Kevin Messacar, MD
Samuel R. Dominguez, MD, PhD
Myron J. Levin, MD
PARASITIC INFECTIONS
Parasitic diseases are common and may present clinically in a variety of ways (Table 43–1). Although travel to endemic areas suggests particular infections, many parasites are transmitted through fomites or acquired from contact with human carriers and can occur anywhere. Some of the less common parasitic infections and those seen primarily in the developing world are presented in abbreviated form in Table 43–2.
Table 43–1. Signs and symptoms of parasitic infection.
Table 43–2. Some parasitic infections rarely seen in developed regions.
Selection of Patients for Evaluation
The incidence of parasitic infections varies greatly with geographic area. Children who have traveled or lived in areas where parasitic infections are endemic are at risk for infection with a variety of intestinal and tissue parasites. Children who have resided only in developed countries are usually free of tissue parasites (except Toxoplasma). Searching for intestinal parasites is expensive for the patient and time-consuming for the laboratory. More than 90% of ova and parasite examinations performed in most hospital laboratories in the United States are negative; many have been ordered inappropriately on patients without exposure to endemic areas. An approach to determining which children with diarrhea need such examinations is presented in Figure 43–1. It can be more cost-effective to empirically treat symptomatic US immigrants with albendazole for common intestinal parasites and to investigate only those whose symptoms persist.
Figure 43–1. Parasitologic evaluation of acute diarrhea.
Immunodeficient children are very susceptible to protozoal intestinal infections. Multiple opportunists are frequently identified, and the threshold for ordering tests should be low for these children.
Swanson SJ et al: Albendazole therapy and enteric parasites in United States-bound refugees. N Engl J Med 2012;366(16):1498–1507 [PMID: 22512482].
Specimen Processing
For tissue parasites, contact the laboratory for proper collection procedures. For intestinal parasites, diarrheal stools may contain trophozoites that die rapidly during transport. The specimen should be either examined immediately or placed in a stool fixative such as polyvinyl alcohol. Fixative vials for home collection of stool are commercially available. They may contain toxic compounds, so they should be stored safely. Fixed specimens are stable at room temperature. Formed stools usually contain cysts that are more stable. It is also best to fix these after collection, although they may be reliably examined after transport at room temperature. The US Centers for Disease Control and Prevention (CDC) have created a website (http://dpd.cdc.gov/dpdx) to assist in the laboratory diagnosis of common parasitic diseases, including specimen collection and processing.
Eosinophilia & Parasitic Infections
Although certain parasites commonly cause eosinophilia, in developed countries other causes are much more common. These include allergies, drugs, and other infections. Heavy intestinal nematode infection causing eosinophilia is easily detected on a single ova and parasite examination. Light nematode infections and common protozoal infections—giardiasis, cryptosporidiosis, and amebiasis—rarely cause eosinophilia. Eosinophilia is also unusual or minimal in more serious infections such as amebic liver abscess and malaria.
The most common parasitic infection in the United States that causes significant eosinophilia with negative stool examination is toxocariasis. In a young child with unexplained eosinophilia and a negative stool examination for parasites, a serologic test for Toxocara may be the next appropriate test. Trichinosis, which is a rare parasitic infection in the United States, causes marked eosinophilia. Strongyloidiasis is a cause of eosinophilia that may be difficult to diagnose with stool examinations. The differential diagnosis of eosinophilia is broad for patients who have been in developing countries (see Table 43–1).
PROTOZOAL INFECTIONS
SYSTEMIC INFECTIONS
1. Malaria
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Residence in or travel to an endemic area (fever in the returning traveler)
Cyclic paroxysms of fever, chills, and intense sweating.
Headache, backache, cough, abdominal pain, nausea, vomiting, diarrhea.
Splenomegaly, anemia.
Can progress to coma, seizures.
Malaria parasites in peripheral blood smear.
General Considerations
Malaria causes approximately 1 million deaths each year, over 80% of which occur in children younger than 5 years of age in sub-Saharan Africa. Over the past 5 years, global efforts towards malaria prevention and treatment have led to declining mortality and morbidity. Approximately 1500 imported cases are diagnosed in the United States each year; local transmission may occasionally take place from imported cases. Human malaria is caused by five Plasmodium species—Plasmodium vivax (most common), Plasmodium falciparum (most virulent), Plasmodium ovale (similar to P vivax), Plasmodium malariae, and Plasmodium knowlesi (a primate parasite recently recognized as a cause of malaria in humans).
The female Anopheles mosquito transmits the parasites. An infected mosquito innoculates sporozoites into the bloodstream of a susceptible host, resulting in infection of hepatocytes. In the hepatic phase, the parasites mature into schizonts, which rupture and release merozoites into the circulation. The parasites infect and rupture red blood cells in the erthrocytic phase, as they mature from trophozoites to schizonts and release additional merozoites. In early stages of infection, asynchronous erythrocytic cycles of hemolysis commonly cause daily fevers. Eventually, synchronous erythrocytic cycles begin as parasites rupture the infected cells at more regular 48- or 72-hour intervals. Survival is associated with a progressive decrease in intensity of cycles. Relapses years later may occur from persistent hepatic infection, which occurs in P vivax and P ovale infections.
Susceptibility varies genetically; certain red cell phenotypes are partially resistant to P falciparum infection (hemoglobin S, hemoglobin F, thalassemia, and possibly glucose-6-phosphate dehydrogenase [G6PD] deficiency). The worldwide distribution of malaria species is determined to some extent by host genetic factors that have evolved in response to selective pressure from malaria. The absence of P vivax from Africa reflects the lack of specific Duffy blood group substances among most native Africans. Recurrent infections result in acquired species-specific immunity, which does not prevent infection, but decreases parasitemia and symptoms. Normal splenic function is an important factor because of the immunologic and filtration functions of the spleen. Asplenic persons develop rapidly progressive malaria with many circulating infected erythrocytes (including mature forms of P falciparum). Maternal immunity protects the neonate.
Clinical Findings
A. Symptoms and Signs
Clinical manifestations vary according to species, strain, and host immunity. Fever and vomiting are the most common presenting symptoms in children. Infants commonly present with recurrent bouts of fever, irritability, poor feeding, vomiting, jaundice, and splenomegaly. Rash is usually absent, which helps distinguish malaria from some viral infections in patients presenting with similar symptoms. In older children, the classic symptoms of fever with chills, rigors, headache, backache, myalgia, and fatigue are more easily elicited. Fever may be cyclic (every 48 hours for all but P malariae infection, in which it occurs every 72 hours) or irregular (most commonly observed with P falciparum). Between attacks, patients may look quite well. If the disease is untreated, relapses cease within a year in P falciparum and within several years in P vivax infections, but may recur decades later with P malariae infection. Infection during pregnancy often causes intrauterine growth restriction or premature delivery but rarely true fetal infection.
Physical examination in patients with uncomplicated cases may show only mild splenomegaly and anemia.
B. Laboratory Findings
The diagnosis of malaria relies on detection of one or more of the five human plasmodia in thick and thin blood smears. Three separate sets of thick and thin smears separated by 12–24 hours in a 72-hour period are recommended to rule out malaria infection. Thick smears are most sensitive for detection of small numbers of malaria parasites; thin smears allow identification of species and semiquantitative determination of percentage of parasitemia.
Most acute infections are caused by P vivax, P ovale, or P falciparum, although 5%–7% are due to multiple species. Identification of the Plasmodium species relies on morphologic criteria and requires an experienced observer (Table 43–3). Bench aids to assist in the identification of Plasmodium species can be found at http://www.dpd.cdc.gov/dpdx/HTML/Malaria.htm. A new US Food and Drug Administration (FDA)-approved antigen detection test is available and approved for rapid diagnostic testing of malaria. This test should be used in conjunction with microscopic examination to confirm diagnosis, look for mixed infection, and quantitate degree of parasitemia. The rapid antigen test has poor sensitivity for low levels of parasitemia. Up-to-date information on rapid diagnostic testing for malaria can be found at www.cdc.gov/malaria/diagnosis_treatment/index.html. Alternative techniques of similar or higher diagnostic accuracy for P falciparum include DNA hybridization and polymerase chain reaction (PCR), which are only available in research and reference laboratories as well as at CDC and some health departments.
Table 43–3. Differentiation of malaria parasites on blood smears.
The degree of parasitemia determined from thin smears is particularly useful in the management of infections caused by P falciparum and P knowlesi, in which high parasitemia (> 5% infected erythrocytes) is associated with high morbidity and mortality and requires hospitalization. Treatment response of P falciparum and chloroquine-resistant P vivax infections is best monitored by daily parasitemia assays. Constant or increased number of infected erythrocytes after 48 hours of treatment or after the second hemolytic crisis suggests an inadequate therapeutic response.
Hemolytic anemia and thrombocytopenia are common; the incidence of leukocytosis is variable.
Differential Diagnosis
Relapsing fever may be associated with borreliosis, brucellosis, sequential common infections, Hodgkin disease, juvenile rheumatoid arthritis, or rat-bite fever. Other common causes of high fever and headache include influenza, Mycoplasma pneumoniae or enteroviral infection, sinusitis, meningitis, enteric fever, tuberculosis, occult pneumonia, or bacteremia. In patients returning from tropical areas with fever, headache, and jaundice, leptospirosis and yellow fever should be included in the differential diagnosis. Clinical features may not reliably distinguish severe malaria from other severe infections in children, so a high index of suspicion in patients with exposure in endemic areas is necessary. Malaria may also coexist with other diseases.
Complications & Sequelae
Severe complications, which are limited to P falciparum and P knowlesi infection, result from hemolysis, microvascular obstruction, and tissue ischemia. The most common complications of malaria in children are cerebral malaria, respiratory distress, severe anemia, and/or hypoglycemia. Cerebral malaria is the most serious and life-threatening complication of malaria in children and may progress to seizures, coma, and death. Approximately 20% of children with cerebral malaria die and 10% have long-term neurologic sequelae. Signs of severe malaria in children include altered mental status, seizures, respiratory distress, hypoglycemia, acidosis, and parasitemia greater than 5%.
Prevention
Malaria chemoprophylaxis should be instituted 2 weeks (weekly regimens) to 2 days (daily regimens) before traveling to an area of endemic infection to permit alternatives if the drug is not tolerated. Because the antimalarial drugs recommended for prophylaxis do not kill sporozoites, therapy should be continued for 1 week (atovaquone-proguanil) or 4 weeks (all other regimens) after returning from an endemic area to cover infection acquired at departure.
No drug regimen guarantees protection against malaria. If fever develops within 1 year (particularly within 2 months) after travel to an endemic area, the possibility of malaria should be considered. Insect repellents, insecticide-impregnated bed nets, and proper clothing are important adjuncts for malaria prophylaxis.
For a full discussion regarding currently recommended medications for malaria prophylaxis, please see the corresponding section in Chapter 45.
Treatment
Treatment for malaria includes a variety of supportive strategies in addition to the antimalarial drugs. It is advisable to hospitalize nonimmune patients infected with P falciparum and P. knowlesi until a decrease in parasitemia is demonstrated, indicating that treatment is effective and severe complications are unlikely to occur. Patients with signs of severe malaria (parasitemia > 5%, cerebral malaria, acidosis, hypoglycemia, shock) require intensive care and parenteral treatment. Malaria due to P knowlesi should be treated like P falciparum malaria as it might progress rapidly into severe disease.
Partially immune patients with uncomplicated P falciparum and P knowlesi infection and nonimmune persons infected with P vivax, P ovale, or P malariae can receive treatment as outpatients if follow-up is reliable. For children, hydration and treatment of hypoglycemia are of utmost importance. Anemia, seizures, pulmonary edema, and renal failure require conventional management. Corticosteroids are contraindicated for cerebral malaria because of increased mortality. In severe malaria, exchange transfusion can be lifesaving, particularly in nonimmune persons with parasitemia greater than 10%.
Choice of antimalarial treatment depends on the immune status of the person, plasmodium species, degree of parasitemia, and resistance patterns in the geographical region of acquisition. An algorithm for the treatment of malaria is shown in Figure 43–2 and a description of the recommended antimalarial drugs available in the United States is provided in Table 43–4. Updated treatment guidelines are available at the Centers for Disease Control and Prevention (http://www.cdc.gov/malaria/diagnosis_treatment/treatment.html). Artemisinin derivatives clear parasites very rapidly and are widely used as key components, often as first-line therapy, in malaria treatment worldwide. These are available in the United States for the treatment of severe malaria only by contacting the CDC (http://www.cdc.gov/malaria/diagnosis_treatment/artesunate.html) or the Malaria Hotline at 770-488-7788.
Figure 43–2. Malaria treatment algorithm. (Adapted from Centers for Disease Control and Prevention. Malaria. http://www.cdc.gov/malaria/resources/pdf/algorithm.pdf.
Table 43–4. Antimalarial drugs available in the United States recommended for use in the treatment of malaria.
Crawley J et al: Malaria in children. Lancet 2010;375:1468–1481 [PMID: 20417858].
Griffith KS et al: Treatment of malaria in the United States. JAMA 2007;297:2264 [PMID: 17519416].
http://www.cdc.gov/malaria/.
http://www.dpd.cdc.gov/dpdx/HTML/Malaria.htm/.
http://www.who.int/malaria/diagnosis_treatment/.
Rosenthal PJ: Artesunate for the treatment of severe falciparum malaria. N Engl J Med 2008;358:1829–1836 [PMID: 18434652].
Taylor SM et al: Does this patient have malaria? JAMA 2010;304:2048–2056 [PMID: 21057136].
2. Babesiosis
Babesia microti is a malaria-like protozoan that infects humans bitten by infected Ixodes scapularis (deer tick), one of its intermediate hosts and vectors. After inoculation, the protozoan penetrates erythrocytes and starts an asynchronous cycle that causes hemolysis. In the United States, the majority of cases occur in the Northeast and upper Midwest from May to October. Babesia infection is also a transfusion-transmissible disease.
Clinical Findings
A. Symptoms and Signs
The incubation period is 1–4 weeks after tick bite, or 1–9 weeks after blood transfusion. Many times the tick bite is unnoticed. Approximately half of infected children are asymptomatic. Symptoms are nonspecific and most commonly include sustained or cyclic fever up to 40.9°C, shaking chills, and sweats. Other associated nonspecific symptoms include malaise, fatigue, anorexia, arthralgias, myalgias, and headache. Physical examination findings are usually minimal, but may include hepatosplenomegaly, jaundice, or dark urine. The disease is usually self-limited, causing symptoms for 1–2 weeks with fatigue that may persist for months. Severe cases have been described in asplenic patients and immunocompromised hosts. Because Babesia, Borrelia burgdorferi, and Anaplasma phagocytophilum share a common vector, physicians should consider the possibility of coinfection in patients diagnosed with any of these pathogens.
B. Laboratory Findings
The diagnosis is made by identifying babesial parasites in blood by microscopic evaluation of thin or thick blood smears or by PCR amplification of babesial DNA. Babesia parasites are intraerythrocytic organisms that resemble P falciparum ring forms. The tetrad form (Maltese cross), if visualized, is pathognomonic. Specific serologic tests are also available through the CDC. Hemolytic anemia, as well as thrombocytopenia, is common.
Treatment
Azithromycin (10 mg/kg up to 500 mg on the first day, followed by 5 mg/kg up to 250 mg/day) in combination with atovaquone (20 mg/kg, up to 750 mg, twice a day) for 7–10 days is the treatment of choice for mild to moderate disease. It has been found to be efficacious and causes fewer adverse side effects than other regimens. For severely ill patients, clindamycin (10 mg/kg, up to 600 mg, every 8 hours) in combination with quinine (8 mg/kg, up to 650 mg, every 8 hours) is standard of care. Longer courses of treatment may be needed in immunocompromised patients. Partial or complete RBC exchange transfusion is indicated for persons with severe babesiosis, as indicated by high-grade parasitemia (≥ 10%); significant hemolysis; or renal, hepatic, or pulmonary compromise.
Gubernot DM et al: Babesia infection through blood transfusion: reports received by the US Food and Drug Administration, 1997-2007. Clin Infect Dis 2009;48:25–30 [PMID: 19035776].
http://www.cdc.gov/parasites/babesiosis/.
http://www.dpd.cdc.gov/dpdx/HTML/Babesiosis.htm.
Vannier E, Krause PJ: Human babesiosis. N Engl J Med 2012;366:2397–2407 [PMID: 22716978].
3. Toxoplasmosis
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Congenital toxoplasmosis: chorioretinitis, microphthalmia, strabismus, microcephaly, hydrocephaly, convulsions, psychomotor retardation, intracranial calcifications, jaundice, hepatosplenomegaly, abnormal blood cell counts.
Acquired toxoplasmosis in an immunocompetent host: lymphadenopathy, hepatosplenomegaly, rash.
Acquired or reactivated toxoplasmosis in an immunocompromised host: encephalitis, chorioretinitis, myocarditis, and pneumonitis.
Ocular toxoplasmosis: chorioretinitis.
Serologic evidence of infection with Toxoplasma gondii or demonstration of the agent in tissue or body fluids.
General Considerations
Toxoplasma gondii is a worldwide parasite of animals and birds. Felines, the definitive hosts, excrete oocysts in their feces. Ingested mature oocysts or tissue cysts lead to tachyzoite invasion of intestinal cells. Intracellular replication of the tachyzoites causes cell lysis and spread of the infection to adjacent cells or to other tissues via the bloodstream. In chronic infection, T gondii appears in bradyzoite-containing tissue cysts that do not trigger an inflammatory reaction. In immunocompromised hosts, tachyzoites are released from cysts and begin a new cycle of infection.
The two major routes of Toxoplasma transmission to humans are oral and congenital. Oral infection occurs after ingestion of cysts from food, water, or soil contaminated with cat feces or from ingestion of undercooked meat or other food products that contain cysts. Oocysts survive for up to 18 months in moist soil. Oocyst survival is limited in dry, very cold, or very hot conditions, and at high altitude, which probably accounts for the lower incidence of toxoplasmosis in these climatic regions. In the United States, less than 1% of cattle and 25% of sheep and pigs are infected with toxoplasmosis. In humans, depending on geographic area, seropositivity increases with age from 0 to 10% in children younger than age 10 years to 3%–70% in adults.
