Diffuse panbronchiolitis in a patient with common variable immunodeficiency: a casual association or a pathogenetic correlation?
© Ginori et al.; licensee BioMed Central Ltd. 2014
Received: 9 December 2013
Accepted: 10 January 2014
Published: 20 January 2014
Diffuse panbronchiolitis (DPB) is an idiopathic inflammatory disease that seems to have an immunological pathogenesis and that causes a severe progressive suppurative and obstructive respiratory disorder. Common variable immunodeficiency (CVID) is the most common serious primary immunodeficiency and it is often associated with respiratory diseases. Herein, we describe a case of DPB in a 41-year-old man affected by CVID. We examined the patient’s lungs, focusing on the characteristics of the inflammatory cells and of the foamy macrophagic nodules typical of DPB. Immunohistochemical typing of the lymphocytic infiltrate showed that B-cells were almost absent, matching the immunological profile of CVID. The case described is the first case reported in the literature of DPB in a patient affected by CVID. Moreover it seems to confirm the correlation between an immunodeficiency status and the development of DPB and provides more information on the accumulation of nodules of foamy macrophages in DPB.
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KeywordsDiffuse panbronchiolitis Common variable immunodeficiency Foamy macrophages Lymphocytes Interstitial lung disease
Diffuse panbronchiolitis (DPB) is an idiopathic inflammatory disease that is characterized by progressive suppurative and obstructive airway disease, which, if left untreated, gives rise to bronchiectases, respiratory failure and death . Chronic pulmonary obstructive disease (COPD) is characterized by irreversible airflow limitation and abnormal inflammatory response to noxious gases, especially cigarette smoke . Many pathogenetic mechanisms seem to be involved in the development of COPD, including delayed apoptosis of neutrophils , aberrant methylation of tumor suppressor genes  and an immune-modulatory role of surfactant proteins such as pulmonary haptoglobin . DPB was proposed as a disease entity, distinct from COPD, by Homma and Yamanaka in the 1960s in Japan, but it was not internationally accepted until the 1980s . The term “diffuse” refers to the distribution of the lesions throughout both lungs, and the term “pan-” refers to the inflammation which involves all the layers of the respiratory bronchioles . Outside Asia, only a limited number of cases have been reported. The prevalence of clinician-diagnosed DPB is 11 cases per 100,000 people , with a male to female ratio of 1.4 to 1 and a median age of 40-60 years. Patients suffer from chronic bacterial infection due to Haemophilus influenzae, Streptococcus pneumoniae and other species in the airways. Bacteria in the airway are gradually replaced by Pseudomonas aeruginosa and the disease is progressive in nature . The prognosis of patients with DPB was poor, with 5- and 10-year survival rates of 62.1 and 33.2%, respectively. However, long-term treatment with erythromycin has increased the 10-year survival rate to >90% . Although nothing is known about the aetiology of this disease, the finding of DPB among East Asians, including Asian emigrants, led to the suggestion that there could be a major susceptibility gene for DPB, located between the Human Leukocyte Antigen (HLA)-A and HLA-B loci . Moreover, DPB has also been compared and associated with cystic fibrosis (CF), bare lymphocyte syndrome (BLS) type I, human T-cell lymphotropic virus type 1 (HTLV-1) and rheumatoid arthritis [6, 9]. Common variable immunodeficiency (CVID) is the most common severe primary immunodeficiency with a reported prevalence of 1:30,000. CVID is a diagnosis of exclusion based on the presence of hypogammaglobulinaemia of at least two immunoglobulin isotypes, recurrent sinopulmonary infections, and impaired functional antibody responses, that include absent isohaemagglutinins, poor responses to protein or polysaccharide vaccines, or both . The cellular characteristics of the immune system in CVID are complex with several numerical and functional defects involving both B and T lymphocytes, natural killer cells, macrophages and monocytes. In patients with CVID, respiratory diseases are a significant cause of morbidity and mortality. Histologic studies revealed that interstitial lung disease (ILD) in the context of CVID may manifest as sarcoid-like granuloma, organizing pneumonia, nonspecific interstitial pneumonia (NSIP), follicular bronchiolitis and lymphocytic interstitial pneumonia (LIP). These different patterns may be found in adjacent zones or even intermingled within one lung specimen . In particular, LIP and follicular bronchiolitis belong to the same spectrum of benign lymphoproliferative disorders of the lungs  and often co-exist in CVID with pulmonary granulomatous diseases. For this reason they have recently been grouped together under the term granulomatous lymphocytic interstitial lung disease (GLILD) . Herein, we present a case of DPB in a man affected by CVID, and a pathogenetic correlation between these two entities is hypothesized. To the best of our knowledge, the association between DPB and CVID has never been described in the literature.
