Diffuse panbronchiolitis
Encyclopedia
Diffuse panbronchiolitis (DPB) is an inflammatory
lung disease of unknown cause. It is a severe, progressive form of bronchiolitis
, which is inflammation of the bronchiole
s, small air passages in the lungs. The term "diffuse" refers to the lesion
s that appear throughout both lungs, while "panbronchiolitis" refers to the inflammation found in all layers of the respiratory bronchioles (the section of the bronchioles involved in gas exchange
). DPB causes severe inflammation of the respiratory bronchioles, nodule
-like lesions in respiratory and terminal bronchiole
s, 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 immune system
resistance to DPB-causing bacteria or a virus, caused by several genes that are found predominantly in individuals of East Asian descent. The highest incidence
occurs among the Japanese, 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. The eventual result of DPB can lead to respiratory failure
and heart problems. Daily treatment of DPB with macrolide
antibiotic
s such as erythromycin
eases symptoms and increases survival time, but the disease has no cure.
, follicular bronchiolitis, respiratory bronchiolitis, mineral dust airway disease, and a number of others.
es), a severe cough with large amounts of sputum (coughed-up phlegm), wheezing, crackles
(respiratory sounds made by obstructions such as phlegm and secretion
s in the lungs), and dyspnea
(shortness of breath). There may be pus
in the sputum, and affected individuals may have fever. Signs of DPB that include dilation (enlargement) of the bronchiolar passages and hypoxemia
(low levels of oxygen in the blood) are revealed via lung X-rays and blood gas
ses (a blood test from an artery
, used to measure the oxygen and carbon dioxide content of the blood), respectively. If left untreated, DPB progresses and signs of bronchiectasis begin to present themselves. These include advancement of the dilation and thickening of the walls of the bronchioles, inflammatory damage to respiratory and terminal bronchiole
s, and pooling of mucus in the lungs. DPB is associated with progressive respiratory failure
, hypercapnia
(increased levels of carbon dioxide in the blood), and can eventually lead to pulmonary hypertension
(high blood pressure in the pulmonary vein
and artery
) and cor pulmonale
(dilation of the right ventricle
, or "right heart failure").
DPB is idiopathic
, which means an exact physiological, environment
al, or pathogen
ic 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 vertebrate
s that is associated with the immune system. It is located on chromosome 6 in humans. A subset of MHC in humans is human leukocyte antigen
(HLA), which controls the antigen-presenting system
, as part of adaptive immunity against pathogens such as bacteria
and virus
es. When human cells are infected by a pathogen, some of them present parts of the pathogen's proteins on their surfaces; this is called antigen presentation. The infected cells then become targets for types of cytotoxic T-cells, which kill the infected cells so they can be removed from the body.
Genetic predisposition for DPB susceptibility has been localized to two HLA haplotype
s unique to Asians, particularly of East Asian descent. HLA-B54
is associated with DPB in Japanese individuals, while HLA-A11
is associated with the disease in Koreans. Several genes within this region of class I HLA
are believed to be a genetic factor responsible for DPB, by allowing increased susceptibility to the disease. The common genetic background and similarities in the HLA profile of Japanese and Korean individuals were considered in the search for a DPB gene. It was suggested that a mutation of a suspected disease-susceptibility gene located somewhere between HLA-B
and HLA-A
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 of this localized area between HLA-B and HLA-A, it was concluded that a DPB susceptibility gene is located within a 200 kb (kilobase, or 1,000 base pair
s) region of the 300 kb telomeric
class I HLA, near the HLA-B locus at chromosome 6p21.3.
Within this localized area of HLA, the search for a genetic cause of DPB has continued. As many genes belonging to HLA remain unidentified, positional cloning (a method used to identify a specific gene for a trait or disease, 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 known to be 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 respiratory similarities between these two diseases, the corresponding success with the same mode of treatment, and the fact that the genetic mutation known to cause BLS I is located within the DPB-causing area of HLA narrows the establishment of a gene responsible for DPB. Environmental factors such as inhaling toxic fumes and cigarette smoking are not believed to play a role in causing the disease.
Cystic fibrosis
(CF), a progressive multi-system lung disease, has been considered in the search for a genetic cause of DPB. This is for a number of reasons. CF, like DPB, causes severe lung inflammation, abundant mucus production, infection, and shows a genetic predominance among Caucasians of one geographic group to the rarity of others; whereas DPB dominates among East Asians, CF mainly affects individuals of European descent. While no gene has been implicated as the cause of DPB, mutation in a specific gene–much more likely to occur in Europeans–causes CF. This mutation in the CF-causing gene
is not a factor in DPB, but a unique polymorphism in this gene is known to occur in many Asians not necessarily affected by either disease. It is wondered if this gene in any state of mutation could contribute to DPB.
s to accumulate at any location in the body where active bacterial or viral infections occur. Inflammation interferes with the activity of pathogens like bacteria and viruses, and serves to clear them from the body. In more advanced cases of DPB, bacteria such as Pseudomonas aeruginosa
cause the proliferation of inflammatory cells into the bronchiolar tissues. However, when P. aeruginosa is not present with DPB, the inflammation continues for an as yet unknown reason. In either circumstance, inflammation in DPB can be so severe that nodules containing inflammatory cells form in the walls of the bronchioles. The presence of inflammation and infection in the airway also results in the production of excess mucus, which must be coughed up as sputum. The combination of inflammation, nodule development, infection, mucus, and frequent cough contributes to the breathing difficulties in DPB.
