Clinical Characteristics and Diagnostic Challenges of COVID−19: An Update From the Global Perspective

Clinical characteristics are essential for the correct diagnosis of diseases. The current review aimed to summarize the global clinical characteristics of the COVID-19 patients systematically and identify their diagnostic challenges to help the medical practitioners properly diagnose and for better management of COVID-19 patients. We conducted a systematic search in PubMed, Web of Science, Scopus, Science Direct, and Google Scholar databases for original articles containing clinical information of COVID-19 published up to 7th May 2020. Two researchers independently searched the databases to extract eligible articles. A total of 34 studies from 8 different countries with 10889 case-patients were included for clinical characteristics. The most common clinical symptoms were cough 59.6, fever 46.9, fatigue 27.8, and dyspnea 20.23%. The prominent laboratory findings were lymphocytopenia 55.9, elevated levels of CRP 61.9, aspartate aminotransferase 53.3, LDH 40.8, ESR 72.99, serum ferritin 63, IL-6 52, and prothrombin time 35.47%, and decreased levels of platelets 17.26, eosinophils 59.0, hemoglobin 29, and albumin 38.4%. CT scan of the chest showed an abnormality in 93.50% cases with bilateral lungs 71.1%, ground-glass opacity 48%, lesion in lungs 78.3%, and enlargement of lymph node 50.7%. Common comorbidities were hypertension, diabetes, obesity, and cardiovascular diseases. The estimated median incubation period was 5.36 days, and the overall case fatality rate was 16.9% (Global case fatality outside China was 22.24%: USA 21.24%, Italy 25.61%, and others 0%; whereas the case fatality inside the Hubei Province of China was found to be 11.71%). Global features on the clinical characteristics of COVID-19 obtained from laboratory tests and CT scan results will provide useful information to the physicians to diagnose the disease and for better management of the patients as well as to address the diagnostic challenges to control the infection.


INTRODUCTION
In late December 2019, the Chinese government officially announced the novel coronavirus (2019-nCoV) outbreak in Wuhan. To contain the virus, Wuhan and eventually the whole Hubei province was put into massive lockdown. The virus, which was later named SARS-CoV-2, got out anyway in other countries of the world. Although limited to China initially, the novel strain of the coronavirus being super contagious compared to the previously known strains has quickly spread across the globe. WHO declared the virus as a global pandemic on March 11, 2020. By then the epicenter of the virus had been shifted from China to Eastern Europe followed by the USA. As updated by the World Health Organization (WHO) on May 28, 2020, the COVID-19 outbreak has reached 213 countries and territories worldwide with 5,593,631 confirmed cases and 353,334 deaths (1).
The virus is yet to be peaked in most of the countries that got infected, and on top of that public health experts have warned that the newest epicenter of the virus could be shifted to the densely populated south and south-east Asia (2). Despite the concerted efforts by every stakeholder, tens of thousands of new cases of COVID-19 have been arising every day. Suddenly the world is facing a severe crisis of ICU beds and artificial respirators. From frontline doctors and nurses to pharmacists, all healthcare professionals are now facing an intense workload. It would take years to develop a vaccine for this novel coronavirus considering the fact that we are yet to see any effective vaccines for the previous coronavirus outbreaks (e.g., SARS & MERS) (3). Besides no well-established and specific anti-viral drug for this virus is available right now. Under this context, it is essential to better elucidate the clinical characteristics of the virus for a clear understanding of the disease and proper management of the patients by the health care providers. Moreover, the diagnosis also coincides with many challenges that include false test results, sampling errors, asymptomatic cases, insufficient testing facilities and lack of consciousness among mass people. Due to higher cost for RT-PCR testing facilities and lack of skilled manpower, many countries could not make it available across every regions, specially remote areas. In addition, due to the unwillingness of the patients arising out of fear of contamination and tendency to avoid procedural complexities, many suspected cases remain undiagnosed. To get the actual scenario of the prevalence and incidences as well as for the proper management of COVID-19 addressing all the diagnostic challenges is of utmost importance. This systematic review presents the summary of published reports up to 7th May 2020 on the clinical characteristics of COVID-19 for a better understanding of the frontiers team

METHODOLOGY Protocol
This systematic review protocol is designed following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) Statement-2009 (4).

