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Depressed CD4:Depressed CD4: Is it always HIV? Is it always HIV?

Aaron J. Loeb, BSN, RNAaron J. Loeb, BSN, RN

Celine Hanson, MDCeline Hanson, MD

Texas Children’s HospitalTexas Children’s Hospital12-14-200612-14-2006

ObjectivesObjectives

• Case PresentationCase Presentation • Emerging TrendsEmerging Trends

• Syphilis and HIVSyphilis and HIV

• Disease ManagementDisease Management• CD4 functionCD4 function

• Infectious Diseases and CD4Infectious Diseases and CD4• CD4 testing/guidelinesCD4 testing/guidelines

• CounselingCounseling

CASE PRESENTATIONCASE PRESENTATION

Case PresentationCase Presentation

Clinical History:Clinical History:

– 30 year old HIV negative male with 30 year old HIV negative male with progressive rashprogressive rash

– Excess fatigue and sleepinessExcess fatigue and sleepiness– Topical/lotions useTopical/lotions use– Denied fever, headache, itchingDenied fever, headache, itching

CD4 TestingCD4 Testing

DateDate 09/0509/05 11/0511/05 12/0512/05 02/0602/06 04/0604/06 08/0608/06 NL NL RangeRange

CD4 %CD4 % 3838 3737 2828 3333 3636 3737 32-54%32-54%

CD4 #CD4 # 510510 471471 273273 710710 600600 699699 484-484-11591159

HIV Rapid Testing HIV Rapid Testing

ResultsResults

05/05 Negative05/05 Negative






Physical ExaminationPhysical Examination

– Fixed macular, reddish-brown rashFixed macular, reddish-brown rash– Central presentation with progression to Central presentation with progression to

extremitiesextremities– Rash highlighted with temperature Rash highlighted with temperature

changechange– No alopecia, lymphadenopathy or No alopecia, lymphadenopathy or

pharyngitispharyngitis


Diagnosis/TreatmentDiagnosis/Treatment

– Clinical secondary syphilis Clinical secondary syphilis confirmed by reactive RPR (1:128)confirmed by reactive RPR (1:128)

– IM Pen G administrationIM Pen G administration– Jarisch-Herxhemier’s reaction Jarisch-Herxhemier’s reaction

following penicillin deliveryfollowing penicillin delivery


CounselingCounseling

– Contact by local Health DepartmentContact by local Health Department– Possible co-infection with HIVPossible co-infection with HIV– Contagious; avoid sexual encountersContagious; avoid sexual encounters– Relevance lowered CD4 to syphilisRelevance lowered CD4 to syphilis

Emerging TrendsEmerging Trends

Syphilis and HIVSyphilis and HIV

History of Syphilis History of Syphilis

NaplesNaples– First well recorded outbreak in 1494First well recorded outbreak in 1494– CDC began tracking in 1941CDC began tracking in 1941

Previous NamesPrevious Names– Great PoxGreat Pox– The French DiseaseThe French Disease– The English DiseaseThe English Disease

Syphilis Demographics Syphilis Demographics SummarySummary

Cities with Highest Reported Rates of Cities with Highest Reported Rates of P&S Syphilis, 2004P&S Syphilis, 2004

Primary and Secondary Syphilis: Primary and Secondary Syphilis: RatesRates

The SouthThe South– Increased: 3.1 versus 3.6 cases per 100,000 Increased: 3.1 versus 3.6 cases per 100,000

population a 16% increasepopulation a 16% increase MenMen

– Increased from 2.6 to 4.7 during 2001-2004Increased from 2.6 to 4.7 during 2001-2004

– Blacks:Blacks: 5.1 times higher than whites in 2003 5.1 times higher than whites in 2003 and 5.6 times higher in 2004 and 5.6 times higher in 2004

WomenWomen– Remained at 0.8 in 2004Remained at 0.8 in 2004

– Decreased from 1.7 to 0.8 from 2000 to 2003Decreased from 1.7 to 0.8 from 2000 to 2003

Syphilis Co-Infection with HIV:Syphilis Co-Infection with HIV:Harris CountyHarris County

1995

19961997

1998

19992000

20012002

20032004

2005

0

50

100

150

200

250

300

350

400

# C

ases

Syphilis (P&S)

Disease ManagementDisease Management

CD4 function and HIVCD4 function and HIV Other Infectious Diseases and CD4Other Infectious Diseases and CD4 CD4 testing/guidelinesCD4 testing/guidelines CounselingCounseling


