Practical Transfusion Medicine 4th Ed.

16. Emerging infections and transfusion safety

Roger Y. Dodd

American Red Cross, Jerome H. Holland Laboratory for the Biomedical Sciences, Rockville, Maryland, USA

The Institute of Medicine in the USA has defined emerging infections as those whose incidence in humans has increased within the past two decades or threatens to increase in the near future. Emergence may be due to the spread of a new agent, the recognition of an infection that has been present in the population but has gone undetected or the realization that an established disease has an infectious origin. Emergence may also be used to describe the reappearance (or re-emergence) of a known infection after a decline in incidence. A proportion of such emerging infections have properties that permit their transmissibility by blood transfusion; perhaps the most notable example has been HIV/AIDS, although there are others, such as West Nile virus (WNV), dengue virus, babesia and malaria. This chapter will explain the basis for emergence of infectious agents and discuss their recognition and management in the context of the safety of the blood supply.

Emerging infections

There is no single reason to account for the emergence of infections, although it is possible to establish relatively broad groupings [1].

·        Failure of existing control mechanisms, including the appearance of drug-resistant strains, vaccine escape mutants or cessation of vector control accounts for a large group of agents.

·        Environmental change can have profound effects, whether through global warming, changes in land utilization or irrigation practice, urbanization or even agricultural practices.

·        Population movements and rapid transportation can introduce infectious agents into new environments where they may spread rapidly and without constraint, as has been the case for WNV in the USA.

·        Human behaviours can contribute in a number of ways: new agents have been introduced into human populations by contact with, or even preparation and consumption of, wildlife; many infections have been spread widely though extensive sexual networks and armed conflicts have led to extensive disease spread.

Of course, many of these factors may also work in combination. Key points are that new or unexpected diseases can appear in any location at any time and that an appropriate understanding of the epidemiology of such diseases can assist in the development of appropriate interventions.

In order to be transmissible by transfusion, an agent must have certain key properties [2].

·        Most importantly, there must be a phase when the agent is present in the blood in the absence of any significant symptoms. Until recently, it was generally thought that such infectivity would reflect a long-term carrier state for the agent in question, as exemplified by HIV, HBV or HCV, although there had been a few cases of transmission of hepatitis A virus, which provokes an acute infection with a relatively short period of asymptomatic viraemia. However, the finding of transfusion transmission of WNV showed that, in epidemic outbreaks, acute infections could be readily transmitted by transfusion.

·        A secondary requirement is that the agent must be able to survive component preparation and storage.

·        Finally, the agent should have a clinically apparent outcome in at least a proportion of cases of infection or it will lack clear relevance to blood safety and its transmission will not generally be recognized. There are some examples of transfusion-transmissible agents that do not seem to cause any significant outcomes, such as GB virus type C/hepatitis G virus (GBV-C/HGV) and torque tenovirus (TTV).

Table 16.1 lists a number of emerging infections that are known, or suspected, to be transfusion transmissible and also notes the factors thought to be responsible for their emergence.

Table 16.1 Selected emerging infections potentially or actually transmissible by blood transfusion.

Agent

Basis for emergence

Notes

Prions

   

vCJD

Agricultural practice: feeding meat and bonemeal to cattle

Of most concern in UK; apparently coming under control

Viruses

   

Chikungunya

Global climate change, dispersion of mosquito vector, travel

Rapid emergence in a number of areas, including Italy; surveillance indicated

Dengue

Global climate change, dispersion of mosquito vector, travel

Similar properties to WNV; surveillance indicated

HBV variants

Selection pressure resulting from vaccination

Mutants may escape detection by standard test methods

HHV-8

Transmission between men who have sex with men and perhaps by intravenous drug use

Transmission by transfusion and transplantation known

HIV

Interactions with wildlife, sexual networks, travel

Classic example of an emerging infection

HIV variants

Viral mutation, travel

May escape detection by standard tests

Influenza

Pandemic anticipated as a result of antigenic change

Possible threat to blood safety, major impact on availability

SARS

Explosive global epidemic, wildlife origin, spread by travel

No demonstrated transfusion transmission, epidemic over

Simian foamy virus

Exposure to monkeys, concern about species jumping and mutation

Regulatory concern over blood safety, intervention in Canada

WNV

Introduction into the USA (probably via jet transport), rapid spread across continent

Recognition of transfusion transmission in 2002 led to rapid implementation of NAT for donors

Bacteria

   

Anaplasma phagocytophilum

Tickborne agent expanding its geographic range

One potential transfusion transmission reported

Borrelia burgdorferi

Tickborne agent expanding its geographic range and human exposure

No transfusion transmission reported

Parasites

   

Babesia spp.

