The Impact of H1N1 Influenza on Cardiovascular Health: A Comprehensive Analysis

Introduction

Influenza A H1N1 strain emerged in April 2009 from a discrete combination of gene segments from North American and Eurasian swine lineages[1]. By May 2009, around 8800 confirmed cases of H1N1 influenza, causing the death of 74 persons, reported from 40 countries [1]. Fever, cough, and shortness of breath are the most commonly reported symptoms at presentation. Respiratory complications include pneumonia, ARDS, and respiratory failure. Pneumonia is the most common complication of H1N1 influenza infection [3].

ICU admission for hospitalized cases ranges between 22-47% with 34-68% requiring mechanical ventilator support [3,4]. Cardiac complications of H1N1 influenza are comparable to other influenza strains. The median age of hospitalized infected cases has been reported to be lower than that expected with seasonal influenza [5]. This study is designed to provide a systematic review and appraise literature focusing on the cardiovascular complications of influenza H1N1 infection.

Method

After a detailed discussion of the aim of the study and the research question, the authors outlined the search strategy. Electronic databases (MEDLINE, EMBASE, Google Scholar, Pub Med) searched using relevant MeSH (Medical Subject Headings) terms for literature published between April 2009 and April 2019. We also manually searched the references of the included studies to confirm the inclusion of all related articles. Using predefined criteria, two reviewers independently reviewed the titles and abstracts of the citations resulting from the search. Full text of the articles thought to be eligible by at least one of the reviewers, obtained. Each reviewer independently reviewed these full texts to judge eligibility to be included in our review. Any disparities within the two reviewers about including studies were discussed and resolved by a third reviewer. A critical review of selected studies commenced with the aid of CASP (Critical Appraisal Skills Programme) appraisal tools [6].

Result

Our search yielded results. papers were selected for full text analysis, of these some were selected for inclusion in the review. We have discussed selected studies using appropriate subheadings.

Acute Myocardial infarction and H1N1

Influenza, as a trigger for cardiovascular diseases, is stated in the literature. The exact mechanism is not clearly understood. However, proposed precipitating factors include acute inflammation, biomechanical stress, and vasoconstriction are [7]. Influenza creates a thrombogenic environment through platelet activation and endothelial dysfunction. Also, infections increase metabolic requirement and may induce hypoxemia, hypotension, or other stress on the vascular system that can lead to the development of an occlusive thrombus and subsequently an acute coronary syndrome [8]. Worldwide there were 74 deaths associated with the first 12 months of H1N12009 pandemic in adults aged >17 years. However, the contribution of myocardial infarction to this figure is unknown [9].

Records from 3927 patients from 2003–2009 showed an incidence ratio for AMI of 4.19 (95% CI 3.18 to 5.53) in the first 1–3 days after an acute respiratory infection, with the risk falling to baseline after 28 days. H1N1 could potentially trigger AMI in vulnerable groups. Although most deaths from H1N1pdm09 occurred in younger people, the death rate in the elderly was much higher than in younger age-groups [10]. Iwanaga N et al. reported a case of AMI in a 52-year-old male hospitalized with H1N1 influenza respiratory illness [11]. Łewicki L et al. reported a case of AMI causing death in pregnant female due to H1N1 influenza during hospitalization [12].

Myocarditis

Myocarditis was a major cause of clinical deterioration in patients affected by H1N1pdm2009 [13]. The influenza myocarditis depends on host immunity, as indicated by anti-H1N1pdm2009 titers [13]. The influenza virus has a low affinity for cardiac myocytes. Increased production of pro-inflammatory cytokines plays a role in the pathogenesis of acute myocarditis associated with the influenza virus. Besides the direct effect of influenza virus infection, pro-inflammatory cytokines contribute to the pathogenesis of severe clinical features, including severe cardiac dysfunction, in influenza patients[13,14] Clinical presentation range from subclinical myocarditis to sudden death, with new-onset arrhythmias, or acute myocardial infarction-like syndromes.

Subclinical myocarditis

ECG, echocardiography and cardiac enzyme determine the frequency of subclinical myocarditis in serologically confirmed influenza cases.

ECG Changes

Case reports and case series described influenza-associated acute myocarditis with the pandemic 2009-H1N1 influenza A virus infection. However, the true prevalence remains unknown[15-17]. Mild reversible cardiac dysfunction was a relatively common complication associated with hospitalized pandemic-2009-H1N1 influenza[15]. Myocarditis mimic symptoms of acute myocardial infarction (MI) an may induce focal myocardial injuries such as ST-segment elevation on ECG. In about 30% of cases of suspected viral myocarditis, abnormalities may be seen only on echocardiogram and ECG [18].

