key: cord-0006467-syuga1j1 authors: Rowe, Emily; Ng, Pei Yi; Chandra, Thiaghu; Chen, Mark; Leo, Yee-Sin title: Seasonal Human Influenza: Treatment Options date: 2014-06-25 journal: Curr Treat Options Infect Dis DOI: 10.1007/s40506-014-0019-z sha: 2a9331dd19572777a7f5188820c6c3811410e6a5 doc_id: 6467 cord_uid: syuga1j1 Seasonal influenza can be a self-limiting illness in healthy individuals but is associated with short-term morbidity and economic burden. Influenza can cause significant morbidity and mortality in young children, the elderly, pregnant and post-partum women, patients with co-morbidities and the immunocompromised. Neuraminidase inhibitors (NAIs) are the treatment of choice for influenza due to widespread resistance to the adamantanes. NAIs are efficacious for the treatment of influenza in ambulatory patients with mild illness, when initiated within 48 h of symptom onset. Early treatment with NAIs has been shown to reduce otitis media in children, and lower respiratory tract complications, resulting in antibiotic therapy, in adults. Evidence on the efficacy of NAIs for the prevention of influenza-related complications in at-risk populations, based on reviews of data from randomised trials is inconclusive. However, observational studies suggest that in hospitalised patients early treatment with NAIs has been associated with reduced mortality. NAIs should be initiated as soon as possible in patients at high-risk of influenza-related complications, with suspected or proven influenza, hospitalised patients and patients with severe or progressive disease. NAIs can be considered in previously healthy patients when therapy can be initiated within 48 h of symptom onset. In previously healthy patients, the therapeutic efficacy of oseltamivir is time-dependent, with maximal benefit observed when therapy is initiated within 48 h of symptom onset. However, several observational studies suggest therapeutic benefit beyond 48 h, in hospitalised patients, severe disease, and patients at high risk of complications, including pregnant women. NAIs should be considered in patients at high risk of influenza-related complications who present late. Further studies are needed to define the optimal timing of NAIs. Oseltamivir-resistant virus has been widely reported but is predominantly an issue in H1N1 seasonal influenza. Zanamivir-resistant influenza virus is rare, and inhaled or intravenous (IV) zanamivir is the treatment of choice in proven or suspected oseltamivir-resistant virus. Intubated patients with severe influenza can be treated with oseltamivir (suspension) administered via nasogastric tube. The commercial dry powder formulation of zanamivir should not be administered, via nebulisation, as it has been associated with ventilator malfunction and mortality. In intubated patients, when there are concerns about gastric absorption, IV zanamivir should be obtained under Emergency Investigational New Drug access schemes. Currently available evidence does not support the use of high-dose or extended-duration oseltamivir in patients with severe influenza, but does require further investigation. Extracorporeal membrane oxygenation has not been shown to be superior to conventional management in patients with influenza-associated acute respiratory distress syndrome and should be considered as salvage therapy. Corticosteriods should not be used in the treatment of severe influenza as this has been associated with increased risk of mortality and bacterial superinfection. Influenza is a contagious respiratory virus transmitted via droplets produced by coughing and sneezing. In the majority of individuals, seasonal influenza is a self-limiting disease but is associated with significant economic burden [1]. However, influenza can cause significant morbidity and mortality in high-risk groups, including the elderly, young children and people with co-morbidities [2•]. In temperate climates, seasonal influenza causes outbreaks during the winter, while in tropical areas there is year-round transmission. There are three major strains of seasonal influenza: A, B and C, but influenza A and B cause the majority of disease. Influenza A is classified into subtypes according to the combination of haemagglutinin or 'H' protein and the neuraminidase or 'N' protein on the surface of the virus [3] . New viruses are created through antigenic shift or drift. A pandemic occurs when a new virus emerges and circulates in a population where there is minimal immunity; this can occur outside the normal influenza season [3] . Symptoms in otherwise healthy adults include fever, cough, headache, runny nose, myalgia and malaise. Cough within 48 h of fever onset is