Conjunctivitis in dupilumab clinical trials.

BACKGROUND: Dupilumab blocks the shared receptor component for interleukin (IL)-4 and IL-13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate-to-severe atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate-to-severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate-to-severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo. OBJECTIVES: To characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials. METHODS: We evaluated randomized placebo-controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47). RESULTS: In most AD trials, dupilumab-treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis. CONCLUSIONS: Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab-treated patients require further study. What's already known about this topic? Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD). In most dupilumab AD trials, dupilumab-treated patients had higher conjunctivitis incidence than those receiving placebo. Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare. Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis. What does this study add? This analysis confirms and extends the results of the individual clinical trials. Baseline disease-related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation-regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis. Patients who responded well to dupilumab had reduced incidence of conjunctivitis. Further study is needed to elucidate the aetiology and treatment of conjunctivitis in dupilumab-treated patients with AD.

Anti-self HLA may be clonally expressed.

A monolayer absorption technique was used to test the hypothesis that killer cells directed to self HLA-associated minor histocompatibility antigens (H-Y) were divisible into subsets. The results showed that sensitized killer cells, which recognized two combined antigens HLA-A2; H-Y and HLA-B7; H-Y could indeed be divided into two populations. One was directed to HLA-A2; H-Y and the other to HLA-B7; H-Y. These results can be interpreted in the context of the altered self hypothesis. However, when interpreted in the context of the dual recognition hypothesis, they strongly suggest that independant clones of killer T cells exist which are committed to the recognition of self HLA.

Viral infection-homograft interactions in a murine model.

The effects on some host defenses of murine cytomegalovirus (MCMV) and(or) EL(4), a mouse ascites homograft, were studied in mice. Assays of cellular and humoral immunity in response to either or both of these perturbations were carried out by quantitation of various immune activities.Limited studies demonstrated no effect of EL(4) inoculation on the host response to MCMV by organ viral titer, duration of viral persistence, or anti MCMV complement-fixing antibody titer. Prior infection with MCMV, however, resulted in greatly reduced numbers of splenocytes, the source in this study of immune effector cells. Residual splenocytes demonstrated less response to both phyto-hemagglutinin and lipopolysaccharide, particularly in the 2-3-wk interval after infection. Similarly, responder cells in mixed lymphocyte cultures were less reactive when derived from infected animals. Lymphocyte-mediated cytolysis of EL(4) was significantly less in mice infected on the day of and 7, 14, and 21 days before the tumor homograft with a return to control levels by 28 days. 90% of the cell-mediated cytolysis could be eliminated by treatment with anti-theta serum. Serum-mediated cytolysis of EL(4) was also reduced in infected animals. No suppressor cells or serum inhibitory factors could be identified in infected animals. Although alternative explanations exist, this study suggests that in infected animals there is a significant reduction in both the number and function of bone marrow-derived and thymus-derived cells directed against the alloantigens in EL(4).

Gross synovial fluid analysis in the differential diagnosis of joint effusion.

AIMS: To develop an objective and easy to complete standardised questionnaire for documentation of synovial fluid (SF) gross appearance and use it in the assessment of patients presenting to the rheumatology service with a joint effusion. METHODS: A standardised questionnaire to record the gross appearance of SF was developed. Interobserver error in recorded observations and direct gross analysis of synovial fluid between four observers was calculated in a pilot study. In a prospective study over 8 months, SF gross analysis and cell count were documented in all patients presenting with a joint effusion. Fusch Rosenthal manual counting chamber was used for calculating SF cell counts. RESULTS: There was good interobserver agreement on direct gross analysis and between questionnaire assessors (mean kappa 0.889). 80 SF samples were collected. Gross analysis was performed in all samples and cell count in 72. Of the specimens thought to be inflammatory on gross analysis, 31% were found to be non-inflammatory based on cell count; however, 12 of these patients had an established inflammatory arthritis. Gross analysis had a sensitivity of 94% and specificity of 58% when used to determine whether SF is inflammatory or non-inflammatory. The positive and negative predictive values were 0.69 and 0.91 respectively. CONCLUSIONS: SF cell count did not add any information when SF gross analysis suggested a non-inflammatory process. Gross analysis was better than cell count to determine a potentially septic joint fluid. Further work needs to be done on the value of SF cell counts if gross analysis suggests the fluid to be inflammatory.

Withholding medical treatment from the severely demented patient. Decisional processes and cost implications.

