Infections In Organ Transplant Recipients Research Articles

Emerging & Rare Fungal Infections in Solid Organ Transplant Recipients

Emerging & Rare Fungal Infections in Solid Organ Transplant Recipients

Dengue Hemorrhagic Fever in a Peripheral Blood Stem Cell Transplant Recipient: The First Case Report

Dengue infection, a mosquito-borne infectious disease in tropical and subtropical areas, has recently become an emerging global disease. Clinical course of dengue infection may be unfavorable in immunocompromised patients. In this report, we present a 16-year-old female patient with acute myeloid leukemia and receiving allogeneic peripheral blood stem cell transplant who was hospitalized at King Chulalongkorn Memorial Hospital, Bangkok, Thailand, due to fever, headache, and myalgia for one day. During hospitalization, she developed capillary leakage syndrome and progressive thrombocytopenia. A diagnosis of dengue hemorrhagic fever was made and confirmed by positive dengue serology and polymerase chain reaction testing. She made a full recovery 14 days after hospitalization. In conclusion, this is the first reported case of dengue hemorrhagic fever in a peripheral blood stem cell transplant recipient. In addition, we review all previous reports of dengue infection in organ transplant recipients.

Clinical Aspects of Invasive Candidiasis in Solid Organ Transplant Recipients

Increasingly potent immunosuppressive agents have dramatically reduced the incidence of rejection of transplanted organs while increasing patients' susceptibility to opportunistic infections. Invasive fungal infections (IFIs) following solid organ transplantation, despite having a lower incidence than bacterial and viral infections, remain a major cause of morbidity and mortality. Fungal infections in patients with different types of solid organ transplant have different incidences, underlying pathogenetic mechanisms and modes of clinical presentation. Two genera, Aspergillus and Candida, are responsible for the vast majority of fungal infections in solid organ transplant recipients accounting for more than 80% of IFIs. Candidaemia is the most frequent clinical manifestation of Candida spp. infection, regardless of the transplanted organ and typically occurs within 1 month of transplantation. Management of fungal infections varies widely among different transplant centres. Large multicentre, randomized controlled trials evaluating risk factors, diagnosis, prophylaxis and treatment strategies for fungal infection in organ transplant recipients are lacking. Consequently, a uniform consensus on each of these does not exist, and clinical practice has evolved mainly from case series, anecdotal experiences and single-centre trials. Targeted prophylaxis is recommended for high-risk liver, pancreas and small bowel patients. Management of established infection is based on guidelines in the general population and should take into consideration prior prophylaxis, severity of infection and the possibility of drug-drug interactions in these immunosuppressed patients.

Dengue hemorrhagic fever in a peripheral blood stem cell transplant recipient: the first case report

Dengue infection, a mosquito-borne infectious disease in tropical and subtropical areas, has recently become an emerging global disease. The clinical course of dengue infection may be unfavorable in immunocompromised patients. In this report, we present a 16-year old female patient with acute myeloid leukemia who received allogeneic peripheral blood stem cell transplant five months prior to presentation. She was hospitalized at King Chulalongkorn Memorial Hospital, Bangkok, Thailand, due to fever, headache, and myalgia for one day. During hospitalization, she developed capillary leakage syndrome and progressive thrombocytopenia. A diagnosis of dengue hemorrhagic fever was made and confirmed by positive dengue serology and polymerase chain reaction testing. She made a full recovery 14 days after hospitalization. Our case possibly acquired dengue virus from infected mosquitoes while visiting her relatives four days before her present illness. In conclusion, this is the first reported case of dengue hemorrhagic fever in a peripheral blood stem cell transplant recipient. In addition, we review all previous reports of dengue infection in organ transplant recipients.

