Helicobacter cinaedi Infections in Emergency Departments: A Descriptive Study

Aim: Helicobacter cinaedi, a Gram-negative spiral bacterium, is a rare cause of bacteremia in humans. Unfortunately, little is known about H. cinaedi infections in emergency departments (EDs). We aimed to describe the clinical features of H. cinaedi infections in the ED. Methods: We conducted a descriptive study at the ED of Kobe City General Hospital (KCGH) in Japan between November 2011 and December 2020. We included all ED patients with H. cinaedi infections. We retrospectively obtained the patient data from electronic medical records and described the patient characteristics, clinical course, and management of H. cinaedi infections. Results: A total of 22 patients in the ED were diagnosed with H. cinaedi infections, and all of them were detected through blood cultures. The chief complaints were vague: fever (18/22, 81.8%), chills (10/22, 45.5%), and localized pain or tenderness (8/22, 36.4%). Patients with complicated cases were also reported in the ED; three patients had vertebral osteomyelitis, two had infected aortic aneurysms, and another two had infected cysts (renal cyst and pancreatic cyst with concomitant empyema). Tetracycline (minocycline) was primarily prescribed and administered intravenously in five of 15 (33.3%) and orally in nine of 20 (45.0%) patients. Only one (4.5%) patient required surgical interventions. None of the patients died in the hospital. Conclusions: We reported the clinical features of H. cinaedi infections in the ED. Although some patients developed complicated infections, the prognosis was not poor under appropriate treatment, and most of them were successfully treated with antibiotics, primarily tetracycline.


Introduction
Helicobacter cinaedi, a Gram-negative spiral bacterium, is a rare cause of bacteremia in humans [1][2][3][4].However, this microorganism is receiving growing attention because increasing numbers of human cases have been reported recently.Nevertheless, the mechanism of infections, as well as clinical aspects, remain incompletely understood.H. cinaedi can invade the bloodstream from the gastrointestinal tract, and this bacterial translocation is regarded as the first step of pathogenesis [5].After entering the bloodstream, H. cinaedi bacteremia sometimes develops secondary foci of infections, such as cellulitis and arthritis, due to an affinity of the bacteria for the skin and joint tissues [1].
In earlier reports of H. cinaedi infections, most cases were considered opportunistic or nosocomial infections, especially among homosexual men and immunocompromised hosts [6][7][8][9].However, communityacquired H. cinaedi infections have recently been reported [10][11][12][13].Furthermore, infections have been reported across all age groups, from newborns to older adults, and include cases of cellulitis, gastroenteritis, arthritis, vertebral osteomyelitis, infected aortic aneurysm, and neonatal meningitis [1].Currently, emergency physicians may be unfamiliar with the diverse clinical presentations of H. cinaedi infections, and the clinical features of H. cinaedi in the emergency department (ED) are inadequately described.We aimed to provide further insights into the clinical features and management of H. cinaedi infections in ED settings.

Study design and settings
This descriptive study was conducted at the ED of Kobe City General Hospital (KCGH) in Japan from November 2011 to December 2020.KCGH is a tertiary care hospital with 760 beds and serves 1.5 million habitants in the city, including both urban and rural areas of approximately 554 km 2 .As a certified critical care center, the ED has an average of 35,000 patient visits and 10,000 ambulance calls per year.On average, half of the severely injured patients in the city are managed in this ED.
Emergency physicians attend to patients in the ED and determine whether they should be admitted.In the ED, we take culture specimens from specific organs based on chief complaints, physical examination, and diagnostic tests.Furthermore, we obtain blood cultures from the following indications: fever (>38°C), shivering chills, unexplained loss of consciousness, circulatory disturbance, an increased respiratory rate (>20 breaths per minute), metabolic acidosis, an elevated or markedly decreased inflammatory response such as white blood cell counts and C-reactive protein levels, or suspected infective endocarditis.If patients are discharged from the ED after blood cultures are obtained, they are contacted immediately when the blood cultures yield positive results.

Selection of participants
The target population comprised patients with culture-confirmed H. cinaedi infections who presented to the ED.First, we selected all patients with H. cinaedi infections identified in any type of specimen from the electronic microbiology database that contains all data of culture specimens in the hospital.We determined whether H. cinaedi was a causative pathogen or not mainly based on clinical diagnoses that the treating physicians determined at their final follow-up day.Infected sites were determined in the same way.In addition, two investigators (KI and YM) independently reviewed medical histories, physical assessments, diagnostic tests including imaging tests, and overall clinical courses in the electronic medical records.When there was a discrepancy between our decision and clinical diagnosis, we planned to inquire about diagnoses to treating physicians.Finally, we excluded patients who visited the general outpatient ward and those infected with H. cinaedi identified from culture specimens following hospitalization.

