- Email: [email protected]
A primer on immunology for the pulmonologist
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Oral Presentations / Paediatric Respiratory Reviews 12S1 (2011) S1–S66
III.4. Obstructive Lung Disease – Lung diseases in children: immunity, viruses or genes? III.4.1 A primer on immunology for the pulmonologist L. Kobrynski. Assistant Professor of Pediatrics, Division of Allergy and Immunology, Emory University, USA Correspondence: Tel.: 404 727 3575. E-mail: [email protected].
What are Primary Immune Deficiencies: Primary Immune Deficiency disorders (PIDD) refer to a group of over 150 distinct defects of the immune system, many of which are due to single gene defects. Congenital defects in various parts of the immune system have been described in humans. Although, the underlying immunologic defects are present at birth, individuals may not become symptomatic until adulthood. Most primary immune deficiencies (PIDDs) are due to single gene defects causing either the absence of a specific protein or a non-functional protein. This distinguishes them from secondary immune defects due to medications, malignancies, or other infections. PIDD can be inherited in an X-linked, autosomal recessive or autosomal dominant fashion. One of the largest clinical phenotypes, Common Variable Immune Deficiency (CVID), has a pattern of variable inheritance, with both AR and AD forms being reported [1] and genetic linkage studies showing a familial predisposition. Despite the differing patterns of disease severity and onset, all patients with PIDD suffer from recurrent infections which cause significant morbidity and mortality. Complement, 5% Phagocytic, 10% Cellular, 5%
Combined, 15% Antibody deficiency, 65%
Fig. 1. Frequency of various primary immune deficiencies.
The true prevalence of PIDD is not known, but it is estimated that 1:1,200 individuals in the United States has been diagnosed with a PIDD [2]. This number is in contrast to previous minimal estimates of 1:10,000 to 1:500,000 based on data from disease registries [3–9] and suggests that many cases of PIDD remain undiagnosed. PIDD are typically classified by the nature of the immune defect, whether it affects antibody production by B cells (humoral immunity), T cell function (cellular immunity), both T and B cell function (combined immune defect), killing of bacteria by neutrophils (phagocytic defect) or complement. Figure 1 shows the breakdown of PIDD by the underlying defect [10] with the largest proportion resulting in defects of antibody production. About 40% of individuals with PIDD present with infections or other findings of PIDD in the first few years of life. The most severe defects, such as Severe Combined Immune Deficiency (SCID), are fatal in early childhood if not treated. Previously PIDD were thought to be pediatric diseases, but the mean age of diagnosis for CVID is 29 years for males and 33 years for females [11]. Most will have a
history of infections for several years prior to diagnosis. In adults the average delay in diagnosis is 5 years. Diagnosis of PIDD, even in the face of symptoms starting early in childhood, may be delayed until adolescence because of a lack of clinical suspicion, underscoring the need for improved awareness of these disorders. Recent results from a UK national audit show that the median delay in diagnosis has decreased from 3.5 years to 1 year [12]. Early diagnosis and treatment has been shown to reduce morbidity and mortality in many PIDD [13] (Buckley SCID BMT). End organ damage, particularly in the lungs, frequently occurs in the first decade of life as a sequelae of infection. Normal host defenses of the respiratory tract: The respiratory tract communicates with the outside environment, thus host defenses against respiratory pathogens are critical. Innate immune defenses are the first line responders against pathogens. The components of the innate immune system in the respiratory tract are the mechanical barriers, the mucous membranes, the mucin containing antimicrobial peptides such as defensins and secretory IgA, the cilia, the cellular effector cells, the phagocytes and NK cells which engulf and kill microbes, the matural antimicrobial agents, defensins, lactoferrin, lysozyme and myeloperoxidase, reactive oxygen species, cytokines and chemokines to recruit effector cells to the site of infection. Innate immunity: Innate immune responses are generally the first line of defense against viral, bacterial and fungal pathogens and involve the activation and recruitment of macrophages, neutrophils and Natural Killer cells with release of chemokines, cytokines, or antimicrobial peptides. Clearance of infectious organisms can be accomplished through binding of serum complement facilitating opsonization of microbes, or by phagocytosis and intracellular killing in phagocytes through reactive oxygen or nitrogen molecules. Humoral immunity: The humoral immune system relies on adaptive immunity to produce antigen specific responses against infectious pathogens. Microbial peptides are presented on the surface of antigen presenting cells (dendritic cells, monocytes/macrophages, B cells) associated with costimulatory major histocompatibility class II (MHCII) molecules. Cognate interaction between T cells and B cells by binding of T cell receptor (TCR) with B cell receptor (BCR) complex and binding of secondary signal (CD40-CD40L or CD28-CTLA4) results in intracellular signaling to trigger clonal proliferation and maturation of antigen specific cells with immunoglobulin heavy chain isotype switching to produce specific IgG or IgA antibodies. Cellular immunity: Cellular immunity involves the activation and proliferation of naïve T cells in response to an antigen. Macrophages or dendritic cells can express microbial peptides on their cell suface with MHCI or MHCII. Recognition of foreign peptides on the cell surface signals T cells to differentiate into effector cells, cytotoxic T cells that kill infected cells, or T helper cells (TH 1) that activate infected macrophages. Cytotoxic T cells exert their effects through enzymes (perforin, granzyme), Fas Ligand, and cytokines (IFN gamma, TNFb, TNFa). TH 1 cells produce interferon gamma, and TNFb and TNFa, activating infected macrophages. Pulmonary disease in primary immunodeficiency: The majority of patients with antibody deficiencies, up to 80%, and neutrophil defects will have more than one episode of pneumonia prior to diagnosis [11,14,15]. Frequently the pattern of infection or identification of the causative pathogen will serve as an indicator to the nature of the immune defect. Table 1 summarizes clinical characteristics of pulmonary infections in different PIDD. Defects in interferon gamma (IFNg) and IL12 axis cause an increased susceptibility to mycobacteria. Defects in IFNgR1, IFNgR2, IL12/IL23 and IL12R are inherited in an AR fashion and affected individuals develop disseminated and life threatening infections with mycobacterium, including BCG and nontuberculous mycobacteria [16,17].
