John Zurlo

A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS

OBJECTIVE To evaluate foscarnet sodium in treating cytomegalovirus retinitis in patients with AIDS. PATIENTS Twenty-four previously untreated persons with AIDS and cytomegalovirus retinitis who were at low risk for loss of their visual acuity. INTERVENTION PATIENTS were randomly assigned to receive either no therapy (delayed treatment, control group) or immediate treatment with intravenous foscarnet at a dose of 60 mg/kg body weight three times a day for 3 weeks (induction regimen) followed by a maintenance regimen of 90 mg/kg once a day. MEASUREMENTS PATIENTS were examined weekly until they reached the primary clinical end point, defined as progression of their retinitis border by 750 microns or the development of a new retinal lesion due to cytomegalovirus. Progression was evaluated using retinal photographs by masked readers. Secondary evaluations included changes in visual acuity, cytomegalovirus shedding in the blood and urine, serum levels of human immunodeficiency virus type 1 (HIV-1) p24 antigen, and total CD4 T lymphocyte counts. RESULTS The mean time to progression of retinitis was 3.2 weeks in the control group (n = 11) compared with 13.3 weeks in the treatment group (n = 13) (P less than 0.001). Nine of 13 patients in the treatment group had positive blood cultures for cytomegalovirus at entry and all nine cleared their blood of cytomegalovirus by the end of the induction period (P = 0.004) compared with one of six patients in the control group. No reductions in p24 levels were seen in the control patients compared with a reduction of more than 50% in p24 levels for all four patients on treatment for whom follow-up levels were available. The main adverse effects of foscarnet treatment were seizures (2 of 13 patients), hypomagnesemia (9 of 13), hypocalcemia (11 of 13), and elevations in serum creatinine above 176.8 mumol/L (2.0 mg/dL) (3 of 13). The control patients received an average of 0.2 units of blood per week compared with an average of 0.6 units of blood per week for the patients on treatment. CONCLUSIONS The administration of foscarnet decreases the rate of progression of cytomegalovirus retinitis in persons with AIDS. Its judicious use is likely to prevent loss of vision in these patients. In this study, however, there was little change in visual acuity in patients in either the immediate or delayed treatment group because only patients with non-sight-threatening disease were selected.

Lack of Clinical Utility of Cytomegalovirus Blood and Urine Cultures in Patients with HIV Infection

