Baricitinib therapy in COVID-19: A pilot study on safety and clinical impactDear Editor , 38.1 (37.7-38.7) 0.356 Breath rate N/min, median (IQR), 23 (19.5-24.2) 22 (19.7-24) 0.665 SpO2 (%),median (IQR) 91 (90-92.5) 92 (91.2-93) 0.157 PaO2/FiO2, median (IQR) 290 (199.2-292.2) 268.6 (264.4-295) 0.603 Pulse rate, median (IQR) 82 (73-88.3) 90 (87.2-94.5) 0.069 SBP mm/Hg, median (IQR) 120 (110-131.2) 105 (100-111.25) 0.003 DBP mm/Hg, median (IQR) 70 (60-80) 62.5 (60-66.25) 0.094 WBC (x10 9 /L), median (IQR) 7.8 (5.8-10.8) 8.2 (7.3-8.8) 0.908 Neutrophils (x10 9 /L), median (IQR) 6,5 (4.5-7.7) 6.9 (6.4-7.6) 0.707 Lymphocytes (x10 9 /L), median (IQR) 0.7 (0.7-1.2) 0.89 (0.7-0.9) 1.0 0 0 Hemoglobin (g/L), median (IQR) 118 (102-134.2) 125 (108-134) 0.568 Platelets (x10 9 /L), median (IQR) 203 (174-227) 366 (340-407) 0.0 0 0 ALT (U/L), median (IQR) 28.5 (23.5-52) 44 (37-50) 0.157 AST (U/L), median (IQR) 34 (26.2-48) 44 (34.7-47) 0.525 Creatinine (mg/dl), median (IQR)1.0 (0.9-1.1) 1.00 (0.9-1) 0.583 CRP (mg/dl), median (IQR) 8.2 (5.8-14.5) 3 (1.5-3.2) 0.002 Procalcitonin ng/ml, median (IQR) 0.7 (0.4-1.1) 1.2 (0.8-2.1) 0.902 MEWS, median (IQR) 3 ( 2-3.25) 3 (3-4) 0.544 Abbreviations and symbols: N = number;% = percentage; °C: grade Celsius; min = minute; SpO2 = peripheral capillary oxygen saturation; PaO2/FiO2 = ratio of arterial oxygen partial pressure to fractional inspired oxygen; SBP = systolic blood pressure; DBP = diastolic blood pressure; WBC = white blood cells; AST = serum glutamic oxaloacetic transaminase; ALT = serum alanine aminotransferase; MEWS = Modified Early Warning Score; IQR: Interquartile range.

The cytokine release syndrome has been proposed as the driver of inflammation in coronavirus disease 2019 (COVID-19). However, studies on longitudinal cytokine profiles in patients across the whole severity spectrum of COVID-19 are lacking. In this prospective observational study on adult COVID-19 patients admitted to two Hong Kong public hospitals, cytokine profiling was performed on blood samples taken during early phase (within 7 days of symptom onset) and late phase (8 to 12 days of symptom onset). The primary objective was to evaluate the difference in early and late cytokine profiles among patient groups with different disease severity. The secondary objective was to assess the associations between cytokines and clinical endpoints in critically ill patients. A total of 40 adult patients (mild = 8, moderate = 15, severe/critical = 17) hospitalized with COVID-19 were included in this study. We found 22 cytokines which were correlated with disease severity, as proinflammatory Th1-related cytokines (interleukin (IL)-18, interferon-induced protein-10 (IP-10), monokine-induced by gamma interferon (MIG), and IL-10) and ARDS-associated cytokines (IL-6, monocyte chemoattractant protein-1 (MCP-1), interleukin-1 receptor antagonist (IL-1RA), and IL-8) were progressively elevated with increasing disease severity. Furthermore, 11 cytokines were consistently different in both early and late phases, including seven (growth-regulated oncogene-alpha (GRO-α), IL-1RA, IL-6, IL-8, IL-10, IP-10, and MIG) that increased and four (FGF-2, IL-5, macrophage-derived chemokine (MDC), and MIP-1α) that decreased from mild to severe/critical patients. IL-8, followed by IP-10 and MDC were the best performing early biomarkers to predict disease severity. Among critically ill patients, MCP-1 predicted the duration of mechanical ventilation, highest norepinephrine dose administered, and length of intensive care stay.

