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Home > Topics > Emerging Issues > TLC vs CD4
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Use of Total Lymphocyte Count vs CD4 Cell Count as a Marker of Immunity in HIV-Infected Adults and Children

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Introduction
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Adult Studies
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Pediatric Studies
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Summary
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References
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Introduction

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Even before researchers discovered that lymphocyte cells consisted of subsets of B cells and cells derived from the thymus (T cells), a decrease in the total number of lymphocytes was known to correlate with lack of cellular immunity and predisposition to severe infections in adults and children.( 1 ) As early as 1964, it was recognized that certain childhood infections such as measles temporarily suppress immune function, as reflected in the total lymphocyte count (TLC).( 2 ) This immune suppression was associated with activation of opportunistic infections such as latent tuberculosis.( 1 ) As the field of immunology advanced, new laboratory tests, such as mitogen and antigen activation of cells in culture, were used to measure immune function directly. Further analysis identified 2 primary categories of T cells: CD4 cells (also known as "helper T cells") and CD8 cells (also known as "killer" or cytotoxic T cells).

Soon after HIV was found to be the cause of AIDS, it was shown that the virus binds to receptors on CD4 cells, enters the cells, and uses them to create new virus, destroying them in the process. This results in the depletion of CD4 cells and immunodeficiency.( 3 ) Early in the epidemic, it was controversial to use the number or percent of CD4 cells as a surrogate marker for immunodeficiency because there were no studies that correlated the total CD4 count or percentage with functional immunity or survival after HIV care and treatment. However, as technology for treating HIV infection advanced, new studies on combination antiretroviral treatment (ART) clearly demonstrated that control of HIV infection correlated positively with a higher CD4 count and the restoration of immunity.( 4 , 5 )

With the increased availability of equipment to perform CD4 counts and the knowledge that CD4 cells were the primary target of HIV, the determination of CD4 count became the standard measure of immunodeficiency in adult HIV-infected patients in resource-rich countries. The relative ease of CD4 cell monitoring also led to its advocacy in treatment guidelines for determining when to start, stop, or change ART and for deciding when to initiate prophylaxis for opportunistic infections (OIs). This is despite the fact that CD4 count does not always correlate with functional immunity; some patients with normal CD4 counts are susceptible to OIs and some patients with significantly depressed CD4 counts do not seem unduly susceptible to OIs.

Whereas the CD4 count became a routine monitoring tool in treating adult patients, it was soon noted that CD4 count was an unreliable measure of functional immunity in HIV-infected infants <18 months of age. Both TLC and CD4 count are high in young infants and slowly decrease with age, reaching adult levels by age 6. In contrast, CD4 count and percentage are stable throughout adult life. Unlike CD4 count, CD4 percentage is relatively stable in young children. Most health care systems therefore recommend using CD4 percentage to guide treatment decisions and monitor HIV treatment in children.( 6 , 7 , 8 )

The determination of CD4 cell count and percentage is too expensive for most health facilities in resource-poor countries to perform routinely. Currently, CD4 counters cost up to US$120,000 and each test costs between US$40 and US$120.( 9 ) In contrast, TLC can be derived easily in resource-poor countries by performing a routine white blood cell count.

TLC is the total white blood cell count multiplied by the lymphocyte percentage; for example, a total white blood cell count of 6,000 cells/µL with a lymphocyte percentage of 30% would result in a TLC of 1,800 cells/µL. The equipment and skills to perform total white blood cell count and differential are readily available in most hospitals and clinics in resource-poor countries, and performing a TLC costs less than US$1, a fraction of the cost of a CD4 cell measurement.( 9 ) The need to rapidly expand the use of ART in resource-poor countries as well as the human resource constraints, cost, and infrastructure concerns surrounding CD4 cell measurements in these settings mentioned above have prompted a series of studies in adults and children to evaluate the utility and predictability of TLC as a measure of immune function and its usefulness in guiding initiation of ART in children and adults.

