Clinical Presentation

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By Christian Hoffmann  &
  Bernd Sebastian Kamps

After an average incubation time of around 5 days (range: 2-14 days), a typical COVID-19 infection begins with dry cough and low-grade fever (38.1–39°C or 100.5–102.1°F), often accompanied by smell and taste diminishment. In a more advanced stage, patients may experience shortness of breath and require mechanical ventilation.

Laboratory findings include lymphocytopenia. In patients with a fatal outcome, levels of d-dimer, serum ferritin, serum lactate dehydrogenase and IL-6 were elevated compared to survivors.

The outcome of COVID-19 is often unpredictable, especially in older patients with comorbidities. The clinical picture ranges from completely asymptomatic to rapidly devastating courses. Much of the clinical data to date is still based on the experiences in China (Table 1 provides an overview of the most important studies). With the massive spread of the infection in Europe and the USA, it will become clear whether these experiences can be transferred to more local conditions.

Incubation period

A pooled analysis of 181 confirmed COVID-19 cases with identifiable exposure and symptom onset windows estimated the median incubation period to be 5.1 days with a 95% CI of 4.5 to 5.8 days (Lauer 2020). The authors estimated that 97.5% of those who develop symptoms will do so within 11.5 days (8.2 to 15.6 days) of infection. Fewer than 2.5% of infected persons will show symptoms within 2.2 days, whereas symptom onset will occur within 11.5 days in 97.5%. However, these estimates imply that, under conservative assumptions, 101 out of every 10,000 cases will develop symptoms after 14 days of active monitoring or quarantine. Another analysis of 158 confirmed cases outside Wuhan estimated a very similar median incubation period of 5.0 days (95 % CI, 4.4 to 5.6 days), with a range of 2 to 14 days (Linton 2020). In a detailed analysis of 36 cases linked to the first three clusters of circumscribed local transmission in Singapore, the median incubation period was 4 days with a range of 1-11 days (Pung 2020). Taken together, the incubation period of around 4-6 days is in line with that of other coronaviruses causing SARS or MERS (Virlogeux 2016).

Of note, the time from exposure to onset of infectiousness (latent period) may be shorter. There is little doubt that transmission of SARS-CoV-2 during the late incubation period is possible (Li 2020). In a longitudinal study, the viral load was high 2-3 days before the onset of symptoms, and the peak was even reached 0.7 days before the onset of symptoms. The authors of this Nature Medicine paper estimated that approximately 44% (95% CI 25-69%) of all secondary infections are caused by such presymptomatic patients (He 2020).

Symptoms

Fever, cough, shortness of breath

Symptoms occur in the majority of cases (for asymptomatic patients, see below). In the largest study published to date (Guan 2020, see Table 1 and 2), fever was the most common symptom in 88.7%, with a median maximum of 38.3 C; only 12.3% had a temperature of > 39 C. The absence of fever seems to be somewhat more frequent than in SARS or MERS; fever alone may therefore not be sufficient to detect cases in public surveillance. The second most common symptom is cough, occurring in about two thirds of all patients.

In the study from Wuhan on 191 patients hospitalized with severe COVID-19 (Zhou 2020), among survivors, median duration of fever was 12.0 days (8-13 days) and cough persisted for 19 days (IQR 12-23 days). Shortness of breath is also common, especially in severe cases (Table 2). Myalgia, chills and headache also may occur.

 

Table 1. Outstanding clinical studies, main characteristics
Guan     2020 Wu       2020 Mizumoto 2020 Zhou   2020
n 1,099 73,314 634 191
China China Japan Wuhan (China)
Median age 47
(IQR 35-58)
NA 58 56
(IQR 46-67)
“Older” age 15.1%
(> 65 yrs)
11.9%

(> 70 yrs)

75.1%

(> 60 yrs)

NA
Female 41.9% NA 49.4% 37.7%
Severe Dis. 15.7% 18.6% NA NA
(CAP definition) (more than mild pneumonia)
Death 1.4% (15)* 2.3% (1,023) 1.1% (7**) 28.3%
*short FU, outcomes unknown at time of data cut-off. **longer FU expected
The study by Guan (N Engl J Med) is the largest clinical cohort to date with 1,099 relatively well documented patients from 552 hospitals in 30 Chinese provinces, admitted as of January 29 (Guan 2020).

The second (Wu 2020) is a report from the Chinese CDC, summarizing what happened in during the first weeks.

