T-Cell Subsets in Health, Infectious Disease, and Idiopathic CD4+T Lymphocytopenia

  1. Jeffrey Laurence, MD
  1. From Cornell University Medical College, New York, New York. Requests for Reprints: Jeffrey Laurence, MD, Department of Medicine, Division of Hematology-Oncology, Cornell University Medical College, 411 East 69th Street, New York, NY 10021. Grant Support: By grants from the U.S. Army Medical Research Acquisition Activity DAMD 17-90-Z-0049 and by grants AI-29119 and AI33322 from the National Institutes of Health.
     
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    Abstract

    Purpose: To update our knowledge about normal absolute values for CD4+ and CD8+ peripheral T-lymphocyte subsets and to show how these values are influenced by infectious disease. These data are discussed in the context of a newly identified syndrome, idiopathic CD4+ T lymphocytopenia and severe unexplained human immunodeficiency virus (HIV)-negative immune suppression (ICL/SUHIS).

    Data Identification: Studies done after 1978, when T-lymphocyte subset analysis using monoclonal antibodies was introduced, identified from a MEDLARS computer search and from personal files.

    Study Selection: All English-language articles that included the number of patients studied; the criteria for patient selection; and the means, ranges, and standard deviations for absolute counts of peripheral T-cell subsets.

    Results of Data Analysis: The effects of certain bacterial, viral, parasitic, and fungal infections; analytic variance; and biologic factors on T-lymphocyte subsets must be considered in assessing such values in health and disease. Quantitative T-cell abnormalities secondary to advanced HIV infection may be dissociated from physiologic changes, congenital disorders, and most other conditions by documentation of absolute CD4 counts of less than 400/mm3, a progressive depletion of CD4 cells, and a CD4:CD8 ratio of less than 1.0. Designation of ICL/SUHIS as a new syndrome, dependent solely on CD4 cell count, raises the possibility that persons with an extraordinary diversity of conditions, including those with stable, physiologic CD4 lymphopenia, will be given the diagnosis.

    Conclusions: Persons with a CD4 count of less than 300 to 400/mm3, a progressive decline in absolute CD4 count, and a CD4:CD8 ratio of less than 1.0 should be aggressively investigated for HIV infection as well as for other causes of immune deficiency, regardless of intercurrent infections. The search for potential novel infectious causes in syndromes such as ICL/SUHIS may be most productive among such a subset of all persons with CD4 counts less than normal levels.

    Despite the myriad abnormalities of immune function seen at all stages of human immunodeficiency virus (HIV) infection, reflected by both qualitative and quantitative T-cell, B-cell, and monocyte alterations, depletion of peripheral CD4+ helper-inducer T lymphocytes remains the best surrogate marker for clinical progression of HIV disease. As a consequence, antiretroviral therapy is used in HIV-seropositive, asymptomatic persons with CD4 counts of less than 500/mm3 and, in certain instances, in persons with counts less than 700/mm3, and prophylaxis against opportunistic infections is recommended when CD4 counts decrease to less than 200/mm3 [1]. In many situations the rate of decline in CD4 count, perhaps reflective of the phenotype of the predominant HIV isolate in a given person, is more predictive of advancing disease than is the absolute count [2]. This reliance on one laboratory value to render several treatment decisions remains dogmatic in the care of patients with HIV infection.

    Recent reports have described patients with CD4+ T lymphopenia in the absence of serologic or virologic evidence of HIV-1 or HIV-2 infection [3-8]. Diagnosis of this syndrome, termed idiopathic CD4+ T lymphocytopenia by the Centers for Disease Control and Prevention [4], relies exclusively on a single measurement of immune status: a CD4 count of less than 300/mm3 on two occasions. The same phenomenon is referred to as severe unexplained HIV-seronegative immune suppression by the World Health Organization [8], with the additional requirement that the patient have a disease indicative of a cellular immune deficiency.

    In some instances, persons with idiopathic CD4+ T lymphocytopenia and severe HIV-negative immunosuppression (ICL/SUHIS) have infections pathognomonic of category B and C HIV infection [3-8], conditions that can influence the production or compartmentalization of T-cell subpopulations, leading to alterations in the numbers of circulating CD4+ or suppressor/cytotoxic CD8+ T cells and the CD4:CD8 ratio. In addition, although previous reviews have quantitated T-cell subsets in asymptomatic, HIV-seronegative persons, little attention has been paid to persons at the lowest limits of these normal ranges. This issue is not simply academic, given that certain patients with ICL/SUHIS are given prophylactic treatment against Pneumocystis carinii pneumonia, perhaps unnecessarily [7].

