Course Of Ganciclovir Research Articles

Cytomegalovirus esophagitis associated with arytenoid cyst in an immunocompetent host

CMV esophagitis is usually encountered in immunocompromised individuals and esophagus is rarely affected in immunocompetent individuals. CMV esophagitis associated with arytenoid cyst has not yet been reported in literature to the best of my knowledge and can be considered in case of recurrence of cyst following excision. The objective of this study is to report the unique presentation of CMV in an immunocompetent patient. A middle-aged immunocompetent lady presenting with dysphagia was diagnosed to have arytenoid cyst. Biopsy from upper esophagus revealed cytomegalovirus inclusion bodies and immunological test were performed to confirm the pathology. The cyst excision lead to recurrence. It was excised again followed by a course of intravenous ganciclovir. Currently, the role of antiviral in treatment of CMV esophagitis in immunocompetent individual is not well established. We have obtained good result in this patient with a course of Ganciclovir following excision of the cyst. The rarity of cytomegaloviral upper esophageal involvement, its association with arytenoid cyst and the utility of antivirus in treatment of an immunocompetent host makes this case report unique and interesting.

Hearing Following Prolonged and Delayed Ganciclovir Treatment in a Murine Cytomegalovirus Model.

Compare hearing outcomes utilizing standard, prolonged and delayed ganciclovir (GCV) therapy in a murine model of cytomegalovirus (CMV). BALB/c mice were inoculated with mouse cytomegalovirus (mCMV) or saline via intracerebral injection on postnatal day 3 (p3). Intraperitoneal GCV or saline was administered at 12 h intervals for the duration of the standard (p3-p17), delayed (p30-p44), or prolonged treatment windows (p3-p31). Auditory thresholds were assessed using distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) testing at 4, 6, and 8 weeks of age. Blood and tissue samples were harvested from mice on p17 and p37 one hour after GCV administration, and their concentrations were assessed via liquid chromatography-mass spectrometry. A delayed course of GCV improved ABR but not DPOAE thresholds in mCMV-infected mice. A prolonged course of GCV did not provide better hearing thresholds than those administered standard treatment. The average GCV concentration in all 17-day-old mice tissue was significantly higher than those in older 37-day-old mice. Delayed GCV treatment provided a hearing benefit on ABR over untreated mCMV infected mice. Prolonged CGV administration showed no benefit compared to a shorter duration GCV treatment. GCV drug concentrations both systemically and in the cochlea are much lower in older mice. These results have potential implications for the clinical management of cCMV infected children. NA Laryngoscope, 134:433-438, 2024.

Elsberg Syndrome Secondary to Cytomegalovirus Infection in an Immunocompetent Patient: A Case Report.

Infectious lumbosacral radiculitis and myelitis, a clinical entity called Elsberg syndrome, is classically linked to HSV-2 and VZV. Here, we report a case of an Elsberg syndrome caused by primary cytomegalovirus (CMV) infection in an immunocompetent patient. Here is a case report at an academic medical center. Cerebral and spinal cord MRI, electroneuromyography, and serum and CSF analysis were performed. We investigated a 31-year-old healthy woman presenting with acute paresthesia of both feet ascending to the pelvic region, urinary retention, and constipation. Neurologic examination revealed symmetrical hyperesthesia of both inferior limbs up to the pelvic region, with patellar and Achilles hyporeflexia. Although MRI was normal, a dysfunction of the S1 left nerve root was observed on electroneurography. CSF analysis was inflammatory. Blood CMV PCR was positive, and anti-CMV IgG/IgM values indicated seroconversion. Taken together, these results strongly suggested an Elsberg syndrome caused by CMV primary infection. After a course of ganciclovir, a marked improvement of the symptoms was observed. This case highlights that CMV primary infection can be a cause of Elsberg syndrome in immunocompetent patients. CMV testing should be discussed in these patients to initiate adequate antiviral therapy.

Ganciclovir Treatment in Symptomatic Congenital CMV Infection at Siriraj Hospital: 11 Year-Review (2008 to 2019)

Background: Congenital cytomegalovirus (CMV) infection is the most common non-genetic cause of permanent sensorineural hearing loss in infants and children. A 6-month course of intravenous ganciclovir or valganciclovir is recommended for treatment of patients with moderate to severe symptomatic congenital CMV disease. Hearing status improvement has been reported in those that received treatment within the first month of life. In Thailand, there has been no data of antiviral treatment in symptomatic congenital CMV patients. Objective: To determine the incidence of symptomatic congenital CMV infection in the past 11 years and to evaluate the hearing, neurological, and developmental outcomes of the antiviral treatment and factors associated with hearing outcomes. Materials and Methods: A retrospective observational study was performed at Siriraj Hospital, between January 2008 and December 2019. The medical records of the patients diagnosed of symptomatic congenital CMV infection (ICD10-P351) were reviewed. Results: The incidence of symptomatic congenital CMV infection was 0 to 1.01 case per 1,000 livebirths. Of the 52 patients, 18 received 6-week course of ganciclovir and five continued with oral valganciclovir for three to six months. Developmental delayed was found in 69.2% (36). No difference in hearing outcomes at 6 and 12 months of age between the patients who did or did not receive treatment. Among 24 (46.1%) children who underwent hearing test at two to three years of age, the birth characteristics, as well as antiviral treatment (attributable risk 0.007, 95% CI –0.4 to 0.4, p=0.973), had no difference in hearing outcome. Long-term disability was diagnosed in the lower proportion among the patients receiving antiviral treatment (attributable risk –0.3, 95% CI –0.5 to –0.1, p=0.030). Conclusion: Symptomatic congenital CMV infection resulted in poor hearing and developmental outcomes. Antiviral treatment reduced risk of disability but did not improve hearing outcomes. The results underscore the need for early diagnosis and initiation of antiviral treatment in infants with symptomatic congenital CMV. Keywords: Congenital infection; CMV; Hearing loss; Ganciclovir; Valganciclovir; Disability