Tickborne agent expanding its geographic range and human exposure

More than 160 transfusion- transmission cases reported

Leishmania spp.

Increased exposure to military and others in Iraq, Afghanistan

Unexpected visceral forms potentially transmissible

Plasmodium spp.

Classic re-emergence, in part due to climate change, travel

Re-emergence threatens value of travel deferral

Trypanosoma cruzi

Imported into nonendemic areas by population movement

Transfusion transmissible, preventable by donor testing

Approaches to the management of transfusion-transmissible emerging infections

As far as it is possible, emerging infections that do, or may, impact on blood safety should be managed in a systematic fashion. In general, this will be the responsibility of agencies that are charged with the maintenance of public health, or the management of the blood supply or its regulation. However, there are a number of areas in which individual professionals can contribute. One of these is the first step, which is the recognition of a transfusion-transmitted infection and its subsequent investigation. It is, in fact, unlikely that the first occurrence of an emerging infection will be seen in a transfused recipient, so it is therefore important that there be a system of assessing the threat and risk of emerging infections for their potential impact on blood safety. This implies a process for evaluating each emerging infection for its transmissibility by this route and for estimating the severity and potential extent of the threat. The risk assessment should help to define the need for and urgency of development and implementation of interventions to reduce the risk of transmission of the agent. Such interventions, if implemented, should be evaluated for efficacy and modified as appropriate.

Assessing the risk and threat of transfusion transmissibility

It is important to have a general awareness of the status of new and emerging infections, with particular reference to your own country or area. Such awareness may involve familiarity with a number of sources of information, ranging from news media, through alerts from local, national and global public health agencies, to specialized resources such as ProMED Mail (an Internet listserver and website that tracks and comments on disease outbreaks) [3]. Other tools continue to become available; e.g. the American Association of Blood Banks (AABB) has developed and is maintaining a listing of potentially transfusion-transmissible infectious agents that has been published in print and on their website: the listing also contains much of the information discussed below, along with a ranking of threat level. Other agencies (e.g. the Centers for Disease Control and Prevention and the World Health Organization) provide general, current information about emerging infectious agents on their websites.

Table 16.2 outlines questions that serve to define the risk of transfusion transmission of each agent and the potential extent and severity of that risk. The primary question is whether or not the disease agent can, in fact, be transmitted by blood. As pointed out above, this is dependent on the presence of an asymptomatic phase during which the disease agent is present in the bloodstream. In some cases, of course, there may already be documentation of transfusion transmission of the agent in question or there may be suggestive evidence, such as transmission by organ transplantation. However, in the latter case, such evidence may not be definitive, as rabies has been transmitted by organ transplantation but is almost certainly not transmissible by blood. The answer to this question is not always readily obtainable, but may often be inferred by considering what is known about the natural transmission route of the infection or from the properties of closely related organisms. The duration of the blood phase of the infection will have a direct impact on the risk of transmission, reflecting the chance that an individual will give blood during the infectious phase.

Table 16.2 Key questions to assess risk of transfusion transmissibility of an infectious agent.

 

1. Have transfusion-transmitted cases been observed?

2. Does the agent have an asymptomatic, bloodborne phase?

3. Does the agent survive component preparation and storage?

4. Are blood recipients susceptible to infection with the agent?

5. Does the agent cause disease, particularly in blood recipients?

6. What is the severity, mortality and treatability of the disease?

7. Are there recipient conditions, such as immunosuppression, that favour more severe disease?

8. Is there a meaningful frequency of infectivity in the potential donor population?

9. Is this frequency declining, stable or increasing?

10. Are there reasons to anticipate any changes in the frequency of donor infectivity?

11. What is the level of concern about the agent and its disease among professionals, public health experts, regulators, politicians, media and the general population?

