1758 PART 5 Infectious Diseases

rummaging in a barnyard. It is in the intermediate host that T. gondii

completes its life cycle.

Sporulated oocysts are environmentally hardy and very infectious;

they are thought to be sources of waterborne outbreaks such as those

reported in Victoria (British Columbia, Canada) and in South America.

In the Northern Hemisphere, T. gondii strains are predominantly of

three genotypes. Strains found in South and Central America are more

virulent than those from the Northern Hemisphere, are frequently of

the type I virulent genotype or atypical genotypes, and are more likely to

be associated with symptomatic disease, usually ocular posterior uveitis.

Ocular toxoplasmosis should be considered in a person from Central or

South America with ocular symptoms and retinal abnormalities. Severe

disease, including sepsis, fever of unknown origin, and pneumonia, has

been reported and should be considered in a patient with travel history

to South or Central America. There are no extensive data about the

prevalence of T. gondii in Africa, but existing studies suggest T. gondii

infection is common.

■ EPIDEMIOLOGY

T. gondii infects a wide range of mammals and birds. Its seroprevalence

depends on the locale and the age of the population. Generally, hot arid

climatic conditions are associated with a low prevalence of infection.

In the United States and most European countries, the seroprevalence

increases with age and exposure. In the United States, seroprevalence

has steadily decreased, with 11% of individuals >6 years old having

serologic evidence of Toxoplasma exposure in a 2011–2014 survey,

with foreign-born Americans having a higher rate of seroprevalence.

In most other regions of the world, the seroprevalence is higher, with

a seroprevalence as high as 78% reported in Brazil. Perhaps because of

increased awareness of foodborne infections, the prevalence of seropositivity has decreased worldwide over the past two decades.

■ TRANSMISSION

Oral Transmission Most cases of human Toxoplasma infection are

thought to be acquired by the oral route. Transmission can be attributable to ingestion of sporulated oocysts from contaminated soil, food,

or water. During acute feline infection, a cat may excrete as many as

100 million oocysts per day. These sporozoite-containing oocysts are

highly infectious and may remain viable for many years in soil or water.

Humans infected during an oocyst-transmitted infection develop

stage-specific antibodies to the oocyst/sporozoite.

Children and adults also acquire infection from tissue cysts containing bradyzoites. Undercooking or insufficient freezing of meat is an

important source of infection in the developed world. Toxoplasmososis

has been associated with eating raw or undercooked food including

ground beef, lamb, or venison or drinking unpasteurized goat milk.

More recent epidemiologic studies have associated acute infections

with ingestion of untreated water or shellfish (oysters, mussels, and

clams).

Transmission via Blood or Organs In addition to being transmitted orally, T. gondii can be transmitted directly from a seropositive

donor to a seronegative recipient in a transplanted heart, heart–lung,

kidney, liver, or pancreas. Viable parasites can be cultured from refrigerated anticoagulated blood, which may be a source of infection in

individuals receiving blood transfusions. T. gondii reactivation has

been reported in bone marrow, hematopoietic stem cell, and liver

transplant recipients as well as in individuals with AIDS. Although

antibody titers generally are not useful in monitoring T. gondii infection, individuals with higher antibody titers may be at relatively high

risk for reactivation after hematopoietic stem cell transplantation

(HSCT). Thus, routine polymerase chain reaction (PCR) screening

of blood from these patients may be in order, although not all centers routinely monitor HSCT patients for toxoplasmosis. Screening

Toxoplasma serologies (donor and recipient) before transplantation

may identify patients potentially at risk for reactivated toxoplasmosis.

Finally, laboratory personnel can be infected after contact with contaminated needles or glassware or with infected tissue.

Transplacental Transmission On average, about one-third of

all women who acquire infection with T. gondii during pregnancy

transmit the parasite to the fetus; the remainder give birth to normal,

uninfected babies. Of the various factors that influence fetal outcome,

gestational age at the time of infection is the most critical (see below).

Recrudescent maternal infection is rarely the source of congenital

disease, although rare cases of transmission by immunocompromised

women (e.g., those infected with HIV or those receiving high-dose glucocorticoids) have been reported. Thus, women who are seropositive

before pregnancy usually are protected against acute infection and do

not give birth to congenitally infected neonates.

There is essentially no risk for congenital infection if the mother

becomes infected ≥6 months before conception. If infection is acquired

<6 months before conception, the likelihood of transplacental infection

increases as the interval between infection and conception decreases.

Women with documented acute toxoplasmosis should be counseled

to use appropriate measures to prevent pregnancy for 6 months after

infection. In pregnancy, if the mother becomes infected during the first

trimester, the incidence of transplacental infection is lowest (~15%),

but the disease in the neonate is most severe. If maternal infection

occurs during the third trimester, the incidence of transplacental infection is greatest (65%), but the infant is usually asymptomatic at birth.

Infected infants who are normal at birth may have a higher incidence of

learning disabilities and chronic neurologic sequelae than uninfected

children. Only a small proportion (20%) of women infected with

T. gondii develop clinical signs of infection. Often the diagnosis is first

appreciated when routine postconception serologic tests show evidence

of specific antibody.

■ PATHOGENESIS

Upon the host’s ingestion of either tissue cysts containing bradyzoites

or oocysts containing sporozoites, the parasites are released from the

cysts by the digestive process. Bradyzoites are resistant to the effect of

pepsin and invade the host’s gastrointestinal tract. Within enterocytes

(or other gut-associated cells), the parasites undergo morphologic

transformation, giving rise to invasive tachyzoites. From the gastrointestinal tract, parasites disseminate to a variety of organs, particularly

lymphatic tissue, skeletal muscle, myocardium, retina, placenta, and

the CNS. At these sites, the parasite infects host cells, replicates, and

invades the adjoining cells. In this fashion, the hallmarks of the infection develop: cell death and focal necrosis surrounded by an acute

inflammatory response.

In the immunocompetent host, both the humoral and the cellular

immune responses control infection; parasite virulence and tissue

tropism may be strain specific. Tachyzoites are sequestered by a variety

of immune mechanisms, including induction of parasiticidal antibody,

activation of macrophages with radical intermediates, production

of interferon γ (IFN-γ), and stimulation of CD8+ cytotoxic T lymphocytes. These antigen-specific lymphocytes are capable of killing

both extracellular parasites and target cells infected with parasites. As

tachyzoites are cleared from the acutely infected host, tissue cysts containing bradyzoites begin to appear, usually within the CNS, skeletal

muscle, and the retina. Toxoplasma secretes signaling molecules into

infected host cells, and these molecules modulate host gene expression,

host metabolism, and host immune response. While it was initially

thought that cysts with bradyzoites are not eliminated by the immune

system, recent studies in the murine model indicate that both CD8+

T cells and alternatively activated macrophages are able to kill cysts in

vivo; some cysts persist, however, and the ability to eliminate cysts may

depend on the genetic background of the infected host.

