Safety of remdesivir in the treatment of acute SARS-CoV-2 infection in pediatric patients.

BACKGROUND: Transaminase and creatinine elevations have been well described in adults treated with remdesivir for COVID-19. It is hypothesized that a similar safety profile exists in children with COVID-19 treated with remdesivir, but available data are limited, especially in children < 12 months. The primary aim of this study was to determine the prevalence and timing of elevations in transaminases and creatinine in children with COVID-19 who were treated with remdesivir. METHODS: This was a retrospective, observational cohort study including all pediatric patients admitted to a single, freestanding children's hospital who were positive for COVID-19 and received at least 1 dose of remdesivir between 1/1/2020 and 5/31/2022. Available baseline and peak transaminase and creatinine concentrations were evaluated. Multivariable logistic regression analysis was performed to identify risk factors for transaminase elevation. RESULTS: A total of 180 patients met inclusion criteria. Creatinine elevation of any grade was noted in 16% and remained elevated only in those with underlying chronic kidney disease. Transaminase elevation of any grade was noted in 58% of patients and remained elevated in only 1%. Older age and critical respiratory disease were associated with higher risk of significant transaminase elevation, whereas non-Hispanic ethnicity was strongly associated with protection against significant transaminase elevation. CONCLUSIONS: In our cohort of hospitalized children with COVID-19 who were treated with remdesivir, most patients experienced only mild transaminitis and normal creatinine concentrations. A limited number of patients experienced laboratory abnormalities which were transient, suggesting a favorable safety profile for remdesivir use in pediatrics.

Two cases of multi-inflammatory syndrome in children (MIS-C) in adults in 2020.

BACKGROUND: Late complications and longer-lasting sequelae of COVID-19 infection in adults can occur. Cardiovascular involvement including reduced ejection fraction, coronary artery aneurysms, and pericardial involvement have been reported. Prompt recognition is the first step and secondly, these cardiovascular phenomena require an alternative set of therapeutics from the standard of care for acute COVID-19 infection. CASE PRESENTATION: Here we describe two cases that fulfill the current case definition of the recently defined multisystem inflammatory syndrome in adults (MIS-A). One patient is a 27-year-old white female and the other a 21-year-old French creole male, both without any prior medical history. Both were hospitalized and found to have significant cardiac dysfunction and treated with IVIG, high dose aspirin, and corticosteroids with resolution of their acute illnesses and cardiac sequelae. CONCLUSION: Not only does the immediate impact of this viral infection need to be addressed, but also the long-term complications that could arise if not recognized and treated promptly as seen in our two cases. Patients can develop acute cardiovascular collapse and cardiogenic shock which requires high level of care and treatment within an intensive care unit. Depending on the complications, patients may require treatment for congestive heart failure, pericarditis, or even coronary artery disease acutely with close follow up to ensure improvement or resolution.

Changes in Bone Mass After Discontinuation of Preexposure Prophylaxis With Tenofovir Disoproxil Fumarate/Emtricitabine in Young Men Who Have Sex With Men: Extension Phase Results of Adolescent Trials Network Protocols 110 and 113.

Human immunodeficiency virus-seronegative men aged 15-22 years who lost bone mineral density (BMD) during tenofovir disoproxil fumarate/emtricitabine preexposure prophylaxis (PrEP) showed BMD recovery 48 weeks following PrEP discontinuation. Lumbar spine and whole body BMD z-scores remained below baseline 48 weeks off PrEP in participants aged 15-19 years. Clinical Trials Registration. NCT01772823 (ATN 110) and NCT01769456 (ATN 113).

Vitamin D3 Supplementation Increases Spine Bone Mineral Density in Adolescents and Young Adults With Human Immunodeficiency Virus Infection Being Treated With Tenofovir Disoproxil Fumarate: A Randomized, Placebo-Controlled Trial.

