Respiration 2007;74:264–275

Genetic Causes of Bronchiectasis: Primary Immune Deficiencies and the Lung

Notarangelo L.D.a, b · Plebani A.b · Mazzolari E.b · Soresina A.b · Bondioni M.P.c
aDivision of Immunology, Children’s Hospital, Harvard Medical School, Boston, Mass., USA; bDepartment of Pediatrics and cDivision of Pediatric Radiology, University of Brescia, Ospedale dei Bambini, Brescia, Italy
email Corresponding Author


 goto top of outline Key Words

  • Immunodeficiency, primary
  • Bronchiectasis
  • Lung

 goto top of outline Abstract

Primary immune deficiencies (PID) comprise a heterogeneous group of genetically determined disorders that affect development and/or function of innate or adaptive immunity. Consequently, patients with PID suffer from recurrent and/or severe infections that frequently involve the lung. While the nature of the immune defect often dictates the type of pathogens that may cause lung infection, there is substantial overlap of radiological findings, so that appropriate laboratory tests are mandatory to define the nature of the immune defect and to prompt appropriate treatment. At the same time, the recent identification of a large number of PID-causing genes now allows early, even presymptomatic diagnosis, thus representing an essential tool for prevention of lung damage. This review article describes the most common forms of PID, their cellular and molecular bases, and the associated lung abnormalities, and reports on available treatment.

Copyright © 2007 S. Karger AG, Basel

goto top of outline Introduction

Bronchiectasis, defined as an abnormal and irreversible dilatation of the bronchi, frequently associated with inflammation [1], is the most common complication of recurrent pneumonia. With improvements in sanitation and nutrition, increased use of antibiotics in the treatment of acute respiratory infections, and childhood immunizations (especially to pertussis and measles), a decline in hospital admission rates for pediatric bronchiectasis has been reported since the 1950s [2]. At the same time, an increasing proportion of patients with bronchiectasis is now recognized to suffer from an underlying disease that predisposes them to develop recurrent or chronic lung infection [3]. In this regard, genetic diseases – including, but not limited to, cystic fibrosis (CF) – are at the frontline [4].

Pulmonary complications are particularly common in immunocompromised children. Although different patterns (bacterial pneumonia, abscesses, fungal lung disease, interstitial pneumonia) are associated with distinct types of immune defects, there is substantial overlap in imaging findings (table 1), so that close collaboration between radiologists and clinical immunologists is necessary to improve diagnostic accuracy. In particular, radiological imaging in the evaluation of patients with possible primary immune deficiency (PID) may fulfill different purposes, such as to identify and confirm the diagnosis, to quantify the extension of the disease, and finally to follow-up the effects of therapy.

Table 1. Most frequent radiological findings in PID

Although initial evaluation is usually based on chest radiography, this is limited by low sensitivity and specificity. In contrast, computed tomography (CT), in particular high-resolution CT (HRCT) is the imaging technique of choice to evaluate pulmonary parenchyma, due to optimal spatial resolution. It is also more sensitive to distinguish between interstitial, airway and airspace diseases [5]. The optimization of pediatric protocols can allow the radiation dose to be kept to a minimum [6].

Bronchiectasis not caused by CF is often perceived to be rare in Western countries. Nikolaizik and Warner [7] found that 1% of children referred for investigation of chronic respiratory symptoms had suppurative lung disease not due to CF, and 27% of these had immunological abnormalities. However, these figures were likely underestimating the real incidence of non-CF bronchiectasis, as HRCT came into clinical practice as the gold standard for radiological diagnosis of bronchiectasis only in the late 1990s. Indeed, a more recent retrospective analysis of children with a history of respiratory symptoms referred to a tertiary center between 1996 and 2002 showed that as many as 9.6% had non-CF bronchiectasis, and 21% of them had immune deficiency [8]. In another study, that reviewed the etiology of non-CF bronchiectasis in 136 pediatric patients followed at 2 tertiary care institutions, PID was identified as the underlying cause in 46 subjects (33.8%) [9].

