UTSW IM Journal Watch February 2016

Edward Jenner (1749 – 1823) Father of Immunology Dr. Jenner was a rural English physician who developed the first vaccine after noticing milkmaids

exposed to cowpox seemed to be immune to smallpox.

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Contents

Dermatology Image Challenge ....................................................................................................................................... 4

EKG Challenge....................................................................................................................................................................... 7

Cardiology ........................................................................................................................................................................... 10

Systemic Search for Present and Potential Portals of Entry for Infective Endocarditis ................... 10

Endocrinology ................................................................................................................................................................... 13

Effects of Testosterone Treatment in Older Men ............................................................................................ 13

Gastroenterology .............................................................................................................................................................. 15

Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease ...................................................... 15

Frozen vs Fresh Fecal Microbiota Transplantation and Clinical Resolution of Diarrhea in Patients

With Recurrent Clostridium difficile Infection ................................................................................................. 16

General Internal Medicine ............................................................................................................................................ 17

Eluxadoline for Irritable Bowel Syndrome with Diarrhea ........................................................................... 17

Efficacy of Bright Light Treatment, Fluoxetine, and the Combination in Patients With

Nonseasonal Major Depressive Disorder ........................................................................................................... 19

Geriatrics ............................................................................................................................................................................. 21

Person-Centered Care: A Definition and Essential Elements ..................................................................... 21

Hematology / Oncology ................................................................................................................................................. 23

Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura ................................................... 23

Hepatology .......................................................................................................................................................................... 24

Nonselective Beta-blockers increase Risk for Hepatorenal Syndrome and Death in patients with

Cirrhosis and Spontaneous Bacterial Peritonitis ............................................................................................. 24

Infectious Diseases .......................................................................................................................................................... 26

Antibiotic Therapy for Adults Hospitalized With Community-Acquired Pneumonia: A Systematic

Review .............................................................................................................................................................................. 26

Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis .............................................. 28

Nephrology ......................................................................................................................................................................... 30

Sevelamer Versus Calcium-Based Binders for Treatment of Hyperphosphatemia in CKD: A Meta-

Analysis of Randomized Controlled Trials ......................................................................................................... 30

Comparative effect of contrast media type on the incidence of contrast-induced nephropathy: a

systematic review and meta-analysis .................................................................................................................. 32

Rheumatology .................................................................................................................................................................... 34

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A Randomized, Controlled Trial of Total Knee Replacement (TKR) ........................................................ 34

When Patients Write the Guidelines: Patient Panel Recommendations for the Treatment of

Rheumatoid Arthritis (RA) ....................................................................................................................................... 35

Faculty and Fellow Mentors ......................................................................................................................................... 36

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Dermatology Image Challenge

Dr. Joshua Owen

A white man in his 50s with a history of coronary artery disease, hypertension, hypothyroidism,

seizure disorder, depression, and alcohol abuse presented to the ED with a 3-day history of a

diffuse, painful, pruritic eruption with fever. He has a single punched-out ulceration on the hard

palate. He also has generalized erythematous papules and pustules on an erythematous base,

some of which are crusted over, on his scalp, face, trunk, extremities (arms > legs), buttocks,

penile shaft, and palms/soles (Figure A-C). He denies recent travel or drug use and admits to

heavy alcohol use daily. He denies starting any new medications.

WHAT IS YOUR DIAGNOSI S?

A. Folliculitis

B. Primary varicella

C. Disseminated zoster

D. Pityriasis lichenoides et varioliformis acuta (PLEVA)

WHICH IS THE MOST IMP ORTANT LAB TO AID IN THE DI AGNOSIS?

A. Bacterial culture of lesion

B. Varicella IgG/IgM

C. HSV IgG/IgM

D. VZV and HSV PCR of lesion

Figure. A) generalized erythematous papules (some crusted) and pustules on scalp, face, and

anterior chest. B) similar generalized eruption on neck and back. C) grouped erythematous

papules and pustules on erythematous base.

C A B

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D IAGNOSIS LAB

C. Disseminated zoster D. VZV and HSV PCR of lesion

D I SCUSSION

Human herpes virus 3 (HHV3) or the varicella-zoster virus (VZV) is responsible for two clinical

syndromes: varicella (chickenpox) and herpes zoster (shingles). Prior to varicella vaccination,

varicella occurred in 90% of US children by age 10. Zoster is the reactivation of latent VZV from

prior varicella; this occurs in about 20% immunocompetent adults compared to 50% of the

immunocompromised.

Latent VZV resides in dorsal root ganglion cells. Upon reactivation, viral replication occurs with

viral spreading along the sensory nerve for that dermatome, causing both the painful

ganglionitis/neuralgia and the skin changes (symptoms without skin changes is called zoster sine

herpete). Skin findings may initially include papules or plaques that become vesicular and

progress to pustules and even bullae. The distribution of lesions classically occurs in a

dermatomal or adjacent dermatomal distribution, not crossing the midline.

If the ophthalmic division of trigeminal nerve (CN V1) is suspected, Hutchinson’s sign refers to the

increased risk of ocular involvement if the tip of the nose has lesions. This indicates involvement

of the nasociliary branch of CN V1 and would prompt an ophthalmology consult. Ramsay Hunt

syndrome refers to the involvement of the geniculate ganglion of the facial nerve (CN VII), with

lesions affecting the external auditory canal, tympanic membrane, and anterior two-thirds of the

tongue/hard palate.

Disseminated cutaneous zoster (defined as >20 vesicles outside primary or adjacent dermatomes)

and visceral zoster occurs in about 10% of the immunocompromised with zoster. However, rare

cases of disseminated zoster have been reported in the absence of immunosuppression.

