Pediatric common variable immunodeficiency: Immunologic and phenotypic associations with switched memory B cells

Yong PL, Orange JS, Sullivan KE. Pediatric common variable immunodeficiency: Immunologic and phenotypic associations with switched memory B cells.
Pediatr Allergy Immunol 2010: 21: 852–858.
© 2010 John Wiley & Sons A/S Recent studies suggest that patients with common variable immunodeficiency (CVID) and low numbers of switched memory B cells have lower IgG levels and higher rates of autoimmune disease, splenomegaly, and granulomatous disease; however, no prior literature has focused exclusively on pediatric cases. We examined the relationship between switched memory B cells and clinical and immunologic manifestations of CVID in a pediatric population. Forty‐five patients were evaluated. Patients were categorized as Group I (<5 switched memory B cells/ml, n = 24) or Group II (≥5 switched memory B cells/mL, n = 21). CD3⁺ T‐cell counts and CD19⁺ B‐cell levels were lower among Group I patients. Only those in Group I had meningitis, sepsis, bronchiectasis, granulomatous lung disease, autoimmune cytopenias, or hematologic malignancies. Segregation of pediatric patients into high risk (Group I) and average risk (Group II) may assist in targeting surveillance appropriately.     

Pulmonary function test in transfusion-dependent beta-thalassemia patients

Beta-thalassaemia is the most common hemoglobinopathies in our region with treatment of regular blood transfusion. Iron overload and hemosiderosis can cause organ involvement. Recent studies have focused on pulmonary involvement and pathophysiology of lung damage. The goal of this study was to investigate the pulmonary abnormalities in thalassemic patients in relation with sign and symptoms and iron overload. The authors studied pulmonary function test (PFT) at the Adult Thalassemia Clinic in Tehran. The history of blood transfusion, iron chelation, respiratory problems, and drug usage was taken. Physical examination, PFT, arterial blood gas (ABG), and chest X-ray (CXR) were done. In total, 139 patients were studied. The mean age was 21.1 years and mean duration of transfusion was 18 years. It was found that 133 patients (95.7%) did not have respiratory problems and only 6 (4.3%) had some respiratory complaints. In CXR, 100 patients (89.3%) had normal lung pattern and others (10.7%) had variable degrees of abnormal lung pattern. In ABG, mean of Po(2) was 73.5% and mean of O(2) saturation was 90.6%. In PFT, 101 patients (72.7%) had restrictive pattern, 35 (25.1%) had normal pattern, and 3 (2.2%) had combined pattern. According to vital capacity, the patients were placed in five categories: 54 patients (38.8%) normal, 37 (26.6%) mild, 35 (25.3%) moderate, 10 (7.2%) severe, and 3 (2.1%) extremely severe pulmonary deficit. There was no statistical significance between PFT results with all variables studied, except duration of blood transfusion, which may be considered a indirect effect of iron load (p = .05, r = .361). According to these results, restrictive pattern was the most common finding (72.7%) in PFT, while 95.7% of patients had no respiratory complaint, and in the chest X-ray group, 89.3% had normal pattern. The authors conclude that the lung may be considered a site for organ damage, and alteration of pulmonary function may be expected in transfusion-dependent patients in spite of no pulmonary symptoms or normal CXR. In recent years, because of new iron chelating drugs, doctors can expect thalassemic patients to have a long life-time and need to increase their quality of life. One way to do this is to evaluate the respiratory system by PFT to prevent the squeal of pulmonary disease.     