Oral Presentations / Paediatric Respiratory Reviews 12S1 (2011) S1–S66
Individuals with cellular immune defects such as Severe Combined Immune Deficiency (SCID) or an absence of the thymus (complete DiGeorge syndrome) present early in life with opportunistic infections, frequently pneumonia due to Pneumocystis jirovecii. Other viral pathogens, parainfluenza 3 and respiratory syncytial virus (RSV), cytomegalovirus (CMV) and Herpes viruses, can cause severe interstitial pneumonitis and may be fatal. Without immune reconstitution, usually achieved by hematopoietic stem cell transplantation in SCID, affected patients will succumb to recurrent viral, fungal and bacterial infections. Combined immune deficiencies include disorders such as WiskottAldrich Syndrome (WAS), Ataxia-Telangiectasia (AT), and Hyper-IgE syndrome. Recurrent pulmonary infections are a common feature for all these disorders. Pyogenic bacteria are the most frequent pathogen, but pneumocystis and other viral pathogens also cause infections. Bronchiectasis is a common complication of respiratory infections in WAS and AT. Pneumatocoeles are characteristic for S. aureus infections in Hyper-IgE. Individuals with antibody deficiencies typically develop bacterial infections of the sinopulmonary tract after maternal antibodies wane after six months of life. Infants with X-linked agammaglobulinemia have an increased frequency of bacterial pneumonias, along with recurrent otitis media, and chronic diarrhea. While many individuals with selective IgA deficiency are asymptomatic, others have a history of frequent otitis media and sinusitis. Some individuals will also be more susceptible to lower respiratory infections and gastrointestinal infections. Many individuals with CVID do not have a notable history of infections until the 2nd decade of life or later. Infections of the sinopulmonary tract occur more frequently than in the general population, with an increase in severity, and are often associated with other sites of infection. Pyogenic bacteria, such as Staph. aureus, Strep. pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, are responsible for the majority of the pulmonary infections, but infections with atypical mycobacterium, and opportunistic organisms may be seen in patients with impaired T cell function and in patients with hyperIgM syndrome. Other antibody deficiencies (NEMO, AR-HyperIgM, selective antibody deficiency) also predispose affected individuals to upper and lower respiratory tract infections. Pneumonia associated complications, bronchiectasis, empyemas, granulomatous lung disease, are seen more frequently in patients with antibody deficiencies (except SAD and IgA deficiency) [18]. Bronchiectasis may already be present at the time of diagnosis (Fig. 2) and end-stage lung disease with respiratory insufficiency is the most frequent cause of death in CVID [11]. Frequently progression of lung disease occurs despite replacement of serum IgG with gammaglobulins [19]. In Chronic Granulomatous Disease (CGD), infections with catalase positive organisms (S. aureus, Pseudomonas sp., Aspergillus, Nocardia,
Fig. 2. CT of bronchiectasis. Bronchial wall thickening in XLA patient.
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Serratia, Klebsiella) can involve multiple sites. The majority of patients will present with a history of pneumonia [14]. The hallmark of the respiratory infections in patients with CGD is the unusually invasive nature of infections with Pseudomonas or Aspergillus, the propensity for abscess formation and the development of noncaseating granulomas. Bronchiectasis is seen less frequently in patient with CGD compared to individuals with antibody deficiency, but can develop after recurrent S. aureus infections. Necrotizing pneumonias due to Pseudomonas species may necessitate lobectomy. In addition to bronchiectasis, other chronic lung changes occur in PIDD. Hilar and mediastinal adenopathy is frequently seen. Bronchiolitis obliterans may develop, or involvement of the airways and the parenchyma can lead to pulmonary fibrosis and pulmlonary hypertension. Subsequent to opportunistic viral or fungal infections, persistent focal ground-glass opacities may be seen on CT scan. Interstitial lung disease occurs in patients over 40 years of age with antibody deficiencies [20]. Multiple pulmonary noncaseating granulomas, sometimes calcified can be seen in patients with CGD and CVID. In both disorders, intracellular pathogens (PJP, mycobacterium) can sometimes be identified in the granulomas (Fig. 3). In CVID these granulomas have been termed “sarcoid-like” [21]. Benign lymphoid hyperplasia involving the lung and gastrointestinal tract occur in as many as 30% of patients with CVID [22]. Non-Hodgkin lymphomas are more prevalent in patients with CVID [11,23]. Thoracic lymphomas may present with enlarged mediastinal nodes, or an anterior mediastinal mass which may compress the airway or blood vessels. The presence of an anterior mediastinal mass in a patient with hypogammaglobulinemia and low or absent B cells is characteristic of Good syndrome [24]. In these cases the development of a thymoma carries a poor prognosis.
Fig. 3. Granulomatous pneumocystis in CVID. Pulmonary nodules containing pneumocystis. Bierry G et al. Radiographics 2009; 29: 1909–20. Courtesy of L Kobrynski.
Evaluation of the patient with suspected primary immunodeficiency: Any patient with a history of recurrent, unusually severe pneumonias, or infection with atypical or opportunistic pathogens should undergo evaluation to identify a possible immune deficiency. The types of infections, their frequency, severity, pathogens involved and the age of onset may suggest the clinical phenotype and can be used to direct the laboratory evaluation. In addition to the history of infections, clinicians should inquire about associated problems and a family history of PIDD. Clinical algorithms have been suggested to help identify individuals with possible PIDD (Fig. 4: JMF 10WS). Laboratory testing can then be used to delineate the immune defect. The pattern of infection is the most useful element to discriminate the different immunologic defects. Table 1 shows the pathogens typically associated with defects in different arms of the immune system. Figure 5 shows a testing algorithm for screening patients for a PIDD [25]. It is worth noting that some tests are available only in specialized laboratories.
