Immunodeficiency in chronic sinusitis: Recognition and treatment Whitney W. Stevens, M.D., Ph.D.,1 and Anju T. Peters, M.D.1
Y P
ABSTRACT
Chronic rhinosinusitis (CRS) is estimated to affect over 35 million people. However, not all patients with the diagnosis respond to standard medical and surgical treatments. Although there are a variety of reasons a patient may be refractory to therapy, one possible etiology is the presence of an underlying immunodeficiency. This review will focus on the description, recognition, and treatment of several antibody deficiencies associated with CRS, including common variable immunodeficiency (CVID), selective IgA deficiency, IgG subclass deficiency, and specific antibody deficiency (SAD). The diagnosis of antibody deficiency in patients with CRS is important because of the large clinical implications it can have on sinus disease management. CVID is treated with immunoglobulin replacement, whereas SAD may be managed symptomatically and sometimes with prophylactic antibiotics and/or immunoglobulin replacement. (Am J Rhinol Allergy 29, 115–118, 2015; doi: 10.2500/ajra.2015.29.4144)
C
hronic rhinosinusitis (CRS) is a disease that affects over 35 million people and involves chronic inflammation of the sinonasal mucosa.1 Symptoms include nasal congestion, sinus pressure, and hyposmia that, by definition, persist for more than 12 weeks.2 Disruptions of the sinonasal epithelial barrier as well as dysregulation of the ensuing immunologic response are thought to be important in CRS pathogenesis.3,4 The role viral and bacterial infections might play in the development of CRS, however, is less defined, but these pathogens can exacerbate clinical symptoms. In general, the mainstay of treatment for CRS has been intranasal and systemic corticosteroids, antibiotics, and surgery.2 However, not all patients with CRS will respond to medical and surgical management, and these individuals along with those who have recurrent sinus infections warrant evaluation for other underlying diseases. Immunodeficiencies may be broadly categorized based upon defects in humoral immunity (e.g., B cells, antibodies, complement), cellular immunity (e.g., T cells, phagocytic cells), or both.5,6 In particular, antibody deficiency is the most common subtype accounting for approximately 50% of all primary immunodeficiency cases. Patients with antibody deficiencies are susceptible to bacterial pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis, and can develop recurrent upper and lower respiratory tract infections.7,8 Antibody deficiency itself is a spectrum of diseases ranging from severe to mild and characterized by different underlying immune pathologies and variable levels of antibody production and function. This review will focus on the description, recognition, and treatment of various antibody deficiencies associated with CRS in adults.
O D
T
O N
ANTIBODY DEFICIENCY DISORDERS OF ADULTS Common Variable Immunodeficiency (CVID) CVID is the most frequent symptomatic antibody deficiency. In this disease, B cells are detected, but there is a reduction in at least two of the three major antibody isotypes. Levels of IgG as well as IgA or IgM 1
Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois A. T. Peters is a consultant/advisor for Baxter. W. W. Stevens has no conflicts of interest to declare pertaining to this article Address correspondence to Anju T. Peters, M.D., Division of Allergy-Immunology, Northwestern University Feinberg School of Medicine, 676 N. St Clair Suite 14018, Chicago, IL 60611 E-mail address: [email protected] Copyright © 2015, OceanSide Publications, Inc., U.S.A.
O C
must be reduced more than two standard deviations below the mean adjusted for age. In addition, patients with CVID have impaired antibody function as evident by poor responses to both polysaccharide and protein antigen vaccines. Clinically, CVID remains a disease of exclusion, because other primary and secondary causes of hypogammaglobulinemia must first be eliminated before the diagnosis of CVID can be established. Although patients must be older than two years of age to be diagnosed with CVID, the average age of diagnosis is more frequently in third and fourth decades of life.9 In a multicenter Italian study examining 224 patients with CVID, the mean age at diagnosis was 22.6 years, whereas the mean age of symptom onset was 16.9 years.10 Similarly, in a French national study of patients with CVID, onset of symptoms occurred at a median age of 19 years, but 40% and 35% of symptoms were present before ages 15 and 5, respectively.11 Such a delay between symptom onset and disease diagnosis may be secondary to numerous factors, including the postponement of immunoglobulin analysis, until more severe symptoms develop and the initial association of clinical symptoms with a more common self-limiting illness. Recurrent infections, viz. involving the upper and lower respiratory tract, are commonly observed in CVID. In one small case series, 74% of patients with CVID reported recurrent episodes of pneumonia.12 In a larger cohort, acute bronchitis and chronic sinusitis were found in 63% and 37% of CVID patients, respectively, at the time of diagnosis.10 Infections alone, however, are not the only manifestation of CVID.13,14 Resnick et al. reported that of 473 CVID patients examined in a retrospective analysis, 68% had noninfectious complications of CVID, including chronic lung disease, autoimmunity, lymphoma, granulomatous disease, or inflammatory gastrointestinal disease.15 Chronic lung disease is the most common of these conditions with as many as 27% of CVID cases being of an obstructive (e.g., asthma), restrictive (e.g., interstitial lung disease), or bronchiectatic pattern.16 CVID is a heterogeneous disease with no known single molecular defect attributed to disease pathogenesis to date. The majority of CVID cases are sporadic, but smaller clusters of familial inheritance patterns do exist.17 In 8%–10% of patients with CVID, a mutation in the transmembrane activator and calcium modulating ligand interactor protein has been reported18 and has been associated with an increased incidence of autoimmune complications.19 However, transmembrane activator and calcium modulating ligand interactor mutations can also be observed in relatives of CVID patients who have normal immunoglobulin levels,20 suggesting that other additional factors are also contributing to disease pathogenesis. Regardless of the underlying mechanism, men and women with CVID on average have a reduced lifespan when compared with the general population.15 Additionally, those patients with noninfectious manifestations of CVID have an 11-fold higher risk of mortality than
American Journal of Rhinology & Allergy
Delivered by Ingenta to: Guest User IP: 5.101.218.29 On: Thu, 30 Jun 2016 06:50:06 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm
115
those with recurrent infections alone.15 Finally, older age at time of diagnosis as well as a longer delay between symptom onset and disease diagnosis have been associated with increased risk of death.21 Taken together, these studies highlight the importance of rapidly identifying CVID in at-risk patients, including those with recurrent sinus infections or refractory CRS.
