Bronchiolitis obliterans – a severe pulmonary condition with concentric fibrous transformation of the submucosal layer within the small airways (bronchioles) resulting in lumen obliteration. The condition is usually caused by host-versus-draft disease. The clinical course is characterized by deterioration in pulmonary function with poor response to treatment.
Presentation
BO course varies in severity and time of onset. It can be mild in onset and deteriorate slowly as well as start acutely with severe symptoms and decline of lung function in days. The symptoms of BO appear at any day between 80 and 700 days after HSCT [10] [11] [12] [13], and include dry cough (in 60-100% of patients), shortness of breath (50-70%) and wheezing (40%). 20% of patients report cold-like symptoms. Approximately 20% of patients are completely asymptomatic, however, show decreased pulmonary function on testing. Fever is absent. All the symptoms are nonspecific.
Entire Body System
- Fever
60 36 3 84 2.15 2.15 15 Male 11 6 Fever Consolidation Consolidation 66 31 3 47 2.12 0.88 16 Female 19 1 Crackles — 75 32 1 13 0.12 0.12 17 Female 60 1 Fever Consolidation BWT 62 35 3 59 2.18 2.18 18 Female 28 9 Crackles — Consolidation 73 36 2 43 1.41 [ncbi.nlm.nih.gov]
BOOP presents clinically with initial “flulike” symptoms, followed by progressive dyspnea (shortness of breath), cough, fever, and weight loss. “Crackling” can be heard within the chest using a stethoscope. [accessscience.com]
- Fatigue
Fatigue and wheezing in the absence of a cold or asthma may also be noted. [1] [2] [3] Symptoms generally progress slowly over weeks to months. [3] Last updated: 10/28/2016 Bronchiolitis obliterans is not thought to be inherited. [web.archive.org]
Two to eight weeks after a respiratory illness or exposure to toxic fumes, dry cough, shortness of breath (especially on exertion), fatigue, and wheezing may occur. Severe cases may require a lung transplant. [secure.ssa.gov]
People with obliterative bronchiolitis suffer from shortness of breath, wheezing, fatigue and night sweats, among other symptoms. It's an irreversible disease, and it can be life-threatening in severe cases. [remedydaily.com]
We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: May 12, 2019 [patientslikeme.com]
- Weight Loss
BOOP presents clinically with initial “flulike” symptoms, followed by progressive dyspnea (shortness of breath), cough, fever, and weight loss. “Crackling” can be heard within the chest using a stethoscope. [accessscience.com]
Fever and weight loss are common. Physical examination demonstrates crackles in the lungs in most patients, and wheezing is present in about one-third. Pulmonary function studies demonstrate restrictive dysfunction and hypoxemia. [healthcentral.com]
Symptoms For The People says the symptoms of popcorn lung include: - Dry cough - Shortness of breath that gets worse after physical exertion - Wheezing - Fatigue - Fever - Night sweats - Weight loss These symptoms are closely related to those of a respiratory [remedydaily.com]
The symptoms of bronchiolitis obliterans may include: Dry cough Wheezing Shortness of breath on exertion Fatigue Fever Night sweats Weight-loss Vaping Liquids Often Exceed Exposure Limits for Flavor Chemicals The National Institute for Occupational Safety [schmidtlaw.com]
- Anemia
We here describe a 10-year-old boy who experienced recurrent infections, mainly in the respiratory system, associated with thrombocytopenia and anemia. Immunological workup showed low numbers of B cells and low IgG, but normal IgM levels. [ncbi.nlm.nih.gov]
Acute graft-versus-host disease and the risks for idiopathic pneumonia after marrow transplantation for severe aplastic anemia Bone Marrow Transplant 1993 12 : 225–231 67. Kantrow SP, Hackman RC, Boeckh M et al. [nature.com]
Anemia should be corrected and patients with good hematopoiesis will often compensate with mildly elevated hemoglobin. [bloodjournal.org]
- Surgical Procedure
