Acquired and Primary

Immunodeficiencies

Cheryl Pikora MD, PhDUniv of Mass Medical School

Outline

Brief overview of causes of acquired immunodeficiencies

Brief discussion of the components of innate and adaptive immunity

Clinical presentations of primary immunodeficiencies

Discussion of pediatric HIV prevention, diagnosis and treatment

Acquired immunodeficiencies

Chemotherapy Breakdown in integumentary barriers Altered microbial colonization Enhanced susceptibility to infection

Neutrophils* T lymphocytes* B lymphocytes* NK cells Peripheral blood monocytes* Fixed-tissue macrophages

Acquired immunodeficiencies

Immunosuppressive drugs Corticosteroids Anti-rejection agents Monoclonal antibodies

Immunomodulatory infections HIV TB Malaria EBV, CMV

Primary Immunodeficiencies: Genetic

Neutrophil function defect

Complement deficiency

B cell deficiency

Specific immunoglobulin deficiency

T cell deficiencies (SCID)

Cells of Innate Immunity

neutrophil macrophage

dendritic cell

natural killer cell

Bacterial and fungal infection: first line of defense: neutrophil

Phagocytosis and secretion of mediators of inflammation:

macrophages

Dendritic cells

PAMP and dendritic cells

Viral PAMP and DC

Natural Killer Cells

The complement cascade

Infection and the response to it

CD4+ help for CD8+ cells and B cells

Th2Th1

Humoral Immunity Cellular Immunity

Memory T and B cells

Immunoglobuins

Humoral vs. Cellular Mediated Immunity (CMI)

Humoral: Extracellular

pathogens

CMI Intracellular

pathogens

Some intracellular microorganisms (other than viruses)

Bacterial, fungal infections,parasites (extracellular):-Neutrophils-Immunoglobulins-Complement

Viral and intracellular bacterial/fungal/parasitic infections:-CD4/CD8 T cells-NK cells

Pediatric HIV infection

HIV/AIDS Statistics in Liberia

Adult prevalence of HIV/AIDS in Liberia estimated to be 5.2%.1

The prevalence rate of HIV in Greater Monrovia is estimated to be 9.5%1

UNICEF has not received reporting on incidence or prevalence of HIV/AIDS in the pediatric population of Liberia.2

1The Basic Package of Health and Social Welfare Services, Republic of Liberia, Ministry of Health and Social Welfare.2http://www.unicef.org/infobycountry/liberia.html

HIV infection

Time (years)

Vir

olo

gic

resp

on

se

Child

Adult

Infection

HIV-1 Particle

KITSO Aids Training Program, Botswana

Helper Function of CD4 Cells

B Lymphocyte

T helper cell (CD4)Macrophage

Antibody secreting (plasma) cell

Infected cell

Cytotoxic T Lymphocyte (CD8)

KilledKITSO AIDS Training Program, Botswana

Immune abnormalities

Hypergammaglobulinemia

Increased CD8+ cells

Decreased CD4+ cells

Decrease in CD4:CD8 ratio < 1

Immune activation (chronic)

HIV may be transmitted to the infant during pregnancy, at the time of delivery, and through breastfeeding; most transmission is thought to take place during delivery

For a mother known to be HIV-infected prenatally, the additional risk of transmission of HIV to her infant through breastfeeding has been estimated at 14%

The risk is as high as 29% for mothers who acquire HIV post-natally

Transmission

Mother-to-Child Transmission of HIV

ARV Therapy and MTCT

• Prevention of prenatal transmission• Women first diagnosed with HIV

infection during pregnancy• HIV-infected women on ART who

become pregnant

High maternal viral load: >5-10,000 copies/ml (e.g., at time of seroconversion and during late HIV disease: CD4 cell counts <100 cells/mm)

Recurrent STDs Malaria interferes with placental

functions and eases viral transmission across the placenta

Vitamin A deficiency Preterm delivery

Factors Which May Increase the Risk of Transmission

Vaginal delivery Duration of rupture of membranes is

longer than 4 hours Placental disruption Invasive procedures during delivery

(e.g., vacuum extraction, episiotomy, use of forceps, fetal scalp monitoring)

