Parasites in the Liver
Bobbi S. Pritt, MD, MSc
9.1 INTRODUCTION
Parasites are an important cause of infections in the liver and biliary tract and are responsible for significant morbidity and mortality in many parts of the world.1,2 The spectrum of parasites includes single-celled protozoa, as well as multicellular roundworms (nematodes), tapeworms (cestodes), flukes (trematodes), and rarely, arthropods (Tables 9.1, 9.2, 9.3, 9.4, and 9.5). Several parasitic infections are classified by the World Health Organization (WHO) as neglected tropical diseases on the basis of their impact on billions of individuals living in developing countries.1 The Centers for Disease Control and Prevention (CDC) has also identified five neglected parasitic infections in the United States as priorities for public health action, of which four can involve the liver.3 This chapter will focus on the most important members of these groups that are likely to be encountered by the anatomic pathologist. It is important to note that the prevalence of these parasites varies widely with the travel history and immune status of the host. It is therefore essential to obtain a good clinical history when evaluating a specimen for parasites.
9.2 PROTOZOA
Entamoeba histolytica (amebiasis, amebic liver abscess)
Definition, etiology, and pathogenesis
The term amebiasis refers to infection with the parasitic ameba, Entamoeba histolytica. This protozoan causes primary intestinal infection and is a rare but important cause of liver disease.4,5 Transmission is through the fecal-oral route, in which individuals become infected primarily through ingestion of cysts in fecally contaminated food and water.6 It is, therefore, unsurprising that infection is most common in resource-limited settings where poor sanitary conditions exist. In developed countries, infection is usually limited to travelers and immigrants from endemic areas.4 It is estimated that 1% of the world’s population (74,000,000 individuals) is infected with E. histolytica and that there are approximately 50 million symptomatic cases and 100,000 deaths each year.7
Following ingestion of the infectious cyst form, the parasite excysts and releases a trophozoite, which colonizes the large intestine and replicates by binary fission.6US Some trophozoites eventually form
cysts, and both cysts and trophozoites are shed in the stool. If the cysts enter the environment and contaminate food or water, then the infection can be passed to other individuals. Infection can also be passed directly through oral-anal intercourse.
cysts, and both cysts and trophozoites are shed in the stool. If the cysts enter the environment and contaminate food or water, then the infection can be passed to other individuals. Infection can also be passed directly through oral-anal intercourse.
Table 9.1 Protozoan infections of the human liver | |||||||||||||||||||||||||||
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Table 9.2 Nematode (roundworm) infections of the human liver | |||||||||||||||||||||||||||
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Table 9.3 Cestode (tapeworm) infections of the human liver | |||||||||||||||
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The trophozoites are normally commensal organisms that feed on intestinal bacteria and do not cause disease. However, they are also capable of invading the bowel wall and causing amebic colitis. In rare cases, the trophozoites will enter the portal blood supply and disseminate to other organs. Importantly, dissemination can occur months to years after initial infection. The liver is the most common site of extraintestinal spread, with the right lobe being four times more likely to be involved than the left lobe because it receives the majority of venous drainage
from the right colon.8 Extraintestinal spread can also occur because of direct intraperitoneal spread.8 In the liver, invasive trophozoites release chemical mediators, which result in hepatocyte death and necrosis. The lesions are devoid of neutrophils unless there is secondary bacterial infection, and therefore the term abscess is a misnomer.8 Some have advocated the use of “pseudoabscess” as an alternate description for E. histolytica liver involvement.
from the right colon.8 Extraintestinal spread can also occur because of direct intraperitoneal spread.8 In the liver, invasive trophozoites release chemical mediators, which result in hepatocyte death and necrosis. The lesions are devoid of neutrophils unless there is secondary bacterial infection, and therefore the term abscess is a misnomer.8 Some have advocated the use of “pseudoabscess” as an alternate description for E. histolytica liver involvement.