PULMONARY FUNCTION TEST IN TRANSFUSION-DEPENDENT β-THALASSEMIA PATIENTS

β-Thalassaemia is the most common hemoglobinopathies in our region with treatment of regular blood transfusion. Iron overload and hemosiderosis can cause organ involvement. Recent studies have focused on pulmonary involvement and pathophysiology of lung damage. The goal of this study was to investigate the pulmonary abnormalities in thalassemic patients in relation with sign and symptoms and iron overload. The authors studied pulmonary function test (PFT) at the Adult Thalassemia Clinic in Tehran. The history of blood transfusion, iron chelation, respiratory problems, and drug usage was taken. Physical examination, PFT, arterial blood gas (ABG), and chest X-ray (CXR) were done. In total, 139 patients were studied. The mean age was 21.1 years and mean duration of transfusion was 18 years. It was found that 133 patients (95.7%) did not have respiratory problems and only 6 (4.3%) had some respiratory complaints. In CXR, 100 patients (89.3%) had normal lung pattern and others (10.7%) had variable degrees of abnormal lung pattern. In ABG, mean of Po₂ was 73.5% and mean of O₂ saturation was 90.6%. In PFT, 101 patients (72.7%) had restrictive pattern, 35 (25.1%) had normal pattern, and 3 (2.2%) had combined pattern. According to vital capacity, the patients were placed in five categories: 54 patients (38.8%) normal, 37 (26.6%) mild, 35 (25.3%) moderate, 10 (7.2%) severe, and 3 (2.1%) extremely severe pulmonary deficit. There was no statistical significance between PFT results with all variables studied, except duration of blood transfusion, which may be considered a indirect effect of iron load (p =. 05, r =. 361). According to these results, restrictive pattern was the most common finding (72.7%) in PFT, while 95.7% of patients had no respiratory complaint, and in the chest X-ray group, 89.3% had normal pattern. The authors conclude that the lung may be considered a site for organ damage, and alteration of pulmonary function may be expected in transfusion-dependent patients in spite of no pulmonary symptoms or normal CXR. In recent years, because of new iron chelating drugs, doctors can expect thalassemic patients to have a long life-time and need to increase their quality of life. One way to do this is to evaluate the respiratory system by PFT to prevent the squeal of pulmonary disease.     

Mortality and morbidity in common variable immunodeficiency

Common variable immunodeficiency (CVID) is a heterogeneous group of disorders, characterized by hypogammaglobulinemia, defective specific-antibody production resulting in recurrent bacterial infections. Delay in diagnosis and inadequate treatment result in increased irreversible complications and mortality. To determine persistent morbidities, mortality rate and survival in Iranian patients with CVID, hospital records of 72 (39 males and 33 females) diagnosed CVID patients were reviewed. Probabilities of survival after diagnosis of CVID were estimated from Kaplan-Meier life tables. Studied patients were enrolled over a 20-year period (1984-2005). The most commonly observed complication was bronchiectasis (24 cases), followed by splenomegaly, intestinal villous atrophy (11 cases), and failure to thrive (10 cases). Post-diagnosis survival was estimated as 65% for the first 6.5 years, which remains the same until 14 years after diagnosis when the survival curve drops to nearly 45%. The mortality rate among patients who had no regular visits and did not receive periodical IVIG was more remarkable when compared with those who had been followed up timely (p-value = 0.001).The most common cause of death was respiratory failure. Based on our observation, it can be highlighted that all patients with CVID, even under regular immunoglobulin replacement, need close monitoring for early detection of complications and introduction of appropriate management.     

Pulmonary and sinus diseases in primary humoral immunodeficiencies with chronic productive cough.

AIMS: To prospectively evaluate sinopulmonary disease in 24 patients with primary humoral immunodeficiency (11 with agammaglobulinaemia, nine with isolated IgA deficiency, and two with common variable immunodeficiency) and chronic productive cough, ascertain the usefulness of chest high resolution computed tomography (HRCT) in evaluating the progression of lung disease, and test a therapeutic approach to chronic sinusitis. METHODS: Pulmonary abnormalities were evaluated using lung function tests and HRCT (Bhalla score); chronic sinusitis was diagnosed clinically and confirmed by flexible fibreoptic endoscopy. Sixteen patients entered the three year follow up. RESULTS: Lung function testing revealed an obstruction in four patients; chest HRCT was abnormal in 16. There was a linear relation between the Bhalla score > or =4 and the number of months with cough/year over the previous two years (clinical score), and between the difference in clinical scores during follow up and in the previous two years and the difference in Bhalla score. The pulmonary lesions did not significantly progress over a three year period. Thirteen patients had chronic sinusitis; 6/10 patients followed up were successfully treated with antibiotics plus topical therapy and two with nasal polypoid disease with endoscopic sinus surgery. CONCLUSIONS: In patients with primary humoral immunodeficiency and chronic productive cough, HRCT is very useful in delineating the extent of lung damage. The correlation between Bhalla score and clinical findings and the favourable outcome of the disease suggests that in most patients chest HRCT should not be repeated annually as previously suggested. Medical therapy seems to be effective in many cases of chronic sinusitis.     

