Abstract
Background
Visceral leishmaniasis (VL) is a chronic protozoal disease caused from the bite of an infected sand fly. VL due to Leishmania infantum is endemic in Afghanistan, although its ...distribution is poorly characterized. The spectrum of VL ranges from asymptomatic to active VL with symptoms of fever, weight loss, organomegaly, and pancytopenia. Most symptomatic patients die without treatment; asymptomatic patients remain at risk lifelong for symptomatic reactivation—especially if immunosuppressed. Travelers returning from VL endemic areas may harbor latent infection years after their return. We aimed to determine the prevalence of asymptomatic VL (AVL) in US military personnel previously deployed to Afghanistan.
Methods
Healthy adult US military personnel who deployed to Afghanistan over summer months were recruited from the Washington DC area. 90 volunteers completed a risk factor survey, blood draw, and had completed results. Diagnostic testing utilized Leishmania
ELISA, interferon gamma release assay (IGRA), and quantitative PCR (qPCR). Statistical analyses included Fisher exact test, Pearson χ2 test, Welch Two Sample t-test, and Mann-Whitney U test. IRB approval was obtained.
Results
The prevalence of AVL (ELISA, IGRA, or qPCR positivity) in the volunteers was 9/90 (10%). Two (2.2%) PCR, 7 (7.8%) ELISA, and no (0%) IGRA samples were positive. AVL+ participants were a median of 10.6 years (range 8 - 18.6) post Afghanistan deployment, and compared to AVL- volunteers, were older (median 50 versus 40 years, p= 0.008) and more likely to self-identify as African-American (n = 5 (56%) vs 16 (20%), p = 0.029). No risk factors for AVL were identified in exploratory analysis of the volunteers’ military roles, types of outdoor exposure, or deployment location within Afghanistan.
Conclusion
In this preliminary cross-sectional analysis of US military personnel who returned from Afghanistan, the prevalence of AVL was 10%–comparable to other published studies on the prevalence of AVL in endemic areas and of concern when one considers the several million US military personnel previously deployed to Iraq and Afghanistan. Due to the persistence of this intracellular infection, clinicians should be alerted for reactivation potential in previously deployed Servicemembers.
Disclosures
Naomi E. Aronson, MD, british medical journal: Honoraria|British Medical Journal: honoraria for writing chapter for Best Evidence|Elsevier: royallties serve as textbook editor|Elsevier: Royalties as text editor|UpTo Date: royalties for writing chapters|UpToDate: royalties for writing chapters|Wellcome Foundation: Honoraria|Wellcome Foundation: program advisory board|Wellcome Trust: Honoraria|Wellcome Trust: program advisory board Naomi E. Aronson, MD, british medical journal: Honoraria|British Medical Journal: honoraria for writing chapter for Best Evidence|Elsevier: royallties serve as textbook editor|Elsevier: Royalties as text editor|UpTo Date: royalties for writing chapters|UpToDate: royalties for writing chapters|Wellcome Foundation: Honoraria|Wellcome Foundation: program advisory board|Wellcome Trust: Honoraria|Wellcome Trust: program advisory board
Bacille Calmette-Guérin (BCG) vaccination is known to cause false-positive tuberculin skin test (TST) results from cross-reactions with mycobacterial antigens. However, the duration of BCG ...vaccination influence on the TST is poorly characterized. The objective of this study was to assess the long-term effect of BCG vaccination on TST reactivity.
Data on TST reactivity were prospectively collected during 1935 to 1947 as part of a clinical trial among Native Americans/Alaskan Natives and were retrospectively collected thereafter between 1948 and 1998. TST induration of ≥ 10 mm was defined as a positive reaction. Kaplan-Meier analysis and multivariate Cox regression were used to compare the time to TST conversion and reversion between the BCG and placebo groups.
BCG vaccination after infancy was associated with an increased risk of TST reactivity in the first 15 years after vaccination (adjusted hazard ratio HR, 2.33). This association remained during the interval 16 to 55 years after vaccination, although the effect was attenuated (adjusted HR, 1.26). Age at vaccination modestly impacted the effect of BCG on TST results in the first 15 years. Positive TST results among the BCG-vaccinated group were more likely to revert to negative results during the first 15 years but not in the latter period.
This study provides evidence that BCG vaccination after infancy may influence TST results beyond the 10-year period conventionally accepted by the Centers for Disease Control and Prevention (CDC), extending up to 55 years after vaccination. This suggests that BCG vaccination should be taken into account when interpreting TST results regardless of the time elapsed since vaccination.
Abstract
Background
Liposomal amphotericin B (L-amB, AmBisome®) is popular for off-label use in the treatment of cutaneous leishmaniasis (CL) using dosing of 3 mg/kg/day for days 1–5, 8, 9, or days ...1–5, 10 with reported clinical cure rates of 46–84%. In rodents, the skin concentration of L-amB is 40-fold less than that in visceral organs. We hypothesize that a specific L-amB regimen targeted to skin concentrations could maximize a beneficial treatment response in CL.
