Doubletree Tape 1

3/6/02

Dr. Comyn:\--And my colleagues are here from the Center of Veterinary
Medicine. We were reviewers in the Office of New Animal Drug Evaluation
and we were so appreciative of you all taking the time to be here to
help us in this workshop and just a few administrative notes before we
get started. These sessions are all going to be taped, the tapes will be
available if anyone would like copies, probably within a couple of weeks
after the break out sessions or after the workshop and I will get
information out to people about that and what I\'ll probably do is do an
e-mail that\'s just to give you information. All of the presentations
will be available as well in the public and the dockets and also on the
CVM website for a period of time so that people will have access to
those and the last thing is we are going to have a break out session
tomorrow afternoon. You can see that in your agenda. If you could stay,
if you have some time to stay and participate in that, that would be
great. You know, I certainly understand a lot of you want to get home
and but anyway if you, if you can we would certainly appreciate it and
the sign up sheet is outside and again we would really appreciate your
participation in that.

All right to start out I would like to introduce you to Dr. Naba Das, he
is the senior veterinary reviewer in the division of therapeutic drugs
for food animals and he is delivering our welcome to this morning and
Dr. Stephan Bonstead. Please welcome Dr. Das. (applause)

**Dr. Naba Das**

Thank you Dr. Gillian. Good morning everyone. My memories are not that
strong so I have to look at what I have written so far, so please pardon
me. On behalf of my colleagues at the college of, at the Center for
Veterinary Medicine\'s Division of Therapeutic Drugs for Food Animals
I\'m pleased to welcome you to this workshop on swine mycoplasma
pneumonia. Dr. Steven Vaughn, our Division Director, was supposed to
welcome you all to this workshop today but unfortunately because of his
family emergency he\'s unable to come. As a result my colleagues have
put their trust on my shoulders to perform this job. As you know the
Food and Drug Administration is a regulatory agency whose mission is to
protect the public health. The Center for Veterinary Medicine is charged
with ensuring that new animal drugs are safe and effective. The Office
of New Animal Drug Evaluation reviews and safety and effectiveness study
reports and decides whether to recommend approval of new animal drugs.
It is a tough job, often times we are frustrated in our evaluation of a
particular disease entity when the pathogen is possible for the disease
is not readily cultured from the diseased animals, and a valid clinical
end points have not happen a disease has several presentations or when
one disease is commonly associated with other organisms. Once set
example is mycoplasma respiratory disease in swine. The swine
respiratory disease caused by *Mycoplasma hyopneumoniae* has been
reported in many countries. This is a very common and economically
important disease of swine. The organism is transmitted through direct
contact within pigs. Weaned, so-called nursery pigs and grower- finisher
pigs are particularly vulnerable. The Swine 2000 survey conducted by the
USDA\'s National Animal Health Monitoring System showed that 39.1% of
deaths in grower- finisher pigs were due to the respiratory diseases. Of
these respiratory diseases the survey listed mycoplasma pneumonia as the
most common respiratory disease in grower - finishers. Cases of pure
mycoplasma pneumonia in swine are rare. Most commonly, the disease
occurs as part of \"Porcine Respiratory Disease Complex\". Clinical
presentation of porcine mycoplasma and respiratory disease complex
varies in severity, with uneven growth rates along littermates, cough,
respiratory distress, and reduced feed intake. Conversely, clinical
signs of pure mycoplasma pneumonia are often subtle and mild with a dry
non-productive cough. Thus it becomes difficult to diagnose infection
with mycoplasmal hyopneumoniae in pigs. Diagnostic methods commonly used
to detect the disease in pigs are serology, culture of organism,
polymerase chain reaction, gross pathology and histopathology. Of these
methods culture is still considered the diagnostic gold standard.
However, because of the difficulty in isolating mycoplasma organisms
from the diseased animals, we look to evaluating the drug\'s
effectiveness based on clinical sponsored animals in food trials. This
creates a labeling problem for the drug product and the claim is, for
the treatment of some swine respiratory disease associated with
*Mycoplasma hyopneumoniae*. In addition, performing susceptibility
testing is difficult when there are only a few clinical isolates to
determine the minimum inhibitory concentrations of the drug product, at
which the isolates are either killed or unable to multiply. The minimum
inhibitory concentration data is important and can be included in the
packet insert to help veterinarians select an effective therapeutic
dose. With all these difficulties in mind, FDA has planned this workshop
to seek scientific input from the public forum to help the agency
determine an acceptable method, in light of the current state of
scientific knowledge for evaluating drug effectiveness against swine
mycoplasma respiratory disease. This workshop is part of CVM\'s leverage
initiative aimed at increasing interaction with industry academia,
practitioners, swine producers, and other government agencies.

The workshop is divided into four sessions. In today\'s session one and
two, speakers will talk about the clinical presentations and cutting
edge research on swine mycoplasma pneumonia. In tomorrow\'s morning
session three, speakers will provide perspectives on evaluating
therapeutic effectiveness against mycoplasma pneumonia. My colleagues
Drs. Julie Punderson, Nabil Anis and Gillian Comyn will moderate these
three first sessions. In tomorrow\'s afternoon break out exercise
session four we will explore various aspects of study design and other
issues in determining drug effectiveness for swine mycoplasma
respiratory disease. My colleague Dr. Cindy Burnsteel will be moderating
the break out session. I want to emphasize that for the break out
session and for the workshop as a whole, we do not intend to propose any
guidance or arrive at a definite study design or protocol. Now, I
believe the job will remain unfinished if I do not recognize and express
my sincere thanks and gratitude to my colleagues who worked so hard to
organize this workshop. Please give a hand to them. (applause)

Now, it is my distinct pleasure to introduce Dr. Lisa Tokach, President
of the American Association of Swine Veterinarians, who has kindly
consented to talk about the association. Thank you, Dr. Tokach.

# Dr. Tokach

Thank you Dr. Das. I\'d like to thank the Center for Veterinary
Medicine, Division of Therapeutic Drug for Food Animals for extending an
invitation to me today and for giving me the opportunity to welcome you
to this workshop on swine mycoplasma pneumonia. As Dr. Das already
mentioned my name is Lisa Tokach. I\'m a swine practitioner from
Abilene, Kansas and I currently, as of the last 24 hours serve as the
President of the American Association of Swine Veterinarians. On behalf
of the AASV, I\'d like to welcome you to Kansas City. As many of you
know because you were there we just concluded our 33 annual AASV
conference. We have over 1600 members representing 23 countries in AASV.
We had over 850 attendees at our conference this year, that just
concluded yesterday. We covered a wide array of topics including disease
diagnostics, reproduction, employee management, animal welfare,
statistics and many more. Mycoplasmal hyopneumoniae was certainly a
topic of our meeting agenda as well. We had two students from Iowa State
University presenting papers regarding M-hyo in our student section.
Keith Earlenson presented mycoplasmal hyopneumoniae zero prevalence and
control strategies on farms participating in the NOM swine 2000 survey.
I know Dr. Bush is going to talk about that in detail, I think today. I
think he\'s on today. Then Matt Winger presented evaluation of the decay
in colostrums deprived pigs, decay of maternal antibodies against M-hyo
in swine. We also had four papers presented in the industrial partners
section by several companies including Bio-vet, Sharing Paw, Fiazer, and
Alfarma. Ten years ago as we moved to promote all in all production to
clean up the health of our confinement herds. We made great progress in
the number of diseases; unfortunately, however as I can attest to from
clinical practice it is not difficult to find mycoplasma positive herds.
In practice, we struggle with the ability to make a quick definitive
diagnosis of mycoplasma and sort it out from the other pathogens that it
often works in concert with. We often don\'t know if it\'s mycoplasma as
the primary pathogen or if it\'s secondary to PRRSV or SIV. I see there
are some other speakers, Dr. Thacker and a few others that are going to
address that topic as well. Ideally we\'d like to eliminate the organism
from our farms all together and through some de-pop, re-pops we have
done that in select farms; however, this is nor practical either fool
proof in all systems. For those we continue to script, to struggle with
appropriate therapies for those suffering from the disease and effective
prevention programs such as vaccination or feed medication. We have some
effective vaccines out there. We, we struggle with the use of those due
to labor, those, the companies out there if you can figure out a way for
us to give it in water, that\'d be great. We hope that through
collaborative efforts such as this one we will have progressed toward a
method of elimination of mycoplasmal hyopneumoniae or at the very least
develop more effective methods of diagnosing, treating, and preventing
the disease in the herds that we monitor. Again, I want to thank Dr. Das
and his team from the CVC for inviting me to the podium this morning. I
hope that you have an educational and productive meeting. Thank you.
(applause)

(Dr. Comyn)

Thank you Dr. Tokach for that greeting from AASV and for some of your
insights about, that your perspective as practitioner. Now, with no
further ado I will hand it over to Dr. Julie Punderson who will start
the first session. Thank you.

