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Clinical Microbiology Reviews, January 2008, p. 60-96, Vol. 21, No. 1
0893-8512/08/$08.00+0 doi:10.1128/CMR.00021-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Transmission of Tropical and Geographically Restricted Infections during Solid-Organ Transplantation
P. Martín-Dávila,1,2* J. Fortún,1,2 R. López-Vélez,1,3 F. Norman,3 M. Montes de Oca,3 P. Zamarrón,3 M. I. González,3 A. Moreno,4 T. Pumarola,5 G. Garrido,6 A. Candela,7 and S. Moreno1Infectious Diseases Department, Ramon y Cajal Hospital, Madrid, Spain,1 Transplant Infectious Diseases Team, Ramon y Cajal Hospital, Madrid, Spain,2 Tropical and Travel Medicine Unit, Ramon y Cajal Hospital, Madrid, Spain,3 Infectious Diseases Department, Clinic Hospital, Barcelona, Spain,4 Microbiology Department, Clinic Hospital, Barcelona, Spain,5 Spanish Transplantation Network, Madrid, Spain,6 Anaesthesiology Department, Transplant Program, Ramon y Cajal Hospital, Madrid, Spain7
SUMMARY INTRODUCTION Tropical and Geographically Restricted Infectious Diseases and Organ Transplantation VIRAL INFECTIONS Infections Caused by HTLV-1/2 Illnesses. (i) ATL. (ii) TSP. Geographic distribution. Diagnostic methods. Routes of transmission. Transplant-related cases. (i) Seroprevalence. (ii) Type of organ transplanted, exposure to blood transfusions, and viral characteristics. (iii) Influence of immunosuppression. Recommendations. Infections Caused by West Nile Virus Geographic distribution. Diagnostic methods. Routes of transmission. Transplant-related cases. Recommendations. Infections Caused by Rabies Virus Geographic distribution. Diagnostic methods. Routes of transmission. Transplant-related cases. Recommendations. FUNGAL INFECTIONS Infections Caused by Coccidioides immitis Geographic distribution. Diagnostic methods. Routes of transmission. Transplant-related cases. Recommendations. Infections Caused by Histoplasma capsulatum Geographic distribution. Diagnostic methods. Routes of transmission. Transplant-related cases. Recommendations. Other Regional Fungal Infections Infections caused by Paracoccidioides brasiliensis. Infections caused by Blastomyces dermatitidis. Infections caused by Penicillium marneffei. PARASITIC INFECTIONS Infections Caused by Plasmodium spp. Geographic distribution. Diagnostic methods. Routes of transmission. Transplant-related cases. Recommendations. Infections Caused by Leishmania spp. Geographic distribution. Diagnostic methods. Routes of transmission. Transplant-related cases. Recommendations. Infections Caused by Trypanosoma cruzi Geographic distribution. Diagnostic methods. (i) Parasitological methods. (ii) Serological methods. (iii) Molecular diagnosis. Routes of transmission. Transplant-related cases. (i) Reactivation. (ii) Transmission via graft. Recommendations. Infections Caused by Strongyloides stercoralis Geographic distribution. Diagnostic methods. Routes of transmission. Transplant-related cases. Recommendations. Infections Caused by Filariae Geographic distribution. Diagnostic methods. Routes of transmission. Transplant-related cases. Recommendations. Infections Caused by Echinococcus spp. Geographic distribution. Diagnostic methods. Routes of transmission. Transplant-related cases. (i) Infections caused by E. granulosus (cystic echinococcosis). (ii) Infections caused by E. multilocularis (alveolar echinococcosis). Recommendations. (i) Cystic echinococcosis. (ii) Alveolar echinococcosis. Infections Caused by Trematodes Geographic distribution. Diagnostic methods. Routes of transmission. Transplant-related cases. (i) Schistosoma spp. (ii) Clonorchis spp. (iii) Other species Recommendations. Other Parasitic Infections Infections caused by Babesia spp. Infections caused by Entamoeba histolytica (amebiasis). Infections caused by free-living amebae. Infections caused by Trypanosoma brucei. Infections caused by Taenia solium (cysticercosis). CONCLUSIONS ACKNOWLEDGMENTS REFERENCES
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In recent years, the increasing number of donors from different regions of the world is providing a new challenge for the management and selection of suitable donors. This is a worldwide problem in most countries with transplantation programs, especially due to the increase in immigration and international travel. This paper elaborates recommendations regarding the selection criteria for donors from foreign countries who could potentially transmit tropical or geographically restricted infections to solid-organ transplant recipients. For this purpose, an extensive review of the medical literature focusing on viral, fungal, and parasitic infections that could be transmitted during transplantation from donors who have lived or traveled in countries where these infections are endemic has been performed, with special emphasis on tropical and imported infections. The review also includes cases described in the literature as well as risks of transmission during transplantation, microbiological tests available, and recommendations for each infection. A table listing different infectious agents with their geographic distributions and specific recommendations is included.
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We are living in an increasingly globalized world in which people have a greater capacity for travel than at any previous time in history. Massive tourist movements, international migration, and increases in world commercial exchanges act as important underlying factors for the emergence and reemergence of specific infectious diseases. The American Centers for Disease Control and Prevention (CDC) have targeted diseases affecting travelers, immigrants, and refugees for the prevention of emerging infectious diseases in the near future (62).
According to the United Nations World Tourism Organization, during 2005, international tourist arrivals worldwide beat all expectations, exceeding 800 million and achieving an all-time record, representing an increase of 42 million compared with previous years. Current predictions for the year 2020 suggest that these figures will reach 1.56 billion. At present, the increase in tourism is most marked in East Asia, the Pacific, South Asia, the Middle East, and Africa, with rates of increase of over 5% per year, compared to the world average of 4.1%. Among the 40 countries in the world that receive the most travelers per year, there are at least 10 countries in tropical and subtropical areas, where the risk of contracting a tropical infection is high (374).
Migration is considered to be one of the defining global issues of the early 21st century. The International Organization for Migration (189) estimated the migrant population worldwide to be 191 million in the year 2005, representing around 3% of the world's population. Between 1965 and 1990, the number of international migrants increased by 45 million, an annual growth rate of about 2.1%. The current annual growth rate is about 2.9%. There are 56.1 million immigrants in Europe (including Russia), 49.9 million in Asia, and 40.8 million in North America; the three countries hosting the largest numbers of international migrants in 2000 were the United States (35.0 million), the Russian Federation (13.0 million), and Germany (7.3 million). There are countries that traditionally have taken in large numbers of immigrants, such as Canada, the United States, and Australia, but nowadays, there are other new countries of destination such as Ireland, Italy, Norway, Portugal, and Spain. The developed world has already entered an era of labor shortage: in Europe alone, the workforce is expected to decline by another 20 million by the year 2030, and there are similar forecasts for other developed regions including countries like Japan, South Korea, and the Russian Federation. The future global work force will be drawn largely from developing countries where tropical infections may be present.
