Severe Cytomegalovirus Infection Research Articles

Advances in antiviral therapy

For many years, acyclovir has been used to treat herpes simplex and varicella zoster infections in adults and children, although new drugs with improved bioavailability and dosage regimens (ie, famciclovir, valaciclovir) are replacing it for the outpatient management of these conditions in adults. Acyclovir remains the treatment of choice for severe herpes infections in both immunocompetent and immunosuppressed patients. Data on the newer antiherpes drugs in children are not available. Treatment of severe cytomegalovirus infections with ganciclovir and foscarnet is difficult because of toxicity; whether improved formulations of these drugs or newer agents prove clinically useful remains to be seen. For the most part, treatment of other herpesviruses is not indicated. The major advance in pediatric HIV treatment is the reduction in vertical transmission with peripartum zidovudine, although the optimal use of antiretrovirals in this situation remains to be determined. The nucleoside analogues zidovudine, zalcitabine, didanosine, and stavudine have been assessed in HIV-infected children; pediatric data about appropriate combinations (eg, with the protease inhibitors and the nonnucleoside reverse transcriptase inhibitors) and dosage regimens lag well behind the adult literature. The effectiveness of ribavirin in respiratory syncytial virus disease is uncertain. Preliminary data suggest that interferons may have a role in the management of chronic hepatitis B and C.

Cordocentesis using the combined technique; needle guide-assisted and free-hand.

Two hundred and sixteen diagnostic cordocenteses were performed using the following technique: A guide was used to deliver the distal end of the needle to the immediate vicinity of the umbilical cord, after which the needle was released from the guide and a free-hand technique was used to enter the umbilical cord. The vessel punctured was identified by its sonographic appearance and flow direction using color Doppler technology. All procedure-related losses which occurred within 2 weeks were analyzed. The gestational age at the time of cordocentesis ranged from 18 to 42 weeks. Most punctures (62%) were performed at the placental insertion of the umbilical cord. In 32% of fetuses the free-floating loop was sampled and in 6% the puncture was performed at the site of cord entry into the fetus. Two fetuses died shortly after cordocentesis. One death occurred at 28 weeks in a fetus with severe cytomegalovirus infection. The other death was due to premature rupture of the membranes after the procedure in a very premature fetus. The overall fetal loss rate was 0.93%. In conclusion, the combination of the two cordocentesis techniques appears safe and highly successful in obtaining fetal blood samples.

Viral lesions of the mouth in HIV-infected patients.

Viral lesions of the mouth in patients with HIV infection are common and these diseases any be a marker for HIV and disease progression. We review the spectrum of oral viral manifestations and discuss treatment modalities. The most common Epstein-Barr virus (EBV)-induced disorder in HIV-infected patients is oral hairy leukoplakia. EBV-related oral B-cell and T-cell lymphoma in AIDS patients has been described repeatedly. Herpes virus type 1 and rarely type 2 may lead to painful and resistant oral ulcers, and systemic treatment with acyclovir, valaciclovir or famciclovir is indicated. In acyclovir-resistant cases foscarnet is the treatment of choice. In recent years it has been documented that Kaposi's sarcoma, which often affects oral mucosa, is probably induced by herpesvirus type 8. Cytomegalovirus was found in 53% of cases with herpesviridae-induced mucosal ulcers as the only ulcerogenic viral agent in AIDS patients. In severe cytomegalovirus infection treatment with ganciclovir is helpful. Viral warts induced by different HPV may occur in the mouth. Several physical treatment modalities are possible in the oral mucosa. In AIDS patients mollusca contagiosa may occur as large and atypical lesions in the face and lips and rarely in the oral cavity. Cryotherapy is a bloodless treatment in such patients.

Muromonab CD3: a reappraisal of its pharmacology and use as prophylaxis of solid organ transplant rejection.

