山田秀人, 山田俊, 水上尚典, 松田秀雄, 若松太, 古谷健一, 室月淳, 八重樫伸生, 池ノ上克, 妊産婦の感染症とその対策 先天性サイトメガロウイルス感染症と免疫グロブリン療法. 産婦人科治療 2008;97(5)：485-93.
Handsfield HH, Chandler SH, Caine VA, Meyers JD, Corey L, Medeiros E, McDougall JK.
Cytomegalovirus infection in sex partners: evidence for sexual transmission.
J Infect Dis. 1985 Feb;151(2):344-8. doi: 10.1093/infdis/151.2.344.
Abstract/Text
To examine the hypothesis that cytomegalovirus (CMV) is sexually transmitted, we determined the prevalences of antibody to CMV and viral shedding in 63 male sex partners of women with or without CMV infection, and CMV isolates from infected couples were compared by DNA restriction enzyme analysis. The prevalence of seropositivity by enzyme-linked immunosorbent assay was 31 (74%) of 42 men whose female partners were seropositive compared with five (31%) of 16 men whose partners were seronegative (P = .008). CMV was isolated from the semen or urine of four (22%) of 18 men whose female partners shed CMV from the cervix or urine compared with none of 42 whose partners were culture negative (P = .013). DNA restriction enzyme typing of CMV isolates from three pairs of sex partners showed that two of the couples were infected with common strains; epidemiologically unrelated isolates gave distinct patterns. Heterosexual contact is a major mode of transmission of CMV among some young adults.
Baroco AL, Oldfield EC.
Gastrointestinal cytomegalovirus disease in the immunocompromised patient.
Curr Gastroenterol Rep. 2008 Aug;10(4):409-16. doi: 10.1007/s11894-008-0077-9.
Abstract/Text
Cytomegalovirus (CMV) has emerged as a significant opportunistic pathogen in the era of immunosuppression. CMV was a common cause of gastrointestinal disease in AIDS patients, but the introduction of highly active antiretroviral therapy has led to a dramatic decline in AIDS-related disease. Among patients with solid organ transplants, CMV has become an increasingly important cause of gastrointestinal disease as more routine use of early CMV prophylaxis has increased delayed-onset disease, which is often tissue invasive at presentation. The role of CMV in inflammatory bowel disease is controversial; treatment may be indicated in selected cases of steroid-refractory disease with evidence of CMV. Diagnosis of gastrointestinal CMV disease generally requires endoscopic biopsy with histologic confirmation. CMV culture of biopsy material may be falsely positive because of contamination from latently infected cells. The standard induction treatment of gastrointestinal CMV disease uses intravenous ganciclovir, though the use of oral valganciclovir is increasing, especially for long-term maintenance or suppression therapy.
Goodgame RW.
Gastrointestinal cytomegalovirus disease.
Ann Intern Med. 1993 Nov 1;119(9):924-35. doi: 10.7326/0003-4819-119-9-199311010-00010.
Abstract/Text
OBJECTIVE: To describe the pathogenesis of gastrointestinal cytomegalovirus (CMV) disease, the types and locations of gastrointestinal lesions, the clinical settings in which they occur, and the specific methods available to diagnose and treat the disease.
DATA SOURCES: Relevant English-language articles were identified through a MEDLINE search from 1985 to 1992. Articles referenced in the bibliographies of these articles and others were searched by hand.
STUDY SELECTION: All articles that documented the occurrence of gastrointestinal CMV infection in humans, based on the finding of typical cytomegalic cells in histologic specimens, were selected for review.
DATA EXTRACTION: Studies were grouped by content pertaining to pathogenesis, clinical setting, gastrointestinal location, diagnosis, or treatment.
DATA SYNTHESIS: Gastrointestinal CMV disease is an erosive or ulcerative process that can occur at any location in the gastrointestinal tract, from mouth to rectum. Cytomegalovirus infection of columnar epithelial cells, endothelial cells, myocytes, and fibroblasts causes tissue destruction and ulceration. Serious CMV disease most frequently occurs with immune deficiency, such as the acquired immunodeficiency syndrome, after organ transplantation, after cancer chemotherapy, and after steroid therapy. Symptoms and signs depend on which part of the gastrointestinal tract is involved. Diagnosis depends on a positive mucosal biopsy that shows the presence of CMV by histopathologic or other techniques. In patients with persistent immune deficiency, progressive intestinal disease and death are frequent. Treatment with ganciclovir or foscarnet often heals intestinal lesions.
CONCLUSIONS: Internists should be aware of the various clinical settings and locations in the gastrointestinal tract in which CMV disease occurs. Patients with immune deficiency and gastrointestinal signs and symptoms should have imaging tests and mucosal biopsies to investigate the possibility of CMV intestinal disease. Treatment with antiviral chemotherapy improves outcome in many patients.
Buckner FS, Pomeroy C.
Cytomegalovirus disease of the gastrointestinal tract in patients without AIDS.
Clin Infect Dis. 1993 Oct;17(4):644-56. doi: 10.1093/clinids/17.4.644.
Abstract/Text
Cytomegalovirus (CMV) infection of the gastrointestinal (GI) tract can cause serious disease in immunocompromised patients. Recipients of solid organ and bone marrow transplants, persons with malignancies, and those receiving immunosuppressive medications are at risk. When CMV infection of the GI tract causes disease, symptoms include pain, ulceration, bleeding, diarrhea, and perforation. All levels of the GI tract, from the oropharynx to the anus, may be involved. Pathological examination of involved gut typically reveals diffuse ulcerations and necrosis with scattered CMV inclusions, although a variety of other abnormalities have been described. Before the introduction of antiviral therapy effective against CMV, mortality was high. However, the use of ganciclovir or foscarnet has improved the prognosis of CMV disease of the GI tract dramatically. CMV infection should be included in the differential diagnosis of GI disease in immunocompromised patients, and the clinician should pursue appropriate diagnostic and therapeutic interventions aggressively.
Rafailidis PI, Mourtzoukou EG, Varbobitis IC, Falagas ME.
Severe cytomegalovirus infection in apparently immunocompetent patients: a systematic review.
Virol J. 2008 Mar 27;5:47. doi: 10.1186/1743-422X-5-47. Epub 2008 Mar 27.
Abstract/Text
BACKGROUND: The morbidity and mortality associated with cytomegalovirus (CMV) infection in immunocompromised patients (especially in HIV-infected patients and transplant recipients), as well as with congenital CMV infection are well known. In contrast, relatively little attention has been paid to the morbidity and mortality that CMV infection may cause in immunocompetent patients.
METHODS: We reviewed the evidence associated with severe manifestations of CMV infection in apparently immunocompetent patients and the potential role of antiviral treatment for these infections. We searched in PubMed, Scopus, and the Cochrane Library for the period of 1950-2007 to identify relevant articles.
RESULTS: We retrieved 89 articles reporting on severe CMV infection in 290 immunocompetent adults. Among these reports, the gastrointestinal tract (colitis) and the central nervous system (meningitis, encephalitis, transverse myelitis) were the most frequent sites of severe CMV infection. Manifestations from other organ-systems included haematological disorders (haemolytic anaemia, thrombocytopenia), thrombosis of the venous or arterial vascular system, ocular involvement (uveitis), and lung disease (pneumonitis). The clinical practice reported in the literature has been to prescribe antiviral treatment for the most severe manifestations of monophasic meningoencephalitis (seizures and coma), ocular involvement, and lung involvement due to CMV.
CONCLUSION: Severe life-threatening complications of CMV infection in immunocompetent patients may not be as rare as previously thought.
Klauber E, Briski LE, Khatib R.
Cytomegalovirus colitis in the immunocompetent host: an overview.
Scand J Infect Dis. 1998;30(6):559-64. doi: 10.1080/00365549850161098.
Abstract/Text
This paper describes 2 immunocompetent patients with cytomegalovirus colitis and reviews all previously reported cases (n = 13). Affected patients were generally older (69.13+/-15.62 y-old) with probable reactivation (n = 8) or younger (43.86+/-19.73 y-old) with probable primary infection (n = 7). The onset of illness was found to be hospital-associated in 4 (50.0%) reactivation cases and 1 (14.3%) primary case. Presenting manifestations included diarrhoea (86.7%), fever (80.0%), gastrointestinal bleeding (66.7%) and abdominal pain (60.0%). Endoscopy showed erosive colitis with multiple (n = 11; 73.3%) or single ulcers (n = 2, 13.3%); biopsy was diagnostic in 12/13 (92.3%) patients. Complications included massive haemorrhage (13.3%), toxic megacolon (13.3%), perforation (13.3%) and protracted inflammatory bowel disease (20.0%; exclusively in primary-infection). The mortality rate was 26.7%. Antiviral-agents were given in 8 (53.3%) cases; assessment of treatment-efficacy was not possible. In conclusion, cytomegalovirus colitis in the immunocompetent-host is a rare but potentially severe erosive disease with significant morbidity. It may occur during primary infection or reactivation; the diagnosis requires careful histopathological examination and the benefit of antiviral-therapy is unknown.
Gallant JE, Moore RD, Richman DD, Keruly J, Chaisson RE.
Incidence and natural history of cytomegalovirus disease in patients with advanced human immunodeficiency virus disease treated with zidovudine. The Zidovudine Epidemiology Study Group.
J Infect Dis. 1992 Dec;166(6):1223-7. doi: 10.1093/infdis/166.6.1223.
Abstract/Text
Data were analyzed from a multicenter observational cohort study of 1002 persons with AIDS or AIDS-related complex (ARC) and total CD4 cell count < 0.25 x 10(9)/L treated with zidovudine between April 1987 and April 1988. Cytomegalovirus (CMV) disease developed in 109 patients (10.9%), with a 2-year actuarial risk of 15%. Manifestations included retinitis (93 patients), esophagitis (10), colitis (8), gastritis (1), hepatitis (1), and encephalitis (1). The probability of CMV disease at 2 years for patients with initial counts < 0.1 x 10(9)/L was 21.4%, compared with 10.3% for patients with initial counts > or = 0.1 x 10(9)/L (P < .001). By proportional hazards analysis, baseline CD4 cell count < 0.1 x 10(9)/L, enrollment diagnosis of AIDS, and homosexuality were significantly associated with subsequently developing CMV disease. Median survival after diagnosis of CMV disease was 173 days, and CMV was an independent predictor of death. CMV contributes to AIDS-related morbidity and mortality. As new anti-CMV drugs become available, prophylaxis should be targeted at individuals with CD4 cell counts < 0.1 x 10(9)/L.
造血細胞移植ガイドライン サイトメガロウイルス感染症 第2版 2011年7月 日本造血細胞移植学会.
Nagata N, Kobayakawa M, Shimbo T, Hoshimoto K, Yada T, Gotoda T, Akiyama J, Oka S, Uemura N.
Diagnostic value of antigenemia assay for cytomegalovirus gastrointestinal disease in immunocompromised patients.
World J Gastroenterol. 2011 Mar 7;17(9):1185-91. doi: 10.3748/wjg.v17.i9.1185.
Abstract/Text
AIM: To investigate the utility of the cytomegalovirus (CMV) antigenemia assay for the diagnosis of CMV gastrointestinal disease (GID).
METHODS: One hundred and thirty immunocompromised patients were enrolled in this study. Patients with a history of anti-CMV treatment and who had not undergone examination using the antigenemia assay were excluded. CMV-GID was defined as the detection of large cells with intranuclear inclusions alone or associated with granular cytoplasmic inclusions by biopsy. Biopsy sections were stained with hematoxylin and eosin and immunohistochemically stained with anti-CMV. We evaluated the association between CMV-GID and patient characteristics (symptoms, underlying disease, medication, leukocyte counts, and antigenemia assay). All patients were checked with an human immunodeficiency virus (HIV) antibody test before endoscopic examination. White blood cell (WBC) counts were obtained from medical records within 1 wk of endoscopy. Leukopenia was defined as a total WBC count < 5000 cells/mm(3). For HIV patients, we also checked CD4+ counts from medical records.
