Which must last after the 10th

Course of COVID-19 and critical sections of the infection

How long does a COVID-19 disease last, when do the first symptoms appear after an infection and how long are people infected with SARS-CoV-2 contagious for contact persons? Above all: What does science now know about it? The typical course of the novel disease is difficult to determine because COVID-19 manifests itself very differently. External influences, such as the age of the sick, the condition of the health system or the population structure in the affected country, play a major role. A rough estimate of the natural course of COVID-19 is still important in order to explain the rules for isolation and quarantine as early as possible to the population and to enable them to form an opinion about the infection process. For journalists, epidemiological measures such as incubation time, serial interval and infectivity can provide important clues as to whether and when other people can be infected by infected people.

The following overview graphic should help to show the course of COVID-19 in a simplified manner. The attached explanations, sorted according to the letters in the graphic, summarize the state of knowledge about the individual time periods in key words. You are welcome to use both for your reporting.

You can download the fact sheet as a PDF here; the graphic as a separate PDF document here.

Overview

     

  • Infographic
  •  

  • a) Latency
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  • b) incubation period
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  • c) Period of infectivity
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  • d) Contagion of other people - the serial interval
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  • e) Time to Isolation of Mild Cases
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  • f) Time from first symptoms to recovery from mild cases
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  • g) Time from first symptoms to hospitalization of severe cases
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  • h) Time to discharge from hospital
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  • i) Fatal outcome from COVID-19
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  • j) When the SARS-CoV-2 PCR test is positive
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  • k) Time until specific antibodies, i.e. immunity, are formed
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  • References that have been cited
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  • Further sources of research
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Infographic

 

In the upper part of the graphic, the course of the COVID-19 disease is shown schematically for mild, moderate and severe cases, starting with the infection of a person.

The periods below that are indicated by arrows describe important epidemiological epidemiological sections that can contribute to the characterization of the disease. Each step in the course of the disease is identified by a letter to which the respective explanatory text is assigned below.

You can download the graphic in high resolution as a PDF here.

a) Latency

     

  • Covers the period between the day on which the person was exposed to the virus (exposure) and became infected until the time when the infected person becomes infectious, i.e. could infect other people, as shown with d) in the graphic [1, Fig 1 for explanation].
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  • So far there is not much reliable information about this value because it is hardly measurable under real conditions [2].
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  • An international study estimates the latency period for COVID-19 to be around 2.5 daysstarting infection based on the earliest known time at which another contact could be infected. The value thus represents an upper limit [2].
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  • Other studies estimate the non-infectious period at 3.5 to 4 days after infection [3] [4].
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  • The Robert Koch Institute (RKI) assumes a latency period of 3 days in its own modeling [5]
    • In the case of COVID-19, the period of latency in the few available studies is shorter than the determined incubation period, which means that infected people can be infectious even before the first symptoms appear (see infectivity c) and serial interval d))
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b) incubation period

     

  • Covers the period from the day of infection to the day the symptoms first appear
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  • Often a Mean between five and six days specified; However, the mean values ​​of various studies fluctuate: They range from four to nine days [2] [3] [6] [7] [8] [9]
    • Attention, these are mean values ​​- incubation times of up to 14 days have even been proven for individual patients, and the usual isolation and quarantine recommendations are based on this [10].
    • In one study, 6.65 percent of the cases examined showed an incubation time of over 14 days [2].
  •  

  • Symptoms reported frequently and very early on are fever and dry cough [11]
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  • Not every infected person gets sick and develops strong symptoms, so the infection then proceeds asymptomatically; It is questionable how many people perceive and report very mild symptoms, such as a scratchy throat, as a sign of illness.
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  • In Germany, 870 of 26,250 confirmed cases (3.3%) have so far reported no symptoms (as of March 26, 2020) [12]
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c) Period of infectivity

     

