|Year : 2020 | Volume
| Issue : 2 | Page : 59-64
Global trends of clinical presentation of COVID-19
Ragini Sharma1, Mradul K Daga2, Govind Mawari2, Vijay Kumar Karra3, Naresh Kumar1, Manish Kumar Jha2, Suresh Kumar1
1 Department of Medicine, Maulana Azad Medical College, New Delhi, India
2 Department of Medicine; Centre for Occupational and Environmental Health, Maulana Azad Medical College, New Delhi, India
3 Department of Health Research, Division of Epidemiology and Communicable Diseases, Indian Council of Medical Research, New Delhi, India
|Date of Submission||16-Apr-2020|
|Date of Decision||23-May-2020|
|Date of Acceptance||27-May-2020|
|Date of Web Publication||07-Jul-2020|
Dr. Mradul K Daga
Department of Medicine, Maulana Azad Medical College, New Delhi - 110 002
Source of Support: None, Conflict of Interest: None
Emerging and reemerging diseases pose global challenges for public health. Pneumonia of unknown origin, given the name COVID-19, began in China in December 2019. On March 11, 2020, the WHO declared it to be a pandemic. Currently, the disease is booming rapidly and impacting the well-being of people and the economy of countries globally. Observational studies have somewhat highlighted clinical findings of the disease, but there are still no decisive data about its global trends. The purpose of this review is to bring to light the huge disparities in the clinical presentation of the disease among countries. The data for this review were obtained from studies pertaining to clinical, laboratory, and imaging features obtained from various journals. It was found that occurrence of the most frequently seen features ranged as – fever (98%–35%), cough (88%–25%), dyspnea (88%–4.8%), and sore throat (61%–8%). A definite reason for this is still obscure. This calls for more conclusive studies to investigate the possible causes of these trends. This might go a long way in increasing our understanding of the disease and improve its diagnosis and treatment.
Keywords: Acute respiratory illness, COVID-19, cough, dyspnea, Middle East respiratory syndrome coronavirus
|How to cite this article:|
Sharma R, Daga MK, Mawari G, Karra VK, Kumar N, Jha MK, Kumar S. Global trends of clinical presentation of COVID-19. Indian J Med Spec 2020;11:59-64
|How to cite this URL:|
Sharma R, Daga MK, Mawari G, Karra VK, Kumar N, Jha MK, Kumar S. Global trends of clinical presentation of COVID-19. Indian J Med Spec [serial online] 2020 [cited 2021 Apr 14];11:59-64. Available from: http://www.ijms.in/text.asp?2020/11/2/59/289118
| Introduction and Background|| |
Coronaviruses are enveloped positive-sense RNA viruses that are found broadly among humans, other mammals, and birds. They are responsible for various respiratory, enteric, hepatic, and neurologic diseases.,
Although most human coronavirus infections are mild, the epidemics of the two betacoronaviruses, severe acute respiratory syndrome coronavirus 2002 (caused by SARS-CoV) in Guangdong Province, China, and Middle East respiratory syndrome coronavirus 2012 (caused by MERS-CoV) in the Middle East, have caused more than 10,000 cumulative cases in the past two decades, with mortality rates of 10% for SARS-CoV and 37% for MERS-CoV.,
Emerging and reemerging pathogens are global challenges for public health. On December 31, 2019, pneumonia of unknown origin detected in Wuhan, Hubei Province, China, was reported to the country office of the WHO. Molecular analysis of lower respiratory tract specimen showed the presence of a novel coronavirus. On January 13, 2020, the first case was reported outside China in Thailand. Following this, there was a rapid rise in cases in mainland China and other countries by human-to-human transmission. The WHO declared it to be a public health emergency on January 30, 2020. On February 11, 2020, it was given the name COVID-19. On March 11, 2020, the WHO declared it to be a pandemic with 118,000 cases in 114 countries.
At present, this disease is spreading rapidly and taking a heavy toll on the health and economy of various countries worldwide. It is of utmost importance to understand the nature of the disease to identify and combat it better. Clinical, laboratory, and imaging features of the disease have been partially characterized in some observational studies all over the world; however, there is no conclusive information regarding their global trends. The purpose of this review is to bring to light variations in the clinical characters of the disease among different regions. These variations hint towards a potential effect of the environment and genetics of the hosts, in different geographical regions, on the disease course.
| Transmission|| |
First few cases of coronavirus reported in China were associated with the Huanan Seafood Wholesale Market Wuhan, indicating the main mode of transmission to be animal to human transmission [Figure 1]. However, subsequent cases brought light to human-to-human transmission, which now is considered the main mode of spread. Spread can occur between people in close contact, i.e., within 6ft of each other through respiratory droplets. Recent studies also indicate that asymptomatic individuals can also cause the spread of the disease. Hence, social distancing has been promoted as the most effective means of preventing transference of the disease.
