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Tuberculosis and Nontuberculous Mycobacterial Infections, edited by Schlossberg David, ASM Press, 2017.

18:32:49.
TUBERCULOSIS
AND NONTUBERCULOUS
MYCOBACTERIAL INFECTIONS

SEVENTH EDITION
 NOTICE

Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in
treatment and drug therapy are required. The authors and the publisher of this work have checked with sources
believed to be reliable in their efforts to provide information that is complete and generally in accord with the
standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical
sciences, neither the editors nor the publisher nor any other party who has been involved in the preparation or publi-
cation of this work warrants that the information contained herein is in every respect accurate or complete, and they
disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained
in this work. Readers are encouraged to confirm the information contained herein with other sources. For example
and in particular, readers are advised to check the product information sheet included in the package of each drug they
plan to administer to be certain that the information contained in this work is accurate and that changes have not been
made in the recommended dose or in the contraindications for administration. This recommendation is of particular
importance in connection with new or infrequently used drugs.
TUBERCULOSIS
AND NONTUBERCULOUS
MYCOBACTERIAL INFECTIONS
EDITED BY DAVID SCHLOSSBERG
Professor of Medicine
The Lewis Katz School of Medicine at Temple University

Adjunct Professor of Medicine

The Perelman School of Medicine at the University of Pennsylvania

Medical Director
Tuberculosis Control Program
Philadelphia Department of Public Health
Philadelphia, Pennsylvania

SEVENTH EDITION

WASHINGTON, DC
Copyright © 2017 American Society for Microbiology. All rights reserved. No part of
this publication may be reproduced or transmitted in whole or in part or reused in any
form or by any means, electronic or mechanical, including photocopying and recording,
or by any information storage and retrieval system, without permission in writing from
the publisher.

Disclaimer: To the best of the publisher’s knowledge, this publication provides informa-
tion concerning the subject matter covered that is accurate as of the date of publication.
The publisher is not providing legal, medical, or other professional services. Any refer-
ence herein to any specific commercial products, procedures, or services by trade name,
trademark, manufacturer, or otherwise does not constitute or imply endorsement,
recommendation, or favored status by the American Society for Microbiology (ASM).
The views and opinions of the author(s) expressed in this publication do not
necessarily state or reflect those of ASM, and they shall not be used to advertise
or endorse any product.

Library of Congress Cataloging-in-Publication Data

Names: Schlossberg, David, editor.

Title: Tuberculosis and nontuberculous mycobacterial infections / edited by
David Schlossberg.
Description: Seventh edition. | Washington, DC : ASM Press, [2017] | Includes
bibliographical references and index.
Identifiers: LCCN 2017012300 (print) | LCCN 2017013859 (ebook) | ISBN
9781555819866 (ebook) | ISBN 9781555819859 (hardcover)
Subjects: LCSH: Tuberculosis. | Mycobacterial diseases.
Classification: LCC RC311 (ebook) | LCC RC311. T824 2017 (print) | DDC
616.99/5--dc23
LC record available at https://lccn.loc.gov/2017012300

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 Dedication

This volume is dedicated to Dr. Menachem M. Meller, with respect, admiration, and affection.

“A faithful friend is the medicine of life.”

—Ben Sira, 6:16
“The Captain of all these men of death that came against him to take him away, was the consumption; for it was
that that brought him down to the grave.”
John Bunyan
The Life and Death of Mr. Badman

The weariness, the fever, and the fret

Here, where men sit and hear each other groan;
Where palsy shakes a few, sad, last gray hairs,
Where youth grows pale, and spectre-thin, and dies;
Where but to think is to be full of sorrow
And leaden-eyed despairs,
Where beauty cannot keep her lustrous eyes,
Or new love pine at them beyond tomorrow.
John Keats
Ode to a Nightingale

There is a dread disease which so prepares its victim, as it were, for death…a dread disease, in which the struggle
between soul and body is so gradual, quiet, and solemn, and the results so sure, that day by day, and grain by grain,
the mortal part wastes and withers away, so that the spirit grows light…a disease in which death and life are so
strangely blended that death takes the glow and hue of life, and life the gaunt and grisly form of death—a disease
which medicine never cured, wealth warded off, or poverty could boast exemption from—which sometimes moves
in giant strides, or sometimes at a tardy sluggish pace, but, slow or quick, is ever sure and certain.
Charles Dickens
Nicholas Nickleby
Contents

Contributors  xi
Preface  xxi

I. General Considerations

1. Tuberculosis in History: Did It Change the Way We Live?   3

Thomas M. Daniel

2. Epidemiology and Host Factors   11

Jay B. Mehta and Asim K. Dutt

3. Perspectives for Developing New Tuberculosis Vaccines Derived

from the Pathogenesis of Tuberculosis   33
Arthur M. Dannenberg, Jr. and Bappaditya Dey

4. Laboratory Diagnosis and Susceptibility Testing for

Mycobacterium tuberculosis  45
Gary W. Procop

5. Diagnosis of Latent Tuberculosis Infection   59

Alfred A. Lardizabal and Lee B. Reichman

6. Treatment of Latent Tuberculosis Infection   67

Connie A. Haley

7. Chemotherapy of Tuberculosis   101

Thomas E. Dobbs and Risa M. Webb

vii
viii Contents

8. The Role of Therapeutic Drug Monitoring in Mycobacterial

Infections  119
Charles Peloquin

9. Therapy of Multidrug-Resistant and Extensively Drug-Resistant

Tuberculosis  129
Barbara J. Seaworth and David E. Griffith

10. Role of Surgery in the Diagnosis and Management

of Tuberculosis  159
Alan D. L. Sihoe

11. Mycobacterium bovis BCG and New Vaccines for the Prevention
of Tuberculosis  187
Timothy Lahey and C. Fordham Von Reyn

12. Tuberculosis—a World Health Organization

Perspective  211
Giovanni Sotgiu, Giorgia Sulis, and Alberto Matteelli

13. Crisis-Affected Populations and Tuberculosis   229

Dominik Zenner

14. Tuberculosis in Enclosed Populations   237

Sorana Segal-Maurer

15. Role of the Health Department in Tuberculosis

Prevention and Control—Legal and Public Health
Considerations  261
Carla Jeffries, Phil LoBue, Terence Chorba, Beverly Metchock,
and Ijaz Kashef

II. Clinical Syndromes

16. Pulmonary Tuberculosis  285

Sarah M. Lyon and Milton D. Rossman

17. Upper Respiratory Tract Tuberculosis   299

Surinder K. Jindal, Aditya Jindal, and Ritesh Agarwal

18. Tuberculous Otomastoiditis  309

Jonathan M. Hand and George A. Pankey

19. Ocular Tuberculosis  313

Daniel M. Albert and Meisha L. Raven

20. Central Nervous System Tuberculosis   331

John M. Leonard

21. Tuberculous Lymphadenitis and Parotitis   343

Juan Carlos Cataño and Jaime Robledo
Contents ix

22. Urogenital Tuberculosis  355

André A. Figueiredo, Antônio M. Lucon, and Miguel Srougi

23. Musculoskeletal Tuberculosis  371

Michael K. Leonard, Jr. and Henry M. Blumberg

24. Cardiovascular Tuberculosis  393

John A. Crocco

25. Gastrointestinal Tuberculosis  411

Eric H. Choi and Walter J. Coyle

26. Tuberculous Peritonitis  433

Urvashi Vaid and Gregory C. Kane

27. Tuberculosis of the Liver, Biliary Tract, and Pancreas   439

G. Shelton McMullan and James H. Lewis

28. Cutaneous Tuberculosis  483

Michael K. Hill and Charles V. Sanders

29. Miliary Tuberculosis  491

Surendra K. Sharma and Alladi Mohan

30. Endocrine and Metabolic Aspects of Tuberculosis   515

Christopher Vinnard and Emily A. Blumberg

31. Hematologic Complications of Tuberculosis    529

Shyam S. Balepur and David Schlossberg

32. Tuberculosis in Infants and Children   541

Gabriella S. Lamb and Jeffrey R. Starke

33. Tuberculosis and Pregnancy—Maternal, Fetal, and Neonatal

Considerations  571
Jane M. Gould and Stephen C. Aronoff

34. Tuberculosis Associated with HIV Infection   577

Jeffrey A. Tornheim and Kelly E. Dooley

35. Diabetes and Tuberculosis   595

Blanca I. Restrepo

36. Tuberculosis and Transplantation   607

José M. Aguado, José Tiago Silva, Palash Samanta, and Nina Singh

37. Biologic Agents and Tuberculosis   623

Claudia C. Dobler

38. Paradoxical Reactions and the Immune Reconstitution

Inflammatory Syndrome  637
L. W. Preston Church, Amit Chopra, and Marc A. Judson
x Contents

III. Nontuberculous Mycobacteria

39. Nontuberculous Mycobacteria—Overview  655

Won-Jung Koh

40. Mycobacterium avium Complex Disease   663

Charles L. Daley

41. Rapidly Growing Mycobacteria   703

Barbara A. Brown-Elliott and Julie V. Philley

42. Mycobacterium kansasii  725

James C. Johnston, Leslie Chiang, and Kevin Elwood

43. Mycobacterium marinum  735

Alexandra Aubry, Faiza Mougari, Florence Reibel, and
Emmanuelle Cambau

44. Mycobacterium bovis and Other Uncommon Members of the

Mycobacterium tuberculosis Complex  753
Jaime Esteban and Maria-Carmen Muñoz-Egea

45. Other Slow-Growing Nontuberculous Mycobacteria   767

Marvin J. Bittner and Laurel C. Preheim

Index  777
Contributors

Ritesh Agarwal
Department of Pulmonary Medicine
Postgraduate Institute of Medical Education & Research
Chandigarh, India
José M. Aguado
University Hospital 12 de Octubre
Unit of Infectious Diseases
Madrid, Spain
Daniel M. Albert
Department of Ophthalmology and Visual Sciences
University of Wisconsin School of Medicine and Public Health
Madison, Wisconsin
Stephen C. Aronoff
Department of Pediatrics
Lewis Katz School of Medicine
Temple University
Philadelphia, Pennsylvania
Alexandra Aubry
Centre National de Référence pour la résistance des Mycobactéries aux
antituberculeux
Sorbonne Université
Université Pierre et Marie Curie
AP-HP Hôpital Pitié-Salpêtrière
Centre d’Immunologie et des Maladies Infectieuses, Team 13, INSERM U1135
Paris, France

xi
xii Contributors

Shyam S. Balepur
ABBCI, Division of Hematology & Oncology
Penn Medicine/Lancaster General Health
Lancaster, Pennsylvania
Marvin J. Bittner
Infectious Diseases Section
VA Medical Center
Departments of Medicine and of Medical Microbiology and Immunology
Creighton University School of Medicine
Omaha, Nebraska
Emily A. Blumberg
Division of Infectious Diseases
Department of Medicine
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, Pennsylvania
Henry M. Blumberg
Division of Infectious Diseases
Emory University School of Medicine
Atlanta, Georgia
Barbara A. Brown-Elliott
Department of Microbiology
The University of Texas Health Science Center
Tyler, Texas
Emmanuelle Cambau
Centre National de Référence pour la résistance des Mycobactéries aux
antituberculeux
Laboratoire de Bactériologie, AP-HP Hôpital Lariboisière
Université Paris Diderot, IAME UMR 1137 INSERM
Paris, France
Juan Carlos Cataño
Section of Infectious Diseases
University of Antioquia Medical School
Medellín, Colombia
Leslie Chiang
Division of Tuberculosis Control
British Columbia Centre for Disease Control
Vancouver, British Columbia, Canada
Eric H. Choi
University of California Riverside School of Medicine and
Riverside Medical Clinic
Riverside, California
Amit Chopra
Division of Pulmonary and Critical Care Medicine
Albany Medical College
Albany, New York
Contributors xiii

Terence Chorba
Division of Tuberculosis Elimination
Centers for Disease Control and Prevention
Atlanta, Georgia
L. W. Preston Church
Ralph H. Johnson VA Medical Center
Charleston, South Carolina
Walter J. Coyle
Scripps Clinic Torrey Pines
La Jolla, California
John A. Crocco
UMDNJ—Robert Wood Johnson Medical School
New Brunswick, New Jersey
Charles L. Daley
Division of Mycobacterial and Respiratory Infections
National Jewish Health
Denver, Colorado
Thomas M. Daniel
Department of Medicine
Case Western Reserve University
University Hospitals Case Medical Center
Cleveland, Ohio
Arthur M. Dannenberg, Jr.
Department of Environmental Health Sciences
Department of Molecular Microbiology and Immunology
Department of Epidemiology
Johns Hopkins Bloomberg School of Public Health
Department of Pathology
Center for Tuberculosis Research
Johns Hopkins School of Medicine
Baltimore, Maryland
Bappaditya Dey
Center for Tuberculosis Research
Johns Hopkins School of Medicine
Baltimore, Maryland
Howard Hughes Medical Institute
Chevy Chase, Maryland
Thomas E. Dobbs
Mississippi State Department of Health
University of Mississippi Medical Center
Jackson, Mississippi
Claudia C. Dobler
Liverpool Hospital and South Western Sydney Clinical School
University of New South Wales
Woolcock Institute of Medical Research
xiv Contributors

University of Sydney
Sydney, New South Wales, Australia
Kelly E. Dooley
Johns Hopkins University School of Medicine
Divisions of Clinical Pharmacology & Infectious Diseases
Center for Tuberculosis Research
Baltimore, Maryland
Asim K. Dutt
Department of Medicine
Meharry Medical College
Nashville, Tennessee
Kevin Elwood
Division of Tuberculosis Control
British Columbia Centre for Disease Control
Vancouver, British Columbia, Canada
Jaime Esteban
Department of Clinical Microbiology
IIS-Fundación Jiménez Díaz, UAM
Madrid, Spain
André A. Figueiredo
Núcleo Interdisciplinar de Pesquisa em Urologia and Department of Surgery/Urology
Federal University of Juiz de Fora
Minas Gerais, Brazil
Jane M. Gould
Department of Pediatrics
Drexel University College of Medicine
Philadelphia, Pennsylvania
David E. Griffith
Heartland National TB Center
University of Texas Health Science Center-UT Health Northeast
San Antonio, Texas
Connie A. Haley
Division of Infectious Diseases and Southeast National Tuberculosis Center
University of Florida
Gainesville, Florida
Jonathan M. Hand
Department of Infectious Diseases
Ochsner Clinic Foundation
The University of Queensland School of Medicine
Ochsner Clinical School
New Orleans, Louisiana
Michael K. Hill
Saint Tammany Parish Hospital
Covington, Louisiana
Contributors xv

Carla Jeffries
Division of Tuberculosis Elimination
Centers for Disease Control and Prevention
Atlanta, Georgia
Aditya Jindal
Jindal Clinics
Chandigarh, India
Surinder K. Jindal
Department of Pulmonary Medicine
Postgraduate Institute of Medical Education & Research
Jindal Clinics
Chandigarh, India
James C. Johnston
Division of Tuberculosis Control
British Columbia Centre for Disease Control
Vancouver, British Columbia, Canada
Marc A. Judson
Division of Pulmonary and Critical Care Medicine
Albany Medical College
Albany, New York
Gregory C. Kane
Department of Medicine
Sidney Kimmel Medical College
The Korman Lung Center
Thomas Jefferson University
Philadelphia, Pennsylvania
Ijaz Kashef
Division of Global Health Protection
Centers for Disease Control and Prevention
Atlanta, Georgia
Won-Jung Koh
Division of Pulmonary and Critical Care Medicine
Department of Medicine
Samsung Medical Center
Sungkyunkwan University School of Medicine
Seoul, South Korea
Timothy Lahey
Dartmouth’s Geisel School of Medicine
Section of Infectious Diseases and International Health
Dartmouth-Hitchcock Medical Center
The Dartmouth Institute for Clinical Practice & Health Policy
Lebanon, New Hampshire
Gabriella S. Lamb
Baylor College of Medicine
Houston, Texas
xvi Contributors

Alfred A. Lardizabal
New Jersey Medical School Global Tuberculosis Institute
Rutgers University
Newark, New Jersey
John M. Leonard
Department of Medicine—Infectious Disease
Vanderbilt University Medical Center
Nashville, Tennessee
Michael K. Leonard, Jr.
Division of Infectious Diseases
Carolinas HealthCare System
Charlotte, North Carolina
James H. Lewis
Division of Hepatology
Department of Medicine
Georgetown University Hospital
Washington, DC
Phil LoBue
Division of Tuberculosis Elimination
Centers for Disease Control and Prevention
Atlanta, Georgia
Antônio M. Lucon
Division of Urology
University of São Paulo Medical School
São Paulo, Brazil
Sarah M. Lyon
Pulmonary, Allergy and Critical Care Division
Department of Medicine
Perelman School of Medicine
University of Pennsylvania
Philadelphia, Pennsylvania
Alberto Matteelli
Department of Infectious and Tropical Diseases
WHO Collaborating Centre for TB/HIV and TB Elimination
University of Brescia
Brescia, Italy
G. Shelton McMullan
Division of Gastroenterology
Georgetown University Hospital
Washington, DC
Jay B. Mehta
Department of Medicine
East Tennessee State University
James H. Quillen College of Medicine
Johnson City, Tennessee
Contributors xvii