The third study describes an outbreak onboard the Diamond Princess cruise ship (Mizumoto 2020).

The fourth study reports from hospitalized patients in Wuhan with severe COVID-19 who have a definite outcome (Zhou 2020).

 

In a meta-analysis of COVID-19 in papers published until February 23, fever (88.7%), cough (57.6%) and dyspnea (45.6%) were the most prevalent clinical manifestations (Rodrigues-Morales 2020). In another review, the corresponding percentages were 88.5%, 68.6% and 21.9%, respectively (Li 2020). As shown in Table 1, some differences between severe and non-severe cases are evident. In the Wuhan study on patients with severe COVID-19, multivariate analysis revealed that a respiratory rate of >24 breaths per minute at admission was higher in non-survivors (63% versus 16%). Others found higher rates of shortness of breath, and high temperature of >39.0 in older patients compared with younger patients (Lian 2020).

A plethora of symptoms have been described in the past few weeks, clearly indicating that COVID-19 is a complex disease, which in no way consists only of a respiratory infection. Although the symptoms are unspecific so that the differential diagnosis encompasses a wide range of infections, respiratory and other diseases, a close look at the patient should nevertheless be taken. The symptoms are briefly discussed below.

Otolaryngeal symptoms (including anosmia)

Although upper respiratory tract symptoms such as rhinorrhea, nasal congestion, sneezing and sore throat are relatively unusual, several groups have recently reported on anosmia and hyposmia as an early sign (Luers 2020, Gane 2020). Interestingly, these otolaryngological symptoms appear to be much more common in Europe than in Asia. However, it is still unclear whether this is a real difference or whether these complaints in the initial phase in China were not recorded well enough. There is now very good data from Europe:

Among 417 mild-to-moderate COVID-19 patients (from 12 European hospitals), 86% and 88% reported olfactory and gustatory dysfunctions, respectively (Lechien 2020). The vast majority was anosmic (hyposmia, parosmia, phantosmia did also occur) and the early olfactory recovery rate was 44%. Females were more affected than males. Olfactory dysfunction appeared before (12%), at the same time (23%) or after (65%) the appearance of other symptoms. There is no doubt that sudden anosmia or ageusia need to be recognized as important symptoms of COVID-19.

“Flu plus ‘loss of smell’ means COVID-19”. Among 263 patients presenting in March (at a single center in San Diego) with flu-like symptoms, loss of smell was found in 68% of COVID-19 patients (n=59), compared to only 16% in negative patients (n=203). Smell and taste impairment were independently and strongly associated with positivity (anosmia: adjusted odds ratio 11, 95%CI: 5‐24). Conversely, sore throat was independently associated with negativity (Yan 2020).

Cardiovascular symptoms and issues

There is growing evidence of direct and indirect effects of SARS-CoV-2 on the heart, especially in patients with pre-existing heart diseases (Bonow 2020). SARS-CoV-2 has the potential to infect cardiomyocytes, pericytes and fibroblasts via the ACE2 pathway leading to direct myocardial injury, but that pathophysiological sequence remains unproven (Hendren 2020). A second hypothesis to explain COVID-19-related myocardial injury centers on cytokine excess and/or antibody mediated mechanisms. Clinically, COVID-19 can manifest with an acute cardiovascular syndrome (termed “ACovCS”). Numerous cases with ACovCS have been described, not only with typical thoracic complaints, but also with very diverse cardiovascular manifestations. Troponin is an important parameter (see below). In a case series of 18 COVID-19 patients who had ST segment elevation, there was variability in presentation, a high prevalence of nonobstructive disease, and a poor prognosis. 6/9 patients undergoing coronary angiography had obstructive disease. Of note, all 18 patients had elevated D-dimer levels (Bangalore 2020).

In patients with a seemingly typical coronary heart syndrome, COVID-19 should also be considered in the differential diagnosis, even in the absence of fever or cough (Fried 2020, Inciardi 2020).

Gastrointestinal symptoms

In the Chinese studies, gastrointestinal symptoms were rarely seen. In a meta-analysis of 60 studies comprising 4,243 patients, the pooled prevalence of gastrointestinal symptoms was 18% (95% CI, 12%-25%); prevalence was lower in studies in China than other countries. Among the first 393 consecutive patients who were admitted to two hospitals in New York City, diarrhea (24%), and nausea and vomiting (19%) were more frequent than in the reports from China (Goyal 2020). Stool viral RNA was detected at higher frequency among those with diarrhea (Cheung 2020). As with otolaryngeal symptoms, it remains unclear whether this difference reflects geographic variation or differential reporting).

