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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_182_библиотеки_им_акад_М_И_Перельмана.pdf
TRICHOMONIASIS
High magnification of this Pap smear shows a cluster
of pear- to kite-shaped Trichomonas vaginalis with
cytoplasmic granules and vesicular nuclei in association
with neutrophilic inflammation.
TERMINOLOGY
Definitions
Greek: "Trikhos" (hair) + "monas" (unit)
ETIOLOGY/PATHOGENESIS
Infectious Agents
Flagellated protozoan
Most common species causing human infection:
Protozoan Parasitic Infections: Morphologic Diagnosis of Protozoa in Anatomic Pathology
IV
Trichomonas vaginalis
Exhibit 4 anterior flagella, single 5th posterior
flagellum, and axostyle (bundle of microtubules)
that passes through cell and protrudes from
posterior end
Other trichomonads seen in humans
Trichomonas tenax: Generally considered
oropharyngeal commensal but rare cases of
respiratory infection caused by T. tenax resulting in
empyema have been reported
Trichomonas hominis: Isolated from human intestinal
tract; considered nonpathogenic but have been
proposed to be associated with diarrhea in some
studies
Trichomonas foetus: Mostly isolated from animals
but human peritonitis caused by T. foetus has been
reported
Pathogenesis
T. vaginalis destroys epithelial cells by direct cell
contact and release of cytotoxic substances
Protozoan internalizes its flagella and switches to
ameboid conformation while adhered to host cells
Transmission among adults occurs almost exclusively
via sexual contact
Infections in neonates are believed to be acquired
from birth canal of infected mothers
Cervical biopsy on H&E stain shows reactive epithelial
changes in association with acute and chronic
inflammation. No microorganism was detected but
concurrent Pap smear revealed trichomoniasis.
CLINICAL ISSUES
Epidemiology
Most common nonviral sexually transmitted disease
worldwide
More prevalent in women than in men
Risk factors: Unprotected sexual intercourse, new or
multiple sex partners, concurrent or history of other
sexually transmitted infections
Presentation
T. vaginalis causes urogenital tract infections
Women: Symptomatic in about 50% of cases
Most common symptom: Vaginitis with mucosal
erythema and greenish yellow, frothy, malodorous
discharge
In ~ 2% of acute infections: Colpitis macularis
(strawberry cervix) can be seen
Men: Asymptomatic in over 75% of cases
Most common symptom: Urethritis with dysuria
and urethral discharge
Treatment
Metronidazole or other nitroimidazoles, such as
tinidazole
Sex partners of infected patients should be treated
concurrently
Prognosis
Women: Untreated infections may progress to
urethritis or cystitis, and are associated with pelvic
inflammatory disease, infertility, increased risk of
cervical cancer, and susceptibility to HIV infection
Men: Untreated infections are associated with
prostatitis, epididymitis, infertility, and increased risk
of prostate cancer
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TRICHOMONIASIS
Etiology
Flagellated protozoan
Most common species causing human infection:
Trichomonas vaginalis
Transmission occurs mostly via sexual contact
Clinical Issues
Most common nonviral sexually transmitted disease
worldwide
T. vaginalis causes urogenital tract infections
Key Facts
More prevalent in women than in men
Risk factors: Unprotected sexual intercourse, new or
multiple sex partners, concurrent or history of other
sexually transmitted infections
Microscopic Pathology
Oval, round, pear-shaped, or kite-shaped protozoa
(length: 10 m; width: 7 m) with eosinophilic
cytoplasmic granules and vesicular nuclei
Associated with acute and chronic inflammation
Protozoan Parasitic Infections: Morphologic Diagnosis of Protozoa in Anatomic Pathology
MICROSCOPIC PATHOLOGY
