influenza

Women are more vulnerable to infections.

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Public-health officials discount role of sex in people’s response to flu and other infections.

Sabra Klein came to the annual meeting of the Society for the Study of Reproduction this week armed with a message that might seem obvious to scientists who obsess over sex: men and women are different. But it is a fact often overlooked by health researchers, says Klein, an immunologist at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland.

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Her research on influenza viruses in mice, presented at the meeting in Montreal, Canada, helps explain why women are more susceptible to death and disease from infectious pathogens — and the reason is intimately linked with reproduction. “She’s one of the people that really gets the bigger picture as far as why do we see these patterns,” says Marlene Zuk, an evolutionary biologist at the University of Minnesota, Twin Cities, in St. Paul.

Women generally suffer more severe flu symptoms than men, for example, despite the fact that they tend to have fewer viruses during an infection. To Klein, this suggests that women quickly mount a substantial immune-system attack to clear infections — and suffer the consequences of the inflammatory responses that flood their systems. “This is where females run into trouble,” Klein says.

She and her collaborators have found this disparity in mice infected with flu viruses1. But when the researchers castrated the males and removed the ovaries from the females, the difference disappeared as the males became more sensitive to infection.

But testes are not simply protective. Klein found that giving the neutered females the female sex hormones oestrogen and progesterone actually protected them from disease.

For females, infections appear to throw these cycling sex hormones out of whack. They elongate the oestrus cycle in non-neutered female mice — stretching the part of the cycle associated with the lowest amounts of oestrogen from 4-5 days to 8-9 days.

Researchers have long known that immunological cells have receptors for sex hormones, and that autoimmune disease strikes women more frequently than men. Nevertheless, Klein says that her work should have implications for current public-health practices.

Women, who are often less likely than men to get vaccinated against flu, should be encouraged to do so, she says. And researchers may want to examine whether hormone-replacement therapies and contraceptive drugs have unintended — possibly positive — effects on some types of infectious disease.

But most importantly, Klein says, medical studies should take sex differences into account. Many epidemiological studies do not break down results by sex, a practice that she has found can obscure crucial trends2. And clinical trials have traditionally worked around the female oestrus cycle, because it can interfere with results.

To Zuk, Klein has provided a voice of reason here. “Why is it viewed as interference when you have interaction with the endocrine system or some other aspect of the reproductive system?” she asks.

“The age-old answer we get is that funding is tight and if we’re going to compare sexes, we’ll have to double the groups,” says Klein. But on the basis of her work, she says, “I don’t know that that’s actually true”.

Source Nature

 

Sixty Percent of Doctors Refuse to Get Flu Shots. Why?

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According to a 2008 survey, only about 4 out of 10 healthcare professionals chose to get a flu shot last year. The next time a physician recommends a treatment to you, especially if it has potentially hazardous side effects (as most do in modern medicine), you might ask them if they would do the same if they were the patient, and if not, why not. If you are fortunate enough to have an open relationship with your provider — as we all should — he or she may just take off the “doctor” hat and tell you person to person their own true opinion, rather than what the HMO, drug company, or medical board often tutor them to say.

Our own wellness, and that of our family’s, is something each of us should be personally responsible for. It is up to us to proactively learn how to best maintain our health and avoid disease. Part of this plan should include a relationship with a healthcare professional that knows us and knows what course is most beneficial for our specific needs. It is best to work with someone who shares your own healthcare philosophy — hopefully one that focuses on prevention through the use of nutrition and other wellness-related lifestyle choices.

Sixty Percent of Doctors Refuse to Get Flu Shots

by Mike Adams, the Health Ranger, December 9, 2008

If flu shots are so good for you, then why do sixty percent of doctors and nurses refuse to get them? ABC News is reporting that only forty percent of health care professionals opted to be vaccinated against the flu last year.

It’s yet another case of health professionals telling patients to do one thing while they do something entirely different themselves. For example, according to surveys published earlier this year, most oncologists would never undergo chemotherapy.

