Particle analysis of surgical lung biopsies from deployed and non-deployed US service members during the Global War on Terrorism.

The role that inhaled particulate matter plays in the development of post-deployment lung disease among US service members deployed to Southwest Asia during the Global War on Terrorism has been difficult to define. There is a persistent gap in data addressing the relationship between relatively short-term (months to a few years) exposures to high levels of particulate matter during deployment and the subsequent development of adverse pulmonary outcomes. Surgical lung biopsies from deployed service members and veterans (DSMs) and non-deployed service members and veterans (NDSMs) who develop lung diseases can be analyzed to potentially identify residual deployment-specific particles and develop associations with pulmonary pathological diagnoses. We examined 52 surgical lung biopsies from 25 DSMs and 27 NDSMs using field emission scanning electron microscopy (FE-SEM) with energy dispersive x-ray spectroscopy (EDS) to identify any between-group differences in the number and composition of retained inorganic particles, then compared the particle analysis results with the original histopathologic diagnoses. We recorded a higher number of total particles in biopsies from DSMs than from NDSMs, and this difference was mainly accounted for by geologic clays (illite, kaolinite), feldspars, quartz/silica, and titanium-rich silicate mixtures. Biopsies from DSMs deployed to other Southwest Asia regions (SWA-Other) had higher particle counts than those from DSMs primarily deployed to Iraq or Afghanistan, due mainly to illite. Distinct deployment-specific particles were not identified. Particles did not qualitatively associate with country of deployment. The individual diagnoses of the DSMs and NDSMs were not associated with elevated levels of total particles, metals, cerium oxide, or titanium dioxide particles. These results support the examination of particle-related lung disease in DSMs in the context of comparison groups, such as NDSMs, to assist in determining the strength of associations between specific pulmonary pathology diagnoses and deployment-specific inorganic particulate matter exposure.

Localized Cutaneous Argyria at the Site of a Prior Melanoma Excision Confirmed by Scanning Electron Microscopy With Energy Dispersive X-ray Analysis.

ABSTRACT: Localized cutaneous argyria is a rare condition caused by the accumulation of silver particles in the skin, leading to blue-gray discoloration. Argyria may mimic melanoma and lead to misdiagnosis. We present a patient with a history of melanoma that developed a blue-gray nodule at a prior melanoma graft. The diagnosis was confirmed using scanning electron microscopy and energy dispersive x-ray analysis. These techniques differentiate argyria from melanoma and can be performed on formalin-fixed, paraffin-embedded, tissue sections. Health care providers should be alert that argyria may mimic recurrent melanoma in patients unaware of silver exposure.

The Department of Veterans' Affairs Depleted Uranium Cohort in the Time of COVID-19: Translating a Traditional Surveillance Protocol to a Telehealth Platform.

OBJECTIVE: In 2021, 37 members of a cohort of depleted uranium-exposed Gulf War I veterans were evaluated using a protocol tailored to accommodate COVID-19 safety practices on a telehealth platform. METHODS: Individual elements of the legacy protocol were reviewed for urgency and feasibility of inclusion in a modified, telehealth platform. RESULTS: The redesigned protocol included a participant readiness for telehealth assessment, nurse and physician telehealth visits, collection of usual health questionnaires, and urine collections for exposure monitoring for uranium and other fragment-related metal measures. CONCLUSIONS: Despite some limitations in scope, the telehealth platform permitted a visual "visit" with surveillance participants who expressed a high comfort level with the format. The telehealth platform has apparent utility for occupational surveillance and should be explored as a standard approach for surveillance outside of public health emergencies.

The Reemergence of Measles.

OBJECTIVES: Present-day pathologists may be unfamiliar with the histopathologic features of measles, which is a reemerging disease. Awareness of these features may enable early diagnosis of measles in unsuspected cases, including those with an atypical presentation. Using archived tissue samples from historic patients, a unique source of histopathologic information about measles and other reemerging infectious diseases, we performed a comprehensive analysis of the histopathologic features of measles seen in commonly infected tissues during prodrome, active, and late phases of the disease. METHODS: Subspecialty pathologists analyzed H&E-stained slides of specimens from 89 patients accessioned from 1919 to 1998 and correlated the histopathologic findings with clinical data. RESULTS: Measles caused acute and chronic histopathologic changes, especially in the respiratory, lymphoid (including appendix and tonsils), and central nervous systems. Bacterial infections in lung and other organs contributed significantly to adverse outcomes, especially in immunocompromised patients. CONCLUSIONS: Certain histopathologic features, especially Warthin-Finkeldey cells and multinucleated giant cells without inclusions, allow pathologists to diagnose or suggest the diagnosis of measles in unsuspected cases.

