Testing. 1 2 3 Testing. Have I been infected with swine flu?

Lots of things make us sick. Right now, many of us are concerned about getting infected with pandemic flu. How do we know if this has happened? There are four basic approaches.

1. Rapid Tests.

These tests probe viral proteins for influenza signals.

Advantages:

• Fast. You can have an answer within 30 minutes.
• Easy to use. Very little training is necessary.
• Cheap. About $20.
• Can tell you if you have Flu A or Flu B.

Disadvantages:

• Can’t tell you which subtype of influenza A you have, ie, whether you have seasonal flu or pandemic flu.
• Fails to detect pandemic flu infection 50% of the time.

Given that the vast majority of Flu A cases are currently due to pandemic flu, someone with a positive result with a Flu A rapid test is almost certainly infected with pandemic flu. However, even if you have a negative result, you may be infected with pandemic flu. A negative result on a Flu A test is not a good reason to deny a patient antiviral treatment.

2. Real-time PCR (RT-PCR).

This assay uses nucleotide probes to examine the genetic material of the virus.

Advantages

• Specific. This method can be used to determine subtype, ie, whether you have been infected with seasonal or pandemic flu.
• Sensitive. This method can detect very small amounts of virus and has been specifically designed to identify pandemic flu infections.

Disadvantages

• Takes 24-72 hours to produce a result in most cases.
• Requires a high level of skill to set up the assay.
• Can be expensive if done manually.
• Can give false negatives if the virus develops mutations in the same regions the probes are directed towards.

RT-PCR is the most practical way to determine whether someone actually has pandemic flu. The first three disadvantages can be greatly mitigated if automated, high throughput protocols are put into place. Although this requires a substantial initial expense and considerable expertise to set up, once in place, large numbers of samples can be processed quickly and cheaply with little need for human involvement.

3. Seroprevalence studies.

This methods involves taking blood samples from individuals and determining whether they have made antibodies to the flu.

Advantages

• Can be performed after a person has been infected.
• Can be done on large numbers of people relatively cheaply.

Disadvantage

• Usually not clinically useful.

The primary utility of this approach is to determine how many people were infected in a particular outbreak. This type of study is essential when determining case fatality rate.

4. Unbiased sequencing.

With this approach, a sample is taken from a patient and everything within that sample is sequenced.

Advantages

• Highest level of sensitivity. No infections will be missed.
• Can detect novel mutations. Mutations that might cause other methods to fail will not affect this technology.
• Can detect novel viruses. Even if an entirely new virus starts to circulate, this method will identify it.

Disadvantages

• Very expensive, although the cost is dropping.
• Requires a very high level of skill to interpret the results. Relatively few laboratories have this capability.

Given the advantages and disadvantages of the different approaches, what is the most sensible strategy to utilise these methods?

Given the high failure rate for Rapid Tests, there is little justification for their use. Decisions on how to treat a patient should initially be guided by clinical judgment rather than this test.

High throughput RT-PCR should be used to test as many patients as possible. This is necessary to determine how many people are actually sick with pandemic flu as opposed to the many other infectious diseases which can cause similar symptoms. This information is critical to determine if the case fatality rate due to pandemic flu is starting to increase or if vaccines are failing.

Seroprevalence studies should be done (in fact, should already have been done) to calculate case fatality rates in different locations. Telephone surveys of influenza-like illness are not acceptable substitutes.

Unbiased sequencing should be reserved for cases of severe flu like illness but which are negative with RT-PCR assays. This would alert us to new strains or viruses.

The technology and expertise exists to put a sensible, 21st century diagnostic strategy in place that would guide correct treatment and inform policy-making. Unfortunately, the CDC seems to lack the necessary knowledge base and/or will to implement an up-to-date detection system.

Multiple infections with pandemic H1N1, implications for vaccine

At PFI_Forum, there have been numerous reports from members that report having been ill with swine flu, twice. However, without testing, it is not possible to be sure that both infections were from the new H1N1 virus. Today, a physician in West Virginia details her own two laboratory-confirmed infections with pandemic flu.

