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Recurrent Infection

Recurrent Infection: Excerpt from The Diagnostic Approach to Symptoms and Signs in Pediatrics

Some children have frequent or recurrentinfections. The important clinical question is whether these areinfections that occur in immunologically normal or compromised hosts.

Principal Causes of Recurrent Infection

1. Normalhost
   1. Upperrespiratory tract infections
   2. Otitis media
   3. Skin infections
   4. Urinary tract infections
   5. Pneumonia
   6. Meningitis
   7. Foreign body
2. Immunologically compromised host
   1. Primaryimmunodeficiency
      1. Primary B-Cell disorders
         1. Transienthypogammaglobulinemia of infancy
         2. X-linked (Bruton) agammaglobulinemia
         3. Common variable immunodeficiency
         4. Selective IgA deficiency
         5. IgG subclass deficiencies
      2. Primary T-cell disorders
         1. Thymichypoplasia (DiGeorge syndrome)
      3. Combined B- and T-cell disorders
         1. Combinedimmunodeficiency
         2. Purine nucleoside phosphorylase deficiency
         3. Severe combined immunodeficiency
         4. Immunodeficiency with thrombocytopeniaand eczema (Wiskott-Aldrich syndrome)
         5. X-linked CD-40 ligand deficiency
         6. X-linked lymphoproliferative disease
         7. Ataxia-telangiectasia
         8. Hyper-IgE syndrome
         9. Cartilage-hair hypoplasia
      4. Disorders of phagocytic function
         1. Congenitalneutropenia
         2. Cyclic neutropenia
         3. Chronic granulomatous disease of childhood
         4. Chediak-Higashi syndrome
      5. Disorders of the complement system
   2. Secondary immunodeficiency
      1. Immunosuppressiveagents
      2. Sickle cell disease
      3. Nephrotic syndrome
      4. Burns
      5. Uremia
      6. Asplenia including splenectomy
      7. Neutropenia
      8. Lymphoid malignancy
      9. Protein-calorie malnutrition
      10. Human immunodeficiency virus infection

Clinical Features and Diagnosis

Normal Host

The following are common recurrent infectionsthat occur in normal hosts.

Upper Respiratory Tract Infections (URIs)

Most commoncause of recurrent infection is viral URI because children are repeatedlyexposed to these pathogens at home, in day-care centers, in school,and in the community.

Infants <1 yr average 3–7respiratory illnesses/yr, whereas children 1–6yrs of age average 8 respiratory infections/yr. Childrenwho are >6 yrs of age have 5–6 respiratory illnesses/yrup to adolescence.

Otitis Media

Perhapsthe single most important factor contributing to recurrent acuteotitis media is eustachian tube dysfunction. Predisposing causesinclude allergic rhinitis, cleft palate, and enlarged adenoid glands.

For unexplained reasons, Native Americansand children with trisomy 21 have high incidence of eustachian tubedysfunction and recurrent otitis media.

Skin Infections

Recurrentimpetigo or cellulitis of lower extremities is usually due to traumaof skin with secondary excoriation.

As isolated finding, these skin infectionsdo not indicate primary immunodeficiency.

Urinary Tract Infections (UTIs)

RecurrentUTIs are frequent in girls, perhaps in part because of colonizationof short urethra by fecal flora. Usual pathogens are gram-negativeenteric bacteria.

Predisposing factors to UTI in bothgirls and boys are urinary tract obstruction and reflux.

Pneumonia

Factors that predispose to recurrent pneumoniainclude bronchopulmonary dysplasia, foreign body aspiration, reactiveairways disease, cystic fibrosis, and gastroesophageal reflux.

Meningitis

Fracture of basilar skull or cribriform plateor midline dermal defect may predispose to recurrent meningitis.

Foreign Body

Because chronic indwelling urinary cathetersand ventricular shunt catheters compromise skin and mucous membranebarriers to infection, they predispose to recurrent urinary tractand shunt infections, respectively.

Immunologically Compromised Host

Primary Immunodeficiency

Major clinicalmanifestation of primary immune deficiency is increased susceptibility toinfection, which can be manifested by increase in frequency, duration,or severity of infection; occurrence of unexpected or severe complications;or infection with unusual organisms.

