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VOLUME 61, NUMBER 3 Infectious Diseases Fall 2010 EDITOR IN CHIEF Joan L. Huffman, MD MANAGING EDITOR Leora Legacy ASSOCIATE EDITORS Raed Assar, MD Hernan Chang, MD Steven Cuffe, MD Ruple Galani, MD Kathy Harris (Alliance) Sunil Joshi, MD James Joyce, MD Neel Karnani, MD Timothy Sternberg, MD
Executive Vice President Jay W. Millson DCMS FOUNDATION BOARD OF DIRECTORS Benjamin Moore, MD, President Todd L. Sack, MD, Vice President Kay M. Mitchell, MD, Secretary J. Eugene Glenn, MD, Treasurer Guy I. Benrubi, MD, Immediate Past President Mohamed H. Antar, MD Raed Assar, MD Ashley Booth Norse, MD J. Bracken Burns, DO Malcolm T. Foster, Jr., MD Jeffrey L. Goldhagen, MD Jeffrey M. Harris, MD Mark L. Hudak, MD Joan L. Huffman, MD Sunil N. Joshi, MD Daniel Kantor, MD Neel G. Karnani, MD John W. Kilkenny III, MD Sherry A. King, MD Harry M. Koslowski, MD Eli N. Lerner, MD R. Stephen Lucie, MD Jesse P. McRae, MD Senthil R. Meenrajan, MD Nathan P. Newman, MD Mobeen H. Rathore, MD Ronald J. Stephens, MD Jeffrey H. Wachholz, MD Anne H. Waldron, MD David L. Wood, MD Northeast Florida Medicine is published by the DCMS Foundation, Jacksonville, Florida, on behalf of the County Medical Societies of Duval, Clay, Nassau, Putnam, and St. Johns. Except for official announcements from the County Medical Societies, no material or advertisements published in NEFM are to be seen as representing the policy or views of the DCMS Foundation or its colleague Medical Societies. All advertising is subject to acceptance by the Editor in Chief. Address correspondence and advertising to: 555 Bishopgate Lane, Jacksonville, FL 32204 (904-355-6561), or email: llegacy@dcmsonline.org. COVER: Shot in the Grand Cayman Islands by Dr. Michael Bernhardt - a self confessed “diveaholic.” See photographer’s profile, p.30.
www . DCMS online . org
Northeast Florida Medicine
Features
11
Another Swine Flu Affair
Mobeen H. Rathore, MD, CPE, Guest Editor
12 Challenges and Successes in Mother to Child Transmission of HIV in Florida Ayesha Mirza, MD
15 Mitigating the H1N1 Pandemic: A Year in Review (CME) Taj Azarian, MPH and Saad Zaheer, MD, MSPH (Pediatric Perspective by Haidee Custodio, MD)
23
Tuberculin Skin Test: Loss of an Old Friend?
Jeffrey Lauer, MD (Pediatric Perspective by Ana Alvarez, MD)
31 Community Associated Methicillin Resistant Staphylococcus Aureus: An Update Nilmarie Guzman, MD (Pediatric Perspective by Nizar Maraqa, MD)
Special Articles
36
Breast Cancer and HIV in the Era of HAART: A Case Report
Departments
4 5 8 9 41
From the Editor’s Desk From the President’s Desk FMA Annual Meeting DCMS Annual Meeting - Save the Date! DCMS History Book
Naeem Latif, MD, Fauzia Rana, MD and Troy Guthrie, MD
Northeast Florida Medicine Vol. 61, No. 3 2010 3
From the Editor’s Desk
Professionalism “Do all the good you can, by all the means you can, in the ways you can, in all the places you can, to all of the people you can, as long as you ever can.” John Wesley
What is professionalism? To “profess”, i.e. confess; the meaning expresses how individuals/groups acknowledge their own basic values such as humanism, altruism, compassion and respect. Beyond that crux, diverse traditions, cultures and priorities abound.1 Concern for professionalism regression grew in the 1980s. The American Medical Association (AMA), Accreditation Council for Graduate Medical Education (ACGME), American Board of Medicine (ABIM) and American College of Surgeons (ACS) stated their commitment to enhance behavior and personal interactions between patients, doctors, medical educators and students.2 In 1999, two decades after standards were set, the American Board of Medical Specialties (ABMS) adopted six general competencies for Board Certification.3 The principles were clear, but were not formally integrated into the educational curriculum until 2007 when residents were introduced to professionalism as one of the AGCME core competencies. Professionalism was defined as “a commitment to carrying out professional responsibilities, adherence to ethical principles, the demonstration of compassion, integrity, respect for others; responsiveness to patient needs that supersedes self-interest; respect for privacy and autonomy; accountability to patients, society and the profession; and sensitivity and responsiveness to a diverse patient population.”4 Many practicing physicians felt unable to achieve the goals of ABMS and ACGME due to the obstacles that come from the evolution from autonomy, expert opinion and self-interest–to acJoan L. Huffman, MD, FACS Editor-in-Chief countability, evidence-based medicine and shared responsibility, therefore, the ABIM Foundation, Northeast Florida Medicine in concert with the American College of Physicians (ACP) Foundation and the European Federation of Internal Medicine, drew up a Physician Charter, emphasizing that professionalism is the basis of the medicine’s contract with society. The charter has been endorsed by over 100 medical organizations in the U.S. and abroad. The fundamental principles of the Charter are primacy of patient welfare, patient autonomy and social justice. There is also a set of professional responsibilities including commitment to: professional competence, honesty with patients, patient confidentiality, maintenance of appropriate relations with patients, improvement quality of/access to care, a just distribution of finite resources, scientific knowledge, maintenance of trust by managing conflicts of interest, and finally, professional responsibilities.5 In this new millennium of cataclysmic changes, how we experience professionalism behavior of another practitioner is by the way they demonstrate, improve and reassess their actions, and change their personal culture, and that of their organization, by attention to their conduct, and self-regulation. Two valuable resources to assist the floundering physician are DVDs entitled: “Medical Professionalism in the New Millennium” and “Professionalism in Surgery, Second Edition” (available from the ACS) which review professionalism and present vignettes in CME format.6 Another way to heighten professionalism is firsthand experience in international patient care in austere conditions with underserved populations: this will instill an appreciation for the extent of human circumstances and imbue sincere compassion, as well as implant a sense of respect and dignity for those in need, and a desire for dedication to service.7 As our definition of professionalism continues to transform in response to technology explosion, disparities in health care needs/available resources, changing market forces, bioterrorism and globalization, what are the challenges you face, and the solutions you have developed to engender public trust? How will you model professionalism in your practice as clinical surgeons and/or surgical teachers? How can we move into the 21st century and in our transit revolutionize professionalism? “Sometimes give your services for nothing and if there is an opportunity of serving one who is a stranger, in financial straits, give full assistance to all such, for where there is love of man, there is also love of the art.” Hippocrates References (web sites accessed on August 2, 2010) 1.
dwolfson82. Post August 20, 2009. In response to: How do you define professionalism? ABIM Online Community. http://www.abimfoundation. org/Forum/default.aspx?g=posts&t=5
2.
Lawrence W. “Is our level of professionalism where it should be?” Bull Am Coll Surg. 2004;89(6):21-25.
3.
Ritchie WP. “The measurement of competence”. Bull Am Coll Surg. 2001;86(4):10-15.
4.
Common Program Requirements: General Competencies. Approved by the ACGME Board February 13, 2007. http://www.acgme.org/outcome/comp/ GeneralCompetenciesStandards21307.pdf
5.
“Medical Professionalism in the New Millennium: A Physician Charter.” Annals of Internal Medicine 2002;136(3):243.
6.
McGinnis, LS. “Presidential Address: Professionalism in the 21st Century.” Bull Am Coll Surg. 2009;94(12) :8-18
7.
Schecter WP and Farmer D. “Surgery and global health: A mandate for training, research and service.” Bull Am Coll Surg. 2006;91(5):36-38.
4 Vol. 61, No. 3 2010 Northeast Florida Medicine
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From the President’s Desk
Rationing or Reality Check?
On April 19. 2010, President Obama nominated Dr. Donald Berwick to be Administrator of the Centers for Medicare and Medicaid Services, Department of Health and Human Services (CMS). Dr. Berwick is President and CEO of the Institute for Healthcare Improvement, and is a professor at Harvard Medical School and the Harvard School of Public Health. There was immediate concern about Dr. Berwick being an avowed proponent of rationed healthcare who favors a government-run system comparable to the one in England. Rather than reflecting yet another example of political grandstanding, the basis for this apprehension comes from Dr. Berwick’s statement, “The decision is not whether or not we will ration care—the decision is whether we will ration with our eyes open.” Naturally, what we as the dispensers of health care have to be concerned with, is whose ‘open eyes’ are being considered? The recess appointment allowed the President to install Berwick while the Senate was on vacation over the July Fourth holiday, thereby bypassing a potentially lengthy confirmation process. As defined by Senator Max Baucus, the Democratic chairman of the Senate Finance Committee, the confirmation process “serves as a check on executive power and protects... all Americans by ensuring that crucial questions are asked of the nominee -- and answered.” Circumventing the procedural process can also impair the nominee, undermining his legitimacy as well as shortening his tenure. Dr. Berwick can only serve until December 2011, a notably shortened time frame in which to make a significant impact.
John W. Kilkenny III, MD 2010 DCMS President
Dr. Berwick is rightfully renowned for his studies on how to improve health care with lowered costs. But he has left himself open to blistering criticism when he advocates health care rationing, when he supports health care reform as a matter of redistributing wealth, and when he exuberantly lauds the British health care system.
Due to its massive size, the unresolved issue in the health-care reform legislation is the lack of any defined plan to improve quality and reduce costs. The actual formulation of regulations is starting, a time of enormous importance for the future of our profession. But the sheer enormity of our federal government’s bureaucracy and its regulatory agencies frequently hinders their effectiveness. Unfortunately, their culpability has been all too evident with a number of recent exigencies: the relationship of the Materials Management Service of the Dept. of Interior and the Oil Drilling Industry; the Securities and Exchange Commission’s oversight of our nation’s worst financial crisis in 80 years; and the all too numerous intelligence failures. Nihilistically these have been described as a ‘sign of the times’ with our pervasive societal losses of shame and accountability. But they demonstrate why we need to be all the more vigilant in knowing what our elected, as well as appointed government officials are thinking and doing when creating health care regulations during the coming year. Considering the prodigious complexity of the problems at hand, along with their proposed solutions, complete transparency with review and inquiry will be critically vital and the diametric opposites of the concept of a recess appointment.
Last year, Medicare spent over $50 billion on the last two months of American’s lives. Most of us state that we’d rather die at home, but 75% currently meet their demise in a hospital or nursing home. Nearly 20% of our population spends their final days in an ICU, where the issues of staggering cost and lack of advanced directives are a constant conundrum. How do we balance the commonly held desire to stay alive as long as possible with the ever shrinking numbers of dollars to accomplish this? Unless there are some generally accepted guidelines (ideally drawn up by physicians) regarding this predicament, no amount of health care reform will succeed. But there is an understandable uneasiness felt when considering the cost-effectiveness of keeping the terminally ill alive. Many believe that health care rationing already exists by virtue of income and insurance coverage. But if we continue to ignore the concept, the impending physician shortage and bankrupting health care costs will emergently force such decisions. Our society needs to be better prepared to deal with death and the decisions that are implicit with it. The health care reform legislation passed in March was designed to slow the growth of Medicare expenses, and to reward the quality of care rather than the quantity. After the furor caused by the politically charged exaggerations of ‘death panels’, there was no addressing any endof-life issues. Incredibly, the legislation also trims Medicare payments for hospice care, which strives to maintain quality of life, manage pain, and offer spiritual guidance during the last stage of life, in a very cost effective fashion. Now, as the particulars of the regulations are being crafted, our input as the purveyors of health care is most vital. Get Ready. From Donald Berwick’s Speech To Britain’s National Health Service - ‘A Transatlantic Review of the National Health Service at 60’: You could have protected the wealthy and the well, instead of recognizing that sick people tend to be poorer and that poor people tend to be sicker, and that any health care funding plan that is just, equitable, civilized, and humane must – must – redistribute wealth from the richer among us to the poorer and less fortunate.” (July 1, 2008) www . DCMS online . org
Northeast Florida Medicine Vol. 61, No. 3 2010 5
Offering the most comprehensive care possible so our patients can achieve the most complete recovery possible. Brooks Rehabilitation has been a leading provider of physical rehabilitation services in Northeast and Central Florida for more than 35 years. With expertise in treating stroke, spinal cord injury, hip fracture/orthopedics, pediatrics, and brain injury, Brooks offers a full continuum of services to support patients, including: • • • • •
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Isn’t It Time You Called The Med Mal Experts? Danna-Gracey is an independent insurance agency with a statewide team of specialists dedicated solely to insurance coverage placement for Florida’s doctors. With offices located throughout Florida, Danna-Gracey works on behalf of physicians – well beyond managing their insurance policy. By speaking, writing and educating, we hope to effect positive change in the healthcare industry. We make it our practice to genuinely care about yours. For more information, please contact Stephanie Johnson at 904.215.7277 or stephanie@dannagracey.com.
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Northeast Florida Medicine Vol. 61, No. 3 2010 7
2010 FMA Annual Meeting
Congratulations to Dr. Miguel Machado, President-Elect of the Florida Medical Association and Shar Donovan, President of the FMA Alliance At the FMA Annual Meeting in Orlando, FL, August 13-15, 2010, Miguel Machado, MD, was elected as President-Elect of the Florida Medical Association. He will be FMA President beginning August 2011. Celebrating the election results are: (L to R)Jennifer Putnam, Dr. Machado’s practice assistant; Lourdes Machado, his daughter; Dr. Machado, and Amaya Munoz, his girlfriend.
Also at the FMA meeting, Mrs. Shar Donovan, an active DCMS Alliance member, was installed as President of the Florida Medical Association Alliance. (see page 41 for more details) Pictured with Mrs. Donovan is her husband, Kevin Donovan, MD (both seated) and their four children (standing, L to R) Luke, Joseph, Troy and Janelle.
DCMS members active on the FMA Board of Governors/ BoG (L to R) Eli Lerner, MD, BoG President’s Appointment; Miguel Machado, MD, President-Elect; Ashley Booth-Norse, MD, BoG District B Representative (First female from Duval County to serve in these roles); W. Alan Harmon, MD, Treasurer; and Nitesh Paryani, MD, Resident member elected to the BoG. Special thanks to all the DCMS physicians who served as delegates, reference committee members and in other leadership roles. 8 Vol. 61, No. 3 2010 Northeast Florida Medicine
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You were HERE
Jacksonville Hyatt
You are going HERE!
The 2010 DCMS Annual Meeting is
DON’T MISS IT! Malcolm Foster, MD, Incoming President Exhibit Hall & Poster Session New date & New location! Wednesday, December 1, 2010
5:45 - 9:00 PM Hyatt Regency Jacksonville Riverfront www . DCMS online . org
Northeast Florida Medicine Vol. 61, No. 3 2010 9
DCMS_QSN/AHEC Ad_July:July
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THE US DEPT. OF HEALTH AND HUMAN SERVICES SAYS:
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because evidence shows that provider advice to quit smoking increases abstinence rates.” The National Cancer Institute projects that if providers assisted even 10% of their tobacco-using patients in quitting, the number of tobacco users in the U.S. would drop by 2 million people annually.
Northeast Florida AHEC offers FREE training to help providers effectively Ask, Advise, and Refer patients to appropriate cessation programs. TRAININGS ARE AVAILABLE ON-SITE, AT LOCAL/REGIONAL CONFERENCES, AND ON-LINE.
In addition, we can help you develop a system that will help you identify tobacco-using patients, and then help them QUIT.
TRAINING TOPICS INCLUDE: • Brief Intervention Training • Motivational Interviewing • NRT Options • Other topics available by discipline
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10 Vol. 61, No. 3 2010 Northeast Florida Medicine
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This Issue’s Focus: Infectious Diseases
Another Swine Flu Affair This issue of the Northeast Florida Medicine journal (NEFM) is dedicated to infectious diseases. Infections are an important and prevalent aspect of medicine and public health, but they remain mostly in the background of our day-to-day work. Infectious disease specialists consider themselves most successful when no one hears about their specialty. Whether it is addressing infections through immunizations, improving public health, preventing nosocomial spread, and/or intervening in person-to-person transmission, infectious disease specialists believe first and foremost in prevention. However, events like were experienced last year with the H1N1 pandemic only serve to identify and highlight the strengths and weaknesses of our practice and preparedness. It is most important that we learn from our experiences and translate this knowledge into our clinical and public health practices. It would thus be irresponsible not to say a few words about the recent H1N1 pandemic. In order to learn from our experiences and improve our response in the future, we must critically scrutinize how we performed. Such reviews, for example, were done after the Swine flu scare of 1975.1 As a nation and state, our response to the 2009 H1N1 pandemic can be best described as “apt and lucky”.2 With the precedent of the 1918 and 1975 epidemics looming large, there was great concern, but there was much uncertainty about the potential virulence of the H1N1 virus. We were “lucky” that the initial information about the highly virulent nature of the H1N1 virus proved to be mostly incorrect. But, we were “aptly” prepared through the production of large amounts of vaccine. In 2009, many of the challenges faced during 1975 with communication and other issues were overcome. However, this doesn’t preclude the need for a critical analysis of the 2009 H1N1 local, regional and national response. We have always learned from our experiences with infectious diseases, e.g., yellow fever, smallpox, polio, malaria, etc. epidemics. We must continue to learn from the 2009 H1N1 epidemic and critically analyze every aspect of our successes and failures. One interesting lesson to be learned from this epidemic is the challenge and difficulty of communication in a system in which the key players are all focused on different aspects of the pandemic. Public health agencies were focused on immunizations; healthcare systems were focused on preventing transmission to patients and protecting their work force to ensure their availability to meet healthcare demands; while physicians were responding to patient needs in their offices. These incongruent Mobeen H. Rathore, MD, CPE Professor & Associate Chairman, Chief foci resulted in confusion, concern and ineffective and inefficient response to various elements of Pediatric Infectious Diseases & Immu- the pandemic. We were lucky that the pandemic proved not to be as bad as it could have been. nology. Wolfson Children’s Hospital & More specifically, four aspects of our response to the epidemic require analysis and improvement: Hospital & General Academic Pediat- Communication: Some believe there was “communication fatigue” about the pandemic. While rics, University of Florida, Jacksonville, that may be true at the national level; a review of regional communication suggests that there Florida were opportunities for improved communication at the local level. The public likes to receive information from local “authorities” and “opinion leaders” with whom they can relate. We need to learn how to better coordinate communication among all levels of the private and public sectors. Guidance: Guidance provided by national professional organizations and governmental agencies was sometimes contradictory, which added to the confusion. This was perhaps the most difficult issue faced by our healthcare systems. Response Systems: We have an excellent emergency response system (ERS) in Florida, but it is primarily focused on natural disasters and bioterrorism. Preparation for these disasters assumes a single or series of related events that require a response from the ERS after the event occurs. It is appropriate for the response to be primarily “reactive” in these types of disasters. Infectious disease epidemics require a “preventive response,” not a “reactive” one. To quote an unknown source, “It is a marathon and not a sprint.” Infectious events can be episodic and come in waves during epidemics. Adjustments must be made to deal optimally with future responses. This was done a century ago for yellow fever.3 This can certainly be done today. Vaccines: Finally, vaccine programs required for the response to epidemics have to be prepared ahead of time and must include frontline providers who can deliver the vaccine. In the 2009 H1N1 epidemic, the vaccine supply was not good enough, timing was not fast enough, delivery was not efficient enough and access was not equitable enough This must be improved before the next epidemic hits us because we may not be as lucky the next time. We are a strong and innovative nation and can always improve our response, but to do so we must have the will and resources. This can best be achieved by a collaborative plan between the public and private sectors.4 I hope you enjoy this issue of NEFM. HIV, H1N1, TB and MRSA are among the most prevalent infectious diseases we continue to face each day, so those topics are addressed and we have added a “Pediatric Perspective” for H1N1, TB and MRSA. In “Successes and Challenges in Mother to Child Transmission of HIV in Florida, “ Ayesha Mirza, MD, writes about the great success in the prevention of mother to child transmission of HIV and highlights the challenges to face in the future. In “Mitigating the H1N1 Pandemic: A Year in Review,” Taj Azarian, MPH and Saad Zaheer, MD, address the public health aspects of the H1N1 epidemic, and Haidee Custodio, MD, provides the “Pediatric Perspective.” This is also the CME article for the issue. In “Tuberculin Skin Test: Loss of an Old Friend?,” Jeffrey Lauer, MD, writes about the ongoing issue of tuberculosis, and Ana Alvarez, MD, presents the “Pediatric Perspective”. And finally, in “Community Associated Methicillin Resistant Staphylococcus Aureus” Nilmarie Guzman, MD, summarizes the problem with MRSA that all of us are dealing with every day, and Nizar Maraqa, MD, provides the “Pediatric Perspective”. Sources: 1. Neustadt RE and Fineberg, HV. The Swine Flu Affair: Decision-Making on a Slippery Slope. University Press of the Pacific, Honolulu, Hawaii. 2005; 2. McNeil, Ronal G. Jr., “US Reaction to Swine Flu: Apt and Lucky”. New York Times January 2, 2010. http://www.nytimes.com/2010/01/02/health/02flu. html. Accessed July 2010; 3.Oshinsky, David M. Polio an American Story. Oxford University Press, New York, Ny. 2006; 4.Pierce John R and Writer James V. Yellow Jack: How Yellow Fever Ravaged America and Walter Reed Discovered Its Deadly Secrets. John Wiley & Sons, Inc. Hoboken, NJ.
www . DCMS online . org
Northeast Florida Medicine Vol. 61, No. 3 2010 11
Successes and Challenges in Mother to Child Transmission of HIV in Florida Ayesha Mirza, MD Editor’s Note: Due to production constraints, Figure 1 is not printed in the journal. It is available online at www. dcmsonline.org as a web illustration. Abstract: Most pediatric human immunodeficiency virus (HIV) infections occur through mother to child transmission (MTCT). Significant progress has been made in the United States (US) and other resource rich countries since the start of the HIV epidemic more than 20 years ago. Prior to the institution of highly active antiretroviral therapy (HAART) one in four babies born to an HIV infected mother would be likely to be infected. Significant milestones have been achieved in the prevention of MTCT of HIV in children. Measures contributing to this success include the institution of the 076 Pediatric Aids Clinical Trials Group (PACTG) protocol and zidovudine (ZDV) administration to both mother and baby, availability of HAART for pregnant women, elective caesarian delivery when indicated, avoidance of breast feeding, opt-out testing for pregnant women as well as rapid testing of pregnant women during labor and delivery when results of HIV tests are not available. While Florida has had a high number of MTCT, significant measures have been undertaken to greatly reduce MTCT in the state. These include the passage of laws by the legislature to facilitate HIV testing as well as ‘opt-out’ testing for pregnant women, educational and outreach programs for pregnant and at-risk women, availability of rapid testing at point of care facilities as well as easy access to free rapid tests through various programs. Barriers to care include access to timely care, retention in care as well as institution of appropriate and timely testing of pregnant women in accordance with the 2006 Centers for Disease Control and Prevention (CDC) guidelines. Continuing education of providers as well as the general public remains the cornerstone of preventive efforts to reduce MTCT.
