IgA deficiency is the most common PID and is noted in as many as 1 in 333 blood donors (Cunningham-Rundles 2001). IgA is secreted onto epithelial surfaces, and is present in smaller amounts in serum as well. Most individuals with IgA deficiency are asymptomatic. However, an increased propensity for infections of the respiratory, gastrointestinal, and genitourinary tracts is seen in some affected individuals. Pyogenic sinopulmonary infections are the most common (Cunningham-Rundles 2001), and the presence of IgA and IgG subclass antibody deficiencies is associated with greater pulmonary damage in children with recurrent respiratory tract infections (Ozkan et al. 2005).

X-linked agammaglobulinemia (XLA) is responsible for approximately 85 % of cases of childhood agammaglobulinemia (Plebani et al. 2002). There may be a family history of an affected brother, uncle, or male cousin. XLA most often results from a mutation in the X-linked gene encoding the Bruton tyrosine kinase. Deficiency of this kinase prevents precursor cells from maturing into circulating B-cells and plasma cells, resulting in impaired production of immunoglobulins of all isotypes (Buckley 2004). Infants with XLA typically present after the first several months of life coinciding the waning of maternally transmitted IgG (Fried and Bonilla 2009). Without IgG therapy, recurrent bacterial infections occur (Fig. 9). Bronchiectasis due to recurring infections usually affects the lower lungs. Similar involvement of both the right and left lungs may help differentiate these patients from those with bronchiectasis related to aspiration (Curtin et al. 1991). Pulmonary insufficiency is a common cause of death. Streptococcus, H. influenzae and Mycoplasma are the most typical cause of infections. There is an increased rate of hepatitis and enterovirus infections, but other viral infections are usually handled normally (Winkelstein et al. 2006). Pneumocystis and other fungal infections are rare. The adenoids, tonsils, and lymph nodes are typically small, while the thymus is usually normal in size. A lateral airway radiograph demonstrating diminutive adenoid tissue is the absence of a history of adenoidectomy can be very helpful in suggesting this diagnosis (Buckley 2004) (Fig. 9).

Common variable immunodeficiency (CVID) is characterized by a failure of terminal differentiation of B-cells to plasma cells, resulting in hypogammaglobulinemia, even though B-cell number may be normal. CVID is usually less severe than agammaglobulinemia and diagnostic delay until the second decade or later is common. The infectious manifestations are otherwise similar to XLA. Unlike the case in XLA, the tonsils, adenoids, and lymph nodes are not small, and may be enlarged. Splenomegaly is seen in about 25 % of cases. Also unlike XLA, CVID is associated with an increased risk for autoimmune cytopenia, lymphoproliferative disease, lymphoma and gastric cancer. The benign lymphoproliferative disease associated with CVID can have a waxing and waning course. The associated lymphadenopathy can be difficult to discern from lymphoma (Cunningham-Rundles 2012) (Fig. 10). The word variable in this disorder refers to the variability of disease severity between patients, and not to temporal variability of disease in a single patient. There are two main phenotypes, one in which infections are characteristic and another in which inflammatory or hematologic complications are prevalent (Cunningham-Rundles 2012).

Approximately three-fourths of CVID patients develop a lung disease with air trapping, bronchiectasis, bronchial wall thickening, and endobronchial mucus plugging closely resembling cystic fibrosis (CF) (Fig. 10). Although this CF-like lung disease is associated with obstructive PFTs, it can be asymptomatic and progress silently. The degree of bronchiectasis at presentation inversely correlates with survival, and the disease can be monitored with a CF-like CT scoring system, although there is no consensus on the optimal surveillance strategy (Touw et al. 2010).

Patients with CVID can also develop granulomatous lymphocytic-interstitial lung disease (GLILD) characterized by noncaseating granulomatous and lymphoproliferative histologic patterns. Findings on chest imaging can include pulmonary nodules, consolidation, and ground-glass or reticular opacities (Fig. 11). GLILD can precede the diagnosis of CVID and is associated with restrictive PFTs, a high prevalence of autoimmune disorders and decreased survival (Park and Levinson 2010).