Gastrointestinal cytomegalovirus infections in organ transplant recipients

Cytomegalovirus (CMV) is a major pathogen for immunocompromised organ transplant recipients. 80 to 90% of all transplant recipients are infected by the virus; however, the incidence of CMV disease is 30 to 40%. Gastrointestinal CMV disease involving any part of the digestive tract occurs in about 10% of all patients receiving solid organ transplantation. Mucosal injury, ulcerations, erosions, haemorrhage, disorders of digestive tract motility, rarely gastrointestinal mass and perforation are the most common pathological findings in CMV disease. Diagnostics is based on endoscopy with mucosal biopsy. Histopathological examination of biopsy samples must look for specific cytomegalic cells with intranuclear (“owl's eye”) and intracytoplasmatic inclusions. Various microbiological, immunohistochemical and molecular biological assays can be performed to detect CMV in the mucosa. In established gastrointestinal CMV disease both gastroenterological and antiviral treatments are needed including intravenous ganciclovir and/or oral valganciclovir. Prevention of disease should be achieved by general prophylaxis in high-risk patients (oral valganciclovir, in special cases hyperimmune globulin); and in medium risk patients by pre-emptive therapy using microbiological surveillance.

Helicobacter pylori in solid-organ transplant recipient

Helicobacter pylori (H. pylori) infection induces a range of upper gastrointestinal diseases including chronic gastritis, peptic ulcer disease, mucosa-associated lymphatic tissue (MALT) lymphoma, and gastric adenocarcinoma with marked individual variability. In the present review, we survey the published reports on H. pylori infection in organ transplant recipients and summarize findings about the prevalence of H. pylori infection and outcomes such as peptic ulcer and MALT lymphoma induced by H. pylori infection after transplantation. The prevalence of H. pylori infection in solid-organ transplant recipients is similar to that in nontransplant controls, but may be decreased after transplantation. H. pylori infection is associated with peptic ulcer disease and MALT lymphoma after solid-organ transplantation, but the incidence of these diseases does not increase under the immunosuppressive treatment after transplantation. The relationship of H. pylori infection to de-novo gastric cancer after transplantation has not been thoroughly investigated. The best management for H. pylori infection in solid-organ transplant recipients has not been established. The association with peptic ulcer disease and MALT lymphoma indicates that H. pylori-positive recipients should be treated for the eradication of H. pylori to avoid upper gastrointestinal diseases after transplantation. However, the efficacy and efficiency of H. pylori eradication therapy before transplantation should be evaluated in future studies.

Immunizations and infectious diseases in pediatric liver transplantation

Liver transplantation (LTx) is an established and effective treatment for children with end-stage and metabolic liver disease. Improved surgical techniques and immunosuppressive regimens have led to enhanced short-term and long-term survival rates, which now approach or exceed 90%. Consequently, more children are being referred for LTx, and an increasing numbers of pediatric centers routinely perform this procedure. Infectious complications are an important cause of morbidity and mortality in children undergoing LTx. However, improvements in immune suppression management along with the availability of new antimicrobial agents and diagnostic tools have resulted in improved treatment and preventative regimens, thus reducing the impact of infectious complications on these children. This review provides an overview of the infectious complications and prevention strategies for children undergoing LTx.

Optimal Prevention of Late‐Onset Cytomegalovirus (CMV) Disease and Other Sequelae of CMV Infection in Organ Transplant Recipients

Optimal Prevention of Late‐Onset Cytomegalovirus (CMV) Disease and Other Sequelae of CMV Infection in Organ Transplant Recipients

