key: cord-1015484-znjmz1ex
authors: Aguiar, M.; Stollenwerk, N.
title: Conditional mortality risk can explain differences in COVID-19 case fatality ratios around the globe
date: 2020-09-06
journal: Public Health
DOI: 10.1016/j.puhe.2020.08.021
sha: f587121d73bde343aba7bbd4851ad0e0e4bd2cdf
doc_id: 1015484
cord_uid: znjmz1ex

Objectives With COVID-19 infections resulting in death according to a hierarchy of risks, with age and pre-existing health conditions enhancing disease severity, the objective of this study is to estimate the condition-specific Case Fatality Ratio (CFR) for different sub-populations in Italy. Study design The design of the study was to estimate the “pre-existing comorbidity”-conditional CFR to eventually explain the mortality risk variability reported around in different countries. Methods We use the available information on pre-existing health conditions identified for deceased patients "positive with SARS-CoV-2" in Italy. We i) estimated the total number of deaths for different pre-existing health conditions categories and ii) calculated a conditional CFR based upon the number of co-morbidities prior to SARS-CoV-2 infection. Results Our results show a 0.6% conditional CFR for a population with zero pre-existing pathology, increasing to 13.9% for a population diagnosed with one and more pre-existing health conditions. Conclusions Condition-specific mortality risks are important to be evaluated during the COVID-19 pandemic, with potential elements to explain the CFR variability around the globe. A careful postmortem examination of deceased cases to differentiate death “caused by COVID-19” from death "positive with SARS-CoV-2” is therefore urgently needed and will likely improve our understanding of the COVID-19 mortality risk and virus pathogenicity.

In December 2019, a severe respiratory syndrome (COVID-19) caused by a new coronavirus (SARS-CoV-2), was identified in China [1] and spread rapidly around the globe. COVID-19 was declared a pandemic by the World Health Organization (WHO) in March, 2020. As of the date of preparation of this manuscript, more than 8 million cases were confirmed with about 450 thousand deaths and a global case fatality ratio (CFR) of approximately 5.5% [2] . CFR is the proportion of deceased cases over the total number of persons diagnosed with a disease during the course of the outbreak. CFR is often used as a disease severity indicator. Many viral diseases affecting humans have a well established CFR such as seasonal influenza (<0.1%) [3] , unvaccinated measles (1-3%) [4] , Severe acute respiratory syndrome -SARS (15%) [5] and Middle Eastern Respiratory Syndrome -MERS (34.4%) [6] , for example, with a pandemic potential without effective control measuers in place. As testing capacities have increased, symptomatic cases of lower severity have been detected producing a slow decline in global COVID-19 CFR. Yet, national CFR vary around the world. As of this writing, Qatar has a CFR below 1%, South Korea around 2.5% and Germany 4.7%, compared with 14.5% in Italy and the United Kingdom and approximately 19% in France [2] .

And why do these reported CFR differ? Do differences relate to differences in population susceptibility to SARS-CoV-2 infection? Since COVID-19 is a new virus, it is likely that overall population susceptibility to infection might be similar while susceptibility to disease expression might differ. Infection rates may be controlled by social distancing and crowding, while the force of infection may be controlled by many factors. Assumptions concerning these variables are used in most modeling approaches used to guide public health authorities during the COVID-19 pandemic.

Many other fundamental questions could be raised such as the capacity of the health systems to cope with a new infectious disease or even the overall health condition of a population, but to understand the CFR reported in different countries, the first question to be answered is: how are the COVID-19 deceased cases reported around the globe? Is it done in a standard format, via a postmortem examination [7] to differentiate death "caused by COVID-19", defined for surveillance J o u r n a l P r e -p r o o f purposes as a death resulting from a clinically compatible illness, from death "positive with SARS-CoV-2", a conditional effect of high viral transmissibility?

Starting on May 13, 2020, the "Coronavirus disease situation reports" from the WHO highlight the importance of defining COVID-19 death following the international guidelines for certification and its classification of COVID-19 as cause of death by confirmed laboratory testing or clinical or epidemiological diagnosis [2] . However, CFR are still reported without considering differences in sub-populations.

