The flaviviruses Zika virus and WNV are discussed separately as pathogens of special interest in sections Zika Virus and West Nile Virus, respectively. The WHO declaration of global public health emergency in relation to the 2015/2016 Zika outbreak in Brazil and Central America prompted international authorities to develop targeted recommendations for the prevention of Zika transmission via organ and tissue transplantation, and these are discussed in detail in section Zika Virus. West Nile virus is also of special interest given its widespread global distribution and the relatively large number of reported cases of transmission via solid organ transplantation, with frequently fatal outcomes. The risks of donor-derived transmission of other arboviruses appear to be relatively low, and there are limited case reports of transmission events in the published literature. One case of possible donor-derived dengue transmission was reported from Singapore in 2005. The recipient was a 23-year-old male with end-stage kidney disease due to lupus nephritis, who received a living donor kidney transplant from his mother, who was known to have had a history of dengue fever 6 months before donation. Five days posttransplant, the recipient developed a high fever and, given the donor history, NAT was performed and returned a positive result for dengue virus serotype 1. Twelve days posttransplant, the recipient developed upper gastrointestinal bleeding, gross hematuria and tachycardia. Three days later, he complained of left flank pain and abdominal distension, and a large retroperitoneal hematoma at the bed of the transplanted kidney was revealed on computed tomography (CT). Emergency surgery to evacuate the hematoma was successful, and repeat NAT was negative for dengue. The recipient then went on to have an uneventful recovery, with resolution of hematemesis and hematuria and excellent graft function. In this case, the clinical presentation of dengue in the transplant recipient was similar to that in immunocompetent persons but with longer duration:19 days versus mean duration of 2 to 7 days.
European guidelines recommend ruling out acute infection with arboviral diseases including dengue, chikungunya and WNV for donors living in or coming from endemic regions or areas with ongoing outbreaks. In Australia and New Zealand, a similar approach would be warranted: where the donor is a resident of or has a history of travel to an endemic region or area with an ongoing outbreak of arboviral disease, acute infection should ideally be ruled out before proceeding with transplantation.
The lung virome consists of transient infections (influenza, human respiratory virus, etc.) as well as resident viruses that are present in both healthy and disease states. Next-generation sequencing techniques have permitted a new appreciation of the diversity of resident viral species within individuals, a large proportion of which remain uncharacterized. Metagenomic studies of samples from cystic fibrosis patients and lung transplant recipients have found that up to 88% of lung virome sequences were unknown. These studies identified a wide range of bacteriophages, as well as herpes virus, adenovirus, human papillomavirus, and torque teno virus. The complexity of the respiratory virome complicates the diagnosis of the causative agent of disease, because pathogenic viruses may be present among the resident viruses of healthy individuals. In an example of this, a metagenomic study of nasopharyngeal aspirates from febrile versus afebrile children detected rhinovirus in both groups.
To date, there has been a single study characterizing the lung virome of lung transplant recipients. Young et al found that the majority (>68%) of reads that could be mapped to reference viruses mapped to various anelloviruses, including torque teno viruses, torque teno midi viruses, torque teno mini viruses and small anelloviruses (each with multiple subtypes). These anellovirus sequences were 56-fold more abundant in bronchoalveolar lavage (BAL) from transplant recipients compared to healthy controls. Anelloviruses are ubiquitous in humans and have not yet been causally linked to human diseases; however, Young et al also observed that high anellovirus loads correlated with dysbiotic bacterial communities in the allograft, that is, the higher the anellovirus titer, the greater the divergence between the corresponding bacterial community and healthy controls. The cause and clinical implications of this observation are not yet clear. Other viruses detected within the lung virome by this study included EBV, human herpesvirus, human papillomavirus, and various bacteriophage genomes (eg, phages of Enterobacteria, Salmonella, Pseudomonas, Streptococcus, and Yersinia). Notably, an average of 81% of reads could not be mapped to reference viruses in the NCBI viral database. The authors speculate that many of these correspond to DNA phage sequences.
Currently, there are minimal data available on the impact of transplanting the lung virome; however, longitudinal studies are underway and the potential importance of the respiratory virome to outcomes of lung transplantation should be noted. Although next-generation sequencing may be of use for lung donor screening in the future, currently, for practical purposes, viral testing of the donor before implantation and BAL postimplantation will capture most viruses provided that samples are properly handled (personal communication A Glanville).
Donors with undiagnosed meningoencephalitis are an uncommon but potentially lethal source of donor-derived infection. Transmission of rabies, LCMV, WNV, Mycobacterium tuberculosis, Cryptococcus, Coccidiodes immitis, Aspergillums, and Balamuthia have occurred when donors with meningitis or encephalitis of unknown cause have been used as organ donors. For this reason, any meningitis or encephalitis without a proven cause should be an absolute contraindication to transplantation, according to the international guidelines.
Recognition of transmissible infections in potential deceased donors with meningoencephalitis is often complicated by the circumstances of brain death, which might not raise the suspicion of the presence of a central nervous system infection, for example, stroke in the case of a patient with amoebic encephalitis, or cocaine use in a patient with intracerebral hemorrhage who had rabies. Distinguishing between such ubiquitous causes of death in potential donors as anoxia, head trauma, or cerebrovascular accident and a potentially transmissible central nervous system infection is extremely difficult. In addition, many of these pathogens are not part of routine donor screening in Australia and New Zealand (or elsewhere) and, therefore, would not be detected as part of a standard donor evaluation. Based on reporting to the United States OPTN Ad Hoc Disease Transmission Advisory Committee, the most common diagnoses for central nervous system infections in deceased donors were tuberculosis, endemic fungi, cryptococcosis, coccidiomycosis, and WNV, followed by syphilis, histoplasmosis, toxoplasmosis, and Chagas disease.
In some cases, donors diagnosed with treatable forms of meningoencephalitis might be safely used for organ transplantation after a suitable period of antimicrobial treatment for the donor and the recipient. Donors with meningoencephalitis of viral origin other than HSV or VZV, however, present an extremely high risk for disease transmission. If the pathogen in unknown or if the suspected pathogen is one for which no treatment options are available, transplantation should be avoided or pursued with extreme caution only after weighing the risks of adverse recipient outcomes with the risks of waiting for another organ. Where the cause of the meningoencephalitis is confirmed as a virus that is amenable to treatment, for example, HSV encephalitis, the organs might be used if the donor is not viremic and provided that the recipient is seropositive pretransplant and/or is given appropriate prophylaxis. Meningitis of bacterial origin is discussed in the Bacteremia and Meningitis section, and WNV is discussed as a special case in the West Nile Virus section.
Published reports of transmission events from donors with unrecognized central nervous system infections highlight the extreme risks associated with such donors, as well as the challenges of recognizing central nervous system infection. In 2004, 4 recipients of organs from a single donor died of encephalitis of unknown cause shortly after transplantation. The donor in this case had presented to the emergency department with nausea, vomiting and difficulty swallowing. He was subsequently admitted to a second hospital with altered mental status requiring intubation, with a fever and fluctuating blood pressures. His toxicology screen was positive for cocaine and marijuana, and a CT of the brain revealed a subarachnoid hemorrhage, which progressed to brain death 4 days after admission. Standard donor screening did not reveal any infection precluding organ donation, and the donor's kidneys, liver and lungs were retrieved for transplantation. Encephalitis developed in all 4 patients within 30 days of transplantation and was accompanied by rapid neurologic deterioration and death an average of 13 days after the onset of symptoms:rabies was subsequently confirmed in all of the organ recipients. Contact investigations revealed that the donor had been bitten by a bat shortly before becoming ill.