Primary or Hereditary Immunodeficiencies

Many genetically determined immune defects have been described in the dog, whereas only a few are known in cats. They occur rarely and are summarized in Table 94-2; some are discussed next in more detail in the Specific Primary or Inherited Immunodeficiencies section of this chapter. They can be broadly classified according to defects of the specific or nonspecific immune system as well as combinations thereof.⁹² The nonspecific immune system, also known as innate or natural immunity, should be functional at birth and available on short notice to protect the host from invasion by all sorts of organisms. It includes physicochemical barriers, phagocytes, complement and other plasma proteins, and natural killer cells. Congenital barrier defects particularly involve the skin and mucous membrane surfaces and are associated with infections of particular organs. A variety of hereditary skin diseases are being further defined and other immunodeficiencies are being recognized. The Ehlers-Danlos syndrome, causing fragile, hyperextendable skin in many dogs and cats as well as the myxedematous skin and immunodeficiencies of shar-peis, predisposes the animals to pyoderma, whereas ciliary dyskinesia in dogs increases the susceptibility to rhinosinusitis and pneumonia. Similarly, X-chromosomal ectodermal dysplasia in German shepherd dogs is associated with skin problems as well as other immunodeficiencies.

Disorders of the phagocytic system involve defects of neutrophils and monocytes as well as the complement system and can lead to pyogenic and granulomatous infections. The granulomatous reaction can occur when neutrophils malfunction and mononuclear cells are recruited. A wide variety of pyogenic bacteria (e.g., staphylococci, Escherichia coli, Klebsiella, Enterobacter) are usually involved, most of which represent resident microflora or pathogens of relatively low virulence. Recurrent infections of the skin, respiratory tract, and oral cavity are common, and intermittent bacteremia and overwhelming sepsis are also seen. Multisystemic amyloidosis, vasculitis, and immune-complex disease are complications that can occur as a result of chronic recurrent or persistent infection. Cyclic hematopoiesis and leukocyte adhesion deficiency (LAD) are examples of serious quantitative and qualitative phagocytic defects, respectively.

The specific immune system can be divided into humoral and cell-mediated immune systems and includes B and T lymphocytes, immunoglobulins, and cytokines.⁹² Deficiencies of B lymphocytes or humoral immunity affect the production of immunoglobulins and lead to increased susceptibility to pyogenic bacterial infections. Deficiencies of T lymphocytes or cell-mediated immunity (CMI) are associated with viral and fungal infections, but intracellular bacterial infections may also occur. Animals with cellular immunodeficiencies may have smaller thymic and tonsillar tissues as well as intestinal and peripheral lymph nodes and decreased numbers of circulating lymphocytes.

The degree of immunodeficiency varies greatly between defects. Infections may be systemic or restricted to a particular organ system such as the skin or respiratory tract. Some immunodeficiencies in neonates lead to overwhelming infections and death within the first few days to weeks of life, whereas others, such as morphologic leukocyte changes, are not consistently associated with any noticeable predisposition to infection. Chédiak-Higashi syndrome in smoke-colored Persian cats is characterized by abnormally large eosinophilic granules in polymorphonuclear leukocytes. It causes no immunodeficiencies but does cause a bleeding tendency resulting from a platelet storage pool disease.²⁰⁶ Similarly, birman cats with acidophilic granulation of neutrophils and dogs and cats with various lysosomal storage diseases (e.g., mucopolysaccharidosis, gangliosidosis, mannosidosis) have granulation or vacuolation of leukocytes without being immunocompromised; frequently they also exhibit a lymphocytosis. The Pelger-Huët anomaly, which is characterized by hyposegmentation of granulocytes, causes no immunodeficiency in animals, despite the fact that the leukograms of affected dogs and cats reveal the most severe left shift with a normal leukocyte count. In foxhounds, in vitro chemotactic response of these neutrophils was mildly diminished, whereas in basenjis no functional abnormalities have been found.^22,170,170

