general virus information · web view2020/03/11 · covid-19 is transmitted via droplets and...

Novel Coronavirus (COVID-19) Literature Collection*

*Unofficial, please see links to original articles for details; do not use as specific guidance

Prior Version: 3/7/2020

Current update: 3/11/2020

Last edit by: AY

Edits made between Current Update and Prior Version date noted in green text

Edits made in past 24-48 hours are noted in blue text

ContentsGeneral Virus Information2Clinical3Clinical Characteristics3Clinical Therapeutic11Brief Overview11Therapeutic Research14Imaging17Basic Science19Virology19Viral Shedding19Public Health / Epidemiology28Modeling28Epidemiology30Transmission/Infection Control44Perspective/ Commentary46Psychological49Epidemiologic Estimates50External References56Clinical56Case Tracking56Models56HAI56

General Virus Information

Disease is called COVID-19 (Coronavirus Disease 2019)

Virus is called SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2)

Viral Basics

· Corona because looks like a crown w/ spikes: Spikes are called 'spike proteins' (S)

· Positive sense ssRNA, large >30kb genomes

· Enveloped

· 120nm in diameter

· 4 regular common cold coronas: NL63, 229E, HKU1, OC43

· Alpha and beta coronaviruses

· Cause 30% of common colds

· Zoonotic coronaviruses (all are betacoronaviruses)

· SARS-CoV-1 (2002-2004)

· MERS-CoV

· SARS-CoV-2 (Severe acute resp syndrome coronavirus 2)

· Infection in humans cause typical, neutralizing antibody response (IgM first then IgG)

· qPCR: can find in BAL/lung, find in nasal washes > oral swabs (it likes deeper sites)

· Uses human ACE2 as receptors - similar to SARS-CoV-1 and NL63 corona virus (Nature Microbio: Letko (February 24, 2020))

· Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound aminopeptidase that has a vital role in the cardiovascular and immune systems. ACE2 is involved in heart function and the development of hypertension and diabetes mellitus. In addition, ACE2 has been identified as a functional receptor for coronaviruses, including SARS-CoV and SARS-CoV-2.

· SARS-CoV-2 infection is triggered by binding of the spike protein of the virus to ACE2, which is highly expressed in the heart and lungs.

· SARS-CoV-2 mainly invades alveolar epithelial cells, resulting in respiratory symptoms. These symptoms are more severe in patients with CVD, which might be associated with increased secretion of ACE2 in these patients compared with healthy individuals. ACE2 levels can be increased by the use of renin–angiotensin–aldosterone system inhibitors.

· (Zheng, Nature 2020) (https://www.nature.com/articles/s41569-020-0360-5)

ClinicalClinical Characteristics

1. COVID-19 and the cardiovascular system

Zheng, Y et al., Nature

March 5th 2020

https://www.nature.com/articles/s41569-020-0360-5

· Among confirmed cases of SARS-CoV-2 infection reported by the National Health Commission of China (NHC), some of the patients first went to see a doctor because of cardiovascular symptoms.

· Presented with heart palpitations and chest tightness rather than with respiratory symptoms, such as fever and cough, but were later diagnosed with COVID-19.

· Among the people who died from COVID-19 reported by the NHC, 11.8% of patients without underlying CVD had substantial heart damage, with elevated levels of cTnI or cardiac arrest during hospitalization. Therefore, in patients with COVID-19, the incidence of cardiovascular symptoms is high, owing to the systemic inflammatory response and immune system disorders during disease progression.

· The mechanism of acute myocardial injury caused by SARS-CoV-2 infection might be related to ACE2. ACE2 is widely expressed not only in the lungs but also in the cardiovascular system and, therefore, ACE2-related signalling pathways might also have a role in heart injury. Other proposed mechanisms of myocardial injury include a cytokine storm triggered by an imbalanced response by type 1 and type 2 T helper cells, and respiratory dysfunction and hypoxaemia caused by COVID-19, resulting in damage to myocardial cells.

· In patients with SARS-CoV-2 infection, underlying CVD can aggravate the pneumonia and increase the severity of symptoms.

· Drug-related heart damage during COVID-19 treatment is a concern. In particular, the use of antiviral drugs should be monitored. In a study of 138 patients with COVID-19, 89.9% were given antiviral drugs. However, many antiviral drugs can cause cardiac insufficiency, arrhythmia or other cardiovascular disorders. Therefore, during treatment of COVID-19, especially with the use of antivirals, the risk of cardiac toxicity must be closely monitored

2. Hypokalemia and Clinical Implications in Patients with Coronavirus Disease 2019

Chen, Dong Jr (PRE-PRINT: medRxiv / UNPUBLISHED)

February 29th 2020

https://www.medrxiv.org/content/10.1101/2020.02.27.20028530v1

· SARS-CoV-2 binds angiotensin I converting enzyme 2 (ACE2) of renin

angiotensin system (RAS) and causes prevalent hypokalemia

· 175 patients with COVID-19 (92 women and 83 men; median age, 46 [IQR, 34-54] years) were admitted to hospital in Wenzhou, China:

· 39 severe hypokalemia-

· 69 hypokalemia

· 67 normokalemia patients

· Gastrointestinal symptoms were not associated with hypokalemia among 108 hypokalemia patients (P>0.05).

· Body temperature, CK, CK-MB, LDH, and CRP were significantly associated with the severity of hypokalemia (P<0.01).

· 93% of severe and critically ill patients had hypokalemia which was most common among elevated CK, CK-MB, LDH, and CRP.

· CK: 14% total had elevated CK; 28% In critically ill and 10% among mod/mild illness

· CK-MB: 22% had elevated CK-MB; 60% in critically ill and 11% in mod/mild illness

· Urine K+ loss was the primary cause of hypokalemia

· The current study illustrated the high prevalence of hypokalemia in the patients with COVID-19 and the positive association between the degree of hypokalemia and the severity of COVID-19. The study also proved that hypokalemia was more attributable to renal loss of K+ than gastrointestinal loss

3. Clinical Characteristics of Coronavirus Disease 2019 in ChinaW. Guan and others, NEJM

February 28 2020

https://www.nejm.org/doi/full/10.1056/NEJMoa2002032

· 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death.

· The median age of the patients was 47 years; 41.9% of the patients were female.

· The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died.

· Only 1.9% of the patients had a history of direct contact with wildlife.

· The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%).

· The median incubation period was 4 days (interquartile range, 2 to 7).

· On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease.

· Lymphocytopenia was present in 83.2% of the patients on admission.

· Most of the patients had elevated levels of C-reactive protein; less common were elevated levels of alanine aminotransferase, aspartate aminotransferase, creatine kinase, and d-dimer. Patients with severe disease had more prominent laboratory abnormalities (including lymphocytopenia and leukopenia) than those with nonsevere disease.

· The median duration of hospitalization was 12.0 days (mean, 12.8).

· During hospital admission, most of the patients received a diagnosis of pneumonia from a physician (91.1%), followed by ARDS (3.4%) and shock (1.1%)

4. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Xiaobo Yang and others, Lancet

February 24th 2020

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30079-5/fulltext

· Of 710 patients with SARS-CoV-2 pneumonia, 52 critically ill adult patients were included.

· The mean age of the 52 patients was 59·7 (SD 13·3) years, 35 (67%) were men,, 51 (98%) had fever.

· 21 (40%) patients had chronic diseases, including cerebrovascular diseases in seven (13·5%) patients, all of whom died at 28 days.

· 32 (61·5%) patients had died at 28 days, and the median duration from admission to the intensive care unit (ICU) to death was 7 (IQR 3–11) days for non-survivors.

· Compared with survivors, non-survivors were older (64·6 years [11·2] vs 51·9 years [12·9]), more likely to develop ARDS (26 [81%] patients vs 9 [45%] patients), and more likely to receive mechanical ventilation (30 [94%] patients vs 7 [35%] patients), either invasively or non-invasively.

· Most patients had organ function damage, including 35 (67%) with ARDS, 15 (29%) with acute kidney injury, 12 (23%) with cardiac injury, 15 (29%) with liver dysfunction, and one (2%) with pneumothorax.

· 37 (71%) patients required mechanical ventilation.

· Hospital-acquired infection occurred in seven (13·5%) patients.

· The survival time of the non-survivors is likely to be within 1–2 weeks after ICU admission.

· Older patients (>65 years) with comorbidities and ARDS are at increased risk of death.

· The severity of SARS-CoV-2 pneumonia poses great strain on critical care resources in hospitals, especially if they are not adequately staffed or resourced.

5. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China

Wang, D et. al, JAMA

February 7th 2020

https://jamanetwork.com/journals/jama/fullarticle/2761044

· 138 consecutive hospitalized patients from Wuhan, Jan-28th 2020

· Median age was 56 years (interquartile range, 42-68; range, 22-92 years) and 75 (54.3%) were men.

· Hospital-associated transmission was suspected as the presumed mechanism of infection for affected health professionals (40 [29%]) and hospitalized patients (17 [12.3%]).

· Common symptoms:

· Fever (136 [98.6%]), Fatigue (96 [69.6%]), and dry cough (82 [59.4%]).

