Smittspridning från symptomfria

Det är nu helt klarlagt att det virus som orsakar Covid-19, SARS-CoV-2, smittar inte endast från dem som har symptom utan också från dem som ännu inte har det (och möjligen också från dem som aldrig kommer att få det). Undersökningar visar att man utsöndrar som mest virus dygnet innan och dygnet efter att symptomen debuterar, och att man kan vara smittsam flera dygn innan dess. Olika sammanställningar kommer fram till olika slutsatser om hur stor andel av smittspridningen som sker från symptomfria individer, men ofta ligger den angivna siffran nära 50 procent (se nedan). En av de bidragande orsakerna torde vara att en person som inte har symptom är mindre försiktig i sitt umgänge med andra. Med tanke på detta är rekommendationen ”stanna hemma om du känner dig sjuk” helt otillräcklig.

Symptomfri smitta är ett av de viktigaste skälen till att man bör använda munskydd i offentliga inomhusmiljöer eller när avstånd inte kan upprätthållas.

Nedanstående lista med evidens är lång. För att snabbt få en uppfattning räcker det att läsa till exempel de här två:

I. Oran et al., “Prevalence of Asymptomatic SARS-CoV-2 Infection”
Annals of Internal Medicine, June 3, 2020 https://www.acpjournals.org/doi/full/10.7326/M20-3012

II. En artikel i New York Times, från den 6 juni, som beskriver hur många regeringar, och inte minst den svenska, i det längsta kämpade mot slutsatsen att man kan smitta utan symptom: Apuzzo, et al. ”How the world missed Covid-19s silent spread” The New York Times https://www.nytimes.com/2020/06/27/world/europe/coronavirus-spread-asymptomatic.html?smid=em-share

Transmission reports (infector-infectee pairs)

Sun, et al.: “Transmission heterogeneities, kinetics, and controllability of SARS-CoV-2”
Preprint
https://www.medrxiv.org/content/medrxiv/early/2020/08/13/2020.08.09.20171132.full.pdf
Finding: Calculation of transmission risk between 1,178 SARS-CoV-2 infected individuals and their 15,648 close contacts based on detailed contact tracing data from Hunan, China. Finding that 80% of secondary transmissions can be traced back to 14% of SARS-CoV-2 infections, indicating substantial transmission heterogeneities. The reconstructed infectiousness profile of a typical SARS-CoV-2 infection peaks just before symptom presentation, with ~50% of transmission occurring in the pre-symptomatic phase.

Du, et al.: “Serial Interval of COVID-19 among Publicly Reported Confirmed Cases”
Emerging infectious Diseases, June 2020
https://wwwnc.cdc.gov/eid/article/26/6/20-0357_article
Finding: 468 transmission events (infector-infectee pairs) were studied. Mean serial interval: 3,96 days. Serial interval was shorter than incubation period, indicating presymptomatic transmission. In addition: In 59 pairs (12.6% of total), serial interval was negative, and infectee developed symptoms before infector (i.e. infectee went through entire incubation period, and developed symptoms, before infector developed symptoms)

Ma, et al., ”Epidemiological parameters of coronavirus disease 2019: a pooled analysis of publicly reported individual data of 1155 cases from seven countries”
LINK to Preprint
Finding: Data from 10,728 reports. 1,155 cases were included, from various countries. The time point of exposure was estimated from 233 pairs of infector-infectee. In 43.78% of infector- infectee pairs, transmission occurred before onset of symptoms in infector. In 3.92% of infector-infectee pairs, infectees’ symptom onset preceded that of infectors’.

Ferretti, et al., “Quantifying SARS-CoV-2 transmission suggests epidemic control with digital contact tracing”
Science, May 8, 2020 https://science.sciencemag.org/content/sci/368/6491/eabb6936.full.pdf
Finding: 40 well-characterized infector-infectee pairs were analyzed. The authors estimated that 46% of transmission was from presymptomatic individuals, 38% was from symptomatic individuals, 10% was from asymptomatic (never symptomatic) individuals, and 6% from environmentally mediated transmission via contamination (the last two routes were speculative). “According to these estimates, presymptomatic transmissions alone are almost sufficient to sustain epidemic growth.”

