Myocarditis and pericarditis in young patients following Campylobacter jejuni enterocolitis infection: a systematic review of case studies

Abstract

Background

Campylobacter is known to be the leading cause of foodborne illness. Campylobacter jejuni, specifically, most commonly causes self-limiting enterocolitis, but infection can lead to extraintestinal manifestations, including rare yet severe cardiac complications, such as myocarditis and/or pericarditis. This review aims to determine whether a relationship exists between the timing of a positive stool culture and the overall clinical course in patients with Campylobacter jejuni-associated myocarditis and/or pericarditis.

Methods

A systematic search was conducted using PubMed, MEDLINE, CINAHL Ultimate, Academic Search Premier, and Nursing and Allied Health Premium databases. A gray literature search was also performed. Covidence.org was used to screen, select, and extract data by two independent reviewers. Following a full-text evaluation, the quality of each study was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Case Reports.

Results

The search resulted in 434 records, of which 7 case reports met the inclusion criteria, each study including one patient. The average number of days from hospital presentation to obtaining a stool sample was 1.7. The average number of days from stool culture obtainment to clinical course improvement was 3.3, with four case studies reporting a range of 2–4 days.

Conclusion

This systematic review raises awareness regarding the manifestations of Campylobacter jejuni, specifically the severe cardiac symptoms that may present in young individuals. Given the significant sequelae that can develop, providers must elicit a thorough history consisting of questions related to recent travel, food consumption, and gastrointestinal symptoms, especially among young individuals presenting with cardiac complaints.

Background

Campylobacter spp., primarily transmitted via the fecal–oral route, are the leading cause of foodborne illness in developed and underdeveloped nations. In the USA, the Foodborne Diseases Active Surveillance Network is responsible for monitoring the incidence of various foodborne pathogens. From the beginning of its surveillance in 1996, the incidence of Campylobacter infections has been progressively increasing. A similar trend has also been noted globally. Campylobacter is a robust species that causes disease in the gastrointestinal tract, including in the jejunum, ileum, and colon. Infection typically presents 3 days after exposure, most commonly occurring through contact with and ingesting contaminated food or water. In patients with severe cases, there is a prodromal period where high fevers, generalized aches, and dizziness occur, and occasionally, patients can present with rigors and delirium. Most individuals who become infected with Campylobacter have much milder cases that are typically self-limiting. Patients frequently experience diarrhea, nausea, vomiting, and abdominal discomfort or pain due to pathogenesis. More than 20 species are recognized, with Campylobacter jejuni and Escherichia coli being among the most common that cause human disease [1].

Campylobacter jejuni is the leading cause of acute diarrhea worldwide [2]. C. jejuni is a Gram-negative bacillus that predominantly causes infection after contact with and ingestion of contaminated or undercooked meat. While some factors of pathogenesis are still unknown, it is suspected that chemotaxis, motility, and bacterial flagella all play a role in attachment to the gut epithelium. It was once thought that the survival of this bacteria outside the gastrointestinal tract was relatively poor; however, more recent research has shown that it can survive across a range of environments. Although Campylobacter jejuni infection is typically characterized by self-limiting enterocolitis, patients have also been found to develop extraintestinal complications. Some of these complications, such as Guillain‒Barré and Reiter syndromes, are thought to be an autoimmune response triggered by C. jejuni infection [1]. Cardiac manifestations, such as myocarditis and pericarditis, are considered to be rare yet severe sequelae of C. jejuni [3].

Myocarditis and pericarditis are inflammation of the heart muscle and outer lining of the heart, respectively. The most common etiological factor of both conditions is typically viral, such as enteroviruses, adenoviruses, human immunodeficiency, and coxsackie viruses. While Salmonella, Shigella, and Staphylococci spp. make up a large part of the bacterial causes of myocarditis and pericarditis, the number of Campylobacter jejuni-related case reports has grown [4]. It has been reported that the incidence of Campylobacter-induced myocarditis is approximately 16.1 per 100,000 persons per year [5]. The pathophysiology of C. jejuni-induced myocarditis and/or pericarditis is not well understood [6]. Several theories have been proposed to explain C. jejuni-associated cardiac involvement, including direct bacterial invasion of the myocardium or pericardium or by circulating toxins [1, 6,7,8]. A postinfectious immune-mediated mechanism is less likely to be contributory due to the relatively short period of time between the onset of gastroenteritis and cardiac symptom development [6, 7].

