P579V 50 16 2013comprise more than 150 different disorders thataffect - PDF document

P579V 50 16, 2013comprise more than 150 different disorders thataffect the development, function, or both of thefect the development, function, or both of themonogenic disorders that follow a simple Mendelianinheritance; however, some PIDs are of more complex R E V I E WR E V I E WR E V I E WR E V I E WR E V I E WAAAAARRRRRTTTTTIIIIICCCCCLLLLLEEEEE P580V 50 16, 2013RIMARY PID PID(Box 1) [4,7].Although this does not include comprehensive list ofall signs and symptoms of PID, patients showing thesesigns must be evaluated further for an underlying PID.While evaluating such children, important clinical featureslike age at presentation, pattern of infection, non-infectious manifestations and family history should alsobe taken into consideration as these give an important clueto the underlying immune defect [5]. Though it is difficultto predict a specific PID on the basis of infections withparticular organisms, they definitely provide an importantclue to underlying immune defect (Table). The importantPID are discussed below..immunodeficiencies (SCID) like Adenosine deaminase(ADA) deficiency, purine nucleotide phosphorylase(PNP) deficiency, RAG1/2 deficiency, chain deficiency, deficiency, and JAK3 deficiency and combinedseen in patients with SCID. Similarly, prolonged, prolonged Omenn syndrome is a rare autosomal recessivecharacterized by symptoms of SCID associated with otherfindings like erythroderma, lymphadenopathy,including developmental delay, hypertonia, spasticity,Characteristic abnormality in ADA deficient SCID includesLymphopenia is commonly seen with patients withdiagnosis. However normal absolute lymphocy

te countdoes not rule out combined immunodeficiency, thus, thusincluding CD40L deficiency..X-linked agammaglobulinemia (XLA) and commonvariable immunodeficiency (CVID) are the commonest.Patients with XLA typically present after 6-9 months ofage when the level of protective maternal IgG starts goingdown [9]. Recurrent sinopulmonary infections due to S.pneumonia or otitis media, and septicemiapresent as early as 2 years of age. There is also anThere is also anOther Well-defined PIDsuch as Ataxia telengiectasia (AT), DiGeorge syndrome,Wiskott-Aldrich syndrome (WAS) and hyper IgEAS) and hyper IgE. Patients with AT or NijmejenBreakage syndrome can present at the age of 6 months todelay. Progressive cerebellar ataxia with discrete orpresent in neonatal period. This defect should beBox 1Warning Signs for Suspicion of PrimaryWarning Signs for Suspicion of Primary• Four or more new ear infections within 1 year. Two or more serious sinus infections within 1 year. Two or more months on antibiotics with little effect. Two or more pneumonias within 1 year. Failure of an infant to gain weight or grow normally. Recurrent, deep skin or organ abscesses. Persistent thrush in mouth or fungal infection on skin. Need for intravenous antibiotics to clear infections. Two or more deep-seated infections including septicemia. A family history of PID P581V 50 16, 2013RIMARYmanifestations of HIES due to STAT3 defect [11]. PatientsTABLE I RIMARYPID CategoryInfectious complicationsCombined T andSystemic viralLymphocyte subsets:gastroenteritis1.T, Tc, Th, B , NK2.DNT cells3.Memory, naïve and activated T cellViruses: All, especial

ly, respiratorysyncytial virus, EBV, parainfluenza1.CD132:type 32.CD1273.CD154pSATA5 expression after stimulation NontuberculouspSTAT3 expression after stimulation including BCGT Toxoplasma gondii,RBC ADA levelsBacteria:S. pneumoniae, H. influenzaeB M. catarrhalis, P. aeruginosa, S. aureus1.B cell numbers: CD19, CD79a, CD202.Intracellular Btk expressioninfections, sepsis,3.nephelometry:Ig G, A, E,M Specific antibody responsesViruses Giardia lambliaBacteria: S.aureus, P. aeruginosadefectsor lung 1.CD18, CD11 expression:diseases, urinary tract2.DHR3.NBTComplementMeningitis, systemic Streptococci,deficiencybacterial infectionsViruses: CMV, HSV P582V 50 16, 2013RIMARYdisseminated viral warts [12]. Autosomal dominant HIESextensibility, pathologic fractures, retained primary, pathologic fractures, retained primaryHIES. Asymptomatic cerebral T2-weighted hyper-increased Arnold Chiari 1 malformations are seen in theArnold Chiari 1 malformations are seen in theWAS patients present with eczema, petechiae andAS patients present with eczema, petechiae andincidence of EBV associated lymphoma is also high inthese patients. Thrombocytopenia with low mean plateletvolume gives important clue for diagnosis of WAS.AS.which leukocyte adhesion deficiency-I (LAD-I), chronicgranulomatous disease (CGD) and severe congenitalneutropenia (SCN) are some of the common diseases.Patients with phagocytic defects usually present inneonatal period. Delayed separation of umbilical cordbeyond 2 weeks along with omphalitis is suggestive of aneutrophil disorder like LAD-I [16], SCN or CGD. Patientswith LAD-II have severe mental retardation, short sta

