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Inborn Errors of Immunity (IEI)
a Sa l i h l i d Ham Dr.Kh f. of Pediatrics a Ass.pro Child with recurrent infections
A common reason for bringing an infant or child for
a medical visit is recurrent infections. The causes are multiple and can be grouped in to four categories: A."normal" child, B. Child with atopic disease, C. Child with another chronic condition, D.Child with an immunodeficiency Recurrent infections? Recurrent infections are defined as: 1. Two or more severe infections in one year, 2.Three or more respiratory infections in one year 3. Need for antibiotics for two months/year. 4.Severe/serious infections 5.Failure to respond to oral antibiotics and/or the need for iv antibiotics or Recurrent infections are infections that are too great hospitalization. in 6. Infections number, toopathogen. with an unusual severe, or too long lasting 7.Unusual complications (eg mastoiditis, pleural effusion, abscesses); 8.Persistent laboratory abnormalities (e g, leukocytosis, elevate ESR/CRP, persistent imaging abnormalities). Factors increase susceptability for infection?
Inadequate clearance of secretions Obstruction Barrier failure
Defect in immune system
Foreign body – CHD Resistant organisms CVline, VPshunt Continuous reinfection : Contaminated water supply, chronically infected pet, Deliberate infection (Munchausen syndrome by proxy) Inborn Errors of Immunity (IEI)
Primary immune system defects are traditionally called
primary immunodeficiencies (PID). However, due to the large number of defects recently described, which include manifestations that are more related to the immune system dysregulation than to its deficiency, this nomenclature has been replaced by Inborn Errors of Immunity (IEI). The child with an immunodeficiency Ten percent of children with recurrent infections have an IEI
NB/ 1.Immunodeficiency may be secondary or primary. 2.Secondary immunodeficiencies usually occur well after infancy, while many PIDs present during the first years of life. 3.Both primary and secondary immunodeficiencycan lead to an increased susceptibility to malignancy and autoimmune disease. 4.PIDs most often affect B cell function, while secondary immunodeficiencies more often affect T cell Incidence:
Primary immunodeficiencies The overall incidence of PIDs is 1 in 10,000. As of 2020, there are 431 identified inborn errors of immunity, many genetically defined, have been characterized . The type and pattern of recurring infections depend on which components of the immune system are affected . Copyrights apply Adaptive immunity B cell defects: T cell defects: Recurrent bacterial sinopulmonary infections or sepsis, particularly Recurrent, severe, or unusual viral infections (VZV, with polysaccharide encapsulated organisms CMV, HSV) Failure to thrive Unexplained bronchiectasis Chronic candidiasis Chronic or recurrent gastroenteritis (often with Giardia or Chronic diarrhea enterovirus) Lymphopenia during the neonatal period or in Failure to thrive infancy Chronic enteroviral meningoencephalitis Pneumocystis pneumonia Arthritis Graft-versus-host disease Severe/neonatal eczematoid or seborrheic rashes Innate immunity Phagocytic defects: Complement defects: Poor wound healing Delayed separation of the umbilical cord Angioedema of face, hands, feet, Lymphadenitis or soft tissue abscesses Hepatosplenomegaly Autoimmune disease, lupus-like symptoms Chronic gingivitis and periodontal disease, oral mucosal Pyogenic bacterial infections (eg, Neisseria ulcerations meningitidis) Infection with catalase positive bacteria and fungi History suggestive of autosomal dominant Recurrent gastrointestinal or genitourinary tract obstruction Copyrights apply inheritance Secondary immunodeficiencies — Secondary immunodeficiencies are more common than PIDs. Over 50 disorders leading to secondary immunodeficiency have been identified When we suspect IEI?
