Articulo de Ingles de Lady

Clin Lab Med 24 (2004) 737–772
Emerging parasitic infections

John D. Christie, PhD, MDa,*,
Lynne S. Garcia, MS, MT, FAAMb
a
Department of Pathology and Laboratory Medicine, Brody School of Medicine at
East Carolina University, Greenville, NC 27834, USA
b
Director, LSG & Associates, 512 12th Street, Santa Monica, CA 90402, USA
In the First World, as exemplified by Canada, Western Europe, and the

United States, the impact of and attention paid to parasitic infections varies.
Indigenous parasitic infections in these regions fall into several categories. A
few infections such as trichomoniasis and pinworm are fairly common;
other parasites are held in check by the host’s immune system and are only
symptomatic when the host becomes immunocompromised. Other infec-
tions, such as cryptosporidiosis and giardiasis, can occur in epidemic form
and cause thousands of clinical infections when the right circumstances
occur. Finally, some parasites are extremely rare, and when cases do occur,
they are brought to the attention of the public by the media.
The impact of parasitic infections in the Third World is brought home to
citizens of the First World when the tourist, soldier, or immigrant returning
or migrating from these less developed countries is infected with parasites
endemic to them. However, only when natural or manmade disasters cause
an increase in the incidence of parasitic diseases in the Third World or when
multinational institutions start campaigns against these diseases in regions
where they are endemic does the true global impact of parasitic diseases
become evident. Because parasitic infections come to the attention of the
scientific and lay populations of developed countries by these various routes,
at any particular time, different parasitic infections may be deemed
‘‘emerging.’’ With this caveat in mind, the authors review those parasitic
infections that can be deemed emerging at this time.
* Corresponding author.
E-mail address: jchristie@pcmh.com (J.D. Christie).
0272-2712/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.cll.2004.05.010
738 J.D. Christie, L.S. Garcia / Clin Lab Med 24 (2004) 737–772
Common infections in the United States

Trichomoniasis and its importance in the transmission of sexually
transmitted diseases
Life cycle
Trichomonas vaginalis has only the trophozoite stage, which measures
7 lm to 23 lm long and 5 lm to 15 lm wide, in its life cycle. This organism,
like the other trichomonads, divides by binary fission. The axostyle is
usually extremely obvious, and the undulating membrane stops halfway
down the side of the trophozoite (Fig. 1). The nuclear chromatin is
uniformly distributed, and there are a large number of siderophil granules
that tend to be most evident around the axostyle. Normal body sites for
these organisms include the vagina and prostate. Apparently the organisms
feed on the mucosal surface of the vagina, where bacteria and leukocytes are
found. The preferred pH for good growth is slightly alkaline or acid, not the
normal pH of the healthy vagina. Although the organisms can be recovered
in urine, in urethral discharge, or after prostatic massage, the pH preference
of the organisms in the male has not been determined. The organisms can be
recovered in the spun urine sediment from both male and female patients.
T vaginalis is site-specific and usually cannot survive outside the urogenital
system. Infection is acquired primarily through sexual intercourse, hence the
need to diagnose and treat asymptomatic males. The organism can survive
for some time in a moist environment such as damp towels and un-
derclothes; however, this mode of transmission is thought to be very rare.
Clinical manifestations
The normal incubation period ranges from 4 to 28 days. Infections
can result in inflammation and large numbers of trophozoites in the tissues
Fig. 1. Trichomonas vaginalis. Note the undulating membrane (stops about midway down the
organism) and the supporting rod protruding from the bottom of the trophozoite (axostyle).
(1000, silver stain.)
J.D. Christie, L.S. Garcia / Clin Lab Med 24 (2004) 737–772 739
and the secretions. Vaginal secretions are liquid, greenish or yellowish,

sometimes frothy, and foul-smelling. As the infection shifts from acute to
chronic, the purulent discharge diminishes, with an associated decrease in
the number of organisms. The onset of symptoms such as vaginal or vulval
pruritus and discharge can be sudden and often occurs during or after
menstruation as a result of the increased vaginal acidity. Approximately
20% of women with vaginal trichomoniasis have dysuria, a symptom that
may occur before other symptoms. Infection in the male may be latent and
asymptomatic or may be present as self-limited, persistent, or recurring
urethritis. In nonspecific urethritis, T vaginalis has been detected in 10% to
20% of subjects and in 20% to 30% of those whose sexual partners had
vaginitis [1].
Diagnosis
Diagnosis is often based on the examination of wet preparations of
vaginal and urethral discharges and prostatic secretions; more than one
specimen may need to be examined to detect the organisms. These
specimens, as well as urine sediment, can be examined using low light and
the low and high dry objectives of the microscope. As the jerky motility of
the trophozoite diminishes, it may be possible to see the movement of the
undulating membrane, particularly under high dry power. Specimens should
never be refrigerated. Motility of T vaginalis in wet mount preparations is
limited, with 35% of organisms nonmotile 30 minutes after placement on a
glass slide [2]. Because the morphology of nonpathogenic Pentatrichomonas
hominis from stool is very similar to that of pathogenic T vaginalis, it is
important to ensure that the specimen is not contaminated with fecal
material, because T vaginalis infection is considered a sexually transmitted
disease. Diagnostic tests other than wet preparations, such as permanent
stains, fluorescent stains, and culture, can also be used. Organisms may be
difficult to recognize in permanent stains; however, if a dry smear is
submitted to the laboratory, Giemsa or Papanicolaou stain can be used.
Chronic Trichomonas infections may cause atypical cellular changes that can
be misinterpreted, particularly on the Papanicolaou smear. Organisms are
routinely missed on Gram stains. Other test options available include latex
agglutination, direct fluorescent antibody staining, immunochromato-
graphic assay and polymerase chain reaction (PCR).
Current relevance
It is estimated that 5 million women and 1 million men in the United
States have trichomoniasis. Worldwide, the annual incidence is estimated to
be more than 170 million cases, which does not include asymptomatic cases
that are not diagnosed or treated. Trichomoniasis is now the most prevalent
nonviral sexually transmitted disease worldwide. These infections have
major health consequences for women, including pregnancy complications,
association with cervical cancer, and predisposition to HIV infection. It has
also been documented that, for HIV-positive men with symptomatic

urethritis, the median HIV RNA concentration in seminal plasma is
significantly higher in men with trichomoniasis than in those without [3].
Infections in HIV-positive individuals

Toxoplasmosis
Life cycle. Humans can acquire infection with Toxoplasma gondii in several
ways: by the accidental ingestion of oocysts shed in cat feces, by the
ingestion of rare or raw meats, in utero, and by transfusion. The most
common means of infection is probably ingestion of rare or raw meats. The
oocysts shed in the cat feces are 9 lm to 11 lm wide by 11 lm to 14 lm long
and contain two sporocysts, each containing four sporozoites. The
organisms are obligate intracellular parasites and are found in two forms
in humans. The actively proliferating tachyzoites are generally seen in the
early, more acute phases of the infection (Fig. 2). The resting forms or cysts
are found primarily in muscle and brain, probably as a result of the host’s
immune response. The cysts contain the more slowly growing trophozoites
or bradyzoites. Bradyzoites encyst approximately 8 to 10 days after entry
into the host and differ from tachyzoites in being more resistant to pepsin,
having a slower generation time, containing cytoplasmic vacuoles that may
serve as carbohydrate stores, and being the only stage to initiate the entero-
epithelial cycle and transform into oocysts in the feline intestine.
The trophozoites (tachyzoites) are crescent-shaped and 2 lm to 3 lm
wide by 4 lm to 8 lm long. One end tends to be more rounded than the
other. Giemsa is the stain of choice; the cytoplasm stains pale blue, with the
nucleus staining red and situated toward the broad end of the organism.
Fig. 2. Toxoplasma gondii. Note the actively proliferating tachyzoites (mouse peritoneal fluid)
(A, 1000, Giemsa stain) and the bradyzoites within the cysts that are seen in human cardiac
tissue (B, 1000, hematoxylin and eosin stain).
There are three infectious stages of T gondii: the tachyzoites in groups,

the bradyzoites in tissue cysts, and the sporozoites in oocysts. Tachyzoites
rapidly multiply in any cell of the intermediate host, including humans and
other animals, and in nonintestinal epithelial cells of the cat, the definitive
host. Bradyzoites are found within the tissue cysts and multiply at a very
slow rate; the cyst may contain few to hundreds of organisms, and
intramuscular cysts may reach 100 lm in size. Although the tissue cysts
may develop in visceral organs such as the lungs, liver, and kidneys, they are
more prevalent in neural and muscular tissues, including the brain, eyes, and
skeletal and cardiac muscle. These intact tissue cysts can persist for the life
of the host and do not cause an inflammatory response.
Clinical manifestations. The large number of individuals who test serolog-