A detailed history should be elicited from patients who present with cardiac manifestations following Campylobacter jejuni-related gastrointestinal symptoms, which, on average, have been noted to appear 2–4 days later [9, 10]. Clinical presentations of myocarditis and pericarditis can include chest pain or tightness, shortness of breath, palpitations, or rapid irregular heartbeat. The diagnosis of C. jejuni can be confirmed via stool culture techniques or culture-independent assays [1]. Additional diagnostic tools, such as an electrocardiogram (EKG), can help support the diagnosis of C. jejuni-induced myocarditis and/or pericarditis. EKG findings may reveal arrhythmias and ST segment changes, although they may be normal in some cases [6, 11]. Further support can be gained from echocardiograms, which may reveal reduced left ventricular ejection fraction, impaired systolic function, and increased left ventricle wall thickness [9]. In patients who present with cardiac manifestations, such as unexplained heart failure, chest pain, or elevated cardiac enzymes, following gastrointestinal symptoms, myocarditis, and/or pericarditis should be considered [6, 12, 13].

The diagnosis of myocarditis or pericarditis following C. jejuni infection can be challenging for providers due to nonspecific symptoms on clinical presentation, especially in younger, immunocompetent patients aged 13–25. The overall incidence of C. jejuni infection is highest in those aged 0–4, with a second peak occurring after age 25 [14]. However, given the increasing number of case reports that have described cardiac manifestations in patients who have been found to have C. jejuni enterocolitis, medical providers need to have a high index of suspicion for this pathogen in this age range. Most cases of myocarditis or pericarditis following C. jejuni infections are mild, but the condition can progress to life-threatening complications or even result in fatal outcomes [6]. This systematic review aims to determine whether a correlation exists between the timing of a positive stool culture result and patients’ overall clinical course for patients aged 13–25. Establishing such an association could potentially allow providers to make an earlier diagnosis of C. jejuni infection and ultimately prevent potential late complications from arising. Ultimately, it is imperative that medical providers accurately diagnose myocarditis and/or pericarditis promptly using appropriate diagnostic tools, such as clinical, laboratory, and cardiac imaging, and identify the cause in this patient population.

Methods

A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines using the EBSCO search engine to search MEDLINE, CINAHL Ultimate, Academic Search Premier, and Nursing and Allied Health Premium simultaneously from their inception to 18 April 2023. A healthcare librarian was consulted to develop the following Boolean search string: “campylobacter jejuni AND (myocarditis OR myopericarditis OR pericarditis OR perimyocarditis)”. The same search was also performed in PubMed and a gray literature search using graylit.org and grayguide.org. Two reviewers (KS and NS) independently screened all titles and abstracts for relevance and completed the subsequent full-text review for eligibility. Retained articles were case reports published in the English language reporting patients aged 13–25 with myocarditis and/or pericarditis following Campylobacter jejuni enterocolitis infection. Additionally, only studies that documented both the timing and the result of the stool culture meeting our inclusion criteria were included. Patients with different Campylobacter species, other gastrointestinal infections, or different cardiac manifestations were excluded. Case reports were assessed for quality using The Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports [15]. Discrepancies in study selection and rating were resolved through discussion or by involving a third reviewer (SJR) as indicated.

Results and review of literature

Study selection

The initial search identified 434 records, of which 211 duplicates were removed, while the gray literature revealed no results. After duplicates were removed, 223 articles were screened, and 125 records were excluded. The full texts of 98 journal articles were reviewed for eligibility, and 91 articles were excluded, with the reasons indicated in the PRISMA flow diagram in Fig. 1 [16]. The remaining seven studies, each report containing one patient, were retained for qualitative synthesis.