Cutaneous Gamna-Gandy bodies: An unusual case of dystrophic calcification.

Dystrophic calcification is a common histopathologic finding that can be concomitant with a plethora of diseases, ranging from self-limited infections to insidious malignancies. Gamna-Gandy bodies (GGBs) are a form of dystrophic calcification associated with chronic hemolysis and are typically observed in the spleen. In this report, we present the case of a 92-year-old man who presented with a 4-mm blue papule that was biopsied given the concern for a blue nevus. The subsequent histopathologic examination of the biopsy specimen showed a dermal organizing hematoma adjacent to pale-yellow to brown, refractile material within fibrotic collagen consistent with GGBs. Scanning electron microscopy with energy-dispersive x-ray analysis (SEM/EDXA) revealed that the structures were composed of carbon (39%), oxygen (32%), iron (16%), phosphorus (7%), calcium (5%), and sodium (1%). Fourier transform infrared spectroscopy identified amorphous calcium phosphate. GGBs have not been previously described in the skin and have been rarely characterized with SEM/EDXA in other sites.

Migrated Bulking Material (Solesta) Presenting as a Vaginal "Cyst": Histopathologic and Chemical Analytical Features.

Performing injections with a bulking agent consisting of nonanimal stabilized hyaluronic acid and dextranomer is a well-tolerated and efficacious treatment for mild to moderate fecal incontinence. Here, we discuss a case of a patient with a history of a bulking procedure for fecal incontinence who presented to the obstetrics/gynecology clinic for evaluation of a new vaginal "cyst," which was excised. Histopathologic examination revealed migrated bulking agent within the excised specimen.

Exenatide-induced granulomatous panniculitis associated with poly(d,l-lactide-co-glycolide).

The extended-release formulation of exenatide for treatment of Type II diabetes mellitus is encapsulated in microspheres composed of poly(d,l-lactide-co-glycolide) (PLGA) and administered weekly. This medication has been reported to potentially cause injection-site reactions such as pruritus, transient nodules, and foreign body reaction. Here, we report a case of exenatide-induced granulomatous panniculitis. Our patient is a 63-year-old female with Type II diabetes presenting for concerns about painful nodules on her abdomen, developing approximately every week over the past year and migrating. Of note, the lesions appeared following exenatide injections in the same locations. Two deep-seated nodules of 1 cm were identified on examination. There were no overlying skin changes, and the lesions were tender to palpation. Punch biopsies of the two lesions were performed, which revealed a septal panniculitis containing amorphous material, along with a mixed inflammatory infiltrate. Gomori methenamine silver (GMS) and acid-fast bacilli (AFB) stains were negative for organisms. On infrared (IR) spectroscopy examination of the biopsy tissue, the spectral characteristics of (tissue) protein and PLGA were seen. Evaluation of the clinical and histopathologic findings, along with the IR spectroscopy match, determined that exenatide-induced panniculitis was the cause of the patient's nodules. This case highlights the importance of clinicians' awareness regarding injection-site reactions.

Pulmonary Pathology Diagnoses in the US Military During the Global War on Terrorism.

