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Idiopathic CD4+ lymphocytopenia

Idiopathic CD4+ lymphocytopenia
Literature review current through: Aug 2023.
This topic last updated: Jun 30, 2023.

INTRODUCTION — Idiopathic CD4+ T cell lymphocytopenia (ICL) is a rare clinical syndrome that is defined by persistent CD4+ T cell lymphopenia in the absence of infection with human immunodeficiency virus (HIV) 1 or any other cause of lymphopenia. It is viewed as a syndrome that likely encompasses different disorders that have in common a reduction of CD4 cell numbers. Patients with ICL typically present with opportunistic infections, malignancies, or autoimmune disorders. The epidemiology, pathogenesis, clinical manifestations, diagnosis, treatment, and prognosis of ICL will be discussed in this topic review.

DEFINITION — ICL is defined by persistent CD4+ T cell lymphopenia without evidence of familial linkage or a transmissible agent [1-5]. CD4+ T cell counts should be below 300 cells/microL or less than 20 percent of total lymphocytes measured at least twice six weeks apart in the absence of any disease or therapy that could be associated with lymphopenia. (See 'Diagnosis' below.)

BACKGROUND — ICL was first described in 1992, at the beginning of the human immunodeficiency virus (HIV) epidemic, following the recognition that acquired immunodeficiency syndrome (AIDS) was caused by HIV-1. A subset of patients suspected of having HIV because of profound CD4+ lymphopenia had no evidence of infection. Some of these individuals also had risk factors for HIV infection. However, a thorough search for an etiologic agent in subsequent years failed to yield a pathogen. The syndrome of ICL describes the immunologic findings in these patients.

EPIDEMIOLOGY — ICL is a rare condition that is found worldwide and has no clear sex predilection [6]. Patients most commonly present in their 40s [6,7]. However, ICL has been described in a small number of infants and children and also in older adults [8-14].

In a review of 230,179 cases referred for evaluation of CD4+ lymphocytopenia or illnesses indicative of immunodeficiency to the United States Centers for Disease Control and Prevention (CDC) AIDS Reporting System during the 1980s and early 1990s, 47 patients (0.02 percent) were diagnosed with ICL [3]. ICL is more prevalent among people with injection drug use disorder and people with hemophilia, although no causative infectious agents have been identified [4,5].

Understanding of this disease is based on several studies describing significant numbers of patients with ICL [7,15-18]:

At the United States National Institutes of Health (NIH), a study to follow ICL patients prospectively and define the natural history of the disorder was conducted from 1992 to 2006 and included information on 39 patients [15].

A subsequent report from the NIH included 91 patients enrolled from 2009 to 2020 and described outcomes during 374 person-years of follow-up [7].

A 2013 review analyzed 258 cases that were described in 143 published papers [16].

In 2014, another large series was reported from France in which 40 patients were followed for a mean of 6.9 years [17].

The findings from these studies are presented throughout this topic.

PATHOGENESIS — ICL is a disorder of unknown etiology and is viewed as a syndrome that likely encompasses different disorders that have in common the reduction of CD4 cell numbers. Because of the clinical similarities with human immunodeficiency virus (HIV) infection, the search for an underlying viral cause was the focus of initial investigations. Subsequently, research has focused on identifying coexistent illnesses and other immunologic abnormalities.

Attempts to identify an infectious agent — An infectious etiology of ICL has not been identified thus far. ICL was initially investigated by the United States Centers for Disease Control and Prevention (CDC) in the early 1990s [3]. Among the 47 initial patients classified as having ICL, approximately 40 percent had engaged in high-risk sexual behavior or had a history of blood or blood product exposure. However, investigation of close contacts, sexual partners, children, blood donors, and recipients of the patients' blood did not demonstrate evidence of transmissibility [3]. An extensive search for a viral etiology, utilizing serologic, culture, and polymerase chain reaction (PCR) testing, was negative [4].

Screening blood donors by assessing CD4+ T cell numbers was suggested because of concerns that an unknown retrovirus was responsible for ICL. In a pilot study of approximately 2000 blood donors, 0.25 percent of HIV-seronegative individuals were found to have transient CD4 lymphocytopenia associated with temporary illnesses. No true cases of ICL were identified, and CD4 cell count donor screening proved to be costly and ineffective [19].

In 1995, an investigation of over 300 HIV-seronegative males with hemophilia and their female sexual partners demonstrated that 2.3 percent of patients (seven men) and one female partner met the ICL case definition, although three patients recovered spontaneously [20]. The presence of hepatitis C antibodies was nearly universal in both sets of patients; however, those individuals with ICL were more likely to have a history of liver disease and splenomegaly, indicating that individuals with ICL were more likely to develop clinical disease following acquisition of hepatitis C.

