Cryptococcosis, lymphoproliferative disorders and modern day chemotherapy regimens

Although well recognized as an opportunistic infection in human immunodeficiency virus (HIV)-infected patients, cryptococcosis is increasingly identified in immunosuppressed HIV-seronegative individuals. The report by Marchand et al. [1] highlights the association between cryptococcosis and cancer, in particular lymphoproliferative disorders, and deficits in cell-mediated immunity. New treatment regimens for lymphoproliferative diseases resulting in profound lymphopenia such as the combination of rituximab, fludarabine and cyclophosphamide or alemtuzumab may result in increased diagnoses of cryptococcosis, particularly in patients not receiving antifungal prophylaxis [2–4]. Between 1988 and 2011, 17 cases of cryptococcal disease (approximately half with central nervous system [CNS] infection) were reported in patients with Hodgkin or non-Hodgkin lymphoma [5]. All except two had received chemotherapy, which included rituximab in two of the recent cases [5]. Cryptococcosis has occurred in at least five patients receiving alemtuzumab for chronic lymphocytic leukemia (CLL), prolymphocytic leukemia or T-cell lymphoma [2,3,6].

Human cryptococcosis is most commonly due to infection with the encapsulated yeast-like Cryptococcus neoformans var. grubii (serotype A), accounting for the majority of infections world-wide [7]. C. neoformans typically occurs in patients with T-cell defects [7]. In contrast, Cryptococcus gattii (CG) traditionally has affected immunocompetent hosts and was more geographically limited to the tropics and subtropics [7]. However, case clusters of CG infection occurred on Vancouver Island, Canada in the late 1990s and subsequently spread to the Pacific northwest of the United States [8]. Despite predominantly affecting the immunocompetent, risk factors for CG infection in the Canadian outbreak included HIV infection, cancer, leukemia, lymphoma, corticosteroid receipt and smoking [9]. A recent Australian survey showed that 28% of cases of CG infection occurred in the immunocompromised: 5% were in patients with acute lymphoblastic leukemia, acute myeloid leukemia and CLL and 3% in those with solid tumors [10]. This has clinical implications because treatment of C. neoformans and CG infection differs [8], and thus laboratories should identify and differentiate between these two species.

Clinical presentations of cryptococcosis are influenced predominantly by the host's immune response [7,8]. Inhalation of cryptococcal basidiospores is thought to result in pulmonary infection, with or without dissemination to other body sites including the CNS [9]. In the immunocompromised, as in the case presented by Marchand et al. [1], cryptococcal meningitis is the commonest presentation, reflecting disseminated infection [7]. Cryptococcus accounted for 7% of cases of culture-positive meningitis at one cancer center between 1993 and 2004, and was found in patients with both hematological malignancy and solid tumor. It was cultured more frequently than either Listeria monocytogenes (3%) or Candida albicans (1%) [11].

In immunocompromised patients, cerebrospinal fluid (CSF) abnormalities may not be pronounced [11], although lymphocytosis, raised protein and normal to low glucose are the typical findings [4]. Diagnosis is by visualization of the fungus by India Ink stain of CSF and/or its recovery by culture [4]. However, cryptococcal antigen (a cryptococcal polysaccharide) can rapidly be detected in serum and CSF in the majority of cases (sensitivity 95–100%) with excellent specificity [4,7,10]. CSF opening pressure should always be measured [8] and may be raised, as in the case presented by Marchand et al. [1]. Repeated lumbar punctures, and even insertion of ventricular-peritoneal shunts or lumbar drains are often needed to control the CSF pressure, which contributes to the morbidity (chiefly neurological deficits) and mortality of cryptococcal meningitis [8,10]. Importantly, diagnosis may be delayed, since cryptococcosis mimics “cancer” with presentation with pulmonary and brain mass lesions or nodules [12], and cases of mediastinal lymphadenopathy mimicking therapy-refractory lymphoma [13]. In one series from a cancer center, cryptococcosis was rarely suspected, and lung cancer, brain tumor, leptomeningeal cancer, cerebrovascular disease or bacterial meningitis were the initial diagnoses [4].

Treatment recommendations for cryptococcosis are based largely on studies performed in normal hosts or patients with HIV infection [8]. Induction therapy with amphotericin B and flucytosine for 2–4 weeks is preferred followed by maintenance therapy with fluconazole, continued during ongoing immunosuppression [8]. Risk factors for death at 3 months in C. neoformans infection include high baseline serum cryptococcal antigen titers (≥ 1:512), lack of flucytosine during induction therapy and abnormal neurology at presentation [14]. In CG infection, patient immunocompromise was associated with increased risk for mortality, and an initial CSF cryptococcal antigen of > 1:256 predicted poor outcome (death or neutrological sequlae) [10].

The interaction between Cryptococcus and the host is a complex one, impacted by immunosuppression. One patient with cryptococcal meningitis during alemtuzumab treatment subsequently developed an immune reconstitution inflammatory syndrome (IRS) characterized by recurrence of symptoms 10 months after diagnosis of disseminated cryptococcosis whilst still receiving suppressive fluconazole therapy [6]. This coincided with recovery of the CD4 cell count to > 0.100 × 10⁹ cells/L. Serum and CSF cryptococcal antigen titers continued to decline and CSF parameters were within normal limits with negative cultures, suggesting the inflammation was due to immune reconstitution and not worsening infection [6,8]. This case demonstrates that IRS can occur with immune reconstitution after chemotherapy with a potent T-cell lympholytic therapy [6], as has been described in immune reconstitution after highly active antiretroviral therapy in HIV-seropositive patients or reduction of immunosuppression in solid organ transplant recipients [8].

In conclusion, cryptococcosis is an important opportunistic infection in patients with defects of cell-mediated immunity. Whilst it may present as meningitis or mimic cancer in the lungs, mediastinum or CNS, diagnosis can be quickly and reliably made by detection of cryptococcal antigen in serum or CSF. Speciation of the organism is recommended. Treatment recommendations include induction and maintenance antifungal treatment as well as aggressive control of raised CSF pressure. The host's immune status impacts on symptoms of cryptococcosis, and IRS has recently been described in patients with hematological malignancy undergoing treatment for Cryptococcus.

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