Introduction
Common variable immunodeficiency (CVID) as an etiology for bronchiectasis needs clinical suspicion and meticulous work up. In countries with high prevalence of tuberculosis and its sequalae, bronchiectasis is a common consequence. By convention when meticulous work up fails to clinch an etiology, bronchiectasis is considered either to be idiopathic or post infective from past. But nowadays with availability of serum immunoglobulin levels by nephelometry had opened up the spectrum of detection of immunodeficiencies as cause.
CVID is a polygenic, heterogenous primary immunodeficiency characterized by a failure in B-cell differentiation leading to defective immunoglobulin production. 2, 1 CVID patients manifest as clinical syndrome comprising of susceptible recurrent sinopulmonary infections with encapsulated organisms along with inflammatory or autoimmune manifestations.
CVID is the most common clinically significant primary immunodeficiency disease. 3 Bronchiectasis in CVID is common but has a late presentation. But the age of onset of CVID being variable range from 20-40 years. However up to 20% may present before the age of 20 years.1 So early diagnosis and treatment can make a difference in outcome and increase productivity in lifetime. As estimated from literatures 1 in 25,000–50,000 subjects develop CVID hence a very rare manifestation to detect. 4, 3, 2 Due to under diagnosis a common delay in detection followed by treatment can occur up to 5–10 years. 5
Hence, we report here this rare case for early detection of an uncommon etiology of bronchiectasis that is CVID along with its complications, whose proper management can make a difference to future morbidity and mortality of the patients.
Case Report
A 16-year-old young boy presented with complain for fever (on & off), cough with mucoid expectoration, wheezing for 1 month. He also complained of increased exertional breathless ness and left sided chest pain for last 10 days. He often suffered from recurrent allergic rhinitis and chest infections since childhood which increased over last 3 years. He was treated by local doctors as per his symptoms over the years. He was treated with antitubercular therapy for a period of 9 months in 2018 as sputum negative pulmonary tuberculosis from local doctors. He was initially examined and managed in the OPD of the Department of Pulmonary Medicine at AIIMS, Patna. He was emaciated, with pallor, clubbing but no lymphadenopathy. His vitals were stable with pulse oximetry showing SpO2 = 98% room air. Respiratory system examination findings had bilateral diffuse coarse crepitations and rhonchi on auscultation. His routine blood investigations showed mild anemia. Sputum examinations for mycobacterium-acid fast bacilli and Gene Xpert were negative. USG abdomen had no organomegaly or abdominal lymphadenopathy. Cultures of blood, and sputum were sterile all throughout our investigations. Chest radiograph showed consolidation in left lower zone and evidence were suggestive of bronchiectasis [Figure 1]. Spirometry was suggestive of reversible airway obstruction. Hence total Serum IgE and Aspergillus specific IgE was advised which eventually was negative. His HIV report was non-reactive and HBV and HCV were negative. ANA screening, ANCA, and rheumatoid factor were also negative. High resolution computed tomography (HRCT) chest was done which confirmed presence of bilateral diffuse cystic bronchiectasis with consolidation in the left lower lobe. [Figure 2 a and b]. Considering the possibility of immunodeficiency disorder, serum IgG, IgM, IgE and IgA was done. His serum Ig levels were low- Ig G <270mg/dl (Level 700-1600mg/dl), Ig M < 15mg/dl (Level 40-230mg/dl, IgA 13mg/dl (Level 70-400mg/dl) and IgE 2.1KU/L (Level 0-113KU/L) by Nephelometry. He was admitted for further evaluation. Primary isolated hypogammaglobulinemia and secondary (drugs and nephrotic syndrome) immunodeficiency was excluded. Hence bronchoscopy and BAL (Bronchoalveolar lavage) was performed for evaluation of consolidation. BAL sample was sterile (negative AFB smear and BACTEC culture and Gene Xpert, negative for Gram stain and culture) with lymphocyte predominance (>25%).
He was treated empirically with antibiotics piperacillin tazobactam with aminoglycoside and macrolide along with bronchodilators for 10 days. Considering the spectrum of evidences, CVID complicated with COP (Cryptogenic Organizing Pneumonia) or GLILD (Granulomatous lymphocytic interstitial lung disease) was diagnosed and treated with intravenous IgG 400mg/kg per month with target serum Ig G trough level >500mg/dl. He was vaccinated with Pneumococcal vaccine during discharge. His pneumonic consolidation resolved spontaneously (thereby no lung biopsy attempted) but developed right sided pleural effusion. (Figure 3). Pleural fluid study was suggestive of tubercular etiology (exudative, lymphocytic, ADA 45 U/L) and was started on ATT. He responded well with resolution of symptoms and is on continuation of ATT treatment. Hence, we presented this case as an unusual etiology of bronchiectasis – CVID complicated with left lower lobe COP/GLILD and right sided tubercular pleural effusion.
Discussion
CVID as a primary immunodeficiency can be diagnosed after proper exclusion of etiologies leading to immunodeficiency like genetic defects, malignancy, nephrotic syndrome or use of immunosuppressant. 6 Accurate diagnosis of immune deficiency is difficult at times and lacks proper work-up. 7, 6 A detailed investigation of past medical history like presence of recurrent allergic sinopulmonary diseases is needful to understand the immunodeficiency, as seen in our case. Possible family history of immunodeficiency in relatives or sibling must be noted, though in our case there was no such history. Maternal antibodies impart immunity to children up to 6 months of age, therefore according to European Society for the Immunodeficiency's (ESID) criteria CVID is usually detected after 2 years of age. ESID criteria needs decreased (< 2 standard deviations of the mean) levels of IgG with reduced IgA and/or IgM, together with failure to mount a significant antibody response to vaccination, in the absence of a known cause. 8, 6 Here we were able to diagnose him at 16 years of age, that too only 20% cases are diagnosed <20years of age. 1 His serum Ig levels were lower, showing IgG <270mg/dl (level700-1600mg/dl), IgE 2.1KU/L (level 0-113KU/L), IgM < 15mg/dl (level40-230mg/dl), and IgA 13mg/dl (level70-400mg/dl) done by Nephelometry.