Functions of CD4 T cells — CD4 is a glycoprotein expressed on the surface of various types of helper and regulatory T cells. It is essential for the interaction of T cells with other cells expressing major histocompatibility complex (MHC) class II, such as B cells and monocytes. The CD4/MHC II interaction is a critical costimulatory event in the response of T cells to antigen. The other required stimulus is the interaction of the T cell receptor (TCR) and antigen. The cytoplasmic domain of CD4 is associated with the protein tyrosine kinase Lck, a member of the Src family of tyrosine kinases. (See "The adaptive cellular immune response: T cells and cytokines".)

Binding of the TCR to antigen without the costimulatory input of CD4/MHC II leads to a state of anergy (unresponsiveness or refractoriness to activation) and possibly even to deletion by apoptosis (programmed cell death). This may be an important mechanism in T cell tolerance. Certain subpopulations of CD4+ T cells are also believed to be important in tumor surveillance. (See "Normal B and T lymphocyte development".)

Mechanism of CD4 cell loss — There is evidence for increased activation and turnover of CD4+ cells in patients with ICL, as well as accelerated CD4+ cell apoptosis [15,16,21]. In addition, a role for autoantibodies as the primary mechanism of CD4 cell depletion has been proposed [22]. In each case, it is unclear if these observations are directly involved in the etiology or merely represent the effect of CD4 depletion. Thymic function and generation of CD4+ cells appears to be intact, as evidenced by normal or increased numbers of T cell receptor excision circles (TRECs), a measure of newly formed T cells released from the thymus gland [17].

Increased activation may be the result of stimulation by an unidentified pathogen, either transiently with impaired homeostatic mechanisms or persistently, resulting in a lasting decrease in the numbers of CD4+ lymphocytes [15]. One study found increased levels of serum lipopolysaccharide (LPS) and markers of CD4+ lymphocyte activation in patients with ICL and hypothesized that abnormally increased microbial translocation through the intestinal wall ("leaky gut") may be an underlying etiology, although it is not known if the gut mucosa in ICL is also lymphopenic [23].

The presence and characteristics of autoantibodies in 51 patients with ICL was compared with 25 healthy controls using a flow-based method [22]. ICL patients had more autoantibodies against greater numbers of autoantigens than healthy controls, and, in a more detailed analysis, 34 ICL patients had antibodies against a range of 35 to 328 human proteins, while healthy controls had none. The prevalence of these autoantibodies did not correlate to the patient's clinical autoimmune status. Thirty percent of patients with ICL had anti-CD4+ T cell immunoglobulin G (IgG), and 29 percent had anti-CD4+ T cell immunoglobulin M (IgM) antibodies. Further experiments suggested that the IgG anti-CD4+ cell antibodies induced natural killer (NK) dependent cytotoxicity of CD4+ T cells. In addition, the presence of antibody dependent cytotoxicity (ADCC) or complement inducing anti-CD4 antibodies was associated with severe lymphopenia. The findings of this study suggest that autoantibodies could be involved in the peripheral destruction of lymphocytes. However, it is also possible that the autoantibodies resulted from a separate process that has not been identified [24].

Another study evaluated whether T cell numbers were decreased at effector sites by comparing rectal/sigmoid mucosal biopsies from patients with ICL and healthy controls [25]. Significant T cell lymphopenia was observed in the mucosal tissue of patients with ICL by flow cytometry and immunohistochemistry compared with healthy controls. However, functional capacity of the T cells, assessed by production of interferon (IFN) gamma and interleukin (IL) 17, was preserved in the mucosa of patients with ICL. In addition, the frequency of myeloid cells (neutrophils and macrophages) was elevated in the colonic mucosa of patients with ICL. Data from this study suggest that patients with ICL, despite gut mucosal lymphopenia and local tissue inflammation, have preserved enterocyte turnover and T helper type 17 cells with minimal systemic inflammation, which is quite a distinct finding from patients who have HIV infection.

Apoptosis may be associated with enhanced expression of Fas and Fas ligand. One study demonstrated that a patient with ICL and disseminated Mycobacterium xenopi infection had overexpression of Fas/CD95c and spontaneous and Fas-induced apoptosis [26]. Patients with stable, physiologic, CD4 cell lymphopenia without opportunistic infections, however, did not demonstrate accelerated apoptosis, suggesting that infection may be a necessary initial stimulus for this phenomenon.

Other immunologic abnormalities — Heterogeneous immune defects have been identified in patients with ICL. However, no unifying theory of pathogenesis to connect these findings has been proposed.

One area of research suggests that the pathogenesis of ICL involves the premature aging of CD4+ T cells. In one study of 20 patients with ICL, the function of CD4+ T cells was found to resemble that of cells from normal older adults [27]. The cells demonstrated increased expression of dual-specific phosphatase 4 (DUSP4), a signaling molecule that can be induced by recurrent stimulation through the TCR. When DUSP4 expression was normalized using a knockdown approach, TCR signaling was partially restored. The cause of recurrent stimulation in this patient population remains unclear, although exposure to an unidentified infectious agent (which was not detected in this study) and an intrinsic cellular defect are both possible explanations.