Beverly Metchock
Division of Tuberculosis Elimination
Centers for Disease Control and Prevention
Atlanta, Georgia
Alladi Mohan
Division of Pulmonary and Critical Care Medicine
Department of Medicine
Sri Venkateswara Institute of Medical Sciences
Tirupati, India
Faiza Mougari
Centre National de Référence pour la résistance des Mycobactéries aux
antituberculeux
Laboratoire de Bactériologie, AP-HP Hôpital Lariboisière
Université Paris Diderot, IAME UMR 1137 INSERM
Paris, France
Maria-Carmen Muñoz-Egea
Department of Clinical Microbiology
IIS-Fundación Jiménez Díaz, UAM
Madrid, Spain
George A. Pankey
Department of Infectious Diseases
Ochsner Clinic Foundation
New Orleans, Louisiana
Charles Peloquin
Infectious Disease Pharmacokinetics Lab
College of Pharmacy
Emerging Pathogens Institute
University of Florida
Gainesville, Florida
Julie V. Philley
Department of Medicine
The University of Texas Health Science Center
Tyler, Texas
Laurel C. Preheim
Infectious Diseases Section
VA Medical Center
Departments of Medicine and of Medical Microbiology and Immunology
Creighton University School of Medicine
Omaha, Nebraska
Gary W. Procop
Department of Laboratory Medicine
Cleveland Clinic
Cleveland, Ohio
Meisha L. Raven
Department of Ophthalmology and Visual Sciences
University of Wisconsin School of Medicine and Public Health
Madison, Wisconsin
xviii Contributors

Florence Reibel
Centre National de Référence pour la résistance des Mycobactéries aux
antituberculeux
Sorbonne Université
Université Pierre et Marie Curie
AP-HP Hôpital Pitié-Salpêtrière
Centre d’Immunologie et des Maladies Infectieuses, Team 13, INSERM U1135
Paris, France
Lee B. Reichman
New Jersey Medical School Global Tuberculosis Institute
Rutgers University
Newark, New Jersey
Blanca I. Restrepo
UT Health Houston
School of Public Health at Brownsville
Brownsville, Texas
Jaime Robledo
Section of Mycobacteria Research
Corporación para Investigaciones Biológicas
Universidad Pontificia Bolivariana
Medellín, Colombia
Milton D. Rossman
Pulmonary, Allergy and Critical Care Division
Department of Medicine
Perelman School of Medicine
University of Pennsylvania
Philadelphia, Pennsylvania
Palash Samanta
University of Pittsburgh Medical Center
Infectious Diseases Section
Pittsburgh, Pennsylvania
Charles V. Sanders
Department of Medicine
Louisiana State University School of Medicine
New Orleans, Louisiana
David Schlossberg
The Lewis Katz School of Medicine at Temple University
The Perelman School of Medicine at the University of Pennsylvania
Philadelphia Department of Public Health
Philadelphia, Pennsylvania
Barbara J. Seaworth
Heartland National TB Center
University of Texas Health Science Center-UT Health Northeast
San Antonio, Texas
Contributors xix

Sorana Segal-Maurer
The Dr. James J. Rahal Jr. Division of Infectious Diseases
NewYork-Presbyterian/Queens
Flushing, New York
Weill Cornell Medicine
New York, New York
Surendra K. Sharma
Division of Infectious Diseases
Department of Medicine
All India Institute of Medical Sciences
New Delhi, India
Alan D.L. Sihoe
Department of Surgery
Li Ka Shing Faculty of Medicine
The University of Hong Kong
Hong Kong SAR, China
José Tiago Silva
University Hospital 12 de Octubre
Unit of Infectious Diseases
Madrid, Spain
Nina Singh
University of Pittsburgh Medical Center
Infectious Diseases Section
VA Pittsburgh Healthcare System and University of Pittsburgh
Pittsburgh, Pennsylvania
Giovanni Sotgiu
Clinical Epidemiology and Medical Statistics Unit
Department of Biomedical Sciences
University of Sassari
Sassari, Italy
Miguel Srougi
Division of Urology
University of São Paulo Medical School
São Paulo, Brazil
Jeffrey R. Starke
Baylor College of Medicine
Houston, Texas
Giorgia Sulis
Department of Infectious and Tropical Diseases
WHO Collaborating Centre for TB/HIV and TB Elimination
University of Brescia
Brescia, Italy
xx Contributors

Jeffrey A. Tornheim
Johns Hopkins University School of Medicine
Division of Infectious Diseases
Baltimore, Maryland
Urvashi Vaid
Department of Pulmonary and Critical Care Medicine
Thomas Jefferson University
Philadelphia, Pennsylvania
Christopher Vinnard
The Public Health Research Institute Center and Department of Medicine
New Jersey Medical School
Rutgers, The State University of New Jersey
Newark, New Jersey
C. Fordham von Reyn
Dartmouth’s Geisel School of Medicine
Section of Infectious Diseases and International Health
Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire
Risa M. Webb
Division of Infectious Disease
University of Mississippi Medical Center
Mississippi State Department of Health
G.V. “Sonny” Montgomery VA Medical Center
Jackson, Mississippi
Dominik Zenner
Centre for Infectious Disease Surveillance and Control
Public Health England
Institute for Global Health
University College London
London, United Kingdom
Preface

We are pleased to present the Seventh Edition of Tuberculosis and

Nontuberculous Mycobacterial Infections.
Tuberculosis remains epidemic in much of the world, causing several million
deaths each year. Although most of these deaths occur in developing nations,
the developed world continues to struggle with tuberculosis, with evolving chal-
lenges from drug resistance, immigration, immunosuppression, and the expand-
ing awareness of nontuberculous mycobacterial infection.
The previous structure of this book has been maintained. Section I presents
basic concepts of epidemiology, pathophysiology, diagnosis, medical and surgi-
cal therapy, resistant tuberculosis, vaccines, tuberculosis in enclosed populations,
and the role of the health department. Section II describes both classic and more
recently described clinical manifestations of tuberculous infection. Virtually every
organ system is included, as are the endocrinologic and hematologic compli-
cations of tuberculosis. Separate chapters address issues unique to pregnancy,
infants and children, HIV infection, and the immune reconstitution syndrome.
Section III comprises nontuberculous mycobacterial infection, with an overview
of clinical syndromes produced by these organisms as well as individual chapters
on Mycobacterium avium-intracellulare, M. fortuitum and other rapidly growing
mycobacteria, M. kansasii, M. marinum, and additional less common pathogenic
mycobacteria.
Four new chapters have been added. “The Role of Therapeutic Drug
Monitoring in Mycobacterial Infections” explores the vital importance of mon-
itoring serum levels of the antituberculosis drugs; “Crisis-Affected Populations
and Tuberculosis” describes the interrelationship of groups affected by social
upheaval; in “Diabetes and Tuberculosis” we see the growing influence of each
of these afflictions on the other; and “Biologic Agents and Tuberculosis” details
the effect of these increasingly used agents on the incidence of tuberculosis. In

xxi
xxii Preface

addition to the new chapters, every chapter has been thoroughly updated. New
clinical data impact our understanding of interferon gamma release assays, the
HIV-tuberculosis interaction, immune reconstitution inflammatory syndrome,
and extremely drug-resistant tuberculosis. The protean presentations of pulmo-
nary and extrapulmonary tuberculosis continue to challenge the clinician, as does
the growing list of nontuberculous mycobacterial pathogens. Epidemiologic is-
sues include airline-associated infection, the explosion of tuberculosis in areas of
the developing world, and the critical roles of the World Health Organization and
departments of public health in tuberculosis control.
We hope that this text continues to provide a complete and user-friendly re-
source for everyone—clinician, scientist, epidemiologist—involved in the diagno-
sis and treatment of tuberculosis and related infections.
I am grateful for the guidance, wisdom, and professionalism of the staff at
ASM Press, particularly Christine Charlip, Megan Angelini, and Greg Payne.

David Schlossberg, MD, FACP

 General
Considerations

I
Tuberculosis and Nontuberculous Mycobacterial Infections, edited by Schlossberg David, ASM Press, 2017.

18:36:01.
Tuberculosis and Nontuberculous Mycobacterial Infections, edited by Schlossberg David, ASM Press, 2017.

18:36:01.
 Tuberculosis and Nontuberculous Mycobacterial Infections, Seventh Edition
Edited by David Schlossberg
© 2017 American Society for Microbiology, Washington, DC
doi:10.1128/9781555819866.ch1

1
Thomas M. Daniel1

Tuberculosis in History: Did It

Change the Way We Live?

INTRODUCTION Captain among these men of death” (2). During the

Tuberculosis is one of the oldest of humankind’s plagues next 200 years this sobriquet would hold, as tuber-
(1). The genus of the causative organism, Mycobacte- culosis became a leading cause of death in Europe and
rium, may be millions of years old. Mycobacterium tu- North America. Then tuberculosis waned, as have all
berculosis probably emerged as a pathogen of our early disease epidemics, for reasons that remain unclear.
ancestors 20,000 to 15,000 years ago in east Africa. A unified concept of tuberculosis first emerged with
As humans peopled the globe, they took their diseases the work of Laënnec in the early 19th century, and from
with them, including tuberculosis. DNA of M. tubercu- that time forward one can recognize the impact that
losis and typical tuberculous lesions containing acid- this disease has had on the way we live. This impact
fast bacilli have been identified in both Egyptian and can be illustrated by the life stories of many individuals,
Peruvian mummies. Further documentation of the an- some often told, others less commonly recounted. A few
cient spread of tuberculosis is contained in ancient texts have been selected for this account.
and is documented at archeological sites.
As Europe emerged from the Middle Ages and the
Industrial Revolution swept into Europe and North IMPACT ON THE PRACTICE OF MEDICINE
America, the lives of inhabitants of those regions For scores of years the treatment of tuberculosis per-
changed dramatically. As computer chips, automobiles, vaded the practice of nearly every physician. Early ther-
and cell phones dominate our age, machines and urban apeutic regimens were intended to remove malevolent
living dominated in the 18th and 19th centuries. The humors and included bleeding, leeches, cupping, and
writings of classical Greek and Roman physicians make vesicants. Sir James Clark, physician to Queen Victoria
it clear that they recognized tuberculosis. Regarding and to the dying John Keats, estimated that pulmonary
the Middle Ages, little is known of most diseases, includ- tuberculosis caused about one-fifth of all deaths in
ing tuberculosis, although royal touching for scrofula Europe and North America in his era, the early 19th
began with Clovis in 496 and archeological sites have century. Clark was a moderate, and his therapy was
revealed bony evidence of the disease. During the 17th largely palliative. He urged restraint in bloodletting and
and 18th centuries, tuberculosis exploded with soaring advocated travel to salubrious climates. “The change of
prevalence. In 1680 John Bunyan described it as “the scene and the constant succession of new objects exert

1
Department of Medicine, Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, OH 44106.

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a direct and most beneficial influence,” he wrote (3). tuberculosis prevalence. Some of them had enormous
Later in that century Sir William Osler recommended influence on the practice of medicine in their times and
optimum nutrition and palliation of symptoms (4). later. Early in the van of these exceptional men of medi-
He also argued for removing patients to favorable envi- cine was René Théophile Hyacinthe Laënnec (10, 11).
ronments, citing the Adirondack experience of Edward Laënnec was born on 17 February 1781 in Quimper
Livingston Trudeau, who retreated to the wilderness, re- on the Brittany coast of France. Because his mother
covered his health, and opened his famous Adirondack was too ill with tuberculosis to care for him, he was
Cottage Sanitarium at Saranac Lake, NY. Trudeau ulti- placed with an uncle. When the latter died of tubercu-
mately succumbed to tuberculosis. losis, Laënnec was sent to the home of a physician un-
In the first half of the 20th century, tuberculosis cle in Nantes. There he began his studies of medicine in
sanatoria assumed a major position in medical care. In 1795, moving to Paris in 1801 to study at the École de
fact, by the mid-1950s, when the advent of chemo- Médicine at the Hôpital Charité under the tutelage of
therapy would lead to the rapid closing of these nearly pioneering anatomist Jean Nicolas Corvisart. In 1804,
ubiquitous institutions, there were 839 sanatoria in while near the end of his medical studies but still a
the United States, comprising more than 130,000 beds student, he presented a paper in which he challenged
for tuberculosis patients (5). The world’s first voluntary existing concepts and argued that disease manifested by
health agency, the National Association for the Study tubercles in whatever part of the body they were found
and Prevention of Tuberculosis, now the American was one disease that should be called tuberculosis.
Lung Association, was founded as an advocacy agency In 1816 Laënnec invented the stethoscope, for which
for sanatorium patients in 1904. he was widely acclaimed. Using his instrument he de-
The modern science of epidemiology owes much scribed most of the physical signs of pulmonary disease,
of its gestation to the work of Wade Hampton Frost. coining such terms as “ronchus” and “egophany,” which
Frost developed tuberculosis in 1918 and recovered are still taught to medical students. Laënnec published
in Asheville, NC, a much-favored location at that time. his work in 1819 under the title De l’Auscultation
In elegant studies of tuberculosis in Williamson County, Médiate; it was translated into English and extensively
TN, Frost first developed the concept of the index case, reworked by John Forbes in 1821 (12). The publication
now known to every epidemiologist and public health of this work and especially its translation into English
investigator (6). Mass radiographic surveys were a prom- mark the beginning of pulmonary medicine as a clinical
inent part of American and Canadian public health specialty.
efforts for two decades, from the mid-1940s until they Laënnec suffered from tuberculosis. He was undoubt-
were abandoned in the face of rapidly declining disease edly infected as a child. While in Nantes he incurred
incidence. a prosector’s wart when he inadvertently inoculated
Modern clinical practice relies upon data collected in his hand while performing an autopsy on an individual
randomized, controlled clinical trials to establish its who had died of tuberculosis. In Paris he increasingly
standards of care. The studies of tuberculosis treatment suffered from respiratory disease. He returned to his na-
protocols conducted by the British Medical Research tive Brittany in 1918 and recovered somewhat. Later he
Council are often cited as pioneering in this arena (7, imported bottles of air from Brittany to his Paris apart-
8). In fact, the first randomized, placebo-controlled, ment. Famous in his time and much sought for his clini-
double-blind clinical trial in the history of medicine cal expertise, he was elected to the French Academy of
was conducted in 1926 and 1927 at the William H. Medicine and, in 1824, made a Chevalier of the Legion
Maybury Sanatorium in Detroit, MI, by J. Burns of Honor. His tuberculous disease progressed, however,
Amberson, B. T. McMahon, and Max Pinner to evalu- and in April 1826 he returned to his beloved Brittany
ate the efficacy of sanocrysin, a gold salt, in treatment for the last time. Tuberculosis claimed his life at age 45
of tuberculosis (9). Twenty-four patients with tubercu- on 13 August 1826. It took from the world one of the
losis were randomly assigned by the flip of a coin to re- greatest physicians of the time, a man of then-unequaled
ceive injections of either sanocrysin or a saline placebo. clinical skills. One can only speculate on what more he
Only the one nurse giving the injections knew which might have contributed to medicine.
patients were in which group. When the results were
analyzed, sanocrysin was found to have no therapeutic
benefit but significant toxicity. IMPACT ON WORLD POLITICS
The life stories of many pioneering tuberculosis Tuberculosis is not prominent in the personal histories
physicians enrich our understanding of the era of great of many of the world’s historically notable politicians

