Multiple myeloma (MM) is incurable, except in some younger patients who undergo allogeneic bone marrow transplantation. However, the clinical outcome of patients with MM has improved significantly over the past 10 years with the use of high-dose chemotherapy and autologous stem cell transplantation (autoSCT).1 Infection is one of the most common complications in patients with MM undergoing autoSCT. The vast majority of infectious complications are caused by bacteria, viruses and fungi, such as aspergillus species or candida species.2 To our knowledge, cryptococcosis has never been reported in patients undergoing autoSCT for the treatment of any diseases, including MM.
A 42-year-old white woman was diagnosed with stage III-B MM (IgGκ) by a serum monoclonal spike of 13 g/dl and 80% plasma cells in the bone marrow. She received three cycles of vincristine, doxorubicin and dexamethasone (VAD) with a good response. AutoSCT was recommended since she did not have an HLA-matched sibling. Stem cells were mobilized with cyclophosphamide 5.0 g/m2 i.v. and 20 × 106/kg CD34+ cells were harvested in February 2001. She underwent an autoSCT after receiving melphalan 200 mg/m2 in April 2001. The patient engrafted promptly and did not develop any major complications in the immediate post-transplant period. She received fluconazole, ciprofloxacin and acyclovir prophylaxis from day +1 post-transplant until neutrophil recovery. Her M-spike decreased significantly to 1.9 g/dl, and bone marrow aspirate/biopsy revealed no increase in plasma cells.
Four months post-autoSCT the patient presented with fever, headache, vomiting and confusion followed by a complex partial seizure. Her past medical history was not significant and she was not on any medication. She denied a history of smoking, alcohol or illicit drug use or a recent history of travel. Pertinent physical findings were a fever of 38.4°C, lethargy, neck stiffness and no focal neurological deficits. MRI scan and electroencephalography (EEG) of the brain were normal. A lumbar puncture revealed an opening cerebrospinal fluid (CSF) pressure of 390 mm of water, protein 210 mg/dl, glucose 14 mg/dl and WBC of 15 × 109/l (90% lymphocytes). India Ink stain was positive for Cryptococcus and Cryptococcal antigen was positive at 1:512 dilutions. Her HIV test was negative. Her CD4/CD8 ratio was 0.4/1. Amphotericin B lipid complex at 5 mg/kg/day i.v. and flucytosine at 100 mg/kg/day orally in divided doses were initiated with daily lumbar punctures for CSF drainage, with the intention of decreasing the CSF pressure to less than 200 mm of water. After 2 weeks, the patient improved clinically and the anti-fungal drugs were switched to oral fluconazole at 400 mg/day for 10 weeks and then 200 mg/day for an indefinite period of time.
Despite exposure to C. neoformans, the infection rate appears to be low in the healthy population because of high natural resistance. T cell-mediated immunity is the predominant component of the host defense mechanism against the fungus. Cryptococcosis is a well-described infection in patients with diseases causing T cell deficiency, such as AIDS or lymphomas.3 Rare reports of cryptococcal infection in a patient with MM have been noted.4 Cryptococcal infections are very unusual in patients with MM due particularly to the fact that cell-mediated immunity is relatively intact even though humoral immunity is significantly deficient.
After AIDS, allogeneic bone marrow and solid organ transplantation are the most frequent risk factors for cryptococcosis, largely due to the effect of high-dose corticosteroids and other immunosuppressive agents on cellular immunity.5 T cells are comprised of a heterogeneous group of short- and long-lived cells, which are themselves capable of substantial mitotic expansion. When T cells are acutely depleted in the context of high-dose cytotoxic antineoplastic therapy during autoSCT, reconstitution of a heterogeneous population of T cells and the re-establishment of T cell immunocompetence is a slow and frequently incomplete process.6 Nordoy et al7 demonstrated persistently low absolute lymphocyte counts, low counts of CD3-positive and CD4-positive cells, and an inverted CD4/CD8 ratio for up to 10 years after autoSCT.
C. neoformans meningitis occurred 4 months post transplant in our patient and her CD4/CD8 ratio was altered. As our patient did not have any other known risk factors for cryptococcal meningitis and patients with MM are not prone to develop cryptococcal meningitis, we presume it was due to delayed recovery of CD4 cells and inverted CD4:CD8 ratio.
We report this case to increase physician awareness that cryptococcosis can occur in post-autologous transplant patients because of T cell-mediated deficiency, particularly CD4+ cells. It is hard to explain why this isolated patient developed C. neoformans meningitis among the many patients with MM who undergo autoSCT.
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Nordoy T, Kolstad A, Endresen P et al. Persistent changes in the immune system 4–10 years after ABMT Bone Marrow Transplant 1999 24: 873 878
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Mendpara, S., Ustun, C., Kallab, A. et al. Cryptococcal meningitis following autologous stem cell transplantation in a patient with multiple myeloma. Bone Marrow Transplant 30, 259–260 (2002) doi:10.1038/sj.bmt.1703646
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