Characteristics and Determinants of Pulmonary Long COVID (preprint)

RATIONALE: Persistent cough and dyspnea are prominent features of post-acute sequelae of SARS-CoV-2 (termed 'Long COVID'); however, physiologic measures and clinical features associated with these pulmonary symptoms remain poorly defined. OBJECTIVES: Using longitudinal pulmonary function testing (PFTs) and CT imaging, this study aimed to identify the characteristics and determinants of pulmonary Long COVID. METHODS: The University of Alabama at Birmingham Pulmonary Long COVID cohort was utilized to characterize lung defects in patients with persistent pulmonary symptoms after resolution primary COVID infection. Longitudinal PFTs including total lung capacity (TLC) and diffusion limitation of carbon monoxide (DLCO) were used to evaluate restriction and diffusion impairment over time in this cohort. Analysis of chest CT imaging was used to phenotype the pulmonary Long COVID pathology. Risk factors linked to development of pulmonary Long COVID were estimated using univariate and multivariate logistic regression models. MEASUREMENTS AND MAIN RESULTS: Longitudinal evaluation 929 patients with post-COVID pulmonary symptoms revealed diffusion impairment (DLCO ≤80%) and restriction (TLC ≤80%) in 51% of the cohort (n=479). In multivariable logistic regression analysis (adjusted odds ratio; aOR, 95% confidence interval [CI]), invasive mechanical ventilation during primary infection conferred the greatest increased odds of developing pulmonary Long COVID with diffusion impaired restriction (aOR=10.9 [4.09-28.6]). Finally, a sub-analysis of CT imaging identified evidence of fibrosis in this population. CONCLUSIONS: Persistent diffusion impaired restriction was identified as a key feature of pulmonary Long COVID. Subsequent clinical trials should leverage combined symptomatic and quantitative PFT measurements for more targeted enrollment of pulmonary Long COVID patients.

Bilateral Axillary Lymphadenopathy After COVID-19 Vaccine Presenting for Lymph Node Surgical Biopsy: A Case Report.

The coronavirus disease 2019 (COVID-19) pandemic ravaged China, made its way to Thailand and Japan, and ultimately spread across the globe. Despite all efforts to contain the virus, hundreds of millions of positive cases and millions of deaths have been reported worldwide. Due to the vastness and severity of this virus, there was a desperate need for a vaccine, quickly. The COVID-19 vaccination was created urgently under emergency use authorization (EUA) by the US Food and Drug Administration (FDA) in less than one year, a process typically taking over 10 years. With this expedited creation time, there is also a shortened time frame for clinical trials, which is commonly used to evaluate for effectiveness and identify any potential side effects or adverse reactions to the created vaccine. We will discuss some potential side effects of receiving the Pfizer-BioNTech COVID-19 mRNA vaccination. In this case report, we discuss one individual who received two doses of the Pfizer-BioNTech COVID-19 mRNA vaccine and experienced a previous unreported adverse side effect of non-self-remitting bilateral axillary lymphadenopathy. This reaction was not originally seen during the clinical trial phase of the vaccine creation, which caused this individual to obtain a full medical workup including ultrasound, computed tomography (CT) scans, and blood work and ultimately needing surgical intervention to have the axillary lymphadenopathy excised. We aim to shed light on a new, undocumented adverse reaction that should be included in physicians' differential diagnoses in individuals after receiving the COVID-19 vaccine, particularly the Pfizer-BioNTech COVID-19 mRNA vaccination. This information could help future patients avoid unnecessary extensive medical workups, surgical procedures, being exposed to anesthesia, or having the burden of additional unwarranted healthcare costs.

COVID-19 bacteremic co-infection is a major risk factor for mortality, ICU admission, and mechanical ventilation.

