RHODE ISLAND M Edical J Ournal

RHODE ISLAND M EDICAl J ournal

Spotlight: RIMJ Timeline of COVID-19 in 2020 See page 74

February 2021 VOLUME 104 • NUMBER 1 ISSN 2327-2228 URGENT RESOURCES FOR URGENT TIMES.

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14 Clinicians’ Update: Kidney Transplantation in End-Stage Renal Disease (ESRD) Reginald Gohh, MD Guest Editor

Reginald Gohh, MD

15 Frailty and Kidney Transplantation George Bayliss, MD

20 Management of Cardiovascular Risk Factors in Dialysis-Dependent End Stage Kidney Disease Harshitha Kota, MD Reginald Gohh, MD

25 Malignancy After Renal Transplantation: A Review Edward Medeiros, DO Basma Merhi, MD

31 Managing Side Effects of Immunosuppressants Krista Mecadon, PharmD

34 transplantation of Hepatitis C-Infected Kidneys into Uninfected Recipients: A Review of the Literature Haley Leesley, MD, MS Adena J. Osband, MD

3 RHODE ISLAND M EDICAl J ournal

8 COMMENTARY why don’t doctors return phone calls? Joseph H. Friedman, MD Gender-based Differences in the Societal Impact of the COVID-19 Pandemic Christina Matulis, MD Mehrnoosh Samaei, MD, MPH Ghada Bourjeily, MD Alyson J. McGregor, MD, MA

67 RIMS NeWS working for You

71 RIMJ Around the World Providence, Rhode Island Dublin, Ireland

74 SPOTLIGHT RIMJ COVID-19 Retrospective Mary Korr

78 HERITAGE Dr. Carl Russell Gross Collection documents RI’s Black History and Heritage GP served his patients for decades but was denied hospital privileges in Providence Mary Korr

4 RHODE ISLAND M EDICAl J ournal

In the news

Dean Gary Liguori 82 86 Martin A. Weinstock, MD of URI College of Health Sciences, Robert Dellavalle, MD updates ACSM’s “Guidelines for basal cell carcinoma chemo- Exercise Testing and Prescription” prevention VA trial funded

Rhode Island 82 87 Brian J. Pickett, MD receives $70.4M to expand COVID-19 Stephanie Krusz, MD testing, vaccine distribution efforts join South County Health Brown researchers 83 as South County Primary Care designing adverse event monitoring system for post-covid-19 vaccination impacts 88 Michael F. Armey, Phd in elderly nursing home residents Melanie Bozzay, Phd of VA, Butler awarded DHHS Trio of centenarian Navy veterans 83 $2.24M grant to study receive COVID-19 vaccination sleep disruption, suicide risk

Lung Association Report 85 89 Lifespan Urgent Care RI has mixed grades in ending tobacco use opens 3rd location in Providence

CARE NEW ENGLAND 86 89 Developer closes expands services in South County on former Memorial Hospital site

People/PLACES

Maria Ducharme, DNP, RN 90 91 Elizabeth Damoura Moreira named Miriam Hospital President appointed Pawtucket's Public Health and Equity Leader Patrick Tigue 90 confirmed as OHIC’s 92 Michael J. Frank, PhD new Commissioner of Carney Center, honored by National Academy of Sciences Tiffney Davidson-Parker 90 named President, COO 92 Marie Ghazal of The Providence Center recognized with RI Foundation Murray Family Prize for Angela Bannerman Ankoma 91 Community Enrichment named V-P, Director of Equity Leadership Initiative 93 Obituaries at Rhode Island Foundation George N. Cooper, Jr., MD Christine Foley, MD 91 David C. Lewis, MD elected to Fellowship Charles J. McDonald, MD in Minimally Invasive Michael Anthony Passero, MD Gynecologic Surgery Board

5 FEBRUARY 2021 VOLUME 104 • NUMBER 1 RHODE ISLAND Rhode Island Medical Society R I Med J (2013) M EDICAl J ournal Publisher 2327-2228 Rhode Island Medical Society

104 President Catherine A. Cummings, MD

1 President-elect 2021 Elizabeth B. Lange, MD Vice president February Thomas A. Bledsoe, MD Case ReportS Secretary 37 Retinopathy in a Full-Term Infant with Cri-du-Chat Syndrome Kara Stavros, MD 1 Nisarg Chhaya, MD; Tineke Chan, MD Treasurer Kwame Dapaah-Afriyie, MD, MBA 40 Iatrogenic Pneumothorax and Pneumomediastinum Executive Director in a Patient with COVID-19 Newell E. Warde, PhD Vijairam Selvaraj, MD; Kwame Dapaah-Afriyie, MD

Editors-in-Chief William Binder, MD Edward Feller, MD ContributionS Associate editor 42 Kenneth S. Korr, MD Childhood Overweight/Obesity and the Physical Activity Environment in Rhode Island Editor-in-Chief Emeritus Joseph H. Friedman, MD Shelby Flanagan, MPH; Michelle L. Rogers, PhD; Lynn Carlson, MA, GISP; Elissa Jelalian, PhD; Patrick M. Vivier, MD, PhD

Publication Staff 47 Lowering A1c Through Integrated Behavioral Health Group Visits Managing editor Mary Korr Siddharth Marthi, BA, MD’22; Jamie Handy; [email protected] Kristin David, PsyD; Martin Kerzer, DO

Graphic designer 51 Treatment Retention in Older Versus Younger Adults Marianne Migliori with Opioid Use Disorder: A Retrospective Cohort Analysis Advertising Administrator DULCINEIA COSME from a Large Single Center Treatment Program [email protected] Alyssa Greenwood Francis, MPH; Julie Croll, MPH; Himanshu Vaishnav, MS; Kirsten Langdon, PhD; Francesca L. Beaudoin, MD, PhD

55 COVID-19 in Pediatric Patients: Observations from the Initial Phase of the Global Pandemic in Rhode Island Rebecca A. Levin, MD; Hoi See Tsao, MD; Siraj Amanullah, MD, MPH; Alicia Genisca, MD; Laura Chapman, MD

61 COVID-19 and Public Interest in Ophthalmic Services and Conditions John C. Lin; Lan Jiang, MS; Ingrid U. Scott, MD, MPH; Paul B. Greenberg, MD, MPH

RHODE ISLAND MEDICAL JOURNAL (USPS 464-820), a monthly publication, is PUBLIC HEALTH owned and published by the Rhode Island Medical Society, 405 Promenade Street, Suite 65 Vital Statistics A, Providence RI 02908, 401-331-3207. All Roseann Giorgianni, Deputy State Registrar rights reserved. ISSN 2327-2228. 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 im- ply sponsorship or endorsement by the Rhode Island Medical Society.

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Advocacy | Tailored Insurance Solutions | Peace of Mind Commentary

Why don’t doctors return phone calls?

Joseph H. Friedman, MD

8 9 EN

All doctors get called who answer the calls, seen every few months so the effects of by their patients. Some saving the doctors a lot medication changes aren’t known for are better than others of time. And since the long periods of time if one relies only in answering them. My nurses are usually less on the actual face-to-face office meeting. patients often report that time constrained, they Usually that is sufficient. It is important their doctors, whether usually spend more time, for patients who are not tolerating med- PCPs or specialists, according to my patients, ications to report this to their treating never call them back. My and seem a lot more daughter, in California, interested, and more doesn’t get her calls re- empathetic. Other offices One neurologist I know wrote turned. Another close rel- have computer “portals” a book for patients and made ative, a physician, herself, in which non-emergency his patients purchase it. When doesn’t get her calls returned. This is calls are handled throughout the day, they called, the secretary such a frequent refrain that I have to probably by nurses or advanced practice would transmit the questions wonder if it is the norm, now, through- providers. out the U.S. As you might expect, One neurologist I know wrote a and he would instruct the sec- some patients call more than others. book for patients and made his patients retary to tell the patient what Most calls are necessary. “This new purchase it. When they called, the sec- chapter to read in his book. medicine is causing side effects. What retary would transmit the questions should I do?” “I’m hallucinating.” “My and he would instruct the secretary to husband is confused. He couldn’t find tell the patient what chapter to read in physician in a timely manner and not the bathroom last night.” “My wife fell his book. As best I could tell, he was simply show up 4 or 6 months later down three times today.” “He’s in the not popular with patients, or his staff. and say, “I took one dose and felt lousy hospital and the doctors won’t listen They felt that he demeaned his patients so I stopped it.” That’s 4 months water to me about his medication schedule.” by his behavior. This made them feel under the bridge. The list is endless. And the patients badly for the patients and also felt that Back in the days before Covid, often feel helpless. Yet some doctors this behavior reflected poorly on them. when I used to occasionally attend don’t call back. I am not sure why that And, I suspect (based on limited personal national meetings, one of my colleagues is. Of course, I assume that most of the experience) that secretaries in medical remarked what a great service I had explanation is time. We want to get practices where the doctors routinely performed by writing an article that home at the end of the day. We don’t fail to answer patient calls resent being was widely distributed by the Ameri- want to call during the day and cause put in the middle. I suspect that the can PD Association. It was an article waiting patients to be taken late into turnover rate for secretaries in these outlining when PD patients should go the office. If we schedule time that we practices is high. to the Emergency Room. I pointed out can’t bill for we lose money. Return calls are crucial in Parkinson’s the common experience of my own Many offices, particularly academic disease, and probably most disorders, patients, who would feel frustrated by centers and group practices, have nurses acute and chronic. In PD, patients are their PD acting up. Their medicines

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 8 Commentary

hadn’t worked all day. The dyskinesias are very important, it was rarely the make the calls. had gotten out of control. Their walking cause of the worsened PD. Obviously, I don’t know why calling patients back was worse than usual. They took their if your doctor doesn’t return calls, you has fallen so out of favor that it appears medication doses too close together may have no choice but to go to the ED. to have become routine, possibly even and were worried. And what happened A study in Manhattan showed that the norm. Perhaps with the introduc- when they went to the ED? They waited PD patients who called frequently tion of telemedicine, with appropriate 3 hours to be seen, had a multitude of generally suffered more from anxiety billing, we doctors won’t feel it such an tests performed, waited another 5 hours than from other PD-related problems. encumbrance and will again consider it for the results to come back and either Some patients call daily with the same part of our routine practice. v the ED doctor then tried to reach me, or problem. What they really want is not the doctor simply told them to go home a cure for the problem, which clearly Author and call their neurologist the next day. wasn’t getting solved, but the reassur- Joseph H. Friedman, MD, is Editor- The message of my article was that if ance that the doctor knows about their in-chief Emeritus of the Rhode Island the problem was related to PD, call the problem, is still there and cares about Medical Journal, Professor and the Chief PD doctor. If it was a medical issue like them. After decades of experience, I still of the Division of Movement Disorders, fever, cough, chest pain, urinary burn- don’t know how to deal with these calls, Department of Neurology at the Alpert ing, then call the PCP or go to the ED. other than to occasionally point out that Medical School of Brown University, ED doctors weren’t neurologists and the problem had been ongoing for a long chief of Butler Hospital’s Movement generally weren’t going to be able to fix time and didn’t sound different this time Disorders Program and first recipient a PD problem, but were adept at dealing than any of the others. This is intended of the Stanley Aronson Chair in Neuro- with general medical conditions such as to be reassuring, but, to be honest, also degenerative Disorders. infections, or chest pain. While these registers a degree of annoyance. But I do

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 9 Commentary

Gender-based Differences in the Societal Impact of the COVID-19 Pandemic

Christina Matulis, MD; Mehrnoosh Samaei, MD, MPH; Ghada Bourjeily, MD; Alyson J. McGregor, MD, MA 10 12 EN COVID-19 has been referred to as the as an increase in sexual exploitation and resource utilization, such as telephone ‘great equalizer,’ given that anyone can arranged marriages.1 Subsequently, these hotlines, but decreased use of shelters be affected by the virus. However, as girls were ostracized upon returning and safe living arrangements.3 the pandemic continues, it has become to school. Implementing unique ways to screen apparent that sociocultural factors are Unique challenges are also evident and support IPV victims, such as intricately tied to vulnerability and ill- among boys, particularly in Latin through telehealth, will be essential ness severity, as well as post-viral com- America, where poverty leading to given the risks to physical and mental plications. There is evolving evidence work demands and societal stereotypes health associated with IPV. regarding the influence of biological sex cause boys to disengage at the second- in COVID-19 susceptibility, pathophys- ary school level.1 It is essential to use Declining Mental Health iology, and more. Additionally, with lessons from previous emergencies to Disasters are often accompanied by an physical distancing, patterns of daily enact services to prevent widening of increase in psychopathologies, such as life have been disrupted and differen- the pre-existing gender gap between PTSD, anxiety, and depression. Early tial consequences relating to societal children worldwide. data confirms that COVID-19 is no dif- gender identity have emerged. While ferent, where the prevalence of depres- not all inclusive, several key sociocul- Intimate Partner Violence sive symptoms in the US is more than 3 tural areas impacted by COVID-19 are Similar to previous emergencies, this times higher than pre-pandemic.4 Those outlined below. pandemic has coincided with a rise in with reduced access to socio-economic intimate partner violence (IPV). While resources and stressors such as job loss Educational Gap IPV affects everyone, globally, the bur- exhibit increased symptoms. Women are Educational systems have been affected den is borne mostly by women, with more likely than men to have depressive worldwide by the need for physical dis- 1 in 3 experiencing sexual violence in symptoms both pre- and during the tancing. It is estimated that 23.8 million their lifetime, according to the World pandemic. Additionally, specific sub- children that were enrolled in school, 11 Health Organization.2 Additionally, populations are differentially affected. million of whom are female, are at risk marginalized communities, such as In Italy, healthcare workers (HCWs) of dropping out.1 The implications of those with lower socioeconomic status reported higher rates of depressive and disrupted education are vast, as many and underrepresented minorities, are post-traumatic stress symptoms (PTSS). children will be without access to dig- particularly at risk. Female sex and single status were asso- ital learning resources and appropriate Social distancing has resulted in vic- ciated with higher levels of depression, nutrition through school lunches. tims being confined to close quarters while female sex and older age were In many countries, access to education with their abusers and without adequate associated with increased PTSS.5 is already tenuous for girls, and during resources for assistance. Key places for Pregnant women are at particularly a pandemic many are pressured to stay IPV screening, like shelters and clinics, high risk, with 18–25% experiencing home to help with housework. During have dramatically decreased, leading anxiety and 18% reporting depression the Ebola epidemic, there was a rise in to difficulty in accessing resources. during pregnancy pre-pandemic.6 This teen pregnancies due to reduced acces- Locally, the RI Coalition for Domestic is increased from baseline US charac- sibility to reproductive resources as well Violence has seen an increase in some teristics, where 8% of the population

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 10 Commentary

experiences depression and 16% expe- persists, these differences must be Global Leadership riences generalized anxiety. recognized to prevent worsening of pre- Although women comprise 70% of Alarmingly, a Canadian study found existing differences in academia. the global health workforce, they con- that pregnant women experienced stitute only 24% of COVID response increased psychological stresses com- Cultural Influences on Mortality committees.14 Low representation of pared to pre-pandemic cohorts, with Thus far, it is established that COVID- women in leadership roles in healthcare 37% reporting depressive symptoms and 19 mortality is reported to be higher in is not new, and not surprisingly, only 57% reporting anxiety. Factors contrib- men, though this may reflect a deeper 3.5% of COVID-19 national task forces uting to this include isolation, job loss, gender disparity. In Afghanistan, men show gender parity.15 Lack of leadership and misinformation disseminated from comprise 70% of COVID-19 cases and skills is not an adequate reason for lack some social and other media platforms. 74% of mortality.9 Is this difference of representation of women in deci- Examining maternal health across dif- due to females’ biological advantage or sion-making bodies. Female-led coun- ferent countries is essential, given this rather due to decreased access to care tries (including Iceland, New Zealand, particularly high-risk group at baseline. and lack of autonomy in healthcare Norway, and Taiwan) had less death per decision making? Additionally, there capita and lower excess mortality due to Impacts on Academic Productivity are other deviations from the worldwide COVID-19. Similarly, states governed Social distancing has caused an inter- trend worth highlighting. According to by females were more successful in section of household, school, and work the Global Health 50/50 and US Gender/ controlling COVID-19.16 While many commitments, inevitably affecting Sex COVID data, there are at least eight factors contribute to these correlations, productivity in academia. Gender dif- countries and nine US states where increased diversity in leadership will ferences have been previously charac- mortality in females exceeds males.10,11 benefit all. terized with regard to compensation, Additionally, female HCWs dispro- tenure, and female representation in the portionately face a higher rate of infec- Conclusion sciences.7 Early research suggests that tion and death from COVID-19. This is Various disparities have emerged with women in academia exhibited decreased partly, but not fully, explained by the the COVID-19 pandemic and recogniz- productivity during the pandemic. higher percentage of women in health- ing those who are disproportionately While there was an increase in overall care. Personal Protective Equipment affected by the virus is critical in order social science-related submissions by (PPE) can effectively lower the risk of to prevent deepening of pre-existing 35% during the first 10 weeks of the infection, but fit testing of respirators inequalities. As the pandemic contin- pandemic, female academic research demonstrates that pass rates are lower ues, efforts must be made to understand productivity dropped 13.9% compared in female and Asian HCWs.12 A study risk based on the interaction of sex, to males.7 In this analysis, males were showed that female sex was an indepen- gender, race, age, and other social deter- found to be more productive than dent risk factor for proven or suspected minants of health. Combining available females, who maintained their baseline COVID-19 infection of HCWs following data with knowledge from previous productivity, suggesting widening of a intubation.13 The CDC has taken into emergencies can help build more equi- gendered productivity gap. account the effects of various facial table societies. v Women consistently authored 20% hairstyles on the functionality of face of academic papers since 2015, but masks in men, yet has failed to consider Disclaimer authored only 12% of COVID-19 related the biological differences between male The views and opinions expressed in this Commentary reflect those of the authors data.8 Reasons are likely multifactorial and female facial contours that predis- alone and not necessarily those of the and include increased home and teach- pose women to increased infection risk institutions or organizations they are ing commitments.8 As the pandemic even with PPE. associated with.

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 11 Commentary

References Authors 1. UNESCO. Addressing the gender dimensions of COVID-related Christina Matulis, MD, Department of Emergency Medicine, school closures COVID-19 education response. Issue Note 3.1. Warren Alpert Medical School of Brown University and Rhode 2020 https://unesdoc.unesco.org/ark:/48223/pf0000373379 [Ac- Island Hospital, Providence, RI. cessed 25 Nov 2020]. Mehrnoosh Samaei, MD, MPH, Division of Sex and Gender in 2. Moreira D, Pinto da Costa, M. The impact of the Covid-19 pandemic in the precipitation of intimate partner violence. Int J Emergency Medicine, Department of Emergency Medicine, Law Psychiatry. 2020;71:101606. Warren Alpert Medical School of Brown University, 3. Zero O, Geary M. COVID-19 and intimate partner violence: a Providence, RI. call to action. R I Med J. 2020;103(5):57-59. Ghada Bourjeily, MD, Department of Medicine, The Miriam 4. Ettman CK, et al. Prevalence of depression symptoms in US Hospital, Warren Alpert Medical School of Brown University, adults before and during the COVID-19 pandemic. JAMA Netw Providence, RI. Open. 2020;3(9):e2019686. Alyson J. McGregor, MD, MA, Director, Division of Sex and 5. Di Tella M, Castelli L. Mental healthcare workers during the Gender in Emergency Medicine (SGEM); Director, Sex and COVID-19 pandemic in Italy. J Eval Clin Pract. 2020;26(6):1583- Gender in Emergency Medicine (SGEM) Fellowship; Associate 1587. Professor of Emergency Medicine, Warren Alpert Medical 6. Lebel C, et al. Elevated depression and anxiety among pregnant School of Brown University, Providence, RI. individuals. J Affect Disord. 2020; 277:5-13. 7. Cui R, Ding H, Zhu F. Gender inequality in research productivi- Correspondence ty during the COVID-19 pandemic. SSRN. 2020. [email protected] 8. Viglione G. Are women publishing less during the pandemic? Here’s what the data say. Nature. 2020;581(7809):365-6. 9. Gupta AH, Faizi F. ‘Data shows fewer Afghan women than men get Covid-19. That’s bad news.’ The New York Times, 3 Oct 2020. https://www.nytimes.com/2020/10/03/world/afghan-women- men.html / [Accessed 15 Oct 2020]. 10. Dataset. Global health 50/50. https://globalhealth5050.org/the- sex-gender-and-covid-19-project/dataset/[Accessed 10 Dec 2020]. 11. US Gender/Sex COVID-19 Data Tracker. Harvard GenderSci Lab 2020. https://www.genderscilab.org/gender-and-sex-in-covid19/ #CaseDeathRatebySex. [Accessed 13 Oct 2020]. 12. Regli A, Sommerfield A, von Ungern-Sternberg BS. The role of fit testing N95/FFP2/FFP3 masks: a narrative review. Anaesthe- sia. 2021;76(1):91-100. 13. Turner MC, Marshall SD. Can gendered personal protective equipment design account for high infection rates in female healthcare workers following intubation? Anaesthesia. 2020:10.1111. 14. ILO. Policy brief: the COVID-19 response: getting gender equal- ity right for a better future for women at work. 2020, 1-11. https://www.ilo.org/wcmsp5/groups/public/---dgreports/---gender/documents/publication/wcms_744685.pdf [Accessed 15 Oct 2020]. 15. van Daalen KR, et al. Symptoms of a broken system: the gender gaps in COVID-19 decision-making. BMJ Glob Heal. 2020;5(10):e003549. 16. Coscieme L, Fioramonti L, Mortensen LF, Pickett KE, Kubisze- wski I, Lovins H, et al. Women in power: female leadership and public health outcomes during the COVID-19 pandemic. medRxiv. 2020; 2020.07.13.20152397.

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 12 Aetna® is proud to support the members of the Rhode Island Medical Society.

Clinicians’ Update: Kidney Transplantation in End-Stage Renal Disease (ESRD)

Reginald Gohh, MD Guest Editor

14 14 EN Kidney transplantation remains the optimal treatment Health, which calls for reform in the organ procurement and option for the management of end-stage renal disease management system in the United States to significantly (ESRD), providing a longer life span, a better quality of life, increase the supply of transplantable kidneys, with the goal and lower healthcare costs compared with long-term dial- of doubling the number of kidneys available for transplant ysis treatment. Given recent encouraging developments in by 2030. Additionally, the order encouraged the expanded the field, this issue of theRhode Island Medical Journal support for living donors through compensation for costs is devoted to discussing clinical topics in transplantation such as lost wages and child-care expenses. relevant to the entire medical community. Rhode Island Hospital established its kidney transplant Ongoing improvements in graft and patient survival in program in 1997 with the goal of providing convenient and both deceased donor and living donor kidney transplants quality services to our local community. We have since per- are reported annually. According to the Scientific Registry formed close to 1,500 kidney transplants, of which approx- of Transplant Recipients (SRTR), the 10-year all-cause graft imately 50% were derived through living donation. This failure rate declined to 51.6% for deceased donor recipients success has required the active involvement of a wide range who underwent transplantation in 2006 compared to 57.2% of healthcare specialists in a multidisciplinary approach. for transplantations performed in 1998. Ten-year death- Our transplant team also emphasizes close consultation and censored graft failure similarly declined from 33.7% to 26.2% cooperation with referring nephrologists and primary care during this period. Living donor recipients who underwent physicians of transplant candidates as they progress from the transplantation in 2006 experienced a 10-year all-cause and initial evaluation to post-operative care and management. death-censored graft failure of 34.2% and 18%, respectively. We hope this issue of RIMJ will help the Rhode Island med- These superior outcomes have been attributed to several ical community meet the ongoing challenges for patients factors, including better organ procurement and preserva- with ESRD seeking successful kidney transplantation. tion, more effective immunosuppressive medications and medication regimens and improved selection of both recipients and donors. Equally encouraging is that more trans- Guest Editor plants are being performed than ever, with the number of Reginald Gohh, MD, Brown Medicine, Division of Nephrology and donors and transplants performed in 2019 in the United Hypertension; Medical Director, Division of Kidney Transplanta- States reaching all-time highs, mostly due to increases in tion, Rhode Island Hospital; Professor of Medicine, Alpert Medical deceased donors. This has resulted in a decline in the num- School of Brown University, Providence, RI. ber of patients waiting for a kidney transplant for the fourth Correspondence year in a row. Nevertheless, the mismatch between organ Reginald Gohh, MD need and supply remains severe, with the average wait time Rhode Island Hospital to receive an organ offer between 3–5 years at most centers 593 Eddy Street and even longer in some regions of the country. Ambulatory Patient Center, 921 It is evident that kidney transplantation should be sought Providence, RI 02903 for all medically and psychosocially qualified patients with 401-444-8562 ESRD. Recently, former President Donald Trump signed Fax 401-444-3283 an Executive Order entitled Advancing American Kidney [email protected]

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 14 KIDNEY Transplantation

Frailty and Kidney Transplantation

George Bayliss, MD

15 19 EN ABSTRACT INTRODUCTION Two significant policy changes, one in the way people Chronic kidney disease is a growing worldwide problem and are put forward for kidney transplants and the other in one from which the US is not immune. And while a func- the way in which kidneys are distributed to people on tioning kidney transplant is seen as the ideal and ultimate the waiting list, make the question of whether some- renal replacement therapy, there is an overall shortage of one is too frail to receive a transplant all the more rel- organs compared to the number of people on the waiting list. evant, particularly in Rhode Island. An executive order The number of people waiting for a deceased donor kidney signed by President Donald Trump1 stresses that efforts has decreased steadily from over 100,000 in 2014 to 92,906 to treat kidney disease need to concentrate on provid- at the start of 2018. Some 33,879 candidates were added to ing more people with kidney transplants and increasing the list in 2018 while 34,591 were removed from the list. the number of organs transplanted rather than discard- The ranks of those removed included 14,784 who received a ed. An effort to decrease waiting times for kidneys in deceased donor kidney transplant and 6,120 who received a large metropolitan areas2 potentially means that young- living donor transplant. It also included 4,193 who died on er, more desirable kidneys will be shipped out of New the waitlist and 4,240 who were removed as too sick.3 The England, leaving longer waiting times and less desirable decline in numbers on the waiting list reflects the effects of organs for transplantation in our region. The net effect an earlier change in kidney allocation policies to help better of these changes may mean that potential older or more match survival of the organ with expected survival of the frail recipients could be faced with accepting kidneys recipient, decrease the number of organs discarded, and that from older or less desirable donors or spend more time backdated credit for waiting time to when a candidate initi- on the waiting list and never receive a credible kidney ated dialysis.4 offer. This raises the specter of poor outcomes from mar- In 2019, President Trump signed an executive order that ginally functioning kidneys transplanted into marginally sought to decrease the number of people receiving in-cen- functioning recipients or increased rates of death on the ter hemodialysis and increase the number of people getting waiting list. While organ allocation policies are beyond dialyzed at home and getting kidney transplants. The order the ability of transplant nephrologists in Rhode Island to envisioned an additional 17,000 kidney transplants.5 More change, we will need to assess patients more closely for recently, efforts to reduce large disparities in waiting times signs of frailty and work with referring doctors to reverse around the country have led to changes in the way points frailty when possible so that patients can take advantage are awarded that are used to determine one’s standing on the of a kidney transplant even if the organ isn’t ideal. This list when an organ is offered. The net effect of this change is article will review the concept of frailty; how to asses it that organs that might have stayed in New England, where in general and in the context of a transplant evaluation; average wait times for a deceased donor kidney are around the risk of frailty in transplant outcomes and the bene- 5 years, would be transported to regions like New York, fits of transplant in reversing frailty; whether markers of where wait times are closer to 10 years.6 While the changes frailty can be improved and whether that improves trans- in kidney allocation will reduce waiting times in some plant outcomes. regions, waiting times will increase in regions that become KEYWORDS: kidney transplant, chronic kidney disease, net exporters of kidneys. These changes raise the possibility frailty assessment, donor waitlists that as older or more frail candidates move on to list, they will have to wait longer and will receive kidneys offers that reflect the diminished survival prospects of the recipient, or risk dying on the list before they are matched with a kidney. To keep transplantation going in the region will require more careful evaluation of candidates as well as increased efforts to improve candidates’ chances of surviving on the waiting list to receive an organ offer and thrive after

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 15 KIDNEY Transplantation

transplantation. The concept of frailty plays into this calcu- standardize assessment of frailty in transplant candidates lus. This paper will review the concept of frailty and address and generate ideas for further research.10 In a survey of AST ways to assess it in general and as part of the transplant members concerned with kidney transplantation, 98.9% evaluation. The paper will look briefly at the risk to patient considered frailty in transplant candidates a risk factor for and transplant outcomes from frailty versus the potential poor outcomes after transplantation, while 93.3% felt the benefit from transplant toward reversing frailty. The paper need for a frailty score in making decisions on whether to will examine potential ways to reverse elements of frailty transplant, and 67.1% thought age should be included in to improve transplant prospects and whether such precondi- assessing frailty. Optimizing dialysis and volume status, tioning works. The literature is vast, but this review will try nutrition, physical therapy and psychotherapy were thought to touch briefly on these important concepts. essential components in improving frailty in patients with kidney disease awaiting transplant in the AST survey. Much work has gone into looking at individual components FRAILTY of frailty, as well as association of age, comorbidities and Frailty is often equated with old age or increased comor- frailty. Reviews on measuring frailty cite up to 75 functional bidities. And while age and illness can factor into frailty, assessment tools available currently, including questionnaires they are not substitutes for frailty. In their seminal paper on assessing physical capacity, tools like the Karnosky Perfor- describing a frailty phenotype, Fried and colleagues wrote mance Scale to assess physical performance, tools to quan- that frailty “may have a biological basis and be a distinct tify perceived frailty like the Fried’s frailty phenotype (FFP), clinical syndrome”7 and sought to develop a standardized a frailty index of cumulative deficits, physical performance definition. Using data from the Cardiovascular Health Study, scores like walking speed, grip strength, ability to stand and they evaluated 5,317 men and women, including 582 Blacks, balance, involuntary loss of muscle mass (sarcopenia), cardio- from 4 to 7 years of follow-up. They defined frailty as a clin- pulmonary fitness testing to assess oxygen utilization.11 ical syndrome based on three or more of five characteristics: In a recent survey of US kidney transplant programs, unintentional weight loss of 10 pounds or more in the previ- McAdams-DeMarco and colleagues found the bulk of pro- ous year (shrinkage), self-reported exhaustion, weakness on grams that responded to the survey (133/202) considered a test of grip strength, slow walking speed over a set dis- frailty a clinically relevant concept (99.2%) but only 96% tance and low physical activity as defined on a standardized said they thought frailty should be used in making decisions questionnaire.8 In their study, frailty was associated with about whether someone was a transplant candidate. The increased age, female gender, Black race, having a lower level survey found great heterogeneity in assessing frailty with of education and income, poorer health, and higher rates of respondents reporting that they used some 18 different tools chronic comorbid diseases and disability. They found that to assess it. The most used test – by 19% of respondents – the frailty phenotype independently predicted falls, wors- was a timed walk. Some 8% of respondents used the FFP ening mobility, hospitalization and death over three years. while 8% used the Montreal Cognitive Assessment and 8% They defined intermediate frailty as having one or two of the also used sarcopenia. Two-thirds of respondents said they characteristics, signaling an increased risk of becoming frail used more than one test.12 over 3–4 years. They defined frailty as a downwardly spiral- Without a standardized method to assess frailty, clinicians ing physiologic process of declining energy utilization and often fall back on perceptions of frailty, which can be deceiv- “loss of homeostatic capability to withstand stressors and ing, with the consequence of potentially denying access to resulting vulnerabilities.” While they noted some overlap transplantation among those perceived as frail. Salter and with disability and illness, they stressed that those concepts colleagues looked at differences in perceived and measured are not synonymous with frailty. frailty in 146 adults undergoing hemodialysis at a single dialysis unit in Baltimore.13 Patient characteristics of frailty as perceived by nurse practitioners, nephrologists or patients NEED TO ASSESS FRAILTY were compared with measured assessment of frailty using There is a clear consensus, however, that frailty is a com- the FFP. Older age and comorbidities were associated with a mon feature of people with end-stage organ damage await- greater likelihood of being perceived as frail by nephrologists ing a transplant. The data also bear this out. According to while women and non-African Americans were more likely a national study pooling data from three major centers, an perceived as frail by nurse practitioners. At the same time, estimated 16.4% of all kidney transplant candidates were of patients classified by the FFP as frail, only 42% were per- considered frail between 2008 and 2018 while 14.3% of all ceived as frail by nephrologists, 39.2% by NPs and 4.9% by kidney transplant recipients were considered frail during the patients themselves. The risk, according to the authors, was same time.9 that older dialysis patients and women perceived as frail but The American Society of Transplantation (AST) spon- not actually demonstrating frailty risked not being listed for sored a consensus conference on frailty in February 2018 to transplantation.

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And yet for frail patients, the risk of not being listed is identified what they described as high-risk kidney trans- significantly higher. In study of 7,078 transplant candidates plant patients (59 years or older, diabetes and or more than between 2009–2018, frail patients were 38% less likely to be three years on dialysis) and evaluated them using the FFP listed for transplant, regardless of age or other demographic and Short Physical Performance Battery. They found that factors. Frail Black kidney transplant candidates were 46% both frailty and physical performance were significantly less likely to be listed than non-frail, non-Black candidates. associated with death on the waiting list (hazard ratio 6.7, They were 32% less likely to be transplanted compared to 95% confidence interval 1.5–30.1; P=0.01). They also found non-frail patients and they were 70% more likely to die on that the relationship between frailty, physical performance the waiting list.14 score and death on the waiting list were independent of age, The relationship between aging, frailty and chronic kid- diabetes or length of time of dialysis.19 ney disease is central since aging increases the risk of poor Time on the waiting list can also increase frailty, such that outcomes from the cumulative burden of correlates for some suggest measuring changes in frailty over the course frailty like cognitive impairment, poly-pharmacy, disability, of time between listing and transplantation. Researchers multiple comorbidities, malnutrition, and dialysis.15 In the at Johns Hopkins noted that 22% of 569 kidney transplant Rhode Island experience, the relationship between age and candidates enrolled in their cohort study of frailty became loss of kidney transplant and death after transplant was sig- increasingly frail while 24% became less so. While Black nificant in patients who were inactive, smoked, had COPD, race was associated with becoming less frail and diabetes had peripheral vascular disease or required dialysis within a was associated with remaining stably frail, the longer can- week after transplantation (delayed graft function).16 didates remained on dialysis, the less likely they were to Age alone does not seem to define frailty in patients become less frail. Given the dynamic change in frailty in undergoing dialysis and transplantation and as a single some patients, these researchers recommended assessing entity, does not portend poorer outcomes. Researchers at frailty at the time of listing and time of transplantation Johns Hopkins, the University of Michigan and the Uni- since candidates who became more frail faced longer hos- versity of California, San Francisco, pooled cohorts to com- pitalization times post-transplant as well as a higher risk of pare frailty in subjects older than 65 and younger than 65 mortality post-transplant.20 Researchers at Columbia Uni- at three time points: within six months of starting dialysis; versity used a timed “get up and go” test for patients on at time of kidney transplant evaluation; at time of admis- the waiting list to see if that might predict outcomes after sion for kidney transplant. Overall, frailty in all three time transplant. In the end, participants in the study who were points was more prevalent in older patients who were also transplanted had shorter times on the test than those who more likely to have slowness and weakness. Younger sub- remained on the waitlist. However, there was no associa- jects were more likely to experience exhaustion in all three tion between test time and probability of removal from the time points. The authors concluded that while frailty was waitlist or prolonged hospitalization after transplantation or more prevalent in older subjects, younger subjects still had a 30-day readmissions.21 high burden.17 A registry-based study at Oslo Hospital of all In an ongoing trial, a group of Canadian researchers hopes potential kidney transplant recipients age 65 or older who to better evaluate whether frailty is associated with death on received a deceased donor kidney transplant between 2000 the waitlist, withdrawal from the waitlist as well as whether and 2014 found no difference in outcomes between those frailty is associated with hospitalization, quality of life and who received a first kidney and those who received a sec- even being listed. Their plan is to evaluate potential can- ond kidney re-transplant. Five-year survival censored for didates using the FFP, the frailty index, the Short Physical death with a functioning graft in those receiving a second Performance Battery and the Clinical Frailty Scale (CFS) at transplant was 88% versus 90% for those receiving a first the time of initial evaluation for listing and annually after transplant (P = 0.475%).18 Risk factors for increased chance that. The goal is to understand the association of frailty and of death with a functioning graft also included longer time outcomes from patient on the waitlist before incorporating on the waiting list before re-transplantation, although the measurement of frailty into the regular waitlist workup.22 authors noted that overall waiting time at their center was The association between waitlist mortality and frailty small such that their findings might be even more applicable is not clear. The CFS, a validated instrument in dialysis at centers with longer waiting times. patients, uses overall clinical impression to award a single point for each degree of perceived frailty. In a cohort of inci- dent dialysis patients assessed between 2009 and 2013, each FRAILTY WHILE WAITING point increase in the CFS was associated with an increase The risk of death on the waiting list for frail patients has led in the hazard ratio of death (HR 1.22; 95% CI, 1.04–1.43; to much thought about whether chances to receive a kidney P=0.02).23 In a separate multi-center study, researchers can be enhanced by “preconditioning” of frail candidates to assessed whether an association existed between frailty on improve physical stamina. Researchers at the Mayo Clinic the waitlist and accumulated burden of comorbidities as

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assessed by the Charlson Comorbidity Index. In a study of FRAILTY AFTER TRANSPLANT 2,086 candidates on the kidney transplant waitlist, 18.1% Does transplantation improve frailty among kidney recipi- were frail and 51% had a high comorbidity burden. They ents? Again, the data appear mixed. Researchers in the Neth- found that among non-frail patients, a high comorbidity erlands studied 176 kidney transplant recipients at their score was associated with a statistically significant risk center in Groningen between 2015 and 2017 and followed of mortality (HR 1.66 95% CI 1.17–2.35). But among frail for up to three years. Using their own frailty scale (Gronin- patients, high burden of comorbid conditions did not show gen Frailty Indicator), they found that 34 non-frail patients an association with mortality. Stratified by age, the higher became frail after transplantation, 125 patients remained comorbidity index portended worse mortality in patients unchanged, and 19 frail patients were no longer frail. The GFI waiting for kidney transplantation who were under 65, while includes 15 questions in eight functional domains including a high burden of comorbidities was not associated with wait- mobility, vision, hearing, nutrition, comorbidities, cogni- list mortality in patients age 65 and greater on the waitlist.24 tion, psychosocial functioning and physical fitness. Changes in cognition and psychosocial functioning contributed most to the shift from not frail to frail after transplantation.29 In INTERVENTIONS contrast, researchers at Johns Hopkins and the University of The question then becomes whether one can intervene with Michigan assessed frailty using the FFP and then examined frail candidates to improve their survival on the waitlist, changes in health-related quality of life (HRQOL) in 443 kid- their chances of getting a kidney and survival after trans- ney transplant patients at their centers between 2014 and plantation. Part of the problem in increasing exercise tol- 2017 for three months post-transplant. At the time of trans- erance among kidney transplant candidates is that people plant, frail patients had worse HRQOL scores than non-frail enter the waitlist already in poor physical shape. According patients, but both groups showed improvement one month to one study, 95% of new starts on dialysis have physical post-transplant. At three months, frail transplant recipi- fitness levels below the 20th percentile for the general popu- ents had statistically significant continued improvement in lation, and just over half (56.4%) are able to walk one block, physical HRQOL but non-frail patents did not. The same 23.8% can climb 24 stairs, and only 18.5% said they could held true for changes in mental HRQOL. Both frail and non- walk a mile.25 Researchers at several centers are looking frail transplant recipients reported improvement in kidney into adapting an exercise module developed by the Ameri- disease specific HRQOL.30 can College of Sports Medicine to create an exercise module for people transitioning to dialysis. The idea is to develop a practical and cost-effective package to help patients starting CONCLUSION dialysis overcome barriers to exercise.26 The topic of frailty in chronic kidney disease and transplan- Researchers at the Mayo Clinic used supervised exercise tation remains in flux. The transplant community knows sessions in frail patients with stage IV chronic kidney disease that frailty is a poor indicator for outcomes in transplan- or greater to see whether their intervention could improve tation. Frailty can affect not only if patient can get trans- strength. They enrolled 21 patients in two supervised out- planted once placed on the waitlist but also whether that patient exercise sessions per week for eight weeks. The person can even get on the list to begin with. As older peo- intervention, which included strength, endurance and flexi- ple undergo transplant evaluation and face the prospect of bility training, led to improvement in frailty parameters like only getting offers of kidneys from more marginal donors, walk speed, grip strength and fatigue, although none of the assessing candidates for frailty and finding ways to reverse changes were statistically significant. Scores on the Short the components of frailty that are amenable to improvement Physical Performance Battery did improve significantly. The becomes all the more important. However, the transplant authors suggest that their results are encouraging and war- community remains divided on the best tool(s) to use to rant evaluation in a larger, multi-site study.27 make the assessment and whether exercise conditioning can The transplant clinic at Stanford University began doing help give people more strength, stamina and improve energy physical assessments of transplant candidates once their metabolism. The Organ Procurement and Transplantation accumulated waiting time put them in the top of the center’s Network (OPTN) has temporarily put on hold the imple- waitlist. Rather than assessing frailty, the clinic assessed 60 mentation of changes in the kidney allocation system while second sit-to-stand and 6-minute walk tests. They found the Department of Health and Human Services reviews that the lower the scores on the two tests, the higher risk of concerns about the changes that were submitted just before removal from the waitlist or death on the waitlist.28 the new rules were due to take effect December 15, 2020. Whatever the outcome of that review, efforts to improve a transplant candidate’s conditioning and stamina could also be important tools in improving access to and survival after kidney transplantation.