The inflammation in DPB persists with or without the presence of two bacteria typically found with the disease (P. aeruginosa and Haemophilus influenzae
), and provides a means to determine several mechanisms of disease pathogenesis. Leukotrienes are eicosanoid
s, signaling molecules
made from essential fatty acid
s, which play a role in many lung diseases by causing the proliferation of inflammatory cells and excess mucus production in the airway. In DPB and other lung diseases, the predominant mediator of neutrophil-related inflammation is leukotriene B4
, which specializes in neutrophil proliferation via chemotaxis
(the attraction of some types of cells to certain molecules specifically designed to attract them).
Inflammation in DPB is also caused by the chemokine MIP-1alpha
and its involvement with CD8+
T cell
s. The leukotriene
s are an important contributor to inflammation in the respiratory tract. Beta defensin
s, a family of antimicrobial
peptide
s found in the respiratory tract, are responsible for further inflammation in DPB when a pathogen such as P. aeruginosa is present. If present with DPB, the human T-lymphotropic virus, type I
, a retrovirus
, modifies DPB pathogenesis by infecting CD4+
T cells (T helper cell
s) and altering their effectiveness in recognizing the presence of known or unknown pathogens involved with DPB. Conversely, in individuals with human lymphotropic virus, onset of DPB increases the frequency of adult T-cell leukemia
.
of the lungs and bronchiolar tissues. Analysis of these tissues can require a lung biopsy
, or the more preferred high resolution computed tomography (HRCT) scan of the lungs. Distinguishing features of the disease that confirm its diagnosis include severe inflammation in all layers of the respiratory bronchioles, and lung tissue lesions that appear as nodules within the terminal
and respiratory bronchioles in both lungs. The nodules appear as opaque
lumps when viewed on X-ray
s of the lung, and are responsible for airway obstruction
in DPB, which is evaluated by a pulmonary function test
, or PFT. HRCT scans often show blockages of some bronchiolar passages with mucus, which is referred to as the "tree-in-bud"
pattern. Other findings observed with DPB include the proliferation of lymphocyte
s (white blood cell
s that fight infection), neutrophil granulocytes (white blood cells involved with inflammation), and foamy histiocytes
(tissue macrophage
s) in the lung lumen
. Bacteria such as H. influenzae and P. aeruginosa are also detectable, with the latter becoming more prominent as the disease progresses. Elevated levels of IgG and IgA
(classes of immunoglobulins) may be seen, as well as the presence of rheumatoid factor
(an indicator of autoimmunity
). Hemagglutination
, a clumping of red blood cells in response to the presence of antibodies in the blood, may also occur. Neutrophils, beta-defensins, leukotrienes, and chemokines can also be detected in bronchoalveolar lavage
(BAL) fluid taken from individuals with DPB.
(finding the correct diagnosis between two or more suspected diseases that have common, or overlapping features) of some obstructive lung diseases, DPB is often considered. 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 nearly exclusive prevalence among individuals with East Asian lineage. 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 obstructive lung diseases, and obstructive respiratory functional impairment is found on pulmonary function testing
. Cystic fibrosis, like DPB, causes severe lung inflammation, excess mucus production, and infection; but DPB does not cause disturbances of the pancreas nor the electrolyte
s, as does CF, so the two diseases are different and probably unrelated.
DPB and bronchiolitis obliterans (or obliterative bronchiolitis, OB) are two forms of primary bronchiolitis. Specific features of both diseases found to overlap include strong cough with large amounts of often pus-filled sputum, nodules viewable on lung X-rays in the lower bronchi and bronchiolar area, and chronic sinusitis. In DPB, the nodules are more restricted to the respiratory bronchioles, while in OB they are often found in the membranous bronchioles (the initial non-cartilaginous section of the bronchiole, that divides from the tertiary bronchus
) up to the secondary bronchus
. OB is a bronchiolar disease with worldwide prevalence, while DPB has more localized prevalence, predominantly in Japan.
Macrolide
antibiotics, particularly erythromycin
, are an effective treatment for DPB when taken regularly over an extended period of time. Long-term treatment of an individual with DPB consists of daily oral administration of erythromycin for an indefinite period lasting two to three years, depending upon the success of treatment. Erythromycin therapy over an extended period has been shown to dramatically improve the effects of DPB, apparent when an individual undergoing treatment for DPB, among a number of disease-related remission criteria, has a normal neutrophil count detected in BAL fluid, and 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. Allowing a temporary break from erythromycin therapy in these instances has been suggested, to reduce the formation of macrolide-resistant P. aeruginosa. In those cases where treatment can be stopped for a time, however, DPB symptoms eventually 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.
The successful results of macrolides in DPB and similar lung diseases stems from managing certain symptoms through immunomodulation (adjusting the immune response), which can be achieved by taking macrolides in low doses
. 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 secretion
s in airways. The antibiotic effects of macrolides are not involved in their beneficial effects toward reducing inflammation in DPB. 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, macrolide therapy still produces substantial anti-inflammatory results.
A number of factors are involved in suppression of inflammation by erythromycin or other macrolides. Macrolides are especially effective at inhibiting the proliferation and activity of neutrophils, by diminishing the ability of interleukin 8
and leukotriene B4
to attract them. 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 greatly inhibits the production of excess mucus.
, and other obstructive lung disease with inflammation. Between 1978 and 1980, results of a nation-wide 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.
