Risk Factors and Patient Profile of Infective Endocarditis due to Gemella spp.

Background. The diagnosis of infective endocarditis is difficult, especially when it involves atypical organisms. Therefore, our study identified risk factors of infective endocarditis caused by rare pathogen, Gemella spp. Methods. A systematic review was conducted to investigate characteristics of endocarditis patients infected with Gemella spp. using the search term “Gemella” and “endocarditis.” Case reports were gathered by searching Medline/Pubmed, Google Scholar, CINAHL, Cochrane CENTRAL, and Web of Science databases. 83 articles were selected for review. Results. Five species of Gemella were identified. Typical patients were males between 31 and 45 years of age. On admission, patients had fever, tachycardia, and normal blood pressure. Common clinical manifestation other than fever included fatigue and weakness, chills and sweating, and nausea, vomiting, diarrhea, and weight changes. One in four reported a history of congenital heart disease, and a recent oral cavity infection. Laboratory tests reveal anemia, leukocytosis, and elevated erythrocyte sedimentation in all age groups, elevated C-reactive protein is observed among adult and geriatric populations only. Mitral and aortic valves were most commonly infected by Gemella spp.. The most common Gemella spp.-susceptible antibiotics were penicillin, vancomycin, cephalosporin, macrolide, and aminoglycosides. However, antibiotic resistance was observed against penicillin, aminoglycoside, and fluoroquinolone. Antibiotic course of at least six weeks resulted in superior clinical improvements than durations under six weeks. Finally, one in two patients underwent valve replacement or repair, with common complications affecting the cardiovascular, neurological, and renal systems. Finally, death occurred in 1 in 8 patients, half of which occurred post-surgical procedure, and the majority occurring equal to or greater than 1 week from admission. Conclusion. Our systematic review highlights the importance of considering rare pathogens, particularly in the presence of predisposing risk factors.


Introduction
Infective endocarditis is a rare disease with an incidence of approximately 3-10 per 100,000 people per year in industrialized countries. [1,2,3,4] Recognizing infective endocarditis is difficult due to the non-specific symptoms, such as sepsis of unknown origin or fevers without recognizing the risk factors. [5] Currently, the accepted criteria for diagnosis are the modified Duke criteria. Furthermore, targeted antibiotic therapy for infective endocarditis should be guided by the results of two to three sets of blood cultures obtained from separate venipuncture sites. Any delay in treatment will have negative effects on clinical outcomes in acute bacterial infectious diseases [6] and raises the risk of developing complications including infectious recurrences, cardiac surgery because of the valvular sequelae of the disease, and death [7].
A number of factors predispose to the development of infective endocarditis, such as age, sex, injection drug use, and dental infection, as well as the presence of co-morbid conditions such as structural heart disease, valvular disease, or intravascular device. Presently, there is ample information available regarding the common causes of infective endocarditis: staphylococci, streptococci, and enterococci. [8,9,10] However, there is limited knowledge for lesser known pathogens. One prominent microorganism is Gemella spp.
Gemella spp. are facultatively anaerobic non-motile and non-spore forming Gram-positive cocci. Due to its misidentification as viridans group group streptococci, [11] it is very likely that Gemella is more important cause of clinical disease than is presently recognized. These are organisms are present in the mouth, gastrointestinal tract, and genitourinary tract of humans and other warm-blood animals, although serious systemic infections such as endocarditis usually lead to the clinical presentations. [12] Although Gemella spp. are associated with previous valvular injury or prosthetic valves, dental surgery, and colorectal surgery, [13] the true mode of infection leading to infective endocarditis still remains unclear.
To understand the pathogenicity of the microorganism, identify risk factors and susceptible patient populations, a systematic review was conducted to elucidate the characteristics of endocarditis patients infected with Gemella spp. based on existing case reports and case series.

Protocol and Registration
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist was adhered to for this systematic review. The protocol was not registered.

Inclusion
Criteria-Only articles that reported the association of the genus of the gram-positive bacteria Gamella spp. and endocarditis were included.

Exclusion
Criteria-Studies were excluded if: (1) they were not case reports or case series, (2) they were not peer-reviewed, and (3) they were not in English.