Whether frequent infections indicatepresence of immunologic disorder depends on age of child, typesof infection, specific pathogens involved, associated findings,and family history of recurrent or unusual infections or childhooddeath.

Primary B-Cell Disorders

Antibody deficiency accounts for largestproportion of primary immunodeficiency disorders. There is increasein risk of recurrent pyogenic infection in children with defectsin B-cell function.

Transient Hypogammaglobulinemia of Infancy

Serum immunoglobulinG reaches its nadir at 3–4 mos of age in normal infantsas maternal IgG levels wane. Levels increase as infants begin toproduce their own IgG.

Transient hypogammaglobulinemia refersto delay in production of IgG beyond 6 mos of age.

Increase in incidence of otitis mediaand sinusitis may occur in affected children until IgG levels becomenormal at 18–36 mos of age. Number and function of B andT cells is normal.

X-Linked (Bruton) Agammaglobulinemia

Due to mutationsin gene at Xq22 that encodes for B-cell protein tyrosine kinase.

Affected individuals are well until6–9 mos of age, when they develop infections with encapsulatedorganisms (e.g., S. pneumoniae, H. influenzae, and S. aureus). Viralinfections are usually not a problem except for enteroviruses, whichcan cause persistent meningoencephalitis. Infections with fungi andP. carinii are unusual. Tonsils are small, and lymph nodes are rarelypalpable.

Diagnosis is confirmed by demonstrationof very low or undetectable serum concentrations of IgG, IgA, IgM,and IgE; absence or low numbers of circulating B cells; and failureof antibody production in response to antigenic stimulation (e.g.,immunizations).

Common Variable Immunodeficiency

Moleculardefect is unknown. Bacterial pathogens and types of infections aresimilar to those found with X-linked agammaglobulinemia.

Presentation is usually in later childhoodor adolescence with recurrent sinusitis, pneumonia, or GI infections.Tonsils and lymph nodes may be normal in size or enlarged.

Number of B-lymphocytes in peripheralblood is normal, but these cells are unable to differentiate normallyinto immunoglobulin-producing cells. Serum immunoglobulin levelsare decreased but higher than in those with X-linked agammaglobulinemia.T cell numbers are normal, but T-cell function may be depressed.

Selective Immunoglobulin A Deficiency

Basic defectleading to serum and secretory IgA deficiency is unknown. SerumIgA is <10 mg/dL, but serum IgG and IgM are normal.T-lymphocyte function is intact.

Some children have no obvious clinicalproblems, whereas others have recurrent infections (otitis media,sinusitis, pneumonia, gastroenteritis) caused by the same pathogensas in other antibody deficiency syndromes.

Some of these individuals may havedecreased IgG subclasses and abnormalities of specific antibodyproduction. Affected children also may have increased incidenceof allergic disorders (allergic rhinitis, eczema, asthma).

Immunoglobulin G Subclass Deficiencies

Despitenormal or increased serum IgG, deficiencies in ≥1 IgG subclassesmay occur.

Isolated or combined deficiency ofIgG1, IgG2, and IgG3 has been associated with increased risk ofinfection, usually otitis media, sinusitis, and pneumonia.

Clinical significance of IgG4 deficiencyis uncertain.

Primary T-Cell Disorders

Individuals with impaired T-cell functionhave increased susceptibility to opportunistic infection.

Thymic Hypoplasia (DiGeorge Syndrome)

Pathogenesisinvolves hypoplasia or aplasia of thymus and parathyroid glands.In >90% of cases, deletion of chromosome 22q11.2is found.

Typical facies consists of downwardslant of palpebral fissures, hypertelorism, low-set ears with notchedpinnae, short philtrum, and mandibular hypoplasia. Conotruncal defects(truncus arteriosus, interrupted aortic arch) are common. Hypocalcemicseizures may occur in first 1–2 wks of life. Other findingsinclude chronic rhinitis, recurrent pneumonia, thrush, and diarrhea.

Although serum immunoglobulin levelsare usually normal, specific antibody responses are decreased. T-cellnumbers are low, and lymphocyte responses to mitogens are usuallydiminished.

Combined B- and T-Cell Disorders

Defect in T-cell number or function impairscell-mediated immunity. Because B cells require helper T cells forproduction of IgG, IgA, and IgE, T-cell defect results in B-celldeficiency even when B cells are competent.