Abbreviation CMVcytomegalovirus Cytomegalovirus (CMV) is frequently cultured in blood, urine, and throat specimens from patients with the acquired immunodeficiency syndrome (AIDS). Some patients with AIDS who become infected with CMV ultimately develop serious end-organ disease such as retinitis, enteritis, and pneumonitis [1-10]. In other patients, no specific end-organ disease can be documented before death. There is considerable suspicion that CMV infection contributes to the fever, weight loss, malaise, and fatigue that are often characteristic of late-stage infection with human immunodeficiency virus (HIV), but it has been difficult to separate the role of CMV from the potential contributions of other microorganisms present concurrently, such as Mycobacterium avium-intracellulare complex, Epstein-Barr virus, or HIV itself. Even when CMV is detected histopathologically at autopsy, the relative contribution of CMV to organ dysfunction or death is often difficult to determine [11]. Cytomegalovirus end-organ disease (for example, retinitis, pneumonitis, and colitis) appears to occur in patients with very low circulating CD4 lymphocyte counts: In two series of patients with CMV retinitis, all 8 patients in one study and all 24 in the other had counts less than 100/mm3 [12, 13]. Despite these data, however, no systematic study has been done of whether culture positivity is predictive of current or subsequent CMV end-organ disease or whether CMV culture positivity correlates with constitutional symptoms frequently observed in HIV infection. In addition, the precise relation between CMV blood or urine culture positivity and CD4 count has not been well defined. Cytomegalovirus cultures require time and money to obtain and therefore should be done only if they yield useful information. Our objective was to determine if CMV cultures are diagnostically or prognostically useful. Methods A list of HIV-infected patients with their initial CMV blood and urine culture results was compiled from the records of the CMV reference laboratory used by the intramural AIDS program at the National Institutes of Health from 1982 to 1989. Included in this list was a group of patients specifically recruited for enrollment in a protocol for the treatment of CMV retinitis. This study has previously been reported [13]. This list was cross-referenced with another patient database file containing CD4 counts done at the reference immunology laboratory. The CD4 count determination done nearest to the date of the CMV culture result was matched with each patient. Once the list was assembled, individual patient medical records were reviewed and data on the following variables were compiled: age; sex; HIV risk factor; history of interferon, acyclovir, ganciclovir, or foscarnet use before CMV culture; history of recent outpatient fevers or two inpatient temperatures higher than 38 C within 7 days of CMV culture; history of weight loss of at least 5 kg during the preceding 6 months; date of ophthalmologic or pathologic diagnosis of CMV end-organ disease (either before death or at autopsy); and number of months of follow-up since the time of CMV culture. Diagnoses of CMV disease were defined as follows: For retinitis, the diagnosis was based on ophthalmologic examination or findings at autopsy; for all other end-organ CMV disease, diagnosis was based on the presence of one or more inclusion bodies as shown by histopathologic examination. For patients who were found to have CMV end-organ disease, CMV culture results and CD4 count at the time nearest the diagnosis of end-organ disease were recorded and used in a separate analysis. Cytomegalovirus isolation was done in duplicate in MRC-5 cells, a human embryonic lung cell line, as previously described [1]. Cultures were done by one microbiologist. All specimens were delivered to the laboratory by special messenger and were usually processed within 1 hour of delivery. All cultures were obtained before the institution of anti-CMV therapy. Blood Culture Ten mL of heparinized blood was allowed to settle in an upright position for 30 to 60 minutes at room temperature. The leukocyte-rich plasma was collected and centrifuged at 200 G for 10 minutes. The plasma was removed, and the cell pellet was then resuspended in phosphate-buffered saline and the cells were inoculated onto MRC-5 cell monolayers. Urine Culture Five-mL samples were mixed with 5000 units of penicillin, 5000 g of streptomycin, and 125 mg of fungizone before inoculation onto the monolayers. All specimens were allowed to absorb the mixture for at least 1 hour at 36 C, and urine cultures were washed once with phosphate-buffered saline. The cells were maintained in Eagles minimum essential medium with Earles salts, 2% fetal calf serum, 100 units of penicillin, 100 mg of streptomycin, and 2.5 mg of fungizone. Media were changed 24 hours after inoculation and twice weekly thereafter for 5 weeks. Blood and urine specimens were collected at various intervals depending on the protocol. Enumeration of lymphocyte subsets was done on peripheral blood mononuclear cells using fluorescent-activated cell-sorting analysis, after staining with various monoclonal antibodies as previously described [14]. The CD4 lymphocytes were identified phenotypically with OKT4 antibody (Ortho Pharmaceuticals, Raritan, New Jersey). Statistical Analysis Relations among CMV culture results, CD4 counts, and end-organ disease were assessed using the chi-square and contingency analyses. The continuity correction was used for 2 2 contingency tables. Means are expressed SE. Results A CD4 count had been done in 393 HIV-infected patients with at least one CMV blood culture result (most also had a urine culture result from the same day). For 28 patients, medical records were missing or contained incomplete data. Of the remaining 365 patients, 322 patients had a CD4 count determination done within 7 days of the CMV culture. These 322 patients were included in the analysis. The group had a mean age of 36.0 years at the time of CMV culture and included 313 men and 9 women. The HIV risk factor status was assessed as follows: 286 patients (88%) were either homosexual or bisexual, 8 were infected via contaminated blood products, 6 were sexual partners of persons at risk for HIV infection, 4 were intravenous drug users, and 3 were hemophiliacs; the risk factor was uncertain in 15 patients. The mean follow-up for the entire group was 11.8 months (range, 0 to 73 months). The relation between both CMV blood and urine culture positivity and the subsequent diagnosis of CMV end-organ disease for patients with CD4 counts 200 cells/mm3 is shown in Figure 1. For this analysis, we used an inception cohort consisting of patients free of CMV disease at the time of the initial CMV culture. Patients with CMV end-organ disease who were recruited for study on the basis of their CMV disease (retinitis [n = 18]) [13] or whose first CMV culture was obtained after the diagnosis of end-organ disease (n = 6) were excluded. Nine of 26 patients (34.6%) with CMV viremia developed end-organ disease compared with 11 of 74 (14.9%) patients without viremia (difference, 19.7% [95% CI, 0.3% to 39.7%]; P = 0.06). Similarly, 15 of 47 patients (31.9%) with CMV viruria developed end-organ disease compared with 4 of 43 patients (9.3%) without viruria (difference, 22.6% [95% CI, 6.7% to 38.5%]; P = 0.02). For CMV viruria, when end-organ disease was diagnosed within 6 months, the difference between the rates of development of disease was 23.1% (95% CI, 8.8% to 37.3%; P = 0.008) when disease was diagnosed before death, the difference was 16.6% (95% CI, 3.4% to 29.9%; P = 0.04) and when disease was diagnosed within 6 months and before death, the difference was 14.7% (95% CI, 3.0% to 26.3%; P = 0.05). For CMV viremia, the difference in rates when end-organ disease was diagnosed within 6 months was 26.5% (95% CI, 8.1% to 44.9%; P = 0.003); when disease was diagnosed both before death and within 6 months, the difference was 19.0% (95% CI, 2.2% to 35.8%; P = 0.01); when end-organ disease was diagnosed before death alone, the difference was 13.6% (95% CI, 3.8% to 31.1%; P = 0.15). Figure 1. Cytomegalovirus (CMV) end-organ disease according to CMV blood and urine culture results in human immunodeficiency virus-infected patients with CD4 counts 200/mm3 and without baseline CMV end-organ disease. n n n n Cytomegalovirus viremia did not correlate with the presence of either fever or weight loss when patients with CD4 lymphocyte counts 200/mm3 were considered. Ten of 41 patients (24.4%) with CMV viremia had fevers compared with 21 of 83 patients (25.3%) without viremia (P > 0.2). Similarly, 15 of 41 patients (36.5%) with CMV viremia experienced significant weight loss compared with 25 of 83 patients (30.1%) without viremia (P > 0.2). No relations could be determined for antiviral therapy because few patients were receiving acyclovir and no patients were receiving ganciclovir or foscarnet at the time of CMV blood or urine culture. Overall, 51 patients were diagnosed with CMV end-organ disease. Of these patients, 19 with retinitis have been previously described [13]. Data from autopsy studies in the current series have also been reported [11]. Retinitis was diagnosed in 28 patients and was the most common end-organ disease, followed by pneumonitis (n = 14) and colitis (n = 7). Isolated adrenal disease was found in 2 patients at autopsy, and 13 patients overall had multiorgan involvement. Among the subgroup of patients without CMV end-organ disease at baseline (n = 25), pneumonitis later developed in 12, retinitis in 7, and colitis in 4. Two patients had adrenal disease at autopsy, and 11 patients overall had multiorgan involvement at autopsy. Specific end-organ involvement did not differ between patients with CMV viremia and those without viremia. In 29 patients who had documented CMV end-organ disease and a CMV culture that was obtained wi

