New study from Penn State estimates that initial COVID-19 infection rate have been more than 80 times greater

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Many epidemiologists believe that the initial COVID-19 infection rate was undercounted due to testing issues, asymptomatic and alternatively symptomatic individuals, and a failure to identify early cases.

Now, a new study from Penn State estimates that the number of early COVID-19 cases in the U.S. may have been more than 80 times greater and doubled nearly twice as fast as originally believed.

In a paper published today (June 22) in the journal Science Translational Medicine, researchers estimated the detection rate of symptomatic COVID-19 cases using the Centers for Disease Control and Prevention’s influenza-like illnesses (ILI) surveillance data over a three week period in March 2020.

“We analyzed each state’s ILI cases to estimate the number that could not be attributed to influenza and were in excess of seasonal baseline levels,” said Justin Silverman, assistant professor in Penn State’s College of Information Sciences and Technology and Department of Medicine. “When you subtract these out, you’re left with what we’re calling excess ILI—cases that can’t be explained by either influenza or the typical seasonal variation of respiratory pathogens.”

The researchers found that the excess ILI showed a nearly perfect correlation with the spread of COVID-19 around the country.

Said Silverman, “This suggests that ILI data is capturing COVID cases, and there appears to be a much greater undiagnosed population than originally thought.”

Remarkably, the size of the observed surge of excess ILI corresponds to more than 8.7 million new cases during the last three weeks of March, compared to the roughly 100,000 cases that were officially reported during the same time period.

“At first I couldn’t believe our estimates were correct,” said Silverman. “But we realized that deaths across the U.S. had been doubling every three days and that our estimate of the infection rate was consistent with three-day doubling since the first observed case was reported in Washington state on January 15.”

The researchers also used this process to estimate infection rates for each state, noting that states showing higher per capita rates of infection also had higher per capita rates of a surge in excess ILI. Their estimates showed rates much higher than initially reported but closer to those found once states began completing antibody testing.

In New York, for example, the researchers’ model suggested that at least 9% of the state’s entire population was infected by the end of March. After the state conducted antibody testing on 3,000 residents, they found a 13.9% infection rate, or 2.7 million New Yorkers.

Excess ILI appears to have peaked in mid-March as, the researchers suggest, fewer patients with mild symptoms sought care and states implemented interventions which led to lower transmission rates. Nearly half of U.S. states were under stay-at-home orders by March 28.

The findings suggest an alternative way of thinking about the COVID-19 pandemic.

“Our results suggest that the overwhelming effects of COVID-19 may have less to do with the virus’ lethality and more to do with how quickly it was able to spread through communities initially,” Silverman explained.

“A lower fatality rate coupled with a higher prevalence of disease and rapid growth of regional epidemics provides an alternative explanation of the large number of deaths and overcrowding of hospitals we have seen in certain areas of the world.”


What is the proportion of people with  SARS-COV-2 who are asymptomatic?

To answer this we searched LitCovid (a subset of Pubmed), medRxiv, Trip, Scholar and Google. We retrieved 21 reports for analysis.

What did we learn (see the table for the analysis)

  • That between 5% and 80% of people testing positive for SARS-CoV-2 may be asymptomatic
  • That symptom-based screening will miss cases, perhaps a lot of them
  • That some  asymptomatic cases  will  become  symptomatic over the next week (sometimes known as “pre-symptomatics”)
  • That children and young adults can be asymptomatic

We also learnt that there  is not a single reliable study to determine the number of  asymptotics. It is likely we will only learn the true extent once population based antibody testing  is undertaken.

