A 27-year-old nonsmoking male, with one child, who had been previously employed in a metal crushing factory, presented with a 3-year history of cough with expectoration, breathlessness (which had increased from modified Medical Research Council grade 1 to grade 4 over 1 year) and intermittent fever for 30 days. There was no history of haemoptysis, weight loss, hearing loss, joint pain, skin rash, known tuberculosis contact or COVID-19 infection. His antenatal history was unremarkable. He was born at term by normal vaginal delivery and had received all age-appropriate vaccinations as per the Indian national immunisation schedule. He had also received two doses of the COVID-19 vaccine in the year 2021. His childhood history included pneumonia and recurrent episodes of diarrhoea at age 6 years (lasting ∼6–8 months). He had received 6 months of empiric anti-tubercular therapy 3 years ago for pulmonary tuberculosis, but the records were unavailable. He was diagnosed with diabetes mellitus 2 years ago. There were records of multiple hospital admissions for recurrent exacerbations with two admissions in the past 1 year, with administration of intravenous and oral antibiotics. His family history was unremarkable, except his mother's death occurred 1 year after his birth, with cause being unknown.
Examination
On admission, his temperature was 38.6°C, respiratory rate 24 breaths per min, pulse 90 beats per min, blood pressure 116/70 mmHg and oxygen saturation was 98% on 1 L·min −1 oxygen. No cyanosis, raised jugular venous pressure, pedal oedema or lymphadenopathy was present; clubbing was noted. Respiratory system examination revealed: 1) mucoid nasal secretion; and 2) impaired percussion note over the right inter-scapular area with bronchial breath sounds and bilateral wheeze. Other systems were unremarkable.
Investigations
Laboratory tests showed a total leukocyte count of 28 630 cells·mm −3 (normal range: 4000–11 000 cells·mm −3 ), haemoglobin of 10.4 g·dL −1 , procalcitonin of 1.25 ng·mL −1 (normal range: 0.2–0.5 ng·mL −1 ) and glycated haemoglobin (HbA1c) of 8.1%. Liver and renal functions were normal except for a mildly reduced total protein of 5.28 g·dL −1 (normal range: 6.4–8.3 g·dL −1 ), globulin of 1.52 g·L −1 (normal range: 2.0–3.5 g·dL −1 ) and albumin of 3.76 g·dL −1 (normal range: 3.4–4.8 g·dL −1 ). Viral serologies including hepatitis B, hepatitis C and HIV were negative. A chest radiograph (posterior–anterior view) showed prominent bronchovascular markings with hyperinflation ( figure 1a ), while high-resolution computed tomography (HRCT) of the thorax revealed diffuse bronchiectasis and basal segments collapse of the left lower lobe ( figure 1b and c). Bronchoscopy was performed and bronchoalveolar lavage (BAL) was obtained. BAL was negative for acid-fast bacilli (AFB), periodic acid–Schiff (PAS), modified AFB and potassium hydroxide mount. GeneXpert testing of BAL was negative for Mycobacterium tuberculosis ; BAL culture grew pan-sensitive Pseudomonas aeruginosa for which culture-directed antibiotics were given.
Task 1
Which underlying disorder could link a childhood history of pneumonia and recurrent diarrhoea to adult-onset bronchiectasis?
Cystic fibrosis
Primary ciliary dyskinesia
Chronic granulomatous disease
Primary antibody deficiency
Answer 1
When linking childhood clues to adult bronchiectasis: childhood recurrent infections or prolonged diarrhoea should always raise suspicion of inborn errors of immunity. However, cystic fibrosis, primary ciliary dyskinesia and chronic granulomatous disease are also possible. Cystic fibrosis often presents early with recurrent infections and malabsorption. Primary ciliary dyskinesia presents with recurrent sinopulmonary and ear infections from childhood with or without infertility and situs inversus . Chronic granulomatous disease leads to recurrent bacterial and fungal infections but diarrhoea is less common. Primary antibody deficiencies best explain this patient's history, as they often begin with pneumonia and gastrointestinal infections in childhood and progress to bronchiectasis in adulthood. The correct option is d.
