Introduction

Primary immunodeficiency diseases (PIDs) are a heterogeneous group of disorders caused by genetic defects affecting the innate and/or adaptive immune system. PID, also known as inborn errors of immunity, manifests as increased susceptibility to infectious diseases, autoimmunity, autoinflammatory diseases, allergy, and malignancy.¹

The respiratory system is one of the most prominent organs causing morbidity and mortality in PIDs. Early diagnosis and treatment of pulmonary complications in PIDs can prevent or slow the development of respiratory complications.²

Comparative studies on the clinical and radiological features of pulmonary complications in adult patients with PID are limited, and so increasing knowledge and providing optimum patient management are critical for extending life expectancy in these patients. Hence, investigating radiological lung findings was the aim of this study for better understanding and early identification of pulmonary complications in adult patients with PID and evaluate the possible relationship between clinical and immunological features and pulmonary function.

Materials and Methods

Study design

This retrospective study was conducted at the Necmettin Erbakan University Faculty of Medicine, Adult Immunology and Allergy Clinic; approved by the local Ethics Committee (Decision No.: 2023/4355); and adhered to all relevant tenets of the Declaration of Helsinki (1975). About 137 adult patients with PID were retrospectively reviewed and followed-up at our institution between 2012 and 2022. When a genetic diagnosis was not available, it was defined according to the criteria of the European Society for Immunodeficiencies (ESID) Registry Working Group.³ When the review was complete, 116 patients with common variable immunodeficiency (CVID), X-linked agammaglobulinemia, selective immunoglobulin A (IgA) deficiency, natural killer (NK) deficiency, hyper-IgE (immunoglobulin E) syndrome, ataxia-telangiectasia syndrome, and severe combined immunodeficiency were included in the study (Figure 1). Their clinical characteristics, laboratory data, high-resolution computed tomography (HRCT), and pulmonary function tests (PFT) were evaluated.

Figure 1 Flow chart of the patients included in the study.

Data collection

Data on the age, sex, age at the time of diagnosis, delay in diagnosis, follow-up time, complaints at admission, smoking status, concomitant autoimmune disease, malignancy, and mortality of the 116 adult PID patients were collected from the hospital’s electronic medical record and archive system. In the initial diagnosis stage, serum immunoglobulin G (IgG), IgA, immunoglobulin M (IgM), IgE, total T cell (cluster of differentiation [CD]3⁺), helper T cell (CD3⁺CD4⁺), cytotoxic T cell (CD3⁺CD8⁺), CD4⁺/CD8⁺ ratio, total B cell (CD19⁺), class-switched memory B (cSMB) cell (CD19⁺CD27⁺IgD^–), NK (CD3^–CD16⁺CD56⁺) cell levels, antibody responses specific to protein and polysaccharide vaccines (tetanus and pneumococci), and isohemagglutinin titers (Anti-A, Anti-B) were recorded. Patients with HRCT in the stable period of the diagnostic process were screened. It was observed that a group of patients underwent PFT during the symptom-free period due to differences in clinicians’ approaches to the follow-up process. Sixty-seven patients who underwent PFT with the appropriate technique were identified and evaluated; those with both solitary fibrous tumor (SFT) and HRCT were evaluated separately.

Serum immunoglobulin measurements

Serum immunoglobulin (Ig) levels were determined using a nephelometric analyzer (Siemens BNII System, Erlangen, Germany).

Specific antibody responses

Pneumococcal polysaccharide antibody titers were measured using a multiplex immunoassay (Elizen, Angleur, Belgium). An impaired response to the Pneumovax-23 vaccine was considered if the postvaccination titer was < 250 mU/mL or less than a twofold increase from the prevaccination titer. Tetanus antitoxin IgG Enzyme-Linked Immunosorbent Assay (ELISA) kits (Novalisa, Vienna, Austria) were used to detect tetanus antibodies. Tetanus antitoxin IgG was recognized as an antibody at a protective level of ≥ 0.1 IU/mL.

Isohemagglutinin titer

To measure the isohemagglutinin titer, blood samples in ethylenediaminetetraacetic acid (EDTA) tubes were centrifuged at 5000 rpm for 1 minute, and then the separated plasma was diluted with saline for titration. Titers ≥ 1:8 were considered normal.