Selective IgA Deficiency
Despite having a quantitative standard for diagnosis, the clinical significance of an IgG subclass deficiency remains controversial. Low levels of IgG subclasses have been reported in as many as 2%–20% of healthy individuals.30 Additionally, the majority of patients in one study who had deletions in the immunoglobulin heavy chain and were thus deficient in IgG1, IgG2, and/or IgG4 were also asymptomatic.31 In contrast, decreased IgG subclass levels have been reported in patients with refractory CRS.32,33 In these studies, however, such correlations have not been proven as causation. Furthermore, it has been suggested that it is the lack of a specific antibody response to polysaccharide antigens more so than a deficiency in IgG subclasses that more prominently contribute to clinical disease.30,33,34
In a patient over four years of age, an IgA level of less than 0.07 g/L in the presence of normal IgG and IgM fulfills the criteria for selective IgA deficiency. This disease is very common particularly in Western countries with a prevalence ranging from 1:173 to 1:3024.22 This prevalence may be increased among patients with refractory CRS with Chee et al. reporting that 16.7% of CRS patients studied had low IgA levels and 6.2% fulfilled criteria for specific IgA deficiency.23 However, in a separate study, IgA levels were not found to significantly correlate with the extent of sinus disease observed on sinus computed tomography imaging.24 Although the majority of patients with IgA deficiency are asymptomatic, a smaller subgroup may develop clinical manifestations of their disease. Recurrent sinopulmonary infections, giardiasis, inflammatory bowel disease, anaphylactic transfusion reactions, and autoimmune diseases such as hemolytic anemia, rheumatoid arthritis, or Grave’s disease have all been observed.8,25 Atopy is also common in patients with IgA deficiency with one study reporting as many as 51% and 49% of patients with specific IgA deficiency having asthma or atopic dermatitis, respectively.26 It is not completely understood why some patients with low IgA levels develop clinical sequela and others do not. Additionally, it remains unclear what causes the decreased production of IgA, but impaired B cell differentiation into activated plasma cells may contribute.25 IgA deficiency typically occurs sporadically within a population, but clusters of an autosomal inheritance pattern have been reported. Genetic studies in small family cohorts suggest a link between the major histocompatibility complexes human leukocyte antigen (HLA)-A1, HLA-B8, HLA-DR3, and IgA deficiency, but further investigations are needed to explore whether this association plays a broader role in disease pathogenesis.27,28 The presence of low IgA levels may not necessarily be due to a selective IgA deficiency, because evolving CVID should be also considered. Additionally, medications including phenytoin, carbamazepine, and sulfasalazine have been shown to reduce serum IgA levels.29 Unlike primary immunodeficiencies, medication-induced reductions in IgA levels may correct once the offending agent is discontinued.
O D
Based upon its heavy chain antigenic epitope, the IgG immunoglobulin can be divided into four distinct subgroups: IgG1, IgG2, IgG3, and IgG4. IgG1 is the most prevalent subclass comprising up to 70% of all total IgG, whereas IgG4 is the least common making up only 2%–6% of the total. Additionally, IgG1 levels typically reach adult concentrations earlier in childhood than the other IgG subclasses. Other differences between the subgroups include half-life in serum, ability to fix complement, and responses to various antigens. IgG1 and IgG3 are typically generated in response to protein antigens, whereas IgG2 and IgG4 are commonly induced after recognition of polysaccharide antigens. Given that IgG subclasses constitute different percentages of the whole, a deficiency in one subclass does not necessarily cause a decrease in total IgG. If, in the presence of normal total IgG levels, an individual IgG subclass is below two standard deviations of the age-adjusted mean, the diagnosis of an IgG subclass deficiency can be made. Importantly, any reduction in total IgG level below two standard deviations of the mean for age precludes a subclass deficiency, and alternative diagnoses should instead be considered.
Unlike patients with an IgG subclass deficiency, patients with SAD have normal levels of both total IgG and IgG subclasses. However, in SAD, there is a deficiency in specific IgG antibodies against polysaccharide antigens. Pneumococcal serotypes greater than 1.3 mcg/mL have been shown to prevent against infection and colonization by S. pneumoniae, and this value is typically considered as the lower limit for a protective antibody level.35 A total of 50%–70% of the pneumococcal serotypes should be at or above a protective level, and a normal response to a polysaccharide pneumococcal vaccine is a conversion of 70% of serotypes to protective levels with a minimum two-fold increase in individual specific antibody levels.35,36 Patients with SAD, however, do not mount a proper humoral immune response after immunization with an unconjugated polysaccharide pneumococcal vaccine. As a result, they continue to have the majority of specific antibody levels below protective levels that, in one study, were lower than the fifth percentile of responses seen by healthy controls.37 Interpretation of specific antibody levels to pneumococcal serotypes can be complicated. For example, the various pneumococcal serotypes do not have equal immunogenicity, with serotype 3 being a more potent immunogen than serotypes 6B and 23F.36 A deficiency in one single pneumococcal serotype has not consistently been associated with SAD to date. Also, a particular antibody level does not necessarily always correspond with disease as an asymptomatic individual, and a patient with clinical symptoms may both have the same specific antibody levels against pneumococcal serotypes. Taken together, additional investigations are warranted to better characterize the specific antibody response to polysaccharide vaccines and how these responses contribute to clinical findings observed in SAD. Clinically, patients with SAD are more susceptible to recurrent infections. In a retrospective study of 75 patients at the Mayo Clinic with SAD, the most frequent infections observed were sinusitis (77%), pneumonia (42%), and otitis (26%).38 In this study, the median age at time of diagnosis was 42 years, whereas the median interval between symptom onset and age of diagnosis was four years.38 Kashani et al. observed that patients with CRS and SAD had an increased incidence of pneumonia when compared with CRS patients without SAD.39 The presence of autoimmunity in SAD remains not clearly defined. The prevalence of SAD in the general population remains unclear. As a further confounder, not all patients with a deficiency in specific antibodies will develop clinical symptoms, and the threshold at which a SAD becomes universally clinically relevant remains unknown. Studies of pediatric patients with recurrent infections found that as many as 15%–23% had SAD.40,41 Of CRS patients undergoing sinus surgery at one tertiary care medical center, 11.6% were found to have SAD,42 whereas in another study, up to 67% of patients with refractory CRS had the disease.34 Such variation in prevalence may be due in part to the different criteria used in the studies to define SAD, but these discrepancies highlight the need for further investigations of disease prevalence.
