Editor’s note: This article is the second in a two-part series about how transition cows’ immune systems are impacted by metabolic factors. Read Part I Metabolic factors affecting the immune system of the transition dairy cow. 

Milk-fever cows are at increased risk of developing mastitis. Low blood calcium (hypocalcemia) has several negative effects. Calcium is necessary for proper contraction of muscle. Severe hypocalcemia prevents leg and other skeletal muscle contraction to the point the clinical syndrome known as milk fever occurs.

Muscle contraction is reduced by any decrease in blood calcium; however, it must be severe before we observe the “downer cow.” Researchers in 1983 demonstrated contraction rate and strength of the smooth muscle of the intestinal tract is directly proportional to blood calcium concentration.

It could become severely reduced before leg muscle contractions were lost. Further, at the end of the teat there is a muscle surrounding the teat opening that must close tightly after milking to avoid milk leakage. Low blood calcium reduces teat sphincter contraction. The open teat canal provides an opportunity for environmental pathogens to enter the mammary gland.

We generally associate milk fever with the day of calving, but we have demonstrated many cows remain subclinically hypocalcemic for much of the first week of lactation. Hypocalcemic cows tend to spend more time lying down than do normocalcemic animals.

Again, this increases teat-end exposure to environmental opportunists in early lactation. It also means they are consuming less feed, making negative energy and protein balance worse.

Beyond its negative effects on muscle contraction and cortisol secretion, low blood calcium has a direct action on the immune cells. In 2006, it was demonstrated cows with low blood calcium also have lower-than-normal levels of calcium inside the cells.

Normally when a white blood cell encounters a pathogen, it causes release of calcium from calcium stores inside the cell. This rise in free calcium levels then activates killing mechanisms the cell uses to halt the infection. Unfortunately, in a hypocalcemic cow, this reduction in intracellular calcium stores means the cell does not mount a strong and quick response to a bacterial invasion.

Ketosis and mastitis susceptibility

Ketosis is the result of a cow being unable to adequately respond to the energy demands imposed by the onset of lactation. In lactation, the amount of energy required for maintenance of body tissues and milk production exceeds the amount of energy the cow can obtain from its diet, especially in early lactation when dry matter intake is still low. As a result, the cow must utilize body fat as a source of energy.

Every good cow will utilize body reserves in early lactation to help it make milk. However, there is a limit to the amount of fatty acid that can be handled and used for energy by the liver (and to some extent, the other tissues of the body).

When this limit is reached, the fats are no longer burned for energy but begin to accumulate within the liver cells as triglyceride. Some of the fatty acids are converted to ketones (acetoacetic acid or beta-hydroxybutyric acid).

The appearance of these ketones in the blood, milk and urine is diagnostic of ketosis. As fat accumulates in the liver, it reduces liver function – and a major function of the liver in the dairy cow is to produce glucose. The disease is also characterized by a decline in blood glucose. The conclusion is: Energy intake must not be compromised during the days around calving.

Any factor restricting feed intake around calving (such as milk fever or retained placenta) increases fat accumulation in the liver, affecting the energy deficit of the cow and increasing the risk of fatty liver or ketosis.

The fresh cow is also in negative protein balance shortly after calving. Generally, this is not perceived to be as big a problem as the negative energy balance of early lactation, but the typical cow will lose 37 pounds body protein during the first two weeks of lactation.

Much of this body protein is being used to support the amino acid and glucose requirements of milk production. Therefore, in many respects, the dairy cow in early lactation is in a physiological state comparable to that of humans and rodents with prolonged protein-calorie restriction.

Glutamine is the most abundant free amino acid in human muscle and plasma and is utilized at high rates by rapidly dividing cells, including leucocytes, to provide energy and optimal conditions for nucleotide biosynthesis. As such, it is considered to be essential for proper immune function.

Plasma glutamine decreases as the cow progresses into the early weeks of lactation, as it is consumed more rapidly than it can be replaced.

Does the relative calorie-protein deficiency of the early lactation cow impact its immune response? In humans, protein-calorie restriction has severe effects on cell-mediated immunity.

There is often widespread atrophy of lymphoid tissues, and this can cause a 50 percent decline in the number of circulating T cells. Surprisingly, antibody responses are intact and phagocytosis of bacteria is relatively normal. However, destruction of bacteria within the phagocytes is impaired.

When white blood cells encounter a virus, they respond by secreting interferons, substances known as cytokines, that will affect nearby cells and improve their resistance to viruses. Blood lymphocytes were isolated from normal cows, and cows with clinical and subclinical ketosis, and then placed into culture to test their ability to produce interferons in response to a viral challenge.