S2458 Can SARS-CoV-2 Enterocolitis Trigger New Onset Inflammatory Bowel Disease ?

Introduction: Prevalence of gastrointestinal symptoms in patients infected with SARS-CoV-2 virus is 6.8% - 61.3%. Most common symptoms include diarrhea (8.1% - 33.7%), nausea/vomiting (1.5% - 26.4%), anorexia (12.1% - 26.4%), and abdominal pain (0 – 14.5%). Management involves treating respiratory manifestation of COVID-19, treating co-existing infections, and supportive care. We present a case of severe hemorrhagic enterocolitis managed with a biologic. Case Description/Methods: 47-year-old woman with COVID-19 pneumonia was admitted for extracorporeal membrane oxygenation. She developed copious amounts of watery diarrhea followed by bloody diarrhea. Stool work-up was negative for infectious causes of diarrhea. Colonoscopy revealed diffusely erythematous and friable mucosa with epithelial loss involving the entire colon and distal ileum. She was managed with rectal tube, blood transfusions, parenteral nutrition. Despite escalating doses of numerous anti-diarrheals, topical as well as systemic steroids, copious volumes of bloody diarrhea continued. Repeat colonoscopic biopsies demonstrated CMV-like inclusions with borderline elevated serologic titers. Despite successful eradication of CMV with prolonged courses of ganciclovir and foscarnet, hemorrhagic diarrhea continued. Several upper and lower endoscopies suggested worsening mucosal erythema and friability, predominantly involving small bowel and colon. Given COVID enterocolitis refractory to all the above treatments, induction therapy with a biologic was considered to treat possible de novo inflammatory bowel disease (IBD) versus immune mediated effects of COVID-19 enterocolitis. After induction doses of Ustekinumab, an IL-12 and IL-23 inhibitor, volume of diarrhea reduced and bloody diarrhea resolved, facilitating removal of rectal tube, resumption of oral nutrition, discontinuation of anti-diarrheals. Patient was discharged on maintenance Ustekinumab. Follow-up endoscopic evaluation demonstrated mucosal healing, with epithelial regeneration and chronic inflammatory changes of crypt distortion. Discussion: SARS-CoV-2 infection triggered an inflammatory cascade in the intestinal tract leading to altered or increased immune response, probably on a background of genetic predisposition, in our patient. Initiation of Ustekinumab, IL-23/IL-12 inhibitor, likely resulted in suppression of the severe systemic inflammatory response, resulting in clinical, endoscopic and pathological response.Figure 1.: (a) demonstrates endoscopic appearance of transverse colon with erythema, friability and hemorrhages prior to treatment with biologic (b) demonstrates epithelial denudation with minimal acute inflammation in colonic mucosa prior to treatment with biologic (c) demonstrates endoscopic appearance of transverse colon with resolving erythema after treatment with biologic (d) demonstrates chronic inflammatory changes with crypt architectural distortion and pyloric gland metaplasia after induction of remission with biologic, many months after initial presentation.

Potentially predictive factors for hearing function improvement in pediatric cytomegalovirus infection therapy

Background Symptomatic congenital cytomegalovirus (CMV) infection has an impact mainly on neurological sequelae, including sensorineural deafness. Because of the long-term impact, early treatment of CMV infection is mandatory. However, predictive factors for hearing function improvement in CMV infection therapy remain unexamined.
 Objective To evaluate potential predictive factors for hearing improvement in pediatric CMV infection therapy.
 Methods All medical record data of patients aged 0-6 years with CMV infection who completed a 6-week course of ganciclovir therapy or a combination of a 4-week course of ganciclovir and a 2-week course valganciclovir from January 2013 to December 2017 were collected. Age at onset of therapy, gender, gestational age, nutritional status, multi-organ involvement, and neurological symptoms were studied as potential predictive factors of hearing improvement in CMV therapy. The effectiveness of CMV infection therapy on improving hearing function was measured with the brainstem evoked response audiometry (BERA) test.
 Results BERA tests proportion in the right, left, and best ear showed significant improvement after therapy. All variables analyzed were not statistically significant as predictive factors for hearing improvement in CMV infection therapy.
 Conclusion Ganciclovir/valganciclovir therapy in CMV infection patients accounted for the improvement of hearing impairment. However, none of the assessed factors were considered predictive for improving hearing function in CMV infection therapy.