Mechanical nasal suction after delivery Breastfeeding and especially mixed

feeding

Factors Which May Increase the Risk of Transmission, continued

PMTCT regimens

Breastfeeding Formula

HIV Mortality

Breastfeeding and MTCT

Pediatric HIV Infection –Common Clinical Presentations Infectious Diseases

Respiratory Illness (PCP, Tuberculosis) Diarrheal Diseases Oral Candidiasis Herpes Zoster

Lymphadenopathy, Hepatomegaly, Parotitis

Persistent fever

Growth failure: Kwashiorkor, Marasmus

Developmental Delay or Regression

Malignancies: Lymphoma, Kaposi’s sarcoma

Diarrheal Illness

Similar prevalence of stool pathogens between HIV infected and uninfected children.

Worse outcomes in HIV infected children.

KITSO AIDS Training, Botswana

Respiratory Illness

Death from respiratory tract infections: PCP: Most common pathogen in HIV-infected

children below six-months of age

Acute pyogenic pneumonia and tuberculosis common in HIV-infected and uninfected children.

KITSO AIDS Training, Botswana

Method of diagnosis Recommendations for use Strength of recommendation/ level of evidence

Virological methods

To diagnose infection in infants aged under 18 months; initial testing is recommended from 6 weeks of age

HIV DNA [A(I)] HIV RNA [A(I)] U p24 ag [CII]

To diagnose HIV infection in mother or identify HIV exposure of infant

A(I)

To diagnose HIV infection in children aged 18 months or more

A(I)

To identify HIV-positive children aged under 18 months and support a presumptive clinical diagnosis of severe HIV disease to allow initiation of ART

A(IV) a

To exclude HIV infection where negative in < 18 month old HIV exposed non breastfed infant

A(I)

HIV antibody testing

To exclude HIV infection where negative and HIV exposed infant discontinued breastfeeding for > 6 weeks

A (IV)

Presumptive diagnosis of severe HIV in HIV exposed infant

Seropositive Infant; AIDS indicator conditions Symptomatic with 2 or > two or more of the following:

oral thrush; severe pneumonia severe sepsis

Other factors to support diagnosis of severe HIV include:

Recent HIV-related maternal death; or Advanced HIV disease in the mother; or No history of PMTCT intervention CD4 <25%

Confirmation of the diagnosis of HIV infection should be sought as soon as possible.

Revised Staging & Classification

Clinical classification

Stage 1 Stage 2 Stage 3 Stage 4No symptoms

Mild Advanced Severe

Immunological classificationNot significant

Mild Advanced Severe

+

WHO clinical staging system

Clinical stage 1 Asymptomatic Persistent generalized lymphadenopathy

Clinical stage 2 Hepatosplenomegaly Papular pruritic eruptions Seborrhoeic dermatitis Funal nail infections Angular cheilitis Lineal gingival erythema (LGE) Extensive human papilloma virus infection or molluscum

infection (> 5% body area) Recurrent oral ulcerations (2 or more episodes in 6 months) Herpes zoster Recurrent or chronic URIs (OM, otorrhea, sinusitis, 2 or

more episodes in any 6 month period)

WHO clinical staging system

Clinical stage 3 Unexplained moderate malnutrition not responding to

standard therapy Unexplained chronic diarrhea for > 14 days Unexplained prolonged fever for > 1 m Oral candidiasis Oral hairy leukoplakia Pulmonary TB Severe bacterial pneumonia (2 or more episodes in 6 m) Acute necrotizing ulcerative gingivitis/periodontitis Lymphoid interstitial pneumonia (LIP) Unexplained anemia (< 8g/dl), neutropenia (< 500) and/or

chronic thrombocytopenia (<30)

WHO clinical staging system Clinical stage 4

Unexplained severe wasting or severe malnutrition not responding to standard therapy

