News

Written by: Christina Gagliardo, MD

Grinsdale JA. Interferon-Gamma Release Assays and Pediatric Public Health Tuberculosis Screening: The San Francisco Program Experience 2005 to 2008.

Grinsdale et al. describe the experience of the San Francisco Department of Public Health’s (SFDPH) use of interferon-gamma release assays (IGRA) in a longitudinal retrospective pediatric cohort in a low TB-prevalence setting.

Latent tuberculosis infection (LTBI) was diagnosed in asymptomatic children with negative chest X-ray and positive QuantiFERON-TB Gold In-tube (QFT), regardless of tuberculin skin test (TST) results, if performed. A small subset of children with a prior or current positive TST and a negative QFT were treated for LTBI at the physician’s individual discretion. Indeterminate QFT tests were repeated and the subsequent test used to establish LTBI status, and for repeated indeterminate QFT tests, diagnosis of LTBI was based on the most recent TST result.

Inclusion criteria for the study were children <15 years of age with a QFT test performed March 1, 2005–December 31, 2008, with 1092 eligible children included. Children had varying risk factors for TB infection including contacts of active TB cases, immigrant children form high-prevalence TB countries who were also BCG vaccinated, and children born in the US being screened for school entry. The study population included 56 (5%) children <2 years of age and 292 (27%) < 5 years of age. QFT-negative/TST-positive discordant results were present in 158 (73%) of children.

976 (89%) of children in the cohort were not treated for LTBI, and observed for a median of 5.7 (range 4-7) years. No cases of active TB were seen in any untreated child during the 5587 person-years of follow-up, including among 146 TST-positive/QFT-negative children. Discordance between TST and QFT was most pronounced in BGC-vaccinated children born outside of the US who were <5 years old (93%) versus 73% in those > 5 years old, consistent with studies showing higher false positive TST results when BCG vaccine was given more recently. This highlights that widespread use of TST in foreign-born children inadvertently leads to increased and potentially unnecessary radiologic studies and LTBI treatment.

The findings of the study suggest that QFT has a high negative predictive value and supports use of IGRAs in screening BCG- and non-BCG vaccinated children, including those <5 years of age, and may prevent unnecessary imaging and treatment for LTBI in many children.

 

Written by: Saul Hymes, MD

Summary

In the June 2016 issue of the “Journal of the Pediatric Infectious Disease Society,” Jiménez-Truque and colleagues report the findings of their prospective longitudinal assessment of S. aureus colonization in student athletes [Jimenez-Truque 2016]. This prospective cohort study examined Vanderbilt University varsity athletes from August 2008 to April 2010. Nasal and oropharyngeal swabs were taken to assess for colonization with both MRSA and MSSA at enrollment and then monthly thereafter. Skin and soft tissue infections were monitored for and recorded. They enrolled 377 athletes and trainers, 224 of whom played contact sports (football, basketball, soccer, and lacrosse; defined using the AAP criteria) and 153 of whom played noncontact sports (cross country, tennis, golf, bowling, swimming, and baseball) or were trainers. Overall, 76.13% of athletes were colonized with S. aureus and 46.4% were colonized with MRSA on at least one occasion, but the prevalence of carriage was dynamic over time. Total S. aureus colonization rates ranged from 34% - 62% and MRSA rates ranged from 8% - 29%. Colonization rates were significantly higher in contact sports participants, ranging from 32% to 62% compared to 18% to 53% in non-contact participants. The colonization rate in the summer was significantly higher than that in the winter, with an OR for MRSA of 1.70 and for MSSA of 1.38. In their discussion, the authors note this was the largest prospective cohort to date of healthy college athletes. The study documented dynamic colonization that changed over the sports seasons, and overall demonstrated significant colonization rates, with real clinical implications, including an MRSA skin and soft tissue infection outbreak that occurred among the football team during their study period.

Commentary

I do not have to convince the readership of PIDSNews that antibiotic resistance is a problem. The CDC’s excellent 2013 threat report [CDC 2013] laid out the scope of the problem, and from the Joint Commission to the Centers for Medicare and Medicaid Services to the United States Executive Branch itself, official practice parameters and even mandates are starting to emerge to guide stewardship and other efforts to reduce antimicrobial resistance and infections with resistant organisms. And yet we don’t understand how best to manage and prevent these infections. While reducing antibiotic use is one key approach, understanding the dynamics of colonization with resistant organisms and how best to time (and where best to place) infection prevention efforts can be key for those organisms that are part of our commensal flora.

As the authors of the present study note, the leading cause of skin and soft tissue infections is S. aureus, a frequent skin and mucous membrane colonizer, with MRSA in particular both more virulent and harder to treat. In recent years MRSA infection rates are declining though the bulk of this is in hospital-acquired (HA) infections where a decline of 54.2% was observed between 2005-2011. Over the same period, only a 5% decline in community-acquired (CA) infections occurred [Dantes 2013]. Given this difference in the rates of decline, CA-MRSA infections are rapidly becoming the more dominant type and further contribution to our knowledge of community S. aureus colonization has the potential to further control these infections.

While the story of MRSA/MSSA infections or colonization in athletes is not a new one [Kazakova 2005], the present study contributes a number of novel findings to the field. First, its prospective nature allowed the authors to show a true seasonality to colonization, related to the particular sporting season. This is not surprising given differences in equipment use, close quarters in locker rooms, and training frequency that could allow for closer contact and spread of organisms, but having it tracked in this way may allow better resource allocation by sports teams. Currently, significant resources may be spent year round on cleaning equipment and on decolonization efforts for players. Armed with this data, programs may find that concentrating those efforts to just before the highest colonization season may be more cost-effective .

Additionally, this study further confirms that contact sports show a higher colonization risk, but it is interesting that it is still fairly high in the noncontact sports. One wonders if this is due to other modes of transmission/colonization, including cross-sports-team social gatherings, dorm living and other aspects of student life, or shared athletic facilities. This, too, is an avenue for further study, as the present study did not examine or control for these other factors. While doing so could be difficult, some form of social network tracking, as has been used for HIV transmission networks [Woodhouse 1994], could prove useful in future studies of this issue.

Finally, this study’s use of oropharyngeal swabs in addition to nasal swabs is of particular interest. The authors note they did not utilize groin or rectal swabs due to concerns of low participant acceptance of such procedures, which is reasonable. But as they show, even the dynamics of nasal vs. oropharyngeal colonization differed, with nasal carriage more common than oropharyngeal overall (31% vs 26%), but the addition of oropharyngeal swabs to nasal swabs increased the detection of S. aureus colonization by 12.4%. Clinically, a negative S. aureus swab from one site is not meaningful, and the same held true here. To truly track S. aureus or other commensal flora colonization, multiple swabs from at least a few if not all possible major sites of colonization should be used in order to maximize the accuracy of detection.

Overall the study adds to our knowledge of colonization dynamics in a population that is known to be at risk for S. aureus infection and to serve as a large reservoir of colonization. In addition, the study offers clear avenues for future research as well as ways to apply the results to day-to-day practice.

References:

  1. Jimenez-Truque N, Saye EJ, Soper N, Saville BR, Thomsen I, Edwards KM, Creech CB. “Longitudinal Assessment of Colonization With Staphylococcus aureus in Healthy Collegiate Athletes. J Pediatric Infect Dis Soc. 2016 Jun;5(2):105-13. Epub 2014 Nov 5.
  2. Antibiotic Resistance Threats in the United States, 2013. The Centers for Disease Control and Prevention, 2013. http://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf 
  3. Dantes R, Mu Y, Belflower R, Aragon D, Dumyati G, Harrison LH, Lessa FC, Lynfield R, Nadle J, Petit S, Ray SM, Schaffner W, Townes J, Fridkin S, for the Emerging Infections Program–Active Bacterial Core Surveillance MRSA Surveillance Investigators. “National Burden of Invasive Methicillin-Resistant Staphylococcus aureus Infections, United States, 2011” JAMA Intern Med. 2013;173(21):1970-1978.
  4. Kazakova SV, Hageman JC, Matava M, Srinivasan A, Phelan L, Garfinkel B, Boo T, McAllister S, Anderson J, Jensen B, Dodson D, Lonsway D, McDougal LK, Arduino M, Fraser VJ, Killgore G, Tenover FC, Cody S, Jernigan DB. “A Clone of Methicillin-Resistant Staphylococcus aureus among Professional Football Players” N Engl J Med 2005; 352:468-475.
  5. Woodhouse DE, Rothenberg RB, Potterat JJ, Darrow WW, Muth SQ, Klovdahl AS, Zimmerman HP, Rogers HL, Maldonado TS, Muth JB, Reynolds JU. “Mapping a social network of heterosexuals at high risk for HIV infection.” AIDS 1994 Sep;8(9):1331-6.

