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Idiopathic CD4 lymphocytopenia and opportunistic infection — an update

Ling Luo, TaiSheng Li
DOI: http://dx.doi.org/10.1111/j.1574-695X.2008.00490.x 283-289 First published online: 1 December 2008

Abstract

A severe CD4 T-cell depletion predisposes humans to opportunistic infections. In recent years, reports of cases of opportunistic infections caused by CD4 T-cell depletion without HIV infection have been accumulating. Such cases, termed idiopathic CD4 T lymphocytopenia (ICL), are very rare. The epidemiologic data do not suggest that the condition is caused by a transmissible agent. Unlike HIV infection, the decrease in the CD4 cell counts of patients with ICL is often slow. The clinical spectrum of ICL ranges from an asymptomatic laboratory abnormality to life-threatening opportunistic infections. However, the pathogens, clinical significance and treatment of ICL patients still await systematic research. This review summarizes the current knowledge of the poorly understood syndrome of idiopathic CD4 lymphocytopenia, providing key insights into the pathogenesis and immunologic characteristics, and suggesting approaches to enhance CD4 T-cell counts.

Keywords
  • CD4 cell count
  • lymphocytopenia
  • opportunistic infection
  • T-cells

Background and definition

HIV was discovered to be the pathogen of AIDS in 1983. Since then, studies on HIV and AIDS have been accumulating. Interestingly, several cases of AIDS-like symptoms without HIV infection have been reported. Such cases have been termed idiopathic CD4 T lymphocytopenia (ICL).

Idiopathic CD4 lymphocytopenia was first defined in 1992 by the Centers for Disease Control and Prevention (CDC) as: (1) CD4+ T-lymphocyte depletion (absolute CD4+ T-lymphocyte level <300 µL−1 or <20% of total lymphocytes at a minimum of two separate time points at least 6 weeks apart); (2) no serological evidence of HIV infection; (3) the absence of any defined immunodeficiency or therapy associated with depressed levels of CD4 T-cells (Centers for Disease Control, 1992).

Epidemiology

ICL is a rare disease. In a review that screened 2713 HIV-seronegative homosexual and bisexual men, none had persistent low lymphocyte counts with an identifiable cause (Vermund et al., 1993). No case was identified in a study that screened 2028 blood donors (Busch et al., 1994). In one study that evaluated 275 blood donors, 970 transfusion recipients and 947 household contacts of transfusion recipients, 12 persons (0.5%) had CD4+ T-lymphocyte counts below 300 cells mm−3 on two or more occasions without an identifiable cause (Aledort et al., 1993). CD4 T lymphocytopenia is uncommon (<1%) in West African HIV-seronegative asymptomatic individuals (Djomand et al., 1994).

In 1993, 47 patients with ICL were reported in a CDC-coordinated effort to describe the epidemiologic, clinical, immunologic, and virologic characteristics of this new syndrome. There was no detectable bias in sex (29 males, 18 females) or age (mean age: 43 years; range 17–78) and no indication that ICL is transmitted sexually. Since then, it is widely accepted that ICL is a heterogeneous syndrome that apparently is not caused by any transmissible agent (Smith et al., 1993).

Some reports reported that persons with hemophilia or other HIV-1 risk factors may be more likely to have ICL. Five of 304 (1.65%) seronegative hemophilic men had persistent lymphocytopenia (<1200 total lymphocytes m−1 and fewer than 300 total CD4+ lymphocytes mL−1) (O'Brien et al., 1995). However, this may reflect an ascertainment bias, in that such persons, particularly men with hemophilia or homosexual men, are more likely to be followed regularly and have their lymphocyte subgroups determined at certain intervals as a part of studies on groups at risk for HIV infection. Therefore they are more likely to be identified as meeting the criteria for ICL (Smith et al., 1993). Because of this bias, it would be inappropriate to conclude that persons with HIV risk factors may be more likely to have ICL. To date, although an unknown infectious agent of immunodeficiency cannot be ruled out definitively, the epidemiologic data do not suggest that the condition is caused by a transmissible agent.

Pathogenesis

The pathogenesis may be multifactorial. To explain this syndrome, researchers have proposed several hypotheses: (1) diminished generation of T-cell precursors; (2) increased T-cell apoptosis; (3) biochemical failure of the CD3-T-cell receptor (TCR) pathway by p56 Lck kinase alteration; (4) defective production of cytokines; (5) CD4 T-cell antibodies.

Diminished generation of T-cell precursors

Investigations of the bone marrow of five ICL patients revealed that the percentage of phenotypically primitive CD34+CD38DR+ cells (which include the lymphoid precursor cells) was decreased, suggesting an involvement of the more primitive bone marrow compartment in de novo T-cell generation. This raises the possibility that the diminished availability of stem cell precursors might contribute to the development of CD4+ T-cell depletion in ICL patients (Isgrò, 2005a, b).

