Advertisement

Primary immune deficiency diseases as unrecognized causes of chronic respiratory disease

Open AccessPublished:October 21, 2017DOI:https://doi.org/10.1016/j.rmed.2017.10.016

      Highlights

      • PIDDs may cause chronic rhinosinusitis, asthma and bronchiectasis.
      • Chronic/recurrent respiratory infections may culminate in COPD.
      • Testing IgG and vaccine antibody responses may help identify PIDD in COPD patients.
      • IgG replacement can improve pulmonary function in PIDD and some COPD patients.

      Abstract

      Background

      More than half of all primary immune deficiency diseases (PIDD) affect antibody production and are well known as causes of recurrent sinusitis and lung infections. Chronic and recurrent infections of the upper and/or lower airways can contribute to inflammatory and obstructive processes in the lower airways which are initially reversible and considered “asthma”, but can eventually cause irreversible remodeling and chronic obstructive pulmonary disease (COPD). Conversely, several lines of evidence suggest that many patients who present with a diagnosis of asthma have an increased incidence of infection, suggesting underlying host-defense defects. Asthma and respiratory infections in the first decades of life are recognized as risk factors for development of COPD, but when patients present with COPD as adults, underlying primary immune deficiency disease may be unrecognized.

      Main findings and conclusions

      Detection of PIDD as a potentially treatable underlying contributor to recurrent/acute exacerbations and morbidity of COPD, and provision of immunoglobulin (Ig) G replacement therapy, when appropriate, may decrease the progression of COPD. Decreasing the severity and rate of exacerbations and admissions should improve the quality of life and longevity of an important subset of patients with COPD, while decreasing costs. Major steps toward achieving these goals include developing a high index of suspicion, more frequent use and appropriate interpretation of screening tests such as quantitative immunoglobulins and vaccine responses, and prompt institution of IgG replacement therapy when antibody deficiency has been diagnosed.

      Keywords

      Abbreviations:

      ACOS (asthma-chronic obstructive pulmonary disease overlap syndrome), BODE (body-mass index, airflow obstruction, dyspnea, and exercise), COPD (chronic obstructive pulmonary disease), CRS (chronic rhinosinusitis), CT (computed tomography), CVID (common variable immune deficiency), ENT (ear, nose and throat), FEV1 (forced expiratory volume in 1 s), FEV1/FVC (ratio of forced expiratory volume in 1 s to forced vital capacity), GOLD (Global Initiative for Chronic Obstructive Lung Disease), HIV (human immunodeficiency virus), Ig (immunoglobulin), MMF (mycophenolate mofetil), MRC (Medical Research Council), PCV (pneumococcal conjugate vaccine), PIDD (primary immune deficiency diseases), PPV-23 (23-valent unconjugated pneumococcal polysaccharide vaccine), SAD (specific antibody deficiency), UK PID (United Kingdom Primary Immunodeficiency), US (United States), USIDNET (United States Immunodeficiency Network)

      1. Introduction

      Primary immune deficiency diseases (PIDDs) are well known as causes of chronic sinusitis and bronchiectasis, but recent studies suggest that some patients with asthma and chronic obstructive pulmonary disease (COPD) also have underlying PIDD which may be undiagnosed [
      • Hens G.
      • Vanaudenaerde B.M.
      • Bullens D.M.
      • Piessens M.
      • Decramer M.
      • Dupont L.J.
      • Ceuppens J.L.
      • Hellings P.W.
      Sinonasal pathology in nonallergic asthma and COPD: 'united airway disease' beyond the scope of allergy.
      ,
      • Exley A.R.
      • Henderson K.
      • Buckenham S.
      • Kimberlin H.
      • Gronlund H.
      • French J.
      • Campbell K.
      • Bilton D.
      • Barker H.
      • Screaton N.
      • Haworth C.S.
      • Floto R.A.
      Diagnosis and management of common variable immuno-deficiency (CVID) in adults with recurrent pulmonary infection.
      ,
      • Baleeiro C.
      • Mull N.
      Prevalence of common variable immunodeficiency (CVID) among patients with recurrent respiratory tract infections.
      ]. A lack of adequate immune defenses leading to recurrent infections may result in a chronic inflammatory response that leads to airway hyper-reactivity and remodeling, and eventually to fixed obstruction. Early in the infectious-inflammatory process, reversible changes may be recognized clinically as asthma. However, persistence can lead to asthma-COPD overlap syndrome (ACOS) [
      • Postma D.S.
      • Rabe K.F.
      The Asthma-COPD overlap syndrome.
      ,
      • Lange P.
      • Colak Y.
      • Ingebrigtsen T.S.
      • Vestbo J.
      • Marott J.L.
      Long-term prognosis of asthma, chronic obstructive pulmonary disease, and asthma-chronic obstructive pulmonary disease overlap in the Copenhagen City Heart study: a prospective population-based analysis.
      ] and/or COPD itself [
      • McGeachie M.J.
      • Yates K.P.
      • Zhou X.
      • Guo F.
      • Sternberg A.L.
      • Van Natta M.L.
      • Wise R.A.
      • Szefler S.J.
      • Sharma S.
      • Kho A.T.
      • Cho M.H.
      • Croteau-Chonka D.C.
      • Castaldi P.J.
      • Jain G.
      • Sanyal A.
      • Zhan Y.
      • Lajoie B.R.
      • Dekker J.
      • Stamatoyannopoulos J.
      • Covar R.A.
      • Zeiger R.S.
      • Adkinson N.F.
      • Williams P.V.
      • Kelly H.W.
      • Grasemann H.
      • Vonk J.M.
      • Koppelman G.H.
      • Postma D.S.
      • Raby B.A.
      • Houston I.
      • Lu Q.
      • Fuhlbrigge A.L.
      • Tantisira K.G.
      • Silverman E.K.
      • Tonascia J.
      • Weiss S.T.
      • Strunk R.C.
      Camp Research Group, Patterns of growth and decline in lung function in persistent childhood asthma.
      ]. Although COPD is historically associated with smoking, 20–30% of patients with COPD have never smoked [
      • Behrendt C.E.
      Mild and moderate-to-severe COPD in nonsmokers: distinct demographic profiles.
      ,
      • Whittemore A.S.
      • Perlin S.A.
      • DiCiccio Y.
      Chronic obstructive pulmonary disease in lifelong nonsmokers: results from NHANES.
      ] and are not deficient in alpha-1 proteinase inhibitor. Asthma and a history of hospitalization for respiratory disease in childhood have been identified retrospectively as important risk factors for later diagnosis of COPD [
      • Shaheen S.O.
      • Barker D.J.
      • Holgate S.T.
      Do lower respiratory tract infections in early childhood cause chronic obstructive pulmonary disease?.
      ,
      • Hayden L.P.
      • Hobbs B.D.
      • C.R. T
      • Wise R.A.
      • Checkley W.
      • Crapo J.D.
      • Hersh C.P.
      on behalf of the COPDGene Investigators
      Childhood pneumonia increases risk for chronic obstructive pulmonary disease: the COPDGene study.
      ].
      Based on the above observations, we propose that chronic/recurrent sinopulmonary infections due to PIDD, which may be undiagnosed, can cause chronic inflammation which results in airway hyper-reactivity, damage, and remodeling. Recognition of the role of PIDD as a contributor to recurrent/chronic infection and airway damage should improve treatment of these potentially preventable forms of COPD or ACOS and lead to an overall reduction in respiratory morbidity in these patients.

