On human rabies cases associated with organ transplants
http://www.100md.com
C. Mehmet Hendekli
rabies;organ,transplant;rabies,symptoms;rabies,antemortem,tests,Onhumanrabiescasesassociatedwithorgantransplants,INTRODUCTION,DISCUSSION,CONCLUSIONS
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On human rabies cases associated with organ transplants (pdf)
Correspondence to Dr.C.Mehmet Hendekli,Hetzendorfer Str.97/4/1,A-1120 Wien Austria
Tel:+43 664 3133223 Fax: +43 1 9716164
E-Mail: hendekli@ieee.org
[Abstract] Rabies is a fatal viral disease that is transmitted to humans almost only by bites. However, although quite rare, other transmission methods like aerosol transmission, faulty vaccines, tissue or organ transplants can also cause human rabies. In the recent years, human rabies cases associated with organ transplants other than corneal transplants, have occurred for the first time in the literature causing the death of a total of seven patients, who received transplants in USA and Germany. In this paper, these cases are discussed aiming to provide a venue for deep critical examination, and some suggestions for the future prevention of such tragedies are presented including a tissue and organ transplant algorithm for safety against rabies transmission.
[Key words] rabies;organ transplant;rabies symptoms;rabies antemortem tests
INTRODUCTION
Rabies is a fatal viral disease affecting the central nervous system (CNS) and is transmitted by the saliva of a rabid mammal. Humans can almost only be infected when an infected animal’s saliva gets through an open wound or mucous surface. With almost 99.8%, bites form the majority of the rabies transmission cases. However, faulty vaccines, aerosol transmission [1~3] and corneal [4～9] or organ transplants [10～12] from undiagnosed donors at the time of the transplantation also result in human rabies.
Once the critical stage inside the incubation period, which does not leave enough time to start a preventive vaccine therapy to let the patient develop neutralising antibodies before the virus attaches itself to the neurons, is reached, there is no more cure or treatment of rabies, although the literature documents a total of six human rabies survivors up to date [13]. However, five cases [14～19] are questioned to this day whether they met all the criteria of a human to survive rabies without treatment, because all patients received either a pre-exposure prophylaxis (PreEP) or post-exposure prophylaxis (PEP) before the onset of the clinical symptoms. Furthermore, among these five cases, only one case [14] had a full recovery without any neurological complications. Only the most recent survival case [20, 21] meets the criteria of a human to recover from rabies without any treatment before the onset of the symptoms. In this specific case [20, 21], the therapy approach involved inducing a coma and using a combination of four different drugs (ketamine, midazolam, ribavirin, and amantadine) to protect the nervous system and boost the immune system of the patient, who was not given any rabies vaccine or human rabies immune globulin (HRIG). However, the prognosis of the full recovery of the patient is still unknown. This female patient survived with choreoathetosis, dysarthria, and an unsteady gait [21], and more than one year after her initial hospitalization, she still receives intensive physical and speech therapy. Furthermore, similar therapy approaches failed in further trials applied to patients in India and Germany, where the approach was tested on the three organ recipients from the female donor with rabies infection. Hence, inother words, though revolutionary, this new therapy approach, which must definitely be encouraged to be applied and further developed, shall not be regarded as a definitive cure of clinical rabies.Such a definitive treatment, which would cure all patients developing the clinical rabies regardless of their age, health status, immune strength, presence of any chronic disease, the method of exposure, etc. does still not exist today [13].
Eight human rabies cases occurred due to corneal transplants [4～9] were already known in the literature, however a total of seven patients died from organ transplants in the recent years in cases involving USA and Germany [10～12], which had not been observed or documented in the literature previously (Figure 1).
Figure 1 Summary of human rabies cases due to organ and tissue transplants with year and country
In the first case [10, 11], the donor, a male from Arkansas, was hospitalized in Texas early May 2004 with severe mental status changes and a low-grade fever and died a few days after admission due to subarachnoid hemorrhage leading to cerebral herniation. The donor's death was attributed to non-infectious causes, although he had reported being bitten by a bat [22]. However, contrary to [22], it is claimed in [11] that friends of the donor indicated he had reported being bitten by a bat, during contact investigations conducted after the rabies diagnosis was made. Donor eligibility screening and testing did not reveal any contraindications to transplantation. His liver and kidneys were transplanted to three recipients, and his iliac artery segment was used to construct a vascular graft for another liver transplant procedure. As a result, each of the recipients developed the clinical rabies within 30 days after transplant and died eventually. The diagnosis of rabies in all four recipients was confirmed by immunohistochemical testing and by the detection of Rabies virus antigen in fixed brain tissue by direct fluorescent antibody (FA) tests.
In the second case [12], the donor, a 26-year-old female from Germany supposed to be a drug user, died in a hospital, where she had been admitted with symptoms like severe headache, anxiety and aggressions, due to cardiac arrest after consuming a cocaine-ecstasy cocktail in December 2004. All resuscitation trials were unsuccessful and donor testing did not reveal any contraindications to transplantation. The organs and tissues to be transplanted were also screened for bacteria and viruses like hepatitis and HIV, but nothing was found. Among the six recipients, only three of them, who received her lung, a kidney and kidney-pancreas, respectively, developed the clinical rabies on average two months after transplant and died despite of the treatment trials with similar methods to the recent therapy approach [21]. The donor was later supposed to have been infected with Rabies virus during a trip in India. However, three other recipients, who received her liver and each cornea, did not develop the symptoms and stayed healthy. They were nevertheless administered rabies PEP.
The paper is organized as follows: The introduction section already briefly presented the rabies disease, its transmission methods, its 100% mortality after onset of clinical symptoms despite a few survivors documented in the literature, and the recent human rabies incidents by organ transplants from infected donors. The next section provides precise information on the rabies pathogenesis and clinical symptoms, which is aimed to be helpful to clinicians, when they are faced up with similar situations, i.e. treat possible organ donors with clinical features strongly suggestive of rabies. The further following section presents some post-and antemortem diagnostic tests and essays. It shall be noted for the reader that the paper rather focuses on rapid intravitam tests for antemortem diagnosis, as it is believed that the most critical time period in the decision of an organ transplant are the few hours or days between the admission of a possible donor at the hospital and his/her death. If a rabies diagnosis was made within this time interval, this would not only prevent the further transmission to any organ or tissue recipient, but also cut down unnecessary financial costs for the preparation of organs or tissues to be transplanted, the operation, etc. Finally, discussion and conclusions are provided at the end.
The main purpose and duties of the paper can be summarized as follows:
· To create a general awareness of the rabies disease and to express that it has not disappeared from the world yet contrary to some assumptions and ignorance in public or even medical communities in some developed countries.