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. 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 macrolide antibiotic erythromycin became the standard for managing DPB, the prognosis significantly improved. In 1990, the association of DPB with HLA was initially asserted.
among the Japanese, at 11 per 100,000 population. Korean, Chinese, and Thai individuals with the disease have been reported as well. A genetic predisposition among East Asians is indicated. Rare cases of DPB in individuals with non-Asian lineage have also been noted. The disease is slightly more common in males, with the male to female ratio at 1.4:2.1. The average onset of the disease is around age 40, and two-thirds of those affected with it are non-smokers.
DPB has been reported in a few Asian immigrants and residents in western countries, including those of Europe and North America. Misdiagnosis has occurred in the west due 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.
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
lung disease of unknown cause. It is a severe, progressive form of bronchiolitis
Bronchiolitis
Bronchiolitis is inflammation of the bronchioles, the smallest air passages of the lungs. It usually occurs in children less than two years of age and presents with coughing, wheezing, and shortness of breath. This inflammation is usually caused by viruses...
, which is inflammation of the bronchiole
Bronchiole
The bronchioles or bronchioli are the first airway branches that no longer contain cartilage or glands in their submucosa. They are branches of the bronchi.The bronchioles terminate by entering the circular sacs called alveoli.- Structure :...
s, small air passages in the lungs. The term "diffuse" refers to the lesion
Lesion
A lesion is any abnormality in the tissue of an organism , usually caused by disease or trauma. Lesion is derived from the Latin word laesio which means injury.- Types :...
s that appear throughout both lungs, while "panbronchiolitis" refers to the inflammation found in all layers of the respiratory bronchioles (the section of the bronchioles involved in gas exchange
Gas exchange
Gas exchange is a process in biology where gases contained in an organism and atmosphere transfer or exchange. In human gas-exchange, gases contained in the blood of human bodies exchange with gases contained in the atmosphere. Human gas-exchange occurs in the lungs...
). DPB causes severe inflammation of the respiratory bronchioles, nodule
Nodule (medicine)
For use of the term nodule in dermatology, see Nodule In medicine, a nodule refers to a relatively hard, roughly spherical abnormal structure....
-like lesions in respiratory and terminal bronchiole
Terminal bronchiole
A terminal bronchiole is a bronchiole at the end of the conducting zone. At the transition into the respiratory zone, alveoli become present.The terminal bronchiole is the most distal segment of the conducting zone. Each of the terminal bronchioles divides to form respiratory bronchioles which...
s, chronic sinusitis
Sinusitis
Sinusitis is inflammation of the paranasal sinuses, which may be due to infection, allergy, or autoimmune issues. Most cases are due to a viral infection and resolve over the course of 10 days...
and intense coughing with large amounts of sputum
Sputum
Sputum is mucus that is coughed up from the lower airways. It is usually used for microbiological investigations of respiratory infections....
production.
The disease is believed to occur when there is susceptibility, or a lack of immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
resistance to DPB-causing bacteria or a virus, caused by several genes that are found predominantly in individuals of East Asian descent. The highest incidence
Incidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...
occurs among the Japanese, 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
If left untreated, DPB progresses to bronchiectasis
Bronchiectasis
Bronchiectasis is a disease state defined by localized, irreversible dilation of part of the bronchial tree caused by destruction of the muscle and elastic tissue. It is classified as an obstructive lung disease, along with emphysema, bronchitis, asthma, and cystic fibrosis...
, an irreversible lung condition that involves enlargement of the bronchioles, and pooling of mucus
Mucus
In vertebrates, mucus is a slippery secretion produced by, and covering, mucous membranes. Mucous fluid is typically produced from mucous cells found in mucous glands. Mucous cells secrete products that are rich in glycoproteins and water. Mucous fluid may also originate from mixed glands, which...
in the bronchiolar passages. The eventual result of DPB can lead to respiratory failure
Respiratory failure
The term respiratory failure, in medicine, is used to describe inadequate gas exchange by the respiratory system, with the result that arterial oxygen and/or carbon dioxide levels cannot be maintained within their normal ranges. A drop in blood oxygenation is known as hypoxemia; a rise in arterial...
and heart problems. Daily treatment of DPB with macrolide
Macrolide
The macrolides are a group of drugs whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered...
antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s such as erythromycin
Erythromycin
Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...
eases symptoms and increases survival time, but the disease has no cure.
Classification
Bronchiolitis generally describes inflammation of the bronchioles. DPB is classified as a form of "primary bronchiolitis", which means that the underlying cause of bronchiolitis is originating from or is confined to the bronchioles. Along with DPB, additional forms of primary bronchiolitis include bronchiolitis obliteransBronchiolitis obliterans
Bronchiolitis obliterans , also called obliterative bronchiolitis and constrictive bronchiolitis , is a rare and life-threatening form of non-reversible obstructive lung disease in which the bronchioles are compressed and narrowed by fibrosis and/or inflammation...
, follicular bronchiolitis, respiratory bronchiolitis, mineral dust airway disease, and a number of others.
Signs and symptoms
Symptoms of DPB include chronic sinusitis (inflamed paranasal sinusParanasal sinus
Paranasal sinuses are a group of four paired air-filled spaces that surround the nasal cavity , above and between the eyes , and behind the ethmoids...
es), a severe cough with large amounts of sputum (coughed-up phlegm), wheezing, crackles
Rales
Crackles, crepitations, or rales are the clicking, rattling, or crackling noises that may be made by one or both lungs of a human with a respiratory disease during inhalation. They are often heard only with a stethoscope...