Children affected by Hyper-IgM syndrome are identified by an elevated or normal IgM level and decreased IgG and IgA levels in serum. There is a normal number of circulating lymphocytes but a defect in signaling between T-cells and B-cells that prevents the switch from producing IgM to IgG or IgA. Most commonly, it is related to an X-linked mutation of the CD40L gene encoding a T-cell surface ligand. Presentation is similar to agammaglobulinemia, with recurrent respiratory and gastrointestinal tract infections by encapsulated bacteria, viruses, fungi and parasites. There is a particular susceptibility for P. jirovecii pneumonia (PCP) (Fig. 12). There is also a proclivity for Cryptosporidium-related diarrhea and sclerosing cholangitis, as well as an increased risk of hepatocellular carcinoma (Winkelstein et al. 2003).

Absence of both T-cell and B-cell function results in severe combined immunodeficiency (SCID), the most severe of the primary immunodeficiencies. A number of different genetic defects can cause SCID, including autosomal recessive and X-linked forms (Chan and Puck 2005). Most cases present between 2 and 6 months of age as protection from maternal antibodies wanes. Recurrent, persistent, severe or opportunistic respiratory infections beginning in early infancy along with thrush, dermatitis, chronic diarrhea or failure to thrive should raise suspicion of SCID. Without HSCT, gene therapy or enzyme replacement therapy, SICD is almost uniformly fatal in the first two years of life, making early diagnosis critical to prevent death from overwhelming infection (Griffith et al. 2009).

The primary role of radiology of the thorax in these children is to evaluate infections that are the main cause of mortality. While SCID patients have a diminutive thymus, physiologic thymic involution in response to stress in normal infants limits the use of this finding for suggesting a diagnosis of SCID (Manson et al. 2000) (Fig. 13). The adenosine deaminase (ADA)-deficient form of SCID is of particular note to radiologists because it is associated with a characteristic chondro-osseous dysplasia that manifests with costochondral junction cupping and splaying, concavity of the lateral margins of the vertebral transverse processes and medial margins of the posterior ribs, and thick growth arrest lines (Chakravarti et al. 1991) (Fig. 13).

While the susceptibility to infections may be similar to SCID, there is no lymphopenia in combined immunodeficiency (CID). Some forms of CID have distinctive clinical features. For example, signal transducer and activator of transcription 5B (STAT5b)-deficiency manifest with severe growth hormone-resistant growth failure beginning after birth, recurrent infection, dysmorphic features, atopic disease, autoimmune diatheses, and chronic lung disease beginning in infancy or childhood. The chronic lung disease is typically in the form of LIP (Fig. 14), and can lead to death from respiratory failure (Nadeau et al. 2011).

DiGeorge syndrome (DGS), also known as velocardiofacial syndrome, is a contiguous gene syndrome due to an inherited autosomal dominant or de novo chromosome 22q11.2 deletion. DGS is characterized by maldevelopment of the third and fourth pharyngeal pouches resulting in distinctive facial features (hypertelorism, saddle nose, short philtrum, low-set ears, cleft palate), conotruncal malformations (including tetralogy of Fallot, interrupted aortic arch, or truncus arteriosus), thymic hypoplasia (leading to immunodeficiency from T-cell lymphopenia and dysfunction) and parathyroid hypoplasia (leading to hypocalcemia from hypoparathyroidism) (Demczuk and Aurius 1995). Presentation in the neonatal period is more often due to hypocalcemia-induced seizures than to immunodeficiency.

DGS may be partial or complete. Partial DGS is associated with mild defects in T-cell numbers and highly variable degrees of immunodeficiency. Patients with partial DGS may experience recurrent sinopulmonary infections. Complete DGS is a form of SCID and is associated with severe T-cell deficiency. Patients with complete DGS are susceptible to opportunistic infections and to graft-versus-host disease from nonirradiated blood products (Jawad et al. 2001).

