Covid-19: four fifths of cases are asymptomatic, China figures indicate

Dear Editor,

We read with great interest the article by Day (2020) commenting on the asymptomatic majority (78%) of those infected with COVID-19 in the Chinese population. (1) Despite many harbouring the infection asymptomatically, we write to highlight that patients may display atypical symptoms - a feature likely under-accounted for by statistics and under-addressed at large by public, healthcare professionals and policy-makers.

COVID-19 exhibits a diverse range of clinical presentations. Whilst classical respiratory symptoms of a dry cough have been underscored, these may be preceded by atypical respiratory symptoms such as haemoptysis. (2) Additionally, progressive gastrointestinal symptoms (diarrhoea, vomiting, abdominal pain) may be the index presentation, even occurring in the absence of other features. (3) Such symptoms have also been described in immunosuppressed patients, highlighting a potential at-risk group. (4) More recently, isolated anosmia or hyposmia has been widely reported as a primary symptom. (5) Ocular manifestations, primarily conjunctivitis, have also been pinpointed in case series, and the possibility of tear transmission has been broached (6). More generally, it is important not to neglect other disease manifestations since they may represent alternative modes of viral dissemination.

In critically ill patients, evidence of raised inflammatory markers suggests that cytokine storm syndrome occurs in COVID-19 and may underlie some atypical presentations. In this context, infected patients presenting solely with cardiac symptoms such as palpitations and chest pain have been reported, often due to underlying virus-induced myocardial injury. (7) Cytokines have also been attributed to certain neurologic symptoms: a patient presenting with fever, cough and altered mental status eventually developed acute necrotising haemorrhagic encephalopathy. (8) Other atypical neurologic presentations include acute cerebrovascular disease and muscle injuries. (9) Notably, the elderly and those with multiple comorbidities are severely affected by COVID-19, and atypical symptoms in these susceptible groups warrant further investigation.

Heightened awareness of these various atypical presentations of COVID-19 has wide-reaching implications. Firstly, the public may be more compelled to undertake precautionary self-isolation, or seek medical attention should concerning symptoms arise. Medical personnel will approach patients with a higher index of suspicion, which is beneficial for both early diagnostic purposes but also for ensuring adequate preventative personal protective equipment (PPE) and hygiene precautions are scrupulously implemented. Furthermore, recognising atypical symptoms allows other screening protocols and biomarkers of disease progression to be investigated. On a national scale, this may facilitate more accurate data collection on confirmed cases which will impact public health policies. The recent development of symptom-tracker applications for mobile phones may assist with this as they allow individuals to rapidly log their symptoms daily, with the objective of collating the information to better characterise the full-spectrum of symptoms that correlate with the disease. (10) Ultimately, by drawing attention to these atypical symptoms, we hope to encourage further investigation, symptom-reporting and awareness of the many guises of COVID-19.

References
1. Day M. Covid-19: four fifths of cases are asymptomatic, China figures indicate. BMJ [Internet]. 2020 Apr 2 [cited 2020 Apr 5];369. Available from: https://www.bmj.com/content/369/bmj.m1375
2. Shi F, Yu Q, Huang W, Tan C. 2019 Novel Coronavirus (COVID-19) Pneumonia with Hemoptysis as the Initial Symptom: CT and Clinical Features. Korean Journal of Radiology [Internet]. 2020 Feb 26 [cited 2020 Apr 5];21. Available from: https://doi.org/10.3348/kjr.2020.0181
3. Pan L, Mu M, Yang P, Sun Y, Yan J, Li P, et al. Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study. :25.
4. Guillen E, Pineiro GJ, Revuelta I, Rodriguez D, Bodro M, Moreno A, et al. Case report of COVID-19 in a kidney transplant recipient: Does immunosuppression alter the clinical presentation? American Journal of Transplantation [Internet]. [cited 2020 Apr 5];n/a(n/a). Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/ajt.15874
5. Hopkins C, Kumar N. Loss of sense of smell as marker of COVID-19 infection.pdf [Internet]. ENT UK. 2020 [cited 2020 Apr 5]. Available from: https://templatearchive.com/loss-sense-smell-marker-covid/
6. Wu P, Duan F, Luo C, Liu Q, Qu X, Liang L, et al. Characteristics of Ocular Findings of Patients With Coronavirus Disease 2019 (COVID-19) in Hubei Province, China. JAMA Ophthalmol [Internet]. 2020 Mar 31 [cited 2020 Apr 5]; Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7110919/
7. Clerkin Kevin J., Fried Justin A., Raikhelkar Jayant, Sayer Gabriel, Griffin Jan M., Masoumi Amirali, et al. Coronavirus Disease 2019 (COVID-19) and Cardiovascular Disease. Circulation [Internet]. [cited 2020 Apr 5];0(0). Available from: https://www.ahajournals.org/doi/abs/10.1161/CIRCULATIONAHA.120.046941
8. Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B. COVID-19–associated Acute Hemorrhagic Necrotizing Encephalopathy: CT and MRI Features. Radiology. 2020 Mar 31;201187.
9. Mao L, Wang M, Chen S, He Q, Chang J, Hong C, et al. Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: a retrospective case series study. medRxiv. 2020 Feb 25;2020.02.22.20026500.
10. New symptom tracking app aims to slow spread of coronavirus [Internet]. [cited 2020 Apr 5]. Available from: https://www.kcl.ac.uk/news/new-symptom-tracking-app-aims-to-slow-spread-...