  • Covers the period during which an infected person is contagious
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  • Real values ​​have to be determined in laborious laboratory experiments; a positive result of the PCR test (see j)) does not necessarily mean infectivity
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  • The end of the latency period is purely theoretically the beginning of infectivity (see latency period a))
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  • So far, no experimental data can be found on how much viral load an infected person has before the onset of symptoms and when and from which dose becomes infectious.
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  • Two studies give the starting point for infectivity with approx 2.5 days before the onset of symptoms on [13] [14], with a maximum of viral load, i.e. infectivity 0.6 days before the onset of symptoms [14].
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  • The RKI assesses this fact as follows: "This early infectiousness makes the detection of cases very difficult before the emergence of follow-up cases and leads to the great relevance of quarantining close contacts" [5]
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  • Evidence of how long an infected person is contagious, give laboratory experiments: Infectivity exists when virus obtained from smears can multiply in cell culture
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  • Detailed study on nine mild to moderately ill patients [15]:
    • Can be grown from throat swabs up to four days after the onset of symptoms in cell culture
    • From lung secretions up to eight days after the onset of symptoms; after ten days only five percent of the samples could be grown; the infectivity has therefore already decreased significantly here.
    • In no case virus could be isolated from samples with a viral load of less than 10 to the power of 6 copies per milliliter (see PCR test j))
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  • The RKI also assumes an average of ten days of infectious phase [5]
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d) Contagion of other people - the serial interval

     

  • The so-called serial interval describes the time span from the onset of symptoms of the infected person (primary case) to the onset of symptoms of an infected person (secondary case) [1]
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  • for COVID-19, the mean values ​​in studies fluctuate between just under less than 4 to more than 7 days [2][3][9][13][14][16][17]
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  • Connection with incubation period:
    • In some studies examining both values ​​for COVID-19, the serial interval is shorter than the incubation time. That suggests that COVID-19 transmitted even before the onset of symptoms (presymptomatic) can be [2] [13] [17]. Among couples of infected people and their infected people in Guangzhou, China, at least 44 percent were presymptomatic transmissions [14].
    • Other studies do not find this effect [9] [18]
  •  

  • The point in time at which an infected person infects someone else (for the first time) is more tangible. A comprehensive international study indicates the following value: On average, one infected person is already infected 0,19 Days before his own symptoms began another person to [2].
  •  

  • In another study, researchers estimate this time to be around 2.5 days before the onset of symptoms [13]
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  • Apparently, SARS-CoV-2 infected people without noticeable / reported symptoms can already infect other people - there is an asymptomatic transmission [2]; this effect was classified as very low in previous evaluations from China [19]. However, it is questionable how many people perceive and report very mild symptoms, such as a scratchy throat, as such.
  •  

  • However, an infected person usually infects more than just one person.
    SARS-CoV-2 is estimated to have a so-called base reproduction rate (R0) of 2 to 2.5 in the early phase in Wuhan, China [19] [9] - in a population that is completely susceptible to the virus and in which no measures have yet been taken to contain the spread. In its own modeling, the RKI assumes an R0 = 2
  •  

  • How many more people an infected person can actually infect depends heavily on the context of the spread: if, for example, an exit restriction has already been introduced, the value of the effective reproduction rate will decrease.
    • An analysis of cases that occurred later around the world estimates this rate at around 1.75 [2]
    • Using intensive contact tracing, as shown in Shenzhen, China, it fell to 0.4 [20]
    • In addition, not every contact who is in direct contact with an infected person is infected. The same study from Shenzhen reports, for example, that only 15 percent of contacts within a household and 10 percent outside of the household fall ill (attack rate).
    • In an as yet unpublished study of Bavarian patients infected in an early cluster and their contact persons, less than five percent of the close contacts were said to have been infected and that only after a 15-minute stay with close face contact in the same room [33].
  •  

e) Time to Isolation of Mild Cases

     

  • The time between the onset of symptoms and isolation of a COVID-19 case plays a major role in successfully containing the pandemic [21]
  •  

  • The shorter this period of time, the fewer contacts an infected person can infect; if the close contacts of an infected person are found early and quarantined, presymptomatic infections of other people are also prevented
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  • In the first cases and related contacts in South Korea, often a role model in the containment of SARS-CoV-2, the time to isolation averaged 4.3 days [18].
  •  

  • In Shenzhen, China, symptomatic cases were isolated within 4.6 days; Contacts of infected people through contact tracing within 2.7 days [20]. Tracking the contacts helped reduce the time by two days in which infectious cases can infect other people.
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f) Time from first symptoms to recovery from mild cases

     

  • Mild to moderate cases can recover in isolation at home, although moderate cases can also be associated with mild pneumonia
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  • The quarantine at home can be ended 14 days after the onset of symptoms if the patient has been symptom-free for 48 hours [22]
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  • According to the current state of knowledge, 80 percent of the cases in China were mild to moderate [19]
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  • In South Korea, the first patients were declared healthy an average of 13 days after diagnosis [18]
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g) Time from first symptoms to hospitalization of severe cases