Italy, the first hard-hit country in Europe, reported on June 11, 2020, a population-CFR of 14.5% after reaching 34167 deaths among 236142 confirmed cases "positive with SARS-CoV-2" Data about the pre-existing health conditions of all infected individuals in Italy are not available to measure the specific CFR for each comorbidity group, however, a detailed report characterizing the deceased patients which were tested positive with SARS-CoV-2 are published, once a week, by the Istituto Superiore di Sanità in Italy. The studied population is divided into groups with "0 preexisting pathology", "1 pre-existing pathology", "2 pre-existing pathologies" and " 3 or more preexisting pathologies" diagnosed before the patient became infected with SARS-CoV-2 [8a]. We note that this report [8a] does not show the correlation between pre-existing pathologies and age, but states that 1.1% of the deceased positive with SARS-CoV-2 were younger than 50 years of age.

Among those, 83 deceased patients were younger than 40 years of age, which are expected to be in the category with a low risk of death "caused by COVID-19". However, for this group, J o u r n a l P r e -p r o o f approximately 75% (N=62) were suffering from severe pre-existing health conditions against 17% (N=14) who did not have any important underlying health condition. Medical records were not available for the remaining patients.

From this perspective, "pre-existing comorbidity"-conditional CFR, which is defined here as the number of deceased cases with one or more pre-existing health conditions prior to SARS-CoV-2 infection divided by the total number of detected infected cases in the population are relevant and important measures to understand the current differences between CFR reported around the globe.

Up to June 11, 2020, 3438 medical records for deceased cases tested positive with SARS-CoV-2 were analyzed, with 4.1% of the deceased cases classified with zero pre-existing pathologies versus approximately 60% of the deceased patients suffering with 3 or more pre-existing pathologies prior SARS-CoV-2 infection. By assuming that the deceased cases characterization in Italy is done randomly as the deaths are reported, we use the stratified data for individuals with zero, one, two, three or more pre-existing conditions to estimate the total number of deaths expected in each category in the population. The "pre-existing comorbidity"-conditional CFR was obtained by dividing the total estimated number of deaths from each category by the overall confirmed cases in the population.

Our results have shown that mortality risk varies significantly between the number of pre-existing pathology groups, with CFR=0.6% for individuals with 0 pre-existing pathology, CFR=2.1% for individuals with 1 pre-existing pathology, CFR=3.1% for individuals with 2 pre-existing pathologies and CFR=8.6% for individuals with 3 or more pre-existing pathologies (see upper part of Table 1 ). By using the aggregated data, the higher CFR estimations were obtained for the group of individuals diagnosed with two or more pre-existing health conditions (CFR=11.7%) and the group of individuals with at least one pre-existing health conditions (CFR=13.9%), see lower part of Table 1 , which are closer to the currently reported CFR in Italy and comparable with the current CFR reported in the United Kingdom [2] , for example, where patient postmortem examination is not used as tool of investigation prior to death notification [7] . However, for the group of J o u r n a l P r e -p r o o f individuals diagnosed with zero and one pre-existing health conditions prior SARS-CoV-2 infection (at most one) is low (CFR=2.7%) and comparable with the current CFR reported in Norway [2] and Republic of Korea [2, 10] . J o u r n a l P r e -p r o o f considering differences in sub-populations, will overestimate the biological disease induced mortality rate.

Condition-specific mortality risks are important to be evaluated during this pandemic, with potential elements to explain the CFR variance in different countries. A careful postmortem examination of deceased cases to differentiate death "caused by COVID-19" from death "positive with SARS-CoV-2" is therefore urgently needed and will likely improve our understanding of the SARS-CoV-2 pathogenicity. As those estimations are not final until the characterization of the deceased cases is finished and data on all medical records for all infected individuals in the populations would become available, this exercise has the objective to discuss the urgent need of using a more standardized method for deceased notification across many nations during the COVID-19 pandemic.

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Caratteristiche dei pazienti deceduti positivi all'infezione da SARS-CoV-2 in Italia Dati al 11 giugno 2020

Analysis on 54 mortality cases of Coronavirus disease 2019 in the Republic of Korea from

COVID-19 infections result in death according to a hierarchy of risks, with age and pre-existing health conditions enhancing disease severity -Current Case Fatality Ratio (CFR) is still reported as a unique number for the whole population

Pre-existing comorbidity"-conditional-CFR has potential elements to explain the CFR variance in different countries. -Disease induced death by SARS-CoV-2 infection is estimated to be much lower than the currently reported CFR value

There is an urgent need to use a more standardized method for death notifications across many nations during the COVID-19 pandemic

BCAM -Basque Center for Applied Mathematics Alameda de Mazarredo