Human adenovirus lung disease: outbreaks, models of immune-response-driven acute lung injury and pandemic potential.

PURPOSE OF REVIEW: An overview of epidemic, human adenovirus (HAdV) lung infections with proposed studies of the viral/host immune response interface to better understand mechanisms of immunopathogenesis, for development of improved responses to a potential HAdV pandemic. RECENT FINDINGS: Emergent HAdV strains 7, 3, 4, 14 are the most common types associated with infection outbreaks. Recent outbreaks have revealed increased community spread, beyond epidemic group settings. The ongoing circulation of these virulent HAdV strains might allow for further HAdV adaptation, with increased HAdV spread and disease severity in the population that could theoretically result in expansion to a pandemic level. SUMMARY: Public health screening has revealed spread of HAdV outbreak strains to the general community. Despite expanded awareness of viral respiratory diseases during the SARS-CoV-2 pandemic, there has been limited, systematic monitoring of HAdV infection in the population. The shift in clinical laboratories to a focus on molecular diagnostics and away from classical methods of viral characterization has reduced the distribution of outbreak HAdV strains to the research community to study mechanisms of pathogenesis. This change risks reduced development of new preventive and therapeutic strategies that could be needed in the event of more widespread HAdV epidemics.

Predictors of mortality, ICU hospitalization, and extrapulmonary complications in COVID-19 patients.

OBJECTIVE: A major coronavirus disease 2019 (COVID-19) outbreak occurred in Northeastern France in spring 2020. This single-center retrospective observational cohort study aimed to compare patients with severe COVID-19 and those with non-severe COVID-19 (survivors vs. non-survivors, ICU patients vs. non-ICU patients) and to describe extrapulmonary complications. PATIENTS AND METHODS: We included all patients with a confirmed diagnosis of COVID-19 admitted to Colmar Hospital in March 2020. RESULTS: We examined 600 patients (median age 71.09 years; median body mass index: 26.9 kg/m2); 57.7% were males, 86.3% had at least one comorbidity, 153 (25.5%) required ICU hospitalization, and 115 (19.1%) died. Baseline independent factors associated with death were older age (>75 vs. ≤75 years), male sex, oxygen supply, chronic neurological, renal, and pulmonary diseases, diabetes, cancer, low platelet and hemoglobin counts, and high levels of C-reactive protein (CRP) and serum creatinine. Factors associated with ICU hospitalization were age <75 years, oxygen supply, chronic pulmonary disease, absence of dementia, and high levels of CRP, hemoglobin, and serum creatinine. Among the 600 patients, 80 (13.3%) had an acute renal injury, 33 (5.5%) had a cardiovascular event, 27 (4.5%) had an acute liver injury, 24 (4%) had venous thromboembolism, eight (1.3%) had a neurological event, five (0.8%) had rhabdomyolysis, and one had acute pancreatitis. Most extrapulmonary complications occurred in ICU patients. CONCLUSION: This study highlighted the main risk factors for ICU hospitalization and death caused by severe COVID-19 and the frequency of numerous extrapulmonary complications in France.

Noninvasive respiratory support and patient self-inflicted lung injury in COVID-19: a narrative review.

COVID-19 pneumonia is associated with hypoxaemic respiratory failure, ranging from mild to severe. Because of the worldwide shortage of ICU beds, a relatively high number of patients with respiratory failure are receiving prolonged noninvasive respiratory support, even when their clinical status would have required invasive mechanical ventilation. There are few experimental and clinical data reporting that vigorous breathing effort during spontaneous ventilation can worsen lung injury and cause a phenomenon that has been termed patient self-inflicted lung injury (P-SILI). The aim of this narrative review is to provide an overview of P-SILI pathophysiology and the role of noninvasive respiratory support in COVID-19 pneumonia. Respiratory mechanics, vascular compromise, viscoelastic properties, lung inhomogeneity, work of breathing, and oesophageal pressure swings are discussed. The concept of P-SILI has been widely investigated in recent years, but controversies persist regarding its mechanisms. To minimise the risk of P-SILI, intensivists should better understand its underlying pathophysiology to optimise the type of noninvasive respiratory support provided to patients with COVID-19 pneumonia, and decide on the optimal timing of intubation for these patients.

