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Pulmonary complications of primary immunodeficiencies

Pulmonary complications of primary immunodeficiencies
Authors:
James Verbsky, MD, PhD
John M Routes, MD
Section Editor:
Jordan S Orange, MD, PhD
Deputy Editors:
Anna M Feldweg, MD
Paul Dieffenbach, MD
Literature review current through: Nov 2022. | This topic last updated: Nov 07, 2022.

INTRODUCTION — Pulmonary disease is common among patients with primary immunodeficiencies (PIDs) [1-4], which are also called inborn errors of immunity (IEIs) [5]. As therapy for these disorders improves and life expectancy of patients with IEIs increases, the prevalence of pulmonary complications is likely to increase in parallel. Consequently, knowledge of the detection and management of pulmonary disorders related to IEIs is critical for optimal management.

This topic will review the pulmonary findings that should raise suspicion of an underlying immune disorder, as well as the various pulmonary conditions that are seen in specific immunodeficiency disorders. Monitoring patients with IEIs for the development of pulmonary problems is also discussed. The evaluation of secondary immunodeficiency (eg, due to underlying diabetes, hemoglobinopathies, malignancy, HIV infection, drug-induced immunosuppression) and an overview of the medical management of patients with immunodeficiency are found separately. (See "Approach to the adult with recurrent infections", section on 'Respiratory tract infections' and "Secondary immunodeficiency induced by biologic therapies" and "Primary immunodeficiency: Overview of management".)

PULMONARY MANIFESTATIONS OF IMMUNODEFICIENCY — The spectrum of pulmonary manifestations in IEIs is broad and includes acute and chronic infection, structural abnormalities (eg, bronchiectasis), malignancy, and dysregulated inflammation resulting in tissue damage (eg, granuloma, pulmonary fibrosis) [6-10]. Pulmonary disease may be the initial manifestation of an IEI, and certain clinical and radiographic findings, such as specific types of pulmonary infections and structural lung abnormalities, should prompt an immunologic evaluation for an underlying IEI, regardless of patient age. The laboratory tests used to evaluate the immune system are reviewed separately. (See "Laboratory evaluation of the immune system".)

Pulmonary infections — Infections that are recurrent, recalcitrant to usual therapy, or due to opportunistic or unusual pathogens are suggestive of a possible underlying IEI.

Recurrent infections — In the general population, recurrent pneumonias (ie, >2/lifetime) are unusual. The association of pneumonia with recurrent sinus infections is also a clue that an IEI may be present. Recurrent pneumonias in a specific lobe are suggestive of structural abnormalities, such as aberrant lung development, neoplasm, or the presence of a foreign body. Pneumonias confined to dependent lobes may indicate recurrent aspiration due to gastroesophageal reflux disease or swallowing abnormalities. In contrast, pneumonias in varying locations of the lung, particularly with interim clearing between episodes, are more indicative of underlying immune dysfunction [11-13]. The presence of unusual complications of pneumonia, such as pneumatoceles or cavitary lesions, is also concerning for immunodeficiency [14,15].

In addition to immunodeficiency, one should take a careful history to exclude other diseases that can lead to recurrent pneumonias. For example, recurrent sinopulmonary infections in the setting of situs inversus or infertility should raise the possibility of primary ciliary dyskinesia (PCD), although PCD can occur without situs inversus or infertility. In males, infertility and recurrent infection can also occur in the setting of cystic fibrosis. (See "Approach to the child with recurrent infections" and "Approach to the adult with recurrent infections".)

Recalcitrant infections — Most uncomplicated community-acquired pneumonias respond to outpatient treatment with oral antibiotics [16]. The need for protracted courses of antibiotics for resolution of pneumonia or the presence of complicated pneumonia (eg, multilobar opacities, empyema, lung abscess) requiring inpatient hospitalization or surgical intervention should raise the possibility of an IEI. (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults" and "Nonresolving pneumonia", section on 'Host factors' and "Pneumonia in children: Epidemiology, pathogenesis, and etiology", section on 'Special populations'.)

Opportunistic/unusual pathogens — Most patients with antibody deficiencies are at low risk for infection by opportunistic or unusual pathogens. In such patients, the only clue to an underlying IEI is the increased frequency or severity of sinopulmonary infections caused by common organisms, such as Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis. (See "Agammaglobulinemia" and "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults".)

However, patients with combined immunodeficiencies or with impaired phagocyte function are at increased risk of infection with opportunistic or unusual pathogens. Pneumonia caused by Pneumocystis jirovecii, Pseudomonas, Burkholderia, Aspergillus, or cytomegalovirus is rare among individuals with normal immune function who have not been recently hospitalized [17-20]. Identification of these and/or other unusual organisms should heighten suspicion for an underlying IEI, such as disorders of primary phagocytic function (eg, chronic granulomatous disease [CGD]) or combined immunodeficiencies (eg, severe combined immunodeficiency [SCID]). The other clinical manifestations and evaluation of these infections are discussed separately. (See "Epidemiology of pulmonary infections in immunocompromised patients" and "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in patients without HIV" and "Epidemiology and clinical manifestations of invasive aspergillosis" and "Overview of cytomegalovirus infections in children".)

Nontuberculous mycobacterial infections also can occur in the context of immunodeficiencies, particularly when there is impaired interleukin (IL)-12/IL-23/interferon (IFN)-gamma signaling or the presence of autoantibodies to IFN-gamma. Impaired signaling can be caused by defects in the IFN-gamma receptors, the IL-12 receptor beta 1 component, the IL-12 p40 subunit, or signal transducer and activator of transcription 1 (STAT1). In addition, nontuberculous mycobacterial infection has been described in patients with defective regulation of nuclear factor (NF)-kappa-B (NF-kappa-B essential modifier [NEMO] or I-kappa-B alpha [NFKBIA]), as well as defects in IRF8, ISG15, GATA2, Tyk2, JAK1, and RORgammaC [21-31]. The evaluation of these defects is discussed separately. (See "Pathogenesis of nontuberculous mycobacterial infections" and "Mendelian susceptibility to mycobacterial diseases: Specific defects" and "Combined immunodeficiencies".)

Specific types of structural/functional lung abnormalities — Certain pulmonary findings are often noted in patients with IEIs.

Hilar and/or mediastinal adenopathy — Thoracic lymph nodes greater than 1 cm in diameter are considered enlarged. Nodes greater than 2 cm in diameter are virtually always abnormal [16]. Mediastinal adenopathy may be an incidental finding on chest radiography, although cough or chest pain may be present. Among patients with IEIs, there are myriad causes of thoracic adenopathy, and the presence or absence of generalized lymphadenopathy (ie, enlargement of ≥3 noncontiguous lymph nodes) can be a helpful differentiating feature [32]. (See "Approach to the adult patient with a mediastinal mass".)

Localized hilar and/or mediastinal adenopathy can be seen in the context of infection (eg, tuberculosis, histoplasmosis), although it is classically associated with either malignancy or granulomatous inflammation [16]:

Numerous IEIs, such as CVID, Wiskott-Aldrich syndrome, ataxia-telangiectasia (AT), and cartilage-hair hypoplasia, are associated with an increased risk of malignancy and may present initially with thoracic adenopathy [33,34]. These can be primary malignancies (eg, lymphoma) or secondary malignancy (eg, metastatic gastric carcinoma, as seen in common variable immunodeficiency [CVID]).

Granulomatous inflammation – Hilar and/or mediastinal adenopathy occurring with granulomatous lung involvement manifest as parenchymal nodules and/or ground-glass abnormalities, are commonly seen in CVID, and can be seen in CGD. The presence of granuloma can be related to infection or chronic inflammation. Other systemic granulomatous diseases such as sarcoidosis can occur in non-immunodeficient patients. (See 'Granulomatous and lymphocytic interstitial lung disease' below.)

