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8.12: Infections in Animals - Biology

8.12: Infections in Animals - Biology


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Learning Outcomes

  • Describe the different types of fungal infections in animals

Fungi can affect animals, including humans, in several ways. A mycosis is a fungal disease that results from infection and direct damage. Mycotoxicosis is the poisoning of humans (and other animals) by foods contaminated by fungal toxins (mycotoxins). Mycetismus describes the ingestion of preformed toxins in poisonous mushrooms. Antibiotics only target prokaryotic cells, whereas compounds that kill fungi also harm the eukaryotic animal host.

Many fungal infections are superficial; that is, they occur on the animal’s skin. Termed cutaneous (“skin”) mycoses, they can have devastating effects. For example, the decline of the world’s frog population in recent years may be caused by the chytrid fungus Batrachochytrium dendrobatidis, which infects the skin of frogs and presumably interferes with gaseous exchange. Similarly, more than a million bats in the United States have been killed by white-nose syndrome, which appears as a white ring around the mouth of the bat. It is caused by the cold-loving fungus Pseudogymnoascus destructans, which disseminates its deadly spores in caves where bats hibernate. Mycologists are researching the transmission, mechanism, and control of P. destructans to stop its spread.

Fungi that cause the superficial mycoses of the epidermis, hair, and nails rarely spread to the underlying tissue (Figure 1). These fungi are often misnamed “dermatophytes,” from the Greek words dermis meaning skin and phyte meaning plant, although they are not plants. Dermatophytes are also called “ringworms” because of the red ring they cause on skin. They secrete extracellular enzymes that break down keratin (a protein found in hair, skin, and nails), causing conditions such as athlete’s foot and jock itch. These conditions are usually treated with over-the-counter topical creams and powders, and are easily cleared. More persistent superficial mycoses may require prescription oral medications.

Systemic mycoses spread to internal organs, most commonly entering the body through the respiratory system. For example, coccidioidomycosis (valley fever) is commonly found in the southwestern United States, where the fungus resides in the dust. Once inhaled, the spores develop in the lungs and cause symptoms similar to those of tuberculosis. Histoplasmosis is caused by the dimorphic fungus Histoplasma capsulatum. It also causes pulmonary infections, and in rarer cases, swelling of the membranes of the brain and spinal cord. Treatment of these and many other fungal diseases requires the use of antifungal medications that have serious side effects.

Opportunistic mycoses are fungal infections that are either common in all environments, or part of the normal biota. They mainly affect individuals who have a compromised immune system. Patients in the late stages of AIDS suffer from opportunistic mycoses that can be life threatening. The yeast Candida sp., a common member of the natural biota, can grow unchecked and infect the vagina or mouth (oral thrush) if the pH of the surrounding environment, the person’s immune defenses, or the normal population of bacteria are altered.

Mycetismus can occur when poisonous mushrooms are eaten. It causes a number of human fatalities during mushroom-picking season. Many edible fruiting bodies of fungi resemble highly poisonous relatives, and amateur mushroom hunters are cautioned to carefully inspect their harvest and avoid eating mushrooms of doubtful origin. The adage “there are bold mushroom pickers and old mushroom pickers, but are there no old, bold mushroom pickers” is unfortunately true.


Diseases Caused due to Fungi in Animals

This is a chronic disease of horses caused by a fungus Histoplasma (Crypto- coccus) farciminosus and characterised by inflam­mation and suppuration of the cutaneous and subcutaneous lymphatic vessels and glands.

Chiefly horses, mules and donkeys but cases have been recorded in cattle.

It gains entry through a wound or abrasion either on the skin or of a mucous surface. The disease is spread by harness, grooming tools etc. which have come in contact with diseased animals. The parasite shows con­siderable vitality outside the animal body.

It is usually a matter of weeks or months (average 6 to 8 weeks) and the spread of disease is slow and insidious. Even by means of experimental inoculation, incubation takes one month.

