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Pleural effusions in non-transplanted cystic fibrosis patients

Open ArchivePublished:December 12, 2016DOI:https://doi.org/10.1016/j.jcf.2016.11.006

      Abstract

      Background

      Pleural effusions are considered rare in cystic fibrosis (CF) patients. There is a paucity of available information in the literature concerning the nature and significance of pleural effusions in non-transplanted CF patients.

      Methods

      We conducted a multicenter retrospective evaluation of non-transplanted adult CF patients. Given the small sample size, only descriptive statistics were performed.

      Results

      A total of 17 CF patients with pleural effusion were identified, of whom 9 patients underwent thoracentesis. The crude incidence of pleural effusion was 43 per 10,000 person-years in hospitalized CF patients at large CF centers. All sampled effusions were inflammatory in nature. All samples submitted for culture grew at least one organism.

      Conclusion

      Pleural effusions are rare in adult non-transplanted CF patients. These fluid collections appear to be quite inflammatory with a higher rate of empyema than in the general population.

      Keywords

      1. Introduction

      Cystic fibrosis (CF) is a disease stemming from impaired cellular transmembrane ion-transportation. This results in dysfunctional airway clearance leading to bacterial colonization and subsequent injury to the lung from repeated bouts of infection [
      • Bombieri C.
      • Seia M.
      • Castellani C.
      Genotypes and phenotypes in cystic fibrosis and cystic fibrosis transmembrane regulator-related disorders.
      ,
      • Pittman J.E.
      • Ferkol T.W.
      The evolution of cystic fibrosis care.
      ]. Patients with CF develop progressive airway obstruction with intermittent exacerbations driven by bacterial overgrowth, inadequate airway clearance and impaired epithelial defense [
      • Rowe S.M.
      • Hoover WS G.M.
      • Sorscher E.J.
      Cystic fibrosis.
      ,
      • O'Sullivan B.P.
      • Flume P.
      The clinical approach to lung disease in patients with cystic fibrosis.
      ]. Despite chronic colonization of the lung and recurrent flares of infection, pleural effusions are considered rare in the CF population [
      • Amodio JBB W.E.
      • Abramson S.
      • Baker D.
      Cystic fibrosis in childhood pulmonary, paranasal sinus, and skeletal manifestations.
      ,
      • Egan T.M.
      • Orenstein DMS R.C.
      Thoracic surgery for patients with cystic fibrosis.
      ,
      • Rolla M.
      • D'Andrilli A.
      • Rendina E.A.
      • Diso D.
      • Venuta F.
      Cystic fibrosis and the thoracic surgeon.
      ]. There is a paucity of data regarding pleural effusions in patients with CF, here we present the first characterization of this disease process in patients with CF.

      2. Methods

      We performed a retrospective review at each participating institution (University of North Carolina in Chapel Hill, Johns Hopkins University, and Pennsylvania State University) after receiving Institutional Review Board approval. Patients were identified by querying the electronic medical records for patients with ICD-9 codes for CF with pulmonary exacerbation (277.02) and pleural effusion (511.9) or pleural effusion associated with pneumonia (511.89) or empyema (510). Patients with CF over the age of 18 who developed a pleural effusion or empyema between January 1, 2010 and December 31, 2015 were eligible for inclusion in the study. Patients with CF who developed pleural effusions after lung transplantation were excluded.
      In order to obtain a crude incidence of pleural effusion in CF patients we asked each CF center to report their average number of CF patients ≥18 years of age over the last several years. We then obtained a measure of person-years at risk by summing the average number of CF patients over 18 years of age for each center and multiplying by 5 years, the duration of the study period. We calculated a crude incidence rate by dividing the total number of CF patient-pleural effusions detected during this study by the estimated person-years at risk.
      All data were stored and analyzed within a Microsoft Excel (Seattle, WA) database. Data analysis consisted of descriptive statistics; specifically, the absolute counts and percentages for qualitative data and median with 25th and 75th percentile values for quantitative data.