T
O N
IgG Subclass Deficiency
116
Y P
Specific Antibody Deficiency (SAD)
O C
March–April 2015, Vol. 29, No. 2
Delivered by Ingenta to: Guest User IP: 5.101.218.29 On: Thu, 30 Jun 2016 06:50:06 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm
EVALUATION OF ANTIBODY DEFICIENCIES IN CRS Although not all patients with an antibody deficiency will have recurrent sinus infections, not all patients with recurrent sinus infections will have an underlying antibody deficiency. A retrospective analysis of 595 patients with CRS seen at a tertiary care hospital over a three-year period found 24.2% of patients studied fulfilled the diagnostic criteria for SAD, 6% for CVID, and 3% for selective IgA deficiency.43 Those CRS patients at a greater risk for having an underlying antibody deficiency include ones with recurrent sinopulmonary infections despite multiple courses of antibiotics and those who continue to have symptoms despite maximal medical and surgical therapies. The evaluation of an antibody deficiency in CRS should first include obtaining a detailed clinical history and physical exam. Attention should especially be focused on symptoms, duration, treatment, and number of recurrent sinus infections as well as if the patient had other infections such as bronchitis, pneumonia, or diarrhea. History of recurrent sinopulmonary infections in association with autoimmune diseases should also raise the suspicion of antibody deficiencies. Next, laboratory tests can be ordered to assess quantitative and functional aspects of humoral and cell-mediated immunity. To start, a complete blood count with differential, quantitative total immunoglobulins for IgA, IgM, and IgG, and specific antibody levels to polysaccharide antigen vaccines against S. pneumoniae and/or H. influenzae should be sent. Pending these initial results, additional studies may be ordered to further evaluate T and B cell numbers by flow cytometry, specific antibody responses to the protein antigen vaccines Tetanus and Diphtheria, and levels of complement. Measurements of IgG subclasses are not typically recommended as part of an initial analysis of a humoral immunodeficiency. In regards to interpretation of specific antibody levels against pneumococcal polysaccharide antigens, antibody levels are generally considered low if they are less than 1.3 mcg/mL for at least 50% of the pneumococcal serotypes measured. If specific antibody levels are low, the polysaccharide pneumococcal vaccine should be administered and, one month after immunization, specific antibody levels should be reassessed.36 An appropriate response to the immunization is considered when specific antibody levels are greater than 1.3 mcg/mL in 50%–70% of the pneumococcal serotypes or there is a four-fold increase in a more than 50% of the given specific antibody level compared with preimmunization.36 It is estimated that as many as 75% of patients who initially had low specific antibodies to polysaccharide antigens will develop a robust response after polysaccharide pneumococcal immunization and thus will not require further testing or management.39,43 However, the higher the specific antibody levels are to a given serotype, the less likely they are to increase after vaccination.36
O D
Y P
T
O N
TREATMENT OF ANTIBODY DEFICIENCIES IN CRS It is important to recognize antibody deficiencies in patients with refractory CRS as this diagnosis can impact overall disease management. Treatment options for CRS patients with antibody deficiencies should be individualized and may include the use of prophylactic antibiotics as well as vaccination with a conjugated pneumococcal antigen vaccine. Immunoglobulin replacement is another option but is usually reserved for patients who fail to respond to vaccinations and have persistent infections. The underlying CRS should also continue to be managed by medical therapy (e.g., intranasal and systemic corticosteroids, early initiation of antibiotics tailored to nasal culture growth) and, when indicated, surgical intervention. Depending on the clinical scenario, referral to an allergist/immunologist may be recommended. In patients with CVID, immunoglobulin replacement has been shown to reduce the number of sinopulmonary infections as well as
acute hospitalizations.44,45 However, a European study reported that only 8% of CVID patients with chronic sinusitis had improvement in their CRS while receiving intravenous immunoglobulin (IVIG).10 This study also saw an increase in the percentage of CVID patients diagnosed with CRS (36%–54%) over a five-year period despite immunoglobulin replacement.10 As with all therapies, the risks and benefits of IVIG should be considered for each patient before initiation. IVIGs are typically administered at a starting dose of 400 mg/kg every three to four weeks, with this dose adjusted accordingly to achieve a trough IgG level greater than 500 mg/L.46 A higher IgG trough of 800 mg/L may also be used, because this level has been suggested to improve pulmonary outcomes.46 Subcutaneous immunoglobulin replacement can also be administered depending on patient preference. However, administration would occur weekly, and measured IgG levels would more closely represent steady state and not trough values. Importantly, the patient’s clinical symptoms and rate of infections should ultimately drive decisions regarding the dose and timing of immunoglobulin replacement therapy.47,48 Unfortunately, immunoglobulin replacement therapy has not been as effective in the management of noninfections complications of CVID (i.e., autoimmunity, chronic lung disease, malignancy). Furthermore, IgG replacement is not indicated in patients with a sole selective IgA deficiency or IgG subclass deficiency unless they have a poor functional response to a pneumococcal polysaccharide vaccine and have recurrent infections.46 Patients with low IgG and low IgA have a small risk of anaphylaxis upon IgG replacement if they have antibodies against IgA. In such circumstances, an IVIG formulation containing low levels of IgA may be used and is commercially available. The use of immunoglobulin replacement in patients with SAD remains controversial. Decreased specific antibodies alone should not be the predominant indication for initiation of therapy but rather clinical symptoms and recurrence of infections should be key determinants. In two retrospective case studies, 18%–40% of evaluated SAD patients received immunoglobulin replacement.38,39 In these reports, patients with SAD who had a history of pneumonia were most likely to undergo replacement therapy,39 and in a separate study, once initiated, there was significant decrease in subsequent infections observed.38 Unlike in CVID, SAD patients receiving IVIG do not have a defined treatment goal for total IgG level, because by definition, they have normal levels of total IgG before initiation of therapy.
O C
CONCLUSIONS In summary, humoral immunodeficiencies should be considered in patients with CRS refractory to standard medical and surgical management. Assessment with detailed clinical histories and immunologic laboratory studies may reveal the presence of CVID, selective IgA deficiency, IgG subclass deficiency, or possibly SAD. The initiation of specialized treatments, including immunoglobulin replacement, should be individualized taking in account both the clinical symptoms and laboratory findings of each patient.
REFERENCES 1. 2.
3. 4.
5.
6.
Hamilos DL. Chronic rhinosinusitis: Epidemiology and medical management. J Allergy Clin Immunol 128:693–707; quiz 708–709, 2011. Fokkens WJ, Lund VJ, Mullol J, et al. European position paper on rhinosinusitis and nasal polyps 2012. Rhinol Suppl 3 p preceding table of contents, 1–298, 2012. Stevens WW, Schleimer RP, Chandra RK, and Peters AT. Biology of nasal polyposis. J Allergy Clin Immunol 133:1503, 2014. Schleimer RP, Kato A, Peters A, et al. Epithelium, inflammation, and immunity in the upper airways of humans: Studies in chronic rhinosinusitis. Proc Am Thorac Soc 6:288–294, 2009. Al-Herz W, Bousfiha A, Casanova JL, et al. Primary immunodeficiency diseases: An update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol 2:54, 2011. Uzzaman A, and Fuleihan RL. Chapter 27: Approach to primary immunodeficiency. Allergy Asthma Proc 33(suppl. 1):S91–S95, 2012.
American Journal of Rhinology & Allergy
Delivered by Ingenta to: Guest User IP: 5.101.218.29 On: Thu, 30 Jun 2016 06:50:06 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm
117
7.
8. 9.
10.
11.
12.
13.
14. 15.
16.
17.
18.
19.
20.
21.
22. 23.
24.
25. 26.
27.
28. 29.
