Pathology of Infectious Diseases: A Volume in the Series: Foundations in Diagnostic Pathology, 1e

678 Pages·2014·244.206 MB·English

by  Gary W. Procop MD, Bobbi Pritt MD MSc (D)TMH

PATHOLOGY OF
INFECTIOUS DISEASES

PATHOLOGY OF
INFECTIOUS DISEASES
A Volume in the Series
FOUNDATIONS IN DIAGNOSTIC PATHOLOGY
EDITED BY
Gary W. Procop, MD, MS
Medical Director, Enterprise Test Utilization and
Pathology Consultative Services
Director, Molecular Microbiology, Parasitology, and
Mycology Laboratories
Professor of Pathology
Cleveland Clinic Lerner College of Medicine
Cleveland Clinic
Cleveland, Ohio
Bobbi S. Pritt, MD, MSc, (D)TMH
Director, Clinical Parasitology and Initial Processing Laboratories
Associate Professor of Pathology
Mayo Clinic College of Medicine
Mayo Clinic
Rochester, Minnesota
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
PATHOLOGY OF INFECTIOUS DISEASES ISBN: 978-1-4377-0762-5
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Library of Congress Cataloging-in-Publication Data
Pathology of infectious diseases / [edited by] Gary W. Procop, Bobbi S. Pritt.
p. ; cm. – (Foundations in diagnostic pathology)
Includes bibliographical references and index.
ISBN 978-1-4377-0762-5 (hardcover : alk. paper)
I. Procop, Gary W., editor. II. Pritt, Bobbi S., editor. III. Series: Foundations in diagnostic pathology.
[DNLM: 1. Infection–diagnosis. 2. Bacterial Infections–diagnosis. 3. Mycoses–diagnosis. 4. Parasitic
Diseases–diagnosis. 5. Virus Diseases–diagnosis. WC 195]
RC112
616.9'0475--dc23
2014010826
Executive Content Strategist: William R. Schmitt
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Printed in China.
Last digit is the print number: 9 8 7 6 5 4 3 2 1
To John Leon Procop, my father, who taught me what to do when the going gets
tough and at the same time was always a fun dad.
–Gary Procop
To my parents, John and Sue Pritt, for their love and inspiration.
–Bobbi Pritt
1
Principles of Infectious Disease
Pathology: An Introduction
■■Michael L. Wilson ■■Gary W. Procop
■■Bobbi S. Pritt
■■DIAGNOSIS OF INFECTIOUS DISEASES: in Figure 1-1, where the starting point is gross ex-
AN INTEGRATED APPROACH amination of specimens, frozen sections, aspirate
smears, or hematoxylin and eosin (H&E)–stained
permanent sections. In this approach, the evaluation
The diagnosis of infectious diseases ranges from straight-
is limited to the sequential use of histologic methods
forward clinical diagnoses to those that are possible only
with or without the accompanying use of microbio-
with the use of advanced molecular methods. Between
logic cultures. This is a cost-effective and adequate ap-
these two extremes are the many infectious diseases for
proach for many common infectious diseases. For more
which an accurate and timely diagnosis requires the
challenging cases, an integrated approach as shown in
combined use of microbiologic cultures, histopathology/
Figure 1-2 is more appropriate. In such an approach,
cytopathology, and molecular methods. It is this broad
several methods are used simultaneously and in paral-
group of infectious diseases where the histopathologist
lel to obtain the most accurate and timely diagnosis,
and medical microbiologist, either alone or together,
including correlating histopathologic findings with the
play a central role in diagnosis.
results of clinical signs and symptoms, other laboratory
As with all clinical or pathologic evaluations, pa-
test results, radiographic findings, and, when appro-
thologists need all available clinical, radiographic, and
priate, consultation with infectious disease pathology
laboratory findings in order to make accurate and
specialists. Ideally, the result of this process is an inte-
timely diagnoses. This is particularly important in in-
grated, composite report that incorporates all of these
fectious disease pathology: many infectious diseases
findings into a summary and interpretation.
are restricted geographically, present with distinctive
(or at least highly suggestive) clinical signs and symp-
toms, can present as localized or disseminated disease,
■■THE INFLAMMATORY RESPONSE IN THE
may be associated with environmental or zoonotic ex-
DIAGNOSIS OF INFECTIOUS DISEASES
posure, and, because many are contagious, can pres-
ent as part of an outbreak or be linked to transmission
from another host. The immune status of the host also The inflammatory response to pathogenic microorgan-
is important, as some infectious manifestations are isms is sufficiently consistent and predictable to usually
seen primarily in the setting of immune compromise. allow pathologists to identify that an infection is present.