Table of studies assessing asymptomatic cases

SettingProportionComment
Diamond Princess cruise ship, Yokohama, Japan  (n=-634 tested positive). [1]18%(95% credible interval  16%-20%).Most infections occurred before the quarantine start.
Vo’Euganeo, 50 km west of Venice, Italian village  [2]50% to 75%—were asymptomaticIn an open letter to the authorities in the Tuscany region
MERS-CoV [3]Increased from 0% to 29%  over timeAs the MERS-CoV progressed over time there was more identification of asymptomatic individuals due to increased surveillance and contacts testing.
328 adults in Shanghai [4]13 (4%)  patients were asymptomatic
Japanese nationals evacuated from Wuhan (n=565) [5]31% (95% CI: 7.7% to 54%)Based on  temperature screening before disembarkation, interviews on symptoms including fever, cough, and non-specific symptoms
23 Residents of a Long-Term Care Nursing Facility King County, Washington[6]10 (43%) had symptoms, and 13 (57%) were asymptomatic.Seven days after testing, 10 of 13 asymptomatics developed symptomsSymptom-based screening could fail to identify approximately half of nursing home residents with COVID-19.
Airport screening of travellers [7]17% undetectable by typical screening proceduresBased on: A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: Lancet. 2020;0(0):S0140-6736(20)30154-9. 
Hospitalised in Beijing, China (n=262)[8]13 (5.0%) asymptomatic cases
391 cases including 148 family index cases in Zhejiang Province  [9]54 (14%)  asymptomatichigher  family  secondary attack rate, the secondary attack rate of spouses is higher than other family members.
Chinese perspective [10]Over the past few days, asymptomatic patients were found in many Chinese cities.Whether asymptomatic people can transmit SARS‐CoV‐2 to others is unclear.Another uncertainty is whether those who are asymptomatic can cause large‐scale infections.
36 children, Zhejiang, China [11]Asymptomatics, 10 (28%)7 had acute upper respiratory symptoms (19%)
Data-based analysis, modelling and forecasting of the COVID-19 outbreak  [12]The number of asymptomatic and mild cases with subclinical manifestations that probably did not present to hospitals for treatment may be substantial; these cases, which possibly represent the bulk of the COVID-19 infections, remain unrecognized,
166 new infections in China  [13]four-fifths of cases are asymptomatic, China figures indicate Numbers quoted  not verifiable
Nanjing, China  (n=24) [14]5 (21%) developed symptoms (fever, cough, fatigue and etc.) during hospitalization.
450 case reports from 93 Chinese cities. [15]estimate that people who had not yet developed symptoms transmitted around 10% of the cases they studied.
 People’s Hospital of Daofu county. Tibetan population (n=83) [16]Asymptomatic carriers 22%median age of asymptomatic carriers was 31 years and 1/3rd  were students, aged <20 years.
WHO Q&A: Similarities and differences – COVID-19 and influenza [17]suggest that 80% of infections are mild or asymptomatic,
Iceland   [18]50% of the people who tested positive had no symptoms.”See also: First results of the voluntary screening in Iceland[19]
CDC [20]A significant number of individuals that are infected actually remain asymptomatic. That may be as many as 25%.
Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease [21]Among children in China, illness severity was lower with 94% having asymptomatic, mild or moderate disease,
Northern Italy, 60 volunteer blood donors [22]40 (67%)  tested positive

Sir Basil’s “fog” is continuing to cover the topic and prevent us from seeing what lies on the other side of the hill.