Literature Search Strategy
We conducted a systematic and comprehensive search of important online databases-PubMed, Web of Science, Science Direct, Scopus, Wiley Online Library, and Google Scholar. The articles published and available online up to 7th May 2020 were considered to include in this study. The keywords used for the searches are included in the Table 1. All the searches were done in the English language only.

Eligibility Criteria
The search results were subjected to a range of inclusion and exclusion criteria, as listed in Table 1. The inclusion criteria mainly include original peer-reviewed articles (articles based on direct clinical data of the COVID-19 patients in various clinical settings). We opted out case reports, meta-analyses, expert opinions, newspaper articles, and commentaries.

Screening and Study Selection
Following the eligibility criteria, two researchers were collaboratively involved in the screening and selection procedure of the articles of interest. The screening procedure was based on the PRISMA-2009 flow diagram, as presented in Figure 1. To   reporting desired clinical parameters like symptoms, laboratory characteristics, and risk factors were included in the review. Case reports were discarded because they do not add significant value when stacked up against case studies. The whole procedure was overseen by two experienced researchers (an expert clinician and supervisor of this project).

Data Extraction and Entry
The full text of the selected articles was thoroughly examined for relevant data of this systematic review that included the  Table 2). We recorded and summarized the extracted data in Microsoft Excel. The whole process was carefully monitored and adjusted, had there been any discrepancies, by two independent expert researchers, including a clinician.

Quality Assessment
The validation instrument called "methodological index for non-randomized studies" (MINORS) was used to assess the methodological quality and bias risk of our data ( Table 3). It is based on eight criteria for non-comparative clinical reviews, and the global acceptance score had been set to 16 (37).

Study Selection and Characterization
The result of our screening and selection protocol has been shown in Figure 1. We initially retrieved 557 articles after removing duplicates that were later shortened to 34 following the screening protocol for the selection of eligible articles. The relevant information of these finally selected articles along, with associated hospital or medical institution names, has been given in Table 2. The total number of case-patients in these studies is 10,889. We retrieved a total of 176 variables regarding these patients that included demographic features, laboratory findings, symptoms, comorbidities, etc. (Tables 4-9) from these articles for the review. Most of the studies were from China, particularly from the Hubei province. For convenience, the data were split into three groups as mentioned earlier. But we inferred our final results after combining them into a single dataset.

Demographic Characteristics
The mean age of the case population was 50.6 years (0.5-94). The percentage of the male population was 60.3% (6567/10889), whereas that of the female population was 39.7% (4322/10889). The case population includes Asian, European and North American patients. Around 14.2% (641/4530) of them were found to be current smokers ( Table 4).

Clinical Symptoms
The most frequently observed clinical symptoms (  (1/3598). A minor portion, 0.56% (20/3598), of the patients of the case population was found to be asymptomatic as well.

Laboratory Findings
The laboratory findings (

Radiological Findings
The results of chest CT scans (

Physical Examinations
The results of the physical examinations (

Clinical Progression Data
The median incubation period of the patients is found to be 5.

Exposure Pattern
A significant portion of the study cases has their exposure history linked to family members or their respective community 28% (680/2427) (

Age-Dependent Effects of COVID-19
It is assumed that, the age of the patients may influence the clinical features, disease progression, complexities, and fatality of the COVID-19. However, we have analyzed and included the available data on this aspect. The notable findings include faster disease progression, higher mortality rate, progressively lower lymphocyte count, higher ICU admission rate, higher mortality rate for those receiving mechanical ventilation, and higher risk of severe heart attack among the older patients ( Table 10).