Background: Tenofovir disoproxil fumarate (TDF) decreases bone mineral density (BMD). We hypothesized that vitamin D3 (VITD3) would increase BMD in youth receiving TDF. Methods: This was a randomized, double-blind, placebo-controlled trial of directly observed VITD3 vs placebo every 4 weeks for 48 weeks in youth aged 16-24 years with HIV, RNA load <200 copies/mL, taking TDF-containing combination antiretroviral therapy (TDF-cART) for ≥180 days. Participants (N = 214) received a daily multivitamin containing VITD3 400 IU and calcium 162 mg, plus monthly randomized VITD3 50000 IU (n = 109) or placebo (n = 105). Outcome was change from baseline to week 48 in lumbar spine BMD (LSBMD). Data presented are median (Q1, Q3). Results: Participants were aged 22.0 (21.0, 23.0) years, 84% were male, and 74% were black/African American. At baseline, 62% had 25-hydroxy vitamin D (25-OHD) <20 ng/mL. Multivitamin adherence was 49% (29%, 69%), and VITD3/placebo adherence 100% (100%, 100%). Vitamin D intake was 2020 (1914, 2168) and 284 (179, 394) IU/day, and serum 25-OHD concentration was 36.9 (30.5, 42.4) and 20.6 (14.4, 25.8) ng/mL at 48 weeks in VITD3 and placebo groups, respectively (P < .001). From baseline to week 48, LSBMD increased by 1.15% (-0.75% to 2.74%) in the VITD3 group (n = 99; P < .001) and 0.09% (-1.49% to 2.61%) in the placebo group (n = 89; P = .25), without between-group difference (P = .12). VITD3 group changes occurred with baseline 25-OHD <20 ng/mL (1.17% [-.82% to 2.90%]; P = .004) and ≥20 ng/mL (0.93% [-.26% to 2.15%]; P = .033). Conclusions: For youth taking TDF-cART, LSBMD increased through 48 weeks with VITD3 plus multivitamin, but not with placebo plus multivitamin, independent of baseline vitamin D status. Clinical Trials Registration: NCT01751646.

Low near infrared spectroscopic somatic oxygen saturation at admission is associated with need for lifesaving interventions among unplanned admissions to the pediatric intensive care unit.

To investigate the association between low near infrared spectroscopy (NIRS) somatic oxygen saturation (<70%) at admission and the need for lifesaving interventions (LSI) in the initial 24 h of a PICU admission. Retrospective chart review of all unplanned admissions to the pediatric intensive care unit (PICU) with NIRS somatic oxygen saturation data available within 4 h of admission, excluding admissions with a cardiac diagnosis. LSI data were collected for the first 24 h after admission. Hemodynamic parameters, laboratory values, illness severity scores and diagnoses were collected. Included PICU admissions were stratified by lowest NIRS value in the first 4 h after admission: low NIRS (<70%) and normal NIRS (≥70%) groups. Rate of LSI from 4 h to 24 h was compared between the two groups. Association of LSI with NIRS saturation and other clinical and laboratory parameters was measured by univariate and multivariate methods. We reviewed 411 consecutive unplanned admissions to the PICU of which 184 (44%) patients underwent NIRS monitoring. A higher proportion of patients who underwent somatic NIRS monitoring required LSIs compared to those without NIRS monitoring (36.4 vs 5.7% respectively, p < 0.0001). The proportion of patients who required LSI was higher in the group with low NIRS (<70%) within the first 4 h compared to those with normal NIRS (≥70%) (77.1 vs 22.1%, p < 0.0001). Fluid resuscitation, blood products and vasoactive medications were the most common LSIs. Multivariable modeling showed NIRS < 70% and heart rate > 2SD for age to be associated with LSIs. ROC curve analysis of the combination of NIRS < 70% and HR >2SD for age had an area under the curve of 0.79 with 78% sensitivity and 76% specificity for association with LSI. Compared to the normal NIRS group, the low NIRS group had higher mortality (10.4 vs 0.7%, p = 0.005) and longer median hospital length of stay (2.9 vs 1.6 days, p < 0.0001). Low somatic NIRS oxygen saturation (<70%) in the first 4 h of an unplanned PICU admission is associated with need for higher number of subsequent lifesaving interventions up to 24 h after admission. Noninvasive, continuous, somatic NIRS monitoring may identify children at high risk of medical instability.

Decline in Bone Mass With Tenofovir Disoproxil Fumarate/Emtricitabine Is Associated With Hormonal Changes in the Absence of Renal Impairment When Used by HIV-Uninfected Adolescent Boys and Young Men for HIV Preexposure Prophylaxis.