From the Charleston Daily Mail, November 5, 2009 (hat-tip Joseph_Roehl_kiwiamerican and Clawdia):

A Cross Lanes pediatrician says she came down with swine flu twice in two months, and she’s among the medical professionals who are puzzled by the occurrence.

Dr. Debra Parsons, a pediatrician at Kid Care West in Cross Lanes, said both she and her son came down with identical flu-like symptoms in August.

Figuring they had the same disease, Parsons swabbed herself and sent the specimen off to a lab. She tested positive for Influenza A, which includes several strains of the flu.

Health officials say that in this region more than 99 percent of people who have been testing positive for Influenza A are later confirmed to have swine flu.

Parsons said that was the case with her family; a more specific follow-up “sub-typing” test at the state lab confirmed she had H1N1.

Parsons and her son recovered from the symptoms but in October they struck again and were much worse, she said. Both had body aches, fever, chills, wheezing, and shortness of breath.

This time Parsons swabbed both herself and her son, and both tests came back positive for Influenza A. She said she pushed for further testing to determine the strain, and the lab ran an immunofluorescence test on the specimens. They again tested positive for H1N1, she said.

Parsons’ second swab was sent to the state lab Wednesday for even further testing and results should be returned in a couple of days or sent to the Centers for Disease Control for follow-up tests, she said.

When the initial test came back positive again, Parsons said she also contacted the CDC to see if it’s possible for someone to contact the swine flu twice.

She said officials at the CDC told her Saturday that it is possible.

But in public statements issued in late October the CDC said people who have had H1N1 don’t need to get the vaccine because they can’t contract the virus again.

So which is it? Does exposure to the virus protect against future infections or not? One would think that such exposure would be at least as good as a vaccine. This is just one report. But if there were large numbers of people who are becoming infected twice with the new H1N1, it would suggest that there is more than one strain of the virus circulating. And if that is the case, then vaccine may not protect against the new version of the virus. Surely the CDC would tell us if this was happening. That is what Dr. Rahul Gupta, director of the Kanawha-Charleston Health Department believes.

Gupta said nothing right now would lead him to believe the virus has mutated.

“There is absolutely no evidence to assert that,” he said. “In fact, (Center for Disease Control director) Dr. Tom Frieden has issued a press release…and he states that the virus is genetically stable. I believe him.”

Given Dr. Frieden’s history of burying bad news, Dr. Gupta might want to reconsider his blind faith in Dr. Frieden’s pronouncements.

malachi at PFI_Forum posted a snippet of an email she received from someone who claims to have information about changes in the pandemic virus:

I talked with **** this morning and he had a conference call with the CDC yesterday…….
They think that the virus is starting to mutate and therefore making the vaccine useless…..

Although I regard this as a rumor, it would be worth asking Dr. Frieden if such a conference call did occur and whether there is any evidence whatsoever suggesting either that exposure to the virus itself or the vaccine is proving ineffective against some strains of the new H1N1.

Just a suggestion.

A message from Dr. Tom Frieden

Worried about bleeding lungs? Bleeding orifices? We, at the CDC, have got you covered. When the bleeding starts, just call our toll free number and one of our professional “watchers” will be dispatched to your home. Within minutes, s/he will be watching you bleed, with the greatest attention and interest. The watching will be intense and focused. We will not stop watching you bleed until, well, there is no more blood left to bleed. Of course, we won’t actually do anything to stop the bleeding. The Tamiflu will be gone by then, there won’t be any vents or ECMO, and vaccine won’t be available for you until Spring Break (by which time you likely won’t need it).

The CDC. Nobody beats us at watching Americans die. We’re just that good.

If you aren’t dead, please answer the phone

Director Frieden of the CDC likes phone surveys. He relies on them for determining how many people have been infected with the new H1N1 despite clear-cut evidence that phone surveys are worthless for this purpose. The number infected is the denominator used when calculating the case fatality rate. The numerator is the number dead. Turns out, Dr. Frieden has found a way to calculate this number, also from phone surveys:

From the CDC Weekly 2009 H1N1 Flu Media Briefing, November 3, 2009:

Joanne Silberner: Thanks.  You mentioned before the idea that half the people with asthma once they’ve gotten sick have not come in.  Where does that number come from?

