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 1st 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 12th 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 (11th 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

Description
Volume52 studies were included (18 from the original search, 34 from the updated)
Quality3 were systematic reviews (of which 2 included meta-analysis), 28 were retrospective cohort studies and 21 were case studies
Applicability29 studies were in China, 9 in Euope, 1 in the US, 1 in the UK and the rest from the rest of the world. Participants were of varying ages and background.
ConsistencyFindings varied between studies, mainly due to the fact that case definition of mild/moderate or severe disease varied and sample sizes were small. Results should be generalised with caution.


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 (5th and 6th 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. 59, 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 studies5,9 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 1st 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 12th May 2020

REFERENCES

1)    Center for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19). 2020. [cited 2020 Mar 20]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html
2)    World Health Organization. Coronavirus disease 2019 (COVID-19) Situation Report – 46. [Internet].2020. [cited 2020 Mar 20]. Available from: https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200319-sitrep-59-covid-19.pdf?sfvrsn=c3dcdef9_2
3)    Critical Appraisal Skills Programme. CASP Cohort Checklist. [Internet]. 2018. [cited 2020 Mar 23]. Available from: https://casp-uk.net/wp-content/uploads/2018/01/CASP-Cohort-Study-Checklist_2018.pdf.
4)    Moola S, Munn Z, Tufanaru C, Aromataris E, Sears K, Sfetcu R, et al. Chapter 7: Systematic reviews of etiology and risk. In: Aromataris E, Munn Z (Editors). Joanna Briggs Institute Reviewer’s Manual. The Joanna Briggs Institute, 2017. Available from: https://reviewersmanual.joannabriggs.org/
5)      Tian S, Hu N, Lou J et al., Characteristics of COVID-19 infection in BeXuijing. Journal of Infection [Internet]. 2020 Feb [cited 2020 Mar 23]; 80: 401–406 DOI: https://doi.org/10.1016/j.jinf.2020.02.018
6)      Xu YH, Dong JH, An WM, et al., Clinical and computed tomographic imaging features of novel coronavirus pneumonia caused by SARS-CoV-2. Journal of Infection [Internet]. 2020 Feb [cited 2020 Mar 23]; 80 (2020) 394–400. DOI: https://doi.org/10.1016/j.jinf.2020.02.017
7)      Yang W, Cao Q and Qin L, et al., Clinical characteristics and imaging manifestations of the 2019 novel coronavirus disease (COVID-19):A multi-center study in Wenzhou city, Zhejiang, China. Journal of Infection [Internet]. 2020 Feb [cited 2020 Mar 23];  80 (2020) 388–393. DOI: https://doi.org/10.1016/j.jinf.2020.02.016.
8)      Wu J, Liu J, Zhao X, Liu C, Wang W, Wang D, et al. Clinical Characteristics of Imported Cases of COVID-19 in Jiangsu Province: A Multicenter Descriptive Study, Clinical Infectious Diseases [Internet]. 2020 Feb [cited 2020 Mar 23]; DOI: https://doi.org/10.1093/cid/ciaa199
9)      Chen J, Qi T, Liu L et al., Clinical progression of patients with COVID-19 in Shanghai, China, Journal of Infection, [Internet]. 2020 Mar [cited 2020 Mar 23]; https://doi.org/10.1016/j.jinf.2020.03.004
10)    Zhao Z, Zhong Z, Xie X, Yu Q, and Liu J. Relation Between Chest CT Findings and Clinical Conditions of Coronavirus Disease (COVID-19) Pneumonia: A Multicenter Study. American Journal of Roentgenology [Internet]. 2020 Feb [cited 2020 Mar 23]; 1-6. doi.org/10.2214/AJR.20.22976
11)     Lo I, Lio C, Cheong H, Lei C, Cheong T, Zhong X, Tian Y, Sin N. Evaluation of SARS-CoV-2 RNA shedding in clinical specimens and clinical characteristics of 10 patients with COVID-19 in Macau. Int. J. Biol. Sci. [Internet]. 2020 Feb [cited 2020 Mar 23]; Vol. 16. doi: 10.7150/ijbs.45357
