Mayo Clinic Internal Medicine Review 2006-2007 SEVENTH EDITION pot

Consultant, Division of Cardiovascular Diseases, Mayo Clinic;Associate Professor of Medicine, Mayo Clinic College ofMedicine; Rochester, Minnesota Eduardo E.. Brady, MD Consultant, Divis

Mayo Clinic Internal Medicine Review

2006-2007 SEVENTH EDITION

Editor-in-Chief Thomas M Habermann, MD

Mayo Clinic Internal Medicine Review

2006-2007 SEVENTH EDITION

MAYO CLINIC SCIENTIFIC PRESS TAYLOR & FRANCIS GROUP

ISBN 0849390591

The triple-shield Mayo logo and the words MAYO, MAYO CLINIC, and MAYO CLINIC SCIENTIFIC PRESS are marks of Mayo Foundation for Medical Education and Research.

©2006 Mayo Foundation for Medical Education and Research.

Printed in Canada.

All rights reserved This book is protected by copyright No part of it may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means—electronic, mechanical, photocopying, recording, or otherwise— without the prior written consent of the copyright holder, except for brief quo- tations embodied in critical articles and reviews Inquiries should be addressed

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For order inquiries, contact Taylor & Francis Group, 6000 Broken Sound Parkway NW, Suite #300, Boca Raton, FL 33487.

www.taylorandfrancis.com

Catalog record is available from the Library of Congress

Care has been taken to confirm the accuracy of the information presented and

to describe generally accepted practices However, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, express or implied, with respect to the contents of the publication This book should not

be relied on apart from the advice of a qualified health care provider The authors, editors, and publisher have exerted efforts to ensure that drug selection and dosage set forth in this text are in accordance with current recommendations and practice at the time of publication However, in view

of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions This is particularly impor- tant when the recommended agent is a new or infrequently employed drug Some drugs and medical devices presented in this publication have Food and Drug Administration (FDA) clearance for limited use in restricted research settings It is the responsibility of the health care providers to ascertain the FDA status of each drug or device planned for use in their clinical practice.

DEDICATED TO

All students of medicine, whatever their level of experience

and whatever their needs

v

he seventh edition of Mayo Clinic Internal Medicine Review 2006-2007 reflects the continued

commitment by the faculty of the Department of Internal Medicine to its mission of scholarship.One of the key traditions in medicine is the passing of knowledge from physician to physician

In 1928, William J Mayo, MD, wrote, “The glory of medicine is that it is constantly movingforward, that there is always more to learn The ills of today do not cloud the horizon of tomorrow,but act as a spur to greater effort.”*This edition is a response to these themes My hope is that thisbook will aid in the study of medicine and in the care of patients

Nicholas F LaRusso, MD

Chair, Department of Internal Medicine Mayo Clinic, Rochester, Minnesota

*Mayo WJ The aims and ideals of the American Medical Association Proceedings of the 66th Annual Meeting

of the National Education Association of the United States, 1928 p 158-63.

vii

T

cientific observations and clinical advances are moving at a remarkable pace These changes require physicians to remain abreast

of the latest developments not only in their areas of expertise but also in areas beyond their sphere of expertise To assist physicians

in this endeavor, the Department of Internal Medicine at Mayo Clinic remains committed to providing continuing medical

education to physicians in a timely manner Mayo Clinic Internal Medicine Review 2006-2007 is designed to meet the needs of

physicians-in-training and practicing clinicians by updating their knowledge of internal medicine, providing a concise review,and also helping them prepare for the certifying and recertifying examinations in internal medicine

The success of the earlier editions of this textbook is exemplified by the number of books published The positive reaction

to and the success enjoyed by the earlier editions prompted the Department of Internal Medicine to proceed with the publication

of this, the seventh, edition

The overall approach to learning medicine can be summed up in two questions What is it? What do you do for it? Ongoingefforts have been made to improve the book and its answers to these questions Each chapter is updated for each edition Overtime, algorithms and diagrams have been added and changed The goal is to have an update that is readable and easy to study.The book is divided into subspecialty topics, each chapter written by an author(s) with clinical expertise in the designatedtopic Images and tables have been enhanced Each chapter has bulleted items that highlight key points These may be summarypoints from previous paragraphs or new points Bulleted items also address typical clinical scenarios These scenarios emphasizeclassic clinical presentations Pharmacy tables are included with many of the chapters The scenarios and pharmacy tables highlighttwo key issues First, the general internist and the subspecialist diagnose diseases in internal medicine Second, the predominanttype of patient management is pharmacologic Knowledge of the indications, toxic effects, and drug interactions is of paramountimportance Multiple-choice questions with a single answer follow each chapter As many clinical cases as possible are included

in the questions This edition has 360 multiple-choice questions The answers with explanatory notes follow the questions.Material in the questions and answers is not included in the index

I thank everyone who offered important ideas for improvement during the development of this book I am grateful to theauthors of the previous editions for providing input into this edition and for permitting the use of some of their materials I amindebted to all authors for their contributions I thank the staffs of the Section of Scientific Publications, Department of Medicine,and Division of Media Support Services at Mayo Clinic for their contributions to this edition The support and cooperation ofthe publisher, Taylor & Francis Group, are gratefully acknowledged

I trust that the seventh edition of Mayo Clinic Internal Medicine Review will serve to update and advance the reader’s knowledge

of internal medicine, as previous editions have done

I hope that you enjoy this review as much as I have

Thomas M Habermann, MD

Editor-in-Chief

ix

S

Consultant, Division of Cardiovascular Diseases, Mayo Clinic;

Associate Professor of Medicine, Mayo Clinic College ofMedicine; Rochester, Minnesota

Eduardo E Benarroch, MD

Consultant, Department of Neurology, Mayo Clinic; Professor

of Neurology, Mayo Clinic College of Medicine; Rochester,Minnesota

Peter A Brady, MD

Consultant, Division of Cardiovascular Diseases, Mayo Clinic;

Assistant Professor of Medicine, Mayo Clinic College ofMedicine; Rochester, Minnesota

Robert D Brown, Jr., MD

Chair, Department of Neurology, Mayo Clinic; Professor ofNeurology, Mayo Clinic College of Medicine; Rochester,Minnesota

Darryl S Chutka, MD

Consultant, Division of Preventive and Occupational Medicine,Mayo Clinic; Associate Professor of Medicine, Mayo ClinicCollege of Medicine; Rochester, Minnesota

Brian A Crum, MD

Consultant, Department of Neurology, Mayo Clinic; AssistantProfessor of Neurology, Mayo Clinic College of Medicine;Rochester, Minnesota

Lisa A Drage, MD

Consultant, Department of Dermatology, Mayo Clinic;Assistant Professor of Dermatology, Mayo Clinic College ofMedicine; Rochester, Minnesota

Stephen B Erickson, MD

Consultant, Division of Nephrology and Hypertension, MayoClinic; Assistant Professor of Medicine, Mayo Clinic College

of Medicine; Rochester, Minnesota

Lynn L Estes, PharmD

Infectious Disease Pharmacist Specialist, Mayo Clinic; AssistantProfessor of Pharmacy, Mayo Clinic College of Medicine;Rochester, Minnesota

Thomas M Habermann, MD

Consultant, Division of Hematology, Mayo Clinic; Professor

of Medicine, Mayo Clinic College of Medicine; Rochester,Minnesota

C Christopher Hook, MD

Consultant, Division of Hematology, Mayo Clinic; AssistantProfessor of Medicine, Mayo Clinic College of Medicine;Rochester, Minnesota

CONTRIBUTORS

xi

Sheila G Jowsey, MD

Consultant, Division of Tertiary Psychiatry and Psychology,

Mayo Clinic; Assistant Professor of Psychiatry, Mayo Clinic

College of Medicine; Rochester, Minnesota

Barry L Karon, MD

Consultant, Division of Cardiovascular Diseases, Mayo Clinic;

Assistant Professor of Medicine, Mayo Clinic College of

Medicine; Rochester, Minnesota

Kyle W Klarich, MD

Consultant, Division of Cardiovascular Diseases, Mayo Clinic;

Assistant Professor of Medicine, Mayo Clinic College of

Medicine; Rochester, Minnesota

Lois E Krahn, MD

Chair, Department of Psychiatry and Psychology, Mayo Clinic,

Scottsdale, Arizona; Professor of Psychiatry, Mayo Clinic College

of Medicine; Rochester, Minnesota

Scott C Litin, MD

Consultant, Division of General Internal Medicine, Mayo

Clinic; Professor of Medicine, Mayo Clinic College of Medicine;

Rochester, Minnesota

William F Marshall, MD

Consultant, Division of Infectious Diseases, Mayo Clinic;

Assistant Professor of Medicine, Mayo Clinic College of

Medicine; Rochester, Minnesota

Marian T McEvoy, MD

Consultant, Department of Dermatology, Mayo Clinic;

Associate Professor of Dermatology, Mayo Clinic College of

Medicine; Rochester, Minnesota

Bryan McIver, MBChB

Consultant, Division of Endocrinology, Diabetes, Metabolism,

and Nutrition, Mayo Clinic, Rochester, Minnesota

Virginia V Michels, MD

Consultant, Department of Medical Genetics, Mayo Clinic;

Professor of Medical Genetics, Mayo Clinic College of Medicine;

Rochester, Minnesota

Clement J Michet, Jr., MD

Consultant, Division of Rheumatology, Mayo Clinic; Associate

Professor of Medicine, Mayo Clinic College of Medicine;

Rochester, Minnesota

Kevin G Moder, MD

Consultant, Division of Rheumatology, Mayo Clinic; AssociateProfessor of Medicine, Mayo Clinic College of Medicine;Rochester, Minnesota

Timothy J Moynihan, MD

Consultant, Division of Medical Oncology, Mayo Clinic;Assistant Professor of Oncology, Mayo Clinic College ofMedicine; Rochester, Minnesota

Paul S Mueller, MD

Consultant, Division of General Internal Medicine, MayoClinic; Assistant Professor of Medicine, Mayo Clinic College ofMedicine; Rochester, Minnesota

Steve R Ommen, MD

Consultant, Division of Cardiovascular Diseases, Mayo Clinic;Associate Professor of Medicine, Mayo Clinic College ofMedicine; Rochester, Minnesota

Robert Orenstein, DO

Consultant, Division of Infectious Diseases, Mayo Clinic;Assistant Professor of Medicine, Mayo Clinic College ofMedicine; Rochester, Minnesota

John G Park, MD

Consultant, Division of Pulmonary and Critical Care Medicine,Mayo Clinic; Instructor in Medicine, Mayo Clinic College ofMedicine; Rochester, Minnesota

Steve G Peters, MD

Consultant, Division of Pulmonary and Critical Care Medicine,Mayo Clinic; Professor of Medicine, Mayo Clinic College ofMedicine; Rochester, Minnesota

John J Poterucha, MD

Consultant, Division of Gastroenterology and Hepatology,Mayo Clinic; Associate Professor of Medicine, Mayo ClinicCollege of Medicine; Rochester, Minnesota

Abhiram Prasad, MD

Senior Associate Consultant, Division of Cardiovascular Diseases,Mayo Clinic; Assistant Professor of Medicine, Mayo ClinicCollege of Medicine; Rochester, Minnesota

Deborah J Rhodes, MD

Consultant, Division of Preventive and Occupational Medicine,Director, Women’s Health Fellowship, and Director, Women’sExecutive Health Program, Mayo Clinic; Assistant Professor

of Medicine, Mayo Clinic College of Medicine; Rochester,Minnesota

xii

Frank A Rubino, MD

Emeritus Member (deceased), Department of Neurology, MayoClinic, Jacksonville, Florida; Emeritus Professor of Neurology,Mayo Clinic College of Medicine; Rochester, Minnesota

Lynne T Shuster, MD

Consultant, Division of General Internal Medicine and Director,Women’s Health Clinic, Mayo Clinic; Assistant Professor ofMedicine, Mayo Clinic College of Medicine; Rochester,Minnesota

Peter C Spittell, MD

Consultant, Division of Cardiovascular Diseases, Mayo Clinic;