Immunocompromised or fetal hosts lack the immune factors necessary to control the spread of tachyzoite infection. This altered immune

state allows the persistence of tachyzoites and gives rise to progressive

focal destruction in affected organs (i.e., necrotizing encephalitis,

pneumonia, and myocarditis).

It is thought that all infected individuals have persistent infection

with cysts containing bradyzoites, but this lifelong infection usually

remains subclinical. Although bradyzoites are in a slow metabolic

phase, bradyzoites can replicate, and cysts do rupture within the CNS.

1759CHAPTER 228 Toxoplasma Infections

These subclinical cycles of cyst ruptures followed by development

of new bradyzoite-containing cysts are the probable source of recrudescent infection in immunocompromised individuals and the most

likely stimulus for the persistence of antibody titers in the immunocompetent host. Although the concept is controversial, the persistence

of toxoplasmosis has been hypothesized to be a contributing factor

to a variety of neuropsychiatric conditions, including schizophrenia

and bipolar disease. In rodents, chronic T. gondii infection clearly has

significant effects on behavior, increasing predation. A role for parasite

remodeling of the host epigenome has been hypothesized to play a

role in long-lasting neuropsychiatric syndromes and is the subject of

ongoing research.

■ PATHOLOGY

Cell death and focal necrosis due to replicating tachyzoites induce

an intense mononuclear inflammatory response in any tissue or cell

type infected. Tachyzoites rarely can be visualized by routine histopathologic staining of these inflammatory lesions. However, immunofluorescent staining with parasitic antigen–specific antibodies can

reveal the organism. In contrast to the inflammatory process caused

by tachyzoites, bradyzoite-containing cysts cause inflammation only

at the early stages of development. Once the cysts reach maturity, the

inflammatory process is blunted, and the cysts remain relatively immunologically quiescent within the brain matrix until they rupture.

Lymph Nodes During acute infection, lymph node biopsy demonstrates characteristic findings, including follicular hyperplasia

and irregular clusters of tissue macrophages with eosinophilic cytoplasm. Granulomas rarely are evident in these specimens. Although

tachyzoites are not usually visible, parasites can be demonstrated by

subinoculation of infected tissue into mice, with resultant disease, or

by PCR. PCR amplification of DNA fragments of Toxoplasma genes

is effective and sensitive in establishing lymph node infection by

tachyzoites.

Eyes In the eye, infiltrates of monocytes, lymphocytes, and plasma

cells may produce uni- or multifocal lesions. Granulomatous lesions

and retinochoroiditis can be observed in the posterior chamber after

acute necrotizing retinitis. Other ocular complications include iridocyclitis, cataracts, and glaucoma. T. gondii is the most common cause of

posterior uveitis in immunocompetent individuals.

Central Nervous System During CNS involvement, both focal

and diffuse meningoencephalitis can be documented, with evidence of

necrosis and microglial nodules. Necrotizing encephalitis in patients

without AIDS is characterized by small diffuse lesions with perivascular cuffing in contiguous areas. In the AIDS population, polymorphonuclear leukocytes may be present in addition to monocytes,

lymphocytes, and plasma cells. Cysts containing bradyzoites frequently

are found contiguous with the necrotic tissue border. As a consequence

of antiretroviral therapy (ART) for AIDS, the incidence of toxoplasmosis has decreased in the developed world. The incidence of toxoplasmosis in underresourced settings is not known due to lack of diagnostic

infrastructure but is likely to be higher than in the United States.

Lungs and Heart Among patients with AIDS who die of toxoplasmosis, 40–70% have involvement of the lungs and heart. Interstitial

pneumonitis can develop in neonates and immunocompromised

patients. Thickened and edematous alveolar septa infiltrated with

mononuclear and plasma cells are apparent. This inflammation may

extend to the endothelial walls. Tachyzoites and bradyzoite-containing

cysts have been observed within the alveolar membrane. Superimposed

bronchopneumonia can be caused by other microbial agents. Cysts and

aggregates of parasites in cardiac muscle tissue are evident in patients

with AIDS who die of toxoplasmosis. Focal necrosis surrounded by

inflammatory cells is associated with hyaline necrosis and disrupted

myocardial cells. Pericarditis is associated with toxoplasmosis in some

patients.

Gastrointestinal Tract Rare cases of human gastrointestinal tract

infection with T. gondii have presented as ulcerations in the mucosa.

Acute infection in certain strains of inbred mice (C57BL/6) results in

lethal ileitis within 7–9 days. This inflammatory bowel disease has been

recognized in several other mammalian species, including pigs and

nonhuman primates.

Other Sites Pathologic changes during disseminated infection

are similar to those described for the lymph nodes, eyes, and CNS.

In patients with AIDS, the skeletal muscle, pancreas, stomach, and

kidneys can be involved, with necrosis, invasion by inflammatory cells,

and (rarely) tachyzoites detectable by routine staining. Large necrotic

lesions may cause direct tissue destruction. In addition, secondary

effects from acute infection of these various organs, including pancreatitis, myositis, and glomerulonephritis, have been reported.

■ HOST IMMUNE RESPONSE

Acute Toxoplasma infection evokes a cascade of protective immune

responses in the immunocompetent host. Toxoplasma enters the host

at the gut mucosal level and evokes a mucosal immune response that

includes the production of antigen-specific secretory IgA. Titers of

serum IgA antibody directed at the tachyzoite surface antigen p30/

SAG1 are a useful marker for congenital and acute toxoplasmosis.

Within the host, T. gondii rapidly induces detectable levels of both

IgM and IgG serum antibodies. Monoclonal gammopathy of the IgG

class can occur in congenitally infected infants. IgM levels may be

increased in newborns with congenital infection. The polyclonal IgG

antibodies evoked by infection are parasiticidal in vitro in the presence of serum complement and are the basis for the Sabin-Feldman

dye test. However, cell-mediated immunity is the major protective

response evoked by the parasite during host infection. Macrophages

are activated after phagocytosis of antibody-opsonized parasites. If the

parasite is not phagocytosed and enters the macrophage, monocytes,

or dendritic cells by active penetration, these “Trojan horses” represent

a mechanism for transport and dissemination to distant organs. Toxoplasma stimulates a robust IL-12 response by human dendritic cells.

The CD4+ and CD8+ T cell responses are antigen-specific and further

stimulate the production of a variety of important lymphokines that

expand the T cell and natural killer cell repertoire. T. gondii is a potent

inducer of a TH1 phenotype, with IL-12 and IFN-γ playing an essential

role in the control of the parasites’ growth in the host. Regulation of the

inflammatory response is at least partially under the control of a TH2

response that includes the production of IL-4 and IL-10 in seropositive

individuals. Human T-cell clones of both the CD4+ and the CD8+

phenotypes are cytolytic against parasite-infected macrophages. These

T-cell clones produce cytokines that are “microbistatic.” IL-18, IL-7,

and IL-15 upregulate the production of IFN-γ and may be important

during acute and chronic infection. The effect of IFN-γ may be paradoxical, with stimulation of a host downregulatory response as well.