Thoracic imaging findings of DGS may include an abnormal cardiac silhouette related to a conotruncal malformation, a narrow mediastinum related to a small thymus, and pneumonia (Fig. 15). Additional findings may include tracheobronchomalacia and anomalies of the ribs or vertebrae (Ryan et al. 1997).

X-linked gene mutations resulting in aberrant structure of the Wiscott-Aldrich syndrome (WAS) protein are responsible for this immunodeficiency. In addition to a role in immune defense, the WAS protein functions in a pathway that protects against autoimmune disease (Notarangelo et al. 2008). Clinical manifestations of WAS include recurrent infections, eczema, elevated IgA, autoimmune disease (vasculitis, colitis, glomerulonephritis), malignancy (especially non-Hodgkin lymphoma associated with Ebstein-Barr virus), and thrombocytopenia with small platelets. Subtypes exist, with phenotypes ranging from mild intermittent thrombocytopenia to the complete syndrome (Massaad et al. 2013). The association of WAS with abnormal blood clotting that leads to bleeding in the first month of life is unique among the forms of PID. Pulmonary infections with encapsulated Streptococcus pneumoniae and Pneumocystis are common in affected children. Herpes virus infections also occur (Buckley 2004) (Fig. 16). The only curative treatment is HSCT or gene therapy (Aiuti et al. 2013).

Hyper-IgE syndrome (HIES) is characterized by a reduction in CD4+ T-cells, eosinophilia and elevated IgE levels. The autosomal dominant form of HIES, also known as Job syndrome, is due to STAT3 gene mutations (Heimall et al. 2010). Job syndrome is characterized by distinctive facial features (broad nasal bridge, high palate, delayed shedding of primary teeth), eczematous dermatitis beginning in infancy, hyper-extensible joints, osteoporosis, fractures, scoliosis, and recurrent Staphylococcus aureus and Candida infections. Skin infections often begin in infancy and can manifest as “cold” abscesses that lack classical symptoms and signs of inflammation. Sinopulmonary infections are common and can occur in patients who remain afebrile, likely due to the impaired inflammatory response. Thoracic findings include recurrent pneumonia, bronchiectasis, postinfectious pneumatoceles, lymphadenopathy, and esophagitis. Pathologic fractures incurred after mild trauma can mimic child abuse (Woellner et al. 2010; Chandesris et al. 2012) (Fig. 17).

Dyskeratosis congenita (DKC) is a progressive multisystem disorder characterized by the clinical triad of nail dystrophy, lacy reticular skin pigmentation, and oral leukoplakia. Additional features may include developmental delay, short stature, cerebellar hypoplasia, esophageal stenosis, urethral stenosis, osteopenia, liver fibrosis, and pulmonary fibrosis. DKC is most often attributable to mutations in genes involved in telomere maintenance, and inheritance may follow an X-linked, autosomal dominant or autosomal recessive pattern. Patients with DKC are at very high risk of aplastic anemia, myelodysplastic syndrome, leukemia, and squamous cell carcinoma. The bone marrow failure does not respond to immunosuppressive therapy (Savage and Alter 2009). Pulmonary fibrosis is a serious complication and accounts for more than 15 % of deaths in DKC. The pulmonary fibrosis occurs earlier in DKC patients who undergo HSCT and is rapidly progressive with a median survival of less than 2 years after onset of pulmonary symptoms. The presenting features of DKC-related pulmonary fibrosis include persistent dry cough, progressive dyspnea, restrictive PFTs, markedly reduced D_LCO, and patchy or diffuse interstitial pulmonary opacities on CXR or CT (Giri et al. 2011) (Fig. 18).