Even though immigrants and travelers may import a wide variety of tropical pathogens, the possibility of dissemination in the Western community is small, as environmental conditions, intermediate hosts, and the specific vectors required are absent. The majority of imported parasitic tropical infections tend to disappear after 3 to 5 years, but some, such as strongyloidiasis and Chagas’ disease, may persist for decades. Nonparasitic diseases may also manifest many years after infection, as is the case for histoplasmosis and human T-cell lymphotropic virus type 1 (HTLV-1) infection.
As a consequence of immunosuppression, microorganisms may become opportunistic, commensals may become pathogens, poorly pathogenic organisms may behave aggressively or in an aberrant fashion, and patients may respond poorly to treatment. As well as possible transmission via blood products, organ transplant recipients may acquire significant tropical diseases in four ways: transmission with the graft (e.g., HTLV-1), de novo infection (e.g., visceral leishmaniasis), reactivation of dormant infection (e.g., histoplasmosis), and reinfection/reactivation in a healthy graft (e.g., Chagas’ disease).
The current situation in Spain may illustrate what may occur in other countries in the near future. In recent years, Spain has received a large unexpected influx of immigrants. Of the 44 million inhabitants in Spain, approximately 4 million are of foreign origin (around 9%), and these figures increase to up to 12% in main cities such as Madrid and Barcelona. Out of approximately 1,500 transplants performed in Spain during the year 2006, 10% were from foreign donors (up to 19% in the main cities), and the percentage of foreign recipients was 3% (up to 9% in the main cities). Nearly 40% of foreign donors and recipients were of Latin American origin, originating from countries where the transmission of Chagas’ disease, among others, may occur. This led to changes in the criteria for donor selection regarding possible transmission of infections (set by the Spanish National Organization for Transplantation). Screening of blood and organ donors with epidemiological risk factors for Chagas’ disease is now mandatory according to Spanish law.
Commercial transplantation is another emerging phenomenon. In Western countries, economic compensation for donation is prohibited. However, patients with end-stage organ disease and without a suitable donor may choose to acquire organs such as kidneys from live donors or even livers from executed prisoners from other countries. Once again, the issue of imported/tropical infections complicating the transplantation process may be raised.
Several guidelines for pretransplant screening have been published recently, including a consensus conference on the immunocompromised patient, the American Society for Transplantation clinical practice guidelines on the evaluation of renal transplant candidates, and the American Society of Transplant Physicians clinical practice guidelines on the evaluation of living renal transplant donors (6, 201). In addition, the CDC, the Infectious Disease Society of America, and the American Society for Blood and Marrow Transplantation have published guidelines for the prevention of infection in hematopoietic transplant recipients (63). A concise review of parasitic infections in transplant patients has also been published (20). All these guidelines include a wide range of the most important infectious agents related to transplantation and the implications for transmission and reactivation. However, these recommendations could be insufficient with respect to specific geographic/endemic agents. In recent years, the role of these microorganisms has increased as a consequence of travel and migration of populations, and these factors should also be considered when both donors and recipients are assessed.
Health professionals working in the field of transplantation will become increasingly involved in the management of donors and recipients from tropical and other geographic areas where certain infections are endemic. Protocols that include screening for these pathogens in the donor may prevent transmission during transplantation. Early identification of infection in the recipient and prompt notification of the other transplant centers involved could prevent complications for other recipients in the case of multiorgan donation.
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HTLV-1 is a double-stranded, enveloped RNA virus (family Retroviridae, subfamily Oncovirus), which belongs to a group of retroviruses known as the leukemia/lymphoma T-cell viruses of primates. HTLV-1 has a global homology of 65% with HTLV-2. It is a virus that exhibits T-cell tropism, causes the proliferation of T cells, and has a tendency to produce persistent infection. HTLV-1 and -2 infections are lifelong infections (232).
HTLV-1 has been implicated in the pathogenesis of adult T-cell lymphoma/leukemia (ATL) and a progressive neurological disease known as tropical spastic paraparesis (TSP) or HTLV-1-associated myelopathy (HAM). In the general population, the time from infection to the appearance of disease may be prolonged, an estimated mean of 20 years, and the risks for patients of developing one of these two illnesses at some point during their lives are 2 to 5% for ATL (263) and 1 to 2% for TSP (239, 299, 304).
Illnesses. (i) ATL. ATL is a non-Hodgkin's mature T-cell lymphoma that has an initial leukemic phase. The disease develops after a long incubation period. ATL occurs mostly in adults at least 20 to 30 years after infection with HTLV-1. The acute form of ATL comprises 55 to 75% of all ATL cases (155, 408, 409). The distribution of the various subtypes varies geographically. The median survival for patients with the acute subtype is less than a year.
(ii) TSP. TSP, designated HAM/TSP by a WHO working group, is characterized by a slowly progressive spastic paraparesis due to white matter degeneration and fibrosis of the thoracic spinal cord (191, 192). HAM/TSP typically develops in up to 4% of HTLV-1-infected patients (273). The majority of individuals are diagnosed in the fourth or fifth decade of life.
In contrast with HTLV-1, there is no definite association between HTLV-2 and any human disease. Isolated cases of TSP-like illness, mycosis fungoides, and lymphocytic leukemia have been reported in patients with HTLV-2 infection (315-317, 422).
Geographic distribution. Although the exact number of HTLV-1-seropositive individuals in the world is not known, it is estimated that up to 15 to 20 million people may be infected (102). The seroprevalence rates differ according to the geographic area, the sociodemographic characteristics of the population studied, and individual risk behaviors (Table 1 and Fig. 1).
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TABLE 1. Geographic distribution of infectious agents
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FIG. 1. World map with geographic distribution (used for Table 1). Note that this map shows a geographic distribution of pathogens as used in Table 1 and does not represent a political distribution.
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The seroprevalence rate for low-risk patients in Europe and the United States is <1%. In areas where the disease is not endemic, such as Europe and North America, HTLV-1 infection is found mainly in immigrants, their offspring and sexual contacts, sex workers, and intravenous drug users (IVDU). Among blood donors in North America and Europe, the seroprevalence is very low, ranging from 0.01 to 0.03% in the United States and Canada (80, 264, 399) to 0.002% in Norway (350) and 0.0056% in Greece (370).
HTLV-2 has been described mainly in IVDU and their sexual contacts as well as in populations of native Amerindians. The infection has been found to be endemic in IVDU populations of the United States, Europe, South America (Brazil), and Southeast Asia (Vietnam) (115, 163, 298, 299).
Diagnostic methods. Following HTLV-1 infection, there is an incubation period of 30 to 90 days prior to seroconversion. HTLV antibody detection is mainly used for diagnosis. Following seroconversion, antibodies persist for life. The serological responses to HTLV-1 and -2 are similar, and specialized tests are needed to differentiate between the two viruses.
