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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_182_библиотеки_им_акад_М_И_Перельмана.pdf
NOCARDIOSIS
A large necrotic pulmonary abscess due to nocardiosis
is shown with central necrosis , hemorrhage , and
relatively spared residual lung.
TERMINOLOGY
Bacterial Infections: Morphological Diagnosis of Bacterial Infections
Definitions
Nocardia from Edmund Nocard (French veterinarian)
ETIOLOGY/PATHOGENESIS
Infectious Agents
Nocardia species
Nocardia asteroides and Nocardia brasiliensis are most
common isolates from human disease
Gram-variable or weakly gram-positive filamentous
bacteria that is acid-fast (Kinyoun or Fite-Faraco)
Hosts who are infected with symptomatic disease are
usually immunosuppressed
CLINICAL ISSUES
Presentation
Pulmonary disease
Fever, cough, night sweats, and chest pain
Neurological disease
Neurological focal deficits
Headache, seizures, behavioral changes
Disseminated nocardiosis
Fever with multiple organ involvement (e.g., brain,
lungs)
Rare presentations
Endocarditis
Keratitis
Endophthalmitis
Sporotrichosis-like lymphangitis
Cellulitis
Mycetoma
II
Laboratory Tests
Testing that supports iatrogenic, acquired, or
congenital immunosuppression
1
Acid-fast stain of a tissue section from an abscess
demonstrates positive filamentous bacteria consistent
with Nocardia species. Culture or molecular tests are
required for definitive speciation.
Treatment
Surgical drainage of lesions may speed treatment and
recovery
Prolonged antibiotic therapy (up to 6 months) with
sulfonamides or trimethoprim/sulfamethoxazole
Prognosis
Neurological involvement: 80% mortality
Other sites: 50% mortality
IMAGE FINDINGS
Radiographic Findings
Lungs with infiltrates with central necrosis (cavitation)
Brain with abscesses or subtle meningitis
MICROBIOLOGY
Bacterial Characteristics
Closely related to Rhodococcus species
Most species contain virulence factor, cord factor
(trehalose-6-6’-dimycolate)
Molecular characterization by 16S rRNA accurate
classifies species in parallel with antibiotic and
biochemical testing
Culture
Grow as strict aerobes on a wide range of media and
temperatures (3 days to several weeks for growth)
Identification by 1st determining antibiotic
resistance to gentamicin, tobramycin, amikacin, and
erythromycin
Followed by determination of reaction to acetamide,
adonitol, inositol, citrate, and colony pigment on
Mueller-Hinton agar
20
Etiology
Nocardia asteroides and Nocardia brasiliensis are most
common isolates from human disease
Clinical Issues
Pulmonary disease
Fever, cough, night sweats, and chest pain
Neurological disease
Neurological focal deficits
Disseminated nocardiosis
Fever with multiple organ involvement (e.g., brain,
lungs)
Microscopic Pathology
Necrotic abscess with neutrophils, neutrophil debris,
and liquefactive necrosis may be found in any
affected site
MACROSCOPIC FEATURES
Abscess Formation
Grossly, large abscesses may be found in affected
organs containing necrotic, liquefactive material
MICROSCOPIC PATHOLOGY
NOCARDIOSIS
Key Facts
Organisms are not visible on routine H&E and lesions
may be paucibacillary
Ancillary Tests
Organisms are easily visualized on silver stains and
Gram stains (gram variable)
Modified acid-fast stain (Kinyoun or Fite-Faraco) will
stain organisms red
Top Differential Diagnoses
Actinomycosis
Negative on acid-fast stains and much less
commonly cause disseminated disease
Candidiasis
Very thin hyphal forms of Candida may be
confused with Nocardia but will not be acid-fast and
should have yeast forms present
Patients with isolated pulmonary nocardiosis and
a unrelated brain lesion (e.g., toxoplasmosis) may
mimic disseminated nocardiosis
Pathologic Interpretation Pearls
Presence of branched filamentous forms on Gram
or silver stains should prompt confirmation with
appropriate AFB stain &/or culture
Bacterial Infections: Morphological Diagnosis of Bacterial Infections
Histologic Features
Necrotic abscess with neutrophils, neutrophil debris,
and liquefactive necrosis may be found in any affected
site
Organisms are not visible on routine H&E, and lesions
may be paucibacillary
ANCILLARY TESTS
Histochemistry
Organisms are easily visualized on silver stains and
Gram stains (gram variable)
Modified acid-fast stain (Kinyoun or Fite-Faraco) will
stain organisms red
DIFFERENTIAL DIAGNOSIS
Actinomycosis
Negative on acid-fast stains and much less commonly
cause disseminated disease
Candidiasis
Very thin hyphal forms of Candida may be confused
with Nocardia but will not be acid-fast and should
have yeast forms present
DIAGNOSTIC CHECKLIST
Clinically Relevant Pathologic Features
Immunosuppression leads to disseminated syndromes
involving lung/brain
SELECTED REFERENCES
1. Yu X et al: Nocardia infection in kidney transplant
recipients: case report and analysis of 66 published cases.
