I

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Icterus



AUTHOR: MAUREEN. CARROLL



EDITOR ETIENNE. CÔTÉ



BASIC INFORMATION image



DEFINITION


Yellow discoloration of the skin and mucous membranes



SYNONYM


Jaundice



EPIDEMIOLOGY



SPECIES, AGE, SEX


Dependent on underlying cause (i.e., hepatobiliary disease, hemolytic anemia). Observed in both dogs and cats of any age.



GENETICS & BREED PREDISPOSITION


For primary liver disease:


• Dogs: Doberman pinschers (inflammatory liver disease), cocker spaniels, Labrador retrievers, Skye terriers

• Cats: Abyssinian (amyloidosis), Asian breeds (feline infectious peritonitis)

For hemolytic anemia: American cocker spaniel, English springer spaniel, Old English sheepdog, Irish setter, poodle



CLINICAL PRESENTATION



HISTORY, CHIEF COMPLAINT



• Hepatobiliary disease:
○ Anorexia, lethargy/weight loss

○ Vomiting/diarrhea

○ Abdominal distension

○ Cranial abdominal pain

○ Polyuria, polydipsia

○ Orange discoloration to the urine

○ Encephalopathy

• Hemolytic anemia:
○ Pallor

○ Anorexia

○ Lethargy, weakness, exercise intolerance

○ Vomiting

○ Orange discoloration to urine

○ Pigmenturia (dark red/brown) if intravascular hemolysis

○ Syncope/collapse


PHYSICAL EXAM FINDINGS



• Yellow discoloration of skin, mucous membranes (gingival, nictitans, sclera, etc.)

• Hepatobiliary disease:
○ Abdominal distention
▪ Cranial abdominal organomegaly

▪ Ascites

○ Dehydration

○ Halitosis

• Hemolysis:
○ Pale mucous membranes

○ Sinus tachycardia, ventricular arrhythmia

○ Fever

○ Respiratory difficulty if pulmonary thromboembolism (PTE)


ETIOLOGY AND PATHOPHYSIOLOGY



• Prehepatic icterus: increase in production of bilirubin due to presentation of excessive amount of heme (e.g., hemolysis)

• Hepatic icterus: abnormality in hepatic bilirubin uptake, conjugation, or excretion

• Posthepatic icterus: extrahepatic biliary system obstruction (bile duct system, gallbladder)


DIAGNOSIS image



DIAGNOSTIC OVERVIEW


Icterus is the result of either hemolysis or hepatobiliary disease. Therefore, in addition to history and physical exam, a hematocrit and assessment of biochemical liver values in serum are indicated in every icteric patient. Serum bile acid levels are not routinely measured in icteric patients unless a patient has both anemia and biochemical evidence of hepatobiliary disease (normal serum bile acid concentrations are consistent with hemolysis rather than cholestasis).



DIFFERENTIAL DIAGNOSIS



• Hepatobiliary disease:
○ Inflammatory/immune-mediated/ infectious:
▪ Idiopathic chronic hepatitis (dogs)

▪ Cholangiohepatitis of cats (suppurative/neutrophilic)

▪ Cholangiohepatitis of cats (lymphocytic)

▪ Secondary to bacterial translocation from the gastrointestinal system

▪ Leptospirosis (dogs)

○ Hepatic lipidosis (cats)

○ Neoplastic:
▪ Lymphoma, hepatocellular carcinoma, hemangiosarcoma, biliary carcinoma, other

○ Extrahepatic obstruction:
▪ Pancreatitis

▪ Cholelithiasis (rare in dogs and cats)

▪ Bile duct neoplasia

▪ Biliary mucocele

▪ Inspissated bile syndrome (cats)

○ Cholestatic drug injury:
▪ Acetaminophen, azathioprine, diazepam, phenobarbital, sulfonamide, many others

○ Extrahepatic sepsis: coliform septicemia most common resulting in cholestasis:
▪ Endotoxin and acute phase reactants interfere with transport of bile acids into canaliculi.

