Cardiac Findings during Uncomplicated Acute Influenza in Ambulatory Adults

MAJOR ARTICLE Cardiac Findings during Uncomplicated Acute Influenza in Ambulatory Adults Michael G. Ison, 1 Vicky Campbell, 2 Chris Rembold, 3 John Dent, 3 and Frederick G. Hayden 1 1 Division of Infectious Diseases and International Health, 2 Breast Care Center, and 3 Division of Cardiology, University of Virginia, Charlottesville Background. Previous studies have reported abnormal cardiac findings in up to 43% of ambulatory adults with influenza. This study was conducted to determine the frequency, magnitude, and duration of myocardial dysfunction in such persons. Methods. We enrolled 30 previously healthy young adults without known cardiovascular disease who presented to the clinic 72 h after onset of influenza symptoms and had a positive influenza antigen test. Most patients received antiviral therapy, and all underwent serial electrocardiography and had blood specimens collected on days 1, 4, 11, and 28 after presentation for measurement of total creatine kinase (CK) level, CK isoenzyme MB (CK- MB) level, troponin I level, and selected cytokine levels. Echocardiography was performed on days 4, 11, and 28. Results. None of the patients had an elevated CK-MB index or troponin I level. Abnormal electrocardiogram findings were noted in 53%, 33%, 27%, and 23% of patients on days 1, 4, 11, and 28, respectively, but none of the findings were considered to be clinically significant. No patient had significant changes in the ejection fraction or abnormal wall motions. Conclusions. Most ambulatory young adults with acute influenza have clinically insignificant abnormal electrocardiogram findings early during the illness. These abnormalities resolve promptly and are not associated with changes in cardiac markers or echocardiogram findings. Influenza virus causes annual epidemics of a respiratory illness characterized by sudden onset of fever, malaise, myalgias, headache, cough, and other respiratory complaints [1]. Although most cases of influenza are uncomplicated, influenza is responsible for 294,000 excess hospitalizations and 36,000 excess deaths each year in the United States [2, 3]. In addition to exacerbation of underlying pulmonary disease and bacterial superinfections, influenza causes exacerbation of congestive heart failure and increased cardiac ischemia, which may contribute to an additional 90,000 deaths per year [4, 5]. Adverse cardiovascular events occur through a number of mechanisms, including fever, vasodilatation, hypovolemia, hypoxia, proinflammatory cytokine elaboration, and procoagulant effects [5]. In addition, influenza has also been recognized to cause direct car- Received 21 June 2004; accepted 29 September 2004; electronically published 10 January 2005. Reprints or correspondence: Dr. Frederick G. Hayden, University of Virginia Health System, PO Box 800473, Private Clinics Bldg., Room 6577b, Charlottesville, VA 22908 (fgh@virginia.edu). Clinical Infectious Diseases 2005; 40:415 22 2005 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2005/4003-0012$15.00 diac changes, including myocarditis and pericarditis. Several older studies have documented cardiac changes associated with acute influenza virus infection in 15% 43% of ambulatory patients and in 14% 75% of hospitalized patients [6 8]. Influenza virus infection has been associated with 1% 18% of myocarditis cases [9 21]. During a recent study of experimentally induced influenza, one subject developed myocardial dysfunction and presumed myocarditis that temporally followed influenza (unpublished data). Consequently, the current study was undertaken to prospectively examine the frequency of cardiac abnormalities in otherwise healthy adults with acute, naturally occurring influenza. CASE REPORT In July 2000, a total of 75 healthy adult volunteers at the University of Virginia (Charlottesville) were experimentally infected with influenza B/Yamagata/88 to assess the prophylactic efficacy of the oral neuraminidase inhibitor peramivir (BCX-1812; also known as RWJ 270201) [22, 23]. The case patient, a 21-year-old man with no previous history of cardiac abnormalities, received the study drug and experienced an adverse Cardiac Findings in Adults with Influenza CID 2005:40 (1 February) 415

cardiac event that was reported to the US Food and Drug Administration. He had a history of monocular blindness secondary to retinoblastoma that had been successfully treated with systemic chemotherapy, including an anthracycline agent, at 2 years of age. The patient was not taking any medications before enrollment into the study. He was a social drinker, consuming up to 12 beers per week, but he did not use tobacco and was physically active. He had no family history of cardiac disease. The prestudy evaluation revealed normal physical examination findings and laboratory studies, with the exceptions of an electrocardiogram (ECG) that revealed T wave flattening in the avf and T wave inversion in lead III and an elevated total creatinine kinase (CK) level of 505 IU/mL. The latter was attributed to his exercise regimen; a second test