Histologic Features
Associated with acute and chronic inflammatory
reaction as well as epithelial reactive changes
Trichomonads tend to lose morphologic characteristics
during fixation and staining
Cytologic Features
Oval, round, pear-shaped, or kite-shaped protozoa
(average length: 10 m; width: 7 m)
Exhibit eosinophilic cytoplasmic granules and
vesicular nuclei
Associated with acute inflammation and lymphocytes
Adjacent squamous cells may show reactive
changes including hyperchromatic nuclei and small
perinuclear halos that mimic low-grade squamous
intraepithelial lesion (LSIL) or atypical cells of
undetermined significance (ASCUS)
Microscopic Examination of Wet Mount
Motile flagellated trichomonads with jerky and
spinning motion
ANCILLARY TESTS
Wet Mount of Vaginal or Cervical Exudates
Sensitivity varies depending on inoculum size
Culture
Culture on traditional Diamond broth medium or its
variants generally takes 2-7 days to obtain result
InPouch culture system combining culture and
microscopy is commercially available with high
sensitivity (> 80%)
Antigen Test
Commercial immunoassay (OSOM Trichomonas Rapid
Test [Genzyme]) on vaginal swab specimen is available
with good sensitivity (> 82%) and specificity (97%)
Molecular Diagnostics
Commercial PCR-based assays are available with better
sensitivities than culture or wet mount methods
DIFFERENTIAL DIAGNOSIS
Other Sexually Transmitted Infections
Symptoms mimic those caused by other sexually
transmitted pathogens, e.g. Neisseria gonorrhoeae,
Mycoplasma genitalium; positive cytology or ancillary
tests confirm diagnosis of trichomoniasis
SELECTED REFERENCES
1. Edwards T et al: Trichomonas vaginalis: Clinical relevance,
pathogenicity and diagnosis. Crit Rev Microbiol. Epub
ahead of print, 2014
2. Zalonis CA et al: Rare case of trichomonal peritonitis.
Emerg Infect Dis. 17(7):1312-3, 2011
IMAGE GALLERY
(Left) Pap smear shows a neutrophilic cluster associated with a T. vaginalis , which can be subtle to detect when the protozoan load is low.
(Center) Pap smear shows 2 T. vaginalis protozoa
multiple filamentous bacteria
through the cell, suggestive of its axostyle.
consistent with Leptothrix vaginalis. A trichomonad appears to have a rod-shaped structure protruding
. One of them appears to have 2 flagella visible in the field. (Right) Pap smear shows
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AFRICAN TRYPANOSOMIASIS
Trypanosoma brucei has a prominent central nucleus ,
a dark-staining kinetoplast at the base of the flagellum ,
and an undulating membrane.
TERMINOLOGY
Abbreviations
Human African trypanosomiasis (HAT)
Synonyms
African sleeping sickness
ETIOLOGY/PATHOGENESIS
Environmental Exposure
Protozoan Parasitic Infections: Morphologic Diagnosis of Protozoa in Anatomic Pathology
East Africa: Zoonosis
Primary reservoir is wild animals
Glossina morsitans (tsetse fly) is primary vector
Tsetse flies transmit rarely to humans
Rapid (weeks) progression to death without
treatment
West Africa: Human to human
Reservoirs are humans (primary) and animals
Glossina palpalis (tsetse fly) is primary vector
Tsetse flies transmit human to human
Chronic (years) progression to death without
treatment
Infectious Agents
Trypanosoma brucei
East Africa: Trypanosoma brucei rhodesiense
West Africa: Trypanosoma brucei gambiense (98%)
The tsetse fly (engorged and not ) transmits
Trypanosoma brucei through a painful bite on exposed
skin, resulting in a large chancre. Infected flies bite more
frequently. (www.who.org)
Presentation
Initial stage: Hemolymphatic
Severe lymphadenopathy
Bite site chancre
Red, indurated, ulcerated
2nd stage: Neurological phase
Symptomatic invasion of central nervous system
Psychiatric manifestations
Circadian cycle disturbances
Irritability, aggression, bizarre behavior
Physical manifestations