Therefore, the amount of information necessary for the The type of inflammatory response—as well as its dis-
diagnosis and treatment of infectious diseases can be tribution in tissues, fluids, and organs—also may allow
substantially greater than that needed for many nonin- the pathologist to categorize the infection as one likely
fectious diseases. It is imperative that clinicians provide caused by bacteria, fungi, mycobacteria, or parasites
this information to pathologists, and that pathologists (Table 1-1). Some histopathologic clues, when combined
make an active attempt to obtain it when it is not ini- with other findings in tissue, help narrow the differen-
tially received. tial diagnosis. One example is the Splendor-Hoeppli
The histopathologic and cytopathologic diagnoses of phenomenon, which is a radial aggregate of eosinophilic
infectious diseases are progressive and sequential pro- material surrounding a nidus of infection. The pro-
cesses that move from the general to the specific based tein was once believed to be composed of aggregates of
on results from a combination of diagnostic meth- antigen-antibody complexes, but it is now known to be
ods. The traditional approach is shown graphically composed of major basic protein. When it is identified
3
4 PATHOLOGY OF INFECTIOUS DISEASES
Initial Examination of Tissue or Fluid
TABLE 1-1
Gross Examination
Frozen Section Patterns of inflammation associated with infection
Impression Smears
Quick Stains for Cytology
Pattern of Inflammation Likely Pathogens
Acute Inflammation Bacterial
Early stages of mycobacterial,
Evaluation of Pattern of
± Microbiological fungal, and parasitic
Inflammation and
Cultures infections
Morphology of Visible
Organisms Granulomatous inflammation Mycobacterial, fungal, rare
bacterial, parasitic
Endothelial damage, focal acute Viral (e.g., viral hemorrhagic
hemorrhage fevers)
Immunohistochemical Stains Rickettsial
Immunoperoxidase Stains Pseudomonas aeruginosa
in Situ Hybridization
Focal necrosis Viral
Bacterial
Ulceration Bacterial
Diagnosis and Report
Mycobacterial
FIGURE 1-1 Fungal
Conceptual approaches to diagnosis: traditional approach. Viral
Parasitic
Initial Examination of Tissue or Fluid
Gross Examination
Frozen Section Bacteria
Impression Smears
Quick Stains for Cytology
Most common bacterial pathogens elicit the acute in-
flammatory immune response, a typical example be-
ing acute bronchopneumonia caused by Streptococcus
Evaluation of Pattern of pneumoniae. The acute inflammatory response consists
NAA Microbiological
Methods Inflammation and Cultures primarily of an infiltrate of segmented neutrophils, al-
Morphology of Visible
though in more severe or prolonged cases the infiltrate
Organisms
can also contain neutrophil precursors. The surround-
ing tissue is often edematous, shows vascular conges-
tion with margination of neutrophils along the vascular
Immunohistochemical Stains endothelium, and may show focal necrosis with severe
Immunoperoxidase Stains
inflammation. As the segmented neutrophils lyse, they
in Situ Hybridization
release cellular debris that can mimic the appearance of
extracellular bacterial cocci, but in general the cellular
debris varies more in size and shape than do cocci. If a
Diagnosis and Report tissue Gram stain is performed, histopathologists should
remember to look for both free bacteria and intracellular
FIGURE 1-2
bacteria. The location of bacteria is determined in part
Conceptual approaches to diagnosis: integrated approach.
by the nature of the infection (e.g., intracellular gram-
positive cocci in pneumococcal pneumonia) and also
in tissue sections it suggests that an infection is caused by the degree of cellular lysis, severity of infection, and
by Sporothrix, some other fungi, Schistosoma eggs, and stage of infection.
others. Although it is not a specific finding, it does help A small number of pathogenic bacteria are associated
the pathologist narrow the differential diagnosis. Thus, with inflammatory responses other than typical acute
although infections in tissues may show considerable inflammation. Rickettsia and other pathogens associated
overlap in their histopathologic characteristics, the type with endothelial infections typically do not cause acute
and distribution of inflammation—and often a combi- inflammation but rather cause vascular leakage with
nation of otherwise nonspecific findings—provides suf- edema of affected tissues. Vascular thromboses and vas-
ficient information for pathologists to order additional cular necrosis may also occur, depending on which rick-
studies in a logical and sequential manner. ettsial pathogen is the cause of the infection. Affected
CHAPTER 1 Principles of Infectious Disease Pathology: An Introduction 5
vessels may show a surrounding cuff of mononuclear rather than be filled with necrotic debris the centers of
inflammatory cells, but in general these bacterial infec- the granulomas are filled with neutrophils. These gran-
tions are not associated with an infiltrate of neutrophils. ulomas do not have a specific name, being referred to
Similarly, Pseudomonas aeruginosa pneumonia is charac- as pyogenic granulomas or mixed inflammation, among
terized by damage to the walls of blood vessels with the other terms. When identified in skin and subcutaneous
subsequent development of acute hemorrhage with or tissues, they are highly suggestive of a cutaneous fungal
without associated acute inflammation. Bacterial infec- infection such as phaeohyphomycosis or chromoblas-
tions that are caused by toxin-producing bacteria, such tomycosis. As with mycobacteria and other causes of
as Clostridium species, may show only extensive tissue granulomas, necrosis of the center of the granulomas is
necrosis with minimal or no inflammation. Rapidly pro- more typical of infections that have persisted for some
gressive infections caused by Streptococcus pyogenes in time. It is important for the diagnostician to remember
skin and subcutaneous soft tissues may progress so rap- that granulomatous inflammation varies considerably in
idly that extensive tissue necrosis occurs before acute its histopathologic appearance.