Written by: Diana Yu, PharmD and Saul Hymes, MD

PIDS, as the premier national organization representing the care of and research into infectious diseases in infants and children, takes part in many conferences every year. At both IDWeek and PAS, PIDS organizes sessions and tracks—and those are well worth attending. But sometimes it’s the smaller meetings that can be the most worthwhile—the best balance of networking and education, especially for those in a particular subfield. Dr. Rana Hamdy wrote a few months earlier in these virtual pages about the PIDS-St. Jude’s annual research conference and what it offers in particular to fellows who would attend. Here we report on the 7th Annual International Pediatric Antimicrobial Stewardship Conference.

Led by Dr. Jason Newland and organized and sponsored by PIDS as well as Children’s Mercy in Kansas City, this conference continues to be a tremendous resource for those already working in the field of stewardship and, for the first time this year, is explicitly aimed as a resource for those new to stewardship as well. The conference attendees are a nearly equal mix of pharmacists and physicians, mirroring the close collaboration between those two positions in stewardship programs nationwide. And while the conference attendance is growing every year, it remains a relatively small (think couple of hundred not couple of thousand) group and a single conference track, which makes networking and focus on content that much easier.

Indeed, networking and fostering collaboration across institutions is a key goal of the conference. The pre-conference began, as it has for the past few years, with a dinner Wednesday night and a meeting Thursday morning for representatives of institutions participating in the Sharing Antimicrobial Reports for Pediatric Stewardship (SHARPS) collaborative, a multi-center quality collaborative aimed at sharing data on antimicrobial resistance and stewardship with the goal of studying and possibly standardizing pediatric stewardship practices that work.

While the SHARPS meeting on Thursday morning was taking place and after a great Grand Rounds by Jason Newland on why antibiotic resistance (and thus stewardship) really matters, a new aspect of the official conference was introduced this year. Typically in past years the stewardship conference would begin at 1 PM, but this year a series of introductory talks were organized for Thursday morning for those new to stewardship—fellows, new PharmD’s, or those just starting a stewardship program. From speaking to a number of fellows and more junior attendees at the morning’s sessions, I learned that the sessions seemed extremely helpful, addressing some of the “why” and more broadly “how” of actually doing antimicrobial stewardship, before the rest of the conference dove deeper into details.

Thursday at lunch saw the 3rd meeting of the Pediatric Hematology-Oncology Stewardship Interest Group, or PHOASIG. Led by Dr. Josh Wolf of St. Jude, this group is organized around the idea that stewardship for patients with pediatric malignancies is fundamentally different from other stewardship areas and more data are needed to understand why and what the best approaches may be. Currently a number of multicenter collaborative research projects are in the works and those interested participants were encouraged to sign up for the email listserv.

Kicking off Thursday afternoon’s sessions, Dr. David Hyun of the Pew Foundation and Dr. Holly Maples of University of Arkansas reviewed recent publications in the primary literature on pediatric antimicrobial stewardship. Dr. Sarah Parker then spoke about the experience of starting and running a stewardship program at Children’s Hospital of Colorado. Their unique “Handshake Stewardship” program allowed them to get near universal buy-in and make stewardship an integral part of every team’s day. Then attendees heard the PIDS ASP fellowship award winners—Dr. Candace Johnson from Children’s Hospital of New York-Presbyterian on ASP activities in pediatric post-acute care facilities, Dr. Caroline Reuter on the role of MALDI-TOF and other rapid diagnostics on stewardship at Lurie Children’s Hospital in Chicago, and Dr. Matthew Thomas on a new smartphone-based antibiogram. The day ended with another new feature of the conference, a panel discussion with questions from the audience. This was a big hit. And before turning in for the evening, attendees were treated to an evening of beer and BBQ at the local Kansas City Boulevard Brewery. It was an evening of good food and good conversation.

On Friday, the second day of the conference, Dr. Eddie Stenehjem from Intermountain Healthcare began the morning by presenting the trials and tribulations of extending stewardship activities to smaller community hospitals within a healthcare system, suggesting that hospitals with fewer resources may need a “simpler” approach and accessibility to ID support. Dr. Ritu Banerjee from Mayo Clinic painted the evolving issues of multi-drug resistant Gram-negative infections, illustrating their increasing rates in children and the limited information on treatment options. Dr. Jonathan Beus from Children’s Hospital of Philadelphia highlighted how data will always be needed to evaluate stewardship efforts and to identify areas of opportunity. Finishing out the morning, Dr. Parker returned to discuss how business plans for stewardship can align with the health systems’ goals, including cost savings, safety, and regulatory requirements.

In the afternoon, Dr. Katherine Fleming-Dutra from the CDC discussed the methods and findings from the recent article released in JAMA about inappropriate antibiotic use in the outpatient setting. Oral abstract presentations from physicians and pharmacists included topics such as integrating rapid diagnostics, usage of clinical care guidelines for musculoskeletal and urinary tract infections, probiotic use to prevent C. difficile infection in hematology/oncology patients, and using electronic resources such as claims data to bolster stewardship efforts. Dr. Hyun returned to the podium to close out the final day of the meeting. He provided insight on the political landscape of antimicrobial stewardship; current challenges to meeting the requirements of the mandated stewardship policies and how the national action plan could affect different areas with limited resources.

All in all, it was, this year as it is every year, a wonderfully dense meeting. Attendees reported feeling that they not only had learned an incredible amount but that they now had a long list of even more articles and papers to review. But new collaborative connections were made, new stewardship programs received useful evidence and support and advice, and those who had not yet started a program came away with concrete notions of how and why to do so. For fellows not yet sure where in the world of Peds ID they are headed, the meeting was a valuable guide to what a career in stewardship can be like. Overall, nearly everyone seemed to enjoy themselves and were looking forward to the 8th annual meeting in 2017.

By Janet R. Gilsdorf, FPIDS, President, Pediatric Infectious Diseases Society

Our mission is noble: To enhance the health of infants, children, and adolescents by promoting excellence in diagnosis, management, and prevention of infectious diseases through clinical care, education, research, and advocacy.

Our progress in achieving the mission is strong and steady.

Pillar 1: Value of PID to health systems

The Society is committed to helping hospitals understand the value of our clinical services and, to that end, it has sponsored an interview-based study of perceptions of our value, which will soon be published, and a comparative study of clinical outcomes with and without PID consultation, which is in progress.

Pillar 2: Recruitment of future ID pediatricians

The Society is committed to maintaining a strong pipeline of PID practitioners and investigators and, thus, 1) is developing recruitment tools for use by fellowship programs, 2) is revising the career brochure, and 3) has produced a series of videos in which our members discuss their career choices. Check out the videos: https://www.youtube.com/watch?v=0Ykv-I7D6FY  
https://www.youtube.com/watch?v=0W2Z9tv9pVs

To engage residents and medical students in PID, the Society, under the leadership of Dr. Buddy Creech, submitted a grant to the NIH to support resident and student participation in the St. Jude/PIDS Pediatric Infectious Diseases Research Conference.

Pillar 3: Training and guidance of PID fellows

The Society continues support of our many fellow-directed resources and activities, such as the Fellows’ Survival Kit, Fellows’ Day at IDWeek, the St. Jude/PIDS Pediatric Infectious Diseases Research Conference and associated transplant ID symposium and HIV course, the Antibiotic Stewardship conference, and research awards, and is developing online educational modules for use in fellow education.

Pillar 4: Research activities related to PID

Research sits squarely at the core the PID Society. To further PID research, the Society is coordinating research opportunities through the PIDS Transplant Network and, NEW THIS YEAR, will offer two research awards for PID members through the generosity of the Pichichero Family Foundation.

Pillar 5: Engagement of new and established PIDS members

The Society membership is at an all-time high of 1340, and we are actively including more members and fellows in Society committees. The Social Media Task Force is engaging members and others in our activities through Twitter. We say hello to the newest members of the Board of Directors: Dr. Susan Coffin and Dr. Bonnie Maldonado, and a fond farewell to Dr. Kris Bryant, with heartfelt thanks for her valuable service on the Board.

