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Bankruptcy Can’t Shield Doctor's Debt to NP FEATURE

Update on Alzheimer Dementia Spectrum: Diagnosis and Management




HIV+ Transplant Donors: Expanding Opportunities to Save HIV Patient Lives Live HIV+ to HIV+ transplants are performed in the US.


A Not-So-Straightforward Case of Endometriosis


Large, Spreading Rash After Illness

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6 Alzheimer’s mulifactorial etiology explored


Update on Alzheimer Dementia Spectrum: Diagnosis and Management Recognizing Alzheimer disease as a continuum is essential in the development of diagnostic tools, management strategies, and disease-modifying therapies.


HIV+ Transplant Donors: Expanding Opportunities to Save HIV Patient Lives The national organ shortage has led researchers to critically re-evaluate organ sources that previously were considered too risky for HIV patients.


Clinical Challenge: A Not-So-Straightforward Case of Endometriosis Recent research suggests that immunologic dysfunction and genetic/epigenetic components are involved in the pathogenesis of endometriosis.

21 Differentiating drug-induced skin reactions


27 NP sues former boss for defamation


Web Roundup A summary of our most recent opinion, news, and multimedia content from ClinicalAdvisor.com.


Dermatologic Look-Alikes Large, Spreading Rash After Illness


Legal Advisor Bankruptcy Can’t Shield Physician From Debt to Nurse Practitioner

All correspondence to: The Clinical Advisor 275 7th Avenue, 10th Floor, New York, NY 10001 For advertising sales, call 201.774.1078. For reprints/licensing requests, contact Customer Service at custserv@haymarketmedia.com. Persons appearing in photographs in “Newsline,” “The Legal Advisor,” and “Features” are not the actual individuals mentioned in the articles.They appear for illustrative purposes only. The Clinical Advisor® (USPS 017-546, ISSN 1524-7317), Volume 23, Number 10. Published 10 times a year, by Haymarket Media, Inc., 275 7th Avenue, 10th Floor, New York, NY 10001. For Advertising Sales & Editorial, call 646.638.6000 (M–F, 9am–5pm, ET). The Clinical Advisor is available on a paid subscription basis at the following annual rates: $75 USA, $85 Canada, $110 for all other foreign, in U.S. dollars, Single copy price: USA $20, Foreign $30. To order or update a paid subscription visit our website at www.ClinicalAdvisor.com or call 800.436.9269. Periodicals postage rate paid at New York, NY, and additional mailing offices. Postmaster: Send changes of address to The Clinical Advisor, c/o Direct Medical Data, 10255 W. Higgins Rd., Suite 280, Rosemont, IL 60018. All rights reserved. Reproduction in whole or in part without permission is prohibited. Copyright © 2020

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NEWS ClinicalAdvisor.com/News

The Role of Drop Teams in Preventing COVID-19 Outbreaks at LTC Facilities The plan included testing residents of long-term care facilities who may show signs of COVID-19, providing infection control planning, education, and prevention, and deploying teams to provide on-site clinical assistance.

HIV, Hepatitis-B Drugs Proven to Reduce Risk of Developing Type 2 Diabetes With each additional year of using NRTIs, patients diagnosed with HIV-1 or hepatitis B in all 5 cohorts had a 3% to 8% reduced hazard of developing type 2 diabetes.

Higher Risk of Active TB Infection in Children Living With Infected Adults Children in this study were aged less than 15 years and were grouped based on symptoms, tuberculin reaction, and chest radiographs features.

CV Adverse Event Risk Increases During COPD The risk of a cardiovascular adverse event of special interest that resulted in hospitalization or death increased during moderate or severe COPD exacerbation events.

NSAIDs Should Be Avoided After 20 Weeks’ Gestation The FDA stated that the use of NSAIDs after 20 weeks of pregnancy may lead to low levels of amniotic fluid surrounding the baby resulting in kidney complications.

MY PRACTICE ClinicalAdvisor.com/MyPractice COVID-19 Vaccine Allocation: Ethical Concerns, Challenges Batya Swift Yasgur, MA, LSW In the event of a likely scarcity of COVID-19 vaccines, a framework must be developed to inform who should get priority immunization.

CLINICAL CHALLENGE ClinicalAdvisor.com/CaseStudy Brady Pregerson, MD Painless Loss of Vision A 44-year-old woman presents with a 24-hour history of painless, gradual loss of vision in her left eye. She describes her vision as “dark and blurry.” The patient’s medical history is significant for pulmonary embolism, renal failure (treated with dialysis), and diabetes. Her vital signs are normal; physical examination is unremarkable except for an afferent pupillary defect and low visual acuity in the left eye. See the full case at: ClinicalAdvisor.com/CaseDec20


Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom Jim Anderson, MPAS, PA-C, DFAAPA The Difference Between Race and Racism in Medical Practice Some of the major theories behind why Black patients have seemingly worse outcomes than White patients cite racism, not race, as the root of the problem.

MEETING COVERAGE ClinicalAdvisor.com/AHA-2020 Complete coverage of the American Heart Association Scientific Session 2020, held virtually from November 13 to 17, 2020. Continues on page 4

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2020 3




ClinicalAdvisor.com Advisor Dx

Interact with your peers by viewing the images and offering your diagnosis and comments. To post your answer, obtain more clues, or view similar cases, visit ClinicalAdvisor.com/AdvisorDx. Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues. Check out some of our latest cases below!


Nodular Growth on Trunk A 40-year-old man presents with a nodular growth on his trunk that has been present for 10 years. It started as an indurated plaque and slowly enlarged to a size of 4 cm. Physical examination reveals an exophytic, irregularly shaped nodule with a reddish hue. The surrounding skin is unremarkable. CAN YOU DIAGNOSE THIS CONDITION?

• • • •

Kaposi sarcoma Squamous cell carcinoma Dermatofibrosarcoma protuberans Cutaneous metastasis

● See the full case at ClinicalAdvisor.com/DermDx_Dec20


In partnership with

Two Episodes of Hip Dislocation A 60-year-old man with obesity presents after 2 episodes of right hip dislocation. The first dislocation occurred when he was getting out of bed. He was taken to the emergency department where he underwent a closed reduction for a hip dislocation. Two weeks after the initial dislocation, the hip dislocated again. WHAT IS THE MOST LIKELY CAUSE OF THE PATIENT’S EARLY FEMORAL STEM SUBSIDENCE?

• Poor fit of the femoral implant • Osteoporotic bone

• Early weight bearing • High body mass index

● See the full case at ClinicalAdvisor.com/OrthoDx_Dec20

4 THE CLINICAL ADVISOR • DECEMBER 2020 • www.ClinicalAdvisor.com


Journal of Orthopedics for Physician Assistants


Update on Alzheimer Dementia Spectrum: Diagnosis and Management Although the cause of Alzheimer disease is not clear, recent research advances have furthered the understanding of Alzheimer dementia as a continuum.



lzheimer disease (AD) is an irreversible neurodegenerative disorder characterized by a decline in a patient’s activities of daily living (ADL) and cognitive abilities, as well as changes in behavior. There are many hypotheses about the causes of dementia, including deposits of amyloid plaques; tau proteins that self-replicate, contributing to neurofibrillary tangles; loss of cells that produce the neurotransmitter acetylcholine; and, more recently, genetic variants and inflammatory conditions.1-7 Although the cause of AD is not clear, recent research advances have furthered the understanding of AD. It now is known that pathophysiologic changes begin years before the disease manifests clinically and that the AD spectrum spans from clinically asymptomatic to severely impaired.8 In addition, biomarkers have been identified and are beginning to be used to aid in diagnosis, instead of diagnosis being based solely on its clinical presentation as has been done historically. Recognizing the concept of AD as a physiologic continuum is essential in the development of diagnostic tools, management strategies, and disease-modifying therapies (DMTs).8.9 Alzheimer Dementia Redefined Almost 30% of older adults meet criteria for Alzheimer disease.

6 THE CLINICAL ADVISOR • DECEMBER 2020 • www.ClinicalAdvisor.com

In 2011, the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association revised the 1984 criteria for AD,10

incorporating scientific advances in the field.11,12 The following clinical dementia rating (CDR) from the new criteria describes clinical disease progression11: • Preclinical (initial stage): brain changes may already be in progress, but clinical symptoms are not yet apparent. • Mild cognitive impairment (MCI): marked by symptoms of memory and/or other thinking problems that are greater than normal for a person’s age and education but do not interfere with his or her independence. • Alzheimer’s dementia (final stage): symptoms such as memory loss, word-finding difficulties, and visual/spatial problems are severe enough to affect the ability to function independently. The main objective of the revised criteria was to be flexible enough to be used by clinicians without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid analysis and by researchers with access to these tools.9 The modified criteria have been reliable for the diagnosis of probable AD, with a sensitivity of 81% and specificity of 70% across more than a dozen clinical pathological studies.12 The modified diagnostic criteria are intended to incorporate the spectrum of severity, ranging from the mildest to the most severe stages of dementia.12 Diagnosis of cognitive impairment should include a patient history obtained directly from the patient and a knowledgeable source (caretaker, relative) in combination with objective cognitive assessment with either a “bedside” mental status examination or neuropsychological testing.12 When the diagnosis is still unclear, neuropsychological testing should be conducted. In addition, the documented deficit must involve at least 2 of the following 5 areas12: 1. Impaired ability to acquire and remember new information: repetitive questions or conversations, misplacing personal belongings, forgetting events or appointments, getting lost on a familiar route. 2. Impaired reasoning and handling of complex tasks, poor judgment: poor understanding of safety risks, an inability to manage finances, poor decision-making ability, and an inability to plan complex or sequential activities. 3. Impaired visuospatial abilities: an inability to recognize faces or common objects or to find objects in direct view despite good acuity, an inability to operate simple implements, and difficulty in orienting clothing to the body. 4. Impaired language functions (speaking, reading, writing): difficulty thinking of common words while speaking, hesitations, and errors in speech, spelling, and writing. 5. Changes in personality, behavior, or comportment: uncharacteristic mood fluctuations, such as agitation, impaired motivation and initiative, apathy, loss of drive, social withdrawal, decreased interest in previous activities, loss of empathy, compulsive or obsessive behaviors, and socially unacceptable behaviors.

