Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

ISARIC-COVID-19 dataset: A Prospective, Standardized, Global Dataset of Patients Hospitalized with COVID-19

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Neurological manifestations of COVID-19 in adults and children

Different neurological manifestations of coronavirus disease 2019 (COVID-19) in adults and children and their impact have not been well characterized. We aimed to determine the prevalence of neurological manifestations and in-hospital complications among hospitalized COVID-19 patients and ascertain differences between adults and children. We conducted a prospective multicentre observational study using the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) cohort across 1507 sites worldwide from 30 January 2020 to 25 May 2021. Analyses of neurological manifestations and neurological complications considered unadjusted prevalence estimates for predefined patient subgroups, and adjusted estimates as a function of patient age and time of hospitalization using generalized linear models. Overall, 161 239 patients (158 267 adults; 2972 children) hospitalized with COVID-19 and assessed for neurological manifestations and complications were included. In adults and children, the most frequent neurological manifestations at admission were fatigue (adults: 37.4%; children: 20.4%), altered consciousness (20.9%; 6.8%), myalgia (16.9%; 7.6%), dysgeusia (7.4%; 1.9%), anosmia (6.0%; 2.2%) and seizure (1.1%; 5.2%). In adults, the most frequent in-hospital neurological complications were stroke (1.5%), seizure (1%) and CNS infection (0.2%). Each occurred more frequently in intensive care unit (ICU) than in non-ICU patients. In children, seizure was the only neurological complication to occur more frequently in ICU versus non-ICU (7.1% versus 2.3%, P < 0.001). Stroke prevalence increased with increasing age, while CNS infection and seizure steadily decreased with age. There was a dramatic decrease in stroke over time during the pandemic. Hypertension, chronic neurological disease and the use of extracorporeal membrane oxygenation were associated with increased risk of stroke. Altered consciousness was associated with CNS infection, seizure and stroke. All in-hospital neurological complications were associated with increased odds of death. The likelihood of death rose with increasing age, especially after 25 years of age. In conclusion, adults and children have different neurological manifestations and in-hospital complications associated with COVID-19. Stroke risk increased with increasing age, while CNS infection and seizure risk decreased with age

Expression of calcineurin activity after lung transplantation: a 2-year follow-up.

The objective of this pharmacodynamic study was to longitudinally assess the activity of calcineurin during the first 2 years after lung transplantation. From March 2004 to October 2008, 107 patients were prospectively enrolled and their follow-up was performed until 2009. Calcineurin activity was measured in peripheral blood mononuclear cells. We report that calcineurin activity was linked to both acute and chronic rejection. An optimal activity for calcineurin with two thresholds was defined, and we found that the risk of rejection was higher when the enzyme activity was above the upper threshold of 102 pmol/mg/min or below the lower threshold of 12 pmol/mg/min. In addition, we report that the occurrence of malignancies and viral infections was significantly higher in patients displaying very low levels of calcineurin activity. Taken together, these findings suggest that the measurement of calcineurin activity may provide useful information for the management of the prevention therapy of patients receiving lung transplantation

Calcineurin activity and acute rejection.

<p>(A) Calcineurin activity (CN-a) was measured before lung transplantation in 52 of the 107 patients enrolled in the participating center. The results are presented as box plots and 10–90 percentile whiskers. We compared CN-a expression prior to transplantation in patients with or without cystic fibrosis (CF) since it is the main initial end-stage lung disease that led to lung transplantation in this cohort of patients and a similar dispersion of the CN-a values was found in CF+ and CF- patients (p = 0.77, Mann-Whitney test). Subsequently, a relationship between extreme values of calcineurin activity and acute rejection was investigated. (B) Comparison across time of the median CN-a levels in patients displaying or not acute rejection: Kernel smoothing curves were generated. The 2 groups of patients displayed similar profiles of CN-a which consist of a phase of enzyme inhibition within the first 10 weeks after transplantation followed by a phase in which enzyme activity is restored. The phase of CN-a inhibition tended to be faster and more marked in patients who had developed acute rejection as compared to patients who were free of acute rejection. Similarly, the increase of enzyme activity to baseline levels tended to be faster and more pronounced in patients who had developed acute rejection.</p

Basal characteriwstics of patients.