In a 42-year old man with intractable pneumothorax after bone marrow transplantation and surgical procedures, extensive thoracolysis was effective as an acute treatment for this disease. [ncbi.nlm.nih.gov]
Lung tissue biopsy, which often requires an open lung surgical procedure, is necessary to confirm the diagnosis of bronchiolitis obliterans. [medicinenet.com]
Respiratoric
- Cough
[…] onset of symptoms about 2-8 wks after infection Disease may evolve for months-years after the initial pneumonia/respiratory illness Clinical Dry Cough (see Cough, [[Cough]]) Dyspnea (see Dyspnea, [[Dyspnea]]) Expiratory Wheezing (see Obstructive Lung [mdnxs.com]
Affected people may experience a dry cough, shortness of breath, and/or wheezing. [web.archive.org]
Affected patients usually feel cough and shortness of breath, however, may show no signs or symptoms initially and demonstrate decrease in lung functions only by diagnostic tests. [symptoma.com]
- Dyspnea
Here, we report the case of a 6-year-old child with recurrent dyspnea since the age of 3, who showed signs and symptoms of bronchiolitis obliterans and radiological signs of bronchial wall thickening and air trapping. [ncbi.nlm.nih.gov]
[…] after infection Disease may evolve for months-years after the initial pneumonia/respiratory illness Clinical Dry Cough (see Cough, [[Cough]]) Dyspnea (see Dyspnea, [[Dyspnea]]) Expiratory Wheezing (see Obstructive Lung Disease, [[Obstructive Lung Disease [mdnxs.com]
The changes in dyspnea, wake-up dyspnea, cough and sputum were measured after 4 months. Dyspnea, wake-up dyspnea, and cough improved after 4 months of N-acetylcysteine administration compared to the control group. [raysahelian.com]
The consequences of bronchiolitis obliterans include dyspnea (shortness of breath), obstructive lung disease, atelactasis, bronchiectasis, and unilateral hyperlucent lung. [healthcentral.com]
- Dry Cough
Affected people may experience a dry cough, shortness of breath, and/or wheezing. [web.archive.org]
Abstract A 61-year-old female presented with a dry cough and fever 4 months after tangential radiation therapy (RT) following conserving surgery for breast cancer. [ncbi.nlm.nih.gov]
Symptoms include a dry cough, shortness of breath, wheezing and feeling tired. These symptoms generally get worse over weeks to months. [en.wikipedia.org]
Two to eight weeks after a respiratory illness or exposure to toxic fumes, dry cough, shortness of breath (especially on exertion), fatigue, and wheezing may occur. Severe cases may require a lung transplant. [secure.ssa.gov]
Symptoms include dry cough, shortness of breath and wheezing. [en.m.wikipedia.org]
- Persistent Cough
BO should be considered in a patient who has persistent cough and dyspnea, especially with a history of fume inhalation or offending drug use. [clinicaladvisor.com]
Medical Management Workers should be promptly referred for further medical evaluation if they have persistent cough; persistent shortness of breath on exertion; frequent or persistent symptoms of eye, nose, throat, or skin irritation; abnormal lung function [web.archive.org]
During and after this illness, persistent and productive cough without fever and haemoptysis was noted, which was evaluated five months post-transplant. [jscimedcentral.com]
At the end of follow-up, 2 patients became symptom-free, 7 patients had infrequent mild cough and preferable general well-being, and 8 patients had persistent cough and wheezing and decreased exercise tolerance. [doi.org]
- Rales
Auscultation of the lungs revealed prolonged expiration and bilateral crepitant rales. CXR revealed bilateral paracardiac infiltration. [ncbi.nlm.nih.gov]
Physical examination showed a body weight of 23 kg, shortness of breath, and no obvious rales in the lungs. High-resolution CT scans showed diffuse ground-glass opacity ( Fig 1B ). [pediatrics.aappublications.org]
Seven months after transplantation, an increase in cough with hypoxemia, dyspenia and worsening fatigue was noted and bilateral medium moist rales were detected on physical examination. [jscimedcentral.com]
