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Laboratory evaluation of primary immunodeficiencies

2009; Elsevier BV; Volume: 125; Issue: 2 Linguagem: Inglês

10.1016/j.jaci.2009.08.043

1097-6825

João Bosco Oliveira, Thomas A. Fleisher,

Respiratory viral infections research

Primary immunodeficiencies are congenital disorders caused by defects in different elements of the immune system. Affected patients usually present clinically with recurrent infections, severe infections, or both, as well as autoimmune phenomena that are associated with many of these disorders. Early diagnosis is essential for referral to specialized care centers and the prompt initiation of appropriate therapy. In this article the authors describe a general approach for the investigation of the most common primary immunodeficiencies, outlining the typical clinical symptoms and most appropriate laboratory investigations. Primary immunodeficiencies are congenital disorders caused by defects in different elements of the immune system. Affected patients usually present clinically with recurrent infections, severe infections, or both, as well as autoimmune phenomena that are associated with many of these disorders. Early diagnosis is essential for referral to specialized care centers and the prompt initiation of appropriate therapy. In this article the authors describe a general approach for the investigation of the most common primary immunodeficiencies, outlining the typical clinical symptoms and most appropriate laboratory investigations. The clinical spectrum of characterized primary immunodeficiencies (PID) has expanded significantly over the past 2 decades, and the underlying genetic basis of the majority of primary immunodeficiencies (PIDs) also has been identified. The accurate diagnosis of patients with PIDs is critical for appropriate therapy and also affords the opportunity to provide appropriate genetic counseling to the patient and his or her family. In virtually all cases the clinical symptoms involve increased susceptibility to infection, and early diagnosis and therapy provides the greatest opportunity to prevent significant disease-associated morbidity. In this setting the laboratory serves as the primary source of diagnostic information used to define the immunologic defect. The optimal use of the laboratory for the diagnosis and characterization of PIDs is the focus of this chapter. The majority of patients with primary antibody deficiencies present with recurrent bacterial infections of the sinopulmonary tract, including recurrent otitis media, sinusitis, and pneumonia (Table I).1Yong P.F. Chee R. Grimbacher B. Hypogammaglobulinaemia.Immunol Allergy Clin North Am. 2008; 28 (vii): 691-713Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 2Conley M.E. Dobbs A.K. Farmer D.M. Kilic S. Paris K. Grigoriadou S. et al.Primary B cell immunodeficiencies: comparisons and contrasts.Annu Rev Immunol. 2009; 27: 199-227Crossref PubMed Scopus (342) Google Scholar The most commonly isolated organism is Streptococcus pneumoniae, but Haemophilus influenzae (often untypeable), Staphylococcus and Pseudomonas species are also seen. Diarrhea affects up to 25% of these patients, often associated with Giardia lamblia infection. However, infections with rotavirus, enterovirus, Campylobacter, Salmonella, and Shigella species might also be found.1Yong P.F. Chee R. Grimbacher B. Hypogammaglobulinaemia.Immunol Allergy Clin North Am. 2008; 28 (vii): 691-713Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar In addition, autoimmune manifestations are seen in up to 25% of these patients, with autoimmune hemolytic anemia and autoimmune thrombocytopenia being most commonly observed. Finally, granulomatous disease involving various organs with particular predilection for the lung might also be present, and in some patients this process can result in significant morbidity.1Yong P.F. Chee R. Grimbacher B. Hypogammaglobulinaemia.Immunol Allergy Clin North Am. 2008; 28 (vii): 691-713Abstract Full Text Full Text PDF PubMed Scopus (24) Google ScholarTable ICommon pathogens and infection sites according to the underlying immune defectAffected immunity armTypical site of infectionCommon pathogensB cellsSinopulmonary tract, GI tract, joints, CNSPyogenic bacteria: streptococci, staphylococci, Haemophilus influenzaeEnteroviruses: ECHO, polioMycoplasma speciesT cellsSepsis, lung, GI tract, skinViruses: CMV,adenovirus, measles, molluscumFungi: Candida and Aspergillus species, Pneumocystis jiroveciPyogenic bacteriaProtozoa: Cryptosporidium speciesPhagocytesSkin infections, lymphadenitis, liver, lung, bone, GI tract, gingivitis/periodontitisBacteria: staphylococci, Serratia marcescens, Burkholderia cepacia, Klebsiella species, Escherichia coli, Salmonella species, Proteus speciesFungi: Candida, Aspergillus, and Nocardia speciesComplementSystemic infections, meningitisPyogenic bacteria: streptococci, Haemophilus influenzae, Neisseria speciesGI, gastrointestinal; CNS, central nervous system; ECHO, echovirus; CMV, cytomegalovirus. Open table in a new tab GI, gastrointestinal; CNS, central nervous system; ECHO, echovirus; CMV, cytomegalovirus. PIDs that commonly manifest some degree of hypogammaglobulinemia include selective IgA deficiency, common variable immunodeficiency, and congenital agammaglobulinemias (both X-linked and autosomal recessive inheritance, Table II). Less common causes include agammaglobulinemia with thymoma (Good syndrome) and X-linked lymphoproliferative syndrome (XLP).1Yong P.F. Chee R. Grimbacher B. Hypogammaglobulinaemia.Immunol Allergy Clin North Am. 2008; 28 (vii): 691-713Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar X-linked agammaglobulinemia should be suspected in all male patients with recurrent otitis and even a single episode of pneumonia, even if the family history is negative. This condition also might present with neutropenia and sepsis by Pseudomonas or Staphylococcus.3Conley M.E. Howard V. Clinical findings leading to the diagnosis of X-linked agammaglobulinemia.J Pediatr. 2002; 141: 566-571Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar Occasionally, the ataxia-telangiectasia syndrome manifests with recurrent infections and upper respiratory tract symptoms associated with IgA deficiency before the onset of overt neurologic signs.4Ersoy F. Berkel A.I. Sanal O. Oktay H. Twenty-year follow-up of 160 patients with ataxia-telangiectasia.Turk J Pediatr. 1991; 33: 205-215PubMed Google Scholar Concomitant bacterial sinopulmonary and opportunistic infections, including low pathogenic mycobacteria, should raise suspicion of a cellular defect that also affects antibody production, such as nuclear factor κB essential modulator (NEMO; also called IKK-γ) or CD40 ligand (CD154) deficiencies.5Hanson E.P. Monaco-Shawver L. Solt L.A. Madge L.A. Banerjee P.P. May M.J. et al.Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity.J Allergy Clin Immunol. 2008; 122 (e1116): 1169-1177Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar, 6Allen R.C. Armitage R.J. Conley M.E. Rosenblatt H. Jenkins N.A. Copeland N.G. et al.CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome.Science. 1993; 259: 990-993Crossref PubMed Scopus (789) Google Scholar Selected complement deficiency and phagocytic defects might also have a clinical presentation similar to that of antibody deficiency and could be considered for investigation (Table II).Table IIDifferential diagnosis of antibody deficiencies and associated laboratory findingsPrimary B-cell disorders Common variable immunodeficiency: low IgG and IgA levels, variable IgM levels, usually normal B-cell numbers Selective IgA deficiency: low IgA levels, normal IgG and IgM levels, normal B-cell numbers Congenital agammaglobulinemia: low IgG, IgA, and IgM levels; undetectable or very low B-cell numbers ( 50 years old with low B-cell numbers) Intracellular flow cytometry or genetic evaluation for BTK (XLA) or SAP/XIAP (XLP) Genetic evaluation of NEMO to rule out anhydrotic ectodermal dysplasia with immune deficiency Fecal α1-antitrypsin, urinary protein, serum albumin, absolute lymphocyte count to exclude gastrointestinal or urinary protein loss or lymphatic loss HIV testing to exclude AIDS Complement function (CH50, AP50) to exclude complement deficiency Karyotype to exclude immunodeficiency, centromeric instability, facial anomalies syndrome Sweat chloride or genetic evaluation to exclude cystic fibrosisBTK, Bruton tyrosine kinase; XLA, X-linked agammaglobulinemia; SAP/XIAP, SLAM-associated protein/X-linked inhibitor of apoptosis. Open table in a new tab BTK, Bruton tyrosine kinase; XLA, X-linked agammaglobulinemia; SAP/XIAP, SLAM-associated protein/X-linked inhibitor of apoptosis. Additional testing focuses on determining the presence or absence of B cells by using flow cytometry. This is particularly useful as a marker for congenital forms of agammaglobulinemia because this group of disorders typically is characterized by absent or extremely decreased circulating B-cell numbers based on the underlying defects that block B-cell development.2Conley M.E. Dobbs A.K. Farmer D.M. Kilic S. Paris K. Grigoriadou S. et al.Primary B cell immunodeficiencies: comparisons and contrasts.Annu Rev Immunol. 