39-year-old female with mild respiratory distress and hypoxia.
Definitive diagnosis of cryptogenic organizing pneumonia is based on a suggestive clinical radiological presentation, the demonstration of the characteristic pathological pattern at lung histopathology, and exclusion of possible causes. (1) It has been included in the American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. (2) The annual incidence of organizing pneumonia is 1.97/100 000 population (1.10/100 000 for the cryptogenic form and 0.87/100 000 for the secondary form) with a mean age of 67 years at the time of diagnosis. (3)
A 39-year-old woman presented to the hospital with a history of fever for three days. She had no medical complaints until two years ago when she was diagnosed with Hodgkin's lymphoma. Six months ago she underwent autologous stem cell transplantation. She had been complaining about shortness of breath and dry cough for one month. She denied smoking tobacco. Her only home medication was albuterol inhaler as needed. On examination, the patient appeared in mild respiratory distress with oxygen saturation of 85 percent on room air. Her lung examination revealed crackles in mid lung zones bilaterally. She did not have any skin rash. The rest of her physical examination was normal. Blood work revealed white blood count of 3,200/ mm3 (4000-11,000/[mm.sup.3]), serum Beta-D-Glucan level 33pg/ml (<60pg/ml), procalcitonin level 0.11ng/ml (0.0-0.5ng/ml). Her hemoglobin, electrolytes, creatinine and liver enzymes were all normal. Her posteroanterior chest radiograph is shown in Figure 1. High-resolution chest CT scan (axial view) is shown in Figure 2A and Figure 2B. The patient was started on antibiotics without any clinical improvement. Flexible bronchoscopy was performed as a result. Surgical pathology of transbronchial biopsy specimen of right middle lobe showed granulation tissue within distal air spaces suggestive of organizing pneumonia. Stains were negative for any bacterial, fungal or viral infection. Exclusion of possible etiologies led to the final diagnosis of cryptogenic organizing pneumonia. An endobronchial ultrasound-guided FNA performed one month prior to presentation was negative for malignancy or infections. This procedure was performed after surveillance chest CT had revealed residual mediastinal lymphadenopathy. In addition, review of her home medications was not suggestive of any potential culprit and she had no history of connective tissue disease. She had also been off immunosuppressive medications for the past six months.
Cryptogenic organizing pneumonia usually presents with progressive and nonspecific symptoms such as mild fever, mild dyspnea, cough, malaise, anorexia, and weight loss. Symptoms that will raise suspicion for connective tissue diseases are prominent arthralgia or myalgia. Physical examination findings may include focal or sparse crackles on auscultation. Subacute presentation is typical with onset over a period of less than 3 months. Diagnosis is usually delayed for six to twelve weeks due to the consideration of infectious pneumonia as one possible differential. (1)
Our patient was started on prednisone 60 mg daily with plan to slowly taper the dose over three to six months. Her clinical improvement was rapid and by day five her cough and shortness of breath were much better and she had no drop in oxygen saturation upon ambulation. She remained asymptomatic on follow-up at three and six months. Corticosteroid therapy was discontinued at about 3 months. The dose and duration for corticosteroid therapy has not been established and is based on clinical judgment. (1,4) Generally, duration of treatment should be six months or longer. Most patients undergo complete remission with corticosteroid therapy but are still at risk of relapse within one to three months when corticosteroids are tapered or discontinued. (2)
The procedure of choice to establish the pathologic diagnosis of organizing pneumonia is video-assisted thoracoscopic surgery (VATS). (4,5) This allows for evaluation of the distribution of the lesions and enhances the exclusion of possible causes. Samples of adequate size can be obtained through VATS. However, transbronchial biopsy may be sufficient in cases with typical clinical and radiographic features. (1,4) Also, transbronchial biopsy can be done under local anesthesia. Consequently, less technical staff maybe required when compared with VATS but the diagnostic yield is less and sample size maybe insufficient to make a definitive diagnosis. CT guided transthoracic biopsy has also been evaluated in the diagnosis of organizing pneumonia in a limited number of cases. (5-7) After literature review and presentation of six cases the authors in one article concluded that CT guided biopsy should be considered as an alternative to transbronchial biopsy. This was because CT guided biopsy had improved diagnostic yield and provided larger tissue sample. These two factors reduce the chances of misdiagnosis. (8) The main complication in the study was pneumothorax ranging from eight to sixty-one percent of cases with up to three to fifteen percent requiring chest drainage. The proportion of cryptogenic organizing pneumonia over secondary cases appears to vary. In one series of twenty-six patients with organizing pneumonia on biopsy about fifteen (58 percent) were classified as cryptogenic. (1)
Some serum biomarkers could be useful to exclude infectious etiologies for respiratory symptoms. A systematic review showed that serum procalcitonin level can be used to guide initiation and duration of antibiotics in acute respiratory infections and was not associated with increased deaths or treatment failure.9 Procalcitonin levels are elevated in bacterial infections, more so in invasive bacterial infections. With regards serum Beta-D-Glucan assay, the pooled sensitivity, and specificity for PCP were nine percent (95 percent confidence interval [95 percent CI], 92-98 percent), and 84 percent (95 percent CI, 83-86 percent) whereas for invasive fungal infections such as aspergillosis and candidiasis the values were 80 percent (95 percent CI, 77-82 percent), and 82 percent (95 percent CI, 81-83 percent).10 In our case both tests were normal. A potential area for future research could be the use of serum biomarkers of infection in the diagnostic work-up of patients with possible non-infectious etiologies of respiratory compromise.