Overview
In contrast to the advances in the developed world, prevention of MTCT is still a major public health challenge in resource limited countries. Availability of funding through the US President’s Emergency Plan for AIDS Relief (PEPFAR), the Bill and Melinda Gates Foundation, The Clinton Global Health Initiative as well as multiple other governmental and private donor agencies have changed the face of the epidemic somewhat, but much work still needs to be done.3 In 2008, 45% of HIV infected pregnant women received antiretroviral drugs to prevent transmission to their newborns compared with 9% in 2004. The number of children newly infected with HIV in Sub Saharan Africa went from 460,000 in 2001 to 390,000 in 2008.4 As would be expected, there are regional differences with some countries doing better than others at reducing MTCT. Compared to this, in the US, the numbers of new HIV Address Correspondence to: Ayesha Mirza MD, UFCARES, Department of Pediatrics, 653-1 West 8th Street, LRC 3rd Floor, Jacksonville, Florida, Ph: 904-244-5012, Fax: 904-244-5341. Email: ayesha.mirza@jax.ufl.edu. 12 Vol. 61, No. 3 2010 Northeast Florida Medicine
infections in children are 100-200 annually, and these numbers continue to decrease. The challenges we face here are of a different nature. Approximately 25% of all people infected with HIV do not know their status, thus many women who are infected with HIV are unaware of their infection. This emphasizes the importance of universal routine testing for HIV as well as opt-out testing for pregnant women.5 The numbers of women infected by HIV has also been growing steadily and, as is seen across the country, disproportionately affects minority women. One of the most significant achievements of our times in HIV research were the results of the PACTG 076 which showed that administration of ZDV to the mother after the first trimester, as well as continued administration of ZDV during labor and delivery and treatment of the newborn up to six weeks of life, resulted in reduction in MTCT by approximately two-thirds (from 8.3% in the ZDV group to 25.5% in the placebo group).1 Other significant milestones have also been achieved since then. The institution of HAART, caesarian delivery for women with an HIV viral load ≥ 1000copies/ml, avoidance of breast feeding as well as using an opt-out approach for HIV testing of pregnant women have all contributed to decreasing the rate of MTCT to less than 1-2 percent.2 (Figure 1, www. dcmsonline.org)
Key Florida Statistics
In Florida in 1987 of reported AID cases, only 11% were women 13 years of age or older. This number increased to 33% in 2009. Women accounted for 26% of the HIV cases reported in 2009. The female population ages 13+ of Florida in 2009 was 63% white and 15% black, in contrast the numbers of white women affected by HIV/AIDS was 18/15 % respectively compared to 66/69% for black women. Heterosexual contact was the major mode of infection (8789%). Through 2008, 1 in 296 women (ages 13+) in Florida were living with HIV/AIDS, including 1 in 64 blacks, 1 in 445 Hispanics, 1 in 1,153 whites and 1 in 466 other races. Through 2009 in Florida, a total of 28,878 women were living with HIV/AIDS, of which 13,842 (48%) were women of childbearing age (25-44). There were 539 (2%) females with HIV/AIDS in the 13-19 year age group which has not traditionally been considered as ‘child bearing’ age.6 Infection among women particularly those of child bearing age becomes important since Florida is second only to New York State in the number of babies born to HIV positive women over the past 20 years. Among states with confidential name based reporting cumulative through 2007, Florida reported 541 cases (9.3%) of HIV infection in children less than 13 years of age, second only to New York which reported 1765 (30.3%) and Texas being a close third www . DCMS online . org
reporting 430 cases (7.4%).7-9Florida also ranks second in the number of cumulative pediatric (AIDS) cases reported through 2007, (n=1,544).10HIV reporting was initiated in Florida in 1997. Through 2008, Florida has reported a cumulative total of 2,374 HIV and AIDS cases. The majority of these cases were perinatally acquired (95%, n=2,250). The remainder, were acquired through blood transfusion, hemophilia or another risk.11
HIV Challenges in Florida
The number of perinatally acquired cases has declined steadily from a peak of 201 cases in 1992 to only 9 so far in 200912 . However, missed opportunities for intervention continue to occur. It requires constant vigilance on the part of providers to make sure that pregnant women have access to care, remain in care and are tested according to the 2006 (CDC) guidelines.13 According to these guidelines for pregnant women: • HIV screening should be included in the routine panel of prenatal screening tests for all pregnant women. • HIV screening is recommended after the patient is notified that testing will be performed unless the patient declines (opt-out screening). • Separate written consent for HIV testing should not be required; general consent for medical care should be considered sufficient to encompass consent for HIV testing. • Repeat screening in the third trimester is recommended in certain jurisdictions with elevated rates of HIV infection among pregnant women
A review of MTCT in Florida from 2002-2009 showed that while overall the number of HIV MTCT in Florida is 1.5%, which is what is expected with use of appropriate perinatal prevention regimens of antiretroviral drugs (i.e. there were 9 (1.5%) perinatally infected children born to 607 HIV infected women in 2008), there were several missed opportunities for prevention.14 Access to care and retention in care were seen as the major issues resulting in less likelihood for the highest risk women to get tested, especially in women of color. While the reasons for this are multifactorial, health-related beliefs such as avoidance and disbelief of HIV serostatus, conceptions of illness and appropriate health care, and negative experiences with, and distrust of health care all contribute to decisions related to access to HIV care. Mental health and stigma also add significantly to the problem. Other factors such as frequent sexually transmitted infections (STI), intravenous drug and substance abuse have also been identified as barriers to appropriate care. Linkage to care and the availability of ongoing care if transferred from one facility to another is also crucial. Perhaps most important of all, testing per the 2006 CDC guidelines, documentation of maternal testing during both the first and third trimesters, status if known to be previously infected, as well as, prompt rapid testing during labor and delivery if status is unknown are all crucial steps in the prevention of MTCT. A retrospective review of HIV exposed infants whose data was reported to the CDC Enhanced Prevention www . DCMS online . org
Surveillance System from1999-2003 (n=8115) showed that for approximately 4% of exposed infants whose data was reported recognized maternal HIV infection was not documented in the exposed infants’ birth record.15 After controlling the data for potential confounding factors such as prenatal HAART to the mother, HAART to the mother during labor and delivery, duration of rupture of membranes, infants without documentation of maternal HIV infection were found to have had 70% increased odds of HIV infection compared with infants with adequate documentation (adjusted OR, 1.7; 95% CI, 1.1-2.6). That is simply not acceptable. Communication lapses such as this are avoidable and inexcusable.
Addressing the Challenges
Florida began to address MTCT in the mid-1990s using a multi-pronged approach which included education and information campaigns for both pregnant women and providers. In 1996 a law (Florida Statutes Title 29§384.31) was passed that required providers to offer all women seen in prenatal care settings an HIV test. Another law passed in 2005 (amends Florida Statutes Title 29§381.004) made it routine to test all pregnant women for HIV and to inform the woman of her right to refuse testing under the ‘opt-out’ approach. It was also broadened to include testing for other STI as well.16 This law was actually implemented in 2007. Florida Administrative Rule 64D-3.042 also states that emergency departments may fulfill the testing requirements stated above by referring (in writing) pregnant women who have not received prenatal care to the local health department for testing. Other measures that have been put in place by the Florida Department of Health (FDOH) include the Baby RxPress Program which provides ZDV to HIV exposed newborns at no cost to the family when they have no other means to pay for the medication. The goals of this program are to ensure that no mother leaves the hospital without ZDV in hand for the baby. In addition, since 2003 more than half of the hospitals in Florida, including Shands Jacksonville, offer rapid HIV testing during labor and delivery. Data from the Pregnancy Risk Assessment Monitoring System (PRAMS) indicate that Florida’s HIV testing rates for pregnant women have increased significantly over the last few years with 86-90 percent of women surveyed reporting that they had discussions with their health care provider about HIV testing.17 Statewide other programs that are available include the Targeted Outreach for Pregnant Women Act (TOPWA) as well as the Advancing HIV Prevention also known as the African American Testing Initiative. Both programs offer free HIV testing, as well as outreach and ongoing education. TOPWA is available for all high risk, as well as HIV infected women, and offers HIV testing, education, linkage to care and intensive case management through pregnancy and beyond.18 Both programs are available in Duval County and at Shands Jacksonville While TOPWA initially started in community venues, expansion into jails was prompted by concerns about the high HIV prevalence among incarcerated women as well as the lack of adequate prenatal care among those who were pregnant. Therefore in February 2002, the FDOH piloted the first TOPWA-funded jail program in Palm Beach County by partnering with the local STI program which had been active Northeast Florida Medicine Vol. 61, No. 3 2010 13
in the jail system for several years.Since then additional jail programs have been implemented in Orange, Hillborough and Miami-Dade counties. TOPWA workers screen all female inmates for program eligibility. They offer on-site pregnancy and HIV testing and counseling along with education about HIV, STI, substance abuse and domestic violence. They also ensure linkage to care both during the period of incarceration as well as once the woman is released from jail. In addition they work with Healthy Start programs to help them gain access to jails to provide prenatal care and related services. In addition to TOPWA, the FDOH currently funds 15 county health departments (including Duval) to implement transitional services in local jails. These jail link programs include counseling and testing for HIV/AIDS, Tuberculosis, hepatitis and other STI, prevention education, pre-release planning for inmates and follow-up services to ensure that inmates are linked to care following release. Pre-release planning programs ensure that inmates have a 30-day supply of their medication, an appointment to begin medical care near their home and a copy of their medical records to expedite treatment.19,20
Conclusion
Significant milestones have been achieved in the prevention of MTCT of HIV in children. The institution of the 076 PACTG protocol and ZDV administration to both mother and baby, availability of HAART for pregnant women, elective caesarian delivery when indicated, avoidance of breast feeding, opt out testing for pregnant women as well as rapid testing of pregnant women during labor and delivery when results of HIV tests are not available have all contributed to this success. Significant measures have also been undertaken to reduce MTCT in Florida. These include the passage of laws by the legislature to facilitate HIV testing as well as ‘opt out’ testing for pregnant women, educational and outreach programs for pregnant and at risk women, availability of rapid testing at point of care facilities as well as easy access to free rapid tests through various programs. Efforts to promote proper education among health care providers and the community in general remain critical as we continue to strive towards the ultimate goal of eliminating MTCT. Primary care providers need to have frequent and open conversations with their patients, particularly young women about the importance of safe sexual practices and HIV testing. HIV testing during pregnancy is also critical and in jurisdictions with high rates of HIV infection, Florida being one of them, it is essential that the 2006 CDC guidelines be followed and providers be aware of and practice in accordance with state laws. In addition in situations where HIV test results are essential and unknown, eg. during labor and delivery, rapid testing at point of care in hospitals and other health care settings can help in providing quick and timely HIV testing. 1.
2.
References
Connor EM, Sperling RS, Gelber R et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Eng J Med 1994;331:1173-80. Jamieson DJ, Clark J, Kourtis AP et al. Recommendations for human immunodeficiency virus screening, prophylaxis
14 Vol. 61, No. 3 2010 Northeast Florida Medicine
and treatment for pregnant women in the United States. Am J Obstet Gynecol 2007;197(3Suppl):S26-32. 3.
Mofenson LM. Prevention in neglected subpopulations: prevention of mother to child transmission of HIV infection. Clin Infect Dis 2010;Suppl 3:S130-48.
4.
UNAIDS Data Report 2009. http://data.unaids.org/pub/ Report/2009/JC1700_Epi_Update_2009_en.pdf. Accessed May 21, 2010.
5.
Marks G, Crepaz N, Janssen RS. Estimating sexual transmission of HIV from persons aware and unaware that they are infected with the virus in the USA. AIDS 2006;20:1447-1450.
6.
HIV/AIDS among women. Florida Fact Sheets. http://www. doh.state.fl.us/Disease_ctrl/aids/updates/facts/09Facts/2009_ Women_Fact_sheet.pdf. Accessed May 25, 2010.
7.
Florida: cumulative reported HIV infections (cases). statehealthfacts.org.http://statehealthfacts.org/profileind.jsp? cat=11&sub=122&rgn=11. Accessed November 24, 2009.
8.
New York: cumulative reported HIV infections (cases). statehealth facts.org. http://statehealthfacts.org/profileind.jsp?cat=11&sub =122&rgn=34. Accessed November 24, 2009.
9.
Texas: cumulative reported HIV infections (cases). statehealthfacts.org. http://statehealthfacts.org/profileind. jsp ?cat=11&sub=122&rgn=45. Accessed November 24, 2009.
10. Florida: cumulative AIDS cases. statehealthfacts.org.http:// statehealthfacts.org/profileind.jsp?cat=11&sub=118&rgn=11. Accessed November 24, 2009. 11. Florida Department of Health, 2008 Fact Sheets. http:// www.doh.state.fl.us/Disease_ctrl/aids/updates/facts/2008_ Pediatric_Fact_Sheet.pdf. Accessed November 24, 2009. 12. Nita Harrell, Florida Department of Health.Personal Communication. September 2009. 13. Revised Recommendations for HIV testing of adults, adolescents and pregnant women in health care settings. MMWR. 2006;55(RR14):1-17. http://www.cdc.gov/mmwr/preview/ mmwrhtml/rr5514a1.htm. Accessed May 24, 2010. 14. Mirza A, Custodio H, Harelle N, Rathore MH et al. Analysis of perinatal HIV transmission in Florida 2002-2009, success and future challenges. Abstract #MOPE0273. International Aids Conference, July 18-23, 2010, Vienna, Austria. 15. Taylor AW, Ruffo N, Griffith J et al. The missing link: documentation of recognized maternal human immunodeficiency virus infection in exposed infant birth records, 24 United States jurisdictions, 1999-2003. Am J Obstet Gynecol 2007;197(3 Suppl):S132-6. 16. The 2005 Florida Statutes.Chapter 384 Sexually Transmitted Diseases. http://www.leg.state.fl.us/Statutes/ i n d e x . c f m ? A p p _ m o d e = D i s p l a y _ St a t u t e & S e a r c h _ String=&URL=Ch0384/SEC31.HTM&Title=->2005>Ch0384->Section%2031#0384.31. Accessed May 24, 2010. 17. Pediatric HIV/AIDS Cases in Florida, through 2007. http:// www.doh.state.fl.us/Disease_ctrl/ aids/trends/epiprof/epiprof_ peds_2007.pdf. Accessed May 24,2010. 18. TOPWA. Information available at: http://www.preventhiv florida. org/Women_Children/TOPWA.htm. Accessed August 2, 2010. 19. Florida DOH Corrections Program. http://www.prevent hivflorida.org/Corrections/DOH_Corrections_Programs. htm. Accessed August 2, 2010. 20. Clark J, Sansom S, Simpson JB, et al. Promising strategies for preventing perinatal HIV transmission: model programs from three states. Matern Child Health J 2006; 10:367-373. www . DCMS online . org
Mitigating the H1N1 Pandemic: A Year in Review
Background - Benefits that Matter!
The Duval County Medical Society (DCMS) attempts to provide its members with the benefits that consistently meet your professional needs. One example of how this is being accomplished is by providing to DCMS members free Continuing Medical Education (CME) opportunities in the subject areas mandated/and or suggested by the State of Florida Board of Medicine to obtain and retain medical licensure. The DCMS would like to thank the St. Vincent’s Healthcare (SVHC) Committee on CME for reviewing and accrediting this activity in compliance with the Accreditation Council on Continuing Medical Education (ACCME). Helena Karnani, MD, Chair of the CME Committee; Betsy Miller, Director, Medical Staff, Quality Management; and Cindy Williamson, CME Coordinator, from SVHC deserve special recognition for their work on behalf of DCMS. This issue of Northeast Florida Medicine includes an article, “Mitigating the H1N1 Pandemic: A Year in Review” authored by Taj Azarian, MPH and Saad Zaheer, MD, MSPH (see pp. 17-22), which has been approved for 1.0 AMA PRA Category 1 credit(s).™ For a full description of CME requirements for Florida physicians (MD/DO), please visit the DCMS website (http://www.dcmsonline. org/cme_requirements.aspx).
Faculty/Credentials: Taj Azarian, MPH, works as a Public Health Preparedness and Surveillance Epidemiologist for the Duval County Health Department located in Jacksonville, FL. Dr. Zaheer, MD, MSPH, is the Program Director, Epidemiology and Bioterrorism Surveillance for the Duval County Health Department Objectives for CME Journal Article 1. Describe the public health response to the 2009 Influenza A (H1N1) Pandemic 2. Identify challenges and successes of the response 3. Generalize the morbidity and mortality of the pandemic and the efficacy of the vaccination campaign
Date of Release: September 3, 2010 Date Credit Expires: September 3, 2011 Estimated time to complete: 1 hr.
Methods of Physician Participation in the Learning Process
1. Read the “Mitigating the H1N1 Pandemic: A Year in Review: article on pages 17-22 2. Complete the Post Test and Evaluation on page 16 3. Cut out & fax the Post Test and Evaluation to DCMS (FAX) 904-353-5848 OR members go to www.dcmsonline.org & submit test online
CME Credit Eligibility
In order to receive full credit for this activity, a minimum passing grade of 70% must be achieved. Only one re-take opportunity will be granted if a passing score is not made on the first attempt. DCMS members and non-members have one year to submit the post test and earn CME credit. A certificate of credit/completion will be emailed, faxed or USPS mailed within 4-6 weeks of submission. If you have any questions, please contact the DCMS at 355-6561, ext. 103, or llegacy@dcmsonline.org.
Faculty Disclosure Information
Mr. Azarian and Dr. Zaheer report no significant relationships to disclose, financial or otherwise with any commercial supporter or product manufacturer associated with this activity.
Disclosure of Conflicts of Interest
St. Vincent’s Healthcare (SVHC) requires speakers, faculty, CME Committee, and other individuals who are in a position to control the content of this educational activity to disclose any real or apparent conflict of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly evaluated by SVHC for fair balance, scientific objectivity of studies mentioned in the presentation and educational materials used as basis for content, and appropriateness of patient care recommendations.
