Early Epidemiological and Clinical Manifestations of COVID-19 in Japan

medRxiv preprint doi: https://doi.org/10.1101/2020.04.17.20070276; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

Early epidemiological and clinical manifestations of COVID-19 in Japan

Running Title: Data analysis of COVID-19 in Japan

Muhammad Qasim*1, Muhammad Yasir2, Waqas Ahmad2, Minami Yoshida1, Muhammad

Azhar3, Mohammad Azam Ali1, Chris Wang4, Maree Gould1.

1. Centre for Bioengineering & Nanomedicine (Dunedin), Department of Food Science, Division

of Sciences. University Of Otago, Dunedin, PO Box 56, Dunedin 9054, New Zealand.

2. Department of Computer Science, University Of Otago, Dunedin, PO Box 56, Dunedin 9054,

New Zealand.

3. Department of Education, Islamic International University Islamabad, 46000, Pakistan

4. Otago Medical School, Sayers Building, 290 Great King Street, Dunedin 9016,New Zealand

*Corresponding author

Muhammad Qasim

Centre for Bioengineering & Nanomedicine (Dunedin), Department of Food Science, Division

of Sciences. University Of Otago, Dunedin, PO Box 56, Dunedin 9054, New Zealand

E.mail: [email protected], [email protected]

Phone No: +64 3 479 7562 M:0064-225318660

NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.04.17.20070276; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

Abstract:

Background: Severe acute respiratory syndrome coronaviruses -2 (SARS-COV2) named as

COVID-19 had spread worldwide and leading to 1,210,956 confirmed cases and 67,594 deaths

Methods: A data of 1192 confirmed cases and 43 deaths due to COVID-19 in Japan collected

from the Ministry of Health, Labour and Welfare of Japan and analysed for different

epidemiological parameters and their clinical manifestations. We used Clauset-Newman-

Moore (CNM) clustering algorithm to develop web-network of confirmed cases to identified

clusters of community transmission.

Results: Out of 1192 confirmed cases, 90.60% were symptomatic and 9.39% were

asymptomatic. The prevalence of COVID19 in males was 56.29% and 43.20 % in females. The

mean interval (±SD) from symptom onset to diagnosis was 6±22.6 days while mean interval

(±SD) from contact to onset of symptoms was 5±19.5 days. People of age range 40-79 were

more infected and deaths median age was 80. The main symptoms were fever, dry cough, fatigue

and pneumonia. The main infected cities were Tokyo (195/1192, 16.35%), Hokkaido (160/1192

13.42%), Aichi (150/1192, 12.58%) and Osaka (145/1192, 12.16%). Only 2.34% cases had

travel history from Wuhan China and Osaka music concert was identify as main cluster for

community transmission. While 556 (46.64%) cases were clinically diagnosed and 557

(46.72%) were confirmed by using RT-PCR.

Conclusions: Other than, declare emergency Japan need to change their approach of

diagnosing COVID-19, as asymptomatic cases prevalence is high and maybe it is reason for

current sudden increase of cases. Screening centre should be establish away from hospitals,

which are treating positive cases.

Keywords: Osaka Music Concert, COVID-19, Japan, Clinical Symptoms, Epidemiology of

COVID-19 medRxiv preprint doi: https://doi.org/10.1101/2020.04.17.20070276; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

Introduction:

As the COVID-19 pandemic insidiously infiltrates and the numbers of infected people and

deaths skyrocket in various locations around the world, an ongoing puzzle has been the

comparatively slow rise of those numbers in Japan.1 But since last week, the numbers in Japan

have begun to climb in a concerning way.2 Until April 7, 2020, there were 3,654 confirmed

cases with 73 deaths reported. These cases exist other than the 712 laboratory-confirmed cases

on the Diamond Princess cruise ship.2,3 On the other hand according to WHO the worldwide

cases of COVID-19 reached to 1,051,635 with 56,985 deaths.2 1st case of COVID-19 reported

in Japan on 15th January, 2020 and he was returned from Wuhan, China the mainland from

where disease started.4 On February 1, a passenger who disembarked from the Diamond

Princess days earlier in Hong Kong tested positive for the COVID-19 coronavirus.3 The ship

was quarantined immediately after it arrived in Japanese waters on February 3 with 3,711

passengers and crew members on board.5 Over the next month, more than 700 people on board

became infected including a nurse and for several weeks, the ship remained the site of the

largest outbreak outside of China.6 The outbreak of this disease has caused the Japanese

government to take drastic measures to contain the outbreak, including the quarantine of

millions of residents in Hokkaido, the Diamond Princess cruise ship and other affected cities.