Combined Immunodeficiency

Characteristicmanifestations include recurrent pulmonary and skin infections,chronic diarrhea, oral and cutaneous candidiasis, and failure tothrive. Serum immunoglobulins may be normal, but impaired antibodyfunction usually occurs.

Cellular immune function studies showlymphopenia, profound decrease in T-cell number, and decreased lymphocyteresponses to mitogens and antigens in vitro.

Purine Nucleoside Phosphorylase Deficiency

Purine nucleosidephosphorylase is an enzyme that functions in purine salvage pathway,so that uric acid can be formed. Mutations in purine nucleosidephosphorylase gene on chromosome 14q13.1 lead to deficiency of thisenzyme and accumulation of toxic metabolites that affect immunefunction.

Spastic diplegia, psychomotor retardation,and autoimmune disorders are common. Serum uric acid concentrationis low.

Immune defects include significantlymphopenia, marked decrease in T cells, impaired T-cell function,and increase in natural killer cells.

Severe Combined Immunodeficiency

Differentmutations are responsible for various syndromes of severe combinedimmunodeficiency (SCID), which are the most severe of all immunodeficiencydisorders. X-linked SCID is most common form of SCID in U.S.

Skin infections, otitis media, pneumonia,chronic diarrhea, persistent candidiasis, and failure to thriveoccur in first few months of life. Infections with viruses, pyogenicbacteria, C. albicans, and P. carinii are common. There is absenceof lymph nodes and thymus.

Certain lab findings characterize SCID:lymphopenia; low or absent serum immunoglobulin levels; very lowor undetectable T cells; delayed cutaneous anergy; lack of antibodyformation after immunization; and absence of lymphocyte proliferativeresponses to antigens, mitogens, and allogenic cells in vitro.

Immunodeficiency with Thrombocytopenia and Eczema (Wiskott-Aldrich Syndrome)

X-linkeddisorder characterized by eczema, thrombocytopenic purpura, andrecurrent infections, including otitis media, pneumonia, meningitis,and septicemia.

Typical serum immunoglobulin patternconsists of normal to mildly decreased IgG, increased IgA and IgE,and low IgM. Antibody responses to polysaccharide antigens are poor.T-cell function is defective with cutaneous anergy and poor lymphocytemitogen response.

Parolini et al. (1998) have shown thatthis disorder also can occur in females by nonrandom inactivationof maternally derived X chromosome, but this is rare.

X-Linked CD-40 Ligand Deficiency

Previouslyreferred to as X-linked immunodeficiency with hyper-IgM. Mutationsin CD154 gene on X chromosome prevent T cells from signaling B cellsthrough CD40 pathway. Isotype switching does not occur, and increasedamount of IgM is produced.

Age of onset is usually from 6 mosto 2 yrs of age with recurrent infections (e.g., otitis media, sinusitis,and pneumonia) caused by pyogenic organisms or P. carinii. Lymphadenopathyand pancytopenia also may occur.

Frequency of autoimmune disorders andcancer is increased.

Although number of B lymphocytes inperipheral blood is normal, serum IgG, IgA, and IgE are very low,whereas serum IgM is normal or markedly increased. T-cell functionmay be normal or impaired. Molecular genetic analysis is confirmatory.

X-Linked Lymphoproliferative Disease

Infectionwith Epstein-Barr virus causes uncontrolled cytotoxic T-cell proliferation inchildren with this disorder. Gene has been mapped to Xq25 and proteinproduced by this gene is known as SAP (SLAM-associated protein).SAP inhibits upregulation of signaling lymphocyte activation molecule(SLAM) and thus prevents uncontrolled lymphoproliferation of Epstein-Barrvirus in normal persons.

Usual presentation is severe infectiousmononucleosis, which can be fatal, primarily because of severe liverinvolvement.

Identification of susceptible individualsbefore infection is possible by molecular genetic analysis.

Survivors have severe cellular immunedefects and may develop hypogammaglobulinemia, aplastic anemia,and lymphoma.

Ataxia-Telangiectasia

Gene locusof this autosomal-recessive disorder has been mapped to chromosome 11q22.3.

Characteristic manifestations includeprogressive cerebellar ataxia, telangiectasias of skin and bulbarconjunctivae, and recurrent sinus/pulmonary infections.