Data collection
We retrospectively obtained the following patient data from the electronic medical records: age, sex, comorbidities (diabetes mellitus, chronic kidney disease (serum creatinine concentration ≥ 2.0 mg/dL), any malignancy, diseases requiring immunotherapy (use of steroids or immunosuppressive drugs), malignant diseases requiring recent chemotherapy (within 30 days of the ED visit)), infected site, laboratory data (white blood cell counts and C-reactive protein levels) from the initial ED visit, incubation days of blood cultures, antibiotic susceptibility, method of antibiotic administration (intravenous and oral), durations of antibiotic therapy (days), in-hospital days, complications or surgical interventions, and in-hospital mortality.

Cultures for H. cinaedi
We collected the data of all patients with H. cinaedi infections from the database at the bacteriological laboratory, including the results of all cultures from any kind of specimen.Blood cultures were observed for at least seven days and processed at the center's laboratory using the BACTEC FX system (Nippon Becton, Dickinson, and Company, Tokyo, Japan).Polymerase chain reaction (PCR) identification was performed in all cases where Gram-negative spiral bacilli were identified using Gram staining.The KAPA2G Robust PCR  1, 2).2023     Patients with recent chemotherapy were more likely to be admitted at initial presentation to the ED compared with those who were discharged (4/11 (18.2%) versus 0/11 (0%)).Furthermore, the C-reactive protein levels were higher in the admitted patients than in the discharged patients (median: 10.7 (IQR: 1.59-12.9)versus 3.41 (IQR: 1.49-10.8)mg/L).
Cellulitis and vertebral osteomyelitis (3/22, 13.6%, for both) were the most common sources of bacteremia, followed by an infected aortic aneurysm, colitis, and infected cysts (renal cyst and pancreatic cyst with concomitant empyema) (2/22, 9.1%, for all).Meanwhile, the sources of infections were not identified in nine patients (40.9%).The overall prognosis of H. cinaedi bacteremia was good; only one patient required surgical intervention, and none died in the hospital.Among the 11 discharged patients at initial presentation to the ED, seven (63.6%) completed their treatment as outpatients without any sequelae.Antibiotics were prescribed to these initially discharged patients only after the blood cultures turned positive.

H. cinaedi bacteremia and microbiological features
H. cinaedi strains were detected in aerobic bottles, and the incubation time ranged from 4 to 11 days (median: 5 (IQR, 5-7) days).Blood cultures yielded a positive result within five days of sampling in 11 of 20 patients (55%) and longer than five days in nine of 20 patients (45%).Two patients had missing data on the incubation time.

Management of H. cinaedi bacteremia
Patients with H. cinaedi bacteremia were treated with antibiotics administered through different routes (Table 4).

TABLE 4: Intravenous and oral antibiotics for patients with H. cinaedi bacteremia
Of them, one patient (1/21, 4.8%) was treated with intravenous antibiotics alone, 14 (14/21, 66.7%) patients were treated with intravenous antibiotics and subsequently oral antibiotics, and six patients (6/21, 28.6%) were treated with oral antibiotics alone.The median total duration of the antimicrobial treatment was 20.5 days (IQR: 14.0-29.3).The duration of the antibiotic treatment exceeded 40 days in six patients with complex infections: vertebral osteomyelitis (three), infected aortic aneurysms (two), and cyst infection (one).
Only one patient required a surgical stent graft replacement for an aortic aneurysm infected with H. cinaedi.Of note, one patient recovered from the infection without receiving antibiotic treatment.The patient was hospitalized and treated for hypokalemia and discharged with potassium correction alone.