Individuals with BOOP may develop small crackling or rattling sounds in the lung (crackles or rales) that are apparent upon physical examination. [rarediseases.org]
[…] months post-BMT Latency of BO : BO typically occurs 4-6 mo later Range: BO has been reported to occur from 30 days-2 yrs post-BMT/SCT (>90% of affected cases develop within 18 mo post-BMT/SCT) Diagnosis CXR : normal-hyperinflated Clinical Bibasilar Rales [mdnxs.com]
Neurologic
- Confusion
Abstract Bronchiolitis obliterans organizing pneumonia (BOOP) represents a kaleidoscope of concepts and morphologies, often being confused with a series of conditions, among which the most feared are Hodgkin's lymphoma and bronchioloalveolar carcinoma [ncbi.nlm.nih.gov]
OB should not be confused with bronchiolitis obliterans organizing pneumonia (BOOP). [radiopaedia.org]
Despite the sometimes confused, and confusing, media reporting around the safety of e-cigarettes, there is growing consensus around the evidence. While not without some risk, when compared to smoking e-cigarettes are far less harmful. [publichealthmatters.blog.gov.uk]
Some researchers prefer the use of COP to avoid confusion with other lung disorders with similar names. The term cryptogenic denotes that the cause of the disorder is unknown. [rarediseases.org]
- Headache
It can also cause nausea, vomiting, headache, drowsiness, delirium and hallucinations in high concentrations. [nationaljewish.org]
Relieve Sinus Pressure and Headaches with Accupressure video by Lindsay Rose, Holistic Health Lifestyle Management by Condition Meehan, MD, is a rheumatologist at National Jewish Health. [pinterest.pt]
HDPM treatment is recommended in other inflammatory lung diseases in children. 75, 76 Reported side effects include transient flushing, headache, mood changes 77 and sinus bradycardia, 78 but no serious long-term events have been described in children [nature.com]
Workup
The diagnosis of BO is made by compilation of clinical, instrumental and laboratory diagnostic data.
Spirometry, lung volumes measure, diffusing capacity for carbon monoxide (DLCO), and arterial blood gases should be ordered for all patients-recipients of HSCT. Airflow obstruction is characteristical hallmark of BO, however, a test may occasionally show normal values, as some cases report. The BO is further differentiated according to the forced expiratory volume in 1 second (FEV1) measures into mild (FEV1 66–80%), moderate (FEV1 51–65%) and severe (FEV1 50%) forms.
General workup should be ordered to exclude other possible causes of symptoms (i.e. infection) and detect complications of the GVHD. It should include complete blood count (CBC) with differential, blood urea nitrogen (BUN), creatinine, liver function tests (total bilirubin and hepatic transaminases), gammaglobulin and urinalysis.
Of the imaging studies, the high resolution computed tomography (HRCT) may be the most useful. It is of the most value when performed with both inspiratory and respiratory views. An expiratory section may show additional zones of air-trapping not detectable on the inspiratory view and the amount of these findings has been shown to correlate with the severity of disease [14] [15]. Other pathological changes may be revealed on the HRCT such as bronchiectasis, thickened septal lines, mosaic or so-called "tree-in-bud" pattern of attenuation [14]. Chest X-ray is not as useful and frequently will show little to no changes. It may reveal some slight hyperinflation.
Transbronchial biopsy, although frequently performed, may miss the pathological tissue as the involvement pattern of OB is often intermittent and mosaic [5]. The biopsies are done to exclude acute rejection of the graft or missed infection. The biopsy is contraindicated in cases of severe bronchiole obstruction or thrombocytopenia. Video assistance if often required for the definitive OB diagnosis by histological study, which may reveal peribronchial neutrophilic and lymphocytic infiltration and fibrosis with partial or complete obliteration of the lumen. Severe cases may show necrotizing bronchitis or bronchiolitis.
