Criteria for Hyperinflammation Developing in COVID-19: Analysis of 2 Cohorts From Different Periods of the Pandemic.

OBJECTIVE: Hyperinflammation (HI) that develops in week 2 of COVID-19 contributes to a worse outcome. Because week 2 laboratory findings can be relatively mild, the available criteria for classification of hemophagocytic lymphohistiocytosis or macrophage activation syndrome are not helpful. METHODS: Our study included a discovery cohort of patients from Turkey with symptomatic COVID-19 who were followed up while hospitalized during the initial wave and a replication cohort of hospitalized patients from a later period, all of whom required oxygen support and received glucocorticoids. Diagnosis of HI was made by an expert panel; most patients with COVID-19-associated HI (HIC) received tocilizumab or anakinra. Clinical and laboratory data from start day of treatment with tocilizumab or anakinra in HIC patients were compared with the data from day 5-6 in patients without HIC. Values maximizing the sensitivity and specificity of each parameter were calculated to determine criteria items. RESULTS: The discovery cohort included 685 patients, and the replication cohort included 156 patients, with 150 and 61 patients receiving treatment for HI, respectively. Mortality rate in HI patients in the discovery cohort (23.3%) was higher than the rate in patients without HI (3.7%) and the rate in patients in the overall replication cohort (10.3%). The 12-item criteria that we developed for HIC showed that a score of 35 provided 85.3% sensitivity and 81.7% specificity for identification of HIC. In the replication cohort, the same criteria resulted in 90.0% sensitivity for HIC; however, lower specificity values were observed because of the inclusion of milder cases of HIC responding only to glucocorticoids. CONCLUSION: The use of the 12-item criteria for HIC can better define patients with HIC with reasonable sensitivity and specificity and enables an earlier treatment start.

Hidden Danger of Sars-Cov-2, Multisystem Inflammatory Syndrome in Adults (Mis-a): First Case Series in a Single Center from Turkiye

Objective: Multisystem Inflammatory Syndrome (MIS) is a con-dition seen in the early post-COVID-19 period and thought to develop with an impaired immune response. It has been usually reported in children but rarely in adults. Here we report the first MIS-A case series from Turkiye.Material and Methods: Six patients who met the Centers for Disease Control and Preventions MIS-A diagnostic criteria were included in the study. The demographic, clinical, laboratory, ra-diological characteristics and therapy regimes and outcomes of the patients were recorded.Results: All of our cases had a history of mild COVID-19. They presented with fever, severe fatigue and hypotension. Abnormal echocardiography findings were detected in five patients. Only one patient had multiple mucocutaneous findings. Common lab-oratory features were lymphopenia, markedly increased C-Reak-tive Protein, procalcitonin, pro-brain natriuretic peptide (pro-BNP), D-dimer, and ferritin. All patients had positive SARS-CoV-2 antibody result. Corticosteroids and/or anakinra were used in five, Intravenous immunoglobulin was used in two patients. Low-mo-lecular-weight heparin (LMWH) was used for all cases. Empirically initiated antibiotic treatments were discontinued after cultures were negative. After anti-inflammatory treatment, the hypoten-sion of the patients resolved, they did not need intensive care follow-up and no mortality was seen in our cases.Conclusions: MIS-A is a severe and mortal condition that causes various clinical pictures and can be confused with sepsis. Anakin-ra, a recombinant IL-1 receptor antagonist, is a significant agent that can be used in the treatment of MIS-A since it blocks the cytokine cascade at an early stage. The satisfactory respons-es will be obtained with early diagnosis and anti-inflammatory treatment. In this period when the pandemic is not over yet, it is necessary to increase the awareness of clinicians about MIS-A, which can be fatal.

Immune modulation as a consequence of SARS-CoV-2 infection.