Paralysis or hemiparalysis
Malaise, weakness, physical apathy
Tremors, movement disorders
Coma multiorgan failure death
Treatment
Drugs
T. brucei gambiense: Pentamidine (1st stage)
eflornithine nifurtimox (2nd stage)
T. brucei rhodesiense: Suramin (1st stage) melarsoprol
(2nd stage)
Melarsoprol carries risk of mortality from treatment
with drug but is the only modality available for 2nd
stage of T. brucei rhodesiense
Prognosis
Without treatment, disease is 100% fatal
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CLINICAL ISSUES
Epidemiology
97% of reported cases (2012)
Democratic Republic of Congo (> 5,000 cases, 84%)
Central African Republic (5%)
South Sudan (5%)
Chad (3%)
MACROSCOPIC FEATURES
General Features
Neuropathological exam at autopsy
Hemorrhagic leukoencephalopathy
Diffuse lymphadenopathy
Reactive lymph node
AFRICAN TRYPANOSOMIASIS
Etiology
East Africa: Rapid (weeks) progression
West Africa: Chronic (years) progression (98%)
Clinical Issues
Initial stage: Hemolymphatic
Severe lymphadenopathy and bite site chancre (early)
2nd stage: Neurological phase
Symptomatic invasion of central nervous system
Without treatment, disease is 100% fatal
Key Facts
Coma multiorgan failure death
Microscopic Pathology
Neuropathology: Meningoencephalitis
"Mott" cells: Plasma cells filled with immunoglobulin
Blood smear: Large, extracellular trypomastigote
forms of parasite
Lymph node FNA: Trypomastigote forms admixed
with reactive lymphoid cells
Protozoan Parasitic Infections: Morphologic Diagnosis of Protozoa in Anatomic Pathology
MICROSCOPIC PATHOLOGY
Histologic Features
Neuropathology: Meningoencephalitis
Meningeal inflammation including subarachnoid
space (plasma cells)
Perivascular collections of mononuclear
inflammatory cells ("cuffing")
Blood vessel and blood-brain barrier compromise
Vessel/parenchymal necrosis
Fibrin deposition
Presence of "Mott" cells: Plasma cells filled with
immunoglobulin
Cytologic Features
Peripheral blood smear
Large, extracellular trypomastigote forms of parasite
Flagellum with dark body at base (kinetoplastid)
Fine-needle aspiration of affected lymph node
Trypomastigote forms admixed with reactive
lymphoid cells
ANCILLARY TESTS
Serologic Testing
Card agglutination test for trypanosomiasis (CATT)
CSF examination (required)
White blood cell count in CSF correlates with
prognosis, dictates treatment
Organisms may be seen
DIFFERENTIAL DIAGNOSIS
Cerebral Malaria (CM)
More rapid onset and clinical course
Coma within 1 week of fever
Coma resolution or death within 48-72 hours with
treatment
Mortality: 10-20%
"Ring" hemorrhages confined to white matter with
parasite sequestration in vessels
Arsenic Toxicity
Melarsoprol is arsenic based
Demyelination and neuron apoptosis
Limited inflammation; lack of plasma cells
SELECTED REFERENCES
1. DPDx - Laboratory Identification of Parasitic Diseases
of Public Health Concern. Centers for Disease
Control and Prevention. http://www.cdc.gov/dpdx/
trypanosomiasisAfrican/index.html. Updated November
29, 2013. Accessed November 14, 2014
2. Singh AP et al: Mechanisms pertaining to arsenic toxicity.
Toxicol Int. 18(2):87-93, 2011
IMAGE GALLERY
(Left) Cross sections of brain at autopsy demonstrate hemorrhagic leukoencephalopathy associated with the final stages of African sleeping
sickness. Neurological lesions are irreversible. (Center) Perivascular cuffing with dense infiltrates of plasma cells is a common in the final stages.
(Right) High magnification of perivascular cuffing demonstrates plasma cells. (www.who.org)
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BABESIOSIS
Spleen from a patient who presented with spontaneous
rupture demonstrates a Babesia parasite within a red
blood cell . A week after the splenectomy, the patient
presented with babesiosis.
