Recent increases in the number of Americans undertaking international travel and in the number of immigrants entering the United States have resulted in an increased need for awareness among primary care physicians of parasitic diseases. Infection with parasitic pathogens generally presents with four major syndromes - fever, eosinophilia, diarrhea, and neurologic disturbance. This article will be limited to fevers associated with parasitic infections.
Almost all parasites that are associated with febrile illnesses are either tissue-invasive or reside in the bloodstream. Such pathogens include both protozoan and helminthic parasites. Among the protozoans that cause invasive infection in man are Plasmodiwn species, Toxoplasma gondii, Entamoeba species, Leishmania species, and the African trypanosomes (Trypanosomabrucei rhoesienseanagambienx). Helminthic pathogens associated with febrile illnesses include Schistosoma species, the filarial nematodes Wuchereria bancrofti and Brugia malayi, Strangyloides stercoraiis, Trichinella spiralis, and Toxocara canis.
Fever as a presenting symptom of parasitic infections often is associated with other localizing symptoms or signs that help the physician to focus on diseases affecting the involved organ systems, but in many situations fever is accompanied by nonspecific (nonlocalizing) manifestations. Because infection by pathogens traditionally classified as parasites is far more prevalent in the tropics, developing countries, and (in some cases) Europe than in the United States, these infections are found most commonly in returning travelers or immigrants from abroad. Consequently, in the differential diagnosis of fever, parasitic infections are more likely to be considered in returned travelers or immigrants. However, it is important to be aware of the increasing prevalence of parasitic infections that are acquired within the United States, from travel or residence in areas that are endemic for parasites such as S stercoralis, Giardta lamblia, and Entamoeba histolytica.
Figure. Algorithm for the evaluation of febrile patients suspected to have common parasitic infections.
Laboratory Testing for Parasitic Infections in a Febrile Individual
A practical approach to evaluating fever in individuals who present with suspected parasitic infections is to divide these individuals into two groups: those with fever accompanied by eosinophilia and those with fever not accompanied by eosinophilia (Figure). While there is some overlap between the two groups, in general, fever without eosinophilia results from infection with protozoa, such as the Plasmodium species, E histolytica, or Leishmania species, while fever accompanied by eosinophilia indicates infections with helminths, particularly tissue-invasive helminths, such as Schistosoma monsoni, Wbancrofti, orTcanis. It must be emphasized, however, that this approach is of practical value only in evaluating fevers, and this grouping does not indicate similarity in pathogenesis by the different organisms.
In narrowing down diagnostic possibilities in a febrile patient with a suspected parasitic infection, useful historical information includes:
* the duration of fevei;
* details of the areas of residence or travel,
* the patient's lifestyle and activities,
* immunization history, and
* knowledge of illness among contacts and family.
While fever patterns can vary tremendously, it is sometimes helpful to determine whether there is a characteristic pattern, especially if malaria is being considered. Similarly, the mode of onset of illness also can be helpful in determining the etiology of fever caused by parasites.
In evaluating such patients, or a patient in whom bacterial etiologies have been considered and ruled out, a thorough history and a targeted physical examination should be followed by screening laboratory tests directed toward detection of parasitic infections (Table 1). This initial screen will help narrow the differential diagnosis. Nonparasitic etiologies of fever must be kept in mind when evaluating patients, and if any procedure points to specific (nonparasitic) conditions that are associated with fever, the diagnostic approach must be modified appropriately. Additionally, the immunologie status of the patient plays a critical role in the pattern and presentation of parasitic infection; in immunocompromised individuals, symptoms can vary markedly from classic descriptions.
FEVER WITHOUT ACCOMPANYING EOSINOPHILIA
Fever in the absence of eosinophilia generally is indicative of protozoan pathogens.1 The most important illness to rule out among parasitic diseases is malaria. Other causes of fever without significant eosinophilia include amebiasis, leishmaniasis, African trypanosomiasis, and acute toxoplasmosis. The patient's history can provide many clues to the diagnosis and can narrow the differential diagnosis.