· Lymphopenia (lymphocyte count, 0.8 × 109/L [interquartile range {IQR}, 0.6-1.1]) occurred in 97 patients (70.3%), prolonged prothrombin time (13.0 seconds [IQR, 12.3-13.7]) in 80 patients (58%), and elevated lactate dehydrogenase (261 U/L [IQR, 182-403]) in 55 patients (39.9%).

· Chest computed tomographic scans showed bilateral patchy shadows or ground glass opacity in the lungs of all patients.

· Thirty-six patients (26.1%) were transferred to the intensive care unit (ICU) because of complications:

· acute respiratory distress syndrome (22 [61.1%])

· arrhythmia (16 [44.4%])

· shock (11 [30.6%]). T

· The median time from first symptom to dyspnea was 5.0 days, to hospital admission was 7.0 days, and to ARDS was 8.0 days.

· Patients treated in the ICU (n = 36), compared with patients not treated in the ICU (n = 102),

were older (median age, 66 years vs 51 years), were more likely to have underlying comorbidities (26 [72.2%] vs 38 [37.3%]), and were more likely to have dyspnea (23 [63.9%]

vs 20 [19.6%]), and anorexia (24 [66.7%] vs 31 [30.4%]).

· As of February 3, 47 patients (34.1%) were discharged and 6 died (overall mortality, 4.3%), but the remaining patients are still hospitalized. Among those discharged alive (n = 47), the median hospital stay was 10 days (IQR, 7.0-14.0).

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

Huang, Chaolin et.al, Lancet

January 24th 2020

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30183-5/fulltext

· 41 hospitalized patients with lab confirmed (rT-PCR) 2019-nCoV

· 73% Male, 32% with uynderlying diseases (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.

Clinical TherapeuticBrief Overview

1. Remdesivir

· Gilead investigational nucleotide (Remdesivir is an adenosine analogue, which incorporates into nascent viral RNA chains and results in pre-mature termination)

· Remdesivir thought to function at a stage post virus entry (Wang, Cell Research 2020)Non-FDA approved, available through compassionate use

· Contact Gilead directly to request using portal: https://rdvcu.gilead.com/

· Passed Phase I clinical safety trials during testing for Ebola (https://www.who.int/ebola/drc-2018/summaries-of-evidence-experimental-therapeutics.pdf?ua=1) though not found to be effective against Ebola

· Showed efficacy against MERS-CoV in monkeys (Emmie de Witt, PNAS 2020) and in mouse-models against SARS

· “One patient in the remdesivir group had hypotension that resulted in cessation of a loading dose of remdesivir and that was followed rapidly by cardiac arrest. However, even in these cases, the deaths could not readily be distinguished from underlying fulminant EVD itself.” (https://www-nejm-org/doi/full/10.1056/NEJMoa1910993

· Ongoing randomize controlled trials for COVID-19 (NCT04252664 and NCT04257656)

2. Chloroquine/Hydroxychloroquine (Plaquenil)

· Widely-used anti-malarial and autoimmune disease drug

· Antiviral activity may be due to increase in endosomal pH and interference with glycosylation of cellular receptors of SARS-CoV – interferes with glycosylation of cellular receptors of SARS-CoV (Gao Biosc Trends 2020)

· Synthetic form of quinine, a compound found in the bark of cinchona trees native to Peru and used for centuries as antimalarial. Chloroquine was an essential element of mass drug administration campaigns to combat malaria throughout the second half of the 20th century, and remains on list WHO essential medicines. After Plasmodium falciparum and vivax began exhibiting resistance to the drug in the 1960s and 1980s, respectively, Chloroquine replaced by similar antimalarial compounds and combination therapies. Chloroquine is still widely used against the three other species of plasmodium and to treat autoimmune disorders and some cases of amebiasis.

· Cheap, safe, used for more than 70 years

· Postulated mechanism: Chloroquine increases endosomal pH needed for virus/cell fusion, and interferes with glycosylation of cell receptors of SARS-CoV. Also has immune modulating activity which may enhance antiviral effect.

· Chloroquine functioned at both entry, and at post-entry stages of the 2019-nCoV infection in Vero E6 cells

· Widely distributed in whole body, including lungs, after given PO (Wang, Cell research letter Jan 2020)

· Initial reports from more than 100 patients showed superiority of chloroquine to control treatment in inhibiting exacerbation of pneumonia, promoting negative conversion, and shortening the disease—per news briefing in China. (Gao Biosc Trends 2020)

· A multicenter collaborative Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus pneumonia recommended chloroquine phosphate for mild, moderate, and severe cases of novel coronavirus pneumonia and without contraindications to chloroquine. (Zhonghua J Tuberc Respir Dis 2020, doi:10.3760/cma.j.issn.1001-0939.2020.0019)

3. Lopinavir/Ritonavir (Kaletra)

· A protease inhibitor combination used to treat HIV

1. Interest came from:

a. Apparent efficacy in small retrospective studies from SARs:

· Decreased risk (2.8% vs 28.5% for historical controls) of progression to severe respiratory illness in a small retrospective study for SARS in 2003

· (Wang, M. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research, 2/4/2020 https://www.nature.com/articles/s41422-020-0282-0)

· Anecdotal benefit against COVID in Thailand (https://www-hkmj-org.laneproxy.stanford.edu/abstracts/v9n6/399.htm)

· Seems unlikely to be effective based on known pharmacodynamics of the drug, pharmacokinetic limitations, specific design of the drug as a protease inhibitor against HIV

· “The in vitro susceptibility of COVID-19 in vitro is > 100 fold less than is wild type HIV-1 to lopinavir. PI drug resistant mutants of HIV-1 that are even more susceptible than is COVID-19 show no response to lopinavir treatment.”

· Kempf, Antiviral Therapy, 2002

· Mixed results about Lopinavir-Ritonavir from small sample size clinical cases:

· Five individuals requiring supplemental oxygen were treated with lopinavir-ritonavir. For 3 of the 5 patients, fever resolved and supplemental oxygen requirement was reduced within 3 days, whereas 2 deteriorated with progressive respiratory failure. Four of the 5 patients treated with lopinavir-ritonavir developed nausea, vomiting, and/or diarrhea, and 3 developed abnormal liver function test results.

· Of note this study used a lower dose (200/100 mg twice daily) of lopinavir/ritonavir. (Young, JAMA 2020 doi:10.1001/jama.2020.3204)

· “A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version),” Mil Med Res. 2020;7(1):4, provided a weak recommendation for use of lopinavir/ritonavir based on benefits found in patients with SARS or MERS, especially with earlier administration. (doi:10.1186/s40779-020-0233-6)

4. Adjunctive Corticosteroid Therapy

· No clinical data exist to indicate that net benefit is derived from corticosteroids in the treatment of respiratory infection due to RSV, influenza, SARS-CoV, or MERS-CoV. (Russell, Clark et al, Lancet 2020)

· The available observational data suggest increased mortality and secondary infection rates in influenza, impaired clearance of SARS-CoV and MERS-CoV, and complications of corticosteroid therapy in survivors. (Russell, Clark et al, Lancet 2020)

· Adjunctive corticosteroids have not shown clinical benefit and delayed viral RNA clearance in other coronavirus disease (SARS and MERS) and may increase risk of side effects (psychosis, diabetes, avascular necrosis) and increased mortality in influenza. (Russell, Clark et al, Lancet 2020)

5. Other agents

· Li G, Clercq ED. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov. 2020;19(3):149-150. doi:10.1038/d41573-020-00016-0

· ACEI/ARBs:

· Letter to Editor in BMJ casts doubt:

· “there is no indication, and no pharmacological base, to prescribe or suggest ARBs or ACE inhibitors for COVID-2019 infection… ARBs act on Angiotensin 2 receptors (AT2), which are not the same as ACE receptors. Akamatsu suggests then the possible use of ACE-inhibitors as potentially effective drugs to prevent COVID-2019 infection, although this class of drugs may worsen respiratory symptoms like cough.…This practice, besides being useless to prevent COVID-2019 infection, may be harmful, leading to inappropriate drug treatments and risk of adverse events, or may instill dangerous over-confidence against the infection risk.”

· https://www.bmj.com/content/368/bmj.m406/rr-11

· Others seem to think it is a reasonable therapeutic angle to explore:

· “A tentative suggestion based on existing therapeutics, which would likely be resistant to new coronavirus mutations, is to use available angiotensin receptor 1 (AT1R) blockers, such as losartan, as therapeutics for reducing the aggressiveness and mortality from SARS-CoV-2 virus infections. This idea is based on observations that the angiotensin-converting enzyme 2 (ACE2) very likely serves as the binding site for SARS-CoV-2, the strain implicated in the current COVID-19 epidemic, similarly to strain SARS-CoV implicated in the 2002–2003 SARS epidemic” (Gurwitz, Drug Dev Res 2020, https://onlinelibrary.wiley.com/doi/pdf/10.1002/ddr.21656)

· Given that ACE2 is a functional receptor for SARS-CoV-2, the safety and potential effects of antihypertension therapy with ACE inhibitors or angiotensin-receptor blockers in patients with COVID-19 should be carefully considered. (https://www.nature.com/articles/s41569-020-0360-5)

· Proposed trial of recombinant ACE in Guangzhou; based on theory that ACEII receptor binding is crucial for COVID virulence: https://clinicaltrials.gov/ct2/show/NCT04287686

Therapeutic Research

1. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

Yao, Xueting, Clinical Infectious Diseases

March 9th 2020

https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa237/5801998

· Theorize that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late-phase in critically ill SARS-CoV-2 infected patients

· Pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2 infected Vero cells

· Hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen whilst considering the drug’s safety profile.

· Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection, as it reached three times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance.

· Hydroxychloroquine was found to be more potent than chloroquine to inhibit SARS-CoV-2 in vitro.

2. Convalescent plasma as a potential therapy for COVID-19

Long Chen, Jing Xiong, Lei Bao, Yuan Shi, Lancet

February 27th, 2020https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30141-9/fulltext

· “Evidence shows that convalescent plasma from patients who have recovered from viral infections can be used as a treatment without the occurrence of severe adverse events. Therefore, it might be worthwhile to test the safety and efficacy of convalescent plasma transfusion in SARS-CoV-2-infected patients.

3. COVID-19: combining antiviral and anti-inflammatory treatments

Justin Stebbing and others, Lancet

February 27th, 2020

https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30132-8/fulltext

· This work demonstrates that the use of an AI-driven knowledge graph can facilitate rapid drug development.

4. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies

Gao, Jianjun et al., BioScience Trends

February 19th 2020

https://www.jstage.jst.go.jp/article/bst/advpub/0/advpub_2020.01047/_article

· Early in-vitro studies showed chloroquine blocked COVID-19 infection at low-micromolar concentration

· Multiple clinical trials in China started to test efficacy in more than 10 hospitals using Chloroquine

· Results from 100 patients so far have demonstrated that Chloroquine Phosphate is superior to control treatment in inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting a virus negative conversion, and shortening the disease course according to the news briefing. Severe adverse reactions to chloroquine phosphate were not noted in the aforementioned patients.

· Given these findings, a conference was held on February 15, 2020; participants including experts from government and regulatory authorities and organizers of clinical trials reached an agreement that chloroquine phosphate has potent activity against COVID-19. The drug is recommended for inclusion in the next version of the Guidelines for the Prevention, Diagnosis, and Treatment of Pneumonia Caused by COVID-19 issued by the National Health Commission of the People's Republic of China

5. Case of the Index Patient Who Caused Tertiary Transmission of Coronavirus Disease 2019 in Korea: the Application of Lopinavir/Ritonavir for the Treatment of COVID-19 Pneumonia Monitored by Quantitative RT-PCR

Lim, Jaegyun, Journal of Korean Medical Science

February 17th 2020

https://jkms.org/DOIx.php?id=10.3346/jkms.2020.35.e79

· 54 y/o M clothing worker with confirmed COVID-19 in S. Korea who presented with mild respiratory symptoms (dry cough, day 7) and intermittent fever (day 5), small consolidation in RUL and GGO in bilat LLs on CT.

· Dx with throat RT-PCR

· 2 tablets Lopinavir 200mg/Ritonavir 50mg PO BID started on hospital day 8 (day 10 of illness)

· Viral load started to decrease on day 2 of administration with little or no coronavirus detectable since

6. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury Russell, Clark et al, Lancet

February 15th 2020


· No clinical data exist to indicate that net benefit is derived from corticosteroids in the treatment of respiratory infection due to RSV, influenza, SARS-CoV, or MERS-CoV.

· The available observational data suggest increased mortality and secondary infection rates in influenza, impaired clearance of SARS-CoV and MERS-CoV, and complications of corticosteroid therapy in survivors.

· If it is present, the effect of steroids on mortality in those with septic shock is small, and is unlikely to be generalisable to shock in the context of severe respiratory failure due to 2019-nCoV.

· Overall, no unique reason exists to expect that patients with 2019-nCoV infection will benefit from corticosteroids, and they might be more likely to be harmed with such treatment.

7. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection

Witt, E. et al, PNAS

February 7th 2020

https://www.pnas.org/content/early/2020/02/12/1922083117

· Remdesivir (GS-5734) effectively inhibited MERS coronavirus (MERS-CoV) replication in vitro, and showed efficacy against Severe Acute Respiratory Syndrome (SARS)-CoV in a mouse model.

· Tested the efficacy of prophylactic and therapeutic remdesivir treatment in a nonhuman primate model of MERS-CoV infection, the rhesus macaque.

· Prophylactic remdesivir treatment initiated 24 h prior to inoculation completely prevented MERS-CoV−induced clinical disease, strongly inhibited MERS-CoV replication in respiratory tissues, and prevented the formation of lung lesions.

· Therapeutic remdesivir treatment initiated 12 h post-inoculation also provided a clear clinical benefit, with a reduction in clinical signs, reduced virus replication in the lungs, and decreased presence and severity of lung lesions.

8. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro (LETTER TO EDITOR)

Wang, M, Cell Research

February 4th 2020

https://www.nature.com/articles/s41422-020-0282-0

· In this study, we evaluated the antiviral efficiency of five FAD-approved drugs:

· Ribavirin, penciclovir, nitazoxanide, nafamostat, chloroquine and two well-known broad-spectrum antiviral drugs remdesivir (GS-5734) and favipiravir (T-705) against a clinical isolate of 2019-nCoV in vitro.

· Remdesivir:

· Remdesivir is an adenosine analogue, which incorporates into nascent viral RNA chains and results in pre-mature termination

· Our time-of-addition assay showed remdesivir functioned at a stage post virus entry

· Our preliminary data (Supplementary information, Fig. S2) showed that remdesivir also inhibited virus infection efficiently in a human cell line (human liver cancer Huh-7 cells), which is sensitive to 2019-nCoV

· Chloroquine

· Chloroquine increases endosomal pH needed for virus/cell fusion, and interferes with glycosylation of cell receptors of SARS-CoV. Also has immune modulating activity which may enhance antiviral effect.

· Chloroquine functioned at both entry, and at post-entry stages of the 2019-nCoV infection in Vero E6 cells

· Chloroquine is widely distributed in the whole body, including lung, after oral administration

· The EC90 value of chloroquine against the 2019-nCoV in Vero E6 cells was 6.90 μM, which can be clinically achievable as demonstrated in the plasma of rheumatoid arthritis patients who received 500 mg administration.

·

Imaging

1. Clinical and CT imaging features of 2019 novel coronavirus disease (COVID-19)

Zhu et.al, Journal of Infection (2020)

February 26, 2020

doi: https://doi.org/10.1016/j.jinf.2020.02.022

· CT images for six female patients aged from 27 to 63 years: None of the patients had underlying diseases such as diabetes, malignant tumour or respiratory disease.

· Our CT study found that COVID-19 has a variety of manifestations. In the early stage of the disease, the lesion can manifest as round nodular-like GGO in the central area of the lung lobe, which is different from the common imaging manifestations that are patchy-like lesion in subpleural region

· CT images showed the lesions are migratory manifested as the absorption of the primary lesions and the emergence of new lesions, which had not been reported yet

· See article for images / more details

2. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study

Heshui Shi and others, Lancet

February 24th 2020


· COVID-19 pneumonia manifests with chest CT imaging abnormalities, even in asymptomatic patients, with rapid evolution from focal unilateral to diffuse bilateral ground-glass opacities that progressed to or co-existed with consolidations within 1–3 weeks.

3. COVID-19 pneumonia: what has CT taught us?

Elaine Y P Lee, Ming-Yen Ng, Pek-Lan Khong, Lancet

February 24th, 2020


· The current literature is partly skewed by the geographical distribution of COVID-19 pneumonia and the preferential use of CT over chest radiograph in China. This preference might be due to the ease of access to CT in China and the lack of requirement for intravenous contrast agent for the examination. Therefore, it is unclear whether the threshold for performing CT evaluation of potential lung changes should be lower when chest radiographs are normal.

4. CT Imaging Features of 2019 Novel Coronavirus (2019-nCoV)

Chung, Michael et al, Radiology

February 4th, 2020

https://pubs.rsna.org/doi/full/10.1148/radiol.2020200230

· Chest CT scans of 21 symptomatic patients from China infected with the 2019 novel coronavirus (2019-nCoV) were reviewed, with emphasis on identifying and characterizing the most common findings.

· Typical CT findings included bilateral pulmonary parenchymal ground-glass and consolidative pulmonary opacities, sometimes with a rounded morphology and a peripheral lung distribution.

· Notably, lung cavitation, discrete pulmonary nodules, pleural effusions, and lymphadenopathy were absent.

· Follow-up imaging in a subset of patients during the study time window often demonstrated mild or moderate progression of disease, as manifested by increasing extent and density of lung opacities.

Basic ScienceVirology

· 2019 novel coronavirus is undergoing active recombination (LETTER TO EDITOR)

Yi, Huiguang, CID

March 4th 2020

https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa219/5781085

· We found five haplotypes (hap_009, hap_017, hap_023, hap_048 and hap_050) forming loops, which typically indicate existing of genetic recombination. However, in rare cases, loops can also be formed by recurring sequencing error or parallel/back mutations.