Fig. 1

2020 PRISMA diagram detailing screening process of articles. *Confounding variables include coinfection with another pathogen or side effects potentially due to vaccination

Study characteristics

All studies included in this systematic review were single case reports on patients aged 13–25 with myocarditis and/or pericarditis following Campylobacter jejuni infection, as displayed in Tables 1 and 3. A total of six males’ [4, 6, 9, 10, 12, 13]and one female’s [11] clinical courses were evaluated. The average age was 19.3 years old, with a male-to-female ratio of 6:1. Of the patients, one male had bronchial asthma noted as a preexisting condition [10], with the six other patients reporting no preexisting medical conditions [4, 6, 9, 11,12,13]. The specific intervention (in other words, the timing of the stool sample) was reported in all cases. The longest time to collect a stool sample was 5 days [10], while the shortest duration was reported on the same day of presentation [6], with an average time of presentation to stool sample of 1.7 days. In each case report, the overall outcome examined was a change in the clinical course, more specifically, normalization of electrocardiogram, laboratory results, and/or symptom resolution. The length of each case study was reported in all of the reports except Daboussi et al., 2020 [6]. The reported hospital admission length ranged from 5 to 11 days (Table 1).

Table 1 Study characteristics of included case reports

Risk of bias

Each report was evaluated using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports [15]. The results are displayed in Fig. 2; while there were some concerns based on the JBI Appraisal, all articles were ultimately retained. Six of the included studies did not include pertinent demographic characteristics, such as race, thereby earning them a “no” in the first category [4, 6, 9, 11,12,13]. Similarly, five of the studies did not include pertinent details regarding medical histories, such as family and psychosocial histories [4, 6, 9, 11, 13]. Yaita et al., 2020 was found to be unclear on reporting any specific treatment given to this patient [10]. While it is noted that the patient received ciprofloxacin and loperamide prior to hospital admission, it is unclear if the providers discontinued this regimen. Of note, no adverse or unanticipated events were mentioned in any of the seven case reports.

Fig. 2

Risk of bias diagram exhibiting critical appraisal for each of the included studies

Clinical presentation

The typical range in the number of days from the onset of gastrointestinal symptoms to hospital presentation was between 2 and 4, with an average of 2.6 days (see Tables 2 and 3). Most patients had an average of 2.3 days between gastrointestinal and cardiac symptom presentation. Several case reports noted 3 days [9, 11, 13], while Daboussi et al., 2020 noted the greatest duration of 5 days [6]. The time it took to develop cardiac symptoms from the onset of gastrointestinal symptoms ranged between 2 and 5 days, with an average of 2.3 days. Of the seven case reports, six performed a stool culture between 0 and 2 days from hospital presentation [4, 6, 9, 11,12,13],with an average time of 1.7 days. Five of these patients were found to have symptom, laboratory, and/or imaging improvement between 5 and 7 days from symptom onset [4, 6, 11,12,13]. Two reports had longer durations to improvement of 9 [10] and 13 days [9]; however, the overall average duration to improvement was 7.6 days. The average number of days from stool culture obtainment to symptom, laboratory, and/or imaging improvement was noted to be 3.3 days, with four case studies reporting a range of 2–4 days [4, 6, 11, 12]. The average length of hospital admission was reported to be 7.3 days. Of note, this information was not provided by Daboussi et al., 2020 [6].

Table 2 Clinical presentation timeline of included case reports

Table 3 Averages and ratio of included case report data

Differential, diagnosis, and treatment

Acute viral illness is a common cause of gastroenteritis and cardiac complications [17], as evidenced by the authors of three studies, who specifically considered it part of their differential diagnosis. Several differential diagnoses were considered across all case studies (see Table 4). In three case reports, viral illnesses were considered, such as Epstein‒Barr, human immunodeficiency virus, echovirus, coxsackievirus, and/or parvovirus [4, 10, 12]. While Chantazaras et al., 2021 did not consider other viral sources, the authors did consider infectious enteritis and acute appendicitis [11]. Two other reports considered acute coronary syndrome less likely given the patient’s age and overall clinical presentation timeline [9, 10], while two case reports did not disclose their differential diagnosis [6, 13].