BACKGROUND: We aimed to define the relative importance of renal and endocrine changes in tenofovir disoproxil fumarate (TDF)-related bone toxicity. METHODS: In a study of daily TDF/emtricitabine (FTC) preexposure prophylaxis (PrEP) in human immunodeficiency virus (HIV)-uninfected young men who have sex with men, we measured changes from baseline in blood and urine markers of the parathyroid hormone (PTH)-vitamin D-fibroblast growth factor 23 (FGF23) axis, creatinine, and renal tubular reabsorption of phosphate (TRP). We explored the relationship of those variables to changes in bone mineral density (BMD). Tenofovir-diphosphate (TFV-DP) in red blood cells was used to categorize participants into high and low drug exposure groups. RESULTS: There were 101 participants, median age 20 years (range 15 to 22). Compared with low drug exposure, high-exposure participants showed increase from baseline in PTH and decline in FGF23 by study week 4, with no differences in creatinine, phosphate, or TRP. At 48 weeks, the median (interquartile range) percent decline in total hip BMD was greater in those with high- compared to low- exposure (-1.59 [2.77] vs +1.54 [3.34] %, respectively; P = .001); in high-exposure participants, this correlated with week 4 TFV-DP (inversely; r = -0.60, P = .002) and FGF23 (directly; r = 0.42; P = .039) but not other variables. CONCLUSIONS: These findings support the short-term renal safety of TDF/FTC PrEP in HIV-seronegative young men and suggest that endocrine disruption (PTH-FGF23) is a primary contributor to TDF-associated BMD decline in this age group. CLINICAL TRIALS REGISTRATION: NCT01769469.

Higher doses of low-molecular-weight heparin (enoxaparin) are needed to achieve target anti-Xa concentrations in critically ill children*.

OBJECTIVES: To demonstrate that low-molecular-weight heparin (enoxaparin) can be used in critically ill pediatric patients to achieve target anti-factor Xa concentrations and determine appropriate dosing corrected for age and illness severity. DESIGN: Retrospective cohort study. SETTING: Single tertiary level PICU. PATIENTS: One hundred ninety-two children age 1 day through 18 years admitted to PICU undergoing every 12-hour enoxaparin therapy with at least one anti-factor Xa concentration obtained. Patients receiving renal replacement therapy or infants with corrected gestational age less than 37 weeks were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We collected patient characteristics including age, weight, height/length, gender, corrected gestational age, illness severity markers, diagnosis, creatinine, enoxaparin dose and times of administration, anti-factor Xa concentrations, and collection times. Only 42% of critically ill children (80 of 192) and only 29% of children (9 of 31) on inotropes achieved recommended target range of anti-factor Xa concentrations on initial recommended enoxaparin dosing (1.5 mg/kg/dose < 2 mo; 1 mg/kg/dose > 2 mo), but 81% were ultimately within target range with dose titration. Increased enoxaparin dose was required to reach target concentrations in younger patients and those with worse illness severity as evidenced by concurrent use of inotropes, previous ICU admission, mechanical ventilation, cardiac surgery, and increased risk of mortality defined by severity-of-illness scores. CONCLUSIONS: Enoxaparin can be used to reach recommended target range of anti-factor Xa concentrations in the PICU patient. However, younger patients and patients with higher illness severity are less likely to achieve target concentrations using currently recommended dosing and may require higher doses of enoxaparin to reach target anti-factor Xa concentrations. Starting enoxaparin dose at least 1.3 mg/kg dosed every 12 hours for treatment of thromboembolic disease in critically ill patients aged 61 days to 1 year or those requiring inotropic support should be confirmed in prospective study.

Association of higher plasma vitamin D binding protein and lower free calcitriol levels with tenofovir disoproxil fumarate use and plasma and intracellular tenofovir pharmacokinetics: cause of a functional vitamin D deficiency?

