both the ELISpot risk category [OR 19 (CI 1.7–2.08)] and the use of mTOR inhibitors from the start of transplantation [OR 0.02 (CI 0.01–0.46)] were significantly associated with BKPyV-nephropathy. Conclusions: Monitoring BKPyV-specific T cells with ELISpot before and after kidney transplantation may help stratify patients by risk of reactivation. Loss of BKPyV immunity at two months is associated with nephropathy, while mTOR-based immunosuppression appears protective. This strategy could guide personalized immunosuppression and surveillance.

Neurological complications associated with influenza (NCIs) are rare events in adults. Influenza-associated encephalopathy is one of the most severe and frequently reported NCIs. The aim of this study is to describe the frequency and characteristics of NCIs in adults during 10 post-2009 pandemic influenza seasons. Data were obtained from the registry of influenza cases admitted to hospitals of the PIDIRAC network for the surveillance of severe hospitalized laboratory-confirmed influenza (SHLCI) cases in Catalonia from October 2010 to March 2020. The variables analyzed were NCI, age, antiviral treatment, vaccination status, and outcome at discharge. During the study period, 9 (1.5‰) of 5931 SHLCI cases presented NCI. Five (55.6%) had influenza A and four (44.4%) had influenza B. Median age was 62 (17–67) years. One case had been vaccinated, all had received antiviral treatment, and five required ICU admission. The mean length of stay was 25.6 days (SD 25.8). Encephalitis was the most frequent complication, occurring in six cases (66.7%). Of these, three cases (50%) were caused by influenza A (two AH1N1pdm09 strains and one AH3N2). The high frequency of influenza-associated encephalitis caused by both type A and B influenza viruses suggests that both should be considered as potential etiologic factors for encephalopathy and other neurological diseases in adults. This recommendation would allow for the prompt antiviral treatment and prevention of severe outcomes.

Enhancing our comprehension of mRNA vaccines may facilitate the future design of novel vaccines aimed at augmenting immune protection while minimising reactogenic responses. Before this design is carried out, it is important to determine whether adaptive immunity correlates with the reactogenicity profile of vaccines. We studied a large cohort that was vaccinated with mRNA vaccines to answer this question. This was an observational study with real-world data. Reactogenicity data were obtained from the VigilVacCOVID study. Immunogenicity (humoral and cellular) data were retrieved from health records. One main population (n = 215) and two subpopulations were defined (subpopulation 1, n = 3563; subpopulation 2, n = 597). Sensitivity analyses were performed with subpopulations 1 and 2 to explore the consistency of results. We analysed the association of the intensity and types of adverse reactions with the development and quantity of elicited antibody titres. As an exploratory analysis in subpopulation 1, we assessed the association between reactogenicity and cellular immunogenicity. A higher incidence of fever, malaise, and myalgia including severe cases was significantly associated with the development and quantity of positive antibody titres. No significant findings were observed with cellular immunity. We observed a positive association between immunogenicity and reactogenicity. These findings can be relevant for the future development of our understanding of how mRNA vaccines function.

Introduction There is no reliable microbiological marker to guide responses to antiviral treatment in kidney transplant recipients (KTR) with COVID-19. We aimed to evaluate the dynamics of subgenomic RNA (sgRNA) RT-PCR before and after receiving treatment with remdesivir compared with genomic RNA (gRNA) RT-PCR and its use as a surrogate marker of viral replication. Methods We analyzed gRNA and sgRNA at baseline and after remdesivir treatment in KTR who received remdesivir for SARS-CoV-2 infection from November 2021 to February 2022. Results Thirty-four KTR received remdesivir for SARS-CoV-2 infection. The median time since transplantation was 80 months (IQR 3–321) and 75% of patients had previously received 3 doses of a mRNA SARS-CoV-2 vaccine. Three patients (8%) were classified with mild, 25 (73%) with moderate, and 6 (17%) with severe SARS-CoV-2 infection. Thirty-two (94%) patients received 5 doses of remdesivir and two patients received 2 doses. The median time between symptom onset to remdesivir treatment was 5 days (IQR 3–8.5). The median days of hospitalization were 6 (IQR 2–112). gRNA was positive in all patients at baseline and after remdesivir. Five (15%) patients had negative sgRNA at baseline and 20 (59%) after receiving remdesivir. Patients presenting with negative sgRNA at baseline were discharged from hospital in ≤ 6 days without complications. Moreover, those with negative sgRNA after remdesivir therapy did not require ICU admission and had favorable outcomes. Nevertheless, patients with positive sgRNA after antiviral treatment presented worse outcomes, with 47% requiring ICU admission and the three (9%) recorded deaths in the study were in this group. Conclusions Based on these data, we hypothesize that sgRNA may have clinical utility to help monitor virologic response more accurately than gRNA in KTR who receive remdesivir. Moreover, patients with negative sgRNA at baseline may not require antiviral treatment and others presenting positive sgRNA at day 5 could benefit from prolonged or combined therapies.