Although an increased susceptibility to opportunistic infections develops, the type of infection varies depending on the type of defect within the immune system. A few immunodeficiency disorders predispose animals to a restricted group of unusual infectious agents. Some male dachshunds appear to be predisposed to Pneumocystis pneumonia, and German shepherd dogs may be prone to systemic aspergillosis, other fungal infections or rickettsioses.¹⁶⁶ Doberman pinschers and Rottweiler dogs are more likely to develop parvoviral disease. Golden and Labrador retrievers and Bernese mountain dogs that had high serum antibody titers to Borrelia burgdorferi were more likely to have glomerulonephritis.⁶⁴ Basset hounds and miniature schnauzers have an increased susceptibility to systemic avian mycobacteriosis, toxoplasmosis, and neosporosis. American and English foxhounds appear to be predisposed to developing leishmaniasis. Great Danes and Dobermans may be more susceptible to cryptococcal infections.¹⁹⁰ A genetic predisposition to demodicosis has been proposed in various canine breeds and families within breeds. The predisposition to develop feline infectious peritonitis (FIP) has also been suggested to have a genetic basis, more commonly in some purebred cats (see Chapter 10). The mechanisms predisposing particular animals to specific infections remain unknown in many breeds.

The previously mentioned key signs of infection (see Box 94-1) develop in animals with a primary immunodeficiency generally early in life. Despite receiving colostrum, clinically affected animals can have illness during the neonatal to juvenile period and can develop recurrent and overwhelming infections that lead to severe debilitation and death before 1 year of age. Several animals, but typically not all, in a litter may be affected, whereas the parents are usually clinically healthy. A genetic predisposition to infection is rarely noted after 1 year of age (e.g., avian tuberculosis in basset hounds). Furthermore, animals with primary immunodeficiencies may have other special clinical manifestations. Hypersensitivity reactions can occur and reflect an overall dysregulation of the immune system caused by a lack of one or more components or a chronic antigen stimulation from inadequate clearance of infections. Chronic systemic infections may also hamper the animal’s growth rate (Fig. 94-1). Characteristic coat color dilutions and increased tendency for surface bleeding are seen for example in collies with cyclic hematopoiesis, Persian cats with Chédiak-Higashi syndrome, and Weimaraners with an incompletely defined immunodeficiency. Nude birman kittens and ectodermal dysplasia are associated with a complete lack or loss of hair.

The mode of inheritance of primary immunodeficiencies has not yet been determined in all cases. Autosomal recessive transmission, with affected males and females born to healthy parents, is usual, but a few exceptions exist. The Pelger-Huët anomaly is inherited as an autosomal dominant trait. An ectodermal dysplasia in German shepherds caused by ectodysplasin (ED)1 gene defect and severe combined immunodeficiency (SCID) caused by two different mutations in the common γ-chain interleukin (IL)-2 receptor in basset hounds and Cardigan Welsh corgis are X-chromosomal recessive disorders, so only males are affected, and the dams and one-half of her female littermates are carriers. Thus, the breed, gender, age of onset, type of infections, and other special characteristics can suggest a particular immunodeficiency. Furthermore, it follows that within a breed the immunodeficiency is typically caused by the same defect and mutation, whereas different breeds can have mutations in the same or different genes.

Secondary or Acquired Immunodeficiencies

All components of the immune system of animals with secondary immunodeficiencies are initially intact and functional but become transiently or permanently impaired during or after an underlying disease condition or exposure to certain agents. Thus, secondary immunodeficiencies occur much more commonly than primary forms and are associated with organ impairment. Depending of the type and severity of the immunosuppression, resulting opportunistic infections may be manifested by a localized or systemic spread. Various barrier disturbances lead to surface infections, such as respiratory tract, urogenital, dermatologic, and gastrointestinal (GI) infections. Furthermore, certain infections, particularly viral diseases in cats, directly impair the immune system, predisposing the animals to secondary bacterial, fungal, or protozoal infections. For example, cats infected with the feline immunodeficiency virus (FIV) harbor more diverse fungal microflora on the hair and mucosal surfaces than noninfected cats,²⁶² which may predispose the FIV-infected cats to a greater prevalence of secondary fungal infections. Feline leukemia virus (FeLV)-infected cats are also more likely than uninfected cats to have clinical illness with hemotropic Mycoplasma infections.

