Visceral leishmaniasis in renal transplant recipients: clinical aspects, diagnostic problems, and response to treatment

Visceral leishmaniasis (VL) is a parasitic infection that uncommonly affects renal transplantation recipients, even in endemic areas. It may be associated with other infections, or masked by these, and may present subclinically and/or atypically for extended periods. The evolution may be particularly severe and diagnosis is often delayed. If not adequately diagnosed and treated, VL can be fatal and so should be suspected in renal transplantation recipients presenting unexplained fever, splenomegaly, and pancytopenia. The authors report 8 cases of VL out of a total of 800 renal transplant recipients from two transplant hospitals centers in Brazil. The clinical, diagnostic, and therapeutic features are reviewed.     

Tuberculous meningitis in a renal transplant recipient

Tuberculous meningitis is a very rare, but serious extrapulmonary complication of mycobacterial infections in immunocompromised patients, such as organ transplant recipients. We describe here a 66-year-old Turkish woman without any history of tuberculosis, who received a renal allograft transplant in 1994. After a pilgrimage to an endemic area for tuberculosis, she presented with fever and headache in August 1998. Clinical examination revealed positive meningism and hyperreflexia. Lymphocytosis was noted in her cerebrospinal fluid (CSF) and Mycobacterium tuberculosis infection was detected by PCR within the CSF. Despite immediate triple antituberculosis therapy, the patient's clinical condition deteriorated rapidly, with the development of septic shock syndrome, and she died three weeks after admission due to cardiovascular and respiratory failure. Mycobacterial infections, including extrapulmonary manifestations, should thus be considered in all renal transplant recipients presenting with unexplained fever. Preventive therapy, i.e. isoniazid prophylaxis, may also be recommended for patients risking exposure in areas endemic for tuberculosis.     

A renal transplant recipient with pulmonary tuberculosis and visceral leishmaniasis: review of superimposed infections and therapy approaches

Visceral leishmaniasis (VL) is an acute or subacute disease that is almost invariably fatal if untreated. It is a rare disease in renal transplant recipients and frequently reported together with other infectious agents. A 39-year-old renal transplant patient was admitted to hospital for elective coronary surgery. In the post-operative period, he developed spiking fever and non-productive cough and his general condition deteriorated. While he was taking medication for non-specific pneumonia, a cavitary lesion occurred in his lung, and he had the diagnosis of pulmonary tuberculosis and antituberculous treatment was started. Despite treatment, his fever continued. As the patient developed pancytopenia and splenomegaly, a bone marrow aspiration was done. Evaluation of bone marrow aspirate indicated Leishmania parasites. He was successfully treated with a more intensive liposomal amphotericin (L-AmB). Complete cure was achieved during follow-up period of 10 months without clinical relapse. In the existence of fever and long-standing pancytopenia, VL should be suspected although the patient had another proved infection and did not live or visit an endemic area. L-AmB usage can be safely preferred for treatment of selected renal transplant recipients with VL as first-line therapy.     

Visceral Leishmaniasis in a Kidney Transplant Recipient: Parasitic Interstitial Nephritis,a Cause of Renal Dysfunction

Visceral leishmaniasis (VL) due to Leishmania infantum is an endemic parasitic infection in the Mediterranean area. It most commonly affects immunosuppressed individuals, especially HIV patients and less frequently organ transplant recipients. Renal involvement seems to be frequent and is mostly associated with tubulointerstitial nephritis, as described in autopsy reports. In the 61 cases of renal transplant recipients with VL reported in the literature, renal dysfunction was noted at clinical presentation and was more frequently observed as a complication of antiparasitic therapy. However, no pathological analysis of the allograft lesions was reported. We present the case of a Swiss renal transplant recipient who developed VL after vacations in Spain and Tunisia, complicated by acute parasitic nephritis in the renal allograft 3 months after a well‐conducted treatment of liposomal amphotericin B.     

