Simple and statistically sound recommendations for analysing physical theories.

Physical theories that depend on many parameters or are tested against data from many different experiments pose unique challenges to statistical inference. Many models in particle physics, astrophysics and cosmology fall into one or both of these categories. These issues are often sidestepped with statistically unsound ad hoc methods, involving intersection of parameter intervals estimated by multiple experiments, and random or grid sampling of model parameters. Whilst these methods are easy to apply, they exhibit pathologies even in low-dimensional parameter spaces, and quickly become problematic to use and interpret in higher dimensions. In this article we give clear guidance for going beyond these procedures, suggesting where possible simple methods for performing statistically sound inference, and recommendations of readily-available software tools and standards that can assist in doing so. Our aim is to provide any physicists lacking comprehensive statistical training with recommendations for reaching correct scientific conclusions, with only a modest increase in analysis burden. Our examples can be reproduced with the code publicly available at Zenodo.

Social norm feedback reduces primary care antibiotic prescribing in a regression discontinuity study.

BACKGROUND: Reducing antibiotic prescribing is a priority for health authorities responsible for preventing antimicrobial resistance. Northern Ireland has high rates of antimicrobial use. We implemented a social norm feedback intervention and evaluated its impact. OBJECTIVES: To estimate the size and duration of the effect of a social norm feedback letter to GPs who worked in the 20% of practices with the highest antimicrobial prescribing. METHODS: The letter was sent in October 2017 to 221 GPs in 67 practices. To assess the effect of the intervention, we used a sharp non-parametric regression discontinuity (RD) design, with prescribing rates in the four calendar quarters following the intervention as the outcome variables. RESULTS: In the quarter following the intervention (October to December 2017) there was a change of -25.7 (95% CI = -42.5 to -8.8, P = 0.0028) antibiotic items per 1000 Specific Therapeutic group Age-sex Related Prescribing Units (STAR-PU). At 1 year, the coefficient was -58.7 (95% CI = -116.7 to -0.7, P = 0.047) antibiotic items per 1000 STAR-PU. The greatest change occurred soon after the intervention. Approximately 18900 fewer antibiotic items were prescribed than if the intervention had not been made (1% of Northern Ireland's annual primary care antibiotic prescribing). CONCLUSIONS: A social norm feedback intervention reduced antibiotic prescribing in the intervention practices. The diminishing effect over time suggests the need for more frequent feedback. The RD method allowed measurement of the effectiveness of an intervention that was delivered as part of normal business, without a randomized trial.

CCL3L1 and CCR5 influence cell-mediated immunity and affect HIV-AIDS pathogenesis via viral entry-independent mechanisms.

Although host defense against human immunodeficiency virus 1 (HIV-1) relies mainly on cell-mediated immunity (CMI), the determinants of CMI in humans are poorly understood. Here we demonstrate that variations in the genes encoding the chemokine CCL3L1 and HIV coreceptor CCR5 influence CMI in both healthy and HIV-infected individuals. CCL3L1-CCR5 genotypes associated with altered CMI in healthy subjects were similar to those that influence the risk of HIV transmission, viral burden and disease progression. However, CCL3L1-CCR5 genotypes also modify HIV clinical course independently of their effects on viral load and CMI. These results identify CCL3L1 and CCR5 as major determinants of CMI and demonstrate that these host factors influence HIV pathogenesis through their effects on both CMI and other viral entry-independent mechanisms.

Directly Detecting Sub-GeV Dark Matter with Electrons from Nuclear Scattering.

Dark matter (DM) particles with mass in the sub-GeV range are an attractive alternative to heavier weakly interacting massive particles, but direct detection of such light particles is challenging. If, however, DM-nucleus scattering leads to ionization of the recoiling atom, the resulting electron may be detected even if the nuclear recoil is unobservable. We demonstrate that including this effect significantly enhances direct detection sensitivity to sub-GeV DM. Existing experiments set world-leading limits, and future experiments may probe the cross sections relevant for thermal freeze-out.

Acute Promyelocytic Leukemia Presenting as Focal Neurologic Findings and Deteriorating Mental Status.

BACKGROUND: Acute promyelocytic leukemia (APL) is a rare but particularly malignant form of acute leukemia that is characterized by a rapid progression to fatal hemorrhage. Survival rates of patients with APL have increased with the introduction of all-trans retinoic acid (ATRA), but early deaths caused by hemorrhage still persist. CASE REPORT: A man with undiagnosed APL presenting with focal neurologic findings and deteriorating altered mental status caused by an intracranial hemorrhage is discussed. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: It is important to consider APL when diagnosing etiologies for intracranial hemorrhage. In addition to standard care, early administration of ATRA is recommended upon clinical suspicion of the disease.

