Ann Allergy Asthma Immunol 111 (2013) S6eS9
Contents lists available at ScienceDirect
Managing comorbid complications in patients with common variable immunodeficiency Mark Ballow, MD Division of Allergy and Immunology, Women & Children’s Hospital of Buffalo and SUNY Buffalo, School of Medicine, Buffalo, New York; Division of Allergy and Immunology, Department of Pediatrics, University of South Florida, Children’s Research Institute, St. Petersburg, Florida
A R T I C L E
I N F O
Article history: Received for publication April 12, 2013. Received in revised form June 25, 2013. Accepted for publication June 28, 2013.
A B S T R A C T
Objective: To review the literature related to the identification and treatment of secondary complications associated with common variable immunodeficiency (CVID). Data Sources: The databases of PubMed and Ovid MEDLINE were searched for articles pertaining to comorbid conditions occurring in patients with CVID and effective treatment for or management of those conditions. Study Selections: Articles were selected based on their relevance to the focus of this review, with an emphasis on clinical phenotypes and biomarkers that can help identify patients with CVID and a secondary complication and issues related to their clinical management. Results: Noninfective complications have generated a better understanding of the pathogenesis and treatment of CVID by helping to define clinical and immunologic phenotypes of this disease. These clinical phenotypes have been correlated with different survival risks. Conclusion: Emerging and ongoing research on clinical phenotypes and biomarkers of CVID may help identify and better target treatment for patients with CVID who will develop secondary complications. It is hoped that through this improved knowledge of outcomes, more appropriate treatment for patients can be targeted. Ó 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Introduction Common variable immunodeficiency (CVID) is a heterogeneous disease that is a B-cell immune deficiency. Next to selective IgA deficiency, it is one of the most common humoral immune deficiencies. CVID is variable in age of presentation, of symptoms, and affected organ systems. Although replacement IgG therapy has changed the occurrence of severe infections in these patients,1 the development of comorbid medical diseases continues to present a challenge to the clinician. This article will discuss some of these comorbid conditions associated with CVID. Clinical Description of CVID Common variable immunodeficiency is the most common B-cell immune deficiency, affecting 1 in 25,000 to 1 in 50,000 people.2 Recurrent sinopulmonary tract infections are the most common clinical presentation. People with CVID have low serum IgG, IgA, and IgM, with at least 2 immunoglobulin isotypes that are more than Reprints: Mark Ballow, MD, Division of Allergy and Immunology, Department of Pediatrics, Women & Children’s Hospital of Buffalo, 219 Bryant Street, Buffalo, NY 14222; E-mail: [email protected]. Disclosures: Dr Ballow is a consultant and a speaker for CSL Behring, Baxter, and Grifols and has participated in review activities for Green Cross and Kedrion. Funding Sources: Support for this supplement was provided by an educational grant from Baxter Healthcare Corporation.
2 standard deviations below normal for age and have poor or absent specific antibody production. Diagnosis is usually made after 4 years of age to exclude other deficiencies that may occur before 4 years of age but typically resolve, such as transient delayed hypogammaglobulinemia of infancy. However, data show that accurate diagnosis of CVID is often delayed up to 4 to 5 years.2 Among the many primary immunodeficiency diseases, CVID is the most common, requiring intravenous immunoglobulin (IVIG) therapy. Genetically, 50% of patients with CIVD share a common HLA haplotype.3e5 In families of patients with CVID, there is an increased prevalence of CVID and IgA deficiency.2e5 CVID is an immunologically heterogeneous disorder, with approximately only 15% of genetic abnormalities associated with it currently identified.6 In addition to the main clinical finding of recurrent sinopulmonary tract infections in most patients (73%) with CVID, other clinical findings include recurrent gastrointestinal (GI) symptoms and chronic GI infections, lymphoproliferative disorder, autoimmune diseases, and, in a subgroup of patients, defects in T-cell function and an increased incidence of lymphoma and gastric cancer. Data show that only about 26% of patients with CVID will present with only infections,7 and that many patients present with these other various medical complications. Up to 20% to 30% of patients also will present with an autoimmune disease. Up to 50% have GI problems. About 15% will present with granulomatous disease, and about 15% will develop malignancy.7e9 Figure 1 shows the broad range of
1081-1206/13/$36.00 - see front matter Ó 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.anai.2013.06.032
M. Ballow / Ann Allergy Asthma Immunol 111 (2013) S6eS9
