Pericardial effusion may be caused by a wide variety of infectious or noninfectious processes 2. Determining these causes previously required invasive procedures often considered inappropriate by treating physicians. As a result, a large proportion of cases are labeled “idiopathic pericarditis.” Viral infections are thought to be responsible for most of these cases. Enterovirus is the most commonly recognized agent causing acute serofibrinous pericarditis, but many other viruses have been implicated by isolating the virus from noncardiac sites such as throat or feces, or by serologic testing 29,31. Potentially treatable infectious agents such as Coxiella burnetii 15, Mycoplasma pneumoniae 20, and Toxoplasma 28 may also cause acute idiopathic pericarditis. Chronic infectious pericarditis is generally caused by Mycobacterium tuberculosis 21 and by a variety of fungi 6,14,30, although idiopathic effusions are again quite common 2. Noninfectious causes of pericarditis include collagen vascular diseases 8 such as lupus erythematous, rheumatoid arthritis, and scleroderma 17; uremic pericarditis, especially in patients on hemodialysis 26; and neoplastic diseases, with or without mediastinal irradiation 3. Other etiologies include hypothyroidism 9,13,33 and postpericardiotomy syndrome 12.
Isolated reports of specific infectious agents involved in pericarditis are numerous but large series are rare 27: the only prospective studies using a thorough and systematic approach to determine the etiology 10,19,22 are those based on pericardial sampling 4,5,16,18. As a result, most studies report a 40%-86% idiopathic rate 29. This is unfortunate because several etiologic agents may benefit from specific treatment. Moreover, the diagnostic criteria of pericarditis are unclear: various symptoms, from a simple rub or murmur or chest pain improved by anteflexion to an acute tamponade, are classified as the same entity. Patients are then enrolled under different diagnostic criteria.
In an effort to improve the diagnostic yield in patients with pericarditis, we prospectively evaluated our diagnostic procedure in all patients with pericardial effusion confirmed by echocardiography over 4 years. We deliberately limited our study to pericardial effusion with the objective criterion of echocardiography and excluded pericarditis without effusion and myocarditis. Since hospital stays are generally short for patients with this disease, we tested for the different etiologies at 1 time. Moreover, to evaluate the predictive value of our tests, we included control patients and retained tests only when significantly different from the control population.
PATIENTS AND METHODS
From May 1998 to December 2002, all patients hospitalized in the departments of cardiology or internal medicine in Marseilles’s university hospital with a diagnosis of pericardial effusion, confirmed by echocardiography, were enrolled in a prospective study and completed a questionnaire and a standardized diagnostic evaluation. Patients with pericardial rub but without effusion were excluded, as were patients with postpericardiotomy syndrome. Pericardial effusion was defined as an echo-free space surrounding the heart in any incidence. Care was taken to distinguish between pleural and pericardial effusion; this distinction was generally easy to make using transthoracic echocardiography. Because an anterior echo-free space may be observed in people without pericardial effusion, the diagnosis was made based on a large echo-free space and/or an associated posterior echo-free space 7. A control group of patients hospitalized for a noninfectious reason was enrolled in order to estimate the predictive value of culturing enterovirus from stool and throat swabs. A second control group of blood donors was sampled to evaluate the predictive value of diagnostic serologies.
Diagnostic tests to be included were selected after a MEDLINE (National Library of Medicine, Bethesda, MD) search of the etiologies of pericarditis and a review of the major infectious diseases and internal medicine reference texts. Diagnostic testing for each etiology with even a small incidence was included. Our diagnostic procedure included the following:
- A questionnaire involving the following clinical diagnostic and epidemiologic data on patients: underlying conditions (such as immunosuppression, prosthetic devices, and collagen diseases); epidemiologic factors (such as contacts with toxins, animals, ingestion of unpasteurized milk, and travel outside the living area within 6 months); clinical symptoms; suspected clinical diagnosis; and an informed consent set.
- The following tests to be done immediately:
- A. A set of 2 blood culture vials, 1 aerobic and 1 anaerobic (Bactec; Becton Dickinson, Sparks, MD), in which the growth of nonfastidious bacteria could be assessed.
- B. Two serum samples in Vacutainer tubes (Becton Dickinson Vacutainer systems, Rutherford, NJ), used to estimate the presence of antibodies against specific infectious agents, antinuclear antibodies (Hep2 Kallestad, Redmond, WA), and serum thyroid-stimulating hormone.