Some patients have low CD8+ T cells. In the series of 39 patients described above, patients with CD8 counts <180 cells/mm3 were found to have a higher risk of serious opportunistic infections and death [15]. This subgroup of patients may represent a more severe variant of ICL. The complete absence of specific CD8+ cells (CD8+28+) has been reported in a small number of patients with ICL [28]. (See 'Prognosis' below.)

Some patients have low B cell numbers or even a complete absence of B cells [15,17,28]. ICL has been associated with increases in immature or transitional B cells and increased serum levels of IL-7 [29].

Patients may have low NK cells as well, and counts <100/mm3 were associated with mortality in the French cohort [17].

Defective expression of C-X-C motif chemokine receptor 4 (CXCR4; which binds the chemokine stromal cell-derived factor 1) on the surface of CD4 cells was demonstrated in a small series of six patients with ICL [30]. The interaction of the receptor/ligand pair is critical for multiple aspects of normal T cell differentiation and trafficking.

The alpha/beta and gamma/delta T cell repertoires of ICL patients are highly restricted, suggesting a problem in differentiation or maturation during T cell development [31].

Biochemical defects of the TCR transduction pathway have been demonstrated, possibly due to an abnormality of tyrosine kinase activity of p56 (Lck) [32,33]. Defects in this kinase appear to impact CD4 cell function and maintenance of adequate numbers of cells.

Findings in one child with ICL suggested dysfunctional thymic T cell maturation [10]. Expression of CD45RA (a marker for naïve T cells) was reduced, coupled with enhanced CD45RO (marker for memory T cells) expression and an increase in gamma/delta TCR-bearing T cells [10]. Accelerated apoptosis was noted only in the CD45RO+ T cell subsets.

Some studies suggest that ICL may be due to decreased bone marrow clonogenic capability or the inability of bone marrow stem cells to mature successfully [34]. Other studies highlight a likely association with perturbation of IL-2 function, as cytokines, especially IL-2, emerged as one of the main possible mechanisms involved in the clinical and pathologic behavior of ICL. One therapeutic approach in controlling life-threatening infections and underlying disorders along with efforts to cure ICL by increasing CD4+ cell counts use cytokine interventions and transplantation, as outlined below [1]. (See 'Therapies to increase CD4 cell counts' below.)

ICL has been associated anecdotally with inflammatory conditions such as IgG4 multiorgan disease, a fibroinflammatory condition characterized by tumefactive lesions, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, and, often, elevated serum levels of IgG4 [35]; associations with systemic lupus erythematosus have also been reported [36], as well as other autoimmune conditions. (See 'Autoimmune disorders' below.)

Cases originally attributed to ICL have been subsequently linked to other immunodeficiencies, including IgM deficiency [37], anti-IFN-gamma antibody syndrome [38], and common variable immunodeficiency [39]. When underlying immunodeficiencies are uncovered, the lymphopenia is no longer considered idiopathic, and therefore ICL criteria is not met.

Possible genetic factors — A small number of specific mutations have been identified in patients initially diagnosed with ICL, and evaluations for genetic inborn errors of immunity (IEIs) that affect T cells should be sought in all patients:

In the 2023 series [7], 6 patients among 108 initially referred were found to have an IEI as a result of genetic studies (either whole exome sequencing or targeted-gene panel sequencing) [40]. In these six, pathogenic variants were detected in NFKB1, PI3KD, FAS, IL2RG, DOCK8, and CD4, and they were excluded from the ICL cohort.

Earlier studies reported hypomorphic mutations in RAG1 [41], UNC119 [42,43], and MAGT1 [44] and chimerism in Janus kinase 3 (JAK3) [45] in other patients presenting with predominant CD4+ lymphopenia.

CLINICAL MANIFESTATIONS — The majority of patients with ICL are symptomatic and present with opportunistic infections, malignancies, and/or autoimmune disorders [1,7,18]. Allergic conditions are seen less commonly. This spectrum of disorders is believed to result from immune dysregulation.

In a French cohort of 40 patients with ICL prospectively recruited and followed for a mean of 6.9 years, 25 experienced opportunistic infections, 14 had autoimmune disorders, 5 had malignancies, and 8 had minimal symptoms or were asymptomatic [17]. Fourteen patients developed acquired immunodeficiency syndrome (AIDS) defining illnesses during the study period.

In a cohort from the United States National Institutes of Health (NIH), 91 patients were followed from 2006 to 2020, for a total of over 374 person-years of follow-up [7]. The majority of participants (58 percent) either presented with or subsequently developed an opportunistic infection. In addition, 35 percent of the cohort had autoimmune disorders, and 14 percent developed malignancies.

A retrospective literature review identified 258 cases of ICL [16]. Most patients (88 percent) had one or more infections. Malignancies were reported in 18 percent, and autoimmune disorders were reported in 14 percent.