The most commonly used serological tests are the enzymatic immunoassays (EIA) prepared with the lysed antigens of the intact HTLV-1 virus. The sensitivities of these methods vary, so samples that test positive initially are retested in order to decrease technical errors. Samples that test positive on two occasions are considered to be reactive. If the sample is reactive using one test only, it is deemed nonreactive. Methods based on immunofluorescent antibodies tests (IFATs) do not distinguish between specific HTLV-1 and -2 antibodies and gene products.
There are additional tests based on Western blot (WB) or radioimmunoprecipitation techniques that facilitate the correct interpretation of reactive samples. These tests can identify antibodies against core (gag) and envelope (env) proteins of HTLV-1 and -2. In order to consider a result a true positive, specimens that are repeatedly reactive using enzyme-linked immunosorbent assay (ELISA) must show immunoreactivity for the gag gene products (p24) and envelope products (gp46 and/or gp61/gp68). WB is the most sensitive confirmatory assay for the detection of antibodies against the gag gene proteins p19, p24, and p28, whereas radioimmunoprecipitation assay-based techniques are more sensitive for the detection of antibodies against glycoproteins gp46 and gp61/gp68. Serum samples that do not meet these criteria but that have immunoreactivity towards at least one of the HTLV gene products (only p19, p19 and p28, or p19 and Env) should be considered to be indeterminate. Serum samples with no immunoreactivity towards HTLV-1 gene products should be considered to be negative (77).
False-positive HTLV-1 EIA results (with negative confirmatory WB results) may be caused by many factors such as the prior use of influenza virus vaccine, some bacterial infections, autoimmune disorders, and multiple pregnancies (61, 74, 235). The majority of nonspecific EIA reactions (59%) are caused by reactivity to HTLV envelope glycoprotein gp21 (230).
PCR nucleic acid sequence-based amplification testing (NAT) or transcription-mediated amplification-based studies could potentially be more specific in identifying false-positive donors. However, currently, there is no commercially available NAT with a turnaround time that would be short enough to solve the problem of donors who are HTLV reactive by EIA. A potential solution would be the development of a commercial NAT multiplex assay that could simultaneously detect hepatitis B and C viruses, human immunodeficiency virus (HIV), and HTLV (421).
Routes of transmission. HTLV-1 can be transmitted through sexual contact and infected blood products, vertically from mother to child, and during transplantation.
Intravenous exposure to blood seems to be the most efficient mode of HTLV-1 transmission. High risk is associated with the transfusion of infected products containing various types of blood cells (packed red cells, whole blood, and platelets) compared to plasma products (240). Cold storage of blood lowers the risk of transmission, presumably due to the death of HTLV-1-infected lymphocytes (106). The risk of seroconversion after transfusion of HTLV-1-contaminated blood products ranges from 40 to 60%, with a time interval before seroconversion of 51 to 65 days after transfusion (240, 271).
Sharing of contaminated needles and syringes by IVDU is another important mode of transmission of HTLV-1 and -2 (115, 205).
Several cases of transmission through organ and bone marrow transplantation have also been described (121, 140, 194, 252, 307, 366). Most cases have occurred in renal transplant patients. In certain cases, the exact route of transmission was difficult to establish, as patients had undergone hemodialysis and lived in areas of endemicity in which seroprevalence was high. In Japan, the proportion of renal transplant patients who are HTLV-1 carriers has been estimated to be around 12%, compared with only 1.2% of the general population (188, 406, 409). The transmission in some of the cases may have been through an infected blood transfusion, as screening of blood was not compulsory in Japan before 1989.
Transplant-related cases. Factors that determine risk of infection with HTLV-1/2 in transplant recipients are as follows (413).
(i) Seroprevalence. In U.S. blood donors, the seroprevalence of HTLV-1 has been determined to be between 0.035 to 0.046%. Surveys of HTLV seroprevalence among blood and tissue donors may not, however, be representative of the seroprevalence among organ donors. Based on the United Network for Organ Sharing data from 1988 to 2000, Shames et al. (335a) reported that the prevalence of HTLV-1 infection in organ donors was 0.027% and that the prevalence of HTLV-2 was 0.064%. However, in another report, Nowicki et al. (269) presented data accumulated during testing of all prospective 1,408 cadaveric organ donors between 2002 and 2003: there were 1.56% donors that were repeatedly reactive by HTLV-1/2 EIA (40% were African American, 20% were Hispanic, and 40% were Caucasian). Approximately 29% of EIA-reactive samples from donors were not confirmed by WB, and another 35% had indeterminate results. Most of the confirmed anti-HTLV-positive donors were positive for HTLV-2-specific antibodies.
Many studies suggest that cases of HTLV in countries with a low seroprevalence are restricted to patients originating from areas of endemicity (HTLV-1), IVDU, and commercial sex workers (HTLV-2). In Spain, a national survey in which 1,298 organ transplant donors and 493 potential recipients were tested for anti-HTLV antibodies was conducted. Of these individuals, none were found to be seropositive for HTLV-1. Only one recipient, a former IVDU, was found to be infected with HTLV-2. In a different survey, HTLV screening of 1,079 immigrants was conducted, and 0.5% were found to be asymptomatic HTLV-1 carriers. All carriers came from areas where HTLV-1 is endemic. No cases of HTLV-2 infection were found among immigrants (365).
(ii) Type of organ transplanted, exposure to blood transfusions, and viral characteristics. Transmission occurs through infected cell products: the risk increases in correlation with the number of leukocytes that are present and decreases with prolonged preservation time.
The mechanisms by which the virus causes disease remain unclear, but a combination of environmental, host, and viral factors may all play a role. Morbidity has been linked to the presence of proviral DNA load and may vary depending on different strains of the virus. The duration of the latency period remains unknown but may be decreased in transplant patients, possibly due to the greater inoculum of the virus transmitted by this method (366).
(iii) Influence of immunosuppression. The possible influence of immunosuppression on disease development remains unclear. Immune suppression in transplanted patients may favor the rapid increase of HTLV-1 proviral DNA and is believed to alter the course of HTLV-1 infection in asymptomatic carriers following transplantation. Several cases of ATL in HTLV-1-positive recipients following transplantation have been reported (371, 415). However, two prospective studies conducted among 31 HTLV-1-positive Japanese recipients of kidney allografts have not recorded any cases of HTLV-1-related diseases after an average follow-up of 8 to 10 years (266, 357). Those studies concluded that immune suppression does not seem to favor the development of ATL or TSP.
Several transplant-related cases of HTLV infection have been reported, especially in countries with high seroprevalence rates. In certain cases, transmission was more closely linked to procedures associated with transplantation, such as the need for blood transfusion, than actual infection via the graft (143, 186, 194). In renal transplant patients who developed HTLV-1-associated lymphoproliferative disorders, another possible route of acquisition could have been during hemodialysis (177).
