Plasmin-alpha2-antiplasmin complex in patients with atrial fibrillation. Stroke Prevention in Atrial Fibrillation Investigators.

Plasmin-alpha2-antiplasmin complex (PAP) is an index of recent fibrinolytic activity. We examined PAP levels in patients with atrial fibrillation (AF) to determine whether these levels are correlated with clinical characteristics associated with stroke risk. We obtained blood for measurement of PAP in a non-random sample of 586 patients with AF on entering the Stroke Prevention in Atrial Fibrillation III Study. PAP levels were measured with an ELISA assay. PAP values were transformed with a natural logarithm (PAPln) prior to all analyses. Older age, female gender, recent congestive heart failure, decreasing fractional shortening, recent onset of AF, and coronary artery disease were each univariately associated with higher levels of PAP (all p<0.05, two-sample t-test, simple linear regression). Older age, recent congestive heart failure, decreasing fractional shortening, and recent onset of AF were independently associated with higher PAP levels by multivariate analysis (linear regression). Among patients receiving warfarin, PAP levels were not correlated with INR levels (linear regression, p=0.60). Patients classified as high-risk for thromboembolism by our risk stratification criteria (systolic blood pressure > 160 mm Hg, prior thromboembolism, recent congestive heart failure, poor left ventricular function, and women over age 75) had higher PAP levels than low-risk patients (antilog mean PAPln 5.6 vs 4.9. p<0.001, two-sample t-test). PAP levels in patients with AF are associated with clinical characteristics predictive of thromboembolism. Elevated PAP levels are particularly associated with poor left ventricular function and are not affected by anticoagulation. PAP levels may be a marker of stroke risk in patients with AF.

Prophylaxis with weekly versus daily fluconazole for fungal infections in patients with AIDS.

We compared the efficacy of a 400-mg once-weekly dosage versus a 200-mg daily dosage of fluconazole for the prevention of deep fungal infections in a multicenter, randomized, double-blind trial of 636 human immunodeficiency virus-infected patients to determine if a less intensive fluconazole regimen could prevent these serious but relatively infrequent complications of AIDS. In the intent-to-treat analysis, a deep fungal infection developed in 17 subjects (5.5%) randomly assigned to daily fluconazole treatment and in 24 (7.7%) given weekly fluconazole during 74 weeks of follow-up (risk difference, 2.2%; 95% confidence interval [CI], -1.7% to 6.1%). Thrush occurred twice as frequently in the weekly versus daily fluconazole recipients (hazard ratio, 0.59; 95% CI, 0.40-0.89), and in a subset of patients evaluated, fluconazole resistance was infrequent. Fluconazole administered once weekly is effective in reducing deep fungal infections in patients with AIDS, but this dosage is less effective than the 200-mg-daily dosage in preventing thrush.

Relationship between prothrombin activation fragment F1.2 and international normalized ratio in patients with atrial fibrillation. Stroke Prevention in Atrial Fibrillation Investigators.

BACKGROUND AND PURPOSE: The prothrombin time (expressed as the international normalized ratio [INR]) is the standard method of monitoring warfarin therapy in patients with atrial fibrillation. Prothrombin activation fragment F1.2 provides an index of in vivo thrombin generation and might provide a better index of the effective intensity of anticoagulation. We examined the relationship between F1.2 and INR in patients with atrial fibrillation. METHODS: We measured INR and F1.2 levels in 846 patients with atrial fibrillation participating in the Stroke Prevention in Atrial Fibrillation III study. Two hundred nineteen (26%) were taking aspirin alone, 326 (39%) were taking adjusted-dose warfarin, and 301 (36%) were taking a low fixed dose of warfarin (1 to 3 mg) plus aspirin (combination therapy). F1.2 levels were measured with an enzyme-linked immunosorbent assay. RESULTS: Patients receiving adjusted-dose warfarin or combination therapy had significantly higher INR and significantly lower F1.2 values than those on aspirin alone (P < or = .0001 for each of the four comparisons). F1.2 values (nanomolar) were inversely correlated with INR (F1.2 = -0.1 + 2.3[1/INR]; R2 = .37; P < .0001; simple linear regression). However, significant variability remained. Among patients receiving warfarin, older patients had higher F1.2 values than younger patients after adjustment for INR intensity (P < .001) in the model. There was no difference in the relationship between F1.2 and INR between men and women. CONCLUSIONS: Increasing intensity of anticoagulation, as measured by the INR, is associated with decreasing thrombin generation as measured by the F1.2 level, but significant variability exists in this relationship. Older anticoagulated patients have higher F1.2 values than younger patients at equivalent INR values. The clinical significance of these differences is not clear. F1.2 measurement might provide information regarding anticoagulation intensity in addition to that reflected by the INR.