Many doctors take vitamins and nutritional supplements, but they won’t tell their patients to do the same because state medical boards have made it illegal for doctors to recommend nutritional therapies.

Thus, much of what medical professionals tell patients stands in contradiction to what they actually believe is best for their health. Flu shots have become the mad cry of quackery in modern medicine, which believes that the human immune system is useless to prevent infectious disease and must be artificially hijacked by invasive medical procedures (a shot) in order to function correctly.

Interestingly, related research just announced today reveals that half a flu shot produces the same results as a full flu shot. But they didn’t test the “no flu shot but extra vitamin D” option, which would have been ever better.

Flu shots are pure quackery combined with clever hucksterism. And if you don’t believe me, just check the medical records of the doctors themselves: Most of them aren’t getting flu shots in the first place. Doctors aren’t stupid people. If they’re not getting flu shots, that tells you probably they think it’s a waste of time.

Sources: oawhealth.com

What does Tamiflu do, and how will we know?

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Jonathan Nguyen-Van-Tam, virologist and researcher from the University of Nottingham, told a group of triallists and virologists last week “we must remember why we’re here—because of the controversies. The clinical world doesn’t believe that Tamiflu works. We should assess whether the regulatory approval/product insert for Tamiflu is valid.”

That group, the MUltiparty Group for Advice on Science (MUGAS) was at a workshop in Brussels on 18 June organised by the European Scientific Working group on Influenza (ESWI) and supported by an unrestricted grant from Roche. Led by several of the original Tamiflu regulatory triallists, the workshop heard plenty of evidence to challenge current claims about Tamiflu’s effects. MUGAS decided to plan and conduct individual participant data (IPD) meta-analyses of the randomised trial data—and observational data. That’s quite a remarkable turnaround, given the strength of claims made by some of the same people over the past decade.

BMJ readers will already be very familiar with growing concerns about oseltamivir’s effectiveness. Earlier this year Professor Harlan Krumholz and co-authors concluded in an editorial in the BMJ that “Despite government claims, we should acknowledge the uncertainty surrounding oseltamivir’s effectiveness and the gaps in publicly available evidence. On the basis of the available data, at best the drug shortens symptoms by about a day when used within the first two days of symptoms, but it has no effect on hospital admissions. In addition, trial data from which to draw conclusions about complications and transmission of flu are lacking.”

WHO made particularly firm claims about oseltamivir in August 2009 during the swine flu (H1N1) pandemic. WHO then stated that, “The guidelines represent the consensus reached by an international panel of experts who reviewed all available studies on the safety and effectiveness of these drugs…Evidence reviewed by the panel indicates that oseltamivir, when properly prescribed, can significantly reduce the risk of pneumonia (a leading cause of death for both pandemic and seasonal influenza) and the need for hospitalization.”

That expert panel advising WHO was anonymous: all its members had signed a confidentiality agreement. But at least one member was identified later as Professor Arnold Monto of the University of Michigan, who coauthored several trials of neuraminidase inhibitors back in the 1990s. The same Professor Monto is one of the four convenors of MUGAS, along with Professor Ab Osterhaus (of Erasmus MC University in Rotterdam, a scientific advisor to Roche, another oseltamivir triallist), Professor Menno de Jong (of Academic Medical Center Amsterdam, virologist and researcher) and Professor Rich Whitley (of University of Alabama at Birmingham, professor of pediatric infectious diseases and an adviser on flu to the Obama administration).

Barry Clinch, Principal Clinical Scientist at F. Hoffmann-La Roche, presented at the MUGAS workshop an overview of all studies in the company’s oseltamivir research programme. His slides showed that in all, 18,928 patients had taken part in trials, observational studies of treatment, and studies of prophylaxis; around 11,500 of them treated with oral oseltamivir. Randomised controlled trials (RCTs) had included 4799 adults and 1368 children and, along with some open label studies, a total of 8078 patients had taken part. All but one of the 12 RCTs took place in the late 1990s. Roche’s lab researchers had also done experimental flu studies and clinical pharmacology studies.