Although T. gondii infection is believed to be recrudescent in

patients with AIDS or other immunocompromised states, antibody

titers are not useful in establishing reactivation or in following the

activity of infection. An absence of positive serologies suggests an

alternative diagnosis, although AIDS patients may have borderline

positive or low serologies. T cells from AIDS patients with reactivation

of toxoplasmosis fail to secrete both IFN-γ and IL-2. This alteration in

the production of these critical immune cytokines contributes to the

persistence of infection. Toxoplasma infection frequently develops late

in the course of AIDS (CD4+ count <100/μL), when the loss of T cell–

dependent protective mechanisms, particularly CD8+ T cells, becomes

most pronounced.

■ CLINICAL MANIFESTATIONS

In persons whose immune systems are intact, acute toxoplasmosis is

usually asymptomatic and self-limited. This condition can go unrecognized in 80–90% of adults and children with acquired infection.

The asymptomatic nature of this infection makes diagnosis difficult

in mothers infected during pregnancy. In contrast, the wide range

of clinical manifestations in congenitally infected children includes

severe neurologic complications such as hydrocephalus, microcephaly,

intellectual disability, and chorioretinitis. If prenatal infection is severe,

multiorgan failure and subsequent intrauterine fetal death can occur.

1760 PART 5 Infectious Diseases

FIGURE 228-2 Toxoplasmic encephalitis in a 36-year-old patient with AIDS. The multiple lesions are

demonstrated by MRI scanning (T1-weighted with gadolinium enhancement). (Courtesy of Clifford Eskey,

Dartmouth Hitchcock Medical Center, Hanover, NH; with permission.)

In children and adults, chronic infection can persist throughout life, with little consequence to the

immunocompetent host.

Toxoplasmosis in Immunocompetent

Patients The most common manifestation of

acute toxoplasmosis is cervical lymphadenopathy.

The nodes may be single or multiple, are usually

nontender, are discrete, and vary in firmness.

Lymphadenopathy also may be found in suboccipital, supraclavicular, inguinal, and mediastinal

areas. Generalized lymphadenopathy occurs in

20–30% of symptomatic patients. Between 20%

and 40% of patients with lymphadenopathy also

have headache, malaise, fatigue, and fever (usually

with a temperature of <40°C [<104°F]). A smaller

proportion of symptomatic individuals have myalgia, sore throat, abdominal pain, maculopapular

rash, meningoencephalitis, and confusion. Rare complications associated with infection in the normal immune host include pneumonia,

myocarditis, encephalopathy, pericarditis, and polymyositis. Signs

and symptoms associated with acute infection usually resolve within

several weeks, although the lymphadenopathy may persist for some

months. In one epidemic, toxoplasmosis was diagnosed correctly in

only 3 of the 25 patients who consulted physicians. If toxoplasmosis is

considered in the differential diagnosis, routine laboratory and serologic screening should precede node biopsy.

In North America and Europe, there are three predominant genotypes, but strains are more genetically diverse in Central and South

America. Genotypes of T. gondii prevalent in South America are more

virulent than those typically seen in North America or Europe. These

genotypes may be associated with acute or recurrent ocular disease

in immunocompetent individuals and have also been associated with

pneumonitis and a fulminant sepsis picture in immunologically normal individuals. Thus, a detailed history, particularly regarding travel

and countries of residence, is critical for establishing a diagnosis.

The results of routine laboratory studies are usually unremarkable

except for minimal lymphocytosis, an elevated erythrocyte sedimentation rate, and a nominal increase in serum aminotransferase levels.

Evaluation of cerebrospinal fluid (CSF) in cases with evidence of

encephalopathy or meningoencephalitis shows an elevation of intracranial pressure, mononuclear pleocytosis (10–50 cells/mL), a slight

increase in protein concentration, and (occasionally) an increase in

the gamma globulin level. PCR amplification of the Toxoplasma DNA

target sequence in CSF is specific for active toxoplasmosis, but not sensitive. The CSF of chronically infected individuals is normal.

Infection of Immunocompromised Patients Patients with

AIDS and those receiving immunosuppressive therapy for lymphoproliferative disorders are at greatest risk for developing acute toxoplasmosis. Toxoplasmosis has also been reported after treatment with

antibodies to tumor necrosis factor. The infection may be due either

to reactivation of latent infection or to acquisition of parasites from

exogenous sources such as blood or transplanted organs. In individuals

with AIDS, >95% of cases of Toxoplasma encephalitis (TE) are believed

to be due to recrudescent infection. In most of these cases, encephalitis

develops when the CD4+ T-cell count falls below 100/μL. In immunocompromised hosts, the disease may be rapidly fatal if untreated. Thus,

accurate diagnosis and initiation of appropriate therapy are necessary

to prevent fulminant infection.

Toxoplasmosis is a principal opportunistic infection of the CNS

in persons with AIDS. Although geographic origin may be related to

frequency of infection, it has no correlation with the severity of disease in immunocompromised hosts. Individuals with AIDS who are

seropositive for T. gondii are at high risk for encephalitis. Before the

advent of current ART, about one-third of the 15–40% of adult AIDS

patients in the United States who were latently infected with T. gondii

developed TE. TE may still be a presenting infection in individuals who

are unaware of their positive HIV status.

The signs and symptoms of acute toxoplasmosis in immunocompromised patients principally involve the CNS (Fig. 228-2). More

than 50% of patients with clinical manifestations have intracerebral

involvement. Clinical findings at presentation range from nonfocal to

focal dysfunction. CNS findings include encephalopathy, meningoencephalitis, and mass lesions. Patients may present with altered mental

status (75%), fever (10–72%), seizures (33%), headaches (56%), and

focal neurologic findings (60%), including motor deficits, cranial nerve

palsies, movement disorders, dysmetria, visual-field loss, and aphasia.

Patients who present with evidence of diffuse cortical dysfunction

develop evidence of focal neurologic disease as infection progresses.

This altered condition is due not only to the necrotizing encephalitis

caused by direct invasion by the parasite but also to secondary effects,

including vasculitis, edema, and hemorrhage. The onset of infection

can range from an insidious process over several weeks to an acute

presentation with fulminant focal deficits, including hemiparesis,

hemiplegia, visual-field defects, localized headache, and focal seizures.

Although lesions can occur anywhere in the CNS, the areas most

often involved appear to be the brainstem, basal ganglia, pituitary

gland, and corticomedullary junction. Brainstem involvement gives

rise to a variety of neurologic dysfunctions, including cranial nerve

palsy, dysmetria, and ataxia. With basal ganglion infection, patients

may develop hydrocephalus, choreiform movements, and choreoathetosis. Toxoplasma usually causes encephalitis, and meningeal

involvement is uncommon. CSF findings may be unremarkable or

may include a modest increase in cell count and in protein—but not

glucose—concentration.