**Julie Punderson**

Good morning, my name is Julie Punderson and I'm a veterinary reviewer
with the Office of New Animal Drug Evaluation. It\'s my pleasure to
introduce our first session this morning and we\'ll focus on the history
clinical presentation and diagnosis of mycoplasmal hyopneumoniae. We
would like you to hold your questions until the end of the second
speaker and we\'ll have a questions and answer session prior to our
break. Our first speaker will be Dr. Brad Thacker from Iowa State
University. Dr. Thacker is a 1978 graduate of the University of
Minnesota, went into private practice but returned to graduate school at
Minnesota then spent eleven years at Michigan State and has now been at
Iowa State for eight years. He will discuss mycoplasma associated with
respiratory disease down on the farm.

**Dr. Brad Thacker**

I really have a tough time talking if I can\'t see my slides. I don\'t
have it memorized. Okay. Thank you for the introduction and it\'s a
pleasure to be here. In preparing this talk I guess we, you all struggle
with how to address the title or the, the charge that\'s put towards you
and so in addition I guess this talk has been somewhat flavored by a
talk I\'m put putting together, a paper I\'ve been putting together that
I have to present in a month for a pharmaceutical company on the role of
antibiotics and the error of amino suppressive diseases. Now, if you
want that for a topic Lisa, try to, try to chew on that one for a while
and so there\'s a lot of issues I think revolving use of antibiotics
certainly in our swine industry and I\'ll allude to this a little bit
later I remember Dr. Ross ten maybe ten years ago and Hank Harris
presented his SEW stuff and peer wide I think Dr. Ross thought he was
going to be out of business cause we\'d get rid of all of the
respiratory diseases and unfortunately that hasn\'t happened and I think
there\'s some reasons for that and we\'ll talk a little bit about that.
I think the, the other thing that, that I\'m going to preface this talk
a little bit is you know, we all tend to see the, this sort of situation
through our eyes. My eyes are I do research, I do clinical work, I do a
lot of secondary opinion investigations and were things have been tried
and haven\'t worked very well and I always go back to one of the things
that Al Lehman told me, he was my mentor in vet school and graduate
school is that we\'re all prisoners of our experiences and so we all
have different experiences that we can bring to the table and in many
respects I think we need to use these kind of experiences. I\'m a firm
believer in the value of doing research but I also recognize the fact
that we will never have enough money to do research that will tell us
how to do everything that we need to do on the farm. And then the final
thing too, is that ultimately all of this kind of technical kind of
stuff has got to be done at the farm level and it\'s got to be done by
the kiss principle because otherwise it doesn\'t get done even if people
are fairly intelligent they just don\'t have time to, time for
complicated procedures.

So, go ahead- so, general characteristics of M-hyo is a obligatory
pathogen of the respiratory tract of the pig, infection is limited to
the airways which actually I think later of people will allude to some
of the immunology of mycoplasma, this is probably a fairly good
advantage for a pathogen. It\'s one of the more well adapted pathogens
that we deal with. Mycoplasma by itself causes little if any reduction
in performance in our experimental setting on mycoplasma pneumonia other
then a little cough starting about 10 days after challenges, kind of a
non-starter, certain is recognized as an initiator, a potentiator of
more serious pathogen, serious respiratory diseases caused by other
primary or opportunistic pathogens, depending on our definition of what
a primary versus an opportunistic pathogen is.

Back up one. Okay, one question I would pose to you too, and one of the
things that, that I know that works in terms of controlling respiratory
disease on farms is to improve the environment. I know that always works
because it always has in the past and so as we, we also need to look at
I think out of the box a little bit and even things like does M-hyo
potentate the impact of bio reactive environmental contaminant such as
endotoxins and bluecans and, and we know that these sorts of things do
effect the function of the respiratory tract that effect is cytokine
mediated that can result in reduced growth. There\'s a whole area that
study of sickness behavior but I think in general mycoplasma infected
herds are at greater risk for developing respiratory disease due to
whatever compared to free herds. Mycoplasma utilizes several mechanisms
to cause disease and I kind of categorize them into two parts. One is
respiratory immune system modulation. There\'s a tremendous attraction
of lymphocytes into the site of infection. Those lymphocytes are not
primed, they\'re not directed towards producing antibodies; they\'re
just non-specifically there. I think Dr. Eileen Thacker will talk a
little bit about some of the cytokine profiles related to infection.
This can be very important. And then the other thing is the classical
thing that we think about in terms of cilia atrophy resulted in reduced
function of innate defense mechanisms.

Okay, how about if I just go like that when I want the slide changed?
Okay so, did we okay. And the ciliary, part of the mucociliary apparatus
and of course cilia atrophy due to mycoplasma cause dysfunction of that
apparatus. Now, the challenge for me on a farm is always to, and I think
that\'s an important issue because that allows things that normally
(cough) would, and I always do that. Now, I don\'t want to make you all
self conscience but I don\'t know how many times per minute we all do a
little swallow, right that\'s the stuff that\'s coming up out of your, I
don\'t want to make you self conscience but that is a normal mechanism
so, so (cough) when you go like that see there, right there I did it.
So, anyway but there\'s other things that we deal with too, dehydration
causes disruption in the fluid layer around the cilia, reduces cilia
activity. This kind of concept is certainly more an issue with feeder
cattle and transport. We all, there\'s some good models there. Ammonia
inhibits the cilia movement. Carbon dioxide has been shown to inhibit
cilia movement. I deal with a lot of naturally ventilated nurseries in
places like Mexico where we have, sometimes the heaters aren\'t
maintained very well. We can have high carbon, carbon monoxide levels.
So, in general the disruption of this apparatus makes the pig more prone
developing pneumonia. Now, the problem we get into is that\'s kind of
like four things here I\'ve identified and they all kind of maybe have
the same outcome or a similar outcome and mycoplasma is just one of
those.

Historically mycoplasma has presented clinically with chronic low to
moderate grade pneumonia and when I say that I think it's on a farm
basis I\'ve never been a real big believer in saying that I have
mycoplasma pneumonia or I have this or I have that because I don\'t
know. I mean from day to day I don\'t know. I\'ve got situation, I\'ll
give you an example. A farm I work with in Illinois, I don\'t know if
there\'s any student, there is a student here, former student Eric,
you\'ve been there and, and it\'s a farm I go to for three days at a
time. I\'ve been going there at least four times a year for 20 years,
live right at the farm and I can remember one situation where I got
there about ten o\'clock at night, started walking through the barns and
the pigs are all coughing and you kind of go, what\'s going on you know?
And, and as it turned out the county road department had put some powder
down on the road outside the barn the day before and it made this big
cloud of dust that got into the ventilation system. You could actually
see the stuff by the exhaust fans and it looked like a flu outbreak.
Now, it only lasted for about 12 hours but, and it\'s gone so I think
that there, when we try to start to always be very refined in this. we
have to, to really back up and say well, yeah they just got respiratory
disease or pneumonia or whatever, very low mortality, reduced growth
rate, feed efficiency is not as a predictable issue with mycoplasma
pneumonia. Why I say that is a lot of times with vaccine studies for
instance you\'ll see improvement in growth rates but you don\'t
necessarily see an improvement in feed conversion. Now, if pigs grow
faster they tend not to be quite as efficient, okay? So, there\'s that
fine line that we always cross and basically recognized in finishing
pigs and this is characterized as Enzootic Pneumonia depending on
especially like in Europe they use this term quite a bit. M-hyo is
believed to be the primary cause of Enzootic Pneumonia, opportunistic
bacteria especially pastoral mastoasta were believed to be the secondary
invaders and I remember one paper I believe from Japan that was
published 10 or 15 years ago where they cultured lungs at slaughter and
basically if there was mycoplasma type of pneumonia invariably those
lung were infected with pasturella. The lungs looked normal from the
same herd from an infected, M-hyo infected herd, they weren\'t able to
culture Pasteurella. So, for me the, the I think the issue for me over
the years as pasturella is well, it's a secondary invader so therefore
it\'s not important and, and I think in some respects that\'s kind of a
narrow view of the world because well, yeah sure, it\'s not, it can\'t
cause disease by itself but if you open the door in comes, it\'s kind of
like opening the door and then the whole Army moves in and kills you.
It\'s important. In a clinical situation, getting back to our acumen at
trying to sort all of this out. And I think the relative contribution of
each bacteria was difficult to ascertain, so we tended to just go on
kind of a basic clinical science. We\'ll talk a little bit more about
diagnostics testing limitations in a minute. But in general pasturella
and other respiratory organisms were not a concern in M-hyo free or what
I would call quiet herds and certainly in the mid 80\'s when we started
understanding the benefit of all in all production it was amazing how
some of these herds would just, I mean sure they had mycoplasma but the
level of pneumonia was so low. I would say also in my experience in
those herds invariably those barns were mechanically ventilated but with
good mechanical ventilation not the kind of ventilation that causes
problems. So, we kind of fixed some of those problems as well.

