Vol. 74, No. 3, 2007
Issue release date: May 2007
Respiration 2007;74:264–275
Thematic Review Series 2007
Add to my selection

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).

 goto top of outline References
  1. Jeanes AC, Owens CM: Chest imaging in the immunocompromised child. Paediatr Respir Rev 2002;3:59–69.
  2. Clark NS: Bronchiectasis in childhood. Br Med J 1963;1:80–88.
  3. Rosen MJ: Cough in the immunocompromised host: ACCP evidence-based clinical practice guidelines. Chest 2006;129:204S–205S.

    External Resources

  4. Cottin V: Clinical genetics for the pulmonologist: introduction. Respiration 2007;74:3–7.
  5. Karadag B, Karakoc F, Ersu R, Kut A, Bakac S, Dagli E: Non-cystic-fibrosis bronchiectasis in children: a persisting problem in developing countries. Respiration 2005;72:233–238.
  6. Rossi UG, Owens CM: The radiology of chronic lung disease in children. Arch Dis Child 2005;90:601–607.
  7. Nikolaizik WH, Warner JO: Aetiology of chronic suppurative lung disease. Arch Dis Child 1994;70:141–142.
  8. Eastham KM, Fall AJ, Mitchell L, Spencer DA: The need to redefine non-cystic fibrosis bronchiectasis in childhood. Thorax 2004;59:324–327.
  9. Li AM, Sonnappa S, Lex C, Wong E, Zacharasiewicz A, Bush A, Jaffe A: Non-CF bronchiectasis: does knowing the aetiology lead to changes in management? Eur Respir J 2005;26:8–14.
  10. Buckley RH: Pulmonary complications of primary immunodeficiencies. Paediatr Respir Rev 2003;4(suppl 1):S23–S31.
  11. Cazzola G, Valletta EA, Ciaffoni S, Roata C, Mastella G: Neutrophil function and humoral immunity in children with recurrent infections of the lower respiratory tract and chronic bronchial suppuration. Ann Allergy 1989;63:213–218.
  12. Barker AF, Craig S, Bardana EJ Jr: Humoral immunity in bronchiectasis. Ann Allergy 1987;59:179–182.
  13. Newson T, Chippindale AJ, Cant AJ: Computed tomography scan assessment of lung disease in primary immunodeficiencies. Eur J Pediatr 1999;158:29–31.
  14. Stead A, Douglas JG, Broadfoot CJ, Kaminski ER, Herriot R: Humoral immunity and bronchiectasis. Clin Exp Immunol 2002;130:325–330.
  15. 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, ed 2. New York, Oxford University Press, 2007, pp 3–15.
  16. Bruton OC: Agammaglobulinemia. Pediatrics 1952;9:722–728.
  17. Vetrie D, Vorechovsky I, Sideras P, Holland J, Davies A, Flinter F, Hammarstrom L, Kinnon C, Levinsky R, Bobrow M, et al: The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 1993;361:226–233.
  18. Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen RC, Klisak I, Sparkes RS, Kubagawa H, Mohandas T, Quan S, et al: Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 1993;72:279–290.
  19. Conley ME: Autosomal recessive agammaglobulinemia; in Ochs HD, Smith CIE, Puck JM (eds): Primary Immunodeficiency Diseases: A Molecular and Genetic Approach, ed 2. New York, Oxford University Press, 2007, pp 304–312.
  20. Furr PM, Taylor-Robinson D, Webster AD: Mycoplasmas and ureaplasmas in patients with hypogammaglobulinaemia and their role in arthritis: microbiological observations over twenty years. Ann Rheum Dis 1994;53:183–187.
  21. Winkelstein JA, Marino MC, Lederman HM, Jones SM, Sullivan K, Burks AW, Conley ME, Cunningham-Rundles C, Ochs HD: X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine 2006;85:193–202.
  22. Liese JG, Wintergerst U, Tympner KD, Belohradsky BH: High- vs low-dose immunoglobulin therapy in the long-term treatment of X-linked agammaglobulinemia. Am J Dis Child 1992;146:335–339.
  23. Broides A, Yang W, Conley ME: Genotype/phenotype correlations in X-linked agammaglobulinemia. Clin Immunol 2006;118:195–200.
