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International Pleural Newsletter                                                       A Publication of the International ...
more than 95% of patients and 20% presented with              is rarely indicated. The pleural effusion resolves afteracce...
Histologic evidence of pleuritis was present in up to        intravenous immunoglobulins), or pleurodesis and93% of SLE pa...
chest pain at the time of diagnosis1. In addition,typical SLS has also been reported in non-SLEpatients (e.g. rheumatoid a...
Treatment of Refractory Pleural                           that the parenteral form was withdrawn from the                 ...
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Pleural thickening 2009 janvol7issue1

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Pleural thickening 2009 janvol7issue1

  1. 1. International Pleural Newsletter A Publication of the International Pleural Network Volume 7 Issue 1 January 2009Editors: Pleural Effusion inRichard W. Light Nashville, TN, USAY.C. Gary Lee Oxford, UK Rheumatic Diseases Guest Editor: Dr José M PorcelCo-Editors:Michael H. Baumann Jackson, MS, USARobert J.O. Davies Oxford, UK Pleural Effusion Associated withJohn E. Heffner Portland, OR, USA Rheumatoid ArthritisInternational Advisors:P Astoul France D Bouros Greece Lone S Avnon MDV C Broaddus USA T E Eaton New ZealandA Ernst USA F V Gleeson UK Mahmoud Abu-Shrakra MDG Hillerdal Sweden S Idell USA Ben Gurion University of the Negev, Beer Sheva, IsraelY Kalomenidis Greece T K Lim Singapore Mahmoud@bgu.ac.ilR Loddenkemper Germany S E Mutsaers AustraliaM Noppen Belgium J M Porcel Spain Pleural disease is the most common thoracicF Rodriguez-Panadero Spain S Romero Candeira SpainS A Sahn USA G F Tassi Italy manifestation in rheumatoid arthritis (RA). PleuralL R Teixeira Brazil F S Vargas Brazil effusion was identified in 3.8% of asymptomatic RAC Xie China A P C Yim Hong Kong patients using chest CT. In most cases it is small andAdministrator: Emma Hedley Oxford, UK without clinical significance1,2. Among patients with emmahedley@orh.nhs.uk exudates, RA was the cause of pleural effusion in 0.6% of 2,346 patients and in 0.75% of 1,200 patients The International Pleural Newsletter is distributed or who underwent thoracoscopy1,2. A literature review web-posted by the: has identified 30 cases of pleural effusion in patients with RA2. The data in this article are based on those American College of Chest Physicians cases. Seventy percent were men with a mean age of Asian Pacific Society of Respirology 56.2 years (range: 32-73)2. The effusion was Asociación Latino Americana del Tórax Belgian Society of Pulmonology diagnosed subsequent to RA in 16 and concurrently Brazilian Thoracic Society in 14 patients. The mean interval (SD) between the British Thoracic Society diagnosis of RA and pleural effusion was 1310.1 Costa Rican Thoracic Society years. In 7 patients the diagnosis of pleural effusion European Respiratory Society came shortly before that of RA2. International Mesothelioma Interest Group The most common pleural effusion-related Italian Association of Hospital Pulmonologists symptoms are chest pain, shortness of breath and/or Singapore Thoracic Society coughing. Patients may also present with fever and South African Thoracic Society weight loss and rarely respiratory distress, cardiac Thoracic Society of Australia & New Zealand Turkish Thoracic Society tamponade and hemodynamic instability. In most cases, the arthritis was active at the time of diagnosis The Newsletter is on line: of pleural effusion. Rheumatoid factor was found in www.musc.edu/pleuralnews 1
  2. 2. more than 95% of patients and 20% presented with is rarely indicated. The pleural effusion resolves afteraccelerated rheumatoid nodulosis1-3. an average of 14 months (range 1-36). The characteristic findings of the RA-associatedpleural effusions are a very low pH in the range of Table 1. Causes of pleural effusions in RA patients based on the6.4-7.14 in 70% of the patients and a glucose content results of thoracentesisof <20 mg/dL in 80%1-4. The low glucose content is pH Glucose Predominant Differential diagnosis otherthe result of consumption by the activated (mg/dL) cell than RA <7.20 <20 Neutrophil Empyemainflammatory cells and a metabolic block preventing <7.20 <20 Lymphocyte TB, malignancytransfer of glucose into the pleural fluid. Low pH <7.20 <20 Eosinophil Drug reaction, methotrexatecorrelated to low glucose levels. The effusions were Normal Normal Lymphocyte TB, malignancy, drug reactionexudates with a mean level of LDH of 2,348 IU/ml Acknowledgments: Dr N Sion-Vardy kindly provided Figures.and a mean total protein of 5.24 mg/dL. The cellcount in the effusions was >3,000 WBC/µL in 67% 1. Balbir-Gurman A, et al. Semin Arthritis Rheum 2006; 35:368-of samples. The differential cell count was found to 78.be of lymphocytic predominance in 37%, neutrophilic 2. Avnon LS, et al. Rheumatol Int 2007; 27:919-25. 