Why Prevnar?

I must have gotten a significantly lower score on typing than Ken got in high
school. That is a huge piece of work. But alas, I love prevnar. My father was a
pediatrician and got to see polio disappear, and I can say I got to see Hib
disease disappear. (I remember giving the hib to a 2 month old the day it was
approved by the FDA to go that young - drug rep happened to come by the office.
3 months latter our group go surveyed by a large teaching hospital who ask if we
had heard yet it was approved...)
When you see bad disease go away, it is hard to forget. We used varivax right
away - it was promised to come out "in a year or two" when I finished residency
in 1985 and I was tired of waiting. (I had to hospitalize a boy for necrotizing
fasciitis associated with varicella just prior the vaccine being avail.) I still
think rotashield had the potential to come out on top - but the politics were
thick and it wasn't a hugely efficacious vaccine. If it had a success rate
similar to HBV, but the same incidence of intususception, I'd use it all the
time. If there were a vaccine for HIV that was 100% effective but caused
unexplained sudden death in 1 per 10000 patients, it could never be brought to
market even in high risk groups - litigation would kill the company although the
vaccine would clearly save 1000 lives for every death. Hard choices.
I think the opportunity to use the immune system instead of the pharmaceutical
system (antibiotics) is great. For the moment, the pneumococcus is often
sensitive to 80/kg amox, but not for long. With Prevnar, I think the use of abx
will go down. This spring I had a child develop severe anterior chest wall pain
and swelling. Turned out to have pneumococcal cellulitis (fasciitis?)! She was
on some immunoactive drugs for her lupus, but a pneumococcal cellulitis
impressed me. It is such a fast and aggressive bug - just ask Jim Henson of the
Muppets fame.
I am sorry it costs so much, but thankful that it is here. I think varicella has
about disappeared in our area and I look forward to less pneumococcal disease. (
I think it causes lots of ears and sinusitis).
-graham barden

Ken Schroeter wrote:

> The key line ends with "kiss your butt goodbye..." :-)
>
> I am more interested in having a discussion than I am in cutting the policy
> to pieces. I am growing concerned about healthcare policy by proxy: drug
> maker makes drug, makes a deal we can't refuse, becomes unquestioned policy.
>
> Thanks, Graham. Grab a cup of coffee, sit back, and tell me what your
> thoughts are.
>
> Ken
>
> ----- Original Message -----
> From: "Ken Schroeter"
> To: "Pedtalk Digest"
> Sent: Sunday, August 06, 2000 4:51 PM
> Subject: Why Prevnar?
>
> > Hello, PedTalk!
> >
> > I'm not sure I understand the excitement about Prevnar...
> >
> > I have reviewed the Kaiser Permanente (KP) study which is the only study
> > that brought Prevnar to market. I didn't experience the Hib introduction
> > and the Rotashield came on and off so fast I didn't have a chance to care
> > about the studies (never gave a dose). I'm not familiar with how long and
> in
> > how many studies these vaccines were reviewed. The varicella studies
> > extended some 20 years before making it to the market here in the US, and
> I
> > strongly supported it's introduction after I did a thorough review. The
> KP
> > PCV7 study took place in three to four years (Oct 1995 - Aug 1998,
> > post-trial f/u through Apr 99). Longer is better, maybe not necessary.
> >
> > I'm impressed by the KP study, and but wonder if I'm missing something...
> I
> > have problems with using Prevnar, mostly why they (most of you I take it)
> > thought a disease of such low incidence and significance was important (is
> > it of low incidence? See below.). I also had problems with the data
> > presentation on OM (the lack of definitions surrounding the diagnosis of
> OM
> > and of who got sent for PE tubes, both ripe with controversy themselves,
> and
> > how they got their numbers).
> >
> > While it is a comprehensive study, I am somewhat reluctant to accept such
> a
> > costly recommendation of which I am not convinced for a disease that like
> > others can be devastating in rare cases, but is not often of much
> > significance in the overwhelming majority. I know there are some pretty
> > smart folks out there who believe in Prevnar, so please help me
> understand.
> > I don't argue that the vaccine works against pneumococcal disease, I just
> > wonder if that matters...
> >
> > Is pneumococcal disease as frequent as the data suggests? Is it really
> that
> > significant when it does occur?