ically positive for T gondii suggests that most infections are benign, with
people exhibiting few or no symptoms. The most severe symptoms are seen
in congenital, transplacental infections and infections in the compromised
patient. Infections in the compromised patient can lead to severe compli-
cations; underlying conditions include various malignancies, such as
Hodgkin’s disease, non-Hodgkin’s lymphomas, leukemias and solid tumors,
collagen vascular disease, organ transplant, and AIDS. The central nervous
system (CNS) is primarily involved in the immunocompromised patient,
with diffuse encephalopathy, meningoencephalitis, or cerebral mass lesions.
More than half of these patients will show altered mental state, motor
impairment, seizures, abnormal reflexes, and other neurologic sequelae.
Even in these compromised patients, studies show that most who receive
chemotherapy for toxoplasmosis will improve significantly or have complete
remission. However, in patients with AIDS, therapy must be continued for
long periods to maintain a clinical response, and Toxoplasma encephalitis
(TE) has been reported as a life-threatening opportunistic infection.
Respiratory disease due to T gondii has been rarely recognized in im-
munocompromised patients, and the few cases that have been reported in
HIV-positive patients have been in association with CNS disease.
Diagnosis. Diagnosis can be made using various serologic or histologic

procedures. The latter include examining biopsy specimens, buffy coat cells,
or spinal fluid and isolating the organism in tissue culture or in laboratory
animals. While some authorities believe that the histologic appearance of
lymph nodes in infected individuals is very characteristic, others consider the
histologic changes to be nonspecific. Because many individuals have been
exposed to T gondii and may have cysts within the tissues, recovery of
organisms from tissue culture or animal inoculation may be misleading; the
organisms may be isolated but may not be the causative agent of disease.
For this reason, serologic tests are often recommended as the diagnostic
approach of choice. However, two representative situations in which the
detection of organisms may be very significant are (1) tachyzoite-positive
smears or tissue cultures inoculated from cerebrospinal fluid and (2) in cases
of acute pulmonary disease, the demonstration of tachyzoites in Giemsa-
stained smears of bronchoalveolar lavage fluid [4].
The serologic diagnosis of toxoplasmosis is very complex and has been
discussed extensively in the literature; a number of additional procedures,
some of which are automated, have been developed and reported in the last
few years [5]. These methods include enzyme immunoassays, some of which
are automated, ELISAs, direct agglutination, immunosorbent agglutina-
tion assays, indirect immunofluorescence assays, immunocapture, and
immunoblot.
Antigen detection is very helpful in the compromised patient in whom
antibody titers are low or absent. This serologic approach can also clarify
low titers (ie, those found in early acute infection or chronic infection). This
test capability can also be helpful in patients with monoclonal gammopa-
thies, whose titers to T gondii may be extremely high without causing the
clinical condition.
Current relevance. In transplant recipients, disease severity depends on

previous exposure to T gondii by the donor and recipient, the type of organ
transplanted, and the patient’s level of immunosuppression. Disease can be
related to reactivation of a latent infection or an acute primary infection.
Serologic tests of sera obtained in the National Health and Examination
Study for 1999 to 2000 indicated that 15.8% of United States civilians are
positive for T gondii IgG antibodies and are thus at risk for reactivation of
latent infection [6].
When the CD4þ T-lymphocyte count of patients who are infected with T
gondii falls below 100,000 per mL, they may develop disease. Often fever
and malaise precede the first neurologic symptoms (eg, headache, confusion,
seizures or other focal signs) that can suggest the diagnosis of toxoplasmo-
sis. Disseminated toxoplasmosis should be considered in the differential
diagnosis of compromised patients with culture-negative sepsis. Although
an inflammatory process is seen during TE in HIV-positive patients,
uncontrolled parasite multiplication is probably the major cause of CNS
lesions. The parasite can enhance HIV-1 replication within host cells, and
HIV-1 itself undermines acquired immunity to the parasite, thus promoting
reactivation of chronic toxoplasmosis.
Microsporidiosis
Life cycle. Microsporidia were recognized as causing disease in animals as
early as the 1920s but were not recognized as human pathogens until the
AIDS pandemic began in the mid-1980s. Several earlier human cases had
been reported but were thought to be very unusual. Currently, multiple
genera and species of microsporidia have been implicated in human
infections, and with more than 1000 known species of microsporidia, one
can expect confirmation of additional human parasites in the future.
The infective spore is the only life-cycle stage that survives outside of the
host; it is usually acquired through ingestion, inhalation, or transmission of
spores through contaminated environmental surfaces. Infection occurs with
the introduction of infective sporoplasm through the polar tubule of the spore
into the host cell. Through binary fission (merogony) or multiple fission
(sporogony), microsporidia multiply extensively within the host cell cyto-
plasm. During sporogony, environmentally resistant spores are formed [7].
Clinical manifestations. In the immunocompromised host, microsporidial

infection may lead to overwhelming disease and death. The first cases of
human microsporidiosis were identified in children with impaired immune
systems, and infections have been widely recognized and studied in
individuals with AIDS, primarily those with fewer than 100 CD4þ
T-lymphocytes. Infection has also been recognized in organ transplant
recipients who are intentionally immunosuppressed before and after trans-
plantation. Symptoms depend on the body site infected, and all body sites
have been parasitized by one or more species. Disseminated infections can
occur in humans. The most commonly encountered infections are those seen
in the gastrointestinal tract, where symptoms include intractable diarrhea,
fever, malaise, and weight loss. AIDS patients, who may be severely
immunodeficient, tend to have four to eight watery, nonbloody stools each
day, which can be associated with nausea and anorexia. Dual infections with
both Encephalitozoon intestinalis and Enterocytozoon bieneusi have been
seen, and disseminated disease can be associated with both genera.
Diagnosis. Although microsporidia have been identified in routine histo-

logic preparations, they do not stain predictably and can be difficult to find.
Although it is not available to all laboratories, electron microscopy is still
considered the best diagnostic method, particularly if organism identifica-
tion to the genus or species level is required [8]. Clinical specimens stained
with modified trichrome stains are acceptable; however, examination of the
material must be performed using the 100 oil immersion objective (Fig. 3).
Other stains, such as Giemsa, are used, as is Calcofluor white, an optical
brightening agent that stains the spore coat. Antigen detection, molecular
methods, cell culture, and serologic testing are currently in development in
the research setting.
Current relevance. Although the sources of human infection are not yet
completely defined, possibilities include human-to-human transmission and
animal-to-human transmission. Many questions related to reservoir hosts
and possible congenital infections remain unanswered. The presence of
microsporidia has been confirmed in tertiary sewage effluent, surface water,
and groundwater. Precautions should be taken when handling body fluids,
and hand washing may be important in preventing primary infections in the
health care setting. Treatment has been somewhat variable, although
Fig. 3. Microsporidial spores. Note the horizontal ‘‘stripes’’ in several of the spores, which
represent the polar tubule (1000, modified Ryan Blue trichrome stain).
a complete parasitologic cure for Encephalitozoon intestinalis is possible with

albendazole. Unfortunately, this drug appears to be ineffective in treating
Enterocytozoon bieneusi infections. Other drugs appear to be static, rather
than cidal.
Epidemics in the United States

Cryptosporidiosis
Life cycle
The developmental stages of Cryptosporidium parvum are found in an
intracellular, extracytoplasmic location within parasitophorous vacuoles of
host cell origin; these vacuoles are found at the microvillous surface of the
host cell. The presence of a thin-walled autoinfective oocyst can lead to an
overwhelming infection in a susceptible host and explains the persistent, life-
threatening infections in immunocompromised patients in the absence of
repeated exposure to oocysts. Oocysts undergo sporogony while in the host
cells and are immediately infective when passed in the stool. The prepatent
period from oocyst ingestion to completion of the life cycle varies from 4 to
20 days in humans. The thick-walled oocyst is environmentally resistant and
shows high levels of resistance to most commercial disinfectants. It is now
recognized that various animals serve as potential sources of human
infections, and direct person-to-person transmission is likely.
In the immunocompetent individual, clinical symptoms include nausea,
low-grade fever, abdominal cramps, anorexia, and 5 to 10 watery, frothy
bowel movements per day, which may be followed by constipation.
These infections are self-limited and usually subside within a few weeks.
However, when CD4þ cell count drops below 200/lL, the infection may
become chronic and not resolve. The difference in outcome can probably be
explained by the development in the immunocompetent host of an immune
response sufficient to eradicate the parasites. In patients in whom immune
system function has been restored, the body is rapidly cleared of C parvum.
Unfortunately, persons with AIDS who are infected with C parvum have
a shorter survival time than those with other opportunistic infections.
However, treatment with highly active antiretroviral therapy (HAART) has
allowed patients to reach a certain immune reconstitution, thereby
improving the outcome in patients with cryptosporidiosis [9].
Diagnosis
A number of diagnostic methods are available for cryptosporidiosis,
including modified acid-fast stains, fluorescent stains, and fecal immuno-
assays (Fig. 4). Currently enzyme, fluorescent, and immunochromato-
graphic immunoassays are available for the diagnosis of cryptosporidiosis.
Although these reagents are highly specific and sensitive, there have been
some problems with false-positive results, leading to several product recalls.
However, overall these methods are more sensitive than special stains, are
easy to perform, and lend themselves to more relevant patient test ordering,
depending on the patient’s history and symptoms. In some patients the
routine Ova and Parasite examination is recommended, whereas in other
patients it is more relevant to perform either a Giardia, a Cryptosporidium,
or a combination Giardia/Cryptosporidium immunoassay. Depending on the
particular kit, fresh, frozen, or preserved fecal specimens can be used for
testing [4]. Although flow-cytometry and PCR methods have been de-
veloped, they remain impractical for most laboratories.
Fig. 4. Cryptosporidium parvum. (A) The Giardia/Cryptosporidium combination fluorescent

