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Cryptogenic Organizing Pneumonia

COP

Cryptogenic organizing pneumonia is a lung disease that results in diffuse interstitial fibrosis, especially involving the distal and respiratory bronchioles, along with alveolar ducts and walls.


Presentation

Symptoms vary considerably from patient to patient, depending on the subtype of the disease. Focal cryptogenic organizing pneumonia is frequently asymptomatic, whereas idiopathic cryptogenic organizing pneumonia is associated with flu-like symptoms. Cryptogenic organizing pneumonia that is caused by connective tissue disease tends to present with dyspnea and cough. On the other hand, some forms may be exceptionally severe and lead to an acute and rapid progression of the disease. For example, fibrotic types of cryptogenic organizing pneumonia can lead to an acute failure of the respiratory system in a matter of a few days.

Cryptogenic organizing pneumonia has,in general, an insidious onset, with symptoms developing in the space of weeks or sometimes months. It is frequently associated with symptoms of an upper respiratory viral infection such as fatigue, weight loss, and general malaise. Cough is the most common symptom associated with the disease, is not accompanied by expectoration but is persistent in nature [8]. Cryptogenic organizing pneumonia can ultimately result in severe shortness of breath, particularly upon exertion. Other rare symptoms that can occur with the condition include hemoptysis, night sweats, joint pain and chest pain [9]. The physical exam will generally exhibit rales and crackles over the involved areas.

