What's up with flu this season?

I've just started seeing patients with influenza this month. No lack of people coming in for "flu" since winter began, but most of these visits are for any number of other circulating viruses. The miserable souls dragging their sorry selves into my exam room here lately have been hit hard and fast with fever, chills, bone-deep aching, headache, and a cough that generates from the depth of their being. All save one passed on flu shots, and the latter had a mild version of all of the above, puzzling until I realized she'd gotten vaccinated earlier which softened the blow.

Good news here is that this year's shot, for those of you who got it, is a good match for the strains currently flying through the air in projectile spittle. The CDC's latest update confirms my observations that true influenza is here, and the predominate strain is A/H3N2 which is not that scary H1N1 "swine" flu that showed up last year (although that one's going around as well). The H3N2 virus hits hardest amongst young children and older adults. And I'm here to tell you that the in-betweeners are pretty darn miserable too.

If you have an underlying illness such as asthma or COPD, beat feet to your doc's at the first sign of true flu. This year's strains are still sensitive to Tamiflu, but official recommendations are that this drug only be given to those who either are at risk for or suffering from progressive disease.

Influenza, antibiotics, and procalcitonin

Sure, I know what procalcitonin is, namely that which is not yet but will be calcitonin or the hormone produced by the thyroid which shuts off bone breakdown. Salmon calcitonin (Miacalcin) nasal spray used to be the only drug available for treatment of osteoporosis before Sally Field and other aging baby boomers elevated this condition to a status worthy of new and better compounds.

So what's this got to do with antibiotics? Nothing that we knew about back when I was in med school, I can assure you of that. An article and editorial in a September issue of JAMA(1), therefore, was quite an eye-opener on just how important it is to continue on with continuing medical education.

First, a word or two about lower respiratory tract infections (LTRI) and antibiotic use, a subject that impacts my patients and my decision-making processes every day, especially as swinish flu slams the Denver area. Why do I closet myself several times an hour with some miserable coughing wretch at great personal risk to my own lower respiratory tract? To distinguish ordinary, show-stopping/week-ruining influenza from its many complications, particularly secondary bacterial bronchitis and pneumonia. Often it's me (don't want to overprescribe antibiotics to avoid complications to the patient and antibiotic resistance to the public) vs. them (No time for this! Need antibiotics! Big test/presentation/trip/wedding coming up! Need antibiotics!).

I check out: how sick are they, how long have they been sick, are they having trouble breathing, is their O2 level low, how do their lungs sound, what color are their secretions. Knowing all the while that they feel miserably sick, any days with flu are too many days, their airways are swollen so of course they feel short of breath, and, of course, their secretions are doubtless gross because flu-sloughed cells in the airway plus gobs of white cells will make that which they hack out green.

Surely there must be a better formula other than my experience + intuition + observations. Enter procalcitonin(PCT), and it's not just for regulating calcium anymore. While the thyroid C-cells make PCT and turn it into calcitonin depending on the biochemical need to drop calcium levels in the blood, all sorts of other tissues release PCT when the body is fighting bacterial attack. Under normal conditions, PCT is barely detectable in the blood but levels can soar 100,000-fold with widespread sepsis as bacteria invade the bloodstream.

So here we have a wonderful demonstration of theragnostics (another concept that's new to me) wherein a diagnostic test--say PCT levels--identifies patients likely to be helped by a certain therapy, and then targeted drug therapy is given--e.g.antibiotics--based on those results. And I, with my expensive cognitive skills, am cut out of the equation thus making therapy not only more scientific and less intuitive, but also more accessible and affordable!

Now of course this is not yet anything you'll find in a Walgreen's TakeCare Clinic (until perhaps a handheld PCT-O-Meter is developed) but the possibilities are exciting. Not only could we know just when to treat acute bronchitis or pneumonia with antibiotics because PCT levels indicate a bacterial source, we could use this test in other puzzling situations such as whether or not artificial joints are infected or a patient with worsening chronic lung disease has an infectious complication.
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1) Schuetz, P et al. Effect of Procalcitonin-Based Guidelines vs Standard Guidelines on Antibiotic Use in Lower Respiratory Tract Infections. JAMA Sept. 9, 2009 Vol 302, No. 10 1059-1066.