      2. PIDD and airway diseases

      Over 300 distinct PIDDs have been described [
      • Bonilla F.A.
      • Khan D.A.
      • Ballas Z.K.
      • Chinen J.
      • Frank M.M.
      • Hsu J.T.
      • Keller M.
      • Kobrynski L.J.
      • Komarow H.D.
      • Mazer B.
      • Nelson Jr., R.P.
      • Orange J.S.
      • Routes J.M.
      • Shearer W.T.
      • Sorensen R.U.
      • Verbsky J.W.
      • Bernstein D.I.
      • Blessing-Moore J.
      • Lang D.
      • Nicklas R.A.
      • Oppenheimer J.
      • Portnoy J.M.
      • Randolph C.R.
      • Schuller D.
      • Spector S.L.
      • Tilles S.
      • Wallace D.
      Practice parameter for the diagnosis and management of primary immunodeficiency.
      ,
      • Immune Deficiency Foundation
      Diagnostic and Clinical Care Guidelines for Primary Immunodeficiency Diseases.
      ]. More than half result in antibody deficiency, but the vast majority of patients with antibody deficiency lack defined genetic defects and carry the diagnosis of common variable immune deficiency (CVID). The most prevalent antibody deficiency syndromes are listed in Table 1 [
      • Sullivan K.E.
      Immune Deficiency Foundation Clinical Focus on Primary Immunodeficiency: Diagnostic Approaches to Antibody Deficiencies.
      ,
      • Chapel H.
      • Cunningham-Rundles C.
      Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions.
      ], and criteria for the diagnosis of CVID are listed in Table 2 [
      • Bonilla F.A.
      • Khan D.A.
      • Ballas Z.K.
      • Chinen J.
      • Frank M.M.
      • Hsu J.T.
      • Keller M.
      • Kobrynski L.J.
      • Komarow H.D.
      • Mazer B.
      • Nelson Jr., R.P.
      • Orange J.S.
      • Routes J.M.
      • Shearer W.T.
      • Sorensen R.U.
      • Verbsky J.W.
      • Bernstein D.I.
      • Blessing-Moore J.
      • Lang D.
      • Nicklas R.A.
      • Oppenheimer J.
      • Portnoy J.M.
      • Randolph C.R.
      • Schuller D.
      • Spector S.L.
      • Tilles S.
      • Wallace D.
      Practice parameter for the diagnosis and management of primary immunodeficiency.
      ,
      • Immune Deficiency Foundation
      Diagnostic and Clinical Care Guidelines for Primary Immunodeficiency Diseases.
      ,
      • Sullivan K.E.
      Immune Deficiency Foundation Clinical Focus on Primary Immunodeficiency: Diagnostic Approaches to Antibody Deficiencies.
      ,
      • Chapel H.
      • Cunningham-Rundles C.
      Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions.
      ]. Although most patients with serious antibody deficiencies have frank hypogammaglobulinemia, some have specific antibody deficiency (SAD), with normal serum immunoglobulin G (IgG) levels but an inability to respond to polysaccharides (Table 3) or other particular types of antigens [
      • Bonilla F.A.
      • Khan D.A.
      • Ballas Z.K.
      • Chinen J.
      • Frank M.M.
      • Hsu J.T.
      • Keller M.
      • Kobrynski L.J.
      • Komarow H.D.
      • Mazer B.
      • Nelson Jr., R.P.
      • Orange J.S.
      • Routes J.M.
      • Shearer W.T.
      • Sorensen R.U.
      • Verbsky J.W.
      • Bernstein D.I.
      • Blessing-Moore J.
      • Lang D.
      • Nicklas R.A.
      • Oppenheimer J.
      • Portnoy J.M.
      • Randolph C.R.
      • Schuller D.
      • Spector S.L.
      • Tilles S.
      • Wallace D.
      Practice parameter for the diagnosis and management of primary immunodeficiency.
      ,
      • Immune Deficiency Foundation
      Diagnostic and Clinical Care Guidelines for Primary Immunodeficiency Diseases.
      ,
      • Sullivan K.E.
      Immune Deficiency Foundation Clinical Focus on Primary Immunodeficiency: Diagnostic Approaches to Antibody Deficiencies.
      ,
      • Orange J.S.
      • Ballow M.
      • Stiehm E.R.
      • Ballas Z.K.
      • Chinen J.
      • De La Morena M.
      • Kumararatne D.
      • Harville T.O.
      • Hesterberg P.
      • Koleilat M.
      • McGhee S.
      • Perez E.E.
      • Raasch J.
      • Scherzer R.
      • Schroeder H.
      • Seroogy C.
      • Huissoon A.
      • Sorensen R.U.
      • Katial R.
      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.
      ]. Patients with selective IgA deficiency may also be at risk for an increased frequency of respiratory infections with a prevalence of respiratory infections requiring hospital visits or admissions more than 3 times higher than that of matched controls [
      • Ludvigsson J.F.
      • Neovius M.
      • Hammarstrom L.
      Risk of infections among 2100 individuals with IgA deficiency: a nationwide cohort study.
      ]. A Korean group reported that amongst adult patients with asthma or COPD, who were found to have an IgG subclass deficiency, nearly 30% also met ≥2 criteria on a screening test of 10 clinical signs of PIDD. This subgroup had significantly higher numbers of hospitalizations (p = 0.012) and exacerbations of asthma or COPD (p < 0.001), and lower FEV1 (p = 0.036) than the group who did not have warning signs of PIDD [
      • Kim J.H.
      • Park S.
      • Hwang Y.I.
      • Jung K.S.
      • Sim Y.S.
      • Kim C.
      • Kim D.G.
      Immunoglobulin G subclass deficiencies in adult patients with chronic airway diseases.
      ].
      Table 1Most prevalent primary antibody deficiencies.
      Data sourced from Refs. [13,14].
      • Selective IgA deficiency
      • CVID
      • Bruton's (X-linked) agammaglobulinemia
      • Autosomal recessive hypogammaglobulinemia
      • Transient hypogammaglobulinemia of infancy
      • Hyper-IgM syndromes
      • Specific (polysaccharide) antibody deficiency
      Abbreviations: CVID, common variable immune deficiency; IgA, immunoglobulin A; IgM, immunoglobulin M.
      a Data sourced from Refs.
      • Sullivan K.E.
      Immune Deficiency Foundation Clinical Focus on Primary Immunodeficiency: Diagnostic Approaches to Antibody Deficiencies.
      ,
      • Chapel H.
      • Cunningham-Rundles C.
      Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions.
      .
      Table 2Diagnostic criteria for CVID.
      Data sourced from Refs. [11–14].
      • 1.
        Markedly reduced serum IgG, in combination with IgA and/or IgM 2 SD below the mean
      • 2.
        Poor or absent response to immunizations
      • 3.
        Absence of any other defined immunodeficiency
      Abbreviations: CVID, common variable immune deficiency; IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M; SD, standard deviation.
      a Data sourced from Refs.
      • Bonilla F.A.
      • Khan D.A.
      • Ballas Z.K.
      • Chinen J.
      • Frank M.M.
      • Hsu J.T.
      • Keller M.
      • Kobrynski L.J.
      • Komarow H.D.
      • Mazer B.
      • Nelson Jr., R.P.
      • Orange J.S.
      • Routes J.M.
      • Shearer W.T.
      • Sorensen R.U.
      • Verbsky J.W.
      • Bernstein D.I.
      • Blessing-Moore J.
      • Lang D.
      • Nicklas R.A.
      • Oppenheimer J.
      • Portnoy J.M.
      • Randolph C.R.
      • Schuller D.
      • Spector S.L.
      • Tilles S.
      • Wallace D.
      Practice parameter for the diagnosis and management of primary immunodeficiency.
      ,
      • Immune Deficiency Foundation
      Diagnostic and Clinical Care Guidelines for Primary Immunodeficiency Diseases.
      ,
      • Sullivan K.E.
      Immune Deficiency Foundation Clinical Focus on Primary Immunodeficiency: Diagnostic Approaches to Antibody Deficiencies.
      ,
      • Chapel H.
      • Cunningham-Rundles C.
      Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions.
      .
      Table 3Assessing serotype-specific responses to pneumococcal capsular polysaccharide vaccine in adults (4–6 weeks after PPV 23).
      Adapted from Table XI in Ref. [11].
      ClassificationConcentrationFold increase in titer
      Normal>1.3 μg/mL for >70% of types≥2-fold for ≥70% of types
      Mild>1.3 μg/mL for >70% of types2-fold for <70% of types
      Moderate>1.3 μg/mL for <70% of types
      Severe>1.3 μg/mL for ≤2 types
      Memory DefectLoss of response within 6 months
      Abbreviations: PPV, pneumococcal polysaccharide vaccine.
      a Adapted from Table XI in Ref.
      • Bonilla F.A.
      • Khan D.A.
      • Ballas Z.K.
      • Chinen J.
      • Frank M.M.
      • Hsu J.T.
      • Keller M.
      • Kobrynski L.J.
      • Komarow H.D.
      • Mazer B.
      • Nelson Jr., R.P.
      • Orange J.S.
      • Routes J.M.
      • Shearer W.T.
      • Sorensen R.U.
      • Verbsky J.W.
      • Bernstein D.I.
      • Blessing-Moore J.
      • Lang D.
      • Nicklas R.A.
      • Oppenheimer J.
      • Portnoy J.M.
      • Randolph C.R.
      • Schuller D.
      • Spector S.L.
      • Tilles S.
      • Wallace D.
      Practice parameter for the diagnosis and management of primary immunodeficiency.
      .
      Identification of new cases of PIDD in both adults and children has been increasing in recent decades though it is still considered rare [
      • Joshi A.Y.
      • Iyer V.N.
      • Hagan J.B.
      • St Sauver J.L.
      • Boyce T.G.
      Incidence and temporal trends of primary immunodeficiency: a population-based cohort study.
      ]. From 2001 to 2006, 15 new diagnoses per 100,000 patient years amongst adults aged 51–75 years were reported in Olmsted County, Minnesota [
      • Joshi A.Y.
      • Iyer V.N.
      • Hagan J.B.
      • St Sauver J.L.
      • Boyce T.G.
      Incidence and temporal trends of primary immunodeficiency: a population-based cohort study.
      ]. A 2007 telephone survey of 10,000 US households, which included 27,000 individuals, estimated the population prevalence of PIDD at 1 in 1200 [
      • Boyle J.M.
      • Buckley R.H.
      Population prevalence of diagnosed primary immunodeficiency diseases in the United States.
      ]. A recent study in Israel reported that the incidence of newly diagnosed PIDD in a highly consanguineous Bedouin population was approximately 1 in 1,800, and in a non-consanguineous Jewish population, 1 in 17,000 [
      • Broides A.
      • Nahum A.
      • Mandola A.B.
      • Rozner L.
      • Pinsk V.
      • Ling G.
      • Yerushalmi B.
      • Levy J.
      • Givon-Lavi N.
      Incidence of typically severe primary immunodeficiency diseases in consanguineous and non-consanguineous populations.
      ]. Other population surveys estimate that the prevalence of CVID amongst adults in Denmark is 1 in 26,000 [
      • Westh L.
      • Mogensen T.H.
      • Dalgaard L.S.
      • Bernth Jensen J.M.
      • Katzenstein T.
      • Hansen A.E.
      • Larsen O.D.
      • Terpling S.
      • Nielsen T.L.
      • Larsen C.S.
      Identification and characterization of a nationwide Danish adult common variable immunodeficiency cohort.
      ]. In Poland, the overall prevalence of PIDD is 1 in 9,400, with 731 cases newly diagnosed in 2014 alone [
      • Pac M.
      • Bernatowska E.
      Comprehensive activities to increase recognition of primary immunodeficiency and access to immunoglobulin replacement therapy in Poland.
      ]. Thus, the incidence and prevalence of PIDD are higher than previously recognized, and are increasing, most likely due primarily to improved recognition. Nevertheless, diagnostic delay continues to be a problem. The United Kingdom Primary Immunodeficiency (UK PID) Registry reported that the median delay between the onset of an increased incidence of infections and the diagnosis of a PIDD is 8 years in adults aged over 30 years old, and a survey by the US Immune Deficiency Foundation found that the average interval between the onset of symptoms and the diagnosis of a PIDD was 12.4 years [
      • Edgar J.D.
      • Buckland M.
      • Guzman D.
      • Conlon N.P.
      • Knerr V.
      • Bangs C.
      • Reiser V.
      • Panahloo Z.
      • Workman S.
      • Slatter M.
      • Gennery A.R.
      • Davies E.G.
      • Allwood Z.
      • Arkwright P.D.
      • Helbert M.
      • Longhurst H.J.
      • Grigoriadou S.
      • Devlin L.A.
      • Huissoon A.
      • Krishna M.T.
      • Hackett S.
      • Kumararatne D.S.
      • Condliffe A.M.
      • Baxendale H.
      • Henderson K.
      • Bethune C.
      • Symons C.
      • Wood P.
      • Ford K.
      • Patel S.
      • Jain R.
      • Jolles S.
      • El-Shanawany T.
      • Alachkar H.
      • Herwadkar A.
      • Sargur R.
      • Shrimpton A.
      • Hayman G.
      • Abuzakouk M.
      • Spickett G.
      • Darroch C.J.
      • Paulus S.
      • Marshall S.E.
      • McDermott E.M.
      • Heath P.T.
      • Herriot R.
      • Noorani S.
      • Turner M.
      • Khan S.
      • Grimbacher B.
      The United Kingdom primary immune deficiency (UKPID) registry: report of the first 4 years' activity 2008-2012.
      ,
      • Immune Deficiency Foundation
      ]. In the Danish study, the median age at onset of symptoms of CVID was 29 years, but the median diagnostic delay was 7 years [
      • Westh L.
      • Mogensen T.H.
      • Dalgaard L.S.
      • Bernth Jensen J.M.
      • Katzenstein T.
      • Hansen A.E.
      • Larsen O.D.
      • Terpling S.
      • Nielsen T.L.
      • Larsen C.S.
      Identification and characterization of a nationwide Danish adult common variable immunodeficiency cohort.
      ]. Delay in diagnosis and institution of appropriate treatment may contribute to cumulative airways damage and eventual COPD.

