Start Spreading the Flus

Photo Credit –CDC PHIL

 

# 8203

 

A new study that appeared in the Proceedings of the Royal Society B yesterday, provides a fresh look at a topic I’ve written about several times in the past; the potential downsides of using antipyretic meds (ibuprofen, acetaminophen or paracetamol, etc) for flu-related fever.

 

While earlier studies have concentrated on the affects of these meds on the individuals taking them, this new study looks at the population-level impact of taking these fever-reducing meds during an influenza outbreak.

 

Fever is the body’s natural reaction to infection, and since most viruses have a narrow `comfort zone’, a spike in temperature can lower the amount of virus the host is carrying  . ..  and shedding.  Another side effect of fever is that it makes you feel miserable, and so people with a fever are more likely to stay home, rather than go to work or school.

 

When you artificially reduce the fever, you not only give the virus a better environment in which to replicate, you are also more likely to go out and infect others.  A double whammy.

 

While neither of these concepts is new, this study attempts to quantify the impact in terms of the virus’s R₀ (R naught) or Basic Reproductive Number, and they calculate the use of fever suppression meds increases the number of annual cases by approximately 5%, resulting in more  than 1,000 additional flu deaths each year in North America.

 

First, a link to the study, then some excerpts from the press release from McMaster University, after which I’ll be back with more.

 

Population-level effects of suppressing fever

David J. D. Earn,  Paul W. Andrews and Benjamin M. Bolker

Abstract

Fever is commonly attenuated with antipyretic medication as a means to treat unpleasant symptoms of infectious diseases. We highlight a potentially important negative effect of fever suppression that becomes evident at the population level: reducing fever may increase transmission of associated infections. 

(Continue . . . )

 

McMaster University researchers find fever-reducing medications may aid spread of influenza

Hamilton, ON (Jan. 21, 2014) -- Contrary to popular belief, fever-reducing medication may inadvertently cause more harm than good.

New research from McMaster University has discovered that the widespread use of medications that contain fever-reducing drugs may lead to tens of thousands more influenza cases, and more than a thousand deaths attributable to influenza, each year across North America. These drugs include ibuprofen, acetaminophen and acetylsalicylic acid.

"When they have flu, people often take medication that reduces their fever. No-one likes to feel miserable, but it turns out that our comfort might be at the cost of infecting others," said lead author David Earn, an investigator with the Michael G. DeGroote Institute for Infectious Disease Research (IIDR) and professor of mathematics at McMaster University.

"Because fever can actually help lower the amount of virus in a sick person's body and reduce the chance of transmitting disease to others, taking drugs that reduce fever can increase transmission. We've discovered that this increase has significant effects when we scale up to the level of the whole population."

The study, published in the Proceedings of the Royal Society B today, was co-authored with McMaster professors Ben Bolker, of the departments of mathematics & statistics and biology and the IIDR, and Paul Andrews of the Department of Psychology, Neuroscience and Behaviour.

(Continue . .. )

 

The authors caution that this work is preliminary, the data is incomplete and heterogeneous, and that more work needs to be done before concrete proposals regarding the use of these drugs can be made.

 

In a real world example of how fever-reducers can increase the public’s exposure to an influenza virus, in  Vietnam Discovers Passengers Beating Thermal Scanners we looked at reports of people using fever reducing meds to evade airline passenger screening during the 2009 H1N1 pandemic.

 

I’ve also written about studies that suggest that the concurrent use of antipyretics may inhibit the immune response when receiving vaccines. In fact, it has even been theorized that one of the reasons that the elderly often develop less-than-robust immunity from the flu vaccine may be due to their frequent consumption of NSAIDs.

 

Several past blogs on this phenomenon include:

 

Anti-Inflammatory Meds And Vaccines

Common Pain Relievers May Dampen Vaccination Benefits

A Few Inflammatory Remarks

 

In a another story  from 2011 - the American Academy of Pediatrics (AAP) released a report on the use of antipyretics in children, suggesting that we ought not over-treat fevers.

 

Clinical Report—Fever and Antipyretic Use in Children

Janice E. Sullivan, MD, Henry C. Farrar, MD,

ABSTRACT EXCERPTS

Fever in a child is one of the most common clinical symptoms managed by pediatricians and other health care providers and a frequent cause of parental concern. Many parents administer antipyretics even when there is minimal or no fever, because they are concerned that the child must maintain a “normal” temperature.

Fever, however, is not the primary illness but is a physiologic mechanism that has beneficial effects in fighting infection. There is no evidence that fever itself worsens the course of an illness or that it causes long-term neurologic complications.

(Continue . . . .)

 

And in early 2013, in Adding To A Feverish Debate, we looked at another study appearing in the Journal of Pediatrics on another possible (albeit, rare) adverse effect seen in a small number of young children with fever and dehydration at a hospital in Indiana who received treatment with NSAIDs.

 

A accompanying press release from Indiana University that warned the administration of NSAIDs to reduce fever may result in AKI - Acute kidney Injury – in young children.

 

Common anti-fever medications pose kidney injury risk for children

Sick children, especially those with some dehydration from flu or other illnesses, risk significant kidney injury if given drugs such as ibuprofen and naproxen, Indiana University School of Medicine researchers said Friday.