By March 24, 2020, there were 1192 confirmed cases of COVID-19 in Japan. In this study,

we analysed the early epidemiological dynamics and clinical manifestations of these confirmed

1192 cases to understand the characteristics of COVID19 pandemic in Japan.4

The epidemiological analysis of the COVID19 pandemic provides a unique opportunity to

characterize its transmission, source of community spread and the effectiveness of screening

processes.7 While clinical manifestation of COVID19 cases will help clinicians to understand

the dynamics of COVID-19 and help them to diagnose asymptomatic cases. The careful

monitoring of cases and demographic data from the general community enables inferences that medRxiv preprint doi: https://doi.org/10.1101/2020.04.17.20070276; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

are critical to modelling the course of the outbreak, that are difficult to make during a widely

disseminated epidemic.8,9 We highlighted the critical transmission parameters, such as; contact

of people with an infected person, places that they visited before infected, demographic data

and prevalence of symptoms. This study will help future monitoring of COVID-19 in

particularly in Japan and generally worldwide to guide respective measures to contain its

spread.

Methods

Data of total 1192 confirmed and 43 deaths has been collected from 15th January to the 24th

March 2020 from daily reports published by the Ministry of Health, Labour and Welfare of

Japan.4 We analysed the data for demographic distribution of cases and epidemiological

parameters such as clusters based upon hospitalisation, travel and contact with positive case

history of confirmed cases. We also analysed the clinical manifestation of confirmed cases such

symptoms, mean intervals time from onset of symptoms until confirmation of COVID19

presence and mean intervals from patients first contact with positive case to onset of symptoms.

In order to understand the community transmission pattern and identify the hotspot for spread

of COVID-19 cases in Japan. We ran a Clauset-Newman-Moore (CNM) clustering algorithm10.

The Clauset-Newman-Moore algorithm forms a cluster on the basis of modularity, that is a

degree of graphing network which divides the network into groups in such a way that there are

many edges within the groups but few between the groups, thus identifying modular clusters.

This clustering helped us to find the web of community transmission and highlight the main

nodes points. We also analysed the hospitalisation history of confirmed cases to find any

possible link of community spread of COVID-19 with health centres. As Japan, did not observed

the complete lock down so we analysed the reason for rapid increase of cases in Japan in first

week of April 2020 by looking into contact history of new cases with previously positive or medRxiv preprint doi: https://doi.org/10.1101/2020.04.17.20070276; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

asymptomatic cases.11 We also analysed the number confirmed cases, clinically diagnosed,

laboratory confirmed or diagnosed based on CT scan and X ray.

Results

The data analysis of total 1192 cases showed that 1080 (90.60%) cases were symptomatic and

112 (9.39%) were asymptomatic as shown in Table 1. Out of 1192 confirmed cases, 671

(56.29%) were male and 515 (43.20%) were female and rest status was unknown. While out

112 asymptomatic cases 105 (93.75%) were within country while 7 (6.25%) were in government

charted flight came from Japan. While only 28 (2.34%) cases had travel history from Wuhan,

China and only 21 (1.80%) cases were linked with Diamond Princess Cruise ship.12 The mean

interval (±SD) from symptom onset to diagnosis was 6±22.6 days while mean interval (±SD)

from first contact with positive case to onset of symptoms was 5±19.5 days. (Table 2)

It has found that the highest number of patients infected with COVID-19 in Japan have ages

ranging between 40-79, as shown in Figure 1. While 69.76% (30/43) of death were male and

majority of deaths age range (70-90) (Figure 1). Young people with ages ranging from 20-40

are the least effected. In plotting the symptoms of COVID19 symptomatic (1080) infected

patients, the results showed that fever (857/1080, 79.35%), cough (459/1080, 42.50%) and

fatigue (316/1080, 29.25%) were the main symptoms found in patients, as shown in Figure. 2.

While only 240/1080 (22.22%) patients showed pneumonia symptoms while 223/1080

(20.64%) showed respiratory or shortness of breath, as shown in Figure.2.

The prevalence of COVID-19 in Japan until March 24, 2020 showed that; Tokyo (195/1192,

16.35%), Hokkaido (160/1192 13.42%), Aichi (150/1192, 12.58%), Osaka (145/1192, 12.16%)

and Hyogo (114/1192, 9.56%) were top five most affected areas, as shown on map Figure 3.

The information about infected people’s occupations was available for only 87/1192 (7.26%)

cases and it was discovered that 29/87 (33.33%) were doctors, paramedical staff and hospital medRxiv preprint doi: https://doi.org/10.1101/2020.04.17.20070276; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

workers as shown in Figure 4. An interesting fact observed in the case of Hokkaido City

Hospital was about 50% of the casualties (i.e. a total of 3) occurred in the same hospital.