Pulmonary and sinus diseases in primary humoral immunodeficiencies with chronic productive cough

Aims: To prospectively evaluate sinopulmonary disease in 24 patients with primary humoral immunodeficiency (11 with agammaglobulinaemia, nine with isolated IgA deficiency, and two with common variable immunodeficiency) and chronic productive cough, ascertain the usefulness of chest high resolution computed tomography (HRCT) in evaluating the progression of lung disease, and test a therapeutic approach to chronic sinusitis. Methods: Pulmonary abnormalities were evaluated using lung function tests and HRCT (Bhalla score); chronic sinusitis was diagnosed clinically and confirmed by flexible fibreoptic endoscopy. Sixteen patients entered the three year follow up. Results: Lung function testing revealed an obstruction in four patients; chest HRCT was abnormal in 16. There was a linear relation between the Bhalla score ?4 and the number of months with cough/year over the previous two years (clinical score), and between the difference in clinical scores during follow up and in the previous two years and the difference in Bhalla score. The pulmonary lesions did not significantly progress over a three year period. Thirteen patients had chronic sinusitis; 6/10 patients followed up were successfully treated with antibiotics plus topical therapy and two with nasal polypoid disease with endoscopic sinus surgery. Conclusions: In patients with primary humoral immunodeficiency and chronic productive cough, HRCT is very useful in delineating the extent of lung damage. The correlation between Bhalla score and clinical findings and the favourable outcome of the disease suggests that in most patients chest HRCT should not be repeated annually as previously suggested. Medical therapy seems to be effective in many cases of chronic sinusitis.     

Chest imaging findings of chronic respiratory disease in HIV-infected adolescents on combined anti retro viral therapy

Early treatment with combination antiretroviral therapy (cART) has improved survival of children perinatally infected with HIV into adolescence. This population is at risk of long term complications related to HIV infection, particularly chronic respiratory disease. Limited data on chest imaging findings in HIV-infected adolescents, suggest that the predominant disease is of small and large airways: predominantly bronchiolitis obliterans or bronchiectasis. Single cases of emphysema have been reported. Lung fibrosis, lymphocytic interstitial pneumonitis, post tuberculous apical fibrocystic changes and malignancies do not feature in this population. Chest radiograph (CXR) is easily accessible and widely used, especially in resource limited settings, such as sub Saharan Africa, where the greatest burden of HIV disease occurs. Lung ultrasound has been described for the diagnosis of pneumonia in children, pulmonary oedema and interstitial lung disease [1], [2], [3]. The use of this modality in chronic respiratory disease in adolescents where the predominant finding is small airway disease and bronchiectasis has however not been described. CXR is useful to evaluate structural/post infective changes, parenchymal opacification and nodules, hyperinflation or extensive bronchiectasis. CXR however, is inadequate for diagnosing small airway disease, for which high resolution computed tomography (HRCT) is the modality of choice. Where available, low dose HRCT should be used early in the course of symptomatic disease in adolescents and for follow up in children who are non responsive to treatment or clinically deteriorating.This article provides a pictorial review of the spectrum of CXR and HRCT imaging findings of chronic pulmonary disease in perinatally HIV-infected adolescents on cART and guidelines for imaging.     

Structural lung changes,lung function,and non‐invasive inflammatory markers in cystic fibrosis