ETIOLOGY/PATHOGENESIS
Infectious Agents
Apicomplexan protozoa of genus Babesia
Babesia microti and B. microti-like
Primary vector for transmission is deer tick Ixodes
scapularis
Babesia divergens and B. divergens-like (WA-1 and MO-1
strains in Washington, California, and Missouri)
Primary vector for transmission is cattle tick Ixodes
Protozoan Parasitic Infections: Morphologic Diagnosis of Protozoa in Anatomic Pathology
ricinus
One of the most common transfusion-associated
infections due to asymptomatic cases
Cases have been reported associated with
transplacental transmission
CLINICAL ISSUES
Epidemiology
Incidence
911 cases were reported in 14 states in 2012
Geographical distribution
B. microti is endemic in northeastern and upper
midwestern USA
B. divergens is found in Europe
B. divergens-like strains WA-1 and MO-1 are
documented in Washington, California, and
Missouri
> 100 species of Babesia worldwide
Seasonality
Transmission mainly from May to September
Peripheral blood smear from a patient with babesiosis
demonstrates 3 pear-shaped merozoites as well as 2
"ring" stage trophozoites within red blood cells.
Complications include acute respiratory distress
syndrome, disseminated intravascular coagulation,
congestive heart failure, renal failure, liver failure,
splenic infarcts or rupture
Risk factors for severe illness include age > 50 years,
asplenic state, and coinfection with HIV or other
immunosuppressive conditions
Coinfections with Borrelia burgdorferi and Anaplasma
phagocytophilum should be evaluated in endemic areas
as all are transmitted by Ixodes species
Laboratory Tests
Parasitemia ranges from 1-20% in patients with
functional spleens
Mild disease is associated with parasitemia of 4-5%
Low hematocrit, elevated LDH, low hemoglobin,
elevated total bilirubin, low haptoglobin,
reticulocytosis, thrombocytopenia, transaminitis
Treatment
Adjuvant therapy
Red cell exchange transfusion should be considered
for patients with parasitemia > 10% at risk for
pulmonary, renal, or hepatic complications with
goal of 90% reduction in parasitemia
Drugs
For B. microti, standard therapy is 7-10 day regimen
of atovaquone plus azithromycin or clindamycin
plus quinine
For B. divergens, standard therapy is clindamycin
and quinine with exchange transfusion, as course is
more frequently fulminant
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Presentation
Symptoms range from mild to severe and usually
develop 1-6 weeks post tick bite
Fatigue, malaise, weakness, fever, chills, sweats,
hemoglobinuria, and jaundice arthralgia
MICROBIOLOGY
Organism
Pear-shaped (a.k.a. piroplasms) apicomplexan parasites
that invade and subsequently lyse red blood cells
Etiology
Apicomplexan protozoa of genus Babesia
Clinical Issues
B. microti is endemic in northeastern and upper
midwestern US
B. divergens-like strains WA-1 and MO-1 are
documented in Washington, California, and Missouri
Symptoms include fatigue, malaise, weakness, fever,
chills, sweats, hemoglobinuria, jaundice arthralgia
BABESIOSIS
Key Facts
Coinfections with Borrelia burgdorferi and Anaplasma
phagocytophilum should be evaluated in endemic areas
as all are transmitted by Ixodes species
Microscopic Pathology
Diagnosis primarily made by blood smear showing
parasites with distinguishing features including
"Maltese cross" (occasional merozoites arranged in
tetrads) &/or intraerythrocytic ring forms
Protozoan Parasitic Infections: Morphologic Diagnosis of Protozoa in Anatomic Pathology
MICROSCOPIC PATHOLOGY
Histologic Features
Diagnosis primarily made by blood smear showing
parasites with distinguishing features including
"Maltese cross" (occasional merozoites arranged in
tetrads) &/or intraerythrocytic ring forms
Blood smear may reveal hemolysis
ANCILLARY TESTS
PCR
18s rRNA PCR is more sensitive than blood smear
Serologic Testing
Indirect immunofluorescent antibody testing available
for asymptomatic individuals
B. microti serologies will not detect WA-1 or MO-1
strains, B. duncani, B. divergens, or B. venatorum
DIFFERENTIAL DIAGNOSIS
Malaria (Plasmodium Species)
Peripheral blood smear parasites may be very difficult
to distinguish and may require PCR for definitive
diagnosis
Babesia lacks hemozoin, is dyssynchronous, shows
tetrads, and has extraerythrocytic forms
Lyme &/or Anaplasmosis
Because of cotransmission in Ixodes vector, these
infections should be evaluated when Babesia is seen
on peripheral smear or suspected due to tick exposure
history
DIAGNOSTIC CHECKLIST
Clinically Relevant Pathologic Features
"Maltese cross": Merozoites arranged in tetrads
Parasites may be intra- or extraerythrocytic, have
round to pear shape
Pathologic Interpretation Pearls
Babesia may be mistaken for malarial parasites such as
ring forms of P. falciparum (clinical history is key)