Joint Sponsorship Accreditation Statement
This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of St. Vincent’s Healthcare and the Duval County Medical Society. St. Vincent’s Healthcare is accredited by the Florida Medical Association to provide continuing medical education for physicians. The St. Vincent’s Healthcare designates this educational activity for a maximum of 1.0 AMA PRA Category 1 credit(s) .TM Physicians should only claim credit commensurate with the extend of their participation in the activity.
www . DCMS online . org
Northeast Florida Medicine Vol. 61, No. 3 2010 15
Mitigating the H1N1 Pandemic: A Year in Review
CME Questions & Answers (Circle Correct Answer)
Free-DCMS Members/$50.00 charge non-members* (Return by September 3, 2011 by FAX: 904-353-5848, by mail: 555 Bishopgate Lane, Jacksonville, FL 32204 OR online: www.dcmsonline.org) 1. What is the name of the Florida Department of Health’s syndromic surveillance system? a. NERVSS b. ESSENCE c. NVSN d. ILInet 2. Which state was the first one to report cases of 2009 Influenza A (H1N1) in the United States? a. Florida b. California c. Texas d. New York 3. At what phase was the WHO Pandemic Alert Level when Florida identified its first case of H1N1? a. Phase 3 b. Phase 4 c. Phase 5 d. Phase 6 4. In Florida, which age group demonstrated the highest rate of influenza hospitalizations due to H1N1? a. 0-4 years of age b. 13-18 years of age c. 25-44 years of age d. >65 years of age
5. Which previous pandemic replaced the then circulating H1N1 influenza virus with a H2N2 virus as the predominant seasonal strain? a. 1957 Asian Flu Pandemic b. 1968 Hong Kong Flu c. 1975 Swine Flu d. 1992 Flu season 6. In Florida, which age group demonstrated the highest rate of influenza hospitalizations due to H1N1? a. 0-4 years of age b. 25-44 years of age c. 50-64 years of age d. >65 years of age 7. Outside of the initial ACIP vaccination target groups, which group had the highest estimated vaccination coverage in Florida? a. Children <6 months of age b. Children aged 6 months-17 years of age c. Adults 25-64 years of age d. Elderly >65 years of age 8. Based on estimates from the BRFSS and NHFS surveys, how many persons in the U.S. were immunized for H1N1 by February 2010? a. 36 million persons b. 72 million persons c. 86 million persons d. 113 million persons
Evaluation questions & CME Credit Information
(Please evaluate this article. Circle one number using this scale: 1= Strongly Agree to 5= Strongly Disagree)
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The article met the stated objectives: 1 2 3 4 5 The article was appropriate to my practice: 1 2 3 4 5 The topic was current and well presented: 1 2 3 4 5 Comments:_______________________________________________________________________ __________________________________________________________________________________________ _________________________________________________________________________________________ Address/City/State/Zip_________________________________________________________________ Phone__________________________Fax_____________________DCMS Member (circle) YES NO *Non-Member Charge ($50.00) - See payment options below Credit card:
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Mitigating the H1N1 Pandemic: A Year in Review Taj Azarian, MPH and Saad Zaheer, MD, MSPH Editor’s Note: Due to production constraints, Figure 2 is not printed in the journal. It is available online at www. dcmsonline.org as a web illustration. Abstract: In April of 2009, a novel influenza A (H1N1) virus was identified in the United States with the definitive characteristics of a pandemic virus. Within weeks, this virus had spread to every region in the country. In the proceeding months, agencies spanning from the international to county and city levels responded to the rapidly expanding public health emergency. In Duval County, the healthcare and public health community united to mitigate the local effects of the pandemic. This response was marked by myriad challenges that were overcome by pre-event preparedness and planning. These successes were driven by a well developed infrastructure and relationships formed through detailed planning for public health emergencies. These strengths allowed us to address the increase of H1N1 cases in our community, subsequent deaths, and the mass vaccination campaign. Ultimately, the severity of this pandemic was lower than initially predicted; however, the number of hospitalizations and deaths were nonetheless considerable. This experience offers lessons which will facilitate the preparation of future influenza outbreaks and pandemic responses.
Overview
The month of April, 2010 marked the one year anniversary of the emergence of a novel pandemic influenza virus within the United States. Despite numerous iterations of this virus’ official title, the 2009 pandemic influenza A (H1N1) virus will be remembered as one of the most reported, documented, studied, and debated public health events in modern history. Now, over a year after the emergence of this virus, we reflect on the challenges and successes that occurred. While vaccination campaigns and numerous studies of the 2009 influenza pandemic are still underway, many agencies are reflecting on the last year to evaluate how they responded. In the dwindling days of the pandemic, as predictions of a third wave of illness began to fade, members of the media were quick to pose the question to the public health (PH) and the medical community as a whole, “How did we respond?” For those that experienced the pandemic first hand; public health officials, health care professionals, and emergency responders, the response was in accordance with the event we had planned for since the 1918 Spanish flu left a devastating mark on mankind. However, as Colin Powell so concisely stated, “No battle plan survives contact with the enemy.”1 Throughout the course of the response, certain topics predominated. These included laboratory testing and surveillance methodologies, infection control recommendations, school closures, pandemic alert level designations, and of course, the vaccine and immunization campaign. As a result, significant Address Correspondence to: Taj Azarian, MPH Duval County Health Department, Jacksonville, Florida. Email: taj_azarian@ doh.state.fl.us.
www . DCMS online . org
advancements have already been made in how these areas are addressed on a local, state, national and international scale, further strengthening future responses to PH emergencies. In addition, the scientific community’s understanding of the epidemiology and pathology of influenza has greatly been improved. Subsequently, changes in the medical diagnosis and management of influenza patients have positively affected prognoses. Moving forward, we continue to examine these topics in finer detail and prepare for our next encounter with the enemy.
The Emergence of a Novel Virus
On April 17, 2009, officials at the Centers for Disease Control and Prevention (CDC) confirmed two cases of swine influenza in children living in neighboring counties in California.2,3 Over the subsequent week, reports of large, high mortality influenza-like illness (ILI) outbreaks in Mexico City fueled growing concerns that the two California cases were only the tip of the iceberg. On April 24, only one week after the initial CDC report, six additional cases in the United States were reported from three states; California, New York, and Texas. The following day, Dr. Margaret Chan, Director General of the World Health Organization (WHO), declared a “public health emergency” in response to the increase in cases reported by the United States and Mexico. Two days later, WHO raised the pandemic alert level to phase 4, signifying verified human-to-human spread of a novel virus. Subsequently, on April 29, as a result of increased human-to-human spread, WHO raised the pandemic alert level to phase 5. This move coincided with the first reported death in the United States and signaled a pandemic was imminent.
A State Responds
In the final days of April, 2009, as the number of states reporting confirmed cases of H1N1 began to grow, the Florida Department of Health (FDOH) prepared in anticipation for the identification of Florida’s first confirmed case. Upon the identification of a novel influenza virus with pandemic capabilities, FDOH enacted response plans delineated in the Bureau of Epidemiology’s Pandemic Influenza Annex. These plans called for implementation of enhanced surveillance and control measures identified in the rapid response and containment portion of this two-stage response. On April 27, 2009, Florida’s acting state epidemiologist, Dr. Richard Hopkins, addressed the epidemiology staff of the state’s 67 county health departments (CHD). This presentation provided an overview of the current situation and outlined the goals of the rapid response and containment portion of Florida’s plan. The primary goal at this stage in the response: surveillance. Two great strengths of FDOH prevailed during the emergence of this novel virus and throughout the pandemic
Northeast Florida Medicine Vol. 61, No. 3 2010 17
response. Primarily, FDOH has strived to continually expand PH surveillance capabilities. Electronic systems exist for the receipt of laboratory results from large private labs, as well as the state PH laboratories. These systems also allow for the electronic reporting of investigative case reports from the CHDs to the state. In addition, hospital emergency department (ED) syndromic surveillance (SS) data are monitored through the Electronic Surveillance System for the Early Notification of Community-based Epidemics (ESSENCE). Florida’s ESSENCE SS system, which is implemented in 138 Florida hospitals, captures an estimated 75% of Florida’s annual ED visits and allows for real-time population-level awareness of PH indicators. ESSENCE was used extensively during the H1N1 response to monitor levels of activity throughout the state. (Figure 1) These systems are flexible and efficient; two qualities which facilitate effective and timely responses to PH emergencies. Secondly, since the threats of Severe acute respiratory syndrome (SARS) and H5N1 Avian Influenza raised concerns among health officials, FDOH has been conducting training sessions to prepare staff how to respond. These trainings, often conducted in conjunction with collaborating state and national agencies, outlined response plans and forged interagency bonds. Ultimately, these two overarching strengths formed the infrastructure and laid the foundation for this response. Combined with the earlier mentioned surveillance systems, the Florida Sentinel Influenza Surveillance Providers Network (ILInet) and the Florida Pneumonia and Influenza Mortality Surveillance System provide the basis for monitoring influenza
activity in Florida annually. CDC’s ILInet is the cornerstone of national influenza surveillance. This program involves the recruitment of sentinel primary care providers throughout the United States which report the number of patients seen weekly with ILI during influenza season. In addition, specimens are collected from these patients and sent to a CDC or Laboratory Response Network (LRN) laboratory for testing and strain typing. This surveillance provides a composite view of national influenza activity and characterization of the circulating influenza viruses. As FDOH ramped up surveillance in the early stages of the response, ILInet providers were requested to increase specimen collection. Health care providers were asked to evaluate patients with ILI and identify individuals with recent travel history to states or countries with documented cases. On May 1, 2009, FDOH Communications Office reported two CDC laboratory confirmed cases of H1N1 in Florida; an 11-year-old male elementary school student in Lee County and a 17-year-old female high school student in Broward County. On that day, pursuant to Florida Statutes, 381.00315, Governor Charlie Crist directed State Surgeon General Dr. Ana Viamonte Ros to declare a PH emergency that allowed the State Surgeon General to take any action necessary to protect the PH. At this point in the pandemic response, CDC had reported 109 confirmed cases of novel influenza in the United States, with one death in a twentythree month old. Nationally, an estimated 298 schools were closed due to cases of H1N1, leaving the issue of school closures within Florida as a high priority topic. Within one
Figure 1 Influenza-like Illness Visits to ED
Visits (by Chief Complaint) to Emergency Departments (ED) as a Percentage of ALL ED Visits, Duval County ESSENCE Participating Hospitals (N=8), Week 40, 2006 through Week 24, 2010. 18 Vol. 61, No. 3 2010 Northeast Florida Medicine
www . DCMS online . org
Figure 3 Number of Specimens Tested
Tested by Florida Bureau of Laboratories and Percent Positive for Influenza - Week 40, 2008 to Week 20, 2010.
day of this announcement, six other Florida counties were reporting cases of H1N1. As the pandemic evolved, the PH surveillance and response objectives evolved as well. On June 11, 2009, Dr. Chan announced the decision to raise the pandemic alert level from phase 5 to 6; stating, “Spread in several countries can no longer be traced to clearly-defined chains of human-to-human transmission. Further spread is considered inevitable”. 4 On that day, nearly 30,000 confirmed cases had been reported in 74 countries. This designation indicated a global pandemic was underway and marked the official transition from the rapid response and containment strategy to community mitigation. By the time the first cases of H1N1 were identified in Florida, the WHO pandemic alert was at phase 5. By May 1, Florida had already shifted to a community mitigation strategy.
A Local County’s Response
On April 27, 2009, the Duval County Health Department (DCHD) activated a joint incident command in conjunction with Jacksonville Fire and Rescue to respond to this rapidly expanding situation. The objectives were to coordinate the local response, maintain situational awareness, and plan for the identification of the county’s first case. Immediately, the need to provide rapid and accurate health information to healthcare professionals was identified. In response to this need, daily health and medical calls were established to update members of the healthcare community. Duval County reported its first confirmed case of H1N1 in a 25-year-old female on May 6, 2009. This was Florida’s 55th confirmed case. In all, Duval County would report 67 www . DCMS online . org
confirmed hospitalizations due to H1N1, including 13 deaths (as of May 15, 2010). In addition, DCHD investigated over 25 ILI outbreaks in settings ranging from schools, daycares, shelters, military facilities, and family households. Case and outbreak investigations were also coupled with a tremendous demand for public information. Calls poured in from the community: healthcare providers reporting cases and requesting testing of patients, concerned citizens who had recently returned from Mexico, rumors of outbreaks, and inquiries from schools and businesses. All DCHD epidemiology and emergency preparedness staff were focused on the influenza response.
Cases
The identification, investigation, and reporting of H1N1 cases was one of the most dynamic aspects of the response. The initial objective was to identify, investigate and report each case of influenza. This key factor was imperative for characterizing the pandemic, estimating the severity, and ultimately determining the details of the PH response. Subsequently, an immediate and dramatic need for laboratory testing emerged. Patients began to present to EDs with ILI in growing frequencies, all requesting testing for H1N1. Local providers and urgent care centers were also greatly affected by a significant increase in visits and accompanying testing demands. Initially, CDC laboratories solely possessed the capability to provide confirmatory testing. In Florida, all requests were approved through the CHD prior to testing at the state PH laboratory and subsequent CDC confirmation. The four FDOH laboratories were quickly overwhelmed. CDC and FDOH issued clinician guidance for the testing Northeast Florida Medicine Vol. 61, No. 3 2010 19
of suspect H1N1 patients and alleviated some of the demand for testing. The Florida Flu Hotline was also established to answer questions from clinicians and community members. Coinciding with the increase in testing requests, a tremendous demand for antivirals caused spot shortages throughout the state. On May 7, 2009, all FDOH laboratories were validated by CDC to provide confirmatory testing for the of H1N1 virus, and by mid-May most states had acquired this capability as well. During the peak of activity, these laboratories performed over 2200 influenza tests in a single week (Figure 2, www.dcmsonline.org and Figure 3, p.19).
observed with seasonal influenza. It would later be identified that people born before 1957 were less susceptible to H1N1 then younger individuals. Why was 1957 the magic year? After its first appearance, the H1N1 virus which caused the 1918 pandemic dominated the circulating influenza strains for almost 40 years until it was replaced in 1957 by a H2N2 influenza virus which caused the Asian Flu Pandemic. While the pre-1957 H1N1 virus was significantly different than the 2009 virus, enough antigenic similarity existed to provide individuals exposed to the pre-1957 virus with protection against the 2009 virus.
In late May, CDC updated its testing guidance to place more emphasis on clinical outcomes and underlying conditions. Between the months of April to July of 2009, FDOH reported all laboratory confirmed cases of H1N1 to the CDC. From July on, FDOH, in accordance with updated CDC guidance, changed to reporting cases meeting select criteria: hospitalizations, including those in pregnant women, and deaths. An unintended result of the continual change in surveillance case definitions and case reporting was considerable confusion regarding the interpretation of these figures by the media and public. This fact also had an effect on the publicâ&#x20AC;&#x2122;s perception of the severity of the pandemic and the transparency of the PH response.
From August 30, 2009, through March 27, 2010, WHO and National Respiratory and Enteric Virus Surveillance System collaborating laboratories in the United States tested 422,648 specimens. Of these, 89,585 (21.1%) were positive: 89,298 (99.7%) were positive for influenza A, and almost all were 2009 H1N1 viruses.5 During August 30, 2009-Mrch 27, 2010, 34 states reported a total of 41,689 hospitalizations associated with laboratory confirmed influenza virus infections to CDC.3 Rates of hospitalization were highest among children aged 0-4years. A total of 2,096 deaths associated with laboratory confirmed influenza virus infections were also reported to CDC during this period. Cumulative influenzaassociated death rates since August 30, 2009, were highest among persons aged 50-64 years and lowest in children.3 Based on these data, and studies conducted by the CDC, estimates of morbidity and mortality were calculated for the time period of April 2009 through April 10, 2010. 6 For this period CDC estimated between 43 million and 89 million cases of 2009 H1N1, between about 195,000 and 403,000 H1N1-related hospitalizations, and between about 8,870 and 18,300 2009 H1N1-related deaths.6 (Figure 4)
In all, Florida reported 1323 hospitalizations between July 28, 2009 and May 15, 2010, including 228 deaths. The highest rate of hospitalizations was observed in the 00-04 age group. The 50-64 year-old age group demonstrated the highest rate of deaths. Furthermore, of the total reported deaths, 84.2% had an identified underlying condition. It was identified early in the pandemic that this virus was sparing older individuals, contrary to what is traditionally
Figure 4 CDC Estimates of 2009 H1N1 Cases in the U.S. by Age Group
20 Vol. 61, No. 3 2010 Northeast Florida Medicine
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Table 1 Estimated Florida H1N1 Vaccination Percentages
%
(95% CI)
Children/6 mos to 17 yrs
32.3
(±6.1)
Persons aged ≥18 yrs
16.1
(±2.1)
Person in initial target groups
28
(±4.1)
Persons aged 25--64 yrs at high risk
21.2
(±5.4)
Persons aged 25-64 yrs/ not initial target groups
11.2
(±3.1)
Persons aged ≥65 yrs
21.8
(±3.4)
Persons aged ≥6 mos
19.5
(±2.1)
Unweighted Sample Size = 9,442
CDC estimated monovalent vaccination coverage among children and adults, Florida by selected age and priority subgroups - U.S., BRFSS and NHFS, end of January 2010.
The Vaccine
The most challenging component of the PH response was the vaccination campaign. Essentially, all mitigation efforts are conducted to slow the spread of the virus, providing more time for scientists to develop a vaccine. The quicker the vaccine is developed and administered, the greater reduction in the pandemic’s morbidity and mortality. Upon identification of the influenza pandemic, several vaccine manufacturers began working on producing enough vaccine to meet the projected demand. It was evident that despite this massive effort to produce sufficient vaccine to rapidly immunize everyone; vaccine would more than likely become available to states in limited allocations. In July 2009, the Advisory Committee on Immunization Practices (ACIP) issued recommendations for the use of influenza A (H1N1) 2009 monovalent vaccine.7 These recommendations were intended to provide vaccination programs and providers with information to assist in planning and to alert providers and the public about target groups comprising an estimated 159 million persons who are recommended to be first to receive the vaccine.7 While the guiding principle of these recommendations was to vaccinate as many persons as possible and quickly as possible, state and local health officials were left as the final decision makers regarding how the vaccine would be administered and distributed. Distribution of 2009 H1N1 vaccine in the United States began on October 5, using a system that allocated available vaccine to states proportional to their populations. On October 14, doses of vaccine began to arrive in small amounts to Duval County. Providers and healthcare facilities were required to order vaccines through a newly created module in Florida SHOTS, the state of Florida’s immunization www . DCMS online . org
H1N1 Pediatric Perspective Haidee Custodio, MD, Fellow Children and young adults were found particularly susceptible to the 2009 H1N1 influenza.1 A wide spectrum of illness was seen with most children having mild disease and presenting mainly with fever, cough and rhinorrhea, and also vomiting and diarrhea.1,2 On the other end of the spectrum were critically ill children many of whom expired from the illness.3,4 The 2009 H1N1 influenza-associated pediatric deaths were twice as many as in the previous season.4 Children with chronic underlying medical conditions such as pulmonary disease, in particular asthma, were thought to be at higher risk for severe disease.1,2,3 Other risk factors included neurodevelopmental conditions, cardiovascular disorders, immunosuppression and obesity. Management of patients included early antiviral use and antibiotics in cases of superimposed bacterial infections.1,2,3 With H1N1 vaccine availability since October 2009, it is hoped that the morbidity and mortality will be less among even the vulnerable populations.
References
1.
Jain S, et al. ”Hospitalized patients with 2009 H1N1 influenza in the United States.” N Engl J Med April-June, 2009;361:1935-1944.
2.
Kumar S, et al. ”Clinical and epidemiological characteristics of children hospitalized with 2009 pandemic H1N1 influenza A infection.” Pediatr Infect Dis J. 2010; 29:591-594.
3.
Lockman JL, et al. “The critically ill child with novel H1N1 influenza A: A case series.” Pediatr Crit Care Med 2010;11:173-178.
4.
CDC. “Number of influenza-associated pediatric deaths.” Available at: http://www.cdc.gov/flu/ weekly/. Accessed on June 18, 2010.
Address Correspondence to: Haidee Custodio, MD, Fellow, Pediatric Infectious Diseases and Immunology, University of Florida, Jacksonville. Email: Haidee.custodio@jax.ufl.edu.
