Produção Nacional
Revisado por pares
Arboviruses Recommendations for Solid-Organ Transplant Recipients and Donors
2018; Wolters Kluwer; Volume: 102; Issue: 2S Linguagem: Inglês
10.1097/tp.0000000000002011
ISSN1534-6080
AutoresMichele I. Morris, Paolo Grossi, Maurício Lacerda Nogueira, Luiz Sérgio Azevedo,
Tópico(s)Viral Infections and Outbreaks Research
ResumoINTRODUCTION OF ARBOVIRUSES This review will focus on the 4 arboviruses endemic in Latin America, 3 of which have been described in solid-organ transplant (SOT) recipients. A multitude of arthropod-borne viruses associated with human disease may circulate in tropical and subtropical regions.1 Physicians should be aware that symptoms of fever, joint pain, and rash of undetermined origin in donors, and transplant candidates and recipients could be related to unusual arboviruses, particularly because recent epidemics have significantly expanded the regions of potential exposure risk. Arbovirus infections should be included in the differential diagnosis of infection in transplant patients so that appropriate testing and treatment can be offered. CHIKUNGUNYA Introduction and Epidemiology Chikungunya (CHIKV) is an arbovirus that causes an acute febrile illness associated with severe polyarthralgia and rash that may progress to chronic arthritis. This RNA virus belongs to the Alphavirus genus of the family Togaviriadae and is widely distributed in tropical and subtropical regions of Africa, islands in the Indian Ocean, and Southeast Asia. Since 2004, global spread of CHIKV infection has occurred through the widespread dissemination of the mosquito vectors, Aedes aegypti and Aedes albopictus (Figure 1). CHIKV likely originated in Africa, with transmission occurring between primates, small mammals, and Aedes mosquitoes. Transmission in Asia occurs directly between humans and mosquitoes. An epidemic in the Indian Ocean in 2005 to 2006 may have been amplified by a glycoprotein mutation that allowed improved viral replication within A. albopictus, a species with wider geographical distribution than A. aegypti. In 2007, transmission outside the tropics resulted in an outbreak in Northern Italy.2 In a recent outbreak that began in the Caribbean in December 2013, over 1.4 million cases of CHIKV were reported involving over 44 countries, many in North and South America.3 There were approximately 2500 cases in the United States in 2014, largely involving returning travelers although 11 cases of local transmission were confirmed in South Florida.4FIGURE 1: Countries and territories in which CHIKV cases have been reported as of April 22, 2016. (CDC.Chikungunya virus geographic distribution. http://www.cdc.gov/chikungunya/geo/index.html. Updated May 12, 2016.)3After an incubation period averaging 2 to 4 days, infection presents with the acute onset of high fever lasting 3 to 5 days. Polyarthralgia with symmetric involvement of multiple joints develops within a few days of fever onset in nearly 90% of patients, and is associated with a rash in almost half of those infected. Symptoms are present in most patients with infection, and generally last 1 to 2 weeks. Joint pain and swelling may persist for months to years after disease onset. CHIKV is known to exacerbate preexisting chronic arthritis. Newborns, patients over 65, and immunocompromised patients are at higher risk for complications or death from acute infection.5,6 Severe manifestations of CHIKV may include neurologic involvement with meningoencephalitis, respiratory failure, myocarditis, and renal and hepatic failure.7 Severe and prolonged arthritis is the most common severe complication.8 Very few cases in SOT recipients have been reported. The first case of CHIKV infection in a SOT recipient was reported by Economopoulou et al9 in a 55-year-old Malaysian-Chinese man who underwent deceased donor liver transplantation in 2001 and 7 years later developed CHIKV infection complicated by encephalitis but with complete resolution. A second case was described in an HIV infected kidney transplant recipient returning to Italy in August 2014 after a recent trip to the Dominican Republic. One month later, the patient complained of persistent arthralgia and difficulty in walking, but had no other complication.6 In 2016, 4 patients from the renal transplant unit in São Paulo (Brazil) presented with CHIKV infection. These patients acquired the disease in Northeast Brazil, where the incidence of CHIKV was among the highest in the country at that time. The clinical picture was typical, except in 1 patient who was