From Skirmishes to Protracted Battles: A Bibliometric Analysis About Human Beings and Coronaviruses From 1991 to 2020

Background: COVID-19 caused unprecedented literature upsurge, and the world has worked together to ght the epidemic. Methods: We conducted a bibliometric analysis to evaluate the research trends and reveal the core contents, based on publication outputs, geographical distribution, collaborations and hot keywords. Results: Our analysis revealed the following: (1) The publication outputs obviously increased after SARS and MERS outbreaks, while sharply on rise during COVID-19 outbreak. Compared with SARS and MERS, COVID-19 aroused more dramatic and prolonged upsurge. (2) Compared with SARS and MERS, COVID-19 caused more widespread and powerful inuences on countries or territories at short notice. Countries or territories displayed more international collaborations and communications to cope with the epidemics, and COVID-19 remarkably boosted the research advancements. (3) Given the keywords, we identied that multiple optional methods were used to cope with the SARS-CoV-2 infection based on the features of biology and immune responses. Conclusions: Epidemics extremely accelerated the research boom and evolution. monocyte-associated tocilizumab-responding cytokine

SARS had been circulating in 32 countries or territories, from November 2002 to August 2003, the cumulative number of infections was 8,422, and the mortality rate reached 10.87%; MERS had been spread to 27 countries from April 2012 to December 2019, and there were 2,496 cases of infections, while the mortality rate was as high as 34.77% [2].
COVID-19 has caused a worldwide pandemic since December 2019, propagating through a surprising speed in a short time. The pattern of the global COVID-19 epidemic has changed dynamically from the rst stage of a single epidemic center (China) in January and February of 2020 to the second stage of multiple epidemic centers (Italy, Iran, and South Korea) in March, and the world began experiencing a rapidly increasing number of cases with an estimated 50,000 cases con rmed globally per day at the end of March [3]. By 26 July, 2020, COVID-19 has been reported in 215 countries or territories, and there were 15,785,641 reported cases, with 4.05% mortality [4].
As for the pathogenicity of SARS-CoV, MERS-CoV and SARS-CoV-2, they share certain similarities in terms of their biological, clinical and epidemiological features. But what is more different, according to genesequencing, the main differences among them are in open reading frame 1a (ORF1a) and the sequence of gene spike coding protein-S [5]. The protein-S of SARS-CoV-2 has the largest sequence divergence, and it has 380 amino acid sequence substitutions [6], contributing to its munity. Given clinical features, COVID-19 varied from mild cases to severe cases, while most cases were mild. SARS and MERS tended to be urgent onset and rapidly progress to severe illness respectively [7]. That may suggest COVID-19 was more insidious. From the above-mentioned facts, COVID-19, SARS and MERS have different morbidity and mortality rates. COVID-19 has the highest prevalence but lowest fatality rate, and MERS had the highest fatality rate. As for spreading features, SARS was characterized by superspreading events, and MERS seemed to be less aggressive, while COVID-19 is unique for its indiscriminate transmission among the general public [5]. Based on the unique biological, clinical and epidemiological characteristics, SARS-CoV-2 provoked a protracted battle to humans.
Publications originating from England, Scotland, North Ireland, and Wales were considered to be from the United Kingdom (UK), while Hong Kong, Macau and Taiwan were distinguished from mainland China due to differences in their political systems.
We used ArcGIS (10.6) to map the geographical distribution of global publication outputs and reported cases of three emerging human pathogenic coronaviruses. Gephi (0.9.2) was used to visualize core countries or territories in the international collaboration network.
All publications were analyzed with following aspects: (a) characteristics of publication outputs; (b) geographical distribution and international collaboration; (c) hot keywords.  [9]. In 2020, 144 countries put into coronavirus researches. USA ranked the rst (3,078), followed by China (2,782), Italy (1,518), UK (1,349) and Canada (588). The publication outputs rapidly increased and the research territories became more diverse following the dramatic and persistent impact of the COVID-19 pandemic.

Characteristics of publication outputs
Internationally co-authored publications varied from 0.45% in 1991-2019 to 10.34% in 2020.
Collaborations between countries or territories became frequent after SARS and MERS outbreaks, while obviously being closer after COVID-19 outbreak (Fig. 3). In 1991-2019, USA took the central position in the collaboration network. USA collaborated with China and UK more closely, while most countries or territories were more inclined to produce single-country publications. In 2020, we identi ed that USA, China, UK, Italy, Canada, Australia and Germany took part in more international-collaborative publications. It turned out that countries or territories strikingly put into more intensive collaborations, with more diversity in cooperation and communication (Fig. 4).
Our results reveal some striking ndings. Firstly, research areas became more diversi ed due to the epidemics of SARS, MERS and COVID-19, while COVID-19 caused more widespread and powerful in uences on countries or territories at short notice. COVID-19 is a globally substantial threat to public health, with severe economic implications. The COVID-19 pandemic calls for increased research on traceability analysis, transmission, diagnosis methods, epidemiology, treatment, prevention, and containment of the disease [10]. Patients in the early outbreak provided large samples of clinical characteristics and predictive spread of COVID-19. Secondly, countries or territories presented more international collaborations and communications to cope with the epidemics, and COVID-19 remarkably boosted the research advancements. Scientists from different countries worldwide have strengthened their research collaborations and launched joint research projects for the prevention and control of the epidemic.

