Immunoglobulin as a treatment for pandemic H1N1 influenza

In the paper I discussed yesterday, (Gordon et al. 2010), there is a brief discussion of the effects of treating pregnant women with severe H1N1 with intravenous pooled immunoglobulin:

Although IgG2 deficiency appears to be associated with H1N1 infection severity, it remains uncertain whether administration of immunoglobulin to patients who are IgG deficient is likely to be therapeutically beneficial. We administered pooled immunoglobulin to some of our patients with severe H1N1 infection who had IgG2 deficiency, but our observations were uncontrolled.

The first author of this paper, Dr. Claire Gordon, was less constrained in her opinion of this therapy in her discussions with the media. From Metro, February 5, 2010:

Well, a 28-year-old trainee may have made the breakthrough medical researchers – and H1N1 sufferers – have been searching for.

Dr Claire Gordon found a particular antibody which helps fight the virus.

The ‘eureka moment’ came when the budding infectious disease specialist treated a 22-year-old pregnant woman who was desperately ill.

‘We were doing our best to try and pull her through,’ said Dr Gordon.

‘We were asking ourselves if there was something we were missing.’

She got the go-ahead to perform an expensive and rarely used immune system blood test – and noticed her patient had very low levels of one particular antibody, named IgG2.

She confirmed the pattern in other swine flu patients – the sicker they were, the lower their IgG2 levels.

When injected with the protein, they began to get better immediately – including the young mother-to-be. Dr Gordon, who works at the Austin hospital in Melbourne, Australia, said: ‘It was very exciting. It gives us something else to work on and think about.’

These results are preliminary. However, given the many people who died in the US and other Northern Hemisphere countries, it is surprising that this therapy was apparently not tried in severe cases, especially in pregnant women. Could the authors have withheld this information from public health authorities pending publication of their paper?

No, they told someone.

They told the WHO.

From stuff.co.nz, February 4, 2010:

The discovery also suggests a potential new treatment for a swine flu infection, as people low in protein could have their levels topped up from donated blood.

The World Health Organisation was alerted to the finding last year, and a paper detailing the research is published this month in the journal Clinical Infectious Diseases.

So, the WHO knew last year. Did they tell the CDC? On the CDC webpage providing H1N1 information for physicians, the only treatment mentioned is antivirals. Why weren’t American doctors told about this option? How many people’s lives would have been saved if they had been told?

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Streptococcus pneumoniae and pandemic H1N1 severity – the data from Argentina

The influenza virus can kill directly. But it can also lower your immune defenses and open you up to bacterial infection. A study that examines the role of bacterial co-infections in the severity of pandemic H1N1 has recently been published in PLoS One.

This study was motivated by the apparently high case fatality rate reported in Argentina. From the paper:

Based on a study in the community of La Gloria, Mexico, where the virus was first detected early in 2009, and worldwide surveillance data and mathematical modeling, the CFR was estimated to be 0.6%. The first case in Argentina was reported on May 17, 2009; by July 16, 2009, just two months later, the number of cases in Argentina totaled 3056, with 137 deaths, representing a computed CFR of 4.5%. Although we could not exclude the possibility that this elevated CFR reflected underreporting of milder infections, the alternative, a bona fide increase due to differences at the level of host or pathogen, might have global implications.

Although some patient risk factors have been associated with a worse outcome, these were not at higher levels in Argentina than other countries, so this could not account for the apparently higher case fatality rates.

To determine whether severe cases had been infected with different strains than mild cases, the complete genomes of 26 viral samples collected from patients with a wide range of symptoms and outcomes were sequenced. No obvious differences were observed.

This left the possibility of bacterial co-infections. 199 samples from people infected with H1N1 were examined for the presence of a wide variety of bacteria and viruses. Many co-infections were found. Pathogens identified included:

…S. pneumoniae (n = 62); H. influenzae (n = 104); human respiratory syncytial virus (RSV) A (n = 11) and B (n = 1); human rhinovirus (HRV) A (n = 1) and B (n = 4); human coronavirus (HCoV) −229 (n = 1) and -OC43 (n = 2); K. pneumoniae (n = 2); A. baumannii (n = 2); S. marcescens (n = 1); and S. aureus (n = 35) and MRSA (n = 6)…

However, only one bacteria was associated with severe cases – S. pneumonia. Further, the effect of this bacteria on outcome was primarily observed in people aged 6 to 55, normally a low risk age group for severe influenza, but one which is at much higher risk with pandemic H1N1 than seasonal flu. This result is not entirely unexpected. As the authors point out:

…recent postmortem analyses indicated lower respiratory tract infection in 22 out of 77 lethal 2009 H1N1pdm cases in the United States (29%); S. pneumoniae was implicated in 10 of these cases.