Similarly, 50% of nurses (i.e. 3) were also treated in the same hospital and this hospital treated

the highest number of infectious patients in Japan. So most probably, this hospital was also a

source of transmitting the infection, as maybe those people who visited this hospital also

became infected. Overall, the history of the patients showed that 90% of the infected patients

had a previous hospitalisation history, as shown in Figure 4. Similarly, 60% of cases with a

previous hospitalisation history had contact with COVID-19 positive cases. While monthly

data showed that patients with a hospital visit history were fewer in start but then increased

gradually, similarly COVID-19 confirmed cases with a history of patient contact showed a

positive trend that increased each day that passed, which confirmed the community

transmission of the virus.

We used the Clauset-Newman-Moore algorithm to find clusters and interlink the patients to

find the centres of the community transmission (Figures 5 and 6). We have found that a patient

A-34 from Aichi (age 60-69) with a travel history from Hawaii (USA), and patient A-347 from

Aichi (age 80-89) had contact history with patient A-229 from the same city and patient A-391

from Hyogo greatly increased the spread of infection within the community. It was also found

that a live music concert was the main point of community spread of COVID-19 in Osaka, as

shown in Figure 6. Many people think that spread of infection was due to a Chinese tourist

that came onto the cruise ship but our findings show that this was not the case.12

The screening methodology of Japan indicated that they have a lower number of tests to

confirm their patients diagnoses and instead rely upon a clinical diagnosis. As data showed that

out of the 1192 patients, 556 (46.64%) cases were clinically diagnosed while almost same

number of patients were confirmed using RT-PCR testing (46.72%) Figure 7. While the

remaining cases were confirmed based upon X-ray or CT Scan. As clinically, it is hard for medRxiv preprint doi: https://doi.org/10.1101/2020.04.17.20070276; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

doctors to diagnose COVID-19 in asymptomatic patients, therefore there are chances many

positive COVID-19 cases lost.

Discussion:

Our study results showed that the main characteristic of COVID-19 in positive patients in Japan

were fever, fatigue and cough. While the main burden of COVID-19 cases were prevalent in

the cities of Tokyo, Hakkadio, Aichi and OSKA. While data analysis showed that, the hospital

was the prime suspect for community transmission of COVID 19. While the Clauset-Newman-

Moore algorithm analysis showed that most of the reported cases have contact with positive

cases within the country and a music concert in Osaka has played a major role for the

community spread of COVID 19. Japan has an excellent public health care system.13 Care is

affordable, so most people see a physician when they are beginning to feel ill, rather than when

the conditions have worsened. So far, the low number of cases until the end of March can be

directly related to the low number of test performed by Japan as they rely more on clinical

diagnosis, X-ray and CT scan reports.14 As our this study showed that mean interval time for

onset of symptoms is 5 days and in other reported studies it is 14-21 days for COVID-19 so

there are many chances that many asymptomatic cases were missed and lost in community.15

While mean interval time from onset of symptoms to diagnostics in case of Japan was found

6±22.6 days while in case of Korea it was 4.3±4.1 days.16 The current sudden rise in COVID

19 cases in Japan now can be link to this fact.

With relation to CT scanners, Japan may have the best diagnostic imaging devices in the world,

as the number per 100,000 people is 101 and their rely more on these second line diagnostics

can pose a threat to their health system or methodology to handle COVID-19

cases.17 Therefore, one key reason for the low number of infections recorded, is that Japan has

imposed strict criteria to be eligible for testing, focusing on giving tests only to people who

have sustained fevers for more than four days, combined with overseas travel, close contact medRxiv preprint doi: https://doi.org/10.1101/2020.04.17.20070276; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

with an infected person or lung symptoms severe enough to warrant hospitalization. The goal

of this approach has not been to identify all the infected people, but rather to focus resources

on those most in need of treatment but it seems recent sudden rise in cases showed, this

approach is not working effectively.

While our CNM) clustering algorithm web graph (Figure 5 and 6) showed that , lack of strict

measure to hold big community gathering dent the Japan measures to mitigate the COVID-19

spread, as most of community transmission cases linked with music concert in Oska.

Furthermore our analysis showed that there almost 10% cases were asymptomatic (Table 1) so

if we model this number its projection shows an alarming picture for Japan.18 Now, Japan has

imposed the state emergency imposed in the capital, Tokyo, and six other prefectures accounting

for about 44% of Japan’s population from April 7 2020 until 6 May 2020 to press the public to

stay home as compared to previous approach to trust on public obedience.19 But our study

suggest they also need to revise their approach for diagnosis of COVID-19 and increase their

laboratory based testing for screening of people at large scale. Second, they need to protect their

health care workers and keep public away from hospital until they really need it. For screening

of public sample collections centre must be set away from hospitals where positive cases are

under treatments.