highly predictive of influenza during peak times of virus circulation [4] . Influenza can be confirmed by culture of respiratory secretions but this is resource-intensive and turnaround time is slower than polymerase chain reaction (PCR). Culture has been superseded by reverse-transcriptase PCR, which is highly sensitive and provides rapid results [2•]. Rapid influenza diagnostic tests that provide results within 30 min are available but sensitivity is only reported to be 40- 70 % [5] . Influenza vaccine is the first choice for the prevention of influenza and has been shown to be effective in preventing disease in healthy adults and older children [6•]. Influenza vaccine has been associated with a reduction in cardiac events in patients with a history of cardiac disease [7] but efficacy is reduced in the elderly [1, 6•]. Live attenuated influenza vaccine is efficacious in young children aged between 6 months and 7 years [1]. Antivirals are highly effective for prophylaxis in exposed individuals but use needs to be weighed against cost, side effects and emergence of viral resistance [8] . The two main classes of antivirals for the treatment of influenza are the adamantanes (M2 ion channel inhibitors) and the neuraminidase inhibitors (NAIs). The NAIs are the first choice for the treatment of seasonal influenza [2•] as the clinical utility of the adamantanes is limited by widespread antiviral resistance [9] . A summary of the currently available influenza antivirals is provided in Table 1 . NAIs are efficacious for the treatment of influenza in ambulatory patients with mild illness, when initiated within 48 h of symptom onset [10] [11] [12] . This review will focus on the treatment of seasonal influenza. Emerging avian influenza is beyond the scope of this paper. [20] . They analysed data from 25 of 67 randomised controlled trials reviewed, but noted a high risk of reporting and publication biases. The investigators concluded that oseltamivir had a modest benefit in previously healthy patients, reducing duration of symptoms by 21 h, but had no effect on hospitalisation [20] . & In 2013, Michiels and colleagues published a systematic review of systematic reviews to address the value of NAIs for the prevention and treatment of seasonal influenza focusing on data from randomised clinical trials [8] . NAIs can reduce the time to alleviation of symptoms in previously healthy adults and children but the effect in the elderly and at-risk individuals is unclear (Fig. 1a) . The use of NAIs was associated with a non-significant reduction in the odds of pneumonia in most study populations (Fig. 1b) , but the metaanalysis did not find any consistent reductions in the odds of hospitalisation (Fig. 1c) . Therefore, while the review documented clear benefits in less definitive outcomes such as time-to-alleviation of symptoms in previously healthy children and adults [8], it was unable to give conclusive evidence on the efficacy of NAIs in patients at the highest risk of influenza-related complications, and highlighted the lack of evidence for the efficacy of NAIs in more definitive outcomes such as pneumonia and hospitalisation. & A systematic review and meta-analysis of 74 observational studies in 2012 by Hsu and colleagues attempted to address the benefits and potential harm of antivirals for the treatment of influenza Oseltamivir & Oseltamivir is administered as an oral formulation (tablet or suspension) as it is readily absorbed from the gastrointestinal tract. The standard treatment dose is 75 mg twice daily for 5 days for healthy adults and children over 12 years of age [24] . & Oseltamivir undergoes hepatic metabolism to its active form but is predominantly cleared by the kidneys. Dose reduction is not required in patients with hepatic impairment but is required in patients with renal impairment ( [41] . Retrospective data suggests that early initiation of NAIs may reduce mortality in children [42] but further studies are needed to understand the role of NAIs for the treatment of children at risk of influenza-related complications. & Weight-based dosing of oseltamivir is recommended in children aged 1-12 years of age [13] . & Oseltamivir pharmacokinetics differ in the very young. Oseltamivir should be dosed at 3.5 mg/kg orally twice daily in children aged between 9 and 11 months, and 3 mg/kg orally twice daily in infants less than 8 months of age [43] . & NAI resistance may be an issue in the paediatric population, with higher rates of post-treatment oseltamivir resistance observed in paediatric patients, but this may be the result of under-dosing in young children, and requires further evaluation [25, 44] . & High rates of