Diffuse panbronchiolitis

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Diffuse panbronchiolitis
High-resolution computed tomography images of the lower chest in a 16-year-old boy with diffuse panbronchiolitis
SpecialtyPulmonology

Diffuse panbronchiolitis (DPB) is an

terminal bronchioles, chronic sinusitis, and intense coughing with large amounts of sputum
production.

The disease is believed to occur when there is susceptibility, or a lack of

viruses, caused by several genes that are found predominantly in individuals of East Asian descent. The highest incidence occurs among Japanese people, followed by Koreans
. DPB occurs more often in males and usually begins around age 40. It was recognized as a distinct new disease in the early 1960s and was formally named diffuse panbronchiolitis in 1969.

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.

respiratory bronchiolitis, mineral dust airway disease, and a number of others.[2] Unlike DPB, bronchiolitis that is not considered "primary" would be associated with diseases of the larger airways, such as chronic bronchitis.[2][3]

Signs and symptoms

Symptoms of DPB include

right ventricle of the heart, or "right heart failure").[6][7]

Cause

The genes for human HLA are located on chromosome 6.

DPB is

environmental, or pathogenic cause of the disease is unknown. However, several factors are suspected to be involved with its pathogenesis (the way in which the disease works).[4]

The

cytotoxic T-cells, which kill the infected cells so they can be removed from the body.[8]

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]

polymorphism (variation) in this gene is known to occur in many Asians not necessarily affected by either disease. It is being investigated whether this gene in any state of mutation could contribute to DPB.[4][9]

Pathophysiology

Inflammation is a normal part of the human immune response, whereby

leukocytes (white blood cells), including neutrophils (white blood cells that specialize in causing inflammation), gather, and chemokines (proteins released from certain cells, which activate or elicit a response from other cells) accumulate at any location in the body where bacterial or viral infections occur. Inflammation interferes with the activity of bacteria and viruses, and serves to clear them from the body. In DPB, bacteria such as Haemophilus influenzae and Pseudomonas aeruginosa can cause the proliferation of inflammatory cells into the bronchiolar tissues. However, when neither bacteria are present with DPB, the inflammation continues for an as yet unknown reason.[4][5] In either circumstance, inflammation in DPB can be so severe that nodules containing inflammatory cells form in the walls of the bronchioles.[4][13] The presence of inflammation and infection in the airways also results in the production of excess mucus, which must be coughed up as sputum.[4][6] The combination of inflammation, nodule development, infection, mucus, and frequent cough contributes to the breathing difficulties in DPB.[4][5]

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

human T-lymphotropic virus, type I, a retrovirus, modifies DPB pathogenesis by infecting T helper cells and altering their effectiveness in recognizing the presence of known or unknown pathogens involved with DPB.[4][9]

Diagnosis

High resolution computed tomography (HRCT) images of the lower chest in a 16-year-old boy initially diagnosed with DPB (left), and 8 weeks later (right) after a 6-week course of treatment with erythromycin. The bilateral bronchiectasis and prominent centri-lobular nodules with a "tree-in-bud" pattern shows noticeable improvement.

The diagnosis of DPB requires

antibodies in the blood, may also occur. Neutrophils, beta-defensins, leukotrienes, and chemokines can also be detected in bronchoalveolar lavage fluid injected then removed from the bronchiolar airways of individuals with DPB, for evaluation.[4][9]

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

alveolar cell carcinoma.[15]

Treatment

Molecular structure of Erythromycin A, an antibiotic used to treat DPB

blood gas (an arterial blood test that measures the amount of oxygen and carbon dioxide in the blood) readings show that free oxygen in the blood is within the normal range.[16][17][20] Allowing a temporary break from erythromycin therapy in these instances has been suggested, to reduce the formation of macrolide-resistant P. aeruginosa.[16] However, DPB symptoms usually return, and treatment would need to be resumed. Although highly effective, erythromycin may not prove successful in all individuals with the disease, particularly if macrolide-resistant P. aeruginosa is present or previously untreated DPB has progressed to the point where respiratory failure is occurring.[17][20]

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,

alveolitis, and other obstructive lung disease with inflammation. Between 1978 and 1980, the results of a nationwide survey initiated by the Ministry of Health and Welfare of Japan revealed more than 1,000 probable cases of DPB, with 82 histologically confirmed. By the 1980s, it was internationally recognized as a distinct disease of the lungs.[4][6]

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

External links