Erroneous immune responses in COVID-19 could have detrimental effects, which makes investigation of immune network underlying COVID-19 pathogenesis a requisite. This study aimed to investigate COVID-19 related alterations within the frame of innate and adaptive immunity. Thirty-four patients clinically diagnosed with mild, moderate and severe COVID-19 disease were enrolled in this study. Decreased ILC1 and increased ILC2 subsets were detected in mild and moderate patients compared to healthy controls. NK cell subsets and cytotoxic capacity of NK cells were decreased in severe patients. Moreover, CD3+ T cells were reduced in severe patients and a negative correlation was found between CD3+ T cells and D-dimer levels. Likewise, moderate and severe patients showed diminished CD3+CD8+ T cells. Unlike T and NK cells, plasmablast and plasma cells were elevated in patients and IgG and IgA levels were particularly increased in severe patients. Severe patients also showed elevated serum levels of pro-inflammatory cytokines such as TNF-α, IL-6 and IL-8, reduced intracellular IFN-γ and increased intracellular IL-10 levels. Our findings emphasize that SARS-CoV-2 infection significantly alters immune responses and innate and acquired immunity are differentially modulated in line with the clinical severity of the disease. Elevation of IL-10 levels in NK cells and reduction of CD3+ and CD8+ T cells in severe patients might be considered as a protective response against the harmful effect of cytokine storm seen in COVID-19.

Remdesivir treatment for patients with moderate to severe COVID-19.

BACKGROUND: Remdesivir, which was first developed for the treatment of Ebola disease but failed to meet expectations, has become hope in the fight against the COVID-19 pandemic. This study aimed to evaluate risk factors for mortality and prognosis of adult moderate/severe COVID-19 patients treated with remdesivir, and safety and tolerability of 5 days of remdesivir treatment. METHODS: This multicenter prospective observational study was conducted in 14 centers in Turkey. Pregnancy or breastfeeding, multiorgan failure, or usage of vasopressors for septic shock, ALT > 5 × the upper limit of the normal range, or eGRF <30 mL/min or dialysis and receiving favipiravir were the exclusion criteria of the study. RESULTS: Among 500 patients, 494 patients were included in the study. On admission, 392 (79.3%) patients had moderate and 102 (20.6%) patients had severe COVID-19. The 28-day mortality was 10.1%. The median of the scores of the seven-category ordinal scale assessed on days 0, 3, 5, 7 were 4 and 3 on day 14. When the survival status of the patients was evaluated according to the time between the remdesivir start date and the end date of the symptoms, no statistically significant difference was found between the medians of the groups (p = 0.404). In multivariable analysis, age (OR, 1.05; 95%CI, 1.02-1.08; p = 0.003), SpO2 level on admission (OR, 3.03; 95%CI, 1.35-6.81; p = 0.007), heart rate (OR, 2.48; 95%CI, 1.01-6.07; p = 0.047), follow-up site at the hospital (clinic/ICU) (OR, 26.4; 95%CI, 11.6-60.17; p < 0.001) were independently associated with increased mortality. Grade 3 adverse event (AE) was observed in 4 (0.8%) patients. None of the patients experienced grade 4 or 5 AEs. DISCUSSION: Remdesivir is a safe and well-tolerated drug and older age, low SpO2 level on admission, tachycardia, and ICU admission are independently associated with increased mortality among patients with moderate/severe COVID-19 receiving remdesivir treatment.

Antineutrophil Cytoplasmic Antibody-Associated Vasculitis and COVID-19: The Clinical Course and Prognosis of 15 Patients From a Tertiary Care Center.