RESULTS: A total of 99 patients were retrospectively selected for analysis. Of the immunocompromised patients, 19 had malignant disease, 18 had autoimmune disease, 19 had disorders of biochemical homeostasis, three had undergone transplantation, and 45 had HIV infection. A total of 50 patients had received immunosuppressive therapy. No patients had inflammatory bowel disease. Fifty-five patients were diagnosed as having CMV-GID. Univariate analysis indicated an association between HIV infection, leukopenia, and positive antigenemia and CMV-GID (P < 0.05). Multivariate analysis using logistic regression revealed that HIV infection and positive antigenemia were the only independent factors related to CMV-GID (P < 0.01). The sensitivity, specificity, positive predictive value, and negative predictive value of antigenemia for CMV-GID were 65.4%, 93.6%, 91.9%, and 71.0%, respectively. In a subgroup analysis, patients with leukopenia displayed low sensitivity and high specificity. Minimal differences in accuracy were seen among patients with or without leukopenia. HIV-infected patients displayed low sensitivity and high specificity. Accuracy barely differed between HIV-positive and -negative patients. In HIV-infected patients, CD4 count < 50 cells/μL resulted in low sensitivity and high specificity. Differences in accuracy among patients were minor, regardless of CD4 count. In patients who had undergone both quantitative real-time polymerase chain reaction (PCR) and antigenemia assay, real-time PCR was slightly more accurate in terms of sensitivity than the antigenemia assay; however, this difference was not statistically significant (P = 0.312).
CONCLUSION: If the antigenemia test is positive, endoscopic lesions are acceptable for the diagnosis of CMV-GID without biopsy. The accuracy is not affected by HIV infection and leukopenia. Either PCR or the antigenemia assay are valid.
Jang EY, Park SY, Lee EJ, Song EH, Chong YP, Lee SO, Choi SH, Woo JH, Kim YS, Kim SH.
Diagnostic performance of the cytomegalovirus (CMV) antigenemia assay in patients with CMV gastrointestinal disease.
Clin Infect Dis. 2009 Jun 15;48(12):e121-4. doi: 10.1086/599116.
Abstract/Text
Of 149 patients with suspected cytomegalovirus (CMV) gastrointestinal disease, 51 (36%) confirmed cases, 6 (4%) probable cases, and 64 (45%) instances of non-CMV gastrointestinal disease were analyzed using the CMV antigenemia assay; 22 patients (5%) with indeterminate gastrointestinal disease were excluded. The sensitivity and specificity of the CMV antigenemia assay (defined as detection of > or =1 positive cells per 200,000 leukocytes) for diagnosis of CMV gastrointestinal disease were 54% (95% confidence interval, 41%-68%) and 88% (95% confidence interval, 77%-94%), respectively.
Mori T, Okamoto S, Matsuoka S, Yajima T, Wakui M, Watanabe R, Ishida A, Iwao Y, Mukai M, Hibi T, Ikeda Y.
Risk-adapted pre-emptive therapy for cytomegalovirus disease in patients undergoing allogeneic bone marrow transplantation.
Bone Marrow Transplant. 2000 Apr;25(7):765-9. doi: 10.1038/sj.bmt.1702227.
Abstract/Text
We prospectively evaluated a risk-adapted pre-emptive treatment with ganciclovir for CMV diseases in patients undergoing allogeneic bone marrow transplantation (BMT). High-level CMV antigenemia (10 or more positive cells on two slides) or CMV antigenemia at any level in patients with grade II-IV acute graft-versus-host disease (aGVHD) were chosen as risk factors. We also retrospectively evaluated virus reactivation in plasma using quantitative real-time polymerase chain reaction (PCR). Fifty patients were evaluable. None of the 27 patients with or without grade I aGVHD developed high-level CMV antigenemia or CMV disease. Among the 23 patients with grade II-IV aGVHD, 12 patients (52%) developed CMV antigenemia and were treated pre-emptively, of whom two developed CMV gastroenteritis or retinitis in spite of therapy. Six of the remaining 11 patients developed CMV gastroenteritis before CMV antigenemia was detectable. All of the eight patients with CMV diseases were successfully treated with ganciclovir and no deaths directly related to CMV disease occurred. In four of the seven evaluable patients with CMV gastroenteritis, real-time PCR was able to detect virus reactivation earlier than CMV antigenemia. Although our risk-adapted pre-emptive therapy effectively reduced CMV-related mortality, further refinements of this approach, particularly in the prevention of CMV gastroenteritis, may be achieved by incorporating real-time PCR.
Fica A, Cervera C, Pérez N, Marcos MA, Ramírez J, Linares L, Soto G, Navasa M, Cofan F, Ricart MJ, Pérez-Villa F, Pumarola T, Moreno A.
Immunohistochemically proven cytomegalovirus end-organ disease in solid organ transplant patients: clinical features and usefulness of conventional diagnostic tests.
Transpl Infect Dis. 2007 Sep;9(3):203-10. doi: 10.1111/j.1399-3062.2007.00220.x. Epub 2007 May 19.
Abstract/Text
We studied the main clinical features, outcome, and laboratory parameters in a group of solid organ transplant (SOT) patients with immunohistochemically proven cytomegalovirus (CMV) disease. Confirmed CMV cases were obtained through databases. Demographics, clinical data, transplantation type, immunosuppressive regimens, donor and recipient CMV serostatus, therapy, outcome and laboratory results, pp65 antigenemia, and qualitative polymerase chain reaction (PCR) for CMV were analyzed. From 1995 to 2004, 31 cases with complete medical records were identified. Disease appeared between 24 and 2538 days after transplantation but most cases presented in the first 100 days. Gastrointestinal CMV disease was the most frequent form (71%), while thrombocytopenia was present in 50% of cases, and leukopenia was less common (35.5%). CMV pp65 antigenemia was positive in 58% of patients, but its sensitivity increased to 71% if performed during the first 6 months. A qualitative CMV PCR technique gave similar results during this period (71.4%). Most patients were treated with intravenous ganciclovir (n=25; 80.6%). In 4 cases (19.4%), use of foscarnet alone or a sequential regimen with ganciclovir-foscarnet was deemed necessary. Surgical procedures were necessary in 5 patients (16%). The death rate reached 13%. CMV end-organ disease can be a life-threatening infection in SOT patients. Gastrointestinal disease was the most frequent end-organ disease. CMV antigen detection is best suited for the early period after transplantation.
Halme L, Höckerstedt K, Salmela K, Lautenschlager I.
CMV infection detected in the upper gastrointestinal tract after liver transplantation.
Transpl Int. 1998;11 Suppl 1:S242-4. doi: 10.1007/s001470050469.
Abstract/Text
As a pilot series on the frequency of gastroduodenal cytomegalovirus (CMV) involvement after liver transplantation, we examined forceps biopsies of 13 consecutive patients who underwent esophagogastroduodenoscopy during the first 3 months after transplantation. CMV was demonstrated in frozen sections by monoclonal antibody and immunoperoxidase staining. In parallel, peripheral blood was examined for CMV pp65 antigenemia. CMV antigens were detected in biopsies of ten patients, in ten cases in the duodenum and in four in the stomach. At the time of endoscopy, sic patients had CMV antigenemia, five of them had a simultaneous positive finding in the duodenum. Although all ten patients with the positive biopsy finding had some gastrointestinal symptoms, only one had severe enteritis. In liver transplant patients, CMV was commonly detected in leukocytes located in the mucosa of the upper gastrointestinal tract, especially in the duodenum. Further investigation is needed to determine the significance of positive CMV findings in the biopsies and their association with the development of severe gastrointestinal symptoms.
Boeckh M, Boivin G.
Quantitation of cytomegalovirus: methodologic aspects and clinical applications.
Clin Microbiol Rev. 1998 Jul;11(3):533-54. doi: 10.1128/CMR.11.3.533.
Abstract/Text
Cytomegalovirus (CMV) is an important pathogen in transplant recipients and human immunodeficiency virus (HIV)-infected individuals. Major progress has been made in developing quantitative detection methods for CMV in recent years. Due to their high sensitivity, these assays can detect CMV early, and quantitation may be useful in predicting the patient's risk for disease and in monitoring the effect of antiviral therapy. This review discusses methodological aspects of currently used quantitative assays for CMV (i.e., viral culture techniques, antigen detection assays, DNA detection assays including PCR, branched-DNA assay, and the DNA hybrid capture assay) and addresses the correlation of systemic and site-specific CMV load and CMV disease in different populations of immunosuppressed patients as well as the response to antiviral treatment. To date, direct antigen detection and molecular techniques have largely replaced traditional culture-based techniques for CMV quantitation. In general, a high systemic CMV load is correlated with CMV disease. This correlation is strong in the HIV-infected population and in solid-organ transplant recipients but less clear in allogeneic marrow transplant recipients. Measuring the viral load at specific anatomic sites may be an alternative way to assess disease activity in situations where the systemic viral load correlates poorly with disease activity. A reduction of the systemic CMV load also correlates with a response to antiviral treatment, but more research is needed to evaluate the role of viral load as a surrogate marker for drug resistance. Due to the widespread use of quantitative CMV detection techniques to direct and monitor antiviral treatment, there is a great need for an assessment of the reproducibility of test results and better standardization of the assays.
Dieterich DT, Rahmin M.
Cytomegalovirus colitis in AIDS: presentation in 44 patients and a review of the literature.
J Acquir Immune Defic Syndr (1988). 1991;4 Suppl 1:S29-35.
Abstract/Text
As part of a double-blind, placebo-controlled study of ganciclovir in cytomegalovirus (CMV) colitis, the clinical characteristics of 44 patients enrolled at one center were analyzed in detail. All were homosexual men who had CMV on colonic biopsy. CMV colitis was the index diagnosis for acquired immune deficiency syndrome (AIDS) in 11 (25%) of the 44 patients. All had diarrhea, but it was intermittent in 13 patients (30%). Bleeding was uncommon, but 35 patients (80%) were febrile (median temperature of 38.9 degrees C). Weight loss was reported by 39 patients (89%), among whom the median loss was 6.8 kg. Endoscopy revealed normal colonic mucosa but CMV on biopsy in 11 patients (25%). Colonoscopic biopsies positive for CMV were found only in the cecum in 7 (39%) of 18 patients. Most patients (54%) had received zidovudine before the diagnosis of CMV colitis. The median time to the development of CMV colitis after the diagnosis of AIDS was 16 months in those patients who had received zidovudine and 3 months in those who had not (p less than 0.02). We conclude that CMV colitis can present early in AIDS and often with such nonspecific signs as fever, intermittent diarrhea, weight loss, and hematochezia. Importantly, it can appear normal on colonoscopy and occurs frequently only in the right colon, necessitating full colonoscopy and multiple biopsies for accurate diagnosis.
Connolly GM, Forbes A, Gleeson JA, Gazzard BG.
The value of barium enema and colonoscopy in patients infected with HIV.
AIDS. 1990 Jul;4(7):687-9. doi: 10.1097/00002030-199007000-00014.
