Clinical Management of Psittacine Birds affected with Proventricular Dilatation Disease

Introduction

Proventricular Dilatation Disease (PDD) is a devastating disease for affected birds. It is also psychologically and financially devastating for their owner/caretaker.  Management of cases requires difficult decisions, initially euthanasia or long term management.  The diagnosis of PDD in an avicultural collection can have devastating financial effects on aviculturists. Counseling as well as establishing a long-term management plan are important aspects of veterinary care.  Clinical management of birds affected with Proventricular Dilation Disease often becomes a flock management problem as so many owners of psittacine birds have multiple birds.  Other alternatives for affected birds might be to place them in a rescue center that handles birds with PDD, or placement of the bird in a home with no other birds.

The social implications of a PDD diagnosis can also be devastating.  Owners may be shunned from bird club functions or social interaction with other bird owners, or find it impossible to find a pet sitter. Counseling for owners needs to include the fact that PDD can be hard to diagnose, can take many forms and can have a very long incubation period.  We have found visually healthy birds that were crop biopsy positive for PDD.  Waiting for the classic clinical signs such as vomiting or passing whole seeds will reveal only the tip of the iceberg.  The bird owner should be encouraged to assess the disease status of his or her other birds, considering each bird individually.  To be in denial and avoid checking other birds in the home is placing them at risk. In our experience, early diagnosis can enhance therapeutic outcome. Mates of birds that succumb to PDD should not be automatically euthanized.  These birds may have natural immunity to the disease and may be the best future breeders for an avicultural community hard hit by PDD. In consultation with your client develop a treatment and control plan. Encourage your client to make the commitment not to bring more birds into the home, placing them at risk, or transfer exposed birds to others without disclosure. 

Crop biopsy is a simple and safe procedure with limited risks. While crop biopsy has a high false negative rate, it is the best diagnostic tool that we have at this time and is useful as a screening tool. Other helpful tests include radiographs, endoscopy and hematology and chemistry profiles.  An exceptional test for live birds is fluoroscopy but this is rarely available to private practitioners. (Gregory, 2002, Boutette & Taylor, 2002)

As an infectious disease that causes inflammation of the nerves and affects the digestive system we must think about- preventing spread, reducing inflammation, aiding digestion and controlling secondary infections.  And we must do this for a long time, probably a year or more.

Treatment considerations

Initial reports of treatment using the anti-inflammatory drug Celicoxib presented the first real hope for birds affected with PDD. (Dalhausen et al, 2002) Nonsteroidal anti-inflammatory drugs ("NSAIDs") are a group of structurally diverse compounds used clinically for the successful treatment of a range of disorders that are associated with pain and/or inflammation. NSAIDs are known to inhibit the cyclooxygenase ("COX") enzymes, which catalyze the conversion of arachidonic acid to the various prostaglandins, and the drugs are believed to exert their analgesic and anti-inflammatory effects through inhibition of the COX enzymes. While the lymphoplasmacytic infiltrates in ganglia appear to be reversed as evidenced by repeated crop biopsies, this drug cannot be considered a preventative or a cure.

We dose Celecoxib at 20 mg/kg once daily if given directly orally. Compounding is not necessary as Celecoxib dissolves well in water.  We use one 200 mg capsule in 10 ml water and dose at 1 ml/kg BW.  Fresh dilutions should be made as frequently as possible as we have observed treatment failures which we feel have been associated with mixing batches which were not used quickly. The length of time that celecoxib is stable in water is unknown.  Unless a bird is extremely tame, it will be stressed by daily oral dosing.  We have had very good success in adding Celecoxib to the bird’s food. We double the dose (40 mg/kg) when we give it in food since we expect them to lose half of it.  We also give the medication on a small amount of food, preferably foods which will absorb the drug, so the chance of them eating it is improved.  In most birds therapeutic response is gradual and many birds do not show much benefit for at least 2 weeks. Full recovery of a clinical case is slow and gradual.