Generalized adenopathy commonly results from systemic infection, rheumatologic disease (eg, sarcoidosis), or secondary immunodeficiency (eg, acquired immunodeficiency syndrome [AIDS]). IEIs that are associated with diffuse adenopathy include autoimmune lymphoproliferative syndrome, certain variants of hyperimmunoglobulin M syndrome, CVID, and other disorders [35].

Obstructive lung disease — Certain types of obstructive lung disease are seen in patients with IEIs, including bronchiectasis and bronchiolitis obliterans (BO). Obstructive lung disease may be detected with the use of routine spirometry, which demonstrates a decreased ratio of the forced expiratory volume in one second (FEV1) to the forced vital capacity (FVC). A mixed obstructive-restrictive pattern may be seen in these patients and requires measurement of lung volumes for characterization.

Bronchiectasis — The development of bronchiectasis, the presence of dilated and thickened airways, is a common pathologic response to repeated pyogenic infections and/or airways inflammation. IEIs are often implicated in the development of bronchiectasis, although other processes (eg, cystic fibrosis, ciliary dysfunction, recurrent aspiration, alpha-1 antitrypsin deficiency, and scarring from prior infections) are in the differential [10,36-39]. Similar to recurrent pneumonia, bronchiectasis limited to dependent lung regions or a localized area of the lung should raise suspicion for a cause other than an IEI, such as recurrent aspiration pneumonia [10].

Bronchiectasis can develop as a consequence of any IEI that predisposes to recurrent, pyogenic infection of the lung [40-43]. Patients with primary antibody deficiencies (eg, X-linked agammaglobulinemia, CVID), certain combined immunodeficiencies (eg, activating mutations of phosphoinositide 3-kinase delta [PI3KD] syndrome [APDS]), and disorders of phagocyte dysfunction (eg, CGD) are particularly susceptible to bronchiectasis. The prevalence of bronchiectasis has decreased with immune globulin replacement in antibody deficiencies. (See "Bronchiectasis in children: Pathophysiology and causes".)

Early forms of bronchiectasis may be reversible, while more advanced forms (eg, saccular bronchiectasis) result in irreversible impairment. Chronic productive cough and dyspnea are common, particularly during infectious episodes, although many patients with bronchiectasis are asymptomatic [44]. Obstructive impairment (ie, reduced or normal FVC, low FEV1, and low FEV1/FVC) is the most frequent finding, but a very low FVC can also be seen in advanced disease, when much of the lung has been destroyed. (See "Bronchiectasis in children: Clinical manifestations and evaluation" and "Clinical manifestations and diagnosis of bronchiectasis in adults".)

Routine chest radiographs are insensitive in detecting bronchiectasis, although increased peribronchial markings may occasionally be present. High resolution computed tomography (HRCT) is the gold standard for the diagnosis of bronchiectasis [36,45,46]. Typical HRCT findings of bronchiectasis include parallel (tram) lines and dilated bronchi that are usually 1.5 times wider in diameter than the accompanying pulmonary artery branch. This cross-sectional configuration resembles a signet ring, thus the name "signet ring sign." Airways affected by bronchiectasis may contain mucopurulent plugs or debris accompanied by postobstructive air trapping. When small airways are affected, peripheral, irregular, short (2 to 4 mm) linear branching markings are noted and are called "tree-in-bud pattern" opacities (image 1). (See "High resolution computed tomography of the lungs", section on 'Airways diseases'.)

Bronchiolitis obliterans — Concentric luminal narrowing of the bronchioles due to inflammation and fibrosis is commonly referred to as bronchiolitis obliterans (BO) or obliterative bronchiolitis. BO may develop after inhalation of toxic fumes, pulmonary infection (eg, Mycoplasma, Legionella), in the context of rheumatologic disease, or after bone marrow/hematopoietic stem cell or lung/heart-lung transplantation [16]. BO is associated with nonspecific clinical complaints, such as insidious cough and dyspnea.

In BO, tests of lung function may be normal or show obstructive changes with air trapping. Diffusing capacity for carbon monoxide (DLCO) is usually reduced, particularly as the disease progresses. Resting hypoxemia is frequently present. The combination of fixed rather than reversible obstructive airways disease on spirometry plus a gas transfer defect manifest by a low DLCO or hypoxemia on exertion is suggestive of BO. Other clues include the absence of radiographic evidence of bronchiectasis or a severity of airflow obstruction that seems out of proportion to the degree of bronchiectasis. BO has been reported in patients with SCID, AT, and CVID [47-49].

Chest radiograph is insensitive for the diagnosis of BO, although bronchial wall-thickening or hyperinflation may be noted. HRCT may be normal or can show nonspecific ground-glass opacities, centrilobular nodularity, air trapping, or bronchial wall-thickening (eg, centrilobular nodules and V- or Y-shaped branching linear opacities) [16,50]. Obtaining inspiratory and expiratory HRCT images may help identify air trapping (mosaic or diffuse), but the absence of air trapping does not exclude the diagnosis. (See "Overview of bronchiolar disorders in adults" and "Overview of bronchiolar disorders in adults", section on 'Chest imaging' and "Bronchiolitis in infants and children: Clinical features and diagnosis", section on 'Radiographic features'.)

If histologic confirmation of BO is required, surgical lung biopsy (open or thoracoscopic) is preferred over transbronchial biopsy, as it provides better sampling of the scattered areas of BO [50,51]. (See "Overview of bronchiolar disorders in adults", section on 'Diagnosis'.)

Restrictive lung disease — Patients with certain IEIs can develop restrictive pulmonary physiology, including diffuse interstitial lung disease (ILD), organizing pneumonia (OP), and/or infiltrative disorders (eg, lymphoma, granuloma). Restrictive lung disease is suggested by a decreased FEV1 and FVC with concomitant normal or increased FEV1/FVC by spirometry, although formal diagnosis requires direct measurement of lung volumes. (See "Cryptogenic organizing pneumonia" and "Overview of pulmonary function testing in adults" and "Overview of pulmonary function testing in adults", section on 'Pulmonary function tests'.)

Interstitial lung disease — Interstitial lung disease (ILD) or interstitial pneumonitis encompasses a broad group of disease processes that result in inflammatory and fibrotic infiltration of the respiratory interstitium. The differential diagnosis of ILD with or without immunodeficiency is broad and includes but is not limited to lymphoid interstitial pneumonia, nonspecific interstitial pneumonia, idiopathic pulmonary fibrosis, sarcoidosis, hypersensitivity pneumonitis, cryptogenic organizing pneumonia (COP), low- and high-grade lymphoma, and granulomatous and lymphocytic interstitial lung disease (GLILD), as well as infection. ILD may be idiopathic (eg, idiopathic pulmonary fibrosis), secondary to rheumatic disease (eg, sarcoidosis, scleroderma), drugs, or occupational/environmental exposures or may occur in the context of IEIs. The frequency of ILD appears to be increased in certain IEIs, such as CVID (including monogenic causes such as CTLA4 or PIK3CD), ataxia telangiectasia, stimulator of interferon genes (STING)-associated vasculopathy of infancy (SAVI), defects in coatomer subunit alpha (COPA), or STAT5b deficiency [52-57]. (See "Approach to the infant and child with diffuse lung disease (interstitial lung disease)" and "Approach to the adult with interstitial lung disease: Clinical evaluation" and 'Interstitial diseases' below and "Diagnostic evaluation of the incidental pulmonary nodule".)

Organizing pneumonia — Organizing pneumonia (OP), formerly known as bronchiolitis obliterans organizing pneumonia, occurs as a consequence of a variety of disease processes (eg, infection, rheumatologic disease, marrow/stem cell or lung/heart-lung transplantation, inhalation of toxic fumes) and drug exposures [16]. OP is called cryptogenic OP (COP) when it is idiopathic. A number of case reports have described isolated OP developing in the course of CVID, although the mechanism is unknown [58-61]. If OP is found in patients with CVID, it is important to exclude GLILD, as OP is one of the prominent histological abnormalities found in this disorder [62]. (See "Cryptogenic organizing pneumonia".)

