Microcirculation disorders in patients with severe COVID-19 and development of bacterial sepsis

It is believed that microcirculation dysfunction in sepsis primarily caused by damage of the endothelium by infectious agents and pro-inflammatory cytokines. Mechanisms of impaired microcirculation in the severe course of COVID-19 and sepsis likely to be similar. However, there are few reports studied microcirculation disorders in patients with COVID-19, and their results are sometimes contradictory. Objective. To assess the microcirculation of patients with severe Covid-19 and the development of bacterial sepsis using nail bed microscopy and laser Doppler flowmetry. Materials and methods. 16 intensive care unit COVID-19 patients subsequently diagnosed with bacterial sepsis were examined. Patients underwent vital capillaroscopy and an occlusive test using laser Doppler flowmetry. The average rate of capillary blood flow, the size of the perivascular zone, the density of capillaries, the presence of intravascular aggregates, the increase in the amplitude of the maximum post-occlusive blood flow and the average value of postocclusive blood flow relative to the initial one were valuated. Additionally, the level of serum proadrenomedullin was evaluated. Studies were performed on the day of admission and in dynamics. Results. By the capillaroscopy analysis, microcirculation disorders were detected in the form of a decrease in the linear speed of capillary blood flow (<400 μm/s), an extention of the perivascular zone (>100 μm), the circulation of microaggregates; the absence of postocclusive hyperemia was determined by an occlusive test. Secondary bacterial infection led to an even greater aggravation of microcirculation disorders: an increase of the perivascular zone, the progression of intravascular aggregation resulting in microthrombosis with a decrease of the density of the capillary network (according to capillaroscopy), as well as a sharp decrease of amplitude maximal increment of blood flow of post-осclusive circulation at the time of an occlusive sample. We also revealed a trend of negative correlation between the level of serum proadrenomedullin and the maximum increase in blood flow during the occlusive test. Conclusion. The secondary bacterial infection in patients with COVID-19 leads to a significant aggravation of microcirculation disorders with the development of perfusion deficiency and interstitial edema. The increased plasma proadrenomedullin level supports the concept of the significant role of endothelial dysfunction in the pathogenesis of severe COVID-10 and bacterial sepsis.

Difference of Procalcitonin Levels in Gram-Positive and Gram-Negative Bacterial Sepsis Patients of Indonesia Army Central Hospital Gatot Soebroto in 2016

Introduction: Procalcitonin is known as a marker of infection and indicator for severity of infections. In sepsis, elevated procalcitonin levels in blood have a significant value that can be used as a sepsis biomarker. The aim of this study was to determine the mean difference of procalcitonin levels in Gram-positive and Gram-negative bacterial sepsis patients.Methods: This study used quantitative method with cross sectional approach. The sample of this study were bacterial sepsis patients of Indonesia Army Central Hospital Gatot Soebroto in 2016 which were divided into two groups: Gram-positive and Gram-negative bacterial sepsis patients with the number of each group was 30 samples. The data were analyzed by using independent t test.Results: This study showed that mean levels of procalcitonin in Gram-positive bacterial sepsis patients was 6.47 ng/ml and Gram-negative was 66.04 ng/ml. There was a significant difference between mean levels of procalcitonin in Gram-positive and Gram-negative bacterial sepsis patients of Indonesia Army Central Hospital Gatot Soebroto in 2016 with p value = 0.000 (p < 0.05).Conclusion: The mean difference of procalcitonin levels in Gram-negative bacterial sepsis patients were higher than Gram-positive bacterial sepsis patients, because Gram-negative bacteria have lipopolysaccharide which is a strong immunostimulator and increases TNF-α production higher than Gram-positive bacteria.

