Coming next: Pathogenesis and clinical signs

There’s no doubt that calves coming into the feedlot are undergoing a big dietary and lifestyle change. Epidemiologically, diet has often been associated with respiratory disease in cattle. “The bigger the diet change, the more susceptible the calves are, but we’ve never known what the link might be,” says Philip Griebel, DVM, PhD, Vaccine and Infectious Disease Organization, University of Saskatchewan. “It may be just the level of energy because the immune system requires energy, or maybe it’s just the level of immune regulation. Diet composition, including trace minerals and vitamins, is going to have a big impact on lung defenses.”

The immune system involves the production of proteins and the generation of a large number of cells, which requires energy. “People who are malnourished become prone to disease,” Griebel continues. “Tuberculosis requires very high energy at the cellular level to fight that type of pathogen. Especially in people, there are very clear examples of compromising nutrition at the level of total energy, and this completely changes the type of immune response generated during infection. It’s not only the magnitude of immune response, but the type of response which is altered as the energy level changes. It’s quite a complex interaction between energy and the immune system.”

What’s the metabolic cost of sickness? “The biggest issue is just getting something into them that will sustain normal homeostasis,” says Breck Hunsaker, DVM, PhD, Livestock Consulting Services and Horton Research Center, Wellington, Colo. “Pete Anderson has presented data (unpublished) showing in the first seven days on feed, if calves are not consuming an average of something like 1.6% of their body weight on a dry matter basis over that period, they have a higher mortality risk.”

The lung is one of those surfaces in the body that’s exposed to the environment and researchers are finding links between what’s going on in the gut and the lungs. An example is the recent evidence that the diet of children who drink raw milk may affect whether they have asthma (due to the regulation of inflammation in the lung). “We’re finding that a lot of immune regulatory cells are generated in the gut and can end up in the lung,” Griebel explains.

Kip Lukasiewicz, DVM, Sandhills Cattle Consultants, Inc., Ainsworth, Neb., has seen calves that will overeat because they’re extremely green and hungry. “You can feed them sick that way,” he says. “And I wonder if it’s the prostaglandin release in the intestinal tract that is initiating some of the inflammatory response? I understand that there is a level of acidosis, but what actually triggers the inflammatory response?”

“We’re finding unique links between what’s going on in the gastrointestinal tract and the immune system,” Griebel says. “For example, leptin, which is emerging as a peptide that’s very important in saiety and fat deposition, also has anti-inflammatory and immune-regulatory functions as well. Thus, there is a complex relationship between the gastrointestinal tract and the immune system which can have a direct effect on immune defenses in the lungs. In terms of  how feedlot management  may compromise lung defenses, getting feed into the animal may be doing much more than just supplying energy. Micronutrients like selenium and vitamin E have very big impacts on regulating inflammation and immune cell functions.”

Duration of stress

Certainly diet and both physical and psychological stressors are factors that compromise basic innate defenses. Discussions about stress need to include duration of stressors and duration of the stress response. Does the stress persist long enough to compromise immune system function sufficiently to create an opportunity for the pathogens to enter? “Many bacterial respiratory pathogens are normal commensals in the upper respiratory tract,” Griebel says. “They have to be able to enter the lung and stay there. The duration of these stressors, I think, is very important, along with how much they alter lung defenses.”

Griebel adds that if animals that are lower on the social hierarchy end up being sick and may not get access to feed bunks and water and if these subservient animals repeatedly enter different groups, they’ll never be able to improve. “If you put them in a treatment pen that’s already over-crowded, their chances of getting back on feed and getting the nutrients they need to fight that infection are fewer and fewer.”

Stress begins at arrival

Lukasiewicz believes stress starts in the receiving period. “We can’t control how these animals were loaded or how they were handled prior to coming to the feedyard,” he says. “But how do we receive them? How do we handle them at processing? At the receiving end we like to have a person standing in the alley as the cattle are coming off the truck. When you allow the animal to walk by you and you don’t stick him with a hotshot, he gets a positive feeling. It’s a good ‘hello.’ Then when we go to process them in 24 or 48 hours and they see that person back there again, they’re comfortable. That type of thing really reduces our level of stress.”

Controlled studies have looked at alveolar macrophage function in calves right after transport and the impact on “shipping fever,” says Griebel. Macrophages are less phagocytic, less able to clear pathogens. “The studies are always done within 24 hours after transport, and in the feedlot, you’re looking at a longer period of susceptibility.”

One of Lukasiewicz’s clients is a 3,500-head farmer/feeder who waits to process cattle, sometimes five to seven days post-arrival. “Their morbidity and mortality rates are the same or lower than those who process within 24 hours. He does everything you tell him on receiving and he has a sense of compassion.” The receiving pens are freshly cleaned with hay in the bunk and clean water in the tank. A day after arrival calves are taken to the drover’s alley to kick up their heels and exercise and the producer can pick out any needing treatment.

“Some people think that requires too much time,” Lukasiewicz says. “But this husband/wife team gets everything done including cleaning, feeding, riding pens, treating and processing. Yet at a large yard, one cowboy riding 5,000 head doesn’t have time to exercise a pen of cattle? I question his compassion and his belief in what he’s doing. Is he there to ride pens or to train his horse? I’m there to reduce the stress level on those cattle, get them on feed and make them comfortable in their pen environment.”

And by doing that, “We’re disrupting the amplification of pathogens,” Griebel adds. “This is just a management procedure, but it can help to maintain lung defenses.”

Hunsaker agrees and says with Mannheimia and work with E. coli, “We’ve shown that morphine and epinephrine are actually a stimulus. So if you have a colony anyway, you now increase replication. The pathogen takes advantage of that.”