Patients with OP often present with subacute cough and dyspnea, and clinical examination may reveal fine inspiratory crackles and tachypnea [51]. A mild-to-moderate restrictive ventilatory defect is most common, although lung function is occasionally normal. The DLCO is reduced in the majority of patients. Resting and/or exercise arterial hypoxemia (each defined by an alveolar-arterial oxygen gradient greater than 20 mmHg) are present in more than 80 percent of subjects. Radiographically, OP is associated with scattered, bilateral alveolar opacities and patchy areas of ground-glass attenuation or consolidation [51]. (See "Cryptogenic organizing pneumonia", section on 'Clinical features'.)

In addition to OP, the differential diagnosis of unresolving radiographic opacities usually includes lung infection and malignancy. Flexible bronchoscopy with bronchoalveolar lavage is usually performed to obtain samples for microbiologic and cytologic analysis. If the diagnosis remains unclear, surgical lung biopsy (usually via thoracoscopy) is often needed, as transbronchial biopsy may not obtain an adequate amount of tissue to differentiate OP from irreversible ILD [16]. Pathologically, OP is characterized by scattered collections of proliferating fibroblasts within peribronchiolar air spaces and alveolar ducts, resulting in persistent alveolar inflammation and fibrosis [51].

One of the most important features of OP is that it typically responds to oral glucocorticoid therapy, with complete radiographic clearing over weeks [51,59-61]. In the reported cases of isolated OP associated with IEI, the response to glucocorticoids was similar to that seen in COP [58-61].

Granulomatous inflammation — The finding of granulomatous inflammation in the lung is nonspecific and may be associated with infectious or noninfectious processes (table 1) [16,63]. Granulomas may be seen in mycobacterial, fungal, and parasitic infections. Noninfectious etiologies include sarcoidosis, hypersensitivity pneumonitis, vasculitides (eg, granulomatosis with polyangiitis), drug reactions (eg, methotrexate, etanercept), lymphoma, and pneumoconioses. Investigations into the etiology of granulomatous lung disease should proceed in a strategic manner, beginning with a thorough patient history of symptoms and time course, followed by studies to determine if pathogenic organisms can be identified, first by noninvasive means, followed by an examination of tissue for histologic analysis and culture [64]. (See "Tuberculosis disease in children" and "Diagnosis and treatment of pulmonary histoplasmosis" and "Coccidioidomycosis: Laboratory diagnosis and screening" and "Diagnosis of pulmonary tuberculosis in adults" and "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".)

Certain IEIs are particularly associated with the development of pulmonary granulomas. For example, patients with CGD are predisposed to infection with fungal pathogens and to granuloma formation even in the absence of identifiable infection [65]. (See 'Chronic granulomatous disease' below.)

Patients with certain immunodeficiencies, such as CVID, hypomorphic mutations in recombination-activating gene 1, damaging mutations in cytotoxic T lymphocyte antigen-4 (CTLA4), BIRC4, lipopolysaccharide responsive beige-like anchor protein (LRBA), NFKB1, KMT2D, and 22q11.2 deletion syndrome [66-72], can develop noncaseating granulomas as part of granulomatous and lymphocytic interstitial lung disease (GLILD). The treatment of GLILD is discussed below. (See 'Granulomatous and lymphocytic interstitial lung disease' below and "Overview of biologic agents and kinase inhibitors in the rheumatic diseases", section on 'Abatacept'.)

Pulmonary alveolar proteinosis — An unusual form of lung disease known as pulmonary alveolar proteinosis (PAP) can occur in a number of primary immune deficiencies. In this disorder, there is accumulation of surfactant components (ie, protein and lipids) in the alveolar spaces due to inappropriate clearance of these molecules by alveolar macrophages. Symptoms can be very mild or may include progressive shortness of breath and fatigue, chronic cough, and sometimes hemoptysis or digital clubbing. Radiographic imaging typically reveals bilateral symmetric alveolar opacities located centrally in mid and lower lung zones. HRCT demonstrates ground-glass opacities, septal reticulations and parenchymal consolidation. Bronchoalveolar lavage is diagnostic and demonstrates milky fluid that contains periodic acid-Schiff (PAS) staining material.

Normal pulmonary macrophage function is essential in the prevention of PAP. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and CD40-CD40L interactions are important in the development of many of the normal physiologic functions of macrophages. Therefore, it is likely that any process that inhibits normal pulmonary macrophage function (genetic mutations, autoantibodies, environmental factors) may lead to a propensity to develop PAP.

Several primary immune deficiencies have been reported to cause PAP, including genetic variants of GM-CSF receptor (CSF2RA, MIM#306250), GATA binding protein 2 (GATA2, MIM #137295), and CD40 ligand, which is a cause of hyperimmunoglobulin M (hyper IgM, CD40LG, MIM#308230) [31,73-76]. Some patients develop PAP due to autoantibodies to GM-CSF, or secondary to environmental exposures (eg, silica), infections such as Pneumocystis jirovecii, or hematologic disorders. (See "Causes, clinical manifestations, and diagnosis of pulmonary alveolar proteinosis in adults" and "Pulmonary alveolar proteinosis in children".)

Treatment is with whole lung lavage, and administration of recombinant GM-CSF has been reported to be beneficial in cases of autoantibodies to GM-CSF. Hematopoietic stem cell transplantation has been shown to be effective in the treatment of PAP in GATA2 deficiency [31,77] and may be beneficial in others. (See "Treatment and prognosis of pulmonary alveolar proteinosis in adults".)

DIAGNOSTIC EVALUATION OF PULMONARY DISEASE — In patients with suspected or known IEI-related pulmonary disease, a systematic approach to diagnostic testing can help expedite and define the goals of treatment. Depending on the clinical history and acuity/severity of the pulmonary process, multiple diagnostic modalities may be needed to establish a diagnosis. Radiographic and laboratory studies are generally employed initially, and histologic and functional testing can further define the disease process and identify therapeutic goals. For patients with known IEIs, knowledge of the primary immune defect, immunologic sequelae of any treatment(s) the patient has received, and the patient's recent environmental exposure history is essential.

Imaging studies — In the radiographic evaluation of pulmonary disease, a conventional chest radiograph is the initial radiographic modality for detecting acute pneumonia in children and adults [78,79]. However, chest radiograph is insensitive in all age groups for detection of certain structural abnormalities, such as bronchiectasis, and may fail to demonstrate clinically important parenchymal abnormalities, such as interstitial lung disease (ILD) [40,80]. (See "Evaluation of diffuse lung disease by conventional chest radiography".)

Computed tomography (CT) of the chest is recommended in the evaluation of patients with IEIs where pulmonary complications are common. A high resolution computed tomography (HRCT) scan is much more sensitive than pulmonary function tests or a chest radiograph and will better define lung abnormalities (eg, bronchiectasis, bronchiole thickening, ground-glass opacities, nodular opacities, small areas of consolidation, pneumatoceles, and hilar or mediastinal adenopathy) that characterize many IEIs [4,40,41,81,82]. For example, a study of 47 patients with CVID who underwent HRCT found clinically significant ILD and airways disease (bronchiectasis and other abnormalities) in 34 and 30 percent of patients, respectively [83]. Only 6 percent of patients in this cohort were known to have ILD or bronchiectasis at baseline. Pulmonary function tests and chest radiograph were abnormal in only a small minority of these patients. (See "High resolution computed tomography of the lungs" and "Approach to the adult with interstitial lung disease: Clinical evaluation".)

Diagnostic studies, such as magnetic resonance imaging (MRI), are an alternative to HRCT scans in evaluation of pulmonary parenchymal abnormalities in patients with possible ILD and underlying radiation sensitivity, such as in ataxia-telangiectasia. (See "Ataxia-telangiectasia" and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis".)