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References 20. Chu NM, Deng A, Ying H, et al. Dynamic frailty before kidney 1. Executive Order on Advancing American Kidney Health. 10 transplantation: time of measurement matters. Transplanta- July 2019. www.whitehouse.gov. (25 December 2020, date last tion. 2019;103:1700-1704. accessed). 21. Michelson AT, Tsapepas DS, Husain SA, et al. Association 2. Organ Procurement and Transplantation Network. Kidney Al- between the “timed up and go test” at transplant evaluation location System. http://optn.transplant.hrsa.gov. (25 December and outcomes after kidney transplantation. Clin Transplant. 2020, date last accessed). 2018;32:e13410. doi: 10.1111/ctr.13410. 3. Hart A, Smith JM, Skeans MA, et al. OPTN/SRTR 2018 Annual 22. Tennankore KK, Gunaratnam L, Suri RS, et al. Frailty and Data Report: Kidney. Am J Transplant. 2020 Jan; 20 Suppl s1: the kidney transplant waitlist: protocol for a multicenter 20-130. doi: 10.1111/ajt.15672. prospective study. Can J Kidney Health Dis. 2020 Sep 4. Israni AK, Salkowski N, Gustafson S, et al. New allocation poli- 10;7:2054358120957430. doi: 10.1177/2054358120957430. cy for deceased donor kidneys in the United States and possible 23. Alfaadhel TA, Soroka SD, Kiberd BA, Landry D, Moorhouse P, effect on patient outcomes. J Am Soc Nephrol. 2014:251842- Tennankore KK. Frailty and mortality in dialysis: evaluation of 1848. a clinical frailty scale. Clin J Am Soc Nephrol. 2015;10:832-40. 5. Remarks by President Trump at signing Executive Order on 24. Perez Fernandez M, Martinez Miguel P, Yinh H, et al. Comor- Advancing American Kidney Health. 10 July 2019. www.white- bidity, frailty and waitlist mortality among kidney transplant house.gov. (25 December 2020, date last accessed) candidates of all ages. Am J Nephrol. 2019;49:103-110. 6. Organ Procurement and Transplantation Network. Eliminate 25. Johansen KL, Chertow GM, Kutner NG, et al. Low level of the use of DSA and region from kidney allocation policy. 3 De- self-reported physical activity in ambulatory patients new to cember 2019. http://optn.transplant.hrsa.gov. (25 December dialysis. Kidney Int. 2010;78:1164-1170. 2020, date last accessed). 26. Jagannathan R, Ziolkowski SL, Weber MB, et al. Physical ac- 7. Fried LP, Tangen CM, Walston J et al. Frailty in older adults: tivity promotion for patients transitioning to dialysis using the evidence for a phenotype. J Gerontol A Biol Sci Med Sci. “Exercise is Medicine” framework: a multi-center randomized 2001;56:M46-M156. pragmatic trial (EIM-CKD trial) protocol. BMC Nephrology. 8. Taylor HL, Jacobs DR Jr., Schucker B, et al. A questionnaire for 2018 Sep 12;19:230. doi: 10.1186/s12882-018-1032-0. the assessment of leisure time physical activities. J Chron Dis. 27. Lorenz EC, Hickson LJ, Weatherly RM, et al. Protocolized ex- 1978;31:741-755. ercise improves frailty parameters and lower extremity impair- 9. Haugen CE, Thomas AG, Chu NM, et al. Prevalence of frailty ment: a promising rehabilitation strategy for kidney transplant among kidney transplant candidates and recipients in the Unit- candidates. Clin Transplant. 2020 Sep;34:e14017. doi: 10.1111/ ed States: estimates from a national registry and multicenter ctr14017. cohort study. Am J Transplant. 2020:20:1170-1180. 28. Cheng XS, Myers J, Han J, et al. Physical performance testing 10. Kobashigawa J, Dadhania D, Bhorade S, et al. Report from the in kidney transplant candidates at the top of the waitlist. Am J American Society of Transplantation on frailty in solid organ Kidney Dis. 2020. doi: 10.1053/j.ajkd.2020.04.009. transplantation. Am J Transplant. 2019;19:984-994. 29. Quint E, Schopmeyer L, Banning LBD, et al. Transitions in frail- 11. Basu A. Role of physical performance assessments and need for ty state after kidney transplantation. Langenbecks Arch Surg. a standardized protocol of selection of older kidney transplant 2020;405:843-850. candidates. Kidney Int Rep. 2019;4:1666-1676 30. McAdams-DeMarco M, Olorundare IO, Ying H, et al. Frailty and 12. McAdams-DeMArco MA, Van Pilsum Rassmussen SA, Chu postkidney transplant health-related quality of life. Transplant. NM, et al. Perceptions and practices regarding frailty in kidney 2018;102:291-299. transplantation: results of a national survey. Transplantation. 2020;104:349-356. Author 13. Salter ML, Gupta N, Massie AB, et al. Perceived frailty and mea- George Bayliss, MD, Division of Organ Transplantation, Rhode sured frailty among adults undergoing hemodialysis: a cross-sec- Island Hospital, Providence, RI; Division of Kidney Diseases and tional analysis. BMC Geriatrics. 2015 Apr 2415:52. doi: 10.1186/ Hypertension, Brown Medicine, E. Providence, RI; Alpert Medical s12877-015-0051-y. School of Brown University, Providence, RI. 14. Haugen CJ, Chu NM, Ying H, et al. Frailty and access to kidney transplantation. Clin J Am Soc Nephrol. 2019;14:576-582. Financial disclosures 15. Harhay MN, Rao MK, Woodside KJ, et al. An overview of frailty in kidney transplantation: measurement, management None and future considerations. Nephrol Dial Transplant. 2020;35: 1099-1112. Correspondence 16. Yango AF, Gohh RY, Monaco AP, et al. Excess risk of renal al- George Bayliss, MD lograft loss and early mortality among elderly recipients is as- Division of Organ Transplantation sociated with poor exercise capacity. Clin Nephrol. 2006;65: 593 Eddy Street 401-407. Ambulatory Patient Center, Floor 9 17. Chu NM, Chen X, Norman SP, et al. Frailty prevalence on Providence, RI 02903 younger end-stage kidney disease patients undergoing dialysis and transplantation. Am J Nephrol. 2020;51:501-510. United States 18. Heldal K, Hartmann A, Lønning K, et al. Should patients older 401-444-8562 than 65 years be offered a second kidney transplant? BMC Ne- Fax 401-444-3283 phrology. 2017;18:13 doi: 10.1186/s12882-016-0426-0. [email protected] 19. Lorenz EC, Cosio FG, Bernard SL, et al. The relationship between frailty and decreased physical performance with death on the kidney transplant waiting list. Prog Transplant. 2019;29: 108-114.

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Management of Cardiovascular Risk Factors in Dialysis-Dependent End Stage Kidney Disease

Harshitha Kota, MD; Reginald Gohh, MD

20 24 EN

KEYWORDS: chronic kidney disease (CKD), management increases CVD and mortality.11–14 Proposed novel risk factors of CVD risk factors, renal replacement therapy (RRT), end that may be contributing to this higher incidence of mortal- stage kidney disease (ESKD) ity and CVD unique to CKD and ESKD population include anemia, volume status, mineral metabolism, electrolyte disarray, albuminuria, uremia and inflammation.15–17

INTRODUCTION Dyslipidemia Over nineteen million patients face progressive chronic Dyslipidemia in the general population is characterized kidney disease (CKD) in the United States.1 The preferred by elevated low density lipoprotein (LDL) which is oxi- treatment with proven clinical outcomes for end stage dized to form atherosclerotic plaques. In contrast, ESKD kidney disease (ESKD) patients remains kidney transplan- patients also develop hypertriglyceridemia, a decrease in tation. Unfortunately, the number of kidney transplants high density lipoprotein cholesterol (HDL-C), an accumu- has reached a plateau in recent years with a simultaneous lation of apolipoprotein B (Apo B) containing lipoproteins, increase in the number of patients awaiting transplantation and increased concentrations of lipoprotein(a) particles.18,19 and the length of time they wait.2 For the majority of these All lipid classes are affected. One hypothesis is that as CKD patients, renal replacement therapy is the initial treatment progresses, so does uremia and oxidative stress. This causes while they await transplantation, during which time they post-translation protein modification of both LDL and HDL face many barriers. One medical barrier is cardiovascular through glycation, oxidation and carbamylation, resulting in disease (CVD), which is reported to be 20 times higher than both a decrease in the quantity and quality of their func- the general population, accounting for 40% of deaths of tion.20–22 This hypothesis may explain why statins have not US dialysis patients.3 By comparison, a 30-year-old dialysis been beneficial in this population. patient bears nearly the same risk as an 80-year-old non-di- The mainstay of guideline therapy has been the use of alysis patient for CVD-related death.4 The complete etiol- statins to reduce LDL levels in the general population and ogy of the increased risk of CVD is not fully understood and in CKD patients.23 Unfortunately these guidelines do not is likely a combination of both traditional and novel risks include ESKD patients due to lack of robust evidence. The factors. The traditional risk factors include non-modifiable SHARP study showed a 17% proportional reduction in major (age and sex) and modifiable (dyslipidemia, diabetes, smok- atherosclerotic events in 3,023 patients on dialysis who were ing, and hypertension) components. This review will discuss randomized to receive simvastatin plus ezetimibe vs pla- ways to address the latter modifiable risk factors. cebo during a 4.9 year follow-up period.24 The 4-D trial and Identification of high risk individuals with the use of the AURORA did not reflect the same outcome, and showed assessment tools such the Framingham Risk Score (FRS- there was no significant difference in either the placebo or CVD) and the ASCVD (American Heart Association (AHA)/ intervention group. The current Kidney Disease Improving American College of Cardiology (ACC) 2013) have been Global Outcomes (KDIGO) and ACC/AHA guidelines do validated in the general population, provide guidance on not support the initiation of statins in ESKD. KDIGO rec- optimal therapy for primary prevention using lifestyle modi- ommends statins for all patients with CKD not on RRT and fications and pharmacological interventions.5 While propos- who are at least 50 years old. For adults 18 to 49 years old als are ongoing for the addition of renal function to current who have CKD, statins are recommended if there is a his- scores or developing new scores, the current use of these tory of coronary artery disease, diabetes mellitus, stroke, tools in CKD and ESKD patients has limited applicabil- or an ASCVD risk > 10%. Statins when initiated prior to ity.6–9 The Pan American Health Organization/World Health dialysis can be continued, as there are no recommenda- Organization (PAHO/WHO) has developed a calculator that tions on discontinuation.25 Extrapolating from hemodialysis includes glomerular filtration rate (GFR) but further studies patients, International Society for Peritoneal Dialysis (ISPD) are needed to assess its applicability.10 Even without the use guidelines refers to KDIGO for dyslipidemia management in of these tools, evidence has established that decreasing GFR peritoneal dialysis patients (PD).26,27

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While statins have become the cornerstone, the latest Smoking Cessation discovery for dyslipidemia treatment is monoclonal anti- Smoking continues to challenge both the general and kid- bodies. Currently, evolocumab and alirocumab are the ney disease populations. It remains the leading cause of pre- available proprotein convertase subtilisin/kexin 9 (PCSK9) ventable death in the United States. While specific data in inhibitors. PCSK-9 binds to hepatocyte receptors and pro- dialysis patients is lacking, cessation is likely to reduce car- motes increased LDL levels.28 Inhibition of this protein by diovascular disease and mortality. Similar strategies involv- evolocumab has shown reduction of LDL levels by 59% and ing nicotine replacement therapy can be utilized as well as a reduction in cardiovascular events.28 Unfortunately there drug therapy such bupropion and varenicline, with vareni- is limited data on safety and efficacy in CKD patients and cline requiring renal dosing. 35 ESKD patients have been excluded from trials so there is a paucity of guidance for use in this patient population.29–31 Eicosapentaenoic acid (EPA) or omega-3 fatty acids Diabetes Management decrease pro-inflammatory cytokines, interleukin-6 and Glycemic control involving dietary modifications, exercise, leukotriene B4 by inhibiting the activation of their gene metformin, SGLT-2 inhibitors and GLP-1R agonists with a production.32 The ACC/AHA guidelines do include recom- target hemoglobin A1C (HbA1C) of < 7% has shown CVD mendations for fish intake twice a week and use of omega-3 and mortality benefit in type 2 diabetic patients in the fatty acids in hypertriglyceridemia. In ESKD patients, general population.37 KDIGO recommends all type 2 dia- omega-3 fatty acids have been studied for an effect on arte- betic patients with GFR greater than 30 (CKD stages 1-3) rio-venous fistula patency with unfortunately no clear ben- be treated with metformin, sodium–glucose cotransporter-2 efit established.25 However, in a small study by Lok, 99 out (SGLT-2) inhibitors with the addition of lifestyle modifica- of 196 ESKD patients who were randomized to receive the tions (physical activity, nutrition and weight loss) to reach supplement demonstrated superior cardiovascular event- a target HbA1c of less than 6.5% or 7%.38 Unfortunately free survival in the fish oil group (HR 0.43 [95% CI, 0.19 to the accuracy of HbA1c measurements in dialysis patients is 0.96], p = 0.035) and a 7.74 point reduction in systolic BP.33 unclear but without an alternative and wide use in clinical Fish oil is generally well tolerated with the major side effects trials, it remains the marker of choice.39 After initiation of being gastrointestinal from belching or flatulence, and taste first-line treatments, additional oral agents will require dose perversion. Nevertheless, use in ESKD patients should be adjustment based on renal function and individualized to individualized.34 the patient.39 The lack of data for HbA1c targets in dialysis patients poses an exceptional challenge for management in dialysis dependent diabetic patients.39 As all cause mortality Aspirin and CVD outcomes are worse in patients with poor glycemic There has been a change in the use of aspirin as primary and these patients are to be evaluated for transplantation, it prevention in the general population as new data has shown is reasonable to provide targeted glycemic control based on less benefit. Recent guidelines recommend patients with observational data. 37,40–43 high calculated CVD risk scores based on traditional factors to initiate therapy.35 Unfortunately, this may not be applicable to ESKD patients Hypertension since there is limited data on mortality benefit. Analysis Deciphering the various definitions and recommendations of hemodialysis patients receiving aspirin prescriptions in for hypertension between guidelines from different societies the DOPPS study demonstrated that an aspirin prescription can add to the complexity of treating this patient popula- was associated with an increase in myocardial infarction tion. While all seem to agree that elevated blood pressure and any cardiac event. 36 In a meta-analysis evaluating CKD increases CVD and mortality, blood pressure thresholds and and use of anti-platelet therapy, there was no clear effect targets for different groups remains an area of debate.44–46 of antiplatelet therapy on the risk of cardiovascular death Blood pressure readings can be taken in office, at home (OR, 0.91; 95% CI, 0.67–1.13; I2 = 0%) or all-cause death (OR, and continuously with an ambulatory pressure monitor- 0.87; 95% CI, 0.71–1.01; I2 = 0.8%) compared with placebo ing (ABPM) device. The 2017 ACC/AHA guidelines defines or usual-care control groups in 27,773 participants from 50 hypertension as an office systolic blood pressure greater trials.36 They did show that for every 1,000 people with CKD than 130 mmHg or diastolic blood pressure of greater than treated, 23 patients would avoid major cardiovascular events 80 mmHg, while the 2018 ESC/ESH guidelines uses an but 9 patients would have a major bleeding episode and 35 office systolic blood pressure of greater than 140 mmHg and/ would have minor bleeding episodes. At this time there is or diastolic blood pressure of greater than 90 mmHg.47–49 In no recommendation to initiate aspirin therapy for primary the ground breaking SPRINT trial, diagnosis of hypertension prevention in ESKD patients. was based on automated cuff readings in an office setting.50 The National Institutes of Health and Care Excellence

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(NICE) recommends confirming an elevated office reading been shown to improve hypertensive control.62 Data from with an ABPM daytime average or home blood pressure aver- meta-analysis suggests the use of pharmacological therapy age of 135/85 mmHg or higher while the European Society is associated with CVD reduction and survival benefit.63,64 of Cardiology/European Society of Hypertension (ESC/ESH) While ACEi have shown efficacy in decreasing left ventric- accepts an average ABPM of greater than 130/80 mmHg to ular mass as well as providing RAAS blockade, use may be be hypertensive.47,48 limited due to side effects.58,61 Multiple agents will mostly Once the hurdle of diagnosis has been achieved, the com- likely be required and should be individualized to each plexity continues in target goals and recommendations on patient. Patients maintained on PD have also been shown the initial pharmacological regimen. Counseling on lifestyle to be chronically volume overloaded as evidenced by ele- modifications such as smoking, diet and exercise is rec- vated atrial natriuretic peptide levels and left atrial volume ommended by the majority of the guidelines at initiation by echocardiography. In general, this is managed by increas- of treatment.44,45,47–49 In both the diabetic and non-diabetic ing the glucose concentration in the dialysate to promote adult CKD population, KDIGO stratifies blood pressure tar- a higher osmotic gradient to promote better ultrafiltration. gets based on albuminuria. When urine albumin excretion However, a high peritoneal dialysate glucose concentration is less than 30mg/24hours the suggested targets are: systolic (PDGC) may induce metabolic syndrome, which has been blood pressure of less than 140 mmHg and diastolic blood associated with a higher CVD mortality in PD patients.58,65 pressure of less than 90 mmHg. When albumin excretion Further data on blood pressure targets and pharmacological is greater than 30mg/ 24hours, the recommended targets regimens is lacking in PD patients. are: systolic blood pressure of less than 130 mmHg and Due to the lack of evidence from quality randomized con- diastolic blood pressure of less than 80 mmHg.51 Angioten- trolled trials or strong recommendations from society guide- sin-converting enzyme inhibitors (ACEi), angiotensin recep- lines, hypertension treatment in advanced CKD (stage 5) and tor blockers (ARB), beta-blockers and diuretics are effective dialysis-dependent ESKD is based on observational data and in the treatment of hypertension. Initial choice of medi- expert opinion.46,63,64 Unfortunately, the lack of clarity on cation should be individualized. In patients with diabetes, this issue most affects patients who are awaiting imminent CKD, and albuminuria, ACEis and ARBs should be consid- transplantation, limiting the optimization of their medical ered first as renin angiotensin aldosterone system (RAAS) management. blockade has shown benefit in reducing albuminuria and preventing CVD events.52,53 Additional therapy should be individualized based on side effects, patient characteristics SUMMARY and co-morbidities. This summary provides guidelines based on the limited Unique to dialysis patients is that blood pressure read- available data in this vulnerable patient population. Given ings can vary when taken pre-, inter- and post-dialysis the high burden of CVD in the ESKD population and treatments in addition to in-dialysis unit, office and home the multiple challenges these patients face, providing a locations.54,55 The relation between the various readings multi-disciplinary approach to mitigate cardiovascular risks has shown a stronger association of home or out of center may result in improved clinical outcomes and benefit these BP readings with CVD and mortality.56,57 The European patients while they wait on the long road to transplantation. Renal and Cardiovascular Medicine (EURECA-m)/Euro- pean Renal Association–European Dialysis and Transplant Association (ERA-EDTA)/ ESH consider home or ABPM values of ≥135/85 mmHg on non-dialysis days and average BP ≥130/80 mmHg over 24-hours respectively for hemodial- References ysis patients and an office BP ≥140/90 for PD patients to be 1. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence diagnostic of hypertension.58 The Kidney Disease Outcomes of chronic kidney disease and decreased kidney function in the Quality Initiative (KDOQI) made a grade C recommendation adult US population: Third National Health and Nutrition Ex- amination Survey. Am J kidney Dis Off J Natl Kidney Found. for a pre-dialysis blood pressure target of less than 140/90 2003;41(1):1-12. doi:10.1053/ajkd.2003.50007 mmHg and post-dialysis blood pressure target of less than 2. U.S. Department of Health and Human Services. OPTN/SRTR 130/80 mmHg.59 2012 Annual Data Report - United States Organ Transplanta- The pathophysiology of hypertension in dialysis-de- tion. Vol 14 Suppl 1.; 2014. 3. United States Renal Data System. 2018 USRDS Annual Data pendent ESKD patients is multifactorial. Proposed factors Report: Epidemiology of Kidney Disease in Teh United States. include salt and volume retention, RAAS and endothelial Bethesda, Maryland; 2018. https://www.usrds.org/annual-data- cell dysfunction, sleep apnea and use of erythropoietin report/previous-adrs/. agents.53,60,61 A low sodium diet (2 grams per day) is rec- 4. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of car- 59 diovascular disease in chronic renal disease. Am J kidney Dis Off ommended. An attempt to optimize volume removal J Natl Kidney Found. 1998;32(5 Suppl 3):S112-9. doi:10.1053/ with aggressive ultrafiltration during hemodialysis has ajkd.1998.v32.pm9820470

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5. Lloyd-Jones DM, Braun LT, Ndumele CE, et al. Use of Risk As- 23. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA sessment Tools to Guide Decision-Making in the Primary Pre- guideline on the treatment of blood cholesterol to reduce ath- vention of Atherosclerotic Cardiovascular Disease: A Special erosclerotic cardiovascular risk in adults: A report of the Amer- Report from the American Heart Association and American ican college of cardiology/American heart association task force College of Cardiology. Circulation. 2019;139(25):E1162-E1177. on practice guidelines. J Am Coll Cardiol. 2014;63(25 PART B): doi:10.1161/CIR.0000000000000638 2889-2934. doi:10.1016/j.jacc.2013.11.002 6. Perkins RM, Bucaloiu ID, Kirchner HL, Ashouian N, Hartle JE, 24. Baigent C, Landray MJ, Reith C, et al. The effects of lower- Yahya T. GFR decline and mortality risk among patients with ing LDL cholesterol with simvastatin plus ezetimibe in pa- chronic kidney disease. Clin J Am Soc Nephrol. 2011;6(8):1879- tients with chronic kidney disease (Study of Heart and Renal 1886. doi:10.2215/CJN.00470111 Protection): A randomised placebo-controlled trial. Lancet. 7. Floege J, Gillespie IA, Kronenberg F, et al. Development and 2011;377(9784):2181-2192. doi:10.1016/S0140-6736(11)60739-3 validation of a predictive mortality risk score from a Euro- 25. Wanner C, Tonelli M. KDIGO Clinical practice guideline for pean hemodialysis cohort. Kidney Int. 2015;87(5):996-1008. lipid management in CKD: Summary of recommendation doi:10.1038/ki.2014.419 statements and clinical approach to the patient. Kidney Int. 8. Weiner DE, Tighiouart H, Elsayed EF, et al. The Framingham 2014;85(6):1303-1309. doi:10.1038/ki.2014.31 predictive instrument in chronic kidney disease. J Am Coll Car- 26. Moon Wang AY, Brimble KS, Brunier G, et al. ISPD cardiovascu- diol. 2007;50(3):217-224. doi:10.1016/j.jacc.2007.03.037 lar and metabolic guidelines in adult peritoneal dialysis patients 9. Matsushita K, Ballew SH, Coresh J. Cardiovascular risk part I – assessment and management of various cardiovascular prediction in people with chronic kidney disease. Curr risk factors. Perit Dial Int. 2015;35(4):379-387. doi:10.3747/ Opin Nephrol Hypertens. 2016;25(6):518-523. doi:10.1097/ pdi.2014.00279 MNH.0000000000000265 27. Wang AY, Brimble KS, Brunier G, et al. ISPD cardiovascular and 10. Ordúñez P, Tajer C. Disseminating cardiovascular disease risk metabolic guidelines in adult peritoneal dialysis patients part assessment with a PAHO mobile app: A public eHealth in- II – management of various cardiovascular complications. Perit tervention. Rev Panam Salud Publica/Pan Am J Public Heal. Dial Int. 2015;35(4):388-396. doi:10.3747/pdi.2014.00278 2015;38(1):82-85. 28. Elsadany BM, Yang Y, Gupta S, Mattana J. Cardiovascular Dis- 11. Van Der Velde M, Matsushita K, Coresh J, et al. Lower estimat- ease and the Kidney Emerging Therapies for Cardiovascular Dis- ed glomerular filtration rate and higher albuminuria are associ- ease: 2020;(June):2020. ated with all-cause and cardiovascular mortality. A collabora- 29. Schmit D, Fliser D, Speer T. Proprotein convertase subtilisin/ tive meta-analysis of high-risk population cohorts. Kidney Int. kexin type 9 in kidney disease. Nephrol Dial Transplant. 2019; 2011;79(12):1341-1352. doi:10.1038/ki.2010.536 34(8):1266-1271. doi:10.1093/ndt/gfz122 12. Vanholder R, Massy Z, Argiles A, et al. Chronic kidney disease 30. Pavlakou P, Liberopoulos E, Dounousi E, Elisaf M. PCSK9 in as cause of cardiovascular morbidity and mortality. Nephrol chronic kidney disease. Int Urol Nephrol. 2017;49(6):1015-1024. Dial Transplant. 2005;20(April):1048-1056. doi:10.1093/ndt/ doi:10.1007/s11255-017-1505-2 gfh813 31. Zheng-Lin B, Ortiz A. Lipid Management in Chronic Kid- 13. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu C. Chronic ney Disease: Systematic Review of PCSK9 Targeting. Drugs. Kidney Disease and the Risks of Death, Cardiovascular Events, 2018;78(2):215-229. doi:10.1007/s40265-017-0858-2 and Hospitalization. N Engl J Med. 2004;351(13):1296-1305. 32. Calder PC. Omega-3 fatty acids and inflammatory processes. doi:10.1056/nejmoa041031 Nutrients. 2010;2(3):355-374. doi:10.3390/nu2030355 14. Beddhu S, Allen-Brady K, Cheung AK, et al. Impact of renal fail- 33. Lok CE, Huber TS, Lee T, et al. KDOQI Clinical Practice ure on the risk of myocardial infarction and death. Kidney Int. Guideline for Vascular Access: 2019 Update. Am J Kidney Dis. 2002;62(5):1776-1783. doi:10.1046/j.1523-1755.2002.00629.x 2020;75(4):S1-S164. doi:10.1053/j.ajkd.2019.12.001 15. Valdivielso JM, Rodríguez-Puyol D, Pascual J, et al. Athero- 34. Omega-3 Fatty Acid Fact Sheet. National Institutes of Health sclerosis in chronic kidney disease: More, less, or just differ- Office of Detary Supplements. https://ods.od.nih.gov/fact- ent? Arterioscler Thromb Vasc Biol. 2019;39(10):1938-1966. sheets/Omega3FattyAcids-HealthProfessional/#h8. doi:10.1161/ATVBAHA.119.312705 35. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA 16. Shastri S, Sarnak MJ. Cardiovascular disease and CKD: Core Guideline on the Primary Prevention of Cardiovascular Dis- curriculum 2010. Am J Kidney Dis. 2010;56(2):399-417. ease: A Report of the American College of Cardiology/Ameri- doi:10.1053/j.ajkd.2010.03.019 can Heart Association Task Force on Clinical Practice Guide- 17. Zoccali C, Mallamaci F, Tripepi G. Traditional and emerging lines. J Am Coll Cardiol. 2019;74(10):e177-e232. doi:10.1016/j. cardiovascular risk factors in end-stage renal disease. Kidney Int jacc.2019.03.010 Suppl. 2003;63(85):105-110. doi:10.1046/j.1523-1755.63.s85.25.x 36. Éthier J, Bragg-Gresham JL, Piera L, et al. Aspirin Prescription 18. Bulbul MC, Dagel T, Afsar B, et al. Disorders of lipid metabo- and Outcomes in Hemodialysis Patients: The Dialysis Out- lism in chronic kidney disease. Blood Purif. 2018;46(2):144-152. comes and Practice Patterns Study (DOPPS). Am J Kidney Dis. doi:10.1159/000488816 2007;50(4):602-611. doi:10.1053/j.ajkd.2007.07.007 19. Moradi H, Vaziri ND, Kashyap ML, Said HM, Kalantar-Zadeh K. 37. Kalantar-Zadeh K, Kopple JD, Regidor DL, et al. A1C and sur- Role of HDL Dysfunction in End-Stage Renal Disease: A Dou- vival in maintenance hemodialysis patients. Diabetes Care. ble-Edged Sword. J Ren Nutr. 2013;23(3):203-206. doi:10.1053/j. 2007;30(5):1049-1055. doi:10.2337/dc06-2127 jrn.2013.01.022 38. International K. KDIGO 2020 Clinical Practice Guideline for 20. De Boer IH, Brunzell JD. HDL in CKD: How good is the Diabetes Management in Chronic Kidney Disease. Kidney Int. “good cholesterol?” J Am Soc Nephrol. 2014;25(5):871-874. 2020;98(4):S1-S115. doi:10.1016/j.kint.2020.06.019 doi:10.1681/ASN.2014010062 39. Speeckaert M, Van Biesen W, Delanghe J, et al. Are there bet- 21. Kwan BCH, Kronenberg F, Beddhu S, Cheung AK. Lipopro- ter alternatives than haemoglobin A1c to estimate glycaemic tein metabolism and lipid management in chronic kidney dis- control in the chronic kidney disease population? Nephrol Dial ease. J Am Soc Nephrol. 2007;18(4):1246-1261. doi:10.1681/ Transplant. 2014;29(12):2167-2177. doi:10.1093/ndt/gfu006 ASN.2006091006 40. Williams ME, Lacson E, Wang W, Lazarus JM, Hakim R. Gly- 22. Gajjala PR, Fliser D, Speer T, Jankowski V, Jankowski J. Emerg- cemic control and extended hemodialysis survival in patients ing role of post-translational modifications in chronic kidney with diabetes mellitus: Comparative results of traditional and disease and cardiovascular disease. Nephrol Dial Transplant. time-dependent cox model analyses. Clin J Am Soc Nephrol. 2015;30(11):1814-1824. doi:10.1093/ndt/gfv048 2010;5(9):1595-1601. doi:10.2215/CJN.09301209

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41. Ricks J, Molnar MZ, Kovesdy CP, et al. Glycemic control and 58. Sarafidis PA, Persu A, Agarwal R, et al. Hypertension in dialy- cardiovascular mortality in hemodialysis patients with dia- sis patients: A consensus document by the European Renal and betes: A 6-year cohort study. Diabetes. 2012;61(3):708-715. Cardiovascular Medicine (EURECA-m) working group of the doi:10.2337/db11-1015 European Renal Association-European Dialysis and Transplant 42. Tomoaki Morioka, Masanori Emoto, et al. Glycemic Control Is Association (ERA-EDTA) and the Hypertension and the Kidney. a Predictor of. Diabetes Care. 2001;24(5). Nephrol Dial Transplant. 2017;32(4):620-640. doi:10.1093/ndt/ 43. Zoungas S, Kerr PG, Lui M, Teede HJ. The impact of glycaemic gfw433 control on outcomes in patients with end-stage renal disease and 59. Assessment HE. K/DOQI clinical practice guidelines for cardio- type 2 diabetes. Nephrology. 2008;13(2):124-127. doi:10.1111/ vascular disease in dialysis patients. Am J Kidney Dis. 2005;45(4 j.1440-1797.2007.00901.x Suppl 3):16-153. doi:10.1053/j.ajkd.2005.01.019 44. Castillo-Rodriguez E, Fernandez-Fernandez B, Alegre-Bellassai 60. Khosla UM, Johnson RJ. Hypertension in the Hemodialysis Pa- R, Kanbay M, Ortiz A. The chaos of hypertension guidelines for tient and the “Lag Phenomenon”: Insights into Pathophysiolo- chronic kidney disease patients. Clin Kidney J. 2019;12(6):771- gy and Clinical Management. Am J Kidney Dis. 2004;43(4):739- 777. doi:10.1093/ckj/sfz126 751. doi:10.1053/j.ajkd.2003.12.036 45. Covic A, Goldsmith D, Donciu MD, et al. From Profusion to 61. Jones R. Hypertension and Hemodialysis: pathophysiology and Confusion: The Saga of Managing Hypertension in Chronic Kid- outcomes in adult and pediatric populations. Pediatr Nephrol. ney Disease! J Clin Hypertens. 2015;17(6):421-427. doi:10.1111/ 2012;27(3):339-350. doi:10.1007/s00467-011-1775-3. jch.12508 62. Agarwal, R, Alborzi, Pooneh, Satyam, et al. Dry-weight re- 46. Kramer HJ, Townsend RR, Griffin K, et al. KDOQI US Com- duction in hypertensive hemodialysis patients (DRIP): A ran- mentary on the 2017 ACC/AHA Hypertension Guideline. Am J domized controlled trial. Hypertension. 2009;53(3):500-507. Kidney Dis. 2019;73(4):437-458. doi:10.1053/j.ajkd.2019.01.007 doi:10.1161/HYPERTENSIONAHA.108.125674. 47. Williams B, Mancia G, Spiering W, et al. 2018 Practice Guidelines 63. Agarwal R, Sinha AD. Cardiovascular protection with anti- for the Management of Arterial Hypertension of the European hypertensive drugs in dialysis patients systematic review and Society of Cardiology and the European Society of Hypertension meta-analysis. Hypertension. 2009;53(5):860-866. doi:10.1161/ ESC/ESH Task Force for the Management of Arterial Hyperten- HYPERTENSIONAHA.108.128116 sion. Vol 36.; 2018. doi:10.1097/HJH.0000000000001961 64. Heerspink HJL, Ninomiya T, Zoungas S, et al. Effect of lower- 48. Guidelines. GH the CM of PH in AU of C. National Institute for ing blood pressure on cardiovascular events and mortality in pa- Health and Clinical Excellence. 2020;(August 2019). tients on dialysis: a systematic review and meta-analysis of ran- Lancet 49. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/ domised controlled trials. . 2009;373(9668):1009-1015. AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA doi:10.1016/S0140-6736(09)60212-9 Guideline for the Prevention, Detection, Evaluation, and Man- 65. Enia G, Mallamaci F, Benedetto FA, et al. Long-term CAPD pa- agement of High Blood Pressure in Adults: A Report of the Amer- tients are volume expanded and display more severe left ven- ican College of Cardiology/American Heart Association Task tricular hypertrophy than haemodialysis patients. Nephrol Dial Force on Clinical Pr. J Am Coll Cardiol. 2018;71(19):e127-e248. Transplant. 2001;16(7):1459-1464. doi:10.1093/ndt/16.7.1459 doi:10.1016/j.jacc.2017.11.006 50. A Randomized Trial of Intensive versus Standard Blood-Pressure Authors Control. N Engl J Med. 2015;373(22):2103-2116. doi:10.1056/ Harshitha Kota, MD, Fellow, Brown Medicine, Division of nejmoa1511939 Nephrology and Hypertension, Alpert Medical School of Brown 51. Becker GJ, Wheeler DC, De Zeeuw D, et al. Kidney disease: University, Rhode Island Hospital, Providence, RI. Improving global outcomes (KDIGO) blood pressure work Reginald Gohh, MD, Brown Medicine, Division of Nephrology and group. KDIGO clinical practice guideline for the management Hypertension, Professor of Medicine, Alpert Medical School of of blood pressure in chronic kidney disease. Kidney Int Suppl. Brown University, Division of Kidney Transplantation, Rhode 2012;2(5):337-414. doi:10.1038/kisup.2012.46 Island Hospital, Providence, RI. 52. Palmer SC, Mavridis D, Navarese E, et al. Comparative efficacy and safety of blood pressure-lowering agents in adults with Correspondence diabetes and kidney disease: a network meta-analysis. Lancet. 2015;385:2047-2056. Reginald Gohh, MD 53. Schmieder RE, Hilgers KF, Schlaich MP, et al. Renin-angiotensin Rhode Island Hospital system and cardiovascular risk. Lancet. 2007;369:1208-1219. 593 Eddy Street 54. Rahman M, GriffinV , Kumar A, Manzoor F, Wright JTJ, Smith Ambulatory Patient Center, 921 MC. A comparison of standardized versus “usual” blood pres- Providence, RI 02903 sure measurements in hemodialysis patients. Am J Kidney Dis 401-444-8562 Off J Natl Kidney Found. 2002;39(6):1226-1230. doi:10.1053/ Fax 401-444-3283 ajkd.2002.33395 [email protected] 55. Roberts, Matthew A, et al. Challenges in Blood Pressure Mea- surements in Patients Treated With Maintenance Hemodialysis. Am J Kidney Dis. 3:463-472. 56. Agarwal R. Blood pressure and mortality among hemodialysis patients. Hypertension. 2010;55(3):762-768. doi:10.1161/HYPER TENSIONAHA.109.144899 57. Bansal N, McCulloch CE, Rahman M, et al. Blood pressure and risk of all-cause mortality in advanced chronic kidney disease and hemodialysis the chronic renal insufficiency cohort study. Hypertension. 2015;65(1):93-100. doi:10.1161/HYPERTENSIO- NAHA.114.04334

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Malignancy After Renal Transplantation: A Review