In a series of 24 patients with ICL presenting between 1993 to 2014, 71 percent had opportunistic infections, 17 percent had malignancies, and 13 percent had an unexplained demyelinating disease and neurologic problems [18].

Clinical manifestations in ICL vary depending on the degree of immunosuppression. With rare exceptions, the degree of lymphopenia predicts disease. Most patients become susceptible to opportunistic infections when the absolute CD4 cell count drops below 200 cells/mm3.

Some individuals have illnesses suggestive of moderate immune suppression (such as recurrent herpes zoster or oral thrush).

Other patients may be clinically indistinguishable from those with advanced human immunodeficiency virus (HIV) infection and present with life-threatening opportunistic infections.

Infections — Patients with ICL may present with infections caused by either by common pathogens, such as human papillomavirus (HPV) and varicella-zoster virus, or by opportunistic organisms, especially Cryptococcus and nontuberculous mycobacteria [7,15-17,46]. However, unlike patients with HIV infection, pneumocystis, toxoplasmosis, mucosal candidiasis, and cytomegalovirus (CMV) retinitis were not frequently seen as presenting opportunistic infections in a series of 91 US patients [7]. In addition, recurrent bacterial infections are not typical in adults with ICL. Adult patients presenting with recurrent bacterial infections usually have additional findings of immune dysfunction and another identifiable cause for CD4 lymphopenia, such as HIV infection or common variable immunodeficiency.

Viral infections — Patients with ICL may develop severe infections related to HPV-related or molluscum contagiosum, as well as complications of varicella-zoster virus, herpes simplex virus, human polyomavirus, CMV (especially retinitis) [15,16,47], and Kaposi sarcoma-associated herpes viruses.

Human papillomavirus — Persistent genital infection with HPV was the most common infection in patients in both the American and French series [7,15,17]. Types 2, 3, and 18 cause various clinical manifestations, including chronic pruritic papules, skin warts, alopecia areata, anogenital dysplasia, and Bowen's disease [17,48-55]. An extraordinary case of generalized verrucosis was reported in a patient with ICL [56]. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus in patients with HIV" and "Condylomata acuminata (anogenital warts) in adults: Epidemiology, pathogenesis, clinical features, and diagnosis".)

Varicella-zoster virus — Varicella-zoster virus, sometimes affecting multiple dermatomes simultaneously, was reported in approximately 10 percent of patients in the United States series [15,57]. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster".)

Fungal infections — Encapsulated fungal infections are also reported in patients with ICL.

Cryptococcus — Cryptococcal meningitis was another common presenting opportunistic infection in the American cohort [7]. Cryptococcal species also infect the lung (pneumonia), bone (osteomyelitis), skin, and musculoskeletal systems and may lead to disseminated infections [12,58-63]. (See "Cryptococcus neoformans infection outside the central nervous system" and "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in patients without HIV".)

Candida — More than 10 percent of patients suffered from chronic mucocutaneous candidiasis in one case series [15]. (See "Chronic mucocutaneous candidiasis".)

Mycobacteria — Patients with ICL may suffer from mycobacterial infections, including tuberculosis and nontuberculous mycobacterial infections [7,15,64,65]. In case series reported from the US, nontuberculous mycobacterial infections were far more common in ICL populations than infections due to Mycobacterium tuberculosis [7]. (See "Clinical manifestations and complications of pulmonary tuberculosis" and "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis" and "Overview of nontuberculous mycobacterial infections".)

Disseminated tuberculosis is believed to be a possible cause of profound lymphocytopenia [66,67]. On the other hand, patients with preexisting CD4 lymphopenia may be at increased risk for tuberculosis. Differentiating between ICL as a cause of severe tuberculosis and tuberculosis as a cause of profound CD4 cell lymphocytopenia can be challenging because, in most cases, T cell subsets were not evaluated until the patient became overtly ill, and it is impossible to say which condition was present first. In a West African study, 14 percent of patients with advanced, disseminated tuberculosis presented with CD4 cell subsets <300 cells/mm3 in the absence of HIV infection [68]. Under such circumstances, the diagnosis of ICL cannot technically be made until the tuberculosis infection has been treated, at which point lymphocytopenia should be reassessed.

