00019606-200803000-00004ArticleDiagnostic Molecular PathologyDiagnostic Molecular Pathology© 2008 by Lippincott Williams & Wilkins.17March 2008
p 21-27Viral Detection and Tumor Necrosis Factor Alpha Profile in Tracheal Aspirates From Children With Suspicion of MyocarditisOriginal ArticlesCarturan, Elisa BSc, PhD*; Milanesi, Ornella MD†; Kato, Yasuchica MD‡; Giacometti, Cinzia MD*; Biffanti, Roberta MD†; Thiene, Gaetano MD, FRCP*; Calabrese, Fiorella MD*Departments of *Medical Diagnostic Science and Special Therapies†Pediatrics, Padua, Italy‡Department of Internal Medicine, Toyoake, JapanResearch Grant from the Ministry of Health, Rome.Reprints: Fiorella Calabrese, MD, Department of Medical Diagnostic Science and Special Therapies, University of Padua Medical School, Via A. Gabelli, 61—35121 Padova, Italy (e-mail:
[email protected]).AbstractPediatric myocarditis is a serious disease resulting in significant morbidity and mortality.
Tracheal aspirate (TA) has been demonstrated to be a sensitive diagnostic tool to detect viral agents responsible for respiratory disorders and myocardial dysfunction. Tumor necrosis factor alpha (
TNFα) is thought to play an important role in the pathogenesis of these disorders. The aim of the present study was to investigate the presence of different viruses and the expression of
TNFα in children with clinical suspicion of myocarditis. Forty-five TAs from children (20 males/25 females, mean age 4.4±5.0 y) with myocardial dysfunction and respiratory symptoms were analyzed for detection of viral genomes by using molecular techniques. In 10 cases endomyocardial biopsy was also performed due to a severe and rapid progression of heart failure.
TNFα mRNAs of TA and
TNFα protein plasma levels were quantified. Viral etiology was detected in 25/45 (56%) cases: the most frequent etiology was enterovirus (19 cases, 59%). Polymerase chain reaction viral concordance was found in TA and endomyocardial biopsy.
TNFα mRNA and
TNFα serum levels were significantly more expressed in viral cases than nonviral cases (1.26±0.76 vs. 0.56±0.76, P=0.001). More impaired cardiac function (particularly ejection fraction) was detected in viral positive than in viral negative cases (39.91±20.09 vs. 55.61±20.36, P=0.04). TA seems to be an excellent tool for viral investigation in pediatric patients with suspicion of myocarditis. The analysis of
TNFα in TA may represent an important marker to better define patient status.In the pediatric population, myocarditis is a serious disease resulting in significant morbidity and mortality. It is the most common cause of heart failure in children and adolescents, and it is regarded as an important predisposing condition of dilated cardiomyopathy or sudden death. Clinical features of the disease are variable, including unexplained congestive heart failure, chest pain, arrhythmias, syncope, and/or sudden death.The diagnosis of
viral myocarditis is usually based on clinical features and echocardiographic evidence of ventricular dysfunction in the setting of either positive peripheral viral cultures, serology, or morphologic evidence of inflammation on the biopsy. Different cardiotropic viruses have been implicated in more than 50% of pediatric cases with inflammatory cardiomyopathy, and adeno and coxsackie viruses have been considered to be the most frequently implicated.1–4 Parvovirus B19 has also been detected in endomyocardial biopsy (EMB) of pediatric transplanted patients.5 The remaining forms may be triggered by other environmental factors such as toxins, cytotoxic chemotherapy, metabolic abnormalities, or more frequently sustained by immunologic mechanisms. The last factor may characterize the autoimmune myocarditis ab initio or more often be the consequence of
viral myocarditis itself.6Whether myocyte damage in the early phase of the disease is primarily linked to the viral presence or to immune-mediated damage is still under discussion; however, it is now accepted that the progression of the disease is mainly sustained by immune mechanisms.6 Among inflammatory cytokines, tumor necrosis factor alpha (
TNFα) is thought to be related to cardiac dysfunction, thus playing a pivotal role in the development and progression of myocarditis.7 Previous studies have demonstrated that there is an association between depressed myocardial function, elevated
TNFα mRNA, and protein levels either in plasma or in the myocardium of patients with myocarditis and dilated cardiomyopathy.8,9 Recently, our group reported an association between elevated level of
TNFα and more impaired cardiac function in
viral myocarditis, showing that the persistent presence of this cytokine was implicated in the disease progression and development of irreversible heart failure.10EMB represents the gold standard method for histologic and molecular diagnoses of myocarditis. The development of molecular biologic techniques, particularly amplification methods such as polymerase chain reaction (PCR) or nested-PCR, allows the detection of low copies of viral genomes even from an extremely small amount of tissue such as EMB. Molecular analysis, performed on EMB, is now considered the best diagnostic tool for rapid, specific, and sensitive detection of
viral myocarditis.1 In children, EMB is far less employed than in adults because it has been considered an unsafe procedure of low diagnostic yield.11,12 A less invasive diagnostic tool might be more easily used, thus achieving a more targeted and rapid treatment.