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Oral Presentations / Paediatric Respiratory Reviews 12S1 (2011) S1–S66
replacement is effective at reducing the incidence of infections, although it may not be as effective in treating bronchiectasis [19]. Recommended dosing is 400–500 mg/kg/month of gammaglobulin given IV or 100–150 mg/kg/wk given subcutaneously [26]. Prophylactic antibiotics are first line therapy to prevent PJP (cotrimoxazole), and to prevent infections in IgA deficiency and selective antibody deficiency (SAD). Antibiotics may also be adjunctive therapy in CVID, XLA and HyperIgM. Patients with CGD require prophylaxis with co-trimoxazole and itraconazole. In addition, therapy with IFN gamma given three days a week was shown to reduce the rate of serious infections [27].
Fig. 4: JMF 10 Warning signs at www.info4PI.org
Table 1: Pulmonary Infections in PIDD Immune defect
T cell or combined
B-cell- antibody
Phagocyte
Complement
Common pathogens (respiratory)
Pneumocystis jirovecii, CMV, EBV, herpes viruses, mycobacteria, Pseudomonas
S. pneumoniae, H. influenzae, S. aureus
S. aureus, Pseudomonas sp., Serratia sp, Klebsiella sp, Nocardia, Aspergillus
Pathology
Interstitial pneumonitis
Sequelae
Pulmonary fibrosis
Necrotizing pneumonia, lung abscess Granulomas, bronchiectasis
Associated features
Failure to thrive, GVHD from maternal cells, BCGosis, dermatitis
Lobar pneumonia, empyema Granulomas, bronchiectasis, interstitial fibrosis Malabsorption, chronic diarrhea autoimmune disease, thymoma
S. pneumoniae, Neisseria meningitidis, E. coli (usually nonpulmonary) Pneumonia infrequent
Other organ abscesses, adenitis, osteomyelitis, periodontitis, delayed separation of umbilical cord
Rare
Bacteremia, meningitis, SLE, glomerulonephritis
Fig. 5: Laboratory testing algorithm.
Treatment: Therapy is aimed at preventing infections and sequelae of infections. For antibody deficiencies, gamma globulin
References [1] Warnatz K, Salzer U, Rizzi M, et al. B-cell activating factor receptor deficiency is associated with adult onset antibody deficiency syndrome in humans. Proc Natl Acad Sci USA 2009; 106: 13945–13950. [2] Buckley RH, Boyle JM. Population prevalence of diagnosed Primary Immune Deficiency in the United States. J Clin Immunol. 2007; 27: 497–502. [3] Baumgart KW, Britton WJ, Kemp A, French M, Roberton D. The spectrum of primary immunodeficiency disorders in Australia. J Allergy Clin Immunol. 1997; 100: 415–23. [4] Fasth A. Primary immunodeficiency disorders in Sweden: cases among children, 1974–1979. J Clin Immunol. 1982; 2: 86–92. [5] Matamoros FN, Mila LJ, Espanol Boren T, Raga Borja S, Fontan Casariego G. Primary immunodeficiency syndrome in Spain: first report of the National Registry in Children and Adults. J Clin Immunol. 1997; 17: 333–9. [6] Ryser O, Morrell A, Hitzig WH. Primary immunodeficiencies in Switzerland: first report of the national registry in adults and children. J Clin Immunol. 1988:479–85. [7] Smith CIE, Ochs HD, Puck JM. Genetically determined immunodeficiency diseases: a perspective. In: Ochs HD, Smith CIE, Puck JM,eds. Primary immunodeficiency diseases: a molecular and genetic approach. New York, NY: Oxford University Press, 1999:. [8] Stray-Pedersen A, Abrahamsen TG, Froland SS. Primary immunodeficiency diseases in Norway. J Clin Immunol. 2000; 20: 477–85. [9] Yarmohammadi H, Estrella L, Doucette J, Cunningham-Rundles C. Recognizing Primary Immune Deficiency in Clinical Practice. Clin Vacc Immunol 2006; 13: 329–332. [10] Buckley RH. Immunodeficiency Disorders: General considerations in Immune Disorders of Infants and Children, Stiehm, Ochs, Winkelstein eds. Elvsevier, Inc. Philadelphia, 2004. [11] Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological feature of 248 patients. Clin Immunol 1999; 92: 34–48. [12] Seymour B, Miles J, Haeney M. Primary antibody deficiency and diagnostic delay. J Clin Pathol. 2005; 58: 546–547. [13] Myers L, Patel D, Puck J, Buckley R. Hematopoietic stem cell transplantation for severe combine immunodeficiency in the neonatal period leads to superior thymic output and improved survival. Blood 2002; 99: 872–878. [14] Winkelstein JA, Marino MC, Johnston Jr RB, et al. Chronic Granulomatous Disease. Report on a national registry of 368 patients. Medicine 2000; 79: 155–169. [15] Oksenhaendler E, Gerard, L, Fieschi C, et al. Infections in 252 patients with common variable immunodeficiency. Clin Infect Dis 2008; 46: 1547–1554. [16] Dorman SE, Picard C, Lammas K, et al. Clinical features of dominant and recessive interferon g receptor 1 deficiencies. Lancet 2004; 364: 2113–2121. [17] Picard C, Fieschi C, Altare F, et al. Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds. Am J Hum Genet 2002; 70: 336–348. [18] Busse PJ, Razvi S, Cunningham-Rundles C. Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency. J Allergy Clin Immunol 2002; 109: 1001–1004. [19] Sweinberg SA, Wodell RA, Grodofsky JM, Greene JM, Conley ME. Retrospective analysis of the incidence of pulmonary disease in hypogammaglobulinemia. J Allergy Clin Immunol 1991; 88: 96–104.