In an article published online Jan. 25 by the Journal of Pediatrics, Jason Misurac, M.D., and colleagues from IU and Butler University reported that nearly 3 percent of cases of pediatric acute kidney injury over a decade could be traced directly to having taken the common nonsteroidal anti-inflammatory drugs, or NSAIDs

(Continue . . .).

 

None of this is designed to demonize a useful, and ubiquitous, class of drugs.  But it is axiomatic that there is no such thing as a 100% safe, 100% benign drug – even those you can buy over the counter.

 

If there is a health benefit to be had, we must weigh that against the (usually very slight) risks of taking the these meds.

 

Although the jury is still out on most of these concerns, and more research is needed, there is an increasing body of evidence that suggests we might want to think twice before automatically reaching for fever reducers in the medicine cabinet.

Adding To A Feverish Debate

Photo Credit –CDC PHIL

#6881

 

Long time readers may recall that during the summer of 2011 we looked at a study (see A Feverish Debate) that questioned the conventional wisdom of using antipyretic meds (ibuprofen, acetaminophen or paracetamol, etc) to reduce influenza-related fever.

 

This contrarian view made headlines when researchers from the Wellington based Medical Research Institute of New Zealand, published a paper (Antipyretic therapy for influenza infection—benefit or harm?) in the New Zealand Medical Journal.

 

You can read the entire paper, but their conclusion read:

 

We conclude that there is an insufficient evidence base to support the use of antipyretics in the treatment of fever from influenza infection.

 

The limited evidence that does exist suggests that the administration of antipyretics may have the potential to increase the severity of influenza illness and the risk of mortality.

 

We suggest that randomised controlled trials of the effect of antipyretics in the treatment of influenza are undertaken as an urgent priority.

 

We are still waiting for results from RCTs to support their concerns, but the idea of letting a fever run its course (at least, up to a point) as part of the body’s natural immune system’s defense isn’t new.

 

In a another story - also from 2011 - the American Academy of Pediatrics (AAP) released a report on the use of antipyretics in children, suggesting that we ought not over-treat fevers.

 

Clinical Report—Fever and Antipyretic Use in Children

Janice E. Sullivan, MD, Henry C. Farrar, MD,

ABSTRACT EXCERPTS

Fever in a child is one of the most common clinical symptoms managed by pediatricians and other health care providers and a frequent cause of parental concern. Many parents administer antipyretics even when there is minimal or no fever, because they are concerned that the child must maintain a “normal” temperature.

 

Fever, however, is not the primary illness but is a physiologic mechanism that has beneficial effects in fighting infection. There is no evidence that fever itself worsens the course of an illness or that it causes long-term neurologic complications.

(Continue . . . .)

 

 

Today, a study appears in the Journal of Pediatrics on another possible (albeit, rare) adverse effect seen in a small number of young children with fever and dehydration at a hospital in Indiana who received treatment with NSAIDs.

 

We’ve a press release from Indiana University that warns the administration of NSAIDs to reduce fever may result in AKI - Acute kidney Injury – in young children.

 

Common anti-fever medications pose kidney injury risk for children

Sick children, especially those with some dehydration from flu or other illnesses, risk significant kidney injury if given drugs such as ibuprofen and naproxen, Indiana University School of Medicine researchers said Friday.

 

In an article published online Jan. 25 by the Journal of Pediatrics, Jason Misurac, M.D., and colleagues from IU and Butler University reported that nearly 3 percent of cases of pediatric acute kidney injury over a decade could be traced directly to having taken the common nonsteroidal anti-inflammatory drugs, or NSAIDs.

 

Although relatively few in terms of percentage of total kidney damage cases, the children with problems associated with NSAIDs included four young patients who needed dialysis, and at least seven who may have suffered permanent kidney damage, the researchers said.

 

"These cases, including some in which patients' kidney function will need to be monitored for years, as well as the cost of treatment, are quite significant, especially when you consider that alternatives are available and acute kidney injury from NSAIDs is avoidable," Dr. Misurac, a fellow in pediatric nephrology, said.

 

Although such drugs have been linked to kidney damage in small, anecdotal reports, the study reported Thursday is believed to be the first large-scale study of the incidence and impact of acute kidney injury caused by NSAIDs.

 

The research team evaluated medical records at Riley Hospital for Children at IU Health in Indianapolis from January 1999 through June 2010 and found 1,015 cases in which patients had been treated for acute kidney injury from any cause.

 

After excluding cases in which the acute kidney injuries could possibly be explained by other factors, such as diseases affecting kidney function, the researchers found 27 cases, or 2.7 percent, in which the only factors were the administration of NSAIDs. In nearly all cases, the NSAIDs were administered before the children were admitted to the hospital. Because many of the 1,015 cases involved multiple potential causes of acute kidney injury, the researchers said the 27 cases are likely an underestimate of the number of cases in which NSAIDs contributed to the kidney damage.

 

Among the researchers' findings:

• Most of the children had been treated with recommended dosages.
• All of the children under the age of 5 needed to undergo dialysis temporarily, were more likely than the older children to be placed in an intensive care unit and needed longer hospital stays.
• The average cost for hospital and kidney specialist fees in the 27 cases was nearly $13,500, and the costs were much higher for younger children. At least $375,000 was spent on the NSAID-associated kidney injury cases at Riley Hospital over the study period, the researchers said, but billing data for other specialists were not available in the database, suggesting that the actual costs were likely much higher.

