Volume 91 No. 6 June 2008

Asthma & Allergy

UNDER THE JOINT VOLUME 91 NO. 6 June 2008 EDITORIAL SPONSORSHIP OF: Medicine
Health The Warren Alpert Medical School of Brown University HODE SLAND Edward J. Wing, MD, Dean of Medicine R I & Biological Science PUBLICATION OF THE RHODE ISLAND M EDICAL SOCIETY Rhode Island Department of Health David R. Gifford, MD, MPH, Director COMMENTARIES Quality Partners of Rhode Island Richard W. Besdine, MD, Chief 158 Neuroprotective Trials: No Longer a Cautious Optimism Medical Officer Joseph H. Friedman, MD Rhode Island Medical Society 159 An Alien Legend With a Bite Nick Tsiongas, MD, MPH, President Stanley M. Aronson, MD EDITORIAL STAFF Joseph H. Friedman, MD CONTRIBUTIONS Editor-in-Chief SPECIAL ISSUE: Asthma and Allergy Joan M. Retsinas, PhD Guest Editor: Russell A. Settipane, MD, FAAAAI Managing Editor Stanley M. Aronson, MD, MPH 160 Special Focus: Allergy & Asthma – Introduction Editor Emeritus Russell A. Settipane, MD, FAAAAI

EDITORIAL BOARD 161 Childhood Asthma and Obesity Stanley M. Aronson, MD, MPH Sheryl J. Kopel, MSc, and Robert B. Klein, MD Jay S. Buechner, PhD 164 Inner City Asthma John J. Cronan, MD Stanley Hoyt Block, MD, FAAAAI James P. Crowley, MD Edward R. Feller, MD 166 The National Asthma Education and Prevention Program (NAEPP) John P. Fulton, PhD Guidelines: Will They Improve the Quality of Care in America? Peter A. Hollmann, MD Sidney S. Braman, MD, FCCP, and Arul Viggs, MBBS Sharon L. Marable, MD, MPH Anthony E. Mega, MD 171 Update On Stinging Insect Allergy Marguerite A. Neill, MD Alan Gaines, MD, FAAAAI Frank J. Schaberg, Jr., MD 174 The Role of Pollens In Allergy Lawrence W. Vernaglia, JD, MPH Henry B. Freye, MD, FAAAAI Newell E. Warde, PhD 184 Latex Allergy OFFICERS Anthony R. Ricci, MD Nick Tsiongas, MD, MPH President 187 Advances In Therapeutic Immunomodulation of IgE-mediated Diane R. Siedlecki, MD Respiratory Disease President-Elect Russell A. Settipane, MD, FAAAAI Vera A. DePalo, MD Vice President COLUMNS Margaret A. Sun, MD 196 IMAGES IN MEDICINE – MR Imaging of Acute Appendicitis in Pregnancy Secretary Jill A. Steinkeler, MD, and Courtney A. Woodfield, MD Mark S. Ridlen, MD Treasurer 197 GERIATRICS FOR THE PRACTICING PHYSICIAN – Case Presentation: Mr. J, Barry Wall, MD an 88 year-old man found on the floor, complaining of Immediate Past President generalized weakness Rebecca Starr, MD, and Ana Tuya Fulton, MD DISTRICT & COUNTY PRESIDENTS Geoffrey R. Hamilton, MD 199 HEALTH BY NUMBERS – Hospitalizations and Associated Costs for Bristol County Medical Society Principal versus Additional Diagnoses of Asthma: Implications Herbert J. Brennan, DO for Monitoring Children’s Health Kent County Medical Society Deborah N. Pearlman, PhD, Nancy Sutton, RD, MS, Sze Liu, MPH, Rafael E. Padilla, MD Janice Fontes, MS, and Jay S. Buechner, PhD Pawtucket Medical Association Patrick J. Sweeney, MD, MPH, PhD 202 PUBLIC HEALTH BRIEFING – Department of Health Promotes e-Licensing Providence Medical Association for Physicians Nitin S. Damle, MD Michael Simoli and Robert Crausman, MD Washington County Medical Society 203 PHYSICIAN’S LEXICON – A Planetary Vocabulary Jacques L. Bonnet-Eymard, MD Stanley M. Aronson, MD Woonsocket District Medical Society 203 Vital Statistics Cover: Image from a series entitled “The Escape Artist,” Acrylic and Collage, by Evan 204 June Heritage Larson. Evan Larson is an award-winning illustrator and graduate of the Rhode Island School of Design. His work has appeared in Medicine and Health/Rhode Island (USPS 464-820), a monthly publication, is owned and published by the Rhode Island Medical Society, 235 Nickelodeon Magazine, American Illustra- Promenade St., Suite 500, Providence, RI 02908, Phone: (401) 331-3207. Single copies $5.00, individual subscriptions $50.00 per year, and $100 tion 26, Project: Romantic as well as galler- per year for institutional subscriptions. Published articles represent opinions of the authors and do not necessarily reflect the official policy of the Rhode Island Medical Society, unless clearly specified. Advertisements do not imply sponsorship or endorsement by the Rhode Island Medical Society. Periodicals postage ies in Rhode Island and Massachusetts. He paid at Providence, Rhode Island. ISSN 1086-5462. POSTMASTER: Send address changes to Medicine and Health/Rhode Island, 235 Promenade St., will soon appear in Best American Comics Suite 500, Providence, RI 02908. Classified Information: RI Medical Journal Marketing Department, P.O. Box 91055, Johnston, RI 02919, 2008 published by Houghton Mifflin. phone: (401) 383-4711, fax: (401) 383-4477, e-mail: [email protected]. Production/Layout Design: John Teehan, e-mail: [email protected]. www.postmodernfrog.blogspot.com. 157 VOLUME 91 NO. 6 JUNE 2008 Commentaries

Neuroprotective Trials: No Longer a Cautious Optimism

You can’t win a race if you can’t find the with active drug and the other with pla- tee supported the project because it found starting line. Yet that is exactly where we cebo and following both, has seized on a the “old” theory just as persuasive as the are in the development of drugs to slow clever idea: the “delayed treatment” para- newer ones, and wasn’t persuaded that down Parkinson’s disease (PD). The drive digm. One group is treated at entry, and newer meant better. We all thought that it to find these drugs has produced trials that the other arm is treated initially with a pla- was worth a shot, even if the odds of suc- assess an intervention despite not knowing cebo, then after a predetermined period cess were slim. I don’t think that any longer. what the disease process is. Let’s take the both groups are treated equally with the There’s a problem basing large trials case of PD. In the 1950s there were de- active drug. If the treatment produces only on theories, when the theories, unsup- bates about where the pathological process a symptomatic benefit then the two groups ported by much data, wax and wane with was. That was definitively answered that de- should end up looking the same, whereas the season. Theories are tremendously cade, until the 1990s when it changed, and if the group treated early does better than important so long as the hypotheses gen- continues to change. In the 1980s there the group treated late, one might hypoth- erate research, but not so good when the were debates about the importance of the esize that early treatment either produces research has to be a lengthy, expensive, Lewy body. That was settled when the Lewy increasing benefits, or that the treatment difficult clinical trial that may siphon off body became a requirement for diagnosis. may slow disease progression. Either in- money from better uses. Ten years ago we figured out what the Lewy terpretation still implies that treating early Like my colleagues, I have thought body is composed of, but we still don’t know produces a better outcome. Pain treat- for many years that it’s better to do some- whether it’s “good” or “bad.” Either this ment, for example, is more effective if be- thing than nothing and either put the ball of condensed protein is gumming up gun early and maintained, so that pain theory to rest, or show that it works. I have the cells, or, by forming a glob, is taking patients can be treated with less medicine come to see things differently. I think that bad proteins out of circulation, keeping the if they are started early and given doses on $10,000,000 is better spent on the basics cells from gumming up. Not only that, but a regular basis, whether needed or not. and not on a single trial that is unlikely to after the 30-year debate, and after the Lewy This doesn’t alter disease progression (e.g., produce benefit. Ten million spent on a body was finally accepted as a requirement cancer pain) but does result in better out- poorly supported clinical trial is ten mil- for the pathological definition of PD, we comes. In PD one will derive the plausible lion stolen from basic research. But the are now probably about to classify two types conclusion that the drug slows the pro- problem, of course, is less simple. It is un- of idiopathic PD, one with and one with- gression, and it will not be disprovable. likely that the $10,000,000 saved would out the Lewy body although no one knows However, it will not be proof and, at the go to PD basic research. More likely it what other differences there are. least, we will know that early treatment, as would go to something unrelated, prob- For many years we’ve focused on the with pain, results in better outcomes (not ably not even to medical research. dopamine deficiency in PD, but, as a re- including side effects). Is the PD community better served cent editorial in Neurology [“The dopam- The federal government has spon- by a large clinical trial or nothing? For this ine hypothesis, beating a dead horse,”] sored expensive trials looking at a variety of question I don’t have an answer. We can pointed out, the dopamine deficiency con- drugs to slow disease progression in PD. talk about how to spend money better, but tributes to many, but not all, of the motor These trials are based on theories of disease too often when government money isn’t deficits in PD, but has little to do with some progression having to do with apoptosis spent on one unrewarding thing, it’s spent motor problems such as dysarthria or freez- (programmed cell death), biochemical on something less useful. ing, and has nothing to do with the demen- death from oxidation and “free radical scav- tia, depression, anxiety, apathy, sleep disor- engers,” abnormal cell protein folding, ab- – JOSEPH H. FRIEDMAN, MD ders, fatigue, or sympathetic dysfunction of normal ubiquitination, and possibly inflam- PD. These are problems that are not un- mation. One trial proposed years ago, but Disclosure of Financial Interests derstood. What parts of the brain are mal- not yet begun, is based on the oxidation Joseph Friedman, MD, Consultant: Acarta functioning have not all been identified, let hypothesis, no longer the theory of the day. Pharmacy, Ovation, Transoral; Grant Research alone their biochemical causes. The trial’s Principal Investigator worried, Support: Cephalon, Teva, Novartis, Boehringer- Clinical trialists and pharmaceutical as he defended his proposal, that the Ingelheim, Sepracor, Glaxo; Speakers’ Bureau: companies, realizing the financial risks of project, in taking so long to get through Astra Zeneca, Teva,Novartis, Boehringer-Ingelheim, funding neuroprotective trials based on the NIH maze, woud have lost its panache GlaxoAcadia, Sepracor, Glaxo Smith Kline the obvious design of treating one group by the time it was reviewed. The commit- 158 MEDICINE & HEALTH/RHODE ISLAND An Alien Legend With a Bite

Three members of the Brown family of Exeter, Rhode Island, often endowed with fangs and red eyes, are mysterious in be- succumbed to consumption [tuberculosis] within a span of four havior and satanic in heritage, are cave or coffin-dwelling, and years; and then their only son, Edwin, also became ill. In 1892, while not carnivorous, both are blood-sucking. little was known of the causes of tuberculosis nor whether su- The overwhelming majority of bats, however, are benevo- pernatural forces underlay such tragedies. lent creatures, exclusively insectivorous and not blood-suck- Edwin’s condition worsened. In desperation, George ing. Indeed, only three bat species are known to consume blood, Brown, his father, sought the counsel of his neighbors, who and all three are confined to the Western Hemisphere. Thus, concluded that the cluster of deaths must have been caused by while bats had been part of the pre-columbian mythology in some family member, already dead, exacting revenge. The South America for millennia, the bat as a surrogate for a vam- group trekked to the Chestnut Hill Cemetery, behind the Bap- pire did not enter European legendry until the Spanish con- tist Church, and dug up the three Brown coffins, seeking a querors of Latin America brought these myths back to Europe, body that showed little significant deterioration. The exhumed along with maize, tobacco and syphilis. body of Mercy Lena Brown, the younger daughter to die of The bat had then been gradually transformed from a timo- consumption, looked intact. Furthermore, her heart contained rous rodent adapted to night flying to a terrorizing wraith, and liquid blood, sure evidence that she had recently consumed a palpable threat to humanity. By the 18th Century, the bat human blood and hence was a vampire. Her heart was ex- had become firmly entrenched in the spells of necromancy and tracted, cremated and its ashes fed to Edwin. Sadly, though, he vampirism. died within weeks. The last decade of the 18th Century and the early decades The Providence Journal reported the Mercy Brown inci- of the 19th Century witnessed the formalization of the vampire dent in detail, accompanied by much discussion on the char- image in the genre novels of Goethe, Polidori, Rhymer and acteristics of vampires [the undead]. Most agreed on their ex- much later, in Bram Stoker’s Dracula. istence since vampires had been part of European folklore for The 20th Century added a new dimension to the spread- millennia. Dr. Michael Bell, a skeptical authority, declared ing malevolence of the vampire bat. Western Hemisphere bats that “A vampire is a corpse that comes to the attention of the were threatening range cattle: one Department of Agriculture community during a time of crisis, and is taken for the cause of document estimated that over a half million cattle died annu- that crisis.” Thus, in his judgment, vampires were scapegoats ally because of rabies encephalitis transmitted from cow to cow “absorbing the ignorance, the fears, and in some cases the guilt by the biting, blood-sucking feral bats. Rabies vaccines are avail- that people have because their neighbors, friends and family able but represent an expensive intervention; and most ranch- are dying.” ers leave their cattle immunologically unprotected. Thus, ra- Somewhere in ancient southeastern Europe, pagan my- bies in cattle was now added to the burdens initiated by vam- thology concerning vengeful creatures returning from the dead pire bats. But do bats play any substantive role in human ra- had evolved into a structured folklore; and by the 13th Cen- bies? tury the threat of revenant vampires tainted the legends of ev- There have been 47 verified, documented cases of indig- ery village. The folkloric vampire was typically male, gaunt enous rabies in Canada and the United States since 1990, and but with a ruddy and bloated face, red eyes, perilously long 43 of these instances were attributable to bat bites. It should fingernails and often was a heretic or one who had been ex- be remembered that untreated rabies is a uniformly fatal form communicated. Some vampire tales, particularly from Roma- of brain inflammation. nia, claimed they could transform themselves readily into wolves Legend and reality, the two companion pillars of human or rabid dogs. credulity, have always served in man’s struggles to understand Today, when most people believe that the earth is spheri- the world around him; and the imagery of howling wolves, cal and that skeptics need not be burned alive, it is strange how rabid dogs, Transylvanian winters, nocturnal bats and unex- persistent the vampire legends have become. Ask an average plained deaths from rabies or other ills all have coalesced to American teenager to describe a vampire: he will render a pre- solidify the vampire myth—whether in Romania or Exeter, cise description down to the black cape, the tuxedo, the high Rhode Island. collar, an insistent hypersexuality, an east European accent, an aversion to garlic, sharp enlarged fangs – and the capacity to – STANLEY M. ARONSON, MD transform himself readily into a bat. Awareness of vampires is now universal. Even Sesame Street contains a vampire puppet, Disclosure of Financial Interests Count Count. Stanley M. Aronson, MD, has no financial interests to disclose. Why the historic association of vampires with bats? Re- wording the question, what behavioral or visible characteris- CORRESPONDENCE tics – apocryphal, contrived or natural - may bats and vam- e-mail: [email protected] pires share? They both are said to be strictly nocturnal while dreading sunlight, are predatory, are fearsome in appearance, 159 VOLUME 91 NO. 6 JUNE 2008 Special Focus: Allergy & Asthma – Introduction Russell A. Settipane, MD, FAAAAI

In the 35 years since the publication of the last allergy For this issue of Medicine & Health / Rhode Island, aca- update in this journal,1 significant advances have occurred, both demic contributions have been provided by members of the in the understanding of the immunology which underlies al- Rhode Island Society of Allergy as well as the Division of Pul- lergic disease pathophysiology as well as in the development of monary and Allergy of the Warren Alpert Medical School at new therapeutic strategies. In 1973, when Guy A. Settipane, Brown University. Subjects range from new research informa- MD, reviewed pathogenic mechanisms in allergy, IgE had been tion to reviews of specific topics. Robert Klein and Sheryl Kopel discovered only six years earlier; arachadonic acid metabolism report on the association of obesity and asthma. Stanley Block was just beginning to be elucidated and interleukins and in- reviews challenges in the treatment of inner city asthma. Sidney flammatory cytokines had yet to be described. Most of the thera- Braman addresses the question as to whether the 2007 “Guide- peutic practices for allergic diseases were employed empirically lines for the Diagnosis & Management of Asthma,” published with little scientific support. by the National Asthma Education and Prevention Program, In the past three decades, research on the epidemiology, will improve the quality of care in America. Alan Gaines re- etiology, diagnosis, treatment and prevention of many allergic views the stinging insect venom immunotherapy and preven- diseases has advanced to the point that it is on par with or ex- tion of anaphylactic deaths. In juxtaposition to the importance ceeds that of other specialties. Evidence-based treatment guide- of indoor allergens discussed by Dr Block, Henry Freye re- lines and practice parameters have been published for a multi- views outdoor aero-allergens, specifically pollen and mold. tude of allergic diseases. Additionally, board certification in the Anthony Ricci discusses latex allergy and its clinical repercus- specialty of allergy/immunology has become rigorous, requir- sions. Finally, Russell Settipane reviews advances in therapeu- ing board certification in internal medicine or pediatrics and a tic immunomodulation of IgE mediated diseases. minimum of 2 years of fellowship training. Allergy/immunol- ogy remains one of the few specialties where Fellows receive REFERENCES both pediatric and adult medicine training; certification is by 1. Settipane GA. New concepts of pathogenic mechanisms in allergy. R I Med J a conjoint board of Pediatrics and Internal Medicine. 1973;56:325-9. Russell A. Settipane, MD, FAAAAI, is Co-Director, Allergy The members of the RI Society of Allergy welcome & Asthma Center, Clinical Associate Professor, Warren Alpert this issue of Medicine & Health/Rhode Island. Medical School of Brown University, and president of the Rhode We hope that in disseminating the latest research Island Society of Allergy. on allergy and asthma, the care of Rhode Island patients will be enhanced. Disclosure of Financial Interests Russell Settipane, MD. Grant Research Support and RI SOCIETY of ALLERGY Speakers’ Bureau: Genentech. MEMBERSHIP ROSTER CORRESPONDENCE Russell Settipane MD, President Russell A. Settipane, MD, FAAAAI Anthony Ricci MD, Vice President Asthma & Allergy Center Doren Ber MD 95 Pitman St Bruce Berlow MD Providence, RI 02906: Stanley Block MD Phone: (401)331-8425 e-mail: [email protected] Henry Freye MD (emeritus) Alan Gaines MD David Katzen MD Donald Klein MD Robert Klein MD Mary Ann Passero MD Robert Settipane MD Jorge Sturam MD Barrie Weisman MD Joel Weltman MD (emeritus) John Zwetchkenbaum MD

