Editor’s note: Last in a series on bovine lung immunology.
Boosting lung defenses can include things like low-stress handling and timely use of respiratory vaccines. Dozens of vaccines are available for use in cattle but you can’t get “immunity in a bottle” without strategic timing and proper management.
If the viral infections are the first ones to start compromising the innate defenses, then clearly immunity to the viruses can play a very important role in minimizing the risk of fatal respiratory infections, says Philip Griebel, DVM, PhD, Vaccine and Infectious Disease Organization, University of Saskatchewan. “Vaccines are not a magic bullet, but what they’re doing is raising the threshold of disease susceptibility. They will increase the threshold for an effective challenge dose. Animals need to be exposed to a greater amount of virus for a greater period of time to overcome immune defenses, before the virus starts to impact lung defenses.” Vaccines can also decrease virus transmission within a group, so they can individually raise the threshold of disease susceptibility for individual animals as well as enhance herd immunity by decreasing the efficiency of virus transmission.
Breck Hunsaker, DVM, PhD, Livestock Consulting Services and Horton Research Center, Wellington, Colo., says there is broad support and use of viral vaccines by feedyard managers; however, some feedyards might rely too much on them, based on reported research that questions vaccine efficacy. “Some of our feedyard managers want to vaccinate and revaccinate and revaccinate, if you let them, with viral vaccines. You have to remind them that timing of administration is critical.”
But vaccines alone can’t do it, and can be overwhelmed. Feedlot vaccination includes onset of immunity, magnitude of response, and duration of immune protection. Vaccines have to be delivered strategically relative to the risk period. “Inducing an immune response isn’t sufficient,” Griebel states. “We have to think about the idea of protective immunity. If we vaccinate on arrival, is that too late? It will depend on the exposure. There is now evidence that some of the modified-live viral vaccines can induce protective immunity within five days. But the effectiveness of this vaccination will depend on where those calves are in that infection cycle. We need to think about vaccines very strategically, relative to risk period.”
Timing of killed vaccines
Research confirms that bacterial vaccines can also prevent fatal respiratory infections, Griebel says.” If you look at vaccines for Mannheimia, and the bacterial leukotoxins, it is clear that these vaccines prevent fatal pneumonia. The bacteria causes lung inflammation and abscessation which severely compromises respiratory function. This lung damage can be sufficient to cause animals to die because there isn’t effective oxygen exchange. Again, bacterial vaccines can raise that threshold of disease susceptibility.”
A killed vaccine, because it has limited antigen load, often requires double immunization to induce an immune response which is protective, Griebel explains. “The standard immunization protocol for most killed vaccines is a two-shot regimen. So the single shot on entry won’t achieve that protective level, whereas the modified-live viral vaccines amplify the amount of antigen and has all the danger signals, supplied by adjuvants in killed vaccines. This enables modified-live vaccines to induce protective immunity much more quickly.”
Kip Lukasiewicz, Sandhills Cattle Consultants, Inc., Ainsworth, Neb., believes the time and place to most effectively use bacterins such as Mannheimia, Pasteurella and Histophilus vaccines is on the ranch two to three weeks prior to weaning. “There’s a lot to be said for the timeliness of when it’s given,” he says. “On the ranch, we recommend Histophilus, Pasteurella and others while the calves are still on the cows and their stress level is very low. They have ample opportunity to acquire a good immune response at that time.”
Lukasiewicz says his experience with Histophilus breaks in a couple of yards over the last few years with myocardial lesions and heart failures was controlled by cleaning pens better and better pen management since Histophilus is shed through feces, urine, nasal secretions, etc. “This year we haven’t had one Histophilus case out of that yard, whereas last year I already had about 14.”
Hunsaker believes because those are killed agents, the timing is much more critical with a bacterin, with a killed agent, than it is with a modified-live antigen. He says there has also been some work done on looking at interference between modified-live vaccine and some Pasteurella/Mannheimia bacterins. “We talk about immune response like it’s an antibody response and I don’t think those two terms are really interchangeable,” he says. “Immunity is really protection, but if we were to use a modified-live at branding and a Pasteurella or a bacterin pre-weaning, would that timing be more suitable for what we’re trying to achieve? When both are given at the same time — if there truly is interference clinically between those two antigens — then maybe we’re not doing ourselves any favor by giving them both.”
Griebel explains that work done by Richard Harland indicated that if vaccines are given in two different sites, such as opposite sides of the neck, there isn’t interference. “You can give them at the same time and not have interference. I think it’s important that people know that they can give both vaccinations if they are at separate sites.” Griebel notes that this work was done with a modified-live IBR/PI3 only.
The ability to neutralize leukotoxins and endotoxins are critical for success when using bacterins, adds D. Scott McVey, DVM, PhD, Veterinary Diagnostic Center, University of Nebraska. That’s where we’ve seen improvement over the last 20 years, like the improvement with the Mannheimia bacterin/toxoids. They’re much better than they used to be. Beyond that, antibodies to many different somatic factors that potentially enhance clearance are important. There are a lot of disclaimers and caveats. We’ve already talked about the weaknesses of bacterial challenge models. We take normal animals and, for experimental purposes, put a ton of bacteria down in the respiratory tract, and then look at usually what counts for registration of a vaccine — comparative lung lesion scores in vaccinates and non-vaccinates. Antibody titers and serologic responses don’t often correlate all that well to that protective response.”