NSAIDs affect kidney function by restricting blood flow to the blood-filtering components of the kidneys, which suggests the risks from the drugs are greater among children who are dehydrated due to the effects of their illness, such as vomiting or diarrhea, Dr. Misurac said.

 

Fever is normal during an infection and not in itself dangerous, he noted, so "one alternative to NSAIDs would be acetaminophen, but another alternative would be no medication at all, at least for a while, to let the body fight the infection."

 

 

In a somewhat related story, I’ve written about studies that suggest that the concurrent use of antipyretics may inhibit the immune response when receiving vaccines.

 

In fact, it has even been theorized that one of the reasons that the elderly often develop less-than-robust immunity from the flu vaccine may be due to their frequent consumption of NSAIDs.

 

Several past blogs on this phenomenon include:

 

Anti-Inflammatory Meds And Vaccines

Common Pain Relievers May Dampen Vaccination Benefits

A Few Inflammatory Remarks

 

For now the evidence against the use of antipyretics (particularly NSAIDs) for fevers and influenza-like illness is very limited.

 

But these reports do show that - even after decades of use by hundreds of millions of people – our understanding of the effects of many commonly used over-the-counter medications remains less than complete.

A Feverish Debate

 

 

 

# 5687

 

Photo Credit –CDC PHIL

 

A topic I’ve written about several times in the past is back in the news again; the advisability of using antipyretic meds (ibuprofen, acetaminophen or paracetamol, etc) for flu-related fever.

 

The eye-catching headline and lede in yesterday’s New Zealand Herald reads:

 

'Don't use paracetamol for fever'

By Martin Johnston

5:30 AM Monday Jul 11, 2011

A respected scientific group has recommended not using paracetamol and several other drugs to reduce flu-related fever, saying they may increase the risk of death.

(Continue . . . )

 

 

The respected scientific group referenced in the article above is Wellington based Medical Research Institute of New Zealand. And their advice runs contrary to what we usually hear from our doctors, the CDC, and the World Health Organization.

 

Constant readers will recall that last May I wrote (see It Gives You Fever) about about a clinical trial this research group was about begin that would examine the merits and risks of taking antipyretics with influenza.

 

The concern is that when we take fever reducers, we lower the body’s temperature to provide symptomatic relief – but we also create a more favorable environment for the virus to replicate.

 

Essentially trading comfort for circumventing the body’s natural defense mechanism.

 

Last year, in A Hot Topic For Further Research I wrote about new research that suggested (but fell short of proving) that we may be better off carrying a bit of a fever – rather than reaching for the pill bottle -  when we have the flu.

 

And while that isn’t exactly a new idea, the evidence to support it has been limited.

 

The study – again conducted by the Medical Research Institute of New Zealand -  appeared in the Journal of the Royal Society of Medicine (registration required for access) – and provided a retrospective analysis of previous animal (not human) studies on the outcomes of the treatment of bacterial and viral infections with antipyretics.

 

The effect on mortality of antipyretics in the treatment of influenza infection: systematic review and meta-analysis

Sally Eyers, Mark Weatherall, Philippa Shirtcliffe, Kyle Perrin, and Richard Beasley

v.103(10); Oct 1, 2010

 

In a review of the existing literature, researchers at the Medical Research Institute of New Zealand and Capital & Coast District Health Board, identified 8 (non-human animal) studies that met their inclusion criteria.

 

They found that the risk of mortality increased by roughly 33% when antipyretics were used in influenza infected animals.  This risk was observed with aspirin, paracetamol, and diclofenac.

 

As I pointed out at the time, there were a lot of limitations to this study, not the least of which is that research on mice, chickens, and ferrets isn’t always applicable to humans.

 

Hence the need for the clinical trial on humans underway in New Zealand.

 

From the Medical Research Institute’s website, a description of goals of the clinical trial.

 

The effect on mortality of antipyretics in the treatment of influenza

Antipyretics are recommended for the symptomatic treatment of influenza infection.  However there is evidence that fever is a protective physiological response, that treating fever secondary to infections may be harmful and that human tropic influenza viruses are variable temperature-sensitive.

In a systematic review and meta-analysis we have identified that in animal models treatment with antipyretics for influenza infection increases the risk of mortality.  There are no randomised controlled placebo-controlled trials of antipyretic use in influenza infection in humans that reported data on mortality and a paucity of clinical data by which to assess their efficacy.

In response to these findings the MRINZ is now undertaking a placebo-controlled randomised trial of paracetamol use in influenza infection. This study is funded by the Health Research Council of New Zealand.

 

The results of that trial are not yet available, and so while the Medical Research Institute is publicly questioning the value of reducing fevers with influenza, they are not yet calling for health authorities to change their existing stance on the use of antipyretics.

 

They also state that using these meds as a pain reliever for muscle aches and headaches when you have influenza, is a reasonable practice.

 

And to round out this debate, the New Zealand Self Medication Industry Association (who have a vested interest in the sale of these products) has weighed in with the following press release.