We have also successfully used tepoxalin (Zubrin, Schering Plough) in a pilot study comparing the use of tepoxalin to celecoxib. Tepoxatin is a combined COX-1 and COX-2 inhibitor as well as a LOX inhibitor (inhibits 5-Lipoxygenase pathway).

In this pilot study 3 groups were compared – Celecoxib on seed mix, tepoxalin on seed mix, and tepoxalin on extruded hypoallergenic diet (HA Diet, Kaytee Products). All birds were crop biopsy positive prior to treatment and after at least 9 months therapy, a second crop biopsy was performed. In group one, nine birds (4 macaws (Ara sp), 2 cockatoos Cacatua sp., and 2 amazons Amazona sp.) were treated with celecoxib on a seed mix.  In group two, eight birds (7 palm cockatoos Probosciger aterrimus and 1 Red Tail black cockatoo, Calyptorhynchus magnificus), were treated with tepoxalin on seeds and nuts and in group three, 14 birds (9 macaws, 4 cockatoos Cacatua sp and a derbyan parakeet psittacula derbiana) were treated with tepozalin on Kaytee, HA diet.  In group one, 2 birds still had positive crop biopsies (a Palm cockatoo and a Blue throated macaw) after 9 months treatment.  In group two, six birds still had positive crop biopsies but all were palm cockatoos. The best results were found in group three, in which lesions typical of PDD were not found in any of the 14 birds. These results may be attributable to the HA diet readily absorbing the medication, the diet being hypo-allergenic in nature, enhanced efficacy of tepoxalin, or possibly because those species are easier to treat effectively than the birds in groups one and two.  We have found Palm cockatoos and hyacinth macaws very difficult to treat effectively as they consume so many of their calories thru nuts and seeds making food administration difficult.

An important potential side effect of Celecoxib, and other COX 2 inhibitors in humans, is bleeding in the gastro-intestinal tract. (Clemett, 2000) An adult female Catalina hybrid macaw (Ara ararauna x Ara macao) that was crop biopsy positive for PDD, died within 7 days of initiation of Celecoxib therapy exhibiting an acute hemorrhagic event in the proventriculus on necropsy.  We routinely monitor birds for development of melina, which could indicate proventricular or intestinal bleeding.  In such cases, celecoxib is discontinued immediately and the bird is evaluated, including a gram stain to detect Clostridium in the feces. A mature female hyacinth macaw (Anodorhynchus hyacinthinus) also seemed to develop hypersensitivity to the drug. This bird had inflammatory skin disease as diagnosed by paired skin biopsy.  She developed severe pruritus locally on the sides of her face while being treated with Celecoxib, which subsided in severity when Celecoxib therapy was discontinued. Most NSAIDS are eliminated by renal clearance and should be used with caution in birds with renal disease. Nephrosis associated with NSAID use in birds is poorly documented. (Echols, 2004)(Echols, 2004)

Husbandry considerations

If possible, keep the birds in roomy cages outside where sunlight and fresh air will help to dilute/inactivate the virus (if present).  It will also enhance their general well being.  Try to keep stress to a minimum.

In clinically affected birds diet should be easily digested since proventricular and ventricular function is affected and GI motility is reduced or delayed. Liquid diets are available commercially for birds that are severely affected. (www.birdcareco.com) Extruded diets (pellets) are good for birds during the long recovery phase since they are easier to digest than seeds. We have been using a hypoallergenic rice-based diet (HA Prescription diet manufactured by Kaytee). An extruded diet also works well because Celecoxib diluted in water is absorbed into the food. 

Supplementing the diet with vegetables that are high in fiber might be beneficial to early cases by stimulating intestinal motility. Cruciferous vegetables are also beneficial sources of raffinose sugars (rich in oligofructosaccarides) which enhance viability of autochinous flora (Lactobacillus and Bifidobacterium), thereby inhibiting gram-negative bacteria and Clostridium. (McDonald, 2003) In advanced cases however these foods may linger in the intestines and ferment.  In our opinion, periodic supplementation of probiotics is beneficial.