From a practical standpoint, what do these results mean? Some might be tempted to conclude that treatment with antibiotics would be more effective than treatment with antivirals. However, when the authors examined this, they found the opposite:

Data concerning antiviral and antibiotic therapy were available for 120 subjects. Risk of severe disease was diminished in subjects who received only oseltamivir. Of 96 subjects receiving oseltamivir alone, 10 (10.4%) had severe disease. In contrast, 13 of 14 patients (92.9%) who received antibiotics without antiviral medication had severe disease (p<0.0001).

This is consistent with many other reports suggesting that treatment with Tamiflu (oseltamivir) is especially effective in limiting severity and preventing death from pandemic H1N1. The authors don’t speculate about why Tamiflu alone is more effective than antibiotic treatment alone, even though a bacterial agent appears to be correlated with severe disease. Perhaps the damage done by the virus gives bacteria such unusual access to lung tissue that antibiotics are not as effective as under normal circumstances. In any case, the results from this study clearly support the continued prescription of Tamiflu to limit damage from both the virus directly, and, perhaps, indirect damage from opportunistic bacteria.

Vaccines against Streptococcus pneumoniae are available. Whether they would reduce severe or fatal cases of pandemic H1N1 has not been demonstrated. However, the current paper provides further rationale for recommending such vaccination and study of its possible effectiveness.

References

Palaciaos et al. (2009) Streptococcus pneumoniae Coinfection Is Correlated with the Severity of H1N1 Pandemic Influenza. PLoS One.

CDC (2009) Bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza A (H1N1) – United States, May-August 2009. MMWR Morb Mortal Wkly Rep 58: 1071–1074.

Pregnancy and the pandemic

Pregnancy puts a lot of stress on a woman’s physiology. So it is not surprising that pregnant women are at increased risk from pandemic flu. One study reported that 25% of pregnant women who became infected with pandemic influenza in 1918 died (Mortimer, 2006). In the flu pandemic of 1958, pregnant women made up half of all the deaths among women of reproductive age in Minnesota (Freeman and Barno, 1959). We don’t know what the case fatality rate for pregnant women is from the current pandemic because we don’t know how many pregnant women have been infected. However, we do know that the risk of death for pregnant women is much higher than average. Although pregnant women make up only 1% of the US population, they have contributed to 6% of the deaths. In poorer countries, the death rate of pregnant women may be even higher.

The risks to unborn young are also substantial. Pregnant women infected with pandemic H1N1 appear to be at increased risk of spontaneous abortion. In the pandemic of 1958, there is some evidence of increased incidence of birth defects. There may be long term effects on the fetus as well. A recent study suggested that people who had been exposed to the 1918 pandemic virus while in the womb were 20% more likely to get heart disease (Mazumder et al. 2009).

The best way for pregnant women to stay safe is to avoid infection with the virus. This can be done by avoiding contact with infected people and by getting vaccinated. Although thimerosol has not been shown to cause any harm, thimerosol-free vaccine is available for pregnant women. Pregnant women should receive inactivated virus, the “shot”, not the attenuated virus “Flumist”. Because of their increased risk, pregnant women are at the top of the priority list for receiving vaccine. They may contact their doctor to find out where and when they can receive vaccine.

If a pregnant woman becomes ill, it is important that she receive rapid treatment for the best outcome. The antiviral drug Tamiflu has been approved for use by pregnant women. It is most likely to work if given within 48 hours after symptoms begin but may be effective after that. If a pregnant woman’s lungs are damaged, she may need to be put on a ventilator. Because some pregnant women do not survive this experience, there have been a number of babies who were delivered by Caesarean section while their mothers were in medically induced comas.

You can find a list of pregnant women who have died of pandemic flu at PFI_Forum on this thread (started and organsied by VA_MOM): US Deaths of Pregnant Women. Warning, this is very difficult reading. You can find video reports about pregnancy and pandemic flu at the PFI_Main Pregnancy page. Some of these can also be difficult to watch.

References

Local Government Board, 48th Annual Report 1918–1919. Supplement containing the report of the medical department. London: Her Majesty’s Stationery Office; 1919. p. 16.

Mazumder et al. (2009) Lingering prenatal effects of the 1918 influenza pandemic on cardiovascular disease. J. Dev. Origins Health Dis.

