(Chest. 2005;128:4013-4017.)
© 2005
American College of Chest Physicians
A 24-Year-Old Woman With Bilateral Pulmonary Infiltrates, Pericardial Effusion, and Bilateral Pleural Effusions*
Chandra K. Katikireddy, MD;
Ganesh Krishna, MD;
Gerald Berry, MD;
John Faul, MD and
Ware Kuschner, MD
* From the Division of Pulmonary and Critical Care Medicine (Drs. Katikireddy and Faul), Stanford University Hospital; Division of Pulmonary Medicine (Drs. Krishna and Kuschner), VA Palo Alto Health Care System; and Division of Pathology (Dr. Berry), Stanford University Hospital, Palo Alto, CA.
Correspondence to: Ware Kuschner, MD, Division of Pulmonary Medicine, 3801 Miranda Ave, Palo Alto, CA 94304-1290; email: kuschner{at}leland.stanford.edu
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Introduction
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A 24-year-old woman presented with a 3-week history of exertional dyspnea and dry cough. Her medical history was remarkable for rheumatoid arthritis (RA). She had no exacerbation of joint symptoms during the prior 2 years. She denied fever or other constitutional symptoms. She took ibuprofen occasionally but no other antirheumatic medications. She was a lifelong nonsmoker. Her review of systems, family, social, and exposure histories were noncontributory.
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Physical Examination
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The patient appeared comfortable, and her vital signs were normal. Arterial oxygen saturation while breathing ambient air at rest was 96%. Auscultation of the lungs revealed fine inspiratory crackles in the mid and lower zones bilaterally. The heart sounds were distant but there was no audible rub. Musculoskeletal examination revealed fixed deformities in the small joints of hands and feet bilaterally. The extremities were without cyanosis, clubbing, or edema.
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Laboratory and Radiographic Findings
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The WBC count was 13.6 x 109/L, with differential of 65% neutrophils, 13% lymphocytes, 10% monocytes, and 5% eosinophils. The hemoglobin was 8.6 g/L, with a mean corpuscular volume of 85 femtoliters. The erythrocyte sedimentation rate was 60 mm/h. Serum chemistry, renal, liver func-tions, and urinalysis were normal. The rheumatoid factor, anti-nuclear antibody, and anti-neutrophil cytoplasmic antibody titers were negative. Results of serologic tests for a spectrum of infections were negative.
The chest radiograph (Fig 1
) was remarkable for enlarged, globular cardiac silhouette and bilateral parenchymal opacities in the right lung more than the left lung. A CT scan of the thorax (Fig 2
) revealed bilateral, patchy alveolar infiltrates, small pleural effusions, and a moderate pericardial effusion. A two-dimensional echocardiogram revealed moderate pericardial effusion with no evidence of pericardial tamponade. Bronchoscopy with BAL was performed. Results of BAL microbiological and cytologic studies were negative.
The patient underwent open-lung biopsy and pericardial biopsy (Fig 3
). As shown in Figure 3, top left, A, the low-power magnification of lung biopsy revealed an organizing pneumonia pattern and increased interstitial cellularity. The bronchiolar and alveolar duct lumens were filled by loose fibromyxoid polypoid aggregates that fill and outline the airways. The adjacent alveolar interstitium was expanded by mononuclear cell inflammatory infiltrates (Fig 3, top right, B). The parietal pericardium was thickened by mature collagenous connective tissue indicative of fibrous pericarditis (Fig 3, bottom left, C). Focal accumulations of chronic inflammation were also noted (Fig 3, bottom right, D).
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Figure 3.. Top left, A: Low-power magnification of lung biopsy showing organizing pneumonia (arrows). Top right, B: Fibromyxoid polypoid aggregates filling the airways and alveolar ducts. Bottom left, C: Fibrous pericarditis (arrow). Bottom right, D: Focal accumulation of chronic inflammatory cells (arrow).
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What is your diagnosis of this patient presenting with bilateral, patchy alveolar pulmonary infiltrates and pleuropericardial effusion? How do you treat this patient?
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Answers: Organizing pneumonia and fibrous pleuropericarditis/effusions secondary to RA. Systemic steroids are the treatment of choice.
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Discussion
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We describe a case of RA with quiescent joint involvement in a patient with organizing pneumonia, pericarditis, and bilateral pleural effusions. RA is associated with a wide spectrum of pulmonary disorders, involving the pleura, parenchyma, interstitium, airways, and vasculature (Table 1
). Pulmonary manifestations are usually seen in cases of longstanding RA, but they may rarely precede the joint symptoms.
Organizing Pneumonia/Bronchiolitis Obliterans Organizing Pneumonia Associated With RA
"Organizing pneumonia" is a rare but well-defined disorder characterized by the organization within the alveoli and alveolar ducts with or without organization within the bronchioles. Davison described this entity as cryptogenic organizing pneumonia in 1983. Epler described the same entity as bronchiolitis obliterans organizing pneumonia (BOOP) in 1985. The generic term organizing pneumonia cryptogenic (primary) or secondary to causes such as RA is preferred to BOOP to avoid confusion with airway disorders such as constrictive bronchiolitis. The etiology of organizing pneumonia is either primary (idiopathic) or secondary to drugs, infections, or connective tissue diseases (Table 2
).