In this case, the patient reported having varicella as a child. His HIV and hepatitis serologies were

negative, CBC and LFTs were unremarkable, and he does not take any immunosuppressing

medications. An important early diagnostic test is PCR of the vesicle or pustule fluid for VZV and

HSV (he was VZV+, HSV-). An important caveat is that that PCR may take 2-3 days to return from

the lab; therefore early consultation with dermatology is important for a rapid Tzanck test that

can be performed at bedside to help confirm the diagnosis when atypical. Other confirmatory tests

include VZV IgG/IgM; IgM is usually negative with zoster reactivation (he was IgG+, IgM-). Given

his positive Hutchinson’s sign, ophthalmology was consulted for possible ocular involvement,

which he did not have. Chest x-ray and abdominal ultrasound were negative for pulmonary or

other visceral involvement. It is important to recognize the possibility of disseminated zoster as

early treatment halts progression. Acyclovir 10 mg/kg IV every 8 hours is indicated for

disseminated zoster, for a total course of 7-10 days or until cropping has ceased.

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REFERENCES

1. Gupta S, Jain A, Tyring SK. A Rare Case of Disseminated Cutaneous Zoster in an

Immunocompetent Patient. BMC Fam Pract. 2005;6:50.

2. Mendoza N, Madkan V, Sra K, Willison B, Morrison LK, Tyring SK. Human Herpesviruses. In:

Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed. Saunders; 2012:1328-34.

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EKG Challenge

Dr. Htet Khine

You are the CCU resident on call at the VA. Although you’ve only admitted one patient, you are

exhausted from EJ-ing your old patients as many of your patients’ PIVs stopped working and they

have “bad veins.” As you are about to take a short nap, you get paged by this number: 71975. It’s

the ED.

Here comes a 65 year-old veteran with history of heart failure, hypertension, hyperlipidemia, CKD

Stage 4, type 2 diabetes, and a pacemaker placed several years ago for reasons patient is unsure of.

He was brought in by the ambulance for chest discomfort and feeling extremely weak. By the time

you saw him, he received a full dose aspirin so far and nasal cannula 2L. Here are the vials: heart

rate 105, blood pressure 170/90, respirations 20, oxygen saturation 100% on 2 L nasal cannula.

The ED physician brings you the EKG.

HOW WOULD YOU DESCRIB E THIS EKG, AND WHAT IS YOUR DIF FERENTIAL?

This is a wide complex tachycardia at a rate ~100 with extremely wide QRS complexes (~400ms).

There is failure to capture.

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Differential for a wide QRS complex

Nonspecific intraventricular conduction delay Aberrant ventricular conduction (bundle branch block) Ventricular excitation syndromes (WPW) Left ventricular hypertrophy Hyperkalemia Hypermagnesemia Pacemaker-generated beat Hypothermia Drug toxicities

WHAT IS THE DIAGNOSIS?

When the QRS duration is extremely wide >200 (as in this case ~400ms), hyperkalemia should

move to the top of the differential. Hyperkalemia would also explain the pacemaker failure to

capture. When the QRS becomes too wide, the pacemaker attempts to trigger during the

refractory period and fails to capture. This is the classic sine-wave pattern of extreme

hyperkalemia.

NEXT STEPS

The ECG is neither sensitive nor specific for diagnosing hyperkalemia.

Check stat labs for electrolytes.

His potassium returns at 8 mmol/L.

Treat the hyperkalemia (membrane stabilization with calcium gluconate, shift potassium into

cells with sodium bicarb and insulin, and increased potassium elimination from the body with

Lasix and kayexelate).

LEARNING POINT S

Serum Potassium (mmol/L) Predicted ECG status 5.5-6.5 Tall tented T waves

Shortened QT interval ST-segment depression

6.5-7.5 Peaked T waves Prolonged PR interval Decreased or disappearing P wave Widening of the QRS Amplified R wave

>8.0 Absence of P wave QRS continues to widen, approaching to sine wave Intraventricular/fascicular/bundle branch blocks

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Severe elevations in potassium level can result in QRS widening and loss of P waves, with eventual

formation of the sine-wave pattern seen in our patient. The rhythm can degenerate into

ventricular fibrillation if the cardiac membrane is not stabilized.

As it happens, our patient overdosed on potassium supplements.

This is the repeat EKG:

The pacemaker is now slowly taking over; pacemaker rate is 100 and capture rate is 50bpm. QRS

now is narrower than prior. The potassium level and has improved to 6.5mmol/L.

REFERENCES

1. Schiraldi F, Guiotto G, Paladino F. Hyperkalemia induced failure of pacemaker capture and

sensing. Resuscitation. Oct 2008;79(1):161-164.

2. Petrov DB. Images in clinical medicine. An electrocardiographic sine wave in hyperkalemia.

The New England journal of medicine. May 10 2012;366(19):1824.

3. Wang YP, Chen BX, Su KJ, et al. [Hyperkalemia-induced failure of pacemaker capture and

sensing: a case report]. Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health

sciences. Dec 18 2014;46(6):980-982.

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Cardiology

Systemic Search for Present and Potential Portals of Entry for Infective Endocarditis

Dr. Stephen Dickson reviewing Delahaye F, M’Hammedi A, et al. J Am Coll Cardiol. 2016 Jan

19;67(2):151-8.

SUMMARY

A group of French physicians conducted a prospective, single center study between 2005 and

2011 to identify the portal of entry (POE) of cases of infective endocarditis (IE). Patients with IE

were systemically evaluated by a stomatologist (a European medical-dentist), an otolaryngologist,

and a urologist. Women were seen by a gynecologist. Patients with cutaneous or periorificial

mucous lesions were seen by a dermatologist. Colonoscopy and EGD was completed on all IE

patients age>50, had a family history of colonic polyposis, or had a culture proven microorganism

of gastrointestinal origin.

Of the 318 patients included in this study, POE was defined in 238 patients (74%). POE

breakdown was most commonly cutaneous (40%), followed by oral/dental (29%) and

gastrointestinal (23%). Staphylococci was identified in 78% of cutaneous POE. Streptococci was

identified in 72% of oral POE. Colonic polyps were found in around half of the gastrointestinal POE

patients. POE was not defined in around one quarter of the patients- in these patients the

microorganisms were approximately 50% of cutaneous habitat, 25% of oral/dental habitat, and

25% of gastrointestinal habitat. Please see the below tables A-D for specific portal of entry data.

COMMENTARY

This paper states IE is a serious disease with an in-hospital mortality rate around 20%.

