Granulomatous Reaction in a Patient With Metastatic Melanoma Treated With Ipilimumab: First Case Reported With Isolated Cutaneous Findings. / Reacción granulomatosa en paciente con melanoma metastásico tratado con ipilimumab: primer caso descrito presentando clínica cutánea únicamente.

Granulomatous sarcoidosis-like reactions affecting multiple organ systems at one time have infrequently been described within weeks to months after initiation of Ipilimumab. We present the first case of a 67-year-old man with isolated cutaneous granulomatous reaction involving the trunk, extremities, and face after eighteen months of treatment with ipilimumab for metastatic melanoma. This case documents the eruption of isolated cutaneous granulomatous reaction as a late treatment-related adverse effect of ipilimumab, highlighting the importance of adequate, prolonged follow-up.

Phase I pharmacokinetic and pharmacodynamic study of the bioreductive drug RH1.

BACKGROUND: This trial describes a first-in-man evaluation of RH1, a novel bioreductive drug activated by DT-diaphorase (DTD), an enzyme overexpressed in many tumours. PATIENTS AND METHODS: A dose-escalation phase I trial of RH1 was carried out. The primary objective was to establish the maximum tolerated dose (MTD) of RH1. Secondary objectives were assessment of toxicity, pharmacokinetic determination of RH1 and pharmacodynamic assessment of drug effect through measurement of DNA cross linking in peripheral blood mononuclear cells (PBMCs) and tumour, DTD activity in tumour and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphism status. RESULTS: Eighteen patients of World Health Organization performance status of zero to one with advanced refractory solid malignancies were enrolled. MTD was 1430 µg/m(2)/day with reversible bone marrow suppression being dose limiting. Plasma pharmacokinetic analysis showed RH1 is rapidly cleared from blood (t(1/2) = 12.3 min), with AUC increasing proportionately with dose. The comet-X assay demonstrated dose-related increases in DNA cross linking in PBMCs. DNA cross linking was demonstrated in tumours, even with low levels of DTD. Only one patient was homozygous for NQO1 polymorphism precluding any conclusion of its effect. CONCLUSIONS: RH1 was well tolerated with predictable and manageable toxicity. The MTD of 1430 µg/m(2)/day is the dose recommended for phase II trials. The biomarkers of DNA cross linking, DTD activity and NQO1 status have been validated and clinically developed.

Patterns of care for HIV-related Pneumocystis carinii pneumonia in a university medical program: a case study.

BACKGROUND/OBJECTIVE: Previous studies have identified large variations in patterns of in-hospital acquired immunodeficiency syndrome (AIDS) care among groups of hospitals and physicians. We evaluated the patterns of care for patients with AIDS-related Pneumocystis carinii pneumonia (PCP) care at a single university program with patients treated at an adjacent county and Veterans' Administration (VA) hospital. All medical care was provided by physicians in a single residency program, but attending physician staffs were separate. SETTING AND PATIENTS: A randomized sample of patients with human immunodeficiency virus (HIV)-related PCP from the two hospitals who received care between 1987 and 1990. RESULTS: During the study years, the VA hospital provided care for approximately one fourth as many AIDS patients as the county hospital. Patients at the VA hospital had a higher bronchoscopy rate (39.7% versus 27.7%, P = .05), higher intensive-care unit (ICU) rate (11.8% versus 2.9%, P = .008), longer hospitalizations (mean length of stay of 18.9 versus 13.9 days, P = .004), but delayed initiation of anti-PCP therapy (median of day 2 versus day 1, P < .05). The odds of death were significantly different between the VA and county hospitals, even after adjusting for differences in important patient characteristics. CONCLUSION: Patterns of in-hospital PCP care differed between the two hospitals of this medical school. Possible explanations include organizational differences related to level of attending physician HIV experience, hospital case loads of AIDS patients, or specific hospital considerations such as concerns over tuberculosis exposure.

Predictors of resource utilization for hospitalized patients with Pneumocystis carinii pneumonia (PCP): a summary of effects from the multi-city study of quality of PCP care.