Searching for an underlying immune defect in patients with chronic lung disease is therefore very important [10]. Since antibodies and phagocytes are the primary defense against recurrent bacterial infections, measurement of serum immunoglobulins and analysis of neutrophil count and function must be considered. In multiple series reported in the literature, common variable immunodeficiency (CVI), X-linked agammaglobulinemia (XLA) and chronic granulomatous disease (CGD) – the prototype of functional defects of neutrophils – were the most common forms of PID associated with bronchiectasis [7,8,9,11,12,13,14]. This review will focus on pulmonary complications in various forms of PID. A summary of the main forms of PID, including inheritance, age at presentation, susceptibility to infections and laboratory approach to diagnosis, is shown in table 2. Importantly, while molecular defects are now known for over 140 defects of the immune system [15], molecular assays are not usually necessary in order to reach a diagnosis of PID, although they are eventually important for genetic counseling and prenatal diagnosis. In most cases, the diagnosis of PID can be established on the basis of a solid physical examination, careful personal and family history, and simple laboratory assays (table 2).

Table 2. Main forms of lymphocytic and phagocytic PID


goto top of outline Agammaglobulinemia

XLA was originally reported by Bruton [16] in 1952, and is characterized by virtual absence of all immunoglobulin isotypes and of circulating B lymphocytes.

The disease is caused by mutations of the Bruton’s tyrosine kinase (BTK) gene [17, 18]. Although BTK expression is not restricted to the B cell lineage, its mutations are particularly detrimental to early B cell development, with an incomplete block at the pre-B cell stage. More recently, autosomal recessive forms of agammaglobulinemia have been identified that are caused by mutations in genes that encode for other components of the pre-B cell receptor and its signaling pathway, such as the μ heavy chain, Igα, λ5 and the adapter protein BLINK [19].

Patients with XLA or autosomal recessive forms of agammaglobulinemia are highly susceptible to infections sustained by encapsulated bacteria (fig. 1a); in addition, mycoplasma can cause chronic pneumonitis [20]. Although infections typically tend to occur after the first 6 months of age, when maternally derived IgG disappears, recent studies indicate that sinopulmonary infections may also occur earlier [21]. Use of high-dose intravenous immunoglobulin (IVIG; >400 mg/kg every 3 weeks), that allows to maintain IgG trough levels at or above 500 mg/dl, has been shown to result in significantly lower infection and hospitalization rates in patients with XLA than when lower doses of IVIG are used [22]. Improvements in outcome are more likely to occur if early diagnosis and treatment are achieved. In addition, it is possible that the nature of the gene defect may impact on the severity of the clinical phenotype and survival into adulthood, as suggested by the fact that adult patients with XLA have a higher representation of splice-site mutations and a lower proportion of frameshift mutations than children with XLA [23].

Fig. 1. Pulmonary changes in patients with humoral immunodeficiencies. a Lung abnormalities in a patient with XLA. HRCT scan shows middle lobe collapse with cylindrical bronchiectases (arrows); other bronchiectases are visible in both lower lobes (arrowheads). b Granulomatous lesions in a patient with CVI. HRCT reveals 2 small and well-defined nodules (arrows) in the right lung. c Pneumatoceles in a patient with hyper-IgE syndrome. Axial chest CT scan shows multiple pneumatoceles in the right lower lobe (arrows).