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 1. TUBERCULOSIS IN HISTORY 5

and leaders. It took the life of France’s Louis XIII. So, the company’s holdings. He traveled between England
also, did tuberculosis bring premature death to Charles and South Africa to negotiate and lead the empire-
IX of England. More notably, in modern times, South building effort.
Africa’s Nelson Mandela developed tuberculosis while In 1902 the 49-year-old Rhodes became ill. The na-
a prisoner but recovered with drug therapy. In none of ture of this illness is not clear, although it was thought
these instances can one assert that the course of world that his heart was failing. Indeed, some biographers
history was altered. dispute the generally held belief that Rhodes had tuber-
The British Empire would seem to owe much to its ex- culosis, arguing that he suffered from congenital heart
plorers who went to Africa seeking relief from tubercu- disease (14); that assertion seems difficult to reconcile
losis. James Bruce, a Scotsman, discovered the Ethiopian with what is known of the course of his disease during
source of the Blue Nile in 1770. Mungo Park explored an often very active life. Rhodes died in South Africa,
West Africa in 1795. Both of these men set off on their a land he loved, on 26 March 1902.
adventurous journeys seeking relief from tuberculosis; Taking place in more recent times, the story of
travel was a common prescription for consumptives at Manuel Quezon and his leadership of the people of
that time. the Philippines reflects his battle with tuberculosis.
Cecil Rhodes brought South Africa under British he- Afflicted with the disease since his youth, he defied it
gemony; he had a lasting impact on the future course and ignored it through an active life of leadership that
of sub-Saharan Africa. When the 17-year-old Rhodes resulted in his election as the first president of the
arrived in South Africa in 1870, the region included Philippine Commonwealth in 1935. In fact, in his auto-
two Boer republics, two British colonies, two indepen- biography, completed during his terminal illness and
dent states, and a number of indigenous territories that published posthumously in 1946, Quezon makes but
England controlled as protectorates. Three years earlier scant reference to his illness (15). In 1927, while in
diamonds had been discovered, and the region was the United States lobbying for the appointment of a
booming with prospectors. Rhodes’s oldest brother, Philippine governor, he was found to have tuberculosis.
Herbert, had preceded him to South Africa by a year Quezon was hospitalized at the Pottenger Sanatorium
and become a planter. In the diamond frenzy, Herbert in Monrovia, CA, but was unhappy with his treatment
had staked a claim that was to yield enormous numbers there and left after a short stay. After the Japanese inva-
of the precious gems. sions of the Philippines in World War II, he left his coun-
Cecil Rhodes was born in Hertfordshire, England, on try to lead a government in exile, initially in Australia
5 July 1853 (13). He developed tuberculosis at age 16 and then in the United States. With his tuberculosis
and went to South Africa to join his brother because a again active, he conducted his government’s affairs from
sea voyage and change in climate were considered likely a cottage at Saranac Lake, where he died following a
to benefit his health. Indeed, he did regain vigorous massive hemoptysis in July 1944 (16).
health and within 2 years was managing his brother’s Josephine Baker, an African-American dancer, chan-
diamond mine. Herbert Rhodes sold his claim in 1873. teuse, and comic who exiled herself to France because
Cecil Rhodes, now a wealthy young man, returned to of racial segregation in American entertainment venues,
England to study at Oxford. His tuberculosis recurred was a remarkable woman, sometimes remembered for
about 6 months later, and within the year he was back dancing at the Folies-Bergère wearing only a bunch of
in South Africa and once more recovering his well-being. bananas (17). During the World War II Nazi occupa-
Rhodes’s business acumen was extraordinary. By tion of France, she was entertaining in Marseilles. The
his 35th birthday, he controlled more than 90% of French underground approached her with a request
South Africa’s diamond production and held a domi- that she serve as a courier of secret messages, exploiting
nant position in its gold mining industry. With some her freedom to travel and carry music on which in-
of his business colleagues, he founded the British South formation was transcribed in invisible ink. Having a
Africa Company. By force or negotiation, he obtained cough, she sought a physician’s order to be released
concessions from local tribal chiefs. In October 1889, from the obligations of a contract and go to Morocco.
Queen Victoria granted the company a royal charter. In- The physician obtained a chest radiograph that showed
vestors eagerly subscribed to its stock offerings. Rhodes bilateral tuberculosis. He told her to go to Morocco
envisioned expansion of his and England’s realms north- and to rest. She left Marseilles but did not rest: she
wards, but the Boer settlers fought this expansion vig- embarked on an espionage career that supported the
orously. Some native tribes revolted. Much of Rhodes’s French resistance effort throughout the German occu-
time and efforts went into consolidating and securing pation of France. Her selfless effort was recognized by

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the French government after the war with the award of He knew the art of felting, and he applied his skill to
Chevalier of the Legion of Honor. Her tuberculosis fur from pelts his hunting friends discarded. Soon he
remained quiescent throughout the rest of her life. had made a broad-brimmed felt hat, which he sold
Rhodes was an exceptional empire builder. Had he for a five-dollar gold piece. The Stetson hat was born.
lived longer, the British hegemony over much of Africa Today, no Western movie is complete without Stetson-
might have been extended further. Quezon and Baker wearing cowboys and cattle rustlers, white hats for
played roles in sustaining the resistance of those living heroes and black ones for villains.
under Japanese and German wartime occupation. Stetson relocated to Philadelphia, PA, where he
founded the John B. Stetson Company and built a fac-
tory. By 1906 he was producing two million hats a
IMPACT ON CIVIL SOCIETY year. He wintered in DeLand, FL, and in 1887 he be-
Not all history is political. The lives of ordinary citizens came a trustee of DeLand College. Two years later he
are often affected by the actions of not-so-ordinary indi- became president of the board of trustees. He donated
viduals. There are numerous instances in which tuber- generously to the college, and in 1889 DeLand College
culosis played a role in these actions and their impact. was renamed Stetson University (20).
Francis of Assisi emerged from prison wasted and an Athletes who made lasting marks on their sports also
apparent victim of tuberculosis (18). During the next suffered from tuberculosis. It took the life of Christopher
decade he led a life of poverty and ministry to the “Christy” (also called “Matty”) Mathewson, perhaps the
poor that led to his sainthood and the founding of the greatest baseball pitcher in the history of the sport (22).
Franciscan order. He succumbed in 1226. Saint Thérèse Pitching for the New York Giants in 1905, Mathewson
of Lisieux died of tuberculosis in 1897 at age 24. John won 31 games out of 39 starts. His earned run average
Harvard, whose 1638 bequest of 400 books and half of that year was 1.27. He worked 339 innings, striking out
his estate put his name on one of America’s most pres- 206 batters and walking only 64. In the World Series
tigious universities, died of tuberculosis. Tuberculosis against Philadelphia that year, he pitched 27 innings,
claimed the life of 43-year-old Louis Braille, who made won three shutouts, and had an earned run average of
writing available to blind persons, in 1852. Alexander 0.00. Mathewson slumped the following year; he was
Graham Bell, the telephone’s inventor, moved with his not well and was plagued by a cough. By 1909 he was
parents from Edinburgh, Scotland, to the putatively back in form, winning 37 games, 12 of them shutouts,
more salubrious Nova Scotia, Canada, in 1870 follow- and losing only 11. His earned run average for the year
ing the death of his two older brothers from tuberculo- was 1.43.
sis. Six years later he made the world’s first telephone Mathewson was born in Factoryville, PA, in 1880.
call. Desmond Tutu developed tuberculosis as a teen- In high school and on sandlots, he played baseball
ager and spent 2 years at the Rietfontein Chest Hos- whenever the opportunity arose. At Bucknell University
pital in South Africa, where he underwent collapse he starred on both football and baseball teams and also
therapy with pneumothorax. George Balanchine was distinguished himself academically. In 1900 he joined
ill with tuberculosis in 1935. Eleanor Roosevelt was the New York Giants to begin his record-setting career
hospitalized with tuberculosis in France as a young in major league baseball. Mathewson was an instant
woman. Ignoring the advice to seek further treatment star on the baseball diamond, success following success.
upon her return to the United States, she embarked In 1915, however, Mathewson began a slump that
on a disease-free, remarkable humanitarian life, only seemed irreversible. One bad year followed another; he
to succumb to disseminated tuberculosis at age 75 was often tired, coughing, and unwell. He dropped
in 1962. from the lineup to become a coach. In 1920 his doctors
John Batterson Stetson was born in Orange, NJ, in gave him the diagnosis of tuberculosis, and in July he
1830, the seventh of 12 children of Stephen Stetson, a went to Saranac Lake, hoping to recover his health. In
hatter (19–21). Apprenticed to the family hat business 1923 he was well enough to assume the position of
as a youth, he developed tuberculosis at about age 21. president of the Boston Braves, but the following year
A standard prescription of the day was travel to the found him back at Saranac Lake. He passed the re-
American West. Thus, Stetson headed west, settling mainder of his life there, succumbing to tuberculosis
first in St. Joseph, MO, were he worked in and later be- on 7 October 1925. Tuberculosis had claimed one of
came owner of a brickyard. The business flourished, baseball’s greatest legends, a 30-game winner in four
but his health did not, so after about 2 years he headed seasons and a Hall-of-Famer from the first year that
further west to Colorado. There he began making hats. institution opened.

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Alice Marble was one of the most outstanding fe- sis, the doctor said. Yet he lived to be 91 without fur-
male competitors in the history of tennis. Her life was ther evidence of the disease.
also touched by tuberculosis (23). Growing up in San Stephen Crane died at age 28 of tuberculosis, but he
Francisco, CA, she was a tomboy who loved sports— had produced his masterpiece, The Red Badge of Cour-
baseball initially but then tennis. Given a racquet while age, 4 years earlier. Amadeo Modigliani died of tuber-
in high school, she soon became the top female player culous meningitis in 1920 at age 35. Finnish composer
on the West Coast. At age 18 she made her debut at Ernst Mielck was said to have been Max Bruch’s favor-
Forest Hills in New York City, losing miserably in sin- ite student. He succumbed to tuberculosis when he
gles but winning the women’s doubles championship was 21 years old. Band leader Chick Webb, “First King
with fellow Californian Bonnie Miller. The following of Swing,” died of tuberculosis at age 34. What works
year she began working with Eleanor “Teach” Tennant, might the genius of these talented persons have yielded
the coach and lifelong friend who would shape her had their lives not been taken by tuberculosis?
raw talent into the form and skills that made her the Frédéric Chopin developed tuberculosis while a
greatest female tennis player of her time. young émigré in Paris. He struggled with his illness,
In May 1934 Marble collapsed during a tournament in constantly sick, slowly losing ground to the “Captain
France. She was carried from the court to the American of Death” but always productive. While seeking relief
Hospital at Neuilly, where she learned she had tuberculo- in Mallorca, Spain, with Georges Sand, his paramour,
sis. She would never play tennis again, was her doctor’s he wrote despairingly to his publisher:
prognosis. She returned to her native California and en-
tered Pottenger’s Sanatorium in Monrovia. An initial 6 I can’t send you the manuscript, for it’s not finished.
I have been sick as a dog these last two weeks; I caught
weeks stretched to 8 months. Marble, gaining weight and cold in spite of 18 degrees of heat, roses, oranges,
losing the physical fitness that had graced her athletic palms, figs and three most famous doctors of the is-
form, was despondent. Then one day she received a letter land. One sniffed at what I spat up, the second tapped
from Carol Lombard, whom “Teach” Tennant also where I spat it from, the third poked about and listened
coached and who had learned of Marble’s illness from how I spat it. One said I had died, the second that I am
dying, the 3rd that I shall die (24).
Tennant. Glamorous movie star Lombard had suffered
disfiguring wounds to her face in an automobile accident
but regained her movie stardom after multiple surgical Yet Chopin did compose while in Mallorca. He
struggled on, increasingly disabled, writing music and
procedures. “I made my career come true, just as you
can—if you’ll fight. If I can do it, so can you,” Lombard performing on the piano until he died at age 39 of pul-
wrote (23). Soon thereafter, Marble walked out of the monary insufficiency resulting from the destruction of
his lungs by tuberculosis.
sanatorium. In 1936 she won the U.S. women’s champi-
onship at Forest Hills. Her disease never recurred. Norwegian painter Edvard Munch was born in 1863
(25). Two weeks after his 13th birthday, tuberculosis
entered his life with a frightening episode of hemopty-
IMPACT ON CREATIVITY IN sis. He later wrote:
LITERATURE AND THE ARTS
The illness followed me all through my childhood and
Creative works of art, music, dance, and literature all youth—the germ of consumption placed its blood-red
express the lives of their creators, and thus tuberculosis banner victoriously on the white handkerchief (25).
in these lives affected their works. Some were greatly
afflicted by the disease, others less so or were treated In fact, he recovered and was then relatively well for
and fared well. And so it is that while the works of the next several years, until tuberculosis recurred when
some reflect their struggles with tuberculosis, the crea- he was 36. One lung was badly damaged, his doctor
tivity of others was little affected. George Balanchine told him, the other less so. He was repeatedly confined
developed tuberculosis shortly after his 1933 arrival in to tuberculosis sanatoria during his middle thirties.
New York City, but it had little influence on his life and Often ill, he lived on to reach the age of 80.
creativity. Igor Stravinsky suffered recurrent bouts of The effect of tuberculosis on Munch’s art is com-
tuberculosis before being treated and cured with newly plicated by his recurrent depression—probably manic-
developed drugs; he lived to be 88 years old. Sarah depressive bipolar disease—which also almost certainly
Bernhardt was given a diagnosis of tuberculosis as a affected his work. There is no doubt that these two
15-year-old but recovered to star on the stage and live illnesses, tuberculosis prominently of the two, had a
to be 78. Andrew Wyeth was ill as a child. Tuberculo- great impact on his work. In his words:

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 8 GENERAL CONSIDERATIONS

I must retain my physical weaknesses; they are an inte- Death from tuberculosis is also described in Jane
gral part of me. I don’t want to get rid of illness, how- Eyre, by Charlotte Brontë, in a passage set in a Cowan
ever unsympathetically I may depict it in my art. . . .
Bridge School:
My sufferings are a part of my self and my art (25).
I am very happy, Jane; and when you hear that I am
Munch often portrayed death. The Sick Child, dat- dead, you must be sure and not grieve; there is nothing
ing to 1885–1886, when Munch had recovered from to grieve about. We must all die one day, and the illness
his adolescent bout with tuberculosis and not yet been which is removing me is not painful; it is gentle and
gradual: my mind is at rest (30).
again stricken, evokes sympathy and serenity. The pale-
faced, red-headed child smiles at her grieving mother,
This part of Jane Eyre is considered by most scholars
a look of serenity on the girl’s face. Death in the Sick-
to be autobiographical, the dying Helen representing
room (1893), The Deathbed (1895), and Dead Mother
Charlotte Brontë’s sister Maria.
and Child (1899) portray quite different images of
Eugene O’Neill was America’s greatest dramatist.
death. They are somber, with gray and black tones,
His plays won four Pulitzer Prizes and the Nobel Prize.
and evoke grief and despair. Their mood is one of unre-
Critics uniformly acclaimed him. He had tuberculosis,
mitting sorrow. Munch was ill, in and out of tuberculo-
and the disease figures prominently in two of his plays.
sis sanatoria, during the years these paintings came
The Straw was written while he was a sanatorium pa-
from his palette.
tient, and it is loosely based on his experiences there. It
Literature is replete with descriptions of tuberculosis,
has not been considered one of his better works. Long
often reflecting the authors’ lives. John Keats, Anton
Day’s Journey into Night is frankly autobiographical
Chekhov, and W. Somerset Maugham all suffered from
and deals with the time when O’Neill was told he must
the disease, and it is reflected in their writings. Katherine
go to a tuberculosis sanatorium. It is a universally
Mansfield, on the other hand, was recurrently ill before
acclaimed masterpiece.
dying following a massive hemoptysis, but she did not
O’Neill was born on 16 October 1888, the youngest
mention tuberculosis in any of her many short stories.
of two surviving sons of successful actor James O’Neill
Striking examples of tuberculosis in literature are pro-
and Ellen O’Neill. The O’Neills were an Irish im-
vided by the novels of the Brontë sisters. The Reverend
migrant family with strong roots in Catholicism, but
Patrick Brontë was plagued with cough throughout the
their family life was disrupted by James O’Neill’s tours
84 years of his life. He almost certainly had chronic tu-
with theatrical companies. As in many Irish families in
berculosis (26, 27). He probably infected his wife and
America at that time, alcohol consumption was frequent
six children, all of whom succumbed to the disease.
and copious. Ellen O’Neill was addicted to opiates (31).
The three of his five daughters who survived to adult-
Eugene O’Neill’s life was marked by a variety of
hood wrote both prose and poetry. Their novels are
excesses and tragedies. Educated initially in boarding
icons of Victorian Age literature.
schools, he entered Princeton University in 1906. He mar-
Emily Brontë died in December 1848. Her death cer-
ried a casual girlfriend, whom he had impregnated—this
tificate stated that her illness was of 2 months’ dura-
would be the first of three marriages—but then deserted
tion, but the letters of her sister, Charlotte, make it
her, left Princeton, and spent more than a year as a sea-
clear that her illness was well established at an earlier
man and wanderer in South America. He returned to
date (28). Emily Brontë’s novel, Wuthering Heights,
divorce his wife and soon thereafter was stricken with tu-
was published in 1847. She may have been ill as she
berculosis. In a sanatorium he began writing plays (32).
was writing; certainly she knew tuberculosis well, for
O’Neill’s powerful, autobiographical drama, Long
she had watched her mother and two sisters, Maria and
Day’s Journey into Night, is set in 1912, the year in
Elizabeth, succumb while she was a child. Wuthering
which O’Neill was found to have tuberculosis, in an
Heights is an extraordinary literary work. A complex
oceanfront house presumably in New London, CT, the
tale of the struggle of good to overcome evil, the work
O’Neill family residence (33). The play was written in
is pervaded by tuberculosis. Malevolent Heathcliff
1940. Initially he asked that it not be published until
mourns the loss of Catherine Earnshaw, who dies of tu-
25 years after his death, but he later relaxed this in-
berculosis early in the book.
junction, and it was produced in 1956, 3 years after his
death. The action of the drama takes place in one day,
The doctor says she must go: he says she’s been in a
consumption these many months.…One night…a fit beginning with a sunny noon and progressing through
of coughing took her—a very slight one…her face a foggy afternoon to a dark midnight. True to the
changed, and she was dead (29). actual O’Neill family history, the Tyrone family of the

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 1. TUBERCULOSIS IN HISTORY 9

play consists of father James, an actor who cannot moved into the 20th and 21st centuries, tuberculosis in-
quite deal with the multiple problems in his family; cidence declined. Fewer dramatic instances of disease
mother Mary, fading from reality during the day and occurred. Yet it robbed baseball of the life of one of its
night as she takes additional amounts of opiates; their greatest athletes in 1925.
oldest son, James, Jr., a drunkard; and their youngest The practice of medicine has reflected the prevalence
son, Edmund, who has just been given a diagnosis of of tuberculosis over the course of time. During the
tuberculosis and told he must go to a sanatorium. Put- sanatorium era, an entire parallel health system de-
ting aside much of the powerfully presented multiple voted itself to the care of consumptives. Tuberculosis
dynamics of this dysfunctional family, Edmund’s tuber- has intruded upon the political arena, but its impact
culosis is central to the tense interactions of the Tyrone has been minor. That Quezon conducted the Philippine
family throughout the long day and night chronicled in government in exile from his bed in Saranac Lake cannot
the play (33). His plight is that his penurious father be said to have changed the course of war in the Pacific.
wants to send him to the “state farm” to avoid paying Josephine Baker’s espionage efforts were commendable,
the $7.00-per-day cost of a private sanatorium, where but the Allies would have won the war without them.
Edmund feels he would be better treated. “So why Civilian life produced more notable examples. Can one
waste money? That’s why you’re sending me to a state imagine John Wayne without a Stetson hat?
farm—,” Edmund challenges his father. His mother re- In the world of creative arts, the impact of tuber-
fuses to accept the diagnosis. “A summer cold makes any- culosis is most readily seen and was often dramatic.
one irritable… It is just a cold! Anyone can tell that!” The Brontë novels presented it prominently, but also
In actuality, Eugene O’Neill was initially hospital- as something not exceptional—as an ordinary, 19th-
ized at Laurel Heights, a Connecticut state farm for con- century, life-ending event. Edvard Munch’s depictions
sumptives, for 2 days before being transferred to highly of death certainly reflected his continuing struggle with
regarded Gaylord Farm Sanatorium on Christmas Eve the disease. No short life taken by tuberculosis is better
of 1912. O’Neill’s disease had begun about 2 months known than that of John Keats. Three months after the
earlier. It presented as pleurisy with effusion, a form of hemoptysis that led him to make his own diagnosis of
tuberculosis with a relatively favorable prognosis. And tuberculosis, he wrote:
O’Neill did well, being discharged after 6 months as
“arrested” (at that time, no patient was ever considered Darkling I listen, and, for many a time
cured, as relapses were common). O’Neill’s tuberculosis I have been half in love with easeful death,
Call’d him soft names in many a mused rhyme,
did not recur. However, he never forgot it during his To take into the air my quiet breath (34).
often tumultuous life, and it was three decades later
that he wrote his dramatic account of the diagnosis.
After an enormously productive if often anguished Citation. Daniels TM. 2017. Tuberculosis in history: did
it change the way we live?, p 3–10. In Schlossberg D (ed),
life, O’Neill died in November 1953 of what was then Tuberculosis and Nontuberculous Mycobacterial Infec-
called Parkinsonism but from a modern perspective tions, 7th ed. ASM Press, Washington, DC. doi:10.1128/
sounds more like Alzheimer’s disease. 9781555819866.ch1.