The diagnosis is made by such criteria: persistent pulmonary dysfunction with FEV1 reduced below normal for more than 3 weeks and if other causes (acute allograft rejection, anastomotic complications, stricture, infections) are ruled out.
X-Ray
- Pulmonary Infiltrate
Abstract The present study describes an adult male who has had recurrent episodes of pulmonary infiltrates with severe acute respiratory failure over a period of 10 yrs. [ncbi.nlm.nih.gov]
Generally, the infiltrates gradually enlarge from their original site or new infiltrates appear as the clinical course progresses; however, migratory or "mobile" pulmonary infiltrates have been reported 6, 14, 15 in 10% to 25% of patients. [jamanetwork.com]
- Pulmonary Infiltrates
Abstract The present study describes an adult male who has had recurrent episodes of pulmonary infiltrates with severe acute respiratory failure over a period of 10 yrs. [ncbi.nlm.nih.gov]
Generally, the infiltrates gradually enlarge from their original site or new infiltrates appear as the clinical course progresses; however, migratory or "mobile" pulmonary infiltrates have been reported 6, 14, 15 in 10% to 25% of patients. [jamanetwork.com]
- Hyperlucent Lungs
associated with obstructive findings ( see unilateral hyperlucent lung, Swyer-James syndrome ). bronchiolitis obliterans a form of bronchiolitis in which the exudate is not expectorated but becomes organized and obliterates the bronchial tubes, causing [medical-dictionary.thefreedictionary.com]
Description Bronchiolitis is inflammation of the bronchioles in the lungs. The consequences of bronchiolitis obliterans include dyspnea (shortness of breath), obstructive lung disease, atelactasis, bronchiectasis, and unilateral hyperlucent lung. [healthcentral.com]
In some instances, they can even develop a form of unilateral hyperlucent lung syndrome, known as Swyer-James Syndrome. Symptoms associated with BO may develop gradually, or they may occur suddenly. [hxbenefit.com]
Unilateral hyperlucent lung syndrome in children. J Pediatr 1971 ; 78 : 250 –60. ↵ Lang WR, Howden CW, Laws J, et al. Bronchopneumonia with serious sequelae in children with evidence of adenovirus type 21 infection. [thorax.bmj.com]
- Bilateral Pulmonary Infiltrates
Epler GRMark EJ A 65-year-old woman with bilateral pulmonary infiltrates. N Engl J Med. 1986;3141627- 1635 Google Scholar Crossref 55. [jamanetwork.com]
Laboratory
- Leukocytosis
Leukocytosis without an increase in eosinophils occurs in about one half of patients. The initial ESR often is elevated. [merckmanuals.com]
Treatment
Only a small amount of data has been received as for improvement of the outcomes in patients with OB with various treatment measures. Immunomodulation and immunosuppression therapy is the mainstay of current views for the treatment options, however, only a few patients have shown reactivity to the therapy.
Corticosteroids are used as a first-line treatment. Prednisone is given at the dose of 1–1.5 mg/kg/day up to 100 mg/day for 4-6 weeks. If patient’s respiratory functions are stabilized, prednisone is tapered and then stopped in 6-12 months. In the cases when no therapeutic effect is achieved with corticosteroids in 1 month, the regimen should be changed to cyclosporine (adjusted to serum level) or azathioprine (2–3 mg/kg/day up to 200 mg/day). Cyclosporine also has shown to prevent development of BO in some cases.
Macrolides have demonstrated some benefit in patients with BO, particularly in those with panbronchitis, probably due to the anti-inflammatory effect of this group of antibiotics.
Despite earlier reports, neither thalidomide nor intravenous immunoglobulin have shown no beneficial therapeutic effect in treatment of BO and GVHD.
The patients on immunosuppressive therapy should also receive prophylaxis for Pneumocystis carinii and Streptococcus pneumoniae at all times, as they are at risk for developing these infections.
Prognosis
Prognosis is usually poor. With appropriate treatment regimen of corticosteroids and immunosuppressants only 8-20% of the patients demonstrate an improvement in pulmonary functions.