Pillar 6: Growth of PIDS Education and Research Foundation

Do you know what PIDSERF is? If not, check it out: http://pidserf.org/about.html. This is the branch of the Society through which monetary gifts are transformed into research awards and educational endeavors for our members and fellows. This year, five awards will be given through PIDSERF. The Resource Development Committee is exploring additional avenues to enrich the PIDSERF award funds.

Pillar 7: Success of JPIDS

The Journal of the Pediatric Infectious Diseases Society is now indexed in PubMed and attracts manuscripts of important studies related to Pediatric Infectious Diseases from both national and international scientists. The success of the Journal translates into the success of the Society.

I look forward to meeting you at IDWeek in New Orleans from Oct 26-30, 2016.

Written by: Rana F. Hamdy, MD, MPH

On March 4-5, 2016, St. Jude Children’s Research Hospital hosted the 15th annual St. Jude/PIDS Research Conference. This two-day conference was held in the new Marlo Thomas Center for Global Education and Collaboration at St. Jude Children’s Research Hospital in Memphis, Tennessee and was attended by 145 participants. In contrast to the much larger IDSA and PAS annual meetings, this intimate venue facilitated meeting and networking with colleagues from across the country.

The conference began Friday morning with the “Frontiers in Infectious Diseases” symposium:

  • Dr. Joshua Wolf from St. Jude Children’s Research Hospital spoke on antibacterial prophylaxis in children with cancer, reviewing current practices and summarizing recent studies that provide guidance in antibacterial prophylaxis for children with acute myeloid leukemia, in particular.
  • Dr. Elaine Tuomanen introduced the next speaker, Dr. Manuel Amieva, noting that he was the first PIDS-St. Jude Postdoctoral Fellow. Now an
    Associate Professor of Pediatric Infectious Diseases and Microbiology & Immunology at Stanford University, Dr. Amieva used beautiful electron microscopy animations to show Helicobacter pylori‘s interactions with epithelial junctions.
  • Dr. Sing Sing Way, from Cincinnati Children's Hospital Medical Center, discussed the immunopathogenesis of prenatal infections, focusing on the role of T regulatory cells in pregnancy tolerance and susceptibility to infection in pregnancy.
  • Presenting remotely from Bethesda, MD, Dr. Barney S. Graham, from National Institutes of Health, presented “RSV Vaccine Development: A Time for Hope,” summarizing the results of historic RSV vaccine trials and new vaccine candidates.
  • Presenting the 2016 John H. Erskine Lecture in Infectious Diseases, Dr. Herbert “Skip” Virgin, IV, from Washington University School of Medicine, presented “Transkingdom Control of Immunity to Virus Infection”, elucidating the complex interactions between the gut virome, viral infections, and the human immune system.

In the afternoon, three PIDS and PIDS-St. Jude Fellowship Award Recipients presented their research in progress. Dr. Elisa Margolis, third year fellow at the University of Washington, presented “Finding the Needle: Microbiome Causality”; Dr. Laura Vella, third year fellow at The Children’s Hospital of Philadelphia, presented “Circulating T Follicular Helper Cells as a Periscope into the Lymph Node”; and Dr. James “Muse” Davis, third year fellow at the University of Wisconsin, presented “A Zebrafish Model of Cryptococcal Infection Reveals Distinct Roles for Macrophages and Neutrophils Responding to Spore and Yeast Forms.”

The day concluded with an impressive poster session with 30 posters representing 19 institutions and 4 countries. Best Poster Awards were awarded to Joy Hazelton, Diego Hijano, and Anita McElroy.

On Friday evening, St. Jude and PIDS hosted dinner at Itta Bena Restaurant – a hidden gem just above BB Kings Blues Club on Beale Street – for an evening of fine dining and live music in a relaxed atmosphere to enjoy the company of colleagues and friends.

The second day of the St. Jude/PIDS research conference began with the Keynote Address and Luminaries in Pediatric Infectious Diseases, followed by career development workshops tailored to fellow trainees.

Dr. Anne Schuchat, Principal Deputy Director for Centers for Disease Control and Prevention, delivered the conference’s keynote address, “Changing Practices and Paradigms: From Perinatal Infections to Pandemics and Beyond.” Dr. Schuchat told the public health stories of her involvement in interventions aimed to prevent Group B Streptococcus neonatal infections, the 2009 H1N1 influenza pandemic, and the Sierra Leone trial to introduce a vaccine against Ebola in 2014-2015.

Dr. Ann Arvin, Professor of Pediatrics at Stanford University, presented the Luminaries in Pediatric Infectious Diseases presentation: “Molecular Mechanisms of Varicella-Zoster Virus (VZV) Pathogenesis and their Clinical Implications”. Dr. Arvin presented her laboratory’s research elucidating the tropism of VZV for T cells and the molecular changes that induce trafficking to skin.

The focus of the conference then turned to career development. Dr. James E. Crowe, Jr, from Vanderbilt University, gave a personally reflective and philosophical presentation entitled “Core Capabilities for Successful Academic Medicine Careers,” inspiring participants to capitalize on their unique quirks and interests in the early stages of their careers.

Dr. Lara Danziger-Isakov (Transplant ID), Dr. Jason Newland (Antimicrobial Stewardship), Dr. Susan Coffin (Infection Control and Prevention), and Dr. Anne Schuchat (Public Health) comprised a group of impressive and inspiring panelists that displayed the breadth and diversity of career opportunities within pediatric infectious diseases. The panelists briefly summarized their career paths and what they love about their careers. The honest and inspiring discussion about career paths that followed was driven by questions from the audience, asked in-person by audience members as well as by Twitter.

Over lunch, there were multiple breakout sessions: NIH K Awards/Loan Repayment Program (led by Drs. Jim Cassat and Scott James), Negotiating Your First Job (led by Drs. Paul Spearman and John Williams), and Work/Life Balance (led by Drs. Lara Danziger-Isakov and Jason Newland).

The conference concluded with additional oral abstract presentations, including: “CMV Infection as a Cause of Fever and Morbidity Among Pediatric Cancer Patients on Maintenance Chemotherapy” (Dr. Paul Sue); “Intestinal Microbiome Alterations May Predict Infection Outcomes in Children with Acute Lymphoblastic Leukemia” (Dr. Hana Hakim); Neonates Fail to Mount a Mucosal Immune Response Against RSV Infection” (Dr. Diego Hijano); “Extended-Spectrum beta-lactamase-producing Enterobacteriaceae in Pediatrics (Dr. Jonathan Strysko); and “Fetal and Adult Progenitors Give Rise to Unique Populations of CD8+ T Cells” (Dr. Brian Rudd).

St. Jude and PIDS hosted yet another successful and well-attended research conference, providing the opportunity for each participant to present original research, to meet and learn from internationally renowned experts in pediatric infectious diseases, and to participate in focused career development workshops specifically tailored to pediatric infectious diseases fellows. From the perspective of a fellow trainee, attending the PIDS/ St. Jude Pediatric Infectious Diseases Research Conference was a high-yield experience to learn new science and to meet colleagues from across the country, opening doors for potential career opportunities and collaborations.

The next conference is scheduled for March 10-11, 2017 in Memphis, Tennessee. Funding is available from St. Jude for each institution to send one trainee and a junior faculty member.

Written by: Rana F. Hamdy, MD, MPH

On March 3, 2016, St. Jude and PIDS hosted the 3rd annual St. Jude/PIDS Pediatric Transplant ID Symposium. This one-day symposium was held the day prior to the St. Jude/PIDS Research Conference and brought together leaders in the field of pediatric transplant ID for presentations and discussions on topics related to infections in children undergoing hematopoietic stem cell or solid organ transplantation.