Tom Frieden: this is from telephone survey day that that we have.  We call randomly households.  We identify a subset of people who have had influenza-like illness in the previous 30 days.  Then for the subset we ask a series of questions about what conditions they have and what they did to seek care.  We don’t know what the baseline is for that.  We haven’t asked that survey, that question on that widespread basis before.  We know we would like more people to seek care if they have an underlying condition with flulike illness.

Joanne Silberner: From the survey you don’t have a sense of what happened to them because you didn’t seek care.  You know that from other information.

Tom Frieden: They were still answering the phone and answering our questions a few weeks later.  In that regard, we think nothing terrible happened.

In other words, because they were able to answer the phone, they weren’t dead. Really? Did they all answer the phone? Every single one? Beause that would be really incredible. No-one went on vacation. No-one went out to dinner. No-one went to a movie. They all just sat home every night waiting for the CDC to call them again. Dr. Frieden must have found the most cooperative bunch of phone survey respondents, ever.

There are lots and lots of problems with phone surveys. Anyone who follows politics knows that such surveys can yield widely varying results. Just ask Matt Drudge. Anyone who uses phone surveys should know what they can and cannot be used for.  I’d really like Nate Silver’s opinion on this, but I’m pretty sure that phone surveys are not a valid way to determine how many people have died of pandemic flu.

But then, I’m not an epidemiologist, so what do I know.

Situation in Eastern Europe – November 2, 2009

Reports of infections and deaths from the Ukraine which appear to be due to pandemic flu continue to increase. The exact number of H1N1 cases, hospitalisations and deaths is unclear. However, one recent report suggests that at least 15,000 have been hospitalised, 170 are in ICUs and 7o are dead. There are unconfirmed rumors of many more dead of a disease so rapid and severe that local doctors believe that it is pneumonic plague. Rapid destruction of the lungs led doctors back in 1918 to initially confuse Spanish Influenza with pneumonic plague. It is possible that the severe pathology being observed in Ukraine today may be misleading physicians into believing that the disease they are observing cannot possibly be flu. Whatever is actually happening in Ukraine, the authorities there appear to be taking it seriously. School closures, bans on public gatherings and movement restrictions have all been enacted to stem the spread of infections.

In Romania, an outbreak occurred in a hotel in Sinaia. 40 people were reported infected. The infected guests and staff, all adults, were transported to a hospital where they are being treated. The hotel has been closed. All hospitals in Romania are now under quarantine. Ukrainian officials in some oblasts have requested that borders with Romania be closed.

Slovakia has closed some borders with Ukraine.

Poland has sent medical supplies to Ukraine and requested that the European Union provide additional aid to Ukraine. Poland is considering closing its border with Ukraine.

Only 59 pandemic flu cases and no deaths have been reported by official sources in Belarus. However, there have been unconfirmed reports by bloggers that the Belarusian government is hiding pandemic deaths.

Bulgaria and Turkey have both reported recent increases in numbers of cases and deaths.

The situation in Russia is unclear. Previous reports suggested that the Russian authorities were hiding cases and deaths. However, 10 deaths have now been reported in Russia.

Although Russia has some capacity to produce its own vaccine, most countries in Eastern Europe do not. Although Ukraine has asked for, and received, some Tamiflu and surgical masks, this is unlikely to cover more than a small portion of the need. We may soon see the true lethality of the new H1N1.

Pandemic Update – November 1, 2009

There have been over 6,500 reported deaths due the new H1N1 virus.

