Unchanged Characteristics and Survival among Critically Ill COVID-19 Patients during First, Second, and Third Waves: A Prospective Observational Cohort.

BACKGROUND: This study was carried out to compare characteristics and outcomes in patients with acute respiratory failure related to COVID-19 during first, second, and third waves. METHODS: We included consecutive adults admitted to the intensive care unit between March 2020 and July 2021. We compared three groups defined by the epidemic intake phase: waves 1 (W1), 2 (W2), and 3 (W3). RESULTS: We included 289 patients. Two hundred and eight (72%) patients were men with a median age of 63 years (IQR: 54-72), of whom 68 (23.6%) died in hospital. High-flow nasal oxygen (HFNO) was inversely associated with the need for invasive mechanical ventilation (MV) in multivariate analysis (p = 0.003) but not dexamethasone (p = 0.25). The day-90 mortality rate did not vary from W1 (27.4%) to W2 (23.9%) and W3 (22%), p = 0.67. By multivariate analysis, older age (odds ratio [OR]: 0.94/year, p < 0.001), immunodeficiency (OR: 0.33, p = 0.04), acute kidney injury (OR: 0.26, p < 0.001), and invasive MV (OR: 0.13, p < 0.001) were inversely associated with higher day-90 survival as opposed to the use of intermediate heparin thromboprophylaxis dose (OR: 3.21, p = 0.006). HFNO use and dexamethasone were not associated with higher day-90 survival (p = 0.24 and p = 0.56, respectively). CONCLUSIONS: In patients with acute respiratory failure due to COVID-19, survival did not change between first, second, and third waves while the use of invasive MV decreased. HFNO or intravenous steroids were not associated with better outcomes, whereas the use of intermediate dose of heparin for thromboprophylaxis was associated with higher day-90 survival. Larger multicentric studies are needed to confirm our findings.

Acute eosinophilic pneumonia-like syndrome post-initiation of vortioxetine.

A man in his mid-30s presented to the emergency department with a 1-week history of fatigue, loss of appetite, fever and productive (yellow) cough. This progressed to requiring admission to intensive care needing a oxygen therapy via high-flow nasal cannula for acute hypoxaemic respiratory failure. He had recently started vortioxetine for major depressive disorder, and his acute symptoms correlated with an increase in the dose of vortioxetine. For more than 20 years, rare but consistent reports of serotonergic medications have been implicated in eosinophilic pulmonary conditions. During this same period, serotonergic medications have become a mainstay solution for a wide range of depressive symptoms and disorders. This is the first report of an eosinophilic pneumonia-like syndrome occurring while consuming the novel serotonergic medication vortioxetine.

Remdesivir and corticosteroids in the treatment of hospitalized COVID-19 patients.

Coronavirus disease 2019 (COVID-19) is a pandemic infection caused by the newly discovered severe acute respiratory syndrome coronavirus 2. Remdesivir (RDV) and corticosteroids are used mainly in COVID-19 patients with acute respiratory failure. The main objective of the study was to assess the effectiveness of remdesivir with and without corticosteroids in the treatment of COVID-19 patients. We conducted a prospective observational study, including adult patients consecutively hospitalized with confirmed COVID-19 and acute respiratory failure. Patients were divided according to treatment strategy: RDV alone versus RDV with corticosteroids. The primary outcome was the time to recovery in both treatment groups. We included 374 COVID-19 adult patients, 184 were treated with RDV, and 190 were treated with RDV and corticosteroid. Patients in the RDV group had a shorter time to recovery in comparison with patients in the RDV plus corticosteroids group at 28 days after admission [11 vs. 16 days (95% confidence Interval 9.7-12.8; 14.9-17.1; p = .016)]. Patients treated with RDV alone had a shorter length of hospital stay. The use of corticosteroids as adjunctive therapy of RDV was not associated with improvement in mortality of COVID-19 patients.

Anakinra in hospitalized COVID-19 patients guided by baseline soluble urokinase plasminogen receptor plasma levels: A real world, retrospective cohort study.