Furthermore, five to 10 percent of IE patients will have additional episodes of infective

endocarditis. Identifying the POE is important for both adequate treatment and prevention of

additional IE episodes. Surprisingly, the most recent guidelines on IE do not mention POE despite

its significance. This prospective study is the first of its kind and provides a detailed investigation

of IE sources through a systematic collaboration of medical specialists. By identifying portals of

entry and correlating with specific microorganisms, this study provides useful data in better

understanding the initial barrier breakdown leading to IE and the organisms involved in IE.

One limitation of this study is the single center aspect which limits the microorganism diversity

observed, especially when applying this data to different geographical locales. Additionally, it is

important to note that any patient with a history of IE is at increased risk for a second episode of

IE, and it may not be from the original POE. It is difficult to know at this stage whether additional

tests to identify POE will result in less recurrent IE, though this is an important first step.

UTSW Link

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Table A: All identified portals of entry (n=238)

Table B: Cutaneous portals of entry (n=96)

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Table C: Oral/dental portal of entry (n=68)

Table D: GI portal of entry (n=56)

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Endocrinology

Effects of Testosterone Treatment in Older Men

Dr. John Matt Hancock, MD reviewing Snyder PJ, et al. N Engl J Med. 2016 Feb 18;374(7):611-24.

SUMMARY

In this very recent article in the New England Journal Snyder et. al. randomly assigned 790 men

age 65 and older with a serum testosterone of 275ng per dl or less and symptoms suggesting

hypoandrogenism to either testosterone gel or placebo for one year. Men who were at risk for

prostate cancer of cardiovascular events were excluded from the trial. Testosterone treatment

increased serum testosterone level to a mid-normal range for men 19-40 years of age. The

increased testosterone level was associated with significantly increased sexual activity as assessed

by a daily questionnaire (P<0.001) as well as significantly increased sexual desire and erectile

function. Physical function as assessed by 6 minute walking distance did not differ between the

testosterone and placebo group neither did vitality as assessed by the Functional Assessment of

Chronic Illness Therapy – Fatigue scale. Men who received testosterone reported slightly better

mood and lower severity of depressive symptoms than those who received placebo. The rates of

adverse events were low and similar between the two arms of the study.

COMMENTARY

This trial seems to show that in men age 65 and older with symptomatic hypogonadism, raising

serum testosterone with topical testosterone gel showed a modest benefit with respect to sexual

function and some benefit with respect to mood and depressive symptoms, but no benefit with

respect to vitality or physical activity assessed by questionnaire and 6 minute walk distance

respectively. This study is important because it is one of the first randomized placebo controlled

trials that show evidence of benefit with testosterone therapy in older men. The benefit however

of increased sexual function was modest at best and a not as robust as the benefit derived from

PDE -5 inhibitors. Expect more exciting results from the testosterone trials in the near future.

UTSW Link

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Gastroenterology

Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease

Dr. Udayan Shah reviewing Lazarus B, et al. JAMA Intern Med. 2016 Feb 1;176(2):238-46.

In a large cohort study, PPI use was associated with CKD.

SUMMARY

This population-based cohort study of the Atherosclerosis Risk in Communities (ARIC) cohort,

consisting of communities in NC, MS, MN, MD, investigated the association of CKD with PPI use.

The study population consisted of 10,482 patients enrolled in the ARIC cohort with a baseline

eGFR > 60 and without HTN, DM, or CV disease at baseline. The study population was followed

from enrollment in 1996-1999 to December 2011 for a median follow-up of 13.9 years. The study

was also replicated in an integrated health system in rural Pennsylvania consisting of 248, 751

patients followed for a median of 6.2 years. The presence of CKD was defined by hospital

discharge ICD codes, cross-linking with the United States Renal Data System registry, or a 25%

decline in eGFR. Medication data was obtained by pill bottle inspection at enrollment and annual

telephone follow-up. Data was adjusted for age, sex, race, study center, socioeconomic status,

cigarette smoking, SBP, BMI, comorbidities, and the use of antihypertensives and anticoagulants.

Sensitivity analysis was performed to investigate the contribution of H2 blockers vs PPI and 1:1

controls were used to evaluate the risk of CKD with ever-use of PPI. There were 56 incidences of

CKD in the 322 PPI users compared to 1,382 events in the 10,160 non-PPI users, a 1.45-fold

difference in unadjusted incidence (P = 0.006) and 1.5-fold difference in adjusted incidence (P =

0.003) in PPI users compared to non-PPI users and H2-blocker users. BID PPI users had a higher

risk of CKD than daily use. Overall, the 10-year ARR was 1.7%.

COMMENTARY

The relationship between PPIs and AKI, specifically due to acute interstitial nephritis, is well-

known. This is the first study demonstrating an association between PPIs and CKD. While only an

observational study, the large population size, use of matched controls, many adjustments for

potential confounders, replication in a second cohort, and possible dose-dependent response

makes this a significant study and potentially adds CKD to the litany of adverse effects from PPI.

While the absolute risk reduction was relatively small, the widespread use of PPIs, especially with

OTC availability, means that many patients would be affected. The potential mechanism of CKD

may be repeated AKI, possibly from bouts of AIN. Further studies investigating the link between

PPIs and the development of CKD are needed to establish causality, but such studies will likely be

difficult to perform given the need for large sample size and long follow-up. Regardless, this study

offers additional rationale for limiting PPI use, especially beyond approved duration of therapy.

UTSW Link

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Frozen vs Fresh Fecal Microbiota Transplantation and Clinical Resolution of Diarrhea in Patients With Recurrent Clostridium difficile Infection

Dr. Udayan Shah reviewing Lee CH. JAMA. 2016 Jan 12;315(2):142-9.

Thawed frozen feces enemas were non-inferior to fresh feces enemas in the treatment of adults

with recurrent/refractory C. diff infection (CDI).

SUMMARY

This double blind RCT conducted at 6 academic medical centers sought to establish the non-

inferiority of frozen and thawed feces enemas compared to fresh feces enemas in the treatment of

recurrent or refractory C. diff infection. The study population consisted of those with recurrent

CDI, defined as C diff symptoms recurring within 8 weeks following the completion of at least 10

days of treatment for CDI, or refractory CDI, defined as persistent or worsening diarrhea despite at

least 5 days of PO vancomycin. Those with neutropenia or toxic megacolon were excluded.