Laboratory testing — In patients with pulmonary disease due to a suspected or known IEI, particularly those who are severely ill, the clinician should consider early use of specialized laboratory testing for definitive diagnosis of the underlying immunodeficiency (if not yet determined) and the infecting organism.

The initial evaluation of immune function in patients with recurrent, recalcitrant, or opportunistic infections includes a complete blood count, serum levels of immunoglobulin (Ig)G, IgA, IgM, and IgE, a total hemolytic complement, and a flow cytometric evaluation of lymphocyte subsets. Further evaluation is usually performed with guidance from an immunology specialist. (See "Approach to the child with recurrent infections", section on 'Laboratory evaluation' and "Approach to the adult with recurrent infections", section on 'Initial immunologic evaluation' and "Laboratory evaluation of the immune system" and "Flow cytometry for the diagnosis of primary immunodeficiencies".)

Microbiologic evaluation to identify the specific infecting organism in patients with pneumonia or a flare of bronchiectasis includes cultures from blood, sputum, and/or bronchoalveolar lavage, antigen detection assays, and pathogen-specific polymerase chain reaction (PCR) tests. (See "Sputum cultures for the evaluation of bacterial pneumonia" and "Approach to the immunocompromised patient with fever and pulmonary infiltrates", section on 'Microbiologic assays' and "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults".)

Serologic testing for antibodies to specific organisms (eg, atypical organisms, viral and fungal infections) are not reliable in patients with IEIs that result in impaired antibody production (eg, combined immunodeficiencies, antibody deficiencies), since many of these patients cannot make specific antibodies in response to infectious agents. Serologic assays are also unreliable in patients receiving antibody replacement therapy, since the antibodies measured may have originated from the donors rather than the patient. When the patient's ability to produce antibodies is in doubt, other diagnostic methods should be used (eg, direct culture, PCR, urine antigen testing). (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults".)

Pulmonary function tests — In patients six years of age and older with evidence of pulmonary disease and a known or suspected IEI, spirometry plus direct measurement of lung volumes (eg, plethysmography) and assessment of diffusing capacity for carbon monoxide (DLCO) are typically performed soon after diagnosis, at a time when the patient is clinically stable. Subsequently, pulmonary function tests are obtained for monitoring and in response to changes in respiratory symptoms. (See "Overview of pulmonary function testing in adults" and "Overview of pulmonary function testing in children" and "Diffusing capacity for carbon monoxide" and "Approach to the adult with interstitial lung disease: Diagnostic testing".)

If obstructive impairment is noted on spirometry, the patient should be assessed for reversibility after bronchodilator administration. This is useful to screen for other disease processes that may be present, such as asthma, or to aid in determining the chronicity of other conditions, such as bronchiectasis. [84]. (See "Pulmonary function testing in asthma", section on 'Bronchodilator responses'.)

A six-minute walk is useful in the evaluation of patients with more advanced pulmonary disease, such as those with a low resting pulse oximetry, a forced vital capacity (FVC) less than 50 percent of predicted, complaint of dyspnea on exertion, or radiographic diffuse parenchymal lung disease. The six-minute walk test assesses exercise tolerance and also hypoxemia with activity [85-87]. (See "Overview of pulmonary function testing in adults", section on 'Six-minute walk test'.)

Histologic evaluation — Histologic examination of pulmonary tissue or mediastinal/hilar lymph nodes is important if the cause of lung infection, bronchiolitis, diffuse parenchymal lung disease, or mediastinal/hilar adenopathy is unclear. The choice of procedure for obtaining tissue depends on the type and location of the abnormality and the anticipated sample size needed for diagnosis:

Lung tissue can be obtained by transbronchial biopsy during bronchoscopy, particularly when the goal is obtaining tissue for microbiologic staining and culture. Transbronchial biopsy may not obtain sufficient tissue to obtain a definitive diagnosis in some conditions such as OP, ILD, or suspected malignancies. Cryobiopsy is a promising technique in the evaluation of such disorders in patients with IEI, although direct studies comparing surgical lung biopsies and cryobiopsies are lacking. Flexible bronchoscopy is minimally invasive and provides easy access to the lung via the airways [88].

Surgical lung biopsy is typically needed for conditions, such as ILD, bronchiolitis, or suspected malignancy, since transbronchial biopsy may not yield sufficient tissue for diagnostic purposes. Surgical lung biopsy may be obtained by video-assisted thorascopic surgery (VATS) or thoracotomy. VATS is increasingly considered to be the optimal modality, as it generally decreases the complications associated with open lung biopsy [44,89-91]. VATS is well-tolerated in children and is associated with less postoperative pain, better postoperative pulmonary function, and shorter hospital stays compared with open thoracotomy [92]. More central lesions and larger peripheral lesions may not be amenable to VATS. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

In patients with mediastinal adenopathy, biopsies of enlarged nodes are obtained via endobronchial ultrasound-guided transbronchial needle aspiration or mediastinoscopy. The choice among these procedures depends on local expertise and on the exact location of the adenopathy (figure 1). (See "Endoscopic ultrasound-guided sampling of the mediastinum: Technique, indications, contraindications, and complications" and "Surgical evaluation of mediastinal lymphadenopathy" and "Endobronchial ultrasound: Indications, contraindications, and complications", section on 'Mediastinal lymphadenopathy of unclear etiology'.)

MONITORING FOR PULMONARY DISEASE — Once a patient has been diagnosed with an IEI, monitoring of lung function and prompt recognition of new complications are important components of medical management because pulmonary disease is a leading cause of morbidity and mortality in these patients. However, the optimal type and frequency of testing is not known. The suggestions listed here are based on clinical experience.

Patients should be asked regularly about the onset of new pulmonary symptoms, including cough, dyspnea, sputum production, hemoptysis, or reduced exercise tolerance and also about any changes in sputum volume or color.

Spirometry is a relatively inexpensive, low risk means of obtaining reproducible measures of lung function. We typically perform repeat spirometry at regular intervals (eg, every 6 to 12 months) to monitor for the development and/or progression of lung disease, even in those who are currently asymptomatic [36,93]. (See "Office spirometry" and "Overview of pulmonary function testing in children", section on 'Spirometry'.)

We often repeat spirometry after treatment of an intercurrent flare of bronchiectasis to determine whether the course of antibiotics has returned the patient's lung function to baseline. (See "Bronchiectasis in adults: Treatment of acute exacerbations and advanced disease".)

Lung volume measurements to assess for the development of a new restrictive process are generally not necessary as part of routine surveillance but are indicated if a patient reports a change in exercise tolerance or if diffuse parenchymal lung disease is noted on imaging studies. We monitor patients with documented restrictive lung disease with routine lung volume measurements and measurements of diffusing capacity (DLCO) every 12 months.

Patients with IEIs usually require periodic imaging to diagnose new pulmonary disorders and manage existing ones, especially when a change occurs in their clinical condition. We typically obtain a conventional chest radiograph if a patient reports an acute change in symptoms and to exclude pneumonia, lung abscess, or empyema. High resolution computed tomography (HRCT) is obtained when a patient has a decrease in lung volumes or diffusing capacity on pulmonary function testing, when findings on the chest radiograph require further delineation, in the evaluation of bronchiectasis or parenchymal lung disease, and if the patient experiences hemoptysis. (See "High resolution computed tomography of the lungs".)

The use of radiation-based imaging studies in patients with IEIs must be conservative and thoughtful, since immunodeficient patients are at higher risk for malignancies at baseline [94-97]. Clinicians should attempt to minimize cumulative radiation exposure by choosing CT protocols that use reduced radiation dose intensity whenever possible. As an example, conventional CT of the chest uses substantially less radiation than HRCT. Radiation exposure is particularly relevant to patients with IEIs that involve radiation sensitivity, including ataxia-telangiectasia and certain forms of severe combined immunodeficiency [44]. In these patients, it is important to discuss alternative imaging modalities with the performing radiologist in order to minimize radiation exposure.