A recent survey on quality of life in 41 adults with a definitive diagnosis of XLA showed that less than a third had chronic lung disease, and even these had minimal disability [24]. On the other hand, several studies have shown that IgG trough levels at around 500 mg/dl or even higher are often inadequate to fully prevent chronic lung disease [25,26,27]. A retrospective analysis on 73 males with molecularly proven XLA has shown that a delayed diagnosis is associated with a higher risk of developing chronic lung disease, and that the risk of developing chronic lung disease during follow-up increases with the duration of follow-up, regardless of serum IgG trough levels [28]. Therefore, prevention of lung disease in XLA remains a challenge, even if mortality rate due to lung disease is lower compared to a few decades ago [21]. No controlled, randomized studies have assessed the potential benefit of long-term antibiotic prophylaxis and/or physiotherapy in preventing chronic lung damage in this group of patients.


goto top of outline Common Variable Immunodeficiency

CVI is the most common form of primary hypogammaglobulinemia, with an estimated prevalence of approximately 1:25,000. Affected patients have a marked reduction of IgG and IgA and/or IgM of at least 2 SD below the mean for age, associated with defective antibody response to protein and polysaccharide antigens [28]. In evaluating patients with hypogammaglobulinemia, alternative causes, such as protein loss (as in some forms of malabsorption or after burning), must be ruled out. Total protein loss is marked by decrease in albumin, whose levels are unchanged in congenital forms of hypogammaglobulinemia, including CVI. Chronic lymphocytic leukemia in adults is another cause of secondary hypogammaglobulinemia.

CVI is characterized by recurrent bacterial infections and an increased risk of autoimmune disease and malignancy [29]. Often considered a disorder of adulthood, CVI has in fact 2 peaks of age at presentation, one in the first decade of life and the other one as young adults.

Most patients with CVI present with recurrent sinopulmonary infections [29, 30]. As many as 75–84% of CVI patients have had at least 1 episode (and often multiple episodes) of pneumonia before diagnosis [29, 31, 32]. Haemophilus influenzae and Streptococcus pneumoniae are the most common pathogens. Complications of acute pneumonia in CVI include pleurisy, empyema and bronchospasm. In addition, recurrent episodes of pneumonia may lead to bronchiectasis, or obstructive or restrictive chronic lung disease. The risk of chronic lung disease is higher in patients with CVI than in those with XLA, perhaps because the latter is diagnosed earlier in life and treated more promptly, whereas diagnostic delay remains a problem in CVI. Indeed, delayed diagnosis and/or inadequate treatment in CVI are associated with an increased risk of developing bronchiectasis [25, 30, 33]. In particular, bronchiectasis has been observed in 42–73% of patients with CVI [34,35,36,37], with a tendency towards a progressive decrease in the incidence during the last decades. This reflects both earlier diagnosis and more effective treatment. Additional factors that may contribute to the risk of bronchiectasis in CVI include unregulated inflammation intrinsic to the disease, and a low number of IgM memory B cells and reduced levels of IgM anti-pneumococcal polysaccharide antibodies in a subgroup of CVI patients [38].

In patients with CVI, bronchiectasis tends to be more common in the middle and lower lobes and the lingula [9, 13, 34], as mucociliary clearance is facilitated by gravity in the upper lobes [39]. However, this topographical location is not specific (as it may also be observed in other non-CF forms of bronchiectasis), and on the other hand patients with hypogammaglobulinemia may occasionally develop bronchiectasis also in the upper lobe or may show a diffuse distribution.

Importantly, in patients with hypogammaglobulinemia, bronchiectasis can be detected by HRCT even if conventional chest X-ray is normal. This means that a low threshold for suspecting bronchiectasis should be used in hypogammaglobulinemic subjects. Some authors have suggested to perform lung HRCT at the time a new diagnosis of hypogammaglobulinemia/agammaglobulinemia is established, and to repeat HRCT periodically during follow-up [40]; however, this policy has been challenged by other authors who suggest to use clinical parameters and pulmonary function tests as a tool to decide when HRCT should be repeated during follow-up [41, 42]. Once bronchiectasis has developed, colonization by Pseudomonas aeruginosa may occur, and this may lead to deterioration of respiratory function.

However, bronchiectasis is not the only type of long-term lung damage that may occur in CVI. A subgroup of patients with CVI develops granulomatous disease [43, 44] (fig. 1b) that may cause interstitial lung disease (also known as sarcoid-like disease) in approximately 10% of the cases [37]. In the majority of these patients, reticulation, often associated with signs of fibrosis, is disclosed by HRCT. A lung nodular pattern is also frequently detected. In this subgroup of patients, pulmonary function tests are often abnormal, with evidence of restrictive changes. These data indicate the need to carefully evaluate patients with interstitial lung disease in order to distinguish those with classic sarcoid from those with CVI.