performed before viral inoculation revealed a CK level of 202 IU/mL. The subject became infected and shed low titers of influenza B virus on study days 3 9; he had no fever and reported only mild nasal symptoms, sore throat, and loss of appetite. On day 4 of the study, an ECG revealed new T wave inversions in leads II, avf, and v4 6 (figure 1). The patient denied having any cardiac symptoms. The CK level in a blood sample obtained 2 days later was 126 IU/mL. Findings of an ECG performed 15 days after infection had returned to those observed at baseline. At the completion of the study, the patient took a 2-week vacation to Indonesia, during which time he experienced upper respiratory infection symptoms (but no cardiac symptoms) for several days and received intranasal steroid therapy. Because of the ECG changes, the patient was asked to return and undergo echocardiography, which revealed left ventricular enlargement with severely reduced systolic function globally and minimal mitral and tricuspid regurgitation 51 days after infection. During a cardiologic evaluation, the patient was asymptomatic, and the examination revealed 6-cm jugular venous distention, normal heart sounds without gallop or rub, and a faint mitral regurgitation murmur. His lungs were clear to auscultation, and he had no hepatomegaly or peripheral edema. Serological tests were negative for Trypanosoma cruzi, cytomegalovirus, the agent of Lyme disease, HIV, coxsackieviruses (A7, A9, A10, A16, and B1 6), rheumatoid factor, and antibody to nuclear antigens. Serological findings were consistent with past Epstein- Barr virus infection. His erythrocyte sedimentation rate was 1 mm/h. Nasal wash samples collected during the study and tested by RT-PCR for enterovirus at the Centers for Disease Control and Prevention (Atlanta, GA) were negative. He was treated with lisinopril (5 mg po q.d.) and was allowed to gradually increase his exercise levels. Successive echocardiograms at 1 month and 5 months later showed progressive improvement in left ventricle function; the final study showed that the ejection fraction level had returned to low normal. The patient was clinically well at 1 year but has since been lost to follow-up. PATIENTS AND METHODS We conducted a prospective, observational cohort study at the University of Virginia during the 2000 2001 and 2001 2002 influenza seasons. Study population. Participants were previously healthy adults aged 18 40 years who presented with a 72-h history of acute influenza symptoms and had nasal wash or nasal swab specimens that tested positive for influenza antigen by means of the QuickVue Influenza test kit (Quidel). Patients with known cardiopulmonary disorders were excluded, as were those with hypertension, chronic medical conditions requiring regular medication or indication for influenza vaccine, or hospitalization for medical illness, injury, or surgery within the past year. Patients who had received an investigational drug or vaccine within the previous 2 months were also excluded. The decision to use antiviral drugs in these patients was at the discretion of the physician caring for the patient. Written informed consent was obtained from each participant in a form approved by the University of Virginia Human Investigation Committee. Individuals were compensated for their participation in this study. Monitoring and sample collection. After confirmation of antigen positivity, medical history was obtained, symptom assessment was performed, vital signs were measured, and limited physical examination was performed to assess for enrollment suitability and to look for complications. At the time of enrollment, an ECG was performed and blood and nasal wash specimens were collected for cytokine assessment and measurement of serum markers of adverse cardiac conditions (i.e., abnormal total CK level, CK isoenzyme MB [CK-MB] level, and troponin I level); nasal wash specimens were also obtained for virus culture and titration. Volunteers were given a diary and were asked to grade 11 symptoms on a 4-point scale (0, no symptoms; 1, mild; 2, moderate; and 3, severe) and record oral temperatures twice daily for 14 days. Symptoms that were assessed included those typically associated with influenza (fever, chills, myalgia, malaise, headache, cough, sore throat, nasal congestion, rhinorrhea, and sputum production), possible cardiopulmonary disease (chest pain, dyspnea, wheezing, and palpitations), and exercise tolerance. Blood specimens were collected during follow-up visits 3 4 days (range, 2 6 days), 10 days (range, 7 14 days), and 28 days (range, 28 42 days) after enrollment for determination of selected cytokine levels and markers of adverse cardiac conditions. In addition, echocardiography and ECG were performed during these 3 visits. ECGs were read initially by a single cardiologist who was masked with respect to the status of the patient s illness. A second cardiologist reviewed the serial ECGs to determine the clinical significance of the findings. Echocardiography was performed by an experienced echocardiography technologist, and 416 CID 2005:40 (1 February) Ison et al.

