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Clinical Aspects of Immunosuppression in Poultry

Author: Hoerr, Frederic J.

Source: Avian Diseases, 54(1) : 2-15

Published By: American Association of Avian Pathologists

URL: https://doi.org/10.1637/8909-043009-Review.1

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Invited Review—

Clinical Aspects of Immunosuppression in Poultry

Frederic J. HoerrA

College of Veterinary Medicine, Auburn University, Auburn, AL 36849

Received 4 May 2009; Accepted and published ahead of print 13 October 2009

SUMMARY. Chickens, turkeys, and other poultry in a production environment can be exposed to stressors and infectiousdiseases that impair innate and acquired immunity, erode general health and welfare, and diminish genetic and nutritional potentialfor efficient production. Innate immunity can be affected by stressful physiologic events related to hatching and to environmentalfactors during the first week of life. Exposure to environmental ammonia, foodborne mycotoxins, and suboptimal nutrition candiminish innate immunity. Infectious bursal disease (IBD), chicken infectious anemia (CIA), and Marek’s disease (MD) are majorinfectious diseases that increase susceptibility to viral, bacterial, and parasitic diseases and interfere with acquired vaccinalimmunity. A shared feature is lymphocytolytic infection capable of suppressing both humoral and cell-mediated immune functions.Enteric viral infections can be accompanied by atrophic and depleted lymphoid organs, but the immunosuppressive features aremodestly characterized. Some reoviruses cause atrophy of lymphoid organs and replicate in blood monocytes. Enteric parvovirusesof chickens and turkeys merit further study for immunosuppression. Hemorrhagic enteritis of turkeys has immunosuppressivefeatures similar to IBD. Other virulent fowl adenoviruses have immunosuppressive capabilities. Newcastle disease can damagelymphoid tissues and macrophages. Avian pneumovirus infections impair the mucociliary functions of the upper respiratory tractand augment deeper bacterial infections. Recognition of immunosuppression involves detection of specific diseases using diagnostictests such as serology, etiologic agent detection, and pathology. Broader measurements of immunosuppression by combinednoninfectious and infectious causes have not found general application. Microarray technology to detect genetic expression ofimmunologic mediators and receptors offers potential advances but is currently at the developmental state. Control methods forimmunosuppressive diseases rely largely on minimizing stress, reducing exposure to infectious agents through biosecurity, andincreasing host resistance to infectious immunosuppressive diseases by vaccination. A longer term approach involves geneticselection for resistance to immunosuppressive diseases, which has shown promising results for MD but equivocal results for IBDand CIA.

RESUMEN. Estudio Recapitulativo por Invitacion—Aspectos clınicos de la inmunodepresion en aves domesticas.Los pollos, pavos y otras aves domesticas que se encuentran en un medioambiente de produccion, pueden estar expuestas a

factores estresantes y a enfermedades infecciosas que pueden afectar la inmunidad innata y adquirida comprometiendo la saludgeneral y el bienestar, y disminuyendo los potenciales genetico y nutricional para una produccion eficiente. La inmunidad innatapuede afectarse por eventos fisiologicos estresantes relacionados al nacimiento y a factores ambientales durante la primera semana devida. La exposicion al amoniaco del ambiente, micotoxinas de origen alimentario y una nutricion deficiente pueden disminuir lainmunidad innata. La enfermedad infecciosa de la bolsa, la anemia infecciosa aviar y la enfermedad de Marek son enfermedadesinfecciosas que incrementan la susceptibilidad a enfermedades virales, bacterianas y parasitarias e interfieren con la inmunidadadquirida mediante la vacunacion. Una caracterıstica compartida es una infeccion linfocida capaz de suprimir la funcion inmunehumoral y celular. Las infecciones virales entericas pueden ir acompanadas de organos linfoides atroficos y con despoblacionlinfoide, pero sus propiedades inmunodepresoras han sido poco caracterizadas. Algunos reovirus pueden causar atrofia de losorganos linfoides y replicarse en los monocitos sanguıneos. Los parvovirus entericos de los pollos y de los pavos ameritan estudiosadicionales relacionados con la inmunodepresion. La enteritis hemorragica de los pavos tiene propiedades inmunodepresorassimilares a las de la enfermedad infecciosa de la bolsa. Otros adenovirus aviares virulentos tienen capacidades inmunodepresoras. Laenfermedad de Newcastle puede danar los tejidos linfoides y los macrofagos. Las infecciones con neumovirus aviar afectan lasfunciones mucociliares del tracto respiratorio superior e incrementan las infecciones bacterianas profundas. El reconocimiento de unestado de inmunodepresion implica la deteccion de enfermedades especificas utilizando pruebas diagnosticas como la serologıa, ladeteccion del agente etiologicos y patologıa. El estudio amplio de la inmunodepresion causadas por la combinacion de agentesinfecciosos y no infecciosos no ha podido ser aplicado de manera general. La tecnologıa de los microarreglos geneticos para detectarla expresion genetica de mediadores y de receptores inmunologicos, ofrece avances potenciales, pero aun esta en proceso dedesarrollo. Los metodos de control para las enfermedades inmunodepresoras se fundamentan principalmente en minimizar el estres,reducir la exposicion de los agentes infecciosos mediante la bioseguridad e incrementar la resistencia a las enfermedades infecciosasinmunodepresoras mediante la vacunacion. Una vision a largo plazo involucra a la seleccion genetica para la resistencia a lasenfermedades inmunosupresoras que ha mostrado resultados promisorios para la enfermedad de Marek, pero ha demostradoresultados inciertos para la enfermedad infecciosa de la bolsa y para la anemia infecciosa aviar.