118
Picard C, Puel A, Bustamante J, et al. Primary immunodeficiencies associated with pneumococcal disease. Curr Opin Allergy Clin Immunol 3:451–459, 2003. Ballow M. Primary immunodeficiency disorders: Antibody deficiency. J Allergy Clin Immunol 109:581–591, 2002. Cunningham-Rundles C. Clinical and immunologic analyses of 103 patients with common variable immunodeficiency. J Clin Immunol 9:22–33, 1989. Quinti I, Soresina A, Spadaro G, et al. Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency. J Clin Immunol 27:308–316, 2007. Oksenhendler E, Ge´rard L, Fieschi C, et al. Infections in 252 patients with common variable immunodeficiency. Clin Infect Dis 46:1547– 1554, 2008. Martínez García MA, de Rojas MD, Nauffal Manzur MD, et al. Respiratory disorders in common variable immunodeficiency. Respir Med 95:191–195, 2001. Agarwal S, and Cunningham-Rundles C. Autoimmunity in common variable immunodeficiency. Curr Allergy Asthma Rep 9:347–352, 2009. Podjasek JC, and Abraham RS. Autoimmune cytopenias in common variable immunodeficiency. Front Immunol 3:189, 2012. Resnick ES, Moshier EL, Godbold JH, and Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood 119:1650–1657, 2012. Busse PJ, Farzan S, and Cunningham-Rundles C. Pulmonary complications of common variable immunodeficiency. Ann Allergy Asthma Immunol 98:1–8; quiz 8–11, 43, 2007. Resnick ES, and Cunningham-Rundles C. The many faces of the clinical picture of common variable immune deficiency. Curr Opin Allergy Clin Immunol 12:595–601, 2012. Salzer U, Chapel HM, Webster AD, et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet 37:820–828, 2005. Zhang L, Radigan L, Salzer U, et al. Transmembrane activator and calcium-modulating cyclophilin ligand interactor mutations in common variable immunodeficiency: Clinical and immunologic outcomes in heterozygotes. J Allergy Clin Immunol 120:1178–1185, 2007. Martinez-Gallo M, Radigan L, Almeju´n MB, et al. TACI mutations and impaired B-cell function in subjects with CVID and healthy heterozygotes. J Allergy Clin Immunol 131:468–476, 2013. Gathmann B, Mahlaoui N, Gerard L, et al. Clinical picture and treatment of 2212 patients with common variable immunodeficiency. J Allergy Clin Immunol 134:116–126, 2014. Singh K, Chang C, and Gershwin ME. IgA deficiency and autoimmunity. Autoimmun Rev 13:163–177, 2014. Chee L, Graham SM, Carothers DG, and Ballas ZK. Immune dysfunction in refractory sinusitis in a tertiary care setting. Laryngoscope 111:233–235, 2001. Hoover GE, Newman LJ, Platts-Mills TA, et al. Chronic sinusitis: Risk factors for extensive disease. J Allergy Clin Immunol 100:185–191, 1997. Cunningham-Rundles C. Physiology of IgA and IgA deficiency. J Clin Immunol 21:303–309, 2001. Aghamohammadi A, Cheraghi T, Gharagozlou M, et al. IgA deficiency: Correlation between clinical and immunological phenotypes. J Clin Immunol 29:130–136, 2009. Schroeder HW Jr, Zhu ZB, March RE, et al. Susceptibility locus for IgA deficiency and common variable immunodeficiency in the HLADR3, -B8, -A1 haplotypes. Mol Med 4:72–86, 1998. Wang N, and Hammarstro¨m L. IgA deficiency: What is new? Curr Opin Allergy Clin Immunol 12:602–608, 2012. Hammarstro¨m L, Vorechovsky I, and Webster D. Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clin Exp Immunol 120:225–231, 2000.
O D
30.
31.
32.
33.
34.
35.
36.
37.
38.
Fried AJ, and Bonilla FA. Pathogenesis, diagnosis, and management of primary antibody deficiencies and infections. Clin Microbiol Rev 22:396–414, 2009. Lefranc MP, Hammarstro¨m L, Smith CI, and Lefranc G. Gene deletions in the human immunoglobulin heavy chain constant region locus: Molecular and immunological analysis. Immunodefic Rev 2:265–281, 1991. Vanlerberghe L, Joniau S, and Jorissen M. The prevalence of humoral immunodeficiency in refractory rhinosinusitis: A retrospective analysis. B-ENT 2:161–166, 2006. May A, Zielen S, von Ilberg C, and Weber A. Immunoglobulin deficiency and determination of pneumococcal antibody titers in patients with therapy-refractory recurrent rhinosinusitis. Eur Arch Otorhinolaryngol 256:445–449, 1999. Alqudah M, Graham SM, and Ballas ZK. High prevalence of humoral immunodeficiency patients with refractory chronic rhinosinusitis. Am J Rhinol Allergy 24:409–412, 2010. Paris K, and Sorensen RU. Assessment and clinical interpretation of polysaccharide antibody responses. Ann Allergy Asthma Immunol 99:462–464, 2007. Orange JS, Ballow M, Stiehm ER, et al. Use and interpretation of diagnostic vaccination in primary immunodeficiency: A working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol 130:S1–S24, 2012. Borgers H, Moens L, Picard C, et al. Laboratory diagnosis of specific antibody deficiency to pneumococcal capsular polysaccharide antigens by multiplexed bead assay. Clin Immunol 134:198–205, 2010. Cheng YK, Decker PA, O’Byrne MM, and Weiler CR. Clinical and laboratory characteristics of 75 patients with specific polysaccharide antibody deficiency syndrome. Ann Allergy Asthma Immunol 97: 306–311, 2006. Kashani S, Grammer L, Schleimer R, et al. Clinical characteristics of patients with chronic rhinosinusitis and specific antibody deficiency. J Allergy Clin Immunol 129:AB68, 2012. Javier FC 3rd, Moore CM, and Sorensen RU. Distribution of primary immunodeficiency diseases diagnosed in a pediatric tertiary hospital. Ann Allergy Asthma Immunol 84:25–30, 2000. Boyle RJ, Le C, Balloch A, and Tang ML. The clinical syndrome of specific antibody deficiency in children. Clin Exp Immunol 146:486– 492, 2006. Carr TF, Koterba AP, Chandra R, et al. Characterization of specific antibody deficiency in adults with medically refractory chronic rhinosinusitis. Am J Rhinol Allergy 25:241–244, 2011. Keswani A, Mehrotra N, Manzur A, et al. The clinical significance of specific antibody deficiency severity in chronic rhinosinusitis. J Allergy Clin Immunol 133:AB236, 2014. Roifman CM, Lederman HM, Lavi S, et al. Benefit of intravenous IgG replacement in hypogammaglobulinemic patients with chronic sinopulmonary disease. Am J Med 79:171–174, 1985. Busse PJ, Razvi S, and Cunningham-Rundles C. Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency. J Allergy Clin Immunol 109:1001–1004, 2002. Orange JS, Hossny EM, Weiler CR, et al. Use of intravenous immunoglobulin in human disease: A review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol 117:S525–S553, 2006. Ballow M. Optimizing immunoglobulin treatment for patients with primary immunodeficiency disease to prevent pneumonia and infection incidence: Review of the current data. Ann Allergy Asthma Immunol 111:S2–S5, 2013. Lucas M, Lee M, Lortan J, et al. Infection outcomes in patients with common variable immunodeficiency disorders: Relationship to immunoglobulin therapy over 22 years. J Allergy Clin Immunol 125: 1354–1360, 2010. e
O N
T 39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
Y P
O C
March–April 2015, Vol. 29, No. 2
Delivered by Ingenta to: Guest User IP: 5.101.218.29 On: Thu, 30 Jun 2016 06:50:06 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm
Y P
ABSTRACT
