On 11 June 2009, the WHO declared a global pandemic of influenza A (H1N1).² The USA continues to report the largest number of H1N1 cases of any country worldwide.⁵ The H1N1 virus subtype differs in its pathogenicity from seasonal influenza, in that it is most virulent in children and young adults, likely due to minimal or no pre-existing immunity to the virus, and in its propensity to infect the lower respiratory tract causing rapidly progressive pneumonia and adult respiratory distress syndrome.⁶

Influenza infection has been estimated to cause up to 36 000 deaths annually in the US.⁷ Mortality is most often related to the development of pneumonia, toxic shock syndrome or cardiac complications.¹ The frequency of myocardial involvement in influenza infection is variable, with incidences as high as 10% reported in the literature.^8–11

Over the subsequent 2 days the patient remained hypotensive despite the use of the IABP and the administration of dobutamine, vasopressin, norepinephrine and milrinone infusions. A percutaneous left ventricular assist device (LVAD) (Impella 2.5; Abiomed-Impella CardioSystems GmbH, Aachen, Germany) was placed for additional support. The patient's status continued to deteriorate despite this aggressive management, prompting the transfer to our tertiary referral centre for further care including possible emergency heart transplantation.

Upon arrival the patient was determined to have multisystem failure with oligoanuric acute renal failure, acute liver failure and respiratory failure. There was evidence of cardiogenic shock: with the Impella LVAD providing 2.4 litres/min of circulatory assistance and with the vasopressor treatment described above, the cardiac index was only 2.1 litres/min/m². An echocardiogram showed global hypokinesis of the left ventricle, inferior wall akinesis, dilated left atrium, dilated inferior vena cava, moderate mitral regurgitation, mild tricuspid regurgitation, mild aortic regurgitation, a small pericardial effusion and a right ventricular systolic pressure of 35–39 mm Hg.

Upon arrival at our centre the dose of oseltamivir was increased to 150 mg orally every 12 h. Due to lack of clinical improvement the Centers for Disease Control and Prevention (CDC) were contacted for compassionate release of peramivir, a novel intravenous neuraminidase inhibitor. Within 24 h of admission oseltamivir was discontinued and the patient was given peramivir 600 mg intravenously every 24 h for a total of 10 days.

Prior to initiating peramivir treatment, the patient's blood and urine were cultured and found to be negative for bacterial growth. HIV by ELISA and HIV PCR viral loads, were obtained to rule out acute retroviral syndrome. Serology testing for legionella, mycoplasma, chlamydia, coxackie virus A and B, respiratory syncytial virus, and influenza A, subtype H1N1 reverse transcriptase (RT)-PCR were obtained. All results were negative including viral respiratory cultures.

Considering the patient's rapid clinical deterioration, a decision was made to empirically administer intravenous immunoglobulin (Flebogamma 5%) 10g intravenous over 8 h in attempts to boost the innate immunity and control the infection as part of the management of acute viral myocarditis.

The negative RT-PCR for influenza H1N1 is likely due to the antiviral treatment prior to admission, which could have controlled or decreased the level of circulating virus. Moreover, the patient's PCR test was performed 9 days after her initial presentation, when viral shedding tends to be low, and a false negative result may occur if inadequate numbers of organisms are present or if the specimen is improperly collected, transported or handled.¹²

The myocardial damage seen in our patient is presumably the result of a combination of the direct effects of the virus at the tissue level and the patient's immune response with massive cytokine release to control the infection. This might also explain her severe presentation despite the lack of evidence of respiratory viraemia by RT-PCR.

The use of intravenous immunoglobulin for influenza A H1N1 is controversial; however immunoglobulin has been used for years in severe cases of influenza. During the influenza pandemic of 1918, severely ill patients received whole blood, plasma or serum from convalescent survivors.¹³ Luke et al,¹⁴ in a meta-analysis of eight studies published from 1918 to 1925 concluded that patients with Spanish influenza (H5N1) pneumonia who received convalescent human blood products experienced significant reduction of the mortality risk. To date, the WHO does not recommend immunoglobulin unless in the context of prospective clinical and virological data collection, but given the severity of the patient's clinical status we felt the potential benefit outweighed the risks associated with this treatment.

Peramivir is a novel neuraminidase inhibitor that may be effective in treating influenza H1N1. The drug's efficacy is still being evaluated in clinical trials for efficacy as an intravenous agent for treating influenza. On 23 October 2009, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for peramivir allowing hospitals to use this drug under special circumstances. Data regarding its use in seriously ill patients with H1N1 influenza are very limited, and the probability of its effectiveness is based on the drug's demonstrated activity as a neuraminidase inhibitor and the treatment benefit in patients with acute, uncomplicated influenza.¹⁵ The use of peramivir in this patient was decided after careful multidisciplinary discussion. Although we could not detect levels of H1N1 virus in nasopharyngeal wash, the patient never had a myocardial biopsy performed and we could not determine if the myocarditis was a result of direct viral effects in the myocardium or a consequence of the massive cytokine release and severe inflammatory response. Considering that the patient had clinically failed prior antiviral treatment with oseltamivir and was mechanically ventilated the only alternative antiviral treatment at that point was intravenous peramivir.

Few cases of influenza-associated myocarditis have been reported in the literature,^16–21 and to the best of our knowledge, none associated with the 2009 pandemic H1N1 strain. In one series, five patients with influenza myocarditis had cardiac involvement occurring between 4 and 9 days after the onset of influenza symptoms, with worsening dyspnoea being the most common presenting symptom.²² Patients either recovered with complete restoration of myocardial function or died within 2 weeks of developing symptoms.²³

Cardiogenic shock has been described in cases of influenza induced myocarditis and left ventricular support measures including inotropic support, IABP and ventricular assist devices have been described.^{17 21–24}The use of ECMO during the 2009 H1N1 pandemic has been described in a recent series for patients with respiratory failure yet no cases have reported its use in primary cardiogenic shock.²⁵

This case illustrates the utility of percutaneous LVADs as a temporising measure when ECMO is not readily available. When the initial LVAD failed, we decided to institute ECMO as it provided reasonable short-term support given her haemodynamic instability, permitted recovery of multiorgan injury and would allow time to complete a transplant evaluation before long-term circulatory support with an implantable LVAD was considered.

This is the first reported case of successful treatment of H1N1 influenza-related fulminant myocarditis with a multidisciplinary state of the art approach using all resources available of an intensive care unit including LVAD, ECMO, intravenous immunoglobulin and peramivir. The successful clinical course in this patient is most likely the result of multiple interventions rather than any of them by themselves. Randomised, controlled trials are needed to determine if alternative therapies improve outcomes in severe cases of influenza infection.