Key words: immunosuppression, chicken, turkey, poultry, infectious bursal disease, chicken infectious anemia, Marek’s disease,ammonia, mycotoxins

Abbreviations: BF 5 bursa of Fabricius; CAV 5 chicken anemia virus; CIA 5 chicken infectious anemia; FAV 5 fowladenovirus; HE 5 hemorrhagic enteritis; HEV 5 hemorrhagic enteritis virus; HVT 5 turkey herpesvirus; IBD 5 infectious bursaldisease; IBDV 5 infectious bursal disease virus; IBV 5 infectious bronchitis virus; MD 5 Marek’s disease; MDV 5 Marek’s disease

ACorresponding author. Thompson-Bishop-Sparks State Diagnostic Laboratory, P.O. Box 2209, 890 Simms Road, Auburn, AL 36831-2209. E-mail:[email protected]

AVIAN DISEASES 54:2–15, 2010

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virus; MHC 5 major histocompatibility complex; NDV 5 Newcastle disease virus; ORT 5 Ornithobacterium rhinotracheale;PEMS 5 poultry enteritis and mortality syndrome; REV 5 reticuloendotheliosis virus; RSS 5 runting stunting syndrome;SE 5 Salmonella enterica serovar Enteritidis; ST 5 Salmonella Typhimurium

Production environments for chickens, turkeys, and other poultryresult in exposure to immunosuppressive stressors and infectiousdiseases. An understanding of the presence and pathogenesis ofimmunosuppressive risk factors is essential to successful managementfor optimal health and welfare and realizing the full contributions ofgenetic and nutritional advancements for efficient production. Thepurpose of this review is to merge research findings with clinical anddiagnostic observations on the causes and pathogenesis of immuno-suppression in the production of poultry.

STRESSORS SUPPRESSING INNATE IMMUNITY

Incubation, hatching, and the posthatch period. Adjustmentsof incubation and hatching conditions generally lag genetic advancesin rate of gain and change in carcass composition such as increasedpectoral muscle mass in high-yield broilers. This creates a challengeto obtain maximal hatchability in the shortest hatch duration;difficult or extended hatching times impose multiple stresses. Thehigh-yielding broiler of today is sensitive to the incubation andhatching environment, while at the same time, it is challenged tomount an immune response to vaccines administered in ovo and inthe immediate posthatch period. Suboptimal incubation can resultin a variable population of chicks with stresses related to bodytemperature, ventilation, and hydration. A difficult hatch candeplete total body energy and add to the nutritional stress that maybe experienced during the first week of age, and beyond (Fig. 1)(103,254). Incubation and hatching stresses are actually modeled bydexamethasone injection, which induces lymphocyte cellular deathby apoptosis (149).

Chick handling, extended transportation times from hatchery tofarm, extended time to first feed intake, and suboptimal broodingmay impose additional physiologic stresses (82). Stresses such asammonia, heat, and electrical shock (as might be experienced as strayvoltage), increase the circulating heterophil percentage and decreasethe lymphocyte percentage (heterophil:lymphocyte ratio) in anadditive manner (157). The blood leukocyte changes are a morereliable indicator of stress than the concentration of plasmacorticosterone (156).

In commercial egg-type layers, physiologic stress associated withthe onset of egg production and the social stress of new penmatesand new housing increase susceptibility to colibacillosis just after themove to the layer house (E. Gingerich, personal comm., 2009).Colibacillosis in older birds is associated with the stress of peckingand scratching trauma related to age-related feather loss.

Housing environment. Ammonia is an irritant gas produced bymicroflora of the cecum from uric acid and amino acids present inthe lumen (119), and in poultry environments, by the action of littermicroflora on feces. Ammonia concentrations are highest in poultryhousing during the coldest months of the year (42). Ammonia causesphotophobia due to conjunctivitis and edema, inflammation, andulceration of the cornea (9,10). Clinical signs and lesions observedwith high ammonia concentrations in poultry houses are somewhatmore severe than predicted from experimental exposure to ammonia(6,189), suggestive of the contributing pathogenic effects of dust,airborne bacteria, and endotoxins, among the other contaminants ofair in poultry houses (42,186,266). At physiologic pH, nonionic

ammonia concentrations remain low but are primarily responsiblefor the toxic effects, and present measurement methods do notdistinguish ionic from nonionic forms (263).

Ammonia induces the secretion of mucus from goblet cells,stimulated by the changes in pH of the airway surface fluid andpossible contributions from nerve stimulation and inflammatorymediators (218). Respiratory mucus is composed of mixedsecretions, chemically distinct, from different cellular synthesizingsites. Changes in the chemical and physical properties of the mucusoccur by selective action on the secretion of one or more of thecontributing glycoproteins (123). This increases the viscoelasticity ofthe mucus and decreases the efficiency of mucociliary clearance ofthe respiratory tract (109,220). Further impairment is due tociliostasis and loss of cilia, increased production of respiratory mucus(71,179), and the accumulation of particulate matter.

Ammonia reduces the clearance of Escherichia coli from the turkeyrespiratory tract (180). In chickens, ammonia exacerbates signs andlesions of mycoplasmosis, and complete ciliostasis has been observed(122). Broilers exposed to ammonia had dose-related respiratorylesions and intestinal lesions from coccidiosis (204). Coccidiosis inthis situation was possibly augmented because of wet conditions inthe litter or depression of cell-mediated immunity.