Hypogammaglobulinaemia can be primary or secondary. Primary causes are usually secondary to inborn errors of immunity, such as common variable immunodeficiency (CVID), X-linked agammaglobulinaemia, selective IgA deficiency, specific antibody deficiency, IgG subclass deficiency and combined immunodeficiencies like hyper-IgE syndrome. Secondary causes include rheumatological diseases (antineutrophil cytoplasmic antibody-associated vasculitis, rheumatoid arthritis, systemic lupus erythematosus), neurological disorders (multiple sclerosis), haematological/oncological malignancies (chronic lymphocytic leukaemia, lymphoma, multiple myeloma), pulmonary diseases (COPD, cystic fibrosis), and protein-losing states (nephrotic syndrome, protein-losing enteropathy) [ 1 ].
Immunological work-up
IgG was 0.092 g·L −1 (normal range: 7–16 g·L −1 ), IgA 0.251 g·L −1 (normal range: 0.7–4 g·L −1 ), IgM 0.184 g·L −1 (normal range: 0.4–2.3 g·L −1 ) and IgE 17.5 IU·mL −1 (normal range: 0–378 IU·mL −1 ). Serum protein electrophoresis showed 65.9% albumin (normal range: 59.8–72.4%), 3.4% alpha-1 globulin (normal range: 1.0–3.2%), 15.1% alpha-2 globulin (normal range: 1.0–3.2%), 13.8% beta globulin (normal range: 7.5–12.9%) and 1.8% gamma globulins (normal range: 8.0–15.8%). Serum immunofixation revealed the absence of all immunoglobulins, with no M band. Flow cytometry of the lymphocyte subset showed 5% CD19 cells (normal range: 6–22%), 79 absolute CD19 cells per µL (normal range: 99–527), 75.86% CD3 (normal range: 57–83%), 25.8% CD4 cells (normal range: 31.45–62.38%), 488 absolute CD4 cells per µL (normal range: 491–1734), 47.5% CD8 cells (normal range: 9.55–38.32%), 898 absolute CD8 cells per µL (normal range: 162–1074) with a CD4/CD8 ratio of 0.54 (normal range: 0.39–3.02), and CD3 − CD16 + 56 + ratio of 6% (6–27%). Isohaemagglutinin antibodies (anti-A and anti-B, IgG and IgM) were absent while his blood group was A positive. The dihydrorhodamine test (neutrophil burst oxidase assay) was negative.
Further evaluation
Contrast-enhanced computed tomography of the abdomen was normal. ENT (ear, nose and throat) examination revealed mucoid secretions in the left ear suggestive of otitis media. Computed tomography of the paranasal sinuses showed maxillary and ethmoid sinusitis ( figure 2 ). Detailed autoimmune work-ups including anti-cyclic citrullinated peptide antibodies, extractable nuclear antigen, antineutrophil cytoplasmic antibodies, rheumatoid factor, antinuclear antibody, Coombs test, thyroid peroxidase antibodies, anti-parietal cell antibody, gliadin deamidated antibody panel (IgG and IgA), anti-endomysial antibody (IgA) and thyroid autoantibodies were negative. C-peptide level was low (0.89 ng·mL −1 ) while islet cell antibody and glutamic acid decarboxylase-65 (IgG) were negative. Complement levels (C3 and C4) were normal. Mantoux test was negative. Serology for cytomegalovirus and Epstein–Barr virus (IgG and IgM) was negative. Spirometry showed a forced vital capacity (FVC) of 1.0 L (28% predicted), forced expiratory volume in 1 s (FEV 1 ) of 0.41 L (13% predicted) and FEV 1 /FVC ratio of 40.8%, with no bronchodilator reversibility. Even after treating the patient with intravenous antibiotics, he had another break-through infection (sputum grew pan-sensitive P. aeruginosa ) after 3 weeks. His repeat serum immunoglobulin levels revealed IgG 0.113 g·L −1 , IgA 0.251 g·L −1 and IgM 0.184 g·L −1 . His IgG3 level was 0.057 g·dL −1 (normal range: 0.15–1.30 g·dL −1 ). BAL fungal and mycobacterial cultures were sterile.
Humoral primary immunodeficiency (PID) should always be suspected in patients with recurrent sinopulmonary infections and otitis media [ 2 ].
Task 2
What are the warning signs of PID in children and adults?