1. Infection caused by an unusual microbial
1.Family history of immunodeficiency or unexplained early death (eg, before age 30 years) organism and/or in an unusual location 2. failure to thrive 2. Complications from a live vaccine (eg, 3.Need for intravenous antibiotics and/or rotavirus, varicella, and [BCG] vaccines) hospitalization . 3. Chronic diarrhea 4.Six or more ear or respiratory tract infections 4. Nonhealing wounds within one year 5. Extensive skin lesions 5.Two or more serious sinus infections or 6. Persistent lymphopenia (<1500 cells/microL pneumonias within one year. in patients over five years and <2500 6.Four or more new ear infections within one year cells/microL in younger children) 7.Two or more episodes of sepsis or meningitis in a lifetime 7. Unexplained autoimmunity or fevers 8.Two or more months of antibiotics with little 8. Hemophagocytic lymphohistiocytosis (HLH) effect 9. Lymphoma or Leukemia in childhood 9.Recurrent or resistant oral or cutaneous 10.Features typical of syndromic PIDs (e g, candidiasis cartilage-hair hypoplasia, Chediak-Higashi 10.Recurrent deep skin or organ abscesses syndrome, ataxia-telangiectasia) clinical patterns suggestive of immunodeficiency Ataxia, telangiectasia, sinopulmonary .and developmental delay ataxia-telangiectasia
Petechiae, easy bleeding, eczema, and chronic discharg ears Wiskott-Aldrich syndrome Coarse features with facial asymmetry, chronic-infected hyper E syndrome eczema, deep-seated abscesses, and scoliosis
Short stature with metaphyseal dystrophy and fine hair cartilage-hair hypoplasia
Abnormal dentition, decreased sweating, and sparse hair associated with ectodermal dysplasia frequent infection suggest
Congenital heart disease, developmental delay, and dysmorphic facies with low- DiGeorge syndrome set ears, hypertelorism, down-turning eyes, and micrognathia
Oral ulcers, gingivitis, and impetigo CGD or leukocyte-adhesion defects
Oculocutaneous albinism Chediak-Higashi disease
Dermatomyositis-like rash in XLA
Lupus-like rash in early complement component
Copyrights apply defects Characteristic Clinical Findings in Some Primary Immunodeficiency Disorders
splenomegaly, autoimmune disorders, nodular lymphoid Common variable hyperplasia of the GI tract, giardiasis, lymphoid immunodeficiency interstitial pneumonia, bronchiectasis Copyrights apply Some Clues in Patient History to Type of Immunodeficiency: organism
Familial clustering of autoimmune disorders (eg, SLE, RA,pernicious anemia) Common variable immunodeficiency or selective IgA Pneumocystis infections, cryptosporidiosis, or toxoplasmosis T-cell disorders or occasionally Ig deficienc Viral, fungal, or mycobacterial (opportunistic) infections T-cell disorder
Staphylococcal infections, infections with gram-negativeorganisms (eg, Serratiaor Klebsiellasp), Phagocytic cell defects or or fungal infections hyper-IgE syndrome
Clinical infection due to live-attenuated vaccines (eg,varicella, polio, BCG) Graft-vs-host disease T-cell disorders due to blood transfusions
Skin infections Recurrent gingivitis Neutrophil defect or Ig deficiency
family history of childhood death or of infections in a maternal uncle that are similar X-linked disorders (eg, SCID to those in the patient X-AG, WAS, hyper-IgM syndrome Initial and Additional Laboratory Tests for Immunodeficiency
At a minimum, the following initial panel is suggested:
●Complete blood count (CBC) with differential ●Chemistry panel, including electrolytes, glucose, blood urea nitrogen (BUN), creatinine, and albumin ●Urinalysis ●Erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) ●IgG, IgM, IgA and IgE levels
Copyrights apply Normal ANCE xclude:congenital neutropnia,LAD(persistent elivateANC Absolute neutrophile count even in absence infection still possibility of LAD
Normal count exclude:
Lymphocyte count T cell defect
Platelet count Normal exclude:WAS
ESR Normal exclude:
chronic bacterial and fungal infection
Copyrights apply Humoral immunity deficiency: Cellular immunity deficiency IgG, IgM, IgA, and IgE levels Absolute lymphocyte count, Isohemagglutinin titers Chest x-ray for Antibody response to vaccine size of thymus in infants only Low immunoglobulin levels will suggest antibody or combined B-cell phenotyping T-cellphenotyping and count using flow immunodeficiencies. An IgG <300 mg/dL, a total Ig (IgG +SPECIFIC IgM + IgA) less than 500 mg/dL, or the complete absence of IgA and/or IgM in aTEST child older than six months suggests an antibody deficiency Phagocytic cell defects Complement deficiency C3 level C4 level CH50 activity (for dihydrorhodamine 123 (DHR) or total activity of the classical pathway) and nitroblue tetrazolium (NBT) AH50 activity (for total activity of the Flow cytometry for CD18 and CD15 alternate Neutrophil chemotaxis complement pathways) Copyrights apply Greneral measure : Avoid infection Antimicrobial therapy to fight and prevent infections Immune globulin replacement therapy Vaccinations Specialized immune globulins Hematopoietic cell transplant Gene therapy Enzyme replacement therapy
Treatment? Copyrights apply General Management of Patients withImmunodeficiency
• Avoid transfusions with blood products unless they are irradiated and cytomegalovirus-negative. • Avoid live virus vaccines, especially in patients with severe T-cell deficiencies or agammaglobulinemia, and in household members. • Use prophylaxis to Pneumocystis jiroveci (carinii) in T-cell immunodeficiency, and in X-linked hyper-IgM. consider antifungal prophylaxis in T-cell immunodeficiency • Follow pulmonary function in patients with recurrent pneumonia. • Use chest physiotherapy and postural drainage in patients with recurrent pneumonia.
