Statins and Influenza: What Is the Current Evidence?

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Table of Contents

Introduction
Why statins?
PPAR Agonist
Clinical Implications
Future study recommendations
Conclusions
References

Introduction

Statins are a group of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors with anti-inflammatory and immunomodulatory effects that might control the host immune response to pandemic influenza virus infection. This class of drugs lowers cholesterol levels in people at the risk of cardiovascular diseases by inhibiting the enzyme HMG-CoA reductase (Fedson, 2006). This inhibition in the liver results in decreased cholesterol synthesis and also of the LDL (low-density lipoprotein) receptors which in turn lead to increased clearance of LDL from the bloodstream. In a case-control study by van de Garde and colleagues, they showed that there was a 50% decrease in pneumonia hospital admissions in diabetic patients administered with statins. Statins are divided into two categories: fermentation-derived and synthetic-derived (Fedson and Dunhill, 2006).

Fermentation statins are extracted from the process of oxidation of organic compounds using an ingenious electron acceptor, which is usually an organic compound. Examples of fermentation-derived statins are Lovastatin, Pravastatin and Simvastatin. Synthetically derived statins are prepared in the laboratory by purposeful execution of chemical reactions. Examples of synthetic statins are Atorvastatin, Cerivastatin, fluvastatin, pitavastatin and Rosuvastatin.

Influenza, also known as flu, is an infectious disease caused by RNA (ribonucleic acid) viruses of the Orthimyxoviridae family that affects mammals and birds. It is transmitted through the air by sneezes, coughs; through bird droppings; contact with infected body fluids such as saliva, feces, blood and nasal secretions; and contact with contaminated surfaces. Sunlight, disinfectants and detergent such as soaps inactivate influenza viruses that is why frequent hand washing reduces the risk of infection. It spreads through seasonal epidemics around the world that leave hundreds of people dead and the appearance of new strains (Fedson and Dunhill 2007).

For instance, in April 2007, a strain named ‘swine flu’ combining genes from pigs. Humans and bird flu evolved in Mexico, United States and has spread in many countries in every continent leading to the declaration by World Health Organization as an epidemic. Symptoms of flu include chills, fever, headache, coughs, sore throat, muscle pains and general discomfort. There are three types of influenza: influenza A which has one species and aquatic birds as natural hosts these include HINI, H2N2, H3N3, H5N1, H7N7, H1N2 and others; influenza B genus with one species and Almost exclusively infects humans; and influenza C which infects dogs, humans and pigs and cause severe illnesses and local epidemics.

Why statins?

In influenza pandemics, adequate supplies of affordable vaccines and antiviral agents are required and which are unavailable to most people in the world especially to the third world (Basler, 2007). I. Adequate supplies will also be a challenge due to concerns of antiviral resistance which will discourage stockpiling. This is the reason effective alternatives are explored such as generic agents that target the host immune response and pandemic virus are being explored.

Studies suggest that statins improve outcomes in pneumonia and bacteremia might be effective against influenza have conducted. These are informed by observations made on severe infections caused by type A H5N1, the 1918 Spanish influenza H1N1 and seasonal influenza A viruses which showed increased levels of several cytokines and chemokines, a response called ‘cytokine storm’. In 2005 Kruger et al carried out a retrospective cohort research that showed a significant survival benefit in bacteremia patients on statin therapy. However, doubts have been raised about the use of statins in the treatment of influenza although it has potential benefits.

One such study by de jong and colleagues (2006) presented details on virological findings on 18 patients with H5N1 and compared with the 8 people with seasonal influenza those with the H5N1 had higher serum cytokine and chemokine levels and high viral load in pharyngeal secretions and therefore the study concluded that the focus of clinical management should be on preventing the intense cytokine response by early diagnosis and effective treatment. This is because all 18 patients sought treatment at an average of 6 days after onset of symptoms.

Interest in immunomodulatory and anti-inflammatory agents for pandemic control focuses on statins, at least initially. Laboratory and clinical research by cardiovascular experts show that statins have high anti-inflammatory and immunomodulatory (pleiotropic) effects (Kruger et al, 2006). These emanate from statins’ modification of intracellular signaling cascades that cause multiplication of effects. This phenomenon is likened to ‘reducing the heat under a boiling kettle’. Heart failure progression can not be prevented only slowed down with therapies. Studies show that the use of statins in patients with coronary diseases prevents the subsequent attack of congestive heart failure( Anorld and Koning, 2006).

The hypothesis has been put forward that inhibition of HMGCoA reductase reduces cholesterol level and reduces the synthesis of mevalonate-derived molecules this way, downregulating cytokines and chemokines production activated in patients with heart failure. However, it has been suggested that cholesterol can be beneficial to heart failure patients in that cholesterol rich-lipoprotein can bind and detoxify bacterial lipopolysaccharide(LPS) which is highly produced in heart failure patients.

This shows two conflicting effects of statins. Van de Garde and colleagues found that in a case-control study, recent prescriptions for statins reduced hospital admissions by 50% in diabetic patients. In another study by Schlienger and co-workers, they showed that in a 30 days current prescription of statins the results were a 53% decrease of pneumonia 30 days mortality. In a different study, Majumdar and colleagues found that there were no beneficial effects of statins prescription and attributed the said benefits found in other studies to ‘healthy user effect’.

