Purulent Streptococcus intermedius Pericarditis in the Setting of Histoplasma Mediastinal Lymphadenitis: A Case Report and Literature Review

Purulent pericarditis is a rare and potentially life-threatening condition characterized by infection of the pericardial space. We describe a case of purulent bacterial pericarditis in a 41-year-old male with no significant medical or surgical history who had concomitant pulmonary Histoplasma infection. Streptococcus intermedius was the bacteria directly responsible for the pericardial infection, though co-infection with histoplasmosis likely predisposed him to develop purulent pericarditis. We hypothesize histoplasmosis caused mediastinal lymphadenopathy, facilitating contact between a necrotic lymph node and the pericardium and contiguous suppuration of bacteria to the pericardial space. We treated S. intermedius and Histoplasma capsulatum with ceftriaxone and amphotericin B, respectively. Additionally, the patient presented in cardiac tamponade requiring emergent pericardiocentesis and drain placement. His course was also complicated by pericardial constriction. Cardiac magnetic resonance confirmed this, showing inflamed pericardium and abnormal septal motion with inspiration, and he had symptoms refractory to antimicrobials and anti-inflammatories. As such, he required pericardiectomy. This case demonstrates maintaining suspicion for secondary infectious foci as a contributor to the pathogenesis of purulent pericarditis is important, as pulmonary histoplasmosis played a pivotal role in allowing S. intermedius to spread to the pericardium but was not the primary infection. It also highlights the multifaceted evaluation and management of purulent pericarditis, highlighting the role of echocardiography and emergent pericardial drainage if cardiac tamponade is present, the importance of targeted antimicrobial therapy, the superior ability of cardiac magnetic resonance to identify pericardial constriction as a sequela of purulent pericarditis, and indications for pericardiectomy.


Introduction
Purulent pericarditis, defined as a local infection of the pericardial space with associated pus formation, is an uncommon but life-threatening diagnosis, with mortality of up to 20% to 30% even with treatment [1].Commonly implicated organisms include Staphylococcus aureus, Streptococcus pneumonia, Viridans group Streptococci, Haemophilus infuenzae, anaerobic bacteria, and tuberculosis [2].Pathways for pericardial infection include hematogenous spread, perforating chest injury, and contiguous extension from an intrathoracic process [3].Predisposing factors have changed over time.In the pre-antibiotic era, a major risk factor was a primary underlying infection (e.g., pneumonia or endocarditis), with 86% of patients having a primary infection as opposed to 22% in the post-antibiotic era [3].Risk factors in the modern era are more often comorbidities such as chronic kidney disease, immunosuppression, malignancy, or recent thoracic instrumentation [3].
Definitive diagnosis of purulent pericarditis itself rests on pericardial fluid analysis with the presence of grossly purulent pericardial fluid being 100% sensitive [2].Less invasive diagnostic modalities that should be employed first include transthoracic echocardiogram (TTE) for quantifying pericardial fluid and evaluating for tamponade [4].Cardiac tamponade is a potentially life-threatening compression of the cardiac chambers due to slow or rapid accumulation of fluid, pus, blood, or gas in the pericardium and is a rare but known sequelae of pericarditis [4].Another potential complication is constrictive pericarditis which is caused by the development of granulation tissue in the pericardium leading to decreased elasticity and impaired ventricular filling.This is generally a chronic process and tends to occur late after untreated or recurrent episodes of acute pericarditis.Adjunctive imaging such as cardiac magnetic resonance (CMR) is useful for diagnosing constrictive pericarditis and can show classic features such as pericardial inflammation, suggested by late gadolinium enhancement of the pericardium, and real-time paradoxical septal motion with respiration [5].
We present a case of acute purulent pericarditis caused by Streptococcus intermedius in a patient with underlying pulmonary histoplasmosis, emphasizing pulmonary histoplasmosis as a unique risk factor in the antibiotic era.Concomitant infection with pulmonary histoplasmosis caused mediastinal lymphadenitis, thereby creating an environment where an enlarged, inflamed lymph node infected with S. intermedius was in proximity to the pericardium.We further emphasize the multimodal evaluation and treatment for purulent pericarditis, including expeditious drainage and targeted antimicrobials, the utility of CMR when there is a concern for progression to constrictive pericarditis, and the possible need for pericardiectomy if pericardial constriction develops.We also review prior cases of S. intermedius purulent pericarditis in the medical literature, showcasing how the organism has been associated with a higher incidence of tamponade and early constrictive pericarditis.