We performed an observational study to determine the prevalence of severe dementia in a general medicine unit, the categories of acute medical care provided to these patients, the process by which treatment decisions are made, and their cost implications. The prevalence of severe dementia was 4.4%. The patients from whom some form of acute medical care was withheld (26 [45.6%] of 57) were more severely ill at admission and had a mortality rate five times higher than those who received full care. Physicians cited family wishes in 75.9% of the decisions to limit care but in only 10.9% of the decisions to give full care. The only differences in charges incurred were due to differential mortality rates in individuals from whom care was withheld. We recommend that hospitals develop and implement protocols for decision making in the care of the severely demented to promote open discussions among providers and families and to increase family contributions to decision making. We believe that the extension of this consultative approach to decisions involving severely demented patients may have the virtue of combining more humane care with more cost-effective care.

Fungal infection following renal transplantation.

Twenty-seven deep fungal infections developed in 22 of 171 patients following renal transplantation. These infections included cryptococcosis (ten), nocardiosis (seven), candidiasis (four), aspergillosis (two), phycomycosis (two), chromomycosis (one), and subcutaneous infection with Phialophora gougeroti (one). Twelve infections occurred in living-related and ten in cadaveric recipients. Nineteen of the 22 patients were male. Infections occurred from 0 to 61 months after transplantation. Complicating non-fungal infections were present concomitantly in 15 patients. Thirteen patients died, eight probably as a result of fungal infection. Appropriate diagnostic procedures yielded a diagnosis in 20 of 27 infections, and therapy was begun in 18 patients. Serologic, culture, and biopsy procedures useful in making rapid diagnoses are advocated in the hope of increasing survival.

Dynamic contrast-enhanced perfusion processing for neuroradiologists: model-dependent analysis may not be necessary for determining recurrent high-grade glioma versus treatment effect.

BACKGROUND AND PURPOSE: Dynamic contrast-enhanced perfusion MR imaging has proved useful in determining whether a contrast-enhancing lesion is secondary to recurrent glial tumor or is treatment-related. In this article, we explore the best method for dynamic contrast-enhanced data analysis. MATERIALS AND METHODS: We retrospectively reviewed 24 patients who met the following conditions: 1) had at least an initial treatment of a glioma, 2) underwent a half-dose contrast agent (0.05-mmol/kg) diagnostic-quality dynamic contrast-enhanced perfusion study for an enhancing lesion, and 3) had a diagnosis by pathology within 30 days of imaging. The dynamic contrast-enhanced data were processed by using model-dependent analysis (nordicICE) using a 2-compartment model and model-independent signal intensity with time. Multiple methods of determining the vascular input function and numerous perfusion parameters were tested in comparison with a pathologic diagnosis. RESULTS: The best accuracy (88%) with good correlation compared with pathology (P = .005) was obtained by using a novel, model-independent signal-intensity measurement derived from a brief integration beginning after the initial washout and by using the vascular input function from the superior sagittal sinus for normalization. Modeled parameters, such as mean endothelial transfer constant > 0.05 minutes(-1), correlated (P = .002) but did not reach a diagnostic accuracy equivalent to the model-independent parameter. CONCLUSIONS: A novel model-independent dynamic contrast-enhanced analysis method showed diagnostic equivalency to more complex model-dependent methods. Having a brief integration after the first pass of contrast may diminish the effects of partial volume macroscopic vessels and slow progressive enhancement characteristic of necrosis. The simple modeling is technique- and observer-dependent but is less time-consuming.

Quality assessment and improvement in group psychotherapy.

OBJECTIVE: The authors sought a practical means of monitoring and evaluating group psychotherapy, using existing clinical resources, for purposes of quality improvement and education on a large general hospital psychiatric service. METHOD: Monitoring indicators were developed which addressed 1) the integration of group psychotherapy into treatment planning and 2) the competence and technique of group psychotherapists. The second indicator was assessed by skilled observers using a newly constructed Group Psychotherapy Rating Scale in direct observation of group psychotherapy sessions. The rating scale was examined for interrater reliability and, as a measure of construct validity, for its ability to distinguish the performance of professional staff therapists from that of trainees. RESULTS: The indicators provided useful monitors of the use and quality of group psychotherapy. The rating scale had satisfactory interrater reliability and construct validity. The immediate constructive educational critique given by the observers of the therapy groups was highly valued by group therapists. CONCLUSIONS: The monitoring and evaluation program proved to be a practical, positive, and inexpensive means of assuring and improving the quality of group psychotherapy in a clinical setting.

