Acquired and Primary Immunodeficiencie s Cheryl Pikora MD, PhD Univ of Mass Medical School

Outline Brief overview of causes of acquired immunodeficiencies Brief overview of causes of acquired immunodeficiencies Brief discussion of the components of innate and adaptive immunity Brief discussion of the components of innate and adaptive immunity Clinical presentations of primary immunodeficiencies Clinical presentations of primary immunodeficiencies Discussion of pediatric HIV prevention, diagnosis and treatment Discussion of pediatric HIV prevention, diagnosis and treatment

Acquired immunodeficiencies Chemotherapy Chemotherapy Breakdown in integumentary barriers Breakdown in integumentary barriers Altered microbial colonization Altered microbial colonization Enhanced susceptibility to infection Enhanced susceptibility to infection Neutrophils* Neutrophils* T lymphocytes* T lymphocytes* B lymphocytes* B lymphocytes* NK cells NK cells Peripheral blood monocytes* Peripheral blood monocytes* Fixed-tissue macrophages Fixed-tissue macrophages

Acquired immunodeficiencies Immunosuppressive drugs Immunosuppressive drugs Corticosteroids Corticosteroids Anti-rejection agents Anti-rejection agents Monoclonal antibodies Monoclonal antibodies Immunomodulatory infections Immunomodulatory infections HIV HIV TB TB Malaria Malaria EBV, CMV EBV, CMV

Primary Immunodeficiencies: Genetic Neutrophil function defect Neutrophil function defect Complement deficiency Complement deficiency B cell deficiency B cell deficiency Specific immunoglobulin deficiency Specific immunoglobulin deficiency T cell deficiencies (SCID) 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 Th2 Th1 Humoral Immunity Cellular Immunity

Memory T and B cells

Immunoglobuins

Humoral vs. Cellular Mediated Immunity (CMI) Humoral: Humoral: Extracellular pathogens 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 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 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 UNICEF has not received reporting on incidence or prevalence of HIV/AIDS in the pediatric population of Liberia. 2 1 The Basic Package of Health and Social Welfare Services, Republic of Liberia, Ministry of Health and Social Welfare. 2

HIV infection

Time (years) Virologic response 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) Killed KITSO AIDS Training Program, Botswana

Immune abnormalities Hypergammaglobulinemia Hypergammaglobulinemia Increased CD8+ cells Increased CD8+ cells Decreased CD4+ cells Decreased CD4+ cells Decrease in CD4:CD8 ratio < 1 Decrease in CD4:CD8 ratio < 1 Immune activation (chronic) 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 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% 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 The risk is as high as 29% for mothers who acquire HIV post-natally Transmission

Mother-to-Child Transmission of HIV Mother-to-Child Transmission of HIV ARV Therapy and MTCT 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 5-10,000 copies/ml (e.g., at time of seroconversion and during late HIV disease: CD4 cell counts <100 cells/mm) Recurrent STDs Recurrent STDs Malaria interferes with placental functions and eases viral transmission across the placenta Malaria interferes with placental functions and eases viral transmission across the placenta Vitamin A deficiency Vitamin A deficiency Preterm delivery Preterm delivery Factors Which May Increase the Risk of Transmission

Vaginal delivery Vaginal delivery Duration of rupture of membranes is longer than 4 hours Duration of rupture of membranes is longer than 4 hours Placental disruption Placental disruption Invasive procedures during delivery (e.g., vacuum extraction, episiotomy, use of forceps, fetal scalp monitoring) Invasive procedures during delivery (e.g., vacuum extraction, episiotomy, use of forceps, fetal scalp monitoring) Mechanical nasal suction after delivery Mechanical nasal suction after delivery Breastfeeding and especially mixed feeding Breastfeeding and especially mixed feeding Factors Which May Increase the Risk of Transmission, continued