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registry. CHDs could then allocate vaccine based on priority and availability. Several methods were utilized to distribute and administer vaccine. In addition to the distribution of vaccine through SHOTS, some CHDs conducted vaccine clinics modeled after points of distribution (PODs) used in mass prophylaxis campaigns. Others focused on school-based vaccinations. Duval County used a combination of PODs targeting first responders and priority distribution of vaccine through SHOTS to providers serving target groups. Vaccine was also made available at the DCHD Immunization Clinic. Vaccine administration tracking proved another surmountable task. While providers were required to register with SHOTS to order vaccine, they were not required to enter doses to administer. This made it difficult to determine geographic and demographic vaccine coverage. FDOH relied on tracking of vaccine doses distributed, partial entries of administered doses in SHOTS, and surveys of vaccine administration sites to estimate coverage.
guidance became an arduous task of its own. As a result, the process for updating guidance, as well as the means of distributing it has greatly been improved. In addition, effective risk communication has always been a crucial component of any PH response. The 2009 H1N1 pandemic could not have emphasized this fact more. At times, this response was met with confusion, concern, and at some points, doubt by the public. The electronic age has revolutionized the means by which individuals obtain information. This, for PH, is a double edged sword. Facts and falsehoods are both easily discovered on the internet, and in that environment, it is often difficult to discern the two. Clear, transparent PH messaging at a national, state, and especially the local level during any emergency must be strengthened. Engaging faith based organizations and approaching schools proved successful in combating misinformation during the H1N1 response. These methods should be applied more broadly.
On December 4, 2009, counties were authorized to expand provision of the H1N1 flu vaccinations beyond the five priority groups based on local availability of vaccine. Duval County expanded vaccination efforts in mid-December. At that point in the vaccination effort, Duval County had distributed 209,200 doses of H1N1 vaccine. At the end of January, 2010, CDC estimated vaccination coverage utilizing the Behavioral Risk Factor Surveillance System (BRFSS) and National 2009 H1N1 Flu Survey (NHFS). Approximately 61 million persons had been vaccinated by the end of 2009.8 By January 29, 2010, approximately 124 million doses had been distributed.8 At the end of February, based on data from BRFSS and NHFS combined, the estimated coverage rate was 24.0%, representing 72 million persons vaccinated.7 In comparison to the national data, Table 1 shows Florida H1N1 vaccination percentages.9 (Table 1, p. 21) Four states in the New England region had estimated 2009 H1N1 vaccination coverage ≥60%. Of the four New England states achieving high coverage in children, three had conducted statewide school vaccination campaigns that coincided with a period of high demand for vaccine.
Overall, the 2009 H1N1 Pandemic brought PH officials from beyond the public’s sight to the frontline of the response. As a result, people were reminded that we are not individuals isolated from one-another. We are all interconnected in a way which allows a virus to circle the globe in a matter of weeks. The ripple effect of this pandemic beyond influenza has subsequently further strengthened the way in which the nation responds to emergencies. Over the subsequent years, officials will continue to study the pandemic, preparing once again for the next encounter with a novel virus.
Summary
Former Secretary of State Colin Powell, CBS: “Face the Nation,” Sunday, Feb. 21, 2010.
2.
CDC. “Swine influenza A (H1N1) infection in two children - Southern California,” March-April 2009. Morb Mortal Wkly Rep 2009;58:400-402.
3.
CDC. “Update: infections with a swine-origin influenza A (H1N1) virus - United States and other countries,” April 28, 2009. Morb Mortal Wkly Rep 2009;58:431-433.
4.
Statement to the press by WHO Director-General Dr. Margaret Chan, 11 June 2009, “World now at the start of 2009 influenza pandemic”.
5.
CDC. “Update: Influenza Activity- United States, August 30, 2009-March 27, 2010, and Composition of the 2010-11 Influenza Vaccine,” April 16, 2010. Morb Mortal Wkly Rep 2010; 59(14);423-430.
6.
CDC. CDC Estimates of 2009 H1N1 Influenza Cases, Hospitalizations and Deaths in the United States, April 2009 – March 13, 2010, April 19, 2009. www.cdc.gov/h1n1flu/ estimates_2009_h1n1.htm. Accessed June 1, 2010.
7.
CDC. “Use of influenza A (H1N1) 2009 monovalent vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP),” 2009. Morb Mortal Wekly Rep 2009;58;1-8.
8.
CDC. “Interim Results: State-Specific Seasonal Influenza Vaccination Coverage- United States, August 2009-January 2010.” April 30, 2010. Morb Mortal Wkly Rep 2010; 59(16);477-484.
9.
CDC. “Interim Results: Influenza A (H1N1) 2009 Monovalent Vaccination Coverage - United States, October-December 2009.” January 22, 2010. Morb Mortal Wkly Rep 2010; 59(02);44-48.
The Recovery
After every incident, there is a period of recovery; a time to rebuild, assess the lessons learned, and continue to plan for the next encounter with the enemy. During these encounters, strengths and weaknesses quickly become apparent. The investment this nation has made to strengthening preparedness and emergency response capabilities were immediately apparent. The infrastructure, response plans, and resources were available to respond to this incident. Within FDOH, surveillance systems, training, and staff demonstrated their ability to meet the demands of a large scale PH response. Among the local medical community, technology, surge capacity, and a dedication to care met the needs of the community. Agencies came together, realizing this was not just a PH response, it was a community response. Without cooperation between these partners, the pandemic could have taken a more severe course. With these strengths, improvements have already been made in several other areas. This may have been the first PH incident where there was too much information for decision makers to process. Continually monitoring changes in 22 Vol. 61, No. 3 2010 Northeast Florida Medicine
References
1.
www . DCMS online . org
Tuberculin Skin Test: Loss of an Old Friend? Jeffrey Lauer, MD Abstract: The tuberculin skin test (TST) has been the only practical and commercially available test approved in the United States up to 2001 for the evaluation of exposure to Mycobacterium (M.) tuberculosis.1 However, with the understanding of the role that interferon gamma (IFN-γ) plays in cell-mediated immune response to M. tuberculosis, there has been the development and growing acceptance of these blood assays for the detection of M. tuberculosis. The strengths and weaknesses of these interferon gamma release assays (IGRAs) are just now beginning to be recognized. Concern for the utility and continued use of the standard TST is coming more into question.
Introduction
TST (also known as PPD) is probably the most routinely and widely used antigen by clinicians and immunologists and the mainstay for the diagnosis of exposure to M. tuberculosis.2 The TST was developed from the extract of the tubercle bacillus, the earliest preparation which Robert Koch named “old tuberculin” (OT). OT consisted of concentrated sterile filtrate of autolyzed, heat-killed liquid culture of M. tuberculosis and began to be used in clinical and epidemiological practices for both veterinary and human medicine soon after its development. The often noted non-specific reactions encountered to OT due to the shared cross-reactive antigens with host encountered environmental antigens, lead Florence Seibert in 1932 to begin development of a purified turberculoprotein from OT.3 In 1942 that preparation was termed “tuberculin purified protein derivative” (PPD) although it still consisted of a mixture of several low-molecular-weight proteins of M. tuberculosis. The prevalence of TB in different groups defined three cut-points recommended for defining a positive tuberculin reaction: >5 mm, >10 mm, and >15 mm of induration. For persons who are at highest risk for developing active TB if infected with M. tuberculosis (i.e., HIV infection, immunosuppressive therapy recipients, recent close contact with infectious TB, or an abnormal chest radiographs consistent with prior TB), >5 mm of induration is considered positive. Those individuals with an increased risk of recent infection or with clinical conditions that increase the risk for progression to active TB, >10 mm of induration are considered positive. These include injection drug users, recent immigrants (i.e., entry into the U.S within the last 5 yr from high prevalence countries), residents and employees of high-risk congregate settings, health care workers, and persons with clinical conditions such as silicosis, diabetes mellitus, chronic renal failure, leukemias and lymphomas, carcinoma of the head or neck and lung, weight loss of >10% ideal body weight, gastrectomy, and jejunoileal bypass. Children younger than Address Correspondence to: Jeff Lauer, MD, Duval County Health Department, Jacksonville, Florida. Email: jeffrey_lauer@DOH. state.FL.edu. www . DCMS online . org
4 yr of age or infants, children, and adolescents exposed to adults in high-risk categories also fall into this category. For persons at low risk for TB, for whom tuberculin testing is not generally indicated and is not routinely recommended, >15 mm of induration is considered positive. An underlying strategy in the control and elimination of TB in the U.S. was contact investigation and treatment of contacts with latent TB infection (LTBI).4,5 This strategy has subsequently developed into “targeted testing” with a key element “don’t test unless you intend to treat and don’t treat unless you expect to complete therapy”; therefore, don’t test unless there is an expectation to complete appropriate therapy.6 The culture filtrate of the PPD varied in the antigenic composition by growth condition, the age of the culture at the time of filtration, the incubation temperature and even when grown under similar culture conditions.7,8 This variability and the known cross-reactivity reaction of the PPD to other environmental mycobacterial species take on increased significance with the changing tuberculosis landscape in the United States. Many countries currently vaccinate their populations with bacilli Calmétte-Guérin (BCG), a vaccine for M. tuberculosis that carries cross-reactive antigens that are found in the current PPD.
Background
Tuberculosis is a major cause of mortality worldwide with an estimated one-third of the world’s population harboring latent infection.9 Five to 10% of those with latent infection will develop active M. tuberculosis disease during their lifetime as the result of reactivation of the bacillus. The majority of the world’s resources for TB elimination are used to diagnose and then treat those with active disease with the Directly Observed Therapy (DOTS) program the mainstay of those efforts. However, the Global Tuberculosis Report 2008 documents the significant lack of culture facilities in the government health sector in most developing countries; the “gold standard” for TB disease identification is growth of M. tuberculosis.10 The significant pool of those already infected and variable length until reactivation does not lend to a shortterm or easy solution to TB eradication using the strategy of DOTS. Those with LTBI often are missed or ignored until they develop active disease and then they contribute to the spread of TB. In the United States, on average, 10 contacts are listed for each person with a case of infectious TB. Approximately 20%30% of all contacts have LTBI, and 1% has TB disease. Of those contacts that ultimately will have TB disease, approximately half acquire disease in the first year after exposure.11 For these reasons, contact investigations constitute a crucial prevention strategy. The Stop TB partnership Working Group on New TB Diagnostics has stressed the importance of developing new Northeast Florida Medicine Vol. 61, No. 3 2010 23
tools for the accurate, rapid identification of drug-resistant TB and reliable detection of latent TB infection. But the resources needed 1) to investigate for those exposed (contact investigation), 2) to treat those with proven infection but no disease, 3) provide therapy for an extended time-frame (standard of care recommendations are for 9 months of isoniazid (INH) daily, 4) to insure completion of LTBI therapy, 5) provide cost of medication and finally 6) offer the follow-up care with monitoring, places an enormous fiscal and manpower strain on resource poor countries. In 2008, there were an estimated 9.4 (range, 8.9–9.9 million) million cases (equivalent to 139 cases per 100,000 population) of TB globally. This is an increase from the 9.3 million TB cases estimated to have occurred in 2007. Most of the estimated number of cases in 2008 occurred in Asia (55%) and Africa (30%), with small proportions of cases in the Eastern Mediterranean Region (7%), the European Region (5%) and the Region of the Americas (3%). Twentytwo countries contribute to 80% of the world’s TB cases. The top five countries in terms of total numbers of cases are India (1.6–2.4 million), China (1.0–1.6 million), South Africa (0.38–0.57 million), Nigeria (0.37–0.55 million) and Indonesia (0.34–0.52 million). India and China alone account for an estimated 35% of TB cases worldwide.9 Those countries that can least afford measures to treat and control tuberculosis are the countries that have the highest TB burden.
TB Prevention and Control
The United States maintains a TB elimination program that covers all aspects of TB control and has largely remained successful because state and local health departments have legal responsibility for the prevention and control of TB in their communities.11 Three priorities are fundamental to the prevention and control of TB.12 The first is identifying persons who have active TB, which entail treating and ensuring completion of appropriate therapy. The second priority is contact investigation to determine whether those exposed to an active case have infection or disease and then providing them with appropriate treatment. The third priority is screening high-risk populations to detect persons who are infected and who could benefit from therapy to prevent the infection from progressing to TB disease. The second and third priorities have at the core “targeted tuberculin testing” to identify persons who have had recent infection with M. tuberculosis and those who have clinical conditions that are associated with an increased risk for progression of LTBI to active TB. Infected persons who are considered to be at high risk for developing active TB should be offered treatment of LTBI irrespective of age. The risk of an inadequate TB elimination program was highlighted in the U.S. by an increase in TB morbidity by 14% from 1985 through 1993.12 Several factors attributed to this increase, including the human immunodeficiency virus (HIV) epidemic, the occurrence of TB in foreign-born persons from countries that have a high prevalence of TB and the transmission of M. tuberculosis in
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congregate settings (e.g., health-care facilities, correctional facilities, drug-treatment centers, and homeless shelters). Also, many of the public health TB programs lacked adequate support for TB control as the available public health funds at the federal, state, and local levels had been restructured when TB cases were declining before 1985. The public health-care infrastructure was subsequently rebuilt to meet the challenge of that resurgence of TB cases and the U.S. has enjoyed a continued decline in TB rates. However, the rate of decline has slowed, and that slowing is likely the result of the same difficulties encountered from 1985 to 1993 and to the reactivation of LTBI already in the communities or imported from aboard not previously treated.12 In 1987 the Centers for Disease Control (CDC) Advisory Committee for the Elimination of Tuberculosis was established with the goal of eradicating tuberculosis for the United States by the year 2010. That goal has not been met. The CDC reported 12,904 active cases for the year 2008 and a case rate of 4.2 cases per 100,000. Although this represents a decline of 2.9% and 3.8%, respectively, compared to 2007 the trend of declining annual case rates has slowed from 5.6% for 1993 through 2002 to annual decline of 2.6% for 2003 through 2008. Eighteen states reported increased case counts from 2007 with California, Texas, New York and Florida accounted for 49% of the national case total. Although 2008 has the lowest active case report in the last several years, the epidemiology of new active cases continues the trend noted from 1993.12 The percentage of cases occurring in foreign-born persons comprises 59% of the national case total. In 14 states, >70% of TB cases occurred among foreign-born persons. The top five countries of origin of foreign-born persons with TB were Mexico, Philippines, Vietnam, India and China. When taken together, foreign-born Hispanics and Asians represent 80% of the TB cases in the foreign-born persons and accounted for 47% of the national case total.12 It is apparent that there is not just a world economy but also a world medical community as it relates to tuberculosis. However, a growing concern exists for drug resistance and multi-drug resistant strains of TB that exist and are now crossing U.S. shores. One percent (1.0%) of reported cases in 2008 had primary multidrug resistance, which is defined as resistance to at least isoniazid and rifampin with no previous history of TB disease. Those areas of the world that are maintaining the TB burden are those that possess the least ability to find and treat those with active disease or to conduct contact investigation and offer LTBI therapy. The IGRAs represent a new generation of diagnostic tools for detecting LTBI.
New Generation Testing
QuantiFeron – In 2001, the QuantiFERON®-TB test (QFT) (manufactured by Cellestis Limited, Carnegie, Victoria, Australia) was approved by the Food and Drug Administration (FDA) as an aid for detecting latent M. tuberculosis infection. This was an in vitro diagnostic test that measures the quantity of interferon-gamma (IFN-γ) released from sensitized
www . DCMS online . org
lymphocytes in whole blood incubated overnight with PPD and control antigens. The initial limitations of QFT include the need to process the blood within 12 hours after collection and the limited laboratory and clinical experience with the assay. Compared with TST, QFT results were less subject to reader bias, error and did not boost amnestic immune response. But like the TST, it assessed response to multiple antigens as it was incubated with PPD. In a CDC-sponsored multicenter trial, concordance of QFT and TST was affected by prior positive TST, BCG vaccination, and reactivity to non-tuberculous mycobacteria (NTM). The interpretation of QFT results, like the TST, had different cutoff values based on the estimated risk for infection with M. tuberculosis. These three criteria, needed for the diagnosis of M. tuberculosis: (mitogen -- nil) and (tuberculin -- nil), are both >1.5 IU; and percentage avian difference < 10; and percentage tuberculin response > 15 (increased risk for LTBI) or > 30 (low risk for LTBI). Using 15 as the percentage tuberculin response cut-off identifies approximately the same number of persons as with using a TST induration of 10 mm. Using 30 as the percentage cut-off identifies approximately the same number of persons as using a TST induration cut-off of 15 mm. The test is considered negative if (mitogen -- nil) > 1.5 IU but (tuberculin -- nil) < 15% (mitogen -- nil). Results are considered indeterminate if (mitogen -- nil) < 1.5 IU, which may be seen among anergic persons.13 QuantiFERON®-TB Gold – On May 2, 2005, a new in vitro test, QuantiFERON®-TB Gold (QFT-G, manufactured by Cellestis Limited, Carnegie, Victoria, Australia), received final approval from the FDA. The test is to assist in diagnosing M. tuberculosis infection, including both LTBI and TB. This enzyme-linked immunosorbent assay (ELISA) test detects the release of interferon-gamma (IFN-γ) in fresh heparinized whole blood when incubated with mixtures of synthetic peptides simulating two proteins present in M. tuberculosis. These two peptides: early secretory antigenic target--6 (ESAT6) and culture filtrate protein--10 (CFP-10) are secreted by M. tuberculosis, pathogenic M. bovis strains, M. kansasii, M. szulgai, and M. marinum. These proteins are absent from all BCG vaccine strains and from other commonly encountered NTM. Whole blood from the patient is incubated with these two peptides in a 24-well plate overnight. T-cells that recognize the antigens will secrete INF-γ. The plate is centrifuged and the plasma transferred to a microtiter plate where antibodies specific for IFN-γ have been coated to the bottom of each well. The formed cytokine-bound antibodies are then detected with another antibody conjugated to an enzyme that catalyzes a colorimetric reaction. The optical density or each well is measured and the concentration of IFN-γ is determined using a standard curve.14 The original QuantiFERON®-TB test (QFT) and the QFTG, use different antigens to stimulate IFN-γ release, different methods of measurement, and different approaches to test interpretation. Like its predecessor, QFT-G interpretation has different cut-off values to define negative, positive or indeterminate and available software supplied by the manufacturer www . DCMS online . org
can be utilized. Certain limitations of QFT-G are similar to those of the TST, such as QFT-G and TST cannot differentiate infection associated with TB disease from LTBI. QFT was approved as an aid for diagnosing LTBI, whereas QFT-G is approved as an aid for diagnosing both LTBI and TB disease. The initial studies using either of IFN-γ release assays were performed in culture-confirmed or clinically highly probable cases of tuberculosis. With the development and approval of QFT-G the original QuantiFERON®-TB test (QFT) is no longer commercially available and an “in field” version of QFT-G was developed; QuantiFERON-TB InTube (QFT-G IT). The antigens are in the tubes allowing “in field” mixing and negating the requirement for sample processing within twelve hours of collection.15 T-Spot TB – T-SPOT.TB is an FDA approved in vitro diagnostic test based on an enzyme-linked immunospot (ELISPOT) method that enumerates the number of effector T-cells responding to stimulation by peptides simulating ESAT-6 and CFP-10 antigens. As with the QFT-G assay, T-cells in individuals with TB infection become sensitized to ESAT-6 or CFP10 in vivo and when the T-cells re-encounter these antigens, ex vivo interferon (IFN-γ)-gamma cytokine is released. With the T-Spot.TB the washed and counted peripheral blood mononuclear cells (PBMCs) are seeded into four microtiter wells where they are exposed to phytohemagglutinin, a mitotic stimulator indicating cell functionality (positive control), a nil control, and two separate panels of TB specific antigens. IFN-γ specific antibodies in the base of the well attach to secreted IFN-γ and are then detected with a second antibody linked to a color detection agent. Each dark spot obtained in the base of the well provides a measure of the abundance of TB sensitive effector T-cells in the peripheral blood. The T-Spot TB assay requires WBC separation which, although more technically complex, allows for a fixed number of WBCs in the assay which is important in the immunosuppressed population.15 For this article, any of the currently available IFN-γ assays (QFT-G, QFT-G IT, or T-Spot TB) will be collectively referred to TIGRA’s (Tuberculosis specific Interferon Gamma Release Assay) when data can be used interchangeably. When a specific assay is noted, the test utilized will be identified.