neuropsychiatric side effects have been observed in children treated with oseltamivir (up to 36 %) and may be the result of ABCB1 polymorphism which increases brain permeability of the drug [45] . Caution should be exercised when prescribing oseltamivir to adolescents due to reports of significant neuropsychiatric events in this age group; symptomatic management should be used in those who are not at high risk of influenza-related complications [46] . [46] . However, widespread use of oseltamivir in Japan has not been associated with increased mortality related to self-harm [52] . A review of clinical trial and postmarketing data by the FDA failed to demonstrate a clear link between oseltamivir and neuropsychiatric events. Influenza-related encephalitis may have contributed to the neuropsychiatric events reported from Japan [46] . Patients treated with oseltamivir should be closely monitored for neuropsychiatric symptoms. & Oseltamivir is contraindicated in patients allergic to any components of the medication. & Zanamivir is well-tolerated, with minor gastrointestinal upset and respiratory symptoms (sinusitis, bronchitis, cough) occurring in approximately 2 % of treated patients. Serious allergic reactions are rare [13] . & Inhaled zanamivir is contraindicated in persons who are unable to use an inhalation device, including young children (G5 years of age), the elderly and patients with functional impairment or impaired conscious level. & Zanamivir has been associated with bronchospasm and is therefore relatively contraindicated in patients with underlying airways disease [30] . & Zanamivir is contraindicated in patients allergic to lactose as it is delivered with a lactose vehicle [30]. High-dose oseltamivir & Standard dosing recommendations of oseltamivir are derived from trials conducted in low-risk patients with mild disease [11] . As oseltamivir is well tolerated at doses up to seven times the standard recommendation [53] , authorities have suggested the use of double-dose oseltamivir, for up to 10 days' duration, for patients with severe disease [54] . However, a multicentre, double-blind, randomised controlled trial did not show improved clinical or virological outcomes in patients with severe influenza treated with double-dose oseltamivir compared with standard dosing [55] . Likewise, in Hong Kong a prospective intervention of highdose oseltamivir did not show significant difference in clinical or virological outcomes between patients treated with standard-dose versus high-dose oseltamivir. However, in a subanalysis of influenza B patients, higher-dose oseltamivir was associated with improved virologic response [56] . At this stage there is inadequate evidence to recommend the use of high-dose or extended-duration oseltamivir. [57, 58] . & While it is accepted that early treatment provides maximal benefit, the efficacy of delayed treatment remains unclear. Observational data suggests that treatment with NAIs beyond 48 h is clinically beneficial in patients with severe [59] or complicated disease [60] and in pregnant women [61] . A recent randomised controlled trial demonstrated that oseltamivir reduced viral shedding and symptom duration in uncomplicated influenza, even when initiation was delayed beyond 48 h [62] . Survival benefit has been observed in patients with influenza A (H5N1) infections who received oseltamivir up to 8 days after symptom onset, but maximal benefit was observed with early initiation of therapy [63] . At this stage there is insufficient data to recommend treatment beyond 48 h in patients at low-risk of influenza-related complications. In patients at high-risk of influenza-related complications, initiation of therapy beyond 48 h should be considered. Further studies are needed to delineate the optimal timing of NAIs. & Adamantanes are no longer recommended for the treatment of influenza as a result of widespread resistance. Resistance to oseltamivir has been widely reported [64] and is a problem in seasonal H1N1 [65] . Significant rates of oseltamivir-resistance have not been found in other subtypes of seasonal influenza [65] . & In a systematic review, the overall incidence of oseltamivir resistance was 2.7 % [66] , but varied by subtype, with higher rates observed in influenza A, especially the H1N1 and H3N2 subgroups [66] . Infection with oseltamivir-resistant virus was associated with influenzarelated pneumonia [66] & Resistance to the NAIs is a result of neuraminidase mutations. The neuraminidase mutations that confer resistance vary with influenza subtype and NAI [67] . & The H275Y mutation, in the N1 subtype, is the most common mutation and confers resistance to oseltamivir [67] . This