      2.1 Evidence for humoral immune deficiency in chronic rhinosinusitis

      While there are relatively few published studies on the prevalence and importance of sinusitis in COPD, Kelemence, et al. [
      • Kelemence A.
      • Abadoglu O.
      • Gumus C.
      • Berk S.
      • Epozturk K.
      • Akkurt I.
      The frequency of chronic rhinosinusitis/nasal polyp in COPD and its effect on the severity of COPD.
      ] reported that in a cohort of COPD patients, 53% met clinical criteria for the diagnosis of chronic rhinosinusitis (CRS), and 64% met computed tomography (CT)-scan criteria for CRS. Patients with CRS hospitalized for COPD exacerbations were 3.3 times more likely than those without CRS to require re-admission or additional prescriptions within 4 weeks (28.6% vs 8.8%, p < 0.009) [
      • Dewan N.A.
      • Rafique S.
      • Kanwar B.
      • Satpathy H.
      • Ryschon K.
      • Tillotson G.S.
      • Niederman M.S.
      Acute exacerbation of COPD: factors associated with poor treatment outcome.
      ].
      Patients with chronic/recurrent sinusitis, especially those who have required surgery, may also have an increased prevalence of antibody deficiency and asthma. In 2001, a study of 79 patients with CRS reported 17.9% with low serum IgG levels, 16.7% with low IgA and 5.1% with low IgM. CVID was diagnosed in 9.9%, and selective IgA deficiency in 6.2% of these patients [
      • Chee L.
      • Graham S.M.
      • Carothers D.G.
      • Ballas Z.K.
      Immune dysfunction in refractory sinusitis in a tertiary care setting.
      ]. A recent study from King Abdullah University Hospital in Jordan reported that 6% of adult patients with CRS had low levels of at least one of the major immunoglobulin isotypes and 14% had low levels of one or more IgG subclasses [
      • Odat H.
      • Alqudah M.
      Prevalence and pattern of humoral immunodeficiency in chronic refractory sinusitis.
      ]. A detailed study of 67 patients with CRS at the University of Iowa reported low IgA, IgG and IgM levels in 3%, 9% and 12%, respectively. IgG subclass levels were low in 6 of 31 tested patients [
      • Alqudah M.
      • Graham S.M.
      • Ballas Z.K.
      High prevalence of humoral immunodeficiency patients with refractory chronic rhinosinusitis.
      ]. Fifty-one were given 23-valent unconjugated pneumococcal polysaccharide vaccine (Pneumovax®, PPV-23; Merck Sharp & Dohme Corp.): 67% failed to produce at least a 4-fold response to more than 7 of 14 measured serotypes and were deemed to have “functional antibody deficiency” (sic) [
      • Alqudah M.
      • Graham S.M.
      • Ballas Z.K.
      High prevalence of humoral immunodeficiency patients with refractory chronic rhinosinusitis.
      ]. A recent meta-analysis of 13 studies which collectively included over 1400 patients reported that 23% of patients with CRS for >1 year not controlled by surgery were deficient in IgA, IgG or IgM [
      • Schwitzguebel A.J.
      • Jandus P.
      • Lacroix J.S.
      • Seebach J.D.
      • Harr T.
      Immunoglobulin deficiency in patients with chronic rhinosinusitis: systematic review of the literature and meta-analysis.
      ]. A 2015 study from Northwestern University reported that amongst 239 adults with CRS, only 64 (27%) had protective titers (≥1.3 μg/mL of IgG) to 7 or more of 14 pneumococcal serotypes at baseline, regardless of prior immunization status. Upon vaccination, only 119 patients (50%) had an adequate response to PPV-23, defined as achieving ≥1.3 μg/mL of antibody to at least 7 serotypes. Fifty-six patients with CRS (23%) failed to respond to the vaccine and were diagnosed with “SAD” [
      • Kashani S.
      • Carr T.F.
      • Grammer L.C.
      • Schleimer R.P.
      • Hulse K.E.
      • Kato A.
      • Kern R.C.
      • Conley D.B.
      • Chandra R.K.
      • Tan B.K.
      • Peters A.T.
      Clinical characteristics of adults with chronic rhinosinusitis and specific antibody deficiency.
      ]; amongst these patients, 71% also carried the diagnosis of asthma [
      • Kashani S.
      • Carr T.F.
      • Grammer L.C.
      • Schleimer R.P.
      • Hulse K.E.
      • Kato A.
      • Kern R.C.
      • Conley D.B.
      • Chandra R.K.
      • Tan B.K.
      • Peters A.T.
      Clinical characteristics of adults with chronic rhinosinusitis and specific antibody deficiency.
      ]. Amongst those patients who responded to the vaccine or had protective antibody levels at baseline, 63% had asthma, as well.
      An association between IgG2 deficiency, poor antibody response to bacterial polysaccharides and recurrent respiratory infections has been recognized for decades. A 1985 study of 20 children with unexplained recurrent sinopulmonary infections and normal total IgG levels revealed that 60% had selective IgG2 deficiency and 6% more had combined IgG2 and IgG3 deficiency [
      • Umetsu D.T.
      • Ambrosino D.M.
      • Quinti I.
      • Siber G.R.
      • Geha R.S.
      Recurrent sinopulmonary infection and impaired antibody response to bacterial capsular polysaccharide antigen in children with selective IgG-subclass deficiency.
      ]. All of these children had recurrent sinusitis, 42% of those with selective IgG2 deficiency had recurrent pneumonia and 42% were diagnosed with asthma. Amongst those with IgG2 and IgG3 deficiency, 67% had recurrent pneumonia and 33% were diagnosed with asthma. The IgG2 deficient patients had poor responses to Haemophilus influenzae polysaccharide vaccine (p < 0.02) despite normal responses to protein antigens [
      • Umetsu D.T.
      • Ambrosino D.M.
      • Quinti I.
      • Siber G.R.
      • Geha R.S.
      Recurrent sinopulmonary infection and impaired antibody response to bacterial capsular polysaccharide antigen in children with selective IgG-subclass deficiency.
      ]. In a recent Dutch study of 90 children with IgG subclass deficiency and/or SAD, IgG2 deficiency was the most prevalent, accounting for 76% of all confirmed subclass deficiencies. Seventy-three percent of these children had ≥4 ear, nose and throat (ENT) infections in the year before the study, 57% had at least one lower airway infection, and 10% already had bronchiectasis [
      • Schatorje E.J.
      • de Jong E.
      • van Hout R.W.
      • Garcia Vivas Y.
      • de Vries E.
      The challenge of immunoglobulin-G subclass deficiency and specific polysaccharide antibody deficiency–a Dutch pediatric cohort study.
      ]. Specific antibody responses were not studied in this cohort [
      • Schatorje E.J.
      • de Jong E.
      • van Hout R.W.
      • Garcia Vivas Y.
      • de Vries E.
      The challenge of immunoglobulin-G subclass deficiency and specific polysaccharide antibody deficiency–a Dutch pediatric cohort study.
      ]. However, a recent report on 54 adult patients with recurrent or severe bacterial respiratory infections and deficiency of 1 or more IgG subclasses revealed that 35% failed to respond to PPV-23, and overall there was a highly significant inverse correlation between IgG2 levels and vaccine response (p < 0.006) [
      • Barton J.C.
      • Bertoli L.F.
      • Barton J.C.
      • Acton R.T.
      Selective subnormal IgG1 in 54 adult index patients with frequent or severe bacterial respiratory tract infections.
      ].
      Taken together, the above findings show that PIDD, including IgG subclass deficiencies and SADs can contribute to CRS, lower airway infections, bronchiectasis, and asthma (discussed below). Although asthma is a frequent co-morbidity with rhinosinusitis regardless of the underlying cause, it may not be useful in identifying the subset of CRS patients with underlying PIDD.

      2.2 Asthma in PIDD

      A recent survey of data in the registries of the Partners Health Care system in Boston and the United States Immunodeficiency Network (USIDNET) suggest that asthma, not bronchiectasis, is the most common respiratory complication amongst US patients with CVID. Asthma was reported in 47% and 33% of patients, respectively; bronchiectasis was reported in less than 15% in both series [

      J. Farmer, L. Yonker, P. Permaul, P. Hesterberg, R. Iyengar, K.E. Sullivan, D. Suez, C. Cunningham-Rundles, J.E. Walter, Comparative analysis of the epidemiology of common variable immunodeficiency (CVID) in a large tertiary care center versus the USIDNET registry. Poster presented at CIS Annual Meeting 2015, Houston, Texas, April 9-12.

      ]. Of note, diagnostic criteria for bronchiectasis were not described and it was not stated if procedures such as high-resolution CT scans were uniformly obtained. It thus seems likely that in some patients with PIDD, upper as well as lower respiratory infection may result in asthmatic bronchoconstriction and remodeling. We postulate that prolonged continuation of this pathophysiology eventually causes irreversible obstructive disease recognized as COPD or ACOS.
      Further evidence linking antibody deficiency and asthma comes from a study of 39 patients diagnosed with IgA deficiency or CVID at a mean age of 34.2 ± 24.4 years: 23.1% were diagnosed with asthma before their PIDD was diagnosed, and another 7.7% were diagnosed with asthma after their PIDD diagnosis, giving a cumulative rate of 30.8%. In contrast, matched controls had a cumulative prevalence of asthma of only 11.5% (p = 0.01) [
      • Urm S.H.
      • Yun H.D.
      • Fenta Y.A.
      • Yoo K.H.
      • Abraham R.S.
      • Hagan J.
      • Juhn Y.J.
      Asthma and risk of selective IgA deficiency or common variable immunodeficiency: a population-based case-control study.
      ]. In two case-control studies, one of Tennessee Medicaid patients, and one in Olmstead County, Minnesota, asthma was found to be the leading underlying risk factor for invasive or serious pneumococcal disease, with odds ratios of 2.4 in both studies [
      • Talbot T.R.
      • Hartert T.V.
      • Mitchel E.
      • Halasa N.B.
      • Arbogast P.G.
      • Poehling K.A.
      • Schaffner W.
      • Craig A.S.
      • Griffin M.R.
      Asthma as a risk factor for invasive pneumococcal disease.
      ,
      • Juhn Y.J.
      • Kita H.
      • Yawn B.P.
      • Boyce T.G.
      • Yoo K.H.
      • McGree M.E.
      • Weaver A.L.
      • Wollan P.
      • Jacobson R.M.
      Increased risk of serious pneumococcal disease in patients with asthma.
      ]. Amongst adults in the Minnesota study, the odds ratio for asthma as a predisposing factor was 6.7 (p = 0.01) [
      • Juhn Y.J.
      • Kita H.
      • Yawn B.P.
      • Boyce T.G.
      • Yoo K.H.
      • McGree M.E.
      • Weaver A.L.
      • Wollan P.
      • Jacobson R.M.
      Increased risk of serious pneumococcal disease in patients with asthma.
      ]. Thus, longstanding airways disease, often characterized as asthma, is frequently associated with increased susceptibility to infection and/or underlying antibody deficiency, even if the latter has not actually been recognized, investigated or diagnosed.
      A recently published long-term follow-up of 684 children with asthma reported that 75% of those with persistent symptoms had abnormal patterns of lung growth and/or function, and of these, 26% had reduced lung growth and pulmonary function decline as young adults. Eighteen percent of the individuals with reduced lung function or growth, with or without an early decline, met criteria for COPD before the age of 30 years [
      • McGeachie M.J.
      • Yates K.P.
      • Zhou X.
      • Guo F.
      • Sternberg A.L.
      • Van Natta M.L.
      • Wise R.A.
      • Szefler S.J.
      • Sharma S.
      • Kho A.T.
      • Cho M.H.
      • Croteau-Chonka D.C.
      • Castaldi P.J.
      • Jain G.
      • Sanyal A.
      • Zhan Y.
      • Lajoie B.R.
      • Dekker J.
      • Stamatoyannopoulos J.
      • Covar R.A.
      • Zeiger R.S.
      • Adkinson N.F.
      • Williams P.V.
      • Kelly H.W.
      • Grasemann H.
      • Vonk J.M.
      • Koppelman G.H.
      • Postma D.S.
      • Raby B.A.
      • Houston I.
      • Lu Q.
      • Fuhlbrigge A.L.
      • Tantisira K.G.
      • Silverman E.K.
      • Tonascia J.
      • Weiss S.T.
      • Strunk R.C.
      Camp Research Group, Patterns of growth and decline in lung function in persistent childhood asthma.
      ]. Thus, persistence of reversible airways disease may eventually result in irreversible chronic airways obstruction.

      2.3 Bronchiectasis in PIDD

      Bronchiectasis is a well-recognized complication of PIDD. A recent review of UK PID Registry data showed that 47% of a cohort of 801 patients with primary hypogammaglobulinemia had bronchiectasis confirmed by high-resolution CT scans, and that patients with bronchiectasis had a significantly longer delay between the onset of symptoms and the beginning of IgG therapy than those without bronchiectasis [
      • Brent J.
      • Guzman D.
      • Bangs C.
      • Grimbacher B.
      • Fayolle C.
      • Huissoon A.
      • Bethune C.
      • Thomas M.
      • Patel S.
      • Jolles S.
      • Alachkar H.
      • Kumaratne D.
      • Baxendale H.
      • Edgar J.D.
      • Helbert M.
      • Hambleton S.
      • Arkwright P.D.
      Clinical and laboratory correlates of lung disease and cancer in adults with idiopathic hypogammaglobulinaemia.
      ]. Furthermore, Lucas, et al. [
      • 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.
      ] reported that patients with primary antibody deficiency and bronchiectasis have lower serum IgG levels with any given dose of replacement therapy than those without bronchiectasis, suggesting that not only delay in the diagnosis of PIDD but also under-treatment contribute to the development of bronchiectasis in PIDD patients. A review of records of patients seen over a 10-year period (2002–2012) in a university hospital in France reported that 6% of adult patients (median age, 61 years) with bronchiectasis carried the diagnosis of an underlying primary immune deficiency [
      • Buscot M.
      • Pottier H.
      • Marquette C.H.
      • Leroy S.
      Phenotyping adults with non-cystic fibrosis bronchiectasis: a 10-year cohort study in a French regional university hospital center.
      ], and a recent US study of nearly 1000 children with non-cystic fibrosis bronchiectasis reported that 16% had PIDD [
      • Brower K.S.
      • Del Vecchio M.T.
      • Aronoff S.C.
      The etiologies of non-CF bronchiectasis in childhood: a systematic review of 989 subjects.
      ]. Bronchiectasis is also common in COPD, and CT-scan evidence of bronchiectasis is associated with a greater frequency of exacerbations, more frequent isolation of pathogens, and more severe airway obstruction [
      • Amalakuhan B.
      • Maselli D.J.
      • Martinez-Garcia M.A.
      Update in bronchiectasis 2014.
      ,
      • Du Q.
      • Jin J.
      • Liu X.
      • Sun Y.
      Bronchiectasis as a comorbidity of chronic obstructive pulmonary disease: a systematic review and meta-analysis.
      ].