Congenital transmission occurs during acute infection of pregnant women. Rarely, fetal infection has been documented in immunocompromised mothers who have chronic toxoplasmosis. Treatment during pregnancy decreases transmission by 60%.
Clinical Findings
Clinical toxoplasmosis can be divided into four groups: (1) congenital infection, (2) acquired in the immunocompetent host, (3) acquired or reactivated in the immunocompromised host, and (4) ocular disease.
A. Congenital Toxoplasmosis
Congenital toxoplasmosis is the result of acute infection during pregnancy and occurs in 1 in 3000 to 1 in 10,000 live births in the United States. The rate of transmission and disease severity in the baby vary according to when in pregnancy the infection is acquired. First-trimester infections lead to congenital infections about 10%–20% of the time, but the clinical disease is severe with microcephaly or hydrocephaly, severe chorioretinitis, hearing loss, convulsions, abnormal cerebrospinal fluid (CSF) (xanthochromia and mononuclear pleocytosis), cerebral calcifications, and mental retardation. Other findings include strabismus, eye palsy, maculopapular rash, pneumonitis, myocarditis, hepatosplenomegaly, jaundice, thrombocytopenia, lymphocytosis and monocytosis, and an erythroblastosis-like syndrome. Infection of a mother in the third trimester results in 70%–90% rate of congenital infection, but the majority of these children are asymptomatic at birth. Many of these children, however, will go on to develop ocular disease later and some will have subtle neurologic deficits.
B. Acquired Toxoplasma Infection in the Immunocompetent Host
Typically, acquired infection in the immunocompetent host is asymptomatic. About 10%–20% of patients develop lymphadenopathy and/or a flu-like illness. The nodes are discrete, variably tender, and do not suppurate. Cervical lymph nodes are most frequently involved, but any nodes may be enlarged. Less common findings include fever, malaise, myalgias, fatigue, hepatosplenomegaly, low lymphocyte counts (usually < 10%), and liver enzyme elevations. Unilateral chorioretinitis may occur. The disease is self-limited, although lymph node enlargement may persist or may wax and wane for a few months to 1 or more years.
Toxoplasmic lymphadenitis must be distinguished from other causes of infectious mononucleosis-like syndromes (< 1% are caused by Toxoplasma). Recovery typically occurs without any specific antiparasitic treatment.
C. Acute Toxoplasmosis in the Immunodeficient Host
Patients infected with human immunodeficiency virus (HIV), and those with lymphoma, leukemia, or transplantation, are at high risk for developing severe disease (most commonly central nervous system [CNS] disease, but also chorioretinitis, myocarditis, or pneumonitis) following acute infection or reactivation. Toxoplasmic encephalitis is one of the most common causes of mass lesions in the brains of persons with HIV/AIDS.
D. Ocular Toxoplasmosis
Ocular toxoplasmosis is an important cause of chorioretinitis in the United States. It can result from reactivation of congenital infection or acquired infection. Congenitally infected individuals are usually asymptomatic until the second or third decade of life when symptomatic eye disease occurs due to the rupture of tissue cysts and the release of bradyzoites and tachyzoites into the retina. Typically, ocular toxoplasmsis presents as a focal necrotizing retinochoroiditis often associated with a preexistent chorioretinal scar, and variable involvement of the vitreous, retinal blood vessels, optic nerve, and anterior segment of the eye. The appearance of the ocular lesion is not specific and mimics other granulomatous ocular diseases.
E. Diagnostic Findings
Serologic tests are the primary means of diagnosis, but results must be interpreted carefully. Reference laboratories with special expertise in toxoplasma serologic assays and their interpretation are essential for establishing a diagnosis and are preferred. Active infection can also be diagnosed by PCR of blood or body fluids; by visualization of tachyzoites in histologic sections or cytology preparations, cysts in placenta or fetal tissues; or by characteristic lymph node histology. IgG antibodies become detectable 1–2 weeks after infection, peak at 1–2 months, and thereafter persist for life. IgM antibodies, measured by ELISA (enzyme-linked immunosorbent assay) or particle agglutination, appear earlier and decline faster than IgG antibodies, but can last for 12–18 months after acute infection. Absence of both serum IgG and IgM virtually rules out the diagnosis of toxoplasmosis. Acute toxoplasmosis in an immunocompetent host is best documented by analyzing IgG and IgM in paired blood samples drawn 3 weeks apart. Because high antibody titers (IgM or IgG) can persist for several months after acute infection, a single high-titer determination is nondiagnostic; seroconversion or a fourfold increase in titer confirms the diagnosis. In the immunocompromised host, serologic tests are not sensitive, and active infection is documented by PCR or finding tachyzoites by histologic examination.
The diagnosis of toxoplasmosis in the older child with visual complaints is usually made by finding T gondii IgG or IgM antibodies in the serum combined with the presence of a typical eye lesion. The diagnosis can be confirmed by detecting T gondii DNA by PCR in the aqueous humor.
Diagnosis of congenital infection, which can be difficult, is made by a combination of serologic testing, parasite isolation, and clinical findings. Prenatally, diagnosis can be made by PCR of amniotic fluid. Postnatally, evaluation of the baby should include Toxoplasma-specific IgG, IgM, IgA, and IgE of the newborn and mother. IgM antibodies indicate an immune response by the infant. Persistence of the other antibodies also indicates infection of the infant. Blood, CSF, and amniotic fluid specimens should be assayed by PCR for the presence of T gondii in a reference laboratory. In addition, the child should have thorough ophthalmologic, auditory, and neurologic evaluation; a lumbar puncture; and computed tomographic (CT) scan of the head (to detect CNS calcifications). A congenital infection is confirmed serologically by detecting persistent or increasing IgG antibody levels compared to the mother, persistently positive IgG antibodies beyond the first year of life, and/or a positive T gondii–specific IgM or IgA antibody test.
Differential Diagnosis
Congenital toxoplasmosis must be differentiated from infection with cytomegalovirus, rubella, herpes simplex, syphilis, listeriosis, erythroblastosis, and the encephalopathies that accompany degenerative diseases. Acquired infection can mimic viral, bacterial, or lymphoproliferative disorders. Ocular toxoplasmosis can mimic other infectious, noninfectious, and neoplastic ocular conditions.
Prevention
Primary prevention of toxoplasmosis in pregnant women (and immunocompromised patients) is an essential public health goal and guidelines have been published by the CDC. These include (1) cook meat until well-done 150°F–170°F (no longer pink in center); (2) peel and/or wash fruits and vegetables thoroughly before eating; (3) wash hands, cutting boards, kitchen surfaces, and utensils after contact with raw meat; (4) avoid drinking untreated water from unsanitary sources; (5) wear gloves when gardening or coming in contact with soil or sand, as cat feces may contaminate them; and (6) if possible, pregnant women should avoid changing cat litter. If they cannot avoid changing cat litter, they should change it daily as oocysts require 48–72 hours to sporulate and become infectious. Serologic screening of pregnant women remains a controversial tool in the prevention of congenital toxoplasmosis.
Treatment
Treatment of acute toxoplasmosis in the immunocompetent host does not require specific therapy, unless the infection occurs during pregnancy. Toxoplasmic chorioretinitis presenting beyond infancy is treated the same way regardless of whether it is due to reactivation or primary infection. Treatment consists of oral pyrimethamine (2 mg/kg maximum 200 mg loading dose followed by 1 mg/kg daily, maximum 75 mg) plus sulfadiazine (100 mg/kg daily, maximum 1500 mg), given with leucovorin (10–20 mg three times a week). In addition, corticosteroids (prednisone 1 mg/kg daily) are given when lesions threaten vision. Treatment is given for 1–2 weeks after the resolution of symptoms. The duration of additional therapy should be guided by frequent ophthalmologic examinations. Pyrimethamine can cause gastrointestinal upset, leukopenia, thrombocytopenia, and rarely, agranulocytosis; weekly complete blood counts should be checked while on therapy.
A year of treatment is recommended for all congenitally infected infants. Children treated with pyrimethamine (loading dose 2 mg/kg daily for 2 days followed by 1 mg/kg daily for 6 months followed by 1 mg/kg every Monday, Wednesday, and Friday for 6 months) plus sulfadiazine (100 mg/kg divided twice daily for 12 months) plus leucovorin (10 mg 3 times a week) have better neurodevelopmental and visual outcomes than historical controls. While on therapy, infants should be monitored for bone marrow toxicity.
In primary maternal infection during the first 18 weeks of pregnancy, spiramycin is recommended to attempt to prevent fetal infection. Spiramycin does not cross the placenta, so does not treat fetal infection. If fetal infection has been documented or if primary maternal infection occurs after the first 18 weeks of pregnancy, pyrimethamine, sulfadiazine, and leucovorin are recommended. Pyrimethamine is teratogenic and should not be used before 18 weeks of gestation.
http://www.cdc.gov/parasites/toxoplasmosis/.
McAuley JB: Toxoplasmosis in children. Pediatr Infect Dis J 2008;27:161–162 [PMID: 18227714].
Montoya JG, Remington JS: Management of Toxoplasma gondii infection during pregnancy. Clin Infect Dis 2008;47(4):554–566 [PMID: 18624630].
Olariu TR et al: Severe congenital toxoplasmosis in the United States: clinical and serologic findings in untreated infants. Pediatr Infect Dis J 2011;30(12):1056–1061 [PMID: 21956696].
Vasconcelos-Santos DV et al: Review for disease of the year: differential diagnosis of ocular toxoplasmosis. Ocul Immunol Inflamm 2011;19:171–179 [PMID: 21595533].
GASTROINTESTINAL INFECTIONS
1. Amebiasis
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Acute dysentery: diarrhea with blood and mucus, abdominal pain, tenesmus.
Or
Chronic nondysenteric diarrhea.
Or
Hepatic abscess.
Amoebas or cysts in stool or abscesses; amebic antigen in stool.
Serologic evidence of amebic infection.
General Considerations
Amebiasis is defined as an infection with Entamoeba histolytica regardless of symptoms. This parasite is found worldwide, but has a particularly high prevalence in areas with poor sanitation and socioeconomic conditions. In the United States, infections are seen in travelers to and emigrants from endemic areas. The majority of infections are asymptomatic (> 90%), but tissue invasion can result in amebic colitis, hepatic abscess, and hematogenous spread to other organs. Transmission is usually fecal-oral. Infections with two other Entamoeba species, E dispar and E moshkovskii, are morphologically indistinguishable from E histolytica. Infections with these species are approximately 10 times more common than infection with E histolytica, but are not thought to cause human disease.
Clinical Findings
A. Symptoms and Signs
Patients with intestinal amebiasis can have asymptomatic cyst passage, or be symptomatic with acute amebic proctocolitis, chronic nondysenteric colitis, or ameboma. Because all E dispar and E moshkovskii infections and up to 90% of E histolytica infections are asymptomatic, carriage is the most common manifestation of amebiasis. Patients with acute amebic colitis typically have a 1- to 2-week history of loose stools containing blood and mucus, abdominal pain, and tenesmus. A minority of patients are febrile or dehydrated. Abdominal examination may reveal pain over the lower abdomen.
Fulminant colitis is an unusual complication of amebic dysentery that is associated with a grave prognosis (> 50% mortality), and is characterized by severe bloody diarrhea, fever, and diffuse abdominal pain. Children younger than age 2 years are at increased risk for this condition. Chronic amebic colitis causes recurrent episodes of bloody diarrhea over a period of years and is clinically indistinguishable from idiopathic inflammatory bowel disease. An ameboma is a localized amebic infection, usually in the cecum or ascending colon, which presents as a painful abdominal mass.
The most common complications of intestinal amebiasis are intestinal perforation, toxic megacolon, and peritonitis. Perianal ulcers, a less common complication, are painful, punched-out lesions that usually respond to medical therapy. Infrequently, colonic strictures may develop following colitis.
Extraintestinal amebiasis can result in liver, lung, and cerebral abscesses, and rarely genitourinary disease. Patients with amebic liver abscess, the most common form of extraintestinal amebiasis, typically present with acute fever and right upper quadrant tenderness. The pain may be dull, pleuritic, or referred to the right shoulder. Physical examination reveals liver enlargement in less than 50% of affected patients. Some patients have a subacute presentation lasting 2 weeks to 6 months. In these patients, hepatomegaly, anemia, and weight loss are common findings, and fever is less common. Jaundice and diarrhea are rarely associated with an amebic liver abscess. In children with fever of unknown origin who live in, or travel to, endemic areas, amebic liver abscess should be considered in the differential diagnosis.
The most common complication of amebic liver abscess is pleuropulmonary amebiasis due to rupture of a right liver lobe abscess. Lung abscesses may occur from hematogenous spread. Cough, dyspnea, and pleuritic pain can be caused by the serous pleural effusions and atelectasis that frequently accompany amebic liver abscesses. Rupture of hepatic abscesses can lead to peritonitis and more rarely to pericarditis. Amebic brain abscess is an infrequent manifestation.
B. Diagnostic Findings
The differential diagnosis of acute amebic colitis includes bacterial (eg, Salmonella spp, Shigella spp, E coli spp, Campylobacter spp), parastitic (eg, Schistosoma mansoni, Balantidium coli), and noninfectious (eg, inflammatory bowel disease, diverticulitis, ischemic colitis) causes of dysentery. Chronic amebic colitis has to be distinguished from inflammatory bowel disease and Cyclospora. Occult blood is present in virtually all cases of amebic colitis and can be used as an inexpensive screening test. Fecal leukocytes are uncommon.
Intestinal amebiasis can be presumptively diagnosed by detecting the parasite on stool examination or mucosal biopsy. However, E histolytica is morphologically identical to nonpathogenic E dispar and E moshkovskii and cannot be easily differentiated by microscopy. The presence of trophozoites with ingested red blood cells in feces is more suggestive of pathogenic E histolytica infection. Ideally, a wet mount preparation of the stool should be examined within 20 minutes after collection to detect motile trophozoites. Otherwise, specimens should be fixed with polyvinyl alcohol or refrigerated to avoid disintegration of the trophozoites. The antigen detection test for stool is very sensitive and more specific, because it detects E histolytica–specific antigens that do not cross-react with E dispar. Colonoscopy and biopsy are most helpful in diagnosing amebic colitis when stool samples lack ova or parasites. Barium studies are contraindicated for patients with suspected acute amebic colitis because of the risk of perforation.
The presence of antibodies against E histolytica can differentiate E histolytica from E dispar infections. Specific antibody is induced by both intestinal and extraintestinal invasive amebiasis. ELISA assays are positive in approximately 95% of patients with extraintestinal amebiasis, 70% with intestinal E histolytica disease, and 10% of asymptomatic patients shedding E histolytica cysts. However, these antibodies persist for years, and a positive result does not distinguish between acute and past infection, but are useful in a traveler from a nonendemic area who is returning from a trip to an endemic area. Ultrasonographic examination and CT are sensitive techniques to detect hepatic abscesses and can be used to guide fine-needle aspiration to obtain specimens for definitive diagnosis. Because an amebic abscess may take up to 2 years to completely resolve on CT scans, imaging techniques are not recommended for therapeutic evaluation. PCR-based testing has the highest sensitivity and specificity for the diagnosis of E histolytica, but is only available in certain research and reference laboratories.
Prevention & Treatment
Travelers to endemic areas need to follow the precautions for preventing enteric infections—drink bottled or boiled water and eat cooked or peeled vegetables and fruits.
Treatment of amebic infection is complex because different agents are required for eradicating the parasite from the bowel or tissue (Table 43–5). Whether treatment of asymptomatic cyst passers is indicated is a controversial issue. The prevalent opinion is that asymptomatic infection with E histolytica, as evidenced by amebic cysts in the stool and a positive serologic test, should be treated in nonendemic areas. If serologic tests are negative, the cysts are more likely to represent infection with the nonpathogenic E dispar, which does not require treatment.
Table 43–5. Treatment of amebiasis.
Asymptomatic E histolytica cyst excreters may be treated with paromomycin, a nonabsorbable intraluminal amebicide. Diloxanide and iodoquinol are alternative intraluminal agents. Metronidazole is not effective against cysts.
Patients with symptomatic intestinal amebiasis or extraintestinal disease require treatment with an absorbable agent, such as metronidazole or tinidazole, followed by an intraluminal agent. Metronidazole has a disulfiram-like effect and should be avoided in patients receiving ethanol-containing medications. Tinidazole, a more potent nitroimidazole against amebic infection, can be used for shorter treatment courses and is well tolerated in children. Treatment of invasive amebiasis should always be followed with an intraluminal cysticidal agent, even if the stool examination is negative. Metronidazole and paromomycin should not be given concurrently, because the diarrhea that is a common side effect of paromomycin may make it difficult to assess response to therapy. In most patients with amebic liver abscess, aspiration is unnecessary and does not speed recovery. Patients with large, thin-walled hepatic abscesses may need therapeutic aspiration to avoid abscess rupture. Drainage may also be considered when response to medical therapy is inadequate.
Fotedar R et al: Laboratory diagnostic techniques for Entamoeba species. Clin Micro Rev 2007;20:511–532 [PMID: 17630338].
Haque R et al: Amebiasis. N Engl J Med 2003;348:1565–1573 [PMID: 12700377].
http://www.dpd.cdc.gov/dpdx/html/amebiasis.htm.
Stanley SL et al: Amoebiasis. Lancet 2003;361:1025–1034 [PMID: 12660071].
2. Giardiasis
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Chronic relapsing diarrhea, flatulence, bloating, anorexia, poor weight gain.
No fever or hematochezia.
Detection of trophozoites, cysts, or Giardia antigens in stool.
General Considerations
Giardiasis, caused by Giardia intestinalis (formerly Giardia lamblia), is the most common intestinal protozoal infection in children in the United States and in most of the world. The infection is classically associated with drinking contaminated water, either in rural areas or in areas with faulty purification systems. Even ostensibly clean urban water supplies can be contaminated intermittently, and infection has been acquired in swimming pools. Fecal-oral contamination allows person-to-person spread. Day care centers are a major source of infection, with an incidence of up to 50% reported in some centers. No symptoms occur in 25% of infected persons, facilitating spread to household contacts. Food-borne outbreaks also occur. Although infection is rare in neonates, giardiasis may occur at any age.