BACKGROUND: Recent single-center reports have suggested that community-acquired bacteremic co-infection in the context of Coronavirus disease 2019 (COVID-19) may be an important driver of mortality; however, these reports have not been validated with a multicenter, demographically diverse, cohort study with data spanning the pandemic. METHODS: In this multicenter, retrospective cohort study, inpatient encounters were assessed for COVID-19 with community-acquired bacteremic co-infection using 48-h post-admission blood cultures and grouped by: (1) confirmed co-infection [recovery of bacterial pathogen], (2) suspected co-infection [negative culture with ≥ 2 antimicrobials administered], and (3) no evidence of co-infection [no culture]. The primary outcomes were in-hospital mortality, ICU admission, and mechanical ventilation. COVID-19 bacterial co-infection risk factors and impact on primary outcomes were determined using multivariate logistic regressions and expressed as adjusted odds ratios with 95% confidence intervals (Cohort, OR 95% CI, Wald test p value). RESULTS: The studied cohorts included 13,781 COVID-19 inpatient encounters from 2020 to 2022 in the University of Alabama at Birmingham (UAB, n = 4075) and Ochsner Louisiana State University Health-Shreveport (OLHS, n = 9706) cohorts with confirmed (2.5%), suspected (46%), or no community-acquired bacterial co-infection (51.5%) and a comparison cohort consisting of 99,170 inpatient encounters from 2010 to 2019 (UAB pre-COVID-19 pandemic cohort). Significantly increased likelihood of COVID-19 bacterial co-infection was observed in patients with elevated ≥ 15 neutrophil-to-lymphocyte ratio (UAB: 1.95 [1.21-3.07]; OLHS: 3.65 [2.66-5.05], p < 0.001 for both) within 48-h of hospital admission. Bacterial co-infection was found to confer the greatest increased risk for in-hospital mortality (UAB: 3.07 [2.42-5.46]; OLHS: 4.05 [2.29-6.97], p < 0.001 for both), ICU admission (UAB: 4.47 [2.87-7.09], OLHS: 2.65 [2.00-3.48], p < 0.001 for both), and mechanical ventilation (UAB: 3.84 [2.21-6.12]; OLHS: 2.75 [1.87-3.92], p < 0.001 for both) across both cohorts, as compared to other risk factors for severe disease. Observed mortality in COVID-19 bacterial co-infection (24%) dramatically exceeds the mortality rate associated with community-acquired bacteremia in pre-COVID-19 pandemic inpatients (5.9%) and was consistent across alpha, delta, and omicron SARS-CoV-2 variants. CONCLUSIONS: Elevated neutrophil-to-lymphocyte ratio is a prognostic indicator of COVID-19 bacterial co-infection within 48-h of admission. Community-acquired bacterial co-infection, as defined by blood culture-positive results, confers greater increased risk of in-hospital mortality, ICU admission, and mechanical ventilation than previously described risk factors (advanced age, select comorbidities, male sex) for COVID-19 mortality, and is independent of SARS-CoV-2 variant.

Outpatient palliative care during the COVID-19 pandemic: a retrospective single centre analysis in Germany.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has challenged health care systems worldwide. In Germany, patients in a palliative care setting have the opportunity to receive treatment by a specialised mobile outpatient palliative care team (OPC). The given retrospective single centre analysis describes the use of OPC structures for terminally ill COVID-19 patients during the height of the pandemic in Germany and aims to characterise this exceptional OPC patient collective. METHODS: First, death certificates were analysed in order to collect data about the place of death of all deceased COVID-19 patients (n = 471) within our local governance district. Second, we investigated whether advance care planning structures were established in local nursing homes (n = 30) during the height of the COVID-19 pandemic in 2020. Third, we examined patient characteristics of COVID-19 negative (n = 1579) and COVID-19 positive (n = 28) patients treated by our tertiary care centre guided OPC service. RESULTS: The analysis of death certificates in our local district revealed that only 2.1% of all deceased COVID-19 patients had succumbed at their home address (n = 10/471). In contrast, 34.0% of COVID-19 patients died in nursing homes (n = 160/471), whereas 63.5% died in an inpatient hospital setting (n = 299/471). A large proportion of these hospitalised patients died on non-intensive care unit wards (38.8%). Approximately 33.0% of surveyed nursing homes had a palliative care council service and 40.0% of them offered advance care planning (ACP) structures for their nursing home residents. In our two OPC collectives we observed significant differences concerning clinical characteristics such as the Index of Eastern Cooperative Oncology Group [ECOG] (p = 0.014), oncologic comorbidity (p = 0.004), as well as referrer and primary patient location (p = 0.001, p = 0.033). CONCLUSIONS: Most COVID-19 patients in our governance district died in an inpatient setting. However, the highest number of COVID-19 patients in our governance district who died in an outpatient setting passed away in nursing homes where palliative care structures should be further expanded. COVID-19 patients who died under the care of our OPC service had considerably fewer oncologic comorbidities. Finally, to relieve conventional health care structures, we propose the expansion of established OPC structures for treating terminally ill COVID-19 patients.