ture,a distinctive facial appearance and the rare Bombay (Hh)phenotype. Eczematous rash with deep seated abscessesis associated with CGD. Infections due to S. aureus,Burkholderia cepacia and andDisseminated atypical mycobacterial infection orDisseminated atypical mycobacterial infection orin the absence of active infection is a common feature ofLAD-I. In severe congenital neutropenia child haspersistently low absolute neutrophil counts (ANC) withelevated monocytes and eosinophils counts. Cyclicneutropenia patients present with drop in ANC every 3-4weeks with fever, infections and mouth ulcers.Diseases of immune dysregulationDiseases of immune dysregulationFamilial Hemophagocytic Lymphohistiocytosis (FHL)that includes Perforin deficiency, UNC13D (Munc13-4)deficiency, Syntaxin 11 deficiency and STXBP2 (Munc18-2) deficiency and Autoimmune Lymphoproliferativediseases in this category. age. Patients with Autoimmune Lymphoproliferativesyndrome (ALPS) present at the median age of around 2years with chronic nonmalignant lymphadenopathy,,Mucocutaneous albinism is seen with patients withGriselli syndrome and Chediak-Highashi syndrome [20].Patients with hemophagocytic lymphohistiocytosis(HLH) (either familial or associated with Chediak-Higashior Griscelli syndrome-II, X-linked lymphoproliferativesyndrome) are associated with varying degrees ofcytopenias with hemophagocytosis seen either in thebone marrow or rarely in the peripheral blood. Patients withALPS generally have elevated ALC with recurrent non-malignant lymphadenopathy and spleno-hepatomegaly.Patients with Evan’s syndrome should be evaluated forunderlying ALPS

as high proportion of these cases haveFAS gene mutation [21]. Autoimmune cytopenias are alsopolyendocrinopathy, enteropathy or X-linked (IPEX)with certain PID. Patients with ALPS are at a higher risk ofEBV-associated lymphoma is common in patients withXLP. . 1 P583V 50 16, 2013RIMARYusually after 5 years of age. Autoimmune disease andpathway. Terminal complement component deficiencieserminal complement component deficienciesComplications such as recurrent pneumonia, meningitis,and peritonitis are seen in complement 3 deficiency. PIDWith wide array of assays being available for evaluationof immune system, it becomes difficult to choose aninvestigation to be performed. The investigations arelargely guided by the clinical presentation of the patient,differential count on the leucocytes and MPV, lymphocyteNitroblue Tetrazolium test (NBT). The panel of antibodiesabsolute and relative number of : B cells (CD19+), T cells(CD3+), T-helper cells (Th, CD3+/CD4+), T-cytotoxic cells(Tc, CD3+/CD8+), Natural Killer (NK) cells (CD3-/CD56+/CD16+), and Activated T cells (CD3+/HLA-DR+). is generally associated withimpaired cellular immunity, whereas the corresponding in children over 2 years of age and in in children over 2 years of age and inalso significantly alter the values of T and B cell subsetsand should be interpreted carefully.clue to the underlying immune defect. Patients with low Tcell counts are likely to have combined T and B cell defectscategory of predominantly antibody deficiency. PatientsHowever, under these broad categories, there are manyLymphocyte subset analysis is abnormal in most cases ofabnormalities i

n T, B, and natural killer (NK) cellfunction. These are categorized broadly as T+ SCID andT-SCID depending on presence or absence of the T cells.There are many genetic defects which can lead to T-SCID phenotype [23]. The B cells and NK cells count in). However, there is significantstudies like pSTAT5 activation in lymphocytes after IL-2stimulation, estimation of enzymes like ADA and PNP inPatients with normal T cell numbers can still have CID.MHC-I or MHC-II deficiency, ZAP 70 deficiency, etc.These patients can be evaluated by doing T cellproliferation assays (for evaluation of T cell function),expression of HLA-DR on T and B cells (for MHC class-IIexpression) and T cell receptor (TCR) V-beta repertoireimmunoglobulin levels (IgG, IgA, IgM, IgE and IgG . 2 Evaluation of patients with T- SCID. P584V 50 16, 2013RIMARYor reduced expression of protein Bruton Tyrosine Kinase(CD154) expression on B cells and T cells respectively.Some patients with these disorders may have normal orvaccine antigens. This approach involves immunizing alook at the absolute neutrophil count (ANC). A patientwith low ANC with early neonatal presentation isCharacteristically, there is marked monocytosis with levelsassociated anemia and mild thrombocytosis attributable toneutrophil count with a periodicity of around 21 days. Atthe nadir, neutrophil counts are generally less than 0.2×10per L. Both SCN andconfirmation of underlying defect can be done byby molecular analysis of the affected gene. Patients withcategory.malignancy, rheumatic diseases or toxins or may be due toinherited genetic defect leading to impaired NK cellTable ) [24]. The