Tracheal aspirate (TA) has been demonstrated to be a sensitive diagnostic tool for etiologic diagnosis of
viral myocarditis which may accompany respiratory disorders.13The aim of the present study was to investigate the presence of different types of viruses and expression of
TNFα in TA from children with clinical suspicion of myocarditis which developed after or at the same time of respiratory disorders.MATERIALS AND METHODSPatientsFrom January 2001 to December 2004, 45 consecutive TAs from children (20 males/25 females), aged 1 month to 15 years (mean age 4.4±5.0 y), were collected in our Institution. The patients were admitted to the Department of Pediatrics Cardiology of Padua Hospital after a complete physical examination. Characteristics of the patients are summarized in Table 1.JOURNAL/dimp/04.03/00019606-200803000-00004/table1-4/v/2021-02-17T195944Z/r/image-tiff Study PatientsThe inclusion criteria for the study were initial presenting symptoms of cardiovascular dysfunction due to a new onset/progression of typical cardiac chest pain, dyspnea, and echocardiography (ST segment alteration or T wave inversion) developed after or at the same time of respiratory disorders.Exclusion criteria were the diagnoses of congenital heart disease.Left ventricle volume and the major cardiac parameters [ejection fraction (EF), shortening fraction] were calculated by 2-dimensional echocardiography and by using the modified Simpson method.14 Different serology parameters, including C reactive protein determination, were also collected (Table 1).Parents or tutors of all children were informed of the aim of the study and gave written informed consent. The Ethical Committee of our Institution approved the protocol.SpecimensTA samples were collected in a sterile manner by instillation of 4 to 10 mL sterile normal saline into the endotracheal tube by suctioning into a sterile trap.Mean volume of aspirate was 5.5 mL (range 4 to 8 mL). All samples were transported on ice and processed immediately or stored at −80°C. The entire sample volumes were centrifuged (12000 rpm) at 4°C for 10 minutes. Total RNA and DNA were extracted simultaneously from TA pellets.15Qualitative and the quantitative evaluation of the nucleic acids were performed using spectrophotometry (Pharmacia Biotech: Gene Quant II, Pharmacia Biotech, Cambridge, UK).The oligonucleotides used to ascertain the quality of extracted RNA or DNA were complementary to the mRNA glyceraldehyde-3-phosphate dehydrogenase (3GPDH) and β-globin gene, respectively.16,17 The reverse transcriptase (RT)-PCR (at least 1 μg of total RNA) was used to evaluate the RNA viruses: enteroviruses, influenza A, and influenza B.2 RT-PCR for the late gene of cytomegalovirus was used to detect not only the presence of cytomegalovirus but also its replicative form.18 PCR (at least 50 ng of total DNA) was used to evaluate DNA viruses: adenovirus, herpes simplex virus, Epstein-Barr virus, and parvovirus B19.2,5 Fifteen microliters of each reaction mixture were analyzed on a 3% Nu-Sieve agarose containing 0.03 μg/mL ethidium bromide. The gels were placed under UV light for visualization of amplified products. Positive and negative control reactions were performed simultaneously in all cases. All samples were analyzed without prior knowledge of clinical data for each patient, and all PCR-positive products were repeated to ensure that they were positive. The sensitivity of our laboratory has been previously described and quoted about 1800 single RNA molecules/PFU.19 Specificity