inflammation can develop. One of the less intuitive in- One distinctive tissue reaction to fungal infection
flammatory responses is that elicited by Brucella spp., occurs with the diverse group of fungi that cause what
Yersinia pestis, Francisella tularensis, Bartonella hense- is variably termed zygomycosis, phycomycosis, or mu-
lae (the causative agent of cat-scratch disease), and the cormycosis. Because the causative fungi all belong to
Chlamydia trachomatis strains that cause lymphogranu- the class Zygomycetes, perhaps the best term is zygo-
loma venereum. Unlike most other bacterial pathogens, mycosis. Infection with any of these agents, which are
these bacteria are associated with the formation of stel- indistinguishable in tissue sections, results in invasion
late necrotizing granulomas in infected tissues. of arterial walls with subsequent vascular occlusion and
Some bacterial infections are associated with patterns thrombosis. Similar findings occur when members of
of infection that are distinctive but may not be recog- the hyaline hyphomycetes (such as Aspergillus) invade
nized due to their relative infrequency in routine clinical pulmonary arteries. Necrosis of infected tissues is the
practice. The foamy macrophages observed with Whipple result of these fungal infections, with minimal acute in-
disease in gastrointestinal biopsies is one example, as is flammation in the early stages of infection.
the similar tissue reaction observed in the spleen with More comprehensive descriptions of the histopatho-
infections caused by Mycobacterium avium complex in logic changes associated with fungal infections are pre-
patients with severe immunosuppression caused by HIV sented in Chapters 23 to 26.
infection. Infections caused by Rhodococcus are typically
associated with malakoplakia. The finding of xantho-
granulomatous inflammation, while nonspecific, strongly
MycoBacteria
suggests a chronic bacterial infection rather than an on-
going fungal or mycobacterial infection.
The histopathologic changes associated with bacte- As with fungi, mycobacterial infections are classically
rial infections are discussed in detail in Chapters 12, 13, associated with granulomatous inflammation. As with
15, 16, 17, 18, and 19. bacteria and fungi, however, mycobacteria elicit a spec-
trum of inflammatory reactions depending on the type
of mycobacterium, the site of infection, and the stage
of infection. Although the immediate tissue response
Fungi
to mycobacterial infection is that of acute inflamma-
tion, this is rarely (if ever) seen in diagnostic speci-
Fungal infections are typically associated with granu- mens: by the time clinical signs and symptoms develop,
lomatous inflammation, which may be necrotizing or the inflammatory response has evolved to the stage of
non-necrotizing depending on the stage of the infection. granulomatous inflammation. Early infections show
Early stages of fungal infections are typically associated non-necrotizing granulomas; if infections persist, the
with acute inflammation, with the evolution of granulo- granulomas will begin to show necrosis of the central
matous inflammation occurring as cell-mediated immu- portions, which eventually become fully necrotic, even-
nity develops. As occurs with mycobacterial infections, tually assuming the classic finding of caseation. At this
the early stages of fungal infections are rarely seen: by stage of the infection, a rim of viable tissue, consisting
the time the patient is symptomatic, or a biopsy is neces- mostly of epithelioid histiocytes, surrounds the central
sary, the infection almost always has progressed to the area of necrosis. From a practical standpoint, the most
stage at which granulomatous inflammation has devel- important feature for the histopathologist is that resid-
oped. One notable exception occurs with cutaneous fun- ual mycobacteria are limited to the interface between
gal infections, where mixed acute and granulomatous the necrotic and viable tissue; mycobacteria are almost
inflammation occurs. In addition, many granulomas in never found in either the necrotic or the viable granu-
cutaneous fungal infections have a necrotic center, but lomatous tissue.