References
CONCLUSIONS
1. Daniel TM. 2006. The history of tuberculosis. Respir
Reflecting on the history of tuberculosis, let us now ask Med 100:1862–1870.
again, did it affect the way we lived? One must con- 2. Bunyan J. 1900. The Life and Death of Mr. Badman. RH
clude that it did, variously at various times, and some- Russell, New York, NY.
times only subtly. During the 19th century, the “Captain 3. Clark J. 1835. A Treatise on Pulmonary Consumption;
of Death” was present in the lives of many. Scarcely Comprehending an Inquiry into the Causes, Nature, Preven-
did a family not count a member or relative who was tion, and Treatment of Tuberculous and Scrofulous Diseases
afflicted. The tuberculous deaths of all six Brontë in General. Carey, Lea, and Blanchard, Philadelphia, PA.
children and their mother may have been remarkable— 4. Osler W. 1892. The Principles and Practice of Medicine.
D Appleton and Company, New York, NY.
perhaps the family carried one of the genetic polymor-
5. Davis AL. 1996. History of the sanatorium movement,
phisms that decrease native resistance—but it was not p 40–54. In Rom WN, Garay SM (ed), Tuberculosis.
out of keeping with the epidemiology of tuberculosis Little, Brown and Company, New York, NY.
at that time. Chopin struggled with his disease but con- 6. Puffer RR, Doull JA, Gass RS, Murphy WJ, Williams
tinued to compose and perform. As the course of history WC. 1942. Use of the index case in the study of tubercu-

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 10 GENERAL CONSIDERATIONS

losis in Williamson County. Am J Public Health Nations 21. Parker VA. August 1976. John B. Stetson, p 6.
Health 32:601–605. SANTA News.
7. Lilienfeld AM. 1982. The Fielding H. Garrison Lecture: 22. Robinson R. 1993. Matty. An American Hero. Christy
Ceteris paribus: the evolution of the clinical trial. Bull Mathewson of the New York Giants. Oxford University
Hist Med 56:1–18. Press, New York, NY.
8. Medical Research Council. 1948. Streptomycin treatment 23. Marble A, Leatherman D. 1991. Courting Danger: My
of pulmonary tuberculosis. BMJ 2:769–782. Adventures in World-Class Tennis, Golden Age Holly-
9. Amberson JB, McMahon BT, Pinner M. 1931. A clinical wood, and High Stakes Spying. St. Martin’s Press, New
trial of sanocrysin in pulmonary tuberculosis. Am Rev York, NY.
Tuberc 24:401–434. 24. Opienski H. 1931. Chopin’s Letters. Translated from
10. Daniel TM. 2004. René Théophile Hyacinthe Laënnec the Original Polish and French. Alfred A Knopf, New
and the founding of pulmonary medicine. Int J Tuberc York, NY.
Lung Dis 8:517–518. 25. Prideaux S. 2005. Edvard Munch. Behind the Scream.
11. Duffin J. 1998. To See with a Better Eye. A Life of R. T. Yale University Press, New Haven, CT.
H. Laennec. Princeton University Press, Princeton, NJ. 26. Gaskin EC. 1857. The Life of Charlotte Brontë. D
12. Laennec RTH. 1962. A Treatise on the Disease of the Appleton and Company, New York, NY.
Chest with Plates Translated from the French of R. T. H. 27. Macnalty AS. 1934. The Brontës: a study in the epidemi-
Laennec with a Preface and Notes by John Forbes. ology of tuberculosis. Br J Tuberc 28:4–7.
Hafner Publishing Company, New York, NY. 28. Spake M (ed). 1954. The Letters of the Brontës. A Selec-
13. Maurois A. 1953. Cecil Rhodes. Translated from the French tion. University of Oklahoma Press, Norman, OK.
by Rohan Wadham. Collins, London, United Kingdom. 29. Brontë E. 1946. Wuthering Heights. Random House,
14. Roberts B. 1987. Cecil Rhodes. Flawed Colossus. WW New York, NY.
Norton & Company, New York, NY. 30. Brontë C. 2003. Jane Eyre. Barnes & Noble Classics,
15. Quezon ML. 1946. The Good Fight. D Appleton-Century New York, NY.
Company, New York, NY. 31. Bowen C. 1959. The Curse of the Misbegotten. A Tale of
16. Taylor R. 1986. Saranac. America’s Magic Mountain. the House of O’Neill. McGraw-Hill Book Company, Inc,
Houghton Mifflin Company, Boston, MA. New York, NY.
17. Baker J-C, Chase C. 1993. Josephine. The Hungry Heart. 32. Carpenter FI. 1979. Eugene O’Neill. Twayne Publishers,
Random House, New York, NY. Boston, MA.
18. Moorman LJ. 1940. Tuberculosis and Genius. The Uni- 33. O’Neill E. 1956. Long Day’s Journey into Night. Yale
versity of Chicago Press, Chicago, IL. University Press, New Haven, CT.
19. Hubbard E. 1911. A Little Journey to the Home of John 34. Keats J. 1935. Ode to a Nightingale (orig. pub. 1812),
B. Stetson. The Roycrofters, East Aurora, NY. p 841–842. In Lowry HF, Thorp W (ed), An Oxford
20. Lycan GL. 1983. Stetson University: The First 100 Years. Anthology of English Poetry. Oxford University Press,
Stetson University Press, DeLand, FL. New York, NY.

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 Tuberculosis and Nontuberculous Mycobacterial Infections, Seventh Edition
Edited by David Schlossberg
© 2017 American Society for Microbiology, Washington, DC
doi:10.1128/microbiolspec.TNMI7-0018-2016

Jay B. Mehta1

2
Asim K. Dutt2

Epidemiology and Host Factors

Tuberculosis is an ancient infection that has plagued HISTORY

humans throughout recorded and archeological history. Tuberculosis appears to be as old as humanity itself.
It is always a surprise to those of us who live in West- Skeletal remains of prehistoric humans dating back to
ern countries that even today the infection remains the 8000 BC, found in Germany, show clear evidence of
cause of higher rates of morbidity and mortality than the disease. Egyptian skeletons dating back from 2500
any other infection in the world. This is because of its to 1000 BC have revealed evidence of Pott’s disease of
great prevalence in the densely populated developing the spine. Ancient Hindu and Chinese writings have
countries; however, the incidence of tuberculosis is documented the presence of the disease. From these
grossly underreported in these countries. According to descriptions, however, it is impossible to differentiate
estimates of the World Health Organization (WHO), in tuberculosis from diseases that produce similar pathol-
2014 there were approximately 9.6 million active ogy. Perhaps the best proof of tuberculosis has come
cases, of which 3 to 4 million cases were infectious, from an Inca mummy of an 8-year-old boy who lived
with positive sputum smears (1). Deaths due to tuber- about 700 AD. The radiographic picture of the lumbar
culosis occur in 1.5 million people worldwide each year spine showed evidence of Pott’s disease, and the smears
(1, 2). The estimates are that a death from tuberculosis of the lesion revealed acid-fast bacilli (AFB), most
occurs every minute. Thus, tuberculosis is still a major likely Mycobacterium bovis.
cause of disease and death, and its elimination will be Tubercle bacilli can remain viable for many years in
extremely difficult as long as poverty, overpopulation, the tissues of healthy persons. When they produce dis-
and multidrug-resistant (MDR) disease characterize ease, it runs a chronic and protracted course that gives
large portions of the earth. Human immunodeficiency ample time for transmission to susceptible hosts. The
virus (HIV) is already deemed the number one prevent- infection can produce disease in a human being after
able cause of death in developing countries (3). decades of dormancy. Thus, the infection becomes
The tubercle bacillus was discovered in 1882 and endemic when a large proportion of the population is
has been the subject of extensive research ever since. infected. It can produce an epidemic, however, when
There is still much to be learned about the nature of the introduced into a population of which only a small por-
organism, its virulence, its genetic characteristics, and tion is immunologically protected by already having
the response of the host to the infection. been infected. The history of tuberculosis in Europe

1
Department of Medicine, East Tennessee State University, James H. Quillen College of Medicine, Johnson City, TN 37614; 2Department of
Medicine, Meharry Medical College, Nashville, TN 37208.

11

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 12 GENERAL CONSIDERATIONS

and North America is better known for the past 150 In England the present epidemic wave began in the
years; however, there is a paucity of historic informa- 16th century and probably reached its peak in about
tion on the epidemiology of tuberculosis in other parts 1780 as a result of the Industrial Revolution and the
of the world (4). growth of cities, which allowed the spread of disease
from person to person. The epidemic then rapidly spread
from England to other large cities in Western Europe,
“EPIDEMIC WAVES” OF TUBERCULOSIS reaching a peak in the early 1800s. In Eastern Europe
When a new infection is introduced into a susceptible the peaks came in about 1870 and 1888, and by 1900
population, the morbidity and mortality rates take the North American and South American epidemic waves
predictable form of an epidemic wave (5). There is a had peaked. In the developing countries of Asia and
sharp rise to a peak, followed by a more gradual descent. Africa the wave has not peaked yet. Thus, as a global
For many infectious diseases this curve is measured in phenomenon, the epidemic is declining in one geographic
weeks or months, but for tuberculosis it is measured area while still rising or just reaching its peak in another.
in decades and centuries. Epidemiological information, Industrialization and overcrowding of the cities can
though incomplete, reflects the incidence and prevalence produce an epidemic of tuberculosis by bringing to-
of disease over a period of two or three centuries. gether large numbers of susceptible people and promot-
The waveform of the tuberculosis epidemic occurs ing transmission of Mycobacterium tuberculosis to new
by natural selection of susceptible persons and runs its hosts. In addition, psychological stresses of urban life
course in about 300 years. Grigg (5) has described, on may lower individual resistance to infection. Grigg (5)
hypothetical grounds, three separate curves of mortali- has published curves to show the major tuberculosis
ty (elimination of susceptible persons), morbidity (dis- waves in two contrasting imaginary settings, rural and
ease in the more resistant), and unapparent infections urban (Fig. 2). These communities are assumed to
(infection without disease in the highly resistant) remain isolated and to have a constant degree of urban-
(Fig. 1). The three curves peak successively at 50- to ization. From the graph, one can conclude that after
100-year intervals. With the decline of the epidemic, elimination of the susceptible persons, the survivors
the death rate declines first, followed by morbidity and, become relatively resistant and the epidemic starts to
finally, by unapparent infections. decline. The rate of decline is exponential, though

Figure 1 Theoretical concept of the development of tuberculosis (TB) in a community. Tu-

berculosis is assumed to appear for the first time at zero. The death rate, rate of morbidity,
and rate of contacts are shown in reference to a living population. All these curves show a
steep ascending limb and a prolonged exponentially decelerated descending limb. Adapted
from reference 5 with permission of the American Thoracic Society.

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 2. EPIDEMIOLOGY AND HOST FACTORS 13

Figure 2 Rate of tuberculosis mortality, morbidity, and contacts at two extreme theoretical
urban and rural settings. These two imaginary communities are assumed to remain isolated
from the rest of the world. The variation in death rates between countries or communities
can be explained by the difference in urbanization, both in time and in space. From reference
5 with permission of the American Thoracic Society.

factors such as war, famine, or flood may temporarily ated an ideal atmosphere for transmission of tuberculo-
interrupt it. The overall decline in morbidity and mor- sis. There is controversial evidence of the presence of
tality is persistent and is still continuing, though it may tuberculosis among the Native Americans until they
have leveled off some in the Western countries, owing were concentrated on reservations. This group reached
to immigration; however, it is difficult to separate the the peak in about 1910 as a consequence of urbaniza-
considerable influence of socioeconomics and cultural tion and crowding, which favored easy spread of the
improvement from racial and genetic factors in the dra- infection.
matic improvement in tuberculosis in the developed Thus, the epidemic of the disease in North America
world (6). started with the earliest peak in the Northeast and then
In the United States tuberculosis was increasing in traveled to the Midwest, Southwest, and West. The
the 17th century. The first available mortality figures Native Americans and Alaskans were the last American
from Massachusetts in 1876 indicated 300 deaths per populations to become involved. From the data from
100,000 population. The peak mortality figure reached the original epidemic, it is obvious that the disease has
in New England was 1,600/100,000 per year in 1800. been in steady decline for more than 100 years, even
With industrial development, the epidemic traveled to though the mortality rate was 113/100,000 per year in
the Midwest years later. The peak was reached in New 1920. At that time tuberculosis was the second most
Orleans, LA, in 1840 and in the West in 1880. Though common cause of death in the United States. The im-
the disease occurred in blacks at a lower rate than in pact of isolation of tubercle bacilli, tuberculin testing,
whites before the Civil War, thereafter, the increase was vaccination with bacillus Calmette-Guérin (BCG), and
massive among blacks, with a peak of 650/100,000 per chemotherapy on the decline of the incidence of tuber-
year in 1890, when emancipation and urbanization cre- culosis has often been exaggerated; the rate of decline

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 14 GENERAL CONSIDERATIONS

ber of organisms in the airborne aerosol also depends

on the expulsive force of the cough and the presence of
cavitation in the lungs (7–9) (Fig. 4).
Other methods of transmission are rare. In the past,
transmission of infection with Mycobacterium bovis
through consumption of milk from infected cows was
common, but this means has been brought under con-
trol in all developed countries by elimination of dis-
eased cattle and pasteurization of milk and milk
products. Transmission is still prevalent in developing
countries due to consumption of unpasteurized milk,
poorly heat-treated meat, and closer contact with in-
fected animals (10). A recent genetic fingerprinting
technique has revealed human-to-human transmission
of M. bovis among HIV-infected persons in hospitals.
Although less frequent, M. bovis as a causative orga-
nism for tuberculosis is identified also in developed
Figure 3 Tuberculosis mortality rates per 100,000 persons countries. Approximately 7% of tuberculosis cases in
in the United States. SM, streptomycin. Adapted from refer- San Diego, CA, are caused by M. bovis (11). The
ence 116 with permission. national TB Genotyping Service isolated M. bovis in
1.4% of 11,860 linked cases during the period from
was well established before the advent of any of these 1995 to 2003. Mostly involved was extrapulmonary
factors (Fig. 3). It does appear that discovery of isonia- disease in young, U.S.-born Hispanics, indicating that
zid (INH) has considerably sharpened the natural infection was possibly related to foodborne exposure
decline in both the morbidity and mortality rates of (12). Tuberculin skin test (TST) conversions among
tuberculosis and has led to a decline in the prevalence contacts revealed the same airborne transmission as in
of the infection in the population (3). M. tuberculosis, regardless of the route of infection
(13). Mycobacterium africanum is commonly found in

TRANSMISSION OF TUBERCULOSIS
Although tuberculosis can affect any organ of the body,
the lungs are virtually always the portal of entry. The
bacilli are most commonly discharged into the atmo-
sphere by aerosolization of pulmonary secretions by a
diseased pulmonary patient in coughing, sneezing,
speaking, and singing. Aerosol droplets dry rapidly,
leaving tiny droplet nuclei, some of which contain a
few bacilli (7). Large droplets fall to the floor, but
droplet nuclei in the range of 1 to 10 μm can be
inhaled, with the larger ones trapped in the upper nasal
passages or expelled into the pharynx by the muco-
ciliary mechanism of the lower respiratory tract and
harmlessly swallowed and digested; smaller droplet
nuclei may reach the alveoli and establish infection.
Droplet nuclei carrying tubercle bacilli are produced by
patients with active pulmonary tuberculosis in propor-
tion to the liquidity of the secretions and the number of
bacilli excreted; i.e., they are most numerous in persons
with a productive cough and positive sputum smears
(8). In several classic studies, Riley (9) showed that Figure 4 Major factors that determine transmission of infec-
droplet nuclei from smear-positive tuberculosis patients tion from a source case to contacts and natural history of tu-
could infect guinea pigs in the environment. The num- berculosis in infected contacts.

