Immune Deficiency

Immunoglobulin levels vs. age

Types of immunity Innate (natural) immunity Innate (natural) immunity  responds to infection regardless of previous exposure to the agent Ex: PNL, phagocytic cells, complement system Acquired (adaptive) immunity Acquired (adaptive) immunity  develops as a result of exposure to previous immunogens Ex: T lymphocytes, B lymphocytes, NK cells

Types of immunodeficiency Primary immunodeficiency Inherited genetic defects in the immune cell development or function or inherited deficiency in a particular immune molecule. Secondary immunodeficiency Loss of previously functional immunity due to infection, toxicity, radiation, splenectomy and malnutrition.

Primary immune deficiency 50% of PIDs are caused by B-cell defect 10% by T-cell defect 20% by combined B- and T-cell defects 18% by phagocytic defects 2% by defects in complement system. 80% of the patients affected by PID are males as most of the PIDs are inherited in X-linked manner.

Primary immunodeficiency is characterized by three cardinal features, (1)Infections (2)Autoimmunity (3) Malignancies.

Ask for the presence of infections That tend to be severe, recurrent, life-threatening caused by unusual pathogens, involving unusual sites and difficult to control or eradicate. Even usual childhood infections may turn serious in patients with PID. Opportunistic infections. Ask for the presence of autoimmunity like autoimmune cytopenias, Autoimmune hemolytic anemia (AIHA), autoimmune thrombocytopenic purpura (AITP) autoantibody to multiple endocrines like in immunodeficiency polyendocrine X-linked (IPEX) syndrome. Ask for the presence of malignancies like Leukemia and Lymphomas.

In children with PID look for signs due to the cause of PID or effects of PIDs. Failure to thrive, Growth retardation, Lymphadenopathy, Hepatosplenomegaly Absent tonsils, Absent lymph nodes, Oral ulcers, oral or perineal thrush, Chronic ear discharge, Typical facies, Presence of ataxia,

Eczema, skin rash, pyoderma marks, marks of healed H. zoster lesions (especially multidermatomal), albinism, Ash-colored hair, heterochromia, Onychomycosis or dystrophic nails, Absent BCG scar in spite of BCG may suggest T-cell defects; and disseminated BCG-Osis is known to occur in patients with T-cell defect.

Jeffrey Modell Foundation :10 pointers to PID Which when present, suggest possibility of PID. It includes: 1. Four or more ear infections in one year 2. Two or more serious sinus infections in one year 3. Two or more pneumonias in one year 4. Two or more months of antibiotics with little effect 5. Failure of an infant to gain adequate weight or grow normally 6. Recurrent deep skin or organ abscesses 7. Persistent thrush in mouth or elsewhere on skin after age of one year 8. Need for intravenous (IV) antimicrobials to clear infections 9. Two or more deep-seated infections including septicemia 10. A family history of PID

Features suggestive of PID in neonates Hypocalcemia Congenital heart defects (conotruncal anomalies) Absence of thymic shadow in CXR Delayed umbilical cord detachment (>30 days)

History Birth history – maternal illness, drug intake, length of gestation, birth weight neonatal problems, umbilical cord detachment Feeding history Growth and development Immunization history – especially live vaccines (OPV, rota virus vaccines), vaccine failure Previous illnesses, school abscences Family history Consanguinity (autosomal recessive immunodeficiencies)

Infection history 1.Age of onset Birth to 6 months – congenital neutropenias, leukocyte adhesion defects, severe combined immunodeficiency (SCID), and complete DiGeorge syndrome. 6 months to 2 years – child with allergy. Persistent diarrhea, chronic cough, or failure to thrive suggests cystic fibrosis, or PID 2 to 6 years – children developing infection in this age group may also fit into any of the 4 categories. Secondary immunodeficiencies resulting from malignancy, nephrotic syndrome, or gastrointestinal problems start at this age. 6 to 18 years – it is unusual for recurrent infections to first present beyond the age of six.

