EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Cryptococcosis is the third most common invasive fungal infection in solid-organ transplant recipients. Patients with cirrhosis are susceptible to pretransplant cryptococcosis infections. Outcomes and optimal treatment of patients with cirrhosis who develop pulmonary cryptococcosis before and after liver transplant are still not defined. Here, we describe a case of cholestatic cirrhosis in a 50-year-old woman with a pretransplant asymptomatic pulmonary nodule. She had taken steroids for more than 1 year before she was admitted to our hospital. This asymptomatic case with a lung nodule was detected via an abnormal chest computed tomography. Cryptococcal pneumonia was diagnosed according to lung biopsy results. Testing for cryptococcal antigens was negative in the serum. The patient received antifungal therapy with amphotericin B followed by oral fluconazole, which was then followed by liver transplant. After antifungal therapy with fluconazole posttransplant, a sustained clinical response was achieved. After literature review of patients with pulmonary cryptococcosis before and after liver transplant, we identified previously reported cases with pulmonary cryptococcosis that resembled lung nodule on imaging. In this report, we aimed to raise the awareness of unrecognized pretransplant cryptococcosis infections in patients with cirrhosis who are waiting for liver transplant and showed the successful management of a patient with pretransplant pulmonary cryptococcosis.

Key words : Autoimmune hepatitis-associated cirrhosis, Immunosuppression, Invasive fungal infections, Lung nodule

Cryptococcosis is an encapsulated yeast-like fungus found in soil and decayed wood contaminated by bird feces.¹ Cryptococcosis, which is the third most common invasive fungal infection (IFI), continues to be a source of morbidity and mortality among solid-organ transplant (SOT) recipients.² Pulmonary cryptococcosis is caused by the inhalation of fungal spores into the respiratory tract.³ Immune suppression is the major underlying mechanism that is involved in the causation of cryptococcal disease. Diseases such as AIDS, diabetes, chronic liver disease, and chronic renal disease, as well as prolonged use of steroids and organ transplant, are commonly associated with the development of cryptococcal disease. The clinical and radiographic features of pulmonary cryptococcosis are quite nonspecific. In this report, we present a case of pulmonary cryptococcosis in a recipient who had a successful outcome after treatment before and after liver transplant.

A 50-year-old female patient who was being evaluated for liver transplant for autoimmune hepatitis-associated cirrhosis was diagnosed with pulmonary cryptococcosis. A computed tomography (CT) scan of her chest showed one possible malignant nodule in the upper-right field of her lung (Figure 1A). She had no respiratory symptoms or neurological involvement. She had no fever, headache, or abdominal pain. She had taken steroids for more than 1 year before she was admitted to our hospital, which is an important risk factor for cryptococcosis. She had no exposure to pigeons or caged birds.

Physical examination of the chest revealed clear breathing sound without wheezing or crackle. Her laboratory tests showed that tumor markers of blood, including carcinoembryonic antigen, cancer antigen 19-9, alpha-fetoprotein, squamous cell carcinoma, and neuron-specific enolase, were all normal, but her CA125 level was slightly increased (66.10 U/ml; reference value is < 35 U/ml). After that, a tuberculosis infection T-cell spot test (T-SPOT.TB; Oxford Immunotec, Abingdon, UK), tests for serum galactomannan and (1,3)-β-D-glucan, and blood culture were performed, but the results were all negative. Serology for human immunodeficiency virus was negative. Blood culture tests for aerobes and fungi were also negative. A positron emission tomography-CT scan showed higher uptake values of fluorodeoxyglucose in the upper right lobe of her lung, indicating the possibility of a malignant tumor (Figure 1B).

To treat the lung nodule, thoracoscopic pulmonary wedge resection was performed, which revealed the nodule to be cryptococcosis infection. A histopathologic examination of the biopsy from the pulmonary nodule showed granulomatous inflammation without tumor cells, and positive periodic acid-Schiff, mucicarmine, and Grocott methenamine silver stains suggested pulmonary cryptococcosis (Figure 2). The capsules of the observed organisms could be visualized by hematoxylin and eosin, periodic acid-Schiff, mucicarmine, and Grocott methenamine silver staining. This indicated the diagnosis of cryptococcal pneumonia instead of a malignant tumor.

We took a lumbar puncture to exclude cryptococcal meningitis. There was no other evidence of cryptococcal disease on clinical examination. One week after thoracoscopic pulmonary wedge resection, a chest scan showed consolidation in the right lung (Figure 3A). After histological diagnosis, initial therapy with intravenous liposomal amphotericin B (0.7 mg/kg/day) plus flucytosine (100 mg/kg/day) was given as antifungal therapy. After antifungal therapy for 2 weeks, a chest CT scan was performed to evaluate the therapeutic effects. This CT scan showed decreased consolidation in the right lung (Figure 3B).

Four months after being diagnosed with cryptococcosis disease, the patient underwent a deceased donor orthotopic liver transplant. Over a 4-month follow-up, the patient had esophageal-gastric fundus variceal bleeding once. Her posttransplant course was uncomplicated. During her posttransplant course, she received an antifungal agent with daily intravenous liposomal amphotericin B (0.7 mg/kg/day) for 6 weeks, followed by consolidation therapy with oral fluconazole (400 mg/day) for 8 weeks. She did not receive immunosuppression-inducing agents. On postoperative day 13, a chest CT scan showed a hyperdense lesion in her right lung. After consolidation, maintenance treatment with oral fluconazole (200 mg/day) was prescribed for 6 months.

