Noninvasive diagnosis of secondary infections in COVID-19 by sequencing of plasma microbial cell-free DNA.

Secondary infection (SI) diagnosis in severe COVID-19 remains challenging. We correlated metagenomic sequencing of plasma microbial cell-free DNA (mcfDNA-Seq) with clinical SI assessment, immune response, and outcomes. We classified 42 COVID-19 inpatients as microbiologically confirmed-SI (Micro-SI, n = 8), clinically diagnosed-SI (Clinical-SI, n = 13, i.e., empiric antimicrobials), or no-clinical-suspicion-for-SI (No-Suspected-SI, n = 21). McfDNA-Seq was successful in 73% of samples. McfDNA detection was higher in Micro-SI (94%) compared to Clinical-SI (57%, p = 0.03), and unexpectedly high in No-Suspected-SI (83%), similar to Micro-SI. We detected culture-concordant mcfDNA species in 81% of Micro-SI samples. McfDNA correlated with LRT 16S rRNA bacterial burden (r = 0.74, p = 0.02), and biomarkers (white blood cell count, IL-6, IL-8, SPD, all p < 0.05). McfDNA levels were predictive of worse 90-day survival (hazard ratio 1.30 [1.02-1.64] for each log10 mcfDNA, p = 0.03). High mcfDNA levels in COVID-19 patients without clinical SI suspicion may suggest SI under-diagnosis. McfDNA-Seq offers a non-invasive diagnostic tool for pathogen identification, with prognostic value on clinical outcomes.

Cardiac complications in children with acute COVID-19 vs multisystem inflammatory syndrome in children (MIS-C).

BACKGROUND: Cardiac involvement can lead to significant morbidity in children with acute COVID-19 or multisystem inflammatory syndrome in children (MIS-C). However, the presentation and outcomes of cardiac involvement may differ among these 2 conditions. We aimed to compare the frequency and extent of cardiac involvement among children admitted with acute COVID-19 vs those with MIS-C. METHODS: We conducted a cross sectional study of patients admitted to our hospital from March 2020 to August 2021 with symptomatic acute COVID-19 or MIS-C. Cardiac involvement was defined by presence of 1 or more of the following: elevated troponin, elevated brain natriuretic peptide, reduced left ventricular ejection fraction on echocardiogram, coronary dilation on echocardiogram, or abnormal electrocardiogram reading. RESULTS: Among 346 acute COVID-19 patients with median age of 8.9 years and 304 MIS-C patients with median age of 9.1 years, cardiac involvement was present in 33 acute COVID-19 patients (9.5%) and 253 MIS-C patients (83.2%). The most common cardiac abnormality was abnormal electrocardiogram in acute COVID-19 patients (7.5%) and elevated troponin in MIS-C patients (67.8%). Among acute COVID-19 patients, obesity was significantly associated with cardiac involvement. Among MIS-C patients, non-Hispanic Black race/ethnicity was significantly associated with cardiac involvement. CONCLUSIONS: Cardiac involvement is much more common in children with MIS-C than in those with acute COVID-19. These results reinforce our standardized practice of performing full cardiac evaluations and follow-up in all patients with MIS-C but only in acute COVID-19 patients with signs or symptoms of cardiac involvement.

Therapy With Allogeneic Severe Acute Respiratory Syndrome Coronavirus-2-Specific T Cells for Persistent Coronavirus Disease 2019 in Immunocompromised Patients.

We administered severe acute respiratory syndrome coronavirus-2 viral-specific T cells (VSTs) under emergency investigational new drug applications to 6 immunocompromised patients with persistent coronavirus disease 2019 (COVID-19) and characterized clinical and virologic responses. Three patients had partial responses after failing other therapies but then died. Two patients completely recovered, but the role of VSTs in recovery was unclear due to concomitant use of other antivirals. One patient had not responded to 2 courses of remdesivir and experienced sustained recovery after VST administration. The use of VSTs in immunocompromised patients with persistent COVID-19 requires further study.

Trajectories of Host-Response Subphenotypes in Patients With COVID-19 Across the Spectrum of Respiratory Support.