Neurologic symptoms

Neuroinvasive propensity has been demonstrated as a common feature of human coronaviruses. These viruses can invade the brainstem via a synapse‐connected route from the lung and airways. With regard to SARS‐CoV‐2, early occurrences such as olfactory symptoms (see above) should be further evaluated for CNS involvement. Potential late neurological complications in cured COVID-19 patients are possible (Baig 2020). A retrospective, observational case series found 78/214 patients (36%) with neurologic manifestations, ranging from fairly specific symptoms (loss of sense of smell or taste, myopathy, and stroke) to more non-specific symptoms (headache, low consciousness, dizziness, or seizure). Whether these more non-specific symptoms are manifestations of the disease itself remains to be seen (Mao 2020).

Especially in patients with severe COVID-19, neurological symptoms are common. In an observational series of 58 patients, ARDS due to SARS-CoV-2 infection was associated with encephalopathy, prominent agitation and confusion, and corticospinal tract signs. It remains unclear which of these features were due to critical illness–related encephalopathy, cytokines, or the effect or withdrawal of medication, and which features were specific to SARS-CoV-2 infection (Helms 2020).

Other and atypical symptoms and manifestations

In a case series from China, 12/38 patients (32%, more common in severe cases) had ocular manifestations consistent with conjunctivitis, including conjunctival hyperemia, chemosis, epiphora, or increased secretions. Two patients had positive PCR results from conjunctival swabs (Wu 2020).

Other new and sometimes puzzling clinical presentations have emerged in the current pandemic. There are case reports of non-specific symptoms, especially in the elderly population, underlining the need for extensive testing in the current pandemic (Nickel 2020).

Other signs of infection such as throat congestion, tonsil swelling, enlargement of lymph nodes or rash were almost inexistent. All symptoms are non-specific so that the differential diagnosis includes a wide range of infections, respiratory disorders that may not be distinguished clinically.

Laboratory findings

The most evident laboratory findings in the large cohort study from China (Guan 2020) are shown in Table 2. On admission, lymphocytopenia was present in 83.2% of the patients, thrombocytopenia in 36.2%, and leukopenia in 33.7%. In most patients, C-reactive protein was elevated to moderate levels; less common were elevated levels of alanine aminotransferase, and D-dimer. Most patients have normal procalcitonin on admission.

Patients with severe disease had more prominent laboratory abnormalities (including lymphocytopenia) than those with non-severe disease. This was also seen in a large retrospective study of hospitalized patients in Wuhan where lymphocyte and leukocyte count was significantly lower in non-survivors. In these, also levels of D-dimer, serum ferritin, high-sensitivity cardiac troponin I, serum lactate dehydrogenase and IL-6 were clearly elevated compared to survivors (Zhou 2020). In particular, D-dimer seemed to be of prognostic value. In the Wuhan study, all patients surviving had low D-dimer during hospitalization, whereas levels in non-survivors tended to increase sharply at day 10. In a multivariate analysis, D-dimer of > 1 µg/mL remained the only lab finding which was significantly associated with in-hospital death, with an odds ratio of 18.4 (2.6-129, p=0.003). However, D-dimer has a reported association with mortality in patients with sepsis. Many of these died from sepsis in the Wuhan study.

Table 2. Percentage of symptoms in the largest cohort to date (Guan 2020). Disease severity was classified according to American Thoracic Society (Metlay 2019) guidelines
Clinical symptoms All Severe Disease Non-
Severe
Fever,% 88.7 91.9 88.1
Cough,% 67.8 70.5 67.3
Fatigue,% 38.1 39.9 37.8
Sputum production,% 33.7 35.3 33.4
Shortness of breath,% 18.7 37.6 15.1
Myalgia or arthralgia,% 14.9 17.3 14.5
Sore throat,% 13.9 13.3 14.0
Headache,% 13.6 15.0 13.4
Chills,% 11.5 15.0 10.8
Nausea or vomiting,% 5.0 6.9 4.6
Nasal congestion,% 4.8 3.5 5.1
Diarrhea,% 3.8 5.8 3.5
Radiological findings
Abnormalities on X-ray,% 59.1 76.7 54.2
Abnormalities on CT,% 86.2 94.6 84.4
Laboratory findings
WBC <4,000 per mm3,% 33.7 61.1 28.1
Lymphocytes <1,500 per mm3,% 83.2 96.1 80.4
Platelets <150,000 per mm3,% 36.2 57.7 31.6
C-reactive protein ≥10 mg/L,% 60.7 81.5 56.4
Lactate dehydrogenase ≥250 U/L,% 41.0 58.1 37.1
AST >40 U/L,% 22.2 39.4 18.2
D-dimer ≥0.5 mg/L,% 46.6 59.6 43.2