mutation is associated with cross-resistance to peramivir but not to zanamivir [67] . & The E119V mutation, in the N2 subtype, confers resistance to oseltamivir but zanamivir usually remains active [67] . & The R292K mutation, also in the N2 subtype, confers resistance to oseltamivir with cross-resistance to zanamivir [67] . & Inhaled or IV zanamivir is currently the treatment of choice for oseltamivir-resistant virus, as resistance is most commonly secondary to the H275Y mutation, to which zanamivir remains active [67] . Extracorporeal membrane oxygenation & ECMO has been shown to improve survival in patients with acute respiratory distress syndrome (ARDS) [68] . However, there is a paucity of evidence for the use of ECMO in patients with influenza and implementation is extrapolated from ARDS trials [69] . & Observational studies of ECMO in patients with influenza-associated ARDS have reported mortality rates between 14 and 41 % [70] [71] [72] [73] . In a meta-analysis of ECMO in H1N1-associated ARDS, median treatment duration was 10 days and mortality ranged from 8 % to 65 %. While this treatment is feasible, patients remain at risk of inhospital mortality [74] . & The risks of ECMO include bleeding, complement activation, air embolism, vascular damage, and infection [75] . & ECMO has not been shown to be superior to conventional management in patients with influenza-associated ARDS [76] and should be considered as salvage therapy. A large, randomised control trial, which includes long-term follow-up, is required to further define the role of ECMO in the management of influenza-associated ARDS. & Influenza-convalescent human blood products have been used throughout history as a treatment for influenza. A meta-analysis examining the use of convalescent blood products during the 1918 influenza pandemic demonstrated reduced mortality in patients with influenza-associated pneumonia [77] . Likewise, in Hong Kong, convalescent plasma was shown to significantly reduce mortality in patients with pandemic influenza who required intensive care support [78] . & IV immunoglobulin (IVIG) contains pooled polyvalent immunoglobulin G (IgG) antibodies extracted from plasma. IVIG has been reported to have improved outcome in a patient with influenza-associated ARDS [79] . Hyperimmune IVIG was shown to be superior to IVIG, with reduction in influenza viral load and mortality in patients with severe influenza requiring intensive care unit support [80] . & Complications of convalescent plasma are similar to those for blood transfusion. Hyperimmune IVIG has been associated with thromboembolic phenomenon [81] . & The use of systemic corticosteroids in patients with influenza has been associated with increased mortality and risk of bacterial superinfection [82] [83] [84] . In a case-control study of patients with severe influenza, requiring ICU support , 90-day mortality was 54 % in patients treated with steroids versus 31 % in those without steroids [83] . & DAS 181 (Fludase) is a recombinant sialidase fusion protein composed of a sialidase catalytic domain and a cell surface-anchoring domain. The compound has completed its initial preclinical development and entered clinical development to determine its efficacy and safety in humans [85] . & Nitazoxanide is an oral antiparasitic that is FDA-approved for treatment of Giardia and Cryptosporidium infections. The compound recently received contract for advanced development as a treatment for drug-resistant influenza. Its mechanism of action against influenza is yet to be fully described [1] . & Additional emerging therapies for the treatment of influenza are outlined in Table 2 . [85] Systemic corticosteroids [82] [83] [84] 108] Seasonal influenza therapy in Japan Japan is at the forefront of seasonal influenza research and is a world leader in the implementation of new, novel and emerging therapies. & The long-acting NAI laninamivir has been approved in Japan since 2010. It is administered as a 40 mg single-dose inhalation, which achieves high intrapulmonary levels for up to 10 days [86] . Laninamivir has been shown to be safe and efficacious for the treatment of influenza, resulting in symptom relief at a median of 4 days [87] . It is active against influenza A and B, but has greatest efficacy against influenza A [88] . Laninamivir has similar efficacy to oseltamivir in patients with underlying respiratory disease and, unlike other inhaled NAIs, has not been shown to cause bronchospasm [89] . & Laninamivir therapy has been shown to be safe in children with influenza. It has similar efficacy to oseltamivir but offers the advantage of a one-time inhalation. It has been shown to be effective