Virus Load in Pigs Affected with Different Clinical Forms of Classical Swine Fever

Summary Classical swine fever (CSF) is an endemic disease in India, but the real magnitude of the problem is not known as only outbreaks of acute CSF are reported and many cases of chronic and clinically inapparent forms of the disease, which manifest a confusing clinical picture, remain undiagnosed. The real status of classical swine fever virus (CSFV) infection can only be known by testing pigs with highly specific and sensitive diagnostic assays. To obtain the baseline prevalence of CSFV infection among pigs in an endemic region where no vaccination was being performed, a real‐time PCR assay was used to detect viral genetic material in tissue samples collected from a slaughterhouse in the northern state of Uttar Pradesh in India. In total, 1120 slaughtered pigs were examined for the presence of CSF suggestive pathological lesions and tissues from suspected cases were tested for the presence of CSFV antigen and nucleic acids by indirect immuno‐peroxidase test and real‐time PCR, respectively. Based on the detection of viral genetic material in the tonsils, the prevalence of CSFV infection among slaughtered pigs was found to be 7.67%. Pigs detected positive for viral genome by quantitative real‐time PCR assay when categorized into different forms of CSF, depending upon the pathological lesions observed, the viral load in the tonsils of some of the pigs with chronic or clinically inapparent form of the disease was similar to that detected in pigs with acute CSF. The results of the study suggested that the risk posed by pigs with chronic disease or those infected but showing no clinical disease may be relatively higher as they can transmit the virus to new susceptible hosts over a longer period of time.     

Histoplasmosis in transplant recipients

Histoplasma capsulatum is a dimorphic fungus that most often causes asymptomatic infection in the immunocompetent population. In immunocompromised patients, including solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients, however, it is likely to cause severe life‐threatening infection. Post‐transplant histoplasmosis (PTH) in SOT is uncommon with an incidence of ≤1% and is even rarer in HCT patients. The majority of PTH in SOT is diagnosed in the first 2 years following transplantation. Histoplasmosis may result from endogenous reactivation of latent infection, de novo post‐transplant acquisition, and donor‐derived infection. Disseminated infection is common. Fever is the most common symptom and clinical features are often nonspecific, but patients with disseminated infection may present with a septic picture. Other features, including pancytopenia and hepatosplenomegaly, may not be prominent early in the course of illness. Contemporary histoplasma antigen assays are the most sensitive tests but cross‐reactivity with antigens of other fungi, including with Aspergillus galactomannan, is not uncommon. Treatment should be continued for at least a year. Histoplasma antigen levels have prognostic value and can be used to monitor the response to therapy. The attributable mortality is approximately 10%. Routine screening of donors and recipients is not currently recommended.     

Human herpesvirus 6, 7, and 8 in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of HHV‐6A, HHV‐6B, HHV‐7, and HHV‐8 in the pre‐ and post‐transplant period. The majority of HHV‐6 (A and B) and HHV‐7 infections in transplant recipients are asymptomatic; symptomatic disease is reported infrequently across organs. Routine screening for HHV‐6 and 7 DNAemia is not recommended in asymptomatic patients, nor is prophylaxis or preemptive therapy. Detection of viral nucleic acid by quantitative PCR in blood or CSF is the preferred method for diagnosis of HHV‐6 and HHV‐7 infection. The possibility of chromosomally integrated HHV‐6 DNA should be considered in individuals with persistently high viral loads. Antiviral therapy should be initiated for HHV‐6 encephalitis and should be considered for other manifestations of disease. HHV‐8 causes Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease and is also associated with hemophagocytic syndrome and bone marrow failure. HHV‐8 screening and monitoring may be indicated to prevent disease. Treatment of HHV‐8 related disease centers on reduction of immunosuppression and conversion to sirolimus, while chemotherapy may be needed for unresponsive disease. The role of antiviral therapy for HHV‐8 infection has not yet been defined.     

