Bronchiolitis obliterans organizing pneumonia (BOOP) is a rare inflammatory form of idiopathic diffuse interstitial lung disorder that was first described in the 1980s as a unique disease entity composed of clinical symptoms such as flu-like illness in many individuals as well as cough and shortness of breath with exertional activities, organized buds of granulation tissue obstructing the alveolar lumen, bronchioles resulting in respiratory failure, wheezing, chronic injury or inflammation. সহজ বাংলা: অতিরিক্ত দাগের মতো টিস্যু তৈরি হওয়া।" data-rx-term="fibrosis" data-rx-definition="Fibrosis means excess scar-like tissue formation after chronic injury or inflammation. সহজ বাংলা: অতিরিক্ত দাগের মতো টিস্যু তৈরি হওয়া।">fibrosis of terminal and distal bronchioles and spirometry showing airflow obstruction, and hemoptysis. The term bronchiolitis obliterans refers to swirls or plugs of fibrous, granulation tissue filling the small bronchiole airways. Organizing pneumonia refers to organized swirls of inflammatory tissue filling the small spherical units of the lungs referred to as alveoli and the alveolar ducts. Individuals with BOOP experience infection, or irritation, often causing pain, swelling, heat, or redness. সহজ বাংলা: শরীরের প্রদাহ; ব্যথা, ফোলা বা লালভাব হতে পারে।" data-rx-term="inflammation" data-rx-definition="Inflammation is the body’s response to injury, infection, or irritation, often causing pain, swelling, heat, or redness. সহজ বাংলা: শরীরের প্রদাহ; ব্যথা, ফোলা বা লালভাব হতে পারে।">inflammation of the bronchioles and alveolar lung spherical units simultaneously, which distinguishes it from other similar inflammatory lung disorders. Though the term pneumonia is used, BOOP is not an infection.
When it occurs after lung transplantation or hematopoietic stem cell transplantation (HSCT), it is called bronchiolitis obliterans syndrome. Although several different known causes of BOOP have been identified, most cases occur for no known reason (idiopathic). Idiopathic BOOP may also be called cryptogenic organizing pneumonia. 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. Others prefer the term BOOP because it is the most recognized term for the disorder, and others refer to it as Epler’s pneumonia.
Symptoms
Symptoms of BOOP vary from person to person depending upon the specific type. For example, people with idiopathic BOOP have a flu-like illness, while people with BOOP associated with an underlying connective-tissue disorder have cough or shortness of breath. Some individuals with BOOP such as focal BOOP may have no apparent symptoms, while others may have severe respiratory distress as in acute, rapidly-progressive BOOP.
Symptoms usually develop slowly over a few weeks or months. The most common symptom is a persistent, nonproductive cough. Some affected individuals develop a flu-like illness characterized by a sore throat, a general feeling of ill health (malaise), weight loss, and fatigue. Eventually, shortness of breath especially from exertional activities may develop. The shortness of breath and cough may become progressively worse.
Individuals with BOOP may develop small crackling or rattling sounds in the lung (crackles or rales) that are apparent upon physical examination. In rare cases, affected individuals may experience chest pain, joint pain (arthralgia), night sweats, or coughing up blood (hemoptysis).
A rapidly progressive form of BOOP exists that can progress from symptom onset to acute respiratory failure in only a few days. This form of BOOP may be associated with an underlying fibrotic process.
Causes
Cryptogenic organizing pneumonia is believed to be a consequence of alveolar injury and is characterized by the formation of organized buds of granulation tissue obstructing the alveolar lumen and bronchioles resulting in respiratory failure
In most cases, the cause of BOOP is unknown and is referred to as idiopathic BOOP. Causes of BOOP include radiation therapy; exposure to certain fumes or chemicals, exposure to birds, post respiratory infections, after organ transplantation; and from more than 35 medications. Systemic disorders associated with BOOP include connective-tissue diseases, immunological disorders, and inflammatory bowel disease. BOOP has also been seen in association with lung abscess, lung cancer, and lymphoma. Importantly, the BOOP ulcer. সহজ বাংলা: শরীরের অস্বাভাবিক দাগ, ক্ষত বা ফোলা অংশ।" data-rx-term="lesion" data-rx-definition="A lesion is an abnormal area of tissue such as a spot, wound, patch, lump, or ulcer. সহজ বাংলা: শরীরের অস্বাভাবিক দাগ, ক্ষত বা ফোলা অংশ।">lesion is seen in individuals with idiopathic pulmonary chronic injury or inflammation. সহজ বাংলা: অতিরিক্ত দাগের মতো টিস্যু তৈরি হওয়া।" data-rx-term="fibrosis" data-rx-definition="Fibrosis means excess scar-like tissue formation after chronic injury or inflammation. সহজ বাংলা: অতিরিক্ত দাগের মতো টিস্যু তৈরি হওয়া।">fibrosis, or IPF, and in these situations, the primary lung disease is the IPF and the secondary process is BOOP.