Chronic rhinosinusitis (CRS) is estimated to affect over 35 million people. However, not all patients with the diagnosis respond to standard medical and surgical treatments. Although there are a variety of reasons a patient may be refractory to therapy, one possible etiology is the presence of an underlying immunodeficiency. This review will focus on the description, recognition, and treatment of several antibody deficiencies associated with CRS, including common variable immunodeficiency (CVID), selective IgA deficiency, IgG subclass deficiency, and specific antibody deficiency (SAD). The diagnosis of antibody deficiency in patients with CRS is important because of the large clinical implications it can have on sinus disease management. CVID is treated with immunoglobulin replacement, whereas SAD may be managed symptomatically and sometimes with prophylactic antibiotics and/or immunoglobulin replacement. (Am J Rhinol Allergy 29, 115–118, 2015; doi: 10.2500/ajra.2015.29.4144)
C
hronic rhinosinusitis (CRS) is a disease that affects over 35 million people and involves chronic inflammation of the sinonasal mucosa.1 Symptoms include nasal congestion, sinus pressure, and hyposmia that, by definition, persist for more than 12 weeks.2 Disruptions of the sinonasal epithelial barrier as well as dysregulation of the ensuing immunologic response are thought to be important in CRS pathogenesis.3,4 The role viral and bacterial infections might play in the development of CRS, however, is less defined, but these pathogens can exacerbate clinical symptoms. In general, the mainstay of treatment for CRS has been intranasal and systemic corticosteroids, antibiotics, and surgery.2 However, not all patients with CRS will respond to medical and surgical management, and these individuals along with those who have recurrent sinus infections warrant evaluation for other underlying diseases. Immunodeficiencies may be broadly categorized based upon defects in humoral immunity (e.g., B cells, antibodies, complement), cellular immunity (e.g., T cells, phagocytic cells), or both.5,6 In particular, antibody deficiency is the most common subtype accounting for approximately 50% of all primary immunodeficiency cases. Patients with antibody deficiencies are susceptible to bacterial pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis, and can develop recurrent upper and lower respiratory tract infections.7,8 Antibody deficiency itself is a spectrum of diseases ranging from severe to mild and characterized by different underlying immune pathologies and variable levels of antibody production and function. This review will focus on the description, recognition, and treatment of various antibody deficiencies associated with CRS in adults.
O D
T
O N
ANTIBODY DEFICIENCY DISORDERS OF ADULTS Common Variable Immunodeficiency (CVID) CVID is the most frequent symptomatic antibody deficiency. In this disease, B cells are detected, but there is a reduction in at least two of the three major antibody isotypes. Levels of IgG as well as IgA or IgM 1
Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois A. T. Peters is a consultant/advisor for Baxter. W. W. Stevens has no conflicts of interest to declare pertaining to this article Address correspondence to Anju T. Peters, M.D., Division of Allergy-Immunology, Northwestern University Feinberg School of Medicine, 676 N. St Clair Suite 14018, Chicago, IL 60611 E-mail address: [email protected] Copyright © 2015, OceanSide Publications, Inc., U.S.A.
O C
must be reduced more than two standard deviations below the mean adjusted for age. In addition, patients with CVID have impaired antibody function as evident by poor responses to both polysaccharide and protein antigen vaccines. Clinically, CVID remains a disease of exclusion, because other primary and secondary causes of hypogammaglobulinemia must first be eliminated before the diagnosis of CVID can be established. Although patients must be older than two years of age to be diagnosed with CVID, the average age of diagnosis is more frequently in third and fourth decades of life.9 In a multicenter Italian study examining 224 patients with CVID, the mean age at diagnosis was 22.6 years, whereas the mean age of symptom onset was 16.9 years.10 Similarly, in a French national study of patients with CVID, onset of symptoms occurred at a median age of 19 years, but 40% and 35% of symptoms were present before ages 15 and 5, respectively.11 Such a delay between symptom onset and disease diagnosis may be secondary to numerous factors, including the postponement of immunoglobulin analysis, until more severe symptoms develop and the initial association of clinical symptoms with a more common self-limiting illness. Recurrent infections, viz. involving the upper and lower respiratory tract, are commonly observed in CVID. In one small case series, 74% of patients with CVID reported recurrent episodes of pneumonia.12 In a larger cohort, acute bronchitis and chronic sinusitis were found in 63% and 37% of CVID patients, respectively, at the time of diagnosis.10 Infections alone, however, are not the only manifestation of CVID.13,14 Resnick et al. reported that of 473 CVID patients examined in a retrospective analysis, 68% had noninfectious complications of CVID, including chronic lung disease, autoimmunity, lymphoma, granulomatous disease, or inflammatory gastrointestinal disease.15 Chronic lung disease is the most common of these conditions with as many as 27% of CVID cases being of an obstructive (e.g., asthma), restrictive (e.g., interstitial lung disease), or bronchiectatic pattern.16 CVID is a heterogeneous disease with no known single molecular defect attributed to disease pathogenesis to date. The majority of CVID cases are sporadic, but smaller clusters of familial inheritance patterns do exist.17 In 8%–10% of patients with CVID, a mutation in the transmembrane activator and calcium modulating ligand interactor protein has been reported18 and has been associated with an increased incidence of autoimmune complications.19 However, transmembrane activator and calcium modulating ligand interactor mutations can also be observed in relatives of CVID patients who have normal immunoglobulin levels,20 suggesting that other additional factors are also contributing to disease pathogenesis. Regardless of the underlying mechanism, men and women with CVID on average have a reduced lifespan when compared with the general population.15 Additionally, those patients with noninfectious manifestations of CVID have an 11-fold higher risk of mortality than
American Journal of Rhinology & Allergy
Delivered by Ingenta to: Guest User IP: 5.101.218.29 On: Thu, 30 Jun 2016 06:50:06 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm
115
those with recurrent infections alone.15 Finally, older age at time of diagnosis as well as a longer delay between symptom onset and disease diagnosis have been associated with increased risk of death.21 Taken together, these studies highlight the importance of rapidly identifying CVID in at-risk patients, including those with recurrent sinus infections or refractory CRS.
