sign in sign up
<<
Home , Hypogammaglobulinemia

REVIEW

MARK E. ROSE, MD DAVID M. LANG, MD* Section of Adult Allergy and Immunology, Head, Section of Adult Department of Department of Pulmonary, Allergy, Allergy and Immunology, Department of and Critical Care Medicine, Pulmonary, Allergy, and Critical Care The Cleveland Clinic Foundation Medicine, The Cleveland Clinic Foundation

Evaluating and managing hypogammaglobulinemia

■ ABSTRACT MAN is hospitalized with shortness of A breath and a productive cough. He has If a patient has frequent or recurrent bronchopulmonary had four episodes of lobar , in dif- or sinus infections, they may be due to low levels of ferent locations, over the past 5 years. He also immunoglobulins. This article describes common primary has had chronic since age 10, which (idiopathic) and secondary forms of hypogamma- was treated with multiple courses of antibi- globulinemia and how to evaluate and manage them. otics, as well as endoscopic sinus surgery 4 years ago. In addition, he has a history of aller- ■ KEY POINTS gic rhinitis and atopic , which is now quiescent. He received a polyvalent Common variable immune deficiency is characterized by pneumococcal vaccine 1 year ago because of severely reduced levels of immunoglobulin (Ig)G and recurrent infections. typically manifests as frequent and recurrent sinus and Previous serologic testing for human lung infections. Monthly intravenous infusions of pooled virus was negative. immunoglobulins to maintain total serum IgG levels The patient currently takes no medica- above 500 mg/dL help reduce the infection rate and tions and has never smoked or used illicit preserve pulmonary function. drugs. A review of systems is negative for mus- culoskeletal, neurologic, cardiovascular, renal, or gastroenterological complaints. Selective IgA deficiency should be managed by treating Lobar pneumonia is confirmed by chest infections, if they occur. Daily doses of may be radiography. treatment for encap- helpful as prophylaxis. sulated organisms is started. A consultation with the allergy and immunology department Patients with hypogammaglobulinemia should be is requested. evaluated to detect possible causes of the condition, including chronic protein-losing gastrointestinal disorders, ■ EVALUATING PATIENTS renal , and certain malignancies. WITH RECURRENT INFECTIONS Patients with frequent and recurrent respira- tory infections should be tested for abnormalities (FIGURE 1). Recurrent infection includes acute sinusitis three or more times a year or pneumonia two or more times a year. However, immune deficiency dis- eases are uncommon in the general popula- tion. Therefore, the negative predictive value of laboratory tests is greater than their positive *The author has indicated that he has received honoraria from, has served as a consultant for, or has carried out clinical research with the AstraZeneca, Aventis, Genetech, GlaxoSmithKline, Ivax, predictive value. This makes it important to Merck, Novartis, Pfizer, and Schering/Key corporations. only test immune function in patients with a

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 2 FEBRUARY 2006 133 Downloaded from www.ccjm.org on September 29, 2021. For personal use only. All other uses require permission. LOW IMMUNE ROSE AND LANG

Five types of immunoglobulins The study of immunoglobulins () began gen, and the constant region confers the effector in the 1890s when Emil von Behring described function of the , ie, its subsequent biolog- “antitoxic activity” in animals immune to diph- ic activity after binding to the antigen. theria. Investigators have since described the Antibodies play three critical roles in adaptive structure of immunoglobulins and their critical : purpose in the adaptive immune response. •They neutralize foreign antigens through Immunoglobulins are the secreted form of the direct binding B-cell antigen receptor. They are Y-shaped pro- • They alter antigens so they are more readily teins consisting of two identical heavy polypeptide engulfed by phagocytes (opsonization) chains and two identical light chains. There are •They recruit immune effector cells and trigger two types of light chains—kappa and lambda, the release of cytokines and to which are functionally identical. In contrast, there destroy foreign antigens. are five types of heavy chains, for which each class All of the immunoglobulins fall into the cate- of immunoglobulin is named: alpha, found in gory of serum proteins called gamma globulins, and immunoglobulin (Ig)A, gamma (IgG), delta a low level of any or all of them is called hypogam- (IgD), epsilon (IgE), and mu (IgM). maglobulinemia. The term is somewhat imprecise, The light and heavy chains each contribute to however, because the categorization is based on form a variable and a constant region. The vari- electrophoresis, and gammaglobulins also include able region recognizes and binds to a specific anti- some proteins that are not immunoglobulins.