· This report provides the first evidence for genetic recombination—a new way of evolution besides mutation in 2019-nCoV. The existing of genetic recombination has the following implications: two different 2019-nCoV strains (here, hap_048 and hap_050) should have coinfected the same cell

· a 2019-nCoV strain might:

· acquire new traits like virulence and drug susceptibility directly from other strains;

· the adaptability of 2019-nCoV to human immune system might be significantly strengthened through genetic recombination;

· the accuracy of diagnosis based on serologic and molecular biology assays might be compromised;

· the transmission tracking based on phylogenetics tree could be misleading since the topology of mutation route is a network rather than a tree.

Viral Shedding

1. Detection of Novel Coronavirus by RT-PCR in Stool Specimen from Asymptomatic Child, China.

Tang A Emerg Infect Dis. doi: 10.3201/eid2606.200301.

March 9th 2020https://wwwnc.cdc.gov/eid/article/26/6/20-0301_article

· An asymptomatic child [10 year old boy] who was positive for a 2019 novel coronavirus by reverse transcription PCR in a stool specimen 17 days after the last known exposure to someone positive with virus. The child was virus positive in stool specimens for at least an additional 9 days from first positive test. Respiratory tract specimens were negative by reverse transcription PCR.

2. Clinical presentation and virological assessment of hospitalized cases of coronavirus disease 2019 in a travel-associated transmission cluster

Woefel, Roman, MedRxiv (PREPRINT)

March 8th 2020

https://www.medrxiv.org/content/10.1101/2020.03.05.20030502v1

· In coronavirus disease 2019 (COVID-19), current case definitions presume mainly lower respiratory tract infection.

· Studied viral load courses by RT-PCR in oro- and nasopharyngeal swabs, sputum, stool, blood, and urine in nine hospitalized cases.

· Infectious virus was detected by cell culture. Active replication was demonstrated by analysis of viral subgenomic replicative intermediates. Serology including neutralization testing was done to characterize immune response.

· Seven cases had upper respiratory tract disease. Lower respiratory tract symptoms seen in two cases were limited.

· Clinical sensitivity of RT-PCR on swabs taken on days 1-5 of symptoms was 100%, with no differences comparing swab and sputum samples taken simultaneously.

· Average viral load was 6.76x10E5 copies per swab during the first 5 days. Live virus isolates were obtained from swabs during the first week of illness.

· Proof of active viral replication in upper respiratory tract tissues was obtained by detection of subgenomic viral RNA. Shedding of viral RNA from sputum outlasted the end of symptoms. Seroconversion occurred after about one week.

· Apart from one patient, all cases were first tested when symptoms were still mild or in the prodromal stage, a period in which most patients would present once there is general awareness of a circulating pandemic disease.

· Diagnostic testing suggests that simple throat swabs will provide sufficient sensitivity at this stage of infection.

· This is in stark contrast to SARS. For instance, only 38 of 98 nasal or nasopharyngeal swab samples tested positive by RT-PCR in SARS patients in Hong Kong. Also, viral load differed considerably. In SARS, it took 7 to 10 days after onset until peak RNA concentrations (of up to 5x105 copies per swab) were reached. In the present study, peak concentrations were reached before day 5, and were more than 1000 times higher. Successful live virus isolation from throat swabs is another striking difference from SARS, for which such isolation (culture) was rarely successful.

· Altogether, this suggests active virus replication in upper respiratory tract tissues, where only minimal ACE-2 expression is found and SARS-CoV is therefore not thought to replicate19. At the same time, the concurrent use of ACE-2 as a receptor by SARS-CoV and SARS-CoV-2 corresponds to a highly similar excretion kinetic in sputum, with active replication in the lung.

· Replication in the throat is strongly supported by our studies of sgRNAtranscribing cells in throat swab samples, particularly during the first 5 days of symptoms.

· Later in the disease, COVID-19 then resembles SARS in terms of replication in the lower respiratory tract.

· “Importantly, the scientists could not grow viruses from throat swabs or sputum specimens after day 8 of illness from people who had mild infections.

· “Based on the present findings, early discharge with ensuing home isolation could be chosen for patients who are beyond day 10 of symptoms with less than 100,000 viral RNA copies per ml of sputum,” the authors said, suggesting that at that point “there is little residual risk of infectivity, based on cell culture.”

· “The study also noted that people who are infected begin to develop antibodies to the virus quickly, typically within six to 12 days. The rapid rise of antibodies may explain why about 80% of people infected with the virus do not develop severe disease.”

· The present study shows that COVID-19 can often present as a common cold-like illness. SARS-CoV-2 can actively replicate in the upper respiratory tract, and is shed for a prolonged time after symptoms end, including in stool. These findings suggest adjustments of current case definitions and re-evaluation of the prospects of outbreak containment.

3. A confirmed asymptomatic carrier of 2019 novel coronavirus (SARS-CoV-2).

Luo SH et al. Chin Med J (Engl). doi: 10.1097/CM9.0000000000000798. [Epub ahead of print]

March 6th 2020

https://journals.lww.com/cmj/Citation/publishahead/A_confirmed_asymptomatic_carrier_of_2019_novel.99353.aspx

· In this study, we identified a confirmed case of asymptomatic 2019-nCoV infection, Patient A [50-year old woman], and reported her clinical follow-ups. Despite largely normal laboratory and chest CT findings, her persistent positivity of the virus nucleic acid in her throat swabs and anal swabs for at least 17 days suggested that she was very likely a healthy carrier. Notably, the detection of nucleic acids in her anal swabs also added to the importance of testing anal swabs or stool samples for the virus, even after respiratory specimens turn negative, in case that COVID-19 is transmittable via a fecal-oral route

4. Evidence for gastrointestinal infection of SARS-CoV-2 In Press, Journal Pre-proof

Gastroenterology, https://doi.org/10.1053/j.gastro.2020.02.055

March 3rd 2020

https://www.sciencedirect.com/science/article/pii/S0016508520302821?via%3Dihub

· From February 1 to 14, 2020, among all the 73 SARS-CoV-2-infected hospitalized patients, 39 (53.42%) including 25 males and 14 females tested positive for SARS-CoV-2 RNA in stool as shown in Supplementary Table 1. The age of patients with positive SARS-CoV-2 RNA in stool ranged from 10 months to 78 years old. Duration time of positive stool ranged from 1 to 12 days. Furthermore, 17 (23.29%) patients remained positive in stool after showing negative in respiratory samples.

5. Viral load measurements from 17 symptomatic patients in Southern China

Letter to Editor, NEJM

February 9th 2020

https://www.nejm.org/doi/pdf/10.1056/NEJMc2001737

6. First Case of 2019 Novel Coronavirus in the United States

Holshue, Michelle et al., NEJM

January 31st 2020

https://www.nejm.org/doi/pdf/10.1056/NEJMoa2001191

· WA state case Serial testing viral RT PCR results over time

Public Health / EpidemiologyModeling

1. Transmission potential of the novel coronavirus (COVID-19) onboard the Diamond Princess Cruises Ship, 2020

Mizumoto, Infectious Disease Modeling

Feburary 29th 2020

· Using modeling and time-series incidence data describing the trajectory of the outbreak among passengers and crew members, we characterize how the transmission potential varied over the course of the outbreak.

· To reconstruct the trajectory of the epidemic, only 197 cases have dates of symptoms onset available out of a total of 300 confirmed symptomatic cases.

· Our estimate of the mean reproduction number in the confined setting reached values as high as ∼11, which is higher than mean estimates reported from community-level transmission dynamics in China & Singapore (~ range: 1.1-7).

· Our findings suggest that Rt decreased substantially compared to during the early phase after the Japanese government implemented enhanced quarantine control.

· Most recent estimates of Rt reached values largely below the epidemic threshold, indicating that a secondary outbreak of the novel coronavirus was unlikely to occur aboard the Diamond Princess Ship.

· As of February 22, 2020, two days after the scheduled two-week quarantine came to an end, a total of 621 symptomatic and asymptomatic people including one quarantine officer, one nurse and one administrative officer tested positive for COVID-19 out of the 3,711 passengers and crew members on board.

·

2. Preparedness and vulnerability of African countries against importations of COVID-19: a modelling study

Gilbert, M. et al., Lancet

2/20/2020https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30411-6/fulltext

· A modelling study estimates that Egypt, Algeria and South Africa are at the highest risk of importing new coronavirus cases in Africa. The three countries are estimated to have the most prepared health systems in the continent and be least vulnerable. However, the authors call for increased resources, surveillance, and capacity building to be urgently prioritised in countries with a moderate risk which are more likely to be ill-prepared to detect cases and limit transmission

3. Reporting, Epidemic Growth, and Reproduction Numbers for the 2019 Novel Coronavirus (2019-nCoV) Epidemic

Tuite, Ashleigh, Fisman, David, Annals of Internal medicine

2/5/2020

· A simple disease-transmission model in which the 2019-nCoV epidemic was modeled with the following parameters:

· Branching process starting in mid-November 2019

· Serial interval of 7 days (time between cases)

· Basic reproduction number (R0) of 2.3 (new cases from each old case), based on available data

· Assuming no intervention

· Findings

· Comparison of cumulative case numbers versus model-generated counts shows that reported case numbers remain lower than modeled estimates, but ascertainment is increasingly complete over time

· Based on previously published model estimates, the fraction of cases reported increased from 2.4% on 12 January 2020 to 11% on 18 January 2020.

