2001 Richard J. Duma/NFID Annual Press Conference and Symposium on Infectious Diseases
Please Choose a Presenter
» David M. Asher, MD
» Linda A. Detwiler, D.V.M.
» R. Gordon Douglas, Jr., M.D.
» Thomas G. Ksiazek, D.V.M., Ph.D.
» John E. McGowan, Jr., M.D.
» Robert A. Whitney, Jr., D.V.M.
US FDA Policies Concerning Suitability of Blood or Plasma Donors Thought to be at Increased Risk of Creutzfeldt-Jakob Disease
By David M. Asher, MD
History.
In November 1987, following the recognition that Creutzfeldt-Jakob disease (CJD) had been accidentally transmitted to some recipients of human cadaveric pituitary growth hormone, the FDA issued a Memorandum to Blood Establishments recommending that all persons who had received that hormone be permanently deferred from donating blood and plasma. In August 1995, the Director of the Center for Biologics Evaluation and Research (CBER) added recommendations to defer other donors at increased risk of CJD: those with a family history of CJD or receipt of a dura mater graft. CBER also recommended retrieval and quarantine of all whole blood and blood components, including plasma, from donors subsequently diagnosed with CJD and retrieval and quarantine of plasma derivatives produced from pools containing a unit from a donor subsequently diagnosed with CJD or recognized to have received human cadaveric pituitary growth hormone.
In December 1996 CBER issued another memorandum to all registered blood establishments and plasma establishments engaged in manufacturing plasma derivatives recommending as a precaution to quarantine and destroy in-date source plasma, plasma derivatives, and transfusion products (red blood cells and platelets) prepared from donors who were later recognized to be at increased risk of developing CJD or who were subsequently diagnosed with CJD. The memorandum again recommended permanent deferral of all donors with CJD or with increased risk of CJD, except that persons who had a relative with CJD could be acceptable donors if both their prion-protein-encoding (PRNP) genes were normal (by nucleic acid sequencing). This policy would have served to defer any donors diagnosed with new-variant CJD (vCJD, the form of CJD thought to result from human infection with the agent of bovine spongiform encephalopathy [BSE]) as well as those with all other forms of CJD. Potential dietary or other exposures to the BSE agent were not yet considered to be established risk factors for CJD.
After a decision by the Surgeon General of the USA, explained at a public meeting in August 1998, in September 1998 CBER announced that its previous policy was to be modified somewhat, so that plasma derivatives prepared from pools to which donors with "classic" forms of CJD (that is, forms other than vCJD) had contributed, would no longer be withdrawn, although the donors would still be permanently deferred and any of their previously donated blood and blood components remaining in inventory, including unpooled plasma, would be retrieved and not used. (This relaxed policy concerning plasma derivatives was considered reasonable because transmission of CJD by human blood has never been convincingly documented in any of several studies, because the process of fractionating plasma was demonstrated to remove very substantial amounts of infectivity from blood experimentally infected with the agents of scrapie and the Gerstmann-Str”ussler variant of CJD, and because withdrawals were contributing to a serious shortage of some important plasma derivatives.)
Recent FDA policy changes.
In its 1998 policy, the FDA continued to recommend that all pooled plasma, manufacturing intermediates and finished plasma derivatives to which any donor later diagnosed with vCJD had contributed should be withdrawn. Fortunately, at the time of this writing, no case of vCJD has been confirmed in the USA by the Centers for Disease Control (CDC).
In June 1999 the FDA Transmissible Spongiform Encephalopathies Advisory Committee (TSEAC) advised that, as an additional precaution, potential blood donors be deferred from donating blood if they had resided in the United Kingdom (UK) for any aggregate period of six months or more from January 1980 taken to be the probable beginning of the BSE outbreak in the UK and the end of 1996, after which an array of precautions designed to protect both animals and humans from exposure to the BSE agent was fully implemented in the UK. This policy was estimated to reduce the risk that a donor might have contracted an infection with the BSE agent (expressed as total number of "donor days" in UK) by about 86% at a predicted cost to the US blood supply of 2.2% of current donors who would have to be deferred.
TSEAC did not advise deferral of donors resident in any other BSE countries. The reason for that advice was that BSE, the probable cause of vCJD in humans, was much more widespread in the UK than in other BSE countries and that considerable uncertainty remains both about the extent of the BSE epidemic and the potential transmissibility of vCJD by blood. FDA accepted the TSEAC advice and issued new guidance recommending, as a precautionary measure, the deferral of potential donors who had resided in the UK for any cumulative period of six months from January 1980 through the end of 1996. When FDA became aware of another potential BSE risk bovine insulin from the UK FDA also recommended deferral of donors who had injected that product after 1980. CBER's policy was fully described in a Guidance for Industry first issued for public comment in August 1999 and in revised form in November 1999. The FDA has issued no formal changes in recommendations concerning donor suitability and CJD since then.