PULMONARY DISEASE IN SPECIFIC TYPES OF PID — Pulmonary manifestations of IEIs include infection, structural disease, and malignancy. Pulmonary disorders are particularly prominent in certain IEIs, several of which are reviewed in this section.

Antibody defects — IEIs that involve significant defects in antibody production or function predispose patients to recurrent pneumonias and the development of bronchiectasis. These complications can largely be prevented by the prompt institution of immunoglobulin replacement. The causative organisms are typically common respiratory tract bacteria. Patients with common variable immunodeficiency (CVID) may also develop various forms of diffuse parenchymal lung disease.

Common variable immunodeficiency — Common variable immunodeficiency (CVID) is a heterogeneous disorder that results in a low serum IgG and low IgA and/or IgM, diminished antigen-specific antibody response, and variable B cell numbers. In addition, some patients with CVID also have CD4+ T cell lymphopenia. Patients with CVID typically present with recurrent upper and lower respiratory tract infections, including sinusitis, bronchitis, and pneumonia [98,99]. Common pathogens include encapsulated and atypical bacteria [99-102]. Immunoglobulin replacement has decreased the incidence of pneumonia and increased life expectancy [103].  

Patients with CVID are at increased risk to develop interstitial lung disease (ILD) and malignancy, especially B cell lymphomas [104,105]. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults".)

Chronic airway disease — Bronchiectasis is the most common obstructive lung disease in patients with CVID, occurring in approximately 20 percent of patients [99,106,107]. Patients with CVID may also have a concomitant history of asthma, although it can be difficult to differentiate a flare of bronchiectasis from asthma [108,109]. Both bronchiectasis and asthma can cause dyspnea, wheezing, cough, sputum production, and airflow limitation on spirometry. Mucous plugging and bronchial wall thickening can be seen on CT. (See "Clinical manifestations and diagnosis of bronchiectasis in adults" and "Bronchiectasis in children: Clinical manifestations and evaluation".)

Interstitial diseases — Fifteen to 30 percent of patients with CVID develop various forms of diffuse parenchymal lung disease, such as mucosa-associated lymphoid tissue (MALT) lymphoma, granulomatous and lymphocytic interstitial lung disease (GLILD), or organizing pneumonia (OP) [108,110-112]. Since ILD may be missed by routine chest radiographs, high resolution computed tomography (HRCT) is indicated in the initial evaluation of patients with CVID. If diffuse parenchymal disease is present on HRCT, surgical lung biopsy (usually via thoracoscopy) may be necessary to establish the underlying diagnosis. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

Several cases of extranodal marginal zone B cell lymphoma (ie, MALT type) involving the lung, pleura, or mediastinal lymph nodes have been reported among patients with CVID [113-115]. HRCT patterns include diffuse reticular, nodular, and consolidative opacities. The diagnosis requires biopsy of affected tissue. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)

Granulomatous and lymphocytic interstitial lung disease — GLILD is the most common cause of diffuse parenchymal lung disease in patients with CVID, occurring in 20 to 30 percent of patients with CVID [62]. GLILD was defined as "a distinct clinico-radio-pathologic interstitial lung disease occurring in patients with CVID, associated with a lymphocytic infiltrate and/or granuloma of the lung, and in whom other conditions have been considered and where possible excluded" in a 2017 British consensus statement [116]. This definition summarized the experience of approximately 30 consultant clinicians caring for an estimated 112 patients with GLILD, which can be viewed as the pulmonary manifestation of a multisystem granulomatous, lymphoproliferative disorder, as patients with GLILD often have splenomegaly and diffuse lymphadenopathy [62,117-120].

Epidemiology and pathogenesis – GLILD typically presents in patients between the ages of 20 and 50 years, although childhood cases have been observed, in particular with patients with LRBA or CTLA-4 deficiency. Females are more frequently affected with GLILD than males and approximately 70 percent have a past history of immune-cytopenias [62]. The etiology of GLILD is unknown. In a small cohort study, the majority of patients with GLILD were found to have human herpesvirus 8 (HHV-8) infection of the lung, suggesting that HHV-8 may underlie the pulmonary and lymphoproliferative complications in a subgroup of patients [117,121]. However, this finding has not been replicated. Overproduction of tumor necrosis factor (TNF)-alpha may also contribute to the propagation of granulomatous disease in these patients [122-125]. Patients with CVID and GLILD appear to be at increased risk for autoimmune diseases and malignancy, particularly non-Hodgkin lymphoma [62,110,111,126-128]. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults", section on 'Autoimmune disease' and "Common variable immunodeficiency in children", section on 'Autoimmune disease'.)

Clinical features – Patients with GLILD are frequently asymptomatic and therefore a screening HRCT of the chest should be performed initially in all patients with CVID [83]. In patients who do not have evidence of ILD on the initial screen, our approach is to repeat HRCT in four to five years, unless the patient experiences a decline in the values of yearly pulmonary function testing (spirometry, lung volumes, diffusing capacity for carbon monoxide [DLCO]) or develops symptoms such as increased dyspnea on exertion, new or altered cough, pronounced fatigue, or night sweats [116,129]. Most patients are not hypoxemic at rest or with ambulation at the time of diagnosis. Splenomegaly and diffuse adenopathy are prominent associated features of GLILD. Liver disease (ie, nodular regenerative hyperplasia) is present in approximately 20 percent of patients with GLILD, enteropathy can occur, and there is frequently a history of autoimmune cytopenias.

Evaluation and diagnosis – Findings on HRCT scan (thin slice, contiguous) that are consistent with GLILD include ground-glass and solid nodular opacities with hilar and/or mediastinal adenopathy [116,120,126,130,131]. Micronodular and macronodular disease is commonly seen, and these abnormalities are predominantly found in the lower lung zones [129]. However, in the 2017 consensus document, experts believed there was no combination of radiologic findings that was sufficiently diagnostic to avoid the need for biopsy [116,129,132]. We generally pursue a tissue diagnosis in patients with symptoms (eg, breathlessness, reduced exercise tolerance, fever, night sweats, weight loss), a decline in FVC or DLCO of 10 percent or greater, or progression on HRCT [116]. Among these, HRCT appears to be the most sensitive.

Other important components of the evaluation include full pulmonary function testing and flexible bronchoscopy with bronchoalveolar lavage (BAL) to exclude infections (eg, bacterial, mycobacterial, and fungal cultures; PCR for viral pathogens). If not previously performed, abdominal CT scan is indicated in patients with GLILD as these patients frequently have splenomegaly and diffuse adenopathy and are at increased risk for developing lymphoma. Granulomas can be found in the spleen, lymph nodes, liver, bone marrow, gastrointestinal tract, skin, and other organs [117-119]. We also monitor spleen size (through physical examination) and liver function tests yearly in patients with GLILD.

A definitive diagnosis of GLILD requires a surgical lung biopsy, preferably via video assisted thoracoscopy rather than thoracotomy. Surgical biopsy is preferred to transbronchial biopsy, as sampling error and insufficient tissue can potentially lead to an erroneous diagnosis of cryptogenic organizing pneumonia or miss other conditions such as lymphoma [133]. As a potential alternative, cryobiopsy, which is less invasive than surgical biopsy, has shown promise in the diagnosis of GLILD [134,135]. If possible, experts favor a search for a genetic cause leading to CVID and GLILD [116]. (See "Pathogenesis of common variable immunodeficiency", section on 'Genetics'.)