Transplantation of solid organ recipients shedding Epstein‐Barr virus DNA pre‐transplant: A prospective study

Epstein‐Barr virus (EBV) poses a significant threat to patient and graft survival post‐transplant. We hypothesized that recipients who shed EBV at transplant had less immunologic control of the virus and hence were more likely to have active EBV infection and disease post‐transplant. To test this hypothesis, we conducted a 5‐year prospective study in primary solid organ transplant recipients. We measured EBV DNA in oral washes and blood samples by quantitative PCR before transplant and periodically thereafter for up to 4 years. Pre‐transplant samples were available from 98 subjects. EBV DNA was detected pre‐transplant in 32 of 95 (34%) and 5 of 93 subjects (5%) in oral wash and blood, respectively. Recipients with and without detectable pre‐transplant EBV DNA were not significantly different demographically and had no significant difference in patient and graft survival (P = .6 for both comparisons) or post‐transplant EBV viremia‐free survival (P = .8). There were no cases of EBV‐related disease or post‐transplant lymphoproliferative disorder (PTLD) in any of the patients with detectable EBV DNA pre‐transplant. In conclusion, detectable EBV DNA pre‐transplant was not associated with differences in patient/graft survival, post‐transplant EBV viremia, or EBV‐related diseases including PTLD.     

Clinical Utility of Cytomegalovirus Viral Load in Bronchoalveolar Lavage in Lung Transplant Recipients

The utility of cytomegalovirus (CMV) viral load (VL) by quantitative hybrid capture assay (Q-HCA) was investigated in bronchoalveolar lavage (BAL) from lung transplant recipients and compared with BAL cultures and blood VL. Forty-three consecutive BAL samples from 27 lung transplant recipients were analyzed. All samples had shell vial (SV) cultures in addition to Q-HCA. Histopathology was done on all lung tissues, and immunohistochemistry (IHC) in those with positive CMV cultures. Fifteen (56%) lung transplant recipients had both positive BAL SV cultures and BAL VL. Five of 15 had CMV pneumonitis with a VL in BAL >500 000 copies/mL (mean: 1638 450). Ten patients without CMV pneumonitis had VL in BAL <500 000 copies/mL (mean 81 820, p = 0.002). High VL in BAL and blood invariably meant CMV pneumonitis, but 2 patients with CMV pneumonitis had high BAL VL but relatively low blood VL. Initial CMV seronegativity was associated with pneumonitis (4/5 vs. 1/10; p = 0.004) and higher BAL CMV VL (p = 0.03). High CMV BAL or blood VL did not correlate with acute rejection or development of bronchiolitis obliterans syndrome (BOS). High CMV VL in BAL in lung transplant recipients is strongly associated with CMV pneumonitis, and may be more predictive than peripheral blood viral load.     

Parasitic infections in organ transplantation

More than 340 parasitic species infect more than 3 billion people worldwide with varying morbidity and mortality. The Tropics constitute the main reservoir of infection with the highest clinical impact, owing to favorable ecological factors. Acquisition of infection, clinical severity, and outcome of a parasitic disease depend on innate and acquired host immunity as well as the parasite's own immune response against the host when infection is established. Organ transplant recipients may acquire significant parasitic disease in 3 ways: transmission with the graft, de novo infection, or activation of dormant infection as a consequence of immunosuppression. Malaria, Trypanosoma, Toxoplasma, and Leishmania are the principal parasites that may be transmitted with bone marrow, kidney, or liver homografts, and microsporidia with xenotransplants. De novo infection with malaria and kala-azar may occur in immunocompromised travelers visiting in endemic areas, while immunocompromised natives are subject to superinfection with different strains of endemic parasites, reinfection with schistosomiasis, or rarely, with primary infections such as acanthamoeba. The list of parasites that may be reactivated in the immunocompromised host includes giardiasis, balantidiasis, strongyloidiasis, capillariasis, malaria, Chagas' disease, and kalaazar. The broad clinical syndromes of parasitic infection in transplant recipients include prolonged pyrexia, lower gastrointestinal symptoms, bronchopneumonia, and meningoencephalitis. Specific syndromes include the hematologic manifestations of malaria, myocarditis in Chagas' disease, acute renal failure in malaria and leishmaniasis, and the typical skin lesions of Chagas' and cutaneous leishmaniasis. Many antiparasitic drugs have the potential for gastrointestinal, hepatic, renal, and hematologic toxicity, and may interact with the metabolism of immunosuppressive agents. It is recommended that transplant clinicians have a high index of suspicion of parasitic infections as an important transmission threat, as well as a potential cause of significant posttransplant morbidity.     