Clinical Findings
A. Symptoms and Signs
Giardia infection is followed by either asymptomatic cyst passage, acute self-limited diarrhea, or a chronic syndrome of diarrhea, malabsorption, and weight loss. Acute diarrhea occurs 1–2 weeks after infection and is characterized by abrupt onset of diarrhea with greasy, malodorous stools; malaise; flatulence; bloating; and nausea. Fever and vomiting are unusual. The disease has a protracted course (> 1 week) and frequently leads to weight loss. Giardiasis can be a self-limited infection in some patients, and in others cause chronic symptoms. Patients who develop chronic diarrhea complain of profound malaise, lassitude, headache, and diffuse abdominal pain in association with bouts of diarrhea—most typically foul-smelling, greasy stools—intercalated with periods of constipation or normal bowel habits. This syndrome can persist for months until specific therapy is administered or until it subsides spontaneously. Chronic diarrhea frequently leads to malabsorption, steatorrhea, vitamins A and B12 deficiencies, and disaccharidase depletion. Lactose intolerance, which develops in 20%–40% of patients can persist for several weeks after treatment, and needs to be differentiated from relapsing giardiasis or reinfection.
B. Laboratory Findings
Giardia antigen detection by means of ELISAs, nonenzymatic immunoassays, and direct fluorescence antibody tests are the standard diagnostic tests in the United States. They have a more rapid return of results, and are more sensitive and specific than stool ova and parasite examination. In resource-poor areas without access to antigen tests, the diagnosis of giardiasis can be made by finding the parasite in stool. For ova and parasite examination, a fresh stool provides the best results. Liquid stools have the highest yield of trophozoites, which are more readily found on wet mounts. With semiformed stools, the examiner should look for cysts in fresh or fixed specimens, preferably using a concentration technique. When these techniques are applied carefully, one examination has a sensitivity of 50%–70%; three examinations increase the sensitivity to 90%. With a careful stool ova and parasite examination or with the use of a new antigen test, direct sampling of duodenal aspirates or biopsy, which was utilized in the past, is now restricted to particularly difficult cases.
Prevention
The prevention of giardiasis requires proper treatment of water supplies and interruption of person-to-person transmission. Where water might be contaminated, travelers, campers, and hikers should use methods to make water safe for drinking. Boiling is the most reliable method; the necessary time of boiling (1 minute at sea level) will depend on the altitude. Chemical disinfection with iodine or chlorine and filtration are alternative methods of water treatment.
Interrupting fecal-oral transmission requires strict hand washing. However, outbreaks of diarrhea in day care centers might be particularly difficult to eradicate. Reinforcing hand washing and treating the disease in both symptomatic and asymptomatic carriers may be necessary.
Treatment
Metronidazole, tinidazole, and nitazoxanide are the drugs of choice for treatment of giardiasis. When given at 5 mg/kg (up to 250 mg) three times a day for 5–7 days, metronidazole has 80%–95% efficacy. The drug is well tolerated in children. Tinidazole has an efficacy approaching 90% when given as a single dose of 50 mg/kg (up to 2 g). Nitazoxanide is available in liquid formulation and requires only 3 days of treatment. Recommended doses are 100 mg (5 mL) every 12 hours for children 12–47 months of age, 200 mg (10 mL) every 12 hours for 4- to 11-year-olds, and 500 mg every 12 hours for children 12 years or older. Furazolidone is sometimes used in children because it is available in suspension. Administered at 1.5 mg/kg (up to 100 mg) four times daily for 7–10 days, it has only 80% efficacy. Furazolidone may cause gastrointestinal side effects, turn urine red, and cause mild hemolysis in patients with G6PD deficiency. For patients who do not respond to therapy, or are re-infected, a second course with the same drug or switching to another drug is equally effective. In cases of repeated treatment failure, albendazole (400 mg/d for 5–10 days), although not specifically recommended in the United States for the treatment of giardiasis, is an effective option.
Escobedo AA et al: Giardiasis: the ever-present threat of a neglected disease. Infect Disord Drug Targets 2010;10(5):329–348 [PMID: 20701575].
http://www.cdc.gov/parasites/giardia/.
Huang DB et al: An updated review on Cryptosporidium and Giardia. Gastroenterol Clin North Am 2006;35:291 [PMID: 16880067].
3. Cryptosporidiosis
Cryptosporidia are intracellular protozoa that gained importance because they cause severe and devastating diarrhea in patients with acquired immunodeficiency syndrome (AIDS) and in other immunodeficient persons. This ubiquitous parasite infects and reproduces in the epithelial cell lining of the digestive and respiratory tracts of humans and most other vertebrate animals. Humans acquire the infection from contaminated drinking water, recreation water sources (including swimming pools, fountains, and lake water), or from close contact with infected humans or animals. Cryptosporidia are the leading cause of recreational water-associated outbreaks in the United States. Petting zoos and day care centers have been other sources of Cryptosporidia outbreaks. Most human infections are caused by C parvum or C hominis, although other species have been reported to cause human disease.
Clinical Findings
A. Symptoms and Signs
Immunocompetent persons infected with Cryptosporidium spp usually develop self-limited diarrhea (2–26 days) with or without abdominal cramps. Diarrhea can be mild and intermittent or continuous, watery, and voluminous. Low-grade fever, nausea, vomiting, loss of appetite, and malaise may accompany the diarrhea. Children younger than age 2 years are more susceptible to infection than older children. Immunocompromised patients (either cellular or humoral deficiency) tend to develop a severe, prolonged, chronic diarrhea which can often result in severe malnutrition, and subsides only after the immunodeficiency is corrected. Other clinical manifestations associated with cryptosporidiosis in immunocompromised hosts include cholecystitis, pancreatitis, hepatitis, biliary tree involvement, and respiratory symptoms.
B. Laboratory Findings
Visualization of Cryptosporodia oocysts in the stool is diagnostic. Direct immunofluorescent antibody (DFA) of stool is the test of choice for visualizing oocysts. Oocysts can also be visualized with a modified Kinyoun acid-fast stain on concentrated stool. ELISA and point-of-care rapid tests are commercially available, but should be confirmed by microscopy.
Prevention & Treatment
Prevention of Cryptosporidium infection is limited by oocyst resistance to some of the standard water purification procedures and to common disinfectants. Enteric precautions are recommended for infected persons. Boiled or bottled drinking water may be considered for those at high risk for developing chronic infection (eg, inadequately treated patients with AIDS).
Immunocompetent patients and those with temporary immunodeficiencies respond to treatment with nitazoxanide, antidiarrheal agents, and hydration. Immunocompromised patients usually require more intense supportive care with parenteral nutrition in addition to hydration and nonspecific antidiarrheal agents. Octreotide acetate, a synthetic analogue of somatostatin that inhibits secretory diarrhea, has been associated with symptomatic improvement but not with parasitologic cure. Nitazoxanide for 3 days is the treatment of choice; recommended doses are 100 mg (5 mL) every 12 hours for children 12–47 months of age, 200 mg (10 mL) every 12 hours for 4- to 11-year-olds, and 500 mg every 12 hours for children 12 years or older. For patients with advanced AIDS, antiparasitic therapy alone has not proven efficacious. Institution of effective anti-retroviral therapy results in elimination of symptomatic cryptosporidiosis.
Cabada MM et al: Treatement of cryptosporidiosis: do we know what we think we know? Curr Opin Infect Dis 2010;23:494–499 [PMID: 20689422].
Davies AP et al: Cryptosporidiosis. BMJ 2009;399:963–967 [PMID: 19841008].
http://www.cdc.gov/parasites/crypto/.
Huang DB et al: An updated review on Cryptosporidium and Giardia. Gastroenterol Clin North Am 2006;35:291 [PMID: 16880067].
4. Cyclosporiasis
Cyclospora spp are ubiquitous coccidian parasites that infect both humans and a variety of animals worldwide. Cyclospora cayetanensis is the only species known to infect humans. Cyclosporiasis is seen in three main epidemiologic settings: sporadic cases in endemic areas (particularly Haiti, Guatemala, Peru, and Nepal), travelers to endemic areas, and in food- or water-borne outbreaks in nonendemic areas, particularly in relation to importation of fresh produce. The incubation period is approximately 7 days (range 2–14 days). Infection may be asymptomatic, cause mild to moderate self-limiting diarrhea, or cause protracted or severe diarrhea. In the immunocompetent host, diarrhea usually lasts 10–25 days but may be followed by a relapsing pattern that can last several months. Diarrhea (5–15 movements per day) is usually watery, sometimes explosive, and often accompanied by nausea, vomiting, abdominal cramping, and bloating. Profound fatigue, anorexia, and myalgias have been reported. The infection can be unusually severe in immunocompromised patients, especially those with HIV/AIDS. Although the illness is self-limited, it may last for several weeks. Diagnosis is based on finding oocysts 8–10 mm in diameter on examination of stool specimens stained with acid-fast stain. PCR of stool is available at the CDC and some reference laboratories. The treatment of choice is trimethoprim-sulfamethoxazole for 7 days.
Ortega YR et al: Update on Cyclospora cayetanensis, a food-borne and waterborne parasite. Clin Micro Rev 2011;23:218–234 [PMID: 20065331].
5. Free-Living Amoebas
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Acute meningoencephalitis: fever, headache, meningismus, acute mental deterioration.
Swimming in warm, freshwater in an endemic area.
Chronic granulomatous encephalitis: insidious onset of focal neurologic deficits.
Keratitis: pain, photophobia, conjunctivitis, blurred vision.
General Considerations
Infections with free-living amoebas are uncommon. Naegleria species, Acanthamoeba species, and Balamuthia amoebas have been associated with human disease, primarily infections of the central nervous system.
Acute meningoencephalitis, caused by Naegleria fowleri, occurs mostly in children and young adults. Patients present with abrupt fever, headache, nausea and vomiting, disturbances in smell and taste, meningismus, and decreased mental status a few days to 2 weeks after exposure. N fowleri is found in warm fresh water and moist soil. Infection is often associated with swimming in warm freshwater lakes and using contaminated tap water for sinus irrigation. CNS invasion occurs after nasal inoculation of N fowleri which travel along the olfactory nerves via the cribiform plate to the brain. The disease is rapidly progressive and nearly universally fatal within a week of symptom onset.
Chronic granulomatous encephalitis, caused by Acanthamoeba or Balamuthia, can occur in immunocompotent patients, but occurs more commonly in immunocompromised patients. There is no association with freshwater swimming. This disease has an insidious onset of focal neurologic deficits, and approximately 50% of patients present with headache. Skin, sinus, or lung infections with Acanthamoeba precede many of the CNS infections and may still be present at the onset of neurologic disease. The granulomatous encephalitis progresses to fatal outcome over a period of weeks to months (average 6 weeks).
Acanthamoeba keratitis is a corneal infection associated with minor trauma or use of soft contact lenses in otherwise healthy persons. Clinical findings of Acanthamoeba keratitis include radial keratoneuritis and stromal ring infiltrate. Amebic keratitis usually follows an indolent course and initially may resemble herpes simplex or bacterial keratitis; delay in diagnosis is associated with worse outcomes.
Clinical Findings & Differential Diagnosis
Amebic encephalitis should be included in the differential diagnosis of acute meningoencephalitis in children with a history of recent freshwater swimming. The CSF is usually hemorrhagic, with leukocyte counts that may be normal early in the disease but later range from 400 to 2600/mL with neutrophil predominance, low to normal glucose, and elevated protein. The etiologic diagnosis relies on finding trophozoites on a wet mount of the CSF. Immunofluorescent and PCR-based diagnostic assays are available through the CDC.
Granulomatous encephalitis is diagnosed by brain biopsy of CT-identified nonenhancing lucent areas. The CSF of these patients is usually nondiagnostic with a lymphocytic pleocytosis, mild to severe elevation of protein (> 1000 mg/dL), and normal or low glucose. Acanthamoeba and Balamuthia amoebas have only rarely been found in the CSF; however, they can be visualized in brain biopsies or grown from brain or other infected tissues. Immunofluorescent and PCR-based diagnostic assays are available through the CDC.
Acanthamoeba keratitis is diagnosed by finding the trophozoites in corneal scrapings or by isolating the parasite from corneal specimens or contact lens cultures.
Prevention
Because primary amebic meningitis occurs infrequently, active surveillance of lakes for N fowleri is not warranted. However, in the presence of a documented case, it is advisable to close the implicated lake to swimming. Sterile or boiled water should be used for sinus irrigation. Acanthamoeba keratitis can be prevented by heat disinfection of contact lenses, by storage of lenses in sterile solutions, and by not wearing lenses when swimming in freshwater or showering.
Treatment
Treatment of acute amebic meningoencephalitis caused by N fowleri should be attempted with high-dose intravenous amphotericin B with the possible addition of miconazole and rifampin. Azithromycin has in vitro and in vivo activity against Naeglaria and may be tried as an adjuvant. Successful treatment of Balamuthia encephalitis has been reported using a combination of flucytosine, pentamidine, fluconazole, sulfadiazine, and a macrolide. Acanthamoeba encephalitis should be treated with a combination of pentamidine, an azole compound, flucytosine, and sulfadiazine.
Acanthamoeba keratitis responds well to surgical debridement followed by 3–4 weeks of topical 1% miconazole; 0.1% propamidine isethionate; and polymyxin B sulfate, neomycin, and bacitracin (Neosporin).
http://www.cdc.gov/parasites/naegleria/.
http://www.cdc.gov/parasites/balamuthia/.
http://www.cdc.gov/parasites/acantamoeba/.
Visvesvara GS: Amebic meningoencephalitides: challenges in diagnosis and treatment. Curr Opin Infect Dis 2010;23(6):590–594 [PMID: 20802332].
Yoder JS et al. Primary Amebic Encephalitis Deaths Associated with Sinus Irrigation Using Contaminated Tap Water. Clin Infect Dis 2012;55(9):e79–e85 [PMID: 22919000].
TRICHOMONIASIS
Trichomonas vaginalis infection is discussed in Chapter 44.
METAZOAL INFECTIONS
NEMATODE INFECTIONS
1. Enterobiasis (Pinworms)
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Anal pruritus.
Worms in the stool or eggs on perianal skin.
General Considerations
This worldwide infection is caused by Enterobius vermicularis. The adult worms are about 5–10 mm long and live in the colon; females deposit eggs on the perianal area, primarily at night, which cause intense pruritus. Scratching contaminates the fingers and allows transmission back to the host (autoinfection) or to contacts through fecal-oral spread.
Clinical Findings
A. Symptoms and Signs
Although blamed for many types of symptoms, pinworms have only definitely been associated with localized pruritus. Adult worms may migrate within the colon or up the urethra or vagina in girls. They can be found within the bowel wall, in the lumen of the appendix (usually an incidental finding by the pathologist), in the bladder, and even in the peritoneal cavity of girls. The granulomatous reaction that may be present around these ectopic worms is usually asymptomatic. Worm eradication may correspond with the cure of recurrent urinary tract infections in some young girls.
B. Laboratory Findings
The usual diagnostic test consists of pressing a piece of transparent tape on the child’s anus in the morning prior to bathing, then placing it on a drop of xylene on a slide. Microscopic examination under low power usually demonstrates the ova. Occasionally, eggs or adult worms are seen in fecal specimens. Parents may also visualize adult worms in the perianal region, often at nighttime while the child is asleep.
Differential Diagnosis
Nonspecific irritation or vaginitis, streptococcal perianal cellulitis (usually painful with marked erythema), and vaginal or urinary bacterial infections may at times resemble pin-worm infection, although the symptoms of pinworms are often so suggestive that a therapeutic trial is justified without a confirmed diagnosis.
Treatment
A. Specific Measures
Treat all household members at the same time to prevent reinfections. Because the drugs are not active against the eggs, therapy should be repeated after 2 weeks to kill the recently hatched adults.
Pyrantel pamoate, available without a prescription, is given as a single dose (11 mg/kg; maximum 1 g); it is safe and very effective. Albendazole (400 mg or 200 mg in children 1–2 years of age) or mebendazole (100 mg) in a single dose is also highly effective for all ages (though not approved by the US FDA).
B. General Measures
Personal hygiene must be emphasized. Nails should be kept short and clean. Children should wear undergarments in bed to diminish contamination of fingers; bedclothes should be laundered frequently; infected persons should bathe in the morning, thereby removing a large proportion of eggs. Although eggs may be widely dispersed in the house and multiple family members infected, the disease is mild and treatable.
Brown MD: Enterobius vermicularis. N Engl J Med 2006;354:e12 [PMID: 16571876].
http://www.cdc.gov/parasites/pinworm/.
2. Ascariasis
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Abdominal cramps and discomfort.
Large, white or reddish, round worms, or ova in the feces.
General Considerations
Together with the whipworm and hookworms (see below), Ascaris comprises the group of “soil-transmitted helminths.” These parasites cause human infection through contact with eggs or larvae that thrive in the moist soil of the tropics and subtropics. Worldwide, more than a billion people are infected with at least one of these parasites, and, especially in less developed countries, it is not uncommon for children to be chronically infected with all three worms. These parasites are strongly associated with acute poverty and lack of clean water and sanitation. Children infected with these worms are at increased risk for malnutrition, stunted growth, intellectual retardation, and cognitive and education deficits. Together, the soil-transmitted helminths are one of the world’s most important causes of physical and intellectual growth retardation.
Ascaris lumbricoides is a worldwide human parasite. Ova passed by carriers may remain viable for months under the proper soil conditions. The ova contaminate food or fingers and are subsequently ingested by a new host. The larvae hatch, penetrate the intestinal wall, enter the venous system, reach the alveoli, are coughed up, and return to the small intestine, where they mature. The female lays thousands of eggs daily.