Zidovudine resistance, syncytium-inducing phenotype, and HIV disease progression in a case-control study. The VA Cooperative Study Group.

A case-control study of patients with progressive (cases) or nonprogressive (controls) disease was designed to determine the association among disease progression, zidovudine sensitivity, and syncytium-inducing phenotype. Viral isolates were screened for sensitivity to zidovudine using a peripheral blood mononuclear cell-based assay and for syncytium-inducing (SI) phenotype in MT2 cell culture. Thirty-four patients, whose disease progressed to AIDS or whose CD4 cell numbers fell < 200 cells/mm3, were matched with 34 patients whose conditions had not progressed or whose CD4 cell numbers remained > 200 cells/mm3. Virus was successfully cultured from both the progressor and the nonprogressor in 17 of these 34 matched case-control pairs. In six of the 17 pairs, virus isolated from the progressor had an IC50 (50% inhibitory concentration) for zidovudine > 1 microM and at least threefold greater than the IC50 of virus isolated from the matched nonprogressor (p = 0.04). In 16 of these 17 pairs the virus isolated from the progressor had the SI phenotype, indicative of high cytopathogenicity, while the virus from the matched nonprogressor had a non-syncytium-inducing phenotype (p < 0.0001). Zidovudine therapy did not appear to select for the SI phenotype in this patient population. A statistically significant association between high-level zidovudine resistance and clinical disease progression was demonstrated. A statistically significant association between the SI phenotype and disease progression was demonstrated. The results suggest that disease progression while being treated with zidovudine therapy may be more closely associated with the SI phenotype than with zidovudine resistance.

Transmission of latent cytomegalovirus in a murine kidney tissue transplantation model.

This paper examines the hypothesis that latent murine cytomegalovirus (MCMV) may be transmitted in kidney tissue to transplant recipients. Balb/c mice were infected with MCMV, and at intervals of less than 1 week to greater than 1 year, transmission of the virus from infected donors was attempted by transplantation of kidney sections or transfusion of blood into uninfected recipients. Graft recipients were killed from 2-4 weeks later, and cultured for MCMV. Restriction endonuclease digestion profiles of viral DNA were performed. Acutely infected donors transmitted MCMV in kidney tissue to 83-66% of untreated, susceptible recipients. Latently infected donors transmitted the infecting strain of virus to 20% of all and 31% of immunosuppressed recipients but to 37% of the syngeneic versus 21% of the allogeneic (P less than .027). Blood transfusions transmitted latent virus to 28% of recipients. In conclusion, kidney tissue may serve as the source of latent virus in this murine transplantation model. Retained blood in the kidney is unlikely to be the only source of virus.

Determinants of the source of cytomegalovirus in murine renal allograft recipients.

Cytomegalovirus is present in a latent state in renal allografts and may be reactivated in recipients. While human and murine strains are alike in that a primary infection occurs in seronegative recipients of a kidney from a seropositive donor, they may differ when the recipient is seropositive. In a murine transplant model, superinfection of a seropositive recipient with a second strain is unusual. Reports in human transplantation indicate that superinfection of a seropositive recipient does occur, however the frequency is unknown. Our studies examine the potential importance of specific viral strains in host and recipient, the contribution of prior humoral immunity in the recipient, and the technical ability to identify distinctive strains of virus in the presence of each other. Our results indicate that reversal of the viral strains in donor or recipient animals does not alter our previous observation that reactivation of the endogenous recipient viral strain predominates as the infecting strain in the posttransplant period. Further, the presence of antibody in nearly all donors and recipients confirms that all animals were originally infected prior to transplantation. Finally, we demonstrated the technical ability to detect one virus in the presence of the other, thus excluding this variable as possibly confounding. We conclude that the endogenous, latent recipient strain of cytomegalovirus in the murine model is preferentially reactivated in the posttransplant interval.

The accuracy of self-report of herpes zoster.