> >
> > Briefly, the KP Study ran from Oct 1995-April 1998:
> >
> > - 18,927 Northern Californian kids received one or more doses of PCV7
> > - 18,941 Northern Californian kids received control
> >
> > 1) At the time of the interim evaluation (study terminated early because
> of
> > "high efficacy"):
> >
> > - 17 cases of "invasive" disease (any sick kid with any pnuemococcal
> > positive culture of any fluid) caused by vaccine serotype occurred in
> > controls who were fully "vaccinated" (None in PCV7 kids. Hence the claim
> > that the vaccine was 100% effective).
> > * 13 bacteremia, 2 sepsis, 1 bacteremic cellulitis, 1 bacteremic
> > pneumonia, no deaths reported
> >
> > - 5 more cases occurred in the "intent to treat" controls (at least one
> but
> > not all 4 doses given) for a total of 22 cases
> > * 2 bacteremia, 2 meningitis, 1 sepsis, no deaths reported
> > * Total disease case incidence of 22/18941 or 0.12% (120/100,000).
> > Vaccinating 18,941 kids prevented disease in only 22 kids, and most of
> those
> > cases were not significant. Allowing for all of these cases represents
> only
> > an incidence of 0.12% vaccine serotype pneumococcal disease that would
> have
> > been prevented by the vaccine. If we include all pneumococcal serotypes
> (see
> > below) we see an incidence of 55/18941 or 0.29% (290/100,000) (crossover
> > immunity for non-vaccine serotypes). This last stat is compelling: see
> > below.
> >
> > 2) "at the time of the final unblinding of the study, there were 40 fully
> > vaccinated cases of "invasive" disease caused by vaccine serotypes, 39
> > occurring in controls".
> > * Adjusting our total disease case incidence: 39/18941 or 0.2%. This
> > reflects the CDC's incidence of disease according to the AAP tech report.
> > * The AAP tech report states the KP results for ALL serotypes, PCV7 and
> > non-PCV7, was 55 cases in controls, 6 in PCV7 kids. Control incidence of
> > 55/18941 or 0.29% (290/100,000).
> >
> > The AAP tech report quotes a pneumococcal case incidence of 228/100,000
> > (probably CDC data, which is an educated guess), or 0.23% incidence of
> > "invasive disease", reflecting what the KP folks report. If the vaccine
> > prevents 290/100,000 (see above), then this is very significant for
> > controlling "invasive" pneumococcal disease. (The CDC definition of
> > "invasive" disease apparently is not very particular: apparently
> pnuemococca
> > l presence in an otherwise sterile body fluid makes the case definition.
> > The reports on Prevnar throw the word "invasive" around to describe this
> > presence like Republicans use the word "liberal" to describe Democrats, as
> > if that's supposed to make the short hairs rise up...). If the entire
> birth
> > cohort (around 3.4 million births per year) were equally at risk (and in
> > reality it is not evenly so) there would be ~7752 cases a year of
> "invasive"
> > pneumococcal disease based on an incidence of 290/100,000. Most of these
> > "invasive" cases are pneumococcal bacteremia, the overwhelming majority of
> > which are benign (most are labeled a viral syndrome and "missed" entirely,
> > yet the kids get better). Most of the "invasive" disease is easily handled
> > as an outpatient with essentially no sequlae. Pneumococcal meningitis in
> its
> > most affected group, infants (now that's invasive), <12 months) has a
> > 10/100,000 (0.01%) statistical incidence. According to the KP study,
> > meningitis occurred only 2/18,941 for an incidence of only 0.01%, same as
> > the CDC data. If we use the 10/100,000 incidence applied to a birth cohort
> > of 3.4 million, there should be around 340 cases of pneumococcal
> meningitis
> > a year. Caveat in interpretation is that most of these cases are probably
> > occurring in the higher risk populations, along with most of the
> significant
> > pneumococcal disease (see Table (1) of the AAP tech report), and not in
> our
> > "regular" population. After 24 months, rates decrease dramatically. The
> high
> > risk kids are the ones who should be vaccinated (oh, and those >65 yo).