afebrile. Arthralgia was mild and transient, and no patient had arthritis or persistent pain. All had full recovery with no complication.10 A more recent review evaluated 13 cases of CHIKV infection in SOT, and the clinical presentation and evolution showed to be similar to those observed in the general population, with no apparent negative impact to the graft.11 Therefore, it is not clear if SOT recipients have an increased risk of complicated CHIKV infection, or if the use of immunosuppression might have played a role in the paucity of symptoms and the early complete recovery. Risk of Transmission Through Transplantation Living and deceased donors from nonendemic areas may be assessed for exposure risk by screening for recent travel. Living donors should be educated to avoid infection before donation. Viremia may be present between 4 days and 3 weeks after a bite from an infected mosquito. Infection transmission may potentially occur through blood, tissue, or transplanted organs during this time. Viremia may be detected by nucleic acid testing. Supporting this potential risk, there are several studies estimating the prevalence of asymptomatic blood donors infectious using polymerase chain reaction (PCR); the maximum rates varies from 0.2% among asymptomatic blood donors from French West Indies in 201412 to 1.9% among asymptomatic blood donors from Puerto Rico in the same year.13 Although there are no documented cases of DDI, donors with possible exposure to actively circulating infection should be screened by PCR testing. It is possible that virus persists in tissue after clearance from blood. CHIKV infection can be transmitted by tissue, with infection reported in 4 of 12 corneal grafts from potential corneal donors, one of whom had no detectable viremia.14 Diagnosis The detection and diagnosis of the disease can be challenging especially in settings where dengue virus (DENV) and zika virus (ZIKV) are endemic. DENV infections are associated with significant cytopenia and less arthralgia, with more severe cases associated with hemorrhage and shock. ZIKV infection is usually asymptomatic or associated with mild disease. High fever and severe arthralgia, often with rash, is more typical of CHIKV. CHIKV infection causes symptoms in most those exposed, with asymptomatic infection in only 3% to 25%.15Table 1 summarizes the most relevant clinical patterns of CHIKV, DENV, and ZIKV infections. Coinfection with both viruses is possible, because they share the same mosquito vectors.TABLE 1: Clinical comparison of arbovirus infections: dengue, CHIKV, and ZikaTwo main diagnostic methods are available, namely, real-time (RT)-PCR and serology—immunoglobulin (Ig)M or IgG. RT-PCR is useful during the initial viremic phase (day 0-7), but classic serological methods are simple and can detect a longer window period of infection (ie, hemagglutination inhibition, complement binding, immunofluorescence, and enzyme-linked immunosorbant assay). IgM is detectable after an average of 2 days by enzyme-linked immunosorbant assay immunofluorescent assay (1-12 days) and persists for several weeks to 3 months. IgG is detected in convalescent samples and persists for years. The sensitivity and specificity of these tests are poorly established, as is the possibility of false-positive reactions resulting from cross-reactivity with other alpha viruses. Treatment and Prevention Infection risk is associated with travel to areas with actively circulating infection, especially during the rainy season. The mosquito vectors are aggressive daytime biters, and travelers should be counseled to use mosquito repellant, wear long pants, long sleeved shirts, and socks, and stay in buildings with air conditioning and adequate screening. Bed nets should be used in hospitals and daycare facilities. Surveillance is also important for early identification of outbreaks. Pending vaccine development, the only effective preventive measures consist of individual protection against mosquito bites and vector control. Control of both adult and larval mosquito populations uses the same model as for DENV. Mosquito breeding sites must be removed, destroyed, frequently emptied, and cleaned or treated with insecticides. The lack of antiviral drugs and vaccines remains a major challenge in the control of CHIKV outbreaks, because current treatment strategies rely on the alleviation of disease symptoms. Recently, a combination of doxycycline and ribavirin showed potent antiviral efficacy by inhibiting entry and replication of CHIKV in Vero cells, and reduced viral