Edward Medeiros, DO; Basma Merhi, MD

25 30 EN

KEYWORDS: renal transplantation, end-stage kidney identified as a risk factor for developing post-transplant disease, post-transplant malignancy, cancer screening in malignancy. Pre-transplant malignancy in either the donor post-transplant renal recipients or recipient, as well as susceptibility to various oncogenic viruses also contribute this risk. Differences in the donor type of transplant are associated with varying malignancy risk. Recipients of living-donor kidneys are at lower risk INTRODUCTION of cancer overall, particularly for genitourinary cancer and Renal transplantation provides a significant mortality post-transplant lymphoproliferative disorder (PTLD).6 benefit to patients with End-Stage Kidney Disease (ESKD) Undoubtedly the most important factor in post-transplant compared to those remaining on renal replacement ther- malignancy occurrence is prolonged exposure to immuno- apy (RRT), with many centers reporting one-year graft sur- suppression – medications required to prevent the trans- vival rates of 95%.1 The increase in allograft “half-life” is planted kidney from rejection. Immunosuppressants impair seen with both living donor kidney transplants (LDKT) and the body’s immune surveillance of oncogenic mutations deceased donor kidney transplants (DDKT), and correlate which would terminate such sequences under normal cir- to advances in immunosuppression options.2 As kidney cumstances. Although improvements in immunosuppres- transplant recipients are living longer, careful monitoring sive therapy has resulted in improvements in long-term for associated complications such as post-transplant malig- graft survival, longer exposure is associated with a higher nancy is necessary. Post-transplant malignancy is the third rate of de novo malignancy in transplant recipients.1 most common cause of death in renal transplant recipients, In the US, the risk of developing NMSC after renal with some malignancies occurring at much higher rates transplantation is more than 20-fold higher than that of compared to the general population.3 Immunosuppres- the general population. The other commonly encountered sant medication as well as oncogenic viruses seem to play post-transplant malignancies are those influenced by onco- a major role in malignancy development. This review will genic viruses (Table 1). Some of the more familiar malig- discuss malignancy after renal transplantation and offer an nancies in the general population such as breast, prostate, approach to caring for these patients. lung, uterine and pancreatic cancers tend to occur at about the same rate (or slightly less frequent) in kidney transplant recipients. Other more common malignancies such as colon, EPIDEMIOLOGY bladder and esophageal cancers occur at a rate approximately When to Suspect Malignancy 2–5 times higher in transplant patients.3 Renal transplant recipients have at least a 3- to 5-fold increase in malignancy incidence compared to the general Table 1. Viruses commonly associated with malignancy after renal trans- population. This increased risk is much more significant for plantation. Adapted from Morath C, Mueller M, Goldschmidt H, Schwenger specific malignancies such as non-melanoma skin cancer V, Opelz G, Zeier M. Malignancy in renal transplantation. J Am Soc Nephrol. (NMSC), while some other more common cancers such as 2004;15(6):1582-8. prostate and lung cancers occur at approximately the same Virus Malignancy Type 1,3 rate in transplant patients. Several donor and recipient Epstein-Barr Virus (EBV) Post-Transplant Lymphoproliferative factors play an important role in malignancy development. Disorder (PTLD) ESKD itself appears to be oncogenic for the development of Human Herpesvirus 8 (HHV-8) Kaposi's Sarcoma renal malignancy, with standardized incidence ratios (SIR) of Human Papillomavirus (HPV) Cervical Cancer 4 1.42 compared to age-matched cohorts without ESKD. This Vulvar Cancer is attributed to the development of acquired cystic kidney Penile Cancer disease in this patient population, which markedly increases Skin and Tonsillar Cancer the risk of developing malignancy in these senescent organs.5 Hepatitus C Virus (HCV), Hepatocellular Carcinoma (HCC) Time spent on dialysis before transplantation has also been Hepatitus B Virus (HBV)

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Transplant recipients should be monitored closely for inhibitors, including sirolimus and everolimus, may have the development of de novo malignancy throughout their anti-neoplastic properties and inhibit angiogenesis of tumor entire post-transplant course, but as alluded to previously, cells.10 More information is needed to make more definitive malignancy risk increases with duration of follow-up. The conclusions regarding mTOR inhibitors and malignancy risk of any malignancy after 10 years of renal transplanta- risk, as one meta-analysis suggests a decrease in NMSC but tion is reported to be almost 14-fold higher than the general an increased risk in prostate cancer.11 population, compared to much lower rates at 1- and 3-years Immunosuppression itself impairs the host’s ability to post-transplant. survey the immune system for potentially hazardous mutations. This is perhaps best demonstrated in the higher incidence of post-transplant skin cancers (specifically NMSC) PATHOGENESIS and viral-related malignancies. It is well known that sun Immunosuppression Regimen/Host Factors/Viral Causes exposure predisposes the host to carcinogens, which can Several factors contributing to post-transplant malignancy eventually lead to skin cancer. The immune system is development have been identified including patient age, sun responsible for identifying mutations associated with car- exposure, previous malignancy, concomitant viral infection, cinogen exposure and terminating them prior to malignancy the type and intensity of immunosuppression and dura- development. Without inhibitory checkpoints in place, tion of dialysis pre-transplant. The effect of the intensity of malignancy develops at much higher rates. Several viruses immunosuppression on malignancy development is demon- are associated with malignancy in immunocompromised strated across the various solid organ transplants and their hosts (Table 1). The viruses encode oncogenic proteins to post-transplant malignancy rates. Heart and lung transplant promote malignancy development.12 In immunocompetent recipients require higher levels of immunosuppression than individuals the viruses do not cause significant illness and their kidney counterparts, and this is associated with a remain dormant. However, the virus activity is unopposed higher incidence of malignancy.7 Immunosuppression inten- in immunosuppressed individuals, and malignancy may sity as an independent risk factor for post-transplant malig- subsequently occur. nancy is also supported by studies comparing higher vs lower Donor factors such as the unknowing donation of neoplas- cyclosporine trough levels, with a 12% reduced incidence tic cells at the time of transplantation are possible, but more in the latter group.8 commonly, malignancy occurs de novo in the recipient. In the “modern era” of immunosuppression, anti-rejec- Host factors play an important role in this risk. For exam- tion regimens have been more customized to the individual ple, the incidence of renal cell carcinoma (RCC) in kidney recipient, based on the perceived risk for rejection. It is now transplant recipients is influenced by male sex, increasing recognized that the development of alloantibodies directed age, African ancestry, acquired cystic kidney disease, and against the graft has a significant adverse impact on allograft the longer duration on dialysis. The underlying etiology survival and the previous practice of reducing the intensity of ESKD can also play a role, as evidenced by the increased of immunosuppression among transplant recipients of older of RCC in patients with tuberous sclerosis. Glomerulone- vintage is no longer standardly applied. Although this prac- phritis (GN) accounts for approximately 10% of the ESKD tice may ultimately improve long-term allograft outcomes, population in developed countries. Many of these disease there is an associated increase in malignancy incidence states require immunosuppression as part of the treatment attributed to heightened immunosuppression exposure. regimen, some of which may be potentially oncogenic (e.g., The type of immunosuppression used may also influence cyclophosphamide). Exposure to such medications may the risk of malignancy in the post-transplant setting. Lim double the risk of post-transplant malignancy compared et al. demonstrated that the risk for malignancy after first to other allograft recipients and should therefore be well- kidney transplantation was significantly higher in patients documented in patient records.14 treated with T cell–depleting antibodies for treatment of acute rejection compared with those recipients not experiencing acute rejection, with most confined to the genitouri- SKIN CANCERS nary tract.9 Similarly, T cell depletion using anti-thymocyte Skin cancers are by far the most common post-transplant globulin as induction therapy has also been associated with malignancy, accounting for approximately 40% of cases.2 higher rates of post-transplant lymphoproliferative disease Patients with fair complexion are at greatest risk, and rates (PTLD) compared to less intense regimens (e.g., anti-IL-2 increase with prolonged sun exposure and geographic loca- receptor antibodies). Furthermore, calcineurin inhibitors tion. In Australia, for example, the cumulative risk of skin (CNIs) such as tacrolimus and cyclosporine raise transform- cancer post-transplant is as high as 45% at 11 years and 70% ing growth factor (TGF-β) levels which may promote tumor at 20 years.3 The risk of melanoma is 3–4 times higher in growth.1 However, not all immunosuppressants are consid- renal transplant recipients, but the non-melanoma skin can- ered oncogenic. Mammalian target of rapamycin (mTOR) cers (NMSC) are far more common. These NMSC include

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basal cell carcinoma (BCC), squamous cell carcinoma (SCC) at 48–81 months.20 The lymphoid proliferations can be local- and Kaposi’s sarcoma. Kasiske et al demonstrated that cumu- ized to lymph nodes or disseminated (extra-nodal) to involve lative incidence of NMSC was 0.3%, 0.9%, 2.3%, 5.0%, and the transplanted organ, or other native organs such as the 7.4% at months 3, 6, 12, 24, and 36 months respectively.15 central nervous system (CNS). In kidney transplant patients, BCC and SCC are responsible for > 90% of skin cancers the most common location for PTLD involves the gastro- post-transplant. Although NMSC is not considered as intestinal tract. Clinical presentation is highly variable and aggressive as some other malignancies, SCC in transplant may include lymphadenopathy, night sweats, weight loss patients carries a 3-year mortality rate of 46% for metastatic or chills. Treatment includes reduction of immunosuppres- disease and recurrence is common.16 Skin surveillance and sion, and often a B-cell directed chemotherapy regimen. ultraviolet (UV) protection is strongly recommended in the However, there is no consensus on how immunosuppression post-transplant period. CNIs such as tacrolimus and cyclo- should be adjusted. sporine are highly associated with NMSC post-transplant and those experiencing recurrent skin cancers typically are frequently converted to alternative regimens such as mTOR ANOGENITAL CANCERS inhibitors to mitigate this risk.17 Once identified, the risk of Anogenital malignant neoplasms occur with a 14- to 50-fold skin cancer recurrence is high, and the clinician should em- increased incidence in kidney transplant patients and phasize the importance of skin surveillance and protection human papilloma virus (HPV) infection plays a major role post-transplant. in the development of such cancers. These include cervical, Kaposi’s sarcoma (KS) is an angioproliferative cutaneous vulvar, vaginal, penile and anal malignancies. 21 The inci- cancer caused by human herpesvirus 8 (HHV-8) in immu- dence of HPV infections in kidney transplant recipients is nocompromised hosts. They are purple-red-bluish lesions 17% to 45%, with a low rate of cytologic alterations found presenting as non-painful, non-pruritic, macules, papules or on pap testing.22,23 Vulvar and vaginal cancers are the least nodules. The incidence of KS is greatly increased in renal common gynecologic cancers in the general population. transplant recipients, particularly in certain ethnic groups Like cervical cancer, most vulvar cancers after transplanta- occurring in up to 5% of transplant patients.18 KS is more tion are HPV-related with the high-risk HPV types playing strongly associated with CNIs than other immunosuppres- the major role in the pathogenesis. Among kidney trans- sants. Visceral involvement of the GI tract or other mucosal plant patients, a younger age at transplantation (18–34yo) surfaces is possible but less common, and outcomes are vari- is associated with increased risk of cervical cancer whereas able. Approximately one-third of patients achieve complete vulvar cancer is more likely to occur at 5 or more years after remission with altering immunosuppression therapy, but transplantation.24 another one-third of patients die at 3 years after diagnosis.3 The choice, duration and intensity of immunosuppressive agents may influence the incidence of gynecological cancer development; however, studies on the direct effect POST-TRANSPLANT LYMPHOPROLIFERATIVE of specific immunosuppressants on gynecologic cancers are DISEASE (PTLD) sparse and conflicting. One hypothesis suggests immuno- PTLD includes several lymphoid disorders such as lym- suppression may contribute to reactivation of latent HPV phomas (both Hodgkin and NHL), lymphoid leukemias and infections, including high-risk oncogenic HPV types.25 A US multiple myeloma. The World Health Organization (WHO) study of 187,649 solid organ transplant recipients (64% renal classifies PTLD into four categories: early lesions, polymor- transplant), did not report an increase in invasive cervical phic, monomorphic, and classical Hodgkin’s lymphoma cancers after transplantation, although it noted an increase (cHL). PTLD has an incidence rate of 1.8% at 10-years of in situ carcinoma; this may be explained by very close fol- post-transplant and is more common in pediatric transplant low-up due to chronic immunosuppression and subsequent recipients. It is typically associated with Epstein-Barr Virus earlier detection of noninvasive cervical lesions. Decisions (EBV) infection, which chronically infects B-cells and leads regarding whether to withdraw or reduce immunosup- to their proliferation. Immunosuppression inhibits T-cell pression after a gynecologic cancer in the post-transplant regulation of the EBV-infected B cells, and uncontrolled pro- population should be individualized. liferation may ensue.19 The risk of PTLD is highest when an EBV (–) patient receives a kidney from an EBV (+) donor. Although PTLD can occur at any time post-transplant, OTHER CANCERS AND THOSE Non-Hodgkin Lymphoma tends to be the most aggressive WITHOUT INCREASED RISK and can occur within the first year after transplant when Other malignancies after renal transplantation occur at vary- immunosuppression is highest and there is more risk for ing rates. Some of the more commonly encountered cancers viral infection. More recent data suggests the interval to dis- in the general population (breast, prostate, lung, pancreas ease onset is increasing to later in the post-transplant course and uterine) occur at about the same rates in renal transplant

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Table 2. Standard Incidence Ratios (SIRs) of various malignancies after renal in transplant patients with compensated cirrhosis. transplantation compared to the general population. A lack of supporting evidence is not the only limitation of cancer screening in renal transplant recipients. Standard Incidence > 20x 10–20x 2–5x 1–2x In the general population, those with a life expectancy Ratio (SIR) of 5–10 years are typically excluded from the cancer Type of NMSC Cervical Colorectal Prostate screening guidelines. Mortality rates in renal transplant Cancer Lip Cancer Vulvar Melanoma Lung patients vary depending on age and comorbidities at time Oropharyngeal Lymphoma Pancreas of transplantation, but it should be noted that mortality Kaposi Sarcoma Renal and Ureter Breast after diagnosis of malignancy is high in this population. Bladder Uterine In Australia and New Zealand, the 5-year survival rate Thyroid Neuroendocrine for a transplant patient after malignancy diagnosis had been less than 10%.27 Those with a malignancy history prior to transplant factor into the limitations as well. recipients. Colon cancer is encountered at a slightly higher Depending on the type of malignancy, patients should be rate in transplant patients, 2–5 times the general population. deemed cancer-free for 2–5 years prior to transplant consid- Finally, urologic malignancies including the bladder, ureters eration. However, with better survival outcomes after trans- and kidneys occur at rates 5–20 times higher in renal transplant compared to maintenance on replacement therapy plant recipients.15 Table 2 contains a more comprehensive (RRT), development of novel chemotherapeutic agents and list of malignancies and their standardized incidence ratios more individualized immunosuppression, there has been (SIRs) after renal transplantation. discussion that the current recommendations may be too restrictive. Prospective data in the transplant population is needed to provide better guidance to the clinician regarding PREVENTION cancer screening. Post-Transplant Cancer Screening Guidelines Although the increased risk of malignancy after renal transplant is well established, there is little evidence to support MANAGEMENT screening guidelines in this complex patient population. 26 The cornerstone of post-transplant malignancy manage- As one might expect, the guidelines are adopted from those ment is the reduction of immunosuppression. Management used for the general population as well as for those cancers depends on the type and severity of malignancy and the ben- seemingly unique to renal transplant recipients. For malig- efits of decreasing immunosuppression to fight the cancer nancies already associated with cancer screening guidelines must be weighed against possible allograft rejection and/or in the general population, many societies suggest utiliz- failure. Targeting a lower immunosuppressant drug level is ing the same approach in renal transplant recipients. This commonplace in the setting of malignancy, and clinicians includes colon, breast, and prostate cancers. Lung cancer may choose to transition from CNI to mTOR inhibitors screening is recommended against by the American Society (especially in the setting of skin cancers). There is some of Transplantation (AST) in renal transplant recipients, as evidence to suggest mTOR inhibitors have anti-neoplastic is the case for renal and other urologic cancers despite their properties and may be helpful in bridging the difficult gap increased incidence in the transplant population.27 Skin can- between malignancy management and allograft protection, cer screening with self-examination and annual dermatology although this is not true of all cancers and more information surveillance for highest-risk transplant patients is recom- is needed. mended, and risk stratification tools exist to aid the clinician Another approach to the management of post-trans- in identifying these individuals.28 Despite these recommen- plant malignancies is to withdraw entire classes of immu- dations, evidence is lacking to support changes in outcomes. nosuppression altogether. Although immunosuppression Cervical cancer is the only gynecologic cancer for which regimens are transplant center-dependent, the majority of there are effective screening tests for the general population programs are still using a three-drug regimen consisting of to detect more treatable precancerous lesions. The American a CNI, anti-metabolite (mycophenolate mofetil or azathio- College of Obstetricians and Gynecologists and AST recom- prine), and prednisone.2 In addition to changing the CNI to mended more frequent, annual screening for cervical cancer an mTOR inhibitor, the clinician may elect to discontinue in renal transplant recipients. Still some other societies rec- the anti-metabolite medication to lower the overall immu- ommend pap testing with pelvic examination every 3 years, nosuppressive burden. This would seem more beneficial in which is in line with the general population guidelines.29 those taking azathioprine, as it has been linked to neoplasia Screening for PTLD/lymphomas are recommended against while mycophenolate mofetil may reduce the relative risk of by most societies, and hepatocellular carcinoma (HCC) some malignancies such as PTLD.30 screening with abdominal ultrasound is only recommended Chemotherapy may be used depending on the type of

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malignancy encountered. Perhaps the most challenging 7. Engels EA, Pfeiffer RM, Fraumeni JF, Jr., Kasiske BL, Israni AK, scenario is when faced with a malignancy which is typically Snyder JJ, et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA. 2011;306(17):1891-901. responsive to immunotherapy. More recent breakthroughs 8. Dantal J, Hourmant M, Cantarovich D, Giral M, Blancho G, in oncology have brought immunotherapy to the forefront of Dreno B, et al. Effect of long-term immunosuppression in kid- cancer treatment. Some of these therapies provide improved ney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens. Lancet. 1998;351(9103):623-8. outcomes compared to the previous standard of care, and the 9. Lim WH, Turner RM, Chapman JR, Ma MK, et al. Acute rejec- immune checkpoint inhibitors have been the most success- tion, T-cell-depleting antibodies, and cancer after transplanta- ful types of immunotherapy to date. The clinical dilemma tion. Transplantation 2014;97:817–825. involves activation of T-cells to combat neoplastic cell 10. Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, growth. Activation of previously dormant T-cells (thanks to Hornung M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular en- immunosuppression) can lead to allograft rejection due to dothelial growth factor. Nat Med. 2002;8(2):128-35. 31 recognition of donor antigen in the kidney. An individual- 11. Yanik EL, Gustafson SK, Kasiske BL, Israni AK, Snyder JJ, Hess ized approach to each transplant patient with malignancy is GP, Engels EA, Segev DL. Sirolimus use and cancer incidence likely best to determine the best course of action. among US kidney transplant recipients. Am J Transplant. 2015 Jan;15(1):129-36. doi: 10.1111/ajt.12969. Epub 2014 Dec 17. 12. Moore PS, Chang Y. Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nat Rev Cancer. SUMMARY 2010;10(12):878-89. In the modern era of immunosuppression, we are seeing 13. Padala SA, Barsouk A, Thandra KC, Saginala K, Mohammed A, Vakiti A, et al. Epidemiology of Renal Cell Carcinoma. World J better outcomes in renal transplant recipients. As a result, Oncol. 2020;11(3):79-87. the effects of prolonged exposure to immunosuppression, 14. Jorgenson MR, Descourouez JL, Singh T, Astor BC, Panzer SE. such as post-transplant malignancy, are more pronounced. Malignancy in Renal Transplant Recipients Exposed to Cyclo- A transplant recipient’s previous medical and oncologic his- phosphamide Prior to Transplantation for the Treatment of Na- tive Glomerular Disease. Pharmacotherapy. 2018;38(1):51-7. tory, opportunistic viral exposures, and immunosuppression 15. Kasiske BL, Snyder JJ, Gilbertson DT, Wang C. Cancers after regimen should all be considered when managing or screen- kidney transplantation in the United States. Am J Transplant. ing for post-transplant malignancy. Screening guidelines 2004 Jun;4(6):905-13. in transplant patients are often adopted from those of the 16. Collins L, Asfour L, Stephany M, Lear JT, Stasko T. Management of Non-melanoma Skin Cancer in Transplant Recipients. Clin general population, and more prospective evidence is needed Oncol (R Coll Radiol). 2019;31(11):779-88. for future guidance. Reduction in immunosuppression is a 17. Campistol JM. Minimizing the risk of posttransplant malignan- cornerstone of post-transplant malignancy management, cy. Transplant Proc. 2008;40(10 Suppl):S40-3. and there is some evidence to suggest mTOR inhibitors 18. Josep M. Campistol, Francesco P. Schena. Kaposi’s sarcoma in and the anti-metabolite mycophenolate mofetil are less renal transplant recipients—the impact of proliferation signal inhibitors Nephrology Dialysis Transplantation, Volume 22, Is- “oncogenic” compared to CNIs or azathioprine. Finally, all sue suppl_1, 1 May 2007, Pages i17–i22. decisions to reduce immunosuppression and/or treat active 19. Al-Mansour Z, Nelson BP, Evens AM. Post-transplant lymphop- malignancy must be weighed with the possibility of allograft roliferative disease (PTLD): risk factors, diagnosis, and current rejection/failure and should be made in consultation with treatment strategies. Curr Hematol Malig Rep. 2013;8(3):173-83. 20. Morton M, Coupes B, Roberts SA, Klapper PE, Byers RJ, Valle- the patient’s transplant team. ly PJ, Ryan K, Picton ML. Epidemiology of posttransplantation lymphoproliferative disorder in adult renal transplant recipients. Transplantation. 2013;95:470–8. References 21. Reinholdt K, Thomsen LT, Dehlendorff C, Larsen HK, Sorensen SS, Haedersdal M, et al. Human papillomavirus-related anogen- 1. Rama I, Grinyo JM. Malignancy after renal transplantation: the ital premalignancies and cancer in renal transplant recipients: role of immunosuppression. Nat Rev Nephrol. 2010;6(9):511-9. A Danish nationwide, registry-based cohort study. Int J Cancer. 2. Danovitch G. 2017. Handbook Of Kidney Transplantation. 6th 2020;146(9):2413-22. ed. Philadelphia: Wolters Kluwer, pp.281-293. 22. Morrison EAB, Dole P, Sun XW, et al. Low prevalence of hu- 3. Morath C, Mueller M, Goldschmidt H, Schwenger V, Opelz man papillomavirus infection of the cervix in renal transplant G, Zeier M. Malignancy in renal transplantation. J Am Soc patients. Nephrol Dial Transplant 1996; 11:1603. Nephrol. 2004;15(6):1582-8. 23. Paternoster DM, Cester M, Resente C, et al. Human papilloma 4. Butler AM, Olshan AF, Kshirsagar AV, Edwards JK, Nielsen ME, virus infection and cervical intraepithelial neoplasia in trans- Wheeler SB, et al. Cancer incidence among US Medicare ESRD planted patients. Transplant Proc 2008;40:1877. patients receiving hemodialysis, 1996-2009. Am J Kidney Dis. 2015;65(5):763-72. 24. Madeleine MM, Finch JL, Lynch CF, Goodman MT, Engels EA. HPV-related cancers after solid organ transplantation in the 5. Stewart JH, Buccianti G, Agodoa L, et al. Cancers of the kidney United States. Am J Transplant. 2013;13(12):3202-3209. and urinary tract in patients on dialysis for end-stage renal disease: analysis of data from the United States, Europe, and Aus- 25. Schiffman M, Doorbar J, Wentzensen N, et al. Carcinogenic hu- tralia and New Zealand. J Am Soc Nephrol 2003;14:197–207. man papillomavirus infection. Nat Rev Dis Primers. 2016; 2: 6. Ma MK, Lim WH, Turner RM, et al. The risk of cancer in recip- 16086. ients of living-donor, standard and expanded criteria deceased 26. Wong G, Chapman JR, Craig JC. Cancer screening in renal trans- donor kidney transplants: a registry analysis. Transplantation. plant recipients: what is the evidence? Clin J Am Soc Nephrol. 2014;98:1286–1293. 2008;3 Suppl 2:S87-S100.

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27. Acuna SA, Huang JW, Scott AL, Micic S, Daly C, Brezden-Mas- Authors ley C, et al. Cancer Screening Recommendations for Solid Organ Edward Medeiros, DO, Brown Medicine, Division of Nephrology Transplant Recipients: A Systematic Review of Clinical Prac- and Hypertension, Alpert Medical School of Brown University, tice Guidelines. Am J Transplant. 2017;17(1):103-14. Division of Kidney Transplantation, Rhode Island Hospital. 28. Jambusaria-Pahlajani A, Crow LD, Lowenstein S, Garrett GL, Melcher ML, Chan AW, et al. Predicting skin cancer in organ Basma Merhi, MD, Brown Medicine, Division of Nephrology and transplant recipients: development of the SUNTRAC screening Hypertension, Alpert Medical School of Brown University, tool using data from a multicenter cohort study. Transpl Int. Division of Kidney Transplantation, Rhode Island Hospital. 2019;32(12):1259-67. 29. Nguyen ML, Flowers L. Cervical cancer screening in immu- Correspondence nocompromised women. Obstet Gynecol Clin North Am. Basma Merhi, MD 2013;40(2):339-357. Division of Kidney Disease & Hypertension 30. Buell JF, Gross TG, Woodle ES. Malignancy after transplanta- Brown Physicians Patient Center tion. Transplantation. 2005;80(2 Suppl):S254-64. 375 Wampanoag Trail, Suite 402 31. Regalla DKR, Williams GR, Paluri RK. Immune checkpoint in- East Providence, RI 02915 hibitors in the management of malignancies in transplant recipients. Postgrad Med J. 2018;94(1118):704-8. 401-649-4060 Fax 401-649-4061 [email protected]

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Managing Side Effects of Immunosuppressants

Krista Mecadon, PharmD

31 33 EN

KEYWORDS: solid organ transplant, immunosuppression, recent years there has been an interest in investigating CNI side effects withdrawal and avoidance regimens in order to avoid the toxicities associated with their long-term use.2 Tacrolimus is very lipophilic and plasma bound, which increases its ability to cross the blood-brain barrier. The presence of tacrolimus in the central nervous system may lead INTRODUCTION to the over production of endothelin, which, if introduced Maintaining an allograft after solid organ transplant (SOT) to vascular smooth muscle, can cause vasocontraction and requires maintenance immunosuppression to prevent rejec- vasospasm. The spectrum of tacrolimus neurological-related tion and preserve organ function. While there have been side effects includes, insomnia, headache, tremor, mood improvements in the toxicities of maintenance regimens changes, and seizures.10 To help prevent these side effects, over the decades, transplant patients are still at high risk therapeutic drug monitoring is used to make sure serum of developing side effects to their immunosuppression ther- concentrations stay within therapeutic range. Analgesic apies. These can range from cosmetic changes, metabolic medications can be used to relieve headache and sleep aids abnormalities, and toxicities to different organ systems.1-3 can be employed to help with insomnia. Conversion to an Medication adherence remains a significant challenge for extended release tacrolimus product may help reduce cer- SOT recipients. While difficult to capture the exact scope of tain peak-related side effects, such as tremors.11 In cases of its prevalence, it has been reported that medication nonad- severe side effects like seizure, discontinuation of tacroli- herence ranges from 22–68% in the SOT community. This is mus may be required. Alternative therapies may conclude significant due to medication nonadherence being identified conversion to cyclosporine, sirolimus, or belatacept. as an independent risk factor for poor outcomes after SOT.4 The nephrotoxicity of CNIs remains a major concern in While there can be many reasons why a patient is non-com- the transplant community. Afferent arteriolar vasoconstric- pliant with their medications, the World Health Organiza- tion, activation of rein-angiotensin-aldosterone-system, and tion identified side effects as a significant treatment-related release of endothelin can lead to acute renal injury. Irrevers- factor for nonadherence.5 SOT recipients may also seek out ible structural abnormalities in the kidney are seen after alternative therapies to self-treat their side effects, which long-term use. Close therapeutic drug monitoring is utilized can have an impact on immunosuppression therapy and to prevent acute renal injury, by avoiding supratherapeutic organ function.6,7 A combination of a calcineurin inhibitor serum concentrations. Use of dihydropyridine calcium chan- (CNI), antimetabolite, and a corticosteroid remains a com- nel blockers in patients with concomitant hypertension may mon maintenance regimen for SOT recipients.8 While effi- counteract the vasoconstriction on the renal artery. There is cacious, these medications are associated with many side no evidence to suggest that tacrolimus is less nephrotoxic effects that can impact patients’ quality of life.1-3 While than cyclosporine. CNI withdrawal and avoidance regimens it may not always be clinically appropriate to change a have been studied with alterative immunosuppression ther- transplant recipient’s medication or reduce their dose, it is apies such as sirolimus, everolimus, or belatacept. While important to recognize and manage these side effects. there may be long-term benefits of limiting CNI use in SOT recipients, these potential benefits must be balanced with the risks of rejection and graft loss.2 CALCINEURIN INHIBITORS Tacrolimus can cause alopecia in 3–6% of patients.12 Cyclosporine was the first CNI used in SOT, which dramat- Vitamin supplementation with biotin may be beneficial in ically changed recipient outcomes.2 Now, tacrolimus has protecting hair strength. If impacting the SOT recipient’s become the CNI of choice due to its lower rejection rates and quality of life, alternative immunosuppression therapies trends for increased patient survival.9 Despite their benefits, may be considered for certain patients. Conversion to cyclo- CNIs are associated with numerous toxicities such as neu- sporine can be considered, but hirsutism and gingival hyper- rotoxicity, nephrotoxicity, development of new onset diabe- plasia can occur.1 Sirolimus or everolimus can be considered, tes after transplant (NODAT), and cosmetic changes.1,2,10 In but acne is a potential cosmetic side effect.

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ANTIMETABOLITES with glucocorticoid steroids are related to the average dose Mycophenolate is the most common antimetabolite cur- and cumulative duration of use.3,16 Steroid reduction and rently used in SOT.8 It has two different preparations; myco- withdrawal may be safe for some SOT recipients, but there phenolate mofetil (MMF) and enteric-coated, mycophenolate are certain patient populations that require life-long use. sodium (EC-MPA). Both preparations are equally efficacious The Scientific Registry of Transplant Recipients (SRTR) and have similar safety profiles.13 Among transplant cen- annual report from 2018 showed that only 30% of kidney ters, there will be varying practices as to whether they pre- transplant recipients are steroid free.8 With their use still fer MMF or MPA for their SOT recipients. Azathioprine is prevalent, it is important that SOT recipients receive moni- an older antimetabolite that has been used for decades in toring for corticosteroid-related side effects. SOT. Azathioprine’s place in therapy is now usually reserved Corticosteroids alter bone metabolism by reducing bone for patients who are unable to tolerate the mycophenolate formation and increasing resorption. These changes in bone products or trying to conceive. metabolism lead to an increase risk of bone fractures.3,16 Gastrointestinal (GI) side effects are common with myco- Bone-protective therapies can be considered for high-risk phenolate products. Mycophenolate, after it is converted to patients when initiating corticosteroid therapy. High-risk mycophenolic acid, disrupts the production of GI epithelial individuals may include patients >65, those with past frac- cells through its anti-proliferative properties.14 Symptoms tures, or those with a history of osteopenia. Calcium, vita- may include diarrhea, nausea, vomiting, dyspepsia, and min D supplementation, and bisphosphonate therapy have abdominal pain. Depending on the severity of the of the GI all been used as bone protective regimens.16 Monitoring of side effect and other infectious causes of diarrhea have been bone mineral density is recommended for high-risk popu- ruled out, it may be reasonable to monitor the patient before lations, prior to steroid corticosteroid therapy and after 1 making any interventions. If symptoms persist or become year of therapy if prednisone doses are expected to be ≥5 mg more severe, dose adjustments may be necessary.14,15 The per day.3 GI side effects of mycophenolate are dose dependent. Total Corticosteroids are associated with precipitating or exac- daily dose reductions may be appropriate for some patients. erbating cardiovascular risks factors such as hypertension, However, lowering doses of immunosuppressive agents can hyperglycemia, hyperlipidemia, and obesity.3 Patients on increase the risk of rejection and additional allograft moni- long-term corticosteroids should be monitored for these side toring should be performed. An alternative strategy to low- effects and counseled on lifestyle modifications with diet ering the total daily dose of mycophenolate is to split the and exercise as appropriate. Additional pharmacologic ther- total daily dose over three or four doses instead of two.15 A apies may need to be initiated if these risk factors cannot be limitation of increasing the dosing interval is that it does controlled despite diet and exercise.1,3,16 make regimens more complicated for patients. The neurologic side effects of corticosteroids can range Bone marrow suppression is another potential side effect from insomnia, irritability, mood changes, mania, and of mycophenolate.16,17 It has been reported that neutrope- depression. The onset of these symptoms usually presents nia occurs in 5–38% in the kidney transplant population. within the first couple of days to weeks of therapy. Manage- The evolution of neutropenia for SOT recipients is multi- ment usually consists of lowering the dose of the cortico- factorial, but medications, infections, and malignancies steroid. However, additional management may include sleep must all be considered.17 After neutropenia is identified and aids, antidepressants, or antipsychotics for certain patients.10 infections have been ruled out, all medications should be assessed for their potential to cause bone marrow suppression. For certain patients, it may be preferred to discon- DIETARY AND HERBAL SUPPLEMENTS tinue other bone marrow suppressing medications prior to The use of alternative medicine has increased in the United adjusting their immunosuppression. If neutropenia persists, States, with 36% of Americans admitting to using herbs, decreasing or discontinuing the mycophenolate product may non-herbal supplements, and vitamins. These products are be required. Based on the degree of neutropenia, granulocyte not subjected to safety and efficacy testing by the FDA and colony-stimulating factors may need to be used until the their manufacturing practices are not regulated, which can absolute neutrophil count recovers to an acceptable limit. lead to product inconsistencies.6 Frequently, dietary and herbal supplements are started without consulting a health care provider. When reconciling medications with SOT CORTICOSTEROIDS recipients, it is important to screen for dietary and herbal Corticosteroids have been utilized in SOT for decades. How- supplement use. For SOT recipients, dietary and herbal sup- ever, their long-term use has been associated with a signif- plements can be associated with drug interactions, immune icant number of side effects including: osteoporosis, bone stimulating effects, and direct organ toxicity.6,7 fractures, cardiovascular disease, psychiatric disturbances, The drug interactions associated with these products can and dermatological changes.3,10 The toxicities associated be clinically significant by affecting serum concentrations

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of immunosuppressant medications. St. John’s Wort is an References inducer of CYP3A4, CYP2C9, and P-glycoprotein (P-gp). The 1. Josephson, MA. Improving Medication Adherence in Transplant use of St. John’s Wort in combination with a CNI would Recipients: Managing Physical Side Effects of Immunosuppres- sion. Medscape. 2005. lead to decreased serum concentrations of cyclosporine or 2. Azzi J, et al. Calcineurin Inihibitors: 40 Years Later, Can’t Live tacrolimus. Ginkgo biloba and milk thistle are inhibitors of Without. J Immunol. 2013; 191(12):5785-5791. CYP3A4, CYP2C9, and P-gp. Turmeric is another inhibitor 3. Liu D, et al. A practical guide to the monitoring and manage- of CYP3A4. The use of these herbs in combination with a ment of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 2013;9(1):30. CNI would increase the serum concentrations of cyclospo- 4. Neuberger JM, et al. Practical Recommendations for Long-term 18 rine or tacrolimus. Management of Modifiable Risks in Kidney and Liver Trans- Some dietary and herbal supplements are marketed as plant Recipients: A Guidance Report and Clinical Checklist by immune stimulants. The concern with these products in the Consensus on Managing Modifiable Risk in Transplantation (COMMIT) Group. Transplantation. 2017;101:S1-S56. the SOT population is that they can precipitate an immune 5. Nevins TE, et al. Understanding Medication Nonadherence af- response and interfere with immunosuppression therapy.7,18 ter Kidney Transplant. J Am Soc Nephrol. 2017;28(8):2290-2301. Echinacea, ginseng, astragalus, and vitamin C are examples 6. Gabardi S, et al. A Review of Dietary Supplement-Induced Renal of herbs and supplements that have immune stimulating Dysfunction. Clin J Am Soc Nephrol. 2007;2(4):757-65. effects and generally should be avoided in the SOT popula- 7. Neff GW, et al. Consumption of dietary supplements in a liver transplant population. Liver Transpl. 2004;10(7):811-5. tion. Vitamin C may also be used to promote wound healing; 8. Special Issue: OPTN/ SRTR Annual Data Report 2018. Am J if its use is required, the risks vs. benefits should be dis- Transplant. 2018;20(1):1-568. cussed with the patient’s transplant provider. 9. Liu J, et al. Tacrolimus Versus Cyclosporine as Primary Immu- Dietary and herbal supplements can also have a direct nosuppressant After Renal Transplantation: A Meta-Analysis and Economics Evaluation. Am J Ther. 2016;23(3):e810-24. effect on renal and hepatic function. Supplements such 10. Anghel D, et al. Neurotoxicity of Immunosuppressive Therapies as chromium, creatine, L-Lysine, and willow bark can be in Organ Transplantation. Maedica. 2013;8(2):170-175. directly nephrotoxic. High-dose vitamin C (>60 g/day), ephe- 11. Langone A, et al. Switching STudy of Kidney Transplant PA- dra, and cranberry have been reported to cause nephrolithi- tients with Tremor to LCP-TacrO (STPATO): an open-label, multicenter, prospective phase 3b study. Clin Transplant. asis. Case reports of supplement-induced rhabdomyolysis 2015;29:796-805. have been reported with use of wormwood oil, licorice, and 12. Shapiro R, et al. Alopecia as a Consequence of Tacrolimus Ther- creatine.6 Herbal supplements that are known to be hepa- apy. Transplantation. 1998;65(9):1284. totoxic include: kava kava, comfrey, DHEA, bee pollen, 13. Chan L, et al. Patient-Reported Gastrointestinal Symptom Bur- vitamin E, green tea, echinacea, turmeric, and valerian.6,7,18 den and Health-Related Quality of Life following Conversion from Mycophenolate Mofetil to Enteric-Coated Mycophenolate Sodium. Transplantation. 2006;81:1290-1297. 14. Davies NM, et al. Gastrointestinal side effects of mycopheno- CONCLUSION lic acid in renal transplant patients: a reappraisal. Nephrol Dial Transplant. 2007;22(9):2440-8. In conclusion, SOT recipients are at high risk for develop- 15. Helderman JH, Goral S. Gastrointestinal Complications of Trans- ing side effects and toxicities to their maintenance immu- plant Immunosuppression. J Am Soc Nephrol. 2002;12:277-287. nosuppressants. It is important to recognize and manage 16. Hsu DC, Katelaris CH. Long-term Management of Patients Tak- these side effects as they can impact patients’ quality of life, ing Immunosuppressive Drugs. Aust Prescr. 2009;32:68-71. affect medication adherence, and cause damage to different 17. Zafrani L, et al. Incidence, Risk Factors and Clinical Conse- quences of Neutropenia Following Kidney Transplantation: A organ systems. Patients should be monitored for potential Retrospective Study. Am J Transplant. 2009;9:1816-1825. side effects and interventions should be made when clini- 18. Natural Medicines. Therapeutic Research Center. 2020. cally appropriate. Patients may require adjunctive therapies to help manage these side effects or modifications to their Author immunosuppressive regimens may be necessary. SOT recip- Krista Mecadon, PharmD, Clinical Pharmacy Specialist, Kidney Transplant, Rhode Island Hospital, Providence, RI. ients should be screened for use of dietary and herbal supplements, due to their potential impact on organ function and Correspondence drug interactions. If changing a SOT recipient immunosup- Krista Mecadon, PharmD pression regimen, the risk and benefits must be considered Rhode Island Hospital and additional graft monitoring is required. 593 Eddy Street APC Building 9th Floor Providence, RI 02903 401-444-4104 [email protected]

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Transplantation of Hepatitis C-Infected Kidneys into Uninfected Recipients: A Review of the Literature