      3. Deficient humoral immunity in COPD

      Data in the literature on the prevalence of PIDD in patients with COPD is sparse. At the level of the target tissue, it seems intuitive that specific antibodies are an important contributor to local host defense and that their absence might contribute to chronic infection. A study of specific antibodies against non-typeable Haemophilus influenzae in COPD patients with frequent exacerbations and positive cultures for this organism showed decreased total IgG (p = 0.0068) and specific antibodies in bronchoalveolar lavage (p = 0.043) [
      • Staples K.J.
      • Taylor S.
      • Thomas S.
      • Leung S.
      • Cox K.
      • Pascal T.G.
      • Ostridge K.
      • Welch L.
      • Tuck A.C.
      • Clarke S.C.
      • Gorringe A.
      • Wilkinson T.M.
      Relationships between mucosal antibodies, non-typeable Haemophilus influenzae (NTHi) infection and airway inflammation in COPD.
      ]. However, we do not know how often antibody deficiency contributes to COPD in clinical practice. A retrospective analysis of 913 patients with COPD and recurrent infections referred to Papworth Hospital showed that 17 already had established diagnoses of CVID, another 18 had suspected CVID confirmed, and 5 new cases of CVID were discovered, giving an overall prevalence of CVID in COPD patients of 4.4% (40/913) [
      • Exley A.R.
      • Henderson K.
      • Buckenham S.
      • Kimberlin H.
      • Gronlund H.
      • French J.
      • Campbell K.
      • Bilton D.
      • Barker H.
      • Screaton N.
      • Haworth C.S.
      • Floto R.A.
      Diagnosis and management of common variable immuno-deficiency (CVID) in adults with recurrent pulmonary infection.
      ]. Amongst 1665 referrals to a pulmonology group in the US for management of COPD, 20 patients were found to have unrecognized hypogammaglobulinemia, 2 had secondary hypogammaglobulinemia associated with other conditions, and 18 had previously unrecognized CVID. Thus, the prevalence of antibody deficiency in patients with COPD was 2.4% (40/1665). Of the 40 patients, 17 started IgG replacement therapy, resulting in improvement in symptoms, decreased sputum production, and decreased frequency of exacerbations [
      • Baleeiro C.
      • Mull N.
      Prevalence of common variable immunodeficiency (CVID) among patients with recurrent respiratory tract infections.
      ].
      A cohort of 29 adult patients with frequent exacerbations of COPD and antibody deficiency was identified at the University of Iowa by chart review and/or referral for immunodeficiency evaluation. Amongst these patients, 76% had IgG below normal, 36% had IgA below normal and 44% had IgM below normal. Fifty-three percent met criteria for Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification 3 or 4. Twenty of the 29 patients were deficient in antibodies against pneumococcal polysaccharides, despite receiving PPV-23. Nine patients were started on IgG replacement, 13 were given chronic oral antibiotic replacement, and 7 had not yet started on specifically targeted therapy at the time of the report. Amongst the patients given IgG and/or antibiotics, the mean number of exacerbations per year fell from 4 to 1 (p < 0.0001), there were no hospitalizations, and the cumulative annual dose of prednisone fell from 930 mg to 0 mg (p = 0.031). Oxygen use increased from 7 to 9 patients [
      • McCullagh B.N.
      • Comellas A.P.
      • Ballas Z.K.
      • Newell Jr., J.D.
      • Zimmerman M.B.
      • Azar A.E.
      Antibody deficiency in patients with frequent exacerbations of chronic obstructive pulmonary disease (COPD).
      ].
      The gamma globulin fraction of serum was analyzed by protein electrophoresis in a longitudinal study of 120 patients (mean age, 72.9 years) admitted to the Hospital of Mataro, Spain for an exacerbation of COPD attributed to infectious etiology [
      • Boixeda R.
      • Capdevila J.A.
      • Vicente V.
      • Palomera E.
      • Juanola J.
      • Albiach L.
      • Rex A.
      • Almirall J.
      Gamma globulin fraction of the proteinogram and chronic obstructive pulmonary disease exacerbations.
      ]. Patients with lower levels of gamma globulin had more severe COPD according to GOLD criteria, the body-mass index, airflow obstruction, dyspnea, and exercise (BODE) index, and the Medical Research Council (MRC) dyspnea scale. Patients with lower gamma globulin levels had more severe reductions in FEV1 (% predicted), lower FEV1/FVC, increased requirements for home oxygen, an increased need for re-admission within 6 months, and a trend (p = 0.054) towards increased mortality within 1 year [
      • Boixeda R.
      • Capdevila J.A.
      • Vicente V.
      • Palomera E.
      • Juanola J.
      • Albiach L.
      • Rex A.
      • Almirall J.
      Gamma globulin fraction of the proteinogram and chronic obstructive pulmonary disease exacerbations.
      ]. The increased severity and morbidity in COPD patients with low IgG levels reported in these studies is consistent with the hypothesis that antibody deficiency contributes to the development and progression of chronic airways disease.
      More recently, IgG levels were measured in stored samples from 1629 patients enrolled in large controlled studies of other therapies for prevention of COPD exacerbations. Patients in the lower quartiles of serum IgG levels in both studies had significantly more exacerbations and hospitalizations for COPD than those in the highest quartile (p < 0.01 for all comparisons) and the overall results suggested an inverse linear relationship between the total IgG level and the risk of exacerbations, extending from below normal IgG into the normal range [
      • Leitao Filho F.S.
      • Won Ra S.
      • Mattman A.
      • Schellenberg R.S.
      • Fishbane N.
      • Criner G.J.
      • Woodruff P.G.
      • Lazarus S.C.
      • Albert R.
      • Connett J.E.
      • Han M.K.
      • Martinez F.J.
      • Leung J.M.
      • Man S.F.P.
      • Aaron S.D.
      • Reed R.M.
      • Sin D.D.
      Serum IgG and risk of exacerbations and hospitalizations in chronic obstructive pulmonary disease.
      ]. Specific antibody titers and vaccine responses were not reported in that study. Cowan et al. reported a retrospective chart review of a cohort of 14 adult patients with frequent exacerbations of COPD who had been started empirically on IgG augmentation therapy [
      • Cowan J.
      • Gaudet L.
      • Mulpuru S.
      • Corrales-Medina V.
      • Hawken S.
      • Cameron C.
      • Aaron S.D.
      • Cameron D.W.
      A retrospective longitudinal within-subject risk interval analysis of immunoglobulin treatment for recurrent acute exacerbation of chronic obstructive pulmonary disease.
      ]. The median IgG level before treatment was 5.9 g/L, but only 5 patients had frank hypogammaglobulinemia (IgG<5 g/L). IgG subclass and specific antibody levels were not reported. The mean FEV1 was 46% of predicted and the mean FEV1/FVC was 43.4. Eight patients were considered to have severe COPD by the GOLD criteria, and 6 had bronchiectasis. After a year of IgG therapy (0.5 g/kg/month), there was a 92% reduction in severe exacerbations of COPD and an 85% reduction in moderate exacerbations (p < 0.0001) [
      • Cowan J.
      • Gaudet L.
      • Mulpuru S.
      • Corrales-Medina V.
      • Hawken S.
      • Cameron C.
      • Aaron S.D.
      • Cameron D.W.
      A retrospective longitudinal within-subject risk interval analysis of immunoglobulin treatment for recurrent acute exacerbation of chronic obstructive pulmonary disease.
      ].
      Many asthma, ACOS, and COPD patients are treated with systemic corticosteroids, which can result in decreased IgG and IgA levels [
      • Butler W.T.
      • Rossen R.D.
      Effects of corticosteroids on immunity in man. I. Decreased serum IgG concentration caused by 3 or 5 days of high doses of methylprednisolone.
      ,
      • Griggs R.C.
      • Condemi J.J.
      • Vaughan J.H.
      Effect of therapeutic dosages of prednisone on human immunoglobulin G metabolism.
      ,
      • Settipane G.A.
      • Pudupakkam R.K.
      • McGowan J.H.
      Corticosteroid effect on immunoglobulins.
      ]. It is difficult to know how many of these patients may have underlying PIDD because Ig and specific antibody levels are not usually checked before steroids are prescribed. Increased susceptibility to infection is commonly acknowledged as a risk of steroid therapy, but analysis of specific antibody titers and/or vaccine responses are not usually performed to determine how significantly steroid therapy contributes to an increased frequency or severity of infection of the sinuses and/or lower airways in any given patient, and the possible benefits of IgG replacement therapy are generally overlooked.
      Other immunosuppressive medications can also cause secondary immune deficiencies which may include hypogammaglobulinemia and can lead to bronchiectasis. Use of B-cell targeting therapies, such as the monoclonal antibody rituximab, for either autoimmune or malignant conditions can result in hypogammaglobulinemia which closely resembles that in primary antibody deficiency, and may have a similar incidence of chronic pulmonary symptoms and bronchiectasis [
      • Kado R.
      • Sanders G.
      • McCune W.J.
      Diagnostic and therapeutic considerations in patients with hypogammaglobulinemia after rituximab therapy.
      ,
      • Duraisingham S.S.
      • Buckland M.
      • Dempster J.
      • Lorenzo L.
      • Grigoriadou S.
      • Longhurst H.J.
      Primary vs. secondary antibody deficiency: clinical features and infection outcomes of immunoglobulin replacement.
      ]. Secondary hypogammaglobulinemia may also occur in the setting of protein-losing diseases and after transplantation. In one single-center series, 8% of 289 kidney transplant recipients who were given mycophenolate mofetil (MMF) suffered recurrent severe chest infections between 1 and 8 years after their transplants. Of these, 7 had bronchiectasis. All of them had hypogammaglobulinemia. No bronchiectasis was observed in transplant patients who did not receive MMF [
      • Boddana P.
      • Webb L.H.
      • Unsworth J.
      • Brealey M.
      • Bingham C.
      • Harper S.J.
      Hypogammaglobulinemia and bronchiectasis in mycophenolate mofetil-treated renal transplant recipients: an emerging clinical phenomenon?.
      ]. This association was confirmed in a more recent multicenter report from France. Forty-six renal transplant recipients, all of whom had been treated with mycophenolic acid, were found to have bronchiectasis. Fifteen of them had hypogammaglobulinemia, but only 6 had been given antibody replacement therapy [
      • Dury S.
      • Colosio C.
      • Etienne I.
      • Anglicheau D.
      • Merieau E.
      • Caillard S.
      • Rivalan J.
      • Thervet E.
      • Essig M.
      • Babinet F.
      • Subra J.F.
      • Toubas O.
      • Rieu P.
      • Launois C.
      • Perotin-Collard J.M.
      • Lebargy F.
      • Deslee G.
      • Spiesser g.
      Bronchiectasis diagnosed after renal transplantation: a retrospective multicenter study.
      ]. Human immunodeficiency virus (HIV) infection has also been associated with asthma and a prevalence of COPD as high as 23% in some studies [
      • Drummond M.B.
      • Kunisaki K.M.
      • Huang L.
      Obstructive lung diseases in HIV: a clinical review and identification of key future research needs.
      ].
      Inadequate antibody responses to respiratory infections and/or vaccines may explain why immunization programs using unconjugated polysaccharide vaccines, such as PPV-23, fail to reduce the morbidity due to COPD [
      • Dransfield M.T.
      • Nahm M.H.
      • Han M.K.
      • Harnden S.
      • Criner G.J.
      • Martinez F.J.
      • Scanlon P.D.
      • Woodruff P.G.
      • Washko G.R.
      • Connett J.E.
      • Anthonisen N.R.
      • Bailey W.C.
      COPD Clinical Research Network, Superior immune response to protein-conjugate versus free pneumococcal polysaccharide vaccine in chronic obstructive pulmonary disease.
      ,
      • Walters J.A.
      • Smith S.
      • Poole P.
      • Granger R.H.
      • Wood-Baker R.
      Injectable vaccines for preventing pneumococcal infection in patients with chronic obstructive pulmonary disease.
      ]. Vaccines containing polysaccharides alone are unable to recruit T-cell help and are often not very immunogenic. In contrast, attaching or “conjugating” the polysaccharides to an immunogenic protein, such as diphtheria toxoid, recruits T-cells which respond to the protein and enhance the B-cell response to the polysaccharides.
      A Cochrane review showed that PPV-23 vaccination of patients with COPD did not reduce the likelihood of exacerbations of COPD, pneumonia, frequency of hospital admissions or mortality [
      • Walters J.A.
      • Smith S.
      • Poole P.
      • Granger R.H.
      • Wood-Baker R.
      Injectable vaccines for preventing pneumococcal infection in patients with chronic obstructive pulmonary disease.
      ]. Furthermore, the antibody response declined with increasing age. A randomized, controlled study of 120 adult patients with COPD compared the response to PPV-23 with the response to a protein-conjugated vaccine (7-valent pneumococcal conjugate vaccine, Prevnar®, PCV-7; Wyeth Pharmaceuticals Inc.) [
      • Dransfield M.T.
      • Nahm M.H.
      • Han M.K.
      • Harnden S.
      • Criner G.J.
      • Martinez F.J.
      • Scanlon P.D.
      • Woodruff P.G.
      • Washko G.R.
      • Connett J.E.
      • Anthonisen N.R.
      • Bailey W.C.
      COPD Clinical Research Network, Superior immune response to protein-conjugate versus free pneumococcal polysaccharide vaccine in chronic obstructive pulmonary disease.
      ]. Patients with histories of asthma were excluded, but COPD patients taking oral corticosteroids were included in the study population. Antibody titers to 5 of the 7 serotypes which are in both vaccines were significantly lower after immunization with PPV-23 as compared with PCV-7. Sixty percent of recipients of either vaccine failed to mount a 2-fold response to type 19F; 41% and 35% of recipients of PPV-23 and PCV-7, respectively, failed to mount a 2-fold response to type 14; and 45–64% of recipients of PPV-23 and 15–43% of recipients of PCV-7 failed to mount 2-fold responses to the 5 remaining serotypes contained in both vaccines [
      • Dransfield M.T.
      • Nahm M.H.
      • Han M.K.
      • Harnden S.
      • Criner G.J.
      • Martinez F.J.
      • Scanlon P.D.
      • Woodruff P.G.
      • Washko G.R.
      • Connett J.E.
      • Anthonisen N.R.
      • Bailey W.C.
      COPD Clinical Research Network, Superior immune response to protein-conjugate versus free pneumococcal polysaccharide vaccine in chronic obstructive pulmonary disease.
      ]. Patients with COPD also had a high rate of failure to respond to influenza vaccine compared to controls (57% vs. 10%, p = 0.036), and their mean increase in antibody titers was much lower than in controls [
      • Nath K.D.
      • Burel J.G.
      • Shankar V.
      • Pritchard A.L.
      • Towers M.
      • Looke D.
      • Davies J.M.
      • Upham J.W.
      Clinical factors associated with the humoral immune response to influenza vaccination in chronic obstructive pulmonary disease.
      ]. There is relatively little data on responses to the newer, 13-valent conjugated pneumococcal vaccine (PCV-13, Prevnar-13®, Wyeth Pharmacueticals, Inc., a subsidiary of Pfizer, Inc.) in asthma or COPD patients. A multicenter study in Italy found no significant association between pharyngeal carriage of pneumococcus in asthmatic children (n = 423) and their pneumococcal vaccination history, although circulating antibody titers were not measured [
      • Esposito S.
      • Terranova L.
      • Patria M.F.
      • Marseglia G.L.
      • Miraglia del Giudice M.
      • Bodini A.
      • Martelli A.
      • Baraldi E.
      • Mazzina O.
      • Tagliabue C.
      • Licari A.
      • Ierardi V.
      • Lelii M.
      • Principi N.
      Streptococcus pneumoniae colonisation in children and adolescents with asthma: impact of the heptavalent pneumococcal conjugate vaccine and evaluation of potential effect of thirteen-valent pneumococcal conjugate vaccine.
      ]. A study of 206 pneumococcal isolates collected from 162 COPD patients suffering acute exacerbations at a single center in Barcelona over a 10-year period showed an increased incidence of non-vaccine serotypes after introduction of PCV-7 and then PCV-13 [
      • Domenech A.
      • Ardanuy C.
      • Tercero A.
      • Garcia-Somoza D.
      • Santos S.
      • Linares J.
      Dynamics of the pneumococcal population causing acute exacerbations in COPD patients in a Barcelona hospital (2009-12): comparison with 2001-04 and 2005-08 periods.
      ]. However, a more recent study from Spain showed that in an 18 month follow-up period, COPD patients who received PCV-13 were less likely to require hospitalization for an acute exacerbation than those who did not receive this vaccine (18% vs. 32%, respectively, p = 0.044). Interestingly, even in the immunized group, the re-admission rate was quite high [
      • Fiqueira-Goncalves J.M.
      • Bethencourt-Martin N.
      • Perez-Mendez L.I.
      • Diaz-Perez D.
      • Guzman-Saenz C.
      • Vina-Manrique P.
      • Pedrero-Garcia A.J.
      Impact of 13-valent pneumococal conjugate polysaccharide vaccination in exacerbations rate of COPD patients with moderate to severe obstruction.
      ].
      The above findings indicate that, amongst patients with COPD, even conjugated polysaccharide and protein vaccines leave significant gaps in protection, and a high proportion fail to mount specific antibody responses.

