While the leading causes of calf illness and death within the first few days after delivery are non-infectious physiological disturbances, after that time, the majority of illness and death losses are attributable to infectious conditions. It is useful to group these infectious conditions based on their underlying pathophysiology, rather than diagnosing them by specific disease agents. Distinguishing between localized viral/protozoal enteritis, bacterial enteritis and septicemia can help focus attention on appropriate sampling for diagnosis, establishment of accurate prognosis, effective treatment measures, and effective preventive practices.

Viral or protozoal enteritis in calves is attributable to organisms that cause superficial damage to the mucosal lining of the intestinal tract. The primary sign of disease is diarrhea (or "scours"), attributable to malabsorption, maldigestion, or hypersecretion. The disease effects and eventual cause of death in affected calves are attributable to the loss of electrolyte-rich body fluids. Without invasion beyond the gastrointestinal mucosa, the organisms involved do not cause significant pathology in other organ systems. The dehydration, depression, weakness, inappetence, and metabolic acidosis that accompany this problem typically occur in direct relation to the severity of the fluid loss. The magnitude of fluid loss and acid-base imbalance and ability of calves to withstand insults are impressive.

The direct cause of calf scours is exposure to and infection by specific infectious agents. Indirect causes include the many factors that increase calf exposure to the microorganisms or decrease calf resistance to infection. The microbes may act individually to cause diarrhea but frequently when a scours outbreak is found in a herd, two or more of these agents can be identified in affected individuals or in the group of scouring calves. Although each of these agents is unique, and they can cause disease in several different ways, the end effect of the infection in the calf is strikingly similar for all of the major scours-causing agents. The four agents that cause the majority of calf scours are rotavirus, coronavirus, cryptosporidia and K-99 E. coli.

Focal bacterial infection can localize in almost any organ system of the calf, but most typically these problems occur in the gastrointestinal tract or respiratory system. In contrast to superficial localized enteritis, these infections could be characterized as severely inflammatory to the infected tissue. Gastrointestinal infection is most common in the neonate, while respiratory infections are more typical of the calf beyond one month of age. Organisms commonly incriminated in gastrointestinal infection include Clostridia and Salmonella spp. These organisms can not only damage tissue locally but also cause severe systemic inflammatory responses due to toxin release. Appropriate treatment of affected calves includes aggressive antibiotic and anti-inflammatory treatment in addition to supportive fluid therapy. Prognosis even with prompt and aggressive treatment is guarded. Calves affected with clostridial enteritis usually die rapidly before the onset of diarrhea due to the profound effects of exotoxin on the vascular system.

Septicemia occurs when the infectious organism spreads beyond the site of invasion and is carried hematogenously so that multiple organs show inflammatory damage concurrently. The prognosis for septicemia is grave unless it is recognized early and aggressive medical therapy is instituted. Successful treatment must be intensive and usually includes supportive fluid therapy, antibiotics, intravenous plasma, anti-inflammatory agents, and often intranasal oxygen delivery.

The invasive types of E. coli are capable of invading beyond the gastrointestinal tract to cause septicemia (microorganisms in the blood). In this instance, the infectious bacteria can spread to any organ in the body, including lungs, brain tissue, kidneys, and joints and can cause severe damage at these infected sites. The Salmonella species of bacteria have been associated with calf enteritis but like the septicemic E. coli, Salmonella has a strong tendency to spread beyond the gut and cause widespread disease.