history of frequent or recurrent infections and The antibody response to the polysaccha- who therefore have a high pretest probability ride antigens is reported with corresponding Immune of an abnormality. normal values. There is a range of antigens to deficiency Basic laboratory tests should be done, which normal individuals will respond. While including a complete metabolic panel and com- no controlled study has determined the num- are plete blood count. Then, the physician should ber of antigens to which one should respond, a uncommon, so evaluate immunoglobulin levels and function. lack of response to all antigens is consistent Immunoglobulin levels. Serum immuno- with impairment of the humoral immune sys- the negative (Ig)G , IgA, and IgM concentrations tem. This information is helpful when deter- predictive are measured using rate nephelometry (total mining how best to manage a patient with value of tests cost $90), a sensitive, reliable test that quanti- recurrent infections and will be discussed in fies antibody levels. The IgE concentration is more detail later in this article. is high measured with an enzyme-linked immunosor- The recently developed pneumococcal bent assay ($57). Levels are reported with nor- conjugate protein vaccine (Prevnar) has com- mal values in units of milligrams per deciliter plicated the evaluation of humoral immune (TABLE 1). function. Its use for testing is controversial Humoral immune function should be and is not generally recommended, as people assessed by measuring antibodies to polysac- may develop antibodies to the conjugated pro- charide antigen before and after immunization tein but not to the capsular antigens. ($574). First, blood should be obtained for Cellular immune function may be com- antibodies to polysaccharide antigens such as promised in patients with recurrent viral or pneumococcus. Then, if the patient has not fungal infections. In such cases one may con- recently received a pneumococcal vaccine, he sider specifically determining T-lymphocyte or she should receive unconjugated polyvalent subsets by flow cytometry and the T-lympho- pneumococcal vaccine. Four weeks after vac- cyte response to protein antigens through cination, blood should be tested again for mitogen stimulation or by performing delayed pneumococcal antibodies. skin testing.

134 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 2 FEBRUARY 2006 Downloaded from www.ccjm.org on September 29, 2021. For personal use only. All other uses require permission. Testing for immune system abnormalities TABLE 1 Normal serum Recurrent infection and/or Infection unresponsive to appropriate therapy immunoglobulin concentrations

IMMUNOGLOBULIN NORMAL VALUES IN ADULTS TYPE (MG/DL) Complete metabolic panel Complete blood count IgG 717–1,411 IgG1 344–966 IgG2 133–622 IgG3 12–138 Normal Abnormal IgG4 1–115 IgA 78–391 Measure immunoglobulin levels Investigate IgM 53–334 Evaluate immunoglobulin response secondary causes to polyvalent pneumococcal vaccine Evaluate T-cell response to protein antigens

FIGURE 1

■ PRIMARY HYPOGAMMAGLOBULINEMIA increased risk of developing the disorder.4 No definitive genetic cause has been identified; Primary hypogammaglobulinemia by defini- susceptibility loci within the major histocom- tion is without a known cause. In adults the patibility complex of chromosome 6 have two most common forms are common variable been associated with CVID in familial stud- immune deficiency (CVID) and selective IgA ies,5 but these loci are also seen in many deficiency. Two others, IgG subclass deficien- autoimmune diseases. cy and deficiency of antibody to a specific The estimated prevalence of CVID is 1 in antigen, are of unclear clinical significance. 20,000 to 100,000.6 It may be diagnosed in CVID generally TABLE 2 summarizes the different features of childhood, but more often presents in adults.7 presents with immunoglobulin deficiency. Consequences of CVID. Patients gener- In all immune-deficient states, physicians ally have recurrent and frequent upper and recurrent and should attempt to rapidly identify complicat- lower respiratory tract infections (eg, sinusitis, frequent ing infections and initiate appropriate therapy , , pneumonia) from encapsu- against the specific microbe. Prophylactic lated organisms.8 In several series of patients respiratory therapy may be of value in some patients. with either recurrent sinusitis or pneumonia, infections the prevalence of hypogammaglobulinemia Common variable immune deficiency was greater than in the general population.9 CVID, a heterogeneous , is From 25% to 48% of patients have characterized by frequent and recurrent infec- splenomegaly.10 tions and decreased concentrations of multi- Patients with CVID are also at increased ple classes of immunoglobulins. IgG levels are risk for a number of noninfectious diseases and more than 2 standard deviations below the should periodically undergo a thorough histo- mean, and the humoral immune response to ry and physical examination to evaluate for polysaccharide antigens is impaired. their presence. In 1999, Cunningham- More than 80% of patients have normal Rundles and Bodian found that patients with numbers of B lymphocytes, but when the lym- CVID had a 20-year life expectancy of only phocytes are presented with an antigen, they 65%, compared with more than 90% in age- fail to differentiate into antibody-secreting matched controls.11 plasma cells.1 Some patients may also have The risk of non-Hodgkin B-cell lym- increased apoptosis of helper T cells and phoma and gastric cancer is particularly decreased T-cell function and signaling.2,3 high.11 Hypogammaglobulinemia-associated Siblings of patients with CVID are at (Good syndrome) has also been