160 MEDICINE & HEALTH/RHODE ISLAND Childhood Asthma and Obesity Sheryl J. Kopel, MSc, and Robert B. Klein, MD

Parallel increases in the prevalence of asthma and obesity trol and Prevention (CDC)6 growth charts before cutoff val- have prompted researchers to examine relationships between the ues are applied. In the 2003 National Survey of Children’s two conditions. We highlight the literature and present preliminary Health, 31% of Rhode Island children ages 6-17 were over- pilot data on asthma and obesity collected on a small sample of Rhode weight (15%) or obese (16%).7 Between 2001-2005, one in Island children attending a 1-week asthma summer camp. five children entering kindergarten in RI was obese.3 As with asthma, racial/ethnic disparities are present: non-Hispanic PREVALENCE RATES OF ASTHMA AND OBESITY blacks and Hispanics, most notably Mexican-Americans, have Asthma, the most common chronic illness in children, af- higher prevalence rates than whites.8 fects approximately 6.2 million children under the age of 18.1 The rise in obesity is attributed to multiple factors: de- Its prevalence has been steadily increasing (Figure 1), and de- creases in physical activities, increases in sedentary activities, spite the rates leveling off, it remains a critical concern. Twelve larger food portions, and a proliferation of calorie-dense con- percent of US children have a lifetime history of asthma, and venience foods.9 Overweight and obese children are at in- 8.8% report currently having the condition.2 Rhode Island creased risk for detrimental short- and long-term outcomes, has an 11% prevalence rate of current asthma in children 0- including early development of cardiovascular disease risk fac- 17 years old—the 5th highest in the US.3 tors,10 early onset Type 2 diabetes,11 psychosocial maladjust- Children from racial and ethnic minorities experience a dis- ment12 and the persistence of obesity into adulthood.13 Addi- proportionate asthma burden.4 From 2001-2005 rates of hos- tionally, research studies implicate obesity in the development pitalizations for asthma among African American children in and course of asthma. Rhode Island were nearly triple the rates of their white counter- parts; and Hispanic children were hospitalized more than twice THE ASTHMA-OBESITY RELATIONSHIP as often as white children.3 Non-Hispanic black and Hispanic Schaub and von Mutius14 cite prospective studies that dem- children, particularly those of Puerto Rican descent, experience onstrate higher rates of incident asthma in children and adoles- higher prevalence rates and morbidity than white children.5 cents with excess weight, some showing the effect only in fe- Overweight in children has become a major concern. Since males, while others also found the effect in boys. High weight is the 1970s, rates have more than quadrupled in US children associated with increases in days wheezing,15 cough/wheeze with between 6-11 years old and have sharply increased in pre- exercise,16 missed school days,17 and emergency department vis- school-aged children and adolescents. (Figure 2) In adults 20 its.18 Obese children may be subject to longer and more inten- years of age and older, raw Body Mass Index (BMI) values are sive treatments than their normal weight peers. In a sample of used to classify weight into categories ranging from underweight children admitted to the ICU for status asthmaticus, Carroll and to obese. (Table 1) In children, BMI is often converted to colleagues19 found that obese patients required longer courses of percentiles by age and sex utilizing Centers for Disease Con- supplemental oxygen, continuous albuterol and intravenous ste-

161 VOLUME 91 NO. 6 JUNE 2008 roids, and had longer ICU and hospital lengths of stay than nor- mal-weight patients. High weight also appears to be related to the persistence of asthma after the onset of puberty.20 Although the majority of research points to excess weight’s impact on asthma, the relationship may be bi-directional. Exer- cise induced bronchospasm (EIB) occurs in the majority of pedi- PHYSICAL ACTIVITY atric asthma cases,21 leading many children to eschew physical ac- With a rate approaching 61%, Rhode Island ranks worst in tivity, often prompted by their parents.17 Maladaptive efforts to the US in the percentage of children and teens who fail to exer- prevent EIB may encourage a sedentary lifestyle. Moreover, lack cise regularly.27 Nationally, about half of all US children get in- of regular physical exertion is implicated in cardiopulmonary de- sufficient amounts of daily exercise.28 Older children, females conditioning, which exacerbates EIB and increases the risk of weight and ethnic minorities have the lowest activity levels.29 Barriers to gain.22 Pulmonary compromise resulting from poorly controlled exercise include limited access to appropriate environments and asthma presents an additional barrier.22 Several studies have found equipment, decreases in school physical education programs, and that youth with asthma take less than half of their prescribed con- preference for sedentary pastimes. Children with asthma may troller medications: this shortfall accounts for increases in morbid- experience relatively lower activity levels than their healthy peers ity, including more frequent symptoms and activity limitations.23 due to the severity of their asthma and their parents’ doubts about A reduction in the use of safer controller medications in persistent the appropriateness of exercise. The real or perceived risk of EIB asthma leads to more asthma exacerbations and the subsequent may also discourage exercise. use of systemic steroid “bursts”. There are quantitatively more po- tential side effects, including weight gain, from even a short course PILOT DATA FROM THE CHILDHOOD ASTHMA of a prednisone-type medication than a full year of an inhaled RESEARCH PROGRAM corticosteroid used daily to prevent symptoms. A number of areas merit further research, including the The literature on the asthma-obesity relationship suggests physiological mechanisms driving the relationship between that each condition can exacerbate the other. Research is un- asthma and obesity, the role of race/ethnicity, and the inter- der way to understand the physiological mechanisms driving ventions that promote physical activity in this population. this relationship. Areas of study include lung mechanics, im- Through the partnership of the Childhood Asthma Research munity and inflammation, genetics, hormones, and gene-by- Program at the Bradley-Hasbro Research Center, and Hasbro environment interactions.16 Children’s Hospital’s Community Asthma Programs (CAP), A complementary line of inquiry focuses on behavioral we have an opportunity to study some of these issues locally, at and psychosocial mechanisms influencing weight control. Firm the CAP asthma summer camp. Last year we began collecting evidence documents that weight loss improves asthma out- descriptive data on obesity and asthma as a first step. comes,24 and weight gain worsens them.25 The majority of Data collection for this pilot project is ongoing and takes weight loss studies in obese adults with asthma have employed place yearly at the CAP Summer Camp—a 1-week overnight radical surgical or dietary weight loss methods.24,26 In chil- camp for children with asthma, held each summer at Camp dren, physical exercise is seen as the more appropriate focus,9 Canonicus in Exeter, RI. The Institutional Review Board at though healthy eating habits are also emphasized. Exercise Rhode Island Hospital approved the protocol, and families also can improve pulmonary function as evidenced by an in- signed informed consent/assent and HIPAA privacy forms. creased Forced Vital Capacity measure. Parent materials were presented in Spanish or English; child forms were presented in English (all campers were fluent). 162 MEDICINE & HEALTH/RHODE ISLAND 85th percentile for BMI experienced more activity limitation than the normal weight campers (F (1,20) = 3.47, p = .08). Weight was not related to children’s self-report of their physical activity. This measure was assessed on the last day of camp; and children’s responses about typical activity levels may have been influenced by their immediate experience of a very active week at camp. Subsequently, we will administer the physical activity questionnaire at the beginning of the week. Additionally we intend to include pedometer measurement of physical activity level. This review of the asthma-obesity relationship and our preliminary findings from a small sample of children attend- ing summer camp indicate that practitioners should promote exercise and provide dietary advice in overweight asthmatic patients. For their heaviest patients, referral for weight loss treat- ment may be indicated. The use of controller medications can help children maintain healthy physical activity as well as avoid the use of systemic steroids and their potential side effects.

REFERENCES 1. American Lung Association. Asthma and Children Fact Sheet. 2006. www.lungusa.org. 2. Air Pollution and Respiratory Health Branch, National Center for Health Statistics. National Health Interview Survey, 2004. Available from: www.cdc.gov/asthma/nhis/04/data.htm. 3. Rhode Island Kids Count. 2007 Rhode Island Kids Count Factbook. Provi- dence, RI; 2007. 4. Mannino DM, Homa DM, et al. MMWR Surveillance Summaries 2002;51:1- During the camp session children completed several ques- 13. tionnaires including the Fels Physical Activity Questionnaire,31 5. Lara M, Akinbami L, et al. Pediatrics 2006;117:43-53. which assesses activity level at school and during leisure time 6. Centers for Disease Control and Prevention. Body Mass Index: About BMI for children and teens. http://www.cdc.gov/nccdphp/dnpa/bmi/ during a typical week. Height and weight are measured for childrens_BMI/about_childrens_BMI.htm. the BMI calculation. During camp drop-off parents complete 7. 2003 National Survey of Children’s Health. National Center for Health Statis- the Child Health Survey for Asthma (CHSA) Child Activity tics, Centers for Disease Control and Prevention. scale,32 which assesses children’s asthma-related physical limita- 8. National Center for Health Statistics. Obesity still a major problem, new data 33 show. Hyattsville, MD: CDC, US Department of Health and Human Ser- tions and the Asthma Control Test (ACT), which utilizes vices; 2004. information about symptom frequency and severity and use of 9. Hill JO, Melanson EL. Med Science in Sports Exercise 1999;31:Suppl., S515- quick relief medications to derive a control score. S21. Table 2 contains demographic and physiological data for 10. Freedman DS, Dietz WH, et al. Pediatrics 1999;103:1175–82. 11. Fagot-Campagna A, Narayan KMV, Imperatore G. Brit Med J 2001:377-8. the 26 campers who took part in research during the first wave 12. Swartz MB, Puhl R. Obesity Reviews 2003;4:57-71. of data collection. Over half (53%) of the children were over- 13. Serdula MK, Ivery D, et al. Prev Med 1993;22:167-77. weight or obese, similar to the proportion of overweight chil- 14. Schaub B, von Mutius, E. Current Opinion Allergy Clin Immunol 2005;5:185- dren in a large national sample (22% vs. 31%, respectively).34 93. 15. Belamarich PF, Luder E, Kattan M. Pediatrics 2000;106:1436-41. However, the proportion of obese children at camp was mark- 16. Tantisira KG, Weiss ST. Thorax 2001;56:64-74. edly higher than the reference sample (31% vs 15%, respec- 17. Luder E, Thomas, M.A., DiMaio, M. J Pediatrics 1998;132:699-703. tively). Selection criteria for camp attendance could partially 18. von Mutius E, Schwartz J, et al. Thorax 2001;56:835-8. account for the higher proportion of obese children, as prefer- 19. Carroll CL, Bhandari A, et al. Pediatric Crit Care Med 2006;7:527-31. 20. Guerra S, Wright AL, et al. Am J Resipiratory Crit Care Med 2004;170:78-85. ence for enrollment is given to those with more severe asthma 21. Milgrom H, Taussig LM. Pediatrics 1999;104:e38. and challenges to control, as indicated by medical history and 22. Clark CJ, Cochrane LM. Current Opinion in Pulmonary Med 1999;5:68-75. prescribed amedications, and these asthma indicators are re- 23. McQuaid EL, Kopel SJ, et al J Pediatric Psychol 2003;28:323-33. 24. Stenius-Aarniala B, Poussa T, et al. Brit Med J 2000;320:827-32. lated to overweight status. 25. Castro-Rodriguez JA, Holberg CJ, et al. Amer J Respiratory Crit Care Med Table 3 shows other trends in this preliminary data set. 2001;163:1344-9. Though our small sample size limited statistical power, our re- 26. Spivak H, Hewitt MF, et al. Amer J Surgery 2005;189:27-32. sults echo findings in the literature. For instance, the girls 27. Annie E. Casey Foundation. Data snapshot: State differences in rates of over- weight or obese youth. 2006. tended to weigh more than the boys, and Hispanic children 28. Annie E. Casey Foundation. Children and teens not exercising regularly - weighed more, on average, than children from other racial/ Comparisons by topic. 2006 [cited 2007 May]. www.aecf.org/kidscount. ethnic backgrounds. Heavier children had more problems with 29. US Department of Health and Human Services. Physical activity and health: control than their slimmer peers (r = -.43, p<.05). Parent re- Adolescents and young adults. Washington, D.C.: CDC; 1996. 30. Lang D, Butz A, et al. Pediatrics 2004;113:341-6. port of children’s asthma-related activity limitations was mar- 31. Treuth MS, Hou N, et al. Med Science in Sports Exercise 2005;37:488-95. ginally related to child weight. Specifically, children above the 32. Asmussen L, Olson L, et al. Pediatrics 1999;104:71. 163 VOLUME 91 NO. 6 JUNE 2008 33. Nathan RA, Sorkness CA, et al. J Allerg y Clin Sheryl J. Kopel, MSc., is Project Man- Disclosure of Financial Interests Immunol 2004;113:59-65. ager, Childhood Asthma Research Program, The authors have no financial inter- 34. Ogden CL, Flegal KM, et al. JAMA 2002;288:1728-32. Bradley-Hasbro Research Center, Rhode ests to disclose. 35. Moorman J, Rudd R, Johnson C, et al. MMWR Island Hospital. 2007;56:1-14; 18-54. Robert B. Klein, MD, is Interim Pe- CORRESPONDENCE 36. Ogden C, Carroll M, et al. JAMA diatrician-in-Chief, Hasbro Children’s Sheryl Kopel, MSc 2006;295:1549-55. 37. Barlow S. Pediatrics 2007;120:S164-92. Hospital, Interim Medical Director, Bradley-Hasbro Research Center, Asthma & Allergy Center, and Professor and Rhode Island Hospital Acknowledgement: This research Interim Chairman, Department of Pedi- 1 Hoppin Street, Suite 204 was supported in part by Rhode Island atrics, Warren Alpert Medical School of Providence, RI 02903 Hospital. The authors wish to thank Eliza- Brown University. Phone: (401)444-7217 beth McQuaid, PhD, for her feedback e-mail: [email protected] on an earlier version of this manuscript.

Inner City Asthma Stanley Hoyt Block, MD, FAAAAI

Inner-city residents with asthma often thought that they had asthma only when FINANCIAL BARRIERS have particularly severe disease. Asthma they were symptomatic; this “no symp- Many patients in the inner city are prevalence is as high as 14.3%1 in children toms, no asthma” belief was associated with uninsured. They cannot easily obtain from poor families compared to 6%2 over- lower use of inhaled steroids.7 Much edu- long-term medications. However, pro- all prevalence for children A large survey cation is needed on an individual and viders can help steer these patients to the of Connecticut families showed an 18.4% group basis to explain the function and pharmaceutical companies’ free medica- prevalence of asthma in Hispanic (mainly use of inhaled steroids, the importance of tion programs. If the patient can control Puerto Rican) children, compared to 7.4% therapy, and the fact that asthma is a his/her asthma and find a job, s/he may in non-Hispanic whites.3 For African chronic disease with continued inflamma- be able to get health insurance. Americans, hospitalization rates for asthma tion of the airways, requiring preventive are almost three times as high as the rates (controller) treatment for those with mild- ENVIRONMENTAL BARRIERS for whites.4 Fatalities from asthma, though persistent, moderate-persistent and severe- Inner-city asthmatics are often ex- unusual, are two to six times more common persistent asthma. Many ethnic groups posed to roaches, mice, mold and dust among African Americans and Latinos than utilize “home” remedies, which may have mites and have little ability to control among whites.5 little or no efficacy in asthma. Sensitive their environment. A study showed that Why the disparity? The multi-fac- discussions, tolerance and education can the combination of cockroach sensitiza- torial answers include genetic predispo- help patients understand that Western tion and exposure to high levels of this sition, barriers to medical care and medi- medicine has much to add and that con- allergen in the home seemed to increase cation, environmental exposures, finan- troller medications, like inhaled steroids, asthma hospitalization, unscheduled cial limitations, language limitations, and can greatly improve the well being of pa- medical visits for asthma, days of wheez- cultural beliefs. tients with persistent asthma. ing, missed school days, and lost sleep.8 The clinician must address these Thus, persistence with a variety of meth- barriers. LANGUAGE BARRIERS ods of roach and rodent avoidance is We will need good interpreters or warranted despite the challenges. Since CULTURAL BELIEFS bilingual providers, if we want to lower poor patients usually rent their homes, Many inner-city asthmatics tradition- the high morbidity of this disease among they sometimes cannot follow the usual ally visit the emergency room when their our growing Latino population. Illiteracy instructions to reduce allergen expo- asthma flares, but do not embark on a pre- is a major problem among inner-city pa- sures. For example, they may be able to ventive program through their primary tients, even among those who speak En- purchase allergy proof encasings for care physicians or allergy or pulmonary glish well. Written plans may work well their box springs, mattress and pillows specialists. Many believe that asthma is for more sophisticated suburban popu- for dust-mite control, but may not be “absent” or “cured” when the asthma is lations, but among patients with limited able to pull up carpeting (a good asymptomatic, and that asthma medica- literacy, written documents may be method of dust mite reduction). Fur- tions are necessary only for acute episodes.6 meaningless—especially if written in a thermore, if they complain to the land- In a group of high-risk, low-income, language other than the patient’s “lan- lord about roaches or rodents, they may mainly Hispanic and African-American guage of comfort”. fear eviction. Nevertheless, many inner- people, over half of those who had asthma city patients can reduce the roach bur-

164 MEDICINE & HEALTH/RHODE ISLAND den by using professional exterminators, short bursts to achieve control during d) Translation services or by buying “roach baits.” The impor- flares. Chronic oral steroids, while ef- e) Educational material in various lan- tance of careful cleaning and avoidance fective, can cause multiple problems. Of guages—at very low literacy levels of food or garbage around the house course, the more complex the regimen, f) Nurse Education—about medica- must be emphasized. Despite these the more education is required to en- tions, spacers, nebulizers, peak flow measures, roach control in multifamily courage adherence. For non-English meters, metered dose inhalers, dry dwellings is often difficult if not impos- speaking families, this is a particular chal- powder delivery systems, preventive sible. Avoidance of smoking (active and lenge. medicines, use of rapid-relief medi- passive) in the home is another impor- cations, emergency plans, etc. tant and cost-saving effort. In the in- OUR EXPERIENCE g) Home visits, when needed, to en- ner-city, families who keep dogs prima- As Medical Director and board-cer- courage compliance and to reduce rily for safety may be reluctant to aban- tified Allergist at The Providence Com- triggers such as dust mites, mold, don their large canine “pets”. Never- munity Health Centers (PCHC), the tobacco smoke, roaches, rodents, theless, if an asthmatic has a large posi- author has staffed an Asthma/Allergy pet dander, etc. tive skin test to “dog” (cat, birds, or other Clinic at one of PCHC’s nine sites for h) Smoking cessation assistance animals), the family should be urged to thirty years. PCHC provides primary i) Help in getting free medications for remove the pet from the home. care (Pediatrics, Ob/Gyn, Internal Medi- the uninsured or underinsured cine and Family Medicine) to 35,000 through Patient Assistance Pro- TREATMENT PLANS patients (one out of six Providence resi- grams and samples. About a third In the inner-city, certain limitations dents) who make over 120,000 visits each of our patients at the Asthma/Al- may require changes in management. year. PCHC started an Asthma/Allergy lergy Clinic are uninsured or un- For example, there is a high “no-show” specialty clinic at its Captiol Hill Health der-insured for medicines. rate for appointments: some patients Center site thirty years ago, serving only “show” when their asthma is exac- mainly inner-city and minority Rhode Through support of a Rhode Island erbating. Therefore, immunotherapy, Islanders (of whom almost 2/3 are Span- legislative grant and a research grant with (also called “allergy shots”) may not be ish speaking). Hasbro Children’s Hospital, our Certi- ideal in an inner-city population, as sev- Since asthma runs in families, the fied Asthma Educator (a Nurse) and her eral missed appointments may require PCHC’s Asthma/Allergy Clinic now Spanish-speaking assistant teach patients starting over in the build-up or mainte- cares for asthma among children and about the importance of controller-medi- nance phase. Similarly, the more simple even grandchildren of its original pa- cines and how to use the inhalers, the medical regimen, the more likely the tients. The PCHC Asthma/Allergy nebulizers, dry-powder delivery systems, patient is to follow instructions. How- Clinic sees asthmatics of all ages (about peak flow meters etc. Low-literacy edu- ever, with culturally and linguistically 40% children and 60% adults). Most cational materials are available for pa- sensitive education, many inner-city pa- of the patients served at the Capitol Hill tients who cannot read English (or Span- tients can be encouraged to follow even Health Center’s Asthma/Allergy Clinic ish) well. The Asthma Educators go over a complicated medical regimen. All asth- are poor; many are uninsured or the entire plan with the patient or par- matics receive a prescription for a short- underinsured. They speak eight lan- ents, after they are seen by the physician, acting bronchodilator (e.g. Albuterol) guages: so that asthma attacks are minimized, ex- by inhaler (and often by nebulizer) to Spanish (58%) pensive emergency room visits become be used on an as needed (not regular) Khmer (Cambodians) – 5% rare, and hospitalizations are avoided. basis. Patients with mild-persistent, Lao – 3% Many patients who previously missed moderate-persistent and severe-persis- Portuguese – 2% much work or school can work or attend tent asthma usually are started on an Hmong – 1% school faithfully. inhaled steroid (with dose dependent on Creole 0.5% Even our most severe asthmatics are severity, risk and control). Patients with Haitian/French – 0.5% usually controlled on a comprehensive more severe asthma often require addi- English 30% program including inhaled steroids (with tional medications, such as long-acting Sign language (deaf patients/ higher doses required for particularly se- beta agonists in addition to inhaled ste- parents) – occasional. vere patients), long acting beta agonists, roids, and may also require leukotriene leukotriene receptor antagonists and en- receptor antagonists (e.g. Montelukast). Regardless of insurance status, the vironmental control. Co-morbidities The most severe allergic asthmatics may Capitol Hill Health Center’s Asthma/ such as gastroesophageal reflux, sinusitis also require every two to four week sub- Allergy Clinic provides the following to and allergic rhinitis, all of which can cutaneous injections of Omalizumab patients: worsen asthma, must be addressed. Only (Xolair), but this medicine’s potential a) Evaluation by the board-certified a few require long-term oral steroids, side effects require significant office Allergist omalizumab or zileuton. Among the most waits (due to reports of anaphylaxis) that b) Spirometry difficult asthmatics to control are those make it more difficult to use in the in- c) Allergy skin tests to determine al- whose asthma is complicated by long- ner-city. Oral steroids are often used in lergens and asthma “triggers” term smoking with the onset of a COPD 165 VOLUME 91 NO. 6 JUNE 2008 component. Similarly, even in non-smok- 5. Mannino DM., Homa DM, et al. MMWR 1198. Disclosure of Financial Interests ers, some immigrants have had severe 47: 1-27. The author has no financial inter- 6. Draft January 2007: National Heart, Lung, and asthma for decades with little or no ef- Blood Institute. National Asthma Education and ests to disclose. fective treatment in their country of ori- Prevention Program. Full report of the Expert gin and now have much “remodeling” Panel; Guidelines for the Diagnosis and Manage- CORRESPONDENCE of their airways, making their asthma and ment of Asthma (EPR-3):273. Stanley Hoyt Block, MD, FAAAAI 7. Draft January 2007: National Heart, Lung, and fixed-airway obstruction almost impos- Blood Institute. National Asthma Education and The Providence Community Health sible to completely control. Even in such Prevention Program. Full report of the Expert Centers Inc. patients, an educational program and Panel; Guidelines for the Diagnosis and Manage- 375 Allens Ave ment of Asthma (EPR-3): 274. medicine can improve their quality of life. 8. Rosenstreich D, Eggleston P, et al. NEJM YEAR Providence, RI 02905-5010 336: 1356-62. Phone: (401) 444 0400 REFERENCES e-mail: [email protected] 1. Crain EF, Weiss KB, et al. Pediatrics 1994; Stanley Hoyt Block, MD, FAAAAI, is 94:356-62. 2. Taggart VS, Fulwood R. Prev Med 1993; 22: Medical Director, The Providence Com- 579-84. munity Health Centers Inc., and Clinical 3. Sly RM. Ann Allergy, Asthma Immunol 2006; Associate Professor, Warren Alpert Medical 26:76-9. School of Brown University. 4. Mannino DM, Homa DM. MMWR 1198. 47: 1-27.