SELECTED REFERENCES
1. Vannier E et al: Human babesiosis. N Engl J Med.
366(25):2397-407, 2012
2. Herwaldt BL et al: Transfusion-associated babesiosis in
the United States: a description of cases. Ann Intern Med.
155(8):509-19, 2011
IMAGE GALLERY
(Left) Peripheral blood smear with babesiosis demonstrates 4 pear-shaped merozoites ("tetrad" form) as well as 2 "ring" stage trophozoites
within red blood cells. A reticulocyte is also seen. (Center) Numerous trophozoite forms in various stages of babesiosis are shown. (Right)
Numerous trophozoite forms in various stages of Babesiosis are shown. These forms appear much smaller than the ring stages of Plasmodium,
the main differential diagnosis.
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MALARIA
Cerebral gray-white junction is shown in a patient
who died of cerebral malaria with classic petechial
hemorrhages limited to the white matter.
TERMINOLOGY
Synonyms
Plasmodium falciparum infection
Plasmodium vivax infection
Plasmodium ovale (subsp curtisi or subsp wallikeri)
infection
Plasmodium malariae infection
Plasmodium knowlesi infection
Miasma (Ancient Greek)
Protozoan Parasitic Infections: Morphologic Diagnosis of Protozoa in Anatomic Pathology
Febris tertiana or Febris quartana (Latin)
Marsh fever
Tertian ague (Middle French)
Definitions
Italian: "Mal" (bad) + "aria" (air)
From association with swamps and disease
Latin: "Plasma" (mold, formation)
From the morphological forms of a mass of nuclei
(schizont)
Latin: "Falx/flac" (sickle) + "parus" (bearing)
From the sickle-shaped form of gametocytes
Latin: "Vivace" (brisk, lively, long lived)
From its periodic recurrence due to liver
reemergence
Latin: "Ovalis" (egg shaped)
From the oval to egg-shaped deformation of red
blood cells during infection
"knowlesi" from Robert Knowles: 1st described P.
knowlesi (1931)
"curtisi" from Christopher Curtis and "wallikeri" from
David Walliker
ETIOLOGY/PATHOGENESIS
Environmental Exposure
IV
Malaria endemicity is closely tied to temperature,
rainfall, and Anopheles mosquito populations
1
Ring hemorrhages in various stages of evolution are
shown in the white matter of the cerebrum of a patient
who died of cerebral malaria. Note lack of hemorrhages
in the gray matter .
Depending on location, endemicity is classified by
transmission status
Stable endemic (holoendemic, hyperendemic,
mesoendemic)
Unstable endemic (hypoendemic)
In highly endemic regions, children bear bulk of
disease and mortality
Adult counterparts achieve nonsterile immunity
from disease
In low-endemicity regions, epidemics may occur and
all ages are at risk for infection
Travelers not on prophylaxis traveling to regions
with malaria and exposed to mosquitos are at risk
for mild to severe disease
Infectious Agents
Plasmodium species protozoa parasites
Single-cell apicoplexan (containing an apicoplast)
Life cycle includes a vector (mosquito) and
vertebrate host
P. falciparum and P. malariae cycle through liver
once
P. ovale and P. vivax may remain in liver as
hypnozoites for long periods
5 main species cause mosquito to human
transmission
P. falciparum, P. ovale (2 subspecies), P. malaria, P.
vivax
P. ovale was found to be 2 subspecies, P. ovale
curtisi and P. ovale wallikeri by molecular studies
but are clinically indistinguishable
1 species causes mosquito-to-human transmission in
presence of primate natural host
P. knowlesi
Organisms are present in peripheral blood (all
species) and sequestered in deep endothelial beds (P.