Explosive outbreaks and historically for me is probably like you know, a
pre 1990, early 90\'s. Explosive outbreaks of respiratory disease were
attributed to SIV, Swine Influenza Virus APP, *Actinobacillus
pleuropneumoniae* or hot *Pasteurella* or some bacteria. SIV was a minor
periodic problem. I work with one herd in Michigan, one of our main
commercial teaching herds and essentially every other fall the whole
time I worked with them they had a flu outbreak, just, just like
clockwork. In the old days we actually were a little concerned about
sometimes differentiating that from pseudo rabies. Now, we don\'t have
to worry about that so much anymore but been involved in a few situation
where this was overlooked. APP was certainly the profit robber and there
were certain situation, mixed sources of feeder pigs, poor understanding
of environmental triggers, pig flow issues as well, that set APP off,
poor understanding of vaconology and even today our vaccines other then
one modified live vaccine that\'s available through Bangor Vet Medica,
none of them contain the most important virulence factor of the, of the
organisms so very limited impact on the disease because of that
deficiency.

Diagnostically, few laboratory capabilities, didn\'t, we didn\'t have
near the amount of tests and, and many times the clients were reluctant
to spend money on the tests however, certainly in some situations we had
more veterinary contact. When I was in practice in Fairmont and New
Alma, Minnesota and in Fairmont most of our herds we went to once a
week, in New Alma it was every other week and so we did a lot of what I
would call kind of hands on medical management, you know these pigs are
coughing a little more. Roy, you probably remember those days you know,
well, let\'s put some CTC in the feed to see if we can slow it down.
Sometimes those were, many times were batch fairers four or five groups
and you kind of managed them by the group that way. Fewer records, less
production in economic data. We used slaughter checks in some situations
but I think at that time we didn\'t have a very good understanding of
how to interpret the data and in total I think we were basing our
decisions on relatively subjective evaluations.

Control wise well, we had no mycoplasma vaccines, I mentioned the
benefit of all in all up by room, the approach that in the situations I
worked in was periodic medication for secondary invaders, the old BMD,
CTC rotation, during stress periods such as weaning, moving from nursery
to finisher. Some farms I had worked with, I remember one farm in
Michigan essentially the pigs moved from phase to phase every four
weeks, that\'s the way the farm was set up and so we would medicate the
first week that they went into the next phase, they\'d get medicated and
sometimes it was just like I said before, based on the severity of the
disease but there was pretty strong veterinary involvement in that.
Saying that the big impacts for me on respiratory disease on a herd
basis has always been in performance as well, better diets, better
ventilation, improved pigful. Those are the big things. Historically,
okay, I want to make that clear, this is like pre-1990, okay, so Dr.
Ross I thought I had this figured out prior to 1992 so, okay, next
slide.

And as I said, subjective evaluations, seat of the pants approach, kind
of the Dr. Schwartz, kind of your approach sometimes, you know, be
critical of the data that you get and go with it, the Lee Iacocca
method, you get 85% of the data that you need and you make a decision,
right? Okay. The limited factors to control at least in terms of
vaccines, even in terms of medication however, we were not uniformly
ineffective, okay? I, I, you know, we did have successes on farms,
absolutely, okay? But we had some things going for us and I think to me
as I look at kind of things on a global basis that the absence of PRRSV
virus is a big deal in the swine industry, the presence of it is a big
deal, smaller herd sizes which bring a lot of attributes in terms of
management in some cases, smaller room sizes, this is one I put a
question mark on because you know, is the micro environment of a barn
different if there\'s a thousand pigs in a room versus two hundred pigs
in the room. These are things that we may never know. And of course,
we\'re probably going to have barns with a thousand pigs in a room in
the future.

So, currently where are we at? Well, I think we\'ve seen an evolution of
swine respiratory disease, more explosive but repeated outbreaks. In a
way this is kind of what APP used to be like, if you think of, not
exactly but I remember farms where you know, Tim Rolla was one of my
partners in, in New Alma and we always had a saying that the most common
diagnosis was yeah you got it again and, and especially in some of these
places where we brought in feeder pigs, we\'d have continual problems
with APP. Somewhat older pigs compared to maybe Enzootic Pneumonia but I
think that\'s a little confusing because to me it\'s more of a
predictable age of onset within a herd or a system and you have farmers
that will tell you that well, I can just about set my clock by this
problem. High morbidity in some situations increase stall out pigs, a
variable but sometimes high mortality okay? And this has been designated
as a porcine respiratory disease complex. Now, this is one of my, a
little bit of one of my pet peeves, I guess is that as veterinarians we
are kind of trained to be kind of what I call, lumpers, okay? We\'ve got
to have a little box to put everything in, right? That\'s what we get
from turning back to reality parallels is that we\'ve got to have a
little box to put everything in and so, that\'s fine you know? But we
still have Enzootic Pneumonia in herds and we can have all kinds of
graduations of this so whether or not these kind of classifications are
helpful or not I think it helps people like Joe Van Sickle write
articles in National Heart Farmer but I think that we see a wide range
of situations.

In additions to M-hyo, certainly PRRSV, flu, *Pasteurella*, Circovirus
type 2 perhaps, still some question of that, (inaudible) cells for
pneumonia which sometimes can be confused or Asus can confuse that
issue, salmonella, emofus parasueous and strepsueous are isolated from
these cases. To me the main difference between Enzootic Pneumonia and
PRDC is the viral component. As I kind of look at it again on a global
basis, PRRSV certainly is the big one there. The changing pattern of SIV
and maybe there should be a question mark for that, certainly we know we
have another strain now that\'s kind of gone through the US swine herd
in the last three years. I would argue that maybe we never understood
SIV very well before because of some of the limitations in diagnostic
testing and again the questions mark of PCV2.

M-hyo often plays a significant role in underlying severity of PRDC or
Enzootic Pneumonia and I think one of the things that, that tells me
that that\'s the case is that M-hyo vaccination tends to be beneficial
in herds with varying degrees of, and presentations of respiratory
disease. Next.

And even in herd, in my experience even in herds that don\'t have what I
would call very significant amount of respiratory disease we will still
see benefit to growth rate by mycoplasma vaccination. Now, to me one of
the more definitive field studies was conducted by a fellow named
Dominic Mass in Belgium and they looked at the benefit of vaccinating
pigs for mycoplasma in fourteen herds. They vaccinated when at four
weeks of age and these were the results. They saw an improvement in
daily gain of 22 grams per day, a reduction in feed conversion, or
improved feed conversion, the biggest benefit economically was decreased
medication costs, a dollar a pig, this was converted to US dollars.
Prevalence and severity of lesions at slaughter was reduced but there
was no difference or no effect on mortality, coughing or carcass
quality. And vaccines tend to work on a single organism, at least on a,
on a direct effect. Now, if that organism has secondary effects like
mycoplasma then you are also going to have secondary benefits for other
diseases as well.

So why PRDC versus Enzootic \[pneumonia\]? What has changed? Well PRRSV
virus again. Pig flow related issues, increasing herd size, age-
segregated rearing, multiple site production, reduced weaning age,
reduced weaning age is a tough one to evaluate because we typically have
been, we only think of it as improving the health status of the pigs,
maybe that\'s not quite right, less attention to pig comfort especially
in the nurseries. As we look at PRDC now, I\'ll give you a case example
here in a minute. You know, many times we think the problem is
manifesting itself in the finisher but if you really dig back it\'s
going back in the nursery and farrowing and when I work with clients to
try and impress on them the fact of try to get to resolve these issues
earlier in the pigs life, I kind of use the analogy of how you build a
house. You have to build a house from the ground up and you need to look
at the foundation, even things like phase feeding have been involved in
several situations where some of the perceived stall out is actually
associated with drops in lycine levels and with some of our leaner pigs
in some situations we may be dropping those licean levels a little
quicker then we should be. Next.

