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Recent rapid responses
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Displaying 1-4 out of 4 published
In their review and meta-analysis van den Hoek and coworkers  show that in large randomised placebo controlled trials statins had no effect on the risk of infections, the accompanying editorial thus concludes that the best evidence now says that statins do not reduce infection .
We extensively studied the effects of statin treatment on polymorphonuclear leukocytes (PMNs), which are key players in the innate immune response against infections. Our investigations focussed on dyslipidaemic subjects at increased cardiovascular risk according to the National Cholesterol Education Program—Adult Treatment Panel III (ATPIII) guidelines . According to our initial findings , in these subjects PMNs show enhanced production of interleukin (IL)-8, and increased reactive oxygen species (ROS) generation and 4-week simvastatin treatment reduces both IL-8 production and chemotaxis at levels comparable to those observed in healthy subjects. When however we performed a follow-up study after long-term (1 year) statin treatment, results indicated that ROS generation by PMNs from high-risk subjects on simvastatin were comparable to those in cells from healthy subjects , however IL-8 production was significantly lower both in resting PMNs (mean difference: -119.1 pg/ml, 25th-75th percentiles: 66.8 to 171.4 pg/ml) as well as after stimulation with fMLP (-280.5 pg/ml , 170.8 to 390.1 pg/ml). It is thus suggested that: (i) the functions of human PMNs are reduced during statin treatment; (ii) distinct functions are affected to different extents (ROS production is just reduced to values found in cells from healthy subjects but IL-8 production is profoundly impaired).
Our studies were performed in small groups of subjects (n= 14-15) and therefore provided no information regarding the possible association between reduced PMN functional responses and increased susceptibility to infections. Nonetheless, results provide some clues about mechanisms potentially contributing to decreased antiinfective defenses during statin treatment. Indeed, statin-induced reduction of the proinflammatory profile observed in subjects at high cardiovascular risk may result in additional benefit for the prevention of vascular events, but also in light of our findings we agree with van den Hoek and collaborators  that detailed reporting of infectious outcomes should be mandatory in statin trials. Infectious events should be also carefully monitored an reported during routinary statin treatment in particular in the long term.
Franca Marino, Luigina Guasti, Marco Cosentino
Center for Research in Medical Pharmacology, University of Insubria, Varese, Italy. E-mail: email@example.com
 van den Hoek HL, Bos WJ, de Boer A, van de Garde EM. Statins and prevention of infections: systematic review and meta-analysis of data from large randomised placebo controlled trials. BMJ 2011; 343: d7281.
 Golomb BA. Do statins reduce the risk of infection? BMJ 2011; 343: d7134.
 Expert Panel on Detection Evaluation Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486-2497.
 Guasti L, Marino F, Cosentino M, Cimpanelli M, Maio RC, Klersy C, Crespi C, Restelli D, Simoni C, Franzetti I, Gaudio G, Marnini P, Grandi AM, Lecchini S, Venco A. Simvastatin treatment modifies polymorphonuclear leukocyte function in high-risk individuals: a longitudinal study. J Hypertens 2006; 24: 2423-30.
 Guasti L, Marino F, Cosentino M, Maio RC, Rasini E, Ferrari M, Castiglioni L, Klersy C, Gaudio G, Grandi AM, Lecchini S, Venco A. Prolonged statin-associated reduction in neutrophil reactive oxygen species and angiotensin II type 1 receptor expression: 1-year follow-up. Eur Heart J 2008; 29: 1118-26.
Competing interests: None declared
Center for Research in Medical Pharmacology, University of Insubria, Via Ottorino Rossi n. 9, Varese, Italy
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1 February 2012
The paper by Van den Hoek et al,  which did not find a protective effect of statins against infections in a meta-analysis of RCTs, in contrast to several meta-analyses of observational studies, leads to predictable reactions that are variants of: “don’t we all know that observational studies are always prone to confounding?” Such reactions forget that there exists already a large literature on the ‘healthy user effect’ of statins that seem to protect against several diseases .