 

Low lymphocytes and high LDH are also used in (not yet validated) risk scores to predict the risk of progression (Ji 2020). Low platelets have different causes (Review: Xu 2020).

In addition to low lymphocytes, LDH and d-dimer, a meta-analysis of 341 patients found that cardiac troponin I levels are significantly increased only in patients with severe COVID-19 (Lippi 2020). It remains to be seen whether troponin levels can be used as a prognostic factor. A comprehensive review on the interpretation of elevated troponin levels in COVID-19 was recently published (Chapman 2020).

In another retrospective observational study of 69 patients with severe COVID-19, the decrease of interleukin-6 (IL-6) levels was closely related to treatment effectiveness, while the increase of IL-6 indicated disease exacerbation. The authors concluded that the dynamic change of IL-6 levels can be used as a marker in disease monitoring in patients with severe COVID-19 (Liu 2020).

There is some data on immunological consequences of COVID-19 from two retrospective studies of 21 and 44 HIV-negative patients with COVID-19, showing significant decreases of CD4+ T-cells in almost all patients, with a more pronounced decline to even less than 200 CD4+ T-cells/µl in severe cases (Chen 2020, Quin 2020). There is also evidence from a larger study on SARS-CoV, showing a prolonged lymphopenia before returning towards normal after five weeks, with the lowest mean CD4+ T-cell count of 317 cells/µl (He 2005). Up to now, however, it remains unclear whether this is of clinical value.

Radiological findings

The primary findings on chest x-ray and CT are those of atypical pneumonia. The predominant CT abnormalities are bilateral, peripheral and basal predominant ground-glass opacity, consolidation, or both (Pan 2020). Patterns of radiological findings are described in a more detail in the chapter Diagnosis.

Asymptomatic cases

When considering asymptomatic patients, it is important to distinguish those in which infection is still too early to cause any symptoms and those who will remain asymptomatic during the whole time of infection. Asymptomatic patients may transmit the virus (Bai 2020, Rothe 2020). In a study from Northern Italy viral loads in nasal swabs between asymptomatic and symptomatic subjects did not differ significantly, suggesting the same potential for transmitting the virus (Cereda 2020). In an outbreak in a long-term care facility, 13/23 residents who tested positive were asymptomatic or presymptomatic on the day of testing (Kimball 2020).

While physicians need to be aware of asymptomatic cases, the true percentage of those who remain asymptomatic during the course of infection is difficult to assess. The probably best data come from 3,600 people on board the cruise ship Diamond Princess (Mizumoto 2020) who became involuntary actors in a “well-controlled experiment” where passengers and crew comprised an environmentally homogeneous cohort. Due to insufficient hygienic conditions, >700 people became infected while the ship was quarantined in the port of Yokohama, Japan. After systematic testing, 328 (51.7%) of the first 634 confirmed cases were found to be asymptomatic. Considering the varying of the incubation period between 5.5 and 9.5 days, the authors calculated the true asymptomatic proportion at 17.9% (Mizumoto 2020).

From a total of 565 Japanese citizens evacuated from Wuhan, the asymptomatic ratio was estimated to be 41.6% (Nishiura 2020). In another study on 55 asymptomatic patents with confirmed SARS-CoV-2, the majority was of middle age and had close contact with infected family members (Wang 2020). In a screening study conducted in Iceland, the number of patients testing positive for SARS-CoV-2 but without symptoms was 44%, although some of these may have been pre-symptomatic (Gudbjartsson 2020).

Taken together, these preliminary studies indicate that around 20-40% of all COVID-19 infected subjects may remain asymptomatic during their infection. But it may well be that we are still quite wrong. Only large-scale field studies on seroprevalence will be able to clarify the exact proportion.