Formaldehyde exposure during hatching is an established practice toreduce the level of contamination of hatching eggs at or near the time oftransfer to the hatcher. The practice has variable application due tooccupational safety concerns. Chick embryos exposed to formaldehydeduring the last 3 days prior to hatch have been shown to developexcessive accumulation of mucus, matted cilia, loss of cilia, andsloughing of the epithelium in the upper respiratory tract (289).

Feed and nutrition. Mycotoxins are a diverse group of biotoxinsproduced as fungal metabolites. Many mycotoxins target componentsof innate and acquired immunity, contributing to an increasedseverity of concurrent infectious disease. Aflatoxin is broadlyimmunosuppressive in chickens, turkeys, and ducks, as shown byincreased severity of concurrent diseases (58,195), vaccination failures(12,203), depletion of lymphoid tissues (29,196), impaired functionsof lymphocytes (75,76,77) and macrophages (27,169,172), and areduction in serum complement (246).

Trichothecenes such as T-2 toxin and diacetoxyscirpenol damageprotective barriers of mucosal membranes and feathers (34,93,95).Trichothecenes cause depletion of lymphoid organs (94), reducelymphocyte mitogenic responses (104,208), and are cytotoxic tomacrophages (124). Fumonisins and other toxins produced byFusarium moniliforme cause lymphoid depletion, reduced antibodyformation, and toxicity to macrophages and lymphocyte functions(31,35,51,120,144,145,152,205,206).

Ochratoxins cause generalized atrophy of lymphoid organs(22,56,134,199); impairment of cell-mediated immunity (57,235),humoral immunity, vaccination responses (55,59,60), and phago-cytic activity (28,199); and increased severity of concurrent diseases(84,87,102,135).

A diverse set of other mycotoxins, including citrinin (165,166),cyclopiazonic acid (73,118,261), sterigmatocystin (243,244), andrubratoxin (273), causes generalized lymphocyte depletion andimmune dysfunction in various poultry species.

Dietary characteristics can modulate a bird’s susceptibility toinfectious challenges. Subtle influences due to the level of nutrients

Immunosuppression in poultry 3


or the types of ingredients may at times be of critical importance tothe immune system (reviewed by Klasing (131)). Adequate nutritionis critical to the development of the immune system in the embryoand the posthatch period during the seeding of lymphoid organs. Areduction in the time that feed is freely available to young broilerchickens results in atrophy of the bursa and thymus (83). Thenutritional requirements for normal lymphoid organ developmentmay not be sufficient for the immune responses required byinfectious disease challenge. In this situation, nutrients formulatedand intended for maintenance and growth are used instead forimmune response, inflammation, and repair.

Fatty acids and vitamins A, D, and E have direct regulatory roleson leukocytes and are essential for maintaining an adequate immuneresponse to disease challenges (1,141,142,236). Rancid fats producefree radicals that are broadly damaging to gut epithelium, liver, andlymphoid tissues (168). Vitamin E is protective of free-radicalformation and is integral to immunoreactive cellular functions;subclinical deficiencies are insidiously damaging to immune functions.

In commercial egg-type layers, nutritional stress occurs inunderweight young hens that are not producing eggs and in olderhens on diets of declining nutritional density. These stresses areassociated with increased susceptibility to infections by E. coli andStaphylococcus spp. (E. Gingerich, personal comm., 2009).

DISEASES SUPPRESSING ACQUIRED IMMUNITY

Infectious bursal disease (IBD). The IBD virus (IBDV,Birnaviridae) is horizontally transmitted and infects young chickens.

IgM+ (B) lymphocytes in the bursa of Fabricius (BF) are targeted(90), causing rapid necrosis and depletion of lymphocytes from thebursal follicles (232). The BF is principally involved, but lymphoidtissues elsewhere (spleen, cecal tonsil, proventriculus) are alsoaffected. The primary response to IBDV infection occurs as aninflux of T lymphocytes (126,127,253). Intrabursal T cells and Tcell–mediated responses are important in viral clearance and arenecessary in promoting recovery from infection (127). Cytotoxic Tlymphocytes (CD4+, CD8+) help to limit viral replication butpromote bursal tissue damage and delay tissue recovery, possiblythrough the release of cytokines and cytotoxic effects (212). Incomparisons of the pathogenesis of vaccine strains of IBDV, themagnitude of the T-cell responses in the BF during IBDV infectionis influenced more by the virulence of the IBDV than the viral loadin the tissue (200). The local T-cell events in the bursa alone maynot be indicative of a rapid and protective immune response (213).

Acute infection may occur as clinical or subclinical disease, andmortality is a feature of very virulent strains of IBDV. During acuteinfections, chickens develop systemic disease and may developlesions in the lymphoid tissues, liver, and kidney, in association withcirculating immune complexes (143,237). Chickens that survive theacute infection clear the viral infection, and bursal follicles arerepopulated with IgM+ B lymphocytes (125). As the virulence of theIBDV strain increases, the follicular repopulation or restitutiondecreases. For individual follicles, two sequelae are observedhistologically: large reconstituted follicles with numerous lympho-cytes in the cortex and medulla, and small poorly developed follicleswith a poorly discernible cortex and medulla (268). Chickens with

