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Background Location and type of clinic where pediatric latent TB infection (LTBI) care is provided are associated with treatment completion and retention in care. Prior research has not evaluated joint clinical management occurring between care settings. Understanding care transfer dynamics and accessibility of clinics can inform pediatric LTBI care service delivery. Methods We conducted a retrospective cohort study of LTBI in children 0-17 years old who were prescribed outpatient treatment in two Boston-area health systems from 2017-2019. We defined “initial clinical setting” (categorized as primary care or TB/infectious diseases clinic) as the location where the first LTBI medication was prescribed. Through chart review, we determined if care was transferred to a different (“final”) clinic setting during treatment. We calculated driving time between a child’s home address and initial and final treatment clinics. The primary outcome was frequency of care transfer after starting treatment. In a secondary analysis, we used two multivariable logistic regression models (adjusted for age, sex, and use of rifamycin-based treatment) to evaluate associations between completion and distance to and type of initial and final treatment clinic. Results We identified 142 children who started LTBI treatment as outpatients; 110 started treatment in primary care clinics and 32 in TB/infectious diseases clinics. Overall, 20/142 (14%) transferred TB care to a different clinic after starting treatment. A total of 101/142 (71%) patients completed treatment. Neither initial treatment location nor driving time to initial clinic were significantly associated with treatment completion (Table 1). However, final treatment in a TB clinic was associated with higher odds of treatment completion than final treatment in a primary care clinic (aOR 2.71 [95%CI 1.06-6.91], P=0.04); time to clinic was not associated with completion (Table 2). Figure 1.Patient transfers after starting LTBI treatment.Table 1.Initial treatment location: Univariable and multivariable analysis of factors associated with treatment completion.1Adjusted for time to clinic and location of initial treatment as well as age, sex, and use of rifamycin-based treatment.Table 2.Final treatment location: Univariable and multivariable analysis of factors associated with treatment completion.1Adjusted for time to clinic and location of final treatment as well as age, sex, and use of rifamycin-based treatment. Conclusion Among children with LTBI in a large metropolitan area, more patients received treatment in primary care clinics than in TB clinics. Care transfers were relatively uncommon after starting treatment. A TB clinic as a final treatment location was associated with increased odds of treatment completion. Disclosures Jessica Haberer, MD, MS, Merck: Advisor/Consultant|Natera: Stocks/Bonds.

Background Understanding barriers and facilitators to latent tuberculosis infection (LTBI) diagnosis and care is needed to successfully treat children/adolescents with LTBI in the US. We explored physicians’ perspectives on pediatric LTBI diagnosis and care, and strategies to improve care. Methods We conducted a convergent mixed methods study with physicians in Massachusetts. Participants were purposefully sampled from primary care clinics (n=10), clinics seeing immunocompromised patients (n=2), and TB clinics (n=2). Physicians participated in individual qualitative semi-structured interviews exploring experience and comfort with LTBI care, and perceived barriers and facilitators to care. We used applied thematic analysis to analyze transcripts. Participants completed surveys to assess comfort with LTBI care and volume of LTBI patients in their care. Results Of the 25 physicians invited, 14 participated. Most participants reported “medium” or “high” comfort with current LTBI guidelines; volume of LTBI care varied by physician type (Table 1). Analysis revealed perceived barriers (Figure 1) at four steps of care: 1) identification of risk and testing for LTBI (e.g., family/patient risk perception, physician knowledge gaps), 2) completion of referral after a positive test (e.g., communication barriers), 3) treatment acceptance and initiation (e.g., lack of social support), and 4) treatment adherence and completion (e.g., adolescents’ emerging autonomy). Facilitators such as protocolized screening, counseling strategies, free medication, and telehealth (Figure 2) overcame some barriers. Important emergent themes included: 1) COVID-19 has induced rapid positive and negative changes in LTBI care in primary care clinics; 2) immigrant adolescents are uniquely at risk for disengagement due to lack of social support; and 3) physicians and clinics are ill-equipped to provide TB care for patients’ close contacts, despite knowledge of need for care. Table 1.Volume of patients by clinician type (N=13 respondents)Figure 1.Barriers to LTBI diagnosis and care.Figure 2.Facilitators of LTBI care. Conclusion Lack of perceived risk, family and clinic resource constraints, and accessibility challenges hindered LTBI care; protocolized screening, telehealth, and free medications were among the facilitators that overcame some but not all barriers. These results will inform improvement of LTBI care within and between clinics. Disclosures Jessica Haberer, MD, MS, Merck: Advisor/Consultant|Natera: Stocks/Bonds.

