Treating parvovirus (Proceedings)

Parvovirus is a virulent infection that most commonly afflicts dogs less than one year of age. The infection is characterized by vomiting, bloody diarrhea, and leukopenia. More recently a new variant of canine parvovirus (CPV2c) has been recognized. This new form of the disease affects a wider range of ages, since vaccination against the typical form (CPV2b) does not generate sufficient protection. In addition, the diarrhea associated with CPV2c tends to be more mucoid than hemorrhagic. Puppies with parvovirus frequently demonstrate dull mentation, fever, tachycardia, tachypnea, and weak pulses, all signs of shock. If left untreated the majority of dogs will die. Treatment, consisting of aggressive supportive care and extended hospitalization, can improve survival rates from approximately 10% to 75-90%.

In order to improve treatment strategies and reduce the severity of disease in affected puppies, it is important to understand the pathophysiology of parvovirus. While the initial insult is the result of viral infection, the destruction of the intestinal crypt cells results in a breakdown in the normal protective intestinal barrier. The viremic phase occurs at 3-4 days after exposure; however clinical signs do not occur until 6-10 days after exposure. It has been shown in several studies that the clinical disease associated with parvovirus infection is the result of bacteremia. The most likely source of bacteremia is bacterial translocation from the injured intestine. In germ-free dogs, the clinical signs of parvovirus infection are negligible. Dogs with parvovirus are actually suffering from gram negative sepsis. In addition, these dogs are severely immunocompromised as a result of viral destruction of white blood cells.

Several specific treatment strategies have been investigated for the treatment of parvovirus. These can be divided into three categories: first, anti-viral approaches; second, strategies directed at bacteremia and endotoxemia; and third, strategies at improving immune function. In order to evaluate the efficacy of a new drug or treatment strategy, double-blinded, placebo controlled clinical trials represent the gold standard. There are few such trials available in veterinary medicine.

Anti-viral strategies

The best anti-viral approach is prevention, through the use of vaccination. This is an extremely effective means to prevent parvovirus; it is however, not helpful in the treatment of clinical disease.

Anti-viral drugs historically are expensive and have not been systematically investigated in the treatment of parvovirus. The one drug that has attracted a lot of attention is Tamiflu, (oseltamivir). This drug is a neuramidase inhibitor for the use in treatment of influenza. Influenza virus depends upon neuramidase for cellular invasion and budding. In theory this is an attractive anti-viral, however parvovirus does not rely on this mechanism for its pathogenesis. It has been theorized that neuramidase may be beneficial in combating bacterial adhesion, because cholera vibrio uses this enzyme to unmask its receptor on cells. The one clinical trial evaluating the efficacy of this treatment in parvovirus failed to show a benefit in survival or duration of hospitalization, however dogs treated with oseltamivir did gain more weight than the controls.

Passive immunity may act through an anti-viral mechanism, however the potentially beneficial effects of plasma in the treatment of parvovirus have never been subjected to controlled clinical trials. In addition, there are many factors in plasma that may be responsible for a treatment effect.

Antibacterial and antiendotoxin treatments

Antibacterial treatment in one experimental study treatment of parvovirus infected dogs, treatment with fluids and antibiotics (procaine penicillin-G 20,000 IU/kg and dihydrostreptomycin 20 mg/kg) improved survival from 10% in untreated dogs to 90%.

Anti-endotoxin treatments have also been investigated. Use of an equine-based anti-endotoxin hyperimmune sera was reported to improve survival in one study; however, in a separate study dogs less than 16 weeks of age had a significant increase in mortality when treated with this product. In a double-blinded, placebo controlled trial, the recombinant endotoxin neutralizing protein, bactericidal permeability increasing protein, failed to improve survival.

Immune modulation

The effects of parvovirus on white blood cells have led to the investigation of several strategies to enhance immune function. The use of serum from recovered dogs may provide passive immunity and improve outcome, however this has not been tested in a clinical trial. Other attempts to enhance the immune system include the use of human recombinant granulocyte stimulating factor. In the one clinical trial investigating this drug, no benefit was seen. In Japan, one group has shown promising results using feline recombinant interferon omega (a Type I interferon). The down side of this treatment approach lies in the understanding of the pathophysiology of parvovirus. The viremic stage precedes clinical signs by several days and therefore this therapy may need to be administered very early to demonstrate benefit.