Opportunistic infections seen less commonly — ICL has been identified in a number of patients with opportunistic infections, including the following:

Pneumocystis jirovecii (carinii) pneumonia [4,15,17,69]

Aspergillosis infecting the larynx [70]

Alternaria species infecting the skin [17]

Toxoplasmosis [71]

Histoplasmosis [15,71]

Hepatitis C [20]

Epstein-Barr virus (EBV) [72]

Cytomegalovirus (CMV; especially retinitis) [15,16,47]

Nocardia brasiliensis pneumonitis [17]

Unusual pathogens, such as Fusobacterium nucleatum, Salmonella typhimurium causing sepsis-like presentations, Actinomycosis species, and Rhodococcus equi [16,73-75]

JC virus and other polyoma viruses in association with progressive multifocal leukoencephalopathy [76-78]

Mucormycosis [79]

Malignancies — A number of neoplastic disorders have been described in ICL patients, similarly to those described in patients with advanced HIV disease or chronically immunocompromised patients with posttransplant lymphoproliferative disorders:

Malignancies related to HPV, such as anal, vulvovaginal, oral, or pharyngeal [7,80,81]

Kaposi sarcoma of the digestive tract or skin [7,82,83]

Lymphomas, including non-Hodgkin lymphomas [47,84,85], leptomeningeal lymphomas [86], intravascular cerebral lymphomas [87], EBV-related lymphoproliferative disease [15], and Burkitt lymphomas [72,88]

Autoimmune disorders — A number of autoimmune conditions, particularly those involving skin and mucous membranes, have been associated with ICL. In the French and American series, 14 and 23 percent were diagnosed with an autoimmune disorder, respectively, either before or after the detection of ICL [15,17]. Reported conditions include the following:

Idiopathic thrombocytopenic purpura [16,17]

Autoimmune hemolytic anemia [16,17]

Sjögren's disease [16,89]

Systemic lupus erythematosus [15,36]

Antiphospholipid antibody syndrome [15]

Polyarteritis/vasculitis [90]

Psoriasis [91,92]

Erosive lichen planus of the scalp [93]

Autoimmune vitiligo [17,94]

Behçet-like syndrome [95]

Vasculitis [16]

Thyroiditis [16,17]

Sclerosing cholangitis [96]

Other associated disorders — Associations with sarcoidosis and idiopathic bronchiolitis obliterans have been described [69,97]. In sarcoidosis specifically, the degree of CD4 lymphopenia was reported to associate with disease activity and may be responsive to anti-tumor necrosis factor (TNF) therapy [98,99].

Allergic conditions such as atopic dermatitis have also been linked to ICL [100].

Asymptomatic ICL — In the French and American series described above, 20 and 13 percent of patients with ICL were asymptomatic or had only minimal symptoms [3,17]. In studies where screening of T cell subsets was performed in cohorts of patients, a very small number of individuals who fulfilled laboratory criteria for ICL were identified. In most cases, this was a transient event, with reversal occurring spontaneously. However, individuals with lower CD4 cell subsets do exist in the general population, and a genetic predisposition is likely accountable for this finding. Limited information is available about such individuals.

EVALUATION — Consensus diagnostic criteria have not been formulated, and the approach described below is based upon the author's clinical experience as well as the evaluation performed in the original Centers for Disease Control and Prevention (CDC) report defining the syndrome [3].

Immunologic testing — The immune evaluation of a patient with suspected ICL is described below. More information about the performance and interpretation of specific tests is found elsewhere (see "Laboratory evaluation of the immune system"). The following tests are recommended:

Complete blood cell count and differential. This demonstrates lymphopenia in most (not all) patients.

Determination of lymphocyte subpopulations by flow cytometry. CD4+ T cells should be below 300 cells/mm3 or less than 20 percent of total lymphocytes on several occasions over several months. In the American series of 91 patients, the median CD4+ T cell number was 80 (range 25 to 168), with a normal reference range of 359 to 1565 [7].

The percentage of CD8+ cells may be increased, although not the absolute numbers. However, abnormalities in CD8+ cells are not consistently observed. In some patients, there may be reduced numbers of CD8+ T cells, natural killer (NK) cells, and CD19+ B cells [17,101].

In vitro studies of T cell function (lymphocyte proliferation), including response to mitogens and response to specific antigens. Lymphocyte proliferation may be depressed or normal [5].

Measurement of serum immunoglobulins (IgG, IgA, and IgM). Immunoglobulin levels may be normal or slightly low.

Autoantibodies to lymphocytes have been demonstrated in ICL patients, although these were highly heterogeneous in nature. A subpopulation of ICL patients was found to have anti-CD4+ T cell antibodies [22]. Although commercially available laboratory assays may not be broadly available to further characterize autoantibodies in ICL patients, research laboratories are able to evaluate the presence and functional activity of such markers, which may serve as therapeutic targets in the future.

Measurement of serum-specific antibodies in vaccinated children and adults, such as titers of anti-tetanus, anti-diphtheria, and anti-pneumococcal antibodies to assess the functional status of the humoral immune system. If titers are low, the patient should be revaccinated and postvaccination titers measured one month later. Vaccination response may be normal or weak, depending upon the degree of immune derangement. Results are usually normal if the only detectable defect is CD4 lymphopenia. (See "Assessing antibody function as part of an immunologic evaluation".)

Exclusion of other infections — We suggest evaluation for human immunodeficiency virus (HIV) 1, HIV-2, tuberculosis, hepatitis B and C, and several other viruses, as described in this section.