It is important to note that differentiating between dementia and MCI depends on whether or not there is disruption in the ability to perform normal daily activities.11 Underlying Pathophysiology

The etiology of AD is multifactorial and not well understood.13 Although there continues to be uncertainty related to the underlying factors contributing to the development of AD,14 such as environment and lifestyle components, there are known factors that need to be understood to better appreciate the complexity of this disease process. Amyloid Plaques Amyloid plaque accumulation in the brain is one of the known factors associated with AD.1 Beta-amyloid is a protein fragment of amyloid precursor protein (APP). Normally these protein fragments are broken down and eliminated, but in AD they accumulate to form hard, insoluble plaques. Amyloid plaques are composed of an extracellular beta-amyloid core surrounded by tissue enriched in lysosome-like organelles.The extracellular beta-amyloid deposits, residing within swollen neuronal axons, cause local impairment in retrograde axonal transport.1 In this state, production and clearance of beta-amyloid are adversely affected.1 Tau and Neurofibrillary Tangles The protein tau forms part of a microtubule structure that supports the transport of nutrients and other substances to and from various parts of the nerve cell.2 In AD, however, abnormal tau is produced, causing collapse of the microtubule structures. In addition, further chemical changes cause tau molecules to adhere to one another, forming threads that join to form neurofibrillary tangles (NFTs) inside neurons.2 By blocking the neuron’s transport system, these tangles disrupt signals between neurons.2 Emerging research indicates that the complex interaction between abnormal tau and beta-amyloid may ultimately cause changes in the brain associated with AD.2 Specifically, abnormal tau accumulates in the brain regions associated with memory, whereas beta-amyloid forms plaques between neurons.When the level of beta-amyloid reaches a critical value, tau spreads rapidly throughout the brain.1,2 There is some uncertainty about whether tau is causal to the disease or a byproduct of the disease process. Although the role of tau in AD is still under investigation, changes in tau are predominantly believed to be a consequence of beta-amyloid and NFTs and, consequently, tau continues to be of major interest as an indicator of the disease mechanism.2 Neurotransmitters The etiology of AD also includes both cholinergic and glutamatergic neuronal involvement.3 In patients with AD,

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2020 7


The modified criteria have been reliable for the diagnosis of AD, with a sensitivity of 81% and a specificity of 70% across more than 12 studies. acetylcholine (ACh) — a neurotransmitter critical for the memory process and learning — decreases in concentration and in function.3 There also are other presynaptic cholinergic deficiencies, including cholinergic neuron loss and decreased activity of acetylcholinesterase (AChE).3 The loss in ACh efficacy and these presynaptic cholinergic changes are the primary factors in the cholinergic cascade hypothesis of AD.3 In addition, a decrease in ACh synthesis and an eventual decrease in ACh uptake by acetylcholine receptors have been documented in AD.4,5 The glutamatergic hypothesis links cognitive decline in AD to neuron damage caused by the overactivation of N-methyl-D-aspartate (NMDA) receptors by glutamate.3 The prolonged low-level activation of NMDA receptors — which are critical to learning and memory — may be attributable to inadequate reuptake of glutamate by cells in the synaptic cleft.3 Inflammatory and Autoimmune Contributors

Inflammation also has been identified as a potential causative agent in neurodegeneration.6 In affected tissues, inflammatory pathway genes are activated, and these inflammatory signals precede neurodegeneration, independent of any infectious etiology.6 Thus far, pharmacologic and genetic ablation studies of multiple neurodegenerative diseases in animals indicate that inflammation is a requisite for pathology.6 This conclusion is noteworthy as it relates to AD, and it appears that inflammation plays a pivotal role in various neurodegenerative diseases.6

POLL POSITION Which of the following is not a known risk factor for Alzheimer disease?

■ Decrease in amyloid plaques ■ Increase in tau neurofibrillary tangles

6.9% 4.4% 23.8%

■ Decrease in acetylcholine ■ Increased activation of N-methyl-D-aspartate


For more polls, visit ClinicalAdvisor.com/Polls.

Genetics Both types of AD — early-onset and late-onset — are thought to have genetic components.7 Early-onset AD occurs between the ages of 30 and 65 years and accounts for less than 10% of all cases.7 Most early-onset AD is caused by an inherited mutation in 1 of 3 genes — APP, presenilin-1 (PSEN1), and presenilin-2 (PSEN2) — that results in early-onset familial AD.7 Each of these mutations plays a role in the breakdown of APP, a protein whose precise function is not understood fully.7 It is known, however, that the breakdown of APP contributes to the formation of amyloid plaques.7 The majority of cases of AD are late-onset, with symptoms becoming evident around age 65 years.The causes of late-onset AD are not understood fully but it is likely that a combination of genetic, environmental, and lifestyle factors contribute to a person’s risk for developing the disease.7 A specific gene has not been identified as directly causing late-onset AD, but having the ε4 genotype of the apolipoprotein E (APOE) gene on chromosome 19 has been linked to an increased risk of the disease.7 Dementia as a Disease Continuum

There is significant support for the idea of identifying AD as a biologic and clinical continuum covering the preclinical (clinically asymptomatic individuals with pathophysiologic changes reflected by biomarker evidence) and clinical (biomarker changes and clinical symptoms of cognitive and functional impairment) phases of dementia.8 These changes in the individual components of the continuum occur in a sequential progressive manner.8 The initial phase of the clinical and pathologic AD cascade starts with disordered beta-amyloid metabolism.15 Various components of AD pathology (AD-P) are known to relate differently to clinically identifiable symptoms. In autopsy studies, researchers have established a much closer correlation between neurofibrillary pathology and cognitive impairment than between amyloid pathology and cognitive impairment.16,17 The physiologic aspect of AD that correlates most highly with cognitive impairment, however, is neurodegeneration.11 Approximately 30% of the elderly with normal cognition have some level of identifiable AD-P: for example, they meet neuropathologic criteria for AD but do not exhibit cognitive symptoms.11 Instead of simultaneous development, it appears that amyloid pathology and neurodegenerative pathology may progress on differing timelines.18 Continues on page 10

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There continues to be uncertainty related to the underlying factors contributing to the development of Alzheimer disease. The clinical continuum includes both cognition and function components. The cognition component is composed of episodic memory, executive function, and verbal fluency, whereas the function component includes both basic and complex ADLs.8 New Diagnostic Modalities

Screening Tools In the primary care setting, cognitive screening tools with sufficient sensitivity are essential to allow clinicians to detect AD. Tools that clinicians may find beneficial to use include those that probe for early changes (eg, 8-item Interview to Differentiate Aging and Dementia, Cognitive Function Instrument), concise global cognitive screens (eg, Mini-Mental State Examination), and more specific tests of episodic memory impairment (eg, 5-Word test).8 If a more detailed assessment is warranted, a neuropsychological evaluation may be performed by a specialist.8,19 Biomarkers Biomarkers of AD typically are divided into 2 groups. The first are biomarkers associated with the accumulation of betaamyloid, which present as abnormal tracer uptake on amyloid positron emission tomography (PET) imaging, and findings of low cerebrospinal fluid (CSF) amyloid-beta 42.12,20 The second group of biomarkers are those associated with degeneration or injury to the neurons; they present as elevated CSF tau, decreased fluorodeoxyglucose (FDG) uptake on PET scan in a specific topographic pattern of the brain, and atrophy in a specific topographic pattern on structural MRI.12,20 Biomarker studies have been conducted on research subjects with very subtle or no apparent symptoms to identify the presence of AD-P in the preclinical phase.11,12,20 Thus far, the incorporation of biomarkers has been more conservative in the diagnosis of symptomatic MCI and AD patients than in preclinical phase patients taking part in research studies.11,12 Clinical features still are considered the primary diagnostic criteria for MCI and AD, and biomarkers are viewed as adjuvant indicators. When possible, biomarkers are used to establish the underlying cause of the clinical impairment in the MCI phase. The intensity of the biomarker, especially markers associated with neuronal injury, also indicates the probability that the disease will progress to the AD phase within a short period of time.11,12,20 In the dementia phase, biomarkers are used to establish a higher or lower level of confidence that AD-P is the underlying cause of a patient’s dementia.11,12,20

Before use of biomarkers is adopted for all disease stages, there needs to be an intensive focus on biomarker standardization.11,12 The levels of proteins and other cellular material in CSF can change years before identifiable symptoms of AD and other brain disorders are present.21 The most commonly used CSF biomarkers for AD are the measurement of the proteins beta-amyloid 42, tau, and phospho-tau (major components of NFTs in the brain).21 In patients with AD, beta-amyloid 42 levels in CSF are low, whereas tau and phospho-tau levels are elevated compared with levels in patients without AD.21 Genetic Testing The Genome-Wide Association Study has identified a number of regions in the genome that may be associated with increased risk for late-onset AD. Researchers have confirmed 33 regions of interest in the AD genome.7 Genetic testing for APOE ε4 is available in both consumer and commercial markets.7 It should be recognized, however, that genetic testing establishes only a component of an individual’s risk profile and must be used judiciously, with the recognition that environment, lifestyle, family medical history, and other genetic factors also will play a role in the development of AD.7 Imaging Studies It is beneficial to perform brain imaging to rule out other organic causes for dementia, such as vascular disease or a tumor. A computed tomography (CT) scan provides images of the brain in greater detail than radiographs and can assist in identifying a brain injury, tumor, stroke, or other contributor to dementia symptoms.19 Magnetic resonance imaging is used clinically and in research to produce images of brain structures and identify abnormal changes such as cerebral atrophy.19 Signs of atrophy may further support a diagnosis of AD or other neurodegenerative condition but on their own cannot establish a specific diagnosis.19 Research shows that patients with dementia often will exhibit abnormal levels of glucose uptake in specific brain regions.19 An FDG PET scan can identify this type of pattern and facilitate diagnosis of the underlying cause of the dementia.19 Amyloid PET scans measure beta-amyloid deposits. High levels of beta-amyloid are associated with amyloid plaques present in AD.19 In addition, a number of tracers can be used with amyloid PET scans to provide diagnostic assistance when AD is suspected but not clearly established by comprehensive assessment.19 This type of imaging also may be helpful in diagnosing dementia in individuals with mild or unusual symptoms, onset

10 THE CLINICAL ADVISOR • DECEMBER 2020 • www.ClinicalAdvisor.com

In the primary care setting, cognitive screening tools with sufficient sensitivity are essential to allow clinicians to detect Alzheimer dementia. at an early age, or other conditions (eg, severe depression) that could contribute to their symptoms.19,20 Conversely, a negative amyloid PET scan can help rule out AD.19,20 Tau PET scans identify abnormal deposition of tau (NFTs).19 There are multiple tau tracers that have been used in research studies to determine their usefulness in clinical practice.19 Research findings support using amyloid and tau PET scans to identify individuals at greatest risk of developing AD.19 This imaging type also has been helpful in selecting clinical trial participants and in evaluating the effect of experimental drugs designed to modify amyloid or tau pathways.19 The Future of Biomarkers

Throughout the past 10 years, advances in biomarkers have allowed for the identification of AD-related changes in the brains of living patients. This is incredible progress because, historically, brain changes could only be studied postmortem. In addition, this has allowed researchers to monitor the disease’s onset, follow its progression, and test promising medications and treatments.19-21 Researchers hope to build on these successes and to advance biomarker research by: • Developing a full complement of biomarkers, specifically those that are less expensive and less invasive, and to evaluate medications to diagnose, prevent, and treat AD • Advancing innovative PET imaging and biomarkers to identify distinctive AD-related brain changes • Using state-of-the-art MRI methodology to measure brain structure, function, and connections • Helping to identify and monitor early-stage disease by developing and refining more sensitive clinical and neuropsychological assessments.19-21 Treatment Modalities

Lifestyle Interventions Although lifestyle interventions may not be considered true emerging therapies, the findings of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) — the world’s first large multidimensional study of lifestyle interventions — are worth noting. FINGER documented that at least a third of AD is determined by modifiable factors.22 There were 4 intervention components in this study: nutritional guidance; physical exercise; cognitive training and social activity; and intensive monitoring and management of metabolic and vascular risk.22 All these components were found to have a profound impact on the progression of dementia in the study.