3. Pettersson T, et al. Thorax 1982; 37:354-61.in 56% and eosinophilic in 7% of samples. There 4. Faurschou P, et al. Thorax 1985; 40:371-5.were no mesothelial cells2. In two cases, the 5. Naylor B. Acta Cytol 1990; 34:465-73.differential cell count changed from neutrophilic tolymphocytic predominance2 at a repeated tap. The presence ofslender, elongatedtadpole cells on a Prevalence and Outcome of Lupus-background of many Associated Pleural Effusionscells, some of which aredecaying, on the Chi Chiu Mok MD FRCPcytology smears, is Tuen Mun and Pok Oi Hospital, Hong Kong SAR, Chinaconsidered to be ccmok2005@yahoo.compathognomic3-5 (left). Systemic lupus erythematosus (SLE) is a chronicThoracoscopic examination of the parietal pleura inflammatory autoimmune disease that may affectshows a "gritty" or frozen appearance, a slightly any system of the body. Involvement of the serousinflamed and thickened surface with small vesicles membranes is one of the diagnostic criteria in theand granules of about 0.5 mm3. On the microscopic American College of Rheumatology classification.examination the mesothelial cells are being replaced Serositis of the pleura, pericardium or peritoneumby palisades of pseudo-stratified epithelioid cells of may lead to pain, fluid accumulation, adhesion and/ormacrophage origin, representing an erupted fibrosis.rheumatoid nodule (below). Calretinin staining may The prevalence of lupus-related pleuritis/pleuralverify a lack of mesothelial effusion varies widely depending on the clinicalcells. These patterns may not criteria used, patient sampling, diagnostic methods,be present on smaller, closed and whether screening investigations were performedpleural biopsies4. and secondary causes of pleural effusion were The differential diagnosis included for analysis. In a study of 520 SLE patientsof pleural effusion among conducted in the 1960s, the cumulative incidence ofpatients with RA is outlined in recurrent pleuritic pain was 45% and that of pleuralTable 1. The presence of the effusion was 30%1. Pleurisy and pleural effusionspathognomic cells precludes were the initial manifestation of SLE in 3% and 1%further investigations and invasive procedures. of patients, respectively. Other studies alsoTreatment modalities include systemic steroids, intra- documented a high prevalence of pleuritic chest pain,pleural steroids, methotrexate and/or other with or without associated pleural effusion, in 41 toimmunosuppressive agents1-4. Surgical pleurectomy 56% of SLE patients during their disease course2,3. 2
  3. 3. Histologic evidence of pleuritis was present in up to intravenous immunoglobulins), or pleurodesis and93% of SLE patients in an autopsy series, but this pleurectomy for symptomatic alleviation.figure is likely to be a composite of all primary 1. Dubois EL, et al. JAMA 1964; 190:104-11.(lupus-related) and secondary causes4. Pleural 2. Estes D, et al. Medicine (Baltimore) 1971; 50:85-95.effusion in SLE is often small to moderate, but 3. Grigor R, et al. Ann Rheum Dis 1978; 37:121-8.occasionally massive. Bilateral involvement is 4. Wang DY. Curr Opin Pulm Med 2002; 8:312-6.present in about half the cases, which may be 5. Toya SP, et al. Semin Arthritis Rheum 2008 June 26.associated with pericardial effusion and ascites. 6. Man BL, et al. Lupus 2005; 14:822-6.Pleuritic chest pain has recently been recognized as acommon initial manifestation of the rare shrinkinglung syndrome in SLE5. In a recent study, we showed that the point Shrinking Lung Syndrome in SLEprevalence of symptomatic lupus-related serositis was12% in 310 Chinese patients with a disease duration Sophie P Toya MDof 7.2 years6. Among the 69 episodes of serositis, George E Tzelepis MD44% were pleuritis/pleural effusion. Bilateral Athens University School of Medicine, Athens, Greeceeffusions occurred in 36% of patients and the most gtzelep@med.uoa.grcommon presenting features were pleuritic chest pain, Shrinking lung syndrome (SLS) is a rarenon-productive cough and dypsnea. However, the complication of systemic lupus erythematosus (SLE)prevalence of pleuritis in this study could have been characterized by unexplained dyspnea, small lungunderestimated as surveillance investigations were volumes, elevation of the diaphragm, and restrictivenot routinely performed. physiology. The exact pathogenesis of serositis in SLE remains SLS may complicate SLE at any time over itselusive. Histologic