US guidelines recommend interferon gamma release assays (IGRAs) for diagnosis of tuberculosis infection in children. In this retrospective cohort study, IGRA use in children 2-17 years of age increased substantially between 2015 and 2021. Testing in inpatient/subspecialty settings (vs. primary care), public (vs. private) insurance, lower age and non-English preferred language were associated with increased odds of receiving an IGRA.

Background and Aims Glecaprevir/pibrentasvir (GLE/PIB) has shown high efficacy and safety in chronic HCV‐infected adults and adolescents; data in children were limited. DORA part 2 is a phase 2/3, nonrandomized, open‐label study evaluating the pharmacokinetics, efficacy, and safety of a pediatric formulation of GLE and PIB in children ages 3 to < 12 years. Approach and Results Children with chronic HCV infection, genotype 1‐6, with or without compensated cirrhosis, were divided into three cohorts by age—cohort 2 (9 to < 12 years), cohort 3 (6 to < 9 years), and cohort 4 (3 to < 6 years)—and given weight‐based doses of GLE and PIB for 8, 12, or 16 weeks. Primary endpoints were sustained virologic response at posttreatment week 12 (SVR12) and steady‐state exposure; secondary endpoints were rates of persistent viremia, relapse, and reinfection. Safety and laboratory abnormalities were assessed. Final pediatric dosages determined to be efficacious were 250 mg GLE + 100 mg PIB (in children weighing ≥ 30 to < 45 kg), 200 mg GLE + 80 mg PIB (≥ 20 to < 30 kg), and 150 mg GLE + 60 mg PIB (12 to < 20 kg). Of 80 participants enrolled and dosed, 96% (77/80) achieved SVR12. One participant, on the initial dose ratio, relapsed by posttreatment week 4; no participants had virologic failures on the final dose ratio of GLE 50 mg/PIB 20 mg. Two nonresponders prematurely discontinued the study. Most adverse events (AEs) were mild; no drug‐related serious AEs occurred. Pharmacokinetic exposures were comparable to those of adults. Conclusions A pediatric formulation of GLE/PIB was highly efficacious and well tolerated in chronic HCV‐infected children 3 to < 12 years old.

COVID-19 disease has been a pandemic caused by a s-coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A life-threatening multisystem inflammatory syndrome (MIS), secondary to SARS-CoV-2 virus infection, sharing common features with Kawasaki disease shock syndrome, staphylococcal/streptococcal shock syndrome, and macrophage activation syndrome in pediatric patients has been described. A total of 27 cases in adults (MIS-A) with a similar presentation have been reported so far. Here we describe the case of a 21-year-old man admitted with abdominal pain, diarrhea, tachycardia, and low blood pressure. He had elevated troponin, ferritin, and interleukin-2 receptor levels and had evidence of myocarditis. He tested positive for SARS-CoV-2 IgG antibody, and a diagnosis of MIS-A was made. Our case adds to the scant literature on this topic, and to our knowledge, it is the first case where anakinra was administered. He recovered well. MIS-A should be considered when young adults present with multiorgan dysfunction.

Introduction While the COVID-19 pandemic continues to have a significant global health impact, rates of maternal to infant vertical transmission remain low (, Highlights • SARS-CoV2 glycoprotein in the placenta does not vary with fetal transmission. • SARS-CoV-2 viral entry protein ACE2 is highly expressed in the villous placenta. • SARSS-CoV-2 viral entry protein TMPRSS2 has low expression in the villous placenta.