Benefits of all in all out in, SEW, this is again, I think an issue we
deal with a lot in research is that we can develop concepts in the lab
or under more controlled conditions and how do we scale those up to
modern production. Scalability is a big issue that\'s over looked in our
industries and with these type of programs, they were demonstrated in
small herds of course, you know ten to fifteen years ago we didn\'t have
many large herds and our small research projects. Control of bacterial
disease was the primary benefit, okay? And in general controlling
bacterial disease is more a concept of controlling organism dose;
elimination is not as necessary. However, viruses have emerged as
important contributors, viruses tend not to be as affected by exposure
dose, for instance with PRRSV a study done at Iowa State, Dr. Yun and
Dr. Zimmerman compared route of inoculation with PRRSV plus dose and
basically what they found is that the dose or route of inoculation had
no impact on the final severity of the disease. Now, it did impact how
quickly the pigs got sick. Okay? And I think that\'s an important,
important issue. If we\'re successful with these sorts of things either
in regards to preventing vertical transmission from the dam to the pig
or prevention of lateral transmission from older pigs or from pigs
outside the herd, we developed fairly, highly susceptible populations of
finishing pigs that are then perhaps more affected by these organisms
get in and contaminate the system.

In addition, applicability of large herds and systems, the concept of
continual pathogens circulation in large breeding herds that are
bringing gilts frequently, compliance with pig flow rules, this is
always a problem with what I would call strict early weaning programs. I
guess one other thing that I would say too, is that the term segregated
early weaning is segregation and early weaning. It\'s not, we tend to
think of those two things together, there\'s really two different
factors. Multiple site finishers, many finishers close together.
There\'s a mile section up north of Ames where there are four companies
that each have a complex on each corner of the section, each one of
those corners houses 5000 pigs, now do you really think that those
companies can keep their disease statuses separately? Not with some of
these viruses. The other thing is and, and one of the more important
factors from a business standpoint is that there has been a lot of
capital investment. There\'s certainly a lot of accountants in companies
and producers and on owner operator farms recognize or feel that they
need to keep these facilities full which then prevents any flexibility
in terms of eliminating disease by sequential population. So a continual
disease. Again, go ahead,

In my experience we had, even on single site operations, we could break
some pretty significant disease problems simply by sometimes selling
feeder pigs for a couple of weeks, kind of sequentially emptying out
barns, making sure that people and pig traffic was kind of a one way
flow pre-PRRSV that worked pretty well, okay? After PRRSV I think we
tend to think more that we need to have fairly, more distinctive
population such as sites because of the transmission of these organisms
within the site. Again multi factorial approach. Some of my bullets are
not showing up here, I\'m not sure why but, it is necessary, okay and I
tend to think of these sorts of things here as improving disease status
and productivity in a general sense, medical things like vaccination,
therapeutics, we talked now about commonazation of new animals, tend to
reduce the impact of specific diseases.

Here\'s, I think the real rub that we have in our industry is that, that
we, we are really struggling with PRRSV and it\'s a, in fact I think
Scott Dees comment in one of this papers about developing the unified
approach for veterinarians so that the producers don\'t think we\'re
idiots, ahs some merit. I don\'t necessarily agree with unifying the
approach maybe we need to admit the fact that in relationship to PRRSV
we are idiots, just accept the fact. We\'re working hard on it, we're in
the explanatory phase but we don\'t have consistent technologies to
control the disease other then de-pop, re-pop and try to get rid of it.
So, in addition, so sometimes technology is not available and certainly
cost comes into it. We can\'t afford every product. When I was at
Michigan State, some of you may know Tony Martin was a resident of mine
and he was doing the extension work and he was always frustrated by his
colleagues in the animal science department would say that a good
vaccination program is when you vaccinate for everything and of course
we would say that well, if you vaccinate for everything, the only thing
you ensure is that you\'re going to go bankrupt, okay? So you have to be
selective. On the other hand you have to develop a strategy that yields
success and, and this is where you get into some real problems because
if you don\'t take an aggressive approach sometimes, do everything
that\'s possible to make the problem better you really never are
successful. Changing one thing at a time maybe the best way to do it
from a scientific standpoint but does have some limitations and success.

Okay, I\'m going to finish up here a little bit on my view of
diagnostics. Now, I know there\'s several talks on diagnostics but I\'m
going to give my clinicians view of diagnostics. First of all
identifying all of the organisms present in a given situation is
essential to formulate treatment, prevention and control strategies. The
clinician\'s challenge is sorting out the relative role that each
organism plays and I tend to think that I need to have an understanding
of this, the role of these organisms at the tissue level and that\'s why
histopath for me is a driving diagnostic issue. The presence of the
organism or demonstrating the presence of the organism is not
sufficient. You have to show that it causes a lesion. At the organ
level, the extent of the lesions. At the animal level, the severity of
signs, organs, number of organs damaged. At the herd level, the number
of animals effected in severity and these are issues that are not easy
to resolve for the clinical veterinarian or the producer however, we
need this kind of evaluation to determine the economic impact to justify
the action we are going to take.

So, gross or visible microscopic lesions are of little diagnostic value
except in APP cases and what I tell my students, if you have an acute
outbreak of respiratory disease, really the only decision you need to
make that day is whether they got APP or not because if they got APP, my
treatment strategy is going to be more like inject all the pigs. If
it\'s not I\'m going to maybe do water medication or some injection.
Lesions of *M. hyo* or SIVand, in a recent case of PRRSV, Circovirus,
looked the same. This I know for sure because of our research and, and
it\'s interesting how you can run along for years as a clinical
veterinarian attributing certain signs and lesions to an organism and
then once you actually study the organism by itself you get a little
different evaluation. For instance, flu experimentally causes very
little coughing. Now, if you put mycoplasma with it you get a lot of
coughing, typical, typical what we all think of as flu but Lisa, if they
don\'t have mycoplasma or anything else they don\'t cough except a very
little bit, okay? This is kind of a interesting case here and there\'s
three veterinarians, I think they\'re all here that came out to Iowa
State, when was that, last fall and I took them out to one of our
production units that\'s managed by a veterinarian over by Carroll,
Iowa, and I said yeah well, I was looking for a case of PRDC, right?
Okay, he says I got something going on, we think it\'s flu. We\'ve been
treating it for flu so on and so forth so we went over and looked at the
pigs and sure enough kind of a classical PRDC flu kind of outbreak,
posted one pig, yep it\'s got SIV, took the tissues back and think Kent
you were the pathologist on this, got PRRSV and Circovirus out of it, so
you know it\'s a tough one. So, we need to verify those lesions by
histopath and organism identification as a clinician the main test that
has really help me is immuno histo chemistry without a doubt that has
been a valuable test on tissues, yes.

This is a slide that I did. I use sometimes in my talks, especially when
I give talks in Latin America where they don\'t have the diagnostic
capabilities and so I\'ll put this slide up and you know, is this
mycoplasma and of course a lot of them will say yeah that looks like
mycoplasma, you\'ve got interior ventral consolidation, kind of lesions
like that, okay? But in fact, go ahead, it\'s next\--

It\'s influenza virus so, again very difficult to tell these things
apart. Next.

Clinical signs are not characteristic to any disease or disease
combinations. I think we\'ve known that for a long time. Next.

With Enzootic Pneumonia and again in the old historical days. I guess
you\'re getting old when you can say it happened a long time ago right?
Diagnosis was often limited knee crops elisions with very little
laboratory testing. Were assessments correct? Probably not. Did we truly
understand the various organisms involved? Probably not. I think the
challenge that I would put forth though is even as we get better
diagnostics do we still understand what\'s going on good enough, you
know? And what is that, what is that barrier or what\'s the, what do we
have to do to be successful? And here\'s one of the things that I think
limits our ability to be successful and that\'s sampling strategies
especially in terms of numbers of animals that we test and I present
this as a case and when I say PRDC \--