Current and Past Infections of HBV Do Not Increase Mortality in Patients With COVID-19.

BACKGROUND AND AIMS: We compared risk of acute liver injury and mortality in patients with COVID-19 and current, past, and no HBV infection. APPROACH AND RESULTS: This was a territory-wide retrospective cohort study in Hong Kong. Patients with COVID-19 between January 23, 2020, and January 1, 2021, were identified. Patients with hepatitis C or no HBsAg results were excluded. The primary outcome was mortality. Acute liver injury was defined as alanine aminotransferase or aspartate aminotransferase ≥2 × upper limit of normal (ULN; i.e., 80 U/L), with total bilirubin ≥2 × ULN (i.e., 2.2 mg/dL) and/or international normalized ratio ≥1.7. Of 5,639 patients included, 353 (6.3%) and 359 (6.4%) had current and past HBV infection, respectively. Compared to patients without known HBV exposure, current HBV-infected patients were older and more likely to have cirrhosis. Past HBV-infected patients were the oldest, and more had diabetes and cardiovascular disease. At a median follow-up of 14 (9-20) days, 138 (2.4%) patients died; acute liver injury occurred in 58 (1.2%), 8 (2.3%), and 11 (3.1%) patients with no, current, and past HBV infection, respectively. Acute liver injury (adjusted HR [aHR], 2.45; 95% CI, 1.52-3.96; P < 0.001), but not current (aHR, 1.29; 95% CI, 0.61-2.70; P = 0.507) or past (aHR, 0.90; 95% CI, 0.56-1.46; P = 0.681) HBV infection, was associated with mortality. Use of corticosteroid, antifungal, ribavirin, or lopinavir-ritonavir (adjusted OR [aOR], 2.55-5.63), but not current (aOR, 1.93; 95% CI, 0.88-4.24; P = 0.102) or past (aOR, 1.25; 95% CI, 0.62-2.55; P = 0.533) HBV infection, was associated with acute liver injury. CONCLUSION: Current or past HBV infections were not associated with more liver injury and mortality in COVID-19.

Chronic liver disease not a significant comorbid condition for COVID-19.

To explore the role of chronic liver disease (CLD) in COVID-19. A total of 1439 consecutively hospitalized patients with COVID-19 from one large medical center in the United States from March 16, 2020 to April 23, 2020 were retrospectively identified. Clinical characteristics and outcomes were compared between patients with and without CLD. Postmortem examination of liver in 8 critically ill COVID-19 patients was performed. There was no significant difference in the incidence of CLD between critical and non-critical groups (4.1% vs 2.9%, p = 0.259), or COVID-19 related liver injury between patients with and without CLD (65.7% vs 49.7%, p = 0.065). Postmortem examination of liver demonstrated mild liver injury associated central vein outflow obstruction and minimal to moderate portal lymphocytic infiltrate without evidence of CLD. Patients with CLD were not associated with a higher risk of liver injury or critical/fatal outcomes. CLD was not a significant comorbid condition for COVID-19.

Dysnatremia is a Predictor for Morbidity and Mortality in Hospitalized Patients with COVID-19.

CONTEXT: Dysnatremia is an independent predictor of mortality in patients with bacterial pneumonia. There is paucity of data about the incidence and prognostic impact of abnormal sodium concentration in patients with coronavirus disease 2019 (COVID-19). OBJECTIVE: This work aimed to examine the association of serum sodium during hospitalization with key clinical outcomes, including mortality, need for advanced respiratory support and acute kidney injury (AKI), and to explore the role of serum sodium as a marker of inflammatory response in COVID-19. METHODS: This retrospective longitudinal cohort study, including all adult patients who presented with COVID-19 to 2 hospitals in London over an 8-week period, evaluated the association of dysnatremia (serum sodium < 135 or > 145 mmol/L, hyponatremia, and hypernatremia, respectively) at several time points with inpatient mortality, need for advanced ventilatory support, and AKI. RESULTS: The study included 488 patients (median age, 68 years). At presentation, 24.6% of patients were hyponatremic, mainly due to hypovolemia, and 5.3% hypernatremic. Hypernatremia 2 days after admission and exposure to hypernatremia at any time point during hospitalization were associated with a 2.34-fold (95% CI, 1.08-5.05; P = .0014) and 3.05-fold (95% CI, 1.69-5.49; P < .0001) increased risk of death, respectively, compared to normonatremia. Hyponatremia at admission was linked with a 2.18-fold increase in the likelihood of needing ventilatory support (95% CI, 1.34-3.45, P = .0011). Hyponatremia was not a risk factor for in-hospital mortality, except for the subgroup of patients with hypovolemic hyponatremia. Sodium values were not associated with the risk for AKI and length of hospital stay. CONCLUSION: Abnormal sodium levels during hospitalization are risk factors for poor prognosis, with hypernatremia and hyponatremia being associated with a greater risk of death and respiratory failure, respectively. Serum sodium values could be used for risk stratification in patients with COVID-19.

