In patients of COVID-19, what are the symptoms and clinical features of mild and moderate cases?

April 1, 2020

Melina Michelen, Nicholas Jones and Charitini Stavropoulou

On behalf of the Oxford COVID-19 Evidence Service Team
Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences
University of Oxford

School of Health Sciences, City, University of London

Correspondence to melina.michelen@city.ac.uk

VERDICT

• Cough was observed in two thirds of cases in a systematic review and the largest cohort studies, suggesting it is unreliable alone as a key diagnostic symptom.
• Fever (< 39.1 °C) was the most frequent symptom for mild and moderate cases of COVID-19, though a recent UK study suggests anosmia may be a stronger predictor of COVID-19 than self-reported fever amongst people in the community.
• Overall, there is still scarce and inconclusive evidence on symptoms that easily distinguish mild and moderate cases of COVID-19 from severe cases.
• The majority of available evidence was from hospitalised patients. Mild and moderate cases were usually defined as those without pneumonia, acute respiratory distress syndrome (ARDS) or Intensive Care Unit (ICU) admission. Applicability to community cohorts is therefore uncertain, though evidence is growing.
• Other reported symptoms include dyspnea, headache, anosmia, diarrhoea, sore throat, fatigue and rhinorrhea.
• The updated search identified new symptoms that were not previously reported, including ocular reaction and skin rash.

BACKGROUND
COVID-19 presents varied clinical features, ranging from asymptomatic to ARDS. The most common symptoms at onset of COVID-19 include fever, cough, and shortness of breath.¹ Yet about 80% of infections are mild (no pneumonia manifestations) or asymptomatic, though still contagious.²  If the virus is not causing serious symptoms, people are less likely to recognise it, take protective measures, or seek medical help, thus affecting the public health efforts to contain the disease. As the virus continues to spread, more mild cases will arise and healthcare professionals need to recognise these to minimise the population, health systems, and economic risks and accurately portray total numbers of COVID-19 infections. Differentiating mild and moderate from severe disease may also help clinicians in more accurately triaging cases.

CURRENT EVIDENCE
The original search was completed on 1^st April 2020. It produced 53 results, 10 were duplicate and 31 were eliminated based on not addressing the question. An additional 6 were included through the google search, for a total of 18 studies. The updated search was completed on 12^th May 2020. It identified 178 results of which 136 were excluded (15 were duplicates, 114 did not focus on mild/moderate symptoms, 5 were non-empirical and 2 were removed due to language barriers.) An additional 34 studies were identified in the review at the update. As evidence is increasing following the more recent update (11^th May) we decided to summarise below the evidence from the systematic reviews and cohort studies only and leave out case studies and reports.

Summary of the body of evidence

Critical appraisal checklist
The CASP checklist³ was used for cohort studies and the JBI Critical Appraisal Checklist⁴  for Case Report. The most common limitations were a small sample size, failure to justify sample size and lack of sufficient evaluation timeframe. Most studies had limited population size and demographics and short evaluation period, limiting the certainty around the final results. The new search identified some studies with larger sample size, however, some symptoms relied on  self-report rather than objective testing.

EMERGING EVIDENCE IN COVID-19

Severity definition

All but two included studies recruited patients from hospital settings only. One was a study from the UK, which collected information from the general public in relation to COVID-19 via a symptom tracker app, called COVID RADAR, ²² while the other study included participants from a community facility designated for isolation of patients³⁶. Mild or moderate cases were generally defined based on less severe clinical symptoms (low grade fever, cough, discomfort) with no evidence of pneumonia ^6,10 and not requiring admission to ICU. However, some studies included people with pneumonia or respiratory tract infections as mild cases ^13,14, as long as they did not develop ARDS, organ failure or have an ICU admission.^{7 9-11} One study did report results for asymptomatic patients, but it is not clear why these people were hospitalised.⁵ The first systematic review²¹ carried forward cases defined as ‘severe’ from the original studies without comparing these definitions of severity. In the second search, several studies relied on guidelines to define severity, including the latest Chinese national recommendations for diagnosis and treatment of respiratory infections caused by 2019-nCoV (5^th and 6^th edition)^{23-25 34, 35, 40}, WHO Interim Guidance²⁹, and the Society of Pediatrics, Chinese Medical Association³². Other studies defined severity based on less severe clinical symptoms and lack of intensive care needs ^{26, 28, 30, 33, 36, 37, 39}, and one study classified survivors as mild and moderate.²⁷

Key findings

The first systematic review found no statistically significant difference in common symptoms between people with severe or mild / moderate COVID-19 infection. ²¹ Two later systematic reviews focused on pediatric patients. One of them showed that 26% of children that were tested positive were asymptomatic, 59% had fever and 46% had cough, while 12% presented gastrointestinal symptoms²⁴. Similar findings were confirmed in the second review of pediatric patients³³.