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 2. EPIDEMIOLOGY AND HOST FACTORS 15

West African countries, where it is an important oppor- Several virulence factors have been identified. Some
tunistic pathogen in patients immunosuppressed due to of them are mycolic acid glycolipids, which can elicit
HIV infection. granuloma formation; catalase-peroxidase, which re-
Although aerosolization of organisms during manip- sists the host cell response; and sulfatides, trehalose
ulation of tuberculous lesions has been implicated in dimycolate, and lipoarabinomannan, which can induce
new infections among health care workers (14, 15), cytokines. Newer virulence factors have been reported
such infection from handling contaminated fomites is in last few years. Genetic analysis of sibling pairs was
not a problem; however, infection can occur by way of used to evaluate genetic markers in one study (20).
inoculation when bacilli are introduced into or through Genotyping of M. tuberculosis isolates has shown a
the skin. Infection from this source is an occupational number of clades that account for certain new cases in
hazard among pathologists and laboratory workers different geographic regions; for example, one strain
who must handle infected issues and tuberculous called CB3.3 was responsible for 10% of new cases in
cultures. Fomites such as books, clothes, bedding, and New York City between 1992 and 1994 (20). For fur-
eating utensils are not involved in the spread of infec- ther details on the subject of mycobacterial virulence,
tion and need no special attention. see chapter 3.
Tuberculosis is clearly an airborne disease due to in-
fection via droplet nuclei in the majority of patients
(16). The close contacts of a smear-positive patient are IMMUNOLOGIC CONSIDERATIONS
at maximum risk of being infected; however, the disease Infection with tubercle bacilli evokes cell-mediated im-
is not as highly infectious as some of the viral infections. munity (CMI) 2 to 8 weeks after infection. Activated T
The ability of the bacilli to cause infection in newly ex- lymphocytes and macrophages form granulomas. Gran-
posed contacts depends on the adequacy of the innate ulomas inhibit replication and spread of organisms (22).
antibacterial defenses of the person. Studies have shown The organisms become sequestered in the granulomas as
that the infection rate among close contacts ranges from dormant foci, which remain contained, and active dis-
25 to 50% even under the worst overcrowded and sub- ease may not occur in the majority of infected persons.
standard conditions (17, 18). In one study the infection CMI against M. tuberculosis evokes development of
rate of 8.9% in close contacts of smear-negative, cul- a positive TST. Alveolar macrophages infected with
ture-positive patients was comparable to that in the M. tuberculosis interact with T lymphocytes through
community (19); however, prolonged close contact with several important cytokines. The macrophages release
such a person can be dangerous. On the basis of epide- interleukins, which stimulate T lymphocytes (mostly
miological data, it appears that exposure generally must CD4-positive lymphocytes) to release gamma inter-
be close and sustained, the environment heavily laden feron (22–24). Gamma interferon stimulates phagocy-
with droplet nuclei, and the prospective host un- tosis of M. tuberculosis in the macrophage (25, 26). It
protected by inborn defenses, previously activated im- may not directly kill M. tuberculosis in the macro-
mune mechanisms, or both if an infection sufficient to phages, partly because the organisms inhibit the cyto-
produce disease is to be established (Fig. 4). Deposition kines’ transcriptional responses (27, 28). Gamma
of M. tuberculosis in the lungs leads to one of four like- interferon is essential for the control of M. tuberculosis
ly outcomes: (i) quick clearance of mycobacteria, (ii) infection (29). The major histocompatibility complex
primary disease, (iii) latent infection, and (iv) reactiva- influences T-cell response, which is antigenic specific
tion of the disease after many years. What happens to (22, 29). The initial host immune response contains
an individual patient who is exposed to the mycobacte- M. tuberculosis infection. Depending on the adequacy
rium depends upon many factors, including number of of CMI, the organisms become sequestered in dormant
organisms, their virulence, host factors, T-cell response, foci and cause no clinical disease in approximately
delayed immunity, and nutritional status (20). 90% of infected persons. Such a person is infected with
these bacilli but not diseased. If the immune response
Virulence of Mycobacteria fails, active disease may occur in some of the remaining
An outbreak involving extensive transmission of a 10% of infected persons; 5% may experience early pro-
virulent strain was reported from two counties in gressive disease within 5 years of exposure. In heavy
Tennessee and Kentucky. Three active cases were re- exposures in hospital personnel, the risk of tuberculosis
sponsible for infecting 311 contacts and five new cases has been shown to be 15% within the first year if the
after a brief contact (21). Several such outbreaks have personnel are not treated prophylactically with isonia-
been reported with newer strains of mycobacteria. zid (INH) (30). The remaining 5% may experience late

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 16 GENERAL CONSIDERATIONS

recrudescent disease after several decades of infection As tuberculosis was declining until 1984 in the
(Fig. 4) (31). Subsequent development of active disease United States, the increased morbidity in elderly pa-
from reactivation of remote infection depends upon tients was remarkable (the end of epidemic wave). The
several factors affecting the host immune response. age distribution of tuberculosis cases in Arkansas over
Immunosuppression with HIV is the greatest single risk the previous 20 years had undergone a dramatic shift
factor. Other medical conditions affecting the immune from more cases in the first decade of life to almost
system, such as uncontrolled diabetes mellitus, chronic no first-decade cases and more than 50% of cases
renal failure, and vitamin D deficiency, may lead to pro- occurring in persons over the age of 65 (40). The great
gression of the disease (32–34). Studies on the immune majority of these cases result from recrudescence of in-
system are unraveling defects which may influence sus- fection acquired many years earlier (41). Between 1985
ceptibility and development of disease. Researchers and 1992, persons 25 to 44 years of age accounted for
have detected defects in the production of gamma inter- more than 80% of the total increase in the number of
feron (24, 35), tumor necrosis factor (TNF) (36, 37) de- cases (42). Considerable evidence has documented the
ficiency in the gamma interferon receptor (38), and linkage of tuberculosis with HIV/AIDS (43, 44). Dor-
interleukin 12 receptor B1 (39). The clinical implica- mant tuberculosis infection progresses to active disease
tions of these findings should be excitingly informative. in persons infected with HIV at a rate of 10% per year.
Furthermore, HIV-infected persons are highly suscepti-
ble to exposure to tuberculosis (45).
RISK FACTORS FOR TUBERCULOSIS With further decline in tuberculosis rates in the
Various factors may influence the risk of developing United States between 1993 and 2008, there is a declin-
tuberculosis in an individual or a population. The age ing trend in tuberculosis rates in all age groups. In
and sex variables are also influenced by the timing 2008, the rates tended to increase with age from a low
of the epidemic in the population (Fig. 5). In the devel- of less than 2 per 100,000 in children to a high of 9 per
oping world tuberculosis rates are highest among 100,000 in men 65 years and older. The rates in men
young adults, indicating primary transmission in this 45 years and older were approximately twice those in
age group. same-age women (46) (Fig. 6).

Figure 5 Tuberculosis mortality by age and sex—a theoretical presentation. A, Period at

height of epidemic; B, period at intermediate state; C, period at end of wave. Adapted from
reference 5 with permission of the American Thoracic Society.

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 2. EPIDEMIOLOGY AND HOST FACTORS 17

Figure 6 Tuberculosis case rates by age group and sex, United States, 2014. Rates tended to
increase with age. The rates in men 45 years or older were approximately twice those in
women of the same age. Reprinted from reference 46.

Industrialization and urbanization provide optimal tuberculosis and HIV infection because of socio-
conditions for transmission owing to crowded living economic status and overcrowding. This combination
conditions with deplorable sanitation and housing. In of circumstances increases tuberculosis reactivation and
all phases of an epidemic the urban areas show higher person-to-person transmission (49). Indeed, for several
rates, and the peak is earlier there than in rural areas. years, 12% of new prisoners were infected each year
Overcrowding of poor and ill-nourished people in the in one prison before the epidemic was discovered and
ghetto areas of large cities continues to produce a rela- terminated by wide application of prophylactic treat-
tively high incidence of disease owing to a greater ease ment with INH (50). Patients in chronic mental
of transmission of the infection. In the United States hospitals and nursing homes experience an incidence
there was a 20% increase in reported cases from 1985 of tuberculosis 10 times greater than that among the
to 1992. Most of the increase of tuberculosis occurred general population (51). Danish workers found that
in cities with populations greater than 500,000 (47). among natural tuberculin reactors, the case rate was
Among the urban poor, the homeless have been identi- 29/100,000 per year, but the risk was 30 times greater
fied as another risk group (47, 48). in persons with abnormal results on chest radiographs
Socioeconomic status and tuberculosis morbidity (52). The risk was only two times greater in persons
have an inverse relationship, although there are many with nothing more than calcified residuals of a primary
factors involved, such as racial differences, crowding, infection.
and availability of health care. The case rate of those in Substance abuse is a common behavioral risk factor
the lowest median income group is approximately among patients with tuberculosis in the United States
eight times that of persons in the highest median in- (53). Injection drug abuse contributes to the high prev-
come group (49). The increased incidence in prisons alence of tuberculosis among drug users (54, 55).
reflects several of these factors: the prevalence of infec- Alcoholics have been found to have a risk of devel-
tion is higher among new prisoners than in the general oping tuberculosis 10 times higher than that of the gen-
population of similar age because there is a weighing eral population in urban areas (56). This risk of active
of prisoners toward the lower end of the socio- tuberculosis is substantially elevated in persons who
economic scale. The close living arrangements also consume more than 40 g of alcohol per day (57).
make transmission to new hosts more likely than in Cigarette smoking increases a relative risk of 1.5 to
normal living. Prisoners are at a greater risk for both 2.0 for the development of tuberculosis (58). Smoking

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18:34:21.
 18 GENERAL CONSIDERATIONS

has been found to be associated with both risk of re- and 7. The mortality rate has shown a steeper decline
lapse of tuberculosis and higher morbidity (59, 60). since the introduction of chemotherapy in 1945. The
Other factors associated with an increased risk of number of tuberculosis cases declined from 84,304 in
developing tuberculosis are HIV infection, diabetes 1953 to 22,255 in 1984 at a rate of 5% per year, for a
mellitus, lymphoma, any chronic debilitating disease, rate of 9.3/100,000 population. The trend reversed dra-
gastrectomy, cancer, silicosis, malnutrition, and immu- matically in 1985. The numbers rose by 3% in 1986, by
nosuppressive therapy. Drugs that inhibit TNF-alpha 5% in 1989, and by 6% in 1990. In 1992, there were
and its receptor are becoming an important risk factor 26,673 reported cases, for a rate of 10.5/100,000 popu-
in the developed nations. As the incidence of diabetes is lation, a 9.4% increase from the previous year. As a
increasing in Southeast Asia, its influence on TB inci- result, it was estimated that over 52,100 excess cases
dence is noticeable (61). Presently, however, HIV infec- occurred between 1985 and 1992 (42).
tion is the strongest risk factor throughout the world The resurgence of tuberculosis between 1985 and
(62–64). 1992 depended on several factors, including knowledge
of the physician, social forces (poverty, homelessness,
drug abuse, and incarceration), evidence of drug-
GENETIC FACTORS resistant cases, increase in immigration from countries
Patients may have a genetic predisposition toward tu- that had a high prevalence of disease, and the political
berculosis. Studies among monozygotic and dizygotic and economic priorities of the nation, i.e., availability
twins (65) and observations regarding tuberculosis risk of the resources of tuberculosis control (74). As tuber-
according to ancestral history (66) have raised consider- culosis declined in the country, several factors were
ation of genetic susceptibility. It also appears that race responsible for the resurgence in 1992 at its peak.
may play a role in individual risk of infection. In studies Public health programs were limited due to decreased
of both nursing home and prison populations, blacks federal funding for tuberculosis control. New public
were twice as likely to become infected as whites under health programs resulted in diversion of funds, and
similar conditions of exposure (67). In vitro studies sup- many state and city governments downgraded their tu-
port these observations: monocytes from black donors berculosis control programs and supervision of chemo-
are relatively permissive of mycobacterial growth (68, therapy. The excess cases of tuberculosis shook the
69). Some correlation of histocompatibility types with authorities, public, and physicians; however, this un-
development of tuberculosis has been observed (70). precedented resurgence of tuberculosis was also due to
Associations between tuberculosis and some HLA tuberculosis occurring in persons with HIV infection.
alleles have been found, as well as polymorphisms in HIV infection had become the most important risk fac-
the genes for natural resistance-associated macrophage tor for tuberculosis (42, 75). In tuberculin-positive
protein (NRAMPI), the vitamin D receptor, and inter- persons, tuberculosis is the first infection to develop,
leukin 1 (34, 71, 72). Although the role is not clear, long before the common opportunistic infections occur.
NRAMPI polymorphism could influence tuberculosis It is important to note that tuberculosis is one of the
susceptibility by regulation of interleukin 10 (73). This very few diseases of HIV-infected persons that can be
may differ with ethnic origin. To what extent these ob- transmitted to healthy persons. Utilizing a new molecu-
servations have influenced the global tuberculosis bur- lar epidemiology technique, restriction fragment length
den remains unclear. It is difficult to separate lifelong polymorphism (RFLP), showed that 40% of cases were
environmental influences from genetic predisposition, due to recent transmission rather than reactivation of
and this should be a fruitful area for future research. previously acquired infection (76). A subsequent RFLP
study indicated a decrease in recent transmission to 19
to 32% in many parts of the country (77).
MORTALITY AND MORBIDITY DATA Other important factors were the size of the popula-
tion and the social organization of the community.
Global Epidemiology Case rates were twice as high in large cities as in
The global epidemiology of tuberculosis is discussed in smaller ones and rural areas. Tuberculosis rates in ur-
detail elsewhere (see chapter 12). ban areas increased 28.6% during this 8-year period
(22 cases/100,000), while the rate of tuberculosis in
Epidemiology in the United States nonurban areas fell by 3% (6.5 cases/100,000) (78).
In the United States, tuberculosis mortality and morbid- Tuberculosis in the United States progressively had
ity rates have been falling steadily, as shown in Fig. 3 become a disease of the elderly, the foreign-born, and

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 2. EPIDEMIOLOGY AND HOST FACTORS 19

Figure 7 Reported tuberculosis (TB) cases, United States, 1982 to 2014. The resurgence of
TB in the mid-1980s was marked by several years of increasing case counts until its peak in
1992. Case counts began decreasing again in 1993, and 2014 marked the 22nd year of de-
cline in the total number of TB cases reported in the United States since the peak of the re-
surgence. From 1992 until 2002, the total number of TB cases decreased 5% to 7%
annually. From 2002 to 2003, however, the total number of TB cases decreased by only
1.4%. An unprecedented decrease occurred in 2009, when the total number of TB cases de-
creased by more than 10% from 2008 to 2009. In 2014, a total of 9,421 cases were reported
from the 50 states and the District of Columbia. This represents declines of 1.5% from 2013
and 64.7% from 1992.

minorities (79). The proportion of cases among minori- born persons with tuberculosis in the 25- to 44-year-old
ties rose from 24% in 1953 to 49% in 1987. The ratio age group were HIV seropositive (45).
of incidence in nonwhites to that in whites had risen Although the largest increase in tuberculosis cases
steadily from 2.9 in 1953 to 5.3 in 1987 (79). The age occurred in blacks and Hispanics aged 25 to 44 years,
distribution of tuberculosis cases indicated profound the age group in which excess AIDS cases also occur,
changes in the racial and ethnic composition. For all an increase among foreign-born persons was also
age groups under 65, tuberculosis was predominately a reported. Thus, factors other than HIV infection had
disease of the minorities, while cases involving non- also contributed to the increase in morbidity. Between
Hispanic whites predominated in persons above age 1986 and 1993, the tuberculosis case rate among the
65 (80). Between 1985 and 1992, 62% of the cases foreign-born increased to 30.1/100,000, compared with
occurred in black and Hispanic populations. The rate 8.1/100,000 for native residents (78, 81).
of tuberculosis among blacks rose to 37.8% (31.7/ Fortunately, the case rate of tuberculosis in the United
100,000 population) (78). According to the Centers for States resumed declining steadily in 1992, from 10.5/
Disease Control and Prevention (CDC), 47% of U.S.- 100,000, which represents a peak after 7 years of resur-

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 20 GENERAL CONSIDERATIONS

gence, to 4.2/100,000 population in 2008. In 2014, a epidemiological sign. From 1992 through 2008, tuber-
total of 9,421 cases were reported from the 50 states culosis case rates declined every year. This was achieved
and the District of Columbia (Fig. 7) (46). This decline by starting four appropriate drug regimens (72 to 87%,
most likely resulted from reinfusion of federal funds for 1993 to 2008) given as directly observed therapy, which
tuberculosis control programs, improved public health rose from 36% in 1993 to 88% in 2008. Completion
efforts, physician and patient education, and implemen- of treatment was in less than a year (from 64 to 84%,
tation of directly observed therapy; however, in 2008, 1993 to 2008) (46). Reporting of new cases improved
59% of the reported patients were born in another during this period (46). There was also considerable im-
country or in a U.S. territory. Half of them had devel- provement in HIV testing (from 46 to 72% in persons
oped disease within 5 years of their arrival to the United between 25 and 44 years old and 30 to 62% in persons
States, and most of them were under the age of 35 years of all ages). Coinfection of tuberculosis and HIV during
(46). The tendency of tuberculosis to be concentrated in the period from 1993 to 2014 was reduced from 63% to
younger age groups among minorities consisting of 9% in persons aged between 25 and 44 years and from
blacks, Hispanics, and the foreign-born is an ominous 48% to 6% for all ages (Fig. 8). Also, drug-resistant

Figure 8 Estimated HIV coinfection in persons reported with tuberculosis (TB), United
States, 1993 to 2014. Shown are minimum estimates of HIV coinfection among persons
reported with TB from 1993 through 2014. Since the addition of the request for HIV status
to the individual TB case report in 1993, incomplete reporting has provided a challenge to
calculating reliable estimates, although reporting improved substantially beginning in 2011.
Results from the cross-matching of TB and AIDS registries have been used to supplement
reported HIV test results. For all ages, the estimated percentage of HIV coinfection in
persons who reported HIV testing (positive, negative, or indeterminate test results) with TB
decreased from 48% to 6% overall from 1993 to 2014 and from 63% to 9% among persons
aged 25 to 44 years during this period.

