IMPORTANCE: Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that was first reported in Wuhan, China, and has subsequently spread worldwide. Risk factors for the clinical outcomes of COVID-19 pneumonia have not yet been well delineated.
OBJECTIVE: To describe the clinical characteristics and outcomes in patients with COVID-19 pneumonia who developed acute respiratory distress syndrome (ARDS) or died.
DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 201 patients with confirmed COVID-19 pneumonia admitted to Wuhan Jinyintan Hospital in China between December 25, 2019, and January 26, 2020. The final date of follow-up was February 13, 2020.
EXPOSURES: Confirmed COVID-19 pneumonia.
MAIN OUTCOMES AND MEASURES: The development of ARDS and death. Epidemiological, demographic, clinical, laboratory, management, treatment, and outcome data were also collected and analyzed.
RESULTS: Of 201 patients, the median age was 51 years (interquartile range, 43-60 years), and 128 (63.7%) patients were men. Eighty-four patients (41.8%) developed ARDS, and of those 84 patients, 44 (52.4%) died. In those who developed ARDS, compared with those who did not, more patients presented with dyspnea (50 of 84 [59.5%] patients and 30 of 117 [25.6%] patients, respectively [difference, 33.9%; 95% CI, 19.7%-48.1%]) and had comorbidities such as hypertension (23 of 84 [27.4%] patients and 16 of 117 [13.7%] patients, respectively [difference, 13.7%; 95% CI, 1.3%-26.1%]) and diabetes (16 of 84 [19.0%] patients and 6 of 117 [5.1%] patients, respectively [difference, 13.9%; 95% CI, 3.6%-24.2%]). In bivariate Cox regression analysis, risk factors associated with the development of ARDS and progression from ARDS to death included older age (hazard ratio [HR], 3.26; 95% CI 2.08-5.11; and HR, 6.17; 95% CI, 3.26-11.67, respectively), neutrophilia (HR, 1.14; 95% CI, 1.09-1.19; and HR, 1.08; 95% CI, 1.01-1.17, respectively), and organ and coagulation dysfunction (eg, higher lactate dehydrogenase [HR, 1.61; 95% CI, 1.44-1.79; and HR, 1.30; 95% CI, 1.11-1.52, respectively] and D-dimer [HR, 1.03; 95% CI, 1.01-1.04; and HR, 1.02; 95% CI, 1.01-1.04, respectively]). High fever (≥39 °C) was associated with higher likelihood of ARDS development (HR, 1.77; 95% CI, 1.11-2.84) and lower likelihood of death (HR, 0.41; 95% CI, 0.21-0.82). Among patients with ARDS, treatment with methylprednisolone decreased the risk of death (HR, 0.38; 95% CI, 0.20-0.72).
CONCLUSIONS AND RELEVANCE: Older age was associated with greater risk of development of ARDS and death likely owing to less rigorous immune response. Although high fever was associated with the development of ARDS, it was also associated with better outcomes among patients with ARDS. Moreover, treatment with methylprednisolone may be beneficial for patients who develop ARDS.
BACKGROUND: The Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) outbreak originating in Wuhan, China, has raised global health concerns and the pandemic has now been reported on all inhabited continents. Hitherto, no antiviral drug is available to combat this viral outbreak.
METHODS: Keeping in mind the urgency of the situation, the current study was designed to devise new strategies for drug discovery and/or repositioning against SARS-CoV-2. In the current study, RNA-dependent RNA polymerase (RdRp), which regulates viral replication, is proposed as a potential therapeutic target to inhibit viral infection.
RESULTS: Evolutionary studies of whole-genome sequences of SARS-CoV-2 represent high similarity (> 90%) with other SARS viruses. Targeting the RdRp active sites, ASP760 and ASP761, by antiviral drugs could be a potential therapeutic option for inhibition of coronavirus RdRp, and thus viral replication. Target-based virtual screening and molecular docking results show that the antiviral Galidesivir and its structurally similar compounds have shown promise against SARS-CoV-2.
CONCLUSIONS: The anti-polymerase drugs predicted here-CID123624208 and CID11687749-may be considered for in vitro and in vivo clinical trials.
<b>BACKGROUND: </b>No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2.<b>METHODS: </b>We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first.<b>RESULTS: </b>A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.31; 95% confidence interval [CI], 0.95 to 1.80). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events.<b>CONCLUSIONS: </b>In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.).