The murine monoclonal antibody muromonab CD3 (OKT3) is directed against the CD3 antigen on peripheral human T cells and effectively blocks all T cell function. Prophylaxis with muromonab CD3 (5mg intravenously once daily for 10 to 14 days) as induction therapy together with corticosteroids, azathioprine and delayed cyclosporin (sequential therapy) optimises early graft function by delaying the potentially nephrotoxic and hepatotoxic effects of cyclosporin until graft function is established. Although clinical data are limited (by inconsistencies in trial design and trial size), prophylactic muromonab CD3-based sequential therapy is significantly more effective than standard triple therapy in the prophylaxis of allograft rejection in renal and hepatic, but not cardiac, transplant recipients. Benefits are particularly notable in patients with delayed graft function. No significant between-treatment differences in patient survival have been observed. The overall efficacy of muromonab CD3- and polyclonal-based prophylactic regimens appears to be similar, although results vary between investigators and confirmation is needed. An anti-interleukin-2 monoclonal antibody-based prophylactic regimen improved graft and patient survival compared with muromonab CD3-based prophylaxis in hepatic transplant recipients. Antimuromonab CD3 antibodies may develop; however, muromonab CD3 may be successfully reused in patients with low titres. Preliminary pharmacoeconomic data suggest that mean drug costs are greater with quadruple immunosuppressive regimens containing muromonab CD3, antithymocyte globulin (ATG) or antilymphocyte globulin (ALG) than with triple therapy. Drug costs with prophylactic muromonab CD3-based regimens were similar or greater than those with polyclonal-based protocols. The first doses of muromonab CD3 are associated with the 'cytokine-release syndrome'. More severe first-dose events include aseptic meningitis, intragraft thromboses, seizures and potentially fatal pulmonary oedema. The incidence and/or severity of cytomegalovirus infection with prophylactic muromonab CD3 based immunosuppression is similar to or greater than that with triple therapy and ATG- or ALG-based regimens. However, the risk of infection and also the observed increase in lymphoproliferative disorders appears to be related to the degree of immunosuppression rather than to the drug itself Thus, sequential muromonab CD3-based therapy is more effective than standard triple therapy (in renal and hepatic transplant recipients) and appears to be similar to that of polyclonal-based regimens in the prophylaxis of transplant rejection. Although the routine use of prophylactic muromonab CD3 in low-risk patients with primary graft function does not appear to be justified, prophylactic muromonab CD3-based therapy has a role in patients at high risk of rejection.

Intestinal cytomegalovirus disease in immunocompromised patients may be ruled out by search for cytomegalovirus DNA in stool samples.

Cytomegalovirus (CMV) PCR from stool specimens was adopted as a diagnostic tool for patients with suspected CMV colitis. After being established, the method was evaluated in 17 AIDS patients and 19 other immunocompromised patients by comparison of PCR results with clinical, histological, and microbiological or virological data. CMV PCR was positive in 4 symptomatic patients with proven CMV colitis and negative in 15 of 16 patients without characteristic histopathology. Neither CMV immunoglobulin G seropositivity nor intestinal symptoms alone were significantly associated with positive PCR results, but severe active systemic CMV infection may lead to a positive PCR. Absence of CMV DNA in stool samples may prove useful in ruling out CMV related colitis.

Infectious complications following pancreatic transplantation: incidence, microbiological and clinical characteristics, and outcome.

The infectious complications following pancreatic transplantation in 34 consecutive recipients were analyzed during a mean follow-up of 39 months. Twenty-seven recipients (79%) developed a mean of 2.1 serious infectious complications. Three of the six deaths (overall mortality, 18%) were infection related. Thirty-three percent of severe infectious episodes were caused by bacteria (72% by gram-positive cocci) and 26% by fungi (87% by Candida species); severe cytomegalovirus (CMV) infection accounted for 33% of infectious complications. CMV disease and organ involvement occurred most frequently in the donor-seropositive/recipient-seronegative group (36%), followed by the donor-seronegative/recipient-seropositive group (25%). In four patients (12%) Epstein-Barr virus (EBV)-related posttransplantation lymphoproliferative disease (PTLD) developed, directly resulting in two deaths. PTLD developed in two of the three EBV-seronegative and two of the 31 EBV-seropositive recipients. Infections due to herpes simplex and zoster viruses and Pneumocystis carinii (2, 3, and 1, respectively) developed in 6 patients. The use of OKT3 for rejection therapy was associated with symptomatic CMV disease and EBV-related PTLD. In summary, severe infectious complications are the main cause of morbidity and death among patients who undergo pancreas transplantation. Aggressive antimicrobial prophylactic regimens are required to decrease the effects of such complications.