      4. Infection as a contributing factor to chronic airways disease

      Seasonal respiratory virus infections are well-recognized causes of asthma exacerbations, and may contribute to COPD exacerbations as well [
      • Eggo R.M.
      • Scott J.G.
      • Galvani A.P.
      • Meyers L.A.
      Respiratory virus transmission dynamics determine timing of asthma exacerbation peaks: evidence from a population-level model.
      ,
      • Djamin R.S.
      • Uzun S.
      • Snelders E.
      • Kluytmans J.J.
      • Hoogsteden H.C.
      • Aerts J.G.
      • Van Der Eerden M.M.
      Occurrence of virus-induced COPD exacerbations during four seasons.
      ]. The concomitant presence of bacterial infection raises the risk even more [
      • Kloepfer K.M.
      • Lee W.M.
      • Pappas T.E.
      • Kang T.J.
      • Vrtis R.F.
      • Evans M.D.
      • Gangnon R.E.
      • Bochkov Y.A.
      • Jackson D.J.
      • Lemanske Jr., R.F.
      • Gern J.E.
      Detection of pathogenic bacteria during rhinovirus infection is associated with increased respiratory symptoms and asthma exacerbations.
      ]. For example, Kloepfer, et al. [
      • Kloepfer K.M.
      • Lee W.M.
      • Pappas T.E.
      • Kang T.J.
      • Vrtis R.F.
      • Evans M.D.
      • Gangnon R.E.
      • Bochkov Y.A.
      • Jackson D.J.
      • Lemanske Jr., R.F.
      • Gern J.E.
      Detection of pathogenic bacteria during rhinovirus infection is associated with increased respiratory symptoms and asthma exacerbations.
      ] recently reported that patients with positive cultures for Streptococcus pneumoniae, Moraxella catarrhalis, or Haemophilus influenzae concomitantly with rhinovirus had a 5-fold increase in odds ratio for asthma exacerbations as compared to those without pathogens. Peltola et al. [
      • Peltola V.
      • Waris M.
      • Kainulainen L.
      • Kero J.
      • Ruuskanen O.
      Virus shedding after human rhinovirus infection in children, adults and patients with hypogammaglobulinaemia.
      ] reported that patients with hypogammaglobulinemia shed rhinovirus for a mean of 41 days after initial symptoms, as compared to household controls with normal immunoglobulin levels, who shed rhinovirus for only 11 days (p < 0.001). There was a highly significant association between duration of symptoms and duration of shedding (p = 0.002) [
      • Peltola V.
      • Waris M.
      • Kainulainen L.
      • Kero J.
      • Ruuskanen O.
      Virus shedding after human rhinovirus infection in children, adults and patients with hypogammaglobulinaemia.
      ]. A comparison of adult-onset asthma patients with non-asthmatics showed that the former had an odds ratio of 7.18 for a lower respiratory tract infection in the preceding 12 months (95% CI, 5.16–9.99) [
      • Rantala A.
      • Jaakkola J.J.
      • Jaakkola M.S.
      Respiratory infections precede adult-onset asthma.
      ].
      Infection is also widely considered a major contributor to the pathogenesis and clinical course of COPD, particularly its acute exacerbations [
      • Hurst J.R.
      • Wedzicha J.A.
      The biology of a chronic obstructive pulmonary disease exacerbation.
      ,
      • Veeramachaneni S.B.
      • Sethi S.
      Pathogenesis of bacterial exacerbations of COPD.
      ,
      • Sethi S.
      • Murphy T.F.
      Infection in the pathogenesis and course of chronic obstructive pulmonary disease.
      ]. Twenty to 30% of COPD exacerbations are attributed to Haemophilus influenzae, and 20–25% to rhinoviruses [
      • Sethi S.
      • Murphy T.F.
      Infection in the pathogenesis and course of chronic obstructive pulmonary disease.
      ], but it is not clear to what extent antibody or other immune deficiencies might contribute to chronic carriage and/or acute infection with these and similar organisms in COPD patients. Persistence of bacteria in the lower airways during stable disease and clinically quiescent periods likely contributes to continuous neutrophilic inflammation in many patients [
      • Finney L.J.
      • Ritchie A.
      • Pollard E.
      • Johnston S.L.
      • Mallia P.
      Lower airway colonization and inflammatory response in COPD: a focus on Haemophilus influenzae.
      ]. Thus, a vicious cycle of infection and inflammation is considered responsible for chronic progression as well as acute exacerbations of COPD [
      • Veeramachaneni S.B.
      • Sethi S.
      Pathogenesis of bacterial exacerbations of COPD.
      ,
      • Sethi S.
      • Murphy T.F.
      Infection in the pathogenesis and course of chronic obstructive pulmonary disease.
      ,
      • Finney L.J.
      • Ritchie A.
      • Pollard E.
      • Johnston S.L.
      • Mallia P.
      Lower airway colonization and inflammatory response in COPD: a focus on Haemophilus influenzae.
      ]. It follows that unrecognized antibody deficiency may be a significant risk factor for increased COPD-related morbidity.

      5. Practical approach to recognition and diagnosis of antibody deficiency and PIDD in patients with chronic respiratory disease

