A case report of X-linked agammaglobulinemia complicated with necrotic pneumonia

Introduction

X-linked agammaglobulinemia (XLA, MIM 300755) is one of the primary humoral immune deficiency diseases caused by a B-cell developmental disorder. It is also attributed to the variation of the Bruton tyrosine kinase (BTK) gene located on the Xq21.3–Xq22 region of the chromosome. Its characteristics include recurrent bacterial infections, immune deficiency, low B-cell count, and low immunoglobulins. Currently, there are rare reports on the association of necrotizing pneumonia (NP) with XLA caused by BTK gene mutations. The clinical data and genetic test results of our patient are reported below in order to enhance clinicians’ understanding of this disease. We present this case in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-353/rc).

Case presentation

An 8-year-old male patient was admitted to our pediatric department, presenting with “recurrent cough, chest pain, and fever for 1 month” (Figure 1).

Figure 1 Timeline of treatment. CT, computed tomography.

One month prior, the child developed right-sided pleuritic chest pain, paroxysmal cough with yellow purulent sputum, and fever (without wheezing). He was evaluated at a provincial children’s hospital, where a chest computed tomography (CT) revealed pulmonary infection, right lung consolidation, and right pleural effusion. Bronchoalveolar lavage (BAL) identified Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas aeruginosa. After 3 weeks of antibiotic therapy, his condition improved, and he was discharged.

However, 3 days before re-admission, symptoms recurred, including right-sided chest pain (worsened by coughing), productive cough with purulent sputum, and fever. A repeat chest CT showed progressive right lung infection and pleural effusion, prompting referral to our hospital. Non associated symptoms: sore throat, rash, headache, vomiting, abdominal pain, diarrhea, or night sweats. Past medical history: generally healthy until 1 year ago, when he experienced post-coronavirus disease 2019 (COVID-19) deterioration in health. Six months prior: hospitalized for severe pneumonia (BAL-confirmed H. influenzae infection), treated with bronchoscopy and antibiotics. Chronic conditions: chronic rhinitis, bilateral otitis media with tympanic membrane perforation, recurrent finger abscesses requiring incision/drainage and digital clubbing. The parents were healthy, and there were no siblings.

Physical examination on admission: temperature: 38.5 ℃, respiration: 52 times/min, heart rate: 142 times/min, blood pressure: 119/75 mmHg (1 mmHg =0.133 kPa), height: 124 cm (−1.5 standard deviation), weight: 21.5 kg. Blood oxygen saturation under normal atmospheric inhalation: 92%, conscious. Alert but fatigued, mild tachypnea, no pharyngeal congestion or lymphadenopathy. Respiratory: coarse breath sounds bilaterally, dry rales in the left lung, wet rales in the right lung. Cardiovascular/abdomen: normal heart sounds, soft/non-tender abdomen, no hepatosplenomegaly. Extremities: digital clubbing observed; no edema. Laboratory findings: blood routine: white blood cells 7.6×10⁹/L, neutrophils (%) 57.7%, lymphocytes (%) 33%, hemoglobin 87 g/L, platelets 202×10⁹/L, C-reactive protein 80.4 mg/L, procalcitonin 0.33 ng/mL, erythrocyte sedimentation rate 49 mm/h. Blood biochemistry: albumin 37 g/L, total protein 52 g/L, other normal. Positive DNA of Mycoplasma pneumoniae. Blood gas analysis, anti-chain O, tumor markers, thyroid function, serum ferritin, preoperative four items, allergen detection, blood culture, sputum culture, adenovirus, respiratory syncytial virus, influenza virus, TB-spot, 1,3-β-D glucose test: all negative. Pleural fluid analysis (thoracentesis): appearance light red, rivalta test (+), 520 nucleated cells/µL (60% lymphocytes). Biochemistry: protein 32.3 g/L, glucose 3.5 mmol/L. Cultures/TB/metagenomics: negative. Immunoglobulins: immunoglobulin M (IgM) <17.5 mg/dL (50–260 mg/dL), immunoglobulin A (IgA) <26.1 mg/dL (85–170 mg/dL), immunoglobulin G (IgG) <146 mg/dL (790–1,307 mg/dL). Lymphocyte subsets: B cells: 0.00% (reference range 3.0–19.0), B lymphocyte absolute number 0/µL (reference range 90–560), NK cell absolute number 80/µL (150–1,100), Total T lymphocyte percentage 96% (reference range 50–87), Total T lymphocyte absolute number 2,227/µL (reference range 955–2,860), B cell count 0 does not match the common variant immunodeficiency disease. Whether the child has primary humoral immune deficiency was further confirmed by genetic testing (Figure 2). The result showed that the child had a BTK gene mutation BTK; NM_000061.2: c.655delG (p.Val219Leufs*10) (Figure 2A). The final diagnosis was XLA.