infectivity in vitro and in vivo.16 Although a human vaccine against CHIKV is not currently available, inactivated and attenuated vaccine candidates have shown promising results in phase I/II trials, and engineered vaccines have proven to be safe and immunogenic in mouse and nonhuman primate models.17 DENGUE Introduction and Epidemiology Dengue is a disease caused by a 4 serotype Flaviridae virus and transmitted by Aedes mosquitoes (DENV-1, DENV-2, DENV-3, and DENV-4). Infection in the Americas occurs from Mexico to Argentina. Dengue cases have also been reported in the southern United States18,19 (Figure 2).FIGURE 2: Dengue risk in the Americas and the Caribbean. (Sharp Tyler M, Perez-Padilla Janice, Stephen H. Waterman, Centers for Disease Control and Prevention. Infectious Diseases Related to Travel. Dengue. In: Centers for Disease Control and Prevention, Brunette GW, eds. CDC Yellow Book 2016. New York, United States: Oxford University Press; 2016.)79According to the World Health Organization, 50 million cases of DENV infections occur annually in the world and 2.5 billion people living in DENV endemic countries are at risk.18 Dengue most frequently presents as an asymptomatic infection or a relatively benign symptomatic disease. The severe forms are dengue hemorrhagic fever and dengue shock syndrome, which may be fatal. The 2009 World Health Organization (WHO) report classified dengue for severity: dengue without warning signs, with warning signs, and severe dengue. It can also be classified as febrile phase, critical phase, and recovery phase.18,20,21 Transplant recipients present with symptoms like those seen in immunocompetent persons, although they may also develop severe manifestations of dengue.22-36Table 2 summarized the reported cases of dengue among transplanted recipients; most of them occurred after kidney transplantation.TABLE 2: Dengue cases reported in transplant recipientsRisk of Transmission Through Transplantation It might be expected that a great number of cases of DENV infection would be transmitted by transplantation, since DENV may be sequestered in organs normally transplanted.37,38 Paradoxically very few transplant-related cases are reported in the literature.26,28,31,36 In endemic areas, it is difficult to ascertain if the disease was transmitted by the donor or acquired by the recipient just before transplantation. Blood transfusions alone are not an important source of DENV.39-41 DENV RNA is detected in 0.2% to 0.4% of blood donors in endemic areas.42,43 Despite the high prevalence of DENV in different world regions, DENV transmission by transplant donors is exceptionally rare. Therefore, it seems reasonable to omit routine DENV screening in transplant donor evaluations. Nonetheless, in DENV endemic regions, we should avoid the use of donors with febrile illness suggestive of active infection. Viremia lasts about 7 days, concomitant with the febrile period. Donors who are known to have had DENV infection can therefore be accepted once they become afebrile, although for safety, it is advisable to wait at least 30 days after the acute illness. Diagnosis Diagnosis is made clinically based on the presence of signs and symptoms, such as high fever, weakness, malaise, headache, myalgia, arthralgia, retro-orbital pain, nausea, and vomiting. A maculopapular rash may be present. Laboratory findings are nonspecific, although thrombocytopenia is common. The diagnosis is confirmed by serology with the presence of IgM and/or by RT-PCR. Previous Flaviviridae infections and previous Yellow Fever (YF) or Japanese encephalitis vaccines may lead to false-positive DENV serology, due to the high level of cross-reactive antibodies produced during Flaviviridae infections. Furthermore, there is an anamnestic response during sequential infections, accompanied by a sudden rise in antibody titers. IgG antibodies appear later, after 7 to 10 days, and remain positive for life. High IgG titers early during the disease, contrasting with low levels of IgM is suggestive of a second DENV infection. RT-PCR is considered the gold standard for DENV diagnosis, with 80% sensitivity and 95% specificity. PCR is positive during the viremic period but becomes negative soon after (6 to 8 days after symptom onset). Viral PCR is also detectable in tissues, urine, and saliva. IgM antibody detection is the most frequently used diagnostic method. IgM typically becomes positive 3 to 5 days after symptom onset and may remain detectable for 3 to 6 months. IgM response is cross-reactive to all 4 DENV serotypes. NS1 is a