Usual immunologic abnormalities areselective absence of serum IgA, low serum IgG and IgE, decreasedor normal specific antibody titers, and diminished proliferativelymphocyte response to mitogens.

Hyper-IgE Syndrome

Autosomal-dominantdisorder, whose gene locus has been mapped to chromosome 4q21. Characterizedby recurrent staphylococcal abscesses (especially skin, lungs, andjoints), pruritic dermatitis, and marked increase in serum IgE.Number of eosinophils is increased in blood and sputum.

Antibody and cell-mediated responsesto antigens are poor.

Cartilage-Hair Hypoplasia

This autosomal-recessivedisorder is a form of short-limbed dwarfism characterized by presenceof fine, sparse, light hair and eyebrows; hyperextensible jointsof hands and feet with inability to extend elbows completely; andradiologic changes (costochondral junction flaring of ribs, scleroticor cystic changes of bone metaphyses).

Gene locus has been mapped to chromosome9p21-p12.

3 patterns of immune dysfunction mayoccur: defective antibody-mediated immunity, combined immunodeficiency,and severe combined immunodeficiency. Affected children are especiallyprone to severe and often fatal varicella infections.

Disorders of Phagocytic Function

Severe congenital neutropenia, cyclic neutropenia,chronic granulomatous disease of childhood, and Chediak-Higashisyndrome are discussed in this section. See Lekstrom-Himes and Gallin(2000) for discussion of other phagocytic defects.

Congenital Neutropenia

This autosomal-recessivedisorder is caused in many cases by mutation in neutrophil elastasegene located on chromosome 19p13.3.

Characterized by recurrent bacterialinfections and failure of myeloid cells to mature from promyelocytesto myelocytes. Absolute neutrophil count is <500 cells/mm³.

Cyclic Neutropenia

Mutationsin neutrophil elastase gene also cause this autosomal-dominant disorder.

Characterized by severe neutropeniathat typically occurs at intervals that last 3–6 days every3–4 wks. Children have fever and mucosal ulcers and maydevelop life-threatening infections during period of neutropenia.

Chronic Granulomatous Disease of Childhood

Genetictransmission is X- linked (most commonly) or autosomal-recessive.

Neutrophils and monocytes ingest butdo not kill catalase-positive microorganisms (S. aureus; S. marcescens;Proteus, Klebsiella, Candida, and Aspergillus species) because offailure to generate superoxide and other reactive oxygen radicals.

Recurrent abscess formation (skin,liver, lung), pneumonia, and osteomyelitis are characteristic findings.

Disease can be diagnosed by nitrobluetetrazolium test or by flow cytometry with dihydrorhodamine dye.

Chediak-Higashi Syndrome

Autosomal-recessivedisorder caused by mutations in lysosomal trafficking regulator gene,which has been mapped to chromosome 1q42.1-q42.2.

Characteristic findings include recurrentbacterial infections, partial ocular and cutaneous albinism, photophobia,nystagmus, peripheral neuropathy, platelet dysfunction with easybruising, and mental retardation. Life-threatening lymphoma-likesyndrome with fever, hepatosplenomegaly, lymphadenopathy, and pancytopeniaalso may occur.

Diagnosis can be established by presenceof giant cytoplasmic granules in neutrophils, monocytes, and lymphocytes.Molecular genetic analysis is definitive.

Disorders of Complement System

Congenitaldeficiencies of all complement components of classical pathway have beendescribed (C1q, C1r, C1rs, C4, C2, C3, C5, C6, C7, C8, and C9) butare rare.

Complement deficiency predisposes topneumonia, cellulitis, abscesses, osteomyelitis, meningitis, andsepticemia caused by pyogenic bacteria. Individuals with C5, C6,C7, C8, or C9 deficiency are particularly susceptible to meningococcaland gonococcal infections.

Decreased total serum hemolytic complement(CH50) determination can be used as screening test for complementdeficiency. If CH50 is low, specific complement levels can be measured.

Secondary Immunodeficiency

Secondary immunodeficiency disorders aremuch more common than primary ones.

Immunosuppressive Agents

Corticosteroidsdepress immunoglobulin synthesis, delayed hypersensitivity response,and accumulation of leukocytes at site of inflammation.

Cyclosporine suppresses cell-mediatedimmunity and some humoral immunity.