Figure 1. Serial electrocardiograms (ECGs) for the case patient. A, Baseline ECG. B, ECG obtained during influenza infection showing new T wave inversions and changes in V1. the echocardiograms were then interpreted by a single cardiologist who was masked with respect to the status of the patient s illness. Routine measurements, including assessment of global function and ejection fraction, were assessed for all echocardiograms [24]. Sample preparation. Nasopharyngeal wash specimens were collected as described elsewhere [25]. Lavage fluid was mixed thoroughly with a syringe, placed on wet ice, and freshly inoculated on Madin-Darby canine kidney cell monolayers. Samples and the resulting products that tested positive for influenza virus underwent serial 10-fold dilutions that were cultured to determine the concentration of virus, which was expressed as the log 10 median number of tissue culture infectious doses of virus (TCID 50 ) per milliliter. Blood was collected in Cardiac Findings in Adults with Influenza CID 2005:40 (1 February) 417

Figure 2. Trend of symptom scores over time. See Patients and Methods for definition. an EDTA tube and immediately centrifuged for 15 min at 800 g, and plasma was recovered and stored at 20 C for later analysis [25]. Determination of cytokine levels. Levels of cytokines (IL- 6, IL-8, IFN-a, and TNF-a) in nasal specimens were measured at the time of enrollment, and serum levels were measured at the time of enrollment and 3 4 and 10 days later. Cytokine levels were determined in the laboratory of Dr. Stephen Straus at the National Institutes of Health (Bethesda, MD) with commercially available ELISA kits, according to manufacturer protocols. The limits of sensitivity were!1 pg/ml for the IL-6 assay (Endogen), 18.1 pg/ml for the IL-8 assay (R&D Systems),!3 pg/ml for the IFN-a assay (Endogen), and!0.18 pg/ml for the TNF-a assay (R&D Systems). Review of ECGs from previous influenza studies. For all experimental human influenza studies done at the University of Virginia in which paired ECGs were obtained, the pre- and postinoculation ECGs were copied from the source documents and provided to a masked cardiologist, who determined abnormal findings and their possible clinical significance. Statistical analysis. Comparisons between cytokine levels measured after inoculation with those determined at baseline were performed using the Wilcoxon rank-sum test. Correlation between symptoms, fever, and cytokine levels was analyzed using Spearman s nonparametric correlation test. Statistical analysis was performed using S-Plus 2000, release 3 (Insightful). RESULTS Patients. A total of 30 young adult patients were enrolled in the study over 2 seasons, of whom 17 participated during the first season, and 13 participated during the second season. The mean age was 21.4 years, and 21 patients (70%) were women. Most patients were given antiviral therapy (20 received oseltamivir, 6 received amantadine, and 1 received rimantadine; 3 did not receive antivirals), and most used antipyretics. During the first year, 8 of 17 patients were infected with influenza B virus, whereas all 13 patients enrolled during the second year were infected with influenza A virus. Among influenza A viruses, subtypes H3N2 and H1N1 were predominant in the first season and second seasons, respectively. One patient who had negative culture results despite a compatible clinical syndrome and a positive influenza antigen test result was kept in the analysis. Serologic studies for detection of influenza virus were not performed. The mean nasal wash viral titer at enrollment was 4.42 log 10 TCID 50 per ml. Illness. Most patients presented within 48 h after symptom onset and reported relatively mild symptoms. The peak mean symptom score (15) was on the initial day of enrollment (figure 2), and most symptoms had improved by day 5 of the study, although 50% of patients had at least 1 symptom still present on day 14 of the study. All had their highest temperature during the first 2 days of the study; fever resolved by study day 3 in all subjects. Cardiac markers. Elevations in the total CK level were found in 2 patients at enrollment (1001 and 5430 IU/mL in patients 1 and 19, respectively), 2 on day 2 (274 and 4929 IU/ ml in patients 14 and 19, respectively), 2 on day 7 (485 and 310 IU/mL in patients 7 and 12, respectively), and 4 on day 28 (264, 2257, 288, and 260 IU/mL in patients 2, 9, 13, and 18, respectively). No patients had an elevated CK-MB index or troponin I level to suggest cardiac cellular damage at enrollment or on any of the subsequent study days (table 1). ECG findings. The majority of patients (53%) had abnormal ECG findings at enrollment, although most findings were classified as not clinically significant by the interpreting physician (tables 1 and 2). At the time of enrollment, 47% of patients had unremarkable ECG findings, whereas 23% had ECG findings that remained unchanged in all 4 time points (5 patients had large QRS complexes, and 1 patient had slight intraventricular conduction delay). Of those with transient abnormal ECG findings at enrollment, 3 patients had peaked T waves, 2 patients had tachycardia, 1 patient had a transient QT shortening, 1 had inferior changes in the ST segment, 1 had transient early repolarization, and 1 had diffuse T wave inversions. The 2 patients with tachycardia, one of the patients with peaked T waves, and the patient with the shortened QT interval had resolution of their ECG abnormalities by study day 2. One patient had enlarged QRS complexes on ECGs performed on the second and seventh study day. One patient had diffuse elevation in the ST segment throughout the study that was interpreted as being consistent with 418 CID 2005:40 (1 February) Ison et al.