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Adult Studies

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Most studies in HIV-infected adults conclude that a decline in TLC is well correlated with a decline in CD4 count, although there is not a direct one-to-one relationship between TLC and CD4 count. These studies also have found that TLC is predictive of immunosuppression as well as virologic and immunologic responses to treatment.( 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 )

There are 2 recent studies on the usefulness of TLC as a surrogate marker to monitor immune response to ART:

  • A 2004 study conducted in the United States evaluated TLC, hemoglobin level, and delayed hypersensitivity skin test (DHST) results as predictors of clinical response to ART. The study found that the following factors independently predicted AIDS-defining illnesses and mortality in patients receiving ART ( 12 ):

    • TLC <850 cells/µL or <1,250 cells/µL

    • CD4 count <200 cells/µL

    • lack of response to DHST

    • total hemoglobin value <10.6 g/dL

  • An observational study of antiretroviral-naive patients in Canada over a 3-year period found that TLC <800 cells/µL and TLC between 800 cells/µL and 1,400 cells/µL were associated with increased risk of mortality.( 10 )

Several studies also have examined the correlation between CD4 count and TLC:

  • In a retrospective evaluation of the ability of TLC and hemoglobin to predict CD4 count conducted in 2003, Spacek and associates evaluated 3,269 individuals from the Johns Hopkins HIV Observational Cohort. They concluded that TLC <1,200 cells/?L was associated with CD4 count <200 cells/µL.( 14 )

  • In another U.S.-based study, Mahajan et al examined the longitudinal variation between changes in patient TLC and concomitant changes in CD4 count following the initiation of ART.( 17 ) The study found that patients with a baseline CD4 count <250 cells/µL who had increases in TLC during the first 2 years on ART also experienced increases in CD4 count >95% of the time, concluding that clinicians should feel confident that positive trends in TLC in patients receiving ART mean that the CD4 count change also is positive.( 17 ) However, decreases in TLC did not predict the direction of CD4 change very well. Patients who had decreases in TLC during the first 2 years on treatment had corresponding decreases in CD4 count only 43-63% of the time. The authors suggest that, when patients have drops in TLC, clinicians should determine whether these declines correlate with other clinical indications of deteriorating immune status such as development of an OI.( 17 ) Overall, during a 2-year period, the direction of change in TLC was a strong marker for a concomitant change in CD4 count (sensitivity 86-94% and specificity 80-85%, depending on the length of the interval between measurements).

  • Badri and Wood followed 266 patients at a hospital in South Africa to determine the usefulness of TLC vs CD4 count and viral load measurements for monitoring patients on ART. They found a significant correlation between changes in TLC and changes in CD4 count. The sensitivity and specificity of an increase or decrease in TLC from baseline as a marker for similar changes in CD4 count were 83.4% and 87.3%, respectively.( 18 )

Based on clinical studies of CD4 count and TLC such as the ones outlined above, the World Health Organization (WHO) recommended in its 2003 guidelines and 2005 meeting report that health facilities without the ability to perform CD4 measurement should use TLC to guide decisions on when to start ART in patients who are mildly symptomatic.( 19 , 20 ) Nevertheless, the WHO continues to recommend that most treatment initiation decisions be guided by CD4 measurement and clinical staging, and cites a need to "emphasize and advocate for wider availability of CD4 testing."( 20 ) For health care facilities in the most resource-limited settings, where CD4 testing usually is unavailable, it is important to emphasize that clinicians need not wait to start ART programs until CD4 counts become available to guide treatment decisions. Clinicians have been able to initiate treatment effectively using WHO clinical staging and can monitor patients with minimal CD4 count measurements, as seen in a recent successful ART project in Malawi where patients received CD4 measurements only on an annual basis.( 21 )

WHO Parameters for Initiating Antiretroviral Treatment

If CD4 lymphocyte testing is available:

  • Initiate ART for all patients with CD4 count <200 cells/µL regardless of clinical stage.