Robroeks CMHHT, Roozeboom MH, de Jong PA, Tiddens HAWM, Jöbsis Q, Hendriks HJ, Yntema J‐BL, Brackel HL, van Gent R, Robben S, Dompeling E. Structural lung changes, lung function, and non‐invasive inflammatory markers in cystic fibrosis.
Pediatr Allergy Immunol 2010: 21: 493–500.
© 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard Cystic fibrosis (CF) lung disease is characterized by chronic airway inflammation and recurrent infections, resulting in (ir)reversible structural lung changes and a progressive decline in lung function. The objective of this study was to investigate the relationship between non‐invasive inflammatory markers (IM) in exhaled breath condensate (EBC), lung function indices and structural lung changes, visualized by high resolution computed tomography (HRCT) scans in CF. In 34 CF patients, lung function indices (forced expiratory volume in 1 s, forced vital capacity [FVC], residual volume, and total lung capacity [TLC]) and non‐invasive IM (exhaled nitric oxide, and condensate acidity, nitrate, nitrite, 8‐isoprostane, hydrogen peroxide, interferon‐gamma) were assessed. HRCT scans were scored in a standardized and validated way, a composite score and component scores were calculated. In general, the correlations between non‐invasive IM and structural lung changes, and between IM and lung function were low (correlation coefficients <0.40). Patients with positive sputum Pseudomonas cultures had higher EBC nitrite levels and higher parenchymal HRCT subscores than patients with Pseudomonas‐negative cultures (p < 0.05). Multiple linear regression models demonstrated that FVC was significantly predicted by hydrogen peroxide in EBC, and the scores of bronchiectasis and mosaic perfusion (Pearson correlation coefficient R = 0.78, p < 0.001). TLC was significantly predicted by 8‐isoprostane, nitrate, hydrogen peroxide in EBC, and the mucous plugging subscore (R = 0.92, p < 0.01). Static and dynamic lung function indices in this CF group were predicted by the combination of non‐invasive IM in EBC and structural lung changes on HRCT imaging. Future longitudinal studies should reveal whether non‐invasive monitoring of airway inflammation in CF adds to better follow‐up of patients.     

Spirometer-triggered high-resolution computed tomography and pulmonary function measurements during an acute exacerbation in patients with cystic fibrosis

OBJECTIVE: To evaluate a high-resolution computed tomography (HRCT) scoring system, clinical parameters, and pulmonary function measurements in patients with cystic fibrosis (CF) before and after therapy for a pulmonary exacerbation. STUDY DESIGN: Patients (n = 17) were evaluated by spirometer-triggered HRCT imaging, clinical parameters, and pulmonary function tests (PFTs) before and after treatment. HRCT scans were reviewed by 3 radiologists using a modified Bhalla scoring system. RESULTS: Bronchiectasis, bronchial wall thickening, and air trapping were identified in all subjects on initial evaluation. The initial total HRCT score correlated significantly with the Brasfield score (r = -.91, P <.001) and several PFT measures. After treatment, there were improvements in the acute change clinical score (ACCS) (P <.001), most pulmonary function measurements, and total HRCT score (P <.05). Bronchiectasis, bronchial wall thickening, and air trapping did not significantly change. Mucus plugging subcomponent HRCT score, slow vital capacity (SVC), forced expiratory volume in 1 second (FEV(1)), and forced vital capacity (FVC) (percent predicted) and reversible and total HRCT scores were most sensitive to change by effect size analysis. CONCLUSIONS: Improvements occurred with treatment in total and reversible HRCT scores, PFTs, and ACCS. Total and reversible HRCT scores and percent predicted SVC, FEV1, and FVC were the most sensitive to change. The greatest change was seen in the mucus plugging subcomponent HRCT score.     

Computed tomography scan assessment of lung disease in primary immunodeficiencies

A wide spectrum of lung disease can complicate primary immunodeficiencies and early recognition influences management and prognosis. Computed tomography (CT) especially high resolution computed tomography (HRCT) has been shown to detect lung disease in adult immunodeficient patients often when the chest radiograph (CXR) is normal, but this has not been studied in children. Twenty-five CT scans [10 HRCT] and CXRs were reviewed in 23 children [14 male, 9 female] with primary immunodeficiency. Eighteen [72%] of the CT scans were abnormal, bronchiectasis being the commonest finding present in eight CT scans in patients with antibody deficiency. In eight cases CT scan revealed changes not seen on CXR (bronchiectasis;interstitial changes; small parenchymal nodules; air trapping;and a small upper lobe cyst) which influenced treatment in six cases. Conclusion CT scans have a valuable role in assessing lung disease in children with primary immunodeficiencies and will detect important changes not visible on CXR. Received: 9 December 1997 / Accepted in revised form: 3 June 1998     