The National Asthma Education and Prevention Program (NAEPP) Guidelines: Will They Improve the Quality of Care in America? Sidney S. Braman MD, FCCP, and Arul Vigg, MBBS Asthma affects 300 million people In fact, strong evidence links anti-inflam- persistent asthma symptoms, the clinician globally.1 Its prevalence has risen over the matory therapy with inhaled corticosteroids should evaluate for environmental causes, last several decades; recent data show that to a reduction in asthma mortality.4 The particularly indoor inhalant allergens (e.g., 22 million Americans are affected. Six NAEPP guidelines define asthma as: “ a house-dust mites, indoor pets and cock- million of these patients are children. chronic inflammatory disease of the airways roaches) as well as exposure to tobacco Worldwide, the prevalence has increased in which many cells and cellular elements smoke. Sometimes allergies can be deter- by 50% every decade. play a role: in particular mast cells, neutro- mined by the medical history. If not, skin In response, the National Asthma phils, eosinophils, T lymphocytes, macroph- or in vitro testing are useful in identifying Education and Prevention Program ages, and epithelial cells. In susceptible in- causative agents.5 Once this is determined, (NAEPP), in an effort coordinated by the dividuals, this inflammation causes recur- a multifaceted comprehensive allergen National Heart, Lung, and Blood Institute rent episodes of coughing (particularly at avoidance plan can be advised. (NHLBI) of the National Institutes of night or early in the morning), wheezing, Health, commissioned an expert panel to breathlessness, and chest tightness. The 2) Use of objective measures of lung develop guidelines that would raise public episodes are usually associated with wide- function to assess the severity of asthma awareness, improve physician recognition spread but variable airflow obstruction that and to monitor the course of therapy of asthma as a growing health problem and is reversible either spontaneously or as a re- The 2007 and previous guidelines improve asthma control. The first expert sult of treatment.” stressed the need for objective measures panel report was offered in 1991, with of asthma because the medical history and updates in 1997, 2002, and 2007: The THE ASTHMA GUIDELINES: FOUR physical examination are not reliable tools Expert Panel Report 3, “Guidelines for the COMPONENTS OF EFFECTIVE to determine the level of lung impairment Diagnosis and Management of Asthma.” MANAGEMENT and exclude other diagnoses. Since symp- www.nhlbi.nih.gov/guidelines/asthma. 1) Environmental control measures to toms result from widespread airflow ob- This paper will highlight the lessons avoid or eliminate factors that precipi- struction, spirometry is extremely useful offered by the guidelines and review the tate asthma symptoms or exacerbations in making a proper diagnosis.6 Spirom- changes made to the Expert Panel Report The NAEPP definition stresses the etry measures the amount of air that is 3.2 episodic nature of asthma. Symptoms may forcefully exhaled after a maximal expira- DEFINITION OF ASTHMA be minimal or nonexistent and can appear tion. It is recommended to monitor lung In 1991, the NAEPP guidelines estab- suddenly with no apparent cause. More function before and after treatment to in- lished asthma as an inflammatory disease, commonly symptoms are the result of spe- sure adequate response. The amount ex-

thereby providing the basis for anti-inflam- cific (aeroallergens) or nonspecific (dust, haled after 1 second, the FEV1, is recorded matory therapy. This has been the founda- cigarette smoke, fumes, cold air, exercise, and considered the most reliable number tion of treatment over the last two decades.3 etc.) exposures. For patients who have to follow the course of disease. If airflow 166 MEDICINE & HEALTH/RHODE ISLAND cation of mild intermittent, the manifestations of asthma are minimized Table 1. mild persistent, moderate by therapeutic interventions and the goals Goals of Asthma Therapy NAEPP 2007 persistent and severe per- of therapy are adequately met. In the 2007 sistent disease encouraged Guidelines, instead of severity driving thera- Reduce Impairment a step care approach. Mild peutic decisions, an assessment of asthma 1. Prevent chronic and troublesome symptoms, intermittent disease with control will determine how the step up daytime or night symptoms and beta agonist therapy algorithm is applied. If the patient 2. Infrequent use of inhaled short-acting beta use two or less times a week has been asymptomatic and does not re- agonist (rescue) therapy. (<2 days a week) requires only as needed quire rescue therapy, step down therapy (a 3. Maintain normal activity levels including short-acting beta agonist reduction in medication) may be exercise, physical activities, work and school. rescue medication. considered.A number of measures of con- 4. Meet patient and family’s expectations of When the disease be- trol have been offered. Some are more satisfaction with asthma care comes persistent (symp- suited for research. Others, such as the 5. Maintain normal or near-normal pulmonary toms occur more than two Asthma Control (ACT), are more suited function times a week), anti-inflam- for clinical use.11,12 The ACT, endorsed by matory therapy is essen- be American Lung Association (ALA), Reduce Risk tial.10 Additional pharma- does not use lung function testing and is a 1. Prevent exacerbations of asthma and need for cotherapy with long-acting questionnaire that can be quickly scored. emergency care and hospitalization beta agonists, leukotriene The test asks the patient: 2. Prevent loss of lung function and for children, pathway modifiers, anti- avoid reduction in lung growth IgE therapy and pred- 1) Has your asthma prevented normal 3. Provide optimal pharmacotherapy with minimal nisone is offered in a activities at home or at work? or no side effects stepwise manner the more 2) Have you had shortness of breath severe the disease. in the past four weeks? obstruction is detected using spirometry, 3) Has your asthma kept you awake at a short-acting beta agonist (also used for 4) Patient education that fosters a night? rescue therapy during an attack) is given partnership among the patient, his or 4) How often have used your asthma to the patient in the pulmonary function her family, and clinicians inhaler in the last four weeks? And, testing laboratory to look for reversibility. Asthma self-management education 5) Overall, how have you made your Asthmatics will usually show partial or com- can provide patients with the skills to con- asthma control in the last four weeks? plete resolution of airflow obstruction af- trol asthma. The patient and all members ter a short-acting bronchodilator (such as of the health care team should agree upon The final score can be used to assess albuterol) is given. Since reversible air- the goals; and sites for self- management control. The 2007 NAEPP Guidelines flow obstruction is the hallmark of asthma, education outside the usual office setting also encourage the doctor to ask the pa- this test is useful in making a diagnosis.7 should be explored. The actions of the tient how satisfied she/ is with his/her Also, the degree of reversibility cor- medications should be discussed and their asthma care: very satisfied, somewhat sat- relates with airway inflammation;8 and potential complications understood. Writ- isfied, not satisfied. patients with a high degree of reversibility ten plans should guide daily care. An ac- The new guidelines broadly classify have a greater chance of developing irre- tion plan for the acute exacerbation of treatment options by age: 0-4, 5-11 and versible airflow obstruction in subsequent asthma will specify when to use oral corti- >12 years. There is new emphasis on years.9 The test can therefore be useful costeroids, when to call the physician and patient education and control of envi- in identifying high risk patients who need when to use emergency services. For asth- ronmental factors. The guidelines stress close monitoring, although research has matics who have frequent symptoms and the identification of co-morbid condi- suggested that current asthma therapies exacerbations or those who poorly perceive tions. The approach to exacerbations of do not prevent progression of the under- their symptoms, hand-held peak flow asthma has been modified, with a simpli- lying disease severity. meters may be useful to monitor daily lung fied classification of severity. function. An action plan for worsening The NIH-sponsored NAEPP clinical 3) Comprehensive pharmacologic lung function may help avoid emergency practice guidelines have shifted the focus therapy for long-term management room visits and near-fatal attacks. from the treatment of acute symptoms to designed to reverse and prevent the prevention of symptoms with anti-in- airway inflammation KEY DIFFERENCES IN THE 2007 flammatory therapy. However, despite The NAEPP guidelines have set ob- NAEPP GUIDELINES these guidelines, many patients are under- tainable goals for care. (Table 1) Previously, The 2007 NAEPP guidelines still ad- treated and, as a result, morbidity and treatment decisions were based on an as- vocate the severity scale, but only during mortality from asthma rermain high.13 sessment of disease severity, determined by the initial assessment, prior to initiating The 2007 NAEPP asthma guidelines sug- patient symptoms, need for short-acting therapy. The 2007 guidelines focus on the gest improvements that are more patient- beta agonist rescue therapy and spirometry assessment of control rather than severity. focused and useful to the clinician.14 or peak flow assessment. A severity classifi- Control is defined as the degree to which 167 VOLUME 91 NO. 6 JUNE 2008 REFERENCES Sidney S. Braman, MD, FCCP, is Di- CORRESPONDENCE 1. Braman SS. Chest 2006; 130:4S-12S. rector, Division of Pulmonary and Critical Sidney S. Braman, MD, FCCP 2. Expert Panel Report 3 (EPR-3): J Allergy Clin Care Medicine, Rhode Island Hospital, and Rhode Island Hospital Immunol 2007; 120:S94-138. 3, Busse WW, Lemanske RF, Jr. NEJM 2001; Professor of Medicine, The Warren Alpert 593 Eddy Street APC 7 344:350-62. Medical School of Brown University. Providence, Rhode Island 02903 4. Suissa S, Ernst P, et al. NEJM 2000; 343:332-6. Arul Vigg, MBBS, was a visiting Phone: (401) 444-8410 5. Dolen WK. Clin Rev Allergy Immunol 2001; student. e-mail: [email protected] 21:229-39. 6. Pellegrino R, Viegi G, et al. Eur Respir J 2005; 26:948-68. Disclosure of Financial Interests 7. Appleton SL, Adams RJ, et al. J Allergy Clin Sidney S. Braman, MD, FCCP. Con- Immunol 2005; 116:976-82. 8. Covar RA, Spahn JD, et al. J Allergy Clin Immunol sultant: Nycomed, GlaxoSmithKline. Grant 2004; 114:575-82. Research Support: GlaxoSmithKline, 9. Ulrik CS, Backer V. Eur Respir J 1999; 14:892-6. Boehringer Ingelheim. Speaker’s Bureau: 10. Bateman ED, Boushey HA, et al. Am J Respir Crit GlaxoSmithKline, Pfizer, Boehringer Care Med 2004; 170:836-44. 11. Nathan RA, Sorkness CA, et al. J Allergy Clin Ingelheim. Immunol 2004; 113:59-65. Arul Vigg, MBBS, has no financial 12. Liu AH, Zeiger R, et al. J Allergy Clin Immunol interests to disclose. 2007; 119:817-25. 13. Fuhlbrigge AL, Adams RJ, et al. Am J Respir Crit Care Med 2002; 166:1044-9. 14 Apter AJ. J Allergy Clin Immunol 2007; 119:563-6.

168 MEDICINE & HEALTH/RHODE ISLAND 169 VOLUME 91 NO. 6 JUNE 2008 170 MEDICINE & HEALTH/RHODE ISLAND Update On Stinging Insect Allergy Alan Gaines, MD, FAAAAI