(respiratory sounds made by obstructions such as phlegm and secretion
Secretion
Secretion is the process of elaborating, releasing, and oozing chemicals, or a secreted chemical substance from a cell or gland. In contrast to excretion, the substance may have a certain function, rather than being a waste product...
s in the lungs), and dyspnea
Dyspnea
Dyspnea , shortness of breath , or air hunger, is the subjective symptom of breathlessness.It is a normal symptom of heavy exertion but becomes pathological if it occurs in unexpected situations...
(shortness of breath). There may be pus
Pus
Pus is a viscous exudate, typically whitish-yellow, yellow, or yellow-brown, formed at the site of inflammatory during infection. An accumulation of pus in an enclosed tissue space is known as an abscess, whereas a visible collection of pus within or beneath the epidermis is known as a pustule or...
in the sputum, and affected individuals may have fever. Signs of DPB that include dilation (enlargement) of the bronchiolar passages and hypoxemia
Hypoxemia
Hypoxemia is generally defined as decreased partial pressure of oxygen in blood, sometimes specifically as less than or causing hemoglobin oxygen saturation of less than 90%.-Distinction from anemia and hypoxia:...
(low levels of oxygen in the blood) are revealed via lung X-rays and blood gas
Arterial blood gas
An arterial blood gas is a blood test that is performed using blood from an artery. It involves puncturing an artery with a thin needle and syringe and drawing a small volume of blood. The most common puncture site is the radial artery at the wrist, but sometimes the femoral artery in the groin or...
ses (a blood test from an artery
Artery
Arteries are blood vessels that carry blood away from the heart. This blood is normally oxygenated, exceptions made for the pulmonary and umbilical arteries....
, used to measure the oxygen and carbon dioxide content of the blood), respectively. If left untreated, DPB progresses and signs of bronchiectasis begin to present themselves. These include advancement of the dilation and thickening of the walls of the bronchioles, inflammatory damage to respiratory and terminal bronchiole
Terminal bronchiole
A terminal bronchiole is a bronchiole at the end of the conducting zone. At the transition into the respiratory zone, alveoli become present.The terminal bronchiole is the most distal segment of the conducting zone. Each of the terminal bronchioles divides to form respiratory bronchioles which...
s, and pooling of mucus in the lungs. DPB is associated with progressive respiratory failure
Respiratory failure
The term respiratory failure, in medicine, is used to describe inadequate gas exchange by the respiratory system, with the result that arterial oxygen and/or carbon dioxide levels cannot be maintained within their normal ranges. A drop in blood oxygenation is known as hypoxemia; a rise in arterial...
, hypercapnia
Hypercapnia
Hypercapnia or hypercapnea , also known as hypercarbia, is a condition where there is too much carbon dioxide in the blood...
(increased levels of carbon dioxide in the blood), and can eventually lead to pulmonary hypertension
Pulmonary hypertension
In medicine, pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion...
(high blood pressure in the pulmonary vein
Pulmonary vein
The pulmonary veins are large blood vessels that carry blood from the lungs to the left atrium of the heart. In humans there are four pulmonary veins, two from each lung...
and artery
Pulmonary artery
The pulmonary arteries carry deoxygenated blood from the heart to the lungs. They are the only arteries that carry deoxygenated blood....
) and cor pulmonale
Cor pulmonale
Cor pulmonale or pulmonary heart disease is enlargement of the right ventricle of the heart as a response to increased resistance or high blood pressure in the lungs ....
(dilation of the right ventricle
Right ventricle
The right ventricle is one of four chambers in the human heart. It receives deoxygenated blood from the right atrium via the tricuspid valve, and pumps it into the pulmonary artery via the pulmonary valve and pulmonary trunk....
, or "right heart failure").
Cause
Idiopathic
Idiopathic is an adjective used primarily in medicine meaning arising spontaneously or from an obscure or unknown cause. From Greek ἴδιος, idios + πάθος, pathos , it means approximately "a disease of its own kind". It is technically a term from nosology, the classification of disease...
, which means an exact physiological, environment
Environment (biophysical)
The biophysical environment is the combined modeling of the physical environment and the biological life forms within the environment, and includes all variables, parameters as well as conditions and modes inside the Earth's biosphere. The biophysical environment can be divided into two categories:...
al, or pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
ic cause of the disease is unknown. However, several known factors are involved with the pathogenesis of DPB.
The major histocompatibility complex
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
(MHC) is a large genomic
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
region found in most vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
s that is associated with the immune system. It is located on chromosome 6 in humans. A subset of MHC in humans is human leukocyte antigen
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
(HLA), which controls the antigen-presenting system
Antigen presentation
Antigen presentation is a process in the body's immune system by which macrophages, dendritic cells and other cell types capture antigens and then enable their recognition by T-cells....
, as part of adaptive immunity against pathogens such as bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
and virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es. When human cells are infected by a pathogen, some of them present parts of the pathogen's proteins on their surfaces; this is called antigen presentation. The infected cells then become targets for types of cytotoxic T-cells, which kill the infected cells so they can be removed from the body.