Conclusion:

Out study showed that people of age above 40 have more risk to be infected and prevalence of

COVID-19 in male of Japan is higher than female. While COVID-19 spread more by cases

infected with in the country through community transmission as compared to foreign visitors.

Second asymptomatic patients rate is almost 10%, which is hard to diagnose them only on medRxiv preprint doi: https://doi.org/10.1101/2020.04.17.20070276; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

clinical bases so laboratory based screening of people at large scale has recommended to contain

and reduce the currents sudden rise of cases. 20

Conflict of Interests: Authors have no conflict of interest

Authors Contribution: Muhammad Qasim: Conceptualization, Methodology, Formal analysis, Investigation Supervision, Writing - original draft. Muhammad Yasir: Formal analysis, Investigation. Waqas Ahmad: Methodology, Investigation. Minami Yoshida: Data collection. Muhammad Azhar: Methodology, Formal analysis. Muhammad Azam Ali: Supervision, Chris Wang: Data collection, Maree Gould, Writing - original draft and review.

Ethical Approval: Study does not involve any direct experiments with human or animal

References

1. Cheng ZJ, Shan J. 2019 Novel coronavirus: where we are and what we know.

Infection. February 2020:1-9. doi:10.1007/s15010-020-01401-y

2. Situation reports. https://www.who.int/emergencies/diseases/novel-coronavirus-

2019/situation-reports/. Accessed April 6, 2020.

3. Zhang S, Diao M, Yu W, Pei L, Lin Z, Chen D. Estimation of the reproductive number

of Novel Coronavirus (COVID-19) and the probable outbreak size on the diamond

princess cruise ship: A data driven analysis. Int J Infect Dis. 2020.

doi:10.1016/j.ijid.2020.02.033

4. Ministry of Health, Labour and Welfare. https://www.mhlw.go.jp/index.html.

Accessed March 18, 2020.

5. Fang Z, Huang Z, Li X, et al. How many infections of COVID-19 there will be in the

“Diamond Princess”- Predicted by a virus transmission model based on the simulation

of crowd flow. arXiv:200210616. 2020.

6. Russell TW, Hellewell J, Jarvis CI, et al. Estimating the infection and case fatality medRxiv preprint doi: https://doi.org/10.1101/2020.04.17.20070276; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

ratio for COVID-19 using age-adjusted data from the outbreak on the Diamond

Princess cruise ship. medRxiv. 2020;2019(March):2020.03.05.20031773.

doi:10.1101/2020.03.05.20031773

7. Qasim M, Ahmad W, Yoshida M, Gould M, Yasir M. Analysis of the Worldwide

Corona Virus (COVID-19) Pandemic Trend;A Modelling Study to Predict Its Spread.

medRxiv. April 2020:2020.03.30.20048215. doi:10.1101/2020.03.30.20048215

8. Lin Q, Zhao S, Gao D, et al. A conceptual model for the coronavirus disease 2019

(COVID-19) outbreak in Wuhan, China with individual reaction and governmental

action. Int J Infect Dis. 2020;93:211-216. doi:10.1016/j.ijid.2020.02.058

9. Cori A, Donnelly CA, Dorigatti I, et al. Key data for outbreak evaluation: Building on

the ebola experience. Philos Trans R Soc B Biol Sci. 2017;372(1721).

doi:10.1098/rstb.2016.0371

10. Clauset A, Newman MEJ, Moore C. Finding community structure in very large

networks. Phys Rev E - Stat Physics, Plasmas, Fluids, Relat Interdiscip Top.

2004;70(6):6. doi:10.1103/PhysRevE.70.066111

11. Chan CM, Tse H, Wong SSY, et al. Examination of seroprevalence of coronavirus

HKU1 infection with S protein-based ELISA and neutralization assay against viral

spike pseudotyped virus. J Clin Virol. 2009;45(1):54-60.

doi:10.1016/j.jcv.2009.02.011

12. Sawano T, Ozaki A, Rodriguez-Morales AJ, Tanimoto T, Sah R. Limiting spread of

COVID-19 from cruise ships - lessons to be learnt from Japan. QJM An Int J Med.

