Purulent Pericardial Effusion in a 14-Year-Old Girl

Abstract

A 14-year-old girl was brought to a local emergency department with complaints consisting of more than 5 weeks of fatigue, chills, intermittent cough, dyspnea, and pleuritic chest pain. Except for infrequent respiratory and ear infections, she had been previously healthy, and her immunizations were up to date. She was born in the United States and had never traveled outside the country. She had not had contact with animals and had no history of alcohol, tobacco, or illicit drug use. Her illness began with a week of cough, rhinorrhea, and occasional shortness of breath, but no fevers. Her symptoms quickly worsened to include fatigue, chills, and bilateral pleuritic pain on deep inspiration. She was seen by her pediatrician and was diagnosed with “pleurisy.” She was instructed to use warm compresses and ibuprofen for her chest pain and was prescribed a course of clarithromycin of unclear duration. Over the next week her symptoms did not abate, causing her mother to substitute the clarithromycin with amoxicillin-clavulanate, which had been prescribed for a sibling's prior illness. After developing fevers as high as 39.4°C for 3 days, she had a chest radiograph which revealed bilateral infiltrates “with enlarged heart,” and was treated with azithromycin. A tuberculin skin was nonreactive at 48 hours. She subsequently defervesced but continued to have dyspnea and fatigue. She then began to experience dysphagia, tachycardia, and left elbow pain that kept her awake at night. She was noted to have extremity swelling, most notably in her left arm. With progressively worsening symptoms and a weight loss of 20 lbs, she finally presented to a local emergency department. Physical examination was significant for jugular venous distension and pitting edema. A chest radiograph revealed cardiomegaly and bilateral pleural effusions. She was given furosemide and maintenance intravenous fluids, started on a dopamine infusion, and transported to the pediatric intensive care unit at Children's Hospital & Research Center Oakland. On admission to the pediatric intensive care unit, her temperature was 35.6°C, heart rate was 147 beats per minute, respiratory rate was 48 breaths per minute, and blood pressure was 100/58 mm Hg while on a dopamine infusion of 7 mcg/kg/min. She had an oxygen saturation of 95% on 2 L of oxygen per minute via nasal cannula. Her physical examination revealed a thin and pale girl with muffled heart sounds, bilateral crackles on auscultation of the lungs, hepatomegaly, and 2+ pitting edema of her extremities. Laboratory studies revealed white blood cell count of 13,400/mm3 (with differential of 69.7% neutrophils, 24.5% lymphocytes, 5.3% monocytes, 0.4% basophils, 0.1% eosinophils), hemoglobin of 10 g/dL, platelet count of 109,000/mm3, erythrocyte sedimentation rate of 34 mm/h, and C-reactive protein of 14.1 mg/dL. A transthoracic echocardiogram revealed a large amount of loculated, echo-dense pericardial fluid with good biventricular heart function while on dopamine. She was taken urgently to the operating room for placement of a pericardial window and blunt dissection of pericardial adhesions. Fifty milliliters of purulent pericardial fluid was drained, and the pericardium was noted to be extremely thickened (Fig., Supplemental Digital Content 1, https://links.lww.com/INF/A160). Postoperatively, she was treated with vancomycin and cefotaxime. Cultures of the pericardial fluid and pericardial tissue revealed the causative pathogen, prompting an infectious disease consultation. Denouement Continued from p. 1140. Cultures from the pericardial tissue and fluid both grew Aspergillus fumigatus in 27 hours. An infectious disease consultant immediately recognized the patient's family. The patient's youngest brother had been diagnosed with chronic granulomatous disease (CGD) 3 years earlier when he had presented with thigh and buttock abscesses due to Serratia. At that time, testing for CGD had been offered to all family members, but the parents declined, and the family was lost to follow-up. Nitro blue tetrazolium testing on the current patient showed no dye reduction, confirming that she, too, had CGD. Vancomycin and cefotaxime were discontinued and treatment with liposomal amphotericin B, voriconazole, and caspofungin was initiated. With the goal of augmenting her immune response, granulocyte infusions and gamma interferon (IFN-γ) were also added to her regimen. Two days after admission, the patient returned to the operating room for a median pericardiectomy and further debridement. The right hilum was densely adherent to the mediastinum. A transesophageal echocardiogram showed a 3-cm vegetation in her right atrium (Fig., Supplemental Digital Content 2, https://links.lww.com/INF/A161). Computed tomography of the chest on day 3 of hospitalization revealed widespread small nodular densities within the lung parenchyma, most prominently in the left lower lobe. Cavitations were also noted in the left lung base. The 3-cm mass in the right atrium extended from the inferior vena cava through right atrial junction to the superior vena cava (SVC) and was contiguous with the posterior and lower pericardium, suggesting direct extension into the heart from the lung and mediastinum (Fig., Supplemental Digital Content 3, https://links.lww.com/INF/A162). Open-heart