Flow cytometric analysis

Peripheral blood samples (2 mL) were collected in tubes anticoagulated with EDTA and tested within 6 hours. Lymphocyte subsets were measured by multicolor flow cytometry using a key panel. The cells were analyzed on a Becton, Dickinson and Company fluorescence-activated cell sorting (BD FACS) Canto II Flow Cytometry System (BD Biosciences, San Jose, CA, USA).

Spirometric analysis

Spirometric measurements were obtained with an nSpire ZAN 100 spirometer (Health Inc., Oberthulba, Germany). The forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and maximal mid-expiratory flow at 25–75% (MMEF25–75) were recorded for each patient. Abnormal lung function was defined as FEV1, FVC, or FEV1/FVC ratio less than 80% or less than 70% predicted for MMEF 25–75. Obstructive, restrictive, and mixed respiratory dysfunction patterns were determined using the American Thoracic Society recommendations.⁴

High-resolution computed tomography scans

Infection-free state and stable period HRCT scans taken during the diagnostic process were obtained. Parenchymal and interstitial findings in the upper, middle, and lower lobes of the lungs and mediastinal lymph nodes were evaluated and divided into two groups: those with and those without radiological lung findings.

Statistical analysis

IBM SPSS (Statistical Package for the Social Sciences) Statistics for Windows 22.0 (IBM Corp., Armonk, NY, USA) was used for the statistical analysis. Continuous variables were expressed as medians with interquartile ranges (IQR: 25th to 75th percentiles) and categorical variables were expressed as numbers and percentages for each category. According to the presence of radiological lung findings, the Mann–Whitney U test was used to evaluate continuous data. Categorical variables were assessed using the Pearson’s chi-squared or Fisher’s exact tests where P ≤ 0.05 was considered as statistically significant.

Results

Clinical and laboratory characteristics of the patients

This study included 116 adult patients with PID. The median age was 40 (range: 28–48) years and there were 51 (44%) females. Moreover, 78.4% presented with infectious causes. The most common type of PID was CVID (72.4%). Subcutaneous or intravenous Ig replacement therapy (IgRT) was given to 86.2% (100/116) of the patients and both IgRT and antibiotic prophylaxis were given to 68.1% (78/116). General characteristics of the patients and immunological parameters at the time of diagnosis are shown in Tables 1 and 2.

Evaluation of the radiological findings

When the HRCTs were evaluated, 64 (55.2%) patients had radiological lung findings where bronchiectasis was the most common (30.2%) and where they were commonly bilateral (73.5%). Unilateral involvement was commonly observed in the right lung (15.6%). The most commonly affected lobe was the lower lobe at a rate of 31.3%, whereas two to three lobes were involved together in 42.2% of the patients. There were two (1.9%) patients who were histopathologically diagnosed with granulomatous lymphocytic interstitial lung disease (GLILD) (Table 3).

Relationship between the pulmonary radiographic findings and pulmonary function tests

PFT was performed on 67 patients using appropriate techniques and compliance. Of these, 24 (35.8%) had normal PFT findings, 23 (34.3%) had obstructive findings, 13 (19.4%) had restrictive findings, and 7 (10.4%) had mixed pattern respiratory dysfunction. The MMEF 25–75 was low in 35 (52.2%) patients. The group with HRCT findings had abnormal PFT findings but no statistically significant difference was observed (P = 0.28). However, when the PFT parameters were compared individually between the two groups, the FVC and MMEF 25–75 values were significantly lower (P = 0.039 and P = 0.048, respectively) (Table 4).

Relationship between the pulmonary radiographic findings and clinical and laboratory findings

The median age and age at the time of diagnosis were significantly older in the group with HRCT findings (P = 0.02 and P = 0.04, respectively). Also significantly lower were serum IgG, IgA, IgM, CD4⁺ T cell, CD4⁺/CD8⁺ ratio, and cSMB cell levels; the mortality rate was higher (P = 0.01). No significant correlation was found between the two groups in terms of the smoking status, PID type, concomitant autoimmune disease, and malignancy (Table 5).