complications found in patients with CVID, with some of the most frequent being bronchiectasis, splenomegaly, iron deficiency, and lymphadenopathy. Optimal treatment for patients with CVID requires monitoring and managing these many potential medical complications when present. The need for addressing CVID and its secondary complications is highlighted by data that consistently show a poorer survival rate in patients with CVID and secondary complications compared with those without complications.7 The following is a more in-depth examination of some of the most common complications and issues related to their clinical management. Gastrointestinal Complications Cunningham-Rundles and Bodian2 reported that 21% of their 248 patients with CVID had GI disease, often presenting with chronic diarrhea and malabsorption. Of these,12% had liver disease caused by biliary cirrhosis, autoimmune hepatitis, or nodular regenerative hyperplasia. In many patients, GI problems stem from an overgrowth of pathogens in the small bowel with Giardia lamblia or other parasites or a variety of bacterial overgrowth including Yersinia species, Campylobacter species, Clostridium difficile, or Salmonella species.8 In addition, these patients are susceptible to chronic viral enterovirus and cytomegalovirus infections and autoimmune GI problems such as celiac disease and inflammatory bowel disease.10 To ensure that these potential GI complications are identified and properly managed, it is important that stool cultures be done, and that they include testing for lactose intolerance and bacteria, with specific attention given to Yersinia and Campylobacter species. Liver function tests also are recommended, as is GI imaging, performed by a gastroenterologist, that may include computed tomography, endoscopy, and biopsies to rule out inflammatory bowel disease or a lymphoproliferative process that may lead to malignancy.10 One simple measure that can be done to decrease the risk of 1 bacterium, G lamblia, is to counsel patients not to swim in lakes, particularly those who live in rural areas. Patients diagnosed with a GI problem should be offered nutritional support.8 These GI manifestations in CVID for the most part do not respond to therapy with IVIG.11 However, IVIG therapy may help eradicate certain GI infections. Several reports have suggested that IVIG may
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help control C difficile colitis.12 In addition, symptoms caused by giardiasis may improve with IVIG treatment.13 Pulmonary Complications Patients with CVID also may have some pulmonary complications. Bronchitis or bronchiectasis is a well-recognized complication, and fortunately the incidence of this complication is lower than in the past, because patients are coming into the clinic sooner and receiving appropriate treatment with IVIG. A 5-year multicenter prospective study by Quinti et al14 reported a decrease in pneumonia, from 39.4% to 22.3%, in patients with CVID after starting IVIG therapy. Those patients with a persistent trough level below 400 mg/dL were at risk for pneumonia on IVIG therapy. In patients with lower IgM and IgA levels at diagnosis, the presence of bronchiectasis was a major comorbidity risk factor for pneumonia. In a long-term study of more than 22 years, Lucas et al15 analyzed the infection outcome and doses of replacement IVIG therapy in patients with CVID receiving immunoglobulin and found that patients with bronchiectasis required higher IVIG doses. They concluded that optimal doses of IVIG need to be individualized for patients depending on underlying bronchiectasis and for particular clinical phenotypes. Bonagura et al16 also emphasized that the aim of replacement therapy is to improve clinical outcome and not “target” a particular IgG trough level. A meta-analysis by Orange et al1 reported that the incidence of pneumonia decreased as IgG trough levels increased from 500 up to 1,000 mg/dL, decreasing the incidence of pneumonia by 5-fold.1 Another pulmonary complication is granulomatous lung disease that affects 8% to 12% of patients with CVID.17 This complication may be diagnosed years before the hypoglobulinemia and is often misdiagnosed as sarcoidosis. These granulomas and lymphoproliferative processes can occur anywhere in the body, but about 54% occur in the lung, 43% in the lymph nodes and spleen, and 32% in the liver. Autoimmune diseases are commonly associated with this granulomatous process, occurring in 54% of patients; the most common are autoimmune thrombocytopenia and hemolytic anemia, and patients who have these diseases have low memory B cells.17e19 Other pulmonary processes that may develop and must be followed closely are lymphoid interstitial pneumonia, which may become lymphoma, and granulomatous-lymphocytic interstitial
Figure 1. Complications associated with common variable immunodeficiency. CLL, chronic lymphocytic leukemia; LIP, lymphoid interstitial pneumonia. Adapted from Chapel and Cunningham-Rundles.7
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M. Ballow / Ann Allergy Asthma Immunol 111 (2013) S6eS9
lung disease (GLILD).20 Some evidence, yet to be confirmed, suggests that human herpes virus 8 may be an underlying etiology of GLILD.21 Whatever the etiology, patients with GLILD have a poorer prognosis.22 They tend to have T-cell deficiency as measured by degenerative responses, and they develop malignancy, such as B-cell lymphoproliferative disease, that can be difficult to diagnose.21,22 Management of patients with CVID and pulmonary complications includes obtaining a baseline high-resolution chest computed tomogram, followed by regular chest x-ray examination (ie, at 5-year intervals) and spirometry on a yearly basis.8 Patients with bronchiectasis should have sputum cultures and sensitivities and spirometry with diffusion capacity, particularly if they have a granulomatous process in which the spirometry with diffusion capacity will be abnormal.8 These patients may