  24. Howard V, Greene JM, Pahwa S, Winkelstein JA, Boyle JM, Kocak M, Conley ME: The health status and quality of life of adults with X-linked agammaglobulinemia. Clin Immunol 2006;118:201–208.
  25. Kainulainen L, Varpula M, Liippo K, Svedstrom E, Nikoskelainen J, Ruuskanen O: Pulmonary abnormalities in patients with primary hypogammaglobulinemia. J Allergy Clin Immunol 1999;104:1031–1036.
  26. Quartier P, Debre M, De Blic J, de Sauverzac R, Sayegh N, Jabado N, Haddad E, Blanche S, Casanova JL, Smith CI, Le Deist F, de Saint Basile G, Fischer A: Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients. J Pediatr 1999;134:589–596.
  27. Plebani A, Soresina A, Rondelli R, Amato GM, Azzari C, Cardinale F, Cazzola G, Consolini R, De Mattia D, Dell’Erba G, Duse M, Fiorini M, Martino S, Martire B, Masi M, Monafo V, Moschese V, Notarangelo LD, Orlandi P, Panei P, Pession A, Pietrogrande MC, Pignata C, Quinti I, Ragno V, Rossi P, Sciotto A, Stabile A; Italian Pediatric Group for XLA-AIEOP: Clinical, immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. Clin Immunol 2002;104:221–230.
  28. Conley ME, Notarangelo LD, Etzioni A: Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol 1999;93:190–197.
  29. Cunningham-Rundles C, Bodian C: Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol 1999;92:34–48.
  30. Hermaszewski RA, Webster AD: Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications. Q J Med 1993;86:31–42.
  31. Watts WJ, Watts MB, Dai W, Cassidy JT, Grum CM, Weg JG: Respiratory dysfunction in patients with common variable hypogammaglobulinemia. Am Rev Respir Dis 1986;134:699–703.
  32. 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.
  33. Martinez Garcia MA, de Rojas MD, Nauffal Manzur MD, Munoz Pamplona MP, Compte Torrero L, Macian V, Perpina Tordera M: Respiratory disorders in common variable immunodeficiency. Respir Med 2001;95:191–195.
  34. Curtin JJ, Webster AD, Farrant J, Katz D: Bronchiectasis in hypogammaglobulinaemia – a computed tomography assessment. Clin Radiol 1991;44:82–84.
  35. Feydy A, Sibilia J, De Kerviler E, Zagdanski AM, Chevret S, Fermand JP, Brouet JC, Frija J: Chest high resolution CT in adults with primary humoral immunodeficiency. Br J Radiol 1996;69:1108–1116.
  36. Thickett KM, Kumararatne DS, Banerjee AK, Dudley R, Stableforth DE: Common variable immune deficiency: respiratory manifestations, pulmonary function and high-resolution CT scan findings. QJM 2002;95:655–662.
  37. Park JE, Beal I, Dilworth JP, Tormey V, Haddock J: The HRCT appearances of granulomatous pulmonary disease in common variable immune deficiency. Eur J Radiol 2005;54:359–364.
  38. Carsetti R, Rosado MM, Donnanno S, Guazzi V, Soresina A, Meini A, Plebani A, Aiuti F, Quinti I: The loss of IgM memory B cells correlates with clinical disease in common variable immunodeficiency. J Allergy Clin Immunol 2005;115:412–417.
  39. Copley SJ, Padley SP: High-resolution CT of paediatric lung disease. Eur Radiol 2001;11:2564–2575.
  40. Gelfand EWGJ, Goldsmith J, Lederman HM: Primary Humoral Immunodeficiency: Optimizing IgG Replacement Therapy. Clin Focus Prim Immune Defic. Towson, Immune Deficiency Foundation, 2003.
  41. Rusconi F, Panisi C, Dellepiane RM, Cardinale F, Chini L, Martire B, Bonelli N, Felisati G, Pietrogrande MC: Pulmonary and sinus diseases in primary humoral immunodeficiencies with chronic productive cough. Arch Dis Child 2003;88:1101–1105.
  42. Busse PJ, Farzan S, Cunningham-Rundles C: Pulmonary complications of common variable immunodeficiency. Ann Allergy Asthma Immunol 2007;98:1–8.