Patients were randomized to either frozen FMT (n=114) or fresh FMT (n=118). The primary

endpoint was set as response, defined by resolution of diarrhea at 13 weeks after up to 2 FMTs

and no antibiotics. Non-inferiority was set at < 15% difference in primary endpoint. Response

rate was 75.0% for the frozen FMT group and 70.3%for the fresh FMT group (p < 0.001 for non-

response). There was no difference in adverse effects.

COMMENTARY

Fecal transplants have been touted as effective treatment for recurrent/refractory C diff

infections. This study was the first RCT directly comparing fresh and frozen feces transplants and

demonstrates that frozen fecal transplants are just as effective as fresh fecal transplants. Frozen

fecal transplants offer a number of advantages over fresh fecal transplants. Donors typically have

to be screened for stool and blood infections, which is not conducive to use in the acute setting.

Furthermore, fresh feces is generally only viable for up to 6 hours, so it is not possible to create

banks of feces. Finally, processing of donor feces requires special laboratory equipment that may

not be available at all institutions. Frozen feces circumvents all of these problems, allowing

banking of stool from acceptably screened and processed stool to be used in the acute setting,

even in institutions that lack the ability to process donor specimens themselves. Single group

studies have demonstrated the use of frozen FMT delivered as capsules rather than enemas, but

head-to-head studies would be beneficial in establishing the optimal delivery method.

UTSW Link

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General Internal Medicine

Eluxadoline for Irritable Bowel Syndrome with Diarrhea

Dr. Stephanie Chiao reviewing Lembo AJ, et al. N Engl J Med. 2016 Jan 21;374(3):242-53.

SUMMARY

Eluxadoline is a new oral agent with mixed opioid effects (μ- and κ-opioid receptor agonist and δ-

opioid receptor antagonist) predicted to be effective in IBS with diarrhea. In this paper, data from

2 phase-3 trials (IBS-3001 and IBS-3002) were presented. A total of 2427 adults with IBS with

diarrhea (according to the Rome III criteria) were randomized to eluxadoline (75 or 100 mg) or

placebo twice daily for 26 weeks (IBS-3002) or 52 weeks (IBS-3001). The primary end point was

the proportion of patients who had a simultaneous decrease in abdominal pain and improvement

in stool consistency on the same day for at least 50% of the days from weeks 1 through 12 and

weeks 1 through 26. A significantly larger percentage of patients on eluxadoline reported

improvement in the primary outcome measure compared to those in the placebo group in both

the IBS-3001 (23.9% with the 75-mg dose and 25.1% with the 100-mg dose vs. 17.1% with

placebo; P = 0.01 for the comparison of 75 mg with placebo and P = 0.004 for the comparison of

100 mg with placebo) and the IBS-3002 trial (28.9% with the 75-mg dose and 29.6% with the

100-mg dose vs. 16.2% with placebo; P<0.001 for the comparison of each dose of eluxadoline with

placebo). The treatment effect was observed within the first week and was maintained throughout

the 26-week assessment period (see figure below). Eluxadoline was also superior in terms of

decreasing stool frequency, urgency, and abdominal pain, and improving scores on the IBS-QOL

questionnaire. The most frequent side effects with eluxadoline were constipation (8.6% in the

100mg group) and nausea (7.5% in the 100mg group), but rates of discontinuation due to adverse

events were low (<2%). There were 5 cases of pancreatitis and 8 cases of acute abdominal pain

with abnormal hepatic enzyme levels, thought to be related to spasm of the sphincter of Oddi, a

phenomenon known to be associated with μ-opioid receptor agonists.

COMMENTARY

Limitations of this study include a relatively short duration for assessment of the primary

endpoint, which leaves open the question of efficacy over time; the lack of an active control arm to

compare to other IBS with diarrhea treatments; and the open question regarding the clinical

relevance of the magnitude of benefit in comparison to likely medication cost. Nevertheless, this

medication appears to be a promising treatment, as it seems to be effective with relatively mild

side effects (all cases of pancreatitis resolved within a week) and lower discontinuation rates than

comparators. Moving forward, studies comparing eluxadoline with other IBS treatments for longer

follow-up are needed, and the medication should be used with caution in those without

gallbladders and those with heavy alcohol use, as both may be associated with increased

sphincter-spasm-related pancreatitis.

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UTSW Link

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Efficacy of Bright Light Treatment, Fluoxetine, and the Combination in Patients With Nonseasonal Major Depressive Disorder

Dr. Stephanie Chiao reviewing Lam RW, et al. JAMA Psychiatry. 2016 Jan 1;73(1):56-63

SUMMARY

In this randomized controlled trial, 122 patients with nonseasonal major depressive disorder

were randomly assigned to an 8 week regimen of (1) light monotherapy and a placebo pill, (2)

antidepressant monotherapy and an inactive negative ion generator as a sham treatment, (3)

combination light and antidepressant treatment, or (4) a placebo pill and an inactive negative ion

generator. The primary endpoint was a change in the Montgomery-Asberg Depression Rating

Scale (MADRS) score, and secondary end points were response (≥50% reduction in MADRS score)

and remission (MADRS score ≤10). Similar to a previous RCT comparing light therapy with dim

red light, this study found that light therapy was efficacious and well tolerated in the treatment of

adults with nonseasonal MDD. For the respective placebo, fluoxetine, light, and combination

groups, response was achieved by 33.3%, 29.0%, 50.0%, and 75.9%, and remission was achieved

by 30.0%, 19.4%, 43.8%, and 58.6%. The difference in primary outcome was statistically superior

for combination therapy and light monotherapy but not fluoxetine monotherapy compared to

placebo.

COMMENTARY

This study is notable, as it is one of the few placebo-controlled RCTs evaluating light therapy alone

or in combination with antidepressants. Furthermore, the results in this study differ from prior

meta-analyses which did not show significant benefits with light therapy. Strengths in this study

include the use of placebo treatment and the sham treatment for light therapy. Weaknesses

include a small sample size, which may have led the study to be underpowered to show a

difference in the anti-depressant monotherapy arm, and possible inadequate dosing of the anti-

depressant. Also, the short duration of the study (8 weeks) does not provide information about

whether light therapy provides a sustained long-term effect. As light therapy appears safe and

well-tolerated, it may be increasingly used in the future to treat non-seasonal MDD if additional

data shows its efficacy.