need to have a biopsy examination with flow cytometry to look for clonality for malignancy. Adequate IVIG or subcutaneous immunoglobulin replacement therapy is the primary treatment for patients with bronchiectasis,15,23 and typically these patients also are treated with prophylactic antibiotics and pulmonary toilet. Boursiquot et al24 recently reviewed their experience of granulomatous disease in patients with CVID. Of 436 subjects, 13.5% were diagnosed with granulomatous disease; 42% of these patients did not require treatment. High-dose steroids (30 to 60 mg/ d) were used in most patients, but other modalities also were used in patients not responding well to steroids, eg, tumor necrosis factor blockers, hydroxychloroquine, methotrexate, and cyclosporine.25,26 Chase et al27 reported their approach to the treatment of GLILD in patients with CVID using combination chemotherapy of rituximab and azathioprine or mycophenolate mofetil. Autoimmune Disease Complications Autoimmune diseases occur in about 20% to 30% of patients with CVID, of which the most common are immune thrombocytopenic purpura and autoimmune hemolytic anemia.8,28 These patients are likely to have decreased switched memory B cells in periphery blood.29,30 Interestingly, IVIG replacement therapy may have a protective effect on the development of autoimmune hematologic disease, based on findings that patients had more episodes of recurrent immune thrombocytopenic purpura and/or autoimmune hemolytic anemia before starting IgG replacement therapy compared with after starting treatment.28 For persistent autoimmune disease, baseline IVIG treatment can be supplemented with a higher dose of immunoglobulin (1 g/kg body weight) once a week for a short time. Other treatments include steroids and, more recently, rituximab in standard doses. A large multicenter study by the European Society of Immunodeficiency of 45 patients with CVID concluded that the outcome of splenectomy does not worsen mortality.31 Other autoimmune diseases that may be present in patients with CVID include rheumatologic and endocrine autoimmune processes and pernicious anemia. In the study by Lucas et al,15 patients with disease-related complications (eg, cytopenias, enteropathy, lymphoid interstitial pneumonitis) received significantly higher doses of IVIG replacement therapy to keep them free of infection. Other patients may have liver disease caused by autoimmune hepatitis or nodular regenerative hyperplasia and should be tested with a liver function test.8,28 Lymphoid Hyperplasia, Splenomegaly, and Cancer Lymphoproliferative processes occur in about 20% of patients with hyperplasia of the lymph nodes and splenomegaly. Lymphoid infiltrates also can occur in other organs such as the kidneys and liver. Biopsies of the lymph nodes may show reactive lymphoid hyperplasia or a granulomatous change. The splenomegaly can be very extensive to cause secondary cytopenia. In a patient cohort followed by Cunningham-Rundles,2,8 approximately 7% of patients developed a lymphoma. These lymphomas are usually extranodal
B-cell type but Epstein-Barr virusenegative, are most commonly diagnosed in the fourth to seventh decade of life, and occur predominantly in women. To rule out lymphoma, patients with granulomatous-lymphoproliferative disease should undergo biopsies and flow cytometry for tumor markers and clonality by molecular analysis.32 Gastric cancers also are found in patients with CVID, although currently these cancers are not diagnosed as often as they were in the past, possibly because of an earlier detection of Helicobacter pylori that has been linked to gastric cancer.33,34 Clinical Phenotypes and Biomarkers Emerging and ongoing research is showing that clinical phenotypes and biomarkers can help identify patients with CVID with one of these secondary complications.6 In addition to poor T-cell function and decreased switched memory B cells,29,30 other clinical phenotypes and biomarkers that may indicate a secondary complication include decreased regulatory T cells,35 very low CD21þ cells,36 high serum levels of B-cell activating factor belonging to the tumor necrosis factor family37 and a proliferation-inducing ligand, and genetic markers.6 Future study of clinical phenotype presentations and biomarkers will help determine their utility in the early identification and potential targeted treatment of these secondary complications in patients with CVID.38 Currently, the United States Immunodeficiency Network (USIDNET) has a comprehensive database for the advancement of collaborative research for primary immunodeficiency diseases. Physicians with patients with CVID and secondary complications are encouraged to register their patients to help with this future line of study. More information on the registry can be found at http://www.usidnet.org/. Conclusion Patients with primary immune deficiency require lifelong IgG therapy to prevent infection. For patients with CVID, the most common type of primary immune deficiency, lifelong treatment also includes adequate diagnosis and management, with appropriate treatments of some secondary complications that may accompany CVID. The need to monitor patients for these complications and treat them when present is highlighted by the poorer prognosis of patients with CVID and secondary complications vs those without. Emerging and ongoing research on clinical phenotypes and biomarkers of CVID may help identify and better target treatment for patients with CVID who will develop secondary complications.