The first signs of the disease are often thickening or “Cording” of a lymphatic vessel and adjacent gland. The lesions start from a wound or abrasion on any part of the body, the commonest site being the legs. The first sign noted is nodules up to a size of a walnut along the lymphatic vessels leading from the site of infection which, as the disease progresses, suppurate. The lymph glands into which the vessel drains swell and often develop large abscesses.

These abscesses and suppurated nodules referred to above ultimately burst—discharging creamy white or faintly yellow thick pus. Later on, these areas turn into ulcers with a red granulating base which have little tendency to heal. The forelimb—from the shoulder to the knee—is perhaps the usual site. Tumour-like masses may be seen at the shoul­der and a thick cord may run down the limb. The larger masses may not burst at all if left alone.

When a limb is affected, it shows consider­able thickening from chronic lymphangitis.

The characteristic feature of the disease is that the affected animal presents no constitutional disturbance even when extensive lesions are present.

Diagnosis (Differential):

This disease may be confused for Farcy. In this disease, the pus is thick and creamy, on examination of which Histoplasma (Cryptococcus) farciminosus is de­monstrable whereas in Farcy, the pus is yellow­ish grey, viscid, occasionally reddish and is oily in appearance. Besides, there is the Mallein test to differentiate Farcy from Epizootic lymphangitis.

Benign cases may heal sponta­neously but malignant cases resist all forms of treatment. In general, exposure to direct sunlight, dry air, good feeding with much nitrogenous food and rest have a favourable influence on the disease and this explains why in tropical and subtropical regions, recovery is’ more frequent than in other countries.

Treatment consists in surgical excision of all affected nodes, cords and ulcers with antiseptic dressing. Ulcers treated locally with a.2% methyl­ene blue solution hastens their healing.

Injection of the following is reported to have excellent results:

This is given intravenously once a day for 8 days and after a gap of one week for another 8 days.

Disease # 2. Ringworm (Dermatomycosis):

This is a parasitic skin disease of man and animals of a contagious nature and is caused by the fungi belonging to the genera Microsporon and Trichophyton. The organisms belong to the two genera of fungi Imperfecti, a large group of fungi whose life history is not completely known.

It occurs in all animals. It is commonest in cattle, occurring chiefly in calves.

Then—in order of susceptibility — horses, dogs, cats, pigs and sheep.

The young ones in all species are more sus­ceptible because of their finer skin, the same ap­plying to fine skin breeds irrespective of age.

Infection may spread from one species to another and to man by direct contacts or indi­rectly through infected articles.

It must be remem­bered that two important contributory causes of ringworm are:

(1) Over-crowding of animals into unhygienic, badly ventilated buildings and

(2) General debility due to under-nourishment. There is of course seasonal variation.

At the commencement, rounded areas without hairs or with stumps of broken hairs are seen. The first manifestation of ringworm is that the skin becomes reddened or inflamed and a little whitish, greyish or yellow serum exudes from its surface and little nodule or vesicle form at each follicle. As a result, greyish or yellowish scales and later thick crusts or scabs form over, the areas, with subsequent develop­ment of suppurating surface under them, which, in course of time, causes these crusts to become loose and fall off.

These areas heal with new hairs growing over them. Sometimes, the lesions coa­lesce to form large irregular-shaped areas. New patches appear and repeat the process. Itching is most pronounced during the initial and terminal stages.

The lesions with crust formation is most com­mon in cattle and in case of horses and other animals, the patches are usually scaly or have a scab.

This is due to Trichophyton verrucosum infection. The lesions are nearly al­ways on the head and neck, rarely on the body. Specially the eyelids, lips, ears and above the jaw are affected. The lesions begin as a raised ring-­like patch on which the hairs stand erect. In a short time, the hairs fall off and the surface of the skin becomes covered with masses of scales heaped up into greyish-yellow crust. In calves, round the mouth and above the eyes, infection having taken place from the mother.

The infection is due to either Trichophyton or Microsporum. The lesions occur on the shoulder, back and flanks. The lesions occur in regular circles and seldom with any pruritis. The hair becomes matted in patches and this gradually extends until the whole area is denuded. The skin becomes raised and greyish white crusts are formed.