The roles of social domains, behavioral risk, health care resources, and chlamydia in spatial clusters of US cervical cancer mortality: not all the clusters are the same

BackgroundWhile high-risk geographic clusters of cervical cancer mortality have previously been assessed, factors associated with this geographic patterning have not been well studied. Once these factors are identified, etiologic hypotheses and targeted population-based interventions may be developed and lead to a reduction in geographic disparities in cervical cancer mortality.MethodsThe authors linked multiple data sets at the county level to assess the effects of social domains, behavioral risk factors, local physician and hospital availability, and Chlamydia trachomatis infection on overall spatial clustering and on individual clusters of cervical cancer mortality rates in 2000–2004 among 3,105 US counties in the 48 states and the District of Columbia.ResultsDuring the study period, a total of 19,898 cervical cancer deaths occurred in women aged 20 and older. The distributions of county-level characteristics indicated wide ranges in social domains measured by demographics and socioeconomic status, local health care resources, and the rate of chlamydial infection. We found that overall geographic clustering of increased cervical cancer mortality was related to the high proportion of black population, low socioeconomic status, low Papanicolaou test rate, low health care coverage, and the high chlamydia rate; however, unique characteristics existed for each individual cluster, and the Appalachian cluster was not related to a high proportion of black population or to chlamydia rates.DiscussionThis study indicates that local social domains, behavioral risk, and health care sources are associated with geographic disparities in cervical cancer mortality rates. The association between the chlamydia rate and the cervical cancer mortality rate may be confounded by other factors known to be a risk for cervical cancer mortality, such as the infection with human papillomavirus. The findings will help cancer researchers examine etiologic hypotheses and develop tailored, cluster-specific interventions to reduce cervical cancer disparities.