Ancient texts record deaths from insect ing and desensitization is not generally for future systemic reactions: from 30% stings. Hieroglyphics on the wall of the indicated in these patients. to 60% of untreated skin-test positive pa- tomb of Egyptian King Menes reportedly Of most concern are the generalized tients with prior reactions will have an- describe his death from a wasp or hornet reactions, especially anaphylaxis, esti- other systemic reaction on intentional sting c. 2641 BC,1 although this is not mated, in retrospective studies, to occur challenge sting.3, 5 These subsequent re- universally accepted.2 The Babylonian in 0.3%-3% of stings.3 Relatively mild actions are frequently of similar intensity Talmud, c. second century BC to third systemic reactions that are limited to the to the original reaction, but may be ei- century AD, refers to a fatal wasp sting.1 dermis with hives, flushing and an- ther milder or more severe. Retrospec- In this country, documented deaths gioedema don’t strictly meet the criteria tive studies of “field” stings in previous from insect sting anaphylaxis occur at the for anaphylaxis;4 these occur more com- stinging insect reactors have also shown rate of about 40 people per year, although monly in children. However, many subsequent reaction rates in the 60% it is likely that additional unrecognized people of any age will react with signifi- range,6 although these studies have in- cases are reported as “sudden deaths.”3 cant respiratory, cardiovascular, and/or definite insect identification and possible The stinging insects implicated in gastrointestinal symptoms as well. The recall bias. anaphylactic reactions are in the Hy- respiratory symptoms can include swell- menoptera order, and in this region con- ing of the throat or larynx with hoarse- IMMEDIATE TREATMENT sist primarily of the Vespids (wasps, yel- ness, coughing or choking, difficulty While “normal” or large local reac- low jackets and hornets) and the Apidae breathing or talking, and stridor or bron- tions require little treatment, systemic (bees). The fire ant, found in the chospasm. Nasal congestion and rhinor- reactions can be life threatening and re- Formidae family, has been implicated in rhea and watery eyes can be present. The quire immediate treatment. If there is anaphylactic reactions and is a problem cardiovascular symptoms can include no history of severe reaction and the only in the Southern United States, but not hypotension and circulatory collapse systemic symptom is mild urticaria, use in New England. with shock. Nausea, vomiting, and loss of H1 and H2 antihistamines may be of bowel control can occur. These symp- sufficient if there is a quick response. TYPES OF REACTIONS toms generally appear within minutes, However, generalized urticaria or appear- The most common, “normal,” reac- but can occasionally present several hours ance of any respiratory or cardiovascular tion to a sting consists of pain, erythema after a sting. Most of the fatalities from symptoms or other signs of systemic ana- and swelling at the sting site.3 This usu- insect stings have been in adults, perhaps phylaxis should be promptly treated with ally starts to subside after a couple of because of coexisting cardiovascular dis- intramuscular epinephrine, which is the hours, and requires only cool compresses ease. (Figure 1) drug of choice for acute systemic allergic and analgesics. While most people who have ana- reactions.7, 8 In adults, the dosage is 0.3 In some cases, a “large local” reac- phylactic reactions to stings do not have to 0.5 mg; in children the dosage is tion will develop with fairly massive local a history of prior reaction, once some- 0.01mg/kg up to 0.3 mg. It may be nec- swelling, increasing over 24-48 hours one has had one anaphylactic reaction essary to repeat the dose for persistent or and lasting up to a week.3 These are to a sting they are at greatly increased risk recurrent symptoms. There is no con- erythematous and warm to the touch, and can be con- fused with cellulitis, which is much less common after a sting. Antihistamines and analgesics can reduce the discomfort, and for severe reactions that are disabling or extensive, a short course of prednisone can reduce the swelling. While these large local reactions will fre- quently recur on future stings, and discussion of stinging insect avoidance is warranted, very few (<5%) will have anaphylaxis on fu- ture stings and venom test- 171 VOLUME 91 NO. 6 JUNE 2008 tracts were not performed until the 1970s. These studies con- firmed the superiority of purified stinging insect venoms in diag- nosing stinging insect allergy and showed the remarkable success of venom immunotherapy (VIT) in preventing future reactions. In fact, VIT in history-positive, skin test positive patients appears to re- duce the risk of subsequent sys- temic sting reactions from 60% to less than 5%. Furthermore, when reactions do occur they generally are milder than the original one.8 There are several different schedules for building up immu- notherapy to effective doses, from ‘Rush” 1 or 2 day protocols, which involve more risk, to the more common schedules, in- creasing doses over several weeks traindication to the use of epinephrine Administration of corticosteroids is or months. Once the maintenance dose in a life-threatening situation, such as frequently part of the treatment of ana- has been reached, usually 100mcg of anaphylaxis.8 phylaxis. Although this has minimal if any each venom which had tested positive, Additional acute treatment depends immediate effect, it may help reduce the the immunotherapy dose is usually given on the symptoms and the response to late phase of acute reactions or shorten every 4 to 6 weeks, although as duration epinephrine. If there is continued hy- the length of symptoms in prolonged re- of therapy increases the interval can potension, consideration should be given actions. sometimes be lengthened to 8 or even 12 to intravenous fluids to treat a functional As for biphasic reactions, in 1 to weeks.8 hypovolemia.7 Use of slow administration 20% of cases of anaphylaxis, including The risks of systemic reactions to VIT of a diluted epinephrine or a vasopressor those to insect stings, there can be a do not appear to be very high, and are intravenously may be indicated in some biphasic reaction with a recurrence of not significantly different than those in- situations. Supine position and elevation symptoms several hours after resolution volved in other allergen immunotherapy. of legs can also be helpful in maintaining after the initial episode.9 Some physicians It is advisable to have the shots adminis- central perfusion. Bronchospasm should have recommended observation for 8-24 tered by a professional trained in the rec- be treated with inhaled beta agonists if it hours after any anaphylactic episode, ognition and treatment of anaphylaxis, does not respond to the initial epineph- while others feel this is impractical be- with epinephrine and other emergency rine treatment. Oxygen should also be cause the vast majority of such patients medications on hand, and for the patient administered for respiratory or circula- will have no further problems. At a mini- to remain in the office at least 20-30 min- tory compromise. mum, it is imperative that patients be utes following each injection. Risk fac- Beta-blockers, commonly prescribed made aware of the possibility of a recur- tors for more severe reactions, either to for cardiovascular indications and mi- rence and be discharged with a means of stings in the wild or to VIT, include graine headaches, can lead to a blunted self-administering epinephrine. arrhythmias, hypertension and other con- response to epinephrine in many patients ditions with significant cardiopulmonary while others may have a paradoxical re- VENOM IMMUNOTHERAPY compromise. The use of beta-blockers sponse and develop acute hypertension While early attempts at desensitizing in patients with venom hypersensitivity when given epinephrine. If a patient on patients with histories of severe reactions is also complex. While these drugs are beta-blockade has continued hypoten- to insect stings using whole body extracts normally considered a contra-indication sion despite epinephrine, glucagon may proved ineffective, subsequent studies to allergen immunotherapy as they make be helpful in restoring blood pressure. using actual venoms from the stinging treatment of anaphylaxis more difficult In patients at significant risk for future insects proved much more useful. In un- (especially with regard to successful use reactions or for whom immunotherapy controlled studies in the 1950s, Dr. Mary of epinephrine), the patients with venom may be prescribed, consideration should Loveless in Connecticut dissected out sensitivity who require beta-blockers for be given to switching from the beta- venom sacs and prepared her own ex- other conditions are already at risk of blocker to an alternative class of medica- tracts with apparent success.10 Compre- anaphylactic reactions, with likely poor tion if possible.7 hensive studies using standardized ex- response to treatment, from possible fu- 172 MEDICINE & HEALTH/RHODE ISLAND ture stings. In these patients the admin- notherapy is stopped even after 5 years, REFERENCES istration of the usually well-tolerated VIT and some experts recommend indefinite 1. Cohen SG, Samter M, eds. Excerpts From Classics nd is often felt justified to decrease the high continuation of shots in those patients.8, in Allerg y, 2 Edition, Carlsbad, CA: Symposia Foundation,1993:4-5. 13 risk of reaction in an unmonitored set- The potential risks and benefits of ei- 2. Chafee FH. J Allergy 1969;43:309. ting.11 ther stopping or continuing the shots 3. Reisman RE. Clinical aspects of Hymenoptera al- needs to be discussed with each patient lergy. In: Levine MI and Lockey RF, eds, Mono- th SELECTION OF PATIENTS AND on an individual basis. graph on Insect Allergy, 4 ed. Pittsburgh: Dave Lambert Assoc, 2003;55-61. VENOMS FOR VIT 4. Sampson HA, Munoz-Furlong A, et al. J Allergy Given the high efficacy and general PREVENTIVE MANAGEMENT Clin Immunol 2006;117:391-7. safety of venom immunotherapy, guide- Any patient who has had more than 5. Graft, DF. Venom immunotherapy. In: Levine MI and Lockey RF, eds, Monograph on Insect Al- lines suggest that this treatment is indi- a local reaction to a Hymenoptera sting lergy, 4th ed. Pittsburgh: Dave Lambert Assoc, cated for anyone at significant risk for a requires preventive measures. For those 2003;103-12. serious IgE mediated systemic reaction to with systemic reactions, referral to an al- 6. Reisman RE. J Allergy Clin Immunol future stings. (Figure 2) This would in- lergist-immunologist for specific IgE test- 1992;90:335-9. 7. Valentine, MD. Treatment of insect sting reac- clude anyone of any age group who re- ing and consideration of venom immu- tions. In: Levine MI and Lockey RF, eds, Mono- 8 acted to a sting with respiratory or car- notherapy is generally indicated. All graph on Insect Allergy, 4th ed. Pittsburgh: Dave diovascular symptoms, including laryn- such patients should also be prescribed Lambert Assoc, 2003;97-102. geal edema, dizziness, palpitations, etc, self-injectable epinephrine and advised to 8. Moffitt JE, Golden, DBK, et al. J Allergy Clin Immunol 2004;114:869-86. and who has confirmatory skin testing or have this always available, and consider- 9. Lieberman P. Ann Allergy Asthma Immunol demonstrable specific IgE. It does ap- ation should be given to having 2 doses 2005;95:217-26. pear, however, that children 16 years of available (either an Epipen Twin-pack or 10. Yunginger, JW. History of Hymenoptera allergy. age and younger who have had systemic a single Twinject) given the possibility of In: Levine MI and Lockey RF, eds, Monograph on Insect Allergy, 4th ed. Pittsburgh: Dave Lambert reactions limited to the dermis (urticaria, prolonged or biphasic reactions. Patients Assoc, 2003: 1-10. flushing, and/or non-life threatening should be advised to always seek imme- 11. Muller UR, Haeberli G. J Allergy Clin Immunol angioedema) represent a special case with diate emergency care if they needed to 2005;115:606-10. little chance of recurrent systemic reac- use the epinephrine as well. Patients 12. Golden DB, Kagey-Sobotka A, et al. NEJM 2004;351:668-74. tion if re-stung, and in whom future re- should consider wearing a medical iden- 13. Reisman RE. Discontinuation of venom immu- actions, if they do occur, are rarely worse tification bracelet or necklace. A fast-act- notherapy. In: Levine MI, Lockey RF, eds, Mono- than the original reaction.12 Many aller- ing oral antihistamine, such as liquid, dis- graph on Insect Allergy, 4th ed. Pittsburgh: Dave gists, therefore, feel that this group need solvable or chewable diphenhydramine, Lambert Assoc, 2003; 125-31. not necessarily be treated with venom may be kept available but should not be Alan Gaines, MD, FAAAAI, is Clini- immunotherapy on a routine basis, and used in place of epinephrine if a systemic cal Assistant Professor of Pediatrics, The War- this is reflected in current guidelines.8 reaction is taking place. ren Alpert School of Medicine of Brown Although some patients may feel they Education regarding avoidance University. can identify the insect that triggered their should be offered to these patients. reaction, these identifications are not usu- Trained professionals can exterminate Disclosure of Financial Interests ally reliable; and current practice is to ini- any known or suspected nests in the im- The author has no financial inter- tiate immunotherapy with all of the hy- mediate vicinity of the patient’s home. ests to disclose. menoptera for which specific IgE is dem- Patients should avoid brightly colored onstrated by either skin or blood test.5 clothing or floral prints, and avoid CORRESPONDENCE strongly scented perfumes that might at- Alan Gaines, MD, FAAAAI DURATION OF VENOM tract insects. These patients should not 95 Pitman Street IMMUNOTHERAPY walk outside without shoes, and should Providence RI 02906 A body of evidence indicates that 3- wear long pants, long-sleeved shirts, Phone: (401) 331-8426 5 years of venom immunotherapy will socks, head coverings and gloves if work- e-mail:againes@cox,net result in long-lasting protection for most ing outdoors (such as gardening). They patients, even if skin tests remain posi- need to be cautious when eating or drink- tive. After such a course, no more than ing outdoors, as stinging insects are at- 10-20% of patients will have systemic tracted to food and beverages and have reactions after subsequent stings, and even been known to be inside open soda most of those will be milder or similar to cans and to sting people in the lips or their previous reaction. Some patients, mouth. mainly those with history of a particularly severe reaction such as shock or loss of consciousness, or who had honeybee al- lergy or had reactions to immunotherapy, still seem to be at fairly high risk for sys- temic reactions to stings if venom immu- 173 VOLUME 91 NO. 6 JUNE 2008 The Role of Pollens In Allergy Henry B. Freye, MD, FAAAAI

One foundation of allergy practice is the slides. This method continued over the next of eliciting reagenic responses. To pro- physician’s knowledge of regional hundred years in many parts of the world, voke symptoms, pollens must be present aeroallergens.1 The periodicity of symptoms including the studies in Providence, RI, by in sufficient numbers and under favor- in asthma, allergic rhinitis, and conjunctivitis Frances Chafee and Guy Settipane.4 In able transport conditions. in a patient with pollenosis can be readily ex- 1981 Jack Farnham5 used a roto-rod col- plained on the basis of exposure to specific lecting system, which utilized a volumetric IMMUNOTHERAPY FOR POLLENOSIS types and quantities of inhaled pollen to which technique to relate particle recoveries to Hyposensitization, or a series of in- he or she is sensitized. A physician should unit volumes of sampled air. Ongoing stud- jections of increasing amounts of pollen know the common “hay fever” plants and be ies continue through a network of stations extract we now call immunotherapy, first familiar with the regional calendar of tree, grass throughout New England.6,7 became popular early in the 20th century. and weed seasons is fundamental. Allergen content was measured in Noon While historic, local and general pol- PHYSICAL ATTRIBUTES OF units (weight/volume) in 1911. Subse- len data are valuable in interpreting skin test AEROALLERGENS quently, more sophisticated purification reactions and choosing antigens for treat- Airborne pollen allergens are prima- of pollens and standardization of their ment, unpredictable meteorological factors rily proteins associated with biogenic par- potency became feasible.8,9,10,11 The Food can cause variations in pollen production, as ticles measuring 2 to 60 ìm. This size and Drug Administration (FDA) ap- happened during El Ni¤o in 1997- 1998.2 enables the smaller pollens to be readily proved the first licensed standardized impacted onto ocular surfaces, inhaled, short ragweed pollen extract (AMB a 1) HISTORICAL PERSPECTIVES and aspirated to trigger symptoms in the in 1981, and grass pollen in 1998.8 Over 130 years ago, Blackley3 first sensitized individual. The particulate As increasing doses of extract are in- popularized the collection and study of grass pollen must therefore contain the specific jected, tolerance to the injected and weed pollen using gravity-collecting antigenic groupings, which are capable aeroallergen develops. Concomitantly, there is an initial increase in serum levels of IgG and IgE antibodies to the specific pollen. Ultimately, a higher plateau of IgG occurs and IgE decreases as immu- notherapy progresses. This down-regu- lation of IgE is felt to be a critical mecha- nism in the improvement seen in allergic rhinitis, allergic asthma and allergic con- junctivitis.11,12 The search for an improved method of immunization has spurred recent re- search. The goal is a vaccine that requires fewer injections, can be given in larger doses with greater safety, and with longer intervals between injections. Aqueous immunotherapy is the cur- rent standard treatment modality. It has been followed by trials of oil-based re- pository injections, alum-precipitated pyridine pollen extract13 and other vac- cines. Most notable is a recent attempt to immunize patients allergic to ragweed with ragweed- toll-like receptor 9 ago- nist vaccine to induce tolerance through the immune system.14 Although oral hyposensitization to pollens has been attempted in this coun- try,15,16 the consensus is that despite its effectiveness in certain individuals, treat- ment in general is less effective than parenteral therapy.15 However, recent 174 MEDICINE & HEALTH/RHODE ISLAND studies of sublingual immunotherapy REFERENCES 15. Feinberg SM, Foran FL., et al. JAMA 1940;115: 23. (SLIT) may signal a change in the treat- 1. Smith EG. Sampling and Identifying Allergenic Pollens 16. Black JH, Holman J. J Allergy 1950;21:148. 17. Frati F, Moingedn P. et al. Asthma Allergy Proceed- ment of pollenosis, particularly in chil- and Molds. San Antonio: Blewstone Press, 1984. 2. Freye HB, King J, Litwin C. Ann Allergy ings 2007;28 (1). dren who are less receptive to parenteral 1999;l82: 114. 18. Sekhsaria S, Singla M, et al. ACAAI Annual Meet- treatment.17 3. Blackley C. Experimental Researches on the Cause ing, Philadelphia, November 2006. An adjunct to therapy has been the and Nature of Catarrhus Aestivas. London: 19. Newman C, Cooper M. National Geographic 1984; 166:4 October. monoclonal antiIgE antibody omalizumab Balliere, Tindall Cox, 1873. 4. Chafee FH, Settipane GA. J Allergy 1964;35:193- for asthma, which can be used in highly- 200. Henry B. Freye, MD, FAAAAI, is a allergic individuals who had been difficult 5. Farnham JE. Atmospheric pollen and Fungi Rhinitis locum tenens allergist. to manage with the usual immunotherapy 2nd ed. Providence, RI: Oceanside Publications, 1991. 18 6. Freye HB, King J. Allergy and Asthma Proceed- alone. ings. July, 2003 Disclosure of Financial Interests 7. Freye H, King J. Fall meeting of the New England The author has no financial inter- CONCLUSION Society of Allergy meeting Woodstock, VT. 2005. ests to disclose. We have described some historical 8. Esch RE. A history of allergen standardization. Greer Lab, Lenoir, NC. 1999 perspectives, methods of pollen collec- 9. Johnstone DE. AMA J Dis Child 1957;94:1. CORRESPONDENCE tion, temporal relationship to allergic 10. Lowell FC, Franklin WA. J Allergy 1963;34:165. Henry B. Freye, MD, FAAAAI symptoms, physical attributes of 11. Norman PS., Lichtenstein LM. J Allergy Clin 22 Elizabeth Court aeroallergens, and the methodology of Immunol 1978;61:370. 12. Creticos PS, Adkinson NS JR, et al. J Clin Invest Mystic, CT 06355 pollen immunotherapy. Not mentioned 1985;76:2247/ Phone: (860) 536-1570 has been the allergist’s singular important 13. Tuft L, et al. Am J Med SC 1965; 250:668. e-mail: [email protected] intervention: environmental control to 14. Creticos PS., Schroeder JT, et al. NEJM 2006; moderate the influence of pollens in the 355 1445-55. treatment of the allergic individual.18

175 VOLUME 91 NO. 6 JUNE 2008 176 MEDICINE & HEALTH/RHODE ISLAND 177 VOLUME 91 NO. 6 JUNE 2008 178 MEDICINE & HEALTH/RHODE ISLAND 179 VOLUME 91 NO. 6 JUNE 2008 180 MEDICINE & HEALTH/RHODE ISLAND THE IMAGING INSTITUTE OPEN MRI • MEDICAL IMAGING