      3. Results

      A total of seventeen CF patients with pleural effusion were identified. (Table 1) The crude incidence of pleural effusion was 0.0043 or 43 per 10,000 person-years. The median age of the patients was 25 (22–31) years. The majority of patients were Caucasian (94%), and the most common comorbid condition was diabetes (41%). A wide range of baseline forced expiratory volumes in 1 min was noted (0.89 L to 3.06 L).
      Table 1Pre-effusion characteristics.
      N = 17
      Age (years)25 (22–31)
      Sex
       Male9 (53%)
       Female8 (47%)
      Race
       Caucasian16 (94%)
       Asian1 (6%)
      Comorbid diabetes7 (41%)
      Other significant comorbidities
       Acute Lymphoblastic Leukemia1 (6%)
       Cirrhosis1 (6%)
       Liver Transplant1 (6%)
      Lung function
       Baseline FEV1 (Liters)1.36 (1.04–1.77)
       Baseline FEV1 (percent of predicted)41% (30%–61%)
      Sputum culture results by organism in 6 months prior to pleural effusion
       Methicillin-sensitive Staph aureus7 (41%)
       Methicillin-resistant Staph aureus4 (24%)
      Pseudomonas aeruginosa14 (82%)
      Stenotrophomonas maltophilia2 (12%)
      Burkholderia cenocepacia1 (6%)
       Fungus or mold8 (47%)
       Cultures positive for only one organism3 (18%)
      Data are presented as the absolute number and percentage or as median and (25th and 75th percentile values). FEV1 = Forced expiratory volume in 1 min.
      All patients had a sputum culture positive in the 6 months prior to the identification of the pleural effusion. (Table 1) Pseudomonas aeruginosa was the most frequently isolated organism (82%). Other organisms isolated from the sputum included mold or fungus (47%), methicillin-sensitive Staphylococcus aureus (41%), and methicillin-resistant Staphylococcus aureus (24%).
      Nine patients underwent sampling and analysis of their pleural fluid with a median volume of 40 (18–55) mL of fluid removed (Table 2). The pH was 7.2 (7.2–7.5). All effusions analyzed were inflammatory with an elevation in lactate dehydrogenase (LDH) of 927 (422–2119) units/mL and a total protein of 4.8 (4.2–5.4) g/dL [
      • Light R.W.
      • Macgregor M.I.
      • Luchsinger P.C.
      • Ball Jr., W.C.
      Pleural effusions: the diagnostic separation of transudates and exudates.
      ]. In addition, there was a neutrophilic predominance in the cell count of 83% (17–88%). Six pleural fluid specimens were submitted for culture; no organisms were detected on gram stain. All six patients subsequently had positive cultures of the fluid (Table 3). Three cultures were polymicrobial and three of the six contained organisms also present on sputum culture.
      Table 2Pleural Effusion characteristics.
      Effusion laterality
       Unilateral16 (94%)
       Bilateral1 (6%)
      Thoracentesis
       No8 (47%)
       Yes9 (53%)
      Volume of pleural fluid removed (mL)40 (18–55)
      White blood cell count (mL)d990 (490–1975)
      Neutrophil percentage83% (17–88)
      Lymphocyte percentage13% (12–23)
      pH7.26 (7.2–7.5)
      Glucose (mg/dL)130 (111–169)
      Protein (g/dL)4.8 (4.2–5.4)
      LDH (Unit/L)927 (422–2119)
      Bacteriology
       Positive culture6 (35%)
      Data are presented as the absolute number and percentage or as median and interquartile range. LDH = Lactate dehydrogenase.
      Table 3Detailed culture results of CF patients with positive pleural fluid cultures.
      Patient numberPleural fluid culture resultsComorbiditiesPre-effusion sputum organismsPost-effusion sputumHome maintenance regimen
      1Enterococcus faeciumALLMSSA, MRSA, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Escherichia coli, and Klebsiella pneumoniaeExpired Prior to CollectionUnclear. On inhaled tobramycin, aztreonam, and colistin on arrival from OSH. Also treated with IV Vancomycin, Bactrim, Piperacillin and Tazobactam, and Meropenem.
      2MSSA, Pseudomonas aeruginosaDMMSSA, Pseudomonas aeruginosa, AspergillusMSSA, Pseudomonas aeruginosa, CandidaStanding oral azithromycin.
      3Staphylococcus epidermidisCKD, OLTPseudomonas aeruginosa, MoldPseudomonas aeruginosaInhaled tobramycin and colistin. Standing oral azithromycin.
      4MRSA, Pseudomonas aeruginosaDMMRSA, Pseudomonas aeruginosa, AspergillusMRSA, Pseudomonas aeruginosa, Stenotrophomonas maltophiliaInhaled aztreonam and DNAase. Standing oral azithromycin.
      5Pseudomonas aeruginosa, Achromobacter, Filamentous FungusDMPseudomonas aeruginosa, Achromobacter, Filamentous FungusPseudomonas aeruginosa, AchromobacterInhaled tobramycin and DNAase.
      6Stenotrophomonas maltophiliaNonePseudomonas aeruginosaPseudomonas aeruginosaInhaled tobramycin, aztreonam, and DNAase. Standing oral azithromycin.
      MSSA = Methicillin-Sensitive Staphylococcus aureus, MSRA = Methicillin-Resistant Staphylococcus aureus, ALL = Acute lymphoblastic leukemia, DM = Diabetes Mellitus, CKD = Chronic Kidney Disease, OLT = Orthotopic liver transplantation.
      All patients were managed in the hospital with IV antibiotics. Four patients underwent chest tube placement; three in the setting of positive pleural fluid culture. Chest tube size ranged from 14 to 28F and the chest tubes were present for a median of 5 (4–9) days. No patients underwent surgical intervention. The median length of stay for all patients was 8 (3–13) days, 7 (3–12) days in patients in whom pleural fluid sampling was performed and 8 (4–11) days for patients with a positive pleural fluid culture. There were no deaths during the index hospitalization, however 3 patients died within the year following the detection of the pleural effusion.