- C. Two sterile tubes/swabs for viral detection in anus and pharynx.
When possible, 2 blood culture vials (1 aerobic and 1 anaerobic) were drawn 1 and 2 hours after the initial evaluation, 2 sterile tubes/swabs were used for viral cultures of stool and throat on the third day, and 2 serum samples were used to detect convalescent antibodies 2–3 weeks after onset.
Antibodies to Coxiella burnetii, Bartonella species, Chlamydia species, Legionella pneumophila, Brucella species, Mycoplasma pneumoniae IgM, Borrelia burgdorferi, and Toxoplasma were detected by using previously described methods 1,32. ELISA testing was performed for cytomegalovirus IgM and IgG, human immunodeficiency virus (HIV), and hepatitis C using the microparticule technique AXSYM (ABBOTT, Chicago, IL) according to the manufacturer’s instructions and for enterovirus IgM using ELISA Test (Virotech, France). The complement fixation test was used (Dade Behring, Marburg, Germany) to detect influenza virus and adenovirus antibodies. Viral culture swabs were placed in 1 mL of transportation media and later inoculated onto continuous cells (monkey kidney carcinoma cells BGM, VERO), dog continuous cells (MDCK), and human embryonic lung (MRC5) fibroblasts in shell vials by methods described previously 23,25. They were incubated at 37 °C for up to 8 days. Myxovirus influenzae direct immunofluorescence detection was performed (MonofluoKit Influenza 52209 BioRad, France) from nasal liquid samples when available.
The diagnosis was considered certain if collagen disease or thyroid dysfunction was diagnosed or if neoplastic cells were found in the effusion or pericardial tissue. In the absence of 1 of these findings, patients with known renal failure or neoplastic disease were considered to have those conditions as the cause of their pericardial effusion. Others cases were considered idiopathic before the results of the kit sampling. Etiology was considered established when there was a 2-fold rise in antibody titers, an antibody titer above a specific cutoff value, or a positive culture (unless values/cultures in control patients were also abnormal/positive). An etiologic diagnosis was not considered when the same prevalence was obtained from both patients and controls.
To estimate the prevalence of each disease in a presumably healthy population, sera from 260 blood donors were tested using the same techniques outlined above. Control patients with noninfectious diseases hospitalized during the study underwent viral throat and rectal cultures.
Values for quantitative variables were expressed as means ± standard deviation (SD). Statistical analysis was performed using the chi-square test and the Fisher exact test. Statistical significance was established at p < 0.05. All analyses were conducted with the SPSS 10.0 Software (SPSS Inc.).
From May 1998 to May 2002, we evaluated 204 patients with pericardial effusion. The mean age of our patients was 54 years (SD, 18 yr; range, 7–93 yr), and 106 (51%) patients were male. Etiologic diagnosis was highly suspected at first examination and confirmed later in 52 cases. This includes thyroid deficiency in 5 cases, collagen vascular diseases in 17 cases (systemic lupus erythematous in 7 cases, rheumatoid arthritis in 8 cases, scleroderma in 2 cases), cancer in 25 cases, and renal insufficiency in 5 cases (Table 1).
Pericardium and pericardial fluid was sampled in 30 cases, which led to 11 diagnoses: 5 cancer and 6 infectious diseases. Tuberculosis was diagnosed in 3 patients, and Streptococcus pneumoniae, Citrobacter freundii, and Actinomyces were isolated in 1 case each. The remaining 141 patients were considered to have idiopathic pericarditis. In this group, viral cultures from pharynx swab were performed 107 times (76%). Convalescent sera tests were completed for only 73 patients (52%). Forty-four patients (31%) were felt to have a definite etiologic diagnosis with noninvasive procedures. For 21 other patients, at least 1 diagnostic test was positive (9 patients with positive antinuclear antibodies between 1/100 and 1/400, 4 patients with positive antibodies to cytomegalovirus, 4 patients with positive antibodies to Toxoplasma, and 4 with positive hepatitis C antibodies), but these findings were not significantly different from controls (Table 2).
