Edited by: Zisis Kozlakidis, International Agency for Research on Cancer (IARC), France
Reviewed by: Patrick Alexander Wachholz, São Paulo State University, Brazil; Meng Rui Lee, National Taiwan University, Taiwan
This article was submitted to Infectious Diseases - Surveillance, Prevention and Treatment, a section of the journal Frontiers in Medicine
†These authors have contributed equally to this work and share first authorship
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Late in December 2019 and early in January 2020, reports of a very progressive pneumonia-like respiratory syndrome, starting in Wuhan, China, induced global health concerns (
This review conforms to the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) statement (
We carried out systematic searches of the literature in the following bibliographical databases: PubMed/Medline, Embase, and Web of Science. Search criteria included case reports and case series articles published up to April 24, 2020, and there were no restrictions regarding publication language. We used Google Translate for eligible articles published in languages other than English. The search terms for our review were: COVID-19, severe acute respiratory syndrome coronavirus 2, novel coronavirus, SARS-CoV-2, nCoV disease, SARS2, COVID-19, 2019-nCoV, coronavirus disease-19, coronavirus disease 2019, and 2019 novel coronavirus.
Studies included in the review met the following criteria: prospective or retrospective descriptive case reports and case series of COVID-19 in the hospital setting which included diagnostic methods, clinical manifestations, laboratory features, treatment, and outcomes. Articles describing experimental approaches as well as reviews and publications without peer-review processes were excluded.
All potentially relevant articles were screened in two stages for eligibility. In the first stage, the titles and abstracts of potentially relevant articles were screened independently by two reviewers (YF, PJ). In the second stage of assessment, the full text of those abstracts which met the inclusion criteria was retrieved and independently reviewed by the same authors. Disagreements and technical uncertainties were discussed and resolved between review authors (AT, SH, MA, MJN).
The extracted data included bibliographic data, patient demographics (e.g., age and gender), radiological and laboratory findings, treatment protocols, and medical consequences. Two authors (AT, SH) independently extracted the data from the selected studies. The data was jointly reconciled, and disagreements were discussed and resolved between review authors (YF, PJ, MA, MJN).
The critical appraisal checklist for case reports provided by the Joanna Briggs Institute (JBI) was used to perform a quality assessment of the studies (
As illustrated in
Flow chart of study selection for inclusion in the systematic review.
Characteristics of the included studies.
Kim et al. ( |
South Korea | 19, Feb, 2020 | Case report | 45 | 1M,1F | 2 | RT-PCR/CT-scan |
Yu et al. ( |
China | 18, Feb, 2020 | Case report | 74.2 | 2M, 2F | 4 | RT-PCR |
Bastola et al. ( |
Nepal | 10, Feb, 2020 | Case report | 32 | M | 1 | RT-PCR |
