Canine parvovirus infection could lead to sepsis, septic shock, MODS and death if left untreated. This lecture aims to present an update of diagnostic tests, prognostic factors, fluid replacement, use of plasma and albumin, use of antibiotics, alternative therapies, gastrointestinal motility and integrity support (i.e., early enteral nutrition) as well as gastrointestinal parasites treatment.
Introduction
Parvoviruses (Parvoviridae) are small, non-enveloped, single-stranded DNA viruses that replicate in actively dividing cells. Canine Parvovirus-1 (CPV-1) was first discovered in the early 1960s and caused mild clinical signs of diarrhoea in dogs. In 1978, a new form of CPV, CPV-2, caused a widespread pandemic in adult domestic and wild dogs. In 1979, CPV-2a was discovered, then progressively worsened in virulence and pathogenicity to CPV-2b discovered in 1984. CPV-2b is now the most prevalent form of canine parvovirus worldwide, however a new genetic variant, CPV-2c, is being found in Europe (Italy) and Asia, as well as North and South America. In susceptible canine populations, parvovirus infection most often presents as a severe systemic and even life-threatening illness. It is associated with a survival rate as low as 9% in the absence of treatment, and 64% with treatment.
Pathophysiology
Infection is acquired by the faeco-oral route of transmission. Canine parvovirus has a predilection to infect rapidly dividing cells of the gastrointestinal tract, lymphoid tissue, and bone marrow, leading to haemorrhagic diarrhoea, vomiting, marked leukopenia, and immunosuppression within 4 to 5 days of exposure. Viral replication within crypt cells causes collapse of the villi and villi necrosis, which leads to a break in the normal blood epithelial barrier. Translocation of enteric bacteria and bacterial endotoxin into systemic circulation, combined with a lack of production of protective leukocytes from the infected bone marrow leads to systemic sepsis, septic shock, SIRS, and can lead to MODS and death if left untreated. The rate of lymphoid and intestinal cell turnover appears to be the main factor determining the severity of the disease. Stress factors, in particular parasitic or weaning, may predispose dogs to clinical disease by increasing mucosal cell activity. Inadequate immunization to parvovirus during the 1st year of life is an additional risk factor for disease. Surviving infected animals will shed parvovirus in their feces for up to 39 days following exposure. These viruses are hardy, persisting for long periods of time in the environment (5–7 months), and are ubiquitous.
Signalment and Clinical Signs
The majority of cases of clinical disease are observed in younger puppies from 6 to 20 weeks of age. Initial clinical signs associated with CPV enteritis are nonspecific, and include anorexia, depression, and fever. They often become progressively worse over time. Lethargy, inappetence, vomiting, diarrhoea (often haemorrhagic) are cornerstones of disease. Weakness can be due to dehydration, or secondary to hypoglycaemia from depletion of glycogen stores and sepsis. The most severely affected animals can develop seizures, thromboembolic disease, disseminated intravascular coagulation (DIC) and death if left untreated.
Laboratory Diagnoses
Practitioners can utilize a readily available cage-side enzyme-linked immunosorbent assay (ELISA) test to demonstrate CPV in the stool of infected puppies. In some cases, false positive or false negative results can occur. However, the presence of a positive test with concomitant clinical signs of vomiting, diarrhoea, lethargy and inappetence support a diagnosis of parvovirus. Other diagnostic tests (i.e., PCR) are also available, but take longer for results.
The white blood cell count (WBC) during CPV enteritis is generally characterized as being low to severely low. Leukopenia occurs in only 50% of affected dogs, and is, therefore, not a sensitive or specific indicator of parvovirus in infected animals. While infected animals are often evaluated for neutropenia, an absolute lymphocyte value of less than 1000 lymphocytes/µL within 48 hours of admission has been correlated to be a negative prognostic indicator in affected animals. Other nonspecific biochemical parameters, which may be altered during parvoviral infection include hypoproteinaemia, hypoalbuminaemia, anaemia, extrahepatic cholestasis of sepsis, pre-renal azotaemia, coagulation defects including thrombocytopenia and prolonged coagulation times, hypoglycaemia, and hypokalaemia. Significantly higher plasma acute phase protein concentrations (C-reactive protein and ceruloplasmin) have been found to be significantly increased in dogs with parvovirus, and can help predict mortality.
Treatment and Monitoring
The cornerstone of management of CPV enteritis remains supportive care.
