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Background Enteroviruses can cause outbreaks of hand-foot-and-mouth disease (characterized by vesicular lesions on the hands, feet, and oral mucosa) or herpangina, usually without life-threatening manifestations. In 1998 an epidemic of enterovirus 71 infection caused hand-foot-and-mouth disease and herpangina in thousands of people in Taiwan, some of whom died. Methods We assessed the epidemiologic aspects of this outbreak. Cases of hand-foot-and-mouth disease or herpangina in ambulatory patients were reported to the Taiwan Department of Health by a mean of 818 sentinel physicians. Severe cases in hospitalized patients were reported by 40 medical centers and regional hospitals. Viruses were isolated by 10 hospital laboratories and the department of health. Results The sentinel physicians reported 129,106 cases of hand-foot-and-mouth disease or herpangina in two waves of the epidemic, which probably represents less than 10 percent of the estimated total number of cases. There were 405 patients with severe ...

Epstein-Barr virus (EBV) plays a major role in the pathogenesis of posttransplant lymphoproliferative disease (PTLD). Patients who undergo primary EBV infection after transplantation are at greater risk of developing PTLD. In this retrospective study, the incidence of EBV infection and associated PTLD in 40 consecutive adult recipients who were seronegative for EBV at the time of liver transplantation were investigated, and risk factors for PTLD were analyzed. Of 37 patients with available timely posttransplant serum samples, 35 (95%) developed primary EBV infection. Of the 40 patients, 13 (33%) developed PTLD a median of 126 days (range, 48-776) after liver transplantation. The factor significantly associated with the development of PTLD was cytomegalovirus disease (relative risk, 7.3; 95% confidence interval, 2.36-22.6; P = .0006). Cytomegalovirus disease is a predictor for the development of PTLD in primary EBV infection after liver transplantation, and it may be a target for prophylactic intervention.

To determine if use of antiherpes drugs protects against the development of AIDS-associated Kaposi's sarcoma (KS), data from 935 homosexual men with AIDS from the Multicenter AIDS Cohort Study were analyzed. In nested case-control analysis, neither acyclovir use for human immunodeficiency virus infection (odds ratio [OR], 0.84 ; 95% confidence interval [CI], 0.56-1.26 ; P =.39) nor acyclovir use for any indication (OR, 1.02 ; 95% CI, 0.76-1.38 ; P =.89) was associated with a reduced risk of KS as initial AIDS diagnosis. In longitudinal analysis, acyclovir was also not protective against developing KS as a late manifestation of AIDS (after initial non-KS AIDS diagnosis). Among men with cytomegalovirus disease, ganciclovir use (relative risk [RR], 0.56 ; 95% CI, 0.22-1.44 ; P =.23) and foscarnet use (RR, 0.40 ; 95% CI, 0.051-3.10 ; P =.38) were associated (although not significantly) with a reduced risk of KS. Thus, acyclovir use does not appear to reduce the risk of KS, but further study of other antiherpes drugs such as ganciclovir and foscarnet is warranted.

While the combination of zidovudine and didanosine is used in HIV-infected patients with more advanced disease, the possibility of a pharmacokinetic interaction between these two drugs remains controversial. Zidovudine doses of 50, 100, and 200 mg, combined with 67, 167, and 250 mg of didanosine were evaluated in 11 asymptomatic HIV-infected patients after receiving 24 weeks of combination therapy in AIDS Clinical Trials Group protocol 143. The pharmacokinetic parameters of zidovudine and didanosine were similar to those obtained with each drug given as monotherapy in other previously published studies. The renal clearance and urinary recovery of glucuronidated zidovudine was reduced when zidovudine was given in combination with didanosine, possibly due to competition for renal tubular secretion. These data suggest that no clinically important pharmacokinetic interaction occurs when zidovudine and didanosine are given together.

To evaluate the safety and efficacy of didanosine (ddl) monotherapy and three different combinations of zidovudine (ZDV) and ddl in asymptomatic human immunodeficiency virus-1 (HIV-1) infection, we conducted an open-label, phase I/II study in 126 asymptomatic HIV-1-infected hemophilic and nonhemophilic subjects with a CD4 count of 200 to 500/mm3 stratified for prior zidovudine treatment and baseline CD4 count. Study arms included arm A, low-dose combination (ZDV 150 mg and ddl 134 mg, daily); arm B, moderate-dose combination (ZDV 300 mg and ddI 334 mg, daily); arm C, high-dose combination (ZDV 600 mg and ddl 500 mg, daily), and arm D, ddl monotherapy (ddl 500 mg, daily). Earlier, more frequent hepatotoxicity was experienced by hemophilic subjects (P = .008), but there were no differences in toxicity between treatment arms (P = .51), nor were there any differences in the rate of development of clinical endpoints by treatment (P = .41). Smaller median CD4 increases occurred over the first 12 weeks for arms A and D, 44/mm3 and 42/mm3, than arms B and C, 105/mm3 and 114/mm3, respectively, (P = .015). Hemophilia status (P = .0004) and prior ZDV experience (P = .044) independently predicted weaker CD4 responses during the first 12 weeks of treatment. Using a regression model and adjusting for hemophilia status, prior ZDV treatment, and baseline CD4, there was a significant reduction in quantitative viral load from baseline by week 12 for all treatment arms combined (P = .0001), with significantly lower median percent reduction for arm A (56.3%) than arms B, C, and D (94.6%, 98.5%, and 91.9%, respectively, P = .015). Although greater hepatoxicity and weaker CD4 responses occur in hemophilic subjects, didanosine monotherapy and combination therapy with zidovudine are safe and effective in asymptomatic HIV-1-infected patients.