Ataxia-telangiectasia (AT) is attributable to autosomal recessive mutations in the ATM gene that encodes a DNA damage response protein. Patients with AT have aberrant T-cells which results in onset of immunodeficiency in infancy. Cerebellar ataxia manifests at toddler age, and is often misdiagnosed as cerebral palsy. Oculocutaneous telangiectasias begin to appear at 3–6 years of age, while growth retardation develops later in childhood. An elevated AFP is characteristic and AFP testing in children with persistent ataxia is advised to avoid diagnostic delay (Cabana et al. 1998). Recurrent sinopulmonary bacterial infections and noninfectious granulomatous inflammation of various tissues are typical. In children and adolescents with AT, S. aureus, H. influenzae, and S. pneumoniae are the predominant respiratory infectious agents, while opportunistic infections are not observed (Schroeder and Zielen 2013). There is extreme susceptibility to DNA damage from ionizing radiation and a high risk of cancer, especially lymphoma, leukemia, and leiomyosarcoma. Life expectancy is only 20–30 years due to the increased mortality from cancer and respiratory disease (Micol et al. 2011).

Thoracic imaging findings can include a small thymus, recurrent pneumonia, bronchiectasis, lymphadenopathy, and a chronic interstitial lung disease unique to ataxia-telangiectasia (AT-ILD). AT-ILD is characterized by lymphocytic infiltrate, bizarre atypical cells, and fibrosis resulting in interstitial and pleural thickening, restrictive PFTs, chronic cough, fever, dyspnea, and an inability to reinflate the lung after pneumothorax (Fig. 19). AT-ILD has a mean age of onset of 17.5 years and a prevalence of at least 25 % in AT patients (Schroeder et al. 2005). Progressive clinical deterioration and death usually ensue within 2 years of diagnosis of AT-ILD, unless steroid therapy is initiated within the first year of onset (McGrath-Morrow et al. 2010).

Due to a defect in the nicotinamide adenine dinucleotide phosphate-oxidase (NAPDH) complex, the phagocytes in children with chronic granulomatous disease (CGD) are unable to generate the superoxide burst necessary for killing ingested micro-organisms. CGD occurs in both X-linked and autosomal recessive forms, with the former being more common and severe.

Symptoms or signs of CGD often develop in the first 2 years of life. Presentation and ongoing complications are related to granuloma and abscess formation. These manifestations are likely due to ongoing inflammatory response to viable microorganisms. Histopathologic studies have shown that the granulomas in these patients may contain relatively few organisms and that the predominant portion of the granulomas results from the exuberant inflammatory response (Moskaluk et al. 1994).

Catalase-positive S. aureus is the most commonly cultured organism in the granulomas. Burkholderia and Serratia are also frequently isolated, while Streptococcus is relatively rare. Fungi and atypical mycobacteria are other causes of infection. Children with CGD are at high risk for invasive aspergillosis, which is the most common cause of mortality (Tabone 2003).

The lungs are the most common site of involvement, with pneumonia occurring in 80 % of patients (Mahdaviani et al. 2013). Lung findings on CT vary depending on the infectious organism and disease chronicity, and may include consolidation, ground-glass opacities, centrilobular opacities, nodules, bronchiectasis, septal thickening, cysts, and parenchymal distortion (Towbin and Chaves 2010). Chronic lung involvement may lead to pulmonary fibrosis, honeycombing, pulmonary hypertension, and development of systemic blood supply to areas of pulmonary infection (pseudo-sequestration) (Matsuzono et al. 1995). Extrapulmonary thoracic manifestations include suppurative lymphadenopathy, pleuritis, empyema, and rib or vertebral osteomyelitis (Khanna et al. 2005). Infections involving both the lungs and the chest wall are highly suggestive of the diagnosis of CGD (Fig. 20). Fluorodeoxyglucose-positron emission tomography (FDG–PET) is more reliable than CT for distinguishing active disease from quiescent disease or scarring (Fig. 21), an important distinction for evaluating therapy response, identifying sites for biopsy or surgical debridement, and planning for HSCT (Gungor et al. 2001) (Fig. 21).

In the Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV (P²C²) Study from the 1990s, pulmonary infection was the most common cause of death, especially in infants and young children (Langston et al. 2001). Since then, there has been a marked decrease in opportunistic pulmonary infections and deaths related to acquired immunodeficiency syndrome (AIDS) in developed countries as a result of the implementation of highly active antiretroviral therapy (HAART) (Gona et al. 2006). Even in developed countries, though, vigilance for opportunistic infections remains important due to noncompliance and drug resistance.