(End of side A)

pick up truck, load up 21 finishing pigs of various ages, anywhere from
three to five months, haul them over to Iowa State, Dr. Mike Gator was a
pathologist on this case and these are the results that we got. Five of
the pigs Mike couldn\'t find any lesions, they were normal. In his, in
the pathologist\'s view they were normal. Five with PMWS type of
lesions. One perhaps SIV, *Pasteurella* so on and so forth. The
challenge for me is that what if I would have only sent two pigs to the
lab? What kind of data would I have gotten out of this situation? I
wouldn\'t have gotten the information they got with 21, right? The other
thing is, is well, okay, it\'s good to have all these diseases and at
the same time we did a serological profile even though we were
vaccinating for mycoplasma with a vaccine that induces tydders by the
time they went through the finishing phase they were zero negative to
mycoplasma on the twin 20 test which to me indicates not that great of
an exposure. SIV, I\'m sorry that should be on positive. Some of these
things aren\'t showing up, they were positive, I\'m sorry. SIV positive.
PRRSV late 18 to 20 days. Did a slaughter check, low average percent
pneumonia, a few pigs with severe ventral pneumonia. Again, my
suggestion here is there were a few pigs that were more affected then
others, okay? So, I think that\'s an issue. Slaughter checks as we look
at that data and even in this case we also need to recognize that these
lesions will heal with time and flu lesions at least experimentally will
heal within two to three weeks. Mycoplasma can heal over a more like a
two to three month period of time. Finally I think the, to me the real
issue is, is how do we, as we look at the progression, the flow,
understanding what\'s going on with these pigs, how do we pin point when
these diseases are really affecting performance. In most situations we
only know for sure what happens during the whole finishing period as
well look at close out dated. To me the challenges to trying to identify
periods of time during that phase where performance is being more
severely effected. And ultimately we need to base our vaccination
prevention and control decisions on economics. Cost, of vaccines and
medications are relatively easy to determine. The benefit with regard to
reducing disease impact is very difficult to determine. That\'s\--

So, in summary my view of mycoplasma associated respiratory disease,
still not smart enough to effectively control respiratory disease in
swine. We need to know more about pathogens. We need to have a better
understanding of environmental stressors and we need better ways to make
economically the sound decisions. The challenge is that every herd
situation is unique and all of these diagnostics and remedial actions
need to be implemented on a farm by farm basis in the industry there\'s
always pressure to take the cookie cutter approach to production. And
certainly even in the big production companies, even as they try to
standardize different aspects of management, diets, so on and so forth,
that cookie cutter approach doesn\'t help because even those fairly
similar farms will still have significant differences that, and
sometimes we recognize what those differences are and sometimes we
don\'t. Next.

In my way of looking at it, laboratory research and diagnostic testing
frames the questions for and defines the limits of the clinicians
approach to each situation. It tells me, gives me a general sense of
what I need to be doing. It doesn\'t tell me exactly what I need to do.
I need to make that decisions at the farm level and so that ultimate
answer lies with the attending clinician that makes the diagnosis and
formulates implements and monitors, monitors is a big part of this
treatment and control programs. That\'s it. And we\'re waiting,
questions are later, right?

(female)

Well we\'re running good on time so I think you could take some
questions.

Dr. Brad Thacker

Yes?

Q So what did you do with that 21 pig group (inaudible)?

A We had a motivational session with the nursery people. We didn\'t, we,
we, yeah we had them, we had them do a few things in the nursery that,
management sorts of things but it wasn\'t anything that they didn\'t
know that they weren\'t supposed to be doing. So, and it was just a
matter of getting back to that concept of we've got to build that pig
from the ground up. Now, in, in so that\'s basically what we\'ve done in
that situation. We were already doing that, okay, we were already
(inaudible) three weeks in the nursery, mycoplasma vaccination,
essentially a CTC, BMD rotation and finishing. So, what else am I going
to do? I mean we, we talked about flu vaccinations but they were
reluctant to spend that kind of money and so and things have gotten
better. The, the thing though John, is that in the last, since that last
two years our finishing performance has really gone up especially in the
last six months and the biggest change has been genetics. We changes
boar lines so, and in fact in this herd that when I started working with
this herd 22 years ago, their finishing barns were empty. Why? Cause
they couldn\'t raise finishing pigs, successfully, okay? What was the
biggest change that I made in the operation to get them to raise
finishing pigs? Improve the diets. The second biggest impact, I took 30
days off the time of market. The second biggest impact was putting walls
in the finishing barns. That did, that improved prey to game, it didn\'t
improve the level of pneumonia at slaughter right away, that took a
little longer but we had this herd down to an average level of pneumonia
at slaughter of one to two percent prior to using mycoplasma
vaccination. So, for three or four years after the vaccine came out we
didn\'t use the vaccine. We started using it and we got an, you know a
sufficient increase in performance to justify the cost. So, does that
make sense?

Q One time or two times?

Dr. Brad Thacker: Two times and we\'re still doing it two times. Once at
weaning, they wean about three weeks of age and then three to four weeks
later. And we were considering one dose but we\'re going to give the one
dose at six to seven weeks of age anyway and the shot at weaning is, it
doesn\'t really effect our labor on that farm the way they do things.
So. Yes?

Q We\'re seeing a lot of (inaudible) with finishing deficiency these
days and uneven sizes of animals and trying to get them to finish all
the same time, you think that the technology hasn\'t kept up, or the
management level hasn\'t kept up with the technology of the larger herd
sizes and try to push these animals as fast as we can?

Dr. Brad Thacker: Well, I think that the, I guess I wouldn\'t have a
blanket statement for that. What I would say is that in my view of pig
production when you say management in the finish area the concept of
someone going out on a daily basis and telling pigs to eat, well,
doesn\'t work, right? And so when you say management, I\'m think more in
terms of how the environment\'s controlled and things like that. Many
times, effective management is more based on resources, resource input.
Now, on the breeding herd, you know I can, and so in the finishing herd
I\'ve got to have good resources, in the breeding herd I can overcome
deficient resources by management. People can overcome those more, not
totally but more and so that\'s why I don\'t to necessary think that
poor management in finishing is a big issue. It can be a big issue but
on the other hand we can overemphasize the impact that husbandry can
have in finishing pigs because there\'s so many other things that play a
bigger role. Yes, Don.

Dr. Don Walters: Brad, do you believe that the antiaprovial approach
could control the treatment of this disease can be effective (inaudible)
and the second part of the question is do you believe labels for such is
important or it\'s just (inaudible)?

Dr. Brad Thacker: Well, first of all I, Don, I always have the same you
know, if you want to watch, ask somebody a question, watch what they do
with their feet, you played basketball right? Used to didn\'t you? Okay,
anyway but you know, so we use them and, and I think they are effective
in certain situation. Now, the dilemma you get into is that you use them
for a while and everything is going very well then how do you keep using
them or do you try to back off and I\'ve had both experiences, you back
off and everything is okay and you back off and you\'re crap on the
farm, you name is, you know? So yeah I think they can work. The labeling
part of it to me, it comes down, the question is how much detail does
the label need to help frame the decision for the clinician? Okay, it\'s
the same issue we had with the diagnostic lab or with research, at what
point is more information or more instructions or more detail of any
value to the clinician. Now, what do I like to have? Well, first of all
I want to know what my withdraw times are, okay? I would like to have a
general sense of what the antibiotic is effective against, okay? In my,
in my opinion that data can be generated in a experimental setting,
okay? If I have more field type of data, that\'s fine but again at that
point I have to make the decision on that farm. So what you find in one
field trial may have nothing to do with what, what I\'m faced with at
this point. Does that make sense or? So, I mean it\'s, I guess I\'d like
to know some pharmacokinetic data with injectables because I do have you
know, some decision making in terms of frequency of administration with
feed and water medication there, it's in there all the time, right? So,
yeah you have to have the pharmacokinetics but I can\'t, I can\'t do
anything about that, that\'s going to be given to me so\-- Is that it?

(Dr. Punderson) (There are voices speaking over top of the introduction)

(inaudible) Dr. Thacker. Our next speaker is Dr. Monty McCaw who will
cover current trends in the presentation of disease associated with
mycoplasmal hyopneumoniae co-infection with PRRSV virus and other
pathogens. Dr. McCaw graduated from Iowa State, did his PhD at Minnesota
and has been at North Carolina for the last 12 years doing a combination
research teaching and industry support role, let\'s welcome Dr. McCaw.

Dr. Monty McCaw

Brad, do you have the nervous stick? The pointer? All right, thank you.

Dr. Thacker

You nervous?

Dr. McCaw

Yeah, yeah you got something to do in your hand.

Dr. Thacker

Supposed to hold it, see you hold it like this.