Fever
  • A 32-year-old woman was referred with high spiking fever, salmon-pink rash in her arms and legs, and polyarthralgia.[ncbi.nlm.nih.gov]
  • RESULTS: Dyspnea was the most common symptom, followed by dry cough and fever. Crackles was the most common physical finding. Mean age at diagnosis of BOOP was 59 years, and 42% were females.[ncbi.nlm.nih.gov]
  • It usually presents with symptoms of dyspnea, cough, fever, weight loss accompanied by the presence of alveolar opacities on chest radiograph. Haemoptysis, described as blood streaking has only rarely been reported as primary presentation of COP.[ncbi.nlm.nih.gov]
  • CASE PRESENTATION: A 33-year-old male presented with a 1-month cough illness and fever lasting for 5 days. The chest radiograph revealed double lower lobe infiltrate, which was unresponsive to antibiotics.[ncbi.nlm.nih.gov]
  • Abstract We report a case of lasting fever and cough with pulmonary infiltrates progressing 4 months after adjuvant radiotherapy following surgery for breast cancer.[ncbi.nlm.nih.gov]
Weight Loss
  • It usually presents with symptoms of dyspnea, cough, fever, weight loss accompanied by the presence of alveolar opacities on chest radiograph. Haemoptysis, described as blood streaking has only rarely been reported as primary presentation of COP.[ncbi.nlm.nih.gov]
  • We report on the case of a previously healthy 10-year-old girl who consulted her doctor for a 2-month history of mild pyrexia, fatigue, weight loss, and exertional dyspnea with no response to amoxicillin.[ncbi.nlm.nih.gov]
  • A flu-like illness, with a cough, fever, a feeling of illness (malaise), fatigue, and weight loss heralds the onset in about 40% of patients.[en.wikipedia.org]
  • ., cough, dyspnoea with exertion, weight loss). Approximately half of cases are heralded by a flu-like illness.[norf.org.uk]
  • The most common symptoms of COP are: Persistent (2-4 months), nonproductive cough Low-grade fever General feeling of not feeling well (malaise) Shortness of breath Loss of appetite Weight loss What Are Risk Factors? The cause of COP is unknown.[lung.org]
Malaise
  • Patients present with cough, dyspnoea and malaise and commonly have bilateral multifocal consolidation on chest radiography, which may show resolution or relapse with or without steroid treatment.[ncbi.nlm.nih.gov]
  • The most common symptoms of COP are: Persistent (2-4 months), nonproductive cough Low-grade fever General feeling of not feeling well (malaise) Shortness of breath Loss of appetite Weight loss What Are Risk Factors? The cause of COP is unknown.[lung.org]
  • […] with fever, malaise, fatigue, and cough.[norf.org.uk]
  • […] pneumonia (COP) is a form of idiopathic interstitial pneumonia characterized by lung inflammation and scarring that obstructs the small airways and air sacs of the lungs (alveoli). [1] Signs and symptoms may include flu-like symptoms such as cough, fever, malaise[rarediseases.info.nih.gov]
  • Patients present with a short history (i.e. less than 2 months) of breathlessness, non-productive cough, weight loss, malaise and fever. There is no association with smoking.[radiopaedia.org]
Fatigue
  • We report on the case of a previously healthy 10-year-old girl who consulted her doctor for a 2-month history of mild pyrexia, fatigue, weight loss, and exertional dyspnea with no response to amoxicillin.[ncbi.nlm.nih.gov]
  • Cough, fatigue and dyspnea were the most common symptoms on admission. We detected OP cases secondary to anthracosis and cyst hydatic besides other well known etiologies.[ncbi.nlm.nih.gov]
  • A flu-like illness, with a cough, fever, a feeling of illness (malaise), fatigue, and weight loss heralds the onset in about 40% of patients.[en.wikipedia.org]
  • We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: May 13, 2019[patientslikeme.com]
  • High Resolution CT Thorax of a forty-eight-year-old woman with an eight-week history of cough, dyspnea with exertion, fatigue, and slight weight loss.[norf.org.uk]
Cough
  • The most common symptom was cough (n 15; 88.2%) and the most common radiological finding (n 10) was consolidation in the inferior lobes on thoracic computed tomography.[ncbi.nlm.nih.gov]
  • Symptoms included dyspnea and cough (n 15) (60%), cough only (n 10) (40%), and fever (n 15) (60%). Twenty-two patients were diagnosed by open lung biopsy and 3 by transbronchial biopsy.[ncbi.nlm.nih.gov]
  • Patients present with cough, dyspnoea and malaise and commonly have bilateral multifocal consolidation on chest radiography, which may show resolution or relapse with or without steroid treatment.[ncbi.nlm.nih.gov]
  • In its most typical presentation, it is characterized by dyspnea and cough, with multiple patchy alveolar opacities on pulmonary imaging.[ncbi.nlm.nih.gov]
  • It usually presents with symptoms of dyspnea, cough, fever, weight loss accompanied by the presence of alveolar opacities on chest radiograph. Haemoptysis, described as blood streaking has only rarely been reported as primary presentation of COP.[ncbi.nlm.nih.gov]
Dry Cough
  • RESULTS: Dyspnea was the most common symptom, followed by dry cough and fever. Crackles was the most common physical finding. Mean age at diagnosis of BOOP was 59 years, and 42% were females.[ncbi.nlm.nih.gov]
  • A 74-year-old female non-smoker presented with a 2-week history of dry cough followed by dyspnea and a fever. The clinical course was fulminant, but we successfully performed bronchoscopy.[jstage.jst.go.jp]
  • In most cases, gradual onset of shortness of breath and dry cough are the most common symptoms. COP is usually treated with oral steroids. What Is COP? COP is a rare condition.[foundation.chestnet.org]
  • Dry cough and shortness of breath of 2 weeks to 2 months in duration usually characterizes BOOP. Symptoms persist despite antibiotic therapy.[ncbi.nlm.nih.gov]
  • A 58-year-old woman with underlying rheumatoid arthritis was admitted to the hospital because of a dry cough and the presence of an abnormal shadow in the right lower lung field.[ncbi.nlm.nih.gov]
Pulmonary Disorder
Dysphagia
  • Vienna, Wilhelminenspital, Vienna, Austria. felix.wantke@wienkav.at Abstract We report of a 46-year-old female patient with cryptogen organizing pneumonia preceding the rare SRP positive necrotising myositis without cardiac involvement and no sign of dysphagia[ncbi.nlm.nih.gov]
Liver Dysfunction
  • The laboratory data showed marked increases in white blood cell count, an erythrocyte sedimentation rate, and C reactive protein, ferritin, and liver dysfunction. All cultures remained negative, as were autoantibodies and rheumatoid factor.[ncbi.nlm.nih.gov]

Workup

Cryptogenic organizing pneumonia is a diagnosis of exclusion. It usually requires extensive workup, including imaging or even a biopsy [10]. Alveolar opacities that are diffuse, bilateral and situated in the peripheries of the lungs with normal lung volume are typical on x-ray. Some cases, however, may show alveolar opacities on only one side of the lungs. Other rare findings include honeycombing or interstitial opacities that may be nodular or irregular and linear. High-resolutioncCT scan commonly shows consolidation in a patchy pattern. This finding is present in approximately 90% of all cases. In addition, it will show dilatation, thickening of the bronchi and ground-glass, small nodular opacities [11]. Patchy opacities tend to occur in the lower lobes and the peripheries of the lung. Findings on high resolution CT scan tend to be far more extensive than those typically found on X-ray.

