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September 2015—Emerging and re-emerging viruses are well and alive, says Sherif Zaki, MD, PhD, chief of the Infectious Diseases Pathology Branch, Centers for Disease Control and Prevention.
Culture, serology, electron microscopy, immunohistochemistry, and molecular techniques have been central to finding viral causes of disease outbreaks. Transmission of unusual viral pathogens from a single donor to multiple recipients of transplanted organs is not an uncommon problem, and it’s a vexing one.
It is difficult to prevent these clusters for several reasons, he said: More than 25,000 transplants are done each year, 100,000 people are on waiting lists, availability of donor organs is limited, and there are few criteria for donor exclusion. While transplant physicians have long been aware of the possibility of donor transmission of “typical” organisms, including cytomegalovirus, hepatitis B and C viruses, and Epstein-Barr virus, in the past 15 years several clusters owing to more unusual organisms have also occurred: microsporidia, lymphocytic choriomeningitis virus (LCMV), West Nile virus, and rabies. He described investigations into clusters of transplant infections caused by lymphocytic choriomeningitis virus and rabies, highlighting the contributions of the pathologist and the laboratory. In the first case a 51-year-old male organ recipient was found dead on the sidewalk with a subdural hematoma. In a second cluster, by contrast, which occurred a few years later, the patients had the same features as in the first, so investigators suspected LCMV from the outset.
In the second case the donor was a mother who cleaned the cage of her daughter’s hamster; the cage was the source of LCMV infection.
In a rabies cluster that occurred in 2004, the CDC was contacted by a pathologist in Texas about two deaths in transplant recipients and a third recipient with altered mental status, who also eventually died.
Further investigation revealed that, while the liver came from a second donor, the artery stump to the liver came from the initial rabies-infected donor. To illustrate further the important part pathology plays in helping to uncover viral causes of outbreaks, Dr.
Subsequent IHC for enterovirus in brain tissue was positive, leading to identification of strain EV 71, the first time this variant had been documented to cause encephalitis. In 1998–1999 an outbreak of severe encephalitis arose in Singapore and Malaysia among those who had close contact with pigs, particularly farmers. In the investigation of Middle East Respiratory Syndrome, or MERS, important information was obtained from a single autopsy of the first patient identified, in Abu Dhabi. The second: the availability of newer technologies such as next-generation sequencing that can complement existing technologies like immunohistochemistry “or clues from light microscopy or culture or electron microscopy. Even more important given the zoonotic linkages with many of the diseases he spoke about—hantavirus, Nipah virus, and filoviruses (the viral hemorrhagic fever agents Ebola and Marburg). While scientists in the CDC’s Infectious Diseases Pathology Branch are often in the middle of the investigation of such viral outbreaks, there is also a role for pathologists in the community. But there and elsewhere it’s critical to remember, he says, “the frontline role of pathology” in diagnosing unexplained deaths, recognizing emerging diseases, and guiding epidemiologic investigations. At the Clinical Virology Symposium in April, he spoke on viral etiology in unexpected deaths, presenting a list of outbreaks of unexplained illnesses in which his branch took part in the past two decades and which turned out to be caused by viruses.
Zaki said, “so something that we thought was uncommon is actually pretty common.” In one recent cluster, LCMV was identified by next-generation sequencing. The connection to a single donor came up in a fortuitous way: The patients’ families discovered it while talking in the ICU waiting room.

If a surgeon doesn’t need a good artery from a donated organ, he or she may save it for another transplant, Dr.
Zaki was asked after his talk for advice on how to prevent clusters of transplant-derived infections with unusual viruses, he said, “When a person is at the door of death and they get an organ, it is hard to be picky.” Aside from routine testing for common infections and obtaining a donor exposure history, such as to pets and rodents, little can be done. Zaki’s laboratory and PCR in the laboratory of Stuart Nichol, PhD, chief of the CDC Viral Special Pathogens Branch.
Children ages five months to six years were dying of cardiogenic shock; EKG abnormalities were documented.
Zaki defines as “expect the unexpected”—is the watchword to identifying and solving mysterious outbreaks, he says.
It’s the One Health concept, an initiative that arose around 1999 during the outbreak of West Nile virus, Dr.
