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Date: May 04, 2020

Heinsberg Study results published Bonn-based research team determine COVID-19 infection fatality rate

The district of Heinsberg in the German state of North Rhine-Westphalia is considered a hot spot for the novel Coronavirus SARS-CoV-2. Following a carnival celebration, the district became one of the first areas in Germany where the pathogen spread and infected large quantities of people. As part of the study, a research team led by Prof. Dr. Hendrik Streeck and Prof. Dr. Gunther Hartmann from the University of Bonn carried out a large study to precisely determine the infection fatality rate for the first time among other findings. The results of the study have been pre-published and are now presented to scientists and the public. Publication in a peer-reviewed journal is to follow.

Focus of the study is the infection fatality rate (IFR), which indicates the ratio of deaths in comparison to those infected. The IFR is different to the case fatality rate (CFR). For various reasons, the IFR is considered the more reliable parameter and there is an international demand to have a more accurate understanding of the fatality of SARS-CoV2. “For the first time, our data enables us to estimate how many people have been infected after the superspreading event. Approximately 15 percent of Gangelt had been infected. The total number of infections allows us to determine the infection fatality rate. In Gangelt, the IFR after the SARS-CoV-2 outbreak is 0.37 percent,” says lead investigator Prof. Dr. Hendrik Streeck, Director of the Institute for Virology at the University Hospital Bonn.

Based on the IFR and the number of deaths, estimations about the total number of infections in similar demographic areas with different infection rates can be made. Comparing this number with the number of officially reported infections leads to an estimate of unreported cases. In Gangelt, this figure is about 5 times higher than the official number of people tested positively. With an extrapolation based on 6,700 SARS-CoV-2 associated deaths in Germany, a total of 1.8 million infections can be assumed. This number of unreported cases is about 10 times higher than the officially reported cases (162,496 on May 3rd, 2020).

“The results can be used to further improve models on the transmission behavior of the virus. Until now, basis for such data has been relatively uncertain,” says co-author Prof. Dr. Gunther Hartmann, Director of the Institute for Clinical Chemistry and Clinical Pharmacology at the University Hospital Bonn and speaker of the Cluster of Excellence, ImmunoSensation. The study also provides important indicators for further research on SARS-CoV-2 such as: the infection risk dependent on age, gender and pre-existing conditions; the increased severity of illness amidst special circumstances of a massive infection incident such as in Gangelt, or on the risk of infection within families.

20% of COVID-19 infections are asymptomatic

The description of symptoms is another aspect the study covers. Loss of smell and taste, as previously identified by Prof. Streeck, are the most striking symptoms for this infection. Interestingly, 22 percent of infected persons in Gangelt were asymptomatic. People who participated in the carnival event had more often symptoms. “In order to examine if physical proximity to participants of the carnival event and the increased aerosol formation through loud speaking or singing lead to a more severe disease progression, we are planning further studies in cooperation with hygiene specialists,” explains Prof. Hartmann.

“Apparently one in five infections occurs without noticeable symptoms suggests that infected persons who secrete virus and can infect others cannot be reliably identified on the basis of recognizable symptoms of the disease,” says Prof. Dr. Martin Exner, head of the Institute for Hygiene and Public Health and co-author of the study. This confirms the importance of general rules of distance and hygiene in the corona pandemic. "Every supposedly healthy person we encounter can unknowingly carry the virus. We must be aware of this and act accordingly," says the hygiene expert.

Studies of multi-person households showed that the risk of infecting another person was surprisingly low. “The infection rate in children, adults and elderly is very similar and is apparently not dependent on age,” says Prof. Streeck. There are also no significant differences between genders.

A total of 919 participants from 405 households

A total of 600 randomly selected households in Gangelt were written to and asked to participate in the study. 919 study participants from 405 households were interviewed and tested between March 30th and April 6th, six weeks after the outbreak of the infection. Researchers took throat swabs and performed blood tests. In the acute phase of the infection in the first one or two weeks, the PCR test, which captures the genetic thumbprint of SARS-CoV-2, is very reliable. Two or three weeks after the infection takes place, the immune system builds antibody responses against the virus, which can be detected by ELISA.

“By combining PCR and ELSIA tests we are able to detect acute as well as elapsed infections,” says Prof. Hartmann. Preliminary studies showed that the ELISA test is false positive in about one percent of the cases. “However, with such high frequency of infections in Gangelt, a one percent false positive rate is not critical,” Hartmann explains. For studies planned to take place across Germany with an estimated infection rate of approximately one to two percent a one percent false positive rate pose rather a problem.