Selective IgA Deficiency
Despite having a quantitative standard for diagnosis, the clinical significance of an IgG subclass deficiency remains controversial. Low levels of IgG subclasses have been reported in as many as 2%–20% of healthy individuals.30 Additionally, the majority of patients in one study who had deletions in the immunoglobulin heavy chain and were thus deficient in IgG1, IgG2, and/or IgG4 were also asymptomatic.31 In contrast, decreased IgG subclass levels have been reported in patients with refractory CRS.32,33 In these studies, however, such correlations have not been proven as causation. Furthermore, it has been suggested that it is the lack of a specific antibody response to polysaccharide antigens more so than a deficiency in IgG subclasses that more prominently contribute to clinical disease.30,33,34
In a patient over four years of age, an IgA level of less than 0.07 g/L in the presence of normal IgG and IgM fulfills the criteria for selective IgA deficiency. This disease is very common particularly in Western countries with a prevalence ranging from 1:173 to 1:3024.22 This prevalence may be increased among patients with refractory CRS with Chee et al. reporting that 16.7% of CRS patients studied had low IgA levels and 6.2% fulfilled criteria for specific IgA deficiency.23 However, in a separate study, IgA levels were not found to significantly correlate with the extent of sinus disease observed on sinus computed tomography imaging.24 Although the majority of patients with IgA deficiency are asymptomatic, a smaller subgroup may develop clinical manifestations of their disease. Recurrent sinopulmonary infections, giardiasis, inflammatory bowel disease, anaphylactic transfusion reactions, and autoimmune diseases such as hemolytic anemia, rheumatoid arthritis, or Grave’s disease have all been observed.8,25 Atopy is also common in patients with IgA deficiency with one study reporting as many as 51% and 49% of patients with specific IgA deficiency having asthma or atopic dermatitis, respectively.26 It is not completely understood why some patients with low IgA levels develop clinical sequela and others do not. Additionally, it remains unclear what causes the decreased production of IgA, but impaired B cell differentiation into activated plasma cells may contribute.25 IgA deficiency typically occurs sporadically within a population, but clusters of an autosomal inheritance pattern have been reported. Genetic studies in small family cohorts suggest a link between the major histocompatibility complexes human leukocyte antigen (HLA)-A1, HLA-B8, HLA-DR3, and IgA deficiency, but further investigations are needed to explore whether this association plays a broader role in disease pathogenesis.27,28 The presence of low IgA levels may not necessarily be due to a selective IgA deficiency, because evolving CVID should be also considered. Additionally, medications including phenytoin, carbamazepine, and sulfasalazine have been shown to reduce serum IgA levels.29 Unlike primary immunodeficiencies, medication-induced reductions in IgA levels may correct once the offending agent is discontinued.
O D
Based upon its heavy chain antigenic epitope, the IgG immunoglobulin can be divided into four distinct subgroups: IgG1, IgG2, IgG3, and IgG4. IgG1 is the most prevalent subclass comprising up to 70% of all total IgG, whereas IgG4 is the least common making up only 2%–6% of the total. Additionally, IgG1 levels typically reach adult concentrations earlier in childhood than the other IgG subclasses. Other differences between the subgroups include half-life in serum, ability to fix complement, and responses to various antigens. IgG1 and IgG3 are typically generated in response to protein antigens, whereas IgG2 and IgG4 are commonly induced after recognition of polysaccharide antigens. Given that IgG subclasses constitute different percentages of the whole, a deficiency in one subclass does not necessarily cause a decrease in total IgG. If, in the presence of normal total IgG levels, an individual IgG subclass is below two standard deviations of the age-adjusted mean, the diagnosis of an IgG subclass deficiency can be made. Importantly, any reduction in total IgG level below two standard deviations of the mean for age precludes a subclass deficiency, and alternative diagnoses should instead be considered.
Unlike patients with an IgG subclass deficiency, patients with SAD have normal levels of both total IgG and IgG subclasses. However, in SAD, there is a deficiency in specific IgG antibodies against polysaccharide antigens. Pneumococcal serotypes greater than 1.3 mcg/mL have been shown to prevent against infection and colonization by S. pneumoniae, and this value is typically considered as the lower limit for a protective antibody level.35 A total of 50%–70% of the pneumococcal serotypes should be at or above a protective level, and a normal response to a polysaccharide pneumococcal vaccine is a conversion of 70% of serotypes to protective levels with a minimum two-fold increase in individual specific antibody levels.35,36 Patients with SAD, however, do not mount a proper humoral immune response after immunization with an unconjugated polysaccharide pneumococcal vaccine. As a result, they continue to have the majority of specific antibody levels below protective levels that, in one study, were lower than the fifth percentile of responses seen by healthy controls.37 Interpretation of specific antibody levels to pneumococcal serotypes can be complicated. For example, the various pneumococcal serotypes do not have equal immunogenicity, with serotype 3 being a more potent immunogen than serotypes 6B and 23F.36 A deficiency in one single pneumococcal serotype has not consistently been associated with SAD to date. Also, a particular antibody level does not necessarily always correspond with disease as an asymptomatic individual, and a patient with clinical symptoms may both have the same specific antibody levels against pneumococcal serotypes. Taken together, additional investigations are warranted to better characterize the specific antibody response to polysaccharide vaccines and how these responses contribute to clinical findings observed in SAD. Clinically, patients with SAD are more susceptible to recurrent infections. In a retrospective study of 75 patients at the Mayo Clinic with SAD, the most frequent infections observed were sinusitis (77%), pneumonia (42%), and otitis (26%).38 In this study, the median age at time of diagnosis was 42 years, whereas the median interval between symptom onset and age of diagnosis was four years.38 Kashani et al. observed that patients with CRS and SAD had an increased incidence of pneumonia when compared with CRS patients without SAD.39 The presence of autoimmunity in SAD remains not clearly defined. The prevalence of SAD in the general population remains unclear. As a further confounder, not all patients with a deficiency in specific antibodies will develop clinical symptoms, and the threshold at which a SAD becomes universally clinically relevant remains unknown. Studies of pediatric patients with recurrent infections found that as many as 15%–23% had SAD.40,41 Of CRS patients undergoing sinus surgery at one tertiary care medical center, 11.6% were found to have SAD,42 whereas in another study, up to 67% of patients with refractory CRS had the disease.34 Such variation in prevalence may be due in part to the different criteria used in the studies to define SAD, but these discrepancies highlight the need for further investigations of disease prevalence.