CD4 function and HIVCD4 function and HIV

The Immune The Immune

SystemSystem

The National Cancer Institute at FrederickThe National Cancer Institute at Frederick

Protects against infectious pathogensProtects against infectious pathogens

Mechanism of protectionMechanism of protectionInnate--natural or native immunityInnate--natural or native immunityAdaptive--acquired or specific immunity Adaptive--acquired or specific immunity

CD4 FunctionCD4 Function

Delayed T cell hypersensitivity responsesDelayed T cell hypersensitivity responses Influence other immune cell activityInfluence other immune cell activity

– Immunoglobulin synthesisImmunoglobulin synthesis– Cellular cytotoxicityCellular cytotoxicity

HIV ReplicationHIV Replication

CD4 as a high affinity receptorCD4 as a high affinity receptor

- gp120 attaches to CCR5 and CXCR4 - gp120 attaches to CCR5 and CXCR4

- gp41 insertion through cell membrane- gp41 insertion through cell membrane

StagesStages

- Acute retroviral- Acute retroviral

- Middle, chronic phase- Middle, chronic phase

- Full-blown AIDS- Full-blown AIDS

Macrophages and monocytes vulnerableMacrophages and monocytes vulnerable

Impact of HIV on CD4Impact of HIV on CD4

Precise mechanism for CD4 loss in HIV disease is not Precise mechanism for CD4 loss in HIV disease is not defineddefined

Potential mechanisms for CD4 loss include:Potential mechanisms for CD4 loss include:– HIV CD4+ cells home to the lymph systemHIV CD4+ cells home to the lymph system

Due to CD62 homing ligand receptor and Fas upregulation after HIV Due to CD62 homing ligand receptor and Fas upregulation after HIV binding to CD4binding to CD4

Signaling to CD4+/HIV infected cells leads to programmed cell death Signaling to CD4+/HIV infected cells leads to programmed cell death (apoptosis) in lymph tissue(apoptosis) in lymph tissue

– Naïve CD4+ T cells are depleted more rapidly in the thymus than Naïve CD4+ T cells are depleted more rapidly in the thymus than memory cellsmemory cells Results in impaired supply of CD4+ T cells to peripheryResults in impaired supply of CD4+ T cells to periphery Increases division rate of naïve T cells and lowers emigration out of the Increases division rate of naïve T cells and lowers emigration out of the

thymusthymus

CD4 and HIV viral loadCD4 and HIV viral loadRisk for AIDS (25 y/o)Risk for AIDS (25 y/o)

CD4#CD4# 5050 200200 500500

Viral Viral loadload

3 x 103 x 1033 6.8%6.8% 1.6%1.6% 0.3%0.3%

3 x 103 x 1044 13.3%13.3% 3.2%3.2% 0.6%0.6%

3 x 103 x 1055 25.1%25.1% 6.3%6.3% 1.2%1.2%

Syphilis and CD4Syphilis and CD4

Syphilis without HIV infectionSyphilis without HIV infection– Independent of gender CD4 decreases as Independent of gender CD4 decreases as

CD8 increasesCD8 increases Syphilis with HIV infectionSyphilis with HIV infection

– CD4 count decreases with increased viral CD4 count decreases with increased viral load of primary and secondary syphilisload of primary and secondary syphilis

– CD4 count increases with syphilis CD4 count increases with syphilis treatment with decreased HIV-RNA countstreatment with decreased HIV-RNA counts


Infectious Diseases and CD4 Infectious Diseases and CD4

Infections that lower CD4 Infections that lower CD4 or CD4/CD8 ratioor CD4/CD8 ratio

Tuberculosis (TB)Tuberculosis (TB) Cytolomegalovirus (CMV)Cytolomegalovirus (CMV) Herpes Simplex Virus (HSV)Herpes Simplex Virus (HSV) Epstein Barr Virus (EBV)Epstein Barr Virus (EBV)

CD4 and TBCD4 and TB

T cell apoptosis has been described in T cell apoptosis has been described in HIV negative individuals with HIV negative individuals with disseminated TBdisseminated TB– Affected cells include CD4 and CD8+ T Affected cells include CD4 and CD8+ T

cellscells

Individuals with extrapulmonary TB Individuals with extrapulmonary TB and/or more severe complications are and/or more severe complications are more likely to have lower CD4+ T cellsmore likely to have lower CD4+ T cells