**Dr. McCaw**

Brad and I have come through probably some very parallel paths and so as
one of the perspectives perceptions that I\'ll share with you are
actually very parallel with what Brad had just presented and those paths
have gone under the tutelage of Dick, Carlos and before I make you guys
feel just too old and Roy\'s been a real mentor in a lot of respects in
the practice side of things. Lisa, who\'s just snuck out and Roberta, I
don\'t think they probably Lisa\'s probably had some practice in the
very many places where a continuous flow is a problem because it didn\'t
exist that much anymore. Roberta, you probably came up in three side
productions, the absolute norm and all and so one side production is a
very uncommon thing. So, we\'re sharing experiences today and from maybe
some different, again, perspectives, hopefully outside of the box as
well as inside of the box but Carlos was one of my mentors that, that
started my PhD program after coming out of practice in Lake City, Iowa
and I think I made it fairly clear I wanted to bridge the gap between
the producer and science and so my presentation will go both ways,
bridging the gap a bit more then where Dr. Thacker focused primarily on
what is the challenges in the field, how are things seen and then very
much so from a historical and a current basis both as covered really
nicely. So, if you would please. Interesting, that Brad, these things
change after you switch computers. Before 1990 as Brad said, mycoplasma
was really pretty insignificant disease at least clinically to those of
us who are in practice also due to just lack of technology as much as
maybe market as well, there weren\'t no vaccines available. We didn\'t
have targeted antibiotic programs even for mycoplasma, so it relatively
said it wasn\'t that big a problem to the producer. We rarely saw
clinical disease outbreaks. I would have to say Brad, I did see one,
somebody that had started out with a SPF herd and then thought they\'d
buy some conventional boors and I called Dick up on that to see what to
do and tetracycline after the fact really wasn\'t going to be helpful to
get them back to an SPF status and again, as Brad pointed out it
facilitates other organisms like APP and *Pasteurella*. In the late
\'80\'s and early 90\'s and through the 90\'s and this is when I went
down to North Carolina and so the paradigm shift maybe occurred there
first, not necessarily it was the wisest place in all the face of the
earth but it at the moment was the most ripe to apply new technology and
new ideas, was the massive paradigm shift in the way we raised hogs and
then during that time frame also, PRRSV was introduced and it\'s
subsequent epidemics and racing through American pig industry and most
of the pig industries of the world. With these two changes then came the
emergence of what we now know as PRDC, a change in mycoplasma, it was
little, yes again, we definitely saw mycoplasma. We saw lesions of
mycoplasma before this but now this has become something that from am
economic viewpoint is a massive problem for, for the industries I know
at North Carolina and around the country. So, an overview of where I
want to go, I\'ll parallel a lot of the comments that Brad has shared on
swine industry changes, PRRSV impact on disease, then is something that
I\'ll share my impact or my, my insights or experiences, ignorance quite
frankly with you and that is the area I work with the most, is PRRSV in
the pig. So, don\'t go home thinking I\'m some sort of the know ledged
based individual for mycoplasma and then closing with what are some of
the challenges that antibiotic therapy today in the swine industry might
face. The changes that we saw again, big industry continuous pig flow,
rearing where we had multiple age groups in a building or a site and
Brad talked about dividing a finisher into rooms, we didn\'t do that, at
that point in time. There was a building or a site of pigs and the
multiple age groups in contact with each other, we never cleaned and
disinfected between groups unless we flat out depopulated a herd, often
times for some massive problems sometimes you could use Pseudorabies as
a excuse but often times other chronic disease problems led to economic,
not necessarily catastrophe but certainly crisis that might lead us to
depopulate a herd and then endemic disease models was the mode of the
day, kind of a daycare school kid model and then again Roy is, you know
gone through many years, that\'s not an insult that\'s a statement of
honor in respect but, because somebody\'s going to say the same thing to
me in about 10 years but it was, that was the way my Dad raised pigs. We
had a barn. We had pigs that we threw out there probably about 12 to 14
weeks of age and we pulled pigs out when they got big enough and Lord
knows how old they were, they just were big enough to go to market. They
all ate out of the same feeders, licene values and phase feedings, it
was just one brand fits all and ammonia levels were pretty high
particularly when you took out the manure and temperature variation when
the side wall had frost on it and the other wall had steam coming off of
it, you know, there was probably a little bit of temperature gradient.
So, a really challenging situation to control disease in.

Continuous flow, to give you a little bit of conceptionalization. I know
we have students these days that only want to know if I was raising dogs
and cats, so this is where this cartoon kind of comes from. We start off
with different age pigs within the building. Go ahead.

And the pigs go out through the building growing but we bring in a new
batch of pigs, this group of pigs has now gotten a little bit older.
This group of pigs now is ready for market, we\'re still bringing in
another group of pigs and the process starts over again. So, this is
what has been seen within continuous flow, this is how the pigs go
through the building and once you get in the building itself, you clean
out one pen to market and you put in new pigs, well the next group to
market and it\'s a little bit dark here but you\'ve got a pig that\'s 24
weeks of age, now nose to nose with a pig that\'s 10 weeks of age and so
that was the impact of, of continuous flow operations and also beyond
that just between this nose to nose contact again, we are taking the
biggest pigs out of there to go to market, the right size of pig, so
would we market this whole pen at a time, potentially not. We would pull
half of the pigs out of that pen and then take the other half that
didn\'t go to market and mix them with another group just one pen down
below that. So a lot of movement of animals, shuffling up and down the
sizes and for, for any of us that have really sat in the barn very long
or watched mixing of sows or mixing of pigs of any groups but pigs are a
very social hierarchy type of animal and so they fight and they will
re-establish that hierarchy and so from a feed gain viewpoint, they\'re
off feed for two or three days because they\'re trying to take care of
business like out in the street and they\'re fighting among each other
and when they\'re fighting they\'re stressed and when they\'re stressed
they are also sharing organisms and potentially trading diseases back
and forth. So, this continuous flow operation was a very stressful
operation as well as one guaranteed to exchange organisms back and forth
and maintain those organisms forever and a day.

So, again we had the changes that came along then, one of the
innovations finally was starting to deal with pigs, groups of pigs as
groups and we did start dividing buildings into rooms and a single age
group now is a group of pigs that were born into a single farrowling
room and within a single week so that the age difference within that
room now is very, very tight instead of having potentially fourteen or
ten different age groups in a room or a building we\'re down to one week
in variation in age and depending on the size of the operation you might
have one age group in a building or potentially even a sight. These pigs
were places at the same time into that building or site or room and then
that room has no other pigs that are added to it, that\'s the strict
form (inaudible) out and then that room is emptied completely and boy it
gives you a chance to clean and disinfect and when you start trying to
control microbial diseases or for that matter keep, keep from getting
food poisoning, cleaning and disinfecting is a pretty big important part
of controlling disease in any situation. So, again we\'re flowing all in
out facility, all the pigs come in as young animals, all the pens were
filled with these pigs, all the same age. They have gone through the
growth stages and go to market all together and we had the cleaning and
disinfecting time before we then load the unit again.

So, this then helped us break the old,-to-young transmission cycle
greatly decreasing contact and exposure between pigs, like we saw on the
continuous flow type of barn but and Brad eluded to this, this must
perfect to be successful and I\'ll get a little bit deeper into that but
if we are successful adding this old, young pig transmission, the other
thing that we result in is naive population, that then puts a high
premium on biosecurity or preventing exposure of this population of pigs
to pathogen. Used to be within the system that was from older pig to
younger pig and also the challenge that we have yet is that it goes from
mother to baby, and to make that break it needs to be perfect to end up
with a perfectly naive population and then we can garner as producers
the advantages of disease free or at least very, very disease clean pig
production and the lack of disease and loss in performance that way. But
that changes the model then from an endemic disease model or Enzootic as
we named mycoplasma from a pneumonia viewpoint into an epidemic disease
model and so it\'s much more dramatic and it isn\'t occurring
immediately upon placement for these pigs in some of these facilities.
So, other changes then kept coming. Again, we just got done talking
about all in or out by group, then we decided that maybe wasn\'t quite
good enough. We maybe, could do better. We could maybe do a better job
of breaking that transmission for the sow to the piglet because we
frankly still had disease problems in the all in or out type finishers
on what we called single sight production. You know, that\'s where you
have farrowing, the nursery and the finisher all on one site or one
farm. So, these changes occurred both in the mid west and proposed
frankly in the mid west by Dr. Hank Harris and in principle by Tom
Alexander as well, from England but the application, the explosive
application occurred in North Carolina because it was right to, to go
get a big wig into hog production and they wanted to do it in a modern
way and they wanted to do it in a way that going into larger sizes would
hopefully have inherent strengths in disease control and so they adopted
a second level of control and it was site level disease control again,
moving from one site production which we used to call farrow to finish.
We had the farrowing rooms, the nursery rooms and the finishing rooms,
again the buildings all on one site.