The infection is caused by four varieties — Trichophyton, Microsporum, Oidmella or Oospora. The lesions are most on head and limbs. These occur in circular patches which become denuded of hairs and later covered with loose crusts or scabs.

Infection is due to Trichophyton, Microsporum and Achorion.

The lesions are similar to what are seen in other animals.

Oral administration of Griseofulvin is the best and simplest method. Hard crusts must be softened and removed be­fore applying the remedy. For softening, equal parts of soft soap and lard are best which is applied with rubbing and left over for 2 to 4 days, with repetition if necessary. Addition of little quantity of Pot. carbonate to the above expedites the soft­ening.

Antiparasitic remedies such as Acid Salicyl, Resorcin, Coal tar, Napthalene, Creosote etc. in an ointment form is to be applied after cleaning as suggested above.

The fungi are known to be sensitive to oil and fat, hence, antiparasitic remedies should have oil or fat base.

In cases in which the lesions are not exten­sive, good results are obtained by application of the following:

Part of Iodine in 1 to 5 parts of alcohol or Xylol. Since this remedy is irritating, it must be used with care.

Several antifungal ointments are now avail­able and can be used safely without causing any irritation.

Disease # 3. Aspergillosis:

This is a disease of mammals and birds produced by the growth of the fungus Aspergillus in the tissues of the body. The most commonly affected is the respiratory tract but it has also been seen in ears, mouth, throat and liver. It runs a slow course and often mistaken for tuberculosis.

The disease is produced by fun­gus Aspergillis where it causes a necrosis or death of cells and formation of small abscesses. Within the body, they grow out hyphae and produce more spores and these spread the infection further.

The animal appears dull and weak and the appetite is poor. There is no rise of temperature. The disease resembles contagious pleuro pneumonia or tuberculosis but symptoms are not characteristic. The breathing is difficult and often accompanied by a dry cough. The ani­mal does not thrive. The nasal discharge contains fungus or its spores.

The disease is not common. It is manifested by sore throat, bronchitis, pneumonia, according to the seat of fungus. It may resemble anthrax or anaemia.

Normally the animal contracts the infection from poultry. It is manifested by epileptic-form convulsions or symptoms that are not unlike those of rabies. There is severe scratch­ing or rubbing of the muzzle and there is dis­charge from nostrils which may be blood-stained. The disease runs a rapid course. Almost all the cases have occurred in the nasal cavities.

The air passages become filled with cheesy material in which the fungus devel­ops and breathing becomes extremely difficult. The bird gapes with its beak and gasps. Frequent sneezing and coughing are noticed. The sick bird remain isolated from the rest of the flock and there may be diarrhoea. A discharge with a repul­sive odour trickles from the mouth and nostrils.

There is no specific treatment and very unsatisfactory. Local infusions of Nysta­tin may be tried in case of valuable animals.


Biology of anti-TNF agents in immune-mediated inflammatory diseases: therapeutic implications

Biologics are increasingly being used to modify the course of immune-mediated inflammatory diseases. Some main agents are monoclonal antibodies and a fusion-protein that target TNF. This group includes adalimumab, infliximab, certolizumab pegol, golimumab and etanercept. Although the efficacy of anti-TNFs is supported by numerous randomized clinical trials, their pharmacokinetics depend on many factors, in particular immunogenicity, which can cause marked and rapid clearance and a consequent decrease in efficacy. Kinetics involve receptors that recognize the Fc fragment of the antibody and are responsible for various processes. Pharmacological advances permit optimizing the pharmacokinetics of anti-TNFs. In this review, we examine the kinetics of anti-TNF biologics, and consequent therapeutic implications, and overview some latest developments in the field. First draftsubmitted: 17 May 2016 Accepted for publication: 15 September2016 Published online: 14 October 2016.

Keywords: Fc receptor γ immunogenicity anti-TNF immune-mediated inflammatory diseases monoclonal antibodies pharmacokinetics.