ObjectiveSARS-CoV-2 infection induces significant inflammatory cytokine production in adults, but infant cytokine signatures in pregnancies affected by maternal SARS-CoV-2 are less well characterized. We aimed to evaluate cytokine profiles of mothers and their infants following COVID-19 in pregnancy.Study DesignSerum samples at delivery from 31 mother-infant dyads with maternal SARS-CoV-2 infection in pregnancy (COVID) were examined in comparison to 29 control dyads (Control). Samples were evaluated using a 13-plex cytokine assay.ResultsIn comparison with controls, interleukin (IL)-6 and interferon gamma-induced protein 10 (IP-10) were higher in COVID maternal and infant samples (pst/2nd Trimester) and late (3rd Trimester) maternal SARS-CoV-2 infections.ConclusionsMaternal SARS-CoV-2 infections throughout gestation are associated with increased maternal and infant inflammatory cytokines at birth with potential to impact long-term infant health.

To characterize losses from the pediatric tuberculosis (TB) infection care cascade to identify ways to improve TB infection care delivery.We conducted a retrospective cohort study of children (age18 years) screened for TB within 2 Boston-area health systems between January 2017 and May 2019. Patients who received a tuberculin skin test (TST) and/or an interferon gamma release assay (IGRA) were included.We included 13 353 tests among 11 622 patients; 93.9% of the tests were completed. Of 199 patients with positive tests for whom TB infection evaluation was clinically appropriate, 59.3% completed treatment or were recommended to not start treatment. Age 12-17 years (vs 5 years; aOR 1.59; 95% CI, 1.32-1.92), non-English/non-Spanish language preference (vs English; aOR, 1.34; 95% CI, 1.02-1.76), and receipt of an IGRA (vs TST, aOR, 30.82; 95% CI, 21.92-43.34) were associated with increased odds of testing completion. Odds of testing completion decreased as census tract social vulnerability index quartile increased (ie, social vulnerability worsened; most vulnerable quartile vs least vulnerable quartile, aOR, 0.77; 95% CI, 0.60-0.99). Odds of completing treatment after starting treatment were higher in females (vs males; aOR, 2.35; 95% CI, 1.14-4.85) and were lower in patients starting treatment in a primary care clinic (vs TB/infectious diseases clinic; aOR, 0.44; 95% CI, 0.27-0.71).Among children with a high proportion of negative TB infection tests, completion of testing was high, but completion of evaluation and treatment was moderate. Transitions toward IGRA testing will improve testing completion; interventions addressing social determinants of health are important to improve treatment completion.

This study aimed to describe maternal characteristics and clinical outcomes of infants born to mothers with positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tests during pregnancy at an urban, safety-net hospital in Boston.We abstracted electronic chart data from 75 pregnant women with positive SARS-CoV-2 tests at any stage of gestation until 72 hours after birth who delivered consecutively between March 31 and August 6, 2020 at our center. We collected clinical data on maternal and infant characteristics, including testing, signs, and symptoms of coronavirus disease 2019 (COVID-19), delivery outcomes, newborn care practices (skin-to-skin care, location of care, and breastfeeding) and 30-day postdischarge infant emergency room visits and readmissions. We described categorical characteristics as percentages for this case series.Among 75 pregnant women, 47 (63%) were Hispanic, 10 (13%) had hypertension, 23 (30%) had prepregnancy obesity, and 57 (76%) had symptomatic SARS-CoV-2 infection. Regarding birth outcomes, 32 (41%) had cesarean delivery and 14 (19%) had preterm birth. Among 75 infants, 5 (7%) had positive SARS-CoV-2 polymerase chain reaction tests in the first week of life, all of whom were born to Hispanic mothers with symptomatic SARS-CoV-2 infection and had clinical courses consistent with gestational age. Six (8%) infants visited the emergency department within 30 days of discharge; one was admitted with a non-COVID-19 diagnosis.At our urban, safety-net hospital among pregnant women with positive SARS-CoV-2 tests, 41% had a cesarean delivery and 19% had a preterm birth. Seven percent of infants had one or more positive SARS-CoV-2 tests and all infants had clinical courses expected for gestational age.· Among 75 pregnant women with SARS-CoV-2 positive testing at our center, five infants (7%) had one or more SARS-CoV-2 positive tests in the first week of life.. · Infants with positive SARS-CoV-2 tests had clinical courses expected for gestational age..