of PCR/RT-PCR or nested-PCR products was confirmed by automated gene sequencing (data not shown).EMB was performed in 10 cases within 1 month from TA due to a severe progression and rapid cardiac failure. Four/five myocardial samples per patient were obtained by EMB from the right ventricular myocardium. The samples fixed in 4% buffered formalin were embedded in paraffin for histopathology and immunohistochemistry. Viral investigation was performed on paraffin-embedded biopsies as previously described.2 In 2 cases, inadequate tissue sampling did not allow histologic and molecular analyses to be performed.Measurement of
TNFα in TATNFα expression was investigated by semiquantitative RT-PCR in 37 TA due to RNA availability.20,21 The relative gene expression was estimated using a housekeeping gene (3GPDH) as a reference. The RT was performed using random hexamer primers, and 3GPDH and
TNFα PCR was conducted for 35 and 37 cycles, respectively. The cycle number was previously determined to ensure that the amount of synthesized products was proportional to the amount of specific mRNA in the original preparation. The linear portion of the PCR amplification was determined by serial dilution of the cDNA samples. The quantification of
TNFα transcript levels was carried out by scanning photographs of gels and analyzing the area under the peaks using ChemiDoc XRS and Quantity One Basic 4.4 software (Bio-Rad Laboratories, Hercules, CA). Levels of mRNA expression were normalized by calculating them as a percentage of 3GPDH mRNA expression levels.22 The band intensity for 3GPDH did not differ significantly within experiments.The cycle number was chosen to ensure that the amount of synthesized products was proportional to the amount of specific mRNA in the original preparation.Measurement of
TNFα in SerumBlood samples from 22 patients were centrifuged for 30 minutes and serum was transferred to plastic tubes. The serum
TNFα levels were measured with a chemiluminescence immunometric assay (Immulite TNF-alpha; EURO/Diagnostic Products Corporation, UK). According to the manufacturer, the detection limit of the assay for
TNFα was 1.7 pg/mL.ControlsTen cases (4 males/6 females, mean age 4.7±3.7 y) affected by recurrent gastroesophageal–related laryngotracheitis, including one with Kartagener syndrome defect, were used as controls. None had evidence of pneumonia or pharyngeal exudates, and none were treated with antibiotics.Statistical AnalysisValues are given as mean±1 SD or as the number of subjects and percentage. The nonparametric Kruskal-Wallis test and the Mann-Whitney U test were used to test equality of population medians among groups. Student t test was used to analyze differences between subgroups with variances assumed to be equal. The difference was considered statistically significant at a level of P<0.05.RESULTSClinico-Hemodynamic Features of PatientsSix of the 45 patients (13%) had a flu-like syndrome that occurred at least 2 weeks before the onset of myocardial dysfunction and respiratory symptoms. There was no seasonality of the infection (10 autumn, 12 winter, 9 spring, and 14 summer). The presenting cardiac-related symptoms were arrhythmias, murmurs, acute heart failure, asthenia, and dyspnea. The patients presented with impaired cardiac function with reduction of SF and EF and mild cardiothoracic ratio. Complete blood counts were normal and the serum parameters did not show any pathologic values, except for an elevated level of C reactive protein (Table 1).TA AnalysisIn all cases, the