Fourteen cases of hypothyroidism and 1 case of hyperthyroidism were discovered by the sampling strategy, as well as 3 cases of collagen vascular disease (positive homogenous antinuclear antibodies at 1/1000). Q fever was the most commonly diagnosed cause of infection (10 cases), representing 4.9% of the entire group of pericardial effusion (see Table 1). From throat swabs, enterovirus was isolated in 7 cases, and adenovirus was cultured in 1. Rectal swabs were positive for enterovirus in 4 cases in which throat culture was also positive. One case of enterovirus, 1 case of influenza virus, 1 case of Bartonella quintana, 1 case of Legionella pneumophila, and 4 cases of Mycoplasma pneumoniae were also detected by serologic testing (seroconversion). Blood cultures were negative except for 1 patient in whom Staphylococcus epidermidis was isolated and considered a contaminant. When patients were classified into 2 groups by age (younger or older than 34 years), we noted a significant difference for Mycoplasma pneumoniae only (p = 0.01), more frequently encountered in the younger group. On the other hand, patients older than 34 years tended to have more hypothyroidism. The limit of 34 years was chosen because no young patients were included in the control group. With an age of 55 years as a cutoff (median age), we did not notice significant differences in etiologic diagnosis between the 2 groups.
The 260-patient control group results are reported in Table 2. The mean age of controls was 59.3 years (SD, 14.2 yr; range, 34–81 yr), and 63 (52%) patients were male. No thyroid dysfunction was diagnosed in the control group. Since our control group was provided by the blood bank, hepatitis C status was obviously negative; however, the local prevalence is estimated at 1% (unpublished data). Antibodies to influenza virus were detected in 1 case, IgM antibodies were detected to cytomegalovirus in 4, and to Toxoplasma in 4. Serologic tests for all other infectious agents were negative. We considered, therefore, that positive results for Q fever and Mycoplasma pneumoniae implicated these as causative agents. Positive nuclear antibodies at the cutoff of 1/100 were detected in 6 cases (5%), but none was detected in 260 cases when using a 1/400 cutoff. Therefore, to improve the positive predictive value of nuclear antibodies, collagen disease was considered only if the titer was greater than or equal to 1/400. For viral isolation, cultures from stools and throat were performed in 93 patients. Four enterovirus species were isolated from rectal swabs and none from the throat (Table 3).
We conducted the current study to determine the etiology of pericardial effusion in our area. The etiology of infectious diseases depends, of course, on local epidemiology, but a systematic approach to determine the etiologies of pericardial effusion is applicable everywhere, even if the prevalence varies from 1 area to another. Our study was conducted for 4 years, which limits seasonal variations on the prevalence of infectious diseases. We first analyzed the efficacy of biologic tests for etiologic diagnosis of pericardial effusion. In this respect, a control group is critical, as shown by the results of our serologic and rectal swab tests. Unless a seroconversion is noted, we discovered that the informative value of positive serology for adenovirus, influenza virus, Toxoplasma, and cytomegalovirus was low, as these did not differ between patients and controls. Without negative controls, we might have claimed that 8 more patients had viral etiologies for pericarditis, which may or may not be true. For example, although 8 cases of pericarditis due to cytomegalovirus infection were proven by culture (4 from a recent prospective study of subxiphoid pericardial biopsy) 4, most reported cases were serologically diagnosed, which may or may not be valid. Physicians should be aware that serologic information may be misinterpreted in the absence of known prevalence. Thus in the current study, relating pericarditis to cytomegalovirus, Toxoplasma, or lupus (when suspected by the presence of antinuclear antibodies), should be done with caution. In addition, the results of viral cultures from rectal swabs must be discounted, while, in contrast, throat swabs appear to be useful. No difference was noted for rectal culture results between patients and controls, and therefore this test cannot be recommended in the evaluation of pericarditis.
Microbiologic exploration of the causes of pericarditis depends on the interests and meticulousness of the treating physician. For example, 2 cases of chronic pericardial effusion caused by Toxoplasma gondii were identified by Sagrista-Sauleda et al 28 only because they had included routine immunofluorescence examination in their study protocol of pericardial fluid. To our knowledge, this etiology was not mentioned in the literature previously. Similarly, the diagnosis of culture-positive mycoplasma/ureaplasma pericarditis was possible only because of the systematic evaluation of fluid and tissue by Kenney et al 11 in their study of 57 patients. In the current study, Q fever was systematically sought because Coxiella burnetii had been mentioned recently as an etiologic agent of pericarditis 15. As a result, during the 4 years of the current study (1998–2002), 10 new cases of Q fever were diagnosed. Pericarditis occurred in 1% of cases of acute Q fever 24, while Coxiella burnetii was found to be the cause in almost 5% of cases in our series of pericarditis. Q fever has a worldwide distribution and has been reported with a high prevalence in Canada, Israel, Australia, the United Kingdom, Switzerland, Spain, and France, but few cases of pericarditis have been described because it is rarely sought in these circumstances. In the 3 countries where the prevalence is the highest (Spain, the United Kingdom, and France), the respective role of epidemiologic specificity and of active research from specialized laboratories remained unclear.