As in previous issuances, the latest FDA Guidance recommends retrieval of previously donated blood and components (including plasma) if post-donation information reveals that a donor should have been deferred for residence in the UK or injection of bovine insulin from the UK, but it does not recommend that pooled plasma, intermediates or derivatives be withdrawn. The FDA believes that, because of the very large size of the pools used as starting material to manufacture plasma derivatives and the great number of US donors who have traveled to the UK, precautionary withdrawal of pooled plasma, intermediates and derivatives for theoretical risk of BSE exposure would be common and would seriously disrupt the supply of plasma derivatives. As noted above, FDA also relies on scientific evidence suggesting that a plasma derivative is much less likely to contain the infectious agent of BSE than whole blood or components. That is why the FDA now recommends the extreme step of withdrawing plasma derivatives only if a donor were to be diagnosed with vCJD something that has not happened.
In January 2001 the TSEAC further advised the FDA to recommend deferring donors who lived in France for any aggregate period of ten years between 1980 and the present. A very narrow majority of TSEAC members also advised a similar deferral policy for donors resident in the Republic of Ireland or in Portugal for ten years during the same years. The TSEAC did not endorse an FDA proposal to recommend deferral for residence in other BSE countries, nor were they persuaded to accede to an even more stringent donor deferral policy publicly proposed by the American Red Cross. The FDA is now attempting to develop a rational policy that would broadly address the theoretical risk posed by donors who may have been infected with the BSE agent while maintaining an adequate supply of blood, components and plasma derivatives. The FDA believes that the theoretical risk can be substantially reduced but cannot be completely eliminated.
Return to the list of presenters.
USDA Actions in Response to Bovine Spongiform Encephalopathy (BSE)
By Linda A. Detwiler, D.V.M.
BSE has not been detected in the United States. In cooperation with the United States Department of Agriculture's Food Safety and Inspection Service (FSIS), the Animal and Plant Health Inspection Service (APHIS) has taken measures in prevention, education, surveillance, and response.
To prevent BSE from entering the country, APHIS has prohibited the importation of live ruminants from countries where BSE is known to exist in native cattle, since 1989. Other products derived from ruminants, such as fetal bovine serum, bonemeal, meat-and-bone meal, bloodmeal, offal, fats, and glands, are also prohibited from entry, except under special conditions or under USDA permit for scientific or research purposes. On December 12, 1997, APHIS extended these restrictions to include all of the countries in Europe due to concerns about widespread risk factors and inadequate surveillance for BSE.
As of December 7, 2000, USDA prohibited all imports of rendered animal protein products, regardless of species, from Europe. This decision followed the recent determination by the European Union that feed of nonruminant origin was potentially cross-contaminated with the BSE agent. The restriction applies to products originating, rendered, processed or otherwise associated with European products. USDA has taken this emergency action to prevent potentially cross-contaminated products from entering the United States. The same type of rendered product from ruminant origin has been prohibited from BSE-infected countries since 1989.
APHIS educates veterinary practitioners, veterinary laboratory diagnosticians, industry, and producers on the clinical signs and pathology of BSE.
APHIS leads an ongoing, interagency surveillance program for BSE in the United States. BSE is a reportable disease. APHIS veterinary pathologists and field investigators have received training, including training from their British counterparts in diagnosing BSE. The surveillance samples include field cases of cattle exhibiting signs of neurological disease, cattle condemned at slaughter for neurologic reasons, rabies-negative cattle submitted to public health laboratories, neurologic cases submitted to veterinary diagnostic laboratories and teaching hospitals, and sampling of cattle that are nonambulatory (downer cattle/fallen stock) at slaughter. APHIS' surveillance program is based on histopathological examination of brains and a technique called immunohistochemistry which tests brain tissues for the presence of the abnormal prion protein. As of May 31, 2001, more than 13,100 brains from the United States and Puerto Rico have been examined with no evidence of BSE or other TSE detected.
APHIS, in cooperation with the Food Safety and Inspection Service, has also drafted an emergency response plan to be used in the event that BSE is identified in United States. In addition, APHIS' TSE Working Group monitors and assesses all ongoing events and research findings regarding TSE. APHIS continually revises and adjusts prevention and diagnostic measures as it receives new information and knowledge.