Background Coronavirus disease 2019 (COVID-19) caused by the enveloped RNA virus SARS-CoV-2 primarily affects the respiratory and gastrointestinal tracts. SARS-CoV-2 was isolated from fecal samples, and active viral replication was reported in human intestinal cells. The human gut also harbors an enormous amount of resident viruses (collectively known as the virome) that play a role in regulating host immunity and disease pathophysiology. Understanding gut virome perturbation that underlies SARS-CoV-2 infection and severity is an unmet need. Methods We enrolled 98 COVID-19 patients with varying disease severity (3 asymptomatic, 53 mild, 34 moderate, 5 severe, 3 critical) and 78 non-COVID-19 controls matched for gender and co-morbidities. All subjects had fecal specimens sampled at inclusion. Blood specimens were collected for COVID-19 patients at admission to test for inflammatory markers and white cell counts. Among COVID-19 cases, 37 (38%) patients had serial fecal samples collected 2 to 3 times per week from time of hospitalization until after discharge. Using shotgun metagenomics sequencing, we sequenced and profiled the fecal RNA and DNA virome. We investigated alterations and longitudinal dynamics of the gut virome in association with disease severity and blood parameters. Results Patients with COVID-19 showed underrepresentation of Pepper mild mottle virus (RNA virus) and multiple bacteriophage lineages (DNA viruses) and enrichment of environment-derived eukaryotic DNA viruses in fecal samples, compared to non-COVID-19 subjects. Such gut virome alterations persisted up to 30 days after disease resolution. Fecal virome in SARS-CoV-2 infection harbored more stress-, inflammation-, and virulence-associated gene encoding capacities including those pertaining to bacteriophage integration, DNA repair, and metabolism and virulence associated with their bacterial host. Baseline fecal abundance of 10 virus species (1 RNA virus, pepper chlorotic spot virus, and 9 DNA virus species) inversely correlated with disease COVID-19 severity. These viruses inversely correlated with blood levels of pro-inflammatory proteins, white cells, and neutrophils. Among the 10 COVID-19 severity-associated DNA virus species, 4 showed inverse correlation with age; 5 showed persistent lower abundance both during disease course and after disease resolution relative to non-COVID-19 subjects. Conclusions Both enteric RNA and DNA virome in COVID-19 patients were different from non-COVID-19 subjects, which persisted after disease resolution of COVID-19. Gut virome may calibrate host immunity and regulate severity to SARS-CoV-2 infection. Our observation that gut viruses inversely correlated with both severity of COVID-19 and host age may partly explain that older subjects are prone to severe and worse COVID-19 outcomes. Altogether, our data highlight the importance of human gut virome in severity and potentially therapeutics of COVID-19.

is the research leader for the Exotic and Emerging Avian Viral Disease Research Unit of the Agricultural Research Service, USDA. His primary research interests are in the understanding and control of avian influenza and Newcastle disease viruses in poultry and other emerging viral diseases that threaten the poultry industry.

Background: SARS-CoV-2 enters the body through inhalation or self-inoculation to mucosal surfaces. The kinetics of the ocular and nasal mucosal-specific-immunoglobulin A(IgA) responses remain under-studied. Methods: Conjunctival fluid (CF, n = 140) and nasal epithelial lining fluid (NELF, n = 424) obtained by paper strips and plasma (n = 153) were collected longitudinally from SARS-CoV-2 paediatric (n = 34) and adult (n = 47) patients. The SARS-CoV-2 spike protein 1(S1)-specific mucosal antibody levels in COVID-19 patients, from hospital admission to six months post-diagnosis, were assessed. Results: The mucosal antibody was IgA-predominant. In the NELF of asymptomatic paediatric patients, S1-specific IgA was induced as early as the first four days post-diagnosis. Their plasma S1-specific IgG levels were higher than in symptomatic patients in the second week after diagnosis. The IgA and IgG levels correlated positively with the surrogate neutralization readout. The detectable NELF “receptor-blocking” S1-specific IgA in the first week after diagnosis correlated with a rapid decline in viral load. Conclusions: Early and intense nasal S1-specific IgA levels link to a rapid decrease in viral load. Our results provide insights into the role of mucosal immunity in SARS-CoV-2 exposure and protection. There may be a role of NELF IgA in the screening and diagnosis of SARS-CoV-2 infection.

Digestive symptoms in COVID-19 patients with mild disease severity: clinical presentation, stool viral RNA testing, and outcomes. Am J Gastroenterol. 2020 Apr 15 [Epub ahead of print].

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Conjunctival and nasal mucosal antibody responses in thirty-four paediatric and forty-seven adult COVID-19 patients were measured. The mucosal antibody was IgA dominant. In the nasal epithelial lining fluid (NELF) of asymptomatic paediatric patients, SARS-CoV-2 spike protein 1 (S1) specific immunoglobulin A (IgA) was induced early. Their plasma S1-specific IgG levels were higher than symptomatic patients. More adult with mild disease had NELF S1-specific IgA than those with severe/critical illness. Within the first week of diagnosis, higher S1-specific antibodies in NELF and plasma and lower vial loads were detected in paediatric than adult patients with mild disease. The IgA and IgG levels correlated positively with the surrogate neutralization readout. The detectable NELF neutralizing S1-specific IgA in the first week after diagnosis correlated with a rapid decline in viral load. This study highlights the effect of nasal IgA in limiting the SARS-CoV-2 replication and provides complementary information to the serum antibody measurements.