To the best of our knowledge, the case reported herein is the first case described in the literature of panbronchiolitis in a patient affected by CVID. The development of granulomatous disease or auto-immunity in CVID are two of the most problematic clinical complications . Although granulomas can be found in many organs, lungs are the most frequent and relevant location . In some patients an intense lymphoid infiltrate is associated with granulomas, realizing what has been termed GLILD . DPB is a rare disease characterized by chronic inflammation of respiratory bronchioles and sinobronchial infection . Inflammatory nodular lesions around the bronchioles occur diffusely throughout the lungs. Histopathologically, the nodules consist of lymphocytes and foamy macrophages around respiratory bronchioles. Interstitial accumulations of foamy macrophages in the wall of respiratory bronchioles and in the surrounding interalveolar septa represent peculiar histological features of DPB. The bronchiolar lumen contains neutrophils. Lymphoid follicles along the airways are also frequently noted. The inflammatory infiltrate destroys the bronchiolar epithelium and extends to peribronchiolar spaces. The cause of diffuse panbronchiolitis is still unknown, although it is reasonable to think that environmental factors and genetic susceptibility contribute to the development of the disease. Immunogenetic studies revealed a strong association with HLA-B54 in Japanese, whereas an association with HLA-A11 was reported in Koreans . Neutrophils and T-lymphocytes, particularly CD8+ cells, together with the cytokines interleukin (IL)-8 and macrophage inflammatory protein-1 are believed to play key roles in the development of DPB. Previous reports have suggested that the accumulation of neutrophils and IL-8 secretion in the airway lumen plays an important role in the pathogenesis of the disease . It is possible to speculate that neutrophil chemotactic factors at the site of inflammation and upregulation of adhesion molecules in the circulation can promote the entry of neutrophils into the airways. The accumulation of activated neutrophils in the airways may damage epithelial cells, by releasing oxidative and proteolytic products, and promote the development of extensive bronchiectases . The pathogenetic significance of bronchus-associated lymphoid tissue (BALT) is less clear, as well as the observed increase, in absolute number, of CD3+ cells. In addition, a significant increase both in the percentage and in the absolute number of activated CD8+ cells has been observed . The number of CD4+ cells is also increased . A marked increases of the number of dendritic cells (DCs), as in our case, is found in both the bronchiolar epithelium and in submucosal tissues of patients with DPB. The observed increase and activation of DCs in DPB may support an enhanced immune response around the bronchioles through the promotion of antigen presentation . The increase of foamy cells is considered a consequence of an abnormal uptake of surfactant proteins by macrophages, caused by airway obstruction or metabolic impairment . However, the interstitial location of foamy macrophages renders these causes unlikely. The hypothesis that a disorder of the immune system is implicated in the pathogenesis and the development of DPB is also supported by the association of DPB with other conditions as CF, BLS, HTLV-1 infection and rheumatoid arthritis . In our patient, PCR detection of most common respiratory viruses (including HTLV-1) was negative. Our case is different from the cases of DPB previously reported in the literature because there is no lymphoid hyperplasia and the nodules of foamy macrophages are more numerous and present both in perivascular and interstitial tissues. Moreover, there are neither sign of GLILD nor of the other granulomatous lesions described in literature in patients affected by CVID. In our case, a not yet identified trigger, probably of infectious origin, caused the accumulation of activated neutrophils in the airways, leading to a sequential activation of inflammatory pathways. In our patient, the reduced B-cell immunocompetence probably played an important role in the activation of an alternative immune response, characterized by CD4+ and CD8+ T-cells and also involving activated macrophages. According to our findings, the formation of nodules of foamy macrophages does not seem to depend on lymphoid hyperplasia, which is absent in our case, but probably depends on an insufficient or altered B or T lymphocytic response. Thus, the B-lymphocytic deficiency in our DPB would have led to an increase of nodules of foamy macrophages, involving also the peribronchial lymphatic and haematic vessels.
The case described herein is interesting not only because it is the first case of DPB in a patient affected by CVID reported in the literature, but also because it further supports the heterogeneity of the clinical manifestations of CVID. It seems to confirm the correlation between an immunodeficiency status and the development of DPB. It provides more information on the accumulation of nodules of foamy macrophages in DPB, but further studies are needed to better understand the pathogenesis of DPB and its relationship with immunodeficiency status. However, it should be remembered that in cases like that reported herein an interdisciplinary case evaluation is necessary to find correct diagnoses .
Written informed consent was obtained from the patient for publication of this Case Report and any all accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
chronic obstructive pulmonary disease
common variable immunodeficiency
human leukocyte antigen
bare lymphocyte syndrome
human T-cell lymphotropic virus type 1
interstitial lung disease
nonspecific interstitial pneumonia
lymphocytic interstitial pneumonia
granulomatous lymphocytic interstitial lung disease
partial pressure of oxygen
pressure of carbon dioxide
New York Heart Association
forced vital capacity
forced respiratory volume in one second
total lung capacity
high resolution computed tomography
haematoxylin and eosin
bronchus-associated lymphoid tissue
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