> >
> > The tech report states that "among children younger than 5 years of age,
> > pneumococcal infections cause an estimated (that's the key word...) 1400
> > cases of meningitis, 17,000 cases of bacteremia, 71,000 cases of
> pneumonia,
> > and 5-7 million cases of otitis media annually". I've no idea how this
> is
> > estimated, but I am amazed at the incidence they describe (I don't know
> who
> > "they" be). There are no reports to the CDC for this disease.
> >
> > The information provided in the Prevnar package insert varies only
> slightly
> > from that found in the KP study (while recording the KP study results,
> > interestingly enough). In addition it notes that between 1986 and 1995,
> > through community based studies, the overall incidence of "invasive"
> > pneumococcal disease in the US was 10-30 cases per 100,000, with the
> highest
> > risk in kids <24 months of 140-160/100,000. They note the incidence of
> > meningitis as 7/100,000, with 8% mortality, 25% neurological sequlae, and
> > 32% hearing loss in survivors. They remind us that most OM is not
> > pneumococcal, estimating 12-24% of all AOM, with Prevnar serotypes
> > accounting only 60% of those cases. (Thems some small numbers for OM...
> > especially if you consider that the diagnosis of AOM is not often
> > discriminantly made).
> >
> > Here is my Achilles heel: I don't believe these numbers. They conflict
> and
> > just don't make sense to me. I find it very hard to believe we are seeing
> > these numbers in this country. (No the data doesn't lie, it may not mean
> > anything).
> >
> > For comparison:
> >
> > Diptheria: In the 1920's there were about 200,000 cases per year, the
> > ncidence was around ~150/100,000 annually with 13,000-15,000 deaths a
> year.
> > By 1940 this dropped to 15/100,000. Diptheria toxoid was usefully
> produced
> > in he 930's, combined with tetanus and pertussis and routinely used in the
> > 940's. Deaths reported in the US did not drop below 100 until 1957, when
> 81
> > were reported. In 1994, two cases were reported, and there were no
> deaths.
> >
> > Tetanus: Immunization introduced in the 1940's, when there were only about
> > 500-600 cases per year (0.4/100,000). Mortality was 30%. In 1996 the
> > incidence was 0.02/100,000 (27 reported cases). In 1950 there were 486
> cases
> > with 336 deaths. In 1995 there were 41 cases reported, 5 deaths.
> >
> > Pertussis: There were 1 million cases between 1940-1945, about 175,000 per
> > year, an incidence of 150/100,000. The vaccine was introduced in the
> > 1940's. Between 1980-1990 the incidence was 1/100,000. There have been
> > cyclic peaks about every 3-5 years with case clusters. In 1950 there were
> > 120,718 cases reported with 1,118 deaths. Deaths dropped below 10 for the
> > first time in 1972 with 6 deaths reported in the US. In 1995 there were
> > 5137 cases reported with 6 deaths.
> >
> > Hib: In the 1980's, the incidence was about 40-50/100,000, with about
> 20,000
> > cases reported annually. The vaccine was introduced in the late 1980's.
> In
> > 1995 there were 1180 cases reported with 12 deaths.
> >
> > Hepatitis B: about 20,000 cases reported annually, though this number is
> > felt to be highly under reported. In 1992 the incidence was about
> > 40/100,000. It had a peak of 70/100,000 in 1985. It is estimated that
> 1.25
> > million persons are chronically infected in the US, with 150,000 to
> 200,000
> > new HBV infections every year.
> >
> > Varicella: Virtually all persons acquire varicella by adulthood. Only
> about
> > 4-6% of all cases get reported to the CDC. Death occurs in 2/100,000
> cases
> > in all ages, 31/100,000 adults. The incidence of kids being hospitalised
> is
> > about 200/100,000. (Preblud et al, 1986).
> >
> > These comparisons help me understand why a disease with an incidence of
> > 290/100,000 would be so important. What I don't understand is why it was
> > not the first to go: it has the highest case incidence of almost every
> > disease we currently vaccinate against. And why am I not seeing this kind
> > of frequency in my 10 years in medicine? Could it be that, like the
> common
> > cold, it's quite frequent, but of little real significance in the general
> > population?
> >
> > After this, and reviewing the Wyeth-Lederle slides and data, I still
> cannot
> > agree with their conclusions, and I have lots of issues :-) Here are a
> > few...
> >
> > 1) Is reducing the frequency of a rarely significant disease worth the
> most
> > expensive vaccination program currently in existence?