Puppies and kittens are particularly vulnerable to infections because of their incompletely developed immune systems. Colostrum intake only during the first day of life transfers maternal-derived antibodies (MDAs) and provides protection during the first few weeks of life in small animals. Although colostrum deprivation has been shown in large animals to result in major neonatal losses, neonatal kittens and puppies kept in high-quality catteries or kennels do not seem to be extremely predisposed to infections. However, a transient hypoglobulinemia after the decline of MDAs in the plasma and before the immunocompetency of 2- to 4-month-old animals can increase the susceptibility to various infections.²⁶¹ Similarly, older animals can again become immunocompromised and susceptible to infection. Various drugs and chemicals as well as nutritional deficiencies can drastically impair the production and function of leukocytes. Known secondary immunodeficiencies in companion animals are listed in Box 94-3, and some are discussed in detail at the end of this chapter.

Diagnostic Studies

Although an immunodeficiency may be suspected on the basis of clinical evidence, specific laboratory tests are generally required to reach a definitive diagnosis.¹¹³ A minimum database of information, including results of a complete blood count, serum chemistry screen, and urinalysis, should always be obtained and can suggest a specific disorder. Results of differential leukocyte count and microscopic evaluation of a blood smear are most important. Neutropenia in the presence of an active bacterial infection is by far the most feared condition. It should be noted that generally, some breeds, such as greyhounds, have low reference values for blood leukocyte counts. Neutropenia can be transient, as it occurs with cyclic hematopoiesis every 12 to 14 days or with parvovirus infection, or can be persistent, as it is seen in animals with cobalamin malabsorption defects or overwhelming infections (sepsis). Lymphopenia may be observed in dogs with a T-cell disorder or SCID. Although leukocytosis is expected during periods of infection, defects in leukocyte adhesion and egress from blood circulation at sites of infection can be associated with disproportionately high leukocytosis for the degree of infection as seen with hereditary LAD or with concurrent glucocorticoid usage. Dachshunds with Pneumocystis pneumonia also have very marked leukocytosis. Nonregenerative anemia with normocytosis or microcytosis, often observed in infected animals, is caused by several factors related to the persistent inflammatory disease state. The erythrocyte count can be within reference limits even if the animals have active infections and during periods of treatment and remission. Careful review of a blood smear can reveal leukocyte abnormalities such as granulation and vacuolation resulting from lysosomal storage diseases or Chédiak-Higashi syndrome,¹⁶⁵ acidophilic granulation of leukocytes in birmans,¹⁴² phagocytized microorganisms, or toxic leukocyte changes that suggest overwhelming bacterial infections.

Serum globulin concentrations are generally higher during chronic infections. Low or normal globulin levels in infected animals can suggest major external losses or diminished production from a humoral (B-cell) immune defect. Indeed, specific immunoglobulin deficiencies have been recognized in dogs. Serum protein electrophoresis may identify a γ-globulin deficiency, but immunoelectrophoresis is required to detect the class and degree of immunoglobulin deficiency. MDAs can only be absorbed during the first day of life and influence the values during the first few weeks. IgM can be synthesized very early in life, whereas the development of IgA can be delayed for months. Thus it is important to compare values with data from age-matched controls. Titers against specific antigens can be measured, followed by evaluation of the antibody response to vaccination against particular agents. However, despite the antibody titer level, cellular immunity is not being assessed. Biopsy specimens of lymph nodes can reveal disorganization with loss of germinal centers and normal paracortical lymphocytes. Decreases in plasma cell populations can also be evident.

T-cell or combined immunodeficiencies cause defective CMI responses. The animal may have prolonged allograft rejection times and decreased delayed-type hypersensitivity to skin testing with viral vaccines, tuberculin, or dinitrochlorobenzene.²²³ Reduced in vitro lymphocyte stimulation results can also be caused by a primary lymphocyte defect or the infection.