Jamieson et al. (2009) H1N1 2009 influenza virus infection during pregnancy in the USA. Lancet. 374:451-8

Mortimer (2006) Influenza-related Death Rates for Pregnant Women. Emerg Infect Dis.

Freeman and Barno (1959) Deaths from Asian influenza associated with pregnancy. Am. J. Obstet. Gynecol. 78:1172-1175.

2009 H1N1 Influenza Vaccine and Pregnant Women: Information for Healthcare Providers. CDC, November 2, 2009.

Preparing for mass casualties

Counting of pandemic flu cases indicates that the number of Americans becoming infected is now increasing at an exponential rate. This has started within the last two weeks. Because deaths usually lag infections by several weeks, we won’t see most of the deaths from this rise in infections until November, although we are already seeing indications of an increase of severely ill people and deaths.

We don’t know if the current exponential increase in pandemic cases in the US will continue or if it will be blunted by vaccine. However, given the minimal amount of vaccine that has been deployed thus far, it seems likely that we will see many more infected people in the immediate future. As many others have suggested, the ability of our health care system to handle the surge in severely ill people is extremely limited. The natural consequence of this is that life-saving treatments will need to be rationed. The natural consequence of that is planned killings.

From the New York Times, October 24, 2009:

Federal officials say the possibility that America’s already crowded intensive care units would be overwhelmed in the coming weeks by flu patients is small but they remain vigilant.

The triage plans have attracted little publicity. New York, for example, released its draft guidelines in 2007, offered a 45-day comment period, and has made no changes since. The Health Department made 90 pages of public comments public this week only after receiving a request under the state’s public records laws.

Mary Buckley-Davis, a respiratory therapist with 30 years experience, wrote to officials in 2007 that “there will be rioting in the streets” if hospitals begin disconnecting ventilators. “There won’t be enough public relations spin or appropriate media coverage in the world” to calm the family of a patient “terminally weaned” from a ventilator, she said.

State and federal officials defend formal rationing as the last in a series of steps that would be taken to stretch scarce resources and provide the best outcome for the public.

The suggestion by federal officials that the possibility that  ICUs overwhelmed by flu patients is “small” is ridiculous. There are already indications that some ICUs are becoming overwhelmed. ECMO, which results in a much better outcome than ventilators, is already being rationed. People who would benefit from it  are already being denied access.

But it can get worse.

Yesterday, President Obama declared a National Emergency with respect to the H1N1 pandemic. Partisans eagerly engaged in a distracting war of words about what this means. It does *not* mean martial law. But it does mean that many rights that people take for granted when receiving medical care may be taken away during the pandemic.

From President Obama’s Proclamation:

…I hereby declare that the Secretary may exercise the authority under section 1135 of the SSA to temporarily waive or modify certain requirements of the Medicare, Medicaid, and State Children’s Health Insurance programs and of the Health Insurance Portability and Accountability Act Privacy Rule throughout the duration of the public health emergency declared in response to the 2009 H1N1 influenza pandemic.

What does section 1135 of the Social Security Act specifiy? Here are some excerpts:

Secretarial Authority.—To the extent necessary to accomplish the purpose specified in subsection (a), the Secretary is authorized, subject to the provisions of this section, to temporarily waive or modify the application of, with respect to health care items and services furnished by a health care provider (or classes of health care providers) in any emergency area (or portion of such an area) during any portion of an emergency period, the requirements of titles XVIII, XIX, or XXI, or any regulation thereunder (and the requirements of this title other than this section, and regulations thereunder, insofar as they relate to such titles), pertaining to—

(1)(A) conditions of participation or other certification requirements for an individual health care provider or types of providers,

(B) program participation and similar requirements for an individual health care provider or types of providers, and

(C) pre-approval requirements;

(2) requirements that physicians and other health care professionals be licensed in the State in which they provide such services, if they have equivalent licensing in another State and are not affirmatively excluded from practice in that State or in any State a part of which is included in the emergency area;

(3) actions under section 1867 (relating to examination and treatment for emergency medical conditions and women in labor) for—

(A) a transfer of an individual who has not been stabilized in violation of subsection (c) of such section if the transfer arises out of the circumstances of the emergency;

(B) the direction or relocation of an individual to receive medical screening in an alternative location—

The contingency plans for a severe pandemic include transferring flu patients from hospitals to “alternative locations”. These may include tent hospitals, hotels or convention centers. I believe the National Emergency proclamation was intended to lay the legal groundwork for directing and relocating flu patients to such treatment centers.

The thing is, severely ill flu patients aren’t going to find ECMO or even ventilators at these “alternative locations”. They will be lucky if they receive morphine to ease their dying.