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[20] Popa V, Colby T, Reich S. Pulmonary interstitial disease in Ig deficiency. Chest 2002; 122: 1594–1603. [21] Fasano MB, Sullivan KE, Sarpong SB, et al. Sarcoidosis and common variable immunodeficiency: report of 8 cases and review of the literature. Medicine 1996; 75: 251–261. [22] Hausser C, Virelizier JL, Buriot D, Griscelli C. Common variable hypogammaglobulinemia in children: clinical and immunologic observations in 30 patients. Am J Dis Child 1983; 137: 833–837. [23] Chua I, Quinti I, Grimbacher B. Lymphoma in common variable immunodeficiency: interplay between immune dysregulation, infection and genetics. Curr Opin Hematol 2008; 15: 368–374. [24] Agarwal S, Cunningham-Rundles C. Thymoma and immunodeficiency (Good syndrome): a report of 2 unusual cases and review of the literature. Ann Allergy Asthma Immunol 2007; 98: 185–190. [25] Lindgren ML, Kobrynski L, Rasmussen S. et al. Applying Public Health Strategies for Primary Immune Deficiency Diseases: a potential approach to genetic disorders. MMWR 2004;53;R1–29. [26] Bonilla FA, Bernstein DA, Khan ZK et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol 2005; 94: S1-S63. [27] Marciano BE, Wesley R, deCarlo ES, et al. Long term interferon-g Therapy for Patients with Chronic Granulomatous Disease. Clin Infect Dis 2004; 39: 692–699.
III.4.2 Increased risk of infections among persons with asthma T.V. Hartert. Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Center for Asthma & Environmental Sciences Research, 6107 MCE, Nashville, TN 37232–8300, USA Correspondence: Tina V. Hartert, M.D., M.P.H. Division of Allergy, Pulmonary and Critical Care Medicine, Center for Asthma & Environmental Sciences Research, 6107 MCE, Vanderbilt University School of Medicine, Nashville, TN 37232–8300, USA. Phone: +1 615 322 3412; fax: +1 615 936 1269. E-mail: [email protected] Keywords: Asthma, Infection, Pneumococcal disease
Are persons with asthma at an increased risk for infections? One of the problems in answering this question is that historically studies of infections and asthma have centered on the impact of respiratory infections on asthma exacerbations, a respiratory disease, rather than focusing on infection susceptibility or infections outside of the respiratory tract. Recent investigations provide biologically plausible explanations for an increased susceptibility to certain viral and bacterial infections among persons with asthma, however, the exact mechanisms for this increased risk are not known. While we know that persons with asthma have a disrupted airway epithelial physical barrier, increased and aberrant mucous production, and other alterations in innate and adaptive immunity, whether these are the mechanisms through which asthmatics have an increased risk or more severe infections is not known. In addition, the medications used to treat asthma may also be immunosuppressive, or could possibly even enhance immune responses specifically among persons with asthma who are prescribed and compliant with their medications. Thus what we do not know, is whether the increased association of infections and infection severity in asthma is an epiphenomenon due to enhanced airway inflammation and/or allergic inflammation resulting in more severe respiratory infections in individuals with a chronic respiratory disease, or whether these differences among persons with asthma truly alter host defense rendering asthmatics more susceptible to bacterial and viral pathogens. What follows is a summary of our current understanding of the data supporting the association of asthma and serious infections, potential mechanisms of host susceptibility to infections, and preventive implications. The data that support biologic plausibility for persons with asthma being at increased risk for particular infections come from several lines of evidence. The first is that asthmatic inflammation may inhibit or alter host defense rendering asthmatics more susceptible to infections. A second is that innate immunity may be altered in
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asthma and this alteration may inhibit antimicrobial host defense and/or response to injury and in this way render asthmatics more susceptible to and less able to resist infections. Lastly, in support of link between response to infections and the underlying chronic disease asthma, are the many known genetic factors that impact patterns of immune response to infectious agents, that are also strongly linked with asthma [1–4]. The body of literature that actually supports an increased risk of infection among persons with asthma is relatively small, and can be conceptually grouped into evidence for increased infection-related morbidity, increased infection latency (propensity to persist and cause chronic infection), and increased invasiveness of infections among asthmatics. Importantly, as asthma is a respiratory disease, we need to understand whether infections outside of the respiratory tract are more common or severe among persons with asthma; unfortunately, in this regard there is little data to my knowledge. Persons with asthma have been shown to have increased rates of pneumococcal nasal colonization, as well as hypopharyngeal colonization as neonates before the development of asthma, which provides strong support for a pre-existing defective immune response among persons destined to develop asthma [5,6]. Data also supports latency of infection among persons with asthma for a number of pathogens, including respiratory syncytial virus, adenovirus, Human rhinovirus, Mycoplasma pneumoniae and Chlamydia pneumoniae. Respiratory-related infection morbidity has also been shown to be higher among persons with asthma. Almirall and colleagues have shown that both asthma and inhaled corticosteroids are risk factors for community-acquired pneumonia in a European population based case-control study among persons age >14 years. Asthma has also been shown to be an independent risk factor for influenza-attributable morbidity among children and pregnant women [7–9]. Previously, our group reported that persons with asthma had a greater than 2-fold increased risk of invasive pneumococcal disease, using the Active Bacterial Surveillance Core data from the US Centers for Disease Control and Surveillance, which identified Streptococcus pneumoniae from sterile sites, (blood cultures, cerebrospinal and joint fluid) among both children and adults [10] A follow-up study by Juhn et al also showed an increased risk of serious pneumococcal disease among persons with asthma [11]. The available evidence from these studies, as is true with nearly all of the investigations looking at the relationship between infections and asthma is that they are based on observational data. While an association between asthma and a subsequent infectious event can reflect causal mechanisms, alternatively, such associations can be the result of other unmeasured factors or characteristics that are closely related to asthma (confounders). However, in both of these investigations of the association of asthma with invasive or serious pneumococcal disease, “asthma” identified those at high-risk, and in both of these studies, the results are strikingly consistent. The consistency of these data suggest that the increased association of clinically significant pneumococcal infection in asthma is not just an epiphenomenon caused by enhanced airway inflammation rendering persons with asthma more clinically symptomatic from pneumococcal respiratory disease, but that allergic inflammation and asthma are associated with or alter host defenses and in this way render persons with asthma more susceptible to pneumococcal disease. The strongest evidence for this true increased susceptibility to pneumococcal disease among persons with asthma lies in the data supporting an increase in invasive infections [10]. This has also been recognized with rhinovirus infections, where persons with asthma are more likely to experience rhinovirus viremia, and this increased susceptibility has been shown to likely relate to defective innate immune responses [11]. The association with increased risk of invasive pneumococcal disease is additionally important, as pneumococcal vaccine is most efficacious for invasive pneumococcal disease. It is important to realize that although these studies have limitations, these observational investigations are likely to be the
Oral Presentations / Paediatric Respiratory Reviews 12S1 (2011) S1–S66
III.4. Obstructive Lung Disease – Lung diseases in children: immunity, viruses or genes? III.4.1 A primer on immunology for the pulmonologist L. Kobrynski. Assistant Professor of Pediatrics, Division of Allergy and Immunology, Emory University, USA Correspondence: Tel.: 404 727 3575. E-mail: [email protected].
