key: cord-339576-0d6sa9pe
authors: Guallar, María Pilar; Meiriño, Rosa; Donat-Vargas, Carolina; Corral, Octavio; Jouvé, Nicolás; Soriano, Vicente
title: Inoculum at the time of SARS-CoV-2 exposure and risk of disease severity
date: 2020-06-14
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.06.035
sha: 
doc_id: 339576
cord_uid: 0d6sa9pe

Abstract A relationship between the infecting dose and the risk of disease severity has not been demonstrated for SARS-CoV-2 infection. Here, we report three clusters of individuals that were exposed to diverse inoculi in Madrid and overall developed divrgent clinical forms of COVID-19. Our data support that a greater SARS-CoV-2 inoculi at the time of exposure might determine a higher risk of severe COVID-19.

A relationship between the infecting dose and the risk of disease severity has been demonstrated for several viral infections, including influenza and SARS [1, 2] . For COVID-19, high viral loads either in saliva, respiratory secretions or blood have been associated with more severe illness [3, 4] . However, it remains unclear whether exposure to a greater viral inoculum could determine a higher risk for developing severe COVID-19. Although intuitive, it has been difficult to obtain such a dose-response data.

Herein we report three clusters of SARS-CoV-2 infection in Madrid, in which infected persons experienced divergent clinical outcomes, namely severe, mild or asymptomatic. We hypothesize that distinct sizes of viral inoculum at the time of exposure could explain their different illness course.

The first cluster was represented by 25 women (age range, 34 to 86 years-old) that lived in a community located on the outskirts of Madrid. The house was wide (2000 m 2 ), with three floors, spacious common ballrooms and halls, high ceilings, and large rooms, as well as a big garden (1500 m 2 ). Lockdown with strict stay home confinement was declared in Madrid on March 14 th . The day before, the index case, a 47-year-old woman, were shopping and visiting relatives. On March 16 th she developed fever, cough, anosmia and dysgeusia. Despite isolation at her room, two household members developed mild symptoms 2-3 days later and another 15 during the following two weeks. Antibody tests performed on April 28 th to all 25 residents identified three additional infected asymptomatic persons, whereas four remained seronegative (Figure 1) . In this cluster, low viral exposures along with social distancing would J o u r n a l P r e -p r o o f account for more benign clinical forms of COVID-19, along with asymptomatic and uninfected cases.

A second cluster of COVID-19 was identified in a group of 12 women (age range, 53 to 85 years-old) that lived together in a flat apartment (650 m 2 ) downtown Madrid. Several of them admitted going outside home multiple times despite lockdown implementation. Furthermore, many acknowledged poor compliance with social distancing measures. Therefore, more than one index case could be expected in this site. From March 21th to 23rd, six of them developed mild to severe COVID-19 symptoms and asked for medical assessment at home or nearby clinics. Three developed bilateral pneumonia, being one hospitalized and requiring intensive care support. From March 25 th to April 3rd another four developed mild to severe symptoms, with one being hospitalized with bilateral pneumonia. Antibody tests on April 28 th confirmed infection in all 12 residents, including two that had remained asymptomatic. In this cluster, indoor continuous viral exposure could account for a wider presentation of clinical forms of COVID-19, being all residents infected.

The third cluster consisted in a group of ten adults (7 male; age range, 56 to 76 years-old) that met within a small conference room (60 m 2 ) during 3 hours on March 4 th . It was ten days before the nationwide lockdown was implemented. The event was held at one health institution downtown Madrid. Three attenders had just arrived from Rome (two) and Milan (one), where they had been for a few days. All attenders were asymptomatic the meeting day and did not take any preventive measure, including setting one next to another and not wearing face masks. Two days later two developed COVID-19 symptoms and the rest within the next week. COVID-19 was severe in at least four individuals, one being hospitalized at the J o u r n a l P r e -p r o o f intensive care unit for nearly one month. Fortunately, he recovered. This cluster reminds many features of one large outbreak reported among members of a choir in the US state of Washington [5] . In this cluster, a large indoor viral exposure seemed to account for infection of all attenders and development of severe clinical forms in half of them.

It is worth to note that of the six major determinants of SARS-CoV-2 susceptibility to infection and risk for disease severity (Figure 2) , the first two clusters only included women, whereas 7 out of 10 in the last cluster were male. The mean age (63.4, 66.3, 62.7 years-old, respectively) and the rate of chronic co-morbidities (roughly two thirds each group, being hypertension the most common) did not differ significantly comparing the three clusters. Information on potential cross immunity with another endemic coronaviruses or genetic variants that could influence SARS-CoV-2 disease course was not available, but all individuals were living in Madrid and were Caucasian. Therefore, we hypothesize that a different inoculum at the time of SARS-CoV-2 exposure could explain the different course of infection in these three clusters.

It is intriguing that most recent SARS-CoV-2 infections seem to be less virulent than those that occurred earlier on the COVID-19 outbreak [6, 7] . Several factors might contribute to this observation, including more frequent late presentations at the beginning of the pandemic.

Alternatively, the new coronavirus could steadily become less pathogenic, as result of coadaptation to the human hosts [8] . However, our findings suggest that most likely it reflects the overall lower size of the inoculum in recent infections as a result of wide social distancing interventions compared to contagions that occurred earlier in the pandemic.

The recognition that exposure to low viral loads is associated with mild or asymptomatic infections would favor a wisely steadily re-opening of activities. For instance, restricting indoor J o u r n a l P r e -p r o o f gatherings where superspreading events are more likely to occur will have a major impact on transmission, whereas other restrictions -on outdoor activity, for example-might be eased.

Promoting activities on open spaces coupled with rapid isolation of symptomatic persons (selfconfinement) and quarantine of contacts would act synergistically halting COVID-19 spread and severity [9] .

Since overall 80% of contagions seem to have derived from only 10% of infected individuals [10] , shifting the SARS-CoV-2 community transmission rate (R 0 ) to less than 2 would require that less than half of the population would need to be infected for producing herd immunity ( Figure 3) . In this scenario, COVID-19 spreading would be expected to be controlled, even in the absence of antivirals or vaccines. Our data support that keeping social distancing would be effective in reducing contagions as well as driving COVID-19 to less severe forms. This information is crucial at a time when re-opening strategies are urgently needed for alleviating the harmful economic impact of prolonged lockdowns. 

Clinical correlation of influenza and respiratory syncytial virus load measured by digital PCR

Initial viral load and the outcomes of SARS

Clinical features and dynamics of viral load in imported and nonimported patients with COVID-19

Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study

High SARS-CoV-2 attack rate following exposure at a choir practice -Skagit County

Association of public health interventions with the epidemiology of the COVID-19 outbreak in Wuhan, China

Reducing risks from coronavirus transmission in the home -the role of viral load

Compounds with therapeutic potential against novel respiratory 2019 coronavirus

Impact assessment of non-pharmaceutical interventions against coronavirus disease 2019 and influenza in Hong-Kong: an observational study

Quantifying the impact of physical distance measures on the transmission of COVID-19 in the UK

Figure 1. Timeframe of SARS-CoV-2 infections and COVID-19 disease severity in persons belonging to groups with different viral exposure