diagnosis of HLH is based on clinicalTABLE II HLH P1.Molecular diagnosis of hemophagocytic2.at least 3 of 4:a.Fever b.Splenomegalyc.Cytopenias (minimum 2 cell lines reduced)Hemoglobin d.Hepatitis3. And at least 1 of 4:a.Hemophagocytosisb.&#x 100;&#x×100;Ferritin 500ng/mLc. sIL2R (age-based)d.Absent or very low NK function4.Other results supportive of HLH diagnosis:a.&#x 100;&#x×100;Hypertriglyceridemia (265 mg/dL)b.Hypofibrinogenemia ()c.Hyponatremia P585V 50 16, 2013RIMARYfibrinogen and sCD25 levels [25]. Further evaluationusing NK cell cytotoxicity assay, Perforin expressionSYNTAXIN-11 by western blot help significantly inlymphoma. If ALPS is suspected based on clinical findings,analysis of peripheral blood circulating TCR ab DNTcells and estimation of serum B12, soluble FAS ligand(sFASL), interleukin (IL) -10 and IL-18 levels. The DNT cells coupled with high serum orplasma levels of either IL -10, IL-18, (sFASL) or vitamin B12FAS AS Suspected Complement DeficiencyIn patients with suspected complement deficiency, initialclassical and final lytic components except C9) and AH 50considerable experience of these assays. To avoidit is advisable that the assays be performed when theoccasions, the specific component defect should beevaluation. Wide array of assays are available forpatients. We need to create awareness about theseMA compiled the data and helped in manuscript writing. The1.Al-Herz W, Bousfiha A, Casanova JL, Chapel H, ConleyME, Cunningham-Rundles C, et al2.Piguet D, Tosi C, Luthi JM, Andresen I, Juge O. Redimune3.Notarangelo LD, Forino C, Mazzolari E. Stem cell4.Subbarayan A, Colarusso G, Hughes

SM, Gennery AR,5.Slatter MA, Gennery AR. Clinical immunology reviewseries: an approach to the patient with recurrent infections6.Winkelstein JA, Marino MC, Ochs H, Fuleihan R, Scholl7.Berrington JE, Flood TJ, Abinun M, Galloway A, Cant AJ.8.Bouma G, Ancliff PJ, Thrasher AJ, Burns SO. Recent9.Wood P, Stanworth S, Burton J, Jones A, Peckham DG, UK Primary Immunodeficiency Network.10.Zi Yin E, Frush DP, Donnelly LF, Buckleyl RH. Primary P586V 50 16, 2013RIMARY11.Woellner C, Gertz EM, Schäffer AA, Lagos M, Perro M,guidelines for hyper-IgE syndrome. J Allergy Clin12.Zhang Q, Davis JC, Lamborn IT, Freeman AF, Jing H,Favreau AJ, 13.Buckley RH. The Hyper-IgE syndrome. Clin Rev Allergy14.Freeman AF, Collura-Burke CJ, Patronas NJ, Ilcus LS,15.Albert MH, Notarangelo LD, Ochs HD. Clinical spectrum,Albert MH, Notarangelo LD, Ochs HD. Clinical spectrum,of print]16.Madkaikar M, Currimbhoy Z , Gupta M, Desai M, Rao M.17.Holland SM. Chronic granulomatous disease. Clin Rev18.Al-Muhsen S, Casanova JL. The genetic heterogeneity of19.Madkaikar M, Mhatre S, Gupta M, Ghosh K. Advances in20.Dessinioti C, Stratigos AJ, Rigopoulos D, Katsambas AD.21.Teachey D, Manno CS, Axsom KM, Andrews T, Choi JK,22.Melaranci C, Ciaffi P, Zerella A, Martinelli V, Cutrera R,23.Walshe D, Gaspar HB, Thrasher AJ, Cale CM, Gilmour24.Henter J, Horne A, Aricó M, Egeler RM, FilipovichAH, Imashuku S, cytosis. Pediatr Blood Cancer. 2006;48:124-31.25.Janka GE. Familial and acquired hemophagocytic26.Caminha I, Fleisher TA, Hornung RL, Dale JK, Niemela JE,FAS mutations in patients with features of the autoimmunelymphoproliferative syndrome. J Allergy Clin Immun