against oseltamivir-resistant virus in the paediatric population [90] . In randomised controlled trials, laninamivir has been shown to be safe and efficacious as prophylaxis against influenza [91] . & Laninamivir has shown promising results in Japan and may have an important role in the treatment of oseltamivir-resistant influenza. & The macrolide class of antibiotics have anti-inflammatory properties and have been investigated in Japan for the treatment of influenza. A retrospective analysis in children treated with NAIs alone or in combination with 5 days of clarithromycin demonstrated higher levels of antiviral secretory IgA and anti-influenza serum IgG in children receiving combination therapy. The re-infection rate over the year post-treatment was reduced in the combination therapy arm [92] . Azithromycin was recently trialled in combination with oseltamivir for the treatment of influenza in adults. Unfortunately, the randomised trial failed to show a reduction in the level of inflammatory cytokines with combination therapy. However, there was a trend towards reduced duration of symptoms in the combination therapy arm [93] . The use of macrolides for the treatment of influenza requires further investigation. & Vitamin D has been proposed as a therapy for a variety of medical conditions. A randomised controlled trial of vitamin D versus placebo, for the prevention of influenza A in children, demonstrated a significant reduction in the incidence of influenza A in the vitamin D arm [94] . This therapy requires additional investigation but may be an option for prevention in countries with a defined influenza season. Influenza and the rates of hospitalization for respiratory disease among infants and young children Neuraminidase inhibitors for preventing and treating influenza in children Very low pandemic influenza A (H1N1) 2009 mortality associated with early neuraminidase inhibitor treatment in Japan: analysis of 1000 hospitalized children Oseltamivir pharmacokinetics, dosing, and resistance among children aged G2 years with influenza Resistant influenza A viruses in children treated with oseltamivir: descriptive study ABCB1 polymorphisms and neuropsychiatric adverse events in oseltamivir-treated children during influenza H1N1/09 pandemia Tamiflu and neuropsychiatric disturbance in adolescents H1N1 2009 influenza virus infection during pregnancy in the USA Maternal and neonatal outcomes after antepartum treatment of influenza with antiviral medications Infant outcomes among pregnant women who used oseltamivir for treatment of influenza during the H1N1 epidemic Safety of oseltamivir in pregnancy: a review of preclinical and clinical data Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza Widespread use of neuraminidase inhibitors in Japan The pharmacokinetics and tolerability of the oral neuraminidase inhibitor oseltamivir (Ro 64-0796/GS4104) in healthy adult and elderly volunteers Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza. Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial A prospective intervention study on higher-dose oseltamivir treatment in adults hospitalized with influenza a and B infections Outcomes of adults hospitalised with severe influenza Impact of neuraminidase inhibitor treatment on outcomes of public health importance during the 2009-2010 influenza A(H1N1) pandemic: a systematic review and meta-analysis in hospitalized patients Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09 Antiviral therapy and outcomes of patients with pneumonia caused by influenza A pandemic (H1N1) virus Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States Efficacy of oseltamivir treatment started within 5 days of symptom onset to reduce influenza illness duration and virus shedding in an urban setting in Bangladesh: a randomised placebo-controlled trial Effectiveness of antiviral treatment in human influenza A(H5N1) infections: analysis of a global patient registry Infections with oseltamivir-resistant influenza A(H1N1) virus in the United States Global assessment of resistance to neuraminidase inhibitors Systematic review of influenza resistance to the neuraminidase inhibitors Detection and management of antiviral resistance for influenza viruses. Influenza Other Respir Viruses Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial A systematic review to inform institutional decisions about the use of extracorporeal membrane oxygenation during the H1N1 influenza pandemic Extracorporeal membrane oxygenation for 2009 influenza A(H1N1) acute respiratory distress syndrome The Italian ECMO network experience during the 2009 influenza A(H1N1) pandemic: preparation for severe respiratory emergency