In some patients with CVI, pulmonary granulomatous changes may coexist with lymphoid interstitial hyperplasia, resulting in granulomatous-lymphocytic interstitial lung disease (GLILD) [45]. Moreover, although rarely, lymphoid interstitial pneumonitis may also be present alone [46, 47]. CVI patients with GLILD have been reported to have poorer prognosis and reduced median survival compared to other CVI patients [45]. Human herpes virus 8 has been detected by polymerase chain reaction and immunohistochemistry in the lungs and blood of patients with GLILD [48].

The heterogeneity of clinical features in CVI may reflect heterogeneity of the cellular and molecular bases of the disease. In particular, linkage analysis in families with CVI (as well as with IgA deficiency) has identified the presence of susceptibility loci within the HLA region on chromosome 6 [49]. Association with MHC class II alleles may contribute to autoimmune manifestations that are observed in a proportion of CVI patients. In addition, three distinct genetic defects have recently been identified in CVI. Mutations of the inducible costimulator (ICOS), a molecule expressed by T cells, have been reported in 1% of the patients [50]. ICOS induces expression of Th2 cytokines, that are important in T/B cell interaction and class switch recombination. More recently, homozygous CD19 mutations have been identified in 2 families with CVI [51]. CD19 sets the tuning for signaling in B cell development, activation and proliferation. Importantly, about 10% of CVI patients are mutated in transmembrane activator and CAML interactor (TACI) [52, 53]. TACI is expressed on the surface of B cells and serves as the receptor for both BAFF and APRIL. TACI–/– mice have enlarged spleen and develop autoantibodies with time, but their antibody response to type II T-independent antigens is decreased. In humans, most patients with TACI mutation are heterozygous, suggesting a dominant-negative effect of the mutant protein. It is possible that this defect contributes to autoimmunity, frequently observed in CVI. Finally, other genetic factors may also contribute to the inflammatory granulomatous changes associated with CVI. In particular, a significant correlation with certain polymorphisms in the tumor necrosis factor gene has been reported [54].

There are several reports of chronic lung disease also in patients with IgA deficiency, particularly when associated with IgG2 deficiency [55, 56]. This is not surprising in view of the possible genetic overlap between IgA deficiency and CVI.

Patients with CVI benefit from immunoglobulin substitution therapy, with a reduction in infection rate and slowing of the progression of bronchiectasis [32]. Subcutaneous immunoglobulins (SCIG) may offer some significant advantage compared to IVIG in the treatment of hypogammaglobulinemia, as they allow to maintain more stable trough levels, carry a lower risk of severe adverse reactions and may improve patients’ compliance [57,58,59]. Because of higher immunoglobulin turnover, high-dose IVIG (600–800 mg/kg every 3 weeks) or higher and/or more frequent administrations of SCIG may be required in hypogammaglobulinemic patients with chronic lung disease [60]. Two studies (one in children with various forms of antibody deficiency and the other in adults with CVI) have suggested that high doses of IVIG (to maintain serum IgG levels above 600 mg/dl) may improve lung disease in some patients [61, 62]. Long-term antibiotic prophylaxis and lung physical therapy should also be considered in patients with CVI, but no controlled trials are available to judge on their efficacy.

