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      SARS-CoV-2 (COVID-19), viral load and clinical outcomes; lessons learned one year into the pandemic: A systematic review

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          Abstract

          BACKGROUND

          Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is diagnosed via real time reverse transcriptase polymerase chain reaction (RT-PCR) and reported as a binary assessment of the test being positive or negative. High SARS-CoV-2 viral load is an independent predictor of disease severity and mortality. Quantitative RT-PCR may be useful in predicting the clinical course and prognosis of patients diagnosed with coronavirus disease 2019 (COVID-19).

          AIM

          To identify whether quantitative SARS-CoV-2 viral load assay correlates with clinical outcome in COVID-19 infections.

          METHODS

          A systematic literature search was undertaken for a period between December 30, 2019 to December 31, 2020 in PubMed/MEDLINE using combination of terms “COVID-19, SARS-CoV-2, Ct values, Log 10 copies, quantitative viral load, viral dynamics, kinetics, association with severity, sepsis, mortality and infectiousness’’. After screening 990 manuscripts, a total of 60 manuscripts which met the inclusion criteria were identified . Data on age, number of patients, sample sites, RT-PCR targets, disease severity, intensive care unit admission, mortality and conclusions of the studies was extracted, organized and is analyzed.

          RESULTS

          At present there is no Food and Drug Administration Emergency Use Authorization for quantitative viral load assay in the current pandemic. The intent of this research is to identify whether quantitative SARS-CoV-2 viral load assay correlates with severity of infection and mortality? High SARS-CoV-2 viral load was found to be an independent predictor of disease severity and mortality in majority of studies, and may be useful in COVID-19 infection in susceptible individuals such as elderly, patients with co-existing medical illness such as diabetes, heart diseases and immunosuppressed. High viral load is also associated with elevated levels of TNF-α, IFN-γ, IL-2, IL-4, IL-6, IL-10 and C reactive protein contributing to a hyper-inflammatory state and severe infection. However there is a wide heterogeneity in fluid samples and different phases of the disease and these data should be interpreted with caution and considered only as trends.

          CONCLUSION

          Our observations support the hypothesis of reporting quantitative RT-PCR in SARS-CoV-2 infection. It may serve as a guiding principle for therapy and infection control policies for current and future pandemics.

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          Most cited references78

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          Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

          Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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            Virological assessment of hospitalized patients with COVID-2019

            Coronavirus disease 2019 (COVID-19) is an acute infection of the respiratory tract that emerged in late 20191,2. Initial outbreaks in China involved 13.8% of cases with severe courses, and 6.1% of cases with critical courses3. This severe presentation may result from the virus using a virus receptor that is expressed predominantly in the lung2,4; the same receptor tropism is thought to have determined the pathogenicity-but also aided in the control-of severe acute respiratory syndrome (SARS) in 20035. However, there are reports of cases of COVID-19 in which the patient shows mild upper respiratory tract symptoms, which suggests the potential for pre- or oligosymptomatic transmission6-8. There is an urgent need for information on virus replication, immunity and infectivity in specific sites of the body. Here we report a detailed virological analysis of nine cases of COVID-19 that provides proof of active virus replication in tissues of the upper respiratory tract. Pharyngeal virus shedding was very high during the first week of symptoms, with a peak at 7.11 × 108 RNA copies per throat swab on day 4. Infectious virus was readily isolated from samples derived from the throat or lung, but not from stool samples-in spite of high concentrations of virus RNA. Blood and urine samples never yielded virus. Active replication in the throat was confirmed by the presence of viral replicative RNA intermediates in the throat samples. We consistently detected sequence-distinct virus populations in throat and lung samples from one patient, proving independent replication. The shedding of viral RNA from sputum outlasted the end of symptoms. Seroconversion occurred after 7 days in 50% of patients (and by day 14 in all patients), but was not followed by a rapid decline in viral load. COVID-19 can present as a mild illness of the upper respiratory tract. The confirmation of active virus replication in the upper respiratory tract has implications for the containment of COVID-19.
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              A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19

              Abstract Background No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. Methods 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 (Sao 2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao 2) to the fraction of inspired oxygen (Fio 2) 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. Results 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, 1.24; 95% confidence interval [CI], 0.90 to 1.72). 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. Conclusions 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.)
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                Author and article information

                Contributors
                Journal
                World J Crit Care Med
                WJCCM
                World Journal of Critical Care Medicine
                Baishideng Publishing Group Inc
                2220-3141
                9 July 2021
                9 July 2021
                : 10
                : 4
                : 132-150
                Affiliations
                Department of General and Colorectal Surgery, KCVA and University of Missouri at Kansas City, Missouri, MO 64128, United States. shenoy2009@ 123456hotmail.com
                Author notes

                Author contributions: Shenoy S designed the study, performed the literature search, wrote and analyzed the data, revised and approved the final manuscript.

                Corresponding author: Santosh Shenoy, MD, Professor, Department of General and Colorectal Surgery, KCVA and University of Missouri at Kansas City, 4801 E Linwood Blvd., Missouri, MO 64128, United States. shenoy2009@ 123456hotmail.com

                Article
                jWJCCM.v10.i4.pg132
                10.5492/wjccm.v10.i4.132
                8291003
                34316448
                6ad7fa9c-7fa1-4ae3-baa5-8a349c9c8d72
                ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.

                This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.

                History
                : 5 February 2021
                : 21 March 2021
                : 15 June 2021
                Categories
                Systematic Reviews

                covid-19,sars-cov-2,viral load,severe sepsis,dynamics,mortality
                covid-19, sars-cov-2, viral load, severe sepsis, dynamics, mortality

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