The identification of the agents infecting an animal is important for diagnostic as well as therapeutic reasons. Appropriate cultures of tissues, body fluids, and excretions for microorganisms and antigen and serologic blood tests are addressed in the chapters on specific infectious agents. Antibody titers can also be used to assess a response to vaccines and humoral immunity. For instance, Rottweilers appear to respond late to parvovirus vaccines and have an increased susceptibility to the infection.

Gross and microscopic histopathology and cytology can reveal certain microorganisms but are most helpful in characterizing the architecture, morphology, maturation, and function of the immune system, such as of the leukocytes, bone marrow, lymph nodes, thymus, and spleen, as well as other barrier systems. In ciliary dyskinesia, morphologic abnormalities of cilia may be identified by electron microscopy, but functional studies by imaging techniques or on respiratory epithelial biopsy specimens are also indicated.

For additional characterization of the immunodeficiencies, special leukocyte studies are often required. Surface marker studies by fluorescent-assisted cell sorters or flow cytometers can differentiate between T and B cells, determine T- and B-cell ratios, and determine the presence or absence of leukocyte adhesion proteins (CD11/18) or IL-2 receptors. Lymphocyte function studies include lymphocyte stimulation and plaque-forming assays for in vitro immunoglobulin production. Phagocyte function studies assess leukocyte adhesion, migration, chemotaxis, phagocytosis, “respiratory burst,” and bactericidal activity. All functional assays should be performed on fresh blood cells (collected within 24 hours) and compared simultaneously with an age- and breed-matched control. Furthermore, in vitro lymphocyte functions are generally impaired and phagocyte functions are enhanced during periods of active infection. Whenever possible, it is advisable to control the infection before studying leukocyte function.

Treatment and Prevention

Successful control of infection in immunodeficient animals depends on the underlying disease as well as the type and severity of the immune defect. In immunocompromised patients, early and aggressive antimicrobial therapy is indicated even for mild infections with nonpathogenic agents. Because of the immunodeficient host’s potential inability to kill bacteria, bactericidal antibacterials are recommended until bacterial infections are controlled. If the underlying disorder causing a secondary immunodeficiency can be corrected, the infection is often easily controlled. The underlying disorder should be treated and triggering agents such as drugs immediately withdrawn.

No practical treatments for primary immunodeficiencies exist, except for parenteral cobalamin administration to animals with hereditary cobalamin malabsorption. Immunocompromised animals with infection generally have a guarded to poor prognosis. Despite aggressive antimicrobial therapy, their infections are difficult to control, leading to overwhelming infections, protracted courses, and recurrences. Some leukocyte defects cause death before 1 year of age, whereas others may not lead to a markedly increased predisposition to infection. In experimental studies, bone marrow transplantation and gene therapy corrected several canine leukocyte defects.137,184 Dogs with hereditary immunodeficiencies and other genetic defects have served as intermediate test subjects between experiments in mice with genetic alterations and treatment of humans to test safety and efficacy of novel therapies. Granulocyte colony-stimulating factor (G-CSF) has been used to increase neutrophil numbers and treat chemotherapy-induced and cyclic neutropenia (see Chapter 2 and the Drug Formulary in the Appendix).

Fresh whole blood can be transfused repeatedly to animals with overwhelming infections and neutropenia or neutrophil dysfunction, but the effect is very transient. Plasma transfusions or immunoglobulin injections can temporarily support animals with humoral immunodeficiencies. However, these products should not be used in animals with complete IgA deficiency, because they can experience anaphylactic reactions to the foreign IgA protein. No commercial canine γ-globulin is available, and the human γ-globulin preparations are exorbitantly expensive, are not targeting animal specific infections, and can cause allergic reactions on repeated use. No data support their use in immunodeficient infected small animals, although they have been successfully used to treat several immune-mediated diseases. Nonspecific immunostimulators have not been documented as being beneficial in animals with cell-mediated immunodeficiencies. However, immunocompromised animals with active infections should not be vaccinated. Furthermore, the use of modified live virus (MLV) vaccines should be avoided in animals with inherited or acquired T-cell defects, because they may develop clinical disease from the vaccine virus.