Comparison and Utility of Tests
Each of the tests (TST and TIGRA) relies on a different immune response and differs in its relative measures of sensitivity and specificity. The TST assesses in vivo delayed-type hypersensitivity (Type IV), whereas TIGRA’s measure in vitro release of IFN-γ. The TST measures response to PPD, a polyvalent antigenic mixture, whereas TIGRA’s measure response to a mixture of synthetic peptides simulating two specific antigenic proteins present in M. tuberculosis. TIGRAs are not affected by prior BCG vaccination and are expected to be less influenced by previous infection with NTM. For the TST, not all infected persons will have a delayed hypersensitivity reaction to a tuberculin test. A large number of factors has been reported to cause a decreased ability to respond to the tuberculin test in the presence of tuberculous infection Northeast Florida Medicine Vol. 61, No. 3 2010 25
including viral infection (measles, mumps, chickenpox and HIV), live virus vaccinations( measles, mumps, rubella, oral polio and yellow fever), overwhelming tuberculosis, other bacterial infections, drugs (corticosteroids and many other immunosuppressive agents), and malignancy.16,17 In a 2008 a systematic review by Madhukar et al identified 22 studies of QFT-G (1369 participants), 13 studies of TSpotTB (726 participants) of mostly adult HIV-negative culture positive cases for TB. The pooled sensitivity for the QFT-G studies was 76% (95% CI, 72% to 80%) and for TSpotTB 90% (CI, 86% to 93%). In head-to-head comparisons between QFT-G and TSpotTB, the TSpot TB had higher sensitivity than the QFT-G, with differences ranging from 3% to 25%.18 The overall consensus is that TIGRA tests have a higher diagnostic sensitivity than the TST in active tuberculosis ranging from 83 to 97% for TB-Spot and 70 to 89% sensitivity for QTF-G. 19-22 But like the TST, a “positive” result for the TIGRA signifies infection and one cannot tell active TB from LTBI. The real utility of TIGRAs may be in identification of LTBI. However, the limitation in using either the TST or TIGRAs is the lack of a “gold standard” when evaluating individuals with TB infection or culture negative TB disease, and this has lead most investigators to use surrogate markers, risk factors (i.e. known exposure to active infectious case or endemic area) or comparison with the TST, for evaluation of these tests in LTBI. When using risk factors in low-endemic regions, there is a higher TIGRAs positivity then with TST.23 When these tests were evaluated during contact investigation, both tests were more sensitive and specific than the TST.24-27 The performance of the TIGRAs in non-immunosuppressed population allowed the approval of these tests and the recommendations for their use in evaluating selected groups.
Performance in Immunosuppressed Persons
An unknown limitation is that the TST and any newer tests might not perform the same for detecting LTBI as they do for detecting M. tuberculosis infection during TB disease. For example, reduction of in vivo IFN-γ release has been attributed to suppressive cytokines associated with TB disease. There is also a suggestion that genetically distinct M. tuberculosis strains invoke different immune responses in the development of human tuberculosis. Rakotosaminmanana, et al evaluated antigen-specific IFN-γ production responses in PBMC from two cohorts in Madagascar in 2004-2006; noting that “modern” M. tuberculosis strains like Beijing and Central Asian (CAS) tended to give lower IFN-γ responses than “ancient” strains like the East African Indian (EAI).28 The majority strain in the United States is the Beijing strain. The performance of TIGRAs, in particular its sensitivity and rate of indeterminate results, is still being determined in persons who are at risk in developing active TB because of impaired immune function. Recognized risk factors for the development of active TB are impaired immune function caused by HIV infection or acquired immunodeficiency syndrome (AIDS), current treatment with immunosuppressive drugs including 26 Vol. 61, No. 3 2010 Northeast Florida Medicine
high-dose corticosteroids, tumor necrosis factor-alpha (TNF-α) antagonists, and drugs used for managing organ transplantation, selected hematologic disorders (e.g., myeloproliferative disorders, leukemias, and lymphomas); specific malignancies (e.g., carcinoma of the head, neck, or lung), diabetes, silicosis, and chronic renal failure. These conditions or treatments are known or suspected to decrease responsiveness to the TST, and they also might decrease production of IFN-γ in the TIGRA’s.29 As a result, like a “negative” TST, a negative or indeterminate result in the IFN-γ assays may not accurately reflect M. tuberculosis infection in these immunosuppressed conditions. TIGRAs rely on functional CD4 T cells and their performance might be negatively influenced by low or impaired CD4 cell counts in HIV-infected individuals providing either false-negative or indeterminate results. Hoffman and Ravn reviewed eight published studies evaluating the sensitivity of QFT-G in HIV-positive individuals with active TB, and they reported a sensitivity of 79 % (95% CI 73.5-83.5) but when the 16.5% of indeterminate results were included, the sensitivity fell to 66% (95% CI 60-17).28 In another evaluation of the T-Spot.TB in four published studies, they found a similar sensitivity when compared to QFT-G of 80.5 (95% CI 69.5-88) with the 9.5% indeterminate results yielding 72% (95% CI 60-81.5). When these same authors reviewed those studies that compared TST results in the same studies with either QFT-G or T-Spot TB, they found a sensitivity of TST to be 43% (95% CI 37-49.5). Possible explanations for the differences between TIGRAs and TST in known active TB cases in HIV-infected individuals is the type of response to each test that is evoked (i.e. a type IV delayed hypersensitivity response in TST compared to response of circulating T cells in IGRAs tests).30 Three studies that compared the TIGRAs sensitivity in HIV-infected and uninfected patients found a lower sensitivity in HIV-positive patients with active TB.21,22,31 In HIV-co-infected individuals it would appear a higher sensitivity of TIGRAs compared with the TST, but TIGRAs sensitivity remains impaired compared to healthy controls.30 In multivariate analysis, a CD4 count < 200/ ml was associated with indeterminate QFT-G and TSPOT results (OR=3.4, 95% CI 1.5-7.7 and OR=3.9, 95% CI 1.8-8.1, respectively.) Some studies indicated that not only the absolute CD4 cell number is important for test accuracy but also the nadir CD4 cell counts.32,33,34 Aichelburg et al reported a significant association between nadir CD4 cell counts and the rate of indeterminate OFT-G IT results.33 Unlike the TST, TIGRAs appear relatively robust to HIV co-infection in people with relatively high CD4 counts, with a trend toward more positive results by TSpot.TB.30 The risk of pulmonary tuberculosis (TB) in rheumatoid arthritis (RA) patients is increased fourfold compared with the general population.35 RA patients treated with tumor necrosis factor (TNF) inhibitors are at higher risk of TB infection than those not so treated. Tuberculosis developed in 14 (0.3%) of 5,000 RA patients in a Japanese post-marketing survey www . DCMS online . org
of infliximab.36 The CDC has recommended evaluation for tuberculosis exposure prior to use of anti-TNF inhibitors.37 In a Japanese cohort, QFT-G testing has been assessed in 118 active pulmonary TB patients with culture-confirmed M. tuberculosis compared with 216 BCG-vaccinated adults with no identified risk for TB. With a cutoff level set at 0.35 IU/ml, the commonly used positive cutoff value, the sensitivity was 89.0% and the specificity was 98.1% for patients with active TB, whereas setting a 0.1 IU/ml cutoff (the lowest level of the intermediate range) resulted in a sensitivity and specificity of 95.8% and 92.0%, respectively. A study by Maeda, T. et al in 2009 aimed at evaluating the sensitivity and specificity of QFT-G in Japanese rheumatoid arthritis patients with a past history of tuberculosis, recommended the use of a cutoff value of 0.1 IU/ml.35 Use of the lower cutoff increased positive QFT-G results from 13.6% to 27.3% in those with a past history of tuberculosis. Children are also in this category of unclear performance characteristics of TIGRAs in the determination of LTBI. There was noted in the retrospective study by Haustein et al that 35% of the study population of 237 children had indeterminate test results with QFT-G with an over representation of indeterminate results in children less than 5 years of age and those with immunodeficiencies. 38 These groups represent children most at risk for disease progression after TB exposure. In young children, TSpotTB appears to have a higher sensitivity than the TST, while QFT-G may have lower sensitivity than the TST. In a 2010 study by Lucas et al evaluated TIGRAs in humanitarian entrants settling in Western Australia.39 At least 524 African and ethnic Burmese children, of which 107 under 3 years of age, were prospectively enrolled in a comparison of the TSpotTB and QFT-GIT. Both tests demonstrated similar rates of positivity in this setting (8% TSpotTb and 10%QFT-IT) but both had significant failure rates (15% of OFT-GIT inclusive result and 14% of TSpotTb results were inclusive). An inadequate T cell response to the mitogen was the predominant reason for QFTGIT indeterminacy while the most common cause of an inconclusive result for the TSpotTB test was failure to isolate sufficient PBMCs. The growing list of data existing on reliability of TIGRAs in immunocompromised patients show that the prevalence of indeterminate results may vary depending on the degree of immunosuppression and the TIGRA test used.40,41 In addition, phytohemagglutinin (PHA) and recall antigens use different IFN-Îł secretion pathways, which may be differentially affected by immunosuppressive conditions.39,42,43 In a study by Lange et al evaluating the indeterminate results obtained in a cohort of immunocompromised patients using QFT-G-IT demonstrated that an indeterminate test result was significantly higher than the control group (similar to previous studies) and that the results differed depending of the disease group.43 Patients with autoimmune diseases had higher percentage of indeterminate results than organ transplant, 7 of 12 systemic lupus erythematosis (SLE) patients www . DCMS online . org
demonstrated indeterminate results and high indeterminate results were noted in stem cell transplant patients. Also noted were higher indeterminate results in females than in males being most pronounced in patients with autoimmune diseases. In their conclusion, different disease states are an independent risk of indeterminate results using QFT-G-IT. A comparison in these groups with T-Spot TB has not been evaluated and may not produce similar results.
Study Conclusions
The conclusions from the published studies to date are that TIGRA test is not confounded by BCG vaccination and are therefore more specific than the TST. TIGRAs are more sensitive than the TST in active tuberculosis, with T.Spot.TB having higher sensitivity than QFT-G. In LTBI, T-Spot.TB probably has higher sensitivity than the TST, while QFT-G seems to have similar sensitivity to the TST. Indeterminate results are common with QFT-G and are strongly associated with immunosuppression, young age, and old age, while indeterminate results with TSpot.TB are rare in all risk groups studied to date.30,40 The impact of treatment on blood test results has been studied for TSpot.TB in tuberculosis patients and in persons with LTBI. In general, the TSpot.TB responses decline with treatment in both active tuberculosis and LTBI. This raises the possibility of using this test to monitor treatment response especially in LTBI therapy, for which no parameters exist to determine treatment success, as a â&#x20AC;&#x153;test of cureâ&#x20AC;?. However, due to the interindividual variation in the rate of decline and that only a minority of individuals become negative after completing treatment, this test as a treatment monitor is limited.40 Interestingly, TSpot. TB values declined with therapy and may reflect dormant viable tubercle bacilli which may progress to active TB. This prompts a concern if the duration of therapy or mediations used to treat TB and/or LTBI be modified to insure a negative TSpot.TB result.
Guidelines and Highlights
General recommendations on the use of TIGRA as part of the infection control program in health-care settings have been included in the most recent revision of the TB infection control guidelines. The CDC recommends the use of QFG in all circumstances in which TST has formerly been used and recently released guidelines for using interferon gamma release assays have just become available.44 European guidelines advise that TIGRAs should be used to confirm the diagnosis of LTBI and as a direct replacement for the TST in persons with suppressed cellular immunity.44 In countries with established market economies, tuberculin skin testing is still the most frequently used TB test due to the relatively lower rates of TB and higher priority of detection and treatment of latent TB in those settings compared to the remaining areas of the world with prioritization to treatment of active cases. The result and its interpretation regardless of the test used for a diagnosis of LTBI requires that TB disease be excluded by medical evaluation, including checking for suggestive symptoms and signs, a chest radiograph, and, when indicated, Northeast Florida Medicine Vol. 61, No. 3 2010 27
examination of sputum or other clinical samples for the presence of M. tuberculosis. A positive TIGRA result should prompt the same public health and medical interventions as a positive TST result. As with a negative TST result, negative TIGRA results should not be used alone to exclude M. tuberculosis infection in persons with symptoms or signs suggestive of TB disease. TIGRA assay usually can be used in place of (and not in addition to) the TST. In situations with serial testing for M. tuberculosis infection, initial two-step testing, which is necessary with the TST, is unnecessary with QFT-G and is not recommended. 45 The majority of healthy adults who have negative TIGRA results are unlikely to have M. tuberculosis infection and do not require further evaluation and no reason exists to follow a positive TIGRA result with a TST. However, for persons with recent contact with persons who have infectious TB, negative TIGRA results should be confirmed with a repeat test performed 8-10 weeks after the end of exposure, as is recommended for a negative TST result. Studies to determine the best time to retest contacts with negative TIGRA results have not been reported. Until more information is available, the timing of TIGRA testing should be the same as that used for the TST . When “window period” prophylaxis (i.e., treatment for presumed LTBI) is indicated for contacts aged <5 years or severely immunocompromised persons who are exposed to highly contagious TB, repeat testing for LTBI is recommended 8-10 weeks after contact has ended. A full course of treatment should be considered even with a negative result from either test at the end of the window period when the rate of M. tuberculosis transmission to other contacts was high or when a false-negative result is suspected because of a medical condition. An indeterminate TIGRA result does not provide useful information regarding the likelihood of M. tuberculosis infection. The options are to repeat TIGRA with a newly obtained blood specimen, administer a TST, or do neither. For persons with an increased likelihood of M. tuberculosis infection who have an indeterminate TIGRA result, administration of a second test, either TIGRA or TST, might be prudent. For persons who are unlikely to have M. tuberculosis infection, no further tests are necessary after an indeterminate TIGRA result. The TIGRAs add a useful tool in the developed counties armamentarium toward TB control and elimination, but is not likely to replace the TST especially in limited resource areas of the world. The PPD has been an invaluable asset since it development and continues its usefulness to this day. 1.
References
American Thoracic Society, CDC. Diagnostic standards and classification of tuberculosis in adults and children. Am J Rspir Crit Care Med 2000;161:1376-95.
2.
Thomas, TM and Janicki, BW. Mycobacterial antigens: a review of their isolation, chemistry, and immunological properties. Microbiol Reviews. 1978; 42:84-113.
3.
Edwards P.Q. and Edwards L.B. Story of the tuberculin test. American Review of Respiratory Diseases 1960; 81:1-49.
28 Vol. 61, No. 3 2010 Northeast Florida Medicine
4.
Hsu, KHK. Contact investigation: a practical approach to tuberculosis eradication. Am. J. Pub Health 1963;53:1761-9.
5.
CDC.CDC Guidelines for the investigation of contacts of persons with infectious tuberculosis: national tuberculosis controllers association and CDC. MMWR 2005;54(RR15);1-37.
6.
CDC. CDC Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR 2000;49(RR6); 1-54.
7.
Seibert F.B. The isolation and properties of the purified protein derivative of tuberculin. American Review of Tuberculosis 1934; 30:713.
8.
Seibert F.B. and Glenn J.T. Tuberculin purified protein derivative: preparation and analyses of a large quantity for standard. American Review of Tuberculosis 1941; 44:9.
9.
Global tuberculosis control. WHO report 2009. (WHO/ HTM/TB/2009.411).
10. Global tuberculosis control: WHO report 2008. WHO/HTM/ TB/2008.393. 11. CDC. Screening for Tuberculosis and Tuberculosis Infection in High-Risk Populations Recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR Recommendations and Reports, September 08, 1995 / 44(RR11);18-34 12. CDC. Reported tuberculosis in the United States, 2008. Atlanta, GA.U.S. Publication year 2009; 1-131. 13. Mazurek, GH and Villarino, ME. CDC. Guidelines for using the Quantiferon-TB test for diagnosing Mycobacterium tuberculosis infection. MMWR 2003;52 (No. RR-2)15-8. 14. Mazurek, GH, Jereb, J, LoBue, P. Guidelines for Using the QuantiFERON®-TB Gold Test for Detecting Mycobacterium tuberculosis Infection, United States December 16, 2005 / 54(RR15);49-55. 15. Food and Drug Administration. T-spot.TB-P070006. http://www.fda.gov/MedicalDevices/ProductsandMedical Procedures/DeviceApprovalsandClearances/PMAApproval/ ucm102794.htm. Accessed July 2010. 16. Mori T, Shiozawa K. Suppression of tuberculin hypersensitivity caused by rubella infection. Am Rev Respir Dis 1985;886-890. 17. Brickman HF, Beaudry, PH and Marks, MI. The Timing of Tuberculin Tests in Relation to Immunization With Live Viral Vaccines Pediatrics: 1975;55:392-396. 18. Madhukar, P, Zwerling, P, and Menzies, D. Systematic Review: T-Cell–based Assays for the Diagnosis of Latent Tuberculosis Infection: An Update. Ann Int Med. 2008;149:177-184. 19. Lalvani, A, Pathan, AA, McShane, H, et al. Rapid detection of Mycobacterium tuberculosis infection by enumeration of antigen-specific T cells. Am J Respir Crit Care Med 2001;163:824-828. 20. Pathan, AA, Wilkinson, KA, Klenermanet, P, et al. Direct Ex Vivo Analysis of Antigen-Specific IFN-γ. J Immunol 2001; 167:5217-5225. 21. Ferrara, G, Losi, M, D’Amico, R, et al. Use in routine clinical practice of two commercial blood tests for diagnosis of infection with Mycobacterium tuberculosis: a prospective study. Lancet 2006; 367:1328-1334. 22. Lee, J.Y, Choi, HJ, Park, I-N, et al. Comparison of two commercial interferon-gamma assays for diagnosing Mycobacterium tuberculosis infection. Eur Respir J 2006; 28:24-30.
www . DCMS online . org
23. Bienek, DR and Chang, CK. Evaluation of an interferon-gamma release assay, T-spot.TB, in a population with a low prevalence of tuberculosis. Int J Tuberc Lung Dis 13(1):1416-1421. 24. Ewer, K, Deeks, J, Alvarez, L, et al. Comparison of T-cell-based assay with tuberculin skin test for diagnosis of Mycobacterium tuberculosis infection in a school tuberculosis outbreak. Lancet 2003; 361:1168-1173. 25. Richeldi, L, Ewer, K, Losi, M, et al. T cell-based tracking of multidrug resistant tuberculosis infection after brief exposure. Am J Respir Crit Care Med 2004; 170:288-295. 26. Shams, H, Weis, S.E., Klucar, P, et al. Enzyme-linked immunosport and tuberculin skin testing to detect latent uberculosis infection. Am J Respir Crit Care Med 2005; 172:1161-1168. 27. Palazzo, R, Spensieri, F, Massari, M, et al. Use of whole-blood samples in in-house bulk and single-cell antigen-specific gamma interferon assays for surveillance of Mycobacterium tuberculosis infections. Clin Vaccine Immuno, 2008;15(2):327-37 28. Hoffmann, M and Ravn, P. The use of interferon-gamma release assay in HIV-infected individuals. Euro Infect Dis, 2010;4(1):23-9 29. Richeldi, L, Losi, M, D’Amico, R., et al. Performance of tests for latent tuberculosis in different groups of immunocompromised patents. Chest 2009; 136:198-204. 30. Goletti, D, Carrara, S, Vincenti, D, et al. Accuracy of an immune diagnostic assay based on RD1 selected epitopes for active tuberculosis in a clinical setting: a pilot study. Clin Microbiol Infect 2006; 12:544-550. 31. Lalvani, A. Diagnosing Tuberculosis Infection in the 21st Century: New Tools To Tackle an Old Enemy. Chest 2007; 131:1898-1906. 32. Jones S, de Gijsel, D, Wallach, FR, et al. Utility of quantiferonTB gold in-tube testing for latent TB infection in HIV-infected individuals. Int J Tuberc Lung Dis, 2007; 11:1900-95. 33. Aichelburg, MC, Rieger, A, Breitenecker, F, et al. Detection and prediction of active tuberculosis disease by a whole-blood interferon-gamma release assay in HIV-1-infected individuals. Clin Infect Dis, 2009; 48:954-62. 34. Rangaka, MX, Wilinson, KA, Seldon, R, et al. Effect of HIV-1 infection on T-cell-based and skin test detection of tuberculosis infection. Am J Resp Crit Care Med, 2007; 175:514-20. 35. Maeda T, Banno, S, Maeda, S. Usefulness and limitations of quantiferon-TB gold in Japanese rheumatoid arthritis patients: proposal to decrease the lower cutoff level for assessing latent tuberculosis infection. Mod rheumatol. 2010; 20:18-23. 36. Takeuchi, T, Tatsuki, Y, Nogami, Y, et al. Postmarketing surveillance of the safety profile of infliximab in 5000 Japanese patients with rheumatoid arthritis Ann Rheum Dis. 2008; 67:189-94. 37. Tuberculosis Associated with Blocking Agents Against Tumor Necrosis Factor-Alpha-California, 2002-2003. CDC. MMWR 2004/53(30);683-686. 38. Haustein, T, Ridout, DA.; Hartley, JC, et al. The likelihood of an indeterminate test result from a whole-blood interferon-gamma release assay for the diagnosis of Mycobacterium tuberculosis infection in children correlates with age and immune status. Pediatr Infect Dis J 2009; 28(8):669-73.