Plasma Microbiome in COVID-19 Subjects: An Indicator of Gut Barrier Defects and Dysbiosis.

The gut is a well-established route of infection and target for viral damage by SARS-CoV-2. This is supported by the clinical observation that about half of COVID-19 patients exhibit gastrointestinal (GI) complications. We aimed to investigate whether the analysis of plasma could provide insight into gut barrier dysfunction in patients with COVID-19 infection. Plasma samples of COVID-19 patients (n = 146) and healthy individuals (n = 47) were collected during hospitalization and routine visits. Plasma microbiome was analyzed using 16S rRNA sequencing and gut permeability markers including fatty acid binding protein 2 (FABP2), peptidoglycan (PGN), and lipopolysaccharide (LPS) in both patient cohorts. Plasma samples of both cohorts contained predominately Proteobacteria, Firmicutes, Bacteroides, and Actinobacteria. COVID-19 subjects exhibit significant dysbiosis (p = 0.001) of the plasma microbiome with increased abundance of Actinobacteria spp. (p = 0.0332), decreased abundance of Bacteroides spp. (p = 0.0003), and an increased Firmicutes:Bacteroidetes ratio (p = 0.0003) compared to healthy subjects. The concentration of the plasma gut permeability marker FABP2 (p = 0.0013) and the gut microbial antigens PGN (p < 0.0001) and LPS (p = 0.0049) were significantly elevated in COVID-19 patients compared to healthy subjects. These findings support the notion that the intestine may represent a source for bacteremia and contribute to worsening COVID-19 outcomes. Therapies targeting the gut and prevention of gut barrier defects may represent a strategy to improve outcomes in COVID-19 patients.

Factors associated with self-reported avoidance of harm reduction services during the COVID-19 pandemic by people who use drugs in five cities in the United States and Canada.

BACKGROUND: This study examines individual-level factors associated with avoiding two important health services for people who use drugs-medications for treatment of opioid use disorder and syringe service programs-during the first year of the COVID-19 pandemic. METHODS: Data come from two subsamples of people who use drugs who were active participants in one of nine cohort studies in Vancouver, British Columbia; Baltimore, Maryland; Los Angeles, California; Chicago, Illinois; and Miami, Florida. Participants were interviewed remotely about COVID-19-associated disruptions to healthcare. We estimated the association of demographic, social, and health factors with each outcome using logistic regression among 702 participants (medication analysis) and 304 participants (syringe service analysis.) Analyses were repeated, stratified by city of residence, to examine geographic variation in risk. RESULTS: There were large differences between cities in the prevalence of avoiding picking up medications for opioid use disorder, with almost no avoidance in Vancouver (3%) and nearly universal avoidance in Los Angeles, Chicago, and Miami (>90%). After accounting for between-city differences, no individual factors were associated with avoiding picking up medications. The only factor significantly associated with avoiding syringe service programs was higher levels of self-reported worry about COVID-19. CONCLUSION: During the first year of the COVID-19 pandemic, geographic differences in service and policy contexts likely influenced avoidance of health and harm reduction services by people who use drugs in the United States and Canada more than individual differences between people.

Potentials of post-mortem CT investigations during SARS-COV-2 pandemic: a narrative review.