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 2 FEBRUARY 2006 135 Downloaded from www.ccjm.org on September 29, 2021. For personal use only. All other uses require permission. LOW IMMUNE GLOBULINS ROSE AND LANG

T ABLE 2 Laboratory evaluation of hypogammaglobulinemia

DISORDER TOTAL IgA IgM IgG PNEUMOCOCCAL IgG SUBCLASS ANTIBODY RESPONSE

Common variable Low Variable Variable Low Impaired immune deficiency Selective IgA Normal Low Normal Variable* Normal deficiency IgG subclass Normal Normal Normal Low* Variable deficiency Selective Normal Normal Normal Variable Impaired antibody deficiency Secondary Low Variable Variable Low Variable hypogammaglobulinemia

* Most commonly IgG2 subclass

reported. It is important that not with hypogammaglobulinemia using intra- be confused with benign lymphoid hyperpla- muscular immunoglobulin injections.17 sia, which is also seen in patients with CVID. Since then, techniques have improved, Patients may develop chronic , with including intravenous administration. Cost of IVIG: or without Giardia infection. Subcutaneous injection is less common but is $10,000 to CVID is associated with systemic lupus equally effective.18 erythematosus, juvenile rheumatoid arthritis, Immunoglobulins are pooled from the sera $15,000 per idiopathic thrombocytopenia purpura, and of thousands of screened donors and typically infusion autoimmune hemolytic anemia.12,13 The rela- given through a peripheral catheter either at tionship between connective tissue diseases home or in a physician’s office—at a cost of and CVID is not fully understood. Some $10,000 to $15,000 per infusion. A dose of patients initially present with an immune 400 mg/kg is recommended every 3 to 4 cytopenia or other autoimmune disease that weeks.19 eventually progresses to CVID.14 The dosage is adjusted on the basis of Patients with IgG deficiency have not symptomatic improvement and IgG trough been found to be at increased risk for levels, which should be measured every 6 ,15 but they are more likely to months or more often if infections persist. develop interstitial lung disease.16 Serum IgG levels should be maintained above IVIG is the cornerstone of managing 500 mg/dL to help eliminate serious infections CVID. Regularly scheduled treatment with and preserve pulmonary function. high doses of intravenous immunoglobulins Side effects of IVIG. Since IVIG is a (IVIG) leads to improved outcomes, including blood product, its administration may raise fewer hospitalizations and severe infections. concerns of viral transmission. Although no In the early 1940s, Edwin J. Cohn devel- case of human immunodeficiency virus trans- oped immunoglobulin fractionation methods. mission through IVIG has been reported, Soon after, Charles Janeway identified transmission occurred in the early patients with recurrent infections and reduced 1990s.20 Donor screening and IVIG purifica- concentration of immunoglobulins. By the tion techniques have since improved,21 and early 1950s, Janeway was treating his patients no known transmission of viral or other infec-

