Opportunistic Infections of the Esophagus Not Responding to Oral Systemic Antifungals in Patients with AIDS: Their Frequency and Treatment

To determine the spectrum of esophageal disease responsible for dysphagia/odynophagia in AIDS patients not responding to current oral antifungals, we studied 49 consecutive patients whose esophageal symptoms failed to improve after a minimum of 3 wk of therapy with oral ketoconazole or fluconazole. An esophageal candidiasis resistant to oral antifungals was the most frequent disease found (22 single infections and four mixed with viruses). Viral esophagitis was identified in 13 cases (eight herpes simplex virus and five cytomegalovirus), and an esophagitis of unknown origin was documented in two patients. Other causes of symptoms included peptic esophagitis (four cases), esophageal stenosis (two cases), and Kaposi's sarcoma of the esophagus (one patient). Most patients with esophageal opportunistic infection experienced prompt relief of symptoms and complete endoscopic resolution on the specific antifungal (amphotericin B or fluconazole iv) or antiviral (acyclovir or gancyclovir iv) therapy, with the exception of those with concomitant fungal and viral infection who responded poorly to treatment. We conclude that most AIDS patients with dysphagia/odynophagia who do not respond to oral antifungals have an opportunistic infection of the esophagus. Nevertheless, specific antifungal or antiviral therapy is worthwhile, because it will eradicate, at least temporarily, the causative pathogens in most such patients.     

Herpes simplex virus resistant to acyclovir. A study in a tertiary care center

STUDY OBJECTIVE: To determine the sensitivity of herpes simplex virus isolates to acyclovir and the importance of resistant isolates in hospitalized patients. DESIGN: Retrospective incidence cohort study. SETTING: All herpes simplex virus isolates cultured over 1 year from patients followed at a tertiary care center. PATIENTS: Consecutive herpes simplex virus isolates were collected from 207 patients, including immunocompetent patients, patients with malignancy, neonates, bone marrow and organ transplant recipients, and patients seropositive for human immunodeficiency virus. MEASUREMENTS AND MAIN RESULTS: A rapid nucleic acid hybridization method was used to assess susceptibility to acyclovir. Acyclovir-resistant herpes simplex viruses were recovered from 7 of 148 immunocompromised patients (4.7%) but from none of 59 immunocompetent hosts. Clinical disease was found in all 7 patients with resistant herpes simplex virus and was more severe in pediatric patients. All resistant isolates were from acyclovir-treated patients and had absent or altered thymidine kinase activity by plaque autoradiography. CONCLUSION: Herpes simplex virus resistant to acyclovir arises relatively frequently in immunocompromised patients and may cause serious disease. Rapid detection of resistance permits antiviral therapy to be individualized. Antiviral susceptibility testing to monitor viral resistance should be encouraged, especially in tertiary care settings.     

The Use of Cyclosporine for Recurrent Hepatitis C After Liver Transplant: A Randomized Pilot Study

Background  

Cyclosporine has antiviral activity in vitro against hepatitis C (HCV). We performed a pilot study to prospectively determine the antiviral effect of cyclosporine during therapy with PEGalfa-2a and ribavirin in liver transplant recipients with recurrent HCV infection.     

Opportunistic infections in patients with inflammatory bowel disease undergoing immunosuppressive therapy

Immunosuppressive agents (azathioprine, methotrexate) are increasingly being used in the treatment of inflammatory bowel disease. The use of immunosuppressive agents is associated with a greater risk of opportunistic infections, the most frequent of which are those caused by cytomegalovirus and varicella zoster virus. We present four cases of opportunistic infections due to Herpesviruses in patients undergoing immunosuppressive treatment with azathioprine for Crohn's disease. We also review the literature published on this topic. Two patients presented cutaneous varicella complicated by pneumonia and esophagitis respectively, one patient had cutaneous herpes zoster and the other had fatal pneumonia possibly caused by the Herpesvirus. In the first three the clinical course of the infection was favorable after withdrawing immunosuppressant treatment and initiating treatment with aziclovir. In patients Crohn's disease azathioprine treatment increases the risk of opportunistic infection by Herpesvirus. However, in the absence of other factors that increase immunosuppression, these infections usually have a benign course with specific antiviral therapy.     