Steroids are beneficial in CVI patients with lung granulomas or lymphoid interstitial infiltrates; cyclosporine and anti-tumor necrosis factor monoclonal antibody represent useful alternatives [63, 64]. One study has reported resolution of lymphoid interstitial pneumonitis with IVIG [46].


goto top of outline Hyper-IgE Syndrome

Hyper-IgE syndrome (HIES) is characterized by recurrent staphylococcal infections, coarse facial features, skeletal abnormalities, defective eruption of permanent teeth and markedly elevated serum IgE. Although HIES is typically inherited as an autosomal dominant trait with variable expressivity [65], an autosomal recessive variant has also been reported [66]. At variance with autosomal dominant HIES, patients with autosomal recessive HIES are also susceptible to viral infections. Recently, a homozygous mutation in the TYK2 gene has been identified in a patient with autosomal recessive HIES [67]. Tyk2 is a tyrosine kinase involved in cytokine-mediated signaling. As a result of Tyk2 deficiency, a skewing to a Th2 cytokine profile occurs.

The majority of patients with HIES develops multiple episodes of pneumonia, leading to pneumatoceles (fig. 1c). Occasionally, pneumothorax may follow due to rupture of the pneumatocele.

Noncomplicated cysts usually have thin walls; conversely, inflammatory processes can determine wall thickness and air-fluid levels within the lesions. Pneumatoceles may persist, progress in size or regress over time. Imaging techniques, in particular CT, are useful to correctly detect the location, size, number and extension of the cysts, in view of possible surgical planning [68, 69].


goto top of outline CGD and Severe Congenital Neutropenia

CGD is a genetically heterogeneous group of disorders characterized by recurrent and severe infections of bacterial or fungal origin [70]. CGD is caused by defective function of the NADPH oxidase, the enzyme responsible for phagocytic respiratory burst and superoxide production. NADPH oxidase comprises 2 membrane-bound proteins (gp91phox and p22phox) and 3 cytosolic components (p47phox, p67phox and p40phox). In addition, some GTP-binding proteins (Rac1, Rac2 and Rap1A) are also involved in NADPH oxidase activation. More commonly, CGD is inherited as an X-linked trait and is due to mutations of gp91phox. However, autosomal recessive variants due to defects of p22phox, p47phox and p67phox are also known. Rarely, patients with CGD-like syndrome due to defects of Rac2 have also been reported [71].

Infections in CGD have an early onset and are mainly due to Staphylococcus aureus, Burkholderia cepacia, Serratia marcescens, Nocardia, and Aspergillus spp. In addition to skin infections, lymphadenitis and liver abscesses, the lungs are frequently involved.

Radiologically, bacterial pneumonia can appear as segmental or lobar parenchymal consolidation (fig. 2a, b), sometimes associated with pleural fluid. Pneumatoceles suggest staphylococcal pneumonia and appear as a central thin-walled lucent cavitation. Pneumatoceles generally occur 10–14 days after the onset of infection, when the patient is clinically improving [72].

Fig. 2. Lung abnormalities in CGD. a Frontal chest radiograph in a 2-year-old male with X-linked CGD demonstrates extensive parenchymal consolidation in the right lower lobe (arrow). b CT scan in the same subject better delineates the extension of pulmonary nodules in the right lung. c Axial chest CT scan in a 28-year-old male with X-linked CGD reveals, in the middle lobe, focal parenchymal consolidation (asterisk), surrounded by an halo of ground-glass attenuation (arrowheads) corresponding to Aspergillus infection. d A CT scan, performed 1 year later in the same subject as in c shows a peripheral nodular mass with chest wall invasion (asterisk) related to fungal infection, in the upper right lobe.

Patients with CGD are at greatest risk to develop invasive pulmonary aspergillosis (fig. 2c, d). In this condition, hyphae proliferate into the endobronchial tree and invade pulmonary vessels, resulting in thrombosis and infarction of the lungs. In the early phase of the disease, plain radiographs or CT scans may show nonspecific, patchy, nodular opacities or segmental or lobar consolidation. In some cases, Aspergillus nodules may be very small and not visible on plain radiographs [73]. Typically, they tend to have a characteristic ‘halo’ of ground-glass attenuation, representing pulmonary hemorrhage. In adult series, approximately 40–50% of cases undergo cavitation over time. Radiographically, the cavitation results in the ‘air crescent sign’ that pathologically represents necrotic lung surrounded by a thin rim of air [74]. Both the halo sign and the air crescent sign, in an appropriate clinical setting, are very suggestive of invasive aspergillosis.

