Description of the condition
Viral upper respiratory tract infections account for the majority of acute presentations to general practice (NICE 2008). Implicated pathogens vary by season and they are commonly due to influenza virus, respiratory syncytial virus and rhinovirus (HPA UK 2012). Considerable overlap exists in the clinical presentation of these infections (Bellei 2008; Eccles 2005) with the majority of affected individuals suffering from a mild, self limiting clinical illness characterised by fever, cough, sore throat, myalgia, headaches and gastrointestinal symptoms.
Influenza, in particular, is a significant cause of morbidity and mortality worldwide, with World Health Organization (WHO) estimates of one billion cases; three to five million cases of severe illness and 300,000 to 500,000 deaths annually (WHO 2008). Complications of influenza include primary viral pneumonia which may lead to adult respiratory distress syndrome (ARDS), secondary bacterial pneumonia and extrapulmonary manifestations including myocarditis and neurological sequelae. Severely ill patients may require prolonged hospitalisation and intensive care support; the associated mortality rate is high (Cheng 2012; Thompson 2003).
Seasonal influenza occurs annually during the winter months in temperate zones of both the Northern and Southern hemispheres and all year round in the tropics (Viboud 2006). Pandemic influenza (due to antigenic shifts of the virus) emerges unpredictably and infrequently with varying disease severity. The case fatality rates of the pandemics in 1918, 1957 and 1968 ranged from 0.2% to 3%, whereas the 2009 pandemic was similar in virulence to seasonal influenza, with an estimated case fatality rate of 0.03% (Donaldson 2010). However, young adults were disproportionately affected compared to seasonal influenza (Viboud 2010). The highest rates of hospitalisation were in children under 15 years of age (Kerkhove 2011).
Specific treatment options for influenza are limited to antiviral drugs such as neuraminidase inhibitors. A Cochrane Review of neuraminidase inhibitors for the treatment of influenza in adults and children reported that the duration of flu-like symptoms was shortened by these drugs. However, the review authors were unable to draw firm conclusions about the effects on complications of influenza, or transmission (Jefferson 2012). Not all reviews are as conservative as Cochrane Reviews (Arunachalam 2011; Hsu 2012) but all acknowledge the lack of robust data relating to outcomes of public health importance, such as severe complications, hospitalisation and death.
Currently, a Cochrane Review of statin use in the treatment of influenza is underway (Khandaker 2011). A Cochrane Review of Chinese medicinal herbs in the prevention and treatment of influenza concluded that the current evidence was insufficient to recommend its routine use (Chen 2007).
Description of the intervention
Corticosteroids are produced endogenously in the adrenal glands from cholesterol and regulated by the hypothalamic-pituitary-adrenal axis (Molenaar 2012). Synthetically derived analogues such as betamethasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone and triamcinolone are commonly used in clinical practice (BNF 2012). However, the evidence base for their use shows wide variation across the different conditions.
In the setting of severe sepsis and septic shock, high doses of corticosteroids in short courses were initially thought to be beneficial (Schumer 1976). However, several meta-analyses later demonstrated no overall benefit in mortality with this regime (Cronin 1995; Lefering 1995). A randomised, double-blind, placebo-controlled study of low-dose hydrocortisone and fludrocortisone (Annane 2002) demonstrated reduced mortality and a reduced need for vasopressor use at 28 days in the treated group. Several double-blind randomised studies later replicated these findings (Keh 2003; Oppert 2005). A systematic review in 2009 reported that low-dose corticosteroid use increased 28-day shock reversal, and reduced intensive care unit length of stay and 28-day mortality, with no associated increase in gastrointestinal bleeding rate, superinfection or neuromuscular weakness (Annane 2009).
When used for the treatment of bacterial meningitis, corticosteroids appear to reduce hearing loss and neurological complications (Brouwer 2010), while in tuberculous meningitis, an improvement in survival has been reported (Prasad 2008).
With relevance to respiratory virus infection, a Cochrane Review of systemic corticosteroid use in all-cause pneumonia found no mortality benefit but a reduction in time to resolution of symptoms (Chen 2011). Similarly, patients given systemic corticosteroids or inhaled corticosteroids in acute sinusitis were more likely to have a shorter time to resolution of symptoms (Venekamp 2011) or were more likely to experience a resolution of their symptoms (Zalmanovici Trestioreanu 2011), respectively. A review of corticosteroid use in croup found a lower symptom score at six hours, re-admission rate and length of stay in the treated group (Russell 2011). No benefits were seen in hospital admission rates, or length of stay in hospital, following systemic or inhaled corticosteroid use in acute viral bronchiolitis in infants and young children (Ricardo 2010). Intranasal corticosteroids used in the treatment of the common cold did not appear to reduce severity or length of illness, although the review was limited by small study numbers (Hayward 2012).
Due to a lack of robust evidence, corticosteroid use in influenza is currently inconsistent. Several studies investigating patients admitted to hospital and intensive care units during the 2009 influenza H1N1 pandemic reported that 30% to 50% had received corticosteroids (Brun-Buisson 2011; Chan 2011; Kim 2011; Martin-Loeches 2011). The World Health Organization consultation on human influenza A (H5N1) infection reported that 47% to 70% of patients received corticosteroids during the 2004 to 2005 outbreak in South East Asia (WHO 2005).
How the intervention might work
Viral replication and production of cytokines through activation of the host innate immune system are central in the pathogenesis of influenza infection (de Jong 2006). Elevated or excessive production of cytokines (hypercytokinaemia) correlates with symptoms and fever in acute influenza (Kaiser 2001). Comparisons between patients with mild and severe pandemic H1N1 influenza have revealed significantly higher levels of cytokines (especially interleukin-6) in the plasma of patients with severe disease (Yu 2011) and similar findings have been replicated in studies of severe seasonal influenza (Heltzer 2009). High levels of pro-inflammatory cytokines such as interleukin-1, interleukin-6 and tumour necrosis factor-α lead to activation of the hypothalamic-pituitary-adrenal axis (Chrousos 1995). The consequent production of corticosteroids is essential to maintain homeostasis during physiological stress through mechanisms such as inhibition of leucocyte trafficking and function, maintenance of epithelial integrity, regulation of vascular tone by inhibition of vasodilators (nitrous oxide) and increased sensitivity to vasopressors, and metabolic effects (Arafah 2006). However, up to 50% of patients with severe sepsis have evidence of adrenal dysfunction due to inadequate production of corticosteroids or impaired peripheral sensitivity to corticosteroids (Patel 2012). Administration of corticosteroids during severe influenza may attenuate this state of adrenal insufficiency.
Why it is important to do this review
There are no widely recognised large, good-quality randomised controlled trial (RCT) data on this topic, but it is not known if less robust trial data exist. Therefore, the authors believe that a systematic review of the evidence is warranted to identify and bring together what RCT data exist and, secondly, in view of the possible lack of robust RCT data, to identify non-RCT data and observational data that would provide further valuable clinical information to guide best practice. Such a review would also provide researchers with a stronger basis for a considered approach regarding further studies (including high-quality RCTs) in this area. If corticosteroids are found to be beneficial, there may be reductions in influenza-related hospitalisations, intensive care admissions, length of hospital stay and mortality. Conversely, if found to be harmful, the current unsystematic use of corticosteroids in influenza should be stopped. Either way, clarification of the role of corticosteroids in the management of influenza should lead to improvements in patient care and savings in healthcare costs.