presence of sufficient nucleic acid for PCR analysis was confirmed by amplification of β-globin for DNA and 3GPDH for RNA. Viral etiology was detected in 25 (55%) of 45 cases, as a single infection in 19/25 (76%) cases, and as double in 4/5 (16%) or triple infections in 2/25 (8%) cases. A total of 32 viruses were detected in 25 patients with the following distribution: enterovirus in 19/32 (59%), adenovirus in 5/32 (16%), cytomegalovirus in 5/32 (16%), parvovirus B19 in 2/32 (6%), and influenza A virus in 1/32 (3%). The most frequent virus was enterovirus (19 cases, 59%), alone (14/19), or associated with other viruses (5/19).Viral PCR negative cases positive for the housekeeping gene were assumed to be really viral negative cases, or the viral load was assumed to be below the sensitivity of the detection method, or the virus was unknown and was not investigated.None of the control samples showed positive amplification for any viruses investigated in the study patients.EMB FindingsHistology and immunohistochemistry showed active myocarditis in 4 cases and borderline myocarditis in 2 according to the Dallas Criteria. Histologic patterns of chronic myocarditis/dilated cardiomyopathy were found in 2 cases. Viral genomes were detected in 3 cases. PCR viral concordance with TA findings (as negative and positive viral detections) was found in all 8 cases processed by molecular analysis. In 2 cases, inadequate tissue sampling did not allow histologic and molecular analysis to be performed; both cases were TA viral positive (enterovirus and adenovirus) (Figs. 1A, B) (Table 2).JOURNAL/dimp/04.03/00019606-200803000-00004/table2-4/v/2021-02-17T195944Z/r/image-tiff Histology and Viral Findings in EMB and TAJOURNAL/dimp/04.03/00019606-200803000-00004/figure1-4/v/2021-02-17T195944Z/r/image-jpeg
A, Representative case of enteroviral infection in a 3-year-old female. a, Histology (hematoxylin and eosin stain): focal inflammatory infiltration with myocardial necrosis; original magnification ×50. b, Immunohistochemistry showed prevalent T lymphocytes (CD3 positive); original magnification×100. Inset. Gel electrophoresis: lane 1: marker VIII; lane 2: RT-PCR of 3GPDH in TA (234 bp); lane 3: RT-PCR of enterovirus in TA (113 bp); lane 4: RT-PCR of enterovirus in EMB case (113 bp); lane 5: RT-PCR of
TNFα in TA case (287 bp); lane 6: RT-PCR of enterovirus negative control (water without template). B, Representative case of viral negative myocarditis in a 4-year-old female. a, Histology (hematoxylin and eosin stain): diffuse inflammatory infiltration, without evident myocardial necrosis (borderline myocarditis); original magnification×50. b, Immunohistochemistry for T lymphocytes (CD3); original magnification×50.
TNFα FindingsTNFα mRNA was investigated in 37 TAs (22 viral positive and 15 viral negative cases) and was detected in 33.
TNFα gene expression was seen in all the positive viral TA cases (22/22, 100%) and in 11 nonviral cases (11/15, 75%).Semiquantitative RT-PCR analysis was assessed in all
TNFα-positive patients (0.97±0.74). The control samples showed negative or low expression of
TNFα (0.30±0.20).The serum
TNFα level was assessed in 22 patients: 8 negative viral (2.4±0.68 pg/mL) and 14 positive viral cases (10.64±11.93 pg/mL).Correlation Between Molecular Data and Clinical DataViral cases showed more impaired EF than nonviral cases (39.91±20.09 vs. 55.61±20.36, P=0.04).
TNFα mRNA levels for
TNFα were significantly higher in viral than in nonviral cases (1.26±0.76 vs. 0.56±0.76, P=0.001) (Fig. 2).