PURPOSE: To document and compare prevalences of pulmonary pathology diagnoses among US Service members deployed during the Global War on Terrorism and non-deployed US service members. Difficulties establishing associations between deployment-related exposures and pulmonary pathology reported among US military service members deployed during the Global War on Terrorism include retrospective estimations of exposures, documenting medical outcomes and lack of comparison groups. METHODS: Pulmonary diagnoses reported between 2002 and 2015 were identified from the records of the former Armed Forces Institute of Pathology and The Joint Pathology Center. Military service and deployment were confirmed by the Defense Manpower Data Center. Diagnoses were reviewed and coded due to variations in diagnostic terminology. Propensity matching and adjusted binomial modeling were applied to comparisons between the deployed and non-deployed to address possible confounding variables. RESULTS: 404 deployed and 2006 non-deployed service members were included. Demographic differences and the date of pathology report complicate unadjusted comparisons. The deployed had no significant increased prevalence of neoplastic conditions. Propensity matching identified a significant increased prevalence of organizing pneumonia in the non-deployed. An adjusted binomial model identified significant increased prevalences of small airways disease, constrictive bronchiolitis and hypersensitivity pneumonitis in the deployed. Both diagnoses were strongly associated with the date of pathology report. Small airways disease, constrictive bronchiolitis comprised 5% of deployed surgical lung biopsy diagnoses. CONCLUSION: This is the largest study of post-deployment pulmonary pathology diagnoses to date, and contains a comparison group. It provides context for studies of pulmonary outcomes among the deployed.

Surveillance of Depleted Uranium-exposed Gulf War Veterans: More Evidence for Bone Effects.

ABSTRACT: Gulf War I veterans who were victims of depleted uranium (DU) "friendly-fire" incidents have undergone longitudinal health surveillance since 1994. During the spring of 2019, 36 members of the cohort were evaluated with a monitoring protocol including exposure assessment for total and isotopic uranium concentrations in urine and a comprehensive review of health outcomes, including measures of bone metabolism and bone mineral density (BMD) determination. Elevated urine U concentrations were observed in cohort members with retained depleted uranium (DU) shrapnel fragments. In addition, a measure of bone resorption, N-telopeptide, showed a statistically significant increase in those in the high DU subgroup, a finding consistent with a statistically significant decrease in bone mass also observed in this high DU subgroup compared to the low DU subgroup. After more than 25 y since first exposure to DU, an aging cohort of military veterans continues to show few U-related health effects in known target organs of U toxicity. The new finding of impaired BMD in the high DU subgroup has now been detected in two consecutive surveillance visits. While this is a biologically plausible uranium effect, it is not reflected in other measures of bone metabolism in the full cohort, which have largely been within normal limits. However, ongoing accrual of the U burden from fragment absorption over time and the effect of aging further impairing BMD suggest the need for future surveillance assessments of this cohort.

Particle Analysis by Scanning Electron Microscopy With Energy Dispersive X-Ray Analysis in Pulmonary Pathology Specimens From U.S. Military Service Members Deployed During the Global War on Terror 2002 to 2015.

INTRODUCTION: Between 2001 and 2015, 2.77 million U.S. military service members completed over 5 million deployments to Southwest Asia. There are concerns that deployment-related environmental exposures may be associated with adverse pulmonary health outcomes. Accurate pulmonary diagnosis often requires histopathological biopsy. These lung biopsies are amenable to chemical analysis of retained particulates using scanning electron microscopy with energy dispersive X-ray analysis (SEM/EDXA). METHOD: A retrospective review of SEM/EDXA data collected in conjunction with pathologic diagnostic consultations at the Joint Pathology Center from 2011 to 2016 was conducted. Sections adjacent to those obtained for pathologic diagnosis were prepared for SEM/EDXA particle analysis, which provides qualitative identification of elements present in each particle and semiquantitative estimations of elemental weight percent. The review includes comparison of the particle analysis data and diagnostic findings, the particle count for the standard field analyzed, and types of particles identified. RESULTS: Nonneoplastic lung biopsy specimens from 25 deployed and 7 nondeployed U.S. service members were analyzed as part of the Joint Pathology Center pathologic consultations. The major exogenous particle types identified in both groups include aluminum silicates, other silicates, silica, and titanium dioxide. Endogenous particle types identified include calcium salts and iron-containing particles consistent with hemosiderin. These particles are present in deployed and nondeployed service members and are particle types commonly identified in lung biopsy specimens from urban dwelling adults. Rare particles containing other elements such as cerium and iron alloys were identified in some cases. Possible sources of these materials include diesel fuel and occupational and other environmental exposures. CONCLUSION: Scanning electron microscopy with energy dispersive X-ray particle analysis of inhaled particulates retained in lung tissue from deployed service members identifies particles commonly present in inhaled dust. In this small case series, we were not able to detect particle profiles that were common and unique to deployed patients only.

The Utility of Spot vs 24-Hour Urine Samples for Metal Determination in Veterans With Retained Fragments.

