Diffuse panbronchiolitis
Diffuse panbronchiolitis | |
---|---|
High-resolution computed tomography images of the lower chest in a 16-year-old boy with diffuse panbronchiolitis | |
Specialty | Pulmonology |
Diffuse panbronchiolitis (DPB) is an
production.The disease is believed to occur when there is susceptibility, or a lack of
If left untreated, DPB progresses to bronchiectasis, an irreversible lung condition that involves enlargement of the bronchioles, and pooling of mucus in the bronchiolar passages. Daily treatment of DPB with macrolide antibiotics such as erythromycin eases symptoms and increases survival time, but the disease currently has no known cure. The eventual result of DPB can be respiratory failure and heart problems.
Classification
The term "bronchiolitis" generally refers to inflammation of the bronchioles.
Signs and symptoms
Symptoms of DPB include
Cause
DPB is
The
Genetic predisposition for DPB susceptibility has been localized to two HLA haplotypes (a nucleotide or gene sequence difference between paired chromosomes, that is more likely to occur among a common ethnicity or trait) common to people of East Asian descent. HLA-B54 is associated with DPB in the Japanese, while HLA-A11 is associated with the disease in Koreans.[9] Several genes within this region of class I HLA are believed to be responsible for DPB, by allowing increased susceptibility to the disease.[7][10] The common genetic background and similarities in the HLA profile of affected Japanese and Korean individuals were considered in the search for a DPB gene.[10] It was suggested that a mutation of a suspected disease-susceptibility gene located somewhere between HLA-B[11] and HLA-A[12] had occurred on an ancestral chromosome carrying both HLA-B54 and HLA-A11. Further, it is possible that a number of genetic recombination events around the disease locus (location on a chromosome) could have resulted in the disease being associated with HLA-B54 in the Japanese and HLA-A11 in Koreans. After further study, it was concluded that a DPB susceptibility gene is located near the HLA-B locus at chromosome 6p21.3. Within this area, the search for a genetic cause of the disease has continued.[9][10]
Because many genes belonging to HLA remain unidentified, positional cloning (a method used to identify a specific gene, when only its location on a chromosome is known) has been used to determine that a mucin-like gene is associated with DPB. In addition, diseases caused by identified HLA genes in the DPB-susceptibility region have been investigated. One of these, bare lymphocyte syndrome I (BLS I), exhibits a number of similarities with DPB in those affected, including chronic sinusitis, bronchiolar inflammation and nodules, and the presence of H. influenzae. Also like DPB, BLS I responds favorably to erythromycin therapy by showing a resolution of symptoms. The similarities between these two diseases, the corresponding success with the same mode of treatment, and the fact that the gene responsible for BLS I is located within the DPB-causing area of HLA narrows the establishment of a gene responsible for DPB.[9] Environmental factors such as inhaling toxic fumes and cigarette smoking are not believed to play a role in DPB, and unknown environmental and other non-genetic causes—such as unidentified bacteria or viruses—have not been ruled out.[4][6][7]
Pathophysiology
Inflammation is a normal part of the human immune response, whereby
The fact that inflammation in DPB persists with or without the presence of P. aeruginosa and H. influenzae provides a means to determine several mechanisms of DPB pathogenesis.[5] Leukotrienes are eicosanoids, signaling molecules made from essential fatty acids, which play a role in many lung diseases by causing the proliferation of inflammatory cells and excess mucus production in the airways.[14] In DPB and other lung diseases, the predominant mediator of neutrophil-related inflammation is leukotriene B4, which specializes in neutrophil proliferation via chemotaxis (the movement of some types of cells toward or away from certain molecules).[4][9]
Inflammation in DPB is also caused by the chemokine
Diagnosis
The diagnosis of DPB requires
Differential diagnosis
In the differential diagnosis (finding the correct diagnosis between diseases that have overlapping features) of some obstructive lung diseases, DPB is often considered. A number of DPB symptoms resemble those found with other obstructive lung diseases such as asthma, chronic bronchitis, and emphysema. Wheezing, coughing with sputum production, and shortness of breath are common symptoms in such diseases, and obstructive respiratory functional impairment is found on pulmonary function testing.[6] Cystic fibrosis, like DPB, causes severe lung inflammation, excess mucus production, and infection; but DPB does not cause disturbances of the pancreas nor the electrolytes, as does CF, so the two diseases are different and probably unrelated.[4][9] DPB is distinguished by the presence of lesions that appear on X-rays as nodules in the bronchioles of both lungs; inflammation in all tissue layers of the respiratory bronchioles; and its higher prevalence among individuals with East Asian lineage.[4]
DPB and
Treatment
