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 Acute symptoms occur 2 to 3 weeks after infection and include high fevers, enlarged spleen and liver, myalgia,

erythematous rash, acute myocarditis, lymphadenopathy, keratitis, and subcutaneous edema of the face, legs, and

feet. There may be symptoms of CN involvement, which carry a very poor prognosis. Myocarditis is confirmed by

electrocardiographi changes, tachycardia, chest pain, and weakness. Amastigotes proliferate within the cardiac

muscle cells and destroy the cells, leading to conduction defects and a loss of heart contractility (see Figure 26).

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Death may occur due to myocardial insufficiency or cardiac arrest. In infants and very young children, swelling of

the brain can develop, causing death.

The chronic stage may be initially asymptomatic (indeterminate stage), and even though parasites are rarely seen

in blood films, transmission by blood transfusion is a serious problem in endemic areas. Chronic Chagas’ disease

may develop years after undetected infection or after the diagnosis of acute disease. Approximately 30% of

patients may develop chronic Chagas’ disease, including cardiac changes and enlargement of the colon and

esophagus. Megacolon results in constipation, abdominal pain, and the inability to discharge feces. There may be

acute obstruction leading to perforation, septicemia, and death. However, the most frequent clinical signs of

chronic Chagas’ disease involve the heart, where enlargement of the heart and conduction changes are commonly

seen.

Laboratory Diagnosis:

Routine Methods. Trypomastigotes may be detected in blood by using thick and thin blood films or the buffy coat

concentration technique. Any of the blood stains can be used for both amastigote and trypomastigote stages.

Molecular Diagnostics. Referral laboratories have used molecular methods to detect infections with as few as one

trypomastigote in 20 mL of blood, but these methods are not routinely used in the field.

Antigen Detection. Immunoassays have been used to detect antigens in urine and sera in patients with congenital

infections and those with chronic Chagas’ disease.

Antigen detection can also be valuable for early diagnosis and for diagnosis of chronic cases in patients with

conflicting serologic test results.

Antibody Detection. Serologic tests for antibody detection include complement fixation, indirect fluorescent

antibody, indirect hemagglutination tests, and ELISA.

Histology. In tissue, amastigotes can be differentiated from fungal organisms because they will not stain positive

with periodic acid-Schiff, mucicarmine, or silver stains.

Therapy:

Nifurtimox (Lampit) and benznidazole (Radamil) reduce the severity of acute Chagas’ disease. In some cases,

surgery has been successfully used to treat cases of chagasic heart disease, megaesophagus, and megacolon.

Leishmania spp:.

Leishmaniasis is caused by more than 20 species of the protozoan genus Leishmania, with a disease spectrum

ranging from self-healing cutaneous lesions to debilitating mucocutaneous infections, subclinical viscerotropic

dissemination, and fatal visceral involvement. Publisheddisease burden estimates place leishmaniasis second in

mortality and fourth in morbidity among all tropical diseases.

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General characteristics:

 The parasite has two distinct phases in its life cycle: amastigoteand promastigote ( Figure27 ). The amastigote

form is an intracellular parasite in the cells of the reticuloendothelial system and is oval, measuring 1.5 to 5 μm,

and contains a nucleus and kinetoplast. Leishmania spp. exist as the amastigote in humans and as the

promastigote in the insect host. As the vector takes a blood meal, promastigotes are introduced into the human

host. Depending on the species, the parasites then move from the bite site to the organs within the

reticuloendothelial system (bone marrow, spleen, liver) or to the macrophages of the skin or mucous

membranes.Depending on the species involved, infection with Leishmania spp. can result in cutaneous, diffuse

cutaneous, mucocutaneous, or visceral disease. In endemic areas with leishmaniasis, co-infection with human

immunodeficiency virus (HIV)-positive patients is common. If co-infected patients are severely

immunocompromised, up to 25% will die shortly after being diagnosed. The use of highly active antiretroviral

therapy (HAART) has dramatically improved the prognosis of these co-infected patients.

Pathogenesis and spectrum of disease:

The first sign of cutaneous disease is a lesion (generally a firm, painless papule) at the bite site. Although a

single lesion may appear insignificant, multiple lesions or disfiguring facial lesions may be devastating for the

patient.

 Usually, the lesions will have a similar appearance and will progress at the same speed. The original lesion

may remain as a flattened plaque or may progress to a shallow ulcer. As the ulcer enlarges, it produces exudate

and often becomes secondarily infected with bacteria or other organisms.

 In mucocutaneous leishmaniasis, the primary lesions are similar to those found in cutaneous leishmaniasis.