 

Tuesday 12 July 2011, 12:13pm

Media release from New Zealand Self-Medication Industry Association

The New Zealand Self-Medication Industry Association (SMI), the industry body representing non-prescription consumer healthcare products, said today it was aware of a recommendation by the Wellington-based Medical Research Institute that antipyretics, such as paracetamol, ibuprofen and aspirin, not be used to reduce flu-related fever.

 

"We have only just received this information and, as the Institute itself said, there was insufficient evidence for the Ministry of Health to change its current position on these products. It's important people do not overreact and stop using antipyretics altogether.

 

Paracetamol and ibuprofen, for example, are well recognized for the relief of pain," commented SMI executive director Tim Roper.

"Fever management guidelines highlight that it is important to treat the patient and not the thermometer - SMI and its members endorse this approach. We are confident that if this approach is used, that these medicines can be used safely.

"Nevertheless, our members welcome the opportunity to work with Medsafe to discuss any matters that may arise, after the Ministry has reviewed the new information."

 

 

Although the jury is still out on all of this (and I’ve not discarded the Tylenol from my medicine cabinet), the American Academy of Pediatrics (AAP) released a report earlier this year on the use of antipyretics in children, suggesting that we ought not over-treat fevers.

 

Clinical Report—Fever and Antipyretic Use in Children

Janice E. Sullivan, MD, Henry C. Farrar, MD,

 

ABSTRACT EXCERPTS

 

Fever in a child is one of the most common clinical symptoms managed by pediatricians and other health care providers and a frequent cause of parental concern. Many parents administer antipyretics even when there is minimal or no fever, because they are concerned that the child must maintain a “normal” temperature.

 

Fever, however, is not the primary illness but is a physiologic mechanism that has beneficial effects in fighting infection. There is no evidence that fever itself worsens the course of an illness or that it causes long-term neurologic complications.

 

Thus, the primary goal of treating the febrile child should be to improve the child's overall comfort rather than focus on the normalization of body temperature.

 

(Continue . . . .)

 

 

And lastly, I would mention that in 2009 I wrote about some of the downsides to taking anti-inflammatory drugs like Aspirin, Tylenol, and Ibuprofen in a blog called  A Few Inflammatory Remarks.

 

It concerned a Lancet study that suggested giving babies acetaminophen (Tylenol) right before or immediately after getting a vaccination may inhibit or lower their immune response.

 

It also discussed several studies from the University of Rochester, that indicate the use of NSAIDs could lower the body’s antibody response.

 

It is axiomatic that there is no such thing as a 100% safe, 100% benign drug – even those you can buy over the counter.  

 

If there is a health benefit to be had, we must weigh that against the (usually very slight) risks of taking the these meds.

 

While the overall risks of taking these drugs are likely exceedingly small, hopefully we’ll soon have research that will help quantify the risks and rewards of using these common fever reducing medicines.

NSAIDs and Prior Heart Attacks

 

 

 

# 5550

 

 

Between over-the-counter sales and prescriptions, NSAIDs (non-steroidal anti-inflammatory drugs) are likely the most commonly consumed class of medication in the world.  Look in just about any medicine cabinet, and you’ll probably find a bottle of aspirin, naproxen, or ibuprofen.

 

While these drugs have long been associated with increased risks of gastrointestinal bleeding, it has only been in recent years that cardiovascular concerns have emerged. 

 

In 2004 Vioxx, a COX-2 inhibitor which had been marketed by Merck as being less likely to cause stomach bleeding, was abruptly pulled from the market after a study showed that prolonged use increased one’s chances of having a heart attack or stroke.

 

Bextra, another COX-2 inhibitor, was also recalled after it was linked to increased cardiovascular accidents and to several rare, but potentially deadly, skin disorders.

 

In 2005, the FDA required the inclusion of a `black box warning’ for prescription NSAIDs and a couple of  years later stiffened the labeling requirements on O-T-C NSAIDs as well.

 

The controversy over their safety has continued, and earlier this year the BMJ published an open access meta-analysis on the safety of NSAIDs.

 

Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis

Abstract

Objective To analyse the available evidence on cardiovascular safety of non-steroidal anti-inflammatory drugs.

Design Network meta-analysis.

 

Data sources Bibliographic databases, conference proceedings, study registers, the Food and Drug Administration website, reference lists of relevant articles, and reports citing relevant articles through the Science Citation Index (last update July 2009). Manufacturers of celecoxib and lumiracoxib provided additional data.

 

Study selection All large scale randomised controlled trials comparing any non-steroidal anti-inflammatory drug with other non-steroidal anti-inflammatory drugs or placebo. Two investigators independently assessed eligibility.

 

Data extraction The primary outcome was myocardial infarction. Secondary outcomes included stroke, death from cardiovascular disease, and death from any cause. Two investigators independently extracted data.

 

Data synthesis 31 trials in 116 429 patients with more than 115 000 patient years of follow-up were included. Patients were allocated to naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, lumiracoxib, or placebo.