○ Anoxia: can lead to cholestasis

• Hemolytic anemia:
○ Idiopathic immune-mediated hemolytic anemia

○ Associated with other immune disorders:
▪ Inflammatory bowel disease

▪ Systemic lupus erythematosus

○ Infectious:
▪ Ehrlichiosis, Rocky Mountain spotted fever, leptospirosis, babesiosis, hemobartonellosis (Mycoplasma haemofelis)

▪ Viral: feline leukemia virus

▪ Bacterial: any chronic infection

○ Neoplasia: lymphoma, common association; any form of neoplasia

○ Microangiopathic hemolysis: commonly associated with hemangiosarcoma, heartworm, disseminated intravascular coagulation (DIC), vasculitis

○ Drug reaction: postvaccinal, sulfonamides, many others

○ Erythrocyte membrane fragility/oxidative damage:
▪ Abyssinian, Somali cats (osmotic fragility)

▪ Hypophosphatemia (phosphorus <1.5 mg/dL)

▪ Oxidative damage (intoxications):
□ Onions (dogs)

□ Acetaminophen (cats)

□ Zinc

○ Red blood cell (RBC) enzyme deficiencies: phosphofructokinase deficiency (English springer spaniel), pyruvate kinase deficiency (Basenji and others), stomatocytosis of malamutes


INITIAL DATABASE



• CBC:
○ Evaluation of plasma in PCV tube is more sensitive for icterus (seen at bilirubin = 1–1.5 mg/dL) than mucous membranes (icterus when bilirubin >2 mg/dL).

• Serum biochemical profile:
○ Alkaline phosphatase is always elevated in cholestatic disease causing icterus.

○ Liver enzymes may be elevated secondary to hypoxemia of severe anemia.

• Urinalysis and culture

• Abdominal radiographs

• Abdominal ultrasound

• Thoracic radiographs


ADVANCED OR CONFIRMATORY TESTING



• Hepatobiliary:
○ Prothrombin time (PT)/activated partial thromboplastin time (APTT)/ platelet count

○ Liver aspirate or biopsy for histopathologic evaluation and culture

○ Amylase/lipase/pancreatic lipase immunoreactivity

○ Infectious disease titers

○ Serial blood cultures, body fluid cultures if suspect sepsis

• Hemolysis:
○ Whole blood smear (spherocytes)

○ Reticulocyte count

○ PT/APTT platelet count to rule out bleeding disorder, disseminated intravascular coagulation (DIC)

○ Antinuclear antibody test

○ Direct Coombs’ test (false-negative results common)

○ Slide agglutination test

○ Direct IFA for RBC isotype-specific antibodies (IMHA)

○ Infectious disease titers/PCR (see Etiology and Pathophysiology above).

○ PCR for RBC enzyme deficiencies

○ Arterial blood gas

○ D-dimer (to rule out PTE associated with hemolytic anemia; high sensitivity, low specificity)

○ Bone marrow aspirate (evaluate for erythrophagocytosis, differentiate from myelodysplasia, pure red cell aplasia, lymphoma).

○ Fecal occult blood to differentiate hemolysis from gastrointestinal blood loss


TREATMENT image



TREATMENT OVERVIEW



• Hepatobiliary disease:
○ Suppress or eliminate the disease process.

○ Manage the metabolic condition.

• Hemolysis:
○ Treat inciting cause (e.g., drug withdrawal, toxin removal).

○ Suppress immune system if indicated.

○ Treat complications such as PTE, DIC.


GENERAL TREATMENT


Because icterus is a clinical sign, not a disease entity, appropriate management depends on identification and treatment of the underlying cause.



POSSIBLE COMPLICATIONS



• PTE: very common with immune-mediated hemolytic anemia
○ Oxygen/heparinization if PTE suspected

• Persistent/worsening anemia
○ RBC transfusion reactions (cross-matching important)

• Hepatic encephalopathy (see p. 501)

• Gastric ulcer (see p. 440)


PROGNOSIS AND OUTCOME image



• Varies with the cause of each disease

• Extrahepatic sepsis: mortality rate usually quite high

• Hemolytic anemia:
○ Prognosis good if inciting cause can be removed

○ Idiopathic immune-mediated hemolytic anemia: 40%–70% mortality rate: prognosis worse with intravascular hemolysis


PEARLS & CONSIDERATIONS image



COMMENTS



• Bilirubin concentrations are usually above 2 mg/dL to result in clinical icterus.

• The purpose of measuring serum bile acids is to assess liver function. Therefore, bile acids are an unnecessary diagnostic test in an icteric patient with a normal PCV.

• PTE diagnosis is sometimes difficult: low Pao2 on an arterial blood gas that is drawn during oxygen therapy is suggestive. High-velocity tricuspid regurgitation also suggestive if a murmur is present. D-dimer for thrombolysis: high sensitivity but poor specificity (i.e., many false-positive results for unrelated conditions).

• Portosystemic shunts do not cause icterus unless a complicating factor (e.g., other concurrent hepatopathy) also is present.