Highlights from the meeting included:

  • Dr. Sandy Feng, Professor of Surgery from the University of California San Francisco began the symposium with an overview of the immune system, immunosuppressive therapeutic agents, and their mechanisms of action, followed by a discussion of the feasibility of immunosuppressive withdrawal in liver transplant recipients.
  • Dr. Steven Holland, Chief of the Laboratory of Clinical Infectious Diseases at the National Institutes of Health, discussed the status of hematopoietic stem cell transplantation as a treatment option for primary immunodeficiency syndromes with myeloid defects including chronic granulomatous disease, Job’s syndrome, and GATA2 deficiency.
  • Dr. Michael Ison, Medical Director of the Transplant & Immunocompromised Host Infectious Diseases Service at Northwestern University Feinberg School of Medicine, described the epidemiology of diarrhea in transplant recipients and discussed the optimal diagnostic approach to these patients.
  • Dr. Brian Fisher, Assistant Professor of Pediatrics at The Children’s Hospital of Philadelphia, presented results from a multicenter clinical research study of the epidemiology and outcomes of respiratory viral infections in HSCT and SOT patients. Dr. Fisher discussed the process of establishing the infrastructure for performing large multi-center clinical epidemiology research studies in pediatric transplant patients, highlighting the opportunities that collaboration via the St. Jude/PIDS Transplant ID Symposium affords, and he invited any interested individuals to join the Transplant Research Network to discuss future opportunities for collaboration.
  • Dr. Theoklis Zaoutis, Professor of Pediatrics and Epidemiology and Chief of the Division of Infectious Diseases at The Children’s Hospital of Philadelphia, reviewed the epidemiology of invasive fungal infections (IFIs) in immunocompromised children; the diagnosis of IFIs, including the role of biomarkers; the evidence for antifungal prophylaxis among HSCT recipients and children with leukemia; and optimal treatment strategies for immunocompromised children with IFIs.
  • Dr. Gregory Storch, Professor of Pediatrics and Molecular Microbiology from Washington University School of Medicine, discussed emerging trends in diagnostic microbiology and the application of new diagnostic testing methods in managing infections in pediatric transplant recipients.
  • Dr. Michael Green, Professor of Pediatrics at Children’s Hospital of Pittsburgh, discussed the role of the Organ Procurement Transplant Network/United Network for Organ Sharing in protecting solid organ transplant recipients from unanticipated donor-derived infections.
  • Dr. Lara Danziger-Isakov, Professor of Pediatrics at Cincinnati Children’s Hospital Medical Center, discussed the components of a pre-transplant evaluation for identifying and mitigating the risk of post-transplant infections.
  • Drs. Hayley Gans and Gabriela Maron presented the top six papers in transplant ID in 2015-2016.

Interspersed between the presentations were interactive breakout sessions built around case presentations, with lively discussions that provided an opportunity to explore variations in practice throughout the country.

A poster session also provided an opportunity to engage other symposium participants and learn about ongoing basic science, translational, and clinical research in pediatric transplant ID.

In total, 124 participants from 54 different institutions and 6 countries attended the St. Jude/PIDS Pediatric Transplant ID Symposium this year. Participants engaged with leaders in the field of pediatric transplant ID, discussed challenging cases and new research, and met colleagues from across the country, building new collaborations and networks. The next St. Jude/PIDS Pediatric Transplant ID Symposium will take place March 9, 2017 in Memphis, Tennessee.

Written by: Parvathi S Kumar MBBS, Andrés Alarcón MD

Since August 2015, a large outbreak of Lassa fever has devastated Nigeria, in West Africa. The index case of the current outbreak was reported from Bauchi in November, 2015.1 Secondary cases have been reported across 19 states in Nigeria. As of March of 2016, the Nigeria Center for Disease Control (NCDC) has reported a total of 254 cases (129 laboratory confirmed cases) and 137 deaths (suspected, probable and confirmed cases) with a case fatality rate (CFR) of 53.9%.2 The neighboring country of Benin detected an outbreak of Lassa fever on January 21st, 2016. Togo notified the World Health Organization (WHO) of its first 2 cases on March 9th 2016, and active surveillance of contacts are being monitored in Togo, Germany, and United States of America (USA). Currently, 2 secondary cases are being cared for in Germany and USA. The American citizen, a physician assistant is receiving care and treatment at Emory University Hospital in Georgia and is reportedly stable. The German patient who represents Europe's first case of locally acquired Lassa fever is being care for in Frankfurt, alongside four family members.

Typically, Lassa fever outbreaks have a low overall mortality rate of 1% with a mortality rate of 15-20% amongst hospitalized individuals.3,4 The unusually high CFR associated with the current outbreak is worrisome and remains unexplained. A heightened awareness resulting from the Ebola virus disease outbreak ravaging the area, coupled with the increasing capability to rapidly and accurately diagnose the condition may be contributing factors. Additionally, prior outbreaks may have been under reported when remote and rural areas of the country were primarily affected.

Lassa virus, an arenavirus, was first described in 1969, and named after the town in Nigeria where the first cases occurred.5 It is a zoonotic acute viral hemorrhagic illness lasting 1-4 weeks; endemic to West Africa, particularly Sierra Leone, Liberia, Guinea (Mano River region), and Nigeria. CDC estimates 100,000-300,000 Lassa virus infections in West Africa per year, with approximately 5,000 deaths.6 The neighboring countries of Benin, Togo, Ghana, and Mali report yearly outbreaks with peaks from December through February.7

The animal reservoir is a rodent of the genus Mastomys, commonly known as the “multimammate rat” that colonizes homes and peri-residential areas. The rodents once infected are typically asymptomatic; however, they can shed the virus in urine and droppings for a long time, possibly for the duration of its life time. Human infections result from direct contact with the rodent’s waste via inhalation or ingestion. Infection can also be acquired in the laboratory or through human to human transmission after exposure to the virus in the blood, tissue or secretions. Following an incubation period of 7-21 days, the infection results in severe hemorrhagic fever in 5-10% of the cases. Typically, the disease has a gradual onset, starting with fever, general weakness, and malaise. The symptoms are closely followed by pharyngitis, muscle pain, retrosternal chest pain, cough, bleeding from the mouth, nose, vagina or gastrointestinal tract, and the potential for associated hypotension and or sepsis.8 Recovery from a milder disease begins 8 to 10 days after disease onset with resolution of symptoms. Of importance, the disease is especially severe if acquired in the 3rd trimester of pregnancy resulting in more than 80% maternal mortality and fetal loss. Deafness secondary to sensorineural hearing (SNH) loss is a major morbidity associated with Lassa fever. It is estimated that SNH loss can occur in up to 25% of patients who survive the disease, making Lassa fever a major cause of deafness in endemic areas.8,9

Due to the increasing international travel and migration patterns, it is important to consider common and uncommon infectious etiologies of febrile illness in returning travelers to the USA or other non-endemic countries. In Lassa fever, ribavirin is most effective when given early in the disease and consideration should be made in consulting an infectious disease specialist to expedite potential compassionate use through the USA Food and Drug Administration (FDA) and Valeant Pharmaceuticals (Aliso Viejo, California). 10

If a case of Lassa fever is suspected, per CDC recommendations, it is prudent to immediately implement hospital infection-control policies, contact state and local health department for contact tracing, treatment recommendations, adherence to proper infection-control strategies, and proper diagnostic laboratory collection.12 Clinicians should notify local health authorities and CDC’s Viral Special Pathogens Branch immediately of any suspected cases of VHF occurring in patients residing in or requiring evacuation to the United States: 404-639-1115 or the CDC Emergency Operations Center at 770-488-7100 after hours.11

References

  1. Press Briefing on the Outbreak of Lassa fever in Nigeria by the Honourable Minister of Health. (Accessed March 25th 2016, at http://www.health.gov.ng/index.php/news-media/9-uncategorised/245-press-briefing-on-the-outbreak-of-lassa-fever-in-nigeria-by-the-honourable-minister-of-health.) 
  2. Lassa fever death rates in Nigeria higher than expected. (Accessed March 27th 2016, at http://www.cnn.com/2016/03/17/health/lassa-fever-outbreak-nigeria/.) 
  3. Ogbu O, Ajuluchukwu E, Uneke CJ. Lassa fever in West African sub-region: an overview. J Vector Borne Dis 2007;44:1-11.
  4. Centers for Disease C, Prevention. Imported Lassa fever--New Jersey, 2004. MMWR Morb Mortal Wkly Rep 2004;53:894-7.
  5. Frame JD, Baldwin JM, Jr., Gocke DJ, Troup JM. Lassa fever, a new virus disease of man from West Africa. I. Clinical description and pathological findings. Am J Trop Med Hyg 1970;19:670-6.
  6. Lassa fever. (Accessed March 25th 2016, at http://www.cdc.gov/vhf/lassa/.) 
  7. McCormick JB, King IJ, Webb PA, et al. A case-control study of the clinical diagnosis and course of Lassa fever. J Infect Dis 1987;155:445-55.
  8. Cummins D, McCormick JB, Bennett D, et al. Acute sensorineural deafness in Lassa fever. JAMA 1990;264:2093-6.
  9. McCormick JB, Webb PA, Krebs JW, Johnson KM, Smith ES. A prospective study of the epidemiology and ecology of Lassa fever. J Infect Dis 1987;155:437-44.
  10. Lassa Fever in Nigeria. (Accessed March 26th 2016, at http://wwwnc.cdc.gov/travel/notices/watch/lassa-fever-nigeria.) 
  11. Imported Lassa Fever --- New Jersey, 2004. (Accessed March 26th 2016, at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5338a2.htm.) 