      4. Discussion

      We report the first characterization of pleural effusions in the non-transplant CF population. The data presented appears to confirm that pleural effusions are rare in this population with pleural effusions found in only 17 patients at three large CF centers over a 5-year period. It is important to note that our incidence calculation is crude and is only reflective of CF patients hospitalized at large CF centers.
      One potential cause for the low number of patients identified may be a lack of awareness of pleural effusion as a complicating factor in CF patients given that proper categorization of pleural effusion in the CF population is undefined. Parapneumonic effusion is defined as a pleural effusion that forms in the pleural space adjacent to pneumonia [
      • Light R.W.
      • Girard W.M.
      • Jenkinson S.G.
      • George R.B.
      Parapneumonic effusions.
      ]. During an exacerbation, CF patients are not considered to have “clinical” pneumonia, but rather an “acute flare” of their chronic suppurative lung infections [
      • Goss C.H.
      • Burns J.L.
      Exacerbations in cystic fibrosis. 1: epidemiology and pathogenesis.
      ]. This difference in terminology may lead to a decreased awareness or lack of urgency in identification and/or sampling of pleural effusions in the CF population.
      Few of the pleural effusions detected were sampled in our cohort. In addition, few interventions were performed other than antibiotic administration. One possible explanation is that prior pleural disease or the limitations of chest radiography led to inappropriate identification of a few patients for our study. Six patients (35%) were found to have positive bacterial cultures of their pleural fluid but these were the only patients in which pleural fluid cultures were obtained. Of the six, three grew organisms in their pleural fluid that were concordant with those detected in their sputum prior to the development of the pleural effusion. This is a lower proportion of concordance between sputum and pleural cultures than previously reported from two military hospitals [
      • Brook I.
      • Frazier E.H.
      Aerobic and anaerobic microbiology of empyema. A retrospective review in two military hospitals.
      ], but higher than that reported in a group of hospitalized Canadian citizens [
      • Ahmed R.A.
      • Marrie T.J.
      • Huang J.Q.
      Thoracic empyema in patients with community-acquired pneumonia.
      ]. One important difference between our CF patient population and the military/Canadian populations in those prior studies is that the sputum samples in our patients were often collected months earlier than the pleural effusions were sampled. Another potential cause of discordance between sputum and pleural cultures is the frequent overgrowth of Pseudomonas sp. on sputum culture which limits the speciation of other organisms, particularly in CF sputum samples [
      • Goss C.H.
      • Burns J.L.
      Exacerbations in cystic fibrosis. 1: epidemiology and pathogenesis.
      ].
      The length of stay in our patient population was consistent with previously published data [
      • Okumura M.J.
      • Campbell A.D.
      • Nasr S.Z.
      • Davis M.M.
      Inpatient health care use among adult survivors of chronic childhood illnesses in the United States.
      ,
      • Kopp B.T.
      • Wang W.
      • Chisolm D.J.
      • Kelleher K.J.
      • McCoy K.S.
      Inpatient healthcare trends among adult cystic fibrosis patients in the U.S..
      ]. There was no clear relationship between the degree of pleural effusion intervention and exploration and hospital length of stay. The small sample size makes drawing definitive conclusions difficult, however, this observation suggests that dedicated management of the pleural effusion may not affect clinical outcomes.
      There are several limitations of our study. Our study is retrospective and is subject to all of the potential biases associated with this type of study. In addition, by relying on ICD-9 codes to identify patients, we may have missed some patients with pleural effusions but for whom no ICD-9 code for pleural effusion was entered or some of the patients may have even been inappropriately identified as having pleural effusions, especially in those without follow-up culture data. Finally, three of the patients we identified arguably had other comorbidities which predisposed them to having pleural effusions including ALL, cirrhosis, and a remote liver transplantation, further reinforcing the notion that pleural effusions are rare in CF.
      In conclusion, we present the first multicenter review of pleural disease in adult patients with CF. Pleural disease, while rare in this population appears to be highly inflammatory with a high prevalence of pleural infection. In CF patients with pleural effusion with a clinical indication for drainage, pleural fluid cultures should be obtained.

      Acknowledgements

      ARB: Contributed to study design, data acquisition, data analysis and interpretation, data integrity management, manuscript preparation, and final approval of the manuscript.
      KN: Contributed to data acquisition and final approval of the manuscript.
      UO: Contributed to data acquisition and final approval of the manuscript.
      CRG: Contributed to data acquisition and final approval of the manuscript.
      KA: Contributed to data acquisition and final approval of the manuscript.
      AFAR: Contributed to study design, data acquisition and final approval of the manuscript.
      LY: Contributed to study design, data acquisition and final approval of the manuscript.
      JAA: Contributed to study design, data acquisition, data analysis and interpretation, data integrity management, manuscript preparation, and final approval of the manuscript.

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