In December 2019, a new coronavirus, SARS-COV-2, caused a cluster of cases of pneumonia in China, and rapidly spread across the globe. It was declared a pandemic by the World Health Organization on March 11th, 2020. Virtual autopsy by post-mortem CT (PMCT) and its ancillary techniques are currently applied in post-mortem examinations as minimally or non-invasive techniques with promising results. In this narrative review, we speculate on the potentials of PMCT and its ancillary techniques, as a viable investigation technique for analysis of suspected or confirmed SARS-COV-2 deaths. An online literature search was performed by using three prefix search terms (postmortem, post-mortem, post mortem) individually combined with the suffix radiology, imaging, computed tomography, CT and with the search terms 'SARS-CoV-2' and 'COVID-19' to identify papers about PMCT and its ancillary techniques in SARS-COV-2 positive cadavers. PMCT findings suggestive for pulmonary COVID-19 in deceased positive SARS-COV-2 infection are reported in the literature. PMCT ancillary techniques were never applied in such cases. PMCT imaging of the lungs has been proposed as a pre-autopsy screening method for SARS-COV-2 infection. Further studies are needed to ascertain the value of PMCT in determining COVID-19 as the cause of death without autopsy histopathological confirmation. We advocate the application of PMCT techniques in the study of ascertained or suspected SARS-COV-2 infected deceased individuals as a screening technique and as a method of post-mortem investigation, to augment the numbers of case examined and significantly reducing infection risk for the operators.

Exploring the impact of pulse oximeter selection within the COVID-19 home-use pulse oximetry pathways.

BACKGROUND: During the COVID-19 pandemic, portable pulse oximeters were issued to some patients to permit home monitoring and alleviate pressure on inpatient wards. Concerns were raised about the accuracy of these devices in some patient groups. This study was conducted in response to these concerns. OBJECTIVES: To evaluate the performance characteristics of five portable pulse oximeters and their suitability for deployment on home-use pulse oximetry pathways created during the COVID-19 pandemic. This study considered the effects of different device models and patient characteristics on pulse oximeter accuracy, false negative and false positive rate. METHODS: A total of 915 oxygen saturation (spO2) measurements, paired with measurements from a hospital-standard pulse oximeter, were taken from 50 patients recruited from respiratory wards and the intensive care unit at an acute hospital in London. The effects of device model and several patient characteristics on bias, false negative and false positive likelihood were evaluated using multiple regression analyses. RESULTS AND CONCLUSIONS: All five portable pulse oximeters appeared to outperform the standard to which they were manufactured. Device model, patient spO2 and patient skin colour were significant predictors of measurement bias, false positive and false negative rate, with some variation between models. The false positive and false negative rates were 11.2% and 24.5%, respectively, with substantial variation between models.

Severity and inpatient mortality of COVID-19 pneumonia from Beta variant infection: a clinical cohort study in Cape Town, South Africa (preprint)

ABSTRACT Background The SARS-CoV-2 Beta variant, associated with immune escape and higher transmissibility, drove a more severe second COVID-19 wave in South Africa. Individual patient level characteristics and outcomes with the Beta variant are not well characterized. Methods We performed a retrospective cohort study comparing disease severity and inpatient mortality of COVID-19 pneumonia between the first and second wave periods at a referral hospital in Cape Town, South Africa. Beta variant infection was confirmed by genomic sequencing. Outcomes were analyzed with logistic regression and accelerated failure time models. Results 1,182 patients were included: 571 during the first wave period and 611 from the second wave. Beta variant accounted for 97% of infections in the second wave. There was no difference in crude in-hospital mortality between wave periods (first wave 22.2%, second wave 22.1%; p = 0.9). Time to death was decreased with higher weekly hospital admissions (16%; 95% CI, 8 to 24 for every 50-patient increase), age (18%; 95% CI, 12 to 24 for every 10-year increase) and hypertension (31%; 95% CI, 12 to 46). Corticosteroid use delayed time to death by 2-fold (95% CI, 1.5 to 3.0). Admission during the second wave decreased time to death after adjustment for other predictors, but this did not reach statistical significance (24%; 95% CI, 47 to -2). There was no effect of HIV on survival. Conclusions There was a trend towards earlier mortality during the second COVID-19 wave driven by the Beta variant, suggesting a possible biological basis. Use of oral prednisone was strongly protective. Key points In Cape Town, South Africa, the second wave of COVID-19, dominated by the Beta variant, was associated with decreased time to inpatient death after adjustment for age, comorbidities, steroid use, and admission numbers. Use of oral prednisone was strongly protective.