Clinch confirmed that investigators were told to always report admissions to hospital during the Roche trials, but warned that “caution should be exercised in interpreting results on hospitalisation.” This is because there were such low event rates: for example in trial WV15671 just 1 of 201 participants was hospitalised. The main intention to treat analyses in the 12 Roche RCTs (for all patients enrolled with flu-like illness and who had at least 1 dose of trial medication) failed to find statistically significant evidence that hospitalisation rates were reduced by oseltamivir when compared against placebo. For the ITTI population (the subset with flu confirmed by culture or >4 fold rise in antibody titre) the overall P value was 0.06 but this was grossly underpowered.

Presenting the key oseltamivir trials that yielded data on flu complications, Clinch explained that a standard case report form was used to collected data on “Secondary illness.” “We didn’t ask physicians to actively look for complications,” he said. “They simply reported them if they thought patients had, for example, sinusitis, otitis media, bronchitis, pneumonia or other chest infections.” Clinicians could also say if patients needed antibiotics or X rays—thereby implying that there might be some secondary illness—but there was no requirement to confirm diagnoses without anything more than a clinical diagnosis. “To be honest, we weren’t that stringent at the time,” acknowledged Clinch. (And, of course, at that time Roche was testing oseltamivir primarily as another antiviral for seasonal flu, not as a lifesaver in a pandemic.) Only two trial protocols required reporting of clinically diagnosed complications (coded as bronchitis, pneumonia, lower respiratory tract complication, or antibiotic prescription occurring >48h after start of treatment with oseltamivir) as a formal secondary endpoint: those among older and at risk participants. Statistical analyses of these outcomes were exploratory, said Clinch.

The ensuing questions and discussion among the MUGAS review board members (some of whom co-authored some of the trials in question) confirmed that “secondary illness” was indeed only a clinical diagnosis, that in most of the trials its reporting was ad hoc, and that Roche does not know the extent of any missing data. Decisions to give antibiotics were made for nonspecified clinical reasons, and, as someone pointed out, antibiotic usage rates will have varied a lot from site to site because of geographical variations in prescribing behaviour.

However, some of the MUGAS virologists said we know from Roche’s original observational studies and from subsequent case series from the H1N1 pandemic that oseltamivir does reduce complications. Do we? Not yet, although Professor Van Tam’s group has conducted a systematic review and IPD meta-analysis of published andunpublished observational study data during the H1N1 pandemic that will be submitted soon for publication. This study was sponsored by Roche but Professor Van Tam said the data agreement gives Roche no access to the data. The authors plan, however, to share the data with other investigators on request.

When asked what proportion of the original Roche oseltamivir research programme had results in the public domain, Clinch said “about 90% in one form or another.” Virologist Fred Hayden, co-author of several Roche trials, asked: “the contentious area is the 8-10 unpublished trials done some time ago. Are there any plans to publish those?” Clinch replied “it’s a good question…we’d like MUGAS to discuss that. Roche has no objection to that.” Professor Osterhaus said that MUGAS wants to analyse the IPD from those trials and to publish the resulting papers in peer reviewed journals.

So, of course, does the Cochrane Acute Respiratory Infections Group, which has been struggling for years to get the unpublished trial data from Roche. That data release has now begun, and the Cochrane group is poring over the partly redacted Clinical Study Reports right now.

So it’s from famine to feast, with two different groups working towards meta-analyses of the unpublished patient-level data on the effects of oseltamivir in flu. Will they come to the same conclusions?

Source: BMJ

Double-Dose Tamiflu No Better Than Standard Dose for Severe Flu.

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A double dose of oseltamivir (Tamiflu) offers no advantage over single-dose therapy among children and adults with severe influenza, according to a BMJ study.

Some 325 patients (three-quarters children) hospitalized with severe flu in Southeast Asia were randomized to either double-dose oseltamivir (150 mg twice daily, or pediatric equivalent) or standard treatment (75 mg twice daily, or equivalent). Detected viruses included various subtypes of seasonal influenza, 2009 pandemic flu, and avian flu.