Abstract/Text
Double contrast barium enema (DCBE) and colonoscopy were prospectively compared with rigid sigmoidoscopy, rectal biopsy and microbiological examination in the analysis of stool specimens in 58 HIV-1-infected patients with diarrhoea (more than three liquid motions/day for greater than 1 month). In 26 patients no cause for the diarrhoea was found. In 17 patients the cause of diarrhoea was microbiological, and in 19 rectal histology provided a specific diagnosis. In all these patients sigmoidoscopic appearances were abnormal except in those with Cryptosporidium alone. Colonoscopy provided additional information in only one individual, with cytomegalovirus ulcers of the transverse colon. DCBE was abnormal in only seven cases (cytomegalovirus in three, Kaposi's sarcoma in two, Giardia lamblia in two) and in no case provided additional information. A combination of stool microbiology and rectal histology gave a sensitivity of 97% with a positive predictive value of 100%. The sensitivities of DCBE and colonoscopy with histology were low (16 and 62%, respectively) although the specificity for each test was high, with high positive predictive values. We conclude that neither barium enema nor colonoscopy add usefully to rigid sigmoidoscopic biopsy and stool microscopy in HIV-positive patients with diarrhoea.
Cho SR, Tisnado J, Liu CI, Beachley MC, Shaw CI, Kipreos BE, Schneider V.
Bleeding cytomegalovirus ulcers of the colon: barium enema nad angiography.
AJR Am J Roentgenol. 1981 Jun;136(6):1213-5. doi: 10.2214/ajr.136.6.1213.
Abstract/Text
Patel SM, Cohen P, Pickering MC, Gazzard BG, Andreyev J.
Successful treatment of acute haemorrhagic cytomegalovirus colitis with ganciclovir in an individual without overt immunocompromise.
Eur J Gastroenterol Hepatol. 2003 Sep;15(9):1055-60. doi: 10.1097/00042737-200309000-00020.
Abstract/Text
Reddy N, Wilcox CM.
Diagnosis & management of cytomegalovirus infections in the GI tract.
Expert Rev Gastroenterol Hepatol. 2007 Dec;1(2):287-94. doi: 10.1586/17474124.1.2.287.
Abstract/Text
Cytomegalovirus (CMV) infection of the GI tract is a common problem in patients immunosuppressed by HIV or organ transplantation. The esophagus and colon are the most common sites of involvement. Recent developments in diagnosis, such as immunohistochemical staining, shell vial assay and PCR, aid in early detection and predicting the prognosis of CMV disease in susceptible individuals. Although current drugs have limitations in terms of toxicity, drug interactions and resistance, newer drugs appear promising.
Parente F, Cernuschi M, Rizzardini G, Lazzarin A, Valsecchi L, Bianchi Porro G.
Opportunistic infections of the esophagus not responding to oral systemic antifungals in patients with AIDS: their frequency and treatment.
Am J Gastroenterol. 1991 Dec;86(12):1729-34.
Abstract/Text
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.
Kraus MD, Feran-Doza M, Garcia-Moliner ML, Antin J, Odze RD.
Cytomegalovirus infection in the colon of bone marrow transplantation patients.
Mod Pathol. 1998 Jan;11(1):29-36.
Abstract/Text
The histologic distinction between cytomegalovirus (CMV) infection and graft-versus-host disease (GVHD) in the colon in bone marrow transplantation (BMT) patients relies heavily on the identification of viral inclusions, because the morphologic features of these two diseases are otherwise similar. The aim of this study was to assess (1) the prevalence of colonic CMV infection in BMT patients with the use of DNA in situ hybridization (ISH); and (2) the sensitivity and specificity of light microscopy in establishing a diagnosis of CMV infection in the colon of these patients. Fifty-five colonic mucosal biopsy samples from 50 consecutive allogeneic BMT patients with diarrhea were evaluated histologically for the presence of typical or atypical (suspicious, but not diagnostic) CMV inclusions and, if negative, for the grade of GVHD. CMV DNA ISH analysis was performed on all of the biopsy specimens and was correlated with the histologic and clinical findings. Histologic analysis revealed only one patient with morphologically typical CMV inclusions. Four other cases contained an isolated atypical mesenchymal cell with features considered suspicious, but not diagnostic, for CMV inclusions. All of these five cases exhibited histologic features that were otherwise indistinguishable from GVHD grades 1 to 2. The single case that was histologically positive for CMV was confirmed by DNA ISH. Of the four histologically atypical cases, only one was confirmed to be CMV positive by DNA ISH. Of the remaining 45 patients, 35 had GVHD, 1 had pseudomembranous colitis, 1 had ischemic colitis, and 8 had no abnormalities found. Light microscopic examination is a sensitive method of screening for CMV infection in the colon of BMT patients but is less specific than DNA ISH. CMV infection is an infrequent cause of colitis in our BMT population.
Muir SW, Murray J, Farquharson MA, Wheatley DJ, McPhaden AR.
Detection of cytomegalovirus in upper gastrointestinal biopsies from heart transplant recipients: comparison of light microscopy, immunocytochemistry, in situ hybridisation, and nested PCR.
J Clin Pathol. 1998 Nov;51(11):807-11. doi: 10.1136/jcp.51.11.807.
Abstract/Text
AIM: To establish the diagnostic value of in situ hybridisation and the nested polymerase chain reaction (PCR) in detecting clinically relevant cytomegalovirus (CMV) infection in upper gastrointestinal biopsies from heart transplant patients.
METHODS: Test sensitivity and specificity for detection of CMV early gene RNA by in situ hybridisation and CMV intermediate early gene by PCR were established and then compared with haematoxylin and eosin (H&E) and immunocytochemical detection of CMV in order to establish the best pathological diagnostic approach. All investigations were carried out on formalin fixed, paraffin embedded tissue.
RESULTS: Nested PCR had the highest test sensitivity, followed by in situ hybridisation and immunocytochemistry with the same sensitivity; H&E had the lowest. H&E and immunocytochemistry were the most specific but both had a significant false negative rate which was less of a problem with PCR. However, PCR gave no other diagnostic information, and in situ hybridisation was no better than immunocytochemistry. Both in situ hybridisation and PCR were technically complex and more expensive.
CONCLUSIONS: H&E and immunocytochemistry represent the best initial screen for CMV and other diseases in upper gastrointestinal biopsies from heart transplant patients. If H&E and immunocytochemistry were negative, nested PCR could significantly increase the diagnostic yield of clinically relevant CMV infection. In situ hybridisation appeared to have no advantages and some drawbacks compared with immunocytochemistry and PCR.
Yoshino T, Nakase H, Ueno S, Uza N, Inoue S, Mikami S, Matsuura M, Ohmori K, Sakurai T, Nagayama S, Hasegawa S, Sakai Y, Chiba T.
Usefulness of quantitative real-time PCR assay for early detection of cytomegalovirus infection in patients with ulcerative colitis refractory to immunosuppressive therapies.
Inflamm Bowel Dis. 2007 Dec;13(12):1516-21. doi: 10.1002/ibd.20253.
Abstract/Text
BACKGROUND: Studies suggest that cytomegalovirus (CMV) infection exacerbates ulcerative colitis (UC) refractory to immunosuppressive therapies. Early and accurate diagnosis of CMV infection is important for the treatment of UC. We evaluated the usefulness of quantitative real-time polymerase chain reaction (PCR) for detecting CMV infection in inflamed colonic mucosa of patients with UC refractory to immunosuppressive therapies.
METHODS: From 2003 to 2006, 30 patients (mean age: 41 +/- 18 years; 14 men, 16 women) with UC refractory to immunosuppressive therapies were enrolled in the study. We evaluated CMV infection by CMV antigenemia, histologic examination, and quantitative real-time PCR for CMV using colonic mucosa and investigated the clinical outcomes of antiviral therapy.
RESULTS: CMV-DNA was detected only in the inflamed colonic mucosa in 17 (56.7%) of 30 patients. Of the 17 CMV-DNA-positive patients, 4 were positive for CMV antigenemia or inclusion bodies on histologic examination; of the 13 CMV-DNA-negative patients none was positive for CMV antigenemia or inclusion bodies. Of the 17 CMV-DNA-positive patients, 12 (70.6%) were treated with ganciclovir for 2 weeks and 10 patients went into remission. Two other patients required colectomy after antiviral therapy. In contrast, of the 13 CMV-DNA-negative patients 12 (92.3%) achieved remission after intensifying their immunosuppressive therapies.
CONCLUSIONS: Quantitative real-time PCR assay for detecting CMV-DNA is useful for early, accurate diagnosis of CMV infection in patients with UC refractory to immunosuppressive therapies, enabling prompt and appropriate treatment.
Cotte L, Drouet E, Bailly F, Vitozzi S, Denoyel G, Trepo C.
Cytomegalovirus DNA level on biopsy specimens during treatment of cytomegalovirus gastrointestinal disease.
Gastroenterology. 1996 Aug;111(2):439-44. doi: 10.1053/gast.1996.v111.pm8690210.
Abstract/Text
BACKGROUND & AIMS: There is no clear and point for the response to treatment of gastrointestinal human cytomegalovirus (HCMV) disease. HCMV-DNA quantitation on gastrointestinal biopsy specimens has proven its value for the diagnosis of gastrointestinal HCMV disease in patients with acquired immunodeficiency syndrome (AIDS). The aim was to study HCMV-DNA levels on gastrointestinal biopsy specimens during the treatment of gastrointestinal HCMV disease.
METHODS: HCMV-DATA quantitation was performed using two different polymerase chain reaction assays on 90 biopsy specimens obtained before anti-HCMV therapy, during the induction phase, or during maintenance therapy for gastrointestinal HCMV disease in 21 patients with AIDS.
RESULTS: HCMV-DNA was detected on all the biopsy specimens ranging from 9 to > or = 80,000 Eq/0.1 microgram DNA. Pretherapeutic mean level was 69,000 +/- 27,000 Eq/0.1 microgram DNA. Induction therapy was followed by a mean decrease of 1.7 +/- 1.3 log10 Eq/0.1 microgram DNA. HCMV-DNA levels decreased during induction therapy to < 1000 Eq/0.1 microgram DNA in 60% of patients but remained > 80,000 Eq/0.1 microgram DNA in 20% of patients. Relapse occurred in all the patients in a mean time of 100 days. HCMV-DNA level at the end of the induction phase seems to influence the time to relapse.
CONCLUSIONS: Quantitation of HCMV-DNA on gastrointestinal biopsy specimens seems to be useful for monitoring gastrointestinal HCMV disease in patients with AIDS.
Ganzenmueller T, Henke-Gendo C, Schlué J, Wedemeyer J, Huebner S, Heim A.
Quantification of cytomegalovirus DNA levels in intestinal biopsies as a diagnostic tool for CMV intestinal disease.
J Clin Virol. 2009 Nov;46(3):254-8. doi: 10.1016/j.jcv.2009.08.008. Epub 2009 Sep 12.
Abstract/Text
BACKGROUND: CMV intestinal disease (CMV-ID) is a serious complication in immunocompromised patients and mainly diagnosed by clinical, endoscopic and histopathologic findings, whereas qualitative CMV-PCR in tissue samples is not recommended for diagnosis due to its low positive predictive value (PPV).
OBJECTIVES: To study the interpretation and diagnostic use of CMV-quantification by PCR in intestinal tissue biopsies to recognize CMV-ID. To develop cut-off intestinal CMV-loads attributing illness to CMV.
STUDY DESIGN: CMV-genome copies in 163 biopsies from the lower intestinal tract of immunocompromised patients were determined by quantitative real-time PCR, normalized to the cell number, and retrospectively compared to histopathological analysis, clinical findings and occurrence of CMV-antigenemia. Two cut-off intestinal CMV-loads, cut-off(histo) and cut-off(clin), were defined using histopathological or clinical criteria as gold standard, respectively.
