Immunodeficiency Imunodeficiency states •Primary –Caused by defined genetic defect –Usually rare, but severe (exception: IgA deficiency) •Secondary –Consequence of some other disease, treatment, environmental factors… –Usually frequent, but usually clinically mild (exceptions: HIV disease, secondary aganulocytosis). Severe combined immunodeficiency (SCID) •Early clinical manifestation (weeks-months) •Severe and complicated infections affecting respiratory and gastrointestinal tract and the skin •Failure to thrive •Frequent diarrhea •Usually lymphocytopenia •T-cell deficiency, B cell present in some patients •Decreased immunoglobulin levels SCID, t-GVHR, generalised BCG-itis SCID infections caused by atypical patogens •Pneumocystis pneumonia •Cytomegalovirus pneumonitis •Disseminated BCG-itis •Infections caused by atypical mycobacteria •Candidiasis of oropharynx, skin • • Pacient se SCID (Sjekel) Patient with SCID Immunoglobulin Deficiencies Clinical manifestations begins at 6-12 months (or late). Susceptibility to infection by encapsulated bacteria (Pneumococcus, Haemophilus). Respiratory tract predominantly affected; patients suffer from recurrent otitis media,bronchitis, sinusitis, pneumonia. Some patients also suffer from meningitis or chronic diarrhea. X-linked agammaglobulinemia •Only boys affected •Clinical manifestation usually begins at 6-12 months •Severe and complicated respiratory tract infections. •Very low levels of all immunoglobulin isotypes. •B-cells not detected. • Common variable immunodeficiency (CVID) •Both sexes affected. •Clinical manifestation begins at any age. •Frequent and severe respiratory tract infections. •Proneness to autoimmune diseases. •Variable decrease of immunoglobulin isotypes, usually markedly decreased IgA and IgG levels. •B-lymphocytes usually present. Selective IgA deficiency •Frequency: 1:400 •Usually only mild manifestation •Predominantly respiratory tract infections •Patients are prone to autoimmune diseases •Beware of anti-IgA antibodies that can cause a severe anaphylactic reaction after artificial IgA administration (by blood, immunoglobulin derivates)! T-cell Deficiences -Early onset of clinical manifestation. - -Increased susceptibility to viral, fungal, mycobacterial, and protozoal infections. - - Respiratory system most frequently affected, but also other systems can be involved. DiGeorge syndrome •Defect in embryonic development of the 3rd and 4th pharyngeal pouches. •Cardiovascular defects (e.g Fallot´s tetralogy, intrrupted aortic arch..) •Hypoparathyroidism ® hypocalcemia ® seizures •Thymic hypoplasia ® T cell deficiency •Typical facies: hypertelorism, micrognatia, low-set, posterior rotated ears. DiGeorgeI DiGeorge syndrome Lokaj34 DiGeorge syndrome Complement deficiencies •Deficiency of C1-C4: autoimmune systemic disorders, susceptibility to bacterial infections •Deficiency C5-C9: susceptibility to bacterial infections, mainly to meningococcal meningitis •Deficiency of C1 INH: hereditary angioedema Hereditary angioedema •Deficiency of C1 inhibitor (C1 INH) •Uncontrolled activation of the complement system after trauma, infection, surgical operation.... •Vasoactive peptides (bradykinin, C3a,C5a) cause increased vascular permeability •Oedema of the skin, respiratory tract (dyspnoe), gastrointestinal tract (cramps, vomiting) HEREDITARY ANGIOEDEMA (HAE) Phagocytic dysfunction •Early onset of clinical manifestation. •Susceptibility to bacterial and fungal infections. •Abscess formation, mainly of the skin, periproctal area, liver, but any area may be affected. Chronic granulomatous disease •Recurrent abscesses mainly of the liver, lungs, periproctal area, suppurative lymphadenitis, osteomyelitis. •Infections are caused mainly by catalase-positive organisms: St. aureus, Candida sp., Serratia marcescens . •Usually early onset of symptoms. •Production of reactive metabolites of oxygen is disturbed (defect of NADPH oxidase). Wiskott-Aldrich syndrome •X-linked disease •Thrombocytopemia ® bleeding tendency •Severe eczema •Immunodeficiency •Severe allergic and autoimmune manifestations •B-cell lymphomas WAS Wiskott-Aldrich syndrome Ataxia telangiectasia •Autosomal recessive •Progressive cerebellar ataxia •Telangiectasis especially on ear