Oehler, Richard L. MD, FACP*; Maldonado, Anibal MD*; Mastorides, Steven M. MD†; Reed, Jennifer L. MD‡
Cryptococcus neoformans is a well-known opportunistic fungal pathogen in the immunocompromised host. Most commonly, invasive cryptococcal infections tend to involve the meninges and/or the respiratory tract,1 but diseases of the skin, prostate gland, and eye are also clinically common. Disseminated cryptococcal disease can involve other body tissues, including the bone.2 Skeletal infection has been less well documented, however. A case review3 estimated 40 published cases of isolated cryptococcal osteomyelitis in the English-language literature from 1956 to 1998. Although frequently associated with the acquired immunodeficiency syndrome, cryptococcal infections also occur in human immunodeficiency virus (HIV)-negative hosts, some of whom may present with idiopathic CD4 lymphopenia.4,5 Intestinal lymphangiectasia (IL), a form of protein-losing enteropathy, can cause T-cell immunodeficiency and CD4 lymphopenia, and disseminated cryptococcal disease has been rarely reported6-8 with this syndrome. In this report, we present the first documented case of cryptococcal skeletal infection associated with primary intestinal lymphangiectasia (PIL) and review the other cases of cryptococcal disease and PIL reported in the English-language literature.
A 59-year-old man was admitted with right distal thigh erythema, edema, and tenderness. Eight months earlier, when his symptoms began, he had been diagnosed with degenerative joint disease and was prescribed with analgesics and supportive therapy. This failed to alleviate his symptoms; thus, he was referred for computed tomography, which revealed a fracture involving the posterior aspect of the right medial tibial plateau. Magnetic resonance imaging did not confirm the fracture but showed areas of osteolysis on the medial femoral condyle and medial plateau. Subsequent plain x-rays and bone scan findings were consistent with the diagnosis of possible osteomyelitis, and a bone biopsy of the right tibia was performed. Pathology results revealed necrotizing granulomatous inflammation with numerous fungal organisms (Fig. 1).
The patient also reported intermittent throbbing headaches for 10 months. His medical history included celiac sprue, diagnosed 7 years earlier, and hyperplastic polyposis coli. Four days earlier, he had developed a low-grade fever (temperature, 100.4°F) but was presently afebrile. He was noted to have tenderness, warmth, and erythema in the right knee region, with a mild prepatellar bursa effusion. The range of motion of the right knee was moderately impaired. Initial blood test results showed a white blood cell count of 11,900 cells/μL, a neutrophil count of 9100 cells/μL, and a lymphocyte count of 700 cells/μL. Cerebrospinal fluid (CSF) analysis revealed 118 white blood cells/μL with 37% lymphocytes. The CSF fungal culture was positive for C. neoformans, and the CSF cryptococcal antigen titer was 1:1024. The HIV antibody enzyme-linked immunoassay and HIV RNA polymerase chain reaction studies were negative. The total CD4 count was 149 cells/μL, the CD4 percentage was 22, and the CD4/CD8 ratio was 0.9.
The patient initially received amphotericin B (AmB) deoxycholate and 5-flucytosine, but the therapy was switched to liposomal AmB on day 8 because of nephrotoxicity. Surgical debridement of the tibia was held secondary to clinical improvement on antifungals. After 4 weeks of induction therapy, a repeat lumbar puncture suggested the clearance of the organisms from the CSF. A declining CSF cryptococcal antigen titer (1:32) was also documented. His distal tibial swelling and discomfort had nearly resolved. His therapy was switched to oral fluconazole (dosage, 400 mg/d), and the patient was discharged. Approximately 3 weeks later, he was readmitted with a relapse of cryptococcal meningitis, although the clinical appearance of his right knee had continued to improve. He was reinduced for 6 weeks, then his therapy was switched to oral voriconazole (dosage, 300 mg orally, bid) for indefinite suppression. He has continued to do well on this regimen.
The long-standing clinical history of celiac sprue was disproved when esophagogastroduodenoscopy revealed numerous lymphangiectasias throughout the small bowel. The small-intestine biopsy (Fig. 2) showed diffuse dilatation of lymphatic channels within the mucosa and the submucosa. No blunting of villi, increased inflammatory infiltrates, or other pathological abnormalities were present. He was placed on a high-protein, low-fat diet, and his blood cell counts, immunoglobulin levels, and lymphocyte subsets are undergoing periodic monitoring.