Cytomegalovirus viremia and resistance patterns in immunocompromised children: An 11-year experience

We noted a recent increase in number of immunocompromised children with CMV viremia at our institution. The purpose of this study was to determine the frequency of CMV viremia in this population and evaluate factors associated with drug-resistant mutations. A retrospective review of immunocompromised hosts, 0–21 years of age, who had CMV viremia during 2007–2017. CMV viremia was detected using PCR assays. Genetic mutation assays were performed using PCR sequencing of the phosophotransferase UL 97 gene and the polymerase UL54 gene of CMV using Quest Diagnostics (San Juan Capistrano, CA, USA) or ARUP Labs (Salt Lake City, UT, USA). Thirty-one patients were identified, including 10 (32%) during the last 2 years. Of the 31 patients, 18 had hematopoietic stem cell transplantation (HSCT), 5 had primary immunodeficiency, 4 had malignancies, 3 had heart transplantation and 1 had new Human Immunodeficiency virus (HIV) infection. Antiviral resistance testing was performed on isolates from seven patients: five with persistent viremia (>1 mo), and two prior to starting antiviral therapy. Resistance was identified in three patients’ isolates: two with common variable immunodeficiency (CVID) and one with recurrent Hodgkin’s lymphoma who had undergone autologous HSCT. The two patients with CVID had chronic diarrhea and malabsorption and had received prolonged oral valganciclovir courses prior to emergence of resistance. The patient with Hodgkin’s lymphoma had received a prolonged IV ganciclovir course. All three tested positive for UL97 mutation and two had both UL97 and UL54 gene mutations. Majority of our patients (21/31) with CMV viremia were transplant recipients and ganciclovir resistance developed in 10%. Two had intestinal malabsorption. Treatment with oral valganciclovir should be avoided in patients with poor gut absorption as that may increase the risk of resistance.

1746. Prevalence and Resistance Patterns of Cytomegalovirus Viremia in Immunocompromised Patients

BackgroundWe noted a recent increase in the number of patients with CMV viremia among immunocompromised children at our institution. The study was undertaken to determine the prevalence of CMV viremia and to evaluate factors associated with the development of antiviral drug resistance.MethodsA retrospective study of immunocompromised hosts 0–21 years of age who had CMV viremia (2007–2017). We collected demographic data as well as details of antiviral therapy and resistance testing.ResultsA total of 31 patients were identified including 10 (32%) during the last 2 years. The age range was 3 months to 20 years (median 12.6 years); 23 (74%) were male and 12 (39%) were African American. Among the 31 patients, 18 had hematopoietic stem cell transplantation, 5 had primary immunodeficiency (2 common variable immunodeficiency, 1 SCID, 1 Langerhans cell histiocytosis, 1 DiGeorge syndrome), 4 had malignancies receiving chemotherapy, 3 with heart transplantation and one 17 year old with newly diagnosed HIV infection who presented with CMV pneumonia and viremia. Antiviral resistance testing was performed on 7 CMV isolates: 5 due to persistent viremia (> 1 months) despite treatment, and 2 prior to starting antiviral therapy. CMV resistance was identified in 3 patients including 2 with CVID and one with Hodgkin’s disease status post bone marrow transplantation. The 2 CVID patients had other comorbidities including chronic diarrhea and malabsorption and were TPN dependent. Both were diagnosed with CMV colitis and one also had pneumonitis. One had received a prolonged oral valganciclovir course (> 1 year) prior to diagnosis of resistance and the other received long-term intermittent oral valganciclovir courses. The patient with Hodgkin’s disease received a prolonged IV ganciclovir course. All 3 tested positive for UL97 mutation and one had both UL97/UL54 gene mutations.ConclusionMost of our patients with CMV viremia were transplant patients. Antiviral drug resistance was detected among 3 of 31 (10%) of our patients during the study period. Two had malabsorption that may have resulted in sub-therapeutic blood levels. Treatment with oral valganciclovir should be avoided in patients with poor gut absorption because it may increase risk of drug resistance.Disclosures All authors: No reported disclosures.

Experience with leflunomide as treatment and as secondary prophylaxis for cytomegalovirus infection in lung transplant recipients: A case series and review of the literature.