Duan and Qin ( |
China | 4, Feb, 2020 | Case report | 46 | F | 1 | RT-PCR/CT-scan |
Fang et al. ( |
China | 19, Feb, 2020 | Case report | 47 | M | 1 | RT-PCR/CT-scan |
Han et al. ( |
China | 19, Feb, 2020 | Case report | 47 | M | 1 | RT-PCR/CT-scan |
Wei et al. ( |
China | 25, Feb, 2020 | Case report | 62 | M | 1 | RT-PCR/CT-scan |
Holshue et al. ( |
USA | 5, Mar, 2020 | Case report | 35 | M | 1 | RT-PCR |
Lim et al. ( |
South Korea | 14, Feb, 2020 | Case report | 54 | M | 1 | RT-PCR/CT-scan |
Shi et al. ( |
China | 4, Feb, 2020 | Case report | 42 | M | 1 | RT-PCR/CT-scan |
Silverstein et al. ( |
Canada | 13, Feb, 2020 | Case report | 56 | M | 1 | RT-PCR |
Wei et al. ( |
China | 17, Feb, 2020 | Case report | 40 | F | 1 | RT-PCR |
Wu et al. ( |
China | 3, Feb, 2020 | Case report | 41 | M | 1 | RT-PCR |
Xu et al. ( |
China | 17, Feb, 2020 | Case report | 50 | M | 1 | RT-PCR |
Winichakoon et al. ( |
Thailand | 26, Feb, 2020 | Case report | 28 | M | 1 | RT-PCR |
Zhan et al. ( |
China | 28, Jan, 2020 | Case report | 38 | 1M, 1F | 2 | RT-PCR |
Fang et al. ( |
China | 7, Feb, 2020 | Case report | 38.5 | 1M,1F | 2 | RT-PCR/CT-scan |
Lin et al. ( |
China | 11, Feb, 2020 | Case report | 37 | M | 2 | RT-PCR/CT-scan |
Liu et al. ( |
Taiwan | 12, Mar, 2020 | Case report | 51 | 1M, 1F | 2 | RT-PCR |
Phan et al. ( |
Vietnam | 27, Feb, 2020 | Case report | Father: 65, Son: 27 | M | 2 | RT-PCR |
Pongpirul et al. ( |
Thailand | 12, Mar, 2020 | Case report | 51 | M | 1 | RT-PCR |
Hao et al. ( |
China | 2, Feb, 2020 | Case report | 60 | M | 1 | RT-PCR/CT-scan |
Hao and Li ( |
China | 17, Feb, 2020 | Case report | 58 | M | 1 | RT-PCR |
Zhang et al. ( |
China | 11, Feb, 2020 | Case report | 3 months | 1M | 1 | RT-PCR |
Bai et al. ( |
China | 17, Feb, 2020 | Case series | 53.4 | 3M/4F | 7 | RT-PCR |
Cai et al. ( |
China | 4, Feb, 2020 | Case report | 7 | 1M | 1 | RT-PCR |
Zeng et al. ( |
China | 17, Feb, 2020 | Case report | 17 days | 1M | 1 | RT-PCR |
Chan et al. ( |
China | 24, Jan, 2020 | Case series | 46 | 3M,3F | 6 | RT-PCR |
Chen et al. ( |
China | 12, Feb, 2020 | Case series | 29.8 | F | 9 | RT-PCR/CT-scan |
Wei et al. ( |
China | 21, Feb, 2020 | Case series | 6 months | 2 M, 7F | 9 | RT-PCR |
Qin et al. ( |
China | 22, Feb, 2020 | Case series | 55.5 | 2M, 2F | 4 | CT-scan |
Wang et al. ( |
China | 9, Feb, 2020 | Case series | 44.2 | 3M, 1F | 4 | RT-PCR/CT-scan |
Xie et al. ( |
China | 12, Feb, 2020 | Case series | 48.4 | M4, F1 | 5 | RT-PCR |
Yoon et al. ( |
Korea | 18, Feb, 2020 | Case series | 54 | 4M, 5F | 9 | CT-scan |
Stoecklin et al. ( |
France | 13, Feb, 2020 | Case series | 36.3 | 2M, 1F | 3 | RT-PCR |
Rothe et al. ( |
Germany | 5, Mar, 2020 | Case series | 33 | NR | 5 | RT-PCR |
Bai et al. ( |
China | 21, Feb, 2020 | Case series | 42-57 | 1M, 5F | 6 | RT-PCR |
Tong et al. ( |
China | 9, May, 2020 | Case series | 31 | 4M, 3F | 7 | RT-PCR |
Feng et al. ( |
China | 16, Feb, 2020 | Case series | 7 | 5M/10F | 15 | RT-PCR |
Zhang et al. ( |
China | 15, Feb, 2020 | Case series | 36 | 5M/4F | 9 | RT-PCR |
Liu et al. ( |
China | 17, Feb, 2020 | Case series | 35 | 10M/20F | 30 | RT-PCR |
Albarello et al. ( |
