Long COVID is characterized by the emergence of multiple debilitating symptoms following SARS-CoV-2 infection. Its etiology is unclear and it often follows a mild acute illness. Anecdotal reports of gradual clinical responses to histamine receptor antagonists (HRAs) suggest a histamine-dependent mechanism that is distinct from anaphylaxis, possibly mediated by T cells, which are also regulated by histamine. T cell perturbations have been previously reported in post-viral syndromes, but the T cell landscape in patients who have recovered from mild COVID-19 and its relationship to both long COVID symptoms and any symptomatic response to HRA remain underexplored. We addressed these questions in an observational study of 65 individuals who had recovered from mild COVID-19. Participants were surveyed between 87 and 408 days after the onset of acute symptoms; none had required hospitalization, 16 had recovered uneventfully, and 49 had developed long COVID. Symptoms were quantified using a structured questionnaire and T cell subsets enumerated in a standard diagnostic assay. Patients with long-COVID had reduced CD4+ and CD8+ effector memory (EM) cell numbers and increased PD-1 (programmed cell death protein 1) expression on central memory (CM) cells, whereas the asymptomatic participants had reduced CD8+ EM cells only and increased CD28 expression on CM cells. 72% of patients with long COVID who received HRA reported clinical improvement, although T cell profiling did not clearly distinguish those who responded to HRA. This study demonstrates that T cell perturbations persist for several months after mild COVID-19 and are associated with long COVID symptoms.

Nitric oxide (NO), produced via inducible NO synthase (iNOS), can modulate polarized epithelial processes such as solute transport. Given the high reactivity of NO, we hypothesized that optimal NO regulation of polarized epithelial functions is achieved through compartmentalization of iNOS, allowing local NO delivery to its molecular targets. Here, we show that iNOS localizes to the apical domain of epithelial cells within a submembranous protein complex tightly bound to cortical actin. We further show that iNOS can bind to the apical PDZ protein, EBP50 (ezrin-radixin-moesin-binding phosphoprotein 50), an interaction that is dependent on the last three COOH-terminal amino acids of iNOS, SAL, but requires the presence of additional unknown cellular proteins. Mutation of these three COOH-terminal residues abolishes the iNOS-EBP50 interaction and disrupts the apical association of iNOS in transfected cells, showing that this COOH-terminal motif is essential for the correct localization of iNOS in epithelial cells. Apically localized iNOS directs vectorial NO production at the apical proximal tubule epithelial cell surface. These studies define human epithelial iNOS as an apical EBP50-binding protein and suggest that the physical association of iNOS with EBP50 might allow precise NO modulation of EBP50-associated protein functions.

Singer and Glynne present evidence to suggest that the short- term benefits of many interventions for treating critical illness may camouflage an underlying tendency to cause harm.

IntroductionA single centre has reported that implementation of an intensive insulin protocol, aiming for tight glycaemic control (blood glucose 4.4 to 6.1 mmol/l), resulted in significant reduction in mortality in longer stay medical and surgical critically ill patients. Our aim was to determine the degree to which tight glycaemic control can be maintained using an intensive insulin therapy protocol with computerized decision support and to identify factors that may be associated with the degree of control.MethodsAt a general adult 22-bed intensive care unit, we implemented an intensive insulin therapy protocol in mechanically ventilated patients, aiming for a target glucose range of 4.4 to 6.1 mmol/l. The protocol was integrated into the computerized information management system by way of a decision support program. The time spent in each predefined blood glucose band was estimated, assuming a linear trend between measurements.ResultsFifty consecutive patients were investigated, involving analysis of 7,209 blood glucose samples, over 9,214 hours. The target tight glycaemic control band (4.4 to 6.1 mmol/l) was achieved for a median of 23.1% of the time that patients were receiving intensive insulin therapy. Nearly half of the time (median 48.5%), blood glucose was within the band 6.2 to 7.99 mmol/l. Univariate analysis revealed that body mass index (BMI), Acute Physiology and Chronic Health Evaluation (APACHE) II score and previous diabetes each explained approximately 10% of the variability in tight glycaemic control. BMI and APACHE II score explained most (27%) of the variability in tight glycaemic control in the multivariate analysis, after adjusting for age and previous diabetes.ConclusionUse of the computerized decision supported intensive insulin therapy protocol did result in achievement of tight glycaemic control for a substantial percentage of each patient's stay, although it did deliver 'normoglycaemia' (4.4 to about 8 mmol/l) for nearly 75% of the time. Tight glycaemic control was difficult to achieve in critically ill patients using this protocol. More sophisticated methods such as continuous blood glucose monitoring with automated insulin and glucose infusion adjustment may be a more effective way to achieve tight glycaemic control. Glycaemia in patients with high BMI and APACHE II scores may be more difficult to control using intensive insulin therapy protocols. Trial registration number 05/Q0505/1.

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