> >
> > - Is my statement flawed? Is pneumococcal disease truly rarely
> significant?
> > We recall Hib, for example, as incredibly frequent in it's hey-day: many
> > report seeing 12-50 cases of HiB meningitis and epiglot[censored] a year. Yet,
> > it's incidence was a fourth of that reported for pneumococcal disease.
> Are
> > we not impressed by the pneumoccoccus? Certainly we want to reduce the
> > episodes of meningitis, but this seems exceptionally rare, and there is no
> > indication that the vaccine really works significantly against it (can an
> > n=2 be considered sufficient to reach such a conclusion?). Which leads me
> > to the next statement...
> > - Since I don't think that pneumococcal disease in the regular herd is
> > "significant", it doesn't matter that the vaccine works (I think the data
> > supports that the vaccine works: 290 cases prevented per100,000 when case
> > incidence is slightly less reflects the 100% effective claim).
> >
> > 2) They note that they expect that routine use of this vaccine "may have a
> > profound effect on the management of infants who present to physicians
> with
> > fever and no localized signs of infection. It is likely that clinical
> > laboratory diagnostic procedures, hospitalizations and presumptive
> > antibiotic use in the vaccinated children will be significantly reduced."
> >
> > - Are they suggesting that we'll not work-up infants with FWOS who look
> sick
> > just because they have received PCV7 vaccination? I think they are... and
> > that's unreasonable to conclude (actually I thought it absurd, a recurring
> > word I found myself using while thinking about this).
> > - Do they think that physicians who are already throwing around
> antibiotics
> > at babies like bath water are going to do so less often because of this
> > vaccination?
> > - We created the resistence and now want to use an expensive vaccine
> instead
> > of antibiotic discipline to overcome it? That's Machiavellian...
> > - FWOS is rarely bacterial, let alone pneumococcal, to begin with... so if
> > we already aren't tapping/blood culturing kids routinely because we are
> not
> > impressed with the prevalence (ie "it's probably viral"), why do we expect
> > to see a significant change in our already loose habits? (How often have
> > you diagnosed bacterial meningitis or bacteremia, or proved that the
> > pneumonia was pneumococcal?)
> > - Oddly, I am mildly aroused by the OM stuff: even lacking useful and
> > important definitions, they reportedly show a reduction in AOM in all
> > comers, and less PE tubes. Can't explain that, and I would argue they
> can't
> > either... And then again, how significant was the reduction really? This
> > part of the study was either weak or I completely didn't understand it.
> But
> > then, I think most people are not very elegant in diagnosing AOM vs SOM vs
> > no OM and think this part of the study was an abstraction of an
> abstraction.
> > I don't know what to make of the data... There is a TM piercing PCV7 study
> > being done in Finland. Oh, goody...
> > - I am also impressed that all of the "invasive" cases were in controls...
> > In a sense the vaccine protected 39 (all comers, most with inconsequential
> > disease) out of 18941 kids, or 205/100,000 (0.2%). Wow... yes, it works,
> but
> > do we care?
> > - Is colonization important, and what suggests that the vaccine will
> > actually reduce colonization if it is?
> > - I remember being equally under impressed by the incidence of "serious
> > bacterial illness" in the original ceftriaxone in FWOS study (lost the
> > reference, anyone have it?).
> >
> > 3) Pyrrhic victory?... At about $58 dollars a dose it significantly
> exceeds
> > any cost savings to society (the vaccine would have to cost < $46), let
> > alone to insurers (cost of each dose would have to be <$18). And all this
> > angst...
> >
> > In 10 years I have seen one child die of overwhelming multi-drug resistant
> > pneumococcal meningitis (the first one reported in North Carolina), and
> > maybe this vaccine would have prevented it. Maybe. My partner has seen
> one
> > case of pneumococcal meningitis in 27 years. Everyone has "heard of one",
> > but how many have actually taken care of one? 2 in 18,941 patients in
> four
> > years of study from 23 medical centers in regular Northern California.
> > Sure, there is morbidity and mortality attached to these cases, but again
> > the incidence of the cases is low to begin with, and the incidence of
> > significant morbidity even lower. I have seen little proven pneumococcal
> > disease, and only one case of it significant enough to make a vaccine like
> > this useful in the "regular"population.
