Reduced dose of foscarnet as preemptive therapy for cytomegalovirus infection following reduced-intensity cord blood transplantation

Although foscarnet is a promising alternative for the treatment of cytomegalovirus (CMV) infection, its toxicity can be significant in patients with advanced age. We retrospectively reviewed medical records of 123 patients (median age of 55; range, 17-79) who received reduced-intensity cord blood transplantation (RI-CBT). Patients preemptively received reduced-dose foscarnet 30 mg/kg twice daily when CMV antigenemia exceeded 10/50,000. Sixty-three patients developed CMV antigenemia on a median of day 34, and 29 received foscarnet preemptively. The median level of CMV antigenemia at the initiation of foscarnet was 30. Median duration of foscarnet administration was 24 days. Adverse effects included electrolyte abnormalities (n=19), renal impairment (n=13), and skin eruption requiring discontinuation of foscarnet (n=1). Preemptive therapy of foscarnet was completed in 18 patients. Seven patients died during foscarnet use without developing CMV disease. The remaining 3 developed CMV enterocolitis 5, 14, and 17 days after initiation of foscarnet. All of them were successfully treated with ganciclovir or foscarnet. Reduced dose of foscarnet is beneficial to control CMV reactivation following RI-CBT; however, it has considerable toxicities in RI-CBT recipients with advanced age. Further studies are warranted to minimize toxicities and identify optimal dosages.     

Phase I-II trial of foscarnet for prevention of cytomegalovirus infection in autologous and allogeneic marrow transplant recipients.

The safety and efficacy of foscarnet for prevention of cytomegalovirus (CMV) infection was evaluated in 19 CMV-seropositive bone marrow transplant (BMT) recipients. All patients received intermittent intravenous (iv) foscarnet: 40 mg/kg every 8 h from 7 days before to day 30 after BMT, then 60 mg/kg once a day until day 75. The main toxicity was transient renal dysfunction, with a greater than 50 mumol/L increase in serum creatinine above baseline in 5 of the 7 autograft recipients and in 6 of the 12 allograft recipients. Only 4 allograft recipients developed CMV infection during foscarnet prophylaxis, and no patient showed evidence of CMV disease. Because 3 allograft recipients receiving concomitant iv amphotericin B showed rapid impairment of renal function, foscarnet prophylaxis should not be given to allograft recipients requiring amphotericin B; otherwise, foscarnet prophylaxis at this dose appears safe after BMT.     

Risk Factors for Cytomegalovirus Retinitis Following Bone Marrow Transplantation From Unrelated Donors in Patients With Severe Aplastic Anemia or Myelodysplasia

Two cases of cytomegalovirus (CMV) retinitis following bone marrow transplantation (BMT) from unrelated donors are reported. 1 patient had been treated for severe aplastic anemia (SAA) and the other for hypoplastic myelodysplastic syndrome (MDS). Because first line therapy with antithymocyte globulin (ATG) and cyclosporin A (CsA) had failed, BMT was performed following a conditioning regimen of ATG, cyclophosphamide, and total lymphoid irradiation. Treatment for CMV retinitis was successfully carried out with gancyclovir (systemic and intraocular injection), foscarnet, and photocoagulation (Case 1) and gancyclovir and foscarnet (Case 2). Both patients also developed Epstein-Barr virus-associated lymphoproliferative disease (EBV-LPD). We compared these 2 cases with 14 SAA patients who did not develop CMV retinitis after BMT using marrow from either HLA-identical siblings (n = 9) or from unrelated donors (n = 5). Unlike the retinitis patients, the latter 5 patients received ATG only once. The retinitis patients had significantly lower CD4+ T-cell levels in their peripheral blood than the 14 patients who did not develop CMV retinitis. We believe that repeated treatment with ATG and transplantation from unrelated donors may lead to immune dysfunction that could increase the likelihood of CMV retinitis, as well as LPD. For such BMT patients, regular ophthalmic examinations and careful testing for CMV antigenemia are recommended.     

Randomized multicenter trial of foscarnet versus ganciclovir for preemptive therapy of cytomegalovirus infection after allogeneic stem cell transplantation

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.     

Foscarnet for treatment of cytomegalovirus infections in bone marrow transplant recipients.

42 episodes of verified or clinically suspected cytomegalovirus (CMV) infection in 40 bone marrow transplant (BMT) recipients were treated with foscarnet (trisodium phosphonophormate hexahydrate). CMV infection was verified in 31/42 treatment episodes. Symptoms treated were pneumonia (n = 17), pancytopenia with or without fever (n = 12), enteritis (n = 5), fever (n = 4), encephalitis (n = 2), retinitis (n = 1) and hepatitis (n = 1). Foscarnet was given as a continuous intravenous infusion. Side-effects observed were increase in serum creatinine (38%), decrease in serum calcium (19%), increase in serum bilirubin (12%), decrease in hemoglobin concentration (7%), increase in serum calcium (5%), increase in serum transaminase (5%), hypophosphatemia (2%) and tremor (2%). CMV was eradicated from blood and/or urine in 11/25 (44%) of assessable treatment episodes with infection verified by isolation. Overall clinical improvements including eradication of CMV, afebrility and/or improvements in laboratory abnormalities were seen in 14/31 (45%) episodes of verified infection. All 15 patients with CMV interstitial pneumonia (CMV IP) died. We conclude that foscarnet is nephrotoxic but otherwise well tolerated with moderate clinical and virostatic effects on CMV infection. The effect on CMV IP is discouraging.     

Allogeneic bone marrow transplantation in patients with follicular lymphoma: a single center study

The role of allogeneic BMT for follicular lymphoma remains to be established. From 1995 to 2000, 16 patients with follicular lymphoma underwent allogeneic BMT at our center. At the time of transplantation, two patients were in complete remission, 11 in partial remission and three had refractory disease. Fourteen patients were transplanted using a standard myeloablative conditioning regimen and two a nonmyeloablative conditioning regimen. With a median follow-up of 1184 days (range 403-1999 days) after BMT, 11 patients were alive, whereas five died of transplant-related mortality. Eight patients remained in CR 284+ to 1022+ days (median 560+ days) after BMT. Two patients relapsed 63 and 1073 days after BMT. They achieved a further complete remission after salvage treatment and remained alive 403 and 1224 days after BMT, respectively. One patient with autologous reconstitution had never been in CR after BMT. He was retreated with salvage chemotherapy but only achieved CR with subsequent rituximab treatment and was still alive, 1999 days after transplantation. The estimated 2-year overall survival and event-free survival rates were 68% and 55%, respectively. Age greater than 37 years at diagnosis, positive recipient CMV serology and ECOG performance status > or =1 at diagnosis were associated with shorter overall survival (P = 0.05, P = 0.009 and P = 0.03, respectively). Ann Arbor III-IV stage at diagnosis was associated with shorter event-free survival (P < 0.04). Allogeneic BMT seems to be effective for patients with follicular lymphoma. However, the relatively high rate of early transplant-related mortality emphasizes the need to define indications and use prospective protocols involving a less toxic transplant procedure.     

Induction and maintenance therapy of cytomegalovirus central nervous system infection in HIV-infected patients

OBJECTIVE: To evaluate the efficacy and safety of the foscarnet-ganciclovir combination in induction therapy (IT) and maintenance therapy (MT) for cytomegalovirus (CMV) central neurological disorders in HIV-infected patients. DESIGN: An open pilot non-comparative multicentre study. METHODS: Thirty-one patients with acute CMV encephalitis (CMVe) (n = 17) or CMV myelitis (CMVm) (n = 14) during the era before highly active antiretroviral therapy (HAART) received intravenous IT with foscarnet 90 mg/kg plus ganciclovir 5 mg/kg twice a day followed by MT. The primary endpoint was clinical efficacy, assessed at the end of the induction phase. RESULTS: The foscarnet-ganciclovir combination in IT resulted in a 74% (23 out of 31 patients) clinical improvement or stabilization. Eight patients did not respond clinically. Side-effects leading to drug discontinuation occurred in 10 patients during IT. Among the 23 patients who qualified for the maintenance phase, CMV disease progressed in 10, with a median time to the first relapse of 126 days (range 64-264 days). Overall, the median survival time was 3 months [95% confidence interval (CI), 2-4 months]. CONCLUSION: The combination of foscarnet and ganciclovir can safely be used for CMV central nervous system (CNS) infection, with an improvement or stabilization in 74% of patients. Life-long MT with this combination is recommended as long as the immune system is profoundly impaired.     

Extracorporeal photopheresis for the treatment of steroid refractory acute GVHD

Extracorporeal photopheresis (ECP) was given to 23 patients with steroid-refractory acute GVHD (aGVHD, grade II (n=10), III (n=7) or IV (n=6)). The median duration of ECP was 7 months (1-33) and the median number of ECP cycles in each patient was 10. Twelve patients (52%) had complete responses. Eleven patients (48%) survived and 12 died, 10 of GVHD with or without infections and two of leukaemia relapse. The average grade of GVHD was reduced from 2.8 (on the first day of ECP) to 1.4 (on day +90 from ECP) (P=0.08), and the average dose of i.v. methylprednisolone from 2.17 to 0.2 mg/kg/d (P=0.004). Complete responses were obtained in 70, 42 and 0% of patients, respectively, with grades II, III and IV aGVHD; complete responses in the skin, liver and gut were 66, 27 and 40%. Patients treated within 35 days from onset of aGVHD had higher responses (83 vs 47%; P=0.1). A trend for improved survival was seen in grade III-IV aGVHD treated with ECP as compared to matched controls (38 vs 16%; P 0.08). ECP is a treatment option for patients with steroid refractory aGVHD and should be considered early in the course of the disease.     

Cytomegalovirus infection in recipients of related and unrelated donor bone marrow transplants: no evidence of increased incidence in patients receiving unrelated donor grafts

Recent reports suggest an increased incidence of cytomegalovirus (CMV) infection in recipients of unrelated donor (UD) bone marrow transplantation (BMT).
In this study we have collated the incidence of CMV infection and disease in sequential UD ( n  = 119) and related donor (RD; n  = 79) BMT performed in a single institution over a 7-year period. Low-risk patients (CMV seronegative recipient and donor) accounted for 51% of UD BMT ( n  = 61) and 62% of RD BMT ( n  = 49), with CMV excretion documented in one RD BMT only. The remaining high-risk patients received identical prophylaxis regimens with aciclovir and intravenous immunoglobulin (IVIG). Two groups consisting of 58 UD BMT (median age 9.0 years, range 0.7–45.3 years) and 30 RD BMT (median age 13.6 years, range 1.6–47.6 years) were analysed. CMV reactivation/re-infection was documented in 15 UD BMT (26%) and 10 RD BMT (33%) ( P  = 0.72), and CMV disease in four UD BMT (8%) and four RD BMT (13%) ( P  = 0.533). In this series the risk of CMV excretion and disease following UD BMT was similar to that following RD BMT.     

Cytomegalovirus infection after autologous bone marrow transplantation with comparison to infection after allogeneic bone marrow transplantation

Cytomegalovirus (CMV) infection was detected in 65 of 143 (45%) autologous bone marrow transplant (BMT) patients. CMV pneumonitis occurred in only 2% of the patients and CMV retinitis occurred in none. Infection occurred in half of the 40 initially seronegative patients and 47% of the 94 initially seropositive patients. Among initially seropositive patients, platelet recovery was slower in infected patients than in those not infected (97 v 35 days median, P = .003), and neutrophil recovery was slightly delayed in infected patients (31 days v 24 days, P = .02). Although the incidence of CMV infection was comparable in autologous and allogeneic BMT patients, CMV pneumonitis was less frequent in autologous BMT patients (2% v 12%, P less than .001). The risk for CMV pneumonitis in autologous BMT patients was comparable with that in allogeneic BMT patients without graft-v-host disease (GVHD) (2% v 6%), but significantly lower than the risk in allogeneic BMT patients with GVHD (2% v 23%, P less than .001).     

Detection of cytomegalovirus infection with the polymerase chain reaction and antigenemia after allogenic bone marrow transplantation

The objective of the work was to evaluate the frequency and time of incidence of cytomegaloviral (CMV) infection and disease in patients after allogeneic bone marrow transplantation (BMT). One hundred patients were followed up (70 with a related and 30 with an unrelated donor), who had transplantations during the period between XI/1996-XI/2000. Methods used: nested-PCR (MIE-gene) and antigenaemia (antigen pp65). Active CMV infection was proved in antigenaemia > or = 5 positive cells or in two consecutive positive PCR. The CMV syndrome was assessed in confirmed CMV infection and otherwise inexplicable febrile conditions and/or a drop of haemogram values. For the diagnosis of CMV pneumonia the clinical picture was needed, evidence of active CMV infection and on the X-ray of the lungs interstitial pneumonia. In 33 patients both methods were used, in 67 only PCR. The first positive test appeared 6-321 days after BMT (median +/- 49 days). CMV infection was proved in 44% cases, CMV syndrome in 30% and CMV pneumonia in 4%. In patients with a related donor CMV infection was found in 34.3%, CMV syndrome in 22.9%, CMV pneumonia in 1.4%. After unrelated donor BMT CMV infection was recorded in 66.7%, CMV syndrome in 46.7% and CMV pneumonia in 10% patients. Two patients died from CMV pneumonia. CMV pneumonia was diagnosed 57-115 days after BMT (median +/- 68 days. The risk of CMV infection is high in both groups of patients, in particular in patients after unrelated donor BMT (66.7%). As far as the development of CMV pneumonia was concerned, the mortality in the authors' group was 50%.     

Phase I-II trial of pentoxifylline for the prevention of transplant-related toxicities following bone marrow transplantation

Disease relapse and transplant related toxicities have limited the application of bone marrow transplantation (BMT) in the treatment for hematologic malignancies. Because elevated levels of tumor necrosis factor alpha (TNF-alpha) have been correlated with the development of transplant related complications, we conducted a phase I-II trial of pentoxifylline (PTX), a xanthine derivative capable of down-regulating TNF-alpha production, in patients with hematologic malignancies undergoing BMT. Thirty consecutive adult patients (median age, 34) were entered and received either an allogeneic (n = 26) or autologous (n = 4) BMT. Patients were enrolled at increasing dose levels (1,200, 1,600, and 2,000 mg/d) from day -10 through day +100 posttransplant. PTX was well tolerated with no significant adverse side effects noted at any of the dose levels administered. The actuarial day 100 survival for these 30 patients was 90% (95% confidence interval 79% to 100%). When compared with a good risk control group, PTX recipients experienced less mucositis (3.7 +/- 1.1 v 18.7 +/- 1.1 days, P = .004), less hepatic venocclusive disease (10% v 65%, P = .001), a lower incidence of renal insufficiency (3% v 65%, P = .0003), required less days of total parenteral nutrition (TPN) (24.0 +/- 1.3 v 35.0 +/- 2.4, P = .001) and were discharged from the hospital earlier than controls (day 26.0 +/- 1.8 v 37.0 +/- 3.8, P = .01). In addition the incidence of graft-versus-host disease (GVHD) greater than or equal to grade II was also reduced among the PTX recipients (35% v 68%, P = .03). PTX at doses in excess of 1,200 mg/d further reduced the severity of mucositis, and TPN requirements resulting in earlier hospital discharge than patients receiving 1,200 mg/d of PTX. In this study oral administration of PTX in doses up to 2,000 mg/d was well tolerated and associated with a reduction in morbidity and mortality in patients undergoing BMT. Prospective randomized trials are currently in progress to test these preliminary observations.     

单倍体骨髓移植后巨细胞病毒感染的防治

目的:研究单倍型骨髓移植后,巨细胞病毒(CMV)感染的预防策略及发病情况。方法:98例单倍型骨髓移植患者,62例及1例CMVpp65阳性供者,接受更昔若韦预防治疗,受者5 mg／kg,2次／d,移植前-9 d～-2 d,31例移植后出现CMV抗原血症阳性患者,其中18／60例预防组,13／35例非预防组阳性病例,接受更昔若韦5 mg／kg,2次／d×2周,后改为5 mg／kg,1次／d,到CMVpp65转阴。移植后CMVpp65每周检测1次。结果:预防组18／60例移植后出现CMV抗原血症阳性,出现中位时间56(25～84)d。非预防组13／35例CMVpp65阳性,中位时间52(19～75)d,前者1例患者(1．6％)发展为CMV结肠炎,后者4例(11．4％),2例CMV肺炎,1例CMV结肠炎,1例CMV脑炎。结论:单倍型骨髓移植后,用CMVpp65检测CMV抗原血症是一种简便,可靠的方法。低剂量短疗程,静脉注射更昔若韦提前预防CMV病可能是一种有效的方法。     

Outcome of transplantation of highly purified peripheral blood CD34+ cells with T-cell add-back compared with unmanipulated bone marrow or peripheral blood stem cells from HLA-identical sibling donors in patients with first chronic phase chronic myeloid leukemia

Outcomes of highly purified CD34(+) peripheral blood stem cell transplantation (PBSCT) for chronic phase chronic myeloid leukemia (CML) (n = 32) were compared with those of PBSCT (n = 19) and of bone marrow transplantation (BMT) (n = 22) in the HLA-compatible sibling donor setting. Median follow-up was 18 months after CD34(+)-PBSCT and unmanipulated PBSCT and 20 months after BMT. CD34(+)-PBSCT was associated with delayed T-cell immune reconstitution at 3 months and 12 months after transplantation compared with PBSCT (P <.001) or BMT (not significant [NS]). The estimated probability of grades II to IV acute graft-versus-host disease (GVHD) was 60% +/- 13% for the PBSCT group, 37% +/- 13% for the BMT group, and only 14% +/- 8% for the CD34(+)-PBSCT group (CD34-PBSCT versus BMT, P <.01; and CD34-PBSCT versus PBSCT, P <.001). The probabilities for molecular relapse were 88% for CD34(+)-PBSCT, 55% after BMT, and 37% after PBSCT (CD34(+)-PBSCT versus PBSCT, P <.03). Cytogenetic relapse probability was 58% after CD34(+)-PBSCT, 42% after BMT, and 28% after PBSCT (NS). After CD34(+)-PBSCT, 26 of 32 patients received a T-cell add-back. Hematologic relapse occurred in 4 of 22 patients after BMT, in 3 of 19 patients after PBSCT, and in only 1 of 32 patients after CD34(+)-PBSCT. The occurrence of a hematologic relapse in patients receiving CD34(+)-PBSC transplants was prevented by donor leukocyte infusions, which were applied at a median of 4 times (range, 1-7 times) with a median T-cell dose of 3.3 x 10(6) x kg/body weight [at a median] beginning at day 120 (range, 60-690 days). The estimated probability of 3-year survival after transplantation was 90% in the CD34(+)-PBSCT group, 68% in the PBSCT group, and 63% in the BMT group (CD34-PBSCT versus BMT, P <.01; and CD34-PBSCT versus PBSCT, P <.03). Transplantation of CD34(+)-PBSCs with T-cell add-back for patients with CML in first chronic phase seems to be safe and is an encouraging alternative transplant procedure to BMT or PBSCT.     

Foscarnet Treatment of Cytomegalovirus Gastrointestinal Infections in Acquired Immunodeficiency Syndrome Patients Who Have Failed Ganciclovir Induction

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.     

A comparison of prophylactic vs pre-emptive ganciclovir to prevent cytomegalovirus disease after T-depleted volunteer unrelated donor bone marrow transplantation

The prophylactic and pre-emptive use of ganciclovir (GCV) both reduce significantly the incidence of CMV disease after sibling BMT but it is unclear which of these strategies is best for volunteer unrelated donor (VUD) BMT patients. We reviewed 49 consecutive patients, who received a T-depleted VUD BMT (from March 1990 to March 1996) for the treatment of CML in chronic phase, and were CMV seropositive before transplant or had a CMV seropositive donor. Patients were conditioned with cyclophosphamide (120 mg/kg for 2 days) and total body irradiation (13.2-14.4 Gy). Prophylaxis for GVHD was cyclosporin A and methotrexate with ex vivo or in vivo T cell depletion. Twenty-seven patients received pre-emptive GCV if CMV infection was detected by short-term culture before day +120 post BMT. Twenty-two patients received prophylactic GCV from engraftment until day +120 post BMT. The probabilities of CMV infection and disease occurring by 1 year post-BMT were greater in the pre-emptive GCV group than in the prophylactic GCV group (73.8% and 64.0% vs 53.1% and 30.0%, respectively; P=0.04 and 0.07). The incidence of death from CMV disease was similar in both groups (3/12 (25%) vs 3/10 (30%), respectively) and there was no difference in 1 year survival (55.6% vs 54.2%, respectively). New strategies are urgently required for the prevention of CMV disease after T-depleted VUD BMT.     

Clinical features and outcomes of cytomegalovirus retinitis after transplantation.

Cytomegalovirus (CMV) infection of the retina is a rarely encountered end-organ disease after transplantation. In order to describe the clinical characteristics and outcomes of CMV retinitis after hematopoietic stem cell and solid organ transplantation, we performed a retrospective review of all cases of CMV retinitis at the Mayo Clinic (Rochester, Minnesota) during 1990-2004. During this 15-year period, CMV retinitis was diagnosed in 14 eyes of 9 patients who had received kidney (n=5), liver (n=2), heart (n=1), and autologous hematopoietic stem cell transplant (n=1). The mean age of the patients was 58 (standard deviation+/-11) years; 6 were male. The median time to diagnosis of CMV retinitis was 9 months (range, 4 months to 13 years) after transplantation. Four (44%) patients had concomitant pneumonitis or hepatitis. Five (55%) patients had bilateral retinitis. Retinal involvement was 10% but 50% in 2 eyes. All patients received induction therapy with intravenous ganciclovir (n=8) or foscarnet (n=1) for a median of 43 days (range, 14-100 days) followed by maintenance therapy with intravenous or oral ganciclovir for a median of 88 days (range, 36-943 days) in 6 (67%) patients. One patient developed bilateral immune recovery uveitis during treatment, and later on progressed to develop rhegmatogenous retinal detachment. During the mean follow-up period of 20 months, visual acuity improved in 4 (28.5%), was stable in 4 (28.5%), and worsened in 6 (43%) eyes. CMV retinitis recurred in 2 patients. In conclusion, CMV retinitis is a rare, progressive, and highly morbid infectious complication of transplantation. The severity of clinical disease at the time of diagnosis may predict poor outcome. Hence, early intervention may be crucial to prevent its progression to irreversible visual loss.     

Primary familial polycythaemia associated with a novel point mutation in the erythropoietin receptor

To identify and treat patients at high risk of cytomegalovirus (CMV) pneumonia after bone marrow transplantation (BMT), we tested for CMV viraemia weekly, and performed broncho-alveolar lavage (BAL) on day 35 post-transplant in 63 recipients. 36 allogeneic BMT recipients were at a high risk of CMV pneumonia (25 CMV-seropositive recipients and 11 patients receiving marrow from a CMV-seropositive donor). Patients with a positive BAL or viraemia received a 14 d course of ganciclovir or foscarnet. CMV was detected in 29 (46%) of the 63 BMT recipients and excretion of CMV in blood and BAL was significantly linked. However, among the 29 patients who excreted the virus, only 10 (35%) shed CMV in blood and BAL at the same time; 19 patients (65%) had detectable CMV in blood (11 patients) or BAL (eight patients) only. Therefore, on the basis of viraemia or BAL alone, 21/29 patients (70%) and 18/29 patients (60%), respectively, would have received antiviral treatment. BAL increased the CMV detection rate by 13% (8/63 patients) relative to viraemia. With this strategy, the incidence of CMV pneumonia was reduced to 3% in allografted patients. Only two of the 19 autografted patients developed fatal CMV pneumonia. We avoided anti-CMV treatment in 54% of all the BMT recipients. In conclusion, CMV should be tested for in both blood and BAL fluid of BMT recipients at high risk of CMV pneumonia.     

Neurologic cytomegalovirus complications in patients with AIDS: retrospective review of 13 cases and review of the literature

Neurological disorders caused by Cytomegalovirus (CMV) in patients with Acquired Immunodeficiency Syndrome (AIDS) are rarely reported in the Highly Active Antiretroviral Therapy (HAART) period. The objective of this study was to describe the main clinical and laboratory features of patients with CMV-related neurological complications in HIV-infected patients admitted to a referral center in S?o Paulo, Brazil. CMV disease requires the identification of the virus in the cerebrospinal fluid (CSF) using Polymerase Chain Reaction (PCR). Thirteen cases were identified between January, 2004 and December, 2008. The median age of patients was 38 years and nine (69%) were men. At admission all patients were aware of their HIV status and only four (31%) patients were on HAART. Patients who were not on antiretroviral therapy before admission received HAART while inpatients. CMV disease was the first AIDS-defining illness in eight (62%) patients. The neurologic syndromes identified were diffuse encephalitis (n = 7; 62%), polyradiculopathy (n = 7; 54%), focal encephalitis (rhombencephalitis) (n = 1; 8%), and ventriculo-encephalitis (n = 1; 8%). Seven (54%) patients presented extra-neural CMV disease and four (31%) had retinitis. The median of CD4+ T-cell count was 13 cells/μL (range: 1-124 cells/μL). Overall in-hospital mortality was 38%. Eight patients used ganciclovir or foscarnet (in-hospital mortality: 50%) and five patients used ganciclovir and foscarnet (in-hospital mortality: 20%). None of the patients fulfilled the diagnosis criteria of immune reconstitution inflammatory syndrome. Four patients were lost to follow-up, and three patients presented immune recovery and discontinued secondary prophylaxis. Although infrequent, distinct neurological syndromes caused by CMV continue to cause high mortality among AIDS patients. Survival depends upon the use of effective antiviral therapy against CMV and the early introduction of HAART.     

CMV infections following allogeneic BMT: risk factors, early treatment and correlation with transplant related mortality.

BACKGROUND. The impact of early detection of CMV infections in allogeneic bone marrow transplantation (BMT) and of early treatment with ganciclovir is still uncertain. METHODS. 98 patients undergoing allogeneic BMT for hematologic malignancies (n = 91) or aplastic anemia (n = 7) were monitored weekly for the expression of the lower matrix protein pp65 of cytomegalovirus (CMV) on peripheral blood cells (PB) and urine sediments (U) as detected by C10 and C11 monoclonal antibodies (Clonab, Biotest) and immunoperoxidase. Bronchoalveolar lavage (BAL) cytospin preparations were also studied in patients with clinically documented interstitial pneumonia. Patients were considered to be infected with CMV if pp65 was detected in PB (n = 15) or BAL cells (n = 6), or in the presence of serum CMV-IgM with (n = 7) or without (n = 3) pp65-positive cells in urine sediments. RESULTS. The overall actuarial risk at 300 days of developing a CMV infection was 35%. CMV serum/status (IgG) pre-BMT of donor and/or recipient predicted the occurrence of CMV infections post-BMT: in neg/neg donor/recipient pairs (n = 17) the actuarial risk at 300 days was 0%, compared to 41% in pairs in which donor and/or recipient were CMV seropositive (n = 81) (p = 0.001). 24/31 patients were treated with ganciclovir (DHPG), and 17 survive. Mortality of patients treated early with DHPG on the basis of CMV antigenemia was 18% compared to 42% for untreated patients (p = 0.9). Pretransplant donor/recipient seropositivity accurately predicted transplant related mortality (TBM): 6% in neg/neg pairs vs 41% in all other combinations (p = 0.008). CONCLUSIONS. The risk of developing CMV infections post-BMT can be predicted by pre-transplant serostatus, diagnosed by monitoring the expression of pp65-protein and correlates with transplant related mortality. The latter appears to be reduced by early treatment with DHPG.