Our second aim was to analyze the value of systematic employment of all diagnostic tests in 1 round in the evaluation of patients with pericardial effusion. In a 1985 study 22, to our knowledge the largest published series, of 231 consecutive patients with primary acute pericardial disease, a specific diagnosis was obtained in only 32 cases (14%) (neoplasm in 13 cases, tuberculosis in 9, inflammatory diseases in 4, toxoplasmosis in 2, purulent pericarditis in 2, and viral diseases in 2). In comparison, after excluding test results for diseases with the same prevalence as in the general population, we still made a definite diagnosis in 52.4% of all cases of pericardial effusion (including those highly suspected clinically) and 31.2% of those cases classified as “idiopathic pericarditis.” The specific etiologies of pericarditis identified in our series were clearly influenced by the disease prevalence in the general population. Malignancy and collagen vascular disease were common, while purulent pericarditis was infrequently encountered. The 3 infectious agents that emerged as important in our series (Q fever and enterovirus, and to a lesser extent, Mycoplasma pneumoniae) are also quite prevalent in our hospital’s referral population. Three patients with tuberculosis were diagnosed in our series: 2 of them were noted in immunocompromised patients (HIV), which is probably a risk factor for tuberculosis. In order to have definite and objective diagnostic criteria of pericarditis with the echocardiography, we deliberately limited our study to pericardial effusion. However, in our experience, influenza virus was frequently encountered during this same period in patients with pericarditis without effusion.
Including tests for noninfectious agents resulted in the unexpected diagnosis of 14 cases of hypothyroidism. Without this systematic strategy, these cases would have been classified as idiopathic pericarditis. These diagnoses were critical because thyroid deficiency is 1 of the rare causes of treatable pericardial effusion. Classically, pericardial effusion appeared late in the course of myxedema. As it is pauci- or asymptomatic, it has not been considered a symptom for the diagnosis of hypothyroidism. However, since echocardiography is now largely prescribed in various conditions, asymptomatic pericarditis is more frequently diagnosed, and it is not uncommon to identify pericardial effusion in a patient not suspected to have hypothyroidism. It then becomes possible to have mild pericardial effusion as the first symptom of hypothyroidism. To the best of our knowledge, no study has reported systematic thyroid-stimulating hormone testing in patients with unexplained pericardial effusion. Our work stresses that thyroid-stimulating hormone should be systematically tested, and that mild pericardial effusion should be considered among the isolated symptoms of hypothyroidism. With adequate medical treatment, most pericardial effusions will resolve slowly but completely 13. In addition, we discovered 1 case associated with hyperthyroidism and 3 with lupus.
The sizes of effusion were noted in case of tamponade only. We did not notice significant differences in the number of etiologic diagnoses between patients with or without tamponade (p = 0.18). However, in the group with tamponade, cancer was clearly found more frequently (p = 0.001).
Using our evaluation strategy for patients with pericardial effusion, we were able to reduce the number of cases classified as idiopathic. In addition, we were able to identify 2 frequently underdiagnosed causes in our area, Q fever and hypothyroidism, both of which are easily treated. We also showed that each center caring for and studying patients with pericarditis should have its own control group to help determine the predictive value of the test. Finally, we validated the use of the Coxiella burnetii, Mycoplasma pneumoniae, and enterovirus serology, thyroid-stimulating hormone, antinuclear antibodies, and throat swabs in the etiologic diagnosis of pericarditis. Some tests, such as blood cultures and rectal swabs and serologic tests for cytomegalovirus and Toxoplasma, are of little use. Despite the fact that the number of idiopathic cases remains high, we propose the use of a systematic procedure, limited to the pertinent tests, to reduce the number of undiagnosed cases of this frustrating illness.
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