Italy | 20, Feb, 2020 | Case series | 66.5 | 1M/1F | 2 | RT-PCR |
Asadollahi-Amin et al. ( |
Iran | 7, Apr, 2020 | Case report | 44 | M | 1 | RT-PCR |
Bhat et al. ( |
USA | 11, Apr, 2020 | Case series | 54.5 | 6M/2F | 8 | RT-PCR |
Chen et al. ( |
China | 1, Apr, 2020 | Case series | 52.6 | 2M/1F | 3 | RT-PCR |
Wang et al. ( |
China | 9, Apr, 2020 | Case series | 42 | 11M/15F | 26 | RT-PCR |
Liu et al. ( |
China | 16, Apr, 2020 | Case series | 54 | 2M/1F | 3 | RT-PCR |
Lu et al. ( |
China | 19, Mar, 2020 | Case series | NM | NM | 3 | RT-PCR |
Lin et al. ( |
China | 22, Feb, 2020 | Case report | 61 | M | 1 | RT-PCR |
Mousavi et al. ( |
Afghanistan | 5, Apr, 2020 | Case report | 35 | M | 1 | RT-PCR |
Hamer et al. ( |
Germany | 26, Mar, 2020 | Case report | 59 | M | 1 | RT-PCR |
Gupta et al. ( |
India | 10, Apr, 2020 | Case series | 40.3 | 14M/7F | 21 | RT-PCR |
Moreira et al. ( |
Brazil | 3, Apr, 2020 | Case report | 73 | M | 1 | RT-PCR |
Gao et al. ( |
China | 24, Mar, 2020 | Case series | 54.6 | 1M/2F | 3 | RT-PCR |
Marchand-Senécal et al. ( |
Canada | 9, Mar, 2020 | Case report | 56 | M | 1 | RT-PCR |
Lin et al. ( |
China | 11, Feb, 2020 | Case series | 37 | 2M | 2 | RT-PCR |
Makurumidze ( |
Zimbabwe | 2, Apr, 2020 | Case series | NM | 2M/6F | 8 | RT-PCR |
Li et al. ( |
China | 7, Apr, 2020 | Case series | 8 | 12M/10F | 22 | RT-PCR |
Li et al. ( |
China | 6, Apr, 2020 | Case report | 74 | F | 1 | CT-Scan |
Li et al. ( |
China | 30, Mar, 2020 | Case series | 61 | 13M/12F | 25 | RT-PCR |
Cheng et al. ( |
Taiwan | 16, Apr, 2020 | Case report | 55 | F | 1 | RT-PCR |
Edrada et al. ( |
Philippines | 14, Apr, 2020 | Case series | 41.5 | 1M/1F | 2 | RT-PCR |
Feng et al. ( |
China | 7, Apr, 2020 | Case report | 34 | M | 1 | CT-Scan |
Woznitza et al. ( |
UK | 2, Apr, 2020 | Case series | 78 | 1M/2F | 3 | RT-PCR |
Zeng et al. ( |
China | 5, Apr, 2020 | Case report | 63 | M | 1 | RT-PCR |
Zhang et al. ( |
China | 18, Mar, 2020 | Case report | 64 | M | 1 | RT-PCR |
Zhou et al. ( |
China | 3, Apr, 2020 | Case series | NM | 1M/3F | 4 | RT-PCR |
Torkian et al. ( |
Iran | 27, Mar, 2020 | Case series | 46 | 2M/1F | 3 | RT-PCR |
Tan et al. ( |
China | 3, Apr, 2020 | Case series | 7 | 3M/7F | 10 | RT-PCR |
Hase et al. ( |
Japan | 2, Apr, 2020 | Case report | 35 | F | 1 | RT-PCR |
Huang et al. ( |
Taiwan | 19, Feb, 2020 | Case series | 73.7 | 2F | 2 | RT-PCR |
Hu et al. ( |
China | 4, Mar, 2020 | Case series | 32.5 | 8M/16F | 24 | RT-PCR |
Hu et al. ( |
Italy | 27, Mar, 2020 | Case report | 53 | F | 1 | RT-PCR |
Kim et al. ( |
South Korea | 6, Apr, 2020 | Case series | 40 | 15M/13F | 28 | RT-PCR |
Kim et al. ( |
South Korea | 3, Feb, 2020 | Case report | 35 | F | 1 | RT-PCR |
Kong et al. ( |
South Korea | 14, Feb, 2020 | Case series | 42.6 | 15M/13F | 28 | RT-PCR |
Lee et al. ( |
Taiwan | 10, Mar, 2020 | Case report | 46 | F | 1 | RT-PCR |
Lescure et al. ( |
France | 27, Mar, 2020 | Case series | 47 | 3M/2F | 5 | RT-PCR |
Wissenberg et al. ( |
Denmark | 3, Apr, 2020 | Case report | 50 | M | 1 | RT-PCR |
Li et al. ( |
China | 1, Mar, 2020 | Case series | 55 | 2M/1F | 3 | RT-PCR |
Summary of the case report and case series findings.