      Guidelines for evaluation and diagnostic criteria for PIDD are available from the Immune Deficiency Foundation and the American Academy of Allergy, Asthma and Immunology [
      • Bonilla F.A.
      • Khan D.A.
      • Ballas Z.K.
      • Chinen J.
      • Frank M.M.
      • Hsu J.T.
      • Keller M.
      • Kobrynski L.J.
      • Komarow H.D.
      • Mazer B.
      • Nelson Jr., R.P.
      • Orange J.S.
      • Routes J.M.
      • Shearer W.T.
      • Sorensen R.U.
      • Verbsky J.W.
      • Bernstein D.I.
      • Blessing-Moore J.
      • Lang D.
      • Nicklas R.A.
      • Oppenheimer J.
      • Portnoy J.M.
      • Randolph C.R.
      • Schuller D.
      • Spector S.L.
      • Tilles S.
      • Wallace D.
      Practice parameter for the diagnosis and management of primary immunodeficiency.
      ,
      • Immune Deficiency Foundation
      Diagnostic and Clinical Care Guidelines for Primary Immunodeficiency Diseases.
      ,
      • Sullivan K.E.
      Immune Deficiency Foundation Clinical Focus on Primary Immunodeficiency: Diagnostic Approaches to Antibody Deficiencies.
      ,
      • Orange J.S.
      • Ballow M.
      • Stiehm E.R.
      • Ballas Z.K.
      • Chinen J.
      • De La Morena M.
      • Kumararatne D.
      • Harville T.O.
      • Hesterberg P.
      • Koleilat M.
      • McGhee S.
      • Perez E.E.
      • Raasch J.
      • Scherzer R.
      • Schroeder H.
      • Seroogy C.
      • Huissoon A.
      • Sorensen R.U.
      • Katial R.
      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.
      ]. Although the recognition of PIDD has increased in recent years, particularly in adults aged over 50 years [
      • Joshi A.Y.
      • Iyer V.N.
      • Hagan J.B.
      • St Sauver J.L.
      • Boyce T.G.
      Incidence and temporal trends of primary immunodeficiency: a population-based cohort study.
      ,
      • Edgar J.D.
      • Buckland M.
      • Guzman D.
      • Conlon N.P.
      • Knerr V.
      • Bangs C.
      • Reiser V.
      • Panahloo Z.
      • Workman S.
      • Slatter M.
      • Gennery A.R.
      • Davies E.G.
      • Allwood Z.
      • Arkwright P.D.
      • Helbert M.
      • Longhurst H.J.
      • Grigoriadou S.
      • Devlin L.A.
      • Huissoon A.
      • Krishna M.T.
      • Hackett S.
      • Kumararatne D.S.
      • Condliffe A.M.
      • Baxendale H.
      • Henderson K.
      • Bethune C.
      • Symons C.
      • Wood P.
      • Ford K.
      • Patel S.
      • Jain R.
      • Jolles S.
      • El-Shanawany T.
      • Alachkar H.
      • Herwadkar A.
      • Sargur R.
      • Shrimpton A.
      • Hayman G.
      • Abuzakouk M.
      • Spickett G.
      • Darroch C.J.
      • Paulus S.
      • Marshall S.E.
      • McDermott E.M.
      • Heath P.T.
      • Herriot R.
      • Noorani S.
      • Turner M.
      • Khan S.
      • Grimbacher B.
      The United Kingdom primary immune deficiency (UKPID) registry: report of the first 4 years' activity 2008-2012.
      ,
      • Immune Deficiency Foundation
      ], the diagnostic delay is still 6–12 years [
      • Edgar J.D.
      • Buckland M.
      • Guzman D.
      • Conlon N.P.
      • Knerr V.
      • Bangs C.
      • Reiser V.
      • Panahloo Z.
      • Workman S.
      • Slatter M.
      • Gennery A.R.
      • Davies E.G.
      • Allwood Z.
      • Arkwright P.D.
      • Helbert M.
      • Longhurst H.J.
      • Grigoriadou S.
      • Devlin L.A.
      • Huissoon A.
      • Krishna M.T.
      • Hackett S.
      • Kumararatne D.S.
      • Condliffe A.M.
      • Baxendale H.
      • Henderson K.
      • Bethune C.
      • Symons C.
      • Wood P.
      • Ford K.
      • Patel S.
      • Jain R.
      • Jolles S.
      • El-Shanawany T.
      • Alachkar H.
      • Herwadkar A.
      • Sargur R.
      • Shrimpton A.
      • Hayman G.
      • Abuzakouk M.
      • Spickett G.
      • Darroch C.J.
      • Paulus S.
      • Marshall S.E.
      • McDermott E.M.
      • Heath P.T.
      • Herriot R.
      • Noorani S.
      • Turner M.
      • Khan S.
      • Grimbacher B.
      The United Kingdom primary immune deficiency (UKPID) registry: report of the first 4 years' activity 2008-2012.
      ,
      • Immune Deficiency Foundation
      ]. The main obstacle is a lack of recognition by physicians and other providers that an underlying, treatable antibody deficiency may be responsible for the patient's chronic/recurrent complaints. The first and most important step in the diagnosis of potential PIDD is carefully documenting the history of infections [
      • Lehman H.
      • Hernandez-Trujillo V.
      • Ballow M.
      Diagnosing primary immunodeficiency: a practical approach for the non-immunologist.
      ]. Although recurrent lobar pneumonias and episodes of bacteremia/sepsis were once hallmarks of PIDD, in the current era of widespread oral antibiotic use these severe infections are much less reliable as indicators of PIDD. The history is now much more likely to feature frequent and prolonged “colds” and other upper respiratory infections; repeated episodes of sinusitis, often requiring prolonged antibiotic treatment and/or surgery; and recurrent/chronic cough and/or wheezing [
      • Immune Deficiency Foundation
      ,
      • Finney L.J.
      • Ritchie A.
      • Pollard E.
      • Johnston S.L.
      • Mallia P.
      Lower airway colonization and inflammatory response in COPD: a focus on Haemophilus influenzae.
      ]. Specific questions may help to differentiate patients with infection as an important contributor from those with allergy and/or exposure to irritating/toxic inhalants.
      We recommend that patients with histories of recurrent respiratory infections, including chronic/recurrent sinusitis, those who report infection as a trigger for exacerbations of asthma, and those with frequent fevers and/or production of purulent sputum undergo screening of serum levels of the major Igs (IgA, IgG, and IgM). If the IgG level is below the lower limit of normal, antibody deficiency is likely. However, it is important that age-specific normal values from the same laboratory are used. Referral to an immunologist should be considered and the extent of the antibody deficiency and any associated B-cell or other lymphocyte abnormalities should be characterized. An algorithm is provided in Fig. 1 to help guide the workup. If the IgG level is within normal limits, but there is a strong history of infection and/or high suspicion of PIDD, IgG subclasses, specific antibody titers and responses to vaccines should be determined. The underlying diagnosis can then be further pursued as suggested by published guidelines [
      • Bonilla F.A.
      • Khan D.A.
      • Ballas Z.K.
      • Chinen J.
      • Frank M.M.
      • Hsu J.T.
      • Keller M.
      • Kobrynski L.J.
      • Komarow H.D.
      • Mazer B.
      • Nelson Jr., R.P.
      • Orange J.S.
      • Routes J.M.
      • Shearer W.T.
      • Sorensen R.U.
      • Verbsky J.W.
      • Bernstein D.I.
      • Blessing-Moore J.
      • Lang D.
      • Nicklas R.A.
      • Oppenheimer J.
      • Portnoy J.M.
      • Randolph C.R.
      • Schuller D.
      • Spector S.L.
      • Tilles S.
      • Wallace D.
      Practice parameter for the diagnosis and management of primary immunodeficiency.
      ,
      • Immune Deficiency Foundation
      Diagnostic and Clinical Care Guidelines for Primary Immunodeficiency Diseases.
      ,
      • Sullivan K.E.
      Immune Deficiency Foundation Clinical Focus on Primary Immunodeficiency: Diagnostic Approaches to Antibody Deficiencies.
      ,
      • Orange J.S.
      • Ballow M.
      • Stiehm E.R.
      • Ballas Z.K.
      • Chinen J.
      • De La Morena M.
      • Kumararatne D.
      • Harville T.O.
      • Hesterberg P.
      • Koleilat M.
      • McGhee S.
      • Perez E.E.
      • Raasch J.
      • Scherzer R.
      • Schroeder H.
      • Seroogy C.
      • Huissoon A.
      • Sorensen R.U.
      • Katial R.
      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.
      ].
      Fig. 1
      Fig. 1Practical approach to recognition and diagnosis of antibody deficiency and PIDD in patients with respiratory disease.
      Abbreviations: CVID, common variable immune deficiency; IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M; PIDD, primary immune deficiency disease; SD, standard deviation; XLA, X-linked (Bruton's) agammaglobulinemia.
      Recent consensus reviews of diagnosis of clinically significant SAD in patients with borderline or normal total IgG suggest determination of the patient's responses to unconjugated polysaccharide vaccines as well as conjugated polysaccharides and protein antigens [
      • Bonilla F.A.
      • Khan D.A.
      • Ballas Z.K.
      • Chinen J.
      • Frank M.M.
      • Hsu J.T.
      • Keller M.
      • Kobrynski L.J.
      • Komarow H.D.
      • Mazer B.
      • Nelson Jr., R.P.
      • Orange J.S.
      • Routes J.M.
      • Shearer W.T.
      • Sorensen R.U.
      • Verbsky J.W.
      • Bernstein D.I.
      • Blessing-Moore J.
      • Lang D.
      • Nicklas R.A.
      • Oppenheimer J.
      • Portnoy J.M.
      • Randolph C.R.
      • Schuller D.
      • Spector S.L.
      • Tilles S.
      • Wallace D.
      Practice parameter for the diagnosis and management of primary immunodeficiency.
      ,
      • Immune Deficiency Foundation
      Diagnostic and Clinical Care Guidelines for Primary Immunodeficiency Diseases.
      ,
      • Sullivan K.E.
      Immune Deficiency Foundation Clinical Focus on Primary Immunodeficiency: Diagnostic Approaches to Antibody Deficiencies.
      ,
      • Orange J.S.
      • Ballow M.
      • Stiehm E.R.
      • Ballas Z.K.
      • Chinen J.
      • De La Morena M.
      • Kumararatne D.
      • Harville T.O.
      • Hesterberg P.
      • Koleilat M.
      • McGhee S.
      • Perez E.E.
      • Raasch J.
      • Scherzer R.
      • Schroeder H.
      • Seroogy C.
      • Huissoon A.
      • Sorensen R.U.
      • Katial R.
      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.
      ,
      • Lehman H.
      • Hernandez-Trujillo V.
      • Ballow M.
      Diagnosing primary immunodeficiency: a practical approach for the non-immunologist.
      ]. In some cases, an empirical trial of IgG replacement therapy, with careful documentation of objective criteria such as frequency of exacerbations and hospitalizations, spirometry, and need for “rescue” medicines and steroids, may be necessary to convince third party payers that treatment is justified.
      IgG therapy in previously undiagnosed or sub-optimally managed patients with PIDD has been shown to ameliorate airway obstruction in those with chronic/recurrent respiratory symptoms [
      • Schwartz H.J.
      • Hostoffer R.W.
      • McFadden Jr., E.R.
      • Berger M.
      The response to intravenous immunoglobulin replacement therapy in patients with asthma with specific antibody deficiency.
      ,
      • Roifman C.M.
      • Levison H.
      • Gelfand E.W.
      High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and chronic lung disease.
      ]. A randomized cross-over study of two different doses of intravenous IgG showed that the frequency of acute infection was substantially reduced and the forced expiratory volume in 1 s and forced vital capacity were significantly increased when PIDD patients with chronic lung disease achieved serum IgG levels ≥500 mg/dL [
      • Roifman C.M.
      • Levison H.
      • Gelfand E.W.
      High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and chronic lung disease.
      ]. Thus, restoring normal serum IgG and specific antibody levels might benefit patients who present with asthma or COPD and are found to have underlying antibody deficiency. Therefore, this treatable underlying cause of COPD should be sought whenever suggested by the patient's history and/or a lack of other causes of COPD such as smoking or alpha-1 proteinase inhibitor deficiency.
      Prevention and/or effective treatment of respiratory infections in patients with underlying antibody deficiency could reduce the number and cost of COPD exacerbations. In 2007, the mean cost of COPD to the Canadian health system included $756 and $9953 for moderate and severe exacerbations, respectively, resulting in annual costs of $646 to $736 million [
      • Mittmann N.
      • Kuramoto L.
      • Seung S.J.
      • Haddon J.M.
      • Bradley-Kennedy C.
      • Fitzgerald J.M.
      The cost of moderate and severe COPD exacerbations to the Canadian healthcare system.
      ]. Costs for COPD exacerbations at a group of 602 US hospitals in 2008 included a mean of $7242 for simple admissions and $20,757 for complex admissions [
      • Dalal A.A.
      • Shah M.
      • D'Souza A.O.
      • Rane P.
      Costs of COPD exacerbations in the emergency department and inpatient setting.
      ]. A recent case series of IgG replacement therapy for patients with COPD with serum IgG levels below 590 mg/dL (mean dose, 500 mg/kg/month) decreased exacerbations from 5.0 ± 2.45/year before IgG to 1.0 ± 1.07/year on treatment [
      • Cowan J.
      • Gaudet L.
      • Mulpuru S.
      • Corrales-Medina V.
      • Hawken S.
      • Cameron C.
      • Aaron S.D.
      • Cameron D.W.
      A retrospective longitudinal within-subject risk interval analysis of immunoglobulin treatment for recurrent acute exacerbation of chronic obstructive pulmonary disease.
      ].

      6. Conclusions

      Antibody deficiency may result not only in sinusitis and acute lung infection, but may also contribute to a continuous inflammatory response in the lower airways which is initially reversible but could eventually cause irreversible obstruction and COPD. Patients with asthma and respiratory infections in the first decades of life are at a greatly increased risk for developing COPD, but when they present as adults with COPD, an underlying PIDD may be unrecognized. Detection of PIDD as a potentially treatable underlying contributor to recurrent/acute exacerbations and cumulative morbidity of COPD, and provision of IgG replacement, may decrease the progression of COPD. Decreasing the severity and rate of exacerbations should improve the quality of life and longevity of an important subset of patients with COPD, while decreasing readmissions and costs. Major steps toward achieving these goals include developing a high index of suspicion, more frequent use of screening tests, such as quantitative Igs and vaccine responses, and prompt institution of IgG replacement therapy when antibody deficiency has been diagnosed. In addition, further studies of the prevalence and importance of PIDD in COPD are needed.

      Declaration of interest

      MB is an employee of CSL Behring LLC and reports salary from and stock ownership in CSL Behring.
      DWC has served on advisory boards for CSL Behring, Grifols, and Baxalta, and has received support for travel and honoraria (to employer). DWC also reports: support for Clinical Program to The Ottawa Hospital Foundation from CSL Behring ; partial grant-in-aids (to employer) from CSL Behring and Grifols.
      BG has received grants from CSL Behring, Grifols, Baxalta/Shire, and ADMA, and has been a consultant for CSL Behring, Diplomat/BioRx Specialty Pharmacy, and ADMA.
      LMM is an employee of CSL Behring and reports salary from CSL Behring.
      ESS has no declaration of interest to report.

      Acknowledgements

      Editorial assistance was provided by Meridian HealthComms Ltd, with funding by CSL Behring .