Cognitive Therapy Psychosocial treatment modalities focus on cognitive stimulation therapy and cognitive remediation and their ability to successfully preserve cognitive function in people with mild to moderate dementia.22 Cognitive stimulation therapy (CST) is a themed activity program implemented during several weeks in small groups led by a trained nurse, occupational therapist, or caregiver. These sessions are structured with activities found to be most beneficial. They include a warm-up activity, a “reality orientation board,” discussion of current news stories, word puzzles, and a practical activity such as baking.22 These programs have been found to enhance the memory and critical thinking skills of people with mild to moderate dementia and to improve their quality of life.22 Cognitive remediation is similar to CST but includes a set of activities that also focuses on learning and exercises designed to improve brain function.22 The associated cognitive training targets cognitive domains most sensitive to aging (episodic memory, executive function, mental speed, and working memory) with a focus on everyday situations.22 Current Therapies Cholinesterase inhibitors (eg, donepezil, rivastigmine, and galantamine) and the NMDA-receptor antagonist memantine have been used for the treatment of AD. The cholinesterase inhibitors prevent AChE from breaking down acetylcholine.8,19 Memantine blocks the influence of glutamate, which is released disproportionately in the brains of those with AD, causing irreparable damage to brain cells.8,19 Although these medications have not been shown to change the overall course of dementia, they can slow its progression. Disease-modifying therapies (DMT) are interventions that can produce an enduring change in the clinical progression of AD by interfering in the underlying pathophysiologic mechanisms of the disease process.23 When DMTs are approved for widespread use, biomarker testing will be essential to aid in diagnosis and monitoring the effect of treatments.23 In addition, biomarker results will be critical to the initiation and termination of treatment regimens and may help determine whether combination therapies are appropriate at the individual level.8,23 Immunization and Immunotherapy Immunizations that target proteins other than tau have become an increasingly pursued therapeutic approach.9 The furthest advanced is a beta-amyloid-based active and passive immunization in AD, which, despite some setbacks, has resulted in some promising results.9,24

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2020 11


Throughout the past 10 years, advances in biomarkers have allowed for the identification of AD-related changes in the brains of living patients. There are some interesting immunotherapies on the horizon as well, including anti-beta-amyloid antibodies that have been specifically developed to hinder the beta-amyloid cascade.25,26 Preclinical studies have substantiated the use of immunotherapy against AD, which has prompted a series of clinical trials.25,26 Phase 3 trials using monoclonal antibodies against beta-amyloid in patients with mild to moderate AD showed some impact on biomarkers; however, the primary end points were not successfully achieved.25,26 It has been proposed that administering anti-beta-amyloid immunotherapy at the early presymptomatic stage (secondary prevention) would improve the therapeutic effect.25,26 Once high-risk individuals have been identified using biomarkers, then it would be advantageous for them to begin chronic long-term immunotherapy.25,26 These treatments pose a challenge to healthcare systems, however, because of issues related to antibody production and the costs of such treatments.25,26 ■

the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984;34(7):939-944. 11. Jack CR, Albert MS, Knopman DS, et al. Introduction to revised criteria for the diagnosis of Alzheimer’s disease: National Institute on Aging and the Alzheimer’s Association Workgroups. Alzheimers Dement. 2011;7(3):257-262. 12. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):263-269. 13. Aizenstein HJ, Nebes RD, Saxton JA, et al. Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol. 2008;65(11):1509-1517. 14. Stern Y. Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol. 2012;11(11):1006-1012. 15. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256(5054):184-185. 16. Gomez-Isla T, Hollister R, West H, et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol.

Amy Arnold Haney, DMSc, PA-C, is a primary care provider who works with short-term rehabilitation patients, long-term care patients, and hospice patients in Jacksonville, Florida.

1997;41(1):17-24. 17. Bennett DA, Schneider JA, Wilson RS, Bienias JL, Arnold SE. Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Arch Neurol. 2004;61(3):378-384.


18. Ingelsson M, Fukumoto H, Newell KL, et al. Early Abeta accumulation and

1. Gowrishankar S, Yuan P, Wu Y, et al. Massive accumulation of luminal

progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology.

protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques.


Proc Natl Acad Sci U S A. 2015;112(28):E3699-3708.

19. National Institute on Aging. Biomarkers for dementia detection and

2. Mandelkow EM, Mandelkow E. Biochemistry and cell biology of tau protein in

research. Published April 2018. Accessed November 4, 2019. https://www.nia.

neurofibrillary degeneration. Cold Spring Harb Perspect Med. 2012;2(7):a006247.


3. Francis PT. The interplay of neurotransmitters in Alzheimer’s disease. CNS

20. Rowe CC, Ellis KA, Rimajova M, et al. Amyloid imaging results from the

Spectr. 2005;10(11suppl18):6-9.

Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol

4. Slotkin TA, Seidler FJ, Crain BJ, Bell JM, Bissette G, Nemeroff CB. Regulatory

Aging. 2010;31(8):1275-1283.

changes in presynaptic cholinergic function assessed in rapid autopsy material

21. Shaw LM, Vanderstichele H, Knapik-Czajka M, et al. Cerebrospinal fluid

from patients with Alzheimer disease: implications for etiology and therapy.

biomarker signature in Alzheimer’s disease neuroimaging initiative subjects.

Proc Natl Acad Sci U S A. 1990;87(7):2452-2455.

Ann Neurol. 2009;65(4):403-413.

5. Xu Y,Yan J, Zhou P, et al. Neurotransmitter receptors and cognitive dysfunction

22. Kivipelto M, Solomon A, Ahtiluoto S, et al. The Finnish Geriatric

in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol. 2012;97(1):1-13.

Intervention Study to Prevent Cognitive Impairment and Disability (FINGER):

6. Richards RI, Robertson SA, Kastner DL. Neurodegenerative diseases have genetic

study design and progress. Alzheimers Dement. 2013;9(6):657-665.

hallmarks of autoinflammatory disease. Hum Mol Genet. 2018;27(R2):R108-R118.

23. Cummings J, Fox N. Defining disease modifying therapy for Alzheimer’s

7. Mayeux R, Stern Y. Epidemiology of Alzheimer disease. Cold Spring Harb

disease. J Prev Alzheimers Dis. 2017;4(2):109-115.

Perspect Med. 2012;2(8):a006239.

24. Ferreira-Vieira TH, Guimaraes IM, Silva FR, Ribeiro FM. Alzheimer’s disease:

8. Aisen PS, Cummings J, Jack CR, et al. On the path to 2025: understanding

targeting the cholinergic system. Curr Neuropharmacol. 2016;14(1):101-115.

the Alzheimer’s disease continuum. Alzheimer’s Res Ther. 2017;9(1):60.

25. Lathuilière A, Laversenne V, Astolfo A, et al. A subcutaneous cellular

9. Nygaard HB. Current and emerging therapies for Alzheimer’s disease.

implant for passive immunization against amyloid-β reduces brain amyloid

Clin Ther. 2013;35(10):1480-1489.

and tau pathologies. Brain. 2016;139(Pt 5):1587-1604.

10. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of

26. Morgan D. Immunotherapy for Alzheimer’s disease. J Intern Med.

Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under


12 THE CLINICAL ADVISOR • DECEMBER 2020 • www.ClinicalAdvisor.com


HIV+ Transplant Donors: Expanding Opportunities to Save HIV Patient Lives The HOPE Act has widened the field of organ donors, improving the survival of HIV-positive patients on organ transplantation waitlists.



More than 109,000 Americans are on an organ transplant waitlist.

ntiretroviral therapy (ART) has transformed the lives of patients with HIV; AIDS-related deaths have declined dramatically and life expectancy of HIV-positive patients rivals that of patients without HIV.1-3 With longer life expectancy, however, comes the potential to develop chronic diseases. End-stage organ diseases, such as end-stage renal disease (ESRD) and liver disease from hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, are now the primary causes of mortality in HIV-positive patients.2,3 Although the incidence of ESRD has been declining, the prevalence has been increasing among patients with HIV.4,5 People living with HIV have an incidence of ESRD that is 2 to 4 times higher than that of people without HIV.5 Most patients with ESRD are treated with dialysis, but solid organ transplantation is the most effective treatment to improve quality of life and reduce mortality.5,6 More than 109,000 Americans are on a waitlist for an organ transplant.7 The organ shortage has led researchers to critically re-evaluate organ sources that previously were considered too risky.8,9 This has led to a number of advances in transplantation, such as the use of organs from HIV-positive donors for HIV-positive recipients and, more recently, a life-saving partial liver transplant from an HIV-positive mother to her HIV-negative child (See Case Study).10 These advances have the potential to improve the chance of survival for HIV-positive patients on organ transplantation waitlists. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2020 13