T
O N
IgG Subclass Deficiency
116
Y P
Specific Antibody Deficiency (SAD)
O C
March–April 2015, Vol. 29, No. 2
Delivered by Ingenta to: Guest User IP: 5.101.218.29 On: Thu, 30 Jun 2016 06:50:06 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm
EVALUATION OF ANTIBODY DEFICIENCIES IN CRS Although not all patients with an antibody deficiency will have recurrent sinus infections, not all patients with recurrent sinus infections will have an underlying antibody deficiency. A retrospective analysis of 595 patients with CRS seen at a tertiary care hospital over a three-year period found 24.2% of patients studied fulfilled the diagnostic criteria for SAD, 6% for CVID, and 3% for selective IgA deficiency.43 Those CRS patients at a greater risk for having an underlying antibody deficiency include ones with recurrent sinopulmonary infections despite multiple courses of antibiotics and those who continue to have symptoms despite maximal medical and surgical therapies. The evaluation of an antibody deficiency in CRS should first include obtaining a detailed clinical history and physical exam. Attention should especially be focused on symptoms, duration, treatment, and number of recurrent sinus infections as well as if the patient had other infections such as bronchitis, pneumonia, or diarrhea. History of recurrent sinopulmonary infections in association with autoimmune diseases should also raise the suspicion of antibody deficiencies. Next, laboratory tests can be ordered to assess quantitative and functional aspects of humoral and cell-mediated immunity. To start, a complete blood count with differential, quantitative total immunoglobulins for IgA, IgM, and IgG, and specific antibody levels to polysaccharide antigen vaccines against S. pneumoniae and/or H. influenzae should be sent. Pending these initial results, additional studies may be ordered to further evaluate T and B cell numbers by flow cytometry, specific antibody responses to the protein antigen vaccines Tetanus and Diphtheria, and levels of complement. Measurements of IgG subclasses are not typically recommended as part of an initial analysis of a humoral immunodeficiency. In regards to interpretation of specific antibody levels against pneumococcal polysaccharide antigens, antibody levels are generally considered low if they are less than 1.3 mcg/mL for at least 50% of the pneumococcal serotypes measured. If specific antibody levels are low, the polysaccharide pneumococcal vaccine should be administered and, one month after immunization, specific antibody levels should be reassessed.36 An appropriate response to the immunization is considered when specific antibody levels are greater than 1.3 mcg/mL in 50%–70% of the pneumococcal serotypes or there is a four-fold increase in a more than 50% of the given specific antibody level compared with preimmunization.36 It is estimated that as many as 75% of patients who initially had low specific antibodies to polysaccharide antigens will develop a robust response after polysaccharide pneumococcal immunization and thus will not require further testing or management.39,43 However, the higher the specific antibody levels are to a given serotype, the less likely they are to increase after vaccination.36
O D
Y P
T
O N
TREATMENT OF ANTIBODY DEFICIENCIES IN CRS It is important to recognize antibody deficiencies in patients with refractory CRS as this diagnosis can impact overall disease management. Treatment options for CRS patients with antibody deficiencies should be individualized and may include the use of prophylactic antibiotics as well as vaccination with a conjugated pneumococcal antigen vaccine. Immunoglobulin replacement is another option but is usually reserved for patients who fail to respond to vaccinations and have persistent infections. The underlying CRS should also continue to be managed by medical therapy (e.g., intranasal and systemic corticosteroids, early initiation of antibiotics tailored to nasal culture growth) and, when indicated, surgical intervention. Depending on the clinical scenario, referral to an allergist/immunologist may be recommended. In patients with CVID, immunoglobulin replacement has been shown to reduce the number of sinopulmonary infections as well as
acute hospitalizations.44,45 However, a European study reported that only 8% of CVID patients with chronic sinusitis had improvement in their CRS while receiving intravenous immunoglobulin (IVIG).10 This study also saw an increase in the percentage of CVID patients diagnosed with CRS (36%–54%) over a five-year period despite immunoglobulin replacement.10 As with all therapies, the risks and benefits of IVIG should be considered for each patient before initiation. IVIGs are typically administered at a starting dose of 400 mg/kg every three to four weeks, with this dose adjusted accordingly to achieve a trough IgG level greater than 500 mg/L.46 A higher IgG trough of 800 mg/L may also be used, because this level has been suggested to improve pulmonary outcomes.46 Subcutaneous immunoglobulin replacement can also be administered depending on patient preference. However, administration would occur weekly, and measured IgG levels would more closely represent steady state and not trough values. Importantly, the patient’s clinical symptoms and rate of infections should ultimately drive decisions regarding the dose and timing of immunoglobulin replacement therapy.47,48 Unfortunately, immunoglobulin replacement therapy has not been as effective in the management of noninfections complications of CVID (i.e., autoimmunity, chronic lung disease, malignancy). Furthermore, IgG replacement is not indicated in patients with a sole selective IgA deficiency or IgG subclass deficiency unless they have a poor functional response to a pneumococcal polysaccharide vaccine and have recurrent infections.46 Patients with low IgG and low IgA have a small risk of anaphylaxis upon IgG replacement if they have antibodies against IgA. In such circumstances, an IVIG formulation containing low levels of IgA may be used and is commercially available. The use of immunoglobulin replacement in patients with SAD remains controversial. Decreased specific antibodies alone should not be the predominant indication for initiation of therapy but rather clinical symptoms and recurrence of infections should be key determinants. In two retrospective case studies, 18%–40% of evaluated SAD patients received immunoglobulin replacement.38,39 In these reports, patients with SAD who had a history of pneumonia were most likely to undergo replacement therapy,39 and in a separate study, once initiated, there was significant decrease in subsequent infections observed.38 Unlike in CVID, SAD patients receiving IVIG do not have a defined treatment goal for total IgG level, because by definition, they have normal levels of total IgG before initiation of therapy.
O C
CONCLUSIONS In summary, humoral immunodeficiencies should be considered in patients with CRS refractory to standard medical and surgical management. Assessment with detailed clinical histories and immunologic laboratory studies may reveal the presence of CVID, selective IgA deficiency, IgG subclass deficiency, or possibly SAD. The initiation of specialized treatments, including immunoglobulin replacement, should be individualized taking in account both the clinical symptoms and laboratory findings of each patient.
REFERENCES 1. 2.
3. 4.
5.
6.
Hamilos DL. Chronic rhinosinusitis: Epidemiology and medical management. J Allergy Clin Immunol 128:693–707; quiz 708–709, 2011. Fokkens WJ, Lund VJ, Mullol J, et al. European position paper on rhinosinusitis and nasal polyps 2012. Rhinol Suppl 3 p preceding table of contents, 1–298, 2012. Stevens WW, Schleimer RP, Chandra RK, and Peters AT. Biology of nasal polyposis. J Allergy Clin Immunol 133:1503, 2014. Schleimer RP, Kato A, Peters A, et al. Epithelium, inflammation, and immunity in the upper airways of humans: Studies in chronic rhinosinusitis. Proc Am Thorac Soc 6:288–294, 2009. Al-Herz W, Bousfiha A, Casanova JL, et al. Primary immunodeficiency diseases: An update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol 2:54, 2011. Uzzaman A, and Fuleihan RL. Chapter 27: Approach to primary immunodeficiency. Allergy Asthma Proc 33(suppl. 1):S91–S95, 2012.
American Journal of Rhinology & Allergy
Delivered by Ingenta to: Guest User IP: 5.101.218.29 On: Thu, 30 Jun 2016 06:50:06 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm
117
7.
8. 9.
10.
11.
12.
13.
14. 15.
16.
17.
18.
19.
20.
21.
22. 23.
24.
25. 26.
27.
28. 29.
