Immunodeficiency may be
(. See also overview of immunodeficiency disease) immune defect may be primary: Genetically determined, usually during early childhood or childhood manifested Secondary: Acquired There are many causes for secondary immunodeficiency, but most immune deficiencies resulting from one or more of the following Systemic diseases (. eg diabetes, malnutrition, HIV infection) Immunosuppressive treatments (. eg cytotoxic chemotherapy, bone marrow ablation prior to transplantation, radiotherapy) Long serious illness (especially critical ill, elderly and / or hospitalized patients) classification primary immunodeficiencies performed according to the main component of the immune system, which has a defect that is not present or defective: Humoral immunity Cellular immunity combi ned humoral and cellular immunity phagocytes complement proteins usually manifest themselves immunodeficiencies as recurrent infections. In children, recurrent infections but are probably due to repeated contact with other children in kindergartens and schools (infants and older children can usually up to 10 respiratory infections in developing). The causes of recurrent infections in children and adults, however, are rather insufficient long antibiotic therapy, resistant organisms and other predisposing diseases (such. As congenital heart defects, allergic rhinitis, ureter or urethral stenosis, primary ciliary dyskinesia, asthma, cystic fibrosis, severe dermatitis ). The suspected immunodeficiencies exists when recurrent infections have the following characteristics: Heavy complexity at several locations resistant to treatment by unusual organisms triggered presence in family members first, it is the typical infections of the upper and lower airways (eg, sinusitis, bronchitis, pneumonia.) and gastroenteritis, but it may also be severe bacterial infections act (z. B. meningitis, sepsis). In children in infancy and young children with developmental disorders and diarrhea (esp. By unusual viruses such as adenoviruses or fungi such as Cryptosporidium sp. Causes) could be an immune deficiency is based. Other signs are skin lesions (eg. As eczema, warts, abscesses, pyoderma, alopecia), candidiasis of the oral or esophageal mucosa, oral ulcers and periodontitis. Less common manifestations are severe viral infections with herpes simplex or varicella zoster virus and CNS disorders (eg. As chronic encephalitis, retarded development, seizures triggering diseases). Excessive use of antibiotics can mask many of the usual signs and symptoms. At immunodeficiencies should (anemia z. B., thrombocytopenia) especially in patients with infections and autoimmune disease are thought. Clarification history and physical examination are helpful, but must be supplemented by an immune function test. For many diseases prenatal tests are available that are indexed if an immune deficiency determined familienanamnestisch and the mutation was found in some family members. Medical history, physicians should determine whether patients have risk factors for infections or there is a history of symptoms for secondary Immundeffekte and / or risk factors for this are available. Family history is very important. The age at which recurrent infections started is important. An appearance before the age of 6 months indicates a T-cell defect because maternal antibodies have a protective effect usually during the first 6 to 9 months. The occurrence in the aged 6 to 12 months can speak for a combined B and T cell or a B-cell defect which are evident with the disappearance of maternal antibodies (about 6 months). The appearance much later than 12 months indicates generally a B-cell defect or a secondary immunodeficiency disorder. In general, the immunodeficiencies is more difficult, the younger the children are the first occurrence of the disorders. Certain immunodeficiencies such. B. variable immunodeficiency (CVID), often do not manifest before adulthood. Certain infections can to determine immunodeficiencies include (see Table: Some information in the medical history to determine the immune deficiency); However, no infection for a particular disorder is specific, and many