• Subtle icterus may be difficult to detect (or “icterus” may incorrectly be detected in a normal patient) when the physical examination is performed in a room illuminated with fluorescent tube lighting.

• Ultra low-dose aspirin may become a new therapeutic to replace heparin in the prevention of PTE.

• Hemolytic anemia can be associated with immune-mediated thrombocytopenia (often referred to as Evans syndrome).

• Blood transfusions can suppress the reticulocyte response.


SUGGESTED READING



Piek CJ, et al. Idiopathic immune-mediated hemolytic anemia: treatment outcome and prognostic factors in 149 dogs. J Vet Intern Med. 2008;22:366-373.


Webster CRL. History, clinical signs, and physical findings in hepatobiliary disease. In: Ettinger SJ, Feldman EC, editors. Textbook of veterinary internal medicine. ed 7. St Louis: Saunders Elsevier; 2010:1612-1626.



Idiopathic Tremor Syndrome



AUTHOR: KERRY SMITH. BAILEY



EDITOR: CURTIS W. DEWEY



BASIC INFORMATION image



DEFINITION



• A brain disorder of unknown etiology that causes spontaneous generalized tremors and is responsive to immunosuppressive doses of corticosteroids

• Tremor refers to a rhythmic oscillatory involuntary movement in the body.


SYNONYMS


Corticosteroid responsive tremor syndrome; white shaker dog syndrome (a poor term, as approximately half of the dogs with idiopathic tremor syndrome do not have a white coat)



EPIDEMIOLOGY



SPECIES, AGE, SEX


The majority of dogs affected with this syndrome are young (<5 years) and of small breeds (<15 kg).



GENETICS & BREED PREDISPOSITION


White dogs, including the West Highland white terrier and Maltese, are overrepresented, although any breed may be affected.



CLINICAL PRESENTATION



HISTORY, CHIEF COMPLAINT



• Owners typically notice an acute onset of a fine, whole-body tremor that often worsens with exercise, stress, and excitement and lessens with rest or sleep.

• The course of the disease is nonprogressive.


PHYSICAL EXAM FINDINGS



• The most notable finding is a fine, whole-body tremor.

• Additional findings may include poor menace responses, head tilt, nystagmus, paresis, tetraparesis, ataxia, seizure activity, and an elevated rectal temperature.


ETIOLOGY AND PATHOPHYSIOLOGY


The exact etiology is unknown but may be the result of an autoimmune-mediated disruption of neurotransmitter metabolism in the central nervous system (CNS), with a decreased conversion of tyrosine to dopamine. Dopamine is an important neurotransmitter for the regulation of movement.



DIAGNOSIS image



DIAGNOSTIC OVERVIEW


A clinical diagnosis generally is reached based on signalment, history, and clinical signs. Advanced tools such as MRI and CSF analysis are helpful in ruling out other causes of tremors.



DIFFERENTIAL DIAGNOSIS



• Congenital abnormal myelin formation (e.g., hypomyelination, dysmyelination)

• Toxicosis (e.g., penitrem A produced by Penicillium in moldy foods, hexachlorophene, and organophosphates)

• Metabolic conditions (e.g., hepatic or uremic encephalopathies)

• Cerebellar disease


INITIAL DATABASE


Basic blood work (CBC, serum chemistry panel) is typically within normal limits.



ADVANCED OR CONFIRMATORY TESTING



• Cerebrospinal fluid analysis is helpful in differentiating idiopathic tremor syndrome from other inflammatory diseases:
○ Results may include minimal to moderate nonsuppurative pleocytosis (lymphocytic, with mean white blood cell count being approximately 16 cells/mcL).

○ This is in contrast to the polymorphonuclear pleocytosis associated with mycotic and bacterial encephalitis and the mixed-cell pleocytosis seen in granulomatous meningoencephalitis and protozoal diseases.

○ The protein concentration is often high in cases of idiopathic tremor syndrome.

• MRI of the brain is typically normal.

• Histopathologic evaluation:
○ Histopathologic lesions are not seen in all dogs with idiopathic tremor syndrome.

○ Abnormalities may include diffuse, mild meningoencephalitis with mild perivascular cuffing and lymphocytic infiltrates throughout the CNS, especially in the cerebellum.


TREATMENT image



TREATMENT OVERVIEW


The goal of therapy is to eliminate tremors and is achieved mainly with corticosteroids, though diazepam can also be used. If tremors return when therapy is complete, they are typically mild and associated with excitement.