Data concerning the use of leflunomide-a drug approved for rheumatoid arthritis with in vitro anticytomegalovirus (CMV) activity-in lung transplant (LT) recipients are scarce. To report the use of leflunomide in LT recipients diagnosed with CMV infection/disease. We performed a single-center retrospective study including LT recipients who received leflunomide for CMV infection or as secondary prophylaxis after viremia clearance. We also conducted a full systematic PubMed search until June 30, 2017. We identified 5 LT recipients in our center plus 7 patients reported in the literature. All patients had previously received ganciclovir (GCV) and foscarnet (FOS), with drug-induced adverse effects described in 6 recipients (50%). Antiviral resistance mutations were observed in 8 patients (66.7%). Leflunomide was prescribed for CMV infection in 9 of 12 patients (75%) and as secondary prophylaxis in 3 patients (25%). Initial decrease of CMV viremia after starting leflunomide was observed in 7 of 9 recipients (77.7%), although this response was only transient in 2 patients. Long-term suppression of CMV viremia was reported in 7 of 12 patients (58.3%). In 3 recipients (25%), leflunomide was discontinued due to adverse effects. Our study has some limitations, such as the small number of patients included, its retrospective nature, and absence of leflunomide drug monitoring in serum. Notwithstanding, in our experience, leflunomide proved to be particularly effective as an anti-CMV secondary prophylaxis treatment and for clearing low-grade viremia. Moreover, leflunomide combined with a short course of GCV or intravitreal FOS also proved to be very effective in some patients. Leflunomide, alone or in combination, could be an effective treatment in selected LT recipients with GCV-resistant CMV infection and as secondary prophylaxis. Further studies are necessary.

Ganciclovir Antiviral Therapy in Advanced Idiopathic Pulmonary Fibrosis: An Open Pilot Study

Hypothesis. Repeated epithelial cell injury secondary to viruses such as Epstein Barr and subsequent dysfunctional repair may be central to the pathogenesis of IPF. In this observational study, we evaluated whether a combination of standard and anti-viral therapy might have an impact on disease progression. Methods. Advanced IPF patients who failed standard therapy and had serological evidence of previous EBV, received ganciclovir (iv) at 5 mg/kg twice daily. Forced vital capacity (FVC), shuttle walk test, DTPA scan and prednisolone dose were measured before and 8 weeks post-treatment. Results. Fourteen patients were included. After ganciclovir, eight patients showed improvement in FVC and six deteriorated. The median reduction of prednisolone dose was 7.5 mg (44%). Nine patients were classified “responders” of whom four showed an improvement in all four criteria, while three of the five “non-responders” showed no response in any of the criteria. Responders showed reduction in prednisolone dosage (P = .02) and improved DTPA clearance (P = .001). Conclusion. This audit outcome suggests that 2-week course of ganciclovir (iv) may attenuate disease progression in a subgroup of advanced IPF patients. These observations do not suggest that anti-viral treatment is a substitute for the standard care, however, suggests the need to explore the efficacy of ganciclovir as adjunctive therapy in IPF.

Octreotide for Symptomatic Treatment of Diarrhea due to Cytomegalovirus Colitis

To report the improvement of diarrhea in a patient with cytomegalovirus (CMV) colitis who was treated with octreotide after failure of loperamide. An 84-year-old male presented with chronic diarrhea and CMV colitis; he had been experiencing protracted diarrhea since 2006. In October 2009 he failed a 21-day course of valgancyclovir 900 mg orally twice daily. Several months later, due to continuing diarrhea and progressive malnutrition, a colonoscopy and subsequent biopsy again showed CMV. In March 2010 he was started on a 28-day course of intravenous ganciclovir 130 mg daily. Three weeks into treatment he continued with copious amounts of diarrhea, with no relief from loperamide, which was titrated from 2 mg/day to 2 mg every 6 hours. On day 20 of ganciclovir treatment he was started on octreotide 50 μg subcutaneously every 8 hours; within a few days, the patient began to experience decreased stool frequency and consistency. He completed the full 28-day course of ganciclovir, with octreotide continuing unchanged, with much improvement in his diarrheal symptoms and improvement in appetite, nutritional status, and quality of life. Studies regarding the treatment of CMV colitis-associated diarrhea are scarce, and are typically limited to treating the underlying cause with antiviral medications and with the addition of antimotility agents. Three cases have been reported in the literature in which octreotide was used for the symptomatic treatment of diarrhea, none of which was refractory to loperamide. This is the first known case of a patient with chronic diarrhea due to CMV colitis that was unresponsive to loperamide, required protracted antiviral treatment (valgancyclovir and gancyclovir), and subsequently experienced relief by the use of octreotide 50 μg subcutaneously every 8 hours.

Ten-year experience of kidney transplantation at the Hospital of Kaunas University of Medicine: demography, complications, graft and patient survival

During 10 years, 163 cadaveric kidney transplantations were performed at the Hospital of Kaunas University of Medicine. The aim of this study was to analyze the first 10-year experience in kidney transplantation and to evaluate the most frequent early and late complications after transplantation, graft and patient survival, and impact of delayed graft function on graft survival. A total of 159 patients were included into the study. Graft and patient survival was calculated at 1, 3, and 5 years after transplantation using the Kaplan-Meier method; graft function was also analyzed. Fifty-three patients (33.3%) in the early period and 72 (55.4%) in the late period had at least one episode of urinary tract infection. Less than half (47.2%) of patients had complications related to immunosuppressive treatment, mostly cytomegalovirus infection, in the late period. The risk of CMV reactivation was 3.98 times higher among recipients who received prophylaxis only with intravenous ganciclovir as compared to patients who received valganciclovir after a brief course of ganciclovir (OR, 3.98; 95% CI, 1.48-8.19; P=0.003). Delayed graft function was observed in 53 cases (33.3%); 37 (23.3%) grafts were lost. Graft and patient survival at 1, 3, and 5 years after transplantation was 85%, 82%, and 71% and 97%, 94%, and 94%, respectively. Graft survival at 1, 3, and 5 years was worse among patients with delayed graft function as compared to patients with good graft function (69%, 69%, 50% vs. 93%, 86%, 84%, respectively; P<0.05). Urinary tract infection was the most frequent complication after kidney transplantation. Reactivation of cytomegalovirus infection was present only in a quarter of our patients. The administration of valganciclovir was associated with a significantly lower incidence of CMV infection/disease. Graft and patient survival was sufficiently good. Delayed graft function was an independent risk factor for worse graft survival.