  • Consider ART for all patients with Stage I and II disease and CD4 count <350 cells/µL. Treatment should be initiated before CD4 count drops below 200 cells/µL.

  • Initiate ART for patients with Stage III disease and CD4 count <350 cells/µL.

  • Initiate ART for patients with Stage IV disease regardless of CD4 count.

If CD4 lymphocyte testing is unavailable:

  • Initiation of ART is recommended for those with Stage III and IV disease, and for those with Stage II disease if the TLC is <1,200 cells/µL.

Source: World Health Organization. Antiretroviral Drugs for the Treatment of HIV Infection in Adults and Adolescents in Resource-Limited Settings: Recommendations for a Public Health Approach (2005 Revision)--Brief Meeting Report. Geneva: WHO; September 2005.

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Pediatric Studies

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Several studies in children indicate that TLC independently predicts mortality and correlates with both CD4 percentage and total CD4 cell count.( 22 , 23 ) However, because TLC is high in children <18 months of age, its reliability as a predictor of mortality in HIV-infected children, as measured by a 12-month period for risk of death, varies with age. For example, in a study of HIV-infected children in the United States, the 12-month risk of death exceeded 15% in children <2 years of age when TLC was 3,800 cells/µL for children >2 years of age, the risk of death exceeded 15% when TLC was 2,300 cells/µL.( 22 , 23 ) The study also found that the risk of death was independently related to CD4 count and viral load, results that are similar to those found in children in resource-poor countries.( 24 )

A study reported by the HIV Pediatric Prognostic Marker Group evaluated longitudinal data on 3,917 children of various ethnic and cultural backgrounds pooled from studies in the United States and Europe. The 12-month risk of death and risk of developing AIDS was measured by the most recent TLC using statistical methods. The researchers then compared their TLC thresholds for increased mortality and AIDS risk with the WHO?s TLC and CD4 percentage thresholds for starting ART.( 25 ) The study found that TLC was a powerful predictor of disease progression despite having a weak correlation with CD4 percentage. This result was not entirely surprising, as TLC measures both CD4 cells and other cells that provide functional immunity. The risk of death and AIDS increased sharply in children >2 years of age with TLC <1,500-2,000 cells/µL and CD4 percentage of 10-15%. In contrast, TLC and CD4 percentage was only a weak prognostic indicator in younger children.

The authors concluded that, when TLC and CD4 percentage were compared at threshold values at which the risk of death was equal, TLC was predictive of death in children as well as the CD4 percentage, but using the TLC threshold to guide the initiation of ART would have resulted in starting treatment earlier.

In the first in 18 months of life, TLC is quite high and rarely falls below 2,500 cells/µL; CD4 percentage rarely is <20%. Because of this phenomenon, most children presenting with early HIV infection would not be eligible for ART under the 2005 WHO guidelines, which set a TLC threshold of <3,400 cells/µL and CD4 percentage <25% for initiating ARV treatment in children <18 months of age. It is anticipated that the 2006 guideline updates will increase both the TLC and CD4 percentage threshold. The inability of CD4 percentage and TLC to predict the degree of immunodeficiency in very young children has led some experts to suggest that treatment should be provided for all HIV-infected infants <18 months of age regardless of either CD4 percentage or TLC.

Treating all HIV-infected infants <18 months of age, regardless of symptoms or CD4 percentages or TLC is one of the options recommended in the U.S. treatment guidelines and perhaps should be an option as well in resource-poor countries where early mortality from HIV is high.( 26 )

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Summary

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It generally is recognized that TLC is a useful predictor of mortality in HIV-infected adults and children. Therefore, in resource-poor countries where cost and infrastructure are significant barriers to expanding access to in ART, TLC in conjunction with clinical staging can be a useful tool for identifying adult patients who require ART when CD4 counts are not available. Research also suggests that it may also be a useful tool for measuring response to treatment, in particular, for gauging positive reactions to treatment.( 17 )

Current guidelines from the WHO acknowledge that TLC may be used to make treatment decisions in resource-poor counties where CD4 counts are not available and patients are mildly symptomatic. For adults with Stage II illness, the current WHO TLC threshold for initiating ART is 1,200 cells/µL.( 20 ) However, the WHO continues to recommend CD4 count as the main laboratory measurement for making decisions about when to start, stop, and change ART.