Evolution of Transplantation in HIV+ Patients

The HIV Organ Policy Equity (HOPE) Act11 was proposed in 2011 after successful kidney and liver transplants were performed from HIV-positive cadavers to HIV-positive recipients in South Africa.12,13 In those early cases, there was no reported evidence of HIV superinfection; organ rejection rates at 1 and 3 years were 8% and 25%, respectively, and 1 of the 4 recipients developed idiopathic glomerulopathy.3,4,12,13 Under the HOPE Act, implemented in November 2013, HIV-positive donor to HIV-positive recipient transplants are permitted in the United States for clinical research under specific guidelines by the National Institutes of Health (NIH).3,8,10 The first such transplants in the United States were performed in 2016 at Johns Hopkins University Medical Center.2,3,10 In 2019,

an HIV-positive living donor donated a kidney to an HIVpositive recipient at Johns Hopkins University Medical Center.8 Under the HOPE Act, donor selection, immunosuppression management, and postoperative management are reviewed carefully for both the donor and recipient. Donor screening is an integral step in the transplant selection process. A prospective donor’s medical history, physical examination, and laboratory results are gathered to determine if they meet entry criteria.14,15 Living and cadaver donors are screened using the same parameters. All donors are assigned a Kidney Donor Profile Index (KDPI); higher scores indicate increased risk for the donor.9,16 Donor criteria vary depending on the study. For most studies, eligible donors must be free of active tuberculosis and opportunistic infections (OIs) and have an undetectable HIV viral load.10,13


HIV-Positive Mother Donates to HIV-Negative Daughter Under the HOPE Act, living HIV-positive organ donors are allowed; however, this practice is not well-accepted ethically due to increased risk for the donor and the potential for HIV infection in the recipient. In 2018, surgeons in South Africa reported on the first case involving an HIV-positive living donor and an HIV-negative recipient.1 A 7-month-old child with biliary atresia had end-stage liver disease.The child was born to HIV-positive parents. Her mother was incidentally diagnosed with HIV at the age of 27 and began antiretroviral therapy (ART) 4 months after diagnosis. After pregnancy, the newborn patient received daily nevirapine prophylaxis for 6 weeks. After delivery, the child was HIV-negative and was exclusively breast-fed. Because of her poor health, the child was referred to Wits Donald Gordon Medical Centre (WDGMC) in Johannesburg, South Africa, for further care and management. The WDGMC program provides pediatric liver transplants from both cadaver and living donors. The inclusion of living donors was approved in 2013, 8 years after the start of the program, in response to the shortage of cadaver organs.The average wait time for liver transplantation is 49 days at WDGMC.1 According to the authors of the study, there is an increased chance of successful liver transplantation in related living donors.2,3 Despite expansion of the donor pool, there had not been a case of living donor liver transplant from an HIV-positive donor to HIV-negative recipient. This child’s case was practically urgent because she was on the liver transplant waitlist for 181 days with life-threatening hematemesis secondary to variceal bleeding. This resulted in intensive care unit admission that involved intubation and

ventilation.The child’s hospital stay was further complicated by Klebsiella pneumoniae infection. The patient had a critical need due to her rapid decline in health. Her mother persistently requested to be a living donor.With careful consideration, the program requested institutional review board approval to perform the liver transplant per guidelines requiring that her mother meet donor criteria: CD4 T-cell count >200 cells/µL, no active tuberculosis infection, no opportunistic infections, and viral suppression for a least 6 months. The patient received a liver transplant at 13 months of age. A left lateral segment hepatectomy was performed on her mother. Preoperative immunosuppression management for the recipient consisted of raltegravir/lamivudine/abacavir the night before transplant. The donor’s ART regimen was unchanged. Intraoperative immunosuppression management of 100 mg of methylprednisolone was given to the child. Postoperative care of the recipient was complicated by pneumonia that was treated with antibiotics. The child was given standard prophylaxis for pneumocystis pneumonia and cytomegalovirus. For 6 months, she received tacrolimus and a corticosteroid taper. HIV status was assessed and showed neither seroconversion nor HIV-1 RNA detection. Post-transplant laboratory results at 225 days also revealed no evidence of HIV-1 DNA. The patient remains on tacrolimus and ART and will receive ART for at least 2 years. References 1. Botha J, Conradie F, Etheredge H, et al. Living donor liver transplant from an HIV-positive mother to her HIV-negative child: opening up new therapeutic options. AIDS. 2018;32(16):F13-F19. 2. Botha J, Fabian J, Etheredge H, Conradie F,Tiemessen CT. HIV and solid organ transplantation: where are we now. Curr HIV/AIDS Rep. 2019;16(5):404-413. 3. Miro JM, Grossi PA, Durand CM. Challenges in solid organ transplantation in people living with HIV. Intensive Care Med. 2019;45(3):398-400.

14 THE CLINICAL ADVISOR • DECEMBER 2020 • www.ClinicalAdvisor.com

Immunosuppression and HIV Treatments

All organ recipients require maintenance immunosuppression to prevent their body from rejecting the organ. In patients with HIV, this cocktail of agents must be given along with whatever ART the patient is taking.The optimal maintenance immunosuppression regimen for HIV organ recipients is not known. The potential for increased toxicity and drug interactions should be considered carefully when determining optimal immunosuppressive therapy (Table).17 Maintenance of immunosuppression can be achieved with calcineurin inhibitors (CNIs), but drug interactions between CNIs and some ART agents, such as protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), can create a challenge in maintenance of immunosuppression.2,12,13 Belatacept is an immunosuppressive agent that is organ safe, does not interact with ART, and has the added benefits of antiviral activity against HIV.2,17,18 Before a transplant, a patient should be on a stable ART regimen. Regimens with a pharmacokinetic booster such as cobicistat or a PI require significant dose adjustments. Tacrolimus, a commonly used CNI, should be added to the ART regimen for patients taking PIs or pharmacokinetic boosters during the peritransplant period. Newer classes of ART, particularly integrase inhibitors, may allow for decreased drug monitoring with therapeutic benefits. For example, in clinical studies, raltegravir shows superior graft outcomes compared with other classes of ART; dolutegravir also provides a genetic barrier to the development of HIV resistance.2,6 Post-transplant (first 5-7 days), typical antibody induction therapy consists of weight-dosed antithymocyte globulin (rabbit), a polyclonal depleting antibody used to prevent and treat acute organ rejection in HIV-positive recipients.

However, the long-term safety of rabbit therapy is considered controversial. Maintenance immunosuppression therapy after transplantation includes prednisone tapered over 3 months, mycophenolate mofetil, and tacrolimus.13,17 Earlier protocols required lifelong antibiotic prophylaxis against Pneumocystis jirovecii.17 Post-transplant monitoring of lab values is crucial to prevent rejection. It is unknown whether an aggressive approach is needed in HIV-positive transplant recipients, but there have been reports of low incidence of OIs.17 Associated Risks

Risks to consider when evaluating HIV-positive to HIV-positive transplantation include HIV superinfection, transfer of resistant virus, and HIV transmission to health care workers.6,12,17 Although studies demonstrate a low rate of OIs in HIV-positive kidney and liver transplants,5,8 the risk of transplanting an HIV-resistant viral strain is a major concern.5 If a recipient contracts a superinfection with a resistant virus, then the recipient often is treated with PIs, which can lead to increased risk for rejection.12 Social risks are a factor as well.The global campaign “U=U” (undetectable = untransmittable) spreads awareness that persons taking ART who have an undetectable viral load have zero risk of sexual transmission of HIV. The same cannot be assumed about potential transmission of HIV via liver transplants.8 In addition, a donor’s race may affect outcomes. Black patients have increased rates of glomerulopathy including HIV-associated nephropathy.3,5 Factors Associated With Rejection

Management of the transplanted organ can be complex due to drug interactions and an increased risk of rejection.8 Compared with HIV-negative recipients, HIV-positive recipients have an

TABLE. Potential Drug Interactions Between ART and Immunosuppressants17 Immunosuppressant Class ART Class

Calcineurin Inhibitors



Pharmacokinetic booster (cobicistat)

• Severe drug interaction • Increase serum creatinine

Significant drug interaction

No expected interaction

Integrase inhibitors

• No clinical interactions • RAL, DTG: increase serum creatinine

No expected interaction

No expected interaction

Boosted protease inhibitors

• Severe drug interaction • IDV: increase risk for cardiovascular events, increase risk for diabetes

Significant drug interaction

No clinical interactions

Non-nucleoside reverse transcriptase inhibitors

Slight potential for drug interaction

• Slight potential for drug interaction • EFV: Increase levels of HDL-C and LDL-C, psychosis, depression

No clinical interactions

ART, antiretroviral therapy; DTG, dolutegravir; EFV, efavirenz; HDL-C, high-density lipoprotein cholesterol; IDV, indinavir; LDL-C, low-density lipoprotein cholesterol; RAL, raltegravir

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2020 15


approximately 3 times higher risk for acute rejection.13 Muller et al examined cumulative survival rates among 27 patients with an HIV-positive to HIV-positive kidney transplant at 1, 3, and 5 years; results were 84%, 84%, and 74%, respectively. Among the 27 patients, 5 patients had an acute rejection episode.13 The cause of the higher rejection rates is still unclear. Many factors, including medications, infections, and organ rejection, affect allograft dysfunction. Increased rejection rates occur especially in the presence of HCV coinfection.6 Malat et al propose that “HIV itself causes immune dysregulation and an inflammatory milieu that enhances allorecognition by humoral and cellular mediated pathways,” which increase rejection rates.2 Another hypothesis accounts for host and drug-related factors: elevated host CD3 levels have been definitively linked to rejection (CD3 + HLA-DR+ cells in HIV+ patients).5 According to Sparkes et al,“continued CNI overexposure can contribute to allograft loss through the development of chronic allograft nephropathy.”18 Dosing of CNIs can be complex due to renal dose adjustments that are needed. Signs and symptoms of acute rejection may not always be present. Monitoring is a crucial part of post-transplant management. Persistently elevated serum creatinine and liver enzymes warrant an allograft biopsy.13,17,18 Infections also can result in post-transplant complications. One study observed the differences between infections in podocytes and tubular cells after kidney transplantation. Results showed a faster decline in graft function in podocytes compared with tubular cells. Researchers suggest this relationship is possibly due to poorer glomerular filtration rates in podocytes.13 In a retrospective study, Araiz et al concluded that patients with HCV/HIV coinfection had higher mortality compared with patients with HCV alone (44.1% vs 33%). Results were of clinical significance but were not statistically significant.1

