James O. Ballard

Natural History of Human Immunodeficiency Virus Infections in Hemophiliacs: Effects of T-Cell Subsets, Platelet Counts, and Age

Serial T-cell subsets and platelet counts were determined in a cohort of 84 hemophiliacs in whom time of seroconversion for human immunodeficiency virus (HIV) antibody could be ascertained. An abrupt decrease in the number of T-helper (T4) cells was seen in 9 patients 12 to 24 months before the acquired immunodeficiency syndrome (AIDS) was diagnosed (p = 0.0007 compared with those who did not develop AIDS). Thrombocytopenia also was associated with an increased risk for AIDS (p = 0.02), as was older age at the time of seroconversion (p = 0.03). Ten patients developed AIDS at 24 to 95 months after seroconversion, for a cumulative incidence (+/- SE) of 18.0% +/- 7.1% at 6 years. Hemophiliacs who had T4 cell counts of less than 200 cells/microL had a 50% +/- 16% cumulative incidence of AIDS within 2 years, indicating that decreasing or very low T4 cell counts have predictive value for the development of AIDS. Furthermore, the data suggest that thrombocytopenia and older age may be markers for a cofactor that increases the risk for AIDS in hemophiliacs.

Predictive Markers for the Acquired Immunodeficiency Syndrome (AIDS) in Hemophiliacs: Persistence of p24 Antigen and Low T4 Cell Count

STUDY OBJECTIVE To investigate the predictive value of assays for human immunodeficiency virus (HIV) p24 antigen, p24 antibody, and gp120 antibody compared with T4 cell counts. DESIGN Prospective cohort selected from persons who had HIV-antibody seroconversion. PATIENTS Eighty-seven persons with hemophilia with an actuarial cumulative acquired immunodeficiency syndrome (AIDS) incidence of 26% (CI, 12% to 40%), 8 years after HIV-antibody seroconversion. INTERVENTION None. MEASUREMENTS AND MAIN RESULTS Human immunodeficiency virus p24 antigen was detected in 8 of 74 (11%) of the patients without AIDS and 7 of 13 (54%) of the patients with AIDS. The 2-year actuarial incidence of AIDS was 24% (CI, 0% to 48%) after detection of p24 antigen, 16% (CI, 0% to 34%) after loss of p24 antibody, 20% (CI, 0% to 45%) after loss of gp120 antibody, 31% (CI, 15% to 47%) after a T4 count of less than 200 cells/microL, and 67% (CI, 31% to 100%) after a T4 count of less than 200 cells/microL among those patients positive for p24 antigen. Very low numbers of T4 and T8 lymphocytes, presence of p24 antigen in serum, and absence of p24 antibody all had some predictive value. However, only p24 antigen (relative hazard 6.0, P = 0.008) and T4 counts (relative hazard 5.3, P = 0.002 with T4 count less than 200 cells/microL) independently predicted AIDS up to 12 months before diagnosis. CONCLUSIONS Strong predictors of AIDS are p24 antigenemia or low T4 counts. Detection of p24 antigen is highly specific and complementary to the greater sensitivity of low T4 counts. These findings have important implications regarding prognosis, counseling, and the planning of clinical trials.

Potential for Bleeding with the New Beta-Lactam Antibiotics

Several new beta-lactam antibiotics impair normal hemostasis. Hypoprothrombinemia has occurred frequently with cephalosporins that possess a methylthiotetrazole substitution (cefamandole, moxalactam, and cefoperazone). The incidence ranges from 4% to 68%, and the risk is greatest in debilitated patients with cancer, intra-abdominal infection, or renal failure. Impaired platelet function caused by perturbation of agonist receptors on the platelet surface has occurred primarily with beta-lactam antibiotics having an alpha-carboxyl substitution (moxalactam, carbenicillin, and ticarcillin). These antibiotics often cause the template bleeding time to be markedly prolonged (greater than 20 minutes). Acylureidopenicillins, which lack the alpha-carboxyl marker, impair platelet function less frequently and only modestly prolong the bleeding time. If serious hemorrhage occurs, hypoprothrombinemia associated with methylthiotetrazole-substituted cephalosporins should be treated with fresh frozen plasma. Likewise, dangerous bleeding due to impaired platelet aggregation requires treatment with platelet concentrates.