Aerosol transmission has also been suggested by increasing aerosol concentration in closed spaces. It may also be possible to acquire infection by touching your mouth, nose, and eyes after touching an infected surface. Hence, handwashing for 20 s with soap, water, or alcohol-based sanitizer is recommended after touching any surface.
| Pathogenesis|| |
The pathogenesis of COVID-19 is still poorly understood. Hence, based on similarities in the clinical manifestation and mode of spread with SARS-CoV and MERS-CoV, information can be taken from studies on them [Figure 2].
The spiked glycoprotein S protein of SARS-CoV2 (COVID-19) first undergoes priming by serine proteases TMPRSS2. It then binds to respiratory epithelial cells by the angiotensin-converting enzyme 2 receptor that was also used by SARS-CoV. SARS-CoV has also been shown to be endocytosed into the cell by clathrin- and caveolae-independent mechanisms. After this, the viral RNA genome is released into the cytoplasm and gets translated, following which the viral genome begins to replicate. After entry into the cell, the viral antigens are presented to the antigen-presenting cells to develop immunity. It occurs through major histocompatibility complex-1 molecule in the case of SARS-CoV. It leads to the development of the humoral and cellular immunity via the B- and T-cells. In certain cases, the development of acute respiratory distress syndrome (ARDS) is accompanied by a cytokine storm.
| Methodology|| |
The authors focused on finding data pertaining to the clinical features of COVID-19 in various studies acquired from PubMed, JAMA, Elsevier, NEJM, and Google Scholar. The main keywords used were “clinical features of” “COVID-19,” “Wuhan Coronavirus,” “SARS CoV-2,” and “CoV 2019” along with the names of the respective countries. Searches were concluded by April 10, 2020. The papers found on initial searches were screened by titles and abstracts. Studies that included clinical symptoms, laboratory findings, and radiological features were included. The studies for review were chosen based on sample size in countries with multiple studies.
| Discussion – Clinical Presentations and Investigations|| |
The COVID-19 disease has a wide clinical spectrum which varies from asymptomatic patients to septic shock and multiple organ dysfunction. COVID–19 may present with mild, moderate, or severe illness. The revised guidelines on clinical management of COVID-19 issued by the Ministry of Health and Family Welfare, India, on March 31, 2020, classifies the clinical syndrome associated with the disease in adults into:
It is found in patients with mild upper respiratory tract viral infection or nonspecific symptoms.
It is found in patients with pneumonia but no signs of severe pneumonia. No radiographic features of pneumonia are seen.
It includes fever or suspected respiratory infection, along with one of these features – respiratory rate >30 breaths/min, severe respiratory distress, and SpO2<90% on room air.
Acute respiratory distress syndrome
This syndrome includes new or worsening respiratory symptoms within 1 week of known clinical insult with unexplained bilateral opacities on chest computerized tomography (CT) and unexplained by cardiac failure or fluid overload.
It includes life-threatening organ dysfunction caused by an impaired immune response to suspected or proven infection.
It includes persisting hypotension despite volume resuscitation, requiring vasopressors to maintain Mean Arterial Pressure ≥65 mmHg, and serum lactate level >2 mmol/L.
The Chinese Center for Disease Control and Prevention published the largest case series of COVID-19 in mainland China (from data up till February 11, 2020) which classified 44,415 patients into mild (81%), severe (14%), and critical (5%) [Figure 3].
In Italy as of April 6, 2020, 17.5% of cases are severe, 39.7% are mild, 4.4% are critical, 18.1% have unspecified symptoms, 13% have fewer symptoms, and 7.4% are asymptomatic [Figure 4].
The clinical manifestations of the disease have a wide spectrum and exhibited a global variation in the prevalence of various features. The main differences have been highlighted in [Table 1].
According to the WHO-China Joint Commission Report, based on 55924 laboratory-confirmed cases, the most common respiratory symptoms include fever (87.9%), dry cough (67.7%), fatigue (38.1%), sputum production (33.4%), shortness of breath (18.6%), sore throat (13.9%), and nasal congestion (4.8%) and nonrespiratory symptoms include headache (13.6%), myalgia or arthralgia (14.8%), chills (11.4%), nausea or vomiting (5.0%), diarrhea (3.7%), hemoptysis (0.9%), and conjunctival congestion (0.8%).