Presenting signs and symptoms are nonspecific and include dyspnea, nonproductive cough, fever, sore throat, malaise, and crackles on physical examination. A febrile flu-like syndrome may precede in approximately one third of cases. Patients typically present with symptomatic duration of < 3 months.
Imaging pattern on chest radiography and CT chest reveal patchy, alveolar infiltrates that may begin as focal lesions but usually become bilateral over time with predilection for periphery and lower lobes. Pulmonary function tests typically reveal restrictive pattern with reduced diffusion capacity.
There are no specific laboratory findings in organizing pneumonia. A moderately raised erythrocyte sedimentation rate (> 60 mm/h) and C-reactive protein may be seen in 30% of patients. A neutrophil leukocytosis may be seen.
Differential cell count of BAL is a characteristic "mixed pattern." BAL demonstrates moderately increased numbers of lymphocytes (approximately 25 to 45%) with a decreased CD4+CD8+ ratio (< 0.9), as well as an increase in both neutrophils (approximately 10%) and eosinophils (approximately 5%, but < 25%). Foamy macrophages (> 20%) and some mast cells and plasma cells may be seen in the BAL. BAL may be helpful in excluding the secondary causes of organizing pneumonia, particularly infections.
The pathognomonic histologic feature of organizing pneumonia is the presence of uniform plugs of edematous fibrous and granulation tissue filling alveolar ducts, alveoli, and bronchioles. The buds extend from one alveolus to the next through the pores of Kohn, giving a characteristic "butterfly pattern." These plugs consist of collagen and elastin with admixed chronic inflammatory cells. There may be variable infiltration of bronchiolar and alveolar walls by inflammatory infiltrate, but the underlying pulmonary architecture is preserved and fibrosis is a very rare finding.
The diagnosis is based on the typical clinicoradiologic data and pathologic features as described above. The "gold standard" for the diagnosis of organizing pneumonia is a surgical lung biopsy. Transbronchial biopsies rarely provide an adequate tissue sample for the diagnosis. Surgical lung biopsy is the preferred diagnostic intervention, as it provides adequate lung specimens for the diagnosis of organizing pneumonia, as well as disclosing associated lesions and clues to the etiology. Conventionally, video-assisted thorascopic surgery (VATS) is preferred to open-lung biopsy for cryptogenic organizing pneumonia and other interstitial lung diseases, as it is widely held to be less morbid, requires a shorter hospital stay, and has fewer long-term sequelae than open-lung biopsy. However, the only randomized trial comparing VATS and open-lung biopsy showed no difference in terms of complications or diagnostic efficacy. Open-lung biopsy may be safer than VATS in patients with severe hypoxia, chronic pleural disease, pulmonary hypertension, or coagulopathy.
Once the diagnosis of organizing pneumonia is established based on clinical, radiologic, and pathologic findings, the etiologic diagnosis should be sought. Clinical and radiologic features of organizing pneumonia are largely indistinguishable in secondary and cryptogenic forms. Cryptogenic organizing pneumonia is the diagnosis of exclusion. If detailed history and laboratory investigations exclude the etiologies such as infections, connective tissue diseases, drugs, and radiation (Table 2), organizing pneumonia may be labeled as cryptogenic.
Organizing pneumonia secondary to infection should be considered in the context of nonresolving infectious pneumonia; commonly they are bacterial, but the are also viral, fungal, and parasitic. A diagnosis of a drug-induced secondary form of organizing pneumonia may be established if withdrawal of the drug results in resolution of disease. Organizing pneumonia secondary to radiation may be seen outside the radiation field, as opposed to radiation pneumonitis, which is restricted to the radiation zone. Associated extrapulmonary features and pulmonary manifestations other than organizing pneumonia such as pleural effusions should raise the suspicion of organizing pneumonia secondary to connective tissue disease or systemic inflammatory disease.
Systemic corticosteroids are the current standard treatment of organizing pneumonia. The ideal dose and duration of the treatment are not known. The rarity of this disease makes it difficult to establish a standard treatment protocol. Different authors recommended varying starting dose of prednisone, from 0.75 to 1.5 mg/kg/d with slow tapering over next several weeks to months. The total duration of treatment varies, but typically it is 6 to 12 months. Relapses usually occur when the dose is tapered to < 20 mg/d. Relapse at a dosage of 
20 mg should raise the suspicion of alternative diagnosis.
Clinical improvement may be seen within 48 h, and chest radiographs show a complete resolution within a few weeks, with no functional or imaging sequelae. The prognosis is usually excellent. Relapses are seen more commonly in secondary forms of organizing pneumonia.
Pleural Involvement in RA
Pleural disease is the most common pulmonary manifestation in RA. Prevalence of histologic pleural disease is reported to be from 38 to 73%, but pleural effusions occur in approximately 5% patients with RA.