Tenofovir disoproxil fumarate (TDF) causes bone, endocrine, and renal changes by an unknown mechanism(s). Data are limited on tenofovir pharmacokinetics and these effects. Using baseline data from a multicenter study of HIV-infected youth on stable treatment with regimens containing TDF (n = 118) or lacking TDF (n = 85), we measured cross-sectional associations of TDF use with markers of renal function, vitamin D-calcium-parathyroid hormone balance, phosphate metabolism (tubular reabsorption of phosphate and fibroblast growth factor 23 [FGF23]), and bone turnover. Pharmacokinetic-pharmacodynamic associations with plasma tenofovir and intracellular tenofovir diphosphate concentrations were explored among those receiving TDF. The mean age was 20.9 (standard deviation [SD], 2.0) years; 63% were male; and 52% were African American. Compared to the no-TDF group, the TDF group showed lower mean estimated glomerular filtration rates and tubular reabsorption of phosphate, as well as higher parathyroid hormone and 1,25-dihydroxy vitamin D [1,25-OH(2)D] levels. The highest quintile of plasma tenofovir concentrations was associated with higher vitamin D binding protein, lower free 1,25-OH(2)D, higher 25-OH vitamin D, and higher serum calcium. The highest quintile of intracellular tenofovir diphosphate concentration was associated with lower FGF23. Higher plasma tenofovir concentrations were associated with higher vitamin D binding protein and lower free 1,25-OH(2)D, suggesting a functional vitamin D deficiency explaining TDF-associated increased parathyroid hormone. The finding of lower FGF23 accompanying higher intracellular tenofovir diphosphate suggests that different mechanisms mediate TDF-associated changes in phosphate handling. Separate pharmacokinetic properties may be associated with distinct TDF toxicities: tenofovir with parathyroid hormone and altered calcium balance and tenofovir diphosphate with hypophosphatemia and FGF23 regulation. (The clinical trial registration number for this study is NCT00490412 and is available online at http://clinicaltrials.gov/ct2/show/NCT00490412.).

Serum 25-hydroxyvitamin D concentration does not correlate with atopic dermatitis severity.

BACKGROUND: An inverse correlation between serum 25-hydroxyvitamin D concentration and atopic dermatitis (AD) severity has been suggested. OBJECTIVE: To determine if a statistically significant relationship exists between serum 25-hydroxyvitamin D concentration and AD severity. METHODS: A cross-sectional study was conducted of patients with AD who were 1 to 18 years of age. An objective Severity Scoring of Atopic Dermatitis (SCORAD) and a serum 25-hydroxyvitamin D concentration were measured for each subject. Statistical analysis was performed using appropriate univariate tests and multivariable models. RESULTS: Ninety-four of 97 enrolled subjects were included in the analysis. Vitamin D deficiency (25-hydroxyvitamin D <20 ng/mL) was present in 37 subjects (39%), insufficiency (25-hydroxyvitamin D 21-29 ng/mL) in 33 (35%), and sufficiency (25-hydroxyvitamin D ≥30 ng/mL) in 24 (26%). The correlation between 25-hydroxyvitamin D concentration and SCORAD was not significant (r = -0.001; P = .99). A multivariate model showed that a lower serum 25-hydroxyvitamin D concentration was significantly associated with age 3 years or older (P < .0001), black race (P < .0001), and winter season (P = .0084). LIMITATIONS: Limitations of this study include the inability to control for natural sunlight exposure, vitamin D intake, and AD treatment; in addition, only a single time point was captured. CONCLUSIONS: Serum 25-hydroxyvitamin D concentration is not significantly correlated with AD severity in our pediatric population.

Overview of Pediatric Procalcitonin Testing Patterns in a Tertiary Care Children's Hospital.

The use of procalcitonin (PCT) has grown over the past decade with increasing reliance on the test to rule out bacterial infection. We retrospectively reviewed the medical records of children <18 years old hospitalized at a tertiary care children's hospital from 2017 to 2019 who had PCT testing performed during their admission. Of 4135 PCT levels collected on 1530 children, 982 (23.7%) were diagnostically low and 1993 (48.1%) were diagnostically elevated. Pediatric intensive care, with 6% of total hospital patients, obtained 41.4% of tests. Thirty-one (2%) patients had an average of 27 PCT levels per patient, accounting for 20% of all tests. Many children had symptoms for which testing is not indicated (eg, skin complaints). The differences in PCT testing by service, inappropriate patterns of repeat testing, and testing performed in patients for whom it is not indicated may identify targets for diagnostic stewardship.