Table 4 Differential diagnosis, imaging, diagnosis, and treatment of included case reports

While two case reports noted normal electrocardiogram results [6, 11], the remaining five patients presented with ST segment changes [4, 9, 10, 12, 13] (Table 4). All patients exhibited elevated levels of either troponin I or T. The combination of obtaining a stool sample in addition to cardiac laboratory and imaging studies led to a diagnosis of myocarditis in five cases [6, 9,10,11, 13] and a diagnosis of myopericarditis in two cases [4, 12]. Regarding pharmacotherapeutic intervention, three case studies reported using a fluoroquinolone antibiotic [4, 9, 13], three cases used a macrolide antibiotic [6, 11, 12], and Yaita et al., 2020 reported no antibiotic use due to symptom improvement by the time Campylobacter jejuni was identified in the stool culture[10]. Of note, the two cases of myopericarditis each used a different class of antibiotics [4, 12]. Cardiac medications, including beta blockers and angiotensin-converting enzyme inhibitors, were reported in two studies [6, 11]. While unclear if antimicrobial therapy improved cardiac outcomes, all patients experienced symptom resolution after treatment.

Discussion

Key findings

This review suggests that there does not appear to be an increased risk of incidence of cardiac complications associated with preexisting medical conditions among younger patients, complicating the ability to make an appropriate diagnosis. Five of the seven patients were noted to be previously healthy with no significant past medical history [4, 6, 9, 11, 13], while one reported a history of bronchial asthma [10] and the last had no reported past medical history [12]. Therefore, since most included patients were likely considered immunocompetent, in good health, and lacking any significant past cardiac history, we postulate that this did not greatly impact their clinical course.

Moreover, our results show a higher incidence among male patients than female patients, with a ratio of 6:1. Our cohort approximates the general patient population affected with myocarditis and/or pericarditis, as myocarditis is more common among males [9]. It is postulated that males are at a greater risk for myocarditis, while females are not, largely due to sex hormones, as it has been found that female patients tend to have greater protection against viral myocarditis largely due to higher levels of estrogen. It is suspected that estrogen offers a certain level of protection against viremia and, furthermore, protects cardiac muscle cells from infection. In contrast, testosterone does not offer this protection [18]. While these findings are related to viral myocarditis, they also reasonably explain why bacterial myocarditis largely affected males in our sample. To the best of our knowledge, no other systematic reviews or meta-analyses have been published focusing on this rare complication of infection.

Clinical relevance

In light of the rising prevalence of Campylobacter infections, it is becoming increasingly important for medical providers to include bacterial pathogens in their working diagnosis. This is especially true in adolescent and young adult patients who present with gastrointestinal and cardiac symptoms. This systematic review showed an average of 2.6 days between gastrointestinal and cardiac symptoms, with the longest duration being 5 days. To diagnose this multifarious condition, a stool culture to detect the pathogen should be performed in a timely manner at the earliest clinical suspicion. While most of the included case reports obtained a stool culture within 2 days of hospital admission [4, 6, 9, 11,12,13], one case report waited 5 days before performing this intervention. In this particular case reported by Yaita et al., 2020, the patient’s symptoms, imaging, and laboratory results had normalized at the time of intervention [10]. In general, performing a prompt stool culture not only allows for a diagnosis to be made sooner, but also allows providers to start antibiotics earlier, thereby altering the clinical course and potentially preventing the development of more severe symptoms.

On average, it took approximately 3 days for patients to start improving following the positive stool culture result and the initiation of a course of appropriate antibiotics. However, it is important to note that although this pattern holds true for most of the case reports [4, 6, 10,11,12,13], Obafemi et al., 2020 appears to be an outlier [9]. The providers working with this particular patient obtained a stool sample in a timely manner, noting a positive result within 1 day of hospital admission. However, the clinical course of this patient does not appear to be influenced by the timing of the stool sample and subsequent initiation of an antibiotic regimen. This patient had the slowest clinical improvement time out of all included patients, spending a total of 13 days in the hospital. It can be postulated that this patient was slow to improve, not due to the timing of intervention but rather due to higher acuity at presentation. This resulted in initial antimicrobial treatment with meropenem but was later switched to ciprofloxacin after obtaining the sensitivity report [9].