Suspicion of this bias led Majumdar et al.  to look for ways to counter this bias: they showed that if a routine analyses was done on a large body of administrative claims data, a seeming protection against a bad outcome of pneumonia was found, but this disappeared upon further adjustment by additional data obtained from medical records - in particular data that encapsulated the notion of an ‘healthy user’ (,e.g., on preventive immunizations and risk factors for community acquired pneumonia). The suspicion of a bias that operates across all studies, and of which the mechanism is clearly shown in a single study, suffices to cast doubt on all other studies and should have led to greater caution in pooling these studies. Conversely, a single study that shows that the bias does not exist, might validate all others.
Meta-analyses of observational data on statins and infections should have identified this problem up front and have divided the studies in those that described the problem and were able to address it vs. those that did not. Meta-analyses of observational studies should continue to follow the advice: “The statistical combination of data should therefore not be a prominent component of reviews of observational studies. More is gained by carefully examining possible sources of heterogeneity between the results from observational studies.” 
 van den Hoek HL, Bos WJ, de Boer A, van de Garde EM. Statins and prevention of
infections: systematic review and meta-analysis of data from large randomised
placebo controlled trials. BMJ. 2011;343:d7281.
 Glynn RJ, Schneeweiss S, Wang PS, Levin R, Avorn J. Selective prescribing led
to overestimation of the benefits of lipid-lowering drugs. J Clin Epidemiol. 2006;59:819-28.
 Majumdar SR, McAlister FA, Eurich DT, Padwal RS, Marrie TJ. Statins and outcomes in patients admitted to hospital with community acquired pneumonia: population based prospective cohort study. BMJ 2006;333:999
 Egger M, Schneider M, Davey Smith G. Spurious precision? Meta-analysis of
observational studies. BMJ. 1998;316:140-4.
Competing interests: None declared
Department Clinical Epidemiology, Leiden University Medical Center
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8 December 2011
Statins, Cholesterol Levels, and the Risk of Infections
Neither van den Hoek et al.'s conclusion1 that statins do not reduce the risk of infections nor Golomb's accompanying editorial2 refer to the possibility that the cholesterol lowering effect of statins could actually have the reverse effect and increase the risk of infections. Golomb offered several possible explanations of the lower rate of infections in the statin arms of some trials, such as indication bias, fewer ill and elderly people, various healthy user effects, and bias from drug company sponsors. Another proxy for high cholesterol levels is lack of adherence to taking statins; in one study that included 85,020 patients without heart disease, 75% were no longer taking statins at the 2-year follow-up.3
Golomb´s most important argument is that the main indication for statins is an elevated cholesterol level, which is associated with resistance to infections and decreased hospital admissions for influenza and pneumonia.4 Additional support comes from the observation that prior to 1900, when infectious diseases were the leading cause of death, people with familial hypercholesterolemia lived longer than the average population of their country.5
An important function of lipoproteins explains why high cholesterol provides protection from infections. It is not generally appreciated that lipoproteins bind and inactivate numerous bacteria and viruses as well as their toxic products. This important function of lipoproteins in innate immunity was demonstrated over 60 years ago by Humphrey and has since been confirmed by more than a dozen research groups.6,7 For instance, lipoproteins inhibit replication and toxin formation by various microorganisms in vitro.6 Aggregates formed between human low-density lipoprotein (LDL) and various microbes and toxins have been visualized by electron microscopy, and these aggregates are suggested to obstruct vasa vasorum during formation of vulnerable plaques.6 Hypocholesterolaemic rats injected with lipopolysaccharide (LPS) endotoxin have a markedly increased mortality compared with normal rats, which is ameliorated if they are pre-treated with an injection of purified human LDL. Similarly, mice with genetic hypercholesterolaemia challenged with LPS or live bacteria have an eightfold increase of LD50 compared to normal controls.6
Thus, epidemiological, observational and laboratory studies all support the conclusion that elevated cholesterol levels reduce the risk of infections. Moreover, the study of 100,000 healthy individuals showed that those with low cholesterol levels at the start were admitted more often to hospital because of an infectious disease during a 15 year follow up.4 As 15-20% of human cancers are estimated to have a viral or bacterial aetiology,8 the anti-infectious properties of the lipoproteins may explain the many associations between low cholesterol levels and cancer.9
Uffe Ravnskov, MD, PhD; independent investigator
Magle Stora Kyrkogata 9, 22350 Lund Sweden
Paul J. Rosch, MD, FACP, Clinical Professor of Medicine and Psychiatry, New York Medical College: President, The American Institute of Stress 124 Park Ave.Yonkers, New York, USA.