Table 9.4 Trematode (fluke) infections of the human liver | ||||||||||||||||||||||||
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Table 9.5 Miscellaneous parasites/parasite-like organisms of the human liver | ||||||||||||||||||
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Clinical features
Greater than 80% of patients with E. histolytica intestinal infection do not have invasive disease and are asymptomatic.4,9 The symptoms of invasive disease range from self-limited watery diarrhea to fulminant necrotizing colitis. Amebic liver abscess occurs in less than 1% of infected individuals and presents as right-upper-quadrant pain and tender hepatomegaly.8 Fever is reported in greater than 90% of cases of amebic liver abscess and is commonly accompanied by profuse perspiration, chills, and weakness.8 Concomitant diarrhea is only reported in <30% of cases of amebic liver abscess, whereas jaundice is seen in approximately 5%.8 For reasons that are not well understood, amebic liver abscess is up to 20 times more common in males than in females and is rare in children.8 The presentation is usually acute, but occasionally is chronic and associated with significant anorexia and weight loss.9
Complications of amebic liver abscess include bacterial superinfection, spread of the lesion across the diaphragm, and rupture into the peritoneal, pleural, or pericardial cavities. Rupture is one of the most commonly reported complications, occurring in up to 20% of cases, and is associated with significant morbidity and mortality.8
Recognition of amebic liver abscess requires a high index of suspicion, particularly in nonendemic settings where this disease is rarely encountered. Laboratory findings include mild anemia, mild to moderate leukocytosis, and normal liver function tests.8 Less commonly, patients may have significant leukocytosis and elevated alkaline phosphatase and transaminases, particularly in the setting of multiple or large abscesses or with secondary bacterial infection. Material aspirated from liver lesions is usually sterile and rarely contains recognizable trophozoites. Furthermore, concurrent intestinal infection is seldom detected in patients with amebic liver abscess using stool microscopy or stool antigen testing. When organisms are identified by microscopy in stool specimens, they must be differentiated by the morphologically identical Entamoeba species, E. dispar, E. moshkovskii, and E. bangladeshi.4,10 Given these limitations, E. histolytica serology is the test of choice for confirmation of invasive disease and has a high sensitivity (>94%) and specificity (>95%) for detection of amebic liver abscess.9 Highly sensitive nucleic acid amplification tests have also been described for use on liver specimens and stool, but their use is limited to specialized reference centers.9
Imaging
Plain film radiographs demonstrate nonspecific findings such as hepatomegaly and right hemidiaphragm elevation (with right lobe involvement), whereas ultrasonography (US) and computed tomography (CT) are useful for defining the nature and extent of the lesions.8,11 Amebic liver abscesses appear as round to oval, hypoechoic lesions with well-defined margins on US and low-density lesions with internal fluid on CT.8
Gross findings
Liver lesions are usually solitary and located in the right lobe near the liver capsule.8 Multiple lesions may also occur. They can vary greatly in size, with extreme cases occupying 80% or more of the lobe.8,12 Lesions contain yellow-gray-red liquid material, which is commonly described as having an “anchovy paste” appearance (Fig. 9.1), whereas the wall has a fibrinous and shaggy appearance.12
Microscopic findings
As mentioned above, the liver lesion does not contain neutrophils unless there is bacterial superinfection. The center of the lesion consists of amorphous necrotic material, and there is generally little inflammation in the surrounding liver (Fig. 9.2).12 Trophozoites may be rare and are usually located in the fibrin at the periphery of the lesion near viable liver tissue. They range in size from 10 to 60 µm in greatest dimension in stool specimens, but rarely exceed 35 µm in biopsy or autopsy specimens.12 Trophozoites have a vacuolated cytoplasm that may contain engulfed erythrocytes and a small, round nucleus with peripheral rim of condensed chromatin and small central karyosome (Fig. 9.3). Cysts are not seen in invasive disease. Since the other Entamoeba spp. do not cause disseminated disease, identification of morphologically compatible trophozoites in liver in the appropriate histologic and clinical setting is diagnostic of amebic liver abscess.