8.12: Infections in Animals - Biology

Infectious disease transmission through organ and tissue transplantation has been associated with severe complications in recipients. Determination of donor-derived infectious risk associated with organ and tissue transplantation is challenging and limited by availability and performance characteristics of current donor epidemiologic screening (e.g., questionnaire) and laboratory testing tools. Common methods and standards for evaluating potential donors of organs and tissues are needed to facilitate effective data collection for assessing the risk for infectious disease transmission. Research programs can use advanced microbiological technologies to define infectious risks posed by pathogens that are known to be transplant transmissible and provide insights into transmission potential of emerging infectious diseases for which transmission characteristics are unknown. Key research needs are explored. Stakeholder collaboration for surveillance and research infrastructure is required to enhance transplant safety.

Multiple clusters of infection associated with allograft transplantation and poor outcomes have been described for recipients. These clusters included infection transmitted to recipients of vascularized organs or tissues such as bone, tendon, skin, or corneas. The exact risk for infection associated with organ or tissue transplantation is unknown but is related to multiple factors, including epidemiology of specific infectious exposures, tissue tropism of the organism, and transmissibility of potential pathogens through transplantation. Even for known pathogens, there are few data on the microbial characteristics that determine transmissibility. Similarly, with regard to new pathogens or pathogens that are found in new regions or populations, i.e., emerging pathogens, there are few data regarding optimal approaches to assessing risks of allograft-associated transmission.

Figure. . . . . . . . . . . . . . . . . . Number of deceased and living organ donors and deceased tissue donors, United States, 1998&ndash2012.

Transplantation of organs and tissues is increasing (Figure). Prospective assessment of the risk for allograft-derived infection is complicated by the variety of potential pathogens and technologies required for detection and by variability between allograft recipients. Such infections must be distinguished from other transplant-associated infections, including nosocomial infections and infections derived from tissue contamination during handling or processing.

In an attempt to prevent donor-derived infections in transplantation, organ and tissue donors are evaluated to identify those that might be more likely to harbor transmissible pathogens. Current donor evaluation protocols rely on reviewing the potential donor’s epidemiologic and clinical history (i.e., donor screening) and communicable disease test results (i.e., donor testing). Donor screening methods include evaluating the donor’s medical history and physical examination results and assessing (often in the form of a questionnaire) the donor for behavioral risk factors associated with a higher prevalence of communicable diseases. Donor testing includes the donor’s microbial culture data (e.g., blood, urine, sputum), serologic assay results (e.g., antibodies against HIV, hepatitis B virus [HBV]), and hepatitis C virus [HCV]), and increasingly, nucleic acid testing (NAT) results, including assays for HIV, HCV, or HBV. Although regulatory requirements and risk-benefit considerations for evaluating organ and tissue donors differ, the fundamental process for donor screening and testing, and the challenges faced in prospectively assessing the risk for donor-derived infection, are similar for organ and tissue donors. Despite the recognized need to address these challenges, there is little consensus regarding direction for improvements in donor evaluations or for identification of future epidemiologic threats posed by allograft transplantation.

In May 2010, the US Food and Drug Administration held a workshop entitled Emerging Infectious Diseases: Evaluation to Implementation for Transfusion and Transplantation Safety. The goal of this meeting was to identify a research agenda to characterize the risk for transmission of donor-derived infections and inform the development of guidelines for emerging infectious diseases (1). The major issues identified are summarized in this review.

Challenges Identifying Potential Pathogens in Transplantation

Identification of gaps in current knowledge regarding disease transmission by transplantation will facilitate development of a research agenda for this field. Despite recognition of possible donor-derived infections in recipients, when investigating such events, confirmation of an association with the transplanted organ or tissue (i.e., imputability) is often uncertain. The incidence of recognized infectious disease transmission in organ recipients is estimated at ≈1% on the basis of limited data (2). Uniquely for tissue transplantation, the incidence of transmission may be further reduced by postprocurement processing. Given the immunocompetence of tissue recipients and routine use of antimicrobial drug prophylaxis, disease transmission appears to be rare. In the face of a recognized recipient infection, it is challenging to determine whether an infection was donor-derived, recipient-derived, nosocomial, or caused by allograft contamination. Policy development regarding optimal donor screening and testing practices will require more complete data on disease risk and extent of transmission.