The histopathology of GLILD is characterized by the presence of lymphocytic interstitial lung disease and/or non-necrotizing granulomas, and peribronchiolar lymphocytic inflammation (picture 1) [129,132,136-138]. Organizing pneumonia is also a prominent finding in addition to the typical histopathologic features of nodular peribronchial inflammation with mature lymphocytes and non-necrotizing granulomas (poorly or well-formed). A combination of three out of these four typical histological findings (lymphocytic and peribronchiolar inflammation, non-necrotizing granuloma and organizing pneumonia) is highly supportive of the diagnosis of GLILD [62]. Biopsy specimens should be immunostained for CD3, CD4, CD8, and CD20 and for Mycobacteria and fungi. Lymphocytes are commonly a mixture of CD4+ T cells, fewer CD8+ T cells, and CD20+ B cells [132]. If histopathology is worrisome for malignancy, B cell clonality studies should be performed to exclude lymphoma.

Differential diagnosis – The differential diagnosis of GLILD includes sarcoidosis [129], interstitial lung disease complicating rheumatic disease (eg, Sjögren syndrome, rheumatoid arthritis), hypersensitivity pneumonitis, organizing pneumonia, high and low grade lymphomas, and granulomatous infections from organisms such as Mycobacteria and fungi. Both GLILD and sarcoidosis are characterized by non-necrotizing pulmonary granulomas, often accompanied by hilar and/or mediastinal adenopathy [112,129,139]. Sarcoidosis, however, has several features that distinguish it from GLILD, such as normal or elevated serum immunoglobulin levels, frequent spontaneous remissions, and micronodular disease that is predominantly located in the upper zones of the lung [129]. In contrast, micro- and macronodular disease in the lower lung zones is found in GLILD, and splenomegaly and autoimmune complications such as immune cytopenias are much more common [119]. (See "Interpretation of lung biopsy results in interstitial lung disease" and "Classification of diffuse lung disease (interstitial lung disease) in infants and children".)

Treatment – All patients with CVID and GLILD should be treated with immune globulin to restore serum IgG levels into the normal range prior to the initiation of treatment of GLILD in case the pulmonary findings represent infectious processes [116,140]. GLILD generally does not respond to immune globulin replacement alone, so additional treatment is pursued for patients with progressive respiratory symptoms, worsening lung function (eg, ≥10 percent decrease in FVC or DLCO), or progression on HRCT despite normalized serum IgG levels.

Definitive data on the best treatment regimen for GLILD is lacking, and it is unlikely that a controlled trial will be done due to the rarity of GLILD [141]. Traditionally, oral glucocorticoids have been the initial therapy of choice [116]. However, many patients do not respond [62], and accumulating data suggest that the combination of rituximab and an antimetabolite drug may be the most effective initial therapy [62,129,133,142,143].

Rituximab with azathioprine or mycophenolate – In a retrospective chart review of 39 patients with CVID and GLILD treated over 12 years at the authors' center, patients received rituximab (375 mg/m2 per infusion) weekly for four weeks, and rituximab infusions were repeated at six-month intervals for three or four courses in total [62]. Rituximab was combined with antimetabolite therapy consisting of either azathioprine (1 to 2 mg/kg daily) or mycophenolate mofetil (250 to 1000 mg twice daily) in those who could not take azathioprine, which was given for a median of 16 months. Approximately one-half of patients had previously relapsed after systemic glucocorticoids. Treatment with either regimen improved HRCT scan scores in 92 percent. Several measures of lung function also improved, although not carbon monoxide diffusion capacity. Relapse-free survival was 57 percent at 5.4 years or longer. Damaging mutations in genes that predispose the development of CVID (TNFRSF13B) or cause a CVID-like IEI (CTLA4, KMT2D, BIRC4) were present in 21 percent of patients. The efficacy of rituximab and antimetabolite therapy was similar in patients with or without damaging mutations. This approach has also been successful in children [143].

Glucocorticoids – In other centers, patients are often initially treated with oral glucocorticoids, with doses ranging widely from 10 mg to 2 mg/kg daily, but most patients require a median dose of 40 mg daily [116]. The evidence for benefit consists of case reports [8,60,144,145]. Although the pulmonary disease may initially respond to glucocorticoids, relapse often occurs when doses are reduced, and side effects are common.

Other immunosuppressive regimens – Other forms of immunosuppression have been successfully used for patients who have progressive disease despite glucocorticoids [116]. Small numbers of patients with GLILD have been successfully treated with TNF antagonists, mycophenolate mofetil, cyclosporine, rituximab alone, and sirolimus [132,146,147]. Abatacept has been shown to be useful in the GLILD associated with CTLA4 or LRBA deficiency [148,149].

Monitoring and prognosis – In patients treated with rituximab and an antimetabolite who are in remission, we monitor with yearly HRCT and pulmonary function testing, including spirometry, lung volumes, and diffusing capacity for carbon monoxide (DLCO). Longitudinal assessment of peripheral blood lymphocyte subsets are also performed as relapses are frequently associated with a reappearance of B cells and an increase in the percentage of activated (HLA-DR+) T cells [62]. If recurrence of GLILD occurs, retreatment with rituximab and antimetabolite therapy appears to be effective in inducing remission. We stop azathioprine or mycophenolate mofetil for significant leucopenia or CD4 counts <200/mm3 until levels increase.  

The presence of GLILD in patients with CVID is associated with significant morbidity and mortality [111,129]. In the authors' experience, untreated GLILD usually leads to progressive respiratory impairment and eventual respiratory failure [129,131], although a more indolent course has also been reported. The impact of various therapies has not been formally evaluated.  

X-linked agammaglobulinemia — X-linked agammaglobulinemia (XLA) is caused by a mutation in Bruton's tyrosine kinase, leading to a defect in B cell development and ultimately resulting in a lack of mature B cells and a profound decrease in immunoglobulin production. Patients with XLA are predisposed to recurrent respiratory tract infection by encapsulated extracellular bacteria (eg, S. pneumoniae and H. influenzae), Mycoplasma species, and less commonly, Staphylococcus aureus and Pseudomonas [100,101,150,151]. Empiric treatment of sinopulmonary infections in patients with XLA should include coverage of atypical bacteria. (See "Agammaglobulinemia".)

Immunoglobulin therapy has increased the life expectancy and decreased the number of pulmonary infections in patients with XLA. However, severe bronchiectasis and cor pulmonale remain a significant cause of morbidity and mortality [6,21,44,81,82,98,150,152]. The early diagnosis and treatment of XLA is important in the prevention and progression of bronchiectasis, although bronchiectasis may develop despite high-dose gammaglobulin replacement therapy [153,154]. When present, bronchiectasis in XLA is generally restricted to the middle and lower lobes. Upper lobe disease is uncommon [6,81,155].

HRCT and pulmonary function tests should be performed in the initial evaluation of these patients to ascertain the presence and/or extent of bronchiectasis and to assess the functional status of the lungs [42,81]. Unlike CVID, XLA does not appear to be associated with an increased incidence of ILD or lymphoma [42].

Combined immunodeficiencies — The most characteristic pulmonary manifestations of combined immunodeficiencies are infections. Viral pathogens and opportunistic infections are common. Patients with these IEIs also develop ILD and lymphadenopathy.

Severe combined immunodeficiency — The term "severe combined immunodeficiency" (SCID) refers to a group of life-threatening IEI disorders that present in infancy with T cell lymphopenia and extreme susceptibility to infection with bacteria, viruses, and fungi (table 2). Pulmonary manifestations of SCID generally include opportunistic infections and ILD, commonly due to P. jirovecii, cytomegalovirus (CMV), adenovirus, respiratory syncytial virus, and/or parainfluenza virus type 3 [156]. Identification of patients with SCID at an early age is critical to prevent the development of pulmonary infections. Patients receiving hematopoietic stem cell transplantation before the age of four months have significantly better survival outcomes, especially if transplant occurs prior to the development of opportunistic infections [157]. (See "Severe combined immunodeficiency (SCID): An overview" and "Severe combined immunodeficiency (SCID): Specific defects".)