· To state that rabies has 100% mortality after onset of clinical symptoms despite the six survivors documented in the literature, and to express that there is no definitive cure of clinical rabies despite some aggressive therapy approach trials, which once enabled a partial recovery of a female teenager.
· To make the medical community aware of the fact that organ and tissue transplants are–perhaps rare–but one clear and undeniable method of rabies transmission.
· To alert the medical community that clinical rabies symptoms can mimic several other diseases or symptoms, and to provide the clinicians with some clues that are helpful to rule out rabies in the diagnosis.
· To clearly indicate that the majority of the patients with human rabies caused by bat Rabies virus variants had no definitive history of a bat bite due to the fact that bats have small teeth and claws.
· To state that at the admission to hospital a human rabies patient may have co-existing diseases or symptoms, which may supersede the rabies symptoms, especially at the prodromal stage of the disease.
· To remind the medical community about the fact that fast resulting rabies intravitam tests do exist, but unfortunately none of them provide an absolute sensitivity.
· To express the necessity of reconsidering and modifying organ transplant procedures.
· To provide a venue for deep critical examination through discussion and conclusions.
RABIES PATHOGENESIS AND CLINICAL SYMPTOMS
Once the exposure to the Rabies virus and transmission occur, the incubation period starts, which is one of the mysteries of rabies. The processes that take place during the incubation period are not fully solved. Several experiments on animals lead to the conclusion that the virus remains at or near the site of exposure during the incubation period. Although the incubation period in humans lasts between 30～50 days on average, it actually has a varying length. Incubation periods of less than a week and on some occasions more than a year–even 5 years -have been reported. There is even one specific case with an incubation period of 19 years and 6 months [23]. The length of the incubation period depends on the following factors:
· The distance of the exposure site to the CNS;
· The severity and dimensions of the wound;
· The amount of virus introduced into the body;
· The immune strength of the individual;
· Whether the site of exposure is rich in nerve cells.
Following the viral replication in muscle within the incubation period, the G protein of the Rabies virus genome binds to nicotinic acetylcholine receptors at the neuromuscular junction [24] towards the end of the incubation period, and the virus travels towards the CNS within motor and sensory axons (via unmyelinated sensory and motor terminals) by retrograde fast axonal transport at a rate of about 50～100 mm per day (centripetal spread) [25]. Neurons are infected in the spinal cord and the virus jumps from neuron to neuron within axons in the CNS up to the brain. Once the brain is infected, finally there is spread of the virus away from the CNS along neuronal pathways(centrifugal spread), which are responsible for infection of the salivary glands, skin, nasal cavities, tears, retina, cornea, heart and some other organs (pancreas, kidney, etc.) [26].
The clinical symptoms can be divided into three stages respectively: prodromal stage, excitation stage, coma stage and death. Even with strong intensive care support, the median period of survival after symptom onset is between 4~21 days. There is a case of a patient, who died 133 days after the onset of symptoms [27].
The prodromal stage typically lasts 2～10 days and is characterized by mild and nonspecific symptoms which can be mistaken for a common cold or flu. These include headache, slight fever, fatigue, sore throat, malaise, nausea, anorexia, cough, and gastrointestinal discomfort. A characteristic symptom suggestive of rabies is burning, itching, tingling or muscle twitching/fasiculations near the site of the bite as the virus multiplies in the sensory nerves from that area within the spinal cord. Very rarely, those symptoms are felt at a site other than the site of the bite [28]. Also, another characteristic symptom at this stage is a slight increase in the libido.
The development of the excitation stage differs in two types of rabies: encephalitic (or furious) rabies and paralytic (or dumb) rabies. The encephalitic rabies occurs in about 80%～85% of the patients and is typically experienced in human rabies caused by stray dog bites. The paralytic rabies covers about 15%～20% of the cases and is mostly experienced after exposures by bats. The excitation stage usually lasts 2～7 days. Paralytic type of patients generally live longer than those suffering from encephalitic rabies. Symptoms of the encephalitic type are periods of confusion, combativeness, anxiety, hallucinations, agitation,apprehension, irritability alternating with periods of calm and normal behavior, as well as periods of depression. At the beginning of the encephalitic excitation stage, the above bizarre symptoms usually last a few minutes, but with the ongoing time the bizarre period lasts longer and the periods of calm behavior are shortened. The patient develops excessive sensitivity to light (photophobia), noise(acousticophobia), touch, gentle breeze (aerophobia), and smell (including garlic) with reaction to these stimuli with facial spasm showing bared teeth. Furthermore, the patient develops hydrophobia resulting in extremely painful, forceful involuntary contractions of upper gastrointestinal, respiratory and diaphragmatic muscles on initiation of swallowing liquids, leading to salivation and the classic “foaming at the mouth”. Even the sight or mention of liquids trigger these muscle spasms. Autonomic dysfunction may also lead to hypersalivation, lacrimation (secretion of tears), perspiration, asymmetrical dilation of constriction of the pupils, absence of corneal reflexes, priapism and spontaneous ejaculation by male patients. It has to be noted that the patient remains fully conscious through the entire excitation stage. The paralytic type however generally lacks the violent symptoms of encephalitic rabies, though occasionally some of the same symptoms occur, such as depression and hydrophobia. This form is characterized by the slow paralysis of the patient, usually starting as a numbness or weakness at the bite site and spreading to the rest of the body over time. Symptoms may include hypertension, tachycardia, confusion, hallucinations and disorientation. Guillain-Barré syndrome like symptoms may also appear.
After leaving the excitation stage, the patient falls into coma stage and death usually occurs as a result of cardiac failure, paralysis (rather encephalitic type) or respiratory failure (rather paralytic type). Sometimes death occurs without coma stage. Among many further clinical features that a human rabies patient experiences once entering the excitation stage, some can be named as cerebral edema, diabetes insipidus, pneumonia, arterial or venous thrombosis, acute renal insufficiency, apnoea, atelectasis, pneumothorax, congestive cardiac failure and cardiac arrest.
PEP treatment window starts immediately with the exposure and lasts until reaching the critical stage inside the incubation period, which does not leave enough time to start a preventive vaccine therapy to let the patient develop neutralising antibodies before the virus attaches itself to the neurons. Once this critical stage is reached or the patient develops the clinical symptoms, the only common method that is widely applied in the management of human rabies is the palliative therapy with strong intensive care support. Furthermore, there is a window for the trial of aggressive therapy approach, which starts immediately after reaching the mentioned critical stage and usually lasts until the end of the prodromal stage or at most up to the very early phases of the excitation stage. Beyond that, not much hopes shall be expected from the aggressive therapy approach, which is assumed to yield more successful results, the earlier it is started.