Use of Valganciclovir for Prevention and Treatment of Cytomegalovirus Disease

The development of a valine ester for ganciclovir has allowed much-improved absorption and bioavailability of oral ganciclovir and has had a significant impact on the prevention and management of cytomegalovirus infection in the immunocompromised host. Valganciclovir offers ~60% bioavailability after oral ingestion. The administration of 900 mg of valganciclovir orally is comparable to a dose of intravenous ganciclovir of 5 mg/kg, although the peak level of ganciclovir is higher than that of oral valganciclovir [ 1 ] . Given this comparability, the use of valganciclovir for preemptive therapy and even for treatment of cytomegalovirus is becoming quite common, even with limited comparative trial data [2]. The article by Len et al [3] from the Spanish Network for Research on Infection in Transplantation (RESITRA) in this issue of Clinical Infectious Diseases reports an observational study that offers some insight into the efficacy of valganciclovir for the prevention and treatment of cytomegalovirus disease. Although this study d sign is not as rigorous as a randomized trial, and although it was subject to some investigator and clinician bias in patient selection, the data are nevertheless compelli g and demonstrate that valganciclovir can be used for preemptive therapy for cy omegalovirus infection in organ transplant recipients [3]. The definitions of success and failure in this study are rigorous, and the number of patients studied was large. Once viral replication was established, it is quite clear that valganciclovir is effective for viral suppression, to prevent progression to cytomegalovirus syndrome or organ disease. The vast majority of the data in this study derive from kidney and liver transplant recipients (and, to a lesser extent, from heart transplant patients); therefore, generalizability of the results to lung or kidney-pancreas transplant recipients is probably not justified. Furthermore, the data provide a limited experience regarding the cytomegalovirus antibody-negative recipients of transplants from antibody-positive donors, who represent the highestrisk group for late-onset and relapse. Thus, additional studies are required for these groups to provide information for such use. However, I think transplant programs can feel confident that the use of valganciclovir for preemptive therapy has merit for the vast majority of organ transplant recipients. In many programs, it is already the standard of care for either prophylaxis or preemptive therapy. Although the US Food and Drug Administration has cautioned against the use of valganciclovir for prevention of cytomegalovirus infection in liver transplant recipients [4], the data here support its use and also are consistent with what many liver transplantation programs are actually using as their protocol. The data from this Spanish group are not as compelling regarding the use of valganciclovir for treatment of invasive cytomegalovirus disease, which they label disease in tables 2 and 3 of their article [3]. The success rate of 75% is less than the success rate for intravenous ganciclovir (87.5%) or intravenous ganciclovir followed by valganciclovir (96.2%). Although the difference was not statistically significant, only 8 patients with focal were treated exclusively with valganciclovir. Although there were only 2 treatment failures, I believe that more experience will be necessary to conclude that valganciclovir therapy is appropriate initial management of tissue invasive disease. The authors do not indicate the lo-

Skin infections in organ transplant recipients

In contrast to the well-described high risk of skin cancer in organ transplant recipients, skin infections in these patients are not as well explored. Skin infections caused by viruses, bacteria or fungi represent a growing diagnostic and therapeutic challenge in the dermatological aftercare of organ transplant recipients. Differing immunosuppressive drugs and their variable dosage in chronologic sequence after transplantation probably influence the type and appearance of skin infections. The typical chronology of skin infections are wound infections, pyoderma or the reactivation of herpes viruses in the first month post-transplant; the main problems in months 2-5 are opportunistic infections and reactivation of varicella-zoster virus. After 6 months as immunosuppression is reduced, the spectrum of causative organisms approaches that of the general population; mycoses and human papilloma virus (HPV) infections dominate. A causal connection exists between infection with oncogenic viruses such as HPV, Epstein-Barr virus and human herpesvirus 8 and specific skin cancers (squamous cell carcinoma, Kaposi sarcoma and post-transplant lymphoproliferative disorders). Dermatological care of organ transplant recipients using appropriate diagnostic methods adapted to the modified clinical pattern may lead to early adequate treatment.