Clinical classification

There is no broadly accepted or valid clinical classification for COVID-19. The largest clinical study distinguished between severe and non-severe cases (Guan 2020), according to the Diagnosis and Treatment Guidelines for Adults with Community-acquired Pneumonia, published by the American Thoracic Society and Infectious Diseases Society of America (Metlay 2019). In these validated definitions, severe cases include either one major criterion or three or more minor criteria. Minor criteria are a respiratory rate > 30 breaths/min, PaO2/FIO2 ratio <250, multilobar infiltrates, confusion/disorientation, uremia, leukopenia, low platelet count, hypothermia, hypotension requiring aggressive fluid resuscitation. Major criteria comprise septic shock with need for vasopressors or respiratory failure requiring mechanical ventilation.

Some authors (Wang 2020) have used the following classification including four categories:

  1. Mild cases: clinical symptoms were mild without pneumonia manifestation through image results
  2. Ordinary cases: having fever and other respiratory symptoms with pneumonia manifestation through image results
  3. Severe cases: meeting any one of the following: respiratory distress, hypoxia (SpO2 ≤93%), abnormal blood gas analysis: (PaO2 <60mmHg, PaCO2 >50mmHg)
  4. Critical cases: meeting any one of the following: Respiratory failure which requires mechanical ventilation, shock, accompanied by other organ failure that needs ICU monitoring and treatment.

In the report of the Chinese CDC, estimation of disease severity used almost the same categories (Wu 2020) although numbers 1 and 2 were combined. According to the report, there were 81% mild and moderate cases, 14% severe cases and 5% critical cases. There are preliminary reports from the Italian National Institute of Health, reporting on 24.9% severe and 5.0% critical cases (Livingston 2020). However, these numbers are believed to strongly overestimate the disease burden, given the very low number of diagnosed cases in Italy at the time. Among 7,483 US heath care workers with COVID-19, a total of 184 (2.1–4.9%) had to be admitted to ICUs. Rate was markedly higher in HCWs older 65 of age, reaching 6.9–16.0% (CDC 2020).

Outcome

We are facing rapidly increasing numbers of severe and fatal cases in the current pandemic. The two most difficult but most frequently asked clinical questions are 1. How many patients end up with severe or even fatal courses of COVID-19? 2. What is the true proportion of asymptomatic infections? We will learn more about this shortly through serological testing studies. However, it will be important that these studies are carefully designed and carried out, especially to avoid bias and confounding.

Case fatality rates

The case fatality rates (CFR) or infection fatality rates (IFR) are difficult to assess in such a dynamic pandemic. CFR can be biased upwards by underreporting of cases and downwards by insufficient follow up or unknown outcome. A downward trend may also indicate improvements in epidemiological surveillance. COVID-19 fatality is likely overestimated and especially early estimates are susceptible to uncertainty about asymptomatic or subclinical infections and several biases, including biases in detection, selection or reporting (Niforatos 2020).

Dividing the number of deaths by the number of total confirmed cases (April 14 for Italy: 13.2%, Sweden 10.6%, Spain 10.4%, South Korea 2.2%, Germany 3.0%) is not appropriate.

The picture is much more complex and these simple calculations probably do not reflect the true mortality in each country without taking into factor three other issues:

  1. The testing policies (and capacities) in a country. This is the most important factor. The fewer people you test (all people, only symptomatic patients, only those with severe symptoms) the higher the mortality. In Germany, testing systems and high lab capacities were established rapidly (Stafford 2020).
  2. Age of the total population and especially of the population which is affected first. For example, in Italy, higher percentages of older people became infected during the first weeks, compared to Germany (where many people acquired SARS-CoV during ski holidays or carnival sessions). Especially if high-risk sites (such as retirement homes) are affected, death cases in the country will increase considerably. For example, a single outbreak in Washington has led to 34 deaths among 101 residents of a long-term care facility (McMichael 2020) – this is exactly the same number of death cases which Australia has reported as whole country on April 4, among a total of 5,635 confirmed COVID-19 cases.
  3. Stage of the epidemic. Some countries have experienced their epidemic grow early, some are still a few days or weeks behind. Death rates only reflect the infection rate of 2-3 weeks previously. In the large retrospective study from Wuhan, the time from illness onset to death was 18.5 days (IQR 15-22 days).