Assistant Professor of Medicine, Mayo Clinic College ofMedicine; Rochester, Minnesota

Karen L Swanson, DO

Consultant, Division of Pulmonary and Critical Care Medicine,Mayo Clinic; Assistant Professor of Medicine, Mayo ClinicCollege of Medicine; Rochester, Minnesota

Zelalem Temesgen, MD

Consultant, Division of Infectious Diseases, Mayo Clinic;

Assistant Professor of Medicine, Mayo Clinic College ofMedicine; Rochester, Minnesota

Charles F Thomas, Jr., MD

Consultant, Division of Pulmonary and Critical Care Medicine,Mayo Clinic; Associate Professor of Medicine, Mayo ClinicCollege of Medicine; Rochester, Minnesota

Sally J Trippel, MD, MPH

Consultant, Division of Preventive and Occupational Medicine,Mayo Clinic; Instructor in Preventive Medicine, Mayo ClinicCollege of Medicine; Rochester, Minnesota

Thomas R Viggiano, MD

Consultant, Division of Gastroenterology and Hepatology,Mayo Clinic; Professor of Medicine, Mayo Clinic College ofMedicine; Rochester, Minnesota

Abinash Virk, MD

Consultant, Division of Infectious Diseases, Mayo Clinic;Assistant Professor of Medicine, Mayo Clinic College ofMedicine; Rochester, Minnesota

Gerald W Volcheck, MD

Consultant, Division of Allergic Diseases, Mayo Clinic; AssistantProfessor of Medicine, Mayo Clinic College of Medicine;Rochester, Minnesota

xiii

CONTRIBUTORS FOR PHARMACY REVIEW

Alma N Adrover, PharmD, MSJeffrey J Armon, PharmDSansana D Bontaveekul, PharmDLisa K Buss, PharmDJulie L Cunningham, PharmD, BCPPLynn L Estes, PharmDJamie M Gardner, PharmDDarryl C Grendahl, RPhAnna C Gunderson, PharmDHeidi D Gunderson, PharmDThomas M Habermann, MDRobert W Hoel, RPh, PharmDTodd M Johnson, PharmDPhilip J Kuper, PharmDJennifer D Lynch, PharmDEric T Matey, PharmDKari L B Matzek, PharmDSusan V McCluskey, RPhKevin W Odell, PharmDJohn G O’Meara, PharmDNarith N Ou, PharmDLance J Oyen, PharmDMichael A Schwarz, PharmDVirginia H Thompson, RPhChristopher M Wittich, PharmD, MDKelly K Wix, PharmDRobert C Wolf, PharmD

1 The Board Examination 1Amit K Ghosh, MD

2 Allergy 9Gerald W Volcheck, MD

3 Cardiology 35Kyle W Klarich, MD, Thomas Behrenbeck, MD, Peter A Brady, MD, Abhiram Prasad, MD, Steve R Ommen, MD,Barry L Karon, MD

4 Critical Care Medicine .147Steve G Peters, MD

5 Dermatology 167Lisa A Drage, MD, Marian T McEvoy, MD

6 Endocrinology 195Bryan McIver, MBChB

7 Gastroenterology and Hepatology 251Robert E Sedlack, MD, Thomas R Viggiano, MD, John J Poterucha, MD

8 General Internal Medicine 323Scott C Litin, MD

9 Genetics 353Virginia V Michels, MD

10 Geriatrics .373Darryl S Chutka, MD

11 Hematology 401Thomas M Habermann, MD

12 HIV Infection .465Zelalem Temesgen, MD

13 Hypertension 493Gary L Schwartz, MD

xv

TABLE OF CONTENTS

14 Infectious Diseases 531William F Marshall, MD, Abinash Virk, MD, Robert Orenstein, DO, John W Wilson, MD, Lynn L Estes, PharmD

15 Medical Ethics 621

C Christopher Hook, MD, Paul S Mueller, MD

16 Men’s Health 635Thomas J Beckman, MD, Haitham S Abu-Lebdeh, MD

17 Nephrology .647Fernando C Fervenza, MD, PhD, Thomas R Schwab, MD, Amy W Williams, MD, Robert C Albright, Jr., DO,Stephen B Erickson, MD

18 Neurology .699Brian A Crum, MD, Eduardo E Benarroch, MD, Robert D Brown, Jr., MD; Frank A Rubino, MD

19 Oncology 751Timothy J Moynihan, MD

20 Preventive Medicine .787Sally J Trippel, MD, MPH

21 Psychiatry 805Lois E Krahn, MD, Sheila G Jowsey, MD

22 Pulmonary Diseases .825John G Park, MD, Timothy R Aksamit, MD, Karen L Swanson, DO, Charles F Thomas, Jr., MD

23 Rheumatology 913Clement J Michet, Jr., MD, Kevin G Moder, MD, William W Ginsburg, MD

24 Vascular Diseases 977Peter C Spittell, MD

25 Women’s Health .999Lynne T Shuster, MD, Deborah J Rhodes, MD

xvi

Many physicians take the American Board of Internal Medicine

(ABIM) certifying examination in internal medicine (IM) annually

The total number of candidates who took the ABIM certifying

examination for the first time in 2004 was 7,056 Of these, 92%

passed the examination Currently, greater importance is being placed

on achieving board certification Many managed-care organizations

now require board certification before employment This chapter is

aimed primarily at candidates preparing for the ABIM’s certifying

or maintenance of certification examination in IM However,

can-didates preparing for non-ABIM examinations also may benefit from

the information, which covers various aspects of preparation for an

examination, strategies to answer the questions effectively, and

avoidance of pitfalls

Aim of the Examination

The ABIM has stated that the certifying examination tests the breadth

and depth of a candidate’s knowledge in IM to ensure that the

candidate has attained the necessary proficiency required for the

practice of IM According to the ABIM, the examination has two

goals: the first is to ensure competence in the diagnosis and treatment

of common disorders that have important consequences for patients,

and the second is to ensure excellence in the broad domain of IM

Examination Format

The examination for ABIM certification in IM requires 2 days to

complete and is divided into four sections of 3 hours each Details

regarding the examination, training requirements, eligibility

require-ments, application forms, and other related information can be

obtained from the ABIM, 510 Walnut Street, Suite 1700,

Philadelphia, PA 19106-3699; telephone numbers: 215-446-3500

or 800-441-2246; fax number: 215-446-3633; e-mail address:

request@abim.org; Internet address: http://www.abim.org

Almost all of the questions are clinical and based on a correctdiagnosis and management Because there is no penalty for guessing

the answers, candidates should answer every question Marking

multiple answers for a single question is not allowed and will cause

the question to be scored as incorrect Most questions are based onthe presentations of patients Among these, 75% are in the setting

of outpatient or emergency room situations, and the remaining 25%are in the inpatient setting, including the critical care unit and nursinghome The ability to answer these questions requires integration ofinformation provided from several sources (such as history, physicalexamination, laboratory test results, and consultations), prioritization

of alternatives, or use of clinical judgment Candidates should knowthat a portion of questions are known as field questions, or pretestquestions, and are included for experimental purposes only and totest the question quality Although field questions are not scored,they cannot be identified during the examination The overall ability

to manage a patient in a cost-effective, evidence-based fashion isstressed Questions that require simple recall of medical facts haveessentially been eliminated The examination is reviewed by practicinginternists to ensure the questions are relevant to a general internalmedicine practice

• Candidates should answer every question; there is no penalty forguessing

• Most questions are based on presentations of patients

• Questions that require simple recall of medical facts are in theminority

A list of normal laboratory values and illustrative materials cardiograms, blood smears, Gram stains, urine sediments, chestradiographs, and photomicrographs) necessary to answer questionsare provided Candidates should interpret the abnormal values onthe basis of the normal values provided and not on the basis of thenormal values to which they are accustomed in their practice or train-ing Candidates for the certifying examination receive an informa-tion booklet several weeks before the examination The bookletprovides a detailed description of the examination, including thetypes of questions used Although much of the information con-tained in this chapter is borrowed from the previous informationbooklets, candidates for ABIM examinations should read the book-let that is sent to them because the ABIM may change various com-ponents of the format of the examination

(electro-1

1 The Board Examination

Amit K Ghosh, MD

• A list of normal laboratory values and illustrative materials

nec-essary to answer questions are provided

• The information booklet is sent several weeks before the

exami-nation by the ABIM and should be read by candidates

Scoring

The passing scores reflect predetermined standards set by the ABIM

Passing scores are determined before the examination and therefore

are not dependent on the performance of any group of candidates

taking the examination

• Passing scores are set before the examination

The Content

The questions in the examination cover a broad area of IM They are

divided into primary and cross-content groups The subspecialties in

the primary content areas have included cardiovascular diseases,

gastroenterology, pulmonary diseases, infectious diseases,

rheuma-tology/orthopedics, endocrinology/metabolism, oncology,

hema-tology, nephrology/urology, neurology, psychiatry, allergy/immunology,

dermatology, obstetrics/gynecology, ophthalmology, otolaryngology,

and miscellaneous The specialties in the cross-content group have

included adolescent medicine, critical care medicine, clinical

epi-demiology, ethics, geriatrics, nutrition, palliative/end-of-life care,

occu-pational/environmental medicine, preventive medicine, women’s

health, and substance abuse Approximately 75% of the questions

test knowledge in the following major specialties in IM: cardiology,

endocrinology, gastroenterology, hematology, infectious diseases,

nephrology, oncology, pulmonary diseases, and rheumatology The

remaining 25% of questions cover allergy/immunology, dermatology,

gynecology, neurology, urology, ophthalmology, and psychiatry

Independent of primary content, about 50% of the questions

encom-pass the cross-content topics Table 1-1 shows the distribution of the

contents for a recent ABIM certifying examination in IM

• About 75% of the questions test knowledge in the major specialties

• About 25% of the questions cover allergy/immunology,

derma-tology, gynecology, neurology, urology, ophthalmology, and

psychiatry

• About 50% of all questions encompass the cross-content topics:

geriatrics, critical care medicine, adolescent medicine, clinical

epidemiology, medical ethics, nutrition, occupational medicine,

preventive medicine, substance abuse, and women’s health

Question Format

Each session contains 90 multiple-choice, single-best–answer questions

The question may include a case history, a brief statement, a

radio-graph, a radio-graph, or a picture (such as a blood smear or Gram stain)

Each question has five possible answers, and the candidates should

identify the single-best answer More than one answer may appear

correct or partially correct for a question Also, the traditionally correct

answer may not be listed as an option In that situation, the one

answer that is better than the others should be selected As notedabove, most questions are based on interactions with patients Somequestions are progressive; that is, more than one question is based

on information about the same patient The examples in thischapter, the questions at the end of each chapter in this book, andthe examples included in the ABIM’s information booklet shouldhelp candidates become familiar with the question format.Furthermore, the national in-training examination taken by mostsecond-year residents in IM provides ample opportunity to becomefamiliar with the question format

• All questions are of the single-best–answer type

• Various study guides should be used to become familiar with thequestion format

2 Mayo Clinic Internal Medicine Review

Table 1-1 Contents of the Certification Examination of the

American Board of Internal Medicine

Select the one best answer for each of the following questions.

1 A 56-year-old woman is referred to you for an evaluation of

dyspnea and chest pain of 6 weeks in duration The chest pain

is nonpleuritic, nonexertional, and located along the lower rightlateral chest cage She has no fever, cough, or chills During thepast few weeks, she has been experiencing constant low backpain The patient underwent right mastectomy 4 years agobecause of carcinoma of the breast with metastatic involvement

of the right axillary lymph nodes She received radiotherapyfollowed by chemotherapy for 24 months Examination nowshows diminished breath sounds in the right lower lung field

Results of the remainder of the examination are unremarkable

A chest radiograph suggests a moderate right pleural effusion

Which one of the following is most likely to be helpful inconfirming the suspected diagnosis?

a Bone scan with technetium Tc99m diphosphonate

b Bone marrow aspirate and biopsy

c Scalene fat pad biopsy

d Thoracentesis

e Mammography

2 A 20-year-old male military recruit returns home from several

weeks of summer training in boot camp He comes to youroffice the following day with a 12-day history of fever (38°C),coryza, pharyngitis, and cough Physical examination discloses

a bullous lesion over the right tympanic membrane and tered crackles in both lung fields Blood cell count shows mildthrombocytopenia A chest radiograph shows patchy alveolar-interstitial infiltrates in both lungs Which one of the following

scat-is the best treatment for thscat-is patient?

