Cell-Free DNA Reveals Hidden Streptococcus anginosus in Cryptogenic Purulent Pericarditis in a Young Adult

Introduction

Purulent bacterial pericarditis is uncommon, and its presentation as a primary site of infection is an extremely rare clinical situation [1]. Before the emergence and accessibility of antimicrobials, it presented mainly as a complication due to contiguity of a pulmonary infection. Currently, intrathoracic surgical procedures and manipulations and immunosuppression are the most common associated factors [2,3]. Streptococcus anginosus belongs to the Streptococcus anginosus group (SAG) – previously known as the Streptococcus milleri group – together with 2 other bacteria: Streptococcus constellatus and Streptococcus intermedius. They are found in the oral cavity, throat, nasopharynx, and gastrointestinal and genitourinary tracts of humans. They are generally prone to abscess formation or cryptogenic infections in various tissues and organs, making diagnosis challenging [4].

Cell-free DNA testing is a non-invasive method that, despite its limitations, has great potential for application in medicine, especially in cases of serious infections in which pathogens are not easily identifiable by traditional microbiological techniques [5].

Case Report

A 27-year-old man sought emergency medical care with fever, dry cough, and pleuritic chest pain without antalgic position that had started 1 week earlier. He denied recent air travel, trauma, or falls and reported alcohol abuse and daily use of marijuana and vaping. Physical examination was unremarkable. Laboratory tests showed a D-dimer level of 460 ng/mL, troponin level of 12 ng/L, white blood cell count of 21 000/μL, and C-reactive protein level of 30.68 mg/dL. The electrocardiogram demonstrated diffuse ST-segment elevation and PR-segment depression in lead II (Figure 1). Chest computed tomography (CT) showed no consolidations. Transthoracic echocardiogram (TTE) showed only laminar pericardial effusion. Blood cultures were collected, he was admitted, and ceftriaxone was administered. Cardiac magnetic resonance imaging showed only a pericarditis pattern with a small pericardial effusion. Pain and fever were controlled with ibuprofen and colchicine. On day 4 of hospitalization, nausea and frequent vomiting began. CT of the abdomen and pelvis did not identify any signs of infection or complication. TTE on day 5 showed a large pericardial effusion with signs of diastolic restriction of the right cavities and an echogenic images inside, suggesting clots. The patient was immediately transferred to the cardiology intensive care unit, where he developed pallor, sweating, jugular distension, and hypotension. Central venous access was obtained, and vasoactive amine was started. Emergency pericardiocentesis yielded 800 mL of straw-colored fluid, and a drain was installed. Antibiotic therapy was escalated to piperacillin/tazobactam. Biochemistry of the pericardial fluid showed an exudate pattern, while bacterioscopy, PCR for Mycobcterium tuberculosis, and general cultures were negative (Table 1). Two days later, TTE showed a localized, homogeneous echogenic image in the pericardial space, with persistent effusion and no signs of diastolic restriction. Inflammatory markers remained elevated. A pleuropericardial window was performed on day 8 of hospitalization, which revealed a significant amount of purulent material and fibrin in the pericardial sac (Figure 2). In this procedure, the previous drain was removed, and a new drain was placed and remained in place for 48 hours. Vancomycin was added to the antimicrobial regimen. Pericardial biopsy was negative for infection or malignancy. Cultures of the fluid and pericardial fragment were also negative. A comprehensive rheumatological panel was performed, including rheumatoid factor, antinuclear antibodies, complement components C3 and C4, anti-Smith antibodies, and anti-cyclic citrullinated peptide antibodies; all results were within normal limits. Serologies for cytomegalovirus, Epstein-Barr virus, Coxsackievirus B, syphilis, HIV, histoplasmosis, paracoccidioidomycosis, as well as the latex agglutination test for Cryptococcus, were negative. Cultures performed at the beginning of hospitalization were negative. Hormonal, renal, and hepatic function test results were within normal ranges. Cell-free DNA testing of a blood sample detected S. anginosus. The patient completed 28 days of intravenous antibiotics before hospital discharge. Weekly TTE, up to the date of discharge, showed a reduction in pericardial thickening and no signs of diastolic restriction on Doppler imaging of mitral inflow, tricuspid inflow, aortic inflow, or suprahepatic vein inflow. At the 6-month follow-up visit, he was asymptomatic. The last TTE showed preserved left ventricular diastolic function and significant improvement in the pericardial effusion with mild laterobasal parietal thickening in the left ventricle, without signs of pericardial adhesion or restriction.

Discussion

Purulent bacterial pericarditis is a rare disease with an acute and life-threatening presentation, with Staphylococcus aureus being the most common etiologic agent in more recent reviews, reflecting the era of widespread access to antimicrobials [3]. Nevertheless, population studies have shown a tendency for an increased incidence of bacteremia by SAG, and the cardiovascular complications caused by these agents may be underestimated in the literature, since the taxonomy of the group appears to be more complex and encompasses more subspecies [2].

Among the risk factors for SAG infections, the following stand out: diseases of the gastrointestinal tract, periodontal disease, neoplasia, diabetes, chronic kidney disease, smoking, and heavy alcohol and drug consumption [6,7].