Arenaviruses and West Nile Virus in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the epidemiology, diagnosis, prevention, and management of infection due to Arenaviruses and West Nile Virus (WNV) in the pre‐ and post‐transplant period. Arenaviruses and WNV have been identified as causes of both donor‐derived and post‐transplant infection. Most data related to these infections have been published in case reports and case series. Transplant recipients may become infected with Arenaviruses if they, or their donors, are exposed to wild rodents or infected pet rodents. Lymphocytic choriomeningitis virus is the most commonly recognized Arenavirus among transplant recipients and should be considered when transplant recipients present with fever, hepatitis, meningitis/encephalitis, and/or multisystem organ failure. WNV is a mosquito‐borne virus, and as such, its incidence varies yearly depending on environmental conditions. WNV in transplant recipients typically presents with fever, myalgias, and rash; approximately one in 40 develop neuroinvasive disease. Due to its morbidity, the Organ Procurement and Transplantation Network recently mandated that transplant centers screen living donors for WNV infection in endemic areas. Little is known about the optimal treatment of Arenaviruses or WNV; reduction in immunosuppression and supportive care are the mainstays of management at present.     

Cryptococcosis in solid organ transplantation—Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of cryptococcosis in the pre‐ and post‐transplant period. The current update now includes a discussion of cryptococcosis, which is the third most common invasive fungal infection in SOT recipients. Infection often occurs a year after transplantation; however, early infections occur and donor‐derived infections have been described within 3 months after transplant. There are two main species that cause infection, Cryptococcus neoformans and C gattii. Clinical onset may be insidious, but headaches, fevers, and mental status changes should warrant diagnostic testing. The lateral flow cryptococcal antigen assay is now the preferred test from serum and cerebrospinal fluid due to its rapidity, accuracy, and cost. A lumbar puncture with measurement of opening pressure is recommended for patients with suspected or proven cryptococcosis. Lipid amphotericin B plus 5‐flucytosine is used as initial treatment of meningitis, disseminated infection, and moderate‐to‐severe pulmonary infection, followed by fluconazole as consolidation therapy. Fluconazole is effective for mild‐to‐moderate pulmonary infection. Immunosuppression reduction as part of management may lead to immune reconstitution syndrome that may resemble active disease.     

Human T‐cell lymphotrophic virus in solid‐organ transplant recipients: Guidelines from the American society of transplantation infectious diseases community of practice

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of Human T‐cell lymphotrophic virus 1 (HTLV)‐1 in the pre‐ and post‐transplant period. HTLV‐1 is an oncogenic human retrovirus rare in North America but endemic in the Caribbean and parts of Africa, South America, Asia, and Oceania. While most infected persons do not develop disease, <5% will develop adult T‐cell leukemia/lymphoma or neurological disease. No proven antiviral treatment for established HTLV‐1 infection is available. The effect of immunosuppression on the development of HTLV‐1‐associated disease in asymptomatically infected recipients is not well characterized, and HTLV‐1‐infected individuals should be counseled that immunosuppression may increase the risk of developing HTLV‐1‐associated disease and they should be monitored post‐transplant for HTLV‐1‐associated disease. Currently approved screening assays do not distinguish between HTLV‐1 and HTLV‐2, and routine screening of deceased donors without risk factors in low seroprevalence areas is likely to result in significant organ wastage and is not recommended. Targeted screening of donors with risk factors for HTLV‐1 infection and of living donors (as time is available to perform confirmatory tests) is reasonable.     