Owners must consider the potential zoonotic risks involved with keeping an immunodeficient animal with infections that can be contagious to humans, particularly immunosuppressed humans exposed to foxhounds with leishmaniasis and miniature schnauzers and basset hounds with avian mycobacteriosis (see Chapter 99).

Primary ciliary dyskinesia, also known as immotile cilia syndrome, is caused by various functional and ultrastructural ciliary abnormalities, including lack of outer or inner dynein arms, abnormal microtubular pattern, random ciliary orientation, and electron-dense cores in the basal body. Because of impaired mucociliary clearance, affected animals have recurrent bacterial rhinitis, sinusitis, and bronchopneumonia with bronchiectasis. Poorly motile or immotile live sperms lead to male infertility, and although evidence is lacking, dysfunction of ependymal cilia can cause hydrocephalus. Otitis media can also occur. The lack of coordinated cilia motility during embryogenesis is responsible for the 50% prevalence of concurrent situs inversus in some forms of primary ciliary dyskinesia. The clinical triad of rhinosinusitis, bronchiectasis, and situs inversus is known as Kartagener’s syndrome.88,214,214

Primary ciliary dyskinesia is inherited by an autosomal recessive trait. It represents a heterogeneous group of defects that have been described in more than a dozen breeds.²⁹⁷ Clinical signs typically begin at a young age, and recurrent respiratory infections lead to death or euthanasia before 1 year of age. However, a few dogs appear clinically healthy for months to years.¹⁰² A diagnosis is reached by documenting an absence of ciliary clearance of a microaggregated albumin that is labeled with technetium-99m and placed through a catheter into the nasal cavity or the tracheal bifurcation and by tissue biopsy of ciliated mucosae with ultrastructural analysis and in vitro motility studies.^50,65 Induction of ciliogenesis can also be determined by use of in vitro cell culture.⁵⁰A mutation in the CCDC39 gene has been found in Old English sheepdogs with axonemal disorganization and abnormal ciliary beating.^205a

Cyclic Hematopoiesis

Cyclic hematopoiesis is characterized by a periodic production and maturation defect of hematopoietic cells in the bone marrow.²¹⁵ In human patients the cycle is 21 days, whereas in dogs it is every 12 to 14 days. Because of the short half-life of granulocytes, severe neutropenia (fewer than 1000/µL) is seen every 12 to 14 days and lasts for 3 to 4 days; thus the synonym cyclic neutropenia syndrome. Serial blood counts are used to reach a definitive diagnosis. During periods of severe neutropenia, dogs are highly susceptible to bacterial infections. Clinical illness appears at 6 to 8 weeks of age with regularly recurring bacterial infections (Fig. 94-2). The chronic exposure leads to systemic amyloidosis, and death can be result from organ failure (of the kidney and other organs) and sepsis before 1 year of age. Furthermore, gingival bleeding can occur from an associated platelet storage pool disease. Affected collies have a silver gray or light beige to tan coat color, and secondary hormonal cycling has been observed.^154,183

Cyclic hematopoiesis was the first reported canine immunodeficiency observed and has only been clearly described in collies that are hypopigmented, hence the term gray collie syndrome. It is inherited as an autosomal recessive trait, but no clinical case has been reported since the 1970s outside of the research colony in this breed. A basset hound with an apparent cyclic hematopoiesis has been observed but not further characterized. Experimentally, bone marrow transplantation completely corrects this syndrome, including the coat color dilution. Furthermore, administration of lithium carbonate at extremely high and otherwise toxic doses is known to induce leukocytosis and can ameliorate the cyclic neutropenia in affected animals. Similarly, injections of G-CSFs, alone or in combination with steel factor, abolish the cycling. Mutations in a leukocyte elastase have been identified in humans with a similar syndrome.²¹⁵ However, the defect in collie dogs is associated with a homozygous mutation of the gene encoding the dog adaptor protein complex 3 β-subunit that directs trans-Golgi export of transmembrane cargo proteins to lysosomes.^17,158

