Charles N. Oster

A controlled trial of early versus late treatment with zidovudine in symptomatic human immunodeficiency virus infection. Results of the Veterans Affairs Cooperative Study.

BACKGROUND Zidovudine is recommended for asymptomatic and early symptomatic human immunodeficiency virus (HIV) infection. The best time to initiate zidovudine treatment remains uncertain, however, and whether early treatment improves survival has not been established. METHODS We conducted a multicenter, randomized, double-blind trial that compared early zidovudine therapy (beginning at 1500 mg per day) with late therapy in HIV-infected patients who were symptomatic and had CD4+ counts between 0.2 x 10(9) and 0.5 x 10(9) cells per liter (200 to 500 per cubic millimeter) at entry. Those assigned to late therapy initially received placebo and began zidovudine when their CD4+ counts fell below 0.2 x 10(9) per liter (200 per cubic millimeter) or when the acquired immunodeficiency syndrome (AIDS) developed. RESULTS During a mean follow-up period of more than two years, there were 23 deaths in the early-therapy group (n = 170) and 20 deaths in the late-therapy group (n = 168) (P = 0.48; relative risk [late vs. early], 0.81; 95 percent confidence interval, 0.44 to 1.59). In the early-therapy group, 28 patients progressed to AIDS, as compared with 48 in the late-therapy group (P = 0.02; relative risk, 1.76; 95 percent confidence interval, 1.1 to 2.8). Early therapy increased the time until CD4+ counts fell below 0.2 x 10(9) per liter (200 per cubic millimeter), and it produced more conversions from positive to negative for serum p24 antigen. Early therapy was associated with more anemia, leukopenia, nausea, vomiting, and diarrhea, whereas late therapy was associated with more skin rash. CONCLUSIONS In symptomatic patients with HIV infection, early treatment with zidovudine delays progression to AIDS, but in this controlled study it did not improve survival, and it was associated with more side effects.

A Randomized, Double-Blind Study of the Efficacy of a 10- or 20-Day Course of Sodium Stibogluconate for Treatment of Cutaneous Leishmaniasis in United States Military Personnel

The recommended treatment for cutaneous leishmaniasis is pentavalent antimony at a dosage of 20 mg/kg/day for 20 days. Some studies conducted in locales in which Leishmania is endemic have suggested that shorter courses of treatment may be as efficacious. We conducted a randomized, double-blind, placebo-controlled study of 10 versus 20 days of sodium stibogluconate (SSG) in United States military personnel who contracted cutaneous leishmaniasis while serving overseas; 19 patients received SSG for 10 days (and placebo for 10 days), and 19 patients received SSG for 20 days. Cure rates were 100% (19 of 19 patients) in the 10-day group and 95% (18 of 19 patients) in the 20-day group. Side effects were more common among patients who received 20 days of therapy. In this group of otherwise healthy young adults, SSG at a dosage of 20 mg/kg/day for 10 days appears to have been therapeutically equivalent and less toxic than the standard 20-day course.

Cutaneous leishmaniasis in Kenya: transmission of Leishmania major to man by the bite of a naturally infected Phlebotomus duboscqi

One leishmanial stock was isolated from a Phlebotomus duboscqi female captured in Baringo District, Kenya, and others from papular lesions that developed at sites where this sandfly had fed on a man. When characterized by cellulose acetate electrophoresis (eight enzymes examined), these isolates proved to be identical to known Leishmania major strains from man and a rodent (Arvicanthis sp.) and different from L. donovani and L. adleri, which also occur in Baringo. This is the first case of human cutaneous leishmaniasis caused by L. major reported from Kenya.

A Randomized Controlled Trial of Local Heat Therapy Versus Intravenous Sodium Stibogluconate for the Treatment of Cutaneous Leishmania major Infection

Background Cutaneous Leishmania major has affected many travelers including military personnel in Iraq and Afghanistan. Optimal treatment for this localized infection has not been defined, but interestingly the parasite is thermosensitive. Methodology/Principal Findings Participants with parasitologically confirmed L. major infection were randomized to receive intravenous sodium stibogluconate (SSG) 20mg/kg/day for ten doses or localized ThermoMed (TM) device heat treatment (applied at 50°C for 30 seconds) in one session. Those with facial lesions, infection with other species of Leishmania, or more than 20 lesions were excluded. Primary outcome was complete re-epithelialization or visual healing at two months without relapse over 12 months. Fifty-four/56 enrolled participants received intervention, 27 SSG and 27 TM. In an intent to treat analysis the per subject efficacy at two months with 12 months follow-up was 54% SSG and 48% TM (p = 0.78), and the per lesion efficacy was 59% SSG and 73% TM (p = 0.053). Reversible abdominal pain/pancreatitis, arthralgias, myalgias, headache, fatigue, mild cytopenias, and elevated transaminases were more commonly present in the SSG treated participants, whereas blistering, oozing, and erythema were more common in the TM arm. Conclusions/Significance Skin lesions due to L. major treated with heat delivered by the ThermoMed device healed at a similar rate and with less associated systemic toxicity than lesions treated with intravenous SSG. Clinical Trial Registration ClinicalTrials.gov NCT 00884377

Cutaneous Leishmaniasis following Local Trauma: A Clinical Pearl

Cutaneous leishmaniasis is acquired from the bite of an infected sand fly and can result in chronic skin lesions that develop within weeks to months after a bite. Local trauma has been implicated as a precipitating event in the development of skin lesions in patients who have been infected with Leishmania species. Here we report a case series and review the literature on patients who developed cutaneous leishmaniasis after local trauma, which may familiarize clinicians with this presentation.

Cutaneous leishmaniasis caused by Leishmania tropica in Kenya

Cutaneous leishmaniasis is endemic in Algeria, but clinical and parasitological data from this area are scarce. In order to document the transmission of this disease in a peri-urban setting, cutaneous lesions from patients living in Constantine City and surrounding areas were spotted on filter paper for diagnosis and species identification using real-time PCR. Surprisingly, Leishmania tropica was detected in 6/69 patients, and confirmation was obtained by sequencing. This observation suggests a modification of the epidemiology of cutaneous leishmaniasis in Algeria and should alert physicians and policy-makers to the risk of antimony treatment failure with this species.9 leishmanial strains, isolated from cutaneous papulonodular lesions on 3 patients, were characterized by cellulose acetate electrophoresis using 7 enzymes. The patterns obtained were indistinguishable from those of a Leishmania tropica reference strain and these 9 strains were similar to L. tropica in failing to infect mice. Although these 3 patients were Americans, their only potential exposure to sandflies was in Kenya, and thus they are believed to be the first cases of cutaneous leishmaniasis due to L. tropica in Kenya.

Lymph node involvement in leishmaniasis

Two U.S. Army soldiers acquired skin lesions of cutaneous leishmaniasis and enlarged lymph nodes while stationed in Panama. In the first case, parasites were histologically identified and cultured from the skin lesion and a contralateral lymph node. In the second case, parasites were cultured from an enlarged lymph node in a nodal group draining the lesion. These findings suggest that metastasis of cutaneous leishmanial infection may be more common than is generally appreciated.

Predictors of HIV-1 disease progression in early- and late-stage patients : the U.S. Army natural history cohort

HIV-infected individuals in both early and late stages of HIV disease were evaluated over 2 years to assess temporal trends and determinants of disease progression. The Walter Reed (WR) staging system was used to categorize patients into an early-stage cohort (WR Stages 1 and 2. N = 1183) and a late-stage cohort (WR Stage 5, N = 260) based on the initial clinical evaluation. Progression was defined as the occurrence of Stage 5 disease or beyond for the early cohort and Stage 6 disease or beyond for the late cohort. The cumulative incidence of progression was 15.7% (137 events) for the early-stage cohort, and 53.7% (85 events) for the late-stage cohort. Baseline CD4+ T lymphocyte (T4) count was the most significant marker of progression: 26% of WR Stage 1 or 2 patients with T4 lymphocytes below 500/mm3 progressed, compared with 12% with T4 lymphocytes at or above 500/m3. In late-stage individuals, 83% with T4 lymphocytes under 200/mm3 progressed, compared with 27% with T4 lymphocytes at or above 200/mm3. Older age was associated with progression in both early-and late-stage groups. Differences in the rates of disease progression were not significant between blacks and whites or between men and women. Two-year rates of progression among the late-stage patients dropped from 78 to 47% between 1986 and 1988. This contrasted with progression rates in the early-stage cohort, which remained stable: 18% for those entering follow-up in 1986 and 17% for those entering follow-up in 1988. These data indicate a significant slowing of HIV disease progression rates and mortality rates among individuals with late-stage disease that is temporally associated with the increased availability and use of therapies. With control of T4 lymphocyte count, age, and calendar time, neither gender nor race was significantly associated with progression in either early-or late-stage patients.

Activation of Macrophages to Kill Rickettsiae and Leishmania: Dissociation of Intracellular Microbicidal Activities and Extracellular Destruction of Neoplastic and Helminth Targets

Mononuclear phagocytes undergo dramatic changes during differentiation from bone marrow stem cells to resident tissue macrophages. Throughout differentiation, cells lose or acquire numerous morphologic, metabolic and functional capacities such that mature, resident macrophages of one tissue often bear little resemblance to resident cells of another. Superimposed on the intrinsic continuum of mononuclear phagocyte differentiation are the reactive changes in macrophages induced by endogenous and exogenous stimuli: the ability of mononuclear phagocytes to respond to a particular stimulus may also change with cell differentiation. This dynamic interaction of cell differentiation and response to a micro-environment, and the resulting heterogeneity among mononuclear phagocytes for many functional characteristics, is clearly illustrated by the effector activities of activated macrophages that we describe in this report. Despite the common regulatory events for induction and expression of transient nonspecific cytotoxic reactions effective against such diverse targets as rickettsiae, leishmania, schistosomula, and neoplastic cells, these effector functions can be dissociated by the cells that perform the effector activity, and the signals that regulate these activities. The differential susceptibility of the various targets to particular killing mechanisms induced by LK in responsive populations only adds to the complexity of these in vitro analyses. The details of effector functions of activated macrophages are unique for each target.

Herpes Zoster and Lymphopenia Associated with Sodium Stibogluconate Therapy for Cutaneous Leishmaniasis

A review of 84 patients with cutaneous leishmaniasis treated with sodium stibogluconate (Pentostam) at our institution revealed that three had developed herpes zoster during or shortly after receiving therapy. Because zoster has been associated with depressed cellular immunity, we prospectively followed serial lymphocyte subpopulations in eight patients with cutaneous leishmaniasis who received Pentostam. By day 7 of therapy, the white blood cell count had fallen by a median of 1.15/mm3, the total lymphocyte count by a median of 804/mm3, and the CD4+ lymphocyte count by a median of 306/mm3 (67% of baseline; confidence interval, 52%-78%). An in vitro cell-viability assay demonstrated that Pentostam is not toxic to human mononuclear cells. The administration of Pentostam for the treatment of cutaneous leishmaniasis results in lymphopenia that may be related to the subsequent occurrence of herpes zoster.