Pleural disease may be clinically silent or manifest as pleurisy or pleural effusion. Other pleural abnormalities include empyema, necrosis, and cavitation of rheumatoid nodule causing an effusion, bronchopleural fistula, and pyopneumothorax.
Pleural effusions are usually small to moderate in size, bilateral, and sometimes are associated with rheumatic pericarditis. They may be associated with other pulmonary parenchymal diseases secondary to RA. Pleural fluid analysis typically shows an aseptic exudate with a low level of glucose (< 20 mg/dL), pH approximately 7.00, low complement levels, and high levels of lactate dehydrogenase (> 1,000 U/L).
Rheumatoid pleural effusions usually do not require specific treatment. Typically, the pleural effusions resolve spontaneously, but they can be chronic and recurrent. There are anecdotal reports of pleural effusions resolving with corticosteroids and other immunosuppressive agents.
Pericarditis/Pericardial Effusion in RA
Clinically significant pericarditis/pericardial effusion is uncommon, but echocardiographic study and autopsy series have shown high prevalence of pericardial disease with or without effusion in up to 50% of patients with RA. Dominant joint symptoms usually overshadow the pericardial symptoms, which explains the discrepancy in frequency in between pericardial clinical symptoms and echocardiographic and autopsy findings. Rheumatoid pericardial effusion is usually exudative.
Pericardial disease is more common during the RA flares. Symptomatic pericarditis, although uncommon, rarely can lead to chronic disease presenting as constrictive pericarditis or cardiac tamponade requiring surgical intervention.
Clinical Course
Our patient was started on an oral systemic steroid, prednisone, at 1 mg/kg qd. The patient showed significant clinical improvement with resolving infiltrates on chest radiography within 2 weeks. Prednisone was gradually tapered off to 20 mg/d in the next 8 weeks without any evidence of recurrence. Prednisone was discontinued after 3 months. The patient remained asymptomatic at the 3-month follow-up visit.
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Clinical Pearls
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- RA flares may present with multiorgan involvement without exacerbation of articular symptoms.
- Bilateral, patchy, alveolar pulmonary infiltrates on chest radiography in patient with RA should suggest organizing pneumonia.
- One should consider RA or other connective tissue disease in a patient presenting with pleuropericardial effusion and bilateral pulmonary infiltrates, as cardiopulmonary manifestations may rarely precede the arthritis.
- Organizing pneumonia secondary to RA typically has a good response to corticosteroids.
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Footnotes
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This work was performed at Stanford University Hospital.
Received for publication May 20, 2005.
Accepted for publication June 14, 2005.
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Suggested Readings
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- Anaya, JM, Diethelm, L, Ortiz, LA, et al (1995) Pulmonary involvement in rheumatoid arthritis. Semin Arthritis Rheum 24,242-254[CrossRef][ISI][Medline]
- Bartter, T, Irwin, RS, Nosh, G, et al Idiopathic bronchiolitis obliterans organizing pneumonia with peripheral infiltrates on chest roentgenogram. Arch Intern Med 1989;149,273-279[Abstract]
- Cordier, JF Organizing pneumonia. Thorax 2000;55,318-328[Free Full Text]
- Cordier, JF Cryptogenic organizing pneumonia. Clin Chest Med 2004;25,727-738[CrossRef][Medline]
- Dedhia, HV, DiBartolomeo, A Rheumatoid arthritis. Crit Care Clin 2002;18,841-852[CrossRef][ISI][Medline]
- Epler, G Bronchiolitis obliterans organizing pneumonia: definition and clinical features. Chest 1992;102(suppl),2S-6S[Abstract/Free Full Text]
- Ippolito, JA, Palmer, L, Spector, S, et al Bronchiolitis obliterans organizing pneumonia and rheumatoid arthritis. Semin Arthritis Rheum 1993;23,70-78[ISI][Medline]
- John, JT, Jr, Hough, A, Sergent, JS Pericardial disease in rheumatoid arthritis. Am J Med 1979;66,385-390[Medline]
- Joseph, J, Sahn, SA Connective tissue diseases and the pleura. Chest 1993;104,262-270[Free Full Text]
- Lettieri, CJ, Veerappan, GR, Helman, DL, et al Outcomes and safety of surgical lung biopsy for interstitial lung disease. Chest 2005;127,1600-1605[Abstract/Free Full Text]
- Riley, DJ Risk of surgical lung biopsy in idiopathic interstitial pneumonias. Chest 2005;127,1485-1486[Free Full Text]
- Shiel, WC, Prete, PE Pleuropulmonary manifestations of rheumatoid arthritis. Semin Arthritis Rheum 1984;13,235-243[Medline]
- Tanoue, LT Pulmonary manifestations of rheumatoid arthritis. Clin Chest Med 1998;19,667[CrossRef][Medline]
- Van Thiel, RJ, Van der Burg, S, Groote, AD, et al Bronchiolitis obliterans organizing pneumonia and rheumatoid arthritis. Eur Respir J 1991;4,905-911[Abstract]
TOP
Introduction
Physical Examination