RESULTS: CMV was detected in 32.5% of biopsies with a more than six log range of CMV-concentrations (1 x 10(-4)-1.4 x 10(2)copies/cell). Notably, biopsies with histopathologically or clinically confirmed CMV-ID had a significantly higher CMV-load (p<0.001). Cut-off(histo) and cut-off(clin) were defined at the intestinal CMV-load of 0.14 and 0.01 copies/cell, respectively, and improved the PPV. However, cut-off(histo) showed a decreased sensitivity for clinically defined CMV-ID cases. Interestingly, many patients with CMV-ID showed no concomitant CMV-antigenemia, suggesting a localized intestinal CMV-replication.
CONCLUSIONS: Quantification of CMV in intestinal biopsies is a useful diagnostic tool allowing the definition of cut-off values that can predict CMV-ID more accurate than qualitative PCR results. Further prospective studies have to clarify wether these cut-offs can improve diagnostics and treatment of CMV-ID in day-to-day clinical practice.
Péter A, Telkes G, Varga M, Sárváry E, Kovalszky I.
Endoscopic diagnosis of cytomegalovirus infection of upper gastrointestinal tract in solid organ transplant recipients: Hungarian single-center experience.
Clin Transplant. 2004 Oct;18(5):580-4. doi: 10.1111/j.1399-0012.2004.00230.x.
Abstract/Text
BACKGROUND: Cytomegalovirus (CMV) is considered to be the major cause of upper gastrointestinal (GI) symptoms in organ transplant recipients. In the diagnosis of GI CMV infection the detection of the virus in the mucosa is essential. The aim of the study was to evaluate the significance of CMV, detected in biopsy specimens from stomach and duodenum of solid organ transplant recipients.
METHODS: Data of 227 elective upper endoscopies on symptomatic organ transplant recipients were evaluated for clinical symptoms, endoscopic changes and conventional histologic alterations of mucosal biopsy samples. Qualitative PCR was performed for detection of the presence of CMV-DNA in each biopsy materials.
RESULTS: CMV-DNA was detected in biopsy samples of 91 patients (40.1%) while only in 20 cases (8.8%) the signs of CMV infections were found by conventional histology (p < 0.00001). No considerable differences could be observed in symptomatic, histologic alterations between CMV-PCR positive and negative groups. There were no endoscopic changes in 25.3% of CMV-PCR positive and 5.1% of negative patients.
CONCLUSIONS: Qualitative PCR is an accurate method for the detection of CMV in the mucosa of the GI tract. Further investigations are needed for determination of the exact pathological role of detected CMV.
Blanshard C, Benhamou Y, Dohin E, Lernestedt JO, Gazzard BG, Katlama C.
Treatment of AIDS-associated gastrointestinal cytomegalovirus infection with foscarnet and ganciclovir: a randomized comparison.
J Infect Dis. 1995 Sep;172(3):622-8. doi: 10.1093/infdis/172.3.622.
Abstract/Text
Patients with symptomatic gastrointestinal disease due to cytomegalovirus (CMV) were randomized to receive open-label ganciclovir (22) or foscarnet (26). Patients were stratified by disease site and concurrent gut infection. Response was assessed by a visual analogue score of symptoms, endoscopic appearances, histologic inflammation, and numbers of CMV inclusions. In each treatment group, 73% had a complete or good clinical response; 83% of foscarnet-treated and 85% of ganciclovir-treated patients showed response by endoscopy, and inclusion bodies disappeared from follow-up biopsies in 73% of these. Most patients (35) developed further evidence of CMV disease during follow-up. The time to progression was not significantly different between recipients (16 weeks) and nonrecipients (13 weeks) of maintenance therapy, although patients were not randomized to receive maintenance or not. Survival in both treatment groups was < 40 weeks and was unaffected by maintenance treatment. Both ganciclovir and foscarnet are effective first-line treatments for gastrointestinal (GI) CMV infection. Maintenance therapy does not prevent progression of disease.
Gerna G, Sarasini A, Baldanti F, Percivalle E, Zella D, Revello MG.
Quantitative systemic and local evaluation of the antiviral effect of ganciclovir and foscarnet induction treatment on human cytomegalovirus gastrointestinal disease of patients with AIDS. Italian Foscarnet GID Study Group.
Antiviral Res. 1997 Mar;34(1):39-50. doi: 10.1016/s0166-3542(96)01020-0.
Abstract/Text
In a group of 29 AIDS patients with biopsy-proven human cytomegalovirus (HCMV) gastrointestinal disease (GID), HCMV GID was shown to correlate mostly with systemic HCMV infection. The antiviral induction treatment (IT) with either ganciclovir (GCV) or foscarnet (PFA) caused a significant reduction in the level of HCMV antigenemia, viremia and leukoDNAemia, and a complete virus clearance or a sharp drop of viral load in the blood of 13/13 patients and in the gastrointestinal (GI) mucosa of 12/13 (92%) patients in the GCV arm, and in the blood of 13/14 (93%) patients and in the GI mucosa of 10/12 (83%) patients in the PFA arm of the study, respectively. Similarly, the clinical response was good in 13/15 (87%) patients in the GCV arm and in 13/14 (93%) patients in the PFA arm. In addition, the finding that 2/6 patients positive for HCMV isolated from both GI mucosa and blood prior to IT were still positive in the GI tract after IT, suggested that IT could be prolonged to clear the virus from GI tract. In conclusion, both GCV and PFA showed a remarkable systemic and local antiviral effect in the treatment of HCMV GID in AIDS patients.
Dieterich DT, Poles MA, Lew EA, Martin-Munley S, Johnson J, Nix D, Faust MJ.
Treatment of gastrointestinal cytomegalovirus infection with twice-daily foscarnet: a pilot study of safety, efficacy, and pharmacokinetics in patients with AIDS.
Antimicrob Agents Chemother. 1997 Jun;41(6):1226-30. doi: 10.1128/AAC.41.6.1226.
Abstract/Text
Ten patients with AIDS and cytomegalovirus (CMV) gastrointestinal infection were included in an open-label study to evaluate the safety, efficacy, and pharmacokinetics of 90 mg of intravenous foscarnet/kg of body weight twice daily accompanied by (pre)hydration of 500 to 750 ml. Efficacy was documented endoscopically, while safety was evaluated clinically by patient reports and physical and laboratory observation. The pharmacokinetics of foscarnet was evaluated after the first dose and following approximately 20 days of therapy. Nine patients (90%) responded histopathologically, nine (90%) responded endoscopically, and nine (90%) responded symptomatically to foscarnet therapy. Adverse events resulted in discontinuance of medication in the case of one patient. The mean maximal concentration was 621 microM following the first dose and 687 microM at steady state (P = 0.11). The apparent elimination rate constant and elimination half-life were not different between dose 1 and steady state. There were no significant changes in foscarnet excretion or renal clearance between dose 1 and steady state. The steady-state volume of distribution was 23.4 liters following the first dose and 19.0 liters at steady state (P < 0.002). Twice-daily foscarnet appeared to be safe and efficacious in the treatment of CMV gastrointestinal disease in this study, resulting in endoscopic or histologic improvement in 9 of the 10 (90%) patients. Minor changes in clearance and volume of distribution noted at steady state compared to single-dose administration are readily explained by study design, known information about foscarnet pharmacokinetics, and changes in body weight and creatinine clearance in the patients.
Whitley RJ, Jacobson MA, Friedberg DN, Holland GN, Jabs DA, Dieterich DT, Hardy WD, Polis MA, Deutsch TA, Feinberg J, Spector SA, Walmsley S, Drew WL, Powderly WG, Griffiths PD, Benson CA, Kessler HA.
Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: recommendations of an international panel. International AIDS Society-USA.
Arch Intern Med. 1998 May 11;158(9):957-69. doi: 10.1001/archinte.158.9.957.
Abstract/Text
OBJECTIVE: To provide recommendations for the treatment of acquired immunodeficiency syndrome-related cytomegalovirus (CMV) end-organ diseases, including retinitis, colitis, pneumonitis, and neurologic diseases.
PARTICIPANTS: A 17-member panel of physicians with expertise in clinical and virological research and inpatient care in the field of CMV diseases.
EVIDENCE: Available clinical and virological study results. Recommendations are rated according to the quality and strength of available evidence. Recommendations were limited to the treatment of CMV diseases; prophylaxis recommendations are not included.
PROCESS: The panel was convened in February 1997 and met regularly through November 1997. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus.
CONCLUSIONS: Although the epidemiological features of CMV diseases are changing in the setting of potent, combination antiretroviral therapy, continued attention must be paid to CMV diseases in patients infected with the human immunodeficiency virus to prevent irreversible endorgan dysfunction. The initial and maintenance treatment of CMV retinitis must be individualized based on the characteristics of the lesions, including location and extent, specific patient factors, and characteristics of available therapies among others. Management of relapse or refractory retinitis must be likewise individualized. Ophthalmologic screening for patients at high risk for retinitis or who have a prior diagnosis of extraretinal disease is recommended. Recommendations for gastrointestinal, pulmonary, and neurologic manifestations are included.
Kaplan JE, Benson C, Holmes KK, Brooks JT, Pau A, Masur H; Centers for Disease Control and Prevention (CDC); National Institutes of Health; HIV Medicine Association of the Infectious Diseases Society of America.
Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America.
MMWR Recomm Rep. 2009 Apr 10;58(RR-4):1-207; quiz CE1-4.
Abstract/Text
This report updates and combines earlier versions of guidelines for the prevention and treatment of opportunistic infections (OIs) in HIV-infected adults (i.e., persons aged >/=18 years) and adolescents (i.e., persons aged 13--17 years), last published in 2002 and 2004, respectively. It has been prepared by the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), and the HIV Medicine Association (HIVMA) of the Infectious Diseases Society of America (IDSA). The guidelines are intended for use by clinicians and other health-care providers, HIV-infected patients, and policy makers in the United States. These guidelines address several OIs that occur in the United States and five OIs that might be acquired during international travel. Topic areas covered for each OI include epidemiology, clinical manifestations, diagnosis, prevention of exposure; prevention of disease by chemoprophylaxis and vaccination; discontinuation of primary prophylaxis after immune reconstitution; treatment of disease; monitoring for adverse effects during treatment; management of treatment failure; prevention of disease recurrence; discontinuation of secondary prophylaxis after immune reconstitution; and special considerations during pregnancy. These guidelines were developed by a panel of specialists from the United States government and academic institutions. For each OI, a small group of specialists with content-matter expertise reviewed the literature for new information since the guidelines were last published; they then proposed revised recommendations at a meeting held at NIH in June 2007. After these presentations and discussion, the revised guidelines were further reviewed by the co-editors; by the Office of AIDS Research, NIH; by specialists at CDC; and by HIVMA of IDSA before final approval and publication. The recommendations are rated by a letter that indicates the strength of the recommendation and a Roman numeral that indicates the quality of evidence supporting the recommendation, so that readers can ascertain how best to apply the recommendations in their practice environments. Major changes in the guidelines include 1) greater emphasis on the importance of antiretroviral therapy for the prevention and treatment of OIs, especially those OIs for which no specific therapy exists; 2) information regarding the diagnosis and management of immune reconstitution inflammatory syndromes; 3) information regarding the use of interferon-gamma release assays for the diagnosis of latent Mycobacterium tuberculosis (TB) infection; 4) updated information concerning drug interactions that affect the use of rifamycin drugs for prevention and treatment of TB; 5) the addition of a section on hepatitis B virus infection; and 6) the addition of malaria to the list of OIs that might be acquired during international travel. This report includes eleven tables pertinent to the prevention and treatment of OIs, a figure that pertains to the diagnois of tuberculosis, a figure that describes immunization recommendations, and an appendix that summarizes recommendations for prevention of exposure to opportunistic pathogens.
Benson CA, Kaplan JE, Masur H, Pau A, Holmes KK; CDC; National Institutes of Health; Infectious Diseases Society of America.
Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America.
MMWR Recomm Rep. 2004 Dec 17;53(RR-15):1-112.
Abstract/Text
The National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, and CDC have developed guidelines for treatment of opportunistic infections (OIs) among adults and adolescents infected with human immunodeficiency virus (HIV). These guidelines are intended for clinicians and other health-care providers who care for HIV-infected adults and adolescents, including pregnant women; they complement companion guidelines for treatment of OIs among HIV-infected children and previously published guidelines for prevention of OIs in these populations. They include evidence-based guidelines for treatment of 28 OIs caused by protozoa, bacteria, fungi, and viruses, including certain OIs endemic in other parts of the world but that might be observed in patients in the United States. Each OI section includes information on epidemiology, clinical manifestations, diagnosis, treatment recommendations, monitoring and adverse events, management of treatment failure, prevention of recurrence, and special considerations in pregnancy. Tables address drugs and doses, drug toxicities, drug interactions, adjustment of drug doses in persons with reduced renal function, and data about use of drugs in pregnant women.
Blanshard C.
Treatment of HIV-related cytomegalovirus disease of the gastrointestinal tract with foscarnet.
J Acquir Immune Defic Syndr (1988). 1992;5 Suppl 1:S25-8.
Abstract/Text
Gastrointestinal cytomegalovirus (CMV) disease occurs in a significant proportion of patients with AIDS. A series of 66 AIDS patients with first-episode gastrointestinal CMV disease diagnosed on the basis of clinical and histopathologic findings were treated with foscarnet as first-line therapy at our institution between January 1987 and January 1991. Primary sites of infection were the colon (28 patients) and the esophagus (22 patients). Foscarnet was administered as a continuous infusion of 200 mg/kg (prior to 1988) or as an intermittent infusion of 60 mg/kg t.i.d. or 90 mg/kg b.i.d., with saline hyperhydration accompanying each infusion. Patients were treated initially for 2 weeks, with an additional 1-2 weeks of treatment being given in those not having a complete response during initial treatment; maintenance therapy was given only in cases of concurrent CMV retinitis. Complete response to foscarnet therapy (resolution of symptoms and endoscopic findings) was observed in 17 esophagitis patients (77%) within 3 weeks, with only 4 patients relapsing (at 1-7 months) and none developing colitis or retinitis. Complete response was observed in 16 colitis patients (57%) within 3 weeks, with relapse occurring in 5. Asymptomatic hypocalcemia occurred in 19.7% of patients and penile ulceration occurred in 6.1%; increases in serum creatinine were observed in five patients (7.6%), but did not require discontinuation of treatment. These findings indicate that foscarnet is an effective first-line treatment for gastrointestinal CMV infection. They also suggest that maintenance therapy with foscarnet may not be required in all patients.
Dieterich DT, Poles MA, Dicker M, Tepper R, Lew E.
Foscarnet treatment of cytomegalovirus gastrointestinal infections in acquired immunodeficiency syndrome patients who have failed ganciclovir induction.
Am J Gastroenterol. 1993 Apr;88(4):542-8.
Abstract/Text
This compassionate-use study examined the efficacy of foscarnet in patients with AIDS and cytomegalovirus (CMV) gastrointestinal disease who had failed ganciclovir induction. Nineteen male homosexuals with AIDS and biopsy-proven CMV gastrointestinal disease who had twice failed standard ganciclovir induction (defined as progression of clinical CMV disease) were studied. Foscarnet 60 mg/kg every 8 h was administered intravenously for 14 days, then maintenance was utilized at 90 or 120 mg/kg every day with 1 L normal saline daily. Endpoints included endoscopic appearance, blinded histopathologic analysis of biopsies for CMV inclusions, and changes in symptoms by 50% from baseline. Patients were evaluated before and 2-3 wk after foscarnet. Histopathologic improvement was seen in 67%, whereas 74% improved clinically after a median duration of 7.5 days (1-12). Among the nine with esophageal disease, six patients (68%) had a clinical response and six of eight (75%) had a pathologic response. Among the 10 with colonic disease, eight patients (80%) had a clinical response and six (60%) had a pathologic response. Reversible elevations in creatinine were seen in two of 17 (12%). Three patients with esophageal disease developed strictures late in therapy requiring dilation. Median survival after foscarnet induction was 5.0 months. Foscarnet appears to induce remission of CMV gastrointestinal disease in 67% of patients when ganciclovir induction has failed. Reversible nephrotoxicity occurred in 12%. Strictures may be a late complication of CMV esophagitis.
Dieterich DT, Poles MA, Lew EA, Mendez PE, Murphy R, Addessi A, Holbrook JT, Naughton K, Friedberg DN.
Concurrent use of ganciclovir and foscarnet to treat cytomegalovirus infection in AIDS patients.
J Infect Dis. 1993 May;167(5):1184-8. doi: 10.1093/infdis/167.5.1184.
Abstract/Text
Ten patients with AIDS and progressive cytomegalovirus disease were treated with ganciclovir and foscarnet concurrently. The patients had received ganciclovir and foscarnet monotherapy a median of 330 days before receiving combination therapy for a median of 80 days. Nine of the 10 patients responded to the combination. No electrolyte abnormalities were noted during combination therapy, but rates of neutropenia (relative rate, combination vs. ganciclovir, 1.99; P = .229) and thrombocytopenia (relative rate, combination vs. ganciclovir, 1.53; P = .616) were higher with combination therapy than with either drug alone. The relative rate of anemia was significantly increased with combination therapy compared with monotherapy (relative rate, combination vs. ganciclovir, 2.69; P = .025). These data suggest that combination ganciclovir and foscarnet therapy after failure of either alone appears to be as effective as standard therapy with single agents. The rate of anemia with combination therapy was significantly greater than either agent alone, but no significant difference was noted among the other parameters of toxicity studied.
Wagstaff AJ, Bryson HM.
Foscarnet. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with viral infections.
Drugs. 1994 Aug;48(2):199-226. doi: 10.2165/00003495-199448020-00007.
Abstract/Text
The DNA polymerase of human herpes viruses, including cytomegalovirus (CMV), and the reverse transcriptase of human immunodeficiency virus (HIV) are selectively inhibited in vitro by the pyrophosphate analogue foscarnet. Inhibition is reversible on withdrawal of foscarnet and additive or synergistic effects have been demonstrated in vitro with other antiviral drugs, including ganciclovir and zidovudine. Foscarnet appears to have negligible effects on host enzymes and cells. Complete or partial clinical resolution of ocular symptoms is obtained in more than 89% of patients with acquired immunodeficiency syndrome (AIDS) and CMV retinitis during foscarnet induction therapy, but relapse occurs soon after ceasing treatment. Maintenance treatment given daily can extend the period of remission considerably. Foscarnet and ganciclovir monotherapy had similar efficacy in the treatment of CMV retinitis in patients with AIDS in several studies, and have been used concomitantly in immunocompromised patients with recalcitrant CMV infections. In 1 trial, patients receiving foscarnet survived for significantly longer than those receiving ganciclovir. Foscarnet has been used successfully in the treatment of limited numbers of immunocompromised patients with CMV-associated gastrointestinal (improvement in over 67% of patients) and other infections. Aciclovir-resistant herpes simplex infections in immunocompromised patients have also been treated successfully with foscarnet. Almost 90% of a foscarnet dose is excreted in the urine. Reversible nephrotoxicity is common during foscarnet therapy, but may be reduced by dosage adjustment and adequate hydration. Anaemia, nausea and vomiting, disturbances in electrolyte levels and genital ulceration have also been associated with administration of the drug. The different tolerability profiles of foscarnet and zidovudine facilitate the use of these agents in combination in patients with AIDS and CMV infection; whereas ganciclovir, like zidovudine, is associated with dose-limiting haematological toxicity. The apparent survival benefits seen in these patients when receiving foscarnet and zidovudine (possibly linked to synergy between zidovudine and foscarnet and/or the inherent anti-HIV activity of foscarnet), appear to offer potentially important advantages for foscarnet over ganciclovir in the treatment of selected patients with AIDS and CMV infections.
Salzberger B, Stoehr A, Heise W, Fätkenheuer G, Schwenk A, Franzen C, Cornely O, Schrappe M.
Foscarnet and ganciclovir combination therapy for CMV disease in HIV-infected patients.
Infection. 1994 May-Jun;22(3):197-200. doi: 10.1007/BF01716702.
Abstract/Text
An open prospective trial of combined ganciclovir and foscarnet therapy for 3 weeks was initiated in 14 episodes of severe CMV-disease in 13 HIV-infected patients (all CDC class IV, age 30-42, median 34 years, CD4+ cell count 0-80, median 10/microliters). In seven episodes of gastrointestinal disease (five colitis, two esophagitis) remission of symptoms and mucosal changes was achieved in five. In seven episodes of retinitis, scarring was achieved in six. Renal toxicity was seen in two patients, moderate hematologic toxicity in eight patients. Overall efficacy was comparable to monotherapy; no new toxicities were seen with the combination of these two drugs.
Martin DF, Sierra-Madero J, Walmsley S, Wolitz RA, Macey K, Georgiou P, Robinson CA, Stempien MJ; Valganciclovir Study Group.
A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis.
N Engl J Med. 2002 Apr 11;346(15):1119-26. doi: 10.1056/NEJMoa011759.
Abstract/Text
BACKGROUND: Valganciclovir is an orally administered prodrug that is rapidly hydrolyzed to ganciclovir. We compared the effects of oral valganciclovir with those of intravenous ganciclovir as induction therapy for newly diagnosed cytomegalovirus retinitis in 160 patients with the acquired immunodeficiency syndrome (AIDS).
METHODS: The primary end point was photographically determined progression of cytomegalovirus retinitis within four weeks after the initiation of treatment. Secondary end points included the achievement of a prospectively defined satisfactory response to induction therapy and the time to progression of cytomegalovirus retinitis. After four weeks, all patients received valganciclovir as maintenance therapy.
RESULTS: Eighty patients were randomly assigned to each treatment group. Of the patients who could be evaluated, 7 of 70 assigned to intravenous ganciclovir (10.0 percent) and 7 of 71 assigned to oral valganciclovir (9.9 percent) had progression of cytomegalovirus retinitis during the first four weeks (difference in proportions, 0.1 percentage point; 95 percent confidence interval, -9.7 to 10.0). Forty-seven of 61 patients (77.0 percent) assigned to intravenous ganciclovir and 46 of 64 (71.9 percent) assigned to valganciclovir had a satisfactory response to induction therapy (difference in proportions, 5.2 percentage points; 95 percent confidence interval, -20.4 to 10.1). The median times to progression of retinitis were 125 days in the group assigned to intravenous ganciclovir and 160 days in the group assigned to oral valganciclovir. The mean values for the area under the curve for the ganciclovir dosage interval were similar at both induction doses and maintenance doses. The frequency and severity of adverse events were similar in the two treatment groups.
CONCLUSIONS: Orally administered valganciclovir appears to be as effective as intravenous ganciclovir for induction treatment and is convenient and effective for the long-term management of cytomegalovirus retinitis in patients with AIDS.
Curran M, Noble S.
Valganciclovir.
Drugs. 2001;61(8):1145-50 ; discussion 1151-2. doi: 10.2165/00003495-200161080-00013.
Abstract/Text
Valganciclovir is a prodrug of ganciclovir which has been developed for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. Oral valganciclovir is rapidly absorbed and hydrolysed to ganciclovir. The oral bioavailability of ganciclovir after oral valganciclovir administration is high. Oral valganciclovir 900 mg provides a daily exposure of ganciclovir comparable to that of intravenous ganciclovir 5 mg/kg. A single, randomised, nonblind study indicated that oral valganciclovir (900mg twice daily for 3 weeks then 900 mg once daily) and intravenous ganciclovir (5 mg/kg twice daily for 3 weeks then 5 mg/kg once daily) were equally effective in the treatment of newly diagnosed CMV retinitis in 160 patients with AIDS. Valganciclovir appears to have a similar tolerability profile to intravenous ganciclovir during induction therapy in patients with AIDS and newly diagnosed CMV retinitis. During maintenance therapy with valganciclovir, the most commonly reported adverse events included neutropenia, anaemia, thrombocytopenia, gastrointestinal (including diarrhoea, nausea, vomiting and abdominal pain), fever, headache, insomnia, peripheral neuropathy, paraesthesia and retinal detachment.
腎移植後サイトメガロウイルス感染症の診療ガイドライン 2011 日本臨床腎移植学会 ガイドライン作成委員会.
Mayoral JL, Loeffler CM, Fasola CG, Kramer MA, Orrom WJ, Matas AJ, Najarian JS, Dunn DL.
Diagnosis and treatment of cytomegalovirus disease in transplant patients based on gastrointestinal tract manifestations.
Arch Surg. 1991 Feb;126(2):202-6. doi: 10.1001/archsurg.1991.01410260092013.
Abstract/Text
Infection due to cytomegalovirus is a substantial cause of morbidity and mortality in immunocompromised patients. In particular, cytomegalovirus infection has been associated with a significant detrimental effect on patient and allograft survival after solid-organ transplantation. We are evaluating a new antiviral agent, ganciclovir 9-[1,3-dihydroxy-2-2 propoxymethyl] guanine (DHPG), used in solid-organ transplant recipients who developed life-threatening cytomegalovirus infections. Between March 1, 1987, and June 30, 1989, we treated 93 solid-organ transplant patients who developed tissue-invasive cytomegalovirus disease. From this group of patients we have identified 14 patients with primary gastrointestinal cytomegalovirus disease who received treatment with DHPG. Tissue diagnosis was made by endoscopy of the upper gastrointestinal tract (11 patients) or colonoscopy (three patients). Invasive cytomegalovirus disease was identified prior to severe complications of the gastrointestinal tract in all but one patient, who suffered colonic perforation prior to treatment with DHPG and subsequently died of bacterial sepsis. While 13 of the 14 patients improved after treatment with DHPG, four patients required additional treatments for recurrent cytomegalovirus disease and recovered. No DHPG toxicity was observed. We believe treatment with DHPG is indicated in this patient population, but that further studies are indicated to fully define the impact of this recommendation on both patient and allograft survival after solid-organ transplantation.
Kaplan CS, Petersen EA, Icenogle TB, Copeland JG, Villar HV, Sampliner R, Minnich L, Ray CG.
Gastrointestinal cytomegalovirus infection in heart and heart-lung transplant recipients.
Arch Intern Med. 1989 Sep;149(9):2095-100.
Abstract/Text
Cytomegalovirus (CMV) causes major morbidity in organ transplant recipients. Gastrointestinal disease was the most prominent manifestation of CMV infection in a population of heart and heart-lung transplant patients, with an incidence of 9.9%, compared with pneumonitis (4.0%) and retinitis (0%), and occurred most frequently in CMV-seronegative recipients of organs from CMV-seropositive donors. Clinical manifestations included gastritis (nine patients), gastric ulceration (four patients), duodenitis (three patients), esophagitis (one patient), pyloric perforation (one patient), and colonic hemorrhage (one patient). Patients with gastrointestinal CMV infection were treated with intravenous ganciclovir sodium therapy, 5 mg/kg twice daily, for 2 to 8 weeks, with positive clinical, endoscopic, histologic, and virologic responses. Relapses occurred in four of nine patients who were followed up for a median period of 18 months. Retreatment resulted in healing of endoscopic lesions and in viral clearing. We conclude that early endoscopic evaluation for CMV is indicated in heart and heart-lung transplant patients with gastrointestinal symptoms. This study further suggests that intravenous ganciclovir therapy is effective for the treatment of gastrointestinal CMV in these patients.
Asberg A, Humar A, Rollag H, Jardine AG, Mouas H, Pescovitz MD, Sgarabotto D, Tuncer M, Noronha IL, Hartmann A; VICTOR Study Group.
Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients.
Am J Transplant. 2007 Sep;7(9):2106-13. doi: 10.1111/j.1600-6143.2007.01910.x. Epub 2007 Jul 19.
Abstract/Text
Intravenous ganciclovir is the standard treatment for cytomegalovirus disease in solid organ transplant recipients. Oral valganciclovir is a more convenient alternative. In a randomized, international trial, recipients with cytomegalovirus disease were treated with either 900 mg oral valganciclovir or 5 mg/kg i.v. ganciclovir twice daily for 21 days, followed by 900 mg daily valganciclovir for 28 days. A total of 321 patients were evaluated (valganciclovir [n = 164]; i.v. ganciclovir [n = 157]). The success rate of viremia eradication at Day 21 was 45.1% for valganciclovir and 48.4% for ganciclovir (95% CI -14.0% to +8.0%), and at Day 49; 67.1% and 70.1%, respectively (p = NS). Treatment success, as assessed by investigators, was 77.4% versus 80.3% at Day 21 and 85.4% versus 84.1% at Day 49 (p = NS). Baseline viral loads were not different between groups and decreased exponentially with similar half-lives and median time to eradication (21 vs. 19 days, p = 0.076). Side-effects and discontinuations of assigned treatment (18 of 321 patients) were comparable. Oral valganciclovir shows comparable safety and is not inferior to i.v. ganciclovir for treatment of cytomegalovirus disease in organ transplant recipients and provides a simpler treatment strategy, but care should be taken in extrapolating to organ transplant recipients not properly represented in the present study.
Lemonovich TL, Watkins RR.
Update on cytomegalovirus infections of the gastrointestinal system in solid organ transplant recipients.
Curr Infect Dis Rep. 2012 Feb;14(1):33-40. doi: 10.1007/s11908-011-0224-6.
Abstract/Text
Cytomegalovirus (CMV) infection of the gastrointestinal tract is the most common manifestation of tissue-invasive CMV disease, and is a significant cause of morbidity and mortality in the solid organ transplantation (SOT) recipient. In addition to the direct effects of the infection, its indirect effects on allograft function, risk for other opportunistic infections, and mortality are significant in this population. The most common clinical syndromes are esophagitis, colitis, and hepatitis; however, infection can occur anywhere in the gastrointestinal tract. Diagnosis is usually by histopathology or viral culture of tissue specimens; molecular assays also often have a role. Antivirals are the cornerstone of therapy for gastrointestinal tract CMV disease and complications such as recurrent infection and antiviral resistance are not uncommon. Prevention with antiviral prophylaxis or preemptive therapy is important. This review summarizes recent data regarding the clinical manifestations, diagnosis, treatment, and prevention of gastrointestinal tract CMV infection in the SOT population.
腎移植後サイトメガロウイルス感染症の診療ガイドライン 2011. 日本臨床腎移植学会.
Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Snydman DR, Allen U, Humar A; Transplantation Society International CMV Consensus Group.
International consensus guidelines on the management of cytomegalovirus in solid organ transplantation.
Transplantation. 2010 Apr 15;89(7):779-95. doi: 10.1097/TP.0b013e3181cee42f.
Abstract/Text
Cytomegalovirus (CMV) remains one of the most common infections after solid organ transplantation, resulting in significant morbidity, graft loss, and occasional mortality. Management of CMV varies considerably among transplant centers. A panel of experts on CMV and solid organ transplant was convened by The Infectious Diseases Section of The Transplantation Society to develop evidence and expert opinion-based consensus guidelines on CMV management including diagnostics, immunology, prevention, treatment, drug resistance, and pediatric issues.
Galiatsatos P, Shrier I, Lamoureux E, Szilagyi A.
Meta-analysis of outcome of cytomegalovirus colitis in immunocompetent hosts.
Dig Dis Sci. 2005 Apr;50(4):609-16. doi: 10.1007/s10620-005-2544-6.
Abstract/Text
There are only a few anecdotal reports of cytomegalovirus (CMV) colitis in immunocompetent hosts. The impact of the disease in this patient population remains poorly understood. The aim of this study was to perform a meta-analysis using individual patient data to determine outcomes of CMV colitis in immunocompetent patients and identify risk factors that might influence prognosis. A literature search was performed from 1980 to 2003 looking for immunocompetent patients with CMV colitis. Immunocompetence was defined as absence of congenital or acquired immune deficiency, transplant, or immunosuppressive medication. Patients were divided by age (<55 versus > or =55) and grouped according to coexisting illnesses. Kaplan-Meier curves were plotted to assess survival. Variables included age, sex, site of acquisition of infection, extent of disease, coexisting illnesses, and treatment modality. A total of 44 patients were identified, with an average age of 61.1. Only 10 were free of any comorbidity. The mean follow-up was 13.4 months. Spontaneous remission occurred in 31.8%, mostly individuals <55 years old. Fourteen deaths occurred, all of which were in patients >55. There was a higher mortality rate among male patients > or =55 (56.9%; P = 0.08), patients with immune-modulating diseases (75.2%; P = 0.10), and those having a colectomy (68.9%; P = 0.09). This analysis underlines the rarity of CMV colitis in patients with an intact immune system. Advanced age, male gender, presence of immune-modulating comorbidities, and need for surgical intervention are factors negatively influencing survival. Conversely, young healthy patients have a good prognosis with no intervention.
Ayulo M, Aisner SC, Margolis K, Moravec C.
Cytomegalovirus-associated gastritis in a compromised host.
JAMA. 1980 Apr 4;243(13):1364.
Abstract/Text
Tokunaga N, Sadahiro S, Kise Y, Suzuki T, Mukai M, Yasuda S, Ogoshi K, Tajima T, Makuuchi H.
Gastrointestinal cytomegalovirus infection in collagen diseases.
Tokai J Exp Clin Med. 2003 Apr;28(1):35-8.
Abstract/Text
Cytomegalovirus infection of the gastrointestinal tract is a rare serious complication in patients with collagen diseases receiving immunosuppressive agents. We report 3 such cases diagnosed by endoscopy followed by proper treatment. The patients include 38 and 53 years old females with systemic lupus erythematosus. They presented epigastric pain after pulse steroid therapy and combination therapy with steroids and cyclophosphamide, respectively. Their endoscopical findings were multiple small gastric erosions. The other patient was a 60-year-old female with polymyositis who developed rectal bleeding after steroid and imuran therapy. Her endoscopical finding was a discrete, irregular rectal ulcer. The diagnosis of all the patients was confirmed by biopsies of those lesions showing giant cell inclusion bodies and positive staining with anti- cytomegalovirus -antibodies. All patients were treated properly with ganciclovir. We should always keep in mind of a cytomegalovirus infection of the gastrointestinal tract in a patient with collagen disease receiving immunosuppressive agents.
Cottone M, Pietrosi G, Martorana G, Casà A, Pecoraro G, Oliva L, Orlando A, Rosselli M, Rizzo A, Pagliaro L.
Prevalence of cytomegalovirus infection in severe refractory ulcerative and Crohn's colitis.
Am J Gastroenterol. 2001 Mar;96(3):773-5. doi: 10.1111/j.1572-0241.2001.03620.x.
Abstract/Text
OBJECTIVES: Cytomegalovirus infection has been reported as a cause of refractory inflammatory bowel disease, but no data are available on its prevalence in severe colitis. The aim of this study was to evaluate the prevalence and outcome of cytomegalovirus infection in a consecutive series of patients with severe steroid refractory colitis admitted to our department from 1997 to 1999.
METHODS: Among 62 patients with severe colitis, 55 with ulcerative colitis and seven with Crohn's disease, 19 (30%) were resistant to intravenous steroids and bowel rest. In all of them, rectal biopsies were examined for cytomegalovirus (the flexible proctoscopy being performed without air insufflation and limited to the first 10 cm). Buffy coat preparation on leukocytes was also performed to detect systemic infection. If cytomegalovirus was not detected, cyclosporine was started.
RESULTS: In seven (five with ulcerative colitis and two with Crohn's disease) out of 19 (36%) patients with refractory disease, cytomegalovirus was diagnosed in the rectal specimens as well as by buffy coat preparation. Five patients went into remission after antiviral treatment (three with ganciclovir and two with foscarnet). One patient did not respond and was operated on. In one patient, cytomegalovirus was found in the surgical specimen.
CONCLUSIONS: Cytomegalovirus infection is a frequent cause of severe refractory colitis. Rectal biopsy should always be performed in severe steroid-resistant colitis.
Dimitroulia E, Spanakis N, Konstantinidou AE, Legakis NJ, Tsakris A.
Frequent detection of cytomegalovirus in the intestine of patients with inflammatory bowel disease.
Inflamm Bowel Dis. 2006 Sep;12(9):879-84. doi: 10.1097/01.mib.0000231576.11678.57.
Abstract/Text
BACKGROUND: Although a growing number of reports have described inflammatory bowel disease (IBD) complicated with cytomegalovirus (CMV) infection, there are limited molecular studies that investigate CMV genome in intestinal sections of patients with IBD.
METHODS: A cross-sectional prospective study was conducted between September 2000 and June 2003 in a cohort of 85 patients diagnosed with IBD (58 with ulcerative colitis and 27 with Crohn's disease) in two adult gastrointestinal referral centers in Athens, Greece. Prevalence of CMV infection was estimated by pathologic studies in intestinal sections and by molecular assays in blood and intestinal tissue samples and compared with a control group of 42 individuals with noninflammatory disease.
RESULTS: Immunohistochemical staining showed CMV antigen in 10 IBD patients (7 with ulcerative colitis; 9 with severe disease), whereas CMV antigen was not detected in any of the controls. CMV genome in both the intestinal tissue and blood was found by polymerase chain reaction in 23 (27.1%) of the total IBD patients, in 18 (31.0%) of those with ulcerative colitis, and in 5 (18.5%) of those with Crohn's disease. In addition, five (5.9%) IBD patients (2 with ulcerative colitis and 3 with Crohn's disease) had detectable CMV genome in their intestinal samples but not in their blood. In the control group, five (11.9%) individuals had detectable CMV genome in their blood, but only one (2.2%) in his intestine.
CONCLUSION: Patients with ulcerative colitis had more often detectable CMV genome in their blood as well as in their intestinal tissue samples as compared with controls (P = 0.022 and P < 0.0001, respectively). However, patients with Crohn's disease had more often detectable CMV genome only in their intestinal tissue samples as compared with controls (P = 0.001). Detection of CMV genome in blood or intestinal tissue was significantly associated with short duration of IBD (P = 0.0088 and 0.04, respectively) but not with age, sex, severity of the disease, activity at colonoscopy, pancolitis, administration of a specific treatment, and surgery. In this cross-sectional prospective study, detection of CMV genome or antigen in the intestine was commonly associated with IBD.
Criscuoli V, Casà A, Orlando A, Pecoraro G, Oliva L, Traina M, Rizzo A, Cottone M.
Severe acute colitis associated with CMV: a prevalence study.
Dig Liver Dis. 2004 Dec;36(12):818-20. doi: 10.1016/j.dld.2004.05.013.
Abstract/Text
BACKGROUND: Cytomegalovirus has been identified as a pathogen that contributes to flares of colitis when detected in colonic specimens of patients with inflammatory bowel disease.
AIM: To determine the overall prevalence and the role of cytomegalovirus infection in a consecutive series of patients with acute severe colitis admitted to our department from 2000 to 2003.
METHODS: Among 42 patients (38 with ulcerative colitis and 4 with Crohn's disease) admitted to our hospital for acute severe colitis, we performed proctoscopy and biopsy together with blood sample for cytomegalovirus determination at the time of admission, regardless of their steroid resistance.
RESULTS: In the 42 patients, we discovered an overall cytomegalovirus infection prevalence of 21.4% (9/42) in our geographical area. In seven patients (16.6%), cytomegalovirus was detected through biopsy. The presence of cytomegalovirus in biopsies was not always predictive of steroid resistance. Three patients with cytomegalovirus in biopsies responded to conventional treatment without needing any antiviral treatment, which suggests that the virus plays only an incidental role.
CONCLUSIONS: Cytomegalovirus is frequently associated with colitis but it is not always pathogenic. Studies on the genotyping of the virus might explain the diversity of its biological behaviour.
Eid AJ, Arthurs SK, Deziel PJ, Wilhelm MP, Razonable RR.
Clinical predictors of relapse after treatment of primary gastrointestinal cytomegalovirus disease in solid organ transplant recipients.
Am J Transplant. 2010 Jan;10(1):157-61. doi: 10.1111/j.1600-6143.2009.02861.x. Epub 2009 Nov 4.
Abstract/Text
Primary gastrointestinal cytomegalovirus (CMV) disease after solid organ transplantation (SOT) is difficult to treat and may relapse. Herein, we reviewed the clinical records of CMV D+/R- SOT recipients with biopsy-proven gastrointestinal CMV disease to determine predictors of relapse. The population consisted of 26 kidney (13 [50%]), liver (10 [38%]) and heart (3 [12%]) transplant recipients who developed gastrointestinal CMV disease at a median of 54 (interquartile range [IQR]: 40-70) days after stopping antiviral prophylaxis. Except for one patient, all received induction intravenous ganciclovir (mean+/-SD, 33.8+/-19.3 days) followed by valganciclovir (27.5+/-13.3 days) in 18 patients. Ten patients further received valganciclovir maintenance therapy (41.6+/-28.6 days). The median times to CMV PCR negativity in blood was 22.5 days (IQR: 16.5-30.7) and to normal endoscopic findings was 27.0 days (IQR: 21.0-33.5). CMV relapse, which occurred in seven (27%) patients, was significantly associated with extensive disease (p=0.03). CMV seroconversion, viral load, treatment duration, maintenance therapy and endoscopic findings at the end of therapy were not significantly associated with CMV relapse. In conclusion, an extensive involvement of the gastrointestinal tract was significantly associated with CMV relapse. However, endoscopic evidence of resolution of gastrointestinal disease did not necessarily translate into a lower risk of CMV relapse.
Reed EC, Wolford JL, Kopecky KJ, Lilleby KE, Dandliker PS, Todaro JL, McDonald GB, Meyers JD.
Ganciclovir for the treatment of cytomegalovirus gastroenteritis in bone marrow transplant patients. A randomized, placebo-controlled trial.
Ann Intern Med. 1990 Apr 1;112(7):505-10. doi: 10.7326/0003-4819-112-7-505.
Abstract/Text
STUDY OBJECTIVE: To determine the efficacy of ganciclovir for the treatment of cytomegalovirus enteritis after bone marrow transplant.
DESIGN: A randomized, double-blind, placebo-controlled trial.
SETTING: Inpatient units of a cancer center.
PATIENTS: Consecutive patients with biopsy-documented cytomegalovirus infection of the gastrointestinal tract. Cytomegalovirus was identified by culture or by immunohistologic or standard histologic analysis.
INTERVENTIONS: Ganciclovir, 2.5 mg/kg body weight every 8 hours for 14 days, or placebo, with dosage adjusted for decreases in renal function. Therapy was discontinued if the neutrophil count or creatinine clearance fell below preset criteria.
MEASUREMENTS AND MAIN RESULTS: Virus cultures of throat, urine, and blood specimens were done before, 3 times weekly during, and weekly for 3 weeks after therapy. Endoscopy was repeated after treatment. Patients were examined, and blood counts, electrolytes, and renal and hepatic function were monitored during therapy. Ganciclovir recipients had cessation of oropharyngeal (P = 0.001) and urinary (P = 0.004) cytomegalovirus excretion and negative cultures of repeat esophageal specimens (P = 0.002) more often than placebo recipients. No difference existed in either clinical symptoms or endoscopic appearance between the groups after treatment. Cytomegalovirus pneumonia occurred in four patients who received ganciclovir and in six who received placebo. One ganciclovir recipient and four placebo recipients were withdrawn from treatment because of neutropenia, but there was no overall difference in the proportional decrease in leukocyte counts between groups.
CONCLUSIONS: Although ganciclovir suppressed cytomegalovirus replication, 2 weeks of treatment was not associated with clinical or endoscopic improvement when compared with supportive care.
Boeckh M, Ljungman P.
How we treat cytomegalovirus in hematopoietic cell transplant recipients.
Blood. 2009 Jun 4;113(23):5711-9. doi: 10.1182/blood-2008-10-143560. Epub 2009 Mar 18.
Abstract/Text
Cytomegalovirus (CMV) continues to cause major complications after hematopoietic cell transplantation (HCT). Over the past decade, most centers have adopted preemptive antiviral treatment or prophylaxis strategies to prevent CMV disease. Both strategies are effective but also have shortcomings with presently available drugs. Here, we review aspects of CMV treatment and prevention in HCT recipients, including currently used drugs and diagnostics, ways to optimize preemptive therapy strategies with quantitative polymerase chain reaction assays, the use of prophylaxis, management of CMV disease caused by wild-type or drug-resistant strains, and future strategies.
Reusser P, Einsele H, Lee J, Volin L, Rovira M, Engelhard D, Finke J, Cordonnier C, Link H, Ljungman P; Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.
Randomized multicenter trial of foscarnet versus ganciclovir for preemptive therapy of cytomegalovirus infection after allogeneic stem cell transplantation.
Blood. 2002 Feb 15;99(4):1159-64. doi: 10.1182/blood.v99.4.1159.
Abstract/Text
The present study compared foscarnet with ganciclovir for preemptive therapy of cytomegalovirus (CMV) infection after allogeneic blood or marrow stem cell transplantation (SCT). Patients with CMV infection, as detected by weekly antigenemia or polymerase chain reaction (PCR) in blood leukocytes, were randomized to intravenous therapy for 2 weeks with either foscarnet at 60 mg/kg or ganciclovir at 5 mg/kg administered every 12 hours; if CMV infection remained detectable, patients received an additional 2 weeks of intravenous foscarnet at 90 mg/kg or ganciclovir at 6 mg/kg given once daily for 5 days per week, after which therapy was stopped. Primary efficacy endpoint was the occurrence of CMV disease or death from any cause within 180 days after SCT. A total of 213 patients were treated with either foscarnet (n = 110) or ganciclovir (n = 103). Kaplan-Meier estimates of event-free survival within 180 days after SCT were similar in the 2 treatment groups (P =.6). During study treatment, severe neutropenia (< 0.5 x 10(9)/L) occurred in 11 (11%) patients on ganciclovir versus 4 (4%) patients on foscarnet (P =.04), and impaired renal function was observed in 5 (5%) patients on foscarnet versus 2 (2%) patients on ganciclovir (P =.4). Neutropenia or thrombocytopenia required discontinuation of ganciclovir in 6 (6%) patients but in no foscarnet-treated patient (P =.03). After allogeneic SCT, preemptive therapy of CMV infection with foscarnet shows similar efficacy as with ganciclovir, but is associated with a lower proportion of patients who develop severe neutropenia and who require discontinuation of antiviral therapy due to hematotoxicity.
Einsele H, Reusser P, Bornhäuser M, Kalhs P, Ehninger G, Hebart H, Chalandon Y, Kröger N, Hertenstein B, Rohde F.
Oral valganciclovir leads to higher exposure to ganciclovir than intravenous ganciclovir in patients following allogeneic stem cell transplantation.
Blood. 2006 Apr 1;107(7):3002-8. doi: 10.1182/blood-2005-09-3786. Epub 2005 Dec 13.
Abstract/Text
Cytomegalovirus (CMV) infection is a major complication after allogeneic stem cell transplantation (SCT). Valganciclovir (V-GCV) is an oral prodrug hydrolyzed to the anti-CMV drug ganciclovir (GCV). A randomized, multicenter, crossover, open-label clinical trial compared exposure to GCV after V-GCV and intravenous GCV (IV-GCV) as preemptive therapy for CMV disease in SCT. The primary objective was to compare exposure to GCV in patients with CMV infection stratified for intestinal graft-versus-host disease (I-GVHD). Secondary objectives were the assessment of safety and efficacy. Patients without I-GVHD had a higher exposure to GCV after V-GCV when compared with IV-GCV (area under the concentration-time curve from drug administration to last observed concentration after 12 hours [AUC(0-12)] 53.8 +/- 17.97 microg/mL . h [mean +/- SD] vs 39.5 +/- 13.91; P < .001; ratio of V-GCV/IV-GCV was 1.4; 90% confidence interval [CI], 1.2-1.5). This was also true in patients with I-GVHD grades I-II (AUC(0-12) 52.9 +/- 21.75 vs 33.1 +/- 12.97 mug/mL . h; P = .018; ratio 1.6; 90% CI, 1.3-2.0). Absolute bioavailability of GCV after V-GCV was approximately 75% in individuals with or without I-GVHD grades I-II. No severe GCV-related toxicity was observed and efficacy and safety was comparable (84-day follow-up). This supports the use of V-GCV in SCT, even in patients with I-GVHD grades I-II. Due to higher exposure after V-GCV compared with IV-GCV, patients should be monitored carefully for safety reasons.
Winston DJ, Baden LR, Gabriel DA, Emmanouilides C, Shaw LM, Lange WR, Ratanatharathorn V.
Pharmacokinetics of ganciclovir after oral valganciclovir versus intravenous ganciclovir in allogeneic stem cell transplant patients with graft-versus-host disease of the gastrointestinal tract.
Biol Blood Marrow Transplant. 2006 Jun;12(6):635-40. doi: 10.1016/j.bbmt.2005.12.038.
Abstract/Text
The pharmacokinetics of ganciclovir after oral valganciclovir versus intravenous ganciclovir were compared in allogeneic stem cell transplant recipients with stable graft-versus-host disease of the gastrointestinal tract. Twenty-two evaluable adult patients were randomized to receive a single dose of open-label study drug (900 mg of oral valganciclovir or 5 mg/kg of intravenous ganciclovir). After a washout period of 2 to 7 days, patients were crossed over to receive the alternate study drug. Ganciclovir and valganciclovir concentrations in plasma were measured over 24 hours after dosing. Noninferiority of 900 mg of valganciclovir relative to intravenous ganciclovir was concluded if the lower limit of the 1-sided 95% confidence interval of the ratio of least-square means of the ganciclovir area under the curve (AUC) for the 2 study drugs was >80%. Valganciclovir was found to be rapidly absorbed and converted into ganciclovir. The ganciclovir exposure after 900 mg of valganciclovir noninferior to that of intravenous ganciclovir (AUC0-infinity, 52.1 and 53.8 microg.h/mL, respectively; 95% confidence interval of the ratio of least square means of AUC0-infinity, 82.48%-118.02%). Oral valganciclovir could be a useful alternative to intravenous ganciclovir in certain stable stem cell transplant patients who require prophylaxis or preemptive therapy for cytomegalovirus infection.
田辺三菱製薬株式会社、総合製品情報概要 デノシン点滴静注用500mg.
田辺三菱製薬株式会社、総合製品情報概要 バリキサ錠450mg.
Takenaka K, Eto T, Nagafuji K, Kamezaki K, Matsuo Y, Yoshimoto G, Harada N, Yoshida M, Henzan H, Takase K, Miyamoto T, Akashi K, Harada M, Teshima T; for Fukuoka Blood and Marrow Transplant Group (FBMTG).
Oral valganciclovir as preemptive therapy is effective for cytomegalovirus infection in allogeneic hematopoietic stem cell transplant recipients.
Int J Hematol. 2009 Mar;89(2):231-237. doi: 10.1007/s12185-008-0249-2. Epub 2009 Jan 17.
Abstract/Text
Between March 2007 and January 2008, the safety and efficacy of oral valganciclovir (VGC) preemptive therapy for cytomegalovirus (CMV) infection was evaluated in ten consecutive patients who received allogeneic hematopoietic stem cell transplantation (HSCT). Patients were screened once or twice per week after engraftment using CMV pp65 antigenemia assay. When more than 2 CMV antigen-positive cells per 50,000 leukocytes were detected, preemptive therapy with oral VGC was initiated at a dose of 900 mg twice daily for 3 weeks. Nine patients (90%) completed the 3-week VGC treatment except for one patient who developed febrile neutropenia. There was no other significant toxicity. CMV antigen-positive cells were rapidly decreased in all nine patients and became undetectable by the end of the VGC treatment. None of the patients developed CMV disease. CMV infection relapsed in four of the ten patients (40%) after the VGC treatment. These observations suggest that preemptive therapy with VGC is effective for preventing CMV disease in allogeneic HSCT patients. Further studies with a large number of patients will be necessary to determine the optimal initial- and maintenance-dose of VGC.
ノーベルファーマ株式会社、総合製品情報概要 ホスカビル注24mg/ml.
Deray G, Martinez F, Katlama C, Levaltier B, Beaufils H, Danis M, Rozenheim M, Baumelou A, Dohin E, Gentilini M.
Foscarnet nephrotoxicity: mechanism, incidence and prevention.
Am J Nephrol. 1989;9(4):316-21. doi: 10.1159/000167987.
Abstract/Text
Foscarnet is a pyrophosphate analogue that has been successfully used in severe cytomegalovirus (CMV) infections. Little is known of the incidence and mechanisms of foscarnet-induced nephrotoxicity as most data comes from recipients of renal allografts or from patients with severe underlying disease or with other nephrotoxic drugs. We have retrospectively analyzed the evolution of renal function after 56 courses of foscarnet. In addition, we have prospectively studied the protective effects of hydration on foscarnet nephrotoxicity (2.5 liters of saline/day during the night before the foscarnet therapy and throughout the course of treatment). Foscarnet-induced acute renal failure was defined as a rise in serum creatinine of at least 25% from the basal value. An increase in serum creatinine occurred in 37 cases out of the 56 courses of foscarnet (66%). The mean serum creatinine prior to foscarnet was 80.5 +/- 3.3 mumol/l and the mean increase was 190 +/- 28.3 mumol/l (range 80-1,000). Peak serum creatinine was higher than 200 and 300 mumol/l in 16 and 13 patients, respectively. Kidney obtained at autopsy from a 30-year-old male with AIDS, CMV pneumonitis and acute renal failure secondary to foscarnet administration showed an extensive tubular necrosis. In the group which was prospectively hydrated only 1 patient had an acute renal failure. The mean serum creatinine at the peak (96 +/- 4 mumol/l) and at the end of the treatment (83 +/- 4 mumol/l) was significantly lower (p less than 0.05) than in non hydrated patients. In conclusion, foscarnet is a highly nephrotoxic drug which induces acute tubular necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Deray G, Katlama C, Dohin E.
Prevention of foscarnet nephrotoxicity.
Ann Intern Med. 1990 Aug 15;113(4):332. doi: 10.7326/0003-4819-113-4-332_1.
Abstract/Text
Söderlund C, Bratt GA, Engström L, Grützmeier S, Nilsson R, Sjunnesson M, Sandström E.
Surgical treatment of cytomegalovirus enterocolitis in severe human immunodeficiency virus infection. Report of eight cases.
Dis Colon Rectum. 1994 Jan;37(1):63-72. doi: 10.1007/BF02047217.
Abstract/Text
PURPOSE: The aim of this study was to describe our experiences of surgical removal of inflamed bowel in cytomegalovirus enterocolitis.
METHODS: Eight homosexual males with a mean age of 41 years (range, 29-59 years) and a mean CD4 count of 21 x 10(6)/l (1-60 x 10(6)/l) with advanced human immunodeficiency virus infection and severe cytomegalovirus enterocolitis were treated with ileocecal resection (4 patients) or right-sided hemicolectomy (4 patients). Symptoms were lower abdominal pain, severe diarrhea, fever, and weight loss, unrelieved by anticytomegalovirus therapy. Radiologic examination showed that ulcerative inflammation was limited to the right colon and terminal ileum. Microscopic examination confirmed the cytomegalovirus enterocolitis. Intermittent cytomegalovirus treatment, usually with foscarnet for 10 to 14 days every 4 to 6 weeks was given postoperatively.
RESULTS: Two minor postoperative complications occurred: a lesser wound infection and a moderate bleeding from the abdominal wound edges. One patient died after three weeks because of gastrointestinal bleeding from an ulcerating Kaposi's sarcoma lesion and another patient died from unrelated causes three weeks after discharge from the hospital. The remaining 6 patients experienced complete or partial palliation of the abdominal symptoms for a mean of 14 months (range, 5-35 months) until death or the end of observation time. One patient is still alive two years after the operation. The overall mean survival was 12 months (range, 0.5-35 months). Recurrent or persistent symptoms and/or signs of cytomegalovirus enterocolitis occurred in four patients after a mean of seven months.
CONCLUSION: Resection of inflamed bowel combined with postoperative anticytomegalovirus treatment leads to excellent palliation and a relatively favorable survival in AIDS patients with cytomegalovirus enterocolitis.
Nakamura T, Nakamura R, Maruyama K, Fukazawa A, Uno A, Hayashi T, Higashi Y, Hosoda Y, Nakamura S.
Refractory ulcerative colitis complicated by a cytomegaloviral infection requiring surgery: report of a case.
Surg Today. 2004;34(1):68-71. doi: 10.1007/s00595-003-2640-1.
Abstract/Text
Cytomegalovirus (CMV) infection has been reported to be a cause of refractory ulcerative colitis (UC). We herein report a case of refractory ulcerative colitis complicated by CMV infection requiring surgery. A 22-year-old man was admitted to our hospital with lower abdominal pain and bloody diarrhea. Under a diagnosis of acute UC, he was treated with prednisone 60 mg/day and sulfasalazine. Since his symptoms appeared to improve, the prednisone dosage was gradually reduced to 20 mg/day. After 5 months, he had an unexpected flare-up with fever and fresh anal bleeding. Colonoscopy demonstrated a punched out ulcer in the sigmoid colon. Biopsies by colonoscopy revealed cytomegalic inclusion bodies. Serologic and immunologic studies also suggested a recent CMV infection. Under a diagnosis of intractable UC complicated by a CMV infection, ganciclovir therapy was carried out, and the steroid therapy was tapered. Although the serum antigenemia became negative after the antiviral therapy, follow-up colonoscopy confirmed the severe stenosis after the punched-out ulcer healed completely. Since his symptoms did not improve, it was necessary to perform an elective proctocolectomy despite antiviral therapy. He was discharged with an uneventful postoperative course. It is important to recognize CMV colitis as a complication of inflammatory bowel disease, particularly in severe steroid-resistant colitis. Furthermore, in cases which fail to respond to antiviral treatment, the patient may ultimately require surgery.