There have been over 1,400 reported deaths in the United States. President Obama has declared a National Emergency with respect to the 2009 H1N1 influenza pandemic. The federal government has released the last of its stockpiled supplies of the children’s version of Tamiflu to the States. Some vaccine has been delivered and administered, but the number of people who wish to be vaccinated greatly exceeds the available supply. This is likely to continue to be true for weeks, if not months. Flu activity continues to be erratic, but appears to be increasing in the densely populated Northeast. New Mexico, Utah and Arizona have the highest incidences of death. Approximately 1 in every 100,000 citizens in those States have already died of pandemic flu.

In Europe, Ukraine has taken draconian steps to stop the rapid spread of influenza in the western oblasts (provinces). Although the number dead is relatively small as compared to the total population, there are reports of thousands in the hospitals. Since deaths lag hospitalisations by several weeks, there may be many more dead soon. In the United Kingdom, ICUs are once again filling up. In Ireland, some patients have been sent to the ECMO Center at Karolinska in Sweden. ECMO is an advanced technology for people with severe respiratory disorders.

In Asia, few cases are being reported in most countries. This is more likely attributable to a desire to hide the extent of the disease, than a true decrease in its spread. The pace of deaths has slowed dramatically in India. However, concern about a more lethal version of the virus has again been expressed due to a new and more severe pathology. South Korea will raise its alert to the highest level next week due to the rapidly increasing numbers of infections and deaths.

There are reports people who exhibit all the symptoms of the new H1N1 but who test negative for it in many countries, including the US, India and Ukraine. Many of these patients have died. Either the reagents developed to detect the H1N1 virus are starting to fail, perhaps due to mutations, or there is an unknown, highly infectious disease capable of causing severe symptoms and death circulating throughout the world.

Multiplying errors

There are two ways to estimate of how many people have been infected with pandemic influenza:

1. Actually measure how many people have been infected by examining their blood for evidence of antibodies against the virus (seroprevalence study).

or

2. Use a fantasy “multiplier” to derive a number from irrelevant datasets.

In a recent study, the CDC decided to go with option number 2.

From: Reed et al. (2009) Estimates of the Prevalence of  Pandemic (H1N1) 2009, United States, April–July 2009. Emerging Infectious Diseases.

To estimate the total number of cases of pandemic (H1N1) 2009, we built a probabilistic multiplier model that adjusts the count of laboratory-confirmed cases for each of the following steps: medical care seeking (A), specimen collection (B), submission of specimens for confirmation (C), laboratory detection of pandemic (H1N1) 2009 (D), and reporting of confirmed cases (E) (Figure).

[snip]

Using this approach, between April and July 2009, we estimate that the median multiplier of reported to estimated cases was 79; that is, every reported case of pandemic (H1N1) 2009 may represent 79 total cases, with a 90% probability range of 47–148, for a median estimate of 3.0 million (range 1.8–5.7 million) symptomatic cases of pandemic (H1N1) 2009 in the United States.

Wow, 79! What data did they rely on to get this magic number? Why, phone surveys of influenza-like illness of course!

From the carefully hidden “Technical” Appendex

In May 2009, after the identification of pandemic (H1N1) 2009 in the United States, a random-digit dialed telephone survey sampled similarly to the BRFSS [Behavioral Risk Factor Surveillance Survey] was conducted using only the ILI module from the 2007 BRFSS and some limited demographic information. Respondents were adults >18 years of age living in the same 9 states where the ILI module was included during the 2007 BRFSS plus New York State. Participants were asked the same set of questions included in the ILI module during the 2007 BRFSS, including ILI in the past month, care- seeking behavior, receipt of antiviral treatment, and influenza vaccination. Participants were also asked the same questions about all members of their household. A total of 1,788 adults responded during a 3-week period.

There is really only one problem with ILI phone surveys – they are worthless. As I wrote in a previous blog: Estimates of case fatality rates based on influenza-like illness are wrong. This is because many viruses, and even allergies, result in flu-like symptoms.

So a “probabilistic multiplier model” based on worthless data is also worthless. Garbage in, garbage out.