The intricate relationship of histoplasmosis and sarcoidosis: a case report

IntroductionHistoplasmosis is an endemic mycosis with most cases of clinical illness reported in North and Central America. Rarely, patients develop progressive disseminated histoplasmosis with extrapulmonary manifestations. These infections are fatal if not appropriately treated.Case presentationWe report a case of progressive disseminated histoplasmosis presenting with fever, progressive dyspnea, and pancytopenia in a 51-year-old Caucasian man who had been treated with chronic steroids for a diagnosis of sarcoidosis made 20 years previously. His presentation was initially mistaken for sarcoidosis but, fortunately, laboratory results showed hematologic abnormalities, and the diagnosis of histoplasmosis was made by bone marrow biopsy.ConclusionsSarcoidosis reduces T cell activity, and the addition of steroids for treatment causes further immunosuppression and vulnerability for development of a disseminated infection. The diagnosis of histoplasmosis depends mainly on clinical presentation and host factors. Although there are diagnostic laboratory tests available, clinicians may need to diagnose histoplasmosis by history and physical examination alone and treat empirically, since awaiting Histoplasma-specific laboratory results would delay initiation of treatment. Primary care providers, hospitalists, and subspecialists alike should be aware of the overlap in clinical and radiological presentations of sarcoidosis and histoplasmosis, and when and how to pursue diagnostic testing for endemic mycoses, since these infections can be fatal in immunosuppressed patients without appropriate treatment.

Questioning the clinical significance of upper gastrointestinal cytomegalovirus disease following heart transplantation.

We performed a retrospective review of patients who underwent esophagogastroduodenoscopy after heart transplantation to determine the clinical setting in which upper gastrointestinal cytomegalovirus disease is identified. No gastrointestinal cytomegalovirus disease was found prior to transplant 51 and this period (from transplant 1 to 50) corresponded to a time when significantly fewer esophagogastroduodenoscopies included biopsy. Patients in whom cytomegalovirus was identified were more likely to have been CMV seronegative and to have received a heart from a seropositive donor (60% vs 20%,P=0.029). In addition, patients with cytomegalovirus used aspirin more commonly (90% vs 31%,P=0.001), and underwent esophagogastroduodenoscopy earlier after transplantation (123d vs 652d,P=0.029). We conclude that factors that increase the use of esophagogastroduodenoscopy and biopsy in the early transplant period increase the likelihood of identifying cytomegalovirus in gastrointestinal tissue. However, the clinical course and significance of cytomegalovirus identified in the upper gastrointestinal tract in heart transplant patients may be difficult to discern.

Comparisons of VLP-based ELISA, neutralization assays with native HPV, and neutralization assays with PsV in detecting HPV antibody responses in HIV-infected women.

OBJECTIVE Human papillomavirus (HPV)-associated cancers are important public health problems in HIV-infected people. Assays based on HPV virus-like particles (VLP) and pseudoviruses (PsV) are commonly used to examine HPV antibody responses in HIV-infected people, but neutralization assays with native HPV have not been utilized and a comparison of these three assays is lacking. We evaluated the agreement of assays using VLP, native HPV and PsV in detecting HPV16 and 18 antibodies in HIV-infected women. METHODS The VLP-based ELISA (VLP-ELISA) was used to detect antibody responses to HPV16 and 18 and cottontail rabbit papillomavirus (CRPV) VLP antigens. Neutralization assays with native HPV (NA-HPV) and with PsV (NA-PsV) were conducted to examine HPV16 or 18 neutralizing antibodies. Intra class correlation coefficients (ICC) and kappa coefficients were used to assess the agreements of seropositivity between the assays. RESULTS The seroprevalence detected by the VLP-ELISA, NA-HPV and NA-PsV in 94 HIV-infected women was 35%, 51% and 27% for HPV16 and 14%, 44% and 21% for HPV18. Cross-reactivity between HPV16 and HPV18 was 0.35, 0.04 and 0.33 (kappa coefficients) for the VLP-ELISA, NA-HPV and NA-PsV. The agreements of seropositivity between the three assays were low. Six women who were HPV16 DNA positive were seropositive by the NA-HPV but only two were HPV16 seropositive by the VLP-ELISA or NA-PsV. One HPV18 DNA positive woman was seropositive by all three assays. Repeated tests indicated excellent reproducibility of the NA-HPV. CONCLUSION HPV serology results vary across different assays. The NA-HPV appears to be a sensitive and reliable approach in detecting natural HPV antibodies in HIV-infected women. The NA-HPV can be applied in both HPV natural history studies and vaccine studies in HIV-infected people.