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 2. EPIDEMIOLOGY AND HOST FACTORS 21

cases declined between 1993 and 2008. MDR (resis- of reported cases of tuberculosis decreased in every age
tance to INH and rifampin) declined from 402 cases in group, race, and ethnicity and for both sexes; however,
1993 to 86 in 2008. Primary MDR tuberculosis de- despite improvement in rates of directly observed
creased from 2.3% in 1993 to approximately 1.1% in therapy, timely completion of treatment, and equaliza-
2007 to 2008. There is no apparent trend in the number tion of MDR tuberculosis rates, there are still some
of extremely drug-resistant tuberculosis cases between disparities in these groups (Fig. 9).
2003 and 2008. Ten cases were reported in 1993, and In 2008, the number of tuberculosis cases dropped
four cases were reported in 2008. In 2008, the number to 12,904, a case rate of 4.2/100,000 population,

Figure 9 Tuberculosis cases by race/ethnicity in the United States, 2014. A total of 83% of
reported cases occurred in racial ethnic minorities, whereas 17% of cases occurred in non-
Hispanic whites. Hispanics are the largest group. Data from reference 46.

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 22 GENERAL CONSIDERATIONS

which was a 3.8% decrease from 2007; this trend has 100,000. Tuberculosis incidence among foreign-born
continued during the period from 2009 to 2015, with a persons in the United States (15.1 per 100,000) has
reduced rate of decline. In 2008, the rate decreased in remained 13 times higher than the rate (1.2) in U.S.-
35 states (3.5/100,000). Among 11 states that supplied born persons (Fig. 10). In 2014, the CDC reported
information on cases during the period from 2003 to 9,421 new cases, which represents a 2.2% decline from
2009, California, New York, and Texas accounted for the value for 2013. Asians continue to have the highest
49% of cases. The data indicate a decreased number of case rate (17.8 per 100,000) among all racial or ethnic
tuberculosis cases among U.S.-born persons and an groups (82).
increased number among foreign-born persons (46). In The tuberculosis mortality rate has been decreasing
2014, the proportion of tuberculosis cases in persons in the United States since the middle of the 20th
born outside of the United States further increased to century. During the prechemotherapy period, the rate
66%; this figure accounted for 47% of the total declined from 194.4/100,000 persons in 1900 to 70/
reported cases nationally. Preliminary data from 2014 100,000 in 1930 and then to 40/100,000 persons in
to 2015 indicate some leveling of this decline; tubercu- 1943. The natural decline may be due to the epidemic
losis incidence remained steady at 3.02 new cases per wave and natural history of the disease, in addition to

Figure 10 Number of tuberculosis (TB) cases in U.S.-born versus foreign-born persons,

United States, 1993 to 2014. This graph illustrates the increase in the percentage of cases
occurring in foreign-born persons during this period, from 29% in 1993 to 66% in 2014.
Overall, the number of cases in foreign-born persons remained virtually level, with approxi-
mately 7,600 to 8,000 cases each year until 2009, when the number dropped to 6,961. That
decreasing trend continued until 2013, with the number of foreign-born cases dropping to
6,189. However, in 2014, the number of foreign-born cases increased to 6,215. The number
in U.S.-born persons decreased from more than 17,000 in 1993 to 3,188 in 2014.

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 2. EPIDEMIOLOGY AND HOST FACTORS 23

improved socioeconomic conditions and public health high prevalence of infection, but they have little place
intervention. As noted above, the mortality rate has in the United States today. In prisons and nursing
shown a steeper decline since the introduction of che- homes it is more practical first to identify those who
motherapy in 1945 (83). After 1954, it reached a low are infected by the use of the TST and to perform X-ray
single-digit figure by 1965 (Fig. 7), and the rate examinations on all reactors to search for active dis-
continues to be low. ease. Thereafter, new infections can be determined by
The case rate for extrapulmonary tuberculosis in the purified protein derivative (PPD) conversion in the
United States has not declined in past years; it remained event of an exposure. Skin testing (TST) with PPD
constant at about 2/100,000 per year from 1969 to (the Mantoux test) thus remains the most cost-effective
1979 (84). The proportion of extrapulmonary tubercu- method for recognizing and detecting new infection
losis increased from 7% in 1963 to 18% in 1987 and (90, 91). Later follow-up testing in the population gives
slowly increased in recent years to 20% of reported evidence of new infection and the disease following
cases (42, 85, 86). More than half of the extra- the infection. Details of skin testing are presented else-
pulmonary cases are due to involvement of the pleura where (see chapter 5).
and lymphatic system, followed by bone and joint TST for detection of latent tuberculosis infection,
diseases, genitourinary involvement, miliary disease, however, has major limitations in that it requires two
meningitis, and peritonitis (Fig. 11). This increase is visits and skilled staff for the test placement and inter-
due to HIV infection. Extrapulmonary tuberculosis can pretation. In addition, TST does not reliably separate
be seen in more than 50% of patients with concurrent reactions from previous immunization with Mycobac-
AIDS and tuberculosis (87, 88). Also, minorities and terium bovis BCG and infection with other environ-
the foreign-born are disproportionately more likely to mental mycobacteria (39, 92). With advancement in
have extrapulmonary disease (81, 86). Persistence of immunology and genomics, T-cell-based in vitro assays
high percentages of extrapulmonary tuberculosis in of interferon released by T cells after stimulation with
spite of the decrease in HIV infection remains a mys- Mycobacterium tuberculosis antigens have been devel-
tery. The effects of immunosuppression due to TNF oped to identify tuberculosis infection. Two gamma
inhibitor drugs and its increasing use in recent years on interferon release assays are available in commercial
extrapulmonary tuberculosis require further study (89). kits: the QuantiFERON-TB Gold assay (Cellestis Ltd.)
and the TB-SPOT-TB (Oxford Immunotec).
Detection of Tuberculosis Infection Gamma interferon detection has higher specificity
and Disease for M. tuberculosis and less cross-reactivity with BCG
In the past, mass radiographic surveys were productive vaccination than TST. The test is unreliable in the sub-
in identifying diseased persons in populations with a group of patients with immunosuppression, including

Figure 11 Reported cases of tuberculosis by anatomic site. Data from reference 117.

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 24 GENERAL CONSIDERATIONS

HIV/AIDS patients, those with extrapulmonary tuber- thereafter, an additional 5% of infected persons devel-
culosis, children, and populations in high-incidence op disease at some future time (31). The rate of devel-
countries. The CDC recommends detection of latent oping disease after recent infection varies considerably
infection via either the PPD or a gamma interferon in different geographic areas. Although tuberculosis
release assay, the latter having the advantage of a single rates have dropped for all racial and ethnic groups,
test for patients (32). Cost-effectiveness needs further disparities still remain. Poverty and malnutrition are
evaluation. important risk factors for tuberculosis (96). Malnutri-
The prevalence of infection varies according to geo- tion deeply affects CMI, which is the key host defense
graphic area and ranges from 2 to 8% according to the against tuberculosis. Primary or latent infection may
socioeconomic factors. The infection rate is higher in progress to active disease in malnourished persons (97).
urban areas (4.1%) and is highest in the poor and dis- In latent infection, the presence of malnutrition may be
advantaged residents of large cities; however, with the an important reactivating factor for the incidence of tu-
present reduction in incidence of tuberculosis, the infec- berculosis (97–99). This may be one of the reasons that
tion rate is much lower now. Tuberculin testing is most tuberculosis incidence is high among immigrants from
effective in detecting infection among the close contacts developing countries.
of newly diagnosed patients. Only about 15 to 20% of HIV-infected persons are highly susceptible to ac-
the contacts are found to be infected in such situations, quiring infection and progressing from infection to clin-
indicating that tuberculosis is less infectious than many ical tuberculosis to a degree that is unprecedented in
other communicable diseases. In rare instances the at- recent history (100). Also, there is often considerable
tack rate of new infection may be as high as 80 to 90% concern regarding the diagnosis of tuberculosis infec-
if a heavy exposure is also a prolonged one. Infectious- tion in HIV-infected individuals because of the high
ness of the index case is rapidly decreased by the insti- prevalence of anergy, which is dependent on the pre-
tution of proper chemotherapy. This fact has been sence of CD4 T lymphocytes (83). Since 1993 there has
amply demonstrated in controlled trials of chemothera- been progressive improvement in the rates of HIV test-
py in the hospital versus the home in Chennai (formerly ing and a decrease in coinfection with tuberculosis
Madras), India (93). There was no greater infection and HIV (Fig. 8). The risk of developing tuberculosis
rate in the close contacts of patients treated at home. after acquiring infection in various groups is shown in
Most of the spread of infection to contacts occurs be- Tables 1 and 2. The percentage of those with TB and
fore the discovery of disease and institution of chemo- HIV coinfection has steadily declined since 1993. In
therapy.
In 1999 to 2000, 4.2% of the United States popula-
tion aged 1 year or older showed tuberculosis infection.
Table 1 Incidence of active tuberculosis in persons with a
Among subjects aged 25 to 74 years, the prevalence of positive tuberculin test by selected risk factorsa
tuberculosis infection decreased from 14.4% in 1971 to
1972 to 5.6% in 1999 to 2000. The decline was greater No. of TB cases/1,000
Risk factor person-years
in the U.S.-born population (12.6 to 2.5%) than in for-
eign-born populations (35.6 to 21.3%). The prevalence Recent TB infection
of infection among foreign-born persons was more Infection <1 yr past 12.9
than eight times that of U.S.-born persons (94). Higher Infection 1–7 yr past 1.6
prevalences of tuberculosis infection were found in HIV infection 35.0–162
Injection drug use
foreign-born persons (18.7%), non-Hispanic blacks/
HIV positive 76.0
African Americans (70%), Mexican Americans (9.4%),
HIV negative or unknown 10.0
and individuals living in poverty (6.1%) (95). A total Silicosis 68
of 63% of cases of latent tuberculosis infection were Radiographic findings consistent 2.0–13.6
found among foreign-born persons. A targeted evalua- with prior TB
tion and treatment of individuals in high-prevalence Weight deviation from standard
groups shall be needed for prevention and control of Underweight by ≥15% 2.6
tuberculosis (32). Underweight by 10%–14% 2.0
The risk of developing disease after acquiring infec- Underweight by 5%–9% 2.2
tion has been observed among Navy recruits, in nursing Weight within 5% of standard 1.1
homes, and in a prison. It was found to be in the range Overweight by ≥5% 0.7
of 5% in the first year, and although it declines rapidly a
Adapted from reference (32).

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 2. EPIDEMIOLOGY AND HOST FACTORS 25

Table 2 Relative risk for developing active tuberculosis by 5.3 times greater than among U.S.-born persons (4.8
selected clinical conditionsa cases/100,000 population) (101). Tuberculosis case
Clinical condition Relative risk rates in foreign-born persons remain higher than those
of the U.S.-born population. From 1993 through 2014,
Silicosis 30
the incidence in U.S.-born persons decreased from 7.4/
Diabetes mellitus 2.0–4.1
100,000 to 2.0, whereas the incidence in foreign-born
Chronic renal failure/hemodialysis 10.0–25.3
Gastrectomy 2–5 persons increased from 5.4/100,000 to 20.3 (Fig. 13).
Jejunoileal bypass 27–63 From 1998 to 2008, among the three top reporting
Solid-organ transplantation states, California, New York, and Texas, there were
Renal 37 decreases in cases among U.S.-born persons (57%)
Cardiac 20–74 which were far greater than the decreases among
Carcinoma of head or neck 16 foreign-born persons (25.3%) (80, 81).
a
Relative to control population, independent of tuberculin test status. Adapted Because the disease develops mostly within 5 years
from reference 118. of arrival and the rate is high among children, most of
the tuberculosis cases in foreign-born persons represent
reactivation or progression of previous disease acquired
2014 only 6% of all tuberculosis cases had a positive
in the country of origin. RFLP analysis often reveals
HIV test (20).
that most of these cases are due to reactivation of latent
infection rather than transmission within communities.
SPECIAL HIGH-RISK GROUPS Generally, HIV infection is not a factor contributing to
the development of disease among foreign-born
Tuberculosis in the Foreign-Born immigrants. Another major issue is that these develop-
Since 1986, tuberculosis disease has been reported in- ing countries have higher rates of drug resistance than
creasingly for foreign-born persons every year. The the United States. Several reports have documented
number and proportion of cases among the foreign- higher rates of resistance in immigrants from Haiti,
born increased from 29% in 1993 to 58% in 2008. Latin America, and Southeast Asia (91, 102).
Five countries that commonly accounted for the cases The most common resistance found is to INH and
were Mexico (23%), the Philippines (11%), Vietnam streptomycin. Primary drug resistance was approxi-
(8.0%), India (8%), and China (5.0%); however, the mately two times higher among foreign-born than
countries varied according to local epidemiological among U.S.-born persons. In foreign-born persons
profile (Fig. 12). The tuberculosis rate among foreign- resistance declined from 12.9% in 1993 to 10.3% in
born persons was 25.3/100,000 population, which was 2008; the rate declined from 6.8 to 4.9% in U.S.-born

Figure 12 Countries of birth for foreign-born persons reported with tuberculosis in the
United States, 2014. Data from reference 46.

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 26 GENERAL CONSIDERATIONS

Figure 13 Trends in tuberculosis (TB) cases in foreign-born persons, United States, 1993 to
2014. The percentage of TB cases accounted for by foreign-born persons increased from
29% in 1992 to 66% in 2014.

persons. Resistance to rifampin is generally low. In culosis in foreign-born persons. Preventive therapy for
2003, drug resistance among initial isolates of M. tu- infected persons, even when vaccinated with BCG, is
berculosis in persons with no previous tuberculosis highly indicated to reduce their incidence of disease.
episodes was more common for foreign-born patients
than for U.S.-born patients. The rate of MDR (resis- Tuberculosis in Health Care Workers
tance to INH and rifampin) among foreign-born With the rapid decline of tuberculosis cases, the risk of
persons was 1.4% (for U.S.-born persons, 0.6%). This disease among health care workers had decreased ac-
has an implication for treatment of the disease, which cordingly; however, several outbreaks of MDR tubercu-
should be initiated with at least four bactericidal drugs. losis and nosocomial transmission of drug-sensitive
The cost of caring for patients with MDR tuberculosis disease in hospital patients and health care workers
is high. Inadequate screening of immigrants for tuber- have occurred (63, 64, 104). In outbreaks of tuberculo-
culosis infection and disease before they enter the sis among hospital personnel, many become infected
United States or inadequate follow-up of those persons (PPD changed from 0 to ≥15 mm). In such situations,
who had abnormal chest radiographic results with neg- 20% of persons may develop culture-positive tubercu-
ative sputum smears are reasons for increases in cases losis within 2 to 4 months, suggesting a large inocula-
among the foreign-born which should be strengthened tion (30). It is alarming that health care workers are at
through improved screening by immigration services, increased risk of contracting tuberculosis in their pro-
both overseas and in the United States (103), by prompt fession (Table 3). Several factors were identified that in-
reporting of suspected cases to public health programs crease exposure and risk of tuberculosis in hospitals.
and by early identification and treatment of tuber- Tuberculosis control measures in hospitals have not

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 2. EPIDEMIOLOGY AND HOST FACTORS 27

Table 3 Risk factors for TST conversion in Canadian for AFB was reported, indicating delays in the diagno-
hospitalsa sis (105) (Fig. 14). Such patients are more likely to
Adjusted 95% confidence transmit disease. Physicians often lack a high index of
Risk factor odds ratio interval suspicion for the presence of tuberculosis in their
patients or hesitate to start therapy without microbio-
Respiratory therapist 6.1 3.1–12.0
Nursing 4.3 2.7–6.9
logical confirmation of the disease, thus prolonging
Housekeeping 4.2 2.3–7.6 exposure of the staff (105). Patients with active tuber-
<2 air changes/ 3.4 2.1–5.8 culosis may have smears negative for AFB in 25 to
h (nonisolation 50% of cases, resulting in diagnostic delays. In 1992, a
patient rooms) survey found that 27% of the hospitals did not have
Physiotherapy 3.3 1.5–7.2 isolation rooms and did not meet standards recom-
Inadequate ventilation 1.0 0.8–1.3 mended for U.S. hospitals (106). Facilities to perform
(isolation rooms) tests for AFB examination were not available in 16%
a
Data from references 119 and 120. of U.S. hospitals caring for patients with tuberculosis.
The CDC reported that only 14% of 2,862 myco-
bacteriology laboratories in the United States per-
been appropriately followed (failure of respiratory formed culture identification and drug susceptibility
isolations and ineffective or absent ventilation and pos- testing (107). For these reasons, diagnosis of tuberculo-
itive-pressure isolation rooms). sis was delayed considerably, resulting in prolonged
With the decline in tuberculosis (4.2/100,000 popu- exposure to infection for patients and hospital workers.
lation in 2008), delay in diagnosis and in initiation of Moreover, comorbidity with HIV infection in some of
early therapy will enhance transmission of infection. In the population increased further risk of infection and
the United States, between 1993 and 2006, an increas- rapid progression of disease with a high mortality rate.
ing proportion of cases of advanced pulmonary tuber- Appropriate implementation of guidelines recom-
culosis with cavitary lung disease and sputum positive mended by the CDC for isolation and treatment of

Figure 14 Trends in advanced pulmonary tuberculosis (APT) adjusted for selected risk
factors, 1993 to 2006. Bars, APT; squares, age adjusted; triangles, foreign-born adjusted;
circles, HIV adjusted; line, unadjusted. Reprinted from reference 105 with permission.