Less frequently, invasive aspergillosis may appear as peribronchial opacities or as focal areas of parenchimal consolidation, associated with presence of Aspergillus deep into the airway basement membrane. This picture is also referred to as aspergillosis of the airways [75].

Continuous antimicrobial prophylaxis of CGD patients with co-trimoxazole and itraconazole [and possibly also with recombinant interferon-γ (IFN-γ)] is effective in reducing the incidence of severe infections [70, 76]; however, the long-term prognosis of CGD, and especially of its X-linked variant, remains controversial, so that stem cell transplantation should be considered if a matched donor is available [77]. With this approach, and under adequate supportive treatment, successful outcome has been reported even if invasive aspergillosis is present [78]. More recently, preliminary but promising results have been obtained with gene therapy [79].

Recurrent bacterial pneumonia and lung aspergillosis may also be observed in patients with SCN, although their incidence has been significantly reduced by treatment with recombinant granulocyte colony-stimulating factor [80]. SCN is characterized by a severely reduced number of circulating neutrophils (consistently below 0.5 × 109/l), often associated with a block in bone marrow myeloid differentiation at the promyelocyte stage. SCN comprises a genetically heterogenous group of disorders. Most often due to mutations of the ELA2 gene (encoding for neutrophil elastase) [81], SCN has recently been shown to be caused also by mutations in HAX1, a mitochondrial protein possibly involved in protecting myeloid cells from apoptosis [82], or in MAPBPID, an endosomal protein involved in intracellular signaling [83].


goto top of outline Severe Combined Immune Deficiencies and Other Defects of T Cell-Mediated Immunity

Severe combined immune deficiencies (SCID) comprise a heterogeneous group of disorders that affect T cell development and variably compromise B and/or natural killer cell maturation and function [84]. More than 30 distinct genetic defects account for combined immunodeficiency in humans [15]. A common feature of SCID infants, which can be easily detected by chest X-ray, is the lack of thymic shadow (fig. 3a).

Fig. 3. Lung and thymic abnormalities in SCID. a Chest radiograph in a 7-month-old female infant with SCID and P. jiroveci infection reveals absence of thymic shadow, associated with bilateral, perihilar interstitial infiltrates, more evident in the left lung, and alveolar infiltrates. b Chest frontal radiograph in a 7-month-old male infant with SCID and CMV pneumonia reveals diffuse bilateral parenchymal consolidation with a tendency to be confluent in the left lung. c Chest CT scan, performed through the lower lobes in the same subject as in b, demonstrates diffuse interstitial infiltrates associated with parenchymal consolidations.

Clinically, SCID is marked by early-onset severe infections that are caused by bacteria, viruses, and opportunistic pathogens [85]. Pneumonia caused by Pneumocystis jiroveci, cytomegalovirus (CMV), adenovirus, parainfluenzae virus type 3 and respiratory syncitial virus is particularly common.

P. jiroveci pneumonia may initially cause diffuse interstitial infiltrates (fig. 3a), and may then progress to alveolar infiltrates that can be focal and asymmetric [1]. Similar features may also be observed during CMV infection (fig. 3b, c) [86]. While severe, P. jiroveci pneumonia and CMV-related pneumonia may be successfully treated with high-dose trimethoprim/sulfamethoxazole or gancyclovir (or foscarnet), respectively. In contrast, pneumonia due to adenovirus or to parainfluenzae virus type 3 are poorly responsive to treatment, even with use of aggressive drugs, such as cidofovir.

Also, in patients with T cell deficiencies, detection of lung abnormalities by HRCT may have significant implications for clinical care. In particular, demonstration of interstitial lung disease may suggest the need of bronchoalveolar lavage and occasionally lung biopsy to search for pathogens (P. jiroveci, viruses) and initiate appropriate and specific treatment.