What are Primary Immune Deficiencies: Primary Immune Deficiency disorders (PIDD) refer to a group of over 150 distinct defects of the immune system, many of which are due to single gene defects. Congenital defects in various parts of the immune system have been described in humans. Although, the underlying immunologic defects are present at birth, individuals may not become symptomatic until adulthood. Most primary immune deficiencies (PIDDs) are due to single gene defects causing either the absence of a specific protein or a non-functional protein. This distinguishes them from secondary immune defects due to medications, malignancies, or other infections. PIDD can be inherited in an X-linked, autosomal recessive or autosomal dominant fashion. One of the largest clinical phenotypes, Common Variable Immune Deficiency (CVID), has a pattern of variable inheritance, with both AR and AD forms being reported [1] and genetic linkage studies showing a familial predisposition. Despite the differing patterns of disease severity and onset, all patients with PIDD suffer from recurrent infections which cause significant morbidity and mortality. Complement, 5% Phagocytic, 10% Cellular, 5%
Combined, 15% Antibody deficiency, 65%
Fig. 1. Frequency of various primary immune deficiencies.
The true prevalence of PIDD is not known, but it is estimated that 1:1,200 individuals in the United States has been diagnosed with a PIDD [2]. This number is in contrast to previous minimal estimates of 1:10,000 to 1:500,000 based on data from disease registries [3–9] and suggests that many cases of PIDD remain undiagnosed. PIDD are typically classified by the nature of the immune defect, whether it affects antibody production by B cells (humoral immunity), T cell function (cellular immunity), both T and B cell function (combined immune defect), killing of bacteria by neutrophils (phagocytic defect) or complement. Figure 1 shows the breakdown of PIDD by the underlying defect [10] with the largest proportion resulting in defects of antibody production. About 40% of individuals with PIDD present with infections or other findings of PIDD in the first few years of life. The most severe defects, such as Severe Combined Immune Deficiency (SCID), are fatal in early childhood if not treated. Previously PIDD were thought to be pediatric diseases, but the mean age of diagnosis for CVID is 29 years for males and 33 years for females [11]. Most will have a
history of infections for several years prior to diagnosis. In adults the average delay in diagnosis is 5 years. Diagnosis of PIDD, even in the face of symptoms starting early in childhood, may be delayed until adolescence because of a lack of clinical suspicion, underscoring the need for improved awareness of these disorders. Recent results from a UK national audit show that the median delay in diagnosis has decreased from 3.5 years to 1 year [12]. Early diagnosis and treatment has been shown to reduce morbidity and mortality in many PIDD [13] (Buckley SCID BMT). End organ damage, particularly in the lungs, frequently occurs in the first decade of life as a sequelae of infection. Normal host defenses of the respiratory tract: The respiratory tract communicates with the outside environment, thus host defenses against respiratory pathogens are critical. Innate immune defenses are the first line responders against pathogens. The components of the innate immune system in the respiratory tract are the mechanical barriers, the mucous membranes, the mucin containing antimicrobial peptides such as defensins and secretory IgA, the cilia, the cellular effector cells, the phagocytes and NK cells which engulf and kill microbes, the matural antimicrobial agents, defensins, lactoferrin, lysozyme and myeloperoxidase, reactive oxygen species, cytokines and chemokines to recruit effector cells to the site of infection. Innate immunity: Innate immune responses are generally the first line of defense against viral, bacterial and fungal pathogens and involve the activation and recruitment of macrophages, neutrophils and Natural Killer cells with release of chemokines, cytokines, or antimicrobial peptides. Clearance of infectious organisms can be accomplished through binding of serum complement facilitating opsonization of microbes, or by phagocytosis and intracellular killing in phagocytes through reactive oxygen or nitrogen molecules. Humoral immunity: The humoral immune system relies on adaptive immunity to produce antigen specific responses against infectious pathogens. Microbial peptides are presented on the surface of antigen presenting cells (dendritic cells, monocytes/macrophages, B cells) associated with costimulatory major histocompatibility class II (MHCII) molecules. Cognate interaction between T cells and B cells by binding of T cell receptor (TCR) with B cell receptor (BCR) complex and binding of secondary signal (CD40-CD40L or CD28-CTLA4) results in intracellular signaling to trigger clonal proliferation and maturation of antigen specific cells with immunoglobulin heavy chain isotype switching to produce specific IgG or IgA antibodies. Cellular immunity: Cellular immunity involves the activation and proliferation of naïve T cells in response to an antigen. Macrophages or dendritic cells can express microbial peptides on their cell suface with MHCI or MHCII. Recognition of foreign peptides on the cell surface signals T cells to differentiate into effector cells, cytotoxic T cells that kill infected cells, or T helper cells (TH 1) that activate infected macrophages. Cytotoxic T cells exert their effects through enzymes (perforin, granzyme), Fas Ligand, and cytokines (IFN gamma, TNFb, TNFa). TH 1 cells produce interferon gamma, and TNFb and TNFa, activating infected macrophages. Pulmonary disease in primary immunodeficiency: The majority of patients with antibody deficiencies, up to 80%, and neutrophil defects will have more than one episode of pneumonia prior to diagnosis [11,14,15]. Frequently the pattern of infection or identification of the causative pathogen will serve as an indicator to the nature of the immune defect. Table 1 summarizes clinical characteristics of pulmonary infections in different PIDD. Defects in interferon gamma (IFNg) and IL12 axis cause an increased susceptibility to mycobacteria. Defects in IFNgR1, IFNgR2, IL12/IL23 and IL12R are inherited in an AR fashion and affected individuals develop disseminated and life threatening infections with mycobacterium, including BCG and nontuberculous mycobacteria [16,17].