Methods
SKH1 477 Elite hairless mice (Charles River), 5 per group, received intravenous L-amB at doses of (A) 3 mg/kg/day for days 1–5, 8, 9, (B) 5 mg/kg/day for 4 days, (C) 10 mg/kg load than 5 mg/kg/day for 3 days, (D)10 mg/kg/day for 2 days, (E) 15 mg/kg/day for 2 days. Serum and skin (back) punch biopsies were collected on day 0, 2, 5, 14, and 21. Nasal mucosa was biopsied on day 21. Tissue samples were homogenized and L-amB was extracted with methanol and acetonitrile. Liquid chromatography–mass spectrometry was performed using these extracted samples on an Agilent 1200 series HPLC and an AB Sciex Q-Trap 4000 mass spectrometer. Experiment conducted twice for confirmation.
Results
L-amB doses were well tolerated by the mice, except weight loss was seen in regimen E. Day 21 serum L-amB levels were 82 ± 3.2 (ng/mL) regimen A, 91 ± 4.2 in B, 89 ± 4 in C, 118 ± 3.7 in D, 98 ± 1.5 in E. Mean L-amB nasal tissue levels on day 21 were 1.33 + 3.2 (ng/mg tissue) regimen A and 6.5 ± 3 in D (P = 0.031). Mean L-amb skin levels on day 14 were 8.4 ± 5.6 (ng/mg tissue) in regimen A, 4.0 ± 1.7 in B, 6.2 ± 3.3 in C, 13.9 ± 7.1 in D, 33.9 ± 24.7 in E. Skin L-amB levels at day 21 were less than 5 (ng/mg tissue) except for regimen D 9.3 ± 4.2 and regimen E 7.8 ± 2.6. SKH1 477 Elite mice did not permit an adequate Leishmania major infection (very tiny lesions when compared with other murine species) to correlate these results clinically in this specific murine model.
Conclusion
While regimens A–D received similar total dosages of L-amB, the skin and nasal mucosal levels were significantly higher in the short, high daily dose regimens compared with the L-amB regimen that is currently used in CL patients. This suggests that better clinical results might be seen by using a L-amB dosing regimen for CL of 10 mg/kg for 2 days, a dose regularly used in the treatment of pediatric visceral leishmaniasis.
Disclosures
All authors: No reported disclosures.
Sodium stibogluconate (Pentostam(R); GlaxoSmithKline) is a pentavalent antimonial compound used in the treatment of leishmaniasis, which has an association with reactivation of varicella zoster virus ...(VZV). We report the first known case of an immunocompetent adult who developed VZV aseptic meningitis and dermatomal herpes zoster during treatment with sodium stibogluconate.
Abstract
Background
Cutaneous leishmaniasis (CL) is a threat to U.S. Military personnel as they deploy to endemic areas. As treatment may require evacuation, CL undermines operations. Elucidating the ...epidemiology of CL in this population is key for prevention.
Methods
We retrospectively reviewed data from a CL sodium stibogluconate treatment trial at Walter Reed Army Medical Center, Washington DC. 412 military members with parasitologically confirmed CL and deployment to Southwest Asia from May 2002 - August 2004 enrolled. Subjects’ CL lesions were counted and measured. 334 subjects completed a risk survey. Given no control group, we used number of CL lesions (NL), total lesion area (TLA), and lesion location as outcomes to assess CL risks. Non-parametric tests and logistic regression were used as appropriate.
Results
Permethrin treated bed net use was associated with lower NL (p = 0.000), TLA (p = 0.024), and odds of head/face lesion (OR 0.12, p = 0.047). Sleeping in a combat uniform was associated with lower TLA (p = 0.000) and odds of leg/foot lesion (OR 0.39, p = 0.023). Use of a permethrin treated uniform (p = 0.002) and N,N-diethyl-meta-toluamide (DEET) insect repellent at night (p = 0.046) were associated with lower NL. Noting unit members with similar lesions was associated with higher NL (p = 0.007) and odds of head/face lesion (OR 12.1, p = 0.019). National Guard status followed by Active Duty was associated with higher NL (p = 0.002) and TLA (p = 0.000) than Reserve. Sleeping in a building was associated with higher TLA (p = 0.008) and odds of arm lesion (OR 2.28, p = 0.016). Sleeping near animal burrows was associated with higher NL (p = 0.031). Sleeping on a cot (p = 0.006), certain ethnicities (p = 0.020) and certain military occupational specialties (p =0.038) were associated with higher TLA. Increasing age (p = 0.001) and years of service (p = 0.000) were positively correlated with TLA.
Conclusion
This is the largest group of U.S. Military members with CL reported and provides insight into risks for CL which will guide preventive efforts to reduce the burden of illness in this population.
The opinions and assertions expressed herein are those of the author(s) and do not reflect the official policy or position of the Uniformed Services University of the Health Sciences, the Department of Defense, or the U.S. Government.
Disclosures
Naomi E. Aronson, M.D., Elsevier: Royalties as text editor, honoraria for chapter writing|UpToDate: royalties for writing chapters.