12. Are there rational and accessible interventions to eliminate or reduce transmission by transfusion?

The actual risk of transmission is a function of the frequency of the infection in the donor population and the length of the period of bloodborne infectivity [4]. The period of infectivity may not, however, be identical to the period during which the infectious agent can be detected in the blood. For example, in the case of WNV, periods of viraemia in excess of 100 days have been measured occasionally, but the actual infectious period may be limited to the week or two prior to the appearance of IgG antibodies. Another difficulty is that the frequency of disease and the frequency of infection may differ greatly, as is again the case with WNV. Nevertheless, it is abundantly clear that individuals who do not develop symptoms may be infectious via their blood donations. Consequently, it may be important to estimate the size of the infected (and infectious) population by laboratory testing rather than through disease reporting. Indeed, organized studies of prevalence rates of infection among donor populations have been used in many circumstances in order to assess the level of risk and to predict the impact of a testing intervention. Examples of this approach include studies on HTLV, trypanosomes (Trypanosoma cruzi), babesia and, more recently, dengue virus, where assessments of the frequency of viraemia are proving valuable. Another important factor is the dynamics of the outbreak. Is the frequency of infection stable or increasing and, if increasing, is change linear or logarithmic and what is the rate of increase? Obviously, rapid increase, as seen in the case of WNV, would imply a need for a more rapid response than would a slow, linear increase, as in the case of T. cruzi.

The severity of disease that may result from a transfusion-transmitted infection is also an important guide to the extent and speed of implementation of any intervention. There are both objective and subjective aspects to such an assessment. Clearly, the severity of the disease and its associated mortality can be defined, but it may also be important to judge the public concern around the disease, which may be disproportionate to its actual public health impact [2]. Another factor that is often presented as important is the extent to which a transfusion-transmitted infection might result in further or secondary infections. In actual fact, transmission of an infection by transfusion will almost certainly not lead to any magnification of an epidemic but, nevertheless, it is something that should be considered.

A word of caution is in order with respect to efforts to use modern laboratory methods to identify previously unrecognized infectious agents. There is increasing enthusiasm for this approach, but it is important to recognize that without any established relationship to a disease state, the results of such searches can be misleading. At this time, for example, it does not appear that either TTV or GBV-C/HGV have any relationship to any disease state and do not seem to offer risk to blood recipients, despite clear evidence of their transmissibility. It is unclear how many other such orphan viruses are awaiting discovery.

The recent recognition and management of a new retrovirus, XMRV, originally thought to be associated with prostate cancer and chronic fatigue syndrome (CFS), is instructive. It was suggested that this virus was a threat to transfusion safety and an organized programme was put in place to evaluate this possibility [5,6]. A complication was that CFS advocates actively promoted the concept of transfusion risk as a means to establish legitimacy (and perhaps funding) for the disease. A key activity was a careful, blinded evaluation of a number of different tests for XMRV, including those used by the laboratories responsible for the original discoveries. This evaluation, along with other studies, revealed that the available tests could not reliably identify the virus or related ones, either in patient samples or negative controls [7]. The original observations were eventually shown to be due to various forms of contamination and XMRV itself was revealed to be a laboratory artefact. While early intervention for an emerging infection may be necessary and appropriate, care should be taken to avoid reacting to situations involving incomplete or imperfect science.