Oral Presentations / Paediatric Respiratory Reviews 12S1 (2011) S1–S66
Individuals with cellular immune defects such as Severe Combined Immune Deficiency (SCID) or an absence of the thymus (complete DiGeorge syndrome) present early in life with opportunistic infections, frequently pneumonia due to Pneumocystis jirovecii. Other viral pathogens, parainfluenza 3 and respiratory syncytial virus (RSV), cytomegalovirus (CMV) and Herpes viruses, can cause severe interstitial pneumonitis and may be fatal. Without immune reconstitution, usually achieved by hematopoietic stem cell transplantation in SCID, affected patients will succumb to recurrent viral, fungal and bacterial infections. Combined immune deficiencies include disorders such as WiskottAldrich Syndrome (WAS), Ataxia-Telangiectasia (AT), and Hyper-IgE syndrome. Recurrent pulmonary infections are a common feature for all these disorders. Pyogenic bacteria are the most frequent pathogen, but pneumocystis and other viral pathogens also cause infections. Bronchiectasis is a common complication of respiratory infections in WAS and AT. Pneumatocoeles are characteristic for S. aureus infections in Hyper-IgE. Individuals with antibody deficiencies typically develop bacterial infections of the sinopulmonary tract after maternal antibodies wane after six months of life. Infants with X-linked agammaglobulinemia have an increased frequency of bacterial pneumonias, along with recurrent otitis media, and chronic diarrhea. While many individuals with selective IgA deficiency are asymptomatic, others have a history of frequent otitis media and sinusitis. Some individuals will also be more susceptible to lower respiratory infections and gastrointestinal infections. Many individuals with CVID do not have a notable history of infections until the 2nd decade of life or later. Infections of the sinopulmonary tract occur more frequently than in the general population, with an increase in severity, and are often associated with other sites of infection. Pyogenic bacteria, such as Staph. aureus, Strep. pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, are responsible for the majority of the pulmonary infections, but infections with atypical mycobacterium, and opportunistic organisms may be seen in patients with impaired T cell function and in patients with hyperIgM syndrome. Other antibody deficiencies (NEMO, AR-HyperIgM, selective antibody deficiency) also predispose affected individuals to upper and lower respiratory tract infections. Pneumonia associated complications, bronchiectasis, empyemas, granulomatous lung disease, are seen more frequently in patients with antibody deficiencies (except SAD and IgA deficiency) [18]. Bronchiectasis may already be present at the time of diagnosis (Fig. 2) and end-stage lung disease with respiratory insufficiency is the most frequent cause of death in CVID [11]. Frequently progression of lung disease occurs despite replacement of serum IgG with gammaglobulins [19]. In Chronic Granulomatous Disease (CGD), infections with catalase positive organisms (S. aureus, Pseudomonas sp., Aspergillus, Nocardia,
Fig. 2. CT of bronchiectasis. Bronchial wall thickening in XLA patient.
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Serratia, Klebsiella) can involve multiple sites. The majority of patients will present with a history of pneumonia [14]. The hallmark of the respiratory infections in patients with CGD is the unusually invasive nature of infections with Pseudomonas or Aspergillus, the propensity for abscess formation and the development of noncaseating granulomas. Bronchiectasis is seen less frequently in patient with CGD compared to individuals with antibody deficiency, but can develop after recurrent S. aureus infections. Necrotizing pneumonias due to Pseudomonas species may necessitate lobectomy. In addition to bronchiectasis, other chronic lung changes occur in PIDD. Hilar and mediastinal adenopathy is frequently seen. Bronchiolitis obliterans may develop, or involvement of the airways and the parenchyma can lead to pulmonary fibrosis and pulmlonary hypertension. Subsequent to opportunistic viral or fungal infections, persistent focal ground-glass opacities may be seen on CT scan. Interstitial lung disease occurs in patients over 40 years of age with antibody deficiencies [20]. Multiple pulmonary noncaseating granulomas, sometimes calcified can be seen in patients with CGD and CVID. In both disorders, intracellular pathogens (PJP, mycobacterium) can sometimes be identified in the granulomas (Fig. 3). In CVID these granulomas have been termed “sarcoid-like” [21]. Benign lymphoid hyperplasia involving the lung and gastrointestinal tract occur in as many as 30% of patients with CVID [22]. Non-Hodgkin lymphomas are more prevalent in patients with CVID [11,23]. Thoracic lymphomas may present with enlarged mediastinal nodes, or an anterior mediastinal mass which may compress the airway or blood vessels. The presence of an anterior mediastinal mass in a patient with hypogammaglobulinemia and low or absent B cells is characteristic of Good syndrome [24]. In these cases the development of a thymoma carries a poor prognosis.
Fig. 3. Granulomatous pneumocystis in CVID. Pulmonary nodules containing pneumocystis. Bierry G et al. Radiographics 2009; 29: 1909–20. Courtesy of L Kobrynski.
Evaluation of the patient with suspected primary immunodeficiency: Any patient with a history of recurrent, unusually severe pneumonias, or infection with atypical or opportunistic pathogens should undergo evaluation to identify a possible immune deficiency. The types of infections, their frequency, severity, pathogens involved and the age of onset may suggest the clinical phenotype and can be used to direct the laboratory evaluation. In addition to the history of infections, clinicians should inquire about associated problems and a family history of PIDD. Clinical algorithms have been suggested to help identify individuals with possible PIDD (Fig. 4: JMF 10WS). Laboratory testing can then be used to delineate the immune defect. The pattern of infection is the most useful element to discriminate the different immunologic defects. Table 1 shows the pathogens typically associated with defects in different arms of the immune system. Figure 5 shows a testing algorithm for screening patients for a PIDD [25]. It is worth noting that some tests are available only in specialized laboratories.