The “death rates” for some selected countries, based on the number of deaths and tests, is shown in Figure 1. These curves reflect test readiness and test capacities. A country such as Sweden, which initially relied on “herd immunity”, differs significantly from countries in which a lot has been tested from the beginning of the epidemic, such as Germany. The USA is still at the beginning, in Korea the outbreak was stopped relatively quickly by intensive tracking measures.

The summarizing report from the Chinese CDC found a death rate of 2.3%, representing 1,023 among 44,672 confirmed cases (Wu 2020). Mortality increased markedly in older people. In the cases aged 70 to 79 years, CFR was 8.0% and cases in those aged 80 years older had a 14.8% CFR. CFR was also elevated among those with cardiovascular diseases (10.5%), chronic respiratory diseases (6.3%) for hypertension (6.0%) and cancer (5.6%). Among 1,716 health care workers (HCW), 14.8% of confirmed cases were classified as severe or critical and 5 deaths were observed. In an updated study, 23/3,387 HCWs in China have died, which corresponds to a mortality of 0.68%. The median age was 55 years (range, 29 to 72), and 11 of the 23 deceased HCWs had been reactivated from retirement (Zhang 2020). Current studies in the USA have found similar rates, mortality estimates were 0.3-0.6% (CDC 2020). Of the 27 HCW who have died from COVID-19 until mid-April, 18 were over 54 years of age. The overall low mortality rates were probably due to the fact that HCWs were younger and healthier, but also that they had been tested earlier and more frequently. However, these rates may better reflect true CFRs.

 

Figure 1. People who tested positive (among 1 million inhabitants, dashed) and deaths (among 10 million inhabitants). “Mortality” reaches 10% at the point where the curves intersect. This has happened for countries such as Spain, Italy or Sweden, but is unlikely for others like Germany, Switzerland or Denmark.

 

An in-depth analysis of 48,557 cases and 2,169 deaths from the epicenter, Wuhan, found lower rates (Wu 2020). The authors estimated an overall symptomatic case fatality risk (SCFR, the probability of dying after developing symptoms) of only 1.4% (0.9–2.1%). Compared to those aged 30–59 years, those aged below 30 and above 59 years were 0.6 (0.3–1.1) and 5.1 (4.2–6.1) times more likely to die after developing symptoms (Wu 2020). Other groups have confirmed these lower rates (Verity 2020).

Again, the most valid data seem to come from the Diamond Princess. As of April 17, the total number of infected reached 712, and 13 patients have died from the disease leading to a CFR of 1.8%. However, this rate may yet increase, as at least 7 patients were in serious condition (Moriarty 2020). If all patients seriously ill at the last follow up (April 14) die, this would result in a CFR of 2.8%. On the other hand, around 75% of the patients on the Diamond Princess were of 60 years or older, many of them in their eighties. Projecting the Diamond Princess mortality rate onto the age structure of the general population, it is obvious that the mortality rate may be much lower in other broader populations. Mortality would be in a range of 0.2-0.4 %.

The mortality rates from the probably well-monitored HCWs also come relatively close to these rates (CDC 2020, Zhang 2020). Again, we will learn more from limited outbreaks affecting homogeneous populations, such as cruise ships and aircraft carriers. Two large “involuntary field studies” are currently taking place: more than 600 seafarers are infected on the US aircraft carrier Theodore Roosevelt (one soldier has already died), and more than 1,000 COVID-19 patients on the French aircraft carrier Charles de Gaulle. These populations are probably young, healthy and correspond more to the general population.

Risk factors for severe disease

From the beginning of the epidemic, older age has been identified as an important risk factor for disease severity (Huang 2020, Guan 2020). In Wuhan, there was a clear and considerable age dependency in symptomatic infections (susceptibility) and outcome (fatality) risks, by multiple folds in each case (Wu 2020). According to the Italian National Institute of Health, an analysis of the first 2,003 death cases, median age was 80.5 years (IQR 74.3-85.9). Only 17 (0.8%) were 49 years or younger, and 87.7% were older than 70 years (Livingston 2020). More recently, another important study had highlighted the severity of COVID-19 in older people (McMichael 2020). In an outbreak reported from King County/Washington, a total of 167 confirmed cases were observed in 101 residents (median age 83 years) of a long-term care facility, in 50 health care workers (HCW, median age 43 years), and 16 visitors. The case fatality rate for residents was 33.7% (34 of 101) and 0% among HCW.