2009; 27: 199-227Crossref PubMed Scopus (342) Google Scholar More recently, characterization of B-cell subsets, particularly directed at memory and immature B cells, has been put forward as a means of further characterizing patients with common variable immunodeficiency.8Wehr C. Kivioja T. Schmitt C. Ferry B. Witte T. Eren E. et al.The EUROclass trial: defining subgroups in common variable immunodeficiency.Blood. 2008; 111: 77-85Crossref PubMed Scopus (652) Google Scholar Studies that test in vitro B-cell signaling and immunoglobulin biosynthesis are generally performed only in research centers. Patients affected by severe combined immunodeficiency (SCID) or other primary conditions with markedly abnormal T-cell function usually manifest failure to thrive and recurrent infections with opportunistic pathogens, such as Candida albicans (thrush), Pneumocystis jiroveci, or cytomegalovirus very early in life (Table I).9Notarangelo L.D. Giliani S. Mazza C. Mella P. Savoldi G. Rodriguez-Perez C. et al.Of genes and phenotypes: the immunological and molecular spectrum of combined immune deficiency. Defects of the gamma(c)-JAK3 signaling pathway as a model.Immunol Rev. 2000; 178: 39-48Crossref PubMed Scopus (92) Google Scholar Other common findings are chronic diarrhea, recurrent bacterial infections affecting multiple sites, and persistent infections despite adequate conventional treatment. SCID is a pediatric emergency because early diagnosis can dramatically improve the clinical outcome. Skin rashes are common, particularly with specific T-cell disorders, including Omenn and Wiskott-Aldrich syndromes.10Villa A. Notarangelo L.D. Roifman C.M. Omenn syndrome: inflammation in leaky severe combined immunodeficiency.J Allergy Clin Immunol. 2008; 122: 1082-1086Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar Other severe cellular or combined defects present with varied clinical symptoms, as listed briefly in Table IV.Table IVMost common T-cell and combined immunodeficiencies and distinctive featuresSCID: failure to thrive, chronic diarrhea, oral thrush, recurrent or severe bacterial, viral and/or fungal infectionsCD40 and CD40 ligand deficiency: recurrent sinopulmonary and opportunistic infections with low IgG and IgA levels and variable IgM levelsWiskott-Aldrich syndrome: easy bruising, eczema, recurrent otitis media, diarrhea, thrombocytopenia with small plateletsDiGeorge syndrome: hypoparathyroidism, cardiac malformations, dysmorphic features, variable T- and B-cell defectsAnhydrotic/hypohidrotic ectodermal dysplasia with immunodeficiency (NEMO or IκBα deficiency): recurrent mycobacterial or pyogenic infections, with or without skin, hair, and nail abnormalities; poor fever responsesXLP: hypogammaglobulinemia, persistent or fatal EBV infectionChronic mucocutaneous candidiasis: recurrent oroesophageal and skin Candida species infection Open table in a new tab Careful analysis of the white blood cell count and differential is of utmost importance when evaluating patients suspected of cellular immunodeficiency disorders. The absolute lymphocyte count must be compared with age-matched control ranges for proper interpretation. Severe lymphopenia in an infant ( 2,000 IU/mL; low TH17 cell numbersOther disorders to be considered Drug-induced neutropenia; autoimmune/alloimmune neutropenia; hypersplenism; chronic mucocutaneous candidiasis; TCII deficiency; hyper-IgM syndrome, XLA; Schwachman-Bodian-Diamond syndrome; warts, hypogammaglobulinemia, immunodeficiency and myelokathexis (WHIM) syndromeNBT, Nitroblue tetrazolium; WASP, Wiskott-Aldrich syndrome protein; G6PD, glucose-6-phosphate dehydrogenase; MPO, myeloperoxidase; XLA, X-linked agammaglobulinemia. Open table in a new tab NBT, Nitroblue tetrazolium; WASP, Wiskott-Aldrich syndrome protein; G6PD, gluco