With erythromycin therapy in DPB, great reduction in bronchiolar inflammation and damage is achieved through suppression of not only neutrophil proliferation, but also lymphocyte activity and obstructive mucus and water secretions in airways.[16] The antibiotic effects of macrolides are not involved in their beneficial effects toward reducing inflammation in DPB.[20] This is evident because the treatment dosage is much too low to fight infection, and in DPB cases with the occurrence of macrolide-resistant P. aeruginosa, erythromycin therapy still reduces inflammation.[16]
A number of factors are involved in suppression of inflammation by erythromycin and other macrolides. They are especially effective at inhibiting the proliferation of neutrophils, by diminishing the ability of interleukin 8 and leukotriene B4 to attract them.[21] Macrolides also reduce the efficiency of adhesion molecules that allow neutrophils to stick to bronchiolar tissue linings. Mucus production in the airways is a major culprit in the morbidity and mortality of DPB and other respiratory diseases. The significant reduction of inflammation in DPB attributed to erythromycin therapy also helps to inhibit the production of excess mucus.[21]
Prognosis
Untreated DPB leads to bronchiectasis, respiratory failure, and death. A journal report from 1983 indicated that untreated DPB had a five-year survival rate of 62.1%, while the 10-year survival rate was 33.2%.[6] With erythromycin treatment, individuals with DPB now have a much longer life expectancy due to better management of symptoms, delay of progression, and prevention of associated infections like P. aeruginosa.[20] The 10-year survival rate for treated DPB is about 90%.[4] In DPB cases where treatment has resulted in significant improvement, which sometimes happens after about two years, treatment has been allowed to end for a while. However, individuals allowed to stop treatment during this time are closely monitored. As DPB has been proven to recur, erythromycin therapy must be promptly resumed once disease symptoms begin to reappear. In spite of the improved prognosis when treated, DPB currently has no known cure.[4][9]
Epidemiology
DPB has its highest prevalence among the Japanese, at 11 per 100,000 population.[4] Korean,[22] Chinese,[23] and Thai[24] individuals with the disease have been reported as well. A genetic predisposition among East Asians is suggested.[9] The disease is more common in males,[25] with the male to female ratio at 1.4–2:1 (or about 5 men to 3 women).[4] The average onset of the disease is around age 40, and two-thirds of those affected are non-smokers, although smoking is not believed to be a cause.[7] The presence of HLA-Bw54 increases the risk of diffuse panbronchiolitis 13.3-fold.[26]
In Europe and the Americas, a relatively small number of DPB cases have been reported in Asian immigrants and residents, as well as in individuals of non-Asian ancestry.[27][28][29] Misdiagnosis has occurred in the West owing to less recognition of the disease than in Asian countries. Relative to the large number of Asians living in the west, the small number of them thought to be affected by DPB suggests non-genetic factors may play some role in its cause. This rarity seen in Western Asians may also be partly associated with misdiagnosis.[7][30]
History
In the early 1960s, a relatively new chronic lung disease was being observed and described by physicians in Japan. In 1969,
Before the 1980s, the prognosis or expected outcome of DPB was poor, especially in cases with superinfection (the emergence of a new viral or bacterial infection, in addition to the currently occurring infection) by P. aeruginosa.[13] DPB continued to have a very high mortality rate before generalized antibiotic treatment and oxygen therapy were beginning to be used routinely in the effort to manage symptoms. Around 1985, when long-term treatment with the antibiotic erythromycin became the standard for managing DPB, the prognosis significantly improved.[20] In 1990, the association of DPB with HLA was initially asserted.[9]
References
- PMID 16493150. Archived from the original(Free full text) on 16 April 2010. Retrieved 16 August 2015.
- ^ PMID 14644923. Archived from the original(Free full text) on 2 December 2009. Retrieved 16 August 2015.
- ^ S2CID 23668839.
- ^ PMID 17012632.
- ^ PMID 11574201.
- ^ PMID 6848335.
- ^ PMID 21610988.
- ^ Morris AG, Hewitt C, Young S (1994). The major histocompatibility complex: its genes and their roles in antigen presentation. Vol. 15. Pergamon.
- ^ S2CID 13600381.
- ^ a b c Online Mendelian Inheritance in Man (OMIM): Panbronchiolitis, Diffuse - 604809 Retrieved 11 November 2011.
- ^ Online Mendelian Inheritance in Man (OMIM): Human Leukocyte Antigen B - 142830 Retrieved 21 September 2011.
- ^ Online Mendelian Inheritance in Man (OMIM): Human Leukocyte Antigen A - 142800 Retrieved 21 September 2011.
- ^ S2CID 24559334.
- PMID 9620941. Archived from the original(Free full text) on 10 May 2007. Retrieved 16 August 2015.
- PMID 21841323.
- ^ PMID 20610825.
- ^ PMID 18339582.
- PMID 25618845.
- S2CID 39880028.
- ^ PMID 15190022.
- ^ PMID 15586558.
- PMID 1504438.
- S2CID 37365518.
- PMID 10511794.
- PMID 8016786.
- ISBN 978-0-7216-0327-8.
- PMID 8756828.
- PMID 10746829.
- PMID 14679410.
- PMID 8977613.
- PMID 5783341.
External links