<p>Data are summarized as frequencies and percentage for categorical variables and as mean±SD for continuous variables. A total of 670 peripheral blood samples (mean of 6±3 samples per patient, range: 2–14) were obtained during the first 24 months following transplantation. Yr: year; M: male; F: female; EBV: empstein barr virus; CMV: cytomegalovirus; CN-a: calcineurin activity; BOS: bronchiolitis obliterans syndrome.</p

Calcineurin activity and cyclosporine blood levels.

<p>The relationship between calcineurin activity (CN-a) and the levels of cyclosporine (CsA) in blood was investigated. No correlation was found between CN-a and the level of CsA in blood.</p

Calcineurin activity and pulmonary function.

<p>Data are summarized as frequencies and percentage. The relationship between calcineurin Activity (CN-a) and the forced expiratory volume in one second (FEV1) ratio was studied from A total of 166 values collected from 87 patients (mean of 2±1 data per patient, range : 1–5).</p

Calcineurin activity and adverse events related to over-immunosuppression.

<p>The onset of events known to be related to over-immunosuppression, such as malignancies and infections, was compared between patients displaying or not low CN-a levels by the Kaplan and Meier method. (A) CN-a and malignancies: the occurrence of malignancies was significantly higher in patients displaying at least one CN-a value below 12 pmol/mg/min during the first 24 months after transplantation as compared to patients with higher CN-a values (28% vs 6%, p = 0.0218, Log-rank test). The examination of the relationship between CN-a and infections was performed by separating the infections of bacterial, viral and fungal origin. (B) CN-a and bacterial infections: the occurrence of 3 episodes of bacterial infections was similar in the 2 groups of patients (18% vs 25%, p = 0.85, Log-rank test). (C) CN-a and fungal infections: the occurrence of 3 episodes of fungal infections was similar in the 2 groups of patients (3.5% vs 0%, p = 0.21, Log-rank test). (D) CN-a and viral infections: the occurrence of 3 episodes of viral infections was significantly higher in patients displaying at least one CN-a value below 12 pmol/mg/min during the first 24 months after transplantation compared to patients with higher CN-a values (15% vs 0%, p = 0.01, Log-rank test).</p

Calcineurin activity, BOS and overall survival.

<p>BOS-free survival was estimated at 5 years after transplantation by the Kaplan and Meier method. (A) Calcineurin activity (CN-a) monitoring during the first 24 months after transplantation: although not statistically significant, the survival without BOS was higher in patients who displayed CN-a levels within the range of 12–102 pmol/mg/min as compared to patients who exhibited at least one CN-a value outside this range of 12–102 pmol/mg/min during the first 24 months following transplantation (76% vs 43%, p = 0.4717, Log-rank test). (B) CN-a monitoring from the 6^th month to the 24^th month after transplantation: the survival without BOS was significantly higher in patients who displayed CN-a levels within the range of 12–102 pmol/mg/min as compared to that of patients who exhibited at least one CN-a value outside this range from the 6^th month to the 24^th months following transplantation (80% vs 40%, p = 0.0118, Log-rank test). (C) CN-a monitoring from the 6^th to the 24^th month after transplantation: the threshold values were further separated in 2 groups : <12 pmol/mg/min, >102 pmol/mg/min. The BOS-free survival in patients from each of these groups was compared to that from patients who displayed CN-a levels within the range of 12–102 pmol/mg/min. A significant reduction of the survival without BOS was found in patients who displayed CN-a levels higher than 102 pmol/mg/min (40% vs 80%, p = 0.037, Log-rank test), whereas a reduction in BOS-free survival in the limit of statistical significance was found in patients who displayed CN-a levels lower than 12 pmol/mg/min (49% vs 80%, p = 0.0574, Log-rank test). (D) Calcineurin activity and overall survival: no significant difference was found in the overall survival between the 2 groups of patients exhibiting calcineurin activity levels within or outside of the range of 12–102 pmol/mg/min.</p