Disseminated Scedosporium Apiospermum Infection in Renal Transplant Recipient: Long-Term Successful Treatment With Voriconazole: A Case Report

Scedosporium apiospermum, the asexual form of Pseudallescheria boydii, is a ubiquitous fungus that represents an unfrequent complication of immune suppression. It accounts for 20% of all non- Aspergillus mold infections in organ transplant recipients. The infection can be localized or disseminated in multiple organs, including lungs, brain, joints, tendons, and skin, and is difficult to treat, due to resistance of S apiospermum to amphotericin B and other antifungal agents. The mortality rate is about 50%. To our knowledge, there are no prospective studies or registries of transplant recipients to guide diagnosis and there are no evidence-based recommendations for the optimal management of this infection. We report a case of S apiospermum infection in a woman with renal transplantation. The first occurrence of infection was a solitary nodule on the forearm, which was surgically excised. Two following relapses were disseminated to the knee, the Achilles tendon, and the skin of the left leg. The infection was successfully treated with voriconazole, but due to the severe iatrogenic immune suppression, a strong reduction in immunosuppressant drugs was needed.

Risk Factors, Clinical Characteristics, and Outcome of Nocardia Infection in Organ Transplant Recipients: A Matched Case-Control Study

Risk factors for Nocardia infection in organ transplant recipients have not been formally assessed in the current era of transplantation. We performed a matched case-control study (1:2 ratio) between January 1995 and December 2005. Control subjects were matched for transplant type and timing. Univariate matched odds ratios were determined and conditional logistic regression was performed to identify independent risk factors. Clinical and microbiological characteristics of all case patients were reviewed. Among 5126 organ transplant recipients, 35 (0.6%) were identified as having cases of Nocardia infection. The highest frequency was among recipients of lung transplants (18 [3.5%] of 521 patients), followed by recipients of heart (10 [2.5%] of 392), intestinal (2 [1.3%] of 155), kidney (3 [0.2%] of 1717), and liver (2 [0.1%] of 1840) transplants. In a comparison of case patients with 70 matched control subjects, receipt of high-dose steroids (odds ratio, 27; 95% confidence interval, 3.2-235; P=.003) and cytomegalovirus disease (odds ratio, 6.9; 95% confidence interval, 1.02-46; P=.047) in the preceding 6 months and a high median calcineurin inhibitor level in the preceding 30 days (odds ratio, 5.8; 95% confidence interval, 1.5-22; P=.012) were found to be independent risk factors for Nocardia infection. The majority of case patients (27 [77%] of 35) had pulmonary disease only. Seven transplant recipients (20%) had disseminated disease. Nocardia nova was the most common species (found in 17 [49%] of the patients), followed by Nocardia farcinica (9 [28%]), Nocardia asteroides (8 [23%]), and Nocardia brasiliensis (1 [3%]). Of the 35 case patients, 24 (69%) were receiving trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia prophylaxis. Thirty-one case patients (89%) experienced cure of their Nocardia infection. Receipt of high-dose steroids, history of cytomegalovirus disease, and high levels of calcineurin inhibitors are independent risk factors for Nocardia infection in organ transplant recipients. Our study provides insights into the epidemiology of Nocardia infection in the current era, a period in which immunosuppressive and prophylactic regimens have greatly evolved.

P712 Risk factors for Nocardia infection in organ transplant recip-ients: a matched case-control study over an 11-year period

P712 Risk factors for Nocardia infection in organ transplant recip-ients: a matched case-control study over an 11-year period

Systemic and cerebrospinal fluid T-helper cytokine responses in organ transplant recipients with Cryptococcus neoformans infection