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replacement is effective at reducing the incidence of infections, although it may not be as effective in treating bronchiectasis [19]. Recommended dosing is 400–500 mg/kg/month of gammaglobulin given IV or 100–150 mg/kg/wk given subcutaneously [26]. Prophylactic antibiotics are first line therapy to prevent PJP (cotrimoxazole), and to prevent infections in IgA deficiency and selective antibody deficiency (SAD). Antibiotics may also be adjunctive therapy in CVID, XLA and HyperIgM. Patients with CGD require prophylaxis with co-trimoxazole and itraconazole. In addition, therapy with IFN gamma given three days a week was shown to reduce the rate of serious infections [27].
Fig. 4: JMF 10 Warning signs at www.info4PI.org
Table 1: Pulmonary Infections in PIDD Immune defect
T cell or combined
B-cell- antibody
Phagocyte
Complement
Common pathogens (respiratory)
Pneumocystis jirovecii, CMV, EBV, herpes viruses, mycobacteria, Pseudomonas
S. pneumoniae, H. influenzae, S. aureus
S. aureus, Pseudomonas sp., Serratia sp, Klebsiella sp, Nocardia, Aspergillus
Pathology
Interstitial pneumonitis
Sequelae
Pulmonary fibrosis
Necrotizing pneumonia, lung abscess Granulomas, bronchiectasis
Associated features
Failure to thrive, GVHD from maternal cells, BCGosis, dermatitis
Lobar pneumonia, empyema Granulomas, bronchiectasis, interstitial fibrosis Malabsorption, chronic diarrhea autoimmune disease, thymoma
S. pneumoniae, Neisseria meningitidis, E. coli (usually nonpulmonary) Pneumonia infrequent
Other organ abscesses, adenitis, osteomyelitis, periodontitis, delayed separation of umbilical cord
Rare
Bacteremia, meningitis, SLE, glomerulonephritis
Fig. 5: Laboratory testing algorithm.
Treatment: Therapy is aimed at preventing infections and sequelae of infections. For antibody deficiencies, gamma globulin
References [1] Warnatz K, Salzer U, Rizzi M, et al. B-cell activating factor receptor deficiency is associated with adult onset antibody deficiency syndrome in humans. Proc Natl Acad Sci USA 2009; 106: 13945–13950. [2] Buckley RH, Boyle JM. Population prevalence of diagnosed Primary Immune Deficiency in the United States. J Clin Immunol. 2007; 27: 497–502. [3] Baumgart KW, Britton WJ, Kemp A, French M, Roberton D. The spectrum of primary immunodeficiency disorders in Australia. J Allergy Clin Immunol. 1997; 100: 415–23. [4] Fasth A. Primary immunodeficiency disorders in Sweden: cases among children, 1974–1979. J Clin Immunol. 1982; 2: 86–92. [5] Matamoros FN, Mila LJ, Espanol Boren T, Raga Borja S, Fontan Casariego G. Primary immunodeficiency syndrome in Spain: first report of the National Registry in Children and Adults. J Clin Immunol. 1997; 17: 333–9. [6] Ryser O, Morrell A, Hitzig WH. Primary immunodeficiencies in Switzerland: first report of the national registry in adults and children. J Clin Immunol. 1988:479–85. [7] Smith CIE, Ochs HD, Puck JM. Genetically determined immunodeficiency diseases: a perspective. In: Ochs HD, Smith CIE, Puck JM,eds. Primary immunodeficiency diseases: a molecular and genetic approach. New York, NY: Oxford University Press, 1999:. [8] Stray-Pedersen A, Abrahamsen TG, Froland SS. Primary immunodeficiency diseases in Norway. J Clin Immunol. 2000; 20: 477–85. [9] Yarmohammadi H, Estrella L, Doucette J, Cunningham-Rundles C. Recognizing Primary Immune Deficiency in Clinical Practice. Clin Vacc Immunol 2006; 13: 329–332. [10] Buckley RH. Immunodeficiency Disorders: General considerations in Immune Disorders of Infants and Children, Stiehm, Ochs, Winkelstein eds. Elvsevier, Inc. Philadelphia, 2004. [11] Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological feature of 248 patients. Clin Immunol 1999; 92: 34–48. [12] Seymour B, Miles J, Haeney M. Primary antibody deficiency and diagnostic delay. J Clin Pathol. 2005; 58: 546–547. [13] Myers L, Patel D, Puck J, Buckley R. Hematopoietic stem cell transplantation for severe combine immunodeficiency in the neonatal period leads to superior thymic output and improved survival. Blood 2002; 99: 872–878. [14] Winkelstein JA, Marino MC, Johnston Jr RB, et al. Chronic Granulomatous Disease. Report on a national registry of 368 patients. Medicine 2000; 79: 155–169. [15] Oksenhaendler E, Gerard, L, Fieschi C, et al. Infections in 252 patients with common variable immunodeficiency. Clin Infect Dis 2008; 46: 1547–1554. [16] Dorman SE, Picard C, Lammas K, et al. Clinical features of dominant and recessive interferon g receptor 1 deficiencies. Lancet 2004; 364: 2113–2121. [17] Picard C, Fieschi C, Altare F, et al. Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds. Am J Hum Genet 2002; 70: 336–348. [18] Busse PJ, Razvi S, Cunningham-Rundles C. Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency. J Allergy Clin Immunol 2002; 109: 1001–1004. [19] Sweinberg SA, Wodell RA, Grodofsky JM, Greene JM, Conley ME. Retrospective analysis of the incidence of pulmonary disease in hypogammaglobulinemia. J Allergy Clin Immunol 1991; 88: 96–104.
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[20] Popa V, Colby T, Reich S. Pulmonary interstitial disease in Ig deficiency. Chest 2002; 122: 1594–1603. [21] Fasano MB, Sullivan KE, Sarpong SB, et al. Sarcoidosis and common variable immunodeficiency: report of 8 cases and review of the literature. Medicine 1996; 75: 251–261. [22] Hausser C, Virelizier JL, Buriot D, Griscelli C. Common variable hypogammaglobulinemia in children: clinical and immunologic observations in 30 patients. Am J Dis Child 1983; 137: 833–837. [23] Chua I, Quinti I, Grimbacher B. Lymphoma in common variable immunodeficiency: interplay between immune dysregulation, infection and genetics. Curr Opin Hematol 2008; 15: 368–374. [24] Agarwal S, Cunningham-Rundles C. Thymoma and immunodeficiency (Good syndrome): a report of 2 unusual cases and review of the literature. Ann Allergy Asthma Immunol 2007; 98: 185–190. [25] Lindgren ML, Kobrynski L, Rasmussen S. et al. Applying Public Health Strategies for Primary Immune Deficiency Diseases: a potential approach to genetic disorders. MMWR 2004;53;R1–29. [26] Bonilla FA, Bernstein DA, Khan ZK et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol 2005; 94: S1-S63. [27] Marciano BE, Wesley R, deCarlo ES, et al. Long term interferon-g Therapy for Patients with Chronic Granulomatous Disease. Clin Infect Dis 2004; 39: 692–699.