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Exploring the Variety of Random
Documents with Different Content
monkeys, and of the prehensile-tailed viverra.
(Cercoleptes.)”
The journal which I wrote at the time in German,
and from which I borrow these extracts, was not
entirely exhausted in the narrative of my travels
(published in French). It contains a circumstantial
description of the nocturnal life of animals; I might
say, of their nocturnal voices in the tropical forests.
And this sketch seems to me to be especially adapted
to constitute one of the chapters of the Views of
Nature. That which is written down on the spot, or
soon after the impression of the phenomena has been
received, may at least claim to possess more
freshness than what is produced by the recollection
of long passed events.
We reached the bed of the Orinoco by descending
from west to east along the Rio Apure, whose
inundations I have noticed in the sketch of the
Deserts and Steppes. It was the period of low water,
and the average breadth of the Apure was only a little
more than 1200 feet; while the Orinoco, at its
confluence with the Apure (near the granite rocks of
Curiquima, where I was able to measure a base-line),
was still upwards of 12,180 feet. Yet this point (the
rock of Curiquima,) is 400 miles in a straight line
from the sea and from the delta of the Orinoco. Some
of the plains, watered by the Apure and the Payara,
are inhabited by Yaruros and Achaguas, who are
called savages in the mission-villages established by
the monks, because they will not relinquish their
independence. In reference to social culture, they
however occupy about the same scale as those
Indians, who, although baptized and living “under
the bell” (baxo la campana), have remained
strangers to every form of instruction and cultivation.
On leaving the Island del Diamante, where the
Zambos, who speak Spanish, cultivate the sugar-
cane, we entered into a grand and wild domain of
nature. The air was filled with countless flamingoes
(Phœnicopterus) and other water-fowl, which
seemed to stand forth from the blue sky like a dark
cloud in ever-varying outlines. The bed of the river
had here contracted to less than 1000 feet, and
formed a perfectly straight canal, which was inclosed
on both sides by thick woods. The margin of the
forest presents a singular spectacle. In front of the
almost impenetrable wall of colossal trunks of
Cæsalpinia, Cedrela, and Desmanthus, there rises
with the greatest regularity on the sandy bank of the
river, a low hedge of Sauso, only four feet high; it
consists of a small shrub, Hermesia castanifolia,
[68]
which forms a new genus of the family of
Euphorbiaceæ. A few slender, thorny palms, called by
the Spaniards Piritu and Corozo (perhaps species of
Martinezia or Bactris) stand close alongside; the
whole resembling a trimmed garden hedge, with
gate-like openings at considerable distances from
each other, formed undoubtedly by the large four-
footed animals of the forests, for convenient access to
the river. At sunset, and more particularly at break of
day, the American Tiger, the Tapir, and the Peccary
(Pecari, Dicotyles) may be seen coming forth from
these openings accompanied by their young, to give
them drink. When they are disturbed by a passing
Indian canoe, and are about to retreat into the forest,
they do not attempt to rush violently through these
hedges of Sauso, but proceed deliberately along the
bank, between the hedge and river, affording the
traveller the gratification of watching their motions
for sometimes four or five hundred paces, until they
disappear through the nearest opening. During a
seventy-four days’ almost uninterrupted river
navigation of 1520 miles up the Orinoco, to the
neighbourhood of its sources, and along the
Cassiquiare, and the Rio Negro—during the whole of
which time we were confined to a narrow canoe—the
same spectacle presented itself to our view at many
different points, and, I may add, always with renewed
excitement. There came to drink, bathe, or fish,
groups of creatures belonging to the most opposite
species of animals; the larger mammalia with many-
coloured herons, palamedeas with the proudly-
strutting curassow (Crax Alector, C. Pauxi). “It is
here as in Paradise” (es como en el Paradiso),
remarked with pious air our steersman, an old
Indian, who had been brought up in the house of an
ecclesiastic. But the gentle peace of the primitive
golden age does not reign in the paradise of these
American animals, they stand apart, watch, and
avoid each other. The Capybara, a cavy (or river-hog)
three or four feet long (a colossal repetition of the
common Brazilian cavy, (Cavia Aguti), is devoured in
the river by the crocodile, and on the shore by the
tiger. They run so badly, that we were frequently able
to overtake and capture several from among the
numerous herds.
Below the mission of Santa Barbara de Arichuna
we passed the night as usual in the open air, on a
sandy flat, on the bank of the Apure, skirted by the
impenetrable forest. We had some difficulty in
finding dry wood to kindle the fires with which it is
here customary to surround the bivouac, as a
safeguard against the attacks of the Jaguar. The air
was bland and soft, and the moon shone brightly.
Several crocodiles approached the bank; and I have
observed that fire attracts these creatures as it does
our crabs and many other aquatic animals. The oars
of our boats were fixed upright in the ground, to
support our hammocks. Deep stillness prevailed, only
broken at intervals by the blowing of the fresh-water
[69]
dolphins , which are peculiar to the river net-work
of the Orinoco (as, according to Colebrooke, they are
also to the Ganges, as high up the river as Benares);
they followed each other in long tracks.
After eleven o’clock, such a noise began in the
contiguous forest, that for the remainder of the night
all sleep was impossible. The wild cries of animals
rung through the woods. Among the many voices
which resounded together, the Indians could only
recognise those which, after short pauses, were heard
singly. There was the monotonous, plaintive, cry of
the Aluates (howling monkeys), the whining, flute-
like notes of the small sapajous, the grunting
[70]
murmur of the striped nocturnal ape
(Nyctipithecus trivirgatus, which I was the first to
describe), the fitful roar of the great tiger, the Cuguar
or maneless American lion, the peccary, the sloth,
and a host of parrots, parraquas (Ortalides), and
other pheasant-like birds. Whenever the tigers
approached the edge of the forest, our dog, who
before had barked incessantly, came howling to seek
protection under the hammocks. Sometimes the cry
of the tiger resounded from the branches of a tree,
and was then always accompanied by the plaintive
piping tones of the apes, who were endeavouring to
escape from the unwonted pursuit.
If one asks the Indians why such a continuous
noise is heard on certain nights, they answer, with a
smile, that “the animals are rejoicing in the beautiful
moonlight, and celebrating the return of the full
moon.” To me the scene appeared rather to be owing
to an accidental, long-continued, and gradually
increasing conflict among the animals. Thus, for
instance, the jaguar will pursue the peccaries and the
tapirs, which, densely crowded together, burst
through the barrier of tree-like shrubs which opposes
their flight. Terrified at the confusion, the monkeys
on the tops of the trees join their cries with those of
the larger animals. This arouses the tribes of birds
who build their nests in communities, and suddenly
the whole animal world is in a state of commotion.
Further experience taught us, that it was by no means
always the festival of moonlight that disturbed the
stillness of the forest; for we observed that the voices
were loudest during violent storms of rain, or when
the thunder echoed and the lightning flashed through
the depths of the woods. The good-natured
Franciscan monk who (notwithstanding the fever
from which he had been suffering for many months),
accompanied us through the cataracts of Atures and
Maypures to San Carlos, on the Rio Negro, and to the
Brazilian coast, used to say, when apprehensive of a
storm at night, “May Heaven grant a quiet night both
to us and to the wild beasts of the forest!”
A singular contrast to the scenes I have here
described, and which I had repeated opportunities of
witnessing, is presented by the stillness which reigns
within the tropics at the noontide of a day unusually
sultry. I borrow from the same journal the
description of a scene at the Narrows of Baraguan.
Here the Orinoco forms for itself a passage through
the western part of the mountains of the Parime.
That which is called at this remarkable pass a Narrow
(Angostura del Baraguan), is, however, a basin
almost 5700 feet in breadth. With the exception of an
old withered stem of Aubletia (Apeiba Tiburbu), and
a new Apocinea (Allamanda Salicifolia), the barren
rocks were only covered with a few silvery croton
shrubs. A thermometer observed in the shade, but
brought within a few inches of the lofty mass of
granite rock, rose to more than 122° Fahr. All distant
objects had wavy undulating outlines, the optical
effect of the mirage. Not a breath of air moved the
dust-like sand. The sun stood in the zenith; and the
effulgence of light poured upon the river, and which,
owing to a gentle ripple of the waters, was brilliantly
reflected, gave additional distinctness to the red haze
which veiled the distance. All the rocky mounds and
naked boulders were covered with large, thick-scaled
Iguanas, Gecko-lizards, and spotted Salamanders.
Motionless, with uplifted heads and widely extended
mouths, they seemed to inhale the heated air with
ecstasy. The larger animals at such times take refuge
in the deep recesses of the forest, the birds nestle
beneath the foliage of the trees, or in the clefts of the
rocks; but if in this apparent stillness of nature we
listen closely for the faintest tones, we detect, a dull,
muffled sound, a buzzing and humming of insects
close to the earth, in the lower strata of the
atmosphere. Everything proclaims a world of active
organic forces. In every shrub, in the cracked bark of
trees, in the perforated ground inhabited by
hymenopterous insects, life is everywhere audibly
manifest. It is one of the many voices of nature
revealed to the pious and susceptible spirit of man.
 ILLUSTRATIONS AND
ADDITIONS.
65. p. 191.—“Characteristic denominations in Arabic and
Persian.”
More than twenty words might be cited by which the Arabs
distinguish between a Steppe (tanufah), according as it may be a
Desert without water, entirely bare, or covered with siliceous sand,
and interspersed with spots of pasture land (Sahara, Kafr, Mikfar,
Tih, Mehme). Sahl is a depressed plain; Dakkah a desolate elevated
plateau. In Persian Beyaban is an arid sandy waste (as the Mongolian
Gobi and the Chinese Han-hai and Scha-mo); Yaila is a Steppe
covered with grass rather than with low-growing plants (like the
Mongolian Küdah, the Turkish Tala or Tschol, and the Chinese
Huang). Deschti-reft is a naked elevated plateau.[IK]

66. p. 191.—“The old Castilian dialects.”

Pico, picacho, mogote, cucurucho, espigon, loma tendida, mesa,
panecillo, farallon, tablon, peña, peñon, peñasco, peñoleria, roca
partida, laxa, cerro, sierra, serrania, cordillera, monte, montaña,
montañuela, cadena de montes, los altos, malpais, reventazon, bufa,
&c.

67. p. 194.—“Where the map had indicated Montes de Cacao.”

On the range of hills from which the lofty Andes de Cuchao have
originated, see my Relation historique, t. iii. p. 238.
 68. p. 197.—“Hermesia.”
The genus Hermesia, the Sauso, has been described by
Bonpland, and is delineated in our Plantes équinoxiales, t. i. p. 162,
tab. xlvi.

69. p. 199.—“The fresh-water dolphin.”

These are not sea dolphins, which, like some species of
Pleuronectes (flat fish which invariably have both eyes on one side of
the body), ascend the rivers to a great distance, as, for instance, the
Limande (Pleuronectes Limanda), which is found as far inland as
Orleans. Some forms of sea fish, as the dolphin and skate (Raia), are
met with in the great rivers of both continents. The fresh-water
dolphin of the Apure and the Orinoco differs specifically from the
Delphinus gangeticus as well as from all sea dolphins.[IL]

70. p. 199.—“The striped nocturnal monkey.”

This is the Douroucouli or Cusi-cusi of the Cassiquiare which I
have elsewhere described as the Simia trivirgata,[IM] from a drawing
made by myself of the living animal. We have since seen the
nocturnal monkey living in the menagerie of the Jardin des Plantes
at Paris.[IN] Spix also met with this remarkable little animal on the
Amazon River and called it Nyctipithecus vociferans.
Potsdam, June 1849.
 HYPSOMETRIC ADDENDA.

I am indebted to Mr. Pentland, whose scientific

labours have thrown so much light on the geology
and geography of Bolivia, for the following
determinations of position, which he communicated
to me in a letter from Paris (October 1848),
subsequent to the publication of his great map.

Nevado of Sorata, South

Longitude. Height.
or Ancohuma. Latitude.
South Peak 15° 51′ 33″ 68° 33′ 55″ 21,286
North Peak 15° 49′ 18″ 68° 33′ 52″ 21,043

Illimani.
South Peak 16° 38′ 52″ 67° 49′ 18″ 21,145
Middle Peak 16° 38′ 26″ 67° 49′ 17″ 21,094
North Peak 16° 37′ 50″ 67° 49′ 39″ 21,060

The numbers representing the heights are, with the

exception of the unimportant difference of a few feet
in the South Peak of Illimani, the same as those in
the map of the Lake of Titicaca. A sketch of the
Illimani, as it appears in all its majesty from La Paz,
was given at an earlier date by Mr. Pentland in the
[IO]
Journal of the Royal Geographical Society. But this
was five years after the publication of the first
measurements in the Annuaire du Bureau des
Longitudes for 1830, p. 323, which results I myself
[IP]
hastened to disseminate in Germany. The Nevado
de Sorata lies to the east of the village of Sorata or
Esquibel, and is called in the Ymarra language,
according to Pentland, Ancomani, Itampu, and
Illhampu. In Illimani we recognize the Ymarra word
illi, snow.
If, however, in the eastern chain of Bolivia the
Sorata was long assumed to be 3962 feet, and the
Illimani 2851 feet too high, there are in the western
chain of Bolivia, according to Pentland’s map of
Titicaca (1848), four peaks east of Arica between the
latitudes 18° 7′ and 18° 25′, all of which exceed
Chimborazo in height, which itself is 21,422 feet.
These four peaks are:—

English feet. French feet.