immunodeficiencies certain common infections (eg., viral or bacterial infections of the respiratory tract) may occur. Some instructions in the history in order to determine the immune defect finding immunodeficiency Recurrent Infections with Streptococcus pneumoniae and Haemophilus influenzae Ig, C2 or IRAK-4 deficiency Recurring Giardia intestinalis (lamblia) infection antibody deficiency Familial clustering of autoimmune diseases (eg., Systemic lupus erythematosus, pernicious anemia) Variable immunodeficiency syndrome or selective IgA deficiency Pneumocystis infection cryptosporidiosis, or toxoplasmosis T-cell disorders or occasionally Ig deficiency viruses, fungi or mycobacteria (opportunistic infections) T-cell malignancies Clinical infection due to live attenuated vaccines (eg. As chicken pox, polio, BCG) T-cell malignancies graft-vs-host disease (through blood transfusions T-cell malignancies staphylococcal infections, infections with gram-negative organisms (eg. B, Serratia and Klebsiella sp), or fungal infections such . B. aspergillosis) phagocytes defects or Hyper-IgE syndrome skin infections Neutrophilenstörung or Ig deficiency Recurrent gingivitis Neutrophilenstörung Recurrent Neisseria infections Certain Komplementdefekte Recurrent sepsis Certain Komplementdefekte, hyposplenism or IgG deficiency deceased children in the family history or infections in a maternal uncle, similar to those of the patient X-linked disorders (eg. B. severe combined immune deficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, Hyper-IgM syndrome) Ig = immunoglobulin; IRAQ = IL-1R-associated kinase Medical Examination patients with immunodeficiency can make a chronically ill feeling or appear quite normal. The skin may include patchy rashes, blisters, pyoderma, eczema, petechiae, alopecia or telangiectasia. In X-linked inherited agammaglobulinemia, X-linked inherited Hyper IgM syndrome, severe combined immunodeficiency (SCID) or other T-cell immunodeficiencies are neck lymph nodes, tonsils and adenoids typically very small or absent, despite a history of recurrent infections. In certain other immune deficiencies (eg. As chronic granulomatous disease), the cervical lymph nodes may be enlarged or ulcerated. The eardrum is often scarred or perforated, and the nostrils are caked, indicating purulent nasal mucus. Chronic cough and rattling noises are common, especially in adults with CVID. Liver and spleen are enlarged in patients with CVID or chronic granulomatous disease often. The muscle and the fat deposits of the buttocks is reduced. In infants, the skin around the anus may be sore due to chronic diarrhea. The neurological examination can reveal developmental delays or ataxia. Further characteristic results suggest a preliminary clinical diagnosis close (see table: Characteristic clinical findings in some primary immunodeficiencies). Characteristic clinical findings in some primary immunodeficiency age group findings * Fault <6 months diarrhea, failure to thrive Life-threatening infection (z. B. pneumonia, sepsis, meningitis) Severe combined immunodeficiency maculopapular rash, splenomegaly Severe Combined Immunodeficiency, when he speaks of a graft versus host disease (z. B. caused by transmitted across the T-cells) accompanied Hypocalcemic tetany, a congenital heart disease, unusual facies with deep-seated ears, developmental delay DiGeorge syndrome Recurrent purulent infections, sepsis C3 deficiency Oculocutaneous albinism, neurological changes, lymphadenopathy Chediak-Higashi syndrome cyanosis, a congenital disease of the heart, liver centerline Congenital asplenia Delayed umbilical cord separation, leukocytosis, periodontal disease, poor wound healing Leukocyte adhesion abscesses, lymphadenopathy, antral obstruction, pneumonia, osteomyelitis Chronic granulomatosis Recurrent staphylococcal abscesses of the skin, lungs, joints and internal organs; pneumatoceles; coarse facial features, itchy dermatitis hyper IgE syndrome chronic gingivitis, recurrent aphthous ulcers and skin infections, severe neutropenia Severe congenital neutropenia Gastrointestinal bleeding (eg. as bloody diarrhea), eczema Wiskott-Aldrich syndrome 6 months to 5 