Nishiura, et al: “Serial interval of novel coronavirus (2019-nCoV) infections” Preprint
https://www.medrxiv.org/content/10.1101/2020.02.03.20019497v2
Finding: 28 infector-infectee pairs. Mean serial interval of 4.0-4.6 days. Serial interval shorter than incubation period, indicating substantial pre-symptomatic transmission. However, serial interval not negative among these pairs.

Zhao, et al.: “Estimating the serial interval of the novel coronavirus disease (COVID-19): A statistical analysis using the public data in Hong Kong from January 16 to February 15, 2020.”
Preprint https://www.medrxiv.org/content/10.1101/2020.02.21.20026559v1
Finding: 21 infector-infectee pairs. Mean serial interval of 4.4 days. Serial interval shorter than incubation period, indicating substantial pre-symptomatic transmission. However, serial interval not negative among these pairs.

Furuse, et al., “Clusters of Coronavirus Disease in Communities, Japan, January–April 2020”
Emerging Infectious diseases, sept 2020 https://wwwnc.cdc.gov/eid/article/26/9/20-2272_article
Finding: 61 case-clusters were identified in Japan, with 22 probable primary case-patients for the clusters. Most were 20–39 years of age and presymptomatic or asymptomatic at virus transmission.

Wei, et al: “Presymptomatic Transmission of SARS-CoV-2 — Singapore, January 23–March 16, 2020”
CDC Morbidity and Mortality Weekly Report (MMWR), April 1, 2020 https://www.cdc.gov/mmwr/volumes/69/wr/mm6914e1.htm
Finding: Investigation of all 243 cases of COVID-19 reported in Singapore during January 23–March 16 identified seven clusters of cases in which pre-symptomatic transmission is the most likely explanation for the occurrence of secondary cases (6.4% of locally acquired cases).

Ganyani, et al: “Estimating the generation interval for COVID-19 based on symptom onset data”
Preprint https://www.medrxiv.org/content/10.1101/2020.03.05.20031815v1
Finding: A modelling study, based on clusters in Singapore and Tianjin, China. The proportion of pre-symptomatic transmission was estimated at 48% for Singapore, and 62% for Tianjin.

Li, et al.: “Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2).”
Science, March 16, 2020 https://science.sciencemag.org/content/early/2020/03/24/science.abb3221
Finding: A study on the fractions of undocumented cases in China, and their contagiousness. The authors estimate that 86% of all infections were undocumented prior to the January 23 travel restrictions. “Per person, the transmission rate of undocumented infections was 55% of documented infections ([46%–62%]), yet, due to their greater numbers, undocumented infections were the infection source for 79% of documented cases.”

Cheng, et al., “High transmissibility of COVID-19 near symptom onset” Preprint https://www.medrxiv.org/content/10.1101/2020.03.18.20034561v1.full.pdf
Finding: Thirty-two confirmed patients were enrolled and 12 paired data (index-secondary cases) were identified among the 1,043 contacts. The secondary clinical attack rate was 0.9%.
The attack rate was higher among those whose exposure to index cases started within five days of symptom onset than those who were exposed later.

Family clusters

Yu, et al.: “A Familial Cluster of Infection Associated With the 2019 Novel Coronavirus Indicating Possible Person-to-Person Transmission During the Incubation Period.”
Journal of Infectious Diseases, Feb 18, 2020 https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiaa077/5739751
Finding: Early report of familial cluster in China, where two people in Shangai were infected by one of two presymptomatic visitors from Shanghai. No other risk factors.

Pan, et al: “Asymptomatic cases in a family cluster with SARS-CoV-2 infection”
Lancet, Feb 19, 2020 https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30114-6/fulltext
Finding: Early report of a family with both symptomatic and asymptomatic infected members.

Huang, et al: “A family cluster of SARS-CoV-2 infection involving 11 patients in Nanjing, China”
Lancet, Feb 28, 2020 https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30147-X/fulltext
Finding: Early report of series of pre-symptomatic transmissions within family cluster in China.

Huang, et al.: “Rapid asymptomatic transmission of COVID-19 during the incubation period demonstrating strong infectivity in a cluster of youngsters aged 16-23 years outside Wuhan and characteristics of young patients with COVID-19: A prospective contact-tracing study.”
Journal of Infection, April 10, 2020 https://www.journalofinfection.com/article/S0163-4453(20)30117-1/fulltext
Finding: Strong infectivity in a cluster of presymptomatic youth in China, outside Wuhan.

