Disseminated Cryptococcus neoformans infection in a left ventricular assist device recipient

Abstract

A 51-year-old man with a medical history of coronary artery disease and dyslipidaemia presented with acute myocardial infarction resulting in cardiogenic shock, necessitating intra-aortic balloon pump placement and extracorporeal membrane oxygenation (ECMO). His hospital course was complicated by several infectious complications including ECMO circuit Pseudomonas aeruginosa bloodstream infection and presumed infected right atrial thrombus. He subsequently underwent urgent left ventricular assist device placement and had a prolonged hospital stay. On day 100 of admission, he developed acute hypoxic respiratory distress with new pulmonary infiltrates. Sputum cultures grew Cryptococcus neoformans. Blood culture also grew C. neoformans after 96 hours of incubation and cryptococcal serum antigen was elevated at 1:20. Cerebrospinal fluid studies from a lumbar puncture were normal. He was treated with 2 weeks of combination antifungal therapy followed by life-long fluconazole suppression.

Background

Disseminated cryptococcal infection is classically seen in the immunocompromised host, most commonly in patients with a low CD4 count consistent with AIDS as well as haematological malignancies. Disseminated infection usually involves the central nervous system (CNS), bloodstream and pulmonary system. However, other visceral organs can be involved as well. Non-HIV-related cryptococcosis is usually secondary to the subspecies Cryptococcus neoformans; however, it can also been seen with C. gattii. We present a case of disseminated cryptococcosis in an HIV negative patient receiving left ventricular assist device (LVAD) therapy. This is the first reported case of disseminated cryptococcal infection in an LVAD recipient and highlights risk of opportunistic infections due to immune system dysfunction after LVAD implantation.¹

Case presentation

A 51-year-old man with a medical history of coronary artery disease (CAD), dyslipidaemia and essential hypertension, presented with an acute ST-segment elevation myocardial infarction resulting in cardiogenic shock. He required haemodynamic support with an intra-aortic balloon pump (IABP) and percutaneous intervention of his left anterior descending coronary artery. His hospital course was complicated by acute critical right lower limb ischaemia due to IABP support, requiring four-compartment fasciotomy. He was then converted to V-A extracorporeal membrane oxygenation (ECMO) support. He subsequently developed severe sepsis due to ECMO circuit associated Pseudomonas aeruginosa bloodstream infection. Echocardiography at that time also revealed a new, presumably infected, right atrial thrombus. Despite broad-spectrum antimicrobial therapy, he continued to have positive blood cultures due to our inability to de-cannulate the ECMO circuits. Therefore, it was decided to urgently refer him for LVAD placement as destination therapy. The LVAD was successfully placed. During LVAD implantation, his right atrial thrombus was removed as well and sent for routine bacterial cultures, these cultures remained negative likely due to ongoing antimicrobial therapy. The thrombus was not sent for further investigations to histopathology. Post LVAD implant blood cultures were negative and he was subsequently placed on chronic oral suppressive therapy with ciprofloxacin. Due to prolonged open chest from a subcutaneous haematoma of his chest wall, he received 2 weeks of prophylactic antifungal therapy with intravenous caspofungin at 50 mg every 24 hours.

The patient was stabilised and transferred from the heart failure intensive care unit to the general ward unit at approximately hospital day 90. His chest wall healed, and his chronic tracheostomy site was de-cannulated. At approximately day 100 of his hospital course, he began to have spontaneous profound epistaxis with increasing leukocytosis of unknown aetiology. Positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro-d-glucose integrated with CT (¹⁸F-FDG PET/CT) revealed a new left lower lobe infiltrate, but no other nodular opacities (figure 1). Imaging also did not show other end organ involvement however there was uptake around the LVAD device itself. His antibiotic coverage was expanded from oral ciprofloxacin to piperacillin/tazobactam due to concern for aspiration pneumonia. Unfortunately, his clinical condition declined, and he went into hypoxic respiratory failure. He was emergently intubated and transferred back to the intensive care unit.

Figure 1.

Positron emission tomography/CT image showing consolidative process in the posterior left lower lobe, most consistent with pulmonary infection.

Investigations

Due to rapid respiratory decline, patient underwent a swab of his previous tracheostomy de-cannulation site, which grew C. neoformans. He subsequently grew C. neoformans from one blood culture set (defined as two peripheral blood culture bottles) after 96 hours of incubation and also had a positive serum cryptococcal antigen titer of 1:20. Sputum culture also grew C. neoformans. He underwent a lumbar puncture with negative India ink stain, cryptococcal antigen and fungal culture of his cerebral spinal fluid (CSF). CSF analysis is detailed in table 1.

Table 1.

Cerebral spinal fluid studies

CSF studies	CSF results	Normal values
Appearance	Clear, colourless	Clear
Protein (mg/dL)	103	15–60 mg/dL
Glucose (mg/dL)	53	40–80 mg/dL
TNC (μL)	2	0–5/μL
Lymphocytes (%)	94%	–
Cryptococcal CSF Ag	Negative	Negative
RBC (10 12/L)	1	<5 RBC/10 12/L
Opening pressure (mm H2O)	220	70–200 mm H2O
Fungal culture	Negative	–

Ag, antigen; CSF, cerebral spinal fluid; RBC, red blood cell; TNC, total nucleated cell count.

Treatment

Due to evidence of disseminated cryptococcosis, the patient was started on induction therapy with flucytosine (5-FC) at 50 mg/kg/day orally in four divided doses and liposomal amphotericin B (AmBisome) at 5 mg/kg every 24 hours. He had a rapid clinical response, with decreasing leukocytosis, clearance of blood cultures, subsequent extubation and stabilisation to the ward floor.