2. Sites of infection: Upper respiratory tract - Most common site, usually viral – Chronic purulent nasal discharge and cough  chronic siunsitis – Chronic or seasonal clear nasal discharge, congestion, itchy eyes, nocturnal cough  allergic disease – Recurrent oral thrush, stomatitis, gingivitis,  t-cell and phagocytic cell disorder Lower respiratory tract – Recurrent pneumonia is rare in normal children or children with allergic disease presence Suggest chronic cardiopulmonary disease or immunodeficiency – Recurrent pneumonia limited to a particular anatomic region  local anatomical abnormality

Blood and brain Bacterial meningitis and sepsis suggest antibody deficiency or complement defect Chronic enteroviral encephalomyelitis occurs in patients with profound antibody deficiency and commonly follows OPV Other Recurrent and or chronic GIT infections occur in patients with IgA deficiency. Recurrent UTI is uncommon in immunodeficiency and suggests structural abnormality Abscesses of the skin, intestine, or LN suggest phagocytic or antibody deficiency

3. Isolated organisms Recurrent sinopulmunary infections with encapsulated organisms  B cell abnormalities Pneumocystis carnii is the hallmark of SCID and other T cell defects Enteroviral meningoencephalitis  x-linked agammaglobulinemia Recurrent staph infections  hyperimmunoglubulin E syndrome Severe candidiasis  abnormal t cell immunity

Physical Examination General appearance, dysmorphic features Failure to thrive (growth charts) Discharging ears, perforated tympanic membrane suggest immunodeficiency Pallor without anemia, allergic shiners, conjunctivitis, transverse nasal crease, clear nasal discharge, suggest allergy Mouth ulcers, gingivitis, oral thrush, poor dentition, suggest immunodeficiency Atopic dermatitis (eczema) suggest allergic disease.

Immunodeficiencies associated with eczema: wiskott-aldrich, hyper IgE, SCID, Diminished or absent tonsils and cervical lymph nodes in the presence of recurrent respiratory infections suggest antibody deficiency. Absence of lymphoid tissue suggest SCID or x – linked agammaglobulinemia Adenopathy and HSM can be seen in IgA deficiency, common variable immunodeficiency, and HIV infection.

Characteristic features of primary immunodeficiency CharacteristicPredominant T- cell defect Predominant B-cell defect Granulocyte defect Complement defect AgeEarly onset,2-6moAfter maternal antibodies diminish,>5m Early onsetAny age Sp pathogen involved Bact:mycobact Viruses:CMV,EBV, adeno Fungi:candida Bacteria: strep. staphylo, hemophilus Virus:entero Bact:staph,pseudo, klebsiella Neisseria,E-coli Affected organFTT, protracted diarrhea, Recurrent sinupulmonary infections, GI infections, malabsorption Skin abscess, suppurative adenitis Meningitis, Recurrent sinupulmonary infections Special featuresGVH diseases, Post vaccination, disseminated BCG Autoimmunity,lymp homa,post vaccination paralytic polio Prolonged attachment of umblical cord, poor wound healing Rheumatoid disotder:SLE, Vasculitis,glomerul onephritis

Clinical patterns of immunodeficiency Wiskott – aldrich syndrome : petechiae, easy bleeding, eczema, chronic draining ears Ataxia – telangiectasia: ataxia, telangiectasia, developmental delay Warts hypogammaglobulinemia infections myelokathexis (WHIM) syndrome : extensive warts or molluscum contagiosum Hyper IgE syndrome: coarse features, chronic infected eczema, deep seated abscesses DiGeorge syndrome: short stature, CHD, developmental delay, low set ears, downturning eyes, micrognathia Chediak Higashi disease: oculocutaneous albinism

Laboratory Evaluation Test for the presence of Clinical complications, especially cultures for infections Test for immune functions.

Organisms isolated: One can pinpoint grossly the type of immunodeficiency defects based on what infecting organism is isolated from the normally sterile sites or from the obvious sites of infection. Polysaccharide containing organisms like pneumococcus, meningococcus or Hib are often isolated from patients with B-cell defects or complement deficiency. Mycobacteria, listeria, viruses and pneumocystis jirovecii are isolated from patients with T-cell defects. Isolation of Gram-negative bacilli infections, especially opportunistic infections like serratia or nocardia should arouse suspicion of phagocytic defects like chronic granulomatous disease (CGD).

S. aureus infection is seen in B-cell defects, phagocytic defects or complement deficiency. Fungal infections are commonly seen in both T-cell defects as well as phagocytic defects. Chronic enteroviral infections including paralytic polio disease are seen in B- cell defects. Recurrent viral infections as well as Giardia infections are seen in both B-cell as well as T-cell defects. Hence, it is important to culture any suspicious site, including invasive procedures like broncho-alveolar lavage (BAL) which are very important to know the infecting organism and also to narrow down the possible background immune defects.