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WARWICK CRANSTON CRANSTON N. PROVIDENCE E. PROVIDENCE 250 Toll Gate Rd. 1301 Reservoir Ave. 1500 Pontiac Ave. 1500 Mineral Spring 450 Vets. Mem. Pkwy. #8 TEL 401.921.2900 TEL 401.490.0040 TEL 401.228.7901 TEL 401.533.9300 TEL 401.431.0080 181 VOLUME 91 NO. 6 JUNE 2008 A Clearer Vision of Health™ theimaginginstitute.com ™ 900 mcg/kg/day (approximately 35 times the maximum human daily intranasal dose in adults based on OMNARIS mcg/m2). (ciclesonide) Pregnancy: Teratogenic Effects Nasal Spray, 50 mcg Pregnancy Category C Oral administration of ciclesonide in rats up to 900 mcg/kg (approximately 35 times the maximum For intranasal use only human daily intranasal dose in adults based on mcg/m2) produced no teratogenicity or other fetal effects. Rx only However, subcutaneous administration of ciclesonide in rabbits at 5 mcg/kg (less than the maximum human daily intranasal dose in adults based on mcg/m2) or greater produced fetal toxicity. This included BRIEFSUMMARY: Please see package insert for full prescribing information. fetal loss, reduced fetal weight, cleft palate, skeletal abnormalities including incomplete ossifications, and INDICATIONS AND USAGE skin effects. No toxicity was observed at 1 mcg/kg (less than the maximum human daily intranasal dose Seasonal Allergic Rhinitis based on mcg/m2). OMNARIS Nasal Spray is indicated for the treatment of nasal symptoms associated with seasonal allergic There are no adequate and well-controlled studies in pregnant women. OMNARIS Nasal Spray, like other rhinitis in adults and children 6 years of age and older. corticosteroids, should be used during pregnancy only if the potential benefit justifies the potential risk to Perennial Allergic Rhinitis the fetus. Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to OMNARIS Nasal Spray is indicated for the treatment of nasal symptoms associated with perennial allergic physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than rhinitis in adults and adolescents 12 years of age and older. humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, CONTRAINDICATIONS most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid OMNARIS Nasal Spray is contraindicated in patients with a hypersensitivity to any of its ingredients. treatment during pregnancy. WARNINGS Nonteratogenic Effects The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such adrenal insufficiency. In addition, some patients may experience symptoms of corticosteroid withdrawal, infants should be carefully monitored. e.g., joint and/or muscular pain, lassitude, and depression. Patients previously treated for prolonged peri- Nursing Mothers ods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored It is not known if ciclesonide is excreted in human milk. However, other corticosteroids are excreted in for acute adrenal insufficiency in response to stress. In those patients who have asthma or other clinical human milk. In a study with lactating rats, minimal but detectable levels of ciclesonide were recovered in conditions requiring long-term systemic corticosteroid treatment, rapid decreases in systemic cortico- milk. Caution should be used when OMNARIS Nasal Spray is administered to nursing women. steroid dosages may cause a severe exacerbation of their symptoms. Pediatric Use Patients who are using drugs that suppress the immune system are more susceptible to infections than The safety and effectiveness for seasonal and perennial allergic rhinitis in children 12 years of age and healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course older have been established. The efficacy of OMNARIS Nasal Spray in patients 6 to 11 years of age for in children or adults using corticosteroids. In children or adults who have not had these diseases or been treatment of the symptoms of seasonal allergic rhinitis is supported by evidence from four adequate and properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration well-controlled studies in adults and adolescents 12 years of age and older with seasonal and perennial of corticosteroid administration affect the risk of developing a disseminated infection is not known. The allergic rhinitis, and one study in patients 6 to 11 years of age with seasonal allergic rhinitis. The efficacy contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. of OMNARIS Nasal Spray for the treatment of the symptoms of perennial allergic rhinitis in patients 6 to If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If 11 years of age has not been established (see CLINICAL TRIALS: Pediatric Patients Aged 6 to 11 Years). exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See The efficacy of OMNARIS Nasal Spray in children 2 to 5 years of age has not been established. The the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, safety of OMNARIS Nasal Spray in children 2 to 11 years of age was evaluated in 4 controlled clinical treatment with antiviral agents may be considered. studies of 2 to 12 weeks duration (see CLINICAL PHARMACOLOGY: Pharmacodynamics, CLINICAL PRECAUTIONS TRIALS, ADVERSE REACTIONS: Pediatric Patients). General Clinical studies in children less than two years of age have not been conducted. Studies in children under Intranasal corticosteroids may cause a reduction in growth velocity when administered to pediatric patients 2 years of age are waived because of local and systemic safety concerns. (see PRECAUTIONS: Pediatric Use). Rarely, immediate hypersensitivity reactions or contact dermatitis Controlled clinical studies have shown that intranasal corticosteroids may cause a reduction in growth may occur after the administration of intranasal corticosteroids. Patients with a known hypersensitivity velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of reaction to other corticosteroid preparations should use caution when using ciclesonide nasal spray since hypothalamic-pituitary-adrenal (HPA)-axis suppression, suggesting that growth velocity is a more sensi- cross reactivity to other corticosteroids including ciclesonide may also occur. tive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced of HPA-axis function. The long-term effects of this reduction in growth velocity associated with intranasal recent nasal septal ulcers, nasal surgery, or nasal trauma should not use a nasal corticosteroid until heal- corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” ing has occurred. In clinical studies with OMNARIS Nasal Spray, the development of localized infections growth following discontinuation of treatment with intranasal corticosteroids has not been adequately of the nose and pharynx with Candida albicans has rarely occurred. When such an infection develops, it studied. The growth of pediatric patients receiving intranasal corticosteroids, including OMNARIS Nasal may require treatment with appropriate local therapy and discontinuation of OMNARIS Nasal Spray. Spray, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged Therefore, patients using OMNARIS Nasal Spray over several months or longer should be examined treatment should be weighed against clinical benefits obtained and the availability of safe and effective periodically for evidence of Candida infection or other signs of adverse effects on the nasal mucosa. noncorticosteroid treatment alternatives. To minimize the systemic effects of intranasal corticosteroids, Intranasal corticosteroids should be used with caution, if at all, in patients with active or quiescent tuber- each patient should be titrated to the lowest dose that effectively controls his/her symptoms. culosis infections of the respiratory tract; or in patients with untreated local or systemic fungal or bacte- Geriatric Use rial infections; systemic viral or parasitic infections; or ocular herpes simplex. Clinical studies of OMNARIS Nasal Spray did not include sufficient numbers of subjects age 65 and over If recommended doses of intranasal corticosteroids are exceeded or if individuals are particularly sensi- to determine whether they respond differently from younger subjects. Other reported clinical experience tive or predisposed by virtue of recent systemic steroid therapy, symptoms of hypercorticism may occur, has not identified differences in responses between the elderly and younger patients. In general, dose including very rare cases of menstrual irregularities, acneiform lesions, and cushingoid features. If such selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, changes occur, topical corticosteroids should be discontinued slowly, consistent with accepted proce- reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant dis- dures for discontinuing oral steroid therapy. ease or other drug therapy. The risk of glaucoma was evaluated by assessments of intraocular pressure in 3 studies including 943 ADVERSE REACTIONS patients. Of these, 390 adolescents or adults were treated for up to 52 weeks and 186 children ages 2 to Adult and Adolescent Patients Aged 12 Years and Older: 11 received treatment with OMNARIS Nasal Spray 200 mcg daily for up to 12 weeks. In these trials, no In controlled clinical studies conducted in the US and Canada, a total of 1524 patients ages 12 years and significant differences in intraocular pressure changes were observed between OMNARIS Nasal Spray older received treatment with ciclesonide administered intranasally. The overall incidence of adverse events 200 mcg and placebo-treated patients. Additionally, no significant differences between OMNARIS Nasal for patients treated with OMNARIS Nasal Spray was comparable to that in patients treated with placebo. Spray 200 mcg and placebo-treated patients were noted during the 52-week study of adults and adoles- Adverse events did not differ appreciably based on age, gender, or race. Approximately 2% of patients cent patients in whom thorough ophthalmologic assessments were performed including evaluation of treated with OMNARIS Nasal Spray 200 mcg in clinical trials discontinued because of adverse events; this cataract formation using slit lamp examinations. Rare instances of wheezing, nasal septum perforation, rate was similar for patients treated with placebo. Adverse events, irrespective of drug relationship, that cataracts, glaucoma, and increased intraocular pressure have been reported following the intranasal occurred with an incidence of 2% or greater and more frequently with OMNARIS Nasal Spray 200 mcg application of corticosteroids. Close follow-up is warranted in patients with a change in vision and with a (N = 546) than with placebo (N = 544) in clinical trials of 2 to 6 weeks in duration included headache history of glaucoma and/or cataracts. (6.0% vs 4.6%), epistaxis (4.9% vs 2.9%), nasopharyngitis (3.7% vs 3.3), and ear pain (2.2% vs 0.6%). Information for Patients In a 52-week long-term safety trial that included 663 adults and adolescent patients (441 treated with Patients being treated with OMNARIS Nasal Spray should receive the following information and instruc- ciclesonide: 227 males and 436 females) with perennial allergic rhinitis, the adverse event profile over the tions. This information is intended to aid them in the safe and effective use of this medication. It is not a treatment period was similar to the adverse event profile in trials of shorter duration. Adverse events con- disclosure of all possible adverse or intended effects. sidered likely or definitely related to OMNARIS Nasal Spray that were reported at an incidence of 1% or greater of patients and more commonly in OMNARIS Nasal Spray versus placebo were epistaxis, nasal Patients who are on immunosuppressive doses of corticosteroids should be warned to avoid exposure to discomfort, and headache. No patient experienced a nasal septal perforation or nasal ulcer during long- chickenpox or measles, and if exposed, to obtain medical advice. Patients should use OMNARIS Nasal Spray term use of OMNARIS Nasal Spray. While primarily designed to assess the long-term safety of OMNARIS at regular intervals since its effectiveness depends on its regular use (see DOSAGE AND ADMINISTRATION). Nasal Spray 200 mcg once daily, this 52-week trial demonstrated greater decreases in total nasal symptom In clinical trials, the onset of effect was seen within 24 to 48 hours with further symptomatic improve- scores with OMNARIS Nasal Spray versus placebo treated patients over the entire treatment period. ment observed over 1 to 2 weeks in seasonal allergic rhinitis and 5 weeks in perennial allergic rhinitis. Pediatric Patients Aged 6 to 11 Years: Initial assessment of response should be made during this timeframe and periodically until the patients Two controlled clinical studies 2 and 12 weeks in duration were conducted in the US and Canada and symptoms are stabilized. included a total of 1282 patients with allergic rhinitis ages 6 to 11 years, of which 913 were treated with The patient should take the medication as directed and should not exceed the prescribed dosage. The OMNARIS (ciclesonide) Nasal Spray 200 mcg, 100 mcg, or 25 mcg daily. The overall incidence of adverse patient should contact the physician if symptoms do not improve by a reasonable time or if the condition events for patients treated with OMNARIS Nasal Spray was comparable to that in patients treated with worsens. For the proper use of this unit and to attain maximum improvement, the patients should read placebo. Adverse events did not differ appreciably based on age, gender, or race. In clinical trials, 1.6% and follow the accompanying patient instructions carefully. Spraying OMNARIS Nasal Spray directly into and 2.7% of patients treated with OMNARIS Nasal Spray 200 mcg or 100 mcg, respectively, discontinued the eyes or onto the nasal septum should be avoided. It is important that the bottle is gently shaken prior because of adverse events; these rates were lower than the rate in patients treated with placebo (2.8%). to use to ensure that a consistent amount is dispensed per actuation. The bottle should be discarded Adverse events, irrespective of drug relationship, that occurred with an incidence of 3% or greater and after 120 actuations following initial priming or after 4 months after the bottle is removed from the foil more frequently with OMNARIS Nasal Spray 200 mcg (N = 380) than with placebo (N = 369) included pouch, whichever occurs first. headache (6.6% vs 5.7%), nasopharyngitis (6.6% vs 5.4%), and pharyngolaryngeal pain (3.4% vs 3.3%). Drug Interactions Pediatric Patients Aged 2 to 5 Years: Based on in vitro studies in human liver microsomes, des-ciclesonide appears to have no inhibitory or Two controlled clinical studies 6 and 12 weeks in duration were conducted in the US and included a total induction potential on the metabolism of other drugs metabolized by CYP 450 enzymes. The inhibitory of 258 patients 2 to 5 years of age with perennial allergic rhinitis, of which 183 were treated with potential of ciclesonide on CYP450 isoenzymes has not been studied. In vitro studies demonstrated that OMNARIS Nasal Spray 200 mcg, 100 mcg or 25 mcg daily. The distribution of adverse events was simi- the plasma protein binding of des-ciclesonide was not affected by warfarin or salicylic acid, indicating no lar to that seen in the 6 to 11 year old children. potential for protein binding-based drug interactions. In a drug interaction study, co-administration of orally inhaled ciclesonide and oral erythromycin, an inhibitor of cytochrome P450 3A4, had no effect on the pharmacokinetics of either des-ciclesonide or erythromycin. In another drug interaction study, co-administration of orally inhaled ciclesonide and oral ketoconazole, a potent inhibitor of cytochrome P450 3A4, increased the exposure (AUC) of des-ciclesonide by approximately 3.6-fold at steady state, while levels of ciclesonide remained unchanged. Therefore, ketoconazole should be administered with caution with intranasal ciclesonide. Manufactured for: Carcinogenesis, Mutagenesis, Impairment of Fertility Sepracor Inc. Ciclesonide demonstrated no carcinogenic potential in a study of oral doses up to 900 mcg/kg (approxi- Marlborough, MA 01752 USA mately 20 and 10 times the maximum human daily intranasal dose in adults and children, respectively, Made in Germany based on mcg/m2) in mice for 104 weeks and in a study of inhalation doses up to 193 mcg/kg (approxi- November 2007 mately 8 and 5 times the maximum human daily intranasal dose in adults and children, respectively, based on mcg/m2) in rats for 104 weeks. Ciclesonide was not mutagenic in an Ames test or in a forward © 2008 Sepracor Inc. Marlborough, MA 01752 All rights reserved. 4/08 OMN135-08 mutation assay and was not clastogenic in a human lymphocyte assay or in an in vitro micronucleus test. However, ciclesonide was clastogenic in the in vivo mouse micronucleus test. The concurrent reference and are registered trademarks of Sepracor Inc. corticosteroid (dexamethasone) in this study showed similar findings. No evidence of impairment of fer- 182tility was observed in a reproductive study conducted in male and female rats both dosed orally up to OMNARIS is a trademark of Nycomed GmbH, used with permission. MEDICINE & HEALTH/RHODE ISLAND

ARI_A87232_Launch_Ad.indd 2 6/5/08 10:24:12 AM NEW Medication delivered where it’s needed. Nasal symptoms get the message. Introducing OMNARIS— a new intranasal corticosteroid spray • Provided 24-hour relief of nasal symptoms in seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR)1-3 Based on average of AM and PM reflective TNSS* Onset of action was seen within 24 to 48 hours, with further symptomatic improvement observed over 1 to 2 weeks in SAR and 5 weeks in PAR2 • Well-tolerated2,4 • Low-volume, alcohol-free, and scent-free2,5 • Novel hypotonic formulation delivers medication to the site2,5,6

INDICATIONS OMNARIS Nasal Spray is indicated for the treatment of nasal symptoms associated with seasonal allergic rhinitis in adults and children 6 years of age and older and with perennial allergic rhinitis in adults and adolescents 12 years of age and older. IMPORTANT SAFETY INFORMATION The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insu" ciency. Intranasal corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. The growth of pediatric patients receiving intran asal corticosteroids, including OMNARIS Nasal Spray, should be monitored routinely. Patients using drugs that suppress the immune system are more susceptible to infection and should avoid exposure to chickenpox or measles. Rare instances of wheezing, nasal septum perforation, cataracts, glaucoma, and increased intraocular pressure have been reported following the intranasal application of corticosteroids. Close follow-up is warranted in patients with a change in vision and with a history of glaucoma and/or cataracts. The development of localized infections of the nose and pharynx with Candida albicans has rarely occurred with OMNARIS. When such an infection develops, it may require treatment with appropriate local therapy and discontinuation of OMNARIS. Ketoconazole should be administered with caution with intranasal ciclesonide due to potential for increased exposure to des-ciclesonide. In clinical trials, adverse events that occurred with an incidence of 2% or greater and more frequently with OMNARIS than placebo were headache (6.0%), epistaxis (4.9%), nasopharyngitis (3.7%), and ear pain (2.2%). * TNSS (Total Nasal Symptom Score) was measured by symptoms of runny nose, itchy nose, sneezing, and nasal congestion. Please see Brief Summary of Prescribing Information on the following page. References: 1. Ratner PH, Wingertzahn MA, van Bavel JH, et al. E" cacy and safety of ciclesonide nasal spray for the treatment of seasonal allergic rhinitis. J Allergy Clin Immunol. 2006;118:1142-1148. 2. OMNARIS [prescribing information]. Marlborough, MA: Sepracor Inc; November 2007. 3. Meltzer EO, Kunjibettu S, Hall N, et NEW al. E" cacy and safety of ciclesonide, 200 µg once daily, for the treatment of perennial allergic rhinitis. Ann Allergy Asthma Immunol. 2007;98:175-181. 4. Chervinsky P, Kunjibettu S, Miller DL, et al. Long-term safety and e" cacy of intranasal ciclesonide in adult and adolescent patients with perennial allergic rhinitis. Ann Allergy Asthma Immunol. 2007;99:69-76. 5. Meltzer EO. Formulation considerations of intranasal corticosteroids for the treatment of allergic rhinitis. Ann Allergy Asthma Immunol. 2007;98:12-21. 6. Sato H, Nave R, Nonaka T, et al. In vitro metabolism of ciclesonide in human nasal epithelial cells. Biopharm Drug Dispos. 2007;28:43-50.

©2008 Sepracor Inc. Marlborough, MA 01752 All rights reserved. 4/08 OMN130-08 and are registered trademarks of Sepracor Inc. 183 OMNARIS is a trademark of Nycomed GmbH, used with permission. Relief With Staying Power. VOLUME 91 NO. 6 JUNE 2008

ARI_A87232_Launch_Ad.indd 1 6/5/08 10:24:09 AM Latex Allergy Anthony R. Ricci, MD

When Christopher Columbus visited ing the products or to the latex plant pro- urological procedures had positive latex Hispaniola in 1496, he observed people teins themselves. IgE antibody is produced skin tests.11 Of 1000 volunteer blood do- playing games with bouncing balls. Re- when the immune system detects an aller- nors, 6.5% had latex-specific immunoglo- turning to Spain with the rubber balls, gen. Histamine and other chemical media- bulin E (IgE) antibodies (men were twice Columbus related how people of the New tors are released, causing erythema, as likely to be sensitized as women, but the World made balls from the liquid of a pruritis, rhinorrhea, hives, rash, and wa- prevalence was not associated with race or tree.1 For three centuries, rubber re- tery, edematous eyes. This can swiftly age).12 Of health care workers respond- mained an unstable product until, in progress to anaphylaxis with labored breath- ing to a self-reported questionnaire, 53% 1839, it was discovered that the elastic ing, a precipitous drop in blood pressure, described a reaction to rubber gloves.13 properties of rubber could be made more rapid pulse, tissue edema and death. permanent through treatment with sul- The AIDS epidemic and subsequent SYMPTOMS OF LATEX ALLERGY fur and heat. 2 Most of the world’s rub- universal precautions have spurred the There are three types of latex allergy ber comes from the tree Hevea use of latex products. The incidence of symptoms brasiliensis. When its bark is cut, liquid latex allergy, as with most allergies, in- latex is released. creases with chronic exposure. 1. Irritant contact dermatitis. The rubber trade began in the Ama- In 1987, 1 billion gloves were im- This nonimmune dermatitis evolves zon basin, but Southeast Asia is the pre- ported into the United States; the follow- gradually over several days and is not dominant manufacturer of the latex used ing year, the number burgeoned to 8 bil- caused by the latex protein, but by glove in most of the world’s 44,000 rubber la- lion!7 Occupations outside of health care compression, antiseptic hand washing, tex products (e.g., tires, footwear, belts also expose workers to the latex protein. numerous glove chemicals, and latex ac- and hoses, medical devices, wire cables, One glove manufacturing plant reported celerators. Patients present with balloons, condoms, diaphragms, rubber a 3.7% prevalence of occupational asthma erythema, scales, and fissures. Avoidance gloves, nipples for baby bottles and paci- caused by latex allergy.8 Workers in latex of latex gloves, use of cotton liners, and fiers). doll manufacturing plants have higher hand care which minimizes skin pressure Latex balloons, gloves, and condoms prevalence of latex sensitization.9 can diminish symptoms. are made by a dipping process. Very soft Persons who have had repeated or ex- products maunfactured by dipping have tended surgeries, par- the highest amount of latex proteins and, ticularly those begin- LATEX ALLERGY AND CROSS REACTIVE FOODS therefore, are the most allergenic. Corn- ning in early life, are Avocado Chestnut starch powder is applied to the molds especially vulnerable. Kiwi Fruit Papaya Potato Passion Fruit during manufacturing to prevent sticki- Patients with spina Banana Melon ness. Water soluble latex proteins, which bifida (myelomenin- adhere to the cornstarch particles, can be gocele), urogenital ab- SOURCES OF LATEX EXPOSURE aerosolized upon removal of the latex normalities or intesti- MEDICAL glove.3 These particles can sensitize nal surgery with ex- Gloves Urinary catheters nearby persons or evoke symptoms in posed mucous mem- Tourniquets Face masks previously sensitized people.4 brane colostomy have Wound drains Adhesive tape Respirable particles can also be shed an increased preva- Injection ports Electrode pads 5 Bulb syringes Matresses from powder-free latex gloves. High ex- lence of latex allergy if Stethoscope Ambu bags posure areas include operating rooms and latex has been used in labor and delivery suites. Sensitized indi- their care. HOUSEHOLD viduals can become symptomatic after ex- Balloons Condoms and diaphragms Rubber bands Toys posure. Some manufacturers of surgical PREVALENCE OF Shoe soles Erasers and household gloves also compound LATEX Sports equipment casein into the glove. This may cause skin SENSITIZATION Clothing, including elastic on underwear reactions in milk-sensitive persons.6 Of 326 atopic Feeding nipples and pacifiers Latex allergy is a hypersensitivity to the children seen at a uni- Powdered latex gloves used in food handling substance obtained from the milky sap of versity hospital,3% Diapers, incontinence and sanitary pads Computer mouse pads the rubber tree. The sensitized person re- had a positive latex Carpet backing acts in an exaggerated manner to a harm- skin test;10 and 9.5% Handles on racquets and tools less substance (an allergen or antigen). A of 325 consecutive latex allergic person can have a reaction to adult inpatients NOTE: For more information see the American Academy of the chemical additives used in manufactur- awaiting surgical or Allergy Asthma & Immunology www.AAAAI.org 184 MEDICINE & HEALTH/RHODE ISLAND 2. Delayed type IV allergic contact together to pass the Rhode Island Latex banned. The hospital has had no new dermatitis. Gloves Safety Act in July, 2001. The law cases of Workers Compensation related The onset of the rash occurs between bans latex glove use by any food handler. to latex since the transition. In fact, sev- 6 to 48 hours after contact with the glove eral latex allergic health care workers have chemicals. Symptoms include erythema, DIAGNOSIS returned to their former jobs without blisters, papules, vesicles, pruritis, and A medical and occupational history consequent symptoms. crusting. which includes questions related to prior Latex allergic patients who must un- latex reactions, in addition to immuno- dergo surgery in a non latex-safe hospital 3. Immediate type 1 hypersensitivity. logic testing, usually diagnoses latex allergy. should be scheduled as the first case of Symptoms usually occur within min- Latex allergy risk factors and the nature of the day when the likelihood of contact utes to several hours after contact with past reactions should be thoroughly inves- with aerosolized latex particles is low. All the latex protein. They include: local and tigated. Frequently, patients will not at- latex rubber tubing and blood pressure generalized urticaria, angioedema, nau- tribute their nasal or bronchial symptoms cuffs must be wrapped to prevent con- sea, vomiting, feelings of impending to latex allergy, but confuse the symptoms tact with the patient. These patients must doom, and abdominal cramps. Aero- with those of allergic rhinitis. None of the be visibly and prominently labeled as la- solized latex particles are frequently the patients who succumbed to fatal latex ana- tex allergic at the bedside and on wrist- causative factor. phylaxis during barium enema examina- bands. Occasionally, latex allergic pa- Anaphylactic reactions to latex have tions, however, had any of the known risk tients are pretreated with steroids, anti- been reported in patients with a history factors other than atopy. 19 Risk factors, histamines, and histamine H2-blockers. of allergic or irritant contact dermatitis. unfortunately, may not always predict po- Anaphylaxis, however, can occur despite It is believed that the disruption in the tential latex allergy reactions. pretreatment.22 skin’s natural protective barrier increases FDA-approved in vitro tests which Latex allergic persons should wear latex protein absorption.14 A patient can measure latex-specific IgE are the only Medic-Alert identification, carry two suddenly develop life-threatening sys- methods available in the United States doses of epinephrine, and carry several temic symptoms after using latex gloves to help diagnose latex allergy.20,21 Be- pairs of nonlatex gloves for use by emer- for many years. cause these tests have a false-negative gency medical personnel. More than 50% of people with la- rate of approximately 20%, their clini- tex sensitivity have a history of atopy.15 cal usefulness is limited. TREATMENT OF ANAPHYLAXIS One in four atopic health care workers Acute latex anaphylactic reactions has a positive skin prick test to latex. Only Rhode Island was must be treated with epinephrine, oxy- 50% of these persons, however, are clini- gen, fluids, and steroids. Maintaining the cally symptomatic.16 the first state to airway and circulation is essential. ban natural rubber Diphenhydramine (Benadryl) may be LATEX AND FOOD ALLERGY used to treat urticaria. Staff wearing la- Bananas, kiwi fruit, chestnuts, avo- latex glove use in tex gloves should not treat a latex allergic cado, and tomato may cross-react with food service. patient. Transporting an acutely ill latex- the latex protein17 and cause anaphylac- allergic patient to a non-latex safe hospi- tic reactions in latex sensitive persons. tal can be extremely dangerous. Apples, figs, melons, celery, potatoes, pa- MANAGEMENT payas, cherries, and peaches have caused The primary treatment of latex al- LONG-TERM LATEX AVOIDANCE oral pruritis, which can progress to more lergy, as with most allergies, is avoidance. Latex-allergic persons benefit by serious symptoms.18 A person who has Reducing exposure to latex in the work- eliminating or reducing their exposure to reactions to any of these foods may have place by using nonlatex, vinyl, or nitrile latex. Asthma and bronchial hyperreac- an increased risk of developing latex al- gloves and nonpowdered, low-protein, tivity has been shown to decrease in latex- lergy. Latex sensitive people should avoid latex gloves, will eliminate or reduce the sensitive workers who reduced or avoided only the food which causes allergic symp- allergen. latex exposure after a median follow-up toms. It is not recommended that these Health care workers must be pro- period of 56 months.23 Twenty latex-sen- patients eliminate all the potentially cross- tected from airborne latex antigen, to sitized anesthesiologists who did not use reacting foods: this could result in un- decrease the risk of future latex sensitiza- latex gloves for 10 to 15 months all be- healthy dietary restrictions. tion. In 1999, the administration de- came asymptomatic; 16 of 18 demon- Latex has been called the “hidden cided to transform the 350-bed Kent strated a decline in latex-specific IgE. food allergy.” Particles can be introduced County Memorial Hospital into a latex Their latex skin test titration end points into food products by preparers’ gloves. safe hospital. This transition occurred did not change appreciably. This suggests Rhode Island was the first state to ban over one year at an approximate cost of that a longer period of avoidance or stricter natural rubber latex glove use in food $250,000. All duct vents and surfaces environmental controls may be necessary service. United States Senator Sheldon were cleaned or changed; all latex was to immunologically improve these pa- Whitehouse, State Representative Eliza- removed. Latex balloons from florists and tients’ sensitivities.24 beth Dennigan, and this writer worked latex gloves worn by rescue workers were 185 VOLUME 91 NO. 6 JUNE 2008 CONCLUSIONS REFERENCES 20. Pharmacia CAP, Pharmacia-UpJohn Diagnostics Liberia recently announced that it 1. Michalovic M. The Story of Rubber. Polymer Sci- Inc, Kalamazoo, Mich.; AlaStat, Diagnostic Prod- ucts Corp., Los Angeles, Calif. will resume exportation of rubber follow- ence Learning Center,2000. 2. Dean W. Brazil and The Struggle for Rubber. Cam- 21. Product approvals: latex sensitivity test. FDA Med ing its three year civil war. This will lead bridge: Cambridge University Press,1987. Bull 1995; 25:2-3. to sensitization and increased latex allergy 3. Beezhold D, Beck WC. Arch 22. Kwittken PL, Becker J, et al. Allergy Proc 1992; in the workers of the restored rubber Surg 1992;127:1354-7. 13:123-7. 23. Vandenplas O, Jamart J, et al. J Allergy Clin plantations as well as dissemination of the 4. Bubak ME, Reed CE, et Al. Mayo Clin Proc 1992;67:1075. Immunol 2002;109:125. minute latex protein particle via food 5. Phillips ML, Meagher CC, Johnson DL. Occup 24. Hamilton RG, Brown RH. J Allergy Clin Immunol preparation and workers’ clothing. Environ Med 2001;58:479. 2000;105:839. Every state should follow Rhode 6. Ylitalo L, Makinen-Kiljunen S, et al. J Allergy Clin Island’s lead and ban the use of latex Immunol 1999;104:177. Acknowledgements 7. Kwittken P, Sweinberg S. Am J Asthma Allergy The author wishes to thank Patricia gloves during the preparation of food in Pediatr 1992; 6:27-33. restaurants, institutional kitchens and 8. Tarlo SM, Wong L, et al. J Allergy Clin Immunol C. Ricci, MD, for her help in prepara- supermarkets. 1990;85:626-31. tion of this manuscript. 9. Orfan NA, Reed R, et al. J Allergy Clin Immunol There has been a significant increase 1994;94:826-30. Anthony R. Ricci, MD, is a Clinical in latex rubber allergy since the imple- 10. Novembre, E, Bernardini R, et al. Allergy mentation of universal precautions in the 1997;52:101. Instructor in Medicine at the Warren late 1980s. People are at a higher risk of 11. Rueff F, Kienitz A, et al. Allergy 2001;56:889. Alpert Medical School of Brown Univer- 12. Ownby DR, Ownby HE, et al. J Allergy Clin sity and in Private Practice in East Green- developing both immediate, type 1, and Immunol 1996; 97:1188. delayed type 4 hypersensitivity to rubber 13. Salkie ML. Arch Pathol Lab Med 1993;117:897. wich, RI. latex. Latex gloves are still frequently used 14. Beezhold D, Beck WC. Arch Surg during surgery and in food-preparation. 1992;127:1354-7. Disclosure of Financial Interests 15. Sussman GL, Tarlo S, Dolovich J. JAMA The author has no financial inter- Hidden latex protein continues to sensi- 1991;265:2844-7. tize unsuspecting, susceptible people. 16. Arellano R, Bradley J, Sussman G. Anesthesiol ests to disclose. Education on allergen avoidance and 1992;77:905-8. cross-reacting allergens can improve man- 17. Blanco C, Carrillo T, et al. Ann Allergy CORRESPONDENCE 1994;73:309-14. Anthony R. Ricci, MD agement and treatment of latex allergy 18. Beezhold DH, Sussman GL, et al. Clin Exp Al- and, hopefully, one day terminate sensi- lergy 1996;26:416-22. 63 Cedar Avenue, Suite 7 tization. 19. Ownby DR, Tomlanovich M, et al. AJR Am J East Greenwich, RI 02818 Roentgenol 1991;156:903-8. Phone: (401) 885-5757 e-mail: [email protected]