2020:19-21. doi:10.1093/qjmed/hcaa092

13. Homepage -Global health Security GHS Index. https://www.ghsindex.org/. Accessed

March 19, 2020. medRxiv preprint doi: https://doi.org/10.1101/2020.04.17.20070276; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

14. Japan’s relatively small coronavirus case count may be a mirage - Vox.

https://www.vox.com/covid-19-coronavirus-explainers/2020/3/28/21196382/japan-

coronavirus-cases-covid-19-deaths-quarantine. Accessed April 8, 2020.

15. Amanat F, Nguyen T, Chromikova V, et al. A serological assay to detect SARS-CoV-2

seroconversion in humans. medRxiv. March 2020:2020.03.17.20037713.

doi:10.1101/2020.03.17.20037713

16. Song J-Y, Yun J-G, Noh J-Y, Cheong H-J, Kim W-J. Covid-19 in South Korea —

Challenges of Subclinical Manifestations. N Engl J Med. April 2020:NEJMc2001801.

doi:10.1056/NEJMc2001801

17. Matsumoto M, Koike S, Kashima S, Awai K. Geographic distribution of CT, MRI and

PET devices in Japan: A longitudinal analysis based on national census data. PLoS

One. 2015;10(5). doi:10.1371/journal.pone.0126036

18. Verity R, Okell LC, Dorigatti I, et al. Estimates of the severity of coronavirus disease

2019 : a model-based analysis. Lancet Infect Dis. 2020;3099(20):1-9.

doi:10.1016/S1473-3099(20)30243-7

19. Japan declares coronavirus emergency and approves a near $1 trillion stimulus

package. https://www.cnbc.com/2020/04/07/japan-declares-coronavirus-emergency-

and-approves-a-near-1-trillion-stimulus-package.html. Accessed April 8, 2020.

20. Mizumoto AK, Kagaya K, Zarebski A. Estimating the Asymptomatic Ratio of 2019

Novel Coronavirus onboard the Princess Cruises Ship , 2020. medrxiv. 2020.

doi:https://doi.org/10.1101/2020.02.20.20025866 .

Figures:

Figure 1: (a) Gender and age distribution of COVID-19 confirmed cases in Japan (b) Age

distribution of deaths due to COVID-19 (c) Gender distribution of deaths due to COVID-19 in

Japan until 24 March 2020

Figure 2: Graph of major symptoms appeared in symptomatic case of COVID-19 in Japan

Figure 3: geographical distribution case of COVID-19 confirmed cases in Japan until March

24, 2020

Figure 4: History of confirmed cases of COVID 19 (a) Pervious Hospitalization (b) has contact

with positive case and (C ) confirmed cases‘s occupations distribution

Figure 5:Clauset-Newman-Moore (CNM) clustering algorithm web-chart showing linkages of

confirmed cases contact with pervious positive case of covid19 in Japan

Figure 6:Clauset-Newman-Moore (CNM) clustering algorithm web-chart showing five main

cluster of community transmission of COVID19 in Japan till 24th March, 2020

Figure 7: Confirmation of COVID-19 positive cases by different diagnostics methods

Tables:

Table 1: Epidemiological parameters of COVID-19 confirmed cases until March 24, 2020 in

Japan

Parameter Cases Within Govt. Data Not No Linked with Total

Number Country Charted Available Travel Diamond

(Japan) flight History Princess Cruise ship from to

China Wuhan

Symptomatic 1080 - - - - - 1080

(90.60%)

Asymptomatic 112 105 7 - - - 112

(9.39%)

Travel History 28 - - 9 1155 28

Wuhan(China) (2.34%)

Were in 21 9 1162 21

Diamond (1.76%)

Princess Cruise

ship

Tables 2: Clinical manifestation of COVID-19 confirmed cases until March 24, 2020 in Japan

Data

Available Data Not Parameter Mean (Days) Total (Complete Available

Data)

Meantime from

Onset of 1000 192 6±22.6 Symptoms to

Confirmation

Meantime from 1192 Contact with

COVID19 148 (112) 1044 5±19.55 positive case to

Onset of

Symptoms

Supplementary files:

Data files of 1192 cases can be provided on request of reviewers medRxiv preprint doi: https://doi.org/10.1101/2020.04.17.20070276; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . medRxiv preprint doi: https://doi.org/10.1101/2020.04.17.20070276; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . medRxiv preprint doi: https://doi.org/10.1101/2020.04.17.20070276; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . medRxiv preprint doi: https://doi.org/10.1101/2020.04.17.20070276; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . medRxiv preprint doi: https://doi.org/10.1101/2020.04.17.20070276; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . medRxiv preprint doi: https://doi.org/10.1101/2020.04.17.20070276; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . medRxiv preprint doi: https://doi.org/10.1101/2020.04.17.20070276; this version posted April 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .