In December 2019, a novel coronavirus (now called SARS-CoV-2) was detected in three patients with pneumonia connected to the cluster of acute respiratory illness cases from Wuhan, China. By the end of February 2020, several were experiencing sustained local transmission of coronavirus disease.
Symptoms, severity and case fatality
By 24 March 2020, 50 569 laboratory-confirmed cases have been reported to the European Surveillance System (TESSy).
Information on symptoms was available for 14 011 cases from 13 countries, mainly (97%) from Germany. Among these cases, the most commonly reported clinical symptom was fever (47%), dry or productive cough (25%), sore throat (16%), general weakness (6%) and pain (5%). The frequency of these symptoms differs notably from those reported from China. Data on cases reported more recently to TESSy may be biased toward the more seriously ill because national policies have shifted focus towards testing of more severe cases.
Preliminary estimates of severity were based on the analysis of data from EU/EEA countries and the UK available in TESSy and online country reports (for countries whose data was incomplete or missing in TESSy).
Among all cases:
- Hospitalisation occurred in 30% (13 122 of 43 438) of cases reported from 17 countries (median country-specific estimate, interquartile range (IQR): 24%, 11-41%)
- Severe illness (requiring ICU and/or respiratory support) accounted for 2 179 of 49 282 (4%) cases from 16 countries (median, IQR: 3%, 2-8%).
Among hospitalised cases:
- Severe illness was reported in 15% (1 894 of 12 961) of hospitalised cases from 15 countries (median, IQR: 16%, 10-24%).
- Death occurred in 1 457 of 12 551 (12%) hospitalised cases from eight countries (median, IQR: 10%, 6-14%).
Age-specific hospitalisation rates among all cases based on TESSy data showed elevated risk among those aged 60 years and above
Robust estimates for case fatality risk for COVID-19 are still lacking and potentially biased by incomplete outcome data and differences in testing policies. The mean crude case-fatality (proportion of deaths among total cases reported) from the EU/EEA and the UK by 23 March 2020 was 5.4% (median country-specific estimate: 0.5%; range: 0.0-9.3%).
Based on a large dataset from cases in China, the overall case fatality risk (CFR) among laboratory-confirmed cases was higher in the early stages of the outbreak (17.3% for cases with symptom onset from 1-10 January) and has reduced over time to 0.7% for patients with symptom onset after 1 February. In data on diagnosed COVID-19 cases in China and South Korea, overall CFR was 2.3%and 0.5%, respectively, and increased with age in all settings, with the highest CRF among people over 80 years of age (14.8% and 3.7%, respectively). Similarly, age-specific estimates of crude case-fatality for Germany, Italy and Spain increased rapidly with age, particularly above 60 years of age. The absolute numbers of deaths also increased with age in each country: those aged 70–79 years accounted for 19% (Germany), 36% (Italy) and 20% (Spain) of all deaths per country; these proportions rose to 74% (Germany), 50% (Italy) and 67% (Spain) among those aged 80 years and above.
Data from a country report for Italy as of 19 March 2020 showed an increased risk of death among males compared with females in all age groups from 50 years and above. The risk of death becomes more pronounced with age, with an overall male-to-female ratio among COVID-19 deaths of 2.4:1. According to TESSy data from Germany as of 24 March 2020, this ratio is 1.6:1, with a particularly increased risk of death among males aged 70–79 years compared to their female contemporaries.
Among deceased patients in Italy until 19 March 2020, 73.8% had hypertension, 33.9% diabetes, 30.1% ischaemic heart disease, 22.0% atrial fibrillation, 19.5% a cancer diagnosed in the last five years. About half (48.6%) of the COVID-19 deaths had three or more comorbidities, 26.6% had two comorbidities, 23.5% had one comorbidity, and 1.2% had none. The most common complications observed in Italy were respiratory insufficiency (96.5%), acute kidney failure (29.2%), acute myocardial damage (10.4%) and bacterial superinfection (8.5%).
Current estimates suggest a median incubation period from five to six days for COVID-19, with a range from one to up to 14 days. A recent modelling study confirmed that it remains prudent to consider the incubation period of at least 14 days.
Over the course of the infection, the virus has been identified in respiratory tract specimens 1-2 days before the onset of symptoms and it can persist up to 8 days in moderate cases and up to 2 weeks in severe cases. In terms of viral load profile, SARS-CoV-2 is similar to that of influenza, which peaks at around the time of symptom onset, but contrasts with that of SARS-CoV, which peaks at around 10 days after symptom onset, and that of MERS-CoV which peaks at the second week after symptom onset. Older age has also been associated with higher viral loads. The high viral load close to symptom onset suggests that SARS-CoV-2 can be easily transmissible at an early stage of infection. Viral RNA has been detected in faeces from day 5 after symptom onset and up to 4 to 5 weeks in moderate cases, as well as in whole blood, serum saliva a,nd urine. Prolonged viral RNA shedding has been reported from nasopharyngeal swabs (up to 37 days among adult patients) and in faeces (more than one month after infection in paediatric patients). It should be noted that viral RNA shedding does not equate with infectivity. The viral load can be a potentially useful marker for assessing disease severity and prognosis: a recent study indicated that viral loads in severe cases were up to 60 times higher than in mild cases.
Basic reproduction number (R0)
Recent modelling of the basic reproductive number (R0) from Italy estimates R0 between 2.76 and 3.25. Researchers from Lombardy who analysed the early phase of the outbreak in their region reported a reduction in R0 shortly after the introduction of mitigation measures.This is consistent with findings from China. A recent review of 12 modelling studies reports the mean R0 at 3.28, with a median of 2.79. Further research is needed to get a more accurate estimate of R0 in the various outbreak settings.
Infection in asymptomatic individuals
Asymptomatic infection at time of laboratory confirmation has been reported from many settings; a large proportion of these cases developed some symptoms at a later stage of infection. There are, however, also reports of cases remaining asymptomatic throughout the whole duration of laboratory and clinical monitoring. Viral RNA and infectious virus particles were detected in throat swabs from two German citizens evacuated from Hubei province on 1 February 2020 who remained well and afebrile seven days after admission to a hospital in Frankfurt. A mother and her child (from a family cluster) who both tested positive by quantitative RT-PCR (nasopharyngeal swab samples) remained asymptomatic (including normal chest CT images during the observation period). Similar viral loads in asymptomatic versus symptomatic cases were reported in a study including 18 patients. Persistent positivity of viral RNA in throat and anal swabs was reported in an asymptomatic female patient after 17 days of clinical observation and treatment.
Transmission in pre-symptomatic stage of infection
No significant difference in viral load in asymptomatic and symptomatic patients has been reported, indicating the potential of virus transmission from asymptomatic patients. Major uncertainties remain with regard to the influence of pre-symptomatic transmission on the overall transmission dynamics of the pandemic because the evidence on transmission from asymptomatic cases from case reports is suboptimal. Pre-symptomatic transmission has also been inferred through modelling, and the proportion of pre-symptomatic transmission was estimated between 48% and 62%. Pre-symptomatic transmission was deemed likely based on a shorter serial interval of COVID-19 (4.0 to 4.6 days) than the mean incubation period (five days). The authors indicated that many secondary transmissions would have already occurred at the time when symptomatic cases are detected and isolated.
Children made up a very small proportion of the 50 068 cases reported to TESSy as of 24 March (with known age (<10 years (1%), 10–19 years (4%)). The male-to-female ratio (1.2:1 overall) was less pronounced in children (1.1 and 1.0 in those aged 10–19 and <10 years, respectively) and increased with age. The age distribution observed in the EU/EEA and the UK reflects testing policies and case definitions, which usually include symptoms, and it is possible that the small proportion of affected children reflects a lower risk of children to develop COVID-19. Current literature indicates that children are as likely to be infected as adults but they experience mild clinical manifestations. Data in TESSy show no difference between age groups in the order of most common symptoms but fever was slight less commonly reported among those aged 10–19 years of age (39%, compared to 47% for all ages) and sore throat was less common among those aged <10 years (10%, compared to 16% for all ages). Asymptomatic cases in infants and children have been also reported. Two studies on patients with positive laboratory results reported that 10/15 (66.7%) and 4/31 (13%) of the children were asymptomatic. Exposure to COVID-19 among children is likely to occur within the family or in a household context.
Pregnant women and neonates
Pregnant women appear to experience similar clinical manifestations as non-pregnant adult patients with COVID-19 pneumonia. There are only two reported cases of mothers with ICU admission and requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO). No maternal deaths have been reported so far. COVID-19 appears to be less lethal for pregnant women than SARS (15% CFR in pregnancy) and MERS (27% CFR in pregnancy). There is limited evidence of severe adverse outcomes, such as miscarriage, preterm birth, stillbirths and foetal distress. No pregnancy losses and only one stillbirth have been reported to date. Intrauterine transmission appears to be unlikely. Elective Caesarean section deliveries have been commonly reported as a precautionary method to avoid perinatal transmission. A confirmed COVID-19 neonatal case has been recently reported, however the mode of transmission remains unclear. A neonate born to a confirmed maternal case had negative laboratory results for COVID-19 and died due to multi-organ failure. The virus has not been found in breastmilk.
Data from Italy corroborate previously identified population groups at higher risk for having severe disease and death. These groups are elderly people above 70 years of age, and people with underlying conditions such as hypertension, diabetes, cardiovascular disease, chronic respiratory disease and cancer. Men in these groups appear to be at a higher risk than females. Chronic obstructive pulmonary disease (COPD), cardiovascular diseases, and hypertension have been identified as strong predictors for ICU admission.
Higher ACE2 (angiotensin converting enzyme II) gene expression may be linked to higher susceptibility to SARS-CoV-2. It has been shown that ACE2 expression in lung tissues increases with age, tobacco use and with some types of antihypertensive treatment. These observations might explain the vulnerability of older people, tobacco users/smokers and those with hypertension; they also highlight the importance of identifying smokers as a potential vulnerable group for COVID-19.