Table 1. Results of laboratory tests and electrocardiography (ECG) for markers of adverse cardiac events in 30 patients with influenza, according to study day. Characteristic Study day 1 2 11 28 CK level, IU/mL Mean 312 265 a 102 b 192 c Range 37 5430 27 4929 33 485 39 2257 Abnormal 2 2 2 4 CK-MB Mean % of total CK level 0.75 0.70 1.30 0.95 Abnormal index 0 0 0 0 Detectable level 4 7 9 11 Abnormal troponin I level 0 0 0 0 ECG findings Normal 47 67 73 77 Normal or unchanged 70 80 93 97 Mean ejection fraction SD Not done 0.64 0.04 0.65 0.05 d 0.66 0.04 e NOTE. Data are % of patients, unless otherwise indicated. Upper limit of normal for creatine kinase (CK) level, 237 IU/mL; for CK isoenzyme MB (CK-MB) index, 5% of total CK level; and for troponin I,!0.05. a P p.85, compared with study day 1. b P p.25, compared with study day 1. c P p.51, compared with study day 1. d P p.53, compared with study day 1. e P p.11, compared with study day 1. pericarditis (figure 3). This patient was asymptomatic, had no abnormal findings on any of her echocardiograms, and had similar findings on an ECG obtained 2 months after enrollment. All other ECGs were normal or unchanged by study day 7. Echocardiography. All patients had normal echocardiograms throughout the study without a significant change in ejection fractions (mean ejection fraction [ SD], 65% 4% ) (table 1). Cytokine responses. Plasma TNF-a, IL-6, and IL-8 levels were detectable at enrollment and decreased over time, whereas there was a steady increase in INF-a levels during the study period. No correspondence between elevated CK levels or transient ECG changes and plasma cytokine levels were noted (data not shown). ECG data from previous University of Virginia studies. Subjects in 4 studies conducted from June 1998 through July 2000 had ECGs performed before and after infection (table 3). Two studies were early treatment trials, and 2 were prophylaxis trials with peramivir. All studies were placebo controlled; 2 used influenza A, and 2 used influenza B. The patient described in the case report participated in the final study. Overall, 16.6% of patients were noted to have new abnormal ECG findings after inoculation. The most frequent findings were sinus arrhythmia, high QRS voltage, and sinus bradycardia. All changes were considered to be not clinically significant by the reviewing cardiologist, and none of the changes were similar to those observed in the case patient (e.g., new T wave inversions). If the case patient is assumed to have developed myocarditis after infection, the estimated risk of such an event after experimental influenza would be 0.4% (1 of 236 patients; 95% CI, 0% 2.0%). DISCUSSION This is the first contemporary study to look for cardiac dysfunction during acute influenza using the multiple modalities of electrocardiography, echocardiography, and serial measurements of markers of adverse cardiac events. We found that previously healthy ambulatory young adults with acute uncomplicated influenza have frequent but clinically insignificant ab- Table 2. Frequency of abnormal electrocardiogram (ECG) findings for 30 patients with influenza. Study day Patients with abnormal ECG findings, % Type of abnormal ECG finding 1 53 T wave changes, tachycardia, early repolarization, short QT, and STsegment elevation 4 33 T wave changes, early repolarization, large QRS complexes, and ST-segment elevation 11 27 Large QRS complexes and ST-segment elevation 28 23 ST-segment elevation NOTE. All ECG findings were considered as not being clinically significant. All changes present at day 28 were present at all time points, suggesting these were normal variants for these patients. Cardiac Findings in Adults with Influenza CID 2005:40 (1 February) 419

Figure 3. Example electrocardiogram for the patient who had persistent ST-segment elevations normal ECG findings during the early stage of illness. These resolve promptly and are not associated with changes in markers of cardiac injury or echocardiogram findings. Older studies [6, 7] were limited by the use of nonspecific CK measurements, which may be reflective of skeletal involvement, and by the nonspecific nature of many of the ECG changes that could be the direct result of respiratory alkalosis or fever and not of influenza itself. A recent study found that most increases in CK levels seen during influenza in ambulatory adults are likely of skeletal muscle origin [8]. Our