Written by: Pranita D. Tamma, MD, MHS

Carbapenem-resistant Enterobacteriaceae (CRE) are just one of three microorganisms designated as having an “urgent” threat level by the United States Centers for Disease Control and Prevention (CDC). These microorganisms have an associated mortality upwards of 60% and are a danger to patients both in the United States and abroad. The prevalence of carbapenem-resistance among Klebsiella spp. causing healthcare-associated infections in US hospitals was 13% between 2009 and 2010, according to the CDC. The majority of US CRE isolates are from adult patients, but CRE infections appears to be a growing concern in children as well.

The term CRE refers to a heterogenous group of resistance mechanisms. The most common include either production of β-lactamases that hydrolyze the β-lactam ring of carbapenem antibiotics (i.e., carbapenemases) or production of extended-spectrum β-lactamases (ESBL) or AmpC β-lactamases in combination with a carbapenem-specific porin loss or mutation.

Carbapenemases are separated into three Ambler classes, distinguished by their structural homology. Class A and D carbapenemases require serine at their active site; while the Class B carbapenemases (i.e., the metallo-β-lactamases), require zinc at their active site. The most well-known members of Class A, B, and D are the KPC, NDM, and OXA carbapenemases, respectively.

CRE are defined as Enterobacteriaceae resistant to any carbapenem. Currently, most clinical microbiology laboratories do not distinguish carbapenemase-producing CRE from non-carbapenemase-producing CRE. Laboratories that do make this distinction usually use phenotypic methods (e.g., chromogenic assays, modified Hodge test, metallo-β-lactamases Etest, etc.) that are generally unable to identify the specific carbapenemase genes involved. Understanding whether CRE are carbapenemase-producing or non-carbapenemase producing has important infection control and antibiotic treatment implications. Carbapenemase-producing Enterobacteriaceae, unlike non-carbapenemase-producing CRE, are most often implicated in clinical outbreaks of CRE as these enzymes are generally harbored on mobile genetic elements (e.g., plasmids, transposons) and can spread easily from organism to organism, and often from patient to patient. With regards to antibiotic selection, some of the newer antibiotic agents in development, including the 2015 US Food and Drug Administration (FDA) approved ceftazidime-avibactam, seem to preferentially have activity against only specific carbapenemase classes.

There are two general treatment principles for the management of CRE infections. First, carbapenem resistance does not always translate to clinical failure upon subsequent treatment with carbapenem agents. Although the Clinical Laboratory Standards Institute breakpoint for meropenem, imipenem, and doripenem is 1 mcg/ml, pharmacokinetic-pharmacodynamic (PK-PD) studies indicate that carbapenems have activity against Enterobacteriaceae for MICs as high as 8-16 mcg/ml. Second, the mainstay of therapy is a combination of at least two agents. A number of observational studies have shown improved survival in patients who receive combination antibiotic therapy, preferably with at least one of the agents being a carbapenem.

It is the opinion of the author that appropriate therapy for an invasive CRE infection consists of either prolonged-infusion meropenem (or doripenem) for MICs of up to 8-16 mcg/ml OR ceftazidime-avibactam (if susceptible in vitro) in addition to a second agent such as an aminoglycoside or polymixin (colistin or polymixin B). Alternative options for second agents include tigecycline and fosfomycin. If meropenem or doripenem is not available, prolonged-infusion imipenem-cilastatin is a reasonable alternative, but limited stability of this agent at room temperature is a concern.

Ceftazidime-avibactam is generally active against Enterobacteriaceae (and Pseudomonas aeruginosa) producing Class A β-lactamases (ESBLs, KPCs), Class C β-lactamases (AmpC), and some Class D β-lactamases (OXAs). It is not active against those producing Class B carbapenemases. Phase 1 data of the pharmacokinetics, safety, and tolerability of a single dose of ceftazidime-avibactam in children as young as 3 months of age are available and Phase 2 studies evaluating ceftazidime-avibactam for children with complicated urinary tract infections and intra-abdominal infections are currently in progress.

Both colistin and polymixin B became clinically available before the establishment of contemporary drug-development procedures resulting in substantial gaps in knowledge of their PK-PD. For both agents, a loading dose is preferred. No head-to-head studies comparing the efficacy of these two agents are available. Colistin B is administered parenterally as an inactive prodrug colistin methanesulfonate (CMS), which is slowly and incompletely converted to colistin. Rapid and extensive renal clearance of CMS may reduce systemic availability of colistin. Because polymixin B does not have a prodrug and clinical data suggest reduced nephrotoxicity with this agent, many experts prefer polymixin B if both agents are available.

Tigecycline is a broad-spectrum, intravenous agent designed to be a poor substrate for tetracycline-specific efflux pumps. Its large volume of distribution results in low concentrations in blood, the epithelial lining fluid of the lungs, and the urinary tract. The FDA discourages the use of tigecycline when alternate agents are available. Parenteral fosfomycin is not available in the US, but for areas of the world where this agent is available, it is a reasonable option for invasive CRE infections. In addition, there are a number of potential CRE-active agents in advanced phases of drug development.

In conclusion, effectively treating CRE infections remains a daunting challenge. Judicious use of antibiotics and proper infection control practices are the cornerstones to decreasing their emergence and transmission.

Written by: Brian Chow, MD

Effectiveness of the influenza vaccine is a perennial question and is monitored and estimated yearly in multiple networks worldwide, including through the CDC sponsored Influenza Vaccine Effectiveness (Flu VE) Network in the U.S. VE is affected by a number of factors, chiefly the antigenic similarity between the strains contained in the annual vaccine (A/H3N2, A/H1N1, and B) and the circulating strain or strains. Patient-centered factors, however, also affect vaccine performance, including age (young and old), health status, and type of vaccine received.

Interim analyses from the Flu VE Network show that for 2015-16, VE is nearly 60% (http://www.cdc.gov/media/releases/2016/flu-vaccine-60-percent.html), an improvement over last year’s vaccine, which had a VE of 23%. The dominant circulating strain this year is the A/H1N1pdm09 virus, which has remained antigenically stable since the 2009 pandemic, whereas the dominant circulating strain last season was A/H3N2 which was a strain antigenically different from the vaccine strain. The theme of lower VE against A/H3N2 compared to A/H1N1pdm09 recurs in multiple studies.

A recently accepted meta-analysis of VE assessed in studies utilizing the test-negative design showed notable differences between A/H3N2 and A/H1N1pdm09 strains(1). The test-negative design is a validated form of a case-control design that evaluates patients presenting with illness, assesses vaccination status, and obtains laboratory confirmation of disease. Odds of influenza positive tests are then compared in vaccinated and unvaccinated groups to estimate VE. The meta-analysis of VE by Belongia and colleagues shows lower VE against A/H3N2 compared with A/H1N1pdm09 in all age groups, including children, over multiple seasons.

One year ago in the February 2015 meeting, the ACIP removed the preferential recommendation for live attenuated influenza vaccine (LAIV) for children age 2 to 8 years. This recommendation was initially put into place based on data from randomized clinical trials showing superior immunogenicity of the LAIV products compared to standard inactivated influenza vaccine (IIV)(2). Comparative studies of VE of LAIV and IIV published recently in Pediatrics and Vaccine, however, have cast doubt on the superiority of LAIV. Using data from four seasons, two years with predominantly A/H1N1pdm09 strains, and two predominantly A/H3N2 strains, Chung and colleagues report in Pediatrics that VE of LAIV against pandemic A/H1N1pdm09 was inferior to IIV, but similar between the two types of vaccines for A/H3N2 and type B (3). These finding were confirmed in Caspard and colleague’s study in Vaccine (4). The findings may be explained by reduced thermal stability of the viral construct for the A/H1N1pdm09 vaccine strain in the LAIV vaccine, leading it to be more susceptible to degradation with deviations from appropriate cold chain handling.

