Pommering

Primary Immunodeficiencies
MEGAN A. COOPER, PH.D., The Ohio State University College of Medicine
and Public Health, Columbus, Ohio
THOMAS L. POMMERING, D.O., Grant Family Practice Residency, Columbus, Ohio
KATALIN KORÁNYI, M.D., Children’s Hospital, Columbus, Ohio
Primary immunodeficiencies include a variety of disorders that render patients more
susceptible to infections. If left untreated, these infections may be fatal. The disorders
constitute a spectrum of more than 80 innate defects in the body’s immune system. Pri-
tion handout on thewarning signs of mary immunodeficiencies generally are considered to be relatively uncommon. There
may be as many as 500,000 cases in the United States, of which about 50,000 cases are
diagnosed each year. Common primary immunodeficiencies include disorders of
humoral immunity (affecting B-cell differentiation or antibody production), T-cell
defects and combined B- and T-cell defects, phagocytic disorders, and complement
pared by The JeffreyModell Foundation, deficiencies. Major indications of these disorders include multiple infections despite
aggressive treatment, infections with unusual or opportunistic organisms, failure to
thrive or poor growth, and a positive family history. Early recognition and diagnosis
can alter the course of primary immunodeficiencies significantly and have a positive
effect on patient outcome. (Am Fam Physician 2003;68:2001-8,2011. Copyright 2003
American Academy of Family Physicians.)
into subgroups based on the component of theimmune system that is affected. This articlereviews the characteristics of some of the more immunodeficiencies are rec-ognized by the World HealthOrganization.1 While most of provides an approach to the initial evaluation childhood, they can manifest later in life.
of patients suspected of having these disorders.
Background
common variable immunodeficiency disor-der, present in patients who are in their 20s or The body’s immune response is made up of 30s. Patients with primary immunodeficiency a diverse network of defenses, including phys- disorders are susceptible to infections that, if ical barriers, cellular components, and soluble two “arms”: first, it mounts rapid, nonspecific deficiencies is uncertain because of the lack of responses (innate immune responses) to ini- a national registry or reporting by govern- tial infection; later, it mounts adaptive im- ment health surveys. In the United States, as many as 500,000 persons have one of the more pathogen. Together, these arms work to main- than 80 primary immunodeficiencies,2 with tain normal host function and resistance to about 50,000 cases diagnosed each year.3 The primary immunodeficiencies appear to affect orchestrated immune response can result in males and females about equally. In a survey an inability to control infection and subse- of more than 2,700 patients conducted by the Immune Deficiency Foundation,3 48 percent The innate immune response involves three of affected patients were male, and 52 percent major cell types: phagocytic cells, such as neu- trophils and macrophages; natural killer cells, Primary immunodeficiencies can be divided which have the ability to lyse foreign cells; andantigen-presenting cells, which are involved in See page 1898 fordefinitions of strength- See editorial on page 1919.
sponse. Complement proteins are an impor- Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright 2003 American Academy ofFamily Physicians. For the private, noncommercial use of one individual user of the Web site. All other rights reserved.