PMTCT regimens

Breastfeeding and MTCT

Pediatric HIV Infection – Common Clinical Presentations Infectious Diseases Infectious Diseases Respiratory Illness (PCP, Tuberculosis) Respiratory Illness (PCP, Tuberculosis) Diarrheal Diseases Diarrheal Diseases Oral Candidiasis Oral Candidiasis Herpes Zoster Herpes Zoster Lymphadenopathy, Hepatomegaly, Parotitis Lymphadenopathy, Hepatomegaly, Parotitis Persistent fever Persistent fever Growth failure: Kwashiorkor, Marasmus Growth failure: Kwashiorkor, Marasmus Developmental Delay or Regression Developmental Delay or Regression Malignancies: Lymphoma, Kaposi’s sarcoma Malignancies: Lymphoma, Kaposi’s sarcoma

Diarrheal Illness Similar prevalence of stool pathogens between HIV infected and uninfected children. Similar prevalence of stool pathogens between HIV infected and uninfected children. Worse outcomes in HIV infected children. Worse outcomes in HIV infected children. KITSO AIDS Training, Botswana

Respiratory Illness Death from respiratory tract infections: Death from respiratory tract infections: PCP: Most common pathogen in HIV-infected children below six-months of age 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. Acute pyogenic pneumonia and tuberculosis common in HIV- infected and uninfected children. KITSO AIDS Training, Botswana

Presumptive diagnosis of severe HIV in HIV exposed infant Seropositive Infant; AIDS indicator conditions AIDS indicator conditions Symptomatic with 2 or > two or more of the following: Symptomatic with 2 or > two or more of the following: oral thrush; oral thrush; severe pneumonia severe pneumonia severe sepsis severe sepsis Other factors to support diagnosis of severe HIV include: Other factors to support diagnosis of severe HIV include: Recent HIV-related maternal death; or Recent HIV-related maternal death; or Advanced HIV disease in the mother; or Advanced HIV disease in the mother; or No history of PMTCT intervention No history of PMTCT intervention CD4 <25% CD4 <25% Confirmation of the diagnosis of HIV infection should be sought as soon as possible. Confirmation of the diagnosis of HIV infection should be sought as soon as possible.

Revised Staging & Classification Clinical classification Stage 1Stage 2Stage 3Stage 4 No symptoms MildAdvancedSevere Immunological classification Not significant MildAdvancedSevere +

WHO clinical staging system Clinical stage 1 Clinical stage 1 Asymptomatic Asymptomatic Persistent generalized lymphadenopathy Persistent generalized lymphadenopathy Clinical stage 2 Clinical stage 2 Hepatosplenomegaly Hepatosplenomegaly Papular pruritic eruptions Papular pruritic eruptions Seborrhoeic dermatitis Seborrhoeic dermatitis Funal nail infections Funal nail infections Angular cheilitis Angular cheilitis Lineal gingival erythema (LGE) Lineal gingival erythema (LGE) Extensive human papilloma virus infection or molluscum infection (> 5% body area) Extensive human papilloma virus infection or molluscum infection (> 5% body area) Recurrent oral ulcerations (2 or more episodes in 6 months) Recurrent oral ulcerations (2 or more episodes in 6 months) Herpes zoster Herpes zoster Recurrent or chronic URIs (OM, otorrhea, sinusitis, 2 or more episodes in any 6 month period) Recurrent or chronic URIs (OM, otorrhea, sinusitis, 2 or more episodes in any 6 month period)