Our patient presented with cryptococcal osteomyelitis of the tibia and was ultimately discovered to have central nervous system (CNS) involvement as well. His initial diagnostic evaluation included tests to rule out an underlying immunodeficiency. A focused laboratory workup revealed hypogammaglobulinemia and CD4 lymphopenia. Acute and subacute/chronic HIV infection was ruled out with HIV polymerase chain reaction, deoxyribonucleic acid, and HIV-1 enzyme-linked immunoassay antibody studies. The patient's susceptibility to cryptococcal infection could have been attributed to idiopathic CD4 lymphopenia; however, because of the hypogammaglobulinemia and history of celiac sprue, the possibility of an immunodeficiency secondary to a protein-losing enteropathy was pursued.
Medical records indicated that the 7-year-old diagnosis of celiac sprue was clinical and not biopsy proven. The diagnosis was further doubted with the discovery of lymphopenia because this finding is not associated with celiac sprue. In fact, the only form of protein-losing enteropathy that produces lymphocyte depletion through the gastrointestinal tract is IL.
Intestinal lymphangiectasia is an established but poorly recognized cause of T-cell deficiency9 and can be due to primary ectasia of enteric lymphatics or due to secondary factors, such as cardiac disease, infection, or chemotherapy, which can cause a loss of lymph with leakage of immunoglobulins and/or lymphocytes into the gut. Primary IL was first described by Waldmann et al in 1961 as a disease of small bowel lymphatics producing protein loss.10 As a congenital disorder, PIL primarily affects small children and adolescents, has no sex preference, and has a mean onset age of approximately 11 years.11 Its manifestations are thought to reflect the anatomical location of the abnormal lymph vessels and the extent of the lymphatic abnormality.12 Common clinical symptoms include hypoproteinemia, low serum immunoglobulins level, lymphocytopenia, anasarca, and severe diarrhea.13 Most individuals present within the first 2 years of life. However, the first published case of disseminated cryptococcal infection with PIL occurred in an adult,6,7 suggesting that the disorder may present later in life and remain undiagnosed for a prolonged period. Our patient was diagnosed at the age of 59 years, but admitted to having chronic diarrhea for at least 2 decades. In fact, this was the reason why a protein-losing enteropathy, such as celiac sprue, was initially suspected. We think that this patient's case of IL was primary because secondary factors, such as cardiac disease, portal hypertension, or infectious or toxic exposures, were not known to be present.
Although the immune deficiency induced by PIL affects both humoral and cellular immunity, opportunistic infections associated with CD4+ lymphopenia seem more clinically significant. It has been determined that the loss of lymphocytes primarily affects naive CD4+ T cells and, less commonly, B cells, natural killer cells, and CD8 cells. This results in the presence of highly differentiated, previously sensitized residual circulating T cells, which proliferate poorly.14 Previous reports have documented skin anergy, impaired allograft rejection, and deficient mitogen-induced in vitro lymphocyte proliferation in these patients.9,15,16 Despite its extensive effects on cellular and humoral immunity, the spectrum of disorders associated with PIL is relatively narrow. In addition to cryptococcal infection, case reports have documented episodes of cutaneous warts17 and lymphoma.18
Comparisons between the 3 published cases (including ours) of cryptococcal disease and IL reveal some similarities and several important differences (Table 1). Fever and headache were common to all 3 cases. All patients had lymphopenia, with total lymphocyte counts well below normal value. The CD4+ lymphocyte values were also markedly reduced in both cases in which this information was reported. All patients received induction therapy with AmB and flucytosine in accordance with accepted guidelines. Perhaps, the most striking distinction among the cases was in their completely different sites of involvement (skin/soft tissue, lung, and bone) and secondary manifestations. Cryptococcemia was documented in only one of the cases, and our patient had the only confirmed case of cryptococcal meningitis. However, it seems likely that all patients in the group had CNS involvement, given the presenting symptoms of headache and altered mental status in the earlier cases. The age at diagnosis also varied widely within the group, suggesting that cryptococcal infection may present as a manifestation of IL in children and in young and mature adults. Primary IL was an established diagnosis in the first 2 cases; however, in our patient, the diagnosis was made secondarily.