Discussion

Radiological lung findings in adult PID patients were investigated herein, and the relationship between their HRCT findings and clinical features, delay in diagnosis, immunological parameters, PFT, and mortality were evaluated. The most common radiological finding was bronchiectasis, where the bilateral and lower lobe involvement was more predominant. The obstructive pattern was the most common among those who underwent PFT, and those with HRCT findings, the obstructive pattern was also the most common; the decrease in the FVC and MEF 25–75 was significant. It was also observed that the mean age and age at the time of diagnosis were older, serum Ig, CD4+ T cell, CD4+/CD8+ ratio; cSMB cell levels were significantly lower; and mortality was higher in the PID patient group with HRCT.

PID has a reported prevalence of between 1:16,000 and 1:50,000. The International Union of Immunological Societies updated the number of PIDs to 485 in 2022, but it suspects that 70–90% of patients are undiagnosed.⁵ Delayed diagnosis remains a problem in adult patients with PID, often due to lack of awareness. The delay in diagnosis has been reported to be 5.5 years for primary antibody deficiencies (PADs),⁶ 4 years for CVID,⁷ and in this study, the mean delay in diagnosis was 3 years. Our lower diagnostic delay time was attributed to the fact that our study included PID patients other than CVID and that these patients presented in childhood and were diagnosed early.

PID awareness studies have reported that patients with PID may present with symptoms of immune dysregulation. In a study of 16,486 PID patients compiled from the ESID registry data, 77% presented with infection and 18% with immune dysregulation.⁸ In this study, infectious causes were observed in 78.4% of the initial presentations and noninfectious causes in 21.6%. Autoimmune conditions were found to accompany 31.9% of the patients, supporting the consideration of autoinflammatory events in terms of PID. The lower frequency of PIDs presenting with autoimmunity is due to the lack of awareness of clinicians and limited diagnostic possibilities for autoinflammatory events. However, thanks to recent developments, the relationship between immune dysregulation and immunodeficiencies is increasingly being elucidated, suggesting that the number of PIDs presenting with autoimmunity will increase.⁹

Antibody deficiencies are the most common among PIDs, and the most common symptomatic antibody deficiency is CVID, which is seen in approximately 75% of cases.¹⁰ Although PIDs are generally considered to be pediatric diseases, CVID is mostly diagnosed in adults.¹¹ In this study, the prevalence of CVID was 72.4%, which was similar to that reported in literature.

It has been proven that there is an increased prevalence of lung disease in adult patients with PID compared to pediatric patients,¹² with radiological lung findings accompanying in approximately 60% of cases.¹³ In this study, abnormal findings on HRCT were detected in 55.2% of patients. Similar to the literature, no significant difference was found between the patients with HRCT findings and the delay in diagnosis;^14,15 however, the median age and age at the time of diagnosis were significantly older. This supports the hypothesis that longer exposure of adult patients to infections and subclinical ongoing autoinflammatory processes may cause chronic damage to the lung.¹⁶ The risk of chronic lung disease increases with the duration of the disease, independent of IgRT; however, it has not been reported to depend on age at the time of diagnosis.¹⁶ Additionally, in this study, 63.2% of the patients had HRCT findings despite receiving antibiotic prophylaxis with IgRT. Despite IgRT and prophylactic antibiotics, the development of structural airway disease appears to progress.¹⁶ Additional factors such as underlying subclinical infection, immune dysregulation, and comorbidities contribute to this.^13,16 Subclinical infections have been detected in patients with PAD and a number of bacteria and viruses have been identified even when patients were not actively infected.¹⁷ Although early intervention with prophylactic antibiotics and/or IgRT can prevent respiratory infections and pulmonary disease morbidity and mortality, chronic lung disease advances in many patients.¹⁸ Conventional chest X-ray imaging detects only one-third of bronchiectasis lesions, even the most common lung finding.⁷ Even in PADs without respiratory symptoms, chest CT and PFT are recommended to look for evidence of chronic lung disease.¹⁰ This will enable radiologists to better assess the spectrum of initial and progressive CT manifestations of pulmonary complications of PIDs.¹⁹ With advances in diagnosis and treatment, an increasing proportion of PID patients now survive into adulthood. Earlier diagnosis may lead to better management of the disease.¹⁹ Therefore, active and accurate screening is mandatory even in well-controlled patients, but the lack of standardized protocols for follow-up is a major challenge to the identification and treatment of pulmonary complications.¹⁰ As chest screening with HRCT has shown that patients with PAD have a much higher proportion of interstitial lung disease (ILD) and bronchiectasis than previously estimated, accurate diagnosis is crucial, especially for the treatment of ILD.²⁰