  43. Mechanic LJ, Dikman S, Cunningham-Rundles C: Granulomatous disease in common variable immunodeficiency. Ann Intern Med 1997;127:613–617.
  44. Fasano MB, Sullivan KE, Sarpong SB, Wood RA, Jones SM, Johns CJ, Lederman HM, Bykowsky MJ, Greene JM, Winkelstein JA: Sarcoidosis and common variable immunodeficiency: report of 8 cases and review of the literature. Medicine 1996;75:251–61.
  45. Bates CA, Ellison MC, Lynch DA, Cool CD, Brown KK, Routes JM: Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin Immunol 2004;114:415–421.
  46. Arish N, Eldor R, Fellig Y, Bogot N, Laxer U, Izhar U, Rokach A: Lymphocytic interstitial pneumonia associated with common variable immunodeficiency resolved with intravenous immunoglobulins. Thorax 2006;61:1096–1097.
  47. Cha SI, Fessler MB, Cool CD, Schwarz MI, Brown KK: Lymphoid interstitial pneumonia: clinical features, associations and prognosis. Eur Respir J 2006;28:364–369.
  48. Wheat WH, Cool CD, Morimoto Y, Rai PR, Kirkpatrick CH, Lindenbaum BA, Bates CA, Ellison MC, Serls AE, Brown KK, Routes JM: Possible role of human herpesvirus 8 in the lymphoproliferative disorders in common variable immunodeficiency. J Exp Med 2005;202:479–484.
  49. Kralovicova J, Hammarstrom L, Plebani A, Webster AD, Vorechovsky I: Fine-scale mapping at IGAD1 and genome-wide genetic linkage analysis implicate HLA-DQ/DR as a major susceptibility locus in selective IgA deficiency and common variable immunodeficiency. J Immunol 2003;170:2765–2775.
  50. Grimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K, Drager R, Eibel H, Fischer B, Schaffer AA, Mages HW, Kroczek RA, Peter HH: Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol 2003;4:261–268.
  51. van Zelm MC, Reisli I, van der Burg M, Castano D, van Noesel CJ, van Tol MJ, Woellner C, Grimbacher B, Patino PJ, van Dongen JJ, Franco JL: An antibody-deficiency syndrome due to mutations in the CD19 gene. N Engl J Med 2006;354:1901–1912.
  52. Castigli E, Wilson SA, Garibyan L, Rachid R, Bonilla F, Schneider L, Geha RS: TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet 2005;37:829–834.
  53. Salzer U, Chapel HM, Webster AD, Pan-Hammarstrom Q, Schmitt-Graeff A, Schlesier M, Peter HH, Rockstroh JK, Schneider P, Schaffer AA, Hammarstrom L, Grimbacher B: Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet 2005;37:820–828.
  54. Mullighan CG, Fanning GC, Chapel HM, Welsh KI: TNF and lymphotoxin-α polymorphisms associated with common variable immunodeficiency: role in the pathogenesis of granulomatous disease. J Immunol 1997;159:6236–6241.
  55. Burks AW Jr, Steele RW: Selective IgA deficiency. Ann Allergy 1986;57:3–13.

    External Resources

  56. Bjorkander J, Bake B, Oxelius VA, Hanson LA: Impaired lung function in patients with IgA deficiency and low levels of IgG2 or IgG3. N Engl J Med 1985;313:720–724.
  57. Gardulf A, Andersen V, Bjorkander J, Ericson D, Froland SS, Gustafson R, Hammarstrom L, Jacobsen MB, Jonsson E, Moller G, et al: Subcutaneous immunoglobulin replacement in patients with primary antibody deficiencies: safety and costs. Lancet 1995;345:365–369.
  58. Gardulf A, Bjorvell H, Andersen V, Bjorkander J, Ericson D, Froland SS, Gustafson R, Hammarstrom L, Nystrom T, Soeberg B, et al: Lifelong treatment with gammaglobulin for primary antibody deficiencies: the patients’ experiences of subcutaneous self-infusions and home therapy. J Adv Nurs 1995;21:917–927.
  59. Nicolay U, Kiessling P, Berger M, Gupta S, Yel L, Roifman CM, Gardulf A, Eichmann F, Haag S, Massion C, Ochs HD: Health-related quality of life and treatment satisfaction in North American patients with primary immunedeficiency diseases receiving subcutaneous IgG self-infusions at home. J Clin Immunol 2006;26:65–72.