In cases in which the etiology and focus of infection are difficult to identify, a review of the physical examination, symptoms, and imaging studies are essential. Our patient did not present with any specific gastrointestinal manifestations, nor did we find any concomitant systemic or infectious disease as a risk factor, nor any oral, dental or oropharyngeal disease. The focus of infection remained cryptogenic. There was a report of alcohol abuse, which could compromise the integrity and permeability of the intestinal mucosa and thus contribute to the translocation of bacteria or toxins. However, the scientific evidence in the literature is limited [8]. We found only 1 case of bacterial pericarditis caused by S. milleri in a patient who abused alcohol and tobacco and was recently diagnosed with lung cancer [9]. In the United States, there is a case report of a 29-year-old man with recurrent noninfectious myopericarditis without evidence of systemic inflammatory, infectious disease, or local trauma, and always after marijuana use [10]. Another 30-year-old man with no comorbidities except marijuana abuse also presented with pericarditis with moderate effusion that did not progress to tamponade or require drainage [11]. Other authors [12,13] have also warned about the use of marijuana and e-cigarettes as emerging causes of pericardial involvement in young people, but none of the cases progressed to bacterial pericarditis.

Bacterial purulent pericarditis may not present the classic symptoms of pericarditis, or it may present nonspecific symptoms of infection or sepsis. If not identified and treated quickly, it can progress to death. When adequately treated, mortality can reach 40% [3]. Notably, the patient in the present case initially presented with chest pain, ECG changes, and fever and had his symptoms controlled. Five days later, he presented with a large pericardial effusion with cardiac tamponade. The clinical course was challenging, as there were no more characteristic signs or symptoms of complicated infection. Immediate pericardial drainage and a subsequent pericardial window were essential for a good outcome.

Initially, treatment with a third-generation cephalosporin alone was used, considering a community-acquired bacterial infection. However, due to clinical deterioration and the need for pericardiocentesis on day 5 of hospitalization, the antibiotic regimen was escalated to also treat Pseudomonas aeruginosa and other hospital-acquired bacteria. Given the persistence of the pericardial effusion despite the antimicrobial escalation and its purulent appearance, the regimen was expanded to include more specific coverage of gram-positive pathogens. Since antimicrobial susceptibility testing was not available, even with the etiological agent identified by molecular methods, we decided to maintain the combination of piperacillin/tazobactam and vancomycin until hospital discharge.

We conducted a brief review (Table 2) of the literature on bacterial pericarditis caused by SAG and identified 30 cases [9,14–40], of which 9 were caused by S. anginosus, followed by S. milleri with 8 cases, considering the old nomenclature. Most patients were male;10 cases evolved to cardiac tamponade, while in 6 other cases, this complication was not reported. Approximately 37% of the cases were due to systemic infections, and only 1 patient reported alcohol and cigarette abuse. A review spanning 2 decades identified 33 cases of purulent pericarditis, of which 5 patients reported chronic diseases, such as alcohol abuse, rheumatoid arthritis, and ulcerative colitis; however, there is no specification of how many patients for each pathology. In this review, of the 33 cases, only 2 were attributed to S. milleri [38]. In a more recent review of 138 patients with infectious pericarditis, alcohol or drug abuse was not identified as a risk factor in the population, and viridans group Streptococcus were found in only 8 cases; it was not specified whether these belonged to the SAG [41].

In all cases studied, as well as in the cohorts described, microbiological diagnosis was possible due to the culture of biological materials, mainly pericardial fluid. In our case, we initially collected blood cultures for aerobic and anaerobic bacteria in the emergency department before initiating third-generation cephalosporins. During hospitalization, blood cultures were collected before each change in the antimicrobial regimen. In addition to the negative blood cultures, pericardial fluid cultures collected at different time points and pericardial fragment cultures were also negative. Tests for immunodeficiency, infectious, inflammatory, and autoimmune diseases were also unrevealing. The use of genomic testing was essential, as it allowed us to identify S. anginosus and continue with the current antimicrobial therapy, since other infectious agents could cause bacterial pericarditis but require another antibiotic or antifungal regimen. The cell-free DNA assay is a rapid and precise technique that enables the detection of circulating DNA fragments in the bloodstream. Its turnaround time ranges from minutes to a few days, depending on the methodology used. The assay demonstrates high specificity, particularly when using next-generation sequencing or digital PCR, which can differentiate cell-free DNA from genomic DNA based on fragment size and degradation patterns. However, contamination risks exist, especially when samples are not promptly processed or are affected by hemolysis. Proper collection, handling, storage, and analysis of the material were performed to ensure our results were reliable [42].

Conclusions

We presented a case of purulent bacterial pericarditis with a cryptogenic focus in a young adult patient with a history of alcohol, marijuana, and e-cigarette abuse. He developed cardiac tamponade but received rapid and adequate hospital therapeutic support, resulting in clinical recovery within weeks. Alcohol and smoking may have facilitated bacterial translocation from the oropharynx to the bloodstream and then to the pericardium. S. anginosus was identified only by molecular research.