Isolated osteomyelitis due to C. neoformans occurs rarely.3 It has been estimated that skeletal involvement occurs in approximately 10% of patients with disseminated cryptococcosis.19 Case reviews3,20 have suggested that the infection tends to affect young to middle-age adults (mean age, 33 years), although individuals at almost any age can be affected. The disorder has a slight male-to-female preference and is more likely to present in a single site. In 1 review,20 evidence of an underlying immunosuppression could be identified in 38% of the cases. Sarcoidosis and tuberculosis were the most common underlying disorders identified.3 The duration of symptoms could range from as little as 2 weeks to as much as 33 months. Common symptoms included soft tissue swelling and tenderness; where joint involvement occurred, synovitis was often diagnosed. Vertebral involvement tended to occur most frequently (25%), followed by involvement of the tibia, femur, and ribs (17%).3 Lumbar puncture studies were negative for cryptococcal antigen and culture in most patients (84%) in which CSF was obtained. In 1 series, 40% of patients received medical treatment alone, 42.5% received medical treatment plus curettage/bone excision, and 7.5% received bone excision exclusively. Although most patients experienced either cure or improvement with each modality, the results suggested a more favorable outcome when debridement was used as part of treatment.20 Most cases were treated with AmB with or without 5-flucytosine as medical therapy.
Several case reports4,21,22 have documented the onset of cryptococcal infection in patients found to have idiopathic CD4 lymphopenia. These were patients with disseminated cryptococcal infection and T-cell deficiency in which no underlying cause could be found. It seems likely that IL could be an unrecognized cause of a significant number of cases of invasive cryptococcal disease in patients with idiopathic CD4 lymphopenia. As with our patient, PIL may remain unrecognized for years or even decades. The nonspecific symptoms of intermittent diarrhea and mild malnutrition may be subclinical or may be attributable to an alternative disorder. In fact, PIL requires the presence of clinical, laboratory, and pathological findings to establish a definite diagnosis. Whether the cellular immune deficiency induced by PIL specifically predisposes patients to have disseminated cryptococcal disease is unclear at this time but is worthy of further investigation. Likewise, it also seems unclear why the hypogammaglobulinemia induced by IL does not always produce significant clinical manifestations (eg, sinopulmonary infections) of a humoral immune deficiency.
The preferred regimen for both CNS and disseminated cryptococcal infection in HIV-negative patients includes a minimum of 2 weeks of induction therapy with AmB plus 5-flucytosine, followed by a 10-week course of oral fluconazole.23 Because our patient also presented with confirmed cryptococcal meningitis, the initial treatment was directed at the clearing of his CNS infection. He received a total of 4 weeks of induction therapy until the elimination of cryptococcal organisms from the CSF could be documented. The factors behind the patient's relapse on fluconazole after 3 weeks were unclear, although medication noncompliance was not suspected. C. neoformans resistant to fluconazole has been previously reported, and this may have explained our patient's relapse after induction therapy.24 Antifungal susceptibilities were not performed on CSF or pathological specimens. This patient has done well on oral voriconazole secondary prophylaxis since his relapse. Indefinite suppressive therapy is planned for as long as his lymphopenia persists, and lifelong therapy may be necessary. The patient's total CD4+ T-cell count had improved to 281 cells/μL within 4 months of diagnosis.
The established therapy for PIL is a low-fat, high-protein, medium-chain triglyceride diet,25,26 and this was instituted in our patient. Intravenous immunoglobulin therapy has not yet been implemented because he has not experienced sinopulmonary infections and would be more likely to lose infused immunoglobulins through his gut. Other approaches to treating PIL include the use of steroids27 and both total parenteral nutrition and enteral nutrition diets.28
In summary, we report the first known case of cryptococcal osteomyelitis associated with PIL, an established but poorly recognized cause of CD4+ T-cell deficiency. It was likely that the patient first developed cryptococcal meningitis, which then progressed to secondary dissemination and tibial involvement. He initially received AmB plus 5-flucytosine followed by oral fluconazole; despite a relapse, he responded well to a second course of induction therapy followed by oral voriconazole. We assert that IL may indeed be an unrecognized cause of a significant number of cases of invasive cryptococcal disease in patients with idiopathic CD4+ T-cell lymphopenia in which no other source of immunodeficiency has been identified.
The authors thank Dr. Jean Guffey Johnson of the James A. Haley Veterans Hospital, Pathology Section, for her assistance in obtaining images for this publication.
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