BACKGROUND: In patients with COVID-19 and baseline soluble urokinase plasminogen receptor plasma (suPAR) levels ≥ 6ng/mL, early administration of anakinra, a recombinant interleukin-1 receptor antagonist, may prevent disease progression and death. In case of suPAR testing unavailability, the Severe COvid Prediction Estimate (SCOPE) score may be used as an alternative in guiding treatment decisions. METHODS: We conducted a monocenter, retrospective cohort study, including patients with SARS-CoV2 infection and respiratory failure. Patients treated with anakinra (anakinra group, AG) were compared to two control groups of patients who did not receive anakinra, respectively with ≥ 6 ng/mL (CG1) and < 6 ng/mL (CG2) baseline suPAR levels. Controls were manually paired by age, sex, date of admission and vaccination status and, for patients with high baseline suPAR, propensity score weighting for receiving anakinra was applied. Primary endpoint of the study was disease progression at day 14 from admission, as defined by patient distribution on a simplified version of the 11-point World Health Organization Clinical Progression Scale (WHO-CPS). RESULTS: Between July, 2021 and January, 2022, 153 patients were included, among which 56 were treated with off-label anakinra, 49 retrospectively fulfilled prescriptive criteria for anakinra and were assigned to CG1, and 48 presented with suPAR levels < 6ng/mL and were assigned to CG2. At day 14, when comparing to CG1, patients who received anakinra had significantly reduced odds of progressing towards worse clinical outcome both in ordinal regression analysis (OR 0.25, 95% CI 0.11-0.54, p<0.001) and in propensity-adjusted multiple logistic regression analysis (OR 0.32, 95% CI 0.12-0.82, p = 0.021) thus controlling for a wide number of covariates. Sensitivities of baseline suPAR and SCOPE score in predicting progression towards severe disease or death at day 14 were similar (83% vs 100%, p = 0.59). CONCLUSION: This real-word, retrospective cohort study confirmed the safety and the efficacy of suPAR-guided, early use of anakinra in hospitalized COVID-19 patients with respiratory failure.

Prevalence of Gabapentinoids and Central Nervous System Depressant Drugs, and Their Association with Risk Factors for Respiratory Depression in Primary Care Patients.

BACKGROUND AND OBJECTIVES: Warnings have been published regarding an increased risk of severe respiratory depression in patients receiving gabapentinoids either alone or in combination with opioids and/or anxiolytics/hypnotics, especially in individuals with a respiratory risk factor. The aim is to report the prevalence of the use of gabapentinoids alone and associated with central nervous system depressant drugs, and possible associated risk factors for respiratory depression, in order to identify the most fragile population and establish intervention strategies. METHODS: We performed a cross-sectional study using computerized prescription records from the northern area of Barcelona at Catalan Institute of Health for 363,007 inhabitants registered during 2021. Patients aged ≥ 18 years with one or more gabapentinoid prescription were included. Age, gender, polypharmacy, adjusted morbidity groups, quantity of chronic diseases, and the number of consultations per year were independent variables. Four age categories were defined (18-64 years, then 64-74, 75-84, and those aged 85 years or older). Descriptive and inferential statistics were employed. Level of statistical significance was 5% (p ≤ 0.05). For the analysis, the SPSS program (version 22) was employed. RESULTS: Of the study sample, 9218 were prescribed gabapentidoids. Overall prevalence of use was 3.0% (women 3.6%, men 2.4%). On the whole, women used more drugs than men. In contrast to their younger counterparts, consumption increased 2.6 times, 3.8 times, and 4.0 times in the 65-74 age group, 75-84 age group, and those aged ≥ 85 years, respectively. Mean age was 65.59 (±15.80) years. Polypharmacy (5-9 drugs) was present in 41.7% of the patients and extreme polypharmacy (≥ 10 drugs) was present in 39.3% of the patients. Regarding renal function, 2396 patients (25.9%) had glomerular filtration that required dose adjustment (76.1% with gabapentin and 23.8% with pregabalin). In 141 patients (5.9%), a total daily dose higher than that authorized (109 with gabapentin, 29 with pregabalin) had been prescribed. The prescription of gabapentinoids combined with opioids and/or anxiolytics/hypnotics was significantly associated with (i) polypharmacy (5-9 drugs, OR: 3.42 [95% CI 3.00-3.88]; ≥ 10 drugs, OR 8.72 [95% CI 7.42-10.25]); (ii) quantity of chronic diseases, OR: 1.14 (95% CI 1.11-1.17); (iii) augmented number of consultations/year, OR: 1.01 (95% CI 1.00-1.01); (iv) female gender, OR: <  1 for men, OR: 0.66 (95% CI 0.60-0.73); (v) being elderly: 65-74 years, OR: 0.71 (95% CI 0.62-0.81); 75-84 years, OR: 0.62 (95% CI 0.54-0.71); ≥85 years, OR: 0.68 (95% CI 0.58-0.81); and (vi) adjusted morbidity groups, OR: 0.90 (95% CI 0.88-0.92), (p <  0.0001). CONCLUSION: Exposure to gabapentinoids occurs in a non-negligible percentage of the population. Greater numbers of combinations of gabapentinoids and opioids and/or anxiolytics/hypnotics were associated with polypharmacy, quantity of chronic diseases, and augmented number of consultations, but not with male gender, older age, and adjusted morbidity groups.