Acknowledgments The author thanks the IME Group for providing editorial support.
References [1] Orange JS, Grossman WJ, Navickis RJ, Wilkes MM. Impact of trough IgG on pneumonia incidence in primary immunodeficiency: a meta-analysis of clinical studies. Clin Immunol. 2010;137:21e30. [2] Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92: 34e48. [3] Volanakis JE, Zhu ZB, Schaffer FM, et al. Major histocompatibility complex class III genes and susceptibility to immunoglobulin A deficiency and common variable immunodeficiency. J Clin Invest. 1992;89:1914e1922. [4] Vorechovsky I, Zetterquist H, Paganelli R, et al. Family and linkage study of selective IgA deficiency and common variable immunodeficiency. Clin Immunol Immunopathol. 1995;77:185e192. [5] Kralovicova J, Hammarström L, Plebani A, Webster AD, Vorechovsky I. Fine-scale mapping at IGAD1 and genome-wide genetic linkage analysis implicate HLA-DQ/DR as a major susceptibility locus in selective IgA deficiency and common variable immunodeficiency. J Immunol. 2003;170: 2765e2775.
M. Ballow / Ann Allergy Asthma Immunol 111 (2013) S6eS9 [6] Yong PF, Thaventhiran JE, Grimbacher B. “A rose is a rose is a rose, ” but CVID is not CVID common variable immune deficiency (CVID), what do we know in 2011? Adv Immunol. 2011;111:47e107. [7] Chapel H, Cunningham-Rundles C. Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions. Br J Haematol. 2009;145:709e727. [8] Cunningham-Rundles C. How I treat common variable immune deficiency. Blood. 2010;116:7e15. [9] Park MA, Li JT, Hagan JB, Maddox DE, Abraham RS. Common variable immunodeficiency: a new look at an old disease. Lancet. 2008;372:489e502. [10] Agarwal S, Mayer L. Pathogenesis and treatment of gastrointestinal disease in antibody deficiency syndromes. J Allergy Clin Immunol. 2009;124: 658e664. [11] Washington K, Stenzel TT, Buckley RH, Gottfried MR. Gastrointestinal pathology in patients with common variable immunodeficiency and X-linked agammaglobulinemia. Am J Surg Pathol. 1996;20:1240e1252. [12] Leung DY, Kelly CP, Boguniewicz M, Pouthoulakis C, LaMonte JT, Flores A. Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile toxin. J Pediatr. 1991;118: 633e637. [13] McEldowney SJ, Moss MH. An uncommon presentation of chronic diarrhea and common variable immunodeficiency improved with IVIG therapy. J Allergy Clin Immunol. 2006;117(suppl):S174. [14] Quinti I, Soresina A, Guerra A, et al. Effectiveness of immunoglobulin replacement therapy on clinical outcome in patients with primary antibody deficiencies: results from a multicenter prospective cohort study. J Clin Immunol. 2011;31:315e322. [15] Lucas M, Lee M, Lortan J, Lopez-Granados E, Misbah S, Chapel H. Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin therapy over 22 years. J Allergy Clin Immunol. 2010;125:1354e1360. [16] Bonagura VR, Marchlewski R, Cox A, Rosenthal DW. Biological IgG level in primary immunodeficiency disease: the IgG level that protects against recurrent infection. J Allergy Clin Immunol. 2008;122:210e211. [17] Ardeniz O, Cunningham-Rundles C. Granulomatous disease in common variable immunodeficiency. Clin Immunol. 2009;133:198e207. [18] Chapel H, Lucas M, Lee M, et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. 2008;112: 277e286. [19] Mechanic LJ, Dikman S, Cunningham-Rundles C. Granulomatous disease in common variable immunodeficiency. Ann Intern Med. 1997;127: 613e617. [20] Park JH, Levinson AI. Granulomatous-lymphocytic interstitial lung disease (GLILD) in common variable immunodeficiency (CVID). Clin Immunol. 2010; 134:97e103. [21] Wheat WH, Cool CD, Morimoto Y, et al. Possible role of human herpesvirus 8 in the lymphoproliferative disorders in common variable immunodeficiency. J Exp Med. 2005;202:479e484. [22] Bated CA, Ellison MC, Lynch DA. Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin Immunol. 2004;114:415e421.