Tong, et al.: “Potential Presymptomatic Transmission of SARS-CoV-2, Zhejiang Province, China, 2020”
Emerging Infectious Diseases, May 2020 https://wwwnc.cdc.gov/eid/article/26/5/20-0198_article
Finding: 2-family cluster infected by likely pre-symptomatic patient.

Bai, et al., “Presumed Asymptomatic Carrier Transmission of COVID-19” JAMA, February 21, 2020 https://jamanetwork.com/journals/jama/fullarticle/2762028
Finding: Familiar cluster of five patients, infected by asymptomatic carrier travelling from Wuhan.

Hu, et al., “Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing, China”
Science China. Life Sciences, March 4, 2020 https://link.springer.com/content/pdf/10.1007/s11427-020-1661-4.pdf
Finding: Clinical characteristics of 24 asymptomatic patients, where some transmitted the infection to others.

Qian, et al.: “A COVID-19 Transmission within a family cluster by presymptomatic infectors in China”
Clinical Infectious Diseases, March 23,2020 https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa316/5810900
Finding: Family cluster where 8 out of 9 family members were infected by pre-symptomatic case (and two remained asymptomatic).

Virus isolation – symptomatic and a/pre-symptomatic

Lee, et al.: “Clinical Course and Molecular Viral Shedding Among Asymptomatic and Symptomatic Patients With SARS-CoV-2 Infection in a Community Treatment Center in the Republic of Korea”
JAMA, August 6, 2020
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2769235
Finding: Study of 303 COVID-19 isolated patients in a community treatment center in South Korea. 110 were asymptomatic at the time of isolation, and of these, 21 developed symptoms during the isolation. Viral loads in asymptomatic patients was similar to that in symptomatic patients.
Additional findings: The median interval of time from detection of SARS-CoV-2 to symptom onset in presymptomatic patients was 15 (13-20) days. The median time from diagnosis to the first negative conversion was 17 days for asymptomatic patients and 19.5 days for symptomatic (including presymptomatic) patients (P = .07).

He, et al.: “Temporal dynamics in viral shedding and transmissibility of COVID-19”
Nature Medicine, April 15, 2020 https://www.nature.com/articles/s41591-020-0869-5
Finding: Temporal patterns of viral shedding in 94 laboratory confirmed cases of covid-19, from day of symptom onset up to 32 days after (414 throat swabs in total). Viral shedding was highest on the day of onset and gradually decreased. Separately, the authors collected data on 77 transmission pairs from publicly available sources, and calculated statistically that infectiousness on average starts 2,5 days before onset of symptoms, and peaks 0,6 days before onset of symptoms. The proportion of pre- symptomatic transmission they estimated at 44%.

To, et al.: “Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study”
Lancet, March 23, 2020 https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(20)30196-1.pdf
Finding: 23 symptomatic patients tested with PCR. Viral load was highest during the first week after symptom onset, and then declined with time (in one patient RNA detected 25 days after symptom onset).

Sutton, et al.: “Universal Screening for SARS-CoV-2 in Women Admitted for Delivery” New England Journal of Medicine, April 13, 2020 https://www.nejm.org/doi/full/10.1056/NEJMc2009316
Finding: 215 pregnant women delivered babies at two New York City medical centers between March 22 and April 4, 2020. Of these, 214 were screened for SARS-CoV-2 (nasopharyngeal swabs). Four women (1,9%) had symptoms of Covid-19, and all four were positive for the virus. Of the remaining 210 symptom-free women, 29 (13,7%) were found positive for the virus. Thus, 87,9% of the SARS-CoV-2-positive women were asymptomatic. Of these, three women developed fever before postpartum discharge.

Cereda, et al.: “The early phase of the COVID-19 outbreak in Lombardy, Italy”
Preprint https://arxiv.org/abs/2003.09320
Finding: Analysis of the first 5,830 laboratory-confirmed cases reported in Lombardy, Italy, with date of symptom onset. Equal viral loads were found in nasal swabs from symptomatic and asymptomatic cases.