Cerebral toxoplasmosis must be differentiated from other opportunistic infections or tumors in the CNS of AIDS patients. The differential diagnosis includes herpes simplex encephalitis, cryptococcal

meningitis, progressive multifocal leukoencephalopathy, and primary

CNS lymphoma. Involvement of the pituitary gland can give rise to

panhypopituitarism and hyponatremia from inappropriate secretion

of vasopressin (antidiuretic hormone). HIV-associated neurocognitive

disorder (HAND) may present as cognitive impairment, attention loss,

and altered memory. Brain biopsy in patients who have been treated

for TE but who continue to exhibit neurologic dysfunction often fails

to identify organisms.

Autopsies of Toxoplasma-infected patients have demonstrated the

involvement of multiple organs, including the lungs, gastrointestinal

tract, pancreas, skin, eyes, heart, and liver. Toxoplasma pneumonia can

be confused with Pneumocystis pneumonia. Respiratory involvement

usually presents as dyspnea, fever, and a nonproductive cough and may

rapidly progress to acute respiratory failure with hemoptysis, metabolic

acidosis, hypotension, and (occasionally) disseminated intravascular

coagulation. Histopathologic studies demonstrate necrosis and a mixed

cellular infiltrate. The presence of organisms is a helpful diagnostic

indicator, but organisms can also be found in healthy tissue. Infection

of the heart is usually asymptomatic but can be associated with cardiac

tamponade or biventricular failure. Infections of the gastrointestinal

tract and the liver have been documented.

1761CHAPTER 228 Toxoplasma Infections

Congenital Toxoplasmosis Between 400 and 4000 infants born

each year in the United States are affected by congenital toxoplasmosis.

Acute infection in mothers acquiring T. gondii during pregnancy is

usually asymptomatic; most such women are diagnosed via prenatal

serologic screening. Infection of the placenta leads to hematogenous

infection of the fetus. As gestation proceeds, the proportion of fetuses

that become infected increases, but the clinical severity of the infection

declines. Although infected children may initially be asymptomatic,

the persistence of T. gondii can result in reactivation and clinical

disease—most frequently chorioretinitis—decades later. Factors associated with relatively severe disabilities include delays in diagnosis and

in initiation of therapy, neonatal hypoxia and hypoglycemia, profound

visual impairment (see “Ocular Infection,” below), uncorrected hydrocephalus, and increased intracranial pressure. If treated appropriately,

upward of 70% of children have normal developmental, neurologic,

and ophthalmologic findings at follow-up evaluations. Treatment for 1

year with pyrimethamine, a sulfonamide, and folinic acid is tolerated

with minimal toxicity (see “Treatment,” below).

Ocular Infection Infection with T. gondii is estimated

to cause 35% of all cases of chorioretinitis in the United States

and Europe. It was formerly thought that the majority of cases

of ocular disease were due to congenital infection. Ocular toxoplasmosis in immunocompetent individuals occurs more commonly than was previously appreciated and has been associated

with outbreaks traced to oocyst contamination of soil or water in

Victoria (British Columbia) and in South America. A variety of

ocular manifestations are documented, including blurred vision,

scotoma, photophobia, and eye pain. Macular involvement occurs,

with loss of central vision, and nystagmus is secondary to poor fixation. Involvement of the extraocular muscles may lead to disorders of

convergence and to strabismus. Ophthalmologic examination should

be undertaken in newborns with suspected congenital infection. As

the inflammation resolves, vision improves, but episodic flare-ups

of chorioretinitis, which progressively destroy retinal tissue and lead

to glaucoma, are common. The ophthalmologic examination reveals

yellow-white, cotton-like patches with indistinct margins of hyperemia.

As the lesions age, white plaques with distinct borders and black spots

within the retinal pigment become more apparent. Lesions usually are

located near the posterior pole of the retina; they may be single but

are more commonly multiple. Congenital lesions may be unilateral or

bilateral and show evidence of massive chorioretinal degeneration with

extensive fibrosis. Surrounding these areas of involvement are a normal

retina and vasculature. In patients with AIDS, retinal lesions are often

large, with diffuse retinal necrosis, and include both free tachyzoites

and cysts containing bradyzoites. Toxoplasmic chorioretinitis may be a

prodrome to the development of encephalitis.

■ DIAGNOSIS

Tissue and Body Fluids The differential diagnosis of acute toxoplasmosis can be made by appropriate culture, serologic testing, and

PCR (Table 228-1). PCR is the mainstay for detection of organisms in

tissue or biological fluids. Although available only at specialized laboratories, the isolation of T. gondii from blood or other body fluids can

be accomplished after subinoculation of the sample into the peritoneal

cavity of mice. If no parasites are found in the mouse’s peritoneal fluid

6–10 days after inoculation, its anti-Toxoplasma serum titer can be

evaluated 4–6 weeks after inoculation. Isolation or PCR of T. gondii

from the patient’s body fluids reflects acute infection, whereas isolation

from biopsied tissue is an indication only of the presence of tissue cysts

and should not be misinterpreted as evidence of acute toxoplasmosis.

Persistent parasitemia in patients with latent, asymptomatic infection

is rare. Histologic examination of lymph nodes may suggest the characteristic changes described above. Demonstration of tachyzoites in

lymph nodes establishes the diagnosis of acute toxoplasmosis. Histologic demonstration of cysts containing bradyzoites confirms prior

infection with T. gondii but may represent latent rather than acute

infection.

Serology Because some diagnostic tests are only available at specialty labs, serologic testing has become the routine method of diagnosis. Diagnosis of acute infection with T. gondii can be established

by detection of the simultaneous presence of IgG and IgM antibodies

to Toxoplasma in serum. The presence of circulating IgA favors the

diagnosis of an acute infection. The Sabin-Feldman dye test, the indirect fluorescent antibody test, and the enzyme-linked immunosorbent

assay (ELISA) all satisfactorily measure circulating IgG antibody to

Toxoplasma. Positive IgG titers (>1:10) can be detected as early as

2–3 weeks after infection. These titers usually peak at 6–8 weeks and

decline slowly to a new baseline level that persists for life. Antibody

avidity increases with time and can be useful in difficult cases during

pregnancy for establishing when infection may have occurred. The

serum IgM titer should be measured in concert with the IgG titer to

better establish the time of infection; either the double-sandwich IgMELISA or the IgM-immunosorbent assay (IgM-ISAGA) should be used.