Prophylaxis against Mycobacterium avium-intracellulare complex infections in human immunodeficiency virus-infected patients.

Infection due to the Mycobacterium avium complex (MAC) accounts for the most frequent AIDS-related opportunistic infections, but MAC infection is usually not the first AIDS-defining event that a patient infected with HIV experiences. The incidence increases linearly over time, at a rate of 20 to 25% per year, after a patient's first AIDS-defining event, and the incidence increases exponentially as the CD4+ cell count approaches zero. There is evidence that MAC may eventually infect most if not all HIV-infected patients who do not die from another HIV-related event. Since MAC infection contributes substantially to the morbidity and mortality of AIDS patients, prophylaxis appears to be mandatory. Rifabutin was the first drug which was shown to be effective in preventing MAC infection, and, recently, prophylaxis with clarithromycin was also found to prevent the disease. The optimal approach to prophylaxis still needs to be defined. Since a large majority of MAC infections occur in patients with CD4+ cell counts below 50/microliter, recommendations regarding the prophylaxis of patients with a history of an AIDS-defining opportunistic event and a CD4+ cell count between 50 and 200/microliter can be individualized, depending for example on how well the patient seems to be responding to antiretroviral treatment. Prophylaxis against MAC should be provided for any HIV-infected patient with a CD4+ cell count less than 50/microliter.

Clarithromycin-induced mania in two patients with AIDS.

Acute psychosis was observed in two patients with AIDS who were treated with clarithromycin for disseminated Mycobacterium avium complex infection. The psychosis resolved when treatment with clarithromycin was discontinued and recurred when it was resumed. An adverse response to clarithromycin therapy is a rare but curable cause of acute psychosis in patients with AIDS.

Initial therapy for acquired immunodeficiency syndrome-associated cryptococcosis with fluconazole.

BACKGROUND: Published opinion has generally favored amphotericin B over fluconazole as initial therapy for acquired immunodeficiency syndrome-associated cryptococcosis, although data that support this recommendation are limited. METHOD: Retrospective review of 30 consecutive patients with acquired immunodeficiency syndrome-associated cryptococcosis seen at a single institution over a 1-year period and given fluconazole, 400 mg/d, as initial therapy. RESULTS: No patient died within the first 30 days of therapy, and none of the 14 patients who died within 1 year had clinically detectable infection when last seen or at death. Pretreatment blood cultures were positive in 26 of 27 patients; cerebrospinal fluid cryptococcal antigen titer was greater than 1:1024 in 12 of 23 patients; and five of 30 patients presented with altered mental status. The median CD4 count at diagnosis was 0.042 x 10(9)/L (42/microL). Eight of 25 patients who were followed up for more than 30 days relapsed, as evidenced by a positive culture; all relapses were successfully treated with fluconazole, either by reinstitution of therapy or by increase of dosage. CONCLUSION: This experience supports the use of fluconazole as initial therapy for acquired immunodeficiency syndrome-associated cryptococcosis.

Detection of Mycobacterium avium-intracellulare complex in bone marrow specimens of patients with acquired immunodeficiency syndrome.

Thirty-seven bone marrow core biopsy specimens from 21 human immunodeficiency virus-infected patients with Mycobacterium avium-intracellulare complex bacteremia were stained using rabbit polyclonal antibodies against Mycobacterium bovis strain Bacillus-Calmette-Guerin (BCG) and Mycobacterium duvalii, as well as Kenyon and Fite stains, to compare sensitivities of these techniques and evaluate possible response to therapy. The patients in this study had participated in a phase I/II trial of liposome-encapsulated gentamicin therapy. Two biopsy specimens had inadequate tissue for evaluation. Thirty-two specimens demonstrated bacilli with anti-M duvalii, 33 with anti-BCG, 20 with Kenyon, and 23 with Fite. Two were negative with all stains. Fifteen biopsy specimens had epithelioid granulomas, 12 had histiocytic granulomas, and 1 had a granuloma of indeterminate type. The remaining seven biopsy specimens had no granulomas. Four of these seven demonstrated bacilli with anti-M duvalii, 5 with anti-BCG, 1 with Kenyon, and 2 with Fite. The number of M avium-intracellulare organisms per milliliter of blood decreased in 14 of 21 patients after liposome-encapsulated gentamicin therapy. However, none of the 11 patients whose pre- and post-therapy bone marrow core biopsy specimens were both evaluable demonstrated a reduction in the number of M avium-intracellulare organisms. The authors concluded that anti-M duvalii and anti-BCG are more sensitive than acid-fast stains for identifying M avium-intracellulare infection in bone marrow core biopsy specimens of patients who have acquired immunodeficiency syndrome (AIDS) with M avium-intracellulare bacteremia. Bone marrow core biopsy specimens may provide a perspective on M avium-intracellulare infection in AIDS patients that differs from the one provided by blood cultures.

Opportunistic events and p17 expression in the bone marrow of human immunodeficiency virus-infected patients.

Bone marrow biopsies from 114 human immunodeficiency virus (HIV)-infected patients were stained with an anti-p17 monoclonal antibody to detect active HIV replication and associated factors. Immunoreactive p17 was found as virus-like particles in macrophages and dendritic cells and occasionally in megakaryocytes in 62 of 114 marrows and was considered evidence of active HIV replication. Immunoreactive p17 was not found significantly more often in the marrows of patients with lower CD4 cell counts; however, it was found significantly more in the marrows of patients with concurrent mycobacterial or fungal infections or lymphoma (chi 2 = 12.1, P < .001). Immunoreactive p17 was even more frequent when these opportunistic diseases were found in the biopsied marrow (chi 2 = 20.5, P < .001). The association of active HIV replication with certain opportunistic diseases, but not with lower CD4 cell counts, raises the possibility that these opportunistic diseases may under some circumstances be a cause as well as a consequence of active HIV replication.

Androgyny predicts empathy for trainees in medicine.

Data from 65 medical students and residents support the hypothesis that scores on a measure of androgyny are predictive of those on an index of empathy but relatively modest predictive accuracy was observed for sympathetic responses. Further exploration is suggested.

Liposome-encapsulated gentamicin treatment of Mycobacterium avium-Mycobacterium intracellulare complex bacteremia in AIDS patients.

TLC G-65, a liposome-encapsulated gentamicin, was given intravenously twice weekly for 4 weeks to AIDS patients with Mycobacterium avium-M. intracellulare complex (MAC) bacteremia at 1.7 mg of gentamicin per kg of body weight per infusion (4 patients), 3.4 mg/kg (10 patients), and 5.1 mg/kg (7 patients). MAC colony counts in blood fell by 75% or more in all three groups (P < 0.005). Drug resistance did not emerge during the study period. Transient renal insufficiency developed in one patient; no other adverse effects were detected. Liposome-encapsulated gentamicin is a potential therapy for MAC infections in AIDS patients.

Two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex infection in AIDS.

BACKGROUND: Disseminated Mycobacterium avium complex infection eventually develops in most patients with the acquired immunodeficiency syndrome (AIDS). This infection results in substantial morbidity and reduces survival by about six months. METHODS: We conducted two randomized, double-blind, multicenter trials of daily prophylactic treatment with either rifabutin (300 mg) or placebo. All the patients had AIDS and CD4 cell counts < or = 200 per cubic millimeter. The primary end point was M. avium complex bacteremia as assessed monthly by blood culture. The secondary end points were signs and symptoms associated with disseminated M. avium complex infection, adverse events, hospitalization, and survival. RESULTS: In the first trial, M. avium complex bacteremia developed in 51 of 298 patients (17 percent) assigned to placebo and 24 of 292 patients (8 percent) assigned to rifabutin (P < 0.001). In the second trial, bacteremia developed in 51 of 282 patients in the placebo group (18 percent) and 24 of 274 patients in the rifabutin group (9 percent) (P = 0.002). Rifabutin significantly delayed fatigue, fever, decline in the Karnofsky performance score (by > or = 20 percent), decline in the hemoglobin level (by more than 10 percent), elevation in alkaline phosphatase, and hospitalization. The incidence of adverse events was similar with rifabutin and placebo. Overall survival did not differ significantly between the two groups, although there were fewer deaths with rifabutin (33) than with placebo (47) during the double-blind phase (P = 0.086). The distribution of minimal inhibitory concentrations of rifabutin among the isolates of M. avium complex did not differ significantly between the treatment groups. CONCLUSIONS: Rifabutin, given prophylactically, reduces the frequency of disseminated M. avium complex infection in patients with AIDS and CD4 counts < or = 200 per cubic millimeter.

Pathology of cytomegalovirus retinitis treated with sustained release intravitreal ganciclovir.

BACKGROUND: An experimental sustained release intraocular device has been designed to deliver ganciclovir over a long period of time. As part of an efficacy trial, the ganciclovir intraocular device was used to treat cytomegalovirus (CMV) retinitis in patients with acquired immune deficiency syndrome (AIDS). METHODS: All patients had active CMV retinitis that had progressed despite intravenous ganciclovir therapy. The ganciclovir intraocular device was inserted into the vitreous cavity by making an inferotemporal full-thickness circumferential sclerotomy and anchored to the incision. Intravenous therapy was then discontinued and patients were followed up at 2-week intervals until death. Seven eyes from five patients were obtained 2 to 10 hours postmortem and submitted for histopathologic examination. Light and electron microscopic studies were performed and correlated to the clinical outcome. Follow-up period after device placement ranged from 16 to 82 days (median, 70 days). RESULTS: All seven eyes showed clinical stabilization of the CMV retinitis. Light microscopy showed varying degrees of retinal atrophy with areas of gliosis. In addition, we observed syncytial megalic cells containing Cowdrey type A inclusions affecting all layers of the retina. Concurrent choroidal infections with Pneumocystis carinii (1) and Mycobacterium avium (2) also were seen. Electron microscopy showed virus particles located mostly at the junction of uninvolved and "healed" retinitis. No evidence of retinal toxic effects or inflammation at the site of ganciclovir intraocular device implant was noted. CONCLUSION: The ganciclovir intraocular device appeared to be effective in controlling the progression of CMV retinitis. The clinical and pathologic results are similar to those observed in the eyes of patients with intravenously administered ganciclovir. The lack of toxic effects and sustained levels of intravitreal ganciclovir may provide an improved therapeutic method of local treatment of CMV retinitis.

Logarithmic relationship of the CD4 count to survival in patients with human immunodeficiency virus infection.

BACKGROUND: Survival, and the incidence of events that define the acquired immunodeficiency syndrome (AIDS), are known to be inversely related to the CD4 count in patients with human immunodeficiency virus infection. We wished to quantify this relationship more precisely, particularly for patients with CD4 counts of less than 50/mm3. METHODS: Prospective surveillance for survival and for all AIDS-defining events was performed on all 2682 patients with human immunodeficiency virus infection who had at least one CD4 count performed at a large urban public hospital during a 3-year period. Product-limit survival and incidence of AIDS-defining events were calculated as a function of baseline CD4 count. RESULTS: The 1-year product-limit survival was 17% +/- 6% for patients after a baseline CD4 count of 1 to 4/mm3; 44% +/- 6% after a count of 5 to 9/mm3; 48% +/- 5% after a count of 10 to 19/mm3; 51% +/- 4% after a count of 20 to 39/mm3; 62% +/- 5% after a count of 40 to 59/mm3; 71% +/- 4% after a count of 60 to 99/mm3; 79% +/- 3% after a count of 100 to 199/mm3; and 92% +/- 2% after a count of 200 to 499/mm3. One-year survival and baseline CD4 count were related by the following formula: percent 1-year survival = 10 + 32(log10 CD4 count) (R2 = .97; P < .001). The 1-year incidence of a first AIDS-defining event and baseline CD4 count were related by the following formula: percent developing AIDS in 1 year = 104-36(log10 CD4 count) (R2 = .89; P < .001). Similar relationships were calculated between the logarithm of the baseline CD4 count and the 1-year incidence of most AIDS-defining events. These relationships were linear over the CD4 range of 1 to 499/mm3 and over follow-up periods of 6 months to 2 years. CONCLUSIONS: The relationship of the CD4 count to survival, and to the incidence of AIDS-defining events, is logarithmic. This relationship helps explain the substantial differences in 1-year survival associated with baseline CD4 counts in the range below 50/mm3.

Control of cytomegalovirus retinitis using sustained release of intraocular ganciclovir.

An experimental intravitreal sustained-release device containing ganciclovir was used to treat 22 patients with acquired immunodeficiency syndrome-associated cytomegalovirus retinitis. Fourteen eyes were excluded (five not involved and nine with macular scarring and/or severe debility). Thirty eyes received the ganciclovir intraocular device implant and were prospectively followed up from 16 to 419 days (median, 125 days). Twenty-seven (90%) of 30 eyes showed stabilization of the retinitis. Nine (33%) of 27 eyes showed reactivation of the retinitis once the device was empty of ganciclovir; seven received a replacement device, with subsequent stabilization of the retinitis. Postoperative complications included vitreous hemorrhage (n = 1), endophthalmitis (n = 1), and progressive retinitis (n = 2). Late retinal detachment was seen in three eyes (11%) at 35 to 140 days. Survival analysis of all 30 eyes revealed the mean time to progression of retinitis to be 19 weeks (133 days). The ganciclovir intraocular device offers a promising alternative for the treatment of cytomegalovirus retinitis associated with acquired immunodeficiency syndrome.