BACKGROUND: Hospitalized patients with severe COVID-19 follow heterogeneous clinical trajectories, requiring different levels of respiratory support and experiencing diverse clinical outcomes. Differences in host immune responses to SARS-CoV-2 infection may account for the heterogeneous clinical course, but we have limited data on the dynamic evolution of systemic biomarkers and related subphenotypes. Improved understanding of the dynamic transitions of host subphenotypes in COVID-19 may allow for improved patient selection for targeted therapies. RESEARCH QUESTION: We examined the trajectories of host-response profiles in severe COVID-19 and evaluated their prognostic impact on clinical outcomes. STUDY DESIGN AND METHODS: In this prospective observational study, we enrolled 323 inpatients with COVID-19 receiving different levels of baseline respiratory support: (1) low-flow oxygen (37%), (2) noninvasive ventilation (NIV) or high-flow oxygen (HFO; 29%), (3) invasive mechanical ventilation (27%), and (4) extracorporeal membrane oxygenation (7%). We collected plasma samples on enrollment and at days 5 and 10 to measure host-response biomarkers. We classified patients by inflammatory subphenotypes using two validated predictive models. We examined clinical, biomarker, and subphenotype trajectories and outcomes during hospitalization. RESULTS: IL-6, procalcitonin, and angiopoietin 2 persistently were elevated in patients receiving higher levels of respiratory support, whereas soluble receptor of advanced glycation end products (sRAGE) levels displayed the inverse pattern. Patients receiving NIV or HFO at baseline showed the most dynamic clinical trajectory, with 24% eventually requiring intubation and exhibiting worse 60-day mortality than patients receiving invasive mechanical ventilation at baseline (67% vs 35%; P < .0001). sRAGE levels predicted NIV failure and worse 60-day mortality for patients receiving NIV or HFO, whereas IL-6 levels were predictive in all patients regardless of level of support (P < .01). Patients classified to a hyperinflammatory subphenotype at baseline (< 10%) showed worse 60-day survival (P < .0001) and 50% of them remained classified as hyperinflammatory at 5 days after enrollment. INTERPRETATION: Longitudinal study of the systemic host response in COVID-19 revealed substantial and predictive interindividual variability influenced by baseline levels of respiratory support.

Trajectories of host-response biomarkers and inflammatory subphenotypes in COVID-19 patients across the spectrum of respiratory support.

Purpose: Enhanced understanding of the dynamic changes in the dysregulated inflammatory response in COVID-19 may help improve patient selection and timing for immunomodulatory therapies. Methods: We enrolled 323 COVID-19 inpatients on different levels of baseline respiratory support: i) Low Flow Oxygen (37%), ii) Non-Invasive Ventilation or High Flow Oxygen (NIV_HFO, 29%), iii) Invasive Mechanical Ventilation (IMV, 27%), and iv) Extracorporeal Membrane Oxygenation (ECMO, 7%). We collected plasma samples upon enrollment and days 5 and 10 to measure host-response biomarkers. We classified subjects into inflammatory subphenotypes using two validated predictive models. We examined clinical, biomarker and subphenotype trajectories and outcomes during hospitalization. Results: IL-6, procalcitonin, and Angiopoietin-2 were persistently elevated in patients at higher levels of respiratory support, whereas sRAGE displayed the inverse pattern. Patients on NIV_HFO at baseline had the most dynamic clinical trajectory, with 26% eventually requiring intubation and exhibiting worse 60-day mortality than IMV patients at baseline (67% vs. 35%, p<0.0001). sRAGE levels predicted NIV failure and worse 60-day mortality for NIV_HFO patients, whereas IL-6 levels were predictive in IMV or ECMO patients. Hyper-inflammatory subjects at baseline (<10% by both models) had worse 60-day survival (p<0.0001) and 50% of them remained classified as hyper-inflammatory on follow-up sampling at 5 days post-enrollment. Receipt of combined immunomodulatory therapies (steroids and anti-IL6 agents) was associated with markedly increased IL-6 and lower Angiopoietin-2 levels (p<0.05). Conclusions: Longitudinal study of systemic host responses in COVID-19 revealed substantial and predictive inter-individual variability, influenced by baseline levels of respiratory support and concurrent immunomodulatory therapies.

Caring for the Critically Ill Patient with COVID-19.

The COVID-19 pandemic has resulted in unprecedented numbers of critically ill patients. Critical care providers have been challenged to increase the capacity for critical care, prevent the spread of syndrome coronavirus 2 in hospitals, determine the optimal treatment approaches for patients with critical COVID-19, and to design and implement systems for fair allocation of scarce life-saving resources when capacity is exhausted. The global burden of COVID-19 highlighted disparities, across geographic regions and among minority patient populations. Faced with a novel pathogen, critical care providers grappled with the extent to which conventional supportive critical care practices should be followed versus adapted to treat patients with COVID-19. Fiercely debated practices included the use of awake prone positioning, the timing of intubation, and optimal approach to sedation. Advances in clinical trial design were necessary to rapidly identify appropriate therapeutics for the critically ill patient with COVID-19. In this article, we review the epidemiology, outcomes, and treatments for the critically ill patient with COVID-19.