136 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 2 FEBRUARY 2006 Downloaded from www.ccjm.org on September 29, 2021. For personal use only. All other uses require permission. tion has since been reported. those with IgA deficiency and normal levels 32 Reactions to treatment with IVIG of IgG2. T-cell mediated immunity is not include headache in up to 50% of patients, impaired. and chills, nausea, fatigue, or myalgia in 5% to Management of selective IgA deficiency 10%. Other reported reactions include is limited to treating associated infections. increased blood pressure,22 aseptic Some advocate prophylactic daily doses of 24 to 72 hours after the infusion,23 and acute antibiotics for patients with multiple, recur- renal failure in older, diabetic patients after rent infections. No intervention is available receiving high-glucose, high-osmolar prepara- to either replace IgA via infusion or increase tions.24 Infusion-related side effects may production of native IgA. diminish with slower infusion rates. Anaphylaxis to IgA in the IVIG prepara- IgG subclass deficiency: tion can also occur: patients who are IgA-defi- Clinical relevance uncertain cient and are exposed to IgA in pooled sera IgG exists as four subclasses. IgG1 normally may develop IgE antibodies against IgA. The has the highest serum concentration, followed use of IgA-depleted IVIG has greatly reduced by IgG2, IgG3, and IgG4, respectively. IgG2 is this risk and is safe for patients who are IgA- specific for polysaccharide antigens, and IgG1 25 deficient, even after long-term use of IVIG. and IgG3 are specific for protein antigens. Because the frequency of IgA deficiency is When the IgG level is reported, the level of relatively high in the population, one should each subclass is measured and added to form a check the IgA level prior to initiating IVIG total. Therefore, patients may have a normal therapy. If low, one should utilize IgA-deplet- level of total IgG despite a markedly reduced ed IVIG, with the first dose given in a moni- IgG subclass. IgG2 is the subclass that is most tored, controlled setting. often low.33 Subclass deficiency is frequently associat- Selective IgA deficiency ed with atopy and can occur in healthy peo- Selective IgA deficiency is characterized by ple. However, a deficiency of either IgG1, low to nondetectable levels of IgA with nor- IgG2, or IgG3 is associated with more frequent Experts 34 mal levels of other immunoglobulin classes. and severe infections. IgG2 subclass defi- debate the Some regard it as being on a continuum with ciency is also more common in patients with CVID, with patients diagnosed with selective selective IgA deficiency and those who are clinical IgA deficiency occasionally progressing to homozygous for C2 deficiency.35 relevance CVID.26 Many experts debate the clinical rele- Selective IgA deficiency is the most com- vance of IgG subclass deficiency—and the use of IgG subclass mon immune deficiency. Its estimated preva- of IVIG to treat it. In a prospective, random- deficiency lence in whites is 1 in 300 to 1 in 80027; in ized placebo-controlled crossover study of 43 Asians the prevalence is lower at 1 in adult patients with symptomatic IgG subclass 15,000.28 It is inherited in an autosomal-dom- deficiency, treatment with IVIG was associat- inant pattern with variable penetrance. ed with significantly fewer days of infection.36 Most patients with IgA deficiency have no However, no other studies have been con- symptoms.29 Others have recurrent upper and ducted to confirm these findings. lower respiratory tract infections. They are also We recommend that patients suspected of at increased risk for and other gas- having a deficiency of an IgG subclass and trointestinal infections, autoimmune diseases recurrent infection be referred to a clinical such as systemic lupus erythematosus and ulcer- immunologist for further evaluation and man- ative colitis, and lymphoproliferative disor- agement. ders.30,31 In one series,10 the risk of concomi- tant autoimmune disease was reported at 22%. Specific antibody deficiency Patients who also have low levels of the with normal immunoglobulins IgG2 subclass or low pneumococcal-specific Deficiencies of specific antibodies are also antibody levels are at higher risk for upper and associated with recurrent infections.37 The lower respiratory tract infections than are condition was discovered when investigators

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 2 FEBRUARY 2006 137 Downloaded from www.ccjm.org on September 29, 2021. For personal use only. All other uses require permission. LOW IMMUNE GLOBULINS ROSE AND LANG

