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      Absent immune response to SARS-CoV-2 in a 3-month recurrence of coronavirus disease 2019 (COVID-19) case

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          Abstract

          Background

          The viral persistence in patients with Coronavirus Disease 2019 (COVID-19) remains to be investigated.

          Methods

          We investigated the viral loads, therapies, clinical features, and immune responses in a 70-year patient tested positive for SARS-CoV-2 for 3 months.

          Findings

          The patient exhibited the highest prevalence of abnormal indices of clinical features and immune responses at the first admission, including fever (38.3 ℃), decreased lymphocytes (0.83 × 10 9/L) and serum potassium (3.1 mmol/L), as well as elevated serum creatinine (115 µmol/L), urea (8.6 mmol/L), and C-reactive protein (80 mg/L). By contrast, at the second and the third admission, these indices were all normal. Through three admissions, IL-2 increased from 0.14 pg/mL, 0.69 pg/mL, to 0.91 pg/mL, while IL-6 decreased from 11.78 pg/mL, 1.52 pg/mL, to 0.69 pg/mL, so did IL-10 from 5.13 pg/mL, 1.85 pg/mL, to 1.75 pg/mL. The steady declining trend was also found in TNF-α (1.49, 1.15, and 0.85 pg/mL) and IFN-γ (0.64, 0.42, and 0.27 pg/mL). The threshold cycle values of RT-PCR were 26.1, 30.5, and 23.5 for ORFlab gene, and 26.2, 30.6, and 22.7 for N gene, showing the patient had higher viral loads at the first and the third admission than during the middle term of the disease. The patient also showed substantially improved acute exudative lesions on the chest CT scanning images.

          Conclusions

          The patient displayed declining immune responses in spite of the viral shedding for 3 months. We inferred the declining immune responses might result from the segregation of the virus from the immune system.

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          Most cited references16

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          SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients

          To the Editor: The 2019 novel coronavirus (SARS-CoV-2) epidemic, which was first reported in December 2019 in Wuhan, China, and has been declared a public health emergency of international concern by the World Health Organization, may progress to a pandemic associated with substantial morbidity and mortality. SARS-CoV-2 is genetically related to SARS-CoV, which caused a global epidemic with 8096 confirmed cases in more than 25 countries in 2002–2003. 1 The epidemic of SARS-CoV was successfully contained through public health interventions, including case detection and isolation. Transmission of SARS-CoV occurred mainly after days of illness 2 and was associated with modest viral loads in the respiratory tract early in the illness, with viral loads peaking approximately 10 days after symptom onset. 3 We monitored SARS-CoV-2 viral loads in upper respiratory specimens obtained from 18 patients (9 men and 9 women; median age, 59 years; range, 26 to 76) in Zhuhai, Guangdong, China, including 4 patients with secondary infections (1 of whom never had symptoms) within two family clusters (Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). The patient who never had symptoms was a close contact of a patient with a known case and was therefore monitored. A total of 72 nasal swabs (sampled from the mid-turbinate and nasopharynx) (Figure 1A) and 72 throat swabs (Figure 1B) were analyzed, with 1 to 9 sequential samples obtained from each patient. Polyester flock swabs were used for all the patients. From January 7 through January 26, 2020, a total of 14 patients who had recently returned from Wuhan and had fever (≥37.3°C) received a diagnosis of Covid-19 (the illness caused by SARS-CoV-2) by means of reverse-transcriptase–polymerase-chain-reaction assay with primers and probes targeting the N and Orf1b genes of SARS-CoV-2; the assay was developed by the Chinese Center for Disease Control and Prevention. Samples were tested at the Guangdong Provincial Center for Disease Control and Prevention. Thirteen of 14 patients with imported cases had evidence of pneumonia on computed tomography (CT). None of them had visited the Huanan Seafood Wholesale Market in Wuhan within 14 days before symptom onset. Patients E, I, and P required admission to intensive care units, whereas the others had mild-to-moderate illness. Secondary infections were detected in close contacts of Patients E, I, and P. Patient E worked in Wuhan and visited his wife (Patient L), mother (Patient D), and a friend (Patient Z) in Zhuhai on January 17. Symptoms developed in Patients L and D on January 20 and January 22, respectively, with viral RNA detected in their nasal and throat swabs soon after symptom onset. Patient Z reported no clinical symptoms, but his nasal swabs (cycle threshold [Ct] values, 22 to 28) and throat swabs (Ct values, 30 to 32) tested positive on days 7, 10, and 11 after contact. A CT scan of Patient Z that was obtained on February 6 was unremarkable. Patients I and P lived in Wuhan and visited their daughter (Patient H) in Zhuhai on January 11 when their symptoms first developed. Fever developed in Patient H on January 17, with viral RNA detected in nasal and throat swabs on day 1 after symptom onset. We analyzed the viral load in nasal and throat swabs obtained from the 17 symptomatic patients in relation to day of onset of any symptoms (Figure 1C). Higher viral loads (inversely related to Ct value) were detected soon after symptom onset, with higher viral loads detected in the nose than in the throat. Our analysis suggests that the viral nucleic acid shedding pattern of patients infected with SARS-CoV-2 resembles that of patients with influenza 4 and appears different from that seen in patients infected with SARS-CoV. 3 The viral load that was detected in the asymptomatic patient was similar to that in the symptomatic patients, which suggests the transmission potential of asymptomatic or minimally symptomatic patients. These findings are in concordance with reports that transmission may occur early in the course of infection 5 and suggest that case detection and isolation may require strategies different from those required for the control of SARS-CoV. How SARS-CoV-2 viral load correlates with culturable virus needs to be determined. Identification of patients with few or no symptoms and with modest levels of detectable viral RNA in the oropharynx for at least 5 days suggests that we need better data to determine transmission dynamics and inform our screening practices.
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            Temporal dynamics in viral shedding and transmissibility of COVID-19