In a report by Gout et al. (143), a 41-year-old male who underwent a heart transplant and received several blood transfusions later developed subacute myelopathy. It was discovered that he had been infected with HTLV-1 from one of the blood transfusions. Remesar et al., who described the transmission of HTLV-1 from a 35-year-old mother to her daughter, reported the first incident of HTLV-1 transmission by organ transplantation (307). The patient was originally from Argentina (a low-seroprevalence area) and had received a kidney graft from her mother. Seroconversion for HTLV-1 was documented 83 days posttransplantation. The infected recipient remained asymptomatic after 4 years of follow-up (307).
In another case reported by Nakatsuji et al. (267), a cadaveric renal transplant recipient developed TSP 4 years after transplantation. At diagnosis, the recipient's serological studies (ELISA and WB) showed antibodies against HTLV-1. There was no history of blood transfusion before or after transplantation. Serology had been negative prior to transplantation, and donor screening was not performed (267). Transmission was believed to have occurred via renal graft transplantation.
Toro et al. (366) reported the transmission of HTLV-1 to three organ transplant recipients from a single donor (two kidneys and one liver) in 2003. Less than 2 years after transplantation, all three recipients developed subacute myelopathy. The donor had been infected by vertical transmission from his mother, who was originally from Venezuela, where seroprevalence is 0.39%. The rapid development of the disease was linked to the high viral inoculum transmitted during the transplantation procedure, the particular virulence of the strain, and the situation of immune suppression of the patients (366). Following this, another report described the development of ATL in another recipient from the same donor (140).
Recommendations. The majority of organ procurement organizations have a policy of rejecting organs from HTLV-1/2-positive donors. The risk of HTLV-1 transmission during solid-organ transplantation (SOT) has been documented (99).
Policies regarding screening recommendations with respect to HTLV-1/2 are different in every country. During the donor suitability evaluation, the determination of donor HTLV-1/2 status is based primarily on the results obtained from EIA. Confirmatory HTLV testing is not always readily available and requires additional time. The timely performance of a confirmatory assay for HTLV may save organ donations from being rejected because of a false-positive screening test. However, long delays in confirmatory testing performed by commercial laboratories may also lead to the loss of grafts. In a survey performed in 1996 by the Organ Procurement Organization in the United States, only 65% of laboratories had routinely performed confirmatory testing for HTLV (105).
Current United Network for Organ Sharing regulations state that members shall not knowingly participate in the transplantation or sharing of organs from donors who are confirmed to be positive for HTLV-1 antibody by an FDA-licensed screening test unless subsequent confirmation testing unequivocally indicates that the original test results were falsely positive (204).
The decision to reject organs from seropositive patients has greater relevance in countries where these diseases are endemic. The criteria outlined by the Japanese Transplant Organization, for example, lead to the rejection of organs from HTLV-1-seropositive patients even if the recipient is seropositive. Based on these criteria, 3 to 5% of potential donors are excluded.
In other countries with low seroprevalence of HTLV-1 and -2, like Spain, the current policy of mandatory testing of anti-HTLV antibodies is applied only to organ donors coming from areas where HTLV-1 is endemic or with a high suspicion of HTLV-1 infection (364).
Taking the changes in migration trends that are occurring into account, there has been a consequent increase in potential donors from areas of endemicity residing in countries where transplant programs exist. Foreign donors with a risk of infection may be difficult to identify, especially if HTLV has been transmitted vertically or sexually. Seroprevalence studies should be performed in order to evaluate possible changes in HTLV-1/2 screening policies, especially if these tests are restricted to donors deemed to be at high risk.
Screening of blood donor candidates has been shown to be an effective strategy in preventing HTLV-1 transmission. Many countries in areas of endemicity have implemented systematic and permanent screening of all blood donors. In nonendemic areas, reports have shown that the risk of HTLV-1 infection might be enhanced in some selected donor populations, and the implementation of policies for selective donor recruitment has been recommended (297).
West Nile virus (WNV) is an arthropod-borne virus that belongs to the Japanese encephalitis complex of Flaviviridae. It is a lipid-enveloped, single-stranded RNA virus. WNV infection is associated with human encephalitis and meningitis. It is transmitted primarily in birds through mosquito bites, while humans are incidental hosts. Incidental mosquito-borne infection may also occur in other mammals including horses, cats, and other domestic animals.
The preclinical incubation period ranges from 2 to 14 days following the bite of an infected mosquito. Although most individuals with WNV remain asymptomatic, approximately 20% of those infected will develop mild symptoms, often indistinguishable from other viral infections, which may last between 3 and 6 days. A transient WNV viremia occurs within 1 to 3 days after infection and lasts 1 to 11 days (with a mean of 6 days). Longer periods of viremia have been noted in some patients with advanced malignancies or taking immunosuppressive drugs (292). Recently, viremia in asymptomatic donors has been shown to persist for longer periods of time (up to 104 days). There is a greater incidence of encephalitis than meningitis, which develops in around 1 in 150 infected patients (294, 333, 334). Elderly patients have been shown to be at greater risk of developing severe neurological disease.
Geographic distribution. WNV was first isolated and identified from a patient infected in the West Nile district of Uganda in 1937 (293). The virus has a widespread distribution in Africa, Asia, the Middle East, and Europe. Human and equine WNV outbreaks in Romania (369), Russia, Israel (387), Italy, and Tunisia (181, 418) from 1996 to 2000 have also been reported.
WNV was first detected in the Western Hemisphere in 1999 during an epizootic outbreak among birds and horses and a meningitis and encephalitis epidemic in humans in the New York City area (70, 292, 323). Over the next 5 years, the virus spread across states of the continental United States, north into Canada, and southward into the Caribbean Islands and Latin America (212).
In the United States, the 2002 epidemic of WNV neuroinvasive disease was the largest ever reported. Between 1999 and 2004, more than 16,000 cases of WNV infection were reported in the United States, with more than 7,000 cases of neuroinvasive disease (161). During 2006, 3,830 infections were identified: 35% had neuroinvasive manifestations, and 3% resulted in death (68).
The incidence of WNV disease is seasonal in the temperate zones of North America, Europe, and the Mediterranean Basin, with peak activity from July through October. In the United States, the transmission season has lengthened as the virus has moved south; in 2003, the onset of human illness began as late as December, and in 2004, it began as early as April (CDC, unpublished data). WNV activity in birds and mosquitoes has been documented year round in states with warm winter climates. Human infection in these areas is therefore a theoretical risk at all times of the year. Transmission of WNV in southern Africa and transmission of Kunjin virus in Australia increase in the early months of the year after heavy spring and summer rainfalls (160).