CD4 and Viral infectionsCD4 and Viral infectionsCMV, HSV and EBVCMV, HSV and EBV

CD4 and CD8+ T cells and neutralizing CD4 and CD8+ T cells and neutralizing antibody are pivotal in human responses to antibody are pivotal in human responses to primary viral infectionsprimary viral infections

CD8+ T cell expansion is typical in CD8+ T cell expansion is typical in symptomatic CMV infection and causes an symptomatic CMV infection and causes an inverted CD4/CD8 ratioinverted CD4/CD8 ratio– Inverted CD4/CD8 ratio is not aytpical in HSV or Inverted CD4/CD8 ratio is not aytpical in HSV or

EBVEBV Peripheral blood CD4 depletion rarely occurs Peripheral blood CD4 depletion rarely occurs

in CMV infectionin CMV infection– Diminished CMV specific CD4+ cells has been Diminished CMV specific CD4+ cells has been

documented in pediatric CMVdocumented in pediatric CMV

Screening for SyphilisScreening for Syphilis

Syphilis Elimination Plan (SEE)Syphilis Elimination Plan (SEE)– CDC formed campaign in 1999CDC formed campaign in 1999– Improve testing and laboratory servicesImprove testing and laboratory services– Goal: make a rapid test available for use in the Goal: make a rapid test available for use in the

U.S. within the next few yearsU.S. within the next few years

Current testing: RPRCurrent testing: RPR– Week waiting periodWeek waiting period

Target HIV testing sitesTarget HIV testing sites

Center’s For Disease Control HIV Center’s For Disease Control HIV GuidelinesGuidelines

Revised September 2006Revised September 2006 There is an urgent need to increase the

proportion of persons who are aware of their HIV-infection status

Expanded, routine, voluntary, opt-out screening in health care settings is needed

Such screening is cost-effective

Bernard Branson MD Revised Recommendations for HIV Testing in Healthcare Settings in the U.S.

Disease Management Disease Management

Testing/GuidelinesTesting/Guidelines– Clinical lymphocyte subset testing provides Clinical lymphocyte subset testing provides

most accurate results when consistent most accurate results when consistent laboratory is used laboratory is used

– Dual (CD3/CD4) and triple antibody staining Dual (CD3/CD4) and triple antibody staining (CD3/CD4/CD45) have eliminated inclusion of (CD3/CD4/CD45) have eliminated inclusion of cells from other lineagescells from other lineages

– Single test assessment should be avoidedSingle test assessment should be avoided Repeat testing using specimens collected at separate Repeat testing using specimens collected at separate

dates dates


Counseling patients with CD4 Counseling patients with CD4 depression depression

Counseling ConsiderationsCounseling Considerations

Counseling for depressed CD4 countCounseling for depressed CD4 count– History of HIV risksHistory of HIV risks

Recommend HIV testingRecommend HIV testing

– Consider other STDs and impact on CD4 Consider other STDs and impact on CD4 testtest History for STDsHistory for STDs Recommend syphilis, TB or viral testingRecommend syphilis, TB or viral testing

– Consider other immune deficienciesConsider other immune deficiencies Idiopathic CD4+ T cell lymphocytopeniaIdiopathic CD4+ T cell lymphocytopenia

Screening For HIVScreening For HIV

High rates of non-return for test results

In 2000, 31% did not return for results of HIV-positive conventional tests at publicly funded sites

HIV rapid testing availability is crucial-Sure Check and Stat Pak approved in May 2006

Screen for high prevalence and high volume settings


Testing for HIVTesting for HIV

Recommendations for Adults and AdolescentsRecommendations for Adults and Adolescents

– Routine, voluntary HIV screening for all persons 13-64 in health care settings, not based on risk

– Repeat HIV screening of persons with known risk at least annually– Opt-out HIV screening with the opportunity to ask questions and the

option to decline– Include HIV consent with general consent for care; separate signed

informed consent not recommended– Prevention counseling in conjunctions with HIV screening in health

care settings is not required


Counseling ChallengesCounseling Challenges

Identifying high risk behaviorIdentifying high risk behavior Educate about mode of transmissionEducate about mode of transmission Possibility of reinfectionPossibility of reinfection Co-infection with HIVCo-infection with HIV

– Correlating possible exposure to syphilis Correlating possible exposure to syphilis exposure exposure

Article References:Article References:

Antas, P.R., Ding, L., Hackman, J., Reeves-Hammock, L., Shintani, A.K., Schiffer, J., Holland, S.M., et al. Antas, P.R., Ding, L., Hackman, J., Reeves-Hammock, L., Shintani, A.K., Schiffer, J., Holland, S.M., et al. (2004). Decreased CD4+ lymphocytes and innate immune responses in adults with previous (2004). Decreased CD4+ lymphocytes and innate immune responses in adults with previous extrapulmonary tuberculosis. extrapulmonary tuberculosis. Journal of Allergy Clinical Immunology Journal of Allergy Clinical Immunology 117(4).117(4).