Nutritional status of the patient should be evaluated. Unexplained weight loss and failure to growth is relatively common symptom in CVID as seen in our case too.
In CVID patients there is recurrent upper and lower respiratory tract infections commonly by encapsulated organisms and atypical organisms. Respiratory tract infections comprised mostly of rhinitis, sinusitis, otitis media and pneumonia. Capsulated organisms mostly included Streptococcus pneumoniae and H influenza. 8, 6, 1 Whereas atypical organisms in CVID patients were mostly Mycoplasma, Ureaplasma species. Gram-negative rods should also be considered, in particular in patients with impaired cellular immunity or prolonged sufferer of CVID. 9, 6 Hence the antibiotic policy to treat must cover these spectra to get early control over infection and stop the sequalae of changes that occurs post repetitive infection and healing. 7 Empirical antimicrobial therapy thereby must include drugs such as macrolides or fluoroquinolones because they cover both encapsulated and atypical organisms. Hence our choice of empirical antibiotics covered the same for left lower lobe consolidation, though his sputum and BAL sample cultures were sterile all throughout the hospitalization.
Opportunistic infections occurred in around 10% of patients with CVID. 10, 6, 1 T-cell abnormalities with CVID had more variable clinical manifestations. Gastrointestinal infection with C. jejuni, Salmonella sp, and Giardia lamblia, Hepatitis C (12%), liver disease such as nodular regenerative hyperplasia, splenomegaly. Non-caseating Sarcoid like granulomatous disease (20%), and NH lymphomas were some of the atypical extra pulmonary manifestations. 14, 13, 12, 11, 10 They are also at risk of developing autoimmune features like neutropenia, thrombocytopenic purpura or hemolytic anemia. 16, 15 However, we did not encounter such manifestations in our case. There was no organomegaly or lymphadenopathy or hepatitis.
Among the list of complications recurrent pneumonia and chest infections leading to late bronchiectasis in CVID was reported to be present in up to 17 to 76% (avg 20%) of patients. 17, 16 In our case also search for etiology of bronchiectasis lead to CVID.
CVID patients may present with complication of restrictive interstitial lung disease with parenchymal lesions on HRCT thorax scan. Lung biopsy on histopathological examination shows granulomatous and lymphoproliferative patterns like lymphocytic interstitial pneumonitis or follicular bronchiolitis or lymphoid hyperplasia. Hence the term granulomatous lymphocytic interstitial lung disease (GLILD) was coined to describe it with prevalence around 10–25% of patients with CVID. 24, 23, 22, 21, 20, 19, 18 GLILD can be progressive with limitation in lung function leading to morbidity and mortality with shortening of median survival from 28 years to 14 years. 19 However, in our case we could not get a lung biopsy done as the focal consolidation resolved on treatment spontaneously despite culture reports being sterile. His BAL cytology report was lymphocyte predominant (>25%). Hence, we considered the possibility of left lower lobe patchy consolidation to be COP or GLILD that resolved during ongoing IgG therapy and antibiotics.
More over during recovery he also developed right sided pleural effusion which was exudative, lymphocyte predominant with ADA 45 U/L favoring Tubercular etiology. Though his sputum and BAL cultures were negative for AFB and Gene xpert. Probably this is the first case we are presenting with CVID complicating with COP or GLILD and Tubercular pleural effusion as per our reference searches.
CVID patients can be classified into 5 types based on phenotype- 1. Autoimmunity 2. Polyclonal lymphocytic infiltration 3. Enteropathy 4. Lymphoid malignancy 5. No complication. This was highlighted in CVID registry in Europe by the European Society for Immunodeficiency. 25 Significant overlap exists between these phenotypes. Common overlap is seen among lymphoproliferative phenotype (GLILD, splenomegaly, and adenopathy) with autoimmune cytopenias, gastrointestinal, and hepatic disease. 13, 12, 11, 24, 23 However in our case we did not encounter any autoimmune cytopenia or evidence of any malignancy in this 16-year-old boy.
Initiation of early appropriate management is the clinical corner stone in CVID patients to prevent delay and its inevitable consequences. The baseline treatment of CVID based on pathology is replacement of antibody by either an intravenous or subcutaneous route. Conventional recommended doses is 400 to 600 mg/kg body weight every month based on monitoring of serum immunoglobulin level. 1 Our patient is receiving a dose (400mg/kg) based on consultation from the Department of Pediatrics. Dosing regime is every 2 weeks (subcutaneous route) or every 3 to 4 weeks (intravenous route). Besides treating him with empirical antibiotics for a duration of 10 days, he is also on Antitubercular therapy for his pleural effusion. Clinically he improved with gain in weight, wheezing subsided, resolution of chest pain and patchy consolidation. He was vaccinated with Influenza & Pneumococcal vaccine 23 serotype during discharge. He will be followed up for prolonged IVIG therapy based on serum level of IgG and ATT therapy.
Conclusion
Quest for etiology of bronchiectasis is important, mere detection is not enough. Hence high degree of suspicion for immunodeficiency as cause and its work up is needed for patient’s better good and future productive life. In this case search for etiology of bronchiectasis, negative Aspergillus work up and low level of IgG, IgE, IgA & IgM clenched the diagnosis. Though IVIG therapy can provide significant improvement in these patients, early diagnosis always prevents morbidity and mortality with improved future prognosis.
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