A case of severe COVID-19 with pulmonary thromboembolism related to heparin-induced thrombocytopenia during prophylactic anticoagulation therapy.

A 53-year-old male Japanese patient with COVID-19 was admitted to our hospital after his respiratory condition worsened on day 9 of the disease. With the diagnosis of severe COVID-19, treatment with remdesivir, dexamethasone, and unfractionated heparin was started for the prevention of thrombosis. Although the patient's respiratory status data improved after treatment, severe respiratory failure persisted. Thrombocytopenia and D-dimer elevation were observed on day 8 after heparin therapy initiation. Heparin-induced thrombocytopenia (HIT) antibody measured by immunological assay was positive, and contrast computed tomography showed pulmonary artery thrombus. The patient was diagnosed with HIT because the pre-test probability score (4Ts score) for HIT was 7 points. Heparin was changed to apixaban, a direct oral anticoagulant, which resulted in a reduction of the pulmonary thrombus and improvement of the respiratory failure. In patients with COVID-19, anticoagulant therapy with heparin requires careful monitoring of thrombocytopenia and elevated D-dimer as possible complications related to HIT. (151/250 words).

Effect of methylprednisolone treatment on COVID-19: An inverse probability of treatment weighting analysis.

OBJECTIVES: While corticosteroids have been hypothesized to exert protective benefits in patients infected with SARS-CoV-2, data remain mixed. This study sought to investigate the outcomes of methylprednisone administration in an Italian cohort of hospitalized patients with confirmed SARS-CoV-2 infection. METHODS: Patients with confirmatory testing for SARS-CoV-2 were retrospectively enrolled from a tertiary university hospital in Milan, Italy from March 1st to April 30th, 2020 and divided into two groups by administration of corticosteroids. Methylprednisolone was administered to patients not responding to pharmacological therapy and ventilatory support at 0.5-1mg/kg/day for 4 to 7 days. Inverse probability of treatment weighting (IPTW) was used to adjust for baseline differences between the steroid and non-steroid cohorts via inverse probability of treatment weight. Primary outcomes included acute respiratory failure (ARF), shock, and 30-day mortality among surviving patients. RESULTS: Among 311 patients enrolled, 71 patients received steroids and 240 did not receive steroids. The mean age was 63.1 years, 35.4% were female, and hypertension, diabetes, heart disease, and chronic pulmonary disease were present in 3.5%, 1.3%, 14.8% and 12.2% respectively. Crude analysis revealed no statistically significant reduction in the incidence of 30-day mortality (36,6% vs 21,7%; OR, 2.09; 95% CI, 1.18-3.70; p = 0.011), shock (2.8% vs 4.6%; OR, 0.60; 95% CI = 0.13-2.79; p = 0.514) or ARF (12.7% vs 15%; OR, 0.82; 95% CI = 0.38-1.80; p = 0.625) between the steroid and non-steroid groups. After IPTW analysis, the steroid-group had lower incidence of shock (0.9% vs 4.1%; OR, 0.21; 95% CI,0.06-0.77; p = 0.010), ARF (6.6% vs 16.0%; OR, 0.37; 95% CI, 0.22-0.64; p<0.001) and 30-day mortality (20.3% vs 22.8%; OR 0.86; 95% CI, 0.59-1.26 p = 0.436); even though, for the latter no statistical significance was reached. Steroid use was also associated with increased length of hospital stay both in crude and IPTW analyses. Subgroup analysis revealed that patients with cardiovascular comorbidities or chronic lung diseases were more likely to be steroid responsive. No significant survival benefit was seen after steroid treatment. CONCLUSIONS: Physicians should avoid routine methylprednisolone use in SARS-CoV-2 patients, since it does not reduce 30-day mortality. However, they must consider its use for severe patients with cardiovascular or respiratory comorbidities in order to reduce the incidence of either shock or acute respiratory failure.

Deciphering the balance of IL-6/IL-10 cytokines in severe to critical COVID-19 patients.