Screening of donor and candidate prior to solid organ transplantation—Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

This updated section of the guideline from the Infectious Diseases Community of Practice of the American Society of Transplantation reviews the screening of donor and candidate prior to solid organ transplantation. Screening of donor and candidate is vital for optimizing post‐transplant outcomes. Risk assessment based on detailed history and appropriate diagnostic evaluation is essential. Serologic screening for certain viral infections is important and aids in immunization counseling and risk mitigation of recipients. In addition to serology, nucleic acid testing for hepatitis B, hepatitis C and human immunodeficiency virus has been required for deceased and living donors. Certain endemic exposure may warrant additional evaluation beyond recommended standard testing. Diagnosed infection in the donor or recipient warrants treatment as well as additional testing and/or prophylaxis to mitigate risk for post‐transplant complications. Certain infections in the immediate pre‐transplant period may warrant delay of transplantation.     

Non‐HLA‐matched 3rd party vascular allograft in renal transplant may lead to sensitization against donor HLA

3rd party donor vessels are often used for vascular reconstruction in organ transplantation. While current practice ensures that 3rd party vessels are blood group matched, HLA matching to the non‐intended recipient is not performed. This practice potentially sensitizes the recipient and may reduce their future chance of renal transplant from a larger pool of donors. We examined our cohort of renal transplant recipients who received non‐HLA‐matched 3rd party vessels for the de‐novo development of donor‐specific HLA antibodies. Our institution's Human Tissue Authority (HTA) blood vessel registers were examined to identify stored donor vessels and their non‐intended recipients. Donor vessel HLA status was cross‐referenced with the recipient HLA status. Between 2004 and 2014, five patients were identified that received 3rd party non‐HLA‐matched vessels for vascular reconstruction during renal transplantation. Three patients (60%) subsequently developed donor‐specific HLA antibodies. These data provide evidence that use of non‐HLA‐matched stored 3rd party vascular grafts may lead to sensitization in the recipient. Where time permits, HLA matching should be performed to avoid this allogeneic response. Laboratories monitoring DSA should be aware of any patient receiving a non‐HLA‐matched 3rd party vascular graft, and recipients may benefit from increased post‐transplant immunological vigilance.     

Intestinal parasites including Cryptosporidium,Cyclospora, Giardia,and Microsporidia,Entamoeba histolytica,Strongyloides, Schistosomiasis,and Echinococcus: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of intestinal parasites in the pre‐ and post‐transplant period. Intestinal parasites are prevalent in the developing regions of the world. With increasing travel to and from endemic regions, changing immigration patterns, and the expansion of transplant medicine in developing countries, they are increasingly recognized as a source of morbidity and mortality in solid‐organ transplant recipients. Parasitic infections may be acquired from the donor allograft, from reactivation, or from de novo acquisition post‐transplantation. Gastrointestinal multiplex assays have been developed; some of the panels include testing for Cryptosporidium, Cyclospora, Entamoeba histolytica, and Giardia, and the performance is comparable to conventional methods. A polymerase chain reaction test, not yet widely available, has also been developed to detect Strongyloides in stool samples. New recommendations have been developed to minimize the risk of Strongyloides donor‐derived events. Deceased donors with epidemiological risk factors should be screened for Strongyloides and recipients treated if positive as soon as the results are available. New therapeutic agents and studies addressing the optimal treatment regimen for solid‐organ transplant recipients are unmet needs.     