Cytomegalovirus infection-associated generalized immune activation in heart allograft recipients: a study of cellular events in peripheral blood and endomyocardial biopsy specimens.

An association between cytomegalovirus (CMV) infection, heart allograft rejection, and arteriosclerosis has been reported. To investigate the mechanisms of this association, the cellular immune response in peripheral blood and the inflammation in heart allografts during antigenemia were studied. CMV antigenemia occurred in 13 recipients. In recipients with severe CMV infection, a significantly weaker immune response was recorded in peripheral blood: fewer lymphoid blast cells (max. 2.4% +/- 0.4%) and large granular lymphocytes (LGL; max. 9.3% +/- 1.4%) were seen than in patients with mild or asymptomatic CMV infection (lymphoid blast cells max. 6.5% +/- 0.8% P < 0.01 and LGLs max. 20% +/- 2.3%, P < 0.05). Thus, a strong immune response with lymphoid activation was associated with clinically good outcome of CMV infection. In heart allograft histology, subendothelial inflammation of small intramyocardial vessels was a characteristic finding during CMV antigenemia compared to CMV-free recipients (at the peak P < 0.01). However, no difference in this mild and short-lived inflammatory response was observed between clinically mild or severe CMV infection. The CMV-linked generalized immune activation and inflammation of the vascular structures might contribute to the initiation of allograft vasculopathy and to the pathogenesis of chronic heart allograft rejection.

The mortality and pathology of HIV infection in a West African city

HIV disease is epidemic in Africa, but associated mortality, underlying pathology and CD4+ T-lymphocyte counts have not previously been evaluated in a representative study. Such data help to determine the management of HIV-positive people. Both HIV-1 and HIV-2 infections are prevalent in Côte d'Ivoire, and the pathology of HIV-2 infection in Africa is unclear. Consecutive adult medical admissions to a large city hospital in Côte d'Ivoire were studied in 1991, and a sample of HIV-positive deaths autopsied. Of 5401 patients evaluated, 50% were HIV-positive; 38% of these died, with a median survival of 1 week. At autopsy (n = 294, including 24% of HIV-positive deaths in hospital), tuberculosis (TB), bacteraemia (predominantly Gram-negative rods) and cerebral toxoplasmosis caused 53% of deaths. TB was seen in 54% of cadavers with AIDS-defining pathology and Pneumocystis pneumonia in 4%. The median CD4+ T-lymphocyte counts in those who died was < 90 x 10(6)/l. Compared with HIV-1-positives, patients with HIV-2-positivity had a greater frequency of severe cytomegalovirus infection, HIV encephalitis and cholangitis. In this population, HIV-positive adults present to hospital with advanced disease associated with high mortality. The three major underlying pathologies (TB, toxoplasmosis and bacteraemia) are either preventable or treatable. TB is an underestimated cause of the 'slim' syndrome in Africa. The patterns of pathology in HIV-2-positive patients suggest a more prolonged terminal course compared with HIV-1. There is an urgent need for attention towards the issues of therapy and care for HIV disease in developing countries.

Rejection-independent cholangitis and cirrhosis following orthotopic liver transplantation

The histologic diagnosis of extrahepatic biliary obstruction in the setting of orthotopic liver transplantation (OLT) may be complicated by nonobstructive factors, such as rejection, preservation injury, drug effects, and infection. Indeed, biopsy specimens from OLT patients frequently exhibit early posttransplant cholestasis, which is likely the result of several of these factors acting in concert. We reviewed the clinicopathologic features of 14 OLT patients whose biopsy specimens displayed prominent cholangitis with “obstructive”-type features. Cholangiograms, Doppler ultrasound examinations, and bacterial cultures were obtained in conjunction with all biopsy specimens. Despite histologic evidence of biliary obstruction, cholangiography revealed obstruction in only one case, leaks in four cases, and nine normal studies. Ten patients had severe systemic bacterial or cytomegalovirus infections. Biliary infection was documented in two cases. Hepatic artery occlusion was diagnosed in one case. The cholangitic pattern persisted in patients with unremitting infections, and two patients developed secondary biliary cirrhosis despite having consistently normal cholangiograms. Features of acute rejection or viral hepatitis were not observed on any biopsy specimen. The presence of this clinicopathologic spectrum was associated with a poor prognosis. Nine patients died and only four patients who responded to antibiotics survived. These findings demonstrate a striking cholangitic response to systemic infections in OLT grafts. The diagnosis of biliary obstruction in OLT liver biopsy specimens cannot be rendered without cholangiographic verification.