immunoassay (400, FITC fluorescent assay). (B) Cryptosporidium oocysts stained with
modified acid-fast stain (1000, modified acid-fast stain).
Current relevance
In January and February 1987, cryptosporidiosis was associated with an
estimated 13,000 cases of gastroenteritis in Carroll County, Georgia.
Cryptosporidium oocysts were identified in the stools of 39% of the persons
examined during the outbreak, with an estimated attach rate of 54% within
Carrolton and 40% overall for the county. The largest reported outbreak in
the United States occurred in March and April 1993 in Milwaukee, resulting in
approximately 300,000 infections. This outbreak led to the development of
more stringent water regulations as well as to that of improved techniques for
oocyst recovery and identification, both in water testing and in clinical
specimens [10,11]. The epidemiologic considerations for cryptosporidiosis
include the importance of transmission by environmentally resistant oocysts,
the existence of numerous potential reservoir hosts for zoonotic transmission,
the documentation of person-to-person transmission within day care centers
and nosocomial transmission within the health care setting, the occurrence of
asymptomatic infections in the carrier state, widespread environmental
distribution resulting in the probability of water transmission, and the link
between cryptosporidiosis and severe, life-threatening disease in individuals
with impaired immune functions. Another concern is the confirmation of HIV
resistance to HAART therapy and what this may mean for any possible
resurgence in severe cryptosporidiosis in the AIDS population.
Rare infections endemic to the United States

Baylisascaris procyonis
Life cycle
Baylisascaris procyonis is an ascarid normally found in raccoons that
causes a very serious zoonotic disease in humans, most often reported in
North America. Raccoons are infected by ingesting infective eggs and larvae
encysted in the tissue of intermediate hosts such as rodents, rabbits, and
birds. The larvae penetrate the mucosa of the small intestine, develop, and
then re-enter the intestinal lumen to mature. Human infections result from
ingestion of eggs that are passed in very large numbers (millions of eggs/day)
in the feces of infected raccoons. Once ingested, the eggs hatch in the
intestinal tract, releasing the immature larvae (Fig. 5). However, rather than
developing into adult worms as in the raccoon, the larvae begin to migrate
extensively throughout the body, causing visceral larva migrans or neural
larva migrans (NLM). Unfortunately, many of these cases have been seen in
young children [4].
An intense inflammatory reaction occurs because of tissue damage caused
by the larval migration [12,13]. The larvae continue to grow during this
Fig. 5. Baylisascaris procyonis. Note (A, 400, D’Antoni’s iodine) the embryonated eggs (from
soil contaminated with raccoon feces) and (B, 400, hematoxylin and eosin stain) tissue cross
section of the larvae in the brain (note the clearly seen lateral alae on the larvae in the right lower
section; the alae are seen as points at the sides of the cross sections).
migratory phase, can reach lengths of 2 mm, exhibit very vigorous migratory
behavior, and remain viable for long periods. They can also invade the eyes,
causing ocular larva migrans (OLM), and the spinal cord and brain, causing
NLM. Permanent neurologic damage, blindness, and death can occur.
Unfortunately, the prevalence of subclinical cases is unknown, and even in
clinical cases, most patients are diagnosed after severe CNS damage has
already taken place. Patients can present with eosinophilic meningoenceph-
alitis or unilateral neuroretinitis. Symptoms generally depend on the number
of eggs originally ingested: the more eggs ingested, the more severe the
symptoms. The larvae invade the CNS approximately 1 to 4 weeks after
infection, with rapid progression. OLM may present with chronic endoph-
thalmitis with retinal detachment, posterior pole granuloma, vitreous
abscess, pars planitis, optic neuritis, keratitis, uveitis, iritis, hypopyon, and
meandering retinal tracts containing larvae. The neural form may vary from
neuropsychologic problems to seizure, convulsions, ataxia, coma, and
death. Patients may exhibit sudden lethargy, irritability, loss of muscle
coordination, decreased head control, spasmodic contractions of the neck
muscles, stupor, nystagmus, obtundation, coma, hypotonia, and hyperre-
flexia. An infant who survived meningoencephalitis demonstrated sequelae
of hemiparesis, inability to sit or stand, ocular muscle paralysis, cortical
blindness, and severely delayed development [14].
Diagnosis
Human infections are rare and often diagnosed by a process of
elimination when all other causes of larva migrans have been explored.
Although results from routine hematologic and cerebrospinal fluid exami-

nations are usually consistent with a parasitic infection, they are nonspecific.
Definitive diagnosis requires the confirmation and identification of larvae in
tissues; this can be difficult, depending on the body site. In most cases, the
clinical history provides the main clues.
Current relevance
The relationship between B procyonis, raccoons, and human infection is
well established. Groups of raccoons tend to defecate in common areas
called latrines, which are usually found off the ground in fallen logs (stacked
firewood), rocky outcroppings, and trees. In Pacific Grove, California,
where extensive investigations have occurred, many latrines are located
directly on the ground, on roofs, in attics, and on steps and fences. The eggs
remain viable in the soil for years; they also have a sticky surface that causes
them to adhere to objects, including human hands and toys. Recognition of
this new human infection and elimination of raccoon latrine sites around
human habitation and recreational areas are critical to control efforts. This
infection can cause extensive damage in the human host, particularly in
young children, and has become a tremendous public health concern. The
distribution of human disease in the United States appears widespread, with
12 cases of fatal encephalitis reported in California and Oregon, New York
and Pennsylvania, and Michigan, Minnesota, and Illinois. Although human
infection has not been reported in the southeastern United States, 22% of 50
raccoons trapped in the Atlanta area were infected with B procyonis [15].
Paragonimus
Life cycle
Lung flukes are endemic in much of the world, including China, Laos,
Thailand, North America, Central and South America, Africa, the
Philippines, and Japan. Paragonimus kellicotti occurs in the United States
and has been reported to cause human disease [16–19]. Its complex life cycle
involves seven distinct phases: egg, miracidium, sporocyst, redia, cercaria,
metacercaria, and adult. Three hosts are required to complete the life cycle:
first intermediate host (snails), second intermediate host (freshwater crabs or
crayfish), and the definitive host (various carnivorous mammals such as
humans, dogs, other canids, wild and domestic cats, pigs, beavers,
mongooses, drills, and mink). Dogs and cats tend to contaminate fresh
water. Unembryonated eggs exit the host in sputum or feces, take 2 to 3
weeks in fresh water to embryonate, hatch, and release free-swimming
miracidia. The miracidia enter the snail, where they multiply over a period
of weeks into sporocysts, redia, and finally cercaria; these invade the tissues
of a suitable crab or crayfish where they encyst as metacercariae. Most
human infections are acquired by ingesting metacercariae from contami-
nated food such as raw or partially cooked crabs or crayfish. Larvae enter
the duodenum of the human host, penetrate the wall of the small intestine,
and enter the peritoneal cavity 30 minutes to 48 hours after excysting. After
5 to 7 days, larvae penetrate the diaphragm and attach to the pleura, invade
the pleura, or enter the parenchyma of the lung and lodge near bronchioles.
The incubation period is about 70 days, but the adult worms may live for
20 years or more in the human host.
During the early stages of the disease, patients are usually asymptom-
atic. If the fluke remains in the abdomen, patients may have palpable
intra-abdominal masses, tenderness, nausea, vomiting, and diarrhea. Un-
like patients with tuberculosis, patients with pulmonary paragonimiasis
tend to have no symptoms other than coughing, typically productive of
rusty sputum with a foul, fishy odor. Some have chest pain and night
sweats, while most patients will have eosinophilia (usually 10% to 30%)
and an incidental lung lesion on a routine chest film. Other body sites may
be involved, including the brain; cases involve findings such as arach-
noiditis, encapsulated abscesses, and granulomas that may calcify and
become encapsulated.
Diagnosis
Microscopic examination of sputum and stool remains the method of
choice for confirming the diagnosis. The eggs measure 80 lm to 120 lm by
45 lm to 65 lm and have opercular shoulders and a thickened shell at the
abopercular end (Fig. 6). Individuals with symptoms of chronic cough,
vague chest pains, and hemoptysis who reside in an endemic area and have
a history of eating raw crayfish or crabs should be suspected of having
paragonimiasis [4]. Because these eggs are operculated, they will not float
using any type of flotation concentration method; the sedimentation
concentration procedure is recommended. In many individuals small
numbers of eggs are present intermittently in the sputum and feces.
Although these cases are often misdiagnosed as pulmonary tuberculosis, it
is important to remember that the Ziehl-Neelsen method for detecting
mycobacteria destroys Paragonimus eggs.
Current relevance
The first case of paragonimiasis was reported in the United States in 1986
in a nonimmigrant adult. It is an important infection to consider in cases
where the history is suggestive, as well as in cases of Southeast Asians who
have resettled in various areas of the United States, such as the central San
Joaquin Valley of California [20]. Human P kellicotti infections within the
United States have been confirmed by finding the characteristic eggs in
sputum, bronchoalveolar lavage fluid, or histologic section.
Fig. 6. Paragonimus kellicotti. Note the typical trematode egg, with the opercular shoulders and
the thickened abopercular end. The eggs measure 80–120 lm by 45–65 lm. (400, D’Antoni’s
iodine.)
Diseases endemic in the Third World and now in the public eye
Malaria
Life cycle
Like Babesia species, the four species of Plasmodium that cause human
malaria are apicomplexans. As such, they have similar reproductive
characteristics: asexual reproduction (merogony) in erythrocytes, sexual
reproduction (gamogony) in an arthropod gut, and formation of sporozoites
(sporogony) in the arthropod host.
Female anopheline mosquitoes act as the vector for transmission of
malaria, ingesting parasitized erythrocytes when they take a blood meal
from an infected human. The macro- and microgametocytes, which
represent female and male pregametes, respectively, mature and become
gametes, which unite to form a zygote. Within 1 day, the zygote differ-
entiates into an ookinete, which burrows through the midgut of the
mosquito and encysts on its outer layer. The ookinete which is now located
in the body cavity (hemocoel) of the mosquito becomes an oocyst in which
mitosis occurs to form sporozoites. After rupture of the oocyst, the
sporozoites enter the hemocoel. Those sporozoites that migrate to the
salivary glands rather than to other sites in the mosquito are injected into
a new human host when the female mosquito feeds [21].
The sporozoites are transported by the blood to the liver, where they
invade hepatocytes. They transform and reproduce by schizogony to yield
10,000 to 30,000 merozoites. The merozoites then lyse the infected