Neurologic Manifestations and Complications of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created a global pandemic. Beyond the well-described respiratory manifestations, SARS-CoV-2 may cause a variety of neurologic complications, including headaches, alteration in taste and smell, encephalopathy, cerebrovascular disease, myopathy, psychiatric diseases, and ocular disorders. Herein we describe SARS-CoV-2's mechanism of neuroinvasion and the epidemiology, outcomes, and treatments for neurologic manifestations of COVID-19.

Critically Ill Patients Treated for Chimeric Antigen Receptor-Related Toxicity: A Multicenter Study.

OBJECTIVES: To report the epidemiology, treatments, and outcomes of adult patients admitted to the ICU after cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. DESIGN: Retrospective cohort study. SETTING: Nine centers across the U.S. part of the chimeric antigen receptor-ICU initiative. PATIENTS: Adult patients treated with chimeric antigen receptor T-cell therapy who required ICU admission between November 2017 and May 2019. INTERVENTIONS: Demographics, toxicities, specific interventions, and outcomes were collected. RESULTS: One-hundred five patients treated with axicabtagene ciloleucel required ICU admission for cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome during the study period. At the time of ICU admission, the majority of patients had grade 3-4 toxicities (66.7%); 15.2% had grade 3-4 cytokine release syndrome and 64% grade 3-4 immune effector cell-associated neurotoxicity syndrome. During ICU stay, cytokine release syndrome was observed in 77.1% patients and immune effector cell-associated neurotoxicity syndrome in 84.8% of patients; 61.9% patients experienced both toxicities. Seventy-nine percent of patients developed greater than or equal to grade 3 toxicities during ICU stay, however, need for vasopressors (18.1%), mechanical ventilation (10.5%), and dialysis (2.9%) was uncommon. Immune Effector Cell-Associated Encephalopathy score less than 3 (69.7%), seizures (20.2%), status epilepticus (5.7%), motor deficits (12.4%), and cerebral edema (7.9%) were more prevalent. ICU mortality was 8.6%, with only three deaths related to cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Median overall survival time was 10.4 months (95% CI, 6.64-not available mo). Toxicity grade or organ support had no impact on overall survival; higher cumulative corticosteroid doses were associated to decreased overall and progression-free survival. CONCLUSIONS: This is the first study to describe a multicenter cohort of patients requiring ICU admission with cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome after chimeric antigen receptor T-cell therapy. Despite severe toxicities, organ support and in-hospital mortality were low in this patient population.

Intractable Coronavirus Disease 2019 (COVID-19) and Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Replication in a Chimeric Antigen Receptor-Modified T-Cell Therapy Recipient: A Case Study.

A chimeric antigen receptor-modified T-cell therapy recipient developed severe coronavirus disease 2019, intractable RNAemia, and viral replication lasting >2 months. Premortem endotracheal aspirate contained >2 × 1010 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA copies/mL and infectious virus. Deep sequencing revealed multiple sequence variants consistent with intrahost virus evolution. SARS-CoV-2 humoral and cell-mediated immunity were minimal. Prolonged transmission from immunosuppressed patients is possible.

A 35-Year-Old Smoker With Dyspnea and Chest Pain.

CASE PRESENTATION: A 35-year-old veteran presented at our clinic with insidious dyspnea on exertion, nonspecific chest pain, and intermittent rash. The patient reported the development of dyspnea over 6 to 8 weeks. He had been physically active before this time but had since developed dyspnea after walking 30 to 61 m (100 to 200 ft) or with any more strenuous physical exertion. He described a nonproductive cough, with bilateral nonspecific chest pain that was worse with exertion. In addition, there was a fleeting, salmon-colored, nonpruritic rash over the bilateral arms and legs that was not responsive to over-the-counter topical steroids. The patient's medical history was notable for a 15-pack-year smoking history, posttraumatic stress disorder, depression, Clostridium difficile colitis, migraines, and alcohol abuse. Surgical history was notable for pyloric myotomy for stenosis and umbilical hernia repair. He lived with his partner and five children and was unemployed at the time because of dyspnea. There were no pets in the home and no prior occupational exposures, including silica, heavy metals, or birds.

New Medical Device Acquisition During Pediatric Severe Sepsis Hospitalizations.