A case of acute liver failure caused by herpes simplex type 2

Unlike mucocutaneous infections, disseminated herpes simplex virus infections are rare and often fatal owing to acute liver failure (ALF). Typically, the course of the disease is rapid and the lack of specific symptoms may result in delay in diagnosis. This study reports a case of genital herpes caused by herpes simplex-type 2 that resulted in ALF. The patient was a 24-y-old woman with a 1 y history of Crohn's disease, treated with oral prednisolone. She was hospitalized with fatigue, anorexia and abdominal pain. Blood tests showed pancytopenia, renal failure and coagulopathy. Pelvic examination revealed signs of severe colpitis and prompt therapy with parenteral acyclovir was initiated. Despite the early institution of antiviral therapy, progressive hepatic coma, gastrointestinal bleeding, oliguria and severe intracranial hypertension characterized the clinical course. The patient received intensive supportive care and recovered without liver grafting. A subsequent screening for immunodeficiency diseases revealed an immeasurable blood mannose-binding lectin (MBL) concentration. 10 weeks after admission, she was discharged for further rehabilitation. This case stresses the importance of suspecting disseminated herpes virus infection in patients with ALF without known aetiology as it may secure prompt initiation of antiviral therapy and reduce the risk that transplantation is needed for survival.     

Management of Chronic Hepatitis B in Special Populations: Immunosuppressed Patients and Chronic Kidney Disease

Hepatitis B virus (HBV) infection remains an important cause of liver disease in the population with chronic kidney disease, including patients on long-term dialysis and renal transplant (RT) recipients. Diminished survival due to hepatitis B has been observed after RT. A thorough evaluation, including liver biopsy as well as assessment of serum markers of HBV replication (ie, hepatitis B e antigen and/or HBV DNA) is required before transplantation. Tolerance to interferon is poor both in dialysis patients and after renal transplant. Oral antiviral therapy now permits safe and potent antiviral treatment of HBV-related liver disease in chronic kidney disease patients with prevention of progressive liver disease. Preliminary evidence shows an improved survival of HBsAg positive renal allograft recipients on antiviral therapy. However, numerous issues concerning the treatment of hepatitis B in the population with chronic kidney disease remain unclear and further clinical trials are needed.     

Treatment of herpes simplex esophagitis in an immunocompetent patient with intravenous acyclovir

A 35-yr-old, immunocompetent male was admitted complaining of severe odynophagia. He was diagnosed as having herpes simplex esophagitis and was started on intravenous acyclovir 5 mg/kg every 8 h on the day of admission. His response was dramatic. Within 24 h he was virtually asymptomatic. Acyclovir therapy in immunocompetent adults with esophagitis has been described in only a handful of cases in the literature, although the therapy is well established in immunocompromised patients. We review the English literature and discuss the efficacy of the therapy. Acyclovir therapy may be beneficial in immunocompetent patients with particularly severe odynophagia.     

Impact of new treatment options for hepatitis c virus infection in liver transplantation

Liver transplant candidates and recipients with hepatitis C virus(HCV)-related liver disease greatly benefit from an effective antiviral therapy. The achievement of a sustained virological response before transplantation can prevent the recurrence of post-transplant HCV disease that occurs universally and correlates with enhanced progression to graft cirrhosis. Previous standard-of-care regimens(e.g.,pegylated-interferon plus ribavirin with or without first generation protease inhibitors,boceprevir and telaprevir) displayed suboptimal results and poor tolerance in liver transplant recipients. A new class of potent direct-acting antiviral agents(DAA) characterized by all-oral regimens with minimal side effects has been approved and included in the recent guidelines for the treatment of liver transplant recipients with recurrent HCV disease. Association of sofosbuvir with ribavirin and/or ledipasvir is recommended in liver transplant recipients and patients with decompensated cirrhosis. Other regimens include simeprevir,daclatasvir,and combination of other DAA. Possible interactions should be monitored,especially in coinfected human immunodeficiency virus/HCV patients receiving antiretrovirals.     

Progressive esophagitis from acyclovir-resistant herpes simplex. Clinical roles for DNA polymerase mutants and viral heterogeneity?