3 A 49-year-old male executive comes to your office with a

6-month history of cough, shortness of breath, and chest tightnesssoon after substantial exertion He notices these symptoms soonafter he finishes a game of racquetball He is a nonsmoker andhas no risk factors for coronary artery disease Results of physicalexamination in your office are normal His weight is normalfor his height The chest radiograph is normal A treadmill test forischemic heart disease is negative Which one of the followingdiagnostic tests is indicated?

a Computed tomography of the chest

b Arterial blood gas studies at rest and after exercise

c Spirometry before and after exercise

d Ventilation-perfusion lung scanning

e Cardiopulmonary exercise testing

4 A 43-year-old asymptomatic man has chronic hepatitis C.Therapy for 12 months with a combination of interferon andribavirin failed to clear the virus Laboratory results are notablefor an alanine aminotransferase value of 65 U/L and normalvalues for bilirubin, albumin, and prothrombin time A liverbiopsy shows a mild lymphocytic portal infiltrate but no fibrosis.Which one of the following statements about this patient is true?

a He should be given lamivudine

b He should have screening for hepatocellular carcinoma andundergo ultrasonography and α-fetoprotein testing every 6months

c He should have endoscopy to look for esophageal varices

d He should be referred for liver transplantation

e He should receive the hepatitis A and B vaccines if he is notalready immune

5 A 45-year-old man comes to your clinic for evaluation of new-onsethypertension Blood pressures obtained elsewhere were 146 to160/84 to 100 mm Hg, and heart rates ranged from 82 to 96beats per minute He does not smoke or drink alcohol He has nohistory of diabetes mellitus His family history is positive forhypertension in his father On physical examination, his bloodpressure is 144/86 mm Hg and body mass index 32 kg/m2.Results of the remainder of the examination are unremarkable.Laboratory test values are as follows: serum sodium 142 mEq/L,serum potassium 4.2 mEq/L, serum chloride 104 mEq/ L, serumbicarbonate 24 mEq/L, glucose 116 mg/dL, blood urea nitrogen

14 mg/dL, serum creatinine 1.0 mg/dL Which one of thefollowing is the best initial test in the evaluation of this patient?

a Renal duplex artery ultrasonography

b Plasma renin/aldosterone ratio

c Measurement of plasma metanephrine

d Overnight oximetry

e Serum cortisol level

6 A 65-year-old man is referred to your practice for a 4-monthhistory of swallowing difficulties His wife reports that the patientstarts coughing and choking immediately after he drinks anyfluid and that he has lost 5 lb He denies any hematemesis ormelena He denies any history of food “sticking” in the supraster-nal region His past medical history includes a cerebrovascularaccident with a right-sided hemiplegia 8 months ago, diabetesmellitus, gastroesophageal reflux, and hypertension On phys-ical examination, the patient is alert and cooperative and hasright-sided hemiparesis His hematocrit value is 42% and bloodglucose 122 mg/dL What is the next best step in the evaluation

of his symptoms?

a Upper endoscopy

b Upper gastrointestinal barium study

c Esophageal manometry

d Magnetic resonance imaging of head

e Computed tomography of neck

Chapter 1 The Board Examination 3

7 A 68-year-old woman was recently admitted to another hospital

with severe back pain At that time, magnetic resonance imaging

of the spine showed moderate bulging disks at L3-4 and L4-5

causing moderate compression of the L4 nerve root Her other

medical problems included hypertension and diet-controlled

diabetes mellitus Medications included hydrochloroiazide 25

mg once a day On physical examination, the blood pressure was

148/96 mm Hg, and the pulse rate was 78 beats per minute

On neurologic examination, there was an antalgic gait and the

straight leg raising test was negative Results of the remainder of

the examination were normal Laboratory values were

hemato-crit 30%, platelet count 110 × 109/L, blood urea nitrogen 60

mg/dL, creatinine 4.0 mg/dL, serum sodium 132 mEq/L, serum

chloride 112 mEq/L, serum bicarbonate 15 mEq/L, serum

calcium 12.5 mg/dL, serum glucose 120 mg/dL On urinalysis,

there was trace proteinuria, no ketonuria or glucosuria, and

no casts Arterial pH was 7.32, and PCO 2was 30 mm Hg What

is the most likely diagnosis?

8 A patient who is positive for human immunodeficiency virus and

has low CD4 counts is receiving multidrug treatment He

com-plains of colicky flank pain, and many crystals are subsequently

noted on urinalysis Which one of the following drugs is most

9 A 34-year-old woman comes to your office with a 4-week history

of hemoptysis, intermittent wheeze, and generalized weakness

On examination, her blood pressure is 186/112 mm Hg She

appears cushingoid and has noted these changes taking place

during the past 12 weeks Auscultation discloses localized

wheez-ing in the left mid lung area The chest radiograph indicates

par-tial atelectasis of the left upper lobe The patient is referred to

you for further evaluations Which one of the following is least

likely to provide useful information for diagnosis and treatment?

a Serum adrenocorticotropic hormone level

b 24-Hour urine test for 5-hydroxyindoleacetic acid level

c Bronchoscopy

d Computed tomography of the chest

e Serum potassium level

10 A 62-year-old woman presents with the onset of eye discomfort

and diplopia She has not noted any other new neurologic

symptoms Neurologic examination shows a normal mentalstatus and neurovascular findings Reflexes are slightly decreased

in the lower extremities Gait and coordination are normal.Cranial nerves show an inability to adduct, elevate, and depressthe eye Pupillary reaction is normal Motor strength testing isnegative Sensation is normal, except there is decreased vibratoryand joint position sensation in the feet What abnormality would

be expected?

a Saccular aneurysm of the cavernous sinus on computedtomography

b Brain stem neoplasm on magnetic resonance imaging

c Left temporal sharp waves on electroencephalography

d Increased fasting blood glucose level

e Increased erythrocyte sedimentation rate

11 A 42-year-old man who is an office worker presents to theemergency department with acute dyspnea He has smoked 11/2 packs per day for 25 years and had been relatively asymp-tomatic except for a smoker’s cough and mild dyspnea onexertion Physical examination findings are not remarkableexcept for slightly diminished intensity of breath sounds overthe right lung and some prolonged expiratory slowing, consistentwith obstructive lung disease The chest radiograph showsextensive infiltrates in the upper two-thirds of the lung fields.Which one of the following conditions is most likely responsiblefor this patient’s symptoms?

a Pulmonary alveolar proteinosis

b Silicosis

c Pulmonary eosinophilic granuloma (histiocytosis X)

d Idiopathic pulmonary fibrosis

e Sarcoidosis

12 In a 34-year-old man with acute myelomonocytic leukemia,fever and progressive respiratory distress develop, and the chestradiograph shows diffuse alveolar infiltrates The patient com-pleted intensive chemotherapy 6 weeks earlier The total leuko-cyte count has remained less than 0.5 × 109/L for more than 3weeks He is currently (for at least 10 days) receiving acephalosporin (ceftazidime) Which one of the following is themost appropriate therapy for this patient?

pleural effusion); 2, a (Mycoplasma infection); 3, c (exercise-induced

asthma); 4, e; 5, d (obstructive sleep apnea); 6, b (oropharyngealdysphagia); 7, c (multiple myeloma); 8, c; 9, b (bronchial carcinoid);

10, d; 11, c (histiocytosis X, or pulmonary eosinophilic granuloma,

4 Mayo Clinic Internal Medicine Review

with spontaneous pneumothorax); 12, d (disseminated aspergillosis

in a leukopenic patient)

Questions 1 through 3 are examples of questions that are aimed

at evaluating knowledge and judgment about problems that are

frequent in clinical practice and for which physician intervention

makes a considerable difference These questions judge the

candi-date’s minimal level of clinical competence These questions include

descriptions of typical clinical features of metastatic breast carcinoma,

Mycoplasma pneumonia, and exercise-induced asthma, respectively.

Therefore, the decision making is relatively easy and straightforward

Questions 4 through 12 are more difficult to answer because they

are structured to reflect excellence in clinical competence rather than

just minimal competence In other words, they require more

exten-sive knowledge (i.e., knowledge beyond that required for minimal

competence) in IM and its subspecialties Although most of the

questions on the examination are based on encounters with patients,

some require recall of well-known medical facts

Preparation for the Test

Training during medical school forms the foundation on which

advanced clinical knowledge is accumulated during residency training

However, the serious preparation for the examination actually starts

at the beginning of the residency training in IM Most candidates

will require a minimum of 6 to 8 months of intense preparation for

the examination Cramming just before the examination is

coun-terproductive and is unlikely to be successful Some of the methods

of preparation for the board examination are described below

Additionally, each candidate may develop her or his own system

• Preparation for the ABIM examination should start at the

begin-ning of the residency traibegin-ning in IM

Each candidate should use a standard textbook of IM Any of those

available should provide good basic knowledge in all areas of IM

Ideally, the candidate should use one good textbook and not jump

from one to another, except for reading certain chapters that are

out-standing in a particular textbook The most effective way to use the

textbook is with patient-centered reading; this should occur

through-out the residency program This book and similar board review

syl-labi are excellent tools for brushing up on important board-relevant

information several weeks to months before the examination They,

however, cannot take the place of comprehensive textbooks of

inter-nal medicine This book is designed as a study guide rather than a

comprehensive textbook of medicine Therefore, it should not be

used as the sole source of medical information for the examination

• Candidates should thoroughly study a standard textbook of IM

• This book is designed as a study guide and should not be used as

the sole source of information for preparation for the examination

The Medical Knowledge Self-assessment Program (MKSAP) prepared

by the American College of Physicians is extremely valuable for

obtaining practice in answering multiple-choice questions The

questions and answers from the MKSAP are very useful to learn the

type of questions asked and the depth of knowledge expected forvarious subjects By design, the MKSAP is prepared for the continuingmedical education of practicing (presumably ABIM-certified)internists rather than for those preparing for initial certification bythe ABIM For maintenance of certification examination purposes,the MKSAP textbook is an excellent aid

Some candidates find it helpful to prepare for the examination

in study groups Formation of two to five candidates per group mits study of different textbooks and review articles in journals Thegroup should meet regularly as each candidate is assigned readingmaterials Selected review articles on common and important topics

per-in IM should be per-included per-in the study materials Indiscrimper-inatereading of articles from many journals should be avoided In anycase, most candidates who begin preparation 6 to 8 months beforethe examination will not find time for extensive study of journalmaterials The newer information in the recent (within 6-9 months

of the examination) medical journals is unlikely to be included inthe examination Notes and other materials the candidates havegathered during their residency training are also good sources ofinformation These clinical “pearls” gathered from mentors will be

of help in remembering certain important points

• Study groups may help cover large amounts of information

• Indiscriminate reading of articles from many journals should beavoided

• Information in the recent (within 6-9 months of the tion) medical journals is unlikely to be included in the examina-tion

examina-Candidates should try to remember some of the uncommon ifestations of the most common diseases (such as polycythemia incommon obstructive pulmonary disease) and common manifesta-tions of uncommon diseases (such as pneumothorax in eosinophilicgranuloma) The large majority of the questions on the examinationinvolve conditions most commonly encountered in clinical practice.Several formulas and points should be memorized (such as the aniongap equation) The clinical training obtained and the regular studyhabits formed during residency training are the most importantaspects of preparation for the examination

man-In general, the examination rarely has questions about specific drugdosages or specific chemotherapy regimens used in oncology Rather,questions are geared toward concepts regarding the treatment ofpatients Questions regarding adverse effects of medications arecommon on the examination, especially when the adverse effect occursfrequently or is potentially serious The candidate is also expected torecognize when a clinical condition is a drug-related event

• Study as much as possible about board-eligible topics

• Learn about the uncommon manifestations of common diseasesand the common manifestations of uncommon diseases

Day of the Examination

Adequate time is allowed to read and answer all the questions; fore, there is no need to rush or become anxious You should watch

there-Chapter 1 The Board Examination 5

the time to ensure that you are at least halfway through the

exami-nation when half of the time has elapsed Start by answering the first

question and continue sequentially Almost all of the questions follow

a case presentation format At times, subsequent questions will give

you information that may help you answer a previous question Do

not be alarmed by lengthy questions; look for the question’s salient

points When faced with a confusing question, do not become

distracted by that question Mark it so you can find it later, then go

to the next question and come back to the unanswered ones at the

end Extremely lengthy stem statements or case presentations are

apparently intended to test the candidate’s ability to separate the

essential from the unnecessary or unimportant information You

may want to underline important information presented in the

question in order to review this information after reading the entire

question and the answer options You are not allowed to bring a

highlighter to the examination

• Look for the salient points in each question

• If a question is confusing, mark it to find it and come back to

the unanswered questions at the end

Some candidates may fail the examination despite the possession of

an immense amount of knowledge and the clinical competence

nec-essary to pass the examination Their failure to pass the examination

may be caused by the lack of ability to understand or interpret the

questions properly The ability to understand the nuances of the

question format is sometimes referred to as “boardsmanship.”