      References

        • Hens G.
        • Vanaudenaerde B.M.
        • Bullens D.M.
        • Piessens M.
        • Decramer M.
        • Dupont L.J.
        • Ceuppens J.L.
        • Hellings P.W.
        Sinonasal pathology in nonallergic asthma and COPD: 'united airway disease' beyond the scope of allergy.
        Allergy. 2008; 63: 261-267
        • Exley A.R.
        • Henderson K.
        • Buckenham S.
        • Kimberlin H.
        • Gronlund H.
        • French J.
        • Campbell K.
        • Bilton D.
        • Barker H.
        • Screaton N.
        • Haworth C.S.
        • Floto R.A.
        Diagnosis and management of common variable immuno-deficiency (CVID) in adults with recurrent pulmonary infection.
        Am. J. Respir. Crit. Care Med. 2009; 179: A3218
        • Baleeiro C.
        • Mull N.
        Prevalence of common variable immunodeficiency (CVID) among patients with recurrent respiratory tract infections.
        Am. J. Respir. Crit. Care Med. 2010; 181: A3187
        • Postma D.S.
        • Rabe K.F.
        The Asthma-COPD overlap syndrome.
        N. Engl. J. Med. 2015; 373: 1241-1249
        • Lange P.
        • Colak Y.
        • Ingebrigtsen T.S.
        • Vestbo J.
        • Marott J.L.
        Long-term prognosis of asthma, chronic obstructive pulmonary disease, and asthma-chronic obstructive pulmonary disease overlap in the Copenhagen City Heart study: a prospective population-based analysis.
        Lancet Respir. Med. 2016; 4: 454-462
        • McGeachie M.J.
        • Yates K.P.
        • Zhou X.
        • Guo F.
        • Sternberg A.L.
        • Van Natta M.L.
        • Wise R.A.
        • Szefler S.J.
        • Sharma S.
        • Kho A.T.
        • Cho M.H.
        • Croteau-Chonka D.C.
        • Castaldi P.J.
        • Jain G.
        • Sanyal A.
        • Zhan Y.
        • Lajoie B.R.
        • Dekker J.
        • Stamatoyannopoulos J.
        • Covar R.A.
        • Zeiger R.S.
        • Adkinson N.F.
        • Williams P.V.
        • Kelly H.W.
        • Grasemann H.
        • Vonk J.M.
        • Koppelman G.H.
        • Postma D.S.
        • Raby B.A.
        • Houston I.
        • Lu Q.
        • Fuhlbrigge A.L.
        • Tantisira K.G.
        • Silverman E.K.
        • Tonascia J.
        • Weiss S.T.
        • Strunk R.C.
        Camp Research Group, Patterns of growth and decline in lung function in persistent childhood asthma.
        N. Engl. J. Med. 2016; 374: 1842-1852
        • Behrendt C.E.
        Mild and moderate-to-severe COPD in nonsmokers: distinct demographic profiles.
        Chest. 2005; 128: 1239-1244
        • Whittemore A.S.
        • Perlin S.A.
        • DiCiccio Y.
        Chronic obstructive pulmonary disease in lifelong nonsmokers: results from NHANES.
        Am. J. Public Health. 1995; 85: 702-706
        • Shaheen S.O.
        • Barker D.J.
        • Holgate S.T.
        Do lower respiratory tract infections in early childhood cause chronic obstructive pulmonary disease?.
        Am. J. Respir. Crit. Care Med. 1995; 151: 1649-1651
        • Hayden L.P.
        • Hobbs B.D.
        • C.R. T
        • Wise R.A.
        • Checkley W.
        • Crapo J.D.
        • Hersh C.P.
        • on behalf of the COPDGene Investigators
        Childhood pneumonia increases risk for chronic obstructive pulmonary disease: the COPDGene study.
        Respir. Res. 2015; 16: 115
        • Bonilla F.A.
        • Khan D.A.
        • Ballas Z.K.
        • Chinen J.
        • Frank M.M.
        • Hsu J.T.
        • Keller M.
        • Kobrynski L.J.
        • Komarow H.D.
        • Mazer B.
        • Nelson Jr., R.P.
        • Orange J.S.
        • Routes J.M.
        • Shearer W.T.
        • Sorensen R.U.
        • Verbsky J.W.
        • Bernstein D.I.
        • Blessing-Moore J.
        • Lang D.
        • Nicklas R.A.
        • Oppenheimer J.
        • Portnoy J.M.
        • Randolph C.R.
        • Schuller D.
        • Spector S.L.
        • Tilles S.
        • Wallace D.
        Practice parameter for the diagnosis and management of primary immunodeficiency.
        J. Allergy Clin. Immunol. 2015; 136: 1186-1205
        • Immune Deficiency Foundation
        Diagnostic and Clinical Care Guidelines for Primary Immunodeficiency Diseases.
        third ed. 2015
        www.primaryimmune.org
        Date accessed: May , 2016
        • Sullivan K.E.
        Immune Deficiency Foundation Clinical Focus on Primary Immunodeficiency: Diagnostic Approaches to Antibody Deficiencies.
        Immune Deficiency Foundation, USA2015
        • 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: 709-727
        • Orange J.S.
        • Ballow M.
        • Stiehm E.R.
        • Ballas Z.K.
        • Chinen J.
        • De La Morena M.
        • Kumararatne D.
        • Harville T.O.
        • Hesterberg P.
        • Koleilat M.
        • McGhee S.
        • Perez E.E.
        • Raasch J.
        • Scherzer R.
        • Schroeder H.
        • Seroogy C.
        • Huissoon A.
        • Sorensen R.U.
        • Katial R.
        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. 2012; 130: S1-S24
        • Ludvigsson J.F.
        • Neovius M.
        • Hammarstrom L.
        Risk of infections among 2100 individuals with IgA deficiency: a nationwide cohort study.
        J. Clin. Immunol. 2016; 36: 134-140
        • Kim J.H.
        • Park S.
        • Hwang Y.I.
        • Jung K.S.
        • Sim Y.S.
        • Kim C.
        • Kim D.G.
        Immunoglobulin G subclass deficiencies in adult patients with chronic airway diseases.
        J. Korean Med. Sci. 2016; 31: 1560-1565
        • Joshi A.Y.
        • Iyer V.N.
        • Hagan J.B.
        • St Sauver J.L.
        • Boyce T.G.
        Incidence and temporal trends of primary immunodeficiency: a population-based cohort study.
        Mayo Clin. Proc. 2009; 84: 16-22
        • Boyle J.M.
        • Buckley R.H.
        Population prevalence of diagnosed primary immunodeficiency diseases in the United States.
        J. Clin. Immunol. 2007; 27: 497-502
        • Broides A.
        • Nahum A.
        • Mandola A.B.
        • Rozner L.
        • Pinsk V.
        • Ling G.
        • Yerushalmi B.
        • Levy J.
        • Givon-Lavi N.
        Incidence of typically severe primary immunodeficiency diseases in consanguineous and non-consanguineous populations.
        J. Clin. Immunol. 2017; 37: 295-300
        • Westh L.
        • Mogensen T.H.
        • Dalgaard L.S.
        • Bernth Jensen J.M.
        • Katzenstein T.
        • Hansen A.E.
        • Larsen O.D.
        • Terpling S.
        • Nielsen T.L.
        • Larsen C.S.
        Identification and characterization of a nationwide Danish adult common variable immunodeficiency cohort.
        Scand. J. Immunol. 2017; 85: 450-461
        • Pac M.
        • Bernatowska E.
        Comprehensive activities to increase recognition of primary immunodeficiency and access to immunoglobulin replacement therapy in Poland.
        Eur. J. Pediatr. 2016; 175: 1099-1105
        • Edgar J.D.
        • Buckland M.
        • Guzman D.
        • Conlon N.P.
        • Knerr V.
        • Bangs C.
        • Reiser V.
        • Panahloo Z.
        • Workman S.
        • Slatter M.
        • Gennery A.R.
        • Davies E.G.
        • Allwood Z.
        • Arkwright P.D.
        • Helbert M.
        • Longhurst H.J.
        • Grigoriadou S.
        • Devlin L.A.
        • Huissoon A.
        • Krishna M.T.
        • Hackett S.
        • Kumararatne D.S.
        • Condliffe A.M.
        • Baxendale H.
        • Henderson K.
        • Bethune C.
        • Symons C.
        • Wood P.
        • Ford K.
        • Patel S.
        • Jain R.
        • Jolles S.
        • El-Shanawany T.
        • Alachkar H.
        • Herwadkar A.
        • Sargur R.
        • Shrimpton A.
        • Hayman G.
        • Abuzakouk M.
        • Spickett G.
        • Darroch C.J.
        • Paulus S.
        • Marshall S.E.
        • McDermott E.M.
        • Heath P.T.
        • Herriot R.
        • Noorani S.
        • Turner M.
        • Khan S.
        • Grimbacher B.
        The United Kingdom primary immune deficiency (UKPID) registry: report of the first 4 years' activity 2008-2012.
        Clin. Exp. Immunol. 2014; 175: 68-78
        • Immune Deficiency Foundation
        Primary Immunodeficiency Diseases in America: 2007.
        (The third national survey of patients)2007
        • Kelemence A.
        • Abadoglu O.
        • Gumus C.
        • Berk S.
        • Epozturk K.
        • Akkurt I.
        The frequency of chronic rhinosinusitis/nasal polyp in COPD and its effect on the severity of COPD.
        COPD. 2011; 8: 8-12
        • Dewan N.A.
        • Rafique S.
        • Kanwar B.
        • Satpathy H.
        • Ryschon K.
        • Tillotson G.S.
        • Niederman M.S.
        Acute exacerbation of COPD: factors associated with poor treatment outcome.
        Chest. 2000; 117: 662-671
        • Chee L.
        • Graham S.M.
        • Carothers D.G.
        • Ballas Z.K.
        Immune dysfunction in refractory sinusitis in a tertiary care setting.
        Laryngoscope. 2001; 111: 233-235
        • Odat H.
        • Alqudah M.
        Prevalence and pattern of humoral immunodeficiency in chronic refractory sinusitis.
        Eur. Archives Oto-Rhino-Laryngology Official J. Eur. Fed. Oto-Rhino-Laryngological Soc. 2016; 273: 3189-3193
        • Alqudah M.
        • Graham S.M.
        • Ballas Z.K.
        High prevalence of humoral immunodeficiency patients with refractory chronic rhinosinusitis.
        Am. J. Rhinology Allergy. 2010; 24: 409-412
        • Schwitzguebel A.J.
        • Jandus P.
        • Lacroix J.S.
        • Seebach J.D.
        • Harr T.
        Immunoglobulin deficiency in patients with chronic rhinosinusitis: systematic review of the literature and meta-analysis.
        J. Allergy Clin. Immunol. 2015; 136: 1523-1531
        • Kashani S.
        • Carr T.F.
        • Grammer L.C.
        • Schleimer R.P.
        • Hulse K.E.
        • Kato A.
        • Kern R.C.
        • Conley D.B.
        • Chandra R.K.
        • Tan B.K.
        • Peters A.T.
        Clinical characteristics of adults with chronic rhinosinusitis and specific antibody deficiency.
        J. Allergy Clin. Immunol. Pract. 2015; 3: 236-242
        • Umetsu D.T.
        • Ambrosino D.M.
        • Quinti I.
        • Siber G.R.
        • Geha R.S.
        Recurrent sinopulmonary infection and impaired antibody response to bacterial capsular polysaccharide antigen in children with selective IgG-subclass deficiency.
        N. Engl. J. Med. 1985; 313: 1247-1251
        • Schatorje E.J.
        • de Jong E.
        • van Hout R.W.
        • Garcia Vivas Y.
        • de Vries E.
        The challenge of immunoglobulin-G subclass deficiency and specific polysaccharide antibody deficiency–a Dutch pediatric cohort study.
        J. Clin. Immunol. 2016; 36: 141-148
        • Barton J.C.
        • Bertoli L.F.
        • Barton J.C.
        • Acton R.T.
        Selective subnormal IgG1 in 54 adult index patients with frequent or severe bacterial respiratory tract infections.
        J. Immunol. Res. 2016; 2016: 1405950
      1. J. Farmer, L. Yonker, P. Permaul, P. Hesterberg, R. Iyengar, K.E. Sullivan, D. Suez, C. Cunningham-Rundles, J.E. Walter, Comparative analysis of the epidemiology of common variable immunodeficiency (CVID) in a large tertiary care center versus the USIDNET registry. Poster presented at CIS Annual Meeting 2015, Houston, Texas, April 9-12.