As previously mentioned, Yaita et al., 2020 waited 5 days before obtaining a stool sample, as the patient had resolution of his cardiac symptoms and improved overall clinical course at the time of intervention. Although his stool culture tested positive for C. jejuni, the patient was treated with conservative measures during the initial hospitalization and was subsequently monitored in the outpatient setting upon discharge. However, the patient returned to the hospital with acute chest pain, leading to the diagnosis of relapse myocarditis. This particular case report highlights the clinical utility of administering antibiotics to patients who test positive for Campylobacter but are found to be asymptomatic or are noted to have significant symptomatic improvement at the time of a positive result. This raises the question of whether giving antibiotic therapy to the patient reported by Yaita et al., 2020 would have prevented his relapse [10]. As such, providers should take into consideration the potential benefits of acquiring a stool sample and administering antibiotics earlier on in a patient’s clinical course if they initially present with cardiac symptoms or other extraintestinal manifestations but are later found to have symptomatic, imaging, and/or laboratory improvement before antibiotic treatment is initiated.

While the timing of obtaining a stool sample is critical in the prompt initiation of the appropriate antibiotic treatment and ultimately symptom resolution, so too are cardiac imaging and laboratory results. Across all included case reports, patients exhibited elevated levels of cardiac enzymes, more specifically, troponin I or T. Additionally, five out of the seven patients had abnormalities noted on their initial electrocardiogram, most commonly ST segment elevation [4, 9, 10, 12, 13]. In patients who present with normal EKG readings, cardiac magnetic resonance imaging (MRI) may play a useful role in diagnosis. If available, cardiac MRIs are able to detect suspected cases of myocarditis and/or pericarditis, as evidenced by myocardial damage, increased T2 signal, and delayed enhancement [6]. A total of three case reports included cardiac MRI as part of their diagnostic imaging [6, 11, 12]. Although less than half of the cases included in this systematic review chose to implement this important diagnostic tool, the ones that did find pertinent abnormalities helped form an accurate diagnosis. Cardiac MRIs have the ability to pick up on changes not otherwise detected by an EKG and tend to be more sensitive, proving to be an additional tool that should be more readily used [6, 11].

Our results indicate that when a young immunocompetent patient presents with a history of gastrointestinal symptoms followed subsequently by acute chest pain, providers should consider myocarditis and/or pericarditis as a differential diagnosis. This diagnosis should especially be considered when observing these symptoms among a younger population and/or male patients. While most cases of myocarditis associated with C. jejuni have a good prognosis, the delay in both diagnosis and treatment can result in significant complications, ranging from permanent cardiac damage to fatality [10]. Therefore, a clinically appropriate timeline, including the timing of stool samples, cardiac imaging, and laboratory results, is imperative to maximize patient outcomes.

Review limitations

While the search strategy was nonspecific in attempting to identify as many reports as possible, there is always the potential that they were not indexed in the database searched. This is further exacerbated by the small sample size of the included reports. In an effort to prevent confounding factors from interfering with the inferences that were made, case reports that mentioned concurrent infection with another pathogen or noted a variable (e.g., recent vaccination) that could have potentially contributed to the development of myocarditis or pericarditis were eliminated, which may have inadvertently excluded other relevant studies.

As this systematic review focused on analyzing a potential correlation between the timing of a young, immunocompetent patient’s stool culture result and their overall clinical course, it was limited to case reports that provided this specific information. Additionally, a young patient population was chosen to exclude older patients more likely to have comorbidities (for example, previous myocardial infarction, end-stage kidney disease, diabetes, autoimmune diseases, or malignancy), as certain factors are known to increase the risk of developing myocarditis and pericarditis to highlight the risk associated with C. jejuni. These conditions could have impacted patients’ clinical progression and possibly influenced the differential diagnoses considered by their medical providers, leading to their exclusion.

While all case reports identified were included, there were some reporting deficits identified by the JBI Critical Appraisal tool [15]. The majority of these studies either did not adequately describe the patient’s demographic characteristics [4, 6, 9, 11,12,13]or did not fully delineate the patient’s medical, family, and psychosocial history in addition to their relevant past interventions and/or outcomes [4, 6, 9, 11, 13].

Conclusion

Significant sequelae of Campylobacter include myocarditis and pericarditis, most commonly affecting young males. While this systematic review does not note a distinct relationship between the timing of obtaining a positive stool culture and a change in the patient’s clinical course, providers must recognize the importance of an early diagnosis in patients with concurrent gastrointestinal and cardiac symptoms. By avoiding specific cardiac imaging modalities that do not aid in diagnosing myocarditis and/or pericarditis, patients will ultimately be diagnosed sooner and have better clinical outcomes.