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TST Pediatric Perspective Ana M. Alvarez, MD There is enough published literature to suggest that Interferon Gamma Release Assays (IGRAs) perform as well in children older than 5 years as in adults. However, several limitations exist to their use in younger children, being the insufficient number of published studies in this specific population the most important one. Most of the literature is on adult populations with some studies including children in much lower numbers. Additionally, the reported number of indeterminate results in the pediatric population has a wide variation, but it has been as high as 35%. This has been attributed to a low mitogen response in young children, and it is probably related to immunologic immaturity1, 2. The American Academy of Pediatrics published recommendations regarding the use of IGRAs in children in 20093. For immune-competent children 5 years of age or older, IGRAs can be used in place of Tuberculin Skin Test (TST). However, these tests are NOT recommended in children younger than 5 years of age or immunocompromised children. Because this population is at high risk of progression and worse outcomes, some experts have recommended using both tests in these children and to interpret a positive result from either test as evidence of infection1,4,5. This practice has economical and practical limitations. The TST continues to be the preferred test for young children.
References
1.
Haustein T, Ridout DA, Hartley JC, et al. The likelihood of an indeterminate test result from a whole-blood interferon-γ release assay for the diagnosis of Mycobacterium tuberculosis infection in children correlates with age and immune status. Pediatr Infect Dis J 2009;28:669-673.
2.
Connell TG, Tebruegge M, Ritz N, et al. Indeterminate interferon-γ release assay results in children. Pediatr Infect Dis J 2010;29:285-286.
3.
American Academy of Pediatrics. Tuberculosis. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL; 2009:680701.
4.
Bamford AR, Crook AM, Clark JE, et al. Comparison of interferon-γrelease assays and tuberculin skin test in predicting active tuberculosis (TB) in children in the UK: a paediatric TB network study. Arch Dis Child 2010;95:180-186.
5.
CDC. Updated guidelines for using interferon-γ release assays to detect Mycobacterium tuberculosis infection – United States, 2010. MMWR 2010;59:(No. RR-5):1-25.
Address Correspondence to: Ana M. Alvarez, MD, Associate Professor of Pediatrics, Pediatric Infectious Diseases and Immunology,University of Florida\Jacksonville, Email: Ana. alvarez@jax.ufl.edu
Northeast Florida Medicine Vol. 61, No. 3 2010 29
39. Lucas, M, Nicol, P, McKinnon, E, et al. A prospective large-scale study of methods for the detection of latent Mycobacterium tuberculosis infection in refugee children. Thorax 2010; 65: 442-448. 40. Connell, TG, Curtis, N, Ranganathan, SC, et al. Performance of a whole blood interferon gamma assay for detecting latent infection with Mycobacterium tuberculosis in children. Thorax 2006; 61:616-620. 41. Elzi, L, Scheger, M, Weber, R, et al. Reducing tuberculosis incidence by tuberculin skin testing, preventive treatment, and antiretroviral therapy in an area of low tuberculosis transmission. Clin Infect Dis 2007; 44:94-102. 42. Stephan C, Wolf, T, Goetsch, U, et al. Comparing quantiferontuberculosis gold, T-spot tuberculosis and tuberculin skin test in HIV-infected individuals from a low prevalence tuberculosis country. AIDS, 2008; 22(18):2471-9. 43. Lange B, Vavra, M, Kern, WV, et al.. Indeterminate results of a tuberculosis-specific interferon-gamma release assay in immunocompromised patients. Eur Respir J 2010; 35:11791182. 44. Mazurek, GH, Jereb, J, Vernon, A, et al. Updated Guidelines for Using Interferon Gamma Release Assays to Detect Mycobacterium tuberculosis Infection — United States, 2010. MMWR 2010;59 (No. RR-5). 45. National Collaborating Centre for Chronic Conditions. Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. 2006; Royal College of Physicians, London. pp. 27-50.
Recognize This Person?
It is Dr. Michael Bernhardt, a DCMS past president and also an underwater photographer. He took the cover photo for this issue when he was in the Grand Cayman Islands. Dr. Bernhardt is a self-confessed “diveaholic.” He has recently been diving in the Gulf of Mexico near Destin, FL (no problems with oil), and he is planning a trip to New Zealand where he will dive at Goat Island and Poor Knights Marine Preserve. Also on that trip he is planning a shark cage dive and a 12 mile hike over a volcanic plain. 30 Vol. 61, No. 3 2010 Northeast Florida Medicine
National Auto Lease (NAL) would like to thank the Duval County Medical Society for endorsing our vehicle lease and purchase plan. NAL has been serving DCMS members and their families since 1998. While providing professional and courteous service, NAL will save you time and money on your vehicle purchase. Remember, we work with all makes and models, new or used and have leasing or financing options. Now to serve DCMS members even better, we have a new location at 2021 Mayport Road under the name of Sabiston McCabe Auto Solutions. It has plenty of quality used cars, trucks and sport utilities vehicles and offers the same service, great prices and friendly assistance...just a different name.
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Community Associated Methicillin Resistant Staphylococcus Aureus: An Update Nilmarie Guzman, MD Abstract: Community associated methicillin resistant Staphylococcus aureus (CA-MRSA) has been identified for over a decade in previously healthy individuals with no recognized risk factors. It has been recognized in countries around the globe and associated with significant morbidity and mortality. Infections range between mild skin and soft tissue infections to necrotizing pneumonia, endocarditis and osteomyelitis. The rapid spread of this organism in particular populations and evidence of epidemics in several countries suggests that CA-MRSA strains are more virulent than hospital associated strains. Further research has provided invaluable information to understand the emergence, molecular characteristics, diagnostic tools and appropriate treatment options for patients infected with CA-MRSA. Controversy still remains in regards to treatment of choice and ideal prevention strategies. This article intends to present an overview of the epidemiology, pathogenesis and molecular characteristics associated with CA-MRSA as well as recommend treatment and prevention modalities.
Introduction
Staphylococcus(S.) aureus is a well recognized human pathogen of worldwide distribution. It is a commensal organism and a leading cause of bacterial infections. For over 50 years this organism has shown a significant ability to develop resistance shortly after exposure to antibiotics. Only ten years after Benzylpenicillin was commercially available, it was no longer effective against S. aureus. In 1961, the first methicillin resistant S. aureus isolates were identified, just 2 years after methicillin was commercially available.1 The following four decades the organism spread worldwide. At the beginning of the epidemic, infections with MRSA were associated with exposure to health-care facilities. Individuals considered at high risk for MRSA acquisition included those with a recent hospitalization, hemodialysis, illicit drug use or contact with a person diagnosed with MRSA infection.2 During the mid 1990s, isolates of MRSA were identified from otherwise healthy individuals in the community without prior exposure to the healthcare system. Further evaluation elucidated that MRSA strains acquired in the community differ from hospital associated strains in epidemiology, nature of infection, and molecular characteristics. Strains were denominated community-associated MRSA or CA-MRSA. CA-MRSA is now prevalent and associated with significant mortality and morbidity rates.
Epidemiology
CA-MRSA S. aureus has been defined as MRSA infection in a patient without a prior history of hospitalization, dialysis, Address Correspondence to: Nilmarie Guzman, MD, Assistant Professor, Department of Internal Medicine, University of Florida, Jacksonville, Florida. Email: nilmarie.guzman@jax.ufl.edu.
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long term care residence in the prior 6-12 months before disease onset, absence of an indwelling line, and a culture obtained less than 48 hours after admission.3 Between 1997-1999, four healthy children in the upper Midwestern region of the U.S. died from sepsis or necrotizing pneumonia secondary to MRSA. Analysis of the outbreak concluded that the etiologic agent was CA-MRSA, also known as MW2. MW2 and other closely related strains, collectively known as pulse-filled type USA400, multilocus sequence type 1 strains were the most prominent community-associated strains in the U.S. before 2001.4,5 In addition, in 2001- 2002, a significant increase was noted in CA-MRSA related skin infections especially among pediatric patients from three different areas including Atlanta, Baltimore and Minnesota.6 Subsequently, other outbreaks were identified involving sports participants, military personnel and prisoners.7-9 In 2003 an alarming increase in CA-MRSA isolates in a childrenâ&#x20AC;&#x2122;s hospital in Corpus Christi, Texas was reported from 1999-2003. In 2003 MRSA accounted for 98% of S. aureus isolates in that institution.10 Further investigation has transpired that CA-MRSA is now an epidemic in North America, mainly in the U.S. Countries such as Australia, New Zealand, United States, UK, France, Finland and Canada were the first ones to report cases of CA-MRSA. A new CA-MRSA clone known as USA300; a strain unrelated to MW2/ST1 was identified in most cases in the U.S., revealing a rapid replacement of USA 400 in most areas. USA300 is now the most common cause of community associated bacterial infections in the U.S.11-14 Cases of CAMRSA have been reported around the globe. During the past 15 years, infections secondary to this organism have become widespread. Surveillance reports have demonstrated that this organism is easily transmissible in the community by close contact even to otherwise healthy individuals. Approximately 30% of individuals without exposure to healthcare facilities are colonized with S. aureus in the nostrils.15 Populations at high risk for CA-MRSA acquisition include household contacts, day-care centers, athletes involved in contact sports, prisoners, native Americans, pacific islanders, children (<2yrs), men who have sex with men, soldiers, individuals with prior MRSA infection and intravenous drug users. Overcrowded setting also represents a risk.16-19 The Centers for Disease Control and Prevention (CDC) in Atlanta have proposed five Câ&#x20AC;&#x2122;s or factors of MRSA transmission: Crowding, frequent skin to skin Contact, Compromised skin integrity, Contaminated items and surfaces, and lack of Cleanliness.20 Northeast Florida Medicine Vol. 61, No. 3 2010 31
Genetics of CA-MRSA
By definition methicillin resistant S. aureus refers to isolates that are resistant to β-lactam antibiotics. S. aureus resistance arises at the mecA gene which encodes for altered penicillinbinding protein (PBPa). MecA gene is located within the Staphylococcal chromosomal cassette (SCCmec). Strains of CA-MRSA contain SCCmectype IV and HA-MRSA strains harbor SCC mec types II and III. The difference in location of mecA gene explains the variation in antimicrobial susceptibility pattern in contrast to hospital associated strains.
Clinical Manifestations
CA-MRSA is associated with a broad spectrum of clinical manifestations. The burden of staphylococcal infections has increased worldwide since the emergence of CA-MRSA. Skin and soft tissue infections represent the majority of the cases, about 90%.21 Skin and soft tissue infections usually present as abscesses or cellulitis, however they can progress to necrotizing skin infections.22 Other clinical manifestations include endocarditis, septicemia, necrotizing pneumonia, septic thrombophlebitis with pulmonary embolization, septicemia with purpura fulminans, and bone and joint infections.23-28 The severity of CA-MRSA infection relies on host immune responses and the presence of virulence factors such as PantonValentine Lleukocidin (PVL) antigen and other toxins.
Virulence Factors
S. aureus has the ability of producing multiple factors that aim in pathogenesis and survival. It is capable of producing molecules that inhibit neutrophil recruitment and phagocytosis.29,30 Some of these molecules degrade and protect from neutrophil-derived reactive oxygen species and antimicrobial compounds. S. aureus evades killing by neutrophils and it has been shown that lysis of neutrophils occurs more rapidly after phagocytosis of CA-MRSA than HA-MRSA.31 S. aureus produces a variety of toxins that target human blood cells such as alfa-hemolysis(Hlα), delta, gamma, δ-hemolysin, γ-hemolysis, PVL and alfa-type phenol-soluble modulin (PSMα) peptides. PVL is a cytolytic toxin implicated as a S. aureus adherence molecule; it also forms pores in membranes of target leukocytes.32 Due to the ability of adhering to extracellular matrix proteins, PVL has been associated with development of necrotizing pneumonia.33 The presence of PVL has also been described in MSSA isolates. PVL positive CA-MRSA strains have been identified in multiple geographic areas with variable prevalence rates.34,35 Strains associated with skin and soft tissue infection in France from 2000-2003 was 1-3% compared to >50 % in U.S.14 Another key virulence factor is Alfa-hemolysin (H1α). Alfa-hemolysin has pore-forming activity toward lymphocytes, monocytes and erythrocytes.36 Expression of alfa-hemolysin is higher in USA 300 isolates.37 Research in murine models indicate that Hlα is a major virulence factor contributing to pneumonia and in light of its relatively high expression in USA 300 strains, it contributes to development of severe CA-MRSA infections.38-39 Recently, alfa-type phenol modulin 32 Vol. 61, No. 3 2010 Northeast Florida Medicine
peptides have been discovered in a search for virulence factors in USA 300 and USA 400 strains that allow high virulence. They have shown both in vivo and in vitro cytolytic effect in human neutrophils. PSMα peptides are produced at increased levels in CA-MRSA strains compared to HA-MRSA strains, which explains the enhanced virulence associated with this organism.40
Diagnosis
S. aureus can be diagnosed by isolating the organism from cultures of tissue, blood, pus or respiratory specimens. It will grow in any non-selective medium. If it is isolated from blood or other sterile site, the specificity is 100%. Antimicrobial susceptibility testing can be done with disc diffusion, broth dilution or automated methods. A latex agglutination test to identify PBP2a is also available.41 Molecular typing techniques have been incorporated to diagnostic testing in order to obtain a prompt diagnostic confirmation in addition to avoiding unnecessary antibiotics. Molecular typing techniques include toxin gene profiling, antimicrobial resistance typing, Pulse Filled Eletrophoresis, (PFGE) multilocus sequence typing, multilocus restriction fragment typing and amplified fragment length polymorphism analysis. Novel techniques used in the United States include PNA-FISH® or Peptide Nucleic Acid Fluorescence In Situ Hybridization and the GeneOhm® StaphSR assay, which is an FDA approved multiplex real time PCR assay. CA-MRSA/USA 300 strains are usually susceptible to cotrimoxazole, tetracyclines, and clindamycin, however this pattern is not uniform.42
Management
Multiple therapeutic options are available for management of MRSA infection either by the oral or parenteral route. Oral agents commonly recommended include clindamycin, tetracyclines, co-trimoxazole, rifampicin and fusidic acid.43-45 Clindamycin is active in vitro in 80% of the isolates and is also active against group A streptococcus. Since resistance is possible, isolates must be tested for clindamycin resistance, especially on isolates resistant to erythromycin. Doxycycline and minocycline are also highly effective in the management of skin and soft tissue infections, however they are contraindicated during pregnancy and children younger than 8-years-old. Co-trimoxazole is active against 90-100% of CA-MRSA isolates. Disadvantages include nephrotoxic potential and it is not recommended during third trimester of pregnancy. Rifampin is not recommended as a single agent since resistance emerges quickly. It must be used in combination with another anti-staphylococcal drug as adjunctive therapy. Linezolid is another drug approved for MRSA pneumonia and skin and soft tissue infections. It is expensive and associated with bone marrow toxicity particularly thrombocytopenia, development of peripheral neuropathy or optic neuritis. Patients taking serotonin uptake inhibitors concomitantly with linezolid are at risk of developing serotonin syndrome. Therefore, linezolid must be reserved for cases were other www . DCMS online . org
drugs are not recommended or contraindicated. Management of skin abscesses involves incision and drainage. For skin abscesses <5cm, incision and drainage usually suffices. In this scenario, antibiotics are recommended in the presence of multiple lesions, severely impaired host defenses, extensive surrounding cellulitis, or severe systemic manifestations of infection such as fever. Several intravenous antibiotics are available for the management of CA-MRSA. Vancomycin remains to be the first line agent recommended. Other agents approved are Daptomycin, linezolid, tygecycline and quinopristin-dalfopristin.46 Several investigational drugs are under study to evaluate their efficacy for the management CA-MRSA infections.They include telavancin, dalbavancin and oritavancin which are derivatives of vancomycin.47-48 They have not shown superiority compared to standard therapies in clinical trials.49 Telavancin has been approved for the management of skin and soft tissue infections. Anti-MRSA beta-lactams such as ceftobiprole and ceftaroline are under study. They have shown to be highly active in rabbit models of endocarditis.50
Prevention
Since the organism is transmitted by close contact, prevention is focused on proper hygiene. Hand washing with soap and water or waterless antibacterial gels is recommended for infected persons or individuals who get in direct contact with a patient. Open and draining wounds must be covered until they are healed. For those individuals who get recurrent MRSA infections, decolonization must be considered. This can be achieved with chlorhexidine. Mupirocin ointment is also recommended, however resistance has been reported. Management of CA-MRSA infections represent a challenge for clinicians mostly due to multidrug resistance and the organism’s ability to evade the immune system. Further research is needed with emphasis on novel prevention strategies and antibiotic options.
References
1.
Jevons MP. Celbenin-resistant staphylococci. BMJ.1961;1:124-125.
2.
Naimi TS, LeDEll Indivi, Como-Sabetti K, et al. Comparison of community and health-care associated methicillin resistant Staphylococcus aureus infection. JAMA. 2003; 290:2976-84.
3.
Centers for Disease Control and Prevention. Four pediatric deaths from community-acquired methicillin-resistant Staphylococcus aureus-Minnesota and North Dakota, 19971999 JAMA.1999; 282:1123–25.
4.
Stemper ME, Brady JM, Qutaishat SS, et al.Shift inStaphylococcus aureus clone linked to an infected tattoo. Emerg Infect Dis. 2006;12:1444-46.
5.
Fridkin SK, Hageman JC, Morrison M, et al. Methicillinresistant Staphylococcus aureus disease in three communities. N Engl J Med. 2005; 352:1436-44.
6.
Ellis MW, Hospenthal DR, Dooley DP, Gray PJ, Murray CK. Natural history of community acquired Methicillin resistant Staphylococcus aureus colonization and infection in soldiers. Clin Infec Dis.2004;39:971-9.
www . DCMS online . org
MRSA: Pediatric Point of View Nizar Maraqa, MD Children have particularly shouldered a big burden of illness caused by the emergence of the Methicillin Resistant Staphylococcus aureus (MRSA) pathogen in recent years.1 The tendency for children to be in close contact with each other, less mastery of proper hygiene, as well as their participation in sporting and other activities linked to the spread of the organism have contributed to Community Acquired MRSA (CA- MRSA) becoming the major cause of skin and soft tissue infections seen in pediatric patients.2 While the virulence of the organism, its pathogenicity, susceptibility to antimicrobial agents and response to therapy have been similar to what is seen in adult patients, certain issues are unique for the pediatric population. Although necrotizing pneumonia, osteoarticular infection, bacteremia and other invasive infections have been described, by far, skin abscesses have been the predominant presentation of CA-MRSA seen in children. The majority of these seem to resolve with spontaneous or surgical drainage, even without concomitant antibiotic therapy, especially when they are of smaller size (<= 5 cm in diameter) occurring in otherwise normal hosts.3,4 When antibiotics are to be prescribed, pediatric practitioners have valuable oral options such as clindamycin and co-trimoxazole (trimethoprim-sulfamethoxazole) available to them in liquid and pill formulations. Use of intravenous antibiotics for treating CA-MRSA in children is usually reserved for the severe or invasive infections. The intravenous antibiotic agents of first choice are similar to those used in adults, namely vancomycin and clindamycin. Fluoroquinolones, daptomycin and tigecycline are not yet approved for use in children. Further studies in children are required before we are able to use many of these and other investigational antibiotics in the fight against CA-MRSA. Hand washing and attention to hygiene remains crucial in combating the spread of CA-MRSA among children in the outpatient and inpatient settings. Decolonization protocols have had varying success in children as they have had in adults. Educating the public and healthcare force about CA-MRSA is crucial in limiting its spread. References
1.
Gerber JS, et al. “Trends in the incidence of methicillinresistant Staphylococcus aureus infection in children’s hospitals in the United States.” Clin Infect Dis. 2009;49(1):65-71.
2.
Kaplan S, Huten K, Gonzalez, B,et al. “Three-year surveillance of community-acquired Staphylococcus aureus infections in children.” Clin Infect Dis. 2005;40:1785-91.
3.