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[23] de Gracia J, Vendrell M, Alvarez A, et al. Immunoglobulin therapy to control lung damage in patients with common variable immunodeficiency. Int Immunopharmacol. 2004;4:745e753. [24] Boursiquot JN, Gérard L, Malphettes M, et al. Granulomatous disease in CVID: retrospective analysis of clinical characteristics and treatment efficacy in a cohort of 59 patients. J Clin Immunol. 2013;33:84e95. [25] Hatab AZ, Ballas ZK. Caseating granulomatous disease in common variable immunodeficiency treated with infliximab. J Allergy Clin Immunol. 2005;116: 1161e1162. [26] Jin JH, Liebhaber M, Roberts RL. Etanercept treatment of cutaneous granulomas in common variable immunodeficiency. J Allergy Clin Immunol. 2006; 117:878e882. [27] Chase NM, Verbsky JW, Hintermeyer MK, et al. Use of combination chemotherapy for treatment of granulomatous and lymphocytic interstitial lung disease (GLILD) in patients with common variable immunodeficiency (CVID). J Clin Immunol. 2013;33:30e39. [28] Wang J, Cunningham-Rundles C. Treatment and outcome of autoimmune hematologic disease in common variable immunodeficiency (CVID). J Autoimmun. 2005;25:57e62. [29] Warnatz K, Denz A, Dräger R, et al. Severe deficiency of switched memory B cells (CD27(þ)IgM()IgD()) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease. Blood. 2002;99:1544e1551. [30] Wehr C, Kivioja T, Schmitt C, et al. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood. 2008;111:77e85. [31] Wong GK, Goldacker S, Winterhalter C, et al. Outcomes of splenectomy in patients with common variable immunodeficiency (CVID): a survey of 45 patients. Clin Exp Immunol. 2013;172:63e72. [32] Cunningham-Rundles C, Cooper DL, Duffy TP, Strauchen J. Lymphomas of mucosal-associated lymphoid tissue in common variable immunodeficiency. Am J Hematol. 2002;69:171e178. [33] Mellemkjaer L, Hammarstrom L, Andersen V, et al. Cancer risk among patients with IgA deficiency or common variable immunodeficiency and their relatives: a combined Danish and Swedish study. Clin Exp Immunol. 2002;130: 495e500. [34] Malphettes M, Gerard L, Carmagnat M. Late-onset combined immune deficiency: a subset of common variable immunodeficiency with severe T cell defect. Clin Infect Dis. 2009;49:1329e1338. [35] Genre J, Errante PR, Kokron CM, Toledo-Barros M, Câmara NO, Rizzo LV. Reduced frequency of CD4(þ)CD25(HIGH)FOXP3(þ) cells and diminished FOXP3 expression in patients with common variable immunodeficiency: a link to autoimmunity? Clin Immunol. 2009;132:215e221. [36] Mouillot G, Carmagnat M, Gérard L, et al. B-cell and T-cell phenotypes in CVID patients correlate with the clinical phenotype of the disease. J Clin Immunol. 2010;30:746e755. [37] Knight AK, Radigan L, Marron T, Langs A, Zhang L, Cunningham-Rundles C. High serum levels of BAFF, APRIL, and TACI in common variable immunodeficiency. Clin Immunol. 2007;124:182e189. [38] Ko J, Radigan L, Cunningham-Rundles C. Immune competence and switched memory B cells in common variable immunodeficiency. Clin Immunol. 2005; 116:37e41.
Contents lists available at ScienceDirect
Managing comorbid complications in patients with common variable immunodeficiency Mark Ballow, MD Division of Allergy and Immunology, Women & Children’s Hospital of Buffalo and SUNY Buffalo, School of Medicine, Buffalo, New York; Division of Allergy and Immunology, Department of Pediatrics, University of South Florida, Children’s Research Institute, St. Petersburg, Florida
A R T I C L E
I N F O
Article history: Received for publication April 12, 2013. Received in revised form June 25, 2013. Accepted for publication June 28, 2013.