Transpl Infect Dis. 13(4):385-91, 2011
2. Sundaram C et al: Pathogenesis and pathology of brain
abscess. Indian J Pathol Microbiol. 49(3):317-26, 2006
3. Yildiz O et al: Actinomycoses and Nocardia pulmonary
infections. Curr Opin Pulm Med. 12(3):228-34, 2006
4. Mootsikapun P et al: Nocardiosis in Srinagarind Hospital,
Thailand: review of 70 cases from 1996-2001. Int J Infect
Dis. 9(3):154-8, 2005
5. Corti ME et al: Nocardiosis: a review. Int J Infect Dis.
7(4):243-50, 2003
6. Pruitt AA: Nervous system infections in patients with
cancer. Neurol Clin. 21(1):193-219, 2003
7. Kiska DL et al: Identification of medically relevant
Nocardia species with an abbreviated battery of tests. J Clin
Microbiol. 40(4):1346-51, 2002
8. Sridhar MS et al: Ocular nocardia infections with special
emphasis on the cornea. Surv Ophthalmol. 45(5):361-78,
2001
9. Salinas-Carmona MC: Nocardia brasiliensis: from microbe
to human and experimental infections. Microbes Infect.
2(11):1373-81, 2000
10. Threlkeld SC et al: Update on management of patients with
Nocardia infection. Curr Clin Top Infect Dis. 17:1-23, 1997
11. Lerner PI: Nocardiosis. Clin Infect Dis. 22(6):891-903; quiz
904-5, 1996
12. Welsh O et al: Treatment of eumycetoma and
actinomycetoma. Curr Top Med Mycol. 6:47-71, 1995
13. Heffner JE: Pleuropulmonary manifestations of
actinomycosis and nocardiosis. Semin Respir Infect.
3(4):352-61, 1988
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Gross Features
(Left) Multifocal areas
of abscess formation
are shown in pulmonary
nocardiosis. (Right) Abscess
and subcapsular
inflammation of the kidney
are shown from a disseminated
case of nocardiosis.
(Left) A large cavitary abscess
is shown from pulmonary
Bacterial Infections: Morphological Diagnosis of Bacterial Infections
nocardiosis with satellite areas
of small abscesses formed
in adjacent lung tissue .
(Right) A cross section of
brain at autopsy demonstrates
multiple large abscesses ,
which showed nocardiosis
consistent with disseminated
disease.
NOCARDIOSIS
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(Left) A solitary abscess
in the basal ganglia due
to nocardiosis is shown at
autopsy on brain section. The
differential diagnosis includes
other bacterial abscess,
toxoplasmosis, and metastatic
cancer. (Right) Pus is found
on the base of the brain in a
case of central nervous system
nocardiosis. Meningitis is less
common than solitary abscess.
Microscopic Features
p
Bacterial Infections: Morphological Diagnosis of Bacterial Infections
NOCARDIOSIS
(Left) A typical section of
an abscess from a case of
nocardiosis demonstrates
diffuse neutrophilic infiltrate
with necrosis and cellular
debris. (Right) High
magnification of a typical
abscess section from a
atient with nocardiosis
demonstrates diffuse
neutrophilic infiltrate
with cellular debris .
(Left) An example of
Nocardia on Gram stain
shows the organisms
to be gram-negative
filamentous bacteria.
The differential diagnosis
includes Actinomyces
and other gram-negative
filamentous or "rods in
chains" bacteria. (Right)
High magnification of a
Gram stain from a patient
with Nocardia shows gramvariable forms, which are
thin and filamentous but lack
spores. An acid-fast stain can
confirm the diagnosis.
(Left) A PAS stain will often
highlight the filamentous
bacteria of nocardiosis but
cannot distinguish it from
actinomycosis. (Right) A
silver stain is the best tool
for screening a tissue section
for any type of bacteria,
including Nocardia species
as seen here.
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SPIROCHETOSIS
Intestinal biopsy demonstrates purple adherent
spirochetes to the brush border consistent with
spirochetosis.