186 MEDICINE & HEALTH/RHODE ISLAND Advances In Therapeutic Immunomodulation of IgE-mediated Respiratory Disease Russell A. Settipane, MD, FAAAAI

Allergic diseases of the airways impose had long been suspected.11 Since then, gen in the home is associated with increased devastating burdens on individuals, as scientists have recognized the central asthma severity.19-21 Notably, patients have well as on society.1,2 Despite treatment pathogenic role of IgE in mediating the improved after their homes’ offending advances, pharmacotherapy improve- allergic response that follows exposure to allergen(s) is eliminated or reduced.22-24 ments, and practice parameters3,4 with environmental allergens and is important diagnosis and management guidelines,5 to the development and persistence of in- SUBCUTANEOUS IMMUNOTHERAPY the “Allergies in America” survey reported flammation.12,13 The following observa- Description an allergic rhinitis prevalence of 14.2% tions highlight the role of IgE. Subcutaneous immunotherapy [often in the adult US population. The major- In the preschool years, when cough- called “conventional immunotherapy” or ity of nasal allergy sufferers, moreover, ing or wheezing in association with com- allergy shots] is the repeated subcutaneous complained that their medications did mon respiratory viral infections is com- administration of allergens (aeroallergens, not provide 24-hour relief, with effective- mon, early sensitization to inhaled aller- hymenoptera venom, drugs, etc) to patients ness wearing off over time.6 gens is associated with the prognosis for with IgE-mediated conditions, to protect The “Asthma in America” survey con- persistent asthma beyond the preschool against the allergic symptoms and inflam- firmed previous estimates of prevalence: 5% years.14,15 Similar observations hold true matory reactions associated with the natu- of Americans, or nearly 15 million people, regarding the association of IgE with adult ral exposure to these allergens.3 It is the suffer from asthma.7 Almost half those per- asthma.16 At Rhode Island Hospital, atopy only therapeutic method available to achieve sons reported that asthma limited their abil- was reported in 58% of adult patients with allergen-specific tolerance. ity to take part in sports or recreation; more asthma attending a pulmonary clinic, than a third said it limited their normal which corresponds to recent national ob- History physical exertion. Over 4000 deaths occur servations.17 Additionally, the diagnosis of Subcutaneous immunotherapy, annually from asthma.5 In Rhode Island, allergic rhinitis has been shown to increase, which emerged as an empiric therapy for there are approximately 12 asthma-related by 3-fold, the risk for the subsequent de- ragweed hayfever in 1900, was first de- deaths per year.8 (Figure 1) velopment of asthma.18 scribed in the literature in 1911.25 Over First line therapy in the management The combination of IgE sensitization the past century, allergen immunotherapy of allergic respiratory disease is identifica- to indoor allergens and high levels of aller- has progressed as a result of improved un- tion and avoidance of environmental aeroallergens. Second line generally com- prises pharmacotherapeutics. “Allergic immunomodulation” encompasses various third line therapies, which attempt to sup- press or modify the immune mechanisms responsible for IgE mediated respiratory disease, particularly asthma. Such therapeu- tic agents include methotrexate, soluble interleukin-4 (IL-4) receptor, anti-IL-5, re- combinant IL-12, cyclosporin A, intrave- nous immunoglobulin (IVIG), allergy im- munotherapy, omalizumab (anti-IgE), and others. This review focuses on the status of three agents: subcutaneous immuno- therapy, sublingual immunotherapy, and monoclonal anti-IgE therapy.

BACKGROUND: THE ROLE OF IGE IN THE PATHOGENESIS OF ALLERGIC DISEASE The discovery of IgE in 19679,10 was probably the single most important mile- stone in the understanding of allergic dis- ease pathogenesis, although its presence 187 VOLUME 91 NO. 6 JUNE 2008 Allergic rhinitis The decision to initiate allergen im- munotherapy depends on the degree to which symptoms can be reduced by avoid- ance and medication, the amount and type of medication required to control symptoms and the adverse effects of medication.

Asthma The same recommendations apply as for allergic rhinitis. Additionally, the EPR-3 Asthma Guidelines state that al- Adapted from the Rhode Island Department of Health. The Burden of Asthma in lergen immunotherapy be considered for Rhode Island: The Role of Poverty. Providence, RI: Rhode Island Department of patients with persistent asthma if there is Health, March 2007. clear evidence of a relationship between symptoms and exposure to an allergen to derstanding of IgE-mediated immunologic Indications which the patient is sensitive.5 Immuno- mechanisms, the characterization of specific Efficacy of allergen immunotherapy therapy is usually reserved for patients antigens and allergens, and the standard- has been demonstrated in the treatment whose symptoms occur all year or dur- ization of allergen extracts. Resources which of allergic rhinitis, allergic conjunctivitis, ing a major portion of the year, and for discuss immunotherapy include the Na- allergic asthma and stinging insect hyper- whom the medication is ineffective, mul- tional Asthma Education and Prevention sensitivity. (See article by Gaines.) tiple medications are required, or the Program’s Expert Panel Report 3: Guide- The presence of specific IgE to the patient will not tolerate the medication. lines for the Diagnosis and Management offending allergen should be docu- Special safety precautions apply for ad- of Asthma5 (EPR-3 Asthma Guidelines) mented by skin test or serologically; and ministering immunotherapy to patients and recent practice parameters on rhinitis4 there should be clinical correlation with with asthma. and immunotherapy.3 symptoms on exposure.

Figure 2. Aeroallergen Survey, Providence RI. Adapted from Chafee FH, Settipane GA. Atmospheric pollen and mold survey. J Allergy Clin Immunol 1964 May-June;35:193-200.48

188 MEDICINE & HEALTH/RHODE ISLAND Administration Schedules Subcutaneous immuno- therapy is usually initiated with once to twice weekly injections at a low dose. During the build-up phase, the dose is usu- ally raised 1 to 3 times a week. The duration of the build-up generally ranges from 3 to 6 months, at which point the maintenance phase begins, and the injection schedule in- terval is slowly increased to a range of every 2 to 4 weeks for inhalant allergens. Alternative allergen im- munotherapy build-up phases include accelerated “cluster” and “rush” schedules, which permit patients to attain thera- Figure 3. Stepwise approach for managing asthma in youths > 12 years of age and adults peutically effective mainte- Key: Alphabetical order is used when more than one treatment is listed within nance doses more rapidly than either preferred or alternative therapy. EIB, exercise-induced bronchopasm; ICS, with conventional build-up inhaled corticosteroid; LABA, long-acting inhaled beta2-agonist; LTRA, leukotriene schedules. These accelerated receptor antagonist; SABA, inhaled short-acting beta2-agonist. approaches are associated with Adapted from Expert panel report 3: Guidelines for the diagnosis and manage- an increased risk of anaphy- ment of asthma. Available online at www.nhlbi.nih.gov/guidelines/asthma/epr3/ laxis.52,53 index.htm; last accessed Jan 29, 2008. Approximately 90% of appropriately selected allergic Mechanism Allergic rhinitis rhinitis patients reaching optimal doses Immunologic changes in response The robust research has shown sub- of subcutaneous immunotherapy will ex- to subcutaneous immunotherapy are cutaneous immunotherapy to be effec- perience improvement within one year complex. Although we have no single tive in a dose dependant manner, with of therapy.54 Therapy typically lasts 3–5 best marker to explain the efficacy of im- optimal doses determined. (Table 1) The years; the majority of patients experience munotherapy, numerous antibody and physician should be familiar with the key a persisting beneficial effect for at least 3 cellular changes have been observed: i.e., aeroallergens in the patient’s region. In years after stopping immunotherapy.55 the modulation of T- and B-cell re- Rhode Island, Chafee & Settipane,48 in Less commonly, patients may experience sponses by the generation of allergen- the 1950s, performed landmark pollen a prompt relapse. specific T regulatory cells; increases in count studies characterizing the local allergen-specific IgG4, IgG1, and IgA; pollen seasons. (Figure 2) (See article by Safety decrease in IgE and decreased tissue in- Freye). There is an inherent risk of local al- filtration by mast cells and eosinophils. lergic reactions (wheal & flare) at the in- Additionally, successful subcutaneous Asthma jection site, as well as systemic anaphylaxis. immunotherapy is associated with a In addition to demonstrating the ef- A prospective study has reported the fre- change towards a non-allergic TH1 ficacy of subcutaneous immunotherapy in quency of systemic reactions to be 0.3% cytokine profile.26 allergic asthma,27,32,34,37,38 immunotherapy of immunotherapy doses, representing may prevent the development of asthma 3.7% of patients. Severe systemic reac- Efficacy in children who have allergic rhinitis.49 tions can be life-threatening and fatal re- Many double-blind, placebo-con- Immunotherapy has also been shown to actions do occur.3 Anaphylactic related trolled, randomized clinical trials demon- prevent the development of new allergic fatalities are rare (1 in 2.5 million injec- strate a beneficial effect of subcutaneous sensitivities in monosensitized children and tions).56 immunotherapy,27-35 for the treatment of al- adults.43,50,51 The EPR-3 Asthma Guide- Given this risk, allergy immuno- lergic rhinitis30 (including ocular symptoms35- lines suggest that immunotherapy should therapy should be administered only in 36), allergic asthma27,32,34,37,38 and stinging in- be considered when there is a significant a setting where procedures that can re- sect hypersensitivity;31,39 and the therapy is allergic contribution to the patient’s symp- duce the risk of anaphylaxis are in place effective in both adults and children.41-47 toms. and where the prompt recognition and 189 VOLUME 91 NO. 6 JUNE 2008 orously studied by FDA- Figure 4. IgE binding to the approved protocols. No high affinity IgE receptor form of SLIT has been ap- (FcεRI). One end of the IgE proved by the FDA for use molecule, the Fab region, in the US at this time. binds to specific components The American Col- (or epitopes) of the allergen, lege of Allergy, Asthma while the other end, the Fc and Immunology and the region (C3 domain), binds with American Academy of high affinity to IgE receptors present on tissue mast cells Allergy, Asthma and and circulating basophils. Immunology’s (AAAAI) (Adapted from Holgate ST. Immunotherapy and Al- Asthma and allergy— lergy Diagnostics Com- disorders of civilization? QJ mittees formed a joint Med 1998;91:171-184.76) task force which recently published an updated re- port on SLIT for the North American allergy community.64

Efficacy Since the first double-blinded, placebo- controlled studies of SLIT were published in 1986, numerous con- trolled trials utilizing treatment of anaphylaxis is ensured. The particularly those who have poorly con- noninjection routes of allergy immuno- preferred location for administration is trolled asthma, compared with those who therapy have been published; the major- in the office of the physician who pre- have allergic rhinitis.56,58 ity reported favorably on this form of im- pared the patient’s allergen immuno- munotherapy.64 But many questions re- therapy extract. Because most systemic SUBLINGUAL IMMUNOTHERAPY main unanswered, including optimum reactions that result from subcutaneous Description dosing (which appears to be considerably immunotherapy occur within 30 minutes A modification of the conventional higher than doses now used), multiple al- of an injection, the allergen immuno- form of subcutaneous immunotherapy is lergen administration, treatment sched- therapy practice parameters recommend a form of mucosal immunotherapy where ules, and duration of treatment. The that patients should remain in the allergen is applied to the oral cavity or more clinical trials underway in the US are lim- physician’s office for at least 30 minutes commonly to the sublingual site - sublin- ited to the study of single allergen prepa- after an injection.3 gual immunotherapy (SLIT). SLIT, con- rations. Preliminary comparative studies Risk factors for severe reactions in- sidered investigational, has generated ex- suggest SLIT is less effective than immu- clude symptomatic asthma and adminis- citement as a potentially more convenient notherapy administered by subcutaneous tration of injections during periods of and safer method of administration.3,59 injection. 65,66 symptom exacerbation. Individual local reactions (wheal & flare) do not appear History Safety to predict subsequent systemic reactions. The first description of oral mucosal From the limited data, SLIT appears However, patients with greater frequency (swallowed) immunotherapy dates back to to have a more favorable safety profile than of large local reactions may be at increased the early 1900s, but this technique failed subcutaneous immunotherapy, which risk for future systemic reactions.57 to gain popularity then. In the last two de- raises the hope that it may allow for home Special precautions are recommended cades, after numerous publications, SLIT administration, thereby expanding the for patients with asthma. Allergen immu- has virtually replaced the conventional form number of patients who can receive spe- notherapy should not be initiated unless the of immunotherapy in many European cific allergen immunotherapy (e.g., young patient’s asthma is stable with pharmaco- countries.60-63 Some US practitioners use children, adults who cannot easily com- therapy. The EPR-3 Asthma Guidelines variations of SLIT; however, the FDA has ply with weekly visits). However, the safety highlight that severe and sometimes fatal not approved the preparations employed of SLIT remains to be rigorously studied, reactions to immunotherapy, especially se- in the US. Additionally, the preparations particularly in asthmatic patients, who of- vere bronchoconstriction, are more fre- administered by US physicians are not the ten are at higher risk for anaphylaxis. quent among patients who have asthma, same as preparations which are being rig- (Table 2)

190 MEDICINE & HEALTH/RHODE ISLAND 191 VOLUME 91 NO. 6 JUNE 2008 192 MEDICINE & HEALTH/RHODE ISLAND region from an anti-IgE antibody produced in mice.10 Less than 5% of the humanized monoclonal anti-IgE antibody comprises resi- dues of murine origin, which minimizes the potential for an immune response toward the non–self protein. 73 Omalizumab is ad- ministered by subcutaneous injection every 2 or 4 weeks, with the dose depending on pre-treatment total IgE level and body mass.