The key symptoms reported in the cohort studies included:

• Fever is the most common symptom among mild to moderate cases.^{5-14, 23-32, 34, 36-41} However, the frequency varied among the studies. In the largest cohort study in Europe, fever was presented in 45.4% of the cases²⁹, while in the two largest studies in China it went up to more than 80%.^40,41
• Cough was the second most common symptom observed in all studies.^{5-14, 23-32, 34-41} The frequency with which it was observed varied among studies, and it was up to 63.2% in the largest European study²⁹ and between 48.7% ⁴¹ and 65.5%⁴⁰ in the two largest Chinese studies. It was observed in 65.7 (95% CI 57.8-73.5) of patients with non-severe disease in the systematic review of studies in the general population²¹ and 46% of the systematic review of pediatric studies.²⁴
• The COVID RADAR survey was the first to report anosmia as a symptom of COVID-19. It found amongst individuals with sufficient symptoms to be given a COVID-19 RT-PCR test, prevalence of anosmia was 3 fold higher (59.4%) in those testing positive than in those testing negative (19.0%). Loss of smell may therefore be a strong predictor of COVID-1 infection. Anosmia in combination with fever, fatigue, persistent cough, diarrhoea, abdominal pain and loss of appetite predicted COVID-19 infection with a specificity of 0.83 (95% CI 0.81 to 0.86) and sensitivity of 0.55 (95%CI 0.50 to 0.59).²² The model performed equally well across different age and sex groups. Since this UK study was published, anosmia has been confirmed in another four studies ^{29, 31, 36, 39}. The frequency ranged from 39.5% of patients in a South Korean study³⁶ to 79.5% in a larger European study³⁹.
• Across studies dyspnea was more frequent in severe cases and indeed, in some studies, was a marker of severe disease. ^{5–9, 14 , 23, 25, 27, 30, 31, 34-37, 40} In the systematic review meta-analysis²¹, dyspnea was present in 44.2% (95% CI 7.8-80.6) of people with severe and 5.7% (0-10.7%) of people with non-severe infection. Two of the largest studies^5,9 report 1.4% of mild cases (compared to 32.6% of severe cases) and 7.6% of mild cases experienced dyspnea, respectively. Normal breathing rates more common in mild cases.^13,14
• Other symptoms reported include headache, ^{5-9,13, 25, 27-29, 31, 34-38, 41} rhinorrhea, ^{7-9,14, 28, 29, 31, 36-38} gastrointestinal symptoms, ^{7-9, 13, 14, 24-32, 34-38, 40} sore throat,^{6-9, 14, 26-32, 34-38, 40} and fatigue. ^{5,9,12,13, 23, 25-27, 29-31, 34-38, 41} Chest pain and tightness were reported in 9 studies varying from less than 5% ^7,8 to up to 40%. ^{23, 28} Expectoration in mild cases varied between 2%⁶ and 56%.¹³ Varied gastrointestinal reaction were reported including diarrhea, nausea, vomiting, poor appetite, and anorexia ^{7-9,13, 14, 24-32, 34-40}
• The updated search identified two more symptoms that were not previously reported; ocular reaction and skin rash. Ocular reaction, including conjunctivitis and visual acuity reduction, was seen in about 1% of the cases reported in the largest European study²⁹, while 4.68% of patients presented with conjunctival congestion in the largest Chinese study⁴¹. Skin rash was reported in 3 cohort studies with ranges from less than 1% in Europe²⁹ and between 2.5-2.9% in China ^{28, 35}.

Limitations

• Evidence is still scarce but it is growing.
• Most studies had short observation periods, small sample sizes and were conducted in a single geographical region, meaning results cannot be immediately generalized.
• Some studies were not only on mild cases but were included because they were mainly on mild cases.⁸
• Majority of studies were conducted in hospital settings.

CONCLUSIONS

• Scarce and inconclusive evidence on symptoms that easily distinguish mild and moderate cases. Additional evidence is needed with longer observation periods and larger population size and a more diverse demographic.
• Fever (< 39.1 °C) and cough are the most frequent symptoms even in mild disease, but relying on cough to diagnose COVID-19 may be misleading as it was observed in less than half of the mild cases in the largest studies of this review.
• There is increasing evidence suggesting anosmia as a key symptom of mild or moderate COVID-19.
• Individual presenting symptoms vary widely but in combination anosmia, fever, fatigue, persistent cough, diarrhoea, abdominal pain and loss of appetite have a reasonable specificity for COVID-19 diagnosis, though average sensitivity.
• Symptoms can have rapid cessation or late onset and some people will also be asymptomatic.

Disclaimer:  the article has not been peer-reviewed; it should not replace individual clinical judgement and the sources cited should be checked. The views expressed in this commentary represent the views of the authors and not necessarily those of the host institution, the NHS, the NIHR, or the Department of Health and Social Care. The views are not a substitute for professional medical advice.

AUTHORS

Melina Michelen is a Masters in Public Health (MPH) student in the School of Health Sciences at City, University of London.
Nicholas Jones is a Wellcome Trust Doctoral Research Fellow at University of Oxford.
Charitini Stavropoulou is a Senior Lecturer in Health Services Research in the School of Health Sciences at City, University of London.

SEARCH TERMS
The original search was completed on 1^st April 2020. The following generic search filters were applied to all databases: 1) Published 2019 to 2020 for relevancy of data; 2) Articles in English. To guide the search, controlled subject headings and keywords of three concepts were used: 1) Terms related to covid-19 OR coronavirus OR 2019-ncov OR covid; 2) terms related to symptoms OR Clinical Features OR signs OR characteristics OR presentation OR symptomatology and; 3) terms related to mild or moderate cases. Databases searched included: Medline and CINAHL through the EBSCO database host for general health peer-reviewed articles and Global Health for global peer reviewed articles through the Ovid database host. In addition, Google, Google Scholar, and CDC publications were searched. An updated search was done on Medline and CINAHL and was completed on 12^th May 2020

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