Lung allocation in the United States, 1995-1997: an analysis of equity and utility.

BACKGROUND: Waiting time for organ transplantation varies widely between programs of different sizes and by geographic regions. The purpose of this study was to determine if the current lung-allocation policy is equitable for candidates waiting at various-sized centers, and to model how national allocation based solely on waiting time might affect patients and programs. METHODS: UNOS provided data on candidate registrations; transplants and outcomes; waiting times; and deaths while waiting for all U.S. lung-transplant programs during 1995-1997. Transplant centers were categorized based on average yearly volume: small (< or = 10 pounds sterling transplants/year; n = 46), medium (11-30 transplants/year; n = 29), or large (>30 transplants/year; n = 6). This data was used to model national organ allocation based solely on accumulated waiting time for candidates listed at the end of 1997. RESULTS: Median waiting time for patients transplanted was longest at large programs (724-848 days) compared to small and medium centers (371-552 days and 337-553 days, respectively) and increased at programs of all sizes during the study period. Wait-time-adjusted risk of death correlated inversely with program size (365 vs 261 vs 148 deaths per 1,000 patient-years-at-risk at small, medium, and large centers, respectively). Mortality as a percentage of new candidate registrations was similar for all program categories, ranging from 21 to 25%. Survival rates following transplantation were equivalent at medium-sized centers vs large centers (p = 0.50), but statistically lower when small centers were compared to either large- or medium-size centers (p < or = 0.05). Using waiting time as the primary criterion lung allocation would acutely shift 10 to 20% of lung-transplant activity from medium to large programs. CONCLUSIONS: 1) Waiting list mortality rates are not higher at large lung-transplant programs with long average waiting times. 2) A lung-allocation algorithm based primarily on waiting-list seniority would probably disadvantage candidates at medium-size centers without improving overall lung-transplant outcomes. 3) If fairness is measured by equal distribution of opportunity and risk, we conclude that the current allocation system is relatively equitable for patients currently entering the lung-transplant system.

Cryptococcal meningitis in the immunocompromised host: intracranial hypertension and other complications.

Cryptococcosis as a complication of the immunocompromised host has dramatically increased in frequency since the start of the AIDS epidemic. This trend has heightened awareness of the complications of cryptococcal meningitis; of these, intracranial hypertension is common, severe, and life-threatening, as exemplified by three cases in our institutions presented here in detail. An aggressive approach to management of this complication has not been the standard of care, but neurosurgical interventional studies combined with physiologic observations suggest early intervention may reduce the devastating morbidity and mortality.

Elevated cerebrospinal fluid pressures in patients with cryptococcal meningitis and acquired immunodeficiency syndrome.

Increased intracranial pressure has been a noteworthy problem in some of our patients with cryptococcal meningitis and acquired immunodeficiency syndrome (AIDS), and this appears to be a feature observed in patients with cryptococcal meningitis reported in the literature. Whereas most attention of clinicians is presently focused on optimizing the antifungal regimen, so as to improve on high failure rates in cryptococcal meningitis in AIDS, little attention has been paid to the problem of intracranial hypertension. We argue that visual loss and some of the cases of death early after the onset of chemotherapy may be related to high cerebrospinal fluid (CSF) pressure, regardless of antifungal therapy. The possible pathophysiologic mechanisms are discussed, and we postulate that the mechanism is reduced CSF outflow possibly due to increased outflow resistance, not necessarily accompanied by prominent cerebral edema. Optimal therapy of this complication is not yet established, but some measures that may be helpful are ventricular shunting, frequent high-volume lumbar punctures, and possibly glucocorticoids.

Transmission of human immunodeficiency virus type 1 by dry-heated clotting factor concentrates. Transfusion Safety Study Group.

The Transfusion Safety Study monitored susceptible persons for human immunodeficiency virus type 1 (HIV-1) infections transmitted by plasma products and blood components. Through December, 1988, 6 subjects without antibody to HIV-1 (anti-HIV-1) became seropositive after receiving dry-heated factor VIII concentrate. The preparations implicated in 3 cases were derived entirely from anti-HIV-1-screened donors. In all instances, HIV-1 infection could be explained by concentrates heated at 60 degrees C for 24-30 h. Limiting consideration to concentrates and components administered after study entry showed that 4 of the seroconversions occurred among 122 subjects given 10 million units of factor VIII concentrates. No seroconversions occurred among 84 subjects given 5 million units of factor IX concentrates, or 83 who received components from over 26,000 unpaid donations. Serologic surveillance of anti-HIV-1-negative subjects provides important information, and should be routine in the management of persons receiving clotting factor concentrates.

Posttransfusion purpura associated with an autoantibody directed against a previously undefined platelet antigen.

Although alloantibody against the PLA1 platelet antigen is usually found in patients with posttransfusion purpura (PTP), the mechanism of destruction of the patient's own PLA1-negative platelets is unexplained. We used a sensitive immunoblot technique to detect antiplatelet antibodies in a patient with classic PTP. The patient's acute-phase serum contained antibodies against three proteins present in control (PLA1-positive) platelets: an antibody that bound to a previously unrecognized platelet protein of mol wt 120,000 [glycoprotein (GP) 120], antibodies that bound to PLA1 (mol wt 90,000), and an epitope of GP IIb (mol wt 140,000). The antibodies against PLA1 and GP IIb did not react with the patient's own PLA1-negative platelets, control PLA1-negative platelets, or thrombasthenic platelets. In contrast, the antibody against GP 120 recognized this protein in all three platelet preparations, but not in Bernard-Soulier or Leka (Baka)-negative platelets. Antibody against GP 120 was not detected in the patient's recovery serum, although the antibodies against PLA1 and GP IIb persisted. F(ab)2 prepared from the patient's acute-phase serum also bound to GP 120. These results suggest that in PTP, transient autoantibody production may be responsible for autologous (PLA1-negative) platelet destruction. In addition, alloantibodies against more than one platelet alloantigen may be found in this disease. The nature of the GP 120 autoantigen and the GP IIb-related alloantigen defined by our patient's serum remains to be determined.

Inhibition of disulfide bonding of von Willebrand protein by monensin results in small, functionally defective multimers.

The biosynthesis of von Willebrand protein by human endothelial cells was impaired by the presence of the carboxylic ionophore monensin. Several processing steps that have been localized to the Golgi apparatus were affected in a dose-dependent manner, including carbohydrate processing, dimer multimerization, and precursor cleavage. Since multimerization was more susceptible to the ionophore than was precursor cleavage, it appears that these processing steps are separate events. As expected, dimer formation, which occurs in the rough endoplasmic reticulum, was unaffected by monensin. Thus, at high concentrations of monensin, only dimer molecules were produced and secreted. The observed inhibition of multimer formation and precursor cleavage were not likely the result of incomplete carbohydrate processing, since inhibition of complex carbohydrate formation by swainsonine did not interfere with the other processing steps. Monensin also affected the capacity of endothelial cells to store von Willebrand protein, as the ratio of secreted to cell-associated protein increased dramatically in the presence of monensin, and the processed forms could not be found in the treated cells. The low molecular weight multimers produced in the presence of monensin did not incorporate in the endothelial cells' extracellular matrix nor did they bind to the matrix of human foreskin fibroblasts. In summary, the presence of monensin in human endothelial cell culture produced experimental conditions that mimic Type IIA von Willebrand disease, in that the cells synthesized and secreted only low molecular weight von Willebrand protein multimers, which were functionally defective.

Detailed analysis of 24 hour ambulatory electrocardiographic recordings during ventricular fibrillation or torsade de pointes.

Although the terminal cardiac rhythm is often well documented in many cases of sudden cardiac death, the antecedent or premonitory arrhythmias are usually not retrievable. The ambulatory electrocardiographic recordings of 12 patients who sustained ventricular fibrillation or torsade de pointes while wearing a long-term electrocardiographic monitor were analyzed in detail. A printout of the entire electrocardiographic recording was made and hand counts of ventricular arrhythmias were correlated with heart rate, QTc interval, RR interval preceding ventricular fibrillation or torsade de pointes and (RR')/QT initiating ventricular fibrillation or torsade de pointes. Common ambulatory electrocardiographic features in these 12 patients experiencing ventricular fibrillation or torsade de pointes included: 1) a period of high density of increasingly frequent or complex ventricular arrhythmias, or both, preceding ventricular fibrillation or torsade de pointes (11 patients); 2) R on T beats frequently initiating ventricular fibrillation or torsade de pointes (9 patients); and 3) repolarization abnormalities present for several hours before ventricular fibrillation or torsade de pointes (7 patients). No consistent relation between the RR and RR' interval initiating ventricular fibrillation or torsade de pointes was found; no consistent alteration in heart rate occurred before ventricular fibrillation or torsade de pointes. Thus, ventricular arrhythmias leading to sudden death in an ambulatory population do not occur in isolation but are preceded by a period of increased ventricular ectopic activity. Future guidelines for assessment of antiarrhythmic drug efficacy should include an evaluation of a drug's impact not only on ectopic beat frequency but also on arrhythmia density.