For SCID, definitive cure is provided by hematopoietic stem cell transplantation (HSCT), with approximately 90% survival if an HLA-matched sibling is available [87]. Good results have also been achieved with haploidentical transplantation [84] and more recently with matched unrelated donor HSCT [88]. However, following nonmatched HSCT, graft-versus-host disease may develop in the lung and result in interstitial lung disease. Finally, gene therapy has been shown to be able to cure some forms of SCID, namely X-linked SCID (due to common γ chain defect) [89] and SCID due to adenosine deaminase deficiency [90]. However, experience in X-linked SCID has also shown the potential risk of neoplastic transformation associated with integration of the transgene into proto-oncogenes [91].

The critical role played by T lymphocytes in controlling viral and opportunistic pulmonary infections is also disclosed by patients with selective defects of T cell-mediated immunity. In particular, mutations in the CD40 ligand (CD40L) gene cause X-linked immunodeficiency with hyper-IgM. Along with impaired class-switch recombination (indicated by low serum levels of IgG and IgA), these patients develop severe and early-onset infections of bacterial, viral and opportunistic origin [92]. Similar features have also been observed in patients with CD40 deficiency and reflect poor interaction between activated T cells and dendritic cells in the immune defense against intracellular pathogens, as well as defective T-B interaction in class-switch recombination [92].

Finally, respiratory problems can also be observed in infants with DiGeorge syndrome. In these patients, pneumonia may associate with, and be aggravated by, concurrent congenital heart anomalies, such as conotruncal defects, or be facilitated by cleft palate, velopharyngeal incompetence or gastroesophageal reflux [93]. Occasionally, infants may present with the so-called complete DiGeorge syndrome, characterized by a severely reduced number of circulating T cells. In this case, opportunistic lung infections may be observed [94].


goto top of outline Lung Disease in Other Immunodeficiencies

Increased susceptibility to pulmonary infections has also been reported in a variety of immunodeficiency syndromes.

Ataxia-telangiectasia is due to mutations of the ATM gene, and is characterized by progressive development of telangiectasias and cerebellar ataxia, increased susceptibility to infections, and a high proclivity to cancer. There is remarkable variability in the incidence and severity of sinopulmonary infections among different series of ataxia-telangiectasia patients, although historically, bacterial pneumonia and chronic lung disease have represented a significant cause of death [95]. This may reflect impaired antibody production due to defective class-switch recombination (a process in which the ATM protein is involved) [96], but swallowing dysfunction and aspiration syndrome may also contribute [97]. Similarly, pneumonia and chronic lung disease have also been reported in other disorders with defective DNA repair, such as Bloom syndrome [98] and Nijmegen breakage syndrome [99].

The Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency due to mutations of the WASP gene, that encodes for a protein expressed in hematopoietic cells that is involved in cytoskeletal reorganization [100]. The immunodeficiency of WAS includes reduced numbers of circulating T and B lymphocytes, impaired function of natural killer cells, low serum IgM with elevated IgA and IgE, and inability to respond to polysaccharide antigens (along with reduced antibody response to T-dependent antigens). Sinopulmonary infections are common in WAS. In particular, patients with WAS are at high risk of infections sustained by encapsulated pathogens; however, complicated Varicella zoster infections (or other herpes virus infections) and P. jiroveci pneumonia have also been reported in a significant number of cases [101]. While prophylactic administration of IVIG and prompt use of antibiotics may reduce the incidence and severity of infections, the only curative treatment for WAS is at present represented by HSCT [102].