Ganciclovir Treatment of Murine Cytomegalovirus Infection in Mice Immunosuppressed by Prior Infection with Friend Leukaemia Virus

Since many of the severe cytomegalovirus infections in humans occur in individuals immunosuppressed by the human immunodeficiency virus, we developed an analogous murine model for studying this disease. BALB/c mice infected with the Friend retrovirus complex (FV) were immunosuppressed (i.e., exhibited reduced spleen-cell mitogenic responses and natural killer cell activity) by 21 days after FV inoculation. Challenge with murine cytomegalovirus (MCMV) at that time led to mortality at doses generally non-lethal to normal mice. Superinfection of FV-infected mice with MCMV reduced spleen cell FV infectious centres and splenomegaly, and extended the lives of mice surviving the MCMV infection. Once-daily ganciclovir treatments of 12.5,25, and 50 mg kg−1 given to dually-infected mice for 5 days starting 24 h after MCMV inoculation resulted in 90–100% survival at 14 days (relative to MCMV inoculation) compared to 15% survival in the placebo group. By 70 days, survival in the drug-treated and placebo groups were 0–5%, these deaths being attributed to FV disease. Ganciclovir treatments reduced MCMV titres in spleen, liver, and kidney during treatment (day 4 of the infection), but lung and salivary gland titres rose between days 7 and 13 in surviving animals. Improved concanavalin A-induced mitogenic responses were noted on day 4 in mice treated with 25 and 50 mg kg−1. These results indicate that the FV/MCMV dual infection in mice can be used as a model for evaluating antiviral agents. Because of the complex nature of the interaction between FV and MCMV, the model may be more appropriate for advanced studies of well-defined viral inhibitors than for routine screening of potential new compounds.

Cytomegalovirus (CMV) excretion as a factor in the severity of CMV disease in kidney and simultaneous kidney and pancreas transplantation

The aim of the study was to evaluate the virological parameters associated with the severity of cytomegalovirus (CMV) disease in renal and simultaneous renal and pancreatic transplantation. The association of the viral profile and the severity of the viral disease was analysed taking into account different confounding variables susceptible to linkage with the severity of the CMV infection and the viral parameters. All the patients transplanted between 1 January 1989 and 31 December 1990, a total of 242, were prospectively followed by viral cultures in blood and urine and by serological methods using the detection of CMV-specific IgM and the complement fixation (CF) test. The samples were taken systematically each week for the first month and then at day 90, 180 and every 6 months and also in cases of clinical manifestations related to viral disease. CMV infection was diagnosed virologically by the presence of viraemia, viruria, IgM, or a significant rise in CMV antibody titre in CF. CMV disease was classified as asymptomatic, mild (fever and/or leukopenia), moderate (fever, leukopenia and liver abnormalities), severe (CMV pneumopathy and/or gastrointestinal disease) or fatal. The incidence of CMV infection was 65% (157/242): 32% asymptomatic, 36% mild, 30% moderate and 2% severe. The presence of IgM was associated with the severity of CMV disease: 51.4% of moderate and severe CMV infections in the group with IgM versus only 16% in the group without IgM (P < 0.0001). The risk of having severe or moderate CMV disease was 3.28 times higher in patients with positive IgM. However the serological changes in CF were not significantly associated with the severity of the viral disease since 34.6 % of the patients with CF changes had a severe form versus 20.8% in the group without CF modification. Viruria was significantly associated with moderate or severe infection: 43.6% of the patients with viruria had severe infection versus only 12.5% in the patients without viruria (P < 0.0002). The risk of having moderate or severe CMV disease was 3.48 times higher in the patients with viruria. Viraemia was also associated with more severe CMV infection: 48.6% of moderate or severe CMV infection in the group of patients with viraemia versus 19% in the group without viraemia (P < 0.0001). The risk of having severe or moderate CMV infection was 2.58 times higher in the patients with viraemia. Viraemia was not more associated with severe CMV infection than viruria. Using the maximum likelihood ratio method and the logistic regression model, CMV-specific IgM, viruria and viraemia were each shown to be associated with the severity of CMV disease and the addition of one parameter to the other(s), whatever the type (except the CF changes) and whatever the order of this addition, did not remove the link between the severity and IgM, viruria and viremia. The incidence of severe and moderate CMV disease increased with the number of positive viral parameters (PVP) from 2% of moderate and severe infections in the group with one PVP, to 28% in the group with two PVP, to 39% in the group with three PVP and 68% in the group with four PVP (trend, 35.95; P < 0.0001). Taking the absolute risk of the group of patients without IgM, viruria or viraemia as the basal level, the observed relative risk of severe CMV infection varied from 6.45 in the group with positive IgM without viruria or viraemia, to 10.74 in the group with positive IgM and viruria without viraemia and to 22.5 in the group with the three positive parameters IgM, viruria and viraemia. The different potential confounding factors (recipient and donor serology, renal or renal and pancreatic transplantation, DR compatibility, rejection before CMV infection) did not modify the link between the viral profile and the severity of CMV disease. This study suggests that the severity of CMV disease might be linked to the overspread of the virus as well as to the consequences of a CMV-specific humoral immune response.