UTSW Link

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Geriatrics

Person-Centered Care: A Definition and Essential Elements

Dr. Emily Bowen reviewing American Geriatrics Society Expert Panel on Person-Centered Care. J Am

Geriatr Soc. 2016 Jan;64(1):15-8.

SUMMARY

In the 2001 report “Crossing the Quality Chasm: A New Health System for the 21st Century,” the

Institute of Medicine established “patient-centered care” as one of six pillars of quality healthcare

and described the concept as “care that is respectful of and responsive to individual patient

preferences, needs, and values, and [ensures] that patient values guide all clinical decisions.”

Since then, there has been a shift to using the term “person-centered care” instead to reflect the

idea of care that extends beyond the strictly clinical or medical. The term has been used

frequently in the health policy literature, but the lack of a standard agreed upon definition makes

research and the establishment of best practices of how to provide person-centered care

challenging. Therefore, the SCAN Foundation (an independent public charity that works to

improve care for older adults) commissioned The American Geriatrics Society and a team from the

University of Southern California Keck School of Medicine to establish a definition and the

essential elements of person-centered care. An inter-disciplinary panel of 14 people from across

the country with expertise in the principles of person-centered care and representing the fields of

gerontology, geriatric medicine and oncology, gerontological social work and nursing, health

policy and finance, law, long-term care delivery, and public health performed an extensive

literature review and then met to come up with a consensus definition and the essential elements

of person-centered care to be used moving forward.

DEFINITION

“Person-centered care” means that individuals’ values and preferences are elicited and, once

expressed, guide all aspects of their health care, supporting their realistic health and life goals.

Person-centered care is achieved through a dynamic relationship among individuals, others who

are important to them, and all relevant providers. This collaboration informs decision-making to

the extent that the individual desires.

ESSENTIAL ELEMENTS

An individualized, goal-oriented care plan based on the person’s preferences

Ongoing review of the person’s goals and care plan

Care supported by an interprofessional team in which the person is an integral team member

One primary or lead point of contact on the healthcare team

Active coordination among all healthcare and supportive service providers

Continual information sharing and integrated communication

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Education and training for providers and, when appropriate, the person and those important to the

person

Performance measurement and quality improvement using feedback from the person and

caregivers

COMMENTARY

Words like person-centered care sound nice, but are often used without a clear definition.

Defining this term and the essential elements is important for policy makers but also important

for us to have an idea of what is actually meant when we read about person-centered care in the

literature or even in the news. Providing true person-centered care is an amazing aspiration, but

there are many barriers to providing this type of care in our current healthcare system. Examples

of barriers include physician workload and inadequate time and reimbursement for

communication and coordination of care, underdevelopment and underutilization of

interprofessional teams, focus on health metrics and quality indicators that may not be reflective

of patient quality of life or patient goals, lack of coordination between healthcare and community-

based resources, and separation of medical records between healthcare systems and settings.

Person-centered care is especially important when caring for older adults who often have complex

medical histories with multiple chronic conditions, whose goals of care may not align with

evidence-based management, who receive care in a variety of settings, and whose care may

require extensive involvement of family, caretakers, and social services. Having a standardized

definition of person-centered care will help in the development of policy and best practices for

providing the highest quality care for all patients, but especially for older adults and others whose

complex care requires intensive coordination and communication.

UTSW Link

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Hematology / Oncology

Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura

Dr. Tri Le reviewing Peyvandi, et al. N Engl J Med. 2016 Feb 11;374(6):511-22

SUMMARY

The TITAN investigators recently published the results of their phase II study of caplacizumab, a

monoclonal antibody that prevents the interaction between platelets and von Willebrand factor

(vWF) under high-shear conditions by binding the A1 domain of vWF, in the treatment of acute,

acquired thrombotic thrombocytopenic purpura (TTP) when added to standard of care. This was a

multi-center, single-blind, randomized, placebo-controlled trial in which 75 patients were

randomized either to standard-of-care (daily plasma exchange and immunotherapy) +

caplacizumab or to standard-of-care + placebo. The primary end point was time to normalization

of platelet count. As compared to placebo, treatment with caplacizumab resulted in a statistically

significant reduction in time to normalization of platelet count (39% reduction, p = 0.005).

Bleeding rates were higher in the caplacizumab group (54% vs 38%).

COMMENTARY

TTP is a disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and

end-organ damage (e.g. renal failure, encephalopathy,) secondary to microthrombi of uncleaved

vWF multimers and platelets. Its pathophysiology is rooted in the functional deficiency of

ADAMTS13, a metalloproteinase that cleaves ultra-large, multimeric vWF particles. These

multimers bind glycoprotein 1b on platelets and result in the aforementionds multimers. The

functional deficiency in ADAMTS13 in acute, acquired TTP is often the result of autoantibodies

against ADAMTS13. The current standard of care in acute acquired TTP involves plasma exchange

and glucocorticoids, which removes anti-ADAMTS13 autoantibodies, replenish ADAMTS13, and

immunologically suppresses production of autoantibodies. While the advent of plasma exchange

and steroids has significantly decreased mortality, the global mortality remains ~15%.

Caplacizumab introduces a new, targeted therapeutic approach to TTP that may ultimately

improve outcomes for TTP. While the sequencing, timing, and patient selection for such agents

remains to be investigated, the advent of new direct, rapid-acting therapies that inhibit the

formation of the pathogenic microthrombi in TTP are exciting advances that may augment current

practice. Interestingly, there is some evidence that N-acetylcysteine may similarly inhibit vWF-

dependent platelet agglutination (Dr. Rambally published a case report on the use of NAC in

refractory TTP – UTSW Link).

UTSW Link

24

Hepatology

Nonselective Beta-blockers increase Risk for Hepatorenal Syndrome and Death in patients with Cirrhosis and Spontaneous Bacterial Peritonitis

Dr. Thalvinder Sangha reviewing Mandorfer M, et al. Gastroenterology. 2014 Jun;146(7):1680-90.e1.