TERMINOLOGY
Bacterial Infections: Morphological Diagnosis of Bacterial Infections
Abbreviations
Intestinal spirochetosis (IS)
Definitions
Greek: "Spira" (spiral) + "khaite" (long hair)
Greek: "Brachys" (short) + "spira" (spiral)
ETIOLOGY/PATHOGENESIS
Infectious Agents
2 members of the Brachyspiraceae family may colonize
humans
Brachyspira aalborgi and Brachyspira pilosicoli
Highly debated whether Brachyspira are human
pathogens or commensals
B. pilosicoli cause diarrheal illness in animals
CLINICAL ISSUES
Epidemiology
Histologic prevalence of 2-16% in western countries
Higher prevalence of 20-62% in HIV patients and men
who have sex with men (MSM)
No correlation between prevalence and immune
status/CD4 count
Some hypothesize IS could be a sexually transmitted
disease
Higher but variable prevalence in developing countries
Site
May affect any region of colon, including rectum and
appendix
Presentation
II
Most healthy adults with histologic evidence of
colonization are asymptomatic
1
An immunohistochemical stain for spirochetes (cross
reacts with Syphillis, Borrelia, and Spirochetosis)
highlights the organisms at the brush border in
spirochetosis.
Vague abdominal pain and chronic diarrhea
In children: Nausea, weight loss, failure to thrive
Treatment
Drugs
Antibiotics: Penicillin benzathine, metronidazole
Antidiarrheals
Prognosis
Variable: Complete resolution to continued chronic
diarrhea
Some reports suggest outcome after therapy is
independent of histologic resolution
MICROBIOLOGY
Characteristics
Fastidious anaerobic spirochetes with slender tapered
ends
B. aalborgi: 2-6 m in length, 0.2 m in diameter
B. pilosicoli: 4-20 m in length, 0.2-0.5 m in
diameter
Culture
Although organisms can be cultured, not part of
routine diagnosis
MACROSCOPIC FEATURES
Endoscopic Findings
Typically normal colonic mucosa
Rare reports of mucosal erosion, edema, erythema,
polypoid appearance
MICROSCOPIC PATHOLOGY
Histologic Features
Basophilic, fringed layer of organisms (3-6 m thick)
24
SPIROCHETOSIS
Etiology
Brachyspira aalborgi and Brachyspira pilosicoli
Clinical Issues
Highest prevalence in HIV patients, MSM, and in
developing countries
Associated with chronic diarrhea and abdominal pain
Children, HIV patients, and MSM are more likely to
be symptomatic
Most healthy adult carriers are asymptomatic
Present along luminal surface of epithelium
Organisms have a corkscrew or spirillar appearance
Spirochetes do not invade mucosa
Cytologic Features
Corkscrew or spirillar bacterial forms
ANCILLARY TESTS
Histochemistry
Positive for silver impregnation stains: Warthin-Starry,
Dieterle, Steiner
Positive for Alcian blue (pH 2.5) and periodic acidSchiff stains
Negative for tissue Gram stain
Immunohistochemistry
Antispirochetal antibodies (also stain Treponema and
Borrelia) will be strongly positive
DIFFERENTIAL DIAGNOSIS
Prominent Luminal Glycocalyx
Negative for silver impregnation stains
Enteroadherent Escherichia coli Infection
Gram-negative, silver-positive, noncurvy (straight)
rods
Bacilli (not spirillar in form)
Key Facts
Endoscopic Findings
Usually normal colonic mucosa
Microscopic Pathology
Basophilic, fringed layer of organisms on luminal
aspect of colonic epithelium
Do not invade colonic mucosa
Ancillary Tests
Positive for silver impregnation stains
DIAGNOSTIC CHECKLIST
Clinically Relevant Pathologic Features
Biopsies should be taken in at-risk populations even if
colonic mucosa is normal
Pathologic Interpretation Pearls
Histologic evidence of colonization may not correlate
with symptoms
SELECTED REFERENCES
1. Tsinganou E et al: Human intestinal spirochetosis--a
2. Ena J et al: Intestinal spirochetosis as a cause of chronic
3. Calderaro A et al: Infective colitis associated with human
4. Esteve M et al: Intestinal spirochetosis and chronic watery
5. Koteish A et al: Colonic spirochetosis in children and
Bacterial Infections: Morphological Diagnosis of Bacterial Infections
review. Ger Med Sci. 8:Doc01, 2010
diarrhoea in patients with HIV infection: case report and
review of the literature. Int J STD AIDS. 20(11):803-5, 2009
intestinal spirochetosis. J Gastroenterol Hepatol. 2007
Nov;22(11):1772-9. Erratum in: J Gastroenterol Hepatol.
22(11):2049, 2007
diarrhea: clinical and histological response to treatment
and long-term follow up. J Gastroenterol Hepatol.