Answer 2
The Jeffrey Modell Foundation has advised recognition of the defined specific warning signs of PID [ 3 ]. Patients experiencing ≥2 of the following signs is suggestive of PID in adults and children.
For adults:
1) ≥2 new ear infections within 1 year
2) ≥2 new sinus infections within 1 year, in the absence of allergy
3) 1 episode of pneumonia per year for >1 year
4) Chronic diarrhoea with weight loss
5) Recurrent viral infections (colds, herpes, warts, condyloma)
6) Recurrent need for i.v. antibiotics to clear infections
7) Recurrent, deep abscesses of the skin or internal organs
8) Persistent thrush or fungal infections on the skin or elsewhere
9) Infection with normally harmless tuberculosis-like bacteria
10) A family history of PID
For children:
1) ≥4 new ear infections within a single year
2) ≥2 serious sinus infections in 1 year
3) Antibiotic therapy lasting ≥2 months with little improvement
4) ≥2 episodes of pneumonia in 1 year
5) Poor weight gain or growth failure in infants
6) Recurrent deep-seated skin or internal abscesses
7) Persistent oral thrush or recurrent fungal skin infection
8) Requirement for i.v. antibiotics to resolve infections
9) ≥2 severe internal infections, such as septicaemia
10) A family history of PID
Upper gastrointestinal endoscopy revealed a normal oesophagus, the stomach revealed punctate erythema involving the antrum and body (corpus) mucosa, consistent with mild gastropathy. A rapid urease test obtained from the antrum for Helicobacter pylori came back positive. The second part of duodenum showed nodular mucosa ( figure 3a ) and a biopsy was obtained. Histopathological examination of the biopsy revealed lymphoid follicles and lymphoid hyperplasia in the lamina propria with depleted plasma cells ( figure 3b and c). Colonoscopy findings were normal; however, rectal biopsy showed depletion of plasma cells ( figure 3d ). Findings were confirmed by immunohistochemistry, lymphoid follicles were positive for CD3, CD20, CD4 ( figure 4a ) and CD8 ( figure 4b ) with a CD4/CD8 ratio ∼1.0. Scanty CD57 positive cells were seen in the lamina propria ( figure 4c ) and CD138 was negative ( figure 4d ). Under normal conditions, the gastrointestinal mucosa is rich in plasma cells that produce IgA, while a smaller proportion of plasma cells also secrete IgG and IgM [ 4 ]. His genetic work-up did not reveal any mutation.
Task 3
What is the probable diagnosis based on clinical course, imaging, immunological study and histopathology?
Answer 3
A diagnosis of CVID with an infection phenotype (bronchiectasis) was established based on criteria outlined by A meratunga et al. [ 5 ] and the European Society for Immunodeficiencies (ESID) [ 6 ]. This was supported by markedly low serum IgG (<2 standard deviations on two occasions, 3 weeks apart), low IgA and IgM, age >4 years, exclusion of secondary causes of hypogammaglobulinaemia, recurrent respiratory and sinus infections, bronchiectasis with poor response to antibiotics, low IgG3 levels, absent isohaemagglutinins, and lymphoid hyperplasia with absent plasma cells on gut biopsy.
The most common antibody-deficiency disorders are X-linked agammaglobulinaemia (XLA; also known as Bruton's agammaglobulinaemia), CVID and selective IgA deficiency. X-linked agammaglobulinaemia occurs due to mutation in the Bruton's tyrosine kinase (Btk) gene, and is characterised by markedly reduced levels of serum IgG, IgA and IgM. It mostly affects males in the first 2 years of life with recurrent sinopulmonary infections, absent lymph nodes and tonsils [ 7 ]. Selective IgA deficiency is characterised by very low or absent circulating IgA (<7 mg·dL −1 ) with normal IgG and IgM in individuals aged ≥4 years [ 8 ]. CVID can present at any age. It should not be diagnosed before the age of 4 years, since younger children are more likely to have other primary immunodeficiencies or transient hypogammaglobulinaemia of infancy which can be hard to differentiate [ 9 ].