H1N1 vaccine--one dose will do!

This just released today on the New England Journal of Medicine web-site. Results from the H1N1 vaccine trials indicate that one dose of the soon-to-be-released shot results in a good response from most adult subjects. Furthermore, no serious adverse effects occurred--just the usual sore arm and the vague flu-ish sort of feeling that is commonly occurs as a result of the immune reaction to the shot.

Vaccine demand is expected to exceed supply through the fall, so this one shot news is good news indeed.

Who should get Tamiflu for H1N1 flu?

If this past weekend is any indication of phone calls to come, I will be busy fielding requests for Tamiflu for suspected 2009 A(H1N1) which is what we're calling swine flu these days. Patients are understandably nervous for themselves and their families with regards to the spread and severity of influenza illness.

There are 2 available antivirals which are active against 2009 A(H1N1)-- oral Tamiflu (oseltamivir) and inhaled Relenza (zanamivir). For some reason, I've always reached for Tamiflu, and a brief search for a comparison of one antiviral to the other suggests that I am just another victim of an effective marketing campaign by Roche Pharmaceuticals. Nevertheless, be it Tamiflu or Relenza, one of the biggest fears per flu-ologists is that the novel H1N1 flu will become resistant to these worthy drugs, and they will be rendered powerless against the bug.

So what does the CDC have to say on the subject? They along with the WHO (the World Health Organization, that is, not the '60's band) recommend that antiviral treatment be undertaken in accord with the following guidelines:

1. Treatment is recommended for all hospitalized patients with confirmed, probable or suspected 2009 H1N1 or seasonal influenza.
2. Treatment generally is recommended for patients who are at higher risk for influenza-related complications.
3. Treatment should be initiated empirically when the decision is made to treat patients who have illnesses that are clinically compatible with influenza. Treatment should not await laboratory confirmation because laboratory testing can sometimes delay treatment and because a negative rapid test does not rule out influenza.(1)

In other words, if the patient is sick enough to be hospitalized with flu-like illness, initiate treatment immediately. While these antivirals work best if initiated in the first 48 hours of illness, evidence suggests that hospitalized patients with seasonal flu fare better with respect to risk of death and length of hospitalization if Tamiflu therapy is started even if it's more than 48 hours after onset. Those known to be at higher risk of flu-related complications include pregnant women, persons who are immunocompromised (undergoing say chemotherapy or treatment for rheumatoid arthritis), or those with underlying medical illnesses such as diabetes, asthma, or heart disease. And finally, if we providers determine that a patient meets one of these criterion, get 'em going on it and don't wait for final proof!

These recommendations highlight the urgency with which certain subgroups of flu victims should be treated. The CDC, therefore, goes on to make further suggestions as to handle the upcoming flu season and the avalanche of requests for antiviral medications. These include:

1. Provide information for patients at higher risk for influenza complications about signs and symptoms of influenza and need for early treatment after symptom onset.
   
2. Ensure rapid access to telephone consultation and clinical evaluation for these patients as well as patients who report severe illness.
3. Consider empiric treatment of patients at higher risk for influenza complications based on telephone contact... if this will substantially reduce delay before treatment is initiated. In selected circumstances, providers may consider giving a prescription for an influenza antiviral to selected patients who are higher risk for influenza complications.
4. Request that patients at higher risk for influenza complications contact the provider if signs or symptoms of influenza develop, obtain the medication as quickly as possible and initiate treatment.
   
5. Counsel patients about influenza antiviral benefits and adverse effects, the potential for continued susceptibility to influenza virus infection after treatment is completed (because of other circulating influenza viruses or if illness was due to another cause).(2)

What about antiviral chemoprophylaxis wherein antivirals are given to at-risk persons exposed to someone who is fluish? Please note in no case do these recommendations include giving Tamiflu to any old person traveling and worried regarding flu exposure except as outlined in the 3rd guideline above.