     

  • Severe cases with more severe pneumonia or even shortness of breath must be treated in hospital; they then usually need some form of ventilation
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  • Extensive data from China show a proportion of severe cases between 7 and 18 percent, depending on whether the outbreak epicenter Wuhan is included or not [23]
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  • In a model, the RKI estimated that around 4.5 percent of all cases in Germany are severe; Another report on the current real cases states that currently 12 percent of all confirmed cases treated in hospital will [24
  •  

  • in other European countries this value fluctuates between three percent (Austria), over 40 (France, Belgium) and even over 50 percent (Spain) [25]
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  • An international study uses the time of diagnosis of pneumonia to determine when patients go to hospital after an average of 5.8 days approaching [11]
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  • Data from China show that sick people come to the hospital about 5 to 9 days after the onset of symptoms. In China, however, cases were not only treated in clinics, they were also isolated there - in this country the latter happens in one's own home [10].
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  • In its own model, the RKI calculates four days from the onset of symptoms to hospital admission
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  • How many COVID-19 patients are currently in Germany in intensive care unitstreated is unclear. A look at other countries allows rough estimates, as broken down in another SMC fact sheet [25]
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  • In Italy, 16 percent of hospitalized patients required intensive care at the beginning of March; in China it was five percent [26]; according to more recent calculations it is currently 13.5 percent in all of Italy [25]
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  • In modeling for Germany, the RKI even assumes that 25 percent of all patients treated in hospitals require intensive medical care, on average one day after hospitalization [5]
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h) Time to discharge from hospital

     

  • One study models that 24.7 days pass from the onset of symptoms until patients treated in hospital can be discharged [27]
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  • The RKI assumes that patients who do not have to be treated in intensive care units remain in the hospital for around 14 days until they can be discharged in good health [5]; Together with the time from the onset of symptoms to hospitalization of four days assumed by the RKI, this makes 18 days from the appearance of the first symptoms to hospital discharge (Correction to a previous version; editor's note)
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  • Knowledge of this long period, in which it is not yet clear what outcome the disease will take, is extremely important for calculating the severity / case mortality
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  • The following criteria must be met so that a patient can be discharged from hospital as recovered [22]:
    • Symptom-free for at least 48 hours
    • Two negative PCR tests 24 hours apart from throat samples
    • Stable cases that are on the mend can also be released into domestic isolation in Germany, where they again remain for 14 days
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  • Data from China suggest that severe to critical cases have completely recovered after a total of three to six weeks from the onset of symptoms [19]
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i) Fatal outcome from COVID-19

     

  • COVID-19 patients die within 18 days of the onset of symptoms (observed median 18.5 [28]; modeled mean 17.8 days [27])
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  • The deceased were treated in hospital for an average of 13 days [10]
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  • the number of deaths therefore develop with a long delay compared to the number of cases - this is important for calculating the severity / case mortality; People who die at time X were therefore infected around 23 to 24 days beforehand
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  • Currently 455 people have died of COVID-19 in Germany; 87 percent of them were 70 years of age or older [24] (as of March 30, 2020); this age-dependent severity of the disease agrees with international results, which report a drastically increased mortality in old age [23] [27]
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  • In modeling, the RKI assumes that 50 percent of intensive care patients will die [5]; It remains unclear how high the real proportion of deaths per patient treated in hospital is.
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j) When the PCR test for SARS-CoV-2 is positive

     

  • The PCR test detects the genetic material of the virus in samples; it reacts not only to the replicable (infectious) virus, but also to any remaining residues (for example towards the end of an infection)
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  • For the test to be positive, there must be enough genetic material of the virus in one milliliter of the sample (viral load)
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  • According to the FDA, the detection limit is around 136 virus copies per milliliter of sample [29]
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  • in another report an equivalent limit in required cycles in the PCR to achieve this amount is given; if not enough copies of the genetic material are available after 40 cycles, the test is rated negative [30]
  •  

  • The test result strongly depends on the sample examined:
    • The quality of the smear plays a role; the throat, for example, has to be swabbed bravely so that enough cell material is removed; this can be painful at times - self-sampling from patients can therefore be flawed
    • Depending on the course, different material must be used: In the initial stage, a throat swab is best; Later, the lung secretions (sputum) must be examined as the infection has migrated deep into the lungs
  •  