Purpose The majority of pregnancies affected by maternal coronavirus disease 2019 (COVID-19) do not result in fetal transmission. However, several studies have identified parenchymal changes in their placental tissues, suggesting a placental response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the maternal–fetal interface. Although many COVID-19 placental studies have focused on the expression of the canonical SARS-CoV-2 entry proteins angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2, further characterization of subcellular molecules involved in viral trafficking have not yet been investigated in these tissues. Of interest are Rab proteins, a family of small GTPase proteins that direct intracellular transport between different endocytic organelles. Rab5 and Rab7 in particular have previously been implicated in HIV and cytomegalovirus invasion of placental trophoblast cells in vitro; the localization of these molecules has not been fully characterized within the human maternal–fetal interface, however, or within placental tissues from SARS-CoV-2–infected pregnancies. Methods Using fluorescent immunohistochemistry, Rab5 and Rab7 placental localization and comparative fluorescence intensity were explored in a cohort of placental tissues from pregnancies affected by maternal COVID-19 disease (COVID, n = 15) compared with contemporary control subjects (Control, n = 10). Fluorescence intensity was quantified by using corrected total cell fluorescence values. Findings Within placental villi, Rab5 was consistently localized in syncytiotrophoblast and cytotrophoblast cells. Rab5 had significantly higher mean (SEM) fluorescence intensity in the COVID cohort (Control, 1.96 [0.16]; COVID, 2.62 [0.09]; P = 0.0014). In contrast, although Rab7 was also localized within placental villous syncytiotrophoblast and cytotrophoblast cells, mean (SEM) Rab7 fluorescence intensity was significantly downregulated in COVID vs Control placentas (Control, 35.9 [4.1]; COVID, 20.1 [0.52]; P = 0.0001). Implications This differential expression of Rab5 and Rab7 suggests that placental endocytic pathways may be altered at the maternal–fetal interface in pregnancies affected by maternal SARS-CoV-2 infection. As key molecules governing intracellular vesicle transport, including viral trafficking, Rab GTPase proteins may be of interest for ongoing studies examining placental responses to COVID-19 in pregnancy., Highlights • RabGTPase proteins are important cell trafficking proteins evaluate in placental tissues affected by COVID-19 disease. • Rab5 is comparatively upregulated in placentas from SARS-CoV-2 positive women. • Rab7 has comparatively low expression in placentas from SARS-CoV-2 positive women.

Background The American Academy of Pediatrics recommends tuberculin skin tests (TSTs) or interferon gamma release assays (IGRAs) to test for tuberculosis (TB) infection in children ≥2 years old, and prioritizes IGRA testing in Bacille Calmette-Guérin vaccine recipients due to cross-reactivity. TSTs require a return visit, which frequently results in loss to follow up. Growing evidence supports accuracy of IGRA testing in pediatric patients, including young children, leading to calls for preferential use of IGRA over TST. We sought to evaluate trends in IGRA use in children over time. Methods We identified all TB infection tests conducted in children 5-17 years old at 2 academic medical systems in Boston from October 2015–January 2021. TSTs were identified using medication administration records, and IGRAs were identified using laboratory records. We computed the proportion of tests per month that were IGRA and TST. We used Pearson correlation to determine the association between month of testing and proportion of tests that were IGRAs. Results 21,471 TB infection tests were obtained from 16,778 patients during our timeframe. Median age of testing was 13.4 years (IQR 9.2 – 16.2 years). During the study period, there was a significant increase in the monthly proportion of TB infection tests that were IGRAs (Pearson correlation coefficient 0.92, P < 0.001). The total number of tests performed per month also increased, with seasonal increases in testing in late summer and early fall and a substantial decline in testing early in the COVID-19 pandemic. Tuberculosis infection tests and proportion IGRA. Total number of tuberculosis infection tests per month and proportion of tests that were interferon gamma release assays, from October 2015 - January 2021. Conclusion Use of IGRAs among patients age 5-17 years of age increased significantly overall and compared to TST in two large Boston healthcare systems over a 5-year period. These results suggest a shift towards blood-based TB infection testing in a low-burden setting, which may improve completion of the pediatric TB infection care cascade. Future research is needed to determine reasons for changing testing modalities, and similar patterns in other settings. Disclosures Gabriella S. Lamb, MD, MPH, Nothing to disclose