Birds with PDD often become anemic and hypo-proteinemic.(Boutette, 2004) The addition of powdered protein supplements such as egg or soy protein provides a readily utilizable source of protein.  We utilize B complex vitamin supplementation to help correct anemia.  We also supplement with Salmon oil, flax seed oil and safflower oil as sources of omega 3 and omega 6 fatty acids. My goal in fatty acid supplementation is 50-250 mg/kg body weight of Omega 3 fatty acids with an omega3:omega 6 ratio of 1:2-1:6. When supplementing extruded diets I use a balance supplement of salmon oil and flax seed oil (high in omega 3 fatty acids) and safflower seed oil (high in Omega 6 fatty acids).  If the bird is eating a primarily seed diet I supplement only with salmon oil and flax seed oil.

Birds with PDD often develop secondary bacterial and fungal infections, especially intestinal infections, because the intestinal motility is poorly coordinated and transit time is increased. These infections should be diagnosed and treated appropriately. In our experience, Clostridium infections are common in birds with PDD and can result in bulky, black, foul smelling feces and potentially death due to necrotizing enteritis. Vaccination for clostridium should be considered. I use a multi-valent bovine clostridium vaccine, administering 0.25 to 1 ml intramuscularly or subcutaneously.  Initially two doses are given two weeks apart with an annual booster. (We have used a number of products but are currently using Vision 8, Intervet Inc, Millisboro, DE).

Gas formation and retention in the gastrointestinal tract is a common finding in birds affected with PDD and can cause discomfort. Gas may be evident radiographically but gas bubbles are also often present in the feces or vomitus.  Surfactants provide some symptomatic relief. (Infant’s Mylicon, Johnson & Johnson, Merck Consumer Pharmaceuticals).  Many birds exhibiting gastrointestinal gas or vomiting respond clinically to combination drug therapy as if they have Helicobacter although infection with Helicobacter has not been confirmed in them. We use Clarithromycin (Biaxin, Abbot Labs), Metronidazole and sucralfate (Carafate (sucralfate, Axcan Scandipharm.)

If PDD affects the central nervous system, the prognosis is guarded. Affected birds show incoordination, tremors, and seizures. Our initial attempts of therapy specifically for birds with the neurological form of PDD involved injections of meloxicam (Metacam, Boehringer Ingelheim, Vetmedica, Inc, 5 mg/ml solution for injection) into the glycogen body, a space in the synsacrum adjoining the spinal cord. We have performed this procedure in three severely affected birds that were having grand-mal seizures, and consulted on two others. While affected birds showed temporary relief of symptoms, they have all subsequently died. 

We subsequently began to use amantadine hydrochloride syrup, 50 mg/5 ml (HI-Tech Pharmacal Co, Inc, Amityville, NY, 11701) with excellent results.  Amantadine was originally used for treatment of influenza (in humans) but was also found to be beneficial in treatment of Parkinson’s disease, traumatic head injury, dementia, multiple sclerosis and cocaine withdrawal.  It is a dopaminergic, nonadrenergic and serotonergic substance and serves as an anti-depressant.  We have found the combination of celecoxib and amantadine (1 ml/kg gm body weight orally SID, or 2 ml/kg in food daily) to be very beneficial in birds exhibiting CNS signs or birds with severe gastrointestinal dilation. Based on long term health monitoring and serial crop biopsies, we feel treatment must be prolonged in birds that are clinically affected-possibly up to a year or more.

We have found metaclopramide to be an important adjunct to management of severe cases. ( 0.5 mg/kg, q 12, PO, or IM) (Carpenter, 2005) We use it in cases with delayed intestinal transit time or intestinal stasis, initially administered by injection and later given orally as the intestinal tract regains motility. (Metoclopramide injection, 5 mg/ml, GensiaSicor, Irvine, CA and  Metoclopramide Oral Solution, 5 mg/5ml Morton Grove Pharmaceuticals, Inc, Morton Grove, IL 60053). An adverse reaction to metoclopramine has been reported in a macaw being treated for PDD. (Massey, 1993) Nutritional adjuncts to therapy that may be beneficial in cases with CNS signs include ginkgo biloba, Vitamin E, alpha lipoic acid, acetyl-L-carnatine and B complex vitamins.

