Romain Lazor

Granulomatosis-associated common variable immunodeficiency disorder: a case–control study versus sarcoidosis

The aim of the present study was to investigate to what extent interstitial lung disease (ILD) in common variable immunodeficiency disorder (CVID)-associated granulomatous disease (GD) is similar to pulmonary sarcoidosis 20 patients with CVID/GD were included in a retrospective study conducted by the Groupe Sarcoïdose Francophone. Medical records were centralised. Patients were compared with 60 controls with sarcoidosis. Clinical examination showed more frequent crackles in patients than controls (45% versus 1.7%, respectively; p<0.001). On thoracic computed tomography scans, nodules (often multiple and with smooth margins), air bronchograms and halo signs were more frequent in patients than controls (80% versus 42%, respectively; p=0.004) as well as bronchiectasis (65% versus 23%, respectively; p<0.001). The micronodule distribution was perilymphatic in 100% of controls and in 42% of patients (p<0.001). Bronchoalveolar lavage analysis showed lower T-cell CD4/CD8 ratios in patients than in controls (mean±sd 1.6±1.1 versus 5.3±4, respectively; p<0.01). On pathological analysis, nodules and consolidations corresponded to granulomatous lesions with or without lymphocytic disorders in most cases. Mortality was higher in patients than controls (30% versus 0%, respectively) and resulted from common variable immunodeficiency complications. ILD in CVID/GD presents a specific clinical picture and evolution that are markedly different from those of sarcoidosis.

DNAI1 Mutations Explain Only 2% of Primary Ciliary Dykinesia

Background: Primary ciliary dyskinesia (PCD) is a rare recessive hereditary disorder characterized by dysmotility to immotility of ciliated and flagellated structures. Its main symptoms are respiratory, caused by defective ciliary beating in the epithelium of the upper airways (nose, bronchi and paranasal sinuses). Impairing the drainage of inhaled microorganisms and particles leads to recurrent infections and pulmonary complications. To date, 5 genes encoding 3 dynein protein arm subunits (DNAI1, DNAH5 and DNAH11), the kinase TXNDC3 and the X-linked RPGR have been found to be mutated in PCD. Objectives: We proposed to determine the impact of the DNAI1 gene on a cohort of unrelated PCD patients (n = 104) recruited without any phenotypic preselection. Methods: We used denaturing high-performance liquid chromatography and sequencing to screen for mutations in the coding and splicing site sequences of the gene DNAI1. Results: Three mutations were identified: a novel missense variant (p.Glu174Lys) was found in 1 patient and 2 previously reported variants were identified (p.Trp568Ser in 1 patient and IVS1+2_3insT in 3 patients). Overall, mutations on both alleles of gene DNAI1 were identified in only 2% of our clinically heterogeneous cohort of patients. Conclusion: We conclude that DNAI1 gene mutation is not a common cause of PCD, and that major or several additional disease gene(s) still remain to be identified before a sensitive molecular diagnostic test can be developed for PCD.

Mutations in DNAH5 account for only 15% of a non-preselected cohort of patients with primary ciliary dyskinesia

Background: Primary ciliary dyskinesia (PCD) is characterised by recurrent infections of the upper respiratory airways (nose, bronchi, and frontal sinuses) and randomisation of left–right body asymmetry. To date, PCD is mainly described with autosomal recessive inheritance and mutations have been found in five genes: the dynein arm protein subunits DNAI1, DNAH5 and DNAH11, the kinase TXNDC3, and the X-linked retinitis pigmentosa GTPase regulator RPGR. Methods: We screened 89 unrelated individuals with PCD for mutations in the coding and splice site regions of the gene DNAH5 by denaturing high performance liquid chromatography (DHPLC) and sequencing. Patients were mainly of European origin and were recruited without any phenotypic preselection. Results: We identified 18 novel (nonsense, splicing, small deletion and missense) and six previously described mutations. Interestingly, these DNAH5 mutations were mainly associated with outer + inner dyneins arm ultrastructural defects (50%). Conclusion: Overall, mutations on both alleles of DNAH5 were identified in 15% of our clinically heterogeneous cohort of patients. Although genetic alterations remain to be identified in most patients, DNAH5 is to date the main PCD gene.