Lee M, Rios, A, Aten, F, et al. “Management and outcome of children with skin and soft tissue abscesses caused by community-acquired methicillin-resistent Staphylococcus aureus.” Pediatr Infect Dis J 2004;23:123-7.
4.
Marcinak J, Frank A. “Treatment of community-acquired methicillin-resistant Staphylococcus aureus in children.” Curr Opin Infect Dis. 2003; 16(3):265-9.
Address correspondence to Nizar Maraqa, MD, Assistant Professor of Pediatrics,Pediatric Infectious Diseases and Immunology, University of Florida, Jacksonville, Florida. Email: Nizar.Maraqa@ jax.ufl.edu.
Northeast Florida Medicine Vol. 61, No. 3 2010 33
7.
Aiello AE, Lowy FD, Wright LN, Larson EL. Methicillin resistant Staphylococcus aureus among US prisoners and military personnel: review and recommendations for future studies. Lancet Infect Dis. 2006;6:335-41.
8.
Kazakova SV, Hageman JC, Matava M, et al. A clone of methicillin resistance staphylococcus aureus among professional football players.N Engl J Med. 2005;352:468-75.
9.
Purcell, K, Fergie J. Epidemic of CA-MRSA infections: a 14 year study at dRiscoll Childrenâ&#x20AC;&#x2122;s hospital. Arch Pediatr Adolesc Med. 2005; 159:980.
10. McDougal LK, Steward CD, Killgore GE, et al. Pulsed-fi eld gel electrophoresis typing of oxacillin-resistant Staphylococcus aureus isolates from the United States: establishing a nationaldatabase. J Clin Microbiol. 2003; 41:5113-20. 11. Miller LG, Diep BA. Clinical practice: colonization, fomites, and virulence: rethinking the pathogenesis of communityassociated methicillin-resistant Staphylococcus aureus infection. Clin Infect Dis. 2008; 46:752-60. 12. Kennedy AD, Otto M, Braughton KR, et al. Epidemic communityassociated methicillin-resistant Staphylococcus aureus: recent clonal expansion and diversification. Proc Natl Acad Sci USA. 2008; 105:1327-32. 13. Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillinresistant S. aureus infections among patients in the emergency department. N Engl J Med. 2006; 355:666-74. 14. Gorwitz RJ, Kruszon-Moran D, McAllister SK, et al. Changes in the prevalence of nasal colonization with Staphylococcus aureus in the United States, 2001-2004. J Infect Dis. 2008; 197:1226-34. 15. Dietrich DW, Auld DB, Mermel LA.Community-acquired methicillin-resistant Staphylococcus aureus in southern New England children. Pediatrics. 2004;113(4):e347-e352. 16. Groom AV, Wolsey DH, Naimi TS, et al. Community-acquired methicillin-resistant Staphylococcus aureus in a rural American Indian community. JAMA. 2001;286:1201-5. 17. Castrodale LJ, Beller M, Gessner BD.Over-representation of Samoan/Pacific Islanders with methicillin-resistant Staphylococcus aureus (MRSA) infections at a large family practice clinic in Anchorage, Alaska, 1996-2000. Alaska Med. 2004;46:88-91. 18. Young DM, Harris HW, Charlebois ED, et al. An epidemic of methicillin-resistantStaphylococcus aureus soft tissue infections among medically underserved patients. Arch Surg. 2004;139:947-53. 19. Centers for Disease Control. www.cdc.gov/niosh/topics/mrsa. Accessed August 2011. 20. Moran GJ. Prevalence of CA-MRSA is variable throughout the world. S. aureus infections among patients in the emergency department. N Engl J Med. 2006; 355:666-74. 21. DeLeo FR, Diep BA, Otto M: Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis caused by communityassociated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med. 2005;352:1445-53. 22. Arnold SR, Elias D, Buckingham SC, et al. Changing patterns of acute hematogenous osteomyelitis and septic arthritis: emergence of community-associated methicillin-resistant Staphylococcus aureus. J Pediatr Orthop. 2006; 26:703-08. 23. Buck JM, Como-Sabetti K, Harriman KH, et al. Community 34 Vol. 61, No. 3 2010 Northeast Florida Medicine
associated methicillin-resistant Staphylococcus aureus, Minnesota, 2000-2003. Emerg Infect Dis. 2005; 11: 1532-38. 24. Francis JS, Doherty MC, Lopatin U, et al. Severe communityonset pneumonia in healthy adults caused by methicillinresistant Staphylococcus aureus carrying the Panton-Valentine leukocidin genes. Clin Infect Dis. 2005; 40:100-07. 25. Gonzalez BE, Hulten KG, Dishop MK, et al. Pulmonary manifestations in children with invasive community-acquired Staphylococcus aureus infection. Clin Infect Dis. 2005; 41: 583-90. 26. Hageman JC, Uyeki TM, Francis JS, et al. Severe communityacquired pneumonia due to Staphylococcus aureus, 2003-04 infl uenza season. Emerg Infect Dis. 2006; 12:894-99. 27. Naimi TS, LeDell KH, Como-Sabetti K, et al. Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA. 2003; 290: 2976-84. 28. De Leo, FR.Host defense and pathogenesis in Staphylococcus aureus infections. Infect Dis Clin North Am. 2009, 23:1734.30. 29. Foster TJ: Immune evasion by staphylococci. Nat Rev Microbiol.2005; 3:948-958. 30. Voyich JM, Braughton KR, Sturdevant DE, Whitney AR, Said- Salim B, Porcella SF, Long RD, Dorward DW, Gardner DJ, Kreiswirth BN et al.: Insights into mechanisms used by Staphylococcus aureus to avoid destruction by human neutrophils. J Immunol. 2005; 175:3907-3919. 31. Tristan A, Benito Y, Montserret R, Boisset S, Dusserre E, Penin F, Ruggiero F, Etienne J, Lortat-Jacob H, Lina G et al.: The signalpeptide of Staphylococcus aureus Panton Valentineleukocidin LukS component mediates increased adhesion to heparan sulfates. PLoS ONE. 2009; 4:e5042. 32. de BS, Tristan A, Etienne J, Brousse N, Vandenesch F, Lina G:Staphylococcus aureus isolates associated with necrotizing pneumonia bind to basement membrane type I and IV collagens and laminin. J Infect Dis. 2004; 190:1506-1515. 33. Bhakdi S, Tranum-Jensen J: Alpha-toxin of Staphylococcus aureus. Microbiol Rev. 1991; 55:733-751. 34. Vandenesch F, Naimi T, Enright MC, et al. Community- acquired methicillin-resistant Staphylococcus aureus carrying PantonValentine leukocidin genes: worldwide emergence. Emerg Infect Dis. 2003;9:978-84. 35. Tristan A, Bes M, Meugnier H, et al. Global distribution of PantonValentine leukocidinâ&#x20AC;&#x201D;positive methicillin-resistant Staphylococcus aureus, 2006. Emerg Infect Dis, 2007; 13:594-600. 36. Li M, Diep BA, Villaruz AE, Braughton KR, Jiang X, DeLeo FR,Chambers HF, Lu Y, Otto M: Evolution of virulence in epidemic community-associated methicillinresistant Staphylococcus aureus. Proc Natl Acad Sci U S A. 2009;106:5883-5888. 37. Montgomery CP, Boyle-Vavra S, Adem PV, Lee JC, Husain AN, Clasen J, Daum RS: Comparison of virulence in communityassociated methicillin-resistant Staphylococcus aureus pulsotypes USA300 and USA400 in a rat model of pneumonia. J Infect Dis. 2008; 198:561-570. 38. Burlak C, Hammer CH, Robinson MA, Whitney AR, McGavin MJ, Kreiswirth BN, DeLeo FR: Global analysis of communityassociated methicillin-resistant Staphylococcus aureus exoproteins reveals molecules produced in vitro and during infection. Cell Microbiol. 2007; 9:1172-1190. www . DCMS online . org
39. Wang R, Braughton KR, Kretschmer D, Bach TH, Queck SY, Li M, Kennedy AD, Dorward DW, Klebanoff SJ, Peschel A et al.: Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA. Nat Med. 2007; 13:1510-1514. 40. Shore AC, Rossney AS, O’Connell B, et al. Detection of SCCmec-associated DNA Segments in multiresistant methicillinsusceptible Staphylococcus aureus (MSSA) and identifi cation of Staphylococcus epidermidis ccrAB4 in both methicillin-resistant S. aureus (MRSA) and MSSA. Antimicrob Agents Chemother. 2008; 52:4407-19. 41. Van Hal SJ, Stark D, Lockwood B, Marriott D, Harkness J. Methicillin-resistant Staphylococcus aureus (MRSA) detection: comparison of two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) with three selective MRSA Agars (MRSA ID, MRSASelect, and CHROMagar MRSA) for use with infection-control swabs. J Clin Microbiol. 2007; 45: 2486-90. 42. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005; 41: 373-406. 43. Nathwani D, Morgan M, Masterton RG, et al. Guidelines for UK practice for the diagnosis and management of methicillinresistant Staphylococcus aureus (MRSA) infections presenting in the community. J Antimicrob Chemother. 2008; 61:976-94. 44. Barton MD, Hawkes M, Moore D. Guidelines for the prevention and management of community-acquired methicillin-resistant Staphylococcus aureus: a perspective for Canadian health care practitioners. Can J Infect Dis Med Microbiol. 2006;17 (suppl C): 4C-24C. 45. Gorwitz RJ, Jernigan DB, Powers JH, Jernigan JA, and Participants in the Centers for Disease Control and PreventionConvened Experts’ Meeting on Management of MRSA in the Community. Strategies for clinical management of MRSA in the community: summary of an experts’ meeting convened by the Centers for Disease Control and Prevention. 2006. Available at http://www.cdc.gov/ncidod/dhqp/pdf/ar/CAMRSA_ExpMtgStrategies.pdf. Accessed August 2010. 46. Micek ST. Alternatives to vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections.Clin Infect Dis. 2007; 45 (Suppl 3): S184–S190. 47. Pan A, Lorenzotti S, Zoncada A. Registered and investigational drugs for the treatment of methicillin-resistant Staphylococcus aureus infection. Recent Patents Anti-Infect Drug Disc. 2008; 3:10-33. 48. Stryjewski ME, Chambers HF. Skin and soft-tissue infections caused by community-acquired methicillin-resistant Staphylococcus aureus. Clin Infect Dis. 2008; 46 (suppl 5): S368-S377. 49. Chambers HF. Evaluation of ceftobiprole in a rabbit model of aortic valve endocarditis due to methicillin-resistant and vancomycin-intermediate Staphylococcus aureus. Antimicrob Agents Chemother. 2005; 49:884-88. 50. Jacqueline C, Caillon J, Le M, et al. In vivo efficacy of ceftaroline (PPI-0903), a new broad-spectrum cephalosporin, compared with linezolid and vancomycin against methicillinresistant and vancomycin-intermediate Staphylococcus aureus in a rabbitendocarditis model. Antimicrob Agents Chemother. 2007; 51:3397-400.
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In the fight against breast cancer, birthdays are signs of progress – and we want to see more of them. You can help create a world with more birthdays by participating in Making Strides Against Breast Cancer, a noncompetitive walk to raise funds and awareness in support of the fight against breast cancer. Visit cancer.org/stridesonline to join us and help create more birthdays in your community. Together, we’ll stay well, get well, find cures, and fight back.
Saturday, October 16, 2010 Registration: 7:30 a.m. Walk Begins: 9:00 a.m.
Call today for more information about the August Kick Off
Downtown Jacksonville - San Marco Square Orange Park - Orange Park Kennel Club Jacksonville Beach - Sea Walk Pavilion For more information on this or the other events in the First Coast Area, please contact Brandy Robinson at 391-3607 or via email at brandy.robinson@cancer.org
© 2010 American Cancer Society, Inc.
Northeast Florida Medicine Vol. 61, No. 3 2010 35
MSABC_3.5x9.5_Jacksonville.indd 1
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Special Case Report
Breast Cancer and HIV in the Era of HAART: A Case Report and Review of the Literature Naeem Latif, MD; Fauzia Rana, MD; and Troy Guthrie, MD Editor’s Note: Due to production constraints, Figures 1-4 are not printed in the journal. They are available online at www.dcmsonline.org as a web illustration. Abstract: The incidence of human immunodeficiency virus (HIV)
infection is rising in U.S. women; however its impact on breast cancer incidence, stage at presentation, response and treatment toxicity remains unknown. To address the impact of HIV infection and the use of Highly Active Antiretroviral Therapy (HAART) on the natural history of breast cancer, we are presenting a case of breast cancer in an HIV infected women and reviewing the literature. A literature search was done through Medline by using key words HIV/AIDS, breast cancer and HAART therapy, restricted to English language. There are mostly case reports and only one large series of 20 cases reported by Hurley et al. Data concerning the impact of HIV infection and HAART therapy regarding pathogenesis, stage at presentation, tumor type, response and toxicity associated with treatment were reviewed. Patients with HIV infection present with more advanced stage and aggressive disease and have poor chemotherapy tolerance. A literature review suggests that the incidence of breast cancer is similar or lower in HIV infected patients compared to general population. The impact of HAART therapy on breast cancer incidence in HIV infected patients is still unclear.
Introduction
Breast cancer is the most commonly diagnosed malignancy and second leading cause of cancer related death among women in United States.1 The incidence of HIV infection in women is rising and it can result in suppression of immune system which increases the risk of malignancy.2, 3 The number of women living with AIDS is also increasing due to HAART therapy. Therefore, more women with HIV infection are at risk of developing breast cancer as the patient population gets older. The acquired immunodeficiency (AIDS) defining neoplasms are Kaposi’s sarcoma, non-Hodgkin lymphoma, and cervical cancer.4 There are malignancies which are more prevalent in AIDS patients than general population. They are called non-AIDS defining cancers (NADCs) such as Hodgkin’s lymphoma, squamous cell carcinoma of anus, liver cancer, head & neck and lung cancer.5,6,7 The data about breast cancer incidence and prognosis in HIV patients is limited and conflicting.8,9 Here we will discuss a case of breast cancer in an HIV infected patient and review the literature to see if there is any association between HIV infection and HAART therapy with regards to breast cancer stage at presentation, response and toxicity to treatment. Address correspondence to: Naeem Latif, MD, Fellow Hematology/Oncology, University of Florida, Jacksonville, FL, 655 W. 8th Street, 4 N, Pavilion, Jacksonville, FL 32209 Email: Naeem.latif@ jax.ufl.edu. 36 Vol. 61, No. 3 2010 Northeast Florida Medicine
Case Report
A 55-year-old African American female presented with a palpable left breast lump. Core needle biopsy of the mass showed poorly differentiated invasive ductal carcinoma. The tumor was estrogen and progesterone receptor positive, Her2 neu positive 3+ by IHC and one lymph node was also positive for metastasis with extra capsular extension. The patient underwent a lumpectomy and auxiliary lymph node dissection. She was started on adjuvant chemotherapy consisting of Doxorubicin and Cyclophosphamide, but with each chemotherapy cycle she developed febrile neutropenia and required hospitalization. After two cycles of chemotherapy, she declined to continue further treatment due to poor tolerance and was started on Aromatase inhibitor hormonal therapy. Six months later she presented with headache and confusion. An MRI of the brain showed 15 mm contrast enhancing right parietal lobe mass. (Figures 1 & 2, dcmsonline.org) The excision biopsy of the mass showed Toxoplasmosis with necrosis and micro calcification. (Figures 3 & 4, dcmsonline.org) Further workup revealed that the patient was HIV positive with high viral load and low CD4 count. The patient was started on HAART therapy for HIV infection and continued with hormonal therapy for the breast cancer. A few months later the patient developed a pericardial and pleural effusion, which was found to be malignant consistent with metastatic breast cancer. She was treated with Docetaxel, Carboplatin, and Trastuzumab with pegylated GCSF support. The patient had an excellent response to treatment with complete resolution of pericardial and pleural effusion without any episodes of febrile neutropenia.
Discussion
Individuals with HIV infection and Immunosuppression after allograft organ transplantation are at higher risk of developing non–AIDS-defining cancers (NADCs).9,10 However the data about breast cancer incidence in these immunosuppressed patients is limited and conflicting.3,7 Although all three AIDS-defining malignancies (Kaposi’s sarcoma, non-Hodgkin lymphoma, and cervical cancer) and many NADCs are associated with a viral pathogenesis, some do not have any known viral oncogenes, and the reasons for their increased incidence in immunosuppressed individuals is unclear.11,12 The degree of immune suppression is directly correlated with the risk of two of the AIDS-defining cancers (Kaposi’s sarcoma and non-Hodgkin’s lymphoma), where the risk increases with declining CD4 cell count.7,13,14,15 Recent data has shown that a low nadir CD4 cell count less than 200/µL was associated with increased incidence of anal, lung, liver , www . DCMS online . org
head & neck cancers and Hodgkinâ&#x20AC;&#x2122;s lymphoma.10,16 However, the association between the degree of immune suppression and the risk of NADCs, including breast cancer, is unclear. The breast cancer incidence in HIV patients is available through retrospective registry studies, and the limitations of these studies are inaccurate and incomplete reporting as well as under recognition of asymptomatic HIV infection in cancer patients.17 There are two large registry studies on cancer incidence in the HIV population. Analysis of the cancer incidence from 1993 to 2000 in a cohort of U.S. women living with and at risk for HIV infection revealed an incidence of 26 versus 4 cancers in HIV-infected women in comparison to the non-infected women, respectively. However, there were no cases of breast cancer in either cohort.17,18. In the second study, data from the AIDS-Cancer Match Registry Study was analyzed to determine the relative risk of developing cancer during a period extending from 60 months prior to the first AIDS-defining illness to 27 months after AIDS diagnosis. This study included 302,834 patients. The relative risk of developing breast cancer in the pre-AIDS infection time period was higher than in the post-AIDS time period and this difference was statistically significant.18 The overall risk of breast cancer in this group was similar to the known risk in the non-HIV population. Therefore, the increased incidence of breast cancer early in the course of HIV infection is most likely related to a heightened recognition of breast cancer at the time of HIV diagnosis due to the closer medical supervision. Reports from Africa and Western countries suggested that immune suppression was protective against the development of breast cancer.19-23 A statistically significant decrease in the incidence of breast cancer during the AIDS epidemic from Tanzania and Italy has been reported.9,24 A possible explanation for this decrease is the high mortality rate in women with HIV infection in developing African countries. However there is also a hypothesis that the lack of immune response to breast cancer is protective.25-27 The evidence supporting the absence of a protective effect of immune suppression on breast cancer development is the unchanged incidence in breast cancer in 5,692 renal transplant patients in the Nordic study.28 Collectively these reports suggest a similar incidence of breast cancer in HIV-infected women and an increased incidence in HIV-infected men as compared to the general population. The total number of reported cases of breast cancer in HIV-infected patients is 48, the first case being reported in 1988.18,29 Two of these cases of breast cancer in HIV-infected patients occurred in young men.30,31 Breast cancer at the time of diagnosis presented at an advanced stage in two-thirds of the cases in the older series. The largest case series of 20 women with breast cancer and HIV is reported by Hurley et al,32 and incidence of stage IV breast cancer was 10%. In another series by Basil et, al, 20% of the patients had stage IV disease.18 www . DCMS online . org
Chemotherapy is used in the treatment of the majority of women presenting with breast cancer either neo-adjuvant or in adjuvant settings.33 The incidence of myelosuppression with chemotherapy appears to be significantly higher in the HIV infected population.18 In one series, four of the five patients developed grade 3 or 4 Neutropena18 and in another case report one patient died from chemotherapy induced toxicity.34 Hurley et al. reported grade 3 or 4 Neutropena in five of seven patients with one treatment related mortality. Myelosuppression was seen in both doxorubicin based regimens as well as with low dose weekly taxane regimens.32 The patient we presented, prior to HIV diagnosis, did not tolerate chemotherapy well and developed febrile neutropenia and required hospitalization with each cycle of AC, possibly due to low CD4 count. However after recognition of HIV infection and treatment with HAART therapy, she tolerated Docetaxel, Carboplatin and Transtruzumab with pegylated GCSF (White blood cell stimulant) support and she did not develop any further episodes of febrile neutropena. Data from the published adjuvant trials in breast cancer demonstrate an expected incidence of grade 4 leukopenia is about 0.3%, and consequently routine prophylactic administration of hematopoietic growth factor support is not recommended.35 Myelosuppression is more prevalent in the HIV population due to poor bone marrow reserve and because of myelosuppression from anti-retroviral therapy such as zidovudine. Antimetabolites (e.g., 5-fluorouracil and methotrexate) may synergistically interact with anti-retroviral nucleoside analogs and possibly other agents resulting in marked toxicity. Therefore, prophylactic use of hematopoietic growth factors in the HIV population receiving chemotherapy for breast cancer should be considered to prevent the morbidity and mortality associated with such therapy. Cytotoxic drugs can potentially suppress immunity in addition to causing myelosuppression.36-40 In non-HIV infected patients, cytotoxic therapy resulted in reduction of the lymphocyte counts as well as NK cell counts without affecting the ability of these cells to lyse target cells. On the other hand, the number and activity of the NK and LAK cells was reduced in the HIV population with respect to the non-infected healthy population even without chemotherapy. Therefore, chemotherapy may complicate HIV-induced immune suppression and facilitate the worsening of HIV infection as reported by Basil and Hurley et al.17,31 In conclusion, there is no evidence that breast cancer incidence is higher among HIV-infected women than in the general population. However, it appears that the natural history of breast cancer in the setting of HIV infection is worse than in the general population. This may be related to a biologically more aggressive breast cancer compounded by the inability to deliver full doses of systemic anti-cancer therapies in this population of patients. Presence of HIV infection may influence the toxicity of the chemotherapy; however it is also possible that chemotherapy may adversely impact the natural history of HIV infection itself. The increased incidence of HIV infections in women is expected Northeast Florida Medicine Vol. 61, No. 3 2010 37
to result in higher prevalence of breast cancer in this setting. Therefore, physicians treating women with breast cancer and HIV infection must be aware of these potential complications of therapy. Treatment plans should include close monitoring of the CD4 count, viral load, chemotherapy-related toxicity, and prophylactic use of growth factor support.