RABIES TESTS FOR POST-AND ANTEMORTEM DIAGNOSES
Right after the above human rabies incidents, the responsible authorities of the involved transplant centers in USA and Germany made some statements [12, 29, 30] rather reflecting a sudden juridical fear or panic that their transplant centers had a legal fault in the resulting human rabies cases. They either claimed that a diagnosis of a possible rabies infection of the donor in prior to a transplant was impossible, or that such testing for rabies could not be done in a timely fashion for utilization of harvested organs. However, there are several tests for the post-and antemortem diagnoses of rabies in humans.For example, FA test for detection of rabies antigen in brain tissue is a rapid and highly sensitive method for the postmortem diagnosis of rabies in animals and humans. It has become a gold standard technique, which almost never yields false results as long as sufficient sampling is considered. Most of the postmortem tests can also be successfully applied intravitam for antemortem diagnosis of rabies. The only problem is that the success of the intravitam tests greatly depends on the stage of the clinical rabies and that none of these tests commit 100% sensitivity. Especially, our biggest concern is the death of an infected donor in the prodromal stage of the disease, which was most probably the situation in the Germany case.
In the prodromal stage of the clinical symptoms, i.e. in the first few days following the onset of the clinical signs, antigen detection by FA test in corneal impressions or skin biopsies is generally sensitive, however virus neutralizing antibodies in cerebrospinal fluid (CSF) and serum usually tend to appear in the excitation stage of the illness. The overall reliability of the FA test for intravitam diagnosis is limited, as a negative result does not necessarily exclude the possibility of rabies infection. The reliability of rabies antigen detection in skin biopsies is much higher at the later stages of the disease, and the overall sensitivity of FA test is higher with skin biopsies than with corneal impressions [31]. However, not even being at the late stages of the clinical symptoms is a guarantee for 100% sensitivity of any intravitam test, as the Rabies virus may be absent from saliva, biopsies or CSF even during the late stages. As a further intravitam diagnosis method, the so called rapid fluorescent focus inhibition (RFFI) test [31] may be used to measure neutralizing antibodies in the serum or CSF of non-vaccinated patients. Another limited sensitivity, but rapid test is the enzyme-linked immunosorbent assay (ELISA) using purified rabies glycoprotein to determine virus neutralizing antibody levels in the serum [31]. A reverse transcription polymerase chain reaction (RT-PCR) assay of saliva and immunofluorescence (IF) assay of skin sections together yielded high sensitive results in a study for intravitam diagnosis of human rabies [32]. In another study [33], a real-time TaqMan RT-PCR assay was able to detect and genotype Lyssavirus templates in significantly fast manner. Moreover, as the results are obtained in real-time, it is possible to take more rapid and appropriate decisions for the patient management. Table 1 presents a comparison of several
Table 1 Comparison of Some Rabies Intravitam Tests
Note:FA，fluorescent antibody；RFFI，rapid fluorescent focus inhibition；CSF，cerebrospinal fluid；ELISA，enzyme-linked immunosorbent assay；RT-PCR，reverse transcription polymerase chain reaction
aNumber of samples；bThis conclusion is based on references [31, 32]；cThis conclusion is based on references[31, 32, 40]；dThis conclusion is based on references[31, 32]；eThis conclusion is based on references[31, 32 ]；fThis conclusion is based on reference [33]
intravitam tests in terms of speed of yielding the test result and reliability.
One further undeniable reality is that both donors in USA and Germany presented obscure neurological and behavioural symptoms at the admission to hospital, which should have denoted the inclusion of rabies in the diagnosis. The corresponding care teams failed to consider this possibility under the organ transplant procedures and policies at that time. Nevertheless, it would be a very easily said sentence to recommend that the safest strategy is to exclude potential donors with obscure neurological signs and symptoms altogether. There is also the other side of the story. Donor availability and a matching organ are the best news that a potential recipient and his/her care team can get in a long waiting queue. One cannot easily recommend the exclusion. Firstly, the situation greatly differs from location. In regions like USA, Canada or Western & Central Europe, where human rabies cases are extremely rare and exist almost only due to imported cases except a few ones in USA caused by bat Rabies virus variants, the probability of having a rabies infected donor would be extremely low. On the other hand, in countries like India, where almost every 15 minutes someone is dying of rabies, or Thailand, where it is not extraordinary for a clinic to have one or two human rabies cases per week, the probability would be quite high.
As a summary, in view of the above explanations and considering the fact that fast resulting rabies intravitam tests do exist, but none of them provide an absolute sensitivity and that false positive test results would cause many more deaths than transmission of rabies via organ or tissue transplants, if potential donors with obscure neurological signs and symptoms altogether were excluded based on these test results, I do propose an algorithm summarized in Table 2 to play a key safety role for the future prevention of such tragedies. Although this algorithm is recommended in specific cases like presence of a donor with obscure neurological and behavioural symptoms and signs, it can actually be generally applied for all organ and tissue transplant procedures, as there may be some rare cases where a rabies positive donor presents two co-existing neurologic diseases at the admission to hospital, whereas the symptoms of the non-viral or non-harmful disease for the recipient may shadow the clinical symptoms of rabies, especially when the donor is at the prodromal stage of the disease.Furthermore, this algorithm can also be implemented in an adaptive manner, if an observation stage is put at the end, from which later the corresponding transplant center can make its own modifications to the algorithm.
DISCUSSION
First of all, one of the most important factors that led to these human rabies tragedies in USA and Germany was the general public ignorance and low level of awareness of this fatal disease. Otherwise, the male donor in the USA would have sought for PEP after being bitten by bat, or the female donor in Germany would have received either PreEP before travelling to India, which is a large canine rabies endemic nation, or PEP after being bitten by a stray dog there. This public unawareness is especially to be observed in rabies-free territories or countries, where human rabies cases are extremely rare. Rabies has not disappeared from the world and it is still a very killing disease [34]. If there had been enough public awareness, the care teams of both donors would have considered rabies in the diagnosis, when the donors had been admitted to hospital with obscure neurological and behavioural symptoms and signs. The male donor in USA had reported being bitten by a bat, as the Arkansas Department of Health determined as a result of its public health investigation [22]. It is even a fact that the majority of the patients with human rabies caused by bat Rabies virus variants had no definitive history of a bat bite [35, 36] due to the fact that bats have small teeth and claws. Therefore, cases like sleeping person awakening to find a bat in the room, or adult finding a bat in a room with a previously unattended child or mentally disabled or intoxicated person, are indications for rabies exposure suspicion and to start PEP immediately. As it is mostly the case by human rabies caused by bat Rabies virus variants, this donor experienced the paralytic type of clinical symptoms, which lack the violent symptoms of encephalitic rabies, and his care team led to organ transplant tragedies by attributing to non-infectious causes for his death. At his last admission to hospital, computed tomography of the brain demonstrated a subarachnoid hemorrhage [11], but alone the fact that he had reported being bitten by a bat, should be enough for rabies suspicion and supersedes and shadows the reality that there is no evidence that the subarachnoid hemorrhage in the organ donor was related to the rabies infection [37].