A B S T R A C T
Objective: To review the literature related to the identification and treatment of secondary complications associated with common variable immunodeficiency (CVID). Data Sources: The databases of PubMed and Ovid MEDLINE were searched for articles pertaining to comorbid conditions occurring in patients with CVID and effective treatment for or management of those conditions. Study Selections: Articles were selected based on their relevance to the focus of this review, with an emphasis on clinical phenotypes and biomarkers that can help identify patients with CVID and a secondary complication and issues related to their clinical management. Results: Noninfective complications have generated a better understanding of the pathogenesis and treatment of CVID by helping to define clinical and immunologic phenotypes of this disease. These clinical phenotypes have been correlated with different survival risks. Conclusion: Emerging and ongoing research on clinical phenotypes and biomarkers of CVID may help identify and better target treatment for patients with CVID who will develop secondary complications. It is hoped that through this improved knowledge of outcomes, more appropriate treatment for patients can be targeted. Ó 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Introduction Common variable immunodeficiency (CVID) is a heterogeneous disease that is a B-cell immune deficiency. Next to selective IgA deficiency, it is one of the most common humoral immune deficiencies. CVID is variable in age of presentation, of symptoms, and affected organ systems. Although replacement IgG therapy has changed the occurrence of severe infections in these patients,1 the development of comorbid medical diseases continues to present a challenge to the clinician. This article will discuss some of these comorbid conditions associated with CVID. Clinical Description of CVID Common variable immunodeficiency is the most common B-cell immune deficiency, affecting 1 in 25,000 to 1 in 50,000 people.2 Recurrent sinopulmonary tract infections are the most common clinical presentation. People with CVID have low serum IgG, IgA, and IgM, with at least 2 immunoglobulin isotypes that are more than Reprints: Mark Ballow, MD, Division of Allergy and Immunology, Department of Pediatrics, Women & Children’s Hospital of Buffalo, 219 Bryant Street, Buffalo, NY 14222; E-mail: [email protected]. Disclosures: Dr Ballow is a consultant and a speaker for CSL Behring, Baxter, and Grifols and has participated in review activities for Green Cross and Kedrion. Funding Sources: Support for this supplement was provided by an educational grant from Baxter Healthcare Corporation.
2 standard deviations below normal for age and have poor or absent specific antibody production. Diagnosis is usually made after 4 years of age to exclude other deficiencies that may occur before 4 years of age but typically resolve, such as transient delayed hypogammaglobulinemia of infancy. However, data show that accurate diagnosis of CVID is often delayed up to 4 to 5 years.2 Among the many primary immunodeficiency diseases, CVID is the most common, requiring intravenous immunoglobulin (IVIG) therapy. Genetically, 50% of patients with CIVD share a common HLA haplotype.3e5 In families of patients with CVID, there is an increased prevalence of CVID and IgA deficiency.2e5 CVID is an immunologically heterogeneous disorder, with approximately only 15% of genetic abnormalities associated with it currently identified.6 In addition to the main clinical finding of recurrent sinopulmonary tract infections in most patients (73%) with CVID, other clinical findings include recurrent gastrointestinal (GI) symptoms and chronic GI infections, lymphoproliferative disorder, autoimmune diseases, and, in a subgroup of patients, defects in T-cell function and an increased incidence of lymphoma and gastric cancer. Data show that only about 26% of patients with CVID will present with only infections,7 and that many patients present with these other various medical complications. Up to 20% to 30% of patients also will present with an autoimmune disease. Up to 50% have GI problems. About 15% will present with granulomatous disease, and about 15% will develop malignancy.7e9 Figure 1 shows the broad range of
1081-1206/13/$36.00 - see front matter Ó 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.anai.2013.06.032
M. Ballow / Ann Allergy Asthma Immunol 111 (2013) S6eS9
complications found in patients with CVID, with some of the most frequent being bronchiectasis, splenomegaly, iron deficiency, and lymphadenopathy. Optimal treatment for patients with CVID requires monitoring and managing these many potential medical complications when present. The need for addressing CVID and its secondary complications is highlighted by data that consistently show a poorer survival rate in patients with CVID and secondary complications compared with those without complications.7 The following is a more in-depth examination of some of the most common complications and issues related to their clinical management. Gastrointestinal Complications Cunningham-Rundles and Bodian2 reported that 21% of their 248 patients with CVID had GI disease, often presenting with chronic diarrhea and malabsorption. Of these,12% had liver disease caused by biliary cirrhosis, autoimmune