Leishmania major
, transmitted in Iraq by the bite of a sand fly
Phlebotomus papatasi
, causes cutaneous leishmaniasis (CL). The sand fly saliva is immunogenic, with both systemic humoral and ...cellular human immune responses resulting from natural exposure. 248 Americans who developed
L. major
infection in Iraq were sex, race/ethnicity, year of Iraq deployment-matched to controls without CL. Using a case-control study design, we compared sand fly saliva-specific human IgG levels and recognized antigens between the two groups. Serologic responses to
Ph. papatasi
salivary gland homogenate were studied with ELISA and Western blot, using serial samples obtained from before travel, during CL treatment (CL) or at time of return to US (controls), as well as (for CL cases) six to 24 months after return to non-endemic US. The mean change in optical density (MCOD), reflecting the change in sand fly saliva-specific IgG before and after exposure in Iraq, was 0.296 (range -0.138 to 2.057) in cases and 0.151 (range -0.454 to1.085) in controls, p<0.001. Low levels of sand fly saliva specific antibody were noted in CL cases by 7-8 months after return to the US. The most frequently recognized
Ph. papatasi
salivary antigens were MW30 (PpSP32) and MW64, although other salivary proteins recognized were MW12/14, 15, 18, 28, 32, 36, 42, 44, 46, 52. Logistic regression suggested that MW15, 28 and 42 were associated with the largest effect on the MCOD. MW30 was the most frequently recognized antigen suggesting a role as biomarker for sand fly exposure and CL risk. Anti-
Ph
.
papatasi
saliva IgG waned within months of return to the US. We also discuss vector antigenic saliva proteins in the context of CL presentation and identify some salivary antigens that may correlate with less lesion area, ulcer versus papule/plaque, race among those with CL.
A 41-year-old man with human immunodeficiency virus (HIV) (CD4 count, 446/mm3) developed a protracted course of abdominal pain, weight loss, and increasing liver function tests after undergoing a ...metronidazole treatment regimen for Giardia enteritis. Three months later, endoscopic retrograde cholangiography (ERCP) showed dilated common and intrahepatic bile ducts and luminal irregularities of the common bile duct. Seven months after the onset of his acute diarrhea, a repeat ERCP with aspiration demonstrated many Giardia trophozoites and cysts in the bile and continued structural abnormalities consistent with cholangiopathy. A 10-day course of high-dose intravenous metronidazole did not resolve these signs or symptoms. A gallbladder ultrasound showed a thickened wall. Laparoscopic cholecystectomy led to resolution of abdominal pain and normalization of serum alkaline phosphatase over an 8-month period. Gallbladder histopathology revealed chronic cholecystitis, but no parasites were seen on hematoxylin and eosin staining or with Giardia antigen enzyme immunoassay testing of the gallbladder. The patient refused to undergo a follow-up ERCP, but a right upper quadrant ultrasound and computed tomography of the abdomen were normal.
Background The effectiveness of systemic antimonial (sodium stibogluconate, Pentostam, SSG) treatment versus local heat therapy (Thermomed) for cutaneous leishmaniasis was studied previously and ...showed similar healing rates. We hypothesized that different curative immune responses might develop with systemic and local treatment modalities. Methods We studied the peripheral blood immune cells in a cohort of 54 cutaneous Leishmania major subjects treated with SSG or TM. Multiparameter flow cytometry, lymphoproliferative assays and cytokine production were analyzed in order to investigate the differences in the immune responses of subjects before, on and after treatment. Results Healing cutaneous leishmaniasis lead to a significant decline in circulating T cells and NKT-like cells, accompanied by an expansion in NK cells, regardless of treatment modality. Functional changes involved decreased antigen specific CD4+ T cell proliferation (hyporesponsiveness) seen with CD8+ T cell depletion. Moreover, the healing (or healed) state was characterized by fewer circulating regulatory T cells, reduced IFN-gamma production and an overall contraction in polyfunctional CD4+ T cells. Conclusion Healing from cutaneous Leishmaniasis is a dynamic process that alters circulating lymphocyte populations and subsets of T, NK and NKT-like cells. Immunology of healing, through local or systemic treatments, culminated in similar changes in frequency, quality, and antigen specific responsiveness with immunomodulation possibly via a CD8+ T cell dependent mechanism. Understanding the evolving immunologic changes during healing of human leishmaniasis informs protective immune mechanisms.
We have previously shown that adoptive transfer of in vitro CD3/CD28 activated autologous CD4+ T cells results in increased CD4 counts and CD4/CD8 ratios in HIV+ subjects. In this report, analysis of ...variable beta (Vβ) chain T cell receptor (TCR) repertoire showed that CD3/CD28 stimulation was able to increase polyclonality within skewed spectra types in vitro. In vivo, two of eight subjects showed increase in TCR diversity and importantly, in no subject did a highly skewed in vivo repertoire emerge. Measurement of proliferative response to alloantigen showed increases following infusions. Response to pharmacological stimulus and lectin via Interferon-γ ELISpot assay showed increases in a subset of subjects following infusions. However, interferon-γ response to HIV antigens and peptides declined concurrent with stable or diminishing latent infectious viral load in CD4+ T cells. These data provide further evidence that adoptive transfer of activated autologous CD4+ T cells can augment the immune system.
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