Intelligent interpretation of the questions is very important for

candidates who are not well versed in the format of multiple-choice

questions Tips on “boardsmanship” include the following:

• All questions whose answers are known should be answered first

• Spend adequate time on questions for which you are certain of the

answers to ensure that they are answered correctly It is easy to

become overconfident with such questions and thus you may fail

to read the questions or the answer options carefully Make sure

you never make mistakes on easy questions

• Read the final sentence (that appears just before the multiple

answers) several times to understand how an answer should be

selected Recheck the question format before selecting the correct

answer Read each answer option completely Occasionally a

response may be only partially correct At times, the traditionally

correct answer is not listed In these situations, select the best

alternative listed Watch for qualifiers such as “next,” “immediately,”

or “initially.”

• Avoid answers that contain absolute or very restrictive words such

as “always,” “never,” or “must.” Answer options that contain

absolutes are likely incorrect

• Try to think of the correct answer to the question before looking

at the list of potential answers Assume you have been given all the

necessary information to answer the question If the answer you had

formulated is not among the list of answers provided, you may have

interpreted the question incorrectly When a patient’s case is

pre-sented, think of the diagnosis before looking at the list of answers

It will be reassuring to realize (particularly if your diagnosis is

supported by the answers) that you are on the “right track.”

• Abnormalities on, for example, the photographs, radiographs,and electrocardiograms will be obvious

• If you do not know the answer to a question, very often you areable to rule out one or several answer options and improve yourodds at guessing

• Occasionally you can use information presented in one question

to help you answer other difficult questions

Candidates are well advised to use the basic fund of knowledge mulated from clinical experience and reading to solve the questions.Approaching the questions as real-life encounters with patients is farbetter than trying to second-guess the examiners or trying to analyzewhether the question is tricky As indicated above, the questions arenever tricky, and there is no reason for the ABIM to trick the can-didates into choosing wrong answers

accu-It is better not to discuss the questions or answers (after theexamination) with other candidates Such discussions usually causemore consternation, although some candidates may derive a falsesense of having performed well in the examination In any case, thecandidates are bound by their oath to the ABIM not to discuss ordisseminate the questions Do not study between examinationsessions, particularly the night between the two examination days

• Approach questions as real-life encounters with a patient

• There are no trick questions

Connections

Associations, causes, complications, and other relationships between

a phenomenon or disease and clinical features are important toremember and recognize For example, Table 1-2 lists some of theconnections in infectious and occupational entities in pulmonarymedicine Each subspecialty has many similar connections, andcandidates for the ABIM and other examinations may want toprepare lists like this for different areas

Computer-based Testing

Candidates currently can take the computer-based test for the tification test examination The computer-based test provides a moreflexible, quiet, and professional environment for examination Thecomputer-based test is administered by Pearson VUE, a companywith around 200 centers in the United States

cer-Candidates are encouraged to access the online tutorial atwww.abim.org/cert/cbt.shtm This tutorial allows the candidate tobecome familiar with answering questions, changing answers, makingnotes electronically, accessing the table of normal laboratory values,and marking questions for review

Maintenance of Certification

The diplomate certificates issued to candidates who have passed theABIM examination in IM since 1990 are valid for 10 years Thetotal number of candidates who took the ABIM maintenance of

6 Mayo Clinic Internal Medicine Review

certification examination for the first time in 2004 was 2,022 Of

these, 82% passed the examination

Enhancements to Maintenance of Certification Program

In January 2006, the ABIM enhanced the maintenance of

certifi-cation program to increase flexibility, incorporate programs developed

by other organizations, and assess performance in clinical practice

The three general components (credentialing, self-evaluation, and

secure examination) were retained, and all self-evaluation modules

now have a points value

Every candidate needs to complete a total of 100 points inself-evaluation modules Unlike the previous system, renewal of morethan one certificate does not necessitate taking additional self-eval-uation modules (i.e., the same number of points, 100, satisfies therequirement to sit for these examinations) Candidates have tocomplete at least 20 points in medical knowledge and at least 20points in practice performance The remaining 60 points may beobtained from completion of modules developed by ABIM andother organizations that meet the ABIM standards (Table 1-3) Thus,one could combine an ABIM practice improvement module (40

Chapter 1 The Board Examination 7

Table 1-2 Example of Connections Between Etiologic Factors and Diseases

Progressive, massive fibrosis Silicosis, coal, hematite, kaolin, graphite, asbestosis

Metals and fumes producing asthma Baker’s asthma, meat wrapper’s asthma, printer’s asthma,

nickel, platinum, toluene diisocyanate (TDI), cigarette cutter’s asthma

Increased incidence of carcinoma Asbestos, hematite, arsenic, nickel, uranium, chromate

cancer

points) with the American College of Physicians MKSAP (3 modules,

60 points), or combination ABIM practice improvement module

(40 points) with 2 ABIM knowledge modules (40 points) and the

ABIM peer and patient feedback module (20 points) All points are

valid for 10 years

The all-inclusive fee structure started in 2006 allows unlimited

access to ABIM self-evaluation modules and one examination Thus,

continuous medical education credits can be earned without any

additional fees for 10 years

The self-evaluation modules evaluate performance in clinical

skills, preventive services, practice performance, fund of medical

knowledge, and feedback from patients and colleagues Successfully

completed self-evaluation modules are valid for 10 years Candidates

may apply to begin the maintenance of certification process any time

after initial certification The ABIM recommends that completion

of the self-evaluation modules be spread out over time It is

antici-pated that a candidate will complete one self-assessment module

every 1 to 2 years The ABIM encourages candidates to enroll within

4 years of certification in order to have adequate time to complete the

program

• Candidates who passed the ABIM certification examination in IM

in 1990 and thereafter have certificates that are valid for 10 years

• The maintenance of certification process is called continuous

professional development and consists of a three-step process

Medical Knowledge and Clinical Skills Self-evaluation

Modules

The medical knowledge module is an open-book examination

con-taining 60 single-best–answer multiple-choice questions regarding

recent clinical advances in IM This module tests the candidate’s

knowledge of IM and clinical judgment The questions are written

by board members and ABIM diplomates Candidates may choose

a module in internal medicine or a subspecialty (focused content).The module is available on paper, CD-ROM, or the Internet.Candidates must achieve a predetermined passing score to establishcredit for the module The module may be repeated as often asnecessary to achieve a passing score

The clinical skills self-evaluation module consists of an open-bookexamination containing audio and visual information pertaining tophysical examination and physical diagnosis and physician-patientcommunication skills The module contains 60 single-best–answermultiple-choice questions It is available on a CD-ROM with Webaccess Candidates must achieve a predetermined passing score toestablish credit for the module The module may be repeated as often

as necessary to achieve a passing score

Performance-based Practice Improvement Module

This module is a computer-based instrument to help candidatesassess the care they provide to patients and to help them develop aplan for improvement Areas of the practice that have potential forquality improvement are identified Completion of this moduleinvolves review of patient charts and comparing them to nationalguidelines Data are submitted electronically to the ABIM to providefeedback Candidates can implement the changes and measure theirimpact over a 2-week to 2-year period

Patient and Peer Feedback Module

Confidential and anonymous feedback regarding the candidate’sprofessionalism, physician-patient communication skills, andoverall patient care skills is obtained from colleagues and patients ofthe candidate by an automated telephone survey The candidateselects 20 colleagues and 40 patients, who are asked to complete a brief,anonymous telephone survey The candidate receives a summary ofthe survey findings

Secure Examination

A comprehensive, secure, computer-based examination is offeredtwo times yearly, currently in May and November The examinationconsists of three modules of 60 single-best–answer multiple-choicequestions Two of the three modules must be in internal medicine,and the third may be internal medicine, a medical subspecialty, or anarea of added qualifications Successful completion of the self-evaluation modules is not required before taking this examination.Questions are based on well-established information and assessclinical judgment more than pure recall of medical information.The examination contains clinically relevant questions To pass thefinal examination, the candidate must achieve a predeterminedpassing score The examination may be repeated as often as it takes

to achieve a passing score The blueprint of the number of questionsfor the maintenance of certification examination is described atwww.abim.org/moc/im.shtm

Details of the maintenance of certification program can be obtainedfrom the ABIM, 510 Walnut Street, Suite 1700, Philadelphia, PA19106-3699; telephone numbers: 800-441-ABIM, extension 3598;fax number: 215-446-3633; Internet address: http://www.abim.org

8 Mayo Clinic Internal Medicine Review

Table 1-3 Maintenance of Certification Program:

Self-evaluation Options and Point Values

Medical knowledge

Any ABIM knowledge module 20

points/module)Practice performance

Any ABIM practice improvement module 40

ABIM peer and patient feedback module 20

New practice performance module TBD

ABIM, American Board of Internal Medicine; ACP MKSAP,

American College of Physicians Medical Knowledge Self-assessment

Program; TBD, to be decided.

Allergy Testing

Standard allergy testing relies on identifying the IgE antibody specific

for the allergen in question Two classic methods of doing this are the

immediate wheal-and-flare skin test (a small amount of antigen is

introduced into the skin and evaluated at 15 minutes for the presence

of an immediate wheal-and-flare reaction) and in vitro testing

Allergy testing that does not have a clear scientific basis includescytotoxic testing, provocation-neutralization testing or treatment,

and “yeast allergy” testing

Patch Tests and Prick (Cutaneous) Tests

Many seem confused about the concept of patch testing of skin as

opposed to immediate wheal-and-flare skin testing Patch testing is

used only to investigate contact dermatitis, a type IV hypersensitivity

reaction Patch tests require about 96 hours for complete evaluation

(similar to tuberculin skin reactivity that requires 72 hours) Most

substances that cause contact dermatitis are small organic molecules

that can penetrate various barriers inherent in the skin surface The

mechanisms of hypersensitivity postulated to explain these reactions

usually involve the formation of haptens of endogenous dermal

pro-teins

Inhalant allergens, in comparison, generally are sizable intactproteins in which each molecule can be multivalent with respect to

IgE binding These molecules penetrate the skin poorly and are

seldom involved in cutaneous type IV hypersensitivity reactions

They cause respiratory symptoms and are identified by prick skin

testing

• Patch testing is used to investigate contact dermatitis

• Prick (immediate) skin testing is used to investigate respiratory

allergy to pollens and molds

Prick, scratch, and intradermal testing involve introducing allergen

to the skin layers below the external keratin layer Each of these

techniques becomes increasingly sensitive (but less specific) because

with the deeper, intradermal tests, allergen is introduced more

closely to responding cells and at higher doses Allergen skin tests

performed by the prick technique adequately identify patients who haveimportant clinical sensitivities without identifying a large number

of those who have minimal levels of IgE antibody and no clinicalsensitivity Intradermal testing is used in selected cases, includingevaluating allergy to stinging insect venoms and to penicillin Drugswith antihistamine properties, such as H1receptor antagonists, andmany anticholinergic and tricyclic antidepressant drugs can suppressimmediate allergy skin test responses The H2receptor antagonistshave a small suppressive effect Corticosteroids can suppress thedelayed-type hypersensitivity response but not the immediate response