lobes and conjunctival sclera •Immunodeficiency •Frequent tumors •Cause: mutation in ATM gene • Telangiektasie u AT-II Ataxia telangiectasia Treatment of primary immunodeficiencies •SCID and other severe immunodeficiencies: bone marrow transplantation, gene therapy in some cases. •Antibody deficiencies: immunoglobulin replacement •Antibiotic prohylaxis • Causes of secondary immunodeficiency •Metabolic - uremia, diabetes, malnutrition •Iatrogenic – cytostatics, immunosuppresants •Malignat tumors •Viral infections - HIV, CMV, measles, infectious mononucleosis •Splenectomy •Stress •Injuries, operations, general anestesia • Secondary immunodeficiency Imunodeficiency after splenectomy •Disturbed phagocytosis, decreased production of antibodies. •The most severe complication is hyperacute pneumococal sepsis. •Prevention: vaccination against Pneumococcus, Haemophilus infl. B, Meningococcus. PNC prophylaxis. Secondary hypogammaglobulinemia •Decreased production of immunoglobulins –Chronic lymphatic leukemia –Lymphoma –Myeloma •Loss of immunoglobulins –Nephrotic syndrome –Exudative enteropathy HIV disease S0241X-012-f007a Downloaded from: StudentConsult (on 19 July 2006 06:18 AM) © 2005 Elsevier Ways of transmission 1.Sexual 2.Parenteral – intravenous drug addicts • previously blood products •3. Vertical – mother to child – transplacental, during delivery, by brestfeeding HIV receptors •CD4 – expressed on helper T lymphocytes, but also on macrophages. Binds to gp120. • •CCR5, CXCR4 – chemokine receptors. Are co-receptors necessary for majority of virus strains to enter the affected cells. Some (in CR approx. 5%) people are deficient for CCR5 – are relatively resistent to HIV infection. In infected patients, slow progression of the disease. S0241X-012-f008 Downloaded from: StudentConsult (on 19 July 2006 06:18 AM) © 2005 Elsevier CD4+ cells mumber and progression of HIV disease Classification of HIV disease (CDC) •3 clinical categories • •A Asymptomatic disese •B „small“ opportunistic infections •C „big“ opportunistic infections and other states that define AIDS Clinical category A •Accute (primary) HIV infection •Asymptomatic HIV infection •Persistent generalised lymphadenopathy (PGL) • HIV PRIMOINFECTION •Acute retroviral syndrome, („mononucleosis-like syndrome“) •Present in 50-70% patients •2-6 weeks after infection Clinical presentaioon of HIV primoinfection •Fever, lympadenopathy, pharyngitis •Rash •Myalgia, arthralgia, diarrhoea, cephalea •Thrush •Neurologic symptoms •Aphtous stomatitis Perzistent generalized lympadenopathy - •More than 3 months •1/3 HIV-infected persons •Lymph nodes 0,5-2,0 cm, painless Clinical category B •Fever >38,5 C more than 1 month •Diarrhoea more than 1 month •Oropharyngeal candidiasis •Vulvovaginal candidiasis • (chronic or difficult to treat) •Recurrent herpes zoster Clinical category C (AIDS) •Pneumocystis pneumonia •Brain abscess caused by Toxoplasma •Esofageal, tracheal, bronchial or lung candidiasis •Chronic anal herpes, herpetic bronchitis, pneumonia •CMV retinitis, generalized CMV infection •Progressive multifocal leukoecephalopathy •Mycobacterial infections • Opportunistic Infections in AIDS Patients - Pneumonia due to Pneumocystis jiroveci (carinii) - Toxoplasma brain abscess - Cytomegalovirus infection (retinitis, colitis) - Mycobacterial infections - Herpes virus and Varicella-Zoster infections Type of oportunistic infections in HIV/AIDS depends on absolute CD4 count Clinical category C ( AIDS ) - tumors • •Kaposhi sarcoma • •Brain lymphoma KaposiV Kaposhi sarcoma Kaposi III Kaposiho sarkom Kaposi sarkoma Pacient s AIDS Wasting syndrome Treatment of HIV-disease •Antiretroviral –Nucleoside inhibitors of reverse transcriptase – binding to the active center of reverse transcriptase –Nonnucleoside inhibitors of reverse transcriptase binding out of the active center of reverse transcriptase –HIV protease inhibitors –Integrase inhibitors –Inhibitors of fusion (CCR5 blocking) – –Combination of anti HIV drugs is always used – •Prophylaxis of Pneumocystis carinii pneumonia (co-trimoxazol), antiviral and antimycotic antibiotics is sometimes used. Diagnosis of HIV infection •Detection of anti-viral antibodies – ELISA –Western blott • •Detection of antigen p 24