Pulmonary complications such as bronchiectasis, peribronchial thickening, air trapping, bronchiolitis, atelectasis, and parenchymal nodules have been demonstrated in PID.²¹ In a cohort study of 117 patients with PID, bronchiectasis was the most common HRCT finding (58.3%), followed by bronchial wall thickening (22.9%) and consolidation (18.8%). It was proven that 64.3% of HRCT findings were bilateral and the right middle lobe was the most commonly affected.²² Other previous studies have shown that bronchiectasis and bronchial wall thickening were the most common findings (14–60%) and the middle or lower lobe was the most commonly affected.^21,23 (21, 23). In this study, the most common radiological finding in all of the PIDs was bronchiectasis (30.2%), followed by sequel fibrotic changes (28.4%) and bronchial wall thickening (17.2%). Unlike previous studies, bilateral involvement was observed more frequently (73.1%). In unilateral involvement, the right lung (15.6%) was dominant. Regarding lobe dominance, lower lobe involvement (31.3%) was predominant, followed by middle-lower lobe (25%). There are not enough studies on the dominant lobe in adult PIDs in literature. However, the fact that bronchiectasis is most commonly seen in the lower lobes supports this.²⁴ It has also been shown that the course of bronchiectasis associated with PAD is similar to bronchiectasis caused by other causes.²⁵ Standardized HCRT scoring methods are needed for effective screening and follow-up of pulmonary complications associated with CVID, especially since CVID is common in adults.^26,27 To help assess lung disease progression in these patients, the scoring system should be based on abnormalities specific to PADs rather than adapted from other diseases such as cystic fibrosis. A scoring method was developed in a study of pediatric patients with stable CVID or CVID-like disorders.²⁷ However, more studies are needed in this regard in adult PID.

Bronchiectasis is less common in selective IgA deficiency than in XLA (an inherited immune disorder caused by an inability to produce B cells or the immunoglobulins [antibodies] that the B cells make) and CVID.²⁸ In this study, the HRCT finding was 60.9% in the antibody deficiency group and lower (37.5%) in the selective IgA deficiency group. This supports the opinion that selective IgA deficiency patients can produce IgG antibodies and are less prone to pulmonary infections.²⁸ The respiratory surface in the upper and lower airways is predominantly covered with secretory IgA (sIgA) and IgM, while IgG is the predominant isotype in the alveolar space.²⁹ Both sIgA and IgM on the bronchial surface originate mostly from mucosa-associated lymph tissue rather than from the systemic circulation.³⁰ Alveolar IgG originates from the systemic circulation by passive diffusion and effectively prevents bacterial infections such as pneumonia.³¹ Since individuals with selective IgA deficiency are generally healthy, sIgA appears to play a negligible role in airway defense. However, the observation that patients with CVID suffer more severely from airway infections than those with very low IgA levels compared to those with higher IgA levels suggests that IgA may at least partially compensate for IgG deficiency in airway defense.³²

GLILD, which is usually specific to CVID, develops in approximately 10% of patients.³³ Impaired T cell function in CVID is a factor in granuloma formation and increased incidence of lymphoproliferative disease, supported by the fact that GLILD is not seen in XLA.³⁴ In this study, GLILD was detected only in CVID. This rate was lower than those reported in the literature and was probably due to the limited possibilities of histopathological diagnosis. The presence of GLILD decreases survival.²⁰ The fact that one of the two GLILD patients in this study died at a young age supports this. As ILD appears asymptomatic in its initial phase, screening all patients with CVID may facilitate early disease detection and enable early treatment that may be less aggressive.²⁶