The severity of COVID-19 is largely determined by the inflammatory response, a "Cytokine storm," that involves both pro- and anti-inflammatory cytokines. In the current study we investigated the balance of pro- and anti-inflammatory status as represented by the levels of IL-6/IL-10 in severe to critical COVID-19 patients. 66 confirmed COVID-19 patients admitted to the ICU were categorized into groups according to the mortality and respiratory failure. Data were collected retrospectively in ICU, including a peripheral immune cells and infection-related biomarker CRP. The measurements of cytokine levels were performed by Immulite analyzer for IL-6 and ELISA sandwich for IL-10. In addition, longitudinal measurement of IL-6 was performed during 5 days post admission. Longitudinal assays showed that IL-6 was sustained at a medium level within 5 days post admission in severe cases who survived or not requiring mechanical ventilation, whereas it was sustained at high levels throughout the disease course in either deceased cases or who developed respiratory failure. The ratio of IL-6/lymphocytes was positively correlated with the risk of mortality, while IL-10/lymphocytes ratio could predict respiratory failure in ICU. IL-6/IL-10 profiling revealed that deceased patients have different magnitudes of both IL-6 and IL-10 cytokine release. Notably, excessive levels of IL-6 concomitant with high levels of IL-10 were more common in diseased COVID-19 patients. Taking into account the IL-6/IL-10 profiling may help clinicians to identify the right time of anti-inflammation treatment and select patients who will respond to anti-cytokine therapies and maintain an adequate inflammatory response for SARS-CoV-2 clearance.

Risk factors for progression to acute respiratory failure after casirivimab and imdevimab administration: A retrospective study.

BACKGROUND: Casirivimab and imdevimab are effective in preventing hospitalization in outpatients with coronavirus disease 2019 (COVID-19); however, disease progression after casirivimab and imdevimab administration has been reported. This study aimed to elucidate the risk factors for disease progression after casirivimab and imdevimab administration. METHODS: This retrospective study included patients with COVID-19 who received casirivimab and imdevimab at Hiroshima City Funairi Citizens Hospital between August 6, 2021, and October 10, 2021. All patients had at least one risk factor for severe disease and were treated on admission. The patients' background characteristics and test results at the first visit were analyzed. The patients were divided into two groups (progressed and improved) based on whether they progressed to acute respiratory failure during hospitalization. RESULTS: Sixty-seven patients were included: 9 patients in the progressed group (median age, 56 years) and 58 patients in the improved group (median age, 51 years). Age, coexistence rate of diabetes, cycle threshold value of polymerase chain reaction test, rate of detectable pneumonia on chest radiographs or chest computed tomography images, lymphocyte count, and the levels of C-reactive protein, interleukin-6, glucose, and glycated hemoglobin were significantly different between the two groups. Multivariate logistic regression analysis revealed that the coexistence of diabetes and the presence of detectable pneumonia on chest radiographs were independent factors predicting the progression to acute respiratory failure. CONCLUSION: Acute respiratory failure after antibody therapy with casirivimab and imdevimab may develop in patients with diabetes or detectable pneumonia on chest radiographs at the first visit.

Can nebulised HepArin Reduce morTality and time to Extubation in patients with COVID-19 Requiring invasive ventilation Meta-Trial (CHARTER-MT): Protocol and statistical analysis plan for an investigator-initiated international meta-trial of prospective randomised clinical studies.

There is significant interest in the potential for nebulised unfractionated heparin (UFH), as a novel therapy for patients with COVID-19 induced acute hypoxaemic respiratory failure requiring invasive ventilation. The scientific and biological rationale for nebulised heparin stems from the evidence for extensive activation of coagulation resulting in pulmonary microvascular thrombosis in COVID-19 pneumonia. Nebulised delivery of heparin to the lung may limit alveolar fibrin deposition and thereby limit progression of lung injury. Importantly, laboratory studies show that heparin can directly inactivate the SARS-CoV-2 virus, thereby prevent its entry into and infection of mammalian cells. UFH has additional anti-inflammatory and mucolytic properties that may be useful in this context. METHODS AND INTERVENTION: The Can nebulised HepArin Reduce morTality and time to Extubation in Patients with COVID-19 Requiring invasive ventilation Meta-Trial (CHARTER-MT) is a collaborative prospective individual patient data analysis of on-going randomised controlled clinical trials across several countries in five continents, examining the effects of inhaled heparin in patients with COVID-19 requiring invasive ventilation on various endpoints. Each constituent study will randomise patients with COVID-19 induced respiratory failure requiring invasive ventilation. Patients are randomised to receive nebulised heparin or standard care (open label studies) or placebo (blinded placebo-controlled studies) while under invasive ventilation. Each participating study collect a pre-defined minimum dataset. The primary outcome for the meta-trial is the number of ventilator-free days up to day 28 day, defined as days alive and free from invasive ventilation.