At 15 months posttransplant, a chest CT scan showed new ground-glass opacities in the right lobe without any other symptom (Figure 3C). After other infections were excluded, the patient was treated with a 3-month course of oral fluconazole 400 mg daily, which led to a sustained clinical response. At 21 months after liver transplant, a chest CT scan showed great improvement in the lesions of the right lung (Figure 3D). The patient was monitored with regular CT examinations, and no recurrence was shown with good graft function 25 months after liver transplant.

Cryptococcosis is a ubiquitous encapsulated yeast that is primarily an opportunistic pathogen in immunocompromised patients. The general incidence of cryptococcosis in SOT recipients ranges from 0.2% to 5%.⁴ Human immunodeficiency virus infection, liver cirrhosis, systemic lupus erythematosus, malignancy, diabetes mellitus, sarcoidosis, and glucocorticoid therapy after SOT are underlying conditions known to increase the risk of cryptococcosis.⁵ T-cell depleting antibodies such as alemtuzumab and antithymocyte globulin can cause profound lymphocyte depletion of CD4-positive T cells and can play a critical role in controlling human cryptococcal infections.⁶ The release of granulysin by cytotoxic CD4-positive and CD8-positive cells and perforin by natural killer cells probably has a role in the effective killing of Cryptococcus species.⁷

Patients with cirrhosis are at a particularly increased risk of having an unrecognized pretransplant cryptococcosis infection because of cirrhosis-associated compromised host defenses.^8,9 This suggests that cryptococcosis should be considered early in patients with end-stage liver disease who present with suspected infections.^9,10 All liver transplant recipients with suspected or proven cryptococcosis should have a thorough evaluation for extrapulmonary disease, including a lumbar puncture, blood tests, and other relevant tissue cultures. Pulmonary infection is a common manifestation of cirrhosis-associated cryptococcosis. Cirrhosis-associated cryptococcosis often has a strikingly high mortality rate. Increasingly, cryptococcosis has been diagnosed in patients with cirrhosis who were transplant candidates and waiting for liver transplant.¹¹ Practical clinical approaches for the management of patients with cirrhosis and cryptococcal disease during transplant selection, to give the patient an appropriate treatment, include evaluation of the appropriate time for transplant, determination of whether the patient can undergo liver transplant, postoperative management, including with regard to immunosuppressive regimens, antifungal agents, and duration of prophylaxis, disease progression or relapse, and allograft rejection.

Pulmonary cryptococcosis is a common IFI frequently seen in immunocompromised patients. Diagnosis of pulmonary cryptococcosis is difficult because of nonspecific clinical signs and radiographic changes. Occult infections may manifest as life-threatening, disseminated cryptococcosis after liver transplant. Pulmonary cryptococcosis manifestations range from asymptomatic colonization or a simple pulmonary nodule on chest radiography to severe pneumonia with respiratory failure. Solitary or multiple nodules with or without cavitary infiltrates are the main radiographic findings of pulmonary cryptococcosis. Nodular pneumonia is the most common presentation of pulmonary cryptococcosis in SOT patients. The serum cryptococcal antigen test has a relatively high sensitivity for detecting cryptococcal meningitis but has a lower diagnostic efficiency for isolated pulmonary cryptococcosis (approximately 50%).¹² (1,3)-β-D-glucan test can be used for many IFIs, such as candidiasis and aspergillosis, but cannot be used for cryptococcus infections.¹³

In our case, the patient had taken glucocorticoids for more than 1 year before she was admitted to our hospital. Her burden of pulmonary cryptococcosis before liver transplant was clearly attributed to the dysfunction of defensive mechanisms due to cirrhosis and the use of immunosuppressive agents. Early diagnosis of pulmonary cryptococcosis in patients with cirrhosis is difficult due to the lack of specific clinical and radiological findings and the fact that pulmonary cryptococcosis can present as a lung mass that mimics lung cancer. Both tissue biopsy and culture are necessary for a definite and rapid diagnosis. Pathologic confirmation is critical in the management of pulmonary cryptococcosis. Our report suggests that liver transplant may be cautiously considered, along with appropriate and adequate antifungal therapy, in patients with cirrhosis disease and pulmonary cryptococcosis prior to liver transplant, if disease control has been achieved with adequate treatment before and after transplant.¹⁴

Disseminated cryptococcosis and severe pulmonary disease can be treated over 3 phases: first is the induction phase, which involves the use of intravenous liposomal amphotericin B (0.7-1 mg/kg) plus flucytosine (100 mg/kg) for a minimum of 2 weeks. The second is the consolidation phase during which oral fluconazole (400-800 mg/d) for 8 weeks is administered. The last phase is the maintenance phase where the use of oral fluconazole (200-400 mg/d) for at least 6 to 12 months is continued. There is limited evidence of outcomes with antifungal therapy for pulmonary cryptococcosis in asymptomatic pretransplant patients who have focal pulmonary nodules. In a previous report, pulmonary cryptococcosis was treated with fluconazole (200-400 mg/d) for 2 weeks before liver transplant, and this was continued for 6 to 12 months posttransplant.¹⁵ Patients who receive calcineurin-inhibitor immunosuppression have an increased risk of pulmonary cryptococcosis, and synergistic interactions of antifungal agents with a calcineurin inhibitor may improve outcomes.¹⁰ Further clinical studies on optimizing antifungal treatment for patients who develop pulmonary cryptococcosis before transplant are needed.

The present case suggests that, with rapid diagnosis, adequate antifungal treatment, and appropriate immunosuppressive regimen, patients with pulmonary cryptococcosis before transplant can undergo successful liver transplant. Clinicians must consider variables factors in a dynamic and individualized way to offer an optimal treatment and to monitor patient’s response to therapy.

Volume: 19 Issue: 3 March 2021

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