Patients with SCID caused by adenosine deaminase deficiency (ADA-SCID) may have specific pulmonary findings that are distinct from other forms of SCID. ADA-SCID patients frequently have characteristic chest radiograph findings, including flaring of the anterior ribs, shortening of the transverse vertebral processes with flattening of the ends (platyspondyly), and thick growth arrest lines. They also have an increased susceptibility to pulmonary insufficiency, possibly due to accumulation of adenosine in the lung [158,159]. Prior descriptions of this phenomenon have been nonspecific, suggesting symptoms of idiopathic respiratory distress or reactive airway disease. However, one case report described a patient with progressive tachypnea and cough, leading to hypoxemia and the need for supplemental oxygen therapy. Diffuse, progressive ILD was detected radiographically. Histologic analysis revealed diffuse interstitial goblet cell hyperplasia and dense inflammatory infiltrates composed of plasma cells, eosinophils, and lymphocytes. Immunohistochemistry was positive for CD8+ T cells, CD20+ B cells, and CD68+ macrophages. The patient's lung disease dramatically improved after treatment with pegylated-ADA [160]. (See "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis".)

Ataxia-telangiectasia — Ataxia-telangiectasia (AT) is an autosomal recessive disorder in which DNA repair is impaired by defects in the ataxia-telangiectasia mutated (ATM) gene, rendering patients exquisitely sensitive to ionizing radiation. Clinically, AT is characterized by cellular and humoral immune deficits, progressive neurologic dysfunction with ataxia, and increased risk of malignancy. The presentation of AT is diverse and varies among patients. Despite the fact that AT is technically a combined immunodeficiency, severe bacterial, viral, and opportunistic infections are uncommon in AT. Patients generally develop recurrent sinopulmonary infections due to common pathogens (eg, Pseudomonas, Haemophilus, and pneumococcus) [161,162]. Neurologic defects leading to poor swallowing can also predispose to recurrent aspiration pneumonia. (See "Ataxia-telangiectasia".)

Patients with AT suffer from various forms of pulmonary disease, which confer significant morbidity and mortality. The most common disorders are recurrent infections and bronchiectasis but also bronchiolitis obliterans and ILD [48,162-164]. In patients with AT, symptoms of ILD are usually nonspecific, including cough, dyspnea, and fever. Early identification of AT-related ILD and assessment of therapeutic response is often limited by reluctance to perform radiographic studies out of concern for radiation sensitivity. For this reason, patients with AT should receive care at specialized centers with expertise in managing this disorder.

In a series of 97 patients with AT and lung disease, 25 had ILD [163]. The mean age of onset of ILD was 17.5 years with a range of 9 to 28 years. CT of the chest in five patients revealed diffuse bibasilar reticular and nodular opacities and interlobular septal thickening but no honeycomb changes. Pleural thickening or effusion was noted in some patients. Histologically, patients with AT-related ILD demonstrate fibrosis with diffuse lymphocytic, lymphohistiocytic, or rarely neutrophilic, parenchymal infiltration [163]. Clonal analyses must be performed to exclude the possibility of malignancy, a known complication of AT. Atypical epithelial and interstitial cells with large hyperchromatic and pleomorphic nuclei are frequently seen but are of unclear significance.

AT-related ILD is often progressive despite antibiotics, oxygen therapy, or supplemental immunoglobulin. In the series mentioned previously, oral prednisone therapy was helpful only in patients with early stage ILD. It was not sufficient to prevent mortality in patients with severe disease [163]. The initial dose was 1 to 2 mg/kg per day for the first month with a subsequent taper over two to three months.

AT also predisposes affected individuals to a >100-fold increased risk of malignancy, most commonly leukemia/lymphoma [165]. In a review of AT patients diagnosed with Hodgkin lymphoma, fever, cough, and adenopathy were associated with the presence of lymphoma, and mortality was 100 percent [166].

Hyperimmunoglobulin M syndrome — CD40/CD40 ligand (CD40L) deficiency, which accounts for most cases of hyperimmunoglobulin M syndrome, causes T cell dysfunction and hypogammaglobulinemia, with variably elevated levels of IgM. Patients with CD40 or CD40L deficiency usually present within the first two years of life with the combination of recurrent upper and lower respiratory tract infections (primarily caused by encapsulated bacteria) and opportunistic infections. Other defects have been associated with elevated levels of IgM and immunodeficiency, as discussed in more detail separately. (See "Combined immunodeficiencies" and "Hyperimmunoglobulin M syndromes".)

Patients with hyperimmunoglobulin M syndrome are susceptible to pulmonary infection from a wide range of pathogens, including bacteria, viruses, and fungi. Opportunistic pathogens, such as P. jirovecii and CMV, are common and frequently result in mortality in untreated individuals [167,168]. Disseminated Histoplasma infection involving the lung has also been reported [169]. Other fungal infections, such as those caused by Cryptococcus spp, may involve the hilar and/or mediastinal lymph nodes [170,171]. Cryptosporidium infections can cause a life threatening ascending cholangitis, particularly in CD40L deficiency. Autoimmunity and malignancy are also increased in patients with hyperimmunoglobulin M syndrome but generally involve hematologic abnormalities, arthritis, and inflammatory bowel disease, rather than conditions affecting the thorax [172]. Patients with CD40L deficiency are also susceptible to PAP [73]. (See 'Pulmonary alveolar proteinosis' above.)

Activating phosphoinositide 3-kinase delta syndrome — A combined immunodeficiency due to an activating mutation in phosphoinositide 3-kinase delta (PI3KD) called activating PI3KD syndrome (APDS) has been described. Patients with this syndrome have increased sinopulmonary infections, lymphoproliferation, and CMV and Epstein-Barr virus viremia. Bronchiectasis due to recurrent pyogenic infections occurs in many. Laboratory features can include lymphopenia and impaired specific antibody production with an elevated IgM [173].

STAT5b deficiency — Deficiency in signal transducer and activator of transcription 5b (STAT5b), one of two STAT5 proteins, leads to a syndrome of immunodeficiency with autoimmunity and pulmonary disease (ILD and bronchiectasis). Patients with STAT5b deficiency exhibit eczema, chronic diarrhea, and increased susceptibility to infections. Pulmonary disease appears prominent in STAT5b deficiency, although it is unclear whether this is driven by infectious processes or is the result of defective immune regulation. The increased susceptibility to infections and autoimmune manifestations of STAT5b deficiency is likely due to defects in responsiveness to interleukin-2, a key cytokine in T cell and regulatory T cell growth and function [54]. (See "Combined immunodeficiencies".)

Other immunodeficiencies

Autoinflammatory/autoimmune syndromes — A number of other inborn errors of immunity can lead to pulmonary inflammation. Defects in coatomer subunit alpha (COPA) present with arthritis, interstitial lung disease (ie, pulmonary hemorrhage, obstruction, restriction, or a diffusion capacity defect) and in some cases had immune mediated glomerulonephritis. COPA is part of the coatomer protein complex, a carrier complex required for vesicular trafficking. Defects in autophagy and endoplasmic reticulum stress appear to lead to autoimmunity [55]. Stimulator of interferon genes (STING)-associated vasculopathy of infancy (SAVI) occurs due to gain-of-function defects in STING, resulting in spontaneous interferon production. Vascular inflammation leads to characteristic rashes, infarction, and interstitial lung disease [56]. Defects in NSMCE3, a DNA repair enzyme, lead to a syndrome of immunodeficiency and interstitial lung disease characterized by interstitial opacities, alveolar damage, eosinophilic and lymphocytic pneumonia, fibrosis, bronchiolitis obliterans, cystic remodeling, hyperinflation, emphysema, and interstitial hemorrhage [174]. (See 'Opportunistic/unusual pathogens' above.)