For malaria, travel to endemic areas, compliance with appropriate prophylactic regimen for the areas of travel, the duration of stay, and the pattern of fever observed can help in identifying malaria as a likely cause of fever. However, it must be emphasized that there may be no particular pattern to the fever, especially early in the disease caused by Plasmodium falciparum, the most dangerous form of malaria. Approximately 1000 cases of malaria are reported to the Centers for Disease Control and Prevention annually, with 48% of reported cases caused by Plasmodium vivax, 39% caused by P falciparum, and 7% caused by Plasmodium ovale and molarne. The majority of cases (83%) among US citizens is acquired in Africa, although only 2% of travelers visit areas in Africa where malaria is endemic.2 Even if chemoprophylaxis has been used, malaria must be considered in the differential diagnosis, since no chemoprophylaxis is totally effective and because of the increasing prevalence of resistant strains of P falciparum, and more recently, P vivax.* In addition to fever, commonly associated symptoms may include headache, back pain, chills, sweats, myalgias, nausea, vomiting, diarrhea, and cough.
Amebiasis, on the other hand, presents with a very different clinical syndrome. A history of a visit to endemic areas such as Mexico, India, western or southern Africa, or Central or South America followed by an iîlness with fever (reported in 30%) and bloody diarrhea should raise the possibility of amebic colitis. The illness is characteristically subacute in onset and is often self-limited. In some cases, 4 to 6 weeks after exposure to E histolytica liver involvement occurs, with right upper quadrant pain and systemic symptoms.4
Toxoplasma gpndii infections cause fever in only a small proportion of cases. In these individuals, a history of exposure to cats is common. The acute illness in symptomatic individuals is characterized by fever, malaise, myalgia, fatigue, headache, and sore throat. Toxoplasmosis in pregnancy is of special concern because of the risk of vertical transmission. Congenital toxoplasmosis, however, is not associated with fever. In immunocompromised hosts, toxoplasmosis can be fulminant and involve the central nervous system and the eye with devastating consequences.
History also can be useful in the diagnosis of visceral leishmaniasis, which is caused by two species, Le.iskma.nia donovani and Leishmania tropica. Both species are prevalent in Asia and Africa. The incubation period is variable, and the onset of disease is insidious. Fever is associated with sweating and systemic symptoms of weight loss and progressive weakness. Abdominal discomfort can result from massive splenic enlargement. Recently, there have been reports of visceral leishmaniasis presenting with few symptoms in soldiers returning from the Persian Gulf.5
A rare parasitic cause of fever is African trypanosomiasis, which results from infection with the flagellate protozoa T brucei gambiense or T rhodesiense transmitted by bites of the tsetse fly in Africa. There are three clinical stages in the course of the typical illness: the trypanosomal chancre, which is an inflammatory lesion at the site of the bite, followed by the hemolymphatic stage, which in turn leads to the meningoencephalitic stage, after a variable period of time.6 The disease is endemic in western Africa and rarely is seen among visitors.