Discussion
CVID is the most common clinically significant PID with a prevalence of about 1 in 25 000 [ 9 ]. It typically presents in adolescence or adulthood, often with recurrent respiratory infections, bronchiectasis, increased susceptibility to gastrointestinal disease, autoimmune disorders and malignancy. The underlying defect is impaired B-cell differentiation and defective antibody production [ 10 ]. Studies have shown a delay of 10.6–17 years from symptom onset to bronchiectasis diagnosis in CVID patients [ 11 ]. CVID is most often classified using either the criteria outlined by A meratunga et al. [ 5 ] or the ESID 2019 criteria [ 6 ], as summarised in table 1 .
TABLE 1
Common variable immunodeficiency (CVID) classification criteria
| A meratunga et al. [ 5 ] classification |
| A. Must meet all major criteria (primary): |
| Hypogammaglobulinaemia (IgG <5 g·L −1 ) |
| Age >4 years |
| Exclude other causes |
| B. Symptoms related to immune system failure (ISF) (≥1): |
| Recurrent, severe, or unusual infections |
| Poor antibiotic response |
| Infections despite prophylactic antibiotics or vaccination |
| Bronchiectasis±chronic sinusitis |
| Inflammatory disorders |
| Autoimmunity |
| C. Supportive laboratory evidence (≥3): |
| Reduced IgA (<0.8 g·L −1 ) and/or IgM (0.4 g·L −1 ) |
| Reduced memory B-cell subsets and/or increased CD21 low subsets by flow cytometry |
| IgG3 deficiency (<0.2 g·L −1 ) |
| Impaired (with age-matched controls) or transient (with age-matched controls) vaccine responses |
| Absent isohaemagglutinins (if not blood group AB) |
| Autoimmunity evidence on serology |
| Genetic variation |
| D. Specific histological markers increasing CVID diagnostic certainty alongside category A and B criteria: |
| Lymphoid interstitial pneumonitis |
| Granulomatous disorder |
| Nodular regenerative hyperplasia of the liver |
| Nodular lymphoid hyperplasia of the gut |
| Absence of plasma cells on gut biopsy |
| European Society for Immunodeficiencies classification [ 6 ] |
| 1. At least one of the following: |
| Increased susceptibility to infection |
| Autoimmune manifestations |
| Granulomatous disease |
| Unexplained polyclonal lymphoproliferation |
| Affected family member with antibody deficiency |
| 2. AND marked decrease of IgG and marked decrease of IgA with or without low IgM levels (measured at least twice; <2 sd of the normal levels for their age) AND at least one of the following: |
| Poor antibody response to vaccines and/or absent isohaemagglutinins |
| Low switched memory B-cells <70% of age-related normal value |
| 3. AND secondary causes of hypogammaglobulinaemia have been excluded ( e.g. infection, protein loss, medication, malignancy) |
| 4. AND diagnosis is established after the fourth year of life (symptoms might be present before) |
| 5. AND no evidence of profound T-cell deficiency, defined as two of the following: |
| CD4 numbers per µL: age 2–6 years <300, 6–12 years <250, >12 years <200 |
| % naïve of CD4: age 2–6 years <25%, 6–16 years <20%, >16 years <10% |
| Absent T-cell proliferation |
In patients with hypogammaglobulinaemia, the diagnosis of CVID should be further considered if they show either of the following: impaired vaccine antibody responses or absent isohaemagglutinins, or reduced switched memory B-cells [ 12 ]. Histopathology provides confirmatory evidence in CVID. The absence of plasma cells and lymphoid hyperplasia on gut biopsy are characteristic features [ 13 ]. These findings are classified under Category D of the criteria outlined by A meratunga et al. [ 5 ] ( table 1 ), and are seen in our case ( figure 3 ). When combined with primary (A) and symptomatic (B) criteria ( table 1 ), this can substantiate the diagnosis without the need for additional tests like vaccine response or memory B-cell analysis [ 12 ].
CVID complications can be infection-related, leading to structural damage such as bronchiectasis, or they can be non-infectious due to immune dysregulation. The latter includes autoimmunity, granulomatous lymphocytic interstitial lung disease (GLILD), gastrointestinal involvement, enteropathy, splenomegaly, and increased risk of solid tumours and lymphoid malignancies [ 9 ]. Autoimmunity and immune dysregulation are common in CVID (25–30%) [ 14 ]. HRCT findings in CVID may be normal or may demonstrate any of the following: airway changes such as bronchiectasis, mucus plugging, or tree-in-bud nodules; features of GLILD including nodularity, ground-glass opacities, and septal thickening with lower lung and peribronchovascular predominance; or other interstitial lung diseases such as organising pneumonia, nonspecific interstitial pneumonia or lymphocytic interstitial pneumonia [ 15 ].