years of paralysis by polio vaccination X-linked agammaglobulinemia severity progressive infectious mononucleosis X-linked lymphoproliferative syndrome inherited Persistent oral candidiasis, nail dystrophy, endocrine disorders (eg. B. hypoparathyroidism, Addison's disease) Chronic mucocutaneous candidiasis> 5 years (including adults) ataxia, recurrent sinopulmonary infections, neurological deterioration, telangiectasia ataxia telangiectasia Recurrent Neisseria meningitis C5, C6, C7 or C8 deficiency Recurrent sinopulmonary infections, malabsorption , splenomegaly, autoimmune diseases, nodular lymphoid hyperplasia of the gastrointestinal tract, giardiasis, lymphoid interstitial pneumonia, bronchiectasis common variable Immunschwäc he Progressive dermatomyositis with chronic Echo virus encephalitis X-linked agammaglobulinemia * In addition to infections. Adapted from Stiehm, ER, Conley ME: immunodeficiency diseases: general considerations, in Immunodeficiency Disease in Infants and Children, ed 4, edited by ER Stiehm. Philadelphia, WB Saunders Company, 1996, p. 212. Initial tests case of suspicion of a clinically relevant secondary immunodeficiency, the studies should focus on these (eg. As diabetes, HIV infection, cystic fibrosis, primary ciliary dyskinesia). Laboratory testing to confirm the diagnosis are required (see table: Original and additional laboratory tests immunodeficiency). Initial screening tests blood count with manual differentiation Quantitative immunoglobulin (Ig) measurements antibody skin test for delayed hypersensitivity original and additional laboratory tests immunodeficiency type Initial tests Additional tests Humoral immune deficiency disorder IgG, IgM, IgA and IgE levels Isohämagglutinin-titer antibody response (on vaccine antigens e.g. . B. Haemophilus influenzae type B, tetanus, diphtheria, conjugated and non-conjugated pneumococcal, meningococcal and antigens) B-cell phenotyping and retries by flow cytometry and monoclonal antibodies directed against B-cell flow cytometry for CD40 and CD40 ligand assessment for mutations in genes that BTK and NEMO encode sweat test Cellular immunodeficiency disorder Absolute lymphocyte count skin tests (on delayed hypersensitivity z. B. using Candida) HIV test X-ray examination of the chest only in infants to reduce the size of the thymus to determine T-cell phenotyping and retries by flow cytometry and monoclonal antibodies to T cells and subsets T-cell proliferative response to mitogenic TREC test (identified a genetic test that infants with abnormal T cells or a low number of T-cells due to SCID or other diseases) Phagocytic cell defects Phagocytic cell number and morphology Flow cytometric oxidative burst measurement with dihydrorhodamine 123 (DHR) or nitroblue ( NBT) flow cytometry for CD18 and CD15 neutrophil chemotaxis Complement deficiency C3-C4-level plane CH50 activity (for the total activity of the classical pathway) and AH50 activity (for total counts of the alternative complement pathways) C1 inhibitor levels and function-specific components assays BTK = Bruton’s tyrosine kinase; C = complement; CH = hemolytic complement; NEMO = nuclear factor-kappa B main modulator; SCID = severe combined immunodeficiency disorder; TREC = T cell receptor-Exzisionskreis. In normal results, a immunodeficiency (especially Ig deficiency) can be excluded. With eye-catching results to identify specific disorders further tests in specialized laboratories are required. Are chronic infections objectively documented initial examinations and specific tests should be performed simultaneously. If clinicians suspect that the immune deficiency disorder could still in its development, it might be necessary that the tests are repeated with a monitor for some time before a final diagnosis is made. A complete blood count can anomalies that are characteristic of specific disorders, in one or more cell types show (e.g., leukocyte, platelet.) As shown in the following cases: I (<1200 cells / ul absolute neutrophil count) A] neutropenia congenitally his or cyclical and occur with aplastic anemia. Lymphopenia (lymphocyte count <2000 / ul at birth <4500 / ul aged 9 months or <1000 / ul in