glycoprotein secreted from virus-infected cells and may be detected in peripheral blood. It correlates with the viremic period and with disease severity. NS1 can be detected up to 9 days after the onset of symptoms and may persist up to 18 days. IgM is less sensitive in a second infection.44 Treatment and Prevention Multiple clinical trials are in progress to evaluate different 4-serotype live-attenuated or inactivated vaccine candidates.45 The DENV vaccine Dengvaxia (CYD-TV), developed by Sanofi Pasteur was first licensed in Mexico in December 2015 and now licensed in other endemic countries, such as Philippines and Brazil.46 Recent findings suggest that seronegative populations could be at higher risk for more severe disease if vaccinated before DENV exposure. This postvaccination DENV infection may be more severe than the disease produced after a second natural DENV exposure, an effect recognized as vaccine-enhanced disease.47 There is no specific antiviral treatment other than supportive care. Prevention includes mosquito avoidance with insect repellents and long-sleeved clothing. The mosquito vector bites during the daytime, especially early morning and late afternoon. YELLOW FEVER Introduction and Epidemiology Yellow fever (YF) is an endemic hemorrhagic fever in tropical areas of South-Central America and Africa (Figure 3). It is caused by the YF virus, the prototype of the Flaviviridae family and Flavivirus genus. Several other important viruses in the Flavivirus genus infect humans causing hemorrhagic fever (such as DENV) or encephalitis, such as West Nile virus and Saint Louis encephalitis virus.48-50 YF is transmitted by mosquito bite. Two different cycles are known: one is sylvatic YF in which the virus is transmitted by jungle or savannah mosquitoes, and the other is the urban cycle, which is centered in the A. aegypti mosquitoes. In most of the Americas, the virus is restricted to sylvatic cycle.50FIGURE 3: Yellow fever risk in Latin America. (Jentes ES, Poumerol G, GershmanMD, et al. The revised global yellow fever risk map and recommendations for vaccination, 2010: consensus of the Informal WHO Working Group on Geographic Risk for Yellow Fever. Lancet Infect Dis. 2011;11:622–632.)80Most cases of YF infection are asymptomatic or cause mild disease. Infection is characterized by the sudden onset of fever with headaches and photophobia. In some patients, the initial symptoms are followed by epigastric pain, arthralgia, myalgia, anorexia, vomiting, and jaundice. These symptoms can be self-limited and usually resolve 5 to 7 days after the onset of the disease. However, in up to 20% of infected patients the hemorrhagic form of the disease may develop. In these patients, hemorrhagic symptoms appear about 48 hours after signs of clinical improvement. Hemorrhagic symptoms appear and are followed by liver and renal failure, shock, and multiorgan failure, with a fatality rate as high as 90%.48-50 Risk of Transmission Through Transplantation As a Flavivirus, transmission of YF infection through organ transplantation or blood transfusion would appear likely, like other Flaviviridae, such as West Nile virus. To the best of our knowledge, there have been no reports of YF transmission by organ or blood, even in databases from endemic countries like Brazil. This is probably due to the small number of cases, mostly confined to rural areas, and the presence of a large vaccinated population. Diagnosis The diagnosis of YF infection is straightforward, with the detection of virus by RT-PCR and/or detection of IgM antibodies. Such tests are generally performed in reference laboratories, where most suspected cases are confirmed. YF infection is a mandatory reportable disease in most of the world. Postmortem diagnosis can be made by pathological examination and immunohistochemistry procedures. Despite the large distribution of the virus the number of cases are limited, especially in the Americas, because of the availability of an effective vaccine.48 Treatment and Prevention Because there is no specific antiviral therapy for YF, the treatment is mostly supportive, including intensive care unit management for severe cases. Vaccination is the most important therapy available. The YF vaccine, developed in the 1930s, is a live attenuated form of YF currently available in 2 different forms, the 17DD (produced in Brazil and available in South America) and the 17D-204, produced in the United States and available in most of the world. Both are equivalent, safe, and well tolerated.48,50,51 The YF vaccine is regulated