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Biggar RJ, Rabkin CS. The epidemiology of AIDS-related neoplasm. Hematol/Oncol Clinic North Amer 10: 997–1009, 1996.
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Remick SC. Non-AIDS-defining cancers. Hematol/Oncol Clinic North Amer 10: 1203–1213, 1996.
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Parker MS, Leveno DM, Campbell TJ, Worrell JA, Carozza SE. AIDS-related bronchogenic carcinoma: fact or fiction? Chest 113: 154–161, 1998.
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Chung M, Chang HR, Bland KI, Wanebo HJ. Younger women with breast carcinoma have a poorer prognosis than older women. Cancer 77: 97–103, 1996.
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Grulich AE, Van Leeuwen MT, et al. Incidence of cancer in people with HIV/AIDS compared with immunosuppressed transplant recipients: A meta-analysis. Lancet 370:59-67, 2007.
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Frisch M, Biggar RJ, Engels EA, et al. Association of cancer with AIDS-related immunosuppression in adults. JAMA 285:1736-1745, 2001.
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M. Intra, V. Ripamonti, Journal of Surgical Oncology et al. Journal of surgical oncology 2005; 91:141-142.
10. Thomas P, David R. Highly Active Antiretroviral Therapy and the Incidence of Non–AIDS-Defining Cancers in People with HIV Infection. JCO 27: 884-890, 2009. 11. Bower M, Powles T, Nelson M, et al. HIV-related lung cancer in the era of highly active antiretroviral therapy. Aids 17:371-375, 2003. 12. Kirk GD, Merlo C, O’Driscoll P, et al. HIV infection is associated with an increased risk for lung cancer, independent of smoking. Clin Infect Dis 45:103-110, 2007. 13. International Collaboration on HIV Cancer. Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults. J Natl Cancer Inst 92:1823-1830, 2000. 14. Clifford GM, Polesel J, Rickenbach M, et al. Cancer risk in the Swiss HIV Cohort Study: Associations with immunodeficiency, smoking, and highly active antiretroviral therapy. J Natl Cancer Inst 97:425-432, 2005. 15. Stebbing J, Gazzard B, Mandalia S, et al. Antiretroviral treatment regimens and immune parameters in the prevention of systemic AIDS-related non-Hodgkin’s lymphoma. J Clin Oncol 22:2177-2183, 2004. 16. Patel P, Hanson DL, Sullivan PS, et al. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992-2003. Ann Intern Med 148:728-736, 2008. 17. Phelps RM, Smith DK, Gardner LI, Carpenter CCJ, Klein RS, Jamieson D, Vlahov D, Schuman P, Holmberg SD. Cancer
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incidence in women with or at risk for HIV infection. Int J Cancer 94(5): 753-757, 200. 18. Basil F. El-Rayes et, al. Breast cancer in women with human immunodeficiency virus infection: implication for diagnosis and therapy. Breast Cancer Research and Treatment 76: 111116, 2002. 19. Spielmann M, Kitschke HJ, Tietje K. Cellular immunity in breast cancer patient. Onkologie 5(suppl): 42-45, 1982 20. Lee YT, Sheikh KM, Quismorio FP, Friou GJ. Circulating antitumor and autoantibodies in breast carcinoma: relationship to stage and prognosis. Breast Cancer Res Treat 6: 57-65, 1985. 21. Rotstein S, Blomgren H, Petrini B, Wasserman J, Nilsson B, Baral E. Blood lymphocyte counts with subset analysis in operable breast cancer: relation to the extent of tumor disease and prognosis. Cancer 56: 1413-1419, 1985. 22. Head JF, Elliott RL, McCoy JL. Evaluation of lymphocyte immunity in breast cancer patients. Breast Cancer Res Treat 26: 77-88, 1993. 23. Stewart T, Grayson H, Tsai SJ, Henderson R, Opezl G. Incidence of de novo breast cancer in women chronically immunosuppressed after organ transplantation. Lancet 346: 796-798, 1995. 24. Amir H, Kaaya EE, Kwesigabo G, et al. Breast Cancer before and during the AIDS epidemic in women and men: A study of Tanzanian Cancer Registry Data 1968 to 1996. J Natl Med Assoc 2000; 92:301-305. 25. Pantanowitz L, Dezube BJ. Breast Cancer in women with HIV/AIDS. JAMA 2001; 285:3090-3091. 26. Head JF, Elliott RL, McCoy JL. Evaluation of lymphocyte immunity in breast cancer patients. Breast Cancer Res Treat 1993; 26:77-88. 27. Pantanowitz L, at. al. Breast Cancer and AIDS. J Natl Med Assoc 2001; 93:40-41. 28. Birkeland SA, Storm HH, Lamm LU, Barlow L, Blohme I, Forsberg B, Eklund B, Fjeldborg O, Friedberg M, Frodin L. Cancer risk after renal transplantation in the Nordic countries, 1964–1986. Int J Cancer 60(2): 183-189, 1995. 29. Lake-Lewin D, Arkel YS. Spectrum of malignancies in HIV positive individuals. Proc Am Soc Clin Oncol 7: 5, 1987 (abstract). 30. Myers AM, McCarty E, Abernathy C, Moore GE. Breast cancer in a man with HIV infection. AIDS 6: 1218-1220, 1992. 31. Widrick P, Boguniewicz A, Nazeer T, Remick SC. Breast cancer in a man with human immunodeficiency virus infection. Mayo Clinic Proc 72: 761-764, 1997. 32. Hurley J, Franco S, Gomez-Fernandez C, Reis I, Velez P, Doliny P, Harrington Jr W, Wilkinson J, Kanhoush R, Lee Y. Breast cancer and human immunodeficiency virus: a report of 20 cases. Clin Breast Cancer 2: 215-220, 2001. 33. Harris J Morrow, Norton L. “Malignant tumors of the breast.” Devita VT, Hellman S, Rosenberg SA. Cancer: Principal and Practice of Oncology. 8th ed, Philadelphia: Lippincott Williams & Wilkins. 34. Garcia-Tejedor et al. Breast cancer and HIV-The adverse effects of chemotherapy: The Breast Journal, Vol 13 Number 6: 616-623, 2007. continued to page 40
www . DCMS online . org
Shar Donovan Installed as New FMA Alliance President Shar Donovan, spouse of Dr. Kevin Donovan, and a past president of the DCMS Alliance, (DCMSA) was installed August 14, 2010 as the Florida Medical Association Alliance’s (FMAA) 83rd President. (see p.8) She has been a member of the FMAA Board of Directors since 2002. Dr. & Mrs. Donovan and their four children have lived in Jacksonville, FL since 1999. During these years Mrs. Donovan has been active in the DCMSA, serving as president in 2003, and the FMAA; she was president-elect last year. About being FMAA President, Mrs. Donovan says, “I am committed to working throughout the state, reaching out to each county to enable more county leaders to become state leaders. I look forward to sharing the FMA Alliance’s vision of supporting the family of medicine through our health projects and legislative advocacy.”
www . DCMS online . org
Northeast Florida Medicine Vol. 61, No. 3 2010 39
continued from page 38 35. Ozer H, Armitage JO, Bennett CL, Crawford J, et al. 2000 update of recommendation for the use of hematopoietic colonystimulating factors: evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol 18(20): 3558-3585, 2000. 36. Brenner BG, Friedman G, Margolese RG. The relationship of clinical and therapeutic modality to natural killer cell activityin human breast cancer. Cancer 56: 1543-1548, 1985. 37. Zielinski CC, Muller C, Kubista E, Staffen A, Eibl MM. Effects of adjuvant chemotherapy on specific and non-specific immune mechanisms. Acta Med Austriaca 17: 11-14, 1990. 38. Sewell HF, Halbert CF, Robins RA, Galvin A, Chan S, Biamey RW. Chemotherapy-induced differential changes in lymphocyte subsets and natural-killer-cell function in patients with advanced breast cancer. Int J Cancer 55: 735-738, 1993. 39. Beitsch P, Lotzova E, Hortobayi G, Pollock R. Natural immunity in breast cancer patients during neoadjuvant chemotherapy and after surgery. Surg Oncol 3: 211-219, 1994. 40. Spina M, Nasti G, Simonelli C, Bertola G, Rossi C, Tirelli U. Breast cancer in a woman with HIV infection: a case report. Ann Oncol 5: 661-662, 1994.
In a MEDICaL MaLPRaCTICE CLaIM: Be ready for anything and everything.
Find it on the Website
Looking for the Post Test for the CME article in this issue or for other CME courses to complete? Go to the DCMS website at www.dcmsonline.org. Click “NEFM”,“Current Issue”, and then “Table of Contents”. The current CME article is listed there (with a Post Test link) OR click “CME Articles” under “NEFM” and see a list of all the CME articles still available for credit. See the digital version of the journal!
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40 Vol. 61, No. 3 2010 Northeast Florida Medicine
Duval BW 3.5x9.5.indd 1
www . DCMS online . org
4/26/10 2:17:44 PM
September is Women in Medicine Month In honor of Women in Medicine month, the DCMS is pleased to highlight the legacies of a few of the female physicians who have impacted our medical community. Patricia Cowdery, MD was instrumental in growing the public health outreach clinics while she served as Duval County Health Unit Director in the 1960’s. Dr. Cowdery also served as Director of the Department of Health, Welfare, and Bio-environmental Services from 1972 to 1988. Gladys Soler, MD served as Director of the Pediatric Clinic at University Medical Center from 1964 until her Gladys Soler, MD Patricia Cowdery, MD retirement in 1992. In this role, she was “The Pediatrician” to the indigent children of Jacksonville for over a quarter century. She also played a major role in teaching general pediatrics to residents and students. Doris Carson, MD practiced obstetrics and gynecology for almost 40 years, including a period as President of the Medical Staff at Baptist Medical Center, the first woman to hold that position. She was the founder of Planned Parenthood of Northeast Florida and worked with many organizations dealing with adolescent health issues. Kay Gilmour, MD was the first female President of the DCMS in 1992. She was a private practice cardiologist, with a special interest in Emergency Preparedness, especially for those with special needs in the event of a natural disaster or community wide emergency. Doris Carson, MD
Kay Gilmour, MD
The impact of these physicians (and many others) on the DCMS and surrounding area will be forgotten and lost unless the DCMS updates its published history. So 157 years of medicine is being chronicled in a coffee table book. Two thirds of the book will include significant events that left a lasting impression on our medical community. The remainder of the book will feature physician and practice histories and profiles, purchased by physicians, families, and groups who want to chronicle their legacy in Jacksonville’s medical history.
Do you have a legacy to share with our medical community? www . DCMS online . org
Contact Mr. John Compton, Publisher at 904-355-6561 x110 johncompton@dcmsonline.org
Northeast Florida Medicine Vol. 61, No. 3 2010 41
A financial advisor dedicated to the medical industry can help you navigate changes in your practice’s finances. The business of medicine, much like your practice itself, is forever evolving. And with new financial opportunities and ongoing concerns — like protecting against fraud, managing risk and anticipating the impact of insurance and reimbursements on cash flow — you need the guidance of an advisor who uniquely understands your industry. At SunTrust, advisors with our Private Wealth Management Medical Specialty Group work solely with physicians and their practices to deliver solutions designed for the medical community. To schedule an appointment with an advisor, call 904.632.2854 or visit suntrust.com/medicine to learn more.
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42 Vol. 61, No. 3 2010 Northeast Florida Medicine
www . DCMS online . org
Florida SHOTS™ GOES W H E R E T H E Y G O ALWAYS ON TIME FOR CLASS Every fall your patients start a new school year. That means new books, pencils and shot records. With Florida SHOTS, Florida’s statewide online immunization registry, you can search and print patient records in under one minute, retrieve patient records from other providers, and stay up-to-date on the latest vaccines.
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www . DCMS online . org
Northeast Florida Medicine Vol. 61, No. 3 2010 43
DCMS Membership Applications These physicians’ applications for membership in the Duval County Medical Society are now being processed. Any information or opinions you may have concerning the eligibility of the applicants listed here may be directed to Ashley Booth Norse, MD, DCMS Membership Committee Chair (904-244-4106 or Barbara Braddock, Membership Director (904-3556561 x107).
Michael J. Boyle, MD
Surgery/Surgical Oncology 21st Century Oncology 7551 Baymeadows Rd. Medical Degree: National University of Ireland Residency: Indiana University School of Medicine Fellowship: University of Miami College of Medicine/Jackson Nominated by: Scot Ackerman, MD; Robert Joyce, MD; Alan Marks, MD
Kevin M. Comar, MD
Gastroenterology Borland-Groover Clinic PA 14546 St. Augustine Rd. #101 Medical Degree: Northeastern Ohio Universities College of Medicine Residency/Fellowship: Virginia Commonwealth University Medical School Nominated by: Marie Reid, MD; Daniel Kohm, MD; Bradford Joseph, MD
Michael L. Freeman, MD
Reproductive Endocrinology/Infertility Florida Institute for Reproductive Medicine 836 Prudential Dr. #902 Medical Degree: University of Florida College of Medicine Residency: Bayfront Medical Center Fellowship: Detroit Medical Center & Wayne State University Nominated by: Kevin Winslow, MD; Kenneth Sekine, MD; Scott Segel, MD
Jennifer Anne Glassman, MD
Family Medicine Family Care Partners 6484 Ft. Caroline Rd. Medical Degree: University of Connecticut School of Medicine Residency: St. Anthony Family Medicine Residency Nominated by: Julius Gorospe, MD; William Carriere, MD; Duane Bork, MD
Gary A. Glicksteen, MD
Internal Medicine Internal Medical Group 8614 Baymeadows Way #100 Medical Degree: University of Cincinnati College of Medicine Residency: Riverside Methodist Hospital Nominated by: Richard Glock, MD; Joseph Stepp, MD; Richard Grochmal, MD
Kevin M. Kaplan, MD
Sports Medicine/Advanced Arthroscopy Jacksonville Orthopaedic Institute 1325 San Marco Blvd. #200 Medical Degree: New York University Medical School Residency: New York University Hospital for Joint Diseases Fellowship: Kerlan Jobe Orthopaedic Clinic Nominated by: Steve Lucie, MD; Carlos Tandron, MD; William Pujadas, MD
Gregory M. Lewis, MD Ophthalmology (Retina) Retina Associates PA 2 Shircliff Way #715 Medical Degree: University of Tennessee School of Medicine Residency: Medical College of Virginia Fellowship: University of Alabama School of Medicine Nominated by: Fred Lambrou, Jr., MD; Walter Gilbert, Jr., MD; Janet Betchkal, MD
Frank W. McDonald, MD
Ophthalmology/Cornea Levenson Eye Associates, Inc. 751 Oak St. #200 Medical Degree: University of Alabama School of Medicine Residency: University of Mississippi Medical Center Fellowship: Cornea & Refractive Surgery Nominated: Jeffrey Levenson, MD; Ronald Singal, MD; Sheldon Singal, MD
Elizabeth Anne Moran, MD
Pediatric Orthopaedics Nemours Children’s Clinic 807 Children’s Way Medical Degree: Boston University School of Medicine Residency: National Naval Medical Center Bethesda Fellowship: Nemours Children’s Clinic Nominated by: John Mazur, MD; Eric Loveless, MD; Kevin Neal, MD
Florence Marie-Louise O’Connell, MD
Dermatology Jacksonville Dermatology Associates PL 8075 Gate Parkway W. #201 Medical Degree: University of Florida College of Medicine Residency: University of Florida College of Medicine Nominated by: Tricia Andrews, MD; Ashley Booth Norse, MD
Brad Douglas Talley, MD
Diagnostic Radiology Drs. Mori Bean & Brooks PA 3599 University Blvd. S. Bldg. 300 Medical Degree: Duke University School of Medicine Residency: Harvard Medical School/
44 Vol. 61, No. 3 2010 Northeast Florida Medicine
Brigham & Women’s Hospital Fellowship: University of Florida College of Medicine Nominated by: Brett Gratz, MD; Dennis Wulfeck, MD; John McKenzie, MD
RESIDENTS/FELLOWS Mayo Clinic Jacksonville Abdominal Transplant Surgery Cynthia L. Leaphart, MD
Anesthesiology Perene V. Patel, MD
Dermatology Tandy S. Repass, MD
Endocrinology Ana Maria Chindris, MD
Family Medicine
Sara Filmalter, MD Amit J. Grover, MD Joshua M. Henry, MD Heidi Hepp, MD Aunna Pourang, MD
Internal Medicine
Christopher Austin, MD Jennifer Crozier, MD Jimmy Moss, MD William Palmer, MD Ryan Peck, MD Patress Ann Persons, MD Gregory L. Repass, MD Philip Tran, MD
Neurology
Rebecca Hurst, MD Glen T. Robinson, MD
Neurosurgery Wilson P. Daugherty, MD
Palliative Care Alva Roche’-Green, MD
Radiation Oncology Richard Lee, MD
Radiology
Madhura Desai, MD John Feldman, MD Jamie Giesbrandt, MD Kirk Giesbrandt, MD Andrew Ginzel, MD Jonathan Malone, MD Matthew Morris, MD
TRANSITIONAL YEAR Kristin M. Eller, MD (Neurology) Sheena Gurwara, MD Yun Sun Lee, MD Johnathan R. Renew, MD (Anesthesiology) Melissa A. Saad, MD www . DCMS online . org
JSMP 2010 Athletic Screenings
The Jacksonville Sports Medicine Program’s (JSMP) 2010 athletic screenings were conducted August 7 for high school athletes and August 14 for middle school athletes (Boys at Nemours Children’s Clinic and girls at Wolfson Children’s Hospital). At least 1,000 student athletes were given free pre-participation athletic screenings by nearly 500 volunteer health professionals. (Physicians, PAs, and allied health professionals) The physician and PA volunteers were coordinated through the Duval County Medical Society. The screenings are not intended to replace annual physical exams by pediatricians and primary care physicians, so students are referred to individual physicians for follow-up care. Pictured: (Top L to R) DCMS members Dr. Ruple Galani and Dr. George Armstrong, Jr.; Mary McCormack, Nemours’ Volunteer Coordinator; and Robert Sefcik, JSMP Executive Director; DCMS member Dr. Kevin Kaplan with a student athlete. (Left, middle) Athletes line up for their screenings; (Left, bottom, L to R) Dr. Armstrong, Dr. Irene Malesic and Jim Mackie, health athletic trainer for Trinity Christian High School.
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Northeast Florida Medicine Vol. 61, No. 3 2010 45
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In a MEDICaL MaLPRaCTICE CLaIM: Be ready for anything and everything.
Decades of experience, true financial stability, and a tough-as-nails defense team make First Professionals a well-rounded — and yes, affordable — choice when it comes to protecting your medical reputation and career. No other Florida medical malpractice provider knows the industry quite like we do, nor do they defend our doctors with as much tenacity. We’re committed to protecting you and everything you’ve got, with everything we’ve got. For more information, contact Shelly Hakes, Director of Society Relations at (800) 741-3742, Ext. 3294.
Endorsed by
Significant discounts available for eligible DCMS members.
You save lives. We save livelihoods.
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