Shrinking Lung Syndrome Successfully Treated with Rituximab and Cyclophosphamide

Shrinking lung syndrome (SLS) is an uncommon feature of systemic lupus erythematosus (SLE) characterized by dyspnea, pleuritic chest pain, diaphragmatic elevation, restrictive ventilatory defect and reduced respiratory muscle strength as measured by volitional tests. We report the case of a 28-year-old woman with overlapping features of SLE and Sjögren syndrome who developed severe SLS while receiving corticosteroids and azathioprine for severe polyarthritis. She was treated with a combination of rituximab and cyclophosphamide, which led to a dramatic improvement in her clinical condition and respiratory function tests. The increase in vital capacity was one of the highest among 35 published cases of SLS. Thus, restoring a near-normal lung function is an achievable goal in SLS, and the use of rituximab, with or without concomitant cyclophosphamide, certainly deserves further study in this setting.

Idiopathic Pulmonary Fibrosis in Switzerland: Diagnosis and Treatment

Idiopathic pulmonary fibrosis (IPF) is a severe progressive and irreversible lung disease. Novel antifibrotic drugs that slow disease progression are now available. However, many issues regarding patient management remain unanswered, such as the choice between available drugs, their use in particular subgroups and clinical situations, time of treatment onset, termination, combination or switch, or nonpharmacologic management. To guide Swiss respiratory physicians in this evolving field still characterized by numerous areas of uncertainty, the Swiss Working Group for interstitial and rare lung diseases of the Swiss Respiratory Society provides a position paper on the diagnosis and treatment of IPF.

Idiopathic Eosinophilic Pneumonias

Eosinophilic lung diseases constitute a broad array of disorders of various origin. Beside infectious, drug-induced, and allergic diseases, 4 idiopathic eosinophilic disorders have been identified.

Many Faces of Bronchiolitis and Organizing Pneumonia.

As the bronchioles have a strategic position between the airways and the alveolar structures, they are at a site where disorders of many origins may develop, including infections, inflammatory and/or fibrosing processes of immune, occupational, environmental, tumoral, and iatrogenic origin, which may result in predominant bronchiolitis and/or organizing pneumonia. This etiologic variety results in many distinct entities and syndromes, common or rare, with new or renewed faces such as bronchiolocentric interstitial pneumonia or organizing pneumonia primed by radiation to the breast.

Pulmonary Involvement in Adult Patients with Inborn Errors of Metabolism

Inborn errors of metabolism (IEM) are rare individually, but taken together, they affect 1 in 1,000 people. Most of the disease becomes apparent at the pediatric age; however, with the identification of late-onset forms, and with improved survival, several of these conditions may be found in adults of all ages. While the lung is not typically a primary site of clinical disease in patients with IEM, in some of them it can be a significantly affected organ with associated severe respiratory complications. Lung involvement can be a late- onset feature of a complex multisystemic disease, but sometimes it can also be the only manifestation of underlying IEM. The aim of this review is to focus on specific IEM associated with lung disease in adults and to provide the reader with an overview of the diagnostic workup, overall disease management, and specific treatments for the respiratory manifestations. Clinical suspicion, early recognition, prompt diagnosis, and appropriate care of the respiratory manifestation are crucial, as they can affect both the life expectancy and the quality of life of these patients.

Diagnostic Value of the CD103+CD4+/CD4+ Ratio to Differentiate Sarcoidosis from Other Causes of Lymphocytic Alveolitis