Diagnostic methods. The most effective method for detecting the infection is the measurement of immunoglobulin M (IgM) antibodies in serum or cerebrospinal fluid (CSF). In documented outbreaks, over 90% of the cases had positive IgM serology, which usually becomes detectable 1 week after infection. The antigenic similarities among viruses of the flavivirus group may cause patients who have been recently vaccinated against yellow fever virus or Japanese encephalitis virus and those who have been recently infected with a related flavivirus to have a positive WNV IgM result (197, 338).
The majority of patients are asymptomatic, and IgM may be detectable for up to 6 months after infection, so an increase in titers between the acute and convalescent phases is needed to confirm acute infection (314).
In order to determine the specificity of antibodies to WNV, serum samples that test positive by ELISA should also be tested by plaque reduction neutralization tests, which are specific for arthropod-borne flaviviruses (388). The detection of viral antigens or nucleic acid in CSF, tissue samples, blood, and other organic fluids is also possible.
Routes of transmission. Cases of human-to-human transmission have been reported in association with blood transfusions and through organ transplantation.
Recent cases of severe encephalitis due to WNV have been described in patients who have received blood transfusions (159, 348), and the CDC and FDA have investigated cases of possible transmission via blood transfusion or organ transplantation (65, 69). During the WNV outbreak that occurred between 2002 and 2003, the CDC received reports of 61 possible cases of transfusion-transmitted WNV infection. Epidemiological studies and testing of available retained donor blood samples demonstrated that blood transfusion was the confirmed source of WNV infection in 23 of these cases, with 19 cases being inconclusive (285). Forty-three percent occurred in patients who were immunosuppressed due to transplantation or cancer. Of these 23 documented cases, 16 donors who had transmitted the infection were identified. Only nine of these cases recalled symptoms suggestive of WNV infection. Serological studies of serum samples obtained at the time of transmission were negative in all of the 16 donors, showing that serology is not useful in detecting potentially infectious (viremic) patients.
During 2003, an additional 23 suspected cases of transfusion-associated WNV infection were reported to the CDC: 6 cases were classified as being confirmed/probable transfusion-transmitted WNV, 11 were noncases, and 6 were unresolved cases (72). A study containing the latest information on WNV transfusion-associated cases between 2003 and 2005 was reported recently by Montgomery et al. (253).
Transplant-related cases. Several cases of WNV transmission through SOT have been described (67, 190, 216). Serological and clinical studies indicate that organ transplant recipients have a risk approximately 40 times that of the general population for neuroinvasive disease after WNV infection. Recipients of infected organs and other immunosuppressed patients typically have prolonged WNV incubation periods during which asymptomatic viremia can be detected, and there may also be a delayed antibody response (190).
The first organ-donor-associated WNV transmission was reported in 2002 (190). Four recipients from the same donor developed fever and neurological symptoms in the posttransplant period, and WNV infection was suspected. The donor had no relevant past medical history and had died due to severe trauma after receiving multiple transfusions from 64 different donors. The heart, liver, and both kidneys were transplanted. All four recipients presented fever and neurological symptoms an average of 15 to 18 days posttransplantation. Three of the four recipients had encephalitis, and one died. Three patients had positive serology for WNV, and in the fourth recipient, WNV was detected in cerebral tissue using nucleic acid and antigen detection techniques as well as viral isolation. Serology was found to be negative for the organ donor before and immediately after receiving the blood transfusions, but samples obtained during the transplantation procedure were positive using nucleic acid detection techniques and viral culture. Transmission was attributed to the transfusion of WNV-positive blood received by the donor the day before organ recovery (69, 71, 190).
Following these cases, others have been reported in the context of organ transplantation. In September 2005, the CDC reported that WNV infection was confirmed in three of four recipients of organs transplanted from a common donor (67). Two recipients subsequently developed neuroinvasive disease, one recipient had asymptomatic WNV infection, and the fourth recipient was apparently not infected. Serum and plasma collected from the donor were retrieved. The samples tested positive for WNV IgM antibodies and IgG by EIA but were negative for WNV RNA by PCR. The organ donor was thought to have been infected via a mosquito bite rather than through a blood transfusion, and a serum sample obtained 1 day before the organs were retrieved had WNV IgM and IgG antibodies but was PCR negative. The lung and liver transplant recipients had severe WNV encephalitis and acute flaccid paralysis with respiratory failure. One kidney recipient had a positive PCR test result in serum 22 days after transplantation and remained asymptomatic, and the other kidney recipient had no evidence of WNV infection (67).
Other articles have reported cases of WNV infection occurring in SOT recipients (12, 15, 44, 101, 158, 210, 215, 265, 305, 337, 383). Most of these cases were community-acquired (de novo) infections or had been acquired through infected blood products. The majority of these patients developed severe neurological disease, and the fatality rate was high, especially in those recipients with more intense immunosuppressive regimens.
Recommendations. The prevention of transfusion-transmitted WNV infection is based on the exclusion of viremic patients. The following factors have raised concerns regarding the safety of the blood supply: (i) most WNV infections are asymptomatic, and thus, viremic donors could not be identified prior to donation; (ii) the estimated risk in epidemic areas could be as high as 2 to 3 cases per 10,000 donors; and (iii) a high incidence of mortality was seen in transfusion recipients. To decrease the risk of transmission, different organizations have elaborated recommendations based on the implementation of more refined donor selection criteria, the quarantine period of blood products, as well as the development and implementation of a test for WNV RNA to screen the blood supply (200, 376).
Screening tests based on specific antibody detection are not useful, as these antibodies appear 1 to 2 weeks after the infection. Screening methods should be based on the detection of nucleic acids (NAT), as antibodies usually appear after the period of viremia. Donor blood could be screened with WNV NAT with a mini-pooled-testing format (52). Routine donor screening using the test kits was implemented in July 2003. Despite the efficacy of this assay, six recipients were infected through blood transfusion in 2003, indicating that the risk of acquiring infection from tainted blood components was not completely eliminated by mini-pooled NAT screening (66).
Organ donors are screened to identify infectious risk on the basis of national organ procurement standards, which are reevaluated continuously. In January 2004, the Health Resources and Services Administration in the United States issued a statement concerning WNV, organ donation, and transplantation. Recognizing that, at this moment, NAT is used only for research and is available from a limited number of laboratories, with turnaround times that may exceed 24 h, the Health Resources and Services Administration did not support the screening of all donors for WNV infection. One study estimated that annual screening could result in the potential loss of 452.4 life years (207).
Based on this, the following recommendations have been made: (i) potential donors with meningoencephalitic or myelitic symptoms of undetermined etiology who reside in specific geographic areas during periods of human WNV activity should be excluded; (ii) if living donors are to be screened with NAT, testing should be performed as close to the time of donation as possible; and (iii) the possibility of WNV infection if an organ recipient develops fever with neurological symptoms should be considered. Appropriate serological tests and early magnetic resonance imaging and lumbar puncture should be performed (101).