Fluid Therapy
Re-establishment of effective circulating blood volume in puppies that present in hypovolaemic shock and fluid replacement for losses secondary to ongoing diarrhoea and vomiting is mandatory. The initial fluid of choice is a balanced electrolyte solution (i.e., lactated Ringer’s solution). The preferred rate and route of initial fluid therapy varies with the condition of the patient. Fluid deficits should be replaced as soon as possible (within 1–2 hours of presentation) in dogs that present in hypovolaemic shock. A short, large-bore catheter (18 or 20 gauge) can be placed in the cephalic or lateral saphenous vein, and fluids for treatment of shock should be administered at a rate and volume dictated by physiologic endpoints. Serum lactate values can be used to guide fluid therapy and evaluate response to methods to improve perfusion. During the maintenance period, frequent urination in a patient with normal renal function, combined with appropriate weight gain, supports that fluid therapy is effective at maintaining hydration and perfusion in the face of gastrointestinal losses.
Due to loss of protein in diarrhoeic faeces, hypoalbuminaemia and decreased colloid osmotic pressure (COP) is common. Albumin can be supplemented in very small patients using fresh frozen plasma at a dose of 15–20 ml/kg for each 5 g/L increase in serum albumin concentration. For larger patients, canine specific or concentrated human albumin (if available) infusion can be provided. To help maintain oncotic pressure, additional use of hydroxyethyl starches at doses of 20–30 ml/kg/day are often proposed but their use remains controversial.
Patients with ongoing anorexia, vomiting, and diarrhoea are prone to the development of hypokalaemia and metabolic acidosis. Potassium chloride is added to the fluids as needed to prevent the development or worsening of hypokalaemia. When possible once to twice daily monitoring of venous blood gas with electrolytes can help guide necessary supplementation. If a patient has refractory hypokalaemia, empiric addition of magnesium in the form of magnesium chloride (0.75 mEq/kg/day IV CRI) should be considered.
Oxygenation and Ventilation
Careful monitoring of a patient’s respiratory rate and effort, as well as pulse oximetry may become necessary in the most severely affected patients. If a patient shows signs of increased respiratory effort or hypoxaemia (SpO2 <94%), oxygen supplementation should be provided.
Treatment of Hypoglycaemia
Hypoglycaemia, secondary to profound malnutrition, hypermetabolism, underlying liver dysfunction, or sepsis, is commonly observed with CPV enteritis. Intravenous supplementation of 2.5–5% dextrose added to the balanced electrolyte solution, may be necessary.
Transfusion
If red cell mass becomes significantly diminished from loss in haemorrhagic faeces, packed red blood cell or whole blood transfusions may become necessary. In general, daily to twice daily monitoring of a patient’s packed cell volume is recommended. If hypocoagulability can be demonstrated, replenishment of coagulation factors in the form of fresh frozen plasma or cryoprecipitate may be warranted.
Antibiotics
Immune status is often severely impaired in patients with parvoviral enteritis. Careful selection of broad-spectrum bactericidal antibiotics that will affect gram-positive and -negative, as well as aerobic and anaerobic bacteria should be considered. The parenteral route is preferred over enteral delivery. A combination of a β lactam antibiotic (ampicillin, 22 mg/kg IV TID) with an aminoglycoside (gentamicin, 6 mg/kg IV SID) or quinolone (enrofloxacin, 5 mg/kg IV SID) will provide excellent coverage against gram-negative and anaerobic bacteria that may translocate from the gut. Aminoglycosides may cause acute renal failure, and should be administered only in well-hydrated patients; enrofloxacin has been associated with the development of cartilage abnormalities in young, growing dogs. In the most severe cases, metronidazole (10–15 mg/kg IV q 8–12 h) can also be added for improved anaerobic coverage.
Antiemetic Therapy, GI Motility and Integrity Protection
Gastrointestinal motility and integrity are severely compromised in the patient with parvoviral enteritis. Antiemetics may be necessary in cases of severe vomiting. The two drugs most commonly used are metoclopramide (1–2 mg/kg/day IV CRI) and maropitant (1 mg/kg IV or SQ q 24 h). Antacids IV could be added (i.e., ranitidine, 1 mg/kg IV q 8 h). Placing a nasogastric tube can allow for both enteral nutrition, as well as gastric decompression as necessary to help prevent additional vomiting. The presence of gastrointestinal parasites can worsen patient morbidity and response to therapy, so careful evaluation of faecal flotation, smears and with ELISA for Giardia, coccidia, Isospora and other gastrointestinal parasites is necessary. Empiric deworming is recommended in severely affected cases.