Haley Leesley, MD, MS; Adena J. Osband, MD

34 36 EN

KEYWORDS: hepatitis C, direct-acting antiviral therapy, acid testing (NAT) in all organ donors.6 Nucleic acid amplifi- sustained viral response, clinical trials cation testing can be used to reveal viremia in a serologically negative patient, and is routinely performed for HIV-1 and HCV in blood donors in the United States.7 Standard serology testing for HCV becomes positive ~70 days following INTRODUCTION infection, ~40 days with enhanced serology testing, and in There is a severe shortage of available deceased donor kid- 3–5 days with nucleic acid testing. This testing has allowed neys for transplantation. In 2018, kidney transplants totaled the creation of a new category of HCV donors, based on com- 22,393, of a national waiting list of 78,675. Only 58% of bined Ab and NAT results.6 Both HCV Ab+/NAT+ and HCV patients removed from the waitlist were done so for trans- Ab-/NAT+ donors are considered HCV positive. Donors who plant; the remaining 42% were removed due to death or are HCV Ab–/NAT– are usually deemed negative. because they became too ill for transplant.1 Annual wait- There are a few conditions in which a person may be list mortality is 5–7% annually, and increases with age and HCV Ab+/NAT– including a false positive HCV antibody comorbidities such as diabetes. As our population ages and test, testing during the window period, donors with previ- the average age on the waitlist increases, this mismatch of ous HCV infection who are in the process of clearing the kidney supply and demand continues to grow. One rising virus while on therapy or have cleared the virus. The most source of deceased donor kidneys is from donors with over- common condition for HCV Ab+/NAT– appears to be prior dose- related death. The opioid crisis in the United States is HCV infection with spontaneous immunologic viral clear- associated with both increasing rates of hepatitis C as well as ance.8 The incidence of spontaneous immunologic clearance overdose-related deaths. Overdose-related death accounted is estimated to be around 25% based on a 2006 systematic for only 1.1% of all donors in 2000 but 13.4% in 2017, and literature review.9 tended to be younger, and more likely to be infected with There is a window period which may occur if a donor dies hepatitis C virus (HCV).2 A recent advisory from the Centers of an intravenous drug overdose and the serologic testing is for Disease Control and Prevention Health Alert Network done a few days after the exposure, for example. In this case revealed an accelerated increase in opioid overdose deaths the Ab may be positive from prior exposure but NAT may during the COVID-19 pandemic.3 not yet be positive from this exposure, leading to HCV Ab+/ In the United States, patients on dialysis have a mortality NAT–. Or if the donor was never previously exposed, they rate that exceeds 20% during the first year of dialysis and may be HCV Ab–/NAT–. Alternatively, if there was no prior 50% after 5 years. The prevalence of chronic kidney disease exposure, and testing was after the 3-5 day period, the donor has steadily risen from 2000-2018.4 Following kidney trans- would be HCV Ab-/NAT+. plantation, most patients receive a doubling in their life In a retrospective review published in the American Jour- expectancy.5 Given the rise in opioid-related deaths, the prev- nal of Transplantation in 2019, short-term outcomes of alence of hepatitis C and the shortage of kidneys in the donor adult deceased donor kidney transplants of HCV uninfected pool, a critical assessment of the criteria for transplantation recipients were compared with either HCV Ab+/NAT- or is necessary. In the last ten years, there have been a few note- HCV Ab+/NAT+. In this study, data was analyzed from worthy changes that affect our understanding of high-risk the OPTN STAR files from the United Network of Organ organs. First, the use of nucleic acid amplification testing Sharing (UNOS), which includes data submitted by mem- to detect viral load, and second, the development of direct- bers on all donors, waitlisted candidates and transplanted acting antiviral medications targeted against hepatitis C. recipients. Patients were included from January 2015 to June 2018, were over the age of 18, and underwent deceased donor kidney transplantation (DDKT). Patients receiving simul- NUCLEIC ACID AMPLIFICATION TESTING taneous kidney-pancreas or other multiorgan transplants In 2015, the US Organ Procurement and Transplant Net- were excluded. The primary outcomes were length of stay, work (OPTN) mandated routine qualitative HCV nucleic delayed graft function, rejection rate, serum creatinine at 6

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months post transplant. Delayed graft function was defined was performed, there was a 2.69 fold higher odds of utilizing as requiring dialysis in the first week post transplant. Sec- high- risk donors. It could be concluded that performing this ondary outcomes included overall graft and patient survival test may influence provider bias about high-risk organs.11 at 12 months. There were 42,240 DDKT recipients studied, with 33,934 DDKT from HCV-uninfected donors to HCV-uninfected recipients, 352 from HCV Ab+/NAT– donors to DIRECT-ACTING ANTIVIRAL THERAPY uninfected recipients and 196 HCV Ab+/NAT+ donors to The advent of HCV direct-acting antivirals (DAAs) has uninfected recipients. There was no statistical difference in allowed for new protocols to be studied in HCV recipients. overall graft survival among the three groups. For HCV Ab+/ These allow for treatment of both patients with ESRD and NAT-, there was no difference in length of stay, rejection those post transplant. There are currently several choices, rate or serum creatinine. Finally, there was no statistically and they are frequently used in combination. There are significant difference in overall graft survival at 12 months many trials using different agents, administered at different post transplant. For HCV Ab+/NAT+ donors to uninfected timing, and for varied duration of treatment. Detailed below recipients, there was actually a lower proportion of delayed are a few representative trials with very promising results. graft function and decreased serum creatinine at 6 months. Elbasvir/grazoprevir was studied in genotype 1 infected There was no difference in graft survival. When compared patients in the C-SURER trial and the pangenotypic com- to the reference group (HCV uninfected donors), uninfected bination of glecaprevir/pibrentasvir in the EXPEDITION recipients of HCV viremic donors had a shorter time on the 4 trial. Both demonstrated excellent safety and efficacy in transplant waitlist and dialysis and a lower KDPI (kidney those with ESRD, including those on dialysis. Elbasvir/gra- donor profile index) score. Lower KDPI score reflects an zoprevir for 12 weeks resulted in a sustained viral response overall better quality donor kidney. These findings are pro- of 99%, and a response of 100% seen with glecaprevir/ foundly clinically relevant, in demonstrating non-inferior pibrentasvir for 12 weeks.8 outcomes with HCV positive organs. A major limitation of The THINKER clinical trial at the University of Pennsyl- the study was that the use of a direct acting antiviral was vania demonstrated excellent allograft function and cure of not included.10 HCV infection in 10 HCV negative patients who received Many single center studies have evaluated the rate of kidney transplants infected with genotype 1 HCV. All recip- transmission of HCV from HCV Ab+/NAT– to an HCV ients had detectable HCV RNA on post-operative day 3, Ab- recipient, with almost all studies reporting a zero rate had elbasvir/grazoprevir initiated, and by 12 weeks had sus- of transmission. The largest of this type of study comes tained viral response.12 Twelve-month follow-up of 20 such from the University of Cincinnati published in 2019, which patients demonstrated HCV cure and comparable allograft analyzed the incidence of HCV transmissions and clini- function to matched HCV-negative recipient controls for cal outcomes in HCV-naive kidney transplant recipients all recipients.13 who received allografts from HCV Ab+/NAT- donors. The A clinical trial at Johns Hopkins University evaluated the primary outcome was incidence of HCV transmission at transplantation of HCV+ donors into negative recipients in 3-months post transplant. For recipients who developed combination with direct-acting antivirals as both pre- and HCV viremia post-kidney transplant, direct-acting anti- post-transplant prophylaxis. Each recipient received grazo- viral therapy was initiated. Secondary outcomes included previr/elbasvir prior to transplantation and continued with post-kidney transplant graft function, graft survival, and daily therapy for 12 weeks. Three patients also took sofos- patient survival at time of follow-up. During the study period buvir due to their strain of HCV. In 7 out of 10 recipients, of July 2016 to February 2018, 163 deceased donor kidney HCV RNA was undetectable at all times. No participant transplants occurred with 52 kidneys (32%) from HCV Ab+/ had virologic or clinical evidence of chronic HCV infec- NAT– donors to HCV negative recipients. There was a sin- tion with a follow-up period of 12 weeks after the discon- gle potential transmission identified. In this one case, the tinuation of DAA and there were no adverse events related donor was tested at day 2 and found to be NAT- and was to treatment.14 transplanted. The recipient returned with HCV RNA posi- Furthermore, there is an ongoing trial now evaluating tivity, so samples from the donor taken from hospital day 4 the safety of HCV+ organ donation with DAA therapy with were sent for NAT and found to be positive. In this case, the a shortened course. Thirty HCV negative patients were donor likely became infected shortly before his death, which enrolled in the trial and received HCV Ab+/NAT+ lung, put him just before the capability for NAT detection, in the kidney, heart, or kidney-pancreas transplants. All recipients window period. This would indicate a 1.69% transmission received a single dose of ezetimibe and glecaprevir/pibren- incidence.6 tasvir before transplant and once a day for 7 days after sur- Interestingly, national surveys conducted by Kucirka and gery. While low-level viremia was transiently detected in 21 colleagues found that providers were more likely to consider of 30 patients, all 30 transplant recipients had undetectable a high-risk organ if NAT was performed. When HCV NAT HCV RNA at 12 weeks post transplant.15

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ADDITIONAL CONSIDERATIONS 3. CDC Health Alert Network. (2020). Increase in Fatal Drug Over- doses Across the United States Driven by Synthetic Opioids The cost of treatment with DAA therapy versus waiting for Before and During the COVID-19 Pandemic (CDCHAN-00438) a HCV Ab- donor was analyzed by Gupta and colleagues https://emergency.cdc.gov/han/2020/han00438.asp in 2018. The group compared renal transplantation from an 4. United States Renal Data System. 2019 USRDS Annual Data Re- HCV+ donor into an HCV recipient followed by immediate port: Epidemiology of Kidney Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive DAA therapy versus HCV recipients continuing dialysis and Kidney Diseases, Bethesda, MD, 2020. and waiting for renal transplantation from an HCV donor, 5. Jones D, You Z, Kendrick JB. Racial/Ethnic Differences in Bar- over a 5-year time frame. Estimates of cost were determined riers to Kidney Transplant Evaluation among Hemodialysis Pa- by Medicare reimbursements or kidney transplant Diagno- tients. Am J Nephrol. 2018;47(1):1-7. 6. Dao A, Cuffy M, Kaiser TE, et al. Use of HCV Ab+/NAT- Donors sis-Related Groups and corresponding provider costs. Their in HCV Naïve Renal Transplant Recipients to Expand the Kid- model estimated that patients receiving HCV+ organs and ney Donor Pool. Clin Transplant. 2019;33(7):e13598. undergoing DAA therapy resulted an estimated $190,000 7. Humar A, Morris M, Blumberg E, et al. Nucleic Acid Testing less cost compared to continuing hemodialysis.16 (NAT) of Organ Donors: is the ‘Best’ Test the Right Test? A Con- sensus Conference Report. Am J Transplant. 2010;10(4):889-99. The discussion of HCV+ kidney offers with potential 8. Te H, Doucette K. Viral hepatitis: Guidelines by the American transplant recipients continues to evolve. As we have more Society of Transplantation Infectious Disease Community of data about donor and recipient status, as well as growing Practice. Clin Transplant. 2019;33(9):e13514. prior experience, we can be more specific in approach and 9. Micallef JM, Kaldor JM, Dore GJ. Spontaneous Viral Clearance Following Acute Hepatitis C Infection: a Systematic Review of counseling. Transplantation of HCV+ into HCV- recipients Longitudinal Studies. J Viral Hepatit. 2006;13(1):34-41. is currently only performed under research protocols, and 10. La hoz RM, Sandıkçı B, Ariyamuthu VK, Tanriover B. Short- very clear informed consent is obtained for participation. Term Outcomes of Deceased Donor Renal Transplants of HCV As this practice may transition from clinical trials to stan- Uninfected Recipients from HCV Seropositive Nonviremic Do- nors and Viremic Donors in the Era of Direct-Acting Antivirals. dard clinical practice, this discussion will need to become Am J Transplant. 2019;19(11):3058-3070. part of the routine transplant consent process, as transplant 11. Kucirka LM, Namuyinga R, Hanrahan C, Montgomery RA, Se- outcomes using HCV+ kidneys in the current DAA era are gev DL. Provider Utilization of High-Risk Donor Organs and comparable. Nucleic Acid Testing: Results of Two National Surveys. Am J Transplant. 2009;9(5):1197-204. 12. Goldberg DS, Abt PL, Blumberg EA, et al. Trial of Transplan- tation of HCV-Infected Kidneys into Uninfected Recipients. N FURTHER DISCUSSION Engl J Med. 2017;376(24):2394-2395. Outcomes from hepatitis C antibody positive donors, either 13. Reese PP, Abt PL, Blumberg EA, et al. Twelve-Month Out- comes after Transplant of Hepatitis C-Infected Kidneys into viremic or not, appear to be as good as hepatitis C negative Uninfected Recipients: A Single Group Trial. Ann Intern Med. organs in terms of length of stay, rate of rejection, serum 2018;169(5):273-281. creatinine and 12-month rates of graft survival. Addition- 14. Durand CM, Bowring MG, Brown DM, et al. Direct-Acting An- ally, the rate of transmission from a NAT-donor remains tiviral Prophylaxis in Kidney Transplantation from Hepatitis C Virus-Infected Donors to Noninfected Recipients: An Open-La- exceedingly low with a single case report of transmission. bel Nonrandomized Trial. Ann Intern Med. 2018;168(8):533-540. In patients that do seroconvert from hepatitis C negative 15. Feld JJ, Cypel M, Kumar D, et al. Short-Course, Direct-Acting to positive, there are multiple drug therapies that exist that Antivirals and Ezetimibe to Prevent HCV Infection in Recipients of Organs from HCV-Infected Donors: a Phase 3, Single-Centre, create sustained virologic response and are well tolerated in Open-Label Study. Lancet Gastroenterol Hepatol. 2020. this patient population. 16. Gupta G, Zhang Y, Carroll NV, Sterling RK. Cost-Effectiveness With this promising data, many questions remain, includ- of Hepatitis C-Positive Donor Kidney Transplantation for Hep- ing the timing of administration of direct-acting antiviral atitis C-Negative Recipients with Concomitant Direct-Acting Antiviral Therapy. Am J Transplant. 2018;18(10):2496-2505. medications – pre-exposure, post-exposure, or even delayed. Additional factors, including insurance coverage of direct- Authors acting antiviral therapy are an important consideration. Per- Haley Leesley, MD, MS, Department of Surgery, Warren Alpert haps in the future, hepatitis C organ donation may become Medical School of Brown University, Providence, RI. the accepted standard practice in renal transplantation and Adena J. Osband, MD, Department of Surgery, Warren Alpert for other organs as well. Medical School of Brown University, Providence, RI. Correspondence Adena J. Osband, MD References Division of Organ Transplantation 1. Hart A, Smith JM, Skeans MA, et al. OPTN/SRTR 2017 Annual Rhode Island Hospital Data Report: Kidney, Am J Transplant 2019;19 Suppl 2:19. 401-444-5285 2. Durand CM, Bowring MG, Thomas AG, et al. The Drug Over- [email protected] dose Epidemic and Deceased-Donor Transplantation in the United States: A National Registry Study. Ann Intern Med. 2018;168(10):702-711.

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Retinopathy in a Full-Term Infant with Cri-du-Chat Syndrome

Nisarg Chhaya, MD; Tineke Chan, MD

37 39 EN ABSTRACT of cri-du-chat. Specifically, whole genome SNP microarray Cri-du-chat (CdC) is a 5p chromosomal deletion syn- analysis was performed in a CLIA-approved laboratory on drome. CdC has numerous systemic associations but the DNA isolated from whole blood of the patient. Analysis only a few ocular manifestations have been documented. identified a terminal, heterozygous deletion at 5p15.33p14.3 In this report we present novel ocular findings of periph- of 20.281 Mb as well as a contiguous heterozygous duplica- eral avascular retina and retinal hemorrhages in a full- tion of 1.593 Mb at 5p14.3 that affected 7 genes, including term female infant, born to non-consanguineous parents, partial copies of CDH18 and CDH12 (cadherin genes) at the who had clinical features of cri-du-chat syndrome and distal and proximal breakpoints. genetic confirmation. The retinal hemorrhages resolved. Follow-up systemic evaluation included an echocardio- However, the temporal avascular retina in our full-term gram which revealed a fenestrated patent foramen ovale patient remained. Further analysis of the 5p locus showed and a mildly dilated ascending aorta. MRI revealed enlarged 3 genes: CTNND2, SEMA5A and SLC6A18 that not only anterior fontanelle without ventriculomegaly. Laryngoscopy fit our patient’s external phenotype and ophthalmoscop- and renal ultrasound were unremarkable. Patient did not ic findings of retinal hemorrhages, but were also key in tolerate oral feeds and subsequently required the placement proper ocular development and neurogenesis, suggesting of a gastric tube on day-of-life 56. a genetic contribution by the short-arm of chromosome The patient was evaluated for screening eye exam at 41 5 to proper retinal maturation. Given these findings and weeks corrected age. On exam, both eyes had responses their association with cri-du-chat, special attention on appropriate for age; pupils were equal round and reactive, screening examinations should include a thorough eval- and intraocular pressures were soft to palpation. Pupils were uation of retinal vascularization in CdC patients, even in consistently resistant to topical mydriatics, as noted in pre- full-term neonates. vious reports.3 External examination revealed hypertelorism, KEYWORDS: cri-du-chat, retinal hemorrhages, a unilateral preauricular skin tag, epicanthal folds, and avascular retina down-slanting palpebral fissures. Handheld slit-lamp examination was unremarkable. Dilated retinal examination of both eyes revealed an unremarkable posterior pole (Figure 1). However, evaluation of the peripheral retina revealed a

CASE REPORT After the mother underwent an Figure 1. Normal fundus photos of the Right (A) and Left (B) eyes uneventful cesarean delivery, a sin- gleton female infant weighing 7.1 lbs. was born at 39 weeks and 2 days gestational age. She was admitted to the neonatal ICU for episodes of respiratory distress, stridor, desaturations and holding events, requiring NCPAP. Bedside scope revealed mild distal tracheo- malacia and grade I subglottic ste- nosis. Additional exam findings of a large anterior fontanelle, retrog- nathia, low resting heart rate and a meow-like cry prompted genetic analysis which revealed a diagnosis

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small avascular area in the far temporal periphery (zone III DISCUSSION in ICROP nomenclature) bilaterally. Overlying the avas- Cri-du-chat syndrome is a genetic condition resulting from cular retina were 10–12 scattered pinpoint hemorrhages a deletion of variable size occurring on the short arm of (Figure 2). By 44 weeks corrected gestational age, hemor- chromosome 5. The incidence ranges from 1:15,000 to rhages had resolved with persistence of avascular retina in 1:50,000 live-born infants.5 The main clinical features are zone III. Most recent fundus examination at 53 weeks cor- a high-pitched monochromatic cry, microcephaly, broad rected age showed the areas of temporal avascular retina had nasal bridge, epicanthal folds, micrognathia, abnormal der- improved slightly but had not completely resolved. matoglyphics, and severe psychomotor and mental impair- ments.1,2 Approximately 85% of cases Figure 2. Color photos of the far retinal periphery of the Right (A, C, E) and Left (B, D, F) eyes. are the result of a de novo partial Boxes highlight areas of peripheral dot-blot hemorrhages and avascular retina. deletion of the short arm of chromosome 5 with 15% from translocation of 5p. 5p15.3 is the critical region for the monochromatic cry while 5p15.2 is associated with the systemic features.2 Numerous ophthalmic manifestations have been reported in the literature: exotropia, down-slanting palpebral fissures, epicanthal folds, hypertelorism, optic atrophy, retinal dysplasia and tortuous retinal blood vessels.3,4,5 Associations with Peter’s anomaly (5p15.33 deletion and 10q21.1 duplication) and Goldenhar syndrome (oculo-auriculo-vertebral spectrum; 5p14 locus) have also been reported in few reports.6,7,8 This case adds to the scant reports on a possible overlap of 5p15 in cri-du-chat with Goldenhar syndrome. Retinal vascular maturation in full- term infants is typically complete by gestational age 38–40 weeks. To our knowledge, our case is the first reported full-term infant with CdC to have an avascular retina and associated retinal hemorrhages. Although retinal hemorrhages eventually resolved, even by gestational age 53 weeks, persistent areas of avascular retina were present. These findings, along with the previously documented finding of retinal dysplasia by Hope et al,6 suggest that certain genes along the 5p14–15 locus may have a role in proper and timely retinal neurogenesis and angiogenesis. Our review of the genes along this patient’s 5p locus revealed 3 candidates that fit our patient’s external phenotype of Goldenhar-like features and ophthalmoscopic findings of retinal hemorrhages: CTNND2, an adhe- sive junction-associated protein of the

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beta-catenin superfamily, SEMA5A, an axonal membrane Authors protein, and SLC6A18, a specific transporter for neurotrans- Nisarg Chhaya, MD, PGY3, Division of Ophthalmology, Alpert mitters, amino acids, and osmolytes.9,10,11 Interestingly, Medical School of Brown University, Providence, RI. CTNND2 and SEMA5A are also important in appropriate Tineke Chan, MD, Division of Ophthalmology, Alpert Medical ocular development and neurogenesis, respectively.9,10 Given School of Brown University, Providence, RI. these findings and the possible association with CdC, a Disclaimer thorough evaluation of retinal vascularization/neurogenesis The views expressed herein are solely those of the authors. even in full-term neonates with cri-du-chat should be Financial Disclosures performed as part of their comprehensive assessment. None

References Correspondence Nisarg Chhaya, MD 1. Niebuhr E. The cri-du-chat syndrome: epidemiology, cytoge- netics, and clinical features. Hum Genet. 1978;44(3):227-275. Brown University doi:10.1007/BF00394291 1 Hoppin Street, Providence RI, 02908 2. Cerruti Mainardi P. cri-du-chat syndrome. Orphanet J Rare Dis. 617-851-1056 2006;1:33. Published 2006 Sep 5. doi:10.1186/1750-1172-1-33 [email protected] 3. Kitsiou-Tzeli S, Dellagrammaticas HD, Papas CB, Ladas ID, Bartsocas CS. Unusual ocular findings in an infant with cri-du- chat syndrome. J Med Genet. 1983;20(4):304-307. doi:10.1136/ jmg.20.4.304 4. Schechter RJ. Ocular findings in a newborn with cri-du-chat syndrome. Ann Ophthalmol. 1978;10(3):339-344. 5. Clark DI, Howard PJ, Patterson A. Ocular findings in a patient with deletion short arm chromosome 5 (cri-du-chat) and ring chromosome 14. Trans Ophthalmol Soc UK.1986;105 (Pt 6):723- 725. 6. Hope WC, Cordovez JA, Capasso JE, et al. Peters anomaly in cri- du-chat syndrome. J AAPOS. 2015;19(3):277-279. doi:10.1016/j. jaapos.2015.01.018 7. Choong YF, Watts P, Little E, Beck L. Goldenhar and cri-du-chat syndromes: a contiguous gene deletion syndrome? JAAPOS. 2003;7(3):226-227. doi:10.1016/s1091-8531(02)42019-8 8. Ala-Mello S, Siggberg L, Knuutila S, von Koskull H, Taskinen M, Peippo M. Further evidence for a relationship between the 5p15 chromosome region and the oculoauriculovertebral anomaly. Am J Med Genet A. 2008;146A(19):2490-2494. doi:10.1002/ ajmg.a.32479 9. Database, GeneCards Human Gene. “CTNND2 Gene (Protein Coding).” GeneCards, www.genecards.org/cgi-bin/carddisp.pl?- gene=CTNND2. 10. Database, GeneCards Human Gene. “SEMA5A Gene (Protein Coding).” GeneCards, www.genecards.org/cgi-bin/carddisp.pl?- gene=SEMA5A. 11. Database, GeneCards Human Gene. “SLC6A18 Gene (Protein Coding).” GeneCards, www.genecards.org/cgi-bin/carddisp.pl?- gene=SLC6A18.

Acknowledgment Umadevi Tantravahi, PhD, Director, Division of Genetics, Depart- ment of Pathology, Women and Infants’ Hospital, Providence, RI.

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CASE REPORT

Iatrogenic Pneumothorax and Pneumomediastinum in a Patient with COVID-19

Vijairam Selvaraj, MD; Kwame Dapaah-Afriyie, MD

32 33 EN ABSTRACT He denied having chest pain, nausea, vomiting, odynopha- Co-occurrence of pneumothorax and pneumomediasti- gia, dysphagia, palpitations or any recent chest trauma. He num is rare in COVID-19 patients. Positive airway pres- denied any history of tobacco use. His home medications were sure therapy used to improve oxygenation may some- aspirin, atorvastatin, pantoprazole, apixaban and tramadol. times worsen clinical outcomes in some patients with Physical exam on admission revealed bilaterally diminished breath sounds in addition to being tachycardic, severe COVID-19 pneumonia. In this case report, we de- tachypneic and hypoxic. He had elevated inflammatory scribe an individual who was diagnosed with COVID-19 markers including an LDH of 582IU/L (100-220 IU/L), ferri- and developed bilateral pneumothorax and pneumome- tin of 2721ng/ml (22-322 ng/ml), and CRP of 206mg/L (0-10 diastinum after initiating non-invasive positive airway mg/L). D dimer was also elevated at 1,332ng/ml (0-300 ng/ pressure therapy. ml). Respiratory viral panel came back positive for SARS- KEYWORDS: COVID-19, SARS-CoV-2, pneumothorax, CoV-2. X-ray imaging revealed multifocal airspace opacities pneumomediastinum, BiPaP suggestive of COVID-19 pneumonia (Figure 1). CT scan of the chest with contrast revealed diffuse bilateral groundg- lass airspace disease. There was no evidence of pulmonary embolism. He was placed on 10 L /min of oxygen through CASE REPORT high flow nasal cannula. He received Dexamethasone, A 77-year-old male with a past medical history of coronary Remdesivir and was enrolled in a Monoclonal Antibody artery disease, paroxysmal atrial fibrillation on lifelong anti- study. In view of concern for presumed bacterial infec- coagulation, cerebrovascular disease with minimal residual tion, he was also started on ceftriaxone and azithromycin. deficits, and recent hospitalization for knee replacement pre- He was also given bronchodilators, incentive spirometer sented to the hospital for evaluation on account of shortness of breath. He also reported dysgeusia and subjective fever. Figure 2. X-Ray imaging of the chest showing new bilateral left greater than right pneumothoraces, pneumomediastinum with subcutaneous Figure 1. X-Ray imaging of the chest showing multifocal airspace opacities. emphysema extending to the soft tissue of the neck.

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and encouraged to prone as per the institutional protocol. low compliance also make the alveoli more prone to rup- On day 2, his oxygen requirements continued to worsen ture, causing free air to track along pulmonary vessels and and he was placed on 50 L/min of 100% FiO2 through Nep- the interstitium to hilum. Corticosteroids may also play a tune device. His CRP and d dimer increased to 211.97mg/L role in spontaneous pneumothorax by delaying healing and and 5,536/ml. He was started on a therapeutic dose of enox- perpetuating air leakage.8 aparin in place of apixaban. Given concern for concurrent Co-occurrence of pneumothorax and pneumomediasti- pulmonary edema, he received 3 doses of furosemide. He num is rare in COVID-19 patients. Non-invasive positive was started on Bilevel positive airway pressure ventilation airway pressure therapy used to improve oxygenation may (BiPap) with inspiratory IPAP of 10cm H20 and expiratory worsen clinical outcomes in some patients with severe EPAP of 8cm H20 at night-time. On day 3, he started com- COVID-19 pneumonia similar to ventilator-induced lung plaining of acute, severe, bandlike chest pain along with injury. Prompt recognition of early signs and symptoms worsening shortness of breath. Physical exam was signifi- of pneumothorax and pneumomediastinum in COVID-19 cant for crepitus in his neck. He was noted to be saturat- patients is necessary to minimize morbidity and mortality. ing 88% on Bipap. X-ray imaging revealed new bilateral left The use of minimum amounts of positive airway pressure greater than right pneumothoraces, pneumomediastinum ventilation to achieve acceptable tissue oxygenation may with subcutaneous emphysema extending to the soft tissue reduce the incidence of this complication. of the neck (Figure 2). D dimer was noted to be 10, 840ng/ml. Bipap was discontinued and patient was placed back on 60 L/min of 100% FiO2 via high flow nasal cannula (HFNC). References 1. Flower L, Carter J-PL, Rosales Lopez J, et al. Tension pneumo- Surgical service was consulted, and he had thorocostomy thorax in a patient with COVID-19. BMJ Case Rep 2020;13. and bilateral chest tube placement. doi:doi:10.1136/bcr-2020-235861. [Epub ahead of print: 17 May In view of persistent hypoxia despite maximum non- 2020]. pmid:http://www.ncbi.nlm.nih.gov/pubmed/32423911. invasive ventilatory therapy, goals of care conversation 2. Ucpinar BA, Sahin C, Yanc U. Spontaneous pneumothorax and were held with the patient and his family. The patient did subcutaneous emphysema in COVID-19 patient: case report. J In- fect Public Health 2020;13:887–9. doi:10.1016/j.jiph.2020.05.012 not want further escalation of care and was transitioned to pmid:http://www.ncbi.nlm.nih.gov/pubmed/32475804. inpatient hospice in line with his goals of care. He died the 3. Mohan V, Tauseen R. Spontaneous pneumomediastinum in following day. COVID-19. BMJ Case Rep 2020;13: e236519. doi:10.1136/bcr-2020- 236519. pmid: http://www.ncbi.nlm.nih.gov/pubmed/32457032. 4. Zhou C, Gao C, Xie Y, et al. COVID-19 with spontaneous pneumome- DISCUSSION diastinum. Lancet Infect Dis 2020; 20:510. doi:10.1016/S1473-3099 (20)30156-0. pmid: http://www.ncbi.nlm.nih.gov/pubmed/32164830. Pneumothorax, defined as the presence of air in the pleural 5. Lacroix M, Graiess F, Monnier-Cholley L, et al. SARS-CoV-2 space, is a potentially lethal condition, and is associated with pulmonary infection revealed by subcutaneous emphysema increased morbidity and mortality. Pneumothorax can be and pneumomediastinum. Intensive Care Med 2020. doi:- doi:10.1007/s00134-020-06078-3. [Epub ahead of print: 19 May categorized as primary, secondary, spontaneous, traumatic 2020]. pmid: http://www.ncbi.nlm.nih.gov/pubmed/32430514. or iatrogenic in etiology. Development of pneumothorax is 6. Pribble CG, Berg MD. Pneumothorax as a complication of bilev- most closely associated with pre-existing lung conditions el positive airway pressure (BiPAP) ventilation, Clinical Inten- and presence of bullae or pneumatoceles. The risk factors for sive Care. 2000; 11:3, 145-147, DOI: 10.3109/tcic.11.3.145.147 this include smoking, male gender and prolonged coughing. 7. Sihoe ADL, Wong RHL, Lee ATH, et al. Severe Acute Respi- ratory Syndrome Complicated by Spontaneous Pneumothorax. Spontaneous pneumothorax and pneumomediastinum have Chest. 2004;125(6):2345-2351. doi:10.1378/chest.125.6.2345. 1-5 been described previously in COVID-19 patients. 8. Das KM, Lee EY, Jawder SE Al, et al. Acute Middle East Respira- Positive airway pressure therapy has been previously asso- tory Syndrome Coronavirus: Temporal Lung Changes Observed ciated with spontaneous pneumothorax.6 The exact inci- on the Chest Radiographs of 55 Patients. Am J Roentgenol. dence is unknown but has been reported in patients with 2015;205(3):W267-S274. doi:10.2214/AJR.15.14445. 9. Sun R, Liu H, Wang X. Mediastinal Emphysema, Giant Bulla, COPD, cystic fibrosis, neuromuscular diseases, Pneumo- and Pneumothorax Developed during the Course of COVID-19 cystis jiroveci pneumonia, SARS and MERS infections.7,8 Pneumonia. Korean J Radiol. 2020;21(5):541-544. doi:10.3348/ There was one previous report of a COVID-19 patient kjr.2020.0180. with new mediastinal emphysema, bulla, and pneumotho- Authors rax after being started on HFNC. The authors speculated Vijairam Selvaraj, MD, Division of Hospital Medicine, The Miriam that the mediastinal emphysema and pneumothorax were Hospital; Warren Alpert Medical School of Brown University, likely related to COVID-19 pneumonia than HFNC itself.9 Providence, RI. Our patient did not have any pre-existing lung conditions, Kwame Dapaah-Afriyie, MD, Division of Hospital Medicine, The history of tobacco use or presence of bullae or pneumato- Miriam Hospital; Warren Alpert Medical School of Brown celes on lung CT that would have facilitated occurrence of University, Providence, RI. pneumothorax or pneumomediastinum. Correspondence Postulated mechanisms of pneumothorax and pneumo- Vijairam Selvaraj, MD mediastinum in COVID-19 include inflammation leading Division of Hospital Medicine to pneumatocele formation and rupture and also subpleu- The Miriam Hospital, 164 Summit Ave., Providence, RI, 02906 ral necrosis leading to bronchopleural fistulas. Increased 413-271-0421 alveolar pressure and diffuse alveolar injury along with [email protected]

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Childhood Overweight/Obesity and the Physical Activity Environment in Rhode Island

Shelby Flanagan, MPH; Michelle L. Rogers, PhD; Lynn Carlson, MA, GISP; Elissa Jelalian, PhD; Patrick M. Vivier, MD, PhD

42 46 EN ABSTRACT not only for the development of psychosocial consequences, Objective: This study seeks to better understand the sleep disorders, lower educational attainment, and bully- relationship between the physical activity environment ing, but are also at an increased risk for the development of and child overweight/obesity in Rhode Island. multiple chronic diseases such as cardiovascular disease and type II diabetes.5,6 Obesity also carries a financial burden. It Methods: Using geographic information systems (GIS), is estimated that, on average, obese children will experience this study calculated distances from residences to physi- $19,000 more in direct medical costs over the course of their cal activity resources to assess the relationship distance life when compared to children who are not obese.7 has with childhood overweight/obesity. In addition to diet, genetics, family environment, and psy- Results: Mean distances in high-risk towns ranged chological factors, research has shown the important role from 0.61 to 3.15 miles compared to physical activity re- that physical activity environments play in a child’s devel- sources in low-risk towns, where distances ranged from opment of overweight and obesity.8,9 However, a systematic 1.25 to 7.43 miles. For each additional mile to reach the review showed that study results are inconsistent, with closest indoor facility, there is a 0.41 (95% CI: –0.78, some studies showing a relationship between the physical –0.03) percentage point decrease in the child overweight/ activity environment and child overweight and obesity and obesity rate. others not showing a relationship.10 In this study, we exam- Conclusion: High-risk block groups and towns have ined the physical activity environment in Rhode Island with higher rates of child overweight/obesity and show short- the following research questions: (1) Do physical activity er distances to physical activity resources. This study environments vary by neighborhood risk at the town and demonstrates that simply having physical activity struc- block group level? (2) Do Rhode Island towns have differen- tures in place is not enough to reduce child overweight/ tial access to physical activity resources? (3) Is a town’s prox- obesity and further research should examine the quality imity to physical activity resources predictive of the town’s and usage patterns of these resources. level of overweight/obesity in children? KEYWORDS: children, overweight/obesity, physical activity resources METHODS Physical Activity Environment In order to assess the physical activity environment in Rhode Island, we used a number of different resources. To INTRODUCTION understand outdoor physical activity space, we obtained Considered by the Centers for Disease Control and Preven- the 2018 State Comprehensive Outdoor Recreational Plan tion (CDC) to be a serious public health issue, childhood (SCORP) geospatial data from the Rhode Island Department obesity currently affects 18.5% of children in the United of Environmental Management (RIDEM), which included States.1 Children who are racial/ethnic minorities, of lower the geographic locations of all public basketball courts, ten- socioeconomic status, and live in households where the nis courts, fields, pools, ice rinks, skate parks, playgrounds, head of household has low educational attainment are dis- and tracks (https://www.rigis.org/datasets/state-comprehen- proportionately affected by childhood overweight/obesity.2,3 sive-outdoor-recreation-plan-scorp-inventory-of-facilities). In Rhode Island, the prevalence of children who are classified In an attempt to create a more comprehensive picture of as overweight/obese (at or above the 85th percentile of the the physical activity environment, we obtained the loca- CDC sex-specific BMI-for-age growth charts) is 31%; how- tions of afterschool and summer programs with a physical ever, the problem is greater in the core cities of Pawtucket, activity component, which were obtained from the United Woonsocket, Central Falls, and Providence, with more than Way of Rhode Island. We also included Girls on the Run of 43% of children affected.4 Rhode Island meeting locations, which is where girls can Children who are overweight/obese are at an increased risk meet to have structured running activities. These were

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obtained via its website (https://www.gotrri.org/Our- Facility analysis identified the shortest walking route to Locations). In addition, indoor recreational facilities were each physical activity variable for 99% of RI residences. All found via a Google search (facilities included indoor rec- distance calculations were summarized to the block group reational spaces that were not included in SCORP; e.g., and town level and combined with sociodemographic and indoor trampoline parks, pools, ice hockey rinks). All data BMI data. Analyses were completed in Stata 16 and SAS 9.4. not already in a geospatial datafile were then geocoded using Descriptive statistics were calculated for variables included ESRI’s World Geocoder (https://www.esri.com/en-us/arcgis/ in the neighborhood and town risk indices, as well as for the products/world-geocoder-for-arcgis) in ArcGIS 10.7.1 and mean distances to physical activity resources at the block exported to a geodatabase. group and town level. Distances were weighted by the total number of residences in each block group or town. Unad- Demographics justed and adjusted weighted linear regression analyses were For each town and for each block group, a risk index was conducted to assess the association between mean travel constructed using eight highly-correlated measures obtained distance to a physical activity resource in each town and the from the 2014–2018 American Community Survey (ACS): prevalence of child overweight and obesity. % adults without high school education, % single-parent As only aggregate and non-human subject data were households, % household crowding (>1 person per room), utilized, no approval was needed from the Institutional % renter-occupied housing units, % vacant homes (exclud- Review board. ing vacation homes), % families below the federal poverty limit, % non-white, and % housing units built before 1950.11 Quintiles were computed for each of the eight measures RESULTS and summed, resulting in a scale ranging from 8–40, with Demographic characteristics of towns and block groups higher scores indicating greater risk. The risk index was cat- are displayed in Table 1. As expected, the mean percentage egorized into high- (≥75th percentile) and low-risk (<75th of each demographic characteristic which comprises the percentile) towns and block groups, a dichotomization used risk index is greater in high-risk towns and block groups previously.11 While only town-level associations of physical compared to low-risk towns and block groups. activity resources with child overweight/obesity rates can The mean distances from residences to each physical be examined, we felt it was also important to understand the activity resource were significantly shorter in high-risk distance to physical activity resources in the smaller geo- block groups than in low-risk block groups (Table 2). Mean graphic unit of block groups, which can better approximate distances in the high-risk block groups ranged from 0.39 a child’s neighborhood. to 2.70 miles compared to physical activity resources in low-risk towns, where the distances ranged from 1.09 to BMI Town-level overweight/obesity prevalence Table 1. Demographic characteristics of Rhode Island towns and block groups by socio- for children between the ages of 2–17 years economic risk classification was obtained from a published statewide assessment of clinical and billing records.4 Low-Risk High-Risk Low-Risk High-Risk Block Groups Block Groups Towns Towns (N=609) (N=199) (N=29) (N=10) Analysis Demographic We calculated the distance from every characteristics (%) Mean SD Mean SD Mean SD Mean SD residence in the state to the closest phys- Non-White 15.53 15.17 63.82 25.04 8.49 3.55 35.27 23.16 ical activity resource. Locations of each Single-Parent RI residence were obtained as a pre-exist- 10.58 11.19 31.25 15.23 9.05 3.88 19.81 7.24 ing geospatial datafile (http://www.rigis. Households Adults 25+ with No org/datasets/e-911-sites), which includes 8.27 6.73 24.40 11.44 6.57 2.94 16.01 8.89 all known buildings and structures in the High School Education Families below state. We limited the structures to those 4.93 7.46 24.92 15.11 4.23 2.47 13.05 7.80 identified as primary residences, multifam- 100% FPL Renter-Occupied ily, mobile homes, other residential, and 30.05 22.19 70.32 15.62 23.39 9.35 52.26 15.10 seasonal homes. We used ESRI’s Closest Households Facility Network Analyst (NA) tool to cal- Vacant Homes 6.50 6.23 14.88 10.10 5.97 2.03 9.45 3.09 culate the distance from each RI residence to each physical activity variable, using the Household Crowding 0.90 2.22 4.71 5.58 0.85 0.72 2.67 1.93 RIGIS E911 spatial datafile of roads as the Housing Units Built 34.79 24.15 62.12 17.92 24.98 9.00 47.25 16.06 basis for the travel network. The Closest before 1950

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Table 2. Weighted average distances by block group-level Table 3. Weighted average distances by town-level socioeconomic risk socioeconomic risk