  60. Roifman CM, Levison H, Gelfand EW: High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and chronic lung disease. Lancet 1987;i:1075–1077.
  61. Manson D, Reid B, Dalal I, Roifman CM: Clinical utility of high-resolution pulmonary computed tomography in children with antibody deficiency disorders. Pediatr Radiol 1997;27:794–798.
  62. de Gracia J, Vendrell M, Alvarez A, Pallisa E, Rodrigo MJ, de la Rosa D, Mata F, Andreu J, Morell F: Immunoglobulin therapy to control lung damage in patients with common variable immunodeficiency. Int Immunopharmacol 2004;4:745–753.
  63. Davies CW, Juniper MC, Gray W, Gleeson FV, Chapel HM, Davies RJ: Lymphoid interstitial pneumonitis associated with common variable hypogammaglobulinaemia treated with cyclosporin A. Thorax 2000;55:88–90.
  64. Smith KJ, Skelton H: Common variable immunodeficiency treated with a recombinant human IgG, tumour necrosis factor-α receptor fusion protein. Br J Dermatol 2001;144:597–600.
  65. Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, Miller JA, O’Connell AC, Puck JM: Hyper-IgE syndrome with recurrent infections – an autosomal dominant multisystem disorder. N Engl J Med 1999;340:692–702.
  66. Renner ED, Puck JM, Holland SM, Schmitt M, Weiss M, Frosch M, Bergmann M, Davis J, Belohradsky BH, Grimbacher B: Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity. J Pediatr 2004;144:93–99.
  67. Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, Takada H, Hara T, Kawamura N, Ariga T, Kaneko H, Kondo N, Tsuge I, Yachie A, Sakiyama Y, Iwata T, Bessho F, Ohishi T, Joh K, Imai K, Kogawa K, Shinohara M, Fujieda M, Wakiguchi H, Pasic S, Abinun M, Ochs HD, Renner ED, Jansson A, Belohradsky BH, Metin A, Shimizu N, Mizutani S, Miyawaki T, Nonoyama S, Karasuyama H: Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 2006;25:745–755.
  68. Hollingsworth CL: Thoracic disorders in the immunocompromised child. Radiol Clin North Am 2005;43:435–447.
  69. Jhaveri KS, Sahani DV, Shetty PG, Shroff MM: Hyperimmunoglobulinaemia E syndrome: pulmonary imaging features. Australas Radiol 2000;44:328–330.
  70. Rosenzweig SD, Uzel G, Holland SM: Phagocyte disorders; in Stiehm ER, Ochs HD, Winkelstein JA (eds): Immunologic Disorders in Infants and Children, ed 5. Philadelphia, Elsevier Saunders, 2004, pp 618–651.
  71. Roos D, Kuijpers TW, Curnutte JT: Chronic granulomatous disease; in Ochs HD, Smith CIE, Puck JM (eds): Primary Immunodeficiency Diseases: A Molecular and Genetic Approach, ed 2. New York, Oxford University Press, 2007, pp 525–549.
  72. Khanna G, Kao SC, Kirby P, Sato Y: Imaging of chronic granulomatous disease in children. Radiographics 2005;25:1183–1195.
  73. Copley SJ: Application of computed tomography in childhood respiratory infections. Br Med Bull 2002;61:263–279.
  74. Thomas KE, Owens CM, Veys PA, Novelli V, Costoli V: The radiological spectrum of invasive aspergillosis in children: a 10-year review. Pediatr Radiol 2003;33:453–460.
  75. Franquet T, Gimenez A, Hidalgo A: Imaging of opportunistic fungal infections in immunocompromised patient. Eur J Radiol 2004;51:130–138.
  76. Gallin JI, Alling DW, Malech HL, Wesley R, Koziol D, Marciano B, Eisenstein EM, Turner ML, DeCarlo ES, Starling JM, Holland SM: Itraconazole to prevent fungal infections in chronic granulomatous disease. N Engl J Med 2003;348:2416–2422.