OBJECTIVES: The objective of this investigation is to explore the utility of using a spot urine sample in lieu of a 24-hour collection in assessing fragment-related metal exposure in war-injured veterans. METHODS: Twenty-four veterans collected each urine void over a 24-hour period in separate containers. Concentrations of 13 metals were measured in each void and in a pooled 24-hour sample using inductively coupled plasma mass spectrometry. To assess the reliability of spot sample measures over time, intraclass correlations (ICCs) were calculated across all spot samples. Lin's concordance correlation coefficient was used to assess agreement between a randomly selected spot urine sample and each corresponding 24-hour sample. RESULTS: In total, 149 spot urine samples were collected. Ten of the 13 metals measured had ICCs more than 0.4, suggesting "fair to good" reliability. Concordance coefficients were more than 0.4 for all metals, suggesting "moderate" agreement between spot and 24-hour concentrations, and more than 0.6 for seven of the 13 metals, suggesting "good" agreement. CONCLUSIONS: Our fair to good reliability findings, for most metals investigated, and moderate to good agreement findings for all metals, across the range of concentrations observed here, suggest the utility of spot urine samples to obtain valid estimates of exposure in the longitudinal surveillance of metal-exposed populations.

Tophaceous pseudogout in a 12-year-old dog, with a review of applicable laboratory tests.

Pseudogout, also known as calcium pyrophosphate dihydrate (CPPD) deposition disease or chondrocalcinosis, is caused by crystalline deposits of CPPD within the extracellular matrix of articular hyaline cartilage and fibrocartilage, and within articular and periarticular connective tissue. Using a variety of laboratory techniques, we diagnosed pseudogout in the right hindlimb digit V of a 12-y-old Standard Poodle. Histologically, the joint, bone, tendon, and dermis were expanded and effaced by masses of mineralized, rhomboid crystals surrounded by macrophages, multinucleate giant cells, fibrous connective tissue, and chondroid and osseous matrix. Rhomboid crystals exhibiting weak-positive birefringence were identified under polarized light using a first-order red compensator filter. Scanning electron microscopy with energy-dispersive x-ray analysis (SEM-EDXA) revealed that the rhomboid crystals were composed of calcium, phosphorus, and oxygen. Fourier-transform infrared (FTIR) microspectroscopy confirmed the presence of calcium pyrophosphate. In dogs, tophaceous pseudogout, which was the variant of pseudogout in our case, occurs as a single, tumor-like periarticular mass that can be invasive and mimic neoplasia. Having ancillary confirmatory testing (SEM-EDXA and FTIR), particularly in unusual histologic scenarios, such as tophaceous pseudogout in dogs, is desirable for confirming the correct diagnosis, even though it is available only at certain reference centers. The pathogenesis of pseudogout is unknown.

Injection of oral medication into the skin confirmed by infrared spectroscopy.

"Skin popping" refers to the practice of injecting drugs, most commonly heroin, subcutaneously or into granulation tissue. Pharmaceutical tablets meant for oral consumption are modified into solutions for injection. Excipients-inactive substances that serve as vehicles for medication-are often not filtered out before injection and result in abscess formation, granulomatous inflammation, and scarring. Common excipients used in the production of pharmaceutical tablets include starch, microcrystalline cellulose, magnesium stearate, silica, and polyvinylpyrrolidone (PVP). Identification of these exogenous materials is valuable in confirming the diagnosis of skin popping, especially when patients may not be forthcoming about their drug use. We present a case of subcutaneous oral medication injection in which PVP and cellulose were identified by Fourier transform infrared spectroscopy. Considering the variable cutaneous manifestations of injection drug abuse, recognition of histopathologic and chemical characteristics of exogenous material from oral medications is helpful for diagnosis and intervention.

The Joint Pathology Center/Vision Center of Excellence Approach to Analyzing Intra-Ocular "Foreign Bodies".