In a study evaluating the PFTs of CVIDs, 60% abnormality was found (38.8% obstructive, 44.4% restrictive, and 16.7% mixed pattern);³⁵ however, another study found 34.5% obstructive, 17.2% restrictive, and 7.4% mixed patterns, similar to the results herein.²² Additionally, studies comparing the PFTs of patients with and without HRCT findings generally showed a weak correlation.^15,35 In this study, PFT abnormalities were more common in the group with HRCT findings and the rate was higher than that reported in literature. Furthermore, a significant decrease in the FVC and MMEF 25–75 parameters were observed. In contrast to our study, in patients with PAD, the decline in FEV1 has been shown to be a more sensitive indicator of pulmonary function than FVC, as expected due to the obstructive nature of bronchiectasis. As in bronchiectasis of all causes, a reduction in the MMEF 25–75 in PID indicates early airway disease in the small airways or bronchioles and may precede other changes in lung function.³⁶ A decrease in MMEF-25-75 may be a harbinger of low FEV1 that may develop later in the disease. Alongside general clinical assessment and physical examination, lung function tests provide useful information about lung performance and the extent and progression of chronic lung disease in patients with PAD. The rate of decline in lung function in PAD is much faster than predicted in both healthy individuals and smokers.³⁷ Therefore, at least annual PFT follow-up (including DLCO [diffusing capacity of the lungs for carbon monoxide] if possible) is recommended.³⁸

In adults with CVID, low IgM, IgG, and cSMB levels were associated with recurrent lower respiratory tract infections, chronic lung diseases, and HRCT abnormalities.^39,40 It has been shown that the absolute numbers of CD4⁺ T cells, naive CD4⁺ T cells, naive CD8⁺ T cells, and cSMB cells are significantly reduced in patients with severe HRCT findings. The absolute number of CD4⁺ T cells and naive CD4⁺ T cells were found to have the highest sensitivity and positive predictive value in identifying patients at risk of ILD.¹⁵ Similarly, in this study, the serum IgG, IgA, IgM, CD4⁺ T cell levels, CD4⁺/CD8⁺ ratio, and cSMB cell levels at diagnosis were significantly lower in the patients with HRCT findings. The low level of these parameters supports the literature and suggests that they may predict the risk of ILD; however, more prospective studies are needed.

Noninfectious pulmonary complications in PAD are common and contribute significantly to morbidity. In CVID in particular, two independent studies have shown that patients with disease-related noninfectious complications have a significantly worse survival prognosis than those without complications. The risk of death was estimated to be 11 times higher than in patients with infection alone.^41,42 The US Immunodeficiency Network database reported the overall mortality in PIDs as 8.7%⁴³ and the ESID Registry Network database reported it as 9.2%.⁴⁴ In more than one-third of these patients, mortality was due to respiratory causes.^11,13 In a study conducted in the Middle East and North Africa (MENA), the general mortality rate was 15.8%, where 27.6% was due to respiratory failure.⁴⁵ In this study, overall mortality was 15.5% and mortality due to respiratory causes was 32.2%, similar to that in MENA. The high mortality rate was thought to be due to the lack of funding for newborn screening, availability of genetic testing, and difficulties in accessing advanced treatment modalities.

This study had limitations. First, it was a retrospective and cross-sectional study. Second, clinical and laboratory diagnostic criteria were used in those without a definitive genetic diagnosis. Third, it was not possible to determine at what point HRCT abnormalities develop and assess progression. Adequate and equal periods of time were not available to follow the development of radiologic findings, the exact number of previous lower respiratory tract infections could not be determined, and SFTs could not be performed in all patients. Therefore, further follow-up studies are needed to evaluate the progression of preclinical pulmonary abnormalities and the development of clinical disease and its association with risk factors.

In conclusion, despite these limitations, very few studies have investigated the relationship between radiological lung findings and clinical features, respiratory functions, and immunological parameters in adult patients with PID. Therefore, the results of this study could shed light on future studies, taking into account the aforementioned limitations. Thus, the development of irreversible noninfectious pulmonary complications may be limited and early deaths due to lung disease could be prevented.