Relapsing cytomegalovirus infection in solid organ transplant recipients

Efforts to prevent relapsed cytomegalovirus (CMV) disease among solid organ transplant (SOT) recipients present clinical challenges. Historically, SOT recipients treated with short courses of ganciclovir, without documented clearance of viremia, had relapse rates of 23-33%. Current treatment often includes much longer courses of valganciclovir, and persistence of viremia at the end of treatment is rare. We sought to determine the rate and risk factors for relapse under those treatment conditions. Records of 1760 SOT recipients from January 2003 to June 2007 were reviewed; 105 cases of CMV viremia were identified. Relapse occurred in 20/105 (19%); 50% had end-organ disease at the time of relapse. Most patients received approximately 3 months of valganciclovir. Clearance of viremia was documented in 19/20 patients with relapse. Multivariable analysis identified receipt of a thoracic organ and diabetes mellitus as risk factors for relapse. Despite long treatment courses with valganciclovir and documented clearance of viremia, CMV relapse remains common among SOT recipients. Better understanding of the epidemiology of CMV among SOT recipients and validation of risk factors for disease relapse should be the focus of future prospective trials. Such trials should include different treatment durations and extended monitoring for relapse.

Long‐term outcomes of cytomegalovirus infection and disease after lung or heart–lung transplantation with a delayed ganciclovir regimen

Information is limited on long-term outcomes after preemptive use of ganciclovir to control cytomegalovirus (CMV) infection in lung transplantation. We studied 78 lung recipients who received antithymocyte globulin induction from 1994 to 2000. All patients received six months of oral acyclovir (800 mg TID). This was interrupted three wk post transplantation for a two-wk course of IV ganciclovir. Additional courses of ganciclovir were administered based on serial virological monitoring. CMV-mismatched patients (R-D+) also received four doses of CMV immunoglobulin between weeks 2 and 8. The one yr cumulative risk of CMV disease was 2% (1/61) in CMV seropositive (R+) patients, but was 37% (6/17) in R-D+ patients (p < 0.0001). Over 4.3 yr of follow-up, patients with CMV infection developed more chronic graft dysfunction caused by bronchiolitis obliterans or bronchiolitis obliterans syndrome than patients without CMV infection (p = 0.012). This effect was also apparent in the subgroup of R+ recipients (p = 0.043). Acute rejection and overall survival were not associated with CMV infection. The use of prophylactic acyclovir and short preemptive courses of ganciclovir effectively controlled CMV disease in R+ patients, but was a relative failure in R-D+ patients. CMV infection was significantly associated with chronic graft dysfunction, even in R+ recipients who had good control of CMV symptoms.

Clinical Features of Cytomegalovirus Anterior Uveitis in Immunocompetent Patients

To describe the clinical presentation of cytomegalovirus (CMV) anterior uveitis in human immunodeficiency virus (HIV)-negative patients. Retrospective, interventional case series. HIV-negative patients with anterior uveitis associated with elevated intraocular pressure (hypertensive anterior uveitis) seen at the Singapore National Eye Centre had their aqueous analyzed for viral deoxyribonucleic acid by polymerase chain reaction, and their records were reviewed for demographic data, ocular findings, laboratory results, and treatment. Aqueous was obtained from 105 of 106 eligible eyes. Twenty-four eyes demonstrated positive results for CMV (22.8%). Eighteen eyes had Posner-Schlossman syndrome (PSS; 75%) at presentation, five eyesba had Fuchs heterochromic iridocyclitis (FHI; 20.8%), and one eye had a presumed herpetic anterior uveitis. Twelve of the 24 eyes were treated with ganciclovir. Of the 12 who completed treatment, all responded clinically, and their aqueous demonstrated negative results for CMV on repeat testing. However, nine had recurrences within eight months of stopping treatment and required further courses of ganciclovir. The 81 CMV-negative eyes included 30 with PSS, 11 with FHI, 27 with uveitic glaucomas of unknown cause, and 13 with presumed herpetic anterior uveitis. CMV anterior uveitis is not uncommon in our immunocompetent patients and it may present as a recurrent acute or chronic inflammation, resembling PSS, herpetic anterior uveitis, or FHI.

Please, Sir, pull down your socks!