> >
> > All this being said, if you are not giving the vaccine and you get the kid
> > with pneumococcal meningitis, kiss your butt goodbye...
> >
> > Jist: I'm not sure I'm impressed, and can't really understand why it was
> > recommended. Was it because it is the only dragon left? I used to trust
> the
> > ACIP, CDC and AAP folks unquestioningly, but after the Rotashield fiasco
> (to
> > say nothing of the Swine Flu vaccine for those of you who remember it), I
> am
> > no longer so complacent. The data looks compelling, but for some reason I
> > don't believe it: I'm just not seeing that significant of disease from the
> > pneumococcus (from my time in San Diego, North Carolina or Tennessee, and
> > now New Hampshire). I do agree high risk kids should get it, but not all
> > kids.
> >
> > - I don't think we'll see a reduction in diagnoses of AOM and PE tubes. We
> > make these diagnoses and referrals
> > inelegantly and the vaccine won't change that...
> > - I don't think we will effectively alter our practice of medicine because
> > of it. A sick kid with FWOS is still a sick kid with FWOS.
> > - I don't think we will positively affect the health of the overwhelming
> > majority of our kids with this vaccine, and that is THE point with a major
> > epidemiological intervention. (What is the goal of Prevnar?) How would we
> > know if we don't see these cases to begin with?
> >
> > I leave you with this to ponder. Recently an accomplished watercolor
> artist
> > in Vermont (I wish I could recall his name), recognized for his
> exceptional
> > skill around the world, received an honor for his work. He prides himself
> > on his traditional skill, and this is what he teaches his students. When
> > asked about "modern art", he basically described it as crap that required
> no
> > skill to produce. We call it art, he asserts, because people bought this
> > crap, later realized it was crap, but kept telling each other how
> > wonderfully artsy it was so it would retain it's value and so they would
> not
> > look the fool for having bought crap. An example that comes to my mind
> would
> > be Picasso. In his early years he was a profoundly skilled artist. I
> think
> > he got lazy, created crap that required no time or skill, and sold it at
> > incredible prices to artsy folks who didn't want to look the fool. And
> many
> > follow, both creators and buyers... of crap. I really want to believe
> > Prevnar isn't, well, modern art.
> >
> > Thanks and let me know why you like Prevnar. Then let's talk again in a
> > couple of years. (How long did it take to see a reduction in Hib disease?
> > Are we yet seeing less VZ and complications?) Maybe I'll see the light.
> >
> > Ken Schroeter, DO, FAAP
> > (not my real name)
> > Laconia, NH
> > (not where I really live)
> > Still holding out on Prevnar
> > (Wanna buy a Picasso?)
> >
> > References:
> >
> > Overtruf,GD and the Committee on Infectious Diseases, Academy of
> > Pediatrics, Technical Report: Prevention of Pneumococcal Infections,
> > Including the use of Pneumococcal Conjugate and Polysaccharide Vaccines
> and
> > Antibiotic Prophylaxis http://www.aap.org/policy/tech6-5.pdf (Policy
> > Statement: http://www.aap.org/policy/pcv76-5.pdf)
> > - This tech paper is wonderfully written and concise.
> >
> > Black et al, "Efficacy, safety and immunogenicity of heptavalent
> > pneumococcal conjugate vaccine in children", Pediatric Infectious Disease
> > Journal, 2000; 19(3):187-195
> >
> > Prevnar Package Insert
> >
> > Various at www.pneumo.com (A Wyeth Lederle Site. Nice, very long,
> > PowerPoint slide show available). Don't waste your time at the Prevnar
> site
> > (www.prevnar.com)
> >
> > My comprehensive unpublished review of the Varicella Vaccine (1995)
> >
> > CDC Pink Book, Epidemiology and Prevention of Vaccine Preventable
> Diseases,
> > 1997
> >
> > This e-mail was sent to members of PedTalk, and several colleagues of
> mine,
> > amongst whom I am a known heretic (amongst other things). Those who are
> not
> > members of PedTalk can subscribe free. To subscribe to
> > PedTalk in digest form, simply send a message to
> > "hidden@email-address" with the phrase "subscribe" in the body
> of
> > the message. I apologise for any grammatical and spelling errors. All
> > slights were made in full earnest :-)
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >
> >