ACUTE GENERAL TREATMENT


Treatment consists of immunosuppressive doses of corticosteroids (i.e., prednisone, 1–2 mg/kg PO q 12 h). Clinical signs often decrease within the first few days of treatment.



CHRONIC TREATMENT



• Once tremors are fully controlled, the dose of prednisone should be gradually decreased over 1-3 months.

• Occasionally, dogs need to be kept on low doses or alternate-day therapy to control tremors.

• Additional tremor control can be achieved with oral diazepam (0.2 mg/ kg PO q 8 h).


PROGNOSIS AND OUTCOME image


Excellent



PEARLS & CONSIDERATIONS image



COMMENTS


The synonym white shaker dog syndrome is a poor term, as approximately half of the dogs with idiopathic tremor syndrome do not have a white coat.



SUGGESTED READING



Sanders G, Bagley RS. Cerebellar diseases and tremor syndromes. In: Dewey CW, editor. A practical guide to canine and feline neurology. Ames, IA: Iowa State Press; 2003:270-271.



Immunodeficiency Syndromes, Cat



AUTHOR & EDITOR: SUSAN M. COTTER



BASIC INFORMATIONimage



DEFINITION


Conditions resulting from a defective immune response. They may be primary, from an inherited defect, or secondary to another disease process or infection. They may be specific, with a defect in either B or T lymphocyte function, or nonspecific, due to a defect in phagocytic cell function or skin or mucosal integrity.



SYNONYMS


Immune or immunologic deficiency



EPIDEMIOLOGY



SPECIES, AGE, SEX



• One rare nonspecific defect is seen in young Persian cats with Chédiak-Higashi disease syndrome.

• All other known specific immunologic defects in cats are acquired and secondary to retroviral (feline leukemia virus [FeLV; see 385], feline immunodeficiency virus [FIV; see 381]) infections. These infections can occur at any age and in either gender, although young cats are most susceptible to FeLV infection.


GENETICS & BREED PREDISPOSITION


Persian cats with a dilute smoke gray coat color and yellow irises may have Chédiak-Higashi syndrome.



RISK FACTORS



• Greater FeLV propagation in crowded multicat households or shelters

• FIV occurs primarily in adult, outdoor, intact male cats.

• Either virus can be spread easily through blood, as in transfusions.


CONTAGION & ZOONOSIS



• FeLV is spread through contact with saliva, respiratory secretions, and milk. Kittens < 4 months old are most at risk from queens or other cats.

• FIV is less contagious and is spread primarily through bite wounds.

• No known zoonotic risk


GEOGRAPHY AND SEASONALITY


Both viruses have worldwide distribution. FIV is more prevalent in countries where cats routinely roam outdoors. Over time, FeLV has decreased in prevalence in countries where testing and vaccination have been used.



ASSOCIATED CONDITIONS & DISORDERS



• Chédiak-Higashi syndrome: slight increased risk for bacterial infections. Bleeding tendencies are also more common with this disease.

• FeLV can cause hematologic neoplasia, myelosuppression, immune-mediated diseases.

• FIV is less pathogenic and more likely associated with stomatitis or neurologic disorders.

• Both FeLV and FIV cause immunodeficiency, which can result in opportunistic infections.

• Almost any infection can occur in cats infected with FeLV or FIV.
○ Examples: bacterial (stomatitis, pyoderma), fungal (dermatophytosis, cryptococcosis), protozoal (toxoplasmosis, cryptosporidiosis), other viral (feline infectious peritonitis, panleukopenia), and hemotropic mycoplasmosis (Mycoplasma haemofelis infection, formerly hemobartonellosis)

○ Some infections may be abnormally persistent or recurrent.

○ Some infections also may be secondary to neutropenia (more common with FeLV than FIV).


CLINICAL PRESENTATION



HISTORY, CHIEF COMPLAINT


Signs may be vague, such as weight loss and lethargy, or may be referable to the specific infection that occurs. Common clinical signs are salivation or dysphagia from stomatitis, chronic nasal discharge from bacterial or viral rhinitis, or diarrhea from enteritis.



PHYSICAL EXAM FINDINGS



• Stomatitis (lymphocytic-plasmacytic proliferative type): more commonly associated with FIV than FeLV (FIV > FeLV; see 1051)

• Signs of neurologic disorders, especially dementia or twitching: FIV > FeLV

• Gingivitis: FeLV ≈ FIV

• Anemia: FeLV > FIV

• Lymphadenopathy (reactive; may be caused by bartonellosis): FeLV > FIV


ETIOLOGY AND PATHOPHYSIOLOGY



• FeLV/FIV (retroviral)-associated im-mune deficiency
○ The subset of lymphocytes most affected by retroviral infection is the CD4 helper T cell. The ratio of CD4 to CD8 cells is also decreased.