Fig. 1. Immunosuppressive interactions in broiler chickens. A high-yield broiler may hatch in an energy-depleted state and be subjected tosuboptimal handling and transportation systems, and experience delays in acquiring nutrition, all while processing attenuated live vaccines thatproduce cytolytic infections. The brooding environment may not meet thermoneutrality, and placement on reused litter creates the potential forexposure to ammonia and potentially immunosuppressive agents such as MD, chicken anemia, and enteric viruses. With the decline of maternalimmunity, active infection by IBDV can be permanently immunosuppressive at or before 14 days of age and, at least, transiently immunosuppressivewhen it occurs at an older age. Also, with declining maternal immunity, CIA can produce a cytolytic infection in the thymus and contribute to theimmunosuppression initiated by IBD. Following this sequence, it is possible for immunocompetency to be compromised in a variable percentage ofthe flock. This can contribute to increased severity of infections by respiratory viruses and the ability to control secondary respiratory infections by E.coli. Coccidiosis and gangrenous dermatitis may likewise emerge as problems from 25 days of age and older. Collectively, this sequence of eventsoccurs to variable degrees and influences livability, feed conversion, condemnation at processing, and total production cost. Each immunosuppressiveinfluence represents a control point to prevent immunosuppression and improve health and welfare.

4 F. J. Hoerr


mostly undifferentiated follicles have reduced ability to mount anantibody response, indicating that B cells in these follicles are unableto produce peripheral B cells with an effective immunoglobulinrepertoire.

Neonatal chickens that survive the acute infection are immuno-suppressed despite repopulation of the bursa with B cells. When IBDoccurs in chickens 14 days of age or younger, B lymphocyte seedingof secondary lymphoid centers is curtailed, resulting in apermanently defective humoral immunity, and leaving the chickensusceptible to secondary infections (49,108,183). In chickens olderthan 14 days, IBD causes transient depression of systemic antibodyproduction and, with necrosis of plasma cells in the Harderiangland, diminished mucosal immunity (48,50,90,99). Cell-mediatedimmunity and heterophil and macrophage functions are alsotransiently depressed (48,50,137).

In the decades since the original descriptions, IBD has becomeubiquitous in most commercial poultry flocks worldwide. Advancesin protecting young chickens from mortality and permanentimmunosuppression have been realized through breeder henimmunization for transfer of high levels of maternal antibody, andvaccination of the young chicken with attenuated strains of IBDV(140). IBD today still occurs in broilers, young breeders, andcommercial layer pullet replacements, but the window of suscepti-bility is about 20 to 30 days of age. This is reflective of vaccinationprograms that provide maternal immunity to progeny, and theeffectiveness of attenuated vaccines in providing acquired immunityto IBDV in the chick (257). In this scenario, the severity andduration of the transient immunosuppression are likely keys to theimpact of IBD and the effectiveness of IBD vaccination programs.As the response and recovery from acute IBDV infection requireintact immune responses, poultry are also vulnerable to otherimmunosuppressive agents and disease.

Bursal disease is caused by classical stains of serotype 1 IBDVassociated with clinical IBD, antigenic variant strains of serotype 1IBDV associated with subclinical disease, and very virulentpathotypes associated with moderate to high mortality(11,61,177). The subclinical characterization of the antigenicvariants is a matter of perspective. In the author’s experience, it isrelatively common for broilers between 20 and 30 days of age tohave clinical signs of huddling, diarrhea, and mild mortality. Atnecropsy, the bursa is small, and histologically, there are apoptosisand necrosis of lymphocytes consistent with acute IBD.

IBD interacts with infectious bronchitis by interfering witheffective immunization, enabling persistent respiratory infections byinfectious bronchitis virus (IBV), and increasing the severity ofnephropathogenic bronchitis (68,81,223,257,267). IBD reduces ordelays the secretory antibody to IBV in tears, allowing a permissiveenvironment for IBV replication in the Harderian gland and thesecretion of infectious virus (72,260).

IBD interacts with Newcastle disease by increasing the severity ofNewcastle disease outbreaks (188), interfering with the antibodyresponse to immunization (8,65,78,192,219), reducing the resis-tance to Newcastle disease virus (NDV) challenge (223), andprolonging the duration of NDV shedding during infection (114).

Under circumstances in which there is early onset of IBD,chickens can have increased risk for Marek’s disease (MD). Exposureto IBD at less than 1 wk of age increases susceptibility to MD (78).Pathogenic bursal disease virus has been shown to transientlydecrease the protection of turkey herpesvirus (HVT) vaccine forvirulent MD virus (MDV) (230). Bursal disease causes decreasedvirus-neutralizing antibody to HVT vaccination and reducesantiviral immunity to MDV (110).

In chickens, IBDV infection leads to persistence of reovirus intissues, and lower antibody response to reovirus compared toreovirus alone (176).

IBD is associated with increased severity of bacterial diseases ofchickens, including salmonellosis, colibacillosis, staphylococcosis,and clostridial infections. Bursal disease and severe enteritis werepredisposing conditions for a severe outbreak of subcutaneousclostridial infection (gangrenous dermatitis) involving Clostridiumperfringens and Clostridium septicum in broilers (96).

Bursal disease increases general susceptibility of SalmonellaTyphimurium (ST) and decreases the humoral immune responseto ST infection in broilers (13,274). In young layer pullets, IBDVcoinfection increased the severity of lesions from Salmonella entericaserovar Enteritidis (SE), increased mortality, and at sexual maturity,increased rate of egg transmission of SE (194).

In most respiratory diseases of poultry, E. coli is the final pathogento express sequentially, following IBDV and other immunosuppres-sors, and a primary respiratory disease. IBD can increase thesusceptibility to E. coli without a predisposing viral infection(105,171,182). The pathogenesis involves the failure of bacterialclearance from the circulating blood once colisepticemia isestablished, even by relatively apathogenic strains of E. coli (222).