Based on preclinical studies showing that CD8+ T lymphocytes of human immunodeficiency syndrome (HIV)-infected subjects have anti-HIV activities, a phase 1 study was undertaken to determine the safety and feasibility of infusing in vitro purified, activated, and expanded CD8+ cells as a therapeutic measure in seven patients with acquired immunodeficiency syndrome (AIDS)-related complex (ARC) or AIDS. Autologous CD8+ cells were first selectively isolated in monoclonal antibody-coated flasks from peripheral blood mononuclear cells recovered by leukapheresis. They were then cultured and expanded with phytohemagglutinin and recombinant interleukin-2 (rIL-2) before infusion. Five cycles of isolations and infusions of increasing numbers of CD8+ T cells were achieved in five of seven subjects. Five cycles could not be completed in two subjects with AIDS whose CD4+ cell counts were < or = 48/microliters. Infusions of CD8+ cells alone were well tolerated. Four patients received rIL-2 by continuous infusion for 5 days with their final cycle of CD8+ cells. All developed reversible adverse effects attributable to rIL-2. After infusion, 111In-labeled CD8+ cells quickly accumulated in the lungs, with less than 10% of the labeled cells remaining in the circulation. After 24 hours, labeled CD8+ cells were reduced in the lungs, but increased and persisted in liver, spleen, and bone marrow. Four of five patients who were treated with multiple infusions of CD8+ cells have improved or remained clinically stable, and the fifth developed Pneumocystis carinii pneumonia but recovered. This study demonstrated that infusion of autologous, in vitro expanded and activated CD8+ cells was feasible and clinically well tolerated in five of seven subjects with advanced HIV infections.

Objective To determine the frequency of Epstein-Barr virus (EBV) oropharyngeal shedding during HIV infection in homosexual men in the Multicenter AIDS Cohort Study. Design The cohort consisted of 210 men who were HIV-seronegative at their baseline study visit, 39 of whom seroconverted to HIV at a later date, and 73 asymptomatic and mildly symptomatic men with HIV infection of indeterminate duration. Methods EBV in throat washings was detected by transformation of newborn cord blood lymphocytes. Results EBV was isolated from 49% (35 out of 71) of the HIV-seropositive and 16% (33 out of 204) of the HIV-seronegative homosexual men tested at their baseline visit. Elevated EBV shedding frequency was noted 6 months before, as well as during the first HIV-seropositive clinic visit, in the men who seroconverted to HIV. Seronegative men who shed EBV at their baseline visit seroconverted to HIV within a shorter period than did non-shedders during 5 years of follow-up. Shedding of EBV was not significantly associated with either abnormal T-cell numbers, clinical symptoms or risk for development of AIDS. Conclusions There is an increased rate of EBV shedding in HIV-seropositive homosexual men that occurs very early in the course of HIV infection.

OBJECTIVE To assess the presence of covert HIV-1 infection. SETTING High-risk seronegative homosexual men from the Pittsburgh portion of the Multicenter AIDS Cohort Study were examined for the presence of HIV-1 infection. PATIENTS, PARTICIPANTS Ten men (group 1) were examined prospectively for the presence of HIV-1 in their freshly-obtained peripheral blood mononuclear cells (PBMC). Furthermore, cryopreserved PBMC from 26 men (group 2) at their first visit (1984-1985) were examined retrospectively for the presence of HIV-1. MAIN OUTCOME MEASURES PBMC samples from groups 1 and 2 were examined for HIV-1 by polymerase chain reaction (PCR) using gag, env and strong-stop (long terminal repeat) specific primers. In addition, fresh PBMC samples from group 1 were examined for HIV-1 by virus culture. RESULTS None of the 10 PBMC samples from group 1 were positive for virus culture and PCR. Only one of the 26 men from group 2 was positive for gag and strong-stop DNA sequences. This PCR-positive, seronegative subject was found to be negative for HIV-1 by PCR at follow-up visits up to 48 months later. None of 15 seronegative, low-risk homosexual men and 12 seronegative heterosexual men were found to be PCR-positive for HIV-1. However, six HIV-1-seropositive men were positive by PCR for gag, env, and strong-stop HIV-1 DNA sequences. CONCLUSIONS These results suggest a low prevalence of covert HIV-1 infection in high-risk seronegative homosexual men in our geographic area.

Although used widely, the effectiveness of zidovudine therapy and primary prophylaxis for Pneumocystis carinii pneumonia (PCP) in HIV-1-infected individuals, has not been assessed in a large cohort. We have done an observational study between October, 1986, and October, 1990, of a cohort of 2145 HIV-1-seropositive men and 371 who seroconverted during the study. A Markov chain transitional analysis was used to examine the effect of zidovudine and PCP prophylaxis on the probability of progression of H IV-1 infection to AIDS (after 6, 12, 18, and 24 months) after follow-up visits categorised into one of six disease states. The six starting states were based on CD4 + lymphocyte counts and the presence of HIV-related symptoms. Use of pre-AIDS zidovudine and PCP prophylaxis was associated with significant reductions in rates of progression to AIDS at 6, 12, 18, and 24 months for participants starting with less than 350 CD4 + lymphocytes/μl. For those starting with 350 or more CD4 + lymphocytes/μl, non-significant protective trends were seen during 12, 18, and 24 month intervals. In multivariate log-linear models virtually all the treatment effect was due to zidovudine. However, after adjusting for the effects of zidovudine, PCP prophylaxis reduced significantly the probability of progression to a first episode of PCP during 6, 12, 18, and 24 month intervals. This study suggests that early primary PCP prophylaxis is effective in preventing first episodes of PCP, and that the efficacy of zidovudine demonstrated in clinical trials can be translated to the population level.

Zidovudine therapy of AIDS patients has been shown to cause only transient improvements in the numbers of circulating CD4+ cells and the in vitro functional activities of cultured lymphocytes. The present studies were undertaken to determine whether prolonged zidovudine therapy enhanced reactivity in two sensitive assays of T-cell function: the ability of phytohemagglutinin (PHA)-stimulated cells to form T-cell colonies and their capacity to express receptors for the growth factor interleukin-2 (IL-2). Treated patients, studied over periods of 20-60 weeks, showed no improvement in colony formation at any time interval, even in plates supplemented with exogenous IL-2. However, mitogen-stimulated T lymphocytes showed a significant increase in the capacity to express IL-2 receptors (CD25). This enhanced expression resulted primarily from activation of the CD8+ cell subset.