OBJECTIVE: The aim of this study was to evaluate incidence rates, prognoses, and disease-related factors associated with poor outcomes in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) who had coronavirus disease (COVID-19). METHODS: Patients with AAV were questioned for a history of COVID-19 in the outpatient setting. Cumulative clinical findings and treatment history were obtained from the patients' medical records. The clinical, laboratory, and imaging findings of inpatients with COVID-19 were recorded. The data of patients who developed symptomatic COVID-19 and/or died of the disease were used for comparison. RESULTS: Eighty-nine patients (47.2% female; mean age, 56 ± 12.5 years) were included. The diagnosis was granulomatosis with polyangiitis in 56 patients (62.9%) and microscopic polyangiitis in 33 (37.1%). Sixty-one (68.2%) and 21 patients (23.6%) had renal and peripheral nerve involvement, respectively. Ten patients had a history of diffuse alveolar hemorrhage. Fifteen patients (16.9%) had COVID-19, including 9 (60%) with severe pneumonia. Twelve patients (85.7%) were hospitalized, 6 (42.9%) were admitted to the intensive care unit, and 5 (35.7%) died. All deceased patients had hypogammaglobulinemia (IgG levels <700 mg/dL) during hospital admission. Symptomatic COVID-19 was associated with higher disease activity, glucocorticoid and rituximab treatments, and glomerular filtration rate <30 mL/min. A history of peripheral nerve involvement, higher organ damage scores, and hypogammaglobulinemia was associated with mortality. CONCLUSIONS: The prognosis was poor in our patients with AAV who had COVID-19, especially those with severe multisystem involvement. Hypogammaglobulinemia was associated with mortality. Serum IgG level monitoring in patients with AAV would be beneficial during the COVID-19 pandemic.

Frequency and severity of COVID-19 in patients with various rheumatic diseases treated regularly with colchicine or hydroxychloroquine.

This study aimed to investigate whether patients regularly using colchicine or hydroxychloroquine (HCQ) have an advantage of protection from coronavirus disease 2019 (COVID-19) or developing less severe disease. Patients who were taking colchicine or HCQ regularly for a rheumatic disease including Familial Mediterranean Fever, Behçet's syndrome, Systemic Lupus Erythematosus, Rheumatoid Arthritis, and Sjogren's syndrome, as well as their healthy household contacts as the control group, were included in the study. The clinical data regarding COVID-19 were collected using a standard form, and serum samples were analyzed for anti-severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) nucleocapsid immunoglobulin G (IgG). A total of 635 regular colchicine users with their 643 household contacts and 317 regular HCQ users with their 333 household contacts were analyzed. Anti-SARS-COV-2 IgG was positive in 43 (6.8%) regular colchicine users and 35 (5.4%) household contacts (odds ratio [OR] = 1.3; 95% confidence interval [CI]:0.8-2; p = 0.3). COVID-19-related symptoms were described by 29 (67.4%) of the patients and 17 (48.6%) household contacts (OR = 2.2; 95% CI :0.9-5.5; p = 0.09), and hospital admission was observed in five (11.6%) and one (2.9%) of these subjects (OR = 4.5; 95% CI: 0.5-40.2; p = 0.1), respectively. Seropositive subjects were observed in 22 (6.9%) regular HCQ users and 24 (7.2%) household contacts (OR = 1.1; 95% CI: 0.6-1.9; p = 0.8). COVID-19-related symptoms occurred in 16 (72.7%) of the 22 patients and 12 (50%) of 24 household contacts (OR = 2.7; 95% CI: 0.8-9.1; p = 0.1). Three patients (13.6%) were admitted to hospital, while one household contact (4.2%) was hospitalized (OR = 3.6; 95% CI: 0.3-37.8; p = 0.2). Being on a regular treatment of colchicine or HCQ did not result in the prevention of COVID-19 or amelioration of its manifestations.