  77. Seger RA, Gungor T, Belohradsky BH, Blanche S, Bordigoni P, Di Bartolomeo P, Flood T, Landais P, Muller S, Ozsahin H, Passwell JH, Porta F, Slavin S, Wulffraat N, Zintl F, Nagler A, Cant A, Fischer A: Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European experience, 1985–2000. Blood 2002;100:4344–4350.
  78. Ozsahin H, von Planta M, Muller I, Steinert HC, Nadal D, Lauener R, Tuchschmid P, Willi UV, Ozsahin M, Crompton NE, Seger RA: Successful treatment of invasive aspergillosis in chronic granulomatous disease by bone marrow transplantation, granulocyte colony-stimulating factor-mobilized granulocytes, and liposomal amphotericin-B. Blood 1998;92:2719–2724.
  79. Ott MG, Schmidt M, Schwarzwaelder K, Stein S, Siler U, Koehl U, Glimm H, Kuhlcke K, Schilz A, Kunkel H, Naundorf S, Brinkmann A, Deichmann A, Fischer M, Ball C, Pilz I, Dunbar C, Du Y, Jenkins NA, Copeland NG, Luthi U, Hassan M, Thrasher AJ, Hoelzer D, von Kalle C, Seger R, Grez M: Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat Med 2006;12:401–409.
  80. Dale DC, Cottle TE, Fier CJ, Bolyard AA, Bonilla MA, Boxer LA, Cham B, Freedman MH, Kannourakis G, Kinsey SE, Davis R, Scarlata D, Schwinzer B, Zeidler C, Welte K: Severe chronic neutropenia: treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry. Am J Hematol 2003;72:82–93.
  81. Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ: Neutrophil elastase in cyclic and severe congenital neutropenia. Blood 2007;109:1817–1824.
  82. Klein C, Grudzien M, Appaswamy G, Germeshausen M, Sandrock I, Schaffer AA, Rathinam C, Boztug K, Schwinzer B, Rezaei N, Bohn G, Melin M, Carlsson G, Fadeel B, Dahl N, Palmblad J, Henter JI, Zeidler C, Grimbacher B, Welte K: HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat Genet 2007;39:86–92.
  83. Bohn G, Allroth A, Brandes G, Thiel J, Glocker E, Schaffer AA, Rathinam C, Taub N, Teis D, Zeidler C, Dewey RA, Geffers R, Buer J, Huber LA, Welte K, Grimbacher B, Klein C: A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14. Nat Med 2007;13:38–45.
  84. Buckley RH: Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Annu Rev Immunol 2004;22:625–655.
  85. Fischer A, Notarangelo LD: Combined immunodefiociencies; in Stiehm ER, Ochs HD, Winkelstein JA (eds): Immunologic Disorders in Infants and Children, ed 5. Philadelphia, Elsevier Saunders, 2004, pp 447–479.
  86. Tamm M: The lung in the immunocompromised patient: infectious complications part 2. Respiration 1999;66:199–207.
  87. Antoine C, Muller S, Cant A, Cavazzana-Calvo M, Veys P, Vossen J, Fasth A, Heilmann C, Wulffraat N, Seger R, Blanche S, Friedrich W, Abinun M, Davies G, Bredius R, Schulz A, Landais P, Fischer A; European Group for Blood and Marrow Transplantation; European Society for Immunodeficiency: Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968–99. Lancet 2003;361:553–560.
  88. Grunebaum E, Mazzolari E, Porta F, Dallera D, Atkinson A, Reid B, Notarangelo LD, Roifman CM: Bone marrow transplantation for severe combined immune deficiency. JAMA 2006;295:508–518.
  89. Hacein-Bey-Abina S, Le Deist F, Carlier F, Bouneaud C, Hue C, De Villartay JP, Thrasher AJ, Wulffraat N, Sorensen R, Dupuis-Girod S, Fischer A, Davies EG, Kuis W, Leiva L, Cavazzana-Calvo M: Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N Engl J Med 2002;346:1185–1193.
  90. Aiuti A, Slavin S, Aker M, Ficara F, Deola S, Mortellaro A, Morecki S, Andolfi G, Tabucchi A, Carlucci F, Marinello E, Cattaneo F, Vai S, Servida P, Miniero R, Roncarolo MG, Bordignon C: Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 2002;296:2410–2413.