Low-Risk High-Risk High-Risk Low-Risk Towns Block Groups Block Groups Towns (N=29) (N=609) (N=199) (N=10) Weighted average Weighted average distance (miles) to: Mean (95% CI) Mean (95% CI) p-value distance (miles) to: Mean (95% CI) Mean (95% CI) p-value Afterschool Afterschool 1.92 (1.75, 2.10) 0.44 (0.41, 0.48) <0.0001 2.38 (1.51, 3.25) 0.81 (0.32, 1.30) 0.0022 programs programs Basketball courts 1.49 (1.38, 1.60) 0.52 (0.48, 0.56) <0.0001 Basketball courts 1.81 (1.31, 2.31) 0.74 (0.52, 0.96) 0.0003 Fields 1.09 (1.02, 1.16) 0.49 (0.46, 0.52) <0.0001 Fields 1.25 (1.03, 1.47) 0.67 (0.37, 0.96) 0.0010 Girls on the Run Girls on the Run 5.90 (5.54, 6.27) 2.70 (2.26, 3.14) <0.0001 7.43 (5.77, 9.09) 2.82 (0.93, 4.71) 0.0004 meeting locations meeting locations Indoor facilities 4.51 (4.15, 4.87) 1.72 (1.38, 2.06) <0.0001 Indoor facilities 4.77 (3.49, 6.05) 3.15 (0.00, 6.88) 0.3758 Playgrounds 1.21 (1.13, 1.30) 0.39 (0.36, 0.42) <0.0001 Playgrounds 1.46 (1.14, 1.77) 0.61 (0.42, 0.80) <0.0001 Summer programs 4.19 (3.96, 4.43) 1.83 (1.54, 2.11) <0.0001 Summer programs 4.59 (3.63, 5.55) 2.82 (0.80, 4.83) 0.1003 Tennis courts 1.68 (1.58, 1,77) 0.91 (0.85, 0.96) <0.0001 Tennis courts 1.97 (1.67, 2,28) 1.02 (0.80, 1.25) <0.0001 Tracks 3.18 (2.98, 3.38) 1.75 (1.63, 1.87) <0.0001 Tracks 3.81 (2.89, 4.73) 1.86 (1.49, 2.24) 0.0003 YMCA/Boys and YMCA/Boys and 3.58 (3.27, 3.89) 0.90 (0.77, 1.03) <0.0001 4.17 (2.77, 5.56) 1.86 (0.00, 4.01) 0.0407 Girls Clubs Girls Clubs

5.90 miles. Playgrounds were the closest physical activity overweight/obesity. Unadjusted models showed that the resource in high-risk block groups (0.39 miles), while fields mean distance to physical activity resources had a signif- were the closest resource in low-risk block groups (1.09 icant inverse relationship with child overweight/obesity miles). Girls on the Run meeting locations were the most rates. However, after adjusting for the town-level risk index, remote resource in both high-risk (2.70 miles) and low-risk only indoor facilities remained statistically significant asso- block groups (5.90 miles). ciated with the town-level rate of child overweight/obesity. For all of the physical activity resources examined, the For each additional mile to reach the closest indoor facil- mean distance was closer to residences in high-risk towns ity, there was a 0.41 (95% CI: –0.78, –0.03) percentage point than in low-risk towns (Table 3); however, the differences decrease in the child overweight/obesity rate. were not statistically significant for indoor facilities and summer programs. Mean dis- Table 4. Unadjusted and adjusted weighted regression models of town-level tances in the high-risk towns ranged from overweight/obesity rates among Rhode Island youth ages 2–17 0.61 to 3.15 miles compared to physical Unadjusted Adjusted* activity resources in low-risk towns where 95% 95% Param Param the distances ranges from 1.25 to 7.43 miles. Distance (in miles) Confidence p-value Confidence p-value Est Est The closest physical activity resources in to: Interval Interval both high- and low-risk towns were play- Afterschool -1.09 (-2.13, -0.05) 0.0399 -0.29 (-1.23, 0.66) 0.5434 grounds (high-risk: 0.61 miles; low-risk: 1.46 programs miles) and fields (high-risk: 0.67 miles; low- Basketball courts -2.60 (-4.26, -0.95) 0.0029 -1.20 (-2.83, 0.43) 0.1450 risk: 1.25 miles). The most remote physical Fields -5.64 (-8.73, -2.56) 0.0007 -2.95 (-6.10, 0.20) 0.0659 activity resources in high-risk towns were Girls on the Run -0.56 (-1.01, -0.11) 0.0158 -0.10 (-0.55, 0.36) 0.6728 indoor facilities (3.15 miles), while Girls on meeting locations the Run meeting locations were the most Indoor facilities -0.57 (-1.03, -0.12) 0.0155 -0.41 (-0.78, -0.03) 0.0333 remote for low-risk towns (7.43 miles). Playgrounds -4.51 (-6.83, -2.18) 0.0004 -2.31 (-4.82, 0.21) 0.0714 Overall, the rate of childhood overweight/ obesity in RI is 31%;3 24% of children liv- Summer programs -0.72 (-1.44, 0.01) 0.0539 -0.28 (-0.91, 0.36) 0.3801 ing in low-risk towns and 35% of children Tennis courts -3.92 (-6.24, -1.61) 0.0015 -1.41 (-4.00, 1.19) 0.2783 living in high-risk towns are classified as Tracks -1.52 (-2.40, -0.64) 0.0013 -0.80 (-1.66, 0.08) 0.0742 overweight or obese. Table 4 shows the YMCA/Boys and -0.65 (-1.21, -0.09) 0.0233 -0.31 (-0.80, 0.18) 0.2017 relationship between the mean distance Girls Clubs from RI residences to each physical activ- *Adjusted for town-level risk index ity resource and the prevalence of child Param Est = parameter estimate

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DISCUSSION prevalence of childhood overweight/obesity. There are a few Physical activity environments were found to vary by neigh- limitations of our study. First, this study did not take into borhood risk at both the town and block group level. The consideration all of the various modes of space which could shortest distance was found for playgrounds and fields at both be used for child play and physical activity. One of the main the town and block group levels, regardless of whether these resources missing from this analysis is resources available to areas had high or low levels of socioeconomic resources. The students within their schools. This limitation could there- most remote physical activity resource for both high- and fore underestimate the physical activity resources that chil- low-risk block groups and towns was Girls on the Run meet- dren have access to. Second, the Closest Network Analyst ing locations and indoor facilities. It is important to keep tool utilized roads as the mode of travel when calculating in mind that previously published studies determine “walk- the distance that would be needed to be traveled in order to able” to be less than half a mile for children8, suggesting that, reach each physical activity resource. Roads were used as on average, most of the resources examined in this study the mode of travel under the assumption that sidewalks are are not easily reached by walking. The distance to physical typically located next to them and would therefore be the activity resources was shorter in high-risk towns and block best estimation of how children may reach each resource. groups than in low-risk towns and block groups showing Under this assumption, the analysis does not take into con- differential access to physical activity resources; however, sideration that children may cross yards or reach physical the mean distances were still not considered “walkable” in activity resources by means that are not sidewalks. Finally, either the high- or low-risk block groups or towns. there were no qualitative assessments completed for any of High-risk block groups and towns in the current study the physical activity structures in this study. While there are characterized by high rates of poverty and higher pro- may be a physical activity structure present, the structure portions of nonwhite individuals. In these areas, we found may not be of great quality, which has been shown to impact residences were in closer proximity to physical activity child utilization.16 resources. Previous research has shown an inconsistent relationship, with some finding increased physical activity resources in neighborhoods with low socioeconomic status12 CONCLUSIONS and in racial minority neighborhoods,13 while others studies This study demonstrates that living in closer proximity to report decreased physical activity resources in lower socio- physical activity structures does not necessarily mean that economic status neighborhoods and racial minority neigh- children are going to utilize them enough to reduce over- borhoods.14 Our study further contributes to inconsistencies weight/obesity. Additional research should examine the within the literature. quality of physical activity environments and resources, as Finally, when investigating the association between the well as actual usage patterns by children living in the com- proximity to physical activity resources and town-level munity. Future studies should also consider assessing crime overweight/obesity rates in children, we found a counter- data as well as traffic patterns due to previous research intuitive relationship, where towns that had higher rates of showing these are both barriers in physical activity among child overweight/obesity also had closer proximity to phys- children.17,18 Furthermore, a database identifying all avail- ical activity resources. This inverse relationship between able physical activity resources should be made available distance to any physical activity resource and child over- to all families to improve knowledge of available physical weight/obesity is consistent with a previous study of the activity resources. built environment (i.e., the man-made structures, features, and facilities where people live) and its relationship with 15 childhood overweight/obesity. These results suggest that References proximity alone to physical activity resources is not a sig- 1. Childhood Obesity Facts. Centers for Disease Control and nificant predictor of child overweight/obesity at the town Prevention. https://www.cdc.gov/obesity/data/childhood.html. Published June 24, 2019. level, after adjusting for the socioeconomic characteristics 2. Ogden CL, Carroll MD, Kit BK, et al. Prevalence of childhood of a town’s population. Further, these results suggest that and adult obesity in the United States, 2011-2012. JAMA. access to physical activity resources is a multidimensional 2014;311:806–814. issue, and factors beyond proximity (e.g. genetics, family 3. Ogden CL, Lamb MM, Carroll MD, Flegal KM. Obesity and So- environment, and nutrition) may play an important role. cioeconomic Status in Children and Adolescents, 2005-2008. NCHS Data Brief No. 51. Hyattsville, MD: National Center for To our knowledge, this is the first proximity analysis con- Health Statistics, 2010. ducted for physical activity resources in the state of Rhode 4. 2020 Rhode Island Kids Count Factbook, Providence, RI: Rhode Island which examines differences in proximity to physical Island KIDS COUNT. http://rikidscount.org/Data-Publications/ RI-Kids-Count-Factbook. activity resources by neighborhood and town-level socioeco- 5. Maffeis C, Tatò L. Long-term effects of childhood obesity on nomic environments. It also examines the town-level rela- morbidity and mortality. Hormone Research in Paediatrics. tionship of proximity to physical activity resources with the 2001;55(Suppl. 1):42-45.

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6. Caird J, Kavanagh J, O’Mara-Eves A, et al. Does being overweight Acknowledgment impede academic attainment? A systematic review. Health Ed- This project was supported by the Hassenfeld Child Health Innova- ucation Journal. 2014;73(5):497-521. tion Institute, Brown University, Providence, RI. 7. Finkelstein EA, Graham WCK, Malhotra R. Lifetime direct medical costs of childhood obesity. Pediatrics. 2014;133(5):854-862. Disclaimer 8. Cerin E, Saelens BE, Sallis JF, Frank LD. Neighborhood Envi- The views in this paper are those of the authors and do not neces- ronment Walkability Scale: validity and development of a short sarily reflect the views of the Hassenfeld Child Health Innovation form. Medicine & Science in Sports & Exercise. 2006;38(9): 1682-1691. Institute. 9. Burdette HL, Whitaker RC. Neighborhood playgrounds, fast food restaurants, and crime: relationships to overweight in low-in- Authors come preschool children. Preventive Medicine. 2004;38(1): Shelby Flanagan, MPH, School of Public Health, Brown University; 57-63. Hassenfeld Child Health Innovation Institute, Brown University, 10. Casey R, Oppert J-M, Weber C, et al. Determinants of childhood Providence, RI. obesity: what can we learn from built environment studies? Michelle L. Rogers, PhD, Hassenfeld Child Health Innovation Food Quality and Preference. 2014;31:164-172. Institute, Brown University; Department of Behavioral and 11. Gjelsvik A, Rogers ML, Garro A, Sullivan A, Koinis-Mitchell D, Social Sciences, School of Public Health, Brown University, McQuaid EL, et al. Neighborhood Risk and Hospital Use for Pe- Providence, RI. diatric Asthma, Rhode Island, 2005–2014. Preventing Chronic Disease. 2019;16:180490. Lynn Carlson, MA, GISP, Hassenfeld Child Health Innovation 12. Wen M, Zhang X, Harris CD, Holt JB, Croft JB. Spatial dispar- Institute, Brown University; Institute at Brown for ities in the distribution of parks and green spaces in the USA. Environment & Society, Brown University, Providence, RI. Annals of Behavioral Medicine. 2013;45(suppl_1):S18-S27. Elissa Jelalian, PhD, Hassenfeld Child Health Innovation Institute, 13. Boone CG, Buckley GL, Grove JM, Sister C. Parks and people: Brown University; Department of Psychiatry and Human An environmental justice inquiry in Baltimore, Maryland. An- Behavior, Warren Alpert Medical School, Brown University, nals of the Association of American Geographers. 2009;99(4): Providence, RI. 767-787. Patrick M. Vivier, MD, PhD, School of Public Health, Brown 14. Moore LV, Roux AVD, Evenson KR, McGinn AP, Brines SJ. University; Hassenfeld Child Health Innovation Institute, Availability of recreational resources in minority and low socioeconomic status areas. American Journal of Preventive Med- Brown University; Department of Health Services, Policy icine. 2008;34(1):16-22. and Practice, School of Public Health, Brown University; 15. Duncan DT, Castro MC, Gortmaker SL, Aldstadt J, Melly SJ, Department of Pediatrics, Warren Alpert Medical School, Bennett GG. Racial differences in the built environment—body Brown University, Providence, RI. mass index relationship? A geospatial analysis of adolescents in urban neighborhoods. International Journal of Health Geo- Disclosure graphics. 2012;11(1):11. There were no financial conflicts of interest to disclose in 16. Lee RE, Booth KM, Reese-Smith JY, Regan G, Howard HH. “The this study. Physical Activity Resource Assessment (Para) Instrument: Eval- uating Features, Amenities and Incivilities of Physical Activity Correspondence Resources in Urban Neighborhoods.” International Journal of Patrick M. Vivier, MD, PhD Behavioral Nutrition and Physical Activity. 2005; 2:13-21. Brown University School of Public Health 17. Kneeshaw-Price SH, et al. “Neighborhood Crime-Related Safety Box G-S121-4 and Its Relation to Children’s Physical Activity.” Journal of Ur- Providence RI, 02912 ban Health. 2015;92(3): 472-489. 401-863-2034 18. Ding D, Sallis JF, Kerr J, Lee S, Rosenberg DE. “Neighborhood Environment and Physical Activity among Youth: A Review.” Fax 401-863-3533 American Journal of Preventive Medicine. 2011; 41(4):442-455. [email protected]

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Lowering A1c Through Integrated Behavioral Health Group Visits

Siddharth Marthi, BA, MD’22; Jamie Handy; Kristin David, PsyD; Martin Kerzer, DO

47 50 EN ABSTRACT Usually, these are offered in addition to a patient’s usual Introduction & Objective: Suboptimal adherence primary care visits, and involve a clinician engaging a to medication and lifestyle modification continues to be cohort of at-risk patients in basic disease and medication a problem in diabetic patients in the US. Previous stud- education and semi-private medical evaluation.2 While the ies have investigated the potential of group educational details of the group visits vary from practice to practice, they visits in improving medication adherence and short-term are almost universally shown to be beneficial to patients. health outcomes, but few have done so using a biopsy- In particular, substantial literature has shown some of the chosocial approach in visits. This study aimed to evalu- benefits to include improving clinician efficiency, reducing ate the effect that group visits, conducted using an inte- health care costs, widening accessibility to quality care, and grated behavioral health model at a primary care practice, increasing patient engagement in their own medical man- had on A1c and distress levels in diabetic adults. agement, which subsequently leads to increased medication adherence and decreased morbidity long-term.3,4 Group vis- Methods: Using the Diabetic Distress Scale (DDS), 15 its for managing diabetes and pre-diabetes have been studied adults were identified as having moderate diabetic dis- as well, and when conducted in addition to usual primary tress (> 3.0) between December 2016 and May 2017 and care follow-up visits, have been shown to decrease A1c lev- invited to attend a group visit in May 2017 to address els, increase medication adherence, and encourage lifestyle identified barriers. Of those, nine attended. The group modification.5-7 Most of these group visits target illnesses visit, conducted by a psychologist, sought to reduce di- with a central focus on basic medical education and medica- abetic distress by targeting behavioral and social factors, tion management tips, with an ancillary focus on behavioral including improving social and familial support, using factors such as nutrition and mood.8 However, the diagnosis diabetes online forums, and improving mind-body con- and management of a chronic illness comes with significant nection. Repeat A1c and DDS measurements for all nine emotional burden that often impedes proper care and med- visit participants were collected three months after. ication adherence. Few previously studied group visits for Results: Group visit participants experienced a decrease chronic illness have been designed with a primary focus on in A1c (p=0.011). All nine participants had a decrease in the biopsychosocial model. their post-intervention DDS. Of the six patients who had In 2017, the team at Associates in Primary Care of Med- positive DDS screens but did not attend, three had in- icine (APCM) in Warwick conducted a pilot study to do so. creased A1c, two had no change, one had a decrease, and APCM has had an integrated behavioral health (IBH) model one did not have a repeat A1c. for several years and employs a psychologist, who is fully inte- Conclusions: Multidisciplinary group visits targeting grated into the providers’ electronic health record, to conduct the biopsychosocial model may be an efficient supple- brief, solution-focused interventions for patients, as needs ment to the individual medical visit to further improve are identified by the medical providers. Group visits focus- control of diabetic distress and short-term morbidity in ing on mindfulness and empowerment for diabetic patients Rhode Island. were led by the in-house psychologist, along with a nurse KEYWORDS: diabetes, group visits, psychosocial, care manager, in order to improve health outcomes, better behavioral health understand and quantify the potential for behavioral health group visits and their impact on quantifiable diabetes measures, and serve as a model for other primary care practices.

INTRODUCTION As chronic illnesses become increasingly prevalent and METHODS taxing to the US healthcare system, group visits have been The Diabetic Distress Scale (DDS) is a questionnaire, first heavily explored as a means of managing various chronic published in 2005, which assesses patients’ distress associ- conditions, including asthma, obesity, and osteoporosis.1 ated with their diabetes and its management in four realms:

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Figure 1. friends, family, and online forums to assist with lifestyle modification and medication adherence. A special empha- DDS: 17-Item Questionnaire Each item is scored on a 1-6 Likert Scale sis was placed on the mind-body connection in diabetes and the link between increasing stress levels, cortisol, and Feeling that diabetes is taking up too much of my mental blood glucose was demonstrated to all participants. The psy- and physical energy every day chologist explored ways in which patients could exercise Feeling that my doctor doesn’t know enough about diabetes healthy assertiveness in order to advocate for themselves and diabetes care and minimize their own stress responses during their day- Feeling angry, scared, and/or depressed when I think about living to-day life. Additionally, cognitive-behavioral therapy (CBT) with diabetes interventions were conducted throughout the visits to nor- Feeling that my doctor doesn’t give me clear enough directions malize patients’ diabetes-related frustrations and improve on how to manage my diabetes perceived control over their illness. A nurse care manager, Feeling that I am not testing my blood sugars frequently enough who was also a certified diabetes educator (CDE), assisted at each session with education regarding topics in healthy Feeling that I am often failing with my diabetes routine eating and medication adherence that were related to the Feeling that friends or family are not supportive enough behavioral issues discussed by the psychologist. At each of self-care efforts visit, relevant handouts and supplementary materials were Feeling that diabetes controls my life created and given to each participant to promote adherence and continued education at home. After participation in Feeling that my doctor doesn’t take my concerns seriously enough multiple sessions, participants were interviewed regarding Not feeling confident in my day-to-day ability to manage diabetes their experiences and feedback. Feeling that I will end up with serious, long-term complications, no matter what I do RESULTS Feeling that I am not sticking closely enough to a good meal plan A1c Eight of the nine (88.9%) group participants experienced a Feeling that friends or family don’t appreciate how difficult living with diabetes can be decrease in A1c at three month follow-up, producing a significant overall decrease in A1c (p = 0.011). Pre- and post- Feeling overwhelmed by the demands of living with diabetes A1c measurements for all nine participants are shown in Feeling that I don’t have a doctor who I can see regularly enough Figure 2. Of the six respondents who did not attend the group about my diabetes visit, three experienced an increased A1c, two experienced Not feeling motivated to keep up my diabetes self management no change in A1c. One patient was lost to follow-up and a repeat A1c was not obtained. A1c levels were measured at Feeling that friends or family don’t give me the emotional support that I would like three-month, six-month, and one-year follow-up in the post- study period for each of the nine initial participants. These emotional burden, physician distress, regimen distress, and results are shown in Figure 3. Of note, some, but not all, of interpersonal distress using a Likert scale.9 The 17-item ques- the nine participants continued to attend group visits that tionnaire was administered to approximately 30 adults with were offered during the post-study period. type two diabetes who visited the clinic between December 2016 and May 2017. A table detailing the contents of the Figure 2. Change in A1c after IBH group visit DDS is shown in Figure 1. Fifteen respondents scored above a 3.0, the threshold for moderate diabetic distress, and were counseled and invited to attend the first group visit. Nine of the fifteen (60%) attended. After the first visit, in May 2017, repeat A1c values were obtained for all fifteen respondents, and repeat DDS scores were obtained for the nine attendees. Four additional visits, referred to as “Diabetes Empower- ment Visits,” were held every other month following data collection. They aimed to help patients understand diabetes distress, review behavioral factors associated with diabetes, understand assertiveness and its role in diabetes management, and explore the mind-body connection. The psychologist worked with groups of patients to identify specific ways to create home environments conducive to diabetic management and construct a circle of support through

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Figure 3. Follow-up A1c levels for nine study participants in reducing emotional distress and improving short-term health outcomes in Rhode Island. These preliminary results showed that both goals were met, demonstrated by the reduction in A1c and DDS levels, supporting the continuation of and further research into this program, both at APCM and across the state. The “Diabetic Empowerment Visits” serve well as an avenue for delivering care using an IBH model. As more primary care practices incorporate IBH and other aspects of the PCMH model, beginning group visits with a focus on the biopsychosocial model may be a feasible first step towards improving provi- sion of high-quality holistic care. Though IBH group visits for diabetic management should be offered in addition to, and not in lieu of, usual diabetes follow-up visits, they have been shown to improve efficiency of subsequent usual visits and greatly increase provider and patient satisfaction in prior studies.2,3 In post-inter- Figure 4. Changes in DDS scores for selected statements vention interviews, one APCM group visit attendee stated that they “always learn something,” and another stated that they gained “the ability to take control of [their] blood sugars.” Though planning and conducting these visits involves considerable investment for the practice, long-term, diabetes group visits have been shown to decrease outpatient visit charges overall.4 Therefore, primary care practices should look to IBH group visits as a potential supplementary program to assist in managing diabetes affecting at-risk populations which they serve. There is a documented positive correlation between high DDS scores and poor glycemic control, measured as increased A1c levels, in type 2 diabetics. This is primarily attributed to patients’ poorer perceived and actual control over their diabetes and poorer medication adherence.10-12 Therefore, while the DDS score was not initially developed with the Diabetic Distress Scores (DDS) intention to act as a proxy for A1c levels, the covariation All nine participants experienced a decrease in DDS scores between DDS and A1c seen in our results is expected. after the first group visit. Of note, for the following state- Our results in Figure 3 begin to evaluate the effectiveness ments on the DDS, all participants reported that distress of the group visits in maintaining improved clinical out- levels decreased substantially: “feeling like diabetes con- comes after the first visit. Group visits focused on diabe- trols my life,” “feeling like I am not sticking closely to a tes have previously been shown to reduce post-intervention meal plan,” “not feeling confident in my day-to-day ability A1c levels for up to two years after cessation of the inter- to manage diabetes,” and “feeling overwhelmed by the vention and return to usual follow-up care.13 Though there demands of living with diabetes.” Average pre- and post-DDS is an apparent and statistically significant reduction in A1c scores for each of these statements are shown in Figure 4. level in our data after the first group visit, because different Repeat DDS values were not obtained for the six respon- subsets of the nine study participants attended each subse- dents who did not participate in the group visit. quent group visit, it is difficult to draw conclusions regarding group visit sustainability using this data alone. For all DISCUSSION participants, the follow-up A1c levels eventually exceeded With the increasing US healthcare burden caused by diabetes the initial post-intervention A1c. However, there was clear and the concurrent rise in support for group visits, this pilot variability in rate and time of A1c increase, and trends could study explored the efficacy of IBH utilization in group visits not be identified.

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By focusing on the components of the DDS which decreased also an efficient way of improving patient and provider sat- most substantially, as shown in Figure 4, we may begin to isfaction. As more primary practices move towards a PCMH determine which aspects of diabetes-related stress are most model of care, this IBH curriculum should serve as a model impacted by the current model of group visits. Of the 17 for other practices. Interventions that target and measure questions included in the DDS, the four statements with a the interaction between psychology and functional health statistically significant decrease in value fall into the subcat- outcomes in diabetes have been underutilized, and further egories of “emotional burden” and “regimen distress.” This study into their impact is warranted. would suggest that the intervention impacted these subcat- egories more than “physician distress” and “interpersonal References distress,” but a larger sample size and study length would be 1. Jaber R, Braksmajer A, Trilling J. Group Visits for Chronic Ill- necessary to more accurately stratify the effects of the group ness Care: Models, Benefits and Challenges. Fam Pract Manag. visits before recommending targeted modifications. 2006 Jan;13(1):37-40. 2. Housden L, Wong ST, Dawes M. Effectiveness of group medical visits for improving diabetes care: a systematic review and me- Limitations ta-analysis. Can Med Assoc J. 2013; 185: E635–44. This pilot study involves a small sample, and due to the 3. Strategy 6M: Group Visits. Content last reviewed March 2020. COVID-19 pandemic, group visits at APCM were tempo- Agency for Healthcare Research and Quality, Rockville, MD. rarily suspended, impeding the collection of further data. 4. Clancy DE, Dismuke CE, Magruder KM, Simpson KN, Bradford D. Do diabetes group visits lead to lower medical care charges?. Group visits are not currently ongoing in a virtual setting, Am J Manag Care. 2008; 14(1): 39-44. but the practice hopes to reinstate group visits in 2021, at 5. Trento M, Passera P, Tomalino M, et al. Group Visits Improve which point more routinely collected data will be analyzed Metabolic Control in Type 2 Diabetes. Diabetes Care. 2001; 24: to evaluate IBH group visit effectiveness using a longer study 995-1000. 6. Davis AM, Sawyer DR, Vinci LM. The Potential of Group Visits period and additional metrics, including PHQ-9 scores, in Diabetes Care. Clinical Diabetes. 2008 Apr; 26(2): 58-62 GAD-7 scores, morbidity, and cause-specific mortality. 7. Clancy DE, Huang P, Okonofua E, et al. Group Visits: Promoting This study focused primarily on the evaluation of the Adherence to Diabetes Guidelines. J Gen Intern Med. 2007 May; initial group visit in May 2017. While additional Diabetic 22(5): 620–624. Empowerment Visits occurred after, not all of the nine ini- 8. University of Colorado. (2010). Diabetes Group Visits. Denver, CO: Lobo I, Keech T. tial attendees returned for each subsequent visit, making 9. Polonsky WH, Fisher L, Earles J, et al. Assessing psychosocial evaluation of sustainability and the long-term A1c values in distress in diabetes: development of the diabetes distress scale. Figure 3 difficult, especially with a small sample size. Fur- Diabetes Care. 2005; 28(3): 626-631. ther, like other studies examining group visit impact, this 10. Fisher L, Glasgow RE, Strycker LA. The Relationship Between 2 Diabetes Distress and Clinical Depression With Glycemic Con- study is subject to selection bias, as the nine patients who trol Among Patients With Type 2 Diabetes. Diabetes Care. May attended the first group visit were likely to be more com- 2010; 33(5): 1034-1036. mitted to reducing their A1c levels than the six who did not. 11. Islam MR, Karim MR, Habib SH, Yesmin K. Diabetes distress Wider use of group visits for chronic illness is needed in order among type 2 diabetic patients. Int J Med Biomed Res. 2013; 2(2): 113-124. to increase the sample size of future studies and reduce loss 12. Gonzalez JS, Shreck E, Psaros C, Safren SA. Distress and type to follow up within the study population, thereby improv- 2 diabetes-treatment adherence: A mediating role for perceived ing result validity and allowing for evaluation of sustain- control. Health Psychol. 2015; 34(5): 505-513. ability. Several variables relating to the group visits should 13. Leung AK, Buckley K, Kurtz J. Sustainability of Clinical Benefits Gained During a Multidisciplinary Diabetes Shared Medical Ap- be considered in these future studies, including frequency pointment After Patients Return to Usual Care. Clin Diabetes. of visits, length of study period, length of follow-up period, 2018; 36(3): 226-231. and format of group visit. Further, if future studies aim to Authors assess sustainability when using small sample sizes, it will Siddharth Marthi, BA, MD’22, Department of Medicine, Warren be crucial to better define patient characteristics that may Alpert Medical School of Brown University. affect diabetes-related morbidity, mortality, and adherence Jamie Handy, CharterCARE Medical Associates. to treatment regimens, including demographic data, co- Kristin David, PsyD, CharterCARE Medical Associates. morbidities, and pre-intervention behavioral factors. Martin Kerzer, DO, Department of Family Medicine, Warren Alpert Medical School of Brown University; CharterCARE Medical Associates. CONCLUSIONS Correspondence IBH group visits for diabetic patients, which focus primarily Siddharth Marthi on addressing emotional distress and mindfulness, may be 222 Richmond St. an effective way to improve short-term diabetic outcomes Providence, RI 02906 and stress associated with diabetes. When conducted along- 862-252-0102 side traditional individualized visits, these group visits are [email protected]

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Treatment Retention in Older Versus Younger Adults with Opioid Use Disorder: A Retrospective Cohort Analysis from a Large Single Center Treatment Program

Alyssa Greenwood Francis, MPH; Julie Croll, MPH; Himanshu Vaishnav, MS; 51 Kirsten Langdon, PhD; Francesca L. Beaudoin, MD, PhD 54 EN ABSTRACT size of the baby boomer cohort, i.e. those born between 2 Objective: To compare treatment retention in a Med- 1946–1964, and their higher prevalence of substance use. In ication for Opioid Use Disorder program between older addition to having a substance use disorder, older adults with and younger adults with opioid use disorder. OUD are more likely than their younger counterparts to be diagnosed with medical and psychiatric comorbidities.3,4 Methods: This retrospective cohort study was conduct- Over 60% of older adults with OUD are expected to be diag- ed from 2015 to 2018 at an urban academic hospital’s opi- nosed with chronic pain, presenting a paradoxical challenge oid and drug treatment center. Participants were adults, for patients seeking recovery.5 This is further complicated 18 and older, diagnosed with Opioid Type Dependence. by a patient’s increased age and rise in comorbidities, due to Older adults were defined as age 50 and older. Poisson the pathologic changes associated with aging and long-term and logistic regression analyses examined whether older medication use – especially within the context of opioids. age was associated with treatment retention. Over the last 15 years, there has been a considerable rise Results: Overall, 288 individual charts were reviewed; in primary heroin-use related hospital admissions for older 123 were aged 18-49, and 78 were aged 50 and older. Old- adults, as well as admissions seeking treatment for OUD.6 er adults were more likely to stay in treatment for six However, a recent systematic review concluded that little months or longer (OR=1.73, [1.02, 2.96], P-value = 0.04] is known about treatment outcomes in older adults.7 Addi- and have a higher number of treatment visits overall tional work is needed to investigate differences in treatment (RR=1.06, [0.98, 1.16] (P-value=0.16). retention for older and younger adults to determine how best Conclusions: Older adults are more likely than to retain these patients in life-saving treatment programs, as younger adults to be retained in long-term treatment in a untreated substance use disorders may worsen medical and Medication for Opioid Use Disorder program. psychiatric comorbidities.3 KEYWORDS: opioid use disorder, buprenorphine, older This study examines the relationship between older adults, comorbidity, chronic pain age and MOUD treatment retention in adults with OUD, attending a large treatment program affiliated with an academic medical center. We also sought to compare characteristics of younger versus older adults in treatment.

INTRODUCTION Medication for Opioid Use Disorder (MOUD), which METHODS includes Methadone, Buprenorphine-Naloxone, and Inject- This retrospective cohort study was conducted among par- able Naltrexone, is the standard of care for adults with ticipants attending an outpatient treatment center over a Opioid Use Disorder (OUD) in the United States.1 MOUD three-year period from May 1, 2015 to May 1, 2018. The treat- is associated with fewer emergency room visits, hospi- ment center was affiliated with an urban academic medical talizations for opioid-related care, and overdoses; over- center that provides MOUD, specifically buprenorphine- all it reduces opioid-related morbidity and mortality, and naltrexone, behavioral therapy, and social services. De-iden- improves the patient’s quality of life.1 Unfortunately, there tified data was extracted from electronic health records is a gap between MOUD use and older adult populations. For (EHR) and included patients over the age of 18 who were older adults with OUD, less than 10% use medication-based diagnosed with Opioid Type Dependence (ICD 9: 304.00; ICD treatment.2but mostly silent, epidemic among older adults. 10: F11.20). Although there is no standard definition of an We sought to analyze the trends in admissions for substance older adult, we defined this population as someone aged 50 abuse treatment among older adults (aged 55 and older years or older in accordance with prior studies.7,8 The study Although MOUD remains underutilized by older adults was approved by the hospital’s institutional review board. with OUD, there is an increasing number of older adults Descriptive and inferential statistics were performed using seeking treatment. This is believed to be largely due to the RStudio version 1.0.136 statistical software (RStudio, Inc.,

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Boston, MA). Bi-variate assessment of sociodemographic retained in treatment for six months or longer compared to variables, median visit length, duration of treatment, and younger adults (P-value=0.05). Older adults were diagnosed average number and type of comorbid conditions were per- with more medical comorbidities (P-value<0.001), while formed to assess the relation amongst older and younger younger adults were diagnosed with more behavioral health adults. To compare characteristics, P-values were calculated conditions (P-value=0.005). A greater, but non-significant, using either Chi-Square or Kruskal-Wallis test by ranks proportion of older adults were diagnosed with chronic depending on the form of data. Unadjusted and adjusted pain (P-value=0.12). There were no significant differences Poisson and logistic regressions were used to assess the rela- between age groups for having a history of alcohol or can- tionship between older age and MOUD retention, defined as nabis use disorder, but younger adults were more likely to attending a greater number of treatment visits or being in have a history of cocaine, amphetamine, or benzodiazepine treatment for six months or longer. use disorder (P-value<0.001).

Number of Treatment Visits RESULTS Although age was not statistically significantly, the unad- Overall, the study sample identified as male (49.0%), white justed Poisson rate ratio for age was 1.06 [0.98, 1.16]; that (81.6%), and non-Hispanic/Latino (91.0%). Amongst older is, among the study population, adults aged 50 years or over adults, the age ranged between 50–77 years, with an aver- had 6% more MOUD treatment visits during the study age age of 58.7. The median number of treatment visits was period compared to those under the age of 50 (Table 1). 6.5 and the median duration of treatment was 79.5 days. When adjusting for gender, race, and comorbidities, the In those aged 50 or older, there was a higher median num- adjusted rate ratio was 1.03 [0.94, 1.13] (P-value = 0.49). In ber of visits (7) and a longer treatment duration (113 days) the adjusted Poisson model, female (RR=0.86 [0.80, 0.94]), compared to younger adults – 6 visits and 63 days, respec- Black or African American (RR=0.93 [0.89, 0.97]), non-His- tively. Older adults were significantly more likely to be panic/Latino (RR=1.27 [1.19, 1.35]), chronic pain (RR=0.72

Table 1. Unadjusted and Adjusted Rate Ratios of MOUD Treatment Visits and Odds Ratios of Long-term Retention in MOUD Treatment

Unadjusted RR P-Value Adjusted RR P-Value Unadjusted OR P-Value Adjusted OR P-Value [95% CI] [95% CI] [95% CI] [95% CI] Age ≥ 50 years old 1.06 0.16 1.03 0.49 1.73 0.04* 1.51 0.19 [0.98, 1.16] [0.94, 1.13] [1.01, 2.96] [0.82, 2.79] Female 0.86 <0.001*** 0.86 <0.001*** 0.90 0.67 0.91 0.75 [0.79, 0.93] [0.80, 0.94] [0.55, 1.47] [0.52, 1.60] Black or African 0.96 0.08 0.93 0.002** 0.87 0.35 0.75 0.09 American [0.91, 1.0] [0.89, 0.97] [0.63, 1.16] [0.53, 1.04] Not Hispanic or Latino 1.28 <0.001*** 1.27 <0.001*** 2.17 < 2.11 0.003** [1.2, 1.36] [1.19, 1.35] [1.41, 3.46] 0.001*** [1.3, 3.57] Comorbid Medical 0.78 0.001** 0.88 0.85 0.24 0.01* 0.53 0.30 Diagnosisa [0.67, 0.90] [0.86, 0.91] [0.07, 0.66] [0.14, 1.64] Chronic Pain 0.65 <0.001*** 0.72 <0.001*** 0.31 0.005** 0.43 0.07 [0.57, 0.73] [0.63, 0.82] [0.13, 0.67] [0.17, 1.03] Comorbid Behavioral 0.75 <0.001*** 0.83 <0.001*** 0.24 <0.001*** 0.34 0.003** Health Diagnosisb [0.69, 0.82] [0.75, 0.92] [0.13, 0.43] [0.17, 0.68] History of Comorbid Substance Use Disorder Diagnosis Alcohol Use Disorder 0.75 <0.001*** 0.84 0.03* 0.25 0.01* 0.53 0.31 [0.65, 0.86] [0.72, 0.98] [0.07, 0.68] [0.14, 1.64] Cannabis Use Disorder 0.40 <0.001*** 1.38 0.01* 0.0 0.98 0.0 0.99 [0.22, 0.64] [1.07, 1.79] [0.0, 0.0] [0.0, 0.0] Other Substance Use 0.77 <0.001*** 0.67 0.001** 0.22 <0.001*** 0.35 0.01* Disordersc [0.69, 0.85] [0.52, 0.85] [0.10, 0.45] [0.15, 0.78] a. “Comorbid Medical Diagnoses” includes Hepatitis C Virus, Chronic Heart Failure, Chronic Kidney Disease, Chronic Pulmonary Disease, and Diabetes. b. “Comorbid Behavioral Health Diagnoses” includes Depression, Anxiety, Bipolar Disorder, Post-Traumatic Stress Disorder, and Schizophrenia. c. “Other Substance Use Disorders” includes Cocaine Use Disorder, Amphetamine Use Disorder, Benzodiazepine Use Disorder. d. *P-value <0.05 e. **P-value <0.01 f. ***P-value <0.001