surgery to debulk the vegetation was deferred because placement of cannulas necessary for cardiopulmonary bypass into the infected inferior vena cava and SVC was felt to carry a high risk of mortality. Over the next 2 weeks, the patient developed acute respiratory distress syndrome requiring intubation and mechanical ventilation. Her clinical course worsened with progressive renal failure and subsequent multisystem organ failure. She expired on the 14th day of her hospitalization. Chronic granulomatous disease was first described in 1957 as an inherited form of immunodeficiency characterized by recurrent pyogenic infections. According to the CGD National Registry,1 70% of CGD patients have the X-linked recessive (XLR) form of the disease while the remaining 30% have an autosomal recessive (AR) form. Today, the incidence of CGD in the United States is approximately 1 in 200,000–250,000 live births. The pathophysiology of CGD stems from a defect in 1 of 4 major structural and regulatory proteins of NADPH oxidase, resulting in the inability of phagocytes to generate reactive superoxide anions and their metabolites, such as hydrogen peroxide, hydroxyl anion, and hypohalous acid. These superoxide radicals and metabolites have important antimicrobial properties. Without the ability to produce these metabolites, patients with CGD are susceptible to infections, particularly those caused by catalase producing microorganisms. These catalase-positive organisms can resist killing by decomposing any remaining hydrogen peroxide into water and oxygen. The catalase producing organisms associated with infections in CGD patients include Serratia marcescens, Burkholderia cepacia, Aspergillus, Klebsiella, Candida albicans, and Salmonella. Pneumonia and sepsis from Aspergillus are the most common causes of death among patients reported to the CGD National Registry. The most common manifestation of invasive aspergillosis (IA) is invasive pulmonary aspergillosis. After seeding of the lungs by conidia, vessel invasion occurs, followed by thrombosis, infarction, and necrosis of the surrounding lung tissue. Pulmonary hemorrhage is often seen in invasive pulmonary aspergillosis. Other sites of IA include the sinuses and upper respiratory tract, bones, brain, and skin. Disseminated disease occurs either by hematogenous spread to distant sites (eg, thyroid, liver, spleen, kidney, bone, heart, and skin) or by contiguous extension from the lungs. Hematogenous spread is common in patients with severe immunosuppression. By far the most common Aspergillus species causing disease is A. fumigatus, making up almost 2/3 of all isolates.2 Although less commonly reported, Aspergillus nidulans is more likely to involve adjacent structures and disseminate, and is generally more refractory to intensive antifungal therapy. Thus, A. nidulans actually leads to higher mortality in CGD patients than A. fumigatus.3 The clinical presentation of IA in patients with CGD differs slightly from that seen in other groups of immunocompromised patients. In a review of aspergillosis in CGD patients, 1 in 3 were asymptomatic at diagnosis and only about 20% had fever. In comparison with neutropenic patients, the course of IA in CGD is more indolent, frequently with local spread of infection to ribs, spine, or long bones.5 One of the unique aspects of our case was the extensive Aspergillus infection involving the heart. Among immunocompetent hosts, Aspergillus infections of the myocardium and pericardium are extremely rare and are generally associated with a history of open-heart surgery. In patients with immunodeficiencies or malignancy, Aspergillus is also an uncommon but lethal cause of pericarditis and is generally associated with disseminated disease, though local extension from pulmonary disease can also occur.5 In a review of 28 case reports involving Aspergillus pericarditis, there were 16 patients with hematologic malignancies, 1 patient with a heart transplant, 2 patients with AIDS, and only 2 patients had CGD.6 The other 7 patients did not have well-defined underlying conditions predisposing to IA. Aspergillus pericarditis and myocarditis were not common enough to be reported as separate entities in the CGD National Registry. Pneumonia was the most prevalent disease (79%) among CGD patients, and Aspergillus was the most commonly isolated pathogen (41%) among CGD patients with pneumonia. The major complication of Aspergillus pericarditis is the development of purulent pericardial effusions and cardiac tamponade.7 Our patient had both lung and cardiac involvement, as demonstrated by computed tomography of her chest. Presumably, an initial pulmonary site of infection led to eventual hematogenous or direct extension into the patient's pericardium, epicardium, myocardium, and endocardium, resulting in an endocardial vegetation. Many of the earliest descriptions of cardiac tissue infections from Aspergillus came from autopsies in disseminated cases of IA. The first report of an Aspergillus infection involving the heart of a child with CGD was in 1982 by Chudwin et al.8 In this series, 4 patients diagnosed with CGD developed biopsy proven Aspergillus pneumonia. One of the patients was hospitalized at 3 1/2 years of age after presenting with abdominal pain and malaise. A chest radiograph revealed cardiomegaly with pericardial effusion. Pericardiocentesis