Circulating miR-147b as a diagnostic marker for patients with bacterial sepsis and septic shock

Background Early diagnosis, precise antimicrobial treatment and subsequent patient stratification can improve sepsis outcomes. Circulating biomarkers such as plasma microRNAs (miRNAs) have proven to be surrogates for diagnosis, severity and case management of infections. The expression of four selected miRNAs (miR-146-3p, miR-147b, miR-155 and miR-223) was validated for their prognostic and diagnostic potential in a clinically defined cohort of patients with sepsis and septic shock. Methods The expression of plasma miRNAs was quantified by quantitative PCR (qPCR) in patients with bacterial sepsis (n = 78), in patients with septic shock (n = 52) and in patients with dengue haemorrhagic fever (DHF; n = 69) and in healthy controls (n = 82). Results The expression of studied miRNA was significantly increased in patients with bacterial sepsis and septic shock. The plasma miR-147b was able to differentiate bacterial sepsis from non-sepsis and septic shock (AUC = 0.77 and 0.8, respectively, p≤ 0.05), while the combination of plasma miR-147b and procalcitonin (PCT) predicted septic shock (AUC = 0.86, p≤ 0.05). Conclusions The plasma miR-147b may be an useful biomarker independently or in combination with PCT to support clinical diagnosis of sepsis and equally prognosis of patients with septic shock.

Overlapping but Disparate Inflammatory and Immunosuppressive Responses to SARS-CoV-2 and Bacterial Sepsis: An Immunological Time Course Analysis

Both severe SARS-CoV-2 infections and bacterial sepsis exhibit an immunological dyscrasia and propensity for secondary infections. The nature of the immunological dyscrasias for these differing etiologies and their time course remain unclear. In this study, thirty hospitalized patients with SARS-CoV-2 infection were compared with ten critically ill patients with bacterial sepsis over 21 days, as well as ten healthy control subjects. Blood was sampled between days 1 and 21 after admission for targeted plasma biomarker analysis, cellular phenotyping, and leukocyte functional analysis via enzyme-linked immunospot assay. We found that circulating inflammatory markers were significantly higher early after bacterial sepsis compared with SARS-CoV-2. Both cohorts exhibited profound immune suppression through 21 days (suppressed HLA-DR expression, reduced mononuclear cell IFN-gamma production), and expanded numbers of myeloid-derived suppressor cells (MDSCs). In addition, MDSC expansion and ex vivo production of IFN-gamma and TNF-alpha were resolving over time in bacterial sepsis, whereas in SARS-CoV-2, immunosuppression and inflammation were accelerating. Despite less severe initial physiologic derangement, SARS-CoV-2 patients had similar incidence of secondary infections (23% vs 30%) as bacterial sepsis patients. Finally, COVID patients who developed secondary bacterial infections exhibited profound immunosuppression evident by elevated sPD-L1 and depressed HLA-DR. Although both bacterial sepsis and SARS-CoV-2 are associated with inflammation and immune suppression, their immune dyscrasia temporal patterns and clinical outcomes are different. SARS-CoV-2 patients had less severe early inflammation and organ dysfunction but had persistent inflammation and immunosuppression and suffered worse clinical outcomes, especially when SARS-CoV-2 infection was followed by secondary bacterial infection.

Circadian Rhythms in Bacterial Sepsis Pathology: What We Know and What We Should Know

Sepsis is a syndrome caused by a deregulated host response to infection, representing the primary cause of death from infection. In animal models, the mortality rate is strongly dependent on the time of sepsis induction, suggesting a main role of the circadian system. In patients undergoing sepsis, deregulated circadian rhythms have also been reported. Here we review data related to the timing of sepsis induction to further understand the different outcomes observed both in patients and in animal models. The magnitude of immune activation as well as the hypothermic response correlated with the time of the worst prognosis. The different outcomes seem to be dependent on the expression of the clock gene Bmal1 in the liver and in myeloid immune cells. The understanding of the role of the circadian system in sepsis pathology could be an important tool to improve patient therapies.