Production of hhjj at the LHC.

Until now, a phenomenologically complete analysis of the hh+2j channel at the LHC has been missing. This is mostly due to the high complexity of the involved one-loop gluon fusion contribution and the fact that a reliable estimate thereof cannot be obtained through simplified calculations in the mt→∞ limit. In this Letter, we report on the LHC's potential to access di-Higgs production in association with two jets in a fully showered hadron-level analysis. Our study includes the finite top and bottom mass dependencies for the gluon fusion contribution.

Spontaneous virologic suppression in HIV controllers is independent of delayed-type hypersensitivity test responsiveness.

BACKGROUND: Delayed-type hypersensitivity (DTH) testing, an in vivo assessment of cell-mediated immunity, is a predictor of HIV disease progression beyond CD4 cell count. We investigated whether preserved DTH responsiveness was characteristic of HIV controllers compared to non-controllers and individuals on suppressive HAART. FINDINGS: DTH testing consisted of ≥ 3 recall antigens applied approximately every 6 months. DTH responses were classified by the number of positive skin tests: anergic (0), partial anergic (1), or non-anergic (≥ 2). HIV controllers were compared to treatment naïve non-controllers (n = 3822) and a subgroup of non-controllers with VL < 400 copies/mL on their initial HAART regimen (n = 491). The proportion of non-anergic results at first DTH testing was similar for HIV controllers compared to non-controllers (81.9% vs. 77.6%; P = 0.22), but tended to be greater in HIV controllers compared to the HAART subgroup (81.9% vs. 74.5%; P = 0.07). Complete anergy was observed in 14 (10.1%) HIV controllers with CD4 counts ≥ 400 cells/uL. For longitudinal testing, the average percentage of non-anergic DTH determinations per participant was higher in HIV controllers compared to non-controllers (81.2 ± 31.9% vs. 70.7 ± 36.8%; P = 0.0002), however this difference was eliminated with stratification by CD4 count: 200-399 (83.4 ± 35.6% vs. 71.9 ± 40.9%; P = 0.15) and > 400 cells/uL (81.2 ± 31.5% vs. 80.4 ± 32.7%; P = 0.76). CONCLUSIONS: Spontaneous virologic control was not associated with DTH responsiveness, and several HIV controllers were anergic despite having elevated CD4 counts. These findings suggest that cellular immunity assessed by DTH is not a principal factor contributing to spontaneous virologic suppression in HIV controllers.

COVID-19 vaccine insights: The news beyond the headlines.

Here is key intelligence on the recommended primary series, boosters, breakthrough infection, adverse events, special population vaccination, vaccine myths, and what the future might hold.

Response to a Serogroup B Meningococcal Disease Case Among Military Trainees.

We describe the public health response to a military trainee who developed serogroup B meningococcal disease while sharing underwater breathing equipment. Despite high transmission risk, with rapid isolation and postexposure prophylaxis administration, there were no secondary cases. This case supports carefully weighing serogroup B meningococcal vaccination in high-risk settings.

Duffy-null-associated low neutrophil counts influence HIV-1 susceptibility in high-risk South African black women.

BACKGROUND: The Duffy-null trait and ethnic netropenia are both highly prevalent in Africa. The influence of pre-seroconversion levels of peripheral blood cell counts (PBCs) on the risk of acquiring human immunodeficiency virus (HIV)-1 infection among Africans is unknown. METHODS: The triangular relationship among pre-seroconversion PBC counts, host genotypes, and risk of HIV acquisition was determined in a prospective cohort of black South African high-risk female sex workers. Twenty-seven women had seroconversion during follow-up, and 115 remained HIV negative for 2 years, despite engaging in high-risk activity. RESULTS: Pre-seroconversion neutrophil counts in women who subsequently had seroconversion were significantly lower, whereas platelet counts were higher, compared with those who remained HIV negative. Comprising 27% of the cohort, subjects with pre-seroconversion neutrophil counts of <2500 cells/mm(3) had a ∼3-fold greater risk of acquiring HIV infection. In a genome-wide association analyses, an African-specific polymorphism (rs2814778) in the promoter of Duffy Antigen Receptor for Chemokines (DARC -46T > C) was significantly associated with neutrophil counts (P = 7.9 × 10(-11)). DARC -46C/C results in loss of DARC expression on erthyrocytes (Duffy-null) and resistance to Plasmodium vivax malaria, and in our cohort, only subjects with this genotype had pre-seroconversion neutrophil counts of <2500 cells/mm(3). The risk of acquiring HIV infection was ∼3-fold greater in those with the trait of Duffy-null-associated low neutrophil counts, compared with all other study participants. CONCLUSIONS: Pre-seroconversion neutrophil and platelet counts influence risk of HIV infection. The trait of Duffy-null-associated low neutrophil counts influences HIV susceptibility. Because of the high prevalence of this trait among persons of African ancestry, it may contribute to the dynamics of the HIV epidemic in Africa.