Clinical Findings
A. Symptoms and Signs
The majority of infections with A lumbricoides are asymptomatic, although moderate to heavy infections are associated with abdominal pain, weight loss, anorexia, diarrhea, and vomiting, and may lead to malnutrition. During the larval migratory phase, an acute transient eosinophilic pneumonitis (Löffler syndrome) may occur. Acute intestinal obstruction has been associated with heavy infections, which is more common in children due to their smaller intestinal diameter and their higher worm burden. Rarely, worm migration can cause peritonitis or appendicitis, secondary to intestinal wall perforation, and common bile duct obstruction, resulting in biliary colic, cholangitis, or pancreatitis.
B. Laboratory Findings
The diagnosis is made by observing the large roundworms (1.5–4 cm) in the stool or by microscopic detection of the ova.
Treatment
Because the adult worms live less than a year, asymptomatic infection need not be treated. Mebendazole (100 mg twice a day for 3 days or 500 mg once), pyrantel pamoate (a single dose of 11 mg/kg; maximum 1 g), and albendazole (400 mg in a single dose, or 200 mg in children 1–2 years of age) are highly and equally effective. In cases of intestinal or biliary obstruction, piperazine (150 mg/kg initially, followed by six doses of 65 mg/kg every 12 hours by nasogastric tube) is recommended because it paralyzes the worms and helps relieve obstruction. However, surgical removal is occasionally required.
Bethony J et al: Soil-transmitted helminth infections: ascariasis, trichuriasis, and hookworm. Lancet 2006;367:1521 [PMID: 16679166].
http://www.who.int/intestinal_worms/.
http://www.cdc.gov/parasites/sth/.
Keiser J et al: Efficacy of current drugs against soil-transmitted helminth infections. JAMA 2008;299:1937–1948 [PMID: 18430913].
3. Trichuriasis (Whipworm)
Trichuris trichiura is a widespread human and animal parasite common in children living in warm, humid areas conducive to survival of the ova. Ingested infective eggs hatch in the upper small intestine. The adult worms live in the cecum and colon; the ova are passed and become infectious after several weeks in the soil. Unlike Ascaris, Trichuris does not have a migratory tissue phase. Symptoms are not present unless the infection is severe, in which case pain, diarrhea, iron deficient anemia, and mild abdominal distention are present. Massive infections may also cause rectal prolapse and dysentery. Detection of the characteristic barrel-shaped ova in the feces confirms the diagnosis. Adult worms may be seen in the prolapsed rectum or at proctoscopy; their thin heads are buried in the mucosa, and the thicker posterior portions protrude. Mild to moderate eosinophilia may be present.
Treatment of trichuriasis with currently available anthelminthic agents is unsatisfactory. Nevertheless, mebendazole (100 mg orally twice a day for 3 days) or albendazole (400 mg in a single dose for 3 days, or 200 mg in children 1–2 years of age) tends to improve gastrointestinal symptoms.
Bethony J et al: Soil-transmitted helminth infections: Ascariasis, trichuriasis, and hookworm. Lancet 2006;367:1521 [PMID: 16679166].
http://www.who.int/intestinal_worms/.
http://www.cdc.gov/parasites/sth/.
Keiser J et al. Efficacy of current drugs against soil-transmitted helminth infections. JAMA 2008;299:1937–1948 [PMID: 18430913].
4. Hookworm
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Iron-deficiency anemia.
Abdominal discomfort, weight loss.
Ova in the feces.
General Considerations
The common human hookworms are Ancylostoma duodenale and Necator americanus. Both are widespread in the tropics and subtropics, with an estimated 600–700 million people infected worldwide. The larger A duodenale is more pathogenic because it consumes more blood, up to 0.5 mL per worm per day.
The adults live in the jejunum. Eggs are passed in the feces and develop and hatch into infective larvae in warm, damp soil within 2 weeks. The larvae penetrate human skin on contact, enter the blood, reach the alveoli, are coughed up and swallowed, and develop into adults in the intestine. The adult worms attach with their mouth parts to the mucosa, from which they suck blood. Blood loss is the major sequela of infection. Infection rates reach 90% in areas without sanitation.
Ancylostoma braziliense and Ancylostoma caninum (the dog and cat hookworm) cause creeping eruption (cutaneous larva migrans). Larvae produce pruritic, reddish papules at the site of skin entry and an intensely pruritic, serpiginous tracks or bullae are formed as they migrate through the skin. Larval can move up to a few centimeters a day and activity can continue for several weeks, but eventually the rash is self-limiting. An advancing, intensely pruritic, serpiginous tunnel in the skin is pathognomonic. Cutaneous larva migrans is a disease of children and others who come in contact with soil contaminated with cat and dog feces. In the United States, the disease is most prevalent in the Southeast. Most cases in the United States are imported by travelers returning from tropical and subtropical areas.
Clinical Findings
A. Symptoms and Signs
Patients with hookworm infection usually are asymptomatic or have complaints of diarrhea. Chronic hookworm infection leads to blood loss and iron deficiency anemia. Heavy infection can cause hypoproteinemia with edema. Chronic hookworm infection in children may lead to growth delay, deficits in cognition, and developmental delay. The larvae usually penetrate the skin of the feet and cause a stinging or burning sensation, followed by an intense local itching (ground itch) and a papulovesicular rash that may persist for 1–2 weeks. Pneumonitis associated with migrating larvae is uncommon and usually mild, except during heavy infections. Colicky abdominal pain, nausea, and/or diarrhea and marked eosinophilia may be observed.
B. Laboratory Findings
The large ova of both species of hookworm are found in feces and are indistinguishable. Microcytic anemia, hypoalbuminemia, eosinophilia, and hematochezia occur in severe cases.
Prevention
Fecal contamination of soil and skin contact with potentially contaminated soil should be avoided.
Treatment
A. Specific Measures
Albendazole (400 mg orally in a single dose, or 200 mg in children 1–2 years of age) is significantly more efficacious than mebendazole or pyrantel pamoate, and is considered the drug of choice for treatment of hookworm infections. Mebendazole (100 mg orally twice a day for 3 days) and pyrantel pamoate (11 mg/kg, to a maximum of 1 g, daily for 3 days) are second-line options.
B. General Measures
Iron therapy may be as important as worm eradication.
Prognosis
The outcome after therapy is excellent, but reinfection is common in endemic areas.
Bethony J et al: Soil-transmitted helminth infections: ascariasis, trichuriasis, and hookworm. Lancet 2006;367:1521 [PMID: 16679166].
Brooker S et al: Human hookworm infection in the 21st century. Adv Parasitol 2004;58:197–288 [PMID: 15603764]
http://www.who.int/intestinal_worms/.
http://www.cdc.gov/parasites/sth/.
Keiser J et al. Efficacy of current drugs against soil-transmitted helminth infections. JAMA 2008;299:1937–1948 [PMID: 18430913].
5. Strongyloidiasis
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Abdominal pain, diarrhea.
Eosinophilia.
Larvae in stools and duodenal aspirates.
Serum antibodies.
General Considerations
Strongyloides stercoralis is unique in having both parasitic and free-living forms; the latter can survive in the soil for several generations. The parasite is found in most tropical and subtropical regions of the world. The adults live in the submucosal tissue of the duodenum and occasionally elsewhere in the intestines. Eggs deposited in the mucosa hatch rapidly; the first-stage (rhabditiform) larvae, therefore, are the predominant form found in duodenal aspirates and feces. The larvae mature rapidly to the tissue-penetrating filariform stage and initiate internal autoinfection. The filariform larvae also persist in soil and can penetrate the skin of another host, subsequently migrating into veins and pulmonary alveoli, reaching the intestine when coughed up and swallowed.
Older children and adults are infected more often than are young children. Even low worm burden can result in significant clinical symptoms. Immunosuppressed patients may develop fatal disseminated strongyloidiasis, known as the hyperinfection syndrome. Autoinfection can result in persistent infection for decades.
Clinical Findings
A. Symptoms and Signs
Chronic S stercorali infections can be asymptomatic or cause cutaneous, gastrointestinal, and/or pulmonary symptoms. At the site of skin penetration, a pruritic rash may occur. Large numbers of migrating larvae can cause wheezing, cough, shortness of breath, and hemoptysis. Although one-third of intestinal infections are asymptomatic, the most prominent features of strongyloidiasis include abdominal pain, distention, diarrhea, vomiting, and occasionally malabsorption.
Patients with cellular immunodeficiencies and those on corticosteroids or chemotherapy may develop disseminated infection, involving the intestine, the lungs, and the meninges. Gram-negative sepsis may complicate disseminated strongyloidiasis.
B. Laboratory Findings
There is no gold standard for diagnosis, which can be difficult because of low parasite load and irregular larval output. Finding larvae in the feces, duodenal aspirates, or sputum is diagnostic. IgG antibodies measured by ELISA or immunoblot are relatively sensitive (83%–93%). The presence of specific antibody, however, does not distinguish between past and present infection and Strongyloides antibody assays can cross-react with other helminth infections. Marked eosinophilia is common. Because the rate of detection of Strongyloides larvae in a single fecal sample is low (~25%), all patients who have visited an endemic area and present with GI symptoms should be evaluated with three serial stool samples (for ova and parasites), and serology (ELISA) for S stercoralis should be performed. Patients with pulmonary symptoms with suspected strongyloides infection should have sputum samples evaluated for the detection of S stercoralis.
Differential Diagnosis
Strongyloidiasis should be differentiated from peptic disease, celiac disease, regional or tuberculous enteritis, and hookworm infections. The pulmonary phase may mimic asthma or bronchopneumonia. Patients with severe infection can present with an acute abdomen.
Prevention & Treatment
Ivermectin (two doses of 0.2 mg/kg given 1–14 days apart) is the drug of choice. Tiabendazole at a dose of 25 mg/kg orally twice orally twice a day for three days is an alternative therapy. Albendazole has a much lower efficacy. Relapses are common. In the hyperinfection syndrome, 1–3 weeks of therapy with ivermectin may be necessary and multiple follow-up stool studies for 2 weeks after therapy are indicated to ensure clearance of larvae. Patients from endemic areas should be tested for specific antibodies and receive treatment before undergoing immunosuppression.
http://www.cdc.gov/parasites/strongyloides/.
Montes M et al: Strongyloides stercoralis: there but not seen. Curr Opin Infect Dis 2010;23:500–504 [PMID: 20733481].
Olsen, A et al: Stronyloidiasis—the most neglected of the tropical diseases? Trns R Soc Trop Med Hyg 2009;103:967–972 [PMID: 19328508].
6. Visceral Larva Migrans (Toxocariasis)
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Visceral involvement, including hepatomegaly, marked eosinophilia, and anemia.
Posterior or peripheral ocular inflammatory mass.
Elevated antibody titers in serum or aqueous fluid; demonstration of Toxocara larvae in biopsy specimen.
General Considerations
Visceral larva migrans is a worldwide disease. The agent is the cosmopolitan intestinal ascarid of dogs and cats, Toxocara canis or Toxocara cati. The eggs passed by infected animals contaminate parks and other areas that young children frequent. Children with pica are at increased risk. In the United States, seropositivity ranges from 2.8% in unselected populations to 23% in southern states to 54% in rural areas. Ingested eggs hatch and penetrate the intestinal wall, then migrate to the liver. Most of the larvae are retained in the liver, but some may pass through the organ reaching the lungs, eyes, muscles, and/or the CNS, where they die and incite a granulomatous inflammatory reaction.
Clinical Findings
A. Visceral Larva Migrans
Toxocariasis is usually asymptomatic, but young children (aged 1–5 years) sometimes present with anorexia, fever, fatigue, pallor, abdominal pain and distention, nausea, vomiting, and cough. Hepatomegaly is common, splenomegaly is unusual, and adenopathy is absent. Lung involvement, usually asymptomatic, can be demonstrated readily by radiologic examination. Seizures are common, but more severe neurologic abnormalities are infrequent. Eosinophilia with leukocytosis, anemia, and elevated liver function tests are typical. ELISA is sensitive, specific, and useful in confirming the clinical diagnosis. Most patients recover spontaneously, but disease may last up to 6 months.
B. Ocular Larva Migrans
This condition occurs in older children and adults who present with a unilateral posterior or peripheral inflammatory eye mass. History of visceral larva migrans and eosinophilia are typically absent. Anti-Toxocara antibody titers are low in the serum and high in vitreous and aqueous fluids.
C. Diagnostic Findings
Hypergammaglobulinemia and elevated isohemagglutinins sometimes result from cross-reactivity between Toxocara antigens and human group A and B blood antigens. The diagnosis is confirmed by finding larvae in granulomatous lesions. High ELISA serology and the exclusion of other causes of hypereosinophilia provide a presumptive diagnosis in typical cases.
Differential Diagnosis
Diseases associated with hypereosinophilia must be considered. These include trichinosis (enlarged liver not common; muscle tenderness common), eosinophilic leukemia (rare in children; eosinophils are abnormal in appearance), collagen-vascular disease (those associated with eosinophilia are rare in young children), strongyloidiasis (no organomegaly; enteric symptoms are common), early ascariasis, tropical eosinophilia (occurring mainly in India), allergies, and hypersensitivity syndromes.
Prevention & Treatment
A. Specific Measures
The clinical benefit of specific anthelmintic therapy is not defined. Treatment with albendazole (400 mg twice a day for 5 days) or mebendazole (100–200 mg twice a day for 5 days) is indicated for severe complications involving the brain, lung, or heart.
B. General Measures
Treating any cause of pica, such as iron deficiency, is important. Corticosteroids are used to treat marked inflammation of lungs, eyes, or other organs. Pets should be dewormed routinely. Other children in the household may be infected. Mild eosinophilia and positive serologic tests may be the only clue to their infection. Therapy is not necessary for these individuals.
Hotez PJ, Wilkins PP: Toxocariasis: America’s most common neglected infection of poverty and a helminthiasis of global importance? PLoS Negl Trop Dis 2009;3(3):e400 [PMID: 19333373].
Rubingsy-Elefant G et al: Human toxocariasis: diagnosis, worldwide seroprevalences and clinical expression of the systemic and ocular forms. Ann Trop Med Parasitol 2010;104:3–23 [PMID: 20149289].
7. Trichinosis
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Vomiting, diarrhea, and abdominal pain within 1 week of eating infected meat.
Fever, periorbital edema, myalgia, and marked eosinophilia.
General Considerations
Trichinella are small roundworms that infest hogs and several other meat-eating animals. Currently, there are eight recognized Trichinella species, with Trichinella spiralis being the most commonly recognized and most adapted to domestic and wild swine. The most important source of human infection worldwide is the domestic pig, but in Europe meat from wild boars and horses caused several prominent outbreaks. The human cycle begins with ingestion of viable larvae in undercooked meat. In the intestine, the larvae develop into adult worms that mate and produce hundreds of larvae. The larvae enter the bloodstream and migrate to the striated muscle where they continue to grow and eventually encyst. Symptoms are caused by the inflammatory response in the intestines or muscle.
Clinical Findings
A. Symptoms and Signs
Most infections are asymptomatic. The severity of clinical disease is strongly correlated with the number of ingested larvae. Infection can be divided into two phases: an intestinal phase and a muscular (or systemic) phase. The initial bowel penetration may cause fever, headache, chills, and gastrointestinal complaints within 1 week after ingestion of contaminated meat. This may progress to the classic myopathic form, which consists of fever, eyelid or facial edema, myalgia, and weakness. Complications, including myocarditis, thromboembolic disease, and encephalitis, occasionally occur. The leading pathologic process of trichinellosis is vasculitis, which can be manifest as a maculopapular exanthem, subungual bleeding, conjunctivitis and subconjunctival hemorrhages, headaches, dry cough, and painful movement of the eye muscles. Severe cerebral involvement or myocarditis can be fatal. Symptoms usually peak after 2–3 weeks but may last for months. Children typically have milder clinical and laboratory findings than adults.
B. Diagnosis
The diagnosis of trichinosis should be based on three main criteria: (1) clinical findings (fever; myalgias; eyelid and/or facial edema; gastrointestinal symptoms; and subconjunctival, subungual, and retinal hemorrhages); (2) laboratory findings (nonspecific eosinophilia and increased levels of muscle enzymes, antibody detection, and/or detection of larvae in a muscle biopsy); and (3) epidemiologic investigation.
Differential Diagnosis
The classic symptoms are pathognomonic if one is aware of this disease. It has to be distinguished from gastrointestinal pathogens, serum sickness, dermatomyositis, typhoid fever, sinusitis (facial swelling is unilateral), influenza with myopathy, toxocariasis, and invasive schistosomiasis.
Prevention
Because a microscopic examination must be performed, meat in the United States is not inspected for trichinosis. Although all states require the cooking of hog swill, hog-to-hog or hog-to-rat cycles may continue. All pork and sylvatic meat (eg, bear or walrus) should be cooked at least >160°F. Freezing meat to at least 5°F for 3 weeks may also prevent transmission. Animals used for food should not be fed or allowed access to raw meat.
Treatment
Albendazole (400 mg twice daily for 8–14 days) is the drug of choice for treatment of trichinosis. Mebendazole is an acceptable alternative and can be given at a dose of 200–400 mg three times a day for 3 days followed by 400–500 mg three times a day for 10 days. Concurrent corticosteroids (prednisone 30–60 mg/d for 10–15 days) are used for treatment of severe symptoms. Administration of analgesics is sometimes required.
Prognosis
Prognosis for severe cases with cardiac and cerebral complications is poor, with a mortality rate around 5%. In milder cases, prognosis is good, and most patients’ symptoms disappear within 2–6 months.
Gottstein B et al: Epidemiology, diagnosis, treatment, and control of trichinellosis. Clin Micro Rev 2009;22:127–145 [PMID: 19136437].
http://www.cdc.gov/parasites/trichinellosis/.
Ozdemir D et al: Acute trichinellosis in children compared with adults. Pediatr Infect Dis J 2005:24:897 [PMID: 16220088].
8. Raccoon Roundworm Infections
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Eosinophilic meningoencephalitis or encephalopathy.
Ocular larva migrans.
Contact with raccoons or raccoon feces.