Background: The CD103 integrin is present on CD4+ lymphocytes of the bronchial mucosa, but not on peripheral blood CD4+ lymphocytes. It has been hypothesized that CD4+ lymphocytes in pulmonary sarcoidosis originate from redistribution from the peripheral blood to the lung, and therefore do not bear the CD103 integrin. Some data suggest that a low CD103+ percentage among bronchoalveolar lavage fluid (BALF) CD4+ lymphocytes discriminates between sarcoidosis and other diagnoses. Objective: To determine the diagnostic value of BALF CD103+ to identify sarcoidosis among other causes of alveolar lymphocytosis in a large retrospective case series. Methods: Among 391 consecutive bronchoalveolar lavages performed at our institution and analyzed by flow cytometry, we identified 207 cases, which were grouped into nine diagnostic categories: sarcoidosis, tuberculosis, non-tuberculous infections, hypersensitivity pneumonitis, non-specific interstitial pneumonia, organizing pneumonia, drug-induced lung diseases, other interstitial lung diseases (ILDs), and other diagnoses. To assess the discriminative value of the CD103+CD4+/CD4+ ratio to distinguish sarcoidosis from other entities, areas under ROC curves (AUC) were calculated. Results: Sarcoidosis patients (n = 53) had significantly lower CD103+CD4+/CD4+ ratios than patients in other diagnostic categories. The AUC was 62% for sarcoidosis compared to all other diagnoses, and 69% for sarcoidosis compared to other ILDs. When combining CD103+CD4+/CD4+ and CD4+/CD8+ ratios, the AUC increased to 76 and 78%, respectively. When applying previously published cut-offs to our population, the AUC varied between 54 and 73%. Conclusions: The CD103+CD4+/CD4+ ratio does not accurately discriminate between sarcoidosis and other causes of lymphocytic alveolitis, neither alone nor in combination with the CD4+/CD8+ ratio, and is not a powerful marker for the diagnosis of sarcoidosis.

Lung Involvement in Sjögren’s Syndrome: Interstitium, Airways, or Both?

function abnormalities in up to 80% [5] , suggesting that subclinical pulmonary involvement is common. Although lung involvement in PSS appears usually mild with stable lung function in most patients [6] , deterioration [7] and acute exacerbations [8] may also occur, with a respiratory mortality at 5 years of 16% [9] . A broad spectrum of lung involvement has been described in PSS, including xerotrachea with chronic cough, lymphocytic bronchial inflammation, lymphocytic interstitial pneumonia, organizing pneumonia, nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia, follicular or constrictive bronchiolitis, primary pulmonary lymphoma, amyloidosis, multiple cysts and pulmonary hypertension [8–11] . In earlier studies, lymphocytic interstitial pneumonia was considered as the dominant pattern of lung involvement [10, 11] . More recently, in two series involving 18 and 33 SLB cases [8, 9] , respectively, NSIP appeared as the most common histopathologic pattern (28 and 61% of cases, respectively), whereas organizing pneumonia, lymphoma, and usual and lymphocytic interstitial pneumonia were less common. In these studies [8–11] , bronchiolitis was only a rare or minor component (11–17% of cases), and obstructive ventilatory impairment occurred in only 9–13% [8, 9] . This was discordant with other studies essentially based on lung function [12] and chest imaging [13] , where small airway disease (SAD) was a frequent finding. The study by Shi et al. [1] confirms that NSIP is a major feature, which was found in 36%. Additionally, in contrast to previous histopathologic data [8–11] , bronchiolitis appears very common, occurring in up to 79% of casIn this issue of Respiration , Shi et al. [1] present a retrospective series of 14 cases of primary Sjögren’s syndrome (PSS) with lung involvement documented by surgical lung biopsy (SLB). PSS is a systemic autoimmune disorder mainly characterized by lymphocytic inflammatory infiltrates of the salivary and lacrymal glands resulting in persistent dryness of the mouth and eyes (sicca syndrome). Its pathogenesis involves chronic immune system stimulation, presumably triggered by the presentation of unknown antigen(s) to CD4+ T lymphocytes by glandular epithelial cells, Tand B-lymphocyte recruitment and activation to form lymphoepithelial lesions, and polyclonal B-lymphocyte proliferation and hyperreactivity, with autoantibody production and hypergammaglobulinemia. In a minority of cases, a sequence of immune and genetic events may eventually lead to low-/ intermediate-grade extranodal B-cell lymphoma. The diagnosis of PSS is currently based on symptoms and signs of inadequate tear production, symptoms and tests indicating impaired salivary gland function, salivary gland histopathology, and presence of anti-SSA and/or antiSSB autoantibodies [2] . Although exocrine gland involvement is a hallmark of the disease, systemic extraglandular manifestations occur in two thirds of cases [3] . The frequency of pulmonary involvement in PSS has been reported to vary broadly. In the largest series of PSS published so far (1,010 patients), the prevalence of symptomatic lung involvement was 11% at diagnosis, and 19% at the 10-year follow-up [3] . However, screening of PSS patients without respiratory symptoms disclosed alveolitis in bronchoalveolar lavage (BAL) in 55% [4] and lung Published online: August 7, 2009