AimsStudies have indicated that chloroquine (CQ) shows antagonism against COVID-19 in vitro. However, evidence regarding its effects in patients is limited. This study aims to evaluate the efficacy of hydroxychloroquine (HCQ) in the treatment of patients with COVID-19.
Main methodsFrom February 4 to February 28, 2020, 62 patients suffering from COVID-19 were diagnosed and admitted to Renmin Hospital of Wuhan University. All participants were randomized in a parallel-group trial, 31 patients were assigned to receive an additional 5-day HCQ (400 mg/d) treatment, Time to clinical recovery (TTCR), clinical characteristics, and radiological results were assessed at baseline and 5 days after treatment to evaluate the effect of HCQ.
Key findingsFor the 62 COVID-19 patients, 46.8% (29 of 62) were male and 53.2% (33 of 62) were female, the mean age was 44.7 (15.3) years. No difference in the age and sex distribution between the control group and the HCQ group. But for TTCR, the body temperature recovery time and the cough remission time were significantly shortened in the HCQ treatment group. Besides, a larger proportion of patients with improved pneumonia in the HCQ treatment group (80.6%, 25 of 31) compared with the control group (54.8%, 17 of 31). Notably, all 4 patients progressed to severe illness that occurred in the control group. However, there were 2 patients with mild adverse reactions in the HCQ treatment group. Significance: Among patients with COVID-19, the use of HCQ could significantly shorten TTCR and promote the absorption of pneumonia.
SignificanceAmong patients with COVID-19, the use of HCQ could significantly shorten TTCR and promote the absorption of pneumonia.
Trial registrationURL: https://www.clinicaltrials.gov/. The unique identifier: ChiCTR2000029559.
Currently, there are no approved specific antiviral agents for novel coronavirus disease 2019 (COVID-19). In this study, 10 severe patients confirmed by real-time viral RNA test were enrolled prospectively. One dose of 200 mL of convalescent plasma (CP) derived from recently recovered donors with the neutralizing antibody titers above 1:640 was transfused to the patients as an addition to maximal supportive care and antiviral agents. The primary endpoint was the safety of CP transfusion. The second endpoints were the improvement of clinical symptoms and laboratory parameters within 3 d after CP transfusion. The median time from onset of illness to CP transfusion was 16.5 d. After CP transfusion, the level of neutralizing antibody increased rapidly up to 1:640 in five cases, while that of the other four cases maintained at a high level (1:640). The clinical symptoms were significantly improved along with increase of oxyhemoglobin saturation within 3 d. Several parameters tended to improve as compared to pretransfusion, including increased lymphocyte counts (0.65 × 109/L vs. 0.76 × 109/L) and decreased C-reactive protein (55.98 mg/L vs. 18.13 mg/L). Radiological examinations showed varying degrees of absorption of lung lesions within 7 d. The viral load was undetectable after transfusion in seven patients who had previous viremia. No severe adverse effects were observed. This study showed CP therapy was well tolerated and could potentially improve the clinical outcomes through neutralizing viremia in severe COVID-19 cases. The optimal dose and time point, as well as the clinical benefit of CP therapy, needs further investigation in larger well-controlled trials.
The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into an emergent global pandemic. Coronavirus disease 2019 (COVID-19) can manifest on a spectrum of illness from mild disease to severe respiratory failure requiring intensive care unit (ICU) admission. As the incidence continues to rise at a rapid pace, critical care teams are faced with challenging treatment decisions. There is currently no widely accepted standard of care in the pharmacological management of patients with COVID-19. Urgent identification of potential treatment strategies is a priority. Therapies include novel agents available in clinical trials or through compassionate use, and other drugs, repurposed antiviral and immune modulating therapies. Many have demonstrated in vitro or in vivo potential against other viruses that are similar to SARS-CoV-2. Critically ill patients with COVID-19 have additional considerations related to adjustments for organ impairment and renal replacement therapies, complex lists of concurrent medications, limitations with drug administration and compatibility, and unique toxicities that should be evaluated when utilizing these therapies. The purpose of this review is to summarize practical considerations for pharmacotherapy in patients with COVID-19, with the intent of serving as a resource for health care providers at the forefront of clinical care during this pandemic.