For HIV testing, we use a fourth-generation combination HIV-1/2 immunoassay that detects HIV p24 antigen and HIV antibodies for both HIV-1 and HIV-2. If positive, a confirmatory HIV-1/HIV-2 antibody differentiation immunoassay should be performed to distinguish between the viruses, as discussed in detail separately. (See "Screening and diagnostic testing for HIV infection".)

On rare occasion, patients with very advanced immunodeficiency and HIV infection, serologic diagnosis alone might not always be reliable in the presence of severe malfunction of the humoral immune system, and this is particularly true in children with advanced disease. In this settings, an HIV-1 nucleic acid test (NAT) is used for confirmation of HIV-1 infection. If the molecular test is negative, it is important to rule out HIV-2 infection.

Testing for tuberculosis should be performed and is discussed separately. (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".)

We test for any active viral infections which could lead to lymphopenia, including serologic assays for hepatitis B and C viruses, Epstein-Barr virus (EBV), human herpesvirus-6, cytomegalovirus (CMV), respiratory syncytial virus, parainfluenza virus, enterovirus, adenovirus, parvovirus B19, coronavirus, and congenital rubella. These infections should be excluded, although exclusive involvement of CD4 cell subsets is very unusual.

Testing for human T-lymphotropic virus (HTLV) 1 and HTLV-2 would be appropriate in areas of the world in which infections with these viruses are prevalent. (See "Human T-lymphotropic virus type I: Virology, pathogenesis, and epidemiology".)

Other possible tests — One or more of the following tests may be indicated if the patient has suggestive symptoms or findings. These tests have revealed underlying causes in small numbers of cases.

Serologic assays for measles virus and human papillomavirus (HPV).

Serologic assays for Mycoplasma, Rickettsia, and Borrelia burgdorferi.

Cultivation of peripheral blood mononuclear cells (PBMCs) with normal PBMCs, lymphoid cell lines, or both, which can suggest the presence of an unidentified pathogen.

Immunobiologic studies including autoimmune profiles, measurements of beta 2-microglobulin levels, and selective typing of human lymphocyte antigen.

Disseminated fungal infections should be excluded if clinically indicated, although they are usually a consequence of prolonged immune suppression rather than a cause of CD4 lymphopenia, as previously discussed. Evaluation may include blood cultures, biopsy of lesions seen on imaging, serum cryptococcal antigen, galactomannan testing for Aspergillus, and other studies. (See "Epidemiology of pulmonary infections in immunocompromised patients" and "Epidemiology and clinical manifestations of invasive aspergillosis" and "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults".)

DIAGNOSIS — ICL is a diagnosis of exclusion. The diagnosis requires the demonstration of CD4+ T cell counts below 300 cells/mm3 or less than 20 percent of total lymphocytes on at least two separate analyses. When a low CD4 count is initially detected, it should first be confirmed that the patient was actually the source of the sample. If there is no underlying illness, then allowing one to three months between measurements is reasonable.

No other immunologic abnormalities should be detected, and no infections that can cause CD4+ lymphopenia should be present. (See 'Immunologic testing' above and 'Exclusion of other infections' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of the clinical presentation of ICL includes acute or chronic retroviral infections, sarcoidosis, common variable immunodeficiency, congenital immunodeficiencies, and immunosuppressive states induced by chemotherapy, neoplastic disease, acute respiratory distress syndrome, or autoimmune disorders [69,102-104]. However, the finding of a predominantly isolated CD4 lymphocytopenia significantly narrows the differential.

Other causes of CD4 lymphocytopenia — Many infectious states can lead to transient CD4 lymphopenia because the cells are being consumed in the infectious process. This is seen in bacterial sepsis, measles, and other serious infections. Alternative diagnoses would be suggested by the clinical presentation and comorbidities. There are few diseases, however, that exclusively affect CD4+ T cell subsets in isolation. Tests to exclude these infections were reviewed previously. (See 'Evaluation' above and 'Other possible tests' above.)

OKT4 epitope deficiency — Patients who appear to have low or absent CD4 cells, in the absence of significant illness, should be evaluated for OKT4 epitope deficiency (OMIM 613949), a condition in which the antigen recognized by the monoclonal antibody most commonly used to detect CD4 cells by flow cytometry, OKT4, is deficient or absent [105,106]. Homozygotes have a complete absence of the epitope, while heterozygotes have approximately 50 percent of the normal level [107].

The monoclonal antibody Leu-3a, or others, can be used to detect CD4 instead in such individuals. Individuals with OKT4 epitope deficiency usually have normal CD4+ T cell number and do not develop infections, although there may be an association with autoimmune conditions [107,108].

Patients with low levels of other cell types — Severe combined immunodeficiency (SCID) disorders and combined immunodeficiencies (CIDs), as well as advanced human immunodeficiency virus (HIV) disease, should be excluded in patients with low CD8 T cells, low B cells, or natural killer (NK) cells.