Finally, a heterogenous group of mendelian susceptibility to mycobacterial infections, which frequently involve the lung, has recently been identified. These disorders are due to impaired function of the IL-12/IL-23-IFN-γ axis. IFN-γ is a Th1 cytokine which is critically important in the defense against intracellular pathogens, and especially mycobacteria. Production of IFN-γ by activated T and natural killer cells is under the control of IL-12 and IL-23, which are secreted by activated macrophages. Mutations of IL-12 p40, IL-12 receptor β-1 subunit, IFN-γ receptor 1, IFN-γ receptor 2 and of the signaling molecule STAT1 have been shown to cause genetically determined susceptibility to mycobacterial disease in humans, in which dissemination to lungs is common and often fatal [103, 104].


goto top of outline Concluding Remarks

With progressive decline in the incidence of chronic lung disease due to recurrent pneumonia in immunocompetent individuals, PID are emerging as a prominent cause after CF. While the pattern of lung damage and in general the type of microorganisms involved may indicate whether defects of innate, humoral or cell-mediated immunity may be in place, there is substantial overlap to require that appropriate investigations be carried out in order to achieve definitive diagnosis. While more than 140 different genetic defects have been identified that can cause PID in humans, the diagnostic approach should be based on simple laboratory assays, whereas genetic testing can in most cases be postponed and follow a focused perspective.

Determination of complete and differential white blood cell count, measurement of serum immunoglobulins and of specific antibodies upon immunization, and evaluation of lymphocyte subsets are the mainstay of diagnosis in PID. Functional assays (such as for CGD, for some forms of combined immunodeficiency and for defects of the IL-12/23-IFN-γ axis) should be reserved for selected cases.

In the diagnostic approach, the clinical significance of IgG subclasses deficiency should be carefully evaluated. While defects of IgG1 most often result in low total serum IgG and increased risk of pulmonary infections, and low serum IgG2 (especially if associated with IgA deficiency) may also carry an increased risk of sinopulmonary infections, the consequences of reduced levels of IgG3 and IgG4 are less obvious. Importantly, analysis of specific antibody production is more informative than measurement of IgG subclasses.

In spite of improved diagnostic opportunities and more widely available diagnostic services, significant diagnostic delay is still a major cause of concern in PID and may increase the risk of chronic lung disease. This reinforces the need to maintain a high threshold of suspicion and to perform accurate diagnostic evaluation.

At the same time, better therapeutic opportunities are now available to patients with PID, including IVIG and SCIG, as well as novel antimicrobial products. In particular, a series of potent antifungal drugs have recently entered clinical practice with excellent efficacy, while there is still a need for more active antiviral compounds, particularly for patients with combined immunodeficiencies.

No clinical trials have ever been performed to demonstrate the potential efficacy of long-term antibiotic prophylaxis and/or chest physical therapy in preventing lung disease in PID. This reflects the rarity of these diseases and consequently the need to organize collaborative efforts that involve multiple centers. In this regard, collaboration between clinicians, scientists, nurses and patients is of utmost importance.


goto top of outline Acknowledgements

This work was partially funded by the European Union’s Euro-Policy-PID project (grant SP23-CT-2005-006411 to L.D.N.), by the Fondazione Camillo Golgi (to A.P.) and by the Associazione Italiana Immunodeficienze Primitive (AIP).

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 goto top of outline Author Contacts

Prof. Luigi D. Notarangelo, MD, Division of Immunology
Children’s Hospital, Harvard Medical School, Karp Building, 9th floor
Room 09210, 1 Blackfan Circle, Boston, MA 02115 (USA)
Tel. +1 617 919 2276, Fax +1 617 730 0709

 goto top of outline Article Information

Previous articles in this series: 1. Contopoulos-Ioannidis DG, Kouri IN, Ioannidis JPA: Genetic predisposition to asthma and atopy. Respiration 2007;74:8–12. 2. Sztrymf B, Yaïci A, Girerd B, Humbert M: Genes and pulmonary arterial hypertension. Respiration 2007;74:123–132.

Number of Print Pages : 12
Number of Figures : 3, Number of Tables : 2, Number of References : 104

 goto top of outline Publication Details

Respiration (International Journal of Thoracic Medicine)

Vol. 74, No. 3, Year 2007 (Cover Date: May 2007)

Journal Editor: Bolliger, C.T. (Cape Town)
ISSN: 0025–7931 (print), 1423–0356 (Online)

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