hepatitis, or nodular regenerative hyperplasia. In many patients, GI problems stem from an overgrowth of pathogens in the small bowel with Giardia lamblia or other parasites or a variety of bacterial overgrowth including Yersinia species, Campylobacter species, Clostridium difficile, or Salmonella species.8 In addition, these patients are susceptible to chronic viral enterovirus and cytomegalovirus infections and autoimmune GI problems such as celiac disease and inflammatory bowel disease.10 To ensure that these potential GI complications are identified and properly managed, it is important that stool cultures be done, and that they include testing for lactose intolerance and bacteria, with specific attention given to Yersinia and Campylobacter species. Liver function tests also are recommended, as is GI imaging, performed by a gastroenterologist, that may include computed tomography, endoscopy, and biopsies to rule out inflammatory bowel disease or a lymphoproliferative process that may lead to malignancy.10 One simple measure that can be done to decrease the risk of 1 bacterium, G lamblia, is to counsel patients not to swim in lakes, particularly those who live in rural areas. Patients diagnosed with a GI problem should be offered nutritional support.8 These GI manifestations in CVID for the most part do not respond to therapy with IVIG.11 However, IVIG therapy may help eradicate certain GI infections. Several reports have suggested that IVIG may
S7
help control C difficile colitis.12 In addition, symptoms caused by giardiasis may improve with IVIG treatment.13 Pulmonary Complications Patients with CVID also may have some pulmonary complications. Bronchitis or bronchiectasis is a well-recognized complication, and fortunately the incidence of this complication is lower than in the past, because patients are coming into the clinic sooner and receiving appropriate treatment with IVIG. A 5-year multicenter prospective study by Quinti et al14 reported a decrease in pneumonia, from 39.4% to 22.3%, in patients with CVID after starting IVIG therapy. Those patients with a persistent trough level below 400 mg/dL were at risk for pneumonia on IVIG therapy. In patients with lower IgM and IgA levels at diagnosis, the presence of bronchiectasis was a major comorbidity risk factor for pneumonia. In a long-term study of more than 22 years, Lucas et al15 analyzed the infection outcome and doses of replacement IVIG therapy in patients with CVID receiving immunoglobulin and found that patients with bronchiectasis required higher IVIG doses. They concluded that optimal doses of IVIG need to be individualized for patients depending on underlying bronchiectasis and for particular clinical phenotypes. Bonagura et al16 also emphasized that the aim of replacement therapy is to improve clinical outcome and not “target” a particular IgG trough level. A meta-analysis by Orange et al1 reported that the incidence of pneumonia decreased as IgG trough levels increased from 500 up to 1,000 mg/dL, decreasing the incidence of pneumonia by 5-fold.1 Another pulmonary complication is granulomatous lung disease that affects 8% to 12% of patients with CVID.17 This complication may be diagnosed years before the hypoglobulinemia and is often misdiagnosed as sarcoidosis. These granulomas and lymphoproliferative processes can occur anywhere in the body, but about 54% occur in the lung, 43% in the lymph nodes and spleen, and 32% in the liver. Autoimmune diseases are commonly associated with this granulomatous process, occurring in 54% of patients; the most common are autoimmune thrombocytopenia and hemolytic anemia, and patients who have these diseases have low memory B cells.17e19 Other pulmonary processes that may develop and must be followed closely are lymphoid interstitial pneumonia, which may become lymphoma, and granulomatous-lymphocytic interstitial
Figure 1. Complications associated with common variable immunodeficiency. CLL, chronic lymphocytic leukemia; LIP, lymphoid interstitial pneumonia. Adapted from Chapel and Cunningham-Rundles.7
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lung disease (GLILD).20 Some evidence, yet to be confirmed, suggests that human herpes virus 8 may be an underlying etiology of GLILD.21 Whatever the etiology, patients with GLILD have a poorer prognosis.22 They tend to have T-cell deficiency as measured by degenerative responses, and they develop malignancy, such as B-cell lymphoproliferative disease, that can be difficult to diagnose.21,22 Management of patients with CVID and pulmonary complications includes obtaining a baseline high-resolution chest computed tomogram, followed by regular chest x-ray examination (ie, at 5-year intervals) and spirometry on a yearly basis.8 Patients with bronchiectasis should have sputum cultures and sensitivities and spirometry with diffusion capacity, particularly if they have a granulomatous process in which the spirometry with diffusion capacity will be abnormal.8 These patients may need to have a biopsy examination with flow cytometry to look for clonality for malignancy. Adequate IVIG or subcutaneous immunoglobulin replacement therapy is the primary treatment for patients with bronchiectasis,15,23 and typically these patients also are treated with prophylactic antibiotics and pulmonary toilet. Boursiquot et