· Our model suggests that (assuming Re remained close to 2.3 after the quarantine on 24 January 2020) reported cases increased to 59% by 31 January 2020 (9930 reported cases vs. 16 860 modeled cases) (1, 2).

· The fraction of cases reported would be even higher if the reproduction number were lower because of control efforts.

· Interactive Model: https://art-bd.shinyapps.io/nCov_control/

Epidemiology

1. Evolving Epidemiology and Impact of Non-pharmaceutical Interventions on the Outbreak of Coronavirus Disease 2019 in Wuhan, China

Wang, C et.al, MedRXiV : PREPRINT / UNPUBLISHED

March 6th 2020

https://www.medrxiv.org/content/10.1101/2020.03.03.20030593v1.full.pdf

· Individual-level data on 25,961 laboratory-confirmed Covid-19 cases reported through February 18, 2020 were extracted from the municipal Notifiable Disease Report System

· Described Epi features

· Evaluated the impact of non-pharmaceutical interventions (aka Societal/Social) on the epidemic in Wuhan, China.

· Compared epi characteristics across 4 periods (periods based on key events and interventions)- used a susceptible-exposed-infectious-recovered model:

· before January 11, January 11-22, January 23 - February 1, and February 2-18.

· Median age of the cases was 57 years and 50.3% were women.

· Attack rate peaked in the third period (January 23 - February 1) and substantially declined afterwards across geographic regions, sex and age groups, except for children (age <20) whose attack rate continued to increase.

· Healthcare workers and elderly people had higher attack rates and severity risk increased with age.

· The effective reproductive number dropped from 3.86 (95% credible interval 3.74 to 3.97) before interventions to 0.32 (0.28 to 0.37) post interventions.

· Interventions:

· Intensive intra-city and inter-city traffic restriction, social distancing measures, and improvement of medical resources within Wuhan city.

· Interventions were estimated to prevent 94.5% (93.7 to 95.2%) infections till February 18.

· We found that at least 59% of infected cases were unascertained in Wuhan, potentially including asymptomatic and mild-symptomatic cases.

· Special efforts are needed to protect vulnerable populations, including healthcare workers, elderly and children. Estimation of unascertained cases has important implications on continuing surveillance and interventions.

2. Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore

Young, Barnaby et. al, JAMA

March 3, 2020


· Description of first 18 cases with COVID-19 in Singapore between Jan 23-Feb 3 2020

· Clinical presentation was a respiratory tract infection with prolonged viral shedding from the nasopharynx of 7 days or longer in 15 patients (83%). Supplemental oxygen was required in 6 patients (33%), 5 of whom were treated with lopinavir-ritonavir, with variable clinical outcomes following treatment.

· Among the 18 hospitalized patients with PCR-confirmed SARS-CoV-2 infection:

· Median age, 47 years; 9 [50%] women

· Clinical presentation:

· Upper respiratory tract infection in 12 (67%)

· Viral shedding from the nasopharynx was prolonged for 7 days or longer among 15 (83%).

· Six individuals (33%) required supplemental oxygen; of these, 2 required intensive care. There were no deaths.

· Virus was detectable in the stool (4/8 [50%]) and blood (1/12 [8%]) by PCR but not in urine.

· Five individuals requiring supplemental oxygen were treated with lopinavir-ritonavir. For 3 of the 5 patients, fever resolved and supplemental oxygen requirement was reduced within 3 days, whereas 2 deteriorated with progressive respiratory failure. Four of the 5 patients treated with lopinavir-ritonavir developed nausea, vomiting, and/or diarrhea, and 3 developed abnormal liver function test results.

3. A Well Infant with Coronavirus Disease 2019 (COVID-19) with High Viral Load

Kam, K et al. , Clin Inf Dis

February 28th 2020

· A well 6-month-old infant with coronavirus disease 2019 (COVID-19) had persistently positive nasopharyngeal swabs to day 16 of admission. This case highlights the difficulties in establishing the true incidence of COVID-19 as asymptomatic individuals can excrete the virus. These patients may play important roles in human-to-human transmission in the community.

· Referred to Singapore’s KK Women’s and Children’s Hospital (KKH) on 4 February 2020. His mother and live-in helper were admitted to the Singapore General Hospital (SGH) isolation unit on 3 February 2020 for pneumonia and were undergoing investigations for COVID-19.

· His mother’s occupation involved close contact with tourists from China; her symptoms of fever and sore throat started on 29 January 2020. Her first nasopharyngeal swab on 3 February 2020 was positive for SARS-CoV-2.

· The infant’s father developed fever and sore throat on 1 February 2020 and was admitted to the National Centre for Infectious Disease (NCID) isolation unit on 4 February 2020 for SARS-CoV-2 testing. As the infant had no remaining well caregivers, he was brought to KKH for clinical assessment and isolation in light of his close contact with confirmed COVID-19 cases.

· The infant was asymptomatic on arrival to the hospital. He was afebrile with no tachypnea. Oxygen saturation was 98% on room air and his lungs were clear to auscultation. As his respiratory status was stable, no chest radiograph was performed.

· A nasopharyngeal specimen taken on admission and tested by rRT-PCR confirmed the diagnosis of COVID-19 infection with low cycle threshold (N gene, 15.57; Orf1ab gene, 13.73), suggesting high viral load.

· On day 2 of admission, he was found to be viremic with detection of SARS-CoV-2 in his blood sample via rRT-PCR. However, stool and urine samples from the same day were negative.

· During this viremic phase, he had 1 temperature record of 38.5°C which normalized within 1 hour. Otherwise, he was afebrile and remained asymptomatic throughout admission. Daily nasopharyngeal swabs continued to be positive for SARSCoV-2 (Figure 1) and eventually became negative on day 17 of admission.

4. COVID-19 outbreak on the Diamond Princess cruise ship: estimating the epidemic potential and effectiveness of public health countermeasures

J Rocklöv et al., Journal of Travel Medicine, https://doi.org/10.1093/jtm/taaa030

February 28, 2020https://academic.oup.com/jtm/advance-article/doi/10.1093/jtm/taaa030/5766334

· The basic reproduction rate was initially 4 times higher on-board compared to the R0 in the epicentre in Wuhan, but the countermeasures lowered it substantially.

· Based on the modeled initial R0 of 14.8, we estimated that without any interventions within the time period of 21 January to 19 February, 2920 out of the 3700 (79%) would have been infected.

· Isolation and quarantine therefore prevented 2307 cases, and lowered the R0 to 1.78.

· We showed that an early evacuation of all passengers on 3 February would have been associated with 76 infected persons in their incubation time.

· Conclusions: The cruise ship conditions clearly amplified an already highly transmissible disease. The public health measures prevented more than 2000 additional cases compared to no interventions. However, evacuating all passengers and crew early on in the outbreak would have prevented many more passengers and crew from infection

5. Results The basic reproduction rate was initially 4 times higher on-board compared to the R0 in the epicentre in Wuhan, but the countermeasures lowered it substantially. Based on the modeled initial R0 of 14.8, we estimated that without any interventions within the time period of 21 January to 19 February, 2920 out of the 3700 (79%) would have been infected. Isolation and quarantine therefore prevented 2307 cases, and lowered the R0 to 1.78. We showed that an early evacuation of all passengers on 3 February would have been associated with 76 infected persons in their incubation time.

6.

7. Conclusions Conclusions: The cruise ship conditions clearly amplified an already highly transmissible disease. The public health measures prevented more than 2000 additional cases compared to no interventions. However, evacuating all passengers and crew early on in the outbreak would have prevented many more passengers and crew from infection.

8.

9. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

Wu, Zunyou, McGoogan, Jennifer; JAMA

February 24, 2020


· Total of 72 314 case records:

· 44 672 were classified as confirmed cases of COVID-19 (62%; diagnosis based on positive viral nucleic acid test result on throat swab samples)

· 16 186 as suspected cases (22%; diagnosis based on symptoms and exposures only, no test was performed because testing capacity is insufficient to meet current needs)

· 10 567 as clinically diagnosed cases (15%; this designation is being used in Hubei Province only; in these cases, no test was performed but diagnosis was made based on symptoms, exposures, and presence of lung imaging features consistent with coronavirus pneumonia)

· 889 as asymptomatic cases (1%; diagnosis by positive viral nucleic acid test result but lacking typical symptoms including fever, dry cough, and fatigue)

· Age distribution (N = 44 672)

· ≥80 years: 3% (1408 cases)

· 30-79 years: 87% (38 680 cases)

· 20-29 years: 8% (3619 cases)

· 10-19 years: 1% (549 cases)

· <10 years: 1% (416 cases)

· Spectrum of disease (N = 44 415)

· Mild: 81% (36 160 cases)

· Severe: 14% (6168 cases)

· Critical: 5% (2087 cases)

· Case-fatality rate

· 2.3% (1023 of 44 672 confirmed cases)

· 14.8% in patients aged ≥80 years (208 of 1408)

· 8.0% in patients aged 70-79 years (312 of 3918)

· 49.0% in critical cases (1023 of 2087)

· Health care personnel infected

· 3.8% (1716 of 44 672)

· 63% in Wuhan (1080 of 1716)

· 14.8% cases classified as severe or critical (247 of 1668)

· 5 deaths

· Importantly, another major goal of China’s current outbreak response activities is to help “buy time” for science to catch up before COVID-19 becomes too widespread. China must now focus on adjusting tactics and strategies as new evidence becomes available. Much remains to be done and many questions remain unanswered. China is very grateful for the help it is receiving from the international scientific, health, and public health communities. The global society is more interconnected than ever, and emerging pathogens do not respect geopolitical boundaries.