Case Presentation
A 41-year-old male with no significant past medical history presented to an outside hospital emergency department with several days of severe pleuritic chest pain, dyspnea, and night sweats.His vitals showed a blood pressure of 86/54 mmHg, a heart rate of 110 beats/minute, a respiratory rate of 21 breaths/minute, and a temperature of 36.5°C.Marked jugular venous distension was present.Initial laboratory work is shown in Table 1 and was notable for elevated inflammatory markers and neutrophilic leukocytosis.Thoracic computed tomography (CT) imaging showed trace pericardial effusion, multiple pulmonary nodules, and mediastinal and hilar adenopathy (Figure 1A) with a necrotic precarinal lymph node (Figure 1B).

Result
Reference range   CT: computed tomography Notably, his presenting electrocardiogram (EKG) showed diffuse J-point/ST elevations in leads 1, avL, and V2-6 and he was taken for percutaneous coronary intervention (Figure 2).However, angiography showed normal coronary arteries.TTE performed post-procedurally demonstrated a moderate pericardial effusion with right ventricular diastolic collapse, consistent with tamponade (Figure 3).He underwent emergent pericardiocentesis and pericardial drain placement with a return of 350 mL of purulent fluid and stabilization of his hemodynamics.Given his pleuritic chest pain, EKG findings, and new purulent effusion, he was clinically diagnosed with acute purulent pericarditis.Empiric antibiotics including vancomycin, cefepime, and doxycycline were started.The decision was made to transfer the patient to a tertiary care center, at which time pericardial gram stain and cultures were pending.Blood cultures and a respiratory viral panel at the outside hospital were negative.The patient denied intravenous drug use, immunocompromising conditions or medications, or a history of thoracic instrumentation or radiation.He did describe recent travel to Kentucky with multiple zoonotic exposures, including temporary residence at a venue with free-range chickens and bats, as well as a visit to a petting zoo.He also reported work as an amateur arborist.

Complete blood count and differential
An extensive infectious workup was obtained to evaluate for the cause of pericarditis.Blood and fungal cultures were normal.Human immunodeficiency virus (HIV), tuberculosis, and syphilis were considered, although HIV, quantiferon gold testing, acid-fast bacilli pericardial fluid cultures, and rapid plasma regain testing, respectively, were negative.There was high suspicion for histoplasmosis given his exposure history, mediastinal/hilar lymphadenopathy, and lack of therapeutic response to broad-spectrum antibiotics and liposomal amphotericin B was started.At this time, a Histoplasma serum antigen was pending.
Notably, pericardial fluid cultures at the outside hospital returned positive for S. intermedius two days after transfer, and antibiotics were narrowed to ceftriaxone.The patient's pericardial fluid analysis is shown in Table 3. Source evaluation included a transesophageal echocardiogram (TEE) to assess for endocarditis which showed no intracardiac vegetation but did show evidence of fibrinous material and loculated fluid in the pericardial space (Figure 4).A dental examination was normal.A nuclear medicine positron emission tomography (NM PET) scan demonstrated hypermetabolic mediastinal and cervical lymph nodes, pericardial fluid (Figure 5A), and asymmetric 18-fluoro-deoxyglucose (FDG) uptake in the left palatine tonsil (Figure 5B).Pulmonary medicine was eventually consulted for bronchoscopy, as it was thought the previously seen necrotic precarinal node may have created a fistulizing tract for bacterial seeding of the pericardium; however, his airway examination was normal.

PET: positron emission tomography
Five days after transfer, his serum antigen test for Histoplasma returned positive and he was given a loading dose of itraconazole.Excluding his pericardial fluid analysis, the patient's infectious evaluation is shown in Table 4.In the following days, his fevers resolved, his pericardial drain output was less than 10 mL per day, and his pain and dyspnea improved.CMR showed normal systolic function and myocardium but also paradoxical diastolic septal motion during inspiration and enhancing, thickened pericardium consistent with constrictive pericarditis (Figure 6).Despite this, given his clinical stability and apparent improvement in his symptoms, it was felt reasonable to trial medical management with follow-up CMR in eight weeks and plans for pericardiectomy if this showed persistent constriction.His drain was removed after a successful clamping trial.His antimicrobial regimen at discharge included linezolid 600 mg twice daily for four weeks and a prolonged course of itraconazole 200 mg daily for three months.He was also discharged on colchicine 0.6 mg twice daily for three months and ibuprofen 800 mg three times daily for two weeks.