SUMMARY

Study design was a retrospective analysis was done of 607 consecutive patients with cirrhosis

who underwent their first paracentesis at Medial University of Vienna between 2006 and 2011

and had bacterial cultures from ascites. The paracentesis was performed in either a diagnostic or

therapeutic setting. The impact of non-selective beta blocker treatment (NSBB) and transplant

free survival was analyzed using cox models. Patients on NSBB had less non-elective

hospitalization days than those without. In patients diagnosed with SBP, NSBB had more inpatient

hospitalization days, were associated with lower transplant-free survival rates. Once a patient

developed SBP, NSBB treatment was associated with lower transplant-free suvival and increase of

58% in mortality risk once developing SBP (Figure). In patients that developed SBP higher rates

of HRS were observed in patients on NSBB compared to those without. Outcome of the study was

up to the development of SBP, NSBB treatment has a beneficial effect on transplant free survival

and reduction in mortality risk of 25%. Transplant-free survival was worse in SBP patients

receiving NSBB treatment with increased morality risk of 58%.

COMMENTARY

Up to the development of SBP, NSBB treatment had effect on transplant-free survival and

reduction in mortality. At the development of SBP in patients receiving a NSBB there was an

increased mortality risk and worse transplant free survival. This information is adding to a

growing body of evidence that there may be a therapeutic “window” in which NSBB provide a

protective effect in patients with cirrhosis. It has already been well documented that there is no

benefit on mortality in the early stages of cirrhosis. This paper adds weight to the fact that the

window may close after the development of SBP. Patients that develop SBP are a distinct group of

critically ill patients with very labile hemodynamics. It is critical for these patients to maintain

circulatory reserve during both the acute phase of an infection and later on. NSBB blunt the

compensatory cardiac function in patients with an already low cardiac output state during the

hemodynamic changes brought on by SBP (increased systemic vasodilation which requires an

increase in cardiac output to maintain adequate MAPs). The paper concludes that we should

discontinue NSBB in patients with SBP, and hypothesizes that we should not re-start them as SBP

is a sign of the window closing for NSBB use. The question becomes is there an opportunity for

this window to re-open in patients who go from decompensated back to compensated cirrhosis.

Further studies, specifically a prospective trial will be needed.

25

UTSW Link

Figure

26

Infectious Diseases

Antibiotic Therapy for Adults Hospitalized With Community-Acquired Pneumonia: A Systematic Review

Dr. Anurag Mehta reviewing Lee JS, et al. JAMA. 2016 Feb 9;315(6):593-602.

SUMMARY

This systematic review provides an evidence-based assessment about three key aspects of

antibiotic therapy for adults hospitalized with community-acquired pneumonia (CAP) in the non-

ICU setting: optimal time for initiation of antibiotic therapy, selection of initial antibiotic regimen,

and timing of safe transition from intravenous to oral antibiotics.

INIT IATION TIME FOR A NTIBIOTIC THERAPY

Five retrospective, two prospective, and one secondary analysis of a randomized controlled trial

were reviewed (all low grade studies as per the GRADE system). The four largest studies showed

that initiation of antibiotics within 4 to 8 hours of presentation was associated with a mortality

benefit (30-day mortality in three and in-hospital mortality in one study). The remaining four

studies showed no significant difference in outcomes.

INIT IAL EMPIRIC ANTIB IOTIC REGIMEN

The benefit of using an empiric antibiotic regimen that covers both typical and atypical bacteria

causing CAP over a regimen that covers only typical bacteria was evaluated. Eleven studies (2

randomized controlled trials, 3 prospective studies, 4 retrospective studies, and 2 secondary

analyses of combined cohort study and clinical trial data) were analyzed for differences in

outcomes between initial antibiotic regimens. The two RCTs were the only studies rated high on

the GRADE system, rest were all low.

1. Beta-lactam plus macrolide therapy (covers both typical and atypical organisms) versus beta-

lactam monotherapy (10 studies): in one RCT, patients receiving beta-lactam monotherapy had a

trend toward being clinically unstable on hospital day 7 and having a higher 30-day mortality than

combination therapy and the trial did not demonstrate non-inferiority of beta-lactam

monotherapy. In the second RCT the results were different, patients receiving monotherapy had a

trend toward decreased 90-day mortality and beta-lactam monotherapy was non-inferior to

combination therapy. However, six of the remaining eight observational studies demonstrated a

mortality benefit of using combination beta-lactam and macrolide therapy over beta-lactam

monotherapy.

2. Fluoroquinolone monotherapy (covers both typical and atypical organisms) versus beta-lactam

monotherapy (4 studies): one RCT comparing these agents showed a trend toward decreased 90-

day mortality in the fluoroquinolone group and beta-lactam monotherapy was not non-inferior to

27

fluoroquinolone monotherapy. The remaining three observational studies showed a consistent

mortality benefit of using fluoroquinolones over beta-lactam monotherapy.

SAFE TRANSIT ION FROM INTRAVENOUS TO ORAL ANTIBIOTICS

One high-quality RCT that used objective clinical criteria (figure 1) for early transition from

intravenous to oral antibiotics as compared to continuous seven days of intravenous antibiotics

was reviewed. The duration of intravenous antibiotic therapy and length of hospital stay were

significantly reduced in the early transition group with no significant differences in terms of

treatment failure (death, hospitalization till day 28 or clinical deterioration).

COMMENTARY

In the United States, CAP is responsible for 600,000 hospital admissions and generating $10.6

billion in healthcare cost every year. Despite advancements in diagnostic testing, the etiologic

agent in CAP is most often not identified, which makes empiric antibiotics the standard of care.

The timing of initiation, empiric regimen selection, and timing of transition from intravenous to

oral antibiotics are of utmost importance. Although most of the conclusions of this review (Figure)

are drawn from low quality observational studies, they are consistent with and support the 2007

practice guidelines for community-acquired pneumonia developed by the Infectious Disease

Society of America and the American Thoracic Society.

USTW link

Figure

28

Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis

Dr. Anurag Mehta reviewing Beardsley J, et al. N Engl J Med. 2016 Feb 11;374(6):542-54.