Recognition of transfusion transmission of emerging infections

There is no simple formula for recognizing that a transfusion-transmitted infection has occurred, particularly in the case of a rare or unusual disease agent. Nevertheless, many such events have been recognized by astute clinicians. Knowledge of the potential for transmission of an emerging infection can be valuable and very likely contributed to the relatively early recognition of transfusion transmission of WNV [8]. Unusual posttransfusion events with a suspected infectious origin should be brought to the attention of experts in infectious diseases or public health agencies for assistance in identification and follow-up. Appropriate investigation of illness occurring a few days or more after transfusion can reveal infections through identification of serologic or molecular evidence of infectious agents in posttransfusion samples. However, such detection is by no means definitive. It is helpful if a pretransfusion patient sample is also available, as this will reveal whether the condition predated the transfusion. Also, recall and further testing of implicated donors will reveal whether one or more of them was the likely source of the infection. Ideally, if the responsible organism can be isolated from both donor and recipient, molecular analyses such as nucleic acid sequencing can demonstrate (or exclude) the identity of the agent from the two sources. There are significant problems in recognizing that infections with a very long incubation period may have been transmitted by transfusion; this was illustrated by HIV/AIDS, which did not result in well-defined illness until many years after exposure. This prevented early recognition of transfusion-transmitted AIDS and further concealed the actual magnitude of the infectious donor population and of the population of infected blood recipients. This implies that, for emerging infections that appear to have lengthy incubation periods, it would be wise to assess transfusion transmissibility by serologic or molecular evaluation of appropriate donor–recipient sample repositories or to engage in some form of active surveillance, such as that used to identify the transmission of variant Creutzfeldt–Jakob disease (vCJD) by transfusion in England [9]. Haemovigilance programmes may contribute to the identification of posttransfusion infections, although they are generally designed to identify well-described outcomes.

Interventions

In the event that an emerging infection is found to be transfusion transmissible and public and professional concern implies a need to protect the safety of the blood supply, there are a number of interventions that could be considered.

A possible, but rather unsatisfactory approach is to focus on the recipient by diagnosing and treating cases that occur. This, of course, works only for treatable infections. It is de facto part of the approach to manage transfusion babesiosis in the USA at this time.

Most interventions are focused on the donor or the donation. In the absence of a test, it may be possible to devise a question that would identify some proportion of donors at risk of transmitting the infection. Such measures are usually neither sensitive nor specific, but may have value, particularly where the disease is localized so that a travel history is sufficient to identify those at risk.

The development and implementation of a test for infectivity in donor blood is usually a more sensitive and specific approach than questioning and for some infections may be the only valid solution. In the past, serologic tests were relied upon, but now nucleic acid testing is also available and may be a better solution, as was the case for WNV. Indeed, a test for WNV RNA was developed and implemented in less than a year in the USA [10]. However, this is not always the optimal solution. For example, some parasitic diseases in particular result in long-term, antibody-positive infection with very low levels of infectious agent in the bloodstream, resulting in only intermittent NAT-positive findings. This is particularly true of Chagas disease, and as most individuals were infected early in life, antibody tests are preferable for identifying potentially infectious donors [11].

An emerging technology that offers some promise is that of pathogen reduction, which is a treatment that inactivates infectious agents in blood while retaining the biological activities of the blood itself. Methods are currently available for plasma and for platelet concentrates and are in use in some countries. It should be noted that available methods may have differing efficacies for different infectious agents and that they may not be fully successful in eliminating very high levels of infectivity for some agents, although this has not been established in practice. A real disadvantage is that no method is currently available for red cells. A pathogen reduction method was implemented for platelets in the island of La Reunion during a large outbreak of chikungunya virus infection.

The precautionary principle is often cited when decisions about interventions to reduce the risk of transfusion-transmitted infections are discussed. In general, it is suggested that, in the absence of any specific information about the efficacy of an intervention, it is appropriate to implement it, as long as it does no harm. This position may be arguable, particularly as commentary on the precautionary principle suggests that it should not be invoked without some evaluation to give assurance that the measure is not extreme and does not exceed other measures taken in known circumstances. In fact, significant measures were taken to reduce the potential risk of transmission of vCJD even before it was known that it was transmissible by transfusion. It can be argued that subsequent events justified the precautions taken, but this may not always be the case [12].

Key points

1. Some emerging infections may threaten the safety of the blood supply.

2. Those responsible for maintaining the safety of the blood supply should be familiar with emerging infections.

3. Physicians responsible for the care of transfused patients should be alert for signs of unexpected infections.

4. The nature and extent of the safety threat offered by emerging infections may be assessed by examination of a fairly simple sequence of questions.

5. If interventions are needed, consideration should be given to the use of donor questions and/or laboratory tests.

6. Care must be taken to balance public concern against good science.

References

1. Morens DM, Folkers GK & Fauci AS. Emerging infections: a perpetual challenge. Lancet Infect Dis 2008; 8: 710–719.

2. Stramer SL, Hollinger FB, Katz LM, Kleinman S, Metzel PS, Gregory KM & Dodd RY. Emerging infectious disease agents and their potential threat to transfusion safety. Transfusion 2009; 49 (Suppl.): 1S–233S.