References 1. Araiz JJ, Serrano MT, García-Gil FA, et al. Intention-to-treat survival analysis of hepatitis C virus/human immunodeficiency virus coinfected liver transplant: is it the waiting list? Liver Transpl. 2016;22(9):1186-1196. 2. Malat GE, Boyle SM, Jindal RM, et al. Kidney transplantation in HIV-positive patients: a single-center, 16-year experience. Am J Kidney Dis. 2019;73(1):112-118. 3. Durand CM, Segev D, Sugarman J. Realizing HOPE: the ethics of organ transplantation from HIV-positive donors. Ann Intern Med. 2016;165(2):138-142. 4. Avettand-Fenoël V, Rouzioux C, Legendre C, Canaud G. HIV infection in the native and allograft kidney: implications for management, diagnosis, and transplantation. Transplantation. 2017;101(9):2003-2008. 5. Werbel WA, Durand CM. Solid organ transplantation in HIV-infected recipients: history, progress, and frontiers. Curr HIV/AIDS Rep. 2019;16(3):191-203. 6. Miro JM, Grossi PA, Durand CM. Challenges in solid organ transplantation in people living with HIV. Intensive Care Med. 2019;45(3):398-400. 7. Health Resources and Services Administration. Organ donation statistics. Accessed November 2, 2020. https://www.organdonor.gov/statisticsstories/statistics.html#:~:text=There%20are%20currently%20over%20 109%2C000,and%20Transplantation%20Network%20National%20Data. 8. Botha J, Fabian J, Etheredge H, Conradie F,Tiemessen CT. HIV and solid organ transplantation: where are we now. Curr HIV/AIDS Rep. 2019;16(5):404-413. 9. Malinis M, Boucher HW. Screening of donor and candidate prior to solid organ transplantation: guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13548. 10. Botha J, Conradie F, Etheredge H, et al. Living donor liver transplant from an HIV-positive mother to her HIV-negative child: opening up new therapeutic options. AIDS. 2018;32(16):F13-F19. 11. US Department of Health & Human Services. Organ Procurement and Transplantation Network. HOPE Act. Accessed October 28, 2020. https:// optn.transplant.hrsa.gov/learn/professional-education/hope-act/. 12. Muller E, Barday Z. HIV-positive kidney donor selection for HIV-positive transplant recipients. J Am Soc Nephrol. 2018;29(4):1090-1095.

Future Research

13. Muller E, Barday Z, Mendelson M, Kahn D. HIV-positive-to-HIV-positive kidney

There is still much to study in the growing field of HIV-positive organ transplantation. Cell-free DNA assays can be used to diagnose allograft injury in kidney transplant recipients, but there are limited data on HIV-positive recipients.17 Further studies with HIV-positive recipients can aid in earlier detection of injury and earlier intervention. Other areas of future study include access to HIV transplants, optimal immunosuppression and ART regimens, management of donor-derived transmission of a resistant HIV strain, and prevention of acute and chronic rejection.16 Transplant research primarily has been on kidney and liver transplants in HIV-positive adults. Further studies are needed on the outcomes of heart, lung, and pancreas transplants, as well as transplants in pediatric populations.17 ■

transplantation-results at 3 to 5 years. N Engl J Med. 2015;372(7):613-620. 14. Abara WE, Collier MG, Moorman A, et al. Characteristics of deceased solid organ donors and screening results for hepatitis B, C, and human immunodeficiency viruses. MMWR Morb Mortal Wkly Rep. 2019;68(3):61-66. 15. Wolfe CR, Ison MG. Donor-derived infections: guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13547. 16. Ruck JM, Segev DL. Expanding deceased donor kidney transplantation: medical risk, infectious risk, hepatitis C virus, and HIV. Curr Opin Nephrol Hypertens. 2018;27(6):445-453. 17. Blumberg EA, Rogers CC. Solid organ transplantation in the HIV-infected patient: guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13499. 18. Sparkes T, Manitpisitkul W, Masters B, et al. Impact of antiretroviral regimen

Eudiah Ochieng, PA-C, is a graduate of Augusta University. Lisa Daitch, MPA, PA-C, is associate professor at Augusta University.

on renal transplant outcomes in HIV-infected recipients. Transpl Infect Dis. 2018;20(6):e12992.

16 THE CLINICAL ADVISOR • DECEMBER 2020 • www.ClinicalAdvisor.com


Clinical Challenge: A Not-So-Straightforward Case of Endometriosis Endometriosis affects approximately 10% of women of reproductive age in the United States, with peak prevalence occurring in those aged 25 to 35 years.


26-year-old White woman presents to the gynecology clinic complaining of a 6-month history of progressively worsening right lower quadrant (RLQ) pain and painful defecation. She reports constant, dull, and throbbing pain, with occasional sharp, stabbing pains that radiate to her lower back and right hip. She also describes a “pulling sensation” in her abdomen during defecation. Her symptoms include fatigue, constipation, bloating, decreased stool caliber, pressure on urination, and deep dyspareunia. The patient notes that symptoms are notably worse the week before menses. She denies weight loss, hematochezia, fever, nausea, vomiting, hematuria, vaginal discharge, dysmenorrhea, and menorrhagia and reports that ibuprofen and polyethylene glycol laxatives have not relieved her pain.


Medical History

The exact etiology of endometriosis is unclear.

Medical history is significant for a hemorrhagic right ovarian cyst that resulted in an emergency department visit 4 months before the onset of the current symptoms. She is an otherwise healthy woman, with no history of pregnancy, abdominal surgery, or sexually transmitted disease. The patient’s menarche occurred at 13 years of age, and her menstrual cycles occur every 28 to 32 days and last 5 to 7 days. Her family history is positive for uterine fibroids and breast and colon cancers. She takes no medications other than those previously mentioned for pain and constipation. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2020 17


On further questioning, the patient admits the dyspareunia began when she was 22 years old. She reports that 3 different gynecologists examined her and failed to identify a cause for her dyspareunia. She was referred to physical therapy for pelvic floor strengthening but was dismissed after her first treatment due to normal pelvic tone. No other treatments or diagnostic tests were offered. Around this time, she also had 2 visits to her primary care provider (PCP) for evaluation of her abdominal pain and gastrointestinal complaints. Her examinations were unremarkable and a hemoccult test was negative. The PCP recommended an over-the-counter laxative and told her to eat a higher fiber diet for her constipation.The PCP also advised her to try a gluten and lactose elimination diet to rule out food allergies.The patient’s symptoms persisted despite these therapies. Her PCP ultimately recommended that she follow up with a gynecology provider due to her recent history of an ovarian cyst. Gynecologic Examination and Imaging

On examination, the patient’s abdomen is soft and nondistended, with bowel sounds active in all 4 quadrants. She has moderate tenderness and guarding during palpation of the right lower quadrant. No abdominal mass is noted and costovertebral angle tenderness is negative. Her vitals are shown in Table 1. During pelvic examination, the patient experiences mild pain on insertion of the vaginal speculum. Her external genitalia, vaginal mucosa, and cervix appear normal. The adnexa of the uterus are moderately tender on bimanual examination. She does not have cervical motion tenderness. Palpation of the uterosacral ligaments and posterior cul-de-sac during rectovaginal examination causes severe pain, and there TABLE 1. Summary of Patient’s Vital Signs Vital Sign


Temperature, ° C


Heart rate, beats/min


Blood pressure, mm Hg


Height, cm


Weight, kg


Body mass index


Abdominal girth, in


Pain score


is palpable fullness in the posterior cul-de-sac. A hemoccult test is negative. On transvaginal ultrasound (TVUS), the uterus is anteverted and measures 8.50 × 4.27 × 4.15 cm, with an endometrial thickness of 0.73 cm. The myometrium appears normal. A small amount of fluid is present in the cul-de-sac.The bladder is compressed by the uterus.The left ovary is located laterally and measures 5.43 × 3.71 × 4.07 cm. It contains multiple simple follicles. No abnormal blood flow is noted.The right ovary is enlarged by an 8.08 × 8.19 × 7.03 cm cyst with a wall thickness of 0.55 cm.The cyst appears homogeneous and hypoechoic, surrounded by poor vascular flow. Assessment and Plan

Differential diagnosis of the patient’s pelvic pain and right adnexal mass includes endometriosis, ovarian cyst, and ovarian tumor. She was offered diagnostic laparoscopy for further assessment. Multiple preoperative laboratory studies were ordered, including urinalysis and culture (UA&C), urine human chorionic gonadotropin (HCG), complete blood count with differential, complete metabolic panel, testosterone (free and total), folate, dehydroepiandrosterone sulfate (DHEAS), follicle-stimulating hormone, luteinizing hormone, progesterone, prolactin, estradiol, cancer antigen 125, and serum HCG. The UA&C and urine HCG were negative; all other results were within normal limits. Operative Findings and Diagnosis

Operative findings were consistent with stage IV endometriosis. Laparoscopic visualization and histology revealed scattered superficial endometriosis on the anterior cul-desac and paravesical areas (Figure 1). The posterior cul-de-sac, uterosacral ligaments, and rectovaginal area had deeper lesions that penetrated through the fibroadipose tissue (Figure 2).The posterior aspect of the right ovary also contained vascular adhesions and endometriosis.All the lesions were treated with vaporization or excision techniques (Figure 3). The large right ovarian cyst appeared benign but adhered to the pelvic sidewall and portions of the loops of bowel. The cyst caused partial torsion of the right fallopian tube (Figure 4) and compression over the loops of bowel, which led to partial distension of the bowels and sigmoid colon.The cyst was aspirated and found to contain a chocolate-like material. Ovarian cystectomy was performed and an endometrioma was confirmed by histologic evaluation of the specimen. Further exploration revealed multiple benign paratubal serous cysts in the left fallopian tube (Figure 5); the largest of these was excised and the rest were aspirated.The left distal ureter also was involved, with dense adhesions that were lysed to restore normal anatomy.The left ovary contained multiple functional cysts.

18 THE CLINICAL ADVISOR • DECEMBER 2020 • www.ClinicalAdvisor.com






FIGURES 1-5. Laparoscopic view of paravesical endometriosis (1); posterior view of cul-de-sac and rectovaginal area with deeper penetration of endometriosis (2); lesions after treatment (3); right ovarian cyst causing torsion of fallopian tube (4); benign paratubal serous cysts (5).

The uterus was normal in shape and contour. Hysteroscopy with endometrial biopsy was performed, and no evidence of malignancy or hyperplasia was found. Peritoneal washing and cytology were free of malignancy. Proctosigmoidoscopy and rectovaginal examination performed at the conclusion of surgery revealed resolution of the thickening and irregularity at the sites of endometriosis treatment.The patient recovered well, with resolution of symptoms.