Hot keywords
There were 11,574 publications with author keywords in 1991-2020. In order to further identify the main research directions and core contents of the coronavirus elds, we classi ed the author keywords into six categories (Table 1). They were "Epidemiological features", "Biological features", "Immune response features", "Age/sex", "Diseases /Symptoms" and "Diagnosis/Therapy". China, as the early outbreak area, conducted numerous studies on the clinical characteristics and biochemical markers of COVID-19, as well as studied on the routes of transmission, effective control of the spread (for instance, rapid outbreak responses and lockdown), epidemiology, diagnosis, treatment (for instance, traditional Chinese medicine) and vaccine of COVID-19. The focus of countries or territories varied from epidemiology, prevention and control, etiology and antibody to transmission, detection and diagnosis, treatment as well as prognosis followed the global spread of the epidemic.

Discussion
"Epidemiological features" mainly focused on transmitting feature and surveillance. Although SARS-CoV, MERS-CoV and SARS-CoV-2 mainly induce respiratory infections, the pathways and affecting factors of transmission will be of great signi cance in prevention and control of epidemic. SARS-CoV and MERS-CoV transmitted with two routes (respiratory droplets and close contact) [5]. Although the primary mode of transmission of SARS-CoV-2 is also via respiratory droplets and contact routes, fomite and aerosol transferring is possible; the fecal oral route may be also a route of transmission [11]. Moreover, the transmission route has been reported even in the cases of asymptomatic patients in many countries and territories [11][12][13], and this route becomes key point of prevent and control. It has suggested that cold chain transmission is also a potential route through long-distance marine products, which may explain the epidemics of Beijing, Qingdao and Dalian in China. It may also provide a reminder to the traceability of the outbreak of Huanan seafood market in Wuhan. The traceability is currently uncertain, and becomes complex and confusing. In addition, vertical transmission may be a pathway [1], and WHO has also indicated the risks of women transmitting COVID-19 to their babies during breastfeeding [14].
Environmental factors (ambient temperature and humidity) have also been studied to understand the COVID-19 transmissions [15]. It turns out that the transmission of SARS-CoV-2 is complicated and diverse. As for preventive measures, face mask, hand hygiene, social distance and ventilation are effective routine methods [16,17].
"Biological features" were associated with the pathogenicity of coronaviruses. The latest studies nd spike protein on SARS-CoV-2 surface binds its receptor, angiotensin-converting enzyme 2 (ACE2) to enter the host cells, while the host transmembrane protease serine 2 (TMPRSS2) is essential for viral entry [18].
Notably, the binding a nity of SARS-CoV-2 for ACE2 is 10-20-fold higher than SARS-CoV [6], contributing to its munity. ACE2 expression and Renin-angiotensin system (RAS) are abnormal in hypertension and obesity, while TMPRSS2 is over-expressed when exposed to androgens, indicating these factors are involved in the pathogenic features of SARS-CoV-2 [19]. The members of RAS, abnormal levels of proin ammatory angiotensin II and anti-in ammatory angiotensin 1-7 may re ect the severity of COVID-19 [19]. ACE2 and TMPRSS2 expression may modulate the infectivity of SARS-CoV-2, becoming a promising target for the early therapies of patients with COVID-19.
"Immune response features" included multiple immune related factors, while immune cells (particularly T lymphocyte, Macrophage and B lymphocyte) and cytokines (interferons, interleukins, chemokine, TNF and C-reactive protein) accounted for large portions. Cytokine storm was the focus during COVID-19 outbreak. Immune responses play essential roles in the interactions between coronavirus infections and the host, while the cytokine storm has direct correlations with the pathogenesis and disease severity. The signs indicate over-elevated in ammatory factors are associated with the deterioration of patients with SARS and MERS, and there is growing evidence that cytokine storms may lead to the pathogenesis of patients with COVID-19, causing the rapid worsening [20].