Knee and hip arthroplasty infection rates in persons with haemophilia: a 27 year single center experience during the HIV epidemic

Summary.  Total joint replacement (TJR) is an option for the management of chronic haemophilic arthropathy. Because surgery is technically challenging, there is a high rate of deep prosthetic infections, particularly in human immunodeficiency virus (HIV)‐infected individuals. We determined the incidence of deep infection rates following total knee and hip arthroplasties in HIV‐seropositive and HIV‐seronegative persons with haemophilia. Fifty‐one primary joint replacements were performed on 32 patients seen at a regional comprehensive haemophilia care center from 1975 to 2002. Thirty prostheses were placed in patients who were HIV‐seropositive prior to surgery (n = 14) or seroconverted later (n = 16). Median age at the time of surgery was 33 years (range: 20–61) among 19 HIV‐seropositive patients and 35 years (range: 26–74) among 13 HIV‐negative patients. Median duration of follow‐up was 83 months (range: 2–323). Rate of primary joint infection per artificial joint‐year by HIV status was compared by Poisson regression. Main outcome measures were the incidence of primary replacement joint infections by HIV status. Deep infections developed in five (9.8%) of 51 replacement joints. There were two infections during 204.15 joint‐years without HIV infection and three infections during 205.28 joint‐years with HIV infection. The incidence rate of joint infection (0.98 vs. 1.46 per 100 joint‐years) was not increased with HIV (relative risk, RR: 1.49, 95% CI: 0.25–8.93, P = 0.66). We conclude that HIV infection is not a contraindication to knee or hip replacement arthroplasty in the appropriate clinical setting.

Primary Pulmonary Hypertension in Patients with Classic Hemophilia

Five patients with classic hemophilia were found to have primary pulmonary hypertension, a disorder not previously recognized in this population. All patients had had their coagulation disorder treated for 10 years or more with self-administered lyophilized concentrates of factor VIII, and all had antibodies to human immunodeficiency virus (HIV). Primary pulmonary hypertension was confirmed by histologic means at autopsy in one patient and by lung biopsy findings in another. In the other three patients, the findings are in agreement with this diagnosis. No patient had underlying cardiac or pulmonary disease, or clinical or pathologic evidence of collagen-vascular disease, vasculitis, parasitic disorders, hemoglobinopathy, or exposure to anorexigenic agents. Whether the primary pulmonary hypertension was related to treatment with lyophilized factor VIII, or to the presence of antibodies to HIV, or both, is unknown.

Impaired hemostasis caused by beta-lactam antibiotics

Beta-lactam antibiotics can directly impair hemostasis by two separate nonimmune mechanisms. First, the NMTT-substituted cephalosporin drugs may cause hypoprothrombinemia by interfering with the hepatic activation of clotting factors II, VII, IX, and X. Second, the antipseudomonal penicillins may cause the bleeding time to be prolonged by interfering with platelet aggregation to physiologic agonists. In surgical patients who are malnourished, have impaired gastrointestinal function, or have renal failure, the potential for these adverse effects is increased. Serious bleeding requires treatment with fresh frozen plasma when hypoprothrombinemia is caused by NMTT-containing cephalosporins, since the prothrombin time returns to baseline relatively slowly after therapy with vitamin K. Hemorrhage caused by beta-lactam-induced platelet dysfunction must be treated with platelet concentrates, since new platelets sufficient to correct the defect do not enter the circulation for several days after treatment with the offending drug is discontinued. The more desirable approach is to prevent hypoprothrombinemia by giving vitamin K prophylaxis and to avoid beta-lactams that impair platelet function in seriously ill patients at increased risk for bleeding.

Septicemia Due to Capnocytophaga (Bacteroides ochraceus) in Hodgkin's Disease

Excerpt To the editor: A recent symposium (1) in the November 1978 supplement issue has emphasized the importance of infections in hospital practice. Patients with malignancies are especially prone...

Neurologic complications of acute myelomonoblastic leukemia of four years' duration

An adult with acute nonlymphoblastic leukemia involving the central nervous system is presented. Unusual features included: (1) Focal signs and radiographic evidence of sagittal sinus occlusion early in the course of disease; (2) progressive meningeal, cranial nerve, and spinal nerve involvement despite a 4-year bone marrow remission; (3) intracerebral tumor formation, and (4) retrobulbar optic neuritis associated with microscopic findings of herpeslike viral particles. The incidence of clinically overt neurologic disease in adults with acute nonlymphoblastic leukemia seems to have increased in tandem with improved chemotherapy. The prophylactic treatment of the central nervous system during prolonged remission of adult acute nonlymphoblastic leukemia may prove of benefit to these patients.

Acquired Dysfibrinogenemia in a Hemophiliac with Hepatoma: Resolution of Fibrinogen Dysfunction Following Chemotherapy

A 17‐year‐old male with previously undiagnosed congenital Factor IX deficiency (13%) presented with gastrointestinal bleeding and a hepatic mass. Prolonged thrombin and Reptilase times, which partially corrected with CaCl2 and a discrepancy between thrombin‐clottable and immunoreactive plasma fibrinogen, suggested a dysfibrinogenemia. Laparotomy disclosed metastatic hepatoma. Adequate hemostasis was obtained with clotting factor replacement, but wound healing was delayed. Patient fibrinogen purified with 2.1 M glycine migrated normally on immunoelectrophoresis and 7.5% polyacrylamide‐SDS gel electrophoresis. However, fibrin monomers prepared from purified patient fibrinogen displayed impaired aggregation at high and low ionic strengths when compared with fibrin monomers from normal and control Factor IX deficient subjects. Aggregation of normal monomers was delayed when mixed 1:1 with patient monomers. Fibrinopeptide release was normal, and total sialic acid content was similar to that of normal and control fibrinogens. Chemotherapy, consisting of 5‐FU given via intra‐arterial hepatic infusion, was accompanied by significant transient clinical improvement which coincided with correction of thrombin clotting times and fibrin monomer aggregation. Reappearance of fibrinogen dysfunction occurred with clinical deterioration prior to death from metastatic hepatoma and sepsis. This case is the first to corroborate the postulated tumor marker role of dysfibrinogenemia in a patient with hepatoma by documenting a direct relationship with response to chemotherapy.

Selective use of daunorubicin for remission-induction chemotherapy in acute non-lymphoblastic leukemia

Twenty‐eight patients with acute non‐lymphoblastic leukemia (ANLL) were started on induction chemotherapy consisting of Cytosine Arbinoside (Ara C) and 6 thioguanine (TG). Daunorubicin (DNR) was used selectively in 20 of 28 patients who failed to respond by day 14 to the Ara C and TG combination. Seven patients, or 25%, achieved complete remission (CR) without requiring DNR during remission induction. The overall response rate was 89% (64% CR and 25% PR). The median duration of survival for the CR group was 578 days. 189 days for the partial remission (PR) group (P = .02). Patients in the age group of 18–40 years and with acute myelomonocytic leukemia subtype had the best response rate. There was no difference in the survival of the DNR treated group of complete responders as compared to DNR non‐treated group. These results suggest that even though the majority of patients do require DNR for the remission induction, a significant number, perhaps as high as 25% of previously untreated patients, will achieve remission without the use of DNR. A significant minority of patients can, therefore, be spared the toxicity of DNR early in the course of their disease.