Endometriosis is a chronic inflammatory disorder caused by the growth of endometrial-like tissue outside the uterine cavity.1 The most common sites of endometriosis are the ovaries, uterosacral ligaments, posterior cul-de-sac, rectosigmoid colon, and bladder.2 It affects approximately 10% of women of reproductive age, with peak prevalence occurring in those aged 25 to 35 years.1,2 Risk factors include first-degree relatives with endometriosis, early menarche, short menstrual cycles, nulliparity, and low body mass index.3 The exact etiology of endometriosis is unclear, but several theories have been proposed. The most widely promoted is Sampson’s theory of retrograde menstruation. During this phenomenon, endometrial tissue enters the peritoneal cavity through the fallopian tubes and implants itself in the peritoneum and surrounding organs, leading to adhesions, inflammation, and chronic pain.1,4 However, retrograde menstruation is a normal occurrence in 90% of women and thus does not explain why only some develop endometriosis.2,3 More recent theories suggest immunologic dysfunction and genetic/epigenetic components are involved in the pathogenesis of endometriosis.3 Studies have shown that women with endometriosis appear to have lower cell-mediated immunity with decreased T-cell and natural killer cell responses, which may alter the ability of the immune system to target and destroy the endometriotic lesions.2,3 A third theory, the theory of Müllerianosis, suggests that during fetal organogenesis, Müllerian cells remain in

the pelvis and differentiate into functioning endometrial glands and stroma under the influence of estrogen.2,3 Still, these theories fail to explain why the tissue of endometriosis has a similar histologic appearance to the endometrium yet functions differently.3 Patients can present with a variety of symptoms, with the most common including dysmenorrhea, menorrhagia, deep dyspareunia, dyschezia, bloating, dysuria, chronic pelvic pain, and infertility. Symptoms do not always correlate with disease severity; patients can be asymptomatic despite having severe endometriosis.2,4 However, symptoms can provide clues to help locate the endometriotic lesions. For example, endometriosis on the rectum or bowels can cause dyschezia and bloating, whereas endometriosis in the posterior cul-de-sac causes dyspareunia.2 Misdiagnosis is very common because symptoms overlap with other pain-related syndromes and gastrointestinal disorders such as irritable bowel syndrome and interstitial cystitis. Because of this, the average length of time between initial symptom presentation and the diagnosis of endometriosis is 7 years.3,4 Definitive diagnosis only can be attained with laparoscopic visualization and biopsy of the endometriotic lesions. The lesions classically have a blue-black or “powder-burned” appearance with endometrial glands, stroma, and hemosiderinladen macrophages revealed on histology.2,3 Endometriosis is also staged based on operative findings.The best-known classification system is the revised American Society for Reproductive Medicine scoring system, which classifies endometriosis based on lesion location and depth of penetration, degree of cul-de-sac involvement, and presence of endometriomas (benign cysts associated with endometriosis) and pelvic adhesions (Table 2).5 Disease extent ranges from minimal (stage I) to severe (stage IV).1,3,6 The current system has been criticized because of the poor correlation with symptoms and predictive prognosis.7 Although definitive diagnosis requires surgery, a presumptive diagnosis can be made from patient history, examination, and imaging. The hallmark finding on examination of a patient

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2020 19


TABLE 2. Staging of Endometriosis5 Stage I

Minimal disease characterized by isolated implants. No adhesions present.

Stage II

Mild disease consisting of superficial implants scattered on the peritoneum and ovaries. No significant adhesions present.

Stage III

Moderate disease consisting of multiple implants, both superficial and deeply invasive. Adhesions may be present on the fallopian tubes and ovaries.

Stage IV

Severe disease characterized by multiple superficial and deep implants, including large ovarian endometriomas. Dense adhesions usually are present.

with endometriosis is tender, nodular thickening along the uterosacral ligaments and posterior cul-de-sac and a fixed, retroverted uterus. However, examination usually reveals nonspecific findings.2,3 Imaging is useful in both ruling out other causes of pelvic pain and in the preoperative assessment of the extent of disease. TVUS, the first-line imaging modality used in this setting, can detect endometriosis in the posterior cul-de-sac, bladder, and rectosigmoid area. Lesions appear as irregular thickening or hypoechoic nodules, and there may be free fluid in the cul-de-sac.3,8 TVUS also has the highest sensitivity and specificity in identifying ovarian endometriomas.These cysts commonly are referred to as “chocolate cysts” because they contain a thick, brown, bloody fluid. They tend to form dense adhesions on the peritoneal wall, bowels, and other surrounding structures. On TVUS, endometriomas classically appear as unilocular cysts, with homogeneous ground-glass echogenicity of the cystic fluid and poor vascular flow.3 There is no cure for endometriosis.The goal of treatment is to suppress pain. Medical therapies generally are offered first and include nonsteroidal anti-inflammatory drugs (NSAIDs) and combined oral contraceptive pills, progestins, danazol, or gonadotropin-releasing hormone analogs.3,4 These medications are intended to control pain by reducing inflammation, suppressing ovarian hormone production, and reducing menstruation.4 Operative laparoscopy is reserved for patients who do not respond to medical treatment or for those with endometriomas or infertility secondary to endometriosis. However, symptoms usually recur at a rate of 44% within 5 years after surgery.3 Therefore, it is recommended that patients begin hormone suppression postoperatively, if tolerable, to help prevent the recurrence of symptoms.4


In the primary care setting, the diagnosis of endometriosis is clinical, based on the patient’s history and physical examination findings.Although physical examination findings may be nonspecific, the presence of tenderness or nodular thickening along the uterosacral ligaments and posterior cul-de-sac or a fixed, retroverted uterus should prompt the diagnosis of endometriosis. Medical therapy should be offered for symptomatic relief. According to the American Academy of Family Physicians, therapy should begin with NSAIDs, which can be followed by hormonal therapy if needed. If the patient fails medical therapy — or if the patient desires pregnancy — referral to a gynecologist for further evaluation is warranted.9 Patient education should also focus on therapy being suppressive, not curative.3,4 Discontinuation of medications and surgical intervention both carry the risk of symptom recurrence.1 If the providers treating the patient in this case had considered endometriosis as the root of her complaints, she may have received intervention much sooner. ■ Cristina Baldassarri, MPA, PA-C, is a physician assistant; E. Rachel Fink, MPA, PA-C, is a physician assistant at Augusta Urology Associates and an assistant professor in the Physician Assistant Program at Augusta University. References 1. Vercellini P, Viganò P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014;10(5):261-275. 2. Davila GW, Kapoor D, Alderman E, et al. Endometriosis. Medscape. https:// emedicine.medscape.com/article/271899-overview. Updated July 25, 2018. Accessed October 31, 2020. 3. Falcone T, Flyckt R. Clinical management of endometriosis. Obstet Gynecol. 2018;131(3):557-571. 4. Nezhat C, Vang N, Tanaka PP, Nezhat C. Optimal management of endometriosis and pain. Obstet Gynecol. 2019;134(4):834-839. 5. American Society for Reproductive Medicine. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67(5):817-821. 6. Schenken RS. Endometriosis: pathogenesis, clinical features, and diagnosis. UpToDate. https://www.uptodate.com/contents/endometriosispathogenesis-clinical-features-and-diagnosis. Updated June 1, 2020. Accessed October 31, 2020. 7. Johnson NP, Hummelshoj L, Adamson GD, et al. World Endometriosis Society consensus on the classification of endometriosis. Human Reproduction. 2017;32(2):315-324. 8. Hudelist G, Ballard K, English J, et al. Transvaginal sonography vs. clinical examination in the preoperative diagnosis of deep infiltrating endometriosis. Ultrasound Obstet Gynecol. 2011;37(4): 480-487. 9. Schrager S, Falleroni J, Edgoose J. Evaluation and treatment of endometriosis. Am Fam Physician. 2013;87(2):107-113.

20 THE CLINICAL ADVISOR • DECEMBER 2020 • www.ClinicalAdvisor.com

Dermatologic Look-Alikes Large, Spreading Rash After Illness LEAH DOUGLAS, BS; YELENA DOKIC, BSA; CHRISTOPHER RIZK, MD



A 62-year-old man with hypertension, obesity, and gout presents with a 4-day history of fever, rash, abdominal pain, and lymphadenopathy. Five weeks earlier, the patient was hospitalized for gout and prescribed allopurinol. Physical examination reveals fever (102 °F); a rash encompassing 60% of his body surface area; cervical, axillary, and inguinal lymphadenopathy; and right upper quadrant tenderness to palpation. Laboratory workup shows leukocytosis with eosinophilia and elevated alanine aminotransferase level of >100 U/L. Histology findings include foci of interface dermatitis and perivascular lymphocytic infiltrates.

A 50-year-old woman presents to the dermatology clinic with a 1-day history of an itchy, pink rash that began on her abdomen and quickly spread to her back, arms, and legs. She reports just finishing a 7-day course of trimethoprim-sulfamethoxazole for an uncomplicated urinary tract infection. On physical examination, she is afebrile and has diffuse, fine, erythematous papules that coalesce into plaques in some areas.The rash is symmetrically distributed on the back and chest, largely sparing the face. Her throat and sclerae are clear, and she has no facial edema or lymphadenopathy.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2020 21

Dermatologic Look-Alikes CASE #1

DRESS Syndrome

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare acute dermatologic emergency.1 DRESS differs from other adverse drug reactions in its idiosyncratic presentation, time of onset in relation to the offending agent, mortality rate, systemic organ involvement, and characteristic laboratory derangements. With the development of novel pharmaceutical agents, such as phenytoin in the 1930s, came reports of new cutaneous and systemic reactions.2 Clinicians began recognizing a constellation of symptoms, including lymphadenopathy, fever, eosinophilia, and rash, emerging several weeks after initiation of a drug from a few specific classes.1 Many names have been used to describe this drug-related syndrome, including anticonvulsant hypersensitivity syndrome, phenytoin/Dilantin syndrome, and drug-induced delayed multiorgan hypersensitivity syndrome.2 In 1996, Bocquet et al proposed the term “Drug Rash with Eosinophilia and Systemic Symptoms”; the R was later changed to “Reaction” to reflect the heterogeneity of possible skin manifestations.3 The true incidence of DRESS syndrome is not well known, but it is estimated to occur in between 1 in 1000 and 1 in 10,000 new drug exposures; the mortality associated with the syndrome ranges from 10% to 20%.4 The reaction can occur in both adults and children.3 The precise pathogenesis of DRESS remains uncertain, but several contributory mechanisms have been hypothesized. Because the most common offending drugs implicated in DRESS are anticonvulsants, the suboptimal functioning of the epoxide hydroxylase enzyme (part of the cytochrome P450 system) is a likely contributor in some patients. Epoxide hydroxylase normally detoxifies the metabolites of aromatic amine anticonvulsant drugs such as carbamazepine, phenytoin, and phenobarbital in the liver.2,5 Deficiency or defects of epoxide hydroxylase metabolism results in an accumulation of toxic intermediates, such as arene oxides, which activate T cells to trigger a systemic immune response or cause direct cytotoxicity.5 Because these intermediates bind to human leukocyte antigens (HLAs) to mediate many effects, certain HLA subtypes likely carry a genetic predisposition to developing DRESS.2,5,6 In most DRESS patients, there is also a rise in titers for several human herpesviruses several weeks after rash onset; therefore, viral reactivation is likely a primary or exacerbating factor in the pathogenesis of DRESS.1,7

