In December 2019, the first outbreak of Coronavirus disease (COVID-19) was detected in Wuhan. ¹ On 30 ^th January 2020, the World Health Organization (WHO) declared COVID-19 outbreak as a “public health emergency of international concern” and on 11 ^th March 2020, COVID-19 was declared a pandemic by the WHO. ² As of September 2023, the coronavirus SARS-COV-2 (severe acute respiratory syndrome coronavirus-2) is responsible for a total of 770 million confirmed cases and 6.9 million confirmed deaths. With the start of COVID-19 vaccination, a total of 3 billion vaccine doses have been administered as per WHO. ³ While, SARS-COV-2 is primarily considered as a respiratory disease known to cause pneumonia and acute respiratory distress syndrome (ARDS), there have been numerous reports about its many extra pulmonary manifestations. Literature suggests that the cardiovascular, gastrointestinal, renal, haematological, neurologic, endocrinologic, ophthalmologic, hepatobiliary and dermatologic systems can all be affected. ⁴ This can result either due to the extrapulmonary dissemination and replication of the SARS-COV-2 or due to the widespread immunopathological sequelae of the disease. ⁵

Bibliometric analysis is the application of statistical methods to evaluate the impact of a manuscript, research performance, author contribution to a particular field and to quantitatively analyse the most influential articles related to a particular field. ⁶

According to our literature search, no current bibliometric analysis has focused on COVID-19 complications. The purpose of this bibliometric analysis was to compile and analyse the top 50 most-cited articles regarding COVID-19 complications across all peer-reviewed scientific journals.

A bibliometric analysis of the most cited articles about COVID-19 complications was conducted in July 2021 using all journals indexed in Elsevier’s Scopus and Thomas Reuter’s Web of Science from November 1, 2019 to July 1, 2021. All journals were selected for inclusion regardless of country of origin, language, medical speciality, or electronic availability of articles or abstracts. The terms were combined as follows:

(“COVID-19” OR “COVID19” OR “SARS-COV-2” OR “SARSCOV2” OR “SARS 2” OR “Novel coronavirus” OR “2019-nCov” OR “Coronavirus”)

AND

(“Complication” OR “Long Term Complication” OR “Post-Intensive Care Syndrome” OR “Venous Thromboembolism” OR “Acute Kidney Injury” OR “Acute Liver Injury” OR “Post COVID-19 Syndrome” OR “Acute Cardiac Injury” OR “Cardiac Arrest” OR “Stroke” OR “Embolism” OR “Septic Shock” OR “Disseminated Intravascular Coagulation” OR “Secondary Infection” OR “Blood Clots” OR “Cytokine Release Syndrome” OR “Paediatric Inflammatory Multisystem Syndrome” OR “Vaccine Induced Thrombosis with Thrombocytopenia Syndrome” OR “Aspergillosis” OR “Mucormycosis” OR “Autoimmune Thrombocytopenia Anaemia” OR “Immune Thrombocytopenia” OR “Subacute Thyroiditis” OR “Acute Respiratory Failure” OR “Acute Respiratory Distress Syndrome” OR “Pneumonia” OR “Subcutaneous Emphysema” OR “Pneumothorax” OR “Pneumomediastinum” OR “Encephalopathy” OR “Pancreatitis” OR “Chronic Fatigue” OR “Rhabdomyolysis” OR “Neurologic Complication” OR “Cardiovascular Complications” OR “Psychiatric Complication” OR “Respiratory Complication” OR “Cardiac Complication” OR “Vascular Complication” OR “Renal Complication” OR “Gastrointestinal Complication” OR “Haematological Complication” OR “Hepatobiliary Complication” OR “Musculoskeletal Complication” OR “Genitourinary Complication” OR “Otorhinolaryngology Complication” OR “Dermatological Complication” OR “Paediatric Complication” OR “Geriatric Complication” OR “Pregnancy Complication”) in the Title, Abstract or Keyword.

A total of 5940 articles were accessed, of which the top 50 most cited articles about COVID-19 and Complications of COVID-19 were selected through Scopus. Each article was reviewed for its appropriateness for inclusion. The articles were independently reviewed by three researchers (JRP, MAM and TS) ( Table 1). Differences in opinion with regards to article inclusion was resolved by consensus.

The inclusion criteria specified articles that were focused on COVID-19 and Complications of COVID-19. Articles were excluded if they did not relate to COVID-19 and or complications of COVID-19, Basic Science Research and studies using animal models or phantoms. Review articles, Viewpoints, Guidelines, Perspectives and Meta-analysis were also excluded from the top 50 most-cited articles ( Table 1).

The top 50 most-cited articles were compiled in a single database and the relevant data was extracted. The database included: Article Title, Scopus Citations, Year of Publication, Journal, Journal Impact Factor, Authors, Number of Authors, Department Affiliation, Number of Institutions, Country of Origin, Study Topic, Study Design, Sample Size, Open Access, Non-Original Articles, Patient/Participants Age, Gender, Symptoms, Signs, Co-morbidities, Complications, Imaging Modalities Used and outcome.