hepatocytes and invade erythrocytes. Infections transmitted by transfusion,
shared syringes needles, or congenitally by the transplacental route do not
have this hepatic (extraerythrocytic) phase of infection. In red blood cells,
the parasites go through a cycle of maturation and schizogony to form
merozoites, which in turn invade more erythrocytes. Some of the mer-
ozoites, rather than going through the cycle of maturation and schizogony,
become gametocytes.
In Plasmodium vivax and P ovale infections, parasites persist in the liver
and cause relapses due to release of merozoites from that organ after
a precipitating incident of some kind. While P falciparum and P malariae do
not have parasites persisting in the liver, patients infected with these species
can have recrudescences due to an exacerbation of a parasitemia below the
level detectable by examination of blood smears [4].
With the destruction of red blood cells associated with the release of
merozoites into the bloodstream, there is an episode of chills followed by
fever and sweating known as the paroxysm. With P vivax and P ovale
infections (benign tertian malarias), the paroxysms tend to occur every 48
hours, which is the time required for one cycle of schizogony. In infections
with P malariae (benign quartan malaria), fevers and chills occur every 72
hours. Although P falciparum, which causes malignant tertian malaria, has
a 48-hour cycle of intraerythrocytic reproduction, paroxysms occur without
any periodicity. As expected, the destruction of erythrocytes eventually
results in a hemolytic anemia with its accompanying manifestations, along
with splenomegaly. Besides direct red cell lysis, other mechanisms are
involved in producing the anemia.
Although all species of Plasmodium can cause severe and fatal infections,
P falciparum carries the greatest risk of complications and death. The
primary reason for the greater pathogenicity of this species compared with
the other three is the adherence of P falciparum–infected erythrocytes to one
another and to the microvascular endothelium. This adhesion results in
obstruction of the microvasculature, leading to tissue hypoxemia and
hypoglycemia. Another consequence of this adhesion is that, unless there
is an overwhelming infection, the only stages of P falciparum seen in the
peripheral blood are the ring trophozoites and the gametocytes. Another
cause of the increased pathogenicity of P falciparum is the high parasitemia
typical of infections with this parasite. The large percentage of parasitized
erythrocytes is probably due to the fact that, unlike the other Plasmodium
species, P falciparum invades red blood cells of all ages. Another contributor
to the high parasitemia is the large number of merozoites produced in each
erythrocytic cycle of P falciparum. The large numbers of parasites with their
accompanying metabolism contribute to the tissue hypoxemia and lactic
acidosis. The protean manifestations of severe P falciparum infections
include cerebral malaria, circulatory collapse (algid malaria), pulmonary

edema, and massive intravascular hemolysis with hemoglobinuria and renal
failure (‘‘blackwater fever’’). In acute falciparum malaria, a transient self-
limiting glomerulonephritis can occur. By contrast, chronic glomerulone-
phritis, which presents as nephrotic syndrome, is typical of P malariae
infections.
In most regions where malaria is endemic, the disease strikes hardest in
children, who, if they survive, develop immunity. With recurrent infections,
an abnormal immune response may develop and result in excessive pro-
duction of IgM, which form aggregates. Accompanying the formation of
these aggregates is hypertrophy of the splenic lymphoid macrophage system,
which results in phagocytosis of the IgM complexes. There is splenic
enlargement, often massive, with the patient presenting with abdominal
distention, vague dragging sensation, and occasional episodes of severe sharp
pain. Laboratory manifestations include those of hypersplenism, peripheral
lymphocytosis, and various types of serologic abnormalities, including
elevations in titers of antimalarial antibodies. This condition, known as the
tropical splenomegaly syndrome, is found in the endemic regions of Africa,
Asia, South America, and the western Pacific. In some parts of Papua New
Guinea, this condition is found in approximately 80% of young adults [21].
Diagnosis
Both in endemic regions and in Canada, the United States, and Western
Europe, the main means of diagnosis is demonstration of the presence of
parasites in thin and thick smears. Besides determining whether the
erythrocytes are parasitized by Plasmodium species, the examination must
ascertain the species of parasite causing the malaria and the degree of
parasitemia, as measured by percentage of erythrocytes containing para-
sites. Because malaria caused by P falciparum can be fatal, examination of
blood smears constitutes a ‘‘stat’’ test that must be available on a 24-hour
basis (Fig. 7). To exclude malaria as a cause of fever, multiple sets of thin
and thick smears must be examined every 12 to 24 hours. Smears taken at
the time of a paroxysm may be unhelpful, because the red blood cells will be
lysing and parasites may not be seen in them.
There are several problems with microscopy as the gold standard for
diagnosis of malaria. Besides the fact that the preparation and reading of
thin and thick smears are technique dependent, intensive training and
continual experience are needed to maintain operator proficiency. The
theoretic lower limits for detection of parasites are 100 and 10 to 20
parasites per lL for thin and thick smears, respectively [21]. However, in one
study under clinical conditions in the United Kingdom, the lower limit of
normal was 500 plasmodia per lL [22]. The importance of well-trained, well-
equipped microscopists as the first line of defense for diagnosis of malaria in
any geographic area cannot be overemphasized. In a study of malaria
diagnosis in clinics in Thailand, smears were examined independently by the
Fig. 7. Plasmodium falciparum. Note the ring forms ([A] thick film; [B] thin film). (1000,
Giemsa stain.)
clinic microscopists and by research microscopists whose diagnosis served as

the gold standard. Of the smears reported positive by the clinic micro-
scopists, 24.3% were negative, while 13.2% of the smears the clinic reported
as negative contained parasites. Moreover, in smears that both the clinic and
the research microscopists reported as positive, 13.7% of the species
identifications were incorrect [23].
The weaknesses of blood smears as a gold standard for diagnosis of
malaria are apparent to most specialists in malariology. Even with expert
microscopy, in endemic areas, chronically infected individuals will have
transient, mild symptoms and low, variable parasitemias [24]. Attempts to
increase sensitivity of smears or to enhance sensitivity of detection methods
have focused on several areas: (1) use of fluorescent dyes to detect parasite
nucleic acid, either alone or in combination with a concentration method
(such as the centrifugal quantitative buffy coat test); (2) PCR that can detect
the equivalent of five parasites per lL of blood, and (3) rapid tests that
detect malarial antigens by immunochromatographic methods. Goals for
the rapid tests include 95% sensitivity compared with microscopy, with
100% sensitivity for detecting a parasitemia of 100 parasites per lL.
Different formats using various malarial antigens, including histidine rich
protein 2 of P falciparum, aldolase from the three non–P falciparum species,
and different LDH isoenzymes from the four different Plasmodium species,
have been tested [21,25,26]. Although these assays have not been used in
routine fieldwork, some of them have already proved their worth. In the
Kapit division of Malaysian Borneo, PCR assays have shown that 58% of
208 people with malaria tested positive for P knowlesi, a natural parasite of
macaque monkeys. Microscopists misidentified these isolates as P malariae
[27]. Unfortunately, the real problem with all these assays may lie in an area
that has nothing to do with their technical performance. In developed
countries, most clinical laboratories do not have sufficient volume of