Lavezzo, et al.: “Suppression of COVID-19 outbreak in the municipality of Vo, Italy”.
Preprint https://www.medrxiv.org/content/10.1101/2020.04.17.20053157v1
Finding: Two surveys (nasopharyngeal swabs) of most of the population of the municipality of Vo, in Italy. Of those who tested positive (2.6% and 1.2%, respectively, of the tested population), 43.2% were found to be asymptomatic. Viral load was equal in symptomatic and asymptomatic cases. Most new infections in the second survey were infected in the community before the lockdown or from asymptomatic infections living in the same household.

Kimball, et al.: “Asymptomatic and Presymptomatic SARS-CoV-2 Infections in Residents of a Long-Term Care Skilled Nursing Facility — King County, Washington, March 2020.” CDC Morbidity and Mortality Weekly Report (MMWR), April 3, 2020 https://www.cdc.gov/mmwr/volumes/69/wr/mm6913e1.htm
Finding: Report on rapid spread in a long-term care nursing facility. Testing of 76 of 82 residents found that 30.3% shed virus, but only half of those infected had symptoms.

Baggett, et al.: “COVID-19 outbreak at a large homeless shelter in Boston: Implications for universal testing”
Preprint https://www.medrxiv.org/content/10.1101/2020.04.12.20059618v1.full.pdf+html
Finding: Of 408 participants in a homeless shelter in Boston, 147 (36.0%) were PCR- positive for SARS-CoV-2. Around 80% were asymptomatic.

Liu et al., “Viral dynamics in mild and severe cases of COVID-19”
Lancet, March 19, 2020 https://www.thelancet.com/action/showPdf?pii=S1473-3099%2820%2930232-2
Finding: 76 patients with COVID-19 were admitted to a hospital in Nanchang, China, and tested for viral loads with nasopharyngeal swabs. “The mean viral load of severe cases was around 60 times higher than that of mild cases, suggesting that higher viral loads might be associated with severe clinical outcomes.”

Arons, et al.: “Presymptomatic SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility”
New England Journal of Medicine, April 24, 2020 https://www.nejm.org/doi/full/10.1056/NEJMoa2008457
Finding: A follow-up study in a nursing facility. Twenty-three days after the first positive test result, 57 of 89 residents (67%) tested positive for SARS-CoV-2 (nasopharyngeal and oropharyngeal swabs). Of these, 27 (56%) were asymptomatic at time of testing, but 24 of them subsequently developed symptoms (median time to onset, 4 days). Viral loads were similarly high in the four symptom groups (residents with typical symptoms, those with atypical symptoms, those who were presymptomatic, and those who remained asymptomatic). It is notable that 17 of 24 specimens (71%) from presymptomatic persons had viable virus by culture 1 to 6 days before the development of symptoms.

Gandhi, et al.: “Asymptomatic Transmission, the Achilles’ Heel of Current Strategies to Control Covid-19”
New England Journal of Medicine, April 24, 2020 https://www.nejm.org/doi/full/10.1056/NEJMe2009758 Editorial.

Zou, et al: “SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients” New England Journal of Medicine, Feb 19,2020 https://www.nejm.org/doi/full/10.1056/NEJMc2001737
Finding: Analysis of viral load in nasal and throat swabs from 17 patients, taken daily. Viral load similar in asymptomatic and symptomatic patients. In symptomatic patients, viral load highest at time of symptom onset.

Nishiura, et al: “Estimation of the asymptomatic ratio of novel coronavirus infections (COVID-19)”
International Journal of Infectious Diseases (preproof) https://www.ijidonline.com/article/S1201-9712(20)30139-9/pdf
Finding: Among Japanese citizens evacuated from Wuhan by February 6, the asymptomatic ratio was estimated at 30.8%.

Comprehensive testing on Iceland (news report): https://edition.cnn.com/2020/04/01/europe/iceland-testing-coronavirus-intl/index.html Finding: On Iceland, 17,900 people have been broadly tested, in two studies. A study of 9,000 people who volunteered to be tested (deCode) found that 1% were shedding virus. Only 50% of them were symptomatic. The other study, based in the National University Hospital, tests cases and their contacts. In that study, about 80% of infected people show symptoms.