The accuracy of self-report of herpes zoster was investigated in the Duke Established Populations for Epidemiological Studies of the Elderly, a longitudinal study of 4162 community-dwelling elderly persons residing in North Carolina, 1986-1993. The authors compared self-reports of zoster with physician diagnosis of zoster and with a zoster verification questionnaire (ZVQ). Compared to physician diagnosis, 3.2% (95% confidence interval 0-61%) of self-reports of zoster (n = 31) were false-positive and no denials of zoster (n = 63) were false-negative. The agreement of self-reports to physician diagnosis was 98.9%, the sensitivity and negative predictive value were 100%, the specificity was 98.4% and the positive predictive value was 96.7%. The ZVQ comparisons were similarly high. These data suggest that the frequency of false-positive and false-negative reports of zoster is low in this elderly population. Zoster self-reports appear to be accurate and suitable for epidemiological investigations.

Paecilomyces varioti endocarditis on a prosthetic aortic valve.

Fungal endocarditis following prosthetic valve surgery has assumed increased importance as a cause of postoperative death. We present, to our knowledge, the first case of the fungus Paecilomyces varioti producing endocarditis on a prosthetic aortic valve. This seems to be an extremely indolent organism which exhibits an apparent response to antibiotic therapyl. In vitro evidence suggests that this fungus is sensitive to attainable serum levels of both 5-fluorocytosine and amphotericin B. However, after viewing the extracted valve and the devastating embolic phenomenon in our patient, we believe that medical therapy alone would not suffice. Thus we suggest that prompt valve replacement be performed in future cases.

Race and stress in the incidence of herpes zoster in older adults.

OBJECTIVES: To examine the effect of black race and acute (negative life events) and chronic (lack of social support) psychological stress on the risk of herpes zoster in late life. DESIGN: A population-based, prospective cohort study. SETTING: Central North Carolina. PARTICIPANTS: Duke Established Populations for Epidemiological Studies of the Elderly, a stratified probability sample of community-dwelling persons more than 65 years of age. MEASUREMENTS: Interviewers administered a comprehensive health survey to the participants in 1986-1987 (P1, n = 4162), 1989-1990 (P2, n = 3336), and 1992-1994 (P3, n = 2568). Incident cases of zoster between P1 and P2 and P2 and P3 served as the dependent variable. Hypothesis-testing variables included race, negative life events, and five measures of social support. Control variables included age, sex, education, cancer, chronic diseases, basic ADLs, instrumental ADLs, depression, self-rated health, hospitalization, and cigarette smoking. Statistical analyses employed chi-square tests and proportional hazards model. RESULTS: At baseline, the sample had a mean age of 73.6 years and was 55% black, 45% white, and 65% female. There were 65 cases of zoster between P1 and P2 and 102 cases of zoster between P2 and P3. From P1 to P2, 1.4% of blacks and 3.4% of whites developed zoster (P < .001). From P2 to P3, 2.9% of blacks and 7.5% of whites developed zoster (P < .001). After controlling for the above variables, blacks were significantly less likely to develop zoster (adjusted risk ratio = 0.35; 95% confidence interval (CI), 0.24-0.51; P < .001). Negative life events increased the risk of zoster, but the result was borderline for statistical significance (adjusted RR = 1.38, 95% CI 0.96-1.97; P = .078). No measures of social support were significantly associated with zoster. CONCLUSION: Black race decreased the risk of zoster in late life significantly. Measures of stress were not significantly related to zoster, but study limitations preclude definitive conclusions. Future research should focus on these factors in larger samples and different populations.

Persistence of antibody in healthcare workers vaccinated against hepatitis B.

A cross-sectional serological survey was undertaken in 82 randomly selected high-risk healthcare workers previously vaccinated with the hepatitis B vaccine. The study design allowed for the identification and testing for hepatitis B surface antibody in equal numbers of employees in six-month intervals up to five years after vaccination. The results showed a consistent decline in antibody level with time, and an increasing proportion of participants with antibody levels below the commonly accepted protective level of greater than or equal to 10 S/N (sample counts/negative control counts) radioimmunoassay units. The percent of vaccinees whose S/N ratio was greater than 10 fell from 10% at one year, to 25% at two years, to over 50% at four years. Based on these figures, as well as the financial costs of hepatitis B in employees and the predictability of booster immunization, it was possible to assess the cost benefit of a hospital policy for reimmunization. At our institution, a strategy of revaccination at fixed intervals could save up to $200,000 over a ten-year period if revaccination was not offered and vaccine efficacy declined. The information obtained should help determine the need for revaccination and the advantages and disadvantages of alternative revaccination strategies.

Brain abscess caused by a variety of cladosporium trichoides.