requests for malaria diagnosis to bring in these assays, while in developing
countries, the cost of the assays is far greater than that of blood smears.
Current relevance
At this time, malaria still constitutes a significant health problem in the
developing world, with annual estimates of deaths between 0.7 and 2.7
million individuals [28,29]. More than 75% of these fatalities are African
children. In sub-Saharan Africa, with the overwhelming burden of global
malaria, changes in climatic and agricultural conditions, political unrest,
population movements, and increasing drug resistance have further in-
creased the prevalence of the disease [30–32]. Similar situations in other
endemic regions have led to an increase in malaria transmission. The
increase in malaria in endemic regions has led to increasing numbers of cases
of imported malaria in Europe, Canada, and the United States. In 2001, the
last year for which published data exist, there were 1383 cases of malaria in
the United States [33]. Eight hundred and ninety-one of these cases were in
United States civilians. This figure represents the highest number of
reported United States civilian cases in 30 years. As a result of the
increasing impact of malaria, several international institutions, including
the World Health Organization (WHO) and the World Bank, philanthropic
organizations, and United States governmental organizations, have started
the Roll Back Malaria initiative [29]. This initiative aims to halve the
malaria burden by the year 2010 with a control strategy that emphasizes
a variety of methods, including rapid clinical case detection and treatment,
use of insecticide-impregnated bed nets, management of malaria during
pregnancy, and focal control of malaria transmission in emergency or
epidemic situations. However, this effort may be doomed to failure, because
there is still a lack of trained, properly paid personnel prepared to work in
the field [32,34].
In the developed countries, malaria transmission can still occur as a result
of imported cases. In the United States, the last reported outbreak occurred
in Palm Beach, Florida in July to August 2003. Of the seven reported cases
of P vivax, six patients reported never having visited regions endemic for
malaria. This outbreak represents the eleventh reported to the Centers for
Disease Control and Prevention since 1992 [35].
African Trypanosomiasis
Life cycle
Tsetse flies, which belong to the genus Glossina and are obligate blood
feeders, transmit Trypanosoma brucei gambiense, causing West African
trypanosomiasis, and T brucei rhodesiense, the parasite responsible for East
African trypanosomiasis. However, these parasites can also be transmitted
by blood transfusions, shared needles, and the congenital route. After
ingestion by the fly, the trypomastigote forms transform to procyclic

trypomastigotes and undergo binary fission. The organisms then leave the
midgut and move to the salivary glands, where they become epimastigotes
and again reproduce by binary fission. The epimastigotes mature into
metacylic trypomastigotes, which are the infective form for humans. This
cycle in the fly takes approximately 3 weeks. The metacyclic trypomastigotes
are injected into the skin when the tsetse fly takes a blood meal. The
parasites move to the lymphatics and eventually reach the blood. They can
reproduce in various tissues and fluids, including cerebrospinal fluid, blood,
and lymph [4]. The African trypanosomes have evolved a defense mecha-
nism in which they change their surface coats every 1 to 2 weeks, thereby
evading the host antibody response. This antigenic variation results in
succeeding waves of parasitemia.
African trypanosomiasis manifests itself clinically as stage 1 and stage 2
diseases [36]. In stage 1 disease, parasites reproduce at the site of infection,
leading to an ulcer known as a trypanosomal chancre. Although the chancre
is seldom reported in Africans, it has been described in approximately 25%
to 40% of Europeans infected with West African sleeping sickness [37].
Accompanying the healing of the ulcer, which takes 3 to 4 weeks, there is
spread to the draining lymph node and bloodstream, resulting in the
hemolymphatic phase of the disease. During this phase of the infection,
there is undulant fever, headache, and general malaise. There may also be
generalized edema, pruritus, and a circinate rash. The rash, which is invisible
on dark skin, purportedly occurs in 50% of Europeans infected with
T brucei gambiense [37].
In the second stage of the disease, there is invasion of the central nervous
system and other internal organs. As the disease progresses, it manifests as
severe headache, changes in sleep patterns, and increasing decline in mental
function. Personality changes occur and can be striking. Besides these
changes, which can be attributed to invasion of the central nervous system,
there are also endocrine abnormalities, including impotence and weight loss.
In untreated cases, coma and death are inevitable.
There are striking differences in the clinical manifestations of East
African and West African trypanosomiasis. East African trypanosomiasis
has a more acute course, whereas the West African form of the disease is
more insidious. In East African trypanosomiasis, fatalities due to pulmo-
nary edema and congestive heart failure can occur in stage 1. Generalized
lymphadenopathy, including Winterbottom’s sign (ie, posterior cervical
lymphadenopathy), is more typical of the West African disease and develops
after several weeks of infection. In East African trypanosomiasis, invasion
of the central nervous system occurs within a few weeks of infection,
whereas it takes months to years for this event to occur in the West African
form of the disease.
Diagnosis
Very high concentrations of IgM along with anemia and thrombocyto-
penia in a patient with the appropriate history should raise the suspicion of
trypanosomiasis. For both forms of disease, the presence of trypomastigotes
in blood, lymph, tissue aspirates, or cerebrospinal fluid (CSF) is diagnostic.
Because the parasite burden is often below that detectable by thick or thin
blood smears, concentration methods are necessary to obtain enough
parasites to see microscopically. Various concentration methods that have
been evaluated and found useful include microhematocrit centrifugation,
minianion exchange columns, and buffy-coat smears. Examination of CSF
for the trypomastigotes is often unrewarding, even after concentration
techniques have been used. The primary diagnostic features of CNS
involvement include increased protein (>25 mg/100 mL), lymphocytosis
(>5000/mL), and the presence of Mott cells containing morulae, which in the
appropriate clinical setting are pathognomonic for African trypanosomiasis.
In West African trypanosomiasis, the numbers of organisms in blood are
so low that examination of smears, even after concentration, is unrewarding.
However, high titers of specific IgM and IgG antibodies occur. Diagnosis of
this form of the disease depends on the card agglutination test, a serologic
test, followed whenever possible by microscopy. Although studies have
shown the high sensitivity of PCR in the diagnosis of Gambian sleeping
sickness, it is unlikely that this methodology will be used for routine
diagnosis in field campaigns.
The trypomastigote with its characteristic posterior kinetoplast, flagel-
lum, and undulating membrane measures 14 lm to 33 lm long by 1.5 lm to
3.5 lm wide (Fig. 8). The organisms are extremely pleomorphic, varying
in morphology from long (30-lm) slender flagellated parasites to short
(15-lm), fat, stumpy forms that do not possess a free flagellum. The latter
forms, which are the infective stage for Glossina, do not divide in the blood,
whereas the slender forms do. The concentration of parasites in the blood is
highest during febrile episodes, and, as for most blood parasites, examina-
tion of multiple daily thick and thin smears may be necessary for detection.
Current relevance
In 1999, only 37,000 cases of human African trypanosomiasis were
reported to WHO. By 2003, 300,000 to 500,000 new cases had occurred. The
problem is greater than these figures indicate, because untreated disease
results in 100% mortality. When disability-adjusted life years (which take
into account mortality rates) are calculated, this disease ranks third in
impact behind malaria and schistosomiasis in sub-Saharan Africa. This
recrudescence is due to the conflicts in Angola, Uganda, the Democratic
Republic of the Congo, and Sudan, which have led to a breakdown in
control programs [30,38]. In sub-Saharan western Africa, where Gambian
sleeping sickness is endemic, these conflicts interrupted control measures
consisting of case finding and chemotherapy of the human population in
Fig. 8. Trypanosoma brucei gambiense (West African trypanosomiasis); T brucei rhodesiense

(East African trypanosomiasis). Note the trypomastigote with slender shape and undulating
membrane. East and West African trypomastigotes cannot be differentiated on the basis of
morphology. (1000, Giemsa stain.)
which it is a chronic, often asymptomatic disease. In sub-Saharan eastern

Africa, where Rhodesian sleeping sickness, a more acute disease than
Gambian sleeping sickness, is endemic, efforts focused on large-scale
operations to control tsetse flies. This strategy was also necessary because
Rhodesian sleeping sickness is an anthropozoonosis, with the parasite found
in large numbers of wild and domestic animals. Civil unrest in Uganda in
the 1980s led to a decline in these control efforts and reversion of cultivated
land to its natural habitat. With the end of conflict, the area was
repopulated. Cattle carrying T brucei rhodesiense were transported into
these areas, which were infested with tsetse flies, resulting in the spread of
West African sleeping sickness into areas previously free of the disease [39].
Given the resurgence of trypanosomiasis, it is not unreasonable to expect
increased numbers of cases outside Africa. Because the Western African
form of trypanosomiasis typically involves low numbers of trypanosomes in
the blood, other diagnostic methods, available only in reference and
research laboratories, will have to be used to diagnose individuals suspected
of having the disease.
Parasites in the blood supply