In the bibliometric analysis of the top 50 most-cited COVID-19 articles, the most cited article was “Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China” by Huang C et al., in The Lancet published in 2020. This article has the highest total number of citations (24775) as well as the highest average number of citations per year (8258) among the top 50 most-cited articles.

The Lancet published the greatest number of articles from the top 50 most-cited list with a total of 9 articles, followed by NEJM with 7 articles and JAMA with 4 articles published respectively. Most of the articles (n=48, 96%) were published in the year 2020 with China (n=29, 34.9%), France (n=10, 12.1%) and Belgium (n=10,12.1%) being the top contributing countries.

In this bibliometric analysis, we found that 54.8% of the total patients were males while 45.2% were female patients. In an article written by Bwire, it was reported that females were more resistant to Covid-19 infection. This could be attributed to various factors such as sex hormones, higher expression of ACE-2 receptors in men and also difference in the lifestyles. ⁵⁷

The incidence of COVID-19 infection was highest in adults between 26-65 years (63.2%), followed by the adults over 65 years of age (26.8%), and least in 12-25 years age group (9.8%). Though it is evident that the older population were more at risk for hospitalizations and deaths due to COVID-19, researchers have not been able to pinpoint a particular reason for the same. The current hypothesis is that this could be as a result of changes to the immune cell repertoire, the epigenome, NAD+ levels, inflammasome activity, biological clocks, and covalent modifications of human and viral proteins. ²² In addition to this, it is not really understood why SARS-CoV-2 damages such a broad array of tissues in older people. ²²

Similar findings were reported in a study conducted by Jakhmola S et al, with the highest incidence of Covid-19 infection in the age groups of 20-49 years and above 50 years, and the least in the paediatric age group. This could possibly be due to lesser expression of the coronavirus (ACE-2) receptors in the nasal epithelium in younger age groups, leading to reduced susceptibility to Covid 19 infection. ⁵⁸ Centers for Disease Control and Prevention (CDC) reported the highest incidence of COVID-19 infection among adults above the age of 80 years and in the age group of 18-24 years during 2020. ⁵⁹

In our analysis, the most common clinical features were fever (28.2%), tachycardia (17.9%) and dry cough (13.8%). Other common features included impaired sense of smell (1.8%), impaired taste sensation (1.8%) and headache (1.5%). Similar to the above-mentioned findings, a study by Cascella M et al, reported the most common symptoms in patients to be fever, dry cough and dyspnoea. Other lesser common symptoms included malaise and headache. ⁶⁰ In a study by Mullol J et al., it was concluded that most viral respiratory infections such as COVID-19 are associated with impairment of sense of smell. The incidence of olfactory and gustatory symptoms varies due to the varied methodology used in various studies. ⁶¹ In addition to this, it is also worth noting that recent studies about COVID-19 have identified possible long-term effects as a result of COVID-19 such as memory loss, difficulty concentrating, disturbances in sleep, and mild irreversible multi organ damage.

Of the total patients analysed in our study, 97.8% patients were found to have comorbidities. Of which, hypertension (30.6%), diabetes mellitus (23.1%) and obesity (12.1%) were the commonest comorbidities found in the patients. Other comorbidities included chronic liver disease (0.34%), endocrine disorders (0.24%) and psychiatric disorders (0.06%). In a study by Sanyaolu et al, that the common comorbidities found were hypertension, diabetes mellitus and obesity, which were associated with poorer outcomes in COVID-19 patients. ⁶²

Of all the patients analysed in our study, 13.9% of patients developed complications following COVID-19 infection. The common complications seen among the patients were acute kidney injury (22.5%), ARDS (18.3%) and sepsis (11.0%). Other complications included thrombosis (3.6%), acute hepatic injury (2.4%) and arrhythmias (2.0%). In the study by Cascella M et al, it was reported that ARDS was the most common pulmonary complication of COVID-19 while extra-pulmonary complications included AKI, cardiovascular complications and prothrombotic complications. ⁶⁰ Similarly, in another study by Isath A et al., the most common complications reported were respiratory failure, AKI, sepsis and thrombosis. ⁶³ ARDS due to COVID-19 usually represents a specific sub type in which the hypoxia occurs as a result of coexistence of non-aerated regions and large areas of low ventilation-perfusion ratio. ¹⁶ Additionally, the excessive inflammatory reactions that occur during COVID-19 can damage the lung cells which then disrupt the alveolar-capillary barrier which is crucial for gas exchange. ¹⁶ Acute kidney injury occurring as a complication in patients with COVID-19 are thought to occur as a result of multiple factors interplaying with each other. This could arise as a result of the direct effects of the virus, cardiovascular morbidity, activation of coagulation pathways, endothelial injury or activation of the renin-angiotensin pathways. Patients with sepsis could develop AKI as a result of the cytopathic effects of SARS-COV-2 on the podocytes and proximal tubule cells. ⁶⁰ In addition to this, the presence of viral particles in renal endothelial cells may also cause endothelial damage which in turn promotes a state of hypercoagulability, and macrophage activation leading to formation of microthrombi and renal microvasculature injury. ⁶⁰