Threat Identification

Identification of potential infectious disease threats can be accomplished by systematic approaches, including outbreak investigations and literature searches, and through routine, intensive searches for new pathogens. Donor-derived infectious disease risks posed to recipients by organ and tissue transplantation have been identified primarily through published descriptions of clusters of allograft recipients with infections, sometimes caused by unusual organisms such as lymphocytic choriomeningitis virus (3,4) or rabies virus (5), or after transmission events associated with blood products. Because viable, transplanted organs are highly efficient vectors for microbial transmission into immunosuppressed hosts, transmission events in organ transplant recipients may serve as sentinel events for emerging infections.

Changing Epidemiology

Identifying potential infectious exposures is accomplished, in part, by obtaining a donor epidemiologic history. Potential organ and tissue donors may reside in, or have migrated between, geographic regions where different organisms are endemic, which confound screening and testing efforts. The changing geographic distribution of pathogens such as West Nile virus (WNV), chikungunya virus, dengue virus, Babesia spp., and Trypanosoma cruzi (i.e., Chagas disease) have resulted in clusters of infections transmitted to organ recipients in regions where the pathogens are not endemic. Epidemiologic shifts and other disease transmission risks discussed below illustrate the need for systematic risk-based approaches to evaluating the transmissibility of pathogens through tissue and organ transplantation.

Transmissibility of an Organism by Transplantation

The transmissibility of an organism by transplantation is generally imputed by after-the-fact recognition of the organism in the blood or tissues of the allograft donor and recipient. Detection and reporting of transmission events is incomplete. The biology of disease transmission from allografts has not been well studied, even for organisms known to be transplantation transmissible. More accurate risk assessment requires data regarding the epidemiology and transmission characteristics of a specific organism in a specific graft type.

Transmission of infection is dependent on a series of factors that are organism and host dependent (Table 1). These factors include the organism type (virulence) and the presence or absence of effective host immune and inflammatory responses. Increasingly potent immunosuppressive agents used to prevent rejection in organ transplant recipients have also increased risks for opportunistic infections and viral infection–mediated malignancies, further complicating the determination of whether a posttransplant event is donor derived.

Experience with Allograft-associated Transmission of WNV

The pathogenesis of WNV infection illustrates the complexity of disease detection and prevention in organ transplantation. WNV is asymptomatic in 80% of immunocompetent persons infected by mosquito bites. WNV viremia in blood donors is typically detected within 1–5 days after infection, depending on whether testing is performed by using individual donation or minipool tests. Detecting WNV viremia may be complicated by low-level viremia. WNV viremia in blood donors generally clears within weeks, although viremia may persist despite the appearance of antibodies within 7–10 days after exposure (6). The value of reports of persistent detection of WNV nucleic acid in urine of some persons years after infection remains to be determined (7).

WNV antibodies do not always protect susceptible cells from infection in vitro (6). In general, the likelihood of central nervous system involvement with WNV infection is greater in immunosuppressed hosts than in healthy persons (8). In all reported organ donor–derived infections with WNV in the United States, 2 of 4 kidney recipients showed development of neuroinvasive disease (WNND) but recovered, 1 showed development of virema and seroconverted but remained asymptomatic, and 1 did not demonstrate transmission. In 2 liver transplantation recipients, 1 showed development of WNV fever but recovered, and another showed development of WNND and permanent neurologic injury. Two heart recipients showed development of WNND but recovered. A recipient showed development of WNND but never recovered (911). Variability in transmission patterns among organ recipients exposed to WNV illustrates the need for studies that will define the organism and host factors governing transmission. Such data also will provide a basis for studies of emerging infectious diseases with unknown transmissibility characteristics.