evaluated humoral immune function with loss of lymph fluid and immunoglobulins in pneumococcal vaccine and observed that the gastrointestinal tract.42 A low-fat, high- some patients with recurrent infections had protein diet can help return circulating normal IgG concentrations but did not form immunoglobulin concentrations to normal.43 antibodies to some or all of the antigens in the Infusion of IVIG successfuly reduced the rate vaccine. of infection in two patients with protein-los- This condition is difficult to definitively ing enteropathy.44 diagnose because the pneumococcal antibody Chronic renal disease. Nephrotic syn- response is variable. The number of antigens drome is commonly associated with reduced that a person’s immune system recognizes but functionally normal immunoglobulins.45 increases from childhood to adulthood,38 and In adults with , hypogam- no reliable standard for age-appropriate maglobulinemia increases the risk of bacterial response has been validated.39 infection. Ogi et al46 treated 18 patients with Reports have described patients with a nephrotic syndrome and secondary hypogam- specific antibody deficiency who improved maglobulinemia with IVIG every 4 weeks to after being treated with IVIG,40 but no place- maintain serum IgG levels to above 600 bo-controlled study has been conducted. mg/dL, which reduced the infection rate. Children undergoing dialysis may develop ■ SECONDARY hypogammaglobulinemia across multiple HYPOGAMMAGLOBULINEMIA immunoglobulin classes. Isolated IgA defi- ciency has been reported in adults on dialy- Secondary hypogammaglobulinemia can be sis.47,48 due to a variety of conditions, which can be divided into diseases of immunoglobulin loss, Diseases of immunoglobulin production diseases of immunoglobulin production, drug- A number of malignancies, including chronic induced states, and high-stress states. lymphocytic leukemia (CLL),49 lymphoma,50 No studies to date have had sufficient and ,51 are associated with If immuno- power to determine the incidence of sec- secondary hypogammaglobulinemia. globulins ondary hypogammaglobulinemia. Thus, if you A known complication of CLL is an detect hypogammaglobulinemia, you should increased risk of infections because of reduced are low, look take a history to try to rule out potential caus- immunoglobulin synthesis.52 Patients with for a cause es. In addition, laboratory surveillance as CLL who have more frequent infections tend described at the beginning of this article to have lower immunoglobulin levels than should be undertaken when managing patients with CLL without recurrent infec- patients with infection and known causes of tions.53 hypogammaglobulinemia such as nephrotic In multiple myeloma, enhanced T-cell syndrome or chronic lymphocytic leukemia. suppression of B cells appears to play an important role in promoting hypogammaglob- Diseases of immunoglobulin loss ulinemia.54 The two most common conditions that can The use of IVIG for treating secondary result in low immunoglobulin levels are pro- hypogammaglobulinemia is under investiga- tein-losing enteropathies and renal disorders. tion, particularly for prophylaxis against infec- Protein-losing enteropathies that com- tion in patients with hypogammaglobulinemia monly present with decreased immunoglobu- secondary to malignancy.55 lins include autoimmune enteropathy and intestinal lymphangiectasia. Medications Autoimmune enteropathy is characterized Medications that can cause reversible sec- by protracted diarrhea, villous atrophy, and ondary hypogammaglobulinemia include: enterocyte autoantibodies. It is mostly seen in Disease-modifying antirheumatic drugs children but also occurs in adults.41 such as sulfasalazine and gold56,57 Intestinal lymphangiectasia is caused by Systemic steroids for asthma, as well as blocked interstitial lymphatics with resultant for bronchopulmonary dysplasia in children.58

140 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 2 FEBRUARY 2006 Downloaded from www.ccjm.org on September 29, 2021. For personal use only. All other uses require permission. Steroid-induced hypogammaglobulinemia is •IgG2 ≤ 12 mg/dL (180) unique in that immunoglobulin levels are •IgG3 ≤ 6 mg/dL (13) diminished while function is preserved. •IgG4 ≤ 9 mg/dL (8) Phenytoin may lead to a CVID-like syn- • IgA ≤ 7.8 mg/dL (85) drome59 or selective IgA deficiency.60 • IgM 9.9 mg/dL (45) Carbamazepine has been implicated in Pneumococcal antibody titers: no anti- IgA and IgM deficiency.53 body response to any of the 12 pneumococcal Androgen replacement therapy can antigens evaluated. cause secondary hypogammaglobulinemia, Complete blood cell count and complete but its clinical significance is uncertain.61 metabolic panel: normal. Computed tomography of the sinuses: High-stress states consistent with chronic sinusitis. Physical stress can reduce immunoglobulin There is no evidence of a disease causing production. During extreme physical activity, hypogammaglobulinemia. athletes can develop reduced concentrations The patient’s clinical picture and labora- of immunoglobulins and increased risk of tory evaluation are consistent with CVID. He infection.62 Military recruits who undergo is treated with IgA-depleted IVIG 400 mg/kg, periods of strenuous exercise, reduced calorie which is well tolerated. intake, and sleep deprivation tend to have He is discharged with recommendations lower concentrations of IgG, IgA, and IgM.54 for outpatient follow-up in the allergy and immunology clinic and to be maintained at a ■ CASE REVISITED total serum IgG level of more than 500 mg/dL. Over the last 5 years, the patient has tol- The allergy and immunology consultant erated his monthly infusions of IVIG with no determines that the patient has no family his- significant adverse reactions. He has experi- tory of recurrent infection, CVID, or selective enced no further episodes of pneumonia and IgA deficiency. has had sinusitis only once every 2 years. No Laboratory evaluation (lower limit of secondary lymphoproliferative or rheumato- normal values in parentheses): logic conditions have developed, and comput- • IgG ≤ 6.6 mg/dL (565) ed tomography scans of the chest have been •IgG1 ≤ 9 mg/dL (450) normal.