Comorbidities | Hypertension | 22 | 44/228 | 19 |
Cardiovascular disease | 6 | 11/137 | 8 | |
Diabetes | 17 | 27/241 | 11 | |
Pulmonary disease | 8 | 13/107 | 12 | |
Clinical manifestations | Fever | 68 | 248/401 | 62 |
Cough | 39 | 195/389 | 50 | |
Dyspnea | 30 | 78/279 | 28 | |
Myalgia/fatigue | 38 | 106/343 | 31 | |
Sputum production | 14 | 49/197 | 25 | |
Sore throat | 20 | 48/164 | 29 | |
Headache | 11 | 37/149 | 25 | |
Diarrhea | 14 | 21/94 | 22 | |
Nausea/vomiting | 8 | 17/84 | 20 | |
Dizziness | 5 | 5/35 | 14 | |
Rhinorrhea | 13 | 22/196 | 11 | |
Chills | 4 | 4/13 | 31 | |
Laboratory findings | Lymphopenia | 24 | 83/185 | 45 |
Leukopenia | 17 | 38/150 | 25 | |
Thrombocytopenia | 8 | 26/69 | 38 | |
High CRP | 18 | 118/197 | 60 | |
High LDH | 14 | 34/77 | 44 | |
High ESR | 10 | 17/42 | 40 | |
High AST | 11 | 23/48 | 48 | |
High ALT | 13 | 22/77 | 28.5 | |
High creatinine kinase | 8 | 9/44 | 20 | |
High creatinine | 4 | 6/32 | 19 | |
CT | Both of GGO and Consolidation | 16 | 32/59 | 54 |
GGO without consolidation | 20 | 48/60 | 80 | |
Unilateral | 11 | 35/87 | 40 | |
Bi lateral | 23 | 76/110 | 69 | |
Complications | ARDS | 11 | 18/86 | 21 |
Hospitalization | 30 | 77/83 | 93 | |
Outcomes | Discharged | 23 | 137/205 | 67 |
Death | 10 | 17/108 | 16 |
Common antiviral treatment modalities included lopinavir (HIV protease inhibitor), arbidiol hydrochloride (influenza fusion inhibitor), and oseltamivir (neuraminidase inhibitor). In
Treatment agents used in the included studies.
Pharmacologic treatment | Antiviral drugs | Lopinavir | 6 | 9/9 | 100 |
Arbidol hydrochloride | 2 | 6/6 | 100 | ||
Oseltamivir | 5 | 1/1 | 100 | ||
Veletonavir | 1 | 1/1 | 100 | ||
Remdesivir | 1 | 1/1 | 100 | ||
Ribavirin | 1 | 1/1 | 100 | ||
Ritonavir | 1 | 1/1 | 100 | ||
Gancyclovir | 1 | 1/1 | 100 | ||
Antibacterial drugs | Moxifloxacin | 4 | 5/5 | 100 | |
Vancomycin | 1 | 1/1 | 100 | ||
Cefepime | 1 | 1/1 | 100 | ||
Meropenem | 2 | 2/2 | 100 | ||
Piperacillin tazobactam | 2 | 2/2 | 100 | ||
Sefoselis | 1 | 1/1 | 100 | ||
Linezolid | 1 | 1/1 | 100 | ||
Levofloxacin | 1 | 1/2 | 50 | ||
Others | Methylprednisolone | 5 | 6/6 | 100 | |
Ambroxol Hydrochloride | 1 | 1/1 | 100 | ||
Acetaminophen | 2 | 2/2 | 100 | ||
Ibuprofen | 2 | 2/2 | 100 | ||
Intravenous Immunoglobulin | 3 | 4/7 | 57 | ||
Guaifenesin | 1 | 1/1 | 100 | ||
Ondansetron | 1 | 1/1 | 100 | ||
Interferon alpha-2b | 2 | 2/2 | 100 | ||
Herbal patent medicine | 2 | 3/3 | 100 | ||
Non-pharmacologic treatment | Oxygen therapy | Non-invasive | 6 | 10/10 | 100 |
The 2019 novel coronavirus has been declared a public health emergency worldwide. The World Health Organization (WHO) declared COVID-19 a pandemic affecting 110 countries around the world with a continued global spread. The 2019-nCoV is likely to be transmitted by asymptomatic individuals (
According to the articles we included, 2019-nCoV can only be transferred from person to person (
Based on our reviewed articles, hypertension, diabetes, cardiovascular disease, and pulmonary disease were the most common morbidities among COVID-19 patients. This point was also mentioned in Alraddadi et al. study about MERS-CoV patients (
According to the included studies, the most common clinical manifestations were fever, cough, dyspnea, and myalgia or fatigue. Less common clinical manifestations included nausea or vomiting, dizziness, rhinorrhea, and chills. Liu et al. reported that infants had mild clinical manifestations and a better prognosis. Furthermore, some asymptomatic cases were seen among children.