Clinicopathological study of liver involvement in cytomegalovirus infection in infant autopsy cases.

To clarify the pathogenesis of hepatic cytomegalovirus (CMV) infection, we clinicopathologically investigated 18 infants and 10 adults with cytomegalic inclusion bodies (CIB) in the liver among a total of 75 autopsy cases with CIB in any organ of the body. CMV infection was confirmed by immunohistochemistry and in situ hybridization. When CIB were present in the liver, CMV infection also tended to be systemic. All the adults were immunocompromised patients, but diseases inducing immunodeficiency were present in only two of the infants. The severe and systemic CMV infections we found in infants might have been associated with congenital CMV infection. Histologically, hepatocyte necrosis, cholestasis, extramedullary hematopoiesis and fatty degeneration were more frequent and prominent in infants than in adults. However, inflammatory cell infiltration was only slight. In addition, the frequent association with premature birth and hypoplasia of the thymus suggested that insufficient development of immunity may result in hepatic CMV involvement in infants. CIB were most frequently observed in hepatocytes in both infants and adults, but in infants they were also frequently seen in the bile duct epithelium. These histopathological findings and the high incidence of jaundice in infant patients suggest that the bile duct is also an important site of CMV proliferation in infants, and that CMV infection may be one cause of infantile jaundice.

9 Infections in the compromised child

Children receiving chemotherapy for malignant diseases show different patterns of infection depending on their underlying disease and its therapy. Granulocytopenia carries the risk of bacterial infection, and also, if prolonged, of fungal infection. Impairment of cell-mediated immunity predisposes to infections with Pneumocystis carinii and is thought to be responsible for severe primary infections with varicella and measles, as well as the severe cytomegalovirus infections seen after allogeneic bone marrow transplantation. Absence or impairment of splenic function predisposes to overwhelming septicaemia with encapsulated organisms, while defects in the normal mechanical barriers to infection provide routes for bacterial and fungal invasion. Despite the lack of physical signs of a normal inflammatory response, clinical evaluation may be critical to the localization of infection in the immunocompromised child. Blood culture and biopsy remain pivotal investigations in the achievement of a microbiological diagnosis. Empirical treatment with a combination of antibiotics has been shown in comparative studies to be effective in initial management of the febrile neutropenic patient: continuing studies are evaluating the role of monotherapy and of different antibiotic combinations, particularly in the light of changing patterns of bacterial infections. Empirical antifungal therapy has been shown to be necessary for persistent or recurrent fever, particularly as persistent fungal infection may compromise the outcome of continuing cytotoxic therapy. Continuing uncertainties over many aspects of management of the infected immunocompromised child provide scope for clinical trials in parallel with trials evaluating new anticancer regimens. The use of new diagnostic methods, the role of prophylaxis, the most appropriate empirical regimen, the evaluation of new antimicrobial agents, all require careful evaluation for efficacy and safety. Perhaps the greatest dilemma of all is how far results from trials in adults can be extrapolated to paediatric practice.