And this is a farm near my home and Roy, you\'ve probably been there a
few times but we have, if I remember correctly, farrowing facility here,
breeding and gestation, nursery\'s over on the side and then grow,
finish all on the same site. So, you have the whole, all the different
age groups are on the site and more then likely somebody might be
working here and then go over here and fix the water that broke and then
they need to maybe load out some pigs from the farrowing house, take
them over to the nursery, a lot of probably, exchange of traffic let\'s
say between these different age groups and potential for a transmission
of disease and probably just as, just as powerful and maybe more
difficult to control was natural transmission to disease from the sow to
the piglet in the, in the farrowing house. But any rate we, we chose to
break up our sites into three site production to try to decrease this
old to young transmission risk. So, now we have specialized sites, sites
that have farrowing only, and then they do include obviously the
breeding herd, so the adults are there and then the babies are there.
Nurseries are on another site and then the finishers are yet to another
site. So, now we\'re adding transportation in between these sites as a,
as a stress point, maybe as a risk point because now we are going to
different places around the county or even around the state and the
country frankly, the trip to the nursery maybe from North Carolina to
Iowa or Indiana or Wyoming. The intentions of three-site production as
it was laid out again by Dr. Harris was to eliminate bacterial and
vertical transmission and initially he did it with antibiotic medication
at birth and through to weaning which would have occurred at about three
to seven days, so very early weaning and physiologically this does not
agree at all with the sow. We separate the piglets to a different site
and that\'s still something that we do do and then it was also then
experimentally in small group sizes. This was brought about by a need to
try to break disease transmission or clean up genetic breeding stock
sources and it was quite successful, very successful on a small group
basis, to create what we call new nucleus herds and, again, clean
genetic sources and this is easier quite frankly then doing cesarean
sections and trying to raise pigs that [in essence are
gnotobiotic]{.mark}, this allowed for colostral uptake and also yet
achieved the goal, we felt, of breaking the bacterial transmission from
sow to piglet.

Our adaptation at least in North Carolina, and quite frankly around the
country, was unmedicated before weaning, we weaned at the standard three
weeks for various reasons again the sow being able to breed her back at
the normal time or at least relatively normal time when she could (a),
be fertile; (b) have a likelihood of becoming pregnant; (c) have a
predictable time of coming back to estra so that the producer could you
know, get her breeded off a lot of efforts, a lot of labor and a lot of
angst actually in searching for the elusive estrus and then we would
still separate these pigs. We still do separate these pigs to different
sites. Along with all of this we went to very large group sizes. You
know we basically went up ten fold increase in size and again Carlos,
when I left Minnesota and went down to North Carolina the herd sizes we
were often times dealing with there in Minnesota are 250 sows, 500 sows
maybe. The normal herd size in North Carolina was 1200 sows and we
quickly went to herds that were 3000 sows in size as, as a norm. Part of
the desire for that was to have in the end a group of pigs in the
finisher with approximately 1000 head of pigs per finishing building,
that seemed to be the goal then they would work backwards from that goal
to determine the number of sows they wanted to have in a site. With that
adaptation we were unsuccessful in preventing disease transmission and
losses with that model and many of these are bacterial diseases and many
of them were viral diseases. We were successful in decreasing many of
these disease losses and maybe not so much from a clinical disease as
much as from a production based as Brad pointed out, feed efficiency,
rate of gains were improved and again this whole structure probably has
facilitated emergence of new albeit delayed syndromes and again
mycoplasma is at the heart of that.

This is one of the earlier forms of nurseries, two buildings, four rooms
each, each room has 1200 pigs in it. So, one weeks of age pig is in each
of those buildings, or each rooms of those buildings, therefore at one
point in time the building may have approximately 4800 pigs in it and
then there is a week down time for each of the different or as the rooms
of pigs are moved off to the finisher, it does have down time for
disinfection and cleaning.

Then we go to finishers and again, these are operated either as a single
age group per finisher or potentially the whole site has one age group
and then we bring in pigs from multiple different farms, one farm\'s
pigs potentially fill a building but those buildings now run all in all
out and have time for cleaning and disinfection between.

So, pre site production adaptation we\'ve found that we basically need
to go to a single site source of pigs that Brad alluded to and age old
method of raising pigs in America and that was the feeder pig and the
feeder pig market and that used to be bringing many, many pigs or some
pigs from many, many different sources, tremendously difficult challenge
in controlling diseases in essence impossible but even with re-site
adaptation in the large sizes we are dealing with we\'ve had a very hard
time in still bringing in anymore then just one source of pigs to effect
disease control and those listen to AASV, we\'ve, we\'ve seen the
attempts and noble attempts by particularly, Kirk Clark in trying to
find ways to medicate pigs or wean them earlier to be able to have
multiple site sources of pigs, again to come into these finishing sites
and nurseries without much disease loss and those have been very, very
difficult challenges to, to achieve. Part of the challenges were that
these, thankfully we can now say in the past of Pseudorabies, TGE and in
general total weaned pneumonia which is a big long laundry list,
particularly APP, *Pasteurella*, etcetera. And, as Brad pointed out, now
PRRSV. There are multiple strains of PRRSV, we\'ll talk a little bit
about that and then each herd has a different status of say virus
circulation going on at any one time. Some herds are in an epidemic
stage, some herds are in a cooling down stage and other herds are in a
quiescent stage. The pigs coming from those herds as Brad is pointing
out, building up, from the foundation up, well, I like to use a computer
analogy, garbage in equals garbage out. Getting a good stable pig to
come into the nursery, the off site nursery in the off site finisher is
a huge challenge today and it\'s most easily met by again, working with
single site sources of pigs to bring into those finishers.

Okay, shifting gears now away from facilities now towards the disease
PRRSV and I will focus heavily on PRRSV and as Brad pointed out, it\'s
an excellent talk for giving on a new emerging problem with Circovirus
in pigs, we\'re not certain of its full role. Is it a facilitator? It
certainly does not seem to be sufficient in and of itself but as, as we
call it PRDC, the C is complex, means multiple infections, multiple
factors of environments and everything else, has emerged as a problem,
huge problem for the industry. So, PRRSV itself, clinical signs it\'s
own presentation in and of itself causes abortions, still births,
mummified fetuses. In an epidemic form it can be very, very dramatic
losses. The piglets coming through will show very high levels of
preweaning mortality and we\'ll discuss mechanism for that and then as
they go on, the survivors going on to the nursery and the finisher, they
too continue to show mortality and high levels of disease and reduced
gains and then as we get into more of an endemic form after the initial
epidemic we see finishing, finishing pig pneumonias. Again, this is were
mycoplasma starts to have a central role in this and a much more
elevated role from the historic view point then it has in the past and
the PRDC complex. PRRSV mortality and disease particularly mortality but
also even disease signs seen during a PRRSV outbreak are very much from
the secondary bacterial diseases. Some quite pivotal work actually by
Pat Halbur that I will state, took strains of PRRSV from different
outbreaks in the early 90\'s and put them into pigs that were
caesarean-derived and colostrum-deprived.

His results were no mortality and he said he\'s done approximately a
thousand or more pigs in this type of system, all he gave them was PRRSV
and so when they\'re in essence bacteria free there was no mortality.
Yes, there was fever, yes the pigs were off feed but they weren\'t dying
and again the clinical presentations often times in a PRRSV herd are
more of the secondary bacterial diseases, meningitis, arthritis,
enteritis caused by things like *Actinobacillus* or more importantly
*Strep. suis,* *Haemophilus parasuis* and these are pet projects of
Carlos\' and then even *E. coli* problems seem to be exacerbated by, by
PRRSV outbreaks.

PRRSV virus infections are immunosuppressive and this has been a very
hard thing to prove and we\'ll still struggling in some respects to show
this real clearly and more importantly we are struggling mightily to try
to understand how it\'s appearing and what are the final impacts of it.
A motto that we developed and are working with is we infect the sow in
late stages of gestation and cause an *in-utero* infection. *In-utero*
infection in known immediately upon isolation of PRRSV, that was one of
the models that they used to fulfill (inaudible) was to infect a
pregnant sow and it caused the fetal problems that we\'ve listed and
then re-isolate the virus back out from the sow and not all piglets die
*in utero* by any means, many of them are born but they are born now
viremic and infected with PRRSV showing signs of thymic atrophy, lymph
node enlargement, interstitial pneumonia and again, very open to
secondary bacterial infections and the lesions that come along with
that. So, these little guys are, are coming from a litter that\'s
probably potentially feral really or certainly from a litter that is
effected with PRRSV, they\'ve already lost weight in uterus, that\'s the
striking thing about this. You look at these little guys and you can see
the back bones often times, their skin wrinkles. I don\'t know if you
can see it but a little bit but along this pig that their skin seems to
wrinkle like a, a wash board it\'s because they\'ve already lost some of
that subcutaneous fat they\'re supposed to have upon birth. So, whether
it\'s [TNF alpha or what ever]{.mark} cytokine [effects]{.mark} that are
going on, they were sick in uterus and they were already trying to fight
off the infection and needed energy apparently to do so and or had
cytokine effects that were mobilizing fats and probably muscle from
their system. Again, lymph node enlargements, these are the kidneys but
just retro to the kidney enlarged internal iliac lymph nodes, lymph
nodes are often times enlarged in thoracic area, this pig also had
secondary pneumonia, very, very typical problems. Carlos used to talk to
us about Hemophilus parasuis is an example, Glassers' disease you know,
is usually a fairly discussion of a fairly classical situation in that
we would never see it unless we dealt with herds that had been like
caesarean-derived for a specific-pathogen-free herds. On the onset of
PRRSV and taking students out to herds every other herd I went to we end
up seeing *Haemophilus,* or Glassers' disease, *Haemophilus parasuis*,
once you had PRRSV so it was normally an endemic infection usually not
clinically seen but with the advent of PRRSV, it was very easy to show
classical Glassers' disease.

