Diffuse panbronchiolitis

Diffuse panbronchiolitis (DPB) is an idiopathic (of unknown cause) inflammatory lung disease, considered to be a type of COPD. It is a severe, progressive form of bronchiolitis, mainly affecting the respiratory bronchioles (the section of the bronchioles involved in gas exchange).

The term "diffuse" refers to the lesions which appear throughout both lungs, while the term "pan-" refers to the inflammation found in all layers of the respiratory bronchioles, both terms describing a common pathology for the disease.

If left untreated, DPB is fatal, usually progressing to bronchiectasis, an irreversible lung conditon that causes respiratory failure.



Prevalence
DPB has the highest incidence among Japanese. Korean, Chinese and Thai cases have been reported as well. A genetic predisposition among East Asians is indicated,  with a lower worldwide prevalence of DPB still usually related to Asian ancestry. However, rare cases of DPB, being those in the western world in individuals with non-Asian lineage, have also been noted.

Symptoms
DPB can be characterized by a number of symptoms and histological features (those detected by analysis of tissues).

These include: chronic bronchial and bronchiolar inflammation, lung tissue lesions, proliferation of lymphocytes (white blood cells that fight infection), neutrophil granulocytes (white blood cells involved with inflammation) and foamy histiocytes (tissue macrophages) in the lung lumen; detectable haemophilus influenzae (an opportunistic bacterium), pseudomonas aeruginosa (another opportunistic bacterium) and pus in the sputum (coughed-up phlegm);  chronic sinusitis (inflamed paranasal sinuses),  hypoxemia (low levels of oxygen in the blood), nodules within terminal and respiratory bronchioles in both lungs,  dyspnea (shortness of breath), elevated IgG and IgA (classes of immunoglobulins), occurrences of elevated rheumatoid factor (an indicator of autoimmunity), and hemagglutination (clumping of antibodies in the blood).

If left untreated, as DPB progresses, signs of bronchiectasis begin to present themselves. These symptoms include chronic shortness of breath, severe cough, pooling of sputum, thickening of bronchiolar walls, hypoxemia, and dilation (enlargement) of the bronchiolar passages. This eventually becomes life-threatening, leading to respiratory failure.

Pathogenesis
DPB remains idiopathic, which means an exact physiological, environmental, or pathogenic cause of the disease is unknown. However, several known factors are involved with the pathogenesis of DPB.

The major histocompatibility complex (MHC) is a large genomic region found in most vertebrates, that is associated with mating and the immune system. It is located on chromosome 6 in humans. A subset of the human MHC is human leukocyte antigen (HLA), which controls the antigen presenting system, as part of adaptive immunity against pathogens such as bacteria and viruses.

Genetic predisposition for DPB has been localized to two HLA haplotypes unique to Asians, particularly of East Asian descent. HLA-B54 is associated with DPB in Japanese patients, while HLA-A11 is associated with the disease in Koreans. One or more candidate genes (a gene suspected to be responsible for a trait or disease) within this region of class I HLA are believed to be the genetic factor responsible for DPB, allowing disease susceptibility related to the structure of the antigen presenting molecules selected by these genes.

Candidate genes within HLA that are most likely involved with DPB suceptibility include: C6orf37 and TAP2.

Another such gene, though not a part of the HLA system, is the gene for interleukin 8 (IL-8) located on chromosome 4. The role of IL-8 to produce inflammation by causing the proliferation of neutrophil granulocytes at any site of pathogenic involvement, in conjunction with strong microsatellite identification with DPB, implicates IL-8 as another candidate gene associated with DPB pathogenesis. This also supports the idea that several factors, including those unrelated to HLA as well as non-genetic, and unknown factors, may cause the disease.

The inflammation common to DPB also provides a means to determine other mechanisms of disease pathogenesis. This may be partly due to the persistence of inflammation in DPB, with or without the presence of the two opportunistic bacteria sometimes found with the disease (haemophilus influenzae, pseudomonas aeruginosa). Inflammation caused by the chemokine MIP-1alpha and its involvement with CD8+ T-cells is believed to be one such mechanism of DPB pathogenesis.

Other factors found with DPB play a part in its pathogenesis by sometimes causing minor variations of it.

Beta defensins, a family of antimicrobial peptides found in the respiratory tract, are responsible for further inflammation in DPB, when associated pathogens like pseudomonas aerugenosa are present.

If present in a DPB patient, the human T-lymphotropic virus, type I, a retrovirus, modifies DPB pathogenesis by infecting CD4+ cells (Helper T-cells) and altering there effectiveness in reducing both known and unknown pathogenic involvement with DPB. Conversely, an onset of DPB causes increased frequency of Adult T-cell leukemia in human lymphotropic virus sufferers.

Treatment
Macrolide antibiotics, such as erythromycin, clarithromycin and roxithromycin, have proven to be an effective long-term treatment for DPB. The successful results of macrolides in DPB and similar lung diseases stems from controlling symptoms through immunomodulation (adjusting the immune response), with the added benefit of low-dose requirements.

With macrolide therapy in DPB, great reduction in bronchiolar inflammation and damage is achieved through suppression of not only neutrophil granulocyte proliferation, but also lymphocyte activity and obstructive mucus and sputum secretions in airways. The antimicrobial and antibiotic effects of macrolides, however, are not believed to be involved in their beneficial effects toward treating DPB. This is evident, as the treatment dosage is much too low to fight infection, and in DPB cases with the occurrence of macrolide-resistant pseudomonas aeruginosa, macrolide therapy still produces substantial anti-inflammatory results.

Advanced cases of DPB, where severely excessive sputum production resistant to macrolides persists, additional therapy with the inhalant tiotropium has been shown to ease these symptoms and the related shortness of breath.