Background The role of Th1 and Th2 mediated cytokine responses in the pathogenesis of Cryptococcus neoformans infection in organ transplant recipients has not been defined. Methods We assessed cytokine levels in the sera and CSF collected prospectively at the time of diagnosis of infection in 25 transplant recipients with cryptococcosis. Serum levels were compared with those in healthy individuals and transplant recipients without cryptococcosis. IFN-γ or IL-12 (Th1)/IL-10 (Th2) ratio < 1.0 was considered a dominant Th2 response. Results Cases had lower ratios of IFN-γ/IL-10 ( p = 0.03) and IL-12/IL-10 ( p = 0.03) compared to healthy individuals. Cytokine responses, however, did not differ significantly for cases vs. transplant controls. Cases with fungemia compared to those without fungemia tended to have higher serum IL-10 levels ( p = 0.07) and lower IL-12/IL-10 ratios ( p = 0.06). CSF ratios of IFN-γ/IL-10 ( p = 0.04) and IL-12/IL-10 ( p = 0.04) were lower in cases with cryptococcal meningitis compared to those without meningitis; 80% (8/10) of the cases with cryptococcal meningitis vs. 0% (4/4) of those without meningitis had CSF IFN-γ/IL-10 ratio of < 1.0 ( p = 0.015). The levels of IL-10 ( p = 0.04) and IFN-γ ( p = 0.04) in the CSF in cases with cryptococcal meningitis were significantly higher than those in their serum, respectively. Conclusions High expression of Th2 phenotype in cryptococcal meningitis and in fungemia suggests that Th dysregulation may contribute to the pathogenesis of cryptococcosis in organ transplant recipients.

Immunotherapy with virus‐specific cytotoxic T lymphocytes after organ transplantation

Adoptive immunotherapy with antigen specific cytotoxic T lymphocytes can favorably impact the outcome of serious herpesvirus infections in organ transplant recipients. Current challenges in this field include the determination of which patients are at highest risk, and the development of protocols that permit more rapid expansion of virus specific effector cells.

Bloodstream infections in organ transplant recipients receiving alemtuzumab: No evidence of occurrence of organisms typically associated with profound T cell depletion

Alemtuzumab is a humanized monoclonal antibody directed against CD52, a cell surface antigen expressed on B and T lymphocytes, monocytes and NK cells. Its use results in a profound decrease in CD4 positive T lymphocytes. Alemtuzumab is used as induction immunosuppression and therapy for rejection in organ transplant recipients in some centers. We followed a cohort of 449 consecutive transplant recipients who received alemtuzumab to determine the occurrence of bloodstream infections, particularly those previously associated with decrease in CD4 positive T lymphocytes. Fifteen percent (69/449) patients had at least one episode of bloodstream infection. However, no patient had bacteremia with Streptococcus pneumoniae, Listeria monocytogenes, non-typhoidal Salmonella or Mycobacterium avium complex. Fungaemia was rare, occurring in 1.5% of patients. The most common organisms isolated from the blood were Staphylococcus aureus (21 episodes), coagulase negative Staphylococcus (14 episodes), Klebsiella pneumoniae (12 episodes), Enterococcus faecium (11 episodes), Pseudomonas aeruginosa (10 episodes), Enterococcus faecalis (9 episodes) and Escherichia coli (7 episodes). We conclude that although alemtuzumab use is associated with profound CD4 positive T lymphocyte depletion, alemtuzumab does not seem to be associated with an increased risk of bloodstream infection with pathogens typically seen in other disorders of CD4 cell depletion, such as acquired immunodeficiency syndrome.