Pulmonary function tests yield variable results. Most patients will show a restrictive pattern with a ratio of forced expiratory volume in 1 second to forced vital capacity that is less than 70%. Nonetheless, approximately 21% of cases exhibit an obstructive defect while some may also show no abnormality.

Blood tests are not very useful in this condition. Results are often non-specific and include leukocytosis and elevated erythrocyte sedimentation rate (ESR). The leukocytosis that is present with the disease is not associated with an elevated eosinophil count.

Biopsy is sometimes necessary to diagnose the disease. Characteristic findings are increased proliferation of granulation tissue as well as evidence of chronic inflammation. Nonetheless, when changes are focal, they are more likely to be associated with various other lung diseases such as hypersensitivity pneumonitis, eosinophilic pneumonia, idiopathic pulmonary fibrosis, infections, lymphoma, vasculitis or pulmonary disease caused by drug sensitivity.

Bronchoalveolar lavage may reveal the presence of plasma cells, mast cells and foamy macrophages. Overall, there is an elevation in the number of activated T cells that exhibit HLA-DR and CD25 expression.

Right Ventricular Hypertrophy
  • The heart weighted 500 g, and showed right ventricular hypertrophy (cor pulmonale).[ncbi.nlm.nih.gov]
Hypercellular Bone Marrow
  • Other pathologic changes were pleural effusion (left, 800 ml: right, 1200 ml), acute liver congestion, prostatic hypertrophy, colon adenoma, and hypercellular bone marrow. The cause of death was respiratory failure due to COP and pleural effusion.[ncbi.nlm.nih.gov]

Treatment

Treatment for cryptogenic organizing pneumonia consists of steroids, although some cases may require resection, especially for focal organizing pneumonia. Unfortunately, spontaneous improvement occurs only rarely [12].

Prednisone is the preferred glucocorticoid agent and is normally administered daily in the morning. Dosage is 1 to 1.5 mg/kg per day, with a maximal value 100 mg per day. This dose should be continued for 4 to 8 weeks and then decreased if the patient is stable for the next 4 to 6 weeks. Nonetheless, patients with severe disease can receive IV glucocorticoid therapy in the form of 125 to 250 mg methylprednisolone every 6 hours for 3 to 5 days.

Treatment should continue for up to 6 months and is stopped if the patient significantly improves and is stable. It should be immediately reinstated if signs of the disease recur. Patient monitoring consists of PFTs (pulmonary function tests) and chest x-rays every 6 to 8 weeks in the first year.

Some cases of COP may not respond well to glucocorticoid therapy and may require immunosuppressive drugs. Cyclophosphamide is the preferred drug and is given at a single dose of 1 to 2 mg/kg daily. Most commonly, the drug is started at 50 mg per day and is increased at monthly intervals, although the maximal dose should not surpass 150 mg per day. A good clinical response may not appear for 3 to 6 months. it is important to note that cyclophosphamide has a number of significant side effects that may require a change of the dose. Hematological side effects are particularly prominent and include anemia, thrombocytopenia, and leukopenia. The latter occurs more commonly and white blood cells should be continuously monitored and their count maintained above 4000/mm3.

Finally, some patients show a response to macrolide antibiotics, especially those with mild symptoms [13]. Scientists hypothesize that the beneficial effects of macrolide antibiotics are related to anti-inflammatory rather than antibacterial effects. Current guidelines recommend the use of macrolides in patients not responsive to glucocorticoids [14].