■ REFERENCES 9. Ekdahl K, Braconier JH, Svanborg C. Immunoglobulin deficiencies and impaired immune response to polysaccharide antigens in adult patients 1. Cunningham-Rundles C. Clinical and immunologic analyses of 103 patients with recurrent community-acquired pneumonia. Scand J Infect Dis 1997; with common variable immunodeficiency. J Clin Immunol 1989; 9:22–33. 29:401–407. 2. Di Renzo M, Zhou Z, George I, Becker K, Cunningham-Rundles C. 10. Curtin JJ, Murray JG, Apthorp LA, Franz AM, Webster AD. Mediastinal Enhanced apoptosis of T cells in common variable immunodeficiency lymph node enlargement and splenomegaly in primary hypogammaglob- (CVID): role of defective CD28 co-stimulation. Clin Exp Immunol 2000; ulinemia. Clin Radiol 1995; 50:489–491. 120:503–511. 11. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: 3. Kondratenko I, Amlot PL, Webster AD, Farrant J. Lack of specific antibody clinical and immunological features of 248 patients. Clin Immunol 1999; response in common variable immunodeficiency (CVID) associated with 92:34–48. failure in production of antigen-specific memory T cells. MRC 12. Michel M, Chanet V, Galicier L, et al. Autoimmune thrombocytopenic pur- Immunodeficiency Group. Clin Exp Immunol 1997; 108:9–13. pura and common variable immunodeficiency: analysis of 21 cases and 4. Vorechovsky I, Zetterquist H, Paganelli R, et al. Family and linkage of review of the literature. Medicine (Baltimore) 2004; 83:254–263. selective IgA deficiency and common variable immunodeficiency. Clin 13. Uluhan A, Sager D, Jasin HE. Juvenile rheumatoid arthritis and common Immunol Immunopathol 1995; 77:185–192. variable hypogammaglobulinemia. J Rheumatol 1998; 25:1205–1210. 5. Schroeder HW Jr, Schroeder HW 3rd, Sheikh SM. The complex genetics of 14. Swaak AJ, van den Brink HG. Common variable immunodeficiency in a common variable immunodeficiency. J Investig Med 2004; 52:90–103. patient with systemic lupus erythematosus. Lupus 1996; 5:242–246. 6. Baumgart KW, Britton WJ, Kemp A, French M, Roberton D. The spectrum 15. Stead A, Douglas JG, Broadfoot CJ, Kaminski ER, Herriot R. Humoral of disorders in Australia. J Allergy Clin immunity and bronchiectasis. Clin Exp Immunol 2002; 130:325–330. Immunol 1997; 100:415–423. 16. Popa V, Colby TV, Reich SB. Pulmonary interstitial disease in Ig deficiency. 7. Kainulainen L, Nikoskelainen J, Ruuskanen O. Diagnostic findings in 95 Chest 2002; 122:1594–1603 Finnish patients with common variable immunodeficiency. J Clin Immunol 17. Berger M. A history of immune globulin therapy, from the Harvard crash 2001; 21:145–149. program to monoclonal antibodies. Curr Allergy Asthma Rep 2002; 8. Pettit SJ, Bourne H, Spickett GP. Survey of infection in patients receiving 2:368–378. antibody replacement treatment for immune deficiency. J Clin Pathol 18. Chapel HM, Spickett GP, Ericson D, Engl W, Eibl MM, Bjorkander J. The 2002; 55:577–580. comparison of the efficacy and safety of intravenous versus subcutaneous

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 2 FEBRUARY 2006 143 Downloaded from www.ccjm.org on September 29, 2021. For personal use only. All other uses require permission. LOW IMMUNE GLOBULINS ROSE AND LANG