And all of this, because the government chose not to close the schools.

For patients with severe flu symptoms, life is spelled E.C.M.O.

The rule of threes defines how long we can live without four necessities:

  1. Three minutes without air
  2. Three hours without shelter in a harsh environment
  3. Three days without water
  4. Three weeks without food

Influenza can make number 1 on that list a challenge.

Air is 78% Nitrogen and 21% Oxygen. We need that Oxygen to live. We take it into our bodies every time we inhale. It travels to our lungs and is then transferred to blood. Red blood cells carry the oxygen to our cells which require it for essential functions.

What happens if our lungs are no longer able to transfer oxygen to our blood? We are in immediate trouble.

The new H1N1 virus can damage our lungs in different ways. In some cases, using a mechanical ventilator to help the patient breathe has been necessary. However, even this step has not been sufficient in some severely ill patients.

In this case, a special technique has been used to deliver Oxygen directly to the patients blood: extracorporeal membrane oxygenation (ECMO). The machine used to deliver ECMO was initially developed for premature babies whose lungs may not have developed sufficiently when they were delivered. However, ECMO has been adapted to be used in adults in extreme cases. And, unfortunately, with the new H1N1 virus, there are lots of extreme cases.

From  JAMA, October 12, 2009:

The spread of the virus [H1N1] to Australia and New Zealand was also associated with a large number of patients admitted to intensive care units (ICUs) across both countries. A proportion of these patients presented with, or developed, severe acute respiratory distress syndrome (ARDS). In some severe cases, extracorporeal membrane oxygenation (ECMO) was commenced for the treatment of refactory hypoxemia, hypercapnia, or both, which occurred despite mechanical ventilation and rescue ARDS therapies.

There have been both anecdotal reports and explicit studies of the effectiveness of ECMO in the treatment of respiratory disorders associated with pandemic flu.

From Medical News Today, September 16, 2009:

Of those referred for consideration of ECMO, 63 percent survived six months without disability compared to 47 percent of those who were assigned to conventional management.

Although it is good to know that survival in severe cases can be improved from 47 to 63% with ECMO, there’s a problem. Lots of people are likely to need ECMO, soon. And we probably do not have enough of the necessary machines and trained personnel to treat everyone who would benefit.

So, once again, we will need to play Lifeboat in the ICU.

Reference

Extracorporeal Membrane Oxygenation for 2009 Influenza A(H1N1) Acute Respiratory Distress Syndrome. Journal of the American Medical Association, October 12, 2009.


Dying for Tamiflu

Yesterday, I wrote about Chloe Lindsey, a 14 year old girl from Fort Worth, Texas who died of the new H1N1 virus. One of the reasons she died was because schools were kept open, despite the fact that it was known that this would result in rapid spread of the virus among children and inevitable deaths.

But this is not the only reason she died.

There are two medicines, Tamiflu and Relenza, which, if taken early enough, greatly reduce the ability of flu viruses to replicate. Treatment with Tamiflu can prevent death from the new H1N1. If you can get it in time.

Chloe Lindsey did not.

From WFAA.com September 29, 2009

Chloe’s symptoms began with a fever Wednesday. By Friday, Osborne said a visit with a Fort Worth doctor confirmed her 14-year-old daughter had the flu, possibly the swine flu.

But, Chloe went home from the doctor’s visit without Tamiflu, the medication that can ease the flu’s severity.

“They were advised by the CDC to not give Tamiflu to people that were normally healthy,” Osborne said. “So, they wouldn’t treat her.”

When Chloe’s fever got worse Friday night, Osborne called the after hours phone line at he doctor’s office and was told to keep watching her.

“Saturday she felt really bad,” she said. “She couldn’t eat or drink or take the medicine.”

It only got worse from there.

“She took a deep breath, it wasn’t very deep, and I could hear crackling in there,” Osborne said. “I said, ‘That’s it; I’m going to the hospital.”

By sunrise Sunday, Chloe was at the hospital.

“Everybody just looked at her and just started running around like crazy,” Osborne said.

By sunset, Chloe was gone.

“I was scared for them to put her to sleep because I was afraid she would never wake up and she didn’t, she didn’t,” Osborne said through tears.

She said she doesn’t blame the doctor, but does question the guidelines that originally ruled out Tamiflu for her daughter.

Dr. Donald Murphey, the director of Pediatric Infectious Diseases at Cook Children’s Medical Center, said it is an unfortunate case of short supply.

“We want to do everything we can for every single kid every day,” he said. “It’s very difficult when resources are stretched and we have to try to balance what’s available.”