Mechanism Omalizumab selectively targets IgE, thereby (1) helping reduce mast-cell de- granulation, limiting the release of inflam- matory mediators, and (2) down-regulat- ing high-affinity IgE receptors. 74 The omalizumab antibody recognizes the C3 domain of human IgE, which is the IgE binding site for the high affinity IgE re- Figure 5. The process of mast cell/basophil “defunctionalization” with anti-IgE ceptor and which is in the vicinity of the low treatment. (A) Cells are capable of responding to a particular allergen when they affinity IgE receptor.75,76 (Figure 4) By bind- express high-affinity IgE receptors (FcåRI) that are occupied by IgE with specific- ing to this domain, the IgE antibody is ity for that allergen; as low as 100 molecules of receptor-bound–specific IgE could blocked from binding to its receptors. initiate the cell-triggering process. (B) When anti-IgE is present in the extracellu- Omalizumab binds to circulating IgE, re- lar environment, it binds to free IgE and forms complexes that are eventually gardless of IgE specificity; as it does so, the removed by the reticuloendothelial system of the liver. (C) Receptor-bound IgE dissociates from FcåRI at a constant rate. Because of the presence of anti-IgE, complexes formed are removed by the he- the cell receptors that are freed are not reoccupied by IgE molecules. (D) Unoc- patic reticuloendothelial system. The result- cupied FcåRI gets internalized because lack of IgE binding fails to stabilize the ing reduction in free serum IgE is around receptor on the cell surface. With reduction of cell-bound IgE, mast cells (and 95%.69,77 However, reduction in free serum basophils) can not respond to allergen and release their inflammatory products. IgE, per se, has no known therapeutic ef- Adapted from Soresi S, Togias A. Mechanisms of action of anti-immuno- fect. The subsequent reduction in mast cell globulin E therapy. Allergy Asthma Proc 2006;27:S15–S23.74 and basophil-bound IgE is responsible for the clinical efficacy of anti-IgE therapy. (Fig- ure 5). When mast cells and basophils do MONOCLONAL ANTI-IGE The 2007 EPR-3 Asthma Guidelines not carry IgE on their surfaces, allergic reac- Description define the place of omalizumab in thera- tions do not occur. After the initiation of Anti-IgE therapy targets an early point peutic paradigms. 5 The Guidelines rec- omalizumab therapy over a period of weeks in the allergic inflammatory cascade. 67 ommend that omalizumab may be con- the IgE binding to receptors on mast and Omalizumab (Xolair, Genentech, South San sidered adjunctive therapy in step 5 or 6 basophils is reduced. This reduction results Francisco, California), a recombinant hu- care for patients who have allergies and in down-regulation of the cell surface IgE manized monoclonal anti-IgE antibody, is severe persistent asthma that is inad- receptors, ultimately leading to a decrease in the first therapeutic agent, specifically tar- equately controlled with the combination the release of mediators in response to aller- geting IgE, to undergo clinical evaluation of high-dose ICS and LABA. (Figure 3.) gen exposure. Inhibiting the immune re- for the treatment of allergic diseases of the 72 All patients with allergic asthma in sponse to allergen reduces acute allergic re- airway. Omalizumab, which has been rigor- whom step 4 therapy fails should be evalu- actions and the inflammatory and physiologi- ously investigated in the treatment of patients ated carefully (preferably by an asthma cal consequences, such as late reductions in with asthma, 68-70 is the sole FDA-approved specialist) before initiating omalizumab to lung function and tissue eosinophilia.78,79 anti-IgE available in the US. 71 Omalizumab’s (1) confirm the diagnosis of asthma, (2) Another potential immunomodulatory FDA approved indication is for adults and identify and treat comorbid conditions role of anti-IgE therapy is to affect antigen adolescents (aged ³12 years) with moderate- associated with poor asthma control, (3) presentation through the removal of IgE to-severe persistent asthma who have a posi- evaluate the possibility of incomplete ad- from the surface of dendritic cells.74,80 tive skin test or in vitro reactivity to a peren- herence with current therapy, and (4) en- nial aeroallergen, and whose symptoms are gage patients in a partnership in which they Efficacy inadequately controlled with inhaled corti- are trained to use medications and envi- The evidence which supported the in- costeroids. In studies with asthma patients ronmental control strategies. corporation of omalizumab as a therapeutic with IgE levels between 30 and 700 IU/ml, Omalizumab’s structure comprises a option by the EPR-3: Asthma Guidelines it has been shown to decrease the incidence human IgG framework on to which is includes the following. Adding omalizumab of asthma exacerbations. grafted the complementarity-determining to inhaled corticosteroids can reduce exac- 193 VOLUME 91 NO. 6 JUNE 2008 erbations and subsequent use of systemic ste- therapy are the inconvenience of re- Asthma Control State Plan 2003-2008. roid bursts, reduce daytime allergic asthma peated injections, and the risk of anaphy- With support by the State and other symptoms and nighttime awakenings and lactic reactions. Thus, a potential use of agencies, together with the implementa- reduce disruptions of daily routine activities. anti-IgE is the application to prime aller- tion of the comprehensive management The vast majority of patients in clinical trials gic patients for more vigorous and safe approach outlined in the EPR-3 Asthma of omalizumab had moderate or severe per- subcutaneous immunotherapy. Studies Guidelines, there is good reason for hope sistent asthma incompletely controlled with have demonstrated that the combination that in Rhode Island, our most severe inhaled corticosteroids. 81 In many patients, of omalizumab and subcutaneous immu- asthma patients will achieve control of but not all, adding omalizumab to inhaled notherapy confer added efficacy to either their disease with reduction in asthma risk, corticosteroids therapy produced a signifi- treatment alone, and confer added safety morbidity and mortality. cant reduction in asthma exacerba- to rush immunotherapy.101-103 tions68,69,70,82,83 a small but significant im- REFERENCES provement in lung function,68,69 and re- SUMMARY 1. Blaiss MS. Allergy Asthma Proc 2007;28:393-7. duced asthma exacerbations and emergency IgE is responsible for activation of al- 2. Settipane RA. Allergy Asthma Proc 1999;20:209-13. 84,85 3. Joint Task Force on Practice Parameters. J Allergy department visits. 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Purello-D’Ambrosio F, Gangemi S, et al. Clin Exp 76. Holgate ST. QJ Med 1998;91:171-84. 2002;109:274-80. Allergy 2001;31:1295-302. 77. Lin H, Boesel K, et al. J Allergy Clin Immunol 103. Rolinck-Werninghaus C, Hamelmann E, et al. 52. Cox L. Ann Allergy Asthma Immunol 2004;113:297–302. Allergy 2004;59:973–9. 2006;97:126-37. 78. Djukanoviæ R, Wilson SJ, et al. Am J Respir Crit 53. Smits WL, Giese JK, Letz KL, et al. Allergy Asthma Care Med 2004;170:583-93. Russell A. Settipane, MD, FAAAAI, Proc 2007;28:305-12. 78. Fahy JV, Fleming HE, et al. Am J Respir Crit Care 54. Gupta P, Grammer LC. Administration of aller- Med 1997;155:1828-34. is Co-Director, Allergy & Asthma Center, gen vaccines. In Allergens and Allergen Immuno- 79. Boulet LP, Chapman KR, et al. Am J Respir Crit Clinical Associate Professor, Warren Alpert therapy, 3rd ed., Lockey RF, Bukantz SC, Bousquet Care Med 1997;155:1835–40. Medical School of Brown University, and J (Eds). New York: Marcel Dekker, Inc, 80. Prussin C, Griffith D, et al. J Allergy Clin Immunol president of the Rhode Island Society of 2004:481–93. 2003;112:1147–54. 55. Durham SR, Walker SM, et al. NEJM 81. Walker S, Monteil M, et al. Cochrane Database Allergy. 1999;341:468-75. Syst Rev 2004;3:CD003559. Disclosure of Financial Interests Russell Settipane, MD. Grant Re- search Support and Speakers’ Bureau: Genentech. Discussion of off-label or investiga- tional usage of products: Omalizumab is being investigated in other disease states; the article does not advocate off-label use of Omalizumab.

CORRESPONDENCE Russell A. Settipane, MD, FAAAAI Asthma & Allergy Center 95 Pitman St Providence, RI 02906: Phone: (401)331-8425 e-mail: [email protected]

195 VOLUME 91 NO. 6 JUNE 2008 Images In Medicine MR Imaging of Acute Appendicitis in Pregnancy Jill A. Steinkeler, MD, and Courtney A. Woodfield, MD

A 23 year old pregnant woman at 14 weeks gestation presented harmful effects of fetal exposure to ionizing radiation,1 US and with a one-day history of epigastric pain that gradually localized to increasingly MRI are the initial modalities of choice for imag- the right lower quadrant. At presentation, the patient was afe- ing the abdomen and pelvis during pregnancy. brile, blood pressure 110/74, and heart rate 85 beats per minute. Acute appendicitis is the most common non-obstetric sur- Physical examination revealed tenderness to palpation in the right gical condition in pregnant patients. Early diagnosis prior to lower quadrant without rebound, guarding or peritoneal signs. rupture confers a fetal loss rate of < 2%, compared to a rate of Laboratory data demonstrated a white blood cell count of 7, he- > 30% after appendiceal rupture.4 MRI has been reported to moglobin 10.4, and platelets 129. Amylase, lipase, liver function have a sensitivity of 100% and specificity of 93.6% for diag- tests, renal function and urinalysis were normal. nosing appendicitis in the pregnant patient.2 MR can also of- An initial right upper quadrant and pelvic ultrasound ten reveal alternative diagnoses for pain, including degener- (US) on the day of admission revealed no sonographic abnor- ated fibroids, hemorrhagic ovarian cysts, ovarian vein throm- mality in the abdomen or pelvis. The appendix was not visual- bosis, ovarian torsion, urolithiasis, inflammatory bowel disease, ized. The patient was subsequently admitted for observation. and small bowel obstruction.3,4 In our pregnant patient with Her right lower quadrant pain persisted, and a magnetic reso- abdominal pain, MRI proved to be diagnostic for acute ap- nance imaging (MRI) of the abdomen and pelvis was per- pendicitis. The role of MRI in imaging pregnant patients with formed on hospital day 3 for further evaluation of her pain. abdominal and pelvic pain will likely increase in the future, MRI of the abdomen and pelvis without gadolinium re- especially when US is limited or nondiagnostic. vealed a high, midline appendix that was dilated distally with intraluminal fluid contents as well as an appendicolith. (Figure REFERENCES 1A) There was associated periappendiceal edema without de- 1. Hurwitz LM, et al. Radiation dose to the fetus from body MDCT during fined fluid collection or abscess formation. (Figure 1B) MRI early gestation. AJR 2006; 186: 871-6. 2. Pedrosa I, Levine D, et al. MR imaging evaluation of acute appendicitis in findings were diagnostic of acute appendicitis. The patient pregnancy. Radiol 2006; 238: 891-9. underwent subsequent emergent appendectomy, and pathol- 3. Pedrosa I, Zeikus EA, et al. MR imaging of acute right lower quadrant pain in ogy confirmed acute suppurative appendicitis. pregnant and nonpregnant patients. Radiographics 2007; 27: 721-43. Evaluation of pregnant patients with abdominal or pelvic 4. Birchard KR, Brown MA, et al. MRI of acute abdominal and pelvic pain in pregnant patients. AJR 2005; 184: 452-8. pain can be a diagnostic dilemma. Especially challenging is the differentiation of normal physiologic changes of pregnancy Jill A. Steinkeler, MD, is a 2nd year Radiology Resident, Rhode from disease entities. For example, upward displacement of the Island Hospital. appendix and physiologic leukocytosis of pregnancy can be Courtney A. Woodfield, MD, is Assistant Professor of Diag- confounding factors. Imaging plays an important role in the nostic Imaging, The Warren Alpert Medical School of Brown work-up of these patients. Due to the theoretical potential University.

Disclosure of Financial Interests The authors have no financial interests to disclose.

CORRESPONDENCE Jill A. Steinkeler, MD Email: [email protected]

Figure Legends: Fig 1 - Acute appendicitis in a 23 year old pregnant female at 14 weeks gestation. (Left) Sagittal T2 weighted image demonstrates a dilated (1.6 cm in diameter) appendix (arrows) with high T2 signal intensity intraluminal fluid and a low T2 signal intensity appendicolith (arrowhead). Intrauterine gestation (curved arrow). (Above) Axial STIR image highlights edema (arrowheads) surrounding the dilated midline appendix (arrow). 196 MEDICINE & HEALTH/RHODE ISLAND THE WARREN ALPERT MEDICAL SCHOOL OF B ROWN UNIVERSITY GERIATRICS FOR THE Division of Geriatrics PRACTICING PHYSICIAN Quality Partners of RI Department of Medicine EDITED BY ANA C. TUYA, MD Case Presentation: Mr. J, an 88 year-old man found on the floor, complaining of generalized weakness Rebecca Starr, MD, and Ana Tuya Fulton, MD

Mr. J is 88-years old, with a medical history of bladder PHYSICAL EXAM cancer, status-post resection with a neo-bladder, right ureteral The patient was thin, slightly diaphoretic, tired-appear- stent and chronic renal insufficiency. He was brought to a ing, but pleasant with a gentle smile. His temperature was local emergency department after his son found him on the 100.9F, blood pressure was 148/64 (not orthostatic), heart rate floor. The patient said that earlier in the day, he was getting up was 64, respirations were 16, and his pulse oximetry was 97% from a chair, felt weak, and slid to the ground. He could not on room air. Head and neck exam was significant for tempo- get up. Review of systems was positive for having chills during ral wasting and dense arcus senilis. Lung and cardiac exams the past few days; decreased appetite, with 6-pound weight were normal. His abdomen was soft, non-tender, non-dis- loss over the last month; and bloody urostomy output over the tended, and there were no palpable organs. He had a left lower past 36 hours and was otherwise negative. quadrant ostomy, with a pink stoma and blood-tinged urine in the ostomy bag. He had no lower extremity or scrotal edema. MEDICAL HISTORY He was alert with intact cognition, and neurological examina- He was diagnosed with bladder cancer in January 2006. tion was normal, although gait was not assessed. Cystoscopic pathology showed grade III papillary urothelial carcinoma invading the lamina propria and muscularis. He LABS underwent 6 courses of BCG intravesicular treatment. Repeat WBC 13.4; 94% polys, no bands. Hgb 10.3, platelets 279. pathology in May 2006 showed muscle invasive disease. In July Chem 7 revealed sodium of 141, potassium 4.8, bicarbonate 23, 2006, Mr. J underwent radical cysto-prostatectomy and ileal BUN 0.5, and creatinine of 5.9. CK was 582, troponin <0.15, loop diversion. He was not treated with chemotherapy or ra- PT 43.2, INR 4.90, AST 50, ALT 67, alkaline phosphatase (ALP) diation, and subsequent CT scans showed no metastasic dis- 507, T Bili 1.3, D Bili 0.5, Albumin 2.5, Protein 7.4, Lactate 1.3. ease. Other medical history included chronic renal failure, U/A showed 2+ blood, 600 protein, 3+ LE, 13RBC, 2WBC. with a baseline creatinine of approximately 2.5 mg/dl, hyper- EKG showed NSR @ 64, 1st degree heart block (unchanged) tension; diet-controlled diabetes mellitius II; hypercholester- Imaging studies: Chest X-ray & CT of the head were nor- olemia, bilateral deep venous thromboses diagnosed in April mal. CT of the abdomen and pelvis showed an obstructing 6mm 2007 (on warfarin); right ureteral stent secondary to obstruc- stone in the distal left ureter with extensive inflammatory strand- tion caused by the bladder cancer; peripheral vascular disease; ing and hydroureter. The liver had a nodular contour. and Gleason 3 Prostate cancer. HOSPITAL COURSE MEDICATIONS Mr. J was admitted with a diagnosis of acute on chronic Warfarin 3 mg daily, amlodipine 10 mg daily, atorvastatin renal failure secondary to an obstructing stone. He was seen 10 mg daily, mirtazepine 30 mg at bedtime, pantoprazole 40 by a urologist, and underwent percutaneous drainage of his mg daily and pentoxyfylline 400 mg twice daily. He had no left kidney and had nephrostomy tubes placed bilaterally. He known drug allergies. received a 7-day course of piperacillin/tazobactam for treat- ment of pyelonephritis. His liver enzymes continued to rise. SOCIAL HISTORY ALP 527, AST 91, ALT 97, T Bili 4.4, D Bili 3.9 after several Mr. J was a retired engineer. He was in the military ap- days. An ultrasound showed coarsened echotexture but no fo- proximately 60 years ago, but had no known exposure to harm- cal lesions. There was no evidence of ductal dilatation, no stones ful substances. He smoked a pipe for several years, but quit 10- and a negative sonographic Murphy’s sign. 15 years ago. He drank alcohol rarely, and never used illicit substances. Prior to his diagnosis of bladder cancer, he had been What is the Differential Diagnosis of active and lived alone. Subsequently, he lived with his son. His Asymptomatic Elevated bilirubin? health and functional status had gradually declined over the Elevation of direct bilirubin is divided into three major last year, with several hospitalizations and short stays in skilled categories: extrahepatic cholestasis (or biliary obstruction), in- nursing facilities (SNF)s for rehabilitation. trahepatic cholestasis, and hepatocellular injury.

197 VOLUME 91 NO. 6 JUNE 2008 Albumin 2.0 and T Protein 7.3. US/ RUQ of the liver indicated coarse echo texture. No biliary dilatation or focal hepatic lesion was seen. The gallbladder was contracted, and the vessels were patent. The patient was admitted, and the consulting Gastroenterology team recommended an MRI/ MRCP. The MRI showed multiple T2 hyper-dense images, suspicious for malignancy. A liver biopsy, per- formed under ultrasound guidance, Once the above possibilities were ruled out, drug-induced showed high-grade transitional cell carcinoma. hepatotoxicity (also known as drug-induced liver injury, or DILI) was raised as a possible etiology for the elevated liver FINAL DIAGNOSIS tests. DILI encompasses a spectrum of clinical disease, ranging Metastatic bladder cancer to the liver with resulting from mild biochemical abnormalities to acute liver failure. It is cholestasis a clinical diagnosis based on history, probability of suspected medication as a cause of liver injury, and exclusion of other RESOLUTION OF CASE causes. The incidence is difficult to determine, and thought to The patient’s oncologist felt that because of the patient’s be under-diagnosed.1 poor performance status, chemotherapy was not an option. The The definition of liver injury is twice the upper limit of nor- patient was discharged to Steere House, and expired two weeks mal levels of ALT or conjugated bilirubin, or a combined in- later under hospice care. crease in levels of AST, ALP, and total bilirubin, with at least one being more than twice the upper level of normal. Elevations in REFERENCES serum enzyme levels (ALT, AST, ALP) indicate liver injury. In- 1. Sgro C, et al. Incidence of drug-induced hepatic injuries. Hepatol 2002;36:451- creases in both total and conjugated bilirubin, decreased plate- 5. 2. Hui CK, et al. Mirtazapine-induced hepatotoxicity, J Clin Gastroenterol let count, or abnormal coagulation studies are indicators of overall 2002;35:270-1. liver function. Clinical patterns of DILI include hepatocellular, 3. Chowdhury N, et al. Classification and causes of jaundice or asymptomatic cholestatic, and a mixed pattern. There are also immunoallergic, hyperbilirubinemia. Up To Date 2007. http://uptodateonline.com, accessed autoimmune, and steato-hepatitis drug reactions. 12/2/2007. 4. Navarro V, Senior J. Drug-related hepatotoxicity, NEJM 2006;16:731-9. The patient’s medications were reviewed to identify pos- 5. Lee W. Drug-induced hepatotoxicity, NEJM 2003;349:474-85. sible causes of DILI. While in the hospital, he had been on 6. Hussaini, Farrington. Idiosyncratic drug-induced liver injury. Expert Opinion piperacillin/tazobactam, an antibiotic known to cause a Drug Safety 2007; Nov 6(6);673-84. cholestatic drug reaction, but he had already completed his 7- 7. Novak D, Lewis J. Drug-induced liver disease. Curr Opinion Gastroenterol 2003; 19: 203-15. day course. He had been taking atorvastatin for over 5 years. 8. Larson A. Drugs and the liver. Up To Date 2007. http://uptodateonline.com, He had been taking mirtazapine for the last 6 months. accessed 12/2/2007. A literature review revealed 2 reports of patients with he- patic injury secondary to mirtazapine:2 a 54-year-old woman on Rebecca Starr, MD, is a Geriatric Medicine Fellow, Warren mirtazapine for 3 years, and a 49-year-old woman on mirtazapine Alpert Medical School of Brown University. for 1 year. Both patients developed elevated liver tests and pro- Ana Tuya Fulton, MD, is Assistant Professor of Medicine, longed jaundice. After they stopped mirtazapine, their liver tests Warren Alpert Medical School of Brown University. returned to normal after a few months. Both atorvastatin, and mirtazapine were stopped. The patient’s liver studies began to Disclosure of Financial Interests decline, and he was discharged to a SNF with a plan for ureteral The authors have no financial interests to disclose. stone removal once his liver studies normalized. Six days after discharge, the patient was readmitted be- cause of abnormal lab values, weakness and anorexia. He felt 8SOW-RI-GERIATRICS-062008 some chills, but denied fever, nausea, vomiting or abdominal THE ANALYSES UPON WHICH THIS PUBLICATION IS BASED were pain. In the ED, his vital signs were normal. His physical exam performed under Contract Number 500-02-RI02, funded by was notable for jaundice and scleral icterus, but no abdominal the Centers for Medicare & Medicaid Services, an agency of pain or distention. His urostomy bag contained dark urine. the U.S. Department of Health and Human Services. The con- tent of this publication does not necessarily reflect the views His labs showed WBC 7.9, hgb 104, platelets 265. His or policies of the Department of Health and Human Services, chem 7 revealed CO2 19, BUN 40, and a creatinine of 3. His nor does mention of trade names, commercial products, or INR was 1.2. U/A showed 1+ bili, 2+ blood, 30 protein, 3+ organizations imply endorsement by the U.S. Government. LE, WBC >180, and RBC 32. AST was 102, ALT 116, ALP The author assumes full responsibility for the accuracy and 703 (482 on discharge); T Bili was 8.2 (3.4), D Bili 5.2 (2.2), completeness of the ideas presented. 198 MEDICINE & HEALTH/RHODE ISLAND RHODE ISLAND DEPARTMENT OF HEALTH • DAVID GIFFORD, MD, MPH, DIRECTOR OF HEALTH EDITED BY JAY S. BUECHNER, PHD