Background. The initially tested dose of zidovudine for the treatment of patients with advanced disease caused by the human immunodeficiency virus type 1 (HIV) was 1500 mg. Although this dose is effective, it is associated with substantial toxicity. Methods. To evaluate the efficacy and safety of a reduced dose, we conducted a randomized controlled trial in 524 subjects who had had a first episode of Pneumocystis carinii pneumonia. The subjects were assigned to receive zidovudine in either a dose of 250 mg taken orally every four hours (the standard-treatment group, n = 262) or a dose of 200 mg taken orally every four hours for four weeks and thereafter 100 mg taken every four hours (the low-dose group, n = 262). Results. The median length of follow-up was 25.6 months. At 18 months the estimated survival rates were 52 percent for the standard-treatment group and 63 percent for the low-dose group (P = 0.012 by the log-rank test). At 24 months the estimated survival rates were 27 percent for the st...

The determinants of cytomegalovirus (CMV) infection and disease can now be understood from studies of newborns, recipients of organ or bone marrow transplants, subjects infected with human immunodeficiency virus, and recipients of blood transfusions. CMV is transmitted to the neonate transplacentally, by passage through a contaminated birth canal, or by ingestion of infected breast milk; to the adult by heterosexual and homosexual sex with an infected partner; and to the transplant recipient by infected organs. A major unsolved problem in the study of CMV is the nature of viral latency. Knowledge regarding the requirements for activation of latent infection at the molecular, cellular, or host level is incomplete. Both viral and host factors may contribute to the successful transmission of CMV by latently infected cells in transplanted organs and transfused blood.

Women attending family planning clinics in western Pennsylvania were enrolled into a prospective epidemiologic study of herpes simplex virus (HSV) infection. Detection of antibodies to HSV-1 and HSV-2 was based on an immunodot assay using type-specific glycoproteins gG-1 and gG-2. Serologic and historical data at enrollment were analyzed for 4527 subjects; the seroprevalence of HSV-2 was 21.6%. By multivariate analysis, HSV-2 infection as determined by seroprevalence was significantly and independently associated with age, years of sexual activity, race, one or more episodes of other genital infections, lower annual family income, and multiple sexual partners. The presence of antibody to HSV-1 was associated with a lower frequency of antibody to HSV-2, suggesting that developed immunity to HSV-1 protected against HSV-2 infection. Of 926 participants who had antibody to HSV-2, only 117 (12.6%) reported a history of genital herpes. Hence the vast majority of HSV-2 infections were inapparent. Although seroprevalence of HSV-2 was higher among black (35.4%) than white (18.5%) women, black women appeared to have significantly less symptomatic genital herpes than white women (7.7% vs. 14.7%, P less than .01).

Huang N, Chou Y-J, Chang H-J, Ho M and Morlock L. Antibiotic prescribing by ambulatory care physicians for adults with nasopharyngitis, URIs, and acute bronchitis in Taiwan: a multi-level modeling approach. Family Practice 2005; Pages 1‐8 of 8. Background. Imprudent prescribing of antibiotics in ambulatory care in Asia is of great concern. However, an adequate understanding of factors associated with antibiotic prescribing patterns in Asia has not been achieved. Objective. Our aim was to identify patient and physician characteristics that influence antibiotic prescribing for adults with nasopharyngitis (common colds), upper respiratory tract infections (URIs) or bronchitis in Taiwan. Methods. Generalized Estimating Equations (GEE) were used to analyze all 128 260 episodes of common colds, URIs and bronchitis generated by a random sample of 137 935 adult National Health Insurance (NHI) beneficiaries (� 18 years old) in Taiwan in 2000. Results. Multivariate analysis results revealed substantial variations across different physician groups. Physician age and accreditation level of the physician’s practice setting were the characteristics most associated with prescribing of antibiotics at the initial encounters for these episodes of care. Urban practising physicians (adjusted OR 1.69, 95% CI 1.29‐2.21) and those who were self-dispensing or with on-site pharmacists (adjusted OR 1.32, 95% CI 1.19‐1.46) were also higher prescribers of antibiotics for adults. Other significant physician predictors included physician specialty, patient volume, and ownership of practice setting. Conclusions. Results suggest that both accessibility to updated medical information and economic incentives of the attending physician may shape prescribing of antibiotics in ambulatory care in Taiwan. Interventions should be developed to influence these modifiable factors to reduce antibiotic prescriptions of questionable value.

SummaryBackgroundThere has not been a comprehensive multi-center study investigating the microbial profile of community acquired pneumonia (CAP) in Taiwan.MethodsA prospective study of adult CAP patients requiring hospitalization between December 2001 and April 2002 was carried out in 13 hospitals in Taiwan. Etiology was determined based on laboratory data from blood and sputum cultures plus serology from paired serum and urine antigen detection tests.ResultsEtiology was assigned to 99 (58.9%) of the 168 patients having the most complete data for etiology determination, with mixed infection in 21 (12.5%) patients. More than half (51.8%) of the patients were>60 years and 63.7% of the patients were males. The most common etiologic agent was Streptococcus pneumoniae (40, 23.8%), the majority (60%, 24 cases) of which was detected by positive urine antigen test. Other common agents included Mycoplasma pneumoniae (24, 14.3%), Chlamydia pneumoniae (12, 7.1%), Influenza A virus (11, 6.5%), Klebsiella pneumoniae (8, 4.8%) and Haemophilus influenzae (8, 4.8%). The prevalence of S. pneumoniae and M. pneumoniae was highest in patients>60 years (25/87, 28.7%), and

In the Taiwan Surveillance of Antimicrobial Resistance programme, isolates were collected from 21 hospitals over a 3-month period in 2000 (TSAR II) and rates of resistance in Gram-positive pathogens were determined. Resistance rates were high including oxacillin resistance in Staphylococcus aureus (60%) and coagulase-negative staphylococci (80%), high-level gentamicin resistance (HLGR) in Enterococcus faecalis (60%) and penicillin non-susceptibility in Streptococcus pneumoniae (69%). Oxacillin resistance had increased from 1998 (TSAR I) and may be spreading into outpatient settings. In contrast, less than 2% enterococci were vancomycin-resistant. No linezolid resistance was found in either staphylococci or enterococci.