To determine whether patient and hospital characteristics were significantly associated with variations in Pneumocystis carinii (PCP) care and outcomes, we analyzed the use of diagnostic tests, intensive care units (ICUs), anti-PCP medications for persons hospitalized with human immunodeficiency virus (HIV)-related PCP, and hospital discharge status. We conducted retrospective chart reviews of a cohort of 2,174 patients with PCP hospitalized in 1987-1990. Outcomes included process of care for PCP and in-hospital mortality rates. Persons with PCP who were more severely ill at admission were more likely to have early medical care, to receive care in an intensive care unit, and to die in hospital. After we adjusted for differences in this severity of illness, we noted that Medicaid patients, injection drug users (IDUs), and patients treated at VA or county hospitals were significantly less likely than others to have diagnostic bronchoscopies and that persons covered by Medicaid, with a previous diagnosis of acquired immunodeficiency syndrome (AIDS), who did not receive prior zidovudine (AZT) or who received care in a VA hospital had the highest chances of in-hospital death. Insurance and risk group characteristics, severity of illness, and hospital characteristics appear to be the most important determinants of the intensity and timing of medical care and outcomes among patients hospitalized with PCP.

Relationship between procedures and health insurance for critically ill patients with Pneumocystis carinii pneumonia.

The objective of the present study was to assess the association between type of health insurance coverage and use of diagnostic tests and therapies among patients with AIDS-related Pneumocystis carinii pneumonia (PCP). Fifty-six private, public, and community hospitals in Chicago, Los Angeles, and Miami were selected for the study, and the charts of 890 patients with empirically treated or cytologically confirmed PCP, hospitalized during 1987 to 1990 were retrospectively reviewed. Patients were classified by insurance status: self-pay (n = 56), Medicaid (n = 254), or private insurance, including health maintenance organizations and Medicare (n = 580). Primary outcomes were the use and timing of bronchoscopy, the type and timing of PCP therapy, and in-hospital mortality. The results indicate that Medicaid patients were less likely than privately insured patients to undergo bronchoscopy (relative odds = 0.61; 95% CI = 0.40, 0.93; p = 0.02) or to have their diagnosis of PCP confirmed (relative odds = 0.51; 95% CI = 0.33, 0.77), after adjusting for patient, severity of illness, and hospital characteristics. Medicaid patients were approximately three-fourths more likely than privately insured patients (relative odds = 1.73; 95% CI = 1.01, 2.96; p = 0.04) to die in-hospital, after adjusting for patient, severity of illness, and hospital characteristics. However, with further adjustment for confirmation of PCP, Medicaid patients no longer had a significantly higher likelihood of dying in-hospital. We conclude that Medicaid patients are less likely to receive diagnostic bronchoscopy than privately insured or self-insured patients, more likely to be empirically treated for PCP, and more likely to die in-hospital.(ABSTRACT TRUNCATED AT 250 WORDS)

Antimicrobial prophylaxis of infection.

Antimicrobial agents are used to prevent infections in a variety of clinical circumstances. In certain instances, the precise indications for prophylaxis remain controversial, and the preferred regimens undergo alterations based upon evolving clinical experience, changing patterns of microbial susceptibility, and innovations in medical and surgical practice. This article outlines the general principles underlying the use of antimicrobial prophylaxis and presents recommendations for the use of such prophylaxis in three areas: (1) surgery involving contaminated, clean-contaminated, and clean procedures; (2) prevention of infections due to specific pathogens, including Neisseria meningitidis, Hemophilus influenzae, Streptococcus pneumoniae, and Streptococcus pyogenes; and (3) prevention of infective endocarditis.

Empirically treated Pneumocystis carinii pneumonia in Los Angeles, Chicago, and Miami: 1987-1990.

Many patients infected with the human immunodeficiency virus (HIV) with symptoms suggestive of pneumonia are treated empirically for Pneumocystis carinii pneumonia (PCP), although other bacterial infections (e.g., tuberculosis) and pulmonary Kaposi's sarcoma may cause identical symptoms. Empiric treatment for PCP may result in misdiagnosis and mistreatment. When the outcomes of cytologically confirmed versus empirically treated PCP cases were evaluated, the most important predictors of in-hospital mortality were severity of illness and use of bronchoscopy. Persons who did not undergo bronchoscopy had higher mortality rates than patients negative by bronchoscopy or cytologically confirmed as positive for PCP (22% vs. 11% vs. 14%, P < .01), although severity of illness and timing of anti-PCP medications did not differ significantly. Compared with cytologically confirmed cases, persons who did not have bronchoscopy were more likely to die than were bronchoscopy-negative patients (P < .05), after adjusting for severity of illness. Bronchoscopy use may have contributed to better outcomes for persons treated for HIV-related PCP.