Lithium toxicity at therapeutic doses as a fallout of COVID-19 infection: a case series and possible mechanisms.

Lithium, a mood stabilizer used in the treatment of bipolar disorder is known for its anti-inflammatory properties with the discussion of its potential use in COVID-19 infection. The SARS-CoV-2 virus causing COVID-19 infection is known to enter the target cells through angiotensin converting enzyme-2 receptors present in abundance in the lung and renal tissue. Recent research supports the evidence for direct renal injury by viral proteins. Here we report two patients with bipolar disorder presenting with lithium toxicity in the presence of COVID-19 infection. Two patients with bipolar disorder, maintaining remission on lithium prophylaxis, presented to the psychiatric emergency with recent-onset fever and altered sensorium. Both the patient's investigations revealed lithium toxicity, elevated serum creatinine, urea and inflammatory markers. Hypernatremia, hyperkalaemia, and hyperchloremia were seen in one patient. Lithium and other psychotropic medications were stopped immediately, and COVID-19 treatment was initiated. Patient with clinical signs of lithium toxicity, hypernatremia, hyperkalaemia, and hyperchloremia developed ventricular tachycardia. He survived and regained consciousness after 2 weeks of aggressive conservative management. However, another patient died of acute respiratory failure on day 3. Possible direct infection of the kidney by SARS-CoV-2 viral proteins can manifest with acute kidney injury and lithium toxicity among patients on long-term lithium therapy. Health professionals treating COVID-19 infection among individuals on lithium therapy should be aware of the possibility of lithium toxicity in the background of renal injury.

[Successful steroid pulse therapy for COVID-19 associated respiratory failure initially mimicking bortezomib-induced lung injury].

From December 2019, a 71-year-old male underwent three cycles of a combination therapy of pomalidomide, bortezomib, and dexamethasone for relapsed multiple myeloma and a very good partial response was achieved. In March 2020, he developed a fever of 38.9°C and computed tomography revealed bilateral ground-glass opacities. Antibiotic therapy was ineffective. Bronchoscopy was performed and bortezomib-induced lung injury was initially suspected. Due to respiratory exacerbation, high-dose steroid therapy was administered, which resulted in a dramatic improvement of the patient's respiratory failure. Thereafter, reverse transcription polymerase chain reaction performed on a preserved bronchial lavage sample tested positive, and thus his diagnosis was corrected to COVID-19 pneumonia. It is difficult to discriminate COVID-19 pneumonia from drug-induced lung disease, as both disorders can present similar ground-glass opacities on computed tomography. Therefore, with this presented case, we summarize our experience with steroid therapy for COVID-19 associated respiratory distress at our institution.

Time to revisit the use of G-CSF after allogeneic haematopoietic cell transplantation in COVID-19 era?

The use of granulocyte colony-stimulating factor (G-CSF) in patients with haematological malignancies is associated with less febrile neutropenia episodes. But in the presence of COVID-19 infection, the administration of G-CSF is challenging as it may trigger a robust inflammatory reaction resulting in cytokine storm, respiratory failure and severe outcomes.

Opioid Use Disorder and COVID-19: Biological Plausibility for Worsened Outcomes.

BACKGROUND: Alarms have been raised that COVID-19 may disproportionately affect certain populations with substance use disorders, particularly Opioid Use Disorder (OUD), however warnings have largely focused on social risks such as reduced availability of services. Objectives: This commentary highlights three plausible biological mechanisms for potentially worsened outcomes in patients with OUD who contract COVID-19. Results: Opioid-related respiratory depression may amplify risks of hypoxemia from COVID-19 viral pneumonia. Complex opioid immune modulation may impact host response to COVID-19, though the effect direction and clinical significance are unclear. Drug-drug interactions may affect individuals with OUD who are co-administered medications for OUD and medications for COVID-19, particularly due to cardiac adverse effects. Conclusions/Importance: There are plausible biological mechanisms for potentially worsened outcomes in patients with OUD who contract COVID-19; these mechanisms require further study, and should be considered in individuals with OUD.