Leukocytes of cows with subclinical ketosis (a +2 score on the urine ketostix test) produced one-quarter as much interferon as non-ketotic cows when exposed to a virus they had never seen before. Cows with a +4 on the urine ketostix test produced less than one-tenth the amount of interferon as normal cows.

Researchers in 2000 examined the relationship between liver fat content and functional properties of neutrophils of dairy cows in the peripartum period. Liver fat content above 40 milligrams per gram, which was considered the upper level of normal, went in parallel with a reduced expression of molecules associated with immune function on blood neutrophils.

What is the energy cost to mount an immune response?

In humans suffering from severe infection-causing sepsis (various degrees of fever, increased white blood cell count and inflammatory protein production), the resting energy expenditure increased progressively over the first week of the infection to around 40 percent above normal maintenance requirement and was still elevated three weeks from the onset of illness. As an aside: Over a three-week period patients lost 13 percent of their total body protein.

No such measurements have been reported for cattle. However, if we are allowed to speculate, we can go through a few calculations. Maintenance energy for a 600-kilogram dairy cow is approximately 9.7 Mcal net energy per day.

If the cow must also increase energy expenditure 40 percent to mount an inflammatory response, the energy requirement increases by nearly 4 Mcal per day. This is roughly equivalent to a requirement that the cow consume an additional 2.4 kilograms of diet (assuming a diet that provided 1.65 Mcal NEl per kilogram). Being ill, this is unlikely to happen.

Can the periparturient cow, already in negative energy balance, be expected to successfully mount a rapid immune response? If it is in fact in negative protein balance as well, will the cow’s immune system produce the immunoglobulins and inflammatory proteins necessary to fight an infection while it is still in the acute phase to prevent it from escalating to a chronic clinical infection?

Steps to take to reduce immune suppression 

Management

Avoid overcrowding. This may be the biggest issue faced on dairies, especially as they expand or try to accommodate the cows they would not breed back in the heat of summer and all become pregnant in the cooler fall months. Each cow should ideally have 30 inches of bunk space before and after calving.

Each cow should have 120 square feet of space to lie down in on a bedded pack, and if freestalls are used in the close-up group, they should be stocked at 85 percent of capacity.

Move cows into the close-up pen well ahead of calving (or better yet, do not move them at all). In freestall systems, it is best not to move the cow into a calving pen until feet are showing. Moving cows in earlier stages of calving causes more problems with stillborn calves.

Under some circumstances, moving cows into smaller maternity pens a day or two before calving can upset feed intake. A researcher examined 10,000 cow records and observed that cows calving within 10 days of a pen change have a much higher risk of being culled and produce less milk. Consider feeding close-up cows twice a day to encourage higher feed intake; pushup of feed is not enough.

Diet considerations

The diet should incorporate some strategy for prevention of hypocalcemia prevention. Currently, we believe high-potassium diets cause the cow to be in a state of metabolic alkalosis (reflected by urine pH above 8.0). Adding palatable anions to the cow’s diet to induce a compensated metabolic acidosis (with urine pH of 6 to 6.5) seems to be one of the more commonly used methods to prevent hypocalcemia.

Adding calcium boluses or drenches can further improve calcium status around calving but do not seem to effectively prevent milk fever on their own. Low-calcium prepartum diets to prevent milk fever are very difficult to implement. However, a zeolite-based product that binds diet calcium and prevents absorption can make this more practical.

Energy content of close-up cows is a hotly debated topic. My own opinion is: The restricted energy diets (high straw or mature grasses) are more forgiving diets. They do seem to reduce displacement of the abomasum. Picking the correct straw and mature grass can reduce diet potassium, making it easier to achieve a low-DCAD diet.

Protein content should supply 80 grams metabolizable protein per 100 pounds bodyweight. With high-straw diets, this may require addition of rumen bypass protein. If there is ever a time to consider addition of bypass amino acids, it is in the dry cow and fresh cow diets to improve protein utilization when it is most needed.

It is important to feed available mineral sources, especially magnesium and the trace minerals. Feeding elevated levels of vitamin E in the pre- and post-fresh diets is advisable.

Pharmaceuticals

Beyond nutrition, there are two pharmaceutical products available that are designed to stimulate non-specific immunity in the cow prior to an expected immune challenge. One consists of DNA in a liposome carrier, which can bind to receptors on the immune cell surface and activate the cell. These activated cells then produce cytokines that help prepare other cells of the immune system to fight off infections.

The second product is granulocyte colony-stimulating factor, a cytokine which causes the bone marrow to produce neutrophils at four to seven times the normal rate for about 10 days. This product creates a pool of neutrophils ready to move into a site of infection and attack the infection with overwhelming numbers of neutrophils.

It will be interesting to see how these products perform in the field – and even more interesting to see what other products can be developed as we learn more about the bovine immune system.  

References omitted but are available upon request. Click here to email an editor.