21(8):1326-33, 2006
adults. Am J Clin Pathol. 120(6):828-32, 2003
MICROSCOPIC FEATURES
(Left) Medium-power view of an intestinal biopsy is shown in a patient with spirochetosis where organisms are adherent to the brush border.
(Center) High-power view of an intestinal biopsy is shown in a patient with spirochetes
shown in a patient with spirochetosis where organisms
are adherent to the brush border. Note the unaffected area .
. (Right) High-power view of an intestinal biopsy is
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WHIPPLE DISEASE
Innumerable nodular white-yellow plaques are present
on the duodenal mucosal surface in this patient with
Whipple disease. (Courtesy F. Mitros, MD and A. Bellizzi,
MD.)
TERMINOLOGY
Bacterial Infections: Morphological Diagnosis of Bacterial Infections
Synonyms
Tropheryma whipplei infection
Definitions
Greek: "Trophe" (food) + "eruma" (barrier)
From George Hoyt Whipple (1st described)
ETIOLOGY/PATHOGENESIS
Environmental Exposure
Infecting organism is more common in soil, animals,
and farmers
Infectious Agents
T. whipplei
Ubiquitous organism that can be isolated from
gastrointestinal tract, stool, oral cavity, and saliva of
healthy persons (10-30%)
Genetic Predisposition
Extremely rare condition (1 case per million annually)
> 85% of affected individuals are male (USA study)
Apparent increased rate in Caucasians
CLINICAL ISSUES
Presentation
Chronic systemic infection affecting gastrointestinal
tract, joints, and central nervous system, usually in
middle age (~ 55 years)
Weight loss, hypoalbuminemia, diarrhea
(steatorrhea), arthralgias, anemia in > 80% of
patients
Lymphadenopathy, abdominal pain, skin
II
pigmentation, fever, neurological signs (headaches
and cognitive changes) in < 50% of patients
1
Hematoxylin & eosin section shows villi distended by a
macrophage infiltrate, with admixed neutrophils and fat
droplets . (From DP: Gastrointestinal.)
Isolated endocarditis cause by T. whipplei
May affect native heart valves or implants
Slowly progressive disease with signs of heart failure
without fever
Other presentations (without gastrointestinal
involvement)
Fever and cough
Pneumonia
Isolated gastroenteritis in children
May be associated with immunosuppression
After start of therapy, immune reconstitution
syndrome (IRIS) (system-wide reaction to bacteria) can
occur
Endoscopic Findings
Pale yellow duodenal mucosa
Dilatation of villi and ectatic lymphatics of mucosa
Laboratory Tests
Diagnostic PCR may be performed on cerebrospinal
fluid, joint fluid, saliva, or stool using 16S rRNA
Treatment
Doxycycline and hydroxychloroquine for 1 year
followed by lifelong doxycycline is recommended
therapy
For CNS treatment, intravenous drugs are required
For IRIS, supportive therapy (corticosteroids,
cytokines) is required in addition to antibiotics
Prognosis
Without antibiotic therapy, 100% mortality (CNS
involvement)
MICROBIOLOGY
Bacterial Characteristics
Gram-positive actinobacteria
26
Etiology
Tropheryma whipplei
Ubiquitous organism found in healthy persons
(10-30%)
Affects gastrointestinal tract, heart valves, central
nervous system, and joints
Extremely rare condition (1 case per million
annually) with genetic predisposition
Clinical Issues
Multisystem chronic infection in middle age (~ 55
years)
Microscopic Pathology
Dense collections of foamy macrophages within
mucosa of small bowel is classic
WHIPPLE DISEASE
Key Facts
Loss of microvilli, lymphatic obstruction, and
deposits of lipid in tissues
In sites outside of gastrointestinal tract, macrophages
containing organisms are found in variable numbers
Ancillary Tests
Strongly PAS positive (with diastase) within
macrophages
Negative for AFB staining
Top Differential Diagnoses
Mycobacterium avium-intracellulare complex infection
Histoplasmosis
Histiocytosis
Bacterial Infections: Morphological Diagnosis of Bacterial Infections
Culture
Not routinely available in microbiology labs
MICROSCOPIC PATHOLOGY
Histologic Features
Dense collections of foamy macrophages within
mucosa of small bowel is classic
In minimal disease, macrophages may be scattered
and special stains difficult to interpret
Liver, esophagus, stomach, and colon have been
documented with diseases in some cases
In chronic disease of liver, granulomas may be
seen without organisms
Loss of microvilli, lymphatic obstruction, and deposits
of lipid in tissues
In sites outside of gastrointestinal tract, macrophages