Immune Function Tests General screening tests: Complete blood count (CBC) Anemia - Recurrent infections, Hemolytic anemia. Absolute neutrophil count (ANC)- Low, will confirm neutropenia as the cause of PID. Absolute lymphocyte count (ALC).- Normal, virtually rules out gross T-cell defects. High white blood cell (WBC) count with persistently high ANC - leukocyte adhesion defect (LAD) Thrombocytopenia with small platelets low mean platelet volume (MPV) - Wiskott Aldrich syndrome (WAS). ESR- Normal, virtually rules out chronic viral or fungal infections. Presence of Howell Jolly bodies in RBCs on peripheral smear - presence of asplenia.

Initial immunologic testing of the child with recurrent infections Complete blood count, differential, ESR Lymphocyte, neutrophils, platelets, Howell jolly bodies, ESR Screening tests for B-cell cefects IgA, if abnormal IgG, IgM measurement Isohemagglutinins Antibody titres to tetanus, diphtheria, H.influenzae Screening test for Tcell defect Absolute lymphocyte count Candida albicans intradermal test Screening test for phagocytic cell defect Absolute neutrophil count Respiratory burst assay Screening test for complement deficiency CH50

B-cell defects: Normally, 10% of the peripheral lymphocytes are B cells. Presence of normal levels of common antibodies rules out the gross B-cell defects. One can do lymphocyte subset study by flow cytometry and serum Ig levels in a patient suspected to have B-cell defect. These patients will have low B-cell count as well as low serum total Ig levels, especially low IgG, IgM and IgA levels. Hyper IgM (HIGM) syndrome have elevated IgM levels. Patients may also show only low IgA levels or IgG subclass deficiency. Job’s syndrome have grossly elevated IgE levels. Test for antibodies to common childhood vaccine antigens like tetanus, diphtheria, Hib or pneumococcal polysaccharide.

T-cell defects: Normally, 70% of peripheral lymphocytes are T cells. Lymphocyte subset analysis will show low T-cell counts and lower T-cell subsets depending on the type of PID. One can also do intradermal delayed hypersensitivity reaction using candida antigen. Presence of BCG scar will rule out gross T-cell defects. Patients with severe combined immunodeficiency (SCID) will have very low ALC. ALC lower than 4,500/cumm in cord blood will pick up severe SCID cases early enough to start prophylactic therapy including BMT before severe and irreversible damage can occur due to intractable infections.

Phagocytic defects: Low ANC will confirm neutropenia as the cause of PID. Respiratory burst test of neutrophils by flow cytometry using rhodamine dye has nearly replaced the nitro blue tetrazolium (NBT) dye test for the diagnosis of CGD, as NBT is difficult to reproduce. Molecular tests have replaced Rebuck’s window test as they are specific and standardized. It includes testing for CD18 or CD11 for LAD1, or CD 15 for LAD2. Natural killer (NK) cells can be similarly enumerated using CD16 or CD56 testing. Hemophagocytic lymphohistiocytosis (HLH) is diagnosed by bone marrow test and confirmed by testing for perforin levels or granzyme levels.

Complement defects: CH50 assay is the most effective screening test for the whole complement cascade. One can also test for individual complement levels in the presence of low CH50 levels.

Management Management of PID include management of Infections Prophylaxis for recurrent infections and Definitive therapy.

Management of the child with recurrent infection Infections should be promptly recognized and treated with emperical antibiotic therapy until appropriate culture results are available Prophylactic antibiotics may be administered Live – virus vaccines and live BCG vaccines must not be administered to the child Only irradiated, leukocyte - poor, virus free should be used if blood transfusion is necessary IVIG should not be administered until there has been a thorough evaluation of the childs immune system. (expensive, side effects)

Definitive therapies: B-cell defects - like X-linked agammaglobulinemia (XLA) can be managed by regular IVIg transfusion. The dose used usually is 400 mg/Kg/dose given as IV infusion over 6–8 hours every 3–4 weeks. IVIg is also helpful in other conditions like WAs, common variable immunodeficiency (CVID) syndrome, some cases of HIGM syndrome. T-cell defects - In general, are best managed by stem cell transplant or thymic transplant early enough before the irreversible damage due to intractable infections has occurred. Defects of adenosine deaminase (ADA) enzyme leading to SCID can be treated by IV pegademase bovine (PEG) ADA infusion or gene therapy.

Specific defects of IL12-INF-γ loop are best managed by daily interferon gamma (IFN-γ) injections, which are extremely expensive but life-saving. Patients with LAD and CGD need stem cell transplant and some cases of LAD2 may respond to fucose infusions. Hemophagocytic lymphohistiocytosis (HLH) can be managed by using HLH 2004 protocol, which included the use of dexamethasone, VP16, cyclosporine and intrathecal methotrexate to achieve control of HLH followed by stem cell transplant as the curative therapy.

Thank you