In addition, transplant recipients should be educated regarding the risk of WNV infection and the use of preventive measures, especially as a recent study performed in Canada found poor rates of compliance among SOT recipients with regard to WNV protection (214).
Rabies virus, genus Lyssavirus, family Rhabdoviridae, causes acute encephalitis, which is nearly uniformly fatal in unvaccinated hosts. It is a zoonosis that can affect both wild and domesticated animals and is transmitted to other animals and humans through close contact with saliva from infected animals (i.e., bites, scratches, and licks on broken skin and mucous membranes). Although many mammals may become infected, the prevalence of infection varies considerably from continent to continent (37). A large number of mammalian animal species are involved in the persistence and transmission of rabies throughout the world. In most countries of Africa, Asia, Latin America, and the Middle East, dogs continue to be the main hosts and are responsible for most of the human deaths from rabies that occur worldwide. In contrast, in North America, most documented human rabies deaths occurred as a result of infection by the silver-haired bat rabies virus variant (404).
Geographic distribution. Rabies virus is widely distributed throughout the world and is present in all continents. According to the World Survey of Rabies for 1999, 45 out of 145 countries and territories reported no rabies virus cases during that year. Many rabies virus-free countries and territories are islands of the developed world (e.g., Japan and New Zealand) and the developing world (e.g., Barbados, Fiji, Maldives, and Seychelles). In addition, parts of northern and southern continental Europe (e.g., Greece, Portugal, and the Scandinavian countries) and Latin America (e.g., Uruguay and Chile) are also free of rabies virus. Worldwide, it is estimated that approximately 55,000 people die of rabies each year. Most of the deaths from rabies reported annually around the world occurred in Asia and Africa, and most of the victims were children: 30 to 50% of the reported cases of rabies, and therefore deaths, occurred in children under 15 years of age (404).
Diagnostic methods. Antigen detection remains the "gold standard" for the diagnosis of rabies virus infection. IFAT is a rapid and sensitive method for diagnosis in animals and humans. Microscopic examination of impressions, smears, or frozen sections of tissue under UV light after they have been treated with antirabies serum or globulin conjugated with fluorescein isothiocyanate is performed. Viral antigen may also be detected by using the IFAT on skin biopsies from patients with clinical rabies virus infection. Test results are independent of the antibody status of the patient.
Rabies virus can be isolated using neuroblastoma cells or following the intracranial inoculation of mice. Virus may be isolated in saliva samples or other biological fluids such as tears and CSF.
Neutralizing antibodies in the serum or CSF of nonvaccinated patients can be measured using a virus neutralization test such as the rapid fluorescent focus inhibition test or the fluorescent antibody virus neutralization test. Virus-neutralizing antibodies in serum tend to appear on average 8 days after clinical symptoms appear. Rabies virus antibodies are infrequently found in CSF. An ELISA has also been used to determine antiglycoprotein antibody levels in the sera of humans and some animal species.
Molecular detection using PCR and nucleic acid sequence-based amplification techniques may be performed, and rabies virus RNA can be detected in several biological fluids and samples (e.g., saliva, CSF, tears, skin biopsy sample, and urine) by these methods (403).
Routes of transmission. Transmission to humans occurs primarily through the bite of an infected animal but can also occur through the direct contact of mucous membranes or open wounds and skin abrasions with infectious material (e.g., saliva, neural tissue, and CSF).
The virus incubates at the inoculation site for a period ranging from 5 days up to several years, depending on the size of the inoculum and the severity and location of the wound. During the incubation period, the virus replicates locally in muscle cells (classic form) or in the epidermis and dermis (bat variant rabies virus). The virus then attaches to nerve endings and moves centripetally from the periphery to dorsal root ganglia and on to the central nervous system (CNS) by axonal transport. In the CNS, the virus has a predilection for the brain stem, thalamus, basal ganglia, and spinal cord, where it selectively replicates intraneuronally, producing encephalomyelitis, and eventually spreads centrifugally along neural pathways to multiple organ and tissue sites (51).
Transplant-related cases. Human-to-human transmission of rabies has been described only in rare isolated cases after transplantation. Eight documented cases of rabies transmission through corneal transplants have been reported (7, 13, 18, 60, 134, 178, 193, 313).
Two reports have described transmission through SOT (162, 346). In 2004, transmission of rabies virus from a common organ donor (with unrecognized rabies virus infection) through the transplantation of solid organs and vascular material was reported in the United States. Four patients received organs (two kidneys and the liver) or vascular tissue (iliac vessel conduit used for hepatic artery reconstruction in another liver transplant recipient) from the organ donor, who had been apparently healthy before dying from a subarachnoid hemorrhage. The four recipients developed encephalitis and died within 30 days following transplantation. By the 27th day following transplantation, all three solid-organ recipients had been readmitted to the hospital with complex symptoms and progressive neurological disease that rapidly progressed to coma and death. The artery allograft recipient developed a confusional state with suicidal ideation on day 26 posttransplant. The patients died an average of 13 days after the onset of neurological symptoms. Postmortem examinations led to the diagnosis of transplant-associated rabies virus infection, which was confirmed by multiple methods in several tissue specimens from the recipients (346).
A similar case of transmission of rabies virus to at least three recipients in Germany has been reported. In 2005, the German Foundation for Organ Transplantation declared three cases of suspected rabies virus infection in a group of six patients who received organs from a common donor who died in late December 2004. In this case, the donor had spent time in India and showed no signs of rabies virus infection. While hospitalized, the organ donor had suffered a cardiac arrest, developed rapid neurological deterioration, and died with clinically unsuspected rabies virus infection. Infection of three of the patients who received organs from the donor was confirmed. These patients had received lung, kidney, and kidney/pancreas transplants (162).
Recommendations. There are no formal recommendations to screen all donors for the presence of rabies virus antibodies, especially as the risk of rabies virus transmission is very low. Burton et al. noted that even if the number of human rabies cases in the United States increased 100-fold, the risk of rabies transmission by organ transplantation would be less than 1 in 1012 (51).
Donor screening could prevent some cases of rabies virus transmission if questions concerning animal bites and donors’ travel history are carefully considered. Questioning the patient and relatives about the possibility of contact with bats anywhere in the world or of any other mammalian bite abroad should identify patients at risk. Also, potential donors with unexplained neurological symptoms should be evaluated for the possibility of CNS infections (217). If there is even a minimal risk of infection, the donor should be tested for rabies virus before transplantation (by skin biopsy, saliva test, and, preferably, a brain biopsy). If there are time restraints or specific diagnostic tests are not available, anyone with a history of possible exposure to rabies virus should not be accepted as a donor.