    This report updates the state of knowledge regarding the range of absolute CD4+ and CD8+ T-cell counts in healthy controls, in HIV-seronegative but HIV at risk persons, and in persons with infectious disease.

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    Variability in Measurements of T-Lymphocyte Subsets

    Differentiating disease-associated or therapy-induced alterations in in vitro immunologic parameters from other sources of variability is essential for accurate interpretation of results. Multiple factors, however, can influence absolute CD4+ and CD8+ T-cell counts.

    Analytic Variability

    The temperature of the specimen in transit, the type of anticoagulant used, and the delay in analysis are of some importance [9]; however, the major source of analytic variability is the actual phenotype measurement, which is typically done using murine monoclonal antibodies and flow cytometric analysis. Absolute subset values are a product of three components: the total leukocyte count, the lymphocyte differential, and the percentage of CD3+ T lymphocytes that express membrane CD4 or CD8. Published guidelines have minimized technical difficulties, including problems of coexpression of CD4 and CD8, contamination of preparations by CD4+ but CD3- non-T cells, and genetic polymorphisms among lymphocyte antigenic determinants [9]. No mandatory standards exist, however, for immunophenotyping by flow cytometric analysis, and limited information is available on the degree of interlaboratory variability. Indeed, both analytic and biologic variability exist in all three test components. One quality assessment found that no technical change related to instrument, monoclonal antibody, or fluorochrome label would significantly improve interlaboratory agreement on CD4 measurements [10]. Yet, it is heartening that a recent multicenter proficiency test of 13 laboratories found that the analytic variability for the percentage and absolute number of CD4+ T cells using specimens from normal controls was 4.1% and 8.4%, respectively, compared with values of 6% and 29.4%, respectively, measured 4 years previously [9].

    Biological Variability

    Biological variability may be even greater in magnitude than analytic variability. First, circannual (seasonal) rhythms may occur, with a 13% change from week to week in total lymphocyte counts [11] and with substantial alteration in absolute CD4 and CD8 counts from month to month [12]. No such variability was seen in the CD4:CD8 ratio or in the total number of CD3+ T lymphocytes [12], however, and persons maintained a fixed, discrete range of CD4 values when followed for periods of 2 [13] or 5 [14] years, even among those with initial values less than 300/mm3.

    Other quantifiable factors that can influence these cell populations include age, sex, ethnic origin, circadian rhythm, physical and psychological stresses, drugs (such as zidovudine, cephalosporins, cancer chemotherapeutic agents, nicotine, adrenal and gonadal steroids), antilymphocyte autoantibodies, and splenectomy [7, 9, 15, 16] (Table 1). Sex need not be taken into account when assessing CD8 counts. In one study, however, the mean CD4 percentages were greater for women than for men by 3.5% (P = 0.0001), and the CD4:CD8 ratio was 0.17 units greater for women than for men [17]. Age also does not affect CD8 values, but an increase of 1.1% per decade occurs in the percentage of CD4+ cells, and a 0.09-unit-per-decade increase in CD4:CD8 ratio in persons older than 20 years [17]. Without appropriate correction, as many as 10% of elderly patients (>70 years) would be classified as having values higher than published normal ranges [17].

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    Table 1. Effect of Psychological and Physical Stressors and Splenectomy on T-Cell Subpopulations*

    Standard values for T-cell subsets have been generated using a Monte Carlo procedure for nongaussian distribution and the best-fit distribution of each parameter [17]. However, the literature offers contradictory assessments, usually based on small samples. For example, although most studies have described age-associated increases in the percentage of CD4+ T cells with no effect on CD8 values, a few noted decreases in the percentage of CD8+ cells [18-20]. Some studies have reported that the absolute number of CD4+ T cells remains stable with advancing age [20], whereas others have shown a decline as lymphocytes constitute a lower percentage of peripheral leukocytes [19]. In one large survey of adolescents between ages 11 and 16 years, absolute counts did not differ from adult values [14]. In addition, the inclusion of heterosexual women did not statistically affect the overall mean values for the various subsets [14]. An earlier report supported these basic tenets, except for the fact that the adult pattern of CD4 counts and CD4:CD8 ratios was not seen in adolescents between ages 12 and 16 years [21].