older children and adults) points to a T-cell Defekthin, as 70% of circulating lymphocytes T cells are. In case of Leukozytenadhäsionsdefekts can cause a persistent leukocytosis. Thrombocytopenia in male infants indicates the Wiskott-Aldrich syndrome. Anemia may due to a chronic disease or autoimmune hemolytic anemia, which may occur with CVID and other immunodeficiencies. However, many anomalies are only temporary manifestations of infection, medication or other factors; Therefore, abnormalities should be confirmed and controlled. Clinical Calculator: Absolute neutrophil count smears of peripheral Blutsollten on Howell-Jolly bodies and other unusual erythrocytes forms are examined, which could indicate a asplenia or splenic dysfunction. Granulocytes morphological abnormalities have (z. B. giant granules with Chediak-Higashi syndrome). Quantitative serum IgSpiegel be determined. Low serum levels of IgG, IgM or IgA suggest a lack of antibodies. However, the test results must be compared with controls same age patients. An IgG levels <200 mg / dL usually indicates a significant antibody deficiency, although such concentrations may occur with protein loss or in nephrotic syndrome even with enteropathy. IgM antibodies can be determined by measurements of the Isohämagglutinin titer (anti-A, anti-B). All patients except infants <6 months and people with blood group AB have natural antibodies with a titer of ? 1.08 (anti-A) or ? 1: 4 (anti-B). Antibodies against blood type A and B, and against some bacterial polysaccharides are in particular disorders selectively deficient (z. B. Wiskott-Aldrich syndrome, complete IgG2 deficiency). In immunized patients IgG antibody titers can be determined by measurements before and after vaccination with antigen (Haemophilus influenzae type B, tetanus, diphtheria, conjugated and non-conjugated pneumococcal and meningococcal antigens). An increase in titer, which is less than twofold increased after 2-3 weeks, has regardless of Ig levels indicate a lack of antibodies. Natural antibodies can also be determined (z. B. Antistreptolysin O, heterophile antibodies). When skin test most immunocompetent adults, toddlers and older children respond to an intradermal injection with 0.1 ml of Candida albicans extract (1: 100 for toddlers and 1: 1000 for older children and adults). Positive reactivity, defined as erythema with an induration of> 5 mm at 24, 48 and 72 hours, excludes a T-cell defect. The lack of response in patients with no previous contact with Candida does not mean that an immune defect. In infants is a chest radiograph useful. A missing Thymusschatten sets the suspicion of a T-cell defect close, especially when the X-ray exposure prior to the occurrence of an infection or other stress factors which can shrink the thymus, was performed. Lateral views of the pharynx may lack tonsils anzeigen.Zusätzliche laboratory tests Further tests are indicated if clinical findings or the first laboratory tests suggest the suspicion of a specific disorder of immune cells or Komplementfunktionen. In patients with recurrent infections and lymphopenia to detect defects lymphocytes phenotyping of lymphocytes is indicated by flow cytometry and monoclonal antibodies to T, B and natural killer (NK) cells. If a cellular immune deficiency disorder is suspected, the T-cell receptor Exzisionskreis- (TREC) test can be performed to identify infants with low number of T-cells. In vitro Mitogenstimulationsstudien be performed to determine the T-cell function, if the tests show a low number or the absence of T cells. When a suspected MHC antigen deficient serological is (no molecular) HLA typing displayed. Some experts recommend screening of all newborns with a TREC test; the test is routinely performed in some US states. be-such as a humoral immune deficiency disorder is suspected, the patient can be tested for specific mutations. B. in the genes that encode for Bruton tyrosine kinase (BTK), CD40 and CD40 ligand, as well as nuclear factor kappa B main modulator (NEMO). A sweat test is usually done during the evaluation to rule out cystic fibrosis. If a combined cellular and humoral immune deficiency disorder, and SCID