· Epi Curve with timing of interventions/developments:

10. Open access epidemiological data from the COVID-19 outbreak

Bo Xu et al , Lancet

2/19/2020


· Open access epidemiological data from the COVID-19 outbreak -- - a centralised repository of individual-level information on patients with laboratory-confirmed COVID-19 (in China, confirmed by detection of virus nucleic acid at the City and Provincial Centers for Disease Control and Prevention), including their travel history, location (highest resolution available and corresponding latitude and longitude), symptoms, and reported onset dates, as well as confirmation dates and basic demographics.

11. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19) 16-24 February 2020

https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf

Excerpts:

· Transmission:

· Droplet vs Airborne:

· COVID-19 is transmitted via droplets and fomites during close unprotected contact between an infector and infectee. Airborne spread has not been reported for COVID-19 and it is not believed to be a major driver of transmission based on available evidence; however, it can be envisaged if certain aerosol-generating procedures are conducted in health care facilities.

· Household transmission:

· In China, human-to-human transmission of the COVID-19 virus is largely occurring in families. The Joint Mission received detailed information from the investigation of clusters and some household transmission studies, which are ongoing in a number of Provinces.

· Among 344 clusters involving 1308 cases (out of a total 1836 cases reported) in Guangdong Province and Sichuan Province, most clusters (78%-85%) have occurred in families.

· Household transmission studies are currently underway, but preliminary studies ongoing in Guangdong estimate the secondary attack rate in households ranges from 3-10%.

· Contact Tracing

· China has a policy of meticulous case and contact identification for COVID-19. For example, in Wuhan more than 1800 teams of epidemiologists, with a minimum of 5 people/team, are tracing tens of thousands of contacts a day. Contact follow up is painstaking, with a high percentage of identified close contacts completing medical observation. Between 1% and 5% of contacts were subsequently laboratory confirmed cases of COVID-19, depending on location.

· Testing at fever clinics and from routine ILI/SARI surveillance

· The Joint Mission systematically enquired about testing for COVID-19 from routine respiratory disease surveillance systems to explore if COVID-19 is circulating more broadly and undetected in the community in China. These systems could include RT-PCR testing of COVID-19 virus in influenza-like-illness (ILI) and severe acute respiratory infection (SARI) surveillance systems, as well as testing of results among all visitors to fever clinics.

· In Wuhan, COVID-19 testing of ILI samples (20 per week) in November and December 2019 and in the first two weeks of January 2020 found no positive results in the 2019 samples, 1 adult positive in the first week of January, and 3 adults positive in the second week of January; all children tested were negative for COVID-19 although a number were positive for influenza. In Guangdong, from 1-14 January, only 1 of more than 15000 ILI/SARI samples tested positive for the COVID-19 virus. In one hospital in Beijing, there were no COVID-19 positive samples among 1910 collected from 28 January 2019 to 13 February 2020. In a hospital in Shenzhen, 0/40 ILI samples were positive for COVID-19.

· Within the fever clinics in Guangdong, the percentage of samples that tested positive for the COVID-19 virus has decreased over time from a peak of 0.47% positive on 30 January to 0.02% on 16 February. Overall in Guangdong, 0.14% of approximately 320,000 fever clinic screenings were positive for COVID-19.

· Susceptibility

· As COVID-19 is a newly identified pathogen, there is no known pre-existing immunity in humans. Based on the epidemiologic characteristics observed so far in China, everyone is assumed to be susceptible, although there may be risk factors increasing susceptibility to infection. This requires further study, as well as to know whether there is neutralizing immunity after infection.

· Transmission in China outside of Hubei

· Given Wuhan’s transport hub status and population movement during the Chinese New Year (chunyun), infected individuals quickly spread throughout the country, and were particularly concentrated in cities with the highest volume of traffic with Wuhan. Some of these imported seeds generated limited human-to-human transmission chains at their destination.

· Given the Wuhan/Hubei experience, a comprehensive set of interventions, including aggressive case and contact identification, isolation and management and extreme social distancing, have been implemented to interrupt the chains of transmission nationwide. To date, most of the recorded cases were imported from or had direct links to Wuhan/Hubei. Community transmission has been very limited. Most locally generated cases have been clustered, the majority of which have occurred in households, as summarized above.

· Of note, the highly clustered nature of local transmission may explain a relatively high R0 (2- 2.5) in the absence of interventions and low confirmed case counts with intense quarantine and social distancing measures.

· Special settings

· We note that instances of transmission have occurred within health care settings prisons and other closed settings. At the present time, it is not clear what role these settings and groups play in transmission. However, they do not appear to be major drivers of the overall epidemic dynamics

· Children

· Data on individuals aged 18 years old and under suggest that there is a relatively low attack rate in this age group (2.4% of all reported cases). Within Wuhan, among testing of ILI samples, no children were positive in November and December of 2019 and in the first two weeks of January 2020.

· From available data, and in the absence of results from serologic studies, it is not possible to determine the extent of infection among children, what role children play in transmission, whether children are less susceptible or if they present differently clinically (i.e. generally milder presentations). The Joint Mission learned that infected children have largely been identified through contact tracing in households of adults.

· Of note, people interviewed by the Joint Mission Team could not recall episodes in which transmission occurred from a child to an adult.

· Clinical; Adult patients

· People with COVID-19 generally develop signs and symptoms, including mild respiratory symptoms and fever, on an average of 5-6 days after infection (mean incubation period 5-6 days, range 1-14 days).

· Most people infected with COVID-19 virus have mild disease and recover. Approximately 80% of laboratory confirmed patients have had mild to moderate disease, which includes non-pneumonia and pneumonia cases, 13.8% have severe disease (dyspnea, respiratory frequency ≥30/minute, blood oxygen saturation ≤93%, PaO2/FiO2 ratio <300, and/or lung infiltrates >50% of the lung field within 24-48 hours) and 6.1% are critical (respiratory failure, septic shock, and/or multiple organ dysfunction/failure).

· Asymptomatic infection has been reported, but the majority of the relatively rare cases who are asymptomatic on the date of identification/report went on to develop disease. The proportion of truly asymptomatic infections is unclear but appears to be relatively rare and does not appear to be a major driver of transmission.

· Individuals at highest risk for severe disease and death include people aged over 60 years and those with underlying conditions such as hypertension, diabetes, cardiovascular disease, chronic respiratory disease and cancer. Disease in children appears to be relatively rare and mild with approximately 2.4% of the total reported cases reported amongst individuals aged under 19 years.

· A very small proportion of those aged under 19 years have developed severe (2.5%) or critical disease (0.2%).

· As of 20 February, 2114 of the 55,924 laboratory confirmed cases have died (crude fatality ratio [CFR2 ] 3.8%) (note: at least some of whom were identified using a case definition that included pulmonary disease). The overall CFR varies by location and intensity of transmission (i.e. 5.8% in Wuhan vs. 0.7% in other areas in China).

· Case fatality Rate

· In China, the overall CFR was higher in the early stages of the outbreak (17.3% for cases with symptom onset from 1-10 January) and has reduced over time to 0.7% for patients with symptom onset after 1 February [RS comment:- compare to 0.85% (6/705) current CFR for passengers on the Diamond Princess] (Figure 4). The Joint Mission noted that the standard of care has evolved over the course of the outbreak.

· Mortality increases with age, with the highest mortality among people over 80 years of age (CFR 21.9%).

· The CFR is higher among males compared to females (4.7% vs. 2.8%). By occupation, patients who reported being retirees had the highest CFR at 8.9%.

· While patients who reported no comorbid conditions had a CFR of 1.4%, patients with comorbid conditions had much higher rates: 13.2% for those with cardiovascular disease, 9.2% for diabetes, 8.4% for hypertension, 8.0% for chronic respiratory disease, and 7.6% for cancer.

· The Joint Mission acknowledges the known challenges and biases of reporting crude CFR early in an epidemic.

· Conclusions:

· The Joint Mission drew four major conclusions from its work in China and four major conclusions from its knowledge of the broader global response to COVID-19:

· Recommendations are offered in five major areas to inform the ongoing response globally and in China

2. China’s uncompromising and rigorous use of non-pharmaceutical measures to contain transmission of the COVID-19 virus in multiple settings provides vital lessons for the global response. This rather unique and unprecedented public health response in China reversed the escalating cases in both Hubei, where there has been widespread community transmission, and in the importation provinces, where family clusters appear to have driven the outbreak.

3. Much of the global community is not yet ready, in mindset and materially, to implement the measures that have been employed to contain COVID-19 in China. These are the only measures that are currently proven to interrupt or minimize transmission chains in humans. Fundamental to these measures is extremely proactive surveillance to immediately detect cases, very rapid diagnosis and immediate case isolation, rigorous tracking and quarantine of close contacts, and an exceptionally high degree of population understanding and acceptance of these measures.