Babesia
Life cycle
Babesiosis is a zoonotic disease transmitted by ticks. In North America
and Europe, the two regions for which good data exist, the predominant
causative agents are Babesia microti and B divergens, respectively [40].
More recently, human babesiosis has been reported from subtropical areas;
human infection is probably common in other areas and may be mistaken
for malaria. Transmission can also occur by transfusion of infected blood

products and transplacentally.
All Babesia species are transmitted by ixodid ticks and belong to the
phylum Apicomplexa. They are closely related to malaria and share similar
reproductive characteristics: asexual reproduction (merogony) in erythro-
cytes, sexual reproduction (gamogony) in an arthropod gut, and formation
of sporozoites (sporogony) in the arthropod host [41]. Thus the life cycle of
Babesia is similar to that of Plasmodium, the genus causing malaria, but with
several significant differences. These differences include the lack of an
extraerythrocytic stage of the life cycle in the mammalian host and asexual
reproduction by budding, rather than by schizogony as occurs in malaria
parasites. The asexual forms are simple rings, pairs, or tetrads, with the
gametocytes being morphologically identical to the asexual forms at
the light microscopic level.
In North America, where most of the clinical cases have occurred, the
disease is transmitted by the bite of the deer tick, Ixodes scapularis.
Although the adult of this species feeds primarily on deer, infection is
acquired by the nymph stage of these ticks from the white-footed mouse,
Peromyscus leucopus. Most infected P leucopus have a low level of
parasitemia, with the parasitemia persisting for life. In the ‘‘large’’ species
of Babesia, in which the trophozoite measures 2.5 lm to 5.0 lm, the tick can
also become infected by the transovarial route.
Classically, human babesiosis due to B microti was described as severe
hemolytic disease causing severe anemia, jaundice, renal failure, and death
in the immunosuppressed, the elderly, patients with severe underlying
medical problems, and particularly individuals who are asplenic. In AIDS
patients with babesiosis, the illness is typified by frequent relapses and
a prolonged duration [40]. Babesia divergens infections from Europe
generally occur in splenectomized patients, who almost always have a fatal
course [41].
In North America, many infections with B microti are asymptomatic.
Those patients who are symptomatic have a self-limited febrile illness that
starts approximately 1 to 4 weeks after a tick bite or 4 to 9 weeks post-
transfusion. Approximately 1 week after the gradual onset of malaise,
anorexia, and fatigue, the patient experiences fever, myalgia, and drenching
sweats. Besides the laboratory manifestations of hemolysis, there may be
mildly elevated hepatic enzymes and thrombocytopenia.
Diagnosis
Definitive diagnosis of babesiosis depends on finding typical trophozoites
in either thick or thin blood smears. These organisms must be distinguished
from the four species of Plasmodium that cause human malaria and, like
Babesia, are parasites of red blood cells. The clinical history may be helpful,
because individuals with malaria generally have a history of travel to areas

endemic for malaria. Because Babesia species only have ring trophozoites,
the species of malaria with which they are mostly likely to be confused is
P falciparum, in which morphologic stages other than rings and gametocytes
are only found in heavy infections. Typically, both of these species also
multiply infected erythrocytes. The other three species of human malaria
generally have all morphologic stages in peripheral blood. The ring
trophozoites of Babesia are more pleomorphic than those of P falciparum
and can also be extracellular. Additionally, Babesia rings are pear- or
spindle-shaped and may be found as tetrads (ie, Maltese crosses) (Fig. 9).
Unfortunately, tetrad forms are rarely found in B microti infections. It
should be emphasized that multiple thick and thin smear collections may be
needed to find Plasmodium or Babesia parasites.
Serologic testing may be useful for chronic infections and for those
individuals who have parasitemias below the limit of detection by
microscopy. The serologic method of choice is an indirect fluorescent
antibody test using an antigen obtained from infected hamster red blood
cells. However, for infections with B divergens, which can be fulminating
rapidly, serologic tests may be useless, because specific antibodies are not
detected for a minimum of 1 week after the beginning of the illness. Other
diagnostic methods include animal inoculation and PCR, neither of which is
available in most clinical laboratories.
Current relevance
The geographic range, causative agents, and prevalence of human
babesiosis in the United States are increasing. Classically, human babesiosis
caused by B microti was limited to the northeastern states of New York,
Fig. 9. Babesia species. Note the small ring forms ([A] thick film; [B] thin film). In (B) some of
the rings form the ‘‘Maltese cross’’ configuration, which can be seen in some Babesia species.
(1000, Giemsa stain.)
Massachusetts, Rhode Island, and Connecticut and restricted areas in

Wisconsin and Minnesota. A recent survey of the inhabitants of Block
Island, Rhode Island found that approximately 10% of the residents had
serologic evidence of infection [42]. Moreover, the northeastern endemic
area should be expanded to include New Jersey, where 40 cases from 38% of
the counties have been described from 1993 to 2001 [43,44]. Several cases
of human babesiosis have been documented in California and the state of
Washington. An organism closely related to B gibsoni caused most of the
cases in the latter state. The cases in California appear to be due to
a protozoon phylogenetically related to but not identical with B gibsoni. The
most recent case described in Washington, along with two cases from
Missouri and Kentucky, is closely related to B divergens, the causative agent
of human babesiosis in Europe [45].
With the advent of PCR technology, humans, like other mammalian
hosts of babesiosis, have been shown to be chronic carriers of the parasite.
Babesial DNA was found in the blood of untreated individuals from
endemic areas for a mean of 82 days [46]. In Minnesota, four cases of
babesiosis that occurred over a period of 6 months were due to multiple
donations by a single infected individual, confirming that infected humans
may remain parasitemic for long periods of time [47].
Babesia microti is the parasitic agent most frequently transmitted by
blood transfusion in the United States, with more than 40 documented cases
of transmission by this means [48]. Hence the increase in geographic range,
number of causative agents, and prevalence of babesiosis is troubling, as is
the persistence of the parasite in the bloodstream. Although methods of
controlling transfusion-associated transmission of the organism have not
been initiated, it would seem to be appropriate to do so. Also troubling is
the fact that, unlike Trypanosoma cruzi, for which the American Association
of Blood Banks (AABB) is developing methods to control transfusion-
associated transmission, Babesia species are intraerythrocytic. Therefore,
transmission of babesiosis is not just due to contamination of platelet
units, as it is with T cruzi, but also involves red cell units. Furthermore,
leukoreduction, which removes T cruzi from blood products, will not be an
effective means of removing Babesia species [49].
American Trypanosomiasis
Life cycle
Trypanosoma cruzi is transmitted by triatomine bugs belonging to the
family Reduviidae. These insects, known colloquially as ‘‘kissing’’ or
‘‘assassin’’ bugs, are peridomestic and feed on a wide variety of animals.
The infected bugs deposit the infective metacyclic trypomastigotes in their
feces as they take a blood meal. Because of itching, the human host then
scratches, causing microabrasions that allow the parasite to gain access to
host cells. The parasite can also be transmitted by blood transfusions, by
contaminated needles, or congenitally. Additional routes of transmission

include ingestion of contaminated food, breastfeeding, and accidental con-
tact with laboratory cultures of the parasite [4].
The trypomastigotes circulate in the blood without multiplying and then
invade nucleated cells, with a predilection for myocardium, neuroglia,
ganglion cells, adipocytes, and cells of the lymphoid-macrophage system.
After entry into the cells, the trypomastigotes transform into amastigotes,
which then reproduce and form pseudocysts. In the pseudocysts the
amastigotes redifferentiate into trypomastigotes, which are long and slender.
These forms escape into the bloodstream to invade new cells. If these slender
trypomastigotes are unable to invade a cell, they transform to short, stubby
trypomastigotes and then to amastigotes. Therefore, blood in infected
humans contains two morphologic forms of trypomastigotes and a varying
number of amastigotes, which can constitute as many as 10% of the total
organisms in that fluid [50].
After ingestion by a bug, the various bloodstream forms become
epimastigotes that reproduce in the posterior midgut. Eight to ten days
later, the epimastigotes transform into the metacyclic trypomastigotes,
which are excreted in the feces.
Infection with T cruzi can be divided into acute and chronic stages, with
some authorities recognizing an indeterminate stage that represents a tran-
sition between the two [36]. Acute disease is generally a pediatric illness, with
mild fever in 10% to 20% of patients and a small group of patients,
approximately 5%, having severe fevers. When clinical manifestations do
occur, they usually begin 7 to 14 days after infection and last for 1 to 2
months. A small, tender red papule, known as a chagoma, may develop at
the site of infection. This papule will enlarge to become hard, red, and dusky
and will resolve after a month. Romaña’s sign, which is unilateral,
bipalpebral, chronic edema, is due to inflammation of the conjunctiva by
parasites that were introduced by the patient’s rubbing infected bug feces
into the eye. The lesion can be accompanied by local lymphadenopathy. A
small minority of patients develop myocarditis, which can result in
congestive heart failure and death. Occasional patients develop meningo-
encephalitis, which generally has a very poor prognosis.
With resolution of acute infection, the indeterminate stage of disease
follows. Lack of signs and symptoms, development of antibodies, and a
subpatent parasitemia characterize this stage.
After many years of infection, individuals develop chronic Chagas’
disease. Although the manifestations of chronic disease are related to
damage during the acute phase, patients with chronic disease may not have
had symptomatic acute disease. The organ most frequently involved in
chronic disease is the heart, with development of cardiomyopathy resulting
in conduction defects and apical infarcts and aneurysms. In approximately