 

Compared with placebo, rofecoxib was associated with the highest risk of myocardial infarction (rate ratio 2.12, 95% credibility interval 1.26 to 3.56), followed by lumiracoxib (2.00, 0.71 to 6.21). Ibuprofen was associated with the highest risk of stroke (3.36, 1.00 to 11.6), followed by diclofenac (2.86, 1.09 to 8.36). Etoricoxib (4.07, 1.23 to 15.7) and diclofenac (3.98, 1.48 to 12.7) were associated with the highest risk of cardiovascular death.

Conclusions Although uncertainty remains, little evidence exists to suggest that any of the investigated drugs are safe in cardiovascular terms. Naproxen seemed least harmful. Cardiovascular risk needs to be taken into account when prescribing any non-steroidal anti-inflammatory drug.

 

 

It should be noted that while the risk of developing cardiovascular complications for those on NSAIDs was 2 to 4 times higher than placebo, in absolute terms the number of adverse events detected was fairly low.

 

Of the seven drugs examined, naproxen appeared to pose the least cardiovascular risk.

 

Jump ahead to today, and we’ve another study – this time appearing in the American Heart Association  Journal Circulation – that looks at the risks of NSAID use among those who have previously had a heart attack.

 

Researchers found that even short duration treatment (1 week) with NSAIDs resulted in a 45% increased risk of death or recurrent M.I. in those who had previously had a heart attack.

 

I’ve some excerpts from the abstract below, but follow the link to read it in its entirety.

 

Duration of Treatment With Nonsteroidal Anti-Inflammatory Drugs and Impact on Risk of Death and Recurrent Myocardial Infarction in Patients With Prior Myocardial Infarction

A Nationwide Cohort Study

Anne-Marie Schjerning Olsen, MB; Emil L. Fosbøl, MD, PhD; Jesper Lindhardsen, MD; Fredrik Folke, MD, PhD; Mette Charlot, MD; Christian Selmer, MD; Morten Lamberts, MD; Jonas Bjerring Olesen, MD; Lars Køber, MD, DMSc; Peter R. Hansen, MD, PhD, DMSc; Christian Torp-Pedersen, MD, DMSc Gunnar H. Gislason, MD, PhD

Background — Despite the fact that nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated among patients with established cardiovascular disease, many receive NSAID treatment for a short period of time. However, little is known about the association between NSAID treatment duration and risk of cardiovascular disease. We therefore studied the duration of NSAID treatment and cardiovascular risk in a nationwide cohort of patients with prior myocardial infarction (MI).

<SNIP>

Conclusions— Even short-term treatment with most NSAIDs was associated with increased risk of death and recurrent MI in patients with prior MI. Neither short- nor long-term treatment with NSAIDs is advised in this population, and any NSAID use should be limited from a cardiovascular safety point of view.

 

The authors write that there were some limitations to this study, most notably:

 

The main limitation of the study is inherent to the observational design. There is a lack of information about important clinical parameters such as blood pressure, body mass index, smoking habits, lipid levels, and left ventricular ejection fraction. Therefore, the effect of unmeasured confounders cannot be excluded.

 

While this study looked at the safety of NSAID use among those who have already had a heart attack, more study is needed to determine the overall cardiovascular safety of this class of medications.

 

The authors conclude by saying:

 

Further studies, preferably randomized clinical studies, are warranted to establish the cardiovascular safety of NSAIDs, but given the additional evidence from randomized trials and other observational studies of selective COX-2 inhibitors and nonselective NSAIDs, the accumulating evidence suggests that we must limit NSAID use to the absolute minimum in patients with established cardiovascular disease.

 

The bottom line is, if you have a history of heart problems and wish to take NSAIDs (even those available over-the-counter), you need to talk to your doctor about the risks.

 

For everyone else, it is important to remember that no drug is 100% safe or benign – even those available O-T-C .

 

That doesn’t mean we shouldn’t use them, but it does mean we should weigh their risks against their benefits, before we take them.

A Hot Topic For Further Research

 

 

 

# 5055

 

 

Look into just about any modern medicine cabinet and you are likely to find the workhorse of over-the-counter medications – antipyretics; fever reducers, that also reduce pain and/or inflammation.

 

Aspirin, paracetamol (acetaminophen), and ibuprofen are often the first (and sometimes only) medicine we reach for when we have the flu.  

 

Today we have some new research that suggests (but falls far short of proving) that we may be better off carrying a bit of a fever – rather than reaching for the pill bottle -  when we have the flu. 

 

And while that isn’t exactly a new idea, the evidence to support it has been limited.

 

It makes sense, of course.  

 

A fever is the body’s way of combating an infection.  And we know human adapted flu viruses replicate in a narrow temperature range, and that replication is inhibited by fever.

 

If we reduce the fever, we are (theoretically, anyway) undermining our body’s own protective immune response. 

 

And that in turn could increase the amount of time we remain ill, and shed the flu virus.

 

First the study in the Journal of the Royal Society of Medicine (registration required for access) – which is a retrospective analysis of previous animal (not human) studies on the outcomes of the treatment of bacterial and viral infections with antipyretics.

 

 

The effect on mortality of antipyretics in the treatment of influenza infection: systematic review and meta-analysis

Sally Eyers, Mark Weatherall, Philippa Shirtcliffe, Kyle Perrin, and Richard Beasley

v.103(10); Oct 1, 2010

In a review of the existing literature, researchers at the Medical Research Institute of New Zealand and Capital & Coast District Health Board, identified 8 (non-human animal) studies that met their inclusion criteria.