Return to the list of presenters.
Vaccine Safety -- Current Issues and How to Deal With Conflicting Information
By R. Gordon Douglas, Jr., M.D.
Vaccine safety is an issue of paramount performance to all -- parents, children, other adults, physicians, vaccine companies and various U.S. Government agencies such as the Food and Drug Administration, National Institutes of Health, and the Centers for Disease Control and Prevention.
Vaccines in use today have a tremendous safety record, and they have been enormously effective in eliminating serious disease or reducing rates to very low numbers. The eradication of smallpox from the world; poliomyolitis from the Americas, Australia, and Europe; marked reduction in disease burden due to measles, mumps, rubella, whooping cough, diptheria, tetanus, and childhood meningitis substantiate this point. Furthermore, they are the only medical interventions that actually are cost-effective, that is for every dollar spent, more than one dollar is saved in other expenses for the health care system.
Adverse reactions do occur to vaccines, almost always in very low rates: 1 in 10, 000 to 1 in 1,000,000. Higher rates of adverse reactionshave precluded licensure. Because vaccines are given to everyone, i.e. 4,000,000 children, one birth cohert, each year or 70,000,000 adults who receive influenza vaccine, it is easy to see how any random health event might be blamed on vaccination. For journalism to be responsible, it is essential to be able to differentiate between anecdotal co-occurrences and true causal relationships.
Return to the list of presenters.
Is the United States Prepared for Viral Hemorrhagic Fever Importations?
By Thomas G. Ksiazek, D.V.M., Ph.D.
Viral hemorrhagic fevers (VHF) is a term used to describe a group of severe, often life-threatening illnesses that can be caused by infection with any of a number of diverse agents from several virus families. These agents are, by and large, exotic to the United States, but they could be imported into this country by an infected traveler. On the basis of our experience with viral hemorrhagic fevers during large outbreaks, the CDC's Special Pathogens Branch has concluded that the most contagious of the viral hemorrhagic fevers are those caused by the Ebola viruses. Other hemorrhagic fever viruses include Marburg, Lassa fever, the New World Arenaviruses, Crimean-Congo hemorrhagic fever, Rift Valley fever, hantaviruses, and several tick-borne flaviviruses. With the exception of Marburg virus, which is similar to the Ebola viruses, these viruses are rarely transmitted to close contacts, such as medical caregivers and family members responsible for nursing care in a non-medical setting. Despite the occurrence of nosocomial transmission that has been a hallmark of Ebola VHF outbreaks in Africa, care for suspected VHF patients in a modern Western clinical setting would have a vastly different level of risk than that seen in the resource-poor environment of developing countries.
In the United States, common use of universal precautions in a health-care setting would limit the potential for virus transmission to those who are at risk because of accidental breaches of procedure, such as needle sticks or auto-inoculation with infected materials. Adherence to current CDC recommendations would foster the safe and expeditious handling of patients while still allowing for medical care of the patients to proceed. Furthermore, recommendations for the handling and shipment of specimens from these patients are based on methods that would substantially reduce the risk for infection among those handling these materials.
The importation of VHF cases into the United States remains a distinct possibility. The most recent such importation in this country was in 1989, when a Lassa fever patient traveled to Chicago from Nigeria. Ebola VHF cases were imported into Europe in 1994 and South Africa in 1996. More recently, there have been cases of imported yellow fever in unvaccinated travelers. Lassa fever has been imported several times into Europe from West Africa in the last 2 years. However, save the instance of the South African importation, there have been no further transmissions beyond the initially identified imported case. Why? Although a number of these viruses have been shown in the laboratory to be experimentally transmissible by a small-particle aerosol, this mode of transmission has not been an epidemiologically important means of infection in medical or family settings. So long as precautions have been taken to diminish the risk for introduction of the infectious virus by cutaneous puncture or into the mucous membranes of susceptible medical care givers, transmission has not occurred. In those instances in which nosocomial transmission has occurred, such as in South Africa or more recently in Uganda, analyses of the circumstances have strongly suggested that breaches of procedures for personal protection were responsible for the exposures which have led to infections.
These observations suggest that, given the known characteristics of the hemorrhagic fever viruses and the current capabilities of Western medicine, the United States is relatively well prepared for responding to an importation of VHF cases. Nevertheless, recent experience shows an increase in the recognition of outbreaks caused by these exotic viruses. This pattern, combined with higher numbers of international travelers, undoubtedly raises the likelihood of VHF importations.
Return to the list of presenters.