Epstein Barré virus-negative diffuse large B-cell lymphoma in an HIV-infected man with a durable complete remission on highly active antiretroviral therapy alone.

We report a unique case of a human immunodeficiency virus (HIV)-infected man with Epstein-Barré virus (EBV) negative diffuse large B-cell lymphoma (DLBCL) that responded solely to highly active antiretroviral therapy (HAART). Our patient presented with a retroperitoneal mass, high viral load, CD4 288 and began therapy with HAART with marked improvement of symptoms. The patient declined chemotherapy since he felt better after HAART, and rescanning at that time demonstrated marked improvement of the lymphoma on HAART alone. Viral load became undetectable, CD4 450 by 8 weeks. By 6 months, the patient had a complete remission verified by positron emission tomography/computed tomography (PET/CT) and has remained in remission to date on HAART alone. We postulate that HIV infection directly precipitated the lymphoma.

Infectious Diseases Specialty Intervention is Associated with Better Outcomes among Privately Insured Individuals Receiving Outpatient Parenteral Antimicrobial Therapy

BACKGROUND Outpatient parenteral antimicrobial therapy (OPAT) can be managed by specialists in infectious diseases (ID) or by other physicians. Better management of OPAT can reduce the likelihood of readmission or emergency department (ED) use. The relative success of ID specialists and other physicians in managing OPAT has received little study. METHODS We analyzed a national database of insurance claims for privately insured individuals under age 65, locating inpatient acute-care stays in 2013 and 2014 that were followed by OPAT. Through propensity scoring, patients who received outpatient ID intervention (ID-led OPAT) were matched 1-to-1 with those who did not (Other OPAT). We estimated regression models of hospital and ED admissions and of total healthcare payments over the first 30 days after discharge. RESULTS The final analytic sample of 8200 observations was well balanced on clinical and demographic characteristics. Soft-tissue infection and osteomyelitis were the most common infections in the index event, each affecting more than 40% of individuals. Relative to those with Other OPAT, people with ID-led OPAT had lower odds of an ED admission (odds ratio [OR] 0.449, 95% confidence interval [CI] 0.311-0.645) or hospitalization (OR 0.661, 95% CI 0.557-0.791) over 30 days, and they accumulated

644Rising Incidence of Syphilis Among Rural HIV+ Men Despite Systematic, Point of Care Prevention Counseling

1488 less in total healthcare payments (95% CI -2 688.56--266.58). CONCLUSIONS Among privately insured individuals below age 65, ID consultations during OPAT are associated with large and significant reductions in the rates of ED admission and hospital admission in the 30 days after index events, as well as lower total healthcare spending.

Trimethoprim-Sulfamethoxazole Revisited

644. Rising Incidence of Syphilis Among Rural HIV+ Men Despite Systematic, Point of Care Prevention Counseling Poonam Mathur, MD; John Zurlo, MD; Patsi Albright, CRNP, PhD; Tonya Crook, MD; Cynthia Whitener, MD; Ping Du, MD, PhD; Medicine, Hershey Medical Center, Hershey, PA; Medicine/Infectious Diseases, Pennsylvania State University, Milton S. Hershey Medical Center, Hershey, PA; Medicine/Public Health Sciences, Pennsylvania State University, Milton S. Hershey Medical Center, Hershey, PA