Azathioprine and 6-mercaptopurine impairDNA and RNA synthesis and thus any immune response dependent oncell proliferation.

Antilymphocyte globulin diminishescutaneous delayed hypersensitivity reactions.

Therapeutic ionizing radiation significantlyimpairs cell-mediated immunity.

Sickle Cell Disease

Factors that increase risk of serious andrecurrent infection in children with sickle cell disease are diminishedsplenic function and decreased opsonic activity against encapsulatedorganisms (e.g., S. pneumoniae).

Nephrotic Syndrome

Septicemia and peritonitis are common recurrentinfections that occur in individuals with nephrotic syndrome. Thereis impaired antibody response to organisms (e.g., S. pneumoniae).

Burns

Becausenatural skin barrier to infection is destroyed in serious burns,septicemia is common complication.

Serum immunoglobulin levels decreasea few days after burn and return to normal in 1–2 wks.T-cell function is also diminished.

Uremia

There isincreased susceptibility to infections of skin, lung, urinary tract,and GI tract in individuals with uremia. Predominant immunologicdefect is impaired cell-mediated immunity.

Abnormal antibody responses to S. pneumoniaeand influenza virus as well as defective neutrophil function alsohave been described.

Asplenia Including Splenectomy

Because spleen plays major role in antibodysynthesis and in clearance of microorganisms from blood, individualswithout a spleen have increased susceptibility to infection. Commonpathogens infecting such individuals include S. pneumoniae, H. influenzaetype b, N. meningitidis, S. aureus, group A Streptococcus, and E.coli.

Neutropenia

Childrenwith severe neutropenia (absolute neutrophil count of <500cells/mm³) have increased susceptibilityto infection.

Causes include drugs (penicillins,sulfonamides, phenothiazines, anticonvulsants), immune neutropenia(isoimmune, autoimmune), hypersplenism, bone marrow replacement(especially malignancy), cancer chemotherapy, and radiation to bonemarrow.

S. aureus and gram-negative entericbacteria are most common pathogens isolated from neutropenic individuals.

Lymphoid Malignancy

Importantfactors in increased susceptibility of leukemic patients to infectionare decrease in number of circulating mature neutrophils and decreasedleukocyte mobilization.

Individuals with lymphoma have impairedantibody production and cell-mediated immunity. Defects of cell-mediatedimmunity often occur in Hodgkin disease.

Protein-Calorie Malnutrition

Bacterialinfections of GI tract, urinary tract, and blood are common in individuals withprotein-calorie malnutrition. So are fungal and parasitic infections.Most common immunologic abnormality is impaired cell-mediated immunity.

Dietary deficiencies of riboflavinand pyridoxine may lead to dermatitis and stomatitis that compromiseskin and mucous membrane barriers to infection.

HIV Infection

Causes spectrumof disease, and most severe form is AIDS.

Individuals at risk include male homosexuals,intravenous drug abusers, female sexual partners of carriers orindividuals with HIV infection, hemophiliacs who have received multipleblood transfusions, other recipients of blood products, and infantsborn to infected mothers.

Infected newborns are often small forgestational age and may develop clinical disease in first 6 mosof life.

Clinical manifestations include fever,diarrhea, failure to thrive, hepatosplenomegaly, generalized lymphadenopathy,parotitis, interstitial pneumonitis, persistent oral candidiasis,cardiomyopathy, hepatitis, nephropathy, lymphoid interstitial pneumonia,and encephalopathy. Recurrent infections (e.g., otitis media, sinusitis,pneumonia, and septicemia) also occur. Opportunistic infectionsare common with pathogens (e.g., P. carinii, cytomegalovirus, herpessimplex virus, varicella-zoster virus, M. tuberculosis, M. aviumcomplex, Cryptosporidium, T. gondii, and C. neoformans).

Principal immunologic abnormalitiesinclude

Diminishednumber of T cells, which is primarily due to decrease in T-helper CD4⁺ cells

Reversed T-helper:suppressor ratio(CD4⁺ to CD8⁺)

Decreased proliferative responses tomitogens (e.g., pokeweed mitogen, phytohemagglutinin, and concanavalinA)

Cutaneous anergy to delayed hypersensitivityantigens

Although there is increase in numberof B cells and immunoglobulin levels, especially IgG and IgA, theseindividuals are unable to generate adequate antibody responses afterexposure to new antigens.