The Bureau of National Health Insurance (BNHI) of Taiwan issued a new reimbursement regulation effective from 1 February 2001 forbidding the use of antimicrobials in ambulatory patients with upper respiratory infections (URI) without evidence of bacterial infection. We evaluated the effect of this regulation by analysing changes in the types of infections diagnosed and the amount of antibiotics prescribed in 1999, 2000 and 2001. Between 1999 and 2001, antimicrobials for respiratory infections decreased from 18.0 to 9.97 DDD/1000 per day or by 44.6% (P=0.0000+). Antimicrobials for URI decreased from 8.32 in 1999 to 3.28 DDD/1000 per day in 2001 or by 60.6% (P=0.0000+); from 2000 to 2001 the decrease was 55.8%. Reduction of antimicrobials for URI from 1999 to 2001 accounted for 62.8% of the reduction of antimicrobials in respiratory infections or 51.3% of the total reduction of antimicrobials. Reduction in aminopenicillins was responsible for most of the decrease.

Objective:To determine factors that correlate with increased antibiotic use among adult inpatients in Taiwan.Design:Retrospective survey of medical records.Setting:14 acute-care hospitals (8 regional hospitals, 6 medical centers) in Taiwan.Participants:A systematic probability sample from each hospital, totaling 663 adult inpatients who were discharged or had died in early 1999.Measurements:Infectious disease physicians at the 14 hospitals collected data from medical records regarding patient demographics, hospitalization, discharge diagnosis, and antibiotics received.Results:A total of 447 (67%) patients received antibiotics for an overall rate of 813 antibiotic-days (number of days patients received each antibiotic)/1,000 patient-days. Both the proportion of beds in intensive care units ([ICUs] Pearson correlation coefficient [r], 0.67; 95% confidence interval [CI95], 0.36-0.89;Pr,0.66; CI95, 0.20-0.88;P=.01) correlated with the mean patient rate of antibiotic-days/hospital-day (MPAUD). In contrast, we found no correlation between the proportion of patients who received antibiotics and the MPAUD. Using multiple linear regression, medical center status was the only independent predictor for increased MPAUD (regression coefficient [b], 0.15; CI95, 0.05-0.24;PConclusions:Antibiotic use is greater in medical centers than in regional hospitals and appears to be independent of surgical case mix or the proportion of ICU beds. Determination of multiple, independent measures of antibiotic use may be necessary to understand the relation between antibiotic use and resistance in hospitals.

Pereira et al.1 report in this issue of the Journal on the high morbidity associated with the transplantation of organs from 13 cadaver donors who were positive for antibodies against the hepatitis...

Infection with a human herpes virus, particularly cytomegalovirus (CMV), has been hypothesized to be a cofactor in the development of atherosclerosis in humans. We investigated the association of prior CMV infection with the presence of atherosclerosis in the coronary arteries of the native heart of 314 individuals undergoing heart transplantation. Age, male gender, race, tobacco use, and previous general and cardiac surgery were also studied as covariables. Factors associated with the presence of coronary atherosclerosis by univariate analysis were age greater than the median of 48 years (odds ratio [OR] = 5.9, 95% confidence intervals [CI] 3.0-11.6; P0.0001), tobacco use (OR = 3.8, 95% CI 2.1-7.0; P0.005), CMV seropositivity (OR = 3.1, 95% CI 1.8-5.5; P0.001), and male gender (OR = 3.0, 95% CI 1.6-5.4; P0.0005). When patients were divided into quartiles based on age, coronary atherosclerosis was shown to be associated with CMV seropositive status only in the youngest quartile of patients (OR = 3.6, 95% CI 1.4-8.9; P0.01) but not in the older three quartiles of patients (OR = 0.9, 95% CI = 0.3-2.4; P0.5). In multiple logistic regression analyses, CMV seropositivity was not a significant independent variable in the whole group of patients (P = 0.13) but remained a significant variable in the youngest quartile of patients (P = 0.01). However, 43% of these younger patients and 29% of all patients with coronary atherosclerosis were seronegative for CMV.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytomegalovirus disease is an important cause of morbidity following liver transplantation. To date there has not been an effective prophylaxis for CMV disease after liver transplantation. One hundred forty-three patients were randomized to receive either high dose oral acyclovir (800 mg 4 times a day) alone for 3 months after transplantation (acyclovir group) or intravenous ganciclovir (5 mg/kg twice a day) for 14 days followed by high dose oral acyclovir to complete a 3-month regimen (ganciclovir group). Of 139 patients available for evaluation, 43 of 71 (61%) patients from the acyclovir group developed CMV infection compared with 16 of 68 (24%) from the ganciclovir group (relative risk, 3.69; 95% confidence interval, 2.07-6.56; P0.00001). Of those randomized, CMV disease was seen in 20 (28%) of the acyclovir group compared with 6 (9%) of the ganciclovir group (relative risk, 5.11; 95% confidence interval, 2.05-12.75; P = 0.0001). The median time to onset of CMV infection was 45 days in the acyclovir group compared with 78 days in the ganciclovir group (P = 0.004). The median time to onset of CMV disease was 40 days in the acyclovir group compared with 78 days in the ganciclovir patients (P = 0.02). With respect to primary CMV infection, there was no difference in the rates in the 2 groups, but tissue invasive disease and recurrent CMV disease were less frequent in the ganciclovir group. It is concluded that a course of 2 weeks of ganciclovir immediately after transplantation followed by high dose oral acyclovir for 10 weeks is superior to a 12-week course of high dose oral acyclovir alone for prevention of both CMV infection and CMV disease after liver transplantation. However, the lack of significant effect in seronegative recipients who received grafts from seropositive donors suggests that other strategies are needed to prevent CMV infection in this high risk population.