Nutrition
Fasting/NPO promotes negative changes in the intestinal mucosa, such as decreased villus height and crypt depth, decreased antioxidants within enterocytes, and increased enterocyte apoptosis, leading to increased permeability of the mucosal barrier and higher chances of bacterial translocation. Parenteral nutrition should only be used when the gastrointestinal tract cannot tolerate any form of enteral feeding, and partial parenteral nutrition to provide calories in combination to enteral feeding is preferable to total parenteral nutrition.
Early enteral feeding in patients with GI diseases has been shown to improve healing of damaged enterocytes, resulted in more rapid clinical improvement, increased weight gain and decreased possibility of bacterial translocation (hence lower risk of development of systemic inflammation and sepsis), and is currently recommended, after 12 hours of hospitalization even when there is persistent vomiting and diarrhoea. The percentages of prescribed nutrition delivered and the frequency of gastrointestinal complications are not significantly different between patients fed continuously and patients fed intermittently via nasoenteric tubes, hence those are both viable options.
It is important to use diets with very high digestibility and with the highest possible energy density to cover the pet’s needs in a reduced feeding volume. Supplementation with EPA and DHA can help limit inflammatory processes, and antioxidants (such as vitamin E, vitamin C, taurine, carotenoids…) can be helpful in restoring antioxidant status and in supporting the immune system.
When tube-feeding puppies, the starting point is the quantity calculated according to RER (resting energy requirement) equation: RER=70 kcal/kg0.75 of current bodyweight, divided into several meals and reached progressively if there has been a period of anorexia. Serial monitoring of bodyweight and body condition is then crucial, to progressively adapt the food quantity to cover the puppy’s energy needs (which might be 2 times higher than RER).
Patient Comfort
Cramping and ileus can decrease feeding tolerance. As opioids often can promote ileus at doses necessary to provide analgesia, lidocaine (30 mcg/kg/min) in combination with low doses of a partial mu agonist such as buprenorphine (0.01 mg/kg IV q 8 h) may be beneficial in improving patient comfort. Nursing care, and patient mobilization are import in maintaining patient cleanliness. Catheter sites should be monitored closely, cleaned and changed daily to evaluate for catheter thrombosis and contamination. Bleach solutions (6%) must be used to clean the animal environment.
Alternative Therapies
Alternative therapies include the use of antiviral drugs such as oseltamivir. None of the alternative therapies have been associated with proven benefit in survival or decreasing patient morbidity. Feline interferon omega has been shown to significantly decrease clinical signs and mortality in naturally infected patients (2.2 units/kg IV once daily for 3 consecutive days). A recent randomized clinical trial (Pereira et al. 2018) showed that faecal microbiota transplantation was associated with faster resolution of diarrhoea in 66 puppies with acute haemorrhagic diarrhoea syndrome due to parvovirus infection.
References
1. Campbell JA, Jutkowitz LA, Santoro KA, Hauptman JG, Holahan ML, Brown AJ. Continuous versus intermittent delivery of nutrition via nasoenteric feeding tubes in hospitalized canine and feline patients: 91 patients (2002–2007). J Vet Emerg Crit Care. 2010;20:232–236.
2. Cave N. Nutritional management of gastrointestinal diseases. In: Fascetti AJ, Delaney SJ, eds. Applied Veterinary Clinical Nutrition. Ames, IA: Wiley-Blackwell; 2012:175–219.
3. Day MJ, Horzinek MC, Schultz RD. Guidelines for the vaccination of dogs and cats. Compiled by the Vaccination Guidelines Group (VGG) of the World Small Animal Veterinary Association (WSAVA). J Small Anim Pract. 2007;48:528–541.
4. Day MJ, Horzinek MC, Schultz RD. WSAVA guidelines for the vaccination of dogs and cats. J Small Anim Pract. 2010;51:1–32.
5. De Cramer KG, Stylianides E, van Vuuren M. Efficacy of vaccination at 4 and 6 weeks in the control of canine parvovirus. Vet Microbiol. 2011;149:126–132.
6. Goddard A, Leisewitz AL, Christopher MM, Duncan NM, Becker PJ. Prognostic usefulness of blood leukocyte changes in canine parvoviral enteritis. J Vet Intern Med. 2008;22:309–316.