Fan, Y.M., Zeng, W.J. & Li, S.F. (2004). Immunophenotypes, apoptosis, and expression of Fas and Bcl-2 from Fan, Y.M., Zeng, W.J. & Li, S.F. (2004). Immunophenotypes, apoptosis, and expression of Fas and Bcl-2 from peripheral blood lymphocytes in patients with secondary early syphilis. peripheral blood lymphocytes in patients with secondary early syphilis. Sexually Transmitted Diseases. Sexually Transmitted Diseases. 31(4). 31(4).

Gamadia, L.E., Rentenaar, R.J., Van Lier, R.A., & Berge, I.J. (2004). Properties of CD4 (+) T cells in human Gamadia, L.E., Rentenaar, R.J., Van Lier, R.A., & Berge, I.J. (2004). Properties of CD4 (+) T cells in human cytomegalovirus infection. cytomegalovirus infection. Human Immunology. Human Immunology. 65 (5). 65 (5).

Grossman, Z., & Paul, W.E. (2000). The impact of HIV on naïve T-cell homeostasis. Grossman, Z., & Paul, W.E. (2000). The impact of HIV on naïve T-cell homeostasis. Nature Medicine (6)Nature Medicine (6)

Hatton, A.E., Montamat-Sicotte, D., Gudgeon, N., Rickinson, A.B., McMichael, A.J. & Calian, M.F. (2003). Hatton, A.E., Montamat-Sicotte, D., Gudgeon, N., Rickinson, A.B., McMichael, A.J. & Calian, M.F. (2003). Characteristics of the CD4 + T cell response to Epstein-Barr virus during primary and secondary Characteristics of the CD4 + T cell response to Epstein-Barr virus during primary and secondary infection. infection. Journal of Expert Medicine 198(6).Journal of Expert Medicine 198(6).

Kofoed, K., Gerstoft, J. Mathiesen, L.R., & Benfield, T. ( 2006). Syphilis and human immunodeficiency virus Kofoed, K., Gerstoft, J. Mathiesen, L.R., & Benfield, T. ( 2006). Syphilis and human immunodeficiency virus (HIV)-1 coinfection: influence on CD4 T-cell count, HIV-1 viral load, and treatment response. (HIV)-1 coinfection: influence on CD4 T-cell count, HIV-1 viral load, and treatment response. Sexually Sexually Transmitted Diseases. Transmitted Diseases. 33(3).33(3).

MMWR, (2006). Primary and Secondary Syphilis ---United States, 2003-2004. MMWR, (2006). Primary and Secondary Syphilis ---United States, 2003-2004. MMWR Weekly. MMWR Weekly. 55(10), pp 269-55(10), pp 269-273.273.

Website ReferencesWebsite References

AIDS Info AIDS Info – http://www.aidsinfo.nih.gov/http://www.aidsinfo.nih.gov/

Centers for Disease Control, HIVCenters for Disease Control, HIV– http://www.cdc.gov/hiv/http://www.cdc.gov/hiv/

Centers for Disease Control, SyphilisCenters for Disease Control, Syphilis– http://www.cdc.gov/std/syphilis/default.htmhttp://www.cdc.gov/std/syphilis/default.htm

Texas Department of State Health Services, Texas Department of State Health Services, HIVHIV– http://www.dshs.state.tx.us/hivstd/info/default.shthttp://www.dshs.state.tx.us/hivstd/info/default.sht

mm Wikipedia, treponema pallidumWikipedia, treponema pallidum

– http://en.wikipedia.org/wiki/Treponema_pallidumhttp://en.wikipedia.org/wiki/Treponema_pallidum

Would like to thankWould like to thank

Dr. Celine HansonDr. Celine Hanson Dr. William T. ShearerDr. William T. Shearer Chivon McMullen-JacksonChivon McMullen-Jackson Study ParticipantStudy Participant

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