DISCUSSION
This systematic review is based on a random effect model. As such, it contains data from studies that took place in different countries, including China, the USA, Japan, South Korea, France, and Singapore. All the studies were published in peer-reviewed articles with patient data between late December 2019 and May 7, 2020. We managed to retrieve data on clinical characteristics of COVID-19 from 10,889 infected patients. Various studies and reports worldwide showed that COVID-19 seems to infect the male population more frequently than it does to female population. Our review also corroborates this claim as 60.3% (6487/10889) of our case population are male and the rest 39.7% (4241/10889) are female. Previously older age had been predicted to be an essential factor for higher mortality in SARS and MERS patients (38). Several studies in our review have reported the same. During the initial transmission period, COVID-19 seemed to affect the elderly more, as reflected by the mean age of 49.8 years (0.5-94) of the case population included in the review attributing to the higher frequency of comorbidities observed among the elderly (39). But in the current situation, it seems that the virus can equally affect everyone irrespective of age. However, it is evident that the clinical characteristics and prognosis of the disease greatly vary among patients with different age groups. Patients over 60 years tend to show  more severe clinical manifestations and relatively longer disease duration, meaning they would require more careful monitoring and more comprehensive medical interventions (40). The Chinese Center for Disease Control and Prevention (CDC) reported that the vast majority (81%) of COVID-19 patients will develop only mild symptoms, and the rest develop severe illness i.e., they will require oxygen therapy (14%) or require ICU treatment (5%) (41). Usually, COVID-19 patients are diagnosed with signs of severe pneumonia. Our review found that the most commonly reported symptoms are dry cough (59.6%), fever (46.9%), fatigue (27.8%), and dyspnea/shortness of breath (20.23%). These symptoms, together with prior contact history with suspected patients, immediately would require medical attention. Other less frequent symptoms include myalgia, diarrhea, headache, anorexia, sore throat, rhinitis, upper airway congestion, expectoration, pneumonia, etc. The symptoms are similar to those of SARS and MERS (42,43). In most cases, the symptoms are mild during the initial days of infection but can be very severe, particularly for the elderly and patients with underlying respiratory diseases. Unlike SARS and MERS, SARS-CoV-2 behaves mildly during the initial stage of infection, making it significantly more contagious than the previous coronaviruses since the condition can go unnoticed in some cases (44). New shreds of evidence emerging from across the globe suggest that the asymptomatic cases of COVID-19 infections are rising (45,46). But our review found that only a small percentage (0.56%) (20/3598) of the patients were asymptomatic which may be attributed to the fact that the initial tests for COVID-19 were only being conducted for patients with a distinct illness. To screen out the asymptomatic cases, experts have emphasized on comprehensive epidemiological investigations of the suspects by disease control specialists. Besides, the asymptomatic patients have shown consistent abnormalities in their CT scan reports for which radiological investigations can be a useful diagnostic tool to find the asymptomatic variants (47).
The most notable laboratory finding of our review is lymphocytopenia found in 55.9% cases (4177/7470). It was also reasonably expected in the influenza virus (H5N1), SARS, and MERS (48). In H5N1 influenza the fall in lymphocyte count had been attributed to dendritic cell (DC) dysfunction suggesting that a similar mechanism related to dysfunctional adaptive immunity can cause the same in COVID-19 patients (49). Besides, another study has demonstrated the correlation between the lymphocytopenia and the clinical severity of SARS-CoV-2 infection. The study also infers that the lymphocytopenia might be an outcome of the death of lymphocytes or the damage of lymphatic organs like thymus or spleen directly by the virus itself (25).
Another significant finding of our review is the elevated level of CRP 61.9% (830/1340) which supports a study that demonstrated elevated CRP levels in COVID-19 patients even though they did not have any kind of coinfections (50). It is to be noted that the CRP level is usually increased in bacterial or viral infections. However, it does not demonstrate a significant elevation in the case of mild viral infections. Another study claimed the potentiality of CRP as a comprehensive predictive factor of COVID-19 prior to the changes in other inflammatoryrelated blood parameters e.g., leucocytes, lymphocytes, and neutrophils (5). Besides, CDC guidelines have also reported an elevated CRP level in COVID-19 patients with higher CRP levels indicative of the severity of the infection and poor prognosis (51). Previously it has been associated with Influenza H1N1 & H7N9 and the SARS epidemic (52,53). In COVID-19 patients, this significantly elevated level of CRP can be explained by the excessive production of inflammatory cytokines due to immune response as well as the damage of the lung alveoli (50).
LDH level has been found to be increased by 40.8% (392/973) in COVID-19 patients. Although it is abundant in tissues, LDH level is low in blood circulation. Elevated LDH, as reported in SARS, reflects tissue necrosis corresponding to hyperactive immunity (54). Besides, viral infections can cause lung tissue damage, which in turn raises the LDH level in blood circulation (55).
Our review revealed abnormal liver function tests in the case of patients with elevated ALT 36.65% (2318/6503) & AST 53.3% (3481/6537) level and lower albumin (38.4%) (187/487) and serum creatinine kinase level (31.9%) (99/310). One report has proposed that the hepatic dysfunction of COVID-19 patients can be linked to direct liver injury via viral hepatitis or due to abnormal levels of blood coagulative and infection-related functions, such as, elevated prothrombin time, D-dimer level, and serum ferritin, as found in our review (56).
We could not find sufficient data on the immunological parameters of the case patients. But one of the studies included in our review reported a higher IL-6 count in 51 (50%) of 99 patients (14). Besides, two recent studies have shown that IL-6 level was substantially increased in both severe and moderate patients. In addition to that, other pro-inflammatory parameters like IL10, IL2, IFN-γ, and TNF-α were found to be higher in more severe patients than in the moderate ones (21,22). The magnitude of the cytokine storm or, more particularly, elevated IL-6 level has been associated with disease severity (13). It has been proposed as an essential parameter to predict respiratory failure risk based on a study that found a significantly higher IL-6 level in patients requiring ventilation (57).
The radiological findings showed that COVID-19 patients are accompanied by an abnormality in their CT scan report in 93.5% (1668/1785) cases. So CT scanning can provide an important base for early diagnosis of the virus. The typical CT scan features include bilateral lung 71.1% (1581/2223) and unilateral lung 17.6% (281/1598). The density characteristics of the lung lesions, found in 78.3% (180/230) cases, was mostly uneven, with ground-glass opacity 48% (432/900) as the primary presentation accompanied by consolidation in 21.88% (140/640) cases. CT scan reports have been demonstrated an association between disease progression and a higher rate of consolidative opacities (58). CT scan reports and the RT-PCR tests are generally found to be harmonious with a few exceptions. CT scan results can be a more specific diagnostic tool for the suspected COVID-19 cases since even the asymptomatic patients have shown abnormalities in their CT scan reports (46,47). The less common CT findings include pleural effusion 20.6% (195/947), pericardial effusion 2.9% (5/170), bronchial wall thickening 30.3% (80/264), and interlobular septal thickening 47.1% (80/170) which have been reported as the disease progresses.
The median incubation period of the SARS-CoV-2 virus has been found to be 5.36 days (1.5-15). National Health Commission of China previously reported an incubation period of 1 to 14 days. The CDC has updated the mean incubation period to be between 2 to 14 days (51). However, various studies together with our findings suggest that the incubation period of SARS-CoV-2 is highly variable and requires more concrete statistically significant results. This high variability in the incubation period of SARS-CoV-2 has warranted a suitable quarantine period of at least 3 weeks to reduce the community transmission of the virus (59). A significant portion of our case patients had one or more comorbidities indicating that a significant portion of our case patients is elderly. They are more likely to develop various chronic or acute clinical conditions on aging. Hypertension (35.9%) (3909/10889), diabetes (20.17%) (2196/10889), obesity (15.95%s) (1737/10889), cardiovascular diseases (13.92%) (1516/10889) and respiratory diseases (e.g., asthma-4.42%; COPD-4.31%) are the most frequent comorbidities found in the case patients of our review. The prevalence of comorbidities can be a major risk factor for severe patients compared to non-severe patients due to higher case fatality and poor prognosis (17). Thus, a proper medical history of the COVID-19 patients, particularly elderly patients, should be documented. Moreover, adequate clinical facilities should be made available for this group of patients.
Age-specific patient data was not sufficiently available in the case of most of our included studies. Still, for some crucial parameters, such as mortality rate and severity of the disease, a pattern was observed across the studies involving the older patients who, in general, possess a higher risk. Table 10 has listed all of the available age-related effects that we were able to retrieve. One of the recent studies has indicated that the children's overall risk factors are not significantly affected by the age and sex (60). Unlike adults, the children are at a lower risk of developing severe symptoms or death.

Diagnostic Challenges of COVID-19
Article search strategy: For the collection of information on diagnostic challenges of COVID-19, we have extensively searched by using the keywords "COVID-19 and diagnostic challenges, " "challenges for the diagnosis of novel coronavirus diseases, " on Pubmed, Web of Science, Science Direct, Scopus, Wiley Online Library, Google Scholar databases and other online websites of reliable sources such as Gavi-The Vaccine Alliance (gavi.org), World Health Organization, US-FDA, etc.

Review Findings on the Diagnosis Challenges of COVID-19
Every day the novel coronavirus is presenting us with new clinical challenges. As countries worldwide are considering to curb the limits on social distancing measures, general testing and rapid diagnosis of the disease have become of utmost importance. Even though various efforts are undertaken both by the government agencies and international bodies, the diagnosis of COVID-19 is still challenging. For convenience, the information on the current challenges for the diagnosis of COVID-19 have been summarized as follows: 1) Although RT-PCR has been regarded as the gold standard for viral detection of SARS-CoV-2, it also comes with few challenges. The equipment and lab facilities required for this testing can be expensive. The testing environment requires a certain biosafety level e.g., BSL-2 cabinets for sample preparation or ideally a negative pressure room (61). Most of the traditional testing centers all around the globe do not have these facilities. On top of that, these facilities require technicians with enough expertise and experience to perform the tests smoothly and flawlessly (62). Therefore, lack of testing centers and expert technicians are the primary diagnostic challenges faced by most of the countries all over the world. For this very reason, many countries failed to start coronavirus testing early in its transmission phase. Even when they had started testing, it was strictly restricted to suspected individuals with clear symptoms of the viral infection (63). Moreover, as countries all over the world are trying to increase their number of testing each day, this has put a serious pressure on the ready availability of reagents for the PCR reactions. Thus, shortage of testing kits is next big challenge to the rapid diagnosis of the disease. 2) Another crucial diagnostic challenge with RT-PCR testing is the risk of eliciting false-negative and false-positive results. It has been found that many patients with typical COVID-19 symptoms and CT features have shown a negative influence in RT-PCR testing (64). Therefore, a negative result should not preclude the patient as a COVID-19 suspect, and it should not be used as the only criterion of diagnosis. Besides, a false result due to human error cannot be overruled as under-trained technicians are performing many of these tests.
3) The collection of the patient sample (throat swab) presents another diagnostic challenge as this requires specific procedures to be followed for the sake of proper sample preparation for RT-PCR testing. Wrong sampling procedures can cause errors in RT-PCR testing (65). Moreover, a global shortage of personal protective equipment (PPE) has put additional challenges as adequate protective measures have to be made available for the staff involved in this sample collection procedure. 4) RT-PCR testing also faces another challenge that arises from the susceptibility of the viral mutations in the SARS-CoV-2 genome. Various studies have shown a rapid evolution of the virus (66,67). Consequently, a false negative result may arise due to mutation in the primer or probe target regions (61). Although they are based on the most conserved regions of the viral genome, a slight variability can decrease the assay performance. 5) Asymptomatic patients have become a major challenge for both the clinicians and the administration. They are difficult to diagnose and isolate and they also pose a more significant threat of rapid and unchecked viral transmission. A recent study has found a similar viral load in asymptomatic patients compared to the symptomatic ones, indicative of their transmission potential (68). Another big concern is that most of these asymptomatic patients will not report to the hospitals or testing centers. Under such circumstances, their diagnosis solely depends on contact tracing or cluster screening by the disease control experts (68). Diagnosis of asymptomatic children is also challenging as their diagnosis is only limited to tracing their family history (69,70). But this task is getting increasingly tricky both due to an overwhelming number of new cases arising each day and the limited workforce of the disease control centers. 6) Although COVID-19 patients have clear chest CT scan manifestations, several studies have reported usual CT scan reports despite being RT-PCR confirmed COVID-19 patients (9,71). One study has found a false negative result of over 12% when attempted to predict the infection based on CT scan reports only (72). These reports clearly mean that clinicians have to be more vigilant in diagnosing the suspected cases of COVID-19 patients and consider multidimensional factors including laboratory parameters, CT scan reports, and other tests. 7) Additionally, most countries do not have a sufficient number of CT scan machines to support widespread testing of the rising number of COVID-19 patients (73). Besides, it takes a lot of effort to disinfect the machines after each test to prevent unwanted viral transmission. 8) Another challenge is that it requires multiple scans (at least 2, 6 days apart) for maximum accuracy in the diagnostic results meaning this would put additional pressure on the already scarce CT scan machines (74). 9) Sometimes suspected patients of the virus are showing unwillingness to come to test centers to confirm the presence of the virus. Some of the developing nations have reported these incidents, which were mostly attributed to the lack of concern, illiteracy, and the fear of social stigma (75). These patients remain undiagnosed for a considerable time till their symptoms get severe to the extent that they need hospitalization. So this group of patients presents us with a severe diagnostic challenge. 10) Serological detection tools utilize the detection of specific antibodies (IgM and IgG) against COVID-19 infections. These antibody tests have the advantage of low cost, fast detection and easy availability but suffer from low sensitivity as is seen with the antibody tests deployed for other coronavirus and influenza virus (76)(77)(78). However, IgM responses vary from person to person and require days to develop once they get infected. Considering that this may not be an useful tool for the accurate diagnosis of the viral infection except in confirming the late cases of COVID-19 and immunity of the recovered individuals (79). Due to these concerns, on April 1, 2020, the FDA granted Emergency Use Authorization (EUA). Still, they repeatedly expressed their doubts about the effectiveness of these tests in detecting the virus early during infection (80).

STRENGTH AND LIMITATIONS
To our knowledge, this is one of the first attempts to summarize the clinical characteristics and diagnostic challenges of COVID-19 taking into considerations of all the available data from global studies and variabilities so that the researchers, health care workers, policy makers and related stakeholders can get a contemporary overview of the COVID-19 situation. The most noticeable limitation of our review is the lack of consistent data on every variable across the studies that we have included, which happened due to underreporting of symptoms, comorbidities, laboratory results, or exposure patterns of the case patients. These initially published studies have some issues related to lack of adequate laboratory testing, which could be attributed to the fact that these studies had to be completed as fast as possible to keep people around the world up to date about the virus and to prepare them fast to manage the disease. Besides, we were able to fetch only a limited amount of data regarding the clinical progression and other epidemiologic characteristics that would otherwise come in handy in defining clinical characteristics. In addition, most of our studies were from China, as no data were available from other countries. It would be better to broaden the geographical scope of our review to get a more global scenario of the clinical characteristics of the outbreak.

CONCLUSION
This systematic review summarized the latest clinical findings of the novel coronavirus outbreak that has virtually affected the whole world. To the best of our knowledge, this is the first large scale review comprising of studies from across the globe focusing on the clinical features of the COVID-19 patients. Laboratory tests and CT scan reports, together with clinical symptoms will provide useful information for the correct diagnosis and better management of the patients. This review provides a comprehensive overview and clear features of the clinical characteristics of COVID-19 which will help the physicians to make proper clinical decisions and correct assessment regarding the patients. Additionally, we have reviewed the challenges being faced for the diagnosis of the disease across the world.
Overcoming these obstacles to the fast and prompt diagnosis of COVID-19 will be crucial for the proper containment of the disease.

DATA AVAILABILITY STATEMENT
All data generated or analyzed in this study have been included in the article. The raw data will be provided by the corresponding and/or by the first author on reasonable request.

AUTHOR CONTRIBUTIONS
SMHI and MMRS: conceived and designed the study; SMHI and PTR: Collected data through article search in different online databases; KAK and MMRS: Checked and verified collected data; SMHI, PTR, MMRS, FK, and SA: Analysis and interpretation of data; SMHI and MMRS: prepared the manuscript draft; AAT, CLP, INM, and LCM critically reviewed the manuscript. LCM was also involved with the planning of the study. All authors read the manuscript, agreed to be accountable for all aspects of the work, and approved the final manuscript.