Many veterans of Operation Iraqi Freedom are now returning to the United States after potential exposure to leishmaniasis. In the past year, large numbers of leishmaniasis cases of a magnitude not ...encountered in the United States since World War II have challenged clinicians in both the military and the civilian sectors. Many Reserve and National Guard troops were deployed to Iraq and are now back in their communities. Hundreds of leishmaniasis cases, which were managed by a few practitioners initially, permitted further appreciation of the epidemiology and diagnostic and treatment options for Old World leishmaniasis. We describe the current situation, with on-the-ground experience, complimented by a literature review, and we provide a practical list of options for the clinician likely to encounter this parasitic infection in the coming months and years.
Incidence of visceral leishmaniasis (VL) in the Indian subcontinent (ISC) has declined by more than 95% since initiation of the elimination program in 2005. As the ISC transitions to the ...postelimination surveillance phase, an accurate measurement of human-vector contact is needed to assure long-term success. To develop this tool, we identified PagSP02 and PagSP06 from saliva of Phlebotomus argentipes, the vector of Leishmania donovani in the ISC, as immunodominant proteins in humans. We also established the absence of cross-reactivity with Phlebotomus papatasi saliva, the only other human-biting sand fly in the ISC. Importantly, by combining recombinant rPagSP02 and rPagSP06 we achieved greater antibody recognition and specificity than single salivary proteins. The receiver operating characteristics curve for rPagSP02 + rPagSP06 predicts exposure to Ph. argentipes bites with 90% specificity and 87% sensitivity compared to negative control sera (P >.0001). Overall, rPagSP02 + rPagSP06 provides an effective surveillance tool for monitoring vector control efforts after VL elimination.
There is uncertainty regarding how to interpret discordance between tests for latent tuberculosis infection.
The objective of this study was to assess discordance between commercially available tests ...for latent tuberculosis in a low-prevalence population, including the impact of nontuberculous mycobacteria.
This was a cross-sectional comparison study among 2,017 military recruits at Fort Jackson, South Carolina, from April to June 2009. Several tests were performed simultaneously with a risk factor questionnaire, including (1) QuantiFERON-TB Gold In-Tube test, (2) T-SPOT.TB test, (3) tuberculin skin test, and (4) Battey skin test using purified protein derivative from the Battey bacillus.
In this low-prevalence population, the specificities of the three commercially available diagnostic tests were not significantly different. Of the 88 subjects with a positive test, only 10 (11.4%) were positive to all three tests; 20 (22.7%) were positive to at least two tests. Bacille Calmette-Guérin vaccination, tuberculosis prevalence in country of birth, and Battey skin test reaction size were associated with tuberculin skin test-positive, IFN-γ release assay-negative test discordance. Increasing agreement between the three tests was associated with epidemiologic criteria indicating risk of infection and with quantitative test results.
For most positive results the three tests identified different people, suggesting that in low-prevalence populations most discordant results are caused by false-positives. False-positive tuberculin skin test reactions associated with reactivity to nontuberculous mycobacteria and bacille Calmette-Guérin vaccination may account for a proportion of test discordance observed.
Abstract
Background
Dengue is a global health problem and the development of a tetravalent dengue vaccine with durable protection is a high priority. A heterologous prime-boost strategy has the ...advantage of eliciting immune responses through different mechanisms and therefore may be superior to homologous prime-boost strategies for generating durable tetravalent immunity.
Methods
In this phase 1 first-in-human heterologous prime-boost study, 80 volunteers were assigned to 4 groups and received a tetravalent dengue virus (DENV-1–4) purified inactivated vaccine (TDENV-PIV) with alum adjuvant and a tetravalent dengue virus (DENV-1–4) live attenuated vaccine (TDENV-LAV) in different orders and dosing schedules (28 or 180 days apart).
Results
All vaccination regimens had acceptable safety profiles and there were no vaccine-related serious adverse events. TDEN-PIV followed by TDEN-LAV induced higher neutralizing antibody titers and a higher rate of tetravalent seroconversions compared to TDEN-LAV followed by TDEN-PIV. Both TDEN-PIV followed by TDEN-LAV groups demonstrated 100% tetravalent seroconversion 28 days following the booster dose, which was maintained for most of these subjects through the day 180 measurement.
Conclusions
A heterologous prime-boost vaccination strategy for dengue merits additional evaluation for safety, immunogenicity, and potential for clinical benefit.
Clinical Trials Registration
NCT02239614.
A heterologous prime-boost vaccination strategy using an inactivated followed by a live-attenuated dengue vaccine demonstrated acceptable safety and produced tetravalent, durable neutralizing antibody titers.
Importance The BCG vaccine is currently the only approved tuberculosis vaccine and is widely administered worldwide, usually during infancy. Previous studies found increased rates of lymphoma and ...leukemia in BCG-vaccinated populations. Objective To determine whether BCG vaccination was associated with cancer rates in a secondary analysis of a BCG vaccine trial. Design, Setting, and Participants Retrospective review (60-year follow-up) of a clinical trial in which participants were assigned to the vaccine group by systematic stratification by school district, age, and sex, then randomized by alternation. The original study was conducted at 9 sites in 5 US states between December 1935 and December 1998. Participants were 2963 American Indian and Alaska Native schoolchildren younger than 20 years with no evidence of previous tuberculosis infection. Statistical analysis was conducted between August 2018 and July 2019. Interventions Single intradermal injection of either BCG vaccine or saline placebo. Main Outcomes and Measures The primary outcome was diagnosis of cancer after BCG vaccination. Data on participant interval health and risk factors, including smoking, tuberculosis infection, isoniazid use, and other basic demographic information, were also collected. Results A total of 2963 participants, including 1540 in the BCG vaccine group and 1423 in the placebo group, remained after exclusions. Vaccination occurred at a median (interquartile range) age of 8 (5-11) years; 805 participants (52%) in the BCG group and 710 (50%) in the placebo group were female. At the time of follow-up, 97 participants (7%) in the placebo group and 106 participants (7%) in the BCG vaccine group could not be located; total mortality was 633 participants (44%) in the placebo group and 632 participants (41%) in the BCG group. The overall rate of cancer diagnosis was not significantly different in BCG vaccine vs placebo recipients (hazard ratio, 0.82; 95% CI, 0.66-1.02), including for lymphoma and leukemia. The rate of lung cancer was significantly lower in BCG vs placebo recipients (18.2 vs 45.4 cases per 100 000 person-years; hazard ratio, 0.38; 95% CI, 0.20-0.74;P = .005), controlling for sex, region, alcohol overuse, smoking, and tuberculosis. Conclusions and Relevance Childhood BCG vaccination was associated with a lower risk of lung cancer development in American Indian and Alaska Native populations. This finding has potentially important health implications given the high mortality rate associated with lung cancer and the availability of low-cost BCG vaccines.
The duration of protection from tuberculosis of BCG vaccines is not known.
To determine the long-term duration of protection of a BCG vaccine that was previously found to be efficacious.
...Retrospective record review using Indian Health Service records, tuberculosis registries, death certificates, and supplemental interviews with trial participants.
Follow-up for the period 1948-1998 among American Indians and Alaska Natives who participated in a placebo-controlled BCG vaccine trial during 1935-1938 and who were still at risk of developing tuberculosis. Data from 1483 participants in the BCG vaccine group and 1309 in the placebo group were analyzed.
Efficacy of BCG vaccine, calculated for each 10-year interval using a Cox regression model with time-dependent variables based on tuberculosis events occurring after December 31, 1947 (end of prospective case finding).
The overall incidence of tuberculosis was 66 and 138 cases per 100 000 person-years in the BCG vaccine and placebo groups, respectively, for an estimate of vaccine efficacy of 52% (95% confidence interval, 27%-69%). Adjustments for age at vaccination, tribe, subsequent BCG vaccination, chronic medical illness, isoniazid use, and bacille Calmette-Guérin strain did not substantially affect vaccine efficacy. There was slight but not statistically significant waning of the efficacy of BCG vaccination over time, greater among men than women.
In this trial, BCG vaccine efficacy persisted for 50 to 60 years, suggesting that a single dose of an effective BCG vaccine can have a long duration of protection.
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.
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 degrees 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.
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.
ClinicalTrials.gov NCT 00884377.
•Transcutaneous immunization (TCI), a needle-free route was used to deliver Leishmania antigens.•TCI resulted in high antibody response to both antigens and adjuvant and a Th1 type cellular ...response.•TCI with SLA/CT was associated with exacerbation of disease after parasite challenge.•Decreased inducible nitric oxide synthase staining was associated with exacerbation.
Leishmaniasis is an expanding health threat worldwide complicated by the absence of an effective vaccine. We investigated transcutaneous immunization (TCI) as a needle-free immunization route which exploits the abundance of antigen presenting cells in the skin to induce both mucosal and systemic immunity. Leishmania (L.) major soluble antigens (SLA) or recombinant Leishmania homolog of receptors for activated C-kinase (rLACK) antigens were delivered transcutaneously together with cholera toxin (CT), to BALB/c mice. Mice were immunized at weeks 1, 4, and 7 with PBS, CT, SLA/CT or rLACK/CT. Two weeks after the final boost, antigen-specific IgG titers, IFN-γ ELISpot, and cytokine levels were assessed in half of the mice and the remainder were challenged with an intradermal (ear) injection of 5 × 104L. major metacyclic parasites. Mice were monitored weekly and sacrificed after 7 weeks to assess the parasite burden and to study the ear lesion immunohistopathology. Our results show that TCI with SLA or rLACK yielded high levels of anti-SLA, anti-rLACK and anti-CT IgG antibodies. A Th1-type of immune response was demonstrated with a high frequency of IFN-γ secreting cells, high levels of IFN-γ production, and lower levels of IL-10 resulting in a high IFN-γ/IL-10 ratio in mice immunized with SLA/CT or rLACK/CT. After parasite challenge, rLACK immunization was not associated with protection. In addition, SLA/CT immunized mice had larger ear lesions and an increased parasite load in the ear. Immunohistochemistry of ear biopsies stained for nitric oxide synthase revealed that staining intensity was diminished in the SLA/CT group compared to the control group. This finding suggested that less parasite killing occurred at the site of the infection.
In conclusion, despite a strong Th1 type profile induced by TCI, exacerbation of infection occurred after challenge with L. major. This also correlated with low induction of nitric oxide.
Visceral leishmaniasis patients have been reported to have a urine concentration defect. Concentration of urine by the renal inner medulla is essentially dependent on a transcription factor, ...NFAT5/TonEBP, because it activates expression of osmoprotective genes betaine/glycine transporter 1 (BGT1) and sodium/myo-inositol transporter (SMIT), and water channel aquaporin-2, all of which are imperative for concentrating urine. Leishmania parasites evade macrophage immune defenses by activating protein tyrosine phosphatases, among which SHP-1 is critical. We previously demonstrated that SHP-1 inhibits tonicity-dependent activation of NFAT5/TonEBP in HEK293 cells through screening a genome-wide small interfering (si) RNA library against phosphatases (Zhou X, Gallazzini M, Burg MB, Ferraris JD. Proc Natl Acad Sci USA 107: 7072-7077, 2010). We sought to examine whether Leishmania can activate SHP-1 and inhibit NFAT5/TonEBP activity in the renal inner medulla in a murine model of visceral leishmaniasis by injection of female BALB/c mice with a single intravenous dose of 5 × 10(5) L. chagasi metacyclic promastigotes. We found that SHP-1 is expressed in the kidney inner medulla. L. chagasi activates SHP-1 with an increase in stimulatory phosphorylation of SHP-1-Y536 in the region. L. chagasi reduces expression of NFAT5/TonEBP mRNA and protein as well as expression of its targeted genes: BGT1, SMIT, and aquaporin-2. The culture supernatant from L. chagasi metacyclic promastigotes increases SHP-1 protein abundance and potently inhibits NFAT5 transcriptional activity in mIMCD3 cells. However, L. chagasi in our animal model has no significant effect on urinary concentration. We conclude that L. chagasi, most likely through its secreted virulence factors, activates SHP-1 and reduces NFAT5/TonEBP gene expression, which leads to reduced NFAT5/TonEBP transcriptional activity in the kidney inner medulla.
Background. Low bone mineral density (BMD) is common among patients infected with human immunodeficiency virus (HIV) and present in higher rates in black subjects. This study assessed vitamin D ...levels in HIV cases versus noninfected matched controls to determine if deficiency was associated with BMD and HIV clinical outcomes. Methods. In total, 271 military beneficiaries with HIV underwent dual energy x-ray absorptiometry (DEXA) screening in 2001-2. Serum 25OH-vitamin D levels were determined using stored serum from the time of DEXA and 6-18 months prior. Two non-HIV-infected controls for each active duty case (n = 205) were matched on age, sex, race, zip code, and season using the Department of Defense Serum Repository (DoDSR). Vitamin D levels < 20 ng/mL were considered deficient. HIV-related factors and clinical outcomes were assessed using data collected in the DoD HIV Natural History study. Results. In total, 165 of 205 (80.5%) active duty HIV cases had 2 matched controls available. HIV cases had greater odds of for vitamin D deficiency (VDD) compared with controls (demographics adjusted paired data odds ratio OR, 1.46, 95% confidence interval CI, .87-2.45), but this was not statistically significant. Blacks were disproportionately deficient (P <.001) but not relative to HIV status or BMD. Low BMD was associated with typical risk factors (low body mass index and exercise levels, alcohol use); given limited available data the relationship between tenofovir exposure and VDD or low BMD could not be determined. Analysis of HIV-specific factors and outcomes such as exposure to antiretrovirals, HIV progression, hospitalizations, and death revealed no significant associations with vitamin D levels. Conclusions. VDD was highly prevalent in black HIV-infected persons but did not explain the observed racial disparity in BMD. Vitamin D deficiency was not more common among HIV-infected persons, nor did it seem associated with HIV-related factors/clinical outcomes.
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