Background COVID-19 transmission from mother to infant suggests that vertical and horizontal transmission of COVID-19 are possible. Here we describe the demographic and clinical characteristics and outcomes of SARS-CoV-2 positive pregnant women and their newborns. Summarized Characteristics of 19 COVID-19 Positive Mothers that Delivered 3/31/20–6/17/20 at Boston Medical Center Methods We collected data from the electronic medical records of pregnant women. Data composed of maternal demographics and morbidities, and symptoms of COVID-19. Descriptive statistics were used to analyze data. Women had positive polymerase chain reaction (PCR) testing done by nasopharyngeal swabs. Each newborn was tested for SARS_CoV-2 by RT_PCR with a nasopharyngeal swab at 24 hours, 48 hours, and day 5 of life. Results 36 women met criteria to be included in this study. 22% had chronic hypertension, 8% had asthma, one had chronic HIV and hepatitis C, 30% had pregnancy-related morbidities including pregnancy-induced hypertension (19%), cholestasis of pregnancy (8%) and gestational diabetes(3%) (Table1) Of the 32 deliveries to date, 17 (53% delivered vaginally and 15 (47%) via C-section. Of the 15 C-sections, 6 (40%) were due to complications related to COVID-19. 38% (14/36) women developed hypoxia. Five newborns (15%) born to SARS-CoV-2 positive mothers had positive PCR testing for SARS-CoV-2. 2 of them were born prematurely and by C section secondary to COVID 19 infection respiratory deterioration. One premature infant tested positive for RT-PCR for SARS-CoV-2 on days 1, 2, and 5. The other one was positive on day 2. The two full-term newborns who tested positive by PCR for COVID 19 after delivery, were not delivered secondary to COVID 19 complications. One infant who was separated from his mother was negative by PCR at days 1,2 and 5 but tested positive later after being in contact with his mother. Conclusion Our population of pregnant mothers had a high incidence of cesarean section secondary to COVID 19 infection complications. They also had a high frequency of chronic health conditions. Infants born to mothers with COVID-19 can have positive PCR tests for SARS-CoV-2 suggesting that both, vertical and horizontal mother to infant transmission is possible. Infants had negative tests before positive tests, suggesting false negative testing may have occurred. Disclosures All Authors: No reported disclosures

Objectives The US National Viral Hepatitis Action Plan calls for major efforts to expand hepatitis C virus (HCV) diagnosis and treatment; prenatal care settings are potential venues for expanding HCV testing. We aimed to characterize the HCV diagnostic cascade for women and infants and investigate factors associated with linkage and follow-up. Study design We used electronic health records for a 10-year cohort of 879 women with opioid use disorder from an obstetric clinic serving women with substance use disorders. Results Altogether, 744 women (85%) were screened for HCV; 510 (68%) were seropositive, of whom 369 (72%) had nucleic acid testing performed and of these 261 (71%) were viremic. Of 404 infants born to HCV-seropositive women, 273 (68%) were tested at least once for HCV, 180 (45%) completed the American Academy of Pediatrics-recommended perinatal HCV screening, and 5 (2.8%) were diagnosed with HCV infection and linked to care. More recent delivery date (2014-2015) was associated with maternal linkage to care (aOR, 2.5; 95% CI, 1.4-4.7). Maternal coinfection with HIV (aOR, 9.0; 95% CI, 1.1-72.8) and methadone maintenance therapy, compared with buprenorphine (aOR, 1.5; 95% CI, 0.9-2.5), were associated with higher rates of infant HCV testing. Conclusions HCV prevalence among pregnant women with opioid use is high and infant HCV screening is imperfect. Programmatic changes to improve both mother and infant follow-up may help to bridge identified gaps in the cascade to cure.

Sickle cell disease (SCD) affects approximately 100,000 people in the US, 12,500 in the UK, and millions worldwide. SCD is typified by painful vaso-occlusive episodes, haemolytic anaemia and organ damage. A secondary complication is infection, which can be bacterial, fungal or viral. Universal newborn screening, routine use of penicillin prophylaxis, availability of conjugated vaccines against S. pneumoniae and comprehensive care programmes instituted during the past few decades in industrialized countries have dramatically reduced childhood mortality and improved life expectancy. Yet patients with SCD remain at increased risk of infection. Unfortunately, the treatment of most bacterial infections that are common in SCD is not based on the results of randomized controlled clinical trials. In their absence, treatment decisions are based on consensus guidelines, clinical experience or adapting treatment applied in other diseases. This leads to wide variation in treatment among institutions and even between treating physicians in a single institution. Prevention of infection, when possible, is most important and we focus on prevention through targeted prophylaxis and vaccination. We will share our management strategies for managing the more common infections in SCD and provide the rationale for our recommendations.