CMR: cardiac magnetic resonance
However, one day after discharge he presented again with recurrent fevers and chest pain.A TTE showed increased loculated pericardial fluid and fibrinous material and evidence of ongoing constrictive pericarditis (Figure 7).Given his persistent constrictive physiology and pericardial inflammation despite medical management, he ultimately underwent pericardiectomy with intra-procedural findings of thick, inflamed pericardium and fibrinous debris in the pericardial space.On discharge, his previous antimicrobial regimen of linezolid and itraconazole was continued and close follow-up with cardiology, cardiac surgery, and infectious disease was arranged.

Discussion
We describe a case of purulent streptococcal pericarditis which was likely abetted by underlying pulmonary infection with Histoplasma.Mechanistically, we believe the patient had either oral pharyngitis or tonsillitis from S. intermedius permitting lymphatic spread.In the setting of mediastinal lymphadenitis caused by pulmonary histoplasmosis, this created a route for S. intermedius to contiguously suppurate to the pericardium from a proximally infected lymph node.
Purulent pericarditis is rarely seen in the antibiotic era, with one retrospective study reporting 33 cases among a population of 593,600 [2].Presenting characteristics include fever, chills, tachycardia, and, more rarely, chest pain and the presence of a friction rub [2,4].The presence of pericardial effusion with macro-or microscopic pus is diagnostic, and cardiac tamponade is observed in 42% to 77% of patients based on previous case series and can cause life-threatening hemodynamic instability [1,2].Laboratory findings are nonspecific and include leukocytosis, anemia, and elevated inflammatory markers [6].
Regarding pathogenesis, one mechanism by which purulent pericarditis can develop is spread from intrathoracic processes [3], and pulmonary histoplasmosis commonly manifests with hilar and mediastinal adenopathy [7], as seen on this patient's chest imaging.Further, while S. intermedius is part of commensal oral flora and is generally considered low virulence, it has been reported as a cause of purulent pericarditis in immunocompetent hosts before [8,9].Given the asymmetric hypermetabolic activity in the left palatine tonsil on PET, the most plausible explanation is oropharyngeal infection by S. intermedius caused transient bacteremia, permitting infection of a lymph node close to the pericardial space.Pulmonary histoplasmosis contributed to this by causing mediastinal lymphadenitis, bringing one or several lymph nodes near and creating a route for S. intermedius to seed the pericardium.Another possibility is direct hematogenous seeding of the pericardium by S. intermedius, though this is less likely as the patient's blood cultures were repeatedly negative even before antibiotic initiation at the outside hospital.
S. intermedius is a member of the Streptococcus milleri group, which also includes Streptococcus constellatus and Streptococcus anginosus.They are traditionally classified as oral commensal bacteria but have been associated with opportunistic infections including abscesses affecting the cardiovascular, pulmonary, gastrointestinal, and central nervous systems [10].S. intermedius has been specifically implicated in brain, liver, lung, and orofacial abscesses, and less frequently pericarditis [10].These organisms are also capable of severe disseminated infection.The pathogenesis of multiple cases of S. intermedius bacteremia has been linked to disruption of the oral mucosal barrier in the context of either oral infection or instrumentation, allowing an invasion of the underlying tissue [10].
Overall, reports of purulent pericarditis due to S. intermedius are rare.We identified six previously reported cases on a search of the literature, with notable features summarized in Table 5 [9,[11][12][13][14][15].To our knowledge, this represents the seventh case of bacterial pericarditis caused by S. intermedius.Prototypical risk factors were absent in 3/7 (43%) cases [9,13,15].Cardiac tamponade was present in a majority of cases, occurring in 5/7 (71%) patients [9,[11][12][13]15].Pericardiocentesis was the initial method of pericardial drainage in all but one case.Notably, three patients developed pericardial constriction [9,13,15] and two underwent pericardiectomy [9,15] during their initial presentation.Only one case identified an obvious mechanism (a fistulizing tract due to esophageal carcinoma) for S. intermedius to spread to the pericardial space [12] while the remainder found no conspicuous source.Collectively, these reports show a majority of patients with reported occurrences of S. intermedius purulent pericarditis were immunocompetent and developed tamponade.They also demonstrate a nontrivial incidence of early-onset constrictive pericarditis requiring more invasive pericardial drainage such as pericardiectomy, similar to our case.While this is a limited sample, these reports suggest S. intermedius purulent pericarditis can occur in the absence of classic risk factors and may be associated with greater morbidity, including a higher incidence of tamponade and earlier progression to constrictive pericarditis.Definitive diagnosis of purulent pericarditis requires pericardial fluid analysis and samples should be sent for gram, acid-fast bacilli, and fungal stains; bacterial and fungal cultures; and a cell count with differential [4].This can assess for other known causes of purulent pericarditis including aerobic/anaerobic bacteria, tuberculosis, and Candida.Fluid studies typically show neutrophilic predominance, elevated lactose dehydrogenase, low glucose, and high protein [4].While we hypothesize histoplasmosis enabled pericardial seeding by S. intermedius, we do not suspect it was the primary cause of this patient's pericarditis.Histoplasma pericarditis is caused by a hypersensitivity reaction to yeast within the mediastinal lymph nodes and is associated with hemorrhagic, lymphocyte-predominant pericardial fluid [7,16,17] which was inconsistent with the fluid analysis here.