            We report temporal patterns of viral shedding in 94 patients with laboratory-confirmed COVID-19 and modeled COVID-19 infectiousness profiles from a separate sample of 77 infector-infectee transmission pairs. We observed the highest viral load in throat swabs at the time of symptom onset, and inferred that infectiousness peaked on or before symptom onset. We estimated that 44% (95% confidence interval, 25-69%) of secondary cases were infected during the index cases' presymptomatic stage, in settings with substantial household clustering, active case finding and quarantine outside the home. Disease control measures should be adjusted to account for probable substantial presymptomatic transmission.
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              Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study

              Summary Background Since December, 2019, an outbreak of coronavirus disease 2019 (COVID-19) has spread globally. Little is known about the epidemiological and clinical features of paediatric patients with COVID-19. Methods We retrospectively retrieved data for paediatric patients (aged 0–16 years) with confirmed COVID-19 from electronic medical records in three hospitals in Zhejiang, China. We recorded patients' epidemiological and clinical features. Findings From Jan 17 to March 1, 2020, 36 children (mean age 8·3 [SD 3·5] years) were identified to be infected with severe acute respiratory syndrome coronavirus 2. The route of transmission was by close contact with family members (32 [89%]) or a history of exposure to the epidemic area (12 [33%]); eight (22%) patients had both exposures. 19 (53%) patients had moderate clinical type with pneumonia; 17 (47%) had mild clinical type and either were asymptomatic (ten [28%]) or had acute upper respiratory symptoms (seven [19%]). Common symptoms on admission were fever (13 [36%]) and dry cough (seven [19%]). Of those with fever, four (11%) had a body temperature of 38·5°C or higher, and nine (25%) had a body temperature of 37·5–38·5°C. Typical abnormal laboratory findings were elevated creatine kinase MB (11 [31%]), decreased lymphocytes (11 [31%]), leucopenia (seven [19%]), and elevated procalcitonin (six [17%]). Besides radiographic presentations, variables that were associated significantly with severity of COVID-19 were decreased lymphocytes, elevated body temperature, and high levels of procalcitonin, D-dimer, and creatine kinase MB. All children received interferon alfa by aerosolisation twice a day, 14 (39%) received lopinavir–ritonavir syrup twice a day, and six (17%) needed oxygen inhalation. Mean time in hospital was 14 (SD 3) days. By Feb 28, 2020, all patients were cured. Interpretation Although all paediatric patients in our cohort had mild or moderate type of COVID-19, the large proportion of asymptomatic children indicates the difficulty in identifying paediatric patients who do not have clear epidemiological information, leading to a dangerous situation in community-acquired infections. Funding Ningbo Clinical Research Center for Children's Health and Diseases, Ningbo Reproductive Medicine Centre, and Key Scientific and Technological Innovation Projects of Wenzhou.
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                Author and article information

                Contributors
                qifasong@126.com
                Journal
                Infection
                Infection
                Infection
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0300-8126
                1439-0973
                28 July 2020
                : 1-5
                Affiliations
                [1 ]Department of Clinical Laboratory, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
                [2 ]Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China
                [3 ]Department of Blood Transfusion, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
                [4 ]Department of Acute Infectious Diseases. HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
                [5 ]Department of Experimental Medical Science, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
                [6 ]Department of Laboratory, Cixi Center for Disease Control and Prevention, Ningbo, China
                [7 ]Central Laboratory, Ningbo City First Hospital, Zhejiang Province, Ningbo, China
                Author information
                http://orcid.org/0000-0001-9753-2924
                Article
                1485
                10.1007/s15010-020-01485-6
                7386381
                32725596
                d7bb964a-a228-488a-8411-9364dc83d8e5
                © Springer-Verlag GmbH Germany, part of Springer Nature 2020

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 5 June 2020
                : 19 July 2020
                Categories
                Original Paper

                Infectious disease & Microbiology
                novel coronavirus (sars-cov-2),coronavirus disease 2019 (covid-19),immune response,recurrence,long-term viral shedding

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