Most forms of SCID present in infancy or early childhood, but less severe forms and some CIDs can present in adults. Molecular diagnostic studies are often necessary to definitively diagnose these disorders. (See "Severe combined immunodeficiency (SCID): An overview" and "Combined immunodeficiencies: An overview".)

NK cell deficiency disorders should be considered in patients with low NK cell counts. (See "NK cell deficiency syndromes: Clinical manifestations and diagnosis" and "NK cell deficiency syndromes: Treatment".)

CD8+ T cell deficiency is a feature of many chronic autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's disease, systemic sclerosis, dermatomyositis, primary biliary cholangitis (also known as primary biliary cirrhosis), primary sclerosing cholangitis, ulcerative colitis, Crohn disease, psoriasis, vitiligo, bullous pemphigoid, alopecia areata, idiopathic dilated cardiomyopathy, type 1 diabetes mellitus, Graves' disease, Hashimoto's thyroiditis (chronic autoimmune thyroiditis), myasthenia gravis, IgA nephropathy, membranous nephropathy, and pernicious anemia. Epstein-Barr virus (EBV) disease has been shown to induce specific CD8 T cell deficiency, and there are data to suggest that vitamin D deficiency may also trigger CD8+ T cell depletion [109].

MANAGEMENT — There is no standard treatment for ICL except for management of the associated conditions and the prompt treatment of infections. Infections (such as mycobacteria) further deplete the CD4 cell pool, and treatment may improve the degree of CD4 specific lymphopenia. There are no controlled trials evaluating different approaches to the management of ICL. Vaccination is also important. Patients who present with an opportunistic infection should be treated and then started on secondary prophylaxis for that particular organism.

Immunizations — Live-virus vaccines should be avoided in all patients with ICL, but other routine vaccinations should be given. This is discussed in detail elsewhere. (See "Immunizations in persons with HIV".)

Patients with CD4 counts <200 cells/mm3 — Antimicrobial prophylaxis for opportunistic infections is recommended for most patients with ICL and CD4+ T cell counts below 200 cells/mm3. Prophylaxis should be continued as long as the CD4 counts remain low.

Prophylaxis against infections — We advocate following the recommendations for antimicrobial prophylaxis for patients with human immunodeficiency virus (HIV), with which there is extensive clinical experience. Although reports suggested that patients with ICL may not be at identical risk for infections [7,15], a relatively small number of patients have been studied. Protocols and indications for initiation are reviewed in detail elsewhere. (See "Overview of prevention of opportunistic infections in patients with HIV".)

In addition, immune globulin replacement should be considered for children with recurrent serious bacterial infections as a presenting symptom. (See "Immune globulin therapy in inborn errors of immunity".)

Patients with recalcitrant infections — Therapies to increase CD4 cell counts may be beneficial to patients in whom infections do not clear with standard antimicrobial treatment. There are no controlled trials evaluating therapies for ICL, and reports in the medical literature are exclusively anecdotal.

Therapies to increase CD4 cell counts

Interleukin 2 – The most widely used treatment to increase CD4+ T cells is interleukin (IL) 2 (aldesleukin) [110]. IL-2 should only be considered in individuals with significant recalcitrant infections and CD4 counts that remain very low (eg, less than 100 cells/mm3). IL-2 will increase CD4 counts in most patients, although it is not clear that these cells are functionally normal.

There are a few case reports of successful use of IL-2 or polyethylene glycol (PEG) IL-2 for this purpose in patients with mycobacterial disease, cryptococcal meningitis, and generalized herpes zoster and gastrointestinal candidiasis [57,70,111-114]. IL-2 therapy has significant side effects and should be administered with informed consent as part of a comprehensive investigational protocol.

Other cytokine therapies – Interferon (IFN) gamma and IL-7 have also been used in patients with ICL [110,115].

Patients with life-threatening complications

Hematopoietic cell transplantation — Allogeneic bone marrow transplantation has been used to treat a small number of patients with severe manifestations of ICL. In an early report, transplantation resulted in restoration of CD4+ T lymphocyte counts in a patient with ICL complicated by opportunistic infections and aplastic anemia [116]. Subsequent reports have described other successfully treated patients [117,118]. In one selected case report, treatment with rituximab and IL-7 in addition to allogenic stem cell transplantation was successful in a child with Epstein-Barr virus (EBV) associated mucosa-associated lymphoid tissue (MALT) lymphoma arising in the salivary gland that was preceded by an ICL diagnosis [119]. The benefits of this intervention would only outweigh the risks for patients with recurrent serious infections not prevented with prophylaxis or other life-threatening complications.

MONITORING — There are no published guidelines for monitoring patients with ICL. For patients who are well, measurement of CD4 subsets twice yearly would be appropriate in most cases. If CD4 counts improve subsequently, the need for prophylaxis against opportunistic infections can be revisited.