Cytomegalovirus Infections in Pediatric Liver Transplantation

From 1986 to 1989, 26 consecutive pediatric liver transplant recipients were followed up at The Hospital for Sick Children, Toronto, Canada. The patients were reviewed to assess the incidence of infection with cytomegalovirus, the severity of disease, and the relationship of recipient and donor serostatus to cytomegalovirus disease. Overall, the incidence of infection was 54% (14/26). Over 90% of patients who were seropositive or whose donors were seropositive developed evidence of cytomegalovirus infection after transplantation. Forty-three percent (6/14) of those with cytomegalovirus infections developed severe, fatal cytomegalovirus disease, despite treatment with immunoglobulins and ganciclovir (Syntex Laboratories Inc, Palo Alto, Calif) or foscarnet sodium (Astra, Pharmaceutical Products Inc, Westborough, Mass). Of all posttransplant deaths, two thirds were associated with severe cytomegalovirus infection. Cytomegalovirus-related deaths occurred in three of four seronegative patients with seropositive donors and three of six seropositive patients with seropositive donors. Therefore, a seropositive donor appeared to be a major risk factor for severe cytomegalovirus disease.

Statistical Power and Polyvalent Immunoglobulin

<h3>To the Editor.—</h3> In a report on their randomized trial of the use of polyvalent immunoglobulin (IgG) for prevention of cytomegalovirus infection after renal transplantation,1 Kasiske et al report that incidence rates of cytomegalovirus infection and moderately severe cytomegalovirus infection were not significantly different between the control group (84% and 77%, respectively) and the group treated with intravenous IgG (67% and 53%, respectively). I was not surprised that these decreases of 21% and 31% from baseline were not significant, since the sample size was quite small (15 treated with intravenously administered IgG, 13 controls), but I was surprised by their statement that this study had a power of .86 to detect a (clinically) significant difference in infection incidence and a power of .91 to detect such a difference in moderately severe infection rates. I therefore worked back from their data to calculate what they had considered to be a significant difference in infection

Ganciclovir

Ganciclovir is a nucleoside analogue with antiviral activity in vitro against members of the herpes group and some other DNA viruses. It has demonstrated efficacy against human cytomegalovirus infections and should be considered a first-line therapy in the treatment of life- or sight-threatening cytomegalovirus infection in immunocompromised patients. Clinical efficacy varies with the underlying aetiology of immunocompromise and the site of disease, and prompt diagnosis and early treatment initiation appear to improve the response. In patients with cytomegalovirus pneumonia, particularly bone marrow transplant recipients, concomitant administration of cytomegalovirus immune globulin may significantly improve clinical outcome. Maintenance therapy to prevent recurrence is usually required by bone marrow transplant recipients until the recovery of adequate immune function, whereas AIDS patients may require indefinite ganciclovir maintenance therapy to prevent disease progression, as ganciclovir (like other antivirals) does not eradicate latent viral infection. Haematological effects occur relatively frequently during ganciclovir administration but are usually reversible. Ganciclovir has not been directly compared with other antiviral drugs because of the absence until recently of other effective treatments. However, comparative studies with foscarnet, particularly in cytomegalovirus retinitis, will be of considerable interest. Thus, ganciclovir represents a major advance in the therapy of severe cytomegalovirus infections in immunocompromised patients. Comparative studies, and investigation of ways of reducing toxicity (intravitreal administration; concomitant use of stimulants of haematopoiesis; use in conjunction with other antivirals with differing mechanisms of action), may further expand its eventual role.

Polyvalent Immune Globulin and Cytomegalovirus Infection After Renal Transplantation

To determine whether polyvalent, immune globulin (IgG) prevents cytomegalovirus (CMV) infection after cadaver renal transplantation, 28 patients were randomly allocated to receive 12 weekly infusions of 500 mg/kg of IgG (n = 15) or no treatment (n = 13). Both groups were similar with respect to age, sex, antigen mismatches, number of diabetics, and pretransplant donor/recipient CMV antibody titers. Moderately severe CMV infections occurred in 10 (77%) of 13 control subjects compared with 8 (53%) of 15 IgG-treated patients (not significant). Among those who developed CMV infections, prophylactic IgG had no effect on the severity or duration of fever, leukopenia, or hepatic enzyme elevations. Since none of the IgG-treated patients or control subjects in this study developed life-threatening CMV complications, a beneficial effect of prophylactic IgG in the small number of patients at risk for more severe CMV infections could not be excluded. However, this investigation suggests that the routine, prophylactic administration of polyvalent IgG, to prevent or to ameliorate CMV infection in unselected cadaver renal transplant recipients, is not warranted.