Zaki said, showing newspaper headlines calling into question the rules for organ transplantation.
The donor, who had a history of drug use, became ill and couldn’t swallow but was not diagnosed. Staining on IHC showed Negri bodies in the brain, which are pathognomonic of rabies infection.
Zaki said, “and went back and reviewed the autopsy.” It was consistent with encephalitis due to West Nile virus.
We can pick up some LCMV infections by serology and PCR, but most infected persons have such a low level of virus that we can’t detect it by laboratory testing.” Neither of the donors in the two clusters Dr. The first clue that an unexpected pathogen was responsible came from a serology test in the special virology section at the CDC showing elevated IgG to hantavirus, suggesting that a hantavirus could be the culprit.
Histochemistry showed hantavirus antigens in the lungs of patients as well as the virus targeting the microcirculation in lung capillaries, causing pulmonary edema.
Many had hand, foot, and mouth disease and many had symptoms of aseptic meningitis, leading investigators to suspect coxsackievirus myocarditis.
Zaki said the autopsy showed he was “far from healthy.” He had bad kidneys, heart disease, liver disease, and atheromas.
As a result, a transplant unit has “bits and pieces of tissue stored in a freezer.” In the case of the fourth rabies-infected recipient, the surgeon pulled from the freezer the artery stump from the infected donor and used it.
Zaki described tested positive for LCMV, even after that virus was identified in the recipients.
You are harvesting tissues and organs, so why not get the brain and other tissues that will allow you to test for infectious agents.” Even if a virus is found a week or two after transplantation, he noted, clinicians can be on the watch for it in the recipient.
Copious amounts of immunoblasts in lymph nodes and circulating in the blood indicated an activated immune system. Tissues from a dozen or so hearts were submitted to the CDC, but there was no evidence of myocarditis.
Getting permission for an autopsy in that part of the world is particularly difficult, he said, and only considerable pressure on the government made it possible. We get a donor history asking whether they have been in situations where they could have been exposed.

Vital information was available from deaths of crows, but it was slow in coming to the attention of the medical community.
First, only one strain of hantavirus was known in the Western Hemisphere, and it was not pathogenic. About two dozen strains of hantavirus are now known throughout the Western Hemisphere, many of them pathogenic. Further investigation showed it was a new encephalitis virus cross-reacting with the recently identified Hendra virus. The coronavirus result was quickly confirmed at the CDC by a number of other techniques, including IHC, serology, and molecular methods.
There was a clustering of cases, which raised concern that the virus may have been transmitted by person-to-person contact, inciting a high level of fear.
Everyone needs to be aware of those and know how to screen for them.” Laboratories in hospitals that perform transplants have assays for the more common viral pathogens, such as herpesvirus and adenovirus. It took six weeks to identify the virus as LCMV by culture, serology, histopathological examination with IHC staining, and electron microscopy. Second, known hantaviruses were associated with hemorrhagic disease of the kidneys, not pulmonary effusion. While the autopsy could not prove or refute this possibility (it turned out to be unfounded), it did show that healthy people are not at high risk, a suggestion borne out in subsequent cases. A government report issued in 2003 stressed the need for public health workers to collaborate with clinicians, veterinarians, and scientists in academia. For uncommon pathogens, one might look in the literature for information about transplant-associated infections, such as rabies, which can be diagnosed by a neuropathology exam and confirmed by special stains.
An alert clinician, or veterinarian or pathologist, may recognize something out of the ordinary. He and his co-investigators recommended: “Rabies should be considered in patients with acute progressive encephalitis of unexplained etiology, especially for potential organ donors. Zaki says, “when you become aware of an unexplained or unusual infection, is to refer such cases to a place such as CDC.
A standard evaluation of potential donors who meet screening criteria for infectious encephalitis should be considered, and risks and benefits for recipients of organs from these donors should be evaluated” (Vora NM, et al. Acupuncture , heat , electrical stimulation channels of energy , body's internal organs, correct imbalances digestion, absorption, and energy production activities, circulation of their energy . Specialization, Materia Medica, internal medicine, diagnosis , examine, refer ,investigations .health shops, pharmacies, prescription, complex remedies, labelled ,individualized ,mental, migraines, asthma, eczema, hay fever, glandular fever, chronic fatigue syndrome.
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