  91. Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, Lim A, Osborne CS, Pawliuk R, Morillon E, Sorensen R, Forster A, Fraser P, Cohen JI, de Saint Basile G, Alexander I, Wintergerst U, Frebourg T, Aurias A, Stoppa-Lyonnet D, Romana S, Radford-Weiss I, Gross F, Valensi F, Delabesse E, Macintyre E, Sigaux F, Soulier J, Leiva LE, Wissler M, Prinz C, Rabbitts TH, Le Deist F, Fischer A, Cavazzana-Calvo M: LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 2003;302:415–419.
  92. Geha RS, Plebani A, Notarangelo LD: CD40, CD40 ligand, and the hyper-IgM syndrome; in Ochs HD, Smith CIE, Puck JM (eds): Primary Immunodeficiency Diseases: A Molecular and Genetic Approach, ed 2. New York, Oxford University Press, 2007, pp 251–268.
  93. Driscoll DA, Sullivan KE: DiGeorge syndrome: a chromosome 22q11.2 deletion syndrome; in Ochs HD, Smith CIE, Puck JM (eds): Primary Immunodeficiency Diseases: A Molecular and Genetic Approach, ed 2. New York, Oxford University Press, 2007, pp 485–495.
  94. Markert ML, Devlin BH, Alexieff MJ, Li J, McCarthy EA, Gupton SE, Chinn IK, Hale LP, Kepler TB, He M, Sarzotti M, Skinner MA, Rice HE, Hoehner JC: Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants. Blood 2007, E-pub ahead of print.
  95. Sedgwick RP, Boder E: Ataxia-telangiectasia; in De Jong JMBV (ed): Handbook of Clinical Neurology, vol 16: Hereditary Neuropathies and Spinocerebellar Atrophies. Amsterdam, Elsevier, 1991, pp 347–423.
  96. Pan-Hammarstrom Q, Lahdesmaki A, Zhao Y, Du L, Zhao Z, Wen S, Ruiz-Perez VL, Dunn-Walters DK, Goodship JA, Hammarstrom L: Disparate roles of ATR and ATM in immunoglobulin class switch recombination and somatic hypermutation. J Exp Med 2006;203:99–110.
  97. Lefton-Greif MA, Crawford TO, Winkelstein JA, Loughlin GM, Koerner CB, Zahurak M, Lederman HM: Oropharyngeal dysphagia and aspiration in patients with ataxia-telangiectasia. J Pediatr 2000;136:225–231.
  98. Wegner RD, German JJ, Chrzanowska KH, Digweed M, Stumm M: Chromosomal instability syndromes other than Ataxia-Telangiectasia; in Ochs HD, Smith CIE, Puck JM (eds): Primary Immunodeficiency Diseases: A Molecular and Genetic Approach, ed 2. New York, 2007, Oxford University Press, pp 427–453.
  99. The International Nijmegen Breakage Syndrome Study Group: Nijmegen breakage syndrome. Arch Dis Child 2000;82:400–406.
  100. Notarangelo LD, Notarangelo LD, Ochs HD: WASP and the phenotypic range associated with deficiency. Curr Opin Allergy Clin Immunol 2005;5:485–490.
  101. Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA: A multiinstitutional survey of the Wiskott-Aldrich syndrome. J Pediatr 1994;125:876–885.
  102. Pai SY, DeMartiis D, Forino C, Cavagnini S, Lanfranchi A, Giliani S, Moratto D, Mazza C, Porta F, Imberti L, Notarangelo LD, Mazzolari E: Stem cell transplantation for the Wiskott-Aldrich syndrome: a single-center experience confirms efficacy of matched unrelated donor transplantation. Bone Marrow Transplant 2006;38:671–679.
  103. Kumararatne DS: Mendelian susceptibility to mycobacterial disease. Respiration 2006;73:280–282.
  104. Remiszewski P, Roszkowska-Sliz B, Winek J, Chapgier A, Feinberg J, Langfort R, Bestry I, Augustynowicz-Kopec E, Ptak J, Casanova JL, Rowinska-Zakrzewska E: Disseminated Mycobacterium avium infection in a 20-year-old female with partial recessive IFNγR1 deficiency. Respiration 2006;73:375–378.

 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
E-Mail luigi.notarangelo@childrens.harvard.edu

 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)

For additional information: http://www.karger.com/RES

Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.