Donor-derived disease transmission reports from tissue transplantation are relatively infrequent. WNV also illustrates some of the challenges faced in detecting donor-derived transmission events in tissue recipients. In contrast to organ- and blood-derived infections, tissue transmission of WNV has not been reported. Lack of similar reports of WNV transmission to tissue recipients may reflect underrecognition, i.e., differences in transmissibility, clinical symptoms, diagnostic approaches, immunosuppression, clinical follow-up of the recipient, and underreporting (12). Detection of infections after tissue transplantation might be delayed when a donor-derived infectious source is less likely to be considered. Clinicians often consider tissue allografts safe despite published reports (1319). Therefore, disease detection is dependent on skills, knowledge, and heightened awareness of clinicians caring for allograft recipients. Despite the absence of reported WNV transmission events, the large volume of tissue grafts and the potential availability of >100 tissue products from individual donors indicate the need for assessing and optimizing methods for identifying potential pathogens in tissue transplantation.

Challenges in Evaluating Donors

There are knowledge gaps in the efficacy of current practices in evaluating, i.e., screening and testing, donors for infectious agents. Screening identifies donor risk factors, but the sensitivity and specificity of current approaches are largely unknown. Serologic assays detect chronic or persistent infections but are less useful for diagnosing more recent infections. Some cases of donor-derived infection in organ transplantation occurred after failures in serologic testing (e.g., window-period cases before seroconversion) (9,1921). NAT is useful for detecting infection only in blood samples of viremic donors and is not available for every potential organism (22).

There is variability in the performance (between specific tests and laboratories) and application (selection of a particular assay by the program performing the test) of assays used in donor testing. This variability limits the ability to compare and interpret existing testing data derived from donor populations that could, in turn, inform decisions regarding optimal assay selection. For example, some organ-procurement organizations use assays indicated for donor testing and others use diagnostic tests. Programs use antibody assays from different manufacturers (resulting in differing performance characteristics), and some use NAT routinely or only in special circumstances (e.g., on the basis of donor characteristics). There are few data regarding the clinical performance of these assays in donor populations.

Additional Challenges

Posttransplant Surveillance

In the absence of routine active surveillance (e.g., posttransplant testing of all recipients to ascertain transmission events), donor-derived infectious disease transmission remains difficult to recognize and document. Current surveillance systems that identify transmission events are passive (i.e., clinicians must diagnose infection, recognize a relationship with transplantation, and report the event). Given the asymptomatic nature of some acute infections with serious, but delayed, sequelae (e.g., HBV), it is unlikely that most transmission events could be detected by passive surveillance alone. Active surveillance would increase knowledge of transmissibility and might detect emerging infectious agents within recipients of organs or tissues. Transmission rates are likely to vary among donor and recipient groups (e.g., by epidemiologic exposures) and among organs and various tissues.

Posttransplant Reporting

There are multiple, potentially confusing, pathways for adverse event reporting (Table 2). The Joint Commission in the United States requires accredited centers to report to manufacturers (i.e., establishments that process and distribute human tissues for transplantation) any transmissions possibly associated with human tissues. Manufacturers must investigate such reports and report to the Food and Drug Administration serious adverse reactions for which there was a reasonable possibility that the cell or tissue caused the reaction (23,24). Such reporting depends on clinician recognition and reporting of an allograft-derived infection underreporting is a recognized limitation of such programs. Given the general lack of awareness of the potential for donor-derived infection and multiple common sources of infection in a transplant recipient, such as the surgical procedure or nosocomial infection, there is great potential for underreporting. Potential organ-associated disease transmissions (infection and malignancy) are reported to the Organ Procurement and Transplantation Network (OPTN). In addition, state and local health departments may also require notification for transplant transmissions. For all of these reporting systems, limitations include lack of uniform reporting criteria and coordinated data collection.