Information Sources and Search Strategies
A comprehensive literature search using Medline/Pubmed, Google Scholar, CINAHL, Cochrane CENTRAL, and Web of Science databases up to and including 1 January 2020 using the terms "Gemella" and "endocarditis."

Study Selection
Initial triage of articles was based on whether titles or abstracts met the inclusion criteria. Full-text articles were reviewed, and those that did not satisfy the inclusion were excluded. A summary of study characteristics is given in Table 1.

Data Collection Process and Data Items
Data extracted from articles included name of first author, year of publication, country, and study design. Variables for which data were sought included viral strain, patient age and sex, presenting complaints on admission, past medical and surgical histories, laboratory tests, diagnostic studies, management of endocarditis, and outcome of the patient.

Synthesis of Results and Summary of Measures
Data were tabulated, evaluated, and summarized.

Risk of Bias across Studies
Potential bias across studies were analyzed within study characteristics. Two independent reviewers evaluated the methodological quality of the eligible studies. A third reviewer evaluated papers where there was no agreement. The Joanna Briggs Institute critical appraisal tool for case reports was selected for use in this systematic review. Bias was evaluated using a checklist of 8 questions. Each question is specified in Supplementary Table S1 concerning risk of bias whereby an overall appraisal was made of each article: risk of bias is low (included), high (excluded), or uncertain (more information is required). For the purpose of this study, an answer of "yes" equal to or greater than 50% of the questions was considered to be low risk of bias. Similarly, an answer of "no" equal to or greater than 50% of questions was determined to be high risk of bias, whereas "unclear" answers were equal to or less than 50% response.

Study Selection
From five databases, 118 articles were selected with relevance to Gemella spp. and endocarditis. 83 case reports were selected once assessed for eligibility.  A PRISMA flow diagram detailing the process of identification, inclusion, and exclusion of studies is shown in Figure 1.

Results of Individual Studies
A summary of findings is presented in Table 1.

Risk of Bias across Studies
Due to the nature of descriptive studies, the results being presented are liable to investigator, procedure, and selection bias.

•
Statistical analyses were not performed as there were no control/comparison group in the included studies.