Prognosis

Prognosis of cryptogenic organizing pneumonia is better than other subtypes of pneumonia and lung disease, particularly in comparison to interstitial lung disease and idiopathic pulmonary fibrosis. Approximately 66% of all patients ultimately recover completely. These patients will have normal chest X-rays by the time the disease resolves and will not exhibit any clinical abnormality. Some patients will very quickly improve, within one or two weeks, although findings specific for pneumonia on serial high-resolution CT scans can still be noticed. For the majority of patients, recovery will be within weeks and up to 3 months. On the other hand, one-third of patients will suffer from a chronic and persistent form of the disease.

50% of all patients will experience at least one episode of relapse of the condition [7]. This most commonly occurs when glucocorticoid intake is stopped, usually after one or three months from the start of the treatment. Relapses, nonetheless, do not influence the long-term prognosis of the condition, with most patients improving when steroids are administered again.

Chest X-rays can also be useful in evaluating the prognosis of cryptogenic organizing pneumonia for specific patients. In general, airspace opacities are indicative of better prognosis relative to interstitial opacities [7]. The latter are more likely to be present in patients who suffer from frequent and recurrent episodes. Treatment is then continuous, with the administration of prednisone and cyclophosphamide.

Etiology

The underlying etiological mechanisms in cryptogenic organizing pneumonia are still unknown and the disease is frequently diagnosed by exclusion [2]. This type of pneumonia is precisely referred to as idiopathic because no particular cause has been identified. The most common causes of pneumonia usually are drugs, radiation for breast cancer treatment, ulcerative colitis, malignancies (particularly those affecting the hematological system), and infection with various organisms, including bacteria, viruses, parasites and fungi [2] [3].

Epidemiology

Cryptogenic organizing pneumonia is a rare disease, although incidence and prevalence have not been exactly determined. One study conducted in a major hospital in Canada reported 6 or 7 cases in a sample of 100,000 individuals who were admitted for inpatient treatment [4]. Another Icelandic study which reviewed statistics over 20 years reported an incidence of 1.1 for every 100,000 individuals [5]. Other published data indicate that 56 to 68% of all cases of organizing pneumonia are cryptogenic.

Sex distribution
Age distribution

Pathophysiology

Cryptogenic organizing pneumonia is characterized by its strong response to steroids and can be differentiated from usual interstitial pneumonia by the fact that progressive fibrosis is reversible. Thus, the fibrosis involving cryptogenic organizing pneumonia can be compared to cutaneous wound healing [6].

The pathophysiologic mechanisms are initiated with an injury to the alveolar epithelium, followed by death and sloughing of pneumocytes. This ultimately leads to the damage of the epithelial basal lamina, with the infiltration of inflammatory cells such neutrophils, eosinophils, and lymphocytes.

The stages of organization of pneumonia can be divided into three: the first stage is defined by the appearance of clusters of fibrinoid inflammatory cells. On the other hand, the second stage is characterized by the occurrence of fibro-inflammatory buds, which result from the migration and proliferation of the fibroblasts within the fibrin remnants of the basal lamina. Finally, mature fibrotic buds are detected in the third stage. Other defining characteristics include the absence of inflammatory cells, the disappearance of fibrin in the alveolar lumen and the transformation of fibroblasts into myofibroblasts.

Prevention

Preventive measures are targeted at the potential complications and in the recovery stage of the disease. They include regular exercise, which may help in improving breathing capacity, as well as vaccination with the influenza vaccine every year and the pneumonia vaccine every 5 years.

Summary

Cryptogenic organizing pneumonia is a rare fibrotic interstitial disease of the lungs of unknown etiology [1]. Breakdown and inflammatory cell infiltration of the basal lamina of the alveolar epithelium are characteristic of the disease. This is followed by invasion and proliferation of fibroblasts and the buildup of a complex reticular network. Presentation varies remarkably from patient to patient and depends on the subtype of the disease. Symptoms develop insidiously and consist of cough, dyspnea, chest pain, joint pain and hemoptysis. Workup is extensive and is aimed at ruling out other lung disorders. Bilateral, diffuse and peripheral alveolar opacities are characteristic on chest X-ray, whereas high resolution computed tomography (CT) scanning shows consolidation in more than 90% of patients. Pulmonary function tests exhibit a restrictive pattern although, in around 20% of patients, they can yield results consistent with an obstructive pathology. A biopsy is sometimes necessary for diagnosis and usually shows proliferation of granulation tissue and chronic inflammatory changes. Treatment consists mostly of glucocorticoids in the form of daily prednisone for up to 6 months. Nonetheless, patients who do not respond may also require immunosuppressive therapy with cyclophosphamide. The latter requires close monitoring of the white blood cell count, as leukopenia is a significant side effect. Macrolide antibiotics are also beneficial in patients with mild disease. Prognosis of cryptogenic organizing pneumonia is generally good, although some patients may develop progressively fatal disease.