  • A high viral load can already be measured on the day the symptoms begin [30] [14], which decreases continuously within the first week; this indicates that the peak of the virus release with the onset of symptoms has already been exceeded [15]
  •  

  • between the first and fifth day after the onset of symptoms, all samples from nine intensively examined patients were positive; after the fifth day the viral load in the smears decreased and only 50 percent of the samples were above the detection limit [15]
  •  

  • One report suggests that viral load levels are not necessarily symptomatic; one asymptomatic case was as high as it was symptomatic [30]; it is so far unclear whether this is more relevant
  •  

  • But: the stronger the symptoms, the longer the patients are also PCR-positive; Peak of the viral load in the lung secretion on day 10/11 after the onset of symptoms in pneumonia; detection of the virus was still possible after the symptoms had subsided [15]
  •  

  • In another study, the virus detection was positive the longer the more severe the course, on average 20 days after the onset of symptoms [28]
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  • So far 483,295 samples have been tested in Germany; the majority since the 11th calendar week. 33,491 samples (6.9%) tested positive for SARS-CoV-2 (as of March 26, 2020) [12]
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k) Time until specific antibodies, i.e. immunity, are formed

     

  • No specific antibodies develop up to the sixth day, after about 12 days they were observed for the first time in mild to moderate cases [15]; in between is the point in time of the so-called seroconversion
  •  

  • Specific antibodies in the blood indicate that an infected person becomes immune to SARS-Cov-2, i.e. the immune system can render this pathogen harmless if it is infected again.
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  • Results from the animal model support these results: Chinese researchers were unable to re-infect rhesus monkeys with SARS-CoV-2 after an initial, completed disease [31]
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  • After antibodies against the virus are detectable for the first time, there follows a phase in which the specificity for SARS-CoV-2 increases because antibody-producing B cells mutate and neutralizing antibodies mature, a process that researchers call immunological maturation.
  •  

  • How long an immunity could last is still unclear
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  • It is known from the related virus SARS-CoV that antibodies can prevent re-infection for up to three years after surviving an infection [32]
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References that have been cited

[1] Milwid R et al. (2016): Toward Standardizing a Lexicon of Infectious Disease Modeling Terms. Front Public Health; 4: 213. DOI: 10.3389 / fpubh.2016.00213.

[2] Ma S et al. (2020): Epidemiological parameters of coronavirus disease 2019: a pooled analysis of publicly reported individual data of 1155 cases from seven countries. MedRxiv. DOI: 10.1101 / 2020.03.21.20040329.
A preprint publication that has not yet been reviewed (to be treated with caution).

[3] Data from the MIDAS network: COVID-19 / parameter_estimates / 2019_novel_coronavirus / estimates.csv. Downloadable from the Github platform. More information about the MIDAS network is available here.

[4] Klein D et al. (2020): Working paper - model-based estimates of COVID-19 burden in King and Snohomish counties through April 7,2020.

[5] at the Heiden M et al. (2020): Modeling of example scenarios of the SARS-CoV-2 epidemic 2020 in Germany. Robert Koch Institute. DOI 10.25646 / 6571.2

[6] Backer JA et al. (2020): Incubation period of 2019 novel coronavirus (2019-nCoV) infections among travelers from Wuhan, China, 20–28 January 2020. Euro Surveill; 25 (5). DOI: 10.2807 / 1560-7917.ES.2020.25.5.2000062.

[7] Guan W et al. (2020): Clinical Characteristics of Coronavirus Disease 2019 in China. NEJM. DOI: 10.1056 / NEJMoa2002032.

[8] Liu T et al. (2020): Transmission Dynamics of 2019 Novel Coronavirus (2019-nCoV). Preprint at the journal The Lancet; Manuscript number: THELANCET-D-20-00553.

[9] Li Q et al. (2020): Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus – Infected Pneumonia. NEJM; 382: 1199-1207. DOI: 10.1056 / NEJMoa2001316.

[10] Linton N et al. (2020): Incubation Period and Other Epidemiological Characteristics of 2019 Novel Coronavirus Infections with Right Truncation: A Statistical Analysis of Publicly Available Case Data. J Clin Med; 9 (2): 538. DOI: 10.3390 / jcm9020538.

[11] Gaythorpe K et al. (2020): Report 8: Symptom progression of COVID-19. Imperial College London COVID-19 Response Team. DOI: 10.25561 / 773.

[12] Robert Koch Institute (2020): Daily situation report by the RKI on Coronavirus Disease-2019 (COVID-19) from March 26, 2020.