12. Field Briefing: Diamond Princess COVID-19 Cases, 20 Feb Update

National Institute of Infectious Diseases, Japan (NIID)

February 21, 2020

https://www.niid.go.jp/niid/en/2019-ncov-e/9417-covid-dp-fe-02.html

· The initial quarantine period (14-day) for the Diamond Princess was 5-19 February 2020

· Additional details on quarantine measures can be found in “Field Briefing: Diamond Princess COVID-19”.

· Disembarkation Procedures:

· Criteria for non-cases:

· 1) completion of a 14-day period w/o sharing a cabin with a confirmed case

· 2) a negative result for a SARS-CoV-2 by PCR in the final days of the period

· 3) no relevant symptoms identified during a medical screening in the final day of the period.

· As of 20 February, > 1600 have been disembarked from the Diamond Princess.

· Testing strategy:

· Initially, testing focused on high-risk persons.

· Beginning on 11 Feb, efforts shifted toward testing all passengers by PCR for SARS-CoV-2. Due to the number of persons on board, these efforts began with passengers over 80, then over 75, then over 70, etc.

· After all passengers had been tested, the focus shifted to testing all crew members.

· Although no international guidelines require PCR testing to clear a quarantine for COVID-19 outbreaks, the Japanese government sought to do so as an additional measure of assurance.

· Results:

· As of 20 February:

· 619 cases have been confirmed (16.7 % of the population on board), including 82 crew and 537 passengers.

· A total 3011 respiratory specimens were tested, and 621 were positive (20.6%), including double tests.

· Persons aboard between 70 and 89 were the most affected (Table 1).

· Epi:

· Among confirmed COVID-19 cases with recorded symptom onset (n=197):

· 34 (17.3 %) with onset dates before 6 February, the first full day of quarantine

· 163 (82.7%) with onset dates on or after the 6th (Figure 1)

· Among these 197 cases, 163 occurred during the quarantine period (48 crew, 115 passengers) with 52–92 among passengers in cabins without a previously confirmed case (Table 2). Of these, 3–7 occurred after the median quarantine day (day 7).

· The proportion of COVID-19 cases confirmed among passengers increased with cabin occupancy (Figure 2).

· A total 318 (51%) of all confirmed cases were asymptomatic when the respiratory specimen was collected (10 crew and 308 passengers)

· Based on the cabin occupancy findings and the number of cases identified in cabins with previously confirmed cases, passengers within cabins may have been exposed to a common source or may have transmitted the virus within cabins. Due to the nature of the ship, individual isolation of all those aboard was not possible. Sharing cabins was necessary, and some crew had to perform essential duties while passengers remained aboard. After accounting for delayed reporting, the peak number of confirmed cases with known onset dates occurred on 7 February. The high number of recently reported cases can be explained by the shift in testing strategy described above, most of which were asymptomatic.

· Due to the lack of symptom presentation, it is not possible to infer when these cases were infected (see Annex A). Some may have been secondary cases within a given cabin. Some may have been infected before the quarantine began. Nevertheless, these asymptomatic cases were detected through testing, disembarked, and transferred to isolation. Their cabin mates have been defined as close contacts with their 14-day isolation reset on the last day the asymptomatic case disembarked. The systematic testing of asymptomatic cases was therefore important and beneficial for identifying potentially infectious individuals before allowing them to disembark. Current global research has scant evidence on asymptomatic transmission of SARS-CoV-2; thus, ongoing efforts to thoroughly investigate asymptomatic cases from Diamond Princess will provide important information for the global COVID-19 outbreak. (Information on the development of symptoms after disembarkation of asymptomatic confirmed cases is being collected.)

· Nearly all disembarked individuals have observed a 14-day quarantine without sharing a cabin with a confirmed case, have received a recent negative PCR-test, and have passed a medical screening for symptoms (e.g. fever, cough,). Individuals who shared a cabin with a confirmed case will be put in isolation until they complete a 14-day beginning after the last day of contact with a confirmed COVID-19 cabinmate. This includes a large proportion of the crew, who admirably performed essential tasks that allowed the quarantine to occur and should be appreciated for their service.

· Although the disembarked persons have passed laboratory testing, medical screening and the 14-day quarantine, they are asked to stay at home, where feasible, 14 days unless absolutely necessary, as an additional precautionary measure. They are asked also to monitor themselves for symptoms and contact a healthcare facility if symptoms develop.

·

13. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus–Infected Pneumonia

Qun Li et al, NEJM, Jan 29 2020

https://www.nejm.org/doi/full/10.1056/NEJMoa2001316?query=RP

· Among the first 425 patients with confirmed NCIP in Wuhan:

· the median age was 59 years and 56% were male.

· The majority of cases (55%) with onset before January 1, 2020, were linked to the Huanan Seafood Wholesale Market, as compared with 8.6% of the subsequent cases.

· The mean incubation period was 5.2 days (95% confidence interval [CI], 4.1 to 7.0), with the 95th percentile of the distribution at 12.5 days.

· In its early stages, the epidemic doubled in size every 7.4 days.

· With a mean serial interval of 7.5 days (95% CI, 5.3 to 19), the basic reproductive number was estimated to be 2.2 (95% CI, 1.4 to 3.9).

14. Secondary attack rate and superspreading events for SARS-CoV-2

Feb 24 2020: Yang Liu, Rosalind M Eggo, Adam J Kucharskihttps://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30462-1/fulltext

Transmission/Infection Control

1. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application.

Lauer SA et al. Ann Intern Med. doi: 10.7326/M20-0504

March 10th 2020

https://www.annals.org/aim/fullarticle/doi/10.7326/M20-0504

· 181 confirmed cases with identifiable exposure and symptom onset windows to estimate the incubation period of COVID-19.

· The median incubation period was estimated to be 5.1 days (95% CI, 4.5 to 5.8 days), to 15.6 days and 97.5% of those who develop symptoms will do so within 11.5 days (CI, 8.2) of infection.

· These estimates imply that, under conservative assumptions, only 101 (1%) out of every 10 000 cases (99th percentile, 482) will develop symptoms after 14 days of active monitoring or quarantine.

· LIMITATION: Publicly reported cases may overrepresent severe cases, the incubation period for which may differ from that of mild cases.

· CONCLUSION: This work provides additional evidence for a median incubation period for COVID-19 of approximately 5 days, similar to SARS. Our results support current proposals for the length of quarantine or active monitoring of persons potentially exposed to SARS-CoV-2, although longer monitoring periods might be justified in extreme cases.

2. Escalating infection control response to the rapidly evolving epidemiology of the Coronavirus disease 2019 (COVID-19) due to SARS-CoV-2 in Hong Kong

Cheng, Vincent et.al, Infection Control & Hospital Epidemiology

March 5th 2020

DOI: 10.1017/ice.2020.58

· A proactive bundled response in Hong Kong’s public hospital system during 42 days of outbreak, the 43 hospitals in network tested 1,275 suspected cases and treated 42 patients with confirmed COVID-19.

· No infections among healthcare workers.

· Bundle includes:

· Lab surveillance (active and enhanced)

· Early airborne infection isolation

· Rapid molecular diagnostic testing

· Contact tracing for HCWs with unprotected exposures in hospital.

· Epidemiological characteristics of confirmed cases, environmental and air samples were collected and analyzed.

· SARS-CoV-2 revealed in 1 (7.7%) of 13 environmental samples, but not in 8 air samples collected at a distance of 10 cm from patient's chin with or without wearing a surgical mask.

3. Air, Surface Environmental, and Personal Protective Equipment Contamination by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) From a Symptomatic Patient

Ong, Sean and Tan, Yian Kim, JAMA

March 4th 2020


· Surface environmental samples taken at 26 sites from 3 patient anterooms and bathrooms at the dedicated SARS-CoV-2 outbreak center in Singapore in airborne infection isolation rooms (12 air exchanges per hour). Personal protective equipment (PPE) samples from study physicians exiting the patient rooms also were collected.

· Specific real-time reverse transcriptase–polymerase chain reaction (RT-PCR) targeting RNA-dependent RNA polymerase and E genes4 was used to detect the presence of SARS-CoV-2

· Samples were collected on 5 days over a 2-week period.

· Patient A’s room was sampled on days 4 and 10 of illness while the patient was still symptomatic, after routine cleaning. All samples were negative.

· Patient B was symptomatic on day 8 and asymptomatic on day 11 of illness; samples taken on these 2 days after routine cleaning were negative

· Patient C, whose samples were collected before routine cleaning, had positive results, with 13 (87%) of 15 room sites (including air outlet fans) and 3 (60%) of 5 toilet sites (toilet bowl, sink, and door handle) returning positive results (Table 2). Anteroom and corridor samples were negative. Patient C had upper respiratory tract involvement with no pneumonia and had 2 positive stool samples for SARS-CoV-2 on RT-PCR despite not having diarrhea. Patient C had greater viral shedding, with a cycle threshold value of 25.69 in nasopharyngeal samples compared with 31.31 and 35.33 in patients A and B

· Only 1 PPE swab, from the surface of a shoe front, was positive. All other PPE swabs were negative. All air samples were negative.

· Significant environmental contamination by patients with SARS-CoV-2 through respiratory droplets and fecal shedding suggests the environment as a potential medium of transmission and supports the need for strict adherence to environmental and hand hygiene.