But even under the best of circumstances, what you see is a reduction of 50% to 80% in the lung lesion scores, McVey says. “It’s not sterilizing immunity and it is generally not very effective. On the other hand, most immune responses, under optimal circumstances to viral vaccines — BHV1, BVD — are pretty good. You can knock down shedding and viremia to almost zero.”
If you compromise the timing of the administration strategically, if you compromise the immune system, it’s not surprising that cattle get overwhelmed with the bacterial infections, McVey says. “We have much better vaccines than they used to be. There is a real research opportunity to define clinically relevant challenge model systems for Histophilus somnus.”
Immunology and treatment
Treatment of bovine respiratory disease hits a feedlot hard economically in drug cost, labor, and performance and mortality of cattle. Sometimes treatment is a guessing game when it’s unknown which pathogens are to blame, and the wrong treatment can be of further detriment to the animal.
Griebel explains that for Mannheimia infections, for example, recruitment of neutrophils is a death sentence, because they can activate a massive inflammatory response causing the destruction of lung tissue. “As a clinical veterinarian, you may not know what’s in that lung. If you knew that it was Mannheimia, then an anti-inflammatory may be absolutely critical. But if there is a Pasteurella multocida infection and it’s being contained by neutrophils, then treating with a corticosteroid may cause the Pasteurella multocida to spread through the lung. We’re dealing with a multi-factorial disease in terms of etiology and many of these therapeutic interventions may be very good for one bacterial infection and may make the disease much worse for another one. We just don’t have the diagnostic tools to know what’s down in that lung.”
And even the right drugs won’t restore the lung to its original state. “Some people buying and using antimicrobial therapies think they are making the lung all new again, that it restores normal function, but it doesn’t,” Hunsaker says. “That’s a tough concept to get across. Once irreversible damage hasbeen done, we just want to minimize that. You may get sudden death of an animal that was treated three months ago. That lung probably supported a 400- or a 500-pound carcass, but it doesn’t support an 800-pound carcass and that’s frustrating for the managers because they’ve spent money on therapy.”
MICs and sensitivity testing
For antibiotics to be effective, it is necessary to maintain a minimum inhibitory concentration. “We must consider the pharmacokinetics of antibiotic therapy,” Griebel states. “I think the failures in lung delivery are often about timing of treatment. When bacteria in the lung enter log-phase growth, we’re fighting a losing battle.” If we treat too early and our minimum inhibitory concentration has dropped, or if we come in too late and the extent of lung damage has reached a point where antibiotics can’t enter the site of infection, then their efficacy is compromised.
And if you’re too early, Hunsaker adds, you may disrupt or interfere with the commensal population to the extent that you allow an opportunity for pathogens to invade.
What frustrates Lukasiewicz are MIC and sensitivity levels of antibiotics. “You can have in vitro MICs that indicate resistance, but then you use the antibiotic in vivo and the anti-biotic works,” he says. “It’s resistant in the Petri dish, but it’s working in the animal. So is it the animal’s ability to metabolize that antibiotic and get it to the area that needs to be addressed?”
Chase answers that by saying there has been work with some antibiotics that shows that macrophages will concentrate some of these drugs. “You just can’t use in vitro testing alone. In vitro testing can be very misleading.”
McVey notes that with sensitivity testing, it very much depends on bug-drug interactions. “I find those kinds of measurements more useful in an epidemiological sense as opposed to a therapeutic sense.”
“The whole concept of sensitivity testing and using that as more than just one piece of information is contrary to what we’re talking about in this multi-factorial setting,” Hunsaker adds. “We have a number of things going on and now we’ve isolated one bug in a lab environment in a Petri dish or a blood agar plate and then making an assessment of that bug in that environment versus the multi-factorial environment of the lung. It is tough to make that leap accurately.”
Another issue is actually getting the antibiotics to the bacteria. “Various bacteria are very good at creating barriers,” Griebel says. “We’ve talked about how Pasteurella multocida can create an abscess, and if there’s no blood flow, then there’s no antibiotic delivery.”
With the antibiotics available, Lukasiewicz says that some people may have the impression if they use an antibiotic that lasts seven to 10 days, they can ignore that animal for seven to 10 days. “It goes back to post-treatment care and animal husbandry, observing those animals on a daily basis,” he says. “Sometimes you need to recognize that you might have to bring them back in the following day and re-drench them or provide an anti-inflammatory — not necessarily giving them another antibiotic, but giving them something to help them out and feel better.”
Some people think every animal in the population is the same and they’ll all respond, but they’re all in a different place on that morbidity curve or in the incubation phase,” adds Hunsaker. “To consider they all ought to be treated the same is probably misleading.”