Clinical feature, diagnosis and therapy were the concerns of clinical practice. "Age/Sex" mainly included children, pregnant woman and older adult. Older adults tend to suffer from infections due to a weakened immunity [1]. Pregnant women and children are special groups during COVID-19 outbreak. They are facing di culties of the surveillance and diagnosis. Pregnant women are more susceptible to infectious diseases due to the immune suppression, moreover, the clinical symptoms of pregnant women are atypical in comparison with the non-pregnant adults. Compared with adults, fewer children are infected with SARS-CoV-2, while their CT imaging presents the non-speci c abnormalities (pure ground-glass opacity or consolidation) unlike the adults [21]. There involved diverse systemic manifestations in "Diseases/Symptoms", possibly due to the wide distribution of receptors and systemic in ammations (cytokine storm). The receptor of SARS-CoV-2 and SARS-CoV, ACE2 is widely distributed in organs (oral, nasal mucosa, nasopharynx, lung, stomach, small intestine, colon, skin, lymph nodes, thymus, bone marrow, spleen, liver, kidney, and brain), and the receptor of MERS-CoV, DPP4 (CD26) is expressed on kidney, small intestine, liver, prostate epithelial cells and activated leukocytes, suggesting that the range of their tissue tropism were broader [7]. The nonspeci c symptoms and manifestations of COVID-19 may cause di culties of diagnosis and management. Based on clinical and epidemiological analyses, older age, male and preexisting comorbidity were identi ed as important risk factors for the development of severe or lethal disease in COVID-19, which were similar to SARS and MERS [22][23][24]. The ve most common comorbidities were hypertension, diabetes, cardiovascular disease, chronic obstructive pulmonary disease and tumor, while higher D-dimer, higher neutrophil/lymphocyte ratio, higher level of Creactive protein, lymphopenia, thrombocytopenia and obesity were the independent risk factors of death in COVID-19 patients [25][26][27]. According to epidemiology and large scale data, diabetes has been identi ed as an important risk factor for mortality and rates of progression to acute respiratory distress syndrome (ARDS) in hospitalized patients with COVID-19 [28,29]. The mortality of comorbid diabetes reached 7.3%, with 2.3% higher than those of non-diabetic patients [30]. Diabetic patients with poor levels of blood glucose tended to have higher death risk and adverse prognosis among COVID-19 patients in hospital, due to preexisting comorbidities or complications and the roles of cytokine storms [29].
It has been con rmed that swab test (PCR nucleic acid determination) and chest CT scan play important roles in detection and diagnosis of coronavirus infections [1]. CT scan has great value in screening and detecting patients with COVID-19 pneumonia, especially in the highly suspicious, asymptomatic cases with negative nucleic acid testing [13]. With regard to therapies, vaccine, antibody, traditional Chinese medicine and targeted drugs are four therapeutic methods. Safe and effective vaccines are currently in clinical trial stage [31]. High-risk groups (for example, medical workers) and high-risk groups (for example, children, pregnant women, older adults and people with preexisting diseases) will be given priority for vaccination. Early signs are that plasma with SARS-CoV-2 antibodies from recovered patients can reduce the mortality in SARS-CoV-2 patients [11]. There are certain emerging therapies to cope with the infections. Hydroxychloroquine, Chloroquine, Lopinavir/ritonavir and Remdesivir have antiviral activity that can control SARS-CoV-2 in-vitro [32]; moreover, Viral entry inhibitors, ACE2 modulators (angiotensin receptor blockers) and TMPRSS2 inhibitors (camostat mesylate) are promising clinical drugs, and it has suggested that Shuanghuanglian oral liquid and Lianhuaqingwen are effective for certain patients with COVID-19 in China [18,33,34]. Given the high level of cytokines in the host, the immunosuppressive drugs targeting the interleukin-6 (IL-6) receptor, tocilizumab are reported to treat COVID-19-related cytokine storms [35], and the application of blood puri cation technology (plasma exchange, blood/plasma ltration, adsorption, perfusion and continuous renal replacement therapy) is helpful to the removal of cytokines and may be bene cial to improve the clinical outcome of critically ill patients [20].

Conclusion
Our study provides further understandings for the research progress and direction of global coronavirus elds. We summarize six categories of features of coronavirus infections, and analyze the implications, revealing the epidemiological and biological properties, clinical features and currently therapeutic methods. These effective experience in preventing, controlling, cutting off transmission routes and treating can be regarded as signi cant guidelines for the epidemics of other countries and territories.

Declarations
Ethics approval and consent to participate: Not applicable.
Consent for publication: Not applicable.
Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Competing interests: No con icts of interest, nancial or otherwise, are declared by the authors.
Funding: Not applicable.
Authors' contributions: Youjuan Fu designed the search strategy with input from Yifei Wang and Chao He, and Youjuan Fu as well as Yuanquan Li carried out the literature searches and screening, and any discrepancies were discussed with Ling Yue and Chao He, and Ling Yue as well as Youjuan Fu wrote the rst draft of the review with input from Chao He, Yuanquan Li, Yifei Wang, Ziyi Zhu, Zhiyang Wang, Jing Li and Wei Chen. Jiayi Huang and Youjuan Fu were responsible for English editing.