There are no pathognomonic physical signs of malaria, but splenomegaly, if present, may be a helpful finding. The pattern of fever may be helpful in distinguishing the infecting species, but partial treatment may alter the classic patterns of fever. Severe falciparum malaria can present with no particular fever pattern, cerebral malaria, renal failure, pulmonary edema, severe edema, and hypoglycemia.7 Any degree of impaired consciousness or signs of cerebral dysfunction should be treated as cerebral malaria. While physical signs in amebic colitis are nonspecific, the presence of blood in the stool or on rectal exam is seen in almost all patients.4 Amebic hepatitis is associated with tender hepatomegaly with characteristic point tenderness over the involved lobe of the liver. Toxoplasmosis, in the acute form, presents with lymphadenopathy, which often involves the cervical chain. There may be few other physical findings, but a maculopapular rash sparing the palms and soles in the appropriate clinical setting should alert the clinician to this diagnosis. Fever in visceral leishmaniasis has a variable pattern with twice daily elevations to 38° to 4O0C and is accompanied by cachexia in most cases. Hepatosplenomegaly occurs with or without associated lymphadenopathy. Massive splenomegaly is characteristic of this disease.8
In African trypanosomiasis, the physical findings differ in the three clinical stages of illness. The chancre is the first stage and typically is a painful and tender raised disk several centimeters in diameter, surrounded by erythema and induration. It appears about 7 to 10 days after the bite of the tsetse fly and lasts about 3 weeks, leaving a scar. The hemolymphatic stage is characterized by periodic remittent fever, malaise, joint pains, and headache. Each episode lasts about 1 week and is associated with generalized lymphadenopathy, splenomegaly, and hepatomegaly. In the encephalitic stage, patients present with persistent headache and abnormal sleep patten often associated with extrapyramidal and cerebellar signs and progressive decrease in level of consciousness.6 This stage earned the disease the common name of "sleeping sickness."
Appropriate Diagnostic Tests for Common Parasitic Infections
Associated Laboratory Abnormalities
Anemia and thrombocytopenia with or without leukopenia are seen in several of these parasitic infections, most notably in malaria and leishmaniasis. Hypoalbuminemia and polyclonal hyperglobulinemia also are found in leishmaniasis. Nonspecific markers of inflammation such as raised sedimentation rates and elevated C-reactive protein levels are common in these systemic parasitic infections. Specific laboratory tests appropriate for each condition are discussed below.
Majaria. The parasite is seen on thick and thin blood smears, although multiple tests may be necessary in light infections. It is of note that the peak of parasitemia usually precedes die fever spike. Infecting species can be ascertained by morphology on Gietnsa stain, and speciation is important for optimal management. Serology has not been found to be useful because of the inability to distinguish active infection from exposure, particularly in residents of endemic areas.2 An important differential for malaria is babesiosis, caused by tick-transmitted zoonotic protozoan parasites, Babesia microti and divergens, which cause fever, hemoglobinuria, and renal failure in severe infections. However, epidemiologie (geographic distribution: northeastern United States and eastern/ southern Europe) and historical factors (occurrence in splenectomized individuals) usually make it easy to distinguish the two diseases.9
Amebiasis. The presence of cysts and trophozoites in the stool is diagnostic of this disease. Definitive diagnosis also can be made by colonoscopy with histological evaluation of scrapings from mucosal ulcers. Serology (enzyme-linked immunosorbent assay [ELISA] for immunoglobulin [Ig] G antibodies) is positive in a large proportion (85%) of cases and is particularly useful in the diagnosis of liver abscesses. The stool may be negative for cysts or trophozoites in individuals with liver abscesses. Interestingly, noninvastve species of Entamoeba do not result in seroconversion.4
Toxoplasmosis. The demonstration of trophozoites in tissue biopsies makes the definitive diagnosis. The presence of cysts alone is not considered diagnostic of active infection. Serology has been found to be variably helpful, the best test being the SabinFeldtnan dye test. It is necessary to demonstrate a fourfold rise in titer by this test for definitive diagnosis, which usually occurs 6 to 8 weeks after infection. The ELISA for IgM has shown promise but is not yet widely available.10
Leisunaniasis. Definitive diagnosis requires the demonstration of amastigote forms of the parasite in infected tissue, which can be bone marrow, spleen, or lymph node aspirates. Serology has not yet proven to be useful in diagnosing active infections.