Genetic predisposition for DPB susceptibility has been localized to two HLA haplotype
Haplotype
A haplotype in genetics is a combination of alleles at adjacent locations on the chromosome that are transmitted together...
s unique to Asians, particularly of East Asian descent. HLA-B54
HLA-B54
HLA-B54 is an HLA-B serotype. B54 is a split antigen from the B22 broad antigen, sister serotypes are B55 and B56. The serotype identifies the more common HLA-B*55 gene products.-Serotype:-Allele distribution:...
is associated with DPB in Japanese individuals, while HLA-A11
HLA-A11
HLA-A11 is a human leukocyte antigen serotype within HLA-A "A" serotype group. The serotype is determined by the antibody recognition of α11 subset of HLA-A α-chains. For A11, the alpha "A" chain are encoded by the HLA-A*11 allele group and the β-chain are encoded by B2M locus. This group...
is associated with the disease in Koreans. Several genes within this region of class I HLA
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
are believed to be a genetic factor responsible for DPB, by allowing increased susceptibility to the disease. The common genetic background and similarities in the HLA profile of Japanese and Korean individuals were considered in the search for a DPB gene. It was suggested that a mutation of a suspected disease-susceptibility gene located somewhere between HLA-B
HLA-B
HLA-B is a human gene that provides instructions for making a protein that plays a critical role in the immune system. HLA-B is part of a family of genes called the human leukocyte antigen complex...
and HLA-A
HLA-A
HLA-A are a group of human leukocyte antigens that are encoded by the HLA-A locus on human chromosome 6p. The HLA genes constitute a large subset of the Major histocompatibility complex of humans. HLA-A is a component of certain MHC class I cell surface receptor isoforms that resides on the...
had occurred on an ancestral chromosome carrying both HLA-B54 and HLA-A11. Further, it is possible that a number of genetic recombination
Genetic recombination
Genetic recombination is a process by which a molecule of nucleic acid is broken and then joined to a different one. Recombination can occur between similar molecules of DNA, as in homologous recombination, or dissimilar molecules, as in non-homologous end joining. Recombination is a common method...
events around the disease locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
(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 of this localized area between HLA-B and HLA-A, it was concluded that a DPB susceptibility gene is located within a 200 kb (kilobase, or 1,000 base pair
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
s) region of the 300 kb telomeric
Telomere
A telomere is a region of repetitive DNA sequences at the end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos "end" and merοs "part"...
class I HLA, near the HLA-B locus at chromosome 6p21.3.
Within this localized area of HLA, the search for a genetic cause of DPB has continued. As many genes belonging to HLA remain unidentified, positional cloning (a method used to identify a specific gene for a trait or disease, when only its location on a chromosome is known) has been used to determine that a mucin-like
Mucin
Mucins are a family of high molecular weight, heavily glycosylated proteins produced by epithelial tissues in most metazoans. Mucins' key characteristic is their ability to form gels; therefore they are a key component in most gel-like secretions, serving functions from lubrication to cell...
gene is associated with DPB. In addition, diseases known to be 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 respiratory similarities between these two diseases, the corresponding success with the same mode of treatment, and the fact that the genetic mutation known to cause BLS I is located within the DPB-causing area of HLA narrows the establishment of a gene responsible for DPB. Environmental factors such as inhaling toxic fumes and cigarette smoking are not believed to play a role in causing the disease.
Cystic fibrosis
Cystic fibrosis
Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...
(CF), a progressive multi-system lung disease, has been considered in the search for a genetic cause of DPB. This is for a number of reasons. CF, like DPB, causes severe lung inflammation, abundant mucus production, infection, and shows a genetic predominance among Caucasians of one geographic group to the rarity of others; whereas DPB dominates among East Asians, CF mainly affects individuals of European descent. While no gene has been implicated as the cause of DPB, mutation in a specific gene–much more likely to occur in Europeans–causes CF. This mutation in the CF-causing gene
Cystic fibrosis transmembrane conductance regulator
Cystic fibrosis transmembrane conductance regulator is a protein that in humans is encoded by the CFTR gene.CFTR is a ABC transporter-class ion channel that transports chloride and thiocyanate ions across epithelial cell membranes...
is not a factor in DPB, but a unique polymorphism in this gene is known to occur in many Asians not necessarily affected by either disease. It is wondered if this gene in any state of mutation could contribute to DPB.
Pathophysiology
Inflammation is a normal part of the human immune response, whereby the immune system causes leukocytes (white blood cells) to gather and chemokineChemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...
s to accumulate at any location in the body where active bacterial or viral infections occur. Inflammation interferes with the activity of pathogens like bacteria and viruses, and serves to clear them from the body. In more advanced cases of DPB, bacteria such as Pseudomonas aeruginosa
Pseudomonas aeruginosa
Pseudomonas aeruginosa is a common bacterium that can cause disease in animals, including humans. It is found in soil, water, skin flora, and most man-made environments throughout the world. It thrives not only in normal atmospheres, but also in hypoxic atmospheres, and has, thus, colonized many...
cause the proliferation of inflammatory cells into the bronchiolar tissues. However, when P. aeruginosa is not present with DPB, the inflammation continues for an as yet unknown reason. In either circumstance, inflammation in DPB can be so severe that nodules containing inflammatory cells form in the walls of the bronchioles. The presence of inflammation and infection in the airway also results in the production of excess mucus, which must be coughed up as sputum. The combination of inflammation, nodule development, infection, mucus, and frequent cough contributes to the breathing difficulties in DPB.
The inflammation in DPB persists with or without the presence of two bacteria typically found with the disease (P. aeruginosa and Haemophilus influenzae
Haemophilus influenzae
Haemophilus influenzae, formerly called Pfeiffer's bacillus or Bacillus influenzae, Gram-negative, rod-shaped bacterium first described in 1892 by Richard Pfeiffer during an influenza pandemic. A member of the Pasteurellaceae family, it is generally aerobic, but can grow as a facultative anaerobe. H...