“Which conclusions can be drawn from the study results depends on many factors that go beyond pure scientific considerations,” says Prof. Streeck. “The evaluation of our findings and their impact on concrete decisions are the responsibility of society and politics.”

In the SARS-CoV-2 pandemic, exceptional rules also apply for scientific publishing. Renowned scientific journals require that papers on the topic of Covid-19 are first uploaded to a preprint server and thus made available immediately to science and health authorities (see https://wellcome.ac.uk/coronavirus-covid-19/open-data). Only following this step, the normal publication process by peer review takes place.


Publication: Infection fatality rate of SARS-CoV-2 infection in a German community with a super-spreading event Hendrik Streeck, Bianca Schulte, Beate M. Kümmerer, Enrico Richter, Tobias Höller, Christine Fuhrmann, Eva Bartok, Ramona Dolscheid, Moritz Berger, Lukas Wessendorf, Monika Eschbach-Bludau, Angelika Kellings, Astrid Schwaiger, Martin Coenen, Per Hoffmann, Birgit Stoffel-Wagner, Markus M. Nöthen, Anna-Maria Eis-Hübinger, Martin Exner, Ricarda Maria Schmithausen, Matthias Schmid and Gunther Hartmann

Link to the publication

 

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Frequently Asked Questions

How has the work been distributed among the participating researchers?

Prof. Hendrik Streeck: “It is not possible to conduct such a large study without help. More than 80 scientists, medical doctors, assistant medical technicians and medical students were involved in the study.” Lead investigator and first author is Prof. Hendrik Streeck (Director of the Institute of Virology); the last author is Prof. Gunther Hartmann (Director of the Institute of Clinical Chemistry and Clinical Pharmacology and speaker of the Cluster of Excellence ImmunoSensation). Prof. Matthias Schmid (Director of the Institute of Medical Biometry, Informatics and Epidemiology (IMBIE), and Prof. Dr. Dr. h.c. Martin Exner (Institute of Hygiene and Public Health) were also in the team.”

What was the focus of the study?

Prof. Hendrik Streeck: “Following a carnival event in Gangelt in the district of Heinsberg, the district became the first area in Germany with a massive COVID-19 outbreak. We started to examine the infected persons and their environment. On this basis, end of March, I met with other scientists in Bonn and we developed a plan to systematically study the number of infections in the community of Gangelt, the local hotspot.”

What are the most important results of the study?

Prof. Hendrik Streeck: “Focus of the study is to determine the number of infected, and the infection fatality rate (IFR), which indicates the ratio of deaths in comparison to those infected. Based on the data, we could calculate for the first time that the IFR in the context of the SARS-CoV-2 outbreak is 0.37 percent. If corrected for additional factors, this figure varies between 0.24 and 0.43 percent. About 15 percent of all persons examined tested positive for SARS-CoV-2. The officially reported infection rate for the community of Gangelt at the time of the study was 3 percent. This means that the real number of infections in Gangelt is about 5-fold higher than the official number. Single-person as well as multi-person households were studied in order to analyse a family cluster effect. The study shows that the probability of infection of a study participant is independent of the household size the person lives in. However, in a household with at least one person infected, the probability of infection for the other persons increases over the average of 15 percent (e.g. the additional risk of infection in a 3-person household is approximately 20 percent). The infection rate in children, adults and elderly does not differ significantly. However, children had a lower infection rate, but due to the relatively low number of children in the study, we don´t know yet whether this difference is statistically significant. The study also demonstrates that participation in carnifal events (a super-spreading event) enhanced the infection rate and the number of symptoms.”

How significant are the results?

Prof. Gunther Hartmann: “The estimated percentage of infected individuals only refers to the town of Gangelt and its specific situation with the super spreading event. It is not representative of other areas in Germany. However, the infection fatality rate is a number that is very helpful to improve model calculations. For example, with all the uncertainties in mind, the IFR applied to 6,700 SARS-CoV-2-associated deaths currently registered in Germany would lead to an estimate of 1.8 million infections in Germany, which is approximately ten-fold higher than the reported number. Thus, our results can be utilized to further improve models on the pandemic. Here, our data contribute important additional information.”

What were the steps taken in the study?

Prof. Hendrik Streeck: “We followed the protocol recommended by the World Health Organization (WHO) (https://www.who.int/publications-detail/population-based-age-stratified-seroepidemiological-investigation-protocol-for-covid-19-virus-infection). A total of 600 randomly selected households in Gangelt were contacted and asked to participate in the study. 1007 study participants from 405 households agreed to participate, and data for the evaluation of the infection status were available from 919 participants.”