Both assays are specific and sensitive, with fewer false-positive results

than other commercial tests. The double-sandwich IgA-ELISA is more

sensitive than the IgM-ELISA for detecting congenital infection in the

fetus and newborn. Although a negative IgM result with a positive IgG

titer indicates distant infection, IgM can persist for >1 year and should

not necessarily be considered a reflection of acute disease. If acute toxoplasmosis is suspected, a more extensive panel of serologic tests can be

performed. In the United States, testing is available at the Remington

TABLE 228-1 Differential Laboratory Diagnosis of Toxoplasmosis

CLINICAL SETTING ALTERNATIVE DIAGNOSIS

DISTINGUISHING

CHARACTERISTICS

Mononucleosis

syndrome

Epstein-Barr virus infection Serology/PCR

Cytomegalovirus infection PCR/viral load/serology

HIV infection Serology/antigen/viral

load

Bartonella infection

(cat-scratch disease)

Biopsy (PCR or culture)/

serology

Lymphoma Biopsy

Congenital infection Cytomegalovirus infection PCR

Herpes simplex virus

infection

PCR

Rubella virus infection Serology

Syphilis Serology

Listeriosis Bacterial culture

Chorioretinitis in

immunocompetent

individual

Tuberculosis Bacterial culture/PCR

Syphilis Serology

Histoplasmosis Serology/culture/antigen

Chorioretinitis in

AIDS patient

Cytomegalovirus infection Characteristic exam

Syphilis Serology

Herpes simplex virus

infection

PCR

Varicella-zoster virus

infection

PCR

Fungal infection PCR/culture

CNS lesions in

AIDS patient

Lymphoma or metastatic

tumor

Tissue biopsy

Brain abscess Culture/biopsy

Progressive multifocal

leukoencephalopathy

PCR for JC virus

Fungal infection Antigen/PCR/biopsy/

culture

Mycobacterial infection PCR/biopsy/culture

Abbreviations: CNS, central nervous system; PCR, polymerase chain reaction.

Source: Reproduced with permission from JD Schwartzman: Toxoplasmosis, in

Principles and Practice of Clinical Parasitology. Hoboken, Wiley, 2001.

1762 PART 5 Infectious Diseases

Laboratory for Specialty Diagnostics (formerly Toxoplasma Serology

laboratory; https://www.sutterhealth.org/pamf/services/lab-pathology/

toxoplasma-serology-laboratory).

Molecular Diagnostics Molecular approaches can directly detect

T. gondii in biologic samples independent of the serologic response.

Results obtained with PCR have suggested high sensitivity, specificity,

and clinical utility in the diagnosis of TE. PCR technology is readily

available. While very specific, depending on the body fluid type tested,

the sensitivity of PCR of body fluids may be low, and diagnostic algorithms typically incorporate serologic testing of blood or body fluids.

Real-time PCR, if available, can provide quantitative results. Isolates

can be genotyped and polymorphic sequences can be obtained, with

consequent identification of the precise strain. Molecular epidemiologic studies with polymorphic markers have been useful in correlating clinical signs and symptoms of disease with different T. gondii

genotypes.

The Immunocompetent Adult or Child For the patient who

presents with lymphadenopathy only, a positive IgM titer is an indication of acute infection—and an indication for therapy, if clinically

warranted (see “Treatment,” below). The serum IgM titer should be

determined again in 3 weeks. An elevation in the IgG titer without an

increase in the IgM titer suggests that infection is present but is not

acute. If there is a borderline increase in either IgG or IgM, the titers

should be reassessed in 3–4 weeks.

The Immunocompromised Host A presumptive clinical diagnosis of TE in patients with AIDS is based on clinical presentation,

history of exposure (as evidenced by positive serology), and radiologic

evaluation. To detect latent infection with T. gondii, HIV-infected persons should be tested for IgG antibody to Toxoplasma soon after HIV

infection is diagnosed. When these criteria are used, the predictive

value is as high as 80%. More than 97% of patients with AIDS and

toxoplasmosis have IgG antibody to T. gondii in serum. IgM serum

antibody usually is not detectable. Although IgG titers do not correlate

with active infection, serologic evidence of infection virtually always

precedes the development of TE. It is therefore important to determine

the Toxoplasma antibody status of all patients infected with HIV. Antibody titers may range from negative to 1:1024 in patients with AIDS

and TE. Fewer than 3% of patients have no demonstrable antibody to

Toxoplasma at diagnosis of TE.

Patients with TE have focal or multifocal abnormalities demonstrable by CT or MRI. Neuroradiologic evaluation should include doubledose contrast CT of the head. By this test, single and frequently multiple

contrast-enhancing lesions (<2 cm) may be identified. MRI usually

demonstrates multiple lesions located in both hemispheres, with the

basal ganglia and corticomedullary junction most commonly involved;

MRI provides a more sensitive evaluation of the efficacy of therapy

than does CT (Fig. 228-2). These findings are not pathognomonic of

Toxoplasma infection, because 40% of CNS lymphomas are multifocal

and 50% are ring-enhancing. For both MRI and CT scans, the rate of

false-negative results is ~10%. The finding of a single lesion on an MRI

scan increases the likelihood of primary CNS lymphoma (in which solitary lesions are four times more likely than in TE) and strengthens the

argument for the performance of a brain biopsy. A therapeutic trial of

anti-Toxoplasma medications is frequently used to assess the diagnosis.

Treatment of presumptive TE with pyrimethamine plus sulfadiazine or

clindamycin results in quantifiable clinical improvement in >50% of

patients by day 3. Leucovorin is administered to prevent bone marrow

toxicity. By day 7, >90% of treated patients show evidence of improvement. In contrast, if patients fail to respond or have lymphoma, clinical

signs and symptoms worsen by day 7. Patients in this category require

brain biopsy with or without a change in therapy. This procedure can

now be performed by a stereotactic CT-guided method that reduces

the potential for complications. Brain biopsy for T. gondii identifies

organisms in 50–75% of cases. PCR amplification of CSF may also

confirm toxoplasmosis or suggest alternative diagnoses (Table 228-1),

such as progressive multifocal leukoencephalopathy (JC virus positive)

or primary CNS lymphoma (Epstein-Barr virus positive).

CT and MRI with contrast are currently the standard diagnostic

imaging tests for TE. As in other conditions, the radiologic response

may lag behind the clinical response. Resolution of lesions may take

from 3 weeks to 6 months. Some patients show clinical improvement

despite worsening radiographic findings.

Congenital Infection The issue of concern when a pregnant

woman has evidence of recent T. gondii infection is whether the fetus is

infected. PCR analysis of the amniotic fluid for the B1 gene of T. gondii

has replaced fetal blood sampling. Serologic diagnosis is based on the

persistence of IgG antibody or a positive IgM titer after the first week of

life (a time frame that excludes placental leak). The IgG determination

should be repeated every 2 months. An increase in IgM beyond the

first week of life is indicative of acute infection. Up to 25% of infected

newborns may be seronegative and have normal routine physical

examinations. Thus, assessment of the eye and the brain, with ophthalmologic testing, CSF evaluation, and radiologic studies, is important in

establishing the diagnosis.