Special stains and immunohistochemistry
Routine hematoxylin and eosin (H&E) is generally sufficient for identification. Periodic Acid Schiff staining may aid in locating amebae by staining their abundant cytoplasmic glycogen, although the deep staining of the trophozoites may obscure the nuclear details needed for confirmation. The rarely used Gridley ameba stain may also be useful for phagocytosed erythrocytes in the trophozoite cytoplasm, but is not commonly available.12
 Figure 9.1 Amebic liver abscess demonstrating necrotic parenchyma. The material removed from the abscess within the vial on the left has a characteristic “anchovy paste” appearance. Image courtesy of Dr. Mae Melvin, Dr. E. West, and the CDC Public Health Image Library. |
 Figure 9.2 Low-power magnification of an amebic liver abscesses consisting of paucicellular necrotic material (H&E, 40 ×). Despite the name, this entity does not generally contain neutrophils. |
 Figure 9.3 Trophozoite of Entamoeba histolytica in an amebic liver abscess demonstrating a characteristic nucleus with a peripheral condensed rim of chromatin and small central karyosome (arrow; H&E, 1,000 ×). Ingested red blood cells are also seen within the cytoplasm (arrow head). The cellular features are less clear than those generally seen in trichrome-stained stool preparations (inset, 1,000×), but are still recognizable. |
Differential diagnosis
The clinical and radiologic differential for amebic liver abscess is broad and includes bacterial abscess, tuberculosis, echinococcal cyst, and metastatic malignancy; these
entities can be excluded during histologic examination by the lack of neutrophils, granulomas, protoscoleces, and malignant cells, respectively. Rarely, trophozoites of the intestinal protozoal parasite, Balantidium coli, can disseminate to the liver and cause similar-appearing necrotic lesions. B. coli trophozoites can be differentiated from E. histolytica trophozoites by their larger size (40 to 100 µm in greatest dimension), large deeply basophilic kidney-bean-shaped macronucleus, and circumferential cilia (Fig. 9.4).13
entities can be excluded during histologic examination by the lack of neutrophils, granulomas, protoscoleces, and malignant cells, respectively. Rarely, trophozoites of the intestinal protozoal parasite, Balantidium coli, can disseminate to the liver and cause similar-appearing necrotic lesions. B. coli trophozoites can be differentiated from E. histolytica trophozoites by their larger size (40 to 100 µm in greatest dimension), large deeply basophilic kidney-bean-shaped macronucleus, and circumferential cilia (Fig. 9.4).13
 Figure 9.4 Trophozoite of Balantidium coli with circumferential cilia (arrow) and large “kidney-bean” shaped macronucleus (arrow head, H&E, 1,000 ×). |
Prognosis and treatment
Amebic liver abscess results in progressive and invariably fatal disease if untreated.8 Fortunately, rapid recognition and management has decreased mortality rates to 1% to 3%.9 Treatment of invasive intestinal disease and extraintestinal disease is with metronidazole or tinidazole, followed by paromomycin or iodoquinol to possibly eradicate intestinal carriage.14 Percutaneous drainage is only indicated for large liver abscesses in which there is a concern for rupture or when bacterial superinfection is suspected.8
Leishmania species (visceral leishmaniasis)
Definition, etiology and pathogenesis
Leishmaniasis is an infection of the reticuloendothelial system caused by protozoan hemoflagellate parasites in the genus Leishmania. There are both visceral and cutaneous forms of infection, and the type and severity depends on the infecting species and host immune response.6 Visceral leishmaniasis, also known as kala-azar, is a potentially fatal form of infection caused by parasites in the Leishmania donovani complex (e.g., L. donovani donovani, L. donovani infantum, L. donovani chagasi).1 The WHO classifies leishmaniasis as a neglected tropical disease, with an estimated 300,000 cases and over 20,000 deaths caused by visceral leishmaniasis each year.1 Visceral infection is found in 82 countries worldwide, with the predominance of cases reported from Brazil, East Africa, and India.1 Factors contributing to ongoing infection include poverty, crowding, and poor access to health care.
Transmission is through the bite of an infected female phlebotomine sandfly.6 Sandflies inject the infective form of the parasite (the flagellated promastigote) into the skin while taking a blood meal, and these forms enter host phagocytic cells through receptor-mediated phagocytosis. The parasite then converts to the nonmotile amastigote stage and replicates inside the host cell. In visceral leishmaniasis, the infected macrophages spread to the local lymph nodes and then disseminate hematogenously to the bone marrow, liver, and spleen, as well as other organs. Infected cells rupture because of ongoing parasite replication, releasing the amastigotes into the tissue to infect new phagocytic cells.6 Humans and canines are important reservoