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REVIEW ARTICLE
J Res Med Sci 2021,  26:41

Clinical manifestation, laboratory and radiology finding, treatment and outcomes of COVID-19: A systematic review and meta-analysis


1 School of Nursing and Midwifery, Tehran University of Medical Sciences, Tehran, Iran
2 School of Nursing and Midwifery, Shahroud University of Medical Sciences, Shahroud, Iran
3 Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
4 Department of Infectious Diseases and Tropical Medicine, Imam-Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran

Date of Submission12-Aug-2020
Date of Decision04-Oct-2020
Date of Acceptance19-Jan-2021
Date of Web Publication30-Jun-2021

Correspondence Address:
[email protected] Mohsen Meidani
Department of Infectious Diseases and Tropical Medicine, Imam-Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jrms.JRMS_900_20

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  Abstract 


Background: Since December 2019, coronavirus (COVID-19) spread throughout the world. The high rate of infection and its unknown nature led specialists to report the condition of patients. The aim of this study is to systematically review of symptoms, laboratory and radiologic findings, treatment, and outcomes of patients with COVID-19. Materials and Methods: Databases such as PubMed, Embase, Scopus, Web of Science, Google Scholar, and Cochrane were searched. Finally, 46 articles were appropriate for the aim of the study. After quality evaluation, the necessary data were extracted and meta-analysis was performed. Results: 4858 articles were retrieved until March 30, 2020. After screening, the full-text of 46 articles was assessed. Of the reported cases, 31.7% had no comorbidities, 21.4% had high blood pressure, 70.6% had fever, and lymphopenia was reported in 55.2% of patients. For 16% bilateral patchy shadowing in radiography and for 51% ground-glass opacity was reported. Outcomes were remarkable for recover to death. Conclusion: COVID-19 leads to healthcare problems for countries. Nonspecific symptoms have made it difficult for differential diagnoses without computed tomography-scan or corona Test, but they are not available in many countries. Therefore, this systematic review can help health care staff to make decisions based on symptoms, treatments, and outcomes..

Keywords: COVID-19, coronavirus, meta-analysis, SARS-CoV-2


How to cite this article:
Nayeri ND, Nadali J, Divani A, Basirinezhad MH, Meidani M. Clinical manifestation, laboratory and radiology finding, treatment and outcomes of COVID-19: A systematic review and meta-analysis. J Res Med Sci 2021;26:41

How to cite this URL:
Nayeri ND, Nadali J, Divani A, Basirinezhad MH, Meidani M. Clinical manifestation, laboratory and radiology finding, treatment and outcomes of COVID-19: A systematic review and meta-analysis. J Res Med Sci [serial online] 2021 [cited 2021 Jul 25];26:41. Available from: https://www.jmsjournal.net/text.asp?2021/26/1/41/320517




  Introduction Top


Recently, a family of viruses with developed and special genome called human coronaviruses has been responsible for a large number of respiratory system diseases. Currently, these viruses are known as one of the main causes of severe respiratory diseases such as bronchitis and bronchiolitis and pneumonia in children, young people, and adults.[1] Six types of coronaviruses have already been identified.[2] Over the past two decades, many people have died from these viruses, ranging from 10% severe acute respiratory syndrome-related coronavirus (SARS-CoV) to 37% Middle East respiratory syndrome-related coronavirus (MERS-CoV).[3] Furthermore, these viruses are known as nosocomial infection agents and impose exorbitant costs to health systems.[1]

Despite the world's familiarity with these types of viruses, in December 2019, a series of cases of pneumonia with unknown etiology emerged in Wuhan, China, which the early symptoms were greatly similar to viral pneumonia. However, a closer examination and analysis of lower lung samples revealed that a type of coronavirus (nCOV) is the cause of the symptoms. This virus is named new coronavirus 2019 or COVID-19 by the WHO.[3] This time, the issue was quite different from previous times. The concern was not related to the mortality rate (MR) from the virus, rather it was about the high rate of its transmission. Furthermore, it was not known how to deal with this disease because of a lack of knowledge.

Despite the lower MR of this virus in comparison with its families, it is worrying due to its high prevalence and contagion so that the number of deaths and infections is very remarkable. Among 1,039,158 people have been infected with this virus in the world until April 4, 2020, 55,163 participants of them died.[4]

Coronaviruses exhibit high resistance in the environment. This feature has made it difficult to control and prevent the disease.[1] Furthermore, the rapid spread and transmission of this virus have caused worldwide concern. Until now more than 200 countries reported to have been infected by this virus and many patients have died.[5] On the other hand, according to the Centers for Disease Control and Prevention report, the incubation period of 2019-nCov is 2–14 days and has recently mentioned this period can also be very momentous in the virus transmission.[6]

Due to the mentioned features of this virus, this worldwide outbreak calls for faster and wisely control by countries.[7] For more effective control and prevention, recognizing the sign and symptoms of the patients in different periods of illness and isolating them plays an important role.[8] However, a variety of symptoms have been mentioned so far, some only just have been added such as Anosmia, hyposmia, and ageusia.[9],[10] Furthermore, symptoms of fever, dry cough, and fatigue in the early stages without the typical symptoms of acute respiratory disease, and later pneumonia-like symptoms, gastrointestinal symptoms such as diarrhea with virus excretion (up to several weeks) and in some cases, central nervous system involvement such as multiple sclerosis has been reported.[1] Although some of the clinical manifestations of SARS, MERS, and COVID appears to be similar, distinct symptoms have also been reported in some patients, so faster differential diagnosis is required for treatment.[3],[11],[12],[13]

Laboratory findings of patients infected by COVID-19 showed lymphopenia and leukopenia. Furthermore, findings of chest computed tomography (CT) scan showed bilateral abnormalities in lung lobes, which are very similar to symptoms of influenza and other respiratory viruses. This pattern made it more difficult to early differential diagnosis.[3],[13] Other laboratory findings showed increased prothrombin time, increased D-dimer, increased liver enzymes, and increased cardiac enzymes in some cases. Pro calcitonin level was reported mostly normal, although these reports were contradictory in different studies.[13],[14],[15]

Although viral diseases usually have an overestimated MR in the early stages, issues are different this time. MRs are rising rapidly as a result of severe contagion, world outbreak, and lack of differential diagnosis and lack of appropriate and specific treatment.[15]

However, many countries are facing lack of facilities such as laboratory testing and sampling, hence priority is given only to subjects with very severe symptoms while recognizing symptoms and their incidence and frequency can have an effective role in the subsequent control of the disease. Since various symptoms have been mentioned in the studies, a systematic review is required to provide a conclusion for health and policymakers.

Likewise, there is no specific treatment for the disease so far, and various countries are trying different drugs and sometimes combinations therapy.[13],[14] The efficacy of these drugs has not been systematically investigated by using patient-centered outcomes such as MR, discharge of hospital, and remission. Therefore, this study was conducted with the aim of recognizing the specific symptoms of COVID-19 as well as its treatments and outcomes as a systematic review with meta-analysis.


  Methods Top


Data sources and search strategy

Based on the PRISMA guide[16] (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), we used an evidence-based model for framing a PICO question model (PICO: Participants, Intervention, Comparison, and Outcomes). The questions posed was the following: What are the symptoms of patients with patients with COVID-19? What are laboratory and radiologic findings in patients with COVID-19? What are the treatments for COVID-19? What are the outcomes of patients with COVID-19? (P) Participants: Patients with COVID-19.(I) Intervention: Treatments performed in patients with COVID-19.© Comparison: Not applicable. (O) Outcomes: Hospitalization, recovery, death.

Since the primary purpose of this study was to conclude of the articles that listed the symptoms or treatments of COVID-19, all valid databases were searched. A broad search was attempted and the search restrictions were moved to include the maximum number of articles in the study without missing any valuable and related article. Then, duplicate entering studies from various databases were removed. After that, all of the titles were read and unrelated articles were deleted.

We search databases- PubMed, Embase, Scopus, Google Scholar, web of sciences, and Cochrane with keywords included coronavirus, COVID 19, symptoms, signs, treatments, outcomes. No time limits were set for searches. However, since the emergence of the disease was in January 2020; the first articles were found on this time; and no studies had been done before. Therefore, all studies before that time were excluded after evaluating the titles. [Diagram 1] shows the flow of assessing studies. Selection criteria and data extraction. Due to the emergence of the disease and to obtain the maximum possible knowledge, there was no restriction on the type of articles in the searching level. However, all the descriptive and analytical studies as well as the observationally reported interventional studies were included in the study. The search keywords and how each site was searched along with the number of articles are listed in [Table 1]. All studies were included until March 30, 2020.

Table 1: Databases and the results of searches

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All articles were assessed based on authors, place of study, sample number, study design, patient characteristics, and symptoms. Furthermore, laboratory findings and treatments used for patients were evaluated completely. Studies lacking the essential components required by the current study objective were excluded from the systematic review; such as being a case report; not mention the definitive diagnosis of COVID-19 with either laboratory tests or definitive symptoms. Furthermore, some articles were removed because they have not assessed symptoms entirely or only, they mentioned one or two nonspecific symptoms.

Quality assessment

Finally, all of 46 remaining articles were reviewed by two reviewers (J. N, A, D) independently and screened studies to identify all potentially eligible studies using the JBI Quality Assessment Tool, whose ratings are included in the [Supplementary Table 1].



Statistical analysis

In this stage, data extracted from all articles were entered into STATA Version 16.0 software (StataCorp LLC Production, College Station, Texas, USA) software for meta-analysis and providing general conclusions about the symptoms and treatments. It should be noted that the heterogeneity of the studies was evaluated according to different symptoms, laboratory findings and treatments, and most of the criteria were heterogeneous in the studies. The Q and tests were used to investigate heterogeneity. Since the articles are heterogeneous, the random model has been used by the maximum likelihood estimation method. To describe each of the signs and symptoms, the ratio and confidence interval (CI) of 95% have been reported.


  Results Top


In this systematic review, 46 articles remained after the final evaluation.[3],[12],[13],[14],[15],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57] The majority of articles were case series (73.3%), 25.7% were descriptive retrospective and <1% were descriptive prospective or epidemiological reports. Although most of the articles were originated in China, other articles–about 5%-were from countries such as Japan, the USA, Australia, France, and Taiwan. Besides, 44.5% of articles were published in March 2020. The characteristics of the studies have presented in [Table 2].
Table 2: Baseline characteristics of all the studies included in the meta-analysis

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The total number of patients reported in these articles was 5570. Slightly more than half of the patients were male (52.74%); and the mean age of the patients was 53.2 (CI: 50.17–56.33) year. The incubation period was reported between 0 and 24 days. Half of the patients reported contact with Chinese people, 15.56% had contact with patients, and 5.94% were exposed to the Huanan seafood market. Moreover, only 1.79% mentioned that they haven't had any contact.

It should be noted that only some articles have dealt with coexisting disorders or clinical characteristics. For example, 16 articles cited coexisting disorders, in which 38% (n = 2969) subjects were present, of which 31.7% had no coexisting disorders. About 21.4% of patients had hypertension (CI = 0.18–0.27); 10.8% had endocrine disorder especially diabetes mellitus (CI = 0.009–0.13); 8.1% had cardiovascular disease (CI = 0.08–0.13); 3.8% had chronic obstructive pulmonary disease or other respiratory diseases (CI = 0.03–0.05); 4.7% had cerebrovascular disease (CI = 0.04–0.07);12.6% had a history of previous surgery (CI = 0.02–0.10); and 6.3% had digestive system disease.

Clinical characteristics

The highest clinical characteristic (about 96% of the total number of patients surveyed) assessed was coughs. They reported that 60.5% of subjects (CI = 0.53–0.63) had dry coughs. However, expectoration and Sputum production was reported in 23.3% (CI = 0.18–0.31). As well as, about 15.8% reported chest pain (n = 225/1419). In this section, the sensitivity of the symptoms was not considered and only the prevalence of symptoms in patients was examined.

The second clinical characteristic (about 94%, equivalent to 5234 people) studied was the temperature which 70.6% of them fever was reported. However, only 5% of subjects had fever >39°. The forest plot of fever is shown in [Figure 1].
Figure 1: Forest plot of fever

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Moreover, 21.1% had a fever <37.5°. Feeling ill, malaise or severe fatigue and weakness had 35.7% prevalence. Shortness of breath/dyspnea existed only in 22.2%. Poor appetite and anorexia were prevalent in about one fourth of patients (23.6%), although, this symptom was examined in only 24% of subjects. Also, 18.5% reported myalgia and 11.1% had headache. Sore throat or pharyngalgia was about 12.2%.

Other signs and symptoms were rigor/chill (12%); diarrhoea/loose bowel movement (9.5%); rhinorrhoea/nasal congestion or sneezing/snotty nose (6.9%); nausea/vomiting (7.5%); dizziness (10.1%). Confusion/loss of consciousness was another important symptom that only assessed 7.7% of patients and 11.65% reported it. Other symptoms reported were tonsils well (2.09%); hmoptysis (1.8%); and hypogeusia/hyposmia (5.1%).

Other signs and symptoms were examined in few patients or they had a lower prevalence including conjunctivitis, abdominal pain, back pain, ataxia, and wheeze. The results of the sensitivity analysis are shown in [Supplementary Table 2].



Laboratory findings

One of the most important laboratory findings in COVID-19 is SpO2. However, only one study has reported this measure with 82 samples that 32.9% had Spo2 between 85% and 94% and 10.1% had Spo2 <85. No one had normal Spo2.

WBC counts were among the most important laboratory criteria; studies reported 58.7% of samples had normal range (3.5–9.5 count, ×109/L) and 24% <3.5 and 10.2% more than 9.5. For half of the samples were reported lymphocytes counts in the normal range (1.1–3.2 count, ×109/L) and 55.2% below normal and only 13.7% above normal. Half of the patients had normal platelet counts, 21.9% had less than normal; and 5.5% (38/681) had platelet more than >350.

As well, ten articles measured Creatine kinase-about 2000 patients-and reported that 10% have been above creatine kinase normal range (171 U/L). In 15 articles which evaluated 2276 patients reported that D-dimer of 26.5% of patients has been >500 mg/l., but an article reported D-dimer in a normal range when they measured 51 people.

Criteria such as erythrocyte sedimentation rate (ESR), Fibrinogen, creatine kinase MB, PT, PTT, BUN, Na, K, and Chloride were reported in a small number of articles, the abnormal rate of which was not noteworthy. Other laboratory findings are shown in [Table 3]. The forest plot of C-reactive protein has displayed in [Figure 2].
Table 3: Laboratory findings and abnormalities in patients with coronavirus disease 2019

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Figure 2: Forest plot of C-reactive protein

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Radiologic findings

Because one of the organs involved in the COVID-19 disease is the lungs, chest radiography and CT-Scan can show the involvement of this tissue. Therefore, some studies have addressed this issue in addition to laboratory findings and symptoms. However, various studies showed different features. Three studies reported bilateral patchy shadowing in 16% (193/1202) in radiology and 18 studies showed Ground glass opacity (GGO) on 51.6% (1579/3055) patients in the CT-scan. The forest plot of GGO is presented in [Figure 3]. Other radiologic features are shown in [Table 4].
Figure 3: Forest plot of ground-glass opacity in computed tomography scan

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Table 4: Radiologic findings in patients with coronavirus disease 2019

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Treatment

COVID-19 is an emergent disease and no specific treatment has been well-known for it, therefore different drugs were used in combination. Oxygen therapy is the first and popular treatment as mentioned Spo2 is decreased in the patients. Antiviral such as oseltamivir, lopinavir/ritonavir (Kaletra), darunavir/cobicistat, and Arbidol were used. Other medications used for COVID-19 are shown in [Table 5].
Table 5: Treatments used for patients with coronavirus disease 2019

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Complications

Although medical staff have tried to provide the best available treatment for patients with COVID-19 severe complications that happened in some of the patients, and has even led to mortality. Some of the most important complications mentioned in the articles are: 22.9% acute respiratory injury/acute respiratory distress syndrome (448/1995); 11.2% septic shock (93/826); 35.1% electrolyte disorder (109/310); 13.6% Disseminated intravascular coagulation (63/461); 10.3% liver disorder (133/1288), and 14.4% ventilator-associated pneumonia (31/215).

Outcomes

Different outcomes have been recorded after getting the disease in the studies including discharge 23% (549/2381); hospitalization 76.9% (1767/2297); recovery 24.1% (493/2042); death 12.4% (311/2502).


  Discussion Top


This study investigated systematically physical symptoms and signs, as well as laboratory and radiological findings and treatment in published studies on patients with COVID-19. Despite the new emergence and lack of confirmed knowledge of the symptoms of the disease and the ways of treatment, many studies have been done on patients with COVID-19 during their physical examination and treatment. In addition to their therapeutic duties, specialists from different countries have provided detailed reports on the patients' condition and their outcomes, as evidenced by the publication of several thousand articles in this field. Despite a lot of articles in this regard, it was tried to observe all of the principles and procedures of systematic review with high quality; so that the studies were evaluated carefully in terms of quality and relevance with the intention of the studies that remained for the final review be valid and invaluable. Hence, 46 articles remained in the final stage. These articles were all reviewed for quality and they were worthy to study.

Slightly more than half of the patients were male. However, studies were heterogeneous (CI = 0.49–0.54; P < 0.001). Given that men have social attendance and COVID-19 is contagious, this can be a possible sensible explanation. Contact with Chinese people was the most reason of transmission, which was expected due to the initial emergence of the disease in China and the most of published papers were from this country.

In this study, most of the studies confirmed the presence of comorbidities in patients with COVID-19. The comorbidities were confirmed not only in COVID-19 but also in previous influenza viral infections such as MERS and H1N1.[58],[59]

The most common symptoms reported were dry cough and fever. These symptoms and the extent of involvement contain important messages. The fact that fever has been reported in two-thirds of patients, and only one-tenth of patients had a fever above 39°C, raises doubts about the use of temperature to separate and quarantine of patients.

Many of the other symptoms are not specific to COVID-19, and they are similar to other virus infections in this family and other viruses that make it difficult to differentiate. However, it is recommended that protective measures be taken even in suspicious cases and the symptoms be considered corona to prevent further spread. Symptoms such as feeling ill, malaise or severe fatigue or weakness, and dyspnea are also seen in other flu and pneumonia.[60],[61],[62] Sore throat or pharyngalgia and rhinorrhea, Nasal congestion, sneezing and snotty nose, as well as rigor/chill are also nonspecific symptoms and have been reported with other influenza and common cold.[63],[64],[65]

Myalgia and headache have also been reported in other pneumonia with other origin.[66] Furthermore, symptoms such as dizziness and confusion/loss of consciousness have been reported before the emergence of COVID-19.[67],[68],[69] Poor appetite, anorexia, nausea/vomiting, and diarrhea/loose bowel movement are also common symptoms of other viral infections and pneumonia.[70],[71],[72]

Laboratory findings suggest that arterial blood saturation is significantly reduced. This finding has also been observed in other pneumonia due to lung tissue damage.[73] Both lymphopenia and lymphocytosis were found in patients. Meanwhile, half of the patient had lymphopenia, while slightly more than one-tenth had Lymphocytosis. This discrepancy can go back to the time of measurement. As the disease progresses, the risk of lymphopenia increases. Some studies confirmed that lymphopenia is a frequent finding in hospitalized patients with community-acquired pneumonia (CAP), affecting approximately 50% of the patients[74] and it is associated with a deregulated immune response, increased severity, and mortality.[75] Some authors suggested that is lymphocytosis evidence of active inflammation in pneumonia.

Although other studies have shown that monocyte was positively correlated with ESR and negatively with body temperature,[76] in the current studies, this correlation has not been evaluated.

The study revealed the platelet counts of one-fifth of evaluated people were lower than normal; it has been noted in other studies so that a study indicated that an increase in mean platelet measurements during admission can predict the prognoses of patients with pneumonia and related to poor outcomes.[77] However, in the current study, only 5.5% had more platelet.

Creatine kinase was also reported to be high in 10% of those measured. This is consistent with other infections that lead to pneumonia.[78] D-dimer was measured in only one article; however, more than a quarter of patients had a high rate of that. However, a study has shown in CAP patients, a D-dimer >2 μg/mL was risk factor associated with in-hospital mortality.[79]

Radiological findings included chest X-ray (CXR) and CT scan of patients in current studies have shown lung tissue involvement. Chest CT scan can be performed after the detection of abnormalities in CXR. Combination of radiological findings with clinical manifestations can lead to better clinical judgment.[80] In current studies, some have shown bilateral patchy shadowing or GGO in CT scans of the lungs. In a multicentre study, this feature has also been confirmed. It showed a mixed and diverse pattern with both lung parenchyma and the Interstitial involved.[81] Another modality is chest CT-scan. It can be ordered in suspected cases with typical symptoms at the first step, or it can be performed after the detection of any abnormalities in CXR.

Therapies in the studies indicated that specialists have used various combination therapies in addition to oxygen therapy. They were usually a combination of antiviral, antibiotic, and miscellaneous treatments. Nevertheless, more specific treatments have been given for other pneumonia or viral infections because of more comprehensive knowledge and broader research.[82],[83]


  Conclusions Top


Up to the present, the studies of COVID-19 usually have been observational, and experts have reported them along with their medical prescriptions. Nevertheless, research is ongoing and new signs and symptoms of the disease are being identified. However, the results of the current study could be useful because it showed the most popular symptoms and the validity of them for identifying and isolating patients. Because some symptoms, such as fever, occur in only two-thirds of people, they are not a good measure of isolation and more measures should be done. Although CT scan is a valid test for detecting the typical pattern of COVID-19 pneumonia, in the early stages of the disease is not recommended since in this period CT scan of lungs may be completely normal. Furthermore, in other forms of COVID-19 which affect organs other than the respiratory system, CT scan is not a valuable diagnostic test.

Further studies in European countries, the United States, and Asia are needed to identify new dimensions of the disease; therefore, systematic reviews can be done regularly.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.


  Supplementary Tables Top




 
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