Pomarape 21,700 20,360
Gualateiri 21,960 20,604
Parinacota 22,030 20,670
Sahama 22,350 20,971
 Berghaus has applied to the chains of the Andes in
[IQ]
Bolivia, the investigation which I published
regarding the proportion, which varies extremely in
different mountain-chains, of the mountain ridge
(the mean height of the passes), to the highest
[IR]
summits (or the culminating points). He finds,
according to Pentland’s map, that the mean height of
the passes in the eastern chain is 13,505, and in the
western chain 14,496 feet. The culminating points are
21,285 and 22,350 feet; consequently the ratio of the
height of the ridge to that of the highest summit is, in
the eastern chain, as 1 : 1·57, and in the western chain
as 1 : 1·54. This ratio, which is, as it were, the
measure of the subterranean upheaving force, is very
similar to that in the Pyrenees, but very different
from the plastic form of the Alps, the mean height of
whose passes is far less in comparison with the
height of Mont Blanc. In the Pyrenees these ratios are
as 1 : 1·43, and in the Alps as 1 : 2·09.
But, according to Fitzroy and Darwin, the height of
the Sahama is still surpassed by 848 feet by that of
the volcano Aconcagua (south lat. 32° 39′), in the
north-east of Valparaiso in Chili. The officers of the
expedition of the Adventure and Beagle found, in
August 1835, that the Aconcagua was between
23,000 and 23,400 feet in height. If we reckon it at
[IS]
23,200 feet it is 1776 feet, higher than Chimborazo.
 [IT]
According to more recent calculations, Aconcagua
is determined to be 23,906 feet.
Our knowledge regarding the systems of
mountains, which, north of the parallels of 30° and
31°, are distinguished as the Rocky Mountains and
the Sierra Nevada of California, has been vastly
augmented during the last few years in the
astronomico-geographical, hypsometric, geognostic,
and botanical departments, by the excellent works of
[IU] [IV]
Charles Frémont, of Dr. Wislizenus, and of
[IW]
Lieutenants Abert and Peck. There prevails
throughout these North American works a scientific
spirit deserving of the warmest acknowledgment. The
remarkable plateau, referred to in p. 34, between the
Rocky Mountains and the Sierra Nevada of
California, which rises uninterruptedly from 4000 to
5000 French (4260 to 5330 English) feet high, and is
termed the Great Basin, presents an interior closed
river-system, thermal springs, and salt lakes. None of
its rivers, Bear River, Carson River, and Humboldt
River, find a passage to the sea. That which, by a
process of induction and combination, I represented
in my great map of Mexico, executed in 1804, as the
Lake of Timpanogos, is the Great Salt Lake of
Frémont’s map. It is 60 miles long from north to
south, and 40 miles broad, and it communicates with
the fresh-water Lake of Utah, which lies at a higher
level, and into which the Timpanogos or Timpanaozu
River enters from the eastward, in lat. 40° 13′. The
fact of the Lake of Timpanogos not having been
placed in my map sufficiently to the north and west,
arose from the entire absence, at that period, of all
astronomical determinations of position of Santa Fé
in New Mexico. For the western margin of the lake
the error amounts to almost fifty minutes, a
difference of absolute longitude which will appear
less striking when it is remembered that my itinerary
map of Guanaxuato could only be based for an extent
of 15° of latitude on determinations made by the
compass (magnetic surveys), instituted by Don Pedro
[IX]
de Rivera. These determinations gave my talented
and prematurely lost fellow-labourer, Herr Friesen,
105° 36′ as the longitude of Santa Fé, while, by other
combinations, I calculated it at 104° 51′. According to
actual astronomical determinations the true
longitude appears to be 106°. The relative position of
the strata of rock salt found in thick strata of red clay,
south-east of the Great Salt Lake (Laguna de
Timpanogos), with its many islands, and near the
present Fort Mormon and the Utah Lake, is
accurately given in my large map of Mexico. I may
refer to the most recent evidence of the traveller who
made the first trustworthy determinations of position
in this region. “The mineral or rock salt, of which a
specimen is placed in Congress Library, was found in
the place marked by Humboldt in his map of New
Spain (northern half), as derived from the journal of
the Missionary Father Escalante, who attempted
(1777) to penetrate the unknown country from Santa
Fé of New Mexico to Monterey of the Pacific Ocean.
South-east of the Lake Timpanogos is the chain of the
Wha-satch Mountains; and in this, at the place where
Humboldt has written Montagnes de sel gemme, this
[IY]
mineral is found.”
A great historical interest is attached to this part of
the highland, especially to the neighbourhood of the
Lake of Timpanogos, which is probably identical with
the Lake of Teguayo, the ancestral seat of the Aztecs.
This people, in their migration from Aztlan to Tula,
and to the valley of Tenochtitlan in Mexico, made
three stations at which the ruins of Casas grandes
are still to be seen. The first halting-place of the
Aztecs was at the Lake of Teguayo, south of Quivira,
the second on the Rio Gila, and the third not far from
the Presidio de Llanos. Lieutenant Abert found on
the banks of the Rio Gila the same immense quantity
of elegantly painted fragments of delf and pottery
scattered over a large surface of country, which, at
the same place, had excited so much astonishment in
the missionaries Francisco Garces and Pedro Fonte.
From these products of the hand of man, it may be
inferred that there was a time when a higher human
civilization existed in this now desolate region.
Repetitions of the singular architectural style of the
Aztecs, and of their houses of seven stories, are at the
present time to be found far to the east of the Rio
[IZ]
Grande del Norte; as, for instance, at Taos. The
Sierra Nevada of California is parallel to the coast of
the Pacific; but between the latitudes of 34° and 41°,
between San Buenaventura and the Bay of Trinidad,
there runs, west of the Sierra Nevada, a small coast
chain whose culminating point, Monte del Diablo, is
3674 feet high. In the narrow valley, between this
coast chain and the great Sierra Nevada, flow from
the south the Rio de San Joaquin, and from the north
the Rio del Sacramento. It is in the alluvial soil on the
banks of the latter river that the rich goldwashings
occur, which are now proceeding with so much
activity.
Besides the hypsometric levelling and the
barometric measurements to which I have already
referred (see page 33), between the mouth of the
Kanzas River in the Missouri and the coast of the
Pacific, throughout the immense expanse of 28° of
longitude, Dr. Wislizenus has successfully prosecuted
the levelling commenced by myself in the equinoctial
zone of Mexico, to the north as far as to lat. 35° 38′,
and consequently to Santa Fé del Nuevo Mexico. We
learn with astonishment that the plateau which forms
the broad crest of the Mexican Andes by no means
sinks down to an inconsiderable height, as was long
supposed to be the case. I give here, for the first time,
according to recent measurements, the line of
levelling from the city of Mexico to Santa Fé, which is
within 16 miles from the Rio del Norte.
 French English
feet. feet.
Mexico 7008 7469 Ht.
Tula 6318 6733 Ht.
San Juan del Rio 6090 6490 Ht.
Queretaro 5970 6362 Ht.
Celaya 5646 6017 Ht.
Salamanca 5496 5761 Ht.
Guanaxuato 6414 6836 Ht.
Silao 5546 5911 Br.
Villa de Leon 5755 6133 Br.
Lagos 5983 6376 Br.
Aguas Calientes 5875 6261 Br.
San Luis Potosi 5714 6090 Br.
Zacatecas 7544 8038 Br.
Fresnillo 6797 7244 Br.
Durango 6426 6848 (Oteiza)
Parras 4678 4985 Ws.
Saltillo 4917 5240 Ws.
from 3600 3836
El Bolson de Mapimi Ws.
to 4200 4476
Chihuahua 4352 4638 Ws.
Cosiquiriachi 5886 6273 Ws.
Passo del Norte (on the Rio
3577 3810 Ws.
Grande del Norte)
Santa Fé del Nuevo Mexico 6612 7047 Ws.

The attached letters Ws., Br., and Ht., indicate the

barometric measurements of Dr. Wislizenus,
Obergrath Burkart, and myself. To the valuable
memoir of Dr. Wislizenus there are appended three
profile delineations of the country; one from Santa Fé
to Chihuahua over Passo del Norte; one from
Chihuahua over Parras to Reynosa; and one from
Fort Independence (a little to the east of the
confluence of the Missouri and the Kanzas River) to
Santa Fé. The calculation is based on daily
corresponding observations of the barometer, made
by Engelmann at St. Louis, and by Lilly in New
Orleans. If we consider that in the north and south
direction the difference of latitude between Santa Fé
and Mexico is more than 16°, and that, consequently,
the distance in a direct meridian direction,
independently of curvatures on the road, is more
than 960 miles; we are led to ask whether, in the
whole world, there exists any similar formation of
equal extent and height (between 5000 and 7500 feet
above the level of the sea). Four-wheeled waggons
can travel from Mexico to Santa Fé. The plateau,
whose levelling I have here described, is formed
solely by the broad, undulating, flattened crest of the
chain of the Mexican Andes; it is not the swelling of a
valley between two mountain-chains, such as the
“Great Basin” between the Rocky Mountains and the
Sierra Nevada of California, in the Northern
Hemisphere, or the elevated plateau of the Lake of
Titicaca, between the eastern and western chains of
Bolivia, or the plateau of Thibet, between the
Himalaya and the Kuen-lün, in the Southern
Hemisphere.
 IDEAS
FOR A

PHYSIOGNOMY OF PLANTS.

When the active spirit of man is directed to the

investigation of nature, or when in imagination he
scans the vast fields of organic creation, among the
varied emotions excited in his mind there is none
more profound or vivid than that awakened by the
universal profusion of life. Everywhere—even near
the ice-bound poles,—the air resounds with the song
of birds and with the busy hum of insects. Not only
the lower strata, in which the denser vapours float,
but also the higher and ethereal regions of the air,
teem with animal life. Whenever the lofty crests of,
the Peruvian Cordilleras, or the summit of Mont
Blanc, south of Lake Leman, have been ascended,
living creatures have been found even in these
[71]
solitudes. On the Chimborazo , which is upwards of
eight thousand feet higher than Mount Etna, we saw
butterflies and other winged insects. Even if they are
strangers carried by ascending currents of air to
those lofty regions, whither a restless spirit of inquiry
leads the toilsome steps of man, their presence
nevertheless proves that the more pliant organization
of animals may subsist far beyond the limits of the
[72]
vegetable world. The Condor , that giant among the
vultures, often soared above us at a greater altitude
than the summits of the Andes, and even higher than
would be the Peak of Teneriffe were it piled upon the
snow-crowned summits of the Pyrenees. Rapacity
and the pursuit of the soft-woolled Vicunas, which
herd, like the chamois, on the snow-covered
pastures, allure this powerful bird to these regions.
But if the unassisted eye shows that life is diffused
throughout the whole atmosphere, the microscope
reveals yet greater wonders. Wheel-animalcules,
brachioni, and a host of microscopic insects are lifted
by the winds from the evaporating waters below.
Motionless and to all appearance dead, they float on
the breeze, until the dew bears them back to the
nourishing earth, and bursting the tissue which
[73]
incloses their transparent rotating bodies, instils
new life and motion into all their organs, probably by
the action of the vital principle inherent in water. The
yellow meteoric sand or mist (dust nebulæ) often
observed to fall on the Atlantic near the Cape de
Verde Islands, and not unfrequently borne in an
easterly direction as far as Northern Africa, Italy, and
Central Europe, consists, according to Ehrenberg’s
brilliant discovery, of agglomerations of siliceous-
shelled microscopic organisms. Many of these
perhaps float for years in the highest strata of the
atmosphere, until they are carried down by the
Etesian winds or by descending currents of air, in the
full capacity of life, and actually engaged in organic
increase by spontaneous self division.
Together with these developed creatures, the
atmosphere contains countless germs of future
formations; eggs of insects, and seeds of plants,
which, by means of hairy or feathery crowns, are
borne forward on their long autumnal journey. Even
the vivifying pollen scattered abroad by the male
blossoms, is carried by winds and winged insects
over sea and land, to the distant and solitary female
[74]
plant . Thus, wheresoever the naturalist turns his
eye, life or the germ of life lies spread before him.
But if the moving sea of air in which we are
immersed, and above whose surface we are unable to
raise ourselves, yields to many organic beings their
most essential nourishment, they still require
therewith a more substantial species of food, which is
provided for them only at the bottom of this gaseous
ocean. This bottom is of a twofold kind: the smaller
portion constituting the dry earth, in immediate
contact with the surrounding atmosphere; the larger
portion consisting of water,—formed, perhaps,
thousands of years ago from gaseous matters fused
by electric fire, and now incessantly undergoing
decomposition in the laboratory of the clouds and in
the pulsating vessels of animals and plants. Organic
forms descend deep into the womb of the earth,
wherever the meteoric rain-waters can penetrate into
natural cavities, or into artificial excavations and
mines. The domain of the subterranean cryptogamic
flora was early an object of my scientific researches.
Thermal springs of the highest temperature nourish
small Hydropores, Confervæ and Oscillatoræ. Not far
from the Arctic circle, at Bear Lake, in the New
Continent, Richardson saw flowering plants on the
ground which, even in summer, remains frozen to the
depth of twenty inches.
It is still undetermined where life is most
abundant: whether on the earth or in the fathomless
depths of the ocean. Ehrenberg’s admirable work on
the relative condition of animalcular life in the
tropical ocean and the floating and solid ice of the
Antarctic circle, has spread the sphere and horizon of
organic life before our eyes. Siliceous-shelled
Polygastrica and even Coscinodiscæ, alive, with their
green ovaries, have been found enveloped in masses
within twelve degrees of the Pole; even as the small
black glacier flea, Desoria Glacialis, and Podurellæ,
inhabit the narrow tubules of ice of the Swiss
glaciers, as proved by the researches of Agassiz.
Ehrenberg has shown that on some microscopic
infusorial animalcules (Synedra and Cocconeis),
other species live parasitically; and that in the
Gallionellæ the extraordinary powers of division and
development of bulk are so great, that an animalcule
invisible to the naked eye can in four days form two
cubic feet of the Bilin polishing slate.
In the ocean, gelatinous sea-worms, living and
[75]
dead, shine like luminous stars , converting by their
phosphorescent light the green surface of the ocean
into one vast sheet of fire. Indelible is the impression
left on my mind by those calm tropical nights of the
Pacific, where the constellation of Argo in its zenith,
and the setting Southern Cross, pour their mild
planetary light through the ethereal azure of the sky,
while dolphins mark the foaming waves with their
luminous furrows.
But not alone the depths of ocean, the waters, too,
of our own swamps and marshes, conceal
innumerable worms of wonderful form. Almost
indistinguishable by the eye are the Cyclidiæ, the
Euglenes, and the host of Naiads divisible by
branches like the Lemna (Duckweed), whose leafy
shade they seek. Surrounded by differently composed
atmospheres, and deprived of light, the spotted
Ascaris breathes in the skin of the earth-worm, the
silvery and bright Leucophra exists in the body of the
shore Nais, and a Pentastoma in the large pulmonary
[76]
cells of the tropical rattle-snake . There are
animalcules in the blood of frogs and salmon, and
even, according to Nordmann, in the fluid of the eyes
of fishes, and in the gills of the bream. Thus are even
the most hidden recesses of creation replete with life.
We purpose in the following pages to consider the
different families of plants, since on their existence
entirely depends that of the animal creation.
Incessantly are they occupied in organizing the raw
material of the earth, assimilating by vital forces
those elements which after a thousand
metamorphoses become ennobled into active
nervous tissue. The glance which we direct to the
dissemination of vegetable forms, reveals to us the
fulness of that animal life which they sustain and
preserve.
The verdant carpet which a luxuriant Flora spreads
over the surface of the earth is not woven equally in
all parts; for while it is most rich and full where,
under an ever-cloudless sky, the sun attains its
greatest height, it is thin and scanty near the torpid
poles, where the quickly-recurring frosts too speedily
blight the opening bud or destroy the ripening fruit.
Yet everywhere man rejoices in the presence of
nourishing plants. Even where from the depths of the
sea, a volcano bursting through the boiling flood,
upheaves a scoriaceous rock. (as once happened in
the Greek Islands); or, to instance a more gradual
phenomenon, where the united labours of the coral
[77]
animal (Lithophytes) have piled up their cellular
dwellings, on the crests of submarine mountains,
until after toiling for thousands of years their edifice
reaches the level of the ocean, when its architects
perish, and leave a coral island. Thus are organic
forces ever ready to animate with living forms the
naked rock. How seeds are so suddenly transported
to these rocks, whether by birds, or by winds, or by
the waves of ocean, is a question that cannot be
decided, owing to the great distance of these islands
from the coasts. But no sooner has the air greeted the
naked rock, than, in our northern countries, it
gradually acquires a covering of velvet-like fibres,
which appear to the eye to be coloured spots. Some of
these are bordered by single and others by double
rows, while others again are traversed by furrows and
divided into compartments. As they increase in age
their colour darkens. The bright glittering yellow
becomes brown, and gradually the bluish-grey mass
of the Leprariæ changes to a dusty black. As the
outlines of this vegetable surface merge into each
other with increasing age, the dark ground acquires a
new covering of fresh circular spots of dazzling
whiteness. Thus one organic tissue rises, like strata,
over the other; and as the human race in its
development must pass through definite stages of
civilization, so also is the gradual distribution of
plants dependent on definite physical laws. In spots
where lofty forest trees now rear their towering
summits, the sole covering of the barren rock was
once the tender lichen; the long and immeasurable
interval was filled up by the growth of grasses,
herbaceous plants, and shrubs. The place occupied in
northern regions by mosses and lichens is supplied in
the tropics by Portulacas, Gomphrenas, and other
low and oleaginous marine plants. The history of the
vegetable covering and of its gradual extension over
the barren surface of the earth, has its epochs, as well
as that of the migratory animal world.
But although life is everywhere diffused, and
although the organic forces are incessantly at work in
combining into new forms those elements which
have been liberated by death; yet this fulness of life
and its renovation differ according to difference of
climate. Nature undergoes a periodic stagnation in
the frigid zones; for fluidity is essential to life.
Animals and plants, excepting indeed mosses and
other Cryptogamia, here remain many months buried
in a winter sleep. Over a great portion of the earth,
therefore, only those organic forms are capable of full
development, which have the property of resisting
any considerable abstraction of heat, or those which,
destitute of leaf-organs, can sustain a protracted
interruption of their vital functions. Thus, the nearer
we approach the tropics, the greater the increase in
variety of structure, grace of form, and mixture of
colours, as also in perpetual youth and vigour of
organic life.
This increase may readily be doubted by those who
have never quitted our own hemisphere, or who have
neglected the study of physical geography. When in
passing from our thickly foliated forests of oak, we
cross the Alps or the Pyrenees and enter Italy or
Spain, or when the traveller first directs his eye to
some of the African coasts of the Mediterranean, he
may easily be led to adopt the erroneous inference
that absence of trees is a characteristic of hot
climates. But they forget that Southern Europe wore
a different aspect, when it was first colonised by
Pelasgian or Carthaginian settlers; they forget too
that an earlier civilization of the human race sets
bounds to the increase of forests, and that nations, in
their change-loving spirit, gradually destroy the
decorations which rejoice our eye in the North, and