Unmasking the Unusual: Cryptococcal Pericarditis in a Patient with Liver Failure – a Rare Occurrence

Introduction

Cryptococcosis is an invasive fungal infection caused by Cryptococcus species complex. C. neoformans is one of the pathogenic species within the genus [1,2]. C. neoformans is a fungus that is widely distributed in the global environment. Humans can acquire C. neoformans infections by inhaling its basidiospore form or small, inadequately encapsulated yeasts [3]. C. neoformans infections are infrequently observed in immunocompetent individuals. It often presents as an opportunistic infection in severely immunocompromised individuals, including patient with human immunodeficiency virus (HIV) infection, malignancies, liver disease, and stem cell or solid organ transplantation [4]. Cryptococcosis occurring in individuals with end-stage liver disease has a high mortality rate [5]. The primary sites of C. neoformans infection are the lungs, leading to pulmonary cryptococcosis, as well as the central nervous system, resulting in meningoencephalitis [6]. Non-meningeal, non-pulmonary cryptococcosis generally reflects disseminated infection [7]. Infection of the pericardium in the setting of liver failure is uncommon. This report describes a 47-year-old man with alcohol use disorder, presenting with acute liver failure and a pericardial effusion associated with C. neoformans.

Case Report

A 47-year-old man with a past medical history of psoriatic arthritis and alcohol use disorder presented to the emergency department (ED) with a 2-week history of progressively worsening generalized malaise and weakness. He also had diffuse joint pain without associated erythema or joint swelling. Upon further questioning, he revealed that he usually consumes 7–8 cans (12 ounces per can) of beer daily. Additionally, he noted recent yellowish skin changes.

In the ED, his vital signs were: temperature 36.8°C, heart rate 128 beats per minute, blood pressure 126/73 mmHg, respiratory rate 24 breaths per minute, and oxygen saturation 95% on room air. The patient appeared ill, but was alert and oriented to person, time, place, and situation. His sclera was icteric, and his skin was jaundiced. The abdomen was distended, soft, and nontender, with positive shifting dullness.

Initial complete blood count (CBC) and comprehensive metabolic panel (CMP) in the ED revealed hemoglobin 12.3 g/dL, platelets 64×103/uL, sodium 118 mmol/L, aspartate transaminase (AST) 502 IU/L, alanine transaminase (ALT) 82 IU/L, total bilirubin 15.7 mg/dL, blood urea nitrogen (BUN) 6 mg/dL, and creatinine 1.66 mg/dL. The patient had a baseline creatinine level of 0.7 mg/dL. Lactic acid was elevated at 11.7 mmol/L. Coagulation studies revealed an international normalized ratio (INR) of 3.6 and a partial thromboplastin time (PTT) of 51 seconds. Blood alcohol was negative. Thyroid-stimulating hormone (TSH) and cortisol levels were both within normal limits.

Computed tomography (CT) of the abdomen and pelvis revealed hepatomegaly with hepatic steatosis, cholelithiasis, and ascites. The patient was given 1 liter of normal saline and was subsequently admitted for further management. A hyponatremia workup showed a serum osmolality of 252 mOsm/kg, urine osmolality of 293 mOsm/kg, and urine sodium of 11 mmol/L, consistent with hypovolemic hyponatremia. He was started on intravenous (IV) Ringer’s lactate. His abnormal liver function test was attributed to alcoholic hepatitis.

In view of the patient’s alcoholic hepatitis, the Maddrey discriminant function factor was calculated, and it was elevated at 179. The patient also underwent paracentesis, and fluid analysis suggested portal hypertension (serum ascites albumin gradient >1.1), with a total protein of 1.5 g/dL, likely indicative of ascites secondary to acute alcoholic hepatitis, with probable cirrhosis. The ascitic fluid cell count showed fewer than 250 polymorphonuclear leukocytes, and the culture came back negative. His blood culture results were also negative. Due to a low suspicion of infection, he was started on prednisone for alcoholic hepatitis.

Following his admission to the hospital, he developed acute liver failure, defined as development of severe acute liver injury for fewer than 26-week duration with impaired synthetic function (INR of ≥1.5), and altered mental status in a patient without cirrhosis or preexisting liver disease [8]. He became increasingly encephalopathic, exhibiting restlessness, agitation, and visual hallucinations. His INR continued to rise, reaching 6.1. AST increased to 609 IU/L, and ALT increased to 99 IU/L. Lactic acid increased to 14.6 mmol/L. He was eventually started on continuous renal replacement therapy to address lactic acidosis. Hyponatremia gradually improved with hypertonic saline. Due to the elevated INR and worsening anemia secondary to blood loss, he received fresh frozen plasma and vitamin K. Subsequently, the INR decreased to 3.1. Lactulose was also initiated for hepatic encephalopathy.