○ Also described with FeLV: secondary decreased ability of B cells to respond to new antigens

○ Thymic atrophy in neonatal kittens can cause “fading kitten syndrome.”

○ FIV is much less pathogenic than is FeLV. Many cats infected with FIV can live for many years without signs of illness (see pp. 381 and 385).

○ Neither FeLV nor FIV causes cytopathic changes or inflammation in tissues. Thus if a fever is present, a second infectious agent is likely to be the cause.

• Chédiak-Higashi–associated immune deficiency (rare disorder)
○ Abnormal neutrophil granules with abnormal function and survival. Bleeding tendencies are a result of platelet function defects.


DIAGNOSISimage



DIAGNOSTIC OVERVIEW



• Proving that an immunodeficiency is present requires specialized testing, not readily available to clinicians (e.g., lymphocyte immunophenotyping, counting of CD4 cells).

• One may assume that cats with retroviral infections may be immunodeficient.


DIFFERENTIAL DIAGNOSIS



• Any unusual, persistent, or recurring infection in any cat might be secondary to a retroviral infection.

• Neutropenia can also be caused by other primary bone marrow disease, drugs, toxins, or may be secondary to an overwhelming infection.


INITIAL DATABASE



• CBC to evaluate for anemia, neutropenia, or thrombocytopenia
○ FeLV/FIV: anemia, neutropenia, or thrombocytopenia. Persistent lymphopenia may occur but is nonspecific.

○ Chédiak-Higashi syndrome produces characteristic large granules in neutrophils.

• Urinalysis to evaluate for proteinuria or infection

• Serum biochemistry profile: usually unremarkable but rarely will reflect visceral organ involvement with opportunistic infections (e.g., pyelonephritis, bacterial translocation via portal circulation). Serum globulin level may be normal or elevated.

• FeLV (antigen) and FIV (antibody) ELISA blood tests are excellent for initial screening.
○ Maternal antibody and vaccination interfere with FIV test but not FeLV.


ADVANCED OR CONFIRMATORY TESTING



• A positive ELISA for either FeLV (antigen) or FIV (antibody) in a cat with signs compatible with an immunodeficiency syndrome is likely to be accurate. A positive test in a healthy cat without known risk factors is more likely to be a false positive and should be confirmed by IFA testing (FeLV) or Western blot (WB; FIV).

• PCR testing for these retroviruses is somewhat variable between labs and is not needed in most situations.

• Specific testing for other infectious diseases as needed (e.g., serologic titers, bacterial culture and sensitivity for purulent/septic processes)

• Bone marrow aspirate and biopsy if cytopenias are present or abnormal cells are circulating

• Testing of CD4 counts not readily available nor prognostic, as not all cats with low counts develop infections.

• When compared to a normal cat, microscopic examination of the shaft of a hair plucked from a cat with Chédiak-Higashi syndrome reveals large, clumped melanin granules.


TREATMENTimage



TREATMENT OVERVIEW



• FeLV/FIV-associated immunodeficiency:
○ Maintain good nutrition and husbandry, including core vaccinations.

○ Keep infected cats indoors for their own protection as well as to protect other cats.

○ Treat any secondary infections early and aggressively.

• Chédiak-Higashi–associated immunodeficiency:
○ Treat secondary infections as they arise; prophylactic treatment if surgery or trauma (bleeding).


ACUTE GENERAL TREATMENT



• Find and treat any secondary infections as quickly and thoroughly as possible.

• Use supportive care and nutritional support as needed.

• No value in FeLV/FIV vaccines for infected cats


CHRONIC TREATMENT



• No drug has proven efficacy in eliminating feline retroviruses.

• Anecdotal benefit has been reported for oral human α-interferon (IFN), Propionibacterium acnes, acemannan, Staph protein A, and PIND-ORF, but so far none of these has been shown to be effective either in decreasing viral replication or prolonging survival in limited controlled clinical trials.

• Recently IFN-omega improved clinical signs and 1-year survival in some cats, but another study in FIV infection showed no benefit.

• Azidothymidine (AZT) at a dose of 5 mg/ kg q 12 h SQ caused improvement in clinical signs and immune function in some cats infected with FeLV or FIV. Anemia can result from long-term use of AZT.


BEHAVIOR/EXERCISE


Immunodeficient cats should be kept indoors, away from other cats.