After leaving the examination bed, he sat down once again and the doctor commented on the result of the last early cytomegalovirus antigen (p65) test, again positive irrespective of the course of ganciclovir administered the previous month. A further course of antiviral drug was scheduled, then the patient was dismissed. At this point, while the patient was crossing to the door, the young fellow stopped the patient: “Please, Sir” – he said – “pull down your socks!”. Two little violet nodules appeared on the upper surface of the left foot (Fig. 1). “Here you are!” – said the fellow as a good new. After the disclosure of the two nodules, the examination of regional lymph nodes (another very frequently skipped phase of physical examination) becomes mandatory. In our patient no nodes were found at the groin. Some days after, a punch biopsy confirmed a Kaposi’s sarcoma (KS) at the plaque stage. Immunosuppression was lightened and the sarcoma regressed and finally disappeared. Finally, his graft function is still stable after reduction of immunosuppressive therapy. Soon after the surgery his immunosuppressive treatment (cyclosporine, azatioprine and steroids) had to be tapered because of toxicity of calcineurine inhibitor and sub-clinical cytomegalovirus infection. Nevertheless, two months after the graft, he suffered from a urinary tract infection by K. pneumoniae, treated with amoxicillin clavulanate. Renal function was only sub-optimal due to an unfavourable match between donor kidney and patient body size; serum creatinine nadir was 2 mg/dl (38.1 ml/min calculated glomerular filtration rate). The occurrence of different infections suggested overimmunosuppression. His sexual profile was not investigated further. As written in medical texts, lesions of KS are characteristic and are not difficult to diagnose [1], but it is necessary to be aware of their occurrence in a specific clinical setting.

The Role of Cytomegalovirus in Immune Thrombocytopenia Purpura.

Immune thrombocytopenia purpura(ITP) is one of the most common causes of acquired thrombocytopenia. Although ITP is believed to result from autoreactive antibodies that lead to platelet destruction, its exact pathogenesis is not known. Cytomegalovirus(CMV) has been implicated as a possible causative agent of ITP. Based on three case reports described here we believe that CMV may be a cause of refractory ITP in certain patients and that eradication of CMV with antiviral therapy will improve the ITP. A 72-year-old man experienced recurrent epistaxis and was found to be thrombocytopenic. He was diagnosed with ITP, and treated with IVIG and solumedrol, with platelets transiently rising to 45K/ul. He suffered a subdural hematoma and was placed on IVIG and prednisone daily and referred for splenectomy. Rituximab was ineffective. Testing for CMV revealed a positive PCR and ganciclovir IV qd, valganciclovir, and cytogam 2 times per week were initiated. With this regimen, the CMV PCR became undetectable and steroids and his anti-CMV medications were weaned off. He now maintains a normal count on no treatment. A 48-year-old male developed ITP which was refractory to treatment with steroids, IVIG, rituximab, danazol, vincristine, anti-thymocyte globulin, and IV anti-D; his platelet count was <20,000/ul and he had marked skin and oral bleeding. After being diagnosed with CMV, he was started on IV ganciclovir and cytogam for several months and was weaned after his PCR became undetectable. In retrospect, he had had mild transaminitis and atypical lymphocytes reported at presentation at another center. He experienced a reactivation of his CMV while being treated with 1 week of steroids for asthma, requiring a second 4 month course of ganciclovir. Currently he receives IVIG every 2-8 weeks. A 3-year-old female was well until 4 months of age, when she developed fevers, thrombocytopenia, elevated liver enzymes and a positive CMV PCR for which she was started on ganciclovir. She developed pancytopenia; bone marrow biopsy was consistent with ITP. She had poor responses to IVIG, IV anti-D and pulse steroids. She suffered from chronic CMV infection for which she received cytogam BIW and initially ganciclovir daily, until its discontinuation secondary to myelosuppression. Once her CMV PCR was negative and her platelets improved to near normal, cytogam was discontinued. Soon after discontinuation her platelet count dropped below 10,000K/ul. She was restarted on the ganciclovir and cytogam without effect. She experienced an intracranial hemorrhage, RSV bronchiolitis, gram positive bacteremia, and respiratory failure with multiple failed extubations and expired at 3 years of age. Toll like receptors 2, 7, and 9 were normal. Several reports have implicated CMV in the pathogenesis of rare cases of ITP. Our previous study suggested that it was at most rarely involved in ITP (Levy, A., 2002; BJH). We describe three cases of refractory ITP associated with CMV. The presentations include severe symptomatic treatment-refractory ITP, fever of unknown origin, and transaminitis. Treatment with immunosuppressive medication may have worsened the CMV-ITP. All cases showed dramatic improvement in platelet counts within 1-2 weeks when ganciclovir and cytogam were instituted. The relationship between CMV and ITP may be explained by immune-mediated destruction of infected platelets or by direct infection of megakaryoblasts by cytomegalovirus(Xiao,Y., 2006). Based on these case reports we believe that CMV infection needs to be considered in cases of refractory ITP and antiviral therapy instituted when infection is identified.