Although chest radiograph findings in our case were ill defined the chest CT findings appeared typical for the so-called "reverse halo sign" or the Atoll sign. It is characterized by central ground-glass opacity surrounded by denser air-space consolidation in the shape of a crescent or a ring. This sign was first described on high-resolution chest CT as being specific for cryptogenic organizing pneumonia.11-14 Now we know that many entities could cause this pattern. Differential diagnoses are shown in Table 1.
In 90 percent of patients with cryptogenic organizing pneumonia CT chest findings will include air space consolidation. (15) The consolidation is typically predominant in the middle and lower lung zones with a subpleural or peribronchovascular distribution. (13) However, nodular or reticulonodular lesions are possible as well. (15) Ground glass opacities have also been seen demonstrated. (16) Figure 3 shows the dramatic improvement in her chest radiograph findings on day five of corticosteroid therapy. Figure 4A and Figure 4B show significant improvement in her chest CT findings one month after discharge.
Figure 5 photomicrograph demonstrates polypoid delicate fibrous organization bodies in some of the airspaces. No polypoid bronchiolitis obliterans is seen on this limited biopsy material. This pattern may be seen in the setting of unresolved infections; connective tissue disease; drug reaction; inhalation of a noxious agent; aspiration; hypersensitivity pneumonitis , radiation; myelodysplastic syndrome; distal to an obstruction; or as a manifestation of graft versus host reaction in the setting of bone marrow transplantation. Patients with pulmonary manifestations of graft versus host disease usually have other clinical manifestations in the skin and gastrointestinal tract. (17-20) Our patient had none of these manifestations, her liver enzymes were normal, and no infectious causes were identified by special stains for microorganisms in this case.
Histopathologic findings of cryptogenic organizing pneumonia include patchy distribution of intraluminal organizing fibrosis, otherwise referred to as plugs of granulation tissue, in distal air spaces including alveoli, and alveolar ducts. These findings are usually accompanied by mild and chronic mononuclear cell interstitial inflammation and mild intraalveolar cellular desquamation. (13)
The diagnosis of cryptogenic organizing pneumonia is by exclusion and usually delayed for several weeks due to treatment for presumed infectious pneumonia. The mainstay of treatment is with corticosteroids. VATS surgery is the gold standard for the pathologic diagnosis of organizing pneumonia. Biomarkers such as procalcitonin and Beta-D-Glucan may aid in the differential diagnosis of organizing pneumonia. The Atoll sign is an important radiological pointer to the possible diagnosis of cryptogenic organizing pneumonia.
(1.) Cottin V, Cordier JF. Cryptogenic organizing pneumonia. Semin Respir Crit Care Med. 2012 Oct; 33(5):462-75. Epub 2012 Sep 21.
(2.) American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2002 Jan 15; 165(2):277-304. Review. Erratum in: Am J Respir Crit Care Med2002 Aug 1; 166(3):426.
(3.) Gudmundsson G, Sveinsson O, Isaksson HJ, Jonsson S, Frodadottir H, Aspelund T. Epidemiology of organizing pneumonia in Iceland. Thorax.2006 Sep; 61(9):805-8. Epub 2006 June 29
(4.) Oymak FS, Demirbas HM, et al. Bronchiolitis Obliterans Organizing Pneumonia. Clinical and roentgenological features in 26 cases. Respiration. 2005; 72(3):254-62.