7. Goy-Thollot I, Hugonnard M, Delsarte JB, Vialard J. Population, clinical, biochemical, and hematological characteristics and outcomes of dogs with parvoviral enteritis: retrospective study in 33 dogs. J Vet Emerg Crit Care. 2010:24. doi:10.1111/j.1476-4431.2010.00566.
8. Holahan M, Abood S, Hautman J, et al. Intermittent and continues enteral nutrition in critically ill dogs: a prospective randomized trial. J Vet Intern Med. 2010;24:520–536.
9. Kocaturk M, Martinez S, Eralp O, Tvarijonaviciute A, Ceron J, Yilmaz Z. Prognostic value of serum acute-phase proteins in dogs with parvoviral enteritis. J Small Anim Pract. 2010;51:478–483.
10. Liu DT, Brown DC, Silverstein DC. Early nutritional support is associated with decreased length of hospitalization in dogs with septic peritonitis: a retrospective study of 45 cases (2000–2009). J Vet Emerg Crit Care. 2012;22(4):453–459.
11. Martin V, Najbar W, Gueguen S, Grousson D, eun Hyone-Myong, Lebreux B, Aubert A. treatment of canine parvoviral enteritis with interferon-omega in a placebo-controlled challenge trial. Vet Microbiol. 2002; 89:115–127.
12. Mazzaferro EM. The parvo puppy: what is the best approach and what’s new? In Proceedings from the 19th International Veterinary Emergency & Critical Care Symposium; 2013; San Diego, CA.
13. McClure V, van Schoor M, Thompson PN, Kjelgaard-Hansen M, Goddard A. Evaluation of the use of serum C-reactive protein concentration to predict outcome in puppies infected with canine parvovirus. J Am Vet Med Assoc. 2013;243:361–366.
14. Mohr AJ, Leisewitz AL, Jacobson LS, Steiner JM, Ruaux CG, Williams DA. Effect of early enteral nutrition on intestinal permeability, intestinal protein loss, and outcome in dogs with severe parvoviral enteritis. J Vet Intern Med. 2003;17:791–798
15. Ohno T, Mochiki E, Ando H, et al. Glutamine decreases the duration of postoperative ileus after abdominal surgery: an experimental study of conscious dogs. Dig Dis Sci. 2009;54:1208–1213.
16. Otto CM, Rieser TM, Brooks MB, Russell MW. Evidence of hypercoagulability in dogs with parvoviral enteritis. J Am Vet Med Assoc. 2000;217:1500–1504.
17. Pereira GQ, Gomes LA, Weese JS, Costa MC. Fecal microbiota transplantation in puppies with canine parvovirus infection. J Vet Intern Med. 2018;1–5.
18. Prittie J. Canine parvoviral enteritis: a review of diagnosis, management, and prevention. J Vet Emerg Crit Care. 2004;14:167–176.
19. Reineke EL, Walton K, Otto CM. Evaluation of an oral electrolyte solution for treatment of mild to moderate dehydration in dogs with hemorrhagic diarrhea. J Am Vet Med Assoc. 2013;243:851–857.
20. Savigny MR, Macintire DK. Use of oseltamivir in the treatment of canine parvoviral enteritis. J Vet Emerg Crit Care. 2010;20:132–142.
21. Sime TA, Powell LL, Schildt JC, Olson EJ. Parvoviral myocarditis in a 5-week-old Dachshund. J Vet Emerg Crit Care. 2015;25:765–769.
22. Unterer S, Busch K, Leipig M, Hermanns W, Wolf G, Straubinger RK, Mueller RS, Hartmann K. Endoscopically visualized lesions, histologic findings, and bacterial invasion in the gastrointestinal mucosa of dogs with acute hemorrhagic diarrhea syndrome. J Vet Intern Med. 2014;28:52–58.
23. Unterer S, Strohmeyer K, Kruse BD, Sauter-Louis C, Hartmann K. Treatment of aseptic dogs with hemorrhagic gastroenteritis with amoxicillin/clavulanic acid: a prospective blinded study. J Vet Intern Med. 2011;25:973–979.
24. Venn EC, Preisner K, Boscan PL, DC Twedt, Sullivan LA. Evaluation of an outpatient protocol in the treatment of canine parvoviral enteritis. J Vet Emerg Crit Care. 2017;27:52–65.
25. Will K, Nolte I, Zentek J. Early enteral nutrition in young dogs suffering from haemorrhagic gastroenteritis. J Vet Med Series A. 2005;52(7):371–376.