Chris Chase, DVM, PhD, South Dakota State University, explains on the swine side that when pigs don’t have a stress load on them, their productivity goes through the roof. “The problem is that as soon as they get a load on them, because they’re so susceptible, they crash. You can see if we tax the immune system with growth and development, there’s a cost to the education in the immune system that brings it along.”

Chase recalls a study by Jon McGlone from Texas Tech where he had a catheter in the ear of pigs and measured natural killer-cell activity. He would then snare the same pig and take a blood sample, and natural killer-cell activity was about 40% less. “Hot-shots and other ‘handling aids’ or any other intervention which results in stress can be very immunosuppressive in ways that people just don’t think about,” Chase says.

In host/pathogen relationships, antibiotics have been effective because they can dampen the bacterial replication rate. “However, stress can compromise bacterial clearance in a number of ways, since stress compromises a variety of innate immune defenses,” Griebel adds.

The problem with commingling

Hunsaker doesn’t like to overlook the risk factor of commingling and its relationship to viral-bacterial synergy and stress. “We have feedyards where they have add-on pens, which means they go to the sale barn every week. It takes them three or four weeks to build a pen and you can pinpoint that as a cause of their problem.”

Hunsaker did some work in Texas looking at risk of castration on arrival compared to commingling. “It was mostly observational, but we saw as much risk associated with commingling as we did with castration on arrival. I think that plays an important role. Re-socialization is a tremendous stressor and can be seen when you introduce new animals into a pen or you introduce groups together. You also get this huge pathogen load they haven’t seen before as they are introduced into the new population. The challenge is high and the resistance is low based on the stress of re-socialization. That’s a factor that the feedyards tend to overlook.”

Lukasiewicz sees the same thing. “When you build those pens every three weeks, you have animals on a different nutritional plane. You’re trying to get the newest ones caught up to the oldest ones. The newest ones may be stressed and maybe had IBR and PI3 and they start shedding and re-expose everybody in the pen. They turn all that back on again and create a whirlwind effect.”

“In our experimental challenges, we have a substantial titer of a specific agent we’re dealing with, but it’s a point-time exposure versus continuous exposure over time,” Hunsaker explains. “Every time we add on, we increase that length of exposure. It seems like a simple solution but it’s hard to get these guys weaned from doing it. There’s always a bargain out there.”

Pen density increases risk

Griebel believes the issue of pathogen amplification is critical. “In our experimental models, the first thing we do is titrate the pathogen to find a dose that causes disease. Animal density is an important factor in amplification since this determines virus transmission to susceptible animals.” Weather is also a factor since most viruses are very sensitive to UVA radiation. “If you get the right weather, you can build up the environmental load of a pathogen and increase efficiency of transmission. It won’t be just the animal density; a lot of factors need to come together.”

Lukasiewicz has a client with a large, closed-herd ranch spread out on 30,000 acres. “When those calves come into the feedyard, they’re so naïve, it doesn’t take much to make them sick, versus ones that have been exposed to pathogens before. They’re on a great vaccination program and everything else at the ranch, but they’re naïve when they get to the feedyard. We have to mass medicate them on arrival.”

“It’s the animal density and it’s the number of naïve animals that keep coming into the population that facilitate disease amplification,” Griebel adds.

“What we do with herd immunity is huge,” according to Hunsaker. “We tend to think on the individual level and manage on the herd level. But this further drives home the point how important it is to have herd immunity. If 80% of the population is resistant, the remaining 20% are not likely to show clinical signs.”

“In regard to animal welfare, I think as a profession we need to start doing some objective measuring,” Griebel states. “Stress is important and certain stressors canw double mortality, but we need objective measurements to determine how important stress may be in disease susceptibility. These measurements would provide us with a more informed way to respond to the animal welfare issue. Is it the fact that animals are being transported for 24 hours or is it how we handle them after they arrive? We need to do some of the research to define which stressors are important, the duration of the stress response, and the impact of combining various stressors if we are to become engaged in the dialogue about animal welfare in an objective and measurable way.” 

This information is from a Bovine Veterinarian roundtable sponsored by Schering-Plough and moderated by Jessica Laurin, DVM.

Parasites and immunology

Parasitemia also alters immunity. Immunologists have developed a paradigm known as TH-1 and the TH-2 immune responses. “Enteric parasites are thought to drive immune responses more towards a TH2 response, which causes less inflammation than the TH-1 or pro-inflammatory response,” explains Philip Griebel, DVM, PhD. “So internal parasites may actually be dampening down the inflammatory response in the lung.” For a Mannheimia hemolytica infection, this may be a good thing, since it may decrease lung damage. For another bacterial pathogen, it might be quite different.

“Clearly there’s a link between what’s going on in the mucosal immune system in the gut and the lung and this may modulate inflammatory responses in the lung,” Griebel continues. “If there’s an over-riding primary viral respiratory infection, that may negate what the parasitism is doing. Stress also accentuates responses to the viral infection, so what’s going on with the parasitism may not be all that important other than compromising nutrient levels.”

However, it’s been shown that an immunosuppressive protein is released by Oesophagostomum spp. “That’s why we have such a hard time with parasites,” notes Chris Chase, DVM, PhD, “because they skew it so there’s no memory. It’s short-term but it’s anti-inflammatory. They want attachment. They don’t want to be moved out of their spot. In terms of vaccination, parasitemia gives us bigger problems because that is when we want a memory response. We want vaccination to have some duration. If we have an animal that’s suffering from a parasitemia, then we’re dealing with a skewed T-helper-2 and we’re going to see less of a vaccine response. It depends on what you’re looking for.”