The most commonly implicated drugs in the development of DRESS syndrome include aromatic anticonvulsants, sulfonamides, dapsone, and allopurinol.4 Although DRESS is largely mediated by a hyperactive immune system, immunosuppression paradoxically has been shown to confer increased risk for development.4 Cases tend to cluster within families, and many cases have been reported among Black patients and patients of East Asian ancestry.4,8 This presumably is due to the inherited nature of genes encoding drug detoxification enzymes (CYP450) and HLA alleles. DRESS syndrome typically presents as a febrile rash with eosinophilia and lymphadenopathy.1 The earliest phase of DRESS may appear similar to a morbilliform drug reaction.9 The cutaneous eruption is highly variable, usually consisting of erythematous maculopapular lesions; however, other features such as vesicles, bullae, purpura, targetoid lesions, and facial edema can be seen.2 Mucosal lesions are present in many cases.4 Visceral organ involvement is the major cause of mortality; hepatitis is the most common cause, but myocarditis, pericarditis, nephritis, pneumonitis, and colitis are also possible manifestations.2,3

The true incidence of DRESS is unknown, but it is estimated to occur in up to 1 in 10,000 new drug exposures. DRESS has a characteristic long latency period of 2 to 8 weeks after initiation of the culprit drug and a prolonged symptomatic period after drug withdrawal.2,4,10 Laboratory workup often will find elevated aminotransferase levels, eosinophilia, leukocytosis, and atypical lymphocytes on blood smear. The histopathologic findings are nonspecific; interface dermatitis is seen in nearly all patients, and other frequent findings include superficial perivascular lymphocytic infiltrates, erythrocyte extravasation, and spongiosis.11-13 In a minority of cases, eosinophils may be seen on histology.13 Conditions that should be considered in the differential diagnosis for DRESS syndrome include other adverse drug reactions (morbilliform drug eruption, Stevens-Johnson syndrome/toxic epidermal necrolysis [SJS/TEN]), viral eruptions (Epstein-Barr virus [EBV], cytomegalovirus [CMV]), and vasculitis [Kawasaki disease]).14,15 DRESS can be distinguished from these other conditions by its delayed onset after drug initiation (particularly when the drug is known to be associated with DRESS), eosinophilia, and internal organ involvement.

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Dermatologic Look-Alikes Although various clinicopathologic diagnostic criteria have been suggested for DRESS, it has been challenging to standardize the diagnostic process because of the varied historical nomenclature, diverse presentation, and uncertainty about the pathophysiologic mechanism.10 In cases suspicious for DRESS, the diagnostic criteria from the European Registry of Severe Cutaneous Adverse Reactions and/or the Japanese Research Committee on Severe Cutaneous Adverse Reactions may help guide diagnosis.10 Withdrawal of the offending drug is key to clinical care; thus, early diagnosis and identification of the causative medication is highly important. Systemic steroids and supportive care (fluid resuscitation, wound changes, etc) are the mainstay of treatment. In patients for whom steroids are contraindicated or ineffective, other immunomodulating agents such as cyclosporine, intravenous immunoglobulin, and mycophenolate have been used successfully.11 Given the significant mortality associated with DRESS, patients should be treated in an intensive care or burn unit.9 Patients who survive are at risk for permanent damage from visceral organ involvement or later development of autoimmune conditions (Graves disease or Hashimoto thyroiditis are particularly common).2,11 For the patient in this case, allopurinol was discontinued immediately. He was admitted to the intensive care unit, where he was treated with high-dose intravenous corticosteroids and given aggressive fluid resuscitation. His elevated liver transaminase levels decreased over the following weeks and his presenting symptoms largely resolved. Annual thyroid function tests were recommended for long-term follow-up, and the patient was advised to avoid allopurinol and other drugs known to be associated with DRESS syndrome.


Morbilliform Drug Eruption

Cutaneous effects are the most frequent manifestation of adverse drug reactions, and morbilliform drug eruptions, also called exanthematous drug eruptions, comprise approximately 95% of these cutaneous reactions.9,16 Morbilliform drug eruptions likely have been present as long as the use of pharmacologic agents, but they became more prevalent and better recognized with the advent of drugs such as penicillin. Much data exist on the epidemiology and risk factors for adverse

drug reactions overall, but limited data are available on cutaneous delayed-type drug hypersensitivity reactions such as morbilliform drug rash specifically.16 This likely is because it is difficult to definitively diagnose these reactions and they are understudied due to their overall benign nature. The prevalence of drug hypersensitivity reactions is estimated at 1% to 6% of the adult population.16 The prevalence of drug hypersensitivity reactions in the pediatric population is thought to be lower, likely due to fewer medications used and relatively immature immune systems.16 Initiation of a drug commonly associated with morbilliform drug eruptions (β-lactam antibiotics, sulfonamides, nonsteroidal anti-inflammatory drugs, antiepileptic agents, allopurinol, etc) is an important risk factor for development of these reactions.9,16,17

The term morbilliform describes a rash that resembles measles, with erythematous, maculopapular lesions that may coalesce. The pathophysiology of morbilliform drug reactions likely involves both Type IVb and IVc hypersensitivity reactions, which usually manifest in the skin.9 These are delayed T-cell– driven processes resulting from direct or indirect T-cell stimulation by drug-derived antigens. In Type IVb hypersensitivity, Th2 helper cells produce cytokines that provoke eosinophilic inflammation.9,18 In Type IVc hypersensitivity, cytotoxic T cells cause direct tissue damage via apoptotic mechanisms.18 The term morbilliform describes a rash that resembles measles, with erythematous, maculopapular lesions that may coalesce.9 These lesions may be urticarial and appear purpuric (particularly in thrombocytopenic patients) or targetoid.The rash often begins on the trunk and progresses in a symmetric fashion toward the extremities.9 Petechiae may appear on the distal extremities, particularly in patients with thrombocytopenia. Patients with morbilliform drug reactions usually are afebrile (or have a low-grade fever) and are healthy overall.The onset of the rash generally is 5 days to 2 weeks after initiation of the culprit drug.The reaction is self-limited, with symptoms usually resolving within 1 to 2 weeks of drug cessation; however, post-inflammatory hyperpigmentation may persist. A skin biopsy is not indicated because histopathologic findings are nonspecific and contribute little to diagnosis. If the diagnosis is under contention and a biopsy is performed, histopathology demonstrates a perivascular mixed infiltrate of

24 THE CLINICAL ADVISOR • DECEMBER 2020 • www.ClinicalAdvisor.com

DRESS Syndrome1-15

Morbilliform Drug Eruption9,16-20

Dermatologic presentation

• Erythematous macules/papules that may coalesce • Other morphologies (bullae, purpura, etc) often present

• Erythematous macules/papules that may coalesce


• High fever nearly always present • Onset: 2-8 weeks • Eosinophilia and lymphadenopathy

• Afebrile or low-grade fever • Onset: 5 days-2 weeks • Pruritus


• Exposure to antiepileptics, sulfonamides, allopurinol, dapsone • Suboptimal functioning of the epoxide hydroxylase enzyme

• Exposure to β-lactams, sulfonamides, NSAIDs, anti-epileptics, allopurinol • Type IVb and IVc hypersensitivity reactions

Characteristic location

• Febrile rash that begins on face and upper body • Mucosal involvement often present • Evidence of visceral damage (eg, elevated transaminases, proteinuria, etc) • Facial edema

• Begins on trunk and progresses toward the extremities • Petechiae may appear on the distal extremities • No evidence of visceral damage


• Nonspecific • Interface dermatitis, superficial perivascular lymphocytic infiltrate, erythrocyte extravasation, and spongiosis

• Nonspecific • Perivascular mixed infiltrate of lymphocytes and histiocytes, interstitial spongiosis, vacuolar interface dermatitis, and eosinophils


• History and physical examination • Temporal association of symptom onset with drug initiation • Laboratory findings (eosinophilia, evidence of visceral damage, atypical lymphocytes on smear, etc.)

• History and physical examination • Temporal association of symptom onset with drug initiation • Exclusion of infectious or rheumatologic etiologies


• Drug cessation • ICU or burn unit • Systemic steroids • Supportive care (fluid resuscitation, etc) • Long-term care of permanent visceral organ complications • Monitoring for development of autoimmune conditions (eg, thyroid)

• Drug cessation • Usually outpatient management • Symptomatic care (topical corticosteroids, oral antihistamines) • Patch testing months later

DRESS, drug reaction with eosinophilia and systemic symptoms; ICU, intensive care unit; NSAID, nonsteroidal anti-inflammatory drugs

lymphocytes and histiocytes, interstitial spongiosis, vacuolar interface dermatitis, and eosinophils.9,19 The morbilliform drug rash generally is a clinical diagnosis based on physical examination and scrupulous history demonstrating temporal association with an agent known to cause a reaction.The patient should be asked about all prescription and over-the-counter medications as well as homeopathic or herbal treatments.20 Making the diagnosis mainly involves excluding other causes of rashes. No specific laboratory tests are indicated for confirmation of the diagnosis.9 In children, a morbilliform rash is visually indistinguishable from various infectious etiologies, including viral exanthems (EBV, CMV, roseola, parvovirus, measles), bacterial exanthems (scarlet fever), and toxin-mediated processes (toxic shock

syndrome, early staphylococcal scalded skin syndrome).9 The differential diagnosis also may include various rheumatologic disorders, such as Kawasaki disease or juvenile idiopathic arthritis, if the patient exhibits suspicious adjoining symptoms. Because a viral or bacterial exanthem is the most likely competing diagnosis in pediatric patients, the diagnostic workup may involve ruling out infection with serologic testing (heterophile antibody, rapid strep, antistreptolysin O tests, etc).9 The presence of associated symptoms such as arthralgias, lymphadenopathy, ocular infection, or high fever is more indicative of a rheumatologic or infectious cause rather than a morbilliform drug reaction.9 In adults, other drug reactions, such as DRESS or SJS/ TEN, are the most important etiologies to be considered in the differential diagnosis.9,20 Because early-phase DRESS or