Otitis media is the most common reason U.S. children receive antibiotics. The requisite 7- to 10-day course of oral antibiotics can be challenging to deliver in children, entails potential systemic toxicity, and encourages selection of antimicrobial-resistant bacteria. We developed a drug delivery system that, when applied once to the tympanic membrane through the external auditory canal, delivers an entire course of antimicrobial therapy to the middle ear. A penta-block copolymer poloxamer 407–polybutylphosphoester (P407-PBP) was designed to flow easily during application and then to form a mechanically strong hydrogel on the tympanic membrane. U.S. Food and Drug Administration–approved chemical permeation enhancers within the hydrogel assisted flux of the antibiotic ciprofloxacin across the membrane. This drug delivery system completely eradicated otitis media from nontypable Haemophilus influenzae (NTHi) in 10 of 10 chinchillas, whereas only 62.5% of animals receiving 1% ciprofloxacin alone had cleared the infection by day 7. The hydrogel system was biocompatible in the ear, and ciprofloxacin was undetectable systemically (in blood), confirming local drug delivery and activity. This fast-gelling hydrogel could improve compliance, minimize side effects, and prevent systemic distribution of antibiotics in one of the most common pediatric illnesses, possibly minimizing the development of antibiotic resistance.

Among 34 Streptococcus pneumoniae (Spn) sequential isolates from middle ear fluid, we found a case of a nontypeable S. pneumoniae (NT-Spn) in a child with acute otitis media (AOM). The strain was pneumolysin PCR positive and capsule gene PCR negative. Virulence of the NT-Spn was confirmed in a chinchilla model of AOM.

We hypothesized that capsular switch event, in which pneumococcus acquires a new capsule operon by horizontal gene transfer, may result in emergence of strains with increased virulence in acute otitis media. Using serotype 6A strain from a patient with invasive pneumococcal disease and clonally distant serotype 6C strain isolated from asymptomatic carrier we created 6A:6C (6A background with 6C capsule) capsular transformants and applied whole genome macro-restriction analysis to assess conservation of the 6A chassis. Next, we assessed complement (C3) and antibodies deposition on surface of pneumococcal cells and tested capsule recipient, capsule donor and two 6A:6C transformants for virulence in chinchilla experimental otitis media model. Both 6A:6C(1 or 2) transformants bound less C3 compared to 6C capsule-donor strain but more compared to serotype 6A capsule-recipient strain. Pneumococci were present in significantly higher proportion of ears among animals challenged with either of two 6A:6C(1 or 2) transformants compared to chinchillas infected with 6C capsule-donor strain [p

We have developed a drug delivery system for prolonged trans-tympanic antibiotic delivery from a single dose administration. Increased permeability to ciprofloxacin of the intact tympanic membrane (TM) was achieved by chemical permeation enhancers (CPEs - bupivacaine, limonene, sodium dodecyl sulfate); this was also seen by CPEs contained within a hydrogel (poloxamer 407) to maintain the formulation at the TM. The CPE-hydrogel formulation had minimal effects on auditory thresholds and tissue response in vivo. CPE-hydrogel formulations have potential for ototopical delivery of ciprofloxacin for the treatment of acute otitis media (AOM) and other middle ear diseases. ©2012 Elsevier Ltd., National Institute of Deafness andCommunicative Disorders - NIDCD (Grant Number R21DC009986)

The acute phase response is an evolutionarily conserved reaction in which physiological stress triggers the liver to remodel the blood proteome. Although thought to be involved in immune defense, the net biological effect of the acute phase response remains unknown. As the acute phase response is stimulated by diverse cytokines that activate either NF-κB or STAT3, we hypothesized that it could be eliminated by hepatocyte-specific interruption of both transcription factors. Here, we report that the elimination in mice of both NF-κB p65 (RelA) and STAT3, but neither alone, abrogated all acute phase responses measured. The failure to respond was consistent across multiple different infectious, inflammatory, and noxious stimuli, including pneumococcal pneumonia. When the effects of infection were analyzed in detail, pneumococcal pneumonia was found to alter the expression of over a thousand transcripts in the liver. This outcome was inhibited by the combined loss of RelA and STAT3. Moreover, this interruption of the acute phase response increased mortality and exacerbated bacterial dissemination during pneumonia, possibly as a result of acute humoral enhancement of macrophage opsonophagocytosis, which was impaired in the mutant mice. Thus, we conclude that RelA and STAT3 are essential for stress-induced transcriptional remodeling in the liver and the subsequent activation of the acute phase response, whose functional role includes compartmentalization of local infection.

Increases in colonization with serotypes of Streptococcus pneumoniae not contained within the 7-valent pneumococcal conjugate vaccine (PCV) have been reported among children following introduction. Serotype 6C has emerged as prevalent in nasopharyngeal colonization and acute otitis media (AOM), though it is uncommonly recovered from children with invasive pneumococcal disease. Vaccine serotypes within PCV7 have been replaced by nonvaccine serotypes without significant changes in the overall carriage rate. We hypothesize 1) that serotypes vary in their ability to evade host defenses and establish AOM following colonization and 2) the observed reduction in pneumococcal otitis results from a reduced disease potential by some ‘replacement serotypes’. We compared the capacity of S. pneumoniae serotypes 6C and 19A to produce experimental otitis media (EOM) in a chinchilla model. The proportion of chinchillas that developed culture positive EOM and density of middle ear infection was evaluated. EOM was found in 28/82 (34%) ears challenged with 6C compared to 13/18(72.2%) with 19A [p = 0.0003]. When disease due to 6C did occur, it was characterized by low-density infection. Our findings demonstrate that challenge with serotype 6C results in EOM less frequently than 19A. These data support the need for greater knowledge regarding differences among serotypes to produce AOM.

Strategies to limit complement deposition on Streptococcus pneumoniae are established as virulence features for invasive disease, but their role in respiratory tract infection requires further analysis. We evaluated complement C3 protein deposition on discordant S. pneumoniae isolates of the same serotype (6A) and their capacity to cause nasopharyngeal (NP) colonization and experimental otitis media (EOM) in an animal model. We compared C3 binding to five 6A isolates from asymptomatic NP carriers with five 6A strains that caused invasive disease, and we observed less C3 (∼10-fold less fluorescence) binding to invasive isolates. We selected two high-level C3-binding carriage and two low-level C3-binding invasive 6A isolates for further study. In the EOM model, 11/12 (92%) ears challenged with a low-level C3-binding 6A strain became infected. Only 2/8 (25%) ears challenged with the discordant high-level C3-binding 6A isolate developed disease ( P = 0.005). Results with the second discordant 6A isolate pair were comparable. Cobra venom factor (CoVF) treatment, which depletes C3 and consumes complement, restored virulence of the high-level C3-binding strain; 8/8 (100%) ears in CoVF-treated animals developed EOM compared to only 25% of ears in naïve animals ( P = 0.007). These studies demonstrate the critical role for complement evasion in pneumococcal EOM. Colonization with carriage isolates that bound high levels of C3 caused EOM in fewer animals compared to low-level C3-binding invasive strains. Thus, limiting C3 deposition on the surface of S. pneumoniae correlates with increased incidence of EOM following NP colonization and barotrauma in the animal model.

We report the annotated draft genome sequences of four serotype 6C Streptococcus pneumoniae isolates of differing genetic backgrounds. Serotype 6C isolates are increasing in prevalence and becoming progressively more resistant to antibiotics. As a result, these strains are likely to become more important in the near future.

In recent decades, there has been extensive development, clinical investigation, licensure and use of fluoroquinolone (FQ) antibiotics, yet none has been licensed for pediatric use since naladixic acid in 1962. Compared with naladixic acid, these new FQs, including ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin and gemifloxacin, have a wide spectrum of antimicrobial activity and favorable pharmacologic properties, but concerns for adverse events have prevented licensure in children. Moreover widespread use of FQ in children would likely further increase the prevalence of FQ resistant pathogens, already described with adult use. Nonetheless physicians who care for children may find themselves faced with therapeutic situations where FQ offer significant benefits for their patients.