Monitoring Progress of Therapy

Therapy can be monitored by periodic physical exam, monitoring body weight, repeated radiographs and evaluation to detect secondary infections. Monitoring by repeated crop biopsies is very useful. A potential complicating effect can be the presence of remnants of suture in follow-up crop biopsies. The presence of this foreign material can result in inflammation that might not be easily distinguished from inflammation associated with the disease.

If monitoring by radiography the composition of the diet must be considered, especially if the bird was initially eating a primarily seed diet at the time of diagnosis and is later changed to an extruded diet. In my experience, birds eating a primarily formulated or extruded diet tend to have a relatively dilated gastrointestinal tract as evident by radiography that can complicate evaluation.

Birds affected with PDD often ingest foreign bodies, especially pieces of wood.  These materials may then be passed in vomitus or feces.  The bird may be ingesting these materials in an attempt to provide relief from intestinal discomfort.  These birds may need toys, perches and cage accessories that cannot be chewed and ingested and may benefit from high fiber vegetables to fill this need.

With patience, perseverance, prolonged therapy, and attention to correction of secondary problems, many birds affected with PDD can be returned to health.  Life expectancy at this time cannot be predicted. Unfortunately until specific testing for the etiologic agent(s) is possible the long-term prognosis is impossible to predict.

Since 2002 we have been working closely with a psittacine rescue facility, Milo’s Ranch, which is devoted to treatment of birds affected with PDD.  A summary of treatment results as of August 2005 is below.  Updated figures will be presented at the conference.

A summary of results in birds treated for PDD at Milo’s Ranch as of August 2005 follows.  *(In a suspicious crop biopsy lymphoplasmacytic inflammation is found surrounding ganglia but not within the ganglia).

25 birds were treated from an initial positive crop biopsy to having 2 consecutive negative crop biopsies

4 birds were treated from an initial positive crop biopsy to suspicious* and are still under treatment

3 birds were treated from an initial positive crop biopsy to not detected on the second biopsy and back to suspicious on the third

4 birds died of the Central nervous system form of PDD

1 bird died of heart failure/athlerosclerosis during treatment

1 bird died of gastric ulceration during treatment

Unfortunately not all results are positive.  A group of 4 yellow collared macaws were treated after a bird died of PDD in the group. Over the next 16 months 1 bird went from negative, to suspicious to positive on crop biopsy.  The bird is clinically free of symptoms. Many birds are still in the active treatment program and were being re-evaluated at the time of writing.

References:

• 1.   Gregory, CR, Ritchie, BR, Latimer, KS, et al. Progress in Understanding Proventricular Dilatation Disease, Proc Assoc Avian Vet, 200, pp. 269-276.

• Boutette, JB, and Taylor, M: Proventricular Dilatation Disease: A review of Research, Literature, Species Differences, Diagnostics, Prognosis and Treatment, Proceeding of Assoc Avian Vet., 2004
• McDonald, D., Feeding Ecology and Nutrition of Australian Lorikeets; Seminars in Avian and Exotic Pet Medicine, Vol 12, No. 4 (October), 2003.
• Dalhausen B, Aldred S., Colaizzi, E., Resolution of clinical proventricular dilation disease by Cyclooxygenase 2 inhibition, Proc Annu Conf. Assoc Avian Vet., 2002: 9-12.

• Clement D, Goa KL, Celecoxib: a review of it’s use in osteoarthritis, rheumatoid arthritis, and acute pain. Drugs, 2000;59:957-980.
• Carpenter, JW, Exotic Animal Formulary, Third Edition, Elsevier, Saunders, St Louis Missouri, 2005.
• Massey, JG, Adverse drug reaction to metaclopramide hydrochloride in a macaw with proventricular dilation syndrome, J Am Vet Med Assoc., 1993, Aug 15;203(4):542-4, Erratum in J AM Vet Med Assoc 1993 Oct 15;203(8):1183.
• Echols, S. Treatment and Management of Avian renal Disease, Proc, Avian Specialty Program, Ann Conf Asso of Avian vets, 2004, 77-85.

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