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Acquired and Primary Immunodeficiencies

Acquired and Primary Immunodeficiencies. Cheryl Pikora MD, PhD Univ 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

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Acquired and Primary Immunodeficiencies

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  1. Acquired and Primary Immunodeficiencies Cheryl Pikora MD, PhD Univ of Mass Medical School

  2. 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

  3. 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

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

  5. Primary Immunodeficiencies: Genetic • Neutrophil function defect • Complement deficiency • B cell deficiency • Specific immunoglobulin deficiency • T cell deficiencies (SCID)

  6. Cells of Innate Immunity neutrophil macrophage dendritic cell natural killer cell

  7. Bacterial and fungal infection: first line of defense: neutrophil

  8. Phagocytosis and secretion of mediators of inflammation: macrophages

  9. Dendritic cells

  10. PAMP and dendritic cells

  11. Viral PAMP and DC

  12. Natural Killer Cells

  13. The complement cascade

  14. Infection and the response to it

  15. CD4+ help for CD8+ cells and B cells Humoral Immunity Cellular Immunity Th2 Th1

  16. Memory T and B cells

  17. Immunoglobuins

  18. Humoral vs. Cellular Mediated Immunity (CMI) • Humoral: • Extracellular pathogens • CMI • Intracellular pathogens

  19. Some intracellular microorganisms (other than viruses)

  20. Bacterial, fungal infections, • parasites (extracellular): • Neutrophils • Immunoglobulins • Complement • Viral and intracellular bacterial/fungal/parasitic infections: • CD4/CD8 T cells • NK cells

  21. Pediatric HIV infection

  22. 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

  23. HIV infection

  24. Virologic response Child Adult Time (years) Infection

  25. HIV-1 Particle KITSO Aids Training Program, Botswana

  26. Helper Function of CD4 Cells Macrophage T helper cell (CD4) Cytotoxic TLymphocyte(CD8) BLymphocyte Infected cell Antibody secreting (plasma) cell Killed KITSO AIDS Training Program, Botswana

  27. Immune abnormalities • Hypergammaglobulinemia • Increased CD8+ cells • Decreased CD4+ cells • Decrease in CD4:CD8 ratio < 1 • Immune activation (chronic)

  28. Transmission • 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

  29. 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

  30. Factors Which May Increase the Risk of Transmission • 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

  31. Factors Which May Increase the Risk of Transmission, continued • 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

  32. PMTCT regimens

  33. Breastfeeding and MTCT

  34. 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

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

  36. 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

  37. 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.

  38. Revised Staging & Classification +

  39. WHO clinical staging system • Clinical stage 1 • Asymptomatic • Persistent generalized lymphadenopathy • Clinical stage 2 • Hepatosplenomegaly • Papularpruritic 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)

  40. 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)

  41. WHO clinical staging system • Clinical stage 4 • Unexplained severe wasting or severe malnutrition not responding to standard therapy • Pneumocystisjiroveci 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-tuberculousmycobacterial 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

  42. Immunological classification- all ages

  43. TLC criteria of severe HIV immunodeficiency (for use only in infants children with confirmed HIV infection, clinical stage 2 & CD4 measurement is not available)

  44. Mortality by WHO stage (from CHAP data courtesy of Di Gibb) 1.00 STAGE 2 0.75 STAGE 3 0.50 Proportion surviving STAGE 4 0.25 0.00 0 .5 1 1.5 2 2.5 Years from randomisation Similar separation in all age groups, although absolute mortality varies

  45. 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.

  46. Recommendations for initiating ART in HIV infected infants

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