Issues of priming and repeat vaccination and influenza VE continue to be investigated. In the March issue of PIDJ, Thompson and colleagues investigate the effects of prior season vaccination and priming in children (5). Priming is defined as 2 doses of vaccine in a single prior season, with alternative definitions of priming also examined. VE was consistently higher when children had received 2 doses of an influenza vaccine in a prior season. Authors also report some carry over protection in the range of 36-40% vaccine effectiveness against A/H3N2 for children vaccinated in the previous season. A carry over effect from prior seasons was also seen in Ohmit’s study in JID of influenza household contacts (6).

Two recent studies in older adults raise concern that statin medications could impair influenza vaccine response and effectiveness. A post hoc analysis of a clinical trial data by Black and colleagues investigating response to an adjuvanted influenza vaccine (7) found lower post-vaccination geometric mean titers in statin users compared to non-users. The second study by Omer and colleagues conducted in a large HMO showed reduced influenza VE against medically attended acute respiratory illnesses among statin users compared to nonusers (8). Laboratory confirmation of influenza illness was not used in this study. These hypothesis-generating studies may not have direct impact on the majority of our pediatric patients, but could potentially affect their caregivers and household contacts.

As influenza vaccine effectiveness studies refine our understanding of who is at risk for reduced vaccine effectiveness, the data remain consistent on one aspect—annual influenza vaccination is still the most effective way to protect against illness. Parents should be counseled that we cannot predict which strain will dominant in a given season, so vaccination with the current strain is warranted. The vaccine may also give protection should type B co-circulate. Additionally, even with some residual protection from the prior year’s vaccine, an annual vaccine is necessary to assure the best protection against influenza.

1. Belongia EA, Simpson MD, King JP, Sundaram ME, Kelley NS, Osterholm MT, et al. Variable influenza vaccine effectiveness by subtype: a systematic review and meta-analysis of test-negative design studies. The Lancet Infectious Diseases. 2016;In press.
2. Ashkenazi S, Vertruyen A, Aristegui J, Esposito S, McKeith DD, Klemola T, et al. Superior relative efficacy of live attenuated influenza vaccine compared with inactivated influenza vaccine in young children with recurrent respiratory tract infections. Pediatr Infect Dis J. 2006 Oct;25(10):870-9.
3. Chung JR, Flannery B, Thompson MG, Gaglani M, Jackson ML, Monto AS, et al. Seasonal Effectiveness of Live Attenuated and Inactivated Influenza Vaccine. Pediatrics. 2016 Feb;137(2):1-10.
4. Caspard H, Gaglani M, Clipper L, Belongia EA, McLean HQ, Griffin MR, et al. Effectiveness of live attenuated influenza vaccine and inactivated influenza vaccine in children 2-17 years of age in 2013-2014 in the United States. Vaccine. 2016 Jan 2;34(1):77-82.
5. Thompson MG, Clippard J, Petrie JG, Jackson ML, McLean HQ, Gaglani M, et al. Influenza Vaccine Effectiveness for Fully and Partially Vaccinated Children 6 Months to 8 Years Old During 2011-2012 and 2012-2013: The Importance of Two Priming Doses. Pediatr Infect Dis J. 2016 Mar;35(3):299-308.
6. Ohmit SE, Petrie JG, Malosh RE, Johnson E, Truscon R, Aaron B, et al. Substantial Influenza Vaccine Effectiveness in Households With Children During the 2013-2014 Influenza Season, When 2009 Pandemic Influenza A(H1N1) Virus Predominated. J Infect Dis. 2016 Apr 15;213(8):1229-36.
7. Black S, Nicolay U, Del Giudice G, Rappuoli R. Influence of Statins on Influenza Vaccine Response in Elderly Individuals. J Infect Dis. 2015 Oct 28.
8. Omer SB, Phadke VK, Bednarczyk RA, Chamberlain AT, Brosseau JL, Orenstein WA. Impact of Statins on Influenza Vaccine Effectiveness Against Medically Attended Acute Respiratory Illness. J Infect Dis. 2015 Oct 28.

Written by: Ann-Christine Nyquist, MD, MSPH

It is election season in the United States and as Super Tuesday is upon us there may be some who are thinking of a moving to Canada if they are unhappy with the ultimate voting results or if they want to get away from campaign ads and robo calls. Not only does Canada entice as a political sanctuary but after you read the latest edition of The Journal of Pediatric Infectious Disease Society you might adopt some of the medical practice guidelines of the Canadians based on an interesting report from Brazil.

de Almeida Torres et al report an epidemiologic investigation and the management of contacts of a 7-year-old patient in Brazil who died with group A streptococcal (GAS) necrotizing fasciitis associated with toxic shock syndrome (1). 105 contacts had throat swabs cultured for GAS strains followed by emm typing and antimicrobial susceptibility testing. Virulence determinants were determined with PCR and sequencing. The authors report isolating from the patient’s wound culture a M1T1 GAS clone susceptible to all antibiotics tested. This same isolate was found in the throat of 36% of close contacts who had greater than 24 hours’ exposure to the index patient in the week prior to illness. The mother and two brothers were symptomatic with pharyngitis. The 29-year-old mother and 6-year-old brother were culture positive for the same GAS clone as the index patient but the 5-year-old brother who was also symptomatic with pharyngitis had a throat culture after the initiation of antibiotics. The father was without symptoms and his throat culture was negative. Expansion of the contact investigation identified 8 of 38 school and classroom contacts who had the same GAS emm type 1 clone on their throat cultures. None of the healthcare workers who cared for the patient had positive GAS throat cultures. Contacts who had GAS positive throat cultures were treated with oral amoxicillin. In addition to throat culture evaluation of contacts, an information campaign to educate about early signs and symptoms of GAS disease was initiated within 24 hours of the death of the index patient. After two months of follow-up there were no additional cases of invasive GAS detected.

Invasive GAS disease has been more frequently reported since the 1980s with seasonal peaks noted from December through March. Clinical manifestations include necrotizing fasciitis, bacteremia, meningitis, septic arthritis, pneumonia with or without empyema, and strep toxic shock syndrome. Risk factors in children include varicella and other skin lesions, influenza, crowding, lower parental income and education. For adults their primary risk factor is exposure to children. The incidence of invasive GAS in children ranges from 0.5 to 5.0 per 100,000 population depending upon age and country. Aboriginal populations have had the highest incidence up to 75 per 100,000 population. According to the 2014 provisional report of the Active Bacterial Core Surveillance (ABCs) Emerging Infections Program the national estimates of invasive GAS cases in all age groups are 4.4/100,000 population averaging 3.96/100,000 population over the last five years (2).

Antimicrobial chemoprophylaxis is routinely recommended for close contacts of cases with N. meningiditis and for H. influenzae type b household contacts if the household has a child less than 4 years of age who is not fully vaccinated. The estimates of number needed to treat (NNT) or provide prophylaxis to prevent one meningococcus case is 200 contacts and for H. influenzae type b cases ranges from 50 to 200 contacts. Risk of GAS infection of close contacts of index patients with invasive GAS infection and the potential value of antibiotic prophylaxis to prevent these infections is unclear and recommendations from different countries are divergent. Based on a US study in the late 1990’s, providing antimicrobial prophylaxis to 750 household contacts would prevent one secondary case of invasive GAS (3).

In 2002, a CDC expert panel did not recommend routine screening for or chemoprophylaxis against GAS for household contacts of index patients with invasive group A streptococcal disease, but they stated that “providers may choose to offer prophylaxis to household contacts who are at increased risk of disease or mortality” (4). This panel did recommend enhanced surveillance and isolate storage with epidemiological investigation initiated in the event of two or more cases of nosocomial postpartum or postsurgical invasive GAS infections caused by the same strain.

This study from Brazil doesn’t conclude whether antibiotic prophylaxis is effective but provides additional recommendations and supportive data regarding invasive GAS epidemiology. The authors recommend antibiotic treatment to close contacts who have been exposed to an index patient for greater than 24 hours per week before the initial disease onset, inclusive of household contacts and school contacts.

So what is a US voter in a quandary to do ... I say vote for the Canadians ... or maybe the Australians.

Since 2006, the Ontario Group A Streptococcal Study Group has recommended that antibiotic prophylaxis with an oral cephalosporin be offered to all household contacts who were in close contact with the index patient with severe invasive GAS infection within the week before the onset of illness (5). A recently published prospective observational study from Australia made the more robust case for routine antibiotic prophylaxis for household contacts of cases regardless of severity of illness (6).