From the data based on 58,277 cases from 11 countries of Europe, majority of which have been received from Germany (99.8%), the most common clinical symptoms that have been reported were fever (35%), dry or productive cough (16%), sore throat (9.1%), malaise (5.3%), and pain (3.5%).
The 10th epidemiology report of Australia details the distribution of the most observed clinical features among 4237 patients as cough – 70.52%, fever – 48.99%, sore throat – 44.77%, headache – 38.7%, and runny nose –27.5%.
Evaluation of the first 18 COVID-19 positive patients in Singapore reported cough in 83%, fever in 72%, sore throat in 61%, diarrhea in 17%, and rhinorrhea in 6%. None of the patients reported with ARDS.
A study on 21 patients from a tertiary care centre in India exhibited 57.1% of the patients to have the common clinical symptoms-fever (42.9%), cough (42.9%), sore throat (23.8%), headache (13.6%) and dyspnea (4.8%).
In Saudi Arabia, the clinical features at presentation seen in 47 patients were respiratory: fever (98%), fever accompanied by chills and rigor (83%), cough (83%), dyspnea (72%), sore throat (21%), chest pain (15%), and runny nose (4%) and nonrespiratory: myalgia (32%), diarrhea (26%), nausea and vomiting (21%), hemoptysis (17%), abdominal pain (17%), and headache (13%).
From the symptomatic data available in the 20 out of 28 case reports provided by an epidemiological survey in Korea, the clinical features seen were f ever (50%), cough (40%), sore throat (35%), fatigue (20%), myalgia (20%), chills (15%), cold (15%), headache (5%), and asymptomatic (15%).
An analysis of 24 patients in Seattle disclosed the clinical manifestations to be cough (88%), shortness of breath (88%), fever (50%), sputum (42%), sore throat (8%), headache (8%), and rhinorrhea (17%).
In Italy, a 52-year-old-man presented with fever, cough, asthenia, headache, myalgia, and photophobia, while a 53-year-old woman exhibited severe fatigue, fever, and dry cough., Another 69-year-old had come with complaints of worsening dyspnea, persistent cough, and weakness. There was also a case of a couple vacationing in Italy who presented with respiratory symptoms and fever which went on to develop ARDS as the disease progressed.
In a study on 1099 confirmed COVID-19 patients in China, the main laboratory findings were lymphocytopenia (83.2%), high C-Reactive Protein (CRP) (60.7%), high D-dimer (46.4%), high lactic acid dehydrogenase (LDH) (41%), thrombocytopenia (36.2%), leukocytopenia (33.7%), high aspartate aminotransferase (AST) (22.2%), high alanine aminotransferase (ALT) (21.3%), high creatine kinases (13.7%), high total bilirubin (10.5%), leukocytosis (5.9%), and high creatinine (1.6%).
A systematic review and meta-analysis of studies in Mainland China reported the mean prevalence of decreased albumin as 75.8% and high sedimentation rate as 41.8%.
In another study conducted in China, the initial plasma levels of interleukin 1B (IL1B), IL1RA, IL7, IL8, IL9, IL10, basic fibroblast growth factor (FGF), granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, interferon γ, interferon γ inducible protein 10 (IP10), monocyte chemoattractant protein 1 (MCP1), macrophage inflammatory protein 1A (MIP1A), macrophage inflammatory protein 1B (MIP1B), platelet-derived growth factor, tumor necrosis factor α (TNFα), and vascular endothelial growth factor were found to be higher in both intensive care unit (ICU) patients and non-ICU patients as compared to healthy adults. Compared with non-ICU patients, ICU patients reported higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα.
Blood reports of cases from Italy showed lymphocytopenia, thrombocytopenia, high LDH, and inflammatory markers., A case report also mentioned the presence of myocyte necrosis markers – high sensitivity troponin T.
In Saudi Arabia, laboratory analysis of 47 patients showed raised LDH (49%), thrombocytopenia (36%), lymphopenia (34%), raised AST (15%), raised ALT (11%), and lymphocytosis (11%).
In Singapore, lymphopenia was present in 39% of the patients, and an elevated CRP level was shown by 38%, while kidney function was normal.
Laboratory analysis in Seattle for 24 patients showed lymphopenia in 75%, raised lactate levels in 53%, raised creatine kinase levels in 50%, raised AST (41%), raised ALT (32%), high troponin levels in 15%, and leukocytosis in 38%.
In China, a study briefed the main abnormal chest radiograph findings as compared to chest CT findings as described in [Table 2].
In Korea, chest CT images revealed bilateral involvement in eight of the nine patients and a unilobar reversed halo sign in the other patient. In total, 77 pulmonary lesions were demonstrated, including small nodular lesions (48%), patchy lesions (39%), and large confluent lesions (13%).
The study in Seattle showed bilateral infiltrates in all chest radiographs. Chest CT revealed bilateral ground-glass opacities in 80% and nodules in 20%.
In Singapore, 33% of the patients had an abnormal chest radiograph finding or lung crepitations.
In a study in Saudi Arabia, all 47 patients revealed abnormal findings – subtle to extensive unilateral and bilateral involvement – on chest radiographs.
Cases reported in Italy described a chest X-ray that showed a doubtful left perihilar hypodiafania and CT scan showed diffuse bilateral interstitial inflammation with subpleural consolidations., On follow–up, the CT scans of the case of the couple revealed uncommon elements such as pleural effusions, an enlarged appearance of pulmonary vessels that was tubular with a sudden caliber reduction, and mediastinal lymphadenopathy.
| Limitations of the Article|| |
This review article has several limitations. There is still a paucity of studies highlighting clinical manifestations of COVID-19 in various countries globally. In this article, we have been able to highlight only a few countries for which large-scale data were available. A few of the studies included in this article have a large sample size, while others are just case reports of individual patients from respective countries, making it difficult to draw a comparison. Large-scale data from more countries would be needed to generate a more definite conclusion for the global trends of clinical manifestations. However, this review article permits the first comparison of clinical features in different countries, signifying its importance. This data could guide further studies to understand the variations worldwide and their causes.
| Conclusion|| |
The current article highlights the worldwide disparities in the clinical presentation of COVID-19. The prevalence of the most common features like fever ranged from 98% (Saudi Arabia) to 47% (Europe), cough ranged from 88% (Seattle) to 25% (Europe), dyspnea ranged from 88% (Seattle) to 4.8% (India), and sore throat ranged from 61% (Singapore) to 8% (Seattle). Most of the patients globally presented with upper or lower respiratory tract infections and signs of viremia. However, the fever range is lower as compared to other viral illnesses, including common flu. Other less common features which were nonuniform and variable in presentation among countries were sputum production, fatigue, myalgia, nausea and vomiting, diarrhea, headache, nasal congestion, chills, hemoptysis, abdominal pain, and conjunctival congestion.
The most widespread laboratory findings were lymphocytopenia (83.2%–34%), thrombocytopenia, raised ALT (32%–11%), raised AST (41%–15%), raised LDH, and raised inflammatory markers. Important differentiating features that stood out were leukocytopenia and thrombocytopenia. The most prevalent radiological findings were ground-glass opacities and unilateral or bilateral patchy and nodular lesions with CT offering more sensitivity than Chest X-ray.
These global variations may simply be due to the different stages at which the patient first presented or demographic variations among countries. However, they may also indicate an underlying geo-temporal effect or ecological effect on the virulence or the evolutionary mechanisms of coronavirus. This may include exposure to certain pathogens providing cross-protection. It may also be due to racial and genetic variations in the host affecting their response to the virus.
COVID-19 disease is a disease of clustering onset associated with high morbidity. Studying clinical variations on a global scale is just one component of a larger strategy to understand the factors responsible for the diversity in response to the virus. More unequivocal studies need to be conducted in this regard to look into the precise reason for this and compliment the global perspective. This shall offer us a better understanding of the etiology of the disease and might form the basis for improved detection and management of COVID-19 in different countries. We advocate that in the present pandemic, any individual with features of flu-like illness or mild fever and fatigue should be investigated and isolated till ruled out to be having COVID 19. This pandemic will change the general human practices and will go a long way to influence the policies to be more prepared for any such challenges in future.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Weiss SR, Leibowitz JL. Coronavirus pathogenesis. Adv Virus Res 2011;81:85-164.
Masters PS, Perlman S. Coronaviridae. In: Knipe DM, Howley PM, editors. Fields Virology. 6th
ed.. Philadelphia, PA, USA: Lippincott Williams & Wilkins; 2013. p. 825-58.
