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). Immunodeficiency – Clinical manifestation • Susceptibility to severe and complicated infections. • Infections may be caused by atypical pathogens. • Increased frequency of ordinary infections is a less significant sign. • Insufficient response to antibiotic treatment. • Increased frequency of tumors, mainly of the lymphatic system. • Increased frequency of autoimmune and allergic diseases. 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 Patient with SCID Immunoglobulin Deficiencies Clinical manifestations begins at 6-12 months (or later), after disappearance of maternal antibodies. 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 • Caused by mutation of Bruton´s thyrosine kinase. • Defect in B-cells development - B-cells are not present in blood. • Clinical manifestation usually begins at 6-12 months • Severe and complicated respiratory tract infections. • Very low levels of all immunoglobulin isotypes. Common variable immunodeficiency (CVID) • The most frequent (approx1:10,000) symptomatic primary immunodeficiency. • 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. DiGeorge syndrome 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). • Diagnostic tests are based on oxidative-reduction capacity of granulocytes – tetrarrhodamide reduction (“burst test“), NBT (nitro blue tetrazolim) reduction. Wiskott-Aldrich syndrome • X-linked disease • Thrombocytopemia  bleeding tendency • Severe eczema • Immunodeficiency • Severe allergic and autoimmune manifestations • B-cell lymphomas Wiskott-Aldrich syndrome Chromosmal instability disorders • Recessive inheritance. • Lead to by disturbed chomosomal breaks repair. • Patients are markedly prone to maligmancies, mainly lymphoim malignancies. • Accompanied by various other symptoms. • As regards accompanied immunodeficiency the most typical are: ataxia tealangiectasia, Nijmegen breakage syndrome, Bloom´s syndrome .. Ataxia telangiectasia • Autosomal recessive • Progressive cerebellar ataxia • Telangiectasis especially on ear lobes and conjunctival sclera • Immunodeficiency • Frequent tumors • Cause: mutation in ATM gene Ataxia telangiectasia Nijmegen breakage syndrome • Autosomal recessive disease of chromosomal instability • Clinically characterized by microcephaly, a distinct facial appearance (bird-like face), short stature, immunodeficiency, radiation sensitivity, and a strong predisposition to lymphoid malignancy. Nijmegen breakage syndrome 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, disturbed „blood filtration“, decreased production of antibodies. • The most severe complication is hyperacute pneumococcal sepsis (OPSI syndrome) . • Prevention: vaccination against Pneumococcus, Haemophilus infl. B, Meningococcus. PNC prophylaxis. Secondary hypogammaglobulinemia • Decreased production of immunoglobulins – Chronic lymphatic leukemia – Lymphoma – Myeloma – B-cells tagreted therapy, immunosuppresive therapy • Loss of immunoglobulins – Nephrotic syndrome – Exudative enteropathy HIV disease Ways of transmission 1. Sexual 2. Parenteral – intravenous drug addicts previously blood products 3. Vertical – mother to child – transplacental, during delivery, by brestfeeding Downloaded from: StudentConsult (on 19 July 2006 06:18 AM) © 2005 Elsevier HIV receptors • CD4 – expressed on helper T lymphocytes, but also on macrophages. Binds to gp120. • CCR5, CXCR4 – chemokine receptors. Are coreceptors 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. 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 Kaposhi sarcoma Kaposiho sarkom Kaposi sarkoma 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 (cotrimoxazol), antiviral and antimycotic antibiotics is sometimes used. Diagnosis of HIV infection • Detection of anti-viral antibodies – ELISA –Western blott • Detection of antigen p 24