WHO clinical staging system Clinical stage 3 Clinical stage 3 Unexplained moderate malnutrition not responding to standard therapy Unexplained moderate malnutrition not responding to standard therapy Unexplained chronic diarrhea for > 14 days Unexplained chronic diarrhea for > 14 days Unexplained prolonged fever for > 1 m Unexplained prolonged fever for > 1 m Oral candidiasis Oral candidiasis Oral hairy leukoplakia Oral hairy leukoplakia Pulmonary TB Pulmonary TB Severe bacterial pneumonia (2 or more episodes in 6 m) Severe bacterial pneumonia (2 or more episodes in 6 m) Acute necrotizing ulcerative gingivitis/periodontitis Acute necrotizing ulcerative gingivitis/periodontitis Lymphoid interstitial pneumonia (LIP) Lymphoid interstitial pneumonia (LIP) Unexplained anemia (< 8g/dl), neutropenia (< 500) and/or chronic thrombocytopenia (<30) Unexplained anemia (< 8g/dl), neutropenia (< 500) and/or chronic thrombocytopenia (<30)

WHO clinical staging system Clinical stage 4 Clinical stage 4 Unexplained severe wasting or severe malnutrition not responding to standard therapy Unexplained severe wasting or severe malnutrition not responding to standard therapy Pneumocystis jiroveci pneumonia (PCP) Pneumocystis jiroveci pneumonia (PCP) CNS toxoplasmosis CNS toxoplasmosis Chronic cryptosporidiosis or isosporidiosis (with diarrhea > 1 mo) Chronic cryptosporidiosis or isosporidiosis (with diarrhea > 1 mo) Cryptococcosis (extrapulmonary) Cryptococcosis (extrapulmonary) CMV infection (onset at > 1 mo in an organ other than liver, spleen or lymph nodes) 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) Chronic HSV infection of > 1 month (orolabial or cutaneous) Progressive multifocal leukoencephalopathy (PML) Progressive multifocal leukoencephalopathy (PML) Candidiasis of the esophagus, trachia, bronchi or lungs Candidiasis of the esophagus, trachia, bronchi or lungs Disseminated non-tuberculous mycobacterial infection 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 Symptomatic HIV + infant < 18 m with 2 or more of the following: oral thrus, +/- severe pneumonia, +/- failure to thrive, +/- severe sepsis Extrapulmonary TB Extrapulmonary TB Lymphoma (cerebral or B cell non-Hodgkin) Lymphoma (cerebral or B cell non-Hodgkin) Kaposi sarcoma (KS) Kaposi sarcoma (KS) HIV encephalopathy HIV encephalopathy CNS toxoplasmosis CNS toxoplasmosis Recurrent severe bacterial infections (2 or more episodes in 1 yr excluding pneumonia) Recurrent severe bacterial infections (2 or more episodes in 1 yr excluding pneumonia) Disseminated mycosis (histo or coccidio) Disseminated mycosis (histo or coccidio) Acquired HIV-related recto-vesico fistula Acquired HIV-related recto-vesico fistula Symptomatic HIV nephropathy or cardiomyopathy 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 Advanced Severe <25<20<15<200

TLC criteria of severe HIV immunodeficiency (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) Years from randomisation STAGE 2 STAGE 3 STAGE 4 Proportion surviving Similar separation in all age groups, although absolute mortality varies

Goals of Treatment Clinical: Prolong life, improve quality of life. Clinical: Prolong life, improve quality of life. Virologic: Achieve maximal suppression of viral load Virologic: Achieve maximal suppression of viral load Viral load should drop by at least 1.0 after 3 months of treatment 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 Viral load should be less than 400 after 6 months of treatment Immunologic: Reverse immune system damage. Immunologic: Reverse immune system damage.

Recommendations for initiating ART in HIV infected infants WHO stage Availability CD4 Age specific treatment recommendation [ A II ] <11 months> 12 months 1CD4CD4 guided No CD4Do not treat 2CD4CD4 guided No CD4TLC guided 3CD4Treat allTreat all; can delay start of ART if CD4 above threshold and child has TB, HOL, LIP No CD4Treat all 4CD4Treat all No CD4

HAART - Mechanism of Action KITSO AIDS Training - Botswana

1 st Line Regimen 2 nd Line Regimen ZDV or d4T ABC PlusPlus 3TCDDI PlusPlus 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?