    It should also be recognized that some blacks and Asians may lack or be heterozygous for one CD4 epitope, defined by the OKT4A monoclonal antibody, but not by the Leu-3a reagent [4, 18]. Otherwise, race does not appear to significantly influence CD4 or CD8 determinations, at least in the absence of physiologic lymphopenia [18, 21].

    Proper accounting of these variables is important in evaluating an individual patient, although these factors are unlikely to lead to a diagnosis of ICL/SUHIS or to be associated with a progressive decrease in any cell population. Biologic variability due to diurnal rhythms may be of greater significance, however. From a nadir at approximately 12:30 hours, CD4 and CD8 counts increase to a peak at about 20:30, whereas CD3 counts reach a zenith somewhat later, at 4:30 [22, 23]. The increment in absolute CD4 counts can be as high as a cumulative 60% [22]. Many laboratories recommend that serial T-cell subset analyses be done on blood samples taken at a standard time of the day [22], but this admonition is rarely addressed in clinical practice or in small studies. Although these changes persist in HIV-positive persons, their magnitude is greatly attenuated [22]. The physiology of this response is unclear, given that neither the circadian organization of steroid secretion from the adrenal cortex nor testis appears to correlate with the 12-hour harmonic of T-lymphocyte circulation [23]. Circadian fluctuations in growth hormone may play a role. Changes in T-cell subsets might also be expected in association with the menstrual cycle, but such alterations have not yet been well documented. Changes linked to pregnancy are noted below.

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    Effects of Pharmacologic, Psychological, and Physical Stressors

    Changes in T-cell subsets may result from the exogenous administration of adrenal or gonadal steroids. Acute glucocorticoid treatment of three volunteers led to suppression of both CD4 and CD8 counts, from a baseline of 920 33 and 510 31, respectively, to 270 4 and 240 0.14 (mean SE), respectively, with a return to normal values within 48 hours [24]. These changes were probably secondary to redistribution of leukocytes among the periphery, bone marrow, lymph node, and spleen, with a decreased efflux from lymphoid organs [25]. Chronic changes secondary to long-term steroid use are less dramatic [26] and must be distinguished from the disease process that prompted use of the drug.

    Transient changes may also be seen after severe physical or psychological stress. In one study of 15 healthy persons [27], cognitive stressors caused elevations in heart rate and blood pressure, without affecting serum cortisol or catecholamine levels or absolute T-lymphocyte subsets (Table 1). Physical stress (ergometry), leading to elevation in heart rate, blood pressure, and serum adrenaline and noradrenaline, has been associated with a concomitant increase in the absolute number of CD8+ T cells relative to CD4+ T cells, resulting in a decrease in the CD4:CD8 ratio (Table 1). Splenectomy has also been linked to a stable increase in the percentage, but not the absolute count, of CD4+ cells; an increase in absolute CD8+ cells; and a decrease in the CD4:CD8 ratio Table 1 [28].

    Other medical conditions accompanied by severe stress may have immediate effects on peripheral T-cell subsets without long-lasting sequelae. The most dramatic changes have been reported after acute myocardial infarction. In one study [29], although absolute CD4 and CD8 counts did not differ statistically between infarct and control groups, a decrease in CD4:CD8 ratios was noted among infarct patients, with these low values typically persisting for 3 or more days after the event. The CD4:CD8 ratios among the 11 infarct patients (0.83 0.43) differed from both control (2.12 1.13, P = 0.001) and acute sepsis cases (1.76 1.05, P = 0.004); however, no statistical difference was seen in ratios between the control and acute sepsis groups [29].

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    Ranges for T-Lymphocyte Subsets in Normal Controls

    Table 2 shows studies of unselected, asymptomatic adults that provided means, standard deviations, and ranges or 95% CIs for absolute CD4 and CD8 counts. All but three included screening for HIV-1 infection by enzyme-linked immunosorbent assay (ELISA). The largest studies [14, 30, 31] specified that attention was paid to the time of day at which blood was drawn, with duplicate determinations and quality control measures in place; all participants were HIV seronegative. The smaller studies usually did not provide specific information about analytic or biologic variables for controls; these data are included for comparison with the more established normal ranges and as specific controls for the studies listed in Tables 3 and 4. (When HIV serologies were not done in these latter instances, a notation has been included in the appropriate table.) Companion data are given for HIV-seronegative pregnant women as well as for HIV-seronegative controls from the two major risk groups for HIV infection: homosexual men and intravenous drug abusers.