containing organisms are found in variable numbers
Suspected cases should always be confirmed with
2nd testing modality (PCR, IHC, FISH)
ANCILLARY TESTS
Histochemistry
Organisms are strongly PAS positive (with diastase)
within macrophages, giving characteristic diagnostic
appearance
Also positive on Gram stain, silver stains, and
Giemsa stain
Can be followed after treatment to determine
response to therapy
Organisms should be negative for AFB staining
Immunohistochemistry
Anti-T. whipplei antibodies confirm presence of
bacteria in tissue samples
In Situ Hybridization
Confirms infection (vs. contamination) in tissue
sections using RNA targets
PCR
Confirms presence of DNA in tissue sections using
DNA targets (16S rRNA) but requires secondary
confirmation (IHC, FISH)
Electron Microscopy
Bacteria with trilaminar cell wall structure
DIFFERENTIAL DIAGNOSIS
Mycobacterium avium-intracellulare
Complex Infection
Dense collections of macrophages in any part of
gastrointestinal tract (usually small bowel) that are
AFB positive
Histoplasmosis
Granulomas are more common, and organisms within
macrophages have halo (PAS and silver positive)
Histiocytosis
Lack of PAS(+) staining in collections of histiocytes
DIAGNOSTIC CHECKLIST
Clinically Relevant Pathologic Features
Systemic disease (symptoms) that may or may not
have gastrointestinal involvement
Pathologic Interpretation Pearls
PAS with diastase demonstrates positive collections of
macrophages that are AFB negative
SELECTED REFERENCES
1. Detlefsen S et al: Histiocytic disorders of the
gastrointestinal tract. Hum Pathol. 44(5):683-96, 2013
2. Moos V et al: Changing paradigms in Whipple’s disease
and infection with Tropheryma whipplei. Eur J Clin
Microbiol Infect Dis. 30(10):1151-8, 2011
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Microscopic Features
p
p
(Left) Hematoxylin & eosin
section shows that the
epithelium overlying the villi is
vacuolated with an admixed
neutrophilic infiltrate. (From
DP: Gastrointestinal.) (Right)
Light microscopy section
shows that the macrophages,
acked with the Whipple
bacillus, are strongly PAS
ositive. Note the admixed
fat droplets. (From DP:
Gastrointestinal.)
(Left) Numerous histiocytes
with abundant foamy
Bacterial Infections: Morphological Diagnosis of Bacterial Infections
cytoplasm and loosely
formed granulomas
are admixed with other
inflammatory cells. (From
DP: Lymphomas.) (Right)
The foamy histiocytes contain
abundant intracytoplasmic
amphophilic material with
a bluish hue. (From DP:
Lymphomas.)
WHIPPLE DISEASE
(Left) The foamy histiocytes
contain abundant
intracytoplasmic diastaseresistant periodic acidSchiff
(DPAS)positive material,
consistent with undigested
Tropheryma whipplei bacilli
and remnants. (From DP:
Lymphomas.) (Right) Gomori
methenamine silver stain
shows that the Tropheryma
whipplei bacilli cell walls
are also positive. (From DP:
Lymphomas.)
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WHIPPLE DISEASE
Radiology, Microscopic, and Special Stains
Bacterial Infections: Morphological Diagnosis of Bacterial Infections
(Left) Contrast-enhanced T1weighted MR shows typical
hypothalamic enhancement
in a patient with CNS
Whipple disease. (From DP:
Neuro.) (Right) Stereotypical
features of CNS Whipple
disease include loose
aggregates of histiocytes,
lymphocytes, and plasma
cells, all with surrounding
reactive astrocytosis .
When only focal, organismfilled macrophages may be
inconspicuous. (From DP:
Neuro.)
(Left) A grayish tinge is
helpful when suspecting
that the cytoplasm of
macrophages are filled
with organisms rather
than generic phagocytized
debris. Organisms are so
numerous that they cannot
be individually resolved.
(From DP: Neuro.) (Right)
Bacteria of Whipple disease
are positive on Grocott
methenamine silver (GMS)
stains. In part, they simulate
fungi, but lack yeast or
hyphal shapes. They are
also too small, even smaller
than histoplasma. (From DP:
Neuro.)
(Left) High-power view
of a PAS-stained section
of CNS Whipple disease
shows the intensely fuchsiacolored cytoplasmic clumps
of bacteria. These dense,
sickle-shaped inclusions
obscure detail, and only in
areas of lesser density are
individual bacteria resolved
. (From DP: Neuro.)
(Right) Immunostaining for
the bacteria Tropheryma
whipplei is a definitive
diagnostic test. (From DP:
Neuro.)
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