Why are supplies low?

Is it because we didn’t know a flu pandemic would occur?

No, we knew.

Is it because we didn’t know Tamiflu would be helpful?

No, we knew.

We don’t have enough because the government decided not to buy enough.

I wrote this blog, back in April 2007:

What’s on the Menu for Treatment of H5N1? Not Tamiflu if You Live in the Florida.

… if Tamiflu is the only antiviral on the pandemic flu treatment menu, why isn’t the US stockpiling sufficient supplies for its population? Perhaps this particular menu item is just too expensive. Tamiflu costs about $110 per course of treatment, retail. The US government is prepared to provide 44 million doses to the states for free and to subsidize the purchase of another 33 million doses of Tamiflu. The government will pick up 25% of the cost (CIDRAP).

Of course, if the States choose not to buy any Tamiflu, then their citizens are out of luck. For example, the residents of the sunshine state better hope an H5N1 pandemic decides to skip Florida (Florida Ignores Federal Help For Flu, The Ledger, March 23, 2007).

Last week the federal government sent a letter to Florida’s Office of Public Health Emergency Preparedness, warning it faced a Friday deadline to purchase $36.7-million worth of discounted antiviral drugs to develop a state stockpile.

Gov. Charlie Crist has put that money in his Department of Health budget request and considers it essential, said Health Department spokeswoman Wendy Riemann.

But the chairman of the House committee in charge of that budget said the five-year shelf life of the drugs leaves him skeptical. “It just doesn’t rank as one of my priorities,” Rep. Aaron Bean, R-Fernandina Beach said last week.

I wonder if having enough Tamiflu is one of Representative Bean’s priorities today?

In Texas, and throughout the country, some Tamiflu is available. But it is only given out under certain conditions. Conditions which prevented Chloe Lindsey from receiving this life-saving medicine. This tragedy was not necessary. Uncaring and short-sighted politicians created this disaster.

What should a concerned parent do?

Here is Chloe’s mother’s advice.

From CBS News.com, September 30, 2009:

Through tears, Tammy said, “The reason we decided to do this (the interview) and what we think is most important for people to know, even in our time of pain, is that I knew Chloe was sick, and even thought the doctor said she was gonna be OK, and they didn’t give her the medicine (Tamiflu, which the Osbornes say wasn’t administered until Chloe had taken a severe turn for the worse), I knew she was really sick. And I would have been more demanding in her treatment, and been more of an advocate for her than I was.

“And I think it’s important to let people know that, even though we’re taught all our lives to trust our doctors, and I do trust my doctor, that nobody knows my child better than me, and that, when I knew something wasn’t right, I should have gone and made somebody do something.”

Parents, trust your instincts. No-one cares more about your children than you do.

Got Tamiflu?

One of the striking features of the list of countries with many cases of the new H1N1 virus is that a few of them have few or no deaths. How can this be? One possibility is that they simply have decided not to report. However, in some cases, it may be that they are treating their patients more quickly with the most effective drug available: Tamiflu.

Japan is noted for its aggressive treatment of seasonal influenza with Tamiflu. Some would say, too aggressive. However, during the current pandemic, the tendency of Japanese doctors to recognise influenza symptoms and write prescriptions for Tamiflu with little prompting may have greatly benefited the Japanese people. Although Japan has recently reported some deaths, their case fatality rate for the new flu is still very low – .033%.

The effectiveness of the Japanese policy of easy Tamiflu prescription was recently remarked upon by Dr. Sugaya of Keiyu Hospital. From Japan Times, August 22, 2009:

“Compared to other countries, Japan has considerably fewer seriously ill patients, and that is because they give out Tamiflu and Relenza,” he said.

While in other countries these drugs are not widely used, partly due to the cost, Japan has a stockpile large enough to treat 60 million people, and doctors are quick to administer them to virtually all H1N1 patients, he said.

Tamiflu and Relenza are more reliable methods of treating the new flu than a vaccine, which will not be ready by fall and in too short supply to give to all those at risk, Sugaya said.

[snip]

Despite the late and inadequate supply of the vaccine, Sugaya remains confident that Japan will be ready to fight the infections come fall.

“As long as proper measures are taken and Tamiflu or Relenza are administered, Japan is fully equipped to deal with the wave,” he said.

Yes, Japan does seem to be relatively well-positioned to deal with the next wave of pandemic flu, at least as long as the virus remains susceptible to Tamiflu.

But what about other countries? Well, the ones with lots of Tamiflu will probably do OK.

But what about the ones that don’t?

Think 1918.