TNFα serum levels were also significantly higher in the viral group compared with the nonviral group (10.64±11.93 vs. 2.4±0.68, P=0.01). None of the negative viral cases exceeded a pathologic cutoff value of 8 pg/mL serum level.JOURNAL/dimp/04.03/00019606-200803000-00004/figure2-4/v/2021-02-17T195944Z/r/image-jpeg
Quantification of transcript level of
TNFα mRNA expression. Data shown are the mean levels of
TNFα, respectively, in viral-positive cases (1.26±0.76), nonviral cases (0.56±0.762), and control cases (0.30±0.20).No statistically significant correlation was found between molecular findings and other clinical parameters (Table 3).JOURNAL/dimp/04.03/00019606-200803000-00004/table3-4/v/2021-02-17T195944Z/r/image-tiff Correlation Between Viral Positive and Negative Patients and TA
TNFα InvestigationDISCUSSIONViral infections of the heart are an important cause of morbidity and mortality both in children and in adults. Idiopathic dilated cardiomyopathy appears as late sequela of acute and/or chronic myocarditis22 either due to persistence of virus23 or to an immune phenomenon occurring secondary to the inciting virus.24 The role of different viruses detected by PCR in the etiology of pediatric myocarditis and cardiomyopathy has been demonstrated in few papers.1–3The true incidence of
viral myocarditis in children is unknown because many children with
viral myocarditis are often asymptomatic until their disease reaches an advanced stage. Viruses represent important etiologic factors in pediatric myocarditis, as recently shown by Rasten-Almqvist et al's25 investigation on sudden infant death syndrome cases which indicated that the incidence of potentially lethal viral myocardial infection is twice as much as the previous estimation (43.5% vs. 16.8%).26 As there are various risks from EMB in young patients with myocarditis, particularly in children and infants with severe cardiac dysfunction, TA may be a useful substrate for viral PCR analysis in patients with respiratory disorders and clinical suspicion of myocarditis. In children, cardiac dysfunction caused by myocarditis may accompany respiratory disorders, which can appear a few weeks before or contemporary with heart failure.26–28 Our viral molecular analyses performed on TA have shown a high frequency (55%) of viral infection. The same high frequency was detected by Towbin's group in children with similar clinical features.13 PCR-viral concordant findings were found in all our cases in which EMB was adequate and also processed for molecular investigation. Unsuccessful results obtained in 2 cases were due to an inadequate number of myocardial samples (Table 2). Previous works have emphasized the importance of the number of cardiac biopsies not only for histologic diagnosis of myocarditis29 but also for molecular viral detection.30 The finding of PCR viral concordance in TA and EMB (as positive and negative viral detection) emphasizes the full value of TA investigation, although the number of cases (8 cases) is small. Further studies including large case series could be useful to confirm our data.As TA and blood
TNFα levels were significantly high in our viral cases with more impaired cardiac function, the detection of this cytokine could represent an important marker for better characterization of patient status (Table 3). Increased circulating
TNFα has been reported in patients with myocarditis and cardiomyopathy.8,10Jibiki et al31 demonstrated that, in fatal myocarditis, there is an overexpression of
TNFα in myocardium from patients with more impaired ventricular function, suggesting that levels of the cytokine may reflect the severity of cardiac dysfunction and inflammation.A high level of
TNFα has recently been detected by our group in EMBs from adult patients with myocarditis, and cytokine overexpression was significantly correlated with impaired cardiac function as well.10 The persistent myocardial overexpression of the cytokine, as demonstrated in the follow-up biopsy or in the explanted heart from patients who died or underwent heart transplantation, is additional data suggesting that
TNFα is implicated in the progression of the disease and the development of irreversible heart failure.10 The exact mechanism through which the cytokine contributes to decrease cardiac function in myocarditis is not well known.Some studies have suggested a negative role mediated by nitric oxide (NO): the decrease of papillary muscle contractility caused by
TNFα and interleukin-6 was blocked when an L-arginine analog was added as a specific inhibitor of NO synthase.32 In fact,