Clinically acquired acyclovir resistance in herpes simplex has usually been associated with a deficiency in viral thymidine kinase, which, in turn, has been linked with attenuated virulence in animal models. Diminished pathogenicity in thymidine kinase-deficient isolates has been partly responsible for controversies about the clinical significance of antiviral resistance. We report on a series of resistant virus isolates from a patient who had severe, progressive esophagitis. These isolates had various thymidine kinase activities, ranging from 2.8% to 130% when compared with the activity of the isolate obtained before treatment; the resistant isolate 615 retained enzyme activity as well as neurovirulence in an encephalitis model. Plaque purification showed a heterogeneous mixture containing at least one acyclovir-resistant, foscarnet-resistant plaque isolate (615.8) fully able to phosphorylate acyclovir. The 3.3-kbp BamHI fragment containing most of the DNA polymerase gene from isolate 615.8 was purified and used to successfully transfer both acyclovir and foscarnet resistance. Acquisition of in-vitro acyclovir resistance was associated with progression of clinical disease, as well as with maintenance of pathogenicity in an animal model and at least one mutation in viral DNA polymerase. Patients with herpes simplex infections that progress during acyclovir therapy should be observed for acquisition of resistance in the setting of antiviral chemotherapy; future studies should also consider the presence of heterogeneous virus populations in such patients.     

CMV esophagitis: sequelae of radiation therapy

Cytomegalovirus (CMV) infection has been commonly described in immunocompromised patients. Antiretroviral therapy in HIV patients and routine antiviral prophylaxis in transplant recipients have helped to curb the majority of clinically significant CMV infections. Patients undergoing chemotherapy are also closely monitored for leucopenia and opportunistic infections. We describe here a case of CMV esophagitis in a patient with a solid tumor and no prior exposure to chemotherapy. This patient was immunocompromised from his recent radiation therapy and concurrent steroid use. This case demonstrates the fact that even without any exposure to chemotherapy, extensive radiation treatment can lead to severe marrow suppression. Early endoscopy in such patients is recommended to avoid delay in the diagnosis of opportunistic infections.     

Management of cytomegalovirus infection and disease in liver transplant recipients

Cytomegalovirus(CMV) is one of the most common viral pathogens causing clinical disease in liver transplant recipients, and contributing to substantial morbidity and occasional mortality. CMV causes febrile illness often accompanied by bone marrow suppression, and in some cases, invades tissues including the transplanted liver allograft. In addition, CMV has been significantly associated with an increased predisposition to acute and chronic allograft rejection, accelerated hepatitis C recurrence, and other opportunistic infections, as well as reduced overall patient and allograft survival. To negate the adverse effects of CMV infection on transplant outcome, its prevention, whether through antiviral prophylaxis or preemptive therapy, is an essential component to the management of liver transplant recipients. Two recently updated guidelines have suggested that antiviral prophylaxis or preemptive therapy are similarly effective in preventing CMV disease in modest-risk CMV-seropositive liver transplant recipients, while antiviral prophylaxis is the preferredstrategy over preemptive therapy for the prevention of CMV disease in high-risk recipients [CMV-seronegative recipients of liver allografts from CMV-seropositive donors(D+/R-)]. However, antiviral prophylaxis has only delayed the onset of CMV disease in many CMV D+/Rliver transplant recipients, and such occurrence of lateonset CMV disease was significantly associated with increased all-cause and infection-related mortality after liver transplantation. Therefore, a search for better strategies for prevention, such as prolonged duration of antiviral prophylaxis, a hybrid approach(antiviral prophylaxis followed by preemptive therapy), or the use of immunologic measures to guide antiviral prophylaxis has been suggested to prevent late-onset CMV disease. The standard treatment of CMV disease consists of intravenous ganciclovir or oral valganciclovir, and if feasible, reduction in pharmacologic immunosuppression. In one clinical trial, oral valganciclovir was as effective as intravenous ganciclovir for the treatment of mild to moderate CMV disease in solid organ(including liver) transplant recipients. The aim of this article is to provide a state-of-the art review of the epidemiology, diagnosis, prevention, and treatment of CMV infection and disease after liver transplantation.     

Hepatitis C virus and kidney disease

Hepatitis C virus (HCV) infection remains frequent in patients on renal replacement therapy and has an adverse impact on survival in infected patients on chronic hemodialysis as well as renal transplant (RT) recipients. Nosocomial spread of HCV within dialysis units continues to occur. HCV is also implicated in the pathogenesis of renal dysfunction often mediated by cryoglobulins leading to chronic kidney disease as well as impairing renal allograft function. The role of antiviral therapy for hepatitis C in patients with renal failure remains unclear. Monotherapy with conventional interferon (IFN) for chronic hepatitis C is probably more effective in dialysis than in non-uraemic patients but tolerance is lower. Limited data only are available about monotherapy with pegylated interferon and combination therapy (pegylated IFN plus ribavirin) for chronic HCV in the dialysis population. Clinical experience with antiviral therapy for acute HCV in dialysis population is encouraging. Interferon remains contraindicated post-RT because of concerns about precipitating graft dysfunction. Sustained viral responses obtained by antiviral therapy in renal transplant candidates are durable after renal transplantation and may reduce HCV-related complications after RT (post-transplant diabetes mellitus, HCV-related glomerulonephritis, and chronic allograft nephropathy).     