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[0.63, 0.82]), behavioral health comorbidities (RR=0.83 [0.75, treated with opioid analgesics.5 Older adults in our cohort 0.92]), alcohol use disorder (RR=0.84 [0.72, 0.98], cannabis were more likely to be diagnosed with chronic pain com- use disorder (RR=1.38, [1.07, 1.79]), and other substance pared to younger adults, but not significantly. This may be a use disorders (RR=0.67 [0.52, 0.85]) were all significant result of underdiagnosing older adults with chronic pain or predictors of the number of treatment visits. indicates that our treatment center sees a large number of younger adults with chronic pain conditions. Six-month Treatment Retention Older adults face several barriers to accessing substance Looking at long-term treatment retention, older adults are use treatment, including stigma, limited number of treat- 1.73 ([1.01, 2.96], P-value=0.04) times more likely to stay ment providers, comorbid medical conditions, and private in MOUD treatment six months or longer compared to treatment programs not accepting Medicare.10 Nationally, younger adults per the unadjusted logistic regression model there are multi-disciplinary treatment programs for older (Table 1). In the multivariate model, age is not statistically adults that combine care for medical comorbidities with significant, but non-Hispanic/Latino (OR=2.11 [1.3,3.57]), MOUD in order to address these barriers.11 In Rhode Island, behavioral health comorbidities (OR=0.34 [0.17, 0.68], and the University of Rhode Island’s Geriatric Education Cen- other substance use disorders (OR=0.35 [0.15, 0.78]) are ter provides an online educational seminar for recognizing significantly associated with long-term treatment retention. and managing opioid use disorder in older adults, but to our knowledge there are no dedicated treatment programs for older adults.12 Future work might explore the effectiveness DISCUSSION of dedicated programs for older adults. Since untreated substance use disorders can worsen progno- Several limitations should be noted within the context of sis of comorbidities, and older adults are more likely to have this research. The sample population is solely representative comorbid diagnoses, it is important to retain patients with of MOUD patients from a single urban healthcare facility, OUD in MOUD treatment to prevent further morbidity and with the majority identifying as non-Hispanic, Caucasian mortality. This study investigated the relationship between males under the age of 50. As many older adults with mul- older age and MOUD treatment retention, using two defi- timorbidity may be managed by a variety of long-term care nitions for treatment retention. Older age was significantly physicians, this research may be missing a key subset of associated with retention in MOUD treatment for greater the population. Additionally, all records were obtained via than six months, but not significantly associated with a EHR of one treatment center. This limits the data by lack- higher number of treatment visits overall. Consistent pre- ing study participant self-report, and missing information dictors across both measurements of retention were ethnic from other treatment centers used per person. Additionally, group, behavioral health comorbid diagnoses, and history study participants received MOUD treatment solely with of cocaine, amphetamine or benzodiazepine use disorder. buprenorphine-naltrexone. Different treatment outcomes These findings align with current literature showing older may be observed in patients receiving alternative therapies. patients have better OUD-related treatment outcomes than their younger counterparts.7,9 One of the main concerns with treating older adults CONCLUSIONS through MOUD programs is pre-existing comorbid diagno- In this single center study, age was associated with long- ses, as the number of comorbidities and subsequent rate of term treatment retention, meaning older adults were likely mortality typically increases with age.7 However, younger to remain in lifesaving MOUD programs once they enroll. In adults in this cohort shared a greater burden of comorbid order to reduce possible mortality from an untreated OUD, conditions compared to older adults, and were more likely older adults should continue to be recruited at a comparable to be diagnosed with a behavioral health or substance use rate to the younger adult population. This study prompts disorder. Younger patients with more medical, behavioral the need to increase engagement of older adults, as it health, and substance use comorbidities were less likely to appears that they are as likely as younger adults to remain in be retained in MOUD treatment, which may indicate that long-term MOUD treatment. younger patients with more comorbidities are less adherent or need less treatment visits to complete a MOUD program. It may also indicate that younger patients with MOUD feel References they are managed appropriately by their primary care phy- 1. Wakeman SE, Larochelle MR, Ameli O, et al. Comparative Ef- sician or other specialist, or older adults with behavioral fectiveness of Different Treatment Pathways for Opioid Use health and substance use conditions are underdiagnosed. Disorder. JAMA Netw Open. 2020;3(2):e1920622. doi:10.1001/ jamanetworkopen.2019.20622 Another issue for MOUD programs is accommodating 2. Chhatre S, Cook R, Mallik E, Jayadevappa R. Trends in sub- therapy regimens for patients with comorbid OUD and stance use admissions among older adults. BMC Health Serv chronic pain, as many pain diagnoses have been historically Res. 2017;17(1):584. doi:10.1186/s12913-017-2538-z

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3. Joshi P, Shah NK, Kirane HD. Medication-Assisted Treatment Authors for Opioid Use Disorder in Older Adults: An Emerging Role for Alyssa Greenwood Francis, MPH, School of Public Health, Brown the Geriatric Psychiatrist. The American Journal of Geriatric University, Providence, RI. Psychiatry. 2019;27(4):455-457. doi:10.1016/j.jagp.2018.12.026 4. Larney S, Bohnert ASB, Ganoczy D, et al. Mortality among Julie Croll, MPH, Department of Emergency Medicine, Alpert older adults with opioid use disorders in the Veteran’s Health Medical School of Brown University, Providence, RI. Administration, 2000–2011. Drug and Alcohol Dependence. Himanshu Vaishnav, MS, Department of Emergency Medicine, 2015;147:32-37. doi:10.1016/j.drugalcdep.2014.12.019 Alpert Medical School of Brown University, Providence, RI. 5. Hser Y-I, Mooney LJ, Saxon AJ, Miotto K, Bell DS, Huang D. Kirsten Langdon, PhD, Department of Psychiatry, Rhode Island Chronic pain among patients with opioid use disorder: Results Hospital; Department of Psychiatry and Human Behavior, from electronic health records data. Journal of Substance Abuse Alpert Medical School of Brown University, Providence, RI. Treatment. 2017;77:26-30. doi:10.1016/j.jsat.2017.03.006 6. Huhn AS, Strain EC, Tompkins DA, Dunn KE. A hidden as- Francesca L. Beaudoin, MD, PhD, Department of Emergency pect of the U.S. opioid crisis: Rise in first-time treatment ad- Medicine, Alpert Medical School of Brown University; missions for older adults with opioid use disorder. Drug and Department of Health Services, Policy, and Practice, School of Alcohol Dependence. 2018;193:142-147. doi:10.1016/j.drugalc- Public Health, Brown University, Providence, RI. dep.2018.10.002 7. Carew AM, Comiskey C. Treatment for opioid use and out- Correspondence comes in older adults: a systematic literature review. Drug and Alyssa K. Greenwood Francis, MPH Alcohol Dependence. 2018;182:48-57. doi:10.1016/j.drugalc- Department of Health Services, Policy and Practice dep.2017.10.007 Brown University School of Public Health 8. Beaudoin FL, Merchant RC, Clark MA. Prevalence and Detec- 121 South Main Street tion of Prescription Opioid Misuse and Prescription Opioid Use Disorder Among Emergency Department Patients 50 Years of Providence, RI 02912 Age and Older: Performance of the Prescription Drug Use Ques- [email protected] tionnaire, Patient Version. The American Journal of Geriatric Psychiatry. 2016;24(8):627-636. doi:10.1016/j.jagp.2016.03.010 9. Mintz CM, Presnall NJ, Sahrmann JM, et al. Age disparities in six-month treatment retention for opioid use disorder. Drug and Alcohol Dependence. 2020;213:108130. doi:10.1016/j.drugalcdep.2020.108130 10. Madras B, Ahmad N, Wen J, Sharfstein J, Prevention, Treatment, and Recovery Working Group of the Action Collaborative on Countering the U.S. Opioid Epidemic. Improving Access to Evi- dence-Based Medical Treatment for Opioid Use Disorder: Strat- egies to Address Key Barriers Within the Treatment System. April 2020. doi:10.31478/202004b 11. Substance Abuse and Mental Health Services Administration. Substance Use Treatment for Older Adults.; 2020. https://www. samhsa.gov/homelessness-programs-resources/hpr-resources/ substance-use-treatment-older-adults. Accessed November 20, 2020. 12. Rhode Island Geriatric Education Center. Opioid Use and the Older Adult. University of Rhode Island; 2020. https://web.uri. edu/rigec/opi/. Accessed November 20, 2020.

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COVID-19 in Pediatric Patients: Observations from the Initial Phase of the Global Pandemic in Rhode Island

REBECCA A. LEVIN, MD; HOI SEE TSAO, MD; SIRAJ AMANULLAH, MD, MPH; ALICIA GENISCA, MD; LAURA CHAPMAN, MD

55 60 EN ABSTRACT cares for the majority of inpatient pediatric patients in the OBJECTIVE: To describe characteristics of children un- state, we aimed to assess how demographic characteristics dergoing SARS-CoV-2 testing during the initial wave of and clinical symptoms differed among SARS-CoV-2-positive infections in Rhode Island. and negative children in Rhode Island during the initial peak of the pandemic.5 METHODS: This is a descriptive study of 729 children tested for SARS-CoV-2 at four emergency departments April 9 to May 7, 2020 in Rhode Island. Demographic in- METHODS formation and symptoms were cataloged for those tested. A retrospective chart review of ED encounters for patients RESULTS: 81 (11%) children tested positive for SARS- less than or equal to 21-years-old who received a SARS-CoV-2 CoV-2. 94% of positive children were symptomatic. test between April 9 and May 7, 2020 was performed. These 74% of positive cases had constitutional symptoms and patients presented to one of four EDs that are part of an inte- 72% had upper respiratory symptoms. While only 34% grated statewide health system including a level one pedi- of those tested were Hispanic, 68% of the SARS-CoV-2- atric trauma center at a tertiary care children’s hospital, an positive cases occurred in Hispanic children. adult level one trauma center and two community EDs. This CONCLUSION: This study details the pediatric popula- healthcare network cares for over 90% of inpatient pediatric tion’s experience during the first wave of the pandemic patients in Rhode Island.5 The study timeframe included the in Rhode Island. It could inform testing allocation strat- two-week period preceding and following the peak in SARS- 1 egies in healthcare settings. It also highlights vulnerable CoV-2 cases on April 23, 2020 in Rhode Island. Given the populations in need of further public health support in limited data regarding SARS-CoV-2 reinfection rates and the our state. difficulty in distinguishing symptoms from a new infection compared to residual symptoms from a prior infection, our KEYWORDS: pediatric, COVID-19, SARS-CoV-2, public study only included the first ED visit during the study time- health, symptoms frame for patients who had repeat visits. Institutional review board approval was obtained. Data was recorded with a standardized REDCap data collection form.6 Patient data collected included patient INTRODUCTION age, sex, preferred language, ethnicity, race, SARS-CoV-2 During the initial wave of the SARS-CoV-2 pandemic in test results, presenting symptoms, pulmonary examina- Rhode Island, the peak of new cases was on April 23, 2020 tion abnormalities, contact with a confirmed SARS-CoV-2 with 419 new SARS-CoV-2-positive cases, or approximately positive person, concurrent medical diagnoses, concurrent 40 cases per 100,000.1 A total of 2953 daily tests were respiratory pathogen infections and disposition from the performed on April 23, 2020 and 13.4% were positive.2 ED (discharge to home, group home, psychiatric hospital or We aimed to provide a thorough depiction of the pediat- admission to a hospital unit). Patients 21 years and younger ric population undergoing SARS-CoV-2 testing in Rhode were included, as pediatric EDs commonly treat patients up Island during the initial peak of the pandemic. Rhode Island to 21 years of age if the patient has not yet transitioned their had relatively broad testing capability of both symptomatic medical care to an adult provider. and asymptomatic patients during this time, enabling us to Patients with pre-existing medical or psychiatric condi- perform a thorough assessment of symptomatology among tions were defined as having a positive past medical history. SARS-CoV-2-positive and negative children.3 Research sug- Patients who had a medical diagnosis that did not consist of gests that children with SARS-CoV-2 infection generally an unspecified viral syndrome or COVID-19 were defined as experience mild disease courses or are asymptomatic.4 having a positive concurrent medical diagnosis. Consistent Initially, pediatric COVID-19 testing in Rhode Island with prior studies, an abnormal pulmonary examination predominantly occurred in the emergency department (ED) included any auscultatory abnormalities such as rhonchi, setting. Using ED data from the healthcare network that crackles/rales or wheeze.7

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17 presenting symptoms were grouped into four catego- RESULTS ries: constitutional (fever of 38 degrees Celsius or higher, Of the 1,979 ED visits during the study period (eligible sam- subjective fever, chills or body aches), upper respiratory ple), a SARS-CoV-2 test was sent for 759 patients. 30 repeat (sore throat, congestion/runny nose, cough or shortness of patient visits (0.04% of SARS-CoV-2-tested patients) were breath), gastrointestinal (abdominal pain, nausea/vomiting excluded to form the final analytic sample of 729 patients or diarrhea) and other symptoms (headache, loss of smell, (Figure 1). Of the 729 children tested for SARS-CoV-2, 81 loss of taste, seizure, chest pain or rash). This symptom list (11%) tested positive. 546 of the 729 (75%) patients were was developed from COVID-19 symptoms described at the classified as having symptoms at the time of testing. 14% time of study in recent adult and pediatric literature as well of symptomatic patients tested positive while only 3% of as those delineated by the Centers for Disease Control and asymptomatic patients were positive. 94% of SARS-CoV-2 Prevention (CDC).7,8 Some patients had multiple symptoms cases occurred in symptomatic patients. in the same or different categories. Asymptomatic patients were defined as those without any of these symptoms. Figure 1. Flowchart of Study Participants Patients who had symptoms suspicious for COVID-19, required hospital admission, or were to be transferred to group home settings or psychiatric facilities were tested for SARS-CoV-2 in the EDs included in this report.3 SARS-CoV-2 testing consisted of a reverse-transcription polymerase chain reaction (RT-PCR) run on patient nasopharyngeal swabs. Four RT-PCR Sars-CoV-2 tests were utilized with the following published limits of detection: GenMark Dx ePlex (1x105 copies/mL),9 Cepheid Infinity/ Genexpert (0.0100 plaque forming units/mL),10 BD Max Sys- tem (40 genome equivalents/mL)11 and Roche Diagnostics

Cobas 6800 (0.007 TCID50/mL – TCID50 is the median tissue culture infectious dose).12 A subset of patients had a respiratory pathogen panel nasopharyngeal swab (RPP) and Group A Streptococcus pharyngeal swab performed. The RPP tested for adenovi- rus, coronavirus (types 229E, HKU1, NL63, OC43), human metapneumovirus, influenza A and B, rhinovirus/enterovi- rus, parainfluenza virus 1 to 4, respiratory syncytial virus A and B, Bordetella pertussis, Chlamydia pneumoniae and Mycoplasma pneumoniae. The Group A Streptococcus phar- Of those who tested positive for SARS-CoV-2, there was yngitis test was performed using a posterior oropharyngeal an unequal distribution between age groups, with the most swab by rapid bedside testing (Sekisui Diagnostics 141 Osom® positive tests occurring among the less than one-year-old Strep A test)13 or RT-PCR if the rapid test was negative. (22%) and 18- to 21-year-old (33%) groups (Table 1). 15% Two researchers completed the standardized chart review. of those tested were less than one-year-old and 22% were Five percent of charts were reviewed by both researchers. 18- to 21-years-old. There was no statistically significant The kappa statistic and percent agreement score for man- difference between males and females in the SARS-CoV-2- ually abstracted data were 0.92 and 98%, respectively. Sta- positive and negative groups. There were substantial racial tistical analyses were performed using STATA/SE version and ethnic differences among SARS-CoV-2-tested patients. 16.0.14 χ2-squared tests and Fisher’s exact tests were used for Among Hispanic patients, one in five tested positive for categorical variables. The Mann-Whitney U test was used SARS-CoV-2. In contrast, one in 20 non-Hispanic patients for comparing median values for the age variable. Logistic tested positive. A greater percentage of positive patients pre- regression was performed to better understand how various ferred Spanish as their primary language (42%) compared to factors may have been related to a SARS-CoV-2 positive test SARS-CoV-2-negative patients (13%). and controlled for presenting symptoms, age and race/eth- The number of patients presenting with each of the indi- nicity. These controls were based on covariates previously vidual 17 symptoms in both groups is outlined in Figure 2 and reported to impact SARS-CoV-2 positivity or complication consolidated into symptom categories in Figure 3. Among rates including age, preferred language and race/ethnicity.7,15 SARS-CoV-2-positive patients, 94% of patients had at least As preferred language was found to be highly correlated one symptom, 74% had a constitutional symptom and 72% with race/ethnicity, it was not included in the final had an upper respiratory symptom. In comparison, among adjusted model. SARS-CoV-2 negative patients, there was a lower prevalence

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Table 1. Demographics of the Study Population of patients with at least one symptom (73%), constitutional symptoms (34%), or upper respiratory Characteristics Total SARS-CoV-2 SARS-CoV-2 P value Tested Negative Positive symptoms (32%). There was no significant differ- (n=729) (n=648) (n=81) ence in gastrointestinal symptoms between the two Age, median (IQR) 13 (2-17) 13 (2-17) 10 (1-19) 0.14 groups. 56% of SARS-CoV-2-positive patients had a known SARS-CoV-2-positive contact compared to Age Group in Years, n (%) only six percent of negative patients. <1 107 (15) 89 (14) 18 (22) 0.001 There was a broad array of concurrent medical 1–5 117 (16) 107 (17) 10 (12) diagnoses among SARS-CoV-2-positive patients. 6–11 113 (16) 98 (15) 15 (19) These included but were not limited to seizures 12–17 232 (32) 221 (34) 11 (14) (three patients, of which one had a history of a prior 18–21 160 (22) 133 (21) 27 (33) seizure disorder), pneumonia (three patients, of which one had new-onset diabetes), asthma exacer- Sex, n (%) bation (one patient), acute otitis media (one patient), Male 359 (49) 313 (48) 46 (57) 0.15 milk protein allergy (one patient), E. coli urinary Female 370 (51) 335 (52) 35 (43) tract infection (one patient) and dental infection Race and Ethnicity, n (%) (one patient). Six SARS-CoV-2-positive patients NH White 337 (46) 322 (50) 15 (19) <0.001 received pharyngeal Group A streptococcus testing, NH Black or African 73 (10) 65 (10) 8 (10) of which three were positive. 20 SARS-CoV-2-posi- American tive patients received RPPs and all were negative. NH Other 64 (9) 61 (9) 3 (4) There were 108 RPPs sent among SARS-CoV-2-negative patients, of which 15 (14%) were positive for a Hispanic 248 (34) 193 (30) 55 (68) respiratory pathogen. The majority of SARS-CoV-2- Not Reported 7 (1) 7 (1) 0 (0) positive patients (82%) were discharged home. 15% Preferred Language, n (%) were admitted to the hospital, and none required English 596 (82) 551 (85) 45 (56) <0.001 an intensive care unit admission (Table 2). 67% of Spanish 120 (17) 86 (13) 34 (42) non-Hispanic white SARS-CoV-2-positive patients Other 13 (2) 11 (2) 2 (3) were discharged home from the ED compared to IQR = interquartile range, NH = non-Hispanic 85% of Hispanic and 75% of non-Hispanic black Percentages may not equal 100% due to rounding. patients. Consistent with the descriptive statistics, several characteristics were found to be associated with Figure 2. Presenting Symptoms Among 729 Children Tested increased SARS-CoV-2 positivity (Table 3). Children with for SARS-CoV-2 constitutional (aOR=5.4; 95% CI 3.1–9.5) or upper respiratory Patients could have multiple symptoms. Symptoms were grouped into categories: constitutional (temperature of at least 38 degrees Celsius, Figure 3. Symptoms were grouped into categories: constitutional (tem- subjective fever, chills, body aches), upper respiratory (sore throat, perature of at least 38 degrees Celsius, subjective fever, chills, body aches), congestion/runny nose, cough, shortness of breath), gastrointestinal upper respiratory (sore throat, congestion/runny nose, cough, shortness (abdominal pain, nausea/vomiting, diarrhea) and other (headache, loss of of breath), gastrointestinal (abdominal pain, nausea/vomiting, diarrhea) smell or taste, seizure, chest pain, rash). and other (headache, loss of smell or taste, seizure, chest pain, rash).

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Table 2. Clinical Characteristics of the Study Population symptoms (aOR=3.9; 95% CI 2.3–6.6) had increased odds of testing positive for SARS-CoV-2. Children Characteristics Total SARS-CoV-2 SARS-CoV-2 P value Tested Negative Positive with gastrointestinal (aOR=0.8; 95% CI 0.5–1.4) or (n=729) (n=648) (n=81) other symptoms (aOR=0.68; 95% CI 0.41–1.14) had Symptomatology, n (%) no significant change in the odds of testing positive. Hispanic children had increased odds of testing Asymptomatic 183 (25) 178 (28) 5 (6) <0.001 positive compared to non-Hispanic white children Symptomatic 546 (75) 470 (73) 76 (94) (aOR=4.9; 95% CI 2.6-8.9). Non-Hispanic Black or a Constitutional 278 (38) 218 (34) 60 (74) <0.001 African American children also had increased odds aUpper Respiratory 265 (36) 207 (32) 58 (72) <0.001 of testing positive for SARS-CoV-2 compared to aGastrointestinal 304 (42) 272 (42) 32 (40) 0.67 non-Hispanic white children, though this result aOther 181 (25) 157 (24) 24 (30) 0.29 was not statistically significant (aOR=2.0; 95% CI 0.8–4.9). When compared to 18- to 21-year-olds, SARS-CoV-2 Positive Contact, n (%) children who were 1- to 5-years-old (aOR=0.2; 95% Yes 84 (12) 39 (6) 45 (56) <0.001 CI 0.1–0.5) and 12- to 17-years-old (aOR=0.3; 95% No 645 (89) 609 (94) 36 (44) CI 0.1–0.7) had decreased odds of testing positive. Pulmonary Examination, n (%) Abnormal 73 (10) 58 (9) 15 (19) 0.007 DISCUSSION Normal 656 (90) 590 (91) 66 (82) The strength of this study was its ability to provide Past Medical History, n (%) a detailed description of the demographic and clini- Yes 398 (55) 368 (57) 30 (37) 0.001 cal characteristics of pediatric patients in relation to No 331 (45) 280 (43) 51 (63) their test results during the initial COVID-19 wave Concurrent Medical Diagnosis, n (%) in Rhode Island. The study sample had a positivity Yes 466 (64) 446 (69) 20 (25) <0.001 rate of 11%, which is consistent with statewide No 263 (36) 202 (31) 61 (75) data comprising both adult and pediatric patients that reported a positivity rate of 13.4% at the peak Disposition from the ED, n (%) of infections. Home 386 (53) 320 (49) 66 (82) <0.001 We detail the presence or absence of 17 clinical Group Home 21 (3) 20 (3) 1 (1) symptoms among SARS-CoV-2-positive and nega- Medical Floor 202 (28) 190 (29) 12 (15) tive pediatric patients. Children with constitutional Admission or upper respiratory symptoms had the highest Intensive Care Unit 35 (5) 35 (5) 0 (0) odds of being SARS-CoV-2-positive. Our find- Admission ings also reinforce the differences in SARS-CoV-2 Psychiatric Admission 79 (11) 77 (12) 2 (3) infection between adults and children. For exam- Other 6 (1) 6 (1) 0 (0%) ple, highly specific COVID-19 symptoms in adults aPatients could have multiple symptoms in the same or different categories. (i.e., loss of taste or smell) were uncommon among Percentages may not equal 100% due to rounding. SARS-CoV-2-positive children, and few children required admission to the hospital.16 This infor- Table 3. Odds Ratios of SARS-CoV-2 Positive Test mation could inform strategies in various healthcare set- by Presenting Symptoms tings for managing patient flow or determining priority to receive rapid testing versus testing that returns within days. OR (95% CI) aOR (95% CI)a While 40% of SARS-CoV-2-positive patients had gastro- Symptomatic 5.8 (2.3-14.5) 3.9 (1.5-10.1) intestinal symptoms, 42% of negative patients did as well. bConstitutional 5.6 (3.3-9.5) 5.4 (3.1-9.5) Interestingly, it has been reported that patients can have bUpper Respiratory 5.4 (3.2-9.0) 3.9 (2.3-6.6) SARS-CoV-2-positive rectal swabs and negative pharyngeal bGastrointestinal 0.9 (0.6-1.5) 0.8 (0.5-1.4) swabs, suggesting that patients with gastrointestinal symp- 17 bOther 1.3 (0.8-2.2) 1.0 (0.6-1.8) toms in our study might have had false negative tests. Greater than half the SARS-CoV-2-positive patients in OR=odds ratio, aOR = adjusted odds ratio, CI = confidence interval this study reported a SARS-CoV-2-positive close contact. aModels adjusted for age and race/ethnicity. Though we could not ascertain patients’ degrees of exposure bPatients could have multiple symptoms in the same or different categories. to individuals known to be SARS-CoV-2-positive, this was consistent with prior literature showing 65% of patients who tested positive had close contact with a family member

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known to be COVID-19 positive.18 This highlights the easy testing at this time was occurring in the ED setting, our spread of infection through close personal contacts. It under- data from a population seeking ED level care may not per- scores the need for statewide resources, public campaigns, fectly reflect COVID-19 symptomatology or prevalence in and provider counseling to have infected patients appropri- the community as a whole. If certain populations such as ately quarantine from others if possible, or alternatively, the Hispanic community utilized the ED disproportionately wear masks within households when a family member is more than others during the initial phase of the pandemic, exhibiting symptoms. this might skew our findings regarding incidence of infec- The prevalence of coinfections was low during the initial tion in specific communities. In addition, by testing all peak. None of the SARS-CoV-2-positive patients who had admitted patients for SARS-CoV-2, our SARS-CoV-2-neg- an RPP performed had a concurrent respiratory infection ative patients represent a sicker sample than the general detected. Among SARS-CoV-2-negative patients who had an population. A higher proportion of SARS-CoV-2-negative RPP, 14% tested positive for an infection. This may have been patients were admitted to the medical floor and intensive partially due to the fact that this initial peak in coronavirus care unit compared to SARS-CoV-2-positive patients in cases occurred in the respiratory “off-season,” when rates of our study. With increased testing availability, the results respiratory illness are relatively low. In the next phase of the of future studies may be more generalizable to the broader pandemic, the hospital system has transitioned to obtaining pediatric population. an expanded RPP that now includes SARS-CoV-2 in addition to the other pathogens listed previously for all symptomatic patients. Beyond its clinical utility, this broader panel will CONCLUSION allow researchers to evaluate rates of coinfection with more Our study provides a thorough description of the children rigor in the upcoming winter months. who underwent SARS-CoV-2 testing during the initial peak In addition to providing clinical data on SARS-CoV-2 of the pandemic. Our data are also consistent with prior anal- infections in children, our study highlights the unequal bur- yses demonstrating the disproportionately large COVID-19 den of COVID-19 among children of different ethnicities and burden among minority communities during that time. This emphasizes the need for targeted advocacy and public health growing body of literature highlights the systemic inequi- efforts for our minority communities. Hispanic children had ties that lead to increased disease burden among vulnerable over four times increased odds of testing positive for SARS- communities and is further evidence that our country must CoV-2 compared to non-Hispanic white children. implement public health policies to combat these inequi- It is difficult to disentangle the complex relationships of ties. These findings could inform allocation of rapid SARS- race/ethnicity and SARS-CoV-2-positivity with associated CoV-2 testing and management of patient flow in various confounders and mediators such as socioeconomic status healthcare settings, and highlight populations in need of and living conditions. In Rhode Island in 2018, 12.9% of the further public health support in our state. population and 17.5% of children lived below the poverty line. Hispanics comprised the largest ethnic group (29.3%) that lived below the poverty line.19 Low socioeconomic status households may be more likely to have additional people References living in the same room with limited space to adequately 1. COVID-19 Data Tracker by Date. Rhode Island Department of quarantine, have fewer resources to mitigate adverse health Health. https://ri-department-of-health-covid-19-data-rihealth. events, and may thus be at higher risk for SARS-CoV-2 trans- hub.arcgis.com. Accessed August 3, 2020. mission.20 Low socioeconomic status may therefore be con- 2. COVID-19 Data Tracker - Testing. Rhode Island Department of Health https://ri-department-of-health-covid-19-response-demogr- tributing to higher odds of SARS-CoV-2-positivity among a3f82-rihealth.hub.arcgis.com. Accessed August 7, 2020. Hispanic children. Prior studies have shown that in addition 3. Lifespan Housewide Algorithm for Coronarvirus COVID-19. to Hispanic children, non-Hispanic black or African-Amer- Lifespan. https://www.lifespan.org/sites/default/files/lifespan- ican children have increased odds of testing positive for files/documents/centers/infectious-diseases/Pedi_Algorithm_ COVID19_3-30-20_v7.pdf. Accessed August 7, 2020. SARS-CoV-2 compared to non-Hispanic white children.15 4. Shekerdemian LS, Mahmood NR, Wolfe KK, et al. Characteris- While we found a similar pattern, inadequate power likely tics and Outcomes of Children With Coronavirus Disease 2019 contributed to our inability to detect this finding with (COVID-19) Infection Admitted to US and Canadian Pediatric statistical significance. Intensive Care Units. JAMA Pediatr. 2020. 5. Lifespan as an Employer. Lifespan. https://www.lifespan.org/ A limitation is the need to interpret our results in a about-lifespan/our-mission/lifespan-employer. Accessed August landscape of evolving SARS-CoV-2 testing capabilities and 5, 2020. stages of reopening. These factors lead to constant change 6. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. in the incidence and prevalence of SARS-CoV-2 in different Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translation- communities, which also affect the pre-test probability of al research informatics support. J Biomed Inform. 2009;42(2): SARS-CoV-2-positivity. While a large amount of pediatric 377-381.

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7. Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID-19 Among Authors Children in China. Pediatrics. 2020;145(6). Rebecca A. Levin, MD, Department of Emergency Medicine, 8. Information for Pediatric Healthcare Providers. Centers for Department of Pediatrics, Brown University School of Public Disease Control and Prevention. https://www.cdc.gov/corona- Health, Warren Alpert Medical School of Brown University, virus/2019-ncov/hcp/pediatric-hcp.html. Published 2020. Ac- Providence, RI. cessed August 13, 2020.

9. ePlex® SARS-CoV-2 Test Assay Manual. GenMarkDx. https:// Hoi See Tsao, MD, Department of Emergency Medicine, www.fda.gov/media/136282/download. Published 2020. Ac- Department of Pediatrics, Brown University School of Public cessed August 14, 2020. Health, Warren Alpert Medical School of Brown University, 10. Xpert® Xpress SARS-CoV-2. Cepheid. https://www.cephe- Providence, RI. id.com/Package%20Insert%20Files/Xpress-SARS-CoV-2/ Siraj Amanullah, MD, MPH, Department of Emergency Medicine, Xpert%20Xpress%20SARS-CoV-2%20Assay%20CE-IVD%20 Department of Pediatrics, Department of Health Services, ENGLISH%20Package%20Insert%20302-3787%20Rev.%20A. Policy and Practice, Brown University School of Public pdf. Published 2020. Accessed August 14, 2020. Health, Warren Alpert Medical School of Brown University, 11. BioGX SARS-CoV-2 Reagents for BD MAX™ System. BD. Providence, RI. https://www.bd.com/en-us/offerings/capabilities/molecular-diagnostics/molecular-tests/biogx-sars-cov-2-reagents. Published Alicia Genisca, MD, Department of Emergency Medicine, 2020. Accessed August 14, 2020. Department of Pediatrics, Warren Alpert Medical School of 12. cobas® SARS-CoV-2. Roche Diagnostics. https://www.fda.gov/ Brown University, Providence, RI. media/136049/download. Published 2020. AccessedAugust 14, Laura Chapman, MD, Department of Emergency Medicine, 2020. Department of Pediatrics, Warren Alpert Medical School of 13. OSOM Strep A Test. Sekisui Diagnostics. https://www.sekisuid- Brown University, Providence, RI. iagnostics.com/products-all/osom-strep-a-test/. Accessed Au- gust 7, 2020. Correspondence 14. StataCorp. Stata statistical software. Version 16.0. College Sta- Rebecca Levin, MD tion TX. 2019. Department of Emergency Medicine 15. Goyal MK, Simpson JN, Boyle MD, et al. Racial/Ethnic and So- Brown University/Hasbro Children’s Hospital cioeconomic Disparities of SARS-CoV-2 Infection Among Chil- 55 Claverick St, Office 243 dren. Pediatrics. 2020:e2020009951. Providence, RI 02903 16. Menni C, Valdes A, Freydin MB, et al. Loss of smell and taste in combination with other symptoms is a strong predictor of [email protected] COVID-19 infection. MedRxiv. 2020. 17. Zhang B, Liu S, Dong Y, et al. Positive rectal swabs in young patients recovered from coronavirus disease 2019 (COVID-19). J Infect. 2020;81(2):e49-e52. 18. Xia W, Shao J, Guo Y, Peng X, Li Z, Hu D. Clinical and CT features in pediatric patients with COVID-19 infection: Different points from adults. Pediatr Pulmonol. 2020;55(5):1169-1174. 19. Poverty Talks: Rhode Island. Center for American Progress. https://talkpoverty.org/state-year-report/rhode-island-2019- report/. Published 2020. Accessed August 3, 2020. 20. Leonard T, Hughes AE, Pruitt SL. Understanding how low-socioeconomic status households cope with health shocks: An analysis of multi-sector linked data. Ann Am Acad Pol Soc Sci. 2017;669(1):125-145.

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COVID-19 and Public Interest in Ophthalmic Services and Conditions

John C. Lin; Lan Jiang, MS; Ingrid U. Scott, MD, MPH; Paul B. Greenberg, MD, MPH

61 64 EN ABSTRACT would help key stakeholders in ophthalmology prepare for Objective: To assess the impact of the COVID-19 a possible second wave. Moreover, it would provide unique pandemic and associated lockdowns on public interest insight into overall patient behaviors, such as balancing in ophthalmology. benefits of seeking treatment for an ophthalmic condition with the risk of contracting COVID-19. To our knowledge Methods: Search interest data for ophthalmic services and based on a computerized search of the PubMed data- and conditions were collected from January 1, 2019 to base, no previous studies have assessed the effect of COVID- June 21, 2020. Temporal statistical analysis was used to 19 and lockdown orders on public interest in seeking identify significant trends. Weekly data on ophthalmic ophthalmic care. services and conditions search interest obtained from Google Trends® is a free tool provided by Google LLC that Google Trends were analyzed with analysis of variance provides data for the 1.2 trillion searches they handle per testing and the generalized linear model based on dates. year.(4) Google Trends® data have been shown to serve as a Results: Ophthalmic services searches decreased after measure of conjunctivitis outbreaks and public interest in the first COVID-19 case in the country (p<0.001); oph- specific treatments or health services.5,6 In this study, we thalmic services and conditions search interest also de- examined the impact of the COVID-19 pandemic and asso- clined after the first COVID-19 case and lockdown or- ciated lockdown orders on Internet search interest for oph- ders in each state (p<0.001). Following the first in-state thalmic services and conditions using Google Trends® data. COVID-19 case, search interest in ophthalmic services fell more than for ophthalmic conditions (p=0.0088). Lockdown and COVID-19 had similar effects on oph- METHODS thalmic services search interest (p=0.2246), but interest Data source in ophthalmic conditions decreased more after lockdown Google Trends is a publicly available database containing than after the first in-state case (p<0.0001). frequencies of anonymized Google searches since 2004.7 For Conclusions: Most of the decrease in search interest each query in Google Trends, the user extracts a “search in ophthalmic services was associated with COVID-19 interest” value ranging from 0 to 100 across specific times rather than lockdown orders, suggesting that public inter- and geographical areas. Search interest is a relative value est in ophthalmic care may be more sensitive to changes that is calculated following the normalization and scaling in the COVID-19 pandemic than lockdown orders. of absolute search volume. Normalization allows research- KEYWORDS: COVID-19, patient care, infodemiology, ers to compare the frequency of searches in different areas search interest, Google Trends accounting for their different population densities, and fixed scaling helps determine changes over time. The value of 100 is assigned to the highest level of search volume within a set location and time period. For example, a search interest value of 8 means that the search intensity at that specific INTRODUCTION time was 8% of peak intensity of all Google searches in a To reduce the transmission of coronavirus disease 2019 particular location and time period. (COVID-19), 43 states and several territories in the United Public interest in ophthalmic services was obtained by States (US) have issued or previously issued lockdown searching ‘ophthalmologist’ in Google Trends, and the orders as of June 18, 2020.1 Trends in patient care have been following internet search terms for eye conditions were impacted by the pandemic, with many public health author- employed based on a previous study:6 ‘basal cell’, ‘blepharitis’, ities issuing guidelines to avoid or defer elective surgeries ‘blindness’, ‘blurred vision’, ‘blurry vision’, ‘cataract’, ‘conjun- and in-person care.2,3 ctivitis’, ‘contact lens’, ‘contact lenses’, ‘double vision’, ‘dry Understanding the impact of the COVID-19 pandemic and eye’, ‘dry eyes’, ‘eye allergies’, ‘eye allergy’, ‘eye flashes’, ‘eye lockdown orders on public interest in ophthalmic services floaters’, ‘eye infection’, ‘eye pain’, ‘eye twitch’, ‘eye twitching’,

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‘eyeglasses’, ‘glasses’, ‘glaucoma’, ‘headache’, ‘itchy eye’, RESULTS ‘itchy eyes’, ‘LASIK’, ‘macular degeneration’, ‘melanoma’, A comparison of trends in ophthalmic services and condi- ‘migraine’, ‘pink eye’, ‘rosacea’, ‘shingles symptoms’, ‘sinus’, tions searches for all states is shown in Table 1. Internet ‘squamous cell’, ‘stye’, ‘uveitis’, and ‘watery eyes’. searches for ophthalmic services decreased significantly The dates for the first confirmed COVID-19 case and after the first COVID-19 case in the country; ophthalmic lockdown orders in each state were recorded from state services and conditions search interest decreased after the government websites and records. The date of the first first COVID-19 case in each state. COVID-19 case in the US was recorded from federal govern- Search interest under the lockdown order was also signifi- ment records.8 cantly lower compared with the first phase Table( 2). Search Data for each state were collected weekly. There were 25 interest in ophthalmic services decreased significantly more weeks of data for each state, with the time frame categorized than search interest in ophthalmic conditions after the first into three phases: Phase 1 (from January 1, 2020 to January in-state COVID-19 case (p=0.0088) but not significantly after 20, 2020, the date of the first confirmed COVID-19 case in the first case in the US or after lockdown. the US), Phase 2 (from January 21, 2020 to the date of the Additionally, there was no significant difference between first confirmed COVID-19 case in each state), and Phase 3 the association of COVID-19 and lockdown with search (following that date until June 20, 2020). interest in ophthalmic services but search interest in To examine the impacts of lockdown orders, the time frame was categorized into four phases: Phase 1 and Phase Table 1. Search interest in ophthalmology based on the 2 as defined previously, a revised Phase 3 (from the date of COVID-19 timeline the first confirmed COVID-19 case in each state to the date Mean search interest Phase 1a, Phase 2b, Phase 3c, p-value of each state lockdown order), and Phase 4 (beyond that date estimate estimate estimate to June 20, 2020). (95% CI) (95% CI) (95% CI) ‘Ophthalmologist’ 6.17 5.63 4.32 <0.0001 Statistical analysis searches, mean (SD) (2.30) (2.75) (2.12) The primary outcomes were search interest in ophthal- Ophthalmology- 10.29 10.41 9.75 <0.0001 mic services and conditions. The mean and standard devi- related searches, (2.01) (2.07) (1.93) ation of the outcomes were calculated for each phase. To mean (SD) examine the impact of ophthalmic services and conditions CI, confidence interval;COV ID-19, coronavirus disease 2019; SD, standard deviation. search volumes, one-way analysis of variance (ANOVA) test aTime before the first COVID-19 case in the US was conducted. Significance level of <0.05 was used for all bTime between the first domestic case and the first in-state case hypothesis testing. cTime after the first in-state case A multivariate generalized linear model with repeated dAll fifty states and Washington, District of Columbia. measures compared the changes in ophthalmic services and conditions Table 2. Change in search interest in ophthalmology associated with occurrence of COVID-19 and search interest across the four phases, state lockdown orders using Phase 1 as a reference and con- Change in search interest Phase 1a, Phase 2b, Phase 3c, Phase 4d, trolling for state fixed effects. The from previous phase estimate estimate estimate estimate temporal relationship between the (95% CI) (95% CI) (95% CI) (95% CI) two search interests for each state ‘Ophthalmologist’ searches 1 -0.59 -1.76 -1.99 was modeled using repeated mea- [reference] (-1.09 – -0.10)* (-2.29 – -1.24)* (-2.48 – -1.50)* sures correlation. We used the same Ophthalmology-related 1 0.06 -0.44 -1.22 method to examine the impacts of searches [reference] (-0.27–0.38) (-0.92 – 0.03) (-1.57 – -0.88)* COVID-19 and lockdown on the two Difference of change in - 0.1645 0.0088 0.0819 search interests, using Phase 4 as the volume for each search reference. interest during each phase

Statistical analyses were performed CI, confidence interval; COVID-19, coronavirus disease 2019; SD, standard deviation. ® using SAS/STAT software (version aTime before the first COVID-19 case in the US 9.4, SAS Institute Inc., Cary, US) and bTime between the first COVID-19 case in the US and the first in-state case R (version 3.4.3, R Core Team, Vienna, cTime between the first in-state case and the state lockdown order Austria).9 dTime following the state lockdown order eExcluded states without lockdown orders prior to June 21, 2020: Arkansas, Iowa, Nebraska, North Dakota, South Dakota, Utah, and Wyoming. *p<0.05

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Table 3. Association of COVID-19 and state lockdown orders on search interest in of their populations. The underlying sample may ophthalmology be more health- and technology-literate than the Mean search interest Phase 1a vs Phase 2b vs Phase 3c vs general population. However, 99.96% of Amer- phase 4d, mean phase 4d, mean phase 4d, mean icans have access to high speed internet,12 and (95% CI) (95% CI) (95% CI) approximately 88% of people use Google for online ‘Ophthalmologist’ 1.99 1.39 0.22 searches,13 indicating that the Google user popula- searches (1.50 – 2.48)* (1.03 – 1.76)* (-0.14 – 0.59) tion likely reflects the general population. More- p-value for difference <.0001 <.0001 .2246 over, there may be different reasons to start a between phases Google search for ‘ophthalmologist’ or ophthalmic Ophthalmology-related 1.22 1.28 0.78 conditions, including personal health and schol- searches (0.88–1.57)* (1.06 – 1.51)* (0.44 – 1.11)* arly interest in the profession or the conditions; p-value for difference .73 .07 <.0001 still, given that significant changes to interest in between phases the ophthalmology profession or ophthalmic con- CI, confidence interval; COVID-19, coronavirus disease 2019; SD, standard deviation. ditions were unlikely over the study period, search aTime before the first COVID-19 case in the US interest should serve as an accurate measure for bTime between the first COVID-19 case in the US and the first in-state case patient interest in ophthalmic services and condi- cTime between the first in-state case and the state lockdown order tions. Also, Google Trends only provides relative dTime following the state lockdown order search volume, so it was not possible to examine *p<0.05 the magnitude of search volume changes. How- ever, search interest data were normalized based ophthalmic conditions had a significantly greater decline on time and geography, which was useful for capturing after lockdown than after the first in-state COVID-19 case change in overall behaviors. In addition, our search strat- (p<0.0001; Table 3). egy may have excluded some pertinent terms, although our approach was consistent with that reported in a previous study.6 Finally, there was policy heterogeneity among DISCUSSION the lockdown mandates, with implementation at different The overall decrease in search interest for ophthalmic ser- times, restrictiveness, and with different populations.14 Our vices may have occurred as many ophthalmology clinics analysis adjusted for the difference in timing among lock- closed or cancelled appointments and/or patient anxieties down mandates by assessing the period after the onset of about COVID-19 overshadowed concerns about their eye COVID-19 and the period after implementation of the conditions. Additionally, with the rise in unemployment, lockdown orders. many patients may have lost their health insurance, pre- cluding seeking treatment for eye conditions.10 Interest in eye conditions relative to ophthalmic services may have decreased less drastically because people who were unable References or unwilling to receive services from an ophthalmologist 1. Lee JC, Mervosh S, Avila Y, Harvey B, Matthews AL. See How All 50 States Are Reopening (and Closing Again) New York, NY: were attempting to learn more about their symptoms or ill- New York Times; 2020 Jul. Accessed July 4, 2020. Available nesses from the internet. from https://www.nytimes.com/interactive/2020/us/states-re- The onset of the COVID-19 pandemic – rather than the open-map-coronavirus.html lockdown orders – was associated with most of the decrease 2. Iacobucci G. Covid-19: all non-urgent elective surgery is suspended for at least three months in England. BMJ. 2020 Mar;368. in public interest in ophthalmic services. This suggests that 3. Centers for Disease Control and Prevention. Non-COVID-19 public interest in ophthalmic care may be more sensitive Care Framework Atlanta, GA: Centers for Disease Control; 2020. to changes in the COVID-19 pandemic than in lockdown Accessed June 24, 2020. Available from https://www.cdc.gov/ coronavirus/2019-ncov/hcp/framework-non-COVID-care.html orders. In addition, search interest in ophthalmic conditions 4. Internet Live Statistics. Google Search Statistics: Internet Live declined significantly more than interest in ophthalmic ser- Statistics; 2020. Accessed June 25, 2020. Available from https:// vices following the lockdown. This may reflect fewer peo- www.internetlivestats.com/google-search-statistics/ ple seeing ophthalmologists and getting their conditions 5. Deiner MS, Lietman TM, McLeod SD, Chodosh J, Porco TC. diagnosed. When the danger of COVID-19 recedes, pent-up Surveillance Tools Emerging From Search Engines and Social Media Data for Determining Eye Disease Patterns. JAMA Oph- demand for ophthalmic appointments and surgeries may thalmol. 2016 Sep;134(9):1024-30. lead to a heavy burden on the healthcare system and sub- 6. Leffler CT, Davenport B, Chan D. Frequency and Seasonal Vari- stantial delays in care.11 ation of Ophthalmology-Related Internet Searches. Can J Oph- thalmol. 2010 Jun;45(3):274-9. This study excluded people who use search engines 7. Google Trends. Explore what the world is searching Mountain other than Google or do not have internet access, and Goo- View, CA: Google LLC; 2020. Accessed June 21, 2020. Available gle search data for each state may not reflect the interests from http://www.google.com/trends

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8. Stokes EK, Zambrano LD, Anderson KN, Marder EP, Raz KM, Authors Felix SEB, et al. Coronavirus Disease 2019 Case Surveillance — John C. Lin, Program in Liberal Medical Education, Brown United States, January 22–May 30, 2020 Atlanta, GA: Centers University; Division of Ophthalmology, Alpert Medical for Disease Control; 2020. Accessed July 4, 2020. Available from https://www.cdc.gov/mmwr/volumes/69/wr/mm6924e2.htm School, Brown University, Providence, Rhode Island.