40% of those who die of Chagas’ cardiomyopathy, the aneurysm and its
associated complications are the cause of death. In the gastrointestinal tract,
there is fibrosis of the parasympathetic plexuses resulting in ‘‘mega’’ disease
(ie, megacolon or megaesophagus) [51].
As transplacental infection can occur in either acute or chronic disease, it
is not surprising that congenital disease is common. In Argentina in 2000,
there were nearly 1000 cases of congenital Chagas’ disease [52]. Although
lesions are observed in nearly every organ, the structures most commonly
affected in congenital disease are heart, esophagus, intestine, brain, skin, and
the skeletal muscles. As might be expected, common manifestations of
congenital infection include stillbirth, postpartum death, low birth weight,
hepatosplenomegaly, anemia, encephalitis, and congenital pneumonitis.
With the onset of the HIV epidemic and increasing levels of iatrogenic
immunosuppression, reactivation of Chagas’ disease became more common.
Immunocompromised patients with reactivated Chagas’ disease develop
a diffuse or multifocal meningoencephalitis [53]. HIV-positive patients may
develop cerebral abscesses, which are not seen in immunocompetent patients
and can be confused with cerebral toxoplasmosis.
Diagnosis
In acute Chagas’ disease, definitive diagnosis involves demonstrating the
presence of the parasite. In immunocompetent patients, multiple examina-
tions of thick and thin smears for the trypomastigote form the cornerstone
of diagnosis [4]. In immunocompromised patients, microscopic examination
of tissue such as bone marrow, CSF, and myocardium for the presence of
amastigotes may be necessary.
In blood smears, the trypomastigote form of T cruzi is 12 lm to 30 lm
long with a C-shape, central nucleus, and large subterminal kinetoplast
(Fig. 10). As previously discussed, the parasites have a dimorphic appear-
ance, with one type being long and slender and the other one short and
broad. Unlike in the African trypanosomes, dividing forms are not seen.
Trypanosoma rangeli, which is also found in Latin America and infects
humans, can be a source of diagnostic confusion. However, it does not cause
human disease and is slightly larger (25 lm to 37 lm) and more slender than
is T cruzi. T rangeli also has a smaller terminal kinetoplast, a better
developed undulating membrane, and a more anterior nucleus. However,
the two species often cannot be distinguished from each other. Moreover,
the parasite can have extremely low levels of parasitemia and can cause
false-positive results in serologic tests for T cruzi [4].
In chronic Chagas’ disease, the cornerstone of laboratory diagnosis is
demonstration of specific IgG. Unfortunately, serologic tests are not
routinely available in the United States. PCR techniques have been
developed for detection of Chagas’ disease but also are not routinely
Fig. 10. Trypanosoma cruzi (American trypanosomiasis). Note the more curved shape (as
compared with the African trypanosomes), undulating membrane, and large kinetoplast.
(1000, Giemsa stain.)
available. Finally, there are classic methods of xenodiagnosis and

hemoculture. Xenodiagnosis, in which bugs are fed on patients with possible
Chagas’ disease and then examined after a suitable time interval for the
presence of parasites, is rarely available in the United States. Hemoculture,
which has as good a yield as xenodiagnosis in experienced hands, is available
in a few research or university-based laboratories.
Current relevance
T cruzi is endemic in rural areas of South and Central America, including
Mexico. Large numbers of individuals from these areas now live in the
United States and Canada, so that there are approximately 50,000 to
100,000 persons infected with T cruzi in these two countries. Many of these
individuals are concentrated in urban areas such as Los Angeles and Miami
[54]. Moreover, some individuals who are seropositive for this parasite were
born in the United States and may have been infected by the transplacental
route. At present, there have been six documented cases of transfusion-
transmitted Chagas’ disease in the United States and Canada. This number
is probably low, because most acute infections are mild with nonspecific
symptoms. Hence American and Canadian physicians, who are unfamiliar
with the disease, probably misdiagnose and under-report it. In addition to
transfusion-transmitted infections, there are reports of Chagas’ disease
acquired by organ donation and bone marrow transplantation in the United
States. T cruzi could also be acquired from stem cell transplants. As a result
of these reports, the AABB is trying to develop a rational strategy to prevent
transfusion transmission of T cruzi. Whether this strategy will involve
additional donor questions for certain individuals, additional laboratory
testing of units, or leukocyte reduction or treatment of units is uncertain at
this time [55].
Travelers and immigrants from endemic regions

Leishmaniasis
Life cycle
Leishmania species are transmitted by the bite of an infected sandfly,
during which the promastigotes are introduced into the skin of the human.
The parasite is found in two morphologic forms, the amastigotes and the
promastigotes. The amastigotes are small (3 lm to 5 lm in diameter), ovoid,
nonmotile intracellular forms, whereas the promastigotes are elongated,
motile extracellular stages. The promastigotes are engulfed by reticuloen-
dothelial cells, and the parasite transforms into the intracellular amastigote
form (Leishman-Donovan body or LD body), a process that takes
approximately 12 to 24 hours. During the last 15 years, leishmaniasis has
emerged as a potential infectious disease related to the Gulf War
(viscerotropic leishmaniasis) and as one of the first and most important
opportunistic infections in HIV-infected patients [30,56].
Viscerotropic leishmaniasis (VTL) is a comparatively mild form of
visceral leishmaniasis infection caused by Leishmania tropica, a protozoan
parasite that usually causes cutaneous and not systemic disease. Gulf War
veterans with viscerotropic leishmaniasis presented with fever, hepatosple-
nomegaly, lymphadenopathy, mild anemia, and modest aminotransferase
elevations. These patients did not have cutaneous manifestations and, unlike
patients with classic visceral leishmaniasis (kala-azar), did not have
pancytopenia or hypergammaglobulinemia. All but 1 of the 12 cases of
systemic L tropica infection had readily discernible pathology.
The majority of the cases of opportunistic infection in HIV-positive
patients have come from Europe, where 7% to 17% of these individuals
with fever have amastigotes. This finding strongly suggests that asymptom-
atic individuals who are infected with Leishmania species may become
symptomatic if immunosuppressed. Depending on the patient’s general
health status and prior exposure to the infection, leishmaniasis may be seen
as an early opportunistic infection or as a complication late in the course of
AIDS. There may be cutaneous lesions, mucocutaneous lesions, or post–
kala-azar dermal leishmaniasis. CD4þ T-lymphocyte counts are usually
fewer than 50/mm3 and are almost always fewer than 200/mm3. The
most common symptoms are fever, splenomegaly, hepatomegaly, and
pancytopenia.
Diagnosis
Unfortunately, there is no accurate and noninvasive screening test for
viscerotropic leishmaniasis. Diagnosis requires painful, often multiple
biopsies of bone marrow and lymph nodes, along with highly specialized
laboratory methods to recover and identify the parasite. The large nucleus
and small kinetoplast in the amastigotes can be seen in tissue after staining
with Giemsa or Wright’s stain. The short intracytoplasmic portion of the
flagellum can also be seen within some of the amastigotes; multiplication
occurs by binary fission within the macrophage until the cell is destroyed
and the parasites released, then phagocytized by other reticuloendothelial
cells (Fig. 11). In cutaneous leishmaniasis, the organisms are usually
confined to the skin, mucocutaneous infections involve the cells of the skin
and mucous membranes, and visceral infections typically involve the spleen,
liver, and bone marrow.
Visceral leishmaniasis is very prevalent among HIV-1–infected patients in
southern Spain, with a high percentage of the cases being subclinical.
Symptoms tend to occur with severe immunosuppression. Depending on the
presentation and body site infected, diagnostic tests ultimately tend to rely
on the demonstration of the actual organisms in clinical specimens. PCR
and a rapid immunochromatographic dipstick are available and tend to
work well; however, there may be sensitivity problems related to the use of
the dipstick as a screening tool. It appears that further development is
required before the dipstick can replace direct agglutination as a diagnostic
test, at least in the endemic areas of the Sudan [57,58].
Current relevance
Based on careful analysis and medical surveillance information collected
on United States troops during the Gulf War, only one endemic
infectious disease was confirmed as causing chronic health problems:
visceral L tropica infection (viscerotropic leishmaniasis). However, this
Fig. 11. Leishmania species. Note the small individual amastigotes (Leishman-Donovan
bodies), within which the nucleus can be seen, and the short bar, which is the primitive
flagellum. (1000, Giemsa stain.)
infection was diagnosed in only 12 United States veterans, and no new cases
have been identified up to 2001. A total of 20 cases of cutaneous
leishmaniasis due to L major infection were diagnosed after the war among
500,000 United States ground troops. Continued surveillance indicates that
it is unlikely that infectious diseases endemic to the Arabian Gulf could
cause long-term health effects, but latent leishmaniasis infection could
progress to clinical disease among some veterans. Gulf War veterans with
objective signs of this infectious disease should be evaluated. The last
veteran diagnosed with viscerotropic leishmaniasis presented within 2 years
of returning from the Gulf War. There is still concern that some veterans
may continue to harbor L tropica organisms that could eventually cause
clinical disease, particularly if the patients were immunocompromised for
any reason. Moreover, the lack of serious infectious disease morbidity
during the Gulf War may not apply to future wars, even in the Arabian
Gulf. The risk of infectious diseases would have been much higher had the
troops been stationed in the riverine valleys of southern Iraq during the
summer. In most tropical regions of the world, insect-borne infectious
diseases are a major threat throughout the year. With the two recent
excursions into Afghanistan and Iraq, leishmaniasis has again become
a problem. During August 2002 to February 2004, 522 troops deployed in
Afghanistan, Iraq, and Kuwait developed cutaneous leishmaniasis caused
by L major [59]. Two soldiers stationed in Afghanistan developed visceral
leishmaniasis due to the L donovani-L infantum species complex [60].
Whether these series represent all of the infected military personnel is still
unknown.
It is important to consider leishmaniasis as an opportunistic infection in
patients who are immunocompromised for any reason, and particularly in
those with AIDS who may have come to the United States from areas
endemic for leishmaniasis. Generally, the only patients who do not relapse
are those in whom immunosuppression is mitigated by means of antire-
troviral therapy or by reduction of corticosteroid and other immunosup-
pressive drugs [56].
Cysticercosis
Life cycle
To complete its life cycle, Taenia solium, the pig tapeworm, is passed
between man, in whom the adult worm lives, and the pig in which the larvae
are found in various tissues. The pig is infected by ingesting human feces
containing tapeworm eggs, whereas human beings ingest pork contaminated
with the larvae. Cysticercosis is the infection of humans with larval stages of
T solium, while taeniasis is the infection of humans with adult tapeworms of
T solium, T saginata (the cow tapeworm), and T asiatica. Humans acquire
cysticercosis primarily through ingestion of T solium eggs in food (Fig. 12).
Fig. 12. Taenia species. The eggs are described as having a thick, radially striated shell
containing a six-hooked embryo, the oncosphere. The eggs of T solium and T saginata look
alike; however, only those of T solium are associated with human cysticercosis. (400,
D’Antoni’s iodine.)
The food is contaminated with eggs either by irrigation of water contam-