He could well have two co-existing neurologic diseases. Moreover, it is worth noting that, especially in the early stages of the clinical symptoms, rabies can mimic many other encephalitides, tetanus, cerebral malaria, rickettsial diseases, poliomyelitis, botulism, simian herpes type B encephalitis, Guillain-Barré syndrome, alcohol withdrawal symptoms, drug or poison intoxication and rabies hysteria. Some clues for clinicians would be that rabies can be ruled out in patients who have an extended duration of illness and whose conditions improve after the onset of symptoms, as otherwise a rabies patient steadily deteriorates until death, as the course of the rabies disease is relentlessly downhill.
A further notable discussion would be the failure of the recent new therapy approach [21], which achieved the survival of a female teenager with neurologic impairment late 2004, by the three of the six organ recipients,who contracted rabies from the female donor in Germany. As mentioned previously, though revolutionary, this new aggressive therapy approach is not a definitive treatment, which would cure all patients developing the clinical rabies regardless of their age, health status, immune strength, presence of any chronic disease, the method of exposure, etc [13]. It is not fully clear and known why the female teenager from Wisconsin survived with this new approach and the role of drugs used in this therapy are a question mark. However, one fact is that those three organ recipients in Germany, who received a similar therapy approach, had also received immunosuppressive therapy to avoid the rejection of transplanted organs, and were already in disadvantage to develop neutralising antibodies for the Rabies virus. Nevertheless, the kidney-pancreas recipient among them had a prolonged survival of 56 days after the onset of symptoms. Moreover, all the three organ recipients were also given interferon-α during their therapies unlike the approach in [21], although it has neurotoxicity.
One last important aspect is that interestingly three further recipients from the same female donor in Germany, both cornea recipients and one liver recipient, did not develop the symptoms and stayed healthy. Once the other three infected recipients developed the clinical rabies, the brain tissue of the donor was examined almost two months after her death and was diagnosed with rabies infection, hence the centrifugal spread of the virus away from the CNS had occurred. However, both transplanted corneas were later found not to be infected with the Rabies virus. The recipients were nevertheless administered rabies PEP and retransplanted new corneas [12]. It is a question mark why the corneas of the donor were not infected by the centrifugal spread, while all other transplanted organs were, i.e. kidneys, lung, pancreas and liver. Although the liver was also infected, the recipient stayed healthy, which was referred by his care team to the fact that as a coincidence he had received PEP almost 15 years ago in his childhood and still had adequate antibody titer, which was confirmed by a test result [38]. Nevertheless, he was administered PEP, after the incidents had come out, and further received a combinational drug therapy.
CONCLUSIONS
More than 100 years after the invention and application of the first rabies vaccine in 1885, human rabies, which ends up with an extremely painful and torturous death, is still a problem in the world. World Health Organization (WHO) reports over 30,000 human deaths per year from rabies, however the actual number including the unreported cases is estimated to be significantly above 60,000 deaths, mostly occuring in India [34]. The literature had already documented eight human rabies cases due to corneal transplants. And in the recent years, a total of seven other organ recipients have died of rabies. Unfortunately, these tragedies can happen again in future, unless organ transplant procedures and strategies will be reevaluated and modified correspondingly, and efforts will be spent to increase the general public awareness of the rabies disease. Some have contemplated the possible utility of testing donor brain in the days after organs have been transplanted and administering PEP to recipients of organs from rabies positive donors. Although there is one example, where the cornea recipient from an infected donor was probably saved through PEP [39], my personal view of such contemplation is:
· It is not ethical to risk it and first infect the recipient with rabies and then provide PEP.
· Organ or tissue transplants from infected donors mostly result in shorter incubation periods at the recipients, who are also generally immunosuppressed to avoid the rejection of transplanted material. Hence, because of shorter incubation period and/or immunosuppression, PEP may not allow the recipient to develop neutralising antibodies timely before the virus attaches itself to the neurons, i.e. when it becomes too late.
· If the possible rabies infection of the donor is diagnosed antemortem through intravitam tests, then also unnecessary costs for the preparation of the recipient/s, removal of organs or tissues to be transplanted, transport of them, the operation, etc. will be cut down.
Obviously, organ and tissue transplant policies and methods shall be modified by enhanced donor screening and testing, and enhanced procedures for storing and tracking the use of donor segments. I believe that applying the proposed algorithm (Table 2) in specific cases like presence of a donor with obscure neurological and behavioural symptoms and signs will be a good safety barrier for the future prevention of such tragedies. Moreover, as mentioned previously, it can be implemented as an adaptive algorithm by observing some parameters with the ongoing time and applying some corresponding modifications later.
Table 2 Safety Algorithm for the Prevention of Human Rabies by Organ and Tissue Transplants
5 RT-PCR:reverse transcription polymerase chain reaction
aA country where the disease is compulsorily notifiable, an effective system of disease surveillance is in operation, all regulatory measures for the prevention and control of rabies have been implemented including effective importation procedures, no case of indigenously acquired rabies infection has been confirmed in man or any animal species during the past two years (this status would not be affected by the isolation of a European Bat Lyssavirus (EBL1 or EBL2), and where no imported case in carnivora has been confirmed outside a quarantine station for the past six months
bA region or country where rabies is present at animal species, but human rabies either occurs due to imported cases, or very rarely due to indigenous rabies mostly caused by bat Rabies virus variants (for example USA)
cA region or country where there are significant number of indigenous human rabies cases per year in addition to rabies at animal species, or large rabies endemic nations (for example India, Thailand)
dThe patient presents obscure neurological and behavioural symptoms and signs and rabies can’t be ruled out
eThe patient still has neurological and behavioural symptoms and signs, but rabies can be mostly ruled out due to some evidences like the patient has an extended duration of illness, or is not steadily deteriorating, or is recovered enough for life support to be removed, if he/she had been placed on it
fThis shall be done in real-time, and some example modifications based on these observations can be taking more risk by reducing the amount of tests at certain steps, considering the impact on donor organ availability through decision-analysis or risk-benefit studies, etc.