Mortality is variable in the available reports, measuring from 14% to 100% in some studies. The mean for mortality rate is 61%. There is an association of rapid decrease in FEV1 with increased mortality.
Etiology
Several etiologies of BO are possible.
The most common cause is a graft-versus-host disease (GVHD) from an organ transplantation procedure. It is primarily caused by type-2 T-helper lymphocytes of the donor and characterized by progressive concentric fibrosis of the small airways. It is rarely seen in autologous type of transplantation. BO from bone marrow transplantation occurs in approximately 9% of patients. BO from stem cell transplantation is much less common. Although BO remains a major life-threatening possible complication in patients after lung transplantation, the procedure itself is greatly improving survival of patients with end-stage pulmonary insufficiency.
The other possible causes include exposure to different toxic materials. Fume-exposure BO occurs after contact with typical acidic toxic fumes (i.e. in silo-fillers). The contact is usually accidental. The disease has a three-period course with two latent phases: during the first few hours and then several days. BO can also result from exposure to mustard gas (i.e. chemical warfare weapon), with one case reported in a man after as much as 14 years after exposure. The symptoms included cough with sputum and shortness of breath. A few cases were described in eastern Asian countries with patients developing toxin-related BO after ingesting the Sauropus androgynus vegetable.
Epidemiology
Due to the lack of standardized criteria for the diagnosis, the reports for incidence of BO vary. Most of the cases are diagnosed clinically by pulmonary function tests showing the pattern of airway obstruction and the histological tests are not performed.
Some studies report 8.3% incidence of BO in 2152 patients-recipients of allogeneic HSCT. In the patients with GVHD the incidence is estimated to be approximately 6-20% in the long-term.
Pathophysiology
The exact pathophysiology of BO remains unknown. Several hypothesis exist for the chain of events of BO development. One suggests that host bronchiolar epithelial cells act as a target of attack for donor cytotoxic T-cells, which is supported by the association of BO and chronic GVHD. Another possible pathophysiological causing events are recurrent aspiration and subsequent infection due to chronic GVHD and/or a malfunction of local immunoglobulin secretion. Due to the high variability in histopathological results of studies of bronchoalveolar lavage (BAL) cell composition and differences in clinical course, a multifactorial chain of events is supposed to be the pathophysiological underlying cause.
The pathophysiology of the graft rejection is complex, usually involving both alloimmune and non-alloimune pathways. Chronic rejection can be further differentiated as chronic vascular, which is less common and constitutes for atherosclerotic process in the vessels of the lungs, or chronic airway rejection, which is more common and comprises the histological definition of BO. The latter is associated with higher morbidity and mortality.
The resulting concentric fibrotic formation in the bronchiolar submucosa is referred to as constrictive bronchiolitis (CB), or fibrosing bronchiolitis in early literature. It is a chronic process of concentric peribronchilar fibrosis of the tissues surrounding the lumen of the bronchiole, in contrast to growing into the lumen per se. CB is characterized by continuous mural thickening of the submucosal layer, fibrosis of collagen fibers and progressive narrowing of the lumen, eventually leading to stasis of the mucus, chronic inflammation or even complete obliteration.
BO tends to result in inflammation of only membranous bronchioles (small noncartilagenous airways) [7] [8], causing encircling fibrosis and consequent narrowing of the lumen. The extent of muscular level involvement differs depending on the stage of the disease. In early course, it may appear hypertrophic, but later it is prone to atrophy and replacement by fibrous tissue. It has been noted, however, that distal respiratory bronchioles usually remain intact.
Histological pattern of BO also varies in the timely manner of disease progression. Early examination may show inflammation of the submucosal layer of small airways, mainly composed of lymphocytic infiltration and resulting in disturbance of epithelium. The deep ingrowth of fibromyxoid granulation tissue and consequent partial or even complete lumen obliteration follow next. Eventually, granulation tissue may organize and form cicatricle pattern on a histological level [9].
Prevention
Prevention should be focused on early diagnosis and aggressive management of associated conditions.