Plasma microbiome in COVID-19 subjects: an indicator of gut barrier defects and dysbiosis (preprint)

The gut is a well-established route of infection and target for viral damage by SARS-CoV-2. This is supported by the clinical observation that about half of COVID-19 patients exhibit gastrointestinal (GI) symptoms. We asked whether the analysis of plasma could provide insight into gut barrier dysfunction in patients with COVID-19 infection. Plasma samples of COVID-19 patients (n=30) and healthy control (n=16) were collected during hospitalization. Plasma microbiome was analyzed using 16S rRNA sequencing, metatranscriptomic analysis, and gut permeability markers including FABP-2, PGN and LPS in both patient cohorts. Almost 65% (9 out 14) COVID-19 patients showed abnormal presence of gut microbes in their bloodstream. Plasma samples contained predominately Proteobacteria, Firmicutes, and Actinobacteria. The abundance of gram-negative bacteria (Acinetobacter, Nitrospirillum, Cupriavidus, Pseudomonas, Aquabacterium, Burkholderia, Caballeronia, Parabhurkholderia, Bravibacterium, and Sphingomonas) was higher than the gram-positive bacteria (Staphylococcus and Lactobacillus) in COVID-19 subjects. The levels of plasma gut permeability markers FABP2 (1282 [plusmn]199.6 vs 838.1[plusmn]91.33; p=0.0757), PGN (34.64[plusmn]3.178 vs 17.53[plusmn]2.12; p<0.0001), and LPS (405.5[plusmn]48.37 vs 249.6[plusmn]17.06; p=0.0049) were higher in COVID-19 patients compared to healthy subjects. These findings support that the intestine may represent a source for bacteremia and may contribute to worsening COVID-19 outcomes. Therapies targeting the gut and prevention of gut barrier defects may represent a strategy to improve outcomes in COVID-19 patients.

Airflow Characteristics in Aeromedical Aircraft: Considerations During COVID-19.

OBJECTIVE: The aeromedical transport of coronavirus patients presents risks to clinicians and aircrew. Patient positioning and physical barriers may provide additional protection during flight. This paper describes airflow testing undertaken on fixed wing and rotary wing aeromedical aircraft. METHODS: Airflow testing was undertaken on a stationary Hawker Beechcraft B200C and Leonardo Augusta Westland 139. Airflow was simulated using a Trainer 101 (MSS Professional A/S, Odense Sø, Syddanmark, Denmark) Smoke machine. Different cabin configurations were used along with variations in heating, cooling, and ventilation systems. RESULTS: For the Hawker Beechcraft B200C, smoke generated within the forward section of the cabin was observed to fill the cabin to a fluid boundary located in-line with the forward edge of the cargo door. With the curtain closed, smoke was only observed to enter the cockpit in very small quantities. For the Leonardo AW139, smoke generated within the cabin was observed to expand to fill the cabin evenly before dissipating. With the curtain closed, smoke was observed to enter the cockpit only in small quantities CONCLUSION: The use of physical barriers in fixed wing and rotary wing aeromedical aircraft provides some protection to aircrew. Optimal positioning of the patient is on the aft stretcher on the Beechcraft B200C and on a laterally orientated stretcher on the AW139. The results provide a baseline for further investigation into methods to protect aircrew during the coronavirus pandemic.