Diagnosis is usually made by serumantibody tests (ELISA and Western blot or other confirmatory tests)in children >18 mos of age. In children <18 mosof age, diagnosis may be confirmed by positive viral blood cultureor demonstration of viral nucleic acids by polymerase chain reaction.

Diagnostic Approach

Recurrentviral URIs in otherwise normal child with normal growth and development occurbecause of recurrent exposure. Such infections rarely indicate underlyingimmune disorder with possible exception of selective IgA deficiency.

Localized defect is usually the problemwhen recurrent infections occur at single anatomic site (otitismedia, urinary tract infection, pneumonia, or meningitis). Tests(e.g., CBC and differential counts; UA; urine, blood, and spinalfluid cultures) and chest radiography are often diagnostic.

Primary or secondary immune deficiencyshould be suspected in children who have

≥2 serious bacterial infections(pneumonia, meningitis, septicemia, osteomyelitis, septic arthritis)

Infection with organisms of low virulence

Chronic sinopulmonary infection

Unusual infecting agents

Incomplete clearing between episodes

Incomplete response to treatment

Frequent findings in children withimmunodeficiency are impaired growth; recurrent or chronic diarrhea,eczema, or thrush; hepatosplenomegaly; recurrent abscesses; recurrentosteomyelitis; small or absent tonsils; and no palpable lymph nodes.Neutropenia, aplastic anemia, hemolytic anemia, and thrombocytopeniaare other common findings.

2 episodes of septicemia or meningitismay indicate asplenia or diminished splenic function, circulatingantibody deficiency, or complement deficiency. Recurrent meningococcalmeningitis or disseminated gonococcal infection may be due to deficiencyof C5, C6, C7, C8, or C9.

≥2 serious pyogenic skin infections(furunculosis, subcutaneous abscesses, or cellulitis), without otherexplanation, that are associated with recurrent otitis media orpneumonia suggest possible neutropenia, defective chemotaxis, ordefective phagocytosis.

Subcutaneous abscess or furunculosisassociated with lymph node, liver, or lung abscess suggests chronicgranulomatous disease.

Protracted diarrhea and persistentoral thrush associated with recurrent otitis media, sinusitis, orpneumonia suggest IgA deficiency or defect in cell-mediated immunity.

Single P. carinii pulmonary infection;L. monocytogenes infection occurring after newborn period; disseminatedor persistent herpes simplex, varicella, or cytomegalovirus infection;or chronic candidiasis of skin or mucous membranes may indicatedefective cell-mediated immunity.

Unusual associated physical exam findingsare suggestive of certain immunologic disorders:

Eczema andpetechiae (Wiskott-Aldrich syndrome)

Partial albinism (Chediak-Higashi syndrome)

Unusual facies with micrognathia, hypertelorism,malformed ears, and congenital heart defects (DiGeorge syndrome)

Ataxia and telangiectasia (ataxia-telangiectasia)

Fine hair with short extremities (cartilage-hairhypoplasia)

Recurrent skin abscesses and eczema(hyper-IgE syndrome)

The following diagnostic tests screenfor most primary immunologic defects. If any of these tests areabnormal, further investigations are necessary as outlined below.

CBC and differential

Analysis of blood smear

Quantitative serum immunoglobulins(IgG, IgA, IgM, IgE)

Functional antibody titers (polio,tetanus, diphtheria) for IgG function and isohemagglutinins (anti-Aand anti-B titers) for IgM function

Skin tests (Candida, tetanus toxoid)for delayed hypersensitivity and cell-mediated immunity

CH50

Chest radiograph (thymic shadow)

Evaluation of Humoral Deficiency

Serum immunoglobulinlevels should be measured (IgA, IgG, IgM) and compared with age-relatednormal values. Even though total serum IgG may be normal, subclassdeficiency may still occur and quantitative measurements of individualsubclasses can be performed.

Antibody function also should be assessed.Antibody responses to usual childhood immunizations (e.g., tetanusand diphtheria) can be determined. In children >18–24mos of age, antibody response to immunization with H. influenzaetype b capsular polysaccharide vaccine should be performed because somechildren respond normally to protein antigens but not to polysaccharideantigens.

