Distinct inflammatory profiles distinguish COVID-19 from influenza with limited contributions from cytokine storm.

We pursued a study of immune responses in coronavirus disease 2019 (COVID-19) and influenza patients. Compared to patients with influenza, patients with COVID-19 exhibited largely equivalent lymphocyte counts, fewer monocytes, and lower surface human leukocyte antigen (HLA)-class II expression on selected monocyte populations. Furthermore, decreased HLA-DR on intermediate monocytes predicted severe COVID-19 disease. In contrast to prevailing assumptions, very few (7 of 168) patients with COVID-19 exhibited cytokine profiles indicative of cytokine storm syndrome. After controlling for multiple factors including age and sample time point, patients with COVID-19 exhibited lower cytokine levels than patients with influenza. Up-regulation of IL-6, G-CSF, IL-1RA, and MCP1 predicted death in patients with COVID-19 but were not statistically higher than patients with influenza. Single-cell transcriptional profiling revealed profound suppression of interferon signaling among patients with COVID-19. When considered across the spectrum of peripheral immune profiles, patients with COVID-19 are less inflamed than patients with influenza.

Severe immunosuppression and not a cytokine storm characterizes COVID-19 infections.

COVID-19-associated morbidity and mortality have been attributed to a pathologic host response. Two divergent hypotheses have been proposed: hyperinflammatory cytokine storm; and failure of host protective immunity that results in unrestrained viral dissemination and organ injury. A key explanation for the inability to address this controversy has been the lack of diagnostic tools to evaluate immune function in COVID-19 infections. ELISpot, a highly sensitive, functional immunoassay, was employed in 27 patients with COVID-19, 51 patients with sepsis, 18 critically ill nonseptic (CINS) patients, and 27 healthy control volunteers to evaluate adaptive and innate immune status by quantitating T cell IFN-É£ and monocyte TFN-α production. Circulating T cell subsets were profoundly reduced in COVID-19 patients. Additionally, stimulated blood mononuclear cells produced less than 40%-50% of the IFN-É£ and TNF-α observed in septic and CINS patients, consistent with markedly impaired immune effector cell function. Approximately 25% of COVID-19 patients had increased IL-6 levels that were not associated with elevations in other canonical proinflammatory cytokines. Collectively, these findings support the hypothesis that COVID-19 suppresses host functional adaptive and innate immunity. Importantly, IL-7 administered ex vivo restored T cell IFN-É£ production in COVID-19 patients. Thus, ELISpot may functionally characterize host immunity in COVID-19 and inform prospective therapies.

Targeted Immunosuppression Distinguishes COVID-19 from Influenza in Moderate and Severe Disease.

Coronavirus disease 2019 (COVID-19) is characterized by a high incidence of acute respiratory failure. The underlying immunopathology of that failure and how it compares to other causes of severe respiratory distress, such as influenza virus infection, are not fully understood. Here we addressed this by developing a prospective observational cohort of COVID-19 and influenza subjects with varying degrees of disease severity and assessing the quality and magnitude of their immune responses at the cellular and protein level. Additionally, we performed single-cell RNA transcriptional profiling of peripheral blood mononuclear cells from select subjects. The cohort consists of 79 COVID-19 subjects, 26 influenza subjects, and 15 control subjects, including 35 COVID-19 and 7 influenza subjects with acute respiratory failure. While COVID-19 subjects exhibited largely equivalent or greater activated lymphocyte counts compared to influenza subjects, they had fewer monocytes and lower surface HLA-class II expression on monocytes compared to influenza subjects and controls. At least two distinct immune profiles were observed by cytokine levels in severe COVID-19 patients: 3 of 71 patients were characterized by extreme inflammation, with greater than or equal to ~50% of the 35 cytokines measured greater than 2 standard deviations from the mean level of other severe patients (both influenza and COVID-19); the other immune profile, which characterized 68 of 71 subjects, had a mixed inflammatory signature, where 28 of 35 cytokines in COVID-19 patients had lower mean cytokine levels, though not all were statistically significant. Only 2 cytokines were higher in COVID-19 subjects compared to influenza subjects (IL-6 and IL-8). Influenza and COVID-19 patients could be distinguished statistically based on cytokine module expression, particularly after controlling for the significant effects of age on cytokine expression, but again with lower levels of most cytokines in COVID-19 subjects. Further, high circulating levels of IL-1RA and IL-6 were associated with increased odds of intubation in the combined influenza and COVID-19 cohort [OR = 3.93 and 4.30, respectively] as well as among only COVID-19 patients. Single cell transcriptional profiling of COVID-19 and influenza subjects with respiratory failure identified profound suppression in type I and type II interferon signaling in COVID-19 patients across multiple clusters. In contrast, COVID-19 cell clusters were enriched for alterations in metabolic, stress, and apoptotic pathways. These alterations were consistent with an increased glucocorticoid response in COVID-19 patients compared to influenza. When considered across the spectrum of innate and adaptive immune profiles, the immune pathologies underlying severe influenza and COVID-19 are substantially distinct. The majority of COVID-19 patients with acute respiratory failure do not have a cytokine storm phenotype but instead exhibit profound type I and type II IFN immunosuppression when compared to patients with acute influenza. Upregulation of a small number of inflammatory mediators, including IL-6, predicts acute respiratory failure in both COVID-19 and influenza patients.