Although HAART has reduced rates of opportunistic infection, bacterial pneumonia still tends to be more severe in HIV-infected children than in HIV-uninfected children related to a higher incidence of abscess and empyema. Streptococcus is the most common pathogen, and manifests as lobar or multilobar patchy consolidation. Mycobacterial infection is more likely to be multilobar or miliary, and is associated with necrotic lymphadenopathy. Pneumonias from respiratory syncytial virus (RSV), cytomegalovirus (CMV), parainfluenza, influenza, adenovirus, or human metapneumovirus infections have diverse radiographic appearances that can be indistinguishable from bacterial pneumonias. A patient age of less than 6 months, a respiratory rate >59 breaths/minute, an O₂ saturation <93 %, and an absence of vomiting are clinical features that suggest P. jirovecii pneumonia (PCP), which classically manifests with bilateral diffuse or patchy ground-glass or reticulonodular opacities with perihilar to peripheral progression, although this appearance overlaps with mycobacterial and viral pneumonia. PCP can also be associated with pulmonary cysts that rupture, leading to pneumothorax or pneumomediastinum (George et al. 2009).

Lymphocytic interstitial pneumonitis (LIP) is a form of pulmonary lymphoid hyperplasia characterized by infiltration of the interstitium by lymphocytes and plasma cells and classically presenting in HIV-infected children older than 2 years of age with chronic or recurrent cough and mild hypoxemia (Theron et al. 2009). The 1987 CDC criteria for a presumptive diagnosis stipulate the persistence of diffuse, symmetrical, reticulonodular or nodular pulmonary opacities for at least 2 months without an identifiable pathogen, or a response to antibiotic therapy (Pitcher et al. 2010). CT reveals nodules in a subpleural, septal, centrilobular, or peribronchial distribution, and ground-glass opacities with or without lymphadenopathy (Becciolini et al. 2001) (Fig. 22). Bronchiectasis and cystic dilated air spaces have also been described (Pitcher et al. 2010). Resolution of LIP in children can be due to response to HAART or corticosteroid therapy, or to immunologic deterioration and progression of HIV disease (Theron et al. 2009).

The immune reconstitution inflammatory syndrome (IRIS) is an exaggerated inflammatory response by the reconstituted immune system occurring 1–6 months after HAART initiation, resulting in apparent clinical worsening. “Unmasking” IRIS occurs in response to a previously unrecognized underlying infection, while “paradoxical” IRIS occurs in response to a previously treated infection. IRIS is most frequently observed in response to mycobacterial, herpes virus, JC virus, PCP, and cryptococcal infections, and can appear as new or worsening lymphadenopathy, pulmonary nodules, or pulmonary consolidation on imaging. IRIS must be distinguished from noncompliance, drug resistance, or newly acquired opportunistic infection, and is treated by NSAIDs, steroids, and discontinuation of HAART (Theron et al. 2009).

A high incidence of swallowing dysfunction and gastroesophageal reflux predisposes to aspiration pneumonia in HIV-infected children. These children may also suffer from odynophagia and dysphagia related to esophagitis caused by Candida or CMV infection. HIV-related cardiomyopathy, antiviral therapy cardiotoxicity, accelerated atherosclerosis and chronic anemia can lead to cardiac failure and pulmonary edema that is misattributed to primary pulmonary infection (Pitcher et al. 2009). In addition, HIV infection is associated with an increased risk of thymic cysts and non-Hodgkin lymphoma, which are covered in the chapter entitled Imaging of the Pediatric Thymus and Thymic Disorders by Sams and Voss, as well as smooth muscle tumors, which are covered in the chapter entitled Pulmonary and Extra-Thymic Mediastinal Tumors by Lyons, Guillerman and McHugh.