Increased T-cell apoptosis

Laurence (1996) reported a possible association of CD4 lymphocyte apoptosis with ICL. Roger (1999) observed an ICL case characterized by a decreased CD4+ T-cell count and an overexpression of Fas/CD95. CD95 (Fas/Apo-1) is a member of the tumor necrosis family (TNF) nerve growth factor superfamily that can directly transduce an apoptotic death signal on trimerization with Fas ligand (Miyawaki et al., 1992). The patient in Mayawaki's study had a high level of spontaneous apoptosis, and all apoptotic cells were identified as being CD4+ T-cells. Kawabata (1992) reported an ICL case with pleural cryptococcosis. A higher percentage of CD95+CD4+ lymphocytes was found in this case compared with healthy volunteers.

Biochemical failures of the CD3-TCR pathway

Hubert (1999) observed a 40% reduction in T-cell proliferation following CD3-TCR stimulation in the CD4 lymphocytes of an ICL patient. There was also a 50% reduction of p56 Lck kinase activity in the T cells compared with a healthy control. The T-cell activity process consists of a cascade of biochemical events triggered by stimulation of the CD3-TCR by the major histocompatibility complex–peptide complex or an mAb specific to CD3 (Hubert et al., 2000). The earliest events involve the T-cell protein tyrosine kinases (PTK), p56, lak, p59, Fyn and ZAP-70, which phosphorylate numerous intracellular substrates of tyrokine residues (Weiss & Littman, 1994; Chan & Shaw, 1996), leading to cytokine gene expression and cell proliferation. In the present study, impaired early biochemical events of the CD3-TCR pathway were detected in some cases.

Defective production of cytokines

TNF-α and IFN-γ production were found to be lower in ICL patients with cryptococcal meningitis (Netea et al., 2004). The results of the present study suggest that in patients with idiopathic CD4 lymphocytopenia there is defective production of cytokines such as TNF-α and IFN-γ (Netea et al., 2004).

Serum levels of IL-7 were significantly higher in patients with ICL compared with healthy donors (Malaspina et al., 2007). Serum levels of IL-7 have been correlated inversely with CD4 T-cell counts in HIV studies (Fry et al., 2001; Napolitano et al., 2001; Malaspina et al., 2006). High serum levels of IL-7 have been proposed to be a compensatory mechanism associated with loss of CD4+ T-cells.

CD4 T-cell antibody

CD4 T-cell antibodies were detected in a patient with ICL (Salit et al., 2007). A much larger proportion of CD4 T-cells were coated with antibodies in the ICL patient than the CD4 T-cells of normal donors. On the basis of this observation, it was postulated that the CD4 T-cell antibodies may be involved in the development of CD4+ T-cell depletion in ICL patients.

Immunologic characteristics of ICL

The decrease in CD4 cell counts of patients with ICL is slow or even absent for a long period. Unlike HIV patients, patients with ICL do not show an increase in CD8+ cells. The studies of patients with ICL showed that among CD4 T-cells, naïve CD45RA+ T-cells are more severely diminished than the memory CD45RO+ population (CD4+CD45+RA+/CD4 ratio 0.18, CD4+CD45+RO+/CD4 ratio 0.8) (Frühwirth et al., 2001). Some reports described low numbers of CD4+CD29+ memory cells and a high percentage of γδ TCR cells in ICL patients (Tassinari et al., 1996). Signorini (2000) also reported that the αβ and γδ T-cell counts of three patients with ICL were strongly repressed.

In 1992, the Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, initiated a prospective study over several years to evaluate the natural history of ICL. Thirty-nine patients (17 men, 22 women) 25–85 years old with ICL were evaluated between 1992 and 2006, and 36 were followed for a median of 49.5 months. Zonios (2008) summarized the clinical and laboratory information obtained from the follow-up of this population. Although the majority of patients (84.6%) had an inverted CD4/CD8 ratio at the time of diagnosis, a normal CD4/CD8 ratio in the other patients reflected a concomitant severe depletion of CD8 T-cell numbers. Indeed, 15 ICL patients had CD8 T-cell counts less than the lower 2.5% of CD8 T-cell counts for the control population (or <180 mm−3) and 23 patients had CD8 T-cell counts of >180 cells mm−3. Immunoglobulins were within normal limits in all patients. Thirteen patients also had low absolute B-lymphocyte counts (or <99 mm−3) and 18 had low absolute natural killer–lymphocyte counts (or <76 mm−3). Immunophenotypical analysis revealed a significantly higher proportion of activated (HLA-DR+) CD4, but not CD8. The CD4 T-cell turnover as measured by Ki-67 was higher in ICL patients. Immunologic analyses revealed that CD8 T lymphocytopenia (<180 mm−3) and CD4 T-cell activation (measured by HLA-DR expression) at presentation were associated with adverse outcome (opportunistic infection-related death).