), and provides a means to determine several mechanisms of disease pathogenesis. Leukotrienes are eicosanoid
Eicosanoid
In biochemistry, eicosanoids are signaling molecules made by oxidation of twenty-carbon essential fatty acids, ....
s, signaling molecules
Lipid signaling
Lipid signaling, broadly defined, refers to any biological signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses...
made from essential fatty acid
Essential fatty acid
Essential fatty acids, or EFAs, are fatty acids that humans and other animals must ingest because the body requires them for good health but cannot synthesize them...
s, which play a role in many lung diseases by causing the proliferation of inflammatory cells and excess mucus production in the airway. In DPB and other lung diseases, the predominant mediator of neutrophil-related inflammation is leukotriene B4
Leukotriene B4
Leukotriene B4 is a leukotriene involved in inflammation. It is produced from leukocytes in response to inflammatory mediators and is able to induce the adhesion and activation of leukocytes on the endothelium, allowing them to bind to and cross it into the tissue...
, which specializes in neutrophil proliferation via chemotaxis
Chemotaxis
Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...
(the attraction of some types of cells to certain molecules specifically designed to attract them).
Inflammation in DPB is also caused by the chemokine MIP-1alpha
CCL4
Chemokine ligand 4, also known as CCL4, is a protein which in humans is encoded by the CCL4 gene.- Function :CCL4, also known as Macrophage inflammatory protein-1β is a CC chemokine with specificity for CCR5 receptors...
and its involvement with CD8+
CD8
CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor . Like the TCR, CD8 binds to a major histocompatibility complex molecule, but is specific for the class I MHC protein. There are two isoforms of the protein, alpha and beta, each encoded by a different gene...
T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s. The leukotriene
Leukotriene
Leukotrienes are fatty signaling molecules. They were first found in leukocytes . One of their roles is to trigger contractions in the smooth muscles lining the trachea; their overproduction is a major cause of inflammation in asthma and allergic rhinitis...
s are an important contributor to inflammation in the respiratory tract. Beta defensin
Beta defensin
Beta defensins are a family of mammalian defensins. The beta defensins are antimicrobial peptides implicated in theresistance of epithelial surfaces to microbial colonization....
s, a family of antimicrobial
Antimicrobial
An anti-microbial is a substance that kills or inhibits the growth of microorganisms such as bacteria, fungi, or protozoans. Antimicrobial drugs either kill microbes or prevent the growth of microbes...
peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
s found in the respiratory tract, are responsible for further inflammation in DPB when a pathogen such as P. aeruginosa is present. If present with DPB, the human T-lymphotropic virus, type I
Human T-lymphotropic virus
Human T-cell Lymphotropic Virus Type 1 , also called the Adult T-cell lymphoma virus type 1, a virus that has been seriously implicated in several kinds of diseases including HTLV-I-associated myelopathy, Strongyloides stercoralis hyper-infection, and a virus cancer link for leukemia...
, a retrovirus
Retrovirus
A retrovirus is an RNA virus that is duplicated in a host cell using the reverse transcriptase enzyme to produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an integrase enzyme. The virus thereafter replicates as part of the host cell's DNA...
, modifies DPB pathogenesis by infecting CD4+
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
T cells (T helper cell
T helper cell
T helper cells are a sub-group of lymphocytes, a type of white blood cell, that play an important role in the immune system, particularly in the adaptive immune system. These cells have no cytotoxic or phagocytic activity; they cannot kill infected host cells or pathogens. Rather, they help other...
s) and altering their effectiveness in recognizing the presence of known or unknown pathogens involved with DPB. Conversely, in individuals with human lymphotropic virus, onset of DPB increases the frequency of adult T-cell leukemia
Adult T-cell leukemia
Adult T-cell leukemia/lymphoma is a rare cancer of the immune system's own T-cells.Human T cell leukemia/lymphotropic virus type 1 is believed to be the cause of it, in addition to several other diseases.-Signs and symptoms:...
.
Diagnosis
The diagnosis of DPB requires analysisMedical test
A diagnostic test is any kind of medical test performed to aid in the diagnosis or detection of disease. For example:* to diagnose diseases, and preferably sub-classify it regarding, for example, severity and treatability...
of the lungs and bronchiolar tissues. Analysis of these tissues can require a lung biopsy
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
, or the more preferred high resolution computed tomography (HRCT) scan of the lungs. Distinguishing features of the disease that confirm its diagnosis include severe inflammation in all layers of the respiratory bronchioles, and lung tissue lesions that appear as nodules within the terminal
Terminal bronchiole
A terminal bronchiole is a bronchiole at the end of the conducting zone. At the transition into the respiratory zone, alveoli become present.The terminal bronchiole is the most distal segment of the conducting zone. Each of the terminal bronchioles divides to form respiratory bronchioles which...
and respiratory bronchioles in both lungs. The nodules appear as opaque
Opacity (optics)
Opacity is the measure of impenetrability to electromagnetic or other kinds of radiation, especially visible light. In radiative transfer, it describes the absorption and scattering of radiation in a medium, such as a plasma, dielectric, shielding material, glass, etc...
lumps when viewed on X-ray
X-ray
X-radiation is a form of electromagnetic radiation. X-rays have a wavelength in the range of 0.01 to 10 nanometers, corresponding to frequencies in the range 30 petahertz to 30 exahertz and energies in the range 120 eV to 120 keV. They are shorter in wavelength than UV rays and longer than gamma...
s of the lung, and are responsible for airway obstruction
Airway obstruction
Airway obstruction is a respiratory problem caused by increased resistance in the bronchioles that reduces the amount of air inhaled in each breath and the oxygen that reaches the pulmonary arteries...
in DPB, which is evaluated by a pulmonary function test
Spirometry
Spirometry is the most common of the pulmonary function tests , measuring lung function, specifically the measurement of the amount and/or speed of air that can be inhaled and exhaled...