examination of the serosal course, ranging from as early as a few months to 24membranes reveals inflammation with infiltration by years from disease onset1. Patients with SLS typicallylymphocytes, plasma cells and macrophages, present with dyspnea, initially on exertion and later atfibrinous exudates, and perivascular fibrinoid rest; pleuritic chest pain is present in the majority ofnecrosis4. Immune complexes, complement activation patients1. On physical exam, patients with SLS mayproducts and immunoglobulins may also be found. have shallow rapid breathing, use of accessoryHowever, these immune-mediated mechanisms may muscles and, occasionally, paradoxical abdominalnot be specific to SLE. Persistent and unresolved movements. Elevation of one or bothinflammation may result in serosal fibrosis and hemidiaphragms is invariably present on chestthickening. radiographs. The volitional tests of diaphragmatic Although lupus pleuritis often responds promptly strength show that the maximal transdiaphragmaticto treatment with non-steroidal anti-inflammatory pressure is diminished, suggesting diaphragmaticdrugs or short courses of glucocorticoids, a small dysfunction.proportion of patients may present with life- The pathophysiology of diaphragmaticthreatening effusion that is refractory to medical dysfunction in SLS is unclear. The possibility of atreatment. myopathic process involving the diaphragm is not In our study, 27% of patients with lupus-related supported by the finding of normal diaphragmaticpleural effusion required thoracentesis for strength in response to magnetic stimulation of thesymptomatic relief6. Although all patients responded phrenic nerve2.to treatment within 2 months, 20% of patients had a Could pleurisy account for the diaphragmaticrecurrence of pleuritis and 10% developed localized dysfunction in SLS? Although it is too premature topleural fibrosis as a sequel. Patients with more firmly attribute diaphragmatic dysfunction toserious or recurrent/refractory pleural effusion may pleurisy, indirect evidence suggests a possiblerequire more aggressive immunosuppressive relationship. First, pleurisy is a prominent feature oftherapies (eg intravenous pulse methylprednisolone, patients with SLS and a recent literature search foundcyclophosphamide, azathioprine, cyclosporin A, that 65% of all reported SLS patients had pleuritic 3
  4. 4. chest pain at the time of diagnosis1. In addition,typical SLS has also been reported in non-SLEpatients (e.g. rheumatoid arthritis) who similarly had IMAGES OF THE PLEURApleuritic chest pain and improved with anti-inflammatory medications3. The occurrence of SLS innon-SLE patients supports the hypothesis that theassociation of diaphragmatic dysfunction in the SLS Pleural Lymphaticsis not unique to SLE but rather reflects the high Soraya Puente MDprevalence of pleurisy in SLE. José M Porcel MD FCCP FACP The mechanism by which pleurisy and its Arnau de Vilanova University Hospital, Lleida, Spainassociated pain may lead to diaphragmatic jporcelp@yahoo.esdysfunction is probably through reflex inhibition ofdiaphragmatic activation, in a manner similar to that The lymphatic systems of the visceral and parietaldescribed following abdominal or thoracic pleura hold roles in pleural fluid turnover. Aprocedures. Although the exact neural pathways distinctive feature of the parietal pleura is theinvolved are not entirely clear, experimental data presence of lymphatic stomata which open directlysuggest that inflammation of the parietal pleura may into the pleural space,lead, through stimulation of the unmyelinated or thin representing the mainmyelinated fibers belonging to the internal intercostal route of pleural fluidnerves, to suppression of phrenic motor neuron absorption.discharge4,5. An additional mechanism may alsoinvolve the ‘phrenic-to-phrenic’ reflex. In animals, A normal human parietalinflammation of the diaphragmatic pleura, through pleural membrane isstimulation of phrenic nerve afferents, may inhibit shown using H&E stainactivation of the intercostal muscles, levator costae, (x200) (left) and Massonas well as the diaphragm5,6. Given the high trichromic stain (x 200)prevalence of pleurisy in SLE and the rarity of SLS, (below).one would speculate that only pleurisy in a regionnear the diaphragm or directly involving the Note the presence ofdiaphragmatic pleura would be responsible for prominent largediaphragmatic dysfunction. Anti-inflammatory lymphatic structurestherapy, the mainstay therapy for the SLS, is (L) in the subpleuralassociated with symptom improvement in the connective tissue.majority of patients1.1. Toya SP, et al. Semin Arthritis Rheum. 2008 in press.2. Hawkins P, et al. Thorax 2001; 56:329-30. This contrasts with3. Ahmed S, et al. Arthritis Rheum 2001; 44:243-45. the appearance of4. Jammes Y, et al. J Physiol 2005; 567:641-50. the visceral pleura5. De Troyer A. J Physiol 1998; 508:919-27. (left; H&E x100).6. Speck DF, et al. J Appl Physiol 1987; 62:941-45. European School of Oncology education course Approach to Pleural Cancer: State of the Art 7 - 8 May 2009: Athens, Greece. For details, see www.eso.net 4