 

They found that the risk of mortality increased by roughly 33% when antipyretics were used in influenza infected animals.  This risk was observed with aspirin, paracetamol, and diclofenac.

Abstract (Excerpt)

Conclusion

In animal models, treatment with antipyretics for influenza infection increases the risk of mortality. There are no randomized placebo-controlled trials of antipyretic use in influenza infection in humans that reported data on mortality and a paucity of clinical data by which to assess their efficacy. We suggest that randomized placebo-controlled trials of antipyretic use in human influenza infection are urgently required, and that these are sufficiently powered to investigate a potential effect on mortality.

 

 

There were a lot of limitations to this study, not the least of which is that research on mice, chickens, and ferrets isn’t always applicable to humans.

 

Particularly since mice (used in many of these studies) can exhibit a fall in body temperature when infected with the influenza virus (Behavioral thermoregulation in mice inoculated with influenza virus), which could skew some of these results.

 

But these findings certainly do invite further study, particularly considering how often use of antipyretics are recommended in the treatment of influenza.

 

In a somewhat related story, over the past couple of years I’ve written about studies that suggest the administration of antipyretics may inhibit the immune response from vaccines.

 

In fact, it has even been theorized that one of the reasons that the elderly often develop less-than-robust immunity from the flu vaccine may be due to their frequent consumption of NSAIDs.

 

Several past blogs on this phenomenon include:

 

Anti-Inflammatory Meds And Vaccines

Common Pain Relievers May Dampen Vaccination Benefits

A Few Inflammatory Remarks

 

 

None of this is offered as medical advice, of course.  For that, I would refer you to your healthcare provider and to the recommendations of your public health departments. 

 

For now, the evidence against the human use of antipyretics (and NSAIDs) in these situations is faint (at best). And so I’m not about to weed out my medicine cabinet over this.  

 

Not yet, anyway.

 

But these reports do illustrate that the complex physiological effects of many over-the-counter medicines – even those used for decades by hundreds of millions of people - remain incompletely understood.

 

A little humility-inspiring lack of certitude with which to start your week.

Anti-Inflammatory Meds And Vaccines

 

 

# 4111

 

I’ve not read the study referenced in the article below, but this is something we’ve discussed on several occasions in the past. 

 

That the use of NSAIDs, and other anti-inflammatory OTC (over-the-counter) medications, could reduce the effectiveness of vaccinations.

 

In October, in A Few Inflammatory Remarks, I discussed the Lancet admonition not to give babies Tylenol to curb vaccine side effects.

 

Last month, in Common Pain Relievers May Dampen Vaccination Benefits I wrote about an ongoing study at the University of Rochester Medical Center  on this very subject.

 

Today’s announcement, regarding animal studies conducted at the University of Missouri, appears to at least partially validate some of these earlier studies.

 

First this press release, then a brief revisiting of some of the other evidence.

 

 

Aspirin, Tylenol May Decrease Effectiveness of Vaccines

Wednesday, December 02, 2009 :: Staff infoZine

Mizzou scientists discover aspirin and Tylenol block enzymes that could inhibit vaccines

Columbia, MO - infoZine - With flu season in full swing and the threat of H1N1 looming, demand for vaccines is at an all-time high. Although those vaccines are expected to be effective, University of Missouri researchers have found further evidence that some over-the-counter drugs, such as aspirin and Tylenol, that inhibit certain enzymes could impact the effectiveness of vaccines.

 

“If you’re taking aspirin regularly, which many people do for cardiovascular treatment, or acetaminophen (Tylenol) for pain and fever and get a flu shot, there is a good chance that you won’t have a good antibody response,” said Charles Brown, associate professor of veterinary pathobiology.

(Continue . . . )

 

 

Although the full impact of adults taking NSAIDs on the immune response from vaccination isn’t known, I confess that I avoided taking NSAIDs for a couple of days after I got my flu shot last month, simply out of an abundance of caution.

This isn’t a medical recommendation, it is simply what I did. You should always discuss any medical decisions with your personal medical care provider.

 

The study which prompted my decision, appeared in The Journal of Immunology, 2006, 177: 7811-7819, is:

 

Cyclooxygenase-2 Inhibition Attenuates Antibody Responses against Human Papillomavirus-Like Particles

Elizabeth P. Ryan*, Christine M. Malboeuf, Matthew Bernard, Robert C. Rose, and Richard P. Phipps 

 

 

(EXCERPT)

 

The widespread use of nonsteroidal anti-inflammatory drugs and Cox-2-selective inhibitory drugs may therefore reduce vaccine efficacy, especially when vaccines are poorly immunogenic or the target population is poorly responsive to immunization.

A little less complex is this summary which appeared in April of 2005 on the University of Rochester Medical Center’s website.

 

Scientists Raise Red Flag Over Some Painkillers and Immunizations

Scientists Raise Red Flag Over Some Painkillers and Immunizations

April 05, 2005

Over-the-counter painkillers such as nonsteroidal anti-inflammatory drugs like ibuprofen, and the newer Cox-2 selective drugs such as Celebrex or Bextra, may reduce the body’s ability to make antibodies, which are crucial for proper function of the immune system, University of Rochester scientists report in the Journal of Immunology.