The Duffy-null state is associated with a survival advantage in leukopenic HIV-infected persons of African ancestry.

Persons of African ancestry, on average, have lower white blood cell (WBC) counts than those of European descent (ethnic leukopenia), but whether this impacts negatively on HIV-1 disease course remains unknown. Here, in a large natural history cohort of HIV-infected subjects, we show that, although leukopenia (< 4000 WBC/mm(3) during infection) was associated with an accelerated HIV disease course, this effect was more prominent in leukopenic subjects of European than African ancestry. The African-specific -46C/C genotype of Duffy Antigen Receptor for Chemokines (DARC) confers the malaria-resisting, Duffy-null phenotype, and we found that the recently described association of this genotype with ethnic leukopenia extends to HIV-infected African Americans (AAs). The association of Duffy-null status with HIV disease course differed according to WBC but not CD4(+) T-cell counts, such that leukopenic but not nonleukopenic HIV(+) AAs with DARC -46C/C had a survival advantage compared with all Duffy-positive subjects. This survival advantage became increasingly pronounced in those with progressively lower WBC counts. These data highlight that the interaction between DARC genotype and the cellular milieu defined by WBC counts may influence HIV disease course, and this may provide a partial explanation of why ethnic leukopenia remains benign in HIV-infected AAs, despite immunodeficiency.

Long-term CD4+ lymphocyte response following HAART initiation in a U.S. Military prospective cohort.

BACKGROUND: Among HIV-infected persons initiating highly active antiretroviral therapy (HAART), early CD4+ lymphocyte count increases are well described. However, whether CD4+ levels continue to increase or plateau after 4-6 years is controversial. METHODS: To address this question and identify other determinants of CD4+ response, we analyzed data for 1,846 persons from a prospective HIV military cohort study who initiated HAART, who had post-HAART CD4+ measurements, and for whom HIV seroconversion (SC) date was estimated. RESULTS: CD4+ count at HAART initiation was ≤ 200 cells/mm3 for 23%, 201-349 for 31%, 350-499 for 27%, and ≥500 for 19%. The first 6 months post-HAART, the greatest CD4+ increases (93-151 cells) occurred, with lesser increases (22-36 cells/year) through the first four years. Although CD4+ changes for the entire cohort were relatively flat thereafter, HIV viral load (VL) suppressors showed continued increases of 12-16 cells/year. In multivariate analysis adjusting for baseline CD4+ and post-HAART time interval, CD4+ responses were poorer in those with: longer time from HIV SC to HAART start, lower pre-HAART CD4+ nadir, higher pre-HAART VL, and clinical AIDS before HAART (P < 0.05). CONCLUSIONS: Small but positive long-term increases in CD4+ count in virally suppressed patients were observed. CD4+ response to HAART is influenced by multiple factors including duration of preceding HIV infection, and optimized if treatment is started with virally suppressive therapy as early as possible.

Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE epsilon4/epsilon4 genotype accelerates HIV disease progression.

Originally recognized for their role in lipoprotein metabolism and cardiovascular disease, apolipoprotein (apo) E isoforms (apoE2, apoE3, and apoE4) have also been implicated to play a key role in several biological processes not directly related to their lipid transport function. For example, apoE4 contributes significantly to neurodegeneration in Alzheimer's disease. However, the role of apoE in infectious diseases is less well defined. Here, by examining a large cohort of HIV(+) European and African American subjects, we found that the APOE epsilon4/epsilon4 genotype is associated with an accelerated disease course and especially progression to death compared with the APOE epsilon3/epsilon3 genotype. However, an association between the epsilon4/epsilon4 genotype and HIV-associated dementia (HAD), a neurological condition with clinicopathological features similar to Alzheimer's disease, was not detected. Consistent with the genotype-phenotype relationships observed, compared with recombinant apoE3, apoE4 enhanced HIV fusion/cell entry of both R5 and X4 HIV strains in vitro. These findings establish apoE as a determinant of HIV-AIDS pathogenesis and raise the possibility that current efforts to convert apoE4 to an "apoE3-like" molecule to treat Alzheimer's disease might also have clinical applicability in HIV disease.