Why doesn’t the CDC simply do a seroprevalence study? They have the reagents. I think they don’t do it for the same reason that they are withholding data from CBS about the real number of cases that occurred in the Spring, they don’t want the public to know how lethal this virus is. The “probabilistic model” vastly overestimates the number of people who were infected because it likely includes many people who were not infected with pandemic H1N1. This results in a larger denominator when calculating case fatality rate. A seroprevalence study would likely show a much lower number of people infected in the Spring. This would naturally result in a much higher case fatality rate than the CDC is publicly promoting. I say publicly because they have internal data suggesting a very high case fatality rate.

Relying on the CDC for case fatality rate information may be dangerous to your health.

Situation in Ukraine – October 30, 2009

There have been recent reports of deaths from the pandemic H1N1 virus in the Ukraine, in the western oblast of Ternopil. The number of confirmed dead varies from 1 to 11 to 30. However, even if 30 are confirmed, this would indicate an incidence of death of .06 per 100,000, a relatively low number compared to many countries. For example, the incidence of death in the US is approximately 0.4 per 100,000. Yet, the Ukranian government has taken extraordinary steps to control the outbreak. These include:

• Closing all schools for 3 weeks
• Banning all public gatherings (movies, concerts, etc.) for 3 weeks
• Restricting movement into and out of the affected region

School closures and limitation of public gatherings were imposed in Mexico and Argentina at the height of their outbreaks. However, internal movement restrictions were never implemented even though the number dead was much higher in these two countries than in Ukraine now.

So, why the dramatic steps in a country with a relatively small outbreak and relatively few deaths compared to other countries? Some possibilities:

1. The government is panicking. They never expected any deaths, had no plan and are over-reacting.
2. The number of deaths is much higher than has been admitted by the government.
3. It is the pattern rather than the number of deaths that is raising the alarm.

Ukraine is in desperate financial trouble. The measures taken today are likely to further damage an already sick economy. It seems unlikely that the politicians would suddenly panick and destroy their economy for a relatively few deaths. So, possibility 1 seems unlikely.

Many governments have been hiding deaths. Option 2 is possible.

There have been reports of health care workers who have died and rapid spread of the virus within a relatively small area. This could mean a more virulent strain of virus. So, option 3 is also possible.

The methods announced today by the Ukrainian government are old school techniques for limiting the spread of disease. They can be effective when rigorously applied. Without large amounts of Tamiflu or vaccine, which the government does not have but is pleading for, social distancing is the only tool they have to limit the spread of the virus. They are wise to use it.

Another report of more virulent pandemic virus in India

Back in September, I wrote a blog that included a report from India suggesting that mutations in the H1N1 pandemic virus were causing rapid death. Now, a new report from India, also suggests that the virus is becoming more virulent.

From DNA, October 28, 2009

Pathologists at the state-run Sassoon General Hospital in Pune took tissue samples from the bodies of the deceased to study the effect of the virus that attacks the respiratory tract. “Our doctors have concluded that the virus has undergone some genomic changes,” said Dr Arun Jamkar, dean, BJ Medical College, Pune. A key discovery is that the virus, which was initially causing a bacterial infection, is now causing a more potent viral infection.

“The viral is now leading to a condition called hyalinisation of alvelar membrane, or thickening of the lung wall by deposition of proteins. Due to this, oxygen supply is severely affected, and even ventilators have been of little help,” said Dr Pravin Shingare, joint director, Directorate of Medical Education and Research (DMER).

The state experts have found that the deaths between August 3 and 25 were largely due to formation of pus on the membrane lining the lungs. “During that period, deaths were caused mostly due to a secondary bacterial infection,” said a professor who was involved in the study. But the deaths caused thereafter were the result of deposition of proteins on the membrane. “The deposition is more severe in the case of recent deaths. It leads to the thickening of the membrane, and therefore oxygen cannot not pass into the body at all,” the professor said.

An alteration in the pathology caused by the virus is significant and deserving of notice. This is demonstrable based on the studies done. However, the investigators go on to speculate:

This finding has led experts to conclude that the virus has indeed undergone some changes and its anti-antigenicity is changing.