Chickens with IBD are more susceptible to Staphylococcus aureus(227), which can express as staphylococcal gangrenous dermatitis(26). In young broiler breeders, staphylococcal and coliform-inducedchondronecrosis and osteomyelitis are predisposed by ad libitumfeeding, resulting in excessive body weight and immunosuppressioninvolving IBD and chicken infectious anemia (CIA) (161,162).

In outbreaks of coccidiosis, IBD and ensuing bursal atrophy areassociated with increases in lesion severity and mortality (86,190)and apparent failure of anticoccidial drug treatments (155).Although immunity to coccidia is not blocked, suboptimalimmunity can occur. Bursal disease has been associated withincreased hemorrhaging during coccidiosis caused by Eimeria tenella(74).

CIA. The chicken anemia virus (CAV, Circoviridae) is verticallytransmitted from a hen that is acutely infected during eggproduction, and it is transmitted to the developing embryo(32,286). When the chick hatches, CAV targets hemocytoblasts inthe bone marrow and lymphocytes (CD4+, CD8+) in the thymus,resulting in aplastic anemia, thrombocytopenia, leukopenia, andthymus depletion in chickens 7 to 14 days of age(100,251,252,285). The chicks develop a fatal gangrenous lesionon the wings called blue wing (17,69,79,163). During the acuteinfection, the virus is shed to penmates through the digestive tractand feather dander (41). Chicks with aplastic anemia areimmunosuppressed and susceptible to adenovirus infections andbacterial disease (184,224). The adeno-associated virus reported inthe early 1970’s by Yates et al. (275) was likely CAV.

Nearly simultaneous with the isolation and characterization ofCAV was recognition by Yuasa et al. (283) of the highly protectiverole of maternal antibody in preventing aplastic anemia in progenychicks. They observed that breeder flocks that were seropositive toCAV produced chicks that were refractory to aplastic anemia anddemonstrated this in challenge studies. Aplastic anemia and bluewing are now largely controlled by ensuring that hens are exposed toCAV prior to the onset of lay (80,221,262). The hen developsantibody to CAV, which is transferred to and protective of theprogeny chick (80,262), even though the hen may continue to shedCAV through the reproductive tract (18). As a result of broadapplication of this basic control method, blue wing disease isobserved less frequently in broiler and layer production today.



From the perspective of poultry production, the prevention ofaplastic anemia and blue wing disease in young chickens by CAVvaccination in breeders provided somewhat false assurance that theCAV problem was resolved (80). It was recognized early on thatchickens older than 14 days could be infected with CAV. The rapiddevelopment of antibody and the lack of clinical signs weresuggestive of age-related resistance to aplastic anemia (284,285).Subclinical immunosuppression by CAV in chickens older than 2wk of age is now recognized as economically important toproduction (164). With the decline of maternal immunity, chickensbecome again susceptible to infection by CAV, which is ubiquitousin poultry environments (240,277). In older chickens, the bonemarrow is spared, but the thymus is infected by CAV and depletedof lymphocytes by apoptosis (112,117,239,255). The chickens haveimpaired T lymphocyte and macrophage activities, and loosebactericidal capability (153) for up to 4 wk postinfection. Materialimmunity can be low in a percentage of chicks during the first weekand is typically depleted by 10 to 14 days of age (240) (B. Hopkins,personal comm.; F. J. Hoerr, unpubl. data), but can persist to 20days of age (256). Depending on the level of exposure, oral intake ofCAV as would occur with natural exposure may require up to 10 to14 days to induce peak virus load in the thymus, which correlateswith the severity of thymus atrophy. Thus, chickens with decliningmaternal immunity become susceptible to CAV at 20–30 days ofage, or perhaps younger if maternal antibody protection is marginal.The thymus depletion is a subclinical event (117), but broilers withCAV-depleted thymuses develop secondary infections, includinggangrenous dermatitis, coccidiosis, and viral and bacterial infectionsof the respiratory tract (86).

The potentially important interaction between IBDV and CAVwas recognized by Yuasa et al. (285), who actually had to neutralizeIBDV (and reticuloendotheliosis virus [REV]) from their infectivematerial used during the initial characterization studies and serialpassage of CAV. Chickens coinfected with IBD have increasedsusceptibility to CAV infection at older ages (282), are moresusceptible to contact infection by CAV, have higher mortality rates(224), and have prolonged acute phase prior to recovery or mortality(36). In chickens 35–40 days of age, IBDV infection enhances CAVinfection by inhibiting virus-neutralizing antibody to CAV, whichprolongs CAV viremia, and there is increased presence of CAV inthe distal intestine (106). In broilers, IBDV infection delays therecovery of the thymus from CAV-induced lymphocyte depletion(256). Although bursal atrophy is a feature of CAV infection, thepathogenesis does not involve CAV replication in the bursa (2). Inbroiler production, the onset of bursal atrophy and thymus atrophy,consistent with bursal disease and CIA, respectively, is suggestive ofthese two diseases being sequential or concurrent subclinicalimmunosuppressive risk factors underlying the presenting clinicaldiseases (86,257).

The pathogenesis of MD can be enhanced or inhibited by CAV,depending on the titer of the challenge dose of MDV (111).

Early CAV infection resulted in decreased protection fromvaccination for either Newcastle disease or laryngotracheitis, andcombined CAV and IBDV challenge also reduced vaccine protectionfrom fowl pox (37). CAV-infected chickens had more severerespiratory reaction to attenuated NDV vaccine, with reduction ingrowth (44).