DRUG INTERACTIONS


Avoid corticosteroids or other immunosuppressive drugs unless absolutely needed. They may increase the risk of infections.



POSSIBLE COMPLICATIONS



• Inability to eradicate some infections

• Bone marrow failure, myelodysplasia, or hematopoietic malignancy, especially from FeLV


RECOMMENDED MONITORING


Monitor weight, since weight loss is often an early sign of complications. Also monitor appetite and activity. Once or twice yearly, CBCs might identify a problem, but healthy FeLV-infected cats generally have normal counts except for lymphopenia.



PROGNOSIS AND OUTCOMEimage



• Previous studies showing 50% mortality for FeLV infection in 2 years and 80% in 3 years were done with multicat households where risks of secondary infections were high. For a single indoor cat, the prognosis is guarded but much better than these figures indicate.

• Many FIV-positive cats will survive for many years without developing signs of illness if they are kept indoors.


PEARLS & CONSIDERATIONSimage



COMMENTS



• Although FeLV and FIV cause immunosuppression, most secondary infections can be treated successfully.

• Keeping these cats indoors and separated from ill or young cats (especially cats with signs of respiratory disease, skin disease, or diarrhea) will protect them from the majority of these infections.


PREVENTION



• FeLV: test kittens at 8 weeks. If negative and from a high-risk environment, repeat in 4 weeks. Isolate FeLV-negative kittens until they are >4 months old and have some natural resistance to FeLV.

• FIV test result can be positive from maternal antibody. Kittens testing positive should be retested after 5 months of age. Young kittens are rarely actually infected with FIV.

• FIV, FeLV: vaccinate only cats at risk (outdoor cats with exposure to other cats or those in multicat households). Neutered male cats are less likely to fight with other cats.


TECHNICIAN TIPS



• Be sure to wash hands thoroughly before and after handling cats carrying retroviruses.

• Most soaps and disinfectants will kill retroviruses, so infected cats may be housed in the same room as other cats so long as cages are cleaned well after they leave.


CLIENT EDUCATION



• Explain the benefits of keeping cats indoors. Never introduce new cats without testing. Indoor cats do not need to be vaccinated against retroviruses.

• For multicat households with endemic FeLV infection, isolate or remove positive cats, vaccinate the rest, and do not bring in new cats. Retest negative cats 3 months later. Repeat until all are negative.

• Spread of virus requires carrier cats, as the virus does not survive outside the cat.


SUGGESTED READING



Hartmann K. Feline leukemia virus infection. In: Greene CE, editor. Infectious diseases of the dog and cat. ed 3. St Louis: Saunders Elsevier; 2006:105-130.


Sellon RK, Hartmann K. Feline immunodeficiency virus infection. In: Greene CE, editor. Infectious diseases of the dog and cat. ed 3. St Louis: Saunders Elsevier; 2006:131-142.


Giger U, Greene CE. Immunodeficiencies and infectious diseases. In: Greene CE, editor. Infectious diseases of the dog and cat. ed 3. St Louis: Saunders Elsevier; 2006:1013-1027.



Immunodeficiency Syndromes, Dog



AUTHOR: TRACEY A. ROSSI



EDITOR: SUSAN M. COTTER



BASIC INFORMATIONimage



DEFINITION


Primary immunodeficiency syndrome: an inherited defect involving either the humoral (B cell) or cell-mediated (T cell) immune system, a combination of the two, or the phagocytic system



EPIDEMIOLOGY



SPECIES, AGE, SEX



• Signs first manifest around 8-12 weeks of age when the protective effects of maternal antibody are lost.

• No sex predilection except for sex-linked severe combined immunodeficiency syndrome (X-SCID)—males


GENETICS & BREED PREDISPOSITION



• Humoral (B-cell) immunodeficiency disorder:
○ Selective IgA deficiency: German shepherd dog, shar-pei, and beagle

○ Complement deficiency: Brittany spaniel

• Cell-mediated (T-cell) immunodeficiency disorder:
○ Thymic hypoplasia: dwarf weimaraner

• Combined (B-cell and T-cell) immunodeficiency disorder:
○ SCID: Jack Russell terrier

○ X-SCID: bassett hound, Cardigan Welsh corgi

• Functional phagocytic immunodeficiency disorder:
○ Canine leukocyte adhesion disorder (CLAD): Irish setter

○ Weimaraner immunodeficiency syndrome: weimaraner


CONTAGION & ZOONOSIS


Most opportunistic infections that affect immunocompromised individuals are overgrowths or infections with organisms that otherwise are not pathogenic to immunocompetent hosts. However, immunocompromised animals are also more susceptible than normal individuals to infection with organisms that are potentially zoonotic (e.g., dermatophytosis) or contagious to other dogs (e.g., respiratory tract pathogens).