Pneumothorax as a Complication of Apnea Testing for Brain Death.

BACKGROUND: Pneumothorax is an under-recognized complication of apnea testing performed as part of the neurological determination of death. It may result in hemodynamic instability or even cardiac arrest, compromising ability to declare brain death (BD) and viability of organs for transplantation. We report three cases of pneumothorax with apnea testing (PAT) and review the available literature of this phenomenon. METHODS: Series of three cases supplemented with a systematic review of literature (including discussion of apnea testing in major brain death guidelines). RESULTS: Two patients were diagnosed with PAT due to immediate hemodynamic compromise, while the third was diagnosed many hours after BD. An additional nine cases of PAT were found in the literature. Information regarding oxygen cannula diameter was available for nine patients (range 2.3-5.3 mm), and flow rate was available for ten patients (mean 11 L/min). Pneumothorax was treated to resolution in the majority of patients (n = 8), although only six completed apnea testing following diagnosis/treatment of pneumothorax and only three patients became organ donors afterward. Review of major BD guidelines showed that although use of low oxygen flow rate (usually ≤ 6 L/min) during apnea testing is suggested, the risk of PAT was explicitly mentioned in just one. CONCLUSION: Development of PAT may adversely affect the process of BD determination and could limit the opportunity for organ donation. Each institution should have preventive measures in place.

Diagnostic implications of soluble triggering receptor expressed on myeloid cells-1 in BAL fluid of patients with pulmonary infiltrates in the ICU.

OBJECTIVE: Prospective single-center study to determine whether the presence of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) has diagnostic utility in patients with pulmonary infiltrates receiving mechanical ventilation and undergoing BAL. DESIGN: Prospective cohort study. SETTING: Barnes-Jewish Hospital, a 1,200-bed urban teaching hospital. PATIENTS: Adult patients with acute respiratory failure undergoing BAL for pulmonary infiltrates. INTERVENTIONS: BAL fluid measurement of sTREM-1 concentration using a Quantikine Human TREM-1 Immunoassay (R&D Systems; Minneapolis, MN). MEASUREMENTS AND MAIN RESULTS: A total of 105 consecutive patients receiving mechanical ventilation and undergoing BAL were enrolled. Of those, 19 patients (18.1%) met definite microbiologic criteria for bacterial or fungal ventilator-associated pneumonia (VAP). Though the mean sTREM-1 concentration was greater in patients with definite VAP (n = 19; 171.9 +/- 158.7 pg/mL) than in patients with definite absence of VAP (n = 21; 96.7 +/- 76.2 pg/mL), this difference was not statistically significant (p = 0.06). A cutoff value for sTREM-1 > 200 pg/mL yielded a diagnostic sensitivity of 42.1% and a specificity of 75.6% for definite VAP. Patients with alveolar hemorrhage had the greatest values for sTREM-1 concentration (n = 9; 555 +/- 440 pg/mL). Receiver operating curve analysis and multivariate logistic regression analysis demonstrated that measurement of sTREM-1 was inferior to clinical parameters for the diagnosis of VAP. CONCLUSIONS: Measurement of sTREM-1 in BAL fluid appears to have minimal diagnostic value for VAP.

Delirium as detected by the CAM-ICU predicts restraint use among mechanically ventilated medical patients.

OBJECTIVE: The first goal of this investigation was to identify individuals with delirium defined by the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) among medical patients with respiratory failure. Our second goal was to compare clinical interventions including use of continuous sedation infusions, the number of ventilator-free days, ICU length of stay, hospital mortality, and use of physical restraints in mechanically ventilated patients with and without delirium. DESIGN: A prospective, single-center, observational cohort study. SETTING: The medical intensive care unit (19 beds) of an urban teaching hospital. PATIENTS: Adult, intubated, and mechanically ventilated patients. INTERVENTIONS: Daily evaluation with the CAM-ICU, outcomes assessment, and prospective data collection. MEASUREMENTS AND MAIN RESULTS: Among 93 patients evaluated using the CAM-ICU, 44 patients (47%) developed delirium (CAM-ICU+) for >/=1 day while in the intensive care unit. Twenty-two patients (24%) had no episodes of delirium recorded (CAM-ICU-), and 27 (29%) remained comatose until extubation or death. A statistically greater number of patients with delirium (CAM-ICU+) received continuous infusions of midazolam (59% vs. 32%, p < .05) or fentanyl (57% vs. 32%, p < .05) and physical soft-limb restraints (77% vs. 50%, p < .05) compared with patients without delirium (CAM-ICU-). CONCLUSIONS: The identification of delirium using the CAM-ICU was associated with greater use of continuous sedation infusions and physical restraints. Additional studies are required to determine how the use of these specific interventions influences the occurrence and the natural history of delirium among critically ill patients.