Beside older age, several risk factors have been evaluated in the current pandemic. In the largest clinical study to date, some comorbidities such as hypertension have been identified as the main risk factors for severe disease and death (Table 3).

Others have confirmed a higher rate for patients with comorbidities such as hypertension or diabetes. In multivariate analysis of hospitalized patients with severe COVID-19, however, no comorbidity remained significantly associated with outcome (Wang 2020, Zhou 2020).

In another retrospective cohort of 487 COVID-19 patients in Zhejiang Province of China with detailed clinical data, severe cases were also older and more male. Severe cases had a higher incidence of hypertension, diabetes, cardiovascular diseases, and malignancy, and less exposure to epidemic area, but more infected family members. In a multivariate analysis, beside older age, male gender (OR 3.68, 95% CI 1.75–7.75, p=0.001) and presence of hypertension (OR 2.71, 95% CI 1.32–5.59, p=0.007) were independently associated with severe disease at admission, irrespective of adjustment of time to admission (Shi 2020). Among 1,590 hospitalised patients from mainland China, after adjusting for age and smoking status, COPD (hazard ratio 2.7, 95%CI 1.4-5.0), diabetes (HR 1.6, 95%CI 1.03-2.5), hypertension (HR 1.6, 95%CI 1.1-2.3) and malignancy (HR 3.5, 95%CI 1.6-7.7) were risk factors of reaching endpoints (Guan 2020). Among the first 393 consecutive patients who were admitted to two hospitals in New York City, obese patients were more likely to require mechanical ventilation (Goyal 2020).

As shown in Table 3, there was a slightly higher rate of current smokers in patients with severe disease. A meta-analysis of 5 studies comprising 1,399 patients observed only a trend but no significant association between active smoking and severity of COVID-19 (Lippi 2020). However, other authors have emphasized that current data do not allow to draw firm conclusions about the association of severity of COVID-19 with smoking status (Berlin 2020).

 

Table 3. Age and comorbidities in the NEJM paper (Guan 2020)
All Severe Disease Non-Severe
Age > 65 15.1 27.0 12.9
Age < 50 56.0 41.7 58.7
Never smoker 85.4 77.9 86.9
Former or current smoker 14.5 22.1 13.1
COPD,% 1.1 3.5 0.6
Diabetes,% 7.4 16.2 5.7
Hypertension,% 15.0 23.7 13.4
Coronary heart disease,% 2.5 5.8 1.8
Cerebrovascular disease,% 1.4 2.3 1.2
Hepatitis B infection,% 2.1 0.6 2.4
Cancer,% 0.9 1.7 0.8
Chronic renal disease,% 0.7 1.7 0.5
Immune deficiency,% 0.2 0 0.2

So far there are no reliable, validated risk scores. The CURB-65 used in community-acquired pneumonia does not seem to be very meaningful. In a study of 208 patients, a new score was developed to predict progression. It is based on age, comorbidities, lymphocytes and LDH and seems to work quite well, but it must still be validated by larger studies (Ji 2020). This also applies to other, sometimes even more complicated scores (Gong 2020).

More research is needed on the deleterious effect of comorbidities, especially with regard to the renin-angiotensin-aldosterone system (RAAS). Hypertension, cardiovascular disease and diabetes share underlying RAAS pathophysiology that may be clinically insightful. In particular, activity of the angiotensin-converting enzyme 2 (ACE2) is dysregulated (increased) in cardiovascular disease (Hanff 2020). As SARS-CoV-2 cell entry depends on ACE2 (Hoffmann 2020), increased ACE2 levels may increase the virulence of SARS-CoV-2 within the lung and heart.

In the largest study to date of 1,099 patients with COVID-19, hypertension was associated with an increased risk (24% versus 13%) of severe course of disease (Guan 2020). However, comedication was not recorded in this study, and several medical societies and reviews explicitly advise against discontinuing ACE inhibitors (Bavishi 2020, ESH 2020, Vaduganathan 2020).

Furthermore, the binding of SARS-CoV-2 to ACE2 appears to lead to an imbalance in the RAS (RAAS) system. Animal studies have shown that this imbalance could even be influenced favourably by ACE inhibitors or sartans in the course of pneumonia (Gurwitz 2020, Sun 2020). The biological plausibility of the salutary effects of RAAS inhibitors is intriguing and several trials of starting losartan in patients with COVID-19 are currently planned.