Vitamin D and its therapeutic relevance in pulmonary diseases.

Vitamin D is customarily involved in maintaining bone and calcium homeostasis. However, contemporary studies have identified the implication of vitamin D in several cellular processes including cellular proliferation, differentiation, wound healing, repair and regulatory systems inclusive of host defence, immunity, and inflammation. Multiple studies have indicated corelations between low serum levels of vitamin D, perturbed pulmonary functions and enhanced incidences of inflammatory diseases. Almost all of the pulmonary diseases including acute lung injury, cystic fibrosis, asthma, COPD, Pneumonia and Tuberculosis, all are inflammatory in nature. Studies have displayed strong inter-relations with vitamin D deficiency and progression of lung disorders; however, the underlying mechanism is still unknown. Vitamin D has emerged to possess inhibiting effects on pulmonary inflammation while exaggerating innate immune defenses by strongly influencing functions of inflammatory cells including dendritic cells, monocyte/macrophages, T cells, and B cells along with structural epithelial cells. This review dissects the effects of vitamin D on the inflammatory cells and their therapeutic relevance in pulmonary diseases. Although, the data obtained is very limited and needs further corroboration but presents an exciting area of further research. This is because of its ease of supplementation and development of personalized medicine which could lead us to an effective adjunct and cost-effective method of therapeutic modality for highly fatal pulmonary diseases.

High value of mid-regional proadrenomedullin in COVID-19: A marker of widespread endothelial damage, disease severity, and mortality.

The widespread endothelial damage due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may lead to a disruption of the adrenomedullin (ADM) system responsible for vascular leakage, increased inflammatory status, and microvascular alteration with multi-organs dysfunction. The aim of this study was to evaluate the role of mid-regional proadrenomedullin (MR-proADM) as a marker of SARS-CoV2 related widespread endothelial damage, clinically identified by organs damage, disease severity and mortality. Patients with SARS-CoV-2 infection has been prospectively enrolled and demographic characteristic, clinical and laboratory data has been evaluated. In the overall population, 58% developed acute respiratory distress syndrome (ARDS), 23.3% of patients died, 6.5% acute cardiac injury, 1.4% of patients developed acute ischemic stroke, 21.2% acute kidney injury, 11.8% acute liver damage, and 5.4% septic shock. The best MR-proADM cut-off values for ARDS development and mortality prediction were 3.04 and 2 nmol/L, respectively. Patients presenting with MR-proADM values ≥2 nmol/L showed a significantly higher mortality risk. In conclusion, MR-proADM values ≥2 nmol/L identify those patients with high mortality risk related to a multiorgan dysfunction syndrome. These patients must be carefully evaluated and considered for an intensive therapeutic approach.

Liver Injury in Liver Transplant Recipients With Coronavirus Disease 2019 (COVID-19): U.S. Multicenter Experience.

BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19) is associated with liver injury, but the prevalence and patterns of liver injury in liver transplantation (LT) recipients with COVID-19 are open for study. APPROACH AND RESULTS: We conducted a multicenter study in the United States of 112 adult LT recipients with COVID-19. Median age was 61 years (interquartile range, 20), 54.5% (n = 61) were male, and 39.3% (n = 44) Hispanic. Mortality rate was 22.3% (n = 25); 72.3% (n = 81) were hospitalized and 26.8% (n = 30) admitted to the intensive care unit (ICU). Analysis of peak values of alanine aminotransferase (ALT) during COVID-19 showed moderate liver injury (ALT 2-5× upper limit of normal [ULN]) in 22.2% (n = 18) and severe liver injury (ALT > 5× ULN) in 12.3% (n = 10). Compared to age- and sex-matched nontransplant patients with chronic liver disease and COVID-19 (n = 375), incidence of acute liver injury was lower in LT recipients (47.5% vs. 34.6%; P = 0.037). Variables associated with liver injury in LT recipients were younger age (P = 0.009; odds ratio [OR], 2.06; 95% confidence interval [CI], 1.20-3.54), Hispanic ethnicity (P = 0.011; OR, 6.01; 95% CI, 1.51-23.9), metabolic syndrome (P = 0.016; OR, 5.87; 95% CI, 1.38-24.99), vasopressor use (P = 0.018; OR, 7.34; 95% CI, 1.39-38.52), and antibiotic use (P = 0.046; OR, 6.93; 95% CI, 1.04-46.26). Reduction in immunosuppression (49.4%) was not associated with liver injury (P = 0.156) or mortality (P = 0.084). Liver injury during COVID-19 was significantly associated with mortality (P = 0.007; OR, 6.91; 95% CI, 1.68-28.48) and ICU admission (P = 0.007; OR, 7.93; 95% CI, 1.75-35.69) in LT recipients. CONCLUSIONS: Liver injury is associated with higher mortality and ICU admission in LT recipients with COVID-19. Hence, monitoring liver enzymes closely can help in early identification of patients at risk for adverse outcomes. Reduction of immunosuppression during COVID-19 did not increase risk for mortality or graft failure.

Coronavirus Disease 2019 and Hypertension: The Role of Angiotensin-Converting Enzyme 2 and the Renin-Angiotensin System.

Hypertension emerged from early reports as a potential risk factor for worse outcomes for persons with coronavirus disease 2019 (COVID-19). Among the putative links between hypertension and COVID-19 is a key counter-regulatory component of the renin-angiotensin system (RAS): angiotensin-converting enzyme 2 (ACE2). ACE2 facilitates entry of severe acute respiratory syndrome coronavirus 2, the virus responsible for COVID-19, into host cells. Because RAS inhibitors have been suggested to increase ACE2 expression, health-care providers and patients have grappled with the decision of whether to discontinue these medications during the COVID-19 pandemic. However, experimental models of analogous viral pneumonias suggest RAS inhibitors may exert protective effects against acute lung injury. We review how RAS and ACE2 biology may affect outcomes in COVID-19 through pulmonary and other systemic effects. In addition, we briefly detail the data for and against continuation of RAS inhibitors in persons with COVID-19 and summarize the current consensus recommendations from select specialty organizations.

Acute respiratory failure in COVID-19: is it "typical" ARDS?

In December 2019, an outbreak of coronavirus disease 2019 (COVID-19) was identified in Wuhan, China. The World Health Organization (WHO) declared this outbreak a significant threat to international health. COVID-19 is highly infectious and can lead to fatal comorbidities especially acute respiratory distress syndrome (ARDS). Thus, fully understanding the characteristics of COVID-19-related ARDS is conducive to early identification and precise treatment. We aimed to describe the characteristics of COVID-19-related ARDS and to elucidate the differences from ARDS caused by other factors. COVID-19 mainly affected the respiratory system with minor damage to other organs. Injury to the alveolar epithelial cells was the main cause of COVID-19-related ARDS, and endothelial cells were less damaged with therefore less exudation. The clinical manifestations were relatively mild in some COVID-19 patients, which was inconsistent with the severity of laboratory and imaging findings. The onset time of COVID-19-related ARDS was 8-12 days, which was inconsistent with ARDS Berlin criteria, which defined a 1-week onset limit. Some of these patients might have a relatively normal lung compliance. The severity was redefined into three stages according to its specificity: mild, mild-moderate, and moderate-severe. HFNO can be safe in COVID-19-related ARDS patients, even in some moderate-severe patients. The more likely cause of death is severe respiratory failure. Thus, the timing of invasive mechanical ventilation is very important. The effects of corticosteroids in COVID-19-related ARDS patients were uncertain. We hope to help improve the prognosis of severe cases and reduce the mortality.