Figure 2 The genetic testing report of the patient and the verification genetic report of the mother. (A) Genetic testing of the proband. (B) Genetic testing verified by the proband’s mother. BTK, Bruton tyrosine kinase.

On the 10^th day of hospitalization, a bronchoscopy with BAL was performed. No Cryptococcus or acid-fast bacilli were found, but Gram staining showed a small number of Gram-negative bacilli. Subsequently, Pseudomonas aeruginosa was cultured positively. Thoracic ultrasound demonstrated loculated right pleural effusion (2.3 cm maximal depth) with minimal left-sided effusion (0.4 cm). Pulmonary function tests indicated severe mixed ventilatory dysfunction with negative bronchodilator response. On the fifth day of hospitalization, an enhanced CT scan indicated extensive bronchiectasis with both columnar and cystic dilation, marked bronchial wall thickening, multiple thin-walled cavities, surrounding patchy consolidations and linear opacities, accompanied by right pleural effusion with lower lobe collapse. The absence of rim enhancement on contrast imaging supported the diagnosis of NP (Figure 3). Repeat bronchoscopy revealed copious purulent secretions persisting after suction in both lower lobes.

Figure 3 The manifestations of necrotizing pneumonia in children on lung CT. (A) Plain scan shows cystic and columnar dilation, significantly thickened wall, multiple thin-walled air bubbles or cystic shadows, multiple patchy and cord-like high-density shadows, some areas of consolidation, and combined with right pleural effusion and atrophy of the lower lobe of the right lung. (B) Enhanced CT shows no obvious edge enhancement. CT, computed tomography.

The treatment regimen included combination antibiotic therapy (β-lactam, oxazolidinone, and macrolide), mucolytics, and intranasal mometasone, along with a single dose of intravenous immunoglobulin (IVIG) (1 g/kg). This resulted in significant clinical improvement with resolution of cough and chest pain. The patient was discharged with instructions for regular immunoglobulin replacement and immunological monitoring. Two-month follow-up via telemedicine revealed interval immunoglobulin supplementation with documented improvements in immunological parameters, pulmonary function, and radiographic findings.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the parents of the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

The BTK gene variant was first reported by Bruton in 1952 (1,2). Currently documented BTK gene mutations predominantly consist of missense mutations, followed by frameshift mutations, splicing mutations, and nonsense mutations (3). As a member of the non-receptor tyrosine kinase Tec family and a crucial signaling molecule, BTK plays an essential role in pre-B cell transformation, primarily facilitating pre-B cell expansion from the pre-B1 to pre-B2 stage (4). The clinical phenotype results from early B-cell developmental arrest, leading to absent or markedly reduced circulating B lymphocytes, hypogammaglobulinemia, and severely impaired antibody production. Notably, BTK mutations do not affect T-cell quantity or function, consistent with our patient’s presentation.

While most BTK mutations demonstrate familial inheritance with maternal carriers, approximately 30–50% of XLA cases occur sporadically through de novo variants. Genetic testing confirmed the normal status of the patient’s mother (Figure 2B). XLA incidence ranges from 1:100,000 to 1:200,000 (5,6), though precise prevalence remains uncertain due to the absence of neonatal screening programs. The disorder exclusively affects males, manifesting clinically as immunodeficiency with recurrent bacterial infections including otitis media, pneumonia, chronic rhinitis, skin infections, and enteritis. Common pathogens include Streptococcus pneumoniae, Haemophilus influenzae type b, Streptococcus pyogenes, Pseudomonas aeruginosa, and Staphylococcus aureus. Over half of patients develop severe infections, as exemplified by our case presenting with NP.