A single center survey study of systemic vasculitis and COVID-19 during the first months of pandemic

Introduction: COVID-19 pandemic created concerns among patients receiving immunosuppressive therapy. Frequency of COVID-19 and impact of lockdown on treatment compliance in patients with vasculitis are largely unknown. Patients and method: Patients with ANCA-associated and large vessel vasculitis that have been followed-up in our clinic were contacted by phone and a questionnaire containing home isolation status, treatment adherence and history of COVID -19 between March 1st and June 30th, 2020 was applied. Results: The survey was applied to 103 patients (F/M: 59/44, mean age: 53.2±12.5). Thirty-three (32%) patients didn?t attend at least one appointment; 98(95.1%) noted that they spent 3 months in home isolation. Five patients (4.8%) received immunosuppressives irregularly and 3(2.9%) developed symptoms due to undertreatment. Four (3.9%) patients admitted to hospital with a suspicion of COVID-19, but none of them had positive PCR or suggestive findings by imaging. COVID-19 diagnosed in a patient with granulomatosis with polyangiitis during hospitalization for disease flare and she died despite treatment. Discussion: Frequency of COVID-19 was low in patients with vasculitis in our single center cohort. Although outpatient appointments were postponed in one-third of our patients, high compliance with treatment and isolation rules ensured patients with vasculitis overcome this period with minimal morbidity and mortality.

Tocilizumab treatment in severe COVID-19: a multicenter retrospective study with matched controls.

Coronavirus disease-2019 (COVID-19) associated pneumonia may progress into acute respiratory distress syndrome (ARDS). Some patients develop features of macrophage activation syndrome (MAS). Elevated levels of IL-6 were reported to be associated with severe disease, and anti-IL-6R tocilizumab has been shown to be effective in some patients. This retrospective multicenter case-control study aimed to evaluate the efficacy of tocilizumab in hospitalized COVID-19 patients, who received standard of care with or without tocilizumab. Primary outcome was the progression to intubation or death. PSMATCH (SAS) procedure was used to achieve exact propensity score (PS) matching. Data from 1289 patients were collected, and study population was reduced to 1073 based on inclusion-exclusion criteria. The composite outcome was observed more frequently in tocilizumab-users, but there was a significant imbalance between arms in all critical parameters. Primary analyses were carried out in 348 patients (174 in each arm) after exact PS matching according to gender, ferritin, and procalcitonin. Logistic regression models revealed that tocilizumab significantly reduced the intubation or death (OR 0.40, p = 0.0017). When intubation is considered alone, tocilizumab-users had > 60% reduction in odds of intubation. Multiple imputation approach, which increased the size of the matched patients up to 506, provided no significant difference between arms despite a similar trend for intubation alone group. Analysis of this retrospective cohort showed more frequent intubation or death in tocilizumab-users, but PS-matched analyses revealed significant results for supporting tocilizumab use overall in a subset of patients matched according to gender, ferritin and procalcitonin levels.

The effect of tocilizumab, anakinra and prednisolone on antibody response to SARS-CoV-2 in patients with COVID-19: A prospective cohort study with multivariate analysis of factors affecting the antibody response.

OBJECTIVES: Disease severity, previous medications and immunosuppressive agents could affect the antibody response against SARS-CoV-2. This study aimed to analyze variables affecting the humoral response to SARS-CoV-2. METHODS: This prospective cohort study included adult patients who recovered from COVID-19 and were admitted to a COVID-19 follow-up unit. Eight patient groups were defined in accordance with the results of thoracic computed tomography (CT), SARS-CoV-2 PCR test, and tocilizumab or anakinra use during active disease. Anti-S IgG antibodies were determined by ELISA in serum samples. Anti-S positive and negative cases were compared. RESULTS: A total of 518 patients were included in the study. SARS-CoV-2 IgG antibodies were positive in 82.8% of patients. SARS-CoV-2 PCR positivity, extent of lung involvement on CT, and time to antibody testing were independently associated with antibody positivity. Tocilizumab, anakinra or prednisolone use was not a factor affecting the antibody response. The rate of antibody response and sample/CO values among antibody-positive patients showed a linear relationship with the extent of lung involvement on CT. CONCLUSIONS: The use of tocilizumab, anakinra and prednisolone for COVID-19 did not affect the antibody response against SARS-CoV-2. The main driver of antibody response among patients with COVID-19 was the extent of pulmonary involvement on CT.