Epstein-Barr virus (EBV) is associated with the development of several B cell malignancies including Burkitt's lymphoma (BL), post-transplant lymphoproliferative disease (PTLD), and AIDS-related lymphomas. The latter two diseases result from EBV-driven B cell proliferation in the absence of normal immunosurveillance and as such, represent a heterogenous family of lymphoproliferative disorders. This article reviews studies on EBV gene expression and antibody development in PTLD and introduces recent information on the levels of EBV+ peripheral blood lymphocytes to discuss possible mechanisms of pathogenesis under varying conditions of immunosuppression.

To examine the effect of acyclovir use on disease progression and survival in human immunodeficiency virus (HIV)-seropositive persons treated with zidovudine.Four university-based or -affiliated clinics.Prospective cohort study of homosexual and bisexual men with semi-annual follow-up. Intent-to-treat Cox models were fit to determine the relation between the use of acyclovir (modeled as a time-dependent covariate) and disease progression, controlling for baseline and time-dependent clinical and laboratory prognostic variables. The acquired immunodeficiency syndrome (AIDS)-free duration and survival time were calculated from the first use of zidovudine. Analysis included study visits 7 to 17 (from 1987 to 1992).786 HIV-seropositive participants in the Multicenter AIDS Cohort Study who began zidovudine therapy before a clinical diagnosis of AIDS; of these, 515 subsequently received acyclovir. Participants were asked at each visit whether they had "used any medication for health reasons not related to AIDS or if they had taken any medication to help fight AIDS or the HIV virus"; 488 patients indicated acyclovir use under either or both questions, and 242 patients indicated only the latter use.The use of acyclovir for any indication was not associated with an effect on progression to AIDS but was associated with a 26% decrease in the risk for death (relative hazard, 0.74; P = 0.07). The use of acyclovir for HIV infection was also not associated with an effect on progression to AIDS but was associated with a 36% decrease in the risk for death (relative hazard, 0.64; P = 0.01). To further investigate these findings, we examined dose, constancy, and timing of acyclovir use. The median daily dose of acyclovir used for HIV infection was between 600 and 800 mg. No apparent dose effect on survival was found. Longer uninterrupted use of acyclovir for any indication was associated with an 18% decrease in the risk for death for three or more consecutive visits (relative hazard, 0.82; P = 0.23), a 28% decrease for four or more consecutive visits (relative hazard, 0.72; P = 0.09), and a 7% decrease per visit based on the cumulative number of visits while the patient received acyclovir (relative hazard, 0.93 per visit increase; P = 0.03). Use of acyclovir for any indication and use of acyclovir for HIV infection were each associated with a 44% decreased probability of death if the drug was used after AIDS developed (P = 0.007 and P = 0.005, respectively) but not before. To further investigate the prolongation of survival, two landmark analyses were done. The first analysis began at a landmark of 1 year after initiation of zidovudine therapy and compared three groups of patients: those who used acyclovir at or before this landmark, those who had never started acyclovir or started the drug after the landmark, and those who had never used acyclovir. The 90% survival times were 1325, 1059, and 982 days, respectively. The second analysis began at a landmark of developing either a CD4 count less than 50 cells/microL or clinical AIDS. The 90% survival times for the three groups were 398, 261, and 176 days, respectively.Our analysis suggests that consistent use of acyclovir at a dose sufficient to suppress herpetic recurrences (that is, 600 to 800 mg/d) has a clinically significant effect on prolonging survival in a well-characterized cohort with extensive previous exposure to herpesvirus infections. Further clinical investigation of low-dose acyclovir with concomitant antiretroviral therapy is warranted.

Objective A Phase I study of subcutaneous recombinant interleukin-2 (rlL-2). Design Sixteen patients with advanced HIV infection receiving 600–1200mg zidovudine per day were divided into three groups, which received sequentially 0.2 x106, 0.7x106 or 2x106 units/m2 per day of rlL-2 subcutaneously for 5 consecutive days. Setting Five-day admission to an academic tertiary care hospital. Patients, participants Sixteen unblinded, non-randomized volunteers. Interventions Subcutaneous rlL-2. Main outcome measures Tolerance, toxicity, hematologic, immunologic and antiviral responses. Results rlL-2 was well-tolerated at the highest dosage, except in two patients who developed significant lymphopenia by the second day of rlL-2 administration, with rebound within 48 h after rlL-2 therapy. The number of eosinophils, CD4+ and CD8+ cells, and percentage of CD16+ (natural killer) cells, remained elevated above baseline for up to 10 weeks. Circulating rlL-2 receptor levels increased transiently during and immediately following rlL-2 administration. A twofold increase in natural killer cell activity against uninfected and HIV-infected targets was observed, but did not persist beyond 10 weeks following rlL-2 administration. There was a transient decrease in blastogenesis to phytohemagglutinin of patients receiving the highest dose of r-IL-2, but no significant change in viral burden. Conclusions Subcutaneous rlL-2 in advanced HIV-infected patients on zidovudine was tolerated with side-effects similar to intravenous IL-2.