Not everyone agrees.

But, the National Institute of Virology (NIV) in Pune has a different opinion. Director of NIV, Dr AC Mishra, said that his team is yet to record any change in the behaviour of the virus. “We still cannot say conclusively that the virus has mutated,” he added.

To conclude that mutations are responsible for changes in pathology, it is necessary to actually sequence the viruses and show an association between specific sequences and specific pathology. This has apparently not yet been done.

The Indian investigators also report another puzzling result:

Jamkar said that another interesting finding of the state experts has been that two-thirds of the influenza H1N1 patients who died actually tested negative for the virus. “As many as 36 suspected cases who died were later found negative for the virus,” he said.

There are lots of viruses that cause respiratory symptoms. However, relatively few of them kill people. This suggests one of two possibilities, either there is a new mystery virus that is killing people in India or the assays the investigator are using are incapable of detecting a mutated form of pandemic H1N1.

These two possibilities can be distinguished by unbiased sequencing. Samples are taken and everything within the samples is sequenced. This would allow investigators to determine whether a mutated H1N1 or a novel virus was causing the mystery deaths in India.

The CDC tells CBS to Talk to the Hand

From a CBS blog by Sharyl Attkisson, October 27, 2009:

In August 2009, CBS News made a simple request of the Centers for Disease Control and Prevention for public documents, e-mails and other materials CDC used to communicate to states the decision to stop testing individual cases of Novel H1N1, or “swine flu.” When the public affairs folks at CDC refused to produce the documents and quit responding to my queries altogether, I filed a formal Freedom of Information (FOI) request for the materials. Members of the news media are entitled to expedited access, which I requested, since this was for a pending news report and on an issue of public health and interest.

[snip]

Two months after my FOI request, the CDC has yet to produce any of these easily retrievable materials.

[snip]

Today, I received a letter from the CDC Freedom of Information office, which even by the normal baffling standards, borders on the absurd. The letter is to inform me that my request for “expedited” treatment of my FOI request has been denied because CDC has determined the request is “not a matter of widespread and exceptional media and public interest.”

First, it seems ill advised to allow the responding agency (which often doesn’t want the info released) to determine whether an issue is of media and public interest and, therefore, subject to expedited treatment. Further, the CDC may be the only agency on the planet to argue that testing and counting of swine flu cases is “not of widespread and exceptional media and public interest.”

CBS News reporting on the topic has been quoted and reproduced internationally by news organizations such as California NPR, radio talk shows and others. [If you believe this matter is of public interest, you can express that view to CDC FOI Officer Lynn Armstrong or Katherine Norris at 404-639-7270 (recording) or 404-639-7395 (fax).]

[snip]

As for the CDC? Their letter denying expedited treatment assures me they are “continuing to process” my request on a non-expedited basis.

Tick, tick, tick…

Sadly, the CDC’s failure to provide information requested by a member of the national press is not surprising. Many of us have encountered similar denials of request for information. The CDC has gone to great lengths to hide certain sorts of information. This is especially true of information related to case fatality rates. They have internal information indicating much higher case fatality rates than they have publicly acknowledged. Their public statements about a “mild” pandemic hinge on large numbers of people being infected but not dying. If they admitted that the number infected had been much lower, earlier in the pandemic when Ms. Attkisson made her request for information, the calculated CFR would obviously be much higher. This is why they have not provided her with the information she seeks, in my opinion. This is also why they do not provide data from seroprevalence studies, in my opinion. Now that the number of people becoming infected is increasing at an exponential rate, telling the truth about case fatality rate would be political dynamite.

The failure of the CDC to provide reasonable information in a timely fashion encourages conspiracy theorists (“They’re going to control your thoughts with a little computer chip in the vaccine!”) and anti-vaccine agitators (“The CDC is hyping the pandemic so they can give your kid autism with a flu vaccine!”). Most of the American public would be reasonable about vaccines if the CDC disclosed all the information that they have. Since they have not, many will wonder why they are hiding information.

Thanks a lot, CDC.