immunoglobulin replacement therapy. J Clin Immunol 2000; 20:94–100. features of adult-onset generalized autoimmune gut disorder. Am J 19. Sewell WA, Buckland M, Jolles SR. Therapeutic strategies in common vari- Gastroenterol 2004; 99:1563–1571. able immunodeficiency. Drugs 2003; 63:1359–1371. 42. Fuss IJ, Strober W, Cuccherini BA, et al. Intestinal lymphangiectasia, a dis- 20. Bjoro K, Froland SS, Yun Z, Samdal HH, Haaland T. Hepatitis C infection in ease characterized by selective loss of naive CD45RA+ lymphocytes into patients with primary hypogammaglobulinemia after treatment with the gastrointestinal tract. Eur J Immunol 1998; 28:4275–4285. contaminated immune globulin. N Engl J Med 1994; 331:1607–1611. 43. Lester LA, Rothberg RM, Krantman HJ, Shermeta DW. Intestinal lym- 21. Chandra S, Cavanaugh JE, Lin CM, et al. Virus reduction in the prepara- phangiectasia and bilateral pleural effusions: effect of dietary therapy tion of intravenous immune globulin: in vitro experiments. Transfusion and surgical intervention on immunologic and pulmonary parameters. J 1999; 39:249–257. Allergy Clin Immunol 1986; 78:891–897. 22. Lemm G. Composition and properties of IVIg preparations that affect tol- 44. De Giacomo C, Maggiore G, Scotta MS, Ugazio AG. Administration of erability and therapeutic efficacy. Neurology 2002; 59(suppl 6):S28–S32. intravenous immunoglobulin in two children with hypogammaglobuline- 23. Sekul EA, Cupler EJ, Dalakas MC. Aseptic meningitis associated with high- mia due to protein losing enteropathy. Clin Exp Immunol 1985; dose intravenous immunoglobulin: frequency and risk factors. Ann Intern 60:447–448. Med 1994; 121:259–262. 45. Fikrig SM, Schiffman G, Phillipp JC, Moel DI. Antibody response to capsu- 24. Sati HI, Ahya R, Watson HG. Incidence and associations of acute renal fail- lar polysaccharide vaccine of streptococcus pneumoniae in patients with ure complicating high-dose intravenous immunoglobulin therapy. Br J nephrotic syndrome. J Infect Dis 1978; 137:818–821. Haematol 2001; 113:556–557. 46. Ogi M, Yokoyama H, Tomosugi N, et al. Risk factors for infection and 25. Cunningham-Rundles C, Zhou Z, Mankarious S, Courter S. Long-term use immunoglobulin replacement therapy in adult nephrotic syndrome. Am J of IgA-depleted intravenous immunoglobulin in immunodeficient sub- Kidney Dis 1994; 24:427–436. jects with IgA antibodies. J Clin Immunol 1993; 13:272–278. 47. Neu AM, Lederman HM, Fivush BA. Hypogammaglobulinemia and fatal 26. Johnson ML, Keeton LG, Zhu ZB, Volanakis JE, Cooper MD, Schroeder HW sepsis in an infant maintained on peritoneal dialysis. Pediatr Nephrol Jr. Age-related changes in serum immunoglobulins in patients with famil- 1993; 7:455–456. ial IgA deficiency and common variable immunodeficiency (CVID). Clin 48. Kuo MC, Hwang SJ, Chang JM, Tsai JC, Tsai JH, Lai YH. Recurrent infec- Exp Immunol 1997; 108:477–483. tions in haemodialysis patients—do not forget selective immunoglobulin 27. Mila Llambi J, Etxagibel Galdos A, Matamoros Flori N. The Spanish A deficiency. Nephrol Dial Transplant 1998; 13:3220–3222. Registry of Primary (REDIP) [in Spanish]. Allergol 49. Aittoniemi J, Miettinen A, Laine S, et al. Opsonising immunoglobulins Immunopathol (Madr) 2001; 29:122–125. and mannan-binding lectin in chronic lymphocytic leukemia. Leuk 28. Kanoh T, Mizumoto T, Yasuda N, et al. Selective IgA deficiency in Japanese Lymphoma 1999; 34:381–385. blood donors: frequency and statistical analysis. Vox Sang 1986; 50:81–86 50. Castellano G, Moreno D, Galvao O, et al. Malignant lymphoma of 29. Weber-Mzell D, Kotanko P, Hauer AC, et al. Gender, age and seasonal jejunum with common variable hypogammaglobulinemia and diffuse effects on IgA deficiency: a study of 7293 Caucasians. Eur J Clin Invest nodular hyperplasia of the small intestine. A case study and literature 2004; 34:224–228. review. J Clin Gastroenterol 1992; 15:128–135. 30. Curzio M, Bernasconi G, Gullotta R, Ceriani A, Sala G. Association of ulcer- 51. Perri RT, Oken MM, Kay NE. Enhanced suppression is directed ative colitis, sclerosing cholangitis and cholangiocarcinoma in a patient toward sensitive circulating B cells in multiple myeloma. J Lab Clin Med with IgA deficiency. Endoscopy 1985; 17:123–125 1982; 99:512–519. 