Hospitalizations and Associated Costs for Principal versus Additional Diagnoses of Asthma: Implications for Monitoring Children’s Health Deborah N. Pearlman, PhD, Nancy Sutton, RD, MS, Sze Liu, MPH, Janice Fontes, MS, and Jay S. Buechner, PhD

Asthma is the most common chronic disease of childhood Patient characteristics included: age (0 to 4, 5- 11, 12- in the United States (US).1 Much of the health care cost of 17), sex (male vs. female), race and ethnicity (black, Hispanic, asthma is for treatment in the hospital. Hospitalizations for white, other race), type of health coverage (public, including pediatric asthma increased in the US over the past decade, but RIte Care and fee-for-service Medicaid, commercial/other self- recently plateaued at historically high levels.2 In 2004, pediat- pay), and census tract of residence, ( poverty or non-poverty). ric asthma hospitalizations in the US were responsible for $330 Records of hospital admissions (2001-2005) were matched million in incurred charges.3 with census tract level variables from the US Census 2000 Sum- Surveillance of pediatric asthma hospitalization rates is es- mary File 3 (SF 3) – Sample Data.5 A poverty census tract was sential to track trends over time, to identify children likely to defined as a census tract where 20% or more of the residents be hospitalized due to asthma, and to quantify the burden of live at or below the federal poverty level, as determined in the disease borne by population subgroups, in particular, children 2000 US Census.6 residing in poverty areas. Much of our knowledge about hos- Rates per 10,000 children aged 0 to 17 years were calcu- pitalizations for childhood asthma comes from studies that de- lated using Rhode Island population for the years 2001-2005 fine an asthma hospitalization as one with a principal diagnosis from the US Census Bureau.7 Analyses of hospital charges of asthma. A retrospective study of 2003 National Hospital and length of stay were stratified by poverty and non-poverty Discharge Survey data found that 75% of all admissions for census tracts. To calculate changes in rates over time, the baseline childhood asthma were assigned a principal discharge diagno- rate was subtracted from the rate in a subsequent year, and the sis of asthma.4 Of the remaining asthma discharges, most were difference was divided by the baseline rate and expressed as a assigned a principal diagnosis of respiratory illness and an ad- percentage. ditional diagnosis of asthma.4 This report explores the implica- tions of using different case definitions of asthma-related hospitalizations, focusing on average length of stay and hospital charges in analyses stratified by neighborhood pov- erty.

METHODS Under licensure regulations, acute-care hospitals in Rhode Island have reported to the Department of Health’s Center for Health Data and Analysis a defined set of data (demographic and clinical) on each inpatient discharge beginning January 1, 1989. This analysis covers inpatient discharges ages 0 – 17 years occurring January 1, 2001 – De- cember 31, 2005. Rate estimates were not adjusted for repeated hospital admissions of the same child during this period. Two mutually exclusive groups of pedi- atric asthma discharges were established: (1) all discharges with a principal diagnosis of asthma (ICD-9-CM diagnosis code 493), and (2) discharges with a principal diagnosis of a respiratory illness (ICD-9-CM codes 460 through 496) plus an additional (secondary or tertiary) diagnosis of asthma. 199 VOLUME 91 NO. 6 JUNE 2008 The average total charge for a pediatric asthma hospitalization with a principal diagnosis of asthma during 2001-2005 was $19,427, with a mean length of stay of 6.0 days. (Table 2) For hospitaliza- tions with a principal diagnosis of respiratory ill- ness and an additional diagnosis of asthma, average charges ($23,045) and length of stay (7.4 days) were both significantly higher than the average charges and length of stay when asthma was the principal diagnosis. Average charges and length of stay for a hospitalization with a principal diagnosis of asthma were significantly higher for children liv- ing in poverty neighborhoods ($25,065 and 7.4 days, respectively), than for children in non-poor communities ($14,579 and 4.9 days, respectively).

DISCUSSION Ongoing surveillance of childhood asthma is necessary to understand changes and patterns in Figure 1. Hospital inpatient discharges with a diagnosis of asthma per 10,000 prevalence and to evaluate the impact of practice population, by position of asthma diagnosis and year of discharge, ages 0 – 17, Rhode Island, 2001 –2005. guidelines and interventions. One impediment to pediatric asthma surveillance is the lack of a “gold standard” definition for hospitalization for child- hood asthma. In this analysis, the addition of pedi- atric hospital discharges with a principal diagnosis of respiratory disease and an additional diagnosis of asthma increased the number of discharges by 37% over the number of discharges with a princi- pal diagnosis of asthma. Furthermore, the age dis- tribution, mean total charges, and mean length of stay for the additional hospitalizations differed sig- nificantly from the corresponding measures for hos- pitalizations with a principal diagnosis of asthma. Most surveillance systems for pediatric asthma in the US capture only hospitalizations with a princi- pal diagnosis of asthma. The findings from this re- RESULTS port suggest that asthma surveillance systems designed to in- Over the period 2001-2005, there were 2,633 pediat- form community- and clinical-based initiatives to decrease hos- ric discharges with a principal diagnosis of asthma, and 980 pitalizations for childhood asthma should consider tracking dis- discharges with a principal diagnosis of respiratory illness and charges where respiratory illnesses are the principal diagnosis an additional diagnosis of asthma. (Table 1) Children in both and asthma is the secondary or tertiary diagnosis. groups were more likely to be younger than age five, boys, non-Hispanic white, and live in non-poverty census tracts. ACKNOWLEDGEMENTS Children hospitalized for a respiratory illness with asthma as We wish to thank Jeanne E. Moorman, MS, Centers for an additional diagnosis were also significantly more likely to Disease Control and Prevention, National Center for Environ- be younger than age five than children with a principal diag- mental Health, Division of Environmental Hazards and Health nosis of asthma. For both groups, slight majorities were en- Effects and Annie Gjlesvik, PhD, Rhode Island Department rolled in publicly-funded insurance. Nearly all had coverage of Health, Diabetes Prevention and Control Program for their to pay for their care. insightful comments on statistical issues. This work was funded Between 2001 and 2003, the rate of discharges per in part by the Agency for Healthcare Research and Quality 10,000 children where asthma was the principal diagnosis in- (AHRQ) 2006-2007 Learning Partnership to Decrease Dispari- creased by 16%, then declined in 2004 and 2005, returning ties in Pediatric Asthma and by the Centers for Disease Con- to the same level as in 2001. (Figure 1) The rate for discharges trol and Prevention (CDC) Grant Cooperative Agreement where respiratory illnesses were the principal diagnosis and Number IU59EH000199-01. The contents of this manu- asthma an additional diagnosis increased by 25% between 2001 script are solely the responsibility of the authors and do not and 2005. necessarily represent the official views of AHRQ or CDC.

200 MEDICINE & HEALTH/RHODE ISLAND REFERENCES Deborah N. Pearlman, PhD, is Research Faculty in the Pro- 1. Gold DR, Wright R. Population disparities in asthma. Annu Rev Public Health gram in Public Health, Warren Alpert Medical School of Brown 2005;26:89-113. University, and Senior Epidemiologist, Rhode Island Department 2. Akinbami LJ, Centers for Disease Control and Prevention National Center for Health Statistics. The state of childhood asthma, United States, 1980 – 2005. of Health. Adv Data 2006 12:1-24. Nancy Sutton, RD, MS, is Program Manager in the Asthma 3. Russo A, Jiang J, Barrett, M. Trends in Potentially Preventable Hospitalizations Prevention Program, Rhode Island Department of Health. among Adults and Children, 1997-2004. H-CUP Healthcare Cost and Uti- Sze Liu, MPH, is a PhD candidate in the Program in Public lization Project. Statistical Brief #36. August 2007. Agency for Healthcare Research and Quality, Rockville, MD. http://www.hcup-us.ahrq.gov/reports/ Health, Center for Population Health and Clinical Epidemiology, statbriefs/sb36.pdf Warren Alpert Medical School of Brown University. 4. Bundy DG. Hospitalizations with primary versus secondary discharge diag- Janice Fontes, MS, is Data Manager in the Center for Health noses of asthma. J Pediatr 2007 ; 150:446-9. Data and Analysis, Rhode Island Department of Health. 5. Bishaw A. Areas with concentrated poverty: 1999. Census 2000 Special Re- ports. CENSR-16 Issued July 2005. http://www.2010census.biz/prod/ Jay S. Buechner, PhD, is Chief, Center for Health Data and 2005pubs/censr-16.pdf Analysis, and Clinical Assistant Professor of Community Health, 6. US Census Bureau. American Community Survey. Census 2000 Summary Warren Alpert Medical School of Brown University. File 3 (SF 3) – Sample Data. http://factfinder.census.gov/servlet/ DatasetMainPageServlet 7. US Census Bureau. Population Estimates. http://www.census.gov/popest/ Disclosure of Financial Interests datasets.html. Page last Mmodified: March 26, 2008. The authors have no financial interests to disclose.

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201 VOLUME 91 NO. 6 JUNE 2008 DAVID GIFFORD, MD, MPH, DIRECTOR OF HEALTH RHODE ISLAND DEPARTMENT OF HEALTH EDITED BY JOHN P. FULTON, PHD

Department of Health Promotes e-Licensing for Physicians, Spring 2008 Michael Simoli and Robert Crausman, MD

After a successful 95% adoption rate during the 2006 low the Department to collect summarized information about physician renewal cycle, the Rhode Island Department of such topics as availability for emergency volunteering, spe- Health is pleased to announce that the online renewal process cialty information, and physician employment in Rhode Is- will continue for physician licenses for the renewal period from land. Participating in this survey is entirely voluntary; responses May 1, 2008 through June 30, 2008. During the month of to the survey will not in any way affect the renewal of your April 2008 physicians eligible for license renewal will have re- license. ceived a notification card in the mail with complete instruc- Renewing online is fast, easy, and secure. You will be able tions about the renewal process. If you did not receive your to renew online any time during the renewal period, day or renewal notification by May 1, 2008, please contact the Li- night, using your Visa or MasterCard credit or debit card. The censing Data Entry Unit at 401-222-1800 or by e-mail at Department also has personal computers available on-site for [email protected]. renewing your license during regular business hours. Staff will Online license renewal (e-Licensing) continues to be one be available 8:30am through 3:30pm Monday through Fri- of the most successful steps toward increasing the Department’s day to assist you with the online renewal process from May 1, efficiency and improving its customer service. 2008 through September 30, 2008. In addition to renewing your license and updating your address information, the Department will again include a Disclosure of Financial Interests workforce survey in the renewal process. This survey will al- The authors have no financial interests to disclose.

202 MEDICINE & HEALTH/RHODE ISLAND Physician’s Lexicon A Planetary Vocabulary

Astrology, centuries ago, was a major and sprightly but volatile. Hermes was the jorative: venereal disease, venery, venality, component of medical education in West- Greek equivalent of Mercury and his name venom and even venerable. ern Europe. Memorizing the constellations, has become legion in medical vocabulary. The planet Earth gives rise to the ad- their configurations and the celestial jour- Along with his fellow Greek divine named jective, earthy; while the planet Mars is the neys of the planets was at least as important Aphrodite, the Greek counterpart of the basis for the adjective, martial. Jupiter, some- as learning human anatomy or the prin- Roman Venus, we encounter the hermaph- times called Jove, provides us with the ad- ciples of purging. Fortunately, the alleged rodite, the biological state of creatures bear- jective jovial. relationship of the stars to our individual ing both male and female sex organs. Her- The planet Saturn, sixth from the sun, destinies has now become little more than metic, describing an airtight sealing, has a crops up in words such as saturnalia, a li- an eccentricity. Astronomy, or astrobiology, more circuitous derivation. When Greek centious festival; saturnine, one with a may yet return to the medical curriculum. culture overtook Egypt following the gloomy disposition; and saturnism, describ- But until that time, the names of the plan- Alexandrian expansion, Hermes, now ing systemic lead poisoning. ets persist, in the vocabulary of contempo- called Hermes Trismegistus [thrice great], Pluto, the ninth planet from the sun, rary medicine, largely as adjectives describ- was equated with the Egyptian god, Toth although some now doubt that it is even ing human mood or behavior, reminding [who, it was claimed, had invented glass and a planet. Nonetheless we have the diag- us of our discarded past beliefs. the ability to seal glass containers by heat.] nosis of plutomania [the mistaken believe Mercury, the Roman messenger to the Thus, to seal any container was to make it that one is rich] as well as the radioactive gods, defines the toxic metal formerly used hermetic. Finally, there is the word herme- plutonium. And then, of course, there is in antiluetic therapy and in certain antisep- neutics, the art of explaining things. Uranus. tics. And a mercurial personality, we are The name Venus forms the basis for told, is one who is capricious, fickle, flighty a variety of nouns and adjectives, many pe- – STANLEY M. ARONSON, MD

RHODE ISLAND DEPARTMENT OF HEALTH VITAL STATISTICS DAVID GIFFORD, MD, MPH DIRECTOR OF HEALTH EDITED BY C OLLEEN FONTANA, STATE REGISTRAR

Underlying Reporting Period Rhode Island Monthly June Cause of Death 12 Months Ending with June 2007 Vital Statistics Report 2007 Number (a) Number (a) Rates (b) YPLL (c) Provisional Occurrence Diseases of the Heart 218 2,745 256.6 3,676.5 Malignant Neoplasms 180 2,264 211.6 5,822.0 Data from the Cerebrovascular Diseases 32 397 37.1 599.5 Division of Vital Records Injuries (Accidents/Suicide/Homicde) 46 575 53.8 9,100.0 COPD 30 437 40.9 392.5

Reporting Period (a) Cause of death statistics were derived from the underlying cause of death reported by Vital Events December 12 Months Ending with physicians on death certificates. 2007 December 2007 (b) Rates per 100,000 estimated population of Number Number Rates 1,067,610 Live Births 1,118 13,341 12.5* Deaths 894 9,925 9.3* (c) Years of Potential Life Lost (YPLL) Infant Deaths (10) (100) 7.5# Neonatal Deaths (8) (79) 5.9# Note: Totals represent vital events which occurred in Rhode Marriages 363 6,786 6.4* Island for the reporting periods listed above. Monthly pro- Divorces 216 2,983 2.8* visional totals should be analyzed with caution because the numbers may be small and subject to seasonal variation. Induced Terminations 545 4,973 372.8# Spontaneous Fetal Deaths 58 920 69.0# * Rates per 1,000 estimated population Under 20 weeks gestation (49) (840) 63.0# # Rates per 1,000 live births 20+ weeks gestation (9) (80) 6.0# 203 VOLUME 91 NO. 6 JUNE 2008  

The Official Organ of the Rhode Island Medical Society

Issued Monthly under the direction of the Publications Committee

VOLUME 1 PER YEAR $2.00

  NUMBER 1PROVIDENCE, R.I., JANUARY, 1917 SINGLE COPY, 25 CENTS

NINETY YEARS AGO, JUNE 1918 FIFTY YEARS AGO, JUNE 1958 George S. Matthews, MD, in “Some Cardio-Vascular Con- Carl E. Badgley, MD, Professor of Surgery, University of siderations in Connection with Advisory Board Draft Exami- Michigan and past president, American Academy of Ortho- nations,” noted that examiners could often easily separate the pedic Surgeons, delivered the First Murray S. Danforth Ora- fit from the unfit; but “not a few, however, tax the mental acu- tion: “Some Problems in the Treatment of Traumatic Distor- men of the examiner.” Indeed, the examiner can “get stranded tion of the Hip.” on the rocks of doubt” or “eddy in the currents of uncertainty.” George W. Waterman, MD, in “Problems of Medical Care The Advisory Board of northern Rhode Island was housed in 1957-58” [the Presidential Address, Rhode Island Medical the Out Patient Department building of Rhode Island Hospi- Society], deplored the waning of the fee-for-service system: tal – fortunately, a quiet spot for hearing heart beats. One writer ”The issue of the fee-for-service without intervention of the had noted that of 9000 cases, 29% were rejected on physical third party with its fixed-fee standard, is that where the fee- grounds, with 2.5% because of the heart, although the author for-service is in force, and where there is free choice of physi- suggested that soldiers with “irritable heart” could be retrained. cian or surgeon, better patient care will result. For when the Carl D. Sawyer, MD, in “Epidemic Meningitis,” recom- bond between patient and doctor is close, and if there exists mended isolation of carriers, because no immunizations had good understanding, as is the normal case, better feelings re- succeeded. garding financial arrangements is bound to exist, the patient Henry A. Jones, MD, in “Report of the First Case of Pella- being allowed to realize his obligations on his own responsibil- gra in 1918,” cited the “old belief ” linking the disease to a ity and the doctor not being irked by having to accept a fee corn diet. The 52 year-old patient, a widow and mother of 3, forced upon him…by a third party.” had left mill work because of swollen feet, to work as a char- Saverio Caputi, JR, MD, in “Treatment of Lead Poison- woman by the day. Her diet favored johnnycakes and corn- ing with Calcium Disodium Versenate: A Case Report,” de- meal puddings. She drank only condensed milk, never fresh scribed a two year old girl, who emerged cured with the treat- milk. Dr. Jones recommended, for treatment, “tonics, strych ment, after 18 days in the hospital. and arsenic, milk and vegetables.” An Editorial, “The Irregular Cults in the War,” praised TWENTY-FIVE YEARS AGO, JUNE 1983 the Surgeon General for recognizing only MDs as medical of- C.P. Pagonis, MD, T.A. Leclerq, MD, and S.R. Allegra, ficers, excluding “osteopaths, chiropractics, and Christian Sci- MD, in “Hypopituitarism with Normal Skull Film and Pitu- entists.” “This is not a time for trying out new systems and treat- itary Tumor,” discussed a 38 year-old man: “Microsurgery by ment. It is a time to rely upon that standard of medicine which the transsphenoidal approach was successful.” has proved the standard for countless ages…” The Clinico-pathological Conference Case Record (Rhode Island Hospital) featured a 71 year-old retired truck driver with chronic lymphocytic leukemia and chronic obstructive pulmonary disease, who had smoked 2 packs a day for 50 years, and drunk 3-4 beers a night. He was hospitalized for “pro- found weakness, dyspnea and fever of four days durations.” The findings were: disseminated aspergillosis with valvulitis and congestive heart failure.” Elihu S. Wing, Jr, MD, described the “First American Description of Calcific Aortic Stenosis.” General William Whipple (1730-85), a signer of the Declaration of Indepen- dence, had ordered an autopsy on his own remains, providing “for this medical milestone.”

204 MEDICINE & HEALTH/RHODE ISLAND

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