Various etiologic agents have been suggested to cause organizing pneumonia including viral infections, toxic gases, medications, gastro-esophageal reflux, radiation therapy, and connective tissue disorders. Smoking is not considered a risk factor for the development of cryptogenic organizing pneumonia. Most patients with cryptogenic organizing pneumonia are non-smokers.
Diagnosis
A detailed history and physical examination should be performed to rule out connective tissue diseases, as they can be associated with organizing pneumonia. A thorough medication and exposure history should also be obtained. The respiratory exam typically discloses inspiratory crackles, but the exam can be normal.
A diagnosis of BOOP may be made based upon a clinical evaluation, a detailed patient history, identification of characteristic findings, and specialized tests such as x-ray studies, especially a high-resolution chest computed tomography or HRCT, pulmonary function studies that include a diffusing capacity test, and often a lung biopsy for microscopic tissue analysis. Lung biopsy may be via conventional transbronchial biopsy which frequently captures the diagnosis, transbronchial cryobiopsy which is newer and recovers a larger bit of tissue, or in selected cases, open lung biopsy. The HRCT scan shows “ground glass” densities that are often triangular with the base of the triangle along the chest wall and the airways can often be seen in the ground-glass opacities.
White cell count is typically elevated with neutrophilia. Inflammatory markers, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP), are commonly elevated. When COP is suspected then testing for autoimmune diseases should be undertaken.
Radiography
The chest radiograph findings in COP include patchy diffuse consolidations mostly involving bilateral lower zones. Other described findings include migratory, irregular, linear, or nodular opacities. Pleural effusions can also be seen.
- High-Resolution Computed Tomography (HRCT) – HRCT of the lungs reveals bilateral patchy peripherally located consolidations or ground-glass opacities. These are often asymmetric. The classic HRCT sign described in COP is the atoll sign, also known as the reverse halo sign. This sign is characterized by a dense outer rim of consolidation around a focal ground-glass opacity. This sign is seen in about 20% of patients with COP and is non-specific as it can be seen in various other infectious and inflammatory conditions. Other less common findings include irregular nodular opacities, cavitary lesions, and pleural effusions. Multiple nodules and cavitary lesions should raise suspicion of malignancy.
- Pulmonary Function Testing (PFT) – PFTs typically reveal a restrictive defect with diffusion impairment. Desaturation with 6-minute walk testing is also commonly noted.
- Bronchoscopy – Flexible bronchoscopy with bronchoalveolar lavage (BAL) is often performed to rule out infections, pulmonary hemorrhage, and malignancy. BAL fluid characteristically has mixed cellularity with neutrophils, lymphocytes, and eosinophils. Significant lymphocyte elevation (approximately 40%) is typical, and CD4/CD8 ratio reveals CD8 predominance. Lack of lymphocytosis on BAL portends a poor prognosis. Marked elevation of eosinophils (greater than 25%) suggests eosinophilic pneumonia or rarely an overlap phenomenon.
- Lung Biopsy – Transbronchial lung biopsies may be attempted but are often inadequate to make a definitive diagnosis due to the small amount of lung tissue obtained and loss of tissue architecture from crushed artifacts. It can help rule out alternative diagnoses. A surgical lung biopsy is often required to make a definitive diagnosis. Wedge biopsies are preferably obtained from at least 2 lobes with distinct radiographic involvement. In patients with a convincing clinical and radiographic presentation, in whom risks of an invasive procedure outweigh benefits, treatment can be started without a lung biopsy, after discussion with the patient.