CLINICAL PRESENTATION



HISTORY, CHIEF COMPLAINT


Recurrent infections that may or may not respond to appropriate therapy. Type of infection may vary with defect in the immune system.



PHYSICAL EXAM FINDINGS



• Humoral (B-cell) immunodeficiency disorder: physical exam findings are largely unremarkable; however, some patients may present with signs associated with chronic/recurring infections; increased incidence of chronic respiratory, skin, and intestinal infections.

• Cell-mediated (T-cell) immunodeficiency disorder: absence of palpable lymph nodes, tonsils are not visible. Affected dogs typically have signs of growth retardation and unthriftiness as compared to the other puppies within the litter.

• Combined (B-cell and T-cell) immunodeficiency disorder: similar findings as for humoral and cell-mediated immunodeficiency disorder

• Functional phagocytic immunodeficiency disorder: fever, generalized lymphadenopathy, dermatitis, pododermatitis, gingivitis, osteomyelitis; striking absence of pus formation and poor wound healing


ETIOLOGY AND PATHOPHYSIOLOGY



• Humoral (B-cell) immunodeficiency: decreased concentrations or absence of certain immunoglobulins, with increased susceptibility to bacterial infections
○ IgA deficiency: mode of inheritance is unknown. Epidemiologic studies show that puppies born to dams with IgA deficiency are at increased risk of developing upper respiratory infections as compared to puppies from dams with normal IgA concentrations.

○ Complement deficiency: autosomal recessive mode of inheritance; dogs that are homozygous for the trait have no detectable C3, required for opsonization of bacteria.

• Cell-mediated (T-cell) immunodeficiency: affected animals have either low numbers of or nonfunctional T cells. Findings include a small thymus and lack of lymph nodes, tonsils, and Peyer’s patches on postmortem examination. Affected animals are at increased risk for infections with intracellular bacterial, fungal, protozoal, and viral organisms.

• Combined (B-cell and T-cell) immunodeficiency:
○ SCID: autosomal recessive: affected individuals are unable to mount an appropriate antigen-specific immune response, owing to a lack of DNA protein kinase (DNA-PK) activity; DNA-PK is required for lymphocyte precursors to mature.

○ X-SCID: sex-linked mutation in the g chain of the interleukin 2 (IL-2) receptor required for normal B-cell and T-cell function. Affected male puppies are able to synthesize IgM, but IgG concentrations are significantly reduced and IgA is not detectable.

• Functional phagocytic immunodeficiency: affected animals have an increased risk for systemic or superficial infections with pyogenic microorganisms.
○ Weimaraner immunodeficiency syndrome: inherited, exact mechanism unknown; neutrophil dysfunction at the site of the lesion. However, there also appears to be a failure to produce IgA and IgG.

○ CLAD: deficiency of leukocyte surface glycoprotein (B2 integrin) associated with leukocyte adherence and egress into affected tissues; failure to express B2 integrin CD18.


DIAGNOSISimage



DIAGNOSTIC OVERVIEW


Affected puppies present with varying, often nonspecific clinical signs and commonly with recurrent infections. It is the recurrence of the infections and the poor response to therapy that warrant further investigation of a primary immunodeficiency syndrome.



DIFFERENTIAL DIAGNOSIS



• Humoral immunodeficiency: varies based on presenting complaint.
○ Upper respiratory infection: Bordetella bronchiseptica

○ Primary ciliary dyskinesia

○ Otitis

○ Stomatitis

○ Staphylococcal dermatitis

○ Atopic dermatitis

• Cell-mediated immunodeficiency:
○ Fungal (e.g., cryptococcosis, aspergillosis, blastomycosis, dermatophytosis)

○ Protozoal (e.g., toxoplasmosis, giardiasis)

○ Viral infections can be seen after vaccination with modified live virus vaccine

○ Intracellular bacteria (e.g., mycobacterial infections)

• Combined immunodeficiency: affected animals are susceptible to bacterial, viral, fungal, and protozoal agents.

• Functional phagocytic immunodeficiency:
○ Sepsis

○ Bacteremia

○ Pelger-Huët: hyposegmentation of nuclei in granulocytes and monocytes; persistent degenerative left shift without toxic change or any signs of illness (it is only an incidental finding).