The most common abnormal laboratory changes were lymphopenia, high concentrations of C-reactive protein, and elevated levels of aspartate aminotransferase; however, we do not know the exact pathogenesis and the reason for these alterations. Laboratory abnormalities may indicate the severity of disease and developing complications. According to Huang et al., most patients with secondary infection had a procalcitonin level >0.5 ng/Ml and ICU patients had higher levels of prothrombin time and D-dimer (
CT scan as a diagnostic tool can be used to evaluate the severity of pulmonary involvement and monitor clinical progression. CT scan has good sensitivity and can be used to establish COVID-19 diagnosis in patients who are highly suspicious based on epidemiologic history and clinical manifestations but have negative PCR-based test results (
ARDS was the most common complication among the confirmed COVID-19 patients; the development of ARDS increased the risk of patient mortality (
Also, the results of the current study are in comparison with the recent large patient cohort studies in the aspect of comorbidities, clinical manifestations, laboratory, and radiological findings, however, there are some differences (
There are many challenges in COVID-19 therapeutic strategies. There is currently no cure for COVID-19. However, pharmacologic and non-pharmacologic symptom management and supportive care measures should be given to all patients with symptomatic COVID-19. Other various therapeutic strategies have been trialed in patients with COVID-19 to slow disease progression. There is a paucity of data surrounding the efficacy of treatments. Of the case controls and case series we included, antiviral agents including HIV protease inhibitors (lopinavir and ritonavir) as well as anti-influenza compounds (oseltamivir and arbidol) were used as treatment regimens. Unfortunately, we didn't have enough information about the efficacy of each regimen; however, according to some studies, anti-HIV based medications could have benefits in more rapid improvement of clinical manifestations and decrease in viral load (
A limitation of this review relates to the potential risk of bias. Bias occurs in the case reports/series studies because their results are not representative and do not represent the truth. A further limitation is that the conclusions are limited due to the case reports and case series. We did not include observational studies and randomized controlled trial (RCT)/quasi-randomized studies, because another study being conducted by the authors. Furthermore, the focus of the reviewed case reports and case series was mainly on the clinical description of the patients with COVID-19, but detailed information on the treatment outcomes and medical consequences were rarely provided. Also, the case number included in this systematic review is low compared with the currently published patient cohort, and this may lead to the declining clinical significance of this manuscript. Finally, our results are limited to younger adults who had been hospitalized during the 4–5 first months of the COVID-19 pandemic.
In conclusion, we discussed the clinical symptoms, laboratory abnormalities, common comorbidities, imaging modalities, and potential therapeutic options in COVID-19. We indicated that the most common symptoms were fever, cough, and dyspnea, but some young infected cases had no signs or symptoms. ARDS was the most common reported complication and was associated with poor prognosis. In the wake of the COVID-19 pandemic, countries are scrambling to produce enough RT-PCR diagnostic tests. Diagnostic information from other surrogate markers would be valuable if markers proved to be sensitive and specific. Namely, we learned that laboratory data like CRP may not only be related to the severity of the disease, but it may be predictive of disease outcomes. Further studies are needed to relate quantified elevations in CRP to disease severity. Due to the high sensitivity of the CT scan, it is considered as a good diagnostic tool. However, it should be kept in mind that a normal CT scan will never rule out the diagnosis of COVID-19 in a highly suspicious case based on history and clinical findings. Lastly, there are different therapeutic strategies for COVID-19 patients, but we don't have enough data for their efficacy. Additional investigations including randomized controlled trials will be necessary to further our understanding of the treatment of COVID-19.
All datasets presented in this study are included in the article/ supplementary material.
MN and MM designed the study and revised the manuscript. MN, AT, MA, YF, PJ, SH, and TC performed the search, data extraction, statistical analysis, and wrote the first draft of the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.