Outcome and follow-up

After 2 weeks of induction therapy, he was continued on high-dose oral fluconazole therapy at 800 mg once daily and reduced to 400 mg once daily thereafter indefinitely. He was also continued on indefinite oral therapy with ciprofloxacin as his LVAD was placed urgently during an active Pseudomonas bloodstream infection. He has done very well as an outpatient with no further recurrence of his fungal or pseudomonas infection. A follow-up (¹⁸F-FDG PET/CT) was performed 8 weeks postinduction therapy with AmBisome and fluconazole with near complete resolution of his left lower lobe infiltrate.

Discussion

We describe an unusual case of disseminated cryptococcosis in a patient receiving LVAD therapy. Cryptococcosis is an invasive fungal infection that is primarily acquired by inhalation and causes pulmonary infection. However, CNS and other organ systems may get infected via haematogenous spread. The two most common species causing human infection are C. neoformans and C. gattii, and infection most commonly occurs in immunocompromised patients.² These include patients with AIDS, chronic liver disease, haematologic malignancy, solid organ transplant recipients and those treated with immunosuppressive medications such as steroids. With the advent of highly active antiretroviral treatment for HIV, cryptococcosis is now being more recognised in non-HIV patients. A retrospective study by Pappas et al, identified 302 patients diagnosed with cryptococcosis between 1996 and 2010. Among these patients, 36% were HIV-positive, 28% were organ transplant recipients and 36% were non-HIV and non-transplant patients.³

The severity of clinical presentation is determined by burden of exposure, virulence of the strain and patient-specific characteristics. Clinical presentation may be subacute or asymptomatic. Non-immunocompromised patients are more likely to develop pulmonary cryptococcosis as their primary manifestation of disease when compared with immunocompromised hosts, as seen in our clinic scenario.⁴

Review of published literature did not identify any published cases of disseminated cryptococcosis in LVAD patients. However, opportunistic infections such as cryptococcosis, should be considered in the differential diagnoses in these high risk patients as they are considered to be on the spectrum of an immunocompromised host. LVAD recipients may develop progressive defects in cellular immunity by loss of Th1-producing CD4 T-cells through activation-induced cell death and secondarily by unopposed activation of Th2-producing CD4 T-cells resulting in B-cell hyperactivity and the subsequent dysregulation of immunoglobulin synthesis.^{1 5 6} Furthermore, our patient presented with a normal absolute lymphocyte count (ALC), but 3 days post-LVAD implantation, he was shown to have an ALC of 890 cells, which is defined as mild to moderately immunosuppressed by current definitions in the literature. Immunosuppression in our patient was likely multifactorial, including immune dysregulation due to LVAD, severe sepsis, cardiogenic shock and critical illness.

As the use of LVADs are being increasingly used in advanced heart failure patients, device-related infections are becoming more common. LVAD infections can be categorised as VAD-specific, VAD-related and non-VAD related as per the International Society of Heart and Lung Transplantation guidelines. VAD-specific infections include pump and cannula infections, pocket infections and percutaneous driveline infections, VAD-related infections include examples such as mediastinitis, infective endocarditis and catheter-related infections and non-VAD infections are defined as those infections that are not related to the VAD device itself, examples include infections such as pneumonia and urinary tract infections. Common risk factors include increased body mass index and younger age, however our patient did not fall under these categories.⁷ Our patient’s primary diagnosis was cryptococcal pneumonia in the setting of positive sputum culture with invasive disease defined as two positive blood cultures and antigenaemia. There is a strong likelihood that he had previously unknown cryptococcal pneumonia with reactivation in the setting of moderate immunosuppression post LVAD implantation.

The most common imaging modalities to date are cardiac ultrasonography or CT imaging to evaluate for device-related infection, however nuclear imaging using positron emission tomography (PET)/CT has now come to the forefront of diagnostic testing. A recently published retrospective study in the Journal of Nuclear Cardiology revealed that PET/CT scanning showed significantly higher sensitivity when compared with radio-labelled leucocyte scan.⁸ When compared with CT imaging, another prospective study showed that PET/CT imaging was a useful technique for identifying LVAD infection and determining the site and pattern of infection which had significant downstream effects for mortality and patient outcomes.⁹

Lastly, management of disseminated cryptococcal infection largely depends on burden of disease, host immunity and dissemination to the CNS, especially in the immunocompromised host. Usually treatment includes an induction phase with AmBisome and 5-FC and a subsequent consolidation/maintenance phase with an oral antifungal agent such as fluconazole. In this particular case, indefinite fluconazole oral therapy was chosen due to initial antigenaemia and concern for secondary seeding of the cardiac device.

Learning points.

• Cryptococcal infection is increasingly being seen in phenotypically normal immunocompetent hosts.

• Left ventricular assist device (LVAD) recipients are more likely to be on the spectrum of immunocompromised due to T- and B-cell dysfunction.

• Clinicians should have strong index of suspicion for opportunistic infections in LVAD recipients as delay in diagnosis and initiation of therapy could be devastating in this patient population.

• Patient with pulmonary cryptococcosis should undergo lumbar puncture for central nervous system infection as it has a major impact on choice and duration of antifungal therapy.

• Published literature on nuclear imaging such as positron emission tomography/CT has shown promise on identifying early infection in LVAD recipients, including infection that was not previously seen on standard of care imaging modalities.