12)     Wei L and JIN D. Clinical Findings of 100 Mild Cases of COVID-19 in Wuhan: A Descriptive Study. [Internet]. 2020 Feb [cited 2020 Mar 23]; Available at SSRN: https://ssrn.com/abstract=3551332
13)     Xu X, Wu X, Jiang X, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ. [Internet]. 2020 Feb [cited 2020 Mar 23]; 368:m606. DOI: http://dx.doi.org/10.1136/bmj.m606
14)     Young BE, Ong SWX, Kalimuddin S, et al. Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore. JAMA. [Internet]. 2020 Feb [cited 2020 Mar 23]; doi:10.1001/jama.2020.3204
15)     Lim J, Jeon S, Shin H, et al. Case of the Index Patient Who Caused Tertiary Transmission of COVID-19 Infection in Korea: the Application of Lopinavir/Ritonavir for the Treatment of COVID-19 Infected Pneumonia Monitored by Quantitative RT-PCR. J Korean Med Sci. [Internet]. 2020 Feb [cited 2020 Mar 23]; 35(6):e79 https://doi.org/10.3346/jkms.2020.35.e79
16)      Ji L, Chao S, Wang Y. et al..Clinical features of pediatric patients with COVID‑19: a report of two family cluster cases. World Journal of Pediatrics. [Internet]. 2020 Feb [cited 2020 Mar 23]; DOI: https://doi.org/10.1007/s12519-020-00356-2
17)      Arashiro T, Furukawa K, Nakamura A. COVID-19 in 2 persons with mild upper respiratory tract symptoms on a cruise ship, Japan. Emerg Infect Dis. [Internet]. 2020 Feb [cited 2020 Mar 23]; DOI: https://doi.org/10.3201/eid2606.200452
18)      Holshue, ML et al. First Case of 2019 Novel coronavirus in the United States. N. Engl. J. Med. [Internet]. 2020 Feb [cited 2020 Mar 23]; DOI: https://doi.org/10.1056/NEJMoa2001191.
19)  Hoehl S, Berger A, Kortenbusch M, et al. Evidence of SARS-CoV-2 infection in returning travelers from Wuhan, China [Letter]. N Engl J Med. 2020 Feb [cited 2020 Mar 23]; doi:10.1056/NEJMc2001899
20)     Rothe, C. et al. Transmission of 2019-nCoV infection from an asymptomatic contact in Germany. N. Engl. J. Med. [Internet]. 2020 Feb [cited 2020 Mar 23]; DOI: https://doi.org/10.1056/NEJMc2001468.
21)      Zhao X, Zhang B, Li P, et al. Incidence, clinical characteristics and prognostic factor of patients with COVID-19: a systematic review and meta-analysis. medRxiv;  [Internet].  2020 Mar [cited 2020 Mar 31]; doi: https://doi.org/10.1101/2020.03.17.20037572 (preprint).
22)      Menni C et al. Loss of smell and taste in combination with other symptoms is a strong predictor of COVID-19 infection. medRxiv;  [Internet].  2020 Mar [cited 2020 April 01]; MEDRXIV/2020/048421(preprint).
23)      Wang, J et al. CT characteristics of patients infected with 2019 novel coronavirus: association with clinical type. Clinical radiology (0009-9260), 75 (6), p. 408. [Internet] 2020 June. [cited 2020 May 11]; DOI: https://doi.org/10.1016/j.crad.2020.04.001
24)     Chang, Tu-Hsuan et al.. Clinical characteristics and diagnostic challenges of pediatric COVID-19: A systematic review and meta-analysis. Journal of the Formosan Medical Association (0929-6646), 119 (5), p. 982. [Internet] 2020 April. [cited 2020 May 11]; DOI: https://doi.org/10.1016/j.jfma.2020.04.007
25)    Chen, Guang et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. The Journal of clinical investigation (0021-9738), 130 (5), p. 2620. [Internet] 2020 May. [cited 2020 May 11]; DOI: 1172/JCI137244
26)    Zhao et al. Clinical characteristics of patients with 2019 coronavirus disease in a non-Wuhan area of Hubei Province, China: a retrospective study. BMC Infectious Diseases; 20(1): 1-8. (8p) [Internet] 2020 April. [cited 2020 May 11]; DOI: https://doi.org/10.1186/s12879-020-05010-w
27)    Wang, D. et al. Clinical course and outcome of 107 patients infected with the novel coronavirus, SARS-CoV-2, discharged from two hospitals in Wuhan, China. Critical Care, 24:188 [Internet] 2020 April. [cited 2020 May 11]; DOI: 1172/JCI137244
28)     Wang X, Zhou Q, He Y, et al. Nosocomial Outbreak of 2019 Novel Coronavirus Pneumonia in Wuhan, China. Eur Respir J 2020; [Internet] 2020 May. [cited 2020 May 11]; DOI: https://doi.org/10.1183/13993003.00544-2020.