Fatal Human Herpes Virus 6 Primary Infection After Liver Transplantation

A 55-year-old white woman, cytomegalovirus (CMV) antibody-positive, underwent orthotopic liver transplantation (LTx) for alcoholic cirrhosis. Twenty-six units of blood products were transfused during surgery. Postoperative immunosuppression combined low-dose prednisone, tacrolimus, and mycophenolate mofetil (MMF). She received no antiviral prophylaxis. By day 16, she developed fever, encephalopathy, ascites, abdominal pain, and diarrhea. Cerebral magnetic resonance imaging was normal and cerebrospinal fluid (CSF) examination showed no meningitis. Abdominal computed tomography was consistent with diffuse small bowel inflammation. Repeated esogastroduodenoscopies showed an inflammatory mucosa with numerous large ulcerations on the esophagus and the whole duodenum (Fig. 1). Biopsies revealed an abraded mucosa, and nuclear and cytoplasmic inclusions were seen in submucosal cells. In CSF, human herpes virus (HHV)-6 DNA was found positive by real-time polymerase chain reaction (PCR) whereas researches for other viruses (herpes simplex viruses 1 and 2, varicella zoster virus, CMV, and Epstein-Barr virus; PCR Herpes Consensus, Argène Biosoft) (1) and JC virus (in-house technique) were negative. HHV-6 DNA, but not CMV or other herpes virus DNA, was also positive in plasma, ascites, and on esophageal and duodenal biopsies. Immunohistochemical examination of these biopsies (anti-HHV-6 monoclonal mouse antibody, 10G6, immunoglobulin G1 isotype; Argène Biosoft, France) showed positive staining inside submucosal cells whereas anti-CMV immunostaining was negative. Viral genome sequencing demonstrated a variant B virus.FIGURE 1.: Diffuse bowel inflammation with thickened and spontaneously enhanced intestinal wall on abdominal computed tomography (A). Large and diffuse esophagal ulcerations observed during an esogastroduodenoscopy (B).A switch to ciclosporin, MMF reduction, and antiviral therapy had no effect. The patient initially received Foscavir, which was discontinued after 11 days because of renal failure, followed by a 4-week course of ganciclovir. Despite antiviral therapy, ascites, diarrhea, and encephalopathy worsened. HHV-6 DNA remained persistently positive in plasma, ascites, and on repeated esophageal and duodenal biopsies. The patient experienced polymicrobial bacteremia (Enterobacter cloacae, Bacteroïdes fragilis and Pseudomonas aeruginosa) attributed to intestinal inflammation, and died on day 65 of related septic shock. Consent for autopsy was not obtained. HHV-6 serology was retrospectively realized in the recipient using two different techniques (indirect immunofluorescent assay and enzyme linked immunosorbent assay; Biotrin International Ltd, Lyon, France). It was found negative on a pretransplant serum and positive 3 weeks after LTx. Both anti-HHV-6 antibodies and HHV-6 DNA PCR detection on the donor serum were negative. Due to a 96.4% seroprevalence rate (2), HHV-6 infection mostly represents reactivation in adult transplant recipients. Although it usually causes little symptoms, severe organ involvement including encephalitis, pneumonitis, and pancytopenia have been reported (3, 4). HHV-6 primary infection is exceptional. Fatal hemophagocytic syndrome after HHV-6A primary infection has been documented after kidney transplantation (5). We describe a case of HHV-6B primary infection with diffuse involvement of esophagus, duodenum, and small bowel. HHV-6-related digestive ulcerations have not been reported so far. In the observation of Randhawa et al. in a heart transplant recipient, HHV-6A infection was associated with gastroduodenitis but no ulceration was found (6). Our case emphasizes the pathogenic role of HHV-6 on the digestive tract. The virus was thought to have been transmitted more likely by the blood products required during surgery, rather than by the graft, because the donor was seronegative for HHV-6. Both HHV-6A and HHV-6B are susceptible in vitro to ganciclovir, Foscavir, and cidofovir (7). Foscavir and ganciclovir, either alone or in combination, have been advocated for the treatment of HHV-6-related neurological diseases (8). However, due to the lack of controlled trial, no specific recommendation can be made for the treatment or prophylaxis of HHV-6 infection in solid organ transplant recipient (7). In our observation, no response to antiviral therapy was observed. Disseminated HHV-6 infection may involve the digestive tract in transplant recipients. Antiviral therapy should be pursued in suspected or documented symptomatic infection, even if clinical and virological responses may be disappointing, as in this case. Whether primary HHV-6 infection is more severe than reactivation is uncertain. The impact of CMV-targeting antiviral prophylaxis remains unknown. Matthieu Revest Christophe Camus Infectious Diseases and Medical Intensive Care Unit Rennes Teaching Hospital Hôpital Pontchaillou Rennes, France Pierre-Nicolas D'Halluin Department of Gastroenterology Rennes Teaching Hospital Hôpital Pontchaillou Rennes, France Sophie Cha Department of Bacteriology, Virology, and Hospital Hygiene Rennes Teaching Hospital Hôpital Pontchaillou Rennes, France Philippe Compagnon Karim Boudjema Department of Digestive Surgery Rennes Teaching Hospital Hôpital Pontchaillou Rennes, France Ronald Colimon Department of Bacteriology, Virology, and Hospital Hygiene Rennes Teaching Hospital Hôpital Pontchaillou Rennes, France Rémi Thomas Infectious Diseases and Medical Intensive Care Unit Rennes Teaching Hospital Hôpital Pontchaillou Rennes, France

A Randomized Trial of Short-Course Preemptive Ganciclovir Compared with Conventional Ganciclovir Therapy To Prevent Cytomegalovirus Infection after Allogeneic Stem Cell Transplantation.