Antibiotic Use and Resistance: Reaching the Tipping Point?
By John E. McGowan, Jr., M.D.
The problem of bacterial resistance has intensified. This problem, evident throughout the world, results in the use of more expensive drugs and greater healthcare cost, and limits greatly the therapeutic options available to treat serious infections.
Current resistance problems are exemplified by several recent developments:
First is the emergence of drug resistance in bacteria virulent enough to cause infection both in persons with normal host defenses, not just those whose defenses are compromised. Strains of methicillin-resistant Staphylococcus aureus (MRSA) now have intermediate susceptibility to vancomycin, the drug of choice for treating MRSA, and other strains are resistant to alternative macrolide antimicrobials. Healthcare-related strains of vancomycin-resistant enterococci (VRE) resistant now are resistant even to our newest effective drugs, like linezolid.
A second problem is that organisms that used to be confined to hospitals and healthcare systems now have moved to the community. MRSA infections now truly have developed in the community. Such infections suggest the eventual need for more complicated treatment for infections known or suspected as due to community Staphylococci. Dealing with these and similar issues will increase the economic impact of resistance for the healthcare system. Yet a third problem is the rise of drug resistance in the community itself. This is exemplified by reports of detrimental clinical impact from strains of Streptococus pneumoniae that are tolerant to the effect of penicillin. These and other strains of pneumoccci have now developed resistance to a variety of drugs that served well for treatment in earlier decades. Very recently, the same pattern now is being seen in other streptococci. A fourth worrisome development is the presence of multiple resistance determinants in several Gram-negative bacteria. The days of "one-organism, one-resistance-factor" are going fast, or may for some organisms already be gone.
The good news is that specific activities that can help deal with resistance are now being identified and validated in studies from the US and around the world. Among these are bringing in new antimicrobials, giving new emphasis to the use of vaccines for organisms which are becoming resistant, validating laboratory methods for detection of antimicrobial resistance (and developing more simple and affordable tests for some new resistance determinants), emphasizing proper implementation of infection control measures, benchmarking studies of resistance and use, including antimicrobial use as a focus of educational programs for prescribers and other healthcare workers; and strengthening efforts to improve antimicrobial use, thereby decreasing selection pressures for emergence of resistance.
The "tipping point," according to Gladwell, is a clear example of contagious behavior--a small number of people who have wider influence start behaving very differently, and that behavior somehow spreads to many others, with a dramatic and rapid impact. The new patterns of bacterial resistance, combined with accumulating data on effective ways to deal with resistance, may mean that a "tipping point" in our battle against bacterial resistance is near.
Return to the list of presenters.
Bovine Spongiform Encephalopathy (BSE, Mad Cow Disease) -- Ongoing Health Concerns in the United States and Europe
By Robert A. Whitney, Jr., D.V.M.
Bovine spongiform encephalopathy(BSE), commonly known as "mad cow disease" is a fatal, chronic, degenerative disease affecting the nervous system of cattle. There have been more than 178,000 cases reported since BSE was first diagnosed in the United Kingdom in 1986. The disease has been confirmed in 13 other countries in Europe, however, over 95% of all cases are in the UK. The UK outbreak was apparently spread by feeding cattle meat and bone meal containing the infectious agent. BSE belongs to a family of diseases known as the transmissible spongiform encephalopathies (TSE's). These diseases share the common characteristics of a long incubation period (3 to 5 years for BSE in cattle), a prolonged, debilitating neurological illness which is always fatal, similar neurological lesions, and no host generated, specific immune response. This family of diseases is found in a number of species of animals and in humans. In addition to BSE in cattle, other examples include scrapie in sheep, transmissible mink encephalopathy (TME) in mink, and chronic wasting disease (CWD) in mule, deer and elk. Examples in humans include Creutzfeld-Jacob Disease (CJD), and Kuru. The spongiform encephalopathies are almost certainly caused by a most unconventional transmissible agent. It appears that a protein without a nucleic acid genome is the source of the infection. This protein, called a "prion" is defined as "a small proteinaceous infectious particle which resists inactivation by procedures that modify nucleic acids". It has been shown that the prion has an altered shape or conformation, and this distorted protein may bind to other proteins and induce them to change their conformation as well, producing a chain reaction that propagates the disease and generates new infectious material. In 1996, a link was established in the UK between BSE in cattle and a new variant of CJD (vCJD) in humans. Neither BSE or vCJD have been reported in the United States, and US agencies have acted quickly with precautionary steps to prevent BSE in cattle and vCJD in humans from occurring in this country.