, or PFT. HRCT scans often show blockages of some bronchiolar passages with mucus, which is referred to as the "tree-in-bud"
Tree-in-bud sign
In radiology, the tree-in-bud sign is a finding on computed tomography scans that indicates some degree of airway plugging.It is associated with infection that has spread endobronchially and is classically associated with tuberculosis and bronchopneumonia...
pattern. Other findings observed with DPB include the proliferation of lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s (white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s that fight infection), neutrophil granulocytes (white blood cells involved with inflammation), and foamy histiocytes
Histiocyte
A histiocyte is a cell that is part of the mononuclear phagocyte system . The mononuclear phagocytic system is part of the organism's immune system...
(tissue macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s) in the lung lumen
Lumen (anatomy)
A lumen in biology is the inside space of a tubular structure, such as an artery or intestine...
. Bacteria such as H. influenzae and P. aeruginosa are also detectable, with the latter becoming more prominent as the disease progresses. Elevated levels of IgG and IgA
IGA
Iga or IGA may stand for:-Given name:* a female given name of Polish origin. The name originates from the female given name Jadwiga and stands for gia,or gina in the USA....
(classes of immunoglobulins) may be seen, as well as the presence of rheumatoid factor
Rheumatoid factor
Rheumatoid factor is an autoantibody most relevant in rheumatoid arthritis. It is defined as an antibody against the Fc portion of IgG. RF and IgG join to form immune complexes that contribute to the disease process...
(an indicator of autoimmunity
Autoimmunity
Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...
). Hemagglutination
Hemagglutination
Hemagglutination, or haemagglutination, is a specific form of agglutination that involves red blood cells . It has two common uses in the laboratory: blood typing and the quantification of virus dilutions.-Blood Typing:...
, a clumping of red blood cells in response to the presence of antibodies in the blood, may also occur. Neutrophils, beta-defensins, leukotrienes, and chemokines can also be detected in bronchoalveolar lavage
Bronchoalveolar lavage
Bronchoalveolar lavage is a medical procedure in which a bronchoscope is passed through the mouth or nose into the lungs and fluid is squirted into a small part of the lung and then recollected for examination. BAL is typically performed to diagnose lung disease...
(BAL) fluid taken from individuals with DPB.
Differential diagnosis
In the differential diagnosisDifferential diagnosis
A differential diagnosis is a systematic diagnostic method used to identify the presence of an entity where multiple alternatives are possible , and may also refer to any of the included candidate alternatives A differential diagnosis (sometimes abbreviated DDx, ddx, DD, D/Dx, or ΔΔ) is a...
(finding the correct diagnosis between two or more suspected diseases that have common, or overlapping features) of some obstructive lung diseases, DPB is often considered. 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
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
layers of the respiratory bronchioles, and its nearly exclusive prevalence among individuals with East Asian lineage. A number of DPB symptoms resemble those found with other obstructive lung diseases such as asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
, chronic bronchitis
Chronic bronchitis
Chronic bronchitis is a chronic inflammation of the bronchi in the lungs. It is generally considered one of the two forms of chronic obstructive pulmonary disease...
, and emphysema
Emphysema
Emphysema is a long-term, progressive disease of the lungs that primarily causes shortness of breath. In people with emphysema, the tissues necessary to support the physical shape and function of the lungs are destroyed. It is included in a group of diseases called chronic obstructive pulmonary...
. Wheezing
Wheeze
A wheeze is a continuous, coarse, whistling sound produced in the respiratory airways during breathing. For wheezes to occur, some part of the respiratory tree must be narrowed or obstructed, or airflow velocity within the respiratory tree must be heightened...
, coughing with sputum
Sputum
Sputum is mucus that is coughed up from the lower airways. It is usually used for microbiological investigations of respiratory infections....
production, and shortness of breath are common symptoms in obstructive lung diseases, and obstructive respiratory functional impairment is found on pulmonary function testing
Pulmonary function testing
Pulmonary Function Testing is a complete evaluation of the respiratory system including patient history, physical examinations, chest x-ray examinations, arterial blood gas analysis, and tests of pulmonary function. The primary purpose of pulmonary function testing is to identify the severity of...
. Cystic fibrosis, like DPB, causes severe lung inflammation, excess mucus production, and infection; but DPB does not cause disturbances of the pancreas nor the electrolyte
Electrolyte
In chemistry, an electrolyte is any substance containing free ions that make the substance electrically conductive. The most typical electrolyte is an ionic solution, but molten electrolytes and solid electrolytes are also possible....
s, as does CF, so the two diseases are different and probably unrelated.
DPB and bronchiolitis obliterans (or obliterative bronchiolitis, OB) are two forms of primary bronchiolitis. Specific features of both diseases found to overlap include strong cough with large amounts of often pus-filled sputum, nodules viewable on lung X-rays in the lower bronchi and bronchiolar area, and chronic sinusitis. In DPB, the nodules are more restricted to the respiratory bronchioles, while in OB they are often found in the membranous bronchioles (the initial non-cartilaginous section of the bronchiole, that divides from the tertiary bronchus
Tertiary bronchus
The tertiary bronchi arise from the secondary bronchi. The respiratory epithelium lining their lumen is surrounded by a layer of smooth muscle. This layer is composed of two ribbons of smooth muscle that spiral in opposite directions...