T cells and limits intracellular infections by Patients with antibody deficiencies often present after six organisms such as viruses, parasites, andmycobacteria. Antibodies, the key feature of months of age, when maternal antibodies are lost, but they the humoral response, are produced by acti- vated B cells to help control the spread ofextracellular pathogens. T-lymphocyte andB-lymphocyte responses are not independent tant class of soluble mediators of the innate of one another; for example, B cells can acti- vate antigen-specific T cells for a cellular inflammation and microbial killing of extra- immune response, while an efficient B-cell antibody response depends in part on T-cell activation of B lymphocytes. Thus, defects in T and B lymphocytes and can be divided into either cell type have the potential to affect cellular and humoral responses. The cellular both cellular and humoral immunity to vary- immune response is mediated primarily by TABLE 1
Clinical Findings in the Major Subgroups of Primary Immunodeficiency Disorders
Encapsulated bacteria: Haemophilus Recurrent infections: sinus infections, otitis influenzae, pneumococci, streptococci Fungi and parasites: Giardia lamblia, Chronic gastrointestinal tract problems, Postvaccination paralytic polio (with live oral Calmette-Guerin infection or paralytic polio Poor wound healingAbscesses, skin infectionsOral cavity infectionsAnorectal infections Information from references 4 through 6. Primary Immunodeficencies
TABLE 2
Selected Primary Immunodeficiency Disorders
differentiation and antibody production (~ 50)Common variable immunodeficiency Bruton’s or X-linked agammaglobulinemia T-cell defects and combined B-cell and T-cell defects (~ 30)Severe combined immunodeficiency Complement deficiencies (at least 16 distinct Information from references 4, and 7 through 9. Characteristics of Primary
tion. Collectively, these disorders account Immunodeficiencies
ciencies are described in the following sections Patients with antibody deficiencies often and summarized in Table 14-6 and Table 2.4,7-9 present after six months of age, when mater- nal antibodies are lost, but they can present in adulthood.10 Typically, these patients developinfections with encapsulated bacteria. Recur- DISORDERS OF HUMORAL IMMUNITY
rent bacterial sinus and pulmonary infections B-cell differentiation and antibody produc- immunodeficiencies. Patients with humoral Severe combined immunodeficiency is characterized bysevere opportunistic infections, or by chronic diarrhea andfailure to thrive in infancy. primary immunodeficiencies have an intact and respiratory tract infections, along with gas- cellular immune system; thus, they are able to trointestinal involvement. All patients with IgA handle most viral and fungal pathogens, a deficiency are at increased risk for allergies and factor that can help to distinguish these disor- autoimmune diseases. Although serum IgA lev- els are below 5 mg per dL, serum IgG and IgM levels are in the normal range. In contrast to patients with common variable immunodefi- ciency, patients with IgA deficiency have a nor- term “common variable immunodeficiency” encompasses a heterogeneous group of disor- Bruton’s or X-linked agammaglobulinemia is caused by mutation or absence of the Bru- (serum IgA levels below 5 mg per dL [0.05 g ton’s tyrosine kinase gene.13 Early B-cell devel- per L]).1,11 Onset can occur after two years of opment is arrested, and serum immunoglobu- age, but the average age of onset is the middle lins (IgG, IgA, IgM) are markedly deficient or to late 20s.10 Patients with common variable totally absent.10 Onset of recurrent bacterial infections is usually at the end of the first year vaccines (decreased IgG antibody response) of life; however, patients with the disorder may and an increased risk of developing auto- not present until the age of three to five years.
T-CELL DEFECTS AND COMBINED
ders, selective IgA deficiency may have the B-CELL AND T-CELL DEFECTS
Disruption of the cellular immune response 700 persons, according to estimates based on is observed in patients with defects in T cells or blood donation analyses), but the disorder is both T and B cells. These primary immuno- deficiency disorders are generally more severe Patients with symptoms often have sinusitis than antibody deficiencies. Affected patientsoften present early in life with failure to thriveand disseminated infection.7 DiGeorge syn-drome is one of the most recognized disorders in this category, and severe combined immun- MEGAN A. COOPER, PH.D., is a medical student at The Ohio State University College odeficiency is the most severe. General features of Medicine and Public Health, Columbus. She earned a doctoral degree in immunol-ogy and natural killer cell biology at Ohio State University.
of this class of diseases include overwhelmingviral and fungal infections.
THOMAS L. POMMERING, D.O., is clinical assistant professor in the Department ofFamily Medicine at Ohio University College of Osteopathic Medicine, Athens, where he earned his doctor of osteopathy degree. In addition, Dr. Pommering is associate migration of the third and fourth branchial director of the Grant Family Practice Residency, Columbus, Ohio, and medical director for sports medicine at Children’s Hospital, also in Columbus. He completed a familypractice residency at Miami Valley Hospital, Dayton, Ohio, and a sports medicine fel- plasia to aplasia of the thymus and parathy- lowship at Grant Medical Center, Columbus.