BackgroundSevere patients with 2019 novel coronavirus (2019-nCoV) pneumonia progressed rapidly to acute respiratory failure. We aimed to evaluate the definite efficacy and safety of corticosteroid in the treatment of severe COVID-19 pneumonia.
MethodsForty-six hospitalized patients with severe COVID-19 pneumonia hospitalized at Wuhan Union Hospital from January 20 to February 25, 2020, were retrospectively reviewed. The patients were divided into two groups based on whether they received corticosteroid treatment. The clinical symptoms and chest computed tomography(CT) results were compared.
ResultsA total of 26 patients received intravenous administration of methylprednisolone with a dosage of 1-2mg/kg/d for 5-7 days, while the remaining patients not. There was no significant difference in age, sex, comorbidities, clinical or laboratory parameters between the two groups on admission. The average number of days for body temperature back to the normal range was significantly shorter in patients with administration of methylprednisolone when compared to those without administration of methylprednisolone (2.06{+/-}0.28 vs. 5.29{+/-}0.70, P=0.010). The patients with administration of methylprednisolone had a faster improvement of SpO2, while patients without administration of methylprednisolone had a significantly longer interval of using supplemental oxygen therapy (8.2days[IQR 7.0-10.3] vs. 13.5days(IQR 10.3-16); P<0.001). In terms of chest CT, the absorption degree of the focus was significantly better in patients with administration of methylprednisolone.
ConclusionOur data indicate that in patients with severe COVID-19 pneumonia, early, low-dose and short-term application of corticosteroid was associated with a faster improvement of clinical symptoms and absorption of lung focus.
BACKGROUND: Dexamethasone, a synthetic glucocorticoid, has anti-inflammatory and immunosuppressive properties. There is a hyperinflammatory response involved in the clinical course of patients with pneumonia due to SARS-CoV-2. To date, there has been no definite therapy for COVID-19. We reviewed the charts of SARS-CoV-2 patients with pneumonia and moderate to severely elevated CRP and worsening hypoxemia who were treated with early, short-term dexamethasone.
METHODS: We describe a series of 21 patients who tested positive for SARS-CoV-2 and were admitted to The Miriam Hospital in Providence, RI, and were treated with a short course of dexamethasone, either alone or in addition to current investigative therapies.
RESULTS: CRP levels decreased significantly following the start of dexamethasone from mean initial levels of 129.52 to 40.73 mg/L at time of discharge. 71% percent of the patients were discharged home with a mean length of stay of 7.8 days. None of the patients had escalation of care, leading to mechanical ventilation. Two patients were transferred to inpatient hospice facilities on account of persistent hypoxemia, in line with their documented goals of care.
CONCLUSIONS: A short course of systemic corticosteroids among inpatients with SARS-CoV-2 with hypoxic respiratory failure was well tolerated, and most patients had improved outcomes. This limited case series may not offer concrete evidence towards the benefit of corticosteroids in COVID-19. However, patients' positive response to short-term corticosteroids demonstrates that they may help blunt the severity of inflammation and prevent a severe hyperinflammatory phase, in turn reducing the length of stay, ICU admissions, and healthcare costs.
Confronting the challenge of the outbreak of COVID-19 should sharpen our focus on global drug access as a key issue in anti-viral therapy testing. The testing and adoption of effective therapies for novel coronaviruses is hampered by the challenge of conducting controlled studies during a state of emergency. The access to direct anti-viral drugs such as ribavirin that have an existing inventory and reliable supply chain may be a priority consideration for therapies developed for the 2019-nCoV infection outbreaks and any strain variants that may emerge. Based on the direct anti-viral activity of ribavirin against 2019-nCoV in vitro and evidence for potency enhancement strategies developed during the prior SARS and MERS outbreaks, ribavirin may significantly impact our ability to end the lingering outbreaks in China and slow outbreaks in other countries. The apparent COVID-19 pandemic provides an opportunity to follow dosage guidelines for treatment with ribavirin, test new therapeutic concepts, and conduct controlled testing to apply the scientific rigor required to address the controversy around this mainstay of anti-viral therapy. This article is protected by copyright. All rights reserved.
BACKGROUND: The effects of convalescent plasma (CP) infusion, one of the treatment options for severe Middle East respiratory syndrome coronavirus (MERS-CoV) infections, have not yet been evaluated.