The rapid and broad microbiological diagnosis of meningoencephalitis (ME) has been possible thanks to the development of multiplex PCR tests applied to cerebrospinal fluid (CSF). We aimed to assess a new multiplex PCR panel (the QIAstat-Dx ME panel), which we compared to conventional diagnostic tools and the Biofire FilmArray ME Panel. The pathogens analyzed using both methods were Escherichia coli K1, Haemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis, Streptococcus agalactiae, Streptococcus pneumoniae, Enterovirus, herpes simplex virus 1–2, human herpesvirus 6, human parechovirus, varicella zoster virus, and Cryptococcus neoformans/gattii. We used sensitivity, specificity, PPV, NPV, and kappa correlation index parameters to achieve our objective. Fifty CSF samples from patients with suspected ME were included. When conventional methods were used, 28 CSF samples (56%) were positive. The sensitivity and specificity for QIAstat-Dx/ME were 96.43% (CI95%, 79.8–99.8) and 95.24% (75.2–99.7), respectively, whereas the PPV and NPV were 96.43% (79.8–99.8) and 95.24% (75.1–99.7), respectively. The kappa value was 91.67%. Conclusions: A high correlation of the QIAstat-Dx ME panel with reference methods was shown. QIAstat-Dx ME is a rapid-PCR technique to be applied in patients with suspected ME with a high accuracy.

Cytomegalovirus (CMV) infection is a relevant cause of morbimortality in patients receiving allogeneic stem cell transplantation (allo-HCT). Foscarnet (FCN) is an effective drug against CMV administered intravenously and usually on an inpatient basis. The Home Care Unit (HCU) for hematologic patients at our hospital designed an at-home FCN administration model to avoid the hospitalization of patients requiring FCN treatment. This study analyzes whether the at-home administration of FCN is as safe and effective as its hospital administration. We collected and compared demographic, clinical, analytical, and economic data of patients with CMV infection post-allo-HCT who received FCN in the hospital (n = 16, 17 episodes) vs. at-home (n = 67, 88 episodes). The proportions of patients with cured CMV infections were comparable between the two groups (65.9% vs. 76.5%, p = 0.395). The median duration of FCN treatment was 15 (interquartile range [IQR] 9–23) and 14 (IQR 11–19) days in the HCU and inpatient cohorts, respectively (p = 0.692). There were no significant differences in the FCN toxicities between groups except for hypocalcemia (26.1% vs. 58.8%, p = 0.007), which was more prevalent in the inpatient cohort. A significant cost-effectiveness was found in the HCU cohort, with a median savings per episode of EUR 5270. It may be concluded that home administration of FCN is a safe, effective, and cost-efficient therapeutic option for patients with CMV infection and disease.

The use of valganciclovir as secondary prophylaxis for cytomegalovirus (CMV) infection in solid organ transplantation (SOT) is the most prevalent therapeutic choice, but it has been dismissed by the presence of resistance and toxicity. Letermovir (LMV) is indicated as primary prophylaxis in hematopoietic stem cell transplantation, but there is scarce clinical data on its use as secondary prophylaxis in SOT. We present two cases of SOT recipients (lung, liver) who underwent LMV secondary prophylaxis. One patient developed the L595S ( UL97 )-resistant mutation to ganciclovir/valganciclovir and experienced several CMV relapses under LMV therapy, but no LMV resistance mutations were detected. The second patient developed the C325F ( UL56 )-resistant mutation to LMV under secondary prophylaxis which was rescued by foscarnet. This observation reviews previously published clinical data on LMV secondary prophylaxis and recommends a cautious use of LMV in the clinical practice due to the early development of UL56 resistance mutations. IMPORTANCE: This observation provides comprehensive data on the clinical correlates of both cytomegalovirus (CMV) genotypic follow-up and clinical monitoring and outcomes for two different solid organ transplantation recipients that received letermovir as secondary prophylaxis. Our study emphasizes that monitoring of CMV disease in the patient and early genotypic detection of resistance mutations are essential when using new antiviral drugs for off-label indication in patients experiencing CMV relapses or not responding to standard antiviral therapy. These cases and the bibliography reviewed can be helpful for other researchers and clinicians working in the field to optimize the use of new treatments for transplant recipients since drug-resistant CMV infection is an important emerging problem even with new developments in antiviral treatment.