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    Table 2. T-Lymphocyte Subsets: Asymptomatic, Predominantly HIV-Seronegative Controls
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    Table 3. T-Lymphocyte Subsets: Infectious Diseases in Previously Healthy Persons*
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    Table 4. Miscellaneous Conditions Associated with Changes in T-Lymphocyte Subsets

    The means for CD4+ and CD8+ T-cell counts presented in each of these reports are remarkably similar, despite differences in sex and the broad age groups included as adults. In one study [14], a small number of these ostensibly healthy persons had stable but very low CD4 counts during a 5-year period, technically fulfilling the criteria for idiopathic CD4+ T lymphocytopenia.

    Clearly, other phenomena must be considered when evaluating CD4+ T-cell counts below the lowest limits of normal. The homeostatic control of peripheral T lymphocytes is susceptible to the various internal and environmental influences described above and conditioned by circulating hormones, cytokines, and other lymphocyte products [46]. In addition, the total number of peripheral T cells appears to be independent of cellular input. In experimental systems, in the absence of either the CD4+ or CD8+ T-cell population, cell loss is routinely compensated for by the remaining subset [46]. This phenomenon is also seen in patients with HIV, given that throughout much of the clinical course the total T-cell levels (CD3+) remain constant in the face of declining CD4 cells, secondary to CD8+ T lymphocytosis [47].

    Regulation of these T-cell populations is rapid and flexible, adapting to environmental changes through selection and amplification of appropriate T-lymphocyte clonal specificities. In adults, T cells are replaced primarily by cell proliferation at the periphery. Although more than 30% of such cells are renewed every 3 days, total numbers are relatively fixed, with lymphocytes at varying stages of differentiation having different probabilities of survival, modulated by the environment [46]. Evaluation of T-cell population kinetics, with documentation of stability in absolute values and attention to the subset ratio, is thus important in defining normal fluctuations in T-cell counts.

    Unlike HIV, which involves a progressive decline in CD4 counts that is typically accompanied by a depressed CD4:CD8 ratio, combined changes of physiologic CD4+ T lymphopenia (low CD4 percentage and absolute counts <400/mm3), and an inverted ratio occurred in only 0.6% of 500 persons enrolled in one large study [14], and even these markedly depressed values were stable during a 5-year period. This observation has been supported by other studies: only 1 of 275 healthy blood donors had a CD4 count of less than 300/mm3 (CD4:CD8 ratio not reported) [48], and none of 2284 HIV-seronegative homosexual men had CD4 counts of less than 300/mm3 with multiple determinations during a 10-year period [49].

    It has been suggested that such persons with an absolute CD4 count physiologically set significantly below the means outlined in Table 2, if infected with HIV, might be expected to progress to a clinical definition of the acquired immunodeficiency syndrome (AIDS) at a more rapid rate than a patient whose baseline CD4 counts were significantly greater than the mean [13]. Some anecdotal data support this contention [50], but no evidence exists that these persons are otherwise compromised immunologically.

    Unless long-term stability of CD4 counts less than the 95% CI and CD4:CD8 ratios of greater than 1.0 are documented, such persons with low CD4 cell counts warrant further evaluation. Indeed, before the identification of HIV-1 and HIV-2 as the primary etiologic agents of AIDS, the possibility of segregating healthy homosexual men from those at potential risk for disease, using a combination of depressed absolute CD4 counts and CD4:CD8 ratio, was suggested [34]. One blood center even conducted a T-lymphocyte subset analysis as an interim screening procedure for a putative AIDS agent [51]. Nearly 2% of 8715 consecutive volunteer blood donors between 17 and 77 years old had CD4:CD8 ratios 0.85, and blood from these persons was not used for clinical purposes. Most had concomitant low CD4 values, and follow-up showed that some belonged to AIDS risk populations, despite denials at the time of donation [51].