9. R Core Team. R: A language and environment for statistical Lan Jiang, MS, Center of Innovation in Long Term Services computing Vienna, Austria: R Foundation for Statistical Com- and Supports, Providence VA Medical Center, Providence, puting; 2018. Accessed June 24, 2020. Available from https:// Rhode Island. www.R-project.org/ Ingrid U. Scott, MD, MPH, Departments of Ophthalmology and 10. Kaiser Family Foundation. Health Insurance Coverage of the Public Health Sciences, Penn State College of Medicine, Total Population San Francisco, CA: Kaiser Family Founda- Hershey, Pennsylvania. tion; 2018. Accessed July 7, 2020. Available from https://www. kff.org/other/state-indicator/total-population/?currentTime Paul B. Greenberg, MD, MPH, Division of Ophthalmology, Alpert frame=0&sortModel=%7B%22colId%22:%22Location% Medical School, Brown University; Section of Ophthalmology, 22,%22sort%22:%22asc%22%7D Providence VA Medical Center, Providence, Rhode Island; 11. Natsis A. Impact of COVID-19 on Deferred Medical Costs and Office of Academic Affiliations, US Department of Veterans Future Pent-Up Demand Schaumburg, IL: Society of Actuaries; Affairs, Washington DC. 2020. Accessed July 8, 2020. Available from http://soa.org/glo- balassets/assets/files/resources/research-report/2020/covid-19- Disclaimer deferred-medical-cost.pdf The views expressed here are those of the authors and do not nec- 12. Federal Communications Commission. Percentage of population essarily reflect the position or policy of the US Department with broadband providers Washington, D.C.: Federal Communi- of Veterans Affairs or the US government. cations Commission,; 2019. Accessed July 4, 2020. Available from https://broadbandmap.fcc.gov/#/area-comparison?version= jun2019&tech=acfosw&speed=25_3&searchtype=county Correspondence Paul B. Greenberg, MD, MPH 13. StatCounter. Search Engine Market Share in United States Of America 2020. Accessed July 5, 2020. Available from https://gs. Division of Ophthalmology, Brown University statcounter.com/search-engine-market-share/all/united-states- Coro Center West, Suite 200 of-america 1 Hoppin St, Providence, RI 02903 14. Dave D, Friedson AI, Matsuzawa K, Sabia JJ. When Do Shelter- 401.444.4669 in-Place Orders Fight COVID-19 Best? Policy Heterogeneity [email protected] Across States and Adoption Time. Econ Inq 2020 Aug.doi:10. 1111/ecin.12944

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 64 VITAL STATISTICS PUBLIC HEALTH Nicole E. Alexander-Scott, MD, MPH director, Rhode island department of health compiled by Roseann Giorgianni, Deputy State Registrar

Rhode Island Monthly Vital Statistics Report Provisional Occurrence Data from the Division of Vital Records

REPORTING PERIOD JULY 2020 12 MONTHS ENDING WITH JULY 2020 VITAL EVENTS Number Number Rates Live Births 996 11,224 10.6* Deaths 809 11,472 10.8* Infant Deaths 6 60 5.3# Neonatal Deaths 3 46 4.1# Marriages 458 5,263 5.0* Divorces 113 2,469 2.3* * Rates per 1,000 estimated population # Rates per 1,000 live births

REPORTING PERIOD JANUARY 2020 12 MONTHS ENDING WITH JANUARY 2020 Underlying Cause of Death Category Number (a) Number (a) Rates (b) YPLL (c) Diseases of the Heart 224 2,434 229.8 3,471.5 Malignant Neoplasms 154 2,231 210.6 4,889.0 Cerebrovascular Disease 43 467 44.1 500.0 Injuries (Accident/Suicide/Homicide) 77 887 83.7 11,945.5 COPD 46 498 47.0 547.5

(a) Cause of death statistics were derived from the underlying cause of death reported by physicians on death certificates. (b) Rates per 100,000 estimated population of 1,059,361 for 2019 (www.census.gov) (c) Years of Potential Life Lost (YPLL).

NOTE: Totals represent vital events, which occurred in Rhode Island for the reporting periods listed above. Monthly provisional totals should be analyzed with caution because the numbers may be small and subject to seasonal variation.

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 65 VITAL STATISTICS PUBLIC HEALTH Nicole E. Alexander-Scott, MD, MPH director, Rhode island department of health compiled by Roseann Giorgianni, Deputy State Registrar

Rhode Island Monthly Vital Statistics Report Provisional Occurrence Data from the Division of Vital Records

REPORTING PERIOD AUGUST 2020 12 MONTHS ENDING WITH AUGUST 2020 VITAL EVENTS Number Number Rates Live Births 1,029 11,275 10.6* Deaths 889 11,496 10.9* Infant Deaths 7 59 5.2# Neonatal Deaths 5 45 4.0# Marriages 683 5,053 4.8* Divorces 82 2,314 2.2* * Rates per 1,000 estimated population # Rates per 1,000 live births

REPORTING PERIOD FEBRUARY 2020 12 MONTHS ENDING WITH FEBRUARY 2020 Underlying Cause of Death Category Number (a) Number (a) Rates (b) YPLL (c) Diseases of the Heart 199 2,426 229.0 3,444.0 Malignant Neoplasms 176 2,252 212.6 4,994.0 Cerebrovascular Disease 47 475 44.8 467.5 Injuries (Accident/Suicide/Homicide) 73 898 84.8 12,085.5 COPD 45 500 47.2 520.0

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Working for You: RIMS advocacy activities

December 1, Tuesday December 10, Thursday December 18, Friday American Medical Association (AMA) Office of the Health Insurance Overdose Prevention Sites Coalition call Advocacy Resource Center (ARC) call Commissioner (OHIC) Telemedicine on opioid legislation Advisory Group: Elizabeth B. Lange, MD, December 21, Monday RIMS Physician Health Committee President-elect; Peter Hollmann, MD, RIMS and Blue Cross & Blue Shield of (PHC): Herbert Rakatansky, MD, Chair Past President Rhode Island (BCBSRI) monthly meeting: Catherine A. Cummings, MD, President; (via teleconference) Meeting with Rhode Island Pharmacist Elizabeth Lange, MD, President-elect December 2, Wednesday Association: Catherine A. Cummings, MD, President; Elizabeth Lange, MD, AMA Center for Health Equity January 4, Monday President-elect; Thomas Bledsoe, MD, conference call RIMS Board of Directors meeting: Past President; Michael E. Migliori, MD, Catherine Cummings, MD, President Medical Preparatory Academy Charter Past President; Sarah Fessler, MD, Past School (MedPrepRI) Board of Directors President; Peter Karczmar, MD, Past January 5, Tuesday meeting: Bradley Collins, MD President Blue Cross & Blue Shield of Rhode Island (BCBSRI) provider call December 3, Thursday December 11, Friday Medical Group Manager’s Association Diabetes Prevention Program Rhode Island General Assembly convenes (MGMA) legislative day Stakeholder Network meeting January 6, Wednesday New England Comparative Effectiveness Overdose Prevention Sites coalition call Rhode Island/American Academy Public Advisory Council (CEPAC) Pediatrics call regarding legislation meeting: Supervised Injection Facilities December 14, Monday and other Supervised Consumption Sites American Cancer Society/Cancer Action American Medical Association (AMA) State Advocacy Summit: Call with Alpert Medical School (AMS) Network call regarding Colorectal Cancer legislation Michael E. Migliori, MD, Chair, students regarding legislation RIMS Public Laws Committee RI American College of Emergency December 4, Friday Physicians (RIACEP/ACEP) Federal Rhode Island Parity Coalition call Advocacy update December 7, Monday Current Procedural Terminology webinar: RIMS NOTES: News You Can Use New England State Executives Peter Hollmann, MD, AMA RVS Update Our biweekly e-newsletter is published Committee meeting regarding telemedicine: on alternate Fridays exclusively for RIMS Newell Warde, PhD December 15, Tuesday members. Contact Dulce Cosme if you’ve AMA Advocacy Resource Center (ARC) State medical society CEOs meeting missed an issue, [email protected]. Executive Committee call (American Association of Medical Society Rhode Island Medical Journal editorial Executives) board: William Binder, MD, and December 16, Wednesday Edward Feller, MD, Editors-in-Chief Primary Care Physician Advisory RIMS Council meeting: Committee meeting (PCPAC): Catherine Cummings, MD, President Elizabeth Lange, MD, President-elect December 8, Tuesday Call with RIDOH regarding AMA Federal Advocacy update call vaccine update December 9, Wednesday 2020 National Policy Roadmap on State-Level Efforts to End the Nation’s RI Department of Health (RIDOH) Board Drug Overdose Epidemic of Medical Licensure and Discipline (BMLD) meeting RI Medical Political Action Committee (RIMPAC) Board: Michael Silver, MD, Governor’s Overdose Intervention and Chair Prevention Task Force: Sarah Fessler, MD, RIMS Past President RIMS Public Laws Committee: Michael E. Migliori, MD, Chair Workers Compensation Advisory Committee meeting December 17, Thursday Call with AMS students regarding American Cancer Society/Cancer Action Advocacy: Michael E. Migliori, MD, Chair Network call regarding Colorectal Cancer RIMS Public Laws Committee legislation RIMS Foundation Board of Trustees: Christine Brousseau, MD, President

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The Rhode Island Medical Society continues to drive forward into the future with the implementation of various new programs. www.nhpri.org As such, RIMS is expanded its Affinity Program to allow for Neighborhood Health Plan of Rhode Island is a non-profit HMO founded in more of our colleagues in health- 1993 in partnership with Rhode Island’s Community Health Centers. Serving care and related business to over 185,000 members, Neighborhood has doubled in membership, revenue work with our membership. RIMS and staff since November 2013. In January 2014, Neighborhood extended its service, benefits and value through the HealthSource RI health insurance ex- thanks these participants for their change, serving 49% the RI exchange market. Neighborhood has been rated by support of our membership. National Committee for Quality Assurance (NCQA) as one of the Top 10 Med- Contact Marc Bialek for more icaid health plans in America, every year since ratings began twelve years ago. information: 401-331-3207 or [email protected]

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We are read everywhere

Over the past 12 months, more than 34,500 unique viewers from 128 countries have read articles in the Rhode Island Medical Journal (RIMJ) or researched topics in its archives.

Top 10 countries in 2020: 1. US 6. Germany 2. Australia 7. China 3. Canada 8. Brazil 4. UK 9. Italy 5. India 10. Japan

PROVIDENCE, RHODE ISLAND Nisarg Chhaya, MD, above, PGY3 ophthalmology resident and author of Retinopathy in a Full-Term Infant with Cri-du-Chat Syndrome (page 37), reads the journal in the LPG Oph- thalmology library at Lifespan's Coro Center.

Viren Rana, DO, right, PGY2 ophthalmology resident, catches up on the RIMJ before starting his clinic at the Providence VA Medical Center Eye Clinic.

Wherever you happen to be quarantining or social distancing, visit the Journal on your mobile device, and send us a photo: [email protected].

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DUBLIN, IRELAND Julie Croll, MPH, author of Treatment Retention for Older versus Younger Adults with Opioid Use Disorder (page 51), wrote to RIMJ, "Just read the last edition of the journal from Dublin, Ireland where we are on our third lockdown. I am a Rhode Island native currently at the Royal College of Surgeons in Ireland, finishing up my third year in the faculty of medicine. Hope everything is going well in lil Rhody, and missing Providence." Inset photo, Julie on the steps of the Royal College of Surgeons of Ireland building in Dublin

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 72

Spotlight

RIMJ COVID-19 Retrospective The following timeline illustrates examples of the Rhode Island Medical Journal’s (RIMJ) coverage of the COVID-19 pandemic as it emerged in the state over the past year.

MARCH 2020 March articles RIDOH Announces 2nd Presumptive Positive COVID-19 Case; Testing 3rd All three individuals from the same European trip; 2 Schools in RI Temporarily Closed Testing in RI RIDOH’s State Health Laboratories to perform COVID testing

APRIL 2020 April articles A View from the Front William Binder, MD, FACEP Co-infection with SARS-CoV-2 and Human Metapneumovirus Francine Touzard-Romo, MD; Chantal Tapé, BA, MD’20; John R. Lonks, MD COVID-19 in a Patient Presenting with Syncope and a Normal Chest X-ray Chantal Tapé, BA, MD’20; Katrina M. Byrd, MD; Su Aung, MD; John R. Lonks, MD; Timothy P. Flanigan, MD; Natasha R. Rybak, MD Lifespan to open triage, testing tents Care New England adds three tent units at Kent CharterCARE erects triage, testing tents outside EDs

Selim Suner, MD, Director MAY 2020 May articles of Disaster Medicine and Preparing for Potential COVID-19 Surge Emergency Preparedness, Convention Center, two other field hospitals ready if needed RIH Department of Emer- gency Medicine, at the CNE COVID-19 testing site opens on Memorial Hospital grounds Convention Center facility. Drs. Caliendo, Kurtis to lead COVID-19 testing and validation task force Herbert Aronow, MD, publishes guidelines on cardiovascular care & COVID-19 Zoom talk on The Great Influenza with author John M. Barry Lessons from 1918

JUNE 2020 June articles Keeping Hospitals Safe During the COVID-19 Pandemic Finding inspiration in a father’s credo Leonard A. Mermel, DO COVID-19: Misinformation Can Kill Ghazal Aghagoli, BS, MD’23; Emily J. Siff, MS; Anastasia C. Tillman, BA, MD’23; Edward R. Feller, MD, FACP, FACG Q&A: Albert S. Woo, MD Forging a New Frontier in 3D Printing during COVID-19 Pandemic

Q&A: Dean Winslow, MD, on Volunteering in Antarctica [photo, left] Currently the only continent without confirmed cases of COVID-19

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 74 Spotlight

AUGUST 2020 August articles From Concerts to COVID: Transforming the RI Convention Center into an Alternate Hospital Site in under a Month Sonya Naganathan, MD; Kelly Meehan-Coussee, MD; Scott Pasichow, MD, MPH; Heather Rybasack-Smith, MD; William Binder, MD; Francesca Beaudoin, MD, PhD; Andrew N. Musits, MD, MS; Elizabeth Sutton, Md; Gianna Petrone, DO; Adam C. Levine, MD, MPH; Selim Suner, MD, MS SARS-CoV-2 Complicated by Sinusitis and Co-Infection with Human Metapneumovirus Abdulrahman Alharthy, MD; Fahad Faqihi, MD; Dimitrios Karakitsos, MD, PhD Acute Vision Loss in a Patient with COVID-19 Vijairam Selvaraj, MD; Daniel Sacchetti, DO; Arkadiy Finn, MD; Kwame Dapaah-Afriyie, MD Short-Term Dexamethasone in Sars-CoV-2 Patients Vijairam Selvaraj, MD, MPH; Kwame Dapaah-Afriyie, MD; Arkadiy Finn, MD; Timothy P. Flanigan, MD RI delegation announces $71.3M in CARES Act funds to five local hospitals COVID-19 testing site opens at Convention Center

Spotlight: Jonas Salk, Medical Sleuth and Scientist; Q & A with Jonathan Salk, MD

SEPTEMBER 2020 September articles Communicating Through COVID-19: Keeping Patients Connected to Loved Ones Anita Knopov, MD; Kelly Wong, MD; Rory Merritt, MD, MEHP COVID-19: Review of Current Recommendations for Return to Athletic Play James Dove, MD; Andrew Gage, MD; Peter Kriz, MD; Ramin R. Tabaddor, MD; Brett D. Owens, MD Q&A with Dr. Ashish K. Jha, New Dean of the Brown School of Public Health

OCTOBER 2020 October articles Why don’t people wear masks? Edward Feller, MD Emergency Mail-in Voting in Rhode Island: Protecting Civic Participation During COVID-19 and Beyond Nicole M. Burns, BS’23; Keyana Zahiri, BS’23; Reetam Ganguli, BS’23; Giovanni Kozel, BS’23; Saba Paracha, BS’23; Kevin P. Tang, BS’24; Oliver Y. Tang, MD’23; Kelly E. Wong, MD Experiences of Rhode Island Assisted Living Facilities in Connecting Residents with Families through Technology During the COVID-19 Pandemic Benjamin Gallo Marin, AB; Patrick Wasserman, AB; John Cotoia, MSc; Manraj Singh, AB; Vira Tarnavska, AB; Linda Gershon, MS; Ian Lester, BA; Rory Merritt, MD

FOCUS SECTION: COVID-19 – A Kidney Perspective Jie Tang, MD, Guest Editor Lifespan/Brown form COVID-19 Biobank

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 75 Spotlight

NOVEMBER 2020 November articles Responding to COVID-19 in an Uninsured Hispanic/Latino Community: Testing, Education and Telehealth at a Free Clinic in Providence Katherine Barry; Meghan Mccarthy; Gillian Melikian; Valerie Almeida- Monroe, MSN, APRN, NP-C; Morgan Leonard; Anne S. De Groot, MD Child Protection: A Guide for Navigating a Disclosure of Sexual Abuse in Rhode Island Amid the COVID-19 Pandemic Surya Manickam, MD, ScM; Brett Slingsby, MD Promoting Social Connectedness among Cardiac Rehabilitation Patients during the COVID-19 Pandemic and Beyond Lori A. J. Scott-Sheldon, PhD; Emily C. Gathright, PhD; Wen-Chih Wu, MD Conceal/Reveal Mask exhibit on display at RIDOH

DECEMBER 2020 December articles Reflections on 2020, the year of COVID Rhode Island Medical Journal Editors On the Frontlines William Binder, MD COVID’s Unexpected Gifts Edward Feller, MD Seismic Shifts in Primary-Care Delivery Kenneth S. Korr, MD Social Isolation of the Most Vulnerable; Behind the Mask Joseph H. Freidman, MD A Pandemic-Inspired Transformation of Primary Care Jeffrey Borkan, MD, PhD; Paul George, MD, MHPE; Eli Y. Adashi, MD, MS Severe, Symptomatic Reinfection in a Patient with COVID-19 Vijairam Selvaraj, MD; Karl Herman, MD; Kwame Dapaah-Afriyie, MD Through Plagues and Pandemics: The Evolution of Medical Face Masks Kelly Pan, Anuva Goel, Liliana R. Akin, Sutchin R. Patel, MD As COVID cases surge, RI opens two field hospitals Frontline workers vaccinated

Christian Arbelaez, MD, an emergency medicine physician, was the first person in Rhode Island to be inoculated against COVID-19. He received the first dose of the Pfizer vaccine on December 14 and the second dose on January 2.

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Dr. Carl Russell Gross Collection Documents RI’s Black History and Heritage GP served his patients for decades but was denied hospital privileges in Providence

Mary Korr 78 RIMJ Managing Editor 81 EN Early years He returned to Providence and set Dr. Gross’ father, William Gross, was up a general medical practice in his a janitor at Rhode Island College who family’s home at 49–51 Olney Street. earned $70 a month. His mother Lena He took care of sick children, deliv- worked in the laundry and Carl tended to ered thousands of babies and, like the the gardens to help pay for his schooling.2 busy general practitioners of the day, The RIC collection, while not autobi- made house calls on nights and week- ographical, offers glimpses of the young ends. Dr. Gross became a member of Mary Korr Carl; one note mentioned he played in the Providence Medical Association RIMJ Managing Editor Jackson’s Band in Pawtucket, another in 1917 and later on, the Rhode Island that the “Gross brothers” sold ads for Medical Society. During World War I, the Providence Chronicle, a newspaper he enlisted in the US Army Medical of the Black community. He completed Corps, and served from 1917–1919. his early schooling in Providence, and then attended the Howard Academy in Denial of hospital privileges Washington, D.C., followed by Howard But while he could serve his country, he University College of Medicine (founded could not fully serve his patients. in 1868, open to all races and genders), He and other Black physicians were graduating as class president in 1913.3 denied hospital staff privileges in Carl Russell Gross, MD [RIC Collection] many hospitals in Rhode Island on account of race, a practice Since 1976, February has been des- that was not singular to this ignated as Black History Month in state. (See Timeline: Organized this country. Chronicling the Black Medicine/Racial Disparities) history and heritage of Rhode Island A biographical sketch at was a lifetime pursuit of Providence Howard University showed he native Carl Russell Gross, MD, applied for staff privileges at (1888–1971). Providence hospitals in 1939 “My first interest in history was and was rejected.3 at the age of ten, in 1898, when I It also stated that in 1942, could hardly wait for the Provi- during World War ll, Dr. Gross dence Evening Bulletin to arrive, resigned from the medical ex- my parents to finish reading it, so aminer’s district draft board I could cut out the pictures of bat- after being only sent Black tleships to paste in my own scrap- draftees to evaluate. book,” he wrote in a collection of his research archived at Rhode Poster announcing exhibit at the Island College (RIC). “There was National Library of Medicine a family scrapbook containing February–May 1988 shows 19th- articles mainly about the Negro century wood engraved illustration which I read. Many old clippings of Howard University. have been transferred to my files [National Library of Medicine, which have been a great source of http://resource.nlm.nih.gov/ interest in my later research.”1 101437595]

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It would take decades, until Court rulings and the passage of the Civ- il Rights Act of 1964 and Medicare and Medicaid legislation the following year, to mandate institutional change. (See Court Ruling & Civil Rights Act.) By that time Dr. Gross had retired from practice. In June 1970, Rhode Island Col- lege awarded Dr. Gross an honorary Doctor of Humanities (DH) degree. Less than a year later, he died in his This editorial appeared in the September 1964 issue of the Rhode Island Medical Journal. home on April 7, 1971 at the age of 82. His obituary in the Rhode Island Timeline: Organized Medicine/Racial Disparities Medical Journal stated his contributions and memberships in various organiza- 1895: The National Medical Association (NMA), open to all races, founded. Two RI physicians served as presidents: Marcus F. Wheatland, MD, 1910; William H. Higgins, MD, 1931. tions, including the Providence Tuber- culosis Society, the Medical Advisory 1939: The American Medical Association House of Delegates adopts a policy discouraging Committee to the Rhode Island Maternal racial discrimination in constituent society membership, but notes that it cannot control their Health Association, the National Confer- membership policies. ence of Christians and Jews, and the Na- 1944: The NMA argues that insofar as medical societies, “particularly in the South,” continue tional Association for the Advancement to “exercise a bar to the membership of Negro physicians,” the AMA should allow “members of Colored People. in good standing of the [NMA] to become members of the constituent societies of the [AMA].” The AMA House of Delegates rejects the proposal on the grounds that membership matters are controlled by constituent societies. Court Ruling & Civil Rights Act of 1964 1963: The Rhode Island Medical Society proposes excluding discriminatory societies from It would take Court rulings and the passage of the AMA, but the idea is rejected for reasons that had remained unchanged for decades: the Civil Rights Act of 1964 to broadly address “progress” is already being made and membership matters are controlled by constituent structural racial inequities in organized medi- societies. cine. In 1963, the case of Simkins v. Moses H. 1964: The AMA passes a resolution stating it is: “unalterably opposed to the denial of Cone Memorial Hospital was adjudicated by the membership, privileges, and responsibilities in county medical societies and state medical United States Court of Appeals, Fourth Circuit. associations to any duly licensed physician because of race, color, religion, ethnic affiliation The lawsuit was brought by Black physicians, or national origin”; however, it did not have enforcement provisions. dentists and patients in North Carolina who 1968: The Massachusetts Medical Society proposes that the AMA amend its Constitution sued defendant hospitals and their administra- and Bylaws, to give the Judicial Council the authority to expel constituent societies for race tors and directors for discrimination because of discrimination in membership policies. The AMA House of Delegates adopts the resolution. their race. The Court of Appeals held that por- tion of Hill-Burton Hospital Survey and Con- 2008: The AMA issues a formal apology for discriminating against black physicians struction Act tolerating “separate-but-equal” well into the 1960s; acknowledged “its past history of racial inequality toward Afri- facilities for separate population groups was can-American physicians.” An editorial in the July 16, 2008 issue of the Journal of the unconstitutional under the due process clause of American Medical Association stated that “the AMA failed, across the span of a century, the Fifth Amendment and the equal protection to live up to the high standards that define the noble profession of medicine.” clause of the Fourteenth Amendment. 2018–2019: In 2018, the AMA adopted policy to define health equity and outline a One year later, with the passage of the Civil strategic framework toward achieving optimal health for all. In 2019 the AMA hired its Rights Act of 1964, Title VI made discrimina- first chief health equity officer to establish the AMA’s Center for Health Equity. tion in hospitals receiving federal funds illegal. 2020: New AMA policy recognizes racism as a public health threat. Policy adopted by phy- With the passage of Medicare and Medicaid leg- sicians at the American Medical Association’s (AMA) Special Meeting of its House of Del- islation in 1965, hospital integration was essen- egates (HOD) in November 2020 recognizes racism as a public health threat and commits tially federally mandated. to actively work on dismantling racist policies and practices across all areas of health care.

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In one of his manuscripts, Dr. Gross of those born in Rhode Island – in his It is fitting, then, to end this Heritage noted he researched history “for pos- records he put an asterisk before their piece in the same way: *Russell Carl terity.” (Excerpts, next page) He took names, and at the bottom of the page Gross, MD, DH. obvious pride in the accomplishments noted: *Native-born Rhode Islander. *Native-born Rhode Islander

March 1, 1957 Providence Journal newspaper clipping in Dr. Gross's file.

References 1. Sketches on Negroes and Events in Rhode Island, 1696-1970. Rhode Island Col- lege, James P. Ad- ams Library Digital Commons, Dr. Carl Russell Gross Col- lection. https://digi- talcommons.ric.edu/ crgross_papers/ 2. Christiansen E. Rhode Island College: Meeting the State’s Needs Through Time. 2016; P. 21. 3. Howard University, Carl R. Gross Col- lection. Staff, MSRC, “Gross, Carl” (2015). Manuscript Division Finding Aids. 86. https://dh.howard. edu/finaid_manu/86

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Excerpts: Notes on Early Black Physicians In 1935, Dr. Gross was appointed to the Rhode Island State Tercentenary Committee which compiled files pertaining to Black history in the following categories, according to his writings: “art, churches, Brown and Pembroke, clubs and organizations, dentistry, education, inventors, law, legislature, medicine, military, pharmacy, press, and nurses.” The following are several samples from Dr. Gross’ medicine folder; each one has a unique story and will be followed up in future Heritage articles.

1893 – Peter Moore, MD, 1st Negro to reg in R.I. 1924 – Rudolph C. Fisher, MD, Classical High; BA Brown, 19; MA Brown, 21; MD Howard, ‘24; Phi 1894 – Marcus F. Wheatland, MD, reg 1894, owner Beta Kappa; X-Ray; in 35 called one of the “Ablest of of one of the first X-ray machines in R.I. Negro Writers”; Brown has his original manuscripts.

1894 – James A. Gilbert, MD – Born in Bermuda, 1924 – *Chester W. Chin, MD, b. East Prov., One of 1867; graduated Howard University School the first of two Negro ophthalmologists to reg in N.Y. of Medicine, 1894; practiced on Thayer Street until 1946; member of the Rhode Island Medical 1952 – At a social gathering a small group heard Society (1895). Dr. Effie Ellis, a resident in Pediatrics at the Prov- idence Lying-In Hospital, tell of the concern of 1900 – Julius J. Robinson, MD, (1872–1924). the white teaching staff as to the future of Negro Graduate of Howard, 1898; internship in Freed- medical students, their opportunities for getting man’s Hospital, Washington D.C, then came to an education and the opening of white medical Providence where he practiced at 247 Cranston schools to Negroes of high scholastic standing, and St. until his death. First president of the NAACP the need of those who are out to help another up in RI, 1913. Member of the Rhode Island Medical the ladder. She told of a Providence boy, premed Society, the Providence Medical Association. at Howard University, on the Dean’s list for three years, who graduates this year and might not be 1903 – William H. Higgins, MD, born in North able to finance himself on account of the drain so Carolina 1873, died in Providence 1938. Graduate far… She wondered if we had 100 friends who would of Leonard Medical College 1902, came to Prov- give $10.00. That is how the Greater Providence idence 1903. Member of the Providence Medical Scholarship Committee was formed. Association, the Rhode Island Medical Society, the What Cheer Medical Society (state Negro), 1957 – Okogbue Okezie, MD, 1st black to interne member and past president [1931] of the National in a gen. hospital in Prov. Medical Association (National Negro)…the Negro equivalent to the American Medical Association 1966 – *Robert J. Robinson, MD, b. Prov. 7-2-18; which would not accept Negro physicians then apptd. by Dr. Goddard, acting director, FDA bureau for membership. Appt’d by the Gov., member and of medicine. EB 3-19-66. elected chairman, RI Board of Podiatry, 1936.

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 81 IN THE NEWS

URI College of Health Sciences Dean Gary Liguori RI receives $70.4M updates ACSM’s “Guidelines for Exercise Testing to expand COVID-19 and Prescription” testing, vaccine KINGSTON – University of Rhode Island College of distribution efforts Health Sciences Dean Gary Liguori, PhD, is the lead Rhode Island has received an infu- editor of the 11th edition of “ACSM’s Guidelines for sion of $70.4 million in federal fund- Exercise Testing and Prescription,” the flagship title ing to bolster the state’s coronavirus from the American College of Sports Medicine, which testing and vaccination programs, sets the standards for the exercise profession. Health U.S. Senator Jack Reed announced Sciences Associate Dean Deb Riebe edited the 10th edi-

tesy o f U RI in a statement on January 25th. tion of the book in 2017, for which Liguori served as an The Centers for Disease Con- associate editor. trol and Prevention (CDC) funding, The book is updated every four to six years, delivering

P hoto C ou r from the COVID-19 emergency the latest evidence-based recommendations and guide- relief package signed into law in lines. Liguori’s edition is due out in March 2021, with exercise standards expected December 2020, was awarded to the to be implemented in the fall. Liguori estimates he and his team of authors – Rhode Island Department of Health including Riebe and Bryan Blissmer, director of the URI Institute for Integrated (RIDOH), and will be used to expand Health and Innovation – revised more than half the content in the book, including COVID-19 testing and vaccine dis- updating research with more relevant studies, deemphasizing antiquated exercise tribution across the state, according advice, and reflecting new techniques for measuring vital signs like ideal heart rate. to the statement from Sen. Reed. “One notable suggestion we made is around people who have open heart sur- Nearly $61 million is allocated to gery,” Liguori said. “Patients have typically been ordered to restrict arm move- support the state’s COVID-19 test- ment for fear of reopening the incision. But really all the evidence says that you ing capacities, contact tracing and can have arm movement; just be thoughtful about it. We’re not telling them to go containment and mitigation efforts, out and do pushups or boxing the next day. But we’re really saying the evidence while an additional $9.5 million will shows, within limits, you don’t have to be so restricted.” enhance vaccine distribution. v Physical activity is also critical for brain health, the subject of a new, standalone chapter Liguori added to the Guidelines. It advocates the benefits of physical activity on everything from Parkinson’s and Alzheimer’s disease, to ADHD, depression and anxiety. The benefits of high-intensity exercise, particularly in regard to various disease states like heart disease and high blood pressure, along with neurological disorders, continues to mount and is emphasized in this edition. “The mode of exercise is not so important; just that you’re really working hard for a short burst of time,” Liguori said. “High intensity activity can be quite effective for a whole host of conditions. But really, any bout of activity, of any length, of any intensity, is helpful and absolutely better than no activity. If you sit at a desk all day, and you can get up periodically, even for just a minute or two to take a walk, that’s much better than not getting up at all throughout the day. The evidence is overwhelming that anything is helpful.” This is not the first book Liguori has worked on with the organization. In addition to serving as associate editor on the previous iteration, he has also served as senior editor on the first edition ACSM Resources for the Exercise Physiologist, and senior editor on the organization’s annual Health Related Physical Fitness Assessment Manual. Editing the “Guidelines for Exercise Testing and Prescrip- tion” was a particular honor for him, given the importance the text holds in the exercise, kinesiology, physical therapy industries and more. “I get a little chill when I think about being the editor,” Liguori said. “As a student and a young professional, one of the things I looked forward to every four or five years was when the new edition would come out, and seeing who was the team that did the new version. I really looked up to those people and admired them. So for me, it is incredibly humbling. It’s something I never even imagined would be on my horizon.” v

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 82 IN THE NEWS

Brown researchers designing adverse Trio of centenarian Navy veterans event monitoring system for receive COVID-19 vaccination post-covid-19 vaccination impacts PROVIDENCE – Three Rhode Island centenarian Navy Veter- ans of World War II received their initial doses of COVID- in elderly nursing home residents 19 vaccine at the Providence VA Medical Center on Jan. 20. PROVIDENCE – The National Institute on Aging (NIA) has 105-year-old Arthur Prisco, of Warwick, and 100-year- awarded a supplemental grant to Brown University School olds Raymond Gannon, of Pawtucket, and Peter Ricci, of Public Health to design an adverse event monitoring of West Warwick, are three of the most recent recipients system to identify adverse health impacts after receipt of of the Moderna COVID-19 vaccine at the Providence VA COVID-19 vaccination by elderly nursing home residents. Medical Center’s COVID-19 Veteran Vaccination Clinic, This new effort, a supplement to the $53.4M NIA IMPACT Collaboratory grant awarded to the School of Public Health and Hebrew SeniorLife in September 2019, provides funding for the School to work with Genesis HealthCare (Gen- esis), one of the nation’s largest post-acute care providers with more than 350 facilities across 25 states. Brown will monitor the occurrence of adverse events following nursing home residents’ receipt of a COVID-19 vaccine in facilities affiliated with Genesis. Since the beginning of the pandemic, Brown and Genesis have been working together to study data and uncover patterns that can be used to develop informed strategies to mitigate the impact of the pandemic in nursing homes. Vincent Mor, PhD, lead investigator and Professor of Health Service, Policy and Practice in the School of Pub- 100-year-old World War II Navy Veteran and Pawtucket resident lic Health, said “Nursing home residents constitute about Raymond Gannon, left, and 105-year- old World War II Navy Veteran 40% of all deaths due to COVID in the nation, but make and Warwick resident Arthur Prisco, after receiving their initial dose. up less than one half of one percent of the US population. [VA Providence HCS photo by Kimberley DiDonato] Residents are in desperate need of protection from the virus 100-year-old World War but no one as sick as a nursing home resident was enrolled II Navy Veteran and West in any of the vaccine trials.” Warwick resident Peter Ricci This work is part of the Centers for Disease Control’s points to his bandage after effort to establish Vaccine Adverse Event Monitoring Sys- receiving his initial dose of tems, particularly focused on the frail elderly who were not the Moderna COVID-19 included in the vaccine trials. vaccine at the Providence Mor added that “We don’t know how frail seniors will VA Medical Center, January react to the vaccine and it will roll out quickly once distri- 20, 2021. bution begins. Under normal circumstances, we would not [VA Providence HCS photo know until most residents have been vaccinated if the rate by Winfield Danielson] of adverse events is higher than expected. Therefore, the ‘real time’ adverse event monitoring system we are estab- located in Building 32 on the main campus, 830 Chalkstone lishing cooperatively with the CDC and Genesis is unique Ave. in Providence. In all, more than 700 Veterans enrolled and critically important to understand how frail seniors with the VA Providence Healthcare System have received will respond to the vaccines.” the vaccine. Additional local collaborations in this work include the “Some people are refusing to get it,” said Ricci. “I say, Rhode Island Quality Institute led by Neil Sarkar, PhD, what have you got to lose?” president and chief executive officer, and Associate Profes- “We’re excited to be taking the offensive against the sor of Medical Science at the Warren Alpert Medical School coronavirus in 2021, offering the Moderna COVID-19 vac- of Brown University. cine to our Veterans at highest risk of severe illness,” said The work is supported by the National Institute on Lawrence Connell, director of the VA Providence HCS. Aging of the National Institutes of Health under Award No. “As vaccine supplies continue to arrive, our ultimate goal U54AG063546. v is to offer free COVID-19 vaccination to all enrolled Veter- ans and VA employees who want it.” v