Ocular Toxoplasmosis The serum antibody titer may not correlate

with the presence of active lesions in the fundus, particularly in cases of

congenital toxoplasmosis. In general, a positive IgG titer (measured in

undiluted serum if necessary) in conjunction with typical lesions establishes the diagnosis. If lesions are atypical and the serum antibody titer

is in the low-positive range, the diagnosis is presumptive. The parasitic

antigen–specific polyclonal IgG assay as well as parasite-specific PCR

may facilitate the diagnosis. PCR of ocular samples has better yield

than PCR of blood. Diagnosis may also be established by ocular fluid

Western blot or comparison of ocular fluid antibody with blood antibody (Goldmann-Witmer coefficient). The clinical diagnosis of ocular

toxoplasmosis can be supported in 60–90% of cases by laboratory tests,

depending on the time of anterior chamber puncture and the panel of

antibody analyses used.

TREATMENT

Toxoplasmosis

CONGENITAL INFECTION

Congenitally infected neonates are treated with daily oral

pyrimethamine (1 mg/kg) and sulfadiazine (100 mg/kg) with folinic

acid for 1 year. Depending on the signs and symptoms, prednisone

(1 mg/kg per day) may be used for congenital infection. Some

U.S. states and some countries routinely screen pregnant women

(France, Austria) and/or newborns (Denmark, Massachusetts).

Management and treatment regimens vary with the country and

the treatment center. Most experts use spiramycin to treat pregnant

women who have acute toxoplasmosis early in pregnancy and use

pyrimethamine/sulfadiazine/folinic acid to treat women who seroconvert after 18 weeks of pregnancy or in cases of documented fetal

infection. This treatment is somewhat controversial: clinical studies, which have included few untreated women, have not proven

the efficacy of such therapy in preventing congenital toxoplasmosis. However, studies do suggest that treatment during pregnancy

decreases the severity of infection. Many women who are infected

in the first trimester elect termination of pregnancy. Those who do

not terminate pregnancy are offered prenatal antibiotic therapy to

reduce the frequency and severity of Toxoplasma infection in the

infant. The optimal duration of treatment for a child with asymptomatic congenital toxoplasmosis is not clear, although most clinicians in the United States would treat the child for 1 year in light

of cohort investigations conducted by the National Collaborative

Chicago-Based, Congenital Toxoplasmosis Study.

INFECTION IN IMMUNOCOMPETENT PATIENTS

Immunologically competent adults and older children who have

only lymphadenopathy do not require specific therapy unless they

have persistent, severe symptoms. Patients with ocular toxoplasmosis are usually treated for 6 weeks with pyrimethamine plus

either sulfadiazine or clindamycin and sometimes with prednisone.

1763CHAPTER 228 Toxoplasma Infections

Trimethoprim-sulfamethoxazole (TMP-SMX) can also be given if

pyrimethamine cannot be obtained (5 mg/kg bid based on TMP).

Treatment should be supervised by an ophthalmologist familiar

with Toxoplasma disease. Ocular disease can be self-limited without

treatment, but therapy is typically considered for lesions that are

severe or close to the fovea or optic disc. Prolonged treatment with

TMP-SMX prevents recurrences of ocular toxoplasmosis while on

treatment and is often considered in individuals with frequent flares

in a 1- to 2-year period. Whether treatment improves long-term

visual outcomes is unclear.

INFECTION IN IMMUNOCOMPROMISED PATIENTS

Primary Prophylaxis Patients with AIDS should be treated for

acute toxoplasmosis; in immunocompromised patients, toxoplasmosis is rapidly fatal if untreated. Despite their toxicity, the drugs

used to treat TE were required for survival prior to ART. The

incidence of TE has declined as the survival of patients with HIV

infection has increased through the use of ART.

In Africa, many patients are diagnosed with HIV infection

only after developing opportunistic infections. Hence, the optimal

management of these opportunistic infections is important if the

benefits of subsequent ART are to be realized. The incidence of TE

in underresourced settings is unknown because serologic testing

and imaging are not available. AIDS patients who are seropositive

for T. gondii and who have a CD4+ T lymphocyte count of <100/μL

should receive prophylaxis against TE.

Of the currently available agents, TMP-SMX appears to be an

effective alternative for treatment of TE in resource-poor settings where the preferred combination of pyrimethamine plus

sulfadiazine is not available. Pyrimethamine is very expensive

in the United States, so many clinicians prescribe TMP-SMX

if pyrimethamine cannot be obtained. The daily dose of TMPSMX (one double-strength tablet) recommended for prophylaxis

of Pneumocystis jirovecii pneumonia (PCP; formerly Pneumocystis

carinii) is effective against TE. If patients cannot tolerate TMPSMX, the recommended alternative is dapsone-pyrimethamine,

which likewise is effective against PCP. Atovaquone with or without

pyrimethamine also can be considered. Prophylactic monotherapy

with dapsone, pyrimethamine, azithromycin, clarithromycin, or

aerosolized pentamidine is probably insufficient. AIDS patients

who are seronegative for Toxoplasma and are not receiving prophylaxis for PCP should be retested for IgG antibody to Toxoplasma

if their CD4+ T-cell count drops to <100/μL. If seroconversion

has taken place, then the patient should be given prophylaxis as

described above.

Discontinuing Primary Prophylaxis Current studies indicate that

prophylaxis against TE can be discontinued in patients who have

responded to ART and whose CD4+ T lymphocyte count has been

>200/μL for 3 months. Although patients with CD4+ T lymphocyte

counts of <100/μL are at greatest risk for developing TE, the risk

that this condition will develop when the count has increased to

100–200/μL has not been established. Thus, prophylaxis should be

discontinued when the count has increased to >200/μL. Discontinuation of therapy reduces the pill burden; the potential for drug

toxicity, drug interaction, or selection of drug-resistant pathogens;

and cost. Prophylaxis should be recommenced if the CD4+ T lymphocyte count again decreases to <100–200/μL.

Individuals who have completed initial therapy for TE should

receive treatment indefinitely unless immune reconstitution, with

a CD4+ T-cell count of >200/μL, occurs as a consequence of combined ART (cART). Combination therapy with pyrimethamine plus

sulfadiazine plus leucovorin is effective for this purpose. An alternative to sulfadiazine in this regimen is clindamycin or TMP-SMX.

Discontinuing Secondary Prophylaxis (Long-Term Maintenance

Therapy) Patients receiving secondary prophylaxis for TE are at

low risk for recurrence when they have completed initial therapy for

TE, remain asymptomatic, and have evidence of restored immune

function. Individuals with HIV infection should have a CD4+ T

lymphocyte count of >200/μL for at least 6 months after cART. This

recommendation is consistent with more extensive data indicating

the safety of discontinuing secondary prophylaxis for other opportunistic infections during advanced HIV disease. A repeat MRI

brain scan is recommended. Secondary prophylaxis should be reintroduced if the CD4+ T lymphocyte count decreases to <200/μL.