OBJECTIVES: Severe sepsis is a significant cause of healthcare utilization and morbidity among pediatric patients. However, little is known about how commonly survivors acquire new medical devices during pediatric severe sepsis hospitalization. We sought to determine the rate of new device acquisition (specifically, tracheostomy placement, gastrostomy tube placement, vascular access devices, ostomy procedures, and amputation) among children surviving hospitalizations with severe sepsis. For contextualization, we compare this to rates of new device acquisition among three comparison cohorts: 1) survivors of all-cause pediatric hospitalizations; 2) matched survivors of nonsepsis infection hospitalizations; and 3) matched survivors of all-cause nonsepsis hospitalization with similar organ dysfunction. DESIGN: Observational cohort study. SETTING: Nationwide Readmission Database (2016), including all-payer hospitalizations from 27 states. PATIENTS: Eighteen-thousand two-hundred ten pediatric severe sepsis hospitalizations; 532,738 all-cause pediatric hospitalizations; 16,173 age- and sex-matched nonsepsis infection hospitalizations; 15,025 organ dysfunction matched all-cause nonsepsis hospitalizations; and all with live discharge. MEASUREMENTS AND MAIN RESULTS: Among 18,210 pediatric severe sepsis hospitalizations, 1,024 (5.6%) underwent device placement. Specifically, 3.5% had new gastrostomy, 3.1% new tracheostomy, 0.6% new vascular access devices, 0.4% new ostomy procedures, and 0.1% amputations. One-hundred forty hospitalizations (0.8%) included two or more new devices. After applying the Nationwide Readmissions Database sampling weights, there were 55,624 pediatric severe sepsis hospitalizations and 1,585,194 all-cause nonsepsis hospitalizations with live discharge in 2016. Compared to all-cause pediatric hospitalizations, severe sepsis hospitalizations were eight-fold more likely to involve new device acquisition (6.4% vs 0.8%; p < 0.001). New device acquisition was also higher in severe sepsis hospitalizations compared with matched nonsepsis infection hospitalizations (5.1% vs 1.2%; p < 0.01) and matched all-cause hospitalizations with similar organ dysfunction (4.7% vs 2.8%; p < 0.001). CONCLUSIONS: In this nationwide, all-payer cohort of U.S. pediatric severe sepsis hospitalizations, one in 20 children surviving severe sepsis experienced new device acquisition. The procedure rate was nearly eight-fold higher than all-cause, nonsepsis pediatric hospitalizations, and four-fold higher than matched nonsepsis infection hospitalizations.

Epidemiology and Outcomes of Cancer-Related Versus Non-Cancer-Related Sepsis Hospitalizations.

OBJECTIVE: Cancer and its treatment are known to be important risk factors for sepsis, contributing to an estimated 12% of U.S. sepsis admissions in the 1990s. However, cancer treatment has evolved markedly over the past 2 decades. We sought to examine how cancer-related sepsis differs from non-cancer-related sepsis. DESIGN: Observational cohort. SETTING: National Readmissions Database (2013-2014), containing all-payer claims for 49% of U.S. PATIENTS: A total of 1,104,363 sepsis hospitalizations. INTERVENTIONS: We identified sepsis hospitalizations in the U.S. National Readmissions Database using explicit codes for severe sepsis, septic shock, or Dombrovskiy criteria (concomitant codes for infection and organ dysfunction). We classified hospitalizations as cancer-related versus non-cancer-related sepsis based on the presence of secondary diagnosis codes for malignancy. We compared characteristics (site of infection and organ dysfunction) and outcomes (in-hospital mortality and 30-d readmissions) of cancer-related versus non-cancer-related sepsis hospitalizations. We also completed subgroup analyses by age, cancer types, and specific cancer diagnoses. MEASUREMENTS AND MAIN RESULTS: There were 27,481,517 hospitalizations in National Readmissions Database 2013-2014, of which 1,104,363 (4.0%) were for sepsis and 4,150,998 (15.1%) were cancer related. In-hospital mortality in cancer-related sepsis was 27.9% versus 19.5% in non-cancer-related sepsis. The median count of organ dysfunctions was indistinguishable, but the rate of specific organ dysfunctions differed by small amounts (e.g., hematologic dysfunction 20.1% in cancer-related sepsis vs 16.6% in non-cancer-related sepsis; p < 0.001). Cancer-related sepsis was associated with an adjusted absolute increase in in-hospital mortality ranging from 2.2% to 15.2% compared with non-cancer-related sepsis. The mortality difference was greatest in younger adults and waned with age. Patients (23.2%) discharged from cancer-related sepsis were rehospitalized within 30 days, compared with 20.1% in non-cancer-related sepsis (p < 0.001). CONCLUSIONS: In this cohort of over 1 million U.S. sepsis hospitalizations, more than one in five were cancer related. The difference in mortality varies substantially across age spectrum and is greatest in younger adults. Readmissions were more common after cancer-related sepsis.