1. Persons who are at higher risk for complications of influenza and are a close contact of a person with confirmed, probable, or suspected 2009 H1N1 or seasonal influenza during that person’s infectious period.
2. Health care personnel, public health workers, or first responders who have had a recognized, unprotected close contact exposure to a person with confirmed, probable, or suspected 2009 H1N1 or seasonal influenza during that person’s infectious period.
3. Antiviral agents should not be used for post exposure chemoprophylaxis in healthy children or adults based on potential exposures in the community, school, camp, etc.
4. Chemoprophylaxis generally is not recommended if more than 48 hours have elapsed since the last contact with an infectious person.

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1. http://www.cdc.gov/h1n1flu/recommendations.htm
2. This is an abbreviated list. See above web-site for the full printed version.

H1N1 and severe respiratory failure

Scientists are ferreting out clues to the ferocity with which this new swinish flu attacks the lower airways in some of its victims. Ferrets demonstrate a susceptibility to influenza A very similar to humans and therefore are used as an animal model in flu investigations.

The above picture(1) shows microscopic sections of ferret airways (that is not a goose!), comparing seasonal H1N1 flu (the usual variety that circulates each winter season) on the left to tissue infected by the 2009 A/H1N1 flu on the right. Violet coloration indicates affected surface cells, and both varieties make a mess out of noses with sloughing sheets of dead nasal tissue full of violet-colored intruders as seen in the top pair of slides.

Moving on down to the trachea (which is the largest central airway lined with rings of cartilage that you can feel in the front of your neck), the ferret with seasonal flu middle picture on left is free of viral invasion but the swine-flu ferret victim on the right has dots of violet flu violation throughout its trachea. Finally, and of importance to this discussion, slides from the bronchioles of both ferrets are pictured at the bottom. This tissue was obtained from the smallest airways that go directly into the alveolae or air sacs that hook up oxygen with blood. Seasonal Flu Ferret has normal bronchioles, flu bug free, but Swine Flu Ferret's tiny air passages are teeming with the little buggers.

What's this got to do with the upcoming flu season? One of my patients, an ICU nurse, shared a disturbing report with me yesterday. She said that her unit has been busy this entire spring to summer with youngish patients suffering from severe swine flu-related bronchiolities (inflammation filling these airways with fluid) requiring ventilator support until the infection started to clear. Her information jibed with an August report from the World Health Organization entitled "Preparing for the second wave: lessons from current outbreaks." Per the WHO document:

"Clinicians from around the world are reporting a very severe form of disease, also in young and otherwise healthy people, which is rarely seen during seasonal influenza infections. In these patients, the virus directly infects the lung, causing severe respiratory failure. Saving these lives depends on highly specialized and demanding care in intensive care units, usually with long and costly stays."

This information highlights not only the importance of widespread immunization against the 2009 A/H1N1 flu (which creates so-called herd immunity, slowing down or preventing the lateral spread of flu from person-to-person due to the large number of vaccine-protected people) but also the paramount importance of immunizations for persons with underlying illnesses, particularly asthma, cardiovascular disease, diabetes, and immunosuppression.
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(1) Munster, VJ, et al. "Pathogenesis and Transmission of Swine-Origin 2009 A(H1N1) Influenza Virus in Ferrets." Science 24 July 2009: Vol. 325. no. 5939, pp. 481 - 483.

Why should I get a flu shot?

Well, there's a hack of a lot of flu coming our way. Consider this:

• Flu viruses reproduce every 8 hours.
• That's a three times daily opportunity to meet and mate with other influenza viruses in the neighborhood.
• If seasonal A(H1N1) rolls in the tracheal hay (that's your airway!) with swine-origin 2009(H1N1), the latter could develop an even more effective way of passing from human to human.

Conclusion? You do NOT want these bad actors fooling around together in your nose and throat. In order to prevent such airway orgies, you need two shots. The CDC currently recommends that you get the seasonal flu vaccine now to prevent crazy long lines in late October when the swine flu vaccine rolls off production lines and into your neighborhood Safeway. So roll up your sleeve, and get shot 1 now.

H1N1 flu shots

Coming soon to your neighborhood supermarket: An ounce of prevention against H1N1.