outbreaks Critically ill patients with 2009 influenza A(H1N1) in Mexico Critically ill patients with 2009 influenza A(H1N1) infection in Canada Extracorporeal membrane oxygenation (ECMO) in patients with H1N1 influenza infection: a systematic review and meta-analysis including 8 studies and 266 patients receiving ECMO Counterpoint: efficacy of extracorporeal membrane oxygenation in 2009 influenza A(H1N1): sufficient evidence? Extracorporeal membrane oxygenation for pandemic influenza A(H1N1)-induced acute respiratory distress syndrome: a cohort study and propensity-matched analysis Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection A case of acute respiratory distress syndrome associated with novel H1N1 treated with intravenous immunoglobulin G Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection Adjunctive therapies and immunomodulatory agents in the management of severe influenza Early corticosteroids in severe influenza A/H1N1 pneumonia and acute respiratory distress syndrome Corticosteroid treatment in critically ill patients with pandemic influenza A/H1N1 2009 infection: analytic strategy using propensity scores Use of early corticosteroid therapy on ICU admission in patients affected by severe pandemic (H1N1)v influenza A infection Novel pandemic influenza A(H1N1) viruses are potently inhibited by DAS181, a sialidase fusion protein Intrapulmonary distribution and pharmacokinetics of laninamivir, a neuraminidase inhibitor, after a single inhaled administration of its prodrug, laninamivir octanoate, in healthy volunteers Clinical efficacy of long-acting neuraminidase inhibitor laninamivir octanoate hydrate in postmarketing surveillance The duration of fever and other symptoms after the initiation of laninamivir octanoate hydrate in the Japanese 2011-2012 influenza season A randomized double-blind controlled study of laninamivir compared with oseltamivir for the treatment of influenza in patients with chronic respiratory diseases Long-acting neuraminidase inhibitor laninamivir octanoate (CS-8958) versus oseltamivir as treatment for children with influenza virus infection Laninamivir octanoate for postexposure prophylaxis of influenza in household contacts: a randomized double blind placebo controlled trial Immunomodulator clarithromycin enhances mucosal and systemic immune responses and reduces re-infection rate in pediatric patients with influenza treated with antiviral neuraminidase inhibitors: a retrospective analysis Efficacy of combination therapy with oseltamivir phosphate and azithromycin for influenza: a multicenter, open-label, randomized study Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren Postmarket drug safety information for patients and providers. Tamiflu (oseltamivir phosphate) information Influenza antiviral medications: summary for clinicians Postmarket drug safety information for patients and providers. Relenza (zanamivir) information Newer influenza antivirals, biotherapeutics and combinations. Influenza Other Respir Viruses Postmarket drug safety information for patients and providers. Peramivir IV questions and answers for health care providers Antiviral therapy for influenza virus infections High-dose N-acetylcysteine therapy for novel H1N1 influenza pneumonia Hypercytokinemia with 2009 pandemic H1N1 (pH1N1) influenza successfully treated with polymyxin B-immobilized fiber column hemoperfusion Use of therapeutic plasma exchange as a rescue therapy in 2009 pH1N1 influenza A: an associated respiratory failure and hemodynamic shock Influenza morbidity and mortality in elderly patients receiving statins: a cohort study Association between use of statins and mortality among patients hospitalized with laboratory-confirmed influenza virus infections: a multistate study Pre-admission statin use and in-hospital severity of 2009 pandemic influenza A(H1N1) disease Clarithromycin has limited effects in nonelderly, non-severe patients with seasonal influenza virus A infection Early use of glucocorticoids was a risk factor for critical disease and death from pH1N1 infection The authors wish to acknowledge Professor Frederick G. Hayden, MD, University of Virginia, Charlottesville, VA, USA, for his invaluable advice on the manuscript, and Dr. Linn Thein Tun for administrative assistance. Emily Rowe declares that she has no conflicts of interest. Yee-Sin Leo declares that she has no conflicts of interest. Mark I. Cheng Chen declares that he has no conflicts of interest. Pei Yi Ng declares that she has no conflicts of interest. Thiaghu Chandra declares that he has no conflicts of interest. This article does not contain any studies with human or animal subjects performed by any of the authors.