Kuiken T, Fouchier RAM, Schutten M, Rimmelzwaan GF, Amerongen GV, Riel DV, et al
. Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome. Lancet 2003 2020;362:263-70.
de Groot RJ, Baker SC, Baric RS, Brown CS, Drosten C, Enjuanes L, et al
. Middle East respiratory syndrome coronavirus (MERS-CoV): announcement of the Coronavirus Study Group. J Virol 2013;87:7790-2.
Gao GF. From “A”IV to “Z”IKV: Attacks from Emerging and Re-emerging Pathogens. Cell 2018;172:1157-9.s.
Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Napoli RD. Features, Evaluation and Treatment Coronavirus (COVID-19). Treasure Islands, Florida: Stat Pearls; 2020. Available from. https://www.ncbi.nlm.nih.gov/books/NBK554776/
. [Last accessed on 2020 Apr 06].
Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al
. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020;181:271-80.
Wang H, Yang P, Liu K, Guo F, Zhang Y, Zhang G, et al
. SARS coronavirus entry into host cells through a novel clathrin- and caveolae-independent endocytic pathway. Cell Res 2008;18:290-301.
Perlman S, Netland J. Coronaviruses post-SARS: Update on replication and pathogenesis. Nature Rev Microbiol 2009;7:439-50.
Liu J, Wu P, Gao F, Qi J, Tachikawa AK, Xie J, et al.
Novel immunodominant peptide presentation strategy: A featured HLA-A*2402-restricted cytotoxic T-lymphocyte epitope stabilized by intrachain hydrogen bonds from severe acute respiratory syndrome coronavirus nucleocapsid protein. J Virol 2010;84:11849-857.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al
. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.
Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72314 cases from the Chinese center for disease control and prevention. JAMA 2020;323:1239-42.
Young BE, Ong SW, Kalimuddin S, Low JG, Tan SY, Loh J, et al
. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in singapore. JAMA 2020;323:1488-14.
Gupta N, Agrawal S, Ish P, Mishra S, Gaind R, Usha G, et al
. COVID 2019 working group *Safdarjung H. (2020). Clinical and epidemiologic profile of the initial COVID-19 patients at a tertiary care centre in India. Monaldi Arch Chest Dis 2020;90(1):1294.
Assiri A, AlTawfq JA, AlRabeeah AA, AlRabiah FA, AlHajjar S, AlBarrak A, et al
. Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: A descriptive study. Lancet Infect Dis 2013;13:752-61.
Ki M. Epidemiologic characteristics of early cases with 2019 novel coronavirus (2019-nCoV) disease in Republic of Korea. Epidemiol Health 2020;42(0):e2020007.
Bhatraju P, Ghassemieh B, Nichols M, Kim R, Jerome K, Nalla A, et al
. Covid-19 in critically Ill patients in the seattle region -” Case series. New England J Med 2020;382:2012-22.
Buonsenso D, Piano A, Raffaelli F, Bonadia N, Donati KG, Franceschi F, et al
. Point-of-care lung ultrasound findings in novel coronavirus disease-19 pneumoniae: A case report and potential applications during COVID-19 outbreak. Europ Rev Med Pharmacol Sci 2020;24(5):2776-80.
Inciardi RM, Lupi L, Zaccone G, Italia L, Raffo M, Tomasoni D, et al
. Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020; doi:10.1001/jamacardio.2020.1096.
Tavazzi G, Pellegrini C, Maurelli M, Belliato M, Sciutti F, Bottazzi A, et al
. Myocardial localization of coronavirus in COVID-19 cardiogenic shock. Europ J Heart Failure 2020;22:911-5
Albarello F, Pianura E, Stefano FD, Cristofaro M, Petrone A, Marchioni L, et al
. 2019-novel coronavirus severe adult respiratory distress syndrome in two cases in Italy: An uncommon radiological presentation. Int J Infect Dis 2020;93:192-7.
Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al
. Clinical characteristics of coronavirus disease 2019 in China. New England J Med 2020;382:1708-20.
Rodriguez-Morales AJ, Cordona-Ospina JA, Gutierrez-Ocampo E, Villamizar-Pena R, Holguin-Rivera Y, Escalera-Antezana JP, et al
. Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis. Travel Med Infect Dis 2020;34:101623.
Yoon SH, Lee KH, Kim JY, Lee YK, Ko H, Kim KH, et al
. Chest radiographic and CT findings of the 2019 novel coronavirus disease (COVID-19): Analysis of nine patients treated in Korea. Korean J Radiol 2020;21:494-500.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]