study confirms this finding, and together, these observations suggest that myocarditis is a very uncommon complication of natural influenza in previously healthy persons. Because of the small sample size of the current study of naturally occurring influenza, there is 95% confidence that the incidence of clinically significant cardiac involvement during influenza in ambulatory adults is!9.5%, using exact methods. If our cohort of experimentally infected subjects is considered, there is 95% confidence that the incidence of clinically significant cardiac involvement during influenza in ambulatory adults is!2.0% This value is consistent with the study by Greaves et al. [8], in which 0 of 152 adult patients in the study had evidence of myocarditis. This results in an estimated incidence (upper 95% confidence limit) of myocarditis complicating influenza of!1.9%. Similarly, a community-based casecontrol study of complications in 342 persons with naturally occurring influenza found no cases of clinically diagnosed myocarditis and an estimated risk (upper 95% confidence limit) of!1.1% [10]. The current study suggests that, although frequently present, ECG changes early during the early stages of influenza are both transient and clinically insignificant. The same cardiologist read all of the ECGs performed in the study of patients who had experimentally induced influenza at the University of Virginia. During these 6 years, only the case patient had changes significant enough to warrant additional work-up. Older studies found more frequent changes. A Finnish study of previously healthy military recruits found that 6 (15%) of 40 patients with influenza had abnormal ECG findings, and all had regional myocardial dysfunction confirmed by echocardiography. The CK-MB level, as measured by electrophoresis, was elevated in 3 of the patients [6]. Such findings are consistent with myocarditis and suggest a much higher risk than observed in this trial. In contrast, other recent studies [8, 9] have documented Table 3. Electrocardiogram changes (ECG) noted in 4 other studies conducted at the University of Virginia (Charlottesville) during 1998 2000. Study Influenza virus type Study type No. (%) of patients with abnormal ECG findings a 1 A Treatment 59 (19) 2 A Prophylaxis 71 (16) 3 B Treatment 30 (7) 4 B Prophylaxis 75 (20) NOTE. A total of 6 influenza studies were performed in which ECG data were collected; only 4 collected both pre- and postinfection ECGs. a The most common ECG findings were sinus arrhythmia and large QRS complex. ECGs were review by a cardiologist (blinded to the condition of the patients) who considered all findings as not being clinically significant. 420 CID 2005:40 (1 February) Ison et al.

infrequent myocarditis secondary to influenza, which is consistent with the findings in the present study. In addition to its small sample size, this study has several other limitations. Most patients had a mild disease course, and so complications would be expected to be less frequent. Additionally, most patients received antiviral therapy for their infection, which potentially explains the mild course. This antiviral therapy may have reduced the likelihood of cardiac complications. A recent analysis of individuals with a policy from a large insurance company during a single influenza season in the United States suggested a protective effect of oseltamivir treatment for influenza against adverse cardiac outcomes, such as unstable angina, myocardial infarction, arrhythmia, or congestive heart failure [26]. In this retrospective study, the outcomes for patients with influenza who were treated with oseltamivir at the first visit were compared with those for patients with influenza who had not received oseltamivir. The adjusted incidence rate ratio for major cardiac outcomes was 0.56 (95% CI, 0.34 0.93) for those without a history of major cardiac disease and 0.81 (95% CI, 0.42 1.41) for those with cardiac disease. An additional limitation is that we enrolled healthy patients who had not had cardiac disease before enrollment. It is likely that the incidence of cardiac abnormalities would be higher if patients with a history of cardiac disease were included. Of note, in a murine model of arteriosclerotic disease, influenza caused severe inflammatory changes in aortic lesions but not in arteriosclerosis-free aortas [27]. 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