The influence of blood transfusion, and particularly the transfusion of blood from cytomegalovirus (CMV)-seropositive donors, on the incidence of primary CMV infection following liver transplantation was studied prospectively in 29 consecutive CMV-seronegative adult liver transplant recipients. Fourteen patients received a liver graft from a CMV- seropositive donor (Group A), whereas for 15 patients, the donor was CMV seronegative (Group B). Eleven patients (79%) in Group A but only two (13%) in Group B developed CMV infection (odds ratio, 23.8; 95% confidence interval, 3.5–169.4). In five Group A patients, primary CMV infection resulted in pneumonitis. There was no statistical difference in the total number of blood units and the number of units of CMV- seropositive blood given to patients who did or did not develop CMV infection in both Groups A and B (odds ratio for unit of CMV- seropositive blood transfused, 1.07; 95% confidence interval, 0.96- 1.19). However, Group A patients who developed CMV pneumonitis received a higher total number of blood units (median, 44) and of CMV- seropositive blood units (median, 18) than did patients who developed other CMV infections (asymptomatic CMV, CMV syndrome, or CMV hepatitis), who received a median of 9 total units of blood and 5 units of CMV-seropositive blood (p = 0.004). It is concluded that the total number of blood units and of CMV-seropositive blood units transfused does not have an effect on the incidence of primary CMV infection after liver transplantation, but it does have an impact on the severity of the infection in recipients of a CMV-seropositive allograft.

Data were collected from 1614 homosexual and bisexual men in 1984 through 1985 and from 1988 to 1992 in Pittsburgh. Of the men entering the study since 1988, 16% reported engaging in unprotected anal receptive intercourse with more than one partner during the 6 months before their visit. Approximately 7% of the younger men and 18% of the men over 22 years of age in the recent cohort were already infected with the human immunodeficiency virus, the same rates as those described 8 years ago. Aggressive risk-reduction programs are needed in high schools and existing networks in the gay community.

Many risk factors, especially immunosuppression, lead to infections after transplantation. Laboratory evaluation often begins before transplantation and needs to be conducted in consideration of other clinical data. With the advent of antivirals, virus diagnosis, particularly of the herpesviruses group including cytomegalovirus, has become a critical part of the care of the posttransplant patient.

Twelve patients developed herpes simplex (HSV) hepatitis a median of 18 days after solid organ transplantation. This is earlier than cytomegalovirus hepatitis, which usually occurs 30-40 days after transplantation. Eight recipients (67%) died, and in seven, the diagnosis was made at autopsy or less than 48 h before death. Clinical manifestations associated with mortality were hypotension, disseminated intravascular coagulation (DIC), metabolic acidosis, gastrointestinal bleeding, and bacteremia. Laboratory abnormalities at diagnosis associated with mortality were high creatinine, low platelet counts, prolonged partial thromboplastin time, and a high percentage of band forms on the blood smear. Disseminated HSV disease was noted in four of six patients who had an autopsy and included involvement of lungs in three and the gastrointestinal tract in three. Five recipients developed DIC and all died. Pathologically, HSV hepatitis has two forms, focal and diffuse. All three patients with diffuse liver pathology died. However, three of seven with focal liver pathology survived with antiviral therapy, which suggests that early diagnosis and treatment may be lifesaving. None of these patients had received prophylactic acyclovir. It is possible that acyclovir prophylaxis may be able to prevent this disease.

The early history of cytomegalovirus (CMV) may be divided into two periods. During the first period, the characteristic cytopathology caused by this virus was recognized and described. It may be called the “period of cytopathology.” The second period was initiated by the isolation of the virus and may be called the “virological period.” Both periods were essential for the elucidation of the expanding spectrum of diseases associated with CMV.

In this chapter we consider the various serologic tests that have been described for the diagnosis of CMV infection. The principles and background of each test are presented along with its utility. The technical details of each procedure are not described, as they have been admirably updated elsewhere (Lennette and Schmidt, 1979; Schmidt and Emmons, 1989). Tests for cellular immunity against CMV and their changes during and after various infections are described in Chapter 7.

Epstein-Barr virus [EBV] is the etiological agent of infectious mononucleosis and is strongly associated with Burkitt’s lymphoma and nasopharyngeal carcinoma (1,2,3). EBV has been implicated in the pathogenesis of post-transplant lymphoproliferative disorders [PTLD], defined as a series of disorders which vary from a severe mononucleosis-like syndrome to B cell lymphoma (4,5,6). From 1981 through 1989, 106 of 3900 [2.9%] pediatric and adult solid organ transplant recipients at the University of Pittsburgh health center developed PTLD. 50% of the patients who developed PTLD were EBV seronegative prior to transplantation and underwent primary EBV infection. Since patients undergoing primary EBV infections within the first 3 to 4 months after transplantation are at greatest risk for the development of PTLD (7,8), virus-host interactions during immunosuppression clearly play a critical role. Our studies have focused on viral factors in the pathogenesis of PTLD, including studies on viral transmission during transplantation and viral gene expression in the PTLD lesions.

Acquired cytomegalovirus infection may be asymptomatic or produce a mononucleosis syndrome. Complications of the latter include pneumonitis, hepatitis, or involvement of the nervous system.

In this issue of the Journal, Regamey et al.1 provide evidence that human herpesvirus 8 (HHV-8) can be transmitted through a kidney transplant. Physicians must be ever aware of new hazards of trans...

Background: We conducted a trial to compare treatment with zidovudine or didanosine in patients with advanced human immunodeficiency virus type 1 (HIV-1) infection who had received little or no previous therapy with zidovudine. Methods: Six hundred seventeen patients with acquired immunodeficiency syndrome (AIDS), advanced AIDS-related complex (CD4 cell count, ≤0.30× 10 9 /L [300/μL]), or asymptomatic HIV (CD4 cell count, ≤0.20× 10 9 /L) received zidovudine, 500 mg/d of didanosine, or 750 mg/d of didanosine in a randomized, double-blind allocation, with cross-over to alternative medication after development of an end point or serious toxic effect. To be eligible, patients must have received either no or up to 16 weeks of zidovudine therapy before entry into the study. Primary end points were development of a new AIDS-defining event or death. Secondary clinical end points were new or recurrent AIDS-defining events, or death, and survival. Results: In the study as a whole, there were no differences in the relative risks (RRs) of the development of end points between treatment groups. However, there was a strong interaction between the relative efficacies of zidovudine and didanosine and previous experience with zidovudine. Among 380 patients with no previous zidovudine therapy, zidovudine was more effective than 750 mg/d of didanosine (RR, 1.43; 90% confidence interval [CI], 1.02 to 2.00), with a similar trend for zidovudine compared with 500 mg/d of didanosine (RR, 1.21; 90% CI, 0.86 to 1.71). However, among 118 patients with more than 8 weeks but no more than 16 weeks of previous zidovudine therapy, 500 mg/d of didanosine was more effective than zidovudine (RR, 0.48; 90% CI, 0.27 to 0.86); there was a similar trend for increased effectiveness of 750 mg/d of didanosine compared with zidovudine (RR, 0.61; 90% CI, 0.36 to 1.03). Among 119 patients who had some but no more than 8 weeks of previous zidovudine therapy, there were no significant differences among the treatment arms. Similar findings were noted in the analysis of the two secondary clinical end points. No significant differences were found in efficacy between the groups receiving 500 and 750 mg/d of didanosine. The major toxic effect associated with zidovudine was hematopoietic (granulocytopenia) and that associated with didanosine was pancreatitis (dosage, 750 mg/d). Conclusions: In patients with advanced HIV disease, zidovudine appears to be more effective than didanosine as initial therapy; however, some patients with advanced HIV disease may benefit from a change to didanosine therapy after as little as 8 to 16 weeks of therapy with zidovudine. (Arch Intern Med. 1995;155:961-974)