KATALIN KORÁNYI, M.D., is professor of clinical pediatrics in the Department of Pedi- caused by a deletion in chromosome 22q11.
atrics at The Ohio State University College of Medicine and Public Health. Dr. Korányi Associated defects include truncal cardiac also is a staff physician in the infectious diseases section and medical director of the malformations (e.g., truncus arteriosis, Fal- pediatric program in human immunodeficiency virus infection at Children’s Hospital,Columbus. She received her medical degree from La Universidad Peruana Cayetano lot’s tetralogy) and dysmorphic facial features.
Heredia, Lima, Peru, and completed a pediatric internship and infectious diseases fel- Other diagnostic criteria include a reduced lowship at Children’s Hospital. Dr. Korányi is board-certified in pediatrics and pediatric CD3+ T-cell count (less than 500 per mm3 Address correspondence to Thomas L. Pommering, D.O., Grant Family Practice Resi- greater than three weeks’ duration.11 [Evi- dency, 2030 Stringtown Rd., Grove City, OH 43123 (e-mail: [email protected]).
Reprints are not available from the authors. TABLE 3
Warning Signs of Primary Immunodeficiency Disorders
Medical history
Physical signs
Severe combined immunodeficiency is asso- T-cell and B-cell function (and sometimes nat- ural killer cell function). This disorder is char- acterized by severe opportunistic infections, or by chronic diarrhea and failure to thrive in infancy. Laboratory findings typically demon- strate severe lymphopenia. About one half of Family history of primary immunodeficiency cases are X-linked, and one half are autosomalrecessive.14 Infants with this primary immun- Adapted with permission from The 10 warning signs of primary immuno- odeficiency disorder are at risk for graft-ver- deficiency. The Jeffrey Model Foundation, Copyright 2003. Accessed October 6, sus-host disease because they lack the ability to 2003, at: http://npi.jmfworld.org/patienttopatient/index.cfm?section=warningsigns&CFID=4441749&CFTOKEN=89405863, with additional information from reject foreign tissue, such as maternal T cells that cross into the fetal circulation in utero.
recessive syndrome characterized by thrombo-cytopenia, small platelets and platelet dysfunc- the most common cause of death in patients tion, eczema, and susceptibility to infections.7 Infants typically present with prolonged bleed- ing from the circumcision site, bloody diar-rhea, or excessive bruising. Patients with this COMPLEMENT DEFICIENCIES
primary immunodeficiency disorder are at risk 2 percent of all primary immunodeficiency Ataxia-telangiectasia (Louis-Bar’s syn- disorders.6 They result from the disruption of drome) is a progressive neurologic disorder one of the proteins involved in the classic or associated with cerebellar ataxia, oculocuta- nonclassic activation pathways of the comple- neous telangiectasias, chronic respiratory ment response.15 Defects in the classic path- infections, a high incidence of malignancy, and variable humoral and cellular immuno- complement deficiency, and patients often deficiency. Patients with this disorder have dif- have a high number of autoimmunity disor- ficulty walking and generally are wheelchair- ders, including lupus-like syndromes. Patients with defects of the alternative pathway charac-teristically present with Neisseria infection.15 PHAGOCYTIC DISORDER: CHRONIC
GRANULOMATOUS DISEASE
Diagnosis of Primary
mmunodeficiencies
WARNING SIGNS AND SYMPTOMS
immunodeficiency, is more common in males The National Institute of Child Health and than in females. In this disease, deficiency of nicotinamide adenine dinucleotide phosphate educational program to raise awareness of oxidase in phagocytes results in defective elimination of extracellular pathogens such as this program, the Jeffrey Modell Foundation bacteria and fungi. Patients with chronic developed a list of warning signs for primary granulomatous disease are more susceptible to infection with catalase-positive organisms along with other common presenting signs, (e.g., staphylococci) that require phagocytic are listed in Table 3.2,6,16 A general approach activity for clearance. Aspergillus infection is to the evaluation of patients with suspected primary immunodeficiency is presented inFigure 1.