The proportion of patients with no detectable viral RNA on day 5 did not differ between the groups (roughly 70%). In addition, the groups did not differ with respect to clinical failure or in-hospital mortality. Findings generally were consistent regardless of patient age or flu type.

The authors say their results “do not support routine use” of double-dose therapy in severe flu. Editorialists agree, adding that the results “could help to preserve oseltamivir stocks during a future pandemic.”

Source: BMJ

H7N9 Seems to Readily Develop Resistance to Neuraminidase Inhibitors.

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The novel influenza A virus H7N9 has shown a “concerning” ability to develop resistance to neuraminidase inhibitors such as Tamiflu (oseltamivir) and Relenza (zanamivir), according to a Lancet study.

Researchers studied 14 patients admitted to a Shanghai hospital with H7N9 influenza. In tracking patients’ viral loads, they noted that two showed persistently high loads after starting neuraminidase inhibitors. Both had also received steroid treatment. A mutation in the virus’s neuraminidase gene was associated with persistent high viral loads and poor clinical outcome.

The researchers wonder what, if any, role the steroid therapy had in the emergence of resistance. They advise early treatment with neuraminidase inhibitors.

Meanwhile, China has reported no new H7N9 cases for 2 weeks. The case count now stands at 131, with 32 deaths.

Source: Lancet

FDA Approves Egg-Free Flu Vaccine for Adults.

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The FDA has approved a new influenza vaccine (marketed as Flucelvax) for adults 18 and older. Flucelvax is the first in the U.S. to be produced using cultured mammalian cells instead of fertilized chicken eggs, and according to the manufacturer, can be made much more quickly than traditional influenza vaccines, which can take months.

In a randomized study of adults aged 18 to 49, Flucelvax was 83.8% effective in preventing influenza compared with placebo. In adults 49 and older, Flucelvax was comparable to the egg-based vaccine Agriflu. Side effects were similar to those seen with other flu vaccines and included fatigue, headache, and pain at the injection site.

Source:  FDA news

Treatment of Influenza with Intravenous Peramivir

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Intravenous peramivir given within 48 hours of influenza symptom onset was well tolerated, reduced fever, and shortened time to resumption of usual activities.

To date, influenza treatments have consisted only of oral (oseltamivir) or topical (zanamivir) neuraminidase inhibitor formulations, but an intravenous option is also being investigated —the selective neuraminidase inhibitor peramivir. This sialic acid analogue is characterized by a strong affinity for influenza neuraminidase and a low off rate. Researchers recently reported the results of a manufacturer-sponsored, phase II, randomized controlled trial investigating the effect of a single dose of intravenous peramivir on the course of community-acquired influenza in previously healthy individuals during the 2007–2008 influenza season in Japan.

Within 48 hours after onset of typical influenza symptoms, 99 study participants received a 300-mg dose of peramivir, 97 received a 600-mg dose, and 100 received placebo. The clinical effectiveness of peramivir became evident within the first 24 hours after treatment initiation, and, by 36 hours, both the 300-mg and the 600-mg dose groups had significantly higher proportions of afebrile patients than the placebo group. Both peramivir groups also had a significantly shorter time to resumption of usual activities (median duration, 126 hours in the 300-mg group, 127 hours in the 600-mg group, and 169 hours in the placebo group) and to reduction of viral shedding; the three groups had similar viral titers at baseline, but by day 3, the proportion of virus-positive patients was significantly lower in the 300-mg group (37%) and the 600-mg group (26%) than in the placebo group (52%). Tolerability of peramivir was excellent.

Comment: Peramivir appears to be a promising new antiviral in the armamentarium against influenza and has already received FDA emergency-use authorization for the treatment of severe pandemic H1N1 influenza. Its intravenous formulation makes it particularly attractive for treating severely ill patients, but dose-finding trials have not yet been completed in this population. Animal studies indicate that multiple doses of peramivir for up to 15 days might be appropriate for such patients.

— Thomas Glück, MD

Published in Journal Watch Infectious Diseases December 1, 2010