Leukocyte Adhesion Deficiency

This leukocyte defect, originally described as canine granulocytopathy syndrome in Irish setters and cattle, is referred to as canine or bovine LAD (or CLAD or BLAD).²⁴³ It is known to be caused by the absence of a family of three leukocyte integrins.^{75,117,284,286} These proteins are heterodimers (CD11a-d/CD18) with a specific α-chain (CD11a-d) and a common β-chain (CD18). In LAD, the β₂-subunit is missing (CD18 deficiency), resulting in a lack of surface expression and function of all leukocyte integrins. The CD11b/18 is the most critical integrin because is the CR3 receptor that binds C3bi and ICAM-1 of activated endothelium, thereby mediating tight adhesion leukocytes. Because of this deficiency, granulocytes are unable to marginate, migrate randomly or by chemotaxis, and kill microorganisms, resulting in an impaired inflammatory response despite marked leukocytosis (Fig. 94-3, A). Furthermore, the in vitro lymphocyte stimulation response is reduced. A single missense mutation substituting a cystine with a serine has been identified in affected Irish setters, and the same mutation has been found in red and white setters.^{75,105,152,160–162}

Affected dogs have a severely increased susceptibility to bacterial and fungal infections. Signs of pyogenic infections develop during the first weeks to months of life, are often recurring, and are poorly responsive to antibacterials. Omphalophlebitis and gingivitis are often the first infections and might be followed by pyoderma, pododermatitis, thrombophlebitis, pneumonia, pyometra, osteomyelitis (especially craniomandibular and metaphyseal), and fatal sepsis. Pups are often stunted or have poor body condition.60,283 The sites of infections exhibit only minimal inflammation and pus formation despite a most severe persistent leukocytosis of 25,000 to 500,000/µL (see Fig. 94-3, B). Regional lymphadenomegaly and poor wound healing are commonly noted. Long-term therapy with bactericidal antibacterials is required to keep affected animals alive.

LAD has been reported in Irish setters worldwide and is an autosomal recessive disease. LAD due to other CD18 mutations also has been documented in Holstein cattle and in humans.¹⁶⁰ Moreover, an adult domestic medium-haired cat with severe leukocytosis and with signs of infection and inflammation has been found to have LAD.¹¹⁶ The diagnosis in dogs is currently made by mutation-specific DNA testing,^{105,161,162,290} whereas a different mutation, β₂-integrin (CD18), was detected in the cat. In the past, demonstration of a lack of neutrophil adherence to glass, plastic, or wool and deficiency of leukocyte glycoproteins CD11/CD18 by flow cytometry analysis were used (see Fig. 94-3, C) (see Web Appendix 5 for commercial laboratories). Carrier dogs can be detected by genetic testing.⁷⁵ If the mutation is not known, leukocyte flow cytometry for CD18 is the most broad and simple screening test in dogs and cats.

Hematopoietic stem cell transplantation of CD18+ donor cells and gene therapy can reverse the defect.¹² Mixed chimeric hematopoietic stem cell transplantation from a histocompatible littermate has been shown to reverse the clinical signs of illness in an affected dog.⁶¹ At times, donor recipients were immunosuppressed with ciclosporin and mycophenolic acid mofetil during the 2 months after transplantation.

German Shepherd Infections

German shepherds are more severely infected with Ehrlichia canis (see Chapter 26), Rickettsia rickettsii (see Chapter 27), Pythium spp. (see Chapter 65), and Aspergillus spp. or Neosartorya spp. (see Chapter 62).¹⁶⁶ Some German shepherd dogs also are predisposed to pyoderma.^43,67,67 These predispositions can involve separate defects that have yet to be defined. Affected dogs have pruritus with a deep pyoderma over the lumbosacral region, which may spread to other regions.²⁵² Coagulase-positive Staphylococcus pseudintermedius is most commonly cultured. Proposed mechanisms for this susceptibility include hypothyroidism, cell-mediated immunodeficiency associated with serum inhibitors or defective helper T cells, and bacterial hypersensitivity reactions to staphylococci.^43,67,70,308 Although the inciting causes may be multivariate, the infection responds favorably to long-term administration of systemic antimicrobials.

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