falciparum)
P. falciparum modulates surface of infected red
blood cell to create "knobs"
24
Etiology
Malaria endemicity is closely tied to temperature,
rainfall, and mosquito populations
Organisms are present in peripheral blood (all
species) and sequestered in deep endothelial beds (P.
falciparum)
Clinical Issues
Cerebral malaria (P. falciparum)
Comatose, peripheral P. falciparum parasitemia
Low platelets, high lactate, hypoglycemia
Placental malaria (P. falciparum)
Symptoms of malaria up to cerebral malaria
Placental is site of sequestration for P. falciparum
parasites expressing a specific type of knob protein
MALARIA
Key Facts
Microscopic Pathology
Brain
Placenta
Top Differential Diagnoses
Severe hypoglycemia of newborn
Fat embolism after traumatic bone fracture
Protozoan Parasitic Infections: Morphologic Diagnosis of Protozoa in Anatomic Pathology
Sequestration of parasites is present in small vessels
from trophozoite to schizont stage
> 20% of vessels parasitized = cerebral malaria
Ring hemorrhages are associated with current or
previous sequestration in cerebral malaria
Active infection: Parasites of various stages
adherent to and within maternal blood space,
pigment-laden macrophages, leukocyte infiltration
Knobs contain highly variable proteins, which
bind to a range of human ligands
During latter half of P. falciparum 48-hour life
cycle, parasites adhere to endothelium and do not
circulate
CLINICAL ISSUES
Epidemiology
Geographic distribution of malaria infection has
changed dramatically within last 100 years, shrinking
to involve only South America, Africa, and South and
Southeast Asia, predominantly
P. falciparum is the most common parasite causing
infection in Africa
Subtropical areas of Central and South America,
Africa, and Southeast Asia
P. vivax is the most common parasite causing infection
outside of Africa
Central and South America, India, and Southeast
Asia
Recent resurgence of P. vivax cases in East Africa are
reported
P. ovale is found is found primarily in sub-Saharan
Africa but is seen in similar distributions to P. vivax
P. malariae is found subtropical areas of Central and
South America, Africa, and Southeast Asia
P. knowlesi is found in Southeast Asia in areas
inhabited by long-tailed macaques
Presentation
Asymptomatic infection
Screened individuals from endemic areas may have
circulating parasites with no clinical symptoms
Treatment of these individuals should be based on
elimination/eradication goals, local drug resistance
prevention efforts, and risk group
Children < 5 years of age and pregnant women
should be treated
Symptomatic infection
Fever and malaise
Most common symptom (and most nonspecific)
Abdominal pain, vomiting, diarrhea
Headache, somnolence, loss of consciousness, coma
Severe disease classification
Severe malaria anemia (P. falciparum)
Disease of very young children in endemic regions
Anemia (hemoglobin < 5 g/dL, hematocrit < 15%)
High risk of mortality without treatment
Antimalaria agents and blood transfusions
Acidosis (P. falciparum)
Disease of children in endemic regions
High respiratory rate with respiratory acidosis
High levels of plasma lactate
Antimalaria agents and ventilatory support
Cerebral malaria (P. falciparum)
Disease of young children in endemic regions, and
all ages in low-endemicity regions
Comatose, peripheral P. falciparum parasitemia
Low platelets, high lactate, hypoglycemia
Antimalaria agents (mortality is 15-25% with
treatment)
Retinal examination by ophthalmoscopy will
reveal malaria-specific retinal changes including
hemorrhages, vessel whitening, and peripheral
whitening
Placental malaria (P. falciparum)
Primigravid women are more at risk in endemic
areas
Placenta is site of sequestration for P. falciparum
parasites expressing a specific type of knob protein
Symptoms of malaria up to cerebral malaria
Antimalaria agents as prophylaxis, delivery
P. vivax severe infection
Age range: Infants up to early 20s (mortality < 1%)
Respiratory failure is primary symptom in "pure P.