Pulmonary function testing and pulmonary Langerhans cell histiocytosis

In a long-term single-center follow-up (median 16-years), we studied high-resolution computed tomography (HRCT) and pulmonary function testing (PFT) in pulmonary LCH. Diffusing capacity corrected for alveolar volume (K(CO)) and total lung capacity (TLC) were significantly decreased (P=0.016 and P=0.030, respectively) in patients with extensive HRCT abnormalities. Patients with late stage disease on HRCT had increased forced expiratory volume (FEV1.0)(P=0.037) and vital capacity (VC)(P=0.036). Disease monitoring is important in pulmonary LCH, and since PFT with diffusing capacity provides a measurement of the current lung function, it may be a valuable tool in monitoring pulmonary LCH, and a good complement to imaging.     

Primary immune regulatory disorders for the pediatric hematologist and oncologist: A case‐based review

An array of monogenic immune defects marked by autoimmunity, lymphoproliferation, and hyperinflammation rather than infections have been described. Primary immune regulatory disorders pose a challenge to pediatric hematologists and oncologists. This paper focuses on primary immune regulatory disorders including autoimmune lymphoproliferative syndrome (ALPS) and ALPS‐like syndromes, immunodysregulation, polyendocrinopathy, enteropathy, X‐linked (IPEX) and IPEX‐like disorders, common variable immunodeficiency (CVID), CVID‐like, and late‐onset combined immunodeficiency (CID) disorders. Hyperinflammatory disorders and those associated with increased susceptibility to lymphoid malignancies are also discussed. Using a case‐based approach, a review of clinical pearls germane to the clinical and laboratory evaluation as well as the treatment of these disorders is provided.     

Hodgkin lymphoma in two siblings with common variable immunodeficiency

Common variable immunodeficiency (CVID) is a heterogeneous group of disorders, characterized by decreased serum immunoglobulin levels, and increased susceptibility to recurrent bacterial infections, malignancies, and autoimmune disorders. In this report, 2 siblings with CVID who developed Hodgkin lymphoma are presented: a 16-year-old girl at stage IIB and her 12-year-old brother at stage IIIB of Hodgkin lymphoma. Their father and 1 uncle were also affected by the same cancer with no immunodeficiency state. The presence of lymphoma should be considered in the patients with CVID, especially in those with family history of malignancies.     

Development of common variable immunodeficiency in a patient with Evans syndrome treated by autologous stem cell transplantation

We describe a case report of a patient who developed common variable immunodeficiency (CVID) after autologous haematopoietic stem cell transplantation (SCT) for recurrent Evans syndrome. The disease manifested as attacks of haemolytic anaemia, thrombocytopenia and neutropenia from the age of 12 years. Presence of autoantibodies to blood elements was confirmed together with C4 deficiency. The patient also suffered from dermatitis herpetiformis Duhring without signs of coeliac disease. Autologous T cell-depleted peripheral blood stem cell (PBSC) transplant following conditioning regimen was performed at the age of 20 years. Immunological reconstitution was incomplete and 2 years after SCT he fulfilled laboratory criteria for common variable immunodeficiency (CVID). The patient was found to be a carrier of a risk haplotype for development of CVID DRB1*03/DQB1*0201. We conclude that T cell-depleted SCT here performed for autoimmune manifestations can hasten development of CVID in genetically predisposed patients.     

A common variable immunodeficient patient who developed acute disseminated encephalomyelitis followed by the Lennox-Gastaut syndrome

Common variable immunodeficiency (CVID) is a primary disorder characterized by impaired antibody production. CVID patients may develop recurrent infections, autoimmune disorders, and malignant lymphomas, but to our knowledge, there is no report on CVID patients who develop acute disseminated encephalomyelitis (ADEM) or the Lennox-Gastaut syndrome. We describe a 1-yr-old female CVID patient with ADEM who evolutionally manifested the Lennox-Gastaut syndrome. She was admitted with convulsions and T2-weighted magnetic resonance imaging (MRI) revealed high-intensity areas in the right temporal lobe and the left fronto-parietal region but she became conscious soon. Her serum findings showed severe hypogammaglobulinemia and a follow up MRI revealed that these areas had diminished. Consequently, she was diagnosed as having CVID with ADEM. After 5 months, she fell to having tonic and absence seizures and we diagnosed her as having the Lennox-Gastaut syndrome from electroencephalograms (EEG) and the seizure pattern. She is now 7 yr old and her tonic seizures are controlled with valproic acid, clobazam, and immunoglobulin replacement therapy which is administrated every 2 wk. It is well known that the immune and neurologic systems have a close relationship. We suspect that a genetic defect in the immune system of our patient might also be associated with the neurologic disorders of ADEM and the Lennox-Gastaut syndrome.     