Discussion
Five species of Gemella were identified in our systematic review, the most common species was Gemella morbillorum and haemolysans. These two species have been members of the genus Gemella since 1988. [93] Gemella spp. are opportunistic pathogens, similar to many other commensal bacteria of the human microbiota, causing severe localized and generalized infections. [94] Less is known about Gemella bergeri, sanguinis, and taiwanensis. Gemella bergeri and sanguinis were also assigned to the Gemella genus in 1998, while Gemella taiwanensis was identified more recently in 2014. [95] The misidentification of Gemella spp.
can be attributed to the inaccuracy of commercial biochemical tests using phenotypic identification systems. [49] Gemella haemolysans and morbillorum have been identified as the causative pathogens in most of the previous cases caused by Gemella spp., yet these findings may be biased by which test are commercially available.
We discovered that males were more prone to infective endocarditis by Gemella spp. The reduced susceptibility of females could be attributed to the protection from X chromosome and sex hormones, which play an important role in innate and adaptive immunity. [96] We also found that the age of the patients ranged between 31 to 45 years. Infective endocarditis predominantly inflicted young adults in low-income countries, [97] while the average patient age in high-income countries was 70 years. [98] The majority of studies in this systematic review originated in high income countries such as USA, UK, and Japan.
Two-thirds of infective endocarditis in low-income countries are caused by communityacquired penicillin-sensitive streptococci entering via the oral cavity leading to rheumatic heart disease. [97] Infective endocarditis in high-income countries, on the other hand, is due to degenerative valve disease, diabetes, cancer, intravenous drug use, and congenital heart disease. [98] This is in large due to improved living standards and availability of antibiotics for streptococcal pharyngitis resulting in substantially reduced incidence of rheumatic heart disease. [99] In parallel, the incidence of cases attributable to oral streptococci has decreased due to oral antibiotic prophylaxis. [100] Interestingly, we showed that one in four patients reported a history of congenital heart disease, such as bicuspid aortic valve, ventricular septal defect, and tetralogy of Fallot. Furthermore, one in four patients had a recent history of oral infection, and one in two had undergone surgical procedure, such as heart valve replacement or dental repairs. This poses the question whether the incidence and prevalence of infective endocarditis by Gemella spp. is under-reported in low-income countries.
Typically, clinical examination of infective endocarditis shows variable signs of disease, with fever present in 90% of cases and cardiac murmurs in 85% of patients. Splenomegaly or cutaneous manifestations, such as petechiae or splinter haemorrhages, are supportive signs. [101,102] Osler's nodes, Janeway lesions, and Roth spots are rare, while signs of complications such as heart failure, stroke, or metastatic infection (eg, vertebral osteomyelitis, peripheral abscess) are more prevalent. [5] Patients with infective endocarditis by Gemella spp. showed fever, tachycardia, and normal blood pressure. The most common clinical manifestations for all patients were fever, fatigue, and chills or sweating. Nausea, vomiting, diarrhea or anorexia were more commonly found in children, while adults displayed chills or sweating. The elderly, on the other hand, exhibited fatigue.
Generally, laboratory tests for infective endocarditis is non-specific, showing raised inflammatory markers and normocytic-normochromic anemia. [103] Our systematic review revealed that patients with infective endocarditis by Gemella spp. have anemia, leukocytosis, and elevated erythrocyte sedimentation rate in all age groups, while the adult and geriatric populations have an elevation in C-reactive protein. Diagnostic studies commonly showed mitral valve vegetation in the pediatric and geriatric population, and aortic valve vegetation in the adult age group. Gemella haemolysans, bergeriae, and sanguinis were mainly found on aortic valves, whereas Gemella morbillorum and taiwanensis were discovered predominantly on mitral valves.
The most common Gemella-susceptible antibiotics are penicillin, vancomycin, cephalosporin, macrolide, and aminoglycosides. However, antibiotic resistance was observed against penicillin, aminoglycoside, and fluoroquinolone. This management is similar current approach to patients with uncomplicated community-acquired native valve or late prosthetic valve endocarditis due to highly sensitive streptococci, where combination therapy with a beta-lactam antibiotic and aminoglycoside is used. [104] Finally, patients who received treatment course for at least six weeks or greater showed greater clinical improvement than patients who received antibiotic therapy for less than six weeks. This finding indicates that special attention should be placed on the duration of treatment for Gemella cases.
One out of two cases in the systematic review underwent either valve replacement or repair where removal of the infected tissues and reconstruction of cardiac morphology were accomplished. Typically, surgery is undertaken in 40-50% of patients with infective endocarditis. [105] In mitral valve infective endocarditis, successful valve repair is achieved in up to 80% of patients. [106] Finally, patients with infective endocarditis by Gemella spp. commonly suffered complications involving the cardiovascular, neurological, and renal systems. Death occurred in one of eight patients, half of which occurred in the post-surgical period with the majority occurring equal to or greater than 1 week from admission. This is similar to in-hospital mortality of infective endocarditis, which is estimated at 20% and increases to 25-30% at six months. [106,107] Although the strength of the study is an extensive review of infective endocarditis due Gemella spp, data were limited with regards to recurrent infections with the same organism.
In conclusion, infective endocarditis by Gemella spp. is more likely to infect men ages 31 to 45 years with a history of congenital heart disease, recent oral infection, or surgical procedures, such as heart valve replacement or dental repairs. Laboratory tests will likely indicate anemia, leukocytosis, and elevated erythrocyte sedimentation rate, while diagnostic studies will commonly show mitral or aortic valve vegetation, which is dependent of population or Gemella species. Infective endocarditis by Gemella spp. is managed by empiric treatment with beta-lactam and aminoglycosides combination therapy for at least 6 weeks in duration, or valve replacement or repair, with death occurring in 12.5% of the cases. Therefore, our systematic review highlights the importance of considering rare pathogens, particularly in the presence of predisposing risk factors. Comparison between antibiotic therapy 6 weeks or more (dark) to treatment duration under 6 weeks (light) (n=51)  Table 3.

Trends of laboratory values of endocarditis patients infected with
Gemella combined and as divided by age group