Pneumocystis jiroveci pneumonia (PCP) CNS toxoplasmosis Chronic cryptosporidiosis or isosporidiosis (with diarrhea > 1 mo) Cryptococcosis (extrapulmonary) CMV infection (onset at > 1 mo in an organ other than liver, spleen or lymph

nodes) Chronic HSV infection of > 1 month (orolabial or cutaneous) Progressive multifocal leukoencephalopathy (PML) Candidiasis of the esophagus, trachia, bronchi or lungs Disseminated non-tuberculous mycobacterial infection Symptomatic HIV + infant < 18 m with 2 or more of the following: oral thrus,

+/- severe pneumonia, +/- failure to thrive, +/- severe sepsis Extrapulmonary TB Lymphoma (cerebral or B cell non-Hodgkin) Kaposi sarcoma (KS) HIV encephalopathy CNS toxoplasmosis Recurrent severe bacterial infections (2 or more episodes in 1 yr excluding

pneumonia) Disseminated mycosis (histo or coccidio) Acquired HIV-related recto-vesico fistula Symptomatic HIV nephropathy or cardiomyopathy

Immunological classification- all ages

HIV associated immunodeficiency

Age related CD4(%CD4+ or absolute count)

<11m (%)

12-35m (%)

36-59m(%)

>5yr(count/%)

Not significant > 35 >30 >25 <500

Mild 30-35 25-30 20-25 350-499

Advanced 25-29 20-24 15-19 201-349

Severe <25 <20 <15 <200

TLC criteria of severe HIV immunodeficiency

Age-specific recommendation to initiate ARTb Immunological

marker

≤11 mo 12 mo-

35 mo

36 mo-

59 mo

5 - 8 years

TLC

≤4000

cells/mm3

≤3000

cells/mm3

≤2500

cells/mm3

≤2000

cells/mm3

(c)

(for use only in infants children with confirmed HIV infection, clinical stage 2 & CD4 measurement is not available)

Mortality by WHO stage

(from CHAP data courtesy of Di Gibb)

0.00

0.25

0.50

0.75

1.00

0 .5 1 1.5 2 2.5

Years from randomisation

STAGE 2

STAGE 3

STAGE 4

Pro

port

ion

su

rviv

ing

Similar separation in all age groups, although absolute mortality varies

Goals of Treatment

Clinical: Prolong life, improve quality of life.

Virologic: Achieve maximal suppression of viral load Viral load should drop by at least 1.0 after 3

months of treatment Viral load should be less than 400 after 6 months

of treatment

Immunologic: Reverse immune system damage.

Recommendations for initiating ART in HIV

infected infantsWHO stage

Availability CD4

Age specific treatment recommendation

[ A II ]

<11 months > 12 months

1 CD4 CD4 guided

No CD4 Do not treat

2 CD4 CD4 guided

No CD4 TLC guided

3 CD4 Treat all Treat all; can delay start of ART if CD4 above threshold and child has TB, HOL, LIP

No CD4 Treat all

4 CD4 Treat all

No CD4

HAART - Mechanism of Action

KITSO AIDS Training - Botswana

1st Line Regimen 2nd Line Regimen

ZDV or d4T ABC

Plus Plus

3TC DDI

Plus Plus

NVP or EFV KAL or NFV or SQV

WHO HAART Recommendation

Primary CTX prophylaxis

HIV-exposed infants & children confirmed HIV uninfected

HIV infected & ART - related immune recovery

CTX d/c when HIV infection has been definitely excluded [A-I]

CTX continued indefinitely

[A-IV]

However if : Child > 5 yrs started CTP during infancy, d/c CTP can be considered where: stable on ART > 12 mo + CD4 > used to initiate CTX prophylaxis + good adherence + secure supply + access to ART [C- IV] & restart if CD4 falls below the initiation threshold or if new or recurrent WHO 2, 3 or 4 conditions occur [A- IV]

Universal Access to comprehensive package of prevention & care

CARE TREATMENT AND SUPPORT FOR ALL HIV EXPOSED Early diagnostic testing for HIV infection Infant feeding counselling and support Co-trimoxazole prophylaxis Assessment, management and follow up of common conditions Regular Growth monitoring, developmental assessment and support Immunization Prevention, screening and management of tuberculosis Prevention and treatment of malaria

Care and support for for uninfected

Care and support where status still

unconfirmed

Care for the infected child

Early Diagnosis

Thank you for your attention!

Any questions?