) up to the secondary bronchus
Secondary bronchus
Secondary bronchi arise from the primary bronchi, with each one serving as the airway to a specific lobe of the lung.-Structure:...
. OB is a bronchiolar disease with worldwide prevalence, while DPB has more localized prevalence, predominantly in Japan.
Treatment
Macrolide
The macrolides are a group of drugs whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered...
antibiotics, particularly erythromycin
Erythromycin
Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...
, are an effective treatment for DPB when taken regularly over an extended period of time. Long-term treatment of an individual with DPB consists of daily oral administration of erythromycin for an indefinite period lasting two to three years, depending upon the success of treatment. Erythromycin therapy over an extended period has been shown to dramatically improve the effects of DPB, apparent when an individual undergoing treatment for DPB, among a number of disease-related remission criteria, has a normal neutrophil count detected in BAL fluid, and blood gas
Arterial blood gas
An arterial blood gas is a blood test that is performed using blood from an artery. It involves puncturing an artery with a thin needle and syringe and drawing a small volume of blood. The most common puncture site is the radial artery at the wrist, but sometimes the femoral artery in the groin or...
(an arterial
Artery
Arteries are blood vessels that carry blood away from the heart. This blood is normally oxygenated, exceptions made for the pulmonary and umbilical arteries....
blood test
Blood test
A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....
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. Allowing a temporary break from erythromycin therapy in these instances has been suggested, to reduce the formation of macrolide-resistant P. aeruginosa. In those cases where treatment can be stopped for a time, however, DPB symptoms eventually 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.
The successful results of macrolides in DPB and similar lung diseases stems from managing certain symptoms through immunomodulation (adjusting the immune response), which can be achieved by taking macrolides in low doses
Dosing
Dosing generally applies to feeding chemicals or medicines in small quantities into a process fluid or to a living being at intervals or to atmosphere at intervals to give sufficient time for the chemical or medicine to react or show the results....
. 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 secretion
Secretion
Secretion is the process of elaborating, releasing, and oozing chemicals, or a secreted chemical substance from a cell or gland. In contrast to excretion, the substance may have a certain function, rather than being a waste product...
s in airways. The antibiotic effects of macrolides are not involved in their beneficial effects toward reducing inflammation in DPB. 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, macrolide therapy still produces substantial anti-inflammatory results.
A number of factors are involved in suppression of inflammation by erythromycin or other macrolides. Macrolides are especially effective at inhibiting the proliferation and activity of neutrophils, by diminishing the ability of interleukin 8
Interleukin 8
Interleukin-8 is a chemokine produced by macrophages and other cell types such as epithelial cells. It is also synthesized by endothelial cells, which store IL-8 in their storage vesicles, the Weibel-Palade bodies...
and leukotriene B4
Leukotriene B4
Leukotriene B4 is a leukotriene involved in inflammation. It is produced from leukocytes in response to inflammatory mediators and is able to induce the adhesion and activation of leukocytes on the endothelium, allowing them to bind to and cross it into the tissue...
to attract them. Macrolides also reduce the efficiency of adhesion molecules
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
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 greatly inhibits the production of excess mucus.
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%. With erythromycin treatment, particularly if used early upon the initial diagnosis, individuals with DPB now have a much longer life expectancy due to increased success in management of symptoms, delay of progression, and prevention of associated infections like P. aeruginosa. The 10-year survival rate for treated DPB is 90%. In DPB cases where treatment with erythromycin has resulted in significant improvement, which sometimes happens after a treatment period lasting longer than 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 has no cure.History
In the early 1960s, a relatively new chronic lung disease was being observed and described by physicians in Japan. In 1969, the name "diffuse panbronchiolitis" was introduced to distinguish it from chronic bronchitis, emphysema, alveolitisAlveolitis
Alveolitis can refer to two inflammatory conditions. It can refer to inflammation of the alveoli in the lungs, or the dental alveolus in the jaw.Alveolus in the jaw is also known as dry socket...
, and other obstructive lung disease with inflammation. Between 1978 and 1980, results of a nation-wide 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.
Before the 1980s, the prognosis or expected outcome of DPB was poor, especially in cases with superinfection
Superinfection
In virology, superinfection is the process by which a cell, that has previously been infected by one virus, gets coinfected with a different strain of the virus, or another virus at a later point in time. Viral superinfections of serious conditions can lead to resistant strains of the virus, which...
(the emergence of a new viral or bacterial infection, in addition to the currently occurring infection) by P. aeruginosa. DPB continued to have a very high mortality rate before generalized antibiotic treatment and oxygen therapy
Oxygen therapy
Oxygen therapy is the administration of oxygen as a medical intervention, which can be for a variety of purposes in both chronic and acute patient care...
were beginning to be used routinely in the effort to manage symptoms. Around 1985, when long-term treatment with the macrolide antibiotic erythromycin became the standard for managing DPB, the prognosis significantly improved. In 1990, the association of DPB with HLA was initially asserted.
Epidemiology
DPB has its highest prevalencePrevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
among the Japanese, at 11 per 100,000 population. Korean, Chinese, and Thai individuals with the disease have been reported as well. A genetic predisposition among East Asians is indicated. Rare cases of DPB in individuals with non-Asian lineage have also been noted. The disease is slightly more common in males, with the male to female ratio at 1.4:2.1. The average onset of the disease is around age 40, and two-thirds of those affected with it are non-smokers.
DPB has been reported in a few Asian immigrants and residents in western countries, including those of Europe and North America. Misdiagnosis has occurred in the west due 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.