Evaluation for Suspected Primary Immunodeficiency
LABORATORY TESTING
Primary immunodeficiency is suspected because the patient has one or more of the following: pected, initial laboratory studies include a complete blood cell count (CBC) with manual Infections with opportunistic pathogensInfections not responsive to repeated differential, quantitative immunoglobulin ments of functional antibodies against immu-nized antigens, and delayed-type hypersensi-tivity skin tests (Table 4).6,16,17 The CBC with manual differential can detect deficiencies inimmune cells and platelets. In most instances,a normal CBC eliminates the diagnosis of T-cell defects or combined B-cell and T-celldefects.
Is there another reason for the infections immunologic function in newborns. Because cystic fibrosis, or structural abnormalities? of engrafted maternal immune cells, neonatesmay have both a falsely elevated lymphocytecount and evidence of graft-versus-host dis-ease.18 If severe combined immunodeficiency is strongly suspected and the lymphocytecount is normal or nearly normal, further investigation is warranted to determine the Serum immunoglobulin levels (IgG, IgM, IgA) When a diagnosis is uncertain, additional tests, such as genetic assays or immunopheno-typing, might be performed in consultation Management of Patients
with Primary Immunodeficiencies
INTRAVENOUS IMMUNE GLOBULIN
been used in the treatment of agammaglob- ulinemia.19 This agent is now standard ther- commonly, IVIG is used in patients with X-linked agammaglobulinemia, commonvariable immunodeficiency, X-linked hyperIgM, severe combined immunodeficiency, FIGURE 1. Algorithm for evaluation of the patient with suspected pri- Wiskott-Aldrich syndrome, and selective IgG mary immunodeficiency. (HIV = human immunodeficiency virus; CBC= complete blood cell count; CH IVIG also is used, or is being considered for Primary Immunodeficencies
TABLE 4
Laboratory Testing for Primary Immunodeficiency Disorders
there is a deficiency in the classic pathway *—Delayed-type hypersensitivity skin testing involves intracutaneous injection of a recall antigen such as Can-dida or tetanus toxoid to a previously sensitized patient; a negative result could signal impaired T-cell responseor lack of exposure.
†—Normal immunoglobulin levels cannot always exclude a deficiency in antibody production; therefore, IgGsubclasses and antibodies to specific antigens after vaccination against diphtheria, tetanus, and pneumococ-cus should be measured if humoral deficiencies are still suspected.
‡—Normal cells change the yellow nitroblue tetrazolium dye to a deep blue color, because of the superoxidegenerated by the oxidative burst function; the neutrophils of patients with chronic granulomatous diseaseremain colorless. Information from references 6, 16, and 17. use, in a wide variety of other illnesses. Conse- quently, its limited availability is a concern.21 with primary immunodeficiency disorderswho otherwise would require bone marrow BONE MARROW TRANSPLANTATION
cal donors can be curative in patients with cel- ANTIBIOTICS AND OTHER THERAPIES
lular immune deficiencies such as severe com- many patients with primary immunodeficien- cies are managed with antibiotics alone or in be beneficial in patients with chronic granulo- matous disease.4,14 Bone marrow transplanta- patients with chronic granulomatous disease, tion currently has no role in the treatment of sulfamethoxazole (Bactrim, Septra) reduces the incidence of severe infections by 50 per- available. Long-term survival may be lower cent.4 Similarly, treatment for complement deficiencies is directed at preventing infection, identical donors. Thus, investigations of and consists of antibiotic prophylaxis and alternative strategies, such as gene therapy, Primary Immunodeficencies
Accessed August 27, 2003, at: http://www.primaryimmune.org/pid/patient_survey_publication.pdf.