Bronchiectasis is seen in approximately 23% of CVID cases (range 0–66%) [ 14 ]. Low IgM is strongly associated with bronchiectasis, along with low IgG, IgA concentrations and decreased CD4 + T-cell counts [ 16 ]. Global Burden of Disease data show that patients with CVID have far higher rates of noncommunicable comorbidities, particularly gastrointestinal disorders, bronchiectasis, autoimmune cytopenia, thyroid disease, interstitial lung disease, solid tumours and lymphoma. They also experience markedly increased infections, including pneumonia, meningitis, otitis media, respiratory infections and diarrhoea [ 9 ]. Treating the underlying immunodeficiency is crucial, as the quality of life in CVID is closely linked to the severity of airflow obstruction and the frequency of exacerbations [ 16 ].
Task 4
Which of the following therapies is not typically indicated in CVID management?
Corticosteroids
Immunoglobulin replacement therapy
Haematopoietic stem cell transplantation
Antibiotics
Answer 4
c) Haematopoietic stem cell transplantation.
Management: Lifelong intravenous or subcutaneous immunoglobulin replacement therapy (IgRT) is the cornerstone for the management of CVID, while corticosteroids and rituximab are used in the management of GLILD and autoimmunity in CVID. Haematopoietic stem cell transplantation is not routinely indicated in CVID, but may be considered in selected severe cases (autoimmune cytopenias, enteropathy, progressive GLILD and severe infections despite standard therapy) [ 17 ].
The cornerstone of treatment is lifelong intravenous or subcutaneous IgRT. The British Society for Immunology and United Kingdom Primary Immunodeficiency Network (UKPIN) recommend IgRT (400–500 mg·kg −1 per month) in CVID patients with any of the following: recurrent bacterial infections, significant immune-mediated complications such as autoimmunity or GLILD, IgG <4 g·L −1 with impaired vaccine responses and increased infection burden, and profound hypogammaglobulinaemia (IgG <2 g·L −1 ) [ 18 ].
Prophylactic antibiotics are indicated in CVID patients with bronchiectasis, persistent infections despite adequate IgRT (IgG ≥8 g·L −1 ), during IgRT withdrawal trials, or prior to IgRT initiation when vaccine responses are poor (IgG ≥4 g·L −1 ) [ 18 ]. Supportive management includes airway clearance, antibiotics for exacerbations, vaccination against Streptococcus pneumoniae , Haemophilus influenzae and Bordetella pertussis , and multidisciplinary follow-up with pulmonologists and immunologists [ 14 ].
In adults with CVID and frequent respiratory infections with or without bronchiectasis, a HRCT of the chest should be performed at least every 5 years to assess the development or progression of bronchiectasis, and surveillance for autoimmune and malignant complications also remains essential [ 19 ]. Lung transplantation has been attempted in CVID but it shows variable outcomes; it can be considered in patients ≤65 years with FEV 1 <30% predicted or with rapid lung function decline, severe pulmonary hypertension, massive haemoptysis, or respiratory failure [ 14 , 20 ].
By the fourth dose of i.v. IgRT (0.5 g·kg −1 per month) the patient was clinically stable off supplemental oxygen, with reduced cough, sputum volume and purulence, breathlessness, and fatigue, and no further pulmonary infections requiring i.v. antibiotics. After five doses, he continues to do well. Repeat serum immunoglobulins showed IgG 1.77 g·L −1 , IgA 0.22 g·L −1 and IgM 0.24 g·L −1 .
Key points
Think of immune deficiency in adults with unexplained bronchiectasis or recurrent infections unresponsive to antibiotics.
Early recognition and immunoglobulin replacement therapy can reduce infection burden and morbidity, and improve quality of life.
Multidisciplinary management, regular follow-up, and educational support are essential for optimal outcomes.
Footnotes
Conflict of interest: The authors have nothing to disclose.
Support statement: No funding declared.
References
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