Chronic granulomatous disease — Chronic granulomatous disease (CGD) is an inherited disorder of phagocyte function, characterized by a mutation in one of five genes that encode NADPH oxidase, a key enzyme responsible for the intracellular generation of reactive oxygen intermediates. CGD manifests clinically as recurrent bacterial and fungal infections due to catalase-positive organisms. Pulmonary infection, including pneumonia, lung abscess, and/or empyema formation, is the leading manifestation of CGD. Aspergillus is the most common pathogen, and approximately one-third of invasive Aspergillus infections were without cough, dyspnea, or fever in one series of 67 adults [175]. Other associated organisms include S. aureus, Nocardia (which frequently results in pulmonary cavitation), and Burkholderia [65,176]. Patients are also susceptible to infection with both M. tuberculosis and nontuberculous mycobacteria [65,175,177]. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis" and "Chronic granulomatous disease: Treatment and prognosis".)

Pneumonia can be complicated by empyema or pulmonary abscess in as many as 20 percent of patients with CGD [178]. Contiguous spread to the pleura, bone, and ultimately disseminated infection is particularly common with pulmonary infections caused by Aspergillus nidulans [175]. Pulmonary infections tend to be protracted, and mediastinal and hilar adenopathy are common.

Noninfectious pulmonary processes occur more often in adults with CGD than children, although less often than pneumonia or abscess formation [65]. Reasons for the development of noninfectious granuloma in CGD are unclear, but dysregulated inflammation is commonly implicated [179-182]. In some patients, granuloma formation is seen with concurrent lymphocytic infiltrate. Some authors have termed this "autoimmune granuloma," based on resolution of these findings after initiation of immunomodulatory therapy [183]. In a separate series, circumscribed nodules or consolidation occurred following a respiratory infection in 7 of 11 patients (6 of 7 followed Aspergillus infection), possibly suggesting a dysregulated response to infection [175]. On biopsy, this radiographic pattern was associated with granulomas, sometimes in combination with neutrophilic or eosinophilic microabscesses. Other patients in this series had increased reticular or ground-glass opacities without prior evidence of infection. The optimal management of these various noninfectious complications is not known, but immunosuppressants including glucocorticoids, thalidomide, hydroxychloroquine, and methotrexate have been tried.

For patients without a prior diagnosis of CGD, granuloma formation in the chest may be mistaken for malignancy or sarcoidosis on imaging studies. Review of the infectious history or development of infection after treatment (eg, glucocorticoids for sarcoidosis) ultimately leads to the diagnosis of CGD [65,184-187]. However, concomitant CGD and sarcoidosis (glucocorticoid-responsive noncaseating granulomata) of the lungs and central nervous system have also been described [186,188].

Pulmonary imaging findings in patients with CGD are often nonspecific. Chest CT scans may reveal consolidation, ground-glass or tree-in-bud opacities, scattered nodules, and/or bronchiectasis (image 2) [187,189,190]. Hilar and/or mediastinal adenopathy are also seen [189]. Furthermore, imaging may reveal extrapulmonary thoracic disease, including contiguous spread of infection to the ribs or vertebrae, resulting clinically in osteomyelitis [189]. Focal scarring and honeycomb formation may follow lung infection.

Given the broad spectrum of pathogens implicated in CGD, effort should be made to identify a causative organism prior to initiating treatment. In particular, special emphasis should be placed on obtaining a thorough exposure history in patients who present acutely with fever, dyspnea, and diffuse pulmonary infiltrates, as acute, fulminant, mulch-related pneumonitis has been observed and constitutes a medical emergency [191,192]. (See "Chronic granulomatous disease: Treatment and prognosis".)

The prognosis of patients with CGD has improved with antifungal and antibacterial prophylaxis and the administration of interferon-gamma, with approximately 55 percent survival at age 30. In addition, HCT can be curative for those with available donors. Patients with CGD do not appear to have an increased predisposition to develop malignancy. Mortality in CGD is generally due to pneumonia and/or sepsis, with Aspergillus most frequently implicated [65,175,176]. (See "Chronic granulomatous disease: Treatment and prognosis", section on 'Prognosis'.)

Hyperimmunoglobulin E syndrome — Hyperimmunoglobulin E syndrome is a group of diseases that present with elevated IgE, recurrent pneumonia, and eczema [193]. Autosomal dominant hyperimmunoglobulin E syndrome is due to mutations in signal transducer and activator of transcription 3 (STAT3) and is associated with pneumatocele formation, skeletal disease (eg, fractures, scoliosis), and vascular abnormalities (eg, cerebral aneurysms, thrombotic events) [194-196]. There are also autosomal recessive forms of hyperimmunoglobulin E syndrome caused by mutations in other molecules. These are associated with other clinical findings. (See "Autosomal dominant hyperimmunoglobulin E syndrome".)

Pneumonia is common in patients with all forms of hyperimmunoglobulin E syndrome and is generally due to infection with S. aureus, S. pneumoniae, or H. influenzae [197,198]. Patients with STAT3 mutations are known to develop bronchiectasis and are uniquely susceptible to secondary pneumatocele formation [198]. Pneumatoceles are thin-walled, air-filled cysts in the lung most commonly caused by infection, particularly S. aureus pneumonia. Many resolve spontaneously, but a minority will enlarge, leading to rupture and pneumothorax. Pneumatocele superinfection, particularly with Pseudomonas and Aspergillus, is a leading cause of mortality in patients with autosomal dominant hyperimmunoglobulin E syndrome [199]. Nontuberculous mycobacteria have also been found in hyperimmunoglobulin E syndrome patients with pneumatoceles [200].

Patients with hyperimmunoglobulin E syndrome are predisposed to malignancy. One case series reported the increase in relative risk of lymphoma at >250, although this was not stratified according to molecular defect [201].

SUMMARY AND RECOMMENDATIONS

Pulmonary disease is a common manifestation of many primary immunodeficiencies (also called inborn errors of immunity [IEIs]) and a leading cause of morbidity and mortality. (See 'Introduction' above.)

Infections that are recurrent, recalcitrant to therapy, or due to opportunistic or unusual pathogens suggest a possible underlying IEI. (See 'Pulmonary infections' above.)

Other pulmonary manifestations of IEIs include bronchiectasis, bronchiolitis obliterans, disordered inflammatory responses (such as granuloma), interstitial lung disease (ILD), mediastinal and/or hilar adenopathy, and malignancy. (See 'Pulmonary manifestations of immunodeficiency' above.)

In the initial evaluation of patients with IEIs that are frequently complicated by pulmonary abnormalities, high resolution computed tomography can reveal pulmonary abnormalities that are not detected by standard chest radiographs or pulmonary function tests, including plethysmography and diffusing capacity for carbon monoxide (DLCO). (See 'Diagnostic evaluation of pulmonary disease' above.)

In patients with IEI and ILD or suspected malignancy, surgical biopsy using video-assisted thorascopic surgery or thoracotomy may be necessary to obtain sufficient pulmonary tissue to definitively establish a diagnosis. (See 'Histologic evaluation' above.)

Routine monitoring for the development of pulmonary disease is essential in all patients with IEIs. (See 'Monitoring for pulmonary disease' above.)

Common variable immunodeficiency is one of the more common IEIs and up to 30 percent of patients develop granulomatous and lymphocytic interstitial lung disease (GLILD). For initial treatment of GLILD, we suggest the combination of rituximab plus an antimetabolite (either azathioprine or mycophenolate mofetil), in preference to glucocorticoids (Grade 2C). While glucocorticoids remain an acceptable initial choice and may be associated with initial improvement, they do not achieve long-term remission, and GLILD tends to recur with tapering. (See 'Granulomatous and lymphocytic interstitial lung disease' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Nicole M Chase, MD, and E Richard Stiehm, MD, who contributed to earlier versions of this topic review.

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Topic 15830 Version 34.0

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