We studied the efficacy and safety of a short course of ganciclovir to prevent cytomegalovirus (CMV) infection in allogeneic hematopoietic stem cell transplantation (HSCT) recipients. In general, preemptive ganciclovir is administered twice daily for 1–2 weeks (induction phase) and then once daily until 6 days after cessation of viremia and antigenemia (maintenance phase). We randomly assigned allogeneic HSCT recipients who had positive shell vial culture for CMV or CMV antigenemia to receive preemptive ganciclovir therapy with or without induction phase (5 mg/kg body weight, twice a day for one week). 32 and 34 patients were randomized to the standard treatment arm and the short course arm, respectively. There were no statistically significant differences in patient characteristics such as age, sex, type of disease, type of transplantation, seropositivity of CMV antibody in donor, seropositivity of CMV antibody in recipient, type of conditioning regimen or GVHD prophylaxis regimen between two groups. The median time to clearance of CMV viremia and antigenemia was 7 d and 9 day, respectively (P = 0.333). Seven patients in the short course arm failed for viral clearance after preemptive therapy and were cross-overed to the standard preemptive therapy, which resulted in clearance of antigenemia and viremia in all patients. The toxicity profile was higher in the standard treatment arm with 5 neutropenia and 1 drug-induced hepatitis whereas there was only 1 neutropenia in the short-course arm. Of 5 patients who experienced neutropenia, 2 died of sepsis. This study shows that the preemptive ganciclovir therapy with maintenance phase alone may be equally effective to the standard treatment arm with less toxicity profile in prevention of CMV disease in allogeneic HSCT recipients. The omission of induction phase in CMV preemptive therapy may allow patients to avoid unnecessary hospital admissions.

T Cell-Mediated Control of HCMV Infection in Pediatric Patients Receiving Hematopoietic Stem Cell Transplantation.

We are studying the development of HCMV-specific CD4+ and CD8+ T cell response after allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients. A new technique was developed to simultaneously detect HCMV-specific CD4+ and CD8+ effector T cells using HCMV-infected autologous dendritic cells as stimulators and intracellular staining of IFN-γ production by T cells. This prospective study is based on monthly determination of both HCMV-specific T cell number and in vitro lymphoproliferative response to crude HCMV antigen. Patients are routinely monitored for HCMV infection/reactivation in blood (by determination of either antigenemia or quantitation of viral DNA) and treated according to a strategy of pre-emptive therapy. So far, of 41 patients receiving HSCT from an HLA-identical related donor (n=18), unrelated donor (n=15) or a T cell-depleted HSCT from a haploidentical relative (n=8), 25 patients have reached day +180, while 16 patients completed a follow-up of 90 days. Among the 28 HCMV-seropositive HSCT recipients, 25 developed HCMV-specific CD4+ and CD8+ T-cell response within the first 60 days after transplantation. In these patients, absolute CD4+ T cell count increased over time, but remained lower than that of healthy controls also at later time points. By contrast, CD8+ T cells reached and maintained absolute levels comparable to those of controls already from day +60. At this time, HCMV-specific CD4+ T cell count was comparable to that of controls, while HCMV-specific CD8+ T cell count was higher than that of controls, with no significant change thereafter. On the other hand, in vitro lymphoproliferative response to HCMV antigen was detectable only in about one half of these patients, even at day +180.HCMV infection was detected in blood of 22 of the 25 patients in whom HCMV-specific T cells were present. It was either self-limiting (n=14) or in 8 patients required shorter ganciclovir course (median 7 days, range 5-14) than in the 3 HCMV seropositive patients who developed HCMV infection in the absence of specific immunity (median 67 days, range 42–82, p<0.001). No patient developed HCMV disease or late viral infections. Conversely, HCMV-specific response was detected in only 3/13 HCMV seronegative recipients (none of whom developing detectable HCMV infection in blood). In these patients, both absolute and HCMV-specific T cell counts were lower than those of both controls and HCMV-seropositive HSCT recipients. Our data suggest that effective HCMV-specific T cell immunity can promptly develop after HSCT (regardless of donor type or T-cell depletion of the graft), particularly in seropositive recipients in whom latent virus may be a major antigenic drive for rapid reconstitution of T cell compartment, especially of CD8+ lymphocytes. On the other hand, transfer of memory T cell immunity from seropositive donors to seronegative recipients does not appear to be always sufficient to permit detection of virus-specific lymphocytes in patient's peripheral blood in the early period after the allograft, possibly also due to the lower chance of in vivo antigen stimulation. The frequent dissociation between IFN-γ production and lymphoproliferative response remains to be explained. Future studies could address modulation of antiviral intervention on the reconstitution of HCMV-specific T cell immune response.