31. Hermaszewski RA, Ratnavel RC, Denman DJ, Denman AM, Webster AD. 52. Tsiodras S, Samonis G, Keating MJ, Kontoyiannis DP. Infection and immu- Immunodeficiency and lymphoproliferative disorders. Baillieres Clin nity in chronic lymphocytic leukemia. Mayo Clin Proc 2000; 75:1039–1054. Rheumatol 1991; 5:277–300. 53. Moreno-Ancillo A, Cosmes Martin PM, Dominquez-Noche C, et al. 32. French MA, Denis KA, Dawkins R, Peter JB. Severity of infections in IgA Carbamazepine induced transient monoclonal gammopathy and immun- deficiency: correlation with decreased serum antibodies to pneumococcal odeficiency. Allergol Immunopathol (Madr) 2004; 32:86–88. 54. Boyum A, Wiik P, Gustavsson E, et al. The effect of strenuous exercise, polysaccharides and decreased serum IgG2 and/or IgG4. Clin Exp Immunol calorie deficiency and sleep deprivation on white blood cells, plasma 1995; 100:47–53. immunoglobulins and cytokines. Scand J Immunol 1996; 43:228–235. 33. Gross S, Blaiss MS, Herrod HG. Role of immunoglobulin subclass and spe- 55. Stiehm ER. Human intravenous immunoglobulin in primary and sec- cific antibody determinations in the evaluation of recurrent infection in ondary antibody deficiencies. Pediatr Infect Dis J 1997; 16:696–707. children. J Pediatr 1992; 121:516–522. 56. Farr M, Tunn E, Bacon PA, Smith DH. Hypogammaglobulinaemia and 34. Ekdahl K, Braconier JH, Svanborg C. Immunoglobulin deficiencies and thrombocytopenia associated with sulphasalazine therapy in rheumatoid impaired immune response to polysaccharide antigens in adult patients arthritis. Ann Rheum Dis 1985; 44:723–724. with recurrent community-acquired pneumonia. Scand J Infect Dis 1997; 57. Snowden N, Dietch DM, Teh LS, Hilton RC, Haeney MR. Antibody defi- 29:401–407. ciency associated with gold treatment: natural history and management 35. Alper CA, Xu J, Cosmopoulos K, et al. Immunoglobulin deficiencies and in 22 patients. Ann Rheum Dis 1996; 55:616–621. susceptibility to infection among homozygotes and heterozygotes for C2 58. Hamilos DL, Young RM, Peter JB, Agopian MS, Ikle DN, Barka N. deficiency. J Clin Immunol 2003; 23:297–305. Hypogammaglobulinemia in asthmatic patients. Ann Allergy 1992; 36. Soderstrom T, Soderstrom R, Enskog A. Immunoglobulin subclasses and 68:472–481. prophylactic use of immunoglobulin in immunoglobulin G subclass defi- 59. Travin M, Macris NT, Block JM, Schwimmer D. Reversible common vari- ciency. Cancer 1991; 68(6 suppl):1426-1429. able immunodeficiency syndrome induced by phenytoin. Arch Intern Med 37. Follin P, Ulanova M, Hahn-Zoric M, Hanson LA. Invasive Haemophilus 1989; 149:1421–1422. influenza type b (Hib) infection in an adult patient with a selective defi- 60. Braconier JH. Reversible total IgA deficiency associated with phenytoin ciency of antibody to the Hib capsular polysaccharide. Clin Infect Dis 1997; treatment. Scand J Infect Dis 1999; 31:515–516. 25:915–917. 61. Yesilova Z, Ozata M, Kocar IH, et al. The effects of gonadotropin treat- 38. Sorensen RU, Leiva LE, Javier FC 3rd, et al. Influence of age on the ment on the immunological features of male patients with idiopathic response to Streptococcus pneumoniae vaccine in patients with recurrent hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2000; infections and normal immunoglobulin concentrations. J Allergy Clin 85:66–70. Immunol 1998; 102:215–221. 62. Reid VL, Gleeson M, Williams N, Clancy RL. Clinical investigation of ath- 39. Go ES, Ballas ZK. Anti-pneumococcal antibody response in normal sub- letes with persistent fatigue and/or recurrent infections. Br J Sports Med jects: a meta-analysis. J Allergy Clin Immunol 1996; 98:205–215. 2004; 38:42–45. 40. Zora JA, Silk HJ, Tinkelman DG. Evaluation of postimmunization pneumo- coccal titers in children with recurrent infections and normal levels of ADDRESS: David M. Lang, MD, Department of Allergy and Immunology, immunoglobulin. Ann Allergy 1993; 70:283–288. C22, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 41. Leon F, Olivencia P, Rodriquez-Pena R, et al. Clinical and immunological 44195.

144 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 2 FEBRUARY 2006 Downloaded from www.ccjm.org on September 29, 2021. For personal use only. All other uses require permission.