However, he continued to decline during his hospitalization. He developed acute hypoxic respiratory failure in the setting of worsening abdominal distension and was eventually intubated. Respiratory status improved with intubation and paracentesis, during which 3900 ml of ascitic fluid was removed. Fluid analysis again did not show consistency with spontaneous bacterial peritonitis, and an ascitic fluid culture was negative. A CT scan of the chest without contrast revealed bibasilar consolidation (with the right side greater than the left) and cardiomegaly with pericardial effusion (Figure 1). He also developed a fever with a temperature of 38°C. Steroids were discontinued, and he was started on broad-spectrum antibiotics for management of pneumonia.

A bedside point-of-care cardiac ultrasound conducted following intubation revealed a finding of pericardial effusion without signs of tamponade. A formal transthoracic echocardiogram (TTE) showed a large pericardial effusion (Figure 2A) with tamponade physiology (Figure 2B). Subsequently, he underwent percutaneous pericardiocentesis via apical approach, during which approximately 500 mL of pericardial fluid was removed. The pericardial fluid was sent for evaluation, including Gram stain, histology, bacterial and fungal culture, acid-fast bacillus (AFB) stain, and mycobacterial culture. Pericardial fluid cytology was negative for malignant cells. AFB stain and mycobacterial culture were both negative. The periodic acid-Schiff (PAS) stain (Figure 3A) and hematoxylin and eosin (H&E) stain (Figure 3B) were both positive for numerous yeasts, with the PAS stain demonstrating pink organisms with characteristic capsule and the H&E stain showing narrow-based budding yeast. The organism was definitively identified as Cryptococcus neoformans var grubii by matrix-assisted laser desorption ionization (MALDI). Blood cultures were negative. Lumbar puncture was not performed due to persistent coagulopathy with elevated INR. The serum cryptococcal antigen test was not done, as the diagnosis of cryptococcal pericarditis is equivalent to disseminated cryptococcal infection. He was started on IV liposomal amphotericin B. Human immunodeficiency virus (HIV) was ruled out by undetectable HIV RNA.

The patient continued to decline during his hospital stay, experiencing worsening liver function, with AST and ALT increasing to 7719 IU/L and 1378 IU/L, respectively. His total bilirubin increased to 33.3 mg/dL, INR increased to 6.7, and lactic acid also rose to 20.3 mmol/L. Thrombocytopenia worsened, with platelet levels decreasing to 24×103/uL. Recurrent blood loss anemia occurred, with evident rectal bleeding, and the hemoglobin level dropped to below 6.3 g/dL. Fibrinogen was also found to be low, at 35 mg/dL.

The patient was given additional fresh frozen plasma, packed red blood cells, cryoprecipitate, and platelet transfusion, resulting in mild improvement of the indices above. His hospital course was further complicated by the rapid accumulation of ascites, leading to worsening respiratory distress that necessitated 2 additional therapeutic paracenteses. There was also a recurrence of a large pericardial effusion requiring pericardiocentesis. Although a pericardial window was considered, it was deferred by the cardiothoracic team due to the patient’s significant hemodynamic instability. The patient became hypotensive and required 3 vasopressors – norepinephrine, vasopressin, and epinephrine. Given the guarded prognosis, the patient’s code status was changed to Do Not Resuscitate, and he eventually died.

Discussion

This case report highlights the critical importance of recognizing infectious pericarditis secondary to cryptococcal infection as the cause of pericardial effusion in a patient with a long history of heavy alcohol use presenting with liver failure. Timely diagnosis is essential for initiating appropriate treatment.

A significant portion of the population has been exposed to C. neoformans, as it is widely distributed in the environment [9]. Cryptococcosis is an invasive fungal infection caused by C. neoformans or C. gattii. The latter primarily exhibits a geographic concentration in South America and western Northern America, whereas the former is distributed globally [2]. Worldwide, approximately 1 million cases of cryptococcosis are reported annually, leading to around 625 000 deaths[10]. In the United States, the estimated incidence of cryptococcosis is approximately 0.4–1.3 cases per 100 000 population and 2–7 cases per 100 000 among individuals with AIDS [11]. C. neoformans infection often presents as an opportunistic infection in severely immunocompromised individuals. Immunosuppression is the major underlying mechanism, with AIDS being the most common immunocompromised conditions seen in patients with cryptococcosis [12,13]. Cryptococcosis typically becomes disseminated upon diagnosis in an HIV-positive patient [14]. Purulent pericarditis due to Cryptococcus species is rare but life-threatening [15]. Alcoholism can be a predisposing factor for disease caused by C. neoformans [16]. Liver cirrhosis has also been reported as a condition that can increase the risk of cryptococcosis. Our patient likely had underlying cirrhosis, given his history of chronic, heavy alcohol use. The presence of ascites was most likely secondary to decompensated cirrhosis. in Among patient with cryptococcal infection, those with decompensated cirrhosis have higher mortality risk than patients without decompensated cirrhosis [12].