Gudbjartsson, et al.: “Spread of SARS-CoV-2 in the Icelandic Population” New England Journal of Medicine, April 14, 2020 https://www.nejm.org/doi/full/10.1056/NEJMoa2006100
Finding: 6% of the population of Iceland was screened (nasopharyngeal and oropharyngeal samples). Of those tested in the general population, 0.8% tested positive for the virus. Of those, 43% were asymptomatic. Children under 10 years of age and females had a lower incidence of SARS-CoV-2 infection than adolescents or adults and males.

Statista, State of Health: “Age distribution of coronavirus (COVID-19) cases in South Korea as of April 3, 2020” (daily update)
https://www.statista.com/statistics/1102730/south-korea-coronavirus-cases-by-age/
Finding: In South Korea, where there is broad testing, the highest proportion of positive cases is found in the age group 20-29 years (27,17%). From this data, it appears that the ratio of asymptomatic cases is dramatically higher in young adults.

Mizumoto, et al., “Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020”
Eurosurveillance, March 2020 https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.10.2000180
Finding: Estimation of true asymptomatics on cruise ship Diamond Princess. The authors arrive at the figure 17.9%. The majority of passengers were in their 60s and 70s.

Moriarty, et al.: “Public Health Responses to COVID-19 Outbreaks on Cruise Ships — Worldwide, February–March 2020”
CDC Morbidity and Mortality Weekly Report (MMWR), March 27, 2020 https://www.cdc.gov/mmwr/volumes/69/wr/mm6912e3.htm
Finding: Among 3,711 Diamond Princess passengers and crew, 712 (19.2%) had positive test results for SARS-CoV-2. Of these, 331 (46.5%) were asymptomatic at the time of testing.
Among 381 symptomatic patients, 37 (9.7%) required intensive care, and nine (1.3%) died.

Koh, et al., “What do we know about SARS-CoV-2 transmission? A systematic review and meta-analysis of the secondary attack rate, serial interval, and asymptomatic infection”
Preprint https://www.medrxiv.org/content/10.1101/2020.05.21.20108746v1.full.pdf
Metaanalysis
Finding: “Based our pooled estimates, 10 infected symptomatic persons living with 100 contacts would result in 15 additional cases in less than 5 days. To be effective, quarantine of contacts should occur within 3 days of symptom onset. If testing and tracing relies on symptoms, one-quarter of cases would be missed.”

Han, et al.: “The transmission and diagnosis of 2019 novel coronavirus infection disease
(COVID‐19): A Chinese perspective”
J. Med. Virol. March 6, 2020 https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.25749 Review.

Aguirre-Duarte: “Can people with asymptomatic or pre-symptomatic COVID-19 infect others: a systematic review of primary data”
Preprint https://www.medrxiv.org/content/10.1101/2020.04.08.20054023v2.full.pdf+html Review.

Oran, et al.: “Getting a handle on asymptomatic SARS-CoV-2 infection”
Scripps Research, April 20, 2020
https://www.scripps.edu/science-and-medicine/translational-institute/about/news/sarc-cov-2- infection/index.html
Review.

Oran et al., “Prevalence of Asymptomatic SARS-CoV-2 Infection” Annals of Internal Medicine, June 3, 2020 https://www.acpjournals.org/doi/full/10.7326/M20-3012
Review.

Apuzzo, et al., “How the World missed Covid-19s Silent Spread”
New York Times https://www.nytimes.com/2020/06/27/world/europe/coronavirus-spread- asymptomatic.html?smid=em-share
Review of initial public health reactions.

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Vetenskapsforum covid-19

Vetenskapsforum Covid-19 arbetar brett med information och upplysning om den pågående pandemin och till den relaterade ämnen och områden. Våra mål är att minska sjuklighet och dödlighet i Covid-19, att minska de kroniska sjukdomstillstånden hos dem som överlever Covid-19. I föreningen har vi kompetens inom bland annat virologi, biologi, molekylärbiologi, epidemiologi, infektionssjukdomar, lungsjukdomar, matematik, statsvetenskap, psykologi, etik och riskforskning. Ordförande i föreningen är Professor Emeritus Anders Vahlne, mer information på https://vetcov19.se/

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