Supportive care

The mainstay of treatment for dogs with clinical signs of parvovirus is supportive care. The dogs are generally dehydrated from decreased oral intake and increased losses through vomiting and diarrhea. Hypovolemic shock may be present in these dogs. Rapid infusion of crystalloids is usually the first line of treatment. Some dogs may require as much as 90 ml/kg, however, it is essential to provide fluid therapy in repeated boluses and then re-evaluate the clinical parameters. If the pulse quality improves, capillary refill time returns to normal, heart rate returns to normal and mentation improves, these are all signs of effective fluid therapy. Some dogs may be hypoproteinemic or resistant to crystalloid bolus and need colloid infusion. After initial bolus therapy, fluid therapy needs to address maintenance (2-4 ml/kg/hr) dehydration (% dehydration x body weight in kg = liters of fluid to be replaced over 6-24 hours) and ongoing losses (estimated volume of vomiting, diarrhea and insensible losses from fever). In a review of records of dogs treated for parvovirus at the University of Pennsylvania, the average rate of fluid administration during the first 24 hours was 10 ml/kg/hr. Fluid therapy supplements that may be required include dextrose and potassium. It is critical in these dogs to calculate the rate of potassium supplementation and not to exceed 0.5 mEq/kg/hr. Regular monitoring of vital signs, electrolytes, glucose, packed cell volume and plasma protein are important in these puppies.

Although the inciting cause of the disease is viral, the immune suppression and gastrointestinal damage lead to bacterial translocation. In fact, it may be the bacterial component that is responsible for the severe clinical signs and mortality. Evidence to support the role of bacteria in the morbidity and mortality of parvovirus comes from several investigations. In germ-free dogs, parvovirus does not lead to clinical signs. Dogs with clinical parvovirus have increased circulating endotoxin and are bacteremic. Based on this evidence antibiotic treatment is warranted in all dogs with parvovirus infection. The choice of antibiotics should be based on selecting safe bactericidal drugs that are available for intravenous administration and are active against enteric bacteria. Cost considerations are also important in these cases. Ampicillin is safe, IV and bactericidal, however the action against E. coli is limited. In many cases, a second drug with better gram negative spectrum will also be included. Enrofloxacin has been shown to have potential damaging effects to cartilage in growing puppies and is generally avoided. Third generation cephalosporins can be used if cost is not prohibitive. The aminoglycosides have excellent action against gram negative organisms and can be used safely at 6 mg/kg once daily in these dogs if they are adequately hydrated.

Vomiting is a major problem in these dogs. It contributes to fluid loss and increases the risk of aspiration pneumonia. It is considered routine therapy to include anti-emetics in the management of parvovirus. Historically, the most commonly used antiemetics were metoclopramide and prochlorperazine. In a retrospective study of anti-emetic therapy in dogs with parvovirus, the use of antiemetics was associated with a longer duration of hospitalization. In a subgroup of dogs in that study, the vomiting was not controlled with administration of anti-emetics. Both of these drugs have potential side effects that should be considered when making decisions about anti-emetic therapy. Metoclopramide acts both locally and centrally. By increasing gastric emptying, it is theoretically possible to increase the risk of intussusception. The central effects can lead to depression or extrapyramidal signs (neurologic signs, tremors). In addition, the ability of metoclopramide to increase prolactin may cause increased cytokine production, which may promote the systemic inflammatory response. Prochlorperazine can exhibit many of the same effects as metoclopramide. In addition, it has a tendency to cause vasodilation which could be a problem in a dog with parvovirus if it is inadequately resuscitated. The sedative effects of prochlorpromazine may be detrimental if vomiting is not adequately controlled, thereby increasing the risk of aspiration. Newer generation anti-emetics (ondansetron, maropitant citrate) may be more efficacious and have less side effects, but have not been studied in clinical trials.

Puppies with parvovirus have generalized activation of their coagulation cascade, leading to an increased risk of thrombosis. No investigations have been conducted to determine if specific therapy with heparin or plasma will safely decrease the hypercoagulability in these dogs.

Nutritional support of dogs with parvovirus can be challenging, however a recent randomized controlled trial of early enteral nutrition versus nothing per os demonstrated earlier clinical improvement and decreased intestinal permeability in the dogs receiving nutritional support.

Current recommendations

Based on currently available information, dogs with parvovirus should be treated similarly to other animals with gram negative sepsis. The cornerstone of treatment is to provide appropriate fluid therapy to support blood pressure and hydration, colloids and plasma as necessary, antibiotics with activity against gram negative bacteria and nutrition. Future double blinded placebo controlled trials should be encouraged to identify other therapies that will provide directed therapy and improve survival and decrease the severity of parvovirus infection. In addition many of the commonly used supportive measures should be critically evaluated for the risk benefit ratio.

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