More recently, the first clinical study has indicated no deleterious effect of RAAS inhibitors in COVID-19. Among 42 of 417 patients admitted to Shenzhen Hospital while on antihypertensive therapy, patients receiving these drugs had a lower rate of severe diseases than those without (5/17 compared to 12/25), and a trend toward a lower level of IL-6 in peripheral blood (Meng 2020). In another study, patients with ACE inhibitors also had no increased risk of severe courses (Wang 2020).

Predisposition

COVID-19 shows an extremely variable course, from completely asymptomatic to fulminantly fatal. In some cases it affects young and apparently healthy people, for whom the severity of the disease is neither caused by age nor by any comorbidities – just think of the Chinese doctor Li Wenliang, who died at the age of 34 from COVID-19 (see chapter Timeline). So far, only assumptions can be made. Is there a genetic predisposition for severe courses? Some preliminary reports suggest that this is the case. For example, a report from Iran describes three brothers aged 54 to 66 who all died of COVID-19 after less than two weeks of fulminating progress. All three had previously been healthy and there were no underlying illnesses (Yousefzadegan 2020).

In addition to the genetic predisposition, other potential reasons for a severe course need to be considered: the amount of viral exposure (probably high for Li Wenliang?), the route by which the virus enters the body, ultimately also the virulence of the pathogen and a possible (partial) immunity from previous viral diseases. All of this will have to be investigated in the coming months.

Overburdened health care systems

Mortality may be also higher in situations where hospitals are unable to provide intensive care to all the patients who need it, in particular ventilator support. Mortality would thus also be correlated with health-care burden. Preliminary data show clear disparities in mortality rates between Wuhan (>3%), different regions of Hubei (about 2.9% on average), and across the other provinces of China (about 0.7% on average). The authors have postulated that this is likely to be related to the rapid escalation in the number of infections around the epicenter of the outbreak, which has resulted in an insufficiency of health-care resources, thereby negatively affecting patient outcomes in Hubei, while this has not yet been the situation in other parts of China (Ji 2020). Another study estimated the risk of death in Wuhan as high as 12% in the epicentre and around 1% in other more mildly affected areas (Mizumoto 2020)­.

The nightmare of insufficient ressources is currently the reality in Northern Italy. In Italy, on March 15, the cumulative death numbers exceeded for the first time those of admissions to intensive care units – a clear sign for a collapsing health care system. Other countries or regions will face the same situation soon.

Reactivations, reinfections

There are several reports of patients who become positive again after negative PCR tests (Lan 2020, Xiao 2020, Yuan 2020). These reports have gained much attention, because this could indicate both reactivations as well as reinfections. After closer inspection of these reports, however, there is no good evidence for reactivations or reinfections, and other reasons are much more likely. Methodological problems of PCR always have to be considered; the results can considerably fluctuate (Li 2020). Insufficient material collection or storage are just two examples of many problems with PCR. Even if everything is done correctly, it can be expected that a PCR could fluctuate between positive and negative at times when the values ​​are low and the viral load drops at the end of an infection (Wölfel 2020). It also depends on the assay used, the detection limit is between a few hundred and several thousand virus copies/mL (Wang 2020).

The largest study to date found a total of 25 (14.5%) of 172 discharged COVID-19 patients who had a positive test at home after two negative PCR results at hospital (Yuan 2020). On average, the time between the last negative and the first positive test was 7.3 (standard deviation 3.9) days. There were no differences to patients who remained negative. This and the short period of time suggest that in these patients, no reactivations are to be expected.

Reactivations as well as rapid new infections would be very unusual, especially for coronaviruses. If a lot of testing is done, you will find a number of such patients who become positive again after repeated negative PCR and clinical convalescence. The phenomenon is likely to be overrated. Most patients get well anyway; moreover, it is unclear whether renewed positivity in PCR is synonymous with infectiousness.

Outlook

Over the coming months, serological studies will give a clearer picture of the true number of asymptomatic patients and those with unusual symptoms. More importantly, we have to learn more about risk factors for severe disease, in order to adapt prevention strategies. Older age is not the only risk factor. Recently, a 106-year-old COVID-19 patient recently recovered in the UK. The precise mechanisms how comorbidities (and comedications) may contribute to an increased risk for a severe disease course have to be elucidated. Genetic and immunological studies have to reveal susceptibility and predisposition for both severe and mild courses. Who is really at risk, who is not? Quarantining only the old is too easy.

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