Common Pain Relievers May Dampen Vaccination Benefits

 

 

# 3943

 

 

This is something we’ve discussed before, but since millions of people will be taking the H1N1 vaccine in the coming weeks and months, it is probably worth repeating.

There are studies that suggest taking common pain relievers such as Tylenol, Ibuprofen, and aspirin around the time of receiving a vaccination might lessen the vaccine’s effectiveness.

Notice the word `suggest’.  This is more theoretical than proven.

 

But we have more than one research study backing up the idea.  I wrote at length about this concept several weeks ago in A Few Inflammatory Remarks.

 

Today, from University of Rochester Medical Center where much of the research on this concept has been done over the past few years, we get this press release outlining the concerns.

 

 

Common pain relievers may dilute power of flu shots

With flu vaccination season in full swing, research from the University of Rochester Medical Center cautions that use of many common pain killers – Advil, Tylenol, aspirin – at the time of injection may blunt the effect of the shot and have a negative effect on the immune system.

 

Richard P. Phipps, Ph.D., professor of Environmental Medicine, Microbiology and Immunology, and of Pediatrics, has been studying this issue for years and recently presented his latest findings to an international conference on inflammatory diseases. (http://bioactivelipidsconf.wayne.edu/)

 

"What we've been saying all along, and continue to stress, is that it's probably not a good idea to take common, over-the-counter pain relievers for minor discomfort associated with vaccination," Phipps said. "We have studied this question using virus particles, live virus, and different kinds of pain relievers, in human blood samples and in mice -- and all of our research shows that pain relievers interfere with the effect of the vaccine."

 

A study by researchers in the Czech Republic reported similar findings in the Oct. 17, 2009, edition of The Lancet. They found that giving acetaminophen, the active ingredient in Tylenol, to infants weakens the immune response to vaccines.

 

Phipps' research has tested whether production of antibodies using a cell culture system was blunted by over-the-counter pain relievers. He found that a variety of pain relievers – even though Tylenol and Advil have different ingredients -- seemed to dilute the production of necessary antibodies to protect against illness.

 

Many of the pain relievers in question are classified as NSAIDs or nonsteroidal anti-inflammatory drugs, which act in part by blocking the cyclooxygenase-2 (cox-2) enzyme. Blocking the cox-2 enzyme is not a good idea in the context of vaccination, however, because the cox-2 enzyme is necessary for the optimal production of B-lymphocytes.

 

Therefore, when a person takes a medication to reduce pain and fever, he or she might also inadvertently reduce the ability of B cells to make antibodies.

 

(Continue . . .)

 

A Few Inflammatory Remarks

 

 

# 3841

 

 

Today in the British Medical Journal, The Lancet, we get a study that suggests that giving babies acetaminophen (Tylenol) right before or immediately after getting a vaccination may inhibit or lower their immune response.

 

A mild fever is a common response to many vaccinations, and is a normal part of the inflammatory response.  Some parents, on the advice of their pediatricians, have routinely given acetaminophen to their children to avoid this reaction.

 

This report in the mainstream press from the AP.   A hat tip to Treyfish on FluTrackers for putting me on the scent of this story.

 

Giving babies Tylenol may blunt vaccine effects

Finding knocks common advice for parents looking to curb fever after shots

updated 6:30 p.m. ET, Thurs., Oct . 15, 2009

 

Giving babies Tylenol to prevent fever when they get childhood vaccinations may backfire and make the shots a little less effective, surprising new research suggests.

 

It is the first major study to tie reduced immunity to the use of fever-lowering medicines. Although the effect was small and the vast majority of kids still got enough protection from vaccines, the results make "a compelling case" against routinely giving Tylenol right after vaccination, say doctors from the U.S. Centers for Disease Control and Prevention.

 

(Continue . . . )

 

The study’s summary is available online. Below are a few excerpts, but follow the link to read the whole thing. Note that paracetamol is the UK name for Tylenol.

 

doi:10.1016/S0140-6736(09)61208-3 

Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials

Summary

Background

Although fever is part of the normal inflammatory process after immunisation, prophylactic antipyretic drugs are sometimes recommended to allay concerns of high fever and febrile convulsion. We assessed the effect of prophylactic administration of paracetamol at vaccination on infant febrile reaction rates and vaccine responses.

<SNIP>

Interpretation

Although febrile reactions significantly decreased, prophylactic administration of antipyretic drugs at the time of vaccination should not be routinely recommended since antibody responses to several vaccine antigens were reduced.

 

 

This isn’t the first indication that certain types of medications can interfere with a vaccine’s effectiveness.   A study several years ago indicated that NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) could lower the body’s antibody response.

 

Tylenol, while an antipyretic, is not an NSAID, which makes the above study all the more interesting.

 

Although the full impact of adults taking NSAIDs on the immune response from vaccination isn’t known, I confess that I avoided taking NSAIDs for a couple of days after I got my flu shot last month, simply out of an abundance of caution. 

 

This isn’t a medical recommendation, it is simply what I did. You should always discuss any medical decisions with your personal medical care provider.