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UNIDOST A.S. Rihtim Cad. Polat Han D：38，Kadikoy Istanbul, TR-34716,Turkey
(Editor Anne)
On human rabies cases associated with organ transplants (pdf)
Correspondence to Dr.C.Mehmet Hendekli,Hetzendorfer Str.97/4/1,A-1120 Wien Austria
Tel:+43 664 3133223 Fax: +43 1 9716164
E-Mail: hendekli@ieee.org
[Abstract] Rabies is a fatal viral disease that is transmitted to humans almost only by bites. However, although quite rare, other transmission methods like aerosol transmission, faulty vaccines, tissue or organ transplants can also cause human rabies. In the recent years, human rabies cases associated with organ transplants other than corneal transplants, have occurred for the first time in the literature causing the death of a total of seven patients, who received transplants in USA and Germany. In this paper, these cases are discussed aiming to provide a venue for deep critical examination, and some suggestions for the future prevention of such tragedies are presented including a tissue and organ transplant algorithm for safety against rabies transmission.
[Key words] rabies;organ transplant;rabies symptoms;rabies antemortem tests
INTRODUCTION
Rabies is a fatal viral disease affecting the central nervous system (CNS) and is transmitted by the saliva of a rabid mammal. Humans can almost only be infected when an infected animal’s saliva gets through an open wound or mucous surface. With almost 99.8%, bites form the majority of the rabies transmission cases. However, faulty vaccines, aerosol transmission [1~3] and corneal [4～9] or organ transplants [10～12] from undiagnosed donors at the time of the transplantation also result in human rabies.
Once the critical stage inside the incubation period, which does not leave enough time to start a preventive vaccine therapy to let the patient develop neutralising antibodies before the virus attaches itself to the neurons, is reached, there is no more cure or treatment of rabies, although the literature documents a total of six human rabies survivors up to date [13]. However, five cases [14～19] are questioned to this day whether they met all the criteria of a human to survive rabies without treatment, because all patients received either a pre-exposure prophylaxis (PreEP) or post-exposure prophylaxis (PEP) before the onset of the clinical symptoms. Furthermore, among these five cases, only one case [14] had a full recovery without any neurological complications. Only the most recent survival case [20, 21] meets the criteria of a human to recover from rabies without any treatment before the onset of the symptoms. In this specific case [20, 21], the therapy approach involved inducing a coma and using a combination of four different drugs (ketamine, midazolam, ribavirin, and amantadine) to protect the nervous system and boost the immune system of the patient, who was not given any rabies vaccine or human rabies immune globulin (HRIG). However, the prognosis of the full recovery of the patient is still unknown. This female patient survived with choreoathetosis, dysarthria, and an unsteady gait [21], and more than one year after her initial hospitalization, she still receives intensive physical and speech therapy. Furthermore, similar therapy approaches failed in further trials applied to patients in India and Germany, where the approach was tested on the three organ recipients from the female donor with rabies infection. Hence, inother words, though revolutionary, this new therapy approach, which must definitely be encouraged to be applied and further developed, shall not be regarded as a definitive cure of clinical rabies.Such a definitive treatment, which would cure all patients developing the clinical rabies regardless of their age, health status, immune strength, presence of any chronic disease, the method of exposure, etc. does still not exist today [13].
Eight human rabies cases occurred due to corneal transplants [4～9] were already known in the literature, however a total of seven patients died from organ transplants in the recent years in cases involving USA and Germany [10～12], which had not been observed or documented in the literature previously (Figure 1).
Figure 1 Summary of human rabies cases due to organ and tissue transplants with year and country
In the first case [10, 11], the donor, a male from Arkansas, was hospitalized in Texas early May 2004 with severe mental status changes and a low-grade fever and died a few days after admission due to subarachnoid hemorrhage leading to cerebral herniation. The donor's death was attributed to non-infectious causes, although he had reported being bitten by a bat [22]. However, contrary to [22], it is claimed in [11] that friends of the donor indicated he had reported being bitten by a bat, during contact investigations conducted after the rabies diagnosis was made. Donor eligibility screening and testing did not reveal any contraindications to transplantation. His liver and kidneys were transplanted to three recipients, and his iliac artery segment was used to construct a vascular graft for another liver transplant procedure. As a result, each of the recipients developed the clinical rabies within 30 days after transplant and died eventually. The diagnosis of rabies in all four recipients was confirmed by immunohistochemical testing and by the detection of Rabies virus antigen in fixed brain tissue by direct fluorescent antibody (FA) tests.
In the second case [12], the donor, a 26-year-old female from Germany supposed to be a drug user, died in a hospital, where she had been admitted with symptoms like severe headache, anxiety and aggressions, due to cardiac arrest after consuming a cocaine-ecstasy cocktail in December 2004. All resuscitation trials were unsuccessful and donor testing did not reveal any contraindications to transplantation. The organs and tissues to be transplanted were also screened for bacteria and viruses like hepatitis and HIV, but nothing was found. Among the six recipients, only three of them, who received her lung, a kidney and kidney-pancreas, respectively, developed the clinical rabies on average two months after transplant and died despite of the treatment trials with similar methods to the recent therapy approach [21]. The donor was later supposed to have been infected with Rabies virus during a trip in India. However, three other recipients, who received her liver and each cornea, did not develop the symptoms and stayed healthy. They were nevertheless administered rabies PEP.
The paper is organized as follows: The introduction section already briefly presented the rabies disease, its transmission methods, its 100% mortality after onset of clinical symptoms despite a few survivors documented in the literature, and the recent human rabies incidents by organ transplants from infected donors. The next section provides precise information on the rabies pathogenesis and clinical symptoms, which is aimed to be helpful to clinicians, when they are faced up with similar situations, i.e. treat possible organ donors with clinical features strongly suggestive of rabies. The further following section presents some post-and antemortem diagnostic tests and essays. It shall be noted for the reader that the paper rather focuses on rapid intravitam tests for antemortem diagnosis, as it is believed that the most critical time period in the decision of an organ transplant are the few hours or days between the admission of a possible donor at the hospital and his/her death. If a rabies diagnosis was made within this time interval, this would not only prevent the further transmission to any organ or tissue recipient, but also cut down unnecessary financial costs for the preparation of organs or tissues to be transplanted, the operation, etc. Finally, discussion and conclusions are provided at the end.
The main purpose and duties of the paper can be summarized as follows:
· To create a general awareness of the rabies disease and to express that it has not disappeared from the world yet contrary to some assumptions and ignorance in public or even medical communities in some developed countries.