Antimicrobials may reduce the number of bacteria, but the animal has to heal itself. Post-treatment care is probably the most important — clean water, a clean pen, adequate feed, and a palatable feed source. Lukasiewicz believes the best medicine of all is free-choice prairie hay. “You want your hospital to be clean. Sometimes they have a better chance of surviving by going back to their home pen instead of staying in the hospital.” Lukasiewicz only wants to leave extremely ill or special-needs cattle in the hospital pen if he can.
But sometimes hospital cattle get ignored, and Lukasiewicz reminds that they need special attention. “We shouldn’t forget the individual animal. If you or I go into a hospital, they’re not going to let us lie in bed and forget about us. Ask the animal to get up and move around. Ask the cowboys or cowgirls to have compassion. Provide a palatable ration. Having hot and cold rations in the hospital is extremely important. Some yards just use leftovers for the hospital. That’s called laziness, not management. If you’re going to have a hospital system, then you’d better manage it. If you have cattle on a cold ration and you give them a ration number five, it’s like giving them a chocolate bar. I don’t recall going to the hospital and getting a chocolate bar. It upsets the digestive tract. And then we take them back to the pen and they fall back a ration causing inconsistencies.”
If cattle are to stay in the hospital pen versus going back to the home pen, Hunsaker cautions that it takes excellent hospital pen management. “I see hospital pen management as being an afterthought because it’s not a profit center,” he says. “The things the cattle have to deal with there are changes in ration, metabolic challenges, re-socialization, and then you’ve basically created a miniature version of a sale-barn environment. We have cattle in the hospital from multiple sources and we bring them in to get them better, but what we really do is create fomites and it becomes an overwhelming challenge.”
Overcrowding of hospital pens on feedlots is a common problem. “Why would you put a sick animal in a pen designed for 10 and then place 50 sick animals in it?” Lukasiewicz asks. He would rather see them back in their home pen with their peers. “Cattle are extremely social animals. They have behavior patterns throughout the day. There’s social licking where they groom each other. They have their little cliques. That social component is really huge.”
Generally, hospital pens require more pen space and more bunk space to be more conducive to healing. “Typically, they put a hay ring in the hospital and they put cattle that weigh 800 pounds in with cattle that weigh 300 pounds,” notes Hunsaker. “They put lame cattle in with the respiratory cases and it’s just not an environment conducive to healing. It’s like a place to get them out of sight and out of mind.”
“People are becoming very sensitive to how we treat animals,” Lukasiewicz adds. “With labor issues as they are, trying to reduce our level of illness is a major obstacle. If we utilize some low-stress techniques in our daily routine, we may find that we spend less time pulling and treating sick cattle and spend more time creating a positive environment for those animals.”
Where do NSAIDs fit in?
Non-steroidal anti-inflammatories (NSAIDs) are sometimes used in supportive care for feedlot respiratory disease. “I think the issue of supportive therapy is critical,” says Philip Griebel, DVM, PhD. “Antibiotics are buying calves time, but in the end, it’s the host’s defenses that must clear the infection. If we’re not supporting those defenses, the immune functions, then the antibiotic will run its course and bacteria will survive. All we’ve done is delayed the problem and maybe reduced the magnitude of it. Unless there are proper supportive therapies to bring in the immune defenses to clear the infection, then the problem won’t resolve.”
Breck Hunsaker, DVM, PhD, adds that work has been done to show that NSAIDs do modulate neutrophilic infiltration. “We talked about the benefits and maybe more important the deleterious effects of those neutrophils. If we can tip the scale in favor of pulmonary macrophages and gamma-delta T-cells to modulate that neutrophilic response, maybe there’s an opportunity to enhance the healing process.”
Unfortunately it gets back to the redundancy of the inflammatory pathways, notes Chris Chase, DVM, PhD. “We know that non-steroidals affect certain areas, and that’s good. There’s an upside in terms of knocking down some of those inflammatory pathways. They are very specific, versus steroids, which are not very specific. You can choose the pathway where it’s involved, so from a strategic standpoint, there are some advantages.”
NSAIDs aren’t the only answer for pain relief, adds Kip Lukasiewicz, DVM. “We have the non-steroidals that provide some pain support, but for how long? Sometimes just getting them to get up and move around and loosening up the joints is better pain control. If you have knee surgery, they have you moving that knee within an hour or two after surgery. Getting those animals up and asking them to move around the pens works.”
D. Scott McVey, DVM, PhD, agrees. “I think there probably are some yet-to-be-understood factors in using that type of therapy,” he says. “A lot of it probably is timing. It’s a tool we don’t know enough about.”
“If we choose pain relief, as veterinarians we need to be aware that we rely very much on clinical symptoms because we can’t talk to the animals,” cautions Griebel. “If we mask the clinical signs, that may leave us in a very difficult situation when evaluating animals’ response to therapy.”
This information is from a Bovine Veterinarian roundtable sponsored by Intervet/Schering-Plough, moderated by Jessica Laurin, DVM.