Patient Information

Cryptogenic organizing pneumonia is a rare and serious disease that targets the lungs. Direct causes have not been identified, although it has been associated with certain drugs, radiation of the breast during breast cancer treatment, ulcerative colitis (a disease of the digestive system), various cancers and infection with microorganisms. It is generally diagnosed after excluding all other possible causes. Patients can have a very variable presentation. In some cases, the condition can be completely asymptomatic while in others it may present very gradually with non-specific symptoms. The most prominent symptoms are coughing, shortness of breath, pain in the chest and in the joints, and the presence of blood in the sputum. The physician may be required to perform a very broad workup to reach the correct diagnosis. This includes blood tests, imaging with X-ray and CT, pulmonary function tests in which the patient is required to repeatedly inhale and exhale, and sometimes even biopsy. Treatment of cryptogenic organizing pneumonia is mostly with steroids, although some cases may be unresponsive and require chemotherapy. The latter can have significant side effects and require very frequent monitoring. Prognosis is good in the majority of cases although some patients may follow a rapidly progressive and fatal course.

References

Article

  1. Vasu TS, Cavallazzi R, Hirani A, et al. Clinical and radiologic distinctions between secondary bronchiolitis obliterans organizing pneumonia and cryptogenic organizing pneumonia. Respir Care. 2009 Aug; 54(8):1028-32.
  2. Cordier JF. Cryptogenic organizing pneumonia. Clin Chest Med. December. 2004; 25(4):727-738.
  3. Epler GR. Bronchiolitis obliterans organizing pneumonia. Arch Intern Med. 2001; 161(2):158.
  4. Alasaly K, Muller N, Ostrow DN, et al. Cryptogenic organizing pneumonia. A report of 25 cases and a review of the literature. Medicine (Baltimore). 1995; 74(4):201.
  5. Gudmundsson G, Sveinsson O, Isaksson HJ, et al. Epidemiology of organising pneumonia in Iceland. Thorax. 2006 Sep; 61(9):805-8.
  6. Kuwano K, Kawasaki M, Maeyama T, et al. Soluble form of fas and fas ligand in BAL fluid from patients with pulmonary fibrosis and bronchiolitis obliterans organizing pneumonia. Chest 2000;118:451–458.
  7. Bartter T, Irwin RS, Nash G, et al. Idiopathic bronchiolitis obliterans organizing pneumonia with peripheral infiltrates on chest roentgenogram. Arch Intern Med 1989; 149:273.
  8. Davison AG, Heard BE, McAllister WAC, et al. Cryptogenic organizing pneumonitis. Q J Med. 1983; 52:382–94.
  9. Mroz BJ, Sexauer WP, Meade A, et al. Hemoptysis as the presenting symptom in bronchiolitis obliterans organizing pneumonia. Chest 1997; 111: 1775–1778.
  10. Poletti V, Cazzato S, Minicuci N, et al. The diagnostic value of bronchoalveolar lavage and transbronchial lung biopsy in cryptogenic organizing pneumonia. Eur Respir J. 1996; 9:2513–2516.
  11. Webb WR, Muller NL, Naidich DP. High-resolution CT of the lung. Lippincott Williams & Wilkins. 2008; ISBN:0781769094.
  12. Epler GR, Colby TV, McLoud TC, et al. Bronchiolitis obliterans organizing pneumonia. N Engl J Med 1985; 312:152.
  13. Ichikawa Y, Ninomiya H, Katsuki M, et al. Low-dose/long-term erythromycin for treatment of bronchiolitis obliterans organizing pneumonia (BOOP). Kurume Med J 1993; 40:65.
  14. Stover DE, Mangino D. Macrolides: a treatment alternative for bronchiolitis obliterans organizing pneumonia? Chest 2005; 128:3611.

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Last updated: 2018-06-21 18:12