· To state that rabies has 100% mortality after onset of clinical symptoms despite the six survivors documented in the literature, and to express that there is no definitive cure of clinical rabies despite some aggressive therapy approach trials, which once enabled a partial recovery of a female teenager.
· To make the medical community aware of the fact that organ and tissue transplants are–perhaps rare–but one clear and undeniable method of rabies transmission.
· To alert the medical community that clinical rabies symptoms can mimic several other diseases or symptoms, and to provide the clinicians with some clues that are helpful to rule out rabies in the diagnosis.
· To clearly indicate that the majority of the patients with human rabies caused by bat Rabies virus variants had no definitive history of a bat bite due to the fact that bats have small teeth and claws.
· To state that at the admission to hospital a human rabies patient may have co-existing diseases or symptoms, which may supersede the rabies symptoms, especially at the prodromal stage of the disease.
· To remind the medical community about the fact that fast resulting rabies intravitam tests do exist, but unfortunately none of them provide an absolute sensitivity.
· To express the necessity of reconsidering and modifying organ transplant procedures.
· To provide a venue for deep critical examination through discussion and conclusions.
RABIES PATHOGENESIS AND CLINICAL SYMPTOMS
Once the exposure to the Rabies virus and transmission occur, the incubation period starts, which is one of the mysteries of rabies. The processes that take place during the incubation period are not fully solved. Several experiments on animals lead to the conclusion that the virus remains at or near the site of exposure during the incubation period. Although the incubation period in humans lasts between 30～50 days on average, it actually has a varying length. Incubation periods of less than a week and on some occasions more than a year–even 5 years -have been reported. There is even one specific case with an incubation period of 19 years and 6 months [23]. The length of the incubation period depends on the following factors:
· The distance of the exposure site to the CNS;
· The severity and dimensions of the wound;
· The amount of virus introduced into the body;
· The immune strength of the individual;
· Whether the site of exposure is rich in nerve cells.
Following the viral replication in muscle within the incubation period, the G protein of the Rabies virus genome binds to nicotinic acetylcholine receptors at the neuromuscular junction [24] towards the end of the incubation period, and the virus travels towards the CNS within motor and sensory axons (via unmyelinated sensory and motor terminals) by retrograde fast axonal transport at a rate of about 50～100 mm per day (centripetal spread) [25]. Neurons are infected in the spinal cord and the virus jumps from neuron to neuron within axons in the CNS up to the brain. Once the brain is infected, finally there is spread of the virus away from the CNS along neuronal pathways(centrifugal spread), which are responsible for infection of the salivary glands, skin, nasal cavities, tears, retina, cornea, heart and some other organs (pancreas, kidney, etc.) [26].
The clinical symptoms can be divided into three stages respectively: prodromal stage, excitation stage, coma stage and death. Even with strong intensive care support, the median period of survival after symptom onset is between 4~21 days. There is a case of a patient, who died 133 days after the onset of symptoms [27].
The prodromal stage typically lasts 2～10 days and is characterized by mild and nonspecific symptoms which can be mistaken for a common cold or flu. These include headache, slight fever, fatigue, sore throat, malaise, nausea, anorexia, cough, and gastrointestinal discomfort. A characteristic symptom suggestive of rabies is burning, itching, tingling or muscle twitching/fasiculations near the site of the bite as the virus multiplies in the sensory nerves from that area within the spinal cord. Very rarely, those symptoms are felt at a site other than the site of the bite [28]. Also, another characteristic symptom at this stage is a slight increase in the libido.
The development of the excitation stage differs in two types of rabies: encephalitic (or furious) rabies and paralytic (or dumb) rabies. The encephalitic rabies occurs in about 80%～85% of the patients and is typically experienced in human rabies caused by stray dog bites. The paralytic rabies covers about 15%～20% of the cases and is mostly experienced after exposures by bats. The excitation stage usually lasts 2～7 days. Paralytic type of patients generally live longer than those suffering from encephalitic rabies. Symptoms of the encephalitic type are periods of confusion, combativeness, anxiety, hallucinations, agitation,apprehension, irritability alternating with periods of calm and normal behavior, as well as periods of depression. At the beginning of the encephalitic excitation stage, the above bizarre symptoms usually last a few minutes, but with the ongoing time the bizarre period lasts longer and the periods of calm behavior are shortened. The patient develops excessive sensitivity to light (photophobia), noise(acousticophobia), touch, gentle breeze (aerophobia), and smell (including garlic) with reaction to these stimuli with facial spasm showing bared teeth. Furthermore, the patient develops hydrophobia resulting in extremely painful, forceful involuntary contractions of upper gastrointestinal, respiratory and diaphragmatic muscles on initiation of swallowing liquids, leading to salivation and the classic “foaming at the mouth”. Even the sight or mention of liquids trigger these muscle spasms. Autonomic dysfunction may also lead to hypersalivation, lacrimation (secretion of tears), perspiration, asymmetrical dilation of constriction of the pupils, absence of corneal reflexes, priapism and spontaneous ejaculation by male patients. It has to be noted that the patient remains fully conscious through the entire excitation stage. The paralytic type however generally lacks the violent symptoms of encephalitic rabies, though occasionally some of the same symptoms occur, such as depression and hydrophobia. This form is characterized by the slow paralysis of the patient, usually starting as a numbness or weakness at the bite site and spreading to the rest of the body over time. Symptoms may include hypertension, tachycardia, confusion, hallucinations and disorientation. Guillain-Barré syndrome like symptoms may also appear.
After leaving the excitation stage, the patient falls into coma stage and death usually occurs as a result of cardiac failure, paralysis (rather encephalitic type) or respiratory failure (rather paralytic type). Sometimes death occurs without coma stage. Among many further clinical features that a human rabies patient experiences once entering the excitation stage, some can be named as cerebral edema, diabetes insipidus, pneumonia, arterial or venous thrombosis, acute renal insufficiency, apnoea, atelectasis, pneumothorax, congestive cardiac failure and cardiac arrest.
PEP treatment window starts immediately with the exposure and lasts until reaching the critical stage inside the incubation period, which does not leave enough time to start a preventive vaccine therapy to let the patient develop neutralising antibodies before the virus attaches itself to the neurons. Once this critical stage is reached or the patient develops the clinical symptoms, the only common method that is widely applied in the management of human rabies is the palliative therapy with strong intensive care support. Furthermore, there is a window for the trial of aggressive therapy approach, which starts immediately after reaching the mentioned critical stage and usually lasts until the end of the prodromal stage or at most up to the very early phases of the excitation stage. Beyond that, not much hopes shall be expected from the aggressive therapy approach, which is assumed to yield more successful results, the earlier it is started.