6 PATHOLOGY OF INFECTIOUS DISEASES
A number of unique patterns of inflammation with
Parasites
mycobacterial infections have also been described. Buruli
ulcer, a tropical infection caused by Mycobacterium ul-
cerans, is manifested by the development of chronic skin The classic description of the histopathologic changes asso-
ulcers that show acute and chronic inflammation at the ciated with invasive parasitic infection is that of a chronic
leading edge of ulcers, with minimal granulomatous in- inflammatory infiltrate with a marked eosinophilic com-
flammation along the edge of ulcers. Tuberculoid lep- ponent. This description, however, is inadequate in many
rosy shows a granulomatous inflammation, particularly ways. For example, some parasitic infections are associated
in a perineural pattern, whereas lepromatous leprosy with minimal or no tissue reaction at all, such as the cysts
shows aggregates of lipid-laden macrophages that may of Toxoplasma gondii observed in brain or skeletal mus-
be filled with Mycobacterium leprae bacilli. The absence cle during the dormant state of infection. Other parasitic
of granulomas in lepromatous leprosy reflects a lack of infections are associated with granulomatous inflamma-
an effective T-cell immune response. Mycobacterium tion, such as cutaneous or mucocutaneous forms of leish-
avium complex infections in patients with profound im- maniasis or the granulomatous pulmonary arteritis seen
munosuppression also are characterized by foamy mac- when schistosome eggs circulate to the lungs. With many
rophages distended by innumerable bacilli, and again parasitic infections, longstanding infection may result in
the absence of granulomas reflects a lack of an effec- marked fibrosis of affected tissues, the best example being
tive T-cell immune response. Mycobacterium marinum the so-called pipe-stem fibrosis seen in livers infected with
causes small subcutaneous granulomas in the skin (usu- Schistosoma japonicum. Last, cutaneous or mucocutane-
ally of the extremities) where the body temperature is ous forms of parasitic infections may be associated with
sufficiently low to support the growth of the bacterium. secondary bacterial infections, which can result in acute
The histopathologic changes associated with myco- inflammation of the affected site, thereby partially obscur-
bacterial infections are discussed in detail in Chapters 20, ing the nature of the underlying infection. It is important
21, and 22. to remember that the various tissue reactions to parasitic
infections are for the most part nonspecific: unless para-
sites are directly visualized, it is not possible to make a
definitive diagnosis in most cases.
Viruses
As with other types of infections, for many parasitic
infections the only clues as to the causative agent are the
Excluding viral cytopathic effects, most viral infections distribution of affected tissues or organs, epidemiologic
are not associated with characteristic inflammatory or information, and a past medical history suggestive of a
other tissue reactions in tissues or organs, although the given parasite. A careful clinical history is a mandatory
distribution of changes within tissue or organs may sug- part of the evaluation of these patients: it is necessary
gest certain viral infections. For example, changes lim- to obtain detailed information as to the patient’s birth-
ited to the liver would suggest certain viral infections place, residence or travel to endemic regions, past clini-
but not others due to the organ- and cell-specific tropism cal signs and symptoms, and previous evaluation and
for many viruses. Other examples include the pattern(s) treatment. Serologic tests may be useful for document-
of acute hemorrhage associated with viral hemorrhagic ing past exposure to parasites, but pathologists should
fevers, changes associated with progressive multifocal remember that serologic tests may only document ex-
leukoencephalopathy caused by JC virus infection, and posure, not disease, and they suffer from a number of
viral myocarditis. That is not to say that a histopatho- pitfalls including lack of sensitivity or specificity as well
logic diagnosis of viral infections is not possible, rather as cross-reactions with similar parasites. Moreover, ac-
that the pattern of inflammation per se is not as charac- curate serologic tests are not widely available for many
teristic as that of many bacterial, fungal, or mycobacte- parasitic infections and are typically limited to large ref-
rial infections. erence laboratories and public health agencies (e.g., the
It is important for pathologists to remember that U.S. Centers for Disease Control and Prevention).
many viral infections can be accompanied by secondary The histopathologic changes associated with parasitic
bacterial infections. Classic examples include bacterial infections are discussed in detail in Chapters 27 and 28.
superinfection during and following viral pneumonias
and bacterial infections following ulcers caused by vi-
ruses (e.g., esophageal ulcers caused by the Herpes sim-
■■CLASSICAL HISTOPATHOLOGY
plex virus or Cytomegalovirus). Depending on the timing
AND CYTOPATHOLOGY
of any biopsy or collection of fluid, the acute inflamma-
tory infiltrate associated with the secondary bacterial in-
fection can easily obscure the underlying viral infection. The first step in histopathologic or cytopathologic di-
The histopathologic changes associated with viral in- agnosis is the recognition of findings that are consis-
fections are discussed in detail in Chapters 2 to 9. tent with an infection. Although in many cases this