African Trypanosomiasis. Parasitemia occurs during febrile illness episodes and can be detected on thick and thin blood smears. The parasite also may be found in cerebrospinal fluid and bone marrow. The card agglutination trypanosomiasis test is a useful serologie test for screening purposes in areas with T brucei gombiense infections.6
Table 2 lists the best available tests for the diagnosis of these parasitic infections. Newer diagnostic tests based on ELISA for antibody isotypes or deoxyribonucleic acid (DN A)-based techniques that detect parasitederived DNA in patient specimens undoubtedly will improve our ability to diagnose infection with these difficult-to-detect parasites.
FEVER ACCOMPANIED BY EOSINOPHILIA
The presence of eosinophilia in a patient with fever should alert the clinician to the possibility of a helminth infection. TKe association of tissue invasion by helminth parasites and eosinophilia has Long been the subject of investigation. Almost all trematode and nematode parasites of humans induce circulating eosinophilia during the invasive stage of infection when the developing larvae pass through the lung (with Ascaris lumbricades, hookworm, or S stercoraiis) or the abdominal viscera and other organs (in the case of T canis and T spirals). Fever accompanies the eosinophilia presumably because of the release of inflammatory cytokines from immune effector cells attacking the invading parasite. Because of the chronicity of infection, serological tests are less helpful in the case of fever associated with these helminth parasites. While the differential diagnosis in this situation is broad, as with protozoan infections, a careful history and directed laboratory investigations can narrow the differential diagnosis. Helminth parasites that cause fever and eosinophilia include S stercoraiis, T canis, W bancrofti, B malati, T spiralis, Schistosoma japonicum, and S mansoni.
Strongyloidiasis is endemic worldwide, including in the southern and southeastern United States, especially in the Appalachian region. The symptoms are nonspecific with vague gastrointestinal complaints such as dull abdominal pain, complaints of a bloated feeling in the abdomen, and diarrhea. Fever is uncommon in the normal (immunocompetent) host, but in immunocompromised patients, hyperinfection can occur with abdominal pain, nausea, vomiting, diarrhea, and malabsorption. Some patients may present with cough, wheezing, and hemoptysis in addition to fever. The fever does not have a characteristic pattern and can be intermittent.
Lymphatic filariasis is caused by infection with W bancrofti or B molaci and is endemic in the tropics, particularly in south and southeast Asia and Africa. Long residence in endemic areas is an important risk factor, but is not necessary to acquire infection. Filariasis usually presents with either asymptomatic eosinophilia or lymphatic obstruction, but in the uncommon situation where it presents as a febrile illness, the fever is high grade, often with shaking chills. The illness is typically acute and is associated with episodic adenolymphangitis. The episodes occur 6 to 10 times per year and usually last 3 to 7 days.11
Toxocara canis infections presenting with fever are associated with visceral larva migrans. This clinical syndrome results from migration of T canis larvae through the liver, lungs, and other tissues. The parasite may have a predilection for the brain.12 The typical patient is a 2- to 7-year-old child who presents with abdominal pain, anorexia, fever; cough, and wheezing. A history of eating dirt and close association with dogs should alert the clinician to this diagnosis. Adult patients present with weakness, pruritis, rash, difficulty in breathing, and abdominal pain.
Trichinosis results from ingestion of improperly cooked meat with encysted larvae of T sfnraiis in the muscle. The incubation period ranges from 1 to 34 days (mean: 8 days). Patients present with diarrhea or constipation and abdominal cramps 2 to 10 days after ingestion of the infected meat. The tissue invasion phase that follows is characterized by myalgia, generalized weakness, headaches, and fever of 38° to 4O0C in almost all patients.13 Pain is remarkable in the masseter and extraocular muscles. A diagnosis of trichinosis often can be made from a good history.