More precisely, .0000005 ounce of prevention which is the teensy-weensy amount of killed viral material that scientists from the CDC, National Institutes of Health, and various licensed pharmaceutical companies inserted into syringes as they launched clinical trials of newly manufactured H1V1 vaccine earlier this month. They expect to analyze study results from mid-September to mid-October and then begin the first public immunization programs before Halloween. The trials will provide important information on the vaccine's safety, efficacy, and whether one or two doses are needed to provide optimal protection. (Study results released 9/10/09 indicated that one dose for adults is sufficient.)

We already know that H1N1 influenza, first identified in Mexico in late winter of this year, is the most common cause of flu-related illness throughout the world at this time. While this new viral strain continues to cause low-levels of new cases in all 50 states, it is currently 'widespread' in Maine and Alaska. But the regular flu season has not even started yet, and once the usual seasonal blend of influenzas A and B hits, we can expect a double whammy of flu-driven illness this fall into winter.

Quite a few of you have called our office with logistical questions about how best to protect yourselves and your families against this onslaught of respiratory crud. Here's the latest information:

What can we expect?

We know that H1N1 flu is quite contagious, easily passed person to person via contaminated secretions from coughs and sneezes, and able to survive on surfaces for up to 8 hours. While the initial reports from Mexico were quite disturbing with respect to the severity of illness caused by this strain, the illness lately has been acting a lot like seasonal flu. It does disproportionately affect persons under 60 and and can be unusually virulent in those under 25. Per Dr. Jay Butler of the CDC, "75% of the [H1N1]hospitalizations are in those aged under 49 and 60% of the deaths are in those under age 49." Studies showed that no young adults demonstrated circulating antibodies to H1N1 at the start of this pandemic whereas many older adults apparently encountered a similar influenza variety in the past and were found to have some immunity to this strain.

Experts are unable to estimate the community prevalence of H1N1 as many cases are too mild to come to medical attention. In addition, as H1N1 becomes more prevalent, the CDC no longer recommends that such mild cases be tested to confirm the presence of this specific virus.

As I've mentioned in previously posts, influenza is a tricky and changeable foe which can mutate rapidly. Thus far, thankfully, studies of the virus from recent cases in the southern hemisphere demonstrate no significant genetic change from northern cases investigated earlier this year.

What's the difference between H1N1 and the seasonal flu?

H1N1 is a novel strain originating in swine (but not caused by consumption of pork!) that developed in North American pigs through the mixing in their respiratory tracts of genetic material from swine, human, and avian flus. It is antigenically distinct from seasonal flu which means that its proteins and genetic material are completely different than the ordinary influenza types that circulate each winter season.

Will I need shots for both?

Absolutely. Separate shots will be available for seasonal and H1N1 flu. Preliminary information released in an online version of The New England Journal of Medicine 9/10/09 indicates one dose will be sufficient for adults; the proper dosing for children is not yet available.

The seasonal flu shot and the H1N1 shot can be taken on the same day--but different arms please! The seasonal shot is already available, however, whereas the first H1N1 vaccines will not be distributed until late October. While the optimal time to receive the seasonal flu shot is October or November to assure that immunity lasts through the entire season, the CDC currently recommends that persons receive the seasonal vaccine as soon as possible to assure that both flu shots can be administered to the largest number of people.

How can I get the H1N1 vaccine?

While the CDC was hopeful that ample vaccine would be available by October, production delays will slow delivery of adequate vaccine until later on in the year. For this reason, certain groups have been assigned top priority for the first wave of vaccinations, chosen due to their risk for more serious disease. These include:

• Pregnant women
• Persons who live with or provide care for infants aged <6>
• Health-care and emergency medical services personnel with direct patient contact
• Children aged 6 months--4 years, and
• Children and teens aged 5--18 years who have high risk medical conditions

What about college-aged children?

The CDC and universities are implementing various programs to limit the spread of H1N1 disease on campus. Some Colorado schools will offer alternative housing for dorm residents whose roommates become ill.

Stay tuned for up-to-date information on the use of anti-viral medications such as Tamiflu for H1N1 prevention and treatment.