inated with human feces or directly by individuals who are infected with
adult T solium. A lesser source of infection is fecal-oral autoinoculation of
individuals who harbor adult tapeworms [4].
After the eggs are ingested, they hatch in the small intestine with the
embryos (oncospheres) invading the wall of the gut. The embryo dissem-
inates hematogenously and develops in the tissues into a cysticercus, which
consists of a membranous wall, liquid, and a small nodule. The nodule
contains an invaginated scolex, which contains suckers and hooks and
a rudimentary body surrounding the scolex. It must be emphasized that,
unless they are infected with the adult T solium in their small intestine,
humans who have cysticercosis represent dead-end hosts.
Infection with cysticerci of T solium results in extraneural and neural
disease [61–63]. Although other structures may be involved, extraneural
disease mainly affects muscle or subcutaneous tissue. Subcutaneous disease
generally presents as small, movable, painless nodules most often found in
the arms or chest, while muscular cysticercosis is generally diagnosed
incidentally as calcifications in the arms or thighs.
In the nervous system, larval T solium infection presents as neuro-
cysticercosis or ophthalmic cysticercosis. Although T solium is the most
common intraorbital parasite, ophthalmic cysticercosis is rare compared
with neurocysticercosis, occurring in 1% to 3% of all infections. Most
neurocysticercosis (ie, approximately 80%) is asymptomatic. The cysticerci,
which are protected by the blood–brain barrier and active immune-evasion
mechanisms, elicit little inflammatory change and remain viable for variable
amounts of time. However, the cyst eventually degenerates, with an
accompanying inflammatory response. The majority of symptoms are
caused by this inflammatory degeneration, with a minority due to mass
effect or blockage of CSF circulation. The most common presentation of
neurocysticercosis is epileptic seizures, which occur in 50% to 80% of
patients with the parenchymal form of the disease. In 20% to 30% of cases,
patients present with the manifestations of intracranial hypertension or
hydrocephalus. When there is an intense inflammatory reaction to a large
number of parasites, there can be an acute encephalitis. This presentation is
more common in children and teenagers.
Diagnosis
There is no unified approach to diagnosis of the disease. Diagnostic
criteria incorporating different degrees of certainty have been proposed for
diagnosis of neurocysticercosis, including ophthalmic disease [64]. Absolute
criteria for definitive diagnosis include histologic demonstration of the
parasite in a biopsy, cystic lesions with a scolex on CT or MRI, and direct
visualization of subretinal parasites by fundoscopic examination. Although
CT is better for detecting calcification, MRI is considered the most accurate
technique available for assessing the degree of infection, the location, and
the evolutionary stage of the parasite. Serum enzyme-linked immunoblot is
considered more sensitive than CSF ELISA, as reflected in the fact that in
the proposed scheme for diagnosis of neurocysticerosis, the former is
considered a major criterion whereas the latter is a minor one.
Current relevance
Neurocysticercosis that is endemic in Latin America, sub-Saharan Africa,
most of Asia, and parts of Oceania is the most common cause of acquired
epilepsy worldwide. However, the disease is also seen in the United States,
with more than 1000 cases of neurocysticercosis annually. Indigenous cases
are also seen in this country. In a study from Los Angeles, 12% of the
seizures seen in an emergency department were attributed to cysticercosis
[65]. A more recent study of radiographically imaged seizure patients in
United States emergency departments revealed that cysticercosis was
responsible for 2.1% of seizures [66]. In sites in the Southwest, the
prevalence was closer to 10%. In a 6-year retrospective study in Oregon,
neurocysticercosis was diagnosed in five individuals who had never left the
country [67]. In two studies of pediatric cysticercosis, the rate of domestic
acquisition of the disease was 17% and 26% [68,69]. Given that many
individuals with cysticercosis do not present until symptoms are far
advanced, and given that the Hispanic migrant and immigrant populations
in the United States are increasing, it is probable that the disease is
underdiagnosed and that its prevalence will increase.
Summary
Parasitic infections have little impact on the health and well being of most
inhabitants of Canada, Western Europe, and the United States. As the
authors have shown in this article, parasites are always ‘‘emerging’’
somewhere and have a significant impact on those areas of the world.
Moreover, as we are becoming an ever smaller global village, catastrophes
and instability in the Third World affect control of parasitic diseases
endemic to those areas, ensuring greater chances of transmission to visitors
there. As shown by the data for imported malaria in the United States, the
potential impact of these diseases is increased by the inadequate prophylaxis
that many of these visitors use on their travels.
The foundation of successful limitation of parasitic diseases in both
developing and developed regions is still accurate and rapid diagnosis. In
spite of the development of other methods besides microscopy, diagnosis of
parasitic diseases depends on well-trained microscopists who use appropri-
ate methods and are able to maintain their competency through continuing
education and frequent proficiency testing. It is worth reiterating that
diagnosis of blood parasites still depends on the following principles: (1)
both thick and thin blood smears are necessary; (2) all requests for blood
parasites smears should be treated as ‘‘stat’’ requests, and (3) multiple blood
smear examinations are necessary to exclude the presence of organisms.
With the return of military and non-military personnel from Iraq, we expect
to see more cases of leishmaniasis, as well as increased drug resistance in
cases of malaria (including primaquine resistance in P vivax).
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Clin Lab Med 24 (2004) 737–772

Emerging parasitic infections

In the First World, as exempliﬁed by Canada, Western Europe, and the

Common infections in the United States

and the secretions. Vaginal secretions are liquid, greenish or yellowish,

also been documented that, for HIV-positive men with symptomatic

Infections in HIV-positive individuals

There are three infectious stages of T gondii: the tachyzoites in groups,

Clinical manifestations. The large number of individuals who test serolog-

Diagnosis. Diagnosis can be made using various serologic or histologic

Current relevance. In transplant recipients, disease severity depends on

Clinical manifestations. In the immunocompromised host, microsporidial

Diagnosis. Although microsporidia have been identiﬁed in routine histo-

a complete parasitologic cure for Encephalitozoon intestinalis is possible with

Epidemics in the United States

Fig. 4. Cryptosporidium parvum. (A) The Giardia/Cryptosporidium combination ﬂuorescent

Rare infections endemic to the United States

Although results from routine hematologic and cerebrospinal ﬂuid exami-

10,000 to 30,000 merozoites. The merozoites then lyse the infected

include cerebral malaria, circulatory collapse (algid malaria), pulmonary

clinic microscopists and by research microscopists whose diagnosis served as

countries, most clinical laboratories do not have suﬃcient volume of

ingestion by the ﬂy, the trypomastigote forms transform to procyclic

Fig. 8. Trypanosoma brucei gambiense (West African trypanosomiasis); T brucei rhodesiense

which it is a chronic, often asymptomatic disease. In sub-Saharan eastern

Parasites in the blood supply

for malaria. Transmission can also occur by transfusion of infected blood

because individuals with malaria generally have a history of travel to areas

Massachusetts, Rhode Island, and Connecticut and restricted areas in

contaminated needles, or congenitally. Additional routes of transmission

in conduction defects and apical infarcts and aneurysms. In approximately

available. Finally, there are classic methods of xenodiagnosis and

Travelers and immigrants from endemic regions

The food is contaminated with eggs either by irrigation of water contam-

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