yielded sterile serous fluid. At 6 years of age, the same patient developed 3 weeks of fever, cough, abdominal pain, and was hospitalized. Chest radiograph then revealed cardiomegaly, bilateral pulmonary infiltrates, and both pleural and pericardial effusions. Biopsy of pericardial and lung tissues grew A. fumigatus. His condition rapidly deteriorated despite treatment with amphotericin B and daily granulocyte infusions. Disseminated A. fumigatus involving the lungs, pericardium, liver, kidneys, spleen, thyroid, and brain was found at autopsy. This patient also developed lung and cardiac involvement, positive cultures for A. fumigatus from pericardial biopsy, and death within weeks despite treatment with amphotericin B and granulocyte infusions. In 1996, Casson et al reported the first case of Aspergillus endocarditis in a pediatric patient with CGD.9 This 3-year-old girl was diagnosed after suffering from unexplained fevers, failure to thrive, cough, heart murmur due to an atrial septal defect, and hepatosplenomegaly. A borderline positive Mantoux test resulted in a presumptive diagnosis of tuberculosis and she was treated with antituberculous medications with no improvement of symptoms. Subsequent liver biopsy demonstrated granulomata and a Nitro blue tetrazolium test showed no dye reduction. Due to continued weight loss and repeated negative bacterial and fungal cultures, it was felt that bone marrow transplantation for treatment of the patient's CGD was indicated. During closure of her atrial septal defect (to prevent paradoxical emboli), in preparation for a bone marrow transplantation, marked pericarditis, as well as a right atrial mass, were unexpectedly discovered. She later underwent surgical removal of this mass, which on culture grew A. nidulans. Subsequent blood cultures grew A. nidulans and the mass recurred, obstructing the SVC. She died 24 days after the surgery. Another interesting aspect of our case was the patient's late age (14 years old) at presentation and diagnosis with CGD. The majority of patients with CGD (76%) are diagnosed before 5 years of age, but up to 10% are diagnosed in the second decade of life. Older age at diagnosis is more commonly seen in patients with the AR forms of CGD, among whom 24% are diagnosed in the second decade of life and 9% even later. In contrast, the XLR form of CGD is diagnosed in the second decade in only 5% of cases and beyond this in only 1%. Consistent with these data, genetic studies revealed that our patient had an AR form of CGD. Another teenaged brother was also found to have CGD, while her 2 sisters and parents were identified as carriers. The patient's mother and father were first cousins, and their family has a long history of consanguineous unions. The CGD National Registry shows that there are other phenotypic differences that exist between these forms of CGD. The XLR form of CGD (as compared with the AR form) is associated with higher prevalence of perirectal abscess, suppurative adenitis, and bacteremia/fungemia. The XLR form of CGD also had a statistically significantly higher mortality of 21.2%, compared with the AR form with 8.6%. Five-year follow-up data were analyzed, and survival estimates showed a slightly greater survival for the AR form (88% vs. 76%), but this was not statistically significant. Aspergillus infections were the most common causes of death in both forms. Although rates of IA were not explicitly reported, both XLR and AR forms of CGD had similar rates of pneumonia (XLR, 41% vs. AR, 47%) and osteomyelitis (XLR, 25% vs. AR, 18%) due to Aspergillus. Treatment of IA, particularly in patients with CGD, remains a challenge. In the past, favorable responses to amphotericin B deoxycholate therapy were seen in about 40% of patients with pulmonary IA, but overall mortality rates remain high at 60%. Both itraconazole and IFN-γ have been shown to be effective in prophylaxis against invasive fungal diseases in CGD patients.10,11 In some case reports, IFN-γ has also been used as adjunctive therapy for CGD patients with IA.12 Granulocyte transfusion has been reserved for CGD patients with life threatening infections not responding to antimicrobials. However, a retrospective analysis found no significant reduction in the rate of persistent infection or death from pulmonary or disseminated fungal infection in CGD patients treated with granulocyte transfusions along with antifungal therapy.13 Over the past decade, newer antifungals have become available and have expanded the armamentarium against IA. Voriconazole, a potent, broad-spectrum triazole, is now recommended as primary therapy for most patients with IA. A large study involving 277 patients with IA concluded that initial therapy with voriconazole resulted in improved survival rates and fewer side effects than with amphotericin B deoxycholate.14 None of the patients in this study had a diagnosis of CGD. Caspofungin, which inhibits glucan synthase and disrupts formation of fungal cell walls, is also approved for treating patients refractory to or intolerant of standard therapies for IA. There are a handful of case reports describing successful treatments of IA in CGD patients using voriconazole, posaconazole (another broad spectrum triazole), and caspofungin.15,16,17 Currently there are insufficient data to show that these newer agents improve mortality in CGD patients with IA.