Cytomegalovirus infection in immunocompromised guinea pigs: A model for testing antiviral agents in vivo

An experimental model for testing antiviral agents against severe cytomegalovirus (CMV) infection in immunocompromised hosts was developed. The model consisted of cyclophosphamide (Cy) treatment of CMV-infected guinea pigs to simulate CMV infection in immunodeficient individuals. Of the 3 Cy regimens tested, a single 300 mg/kg dose administered one day after virus inoculation resulted in the most severe CMV infection considering mortality rates, mean day of death and loss of body weight. Evaluation of responses to both T and B cell mitogens suggested that the severe and lethal CMV infection resulted from the combined immunosuppressive effect of Cy and CMV. The nucleoside analog [9-(1-3-dihydroxy-2-propoxymethyl)guanine (DHPG) was used to assess the usefulness of the CMV-infected immunocompromised host model. DHPG (100 mg/kg/day for 8 days) prevented death but did not reduce virus infectivity titers in blood of Cytreated, CMV-infected guinea pigs. This model of CMV infection in immunocompromised guinea pig is a relevant and convenient experimental tool for the assessment of candidate anti-CMV agents under well-defined experimental conditions, such as appropriate CMV inoculum and Cy regimen.

Efficacy of Ganciclovir in Liver and Kidney Transplant Recipients with Severe Cytomegalovirus Infection

Twelve liver and 5 kidney transplant recipients with severe cytomegalovirus infection were treated with Ganciclovir (7.5 mg/kg/day, intravenously). Ten were evaluable (compatible clinical picture, organ involvement shown histopathologically or by culture, viremia, and absence of concomitant infection). All 17 patients were studied for adverse drug side effects. A total of 9 evaluable patients survived the infection; 1 died during treatment due to infection or drug toxicity. A death 19 days after completion of treatment was due to unrelated causes. Patients became afebrile after 2-9 days (mean, 5.3 days) of treatment. Liver function improved, pulmonary infiltrates cleared, and hypoxemia reversed during therapy. Viremia ceased during therapy in 9 patients; asymptomatic viruria persisted or recurred in 6 of 7 patients studied. No relapses occurred during follow-up (7-17 months; mean, 13 months). Transient neutropenia and thrombocytopenia occurred in 3 and 1 patients, respectively. Ganciclovir appears promising for treatment of severe CMV infection in patients with kidney or liver transplants.

Cytomegalovirus infections in heart and heart-lung transplant recipients

Of the first 250 heart and 41 heart-lung transplant recipients in the Papworth series, 244 who survived for longer than one month after transplantation were studied for evidence of cytomegalovirus (CMV) infection by serological methods. Overall, 43 (17.6%) patients acquired primary CMV infection and 76 (31.1%) had evidence of CMV reactivation or reinfection. The source of CMV infection was found to be important. CMV infection was more severe when acquired from the donor organ than from blood or blood products and all seven fatal primary CMV infections were associated with CMV antibody-positive donors. Thus, we now have a CMV matching policy in our unit; whenever possible organs from CMV antibody-positive donors are not given to CMV antibody-negative recipients. Those CMV antibody-positive recipients who received organs from CMV antibody-positive donors had more severe CMV reactivation or reinfection than those who received organs from CMV antibody-negative donors. The severity of CMV disease was found to be dependent on the degree of immunosuppression patients received and heart-lung transplant recipients had more serious CMV infections than heart transplant patients. The severity of CMV infections in heart-lung transplant recipients was modified in the later part of the series by the use of prophylactic anti-CMV hyperimmune globulin and treatment of CMV infection with ganciclovir. While 75% of heart-lung transplant recipients who did not receive this treatment died of primary donor-acquired CMV infection, all three comparable patients given CMV hyperimmune globulin and ganciclovir survived. The outcome of CMV infections in the Papworth heart and heart-lung transplant recipients is compared with that in other comparable transplant centres.