In our analysis, 57.8% patients recovered without any complications, while 31.1% were hospitalised, and 11.1% deceased due to the illness. Similar findings were reported in a study by Isath A et al., where 51.4% patients recovered and were discharged home, and the overall inpatient mortality was reported to be 13.2%. Most of the patients with comorbidities were associated with higher number of complications and mortality. ⁶³

During the early days of COVID-19, remdesivir was a popular treatment in the course of a COVID-19 infection. However, in a study held by Wang Y, it was found that the use of remdesivir did not significantly change the time to clinical improvement compared to placebo. In the subgroup of patients who had symptoms for 10 days or less, those treated with remdesivir showed a non-statistically significant, yet faster improvement. ³³ Adverse events were slightly more common in the remdesivir group, affecting 66% of its recipients, compared to 64% in the placebo group. ³³ In a study held among critically ill patients, it was found that patients had a shorter duration of mechanical ventilation when treated with oseltamivir. ⁶⁴ Additionally, in the same study it was also found that there was no significant difference in the hospital mortality rates of these patients. ⁶⁴ As per current guidelines, the United States National Institute of Health (NIH) recommends against the use of systemic corticosteroid therapy for patients with mild to moderate COVID-19 infection and in those patients that do not require supplemental oxygen therapy. ⁶⁵ It was found that systemic corticosteroid therapy is only beneficial when used in patients who require supplement oxygen therapy (conventional oxygen, high flow nasal cannula oxygen, non-invasive ventilation, mechanical ventilation or extracorporeal membrane oxygenation). ^{65 , 66} Although there was a widespread use of corticosteroids during the early days of COVID-19, ⁶⁶ the NIH has now recommended against the use of it in mild or moderate cases. ⁶⁵ In another study, the authors researched the benefit of using anticoagulants as a treatment for COVID-19. The authors found that there was no significant difference in 28-day mortality rates between patients treated with heparin and those who were not. However, among patients with a SIC score of 4 or higher, or with D-dimer levels more than six times the upper limit of normal, those who received heparin had significantly lower 28-day mortality rates compared to those who did not receive heparin. ³⁴

The authors of the studies have recommended and stated that vaccination campaigns have been pivotal. Empirical studies demonstrate a marked reduction in infection rates, severity of clinical manifestations, and mortality associated with COVID-19 following the administration of authorized vaccines. These biological agents not only confer individual protection but also contribute to herd immunity, thereby attenuating community-level transmission. ²¹

Moreover, mechanical barriers such as facial masks have emerged as critical in impeding viral dissemination. A consensus in the scientific community advocates for the utilization of higher filtration efficiency respirators (e.g., N95, KN95) in public settings, especially where physical distancing cannot be maintained and in poorly ventilated indoor environments. ²²

As a limitation of the present study, it is important to note that the analysis does not delve into network visualizations among authors or collaborative research endeavors involving multiple institutions and countries. These aspects are beyond the scope of the bibliometric analysis conducted in this research. Furthermore, the authors did not utilize specialized analysis tools such as VOS viewer or Biblioshiny. Additionally, the validation of article contents was performed manually by individual authors and recorded in a data sheet. ⁶⁷

This article offers a quick overview of the most influential literature and how COVID-19 research has evolved over time. This insight can be instrumental for authors, offering guidance on creating impactful research in the future. In conclusion, as evidenced by the analysis of the 50 most-cited articles on COVID-19 and its complications, it is apparent that understanding the most common symptoms such as fever, tachycardia, and dry cough is crucial for both clinicians and researchers. In this analysis, it was found that the most common complications found in patients with COVID-19 were acute kidney injury (AKI) and acute respiratory distress syndrome. The occurrence of AKI can be explained as a result of the direct effects of the virus or as a result of activation of multiple physiologic pathways which eventually lead to renal microvascular injury. ARDS can occur as a result of the excessive inflammatory reactions during the infection leading to a disruption of the alveolar-capillary barrier thereby affecting the individuals gas exchange. With China leading in publications on the subject and The Lancet emerging as the primary journal for disseminating COVID-19 research, it is clear that the global scientific community has mobilized to address this pressing issue. Moreover, recognizing prevalent comorbidities like hypertension (HTN) and diabetes underscores the need for comprehensive management strategies. By leveraging insights from these influential publications, researchers can navigate the complex landscape of COVID-19 research effectively, ultimately contributing to our collective efforts to combat this pandemic. Overall, this method serves as a strategic tool for staying updated and contributing meaningfully to the field of COVID-19 research.