Reticular Dysgenesis: A Rare Immunodeficiency in a Neonate With Cytopenias and Bacterial Sepsis

Severe combined immunodeficiency (SCID) consists of a group of disorders defined by abnormal B and T cell development that typically results in death within the first year of life if undiagnosed or untreated. Reticular dysgenesis (RD) is a rare but especially severe form of SCID that is caused by adenylate kinase 2 deficiency and is characterized not only by lymphopenia but also by profound neutropenia. RD predisposes patients to viral and fungal infections typical of SCID as well as serious bacterial infections atypical in the neonatal period in other SCID types. RD is also associated with sensorineural hearing loss not typically seen in other forms of SCID. Without rapid diagnosis and curative hematopoietic stem cell transplantation, RD is fatal within days to months due to overwhelming bacterial infection. The inclusion of the T cell receptor excision circle assay nationally in 2017 on the newborn screen has facilitated diagnosis of SCID in the neonatal period. This case reports on a male infant with RD who presented after preterm birth with severe cytopenias and a gastrointestinal anomaly and ultimately developed severe bacterial sepsis. Postmortem bone marrow evaluation and panel-based gene sequencing identifying 2 novel variants in the adenylate kinase 2 gene provided confirmation for a diagnosis of RD. This case emphasizes the importance of thorough diagnostic evaluation, including the newborn screen, in neonates and infants with persistent and unexplained cytopenias. Prompt hematology and/or immunology referral is advised for disease management and to facilitate hematopoietic stem cell transplantation to optimize long-term survival.

Comparison of efficacy of a 7-day versus a 14-day course of intravenous antibiotics in the treatment of uncomplicated neonatal bacterial sepsis: study protocol of a randomized controlled non-inferiority trial

Background Neonatal sepsis is a global public health problem. There is no consensus regarding the optimum duration of antibiotics for culture-proven neonatal sepsis. Published randomized controlled trials (RCTs) comparing shorter versus longer courses of antibiotics provide low-quality evidence with serious risk of bias. We hypothesized that among neonates with uncomplicated culture-proven sepsis, antibiotic duration of 7 days is not inferior to 14 days. Methods This is a multi-centric, parallel-group, stratified, block-randomized, active-controlled, non-inferiority trial with outcome assessment blinded. Stratification is by center and birth weight. Neonates weighing ≥1000 g at birth, with blood-culture-proven sepsis (barring Staphylococcus aureus and fungi), without conditions warranting > 14 days antibiotics, and who clinically remit, are enrolled in the RCT on day 7 of administration of sensitive antibiotics. They are randomly allocated to no further antibiotics (intervention arm: total 7 days) or 7 more days of the same antibiotics (control arm: total 14 days). Allocation is concealed by opaque, sealed envelopes. The primary outcome is “definite or probable relapse” within 21 days after antibiotic completion. Secondary outcomes include definite and probable relapses at various timepoints until day 35 post-randomization, secondary infections, and adverse events. The neonatologist adjudicating probable relapses and lab personnel are blinded. Three hundred fifty subjects will be recruited in each arm, assuming a non-inferiority margin of 7%, one-sided alpha error 5%, and power of 90%. Analysis will be per protocol and by intention-to-treat. An independent Data Safety Monitoring Board monitors adverse events and will perform one interim analysis when 50% of expected primary outcomes have occurred or 50% of subjects have completed follow-up, whichever is earlier. O’Brien-Fleming criteria will be used to stop for mid-term benefit and Pocock’s to stop for mid-term harm. A priori subgroup analyses are planned by birth weight categories, gram-stain status of pathogens, and radiological pneumonia. Discussion This trial will provide evidence to guide practice regarding optimum duration of antibiotics for culture-proven neonatal bacterial sepsis. If a 7-day regime is proved to be non-inferior to a 14-day regime, it is likely to reduce hospital stay, costs, adverse effects of drugs, and nosocomial infections. Trial registration Clinical Trials Registry India CTRI/2017/09/009743. Registered on 13 September 2017.