Isolated cutaneous cryptococcosis in clinically unsuspected idiopathic CD4 lymphocytopenia.

Idiopathic CD4 lymphocytopenia first defined in 1992 by the U.S. Centers for Disease Control and Prevention, as the repeated presence of a CD4(+) T-lymphocyte count of fewer than 300 cells/cumm or of <20% of total T-cells with no evidence of human immunodeficiency virus (HIV) infection and therapy that might cause depressed CD4 T-cells. Most of the cases present with systemic opportunistic infections. We report a case without risk factors or laboratory evidence of HIV infection, presenting with cutaneous cryptococcal infection, diagnosed on cytology.

Introduction

Idiopathic CD4 lymphocytopenia (ICL) was defined by the United States Centers for Disease Control and Prevention as a clinical condition in patients with depressed numbers of circulating CD4 T-lymphocytes (<300 cells/μL or <20% of total T-cells) on more than one occasion at least 6 weeks apart, with no laboratory evidence of infection with human immunodeficiency virus (HIV)-1 or HIV-2, and the absence of any defined immunodeficiency or therapy associated with depressed levels of CD4 T-cells.[1] Different case reports of ICL associated with different opportunistic diseases and clinical conditions, mostly fungal, parasitic, and viral infections have been published.[23] We report a case presenting with cutaneous cryptococcal infection, diagnosed on cytology.

Case Report

A 50-year-old patient, with no history of any prolonged illness in the past, presented with a painless and progressive swelling on the left side of the chest wall for past 6 months. He had no risk factors for HIV infection and had not received any immunosuppressive therapy. General physical examination was within normal limits. On local examination, the swelling was firm, mobile and nontender measuring 1 cm × 1 cm in size. Fine-needle aspiration cytology yielded thick yellow aspirate and giemsa stained smears revealed a necrotizing suppurative granulomatous inflammation with numerous yeasts of Cryptococcus surrounded by clear halos, present within multinucleated giant cells and in the intercellular spaces [Figures 1 and 2]. Yeast forms were further demonstrated on silver methenamine and periodic acid-Schiff stain and mucicarmine highlighted the capsule. Thus, a final diagnosis of subcutaneous cryptococcal infection was given. Patient was advised culture studies and CD4 and CD8 counts to rule out any underlying immunodeficiency.

Figure 1

Fine-needle aspiration smear showing plasma cells and suppuration, (MGG, ×400. Inset: Mucarmine highlighting the capsule, ×600)

Figure 2

Fine-needle aspiration smear showing giant cells showing many yeast forms of Cryptococcus (arrow), (MGG, ×200. Inset: Periodic acid-Schiff, ×400)

Patient tested negative for HIV (1 and 2) and HBsAg. CD4 count was found to be low (165/ μL or 27%). Therefore, a clinical impression of isolated CD4 lymphocytopenia was made. The patient was started on oral fluconazole 300 mg OD. After 3 months of therapy, his CD4 counts increased to 250 cells/μL while CD8 count was within normal limits with a CD4/CD8 ratio of 0.63 (normal –0.9-2.5). The swelling resolved and the patient improved clinically. At last clinical visit, the patient was asymptomatic with total leukocyte count of 6,700 cells/μL and CD4 count of 264 cells/μL.

Discussion

Idiopathic CD4 lymphocytopenia in an immunocompetent adult is very rare, unlike transient CD4 lymphocytopenia, which is common and occur in 0.4-4.1% healthy HIV-negative individuals at any given time.[2] It is a heterogeneous condition diagnosed typically in middle age, usually after an opportunistic infection.[2] It can also be an incidental laboratory finding. In the largest survey to date, involving 47 ICL patients, it was found in mean age-group of 43 ± 14 years (range 17-78 years) and 29 patients reported no risk factors for HIV infection.[3]

Various opportunistic bacterial, viral, parasitic, and fungal diseases may depress CD4 cell counts, but usually without inversion of the CD4:CD8 ratio.[4] The lymphocytopenia associated with these infections is transient and therefore probably “physiologic” responses to an alteration of the cytokine and inflammatory environment. The most important differential diagnosis of CD4 lymphocytopenia is HIV infection. In contrast to ICL, HIV infection shows an invariably progressive drop in CD4 counts.