Diagnostic evaluation revealed undetectable immunoglobulin levels and complete B-cell absence (0/µL), prompting genetic analysis that identified the pathogenic BTK variant (NM_000061.2:c.655delG, p.Val219Leufs*10), confirming XLA diagnosis.

According to previous reports, the onset age of XLA is mostly in infancy (7,8), and in China, it is concentrated in the range of 4–9 years old (9). The diagnosis age of this patient was 8 years old. Some patients still received diagnosis until adulthood, and they were older. It is speculated that this might be because the mutation only changed a single amino acid, and it had little impact on the function of protein coding (9,10). Whether there is a genotype-phenotype relationship between BTK gene variations and clinical severity is currently lacking clear evidence. Some studies have reported that the severity of the phenotype and the differences in clinical manifestations among different individuals are not related to the degree of deficiency. Additionally, there are differences in the diagnosis age in different regions, which may also be related to various factors such as local medical and economic levels, and public awareness (11-13).

NP was first proposed by René Laennec and was more frequently reported in adults. NP is a liquefactive necrosis of the lung parenchyma caused by various factors. The presence of lung tissue consolidation is a prerequisite, which subsequently leads to multiple cystic cavities and cavities in the lungs. In the early pulmonary imaging, a lung consolidation shadow is presented. In the later stage, single or multiple thin-walled cavities or low-density changes occur in the lung tissue, and there is no obvious enhancement at the edge of the lung on enhanced CT, with an air-fluid level in the cavity. It is more common on the right side (14). Previously, NP was considered a pathological diagnosis. The lung tissue biopsy showed destruction of normal lung tissue structure, necrosis of alveolar epithelial cells, embolism of alveolar capillaries, fibrous tissue hyperplasia, and neutrophil infiltration. However, biopsy has the problems of invasive operation, difficult sampling, and difficulty in obtaining cooperation from parents and children. Currently, clinical diagnosis mainly relies on imaging detection, and more and more scholars believe that NP is also an imaging diagnosis (15).

Previous studies have suggested that bacterial infections, especially Streptococcus pneumoniae and Staphylococcus aureus, are the main pathogens causing NP. However, with the increase in case reports, it has been found that various pathogens can all cause the occurrence of NP (16). In this case, the lung lavage fluid of the child tested positive for Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, and Mycoplasma pneumoniae. In recent years, mycoplasma infections have been on the rise, and its proportion in the pathogens causing NP is become increasingly significant. Some studies have reported that in 30 NP, the proportion of mycoplasma infection was as high as half (17). With the prevalence of adenovirus and influenza virus, NP caused by these viruses has also been reported (16). The pathogenesis of NP caused by different pathogens is also different. Currently, many researchers believe that one is the direct damage of pathogenic microorganisms and their toxins to the lung tissue (18), and the other is the immune disorder of the body, which activates macrophages and releases interleukin (IL)-6, IL-8, endothelial cell adhesion factors, etc. which can directly act on the adjacent lung epithelial cells and cause acute lung injury. At the same time, Mycoplasma pneumoniae can have the same cross-reactive antigens with the human body’s own tissues, thereby forming circulating immune complexes and leading to autoimmune reactions (19). The third is that bacterial emboli or microthrombi block capillaries, causing ischemia, liquefaction, and even necrosis of the affected lung tissue, and subsequently forming multiple cavities and cystic cavities.

Conclusions

In clinical practice, children with a history of recurrent infections should undergo early immunological evaluations, including serum immunoglobulin levels and lymphocyte subset analysis, to screen for potential immunodeficiency disorders. With the rapid advancement of genetic testing technologies, children suspected of having inherited immune deficiencies should undergo molecular diagnostics as early as possible to facilitate accurate diagnosis.

For patients diagnosed with XLA, early and standardized IVIG replacement therapy is crucial to reduce infection frequency, improve quality of life, and optimize long-term prognosis.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-353/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-353/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-353/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the parents of the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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