What methods were applied for SARS-CoV-2 testing?

Prof. Gunther Hartmann: “We combined PCR testing for the presence of virus with the analysis of virus-specific antibodies. This way we cover the early phase of infection and the time after an infection resolved. The community of Gangelt is such an ideal model for our study because there was a transient wave of infections causing a high number of infected people which allows for a reliable serological analysis.”

How reliable are these tests?

Prof. Gunther Hartmann: “According to the manufacturer and preliminary studies carried out by the researchers, ELISA test results have a specificity of 98-99 percent, a figure which is confirmed by validations by Prof. Christian Drosten, Berlin. The study was carried out in Gangelt with a high prevalence, i.e. an area where SARS-CoV-2 is virus has widely spread, in our study 15 % of individuals. Here, an error rate of one percent is not as critical as in areas with one or two percent. This error rate in the ELISA test is corrected mathematically.”

To which extent can you exclude confusing the SARS-CoV-2 with common cold coronaviruses?

High specificity of the ELISA means that other coronaviruses are not detected. There is cross-reactivity with SARS-1, but this virus was never present in Germany. In addition, we carried out neutralization assays. To verify, we examined blood samples of patients tested positive for other corona viruses, taken prior to the outbreak of the current pandemic, which all were negative.

Can you tell us anything about the course of the infection and severity of symptoms?

Prof. Hendrik Streeck: “A total of 22.1 percent of those infected showed no symptoms at all. People who participated in a carnival event were more often infected with SARS-CoV-2 and showed more severe symptoms than people who did not participate in such events. It is possible that the viral load upon initial infection was higher at carnival events.”

How many people were tested positive for the virus?

Prof. Hendrik Streeck: „In April 2020, 14 percent of those tested in Gangelt already carried antibodies against the virus. Viruses were only detected in a small fraction of study participants (2.4 percent).”

Which results did you obtain on infection rates in private households?

Prof. Martin Exner: “In private households with one member carrying the virus, the risk of infection for other members of the household is increased. For example, the risk of infection in a 3-person household is increased by 20 percent. The rates of new infections in children, adults and elderly people are not significantly different, but are somewhat lower in children, but numbers of children in this study are too small. There are also no differences between genders.”

Without an autopsy, we cannot clarify whether a SARS-CoV-2 patient’s cause of death actually is SARS-CoV-2 or another disease. Have you considered this uncertainty when determining the Infection Fatality Rate (IFR)?

Prof. Hendrik Streeck: “There is no information on the actual cause of death of patients who were tested positive for COVID-19.”

Are these findings representative for Germany, other countries and the world?

Prof. Hendrik Streeck: “We are dealing with a so-called super-spreading event, which is why our findings can only to a limited extent be applied to the rest of Germany or other countries. Nonetheless, the data we have collected on this event offers important scientific starting points because infections in Gangelt occurred very early and vigorously compared to the rest of Germany. Our findings can be used to improve models simulating the spread of the virus, for example.”

Which measures against the virus can be deduced?

Prof. Hendrik Streeck: “We have collected and analyzed data. Drawing conclusion from this data depends on many aspects that go beyond the scope of science. Evaluating our findings and translating them into concrete decisions is the responsibility of politics.”

What use does your study have for science, politics and society?

Prof. Hendrik Streeck: “The Heinsberg Study is the first to collect extensive data on the occurrence of COVID-19 infections in a hot spot. The study offers starting points for follow-up research. The Robert Koch Institute, the Charité in Berlin, the University of Munich (LMU) and the Helmholtz Association are now conducting studies with a similar approach.”

What was your motivation to conduct this study?

Prof. Dr. Hendrik Streeck: “When infections first started to occur in Gangelt, we supported the local health authority in Heinsberg with SARS-CoV-2 diagnostics. I soon realized that the region was a type of “miniature Germany” which was ahead of the rest of the country by a couple of weeks. It therefore made sense to examine the situation in detail in the context of a scientific study.”

What were the costs of the study? Who financed the study?

Prof. Hendrik Streeck: “The state of North Rhine-Westphalia allocated €65,000 to this study, without connecting any conditions. The actual costs exceed this sum several-fold. Around 80 medical students supported us in taking samples. Costs for diagnostics are in the upper five-digit range. Around 75 percent of the costs are covered by funds provided by the involved institutes.”

Why are you publishing the study on a preprint server first?

Prof. Gunther Hartmann: “Renowned scientific journals require that papers on the topic of COVID-19 are first uploaded to a preprint server and thus made available immediately to science and health authorities (see https://wellcome.ac.uk/coronavirus-covid-19/open-data).”

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