Coordinating and Sharing Aggregated Donor Screening and Testing Data

One deceased donor may supply organs, eyes, and numerous other tissues, which may be widely distributed over time and geographically. Some deceased donors are tested many times (by organ procurement organizations (OPOs), eye banks, and tissue banks). Collecting and sharing of donor data are challenging in the absence of linked, unique identifying information for each donor (e.g., donor identification number) (25) and centralized data sharing systems. Epidemiologic data (e.g., incidence of infections in the donor population by allograft type and geographic region) and other data (e.g., donor test results correlated with individual recipient testing) need to be aggregated and accessible by contributing OPOs, eye banks, and tissue banks to assess the associated transmission risk. These data could be compared with information collected from blood screening tests for the same donors. Efforts were initiated to improve communication of recipient outcome data between the organ and tissue transplant communities in a pilot project. However, major issues remain to be addressed, such as standard definitions and incentives for participation, before a useful system could be deployed nationally (12). Such data could be used in evaluating effectiveness of current donor screening and testing strategies and developing standardized research methods for use in assessing donor evaluation tools.

Quality of Donor Screening and Testing Data

Donor screening protocols should reduce the likelihood that tissues or organs that would transmit infection will be procured, while preserving availability (avoiding false-positive test results). Effectiveness of current donor screening procedures has not been systematically evaluated. To develop data useful for assessing donor screening practices, high-quality data must be collected by using standardized protocols and assays of known performance characteristics. The nonuniformity of protocols used to screen donors among various organizations impedes critical assessment of donor evaluation protocols. One initiative to bridge this gap is the development and validation of the proposed Uniform Donor History Questionnaire for Organ, Tissue, and Eye Donors (26).

Screening donors through donor history questionnaires can reduce transmission risk only to the degree of the accuracy and completeness of the information provided. This effort is limited by obtaining information by proxy (i.e., from the families of deceased donors) and incomplete information about prior infectious exposures. As a result, testing donor specimens for known transmissible organisms is required to further reduce risks by excluding the infected potential donor or guiding clinical care of recipients. Given the changing epidemiology of infection, a major challenge is developing new assays for emerging infectious diseases. New assay development is typically resource-intensive and too slow to reflect rapid shifts posed by epidemic disease (e.g., assays for severe acute respiratory syndrome), but can be accomplished over time (e.g., assay development during a WNV infection outbreak). New approaches to assay development and for evaluating such assays in organ and tissue donor populations, together with streamlined approaches to evaluating assay effectiveness in a manner appropriate to regulatory review, could enable more effective responses to threats of emerging infectious diseases.

Addressing Gaps: Key Research Needs

There are immediate clinical needs (e.g., optimizing assays and information sharing between suppliers and clinical centers) and long-term research opportunities in the field of allograft transplantation. A structured approach to addressing gaps in scientific knowledge, perhaps through an overarching Department of Health and Human Services strategy, is needed to enhance the safety of organ and tissue transplantation. The data required fall into several general areas as described below and summarized in Table 3.

Denominator Data

Baseline data for the number and types of tissue grafts distributed each year are available only through voluntary reporting to the American Association of Tissue Banks and are limited by a lack of coding and traceability after tissues are delivered to end users (e.g., hospitals, dental clinics, surgical centers). Individual tissue banks rely on hospitals to return implant cards to assess use of allograft materials compliance is voluntary and accuracy of the data is limited by incomplete return rates. Regulatory mandates require OPO and organ transplant programs to report extensive data to the OPTN on all solid-organ donors (living and deceased), candidates on the waiting lists, and recipients. However, the discard rate of donor organs on the basis of microbiologic testing are not collected by OPTN and are retained at the local OPO rather than the national level. Improved testing might change the denominator by increasing or decreasing the number of available allografts for transplantation collection of these data is needed to guide decisions regarding optimal donor testing in organ transplantation (27,28).

Seroprevalence Data

The prevalence of infectious disease in potential organ and tissue donors has not been systematically evaluated. Studies of blood and organ donors suggest that the probability of viremia for HIV, HCV, HBV, and human T-cell lymphotropic virus in the United States is higher in tissue and organ donors than in first-time blood donors (29,30). Prospective data collection is needed to define baseline seroprevalence in different donor populations these data could be used to develop enhanced strategies for donor screening and testing to prevent disease transmission.

Transmissibility Data

Data are needed regarding the transmissibility of potential pathogens by the type of organ or tissue transplanted. Current programs focus on excluding donors with risk factors for, or serologic markers of, blood-borne pathogens. The transmissibility of infection from organs or tissue donors with various nonspecific clinical syndromes (e.g., pneumonia, meningoencephalitis, sepsis) is unknown. Clinical data (based on cultures and serologic studies) and preclinical data from animal studies would enable more evidence-based decisions regarding donor eligibility.