Esophageal disease in the acquired immunodeficiency syndrome: etiology, diagnosis, and management.

Esophageal disease is a common complication and cause of morbidity in patients with human immunodeficiency virus (HIV) infection. Opportunistic esophageal diseases may occur in patients with long-standing infection or may be the initial manifestation of HIV disease. Although a variety of both opportunistic and nonopportunistic disorders result in esophageal disease in this population, candidal esophagitis is the most common cause of symptomatic disease. Ulcerative esophagitis resulting from cytomegalovirus and idiopathic esophageal ulceration constitute the next most important etiologies. In contrast to other immunocompromised hosts, herpes simplex virus esophagitis appears to be relatively uncommon. Multiple simultaneously discovered esophageal disorders have been documented in up to 50% of patients. Opportunistic neoplasms are an infrequent cause of symptomatic disease. Candidal esophagitis may present with either dysphagia or odynophagia, and oropharyngeal candidiasis is usually present at the time of diagnosis. In contrast, ulcerative esophagitis is usually first manifested by moderate to severe odynophagia. Barium esophagography and upper endoscopy are the most commonly employed diagnostic modalities for the evaluation of the symptomatic patient. Although barium esophagography may identify specific abnormalities, this procedure appears to be relatively insensitive for the detection of mild candidal disease as well as nondiagnostic for ulcerative lesions when compared with endoscopy. In the HIV-infected patient with new-onset esophageal symptoms, an empiric trial of a systemically acting oral antifungal agent should probably be the initial management strategy. If the patient does not respond to standard therapy within 1 to 2 weeks, an endoscopic evaluation appears to be the most cost-effective diagnostic test given the diversity of potential disorders, the possibility of one or more co-pathogens or diseases, the potential for an immediate diagnosis, and the availability of mucosal biopsy to make a definite diagnosis of ulcerative or mass lesions. Given the presently available therapy for these diverse processes, establishing a definitive diagnosis in the symptomatic patient not responsive to empiric antifungal therapy is warranted.     

Acute esophageal necrosis (black esophagus) in the renal transplant recipient: manifestation of primary cytomegalovirus infection

We report a severe case of cytomegalovirus (CMV) esophagitis in a renal transplant recipient presenting as acute esophageal necrosis (AEN, 'black esophagus'). AEN is an uncommon entity that is a result of mucosal necrosis and has been described only a few times previously. To our knowledge, this is the first report of AEN due to a CMV infection. The disease was manifested by abdominal and epigastric pain, thrombocytopenia, leukopenia, and elevated liver enzymes. Upper endoscopy showed acute esophageal necrosis. Ganciclovir therapy was initiated immediately and resulted in a complete remission of symptoms. We conclude that the possibility of CMV infection should be suspected in any patient presenting with cytopenia, elevated liver enzymes, and epithelial gastrointestinal lesions in the first 6 months after transplantation, and that early viral detection and antiviral therapy can be lifesaving.     

Chromosomally integrated human herpesvirus‐6 in transplant recipients

Human herpesvirus‐6 (HHV‐6) is unique among human herpesviruses because of its ability to integrate into chromosomes. This entity, termed chromosomally integrated HHV‐6 (CIHHV‐6), is often mistaken for active infection and treated unnecessarily. The clinical significance of CIHHV‐6 in transplant recipients is not defined. Herein, the clinical characteristics of 7 liver transplant patients with CIHHV‐6 from our recent study, together with 14 other published cases of CIHHV‐6 were reviewed. Of the 21 cases, CIHHV‐6B was reported most commonly among solid organ transplant recipients, while CIHHV‐6A was mostly seen in allogeneic hematopoietic stem cell recipients. None of the 21 patients developed clinical symptoms related to HHV‐6 after transplantation. However, antiviral therapy was administered to 5 asymptomatic patients mistaken to have HHV‐6 infection because of their very high HHV‐6 DNA levels, 3 who developed symptomatic cytomegalovirus disease, and 1 with graft‐versus‐host disease that was mistaken for HHV‐6 infection. In patients who received antiviral therapy, there was no apparent decline in HHV‐6 DNA load, although change in viral kinetics is difficult to discern in the setting of high baseline HHV‐6 DNA load. Clinicians should be aware of this entity of CIHHV‐6 so that antiviral therapy can be considered in the proper clinical context.     