SUMMARY

This randomized, double-blind, placebo-controlled trial evaluated the benefit of using adjunctive

dexamethasone with combination amphotericin B and fluconazole therapy in treating adult

patients with HIV-associated cryptococcal meningitis. Patients with HIV infection, a clinical

syndrome of cryptococcal meningitis, and microbiologic confirmation of the disease were

recruited in 13 hospitals in Southeast Asia and sub-Saharan Africa. 451 patients underwent

randomization and were treated with two weeks of induction therapy consisting of amphotericin

B and fluconazole followed by eight weeks of consolidation therapy with fluconazole and then

maintenance therapy with fluconazole. 224 patients received dexamethasone for six weeks and

226 patients received identical placebo. The primary outcome of interest was survival after 10

weeks of randomization and secondary outcomes included survival at 6 months, disability at 10

weeks and 6 months, visual acuity at 10 weeks, rate of decrease in cryptococcal counts in the CSF,

and CSF opening pressure during the first two weeks. The trial was stopped early because of

concerns that patients receiving dexamethasone had more adverse events, disability and

decreased fungal clearance in the CSF. By 10 weeks, 47% patients in the dexamethasone group

and 41% in the placebo group had died. There was no significant difference in 10-week survival

between the two groups, but tests for non-proportional hazards were significant suggesting a time

dependent change in the effects of dexamethasone. Exploratory analyses (for days 44 to 71 of the

trial) showed a significantly higher hazard ratio for death in the dexamethasone group. The 6

month mortality was 57% in the dexamethasone group as compared to 49% in the placebo group

(not statistically significant). However, there was a trend toward harm with dexamethasone use.

Dexamethasone was also associated with a significantly higher risk of disability at 10 weeks and 6

months, a significantly slower rate of decline in the number of cryptococcal colony-forming units

in the CSF during the first two weeks of treatment, a significantly greater number of adverse

events, and a significantly greater reduction in CSF opening pressure.

COMMENTARY

HIV-associated cryptococcal meningitis is estimated to cause more than 600,000 deaths each year.

The 10-week mortality in patients receiving combination antifungal therapy with amphotericin B

and either fluconazole or flucytosine is more than 30% with most survivors having significant

disability. Adjunctive treatment with dexamethasone has been shown to improve outcomes in a

subset of patients with acute bacterial and TB meningitis and could have been helpful in patients

with HIV-associated cryptococcal meningitis. The results of this study indicate that the dose and

regimen of dexamethasone used was associated with increased disability and adverse events. The

trial had to be stopped early because of these concerns and consequently the study did not have

enough statistical power to reach significant results for its primary outcome, survival at 10 weeks.

However, the hazard ratios for survival at 10 weeks and 6 months did not favor dexamethasone

29

use with a trend suggestive of harm. These results were consistent in both Asia and Africa. The

reasons for worse outcome with dexamethasone are unclear, but attenuation of cytokine levels

that help clear the fungus is a possibility. Current Cryptococcal treatment guidelines do

recommend using steroids in patients with cryptococcomas with CNS mass effect, acute

respiratory distress syndrome or immune reconstitution inflammatory syndrome (IRIS). These

events are rare, and the basis for these recommendations is largely case series or non-randomized

studies and expert opinion. However, for the majority of patients with cryptococcal CNS disease,

adjuvant glucocorticoids do not provide a benefit but rather likely cause harm and should not be

used.

USTW link

Figure

30

Nephrology

Sevelamer Versus Calcium-Based Binders for Treatment of Hyperphosphatemia in CKD: A Meta-Analysis of Randomized Controlled Trials

Dr. Natalia Rocha reviewing Patel et al. Clin J Am Soc Nephrol. 2016 Feb 5;11(2):232-44.

SUMMARY

Patients with CKD are at increased risk of disorders of calcium and phosphorus metabolism

associated with hyperparathyroidism. Observational studies have tied high serum phosphate

concentrations with adverse outcomes in patients with chronic kidney disease and thus,

guidelines suggest dietary restriction of phosphate and use of phosphate binders to treat

hyperphosphatemia. The most common pharmacological strategies for reduction in the levels of

serum phosphate are calcium based (CCB) and the noncalcium based (non-CCB) sevelamer. The

question regarding which strategy has a better impact on mortality remains elusive and it is

unclear if non-CCB which are 4 to 10 times more expensive then CCB are worth the additional

money spent. Meta-analysis including randomized and non-randomized trials have shown a trend

towards decrease in all-cause mortality for non-CCB, but limitations including low power and

inclusion of non-randomized trials prevented clinicians from making an evidence based decision.

With this in mind, Patel et al conducted a meta-analysis including 25 randomized controlled trials

to compare sevelamer versus CBBs in CKD stages 3–5D. They found a 46% reduction in all–cause

mortality risk for sevelamer (Figure), but no differences in cardiovascular mortality. Patients on

sevelamer had higher rates of PTH level control, reduced risk of hypercalcemia and lower calcium,

however, their phosphate levels were similar to patients on calcium based formulations.

COMMENTARY

This is a large meta-analysis comparing sevelaver vs calcium based strategies. The studies

included have significant heterogeneity when it comes to baseline characteristics such as age and

mean time since starting dialysis. Some of the trials included in the study had a significant number

of patent’s who lost follow up. Most importantly, a high discrepancy was found in terms of CV

mortality between the studies included in this meta-analysis. It is unclear if this study has high

enough quality to settle the dispute.

UTSW Link

31

Figure: Effect of sevelamer versus calcium-based binders on all-cause mortality in patients with CKD.

32

Comparative effect of contrast media type on the incidence of contrast-induced nephropathy: a systematic review and meta-analysis

Dr. Natalia Rocha reviewing Eng et al, Ann Intern Med. 2016; Published online 2 February 2016.