• Intradermal skin tests are more sensitive but less specific thanprick skin tests

• Intradermal skin testing is used to investigate allergy to insectvenoms and penicillin

In Vitro Allergy Testing

In vitro allergy testing initially involves chemically coupling allergenprotein molecules to a solid-phase substance The test is then con-ducted by incubating serum (from the patient) that may containIgE antibody specific for the allergen that has been immobilized tothe membrane for a standard time The solid phase is then washedfree of nonbinding materials from the serum and incubated in asecond solution containing a reagent (e.g., radiolabeled anti-IgEantibody) The various wells are counted, and the radioactivity iscorrelated directly with the preparation of a standard curve in whichknown amounts of allergen-specific IgE antibody were incubated with

a set of standard preparations of a solid phase In vitro allergy testinguses the principles of radioimmunoassay or chromogen activation

It is important to understand that this test only identifies thepresence of allergen-specific IgE antibody in the same way that theallergen skin test does Generally, in vitro allergy testing is not assensitive as any form of skin testing and has some limitations because

of the potential for chemical modification of the allergen proteinwhile it is being coupled to the solid phase by means of covalentreaction Generally, it is more expensive than allergen skin tests and has

no advantage in routine clinical work In vitro allergy testing may

be useful clinically for patients who have been taking antihistamines

9

2 Allergy

Gerald W Volcheck, MD

and in whom no positive histamine responsiveness can be induced

in the skin or for patients who have primary cutaneous diseases that

make allergen skin testing impractical or inaccurate (e.g., severe

atopic eczema with most of the skin involved in a flare)

• Skin testing is more sensitive and less expensive than in vitro

allergy testing

Asthma

Pathology

The pathologic features of asthma have been studied chiefly in fatal

cases; some bronchoscopic data are available about mild and

moderate asthma The histologic hallmarks of asthma are listed in

Table 2-1

• The histologic hallmarks of asthma include mucous gland

hyper-trophy, mucus hypersecretion, epithelial desquamation, widening

of the basement membrane, and infiltration by eosinophils

Pathophysiology

Bronchial hyperresponsiveness is common to all forms of asthma

It is measured by assessing pulmonary function before and after

exposure to methacholine, histamine, cold air, or exercise Prolonged

aerosol corticosteroid therapy reduces bronchial hyperresponsiveness

Prolonged therapy with certain other anti-inflammatory drugs, for

example, cromolyn sodium or nedocromil, also reduces bronchial

hyperresponsiveness Note that although both cromolyn and

nedocromil were originally touted as “antiallergic” (they inhibit mast

cell activation), they affect most cells involved in inflammation; also,

the effects on these cells occur at lower doses than those that inhibit

mast cell activation

• Bronchial hyperresponsiveness generally is present in all forms of

• In the immediate-phase reaction, mast cells and basophils areimportant

In the so-called late-phase reaction to allergen exposure, the bronchidisplay histologic features of chronic inflammation and eosinophilsbecome prominent in the reaction

• In the late-phase reaction, eosinophils become prominent Patients who have chronic asthma and negative results on allergyskin tests seem to have an inflammatory infiltrate in the bronchi andhistologic findings dominated by eosinophils when asthma is active.Patients with sudden asphyxic asthma may have a neutrophilic ratherthan an eosinophilic infiltration of the airway

Various hypotheses explain the development of nonallergicasthma One proposal is that the initial inflammation represents anautoimmune reaction arising from a viral or other microbial infec-tion in the lung and, for reasons unknown, inflammation becomeschronic and characterized by a lymphocyte cytokine profile in whichinterleukin (IL)-5 is prominent The intense eosinophilic inflam-mation is thought to come from the IL-5 influence of T cells in thechronic inflammatory infiltrate Airway macrophages and plateletshave low-affinity IgE receptors on their membranes and are activated

by cross-linking of these receptors by allergen, suggesting that somephases of lung inflammation in allergy may involve the macrophage

as a primary responder cell

• IL-5 stimulates eosinophils

• Airway macrophages and platelets have low-affinity IgE receptors.The two types of helper T cells are TH1 and TH2 In general, TH1cells produce interferon-γ and IL-2, and TH2 cells produce IL-4 andIL-5 IL-4 stimulates IgE synthesis Hence, many clinical scientistsbelieve that atopic asthma is caused by a preferential activation ofTH2 lymphocytes

• IL-4 stimulates IgE synthesis

• TH2 lymphocytes produce IL-4 and IL-5

Important characteristics of cytokines are summarized in Table 2-2

10 Mayo Clinic Internal Medicine Review

Table 2-1 Histologic Hallmarks of Asthma

Mucous gland hypertrophy

Mucus hypersecretion

Alteration of tinctorial and viscoelastic properties of mucus

Widening of basement membrane zone of bronchial epithelial

membrane

Increased number of intraepithelial leukocytes and mast cells

Round cell infiltration of bronchial submucosa

Intense eosinophilic infiltration of submucosa

Widespread damage to bronchial epithelium

Large areas of complete desquamation of epithelium into

airway lumen

Mucous plugs filled with eosinophils and their products

Occupational Asthma

Every patient interviewed about a history of allergy or asthma must

be asked to provide a detailed occupational history A large fraction

of occupational asthma escapes diagnosis because physicians obtain

an inadequate occupational history An enormous range of possible

industrial circumstances may lead to exposure and resultant disease

The most widely recognized types of occupational asthma are listed

in Table 2-3

• Inquiry into a possible occupational cause of asthma is important

for all patients with asthma

As new industrial processes and products evolve, occupational

asthma may become more common An example of this is

latex-induced asthma among medical workers, associated with the

widespread use of latex gloves The incidence of occupational

asthma is estimated to be 6% to 15% of all cases of adult-onset

asthma

• Allergy to latex is an important cause of occupational asthma

Gastroesophageal Reflux and Asthma

The role of gastroesophageal reflux in asthma is not known Twomechanistic hypotheses are 1) reflex bronchospasm from acid in thedistal esophagus and 2) recurrent aspiration of gastric contents.Although a well-documented reflex in dogs links acid in the distalesophagus to vagally mediated bronchospasm, this reflex has notbeen demonstrated consistently in humans The other hypothesis

is that gastric contents reach the tracheobronchial tree by ascending

to the hypopharynx

Asthma-Provoking Drugs

It is important to recognize the potentially severe adverse response thatpatients with asthma may show to β-blocking drugs, β1and β2blockers, including β1selective β-blocking agents Patients withasthma who have glaucoma treated with ophthalmic preparations

of timolol and betaxolol (betaxolol is less likely to cause problems)may experience bronchospasm

• β-Blocking drugs, including eyedrops, can cause severe adverseresponses

Chapter 2 Allergy 11

Table 2-2 Characteristics of Cytokines

Endothelial cellsMonocytes

Macrophages

Stimulates MHC expressionInhibits TH2 activity

Macrophages

Mast cellsMacrophages

GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; TH, helper

T cell; TNF, tumor necrosis factor.

• So-called β1selective β-blocking agents such as atenolol may also

provoke asthma

Persons taking angiotensin-converting enzyme inhibitor drugs may

develop a chronic cough that can mimic asthma This cough may not

be accompanied by additional bronchospasm

• Angiotensin-converting enzyme inhibitors can cause coughing

Aspirin ingestion can cause acute, severe, and fatal asthma in a small

subset of patients with asthma The cause of the reaction is unknown

but probably involves the generation of leukotrienes Most of the

patients affected have nasal polyposis and hyperplastic pansinus

mucosal disease and are steroid-dependent for control of asthma

However, not all asthma patients with this reaction to aspirin fit the

profile Many nonsteroidal anti-inflammatory drugs can trigger the

reaction to aspirin; the likelihood of a drug causing the reactioncorrelates with its potency for inhibiting cyclooxygenase enzyme.Structural aspects of the drug seem unrelated to its tendency toprovoke the reaction Only nonacetylated salicylates such as cholinesalicylate (a weak cyclooxygenase inhibitor) seem not to provoke thereaction Leukotriene-modifying drugs may be particularly helpful

• Antihistamines are not contraindicated in asthma

Cigarette Smoking and Asthma

A combination of asthma and cigarette smoking leads to acceleratedchronic obstructive pulmonary disease Because of accelerated decline

in irreversible obstruction, all asthma patients who smoke should

be told to stop smoking

Environmental tobacco smoke is an important asthma trigger

In particular, children with asthma who are exposed to mental smoke have more respiratory infections and asthma attacks

environ-Medical History

A medical history for asthma includes careful inquiry about symptoms,provoking factors, alleviating factors, and severity Patients withmarked respiratory allergy have symptoms when exposed to aeroal-lergens and often have seasonal variation of symptoms If allergy skintest results are negative, one can be reasonably certain that the patientdoes not have allergic asthma

• In allergic asthma, symptoms are either sporadic and consistentlyrelated to exposure or are seasonal

Respiratory infections (particularly viral), cold dry air, exercise, andrespiratory irritants can trigger allergic and nonallergic asthma

• Patients with allergic asthma are likely to respond to many immunologic triggers

non-• Cold dry air and exercise can trigger asthma

Assessment of Severity

Asthma is mild intermittent if 1) the symptoms are intermittent(two times a week or less), 2) continuous treatment is not needed,

12 Mayo Clinic Internal Medicine Review

Table 2-3 Industrial Agents That Can Cause Asthma

Canine or feline saliva

Horse dander (racing workers)

Rodent urine (laboratory animal workers)

and 3) the flow-volume curve during formal pulmonary function

testing is normal between episodes of symptoms Even for patients

who meet these criteria, inflammation (albeit patchy) is present in the

airways and corticosteroid inhaled on a regular basis diminishes

bronchial hyperresponsiveness

• Corticosteroid inhaled regularly diminishes bronchial

hyper-responsiveness

Asthma is mild persistent or moderate when 1) the symptoms occur

with some regularity (more than two times a week) or daily, 2) there

is some nocturnal occurrence of symptoms, or 3) asthma exacerbations

are troublesome For many of these patients, the flow-volume curve

is rarely normal and complete pulmonary function testing may show

evidence of hyperinflation, as indicated by increased residual volume

or an increase above expected levels for the diffusing capacity of the

lung for carbon dioxide Patients with mild, moderate, or severe

persistent asthma should receive treatment daily with

anti-inflam-matory medications, usually inhaled corticosteroids

Asthma is severe when symptoms are present almost ously and the usual medications must be given in doses at the upper

continu-end of the dose range to control the disease Most patients with severe

asthma require either large doses of inhaled corticosteroid or oral

prednisone daily for adequate control Most of them have been

hospitalized more than once for asthma The severity of asthma can

change over time, and one of the first signs that asthma is not well

controlled is the emergence of nocturnal symptoms

• Nocturnal symptoms suggest that asthma is worsening

Methacholine Bronchial Challenge

If a patient has a history suggestive of episodic asthma but has normal

results on pulmonary function tests on the day of the examination,

the patient is a reasonable candidate for a methacholine bronchial

challenge The methacholine bronchial challenge is also useful in

evaluating patients for cough in whom baseline pulmonary function

appears normal Positive results indicate that bronchial

hyperre-sponsiveness is present (Table 2-4) Some consider isocapneic

hyper-ventilation with subfreezing dry air (by either exercise or breathing

a carbon dioxide/air mixture) or exercise testing as alternatives to a

methacholine challenge

Do not perform a methacholine challenge in patients who havesevere airway obstruction or a clear diagnosis of asthma Usually, a