    Other studies examining persons at high risk for HIV who were repeatedly seronegative for HIV by ELISA and immunoblotting but who had HIV-1 proviral DNA detectable by polymerase chain reaction [35, 52], support the use of CD4 counts in conjunction with the CD4:CD8 ratio. Similarly, among male homosexual couples discordant for HIV-1 antibodies, those without evidence for HIV infection by polymerase chain reaction amplification of proviral DNA had stable CD4+ T-cell counts and CD4:CD8 ratios greater than 1, regardless of the absolute number of cells in these subsets [53]. This finding further supports our recommendation that all persons with a CD4 count of less than 400/mm3 and a CD4:CD8 ratio less than 1.0 should be investigated for HIV, as well as for other causes of immune deficiency, and that the definition of ICL/SUHIS be restricted to patients with less than 300 to 400 CD4+ cells/mm3, an inverted ratio, and evidence of a progressive decline in CD4+ cells. A similar approach, together with the aggressive tracing of donors and recipients, has been recommended within the transfusion community to investigate cases of idiopathic CD4+ T lymphocytopenia [54] and is further discussed here.

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    T-Lymphocyte Subsets in Infectious Disease

    As reported in Table 3, common pathogenic and opportunistic bacterial, viral, parasitic, and fungal diseases can cause transient alterations in T-lymphocyte subsets. These changes may be superimposed on various functional immune defects associated with such infections [68] as well as on ill-defined syndromes of putative infectious etiology sometimes linked to decrements in CD4 counts, such as the chronic fatigue syndrome [69]. Even immunizations may affect absolute numbers of T-cell subsets, transiently but significantly depressing CD4:CD8 ratios to less than 1.0 in 25% of cases in one study [70].

    Two risk factors for HIV, intravenous drug abuse (see Table 2) and clotting disorders (see Table 4), are not necessarily associated with significant alterations in absolute peripheral CD4+ or CD8+ T-cell counts, despite the fact that chronic antigenic exposure might have been expected to render these patients particularly susceptible to lymphocyte subset alterations. Infections linked to at least transient depression in CD4 counts (including tuberculosis, hepatitis B, and Epstein-Barr virus-associated mononucleosis) are usually associated with a CD4:CD8 ratio greater than 1.0, even if it is statistically lower than control ratios. This finding also appears to be typical of other opportunistic infections seen in patients with HIV, including toxoplasmosis and P. carinii pneumonia (see Table 3). For oral candidiasis [64, 65] and cryptococcosis [66, 67], the numbers of HIV-seronegative patients studied are still too small to permit definitive conclusions.

    The major exception to the generalization that infectious disorders do not cause a low CD4 count in conjunction with a CD4:CD8 ratio of less than 1.0 is acute cytomegalovirus infection, in which depression of CD4 counts is typically accompanied by a marked increase in CD8 values (see Table 3). Both usually return to baseline after resolution of cytomegalovirus disease, with no statistical difference in absolute CD4+ or CD8+ T-cell counts in cytomegalovirus-seropositive compared with seronegative persons (see Table 2). Human T-cell lymphotropic virus type II (HTLV-II) occurs in a substantial portion of intravenous drug abusers and some homosexual men at risk for HIV and is capable of altering CD4 counts for prolonged periods. In HTLV-II-positive persons whose T cells do not exhibit spontaneous proliferation in vitro, T-cell subsets do not differ from those of normal controls [61]. Among most HTLV-II- positive persons whose cells do exhibit such spontaneous growth, however, a significant increase in both CD4+ and CD8+ T-cell subsets, without alteration in CD4:CD8 ratio, has been reported (see Table 3).

    Lymphopenia, with artificial lowering of absolute counts, affects T-cell phenotype in the presence of certain infectious diseases or congenital disorders. Reference ranges for analysis of disease-related variations by T-cell subset percentages may be more appropriate in this setting [17, 71], but these results do not alter our approach to assessing T-cell changes.

    Transient alterations in CD4 values in infectious diseases also occur in HIV-seropositive persons. These changes may have clinical relevance, although their pathophysiologic nature is incompletely understood. For example, primary cytomegalovirus infection in HIV-positive persons may initiate a more rapid and substantial decline in CD4+ T-cell counts than in HIV-positive controls not exposed to cytomegalovirus [72]. The risk for advanced HIV disease in cytomegalovirus-seropositive persons was 2.5 times that of a similar cytomegalovirus-negative cohort [72].