3. http://www.promedmail.org/.

4. Glynn SA, Kleinman SH, Wright DJ & Busch MP. NHLBI Retrovirus Epidemiology Study. International application of the incidence rate/window period model. Transfusion 2002; 42: 966–972.

5. Klein HG, Dodd RY, Hollinger FB, Katz LM, Kleinman S, McCleary KK, Silverman RH & Stramer SL, for the AABB Interorganizational Task Force on XMRV. Xenotropic murine leukemia virus-related virus (XMRV) and blood transfusion: Report of the AABB Interorganizational XMRV Task Force. Transfusion 2011; 51: 654–661.

6. Simmons G, Glynn SA, Holmberg JA, Coffin JM, Hewlett IK, Lo SC, Mikovits JA, Switzer WM, Linnen JM & Busch MP, for the Blood XMRV Scientific Research Working Group (SRWG). The blood xenotropic murine leukemia virus-related virus scientific research working group: mission, progress, and plans. Transfusion 2011; 51: 643–653.

7. Simmons G, Glynn SA, Komaroff AL, Mikovits JA, Tobler LH, Hackett Jr J, Tang N, Switzer WM, Heneine W, Hewlett IK, Zhao J, Lo SC, Alter HJ, Linnen JM, Gao K, Coffin JM, Kearney MF, Ruscetti FW, Pfost MA, Bethel J, Kleinman S, Holmberg JA & Busch MP, for the Blood XMRV Scientific Research Working Group (SRWG). Failure to confirm XMRV/MLV in the blood of patients with chronic fatigue syndrome: a multi-laboratory study. Science 2011; 334: 814–817.

8. Biggerstaff BJ & Petersen LR. Estimated risk of West Nile virus transmission through blood transfusion during an epidemic in Queens, New York City. Transfusion 2002; 42: 1019–1026.

9. Hewitt PE, Llewelyn CA, Mackenzie J & Will RG. Creutzfeldt–Jakob disease and blood transfusion: results of the UK Transfusion Medicine Epidemiological Review study. Vox Sanguinis 2006; 91: 221–230.

10. Dodd RY. Perspective: emerging infections, transfusion safety and epidemiology. New Engl J Med 2003; 349: 1205–1206.

11. Benjamin RJ, Stramer SL, Leiby DA, Dodd RY, Fearon M & Castro E. Trypanosoma cruzi infection in North America and Spain: evidence in support of transfusion transmission. Transfusion 2012. Early online publication, DOI: 10.1111/j.1537-2995.2011.03554.x.

12. Wilson K & Ricketts MN. The success of precaution? Managing the risk of transfusion transmission of variant Creutzfeldt–Jakob disease. Transfusion 2004; 44: 1475–1478.

Further reading

Alter HJ, Stramer SL & Dodd RY. Emerging infectious diseases that threaten the blood supply. Semin Hematol 2007; 44: 32–41.

Biggerstaff BJ & Petersen LR. Estimated risk of transmission of the West Nile virus through blood transfusion in the US, 2002. Transfusion 2003; 43: 1007–1017.

Dodd RY & Leiby DA. Emerging infectious threats to the blood supply. Annual Rev Med 2004; 55: 191–207.

Mackenzie JS, Gubler DJ & Petersen LR. Emerging flaviviruses: the spread and resurgence of Japanese encephalitis, West Nile and dengue viruses. Nat Med (Suppl.) 2004; 10(12): S98–S108.

Stramer SL, Fang CT, Foster GA, Wagner AG, Brodsky JP & Dodd RY. West Nile virus among blood donors in the United States, 2003 and 2004. N Engl J Med 2005; 353: 451–459.

Tomashek KM & Margolis HS. Dengue: a potential transfusion-transmitted disease. Transfusion 2011; 51: 1654–1660.

Weiss RA & McMichael AJ. Social and environmental risk factors in the emergence of infectious disease. Nat Med (Suppl.) 2004; 10(12): S70–S76.