If immunoglobulin levels and antibodytiters are decreased, next step is enumeration of B cells in peripheralblood by flow cytometry. Beyond these tests, immunologic consultationshould be requested. Studies (e.g., in vitro mitogen or antigendriven B-cell proliferation and immunoglobulin secretion) may beneeded to delineate functional B-cell defects.

Evaluation of Cell-Mediated Immunity

Should includeCBC, including absolute lymphocyte count, chest radiograph, anddelayed hypersensitivity skin tests. Presence of lymphopenia ishelpful because it occurs with T-cell disorders. Absence of thymussilhouette also may occur in some T-cell disorders, but thymus alsomay involute with stress.

Best screening test for delayed-typehypersensitivity testing is Candida skin test or standardized panelof antigens prepared for this purpose. Presence of ≥1 positivedelayed-type skin tests generally indicates intact cell-mediatedimmunity. However, prior exposure of the antigen is a prerequisite. Positiveresponse to some antigens does not ensure normal cell-mediated immunityto all antigens, and depression of reactivity may occur with acuteviral infections. Frequently, children <1 yr of age areunresponsive to all antigens on the panel.

Indirect assessment of T-cell functionmay be determined by enumeration of peripheral blood T-lymphocytesusing monoclonal antibodies to cell surface determinants. Otherspecialized tests measuring cell-mediated immunity include lymphocyteproliferation in vitro with mitogens, antigens, and allogenic cells.

Evaluation of Phagocytic Function

Number andfunction of phagocytic cells must be ascertained.

Number can be detected using WBC countand differential.

Function of phagocytic cells–cellmotility (chemotaxis), ingestion (phagocytosis), and intracellularkilling (bactericidal activity) can be determined by different assays.

An immunologist can help with selectionand interpretation of these tests.

Evaluation of Complement Deficiency

Complementdeficiencies C1–C9 can be detected by CH50 assay.

This assay depends on functional integrityof these complement components, and deficiency of any componentresults in marked decrease or absence of total hemolytic complementactivity.

If the assay is low, individual complementcomponents can be measured to determine which component is deficient.

References

1. Behrman RE, et al., eds. Nelson textbookof pediatrics, 16th ed. Philadelphia: WB Saunders, 2000.
2. Buckley RH. Primary immunodeficiency diseases due todefects in lymphocytes. N Engl J Med 2000;343:1313–1324.
3. Hill HR. Evaluating the patient with recurrent infections.South Med J 1977;70:230–235.
4. Johnston RB. Recurrent bacterial infections in children.N Engl J Med 1984;310:1237–1243.
5. Lekstrom-Himes JA, Gallin JI. Immunodeficiency diseasescaused by defects in phagocytes. N Engl J Med 2000;343:1703–1714.
6. McMillan JA, et al., eds. Oski's pediatrics,3rd ed. Philadelphia: Lippincott Williams & Williams, 1999.
7. Nathan DG, Orkin SH, eds. Nathan and Oski'shematology of infancy and childhood, 5th ed. Philadelphia: WB Saunders,1998.
8. Online Mendelian Inheritance in Man (OMIM). McKusick-NathansInstitute for Genetic Medicine, Johns Hopkins University (Baltimore,MD) and National Center for Biotechnology Information, NationalLibrary of Medicine (Bethesda, MD), 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim.
9. Parolini O, et al. X-linked Wiskott-Aldrich syndromein a girl. N Engl J Med 1998;338:291–295.
10. Rudolph AM, ed. Rudolph's pediatrics, 20thed. Stamford, CT: Appleton & Lange, 1996.
11. Stiehm ER. Clinical and laboratory evaluation of thechild with suspected immunodeficiency. Pediatr Rev 1985;7:53–61.
12. Stiehm ER, ed. Immunologic disorders in infants andchildren, 4th ed. Philadelphia: WB Saunders, 1996.
13. Zitelli BJ. Recurrent infections. In: Gartner JC Jr,Zitelli BJ, eds. Common and chronic symptoms in pediatrics. St.Louis: Mosby-Year Book, 1997:381–396.

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Book Source Details

• Book Title: The Diagnostic Approach to Symptoms and Signs in Pediatrics
• Author(s): Paul S. Bellet
• Year of Publication: 2006
• Copyright Details: The Diagnostic Approach to Symptoms and Signs in Pediatrics, Copyright © 2006 Lippincott Williams & Wilkins.

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