Risk Mitigation Strategies

Processing methods vary with regard to diverse technologies and strategies used and types of tissue processed. There are few data regarding the effect of tissue processing on decreasing or eliminating infectious organisms. Similarly, the effect on the risk for transmission of infection of antimicrobial drug therapy in donors or recipients is unknown. Increasingly, some organs (notably kidneys) undergo pump perfusion before implantation, but the effect of this manipulation on disease transmission is unknown.

Donor Questionnaires

As discussed, standardizing and validating current donor screening tools is an essential first step in collecting and analyzing data for donor risk factors and in developing refined strategies for screening and testing donors. Prospective studies comparing results of donor history questionnaires and those of microbiological testing should be performed to evaluate the effectiveness of donor-screening strategies. The availability of tissues and organs for transplantation could be increased without compromising safety.

Research Infrastructure

There is currently no established network or infrastructure for systematically collecting and analyzing organ and tissue donor data. Given the need for additional data to provide a scientific basis for evaluating and managing allograft donors and recipients, stakeholders must develop mechanisms to prioritize and implement joint research programs. To perform the necessary research, the allograft transplant communities need to develop systems to harmonize labeling nomenclature and data elements (product names and data that are contained on product labels), data collection methods, and mechanisms for data sharing. Elements needed to develop such a research infrastructure will include shared data repositories and software for collecting and analyzing surveillance data from donors and recipients common epidemiologic data elements and universal donor identifiers that link all allograft types to the original donor (25), protocols, and standardized nomenclature. Such a networked infrastructure is essential for rapid traceability of tissues and organs from common donors when donor-derived disease outbreaks occur in transplant recipients (12).

Risk Assessment

Newly developed datasets derived from these proposed research activities will enable development of risk assessment models similar to those used to characterize or predict infectious disease risks in blood donor populations (31). Use of such models would further define targets for future research efforts and for clinical investigations of future outbreaks.

Conclusions

Disease transmission through organ and tissue transplantation has been documented. Recognizing emerging infectious diseases in organ and tissue transplantation is challenging because of nonstandardization of donor evaluations and data collection, pathogen characteristics, and recipient surveillance. Quantifying risk is further complicated by the absence of data regarding the factors affecting disease transmission. Gaps in systematic identification and characterization of the scope and magnitude of donor-derived infectious disease transmissions through organ and tissue transplantation remain a major hurdle to improvements in assessing risk and in developing more effective donor screening and testing strategies. These gaps can be addressed by a shared, overarching research agenda among the allograft communities. Areas of focus for research include compiling donor evaluation (donor screening and testing) and posttransplant recipient surveillance data and disease transmissibility data (basic mechanisms and clinical factors) and assessing the efficacy of mitigation strategies. Prioritizing the research agenda can be best driven by collaboration between government (i.e., regulatory, public health, policy), industry (e.g., tissue manufacturing, supply, test manufacturers), and the allograft transplant provider community (clinicians, hospitals, professional organizations, OPOs, tissue banks and processors). Each stakeholder has unique perspectives, experiences, and resources to share in enhancing the safety of organ and tissue transplantation and benefit the greatest number of recipients.

Dr Greenwald is chief of the Tissue and Reproduction Branch, Division of Human Tissues, Food and Drug Administration in Rockville, Maryland. Her research interests are infectious disease test performance, donor testing and screening, and organ and tissue transplantation safety.

References

Figure
Tables

Suggested citation for this article: Greenwald MA, Kuehnert MJ, Fishman JA. Infectious disease transmission during organ and tissue transplantation. Emerg Infect Dis [serial on the Internet]. 2012 Aug [date cited]. http://dx.doi.org/10.3201/eid1808.120277

Please use the form below to submit correspondence to the authors or contact them at the following address:

Melissa A. Greenwald, Division of Human Tissues, Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852, USA

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