PPAR Agonist

Peroxisome proliferator-activated receptor (PPAR) is a fibrate gemfibrozil family of drugs that have been produced as generics in the developing world. PPAR Agonists have anti-inflammatory and immunomodulatory activities, which makes them potential treatment agents agonist influenza. In an experimental study with mice infected with H2N2 and treated with PPAR agonist mortality reduced significantly with 52%of control mice compared to 26% of those treated (Stacy, 2004). However, the study did not include the possible effects of treatment on virus replication or dissemination. Studies have also failed to show the direct antiviral effect of PPAR Agonist although it affects several intracellular pathways crucial for influenza viral replication and also they act synergistically to affect some of the pathways.

Combination therapy of PPAR agonists and statins in patients of diabetes mellitus and cardiovascular diseases show addiction. It is, however, safe and well-tolerated for a prolonged therapy of fibrates in adults which leads to the conclusion that short-term acute treatment of influenza would be acceptable if effective. Experimental studies so far are yet to show that treating H5N1 or the 1918 influenza H1N1 virus infections with antiinflammatory and the immunomodulatory agent is beneficial (Ooi et al, 2004). PPAR agonist findings of reduced mortality in influenza H2N2 in infected mice are of great significance. This indicates that improved outcomes of severe influenza virus infection could be done by modifying cell signaling. With an agent that is antiviral.

Clinical Implications

Large-scale clinical trials of lipid-lowering statins have led to a revolution in the management of atherosclerosis. Moreover, statins influence other cellular pathways that involve inflammatory, oxidative and thrombotic processes. The effects which beneficially modify the anthropogenic process are associated with the success of the trial (Kramer, 2005). Currently, the clinical benefits of statin therapy emanate from the lowering mechanism of low-density lipoprotein and will remain the focus of risk reduction approaches in clinical practice.

In the trials on statin therapy, beneficial effects have been demonstrated on rates of cardiovascular events and three statin lovastatin, pravastatin, and simvastatin were used in trials have shown beneficial effects on myocardial, stroke, revascularizations and mortality ( Mortenson et al 2006). Mortenson et al continue to say that community-acquired pneumonia and COPD patients can be protected with statins.

Future study recommendations

Future areas of study should focus on finding an agent with no anti-racial activity that would effectively modify steps in cell signaling. This agent would target the host’s response without attacking the virus (Peiris, 2007). Studies should also focus on identifying effective, inexpensive and universally available, one or more effective antiinflammatory and immunomodulatory agents (Majamdar, 2007).

Studies should also focus on how much low-density lipoprotein cholesterol should be lowered in long term trials in order to determine safety levels and generate such data (Palamara, 2005)

Research is also needed to understand the benefits of specific statins at the precise doses in particular patient groups of influenza virus (Chong and Sullivan, 2007).

Conclusions

In conclusion, statins are important in the treatment influenza virus due to their benefits demonstrated so far by the many trials done so far. Their benefits, which include reducing atherosclerosis, direct and indirect antioxidant effects, anti-inflammatory effects, inhibition of cardiac hypertrophy among other benefits. Does this mean we just grab simvastatin or any other statin on the first onset of influenza? Further studies are required to sufficiently link statins to the successes in morbidity and mortality demonstrated by current studies (Allison and Adel, 2005). However, with the imminent danger of a global pandemic where 85% of the world will not have meaningful access to pandemic vaccines or antiviral agents, the time to act is now on research to determine whether these alternative agents are useful or not.

In countries without these treatments, it is imperative to come up with new approaches to confront the pandemic (Stacy, 2004). They can support new research that studies existing agents that promise antiviral or inflammatory and immunomodulating activities. These can be identified among the existing agents which can be produced as generic and made affordable to people all over the world.

Name of the author	year	Number of patients with pneumonia/controls	outcomes
va de Garde	2005	4719/15322	pneumonia hospital admission
Schlenger et al	2006	1227/4734	pneumonia hospital admission 30-day pneumonia mortality
Martenson et al	2006	1566/7086+	30-day pneumonia mortality
Majumdar et al		325/3090+	Hospitality mortality/ ICU admission
Forest et al	2007	604/76,232	mortality risk and survival time

Table: Recent treatment with statins in patients hospitalized with pneumonia. Source: Majamdar et al, 2007.

References

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Basler, C.F, (2007). Influenza viruses: basic biology and potential drug targets. Infect Disord Drug Targets. 7:282-93.

Fedson, D. (2006). Pandemic influenza: a potential role for statins in treatment and prophylaxis. Clin Infect Dis 2006; 43: 199–205.

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Alison,M and Adel M. (2005). Forum on Microbial Threats. National Academies Press.

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Kramer, M.A. (2005). Trends in Cholesterol Research. Nova Publishers.

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Arnold R, Koning W. (2006). Peroxisome proliferator-activated receptor-gamma agonists inhibit the replication of syncytial(RSV) in human lung epithelial cells. Virlogy; 350: 335 46.

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