Clinical outcomes of elite controllers, viremic controllers, and long-term nonprogressors in the US Department of Defense HIV natural history study.

Durable control of human immunodeficiency virus (HIV) replication and lack of disease progression in the absence of antiretroviral therapy were studied in a military cohort of 4586 subjects. We examined groups of elite controllers (ie, subjects with plasma HIV RNA levels of <50 copies/mL; prevalence, 0.55% [95% confidence interval {CI}, 0.35%-0.80%]), viremic controllers (ie, subjects with plasma HIV RNA levels of 50-2000 copies/mL; prevalence, 3.34% [95% CI, 2.83%-3.91%]), and subjects with a lack of disease progression (ie, long-term nonprogressors [LTNPs]) through 7 years of follow-up (LTNP7s; prevalence, 3.32% [95% CI, 2.70%-4.01%]) or 10 years of follow-up (LTNP10s; prevalence, 2.04% [95% CI, 1.52%-2.68%]). For elite and viremic controllers, spontaneous virologic control was established early and was typically observed when the initial viral load measurement was obtained within 1 year of estimated seroconversion. Elite controllers had favorable time to development of AIDS (P=.048), a CD4 cell count of 350 cells/microL (P= .009), and more-stable CD4 cell trends, compared with viremic controllers. LTNPs defined by 10-year versus 7-year criteria had a longer survival time (P=.001), even after adjustment for differing periods of invulnerability (P= .042). Definitions of controllers and LTNPs describe distinct populations whose differing clinical outcomes improve with the stringency of criteria, underscoring the need for comparability between study populations.

PDL-1 upregulation on monocytes and T cells by HIV via type I interferon: restricted expression of type I interferon receptor by CCR5-expressing leukocytes.

The programmed death (PD)-1 interacts with its ligand (PDL-1) delivering a negative signal to T cells. During human immunodeficiency virus (HIV)-1 infection PD-1 and PDL-1 expressions are increased. Here we show that monocytes and CCR5(+) T cells of HIV-uninfected donors upregulated PDL-1 upon in vitro exposure to HIV. HIV-induced PDL-1 required interferon (IFN)-alpha, but not IFN-gamma, production. Inhibition of endocytosis, required for HIV-induced IFN-alpha production, prevented PDL-1 upregulation. IFN-alpha-inducing Toll-like receptor (TLR) agonists increased PDL-1 on monocytes and CCR5(+) T cells. CD80 and CD86 were also increased on monocytes and CCR5(+) T cells after HIV exposure, but only CD80 was IFN-alpha-dependent. IFN-alpha-receptor subunit 2 (IFNAR2), was expressed only by CCR5(+) T cells and monocytes, explaining why these leukocytes responded to HIV-induced IFN-alpha. Finally, T cell proliferation was improved by PDL-1 blockade in HIV-treated PBMC. In the setting of HIV infection, IFN-alpha may negatively affect T cell responses by inducing PDL-1.

Effectiveness of highly-active antiretroviral therapy by race/ethnicity.

OBJECTIVE: To determine the effectiveness of HAART by race/ethnicity. DESIGN: Prospective multicenter cohort study. METHODS: We studied 991 African-Americans and 911 European-Americans enrolled in the United States Military's Tri-Service AIDS Clinical Consortium Natural History Study who had dates of HIV seroconversion known within 5 years and followed between 1990 and 2002. We determined the rate of disease progression to AIDS and death for subjects in this cohort. Multivariable models evaluated race, pre-HAART (1990-1995) and HAART (1996-2002) eras, age, gender and military service. RESULTS: In the pre-HAART era, African-Americans had a statistically nonsignificant trend towards better outcomes: the relative hazards (RH) of AIDS and death for African-Americans compared to European-Americans were 0.85 [95% confidence interval (CI), 0.68-1.05] and 0.77 (95% CI, 0.55-1.08), respectively. In the HAART era, outcomes were similar by race: 1.17 (95% CI, 0.86-1.61) for AIDS and 1.11 (95% CI, 0.81-1.53) for death with overlapping Kaplan-Meier curves. Relative to the pre-HAART era, the adjusted RH of AIDS in the HAART era was 0.41 (95% CI, 0.31-0.54) and 0.30 (95% CI, 0.22-0.40) for African-American and European-American participants, respectively. Analogous RH for death were 0.55 (95% CI, 0.38-0.80) and 0.38 (95% CI, 0.27-0.54). The precipitous declines in AIDS and death in the HAART era were not statistically different by race. CONCLUSIONS: : In a large multi-racial cohort with equal access to health care, HIV treatment outcomes by race/ethnicity were similar.