by international law and is required for entrance and transit in some countries. The previous 10-year booster dose YF vaccine is no longer necessary and the WHO currently recommends a single lifetime dose of YF vaccine.52 This live vaccine is officially contraindicated by the Centers for Disease Control and Prevention (CDC) in transplant patients and patients receiving immunosuppressive therapy.53 Physicians face complicated management decisions when weighing the requirement for mandatory vaccination for travel to some countries, the lethality of the severe form of YF, and the vaccine contraindication in immunocompromised patients.50,51 Transplant practitioners should note that vaccine-induced antibodies against YFV persist after solid organ transplantation,54 so pretransplant vaccination in immunocompetent transplant candidates likely to travel to YF endemic areas may be the best approach. In addition, posttransplant YF vaccination has been done successfully. A case series of 19 patients from Brazil reported that YF vaccination in solid-organ recipients did not induce severe complications.55 Successful posttransplant vaccination has been performed elsewhere in solid organ and bone marrow transplant patients.56,57 The use of vaccine followed by intravenous immunoglobulin has also been reported.58 Unfortunately, with few reports of successful vaccination of immunocompromised patients and the significant risk of severe reaction associated with administering live vaccine to patients posttransplant, unvaccinated transplant patients should be counseled to avoid travel to YF endemic areas where they may be exposed to a potentially fatal infection. Transplant recipients who live in YF areas or for whom travel is unavoidable will require a physician's letter with a stamp from a YF travel clinic, indicating that YF vaccine is contraindicated to travel. Unvaccinated travelers should be counseled to avoid travel during periods of high YF transmission risk and to use all possible mosquito avoidance precautions. ZIKA VIRUS Introduction and Epidemiology ZIKV is a Flavivirus with 2 lineages: African and Asian. It was first described in 1947 in the Zika forest in Uganda in a Rhesus monkey. The African ZIKV largely infected nonhuman primates and Aedes mosquitoes. Human infection appeared to be rare, with the first case of ZIKV disease reported in 1954.59 Transmission of the Asian ZIKV incorporated urban vectors, such as A. aegypti and A. albopictus; but until 2015, human ZIKV disease was rare with 13 case reports in 57 years,60 and infection was not considered an important public health problem. The first disease detection outside Africa and Asia was reported in 2007 in Micronesia. ZIKV began spreading rapidly in the Americas in 2014, with the first autochthonous cases in America reported in Brazil in March 201561 (Figure 4). The current ZIKV epidemic is spreading rapidly in the Americas, with transmission documented in 35 countries and territories, as well as 7 in Oceania and 1 in Africa.62FIGURE 4: World map of areas with risk of Zika. (Centers for Disease Control and Prevention. World map of areas with risk of Zika. http://www.cdc.gov/zika/geo/active-countries.html. Updated May 25, 2017.)62ZIKV is transmitted by Aedes mosquitoes, with different species depending on the region. A. aegypti and A. albopictus species are the predominant vectors. Both species are aggressive daytime biters and thrive in densely populated urban areas, increasing the likelihood of human infection. As most ZIKV cases are mild or asymptomatic, it is very difficult to estimate the real incidence of disease. Human ZIKV infection may be asymptomatic in up to 80% of the cases. Symptomatic infections are generally mild, though it may manifest as a flu-like illness that can be virtually indistinguishable from DENV and CHIKV infections, with fever, malaise, skin rash, itching, headache, conjunctivitis, arthralgias, and myalgias. Abdominal pain, nausea, vomiting, diarrhea, and dizziness may also occur.63-65 Recently, ZIKV infections have been associated with congenital microcephaly and Guillain-Barré syndrome,66 as well as acute demyelinating encephalomyelitis.67 ZIKV can also be transmitted by alternative modes, including sexual, mother-to-child, nonhuman primate bites, accidental laboratory exposure, blood transfusion, and transplantation.68 A search in PubMed showed few recent reported cases of ZIKV infection transmission by platelet transfusion from infected donors from Brazil.69,70 Risk of Transmission Through Transplantation Because ZIKV