Reference
As in our case, purulent pericarditis is often accompanied by EKG findings consistent with acute pericarditis (i.e., diffuse ST elevations and PR depression throughout the precordial and limb leads) but may be normal in up to a third of presentations [4].Echocardiography can quickly and noninvasively quantify pericardial fluid and assess for tamponade [4].CMR has emerged as a highly useful aid for evaluating pericardial disease through its ability to characterize pericardial inflammation, effusion, myocardial involvement, and constrictive physiology [5].Of the various cardiac imaging modalities, it is helpful to assess for progression to constrictive pericarditis through its superior ability to assess the degree of pericardial thickening, the presence of inflammation with contrast enhancement, and to identify paradoxical diastolic septal motion with inspiration, which is a highly specific feature for constriction [5].It may also have an especially important role in differentiating pericardial effusions based on T1 and T2-weighted signal intensities; purulent effusions will typically manifest with low T1 but high T2 signal intensity [5].
Management consists of pericardial drainage and antimicrobials [6].Pericardiocentesis is often the most expeditious method of draining the pericardial space but more invasive and complete options include pericardiotomy, pericardiectomy, and video-assisted thoracic surgery [6].Notably, constrictive pericarditis can arise if pericardiocentesis is employed as the primary drainage method [2], which likely occurred in this case.Pericardiectomy entails removing as much of the constricting visceral pericardial layers as feasible while not damaging the phrenic nerves [4].It is the standard of care for pericardial evacuation in cases of chronic constrictive pericarditis refractory to medical management but also considered in the setting of loculated or reaccumulating pericardial effusion [4,18].We suspect the reason this patient presented again so quickly after his initial discharge was because he had persistent purulent pericarditis inadequately treated with pericardiocentesis and drain placement alone.This has been documented in prior case reports, especially when loculations and fibrinous material are present in pericardial fluid [19].As seen on this patient's TEE, both fibrin and loculations were observed in the pericardial space before pericardial drain removal and had an increased burden on readmission echocardiography.
Antibiotics should be directed against the causative organism.In this case, it was important to treat both the bacteria cultured from the patient's pericardial fluid and the histoplasmosis we felt predisposed him to infection.Treatment of Histoplasma usually consists of itraconazole but amphotericin B is recommended in severe or disseminated cases [20].As with other causes of pericarditis, nonsteroidal anti-inflammatory drugs and colchicine may prevent recurrence [4].

Conclusions
Purulent pericarditis carries high mortality and requires a multifaceted approach to evaluation and management.Urgent recognition with pericardial fluid analysis and treatment with drainage and antibiotics is imperative.Here, it was important to treat both S. intermedius and the patient's pulmonary histoplasmosis as we suspect the latter was a secondary infection that enabled the primary organism, S. intermedius, to suppurate to the pericardium.Additionally, echocardiography is indicated for detection and quantification of pericardial fluid and CMR is highly useful for evaluating the degree of pericardial disease and progression to constrictive pericarditis.When constrictive physiology develops, symptoms are refractory to medical management, and/or when the pericardial effusion reaccumulates or becomes loculated, more complete methods of pericardial drainage such as pericardiectomy may be necessary.In addition to highlighting the comprehensive treatment approach necessary to care for patients with purulent pericarditis, our case highlights the uniqueness of concurrent Histoplasma infection as a key risk factor in the antibiotic era and adds to the limited literature suggesting S. intermedius may be associated with more severe presentations of purulent pericarditis.

FIGURE 1 :
FIGURE 1: Chest CT showing (A) bilateral mediastinal and hilar adenopathy and (B) central area of low attenuation in the precarinal lymph node complex suggesting possible necrosis (yellow arrow).

Table 2
). Troponin levels peaked at 43 ng/L and normalized over the next two days.Test Result Reference range Complete blood count and differential Hemoglobin 10.8 g/dL 13.5-17.0g/dL White blood cell count 28.8 K/µL 4.0-10.0K/µL