METHODS: Serological responses of CP-infused MERS patients during the 2015 Korean MERS outbreak at a tertiary care centre were evaluated. Serological activity was evaluated with anti-MERS-CoV enzyme-linked immunosorbent assay (ELISA) immunoglobulin (Ig)G, ELISA IgA, immunofluorescence assay IgM and plaque reduction neutralization test (PRNT). Donor plasma and one or two recipient's serum samples per week of illness including one taken the day after each CP infusion were evaluated. For sensitivity and specificity analysis of ELISA IgG in predicting neutralization activity, a data set of 138 previously evaluated MERS-CoV-infected patients was used.
RESULTS: Three of thirteen MERS patients with respiratory failure received four CP infusions from convalesced MERS-CoV-infected patients, and only two of them showed neutralizing activity. Donor plasma with a PRNT titre 1:80 demonstrated meaningful serological response after CP infusion, while that with a PRNT titre 1:40 did not. ELISA IgG predicted neutralization activity of a PRNT titre ≥1:80 with more than 95% specificity at a cutoff optical density (OD) ratio of 1.6, and with 100% specificity at an OD ratio of 1.9.
CONCLUSIONS: For effective CP infusion in MERS, donor plasma with a neutralization activity of a PRNT titre ≥1:80 should be used. ELISA IgG could substitute for the neutralization test in resource-limited situations.
Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that was first reported in Wuhan, China, and has subsequently spread worldwide. Risk factors for the clinical outcomes of COVID-19 pneumonia have not yet been well delineated.
OBJECTIVE:
To describe the clinical characteristics and outcomes in patients with COVID-19 pneumonia who developed acute respiratory distress syndrome (ARDS) or died.
DESIGN, SETTING, AND PARTICIPANTS:
Retrospective cohort study of 201 patients with confirmed COVID-19 pneumonia admitted to Wuhan Jinyintan Hospital in China between December 25, 2019, and January 26, 2020. The final date of follow-up was February 13, 2020.
EXPOSURES:
Confirmed COVID-19 pneumonia.
MAIN OUTCOMES AND MEASURES:
The development of ARDS and death. Epidemiological, demographic, clinical, laboratory, management, treatment, and outcome data were also collected and analyzed.
RESULTS:
Of 201 patients, the median age was 51 years (interquartile range, 43-60 years), and 128 (63.7%) patients were men. Eighty-four patients (41.8%) developed ARDS, and of those 84 patients, 44 (52.4%) died. In those who developed ARDS, compared with those who did not, more patients presented with dyspnea (50 of 84 [59.5%] patients and 30 of 117 [25.6%] patients, respectively [difference, 33.9%; 95% CI, 19.7%-48.1%]) and had comorbidities such as hypertension (23 of 84 [27.4%] patients and 16 of 117 [13.7%] patients, respectively [difference, 13.7%; 95% CI, 1.3%-26.1%]) and diabetes (16 of 84 [19.0%] patients and 6 of 117 [5.1%] patients, respectively [difference, 13.9%; 95% CI, 3.6%-24.2%]). In bivariate Cox regression analysis, risk factors associated with the development of ARDS and progression from ARDS to death included older age (hazard ratio [HR], 3.26; 95% CI 2.08-5.11; and HR, 6.17; 95% CI, 3.26-11.67, respectively), neutrophilia (HR, 1.14; 95% CI, 1.09-1.19; and HR, 1.08; 95% CI, 1.01-1.17, respectively), and organ and coagulation dysfunction (eg, higher lactate dehydrogenase [HR, 1.61; 95% CI, 1.44-1.79; and HR, 1.30; 95% CI, 1.11-1.52, respectively] and D-dimer [HR, 1.03; 95% CI, 1.01-1.04; and HR, 1.02; 95% CI, 1.01-1.04, respectively]). High fever (≥39 °C) was associated with higher likelihood of ARDS development (HR, 1.77; 95% CI, 1.11-2.84) and lower likelihood of death (HR, 0.41; 95% CI, 0.21-0.82). Among patients with ARDS, treatment with methylprednisolone decreased the risk of death (HR, 0.38; 95% CI, 0.20-0.72).
CONCLUSIONS AND RELEVANCE:
Older age was associated with greater risk of development of ARDS and death likely owing to less rigorous immune response. Although high fever was associated with the development of ARDS, it was also associated with better outcomes among patients with ARDS. Moreover, treatment with methylprednisolone may be beneficial for patients who develop ARDS.