RABIES TESTS FOR POST-AND ANTEMORTEM DIAGNOSES
Right after the above human rabies incidents, the responsible authorities of the involved transplant centers in USA and Germany made some statements [12, 29, 30] rather reflecting a sudden juridical fear or panic that their transplant centers had a legal fault in the resulting human rabies cases. They either claimed that a diagnosis of a possible rabies infection of the donor in prior to a transplant was impossible, or that such testing for rabies could not be done in a timely fashion for utilization of harvested organs. However, there are several tests for the post-and antemortem diagnoses of rabies in humans.For example, FA test for detection of rabies antigen in brain tissue is a rapid and highly sensitive method for the postmortem diagnosis of rabies in animals and humans. It has become a gold standard technique, which almost never yields false results as long as sufficient sampling is considered. Most of the postmortem tests can also be successfully applied intravitam for antemortem diagnosis of rabies. The only problem is that the success of the intravitam tests greatly depends on the stage of the clinical rabies and that none of these tests commit 100% sensitivity. Especially, our biggest concern is the death of an infected donor in the prodromal stage of the disease, which was most probably the situation in the Germany case.
In the prodromal stage of the clinical symptoms, i.e. in the first few days following the onset of the clinical signs, antigen detection by FA test in corneal impressions or skin biopsies is generally sensitive, however virus neutralizing antibodies in cerebrospinal fluid (CSF) and serum usually tend to appear in the excitation stage of the illness. The overall reliability of the FA test for intravitam diagnosis is limited, as a negative result does not necessarily exclude the possibility of rabies infection. The reliability of rabies antigen detection in skin biopsies is much higher at the later stages of the disease, and the overall sensitivity of FA test is higher with skin biopsies than with corneal impressions [31]. However, not even being at the late stages of the clinical symptoms is a guarantee for 100% sensitivity of any intravitam test, as the Rabies virus may be absent from saliva, biopsies or CSF even during the late stages. As a further intravitam diagnosis method, the so called rapid fluorescent focus inhibition (RFFI) test [31] may be used to measure neutralizing antibodies in the serum or CSF of non-vaccinated patients. Another limited sensitivity, but rapid test is the enzyme-linked immunosorbent assay (ELISA) using purified rabies glycoprotein to determine virus neutralizing antibody levels in the serum [31]. A reverse transcription polymerase chain reaction (RT-PCR) assay of saliva and immunofluorescence (IF) assay of skin sections together yielded high sensitive results in a study for intravitam diagnosis of human rabies [32]. In another study [33], a real-time TaqMan RT-PCR assay was able to detect and genotype Lyssavirus templates in significantly fast manner. Moreover, as the results are obtained in real-time, it is possible to take more rapid and appropriate decisions for the patient management. Table 1 presents a comparison of several
Table 1 Comparison of Some Rabies Intravitam Tests
Note:FA，fluorescent antibody；RFFI，rapid fluorescent focus inhibition；CSF，cerebrospinal fluid；ELISA，enzyme-linked immunosorbent assay；RT-PCR，reverse transcription polymerase chain reaction
aNumber of samples；bThis conclusion is based on references [31, 32]；cThis conclusion is based on references[31, 32, 40]；dThis conclusion is based on references[31, 32]；eThis conclusion is based on references[31, 32 ]；fThis conclusion is based on reference [33]
intravitam tests in terms of speed of yielding the test result and reliability.
One further undeniable reality is that both donors in USA and Germany presented obscure neurological and behavioural symptoms at the admission to hospital, which should have denoted the inclusion of rabies in the diagnosis. The corresponding care teams failed to consider this possibility under the organ transplant procedures and policies at that time. Nevertheless, it would be a very easily said sentence to recommend that the safest strategy is to exclude potential donors with obscure neurological signs and symptoms altogether. There is also the other side of the story. Donor availability and a matching organ are the best news that a potential recipient and his/her care team can get in a long waiting queue. One cannot easily recommend the exclusion. Firstly, the situation greatly differs from location. In regions like USA, Canada or Western & Central Europe, where human rabies cases are extremely rare and exist almost only due to imported cases except a few ones in USA caused by bat Rabies virus variants, the probability of having a rabies infected donor would be extremely low. On the other hand, in countries like India, where almost every 15 minutes someone is dying of rabies, or Thailand, where it is not extraordinary for a clinic to have one or two human rabies cases per week, the probability would be quite high.
As a summary, in view of the above explanations and considering the fact that fast resulting rabies intravitam tests do exist, but none of them provide an absolute sensitivity and that false positive test results would cause many more deaths than transmission of rabies via organ or tissue transplants, if potential donors with obscure neurological signs and symptoms altogether were excluded based on these test results, I do propose an algorithm summarized in Table 2 to play a key safety role for the future prevention of such tragedies. Although this algorithm is recommended in specific cases like presence of a donor with obscure neurological and behavioural symptoms and signs, it can actually be generally applied for all organ and tissue transplant procedures, as there may be some rare cases where a rabies positive donor presents two co-existing neurologic diseases at the admission to hospital, whereas the symptoms of the non-viral or non-harmful disease for the recipient may shadow the clinical symptoms of rabies, especially when the donor is at the prodromal stage of the disease.Furthermore, this algorithm can also be implemented in an adaptive manner, if an observation stage is put at the end, from which later the corresponding transplant center can make its own modifications to the algorithm.
DISCUSSION
First of all, one of the most important factors that led to these human rabies tragedies in USA and Germany was the general public ignorance and low level of awareness of this fatal disease. Otherwise, the male donor in the USA would have sought for PEP after being bitten by bat, or the female donor in Germany would have received either PreEP before travelling to India, which is a large canine rabies endemic nation, or PEP after being bitten by a stray dog there. This public unawareness is especially to be observed in rabies-free territories or countries, where human rabies cases are extremely rare. Rabies has not disappeared from the world and it is still a very killing disease [34]. If there had been enough public awareness, the care teams of both donors would have considered rabies in the diagnosis, when the donors had been admitted to hospital with obscure neurological and behavioural symptoms and signs. The male donor in USA had reported being bitten by a bat, as the Arkansas Department of Health determined as a result of its public health investigation [22]. It is even a fact that the majority of the patients with human rabies caused by bat Rabies virus variants had no definitive history of a bat bite [35, 36] due to the fact that bats have small teeth and claws. Therefore, cases like sleeping person awakening to find a bat in the room, or adult finding a bat in a room with a previously unattended child or mentally disabled or intoxicated person, are indications for rabies exposure suspicion and to start PEP immediately. As it is mostly the case by human rabies caused by bat Rabies virus variants, this donor experienced the paralytic type of clinical symptoms, which lack the violent symptoms of encephalitic rabies, and his care team led to organ transplant tragedies by attributing to non-infectious causes for his death. At his last admission to hospital, computed tomography of the brain demonstrated a subarachnoid hemorrhage [11], but alone the fact that he had reported being bitten by a bat, should be enough for rabies suspicion and supersedes and shadows the reality that there is no evidence that the subarachnoid hemorrhage in the organ donor was related to the rabies infection [37].