Okay, some measures of immunosuppression that we\'re seeing in this *in
utero* infected pig model is peripheral blood mononuclear cells, the
CD4, CD8 ratio of the lymphocytes are being reversed and then in this
again, this model, we looked at baby pigs at zero days of age, fourteen
days of age, 67 days of age and this is basically birth, approximately
weaning and going to the nursery and then leaving the nursery at
approximately 10 weeks of age, going onto finishing. This bar, the
orange bar is the PRRSV infected piglets, again the mother was infected
approximately two weeks before farrowing and then transplacental
infection versus the non-infected controls. So, we see a massive up, up
tick in or for an expression of interferon gamma, cytokine signal being
expressed in these pigs peripheral blood mononuclear cells and I will
preface this by we do need to take a look at the lymph nodes and other
regions of the immune system but this is the initial study we went with
and so we are looking at peripheral blood cells. Go ahead.

[IL-6 levels]{.mark} were also significantly increased in these early
ages. IL-10 greatly increased expression levels of isle ten both at
birth and again still significantly increased by the time we weaned
them[.]{.mark} IL-12 levels were unchanged but then we looked then at
the ratio of IL-12 to IL-10 again a significant suppression of that
ratio, all these platters were very, very similar to those seen in AIDS
patients. So, whether it\'s using the same mechanisms as AIDS or not,
certainly it would appear that there is some commonality because again
these pigs are very susceptible to secondary bacterial infections. It
was very easy to reproduce a *Strep. suis* and PRRSV disease outcome or
model when we use these types of pigs versus the efforts that were done
prior to this and even [SIVS]{.mark}to try to recreate the field PRDC,
the field nursery disease complex which we may thing is and still is I
think horizontal transmission involved as well. So the *in-utero*
infected PRRSV pig, it\'s immuno suppressed, very susceptible to
secondary bacterial infections. These pigs are long term viremic. Dave
Menfield from South Dakota State University and his people have shown
these pigs are carrying the virus upwards of 210 days after birth and
this means that their immune system has yet to clear the virus. So, they
have some sort of deficits in their immune system that they\'re carrying
the virus that long. These pigs become Typhoid Marys not only of PRRSV
but because they are immuno suppressed they\'re carrying other bacteria.
I think that\'s one of the things that building that, that foundation
from the ground up or the garbage in, garbage out principle, we are
carrying problems into the farrowing house, or into the nursery from the
farrowing house that pre-PRRSV we probably didn\'t and so with this
we\'ve got to control the sow PRRSV circulation of infection within the
sow herd to prevent this vertical transmission to have a hope of
controlling finishing pig PRRSV in the long term situations. So, we\'ve
got a great artist in our school and the bacteria are catching a ride on
this PRRSV infected pigs and immuno compromised pigs in large numbers
and we\'re shipping them off to the nursery and hoping through three
side production and all in, all out production, we\'ve got a group of
clean pigs but we\'ve got this Trojan pig sneaking in there and may not
be very many of them, it doesn\'t take very many to go on in,
contaminate the rest of that group and then obviously start setting off
problems like PRDC.

A friend of mine, a colleague of mine and definitely friend first is Dr.
John Roberts, he\'s working with us at NC State now and he\'s studied
more on the epidemiology side of the world came across an equation
that\'s also been used by researchers in Holland to try to explain PRRSV
spread within herd and potentially the disease complexes that we\'re
seeing. It actually, I think has some definite application. The
incidents were the, the development of new cases or individuals of
sickness within a population is I, transfer probability I think is
probably been increased by the fact that PRRSV is immunocompromised.
That transfer that are in PRRSV-infected pigs remain a compromise
transfer probability of say *Strep. suis*, of maybe bringing in
mycoplasma, of bringing in *Pasteurella* or other types of infection
into that, that mix. Contact, we have probably decreased again with the
industry changes that Brad and I have discussed, quantity of infected
pigs though is probably one of the driving factors to why we\'re seeing
a delayed type of pneumonia versus the endemic model of years past. And
the group size is in the equation and again with modern production
systems often times that\'s very large. Go ahead, please.

The red line might show a PRRSV epidemic and let\'s say maybe half of
the pigs are born or become infected very quickly after birth with
PRRSV. They go on into the nursery and again nursery phase occurs or
moving to the nursery occurs at three weeks of age and I apologize for
not putting a line in there for you. And so by the, by the time ten
weeks of age comes a long, we are moving those pigs out of the nursery,
all of us had been practiced chasing PRRSV have found many groups of
nursery pigs that are a 100% positive, zero positive for PRRSV. And
these little groups of pigs definitely have had disease problems already
and then actually disease problems are not that great although they
certainly aren\'t without disease problems in those groups that are very
(inaudible) to PRRSV. But what we see after an outbreak is maybe months
maybe even to a half a year or more after an outbreak pigs go through
the nursery phase now and if we\'re testing 30 animals we can end up
with zero animals on a test of 30 that are zero positive to PRRSV, that
group looks like that didn\'t have PRRSV go through. Now, that\'s a
function I think again, at a level of testing that if we would have
tested more pigs we would find a few that had PRRSV and they end of
being those Trojan pigs, those typhoid Marys that I\'m trying to allude
to. Now, using that equation that I showed you and just presuming a
doubling of the number of infected pigs each time you move here you\'re,
you\'re increasing the number of infected pigs or percent of infected
pigs let\'s say, with each one of these moves what was said, you\'re
getting close to a hundred percent infection just after that 18 week
wall that our producers dis-affectionately call PRDC. So, during this
phase is a lot of activity now of transmission of PRRSV between the pigs
probably other bacteria certainly are jumping in again, mycoplasma as
we\'re here today to talk about but this is I think why, we\'re seeing a
shifting of the pneumonia problems or even the disease problems into the
mid to late finishing stage is that we\'re getting a very low prevalence
of PRRSV coming into the nursery, we don\'t see it by the diagnostic
tests that we\'re using and it\'s not it\'s a bad test, it\'s just we
from a cost savings view point don\'t use it to the level it\'s maybe
necessary to find low prevalence but that group was infected and in fact
now the disease, the infection is causing disease in that group.

So, horizontal nursery pig transmission of PRRSV and in particular
finish pig spread is definitely occurring. It\'s critical I think to
finish your disease problems with M-hyo, again resulting in PRDC as Brad
talked about (inaudible) is definitely playing a role. Maybe a role
maybe not a role as controversial as the porcine respiratory crona virus
it\'s certainly there. It has been isolated multiple case and now a
questioning role of where this porcine circovirus-2, come in. We\'re in
the very early stages of trying to figure that out and as Brad pointed
out, we need, have needs for diagnostic techniques, diagnostic tools
that we\'re just now developing those and let alone the knowledge and
wisdom of how to take those results and go back to the farm and say this
is a component of the disease problem and even more important to the
producer is this is what you do about it.

PRDC and particularly PRRSV immunosuppression though is very difficult
to recreate experimentally Eileen and Pat Halber have been successful
using a very severe PRRSV strain that Pat alsolet, isolated from the
field and then using other things like dexomethozone Jeff Zimmerman has
shown *Salmonella choleraesuis* and in PRRSV. Carlos is one of the only
people at a meeting in Copenhagen some years back to demonstrate a
weaned pig PRRSV infection and then adding Strep to that pig to get
disease out of that situation and at the end of the meeting after
everybody else had gone up, all the other laboratories of the world had
gone up and basically said we couldn\'t do it, Carlos stood up and said
folks we don\'t have the answer and going away from that meeting Carlos
said that was a hard bone for me to chew on. We sat in a café afterwards
and actually talked about that and that was in the (inaudible) in some
respects of looking at the *in-utero* infection model. I still \--(End
of tape)