Parvovirus-therapeutic options (Proceedings)

Canine Parvovirus (CPV) is a family of viruses that cause vomiting, hemorrhagic diarrhea, and leukopenia. The virus can infect dogs of any age but, because of effective client education and early, aggressive vaccination protocols, is commonly noted in dogs less than 1 year of age. There are currently 2 active variants of the virus in the United States - CPV-2b and CPV-2c – of which the latter is the most recent and most virulent to appear. CPV infection is acquired by the fecal-oral route. Initial viral replication occurs in extra-intestinal lymphoid tissues, where the virus is spread through the blood to other lymphoid tissues where the cycle is repeated, eventually resulting in intestinal epithelial infection. The virus then localizes to the crypt epithelium, bone marrow, and other lymphoid tissues, where it produces crypt epithelial cell necrosis, diarrhea, leukopenia, and lymphoid destruction and depletion.

Diagnosis

Patients suspected of being infected with Parvovirus are commonly young dogs (age 6 weeks to 6 months) of any breed that are under-vaccinated. Presenting signs include vomiting, diarrhea that is commonly hemorrhagic, and anorexia. Initial triage examination findings commonly include hyperthermia or hypothermia, tachycardia, altered pulse quality, tachypnea, evidence of dehydration, abdominal discomfort, along with the vomiting and diarrhea.

Initial biochemical abnormalities commonly found in patients suspected of being infected with canine Parvovirus include leukopenia/neutropenia, hypoalbuminemia due to enteric losses, azotemia due to dehydration, hypokalemia, and hypoglycemia. Due to decreased perfusion from dehydration, metabolic acidosis and increased serum lactate concentrations are noted on blood gas analysis. Due to enteric losses and a systemic inflammatory response, coagulopathy may be present.

In-hospital confirmation of canine parvovirus infection is achieved through the use of a SNAP test. These tests are easily performed and require a small sample of stool from the patient. These tests have been shown to detect the current CPV-2b and CPV-2c variants of the virus. Whether these tests show false positive results due to recent vaccine is a subject for debate. A recent study showed that these tests did not produce positive results as a result of vaccination with modified live Parvo vaccines, suggesting this test when positive indicated infection with wild type CPV-2.

Therapy

Standard therapy for the CPV infected patient includes intravenous fluids, electrolyte and glucose replacement, antibiotics, anti-emetics, gastro cytoprotective medications, and analgesics. Intravenous fluid therapy is commonly administered with crystalloid and colloidal fluids. The crystalloid fluids are the mainstay of fluid therapy for the CPV infected patient. Crystalloid fluids consist primarily of water with a sodium or glucose base, plus the addition of other electrolytes and/or buffers. Replacement crystalloid solutions contain dissolved solutes that approximate the solute concentration found in plasma water. These solutions are indicated for the rapid replacement of intravascular volume and electrolytes as seen with severe volume depletion secondary to the losses associated with vomiting and diarrhea. With replacement crystalloid fluids, only 20-25% of the infused volume of fluid remains within the intravascular space 1 hour after infusion. Therefore, large volumes of replacement crystalloids need to be administered initially to replace intravascular volume and are continued to replace the ongoing losses from the vomitus and diarrhea.

Colloids are high molecular weight compounds that do not readily leave the intravascular space. They exert their effect of expanding intravascular volume by holding and potentially drawing water into the vasculature. Colloid fluid solutions are indicated for the treatment of hypovolemia, sepsis, and other inflammatory conditions where crystalloid fluids may leak from the vasculature, all present in the Parvovirus infected patient. They are also used to improve colloid oncotic pressure in patients with low albumin from protein loss secondary to gastro-enteric losses. Common colloidal solutions used in Parvovirus patients include plasma and synthetic compounds such as Hetastarch and Oxyglobin™.