Haemophilus b conjugate vaccine, meningo- 4. Segal BH, Holland SM. Primary phagocytic disor- ders of childhood. Pediatr Clin North Am 2000;47: 5. Woroniecka M, Ballow M. Office evaluation of chil- dren with recurrent infection. Pediatr Clin North patients with adenosine deaminase deficiency (a subtype of severe combined immunodefi- 6. Paul ME, Shearer WT. The child who has recurrent infection. Immunol Allergy Clin North Am 1999; ciency) and cytokine therapy in patients with 7. Buckley RH. Primary cellular immunodeficiencies. J Allergy Clin Immunol 2002;109:747-57.
Vaccines and Blood Products:
8. Winkelstein JA, Marino MC, Johnston RB Jr, Boyle J, Curnutte J, Gallin JI, et al. Chronic granuloma- Cautions and Contraindications
tous disease. Report on a national registry of 368 patients. Medicine [Baltimore] 2000;79:155-69.
9. Sorensen RU, Moore C. Antibody deficiency syn- ciencies should not receive live virus vaccines, dromes. Pediatr Clin North Am 2000;47:1225-52.
including live oral poliovirus vaccine (OPV).
10. Ballow M. Primary immunodeficiency disorders: Because of the risk of infection, OPV also antibody deficiency. J Allergy Clin Immunol 2002;109:581-91.
should not be given to persons in close contact 11. Conley ME, Notarangelo LD, Etzioni A. Diagnostic with these patients.14 In addition, most patients criteria for primary immunodeficiencies. Represent- with primary immunodeficiencies should not ing PAGID (Pan-American Group for Immunodefi-ciency) and ESID (European Society for Immunode- receive measles, bacille Calmette-Guérin, and ficiencies). Clin Immunol 1999;93:190-7.
varicella vaccines. One exception would be 12. Clark JA, Callicoat PA, Brenner NA, Bradley CA, patients with B-cell deficiency, who should Smith DM Jr. Selective IgA deficiency in blooddonors. Am J Clin Pathol 1983;80:210-3.
13. Gaspar HB, Kinnon C. X-linked agammaglobuline- mia. Immunol Allergy Clin North Am 2001;21:23-43.
receive cytomegalovirus-negative irradiated 14. Ten RM. Primary immunodeficiencies. Mayo Clin blood products because of the risk of infec- 15. Frank MM. Complement deficiencies. Pediatr Clin tion and graft-versus-host disease from lym- phocytes in the donor blood. Patients with 16. Buckley R. The child with the suspected immuno- deficiency. In: Behrman RE, Kliegman RM, Jenson IgA deficiency need to be informed about the HB, eds. Nelson textbook of pediatrics. 16th ed.
possibility of having a serious reaction to Philadelphia: Saunders, 2000:588-90.
plasma or blood transfusions, because of anti- 17. Sorensen RU, Moore C. Immunology in the pedia- trician’s office. Pediatr Clin North Am 1994;41: 18. Muller SM, Ege M, Pottharst A, Schulz AS, Schwarz The authors indicate that they do not have conflicts K, Friedrich W. Transplacentally acquired maternal of interest. Sources of funding: none reported. T lymphocytes in severe combined immunodefi-ciency: a study of 121 patients. Blood 2001;98: 19. Schwartz SA. Intravenous immunoglobulin treat- 1. Primary immunodeficiency diseases. Report of a ment of immunodeficiency disorders. Pediatr Clin WHO scientific group. Clin Exp Immunol 1997;109 20. Busse PJ, Razvi S, Cunningham-Rundles C. Efficacy 2. The 10 warning signs of primary immunodeficiency.
of intravenous immunoglobulin in the prevention The Jeffrey Modell Foundation, Copyright 2003.
of pneumonia in patients with common variable Accessed October 6, 2003, at: http://npi.jmfworld.
immunodeficiency. J Allergy Clin Immunol 2002; org/patienttopatient/index.cfm?section=warning signs&CFID=4441749&CFTOKEN=89405863.
21. Sacher RA; IVIG Advisory Panel. Intravenous im- 3. Primary immune deficiency diseases in America.
munoglobulin consensus statement. J Allergy Clin The first national survey of patients and specialists.

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