In broiler flocks in Alabama, peak isolation of cycling vaccinestrains of IBV coincides with the onset of bursal atrophy attributableto IBDV infection at 20–30 days of age, and thymus atrophyattributable to subclinical CAV infection that emerges at 30–40 daysof age (92,257). Experimental evaluation of the immunodeficiency

created by coinfection with CAV and IBDV on the outcome of IBVinfection revealed that clinical signs and histologic lesions were morepersistent in immunodeficient chickens. At the same time, IBV RNAconcentrations in tracheas and lachrymal fluids were higher andmore persistent in immunodeficient chickens. Coinfection withCAV and IBDV reduced B cells and T helper cells in the Harderianglands and cecal tonsils in response to IBV, and slowed the kineticsand/or reduced the magnitude of the mucosal immune responseagainst IBV (260).

CAV infection is a risk factor for bacterial infections, due toreduced bactericidal capabilities of macrophages from infection byCAV that can last for up to 28 days (153,154). CAV is associatedwith staphylococcal infections (69,161) and gangrenous dermatitis(16,86,202,224). Respiratory infections typically involve E. coliinfections as the chief cause of mortality and losses at processing.Increased medication costs linked to bacterial infections are onefactor in the association of CAV with decreased performance andprofitability of broilers (158,164).

MD. MD causes immunosuppression and lymphoma formationin chickens. The history of MD vaccination reflects the ongoingemergence of virulent strains of Marek’s disease virus (MDV)capable of breaking through protection of once-effective vaccines.Infection by MDV causes lymphocytolytic infection and atrophy ofthe BF and thymus (23), lymphopenia, and reduced humoralimmune response (62,107,132). The degree of immunosuppressionis a criterion of virulence of emerging strains (269). Vaccines thatprotect against lymphoma formation by virulent MDV have asparing effect on immunosuppression but may not provide completeprotection (107,214). Despite the immunosuppressive potential ofMDV, detection of MD-induced immunosuppression is a diagnosticchallenge, given the ubiquitous nature of IBDV and CAV. Anindirect but practical approach to this is that immunosuppression byMD should be expected to accompany emerging problems with MDlymphomas, skin tumors, or other MD syndromes.

Interactions of MD with IBD and CIA are described in thepreceding respective sections.

Retroviral tumor diseases. Avian leukosis of chickens andreticuloendotheliosis of turkeys, chickens, and other avian speciescause tumors, reduced productivity, immunosuppression, and otherproduction problems in affected flocks (64). In chickens, replicationcompetent REV strain A and chicken syncytial virus have beenshown to cause a runting syndrome and bursal atrophy (67).Chickens with tolerant infections by REV become immunode-pressed (270), which may contribute to the development of acuteleukemia by inhibiting the proliferation of cytotoxic cells directedagainst the tumor cell antigens (15,265). Chicks infected with REVand challenged with NDV developed more severe clinical signs andhad reduced antibody response and prolonged recovery time (280).A myeloblastosis strain of avian leukosis virus capable of inducingosteopetrosis caused atrophy of lymphoid organs and decreasedmacrophage function and bacterial clearance (38,39,238). Anerythroblastosis strain of ALV caused thymus atrophy and decreasedT-cell competencies (210).

Hemorrhagic enteritis (HE) of turkeys and otheradenovirus infections. The adenovirus that causes HE of turkeys(HEV, type II avian adenovirus) causes acute cytopathic infection ofIgM+ lymphocytes (B cells) and macrophages (247). The infectionsuppresses B lymphocyte and macrophage functions, leaving poults 6to 11 wk of age susceptible to E. coli infections (167). The acuteclinical disease is an immune-mediated (T lymphocyte) HE of theproximal small intestine (248), for which the pathogenesis involvesproinflammatory cytokines (211). The acute phase also is

6 F. J. Hoerr


characterized by splenomegaly (231), with virus replicating primarilyin the spleen and cecal tonsils. Active infections are indicated bylarge intranuclear inclusion bodies in reticuloendothelial cells and inrenal tubular epithelium (167). Acute HE exacerbates E. coliinfections in the immunosuppressed poults (242) and initiatesseroconversion to HEV (167). An E. coli septicemia syndromeinvolving synovitis, osteomyelitis, and hepatitis with green discol-oration of the liver is a sequela to HE infection in 8- to 11-wk-oldturkeys (52).

Although they are caused by different viruses, HE in turkeys hasimmunosuppressive effects similar to IBD in chickens (225). Bothviruses target IgM+ lymphocytes (B cells) and macrophages, and theacute stage of the disease is followed by immunosuppression andincreased susceptibility to infectious disease. Virulent HEV andavirulent vaccine strains can predispose turkeys to bacterial infection(185,197,258). HE reduced the response to vaccination of turkeysagainst Newcastle disease (181).

Virulent strains of fowl adenovirus (FAV) capable of outbreaks ofinclusion-body hepatitis in the absence of immunosuppression byIBD or CIA have marked tropism for lymphoid tissues. Atrophy ofthe bursa, thymus, and spleen occurred with challenge studiesinvolving FAV serotypes 1, 4, and 8 (228,234) and an isolate notfurther typed (178). These virulent FAVs have viral tropism forlymphocytes and cause impairment of humoral and cellular immunecompetencies. The severity was augmented by aflatoxin (233).Multiple avian adenovirus strains can increase susceptibility to E. coliinfection in chickens (46,222).