Let’s vote for a new path and align with our Canadian, Australian, and Brazilian colleagues.

We should carefully discuss management options and risks and invasive GAS surveillance with the family, including the possible option of antibiotic prophylaxis for all household contacts of any patient with invasive GAS disease.

I am Chris Nyquist and I approve of this message.

References:

  1. de Almeida Torres RSL, dos Santos TZ, de Almeida Torres RA, et al. Management of Contacts of Patients With Severe Invasive Group A Streptococcal Infection. J Pediatr Infect Dis Soc 2016; 5: 47-52. DOI:10.1093/jpids/piu107.
  2. Centers for Disease Control and Prevention. 2014. Active Bacterial Core Surveillance Report, Emerging Infections Program Network, Group A Streptococcus, provisional report—2014. Available via the internet: http://www.cdc.gov/abcs/reports-findings/survreports/gas14.pdf. Accessed February 26, 2016.
  3. Robinson KA, Rothrock G, Phan Q, et al. Risk for severe group A streptococcal disease among patients’ household contacts. Emerg Infect Dis 2003;9:443-7.
  4. Prevention of invasive group A streptococcal disease among household contacts of case patients and among postpartum and postsurgical patients: recommendations from the Centers for Disease Control and Prevention. Clin Infect Dis 2002;35:950-9.
  5. Public Health Agency of Canada. Guidelines for the prevention and control of invasive group A streptococcal disease. Can Commun Dis Rep Wkly 2006;1-32.
  6. Carapetis JR, Jacoby P, Carville K, et al. Effectiveness of clindamycin and intravenous immunoglobulin, and risk of disease in contacts, in invasive group A streptococcal infections. Clin Infect Dis 2014;59:358-65.

CDC has issued “Interim Guidelines for Preventing Sexual Transmission of Zika Virus” and “Updated Interim Guidelines for Health Care Providers Caring for Pregnant Women and Women of Reproductive Age with Possible Zika Virus Exposure.”

Written by: Pui-Ying Iroh Tam, MD

When is the testing that we do too much? This is not at all a novel issue, but a dilemma that physicians have long voiced. In fact, in 2012, 42% of US primary care physicians believed that patients in their own practices were receiving too much care, which occurred most commonly as a result of malpractice concerns (76%), clinical performance measures (52%), and inadequate time to spend with patients (40%) [1].

Recently, I consulted on an 11 month-old male who had been transferred from a rural hospital with several days of fever and an expanding rash that began on his buttocks. On exam he was noted to have red, cracked lips, but there was no bulbar conjunctival injection, nor any of the other features of Kawasaki disease. Most notable were the targetoid lesions on his face, chest and trunk, which were clearly evident at the time of our involvement in his care.

Given the history of sick contacts in the household, and mindful also of the rare but fatal adverse effects of intravenous immunoglobulin therapy that I had personally witnessed, I elected further testing to investigate for infectious causes such as mycoplasma and herpes simplex virus, among others. I had thought that my workup would help rule out other potential etiologies and would bring clarity to the management of an infant with possible atypical Kawasaki. However, when the next attending came on-service a few days later, all the pending tests proved to be more of an encumbrance than an assistance, since the consult team now felt bound to follow up on the results – though my more experienced colleague felt quite certain that the patient had Kawasaki.

The healthcare costs that have been generated as a result of overtesting are increasing and unsustainable: in 1980, costs were $253 billion, in 1990 it was $714 billion, and in 2008 it was $2.2 trillion [2]. Out of this, excessive testing is believed to cost $200-250 billion per year [3]. One paper examining high-value cost-conscious care provided a list of 37 clinical situations in which a test did not reflect high-value care. The six relevant infectious disease scenarios included [2]:

  1. Serologic testing for suspected early Lyme disease;
  2. Serologic testing for patients with chronic nonspecific symptoms and no clinical evidence of disseminated Lyme disease;
  3. Performing sinus imaging studies for patients with acute rhinosinusitis in the absence of predisposing factors for atypical microbial causes;
  4. Performing pre-discharge CXR for hospitalized patients with community-acquired pneumonia who are making a satisfactory clinical recovery;
  5. Obtaining CT scans in patients with pneumonia that is confirmed by CXR in the absence of complicating clinical or radiographic features; and
  6. Performing follow-up imaging studies of incidentally discovered pulmonary nodules ≤4 mm in low-risk individuals.

However, if we expanded this to other aspects of pediatric infectious diseases practice, should we not also include in the list of unnecessary overtesting: daily complete blood count with differentials and inflammatory markers in patients who are making a satisfactory clinical recovery; the ordering of both C-reactive protein and erythrocyte sedimentation rate tests in patients with suspected illness, infection or inflammation; or even the repetitive ordering of blood cultures for febrile patients after the first several sets are negative? If one accounts not only for excessive testing but also follow up testing for unnecessary diagnostic tests and procedures, as well as extra days in the hospital, nearly one-third of all healthcare spending – or $800 billion – is wasted [3], without arguably an improvement in clinical outcomes.

With this patient one could fault the numerous studies I requested, which all ended up being negative, as prevarication. Eventually, intravenous immunoglobulin therapy was administered to the patient, who rapidly defervesced, clinically improved and was discharged soon after. In retrospect, the reasoning behind the workup could be attributed to all the survey responses listed above, as well as by my limited experience [4], particularly compared to that of my older colleague. As a specialty that relies heavily on diagnostic testing to manage and follow our patients, we are as much bound by the need to consider high-value, cost-conscious care as other physicians. In the primary care survey, 76% of respondents stated that they were interested in learning how aggressive or conservative their own practice style was compared with that of other physicians in their community [1]. This openness and receptivity is something that we as a specialty should also be cognizant of, and the findings of which we should strive to address, for the sake of our patients.

References

  1. Sirovich BE, Wooshin S, Schwartz LM. Too Little? Too Little? Too Much? Primary care physicians' views on US health care: a brief report. Arch Intern Med. 2011 Sep 26;171(17):1582-5. doi: 10.1001/archinternmed.2011.437.
  2. Qaseem A, Alguire P, Dallas P, Feinberg LE, Fitzgerald FT, Horwitch C, Humphrey L, LeBlond R, Moyer D, Wiese JG, Weinberger S. Appropriate use of screening and diagnostic tests to foster high-value, cost-conscious care. Ann Intern Med. 2012 Jan 17;156(2):147-9. doi: 10.7326/0003-4819-156-2-201201170-00011.
  3. Reuters. American College Of Physicians Tackles Issue Of Excessive Medical Testing. 7 December 2015. http://www.huffingtonpost.com/2012/02/16/american-college-of-physicians-medical-testing_n_1281277.html. Accessed 7 Dec 2015.
  4. Grady D. Reasons for overtreatment: comment on "Too little? Too much? Primary care physicians' views on US health care". Arch Intern Med. 2011 Sep 26;171(17):1586. doi: 10.1001/archinternmed.2011.461.

Written by: Galit Holzmann-Pazgal, MD

Zika virus is a previously relatively unknown flavivirus. Originally discovered in 1947 in the Zika forest of Uganda when a rhesus monkey developed infection, it was subsequently reported only sporadically in humans from 1951-1981 via serologic evidence in people from multiple African countries and parts of Asia.

The first large outbreak outside of Africa and Asia was reported in 2007 in the Federated States of Micronesia. Illness was relatively mild consisting of rash, arthralgia and conjunctivitis. Subsequently, the virus spread further, and an outbreak was reported in French Polynesia in 2013. This outbreak was characterized by more severe illness including neurologic and autoimmune complications such as Guillain Barré syndrome.

In 2014, localized (autochthonous) transmission was first reported in Chile (Easter Island). In 2015, Brazil confirmed autochthonous transmission with subsequent spread within the country and in late 2015, reported a 20 fold annual increase in cases of newborns born with microcephaly linked to maternal infection with Zika virus during pregnancy. The virus was also determined to be spreading throughout Central and South America. In December of 2015, the first confirmed case of Zika virus locally transmitted in Puerto Rico was confirmed, and in January of 2016 the first U.S. case of a newborn born with microcephaly due to Zika virus infection was reported in Hawaii. That infant’s mother likely became infected in Brazil. No autochthonous transmission in the United States has been reported to date.

Zika virus is spread via the bite of the Aedes species of mosquitos, particularly Aedes aegypti, the same mosquito responsible for the spread of Dengue and Chikungunya in the Americas. It is a single stranded RNA flavivirus related to Dengue, Yellow Fever and West Nile Virus. Additional routes of transmission include perinatal and in utero. There are also reports of Zika virus RNA in blood and semen with solitary reports of possible sexual and transfusion related transmission.