vivax"
Malnutrition, gastrointestinal diseases, sepsis, and
HIV in combination with P. vivax has increased
mortality
P. knowlesi severe infection
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Clinically similar to P. falciparum with respiratory
symptoms predominating, renal failure, and
thrombocytopenia, but without coagulopathy
Mortality from disease is < 2% (significantly
higher than other non-falciparum malarias)
Laboratory Tests
Peripheral blood smear (primary diagnostic tool)
Identification of blood-stage parasites with
quantification and speciation based on morphology
P. falciparum = ring-stage parasites in small
infected cells and banana-shaped gametocytes
P. vivax = Schffner dots, amoeboid forms, large
infected cells
P. ovale = Schffner dots, oval large infected cells
with fimbria, "comet form"
P. malariae = small infected cells, "band" forms,
"daisy" forms
P. knowlesi = very similar to (often confused with)
P. malariae (PCR required for definitive diagnosis)
Best estimate of response to therapy (decreasing
parasitemia)
Rapid diagnostic tests ("dipsticks")
Assess presence of Plasmodium-specific antigens in
peripheral blood by lateral flow assay with antibody
detection
Primarily available for P. falciparum and P. vivax
Usually sufficiently captures P. ovale, P. malariae, and
P. knowlesi nonspecifically
Peripheral Blood PCR
Single or multispecies primer sets, which detect
presence of DNA
May remain positive for weeks after successful
treatment of disease
Protozoan Parasitic Infections: Morphologic Diagnosis of Protozoa in Anatomic Pathology
Complete blood count
Thrombocytopenia (P. falciparum, P. knowlesi)
Treatment
Adjuvant therapy
Blood transfusions are life-saving in severe malaria
anemia
Red blood cell exchange is used in severe disease,
with some success
Fluid rehydration, respiratory support, dialysis, and
other intensive care measures may be required in
severe disease
Drugs
Standard of care for most clinical cases is 2-drug
combination therapy with an artemisinin agent for
P. falciparum
Intravenous artesunate for severe disease is
recommended therapy of choice for P. falciparum
Intermittent preventive therapy (IPT) for malaria
in pregnancy is sulfadoxine/pyrimethamine,
which is effective despite resistance in most
endemic areas
P. vivax/P. ovale = chloroquine with primaquine (liver
stages)
P. malariae = chloroquine
P. knowlesi = chloroquine with primaquine
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MALARIA
Prognosis
MICROBIOLOGY
Parasite Characteristics
Culture
Life Cycle
Overall mortality from malaria infection is < 1%
Cerebral malaria is 15-20%, regardless of treatment/
intervention
Pediatric endemic patients succumb within 48 hours
(or recover)
Patients in low-endemicity areas may succumb
quickly or after several weeks (multiorgan failure)
Apicoplexan parasites with large-for-organism
size genomes (30 Mbp) organized into 14 haploid
chromosomes
Obligate intracellular stages (asexual) within human
host
Highly diverse parasite with surface antigen families
50x more diverse than human leukocyte antigen
families
Resistance to antimalaria compounds develops
primarily through parasite genetic diversity, variable
drug pressure, and recombination in highly endemic
areas
P. falciparum (48-hour life cycle) can be grown in cell
culture media with red blood cells, human serum, and
high carbon dioxide environment at 37 C for research
purposes
P. knowlesi (24-hour life cycle) can be grown under
similar conditions to P. falciparum
To date, P. vivax, P. ovale, and P. malariae cannot be
propagated in long-term culture
Sexual cycle (mosquito: 10-18 days)
Mosquitoes take a blood meal from a human and
ingest male and female gametocytes
In midgut of mosquito, male exflagellates
into a microgametocyte, which enters female
macrogametocyte and results in an ookinete
forming
Ookinete is mobile and migrates to midgut wall
and forms oocysts
Within oocysts, infected sporozoite forms develop
which, when mature, migrate to mosquito salivary
glands (8-15 days)
At the next blood meal, sporozoites enter skin
with mosquito saliva
Asexual cycle (human, disease causing)
Within a few minutes, the sporozoites migrate
through the blood to the liver and penetrate