20% decrease in forced expiratory volume in 1 second (FEV1) is

considered a positive result

• Patients with suspected asthma and normal results on pulmonary

function tests are candidates for methacholine testing

Differential Diagnosis

The differential diagnosis of wheezing is given in Table 2-5

Medications for Asthma

Medications for asthma are listed in Table 2-6 Currently, the only

anticholinergic drug available in the United States for treating asthma

is ipratropium bromide, although it is approved only for treatingchronic obstructive pulmonary disease Several short-acting β-adrenergic compounds are available, but albuterol or pirbuterol isprobably prescribed most More side effects occur when thesemedications are given orally rather than by inhalation Nebulizedβ-agonists are rarely used long-term in adult asthma, although theymay be life-saving in acute attacks For home use, the metered-doseinhaler or dry powdered inhalation is the preferred delivery system.Salmeterol and formoterol are two long-acting inhaled β-agonists.Both should be used in combination with inhaled corticosteroids.Theophylline is effective for asthma but has a narrow therapeuticindex Note that drug interactions (cimetidine, erythromycin, andquinolone antibiotics) can increase the serum level of theophylline

• Theophylline has a narrow therapeutic index

• β-Agonists are best delivered by the inhaler route

Cromolyn and nedocromil are inhaled anti-inflammatory medicationsthat are appropriate for treatment of mild or moderate asthma The

Chapter 2 Allergy 13

Table 2-4 Medical Conditions Associated With Positive Findings

on Methacholine Challenge

Current asthmaPast history of asthmaChronic obstructive pulmonary diseaseSmoking

Recent respiratory infectionChronic cough

Allergic rhinitis

Table 2-5 Differential Diagnosis of Wheezing

Pulmonary embolismCardiac failureForeign bodyCentral airway tumorsAspiration

Carcinoid syndromeChondromalacia/polychondritisLöffler syndrome

BronchiectasisTropical eosinophiliaHyperventilation syndromeLaryngeal edema

Vascular ring affecting tracheaFactitious (including psychophysiologic vocal cord adduction)

α1-Antiprotease deficiencyImmotile cilia syndromeBronchopulmonary dysplasiaBronchiolitis (including bronchiolitis obliterans), croupCystic fibrosis

5-lipoxygenase inhibitor zileuton and the leukotriene receptor

antag-onists zafirlukast and montelukast are approved for treatment in

mild persistent asthma These agents work by decreasing the

inflam-matory effects of leukotrienes Zileuton can cause increased liver

function test results Cases of Churg-Strauss vasculitis have also been

linked to zafirlukast, although a clear cause-and-effect relationship has

not been established

Corticosteroid Therapy

Many experts recommend inhaled glucocorticoids for mild persistent

asthma because of the potential long-term benefits of reduced

bronchial hyperresponsiveness and reduced airway remodeling

(fibrosis) Long-term use of β-agonist bronchodilators may

adverse-ly affect asthma; this also argues for earlier use of inhaled

glucocor-ticoids Asthma mortality has been linked to the heavy use of

β-agonist inhalers This association may simply reflect that patients

with more severe asthma (who are more likely to die of an asthma

attack) use more β-agonist inhalers However, prolonged and heavy

use of inhaled β-agonists may have a direct, deleterious effect on

asthma, although this has not been proved Certainly, asthma patients

with regularly recurring symptoms should have inhaled

corticos-teroids (or cromolyn or nedocromil) as part of the treatment

• Prescribe inhaled glucocorticoids for mild, moderate, and severe

persistent asthma

• Long-term use of β-agonist bronchodilators may worsen asthma

The inflammatory infiltrate in the bronchial submucosa of asthma

patients likely depends on lymphokine secretory patterns

Corticosteroids may interfere at several levels in the lymphokinecascade

Bronchoalveolar lavage and biopsy studies show that steroids inhibit IL-4, IL-5, and granulocyte-macrophage colony-stimulating factor in asthma

cortico-Monocytes or platelets may be important in the asthmaticprocess Corticosteroids modify activation pathways for monocytesand platelets Furthermore, corticosteroids have vasoconstrictiveproperties, which reduce vascular congestive changes in the mucosa,and they tend to decrease mucous gland secretion

• Corticosteroids reduce airway inflammation by modulatingcytokines

• Corticosteroids can inhibit the inflammatory properties ofmonocytes and platelets

• Corticosteroids have vasoconstrictive properties

• Corticosteroids decrease mucous gland secretion

The most common adverse effects of inhaled corticosteroids aredysphonia and thrush These unwanted effects occur in about 10%

of patients and can be reduced by using a spacer device and rinsingthe mouth after administration Usually, oral thrush can be treatedsuccessfully with oral antifungal agents Dysphonia, when persistent,may be treated by decreasing or discontinuing the use of inhaledcorticosteroids

Detailed study of the systemic effects of inhaled corticosteroidsshows that these agents are much safer than oral corticosteroids.Nevertheless, there is evidence that high-dose inhaled corticosteroidscan affect the hypothalamic-pituitary-adrenal axis and bone metab-olism Also, high-dose inhaled corticosteroids may increase the risk

of future development of glaucoma, cataracts, and osteoporosis.Inhaled corticosteroids can decrease growth velocity in children andadolescents The effect of inhaled corticosteroids on adult height isnot known, but it appears to be minimal

Poor inhaler technique and poor compliance can result in poorcontrol of asthma Therefore, all patients using a metered-dose inhaler

or dry powder inhaler should be taught the proper technique ofusing these devices Most patients using metered-dose inhaledcorticosteroids should use a spacer device with the inhaler

• The most common cause of poor results is poor inhaler technique

• Patients should use a spacer device with metered-dose inhaledcorticosteroids

Anti-IgE Treatment With Omalizumab

Omalizumab is the first recombinant humanized anti-IgE clonal antibody approved for use in asthma It blocks IgE binding tomast cells and is indicated for refractory moderate to severe persistentallergic asthma It is approved for use in patients 12 years and olderwith positive skin or in vitro allergy testing Dosing is based on thepatient’s IgE level and body weight The dosage is typically 150 to

mono-375 mg subcutaneously every 2 to 4 weeks

• Omalizumab is approved for use in refractory moderate to severepersistent asthma

14 Mayo Clinic Internal Medicine Review

Table 2-6 Medications for Asthma

Bronchodilator compounds

Anticholinergic drugs (ipratropium bromide)

β2-Agonist drugs

Short-acting (albuterol, pirbuterol)

Long-acting (salmeterol, formoterol)

Leukotriene receptor antagonists (zafirlukast, montelukast)

Lipoxygenase inhibitors (zileuton)

Goals of Asthma Management

The goals of asthma management are listed in Table 2-7

Management of Chronic Asthma

Baseline spirometry is recommended for all patients with asthma,

and home peak flow monitoring is recommended for those with

moderate or severe asthma (Fig 2-1)

• Spirometry is recommended for all asthma patients

• Home peak flow monitoring is recommended for those with

moderate or severe asthma

Environmental triggers should be discussed with all asthma patients,

and allergy testing should be offered to those with suspected allergic

asthma or with asthma that is not well controlled Although allergy

immunotherapy is effective, it is recommended only for patients with

allergic asthma who have had a complete evaluation by an allergist

Management of Acute Asthma

Inhaled β-agonists, measurements of lung function at presentation

and during therapy, and systemic corticosteroids (for most patients)

are the cornerstones of managing acute asthma (Fig 2-2) Generally,

nebulized albuterol, administered repeatedly if necessary, is the first

line of treatment Delivery of β-agonist by metered-dose inhaler can

be substituted in less severe asthma attacks Inhaled β-agonist delivered

by continuous nebulization may be appropriate for more severe disease

• Inhaled β-agonist can be delivered by intermittent nebulization,

continuous nebulization, or metered-dose inhaler

It is important to measure lung function (usually peak expiratory

flow rate but also FEV1whenever possible) at presentation and after

administration of bronchodilators These measurements provide

invaluable information that allows the physician to assess the severity

of the asthma attack and the response (if any) to treatment

Patients who do not have a prompt and full response to inhaledβ-agonists should receive a course of systemic corticosteroids Patients

with the most severe and poorly responsive disease should be treated

on a hospital ward or in an intensive care unit

• Measure pulmonary function at presentation and after giving

bronchodilators

• Most patients with acute asthma need a course of systemic

cor-ticosteroids

Allergic Bronchopulmonary Aspergillosis

Allergic bronchopulmonary aspergillosis is an obstructive lung disease

caused by an allergic reaction to Aspergillus in the lower airway The

typical patient presents with severe steroid-dependent asthma Mostpatients with this condition have coexisting asthma or cystic fibrosis

• Allergic bronchopulmonary aspergillosis develops in patients withasthma or cystic fibrosis

The diagnostic features of allergic bronchopulmonary aspergillosisare summarized in Table 2-8 Fungi other than Aspergillus fumigatus

can cause an allergic bronchopulmonary mycosis similar to allergicbronchopulmonary aspergillosis

Chest radiography can show transient or permanent infiltratesand central bronchiectasis, usually affecting the upper lobes (Fig.2-3) Advanced cases show extensive pulmonary fibrosis

Allergic bronchopulmonary aspergillosis is treated with systemiccorticosteroids Total serum IgE may be helpful in following thecourse of the disease Antifungal therapy has not been effective

Chronic RhinitisMedical History

Vasomotor rhinitis is defined as nasal symptoms occurring in response

to nonspecific, nonallergic irritants Common triggers of vasomotorrhinitis are strong odors, respiratory irritants such as dust or smoke,changes in temperature, changes in body position, and ingestants such

as spicy food or alcohol This is considered a nonallergic rhinitis

• Vasomotor rhinitis is defined as nasal symptoms in response tononspecific stimuli

Historical factors favoring a diagnosis of allergic rhinitis include a

history of nasal symptoms that have a recurrent seasonal pattern(e.g., every August and September) or symptoms provoked by being

near animals Factors favoring vasomotor rhinitis include symptoms

provoked by strong odors and changes in humidity and temperature

• Allergic rhinitis has a recurrent seasonal pattern and may beprovoked by being near animals

• Triggers of vasomotor rhinitis include strong odors and changes

in humidity and temperature

Chapter 2 Allergy 15

Table 2-7 Goals of Asthma Management

No asthma symptoms

No asthma attacks

Normal activity level

Normal lung function

Use of safest and least amount of medication necessary

Establish therapeutic relationship between patient and provider

Table 2-8 Diagnostic Features of Allergic Bronchopulmonary

Aspergillosis

Clinical asthmaBronchiectasis (usually proximal)Increased total serum IgE

IgE antibody to Aspergillus (by skin test or in vitro assay) Precipitins or IgG antibody to Aspergillus

Radiographic infiltrates (often upper lobes)Peripheral blood eosinophilia

16 Mayo Clinic Internal Medicine Review

Symptoms of asthma

Previous diagnosis of asthma?

Yes

Interval evaluation

• History and physical

• Assess asthma triggers/allergens

• Measure pulmonary function – Spirometry

– PEFR

• Consider consultation and/or allergy testing

Assess asthma severity

Step care of pharmacologic treatment

• Environmental control measures

• Emphasize need for regular follow-up visits

Schedule regular follow-up visits

Fig 2-1.Diagnosis and management of asthma PEFR, peak expiratory flow rate.

Chapter 2 Allergy 17

Signs and symptoms of acute asthma Initiation of asthma action plan

Homemanagementsuccessful?

Yes

No

No

Yes

Continue home management

Office visit/urgent care/ED

• Review history

• Evaluate causes of exacerbation

• Consult asthma action plan

• Consider alternative diagnosis

Individualized decision related to

hospitalization, extended observation,

Goodresponse

Incomplete orpoor response

Fig 2-2.Management of acute asthma in adults ED, emergency department; PEFR, peak expiratory flow rate (Used with permission of Institute of Clinical Systems Integration.)

Factors common to allergic rhinitis and vasomotor rhinitis (thus,

without differential diagnostic value) include perennial symptoms,

intolerance of cigarette smoke, and history of “dust” sensitivity

Factors that suggest fixed nasal obstruction (which should prompt

physicians to consider other diagnoses) include unilateral nasal

obstruction, unilateral facial pain, unilateral nasal purulence, nasal voice

but no nasal symptoms, disturbances of olfaction without any nasal

symptoms, and unilateral nasal bleeding (Table 2-9)

• Perennial symptoms, intolerance of cigarette smoke, and history

of “dust” sensitivity are common to allergic and vasomotor rhinitis

• House dust mite sensitivity is a common cause of perennial allergic

rhinitis

Allergy Skin Tests in Allergic Rhinitis

The interpretation of allergy skin test results must be tailored to the

unique features of each patient

1 For patients with perennial symptoms and negative results

on allergy skin tests, the diagnosis is vasomotor rhinitis

2 For patients with seasonal symptoms and appropriately

pos-itive allergy skin tests, the diagnosis is seasonal allergic rhinitis

3 For patients with perennial symptoms, allergy skin tests

positive for house dust mite suggest house dust mite allergic

rhinitis In this case, dust mite allergen avoidance should be

recommended Patients should encase their bedding with

allergy-proof encasements, remove carpeting from the

bedroom, and keep the relative humidity in the house at40% to 50% or less

Corticosteroid Therapy for Rhinitis

The need for systemic corticosteroid treatment for rhinitis is limited.Occasionally, patients with severe symptoms of hay fever may benefitgreatly from a short course of prednisone (10 mg four times daily

by mouth for 5 days) This may induce sufficient improvement sothat topical corticosteroids can penetrate the nose and satisfactorylevels of antihistamine can be established in the blood Severe nasalpolyposis may warrant a longer course of oral corticosteroids.Sometimes, recurrence of nasal polyps can be prevented by continueduse of topical corticosteroids Polypectomy may be required if nasalpolyps do not respond to treatment with systemic and intranasalcorticosteroids

• Treatment of nasal polyposis can include oral prednisone, followed

by topical corticosteroids

In contrast to systemic corticosteroid therapy, topical corticosteroidagents for the nose are easy to use and have few adverse systemiceffects Intranasal corticosteroids may decrease growth velocity inchildren

• Intranasal corticosteroids may decrease growth velocity in children.Long-term treatment with decongestant nasal sprays may have

“addictive” potential (a vicious cycle of rebound congestion called

“rhinitis medicamentosa” caused by topical vasoconstrictors) Incontrast, inhaled corticosteroid does not induce dependence

• Unlike decongestant nasal sprays, intranasal corticosteroid doesnot induce tachyphylaxis and rebound congestion

A substantial number of patients with vasomotor rhinitis also have

a good response to intranasal (topical aerosol) corticosteroid therapy,especially if they have the nasal eosinophilia or nasal polyposis form

of vasomotor rhinitis

• Many patients with vasomotor rhinitis have a good response totopical aerosol corticosteroid therapy

18 Mayo Clinic Internal Medicine Review

Fig 2-3.Chest radiograph in allergic bronchopulmonary aspergillosis

shows cylindrical infiltrates involving the upper lobes.

Table 2-9 Differential Diagnosis of Chronic Rhinitis

Allergic rhinitisVasomotor rhinitisRhinitis medicamentosaSinusitis

Nasal polyposisNasal septal deviationForeign bodyTumor

If a patient with hay fever does not receive adequate relief with

topical corticosteroid plus antihistamine therapy, it may indicate the

need for systemic corticosteroid treatment and the initiation of

immunotherapy

• If pharmacologic management fails, allergy immunotherapy

should be considered for patients with allergic rhinitis

An unusual side effect of intranasal corticosteroids is nasal septal

per-foration Dry powder spray cannisters deliver a powerful jet of

par-ticulates, and a few patients have misdirected the jet to the nasal septum

• Rarely, topical corticosteroid nasal sprays cause perforation of the

nasal septum

Antihistamines and Decongestants

Antihistamines antagonize the interaction of histamine with its

receptors Histamine may be more causative than other mast cell

mediators of nasal itch and sneezing These are symptoms most often

responsive to antihistamine therapy

Pseudoephedrine is the most common agent in nonprescriptiondrugs for treating cold symptoms and rhinitis and usually is the

active agent in widely used proprietary prescription agents

Phenylpropanolamine has been removed from the market because

of its association with hemorrhagic stroke in women Several

prescription and nonprescription combination agents combine an

antihistamine and decongestant Decongestant preparations are often

the only therapeutic option for patients with vasomotor rhinitis

unresponsive to topical glucocorticoids

• Pseudoephedrine is the most common decongestant in

nonpre-scription preparations

Middle-aged and older men may have urinary retention caused by

antihistamines (principally the older drugs that have anticholinergic

effects) and decongestants Although there has been concern for years

that decongestants may exacerbate hypertension because they are

α-adrenergic agonists, no clinically significant hypertensive response has

been seen in patients with hypertension that is controlled medically

• Antihistamines and decongestants may cause urinary retention in

men

• The elderly are more sensitive to the anticholinergic effects of

antihistamines

Immunotherapy for Allergic Rhinitis

Until topical nasal glucocorticoid sprays were introduced, allergen

immunotherapy was considered first-line therapy for allergic rhinitis

when the relevant allergen was seasonal pollen of grass, trees, or

weeds Immunotherapy became second-line therapy after topical

corticosteroids were introduced because immunotherapy 1) requires

more time commitment during the build-up phase and 2) carries a

small risk of anaphylaxis to the immunotherapy injection itself

However, immunotherapy for allergic rhinitis can be appropriate

first-line therapy in selected patients and is highly effective

Immunotherapy is usually reserved for patients who have nosatisfactory relief from intranasal corticosteroids or who cannot tolerateantihistamines Controlled trials have shown a benefit for pollen,dust mite, and cat allergies and a variable benefit for mold allergy.Immunotherapy is not used for food allergy or nonallergic rhinitis.The practice is less uniform with respect to mold allergens, withendorsement divided in the subspecialty

• Immunotherapy usually is reserved for patients who receive norelief from intranasal glucocorticoids or who cannot tolerateantihistamines

• Controlled trials have shown that immunotherapy is effective forallergic rhinitis

• Anaphylaxis is a risk of immunotherapy

• Immunotherapy for allergic rhinitis can be first-line therapy inselected patients

Environmental Modification

House Dust Mites

House dust mites are so small that they cannot maintain their owninternal water unless the ambient humidity is high They eat all kinds

of organic matter but seem to favor mold and epidermal scale shed

by humans They occur in all human habitations, although thepopulation size varies with local conditions The only geographicareas free of house dust mites are at high elevations with extremedryness

• House dust mites require high humidity to survive

• They are found in nearly all human habitations

Areas in the home harboring the most substantial mite populationsare bedding and fabric-upholstered furniture (heavily used) and anyarea where carpeting is on concrete (when concrete is in contact withgrade) Although carpeting is often cited as an important mite-relatedproblem, carpet on wooden floors in a dry, well-ventilated houseusually harbors only a small number of dust mites Aerosol dispersion

of allergen from this source is not great compared with that frombedding and furniture To prevent egress of allergen when the mattressand pillows are compressed by occupancy of the bed, encase thebedding (and sometimes, when practical, furniture cushions) inplastic dust-proof encasements To some degree, this also preventsinfusion of water vapor into the bedding matrix These two factorscombine to markedly decrease the amount of airborne allergen Incontrast, recently marketed acaricides that kill mites or denature theirprotein allergens have not proved useful in the home Measures forcontrolling dust mites are listed in Table 2-10

• Dust mite is an important respiratory allergen

• The most substantial mite populations are in bedding and upholstered furniture

fabric-• Plastic encasements prevent egress of allergen

• Chemical sprays (acaricides) capable of either killing mites ordenaturing the protein allergens are not substantially helpful whenapplied in the home

Chapter 2 Allergy 19

Air conditioning, which enables the warm-season home to remain

tightly closed, is the principal defense against pollinosis Most masks

purchased at local pharmacies cannot exclude pollen particles and

are not worth the expense Some masks can protect the wearer from

allergen exposure These include industrial-quality respirators designed

specifically to pass rigorous testing by the Occupational Safety and

Health Administration (OSHA) and the National Institute for

Occupational Safety and Health (NIOSH) and be certified as capable

of excluding a wide spectrum of particulates, including pollen and

mold These masks allow persons to mow the lawn and do yard

work, which would be intolerable otherwise because of exposure to

pollen allergen

• Only industrial-quality masks are capable of excluding pollen

particles

Animal Dander

No measure can compare with getting the animal completely out

of the house No air filtration scheme that is feasible for average

homeowners to install can eliminate allergen from an actively

elab-orating animal If complete removal is not tenable, some partial

measure must be considered

If the house is heated or cooled by a forced-air system with

ductwork, confining the pet to a single room in the house is only

partially effective in reducing overall exposure, because air from

every room is collected through the air-return ductwork and

redistributed through a central plenum If air-return ducts are

sealed in the room where the animal is kept and air can escape

from the room only by infiltration, exposure may be reduced The

room selected for this measure should be as far as possible from

the bedroom of the person with the allergy Naturally, the person

should avoid close contact with the animal and should consider

using a mask if handling the animal or entering the room where the

animal is kept is necessary Most animal danders have little or nothing

to do with animal hair, so shedding status is irrelevant Bathing

cats about once every other week may reduce the allergen load in

the environment

• Complete avoidance is the only entirely effective way to manage

allergy to household pets

Sinusitis

Sinusitis is closely associated with edematous obstruction of the sinusostia (the osteomeatal complex) Poor drainage of the sinus cavitiespredisposes to infection, particularly by microorganisms that thrive

in low oxygen environments (e.g., anaerobes) In adults, Streptococcus pneumoniae, Haemophilus influenzae, anaerobes, and viruses are

common pathogens In addition, Branhamella catarrhalis is an

important pathogen in children

Important clinical features of acute sinusitis are purulent nasaldischarge, tooth pain, cough, and poor response to decongestants.Findings on paranasal sinus transillumination may be abnormal

• Purulent nasal discharge, tooth pain, and abnormal findings ontransillumination are important clinical features of sinusitis.Physicians should be aware of the complications of sinusitis, whichcan be life-threatening (Table 2-11) Mucormycosis can cause recur-rent or persistent sinusitis refractory to antibiotics Allergic fungalsinusitis is characterized by persistent sinusitis, eosinophilia, increased

total IgE, antifungal (usually Aspergillus) IgE antibodies, and fungal

colonization of the sinuses Wegener granulomatosis, ciliary nesia, and hypogammaglobulinemia are medical conditions that cancause refractory sinusitis (Table 2-12)

dyski-Untreated sinusitis may lead to osteomyelitis, orbital and orbital cellulitis, meningitis, and brain abscess Cavernous sinusthrombosis, an especially serious complication, can lead to retrobulbarpain, extraocular muscle paralysis, and blindness

peri-Persistent, refractory, and complicated sinusitis should beevaluated by a specialist Sinus computed tomography (CT) is thepreferred imaging study for these patients (Fig 2-4)

Amoxicillin, 500 mg three times daily, or famethoxazole (one double-strength capsule twice daily) for 10 to 14days is the treatment of choice for uncomplicated maxillary sinusitis.The sensitivity of plain radiography of the sinuses is not asgood as that of CT (using the coronal sectioning technique) Good-quality coronal CT scans show greater detail about sinus mucosalsurfaces, but CT usually is not necessary in acute uncomplicatedsinusitis CT is indicated, though, for patients being considered for

trimethoprim-sul-a sinus opertrimethoprim-sul-ation trimethoprim-sul-and for those in whom sttrimethoprim-sul-andtrimethoprim-sul-ard tretrimethoprim-sul-atment forsinusitis fails However, patients with extensive dental restorationsthat contain metal may generate too much artifact for CT to beuseful For these patients, magnetic resonance imaging techniquesare indicated

20 Mayo Clinic Internal Medicine Review

Table 2-10 Dust Mite Control

Encase bedding and pillows in airtight encasements

Remove carpeting in bedroom

Remove upholstered furniture from bedroom

Remove all carpeting laid on concrete

Discontinue use of humidifier

Wash bedding in hot water

Run dehumidifier

Table 2-11 Complications of Sinusitis

OsteomyelitisMeningitisSubdural abscessExtradural abscessOrbital infectionCellulitisCavernous sinus thrombosis