Crescentic glomerulonephritis and eosinophilic interstitial infiltrates in a patient with hypereosinophilic syndrome.

Crescentic glomerulonephritis with immune complex deposition and acute eosinophilic interstitial nephritis developed in a patient with the hypereosinophilic syndrome. Acute renal failure ensued but was rapidly reversed by high-dose oral prednisone. Confounding factors and unusual findings are described with a review of recent literature. This mode of presentation has not previously been reported.

Laparoscopic and histologic findings in patients with the human immunodeficiency virus.

Hepatic dysfunction frequently develops in patients infected with the human immunodeficiency virus (HIV). This retrospective study was undertaken to determine the laparoscopic and histologic findings in a group of HIV-seropositive patients with or without the acquired immune deficiency syndrome (AIDS). Fifty-four patients, 44 with AIDS and 10 HIV-positive, underwent laparoscopic examination and visually guided biopsies for the assessment of clinical or biochemical evidence of liver injury. Significant abnormalities were detected in 31/44 (70%) AIDS patients and 3/10 (30%) HIV-positive patients. Overall, specific laparoscopic findings were described in 25/54 (46%). The most common findings were peritoneal involvement, massive intra-abdominal adhesions, focal lesions of the liver or spleen, and diffuse nodularity of the liver; these were usually related to opportunistic infections or neoplasms such as non-Hodgkin's lymphomas and Kaposi's sarcoma. No procedure-related deaths occurred. Laparoscopy is a safe and accurate method to detect underlying disease in a selected population of HIV-seropositive patients.

Asthma management preceding an emergency department visit.

BACKGROUND: The burden of illness from asthma in North America has not decreased despite advancements in understanding disease pathogenesis and improved pharmacotherapeutics. This study examined the adequacy of preventive measures applied to asthma. METHODS: Using a standardized self-administered questionnaire, 111 consecutive patients presenting to the emergency department because of asthma were surveyed about their "usual" level of disability from asthma, usual medications, self-management plans to deal with an asthma attack, and environmental control measures. RESULTS: Twenty-five percent of subjects suffered sleep disturbance more than 15 days per month, had work/school attendance affected more than 14 days per year, and previously visited an emergency department twice in the past year. Thirty-seven percent had no effective plans to deal with an attack and another 32% had plans that were never discussed with a physician. Although 78% reported that cigarette smoke aggravated their asthma, one third of these were exposed at home. CONCLUSIONS: For a significant proportion of adults requiring emergency health services for asthma, preexisting management was poor by current standards. We recommend that patients be screened by emergency physicians and those with identifiable inadequacies in usual care be referred to physicians with expertise in asthma management.

Hepatobiliary cryptosporidiosis and cytomegalovirus infection mimicking metastatic cancer to the liver.

A cholestatic syndrome caused by sclerosing cholangitis and papillary stenosis has been described in patients with the acquired immunodeficiency syndrome and hepatobiliary cryptosporidiosis and cytomegalovirus infection. The case of a 41-year-old homosexual man with the acquired immunodeficiency syndrome who presented with abdominal pain, diarrhea, fever, and cholestasis is reported. A percutaneous transhepatic cholangiogram showed that the extrahepatic and right-sided intrahepatic ducts were normal. Computerized tomography of the abdomen showed multiple hypodense lesions in the liver. Guided needle biopsies of several of these lesions showed severe confluent necrotizing pericholangitis with cytomegalovirus-infected cells. Numerous cryptosporidia were seen attached to biliary epithelium. The unique histopathologic and radiographic features of this case should be added to the spectrum of hepatobiliary manifestations of the acquired immunodeficiency syndrome.

Severe exacerbations of COPD and asthma. Incremental benefit of adding ipratropium to usual therapy.

Single dose studies have assessed the utility of ipratropium bromide alone or with beta agonists in the short- and long-term management of chronic obstructive lung disease and asthma. We performed a randomized, double-blind trial to assess the incremental benefit over 24 hours of adding ipratropium vs placebo to a standardized regimen of medications commonly used in the acute and subsequent hospital management of COPD and asthma. Sixty-eight subjects received nebulized salbutamol, intravenous methylprednisolone, intravenous aminophylline, and antibiotics and were randomized to receive either 80 micrograms of ipratropium or placebo via metered dose inhaler and spacing device with each salbutamol treatment (6 to 8 times per day). Among the 50 patients who completed the study, there were no significant differences between ipratropium and placebo groups with respect to baseline FEV1, FVC, and PaCO2. The improvement of FEV1 from baseline to 24 hours was 294 (SD = 568) ml in the ipratropium group vs 393 (SD = 622) ml in placebo group. Adjusting FEV1 by age, gender, and smoking did not significantly alter the findings. Those with an admission diagnosis of asthma showed larger 24 hour FEV1 responses (487 ml in ipratropium vs 801 ml in placebo) than those with COPD (149 ml ipratropium vs 102 ml in placebo). However, within these two strata, there were no significant differences in FEV1 improvement between ipratropium and placebo groups. This study suggests that if ipratropium is used in the initial emergency treatment of COPD or asthma, it could safely be discontinued by 24 hours in order to reduce the cost and complexity of therapy.

A multicenter clinical trial of oral ribavirin in HIV-infected patients with lymphadenopathy. The Ribavirin-LAS Collaborative Group.

A double-blind, randomized, placebo-controlled trial comparing two daily doses of oral ribavirin and placebo was conducted at four medical centers. One hundred sixty-four adult men with lymphadenopathy were enrolled over a 2-month period and randomized to receive ribavirin 800 mg (53 subjects), ribavirin 600 mg (55 subjects), or placebo (56 subjects). Active treatment was administered for 24 weeks followed by a 4-week washout period. Nine subjects receiving placebo, four receiving ribavirin 600 mg, and none in the 800 mg group developed AIDS during the 24 weeks of active treatment. One patient randomized to the 800 mg group had Kaposi's sarcoma at study entry and was included in the intent-to-treat analysis. An overall significant difference in progression to AIDS was observed among the three treatment groups (p = 0.028) with patients randomized to receive 800 mg having a significantly longer time to AIDS than placebo patients (p = 0.012; relative risk, 9.0; 95% confidence interval, 1.1 to 70.8). There was no significant difference between the 600 mg and placebo groups (p = 0.15; relative risk, 2.3; 95% confidence interval, 0.7 to 7.6). Baseline CD4 cell count and hematocrit made independent contributions and formed a multivariate prognostic set for these progression data. The significant treatment superiority of 800 mg compared to placebo remained after adjustment for these factors (p = 0.019). After deletion of patients with major protocol violations at entry, the difference between the 800 mg and placebo treatment remained significant (p = 0.021).(ABSTRACT TRUNCATED AT 250 WORDS)

Infections associated with indwelling devices: infections related to extravascular devices.

PIP: Infection complications of indwelling extravascular devices are reviewed including endotracheal tubes, urological catheters, cerebrospinal shunts, ocular prostheses, orthopedic protheses, peritoneal dialyses catheters, and IUDs. For each device a small number of pathogens accounts for the majority of infections. For most devices, infections of host skin origin, especially coagulase negative staphylococci are responsible. IUDs are exceptional because most are associated with bacteria which cannot be detected by usual culture methods. Acute endometritis may follow insertion, and pelvic inflammatory disease may develop rarely. For urinary catheters, gram negative bacilli from the bowel or antibiotic resistant hospital acquired organisms are common. Most foreign body infections require removal of the device before cure is possible. Exceptions are peritoneal dialysis catheters, intraocular lenses and some cases of prosthetic valve endocarditis by penicillin susceptible streptococci. Most infections originate during surgical implantation. Minimizing tissue trauma and operating time will reduce risk. Prophylactic antibiotics are appropriate for placement of artificial heart valves, joints and vascular grafts.^ieng

Tuberculosis and nontuberculous mycobacteriosis in patients with AIDS.