Enteric viral diseases. Viral enteritis syndromes in chickens andturkeys (runting stunting syndrome [RSS]; poultry enteritis andmortality syndrome [PEMS]) involve one or more etiologic viruses,and contributing management issues such as short down timebetween flocks. Astrovirus, rotavirus, reovirus, parvovirus, and othershave been identified in young broilers (7–14 days) and youngturkeys with diarrhea and growth reduction. In the author’sexperience, broilers with RSS commonly show atrophy of the BFand thymus at necropsy, and histologically mild to moderatelymphocyte depletion. Similar lesions have been reported for RSScases in broilers in Australia (215) and Mississippi (173), and inturkeys in Ireland (160). The pathogenesis is not known. In theUnited States, chicks with acute RSS typically consume litter and thelesser mealworm Alphitobius diaperinus (Panzer). This interferencewith normal feeding behavior and interrupted nutrition couldcontribute to atrophy of lymphoid tissues (83). In some cases,histologic examination of liver shows bile duct proliferation in oneor more chicks per case, suggestive of contributions to immuno-suppression by hepatotoxicity from natural toxins.

Lymphocyte depletion in the lymphoid tissues occurs in turkeyswith PEMS (207). Turkey enteric coronavirus is associated withPEMS (24), and turkeys inoculated with coronavirus and E. colideveloped lymphocyte necrosis and depletion in the BF (85).Thymus atrophy is a lesion also associated with PEMS, and it occursin turkeys inoculated with astrovirus (14,133,229). A small roundvirus, possibly an enterovirus or astrovirus, can replicate in lymphoidtissues of turkeys, causing lymphocyte necrosis and depletion oflymphoid organs, and corresponding reductions in lymphocytesubpopulations in circulating blood (207,226,249,281).

Virulent strains of avian reovirus cause atrophy of lymphoidtissues and interfere with humoral immunity (43,174,175,217,241).Reoviruses can replicate in monocytes but not in lymphocytes (170);thus, the lymphoid atrophy is not caused by reovirus tropismspecifically for lymphocytes, in contrast to IBDV, CAV, MDV, andsome of the other enteric viruses.

Goose parvovirus is the etiology of a fatal hepatitis in young geese(Derzsy’s disease) (20). A parvovirus related to but distinct fromgoose parvovirus causes degenerative rhabdomyopathy in Muscovyducklings (201,271). Chickens and turkeys can be infected byparvoviruses, which may have a role in naturally occurring entericinfections (45,288). A chicken parvovirus has been shown to bevertically transmitted, and hatched broiler chicks had growthretardation, feather dysplasia, and bone disorders (128,129,130).Some mammalian parvoviruses have the potential to be immuno-suppressive, or exert their pathologic effects in immunosuppressedhosts (7,159,216). There is some confusion in the literature aboutCAV and a parvovirus-like virus (80), possibly due to the fact thatboth are small viruses not readily differentiated by morphology inclinical specimens.

Respiratory viruses. Newcastle disease causes lymphocytenecrosis and depletion from lymphoid organs (4,33), and it causesapoptosis of peripheral blood lymphocytes and mononuclear cells(136,138), which may increase susceptibility to secondary bacterialinfection.

Cases of pneumovirus infections in turkeys are characterized byconcurrent bacterial and viral coinfections. Pneumovirus replicatesand causes cytopathology in the upper respiratory epithelial cells(25), causing impairment of protective clearance mechanisms. Themechanism of immunosuppression appears to involve innaterespiratory immunity more than acquired immunity. Pneumovirusinfection augments bacterial infection of the lung and air sacs, andwith more invasive bacterial infection, there is deeper (bronchial)infection by the pneumovirus (150). Avian pneumovirus infectionsrender turkeys more susceptible to infections by E. coli, Ornitho-bacterium rhinotracheale (ORT), and Bordetella avium (113,148);exacerbate infections by Chlamydophila psittaci (147); increase theseverity to avian paramyxovirus challenge (151); and decrease theefficacy of HE vaccine (30). Chickens with pneumovirus infectionsbecome more susceptible to E. coli (5,150) and ORT (259). This canmanifest as swollen head syndrome with rhinitis, sinusitis, facialcellulitis and edema, and inflammation of the cranial air spaces(150).

Other potentially immunosuppressive diseases and agents. E.coli infections alone can induce marked lymphocyte depletion fromthe bursa and thymus in chickens (182). Infection of turkeys byeastern equine encephalomyelitis and Highlands J. viruses causeslymphocyte necrosis and depletion from lymphoid tissues (66).

MEASUREMENTS OF IMMUNOSUPPRESSION

For the poultry diagnostician, detection of immunosuppressionlargely focuses on detecting specific diseases by serologic surveillance,isolation, or molecular detection of the etiologic agent, orpresumptive lesions identified at necropsy or by histopathology.Assays to assess immunocompetency are largely used in the researchlaboratory; however, a broader approach could assess combinedenvironmental and infectious contributions of immunosuppression(47).

The heterophil:lymphocyte ratio in the circulating blood is ageneral indicator of stress and may provide general assessment ofimmunocompetency (91). Measurements of chicken interferon-alpha and interferon-gamma mRNA have been proposed as a generalassessment of immune function. Both are increased by subclinicalinfections by either IBDV or CAV (209), and could be assessedfollowing a brief laboratory challenge by inactivated Newcastle virus(187). Interleukin-2 has been proposed as a general measure of cell-mediated competency in the chicken intestine (40). Whole-blood



lymphocyte stimulation assay is a relatively simple assay ofcirculating T-cell responses and has application for the evaluationof coccidiosis outbreaks and of vaccine efficacy (250). Functionalassessment of peripheral blood monocytes has been proposed toassess immune function of cattle, including ingestion of Staphylo-coccus aureus, antibody-dependent cell-mediated cytotoxicity, andchemiluminescent assays (245). While these proposals have existedfor some time, none has seen consistent application or gainedcommon acceptance.