The Cardiac Toxicity of Chloroquine or Hydroxychloroquine in COVID-19 Patients: A Systematic Review and Meta-regression Analysis (preprint)

ImportanceThe antimalarial agents chloroquine (CQ) and hydroxychloroquine (HCQ) have been proposed as a potential treatment for COVID-19 due their effect on several cellular processes that impact viral replication. Although more than 100 ongoing trials are testing their efficacy, CQ and HCQ are being used widely in clinical practice, exposing COVID-19 patients to potentially significant cardiac adverse effects. ObjectiveTo systematically review the literature and estimate the risk of cardiac toxicity in patients receiving CQ or HCQ for COVID-19. Data SourcesA systematic search was conducted on May 27, 2020 of Ovid EBM Reviews, Ovid Embase (1974+), Ovid Medline (1946+ including epub ahead of print, in-process & other non-indexed citations), Scopus (1970+) and Web of Science (1975+) and preprint servers (Medrvix and ResearchSquare) and manual search of references lists. Study SelectionStudies that included COVID-19 patients treated with CQ or HCQ, with or without azithromycin, were included as follows: (1) COVID-19 patient population, (2) the study included more than 10 patients receiving either one of the medications, (3) reported electrocardiographic changes and/or cardiac arrhythmias. Data Extraction and SynthesisStudy characteristics and endpoints incidence were extracted. Due to the very low incidence of torsades de pointes (TdP) and other endpoints (rare events), the arcsine transformation was used to obtain a pooled estimate of the different incidences using a random-effects meta-analysis. Meta-regression analyses were used to assess whether the incidence of different endpoints significantly varied by multiple study-level variables specified a priori. Main Outcomes and MeasuresPooled Incidence of: (1) change in QTc value from baseline [≥] 60 ms, (2) QTc [≥] 500 ms, (3) the composite of endpoint 1 and 2, (4) TdP arrhythmia or ventricular tachycardia (VT) or cardiac arrest, (5) discontinuation of treatment due to drug-induced QT prolongation or arrhythmias. ResultsA total of 19 studies with a total of 5652 patients were included. All included studies were of high methodological quality in terms of exposure ascertainment or outcome assessment. Among 2719 patients treated with CQ or HCQ, only two episodes of TdP were reported; the pooled incidence of TdP arrhythmia or VT or cardiac arrest was 3 per 1000, 95% CI (0-21), I2=96%, 18 studies with 3725 patients. Among 13 studies of 4334 patients, the pooled incidence of discontinuation of CQ or HCQ due to prolonged QTc or arrhythmias was 5%, 95% CI (1-11), I2=98%. The pooled incidence of change in QTc from baseline of [≥] 60 ms was 7%, 95% CI (3-14), I2=94% (12 studies of 2008 patients). The pooled incidence of QTc [≥] 500 ms was 6%, 95% CI (2-12), I2=95% (16 studies of 2317 patients). Among 11 studies of 3127 patients, the pooled incidence of change in QTc from baseline of [≥] 60 ms or QTc [≥] 500 ms was 9%, 95% CI (3-17), I2=97%. Mean/median age, coronary artery disease, hypertension, diabetes, concomitant QT prolonging medications, ICU care, and severity of illness in the study populations explained between-studies heterogeneity. Conclusions and RelevanceTreatment of COVID-19 patients with CQ or HCQ is associated with a significant risk of drug-induced QT prolongation, which is a harbinger for drug-induced TdP/VT or cardiac arrest. CQ/HCQ use resulted in a relatively higher incidence of TdP as compared to drugs withdrawn from the market for this particular adverse effect. Therefore, these agents should be used only in the context of randomized clinical trials, in patients at low risk for drug-induced QT prolongation, with adequate safety monitoring. Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the risks of different cardiac toxicities in patients receiving chloroquine (CQ) or hydroxychloroquine (HCQ) for COVID-19. FindingsIn this systematic review, treatment of COVID-19 patients with CQ or HCQ is associated with a clinically significant risk of drug-induced QT prolongation, and torsades de pointes (TdP) arrhythmia/ventricular tachycardia/cardiac arrest in a relatively higher incidence compared to drugs withdrawn from the market for such adverse effects. MeaningThese agents should be used only in the context of clinical trials, in patients at low risk for drug-induced QT prolongation, with adequate safety monitoring.