Plasma transfusion is occasionally administered to CPV infected patients. Aside from its colloidal effect, plasma provides albumin, immunoglobulins, and coagulation factors. Albumin is an important constituent for the transport of many drugs. Decreased albumin concentrations can lead to poor distribution of highly albumin bound medications such as buprenorphine. Administration of fresh-frozen plasma from regularly immunized donor animals is a means of providing antibodies against circulating parvovirus. This is an effective means of neutralizing the virus in clinical patients. Because these patients commonly have a systemic inflammatory response, they may become coagulopathic. In these situations, administration of fresh frozen plasma will help resolve this condition.

Often, crystalloid fluids are supplemented with dextrose and/or electrolytes. Since most CPV infected patients are young puppies, they have a decreased capacity to produce endogenous blood glucose and are anorectic, preventing the oral intake of glucose-producing substrates. This is especially true for toy breed dogs. Thus, monitoring of blood glucose and supplementation of fluid therapy with parenteral dextrose is necessary. Concentrations of 2.5-5.0% are commonplace, although solutions of up to 10% are occasionally necessary. If high concentrations of dextrose are necessary, these should be administered via a central catheter to prevent vasculitis secondary to their increased osmolarity.

Hypokalemia is the most common electrolyte abnormality noted in the CPV infected patient. These patients can lose large amounts of potassium in the vomitus and diarrhea. Hypokalemia can lead to muscle weakness, gastrointestinal ileus, polyuria, cardiac arrhythmias, and general malaise, worsening the clinical condition of the patient. Daily monitoring of the patient's serum potassium and parenteral supplementation of potassium in the patient's fluid therapy is needed as determined by this monitoring. Potassium can be added to the crystalloid fluid therapy at concentrations up to 80mEq/L. The administration rate of potassium containing fluids should not exceed 0.5mEq/kg/hr. At doses higher than this, cardiac arrhythmias can be observed.

Because of the immune-compromised nature of these patients, they are susceptible to developing sepsis from several sources. Bacteria of gut origin or their endotoxin can pass through the intestine's mucosal defenses due to damage of the intestinal villus, a process known as bacterial translocation. Nosocomial infections are infections that are acquired during hospitalization and are not present or incubating at the time of admission. Parvovirus infected patients are susceptible to these types of infections because they commonly have indwelling devices such as IV catheters, and are handled frequently by multiple nurses. Sources for these infections include non-sterile placement of invasive devices, environmental contaminants, and transfer through fomites such as staff or other patients. Antibiotics are routinely prescribed to prevent and help combat this. In mildly affected patients, single agent antibiotics are often prescribed. In severely affected patients (leukopenia/neutropenia), broad spectrum antibiotics are administered in combination against gram positive and gram negative organisms are warranted. Ampicillin is safe, IV and bactericidal, but has limited effectiveness against certain gram negative bacteria such as E. coli. Thus, either potentiated penicillin such as ampicillin + sulbactam or a second antibiotic with better gram-negative spectrum is often included. The aminoglycosides (gentamycin, amikacin) have excellent action against gram-negative organisms and can be used safely once daily in these patients once they are adequately hydrated. Enrofloxacin has also been used but has been shown to have potential damaging effects to developing cartilage in growing puppies. Third generation cephalosporins (ceftazidime) can be used if cost is not prohibitive.

Vomiting is a major problem in the Parvovirus infected patient. Vomiting, if uncontrolled, leads to continued fluid and electrolyte losses, as well as increases the risk of aspiration pneumonia in these debilitated patients. While vomiting, the parvovirus infected patient will not intake oral nutrition, delaying the intestinal healing process. Control of vomiting can be achieved through the use of several different anti-emetics. Metoclopramide, prochlorperazine, dolasetron, ondasetron, and maropitant have all been used to control vomiting in CPV infected patients. Each of these anti-emetics has a different mechanism of action and thus, in patients with protracted vomiting despite single agent therapy, combinations of these medications can be used. Reflux esophagitis is a common finding in patients that have protracted vomiting. The use of gastric cytoprotective medications such as famotidine or ranitidine as well as sucralfate can help treat these complications.