Untreated primary lesions may develop into the mucocutaneous form in up to 80% of the cases. Dissemination to

the nasal or oral mucosa may occur from the active primary lesion or may occur years later after the original

lesion has healed. These mucosal lesions do not heal spontaneously, and secondary bacterial infections are

common and may be fatal. Also, untreated visceral leishmaniasis will lead to death; secondary bacterial and viral

infections are also common in these patients. The incubation period ranges from 10 days to 2 years,

usually being 2 to 4 months. Common symptoms include fever, anorexia, malaise, weight loss, and, frequently,

diarrhea.

Figure 27, Leishmania donovani parasites in Kupffer cells of liver (2000×). B, Leishmania sp.

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Clinical signs include nontender enlarged liver and spleen, swollen lymph nodes, and occasional acute

abdominal pain. Darkening of facial, hand, foot, and abdominal skin (kala-azar) is often seen in light-skinned

persons in India. Death may occur after a few weeks or after 2 to 3 years in chronic cases. The majority of

infected individuals will be asymptomatic or have very few or minor symptoms that will resolve without therapy.

Since 1990, an increase in leishmaniasis in organ transplant recipients has been documented. Most of these cases

have been visceral leishmaniasis.

Laboratory diagnosis:

After the cutaneous lesion exudate is removed, these lesions should be thoroughly cleaned with 70% alcohol.

Specimens can be collected from the margin of the lesion by aspiration, scraping, or punch biopsy or by making

a slit with a scalpel blade. Smears can be prepared from the material obtained and stained with any of the blood

stains; biopsy specimens should also be submitted for routine histologic examination. Specimens for visceral

disease include lymph node aspirates, liver biopsy specimens, bone marrow specimens, and buffy coat

preparations of venous blood. Amastigotes with reticuloendothelial cells have been detected in a number of

different specimens from HIV-positive patients.

Stained smears can be examined for the presence of the amastigotes. Although the specimens can be cultured

using special techniques, these procedures are not routinely available.

PCR methods have excellent sensitivity and specificity for direct detection, for identification of causative

species, and for assessment of treatment efficacy; although not routinely available, they can be performed at

some reference centers. A rapid immunochromatographic dipstick test using the recombinant K39 antigen has

become available for the qualitative detection of total anti–Leishmania immunoglobulins.

 In patients with severe visceral leishmaniasis (kalaazar), there is a characteristic hypergammaglobulinemia,

including both IgG and IgM. In highly suspect patients for the diagnosis of visceral leishmaniasis (assuming they

are immunocompetent), if hypergammaglobulinemia is not present, this may be used to rule out the original

diagnosis. Although serologic testing is available from some reference centers such as CDC, serologic assays are

not very useful for the diagnosis of mucocutaneous and visceral leishmaniasis.

THERAPY:

 In simple cutaneous leishmaniasis, lesions usually heal spontaneously, although treatment options include

cryotherapy heat, photodynamic therapy, surgical excision of, lesions, and chemotherapy. Standard therapy

consists of injections of antimonial compounds; however, relapse is quite common and the patient response

varies depending on the Leishmania species and type of disease.

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Other Protozoa:

Amebae, Flagellates (Other Body Sites):

 Amebae:

Naegleria fowleri

Acanthamoeba spp.

Balamuthia mandrillaris

 Flagellates:

Trichomonas vaginalis

Trichomonas tenax

 Coccidia (Other Body Sites):

 Coccidia:

Toxoplasma gondii

Free-living amebae:

 Infections caused by small, free-living amebae belonging to the genera Naegleria, Acanthamoeba, and

Balamuthia are generally not very well-known or recognized clinically.

Also, methods for laboratory diagnosis are unfamiliar and not routinely offered by most laboratories.

However, approximately 310 cases of primary amebic meningoencephalitis (PAM) caused by Naegleria

fowleri and more than 150 cases of granulomatous amebic encephalitis (GAE) caused by Acanthamoeba spp.

and Balamuthia mandrillaris (including several cases in patients with acquired immunodeficiency syndrome

[AIDS]) have been documented.Other infections caused by these organisms result in Acanthamoeba keratitis,

now numbering more than 750 cases and related primarily to poor lens care in contact lens wearers.

Additionally, both Acanthamoeba spp. and B. mandrillaris can cause cutaneous infections in humans.

Sappinia pedata, a free-living ameba normally found in soil contaminated with the feces of elk and buffalo,

was identified in an excised brain lesion from a 38-year-old immunocompetent man who developed a frontal

headache, blurry vision, and loss of consciousness following a sinus infection. Additionally,

Paravahlkampfia francinae, a new species of the free-living ameba genus Paravahlkampfia, was recently

isolated from the cerebrospinal fluid (CSF) of a patient with a headache, sore throat, and vomiting, symptoms

typical of primary amebic meningoencephalitis (PAM) caused by Naegleria fowleri from the environment.