BK virus-associated renal problems—clinical implications

BK virus (BKV), a human polyomavirus, infects most of the human population, but clinically relevant infections are usually limited to individuals who are immunosuppressed. After primary infection, BKV remains latent in the kidneys and can be reactivated in immune deficiency conditions, including transplantation. As primary infection occurs in childhood, BKV may be particularly important in the pediatric transplant population. BKV is associated with tubulointerstitial nephritis and ureteric stenosis in renal transplant recipients and hemorrhagic cystitis in bone marrow transplant recipients. There are increasing reports of BKV causing nephropathy and cystitis in non-renal solid organ transplant recipients and other immunodeficiency diseases. This might be related to the use of more potent immunosuppressive regimens or increasing awareness of BKV as an important pathogen. Diagnosis of BKV disease is by biopsy. Histopathological changes in renal biopsy specimens may mimic rejection or drug toxicity, but BKV nuclear inclusions can be seen. Treatment is by reduction of immunosuppression. Antiviral agents such as cidofovir are showing promise. BKV DNA polymerase chain reaction in blood or biopsy may be helpful in monitoring therapy. The impact of BKV disease in children is not well understood and prospective studies are needed to elucidate this further. This article reviews the current understanding of BKV-associated renal problems.     

Visceral leishmaniasis after kidney transplantation: Report of a new case and a review of the literature

Visceral leishmaniasis (VL) is a parasitic disease, caused by protozoa of the genus Leishmania, transmitted by the phlebotomies sand fly. In the last 20 years, the increasing frequency of organ transplantations and the improvement of associated immunosuppressive treatments have led to the recognition of several cases of VL complicating organ transplantation. Actually, less than 100 cases of VL after kidney transplantation are reported in the literature. In this context, VL is fatal without antileishmanial treatment which constitutes a difficult challenge.We report a case of VL in Tunisian renal transplant recipient treated successfully by liposomal amphotericin B (Ambisome®, Gilead Sciences Inc). Also, we review the epidemiological, clinical, biological and therapeutic aspects of VL associated with renal transplantation reported in the literature.Our report identifies that VL should be suspected in renal transplant recipients presenting unexplained fever, splenomegaly and pancytopeny. It also suggests a serological testing for leishmaniasis in the pre-operative check-up of transplant patients and donors living or traveling in endemic areas of leishmaniasis. Moreover, recipients should be tested regularly for leishmaniasis after transplantation. Liposomal amphotericin B may be considered the treatment of choice of VL, since it has a lower incidence of side effects.     

Hepatitis E Virus Seroprevalence in Free‐Ranging Deer in Canada

Hepatitis E virus infection (HEV) is an important public health concern not only in traditional endemic areas, but also in some industrialized countries where both domesticated and wild animals have been recognized as potential zoonotic reservoirs implicated in HEV transmission. While the prevalence of infection in the deer population in Europe and Asia has been thoroughly investigated, it remains largely undetermined in North America. We assessed the presence of HEV in three different species of free‐range deer in Canada. The seroprevalence of HEV among deer in Canada was 8.8% in white‐tailed deer, 4.5% in mule deer and 3.2% in caribou. Hepatitis E virus RNA was not detected. Overall, data indicate that HEV infection occurs in deer in Canada. The absence of viraemia and the low seroprevalence especially in barren‐ground caribou which is an important part of the diet in many northern communities suggests that the risk of zoonotic transmission may be less pronounced compared to other countries.     

Visceral Leishmaniasis in Renal Transplant Recipients: Report of 2 Cases

Visceral leishmaniasis is a disease caused by the protozoan Leishmania and is transmitted by Lutzomyia longipalpis (sand fly). It is an endemic parasitic infection in numerous areas around the Mediterranean basin. Though immunocompetent patients may not develop the disease, in transplant recipients the use of corticoids and intensified immunosuppressants to prevent graft rejection may accelerate the disease, causing severe damage to the liver, spleen, and hematopoietic system. We report 2 cases of visceral leishmaniasis with an atypical presentation in transplant recipients. The first patient, who had a kidney transplant, was treated successfully with liposomal amphotericin B, and the second patient, a combined kidney-pancreas transplant recipient, suffered a relapse 3 years after treatment. Visceral leishmaniasis should be considered in the differential diagnosis of pancytopenia or unexplained fever occurring after organ transplantation in patients living in endemic areas or returning from endemic countries.