A brain abscess caused by a new variety of Cladosporium trichoides occurred in a previously healthy man. A reversed T-suppressor/helper cell ratio was noted as the only immunologic abnormality. He required three surgical procedures, the last an occipital lobectomy, and antifungal chemotherapy to control his disease. He received 2,068 mg of amphotericin B and one year of flucytosine at 6 g per day. Ten months after the last surgery he is without evidence of disease. C. trichoides var. chlamydosporum was isolated from the abscess. It differed from C. trichoides by producing chlamydospores in vitro and only hyphae in the brain abscess. On modified Sabouraud agar, the fungus did not grow at 25 degrees C and grew poorly at 30 degrees C and 37 degrees C. Histologic sections revealed necrosis, no encapsulation, and no epitheliod cells.

Association between genetic variation at the porphobilinogen deaminase gene and schizophrenia.

There is growing evidence that some genetic predisposition is important in the etiology of schizophrenia. We have sought to implicate a major gene by performing a candidate gene association study comparing the allele frequencies of seven restriction fragment length polymorphisms (RFLPs) at six loci in both a psychiatrically normal control group (N = 51) and an affected (schizophrenia or schizoaffective disorder) group (N = 55). Each group comprised Caucasians of northern European origin. The candidate areas (D5S39, D5S78, dopamine receptor D2 (DRD2), D11S29, porphobilinogen deaminase (PBGD), and D11S84) were selected on the basis of prior cytogenetic findings in schizophrenics, linkage studies, and/or implicated gene products. The presence of a polymorphic ApaLI site within the PBGD gene showed a significant association with the presence of illness (P = 0.02). The relative risk of possessing the allele with the ApaLI site was 2.10. No significant association was found with any of the six other RFLPs. Our data suggests that either the PBGD gene itself or an unknown gene linked to and/or in linkage disequilibrium with the PBGD locus predisposes some individuals to schizophrenia. Independent replication of these findings will be required to determine their relevance to schizophrenia.

Yersinia enterocolitica inguinal lymphadenitis.

Inguinal lymphadenitis is associated with a well-defined group of etiologic agents including many sexually transmitted diseases and nonvenereal agents including Yersinia pestis (bubonic plague). We report herein the first case of a second Yersinia species--Yersinia enterocolitica--presenting like bubonic plague with bilateral inguinal lymphadenitis.

Outcome at 6 months for 50 adolescents with major depression treated in a health maintenance organization.

OBJECTIVE: To examine the short-term outcome of adolescents with major depressive disorder treated in a health maintenance organization (HMO) setting. METHOD: Fifty consecutive adolescents meeting DSM-IV criteria for major depressive disorder at intake to an HMO clinic completed a Beck Depression Inventory (BDI), Columbia Impairment Scale, and Youth Self-Report (YSR), and a parent completed a Child Behavior Checklist at intake and 2, 4, and 6 months later. RESULTS: Thirty-three percent, 40.6%, and 33% of reporting subjects showed improved mood (defined as BDI score < 9), with 78%, 64%, and 72% reporting (defined as completing a BDI) at 2, 4, and 6 months, respectively. Initial level of impairment correlated with BDI score at 2 months (p = .02) and 4 months (p = .01). Attention problems at intake as measured by the YSR correlated with BDI score at 2 months (p = .002) and 6 months (p = .003). CONCLUSIONS: A minority of adolescents treated with limited, nonspecific psychotherapy and selective serotonin reuptake inhibitors have a BDI score of less than 9 at 2, 4, or 6 months. Self-report of attention problems at intake correlates with ongoing depressive symptomatology.

Enhanced green fluorescent protein as a marker for localizing murine cytomegalovirus in acute and latent infection.

A recombinant murine cytomegalovirus (mCMV) that expresses enhanced green fluorescent protein (EGFP) under control of the native immediate-early 1/3 promoter was constructed to detect directly sites of viral activity in latent and reactivated infections. The recombinant virus had acute and latent infection characteristics similar to those of wild-type mCMV. Rare green-fluorescing foci were observed in paraffin sections from lungs and spleens infected latently. Positive immunoperoxidase staining for EGFP in sections of the same lung tissues suggests that these cells may be sites of restricted viral gene expression. EGFP was detected easily in tissue explants reactivating from latent infection in vitro. Morphology and adhesion characteristics of fluorescing cells suggest that viral reactivation occurs in tissue macrophages in explant cultures. The observations presented in this study demonstrate the usefulness of EGFP-expressing recombinants as tools for direct tracking of mCMV activity in vivo and in vitro.