A functional genomics approach to the study of avian innateimmunity uses cDNA microarray, which is capable of testing forover 4000 genes (121). The avian innate immunity microarraycontains 25 avian interleukin, chemokine, and cytokine elements.The array also contains elements for several innate immunepathways, including genes involved in the Toll-like receptorpathway, avian interferon/antiviral response pathway genes, andgenes involved in apoptosis, antigen presentation, and the oxidativeburst. The avian specific microarray can test for global geneexpression patterns in a number of immunologically relevant tissuesand in chickens, turkeys, and ducks. The array has also beenevaluated for its ability to monitor the avian immune response toboth bacterial (avian pathogenic E. coli) and viral (avian influenza)avian pathogens.

Analysis of cytokine and chemokine gene expression followingcoccidiosis revealed that the primary response to coccidiosis is robustin immunocompetent chickens (97,98). This procedure holds thepotential for characterizing specific immune response deficienciesoccurring as a result of some of the immunosuppressive conditionsdescribed herein.

CONTROL OF IMMUNOSUPPRESSION

The control of immunosuppressive diseases depends on biosecur-ity to prevent exposure to the causes of immunosuppressive diseases,and increasing the resistance to challenge from immunosuppressiveagents through immunization and genetic selection. Today, withever-expanding flock sizes and increasing farm size, litter is reuseddue to economic and environmental constraints, cleaning anddisinfection become seasonal events rather than occurring after eachflock, and there is variable application of all-in, all-out management.These factors all contribute to an environment where challenge fromubiquitous immunosuppressive agents is virtually certain. MD, IBD,and CIA are not unique to these environments, but they are aconstant challenge due to the ability of many animals to replicateand shed large quantities of virus.

Immunosuppression has historically cost the poultry industry inincreased mortality and in performance factors during rearing, and ithas negatively impacted the processing of chickens due to associatedhealth problems. Strategies to control immunosuppression inbroilers and commercial layers are largely based on vaccinationprograms for breeders and broiler progeny, and management tominimize stress during rearing (70).

The genes of the major histocompatibility complex (MHC)encode proteins that are essential in the functioning of the immunesystem. The MHC antigens of chickens are cell-surface glycoproteinsof three different classes: class I (B-F), class II (B-L), and class IV (B-G), which are essential in the regulation of cell–cell interactions(139). A second histocompatibility complex of genes occurs in thechicken, Rfp-Y, composed of MHC class I and class II genes (264).Immunogenetic selection for specific resistance to immunosuppres-sive infectious diseases has yielded variable results. Strong associationof genes for resistance to MD (19,146,198,264) has resulted in the

greatest application to genetic selection. Selection for specificimmunogenetic traits is a challenge because selection for diseaseresistance must be balanced with desired production traits (88,287).Immunogenetic associations for resistance to IBD are equivocal(21,101,116), but differences occurred in the antibody response ofvarious MHC haplotypes to IBDV infection (63) and to inactivatedIBDV vaccine (115). CAV infects cells bearing class II antigens inthe bone marrow and T-helper lymphocytes in the thymus (3). AnMHC effect on resistance to CAV infection was not detected (114),but induced mutations on CAV had an effect on virus replication,cytopathogenicity, and down regulation of MCH class I genes ininfected cells (193).

Immunogenetic control of general antibody responsiveness iscomplex with multiple loci of MHC genes involved (279). As anexample of the complexity of these associations, the selection ofchickens as high-antibody responders had no effect on geneticresistance to E. coli infection (54) or Eimeria tenella coccidiosis (53).The MHC has been primarily identified with genetic control ofimmune response and disease resistance, but lesser characterizedgenes outside of the MHC also regulate immunoresponsiveness(139). The existence of Toll-like receptors in chickens and turkeysprovides a genetic basis for selection for enhanced innate immunity(89,276). Understanding the interaction of adjuvants with immu-nogenetics may lead to improved vaccines (278).

PERSPECTIVE

With current MD vaccines keeping MD under control, IBD andCIA are currently the two major immunosuppressive diseases inbroiler production. The two diseases are largely subclinical, occursequentially or concurrently, and are detected along with secondarydiseases during diagnostic investigation. The vaccine repertoires forIBD and MD are greater than for CIA. The relative role of MDcould increase in areas where MD vaccine and management areunable to control emerging virulent MDV strains with antigenicdifferences to existing vaccines.

Enteric viruses are increasingly recognized as ubiquitous inchicken and turkey production (191). Thus, ongoing challenge byone or more of the enteric viruses can be anticipated with horizontaland possible vertical transmission. The circumstances that determineclinical or subclinical expression are largely not defined, but theemerging evidence is that one or more of the enteric viruses areimmunosuppressive. Characterizations of the enteric viruses, theirpathogenesis singly and in combination, and methods for preventionand control merit further study.

The utilization of feed grains for ethanol production yieldscoproducts that will be used in feeds for livestock (272) and poultry.Distillers’ dried grains with solubles have reduced nutritional valueand concentrated mycotoxins relative to the original grain. Thisemerging issue will impact poultry production, although to whatdegree is not known. Subclinical immunosuppression fromnutritional and toxicologic causes is one possible effect.

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ACKNOWLEDGMENTS

The author thanks Eric Gingerich, Kenton Kreager, and SusanLockaby for assistance with this manuscript.



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