General Considerations
Human infections with Baylisascaris procyonis, the raccoon roundworm, are increasingly recognized, particularly in children. The definitive host of this ascarid is the raccoon. Humans who ingest the eggs excreted in raccoon feces become intermediate hosts when the larvae penetrate the gut and disseminate via the bloodstream to the brain, eyes, viscera, and muscles. Young age, pica, and exposure to raccoon feces represent the main risk factors for this infection. Most of the infections are asymptomatic, but cases of severe encephalitis (neural larva migrans) and endophthalmitis (ocular larva migrans) occur. Symptoms typically begin 2–4 weeks after inoculation. CNS infections characteristically present as acute, rapidly progressive encephalitis with eosinophilic pleocytosis of the CSF (varies from 4% to 68% eosinophils in mild pleocytosis). Both CNS and ocular infections resemble other larva migrans infections such as toxocariasis; therefore B procyonis should be considered in the differential diagnosis of these infections when Toxocara serology is negative. The diagnosis of B procyonis is established by observing the larvae on examination of tissue biopsies or by serology (of serum or CSF), and should be considered in the differential diagnosis in anyone with CSF eosinophilia. Antihelmintic drugs have not been shown to have any beneficial effect for the treatment of baylisascariasis, since they lack larvicidal effects in human tissues. Nevertheless, albendazole (20–40 mg/kg/d for 1–4 weeks) has been used to treat most cases, together with anti-inflammatory drugs. Complete resolution of symptoms has not been achieved thus far. Immediate prophylactic treatment with albendazole (25 mg/kg daily for 20 days) should be considered for those with known ingestion of raccoon feces.
Gavin PJ et al: Baylisascariasis. Clin Microbiol Rev 2005;18:703 [PMID: 16223954].
http://www.cdc.gov/parasites/baylisascaris/.
Murray WJ, Kazacos KR: Raccoon roundworm encephalitis. Clin Infect Dis 2004;39:1484–1492 [PMID: 15546085]
CESTODE INFECTIONS (FLUKES)
1. Taeniasis & Cysticercosis
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Mild abdominal pain; passage of worm segments (taeniasis).
Focal seizures, headaches (neurocysticercosis).
Cysticerci present in biopsy specimens, on plain films (as calcified masses), or on CT scan or magnetic resonance imaging (MRI).
Proglottids and eggs in feces; specific antibodies in serum or CSF.
General Considerations
Pigs are the usual intermediate host of the tapeworm Taenia solium. Human cysticercosis occurs when the eggs, which are excreted in the feces of a person infected with the parasite, are ingested. Importantly, cysticercosis cannot be acquired by eating pork. Ingestion of infected pork results in adult tapeworm infection (taeniasis) because infected pork contains the larval cysts that develop into the adult tapeworm but does not contain the eggs which cause cysticercosis.
Larvae released from ingested eggs enter the circulation to encyst in a variety of tissues, especially muscle and brain. Full larval maturation occurs in 2 months, but the cysts cause little inflammation until the larvae die months to years later. Inflammatory edema ensues with calcification or disappearance of the cyst. A slowly expanding mass of sterile cysts at the base of the brain may cause obstructive hydrocephalus (racemose cysticercosis).
T solium and the beef tapeworm (Taenia saginata), which can causes taeniasis but not cysticercosis, are distributed worldwide. Contamination of foods by eggs in human feces allows person-to-person spread without exposure to meat or travel to endemic areas. Asymptomatic cases are common, but T solium is the most common helminth infection of the CNS and a leading cause of acquired epilepsy in the world.
Clinical Findings
A. Symptoms and Signs
1. Taeniasis—In most tapeworm infections, the only clinical manifestation is the passage of fecal proglottids, which are white, motile segments of tapeworm 1–2 cm in size. They occasionally crawl out onto the skin and down the leg, especially the larger T saginata. Children may harbor the adult worm for years and complain of abdominal pain, anorexia, and diarrhea.
2. Cysticercosis—In the parenchymatous form, the parasite lodges in the brain as a single or multiple cysts. Pericystic inflammation results in granuloma formation, which is the cause of seizures in most patients. The initial stage of the cyst is viable, where the scolex exists within the cyst and there is minimal or no enhancement due to a limited host immune response. As the scolex dies, either due to the host immune response or cysticidal treatment there is a strong immune response, characterized by strong enhancement on CT or MRI. As the cyst further degenerates, it calcifies, which is recognized as punctuate calcification on CT scan. Brain cysts may remain silent or cause seizures, headache, hydrocephalus, and basilar meningitis. Rarely, the spinal cord is involved. Neurocysticercosis manifests an average of 5 years after exposure, but may cause symptoms in the first year of life. In the eyes, cysts cause bleeding, retinal detachment, and uveitis. Definitive diagnosis requires histologic demonstration of larvae or cyst membrane. Presumptive diagnosis is often made by the characteristics of the cysts seen on CT scan or MRI. The presence of T solium eggs in feces, which is uncommon with cysticercosis (see above), supports the diagnosis.
B. Laboratory Findings
Neuroimaging is the mainstay of diagnosis of neurocysticercosis. The diagnosis should be suspected in any patient who has lived in an endemic area and presents with a compatible clinical picture and suggestive lesions on CT scans.
Eggs or proglottids may be found in feces or on the perianal skin (using the tape method employed for pinworms). Eggs of both Taenia species are identical. The species are identified by examination of proglottids.
Peripheral eosinophilia is minimal or absent. CSF eosinophilia is seen in 10%–75% of cases of neurocysticercosis; its presence supports an otherwise presumptive diagnosis.
ELISA antibody titers are eventually positive in up to 98% of serum specimens and over 75% of CSF specimens from patients with neurocysticercosis. Solitary cysts are associated with seropositivity less often than are multiple cysts. High titers tend to correlate with more severe disease. CSF titers are higher if cysts are near the meninges.
The differential diagnosis of neurocysticercosis includes tuberculous granuloma, microabscesses, focal meningoencephalitis, arachnoid cyst, neoplasms, and vascular lesions.
Treatment
A. Taeniasis
Praziquantel (5–10 mg/kg once) and albendazole are equally effective. Feces free of segments or ova for 3 months suggest cure.
B. Cysticercosis
The treatment modalities for neurocysticercosis include cysticidal agents (to kill larvae), corticosteroids (to decrease or prevent the inflammatory reaction), antiepileptic drugs (if seizures are present), and surgery (to remove cysts or for placement of a shunt for hydrocephalus). Most experts would recommend treatment with a cysticidal agent in most cases of neurocysticercosis, except in patients with inactive, calcified lesions. In patients with viable parenchymal cysts, cysticidal therapy decreases the burden of parasites and the number of seizures. Similarly, cysticidal therapy is associated with more complete and faster resolution on imaging and fewer seizures in patients with a single, small enhancing lesion. Ophthalmic examination should be conducted prior to cysticidal therapy to rule out intraocular cysts.
Albendazole, 15 mg/kg/d (maximum, 800 mg) divided in two doses daily for 8–15 days, is the treatment of choice. Larval death may result in clinical worsening because of inflammatory edema. A concurrent course of dexamethasone (0.1mg/kg/day to a max of 6 mg/day) is recommended to decrease these symptoms. Corticosteroids are mandatory treatment for large intraventricular cysts and encephalitis (dexamethasone 0.1 mg/kg/day or prednisolone 1 mg/kg/day for as long as needed). Giant subarachnoidal cysts may require more than one cycle of therapy or surgery (or both). Minimally invasive neurosurgery (neuroendoscopic extraction) is the currently recommended management of intraventricular cysts. Follow-up scans every several months help assess the response to therapy.
Prevention
Prevention requires proper cooking of meat, careful washing of raw vegetables and fruits, treating intestinal carriers, avoiding the use of human excrement for fertilizer, and providing proper sanitary facilities.
Prognosis
The prognosis is good in intestinal taeniasis. Symptoms associated with a few cerebral cysts may disappear in a few months; heavy brain infections may cause death or chronic neurologic impairment. Seizures may persist even in those patients with only calcified lesions and anticonvulsants may be needed indefinitely.
Garcia HH et al: Cysticercosis of the central nervous system: how should it be managed? Curr Opin Infect Dis 2011;24:423–427 [PMID: 21788891].
http://www.cdc.gov/parasites/cysticercosis/.
Sinha S, Sharma BS: Neurocysticercosis: a review of current status and management. J Clin Neurosci 2009;16:867–876 [PMID: 19394828].
2. Hymenolepiasis
Hymenolepis nana, the cosmopolitan human tapeworm, is a common parasite of children; Hymenolepis diminuta, the rat tapeworm, is rare. The former is capable of causing autoinfection. Larvae hatched from ingested eggs penetrate the intestinal wall and then reenter the lumen to mature into adults. Their eggs are immediately infectious for the same or a new host. The adult is only a few centimeters long. Finding the characteristic eggs in feces is diagnostic.
H diminuta has an intermediate stage in rat fleas and other insects; children are infected when they ingest these insects.
Light infections with either tapeworm are usually asymptomatic; heavy infection can cause diarrhea and abdominal pain. Therapy is with praziquantel (25 mg/kg once).
http://www.cdc.gov/parasites/hymenolepis/.
3. Echinococcosis
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Cystic tumors of liver, lungs, kidneys, bones, brain, and other organs.
Eosinophilia.
Urticaria and pruritus if cysts rupture.
Protoscoleces or daughter cysts in the primary cyst.
Positive serology.
Epidemiologic evidence of exposure.
General Considerations
Dogs, cats, and other carnivores are the hosts for Echinococcus granulosus. Cystic and alveolar echinococcosis (hydatid disease) cause significant morbidity and mortality worldwide. Endemic areas include Australia, New Zealand, and the southwestern United States, including Native American reservations where shepherding is practiced. The adult tapeworm lives in sheep intestines, and eggs are passed in the feces. When ingested by humans, the eggs hatch, and the larvae penetrate the intestinal mucosa and disseminate via the bloodstream to produce cysts; the primary sites of involvement are the liver (60%–70%) and the lungs (20%–25%). A unilocular cyst is most common. Over time, the cyst may reach 25 cm in diameter, although most are much smaller. The cysts of Echinococcus multilocularis are multilocular and demonstrate more rapid growth.
Clinical Findings
A. Symptoms and Signs
The clinical manifestations of echinococcosis are variable and depend primarily on the site, size, and condition of the cysts. The rates of growth of cysts are variable, and range between 1 and 5 cm in diameter per year. A slowly growing cyst often goes unnoticed until it causes dysfunction due to its size. Liver cysts can cause hepatomegaly, right upper quadrant pain, nausea, and vomiting. If a cyst ruptures, the sudden release of its contents can result in a severe allergic reaction. Cysts may cause biliary obstruction. Most hepatic cysts are in the right lobe.
Rupture of a pulmonary cyst causes coughing, dyspnea, wheezing, urticaria, chest pain, and hemoptysis; cyst and worm remnants are found in sputum. Brain cysts may cause focal neurologic signs and convulsions; renal cysts cause pain and hematuria; bone cysts cause pain.
B. Laboratory Findings
Antibody assays are useful to confirm a presumptive diagnosis, but some patients with echinococcosis do not have a detectable immune response (related to the integrity of the cyst and sequestration of echinococcal antigens inside the cyst). ELISA is the method most widely used for antibody testing.
Confirmation may be obtained by ultrasonography-guided fine-needle aspiration coupled with parasitologic examination for protoscoleces, rostellar hooks, antigens, or DNA. Eosinophilia is present in only about 25% of patients. Serologic tests are useful for diagnosis and follow-up of therapy.
C. Imaging
The presence of a cyst-like mass in a person with appropriate epidemiologic exposure supports the diagnosis. Visualization of daughter cysts is highly suggestive of echinococcosis. CT, MRI, and ultrasonography are useful for the diagnosis of deep-seated lesions. Abdominal ultrasonography is the most widely used diagnostic tool. Pulmonary or bone cysts may be visible on plain films.
Differential Diagnosis
Tumors, bacterial or amebic abscess, cavitary tuberculosis (pulmonary), mycoses, and benign cysts must be considered.
Complications
Sudden cyst rupture with anaphylaxis and death is the worst complication. If the patient survives, secondary infections from seeding of daughter cysts may occur. Segmental lung collapse, secondary bacterial infections, effects of increased intracranial pressure, and severe renal damage due to renal cysts are other potential complications.
Treatment
There is no “best” treatment option for cystic echinococcus and no clinical trial has compared all the different treatment modalities. Treatment indications are complex and based on cyst characteristics, available medical/surgical expertise and equipment, and adherence of patients to long-term monitoring. Because treatment involves a variety of options and expertise, patients should be referred to recognized reference and national/regional treatment centers, whenever available. Definitive therapy of E multilocularis requires meticulous surgical removal of the cysts. A surgeon familiar with this disease should be consulted. Albendazole chemotherapy should be initiated for several days prior to surgery. Chemotherapy alone has been shown to cure about one-third of patients. Albendazole (15 mg/kg/d divided in 2 doses for 3 months, max 400 mg twice daily), sometimes with the addition of praziquantel, is the regimen of choice. A third treatment option is a four-step procedure (PAIR; puncture, aspiration, injection, and reaspiration). This procedure consists of (1) percutaneous puncture using ultrasound guidance, (2) aspiration of liquid contents, (3) injection of a protoscolicidal agents (95% ethanol or hypertonic saline for at least 15 minutes), and (4) reaspiration. PAIR is indicated for uncomplicated cases. If the cyst leaks or ruptures, the allergic symptoms must be managed immediately. For alveolar echinococcus, radical surgery for complete resection of the cyst is the goal. In some patients (particularly in those in whom complete resection is not possible), lifetime chemotherapy may be required.
Prognosis
Patients with large liver cysts may be asymptomatic for years. Surgery is often curative for lung and liver cysts, but not always for cysts in other locations.
Brunetti E et al: Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans. Acta Trop 2010;114:1–16 [PMID: 19931502].
http://www.cdc.gov/parasites/echinococcosis/.
McManus DP et al: Diagnosis, treatment, and management of echinococcosis. BMJ 2012;344:e3866 [PMID: 22689886].
Moro P, Schantz PM: Echinococcosis: a review. Int J Infect Dis 2009;13:125–133 [PMID: 18938096].
TREMATODE INFECTIONS
Schistosomiasis
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Transient pruritic rash after exposure to freshwater.
Fever, urticaria, arthralgias, cough, lymphadenitis, and eosinophilia.
Weight loss, anorexia, hepatosplenomegaly, or hematuria.
Eggs in stool, urine, or rectal biopsy specimens.
General Considerations
One of the most common serious parasitic diseases, schistosomiasis, is caused by several species of Schistosoma flukes. Schistosoma japonicum, Schistosoma mekongi, and S mansoni involve the intestines and Schistosoma haematobium, the urinary tract. The first two species are found in eastern and southeastern Asia; S mansoni in tropical Africa, the Caribbean, and parts of South America; and S haematobium in Africa. Important transmission sites include Lake Malawi and Lake Victoria in Africa, Poyang and Dongting Lakes in China, and along the Mekong River in Laos.
Infection is caused by free-swimming larvae (cercariae), which emerge from the intermediate hosts, certain species of freshwater snails. The cercariae penetrate human skin, migrate to the liver, and mature into adults, which then migrate through the portal vein to lodge in the bladder veins (S haematobium), superior mesenteric veins (S mekongi and S japonicum), or inferior mesenteric veins (S mansoni). Clinical disease results primarily from inflammation caused by the many eggs that are laid in the perivascular tissues or that embolize to the liver. Escape of ova into bowel or bladder lumen allows microscopic visualization and diagnosis from stool or urine specimens, as well as contamination of freshwater and infection of the snail hosts that ingest them.
Clinical Findings
Much of the population in endemic areas is infected but asymptomatic. Only heavy infections produce symptoms.
A. Symptoms and Signs
Schistosomiasis progresses in three distinct phases: acute, chronic, and advanced disease. The cercarial penetration may cause a maculopapular, pruritic rash, comprising discrete, erythematous, raised lesions that vary in size from 1 to 3 cm. The symptoms of acute schistosomiasis (Katayama syndrome) can last from days to weeks, and can include fever, malaise, cough, diarrhea, hematuria, and right upper quadrant pain. The chronic stages of disease are characterized by hepatic fibrosis, portal hypertension, splenomegaly, ascites, and bleeding from esophageal varices. The chronic inflammation in the urinary tract associated with S haematobium infections may result in obstructive uropathy, stones, infection, bladder cancer, fistulas, and anemia due to chronic hematuria. Terminal hematuria in children from an endemic region is a red flag for urinary schistosomiasis. Spinal cord granulomas and paraplegia due to egg embolization into the Batson plexus have been reported.
B. Laboratory Findings
The diagnosis is made by finding the species-specific eggs in feces (S japonicum, S mekongi, S mansoni, and occasionally S haematobium) or urine (S haematobium and occasionally S mansoni). If no eggs are found, concentration methods should be used. Because the shedding of eggs can vary, three specimens should be obtained. Urine specimens should be collected between 10 AM and 2 PM to coincide with the timing of maximal egg secretion. Testing should wait until 2 months after the last known freshwater contact as this is the time required for worms to start producing eggs following infection. A rectal biopsy may reveal S mansoni and should be done if other specimens are negative. Serological tests are also available and may be helpful in making the diagnosis in patients who are not excreting eggs. Peripheral eosinophilia is common, and eosinophils may be seen in urine.
Prevention
The best prevention is to avoid contact with contaminated freshwater in endemic areas. Efforts to destroy the snail hosts have been successful in areas of accelerated economic development.
Treatment
A. Specific Measures
Praziquantel is the treatment of choice for schistosomiasis. A dosage of 40 mg/kg/d in two divided doses (S mansoni or S haematobium) over 1 day or 20 mg/kg three times a day (S japonicum or S mekongi) over 1 day is very effective and nontoxic. Praziquantel has no effect on eggs and immature worms and therefore a repeat dose 4–6 weeks later is sometimes needed.
B. General Measures
Therapy of nutritional deficiency or secondary bacterial infections may be needed. The patient’s urinary tract should be evaluated carefully in S haematobium infection; reconstructive surgery may be needed. Hepatic fibrosis requires careful evaluation of the portal venous system and surgical management of portal hypertension when appropriate.
Prognosis
Therapy decreases the worm burden and liver size, despite continued exposure in endemic areas. Early disease responds well to therapy, but once significant scarring or severe inflammation has occurred, eradication of the parasites is of little benefit.