Viral Infections Affecting the Skin in Organ??Transplant Recipients

Viral skin infections are common findings in organ transplant recipients. The most important etiological agents are the group of human herpesviruses (HHV), human papillomaviruses (HPV), and molluscum contagiosum virus. HHV that are important in this group of patients are herpes simplex virus (HSV) types 1 and 2, varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), HHV-6 and -7, and HHV-8, which causes Kaposi sarcoma (KS). HSV infections are characterized by their ability to establish latency and then reactivate at a later date. The most common manifestations of HSV infection in organ transplant recipients are mucocutaneous lesions of the oropharynx or genital regions. Treatment is usually with acyclovir, valaciclovir, or famciclovir. Acyclovir resistance may arise although the majority of acyclovir-resistant strains have been isolated from AIDS patients and not organ transplant recipients. In such cases, alternatives such as foscarnet, cidofovir, or trifluridine may have to be considered. VZV causes chickenpox as well as herpes zoster. In organ transplant recipients, recurrent herpes zoster can occur. Acute chickenpox in organ transplant patients should be treated with intravenous acyclovir. CMV infection occurs in 20-60% of all transplant recipients. Cutaneous manifestations, which include nonspecific macular rashes, ulcers, purpuric eruptions, and vesiculobullous lesions, are seen in 10-20% of patients with systemic infection and signify a poor prognosis. The present gold standard for treatment is ganciclovir, but newer drugs such as valganciclovir appear promising. EBV is responsible for some cases of post-transplant lymphoproliferative disorder, which represents the greatest risk of serious EBV disease in transplant recipients. HHV-6 and HHV-7 are two relatively newly discovered viruses and, at present, the body of information concerning these two agents is still fairly limited. KS is caused by HHV-8, which is the most recently discovered lymphotrophic HHV. Iatrogenic KS is seen in solid-organ transplant recipients, with a prevalence of 0.5-5% depending on the patient's country of origin. HPV is ubiquitous, and organ transplant recipients may never totally clear HPV infections, which are the most frequently recurring infections in renal transplant recipients. HPV infection in transplant recipients is important because of its link to the development of certain skin cancers, in particular, squamous cell carcinoma. Regular surveillance, sun avoidance, and patient education are important aspects of the management strategy.

臓器移植領域における深在性真菌症：予防と先制治療は如何にあるべきか？

Although the opportunity to discuss infectious complications in solid organ transplantation is increasing in Japan as elsewhere, the length of clinical experience in extra-renal transplantation is still short and even experience in living donor organ transplant is very limited except for those involving the kidney or liver transplantation. Risk of invasive fungal infection in organ transplant recipients is highly dependent on the immunocompromised status accompanying end-stage organ failure before transplant operation and on the resultant history of infectious complications. These factors as well as surgical and postoperative should be incorporated in a systematic and dynamic manner to evaluate risk of invasive fungal infection. In addition to prophylactic management based on such risk evaluation, it is desirable that preemptive treatment be started on quantification of clinical symptoms, imaging diagnosis, screening culture, and serological indices. Emergence of newer and more potent antifungal agents with lower toxicity potentially changes the concept of antifungal treatment. On the other hand, early and impression-oriented preemptive treatment has tended to increase. It is still questionable whether the knowledge obtained from Western experience can be directly applied to solid organ transplant medicine in Japan. Extensive and detailed clinical experience is mandatory to pursue diagnosis, epidemiology, and risk factors in Japan and establish our criteria for prophylactic and preemptive use of antifungal agents.

Disseminated Acanthamoebiasis after Lung Transplantation

Protozoan infections in organ transplant recipients are rare. We report a fatal case of disseminated acanthamoebiasis in a bilateral lung transplant recipient that presented with cutaneous lesions, respiratory failure, and seizures. Acanthamoeba infection may be identified in transplant recipients with exposure to water who develop non-healing cutaneous ulcers with granulomatous inflammation. Cutaneous lesions are the initial manifestation of infection and a harbinger of dissemination. Early institution of combination anti-microbial therapy is therefore necessary for effective treatment and prevention of lethal spread to the central nervous system.

Intracranial Granuloma and Skull Osteolysis: Complication of a Primary Cutaneous Cryptococcosis in a Kidney Transplant Recipient

Cryptococcosis is the third most common invasive fungal infection in organ transplant recipients after candidiasis and aspergillosis. It occurs almost exclusively in the late posttransplantation period (>6 months after the initiation of immunosuppression). Subclinical onset of meningitis is the usual clinical presentation. Despite initiation of therapy, the mortality rate associated with this infection in this patient population remains high. To the best of our knowledge, this report describes one of the first cases of a rare entity: a primary cutaneous cryptococcosis in a renal transplant recipient disclosed by skull osteomyelitis and pseudotumoral intracranial extension. Surgical debridement and azole antifungal therapy were performed. Ten months after the onset of treatment, the patient feels good, clinical examination findings are normal, and no sign of evolutive cryptococcosis is noted.