It is too early to know how long the protective immune response against SARS-CoV2 will last, as this will require longitudinal serological studies that follow patients’ immunity over an extended period of time. Evidence from other coronavirus infections (SARS and MERS) indicates that immunity may last for up to three years and re-infection with the same strain of seasonal circulating coronavirus is highly unlikely in the same or following season. This could also hold true for SARS-CoV2 as there is emerging evidence from early studies suggesting that that individuals develop antibodies after infection and are likely to be immune from reinfection in the short term.
The four coronaviruses that are endemic in human populations are responsible for 10–15% of common cold infections and display a marked winter seasonality in temperate climates, with a peak between December and April, but are hardly detected in the summer months. The seasonality of coronaviruses might be driven, in part, by environmental conditions and host susceptibility, because coronaviruses are more stable under low and midrange relative humidity (20–50%) when the defence mechanisms of the airways are suppressed. However, based on preliminary analyses of the COVID-19 outbreak in China and other countries, high reproductive numbers were observed not only in dry and cold districts but also in tropical districts with high absolute humidity, such as in Guangxi and Singapore. There is no evidence to date that SARS-CoV-2 will display a marked winter seasonality, such as other human coronaviruses in the northern hemisphere, which emphasises the importance of implementing intervention measures such as isolation of infected individuals, workplace distancing, and school closures.
Survival in the environment
Recent publications have evaluated the survival of SARS-CoV-2 on different surfaces. The environmental stability of viable SARS-CoV-2 is up to 3 hours in the air post aerosolisation, up to 4 hours on copper, up to 24 hours on cardboard, and up to 2–3 days on plastic and stainless steel, albeit with significantly decreased titres. These findings are comparable with the results obtained for environmental stability of SARS-CoV-1. However, as these are results from experimental studies, they do not directly translate to fomite infectivity in the real world.
Different levels of environmental contamination have been described in rooms of COVID-19 patients, ranging from 1 positive out of 13 samples to 13 out of 15 samples testing positive for SARS-CoV-2 before cleaning. No air samples were positive in these studies, but one sample from an air exhaust outlet was positive indicating, according to the authors, that virus particles may be displaced by air and deposited on surfaces.
In a study of environmental contamination in a Chinese hospital during the COVID-19 outbreak, SARS-CoV-2 was detected in environmental samples from intensive care units (ICU) dedicated to COVID-19 care, a COVID-19-dedicated obstetric isolation ward, and a COVID-19-dedicated isolation ward. SARS-CoV-2 was also detected on objects such as the self-service printers used by patients to self-print the results of their exams, desktop keyboards and doorknobs. Virus was detected most commonly on gloves (15.4% of samples) but rarely on eye protection devices (1.7%). This evidence indicates that fomites may play a role in transmission of SARS-CoV-2 but the relative importance of this route of transmission compared to direct exposure to respiratory droplets is still unclear.
There is currently no approved specific treatment or vaccine against COVID-19 infection. Patients require supportive care and oxygen supplementation. This can be done through non-invasive ventilation (if performed in a negative pressure room or through a helmet) or via mechanical ventilation. Critically ill patients may also require vasopressor support and antibiotics for secondary bacterial infections. Clinician reports from Italy and the USA refer to a number of complications such as cardiomyopathy and sudden onset death, as well as thromboembolic episodes (pulmonary embolism). Data collection through the World Health Organization’s COVID-19 Clinical Network is ongoing to assess the frequency of these complications.
A number of pharmaceuticals are being used for severe and critically ill patients as potential treatments against SARS-CoV-2, including ribavirin, interferon β-1a, the antiviral combination lopinavir/ritonavir, the antimalarial chloroquine/hydroxychloroquine, the antiviral nucleotide analogue remdesivir and the antiviral favipiravir. It is important that the available pharmaceuticals are carefully assessed in randomised controlled trials (RCTs); several clinical trials are recruiting patients globally to assess the effect of different treatment options.
A randomised, controlled, open-label trial of lopinavir/ritonavir in 199 COVID-19 patients in China failed to show any favourable effect on the clinical course or the mortality compared to standard treatment. Hydroxychloroquine has been shown in vitro to alter the uptake of the virus in cells, and a small case series and trial have reported its use in patients during this outbreak in China and Europe. It remains one of the possible therapies that needs to be evaluated through an adequately sized RCT. Systemic use of steroids is not recommended because they might increase the viral replication and shedding of the virus along with other steroid-related side effects. Other approaches are also assessed such as the blocking of the inflammatory cascade by IL6- & IL4- blockers.
Reports that non-steroidal anti-inflammatory drugs worsen COVID-19 through increased expression of angiotensin-converting enzyme 2 (ACE2), whose receptor is used by SARS-CoV-2 to enter the target cells, are not supported by evidence.