Perspective/ Commentary

1. Lessons for managing high-consequence infections from first COVID-19 cases in the UK

Peter Moss and others, Lancet, Feb 27 2020


· “When tested, neither of these people clearly met the current case definition, and had criteria been strictly applied, testing might not have been done. A decision to test was made because of high clinical suspicion and in response to latest available information about the distribution of infection. It is important that testing is appropriately targeted, and this is best done by applying clear case definitions. However, with any newly emerging infection, case definitions must evolve rapidly as information accrues. There should also be room for flexibility on the basis of discussion with clinical and public health experts…”

· “Although many areas (as in this case) do have effective local arrangements based on locally commissioned isolation facilities, there are other parts of the country where there are no such facilities and expertise in managing highly transmissible infections is limited. The HCID Units should be supported by a second tier of appropriately commissioned regional facilities so that high-risk suspected cases can be assessed safely and risk of nosocomial transmission minimised.

2. COVID-19: preparing for superspreader potential among Umrah pilgrims to Saudi Arabia Shahul H Ebrahim, Ziad A Memish, Lancet Feb 27 2020


· “…Given Saudi Arabia's track record of hosting pilgrims amidst the 2009 H1N1 pandemic, a declared PHEIC, the country could quickly activate advisories, infrastructure, and provisions for pilgrims. We do not need to wait for the first case to emerge in Saudi Arabia's holy sites. The time for preparedness is now.

3. Covid-19 — Navigating the Uncharted

Anthony S. Fauci, M.D., H. Clifford Lane, M.D., and Robert R. Redfield, M.D., NEJM, Feb 28 2020

https://www.nejm.org/doi/full/10.1056/NEJMe2002387

· A robust research effort is currently under way to develop a vaccine against Covid-19. We anticipate that the first candidates will enter phase 1 trials by early spring.

· Therapy currently consists of supportive care while a variety of investigational approaches are being explored:

· lopinavir–ritonavir

· interferon-1β

· the RNA polymerase inhibitor remdesivir

· chloroquine

· a variety of traditional Chinese medicine products

· Once available, intravenous hyperimmune globulin from recovered persons and monoclonal antibodies may be attractive candidates to study in early intervention.

4. Responding to Covid-19 — A Once-in-a-Century Pandemic?

Bill Gates, NEJM, Feb 28 2020

https://www.nejm.org/doi/full/10.1056/NEJMp2003762

· “…These are the actions that leaders should be taking now. There is no time to waste.”

5. Escaping Pandora’s Box — Another Novel Coronavirus

David M. Morens, M.D., Peter Daszak, Ph.D., and Jeffery K. Taubenberger, M.D., Ph.D., NEJM Feb 26, 2020

https://www.nejm.org/doi/full/10.1056/NEJMp2002106

· “We have created a global, human-dominated ecosystem that serves as a playground for the emergence and host-switching of animal viruses, especially genetically error-prone RNA viruses, whose high mutation rates have, for millions of years, provided opportunities to switch to new hosts in new ecosystems. It took the genome of the human species 8 million years to evolve by 1%. Many animal RNA viruses can evolve by more than 1% in a matter of days. It is not difficult to understand why we increasingly see the emergence of zoonotic viruses.

· “We are taking swift public health actions to prevent an emergence from becoming a pandemic, including isolation of patients and contacts to prevent secondary spread. But will these actions be adequate? Most experts agree that such measures could not have prevented the 1918 influenza pandemic…”

· Defining the Epidemiology of Covid-19 — Studies Needed Marc Lipsitch, David L. Swerdlow, and Lyn Finelli, Dr.P.H. https://www.nejm.org/doi/full/10.1056/NEJMp2000929

6. What to do next to control the 2019-nCoV epidemic?

Wang, Fu-Sheng, Zhang Chao, Lancet, Feb 8 2020


· Commentary from Chinese physicians on outbreak course and control efforts

· “…there will be a huge increase in people returning from trips after the Chinese Spring Festival vacation; and it may be difficult to control the outbreak due to the lack of adequate medical resources in epidemic communities and rural areas of Hubei province.”

· “The basic and essential strategies that we should stick to remain the early detection, early diagnosis, early isolation, and early treatment of the disease.”

7. Offline: 2019-nCoV—“A desperate plea”

Richard Horton, Lancet, Feb 8 2020


· “A desperate plea from an ordinary citizen” regarding effects on daily life

· “The bottom line is, a large population in China is suffering, not just from the virus but from the resulting isolation, high uncertainty, anxiety, and stress, reduced resources and freedom for daily living, and loss of income…”

8. Indian pharma threatened by COVID-19 shutdowns in China

Patralekha Chatterjee, Lancet, Feb 29, 2020

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30459-1/fulltext#%20

· India supplies low-cost generic drugs to millions of people, both within and outside the country. But Indian pharmaceutical companies procure almost 70% of the active pharmaceutical ingredients (APIs) for their medicines from China, the world's leading producer and exporter of APIs by volume. As factories in China are closed to try to stem the coronavirus disease 2019 outbreak, pharmaceutical companies and the Indian Government are becoming concerned over the vulnerability of the Indian pharmaceutical supply chain…

Psychological

1. The psychological impact of quarantine and how to reduce it: rapid review of the evidence

Samantha K Brooks and others, Lancet, Feb 26, 2020https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30460-8/fulltext

· Why is this Review needed?

Quarantine is often an unpleasant experience for those who undergo it. Separation from loved ones, the loss of freedom, uncertainty over disease status, and boredom can, on occasion, create dramatic effects. Suicide has been reported,5 substantial anger generated, and lawsuits brought6 following the imposition of quarantine in previous outbreaks. The potential benefits of mandatory mass quarantine need to be weighed carefully against the possible psychological costs.7 Successful use of quarantine as a public health measure requires us to reduce, as far as possible, the negative effects associated with it.

Key messages

•Information is key; people who are quarantined need to understand the situation

•Effective and rapid communication is essential

•Supplies (both general and medical) need to be provided

•The quarantine period should be short and the duration should not be changed unless in extreme circumstances

•Most of the adverse effects come from the imposition of a restriction of liberty; voluntary quarantine is associated with less distress and fewer long-term complications

•Public health officials should emphasise the altruistic choice of self-isolating

Epidemiologic Estimates

UNOFFICIAL

From CDC Modeling Team

Last updated: March 6th 2020

TIME OF EMERGENCE

Author

Most likely value

Plausible range

Rambaut et al.

Early Dec 2019

Early Nov–mid-Dec 2019

Andersen et al.

Early Dec 2019

Early Oct–late Dec 2019

Zhang & Wang

Dec 17, 2019

Dec 5 – 23, 2020

ESTIMATES OF ILLNESS IN WUHAN, CHINA

Author

(links to summary below)

Exported case # – date of estimate

Most likely outbreak size

Plausible range

Imai et al.

7 – by Jan 18 2020

4,000

1,000–9,700

Chinazzi et al.

by Feb 7 2020

58,956

90% CI 40,759 - 87,471

Ming et al.

N/A –by Jan 28 2020

95,933 (assuming 10% detection of cases)

-

Gardner et al

40 – by Jan 31 2020

58,000

Wu et al.

55 – by Jan 25 2020

75,815 individuals

95% CrI 37,304–130,330

Cao et al.

N/A – in first 80 days of epidemic

35,454

Du et al.

19 - by Jan 22 2020

12,400

95% CrI: 3.112 – 58,465

Kucharski et al.

By Jan 23 2020

29,500

14,300-85,700

Jung et al.

Onset Dec 8 2019 – Jan 24 2020

6,924

95% CI: 4885, 9211

Jung et al.

20 – by Jan 24 2020

19,289

95% CI: 10,901 - 30,158

Hermanowicz

By Feb 6 3030

65,000

This is for Mainland China

Lin et al.

By Jan 11 2020

4,090

95% CI: 3,975 – 4,206

Lin et al.

By Feb 9 2020

56,833

95% CI: 55,242 – 58,449

Zhao et al.

By Feb 2, 2020

110,000

95% CI: 40,000-310,000

Mizumoto et al.

By Feb 9, 2020

983,006

95%CrI: 759,475– 1,296,258

Zhou et al.

By Jan 23 2020

2,868.7 ± 1,739.0

Zhou et al.

By Feb 12 2020

52,185.4 ± 31,621.4

Wan et al.

Peak on Feb 19 2020

45,000

Fu et al.

By Feb 14 2020

46,607

95% CI: (41245, 58129)

Bo Zhang et al.

By April

42,073

Anastassopoulou et al.

By Feb 29 2020

160,000

90% CI: 84,000-330,000

Li et al.

By Feb 8 2020

14,982

Liu et al.

By March 3 2020

63,800

In Hubei

Tang et al.

By Jan 25, 2020

61,596

[58,344 – 64,847]

Zhang et al.

By February 24, 2020

48,530

95% CI: (41,360 – 95,450)

Zhao et al.

By late-March 2020

49,510

Zhuang et al.

By Jan 23 – Changjian

1326

(95% CI: 1177-1484)

Zhuang et al.

By Jan 23 – Tencent

1151

(95% CI: 1018 – 1292)

Zhuang et al.

By Jan 23 – Baidu

5277

(95% CI: 4732 – 5859)

ONSET TO FIRST MEDICAL VISIT

Author

Most likely value

Notes

Li et al.

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