Objective. —To identify clinical and epidemiological factors associated with failure of Pneumocystis carinii pneumonia (PCP) prophylaxis in those receiving primary and secondary prophylaxis. Design. —Longitudinal cohort study of participants infected with human immunodeficiency virus type 1 in the Multicenter AIDS Cohort Study who used PCP prophylaxis regimens after their T-helper lymphocyte counts had decreased to less than 0.200×10 9 /L (200/μL). Main Outcome Measure. —Occurrence or recurrence of PCP. Results. —A total of 476 participants reported taking one or more of the following regimens: trimethoprim-sulfamethoxazole (TMP-SMX), dapsone, and/or aerosolized pentamidine—367 as primary prophylaxis and 109 as secondary prophylaxis after a previous episode of PCP. A total of 92 (20%) developed PCP despite prophylaxis. The mean failure rates per person-year of follow-up were 16.0% for those receiving primary prophylaxis and 12.1% for those receiving secondary prophylaxis ( P =.19). Median times to death after initiation of primary or secondary prophylaxis were 2.0 and 1.2 years, respectively. The main predictor for failure of PCP prophylaxis was profound T-helper lymphocytopenia; 86% of failures occurred after T-helper cell counts decreased to less than 0.075×10 9 /L and 76% occurred after counts decreased to less than 0.050×10 9 /L. In multivariate time-dependent analysis, when compared with counts between 0.100×10 9 /L and 0.200×100 9 /L, the risk ratio for failure with counts less than 0.050×10 9 /L was 2.90 ( P P =.01). Use of TMP-SMX as the prophylaxis regimen was protective but did not eliminate failure (ie, a time-dependent risk ratio of 0.55; P =.03). Conclusions. —These findings strongly support identifying improved methods of PCP prophylaxis once T-helper cell counts decrease to less than 0.075×10 9 /L or 0.100×10 9 /L. Given this severe degree of immunosuppression, an inherently more effective regimen against P carinii is required. ( JAMA . 1995;273:1197-1202)

In Reply.— We share Dr Harder's general concern about the loss of objectivity in scientific research. However, we firmly believe this concern is not applicable to the public health conclusions drawn in our article. Our article concludes, in essence, that the sexual transmission efficiency of hepatitis B virus (HBV) is 8.6-fold that for human immunodeficiency virus among homosexual men studied and that insertive anal intercourse was the major risk factor identified for HBV seroconversion. Our suggestions for HBV prevention among homosexual men, as stated in our article, include both immunization and use of condoms during sexual intercourse. Dr Harder has taken issue with our statement that condoms used during homosexual anal intercourse would be of benefit for prevention of HBV infection because we did not specifically test this hypothesis. His suggested conclusion is for the proscription of all anal intercourse. Since unprotected heterosexual vaginal intercourse is a well-known risk

The relative sexual transmission efficiency of hepatitis B virus (HBV) and human immunodeficiency virus type 1 (HIV-1) was investigated by a prospective study of homosexual men in Pittsburgh, Pa, from the Multicenter AIDS Cohort Study. During the 30-month follow-up, 19.8% and 7.8% of the initially seronegative HBV and HIV-1 groups were estimated to seroconvert to HBV and HIV-1, respectively. The significantly higher cumulative HBV seroconversion rate occurred despite a much lower prevalence of hepatitis B carriers (7% were hepatitis B surface antigen positive) compared with HIV-1 carriers (22% were HIV-1 antibody positive). The sexual exposure profile of HBV and HIV-1 seroconverters was similar during the 6 months prior to seroconversion, supporting the link between anal intercourse and acquisition of either infection. However, insertive, not receptive, anal intercourse was the major risk factor identified for HBV seroconversion, suggesting that transurethral exposure is an important mode of transmission. These data suggest that HBV is transmitted 8.6-fold more efficiently than HIV-1 among homosexual men studied and underscore the benefits of both HBV immunization and use of condoms during intercourse to prevent HBV infection.

We studied infections in 101 consecutive patients who underwent liver transplantation between July 1984 and September 1985. The mean length of follow-up was 394 days. Eighty-three percent of population had 1 or more episodes of infection and 67% of the population had severe infections. The overall mortality was 26/101 (26%) and 23 of 26 deaths (88%) were associated with infection. Seventy percent of severe infections occurred in the first 2 months after transplantation. The most frequent severe infections were abdominal abscess, bacterial pneumonia, invasive candidiasis, Pneumocystis pneumonia, and symptomatic cytomegalovirus infection. Patients with more than 12 hours of cumulative surgical time had a higher rate of severe infections (P less than 0.001), particularly fungal (P less than 0.001) and bacterial (P less than 0.01) infections. Also, the use of choledocho-jejunostomy was associated with a higher rate of infection in patients who had more than 1 transplant operation (P less than 0.02). No increase in infection was found in patients who received azathioprine, or more than the median number of steroid boluses or "recycles"; but patients who received OKT3 therapy had a higher rate of protozoal infections (P less than 0.05). A result similar to that of our previous studies was a strong relation between the number of severe fungal infections and prolonged courses of antibiotics after transplant operation (P less than 0.001). Pretransplant manifestations of severe liver disease such as ascites, encephalopathy, and gastrointestinal bleeding were not associated with higher rates of infection after transplantation, but high serum levels of ALT were. Patients with lower ratios of T-helper to T-suppressor lymphocytes had more severe viral (P less than 0.02) and fungal (P less than 0.01) infections after transplantation.