al24 recently reviewed their experience of granulomatous disease in patients with CVID. Of 436 subjects, 13.5% were diagnosed with granulomatous disease; 42% of these patients did not require treatment. High-dose steroids (30 to 60 mg/ d) were used in most patients, but other modalities also were used in patients not responding well to steroids, eg, tumor necrosis factor blockers, hydroxychloroquine, methotrexate, and cyclosporine.25,26 Chase et al27 reported their approach to the treatment of GLILD in patients with CVID using combination chemotherapy of rituximab and azathioprine or mycophenolate mofetil. Autoimmune Disease Complications Autoimmune diseases occur in about 20% to 30% of patients with CVID, of which the most common are immune thrombocytopenic purpura and autoimmune hemolytic anemia.8,28 These patients are likely to have decreased switched memory B cells in periphery blood.29,30 Interestingly, IVIG replacement therapy may have a protective effect on the development of autoimmune hematologic disease, based on findings that patients had more episodes of recurrent immune thrombocytopenic purpura and/or autoimmune hemolytic anemia before starting IgG replacement therapy compared with after starting treatment.28 For persistent autoimmune disease, baseline IVIG treatment can be supplemented with a higher dose of immunoglobulin (1 g/kg body weight) once a week for a short time. Other treatments include steroids and, more recently, rituximab in standard doses. A large multicenter study by the European Society of Immunodeficiency of 45 patients with CVID concluded that the outcome of splenectomy does not worsen mortality.31 Other autoimmune diseases that may be present in patients with CVID include rheumatologic and endocrine autoimmune processes and pernicious anemia. In the study by Lucas et al,15 patients with disease-related complications (eg, cytopenias, enteropathy, lymphoid interstitial pneumonitis) received significantly higher doses of IVIG replacement therapy to keep them free of infection. Other patients may have liver disease caused by autoimmune hepatitis or nodular regenerative hyperplasia and should be tested with a liver function test.8,28 Lymphoid Hyperplasia, Splenomegaly, and Cancer Lymphoproliferative processes occur in about 20% of patients with hyperplasia of the lymph nodes and splenomegaly. Lymphoid infiltrates also can occur in other organs such as the kidneys and liver. Biopsies of the lymph nodes may show reactive lymphoid hyperplasia or a granulomatous change. The splenomegaly can be very extensive to cause secondary cytopenia. In a patient cohort followed by Cunningham-Rundles,2,8 approximately 7% of patients developed a lymphoma. These lymphomas are usually extranodal
B-cell type but Epstein-Barr virusenegative, are most commonly diagnosed in the fourth to seventh decade of life, and occur predominantly in women. To rule out lymphoma, patients with granulomatous-lymphoproliferative disease should undergo biopsies and flow cytometry for tumor markers and clonality by molecular analysis.32 Gastric cancers also are found in patients with CVID, although currently these cancers are not diagnosed as often as they were in the past, possibly because of an earlier detection of Helicobacter pylori that has been linked to gastric cancer.33,34 Clinical Phenotypes and Biomarkers Emerging and ongoing research is showing that clinical phenotypes and biomarkers can help identify patients with CVID with one of these secondary complications.6 In addition to poor T-cell function and decreased switched memory B cells,29,30 other clinical phenotypes and biomarkers that may indicate a secondary complication include decreased regulatory T cells,35 very low CD21þ cells,36 high serum levels of B-cell activating factor belonging to the tumor necrosis factor family37 and a proliferation-inducing ligand, and genetic markers.6 Future study of clinical phenotype presentations and biomarkers will help determine their utility in the early identification and potential targeted treatment of these secondary complications in patients with CVID.38 Currently, the United States Immunodeficiency Network (USIDNET) has a comprehensive database for the advancement of collaborative research for primary immunodeficiency diseases. Physicians with patients with CVID and secondary complications are encouraged to register their patients to help with this future line of study. More information on the registry can be found at http://www.usidnet.org/. Conclusion Patients with primary immune deficiency require lifelong IgG therapy to prevent infection. For patients with CVID, the most common type of primary immune deficiency, lifelong treatment also includes adequate diagnosis and management, with appropriate treatments of some secondary complications that may accompany CVID. The need to monitor patients for these complications and treat them when present is highlighted by the poorer prognosis of patients with CVID and secondary complications vs those without. Emerging and ongoing research on clinical phenotypes and biomarkers of CVID may help identify and better target treatment for patients with CVID who will develop secondary complications.
Acknowledgments The author thanks the IME Group for providing editorial support.
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