Cryptococcus fungi are often discovered thriving in diverse environments, ranging from soil enriched with avian excrement to decomposing wood and the recesses of trees [17]. Inhalation of basidiospores or desiccated yeast cells from the environment is the primary route of acquiring C. neoformans infection. The initial infection is usually asymptomatic and remains contained in healthy individuals. In immunosuppressed individuals, the disease spreads from its initial site of infection through hematogenous dissemination [18]. Another mechanism for infection development is the reactivation of the organism at the original infection site after several years, once the patient becomes immunocompromised [17,18]. The pharmacological treatment for cryptococcal infections varies based on the infection site and severity of symptoms.

Alcohol, one of the most widely consumed substance in the United States, poses extensive health risks that affect both individual patients and the overall healthcare system. Alcohol use disorder is a medical condition characterized by the inability to stop or control alcohol use, even when it leads to negative social, occupational, or health outcomes [19,20]. Chronic alcohol consumption severely impacts the immune system by reducing the number and function of T and B cells, leading to increased susceptibility to both viral and bacterial infections [21]. Chronic alcohol use can lead to thiamine deficiency, resulting in Korsakoff syndrome, which is characterized by anterograde and retrograde amnesia. It can also cause peripheral neuropathy, gait abnormalities, worsen psychiatric conditions such as depression, and increase the risk of stroke and dementia [22]. Furthermore, alcohol significantly damages the liver, causing conditions such as fatty liver, alcoholic hepatitis, fibrosis, and cirrhosis, which can progress to liver failure or liver cancer [22,23].

There are multiple mechanisms behind liver disease being an independent risk factor for invasive C. neoformans disease. Patients with liver disease can experience a range of immune system impairments, including impaired cell-mediated immunity, phagocytic dysfunction, reduced antibody and immunoglobulin levels, and complement deficiencies, all of which can increase their susceptibility to disseminated cryptococcal infections [12,15,18,24].

Pericarditis secondary to C. neoformans is rarely reported in the medical literature, especially in patients with liver disease, as in our patient. Given the advancement of his liver failure, it is our conjecture that his compromised immune system led to the development of disseminated cryptococcal infection, ultimately resulting in infective pericarditis. Cryptococcosis in patients with cirrhosis has an alarmingly high mortality rate, reaching 81% [24].

Given the rarity of cryptococcal pericarditis, and the lack of substantial specific studies for individual body sites except for pulmonary and central nervous system (CNS) cryptococcosis, the optimal treatment for pericarditis remains uncertain [7,25]. Guideline from the Infectious Disease Society of America (IDSA) recommend treating non-meningeal, non-pulmonary cryptococcosis in non-HIV infected and non-organ transplant patients as CNS disease [7]. The guidelines from the World Health Organization also recommend treating disseminated cryptococcal disease in the same manner as meningitis [14]. The choice of drugs and the duration of therapy are determined by the severity of the disease, the response to treatment, and the patient’s immune status. Amphotericin B is one of the main drugs used as induction therapy, followed by fluconazole as consolidation and maintenance therapy [7].

Our patient was started on IV liposomal amphotericin B; unfortunately, due to the severity of his condition, he died before the effects of the treatment could be observed.

Conclusions

This report describes the case of an adult with alcohol use disorder who developed acute liver failure complicated by cryptococcal pericarditis. C. neoformans pericarditis in a patient with acute liver failure is rare. Atypical manifestations of fungal infections, including cryptococcal pericarditis, should always be considered in liver failure presenting with pericardial effusion. The primary route of Cryptococcus acquisition is thought to be through the pulmonary system. Typically, an asymptomatic or subclinical initial infection serves as the source for hematogenous dissemination, leading to its localization at other sites. Our case highlights the rarity and intricacies of cryptococcal pericarditis, a condition with a high mortality rate, necessitating swift recognition, diagnosis, and management through a multidisciplinary approach.