Herpes simplex virus colitis complicating ulcerative colitis: A case report and brief review on superinfections

In patients with inflammatory bowel disease herpes simplex virus infection has been described as a major cause of morbidity and mortality, especially in immunocompromised individuals. Here we present the case of a 35-year old woman with an exacerbation of ulcerative colitis caused by herlpes simplex virus infection (HSV-2). The diagnosis was confirmed histologically following subtotal colectomy. After intravenous treatment with aciclovir for 2 weeks postoperative hematochezia stopped. Herpes simplex virus colitis is a rare but potentially fatal complication of immunosuppressive treatment in patients with inflammatory bowel disease. Prompt diagnosis and efficient antiviral therapy are mandatory to improve prognosis.     

Leflunomide failure to control recurrent cytomegalovirus infection in the setting of renal failure after allogeneic stem cell transplantation

Cytomegalovirus (CMV) reactivation is common in the allogeneic stem cell transplant setting but the incidence of CMV organ disease and mortality has been dramatically reduced by prophylactic or preemptive antiviral therapy. We report the case of a CMV-seropositive 46-year-old man with non-Hodgkin's lymphoma who underwent an unrelated allogeneic stem cell transplant from a CMV-seronegative HLA-matched unrelated donor. CMV encephalitis and colitis developed that was refractory to single-agent therapy. The CMV isolate demonstrated genotypic resistance to both ganciclovir and foscarnet. CMV disease was controlled by prolonged combination ganciclovir and cidofovir therapy, but severe renal dysfunction developed. Leflunomide was selected as a last resort to avoid the nephrotoxicity of cidofovir. CMV antigenemia rapidly increased following leflunomide administration, necessitating discontinuing this agent and resuming prior antiviral therapy. The pharmacokinetics of leflunomide in the setting of renal insufficiency is presented. Options for salvage therapy in refractory CMV disease in allogeneic stem cell transplant recipients are briefly reviewed.     

Viral pneumonia in recipients of solid organ transplants

Viral pulmonary infections are a major cause of morbidity and mortality in solid organ transplant recipients. The herpes viruses-cytomegalovirus, herpes simplex virus, varicella zoster virus, and Epstein-Barr virus--cause most of the viral infections in this population. Respiratory syncytial virus, adenovirus, and human immunodeficiency virus also cause pneumonitis in the transplant recipient. Differences in the clinical and laboratory presentation of pneumonitis due to the various viral agents can provide clues to the etiology. However, definitive diagnosis requires laboratory identification of the virus or appropriate serologic changes. With cytomegalovirus, herpes simplex virus, Epstein-Barr virus, and adenovirus, one must take care to distinguish between asymptomatic shedding of the virus and disease produced by the virus. Advances in diagnostic techniques such as rapid antigen detection, nucleic acid hybridization, and gene amplification may allow an earlier diagnosis of viral pneumonia. Advances in risk reduction with appropriate pairing of donors and recipients, improved immunosuppressive regimens, vaccination, and prophylactic administration of antiviral agents may reduce the incidence of viral infection. Finally, advances in anti-viral therapy have made possible the successful treatment of pneumonia due to some of the viral agents.     

Synchronous herpes simplex virus and cytomegalovirus esophagitis

Infective esophagitis is a rare disease, affecting mostly immunocompromised patients. Very few cases of a multiple viral infection have been reported. We present a case of combined cytomegalovirus (CMV) and herpes simplex virus (HSV) esophagitis in an 81-year-old female with extracapillary sclerosing glomerulonephritis treated for five months with steroids and chemotherapy. She died of septic shock. At autopsy, erosive and ulcerative esophagitis was found in the distal half of the esophagus. Slides were stained by HE, and the immunohistochemical avidin-biotin method was used to detect HSV and CMV infection. On histological examination of the esophagus, epithelial giant cells with intranuclear viral inclusions showing HSV immunopositivity were found at the margin of the ulcerations. Giant cells with intranuclear inclusions with CMV immunopositivity were also found in the mesenchymal cells obtained from the ulcer bed. Long-term immunosuppressive therapy provoked an immune deficiency, evidenced by grave leukopenia and depletion of all bone marrow elements. Diagnosis of HSV and CMV esophagitis is important to evaluate the risk of hemorrhage and esophageal perforation in esophagitis.