118
Picard C, Puel A, Bustamante J, et al. Primary immunodeficiencies associated with pneumococcal disease. Curr Opin Allergy Clin Immunol 3:451–459, 2003. Ballow M. Primary immunodeficiency disorders: Antibody deficiency. J Allergy Clin Immunol 109:581–591, 2002. Cunningham-Rundles C. Clinical and immunologic analyses of 103 patients with common variable immunodeficiency. J Clin Immunol 9:22–33, 1989. Quinti I, Soresina A, Spadaro G, et al. Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency. J Clin Immunol 27:308–316, 2007. Oksenhendler E, Ge´rard L, Fieschi C, et al. Infections in 252 patients with common variable immunodeficiency. Clin Infect Dis 46:1547– 1554, 2008. Martínez García MA, de Rojas MD, Nauffal Manzur MD, et al. Respiratory disorders in common variable immunodeficiency. Respir Med 95:191–195, 2001. Agarwal S, and Cunningham-Rundles C. Autoimmunity in common variable immunodeficiency. Curr Allergy Asthma Rep 9:347–352, 2009. Podjasek JC, and Abraham RS. Autoimmune cytopenias in common variable immunodeficiency. Front Immunol 3:189, 2012. Resnick ES, Moshier EL, Godbold JH, and Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood 119:1650–1657, 2012. Busse PJ, Farzan S, and Cunningham-Rundles C. Pulmonary complications of common variable immunodeficiency. Ann Allergy Asthma Immunol 98:1–8; quiz 8–11, 43, 2007. Resnick ES, and Cunningham-Rundles C. The many faces of the clinical picture of common variable immune deficiency. Curr Opin Allergy Clin Immunol 12:595–601, 2012. Salzer U, Chapel HM, Webster AD, et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet 37:820–828, 2005. Zhang L, Radigan L, Salzer U, et al. Transmembrane activator and calcium-modulating cyclophilin ligand interactor mutations in common variable immunodeficiency: Clinical and immunologic outcomes in heterozygotes. J Allergy Clin Immunol 120:1178–1185, 2007. Martinez-Gallo M, Radigan L, Almeju´n MB, et al. TACI mutations and impaired B-cell function in subjects with CVID and healthy heterozygotes. J Allergy Clin Immunol 131:468–476, 2013. Gathmann B, Mahlaoui N, Gerard L, et al. Clinical picture and treatment of 2212 patients with common variable immunodeficiency. J Allergy Clin Immunol 134:116–126, 2014. Singh K, Chang C, and Gershwin ME. IgA deficiency and autoimmunity. Autoimmun Rev 13:163–177, 2014. Chee L, Graham SM, Carothers DG, and Ballas ZK. Immune dysfunction in refractory sinusitis in a tertiary care setting. Laryngoscope 111:233–235, 2001. Hoover GE, Newman LJ, Platts-Mills TA, et al. Chronic sinusitis: Risk factors for extensive disease. J Allergy Clin Immunol 100:185–191, 1997. Cunningham-Rundles C. Physiology of IgA and IgA deficiency. J Clin Immunol 21:303–309, 2001. Aghamohammadi A, Cheraghi T, Gharagozlou M, et al. IgA deficiency: Correlation between clinical and immunological phenotypes. J Clin Immunol 29:130–136, 2009. Schroeder HW Jr, Zhu ZB, March RE, et al. Susceptibility locus for IgA deficiency and common variable immunodeficiency in the HLADR3, -B8, -A1 haplotypes. Mol Med 4:72–86, 1998. Wang N, and Hammarstro¨m L. IgA deficiency: What is new? Curr Opin Allergy Clin Immunol 12:602–608, 2012. Hammarstro¨m L, Vorechovsky I, and Webster D. Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clin Exp Immunol 120:225–231, 2000.
O D
30.
31.
32.
33.
34.
35.
36.
37.
38.
Fried AJ, and Bonilla FA. Pathogenesis, diagnosis, and management of primary antibody deficiencies and infections. Clin Microbiol Rev 22:396–414, 2009. Lefranc MP, Hammarstro¨m L, Smith CI, and Lefranc G. Gene deletions in the human immunoglobulin heavy chain constant region locus: Molecular and immunological analysis. Immunodefic Rev 2:265–281, 1991. Vanlerberghe L, Joniau S, and Jorissen M. The prevalence of humoral immunodeficiency in refractory rhinosinusitis: A retrospective analysis. B-ENT 2:161–166, 2006. May A, Zielen S, von Ilberg C, and Weber A. Immunoglobulin deficiency and determination of pneumococcal antibody titers in patients with therapy-refractory recurrent rhinosinusitis. Eur Arch Otorhinolaryngol 256:445–449, 1999. Alqudah M, Graham SM, and Ballas ZK. High prevalence of humoral immunodeficiency patients with refractory chronic rhinosinusitis. Am J Rhinol Allergy 24:409–412, 2010. Paris K, and Sorensen RU. Assessment and clinical interpretation of polysaccharide antibody responses. Ann Allergy Asthma Immunol 99:462–464, 2007. Orange JS, Ballow M, Stiehm ER, et al. Use and interpretation of diagnostic vaccination in primary immunodeficiency: A working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol 130:S1–S24, 2012. Borgers H, Moens L, Picard C, et al. Laboratory diagnosis of specific antibody deficiency to pneumococcal capsular polysaccharide antigens by multiplexed bead assay. Clin Immunol 134:198–205, 2010. Cheng YK, Decker PA, O’Byrne MM, and Weiler CR. Clinical and laboratory characteristics of 75 patients with specific polysaccharide antibody deficiency syndrome. Ann Allergy Asthma Immunol 97: 306–311, 2006. Kashani S, Grammer L, Schleimer R, et al. Clinical characteristics of patients with chronic rhinosinusitis and specific antibody deficiency. J Allergy Clin Immunol 129:AB68, 2012. Javier FC 3rd, Moore CM, and Sorensen RU. Distribution of primary immunodeficiency diseases diagnosed in a pediatric tertiary hospital. Ann Allergy Asthma Immunol 84:25–30, 2000. Boyle RJ, Le C, Balloch A, and Tang ML. The clinical syndrome of specific antibody deficiency in children. Clin Exp Immunol 146:486– 492, 2006. Carr TF, Koterba AP, Chandra R, et al. Characterization of specific antibody deficiency in adults with medically refractory chronic rhinosinusitis. Am J Rhinol Allergy 25:241–244, 2011. Keswani A, Mehrotra N, Manzur A, et al. The clinical significance of specific antibody deficiency severity in chronic rhinosinusitis. J Allergy Clin Immunol 133:AB236, 2014. Roifman CM, Lederman HM, Lavi S, et al. Benefit of intravenous IgG replacement in hypogammaglobulinemic patients with chronic sinopulmonary disease. Am J Med 79:171–174, 1985. Busse PJ, Razvi S, and Cunningham-Rundles C. Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency. J Allergy Clin Immunol 109:1001–1004, 2002. Orange JS, Hossny EM, Weiler CR, et al. Use of intravenous immunoglobulin in human disease: A review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol 117:S525–S553, 2006. Ballow M. Optimizing immunoglobulin treatment for patients with primary immunodeficiency disease to prevent pneumonia and infection incidence: Review of the current data. Ann Allergy Asthma Immunol 111:S2–S5, 2013. Lucas M, Lee M, Lortan J, et al. Infection outcomes in patients with common variable immunodeficiency disorders: Relationship to immunoglobulin therapy over 22 years. J Allergy Clin Immunol 125: 1354–1360, 2010. e
O N
T 39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
Y P
O C
March–April 2015, Vol. 29, No. 2
Delivered by Ingenta to: Guest User IP: 5.101.218.29 On: Thu, 30 Jun 2016 06:50:06 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm
