Is routine post-operative surveillance for cytomegalovirus infection following heart transplantation necessary?

OBJECTIVE: Cytomegalovirus infection (CMV) is an important cause of morbidity and mortality following cardiac transplantation. The purpose of the present study was to ascertain whether routine post-operative screening for CMV infection influenced clinical management. METHODS: Laboratory and case notes of 220 patients who received cardiac transplantation between November 1986 and October 1996 were reviewed. The range of follow-up was one to 120 (median 36) months. CMV surveillance involved blood tests for early antigen detection weekly for the first 6 post-operative weeks, fortnightly thereafter until the end of the third post-operative month and every 6 weeks to the end of the first post-operative year. Otherwise monitoring was performed if the patients had clinical symptoms suggestive of CMV infection. CMV sero-negative IgG recipients (R) of sero-positive IgG donor (D) organs and/or blood products received hyper-immune gammaglobulin for the first three post-operative months. Four patient groups were noted, namely R+D+ (59 patients), R+D- (70 patients), R-D+ (35 patients) and R-D- (56 patients). RESULTS: CMV antigenaemia was present in 40% (89) of patients and 48% (43) of these patients developed clinical features of CMV infection and received ganciclovir therapy. The distribution of clinical CMV infection requiring treatment was 25% (9/35) in the R+D- group, 50% (16/32) in the R+D+ group and 85% (18/22) in the R-D+ group. None of the patients in the R-D- group developed CMV antigenaemia. Forty six (52%) patients who were CMV antigen positive but who did not develop symptoms were not treated with ganciclovir and have remained well. CONCLUSION: Our results suggest that routine screening for CMV following cardiac transplantation is unnecessary. Surveillance did not result in the instigation of treatment for CMV unless there were associated clinical features of CMV infection.

Molecular epidemiology of varicella-zoster virus in East London, England, between 1971 and 1995.

The molecular epidemiology of varicella-zoster virus in London, England, between 1971 and 1995 was examined by using two informative polymorphic markers, variable repeat region R5 and a BglI restriction site in gene 54. Viruses from 105 cases of chickenpox and 144 of zoster were typed. Two alleles of R5, A and B, were found at prevalences of 89 and 6%, respectively. No difference in allele frequency between the zoster and chickenpox cases was found, and no change in the frequencies of these alleles was observed to occur over time. By contrast, a BglI restriction site (BglI+) was found with increasing frequency over time among cases of varicella (P < 0.005) and, to a lesser extent, cases of zoster. The BglI+ polymorphism was strongly associated (P < 0.0005) with zoster in subjects who had immigrated to the United Kingdom from countries with low adult immunity to varicella (LAIV). Sixty-three percent of the subjects with zoster who had emigrated from countries with LAIV carried the BglI+ virus, in contrast to 10% of adults who had grown up in countries with high adult immunity to varicella. The significance of these data, in view of the changing epidemiology of chickenpox, is discussed.

A polymerase chain reaction to detect a spliced late transcript of human cytomegalovirus in the blood of bone marrow transplant recipients.

A reverse transcription (RT) nested polymerase chain reaction (PCR) procedure is described for detecting RNA to a spliced late gene (SLG) of human cytomegalovirus (CMV), the product of which (175 bp) is easily differentiated in agarose gels from the product when the target is unspliced viral RNA or DNA (258 bp). The SLG-RT-PCR has been compared against a semi-quantitative PCR for CMV DNA in buffy-coat specimens collected weekly after bone marrow transplantation from 3 patients and against the results of culturing these specimens for CMV both by conventional virus isolation, based on the detection of cytopathic effect, and by the early detection of infected cells by staining with virus-specific monoclonal antibodies. The detection of CMV RNA by SLG-RT-PCR correlated well with the detection of infective virus but only when the results of both culture methods were combined, in that neither culture method alone was as sensitive as the SLG-RT-PCR. The presence of SLG RNA in the circulation is of value as a marker of active CMV infection.

Three weeks of ganciclovir for cytomegaloviraemia after allogeneic bone marrow transplantation.

Cytomegaloviraemia diagnosed by early antigen detection or conventional viral culture from blood occurred 7-71 days (median 41 days) after transplant in 25 of 38 consecutive patients undergoing bone marrow transplantation (BMT) from HLA-identical siblings for haematological malignancies where patient and/or donor were CMV-seropositive. Prophylactic ganciclovir, high-dose intravenous acyclovir or immunoglobulin were not administered. Viraemia was treated with a short 3-week course of ganciclovir (10 mg/kg x 1 week, 5 mg/kg x 2 weeks). Clearance of viraemia occurred 3-47 days (median 6 days) after starting anti-viral therapy in 20 patients (18 with ganciclovir, 2 with foscarnet), and before therapy in 3 patients. The remaining 2 patients received inadequate anti-viral therapy for various reasons and died of CMV pneumonitis. There was no clinical evidence of CMV disease in the 13 patients who did not develop viraemia. One patient treated with ganciclovir before adequate haematological recovery died of graft failure. A second episode of viraemia occurred in four patients, and a third in one. We conclude that a short 3-week course of ganciclovir is adequate in most patients developing cytomegaloviraemia after allogeneic BMT. Treatment is not necessary in all patients but some inadequately treated patients develop CMV disease. Ganciclovir is tolerated well but may cause severe myelosuppression if used prior to adequate marrow recovery.

Association of cytomegalovirus infection with post-transplantation cardiac rejection as studied using the polymerase chain reaction.

The relationship between cytomegalovirus (CMV) infection and cardiac allograft rejection is controversial, some authors reporting a significant association, others not, on the basis of the results of conventional virological diagnosis by culture or serology. This problem was reinvestigated in 88 patients using a semi-quantitative nest polymerase chain reaction (PCR) procedure for detecting CMV DNA in endomyocardial biopsy specimens. Significantly more positive biopsies were obtained from patients with moderate (grade 2; P = 0.02) or severe (grade 3a-4; P = 0.03) rejection than with no or mild (grade 0-1b) rejection, whereas there was no significant association between rejection and CMV as diagnosed by virus isolation from urine, throat or blood, or by the detection of CMV-IgM. PCR-positive biopsies originated most frequently from CMV-antibody positive recipients (R+) of hearts from seropositive donors (D+), in association with moderate or severe rejection rather than with mild or no rejection The detection of CMV in the heart thus seemed to be related more to R+D+ serological status than to severity of rejection, that is, to circumstances that favoured co-infection with strains of CMV from both donor and recipient. Studies on sequential biopsy specimens from selected patients also provided evidence that CMV infection and rejection were not always related events. The PCR was able to differentiate latent from active CMV infection; moreover, some seronegative individuals gave repeatedly positive biopsies, thereby supporting the work of others that some patients undergo CMV infection without mounting a detectable antibody response.(ABSTRACT TRUNCATED AT 250 WORDS)

Discordant results obtained on testing sera from immunocompromised patients for cytomegalovirus IgG by enzyme-linked immunosorbent assay and radioimmunoassay.

The investigation of sera from immunocompromised patients for antibody to CMV by ELISA, RIA, immunofluorescence (IF) and complement-fixation (CF) revealed discrepancies that reflected differences in test specificity rather than sensitivity and suggested that for the long-term serological follow-up of such patients it would be advisable not to rely on only a single assay procedure.

Cytomegalovirus pneumonia: the use of ganciclovir in marrow transplant recipients.

Sixteen bone marrow transplant recipients with cytomegalovirus pneumonia diagnosed by rapid, non-invasive methods were treated with ganciclovir. Seven patients survived the acute infection and there were five long term survivors. Excellent in-vivo suppression of cytomegalovirus was observed. Marrow toxicity was noted in four patients but was rapidly reversible and not life threatening. Clinical features common to surviving patients included good clinical condition, insidious development of infection and evidence of normal alveolar gas exchange. The fulminant onset of symptoms, radiographic abnormalities and hypoxaemia were characteristic of non-survivors. These results offer some encouragement towards further study of ganciclovir for the early treatment of cytomegalovirus pneumonia. To identify such patients, the use of rapid diagnostic methods and aggressive viral surveillance is recommended. Convincing evidence for the efficacy of this drug will only emerge from randomized prospective studies.

The prophylactic role of intravenous and long-term oral acyclovir after allogeneic bone marrow transplantation.

Eighty-two patients were randomly allocated to receive intravenous acyclovir 5 mg kg-1 t.d.s. for 23 days followed by oral acyclovir 800 mg 6-hourly for 6 months or matching placebos after allogeneic bone marrow transplantation. Herpes simplex and varicella zoster virus infections were significantly reduced during the period of administration of acyclovir. No reduction in cytomegalovirus infection was demonstrated. The drug was not toxic.

Detection of IgM antibodies against cytomegalovirus: comparison of two radioimmunoassays, enzyme-linked immunosorbent assay and immunofluorescent antibody test.

The sensitivity and specificity of direct antibody radioimmunoassay (RIA), M-antibody capture RIA (MACRIA), enzyme-linked immunosorbent assay (ELISA), and the immunofluorescent antibody (IFA) test for the detection of CMV-specific IgM was compared using 40 sera selected from different groups of patients. RIA, MACRIA, and ELISA gave concordant results with thirty-two sera but discordant results with eight sera, of which three were cord sera from congenitally infected babies, three were from immunocompromised patients with recurrent CMV infections, and two were from patients with lymphadenopathy and Paul-Bunnell-positive mononucleosis, respectively. RIA, MACRIA, and ELISA were of similar sensitivity with sera from adult patients, but ELISA was apparently less sensitive than RIA and MACRIA for the detection of CMV IgM in cord serum. By comparison IFA was significantly less sensitive than the other three tests. Rheumatoid factor is reactive in RIA, ELISA, and IFA but can efficiently be removed by absorption with latex-IgG beads or cross-linked human IgG.

Cytomegalovirus complement-fixing IgM antibody.

Cytomegalovirus (CMV)-specific IgM that fixes complement in the presence of CMV antigen was demonstrated in sera from five patients with primary CMV infection. The CF reaction, demonstrable in the IgM fractions of the sera, was not affected significantly by absorption with aggregated IgG but was abolished by treatment with 2-mercaptoethanol. The IgM antibody was readily detected in CF tests with crude cell-extract antigens, prepared from CMV-infected tissue culture cells, or with purified enveloped-virion antigen but not with CMV-soluble antigens.