If organ transplantation from a rabies virus-infected donor occurs, prompt preemptive treatment with rabies virus vaccine and rabies virus immunoglobulin is indicated. Recipients of transplanted organs and the contacts of the infected donor exposed to saliva or other potentially infected secretions or tissues should receive rabies virus immunoglobulin and initiate a course of rabies virus vaccination (217, 403).
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Several species of Coccidioides can cause disease in humans. In addition to Coccidioides immitis, Coccidioides posadasii has been described recently as the likely etiologic agent of coccidioidomycosis originating outside California (30).
Primary coccidioidomycosis is a pulmonary infection in which as many as 60% of subjects may be asymptomatic. The illness begins 1 to 3 weeks after the inhalation of arthroconidia and presents with fever, cough, and pulmonary infiltrates. The usual course of the disease is a tendency to resolution over a period of several weeks. However, in immunosuppressed patients, including transplant recipients, primary coccidioidomycosis may develop into progressive disease with dissemination. In its disseminated form, coccidioidomycosis may involve almost any organ, with the most common sites of involvement being the lungs, skin and soft tissue, bones, joints, and meninges.
Geographic distribution. Coccidioides spp. have a distribution that encompasses semiarid to arid life zones, principally in the southwestern United States and northern Mexico, where they are endemic (349). Coccidioides is also found in parts of Argentina, Brazil, Colombia, Guatemala, Honduras, Nicaragua, Paraguay, and Venezuela (90). Hyperendemic areas include Kern, Tulare, and Fresno counties in the San Joaquin Valley of California and Pima, Pinal, and Maricopa counties in Arizona. Residence or travel to these areas of endemicity is a risk factor for infection.
Diagnostic methods. The diagnosis of coccidioidomycosis is based on clinical suspicion supported by microbiological, histopathological, or serological evidence. Approved skin test reagents are no longer commercially available. Direct examination of clinical specimens such as organic fluids, sputum, and tissue in 10% KOH may show spherules with a thick wall and endospores.
Culture provides a definitive diagnosis. Blood cultures may also occasionally yield positive results for patients presenting with overwhelming infection (88). Urine fungal culture could be useful for the diagnosis of disseminated coccidioidomycosis. Histopathological findings of Coccidioides spp. in its host forms include the presence of typical large spherules. Immunological methods using complement fixation (CF) and immunodiffusion (ID) using the complement-fixing antigen have also been used (280), and more recently, EIA for coccidioidal IgG and IgM antibodies has been used (242). Immunodiffusion using the complement-fixing antigen and EIA are the most commonly used tests in clinical practice. False-positive coccidioidal serological results have been documented in candidates for lung transplantation who had underlying cystic fibrosis due to the high circulating levels of nonspecific or cross-reacting serum proteins that interfered with the test (108), and therefore, results must be interpreted with care.
Routes of transmission. Coccidioides sp. infection is acquired following the inhalation of arthroconidia. Cases of human-to-human transmission have been described in the context of SOT.
Transplant-related cases. Coccidioidomycoses complicating the postoperative course of renal, heart/heart-lung, liver, or small bowel transplant recipients have been reported (32, 34, 35, 43, 249, 368, 405).
During transplantation, possible routes of transmission include (i) reactivation of latent infection, (ii) posttransplant de novo infection of recipients who live or travel to areas of endemicity, and (iii) transmission secondary to transplantation of organs from an infected donor. Posttransplant reactivation of coccidioidomycosis has been the mechanism most frequently described.
Most of the case series and individual case reports are from areas of endemicity or involved patients who had been former residents in these areas. In a few cases, brief visits to areas of endemicity had been sufficient for the infection to be acquired (35).
The risk of developing symptomatic coccidioidomycosis is increased by a history of prior coccidioidomycosis, positive coccidioidal serological tests at transplantation, or clinical evidence of active infection at transplantation. After transplantation, the main risk factor for developing coccidioidal infection is antirejection therapy (high-dose corticosteroids and mainly the use of polyclonal antilymphocyte or antithymocyte preparations and monoclonal therapies such as muromonab-CD3 [OKT3]). Dissemination is common in transplant recipients, up to 75% in some series, with or without concurrent pulmonary involvement (33, 173).
Coccidioidomycosis after SOT can occur at any time, but the period associated with the highest risk is the first year posttransplantation: 70% of cases develop in this period, with 50% occurring during the first 3 months (35). Overall mortality was 60% to 72% for the first cases described (86), but recent reports indicate that mortality has been lower than in earlier years, ranging from 0 to 33% (33, 154).
The clustering of cases in the first year and the frequency with which these patients have evidence of prior infection indicate that posttransplantation coccidioidomycosis is often a result of reactivation rather than a de novo infection following transplantation. The importance of prophylaxis in these patients has been demonstrated in different studies (35, 126).
The transmission of coccidioidomycosis with grafts has been well documented in certain cases, although this may be difficult to demonstrate in areas of endemicity, where there is significant background seropositivity. This may be illustrated by the results of a prospective serological survey of healthy potential live kidney or liver donors performed in Arizona, which revealed a seroprevalence of 1.9% (31).
Reports of transmission due to infected donor lungs, liver, and kidneys have been published (249, 368, 405). In all these cases, coccidioidal infection developed in the early posttransplant period. In one report, a patient from North Carolina developed fatal coccidioidomycosis soon after bilateral lung transplantation. The donor had previously traveled to Mexico, and the recipient had no history of travel to an area where C. immitis is endemic (249). Another lung transplant recipient developed fulminant pneumonia in the immediate postoperative period after transplantation. The recipient's serological tests had been negative 2 years before the procedure. The donor had been born in Arizona, and a postmortem study confirmed C. immitis in a lymph node (368).
Wright et al. described two cases (in a liver recipient and a kidney recipient) of rapidly fatal, disseminated coccidioidomycosis that occurred in organ transplant recipients who had never visited or lived in an area where C. immitis is endemic (405). Both subjects had received an organ from the same donor, an individual with unrecognized active coccidioidomycosis at the time of death (405). Postmortem examination of liver and kidneys appeared to be normal, and these had been harvested for transplantation. One month later, examination of permanent histopathological specimens of brain and basilar meninges revealed multinucleated giant cells containing fungal organisms consistent with C. immitis. The results of premortem serum CFA tests were positive for C. immitis, at a titer of 1:32. After the deaths of the two other SOT recipients, the recipient of the other kidney received prophylactic itraconazole and continued this regimen for 3 months. The patient remained completely asymptomatic for 2 years after transplantation. The kidney graft had been in cold isotonic solution for 37 h before transplantation, and it is possible that the viability of C. immitis was significantly impaired by the prolonged exposure to cold.
Recommendations. Serological screening for coccidioidomycosis in transplant donors or recipients coming from or residing in areas of endemicity is recommended. EIA for IgG and IgM, complement fixation for IgG, and immunodiffusion for IgM and IgG are the available serological tests in areas of endemicity. The routine serological screening of donors from areas of endemicity may help identify infections, but the results of such screening would not necessarily make the rejection of the donor organ mandatory, especially after bearing in mind the current donor shortages.