Influence of the timing of antiretroviral therapy on the potential for normalization of immune status in human immunodeficiency virus 1-infected individuals.

IMPORTANCE: In individuals with human immunodeficiency virus 1 (HIV-1) infection who are receiving antiretroviral therapy (ART), factors that promote full immune recovery are not well characterized. OBJECTIVE: To investigate the influence of the timing of ART relative to HIV-1 infection on normalization of CD4+ T-cell counts, AIDS risk, and immune function. DESIGN, SETTING, AND PARTICIPANTS: Participants in the observational US Military HIV Natural History Study with documented estimated dates of seroconversion (EDS) who achieved virologic suppression with ART were evaluated. Markers indicative of immune activation, dysfunction, and responsiveness were determined. Responses to hepatitis B virus (HBV) vaccine, an indicator of in vivo immune function, were also assessed. The timing of ART was indexed to the EDS and/or entry into the cohort. The CD4+ counts in HIV-1-uninfected populations were surveyed. MAIN OUTCOMES AND MEASURES: Normalization of CD4+ counts to 900 cells/µL or higher, AIDS development, HBV vaccine response, as well as T-cell activation, dysfunction, and responsiveness. RESULTS: The median CD4+ count in HIV-1-uninfected populations was approximately 900 cells/µL. Among 1119 HIV-1-infected participants, CD4+ normalization was achieved in 38.4% vs 28.3% of those initiating ART within 12 months vs after 12 months from the EDS (P = .001). Incrementally higher CD4+ recovery (<500, 500-899, and ≥900 cells/µL) was associated with stepwise decreases in AIDS risk and reversion of markers of immune activation, dysfunction, and responsiveness to levels approximating those found in HIV-1-uninfected persons. Participants with CD4+ counts of 500 cells/µL or higher at study entry (adjusted odds ratio [aOR], 2.00; 95% CI, 1.51-2.64; P < .001) or ART initiation (aOR, 4.08; 95% CI, 3.14-5.30; P < .001) had significantly increased CD4+ normalization rates compared with other participants. However, even among individuals with a CD4+ count of 500 cells/µL or higher at both study entry and before ART, the odds of CD4+ normalization were 80% lower in those initiating ART after 12 months from the EDS and study entry (aOR, 0.20; 95% CI, 0.07-0.53; P = 001). Initiation of ART within 12 months of EDS vs later was associated with a significantly lower risk of AIDS (7.8% vs 15.3%; P = .002), reduced T-cell activation (percent CD4+HLA-DR+ effector memory T cells, 12.0% vs 15.6%; P = .03), and increased responsiveness to HBV vaccine (67.9% vs 50.9%; P = .07). CONCLUSIONS AND RELEVANCE: Deferral of ART beyond 12 months of the EDS diminishes the likelihood of restoring immunologic health in HIV-1-infected individuals.

Long-term efficacy of routine access to antiretroviral-resistance testing in HIV type 1-infected patients: results of the clinical efficacy of resistance testing trial.

The long-term efficacy of making resistance testing routinely available to clinicians has not been established. We conducted a clinical trial at 6 US military hospitals in which volunteers infected with human immunodeficiency virus type-1 were randomized to have routine access to phenotype resistance testing (PT arm), access to genotype resistance testing (GT arm), or no access to either test (VB arm). The primary outcome measure was time to persistent treatment failure despite change(s) in antiretroviral therapy (ART) regimen. Overall, routine access to resistance testing did not significantly increase the time to end point. Time to end point was significantly prolonged in the PT arm for subjects with a history of treatment with > or =4 different ART regimens or a history of treatment with nonnucleoside reverse-transcriptase inhibitors before the study, compared with that in the VB arm. These results suggest that routine access to resistance testing can improve long-term virologic outcomes in HIV-infected patients who are treatment experienced but may not impact outcome in patients who are naive to or have had limited experience with ART.