Gary DJ et al: Diagnosis and management of schistosomiasis. BMJ 2011;342:d2651 [PMID: 21586478].
http://www.cdc.gov/parasites/schistosomiasis/.
http://www.who.int/topics/schistosomiasis/.
Mycotic Infections
Fungi can be classified as yeasts, which are unicellular and reproduce by budding; as molds, which are multicellular and consist of tubular structures (hyphae) and grow by elongation and branching; or as dimorphic fungi, which can exist either as yeasts or molds depending on environmental conditions. Categorization according to anatomic and epidemiologic features is shown in Table 43–6. Fungal cells are taxonomically distinct from plant and animal cells. These differences, especially cell wall and cell membrane components, are utilized for diagnosis and are the basis of specific therapy.
Table 43–6. Pediatric fungal infections.
In the United States, systemic disease in normal hosts is commonly caused by three organisms—Coccidioides, Histoplasma, and Blastomyces—which are restricted to certain geographic areas. Prior residence in or travel to these areas, even for a brief time, is a prerequisite for inclusion in a differential diagnosis. Of these three, Histoplasma most often relapses years later in patients who are immunosuppressed.
Immunosuppression (especially depressed T-cell–mediated immunity), foreign bodies (eg, urinary and central catheters), ulceration of gastrointestinal and respiratory mucosa, severe burns, broad-spectrum antimicrobial therapy, malnutrition, HIV infection, and neutropenia or neutrophil defects are major risk factors for opportunistic fungal disease.
Laboratory diagnosis may be difficult because of the small number of fungi present in some lesions, slow growth of some organisms, and difficulty in distinguishing normal colonization of mucosal surfaces, by some fungi, from infection. A tissue biopsy with fungal stains and culture is the best method for diagnosing systemic disease with some fungi. Repeat blood cultures may be negative even in the presence of intravascular infections. Serologic tests are useful for diagnosing coccidioidomycosis and histoplasmosis, and antigen detection in urine and blood is useful for diagnosing blastomycosis, histoplasmosis, cryptococcosis, and aspergillosis.
The common superficial fungal infections of the hair and skin are discussed in Chapter 15.
Chen SC, Playford EG, Sorrell TC: Antifungal therapy in invasive fungal infections. Curr Opin Pharmacol 2010;10(5):522 [PMID: 20598943].
Hage CA, Knox KS, Wheat LJ: Endemic mycoses: overlooked causes of community acquired pneumonia. Respir Med 2012;106(6):769 [PMID: 22386326].
Oz Y, Kiraz N: Diagnostic methods for fungal infections in pediatric patients: microbiological, serological, and molecular methods. Expert Rev Anti Infec Ther 2011; 9(3):289 [PMID: 21417868].
Smith JA, Kauffman CA: Pulmonary fungal infections. Respirology 2012;17(6):913 [PMID: 22335254].
Blastomycosis
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Residence in, or travel to, an endemic area.
In immunocompetent patients, most often a self-limited flu-like illness; acute pneumonia occurs in a minority of cases.
Complications include progressive pneumonia and disseminated disease (CNS, skin, bone and joints, genitourinary tract).
Diagnosis by culture of specimens from bronchoscopy, skin, or other tissue.
General Considerations
The causative fungus, Blastomyces dermatitidis, is found in soil primarily in the Mississippi and Ohio River valleys, additional southeastern and south central states, and the states bordering the Great Lakes. Transmission is by inhalation of spores. Subclinical disease is common. Severe disease is much more common in adults and males. In children, infection rates are similar in both sexes.
Clinical Findings
A. Symptoms and Signs
Primary infection is often unrecognized or produces pneumonia. Acute symptoms include cough with purulent sputum, chest pain, headache, weight loss, night sweats, and fever. These occur several weeks to months after inoculation. Acute infection is often seen in conjunction with heavy point source exposure (such as around excavations). Infection is most often self-limited in immunocompetent patients, but in some patients an indolent progressive pulmonary disease occurs after an incubation period of 20–100 (median 45) days. Cutaneous lesions usually represent disseminated disease; local primary inoculation is rare. Skin lesions are slowly progressive and ulcerative with a sharp, heaped-up border or verrucous appearance. Bone disease resembles other forms of chronic osteomyelitis. Lytic skull lesions in children are typical, but long bones, vertebrae, and the pelvis may be involved. Extrapulmonary disease occurs in 25%–40% of patients with progressive disease. A total body radiographic examination is advisable when blastomycosis is diagnosed in the skin or another nonpulmonary site. Lymph nodes and brain may be involved, but the genitourinary tract involvement characteristic of dissemination in adults is rare in prepubertal children.
B. Laboratory Findings
An initial suppurative response is followed by an increase in the number of mononuclear cells, and subsequent formation of noncaseating granulomas. Diagnosis requires isolation or visualization of the fungus. Pulmonary specimens (sputum, tracheal aspirates, or lung biopsy) may be positive using conventional stains or fungal cell wall stains. The budding yeasts are thick-walled, have refractile walls, and are very large and distinctive (figure-of-eight appearance). The fungus can be grown readily in most laboratories, but a week is often required. Sputum specimens are positive in more than 80% of cases and in almost all bronchial washings, and skin lesions are positive in 80%–100%. Antibody tests are generally not helpful for diagnosis, but an ELISA antigen detection method, similar to that used for histoplasmosis, readily detects Blastomyces antigen in serum, urine, and lung lavage fluids. In this assay, there is cross-reactivity with histoplamosis.
C. Imaging
Radiographic lobar consolidation and fibronodular interstitial and alveolar infiltrates are typical; effusions, hilar nodes, and cavities are less common. The paucity of cavitation distinguishes acute blastomycosis from histoplasmosis and tuberculosis. Miliary patterns also occur with acute infection. Chronic disease can develop in the upper lobes, with cavities and fibronodular infiltrations similar to those seen in tuberculosis. However, unlike tuberculosis or histoplasmosis, these lesions rarely caseate or calcify.
Differential Diagnosis
Primary pulmonary infection resembles acute viral, bacterial, or mycoplasmal infections, and is generally confused with atypical community-acquired pneumonia. Blastomycosis should be considered when a significant pulmonary infection in an endemic area fails to respond to antibiotic therapy. Subacute infection mimics tuberculosis, histoplasmosis, and coccidioidomycosis. Chronic pulmonary or disseminated disease must be differentiated from cancer, tuberculosis, or other fungal infections.
Treatment
If the patient is symptomatic at the time of diagnosis, and has moderately severe or life-threatening blastomycosis (especially if immunocompromised patient), or has CNS infections, therapy should be initiated with the lipid formulation of amphotericin B (3–5 mg/kg intravenously) for 1–2 weeks or until improved. This is followed by oral itraconazole (5–10 mg/kg/d; divided into two doses) for 6 months. Itraconazole drug levels are valuable for monitoring therapy in severely ill patients. Mild to moderate blastomycosis is often treated with oral itraconazole alone for 6–12 months. Bone disease may require a full year of itraconazole therapy. Surgical debridement is required for devitalized bone, drainage of large abscesses, and pulmonary lesions not responding to medical therapy.
Bariola JR et al: Detection of Blastomyces dermatiditis antigen in patients with newly diagnosed blastomycosis. Diagn Microbiol Infect Dis 2011;69(2):187 [PMID: 21251563].
Fanella S, Skinner S, Trepman, Embil JM: Blastomycosis in children and adolescents: a 30-year experience from Manitoba. Med Mycol 2011;49(6):627 [PMID: 20110718].
Hage CA, Knox KS, Wheat LJ: Endemic mycoses: overlooked causes of community acquired pneumonia. Respir Med 2012;106(6):769 [PMID: 22386326].
Candidiasis
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
In normal or immunosuppressed individuals: superficial infections (oral thrush or ulcerations, vulvovaginitis, erythematous intertriginous rash with satellite lesions); fungemia related to intravascular devices.
In immunosuppressed individuals: systemic infections (candidemia with renal, hepatic, splenic, pulmonary, or cerebral abscesses); chorioretinitis; cutaneous nodules.
In either patient population: budding yeast and pseudohyphae are seen in biopsy specimens, body fluids, or scrapings of lesions; positive culture.
General Considerations
Disease due to Candida is caused by Candida albicans in 60%–80% of cases; severe systemic infection may also be caused by Candida tropicalis, Candida parapsilosis, Candida glabrata, and a few other Candida species. Speciation is important because of differences in pathogenicity and response to antifungal therapy. In tissue, pseudohyphae or budding yeast (or both) are seen. Candida grows on routine media more slowly than many bacteria; growth is usually evident on agar after 2–3 days and in blood culture in 2–7 days.
C albicans is ubiquitous, usually in small numbers, on skin, mucous membranes, or in the intestinal tract. Normal bacterial flora, intact epithelial barriers, neutrophils, and macrophages in conjunction with antibody and complement and normal lymphocyte function are factors in preventing invasion. Disseminated infection is almost always preceded by prolonged broad-spectrum antibiotic therapy, instrumentation (including intravascular catheters), and/or immunosuppression. Patients with diabetes mellitus are especially prone to superficial Candida infection; thrush and vaginitis are most common. Candida is the fourth most common blood isolate in hospitals in the United States and is a common cause of catheter-related urinary tract infection.
Clinical Findings
A. Symptoms and Signs
1. Oral candidiasis (thrush)—Adherent creamy white plaques on the buccal, gingival, or lingual mucosa are seen. These may be painful. Lesions may be few and asymptomatic, or they may be extensive, extending into the esophagus. Thrush is very common in otherwise normal infants in the first weeks of life; it may last weeks despite topical therapy. Spontaneous thrush in older children is unusual unless they have recently received antimicrobials. Corticosteroid inhalation for asthma predisposes patients to thrush. HIV infection should be considered if there is no other reason for oral thrush, or if it is persistent or recurrent. Angular cheilitis is the name given to painful erythematous fissures caused by Candida at the corners of the mouth, often in association with a vitamin or iron deficiency.
2. Vaginal infection—Vulvovaginitis occurs in sexually active girls, in diabetic patients, and in girls receiving antibiotics. Thick, odorless, cheesy discharge with intense pruritus is typical. The vagina and labia are usually erythematous and swollen. Outbreaks are more frequent before menses.
3. Skin infection
A. DERMATITIS—Diaper dermatitis is often due entirely or partly to Candida. Pronounced erythema with a sharply defined margin and satellite lesions is typical. Pustules, vesicles, papules, or scales may be seen. Weeping, eroded lesions with a scalloped border are common. Any moist area, such as axillae, under breasts, and inguinal or neck folds, may be involved.
B. CONGENITAL SKIN LESIONS—These lesions may be seen in infants born to women with Candida amnionitis. A red maculopapular or pustular rash is seen. Dissemination may occur in premature infants or in term infants after prolonged rupture of membranes.
C. SCATTERED RED PAPULES OR NODULES—Such findings in immunocompromised patients may represent cutaneous dissemination.
D. PARONYCHIA AND ONYCHOMYCOSIS—These conditions occur in immunocompetent children, but are often associated with immunosuppression, hypoparathyroidism, or adrenal insufficiency (Candida endocrinopathy syndrome). The selective absence of specific innate and T-cell responses to Candida can lead to marked, chronic skin and nail infections called chronic mucocutaneous candidiasis.
E. CHRONIC DRAINING OTITIS MEDIA—This problem may occur in patients who have received multiple courses of antibiotics and are superinfected with Candida.
4. Enteric infection—Esophageal involvement in immunocompromised patients is the most common enteric manifestation, resulting in substernal pain, dysphagia, painful swallowing, and anorexia. Nausea and vomiting are common in young children. Most patients do not have thrush. Stomach or intestinal ulcers also occur.
5. Pulmonary infection—Because the organism frequently colonizes the upper respiratory tract, it is commonly isolated from respiratory secretions. Thus, demonstration of tissue invasion is needed to diagnose Candida pneumonia or tracheitis. It is rare, seen mainly in immunosuppressed patients and patients intubated for long periods, usually while taking antibiotics. The infection may cause fever, cough, abscesses, nodular infiltrates, and effusion.
6. Renal infection—Candiduria may be the only manifestation of disseminated disease. More often, candiduria is associated with instrumentation, an indwelling catheter, or anatomic abnormality of the urinary tract. Symptoms of cystitis may be present. Masses of Candida may obstruct ureters and cause obstructive nephropathy. Candida casts in the urine suggest renal tissue infection.
7. Other infections—Myocarditis, meningitis, and osteomyelitis usually occur only in immunocompromised patients or neonates, generally in those with high-grade candidemia. Endocarditis may occur on an artificial or abnormal heart valve, especially when an intravascular line is present.
8. Disseminated candidiasis—Skin and mucosal colonization precedes, but does not predict dissemination. Too often, dissemination is confused with bacterial sepsis. This occurs in neonates—especially premature infants—in an intensive care unit setting, and is recognized when the infant fails to respond to antibiotics or when candidemia is documented. Invasive disease can occur in > 50% of very low-birth-weight infants. These infants often have unexplained feeding intolerance, cardiovascular instability, apnea, new or worsening respiratory failure, glucose intolerance, thrombocytopenia, or hyperbilirubinemia. A careful search in immunocompromised patients should be carried out for lesions suggestive of disseminated Candida (retinal cotton-wool spots or chorioretinitis; nodular dermal abscesses). If these findings are absent, diagnosis is often based presumptively on the presence of a compatible illness in an immunocompromised patient; a burn patient; or a patient with prolonged postsurgical or intensive care unit course who has no other cause for the symptoms; and who fails to respond to antimicrobials. Such patients usually have Candida colonization of mucosal surfaces. Treatment for presumptive infection is often undertaken because candidemia is not identified antemortem in many such patients.
Hepatosplenic and renal candidiasis occurs in immunosuppressed patients. The typical case consists of a severely neutropenic patient who develops chronic fever, variable abdominal pain, and abnormal liver function tests. No causative bacterial pathogen is isolated, and there is no response to antimicrobials. Symptoms persist even when neutrophils return. Ultrasound or CT scan of the liver, spleen, and kidney demonstrates multiple round lesions. Biopsy is needed to confirm the diagnosis.
B. Laboratory Findings
Budding yeast cells are easily seen in scrapings or other samples. A wet mount preparation of vaginal secretions is 40%–50% sensitive; this is increased to 50%–70% with the addition of 10% potassium hydroxide to the sample. The use of a Gram-stained smear is 70%–100% sensitive. The presence of pseudohyphae suggests tissue invasion. Positive cultures from nonsterile sites may reflect colonization and need to be carefully evaluated, but Candida should never be considered a contaminant in cultures from normally sterile sites. Ninety-five percent of positive blood cultures will be detected within 3 days, but cultures may remain negative (10%–40%) even with disseminated disease or endocarditis. Candida in any number in appropriately collected urine suggests true infection. Antigen tests are not sensitive or specific enough for clinical use. The ability of yeast to form germ tubes when incubated in human serum gives a presumptive speciation for C albicans.
Differential Diagnosis
Thrush may resemble formula (which can be easily wiped away with a tongue blade or swab, revealing normal mucosa without underlying erythema or erosion), other types of ulcers (including herpes), burns, or oral changes induced by chemotherapy. Skin lesions may resemble contact, allergic, chemical, or bacterial dermatitis; miliaria; folliculitis; or eczema. Vulvovaginitis needs to be distinguished from other causes of vaginal discharge and discomfort. Candidemia and systemic infection should be considered in any seriously ill patient with the risk factors previously mentioned.
Complications
Failure to recognize disseminated disease early is the greatest complication. Arthritis and meningitis occur more often in neonates than in older children. Blindness from retinitis, massive emboli from large vegetations of endocarditis, and abscesses in any organ are other complications. The greater the length or extent of immunosuppression, and the longer the delay before therapy, the more likely that complications will occur.
Treatment
A. Oral Candidiasis
In infants, oral nystatin suspension (100,000 units four to six times a day in the buccal fold after feeding until resolution) usually suffices. Nystatin must come in contact with the lesions because it is not absorbed systemically. Older children may use it as a mouthwash (200,000–500,000 units five times a day), although it is poorly tolerated because of its taste. Clotrimazole troches (10 mg) four times a day are an alternative in older children. Prolonged therapy with either agent or more frequent dosing may be needed. Painting the lesions with a cotton swab dipped in gentian violet (0.5%–1%) is visually dramatic and messy, but may help refractory cases. Eradication of Candida from pacifiers, bottle nipples, toys, or the mother’s breasts (if the infant is breast-feeding and there is candidal infection of the nipples) may be helpful.
Oral azoles, such as fluconazole (6 mg/kg/d), are effective in older children with candidal infection refractory to nystatin. Discontinuation of antibiotics or corticosteroids is advised when possible.
B. Skin Infection
Cutaneous infection usually responds to a cream or lotion containing nystatin, amphotericin B, or an imidazole (miconazole, clotrimazole, and others). Associated inflammation such as severe diaper dermatitis is helped by concurrent use of a topical mild corticosteroid cream, such as 1% hydrocortisone. One approach is to keep the involved area dry; a heat lamp and nystatin powder may be used. Suppression of intestinal Candida with nystatin and eradicating thrush may speed recovery and prevent recurrence of the diaper dermatitis.
C. Vaginal Infections
Vulvovaginal candidiasis (see Chapter 44) is treated with clotrimazole, miconazole, triazoles, or nystatin (cheapest if generic is used) suppositories or creams, usually applied once nightly for 3–7 days. A high-dose topical clotrimazole formulation need be given for only a single night. Oral azole therapy is equally effective. A single 150-mg oral dose of fluconazole is effective for vaginitis. It is more expensive but very convenient. Candida balanitis in sexual partners should be treated, but no controlled study has shown that treating colonization of male sexual partners prevents recurrence in females. Frequent recurrent infections may require elimination of risk factors, the use of oral therapy, or some prophylactic antifungal therapy, such as a single dose of fluconazole weekly for 6 months.
D. Renal Infection
Candiduria in an immunocompetent host with a urinary catheter may respond to its removal. Candiduria is treated in all high-risk patients, usually with a 7- to 14-day course of fluconazole (3–6 mg/kg/d), which is concentrated in the urine. Amphotericin B may be required in patients with fluconazole-resistant organisms. Renal abscesses or ureteral fungus balls require intravenous antifungal therapy, and surgical debridement may be required. Removal of an indwelling catheter is imperative.