[13] Tindale LC et al. (2020): Transmission interval estimates suggest pre-symptomatic spread of COVID-19. MedRxiv. DOI: 10.1101 / 2020.03.03.20029983.
A preprint publication that has not yet been reviewed (to be treated with caution).

[14] He X et al. (2020): Temporal dynamics in viral shedding and transmissibility of COVID-19. MedRxiv. DOI: 10.1101 / 2020.03.15.20036707.
A preprint publication that has not yet been reviewed (to be treated with caution).

[15] Woelfel R et al. (2020): Clinical presentation and virological assessment of hospitalized cases of coronavirus disease 2019 in a travel-associated transmission cluster. MedRxiv. DOI: 10.1101 / 2020.03.05.20030502.

[16] Zhao S et al. (2020): Estimating the serial interval of the novel coronavirus disease (COVID-19): A statistical analysis using the public data in Hong Kong from January 16 to February 15, 2020. In Review - Infectious Diseases of Poverty. DOI: 10.21203 / rs.3.rs-18805 / v1.

[17] Nishiura H et al. (2020): Serial interval of novel coronavirus (2019-nCoV) infections. MedRxiv. DOI: 10.1101 / 2020.02.03.20019497.
A preprint publication that has not yet been reviewed (to be treated with caution).

[18] Ki M et al. (2020): Epidemiologic characteristics of early cases with 2019 novel coronavirus (2019-nCoV) disease in Korea. Epidemiol Health 2020; 42: e2020007. DOI: 10.4178 / epih.e2020007.

[19] World Health Organization: Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19).

[20] Qifang B et al. (2020): Epidemiology and Transmission of COVID-19 in Shenzhen China: Analysis of 391 cases and 1,286 of their close contacts. MedRxiv.
A preprint publication that has not yet been reviewed (to be treated with caution).

[21] Hellewell J et al. (2020): Feasibility of controlling COVID-19 outbreaks by isolation of cases and contacts. Lancet Glob Health; 8 e488-96. DOI: 10.1016 / S2214-109X (20) 30074-7.

[22] Robert Koch Institute (March 16, 2020): COVID-19: Criteria for discharge from hospital or from domestic isolation.

[23] Feng Z et al. (2020): The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team (2020): The Epidemiological Characteristics of an Outbreak of 2019 Novel Coronavirus Diseases (COVID-19) - China 2020. CCDC Weekly; Vol. 2.

[24] Robert Koch Institute (2020): Daily situation report of the RKI on Coronavirus Disease-2019 (COVID-19) from March 30, 2020.

[25] Science Media Center (2020): Utilization of intensive care units: Figures from Germany and Europe. Status: March 24, 2020.

[26] Grasselli G et al. (2020): Critical Care Utilization for the COVID-19 Outbreak in Lombardy, Italy: Early Experience and Forecast During an Emergency Response. JAMA. DOI: 10.1001 / jama.2020.4031.

[27] Verity R et al. (2020): Estimates of the severity of COVID-19 disease. The Lancet Infectious Diseases. DOI: 10.1016 / S1473-3099 (20) 30243-7.

[28] Zhou F et al. (2020): Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet; 395 (10229): 1054-1062. 10.1016 / S0140-6736 (20) 30566-3.

[29] Quest Diagnostics (undated): SARS-CoV-2 RNA, Qualitative Real-Time RT-PCR (Test Code 39433). Provided by the Food and Drug Administration.

[30] Zou L et al. (2020): SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients. NEJM; 382: 1177-1179. DOI: 10.1056 / NEJMc2001737.

[31] Bao L et al. (2020): Reinfection could not occur in SARS-CoV-2 infected rhesus macaques. BioRxiv. DOI: 10.1101 / 2020.03.13.990226.
A preprint publication that has not yet been reviewed (to be treated with caution).

[32] Wu L et al. (2007): Duration of Antibody Responses after Severe Acute Respiratory Syndrome. Emerging Infectious Diseases; 13 (10): 1562-1564. DOI: 10.3201 / eid1310.070576.

[33] NDR Info: Coronavirus update - episode 24. As of March 30, 2020.
Prof. Christian Drosten speaks about these results in the podcast from minute 25; however, they cannot yet be found in the database or on preprint servers.

Further sources of research

The collected SMC material on the SARS-CoV-2 coronavirus and the COVID-19 disease can be found at https://www.sciencemediacenter.de/alle-angebote/coronavirus/.