may be detected in the blood during acute disease, like other arbovirus infections, the potential risk for transmission through blood transfusion or transplantation of organs and tissues is of concern. Furthermore, most individuals with ZIKV infection are asymptomatic, increasing the risk of transmission from donors with unrecognized infection. The potential risk is confirmed by the report that about 3% of blood donors who were asymptomatic at the time of blood donation tested positive using a specific ZIKV nucleic acid test (NAT) implemented for routine screening of blood donors during the outbreak in French Polynesia, with an estimated infection rate of about 11% of the population.71 Unfortunately, a laboratory test for routine screening is not currently available in many American countries with reported autochthonous ZIKV transmission, and prevention of donor-derived infection through blood, organs, and tissues currently relies on clinical screening to identify signs and symptoms suggesting previous ZIKV infection. A 30-day deferral policy for donation was officially announced in Brazil.72 Because the infection is endemic in countries where autochthonous transmission is active, a temporary deferral policy for donors who are "at epidemiological risk" is not viable, as it would have considerable negative impact on donor availability. For countries without transmission, guidelines exist for donor screening.73 It is clear that donor-derived ZIKV transmission is possible, as documented in a recent report of a patient with ZIKV infection who was infected through a blood transfusion from an otherwise asymptomatic donor.74 This documented transmission reinforces the need to establish an active surveillance system with streamlined access to retrospective ZIKV diagnosis in both donors and recipients transplanted in countries with current and future high risk for ZIKV circulation. Diagnosis The diagnosis of ZIKV infection is complicated by similarities to the clinical presentation of DENV and CHIKV clinical manifestations, arboviruses with similar geographic distribution. The WHO has developed a case definition of ZIKV, which should guide the use of diagnostic tests as they are developed and made commercially available.75 Currently available serological tests are of limited value due to the high immunological cross-reactivity between the Flaviviridae species, and confirmatory diagnosis is based on laboratory evidence of recent ZIKV infection, defined by the detection of ZIKV RNA or antigen in the blood or other fluids or IgM antibodies against ZIKV positive and confirmation by plaque reduction neutralization test (PRNT).75 The exact duration of viremia is unknown, but likely to be present for only 7 or 8 days after symptom onset. Data from other Flaviviridae infections suggest that IgM may be measureable at the time viremia resolves and is likely to be detectable for several months.60 If PRNT is not available, samples positive by ZIKV antibodies and negative by DENV antibodies may be interpreted as a presumptive recent ZIKV infection, although this approach requires further validation. Although PRNT offers detection of ZIKV-specific neutralizing antibodies, this test also has shown cross-reactivity in samples of patients with previous Flavivirus exposure, and serological results should be carefully interpreted. Treatment and Prevention Like the previously reviewed arboviruses, there is no specific treatment for ZIKV and no vaccine currently available. Disease prevention is similar, based on mosquito avoidance using insect repellents, and long-sleeved clothing and trousers. Public health measures to reduce mosquito vector populations are crucial to lower transmission risk. Transplant recipients who wish to become pregnant should strongly consider delaying pregnancy while ZIKV is actively circulating in their region. Pregnant women should be counseled to avoid travelling to countries known to have active ZIKV transmission, or if travel is unavoidable, they should adhere strictly to protective measures. Transplant candidates and potential donors from areas with no autochthonous infection should avoid travel to endemic areas within 30 days of transplant or donation. All transplant recipients and living donors should avoid sexual contact with men who have traveled to an endemic area within the past 6 months. Some studies suggest that ZIKV persists longer in urine, so potential kidney donors should avoid travel to endemic areas when possible until the risk of transmission is better understood.76,77
Referência(s)