Other noninfectious causes of ICL include hematological malignancies like non-Hodgkin lymphoma (large cell lymphoma, mucosa-associated lymphoid tissue lymphoma, Burkitt lymphoma), mycosis fungoides, and the myelodysplastic syndrome.[5] Autoimmune diseases and chemotherapy drugs such as cyclophosphamide and methotrexate have also been found to be associated with CD4 lymphocytopenia with normal CD4:CD8 ratios.[6]

The spectrum of opportunistic infections in ICL overlaps with those found in HIV-positive patients with comparable CD4 T-cell counts. Cryptococcosis and nontuberculous mycobacterial infections are the most frequently opportunist infections reported in ICL.[7] Ahmad et al.[6] reviewed 258 cases of ICL out of which 87.6% had at least one opportunistic infection. Cryptococcus neoformans infections were the most common (69 cases) with meningitis being the most common infection, followed by pneumonia and then osteomyelitis. Four cases of cryptococcal meningitis have been described by Rιgent et al.[8] in patients of ICL. To the best of our knowledge, only two cases of primary cutaneous cryptococcosis in lymphocytopenia have been reported in English literature.[910]

Other associated infections include: Pneumocystis jiroveci pneumonia, cerebral toxoplasmosis, histoplasmosis, pulmonary and extrapulmonary candidiasis, oral or genital herpes simplex, human papillomavirus infection, molluscum contagiosum and Cytomegalovirus infection.[6] Their appearance in an HIV-negative patient should alert the clinician to investigate for ICL.

Idiopathic CD4 lymphocytopenia is still considered a disorder of unclear etiology. The pathogenesis of ICL is believed to be a transient lymphocytopenia probably a “physiologic” response to an alteration of the cytokine and inflammatory environment leading to diminished generation of T-cell precursors and a decreased clonogenic capacity of bone marrow progenitors. This has been attributed due to a disturbed cytokine environment with increased (tumor necrosis factor-α) and decreased interleukin-2 levels.[4] A variety of acute and chronic infections may be the cause of depleted CD4 counts without affecting CD8 T-cells.[4]

Two factors may be related to CD4+ lymphocyte function in developing ICL. First, increased CD4 activation, due to stimulation by an unidentified pathogen, resulting in a persistent decrease in the number of CD4+ lymphocytes.[7] Lee et al. found increased levels of serum markers of CD4+ lymphocyte activation in patients with ICL and hypothesized that abnormally increased microbial translocation through the intestinal wall may be an underlying etiology.[7] Second, apoptosis of CD4+ lymphocyte may be associated with enhanced expression of Fas and Fas ligand.[6]

There appears to be two subtypes of ICL in terms of the presence or absence of CD8 T-lymphocytopenia. This observation precludes the use of the CD4/CD8 ratio for diagnostic purposes in ICL and supports that it is a heterogeneous syndrome that could be further accompanied by B-cell and/or NK-cell lymphocytopenia.[7]

The subcutaneous cryptococcosis in our case was secondary to CD4 lymphocytopenia, and it improved following antifungal therapy. Because of the sustained CD4 T-lymphocyte depletion, absence of serological evidence of HIV infection, and the absence of any immunosuppressive therapy associated with T-cell depletion, our patient met the existing criteria for ICL. Prophylaxis against opportunistic infections is advised using the protocols advocated for HIV-1 infected patients with advanced disease.

In a prospective study by Zonios et al.[7], the CD4 T-cell counts in their patients remained <300/mm3 for several years without progression of lymphocytopenia over time. One-fifth of their patients resolved their lymphocytopenia within 3 years of diagnosis. Therefore, they suggested that it is reasonable to strictly follow up ICL patients during the first 3 years because of the risk of serious infections and the possible normalization of CD4 T-cell counts, allowing discontinuation of any prophylaxis. The treatment of ICL includes therapy of underlying conditions; treatment and prophylaxis of secondary complications, especially of the opportunistic infections.

Conclusion

Idiopathic CD4 lymphocytopenia is a heterogeneous and distinctive condition, quite different clinically and immunologically from HIV. A high index of suspicion is required to diagnose ICL. Opportunistic infections in immunocompetent hosts should lead to a prompt workup for this condition. Cytologic diagnosis of cutaneous cryptococcosis in this case led to the identification of this rare entity, in a clinically unsuspected case.