are suspected, the patient can be tested for certain typical mutations (z. B. IL-2 receptor-gamma [IL-2RG or IL-2R?] gene). If Phagozytendefekte be presumed to be CD15 and CD18 as measured by flow cytometry and neutrophil chemotaxis is tested. A flow cytometry-oxidatively (Respiratory) – Burst assay (measured over Dihydrorhodamine 123 [DHR] or Nitro Blue tetrazolium [NBT]) to determine if O2 radicals are produced during phagocytosis; its absence is characteristic of chronic granulomatous disease. When indicate kind or course of the infection on a Komplementdefekt, the required dilution of the serum is determined, the lysed 50% of the antibody loaded erythrocytes. This test (CH50 called) can be detected defects of the complement the classical complement pathway. Which component is abnormal, is not displayed. A similar assay (AH50) can be performed to display Komplementdefekte on the alternative pathway. Should be noted, suggesting lymphocyte or Phagozytendefekte in the investigation or preliminary tests anomalies are for more accurate characterization of specific disorders further tests required (see table: Specific and advanced laboratory tests for immunodeficiency *). Specific and advanced laboratory tests in immunodeficiency * Test Indications interpretation humoral immunodeficiency disorder * Measurement of IgE level abscesses They are levels in patients with abscesses and pneumatoceles (Hyper IgE syndrome) high, with partial T-cell deficiency, allergic diseases or parasitic infections , The mirrors can be both high and low in patients with incomplete B cell defect or -Defizienz. Sole occurrence of a deficiency is not clinically significant. B cell quantitation with flow cytometry low Ig-values ??<1% B cells suspected X-linked agammaglobulinemia. at Ommen's Syndrome lymph node biopsy B-cells are absent in some patients with lymphadenopathy to determine whether germinal centers are normal and to cancer and infections exclude interpretation varies by histology genetic testing (genetic sequencing or mutation analysis) B cells <1% (detected by flow cytometry ) suspected interference by one or more characteristic mutations abnormalities in genes set the diagnostic near or confirm them, as in the following cases: BTK: X-linked agammaglobulinemia SAP : -chromosomal inherited lymphoproliferative syndrome NEMO: a combined immunodeficiency The results can also provide prognostic information. T cell-deficient T-cell count by flow cytometry and monoclonal antibodies lymphopenia, suspected SCID or complete DiGeorge syndrome interpretation varies depending on the type of molecular SCID. T-cell proliferation analyzed the cell division, antigens or irradiated allogeneic leukocytes A small percentage of T cells, lymphopenia, suspected SCID or complete DiGeorge syndrome Low or absent uptake of radioactive thymidine during cell division shows a T-cell or a combined defect. Recognition of antigens (z. B. class II MHC molecules) using monoclonal antibodies or serologic HLA typing suspected MHC deficiency, lack of MHC-stimulation by cells The absence of class I or class II HLA antigens by serological HLA typing diagnoses an MHC antigen deficiency. RBC adenosine deaminase assay severity lymphopenia values ??are at a certain form of SCID low purine nucleoside phosphorylase assay severity persistent lymphopenia values ??are low when combined immune deficiency with normal or elevated Ig levels. T cell receptor and signal transduction assays phenotypically normal T-cells that proliferate in response to mitogen not normal antigen. Interpretation ist je nach Test unterschiedlich T-Zell-Rezeptor-Exzisionskreis-(TREC)-Test Screening für SCID und andere T-Zellenerkrankungen Niedrige Anzahlen deuten auf einen Defekt hin, der die Entwicklung oder die Reifung der T-Zellen unterbricht oder die Apoptose von T-Zellen verursacht. Kombinierte humorale und zelluläre Immunschwächestörungen Gentests Ein vermutetes kombiniertes Immundefizienzsyndrom Anomalien in Genen deuten bestimmte Störungen an oder bestätigen sie; z. B. deuten Anomalien in NEMO auf kombinierte Immunschwächestörungen mit Defekten der NF-kappa B-Regulierung und Anomalien in IL-2R? auf SCID hin.