E. Systemic Infection
1. Disseminated Candida infection—Systemic infection is dangerous and resistant to therapy. Surgical drainage of abscesses and removal of all infected tissue (eg, a heart valve) are required for cure. Hepatosplenic candidiasis should be treated until all lesions have disappeared or are calcified on imaging studies. Treatment of systemic infection has traditionally utilized amphotericin B, but lipid forms of amphotericin B retain the antifungal potency of the free drug and are much better tolerated. Although they are much more expensive than amphotericin B, they are indicated for patients who are intolerant of conventional therapy and for those whose infection is refractory to treatment or who have a high likelihood of developing renal toxicity from such therapy.
Flucytosine (50–75 mg/kg/d orally in four doses; keep serum levels < 75 mcg/mL) may be additive or synergistic to amphotericin B. Unlike amphotericin B, flucytosine penetrates tissues well. It should not be used as a single agent in serious infections because resistance develops rapidly.
Fluconazole and itraconazole (best absorbed from the liquid solution) and newer azole drugs, such as voriconazole and posiconazole, and a new class of drugs, echinocandins, are used interchangeably or in conjunction with amphotericin. They are often preferred because in general they are less toxic. They are acceptable alternatives for serious C albicans infections in nonneutropenic patients and are often effective as first-line therapy in immunocompromised patients. Fluconazole is well absorbed (oral and intravenous therapy are equivalent), reasonably nontoxic, and effective for a variety of Candida infections. Fluconazole dosage is 8–12 mg/kg/d in a single daily dose for initial therapy of severely ill children. Selected patients with prolonged immunosuppression (eg, after bone marrow transplantation) should receive prophylactic azole, echinocandin, or intermittent amphotericin B prophylaxis. The decision to use systemic azole therapy should include consideration of the local experience with azole-resistant Candida and if the patient had recent prophylaxis or treatment with azoles. Susceptibility testing for Candida species is now available to guide this decision. Candida glabrata and C krusei are common isolates that may be resistant to fluconazole; these are often susceptible to the newer azoles and echinocandins. Candida lusitaniaeis usually resistant to amphotericin.
Correction of predisposing factors is important (eg, discontinuing antibiotics and immunosuppressives, improving control of diabetes, and removing infected devices and lines).
2. Candidemia—Infected central venous lines must be removed immediately; this alone often is curative. If the infection is considered limited to the line and environs, a 14-day course (after the last positive culture) of a systemic antifungal agent following line removal is recommended for nonneutropenic patients. This is because of the late occurrence of focal Candida infection, especially retinal infection, in some cases. Persistent fever and candidemia suggest infected thrombus, endocarditis, or tissue infection.
Prognosis
Superficial disease in normal hosts has a good prognosis; in abnormal hosts, it may be refractory to therapy. Early therapy of systemic disease is often curative if the underlying immune response is adequate. The outcome is poor when therapy is delayed or when host response is inadequate.
Katragkou A, Roilides E: Best practice in treating infants and children with proven, probable or suspected invasive fungal infections. Curr Opin Infect Dis 2011;24(3):225 [PMID: 21455060].
Moudgal V, Sobel J: Antifungals to treat Candida albicans. Expert Opin Pharmacother 2010;11(12):2037 [PMID: 20536294].
Pappas PG et al: Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009;48:503 [PMID: 19191635].
Zaoutis T: Candidemia in children. Curr Med Res Opin 2010;26(7):1761 [PMID: 20513207].
Coccidioidomycosis
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Residence in, or travel to, an endemic area.
Primary pulmonary form: fever, chest pain, cough, anorexia, weight loss, and often a macular rash, erythema nodosum, or erythema multiforme.
Primary cutaneous form: skin trauma followed in 1–3 weeks by an ulcer and regional adenopathy.
Spherules seen in pus, sputum, CSF, joint fluid; positive culture.
Appearance of precipitating (early) and complement-fixing antibodies (late).
General Considerations
Coccidioidomycosis is caused by the dimorphic fungus Coccidioides (immitis or posadasii), which are endemic in the Sonoran Desert areas of western Texas, southern New Mexico and Arizona, southern California, northern Mexico, and South America. Infection results from inhalation or inoculation of arthrospores (highly contagious and readily airborne in the dry climate). Even brief travel in or through an endemic area, especially during windy seasons, may result in infection. Human-to-human transmission does not occur. More than half of all infections are asymptomatic, and less than 5% are associated with significant pulmonary disease. Chronic pulmonary disease or dissemination occurs in less than 1% of cases.
Clinical Findings
A. Symptoms and Signs
1. Primary disease—The incubation period is 10–16 days (range, 7–28 days). Symptoms vary from those of a mild fever and arthralgia to severe influenza-like illness with high fever, nonproductive cough, pleurisy, myalgias, arthralgias, headache, and night sweats. Upper respiratory tract signs are uncommon. Severe pleuritic chest pain suggests this diagnosis. Signs vary from none to rash, rales, pleural rubs, and signs of pulmonary consolidation. Weight loss may occur.
2. Skin disease—Up to 10% of children develop erythema nodosum or erythema multiforme. These manifestations imply a favorable host response to the organism. Less specific maculopapular eruptions occur in a larger number of children. Skin lesions can occur following fungemia. Primary skin inoculation sites develop indurated ulcers with local adenopathy. Contiguous involvement of skin from deep infection in nodes or bone also occurs. The presence of chronic skin lesions should lead to a search for other areas of infection (eg, lungs).
3. Chronic pulmonary disease—This is uncommon in children. Chronic disease is manifested by chronic cough (occasionally with hemoptysis), weight loss, pulmonary consolidation, effusion, cavitation, or pneumothorax.
4. Disseminated disease—This is less common in children than adults, and is more common in infants, neonates, pregnant women (especially during the third trimester), black people, Filipinos, American Indians, and patients with HIV or other types of immunosuppression. More than one organ may be involved. The most common extra-pulmonary sites involved are bone or joint (usually a single bone or joint; subacute or chronic swelling, pain, redness), nodes, meninges (slowly progressive meningeal signs, ataxia, vomiting, headache, and cranial neuropathies), and kidneys (dysuria and urinary frequency). As with most fungal diseases, the evolution of the illness is usually slow.
B. Laboratory Findings
Direct examination of respiratory secretions, pus, CSF, or tissue may reveal large spherules (30–60 μm) containing endospores. These are the product of coccidioidal spores germinating in tissue. The organism is detected by using periodic acid–Schiff reagent, methenamine silver, and calcofluor stains. Fluffy, gray-white colonies grow within 2–5 days on routine fungal and many other media. CSF cultures are often falsely negative.
The sedimentation rate is usually elevated. Eosinophilia may occur, particularly prior to dissemination, and is more common in coccidioidomycosis than in many other conditions with similar symptoms. Meningitis causes a mononuclear pleocytosis (70% contain eosinophils) with elevated protein and mild hypoglycorrhachia.
Antibodies consist of precipitins (usually measurable by 2–3 weeks in 90% of cases and gone by 12 weeks) and complement-fixing antibodies (delayed for several weeks; appear as the precipitins are falling and should disappear by 8 months). Thus, serum precipitins usually indicate acute infection. The extent of the complement-fixing antibody response reflects the severity of infection. Persistent high levels suggest dissemination. Excellent ELISA assays, which detect IgM and IgG antibodies against coccidioidal antigens, become positive in some patients as early as 1–3 weeks after onset of symptoms. The presence of antibody in CSF indicates CNS infection; CSF and serum antibody titers correlate with disease progression and response to therapy.
Galactomannan antigen from Coccidioides is detected in urine and serum of patients. This occurs more frequently in severe disease compared to moderate disease. Testing both types of specimens should provide a diagnosis overall in more than 75% of patients.
C. Imaging
Approximately half of symptomatic infections are associated with abnormal chest radiographs—usually infiltrates with hilar adenopathy. Pulmonary consolidation, effusion, and thin-walled cavities may be seen. About 5% of infected patients have asymptomatic nodules or cysts after recovery. Unlike tuberculosis reactivation, apical disease is not prominent. Bone infection causes osteolysis that enhances with technetium. Cerebral imaging may show hydrocephalus and meningitis; intracranial abscesses and calcifications are unusual. Radiographic evolution of all lesions is slow.
Differential Diagnosis
Primary pulmonary infection resembles acute viral, bacterial, or mycoplasmal infections; subacute presentation mimics tuberculosis, histoplasmosis, and blastomycosis. Chronic pulmonary or disseminated disease must be differentiated from cancer, tuberculosis, or other fungal infections.
Complications
Dissemination of primary pulmonary disease is associated with permissive ethnic background, prolonged fever (> 1 month), a negative skin test, high complement-fixation antibody titer, and marked hilar adenopathy. Local pulmonary complications include effusion, empyema, and pneumothorax. Cerebral infection can cause noncommunicating hydrocephalus due to basilar meningitis.
Treatment
A. Specific Measures
Mild pulmonary infections in most normal patients require no therapy. These patients should be assessed for 1–2 years to document resolution and to identify any complications. Antifungal therapy is used for prolonged fever, weight loss (> 10%), prolonged duration of night sweats, severe pneumonitis (especially if persisting for 4–6 weeks), or any form of disseminated disease. Neonates, pregnant women, high-risk racial background, and patients with high antibody titers also receive treatment.
Lipid formulation of amphotericin B is used to treat extensive pulmonary or disseminated disease or disease in immunosuppressed patients (2–5 mg/kg/d). In general, the more rapidly progressive the infection, the more compelling the case for amphotericin B therapy. For less severe disease and for meningeal disease, fluconazole or itraconazole are preferred (duration of therapy is 3–6 months or is lifelong for meningeal disease). Measurement of serum levels is suggested to monitor therapy. Chronic fibrocavitary pneumonia is treated for at least 12 months. Itraconazole may be superior to fluconazole. Refractory meningitis may require prolonged intrathecal or intraventricular amphotericin B therapy. Pregnant patients should not receive azoles.
B. General Measures
Most pulmonary infections require only symptomatic therapy, self-limited activity, and good nutrition. Patients are not contagious.
C. Surgical Measures
Excision of chronic pulmonary cavities or abscesses may be needed. Infected nodes, sinus tracts, and bone are other operable lesions. Azole therapy should be given prior to surgery to prevent dissemination and should be continued for 4 weeks arbitrarily or until other criteria for cure are met.
Prognosis
Most patients recover. Even with amphotericin B, however, disseminated disease may be fatal, especially in those racially predisposed to severe disease. Reversion of the skin test to negative or a rising complement-fixing antibody titer is an ominous sign. Individuals who later in life undergo immunosuppressive therapy or develop HIV may experience reactivation of dormant disease. Thus, some transplant and oncology programs determine prior infection by serology and either provide prophylaxis or observe patients closely during periods of intense immune suppression.
Hage CA, Knox KS, Wheat LJ: Endemic mycoses: overlooked causes of community acquired pneumonia. Respir Med 2012;106(6):769 [PMID: 22386326].
Shehab ZM: Coccidioidomycosis. Adv Pediatr 2010;57(1):269 [PMID: 21056742].
Cryptococcosis
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Acute pneumonitis in immunocompetent individuals.
Immunosuppressed patients especially vulnerable to CNS infection (headache, vomiting, cranial nerve palsies, meningeal signs; mononuclear cell pleocytosis).
Cryptococcal antigen detected in CSF; also in serum and urine in some patients.
Readily isolated on routine media.
General Considerations
Cryptococcus neoformans is a ubiquitous soil yeast. It appears to survive better in soil contaminated with bird excrement, especially that of pigeons. However, most infections in humans are not associated with a history of significant contact with birds. Inhalation is the presumed route of inoculation. Infections in children are rare, even in heavily immunocompromised patients such as those with HIV infection. Immunocompetent individuals can also be infected, especially by Cryptococcus gattii, which is an emerging pathogen in Canada and the Pacific Northwest. Asymptomatic carriage does not occur.
Clinical Findings
A. Symptoms and Signs
1. Pulmonary disease—Pulmonary infection precedes dissemination to other organs. It is frequently asymptomatic (ie, many older children and adults have serologic evidence of prior infection) and less often clinically apparent than cryptococcal meningitis. Pneumonia is the primary manifestation in one-third of patients; CNS disease is the primary manifestation in 50% of patients. Cryptococcal pneumonia may coexist with CNS involvement. Symptoms are nonspecific and subacute—cough, weight loss, and fatigue.
2. Meningitis—The most common clinical disease is meningitis, which follows hematogenous spread from a pulmonary focus. This is much more likely to occur in an immunosuppressed patient (especially HIV). Symptoms of headache, vomiting, and fever occur over days to months. Meningeal signs and papilledema are common. Cranial nerve dysfunction and seizures may occur.
3. Other forms—Cutaneous forms are usually secondary to dissemination. Papules, pustules, and ulcerating nodules are typical. Bones (rarely joints) may be infected; osteolytic areas are seen, and the process may resemble osteosarcoma. Many other organs, especially the eyes, can be involved with dissemination.
B. Laboratory Findings
The CSF usually has a lymphocytic pleocytosis; it may be completely normal in immunosuppressed patients with meningeal infection. Direct microscopy may reveal organisms in sputum, CSF, or other specimens. The capsular antigen can be detected by latex agglutination or ELISA, which are both sensitive (> 90%) and specific. False-negative CSF tests occur rarely. Serum, CSF, and urine should be tested if this infection is suspected. The serum may be negative if the only organ infected is the lung. The organism grows well after several days on many routine media; for optimal culture, collecting and concentrating a large amount of CSF (10 mL) is recommended, because the number of organisms may be low.
C. Imaging
Radiographic findings are usually lower lobe infiltrates or nodular densities; less often effusions; and rarely cavitation, hilar adenopathy, or calcification. Single or multiple focal mass lesions (cryptococcoma) may be detected in the CNS on CT or MRI scan.
Differential Diagnosis
Cryptococcal meningitis may mimic tuberculosis, viral meningoencephalitis, meningitis due to other fungi, or a space-occupying CNS lesion. Lung infection is difficult to differentiate from many causes of pneumonia.
Complications
Hydrocephalus may be caused by chronic basilar meningitis. Symptomatic and recalcitrant intracranial hypertension is common. Significant pulmonary or osseous disease may accompany the primary infection or dissemination.
Treatment
Patients with symptomatic pulmonary disease should receive fluconazole for 3–6 months. All immunocompromised patients with cryptococcal pulmonary disease should have a lumbar puncture to rule out CNS infection; this should also be done for immunocompetent patients with cryptococcal antigen in the serum. Severely ill patients should receive amphotericin B (0.7 mg/kg/d). Meningitis is treated with amphotericin B (increase dose to 1 mg/kg/d) and flucytosine (100 mg/kg/d). This combination is synergistic and allows lower doses of amphotericin B to be used. Induction therapy is usually 2 weeks for CNS infections. Fluconazole can be substituted for flucytosine. After this, fluconazole alone (10 mg/kg/d) is maintained for 8 weeks and then continued at a reduced dose (determined by moderate serum levels) for an additional 6–12 months. Fluconazole is the preferred maintenance therapy to prevent relapses in high-risk (eg, HIV) patients. CSF antigen levels should be checked after 2 weeks of therapy. Intracranial hypertension is treated by frequent spinal taps or a lumbar drain.
Prognosis
Treatment failure, including death, is common in immunosuppressed patients, especially those with AIDS. Lifelong maintenance therapy may be required in these patients. Poor prognostic signs are the presence of extrameningeal disease, fewer than 20 cells/μL of initial CSF, and initial CSF antigen titer greater than 1:32.
Brizendine KD, Baddley JW, Pappas PG: Pulmonary cryptococcosis. Sem Respir Crit Care Med 2011;32(6):727 [PMID: 22167400].
Desalermos A, Kourkoumpetis TK, Mylonakis E: Update on the epidemiology and management of cryptococcal meningitis. Expert Opin Pharmacother 2012;13(6):783 [PMID: 22424297].
Smith JA, Kauffman CA: Pulmonary fungal infections. Respirology 2012;17(6):913 [PMID: 22335254].
Histoplasmosis
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Residence in or travel to an endemic area.
Pneumonia with flulike illness.
Hepatosplenomegaly, anemia, leukopenia if disseminated.
Histoplasmal antigen in urine, blood, bronchoalveolar lavage fluid or CSF.
Detection by staining the organism in smears or tissue, or by culture.
General Considerations
The dimorphic fungus Histoplasma capsulatum is found in the central and eastern United States (Ohio and Mississippi River valleys), Mexico, and most of South America. Soil contamination is enhanced by the presence of bat or bird feces. Infection is acquired by inhaling spores that transform into the pathogenic yeast form seen in infected tissues, especially within macrophages. Infections in endemic areas are very common at all ages and are usually asymptomatic. Over two-thirds of children are infected in these areas. Reactivation is rare in children, but occurs after treatment with immune suppressive agents, such as biological response modifiers and chemotherapy. Reactivation may occur years after primary infection. Reinfection also occurs. The extent of symptoms with primary infection or reinfection is influenced by the size of the infecting inoculum.
Clinical Findings
Because human-to-human transmission does not occur, infection requires exposure in the endemic area—usually within prior weeks or months. Congenital infection does not occur.
A. Symptoms and Signs
1. Asymptomatic infection (90% of infections)—Asymptomatic histoplasmosis is usually diagnosed by the presence of scattered calcifications in lungs or spleen and a positive skin test or serology. The calcification may resemble that caused by tuberculosis, but may be more extensive than the usual Ghon complex.
2. Pneumonia—Approximately 5% of patients have mild to moderate disease. The cause of this illness is usually not recognized as being histoplasma. Acute pulmonary disease may resemble influenza with fever, malaise, myalgia, arthralgia, and cough occurring 1–3 weeks after a heavy exposure (may be longer with less intense exposure). The subacute form resembles infections such as tuberculosis with cough, weight loss, night sweats, and pleurisy. Chronic disease is unusual in children. Physical examination may be normal, or rales may be heard. A small number of patients may have immune-mediated signs such as arthritis, pericarditis, and erythema nodosum. The usual duration of the disease is less than 2 weeks, followed by complete resolution, but symptoms may last several months before resolving without antifungal therapy.