hepatocytes
Within infected hepatocyte, sporozoite transforms
and multiplies into thousands of merozoites within
a liver schizont (5-16 days)
Liver schizont ruptures, which releases the
merozoites into circulation
Within a few minutes in circulation, all merozoites
have invaded red blood cells
26
Parasite matures as an early trophozoite (ring), and
then later stage trophozoites
In P. falciparum, only ring forms circulate as
later trophozoite stages and schizont stages are
sequestered through adherence to endothelium
Trophozoites become schizonts when parasite
replicates to form 16-24 merozoites
When mature, schizont ruptures, releasing
merozoites, which reinvade red blood cells
Merozoite to schizont cycle is 24-72 hours,
depending on species
Gametocytogenesis
Through unclear mechanisms, some trophozoites
are destined to become gametocytes
When asexual trophozoites are sequestering in deep
tissues, developing gametocytes move into bone
marrow
After 5-7 days, the gametocytes are mature and
return to circulation as infective banana-shaped
forms
These forms are taken up by mosquitoes during a
blood meal
MACROSCOPIC FEATURES
Brain
Pediatric cerebral malaria
Swollen and congested brain purple/gray
discoloration petechial hemorrhages in the white
matter
Purple/gray discoloration is related to malaria
pigment content
Petechial hemorrhages occur in mid- to late-stage
disease
Adult cerebral malaria
Congested brain purple/gray discoloration
petechial hemorrhages in white matter
Brain swelling/edema is not commonly seen in
adults
Liver
Fatal malaria
Dark purple to black discoloration secondary to
malaria pigment
Spleen
Fatal malaria
Enlarged, often massive spleen
Dark purple to black discoloration secondary to
malaria pigment
Acute abdomen
Spleen may rupture (more common in travelers)
Multiorgan Failure
In fatal adult cerebral malaria, prolonged illness with
multiorgan failure may lead to common nonspecific
features such as heavy, infiltrated lungs, boggy,
swollen kidneys, and scattered tissue hemorrhages
MALARIA
MICROSCOPIC PATHOLOGY
Histologic Features
Brain
Lung
Liver
Spleen
Bone marrow
Heart, kidney, gastrointestinal tract, and other organs
Placenta
Sequestration of parasites is present in small vessels
from trophozoite to schizont stage
Density/quantity of sequestration is directly
related to pathological diagnosis
> 20% of vessels parasitized = cerebral malaria
< 20% of vessels parasitized = severe malarial
anemia, incidental malaria, other cause of death
Associated with demyelination of adjacent tissue,
blood brain barrier compromise (leakage), and
axonal injury
Ring hemorrhages are associated with current or
previous sequestration in cerebral malaria
Parasite elements (e.g., sequestered parasites,
pigment globules, red cell ghosts) in vessel
adjacent to hemorrhage
Fibrin thrombi present in vessel adjacent to
hemorrhage
With long survival, progress to "healing" stage of
Drck granuloma
Microinfarctions: Tissue is rarified with scattered
dead neurons when adjacent to blood vessel with
ring hemorrhage
Substantial amounts of parasite hemozoin pigment
within macrophages, with limited sequestered
parasite biomass
Macrophages with parasite hemozoin pigment
found throughout parenchyma (active infection) or
concentrated in portal triads (prior infection)
Primary site of parasite clearance with massive loads
of hemozoin pigment in any malaria patient
Red pulp is greatly expanded with macrophages &/
or parasites in development
White pulp is normal or may be very prominent/
reactive
Increased numbers of gametocytes in development
are found in marrow parenchyma (developmental
niche)
Sequestration of parasites is present is small vessels
from trophozoite to schizont stage
May be seen in any type of malaria diagnosis but
massively increased in cerebral malaria (total body
density is elevated)
Active infection: Parasites of various stages adherent
to and within maternal blood space, pigment-laden
macrophages, leukocyte infiltration
Prior infection: Fibrin-entrapped collections of
malaria pigment
Protozoan Parasitic Infections: Morphologic Diagnosis of Protozoa in Anatomic Pathology
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