Laboratory diagnosis of Bartonella infections.

Bartonella species are pathogens of emerging and reemerging significance, causing a wide array of clinical syndromes. In North America and Europe, they are increasingly recognized as a cause of culture negative endocarditis, neuroretinitis, and disease among homeless, HIV-infected, and other immunosuppressed individuals. In South America, bartonellosis continues to plague those in endemic regions and poses a significant threat to travelers in these areas. As the clinician is increasingly faced with these illnesses, which may be difficult to diagnose, laboratory techniques to confirm or refute the diagnosis are becoming increasingly important. Culture methods have improved over the past decade demonstrating increased sensitivity, but still require prolonged periods before isolation of the organism. Specimen handling, media selection, and growth conditions all may affect results and must be optimized in order to provide the highest likelihood of recovering the organism. Pure culture of the bacteria not only provides morphologic information, but also provides material for further diagnostic testing. Work with liquid media, which may provide a more rapid means of cultivation has shown some promise and should continue to be pursued. Improved blood culture techniques were a primary factor in the discovery of Bartonella endocarditis and continued improvements will likely demonstrate further clinical insights. Serologic testing for B henselae infections has become the cornerstone of clinical diagnosis, replacing the skin test that was poorly standardized and posed a potential risk to the patient. Immunofluorescence assays have been well characterized and validated in clinical trials, however they are not universally available. Vero cell cocultivated antigens appear to provide higher sensitivity and specificity when compared with agar-derived antigens. IFA assays are inherently difficult to perform, requiring significant expertise to provide reproducible results. On the contrary, enzyme immunoassays offer ease of use and a high level of reproducibility, however ideal antigens for use in the diagnosis of Bartonella infections have not been clearly identified. Continued work to define antigenic targets of the human response to infection and incorporation of these into a widely available EIA will provide a cost-effective tool for the clinician and epidemiologist alike. Due to the close phylogenetic relationship of B henselae and B quintana, differentiation between these species by serologic means may prove difficult. Molecular techniques including PCR offer high sensitivity and specificity, rapid availability of information, and the ability to differentiate Bartonella organisms at the highest level. Results of studies to date are promising and as methods are refined it will be important to conduct clinical studies to define the role of these assays. In disseminated Bartonella infections such as bacillary angiomatosis, peliosis, endocarditis, and urban trench fever, PCR currently offers the ability to establish the diagnosis when other tests may be unrevealing. For CSD, this technique should be used as a confirmatory technique when the diagnosis is unclear by other means. PCR analysis of blood specimens offers a minimally invasive approach to diagnosis, but clinical data are scarce and further studies are needed. As DNA microarrays move into the clinical arena, specific hybridization probes may allow improved identification and differentiation of Bartonellae at the molecular level.

Visceral leishmaniasis with associated immune dysregulation leading to lymphoma.

OBJECTIVE: We describe an atypical presentation of visceral leishmaniasis (VL) complicated by Epstein-Barr virus (EBV)-lymphoproliferative disorder and angioimmunoblastic T-cell lymphoma in a U.S. Government contractor recently deployed to Iraq and Afghanistan. METHODS: We performed a search of PubMed (1966-2012) using the terms visceral, leishmaniasis, operation, iraqi, freedom, desert, storm, EBV, lymphoproliferative, angioimmunoblastic, and lymphoma. The purpose of the search was two-fold: to find reported cases of VL during U.S. military operations and to ascertain if lymphoproliferative disorder (specifically, because of EBV) was ever described as a sequelae of VL. RESULTS: Case series of VL acquired in the Middle East between 1990 and 2012 showed that while fever, abdominal pain, and hepatosplenomegaly were common signs and symptoms of VL, diffuse lymphadenopathy (our patient's presentation) was rare. Moreover, VL in and of itself lends to profound immune dysregulation, leading to a myriad of complications to include EBV-lymphoproliferative diseases. CONCLUSIONS: Diffuse lymphadenopathy because of VL is a very atypical presentation for infection acquired in the Middle East. Clinicians must be mindful of the extreme immune dysfunction that occurs as a result of this potentially fatal infection and the associated complications to include EBV-related lymphoproliferative disorders and lymphoma.