Neutropenia is common in children undergoing chemotherapy for cancer or allogeneic HSCT, and confers a high risk of invasive fungal disease (IFD) by mold (most frequently Aspergillus) or yeast (most frequently Candida). The lungs are the most common site of deep organ involvement by IFD. In a neutropenic patient with fever or respiratory symptoms or signs, the traditional approach has been to obtain a CXR, give early empiric broad-spectrum antibacterials, and add empiric antifungals for suspected invasive fungal disease (IFD) if the fever or respiratory symptoms or signs persist >96 h. In the presence of a deficient immune response, findings of infection are often absent or subtle and nonspecific on CXR, so that chest CT is preferred. However, even the yield of chest CT is low in this setting. In a study of 52 pediatric oncology patients with persistent febrile neutropenia, only 18 % of the initial (mean of 5 days of febrile neutropenia) CT scans were positive, and alterations in therapy were made in only 3 % based on the findings of initial CT. Repeat (mean of 17 days of febrile neutropenia) CT had a much higher yield, being positive in 52 % of cases and directing a change in therapy in 20 %. Respiratory symptoms or signs were present in only a minority of cases with a positive chest CT, while all patients with a concern for occult IFD had findings on chest CT, suggesting that initial chest CT should be limited to patients without localized signs or symptoms (Agrawal et al. 2011).

Rather than administering empiric antifungals in all patients at risk with persistent febrile neutropenia, a “pre-emptive” or “diagnostic-driven” approach of administering antifungals only in the setting of either microbiologic (cytology, direct microscopy, culture, ß-D-glucan or galactomannan assay of serum, or bronchoalveolar lavage fluid) or chest CT evidence of probable IFD may reduce unnecessary therapy without compromising prognosis (Castagnola et al. 2014). The European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC-MSG) chest CT criteria for probable IFD are the presence of well-circumscribed pulmonary lesions (with or without a “halo” sign), an “air-crescent” sign, or a cavity in the appropriate clinical setting (De Pauw et al. 2008).

The “halo” sign consists of a ground-glass halo of alveolar hemorrhage around a nodular or consolidative focus of infarcting lung from fungal vascular invasion and thrombosis that occurs early in IFD. A “reversed halo” sign of focal ground-glass opacity surrounded by a crescent or ring of consolidation may also be observed with early IFD (Georgiadou et al. 2011). An “air-crescent” sign or cavitation is the result of neutrophil recovery with release of proteases that resorb necrotic tissue (McAdams et al. 1995). In the course of IFD, a “halo” sign, nodule, or consolidation is typically visible on chest CT within 5 days of fever onset (Fig. 7). Early initiation of antifungals based on detection of the “halo” sign on chest CT is associated with better response to treatment and improved survival (Greene et al. 2007). Despite effective antifungal therapy, an increase in lesion number and size may be observed for 7–10 days followed by a plateau for a few days, and should not be confused for progressive disease. The “air-crescent” sign and cavitation develop in 2–3 weeks, dependent on the timing of neutrophil recovery (Caillot et al. 2001) (Fig. 7). Refractory IFD is suggested by no decrease in lesion number or size or by lack of development of an “air-crescent” sign or cavitation after 2–3 weeks, but initial or maximal lesion size or number does not impact outcome (Horger et al. 2005). After 2–3 weeks, reappearance of a “halo” sign, development of new lesions, or an increase in wall thickness of a cavitary lesion suggests relapsed or new infection (Fig. 7). Even after clinical remission, there may be fibrotic or thin-walled cavitary remnants visible on chest imaging (Gefter et al. 1985).

The chest imaging findings of IFD are not entirely specific and can also be observed in immunocompromised children with Myobacterium, Nocardia, Pseudomonas, or herpes virus infections (Gasparetto et al. 2008). Following allogeneic HSCT, children are susceptible not only to opportunistic pulmonary infections, but also to noninfectious pulmonary disorders such as alveolar hemorrhage, pulmonary edema, drug reaction, lymphoproliferative disease, organizing pneumonia, bronchiolitis obliterans, graft-versus-host disease, and idiopathic pneumonia syndrome. These disorders can cause considerable morbidity and mortality in the post-transplant setting, and can be difficult to distinguish on the basis of imaging findings, so that correlation with clinical features, identification of risk factors and institution of preventative measures are paramount in management (Sakaguchi et al. 2012).