Clinical features and diagnosis of ICL

The clinical spectrum of ICL ranges from an asymptomatic laboratory abnormality to life-threatening complications that imitate the clinical course of AIDS patients. ICL is typically revealed by the emergence of opportunistic infection. The cases of ICL were reported to be complicated by varieties of opportunistic infections, including cryptococcus, mycobacteria, pneumocystis carini, candidiasis and cytomegalovirus (Table 1). Cryptococcus is one of the most commonly described infections in the literature. It is suggested that cases with opportunistic infections should be checked for CD4+ T lymphocytopenia.

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Table 1

Opportunistic infections in ICL patients

CategoryInfection agentsReferences
BacteriaMycobacterium avium intracellulareIshida et al. (1998)
Mycobacterium tuberculosisKony et al. (2000), Hirasaki et al. (2000), Calbo Mayo et al. (2005)
Vargas et al. (2005)
Mycobacterium mucogenicumAnzalone et al. (1996)
Mycobacterium kansasiiBurg et al. (1994)
Salmonella typhimurium
FungusCryptococcusZaharatos et al. (2001), Cheung et al. (2003), Kawabata et al. (2004), Lepur et al. (2005), Zonios et al. (2007)
Pneumocystis jiroveciiDuncan et al. (1993), Matsuyama et al. (1998), Longo et al. (1999)
Candida albicansCalbo Mayo et al. (2005) Robert et al. (1993)
Histoplasma capsulatum
VirusCytomegalovirusLongo et al. (1999), Hamanishi et al. (1999),
Varicella zoster virusHochauf et al. (2005)
Human herpes virus-8Richetta et al. (2007)
HPVPasic et al. (2005)
JC virusHaider et al. (2000)
ParasiteToxoplasmosisPlonquet et al. (2003)
ProtozoanLeishmaniasisLópez-Medrano et al. (2007)

Zonios 's (2008) study found that cryptococcal and nontuberculous mycobacterial infections were the major presenting opportunistic infections of ICL. In that study, 15 (41.6%) patients were diagnosed with infections potentially related to ICL during follow-up, most of them during the first 3 years, consisting mostly of human papilloma virus (HPV), dermatomal varicella zoster virus (VZV), and mucosal candidiasis. Five patients (13.8%) developed ‘AIDS defining clinical conditions’ (category C HIV infections) during the first 24 months of follow-up: two episodes of Mycobacterium avium complex (MAC) (64 and 160 CD4 cells mm−3, respectively); one episode of Pneumocystis jirovecii pneumonia (PCP) (22 CD4 cells mm−3); one episode of progressive multifocal leukoencephalopathy (PML) (7 CD4 cells mm−3); and one episode of Epstein–Barr virus-related lymphoproliferative disease, which evolved into B-cell lymphoma (25 CD4 cells mm−3). ‘AIDS defining clinical conditions’ and death were interrelated and three of these patients eventually died from MAC, PML, and B-cell lymphoma, respectively. Of the 39 ICL patients, seven patients (17.9%) had no reported opportunistic infections and none of the seven patients received any immunosuppressive or immunomodulatory treatment following diagnosis of ICL, except for one patient treated with IFN-α for widespread genital HPV infection. Six patients (15.4%) had evidence of persistent lymphocytopenia long before they were diagnosed with ICL, from 9 months to >10 years earlier.

The most important differential diagnosis of ICL is HIV infection. Compared with HIV infection, the decline of CD4 cell counts of the patients with ICL is slow or even absent over time. ICL patients usually do not have increased numbers of CD8 T lymphocytes, whereas HIV patients have an early increase in CD8+ cells in response to the infection. The ICL patients had either normal or slightly low immunoglobulin levels, whereas immunoglobulin levels are usually elevated in patients with HIV infection. This may also be due to a lack of help from CD4+ T-cells in immunoglobulin production in ICL, in contrast to the direct stimulation of production seen in HIV infection (Chess et al., 1984; Spira et al., 1993; Katsutaka, 1997). Other infectious agents such as bacterial, viral (Ebstein–Barr virus and cytomegalovirus), parasite, and fungus can depress CD4 cell counts. The changes associated with these infections are mostly transient (Laurence, 1993; Walker & Warnatz, 2006).