- Pulmonary function testing – It is essential for diagnosis. Spirometry demonstrates airflow obstruction that does not reverse with inhaled bronchodilator challenge. Forced expiratory volume in one second (FEV1) will be reduced, and the ratio of FEV1 to forced vital capacity (FEV1/FVC) is also reduced. Hyperinflation may occur, and hence total lung capacity (TLC) may be increased with air trapping. Diffusion capacity (DLCO) is usually reduced. [rx][rx][rx]The degree of FEV1 decline from post-transplant value determines the stage of bronchiolitis obliterans syndrome in lung transplant.
- Chest CT imaging – may show bronchial wall thickening, a mosaic pattern with patchy areas of hypo attenuation. If there are dynamic images with inspiratory and expiratory films, a mosaic pattern persists due to air trapping from small airway disease.
Treatment
In some patients, the symptoms of BOOP may resolve without treatment, especially in the post-breast radiation type. In some mild cases such as individuals without symptoms or who have a non-progressive disease, the process can be monitored and treated later if necessary. Most individuals with BOOP require treatment with anti-inflammatory, corticosteroid medication, usually in the form of prednisone. This therapy often results in dramatic improvement with resolution of symptoms within days or weeks. In some situations, the BOOP may recur as the dose is decreased, but the BOOP will respond to an additional course of treatment.
Hence, increasing or adding immunosuppressive agents like tacrolimus, cyclosporine, mycophenolate mofetil, and prednisone has been used to treat bronchiolitis obliterans syndrome after transplant. Azithromycin has also been shown to decrease the incidence of bronchiolitis obliterans syndrome and improvement in lung function. The combination of inhaled fluticasone, oral montelukast, and azithromycin triple therapy has also been shown to decrease the decline in lung function in bronchiolitis obliterans syndrome post-HSCT.
The vast majority of patients with progressive symptoms and diffuse radiographic involvement are treated with oral glucocorticoids resulting in marked improvement in symptoms. British Thoracic Society guidelines recommend initiating prednisone at a dose of 0.75 to 1 mg/kg per day and weaning over 6 to 12 months. Alternative regimens include starting prednisolone at a dose of 1 to 1.5 mg/kg for 3 months and then tapering or starting methylprednisolone 0.5 to 1 g intravenously (IV) for the first 3 days followed by prednisolone at 20 mg daily, then tapering based on clinical response. Some authors have tried shorter courses tapered over 3 to 6 months with similar relapse rates. Regardless of the regimen, the initial dose is typically maintained for 4 to 8 weeks. Patients should be followed closely with follow-up clinical examination, pulmonary function testing, and chest radiographs. Relapses are common when tapering steroids but do not seem to affect the outcome. Delayed onset of initial treatment and evidence of cholestasis on laboratory testing is shown to be associated with multiple relapses. The last effective dose of glucocorticoids should be reinstituted at the earliest sign of worsening disease. Other groups have attempted lower doses of glucocorticoids to reduce cumulative steroid exposure, with slightly higher relapse rates but overall no change in morbidity and mortality. Close monitoring for adverse effects of glucocorticoids is recommended. Surgical resection is not recommended as a treatment.
Extracorporeal photopheresis has also been successfully used to slow the decline in lung function from bronchiolitis obliterans syndrome. In non-transplant-related bronchiolitis obliterans, removal from offending agents is essential. Immunosuppression with corticosteroids and cytotoxic agents like cyclophosphamide has been used for bronchiolitis obliterans related to rheumatoid arthritis but has not been beneficial for bronchiolitis obliterans from toxic inhalation or post-infectious etiology.
Patients who are unable to taper off glucocorticoids or have significant side effects from glucocorticoids can be started on a steroid-sparing agent, although COP is an unapproved indication for all steroid-sparing medications. Azathioprine and mycophenolate mofetil, among others, have been reported in case series for successful management of COP.
The rapidly progressive form of BOOP is treated with intravenous corticosteroid medication and sometimes with Cytoxan. Individuals with. secondary BOOP may improve after treating the underlying condition. Additional treatment is symptomatic and supportive.
Investigational Therapies
For individuals who do not respond to steroid therapy, other agents have been used including cyclophosphamide, erythromycin in the form of azithromycin, and Mycophenolate Mofetil (CellCept). These agents have been beneficial to individuals with BOOP on a case-by-case basis reported in the medical literature (anecdotally). However, research is needed to determine the long-term safety and effectiveness of these potential treatment options for individuals with BOOP.
References