Thirty-six patients with AIDS and culture-proven nontuberculous mycobacteriosis were compared to 20 patients with acquired immunodeficiency syndrome (AIDS) and tuberculosis with regard to clinical signs, symptoms, and diagnostic methods. Patients with nontuberculous mycobacteriosis were more often younger and homosexuals, while patients with tuberculosis were usually Haitian-American or users of intravenous drugs. A majority of patients with tuberculosis presented with fever and weight loss. These symptoms were seen in approximately 50 percent of the patients with nontuberculous mycobacteriosis. A distinct syndrome of dyspnea, chills, hemoptysis, and chest pain was seen in a significant minority of patients with nontuberculous mycobacteriosis. Lymphadenopathy was seen almost exclusively in patients with tuberculosis. Pulmonary sources (expectorated sputum or bronchoscopy specimens) were the most common source of diagnosis in both groups. Patients in both groups in whom the diagnosis was obtained from pulmonary sources frequently had negative chest x-ray films on presentation. Cavitary disease was absent from both groups.

Safety and efficacy of sulfamethoxazole and trimethoprim chemoprophylaxis for Pneumocystis carinii pneumonia in AIDS.

The safety and efficacy of sulfamethoxazole and trimethoprim in the prevention of Pneumocystis carinii pneumonia associated with the acquired immunodeficiency syndrome (AIDS) were evaluated. Sixty patients with a new diagnosis of Kaposi's sarcoma and no history of opportunistic infections were randomly assigned to receive 800 mg of sulfamethoxazole and 160 mg of trimethoprim twice per day or no therapy. None of the 30 patients receiving sulfamethoxazole and trimethoprim developed P carinii pneumonia. Sixteen of the 30 patients receiving no suppressive therapy developed P carinii pneumonia. Development of P carinii pneumonia was associated with the stage of Kaposi's sarcoma, B subtype disease, and the presence of 0.20 X 10(9)/L (200/mm3) or fewer CD4 cells at study entry. The proportion of patients surviving and the mean length of survival were significantly greater in the treatment group compared with the control group. Adverse reactions occurred in 15 patients (50%).

Progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. A review of the literature with a report of sixteen cases.

Progressive multifocal leukoencephalopathy, a common complication of infections with human immunodeficiency virus (HIV), occurs in as many as 3.8% of patients with the acquired immunodeficiency syndrome (AIDS). We report 16 cases and review 12 previously reported cases of progressive multifocal leukoencephalopathy associated with HIV infection. This illness was the presenting manifestation of HIV infection in 8 cases. Limb weakness, gait abnormalities, visual loss, aand altered mental status were the commonest initial complaints. Computed tomography of the brain frequently showed hypodense, nonenhancing white matter lesions. Magnetic resonance imaging was more sensitive than computed tomography in detecting lesions. Cerebrospinal fluid analysis and electroencephalography were nondiagnostic. Impaired cell-mediated immunity was typically noted, even in the absence of other immunodeficiency-associated illnesses. Death occurred within 10 days to 18 months of the onset of symptoms in 22 patients. However, 4 patients remain alive at 3 to 23 months; of these 4, 2 have had significant improvement without treatment. Various therapies were unsuccessful.

Evaluation of heterosexual partners, children, and household contacts of adults with AIDS.

Forty-five adults with the acquired immunodeficiency syndrome (AIDS) and their 45 spouses, 109 children, and 29 household contacts were studied for evidence of heterosexual, perinatal, and household spread of human T-cell lymphotropic virus type III (HTLV-III) infection. Of the 45 spouses enrolled, 26 (58%) had antibody to HTLV-III, including 12 (71%) of 17 male spouses and 14 (50%) of 28 female spouses. Of the 12 seropositive male spouses, nine were seropositive at enrollment and three had seroconversion. Of the 14 seropositive female spouses, four were seropositive at enrollment and ten seroconverted. Lack of barrier contraceptive use and oral sex were associated with seroconversion. Of the 109 children enrolled, 15 had AIDS or an AIDS-related illness, two had evidence of passive transfer of maternal antibodies, and two had HTLV-III infection acquired outside the household. None of the 90 seronegative children seroconverted. Of 29 household contacts studied, none developed antibody to HTLV-III.