Other conditions which can present with low CD4 counts include common variable immunodeficiency, primary Sjögren's syndrome (SS) and immunosuppressive medication. Common variable immunodeficiency can present with low CD4+ counts and opportunistic infections but is associated with generally low levels of immunoglobulins, differentiating this condition from ICL (Rabab et al., 1997). In primary SS an increased prevalence of CD4+ T lymphocytopenia has been found. In Kirtava 's (1995) study, the prevalence of ICL among 115 patients with SS was 5.2%, which is significantly higher than the rates reported for any other patient or population groups. Immunosuppressive medication such as corticosteroids and cyclophosphamide can produce severe depression of lymphocytes and CD4 cells (Glück et al., 2005; Minnee et al., 2005). The diagnosis of ICL can be made only after all these other conditions which can present with low CD4 T-lymphocyte counts have been ruled out.

Some case reports described diagnosis of a B-cell non-Hodgkin's lymphoma several years after the onset of CD4 lymphocytopenia and persistence of CD4 lymphocytopenia after complete remission of lymphoma, which raises the possibility that the malignancy was a consequence rather than the cause of immunodeficiency in these patients. The increased percentage of CD34+CD19+CD10+ cells also suggests an expanded B lymphopoiesis in ICL patients. Accessory cells, by release of IL-6 or IL-7, may support the adherence and the growth of poorly differentiated pro-B cells. These cells are at risk of neoplastic transformation and may be responsible for the increased risk of lymphoma in ICL patients (Hanamura et al., 1997; Campbell et al., 2001; Busse & Cunningham-Rundles, 2002).

Treatment

The treatment of ICL mainly consists of prophylaxis and treatment of opportunistic infections and (still experimental) approaches to increase CD4 T-cell counts.

Prophylaxis and treatment of opportunistic infections

When CD4 counts fall below 200 cells µL−1, patients with HIV are at risk for opportunistic infections (http://www.hiv.medicine.com). Guidelines for patients with ICL are not available, and thus the current recommendations are based mainly on experience with HIV-infected patients. Prophylaxis against pneumocystis is recommended when CD4 T-cell counts fall below 200 cells µL−1. Cryptococcus as well as relapsing multisegmental herpes infection may require lifelong secondary prophylaxis. Antimycobacterial medication has been reported to produce improvement of CD4 T-cell counts in CD4 lymphocytopenia with mycobacterial infections (Walker & Warnatz, 2006).

Approaches to increase CD4 T-cell counts

Some studies suggested IL-2 therapy for ICL as an option to increase CD4 counts (Rundles et al., 1999; Warnatz et al., 2000). A female patient with ICL who had chronic severe mycobacterial disease, was given weekly subcutaneous injections of polyethylene glycol–IL-2, 50 000 U m−2 for 5.5 years (Warnatz et al., 2000). This treatment resulted in normalized T-cell functions and increased CD4 cell numbers, and thereby substantial clinical improvement. The proportion of CD4+CD45+RA+/CD4 (naïve) cells increased (ratio 0.23) and the proportion of CD4+CD45+RO+/CD4 (memory) cells decreased (ratio 0.55). Rundles and colleagues reported that subcutaneous therapy with IL-2 substantially improved the clinical outcome of a patient with relapsing herpes zoster infection due to ICL (Rundles et al., 1999). Yilmaz-Demirdag (2008) reported that a 16-year-old male patient with ICL, who had cryptococcal meningitis, was successfully treated by the addition of recombinant IL-2 therapy to antifungal therapy. The patient received prolonged courses of multiple antifungal therapy and recombinant IL-2 therapy, with clearance of infection from the central nervous system. Recombinant IL-2 therapy was initiated and within a few months, his CD4 cell count started to increase.

Other cytokines such as IFN-γ and IL-7 are being tested. One ICL patient with progressive cryptococcal meningitis resistant to antifungal therapy was administered recombinant IFN-γ, which resulted in a sustained clinical recovery from cryptococcus (Netea et al., 2004). Three ICL patients with refractory disseminated nontuberculous mycobacterial infections were administered IFN-γ subcutaneously two or three times weekly in a dose of 25–50 µg m−2 in addition to antimycobacterial medications. There was sustained clinical improvement. The CD4 cell counts of two of the three ICL patients increased (Holland et al., 1994).

In studies with animal models, juvenile rhesus macaques were injected subcutaneously with simian IL-7. Recombinant IL-7 induces proliferation of naïve macaque CD4 and CD8 T-cells in vivo, demonstrating that IL-7 may be of benefit in the treatment of T-cell depletion (Moniuszko et al., 2004). Administration of IL-7 stimulates the expansion of CD4 T-cell in baboons rendered severely lymphopenic by total body irradiation and antithymocyte globulin. Median CD4 T-cell count at the end of treatment was higher in the IL-7-treated animals than in placebo-treated animals (Ahn et al., 2005).

Footnotes

  • Editor: Willem van Eden

References

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