He could well have two co-existing neurologic diseases. Moreover, it is worth noting that, especially in the early stages of the clinical symptoms, rabies can mimic many other encephalitides, tetanus, cerebral malaria, rickettsial diseases, poliomyelitis, botulism, simian herpes type B encephalitis, Guillain-Barré syndrome, alcohol withdrawal symptoms, drug or poison intoxication and rabies hysteria. Some clues for clinicians would be that rabies can be ruled out in patients who have an extended duration of illness and whose conditions improve after the onset of symptoms, as otherwise a rabies patient steadily deteriorates until death, as the course of the rabies disease is relentlessly downhill.
A further notable discussion would be the failure of the recent new therapy approach [21], which achieved the survival of a female teenager with neurologic impairment late 2004, by the three of the six organ recipients,who contracted rabies from the female donor in Germany. As mentioned previously, though revolutionary, this new aggressive therapy approach is not a definitive treatment, which would cure all patients developing the clinical rabies regardless of their age, health status, immune strength, presence of any chronic disease, the method of exposure, etc [13]. It is not fully clear and known why the female teenager from Wisconsin survived with this new approach and the role of drugs used in this therapy are a question mark. However, one fact is that those three organ recipients in Germany, who received a similar therapy approach, had also received immunosuppressive therapy to avoid the rejection of transplanted organs, and were already in disadvantage to develop neutralising antibodies for the Rabies virus. Nevertheless, the kidney-pancreas recipient among them had a prolonged survival of 56 days after the onset of symptoms. Moreover, all the three organ recipients were also given interferon-α during their therapies unlike the approach in [21], although it has neurotoxicity.
One last important aspect is that interestingly three further recipients from the same female donor in Germany, both cornea recipients and one liver recipient, did not develop the symptoms and stayed healthy. Once the other three infected recipients developed the clinical rabies, the brain tissue of the donor was examined almost two months after her death and was diagnosed with rabies infection, hence the centrifugal spread of the virus away from the CNS had occurred. However, both transplanted corneas were later found not to be infected with the Rabies virus. The recipients were nevertheless administered rabies PEP and retransplanted new corneas [12]. It is a question mark why the corneas of the donor were not infected by the centrifugal spread, while all other transplanted organs were, i.e. kidneys, lung, pancreas and liver. Although the liver was also infected, the recipient stayed healthy, which was referred by his care team to the fact that as a coincidence he had received PEP almost 15 years ago in his childhood and still had adequate antibody titer, which was confirmed by a test result [38]. Nevertheless, he was administered PEP, after the incidents had come out, and further received a combinational drug therapy.
CONCLUSIONS
More than 100 years after the invention and application of the first rabies vaccine in 1885, human rabies, which ends up with an extremely painful and torturous death, is still a problem in the world. World Health Organization (WHO) reports over 30,000 human deaths per year from rabies, however the actual number including the unreported cases is estimated to be significantly above 60,000 deaths, mostly occuring in India [34]. The literature had already documented eight human rabies cases due to corneal transplants. And in the recent years, a total of seven other organ recipients have died of rabies. Unfortunately, these tragedies can happen again in future, unless organ transplant procedures and strategies will be reevaluated and modified correspondingly, and efforts will be spent to increase the general public awareness of the rabies disease. Some have contemplated the possible utility of testing donor brain in the days after organs have been transplanted and administering PEP to recipients of organs from rabies positive donors. Although there is one example, where the cornea recipient from an infected donor was probably saved through PEP [39], my personal view of such contemplation is:
· It is not ethical to risk it and first infect the recipient with rabies and then provide PEP.
· Organ or tissue transplants from infected donors mostly result in shorter incubation periods at the recipients, who are also generally immunosuppressed to avoid the rejection of transplanted material. Hence, because of shorter incubation period and/or immunosuppression, PEP may not allow the recipient to develop neutralising antibodies timely before the virus attaches itself to the neurons, i.e. when it becomes too late.
· If the possible rabies infection of the donor is diagnosed antemortem through intravitam tests, then also unnecessary costs for the preparation of the recipient/s, removal of organs or tissues to be transplanted, transport of them, the operation, etc. will be cut down.
Obviously, organ and tissue transplant policies and methods shall be modified by enhanced donor screening and testing, and enhanced procedures for storing and tracking the use of donor segments. I believe that applying the proposed algorithm (Table 2) in specific cases like presence of a donor with obscure neurological and behavioural symptoms and signs will be a good safety barrier for the future prevention of such tragedies. Moreover, as mentioned previously, it can be implemented as an adaptive algorithm by observing some parameters with the ongoing time and applying some corresponding modifications later.
Table 2 Safety Algorithm for the Prevention of Human Rabies by Organ and Tissue Transplants
5 RT-PCR:reverse transcription polymerase chain reaction
aA country where the disease is compulsorily notifiable, an effective system of disease surveillance is in operation, all regulatory measures for the prevention and control of rabies have been implemented including effective importation procedures, no case of indigenously acquired rabies infection has been confirmed in man or any animal species during the past two years (this status would not be affected by the isolation of a European Bat Lyssavirus (EBL1 or EBL2), and where no imported case in carnivora has been confirmed outside a quarantine station for the past six months
bA region or country where rabies is present at animal species, but human rabies either occurs due to imported cases, or very rarely due to indigenous rabies mostly caused by bat Rabies virus variants (for example USA)
cA region or country where there are significant number of indigenous human rabies cases per year in addition to rabies at animal species, or large rabies endemic nations (for example India, Thailand)
dThe patient presents obscure neurological and behavioural symptoms and signs and rabies can’t be ruled out
eThe patient still has neurological and behavioural symptoms and signs, but rabies can be mostly ruled out due to some evidences like the patient has an extended duration of illness, or is not steadily deteriorating, or is recovered enough for life support to be removed, if he/she had been placed on it
fThis shall be done in real-time, and some example modifications based on these observations can be taking more risk by reducing the amount of tests at certain steps, considering the impact on donor organ availability through decision-analysis or risk-benefit studies, etc.
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