 

 

The study which prompted my decision, appeared in The Journal of Immunology, 2006, 177: 7811-7819, is:

 

Cyclooxygenase-2 Inhibition Attenuates Antibody Responses against Human Papillomavirus-Like Particles

Elizabeth P. Ryan*, Christine M. Malboeuf, Matthew Bernard, Robert C. Rose, and Richard P. Phipps  

Vaccination to generate protective humoral immunity against infectious disease is becoming increasingly important due to emerging strains of virus, poorly immunogenic vaccines, and the threat of bioterrorism.

 

We demonstrate that cyclooxygenase-2 (Cox-2) is crucial for optimal Ab responses to a model vaccine, human papillomavirus type 16 virus-like particles (HPV 16 VLPs). Cox-2-deficient mice produce 70% less IgG, 50% fewer Ab-secreting cells, and 10-fold less neutralizing Ab to HPV 16 VLP vaccination compared with wild-type mice.

 

The reduction in Ab production by Cox-2–/– mice was partially due to a decrease in class switching. SC-58125, a structural analog of the Cox-2-selective inhibitor Celebrex reduced by 70% human memory B cell differentiation to HPV 16 VLP IgG-secreting cells.

 

The widespread use of nonsteroidal anti-inflammatory drugs and Cox-2-selective inhibitory drugs may therefore reduce vaccine efficacy, especially when vaccines are poorly immunogenic or the target population is poorly responsive to immunization.

 

A little less complex is this summary which appeared in April of 2005 on the University of Rochester Medical Center’s website.

 

 

Scientists Raise Red Flag Over Some Painkillers and Immunizations

Scientists Raise Red Flag Over Some Painkillers and Immunizations

April 05, 2005

Over-the-counter painkillers such as nonsteroidal anti-inflammatory drugs like ibuprofen, and the newer Cox-2 selective drugs such as Celebrex or Bextra, may reduce the body’s ability to make antibodies, which are crucial for proper function of the immune system, University of Rochester scientists report in the Journal of Immunology.

 

Although it is well known that these types of medicines clamp down on inflammation by altering the function of many different types of cells, this is the first time scientists have shown a direct connection between the popular painkillers and B lymphocytes, or white cells known as B cells. The UR group showed that human B cells highly express the Cox-2 enzyme, and that blocking the enzyme activity is what reduces the B cells’ ability to make antibodies.

 

The Cox-2 connection to B cells has both positive and negative implications for the immune system, according to corresponding author Richard P. Phipps, Ph.D., professor of Environmental Medicine, and Microbiology and Immunology, at the UR Medical Center. Lead author on the paper is graduate student Elizabeth Ryan.

 

The primary role of B cells is to make the antibodies that lock onto infectious bugs and fight them off. B cells also serve as the immune system’s memory by recognizing and eliminating germs that have previously tried to infect us.

 

So, for example, when a person is vaccinated the goal is to promote an immune response by making antibodies to protect against a certain illness. But if the vaccinated patient takes a Cox-2 selective inhibitor, or an NSAID such as Advil or aspirin, to ease pain at the injection site, the drug could reduce the amount of antibody produced by the vaccine. In the military, where soldiers receive multiple vaccines, the problem could be greater, Phipps said.

(Continue . . . )

 

And again from the University of Rochester, we get a more recent study which seems to reaffirm earlier suspicions.

 

Ibuprofen and other widely used non-steroidal anti-inflammatory drugs inhibit antibody production in human cells

Simona Bancos^a, Matthew P. Bernard^a, David J. Topham^b and Richard P. Phipps^a 

 

Available online 5 April 2009.

Abstract

The widely used non-steroidal anti-inflammatory drugs (NSAIDs) function mainly through inhibition of cyclooxygenases 1 and 2 (Cox-1 and Cox-2). Unlike Cox-1, Cox-2 is considered an inducible and pro-inflammatory enzyme.

 

We previously reported that Cox-2 is upregulated in activated human B lymphocytes and using Cox-2 selective inhibitors that Cox-2 is required for optimal antibody synthesis. It is not known whether commonly used non-prescription and non-Cox-2 selective drugs also influence antibody synthesis. Herein, we tested a variety of Cox-1/Cox-2 non-selective NSAIDs, namely ibuprofen, tylenol, aspirin and naproxen and report that they blunt IgM and IgG synthesis in stimulated human peripheral blood mononuclear cells (PBMC).

 

Ibuprofen had its most profound effects in inhibiting human PBMCs and purified B lymphocyte IgM and IgG synthesis when administered in the first few days after activation. As shown by viability assays, ibuprofen did not kill B cells.

 

The implications of this research are that the use of widely available NSAIDs after infection or vaccination may lower host defense. This may be especially true for the elderly who respond poorly to vaccines and heavily use NSAIDs.

 

 

One of the problems with vaccines, and with any medicine for that matter, is that other drugs we take and sometimes even the foods we eat, can interfere with (or exacerbate) their effects.

 

We know the immune response to vaccines can vary widely from one person to the next.  While there are likely many factors at work (including individual differences in our immune systems), the co-administration of other medicines can’t be ignored.

 

More research is obviously needed, but knowing about some of these interactions now can allow us to make better choices in the interim.