For areas where this organism is not endemic and Coccidioides serology is not routinely performed, it is important to establish the donor's history of travel to areas of endemicity in order to assess the relative risk of coccidioidomycosis. If risk of infection exists (donors with a history of traveling to or living in areas of endemicity), a Coccidioides sp. serological test must be performed at local reference laboratories.
If the donor had a history of remote coccidioidomycosis or radiological changes of prior coccidioidomycosis or had lived in or traveled to areas of endemicity, prophylaxis with oral fluconazole after transplantation could be started until the results of the serological studies become available. If a positive result is obtained and the transplant has already been performed, active illness must be excluded. If no focus is found, prophylaxis with fluconazole or itraconazole should continue for 6 months. After transplantation, all patients should be monitored serologically every 3 to 4 months during the first year and yearly thereafter (36).
Guidelines for the management of coccidioidal infection have been published (127, 128), and recently, posaconazole has been accepted by the American Thoracic Society and European Medicines Agency for coccidioidal therapy. Transplant recipients have received the drug without complications (10).
Histoplasmosis is an endemic mycosis caused by Histoplasma capsulatum (family Ascomycetes). It is a soil-based fungus acquired by the inhalation of mycelial fragments and microconidia and is most often found in river valleys where specific temperature and humidity conditions favor its growth. High concentrations of the mold phase of H. capsulatum are also found in soil that is rich in nitrogen, as occurs in areas in which large flocks of birds roost (203). Infection is common in areas of endemicity, and most affected people have been infected before adulthood. The extent of disease is determined by the inoculum of conidia inhaled into the lungs and the immune response of the host to the conidia. Almost all those infected with H. capsulatum have asymptomatic hematogenous dissemination, but only rarely does this lead to symptomatic disease.
Geographic distribution. H. capsulatum is endemic in the Mississippi and Ohio River valleys, Central America, and certain areas of Southeast Asia and the Mediterranean basin.
Diagnostic methods. Growth of H. capsulatum from tissue or fluid samples is used to establish a definitive diagnosis of histoplasmosis (389), although the organism can take weeks to grow in vitro. Blood cultures, especially those using the lysis-centrifugation system (isolator tube), are more sensitive for patients who have disseminated infection than for those who have pulmonary disease only. Measuring the cell wall polysaccharide antigen of H. capsulatum in urine is a sensitive diagnostic tool for patients who have disseminated infection (394). Antigen is rarely detected in patients who have chronic pulmonary histoplasmosis or granulomatous mediastinitis, but it is positive in approximately 80% of those who have acute pulmonary histoplasmosis. Cross-reactivity can occur with blastomycosis, paracoccidioidomycosis, and penicilliosis, and false-positive results in serum have been observed in 16% of SOT patients who received rabbit antithymocyte globulin (391). Detection of antigen in body fluids (e.g., bronchoalveolar lavage fluid and CSF) offers a valuable approach for rapid diagnosis in patients with progressive disseminated histoplasmosis and diffuse pulmonary histoplasmosis (392, 395).
The development of PCR for detecting H. capsulatum in blood and tissue samples taken from patients who have disseminated histoplasmosis is in progress. Although several assays were reported to be useful, the accuracies of these methods are unclear, and therefore, none are in routine clinical use (29, 42), especially as published studies have not demonstrated superiority compared with standard methods (29, 358).
Serology plays an important role in the diagnosis of certain forms of histoplasmosis (389). The standard assays are CF and ID. The sensitivity of the CF and ID assays is approximately 80%, and the use of both assays increases the diagnostic yield (202). Patients who have chronic cavitating pulmonary histoplasmosis and chronic progressive disseminated histoplasmosis almost always have positive results with both assays. However, in patients who are immunosuppressed and who cannot mount an adequate antibody response, serology is rarely useful and should not be relied upon for the diagnosis of histoplasmosis. In early studies, a specific radioimmunoassay was found to be more sensitive than ID or CF for antibody detection following acute histoplasmosis (390).
For the screening of asymptomatic donors with positive risk factors for histoplasmosis infection (past history of travel to or residence in areas of endemicity), serological methods based on antibody detection (CF or IF assays) would be of use, as fungal burdens in these individuals would be expected to be low. If acute histoplasmosis is suspected in the donor, detection of urinary antigen or culture/histopathological examination of other specimens could be used.
Routes of transmission. Histoplasma sp. infection results from the inhalation of the microconidia, but isolated cases of human-to-human transmission during transplantation have also been described (227).
Transplant-related cases. Disease may develop due to the reactivation of latent lesions or from new exposure in zones where Histoplasma is endemic (286, 354, 401), but transmission of histoplasmosis from donor to recipient via graft has also been described (227).
In the cases described in the literature, symptoms started a median of 1 year after organ transplantation, and the majority of cases occurred in the first 18 months. Pulmonary involvement is common, and immunosuppressed patients can develop severe life-threatening pneumonia, although other varied manifestations have been observed in transplant patients (48, 125, 259, 354, 401, 414). In this respect, the presentation and clinical course of histoplasmosis in the SOT population appear to be somewhat less severe than histoplasmosis in the AIDS population (393).
A study performed in Indianapolis, IN, at a medical center located in an area of hyperendemicity demonstrated that histoplasmosis is a rare infection following the immunosuppression of allogeneic bone marrow transplantation (BMT) or SOT (377). In this study, 18% of the recipients had CF titers that were positive for H. capsulatum, and chest X rays showed findings consistent with past histoplasmosis in 4% of the recipients. All allogeneic BMT recipients received prophylaxis with fluconazole, but SOT recipients were not routinely treated with systemic antifungal prophylaxis. During the posttransplant period, no cases of histoplasmosis in BMT or SOT patients were diagnosed. The low incidence of histoplasmosis in immunocompromised patients, in the absence of an outbreak, provides evidence against reactivation as a significant mechanism for histoplasmosis. In areas of endemicity, an increase in the incidence of histoplasmosis in transplant patients during two large outbreaks has been reported (286, 396), but these cases probably represent newly acquired infections.
However, other authors postulated reactivation as a pathological clinical form. Davies et al. reported an estimated incidence of histoplasmosis of 0.4% in renal transplant recipients in Minnesota, an area of low prevalence (94).
Although rare, a third mode of acquisition of histoplasmosis in transplant patients may be transmission through an infected allograft from a patient with unrecognized histoplasmosis. Two cases of disseminated histoplasmosis in residents from nonendemic areas, developing 8 and 9 months following transplantation from a donor who resided in an area of endemicity, have been reported (227). DNA fingerprinting confirmed that the isolates were identical, proving that they were transmitted with the allograft. The donor <