As stated above, the use of TLC and CD4 count in infants and children is complex because values for these immunologic markers are high and variable during the first 18 months of life. Current WHO ART guidelines recommend using TLC to guide treatment decisions only when CD4 counts are not available and the patient is in WHO Stage II disease. For children with Stage II illness, the current WHO TLC threshold for initiating ART is <3,400 cells/µL for those <18 months of age and <2,300 cells/µL for those >18 months of age.( 6 ) It is anticipated that these thresholds will be increased in the 2006 guideline updates.

It is important to recognize that both CD4 count and TLC are surrogate markers of functional immunity. They should be used as adjuncts to treatment decisions, not the sole decision-making tool. As in all clinical care and treatment situations, particularly those involving life-threatening diseases such as HIV infection, laboratory evaluation should be used conjunction with clinical evaluation. Regardless of these laboratory parameters and WHO staging, health care providers should use their best clinical judgment to determine when treatment is necessary, especially in resource-poor areas with limited diagnostic tools.( 21 )

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References

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1. transparent gif World Health Assembly. Infant and Young Child Nutrition. The 54th World Health Assembly; May 18, 2001; Geneva. Resolution WHA 54.2.
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2. transparent gif Isom JB, Gordy PD, Selner JC, et al. Immunosuppression and infection. N Engl J Med. 1964 Nov 12;271:1068-9.
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4. transparent gif Seligmann M, Pinching AJ, Rosen FS, et al. Immunology of human immunodeficiency virus infection and the acquired immunodeficiency syndrome. An update. . Ann Intern Med. 1987 Aug;107(2):234-42.
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5. transparent gif Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):185-91.
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6. transparent gif World Health Organization. Antiretroviral Drugs for the Treatment of HIV Infection in Infants and Children in Resource-Limited Settings: Recommendations for a Public Health Approach (2005 Revision)--Brief Meeting Report. Geneva: World Health Organization; September 2005. Available at: www.who.int/3by5/Pediatricreport_June2005.pdf Accessed May 23, 2006.
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7. transparent gif U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. November 3, 2005. Available at: www.aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=8&ClassID=1 Accessed May 23, 2006.
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8. transparent gif Sharland M, Blanche S, di Zub G, et al. PENTA Guidelines for the Use of Antiretroviral Therapy. Paediatric European Network for the Treatment of AIDS; July 2004. Available at: www.ctu.mrc.ac.uk/penta/guidelin.pdf Accessed May 23, 2006.
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9. transparent gif Kumarasamy N, Mahajan AP, Flanigan TP, et al. Total lymphocyte count (TLC) is a useful tool for the timing of opportunistic infection prophylaxis in India and other resource-constrained countries. J Acquir Immune Defic Syndr. 2002 Dec 1;31(4):378-83.
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10. transparent gif Bedell R, Heath KV, Hogg RS, et al. Total lymphocyte count as a possible surrogate of CD4 cell count to prioritize eligibility for antiretroviral therapy among HIV-infected individuals in resource-limited settings. Antivir Ther. 2003 Oct;8(5):379-84.
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11. transparent gif Ledergerber B, Lundgren JD, Walker AS, et al; PLATO Collaboration. Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes. . Lancet. 2004 Jul 3-9;364(9428):51-62.
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12. transparent gif Anastos K, Shi Q, French AL, et al. Total lymphocyte count, hemoglobin, and delayed-type hypersensitivity as predictors of death and AIDS illness in HIV-1-infected women receiving highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2004 Apr 1;35(4):383-92.
