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STAT2 is a transcription factor activated by type I and III IFNs. We report 23 patients with loss-of-function variants causing autosomal recessive (AR) complete STAT2 deficiency. Both cells transfected with mutant STAT2 alleles and the patients' cells displayed impaired expression of IFN-stimulated genes and impaired control of in vitro viral infections. Clinical manifestations from early childhood onward included severe adverse reaction to live attenuated viral vaccines (LAV) and severe viral infections, particularly critical influenza pneumonia, critical COVID-19 pneumonia, and herpes simplex virus type 1 (HSV-1) encephalitis. The patients displayed various types of hyperinflammation, often triggered by viral infection or after LAV administration, which probably attested to unresolved viral infection in the absence of STAT2-dependent types I and III IFN immunity. Transcriptomic analysis revealed that circulating monocytes, neutrophils, and CD8+ memory T cells contributed to this inflammation. Several patients died from viral infection or heart failure during a febrile illness with no identified etiology. Notably, the highest mortality occurred during early childhood. These findings show that AR complete STAT2 deficiency underlay severe viral diseases and substantially impacts survival. ispartof: J Clin Invest vol:133 issue:12 pages:e168321- ispartof: location:United States status: Published online

Background Data in the literature about HSV reactivation in COVID-19 patients are scarce, and the association between HSV-1 reactivation and mortality remains to be determined. Our objectives were to evaluate the impact of Herpes simplex virus (HSV) reactivation in patients with severe SARS-CoV-2 infections primarily on mortality, and secondarily on hospital-acquired pneumonia/ventilator-associated pneumonia (HAP/VAP) and intensive care unit-bloodstream infection (ICU-BSI). Methods We conducted an observational study using prospectively collected data and HSV-1 blood and respiratory samples from all critically ill COVID-19 patients in a large reference center who underwent HSV tests. Using multivariable Cox and cause-specific (cs) models, we investigated the association between HSV reactivation and mortality or healthcare-associated infections. Results Of the 153 COVID-19 patients admitted for ≥ 48 h from Feb-2020 to Feb-2021, 40/153 (26.1%) patients had confirmed HSV-1 reactivation (19/61 (31.1%) with HSV-positive respiratory samples, and 36/146 (24.7%) with HSV-positive blood samples. Day-60 mortality was higher in patients with HSV-1 reactivation (57.5%) versus without (33.6%, p = 0.001). After adjustment for mortality risk factors, HSV-1 reactivation was associated with an increased mortality risk (hazard risk [HR] 2.05; 95% CI 1.16–3.62; p = 0.01). HAP/VAP occurred in 67/153 (43.8%) and ICU-BSI in 42/153 (27.5%) patients. In patients with HSV-1 reactivation, multivariable cause-specific models showed an increased risk of HAP/VAP (csHR 2.38, 95% CI 1.06–5.39, p = 0.037), but not of ICU-BSI. Conclusions HSV-1 reactivation in critically ill COVID-19 patients was associated with an increased risk of day-60 mortality and HAP/VAP. Supplementary Information The online version contains supplementary material available at 10.1186/s13054-021-03843-8.

Highlights • Remdesivir has been found to be an in-vitro potent inhibitor of RNA viruses including SARS-CoV-2 but its in-vivo potency is still under active investigations. • In this work, we depict the clinical features of 5 hospitalized COVID-19 patients under remdisivir compassionate use. • Remdisivir infusion was associated with decreasing viral loads from nasopharyngeal samples despite active replication in the lower respiratory tract area evidenced for two patients. • The treatment had to be interrupted for potential side effects for 4 out 5 patients including two alamine aminotransferase (ALT) elevation and two renal failure cases., The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as responsible for the COVID-19 outbreak worldwide. Data on treatment are scare and parallels are made between SARS-CoV-2 and other coronavirus. Remdesivir is a broad spectrum antiviral with efficient in vitro activity against SARS-CoV-2 and controversial evidence of clinical improvement in severe COVID-19 patients. We aimed to describe the clinical outcome and virological monitoring of the first five COVID-19 patients admitted in ICU for severe pneumonia related to SARS-CoV-2 and treated with remdesivir in the University hospital of Bichat, Paris, France. SARS-CoV-2 RT-qPCR in blood plasma, lower and upper respiratory tract were monitored. Among the five treated patients, two needed mechanical ventilation and one high flow cannula oxygen. A significant decrease in SARS-CoV-2 viral load from upper respiratory tract was observed in most cases but two died with active SARS-CoV-2 replication in the lower respiratory tract. Plasma samples were positive for SARS-CoV-2 in only one patient. Remdesivir was interrupted for side effects among four patients, including 2 ALT elevations (3 to 5 N) and 2 renal failures requiring renal replacement. This case series of five COVID-19 patients requiring ICU for a respiratory distress and treated with remdesivir, highlights the complexity of remdesivir use in such critically ill patients.

Background Multiplex PCR tests have improved our understanding of respiratory viruses' epidemiology by allowing their wide range detection. We describe here the burden of these viruses in hospital settings over a five-year period. Methods All respiratory samples from adult patients (>20 years old) tested by multiplex-PCR at the request of physicians, from May 1 2011 to April 30 2016, were included retrospectively. Viral findings are reported by season, patient age group, respiratory tract region (upper or lower) and type of clinical unit (intensive care unit, pneumology unit, lung transplantation unit and other medical units). Results In total, 7196 samples (4958 patients) were included; 29.2% tested positive, with viral co-infections detected in 1.6% of samples. Overall, two viral groups accounted for 60.2% of all viruses identified: picornaviruses (rhinovirus or enterovirus, 34.3%) and influenza (26.6%). Influenza viruses constituted the group most frequently identified in winter (34.4%), in the upper respiratory tract (32%) and in patients over the age of 70 years (36.4%). Picornavirus was the second most frequently identified viral group in these populations and in all other groups, including lower respiratory tract infections (41.3%) or patients in intensive care units (37.6%). Conclusion This study, the largest to date in Europe, provides a broad picture of the distribution of viruses over seasons, age groups, types of clinical unit and respiratory tract regions in the hospital setting. It highlights the burden associated with the neglected picornavirus group. These data have important implications for the future development of vaccines and antiviral drugs.

Background To date, only influenza and RSV testing are recommended for respiratory viruses’ detection in paediatric units. In this study, we described, according to seasons, ages and clinical units, the results obtained in children (

Additional file 1. Table E1. Univariable and multivariable Cox models investigating the association between HSV-1 reactivation and mortality at day 60. Table E2. Univariable and multivariable Cox models investigating the association between HSV-1 reactivation and mortality at day 60 in respiratory samples. Table E3. Univariable and multivariable Cox models investigating the association between HSV-1 reactivation and mortality at day 60 in blood samples. Table E4. Univariable and multivariable cause specific models investigating the association between HSV-1 reactivation and HAP/VAP. Table E5. Univariable and multivariable cause specific models investigating the association between HSV-1 reactivation in blood and HAP/VAP.

Additional file 1. Table E1. Univariable and multivariable Cox models investigating the association between HSV-1 reactivation and mortality at day 60. Table E2. Univariable and multivariable Cox models investigating the association between HSV-1 reactivation and mortality at day 60 in respiratory samples. Table E3. Univariable and multivariable Cox models investigating the association between HSV-1 reactivation and mortality at day 60 in blood samples. Table E4. Univariable and multivariable cause specific models investigating the association between HSV-1 reactivation and HAP/VAP. Table E5. Univariable and multivariable cause specific models investigating the association between HSV-1 reactivation in blood and HAP/VAP.