The symptoms of Zika virus infection include fever, headache, malaise, arthralgia/myalgia, maculopapular pruritic rash and conjunctivitis. Many of these symptoms are similar to Dengue and Chikungunya but are typically milder. Severe disease is rare. It is estimated that 1/5 infected people will develop symptoms. The incubation period ranges from a 2-7 days and duration of illness is usually just a few days but can last up to a week.

Diagnosis can be made via RT-PCR on acute phase samples (within a week of symptom onset). In addition, serology can be performed. IgM testing should be done > 4 days after symptom onset. As Zika virus typically occurs in areas with other mosquito borne illnesses such as Dengue and Chikungunya, these infections must also be considered in the differential of symptomatic patients and returning travelers. Diagnosis can be complicated by cross reactivity of Zika virus antibodies with other flaviviruses.

Testing is available via the CDC or some state health departments. Information can be found at http://www.cdc.gov/zika/hc-providers/diagnostic.html. An algorithm specifically for testing of pregnant women with potential exposure to Zika virus has recently also been released by the CDC. http://www.cdc.gov/mmwr/volumes/65/wr/mm6502e1er.htm 

Care of infected individuals is supportive. There are no currently available antivirals or vaccine available for Zika virus.

At this time, there are CDC travel alerts (level 2) to areas of the world with ongoing local transmission of Zika virus. Travel to these areas is discouraged for pregnant women and steps to avoid mosquito bites should be taken in affected geographic locations. http://wwwnc.cdc.gov/travel/notices

In conclusion, Zika virus is an emerging pathogen with rapidly spreading global significance. Since the vector of spread, the Aedes mosquito, is found throughout the world and is common in urban areas with dense populations, the virus is likely to continue spreading through both South/Central America and possibly the Southern United States.

References:

  1. Hayes EB, Zika virus outside of Africa. Emerging Infectious Diseases 2009 Sep; 15(9):1347-50.
  2. Zika virus outbreaks in the Americas. Wkly Epidemiol Rec. 2015 Nov 6; 90(45): 609-10.
  3. www.cdc.gov/Zika

The CDC, in consultation with the American Academy of Pediatrics, has developed interim guidelines for the evaluation, testing, and management of infants born to mothers who traveled to or resided in an area with Zika virus transmission during pregnancy. The document provides guidance to healthcare providers caring for 1) infants with microcephaly or intracranial calcifications detected prenatally or at birth or 2) infants without these findings whose risk is based on maternal exposure and testing for Zika virus infection.

Pediatric healthcare providers should ask mothers of newborns with microcephaly or intracranial calcifications about their residence and travel while pregnant and about any symptoms of illness compatible with Zika virus disease (acute onset of fever, rash, joint pain, and red eyes). Healthcare professionals should also obtain the results of any Zika virus testing performed before the mother gave birth.

The Interim guidelines recommend that doctors and their teams consider possible clinical issues when caring for infants who might have been infected with Zika virus infection. For example, cranial ultrasound is recommended for all infants with possible Zika virus infection unless prenatal ultrasound results in the third trimester demonstrated no brain abnormalities. Also recommended for all infants with possible Zika virus infection, regardless of symptoms, are repeat hearing screening and developmental monitoring.

Treatment of Zika virus infection in babies is supportive and should address the infant’s specific needs. Investigations are ongoing to better understand what services will be most appropriate for affected children as they grow.

These interim guidelines will be updated as more information becomes available.

The guidelines can be found here: http://dx.doi.org/10.15585/mmwr.mm6503e3er 

Please forward to other colleagues as appropriate. If you have additional questions related to Zika virus, please contact CDC-Info at 1-800-CDC-Info or http://www.cdc.gov/cdc-info/.

Written by: Janet Gilsdorf, MD, FPIDS

As 2015 slips behind us, it’s a good time to reflect on the many successes of the Pediatric Infectious Diseases Society over the past year. Our journal, JPIDS, was accepted for MEDLINE indexing, meaning ...

Written by: Gregory P. DeMuri, MD

Article Summary

In the December issue of the Journal of the Pediatric Infectious Diseases Society Koningstein and colleagues report the results of an epidemiological study of extended-spectrum-cephalosporin-resistant (ESC-R) Escherichia coli in day-care centers in the Netherlands.1 This study was performed over a 22 month period from 2010-2012 in 44 different day care centers throughout the country. It was conducted as a part of a national prospective cohort study of infectious diseases in day care centers. Stool samples were taken from randomly assigned attendees monthly and cultured for E. coli. Isolates were screened for ESC-R using disk diffusion testing and confirmed by PCR. In addition, demographic and environmental risk factors were studied.

Overall, 852 stool samples were analyzed from the study population. The mean age of sampled children was 20 months. The authors found that 38 of 852 (4.5%) of children were colonized with ESC-R E.coli. There was a trend for an increase in the prevalence during the first part of the study compared to the second: 3.2% in 2010-2011 and 5.8 % in 2012 though the results did not achieve statistical significance. The majority of ESC-R E. coli strains detected contained blaCMY-2, blaCTX-M-1, or cAmpC mutations. Significant risk factors for ESC-R colonization in day care center attendees were: age < 1 year old, attending centers where paper towels were available, restricting ill children from attending day care, performing extra checks on handwashing of ill children, and always reporting notifiable diseases to local health authorities. The authors conclude that day care attendance leads to exposure to both colonizing agents such as ESC-R E. coli and community –associated pathogens such as respiratory viruses, resulting in the higher chances of receiving antibiotic treatment, which may impact on ESC-R carriage, especially in infants. They call for further study of day care practices to prevent colonization and infection with these organisms.

Comments

This study caught my attention after I consulted on a 6 month old infant who had been admitted to the hospital for a febrile UTI secondary to E. coli. The infant had been treated with an oral cephalosporin and then admitted when susceptibility testing showed resistance to all cephalosporins, and all oral agents. She was treated with a course of meropenem and discharged. What is a bit disturbing is that she had no traditional risk factors for a multi-drug resistant organism; no prior illnesses and no prior antimicrobial exposure. She did, however, attend day care. What should have been treatable with an oral antimicrobial required several days of inpatient IV therapy.

In this investigation about 5% of children attending day care harbored ESC-R E. coli in the stool and a trend in increased detection was observed over the 22 month study period. This study has several limits in interpretation. First, it was done in the Netherlands and the results may not apply to other populations of children. Secondly, this was a study of colonization as all study subjects were asymptomatic. The rate of drug resistance in invasive strains might be different. In addition, children not attending day care were not included as controls. Nonetheless the results are concerning. In this same issue of JPIDS Stillwell et al describe an outbreak of KPC-3 carbapenem resistant Klebsiella pneumoniae in a US pediatric hospital.2 Also in this issue Drew et al studied 551 isolates of ESBL for the UK producing Enterobacteriaceae and found extensive associated antimicrobial resistance in these isolates and the only consistent antibiotic class to which the isolates remained susceptible were the carbapenems.3

Children in day care settings tend to be the canaries in the coal mine for pediatric infectious diseases. The detection of antibiotic resistant, gram-negative organisms in presumably healthy children is disturbing. Further epidemiologic studies are needed to track these organisms and to determine effective means of controlling spread in the population. Meanwhile the results of this study may suggest that in the near future we will treat more and more “community acquired” multidrug-resistant, gram-negative infections in children.

References

  1. Koningstein M, Leenen MA, Mughini-Gras L, et al. Prevalence and Risk Factors for Colonization With Extended-Spectrum Cephalosporin-Resistant Escherichia coli in Children Attending Daycare Centers: A Cohort Study in the Netherlands. J Pediatric Infect Dis Soc 2015;4:e93-9.
  2. Stillwell T, Green M, Barbadora K, et al. Outbreak of KPC-3 Producing Carbapenem-Resistant Klebsiella pneumoniae in a US Pediatric Hospital. J Pediatric Infect Dis Soc 2015;4:330-8.
  3. Drew RJ, Ormandy EE, Ball K, et al. Antimicrobial Susceptibility Patterns Among Extended-Spectrum beta-Lactamase-Producing Enterobacteriaceae in a Large Pediatric Hospital in the United Kingdom. J Pediatric Infect Dis Soc 2015;4:e147-50.
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