(5.) Haviv YS, Breuer R, Sviri S, Libson E, Safadi R. CT-guided biopsy of peripheral lung lesions associated with BOOP. Eur J Med Res 1997; 2: 44-46
(6.) Lee YH, Kim YR, Ji JD, Shim J.J., Kang KH, Lee JH, et al. A case of BOOP developed during bucillamine treatment for rheumatoid. Korean J Intern Med 2001; 16: 36-39
(7.) Safadi R, Berkman N, Haviv YS, Ben-Yehuda A, Amir G, Naparstek Y. Primary non-Hodgkin's lymphoma of the lung presenting as bronchiolitis obliterans organizing pneumonia. Leuk Lymphoma 1997; 28: 209-213.
(8.) Metzger F, Pernet D, et al. The contribution of CT-guided transthoracic lung biopsy to the diagnosis of organising pneumonia. RevMalRespir. 2010 Sep; 27(7):e6-16. doi: 10.1016/j.rmr.2009.12.002. Epub 2010 May 18
(9.) Schuetz P, Muller B, Christ-Crain M, Stolz D et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2012 Sep 12; 9: CD007498. doi: 10.1002/14651858.CD007498.pub2.
(10.) Onishi A, Sugiyama D, Kogata Y, et al. Diagnostic accuracy of serum 1,3-p-D-glucan for pneumocystis jiroveci pneumonia, invasive candidiasis, and invasive aspergillosis: systematic review and meta-analysis. J Clin Microbiol. 2012 Jan; 50(1):7-15. doi: 10.1128/JCM.05267-11. Epub 2011 Nov 9.
(11.) Godoy M, Viswanathan C, Marchiori M, Truong M, Benveniste M, Rossi S, Ma rom E. The reversed halo sign: update and differential diagnosis. Br J Radiol. 2012 September; 85(1017): 1226-1235
(12.) Marchiori E, Zanetti G et al. Reversed halo sign on computed tomography: state-of-the-art review. Lung. 2012 Aug; 190(4):389-94. doi: 10.1007/s00408012-9392-x. Epub 2012 May 10.
(13.) Kim SJ, Lee KS et al. Reversed halo sign on high-resolution CT of cryptogenic organizing pneumonia: diagnostic implications. AJR Am J Roentgenol. 2003 May; 180(5):1251-4.
(14.) Walsh SL, Robertson BJ. Images in thorax: The atoll sign. Thorax. 2010 Nov; 65(11):1029-30. doi: 10.1136/thx.2010.139360. Epub 2010 Sep 6.
(15.) Garcia Aguilar DJ, Cobos Moreno I, et al. Atypical radiological
presentation of a cryptogenic organising pneumonia. Arch Bronconeumol. 2010; 46(9): 496-7.
(16.) Narula T, Narula S, Krishnan S. Rare diagnosis, odd appearance: atypical radiologic presentation of cryptogenic organizing pneumonia. Chest 2014 Mar 1; 145(3 Suppl):214A. doi: 10.1378/chest.1826516.
(17.) Yousem, S.A. The Histological Spectrum of Pulmonary Graft-Versus-Host Disease in Bone Marrow Transplant Recipients. Human Pathology 26; 1995: 668-675.
(18.) Travis, WD et al AFIP Atlas. Non-Neoplastic Disorders of the Lower Respiratory Tract. Fascicle 2. 1st Series. 2002: 82-89.
(19.) Colby TV. Pathologic Aspects of Bronchiolitis Obliterans Organizing Pneumonia. Chest 1992; 102: 38S-43S
(20.) King TE Jr. and Mortenson RL. Cryptogenic Organizing Pneumonitis. The North American Experience. Chest 1992; 102: 8S-13S.
Drs. Okoye, Kaphle, Kheir and Salerno are affiliated with the Department of
Pulmonary Diseases, Critical Care & Environmental Medicine, Tulane University Health Sciences Center, New Orleans, LA. Dr. Daroca is affiliated with the Department of Pathology, Tulane University Health Sciences Center, New Orleans, LA.
Table 1: Differential diagnosis of the Atoll sign. Cryptogenic organizing pneumonia Invasive pulmonary fungal infections Paracoccidioidomycosis Pneumocystis pneumonia Tuberculosis Community-acquired pneumonia Lymphomatoid granulomatosis Granulomatosis with polyangiitis Lipoid pneumonia and sarcoidosis Pulmonary neoplasms and infarction Following radiation therapy Following radiofrequency ablation of pulmonary malignancies High-risk ethnicity (%) HTN/HTN medications (%) HDL Cholesterol <35 and/or Triglyceride >250 (%) PCOS (%) History of CVD (%)
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|Author:||Okoye, Obinna; Daroca, Philip J., Jr.; Kaphle, Upendra; Kheir, Fayez; Salerno, Daniel|
|Publication:||The Journal of the Louisiana State Medical Society|
|Article Type:||Clinical report|
|Date:||Jan 1, 2016|
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