Acute Chest Syndrome: A Bibliometric Analysis of the Top 100 Most Cited Articles

Acute chest syndrome (ACS) is a major cause of morbidity and mortality in patients with SCD (SCD). The analysis of research productivity and trends in ACS may serve as a valuable guide for investigators, institutions, and funding agencies to plan the future directions of research. The current review aims to evaluate the productivity and trends of publications related to ACS in adults by analyzing the top 100 most cited articles. A bibliometric analysis of the top 100 most cited articles related to ACS in adults was conducted on May 20, 2021. The Scopus database was searched to identify the top-cited articles. The following term was applied: “acute chest syndrome” in the fields of title, abstract, and keyword. The most cited article received a total of 776 citations, while the least cited received a total of 10 citations. Over half of the identified articles received 35 citations or less. The articles originated in 12 different countries; the overwhelming majority of articles originated in the United States (n = 75), with small contributions from developing countries with a high prevalence of sickle cell disease. Blood and American Journal of Hematology published the largest number of articles, with nine articles each. The Author “Vichinsky, E.P.” has the largest contribution with a total of 10 articles. The plethora of the highly cited articles were Observational studies, while randomized controlled trials were represented by seven articles. The present study demonstrates that research in ACS may be receiving less attention than it should. Therefore, research empowerment and adequate funding are of paramount importance to improve research productivity and quality. Additionally, more collaborative efforts should be encouraged to reduce the gap between developed and developing countries.


Introduction And Background
Among patients with SCD, acute chest syndrome (ACS) is a leading cause of death [1].It is characterized by new radiodensity on chest radiographs along with respiratory symptoms and/or fever [2].According to the Cooperative Study of Sickle Cell Disease (CSSCD), about half of patients with SCD, including both adults and children, experienced an episode of ACS [3].Adults tend to have greater disease severity and higher mortality than children [4].The higher mortality among adult patients is attributed to the increased incidence of fat emboli [4,5].Therefore, prompt management, more research, and robust clinical trials are warranted to enhance the outcomes of patients with ACS.
Bibliometric analysis is a statistical method employed to assess productivity and trends in a particular area of research.Bibliometric analyses serve as valuable guides for investigators, institutions, and funding agencies to plan the future direction of research.There are limited analyses that have assessed the productivity and trends in SCD, including its complications.Recently, Musa et al. evaluated the global productivity of research on SCD between 1900 and 2020 using the Web of Science [6].A total of 11,917 documents were retrieved, with an average of 27.34 citations for each document [6].Similarly, Okoroiwu et al. investigated the productivity and trends of SCD research published over two decades (1997-2017) using the Scopus database [7].A total of 19,921 documents were retrieved [7].The review demonstrated that there is an exponential growth of scientific output on SCD, indicating a growing interest in this area of research [7].To our knowledge, analyses concerning specific complications of SCD, including ACS, have not been conducted before.Therefore, the current review aims to evaluate the productivity and trends of publications related to ACS in adults by analyzing the top 100 most cited articles.

Review Search strategy
A bibliometric analysis of the top 100 most cited articles related to ACS in adults was conducted on May 20, 2021.The Scopus database was searched to identify the top-cited articles.The following term was applied: "acute chest syndrome" in the fields of title, abstract, and keyword (TITLE-ABS-KEY("acute chest syndrome")).The search yielded a total of 1,976 results, which were sorted based on the highest citation.No time restriction or any other filters were applied.Subsequently, titles, abstracts, and full texts were screened by two independent reviewers to ensure the relevance and eligibility of included publications.Each reviewer created a list of the top 100 most cited articles.Eventually, any discrepancies between the two lists were resolved through discussion.

Inclusion Criteria
This review aimed to explore the top 100 most cited articles written about ACS in adults.Original articles (clinical or basic) were considered; therefore, textbooks, review papers, abstracts, and case reports were excluded.Articles primarily investigating, but not necessarily exclusively, ACS were considered.The primary area of investigation was determined by screening introductions and objectives, where the primary focus should be clearly elaborated.The adult age group was the primary focus of this review; therefore, with basic science studies being an exception, any article involving adult subjects (18 years or older) was considered.In summary, the characteristics of eligible articles were as follows: (1) Original articles, (2) primarily investigating ACS, (3) involving adult subjects (18 years or older), and (4) Ranked as one of the top 100 most cited articles.
The citation count is influenced by many factors, including the passage of time.Subsequently, the current review may exclude relatively recent articles that may have a significant impact.Therefore, a second screening was carried out to extract the recent top 20 most cited articles.The results were filtered by year, and the search was limited to articles published between 2016 and 2021.Additionally, only original articles were considered, potentially posing a limitation in identifying a number of highly cited review papers or guidelines.Therefore, the top 10 highly cited systematic reviews or guidelines were extracted.No filter was applied at this stage.