NAEGLERIA FOWLERI:

General characteristics

There are both trophozoite and cyst stages in the life cycle, with the stage present primarily dependent on

environmental conditions. Trophozoites can be found in water or moist soil and can be maintained in tissue

culture or other artificial media. The amebae may enter the nasal cavity by inhalation or aspiration of water,

dust, or aerosols containing the trophozoites or cysts. N. fowleri is incapable of survival in clean, chlorinated

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water. Following inhalation or aspiration, the organisms then penetrate the nasal mucosa, probably through

phagocytosis of the olfactory epithelium cells, and migrate via the olfactory nerves to the brain.

The trophozoites can occur in two forms: ameboid and flagellate ( Figure 28). The size ranges

from 7 to 35 μm. The diameter of the rounded forms is usually 15 μm. There is a large, central karyosome

and no peripheral nuclear chromatin. The cytoplasm is somewhat granular and contains vacuoles. The

ameboid form organisms change to the transient, pear-shaped flagellate form when they are transferred from

culture or teased from tissue into water and maintained at a temperature of 27° to 37° C. These flagellate

forms do not divide, but when the flagella are lost, the ameboid forms resume reproduction. Cysts are

generally round, measuring from 7 to 15 μm with a thick double wall.

Pathogenesis and spectrum of disease

Primary amebic meningoencephalitis (PAM) caused by N. fowleri is an acute, suppurative infection of the brain

and meninges (Figure 29). With extremely rare exceptions, the disease is rapidly fatal in humans. The period

between organism contact and onset of symptoms such as fever, headache, and rhinitis varies from a few days

to 2 weeks. Early symptoms include vague upper respiratory tract distress, headache, lethargy, and occasionally

olfactory problems. The acute phase includes sore throat; a stuffy, blocked, or discharging nose; and severe

headache.

Progressive symptoms include pyrexia, vomiting, and stiffness of the neck. Mental confusion and coma

usually occur approximately 3 to 5 days before death, which is usually caused by cardiorespiratory arrest and

pulmonary edema.

PAM resembles acute bacterial meningitis, and these conditions may be difficult to differentiate. Unfortunately,

if the CSF Gram stain is interpreted incorrectly as a false positive, the resulting antibacterial therapy has no

impact on the amebae and the patient will usually die within a few days.

Figure 28 Naegleria fowleri, Acanthamoeba spp. Diagram of trophozoites and cysts . Flagellate and

cyst forms of Naegleria fowleri; (lower row) trophozoite and cyst of Acanthamoeba spp.

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Laboratory diagnosis

Routine Methods

Clinical and laboratory data usually cannot be used to differentiate pyogenic meningitis from PAM. A high

index of suspicion is often critical for early diagnosis.

Most cases are associated with exposure to contaminated water through swimming or bathing. There is

normally an incubation period of 1 day to 2 weeks, and then a course of 3 to 6 days, most often ending in death.

Analysis of the CSF will show decreased glucose and increased protein concentrations. The leukocyte count

will range from several hundred to >20,000 cells per mm3. Although Gram stains and bacterial cultures of CSF

will be negative, serious patient complications can occur as the result of incorrect therapy if false-positive Gram

stains are reported.

A confirmed diagnosis is made by the identification of amebae in the CSF or in biopsy specimens. CSF should

be placed on a slide, under a cover slip, and observed for motile trophozoites; smears can be stained with any of

the blood stains. It is important not to mistake leukocytes for actual organisms or vice versa. This type of

misidentification often occurs when using a counting chamber and the amebae sink to the bottom and round up,

hencethe recommendation to use just a regular slide and cover slip. Depending on the temperature and lag time

between specimen collection and examination, motility may vary.

Slides may be warmed slightly to improve motility. The most important differential characteristic is the

spherical nucleus with a large karyosome.

Specimens should never be refrigerated before examination, and CSF should be centrifuged at a slow speed

(250× g). If N. fowleri is the causative agent, only trophozoites are normally seen, whereas cysts and

trophozoites can be seen with Acanthamoeba spp.

Other Methods:

Most cases are diagnosed at autopsy; confirmation of tissue findings must include culture and/or special

staining with monoclonal reagents in indirect fluorescent antibody procedures.

Therapy:

Although many antimicrobial and antiparasitic drug have been screened for activity against N. fowleri, only a

few patients have recovered after receiving intrathecal and intravenous injections of amphotericin B or in

combination with miconazole.

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