TNFα seems to cause an increase of inducible NO synthase activity in myocytes, and thus the cytokine could modulate inotropic responsiveness.33Plasma concentration of C reactive protein is a precise and objective index of inflammatory activity. Some authors have reported that C reactive protein may be considered an important indicator of clinical severity in patients with myocarditis being strictly related to decreased EF.34 In our work, we found an elevated C reactive protein concentration in all patients with myocarditis suspicion, without any significant difference between viral and nonviral cases.In summary our findings confirm that TAs are useful substrates for PCR analysis in pediatric patients with clinical suspicion of myocarditis. TA PCR may provide a safer means of arriving at an etiologic diagnosis in
viral myocarditis than EMB, especially when the right ventricular is free and all outflow tracts are pathologically thinned.The detection of
TNFα in TA and in blood samples may represent an important marker to better define patient status. Further studies including large case series could be useful to confirm the full value of TA. Molecular investigations in EMB as in TA represent ancillary diagnostic tools which should always be combined with clinical data or a more correct final clinico-pathologic diagnosis of myocarditis.REFERENCES1. Martin AB, Webber S, Fricker FJ, et al. Acute myocarditis. Rapid diagnosis by PCR in children. Circulation. 1994;90:330–339.[Context Link][Full Text][CrossRef][Medline Link]2. Calabrese F, Rigo E, Milanesi O, et al. Molecular diagnosis of myocarditis and dilated cardiomyopathy in children: clinicopathologic features and prognostic implications. Diagn Mol Pathol. 2002;11:212–221.[Context Link][Full Text][CrossRef][Medline Link]3. Calabrese F, Thiene G. Myocarditis and inflammatory cardiomyopathy: microbiological and molecular biological aspects. Cardiovasc Res. 2003;60:11–25.[Context Link][CrossRef][Medline Link]4. Bowles NE, Ni J, Kearney DL, et al. Detection of viruses in myocardial tissues by polymerase chain reaction. Evidence of adenovirus as a common cause of myocarditis in children and adults. J Am Coll Cardiol. 2003;42:466–472.[Context Link][CrossRef][Medline Link]5. Schowengerdt KO, Ni J, Denfield SW, et al. Association of parvovirus B19 genome in children with myocarditis and cardiac allograft rejection: diagnosis using the polymerase chain reaction. Circulation. 1997;96:3549–3554.[Context Link][Full Text][CrossRef][Medline Link]6. Liu PP, Mason JW. Advances in the understanding of myocarditis. Circulation. 2001;104:1076–1082.[Context Link][Full Text][CrossRef][Medline Link]7. Matsumori A. Cytokines in myocarditis and cardiomyopathies. Curr Opin Cardiol. 1996;11:302–309.[Context Link][Full Text][CrossRef][Medline Link]8. Matsumori A, Yamada T, Suzuki H, et al. Increased circulating cytokines in patients with myocarditis and cardiomyopathy. Br Heart J. 1994;72:561–566.[Context Link][Medline Link]9. Habib FM, Springall DR, Davies GJ, et al. Tumour necrosis factor and inducible nitric oxide synthase in dilated cardiomyopathy. Lancet. 1996;347:1151–1155.[Context Link][Full Text][CrossRef][Medline Link]10. Calabrese F, Carturan E, Chimenti C, et al. Overexpression of tumor necrosis factor (TNF) alpha and TNF alpha receptor I in human
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A, Representative case of enteroviral infection in a 3-year-old female. a, Histology (hematoxylin and eosin stain): focal inflammatory infiltration with myocardial necrosis; original magnification ×50. b, Immunohistochemistry showed prevalent T lymphocytes (CD3 positive); original magnification×100. Inset. Gel electrophoresis: lane 1: marker VIII; lane 2: RT-PCR of 3GPDH in TA (234 bp); lane 3: RT-PCR of enterovirus in TA (113 bp); lane 4: RT-PCR of enterovirus in EMB case (113 bp); lane 5: RT-PCR of
TNFα in TA case (287 bp); lane 6: RT-PCR of enterovirus negative control (water without template). B, Representative case of viral negative myocarditis in a 4-year-old female. a, Histology (hematoxylin and eosin stain): diffuse inflammatory infiltration, without evident myocardial necrosis (borderline myocarditis); original magnification×50. b, Immunohistochemistry for T lymphocytes (CD3); original magnification×50.
Quantification of transcript level of
TNFα mRNA expression. Data shown are the mean levels of
TNFα, respectively, in viral-positive cases (1.26±0.76), nonviral cases (0.56±0.762), and control cases (0.30±0.20). Correlation Between Viral Positive and Negative Patients and TA
TNFα InvestigationViral Detection and Tumor Necrosis Factor Alpha Profile in Tracheal Aspirates From Children With Suspicion of MyocarditisCarturan Elisa BSc PhD; Milanesi, Ornella MD; Kato, Yasuchica MD; Giacometti, Cinzia MD; Biffanti, Roberta MD; Thiene, Gaetano MD, FRCP; Calabrese, Fiorella MDOriginal ArticlesOriginal Articles117p 21-27