BACKGROUND: The Military Health System recognizes the importance of analyzing "foreign bodies" removed from US service members through several policy documents. This activity focuses on detecting potentially toxic metals. Intra-ocular "foreign bodies" (IOFBs) represent a small, clinically important subset. The development of ocular metallosis with iron and copper fragments is a specific local reaction to IOFBs. The results of the compositional analysis of removed IOFBs can influence clinical management decisions aimed at optimizing the preservation of sight. METHOD: The Joint Pathology Center (JPC) and Vision Center of Excellence (VCE) have established a pathway for the analysis of IOFBs removed from Department of Defense and Veterans Health Administration patients. The analysis of IOFBs uses analytical methods to provide information about the fragments' surface elemental and molecular composition. RESULTS: Metallic specimens analyzed included iron and copper-containing fragments. Non-metallic IOFBs analyzed include glass, plastic (polyurethane), and nitro-cellulose fragments. CONCLUSION: The JPC/VCE approach to analyzing IOFBs promotes uniform handling and shipping of specimens to minimize contamination. The analytical approach allows for the characterization of IOFBs with a wide variety of compositions. The results support clinical management decisions aimed at optimal treatment for the preservation of patients' visual acuity.

Simultaneous Determination of Uranium and Depleted Uranium Isotopic Ratio Using Inductively Coupled Mass Spectrometry.

We have developed and validated a method for the simultaneous quantitative measurement of total uranium (TU) and uranium 235 U/238 U isotopic ratio (UIR) in urine by inductively coupled plasma mass spectrometry (ICP-MS) using a Thermo Scientific iCAP-Q instrument. The performance characteristics of the assay were determined to be in compliance with clinical laboratory standards. The assay was linear in the concentration range of 1.0 to 500.0 ng/liter TU. The method was precise and accurate with limits of detection of 2.5 ng/liter for TU and 9.8 ng/liter for UIR. The accuracy was >93% and the coefficient of variation (% CV) was <5.0% for both TU and UIR. All results were within established guidelines and agreed-upon criteria, and the results fell within the certified range for the reference controls. The method has thus been shown to be effective as a simple, precise, and sensitive analytical technique for testing urine samples. © 2018 by John Wiley & Sons, Inc.

Surveillance results and bone effects in the Gulf War depleted uranium-exposed cohort.

A small group of Gulf War I veterans wounded in depleted uranium (DU) friendly-fire incidents have been monitored in a clinical surveillance program since 1993. During the spring of 2017, 42 members of the cohort were evaluated with a protocol which includes exposure monitoring for total and isotopic uranium concentrations in urine and a comprehensive assessment of health outcomes including measures of bone metabolism, and for participants >50 years, bone mineral density (BMD) determination. Elevated urine U concentrations were observed in cohort members with retained DU shrapnel fragments. Only the mean serum estradiol concentration, a marker of bone metabolism, was found to be significantly different for lower-vs- higher urine U (uU) cohort sub-groups. For the first time, a significant deficit in BMD was observed in the over age 50, high uU sub-group. After more than 25 years since first exposure to DU, an aging cohort of military veterans continues to exhibit few U-related adverse health effects in known target organs of U toxicity. The new finding of reduced BMD in older cohort members, while biologically plausible, was not suggested by other measures of bone metabolism in the full (all ages) cohort, as these were predominantly within normal limits over time. Only estradiol was recently found to display a difference as a function of uU grouping. As BMD is further impacted by aging and the U-burden from fragment absorption accrues in this cohort, a U effect may be clarified in future surveillance visits.

Determination of Thirteen Trace and Toxic Elements in Urine Using Inductively Coupled Mass Spectrometry.

We developed and validated a method for the assessment of thirteen separate trace and toxic elements using Inductively Coupled Plasma-Mass Spectrometry (ICP-MS). Included elements were as follows: aluminum, chromium, manganese, iron, cobalt, nickel, copper, zinc, arsenic, molybdenum, cadmium, tungsten, and lead. The measurements of all elements in urine samples were conducted using ICAP-Q ICP-MS in a single method. The performance characteristics of the assay were determined according to clinical laboratory standards. The assay was linear in the concentration range of 1.0 to 1000.0 µg/liter for all elements. The method was precise and accurate with limits of quantitation of 1 µg/liter for chromium, manganese, cobalt, nickel, copper, cadmium, tungsten, and lead; 2 µg/liter for iron and arsenic; 5 µg/liter for aluminum; and 50 µg/liter for zinc. This method has successfully been used for the assessment of all thirteen elements included in urine and has been shown to be effective as a simple, precise, and sensitive analytical technique for biological monitoring of urine samples. © 2018 by John Wiley & Sons, Inc.