12/02/2024 Ass.prof Dr.khalid Hama 21
• Consider using prophylactic antibiotics because infections can quickly disseminate. • Examine diarrheal stools for Giardia lamblia and Clostridium difficile. • Avoid unnecessary exposure to individuals with infection. • Boil water for T-cell defects and hyper-IgM syndrome (Cryptosporidium risk). • Use immunoglobulin for severe antibody deficiency states (400–600mg/kg q3–4 wk IV). • BMT for T cell and Innate defect
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Take home massage
12/02/2024 Ass.prof Dr.khalid Hama 23
1 All patients with primary immunodeficiency diseases require immunoglobulin replacement therapy to prevent infections.
True or False
false 2
Which of the following would be most worrisome for the presence of a primary immunodeficiency disease consisting of a problem with T cell defect? A. Recurrent ear, sinus and lung infections B. Recurrent thrush (an infection of the mouth caused by yeast) or no thymus on chest x-ray C. Recurrent skin abscesses or poor wound healing D. Recurrent warts
B 3 Which of the following would be most worrisome for the presence of a primary immunodeficiency disease consisting of a problem with neutrophil function? A. Recurrent ear, sinus and lung infections B. Recurrent thrush, no thymus on chest x-ray C. Recurrent skin abscesses or poor wound healing D. Recurrent warts
C 4 Intravenous immunoglobulin (IVIG) is the preferred therapy for patients with primary antibody deficiencies. IVIG can cause anaphylactic reaction in the following condition: a) IgG deficiency b) IgM deficiency c) IgA deficiency d) IgE deficiency e) IgD deficiency
Ans….. . (C ) Copyrights apply 5 A child appears with systemic lupus erythematosus (SLE)-like syndrome without characteristic SLE serology. Most likely complement deficiency is: a) C 5 b) C 6 c) C 7 d) C 8 e) C 1q
e Ans…... . ( ) C1q deficiency Copyrights apply 6 A 2-year-old boy appears with fever and cough for the last 3 days. Past medical history revealed three episodes of pneumonia,one episode of meningitis, and four episodes of otitis media. Blood culture is performed. The next diagnostic study: a) Spinal tap b) Chest X-ray c) Urine culture d) Serum immunoglobulins e) Lung CT scan
Ans…. (d)
Copyrights apply A 3-month-old female infant appears in the ER with history of diarrhea for the last 3 weeks and rashes in the diaper and oral area for the last 10 days. Mother denies any fever and URI symptoms. Past medical history reveals otitis media and pneumonia. Physical examination reveals failure to thrive (FTT), oral and perineal candidal infections. Most likely diagnosis: a)Severe combined immunodeficiency (SCID) b) Chronic granulomatous disease c) Milk intolerance causing diarrhea d) Marasmus e) Kwashiorkor
(a) Copyrights apply Last A female child was admitted in the pediatric ward for anemia. Her hemoglobin was 6 mg/dL and hematocrit was 18. During the packed-RBCs transfusion, she developed severe anaphylactic reactions. The blood was returned to the blood bank for further checking. Blood transfusion was stopped immediately. The test resultsrevealed that the girl received properly matched blood. Most likely diagnosis: a) Selective IgA deficiency b) Minor group incompatibility c) ABO incompatibility d) Rh-hemolytic disease e) Selective IgM deficiency
Diagnostic Bacteriology_ a Study Guide -- Bartelt, Margaret a -- 2000 -- Philadelphia_ F.a. Davis -- 9780803603011 -- Cbf4b694b3f38b4d2c4c37e510211a57 -- Anna’s Archive
Diagnostic Bacteriology_ a Study Guide -- Bartelt, Margaret a -- 2000 -- Philadelphia_ F.a. Davis -- 9780803603011 -- Cbf4b694b3f38b4d2c4c37e510211a57 -- Anna’s Archive