Variables
The following variables were extracted: Year of publication, total citation, citation excluding self-citation, average citation per year, highest citation year, publishing journal, journal's CiteScore, country affiliation (considered the first author's affiliation), general study design (observational or experimental), specific study design (cross-sectional, case-control, cohort, randomized control trials, quasi-randomized, or basic research), funding (funded, non-funded, not mentioned), sample size (≤100, >100 -≤ 300, > 300 -≤ 600, or > 600).Additionally, the number of investigators, the first author's name, gender, h-index, and the number of contributed articles (from the top 100 most cited) were extracted.The variables were extracted manually and managed in an Excel sheet.

Statistical Analysis
The data were coded and analyzed using the Statistical Package for the Social Sciences, version 26.0 (IBM Corp., Armonk, NY, USA).Descriptive statistics were used to describe the productivity and trends of included articles.The years of publication were grouped into five-year intervals.The average citation per year was rounded to the nearest whole number.
Inferential statistics were run to evaluate the relationship between different variables.Pearson's correlation coefficients were calculated to assess the correlation between the journals' CiteScore and the number of published articles and total citations received by each journal, respectively.Furthermore, Pearson's correlation coefficient was calculated to assess the correlation between the number of investigators and total citations.A Kendall's tau-b test was employed to evaluate ranking discrepancies of included articles after disregarding self-citations.A Kruskal-Wallis H test was employed to assess the relationship between citation and study design.

Citation Trends
The top 100 most cited articles are shown in Table 1.The most cited article received a total of 776 citations, while the least cited received a total of 10 citations.Concordantly, the most cited article received the highest rate of citations (35 per year).Kendall's tau-b test demonstrates a very strong, positive correlation between the rankings of articles, including and excluding self-citations (τb = 0.910, p < 0.00).

Countries and Years
The articles originated in 12 different countries, as shown in Table 2. Nevertheless, the overwhelming majority of articles originated in the United States (n = 75).The publication year distribution was grouped into five-year windows, as shown in Figure 1.There was an upward trend in the number of highly cited articles as a function of the year.About a quarter of the top 100 cited articles were published between 2009 and 2013.

Journals
The top 20 most cited journals are shown in Table 3.A total of 45 journals were identified.Blood and the American Journal of Hematology published the largest number of articles, with nine articles each.
Additionally, the highest citations were received by Blood (1,712), followed by the New England Journal of Medicine (981) and the American Journal of Respiratory and Critical Care Medicine (484).The correlation between the CiteScore and the number of published articles was insignificant (r = 0.72, p = 0.646).However, the CiteScore and total citations were found to be moderately positively correlated (r = 0.482, p = 0.001).

Investigators
The top 20 contributing first authors are listed in Table 4. "Vichinsky, E.P." has the largest contribution with a total of 10 contributed articles.Concordantly, he secured the highest h-index (81).The number of investigators and average citation per year were found to be weakly positively correlated (r = 0.330, p = 0.001).The majority of research was funded (n = 60), while a minority was not (4); the funding was not mentioned in the rest of the articles (n = 36).

Study Designs
The study designs are shown in Table 5. Observational studies constitute the vast majority of the conducted (n = 85) and cited studies (n = 5,438), with cohort study being the most frequently employed study design (n = 43).On the contrary, experimental studies constituted a minor fraction (n = 15), with RCT being only represented by seven studies.A Kruskal-Wallis H test showed that total citations were not affected by study design (H = 5.926, p = 0.548).The sample size categories are shown in Table 6.The majority of the studies involved a sample size of 100 participants or fewer (n = 62).On the other hand, only a total of five studies included a sample size of more than 600 participants.

Recent and Review Publications
The top 20 most recently cited articles are listed in Table 7.The most cited recent article received 21 citations, while the least cited received four citations.A total of 12 studies were not identified in the initial list of the top 100 most cited articles.The top 10 most cited systematic reviews and guidelines are listed in Table 8.This list represents all identified systematic reviews and guidelines found by our search.Two of the identified review papers have not received any citations.

Productivity
The highest number of citations has not exceeded a total of 776 citations.In a previous report, the highestcited article related to SCD received a total of 7,507 citations [6].Productivity in other areas of medicine is considerably larger; this suggests lower research activity and less interest in SCD and related complications [8][9][10].Over half of the identified articles received 35 citations or less, further suggesting decreased productivity.Lower productivity may hinder the development of new and more effective treatments for ACS.
One study compared the funding between SCD and cystic fibrosis, which has a lower prevalence, and the associated research productivity; the study highlighted funding disparities between SCD and cystic fibrosis, which might contribute to decreased research productivity and ancillary therapeutic invention [11].Therefore, more efforts are warranted to enhance research productivity and the development of novel treatments for ACS.