Pain is a common finding in the CPV patient due to the gastro-intestinal pathology and intestinal spasm/cramping, and/or reflux esophagitis secondary to persistent vomiting. Pain in these patients may be manifested as continued decreased activity, altered mentation, changes in vital signs, and continued emesis. Many of these patients will grunt and/or vomit upon palpation of the abdomen. Pain control can improve patient comfort, decrease vomiting, and thus potentially decrease the time in hospital. Buprenorphine has shown efficacy for visceral and soft tissue pain, and is a good choice in these patients. Morphine, hydromorphone, and constant rate infusions of fentanyl have also been used successfully to ameliorate the pain associated with parvovirus infection.

Adjunct Therapy

Nutrition

Parvovirus infected patients are not able to tolerate enteral nutrition due to the vomiting, abdominal discomfort, and gastro-intestinal pathology. However, the gastro-intestinal tract receives it's nutrients from intra-luminal absorption. When the gastro-intestinal tract does not receive sufficient nutrients, several pathologic consequences can occur. These include villous atrophy leading to increased mucosal permeability and bacterial translocation, decreases in gut-associated lymphoid tissue (GALT), and decreased surface area for absorption of nutrients. Micro-enteral nutrition is the delivery of small amounts of water, electrolytes, and readily absorbed nutrients directly to the gastro-intestinal tract to maintain or improve mucosal cell integrity. Micro-enteral nutrition may assist these patients by allowing gastric decompression, improving regional GI blood flow, providing protection against GI bacterial and endotoxin absorption, and promoting progressive gastric motility. Microenteral nutrition does is not intended to provide for the systemic nutrient needs of the patient. Microenteral nutrition should be augmented by full enteral nutrition as soon as the patient can tolerate it, or supplemented via parenteral nutrition as necessary.

Microenteral nutrition is commonly delivered by naso-esophageal or naso-gastric feeding tubes. These devices are relatively easy to place. Once placed, continuous infusions of glucose containing solutions supplemented with electrolytes (Rebound Oral Electrolyte Solution) or polymeric liquid diets such as Clinicare or Rebound Liquid Diet can be administered at low rates (up to 2ml/kg/hr)

Glutamine supplementation is a hot topic in veterinary nutrition. In human nutrition, glutamine is a conditionally essential amino acid that has multiple functions in the sick or injured. Glutamine is the preferred energy source in enterocytes, immune cells, and endothelial cells, among others. Glutamine is a "competence factor" necessary for intestinal cell proliferation, intestinal fluid and electrolyte absorption, and mitogenic response to growth factors. Glutamine deprivation produces apoptosis. It is available as a stable powder and is supplemented at a dose of at least 1 gram/kg body weight per day. Glutamine has been experimentally shown to decrease the time of post-operative gastro-intestinal ileus in dogs. Glutamine supplementation within the microenteral nutrition in CPV patients may be beneficial and provides little known downside. However, further studies regarding the necessity of this amino acid in critically ill undernourished patients are still pending for our veterinary patients.

Oseltamivir (Tamiflu)

Anecdotal evidence has reported that oseltamivir reduces the morbidity associated with Parvovirus. Oseltamivir is a neuramidase inhibitor originally developed for treatment of human influenza virus. However, Parvovirus does not use neuramidase for replication. Instead, oseltamivir may have benefit by reducing the enteric bacterial population from permeating the enteric mucin layer, thus decreasing bacterial translocation. A recent clinical study using oseltamivir in 35 Parvovirus infected patients showed no statistically significant differences in days in hospital with SIRS, white blood cell counts, duration of hospitalization, extent of vomiting or diarrhea, or mortality. Further clinical evaluation of oseltamivir is warranted before considering it as a mainstay of therapy.

Enteric Parasite Control

The presence of intestinal parasites has been identified as a factor which can exacerbate Parvovirus infection by enhancing intestinal cell turnover and subsequent viral replication. Fecal parasite examinations should be routinely performed on all patients infected with Parvovirus. Appropriate anti-parasiticides based on these results should be administered once vomiting is controlled.

Other Novel Therapies

The use of canine lyophilized IgG isolated from hyperimmune dogs and convalescent plasma from a recently parvovirus infected dog have been suggested to have benefit in severely affected CPV patients. However, further investigation regarding the efficacy of these therapies is needed before they may be recommended.

References furnished upon request