■ PREVENTION

All HIV-infected persons should be counseled regarding sources of

Toxoplasma infection. The chances of primary infection with Toxoplasma can be reduced by not eating undercooked meat and by avoiding oocyst-contaminated material (i.e., a cat’s litter box). Specifically,

lamb, beef, pork, and venison should be cooked to an internal temperature of 63°C (145°F) measured in the thickest portion of the cut and

rested for 3 minutes. Ground meat should be cooked to 71°C (145°F),

whereas poultry should be cooked to 74°C (165°F). Hands should be

washed thoroughly after work in the garden, and all fruits and vegetables should be washed. Ingestion of raw shellfish is a risk factor for

toxoplasmosis, given that the filter-feeding mechanism of clams and

mussels concentrates oocysts.

If the patient owns a cat, the litter box should be cleaned or changed

daily, preferably by an HIV-negative, nonpregnant person; alternatively, patients should wash their hands thoroughly after changing the

litter box. Litter boxes should be changed daily if possible, as freshly

excreted oocysts will not have sporulated and will not be infectious.

Patients should be encouraged to keep their cats inside and not to

adopt or handle stray cats. Cats should be fed only canned or dried

commercial food or well-cooked table food, not raw or undercooked

meats. Patients need not be advised to part with their cats or to have

their cats tested for toxoplasmosis. Blood intended for transfusion into

Toxoplasma-seronegative immunocompromised individuals should be

screened for antibody to T. gondii. Although such serologic screening

is not routinely performed, seronegative women should be screened

for evidence of infection several times during pregnancy if they are

exposed to environmental conditions that put them at risk for infection

with T. gondii. HIV-positive individuals should adhere closely to these

preventive measures.

Acknowledgment

The author would like to acknowledge Dr. Lloyd Kasper for his numerous

contributions to our understanding of the pathogenesis of toxoplasmosis

and his essential role in preparation of this chapter for prior editions.

■ FURTHER READING

Cortés JA et al: Approach to ocular toxoplasmosis including pregnant

women. Curr Opin Infect Dis 32:426, 2019.

Jones JL et al: Toxoplasma gondii infection in the United States,

2011–2014. Am J Trop Med Hyg 98:551 2018.

Peyron F et al: Congenital toxoplasmosis in France and the

United States: One parasite, two diverging approaches. PLoS Negl

Trop Dis 11:e0005222, 2017.

Schumacher AC et al: Toxoplasmosis outbreak associated with Toxoplasma gondii-contaminated venison−high attack rate, unusual clinical presentation, and atypical genotype. Clin Infect Dis 72:1557, 2021.

Wang ZD et al: Prevalence and burden of Toxoplasma gondii infection

in HIV-infected people: A systematic review and meta-analysis.

Lancet HIV 4:e177, 2017.

1764 PART 5 Infectious Diseases

PROTOZOAL INFECTIONS

■ GIARDIASIS

Giardia duodenalis (also known as G. lamblia or G. intestinalis) is

a cosmopolitan protozoal parasite that inhabits the small intestines

of humans and other mammals. Giardiasis is one of the most common parasitic diseases in both developed and developing countries

worldwide, causing both endemic and epidemic intestinal disease and

diarrhea.

Life Cycle and Epidemiology (Fig. 229-1) Infection follows

the ingestion of environmentally hardy cysts, which excyst in the small

intestine, releasing flagellated trophozoites (Fig. 229-2) that multiply

by binary fission. Giardia remains a pathogen of the proximal small

229

bowel and does not disseminate hematogenously. Trophozoites remain

free in the lumen or attach to the mucosal epithelium by means of a

ventral sucking disk. As a trophozoite encounters altered conditions,

it forms a morphologically distinct cyst, which is the stage of the parasite usually found in the feces. Trophozoites may be present and even

predominate in loose or watery stools, but it is the resistant cyst that

survives outside the body and is responsible for transmission. Cysts

do not tolerate heating or desiccation, but they do remain viable for

months in cold fresh water. The number of cysts excreted varies widely

but can approach 107

 per gram of stool.

Ingestion of as few as 10 cysts is sufficient to cause infection in

humans. Because cysts are infectious when excreted, person-to-person

transmission occurs where fecal hygiene is poor. Giardiasis is especially

prevalent in day-care centers; person-to-person spread also takes place

in other institutional settings with poor fecal hygiene and during anal–

oral contact. If food is contaminated with Giardia cysts after cooking

or preparation, foodborne transmission can occur. Waterborne transmission accounts for episodic infections (e.g., in campers and travelers)

and for major epidemics in metropolitan areas. Surface water, ranging

from mountain streams to large municipal reservoirs, can become

contaminated with fecally derived Giardia cysts. The efficacy of water

as a means of transmission is enhanced by the small infectious inoculum of Giardia, the prolonged survival of cysts in cold water, and the

resistance of cysts to killing by routine chlorination methods that are

adequate for controlling bacteria. Viable cysts can be eradicated from

water by either boiling or filtration.

In the United States, Giardia (like Cryptosporidium; see below) is a

common cause of waterborne epidemics of gastroenteritis. Giardia is

common in developing countries, and infections may be acquired by

travelers.

There are several recognized genotypes or assemblages of G. duodenalis. Human infections are due to assemblages A and B, whereas other

assemblages are more common in other animals, including cats and

dogs. Like beavers from reservoirs implicated in epidemics, dogs and cats

have been found to be infected with assemblages A and B; this finding

suggests both that these animals may have been infected from human

sources and that they might be sources of further human infections.

Giardiasis, like cryptosporidiosis, creates a significant economic

burden because of the costs incurred in the installation of water

filtration systems required to prevent waterborne epidemics, in the

management of epidemics that involve large communities, and in the

evaluation and treatment of endemic infections.

Pathophysiology The reasons that some, but not all, infected

patients develop clinical manifestations and the mechanisms by

which Giardia causes alterations in small-bowel function are largely

unknown. Although trophozoites adhere to the epithelium, they

are not invasive but may elicit apoptosis of enterocytes, epithelial

barrier dysfunction, and epithelial cell malabsorption and secretion.

Consequent lactose intolerance and, in a minority of infected adults

Protozoal Intestinal

Infections and

Trichomoniasis

Peter F. Weller

Cysts and trophozoites

are passed in the stool

into the environment.

Excystation follows

exposure to stomach acid

and intestinal proteases,

releasing trophozoite forms

that multiply by binary

fission and reside in the

upper small bowel adherent

to enterocytes.

Cysts are ingested (10–25 cysts)

in contaminated water or food or

by direct fecal-oral transmission

(as in day-care centers).

Causes: Asymptomatic infection,

acute diarrhea, or chronic diarrhea

and malabsorption. Small bowel may

demonstrate villous blunting, crypt

hypertrophy, and mucosal inflammation.

Encystation occurs under

conditions of bile salt

concentration changes and

alkaline pH.

Smooth-walled cysts can

contain two trophozoites.