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Dermatologic Look-Alikes SJS/TEN may mimic a morbilliform drug rash, it is important to maintain vigilance as the clinical course evolves. Other etiologies to consider include pityriasis rosea, allergic contact dermatitis, secondary syphilis, and acute cutaneous lupus erythematosus.9 In adults, warning signs, such as high-grade fever, facial edema, evidence of visceral damage (elevated transaminases, hematuria, proteinuria, etc), mucosal involvement, and hemodynamic instability, should elicit immediate concern for more severe drug reactions.9,20 The immediate management of morbilliform drug eruptions mainly involves drug cessation and symptomatic care.9 Topical corticosteroids and oral antihistamines can help relieve pruritus; with extreme symptoms, systemic corticosteroids may be considered if an infection has been excluded.9 If the drug in question is indispensable to the patient’s health and no viable alternatives exist (often the case with antiretrovirals or antituberculous drugs), continuing the medication and “treating through” the rash with supportive measures may be necessary.9 The patient in this case was symptomatically treated with topical corticosteroids and oral antihistamines and was counseled that her symptoms likely would resolve within 1 to 2 weeks. She was advised that she may have a sulfa drug allergy and that allergy testing several months after symptom resolution could be considered. ■

with allopurinol — a Canadian missed opportunity [formula: see text]. J Cutan Med Surg. 2019;23(6):595-601. 9. Hall JC, Hall BJ, eds. Cutaneous Drug Eruptions. Springer-Verlag; 2015. 10. Kim DH, Koh YI. Comparison of diagnostic criteria and determination of prognostic factors for drug reaction with eosinophilia and systemic symptoms syndrome. Allergy Asthma Immunol Res. 2014;6(3):216-221. 11. Cho YT, Yang CW, Chu CY. Drug reaction with eosinophilia and systemic symptoms (DRESS): an interplay among drugs, viruses, and immune system. Int J Mol Sci. 2017;18(6):1243. 12. Borroni G,Torti S, Pezzini C, et al. Histopathologic spectrum of drug reaction with eosinophilia and systemic symptoms (DRESS): a diagnosis that needs clinico-pathological correlation. G Ital Dermatol Venereol. 2014;149(3):291-300. 13. Ortonne N, Valeyrie-Allanore L, Bastuji-Garin S, et al. Histopathology of drug rash with eosinophilia and systemic symptoms syndrome: a morphological and phenotypical study. Br J Dermatol. 2015;173(1):50-58. 14. De A, Rajagopalan M, Sarda A, Das S, Biswas P. Drug reaction with eosinophilia and systemic symptoms: an update and review of recent literature. Indian J Dermatol. 2018;63(1):30-40. 15. Bachot N, Roujeau JC. Differential diagnosis of severe cutaneous drug eruptions. Am J Clin Dermatol. 2003;4(8):561-572. 16. Gomes ER, Kuyucu S. Epidemiology and risk factors in drug hypersensitivity reactions. Curr Treat Options Allergy. 2017;4(2):239-257. 17. Bigby M. Rates of cutaneous reactions to drugs. Arch Dermatol. 2001;137(6):765-770. 18. Thomas WR, Cunningham PT. Hypersensitivity: Immunological. In: eLS.

Leah Douglas, BS, andYelena Dokic, BSA, are medical students at Baylor College of Medicine, and Christopher Rizk, MD, is a dermatologist affiliated with Baylor College of Medicine, in Houston,Texas.

John Wiley & Sons, Ltd; 2015. 19. Weyers W, Metze D. Histopathology of drug eruptions - general criteria, common patterns, and differential diagnosis. Dermatol Pract Concept. 2011;1(1):33-47. 20. Lehloenya RJ. Cutaneous adverse drug reactions. Contin Med Educ J.



1. Revuz J, Roujeau JC, Kerdel F, Valeyrie-Allanore L, eds. Life-Threatening Dermatoses and Emergencies in Dermatology. Springer-Verlag; 2009. 2. Choudhary S, McLeod M, Torchia D, Romanelli P. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. J Clin Aesthet Dermatol. 2013;6(6):31-37. 3. Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (drug rash with eosinophilia and systemic symptoms: DRESS). Semin Cutan Med Surg. 1996;15(4):250-257. 4. Husain Z, Reddy BY, Schwartz RA. DRESS syndrome: part I. clinical perspectives. J Am Acad Dermatol. 2013;68(5):693.e1-e14. 5. Bohan KH, Mansuri TF, Wilson NM. Anticonvulsant hypersensitivity syndrome:

Case Study Library

implications for pharmaceutical care. Pharmacotherapy. 2007;27(10):1425-1439. 6. Mullan KA, Anderson A, Illing PT, Kwan P, Purcell AW, Mifsud NA. HLA-associated antiepileptic drug-induced cutaneous adverse reactions. HLA. 2019;93(6):417-435. 7. Kano Y, Hiraharas K, Sakuma K, Shiohara T. Several herpesviruses can reactivate in a severe drug-induced multiorgan reaction in the same sequential order as in graft-versus-host disease. Br J Dermatol. 2006;155(2):301-306. 8. Ponzo MG, Miliszewski M, Kirchhof MG, Keown PA, Dutz JP. HLA-B*58:01

Check out all of our case studies in obesity, diabetes, and other important topics in primary care — along with our clinical challenges — by visiting us at: ClinicalAdvisor.com/Case-Study

genotyping to prevent cases of DRESS and SJS/TEN in East Asians treated

26 THE CLINICAL ADVISOR • DECEMBER 2020 • www.ClinicalAdvisor.com


Bankruptcy Can’t Shield MD’s Debt


Ms J was a certified adult nurse practitioner (NP) in her state when Dr C, an infectious disease specialist, hired her. Under a collaborative practice agreement, Ms J’s job was to assist in communicating with patients, gathering patient information, and conducting prerounds at hospitals. After several months of work, it became apparent to Ms J that the position was not a good fit for her. She decided to wait until she had worked for a year before she gave notice. Dr C seemed happy with her work, as evidenced by positive performance reviews he provided to the hospitals where Ms J had practice privileges. When Ms J had been employed for about a year, Dr C prepared a performance review for her, rating her “excellent” in every category and stating that there had been no complaints about her.The next day, Ms J was offered a job with a competing infectious disease specialty practice that she thought was a better fit. She gave Dr C a resignation letter, allowing for 3 weeks’ notice as required by their agreement. Dr C did not take the news well. He seemed shocked and surprised at Ms J’s desire to leave


Nurse practitioner sues former boss for defamation and wins, only to have him declare bankruptcy. The NP’s new employer did not want to hire her while an investigation was ongoing; she was out of work for a year.

“a wonderful working relationship.” Dr C met with Ms J twice after receiving the resignation letter. During the first meeting, which occurred the week she had given notice, he tried to convince her to stay with his practice. Ms J declined. The second meeting took place after Dr C discovered that Ms J would be going to a competitor. It was at this meeting that he showed her a letter criticizing her professional competence, work commitment, and moral character. He implied that he was going to send this letter to the state Nursing Board and to others and suggested that Ms J might want to reconsider her decision to leave the practice. Ms J did not reconsider. Dr C sent the letter to the state Nursing Board and the hospitals at which Ms J had privileges. The letter triggered an investigation by the Nursing Board and resulted in temporary suspension of her privileges at the hospitals. Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

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LEGAL ADVISOR Dr C defended the letter to the Nursing Board, claiming that he rated Ms J “excellent” in her evaluation in error and had meant that evaluation for a different NP. After a 9-month investigation and review, the Nursing Board dismissed the complaint against Ms J, finding no evidence of any wrongdoing on her part. However, Ms J’s new employer had not wanted to hire her while a Nursing Board investigation was going on, so she was out of work for almost a year. After the Nursing Board’s decision, Ms J hired a plaintiff ’s attorney and sued Dr C for defamation. The case went to a full jury trial, during which it was determined that the physician’s statements about Ms J were false and had been harmful to her career. The jury did not agree with Dr C’s argument that the letter was not designed to negatively affect Ms J but to protect her future patients. At the end of the trial, the jury found for Ms J and awarded her $150,000 for damage to her professional reputation caused by the false statements in the letter. Dr C declared bankruptcy

The court held that Dr C’s actions were willful, malicious, and harmful to Ms J’s professional reputation. and sought to have his debts, including the judgment owed to Ms J, discharged under Chapter 11 of the US Bankruptcy Code. Ms J appealed to the US Bankruptcy Court asking it to find the debt nondischargeable.

in his employ, and then sent it to the Board of Nursing and the hospitals at which Ms J practiced. Dr C, the court noted, is a highly intelligent individual and knew exactly what would happen when he sent that letter — an investigation would start and Ms J might lose her license and practice privileges. They agreed that statements were made willfully. Dr C also acted maliciously in sending the letter, according to the court. He made false and defamatory statements intended to harm Ms J.The statements were not made for some altruistic purpose of helping future patients, as he claimed, but rather they were made in anger because Ms J was leaving to work for a competitor.The court held that Dr C’s actions were willful, malicious, and deliberately caused harm to Ms J’s professional reputation and, thus, the debt Dr C owed to Ms J could not be discharged by bankruptcy. Protecting Yourself

This scenario took years to unfold. The original events took place in 2005, yet this decision by the Bankruptcy Court occurred in 2020. Legal actions can be agonizingly protracted. It is always best to act professionally. Dr C reacted poorly, immediately, and emotionally to the news that his employee was leaving. He compounded his unprofessional response by threatening Ms J with a letter containing false information. When the threat itself did not work, he followed through.Was he entitled to feel upset that a valued employee was leaving? Yes. But that should have been the extent of it. Everything he did after that was unprofessional and wrong. ■ Ann W. Latner, JD, a former criminal defense attorney, is a freelance medical writer in Port Washington, New York.

The Court Decision

The court noted that Section 523(a)(6) of the Bankruptcy Code excepts debts from discharge for “willful and malicious injury by the debtor to another entity or to the property of another entity.” To prevail, it must be shown that the debtor (Dr C): “1) deliberately and intentionally, 2) injured the plaintiff or the plaintiff ’s property; 3) by a willful and malicious act.” The Court pointed out that willfulness and malice are separate and distinct. Willfulness implies intentional behavior; malice connotes a malevolent purpose. The court noted that most of the facts were established in the defamation trial and that these facts established that Dr C deliberately and intentionally injured Ms J’s career, reputation, and prospects.The only thing to determine was whether the false statements were made “willfully and maliciously.” The court held that, as to the willfulness prong, Dr C deliberately wrote the letter, initially as a threat to get Ms J to stay 28 THE CLINICAL ADVISOR • DECEMBER 2020 • www.ClinicalAdvisor.com

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Clinical Advisor December 2020 Issue  

Clinical Advisor December 2020 Issue