Kilmer S. McCully, MD, Pathology and Laboratory Medicine Service VA Boston Healthcare System, West Roxbury MA, USA, Department of Pathology, Harvard Medical School, Boston MA, USA.
1. Van den Hoek HL, Bos WJW, De Boer A, van de Garde EMW. Statins and prevention of infections: systematic review and meta-analysis of data from large randomised placebo controlled trials. BMJ 2011; 343:d7281.
2. Golomb BA. Do statins reduce the risk of infection? BMJ 2011;343:d7134.
3. Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA 2002;288:462-7.
4. Iribarren C, Jacobs DR Jr, Sidney S, Claxton AJ, Gross MD, Sadler M, Blackburn H. Serum total cholesterol and risk of hospitalization, and death from respiratory disease. Int J Epidemiol 1997;26:1191-202.
5. Sijbrands EJG, Westendorp RGJ, Defesche JC, de Meier PHE, et al. Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study. BMJ 2001; 322:1019-1023.
6. Ravnskov U, McCully KS. Vulnerable plaque formation from obstruction of vasa vasorum by homocysteinylated and oxidized lipoprotein aggregates complexed with microbial remnants and LDL autoantibodies. Ann Clin Lab Sci. 2009;39:3-16.
7. Han R. Plasma lipoproteins are important components of the immune system. Microbiol Immunol 2010;54:246–53.
8. Burnett-Hartman AN, Newcomb PA, Potter JD. Infectious agents and colorectal cancer: a review of Helicobacter pylori, Streptococcus bovis, JC virus, and human papillomavirus. Cancer Epidemiol Biomarkers Prev 2008;17:2970-2979.
9. Ravnskov U, McCully KS, Rosch PJ. The statin-low cholesterol-cancer conundrum. Q J Med, 2011, In Press.
Competing interests: None declared
Magle Stora Kyrkogata 9, 22350 Lund, Sweden
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1 December 2011
Statins pleotropic effects have led many to believe it may be the panacea for all ills. The anti-inflammatory properties of these HMG-CoA reductase inhibitors mean that statins are being used in ever increasing wide-ranging endeavors, from the treatment of sepsis to macular degeneration. A word of caution should prevail, as blockage of the mevalonate pathway, though very useful in many conditions, results also in low levels of ubiquinone(1). Ubiquinone is needed for ATP generation via mitochondrial oxidative phosphorylation(2).
It should be noted that hypocholesterolaemia ( a marker for the action of statins) is an independent predictor of increased mortality in patients with advanced heart failure(3-4). It has also been associated with poorer outcome in critically ill surgical patients (5) and the elderly(6)
As trials investigate further utility of this wide acting drug, we should remember Hippocrates’ first tenet – “Primum non nocere”
1. Brookes Z, McGown C, Reilly C. Statins for all: the new premed? British journal of anaesthesia 2009;103(1):99.
2. Molyneux SL, Florkowski CM, George PM, Pilbrow AP, Frampton CM, Lever M, et al. Coenzyme Q10:: An Independent Predictor of Mortality in Chronic Heart Failure. Journal of the American College of Cardiology 2008;52(18):1435-41.
3. Horwich TB, Hamilton MA, MacLellan WR, Fonarow GC. Low serum total cholesterol is associated with marked increase in mortality in advanced heart failure. Journal of cardiac failure 2002;8(4):216-24.
4. Rauchhaus M, Clark AL, Doehner W, Davos C, Bolger A, Sharma R, et al. The relationship between cholesterol and survival in patients with chronic heart failure. Journal of the American College of Cardiology 2003;42(11):1933-40.
5. Gui D, Spada P, De Gaetano A, Pacelli F. Hypocholesterolemia and risk of death in the critically ill surgical patient. Intensive care medicine 1996;22(8):790-94.
6. Schatz IJ, Masaki K, Yano K, Chen R, Rodriguez BL, Curb JD. Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study. The lancet 2001;358(9279):351-55.
Competing interests: None declared
IMPERIAL COLLEGE, 4th Floor, Lift Bank D, Imperial College London Chelsea & Westminster Hospital NHS Foundation Trust 369 Fulham Road London SW10 9NH
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