  5. 5. Treatment of Refractory Pleural that the parenteral form was withdrawn from the market several years ago. Talc pleurodesis was Effusion in SLE reported in six patients, either as a powder Gideon Nesher MD (poudrage), or as a suspension in saline (slurry). Five Maher Deeb MD had complete resolution of the fluid without Gabriel S Breuer MD recurrences. Complications were observed in two Shaare-Zedek Medical Center, Jerusalem, Israel patients: one developed empyema, and the other (who nesherg@szmc.org.il underwent bilateral pleurodesis) developed a restrictive defect.Pleuritis-related pleural effusions in systemic lupus The main side effect of pleurodesis is pain, whicherythematosus (SLE) are usually small or moderate may last for a few days3. Rarely, debilitating pain(400-1000mL); massive effusions are uncommon1. may last longer4. Mild fever may also be present for aTreatment should be individualized: small few days. Lung function is not significantly affectedasymptomatic effusions may not require treatment; in most cases. However, there have been some reportsnon-steroidal anti-inflammatory drugs are useful for of transient respiratory failure3,5, developing within amild pleurisy while corticosteroid therapy is indicated day of the procedure. Other uncommon complicationsfor more severe cases1. Most patients respond of talc pleurodesis include granuloma formation andpromptly. When the fluid volume is large and causing empyema. Finally, mechanical shunts, either pleuro-shortness of breath, aspiration is necessary. Rarely peritoneal or pleuro-venous, may be appropriate forare repeated thoracentesis or other local or systemic some non-malignant cases. However, data on the usetherapies required. of such procedures in refractory SLE-related The following are data on massive refractory lupus effusions are limited6.pleurisy from a review of the English-language In summary, refractory massive pleural effusion isliterature over the past 25 years2. Systemic therapy uncommon in SLE, but the affected patients pose aincluded immunosuppressive drugs, plasmapheresis difficult management problem. Due to the smalland intravenous immunoglobulin. Immunosuppresive number of patients reported in the literature, it istherapy with azathioprine, cyclophoshamide, difficult to determine the optimum intervention.cyclosporine, methotrexate or hydroxychloroquine, in When refractory pleural effusion is part of anaddition to corticosteroids, generally did not prevent exacerbation of SLE, the treatment of choice wouldfluid accumulation. Plasmapheresis was reported in be systemic. Local therapy should be employed ifone case, but it failed to achieve resolution of the systemic therapy fails, or in cases where pleuraleffusion. Intravenous immunoglobulin (IVIG) effusion is the only manifestation of SLE. Talctherapy was reported in two patients. In one case, the pleurodesis seems to be the preferred method of localeffusion recurred two months after the last dose. In therapy.the other patient, IVIG therapy was followed by 4months of treatment with cyclosporine and no fluid 1. D’Cruz D, et al. In: Wallace DJ, Hahn BH, eds. Dubois’accumulation was observed during a two-year follow- Lupus Erythematosus, 7th ed, pp. 678-99. Philadelphia, 2007. 2. Breuer GS, et al. Semin Arthritis Rheum 2005, 34:744-9.up. 3. de Campos JR, et al. Chest 2001; 119:801-6. Local therapy included intra-pleural corticosteroid 4. Milton R, et al. Ann Thorac Surg 2003; 76:1740-1.injections, pleurodesis with talc or tetracycline, and 5. Bondoc AY, et al. Cancer Invest 2003; 21:848-54.pleurectomy. Intra-pleural corticosteroid injections 6. Artemiou O, et al. Ann Thorac Surg 2003; 76:231-3.were reported in three SLE patients, with nobeneficial response whereas pleurectomy wasdescribed in three other patients, with variableresponses. Regarding pleurodesis, the use oftetracycline as a sclerosing agent was reported in four If you have any comment on the Newsletter orpatients: two of which had a favorable response, one interesting cases of pleural disease, contact:had a transient response and pleurodesis failed in the Ms Emma Hedley emma.hedley@orh.nhs.ukother one2. The primary problem with this agent is 5

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