29)      Lechien, Jerome R. Clinical and Epidemiological Characteristics of 1,420 European Patients with mild‐to‐moderate Coronavirus Disease 2019. Journal of internal medicine (0954-6820) [Internet] 2020 April. [cited 2020 May 11]; DOI: https://doi.org/10.1111/joim.13089
30)     Han, C. et al. Digestive Symptoms in COVID-19 Patients With Mild Disease Severity Clinical Presentation, Stool Viral RNA Testing, and Outcomes. The American Journal of Gastroenterology (0002-9270), p. 1. [Internet] 2020 April. [cited 2020 May 11]; DOI: 14309/ajg.0000000000000664
31)      Tostmann Alma et al . Strong associations and moderate predictive value of early symptoms for SARSCoV-2 test positivity among healthcare workers, the Netherlands. Euro Surveill25(16):pii=2000508. [Internet] 2020 March. [cited 2020 May 11]; DOI: https://doi.org/10.2807/1560-7917.ES.2020.25.16.2000508
32)      Shen, Q. et al. Novel coronavirus infection in children outside of Wuhan, China. Pediatric pulmonology (8755-6863), 55 (6), p. 1424.[Internet] 2020 April. [cited 2020 May 11]; DOI: https://doi.org/10.1002/ppul.24762
33)      Castagnoli, R. et al. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Children and Adolescents A Systematic Review. JAMA pediatrics (2168-6203) [Internet] 2020 April. [cited 2020 May 11]; DOI: 1001/jamapediatrics.2020.1467.
34)      Du, W. et al. Clinical characteristics of COVID-19 in children compared with adults in Shandong Province, China. Infection (0300-8126) [Internet] 2020 April. [cited 2020 May 11]; DOI: 1007/s15010-020-01427-2
35)      Sun, L. et al. Clinical Features of Patients with Coronavirus Disease 2019 (COVID‐19) from a Designated Hospital in Beijing, China. Journal of medical virology (0146-6615) [Internet] 2020 May. [cited 2020 May 11]; DOI: 10.1002/jmv.25966
36)     Kim G-u et al. Clinical characteristics of asymptomatic and symptomatic patients with mild COVID-19. Clinical Microbiology and Infection. [Internet] 2020 May. [cited 2020 May 11]; DOI: https://doi.org/10.1016/j.cmi.2020.04.040.
37)      Kujawski, S.A., Wong, K.K., Collins, J.P. et al.Clinical and virologic characteristics of the first 12 patients with coronavirus disease 2019 (COVID-19) in the United States. Nat Med (2020). [Internet] 2020 April. [cited 2020 May 11];  DOI: https://doi.org/10.1038/s41591-020-0877-5
38)     Cai Q, Huang D, Ou P, et al. COVID-19 in a designated infectious diseases hospital outside Hubei Province, China. Allergy. 2020;10.1111/all.14309. [Internet] 2020 April. [cited 2020 May 11]; DOI:1111/all.14309.
39)     Lechien JR, Chiesa-Estomba CM, De Siati DR, et al. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur Arch Otorhinolaryngol. 2020;1‐11. [Internet] 2020 April. [cited 2020 May 11]; DOI: doi:10.1007/s00405-020-05965-1
40)     Feng Y, Ling Y, Bai T, et al. COVID-19 with Different Severity: A Multi-center Study of Clinical Features. Am J Respir Crit Care Med. 2020;10.1164/rccm.202002-0445OC. [Internet] 2020 April. [cited 2020 May 11]; DOI:1007/s00405-020-05965-1
41)     ChenL, Deng C, Chen X, et al. Ocular manifestations and clinical characteristics of 534 cases of COVID-19 in China: A cross-sectional study. medRxiv 2020;2020.03.12.20034678. [Internet] 2020 March. [cited 2020 May 11];  DOI: https://doi.org/10.1101/2020.03.12.20034678