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13. transparent gif Anastos K, Barron Y, Cohen MH, et al. The prognostic importance of changes in CD4+ cell count and HIV-1 RNA level in women after initiating highly active antiretroviral therapy. .Ann Intern Med. 2004 Feb 17;140(4):256-64.
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14. transparent gif Spacek LA, Griswold M, Quinn TC, et al. Total lymphocyte count and hemoglobin combined in an algorithm to initiate the use of highly active antiretroviral therapy in resource-limited settings.
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15. transparent gif Anastos K, Barron Y, Miotti P, et al; Women's Interagency HIV Study Collaborative Study Group. Risk of progression to AIDS and death in women infected with HIV-1 initiating highly active antiretroviral treatment at different stages of disease. Arch Intern Med. 2002 Sep 23;162(17):1973-80.
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16. transparent gif Mwamburi DM, Ghosh M, Fauntleroy J, et al. Predicting CD4 count using total lymphocyte count: a sustainable tool for clinical decisions during HAART use. Am J Trop Med Hyg. 2005 Jul;73(1):58-62.
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17. transparent gif Mahajan AP, Hogan JW, Snyder B, et al. Changes in total lymphocyte count as a surrogate for changes in CD4 count following initiation of HAART: implications for monitoring in resource-limited settings. J Acquir Immune Defic Syndr. 2004 May 1;36(1):567-75.
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18. transparent gif Badri M, Wood R. Usefulness of total lymphocyte count in monitoring highly active antiretroviral therapy in resource-limited settings. AIDS. 2003 Mar 7;17(4):541-5.
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19. transparent gif World Health Organization. Scaling Up Antiretroviral Therapy in Resource-Limited Settings: Guidelines for a Public Health Approach--2003 Revision. Geneva: World Health Organization; 2004. Available at: http://www.who.int/hiv/pub/prev_care/en/arvrevision2003en.pdf . Accessed May 23, 2006.
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20. transparent gif World Health Organization. Antiretroviral Drugs for the Treatment of HIV Infection in Adults and Adolescents in Resource-Limited Settings: Recommendations for a Public Health Approach (2005 Revision)--Brief Meeting Report. September 2005. Available at: http://www.who.int/3by5/ARVmeetingreport_June2005.pdf . Accessed May 23, 2006.
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21. transparent gif Ferradini L, Jeannin A, Pinoges L, et al. Scaling up of highly active antiretroviral therapy in a rural district of Malawi: an effectiveness assessment. Lancet. 2006 Apr 22;367(9519):1335-42.
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22. transparent gif Mofenson LM, Harris DR, Moye J, et al; NICHD IVIG Clinical Trial Study Group. Alternatives to HIV-1 RNA concentration and CD4 count to predict mortality in HIV-1-infected children in resource-poor settings. Lancet. 2003 Nov 15;362(9396):1625-7.
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23. transparent gif Mofenson LM, Harris DR, Rich K, et al. Serum HIV-1 p24 antibody, HIV-1 RNA copy number and CD4 lymphocyte percentage are independently associated with risk of mortality in HIV-1-infected children. National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial Study Group. AIDS. 1999 Jan 14;13(1):31-9.
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24. transparent gif Taha TE, Kumwenda NI, Hoover DR, et al. Association of HIV-1 load and CD4 lymphocyte count with mortality among untreated African children over one year of age. AIDS. 2000 Mar 10;14(4):453-9.
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25. transparent gif HIV Paediatric Prognostic Markers Collaborative Study. Use of total lymphocyte count for informing when to start antiretroviral therapy in HIV-infected children: a meta-analysis of longitudinal data. Lancet. 2005 Nov 26;366(9500):1868-74.
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26. transparent gif U.S. Department of Health and Human Services. HGuidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. November 3, 2005. Available at: http://www.aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=8&ClassID=1 . Accessed May 23, 2006.
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