Pediatric Orbital Cellulitis/Abscess: Microbiology and Pattern of Antibiotic Prescribing.

INTRODUCTION: The treatment for pediatric orbital cellulitis/abscess is trending towards intravenous antibiotic management alone in appropriate cases. Without cultures to guide therapy, knowing the local microbiology is of utmost importance in managing these patients. METHODS: We conducted a retrospective case series for patients age 2 months to 17 years, who were hospitalized between January 1, 2013, and December 31, 2019, to evaluate the local microbiology and pattern of antibiotic prescribing in pediatric orbital cellulitis. RESULTS AND DISCUSSION: Of 95 total patients, 69 (73%) received intravenous antibiotics only and 26 (27%) received intravenous antibiotics plus surgery. The most common organism cultured was Streptococcus anginosus, followed by Staphylococcus aureus, and group A streptococcus. Methicillin-resistant Staphylococcus aureus (MRSA) prevalence was 9%. MRSA-active antibiotics remain the most frequently used antibiotics.

Higher Weight-Based Doses Are Required to Achieve and Maintain Therapeutic Voriconazole Serum Trough Concentrations in Children.

OBJECTIVE: Children require weight-based voriconazole doses proportionately larger than adults to achieve therapeutic serum trough concentrations (1-6 mcg/mL). The objective of this quality improvement project was to determine the initial dose, proportion of patients achieving target concentrations with initial dosing, and subsequent therapeutic drug monitoring and dose modifications needed to achieve and maintain therapeutic voriconazole concentrations in children. METHODS: This retrospective study evaluated children aged <18 years treated with voriconazole during the study period. Dosing and therapeutic drug monitoring (TDM) values were collected and compared by age. Data are presented as median (IQR), unless otherwise stated. RESULTS: Fifty-nine patients, aged 10.4 (3.7-14.7) years and 49% female, met inclusion criteria; 42 had at least 1 steady-state voriconazole serum trough concentration measured. Twenty-one of 42 (50%) achieved the target concentration at the first steady-state measurement. An additional 13 of 42 (31%) achieved the target following 2 to 4 dose modifications. The dose required to first achieve a value in the target range was 22.3 (18.0-27.1) mg/kg/day in children aged <12 years and 12.0 (9.8-14.0) mg/kg/day in children aged ≥12 years. After reaching the target, 59% and 81% of repeated steady-state measurements were in the therapeutic range in patients aged <12 years and ≥12 years, respectively. CONCLUSIONS: Reaching therapeutic voriconazole serum trough concentrations required doses larger than currently recommended by the American Academy of Pediatrics. Multiple dose adjustments and TDM measurements were required to achieve and maintain therapeutic voriconazole serum concentrations.

Vitamin D3 decreases parathyroid hormone in HIV-infected youth being treated with tenofovir: a randomized, placebo-controlled trial.

BACKGROUND: The study goal was to determine the effect of vitamin D (VITD) supplementation on tubular reabsorption of phosphate (TRP), parathyroid hormone (PTH), bone alkaline phosphatase (BAP), and C-telopeptide (CTX) in youth infected with human immunodeficiency virus (HIV) receiving and not receiving combination antiretroviral therapy (cART) containing tenofovir disoproxil fumarate (TDF). METHODS: This randomized, double-blind, placebo-controlled multicenter trial enrolled HIV-infected youth 18-25 years based on stable treatment with cART containing TDF (n = 118) or no TDF (noTDF; n = 85), and randomized within those groups to vitamin D3, 50 000 IU (n = 102) or placebo (n = 101), administered at 0, 4, and 8 weeks. Outcomes included change in TRP, PTH, BAP, and CTX from baseline to week 12 by TDF/noTDF; and VITD/placebo. RESULTS: At baseline, VITD and placebo groups were similar except those on TDF had lower TRP and higher PTH and CTX. At week 12, 95% in the VITD group had sufficient serum 25-hydroxy vitamin D (25-OHD; ≥20 ng/mL), increased from 48% at baseline, without change in placebo (P < .001). PTH decreased in the TDF group receiving VITD (P = .031) but not in the noTDF group receiving VITD, or either placebo group. The decrease in PTH with VITD in those on TDF occurred with insufficient and sufficient baseline 25-OHD (mean PTH change, -7.9 and -6.2 pg/mL; P = .031 and .053, respectively). CONCLUSIONS: In youth on TDF, vitamin D3 supplementation decreased PTH, regardless of baseline 25-OHD concentration. CLINICAL TRIALS REGISTRATION: NCT00490412.