Discussion
In this descriptive study conducted at a single ED in Japan, we reported the patient characteristics and common clinical practices for H. cinaedi infections.The patients with H. cinaedi infections presented to the ED with vague clinical features, making it difficult to obtain an accurate diagnosis, and complicated infections were often the cases, including vertebral osteomyelitis and infected aortic aneurysms, unlike the previously reported cases in the primary care settings.Of note, H. cinaedi was detected only in blood cultures, and the duration of blood cultures exceeded five days in 45% of the patients.
Our study adds to the existing literature by providing a more detailed picture of H. cinaedi infections in emergency settings.In this study, patients with complicated cases, such as vertebral osteomyelitis, infected aortic aneurysms, and infected cysts, were more commonly reported in emergency settings; these cases were primarily documented in case reports conducted in primary care settings [14][15][16][17][18][19][20][21].These complicated cases required antibiotic therapy for over 40 days; however, the prognoses were not poor with appropriate treatments, with only one patient requiring surgical intervention.Meanwhile, stable patients with H. cinaedi bacteremia can be safely managed in outpatient settings with close follow-ups, provided that they do not have any complicated concomitant source of infections and are not immunocompromised.Indeed, the clinical courses and outcomes, such as complications and need for surgical treatments, in-hospital days, and mortality, were not aggravated in the present study.On the contrary, immunocompromised patients, especially those with recent chemotherapy, were likely admitted at the first visit to the ED in the present study, and previous studies also pointed out that those patients are at risk for recurrence [8,9,[22][23][24][25][26][27].
The diagnoses of H. cinaedi would have been missed when the general observation period for blood cultures was employed, as the time to positive blood culture was longer than five days.Our bacteriological laboratory employed a minimum observation period of seven days for blood cultures, which potentially facilitated the detection of H. cinaedi bacteremia in a greater number of patients.Furthermore, H. cinaedi was detected only in blood cultures and not in other specimens, such as bone and vessel wall tissues.These findings highlight the importance of blood cultures for detecting H. cinaedi infections in EDs.
As regard the antibiotic of choice, the optimal choice has not yet been known.Although there has not been sufficient evidence and recommended guidelines, susceptibility for tetracycline, aminoglycosides, and carbapenem and resistance to quinolones and macrolides have been reported [1].We primarily treated with intravenous or oral tetracycline for H. cinaedi infections, and indeed all H. cinaedi isolates were susceptible to tetracyclines.Furthermore, the treatment of complex infections often necessitates a prolonged course of antimicrobial therapy to achieve a complete cure.Indeed, the present study demonstrated that approximately 30% of the patients underwent antimicrobial therapy for more than 40 days and were diagnosed with complex infections: three patients had vertebral osteomyelitis, two had infected aortic aneurysms, and one had a cyst infection.We also recommend a 14-day antibiotic course for most patients, with a longer duration considered for immunocompromised patients to prevent recurrence [10].The optimum duration of treatment might vary depending on the specific source of infection in each patient.
This study had several limitations.First, it was descriptive in nature, and no control groups were established for comparison; hence, we could not draw conclusive clinical recommendations.Further studies are warranted to evaluate the optimal choice and route of antibiotic treatment for H. cinaedi infections.Second, the present study was performed at a single ED, which may have introduced a selection bias.The patients included in the present study might have more severe cases, as the study setting was a tertiary care centre.Finally, it is difficult to generalize the findings of the present study to other communities, where medical systems and resources differ.For example, admission criteria may vary in other countries, as well as the antibiotic preference and availability.Further studies of diverse patient populations are warranted.

Conclusions
The diagnosis of H. cinaedi infections may be challenging owing to its rarity and unfamiliarity; performing blood cultures appropriately is the key to prompt and accurate diagnoses.In emergency settings, complicated cases of H. cinaedi bacteremia were more frequently observed.However, the prognosis of H. cinaedi bacteremia was good when it was managed with appropriate antibiotics, although the optimal treatment strategy has not yet been proven.Further studies are required to develop an individualized approach based on the patient's infection and immunological status.

FIGURE 1 :
FIGURE 1: Patient flow of the study ED, emergency department; KCGH, Kobe City General Hospital

TABLE 2 : Characteristics of patients with H. cinaedi bacteremia in the emergency department
The youngest patient was 32 years old, while the oldest was 91 years old (median: 65.5 (IQR: 49.3-63.3)years).The most common chief complaints and findings in the ED were fever (18/22, 81.8%), chills (10/22, 45.5%), and localized pain or tenderness at the site of infection (8/22, 36.4%).In addition, patients often presented with a history of recent digestive symptoms, such as diarrhea, nausea/vomiting, or abdominal pain (6/22, 27.3%).Diabetes mellitus was reported in seven of the 22 (31.8%)patients, while hematological malignancies or solid tumors were reported in five of the 22 (22.7%)patients.In addition, four of the 22 (18.2%)patients had recent chemotherapy, and another four of the 22 (18.2%)patients presented with chronic kidney disease.Three (13.6%) patients had no comorbidities.

TABLE 3 : Antimicrobial susceptibility of H. cinaedi isolates obtained from patients presenting to the emergency department
We demonstrated antibiotics and a number of H. cinaedi samples susceptible/total number of the tested samples (%).