A rare parasitic etiology of fever is schistosomiasis, which in its acute form can present with high-level eosinophilia and intermittent fevers. This form of disease, also known as Katayama fever, is rare and generally seen in previously uninfected individuals. The syndrome occurs 4 to 6 weeks after exposure to cercariae- infested water and is characterized by high fevers, weight loss, abdominal pain, diarrhea, and hematochezia. Katayama fever can be caused by S japonicum and S mansoni but rarely by S hematobium. Areas endemic for these parasites include sub-Saharan and equatorial Africa and the Far East.14
In Strongyloidiasis, there may be few physical findings, although occasionally larva currens, a rapidly evolving serpiginous rash caused by migrating infective larvae, can be seen on the thighs. The adenolymphangitic manifestation of lymphatic filariasis presents with enlarged painful lymph nodes and, occasionally, with lymphedema associated with fever. A characteristic feature is retrograde lymphangitis. Visceral larva migrans also may present with few or no physical signs. Liver enlargement occurs in a minority of patients. Unlike the other infections discussed here, trichinosis can present with the pathognomonic findings of periorbital edema and muscle tenderness. Central nervous system abnormalities such as seizures, polyneuritis, and meningitis also are seen in this disease. Acute schistosomiasis is a dramatic illness, with a characteristic history (discussed above). Hepatosplenomegaly is common, as is generalized lymphadenopathy.
Associated Laboratory Abnormalities
Apart from the eosinophilia, which can be marked (>1000/mm3), these infections commonly are accompanied by elevated serum IgG and IgE, distinguishing them from many other causes of eosinophilia. Toxocara cams infections are associated with leukocytosis and elevated anti-A or anti-B isohemagglutinin. Elevated levels of muscle enzymes (creatine phosphokinase and lactate dehydrogenase) are characteristic of T sfnroits infections. Patients with Katayama fever (acute schistosomiasis) often have negative stool and urine tests initially. The syndrome is thought to result from a hypersensitivity to antigens from the surface of migrating schistosomulae.14
The stool examination is essential in the work-up of patients with suspected strongyloides because the presence of larvae establishes the diagnosis. However, the parasitic load often is very low, and the yield of a stool examination may be improved by concentration of the stool or techniques such as Baermann concentration or culture.15 A parasitic diagnosis usually is easier in a setting of hyperinfection because of much larger numbers of worms. In these patients, filariform larvae can be found in the sputum.
Serologie tests have been developed to detect antigen-specific antibodies, and the best test is an ELISA, which has high sensitivity and specificity (85% to 90% ).15 Cross-reactivity of this test with filariasis and schistosomiasis, however, has remained a problem. Lymphatic filariasis does not have any characteristic associated laboratory abnormalities, but filtration of blood collected at the time of peak microfilaremia (between 10:00 PM and midnight for periodic strains of W bancrofti and B malati, or midday for nonperiodic strains only found in the South Pacific and Oceania) can establish a diagnosis in microfilaremic individuals. Serological tests can be helpful in the diagnosis of acute schistosomiasis, although early in the course of the disease eggs may be absent from urine and stool, and serology may be negative. Repeating the test after 3 to 4 weeks can establish the diagnosis, although the treatment should not be withheld if suspicion is strong.14
Table 2 lists the best available tests for diagnosis of these infections, but newer diagnostic tests that are currently in development will improve our ability to make a definitive diagnosis.
After the diagnostic work-up outlined above indicates a specific diagnosis, treatment should be tailored to the causative agent. Discussion of treatment options is beyond the scope of this review, and the reader is referred to excellent reviews on the subject.16'18 In some situations, particularly if malaria is suspected, it may be necessary to commence treatment empirically based on the patient's history and available information of the geographic distribution of the suspected pathogen.
Febrile patients in whom a parasitic etiology is suspected can be classified broadly into two categories for the purpose of diagnostic evaluation based on the presence or absence of accompanying eosinophilia. Generally, the absence of eosinophilia indicates a protozoan etiology while the presence of eosinophilia is associated with tissue- in vasi ve helminthic infections. The history and physical examination often points to a specific diagnosis that can be confirmed by appropriate laboratory tests.
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Laboratory Testing for Parasitic Infections in a Febrile Individual
Appropriate Diagnostic Tests for Common Parasitic Infections