○ Other infectious disease that would cause a neutrophilic leukocytosis with a left shift


INITIAL DATABASE


Appropriate diagnostic testing based on clinical presentation:


• Minimum database: CBC, serum biochemistry profile, urinalysis with culture and sensitivity, fecal examination, thoracic radiographs

• Humoral (B-cell) immunodeficiency disorder: minimum database within normal limits

• Cell-mediated (T-cell) immunodeficiency disorder: normal/decreased lymphocyte count

• Combined (B-cell and T-cell) immunodeficiency disorder: normal/decreased lymphocyte count (average 1000/mL); possibly low total protein due to low globulin levels; agammaglobulinemia (protein electrophoresis)

• Functional phagocytic immunodeficiency disorder: persistent leukocytosis with regenerative left shift; neutrophil count > 200,000/mL


ADVANCED OR CONFIRMATORY TESTING



• Specific tests performed should be geared toward the clinical presentation and tailored to the suspected immunodeficiency. Commonly considered tests include abdominal ultrasound, transtracheal wash with culture and sensitivity, bone marrow aspirate or core biopsy, lymph node biopsy, lesional biopsy. With CLAD, biopsy of lesion shows bacteria and possibly necrosis but no infiltration of neutrophils.

• Humoral immunodeficiency: serum protein electrophoresis to evaluate immunoglobulin concentrations, serum immunoglobulin quantitation, quantitation of serum C3 for C3 deficiency

• Cell-mediated immunodeficiency: lymphocyte transformation (blastogenesis) evaluates the ability of the T cell to proliferate after stimulation; measurement of growth hormone or insulin-like growth factor 1 if dwarfism is suspected (testing generally available only in research laboratories).

• Functional phagocytic immunodeficiency:
○ Bactericidal assays: measure the ability of neutrophils to kill bacteria.

○ PCR: to identify affected, normal, or carrier animals


TREATMENTimage



TREATMENT OVERVIEW


A substantial degree of variation in severity may exist for a given immunodeficiency syndrome. Therefore, treatment intensity, treatment success, and prognosis are individually variable and must be determined case by case. Some individuals require minimal or no treatment (e.g., intermittent antimicrobial treatment during clinical exacerbation), whereas in others, euthanasia is the most humane option. Control opportunistic infections with antimicrobials and supportive care; hospitalize when necessary.



ACUTE GENERAL TREATMENT


Supportive care to treat opportunistic infections:


• For example, antibiotics for confirmed bacterial infections. Empirical antibiotics may be used initially, pending culture and sensitivity results. Antibiotic type should be selected based on suspected bacterial population of involved site:
○ Skin: gram-positive bacteria most common; consider cephalosporins (e.g., cephalexin or cefadroxil, 22 mg/kg PO q 8-12 h) or penicillins (e.g., amoxicillin, 22 mg/kg PO q 8 h; or ampicillin, 22 mg/kg IV q 8 h).

○ Oral cavity and respiratory tract:
▪ Gram positive cocci: consider cephalosporins, 22 mg/kg PO, IV q 8 h; or trimethoprim-sulfadiazine, 15 mg/kg SQ, IM, IV q 12 h

▪ Gram negative rods: trimethoprim-sulfadiazine, 15 mg/kg SQ, IM, IV q 12 h; or enrofloxacin, 5-10 mg/kg IV q 24 h; or gentamicin, 8 mg/kg IV, IM, SQ q 24 h

▪ Bordetella infection: gentamicin, 9 mg/kg IV, IM, SQ q 24 h; or doxycycline, 5 mg/kg IV, PO q 12 h; or chloramphenicol, 50 mg/kg IV, SQ, PO q 8 h

▪ Mixed populations: consider fluoroquinolones (enrofloxacin, 5 mg/kg PO or slow IV q 12 h), or β-lactamase–resistant penicillins (e.g., amoxicillin-clavulanate, 10-20 mg/kg PO q 12 h), or macrolides (e.g., azithromycin, 5-10 mg/kg PO q 24 h × 1-5 days).

• Due to strong possibility of opportunistic fungal, viral, and protozoal infections, empirical antibiotic therapy may be inadequate or may select for resistant strains of bacteria; diagnostic samples for culture should be obtained before initiating antibiotic treatment, and judicious antibiotic use is warranted.

• Nebulization and coupage for bacterial pneumonia (see pp. 887 and 1310)
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Jul 24, 2016 | Posted by in SMALL ANIMAL | Comments Off on I

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