SUMMARY

Contrast induced nephropathy is a common cause of renal dysfunction and it is associated with a

significantly increase in mortality. Modern contrast media are classified according to their

osmolality. Since the 1990, low-osmolar contrast media (osmolality 2 to 3 times higher than

plasma) have been the usual choice when a contrasted study is needed. Later on, iso-osmolar

contrast media became available, with the theoretical advantage over low-osmolar contrast and

the promise to be safer. However, no concrete evidence is available to demonstrate such a

difference in outcomes. With this in mind, Eng et al performed a meta-analysis comparing the

incidence CIN with the use of low and iso-osmolar contrast media. They found a slight reduction in

CIN risk with iso-osmolar contrast (pooled relative risk, 0.80 [95% CI, 0.65 to 0.99]; P =0.045)

which did not exceed a minimally important relative risk of 0.25. No differences were found on

need for renal replacement therapy, CV outcomes or death.

COMMENTARY

Several studies included in this meta-analysis provided insufficient description of indications for

the contrast study, severity of underlying kidney dysfunction and total contrast volume

administered, creating a significant heterogeneity. Since the goal of this meta-analysis was to

evaluate renal outcomes, studies that did not report rates of CIN where excluded, including the

ones focused on CV outcomes. For this reason, no conclusions can be drawn on non-renal

outcomes such as all cause and CV mortality.

UTSW Link

33

Figure: Graphical summary of meta-analysis of randomized, controlled trials comparing iodixanol and

LOCM with contrast-induced nephropathy as the primary outcome.

34

Rheumatology

A Randomized, Controlled Trial of Total Knee Replacement (TKR)

Dr. Arjun Gupta reviewing Skou, et al. N Engl J Med. 2015 Oct 22;373(17):1597-606.

SUMMARY

This RCT from Denmark compared TKR to non-surgical treatment for the management of

moderate to severe knee unilateral OA. They randomized 100 eligible patients— 50 to non-

surgical treatment (12 weeks of individualized exercise, education, dietary advice, insoles and

pain medication) and 50 to TKR followed by non-surgical treatment. The primary outcome was

the between-group difference in change from baseline to 12 month Knee Injury and Osteoarthritis

Outcome Score (KOOS4 score) — a mean of scores for pain, symptoms, ADL and QOL, scored from

0 (worst)to 100 (best). A battery of secondary outcomes that measured additional aspects of knee

function were also recorded.

Baseline characteristics were similar between the two groups. On intention to treat analysis,

KOOS4 scores improved by 32 units as compared to 16 in the non-surgical group, a statistically

significant adjusted mean difference of 15.8. The TKR group also had greater improvements in

their scores in the 4 subscales of the KOOS score and the Timed Get Up and Go Test. The

percentage of patients who had an improvement of at least 15% (a clinically important difference)

in the score for pain after 1 year was 85% in the total-knee-replacement group and 68% in the

nonsurgical-treatment group. 26% patients in the non-surgical group eventually ended up

undergoing TKR. However, serious adverse events were more common for the TKR group (8 vs 1)

including 3 DVTs, 1 deep infection, 1 knee manipulation requirement and 1 supracondylar femur

fracture in the TKR group.

COMMENTARY

Both TKR and a structured non-surgical program resulted in clinically relevant improvements in

pain and function. Whether community based patients in a non-study based environment will be

able to receive and comply with the multimodality non-surgical therapy remains a question.

Further, prior studies have not evaluated longer term outcomes (>1 year). TKR resulted in

significantly greater improvements (especially pain) in outcomes compared to non-surgical

therapy. However the TKR group experienced higher rates of serious adverse events as compared

to the nonsurgical group. The decision for TKR needs to be carefully individualized in each patient.

Shared decision making and balancing of the surgical/peri-operative risks vs potential

advantageous outcomes for each patient is essential.

UTSW Link

35

When Patients Write the Guidelines: Patient Panel Recommendations for the Treatment of Rheumatoid Arthritis (RA)

Dr. Arjun Gupta reviewing Fraenkel, et al. Arthritis Care Res (Hoboken). 2016 Jan;68(1):26-35.

SUMMARY

The purpose of this study was to determine the feasibility and value of developing guideline

recommendations by a patient panel, and comparing the patients' recommendations to ones

developed by a physician- panel. 10 patients with RA completed 8 hours of training on evidence-

based medicine and guideline development. They constituted a voting panel and, with 2 American

College of Rheumatology staff with expertise in guideline development and a physician facilitator,

subsequently met at a face-to-face meeting to develop recommendations. They applied the GRADE

methodology to formulate recommendations on 18 questions that were rated to have moderate to

high evidence. The patient panel developed recommendations for 16 of the 18 questions; for the

other 2, the panel thought there were insufficient data to support a recommendation. For 13 of the

16 questions, the patient panel recommended the same course of action as did the physician-

panel. Differences were due to how the 2 panels valued the balance between benefits and harms.

Sample: In DMARD (disease modifying anti-rheumatic drugs)-naïve patients with early

moderate/high disease activity RA, patients unanimously voted whereas physicians strongly

voted for initiating 1 DMARD vs 2 DMARDs. Both panels recognized that burden of taking 2 drugs

was more than 1 drug. Patient panel interpreted data as no difference in safety/ efficacy, while

physician panel noted a little difference.

COMMENTARY

There is widespread agreement that patients should be involved in the development of practice

guidelines. Standard guidelines weigh in evidence and trade off risk, benefit and harm. Diseases

such as RA affect QOL, and require individualized care by patients and their families- they often

recognize what is best for them and value harm and benefit differently than providers. The results

of this study could herald a shift where panel composition for guideline recommendations

includes both physicians and patients. The value of this novel pilot study is that 1) patients and

physician-dominated panels developed same/similar recommendations for most questions, and 2)

we can learn more about patient preferences when opinions differed. Patient preferences, when

incorporated into guidelines, may help improve adherence to recommendations, although this has

yet to be formally tested.

UTSW Link

36

Faculty and Fellow Mentors

We would like to acknowledge and thank the faculty and fellow mentors for this edition of IM

Journal Watch:

Section Mentor

Dermatology Image Challenge Dr. Mauskar

EKG Challenge Dr. Bhatt (fellow) Cardiology Dr. Rohatgi

Endocrinology Dr. Gruntmanis Gastroenterology Dr. Petrasek (fellow)

General Internal Medicine Dr. Cutrell Hematology / Oncology Dr. Shen

Hepatology Dr. Petrasek (fellow)

Infectious Diseases Dr. Cutrell

Nephrology Dr. Sambandam

Rheumatology Dr. Makris