References

  1. Mizumoto K, Kagaya K, Zarebski A, et al. Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020. Euro Surveill 2020;25.
    doi:10.2807/1560-7917.ES.2020.25.10.2000180
  2. Day M. Covid-19: identifying and isolating asymptomatic people helped eliminate virus in Italian village. BMJ 2020;368:m1165.
  3.  Al-Tawfiq JA. Asymptomatic coronavirus infection: MERS-CoV and SARS-CoV-2 (COVID-19). Travel Med Infect Dis 2020;:101608.
  4.  Zhou X, Li Y, Li T, et al. Follow-up of the asymptomatic patients with SARS-CoV-2 infection. Clin Microbiol Infect Published Online First: 28 March 2020.
    doi:10.1016/j.cmi.2020.03.024
  5.   Nishiura H, Kobayashi T, Suzuki A, et al. Estimation of the asymptomatic ratio of novel coronavirus infections (COVID-19). Int J Infect Dis Published Online First: 13 March 2020. doi:10.1016/j.ijid.2020.03.020
  6.   Kimball A, Hatfield KM, Arons M, et al. Asymptomatic and Presymptomatic SARS-CoV-2 Infections in Residents of a Long-Term Care Skilled Nursing Facility – King County, Washington, March 2020. MMWR Morb Mortal Wkly Rep 2020;69:377–81.
  7.    Quilty BJ, Clifford S, Flasche S, et al. Effectiveness of airport screening at detecting travellers infected with novel coronavirus (2019-nCoV). Eurosurveillance. 2020;25.
    doi:10.2807/1560-7917.es.2020.25.5.2000080
  8.  Tian S, Hu N, Lou J, et al. Characteristics of COVID-19 infection in Beijing. J Infect 2020;80:401–6.
  9.    Sun WW, Ling F, Pan JR, et al. [Epidemiological characteristics of 2019 novel coronavirus family clustering in Zhejiang Province]. Zhonghua Yu Fang Yi Xue Za Zhi 2020;54:E027.
  10.     Han Y, Yang H. The transmission and diagnosis of 2019 novel coronavirus infection disease (COVID-19): A Chinese perspective. J Med Virol Published Online First: 6 March 2020. doi:10.1002/jmv.25749
  11.    Qiu H, Wu J, Hong L, et al. Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study. Lancet Infect Dis Published Online First: 25 March 2020.
    doi:10.1016/S1473-3099(20)30198-5
  12.    Anastassopoulou C, Russo L, Tsakris A, et al. Data-based analysis, modelling and forecasting of the COVID-19 outbreak. PLoS One 2020;15:e0230405.
  13.    Day M. Covid-19: four fifths of cases are asymptomatic, China figures indicate. BMJ 2020;369:m1375.
  14.     Hu Z, Song C, Xu C, et al. Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing, China. Science China Life Sciences. 2020. doi:10.1007/s11427-020-1661-4
  15.     Newman T. COVID-19: Study estimates rate of ‘silent transmission’. Medical News Today. 2020.https://www.medicalnewstoday.com/articles/covid-19-study-estimates-rate-of-silent-transmission (accessed 5 Apr 2020).
  16.     Song H, Xiao J, Qiu J, et al. A considerable proportion of individuals with asymptomatic SARS-CoV-2 infection in Tibetan population.
    doi:10.1101/2020.03.27.20043836
  17.   Q&A: Similarities and differences – COVID-19 and influenza. https://www.who.int/news-room/q-a-detail/q-a-similarities-and-differences-covid-19-and-influenza (accessed 5 Apr 2020).
  18.    Renwick D. Have I already had coronavirus? How would I know and what should I do? the Guardian. 2020.http://www.theguardian.com/us-news/2020/apr/05/have-i-already-had-coronavirus-how-would-i-know (accessed 5 Apr 2020).
  19.    Otmani M. COVID-19: First results of the voluntary screening in Iceland – Nordic Life Science – the leading Nordic life science news service. Nordic Life Science – the leading Nordic life science news service. 2020.https://nordiclifescience.org/covid-19-first-results-of-the-voluntary-screening-in-iceland/ (accessed 5 Apr 2020)
  20.      NPR Choice page. https://www.npr.org/sections/health-shots/2020/03/31/824155179/cdc-director-on-models-for-the-months-to-come-this-virus-is-going-to-be-with-us?t=1586065796492 (accessed 5 Apr 2020).
  21.     CDC. Coronavirus Disease 2019 (COVID-19). Centers for Disease Control and Prevention. 2020.https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html#Asymptomatic (accessed 5 Apr 2020).
  22.    Coronavirus, Castiglione d’Adda è un caso di studio: ‘Il 70% dei donatori di sangue è positivo’. lastampa.it. 2020.https://www.lastampa.it/topnews/primo-piano/2020/04/02/news/coronavirus-castiglione-d-adda-e-un-caso-di-studio-il-70-dei-donatori-di-sangue-e-positivo-1.38666481 (accessed 5 Apr 2020).


More information: Justin D. Silverman et al, Using influenza surveillance networks to estimate state-specific prevalence of SARS-CoV-2 in the United States, 22 June 2020, Science Translational MedicineDOI: 10.1126/scitranslmed.abc1126 , stm.sciencemag.org/content/ear … scitranslmed.abc1126

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