Bone marrow transplantation for CVID‐like humoral immune deficiency associated with red cell aplasia

Patients with common variable immunodeficiency (CVID) have a higher incidence of autoimmune disease, which may mark the disease onset; however, anemia secondary to pure red cell aplasia is an uncommon presenting feature. Here, we describe a case of CVID‐like humoral immune deficiency in a child who initially presented with red cell aplasia and ultimately developed progressive bone marrow failure. Although bone marrow transplantation (BMT) has been associated with high mortality in CVID, our patient was successfully treated with a matched sibling BMT and engrafted with >98% donor chimerism and the development of normal antibody titers to diphtheria and tetanus toxoids.     

Chest x-ray findings in the acute phase of Kawasaki disease

We reviewed the chest x-ray (CXR) findings and clinical courses of 129 patients with Kawasaki disease and found abnormal CXR findings in 14.7% of the patients. Reticulogranular pattern was the most frequent abnormality (89.5%), while peribronchial cuffing (21.1%), pleural effusion (15.8%), atelectasis (10.5%) and air trapping (5.3%) were also seen. In each of these patients, CXR abnormalities appeared within 10 days after the onset of illness. In the group with abnormal CXR findings, a statistically significant increase was noted in duration of fever, incidence of adventitious sounds, serum CRP levels and incidence of coronary arterial lesions and pericardial effusion, as compared with the group having normal CXR findings. The pathological basis of these CXR changes is not clear, since no biopsy or autopsy specimen was obtained from these patients, none of these patients showed definite heart failure, it is difficult to consider that abnormal CXR findings were due to heart failure. On the other hand, physical signs and previous pathological reports suggested that the causes of abnormal CXR findings were lower respiratory tract inflammation and/or pulmonary arteritis.     

儿童原发性免疫缺陷病的免疫学改变及分析

目的了解儿童原发性免疫缺陷病(PID)患儿的实验室免疫检查特点,为临床早期诊断PID提供依据。方法对76例PID患儿的免疫学检查包括细胞免疫和体液免疫指标进行回顾性总结及分析。结果体液免疫检查中,普通变异型免疫缺陷病(CVID)及联合免疫缺陷病的IgG均降低,尤以CVID降低更为明显,且伴IgA及CD19+B细胞明显降低;IgA降低主要见于CVID、选择性IgA缺乏症(IgAD)及共济失调毛细血管扩张症(AT);低丙种球蛋白血症患儿IgG、IgA及CD19+B细胞均降低。细胞免疫功能中CD3+、CD4+T细胞降低主要见于细胞免疫缺陷病、联合免疫缺陷病及DiGeorge综合征(DGS);AT患儿的CD4+/CD8+比例也降低。8例CVID患儿检测T细胞功能亚群及活化指标,其中5例患儿的CD4+/CD8+比例倒置(CD4+/CD8+<0.9);与对照组相比,CVID患儿的CD4+HLA-DR+和CD8+CD45RO+T细胞比例明显升高,CD4+CD45RA+T细胞比例明显降低(P均<0.01)。结论儿童原发性免疫缺陷病免疫学改变各异。CVID患者体内T细胞过度活化,可能是CVID患者容易罹患自身免疫性疾病的原因之一。     

Pulmonary Alveolar Proteinosis Secondary to Pneumocystis jiroveci Infection in an Infant with Common Variable Immunodeficiency

The authors report an infant with common variable immunodeficiency (CVID) with Pneumocystis pneumonia who developed secondary pulmonary alveolar proteinosis (PAP). This is the youngest infant reported to develop PAP secondary to Pneumocystis infection in an immunocompromised state. He was effectively managed with anti-microbials, frequent lung toilet, optimized mechanical ventilation, and supportive care.