Other issues:

Patients should be evaluated for manifestations of infection with human papillomavirus (HPV), with careful examination of the anogenital regions and, in female patients, regular gynecologic care.

Live vaccines should be avoided in patients with CD4 counts <200 cells/mm3.

It would not be advisable for these individuals to donate blood, as an unidentified infectious etiology may ultimately be identified in some patients.

PROGNOSIS — The prognosis of patients with ICL ultimately depends on the degree and duration of immune suppression and the presence and type of associated infections and comorbidities and may also be a reflection of different underlying etiologies. Thus, the prognosis is variable:

In a small group of patients, lymphopenia can be a temporary finding that reverses over time [17,20].

In most of the cases reported, CD4 cells stabilize at a low level rather than continuing to fall as in human immunodeficiency virus (HIV) infection, although there are reports of ICL patients with gradual ongoing decline in CD4 cells [15,101].

In the French cohort, 6 of 40 patients died during the study period (15 percent) [17]. Only two of the six deaths were related to infections (cerebral Mycobacterium tuberculosis infection and sepsis from Escherichia coli with multiorgan failure). All-cause mortality was associated with CD4 <150 cells/mm3 and low natural killer (NK) cell count (<100 cells/mm3).

In the initial American series from the National Institutes of Health (NIH), patients with low CD8+ T cell counts at presentation appeared to be at higher risk of death from opportunistic infections [15]. Four patients died of an opportunistic infection or a condition directly related to an opportunistic infection, and three additional patients died of causes deemed unrelated to ICL. In the later American series, the rate of death was similar to that of the general population [7].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

Definition – Idiopathic CD4+ lymphocytopenia (ICL) is a clinical syndrome characterized by persistent CD4+ T lymphocyte depletion below 300 cells/mm3 or less than 20 percent of total lymphocytes in the absence of human immunodeficiency virus (HIV) 1 or 2 infection or other known causes of immunodeficiency. (See 'Introduction' above and 'Definition' above.)

Epidemiology – ICL is a rare disorder that has been reported around the world. It is most commonly identified in adults, although it can affect infants and children. There is no clear sex predilection. (See 'Epidemiology' above.)

Etiology/pathogenesis – The etiology or etiologies of ICL are unknown, but theories include destruction of CD4+ T cells by autoantibody-mediated dependent cytotoxicity (ADCC), increased CD4+ activation and turnover, and/or accelerated apoptosis (programmed cell death) in patients with advanced immune suppression and opportunistic infections. (See 'Pathogenesis' above.)

Clinical manifestations – Clinical manifestations range from an isolated laboratory finding without clinical illness to life-threatening opportunistic infections. Most patients experience infections, and a minority develop autoimmune disorders or malignancies. Clinical manifestations depend on the duration and degree of immune suppression. (See 'Clinical manifestations' above.)

Evaluation and diagnosis – ICL is a diagnosis of exclusion. CD4+ T cell counts should be confirmed to be low on at least two occasions separated by at least six weeks. HIV infection, genetic inborn errors of immunity (IEI), malignancies, and exogenous causes of immune dysfunction must be excluded. (See 'Evaluation' above and 'Diagnosis' above and 'Differential diagnosis' above.)

Management – The management of ICL should be directed at treatment of associated conditions. There are no formal guidelines for treatment or monitoring. (See 'Management' above.)

For patients with CD4 counts <200 cells/mm3, we suggest prophylaxis against opportunistic infections using the protocols developed for patients with acquired immunodeficiency syndrome (AIDS) (Grade 2C). Prophylaxis against cryptococcal infections may be of particular importance in patients with ICL because it is the most frequently reported serious infection. (See 'Prophylaxis against infections' above.)

For patients who present with an opportunistic infection, we suggest that secondary prophylaxis for that specific infection be administered following appropriate treatment (Grade 2C).

For children who present with recurrent bacterial infections, we suggest immune globulin replacement (Grade 2C). (See 'Prophylaxis against infections' above.)

For patients with CD4 counts that are persistently very low (eg, <100 cell/mm3) and who suffer from recalcitrant or recurrent infections that cannot be prevented or treated by other means, we suggest experimental therapies to increase CD4 counts (Grade 2C). Interleukin (IL) 2 has been used in this setting, although it should be administered in the setting of an investigational protocol because of potentially severe adverse effects. Hematopoietic cell transplantation has been used successfully as a heroic measure in patients with symptomatic advanced CD4 lymphocytopenia. (See 'Therapies to increase CD4 cell counts' above.)

Prognosis – The prognosis is variable and depends largely on the severity of the clinical presentation, with most severe infections occurring at diagnosis or soon thereafter. In most patients, CD4 values remain stable rather than progressing to the very low levels seen in untreated HIV infection. Concomitant CD8+ lymphocytopenia confers an increased risk of opportunistic infections and lower CD4 (<150 cells/mm3), and low natural killer (NK) cell counts may be a predictor of mortality. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.

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Topic 3917 Version 26.0

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