Cysts can survive in the environment

(up to several weeks in cold water). They may

also infect nonhuman mammalian species.

FIGURE 229-1 Life cycle of Giardia. (Reproduced with permission from RL Guerrant

et al [eds]: Tropical Infectious Diseases: Principles, Pathogens and Practice, 2nd

ed, Elsevier, 2006.)

FIGURE 229-2 Flagellated, binucleate Giardia trophozoites.

1765CHAPTER 229 Protozoal Intestinal Infections and Trichomoniasis

and children, significant malabsorption are clinical signs of the loss

of epithelial brush-border enzyme activities. In most infections, the

morphology of the bowel is unaltered; however, in chronically infected,

symptomatic patients, the histopathologic findings (including flattened

villi) and the clinical manifestations at times resemble those of tropical

sprue and gluten-sensitive enteropathy. The pathogenesis of diarrhea

in giardiasis is not known.

The natural history of Giardia infection varies markedly. Infections

may be asymptomatic, transient, recurrent, or chronic. G. duodenalis

parasites vary genotypically, and such variations might contribute to

different courses of infection. Parasite as well as host factors may be

important in determining the course of infection and disease. Both

cellular and humoral responses develop in human infections, but their

precise roles in disease pathogenesis and/or control of infection are

unknown. Because patients with hypogammaglobulinemia suffer from

prolonged, severe infections that are poorly responsive to treatment,

humoral immune responses appear to be important. The greater susceptibilities of the young than of the old and of newly exposed persons

than of chronically exposed populations suggest that at least partial

protective immunity may develop.

Clinical Manifestations Disease manifestations of giardiasis

range from asymptomatic carriage to fulminant diarrhea and malabsorption. Most infected persons are asymptomatic, but in epidemics,

the proportion of symptomatic cases may be higher. Symptoms may

develop suddenly or gradually. In persons with acute giardiasis, symptoms develop after an incubation period that lasts at least 5–6 days

and usually 1–3 weeks. Prominent early symptoms include diarrhea,

abdominal pain, bloating, belching, flatus, nausea, and vomiting.

Although diarrhea is common, upper intestinal manifestations such

as nausea, vomiting, bloating, and abdominal pain may predominate.

The duration of acute giardiasis is usually >1 week, although diarrhea

often subsides. Individuals with chronic giardiasis may present with

or without having experienced an antecedent acute symptomatic

episode. Diarrhea is not necessarily prominent, but increased flatus,

loose stools, sulfurous belching, and (in some instances) weight loss

occur. Symptoms may be continual or episodic and may persist for

years. Some persons who have relatively mild symptoms for long periods recognize the extent of their discomfort only in retrospect. Fever,

the presence of blood and/or mucus in the stools, and other signs and

symptoms of colitis are uncommon and suggest a different diagnosis

or a concomitant illness. Symptoms tend to be intermittent yet recurring and gradually debilitating, in contrast with the acute disabling

symptoms associated with many enteric bacterial infections. Because

of the less severe illness early on and the propensity for chronic infections, patients may seek medical advice late in the course of the illness;

however, disease can be severe, resulting in malabsorption, weight

loss, growth retardation in children, and dehydration. A number of

extraintestinal manifestations have been described, such as urticaria,

anterior uveitis, and arthritis; whether these are caused by giardiasis or

concomitant processes is unclear.

Giardiasis can be severe in patients with hypogammaglobulinemia

and can complicate other preexisting intestinal diseases, such as that

occurring in cystic fibrosis. In patients with AIDS, Giardia can cause

enteric illness that is refractory to treatment.

Diagnosis (Table 229-1) Giardiasis is diagnosed by detection of

parasite antigens in the feces, by identification of cysts in the feces or of

trophozoites in the feces or small intestines, or by nucleic acid amplification tests (NAATs). Cysts are oval, measure 8–12 μm × 7–10 μm, and

characteristically contain four nuclei. Trophozoites are pear-shaped,

dorsally convex, flattened parasites with two nuclei and four pairs of

flagella (Fig. 229-2). The diagnosis is sometimes difficult to establish.

Direct examination of fresh or properly preserved stools as well as

concentration methods should be used. Because cyst excretion is variable and may be undetectable at times, repeated examination of stool,

sampling of duodenal fluid, and biopsy of the small intestine may be

required to detect the parasite. Tests for parasitic antigens in stool are

at least as sensitive and specific as good microscopic examinations and

are easier to perform. Newer NAATs are highly sensitive.

TREATMENT

Giardiasis

Cure rates with metronidazole (250 mg thrice daily for 5 days)

are usually >90%. Tinidazole (2 g once by mouth) may be more

effective than metronidazole. Nitazoxanide (500 mg twice daily for

3 days) is an alternative agent for treatment of giardiasis. Paromomycin, an oral aminoglycoside that is not well absorbed, can be

given to symptomatic pregnant patients, although information is

limited on how effectively this agent eradicates infection.

Almost all patients respond to therapy and are cured, although

some with chronic giardiasis experience delayed resolution of symptoms after eradication of Giardia. For many of the latter patients,

residual symptoms probably reflect delayed regeneration of intestinal brush-border enzymes. Continued infection should be documented by stool examinations before treatment is repeated. Patients

who remain infected after repeated treatments should be evaluated

for reinfection through family members, close personal contacts,

and environmental sources as well as for hypogammaglobulinemia.

In cases refractory to multiple treatment courses, prolonged therapy

with metronidazole (750 mg thrice daily for 21 days) or therapy

with varied combinations of multiple agents has been successful.

Prevention Giardiasis can be prevented by consumption of uncontaminated food and water and by personal hygiene during the provision of care for infected children. Boiling or filtering potentially

contaminated water prevents infection.

■ CRYPTOSPORIDIOSIS

The coccidian parasite Cryptosporidium causes diarrheal disease that

is self-limited in immunocompetent human hosts but can be severe in

persons with AIDS or other forms of immunodeficiency. Two species

of Cryptosporidium, C. hominis and C. parvum, cause most human

infections.

Life Cycle and Epidemiology Cryptosporidium species are

widely distributed in the world. Cryptosporidiosis is acquired by the

consumption of oocysts (50% infectious dose: ~132 C. parvum oocysts

in nonimmune individuals), which excyst to liberate sporozoites that

TABLE 229-1 Diagnosis of Intestinal Protozoal Infections

PARASITE STOOL O+P FECAL ACID-FAST STAIN FECAL ANTIGEN IMMUNOASSAYS FECAL NAATS OTHER

Giardia + + + DFA

Cryptosporidium ± + + + DFA

Cystoisospora ± + +

Cyclospora ± + +

Dientamoeba ± + +

Balantidium +

Microsporidia – + Special fecal stains,

tissue biopsies

Abbreviations: DFA, direct immunofluorescence assay; NAATs, nucleic acid amplification tests; O+P, conventional ova and parasites.