        • Urm S.H.
        • Yun H.D.
        • Fenta Y.A.
        • Yoo K.H.
        • Abraham R.S.
        • Hagan J.
        • Juhn Y.J.
        Asthma and risk of selective IgA deficiency or common variable immunodeficiency: a population-based case-control study.
        Mayo Clin. Proc. 2013; 88: 813-821
        • Talbot T.R.
        • Hartert T.V.
        • Mitchel E.
        • Halasa N.B.
        • Arbogast P.G.
        • Poehling K.A.
        • Schaffner W.
        • Craig A.S.
        • Griffin M.R.
        Asthma as a risk factor for invasive pneumococcal disease.
        N. Engl. J. Med. 2005; 352: 2082-2090
        • Juhn Y.J.
        • Kita H.
        • Yawn B.P.
        • Boyce T.G.
        • Yoo K.H.
        • McGree M.E.
        • Weaver A.L.
        • Wollan P.
        • Jacobson R.M.
        Increased risk of serious pneumococcal disease in patients with asthma.
        J. Allergy Clin. Immunol. 2008; 122: 719-723
        • Brent J.
        • Guzman D.
        • Bangs C.
        • Grimbacher B.
        • Fayolle C.
        • Huissoon A.
        • Bethune C.
        • Thomas M.
        • Patel S.
        • Jolles S.
        • Alachkar H.
        • Kumaratne D.
        • Baxendale H.
        • Edgar J.D.
        • Helbert M.
        • Hambleton S.
        • Arkwright P.D.
        Clinical and laboratory correlates of lung disease and cancer in adults with idiopathic hypogammaglobulinaemia.
        Clin. Exp. Immunol. 2016; 184: 73-82
        • 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 (e4): 1354-1360
        • Buscot M.
        • Pottier H.
        • Marquette C.H.
        • Leroy S.
        Phenotyping adults with non-cystic fibrosis bronchiectasis: a 10-year cohort study in a French regional university hospital center.
        Respir. Int. Rev. Thorac. Dis. 2016; 92: 1-8
        • Brower K.S.
        • Del Vecchio M.T.
        • Aronoff S.C.
        The etiologies of non-CF bronchiectasis in childhood: a systematic review of 989 subjects.
        BMC Pediatr. 2014; 14: 4
        • Amalakuhan B.
        • Maselli D.J.
        • Martinez-Garcia M.A.
        Update in bronchiectasis 2014.
        Am. J. Respir. Crit. Care Med. 2015; 192: 1155-1161
        • Du Q.
        • Jin J.
        • Liu X.
        • Sun Y.
        Bronchiectasis as a comorbidity of chronic obstructive pulmonary disease: a systematic review and meta-analysis.
        PloS One. 2016; 11: e0150532
        • Staples K.J.
        • Taylor S.
        • Thomas S.
        • Leung S.
        • Cox K.
        • Pascal T.G.
        • Ostridge K.
        • Welch L.
        • Tuck A.C.
        • Clarke S.C.
        • Gorringe A.
        • Wilkinson T.M.
        Relationships between mucosal antibodies, non-typeable Haemophilus influenzae (NTHi) infection and airway inflammation in COPD.
        PloS One. 2016; 11: e0167250
        • McCullagh B.N.
        • Comellas A.P.
        • Ballas Z.K.
        • Newell Jr., J.D.
        • Zimmerman M.B.
        • Azar A.E.
        Antibody deficiency in patients with frequent exacerbations of chronic obstructive pulmonary disease (COPD).
        PloS One. 2017; 12: e0172437
        • Boixeda R.
        • Capdevila J.A.
        • Vicente V.
        • Palomera E.
        • Juanola J.
        • Albiach L.
        • Rex A.
        • Almirall J.
        Gamma globulin fraction of the proteinogram and chronic obstructive pulmonary disease exacerbations.
        Med. Clin. 2017; 149: 107-113
        • Leitao Filho F.S.
        • Won Ra S.
        • Mattman A.
        • Schellenberg R.S.
        • Fishbane N.
        • Criner G.J.
        • Woodruff P.G.
        • Lazarus S.C.
        • Albert R.
        • Connett J.E.
        • Han M.K.
        • Martinez F.J.
        • Leung J.M.
        • Man S.F.P.
        • Aaron S.D.
        • Reed R.M.
        • Sin D.D.
        Serum IgG and risk of exacerbations and hospitalizations in chronic obstructive pulmonary disease.
        J. Allergy Clin. Immunol. 2017; 140: 1164-1167
        • Cowan J.
        • Gaudet L.
        • Mulpuru S.
        • Corrales-Medina V.
        • Hawken S.
        • Cameron C.
        • Aaron S.D.
        • Cameron D.W.
        A retrospective longitudinal within-subject risk interval analysis of immunoglobulin treatment for recurrent acute exacerbation of chronic obstructive pulmonary disease.
        PloS One. 2015; 10: e0142205
        • Butler W.T.
        • Rossen R.D.
        Effects of corticosteroids on immunity in man. I. Decreased serum IgG concentration caused by 3 or 5 days of high doses of methylprednisolone.
        J. Clin. Investigation. 1973; 52: 2629-2640
        • Griggs R.C.
        • Condemi J.J.
        • Vaughan J.H.
        Effect of therapeutic dosages of prednisone on human immunoglobulin G metabolism.
        J. Allergy Clin. Immunol. 1972; 49: 267-273
        • Settipane G.A.
        • Pudupakkam R.K.
        • McGowan J.H.
        Corticosteroid effect on immunoglobulins.
        J. Allergy Clin. Immunol. 1978; 62: 162-166
        • Kado R.
        • Sanders G.
        • McCune W.J.
        Diagnostic and therapeutic considerations in patients with hypogammaglobulinemia after rituximab therapy.
        Curr. Opin. Rheumatology. 2017; 29: 228-233
        • Duraisingham S.S.
        • Buckland M.
        • Dempster J.
        • Lorenzo L.
        • Grigoriadou S.
        • Longhurst H.J.
        Primary vs. secondary antibody deficiency: clinical features and infection outcomes of immunoglobulin replacement.
        PloS One. 2014; 9: e100324
        • Boddana P.
        • Webb L.H.
        • Unsworth J.
        • Brealey M.
        • Bingham C.
        • Harper S.J.
        Hypogammaglobulinemia and bronchiectasis in mycophenolate mofetil-treated renal transplant recipients: an emerging clinical phenomenon?.
        Clin. Transplant. 2011; 25: 417-419
        • Dury S.
        • Colosio C.
        • Etienne I.
        • Anglicheau D.
        • Merieau E.
        • Caillard S.
        • Rivalan J.
        • Thervet E.
        • Essig M.
        • Babinet F.
        • Subra J.F.
        • Toubas O.
        • Rieu P.
        • Launois C.
        • Perotin-Collard J.M.
        • Lebargy F.
        • Deslee G.
        • Spiesser g.
        Bronchiectasis diagnosed after renal transplantation: a retrospective multicenter study.
        BMC Pulm. Med. 2015; 15: 141
        • Drummond M.B.
        • Kunisaki K.M.
        • Huang L.
        Obstructive lung diseases in HIV: a clinical review and identification of key future research needs.
        Seminars Respir. Crit. Care Med. 2016; 37: 277-288
        • Dransfield M.T.
        • Nahm M.H.
        • Han M.K.
        • Harnden S.
        • Criner G.J.
        • Martinez F.J.
        • Scanlon P.D.
        • Woodruff P.G.
        • Washko G.R.
        • Connett J.E.
        • Anthonisen N.R.
        • Bailey W.C.
        COPD Clinical Research Network, Superior immune response to protein-conjugate versus free pneumococcal polysaccharide vaccine in chronic obstructive pulmonary disease.
        Am. J. Respir. Crit. Care Med. 2009; 180: 499-505
        • Walters J.A.
        • Smith S.
        • Poole P.
        • Granger R.H.
        • Wood-Baker R.
        Injectable vaccines for preventing pneumococcal infection in patients with chronic obstructive pulmonary disease.
        Cochrane Database Syst. Rev. 2010; : CD001390
        • Nath K.D.
        • Burel J.G.
        • Shankar V.
        • Pritchard A.L.
        • Towers M.
        • Looke D.
        • Davies J.M.
        • Upham J.W.
        Clinical factors associated with the humoral immune response to influenza vaccination in chronic obstructive pulmonary disease.
        Int. J. Chronic Obstr. Pulm. Dis. 2014; 9: 51-56
        • Esposito S.
        • Terranova L.
        • Patria M.F.
        • Marseglia G.L.
        • Miraglia del Giudice M.
        • Bodini A.
        • Martelli A.
        • Baraldi E.
        • Mazzina O.
        • Tagliabue C.
        • Licari A.
        • Ierardi V.
        • Lelii M.
        • Principi N.
        Streptococcus pneumoniae colonisation in children and adolescents with asthma: impact of the heptavalent pneumococcal conjugate vaccine and evaluation of potential effect of thirteen-valent pneumococcal conjugate vaccine.
        BMC Infect. Dis. 2016; 16: 12
        • Domenech A.
        • Ardanuy C.
        • Tercero A.
        • Garcia-Somoza D.
        • Santos S.
        • Linares J.
        Dynamics of the pneumococcal population causing acute exacerbations in COPD patients in a Barcelona hospital (2009-12): comparison with 2001-04 and 2005-08 periods.
        J. Antimicrob. Chemother. 2014; 69: 932-939
        • Fiqueira-Goncalves J.M.
        • Bethencourt-Martin N.
        • Perez-Mendez L.I.
        • Diaz-Perez D.
        • Guzman-Saenz C.
        • Vina-Manrique P.
        • Pedrero-Garcia A.J.
        Impact of 13-valent pneumococal conjugate polysaccharide vaccination in exacerbations rate of COPD patients with moderate to severe obstruction.
        Rev. Esp. Quimioter. 2017; 30: 269-275
        • Eggo R.M.
        • Scott J.G.
        • Galvani A.P.
        • Meyers L.A.
        Respiratory virus transmission dynamics determine timing of asthma exacerbation peaks: evidence from a population-level model.
        Proc. Natl. Acad. Sci. U. S. A. 2016; 113: 2194-2199
        • Djamin R.S.
        • Uzun S.
        • Snelders E.
        • Kluytmans J.J.
        • Hoogsteden H.C.
        • Aerts J.G.
        • Van Der Eerden M.M.
        Occurrence of virus-induced COPD exacerbations during four seasons.
        Infect. Dis. (Lond). 2015; 47: 96-100
        • Kloepfer K.M.
        • Lee W.M.
        • Pappas T.E.
        • Kang T.J.
        • Vrtis R.F.
        • Evans M.D.
        • Gangnon R.E.
        • Bochkov Y.A.
        • Jackson D.J.
        • Lemanske Jr., R.F.
        • Gern J.E.
        Detection of pathogenic bacteria during rhinovirus infection is associated with increased respiratory symptoms and asthma exacerbations.
        J. Allergy Clin. Immunol. 2014; 133: 1301-1307
        • Peltola V.
        • Waris M.
        • Kainulainen L.
        • Kero J.
        • Ruuskanen O.
        Virus shedding after human rhinovirus infection in children, adults and patients with hypogammaglobulinaemia.
        Clin. Microbiol. Infect. 2013; 19: E322-E327
        • Rantala A.
        • Jaakkola J.J.
        • Jaakkola M.S.
        Respiratory infections precede adult-onset asthma.
        PloS One. 2011; 6: e27912
        • Hurst J.R.
        • Wedzicha J.A.
        The biology of a chronic obstructive pulmonary disease exacerbation.
        Clin. Chest Med. 2007; 28: 525-536
        • Veeramachaneni S.B.
        • Sethi S.
        Pathogenesis of bacterial exacerbations of COPD.
        COPD. 2006; 3: 109-115
        • Sethi S.
        • Murphy T.F.
        Infection in the pathogenesis and course of chronic obstructive pulmonary disease.
        N. Engl. J. Med. 2008; 359: 2355-2365
        • Finney L.J.
        • Ritchie A.
        • Pollard E.
        • Johnston S.L.
        • Mallia P.
        Lower airway colonization and inflammatory response in COPD: a focus on Haemophilus influenzae.
        Int. J. Chronic Obstr. Pulm. Dis. 2014; 9: 1119-1132
        • Lehman H.
        • Hernandez-Trujillo V.
        • Ballow M.
        Diagnosing primary immunodeficiency: a practical approach for the non-immunologist.
        Curr. Med. Res. Opin. 2015; 31: 697-706
        • Schwartz H.J.
        • Hostoffer R.W.
        • McFadden Jr., E.R.
        • Berger M.
        The response to intravenous immunoglobulin replacement therapy in patients with asthma with specific antibody deficiency.
        Allergy Asthma Proc. 2006; 27: 53-58
        • Roifman C.M.
        • Levison H.
        • Gelfand E.W.
        High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and chronic lung disease.
        Lancet. 1987; 1: 1075-1077
        • Mittmann N.
        • Kuramoto L.
        • Seung S.J.
        • Haddon J.M.
        • Bradley-Kennedy C.
        • Fitzgerald J.M.
        The cost of moderate and severe COPD exacerbations to the Canadian healthcare system.
        Respir. Med. 2008; 102: 413-421
        • Dalal A.A.
        • Shah M.
        • D'Souza A.O.
        • Rane P.
        Costs of COPD exacerbations in the emergency department and inpatient setting.
        Respir. Med. 2011; 105: 454-460