Incidence and risk factors for venous thromboembolism in critically ill children with cardiac disease.

Cardiac disease is a risk factor for venous thromboembolism (VTE) in children. In this study, we investigated the incidence and risk factors of VTE in critically ill children with cardiac disease, who were prospectively followed-up for VTE after admission to a tertiary care pediatric intensive care unit (PICU). Risk factors were compared between VTE cases and (1) patients in the cohort who did not develop VTE and (2) the next three cardiac patients sequentially admitted to the PICU (case control). Forty-one cases of VTE were identified from 1070 admissions (3.8%). Thirty-seven percent of VTE cases were central venous catheter (CVC)-associated, and 56% of cases were intracardiac. Sixty-six percent of patients were receiving anticoagulation at the time of VTE diagnosis. Increased VTE incidence was associated with unscheduled PICU admission, age <6 months, extracorporeal membrane oxygenation, increased number of CVCs, increased number of CVC days, higher risk of mortality score, and longer PICU stay. Using logistic regression, VTE was associated with single-ventricle physiology (odds ratio [OR] 11.2, 95% CI 3.0-41.9), widened arterial-to-somatic oxygen saturation gradient (SpO(2)-rSO(2) >30) (OR 4.3, 95% CI 1.1-16), and more CVC days (OR 1.1, 95% CI 1.04-1.13). Risk factors for VTE in critically ill children with cardiac disease include younger age, single-ventricle cardiac lesions, increased illness severity, unscheduled PICU admission, and complicated hospital course.

Imaging Practices and Implications in Young Infants With Urinary Tract Infection.

OBJECTIVES: Management of infants aged ≤60 days with urinary tract infections (UTI) is challenging. We examined renal imaging in infants aged ≤60 days with UTI at a tertiary care children's hospital to identify the impact of standardizing renal ultrasound (RUS) interpretation. METHODS: We retrospectively studied infants aged ≤60 days hospitalized for UTI or fever with urine culture and renal imaging obtained and final diagnosis of UTI. RUS initially had noncriterion-based (NCB) interpretation by experienced pediatric radiologists. For this study, a single pediatric radiologist used a criterion-based (CB) hydronephrosis grading system to reinterpret films initially classified as "abnormal" on the NCB reading. We compared final renal imaging results between NCB and CB groups. RESULTS: Of 193 infants, 180 (93%) had inpatient RUS with 114 (63%) abnormal NCB interpretation. Of those with initially abnormal NCB interpretation, 85 OF 114 (75%) had minor and 29 OF 114 (25%) had significant abnormality by CB reinterpretation. In follow-up, the CB "minor abnormality" group showed 25% abnormal renal imaging, whereas the "significant abnormality" group showed 77% abnormal renal imaging with 54% having high-grade reflux on a voiding cystourethrogram (VCUG). Patients with CB inpatient RUS minor abnormality showed 3% abnormal RUS at follow-up, but 13% showed high-grade reflux on VCUG. CONCLUSIONS: Standardized RUS interpretation in young infants with UTI improved the accuracy of identification of abnormalities on follow-up renal imaging. In patients with CB minor abnormality on inpatient RUS, our results suggest limited utility of follow-up RUS; however, follow-up VCUG remained useful to identify high-grade reflux.

COVID-19 Pandemic Exacerbates Childhood Immunization Disparities.

BACKGROUND: The objective of this study was to measure the recovery of routine pediatric immunization after a period of reduced vaccine administrations in the early weeks of the COVID-19 pandemic. METHODS: We recorded data on vaccines administered in Children's Wisconsin primary care or urgent care clinics from January 2019 through December 2020 and aggregated data by date and insurance type. RESULTS: During the gradual reopening period after week 21 in 2020, vaccine administration returned to prepandemic levels for children with commercial insurance but remained below baseline rates until the end of 2020 for children with Medicaid insurance. DISCUSSION: The decline in pediatric vaccination in 2020 disproportionately affected children with Medicaid insurance.