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1 www.cdc.gov/tobacco/data_statistics/fact_sheets/cessation/quitting/index.htm IN THE NEWS

Lung Association Report: Rhode Island has mixed grades in ending tobacco use State earns F grade for prevention funding; D grade in new flavored tobacco category

PROVIDENCE – This year’s “State of Rhode Island’s Grades e-cigarettes – setting them up for a life- Tobacco Control” report from the “State of Tobacco Control” 2021 grades time of addiction to nicotine. Ending American Lung Association grades fed- states and the District of Columbia in the sale of flavored tobacco products, eral and state efforts to reduce tobacco five areas that have been proven to pre- including menthol, will not only help use and calls for meaningful policies vent and reduce tobacco use and save end youth vaping, but will also help that will prevent and reduce tobacco lives. Rhode Island received the follow- address the disproportionate impact of use and save lives. The report finds that ing grades: tobacco use and exposure to second- Rhode Island had mixed grades on its 1. Funding for State Tobacco Prevention hand smoke on Black and Brown com- efforts to reduce and prevent tobacco Programs – Grade F munities. Menthol cigarettes remain use, earning an F grade for tobacco pre- 2. Strength of Smokefree Workplace Laws – a key vector for tobacco-related death vention and control funding and a D Grade A and disease in Black communities, grade for flavored tobacco products. 3. Level of State Tobacco Taxes – Grade B with nearly 85% of Black Americans Tobacco use remains the nation’s 4. Coverage and Access to Services to Quit who smoke using them. leading cause of preventable death and Tobacco – Grade C “Kids follow the flavors and ending disease, taking an estimated 480,000 5. New: Ending the Sale of All Flavored the sale of all flavored tobacco products lives every year. Much like COVID- Tobacco Products – Grade D in Rhode Island is key to ending the 19, tobacco use and secondhand smoke The report finds that while Rhode youth e-cigarette epidemic and youth exposure disproportionately impacts Island has taken significant steps to tobacco use overall. We call on legis- certain communities, including com- reduce tobacco use, including prohib- lators in Rhode Island to prohibit the munities of color, LGTBQ+ Amer- iting the sale of flavored e-cigarettes sale of all flavored tobacco products, icans and persons of lower income. in the state, elected officials must do including menthol.” said Fitzgerald. To address this critical public health more to protect youth from all tobacco The American Lung Association also threat, “State of Tobacco Control” products. With 1 in 5 teens vaping, encourages Rhode Island to increase provides a roadmap for the federal and children are becoming the next gener- funding for prevention and control state policies needed to prevent and ation addicted to tobacco. Youth vap- funding, equalize taxes for all tobacco reduce tobacco use. ing and tobacco use overall is largely products, and prohibit the sale of “In Rhode Island, our high school driven by flavored tobacco products, tobacco products in pharmacies. tobacco use rate remains at 33.3%. The and the 19th annual report has added “Despite receiving over $188 million surge in youth vaping combined with a new state grade calling for policies from tobacco settlement payments and the fact that smoking increases the to end the sale of all flavored tobacco tobacco taxes, Rhode Island only funds chance of severe COVID-19 symptoms, products, including menthol cigarettes, tobacco control efforts at 13.5% of the make it more important than ever for flavored e-cigarettes and flavored level recommended by the CDC. The Rhode Island to implement the proven cigars. Rhode Island received a D grade Lung Association believes the funds measures outlined in ‘State of Tobacco in this category, recognizing its prog- should be used to support the health Control’ to prevent and reduce tobacco ress in restricting flavored e-cigarettes of our communities, and to prevent use,” said American Lung Association in all locations, but calling for further tobacco use and help smokers quit, and Senior Manager of Advocacy in Rhode action prohibiting the sale all flavored not switch to e-cigarettes. These pro- Island, Daniel Fitzgerald. tobacco including menthol cigarettes. grams are also critical for helping to In 2019, about 8,000 kids began vap- end tobacco-related health disparities,” ing every day – typically with flavored said Fitzgerald. v

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 85 IN THE NEWS

Basal cell carcinoma chemoprevention CNE expands services in South County VA trial funded Includes programs, clinics for behavioral health and

PROVIDENCE – Researchers from VA healthcare systems addiction issues, women’s healthcare, bariatrics across the country will participate in a basal cell carci- Care New England has opened additional programs and noma preventive medication trial that received a funding clinics at its current South County location in South decision January 8. Kingstown. Among the programs and services that have Study chair Dr. Martin A. Wein- now been expanded in South County are behavioral health, stock, Chief of Dermatology Research women’s healthcare and surgical weight loss. for the VA Providence Healthcare Sys- tem, and professor of Dermatology and Butler Hospital programs Epidemiology at Brown University, and To offer care to people with behavioral health and addiction co-chair Dr. Robert Dellavalle, issues, Butler Hospital will offer recovery stabilization ser- Chief of Dermatology for the VA Eastern vices to patients in South County and throughout Rhode Colorado Health Care System, and pro- Island, at its new facility, located at 20 Commons Corner fessor of Dermatology and Public Health Way, Building 12 in Wakefield, RI. Programs include Inten- at the University of Colorado School of sive Outpatient Programs (IOP) for substance use, medi- Dr. Martin A. Weinstock Medicine, will research imiquimod, a cation assisted therapy, early recovery groups, outpatient topical medication with minimal side therapy, and outpatient psychiatry. effects, as a preventive measure against W&I, Kent women’s healthcare programs basal cell carcinoma, known as BCC, In addition, in an effort to provide easy access to women’s which is the most common cancer in healthcare, and to create a more comprehensive women’s the United States. health center in South County, Women & Infants Hospi- The six-year, $34 million trial, funded tal and Kent Hospital, is expanding breast health services, by the VA Cooperative Studies Program, urogynecology, prenatal services and other programs in its will recruit more than 1,600 partici- South County location. pants at 17 VA medical centers, includ- The Care New England Center for Health has opened a ing male and female veterans at high Urogynecology and Pelvic Floor clinic at 49 South County risk for BCC. The study will follow par- Commons Way in South Kingstown, to offer a full spec- Dr. Robert Dellavalle ticipants actively for three years, with trum of women’s care to patients located in the southern an additional year of passive follow-up. part of the state. “This study is important for VA because active duty The High Risk Breast Program offers such services as military and Veterans are at higher risk for developing basal close examination and imaging of higher density breast cell carcinoma,” said Weinstock. “If this trial finds that tissues, and other factors that may genetically increase imiquimod is successful at preventing BCC, it would fun- chances of being affected by breast disease. damentally transform our approach to the disease.” BCC generally occurs on the face and requires surgery to Center for Surgical Weight Loss avoid serious complications. If the medication proves effec- Also, recently, Care New England’s Center for Surgical tive, it may avoid these complications, reduce skin damage Weight Loss has opened an additional office at 49 South and scarring, and reduce the need for medical visits and the County Commons Way, where Dr. Jeannine Giovanni, resulting costs, as well. In addition to evaluating effective- Director of Bariatric Surgery, and Dr. Lindsay Tse, bari- ness of the treatment, researchers will collect genetic mate- atric surgeon, provide patients in South County with easier rial from some of the participants to determine factors that access to surgical weight loss consultation and treatment. v may indicate greater risk reduction and better tolerance of imiquimod therapy, to help target therapy to those with greater potential for BCC prevention from the medication with fewer bothersome side effects. v

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 86 IN THE NEWS

Partners in Primary Care joins South County Health as South County Primary Care Drs. Brian J. Pickett, Stephanie Krusz join South County Health Medical Staff

CRANSTON – South County Health, Dr. Pickett received his medi- along with Brian J. Pickett, MD, cal degree from Ross University and Stephanie Krusz, MD, recently School of Medicine, Dominica, announced that Partners in Primary West Indies and completed his Care, a two-physician primary care residency and internship at Brown practice located at 905 Pontiac Ave- University/Memorial Hospital of nue in Cranston, is now part of the Rhode Island. A board-certified physician, he is currently the physician-in-chief for the Rhode Island State Police, a position he has Dr. Brian J. Pickett Dr. Stephanie J. Krusz held since 2002. Dr. Krusz, an Air Force vet- “We are thrilled to welcome Dr. eran who served as General Pickett and Dr. Krusz to the South Medical Officer and Medical County Health team,” said Aaron Director of Emergency Ser- Robinson, President/CEO of South vices at Hanscom Air Force County Health. “These physicians are Base, Massachusetts, and Osan known for their focus on the individual Air Force Base, South Korea, needs of their patients while bringing respectively, is board-certi- a record of high-quality service. Their fied in internal medicine. She approach to medicine is a perfect match received her medical degree for the South County Health culture. from Brown University Medi- We look forward to working with them cal School and completed resi- as they continue to serve the Cranston dency at David Grant Medical community.” Center, Travis Air Force Base, In addition to the new Cranston California. location, South County Health oper- Dr. Pickett and Dr. Krusz, along with their ates Primary Care practices staff, stand next to the outdoor sign bearing in East Greenwich, Wake- the practice’s new name at 905 Pontiac Ave. field, and Westerly. v

South County Health Medical Group. As of January 1, 2021, the practice was [L–R] Dr. Stephanie J. Krusz, Dr. renamed South County Primary Care – Brian J. Pickett, and Aaron Rob- Cranston. It is now part of the South inson, President/CEO of South County Health system in Wakefield. A County Health, cut the ribbon to formal ribbon-cutting ceremony took celebrate the practice joining the place on January 25th. South County Health system.

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 87 IN THE NEWS

Researchers at Providence VA, Butler awarded DHHS $2.24M grant to study sleep disruption, suicide risk

PROVIDENCE – Butler Hospital greatest suicidal risk, modeled at has announced that the Depart- the individual level.” ment of Health and Human Ser- The proposed study builds vices has awarded it a research upon Armey and Bozzay’s team’s grant in the amount of $2.24 extensive expertise in sleep/wake million for its study, Dynamic cycles, psychophysiology, deep Impacts of Sleep Disruption on phenotyping, and multi-method, Ecologically Assessed Affective, multivariate, ecologically valid Behavioral, and Cognitive Risk models of suicide vulnerability Factors for Suicide, which will try in high-risk psychiatric popu- to identify proximal predictors Dr. Michael Frederick Armey Dr. Melanie Bozzay lations. During their upcoming of suicide risk. research, they will examine how The principal investigators for the grant are Michael a holistic model of atypical sleep relates to known trait (base- Frederick Armey, PhD, Research Psychologist, Butler line neurocognitive performance; e.g., greater impulsive ten- Hospital, Associate Professor of Research, Department of dencies, higher loss sensitivity, reduced ability to regulate Psychiatry and Human Behavior, The Warren Alpert Med- emotions) and state (time-varying, occurring hours to days ical School of Brown University, Associate Director of the before suicidal ideation and behavior; e.g., momentary fluc- Consortium for Research Innovation in Suicide Prevention tuations in emotional reactivity, impulsivity; greater emo- (CRISP), The Warren Alpert Medical School of Brown Uni- tional lability; greater isolative tendencies), risk factors for versity, and Melanie Bozzay, PhD, Postdoctoral Fellow suicide, and examine how these factors together proximally at The Warren Alpert Medical School of Brown University influence suicidal ideation and confer risk for future suicidal and the Providence VA Center for Neurorestoration and behavior. Neurotechnology. For their study, Armey and Bozzay intend to recruit 200 “While we know who, in general, is at risk for suicide, psychiatric inpatients at high risk for suicide and conduct a such as people with mental illness, older adults, men, vet- baseline assessment of sleep/wake functioning and trait risk erans, and others, these are huge groups, and even in people factors and use laboratory-based tasks coupled with psycho- identified at risk, the chance of any one individual dying by physiology (i.e., event-related potentials, heart rate variabil- suicide remains low. So, we can use proximal predictors of ity, and electrodermal activity) to phenotype risk processes risk - in the case of this study, technology to monitor sleep linked to arousal and cognitive systems. This baseline and affective, behavioral, and cognitive predictors of suicide assessment will be followed by four weeks of EMA and digi- risk - in the real world,” said Dr. Armey. tal phenotyping coupled with actigraphy to characterize key “We follow patients after they’re discharged from the state risk factors. hospital. They wear a sleep monitor watch and complete “We will conduct follow-up assessments at 1-, 3-, and questionnaires on their phones to give us a clearer picture of 6-months post-hospital discharge to determine how our each individual’s risk profile. Although this technology and proximal model of risk prospectively predicts suicidal ide- approach is fairly new, we published a paper back in 2018 ation and behavior. The proposed study aims to character- that showed our approach is between two and three times ize proximal risk for suicide using intensive longitudinal better at linking emotional disturbance to elevations in sui- methods and to identify “windows” of greatest risk for suicidal ideation over a three-week, post-hospital discharge,” cide, which may vary from person to person, that serve as he added. markers for intensive intervention. Finally, we will leverage According to Dr. Bozzay, “Suicidal ideation and behavior this extensive dataset to develop a model of the sleep-sui- are growing public health problems in the United States. cide relationship emphasizing the contribution of trait and Unfortunately, our current ability to predict suicide is state factors. The results of this study have the potential only slightly above chance, which may be attributable to greatly enhance our understanding of the phenomenol- to an overreliance on distal or cross-sectional risk factors ogy of suicide risk as it exists in the real world, with the that are weak proximal predictors of suicide risk. Modeling potential to improve our ability to predict, prevent, and the complex process by which atypical sleep impacts daily intervene using both traditional and technology-enhanced functioning in conjunction with established proximal risk psychotherapies,” added Dr. Armey. v factors can aid in identifying contexts and time periods of

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 88 IN THE NEWS

Lifespan Urgent Care opens 3rd location in Providence

PROVIDENCE – A new Lifespan Urgent Care facility has opened at 66 Branch Ave., the site of the former Benny’s. Lifespan Urgent Care opened the first location in Septem- ber 2019 in Warwick (17 Airport Rd., at Hoxsie Four Corners) and the second location in November 2019 in Middletown (1360 West Main Rd., in the Stop & Shop plaza). Visiting a Lifespan Urgent Care, a program of Lifespan Physician Group, has the added benefit of seamless access to a patient’s electronic medical records on the MyLifespan patient portal as well as to Lifespan emergency services and specialists if needed. Patients who need to visit Lifespan Urgent Care can just walk in, they can register online and reserve a time slot for a face-to-face appointment, or for patients with certain conditions, video visits are available. All Lifespan Urgent Care facilities are under the super- vision of medical director Olivier Gherardi, DO. v

Developer closes on former Memorial Hospital site Plans Set for Veterans Housing and Education Center

PAWTUCKET – Mayor Donald R. Grebien and Lockwood of work and thorough review, with the completion of an Development Partners’ President Charles Everhardt approval process by the Rhode Island Attorney General, announced that they have finalized the closing of the former using the “Cy Prés” doctrine. Memorial Hospital site from Care New England. Lockwood Lockwood and VSUSA will develop the site into a 390,000 has proposed redeveloping the long-vacant property into a sq. ft. campus that will include over 200 apartments prior- housing and education center for veterans. itized for senior veterans, an adult day healthcare facility “The City of Pawtucket has long supported the redevelop- for therapy and other social services, a career training and ment of the underutilized former Memorial Hospital site to education program for newly-transitioned veterans intent a project that benefits and meets the community’s needs,” on reskilling or upskilling for the civilian workforce, and said Mayor Donald R. Grebien, who introduced Lockwood medical and lab space to address veterans’ as well as the to Care New England. “We thank Charles and his team for community’s whole health needs. The development will their transformational vision to bring a veterans’ facility and also include dormitory space for veterans participating in the ancillary economic development that it will create to our the career training and education program with an emphasis community. The City will also continue to fiercely advocate on medical careers. for medical services for the community as a whole.” This economic development project is expected to cost Lockwood and Veteran Services USA (VSUSA) are design- $70 million and create up to 500 jobs during construction, ing a revitalization plan with the view to transform the which includes 3rd-party consultants and construction vacant Memorial Hospital into a safe, clean, and enjoyable workers, and up to 60 permanent jobs in the community place to live for Rhode Island’s aging veteran community. after the project is complete. “For our senior veterans, our goal is to create affordable All buildings on the site will be retained and enhanced as housing with therapeutic amenities. Our staff will strive part of this historic preservation project. Lockwood is com- to instill a positive spirit while aiming to enhance a better mitted to following sustainable practices in the redevelop- quality of life for every resident,” said Charles Everhardt. ment of this project and will include extensive landscaping “For our younger veterans, our goal is to provide training and other amenities within the campus. and education to carefully position them into the healthcare The zoning and permitting process is set to begin by mid- workforce, enabling each veteran to excel and shine with 2021 with interior demolition anticipated for late-2021. Con- their passion to serve others.” struction for the project is slated to commence in 2022 with Lockwood’s purchase of the site, which includes the main completion in 2023. As part of a transparent process, the hospital building, is the culmination of over 18 months project will include opportunities for community input. v

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 89 People / PLACES

Appointments Maria Ducharme, DNP, RN, named Miriam Hospital President

PROVIDENCE – Maria Ducharme, DNP, Patrick Tigue confirmed as RN, NEA-BC, has been promoted from her OHIC’s new Commissioner position as senior vice president of patient care services and chief nursing officer to Following the retirement of Commissioner Marie Ganim, president of The Miriam Hospital, which Patrick Tigue has joined the Office of the Health Insurance became effective Jan. 1, 2021. She suc- Commissioner (OHIC) in January serving as the agency’s new ceeds Arthur J. Sampson, who retired at commissioner. In December of last year, after being nominated the end of 2020 after serving as president by Governor Gina Raimondo, Tigue was unanimously approved since 2012. by the Rhode Island State Senate Health and Human Services Dr. Ducharme, who has spent her entire professional career committee and approved by the full Senate afterward. at The Miriam Hospital, was appointed following a national Prior to joining OHIC, Commissioner Tigue served as the search. Following her graduation from Rhode Island College in Assistant Secretary for Health and Medicaid director for RI’s 1987, she was hired as a cardiovascular medical/surgical nurse. Executive Office of Health and Human Services where he led In 2010, she was named senior vice president for patient care the state’s Medicaid program, which under his leadership served services and chief nursing officer of The Miriam. approximately 300,000 residents and had an annual budget of She has led some of The Miriam’s most ambitious and suc- approximately $2.5 billion. cessful efforts to achieve excellence in the quality of patient Commissioner Tigue plans to accelerate and expand upon the care at the hospital. Most recently, she has helped lead the ongoing successes OHIC has achieved in expanding access, par- hospital’s response to COVID-19, directly overseeing the re- ity, and affordability of health care in our state. In particular, finement and deployment of new safety protocols developed in Commissioner Tigue has laid out six items in which he will be response to the coronavirus pandemic. Under her stewardship, focused on as he begins his tenure as commissioner: The Miriam attained four-year Magnet recognition – considered • Continuing to ensure that Rhode Islanders receive adequate the gold standard for nursing excellence – six consecutive times, coverage for COVID-19 testing, treatment, and care. which is a feat accomplished by only three other hospitals in the • Leveraging the regulatory structure within OHIC to acceler- United States. ate delivery system reform. Dr. Ducharme earned a Doctor of Nursing Practice from • Continued implementation of the Affordability Standards. Massachusetts General Hospital Institute of Health Professions (2015), a Master of Science degree in nursing from the Univer- • Continuing to increase behavioral health care access and sity of Rhode Island (1996), and a Bachelor of Science degree in ensure parity between behavioral and physical health care nursing from Rhode Island College (1987). services. She lives with her husband, ophthalmologist Joseph Ducharme, • Advancing the statewide expansion of telehealth services. MD, in her native Barrington, where she graduated from Bar- • Continuing on the success of the RI Cost Trends Project. v rington High School in 1982. They have three children. v

Providence Center names Tiffney Davidson-Parker President, COO

PROVIDENCE – Tiffney Davidson-Parker is SVP, CNE Behavioral Health Service Line. the new President and COO of The Providence Davidson-Parker recently served as the Founder Center. Her first day was January 11, 2021. and Chief Executive Officer for Universal Thera- “Davidson-Parker was selected after a national peutic Services (UTS) in South Carolina – an out- search for a new President and COO of The Prov- patient behavioral healthcare community-based idence Center. Her experience and educational agency, serving the ages of two and beyond. During background makes her an ideal candidate to lead her service, the organization served 400+ families, The Providence Center’s health care services and secured an ethnically diverse team of clinicians social programs. Throughout her career, Tiffney and established multiple sustained partnerships. has served in many roles to evaluate and strength- Previously, as Chief of Operations for Visions of en systems of care for children, families, and those Greatness (VOG), she implemented six programs with medical and mental illness, which will make her a valued and obtained a three-year CARF accreditation with a letter of asset to our TPC community and Care New England,” said high honors sent to the Governor’s Office of South Carolina, Mary Marran, President and COO, Butler Hospital, and and an invitation to become a CARF Evaluator. v

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 90 People / PLACES

Appointments

Angela Bannerman Ankoma Christine Foley, MD, elected named V-P, Director of the to Fellowship in Minimally Equity Leadership Initiative Invasive Gynecologic at Rhode Island Foundation Surgery (FMIGS) Board Angela Bannerman Ankoma, MS, Christine Foley, MD, of Women has been appointed a vice president of the & Infants Hospital, was elected to Rhode Island Foundation. The Providence the Fellowship in Minimally Inva- resident will lead the Equity Leadership sive Gynecologic Surgery (FMIGS) Initiative, which is one aspect of the Board by the current FMIGS fellows Foundation’s broad, 3-year, $8.5 million and program directors. She will serve plan to eliminate inequality and racial disparities and promote as Fellows Representative during this two-year commitment, inclusion and diversity. Ankoma will also serve as a member of which began in January 2021. the Foundation’s leadership team. The FMIGS Board is part of AAGL and is an international Most recently, she was Executive Vice President, Director organization charged with overseeing the current MIGS fellow- of Community Investment, at the United Way of R.I., where ships. The mission of the FMIGS Board is to provide a uniform she served as a member of the executive team and led the or- training program for gynecologists who have completed their ganization’s grant-making, public policy, government relations, residency and desire to acquire additional knowledge and surgi- research and evaluation activities. cal skills in minimally invasive gynecologic surgery (MIGS) so Previous to the United Way, Ankoma was Chief of the Office they may: serve as a scholarly and surgical resource for the com- of Minority Health at the Rhode Island Department of Health munity in which they practice; have the ability to care for pa- (RIDOH), where she implemented the Minority Health Plan tients with complex gynecologic surgical disease via minimally for Action; and was Co-Director of RIDOH’s Health Equity invasive techniques; establish sites that will serve a leadership Institute. role in advanced endoscopic and reproductive surgery; and Ankoma has a Master of Science in Social Work and a Master further research in minimally invasive gynecologic surgery. v of Science in Public Health from Columbia University and a BA in Africana Studies and Psychology from Connecticut College. “Angela will work across and within departments at the Pawtucket appoints Public Foundation to maximize this effort’s impact, and will recruit and steward a community advisory committee to assist in de- Health and Equity Leader veloping the Equity Leadership Initiative,” said Neil D. Stein- PAWTUCKET – Amid the ongoing berg, president and CEO of the Foundation. “One effort of the national concerns and the corona- Equity Leadership Initiative will be to identify, cultivate, men- virus pandemic that has affected tor and seek access and opportunity for individuals who identify Pawtucket communities dispropor- as Black, Hispanic or Latino, Indigenous and Asian, from across tionately, the City of Pawtucket has sectors, to help build a pipeline of future leaders in established appointed a Public Health and Equi- positions of influence throughout the state.” ty Leader, Elizabeth Damoura “I am pleased to join the Foundation’s team and lead this Moreira of Pawtucket. effort. Community foundations have a rich history of commu- She begins on February 1st and will focus on coronavirus re- nity leadership. I am enthusiastic about the Foundation’s lead- sponse efforts within the community while leading the BEAT ership in advancing racial equity by addressing the underlying, COVID-19 initiative. She will also focus on working with the long-standing structures and systems that perpetuate racism Rhode Island Department of Health and different community and injustice. I am excited to support the next generation of groups on distribution coordination for the vaccine. v industry leaders – bank presidents, hospital CEOs, and leaders in academia and K-12 education; corporate executives, policy- makers, judges and more – who are people of color.” v

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 91 People / PLACES

Recognition RI Free Clinic Exec Marie Ghazal recognized with RIF’s Murray Family National Academy Prize for Community of Sciences honors Enrichment Carney Center’s The 2020 Murray Family Prize for Michael J. Frank, PhD Community Enrichment at the WASHINGTON – The National Rhode Island Foundation has been Academy of Sciences will hon- awarded to Marie Ghazal, exec- or 20 individuals with awards utive director of the Rhode Island Free Clinic in Providence. in recognition of their extraor- With the honor, Ghazal received $50,000 in recognition of dinary scientific achievements her long commitment to helping Rhode Islanders with cultural in a wide range of fields span- and language barriers and economic challenges obtain affordable ning the physical, biological, social, and medical sciences. health care. There are no restrictions on the use of the money. Among the recipients is Michael J. Frank, PhD, Direc- “Marie’s passionate commitment to serving the commu- tor of the Carney Center for Computational Brain Science and nity around her is an inspiring standard for others to follow. Professor of Cognitive, Linguistic and Psychological Sciences at We take enormous pride in honoring her for her drive and her the Carney Institute for Brain Science at Brown University, who achievements,” said Paula McNamara, daughter of Terrence will receive a 2021 Troland Research Award for his pioneering and Suzanne Murray, who along with her family established contributions to the new field of computational psychiatry and the Murray Family Prize for Community Enrichment at the neurology. Foundation. A primary driver of theoretical advances in learning and deci- A resident of Rumford, Ghazal has been executive director of sion making for more than 15 years, Frank’s work has advanced the R.I. Free Clinic since 2010. Under her leadership, the Prov- the understanding of deep underlying cognitive algorithms and idence nonprofit organization has expanded access to health their biological mechanisms through computational models care, dental care, specialty services and training to provide and original experimentation. 10,000 patient visits annually, as well as opening a COVID-19 Beyond his groundbreaking theoretical and experimental ad- test site this year. vances, Frank has created new strategies for integrating com- “I have dedicated my nursing public health career to increas- putation with experimentation, and further mapping these ing access to health care for those in need. I am deeply honored findings to real-world applications. Most notably, he is a co-cre- to be recognized by the Murray Family for the impact my work ator and an active leader in the new and emerging field of com- has made in addressing inequalities in health care in our state, putational psychiatry, building a deeply theoretically principled especially in our minority and underserved communities,” link from psychological and neuroscientific insights to clinical said Ghazal. definition and ultimately practice. A corps of more than 800 volunteer doctors, nurse practi- Two Troland Research Awards of $75,000 are given annually tioners, nurses and medical support staff help provide care. In to recognize unusual achievement by early-career researchers addition, Ghazal has successfully secured the partnership of (preferably 45 years of age or younger) and to further empirical key partners including CVS Health, Blue Cross & Blue Shield of research within the broad spectrum of experimental psychology. Rhode Island and Amica among many others. The winners will be honored in a virtual ceremony during the Ghazal serves on the Rhode Island Action Coalition’s Future National Academy of Sciences’ 158th annual meeting. v of Nursing: Campaign for Action and has also served in leadership positions at Providence Community Health Centers, Blackstone Valley Community Action Program, Central Falls Health Center and the Pawtucket Heart Health Program. “It is important to celebrate the positive contributions of Rhode Islanders like Marie who are striving diligently and hum- bly to serve others,” said Neil D. Steinberg, the Foundation’s president and CEO. “We are grateful to the Murray family for honoring the remarkable leaders whose dedication improves the lives of those around them and provides hope.” v

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 92 Obituaries

George N. Cooper, Jr., MD, of East Greenwich, David C. Lewis, MD, 85, passed passed away peacefully on December 13, 2020. A car- away at his home on December 2, diovascular surgeon and pioneer in valve replacement surgery, 2020. He was the beloved husband Dr. Cooper was deeply dedicated to providing excellent and of the late Eleanor (Levinson) Lew- compassionate care to all his patients and has made a differ- is. Dr. Lewis brought an intensity ence in the lives of so many. He grad- of curiosity and purpose to all of his uated from Seton Hall Medical School endeavors from medicine and addic- in 1961 and completed his internship, tion studies to nature photography. residency and two years active duty as He was a pioneer in the medical field a Captain in the U.S. Air Force in from of addictions. Throughout his career 1966–1968. He also proudly served his he advocated for compassionate and scientifically appropriate country as a Colonel in the U.S. Army treatment for addicts, and proper training for all physicians. He Reserve from 1981 to 1991. was the Professor Emeritus of Community Health and Medicine In 1971, he moved with his family and the Donald G. Millar Distinguished Professor Emeritus of from Milwaukee, WI, to Edgewood, RI, and began a successful Alcohol and Addiction Studies at Brown University. surgical practice that spanned nearly 35 years at Rhode Island Dr. Lewis was a graduate of Brown University and Harvard Hospital and Kent Hospital. He went on to establish the North- Medical School. In 1982, he founded the Brown University Cen- east Vein and Laser Center in Warwick, RI, retiring in 2020. ter for Alcohol and Addiction Studies and directed the Center A deeply faithful man with a great love for his country, George for eighteen years. Prior to founding the Center, he was Chair Cooper’s greatest love was his family. He recently said, “I was of the Department of Community Health at Brown. He founded blessed with nine children, each a precious jewel and uniquely a think tank of physicians and lawyers advocating for preven- gifted,” while sharing a wise proverb, “for each suffering there tion and treatment over incarceration for substance use disor- are also a thousand joys.” ders called Physicians and Lawyers for National Drug Policy After moving to Rhode Island, it was sailing that became his (PLNDP). other great love. Self-taught at first, he applied his innate drive Dr. Lewis was a member of numerous Boards of Directors, in- and passion to becoming a true yachtsman who derived and cluding the Drug Policy Foundation, National Council on Alcohol- generously shared his soul-expanding joy of sailing and racing ism and Drug Dependence, the Association for Medical Education around Narragansett Bay for almost 50 years. And, so in honor and Research in Substance Abuse (AMERSA) and the Coalition of his life, his great loves, his many contributions, and the joy on Physician Education in Substance Use Disorders (COPE). he shared with so many, we bid him a fond and loving farewell. A true academic at heart, he advised Presidents, members of Fair winds, following seas, and Godspeed on your final, infinite Congress, Governors, philanthropists in all aspects of the field voyage, Captain. of addiction, from recovery to decriminalization and legaliza- Dr. Cooper is survived by his wife of 38 years, Ann Biderman tion of drugs. He was always seeking to learn more about the Cooper, and his two sisters Loretta Witt (husband Tom) of West challenges around addictions. Dr. Lewis was the author of over Germantown, PA, and Margaret Cooper of Chestnut Hill, PA. 400 publications, and has an international reputation for his He was predeceased in 2007 by his brother James Cooper (wife work on prevention and treatment of substance use disorders, Kum Son) of Spanaway, WA; and in 2014 by his wife of 20 years, medical education and public policy. Mary G. Cooper (Lillis) of East Greenwich, RI. He was a lifelong lover of photography and traveled the world He is also survived by his nine children: Cecilia Cooper of extensively with his wife, Eleanor, for adventure and photo op- Warwick, Mary Clare Brandt (husband John Brandt) of Marlton, portunities. He was an active member of the North American NJ; Maureen MacPhail (husband Douglas MacPhail) of East Nature Photography Association and the National Association Longmeadow, MA; George N. Cooper III (wife Lisa Cooper) of of Photoshop Professionals. His work can be seen at: www. East Greenwich; Lorraine Hamilton (husband Neal Hamilton) davidclewisphotography.com/. of Plainville, MA; Roseann Ferri of North Kingstown; Timo- He is survived by his children, Deborah Lewis (Martin My- thy Parker of Newport; Caroline Leitao (Husband Ian Leitao) ers) and Steven Lewis (Laura Wiessen); and grandchildren Frieda of Newport; and Jonathan Cooper (husband Matthew Ryan) Myers, Levi Myers, Noa Lewis and Rose Lewis. His children and of New York, NY; and his nine grandchildren: Mia Cooper, grandchildren were the light of his life. From singing songs to John (Jack) Brandt III, Kevin Brandt, Liam Hamilton, Douglas telling stories, he loved nothing more than being with family. MacPhail, George MacPhail, Charles Ferri, Luisa Ferri, and, Contributions in his memory may be made to the New Israel Griffin Cooper. v Fund, PO Box 177, Lewiston, ME 04243. v

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Charles J. McDonald, MD, 89, an Diseases; and served on numerous committees and internationally recognized dermatolo- study groups of the National Cancer Institute, the gist/oncologist died on Sunday, January 10, 2021, National Institute of General Medical Sciences, and after a long illness. He was the son of the late the Institute of Medicine of the National Academy George B. McDonald and Bertha Harbin McDonald of Science. Nixon and the stepson of Mr. Thomas Nixon. He A member of the Howard University Board of also leaves his only sibling, sister Laura Nixon. Trustees for twenty years, Dr. McDonald chaired Dr. McDonald was born in Tampa, Florida in the Advisory Board to the Cancer Center of the Col- 1931 and lived in Bristol, Rhode Island for the lege of Medicine, and was vice chair of the Board’s last 36 years with his wife, Maureen (McDonald) Health Affairs Committee. McDonald. They were married for just under 40 years. Active in the affairs of the American Cancer Society for three In addition to his wife, Dr. McDonald is survived by his four decades, Dr. McDonald became national president of the Ameri- children: Charlesetta Arline, Marc McDonald, (Brenda), Nor- can Cancer Society in 1998, the only dermatologist ever to have man Douglas McDonald (Sara), and Eric McDonald (Valerie held that post. During his tenure, Dr. McDonald led new efforts Cook). He was proud of his grandchildren and the growing num- to improve diversity within the organization, coalesced national ber of his great grandchildren, as well as his Massachusetts and program efforts in childhood cancer, and spearheaded new pro- Connecticut nieces and nephews and their families. gram initiatives in prostate cancer in African American men. A pioneer in translational research, bringing proven research Among local and regional positions of leadership, Dr. McDon- advances from the laboratory to application at the bedside or ald was a member of the Rhode Island State Board of Education, in the office, Dr. McDonald has been recognized in Best Doc- a trustee of Citizens Bank, a trustee of the Providence Public Li- tors in America and America’s Top Doctors for two decades. brary, and a member of the group of founders of the Providence He has lectured at medical schools and conferences through- Health Centers. He was a member of the executive board of the out the United States, Europe, Asia, and South America on the New England Regional Manpower Development Program of the use of cancer drugs (cytotoxic and immune modulating agents) U.S. Department of Health and Human Services. For some ten in non-cancerous systemic illnesses and skin diseases. His re- years, Dr. McDonald served as a trustee of Lifespan, the largest search and experience in these areas and in the development of health provider in southern New England. He was inducted into safe and effective treatments for skin cancer and systemic au- the Rhode Island Hall of Fame in 2013. In 2014, he was awarded toimmune diseases have been published in some 200 scientific an honorary Doctor of Health degree from Rhode Island College. articles, book chapters and his own textbook. In Rhode Island, Dr. McDonald received awards for community As founding chairman of the Brown University Medical service from the NAACP, the Hospital Association of Rhode Is- School’s Department of Dermatology, Dr. McDonald has trained land, the Ministerial Alliance, the John Hope Settlement House hundreds of medical students and Dermatology residents. He and the Urban League. For several years he proudly served as was honored by the Brown Medical School Alumni with their a trustee of Bryant University. In 2012, he was honored by the highest award for “teaching, mentoring, and contributions to Rhode Island Medical Society with the Charles L. Hill Award for the community both locally and nationally,” the W.W. Keen “leaving a magnificent legacy of caring and accomplishment.” Award. He received a Distinguished Alumni Award from the Dr. McDonald earned his undergraduate degree in Chemistry Howard University College of Medicine; Howard University’s at North Carolina A&T University at age 19, followed by a Mas- Distinguished Postgraduate Achievement Award in the fields of ter’s Degree in Zoology at the University of Michigan. In 1952, Medicine and Community Service; and the Candle in Medicine he joined the United States Air Force, serving as a flight offi- Award from Morehouse College, among many other academic cer and intelligence officer in the Strategic Air Command and citations. achieving the rank of Major. In 1956, he entered Howard Uni- Long active in the professional associations of his field, Dr. versity Medical School, graduating first in his class in 1960. He McDonald served as president of the American Dermatologi- completed residencies in internal medicine and dermatology; cal Association, as an officer of the American Academy of Der- and a fellowship in clinical pharmacology and medical oncology matology, the Residency Review Committee for Dermatology, at Yale University Medical School in 1966. Upon completion of and as a board member of a number of related organizations in his training, he joined the Yale Medical School faculty in Med- Dermatology and Medicine. icine and Pharmacology. In 1968, he moved to Providence to Dr. McDonald was a member of the FDA Advisory Panel for join the faculty of the young Brown University Medical School Dermatology, a member of the first National Advisory Board for to play his part in helping build it into excellence. Dr. McDon- the National Institute for Arthritis, Musculoskeletal and Skin ald was a skilled and compassionate physician, a spectacular

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 94 OBITUARIES

husband, a loving father, a loyal and generous friend, an encour- Medical School and received his MD at the Harvard Medical aging teacher and colleague. He was grateful for each one of his School. He was an internal medicine resident and pulmonary achievements and, always, for the many people who helped him fellow at Duke University Hospital before serving 2 years in the succeed. US Army Medical Corps at Ireland Army Hospital in Fort Knox, If you would prefer to support a cause in his memory, please KY. Although he had many intellectual interests including his- consider The Providence Public Library, 150 Empire Street, tory, science and music, he also liked working with his hands. Providence 02903, or, the Charles and Maureen McDonald He built a center speaker to complement his Klipschorns, so Endowed Scholarship Fund, Howard University, P.O. Box that he could blast everything from Bach’s baroque cantatas to 417853, Boston, MA 02241-7853. v The Who’s rock opera in his living room in Barrington, RI. He and his family cruised Narragansett Bay in the 22-foot power boat which he maintained himself. He also worked on his 1960 Michael Anthony Passero, MD, 75, passed Mark II Jaguar when he had any time to spare from his 50- or away peacefully at home in Pittsburgh, PA, on Jan- 60-hour work week. uary 6, 2021 from complications of Above all he was a man who was interested in people. He Parkinson’s disease. took the time to listen to family, friends, colleagues, employ- He spent most of his professional ees, patients and students. He remembered their names, their life in Providence, RI. His patients family members and their hobbies. If he was walking down a and their families fondly remember hallway in the hospital, buying groceries in the supermarket, him as a knowledgeable, competent or tinkering with his car, someone would always stop to talk to and compassionate pulmonary phy- him. In addition to his loving wife of 51 years, he leaves his sons sician. He influenced generations Michael and Christopher, daughters-in-law Parul Gujarathi and of physicians teaching medical stu- Vida Passero, granddaughters Evangelina and Cecilia, his broth- dents, internal medicine residents er Frank Passero and sister-in-law Rosara Passero and their chil- and pulmonary fellows at the Roger Williams Medical Center dren and grandchildren, his wife’s brothers and their families and the Brown University Program in Medicine. as well as numerous cousins, nieces and nephews. Donations A passionate audiophile, he was a music major at Dartmouth in his name may be made to the charity of your choice. Online College. He met his future wife, Mary Ann, at Dartmouth condolences may be left at www.mccabebrothers.com. v

RIMJ Archives | February ISSUE Webpage | RIMS February 2021 Rhode island medical journal 95