3. Disseminated infection (5% of infections)—Fungemia during primary infection probably occurs in the first 2 weeks of all infections, including those with minimal symptoms. Transient hepatosplenomegaly may occur, but resolution is the rule in immunocompetent individuals. Heavy exposure, severe underlying pulmonary disease, and immunocompromise are risk factors for progressive reticuloendothelial cell infection with anemia, fever, weight loss, organomegaly, bone marrow involvement, and death. Dissemination may occur in otherwise immunocompetent children; usually they are younger than age 2 years.
4. Other forms—Ocular involvement consists of multifocal choroiditis. This usually occurs in immunecompetent adults who exhibit other evidence of disseminated disease. Brain, pericardium, intestine, and skin (oral ulcers and nodules) are other sites that can be involved. Adrenal gland involvement is common with systemic disease.
B. Laboratory Findings
Routine tests are normal or nonspecific in the benign forms. Pancytopenia is present in many patients with disseminated disease. The diagnosis can be made by demonstrating the organism by histology or culture. Tissue yeast forms are small and may be mistaken for artifact. They are usually found in macrophages, occasionally in peripheral blood leukocytes in severe disease, but infrequently in sputum, urine, or CSF. Cultures of infected fluids or tissues may yield the organism after 1–4 weeks of incubation on fungal media, but even cultures of bronchoalveolar lavage or transbronchial biopsy specimens in immunocompromised patients are often negative (15%). Thus, bone marrow and tissue specimens are needed. Detection of histoplasmal antigen in blood, urine, CSF, and bronchoalveolar lavage fluid is the most sensitive diagnostic test (90% positive in the urine with disseminated disease, 75% positive with acute pneumonia), but false-negative results may occur. Both urine and serum should be tested for optimal results. The level of antigen correlates with the extent of the infection, and antigen levels can be used to follow the response to therapy and to indicate low-grade infection persisting after completion of therapy (eg, in a child with HIV infection).
Antibodies may be detected by immunodiffusion and complement fixation; the latter rises in the first 2–6 weeks of illness and falls thereafter unless dissemination occurs. Cross-reactions occur with some other endemic fungi. A single high titer or rising titer indicates a high likelihood of disease, but antigen detection has replaced serology as a rapid diagnostic test.
C. Imaging
Scattered pulmonary calcifications in a well child are typical of past infection. Bronchopneumonia (focal mid-lung infiltrates) occurs with acute disease, often with hilar and mediastinal adenopathy, occasionally with nodules, but seldom with effusion. Localized or patchy infiltrates occur in subacute disease. Apical cavitation occurs with chronic infection, often on the background of preexisting pulmonary infection.
Differential Diagnosis
Pulmonary disease resembles viral infection, other causes of community acquired pneumonia, tuberculosis, coccidioidomycosis, and blastomycosis. Systemic disease resembles disseminated fungal or mycobacterial infection, leukemia, histiocytosis, or cancer.
Treatment
Most patients with acute pulmonary disease will benefit from oral itraconazole. Those with subacute disease are generally better when the diagnosis is established, but if still symptomatic should receive oral therapy. Treatment with lipid formulation of amphotericin B (2–5 mg/kg/d) is indicated for severe pulmonary disease (diffuse radiographic involvement); disseminated disease; or when endovascular, CNS, or chronic pulmonary disease is present; and for children younger than age 1 year. Disseminated disease in infants may respond to as few as 10 days of amphotericin B, although 4–6 weeks is usually recommended. Patients with severe disease (especially pulmonary) may benefit from a short course of corticosteroid therapy. Surgical excision of chronic pulmonary lesions is rarely required. Itraconazole (3–5 mg/kg/d for 6–12 weeks; achieve peak serum level of > 1.0 mcg/mL) appears to be equivalent to amphotericin B therapy for mild disease and can be substituted in severe disease after a favorable initial (2 weeks) response to amphotericin B. With chronic pulmonary, CNS, or disseminated disease, prolonged therapy for at least a year should be considered.
Quantitation of fungal antigen is useful for directing therapy, and should be monitored for 1 year after successful treatment of severe disease. Relapse may occur in up to 15% of patients with treated chronic disease. Histoplasmosis can reactivate in previously infected individuals who subsequently become immunosuppressed. Chronically immunosuppressed patients (eg, those with HIV) may require lifelong maintenance therapy with itraconazole.
Prognosis
Patients with mild and moderately severe infections have a good prognosis. With early diagnosis and treatment, infants with disseminated disease usually recover; the prognosis worsens if the immune response is poor.
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McKinsey DS, McKinsey JP: Pulmonary histoplasmosis. Sem Respir Crit Care Med 2011;32(6):735 [PMID: 22167401].
Sporotrichosis
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Subacute cutaneous ulcers.
New lesions appearing proximal to existing lesions along a draining lymphatic.
Absence of systemic symptoms.
Isolation of Sporothrix schenckii from wound drainage or biopsy.
General Considerations
Sporotrichosis is caused by Sporothrix schenckii, a dimorphic fungus present as a mold in soil, plants, and plant products from most areas of North and South America. Spores of the fungus can cause infection when they breach the skin at areas of minor trauma. Sporotrichosis has been transmitted from cutaneous lesions of pets.
Clinical Findings
Cutaneous disease is by far the most common manifestation. Typically at the site of inapparent skin injury, an initial papular lesion will slowly become nodular and ulcerate. Subsequent new lesions develop in a similar fashion proximally along lymphatics draining the primary lesion. This sequence of developing painless, chronic ulcers in a linear pattern is strongly suggestive of the diagnosis. Solitary lesions may exist and some lesions may develop a verrucous character. Systemic symptoms are absent and laboratory evaluations are normal, except for acute-phase reactants. The fungus rarely disseminates in immunocompetent hosts, but bone and joint infections have been described. Cavitary pneumonia is an uncommon manifestation when patients inhale the spores. Immunocompromised patients, especially those with HIV infection, may develop disseminated skin lesions and multiorgan disease with extensive pneumonia.
Differential Diagnosis
The differential diagnosis of nodular lymphangitis (sporotrichoid infection) includes other endemic fungi and some bacteria, especially atypical mycobacteria, pyoderma gangrenosum, nocardiosis, and syphilis. Diagnosis is made by culture. Biopsy of skin lesions will demonstrate a suppurative response with granulomas and provides the best source for laboratory isolation. Occasionally, the characteristic yeast will be seen in the biopsy.
Treatment & Prognosis
Treatment is with itraconazole (200 mg/d or 5 mg/kg/d) for 2–4 weeks after lesions heal, usually 3–6 months. Prognosis is excellent with lymphocutaneous disease in immunocompetent children. Pulmonary or osteoarticular disease, especially in immunocompromised individuals, requires longer therapy. Amphotericin B may be required for disseminated disease, CNS disease, and severe pulmonary disease. Surgical debridement may be required.
Barros MB, de Almeida Paes R, Schubach AO: Sporothrix schenckii and sporotrichosis. Clin Micro Rev 2011;24(4):633 [PMID: 21976602].
Vasquez-del-Mercado E, Arenas R, Padilla-Desgarenes C: Sporotrichosis. Clin Dermatol 2012;30(4):437 [PMID: 22682194].
PNEUMOCYSTIS AND OTHER OPPORTUNISTIC FUNGAL INFECTIONS
The name of this category indicates that fungi that are normally not pathogenic, or do not cause severe disease, may do so when given the opportunity by changes in host defenses. They occur most commonly when patients are treated with corticosteroids, antineoplastic drugs, or radiation, thereby reducing the number or function of neutrophils and T cells. Inborn errors in immune function (combined immunodeficiency or chronic granulomatous disease) may also be complicated by these fungal infections. Opportunistic infections are facilitated by altering the normal flora with antibiotics and by disruption of mucous membranes or skin with antineoplastic therapy or indwelling lines and tubes.
Table 43–7 indicates that filamentous fungi are prominent causes of severe systemic fungal disease in immunocompromised patients. Aspergillus species (usually fumigatus) and Zygomycetes (usually Mucorales) cause subacute pneumonia and sinusitis and should be considered when these conditions do not respond to antibiotics in immunocompromised patients. Aspergillus species also commonly cause invasive disease in patients with chronic granulomatous disease. Mucormycosis is especially likely to produce severe sinusitis in patients with chronic acidosis, usually when the diabetes is poorly controlled. This fungus may invade orbit and cause brain infection. Mucormycosis also occurs in patients receiving iron chelation therapy. These fungal infections may disseminate widely. Imaging procedures may suggest the etiology, but they are best diagnosed by aspiration or biopsy of infected tissues. A characteristic CT finding is the “halo sign,” which is a ground-glass opacity surrounding a pulmonary nodule or mass. The “reversed halo sign” is a focal rounded ground-glass opacity surrounded by a crescent or complete ring of consolidation. Detection of mannose in blood and alveolar fluid is sometimes useful for the diagnosis of aspergillosis and detection of β-D-glucan in blood and alveolar fluid should soon be available for the diagnosis of other opportunistic pathogens.
Table 43–7. Unusual fungal infections in children.
Although Cryptococcus can cause disease in the immune competent hosts, it is more likely to be clinically apparent and severe in immunocompromised patients. This yeast causes pneumonia and is a prominent cause of fungal meningitis. Candida species in these patients cause fungemia and multiorgan disease, with lungs, esophagus, liver, and spleen frequently affected (see the section Disseminated Candida Infection earlier).
Opportunistic fungal infections should always be included in the differential diagnosis of unexplained fever or pulmonary infiltrates in immunocompromised patients. These pathogens should be aggressively pursued with imaging studies and with tissue sampling when clues are available. Cryptococcus and Aspergillus may be demonstrated with specific antigen tests. Opportunistic infections are difficult to treat because of the deficiencies in host immune response. Treatment should be undertaken with consultants who are expert in managing these infections. Voriconazole is the drug of choice for many mold infections, but both echinocandins and amphotericin B are good alternatives. Combinations of current antifungal drugs are being tested to improve the outcome. Many children who will have depressed phagocytic and T-cell–mediated immune function for long periods (eg, after hematopoietic stem cell transplants) should receive antifungal prophylaxis during the period of severe immune suppression, most often fluconazole or itraconazole. Very-low-birth-weight infants, who are at high risk for systemic Candida infection, often receive similar prophylaxis for prolonged periods.
Malassezia furfur is a yeast that normally causes the superficial skin infection known as tinea versicolor (see Chapter 15). This organism is considered an opportunist when it is associated with prolonged intravenous therapy, especially when central lines used for hyperalimentation. The yeast, which requires skin lipids for its growth, can infect lines when lipids are present in the infusate. Some species will grow in the absence of lipids. Unexplained fever and thrombocytopenia are common. Pulmonary infiltrates may be present. The diagnosis is facilitated by alerting the bacteriology laboratory to add olive oil to culture media. The infection will respond to removal of the line or the lipid supplement. Amphotericin B may hasten resolution.
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Karageorgopoulos DE et al: β-D-Glucan assay for the diagnosis of invasive fungal infections: a meta-analysis. Clin Infect Dis 2011;52(6):750 [PMID: 21367728].
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Spellberg B et al: Recent advances in the management of mucormycosis: from bench to bedside. Clin Infect Dis 2009;48:1743 [PMID: 19435437].
PNEUMOCYSTIS JIROVECI INFECTION
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Significant immunosuppression.
Fever, tachypnea, cough, dyspnea.
Hypoxemia; diffuse interstitial infiltrates.
Detection of the organism in specimens of pulmonary origin.
General Considerations
Although classified as a fungus on the basis of structural and nucleic acid characteristics, Pneumocystis responds readily to antiprotozoal drugs and antifols. It is a ubiquitous pathogen. Initial infection is presumed to occur asymptomatically via inhalation, usually in early childhood, and to become a clinical problem upon reactivation during immune suppression. There is evidence that person-to-person transmission may contribute to symptomatic disease in immune compromised individuals. In the normal host clinical disease rarely occurs. A syndrome of afebrile pneumonia similar to that caused by Chlamydia trachomatis in normal infants has been described, but its etiology is rarely appreciated. Whether by reactivation or new exposure, severe signs and symptoms occur chiefly in patients with abnormal T-cell function, such as hematologic malignancies and organ transplantation. Pneumocystis also causes severe pneumonia in patients with γ-globulin deficiency and is an AIDS-defining illness for children with advanced HIV infection. Prophylaxis usually prevents this infection (see Chapter 41).
Prolonged, high-dose corticosteroid therapy for any condition is a risk factor; onset of illness as steroids are tapered is a typical presentation. Severely malnourished infants with no underlying illness may also develop this infection, as can those with congenital immunodeficiency. The incubation period is usually at least 1 month after onset of immunosuppressive therapy.
Infection is generally limited to the lower respiratory tract. In advanced disease, spread to other organs occurs.
Clinical Findings
A. Symptoms and Signs
In most patients, a gradual onset of fever, tachypnea, dyspnea, and mild, nonproductive cough occurs over 1–4 weeks. Initially the chest is clear, although retractions and nasal flaring are present. At this stage the illness is nonspecific. Hypoxemia out of proportion to the clinical and radiographic signs is an early finding; however, even minimally decreased arterial oxygen pressure values should suggest this diagnosis in immunosuppressed children. Tachypnea, nonproductive cough, and dyspnea progress. Respiratory failure and death occur without treatment. In some children with AIDS or severe immunosuppression from chemotherapy or organ transplantation, the onset may be abrupt and progression more rapid. Acute dyspnea with pleuritic pain may indicate the related complication of pneumothorax.
The general examination is unremarkable except for tachypnea and tachycardia; rales may be absent. There are no upper respiratory signs, conjunctivitis, organomegaly, enanthem, or rash.
B. Laboratory Findings
Laboratory findings reflect the individual child’s underlying illness and are not specific. Serum lactate dehydrogenase levels may be elevated markedly as a result of pulmonary damage. In moderately severe cases, the arterial oxygen pressure is less than 70 mm Hg or the alveolar-arterial gradient is less than 35 mm Hg.
C. Imaging
Early chest radiographs are normal. The classic pattern in later films is that of bilateral, interstitial, lower lobe alveolar disease starting in the perihilar regions, without effusion, consolidation, or hilar adenopathy. High-resolution CT scanning may reveal extensive ground-glass attenuation or cystic lesions. Older HIV-infected patients present with other patterns, including nodular infiltrates, lobar pneumonia, cavities, and upper lobe infiltrates.
D. Diagnostic Findings
Diagnosis requires finding characteristic round (6–8 mm) cysts in a lung biopsy specimen, bronchial brushings, alveolar washings, induced sputum, or tracheal aspirates. Tracheal aspirates are less sensitive, but are more rapidly and easily obtained. They are more often negative in children with leukemia compared with those with HIV infection; presumably, greater immunosuppression permits replication of a larger numbers of organisms. Because pneumonia in immunosuppressed patients may have many causes, negative results from tracheal secretions should prompt more aggressive diagnostic attempts. Bronchial washing using fiberoptic bronchoscopy is usually well tolerated and rapidly performed.
Several rapid stains—as well as the standard methenamine silver stain—are useful. The indirect fluorescent antibody method is most sensitive. These methods require competent laboratory evaluation, because few organisms may be present and many artifacts may be found.
Differential Diagnosis
In immunocompetent infants, C trachomatis pneumonia is the most common cause of the afebrile pneumonia syndrome described for Pneumocystis. In older immunocompromised children, the differential diagnosis includes influenza, respiratory syncytial virus, cytomegalovirus, adenovirus, and other viral infections; bacterial and fungal pneumonia; pulmonary emboli or hemorrhage; congestive heart failure; and Chlamydia pneumoniae and M pneumoniae infections. Lymphoid interstitial pneumonitis, which occurs in older infants with untreated HIV infection, is more indolent and the patient’s lactate dehydrogenase level is normal (see Chapter 41). Pneumocystispneumonia is rare in children who are complying with prophylactic regimens.
Prevention
Children at high risk for developing Pneumocystis infection should receive prophylactic therapy. Children at risk include those with hematologic malignancies, children who for other reasons are receiving intensive chemotherapy or high-dose corticosteroids, and children with organ transplants or advanced HIV infection. All children born to HIV-infected mothers should receive prophylaxis against Pneumocystis starting at age 6 weeks until HIV infection has been ruled out or, if the infant is infected for the first year of life, when the patient’s immunologic status will determine additional prophylaxis (see Chapter 41). The prophylaxis of choice is trimethoprim-sulfamethoxazole (150 mg/m2/d of trimethoprim and 750 mg/m2/d of sulfamethoxazole) for 3 consecutive days of each week. Alternatives to this prophylaxis regimen are described in Chapter 41.
Treatment
A. General Measures
Supplemental oxygen and nutritional support may be needed. The patient should be in respiratory isolation.
B. Specific Measures
Trimethoprim-sulfamethoxazole (20 mg/kg/d of trimethoprim and 100 mg/kg/d of sulfamethoxazole in four divided doses intravenously or orally if well tolerated) is the treatment of choice. Improvement may not be seen for 3–5 days. Duration of treatment is 3 weeks in HIV-infected children. Methylprednisolone (2–4 mg/kg/d in four divided doses intravenously) should also be given to HIV-infected patients with moderate to severe infection (partial oxygen pressure < 70 mm Hg or alveolar-arterial gradient > 35) for the first 5 days of treatment. The dosage is reduced by 50% for the next 5 days and further by 50% until antibiotic treatment is completed. If trimethoprim-sulfamethoxazole is not tolerated or there is no clinical response in 5 days, pentamidine isethionate (4 mg/kg once daily by slow intravenous infusion) should be given. Clinical efficacy is similar with pentamidine, but adverse reactions are more common. These reactions include dysglycemia, pancreatitis, nephrotoxicity, and leukopenia. Other effective alternatives utilized in adults include atovaquone, trimethoprim plus dapsone, and primaquine plus clindamycin.
Prognosis
The mortality rate is high in immunosuppressed patients who receive treatment late in the illness.
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