To better define the frequency and clinical characteristics of herpes simplex virus (HSV) infection in adult patients with acute myelogenous leukemia (AML), the authors prospectively studied 29 patients undergoing remission induction chemotherapy with twice weekly throat wash cultures for an average of 25.3 days. Ten seropositive patients (34.5%) shed HSV at least once. Eight patients were asymptomatic. Two episodes of herpes labialis were severe and persistent, but no visceral dissemination was observed. Reactivation of HSV infections in AML patients presumably with marked immunosuppression occurs, but less frequently and more benignly than has been suggested. Daunomycin and cytosine arabinoside, which can inhibit HSV replication, may have accounted for this lower frequency of reactivation.

Infectious episodes were analyzed in 14 heart-lung transplant recipients who survived more than one week after transplantation. These patients had higher rates of infection than heart transplant recipients at our institution (P less than 0.01) and greater than 90% of all infections were potentially life-threatening. A total of 67% of all infections involved the lung or thoracic cavity as a primary site, and most of the rest were disseminated viral or fungal infections. Pneumocystis carinii infections occurred in six patients and were more common in this group than in patients who received heart transplants in the same period (P less than 0.005). Two patients followed more than one year developed a syndrome of chronic sputum production and bronchial colonization with Pseudomonas aeruginosa, which required recurrent treatment with i.v. antibiotics for symptomatic relief. The high rate of pulmonary infections in these patients presents a challenge to clinical management, and suggests that intensive and invasive monitoring for pulmonary infection is desirable.

We performed a retrospective serologic survey of 583 organ donors and 1043 transplant recipients for antibodies to human immunodeficiency virus type 1 (HIV-1). Two (0.34%) of the 583 donors and 18 (1.7%) of the 1043 recipients had HIV-1 antibodies by enzyme immunoassay and by Western blot. Two of 5 seropositive recipients tested also had blood cultures positive for HIV-1. Seven (0.7%) of the 1043 transplant recipients had antibodies to HIV-1 before transplantation; 2 of these had hemophilia A, and 5 had previous transfusions. Eleven (1.3%) of 860 recipients followed for 45 days or more seroconverted to HIV-1 a mean of 96 days after transplantation. Likely sources of HIV-1 infection for 3 of these 11 recipients included a seropositive organ donor in 1 patient and high-risk blood donors in 2 patients. A definite source of HIV-1 infection was not found for the other 8 recipients, 3 of whom seroconverted to HIV-1 after institution of blood donor screening for HIV-1 antibodies. Seroconversion to HIV-1 was less common in kidney recipients than in liver, heart, or multiple-organ recipients (P less than 0.02). Nine (50%) of the 18 HIV-1 seropositive transplant recipients died a mean of 6 months after transplant surgery, and 9 (50%) are still alive a mean of 43 months after transplantation. AIDS-like illnesses occurred in 3 of the dead and 1 of the living patients and included pneumocystis pneumonia (3 cases), miliary tuberculosis (1 case), and recurrent cytomegalovirus infection (1 case). These data suggest that the course of HIV-1 infection is not more severe in transplant recipients receiving cyclosporine than in other hosts and that, despite screening of blood and organ donors, a small number of transplant recipients will become infected with HIV-1.

The differential diagnosis of liver dysfunction after orthotopic liver transplantation can be difficult. Cytomegalovirus (CMV) hepatitis is one possibility. This report reviews our experience with 17 cases of pathologically proven CMV hepatitis following liver transplantation and demonstrates the need for percutaneous liver biopsies to establish the diagnosis. There were seven pediatric patients (ages 2–11 years, five males, two females) and ten adult patients (ages 17–53 years, eight males, two females). The most common symptoms were prolonged fever (15 patients, with a mean duration of 22 ± 5.5 days), elevation in total bilirubin (14 patients), and elevation in liver enzymes (15 patients); all symptoms were also found in rejection. Leukopenia and thrombocytopenia, reported to frequently occur with CMV infection, were found in only three and five patients, respectively. Twelve patients with the above symptoms underwent percutaneous biopsy on one or more occasions to differentiate CMV hepatitis from rejection. The diagnosis was made at retransplantation in five patients. CMV hepatitis followed treatment for acute rejection in 14 patients and occurred without additional immunosuppression in three patients. All patients were maintained on cyclosporine and prednisone. Acute rejection episodes were treated with a 5‐day tapering dose of steroids (17 courses in 12 patients), OKT3 monoclonal antibody [Ortho (4 patients)] antithymocyte globulin [Upjohn (2 patients)], and azathioprine (1 patient). CMV was isolated from urine (nine patients), blood (nine patients), throat (seven patients), lungs (two patients), and other organs (two patients). CMV was cultured from the liver biopsy specimens in five of the seven attempts in pediatric patients. When the diangosis was confirmed in the absence of rejection, immunosuppression was routinely lowered. When rejection occurred concomitantly with CMV hepatitis, therapy had to be individualized. Retrospectively, three patients treated for rejection were noted at retransplantation to have only CMV hepatitis, and all three paients died. A high index of suspicion and the judicioususe of liver bopsies is essential in order to differentiate CMV hepatitis from other causes of posttransplant liver dysfunction. Copyright © 1988 Wiley‐Liss, Inc., A Wiley Company