Publications Trends
Millions of people around the world are affected by SCD.It is particularly prevalent in Central and South America, Saudi Arabia, India, and Mediterranean countries.For example, in Jamaica, one in every 150 persons is affected by SCD [12].In Saudi Arabia, approximately one in every 260 persons has SCD [13].Despite having a lower prevalence, the USA contributed the vast majority of highly cited articles in ACS, with minimal contributions from developing countries.Developing countries, especially economically disadvantaged nations, may be disproportionately affected by the burden of SCD complications.Therefore, the gap between developed and developing countries should be bridged, and more collaborative efforts should be encouraged.
The largest number of publications were published in "Blood" and "American Journal of Hematology," with nine articles each.In concordance, previous bibliometric analyses identified these two journals as the most productive journals in SCD [6,7].Hence, these journals could be recommended for investigators interested in this field."Vichinsky, E.P." (h-index = 81) has been identified as the most contributing author with a total of 10 articles.In agreement with our result, Okoroiwu et al. identified "Vichinsky, E.P." as the most contributing author in SCD research; however, Musaa et al. identified "Serjeant GR" as the most productive author [6,7].Highlighting the most contributing authors in ACS may help investigators around the world plan future directions and collaborations.
It has been noted that author self-citations account for one in 15 citations of articles published in highprofile general medicine journals [14].Though the self-citation phenomenon may inflate the importance of some scientific literature, we found that self-citation has no significant impact on the final ranking of articles [15].
The plethora of highly cited articles was observational in design.Approximately half of those were cohort studies, which yield stronger evidence than other types of observational studies.On the other hand, we identified a paucity of RCTs, with only seven articles represented in the list.Generally, RCTs are the best study type for proving causality.Slightly below two-thirds of studies enrolled a sample size of less than 100.Notably, the power of a study, the probability of establishing a statistically significant result, is inherently related to the sample size [16].Therefore, research empowerment and adequate funding are crucial to ensure the integrity of the literature.

Top Three Cited Articles
In 2000, the National Acute Chest Syndrome Study Group published the most cited articles related to ACS.The study was published in "The New England Journal of Medicine," with "Vichinsky, E.P." being the first author.In this multicenter study, which involved 30 centers, a total of 671 episodes of ACS were analyzed to determine the cause and outcome [4].Interestingly, approximately half of the patients were initially hospitalized for another cause, such as a painful crisis [4].The cause of ACS was found in 38% of all episodes.The most commonly identified causes were pulmonary fat embolism and infection; pulmonary emboli and bronchopneumonia were the most common causes of death [4].Additionally, the study has demonstrated that phenotypically matched transfusions and the use of bronchodilators improved oxygenation and clinical outcomes.With aggressive management, most patients with respiratory failure will successfully recover [4].Nevertheless, ACS was associated with a 3% mortality rate [4].
The year 1994 witnessed the publication of the second most cited article related to ACS by Castro et al., involving participants of CSSCD.In that study, a total of 3,751 patients with sickle cell disease (SCD), who were followed for at least two years, were examined to determine the incidence and risk factors of ACS [3].The total number of events was 2,100.The incidence was highest among patients with homozygous (SS) SCD and lowest among patients with sickle cell-beta(+) thalassemia [3].The incidence was significantly correlated with younger age groups.However, a higher mortality rate was observed in adults with a higher incidence rate [3].Furthermore, they identified higher steady-state Hb levels and lower fetal Hb as independent risk factors for ACS among patients with SS disease [3].
In 1997, Vichinsky et al. published the third most cited article, where they examined the clinical presentation and course of ACS, analyzing the participants of CSSCD [17].Adults commonly presented with dyspnea, chills, and severe pain, and they were often afebrile.Multilobe and lower lobe disease were commonly observed in adults [17].Besides, mortality was four times higher in adults than in children.Rapid development of respiratory failure was generally seen in fatal cases [17].

Limitations
A number of limitations should be considered in this analysis.First, we searched a single database, which restricts the identification of highly cited articles.Second, many non-English articles might not be identified due to the possibility of English language bias in the utilized database.Third, textbooks and abstracts of conference proceedings are not included in the present analysis, and therefore, some of the highly cited publications may be omitted.Finally, the ranking of articles is based on citations, and the importance of an article should not be solely based on citation count.Nevertheless, citation count is still considered a valuable supplementary tool to assess the impact of a particular publication [18].

Conclusions
ACS has been identified as a major cause of morbidity and mortality in patients with SCD.The present bibliometric analysis highlights the characteristics of the top 100 most-cited articles in ACS research.The study demonstrates that research on ACS is receiving less attention than it should, and this may impede the development of novel treatments.Increasing funding and support may be required to boost research productivity in this field.Furthermore, the vast majority of highly cited articles are generated in the US, with a small contribution from developing countries with a high prevalence of SCD.Therefore, more collaborative efforts should be encouraged to reduce the gap between developed and developing countries, ensuring that these disadvantaged populations are not disproportionately affected.Additionally, a paucity of highly cited RCTs is noted, and a considerable number of studies had a relatively small sample size.Therefore, research empowerment and adequate funding are of paramount importance to improve research productivity and quality.The present work may serve as guidance to investigators and funding agencies to plan the future direction of ACS research with hope that the future of research in this area becomes more fruitful.Exploring future directions could involve a concentrated effort on preventive interventions and innovative therapeutic options in ACS.

1TABLE 7 : 13 1 16 3 4 Vitamin D supplementation for sickle cell disease 9 5 9 6 5 7 2 8 2 9
Platelet extracellular vesicles drive inflammasome-IL-1βdependent lung injury in sickle cell disease 2 Hemin causes lung microvascular endothelial barrier dysfunction by necroptotic cell death 3 Pulmonary platelet thrombi and vascular pathology in acute chest syndrome in patients with sickle cell disease4 Rapidly progressive acute chest syndrome in individuals with sickle cell anemia: a distinct acute chest syndrome phenotype 5 Association of plasma CD40L with acute chest syndrome in sickle cell anemia 6 Score Predicting Acute Chest Syndrome During Vaso-occlusive Crises in Adult Sickle-cell Disease Patients 7 Acute chest syndrome among children hospitalized with vasoocclusive crisis: A nationwide study in the United States 8 Exosomes contribute to endothelial integrity and acute chest syndrome risk: Preliminary findings 9 Bedside lung ultrasound during acute chest syndrome in sickle cell Disease 10 Extracorporeal Life Support for Severe Acute Chest Syndrome in Adult Sickle Cell Disease: A Preliminary Report 11 Augmented NRF2 activation protects adult sickle mice from lethal acute chest syndrome 12 Association of guideline-adherent antibiotic treatment with readmission of children with sickle cell disease hospitalized with acute chest syndrome 13 Exhaled nitric oxide: Not associated with asthma, symptoms, or spirometry in children with sickle cell anemia 14 Pulmonary vascular dysfunction and cor pulmonale during acute respiratory distress syndrome in sicklers 15 Accuracy of Point-of-care Lung Ultrasonography for Diagnosis of Acute Chest Syndrome in Pediatric Patients with Sickle Cell Disease and Fever 16 Original Research: Acute chest syndrome in sickle cell disease: Effect of genotype and asthma 17 Factors associated with mechanical ventilation use in children with sickle cell disease and acute chest syndrome18 Aeroallergen sensitization predicts acute chest syndrome in children with sickle cell anaemia 19 Early noninvasive ventilation and nonroutine transfusion for acute chest syndrome in sickle cell disease in children: A descriptive study 20 Inflammatory and endothelial markers during vaso-occlusive crisis and acute chest syndrome in sickle cell disease The top 20 recent most cited articles in ACS research TC: Total citations 2024 Albarbari et al.Cureus 16(1): e52545.DOI 10.7759/cureus.5254510 of Guideline on the management of acute chest syndrome in sickle cell disease 73 2 Inhaled nitric oxide for acute chest syndrome in people with sickle cell disease Nitric oxide metabolism and the acute chest syndrome of sickle cell anemia 13 Blood transfusions for treating acute chest syndrome in people with sickle cell disease Inhaled bronchodilators for acute chest syndrome in people with sickle cell disease Obstructive sleep apnea in sickle cell disease carriers | [Apneia obstrutiva do sono em portadores da anemia falciforme] Antibiotics for treating acute chest syndrome in people with sickle cell disease How I Treat Acute Chest Syndrome in Asthmatic Children with Sickle Cell Disease.A Practical Review 0 10 Respiratory therapy in children with sickle cell disease and acute chest syndrome | [Fisioterapia respiratória em crianças com doença falciforme e síndrome torácica aguda] 0

TABLE 1 : The top 100 most cited articles in ACS research
TC: Total citations; ESC: citations excluding self-citations; C/Y: citation per year; HCY: highest citation year.

TABLE 2 : Country distribution of the top 100 most cited article in ACS
TC: Total citations; TP: Total publication

TABLE 3 : The top 20 most cited journal in ACS
TC: Total citations; TP: Total publication

TABLE 6 : Sample sizes of the most cited study
TC: Total citations; TP: Total publication

TABLE 8 : The top 10 most cited guidelines and reviews in ACS
TC: Total citations