III.4.2 Increased risk of infections among persons with asthma T.V. Hartert. Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Center for Asthma & Environmental Sciences Research, 6107 MCE, Nashville, TN 37232–8300, USA Correspondence: Tina V. Hartert, M.D., M.P.H. Division of Allergy, Pulmonary and Critical Care Medicine, Center for Asthma & Environmental Sciences Research, 6107 MCE, Vanderbilt University School of Medicine, Nashville, TN 37232–8300, USA. Phone: +1 615 322 3412; fax: +1 615 936 1269. E-mail: [email protected] Keywords: Asthma, Infection, Pneumococcal disease
Are persons with asthma at an increased risk for infections? One of the problems in answering this question is that historically studies of infections and asthma have centered on the impact of respiratory infections on asthma exacerbations, a respiratory disease, rather than focusing on infection susceptibility or infections outside of the respiratory tract. Recent investigations provide biologically plausible explanations for an increased susceptibility to certain viral and bacterial infections among persons with asthma, however, the exact mechanisms for this increased risk are not known. While we know that persons with asthma have a disrupted airway epithelial physical barrier, increased and aberrant mucous production, and other alterations in innate and adaptive immunity, whether these are the mechanisms through which asthmatics have an increased risk or more severe infections is not known. In addition, the medications used to treat asthma may also be immunosuppressive, or could possibly even enhance immune responses specifically among persons with asthma who are prescribed and compliant with their medications. Thus what we do not know, is whether the increased association of infections and infection severity in asthma is an epiphenomenon due to enhanced airway inflammation and/or allergic inflammation resulting in more severe respiratory infections in individuals with a chronic respiratory disease, or whether these differences among persons with asthma truly alter host defense rendering asthmatics more susceptible to bacterial and viral pathogens. What follows is a summary of our current understanding of the data supporting the association of asthma and serious infections, potential mechanisms of host susceptibility to infections, and preventive implications. The data that support biologic plausibility for persons with asthma being at increased risk for particular infections come from several lines of evidence. The first is that asthmatic inflammation may inhibit or alter host defense rendering asthmatics more susceptible to infections. A second is that innate immunity may be altered in
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asthma and this alteration may inhibit antimicrobial host defense and/or response to injury and in this way render asthmatics more susceptible to and less able to resist infections. Lastly, in support of link between response to infections and the underlying chronic disease asthma, are the many known genetic factors that impact patterns of immune response to infectious agents, that are also strongly linked with asthma [1–4]. The body of literature that actually supports an increased risk of infection among persons with asthma is relatively small, and can be conceptually grouped into evidence for increased infection-related morbidity, increased infection latency (propensity to persist and cause chronic infection), and increased invasiveness of infections among asthmatics. Importantly, as asthma is a respiratory disease, we need to understand whether infections outside of the respiratory tract are more common or severe among persons with asthma; unfortunately, in this regard there is little data to my knowledge. Persons with asthma have been shown to have increased rates of pneumococcal nasal colonization, as well as hypopharyngeal colonization as neonates before the development of asthma, which provides strong support for a pre-existing defective immune response among persons destined to develop asthma [5,6]. Data also supports latency of infection among persons with asthma for a number of pathogens, including respiratory syncytial virus, adenovirus, Human rhinovirus, Mycoplasma pneumoniae and Chlamydia pneumoniae. Respiratory-related infection morbidity has also been shown to be higher among persons with asthma. Almirall and colleagues have shown that both asthma and inhaled corticosteroids are risk factors for community-acquired pneumonia in a European population based case-control study among persons age >14 years. Asthma has also been shown to be an independent risk factor for influenza-attributable morbidity among children and pregnant women [7–9]. Previously, our group reported that persons with asthma had a greater than 2-fold increased risk of invasive pneumococcal disease, using the Active Bacterial Surveillance Core data from the US Centers for Disease Control and Surveillance, which identified Streptococcus pneumoniae from sterile sites, (blood cultures, cerebrospinal and joint fluid) among both children and adults [10] A follow-up study by Juhn et al also showed an increased risk of serious pneumococcal disease among persons with asthma [11]. The available evidence from these studies, as is true with nearly all of the investigations looking at the relationship between infections and asthma is that they are based on observational data. While an association between asthma and a subsequent infectious event can reflect causal mechanisms, alternatively, such associations can be the result of other unmeasured factors or characteristics that are closely related to asthma (confounders). However, in both of these investigations of the association of asthma with invasive or serious pneumococcal disease, “asthma” identified those at high-risk, and in both of these studies, the results are strikingly consistent. The consistency of these data suggest that the increased association of clinically significant pneumococcal infection in asthma is not just an epiphenomenon caused by enhanced airway inflammation rendering persons with asthma more clinically symptomatic from pneumococcal respiratory disease, but that allergic inflammation and asthma are associated with or alter host defenses and in this way render persons with asthma more susceptible to pneumococcal disease. The strongest evidence for this true increased susceptibility to pneumococcal disease among persons with asthma lies in the data supporting an increase in invasive infections [10]. This has also been recognized with rhinovirus infections, where persons with asthma are more likely to experience rhinovirus viremia, and this increased susceptibility has been shown to likely relate to defective innate immune responses [11]. The association with increased risk of invasive pneumococcal disease is additionally important, as pneumococcal vaccine is most efficacious for invasive pneumococcal disease. It is important to realize that although these studies have limitations, these observational investigations are likely to be the