Plasma and intracellular population pharmacokinetic analysis of tenofovir in HIV-1-infected patients.

The relationships among the dose of tenofovir disoproxil fumarate (TDF), tenofovir (TFV) plasma concentrations, and intracellular TFV diphosphate (TFV-DP) concentrations are poorly understood. Our objective was to characterize TFV and TFV-DP relationships. Data were pooled from two studies in HIV-infected persons (n = 55) on stable antiretroviral therapy. TFV and TFV-DP were measured with validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods. Nonlinear mixed effects modeling (NONMEM 7) was used to develop the population model and explore the influence of covariates on TFV. A sequential analysis approach was utilized. A two-compartment model with first-order absorption best described TFV PK (FOCEI). An indirect stimulation of response model best described TFV-DP, where formation of TFV-DP was driven by plasma TFV concentration. Final plasma population estimates were as follows: absorption rate constant, 1.03 h(-1); apparent clearance (CL/F), 42 liters/h (33.5% interindividual variability [IIV]); intercompartment clearance, 181 liters/h; apparent central distribution volume (Vc/F), 273 liters (64.8% IIV); and apparent peripheral distribution volume (Vp/F), 440 liters (46.5% IIV). Creatinine clearance was the most significant covariate on CL/F and Vc/F. The correlation between CL/F and Vc/F was 0.553. The indirect response model for TFV-DP resulted in estimates of the maximal intracellular concentration (E(max)), the TFV concentration producing 50% of E(max) (EC(50)), and the intracellular elimination rate constant (k(out)) of 300 fmol/10(6) cells (82% IIV), 100 ng/ml (106% IIV), and 0.008 h(-1), respectively. The estimated k(out) gave an 87-h TFV-DP half-life. A predictive check assessment indicated satisfactory model performance. This model links formation of TFV-DP with plasma TFV concentrations and should facilitate more informed investigations of TFV clinical pharmacology.

Mycobacterium avium intracellulare infection coexistent with nodular lymphocyte predominant Hodgkin lymphoma involving the lung.

A 5.5-year-old asymptomatic Hispanic/African American male presented with matted lymph nodes in the neck and reticulonodular opacities in the right upper lung. An extensive diagnostic work up was performed to rule out infectious etiologies. Biopsies of the lymph node and lung tissue were diagnostic of nodular lymphocyte predominant Hodgkin lymphoma. Two weeks into the chemotherapy, gastric aspirates grew Mycobacterium avium intracellulare. This is the first case of nodular lymphocyte predominant Hodgkin lymphoma involving the lung with coexistent Mycobacterium avium intracellulare.

H1N1 hemagglutinin-inhibition seroprevalence in Emergency Department Health Care workers after the first wave of the 2009 influenza pandemic.

STUDY OBJECTIVE: The 2009 H1N1 pandemic (H1N1pdm) virus has been associated with high rates of asymptomatic infections. Existing influenza infection control policies do not address potential transmission through exposure to asymptomatic infected individuals in health care settings. We conducted a seroprevalence study of H1N1pdm infection to determine whether health care workers (HCWs) in the emergency department showed increased evidence of infection during the first wave of the pandemic than that previously reported in adults in the community. METHODS: Blood samples and demographic and clinical data were collected from eligible emergency department HCWs. Subjects' sera were tested for presence of antibodies specific for seasonal H1N1 and H1N1pdm viruses by hemagglutination-inhibition assay. RESULTS: One hundred eight subjects were enrolled, of which 20 (18.5%) were seropositive for H1N1pdm and 52 (48%) for seasonal H1N1. The median age of H1N1pdm-seropositive subjects was 32 years (range, 24-59 years). Of H1N1pdm-seropositive subjects, 35% were asymptomatic. Rates of H1N1pdm detection in HCWs (18.5%) were significantly higher than those observed previously in an identical age cohort in the community (2.6%, n = 262). CONCLUSIONS: The higher serodetection rates in adults observed in the current study suggest potentially significantly more frequent infections in HCWs than in the general population. Further investigations are needed to ascertain the relative incidence of influenza infections in HCWs and non-HCWs, to study influenza transmission by asymptomatic infected subjects and ascertain the burden of such transmission in health care settings.