Decreasing time of allograft ischemia by lowering mechanical ventilation lenght for donors has shown some success in prevention. Blood products exchange and cardiopulmonary shunts should be avoided [16].
Summary
Bronchiolitis obliterans (BO) is a severe pulmonary condition, usually a complication following the organ transplantation procedure. Lungs are the most common solid organs affected by severe rejections [1] [2], however, despite BO remaining a leading cause of death past the first year of lung transplantation [3] [4], the procedure is sometimes the only option for patients with advanced pulmonary disorders and high stages of pulmonary insufficiency. A few rare cases of BO were reported to result from exposure to toxins.
The most prominent clinical manifestation of BO is the deterioration of forced expiratory volume in 1 second (FEV1) with no response to bronchodilators therapy [5] [6]. The functional decrease is a result of small airway obliteration. Patients usually experience following symptoms: dry cough, wheezing, dyspnea and cold-like symptoms, however, there is no fever in OB clinical course. None of the symptoms are specific enough, however.
The diagnosis is usually clinical and made by identifying a decrease in FEV1 while excluding all the other possible causes (i.e. infection). Lung biopsy may not be significantly informative as it can miss the lesion. Histological study will show inflammation of the submucosal layer of small airways, mainly composed of lymphocytic infiltration and disturbance of epithelium. In late stages of the disease the pathological process results in narrowing and obliteration of the airway lumen. The lesions do not extend into the alveoli and are limited to bronchioles.
Chest X-ray is usually non-informative and may only show a slight hyperinflation. High resolution computed tomography (HRCT) is the imaging modality of choice. It should be done both in expiration and inspiration states. HRCT may reveal air-trapping which is not only diagnostic, but also correlates with the severity of BO. General workup should include complete blood count with differential, blood urea nitrogen, creatinine, liver function tests, gammaglobulin and urinalysis to rule out other causes.
Current view on the treatment implies the use of immunosuppression and immunomodulation agents. First-line management is with corticosteroids. If steroids have no effect on pulmonary function improvement, cyclosporine and azathioprine may be introduced.
Patient Information
Bronchiolitis obliterans (BO) is a condition involving the lung’s smallest airways – the bronchioles. It is usually a complication following an organ transplant, as body immune system is reacting to a foreign structures, but rarely can be caused by inhaled toxins, such as poisonous vegetables or warfare chemicals.
The inflammation in the bronchioles results in extensive scarring of these tiny structures and leads to their obliteration. Affected patients usually feel cough and shortness of breath, however, may show no signs or symptoms initially and demonstrate decrease in lung functions only by diagnostic tests. The symptoms may appear in the first months after transplantation or be delayed for years.
For the diagnosis of BO special studies are used to assess lungs functioning, such as spirometry, when patient exhales forcefully into a tube. This helps doctors to measure lungs volumes and obtain an idea of how well they work. Imaging studies may also be done to see the extent of the disease.
BO cannot be cured and the doctors’ efforts are concentrated on slowing the progression and stabilizing the functional state of the lungs. It is important to diagnose BO early as it may be crucial to start therapy as soon as possible to prevent dangerous complications. The medications to decrease immune response of the body such as corticosteroids or immunosuppressant may be used for that. However, the response to treatment is usually not sufficient.
References
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- Arcasoy SM, Kotloff RM. Lung transplantation. N Engl J Med. 1999; 340:1081-91.
- Verleden GM. Chronic allograft rejection (obliterative bronchiolitis). Semin Respir Crit Care Med. 2001; 22:551-8.
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- Yousem SA, Duncan SR, Griffith BP: Interstitial and airspace granulation tissue reactions in lung transplant recipients. Am J Surg Pathol 1992, 16:877-84.
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- Bankier AA, Van Muylem A, Knoop C, Estenne M, Gevenois PA. Bronchiolitis obliterans syndrome in heart-lung transplant recipients: diagnosis with expiratory CT. Radiology. 2001; 218:533-9
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