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    Congenital Conditions That May Be Recognized Late in Life

    Common variable immunodeficiency may lead to altered CD4 counts recognized in later life. It is an important exclusion criterion for ICL/SUHIS [4, 8]. Although progressive decreases in CD4+ T cells were not documented during a 2-year follow-up of HIV-seronegative and culture-negative patients with common variable immunodeficiency [73], including those with low baseline CD4 values [39], initial absolute counts may be substantially less than the usual mean. Although CD4: CD8 ratios of less than 1.0 are unusual in common variable immunodeficiency [73], they have been reported [39, 74], unfortunately, in the absence of documentation of HIV serostatus. In these cases, CD4+ T-cell subset analysis may be illuminating because decrements in CD4 count appear to be secondary to a dramatic deficit in those cells that induce CD8+ suppressor cells, the CD4+ CD45RA+ population (126 91 compared with 384 142 in controls; P < 0.001), whereas the CD4+ CD29+ memory subset, which induces helper cells, remains unaffected [39].

    All of these analyses beg the issue of qualitative defects in CD4+ T-cell function occurring in the absence of quantitative changes. Such alterations are seen in the early stages of HIV infection [75] and may underlie increased susceptibility to opportunistic infections occurring in the absence of changes in absolute CD4 count. They are beyond the scope of this review.

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    Importance of Biologic Variability in Assessing CD4+ T Lymphocytopenia and Severe Unexplained HIV-Negative Immunosuppression

    Because myriad factors can affect T-cell subsets, changes in CD4+ T-cell counts should be investigated over time, together with the CD4:CD8 ratio, particularly in the context of intercurrent disease. This is especially important in evaluating patients with ICL/SUHIS and should aid in refining its definition. For example, case 5 from our original five reports of idiopathic CD4+ T lymphocytopenia [3] was a sexually active homosexual man, negative for HIV by serologic testing and DNA amplification by polymerase chain reaction, who had pulmonary tuberculosis, a persistent but stable CD4 count of less than 300/mm3, and a CD4: CD8 ratio of less than 1.0. Six months after successful therapy for his tuberculosis, his CD4 counts increased to more than 600/mm3, making the diagnosis of ICL/SUHIS untenable. Indeed, in all of the few patients with ICL/SUHIS investigated by reverse transcriptase measurements in viral cultures [4, 6], no evidence for retroviral activity has been found. These patients have not shown progressive declines in their CD4 counts, however, and thus have been accurately described as not having an HIV-like immunologic picture.

    It has been estimated recently that more than 300 000 persons in the United States alone would meet the current definition of idiopathic CD4+ T lymphocytopenia, with the possible involvement of a novel agent(s) lost within this mixture of uncertain lower truncation point for CD4 distribution and statistical variations [76]. Thus, the failure to detect a lymphocytopathic or retrovirus or other micro-organisms should not discourage a thorough analysis of that subset of ICL/SUHIS patients with T-cell changes more characteristic of HIV. They should undergo extensive evaluation for HIV or other recognized or novel infectious causes of immune deficiency [3, 77]. Such patients represent a very small fraction of the total cases reported to the Centers for Disease Control and Prevention and the World Health Organization [3-8]. I believe that it is these persons, however, for whom pneumocystis prophylaxis should be considered after CD4 counts decrease to less 200/mm3, regardless of whether a retrovirus or other infectious agent has been identified.

    In the absence of clear epidemiologic support for a transmissible agent, however, any recommendation concerning ICL/SUHIS must be presented with great reserve. For example, a novel retrovirus was reported to have been isolated from two HIV-seronegative patients with common variable immunodeficiency [78] who, unlike the typical cases summarized here (see Table 4), had very low CD4 counts as well as depressed CD4:CD8 ratios. Follow-up showed that these patients were actively infected with HIV-1, even if incompetent to mount a serologic response to it [73].

    Finally, apart from T-cell subset analyses, AIDS in the pre-AIDS era had been described [79] before recognition of ICL/SUHIS, but in only 1 of these 19 patients with opportunistic infections were CD4 counts measured. Indeed, my colleagues and I had previously documented P. carinii pneumonia in patients with normal CD4 counts and CD4:CD8 ratios [63], and similar reports of AIDS-linked illnesses in patients with normal CD4 counts and T-cell subset ratios have been published [80]. It is only through careful follow-up of patients screened in the manner suggested here, using historical knowledge of the effects of various infectious diseases and conditions on immunophenotyping, that complex issues such as physiologic CD4+ lymphopenia, ICL/SUHIS, requirements for institution of prophylactic antibiotics, and potential new infectious agents associated with alterations in T-cell subsets can be assessed.

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