• Sinus imaging is indicated for recurrent sinusitis

• Sinus CT is preferred to sinus radiography for complicated sinusitis

Urticaria and Angioedema

The distinction between acute and chronic urticaria is arbitrary and

based on the duration of the urticaria If it has been present for 6

weeks or longer, it is called chronic urticaria

Secondary Urticaria

Most patients simply have urticaria as a skin disease (chronic idiopathic

urticaria), but occasionally it is the presenting sign of more serious

internal disease It can be a sign of lupus erythematosus and other

connective tissue diseases, particularly the “overlap” syndromes that

are more difficult to categorize Malignancy, mainly of the

gastroin-testinal tract, and lymphoproliferative diseases are associated with

urticaria, as occult infection may be, particularly of the gallbladder

and dentition Immune-complex disease has been associated with

urticaria, usually with urticarial vasculitis, and hepatitis B virus has been

identified as an antigen in cases of urticaria and immune-complex

disease

• Urticaria can be associated with lupus erythematosus and other

connective tissue diseases, malignancy, infection, and

immune-complex disease

A common cause of acute urticaria and angioedema (other than the

idiopathic variety) is drug or food allergy However, drug or food

allergy usually does not cause chronic urticaria

• Chronic urticaria and angioedema are often idiopathic

• A common secondary cause of acute urticaria and angioedema is

drug or food allergy

Relation Between Urticaria and Angioedema

In common idiopathic urticaria, which lasts 2 to 18 hours, the

lesions itch intensely because histamine is one of the causes of wheal

formation

• Typical urticarial lesions last 2-18 hours and are pruritic

The pathophysiologic mechanism is similar for urticaria and

angioede-ma The critical factor is the type of tissue in which the capillary leak

and mediator release occur Urticaria occurs when the capillary eventsare in the tightly welded tissue wall of the skin—the epidermis.Angioedema occurs when capillary events affect vessels in loose con-nective tissue of the deeper layers—the dermis Virtually all patientswith the common idiopathic type of urticaria also have angioedemafrom time to time When urticaria is caused by allergic reactions,angioedema may also occur The only exception is hereditaryangioneurotic edema (HANE), which is not related to mast cellmediator release but is a complement disorder Patients with thisform of angioedema rarely have urticaria

C1 Esterase Inhibitor Deficiency

If HANE is strongly suspected, the diagnosis can be proved by theappropriate measurement of complement factors (decreased levels

of C1 esterase inhibitor [quantitative and functional] and C4 [alsoC2, during an episode of swelling])

• Levels of C1 esterase inhibitor and C4 are decreased in HANE.The duration of individual swellings varies Many patients withHANE have had at least one hospitalization for what appeared to

be intestinal obstruction If they avoid laparotomy on these occasions,the obstruction usually resolves in 3 to 5 days Cramps and diarrheamay occur

Lesions in HANE do not itch The response to epinephrine is

a useful differential point: HANE lesions do not respond well toepinephrine, but common angioedema usually resolves in 15 min-utes or less Laryngeal edema almost never occurs in the common

idiopathic type of disease (although it may occur in allergic

reac-tions, most often in insect-sting anaphylaxis cases); however, it is

relatively common in HANE (earlier articles cited a 30% mortality

rate in HANE, with all deaths due to laryngeal edema) HANE

episodes may be related to local tissue trauma in a high percentage

of cases, with dental work often regarded as the classic precipitating

factor

• Most patients with HANE have been hospitalized for “intestinal

obstruction.”

• HANE lesions do not respond well to epinephrine

• In HANE, laryngeal edema is relatively common

• Dental work is the classic precipitating factor for HANE

The common idiopathic form of urticaria and angioedema is usually

unrelated to antecedent trauma except in special cases of

delayed-pressure urticaria, in which hives and angioedema follow minor

trauma or pressure to soft tissues (e.g., to the hands while playing

golf) The response to pressure distinguishes this special form of

physical urticaria from HANE

It is reasonable to perform C4 and C1 esterase inhibitor assays

(functional and quantitative) for all patients with unexplained

recurrent angioedema, especially if urticaria is not present

The three major types of HANE-like disorders are as follows:

1 Classic HANE is a genetic dysregulation of gene function

for C1 inhibitor that is inherited in an autosomal dominant pattern

Therapy with androgens (testosterone, stanozolol, and danazol)

reverses the dysregulation and allows expression of the otherwise

normal gene, resulting in half-normal plasma levels of C1, which

are sufficient to eliminate the clinical manifestations of the disease

• Classic HANE is a genetic dysregulation (autosomal dominant)

• Testosterone, stanozolol, and danazol reverse the dysregulation

2 In some cases of HANE, the gene for the C1 inhibitor

mutates, rendering the molecule functionally ineffective but

quan-tifiable in the blood Thus, plasma levels of the C1 inhibitor molecule

may be normal in these patients This is the basis for requesting

immunochemical and functional measures of serum C1 inhibitor

(with immunochemical measures only, the diagnosis is missed in

cases of normal levels of an inactive molecule) Both classic HANE

(low levels of C1 esterase inhibitor) and classic HANE with the

mutated gene for C1 inhibitor (nonfunctional C1 esterase inhibitor)

are inherited forms of the disease However, the proband may start

the mutational line in both forms of HANE, so the family history

is not positive in all cases

• HANE with normal levels of C1 esterase inhibitor but

non-functional (by esterase assay) indicates a gene mutation

3 C1 esterase inhibitor deficiency may be an acquired disorder

with malignancy or lymphoproliferative disease Plasma levels for

C1, C4, and C1 esterase inhibitor are low in acquired C1 esterase

inhibitor deficiency The hypothesis for the pathogenesis of this form

of angioedema is that the tumor has or releases determinants that

fix complement, and with constant consumption of complementcomponents, a point is reached at which the biosynthesis of C1inhibitor cannot keep up with the consumption rate, and the relativedeficiency of C1 inhibitor allows episodes of swelling

• C1 esterase inhibitor deficiency can be an acquired disorder inmalignancy or lymphoproliferative disease

• C1 levels are low in acquired C1 esterase inhibitor deficiency

Physical Urticaria

Heat, light, cold, vibration, and trauma or pressure have been

report-ed to cause hives in susceptible persons Obtaining the history is theonly way to suspect the diagnosis, which can be confirmed by apply-ing each of the stimuli to the patient’s skin in the laboratory Heat can

be applied by placing coins (soaked in hot water for a few minutes)

on the patient’s forearm Cold can be applied with coins kept in afreezer or with ice cubes For vibration, a laboratory vortex mixer orany common vibrator can be used A pair of sandbags connected by

a strap can be draped over the patient to create enough pressure tocause symptoms in those with delayed pressure urticaria Unlikemost cases of common idiopathic urticaria, in which the lesionsaffect essentially all skin surfaces, many cases of physical urticariaseem to involve only certain areas of skin Thus, challenges will bepositive only in the areas usually involved and negative in other areas.Directing challenges to the appropriate area depends on the history

• For physical urticaria, the history is the only way to suspect thediagnosis, which can be confirmed by applying stimuli to thepatient’s skin

Food Allergy in Chronic Urticaria

Food allergy almost never causes chronic urticaria However, urticaria(or angioedema or anaphylaxis) can be an acute manifestation oftrue food allergy

• Food allergy almost never causes chronic urticaria

• Food allergy may cause acute urticaria, angioedema, or anaphylaxis

Histopathology of Chronic Urticaria

Chronic urticaria is characterized by mononuclear cell perivascularcuffing around dermal capillaries, particularly involving the capillaryloops that interdigitate with the rete pegs of the epidermis This is theusual histologic location for most skin mast cells It appears that there

is about a tenfold increase in the number of mast cells in the cuffcompared with the normal value However, the number of mast cells

is still small compared with that of other round cells in the cuff Thishistologic picture is consistent throughout the skin, regardless ofrecent active urtication Most pathologists consider “vasculitis” toindicate actual necrosis of the structural elements of blood vessels;thus, the typical features of chronic urticaria do not meet the criteriafor vasculitis Immunofluorescence studies on chronic urticaria biopsysamples are negative for fibrin, complement, and immunoglobulindeposition in blood vessels

Urticarial vasculitis shows the usual histologic features of cytoclastic vasculitis

leuko-22 Mayo Clinic Internal Medicine Review

• The characteristic histopathologic feature of chronic urticaria is

a mononuclear cell perivascular cuff around capillaries

Management of Urticaria

The history is of utmost importance if the 2% to 4% of cases of

chronic urticaria actually due to allergic causes are to be discovered

A complete physical examination is needed, with particular attention

to the skin (including some test for dermatographism) to evaluate

for the vasculitic nature of the lesions and to the liver, lymph nodes,

and mucous membranes Laboratory testing need not be exhaustive:

chest radiography, a complete blood count with differential count

to discover eosinophilia, liver enzymes, erythrocyte sedimentation

rate, serum protein electrophoresis, total hemolytic complement,

antinuclear antibody, urinalysis, and stool examination for parasites

Only if the patient has strong allergic tendencies and some element in

the history suggests an allergic cause is allergy skin testing indicated

However, patients with idiopathic urticaria often have fixed ideas

about an allergy causing their problem, and skin testing often helps

to dissuade them of this idea

• The history is of utmost importance in diagnosing allergic urticaria

• Laboratory testing may include chest radiography, eosinophil

count, liver enzymes, erythrocyte sedimentation rate, serum

protein electrophoresis, total hemolytic complement, and stool

examination for parasites

Management of urticaria and angioedema consists of blocking

histamine, beginning usually with H1antagonists The addition

of H2antagonists may be helpful Tricyclic antidepressants, such

as doxepin, have potent antihistamine effects and are useful

Systemic corticosteroids can be administered for acute urticaria

and angioedema or for very severe chronic idiopathic urticaria

The clinical syndrome of food allergy should prompt patients to

provide a history containing some or all the following: For very

sensitive persons, some tingling, itching, and a metallic taste in the

mouth occur while the food is still in the mouth Within 15 minutes

after the food is swallowed, some epigastric distress may occur There

may be nausea and rarely vomiting Abdominal cramping is felt

chiefly in the periumbilical area (small-bowel phase), and lower

abdominal cramping and watery diarrhea may occur Urticaria or

angioedema may occur in any distribution, or there may be only

itching of the palms and soles With increasing clinical sensitivity to

the offending allergen, anaphylactic symptoms may emerge, including

tachycardia, hypotension, generalized flushing, and alterations of

consciousness

In extremely sensitive persons, generalized flushing, hypotension,and tachycardia may occur before the other symptoms Most patientswith a food allergy can identify the offending foods The diagnosisshould be confirmed by skin testing or in vitro measurement ofallergen-specific IgE antibody

• Allergic reactions to food usually include pruritus, urticaria, orangioedema

Common Causes of Food Allergy

Items considered the most common allergens are listed in Table 2-13

Food-Related Anaphylaxis

Food-induced anaphylaxis is the same process involved in acuteurticaria or angioedema to food allergens, except the severity of thereaction is greater in anaphylaxis Relatively few foods are involved

in food-induced anaphylaxis; the main ones are peanuts, shellfish,and nuts Patients with latex allergy can develop food allergy tobanana, avocado, kiwifruit, and other fruits

• Anaphylaxis to food can be life-threatening

• There is cross-sensitivity between latex and banana, avocado, andkiwifruit

Allergy Skin Testing in Food Allergy

Patients presenting with food-related symptoms may have foodallergy, food intolerance, irritable bowel syndrome, nonspecificdyspepsia, or one of many nonallergic conditions A careful anddetailed history on the nature of the “reaction,” the reproducibility

of the association of food and symptoms, and the timing of toms in relation to the ingestion of food can help the clinician form

symp-a clinicsymp-al impression

In many cases, allergy skin tests to foods can be helpful If theallergy skin tests are negative (and the clinical suspicion for foodallergy is low), the patient can be reassured that food allergy is not thecause of the symptoms If the allergy skin tests are positive (and theclinical suspicion for food allergy is high), the patient should becounseled about the management of the food allergy For highlysensitive persons, this includes strict and rigorous avoidance of theoffending foods These patients should also be given an epinephrinekit for self-administration in case of emergency

If the diagnosis of food allergy is uncertain or if the symptomsare mild and nonspecific, sometimes oral food challenges are helpful

An open challenge is usually performed first If negative, the diagnosis

of food allergy is excluded If positive, a blinded placebo-controlledchallenge can be performed