Triple Reassortment Swine Influenza*

*aka Triple Reassortant Swine Influenza

"Six of the eight genetic segments of this virus strain are purely swine flu and the other two segments are bird and human, but have lived in swine for the past decade."
---Raul Rabadan, PhD, computational biologist at Columbia University

And that is why pigs are dubbed "mixing bowls" for influenza viruses. While humans are susceptible to human influenza viruses and somewhat less so to the swine varieties (at least up until now), our airways don't provide particularly good handholds for those influenza subtypes that seek out birds. Pigs, on the other hand, have receptors on the surfaces of their tracheal cells that welcome strains from all three species. From porcine throats and lungs, therefore, emerge new flu varieties with the potential to cause dangerous human disease.

These new flus are called triple-reassortment swine influenza A viruses as they contain genetic material from bird, human, and pig influenza viruses. Until recently, the pigs of North America kept their flu to themselves with sporadic reports of human infections generally limited to those most exposed to pigs in their daily work. Now, however, with another flip of their surface proteins--and flu viruses reproducing every 8 hours have 3 opportunities per day to mix, match, and mutate their DNA in a promiscuous sort of way--the little swinish devils have brought these reassorted flus to human airways. Furthermore, this newest genetic triple threat passes easily from one infected human to another.

With all this mating and mutating, therefore, epidemiologists are finding it hard to predict what's in store as the swine flu (and it is a swine flu no matter what it's called, passed at first from live pigs not pork meat) makes it way back to the Northern hemisphere big time. Fortunately, vaccine production is underway, and immunization programs should begin next month. More on that soon.

What's a Phase 6 pandemic?

WITHOUT A VACCINE, CDC ESTIMATES GRIM FOR SWINE FLU Denver Post, July 25, 2009

Grim?!? Whoa, that's a pretty strong word. In this weekly flu update, we'll check out the ease with which the H1N1 (formerly known as swine) flu spreads from person to person, and why the CDC is hoping for a timely vaccine against the virus.

What's a Phase 6 pandemic?

Sounds serious, and indeed it is insofar as it speaks of the ease with which this little hummer spreads from one human to the next.

The World Health Organization (WHO) has developed a 6-tiered approach that classifies the worldwide threat from strains of animal influenza newly arrived in human airways. Each higher level indicates an increased penetrance of the virus into human populations. By Phase 6--the current global level of the H1N1 flu--the virus has shifted into a lean, mean, human-to-human infecting machine in at least two countries of one WHO region and with spread detected in at least one country of a different region. This particular influenza virus, therefore, reached Phase 5 once it spread from person to person in Mexico and the United States; its subsequent spring '09 appearance in the Southern hemisphere then raised the threat to level 6.

Experts agree so far that this variety of influenza has a 'substantially higher' rate of transmissibility than the usual seasonal flu although this in itself does not mean that it's more lethal.

So what's transmissibility and what's the H1N1 score?

Influenza is quite contagious as it thrives in infected respiratory secretions and effectively spreads those viral laden droplets into the environment via juicy sneezes and coughs. The smaller the droplet, the longer it floats through the air and the further it penetrates into the airway of the unlucky recipient who inhales it. If the virus is novel--meaning that large portions of the population have never encountered this particular bug before--the risk of contagion is even higher.

Epidemiologists express transmissibility as reproductive number (R0 or R-zero) which is the number of cases caused by one infected person. If the R0 is less than one, the disease fades away, whereas rising R0 numbers mean that the spread of the disease is increasingly harder to contain. Experts think that an R0 more than 2 renders such measures as closing schools and screening visitors from other countries for signs of the disease as virtually useless.

So what's the R0 of H1N1? Compared to the seasonal flu with an average R0 of 1.3, estimates for H1N1 vary between 1.3 to more than 2. Calculating an accurate R0 for novel H1N1 flu is very complicated considering the many unknowns about this pandemic such as the incubation time and the percentage of cases mild enough to escape official notice. But we must assume that H1N1 is sporting a fairly robust R0 considering its current worldwide status, and, for that reason, we desperately need a vaccine to slow the spread of infection.

Upcoming info

The important thing in containing this pandemic, therefore, is the development and widespread use of an effective vaccine. More on that subject next week.