ECG changes include ST-segment changes, T-wave inversion, flattening of the T wave, sinus bradycardia, sinus tachycardia, nodal rhythm, and atrial fibrillation. These findings are consistent with the perception that influenza virus infection causes mild myocarditis shown by serial ECG changes during acute infection [19]. Ukimura A et al. described ECG abnormalities including ventricular fibrillation in 3 patients, complete AV block in 4 patients, ST elevation in 4 patients, giant negative T-waves in 1 patient, and atrial fibrillation in 1 patient, in patients affected by influenza H1NI infection. Among them, two patients emergently admitted because of cardiopulmonary arrest due to ventricular fibrillation or complete AV block [20].

Cardiac enzyme

Cardiac biomarkers such as troponin I elevated in about 35% of patients with suspected myocarditis, and in 31% to 85% of critically ill patients with sepsis [21]. The Japanese Circulation Society Clinical Research Committee on Myocarditis Associated with Influenza Pandemic A (H1N1) 2009 reported that cardiac enzymes were elevated in 14 patients with peak serum creatine kinase concentration of 800 to 25,244 (IU/L). Quantitative troponin testing measured in 4 patients and found elevated in all patients. Qualitative quick troponin testing measured in 3 patients and found positive in 1 patient [20]. Chacko B et al. reported mean CK-MB level (n = 34) done 1.9 ± 1.5 days after hospital admission was 106 ± 137 U/L (reference range b24 U/L). The baseline CK-MB fraction was 20% ± 26% of the total CK (N6% indicating myocardial injury). All 37 patients had troponin I estimation; the baseline value at 1.9 ± 1.5 days after hospital admission was 3.1 ± 7.7 (95% CI 1.4-2.4) ng/mL. The repeat troponin I assay (n = 22) was 10.8 ± 22.6 ng/mL (95% CI 0.8-20.8). Myocardial injury (troponin I level N1.5 ng/mL) was evident in 17 patients (46%)[22].

Echocardiographic features

Ukimura A et al. described echocardiographic abnormalities of left ventricular wall motion in 14 patients and pericardial effusion in 2 patients [20]. Erden I reported echocardiographic manifestations of pandemic 2009 (H1N1) influenza virus infection in twenty-eight young patients hospitalized for at least 24 h due to an influenza-like illness and tested positive for pH1N1 by a real-time polymerase chain reaction. The echocardiographic variables appeared similar except left ventricular end-systolic dimension, which significantly increased in the patient group (P = 0.042) [21]. Mean systolic velocities of pH1N1 infected patients and control group were statistically similar [21]. Early diastolic velocity decreased, and late diastolic velocity increased in the patient group [21]. Isovolumetric contraction time and isovolumetric relaxation time prolonged and ejection time shortened in pH1N1 infected patients.

Therefore, global myocardial performance index appeared significantly higher in pH1N1 infected patients (p < 0.001)[21]. Chacko B et al. reported transthoracic echocardiogram performed in 28 patients infected with pH1N1 infection. 20 (71%) patients had reduced EF. The initial echocardiogram showed a low EF in 16 patients. Five patients with a normal initial echocardiogram had a repeat evaluation; 4 had a low EF. The mean baseline EF in 24 patients in whom it was measured was 46% ± 16% (95% CI 39 to 53). The SVI reduced in 16 of 17 patients with two patients had a normal EF. The cardiac index, measured in 17 patients,found normal in 8 and reduced in 9 patients. 19 (51.4%) patients had Global dysfunction on echocardiogram. Global myocardial dysfunction due to presumed myocarditis was evident in 14 patients (37.8%). In 12 patients, myocarditis occurred early in the course of ICU, at 2.3 ± 1.2 days of admission [22].

Myocarditis causing clinical cardiac dysfunction and fulminant myocarditis

Davidović G et al. reported a case of a 19-year-old male admitted with a diagnosis of suspected acute pericarditis and acute coronary syndrome. The diagnostics workup revealed fulminant myocarditis. During the course of hospitalization, the patient's condition deteriorated, and the patient died. Clinical course, postmortem pathohistological findings, and virus serology indicated that an H1N1 viral caused fulminant myocarditis [23]. Al-Amoodi M et al. reported 2 cases of fulminant myocarditis as a complication of H1N1 influenza infection. Early recognition and initiation of aggressive cardiac support are essential[24]. Khouzam RN et al. described a 36-year-old manifesting heart failure secondary to fulminant myocarditis. Despite aggressive management, the patient died of cardiac arrest.

Postmortem H1N1 polymerase chain reaction assay produced positive results confirming the diagnosis of fulminant viral myocarditis [25]. Liao YC et al. presented a case of an adult male who contracted H1N1 infection followed by fulminant myocarditis. Extra-corporeal membrane oxygenation support in conjunction with an Oseltamivir led to complete recovery from cardiogenic shock [26]. Cobas M et al. reported a middle-aged patient diagnosed with influenza A H1N1 presented with a severe refractory cardiogenic shock. Successful treatment involved the use of a left ventricular assist device, extracorporeal membrane oxygenation, and peramivir [27]. Mohite PN et al. reported a case of fulminant myocarditis associated with H1NI virus treated successfully using extra-corporal membrane oxygenation [28]. Davoudi AR et al. reported a case of fulminant myopericarditis presenting with acute heart failure and cardiogenic shock in a previously healthy young woman.

The H1N1 influenza A virus sequences were identified in the throat and pericardial fluid, suggesting a viral source of the infection [29]. Adedayo O et al. presented a case of severe acute heart failure and arrhythmia due to fulminant myocarditis secondary to H1N1 in a 50- year old obese man with diabetes mellitus [30]. Barbandi M et al. presented a case series of adult patients with acute reversible cardiomyopathy associated with influenza A (H1N1) infection [31]. Komai T et al. presented a case of a 51-year-old male with worsening fatigue. Transthoracic echocardiography (TTE) revealed left ventricular dysfunction with an ejection fraction of 30% and marked thickening of the left ventricular wall. A TTE performed four months earlier to the admission was normal. Despite aggressive pharmacological and mechanical circulatory support; the patient underwent cardiac arrest and died. Reverse transcriptase–polymerase chain reaction using autopsy specimen showed influenza A (H1N1) M2 gene unique to novel influenza positive in the left ventricle, the right ventricle, and the left lung [32]. Early supportive measures including inotropic support, intra-aortic balloon pump, and extracorporeal membrane oxygenation, played an important role in patient management. Full recovery is possible in patients who survive the acute illness [24].

Cardiac Arrythemia

The clinical manifestations of myocarditis caused by influenza pandemic A (H1N1) varied. Ukimura A et al. reported 10 patients diagnosed with fulminant myocarditis developed fatal arrhythmias. The cardiopulmonary arrest was the first cardiac symptom in 2 patients. Syncope due to complete AV block was the first cardiac symptom in 1 patient requiring temporary pacemaker implantation[20]. Beinart R et al.reported a case of an 18‐year‐old female presented with respiratory failure secondary to H1N1 infection. She subsequently developed a high‐degree atrioventricular (AV) block which persisted over 2 weeks following complete resolution of respiratory symptoms [33].

Pericarditis

The most common cause of pericarditis is a viral infection. Myocarditis and pericarditis broadly share the same similar pathophysiology. “Myopericarditis” describes a primarily “pericarditis” syndrome with underlying myocarditis. Pericarditis or myopericarditis in the setting of influenza infection is often mild and uncomplicated. Though, isolated case reports of influenza pericarditis causing serious complications do exist. The clinical and laboratory characteristics of patients with confirmed H1N1 virus infection pericarditis to total cases with Influenza-Like Illness (ILI) are similar [34]. Sidhu RS et al. reported patient preceding symptoms of an influenza-like illness for seven days and presented with cardiogenic shock secondary to tamponade [35 ]. Knežević Praveček M et al. reported a 50-year-old female with a pericardial effusion due to H1N1, without tamponade, of which the patient responded to medical management with high dose ibuprofen and Oseltamivir [36].

Conclusion

World Health Organization declared H1N1 influenza a global pandemic in June 2009. Cardiovascular involvement in acute influenza infection can occur through direct effects of the virus on the myocardium or through exacerbation of the existing cardiovascular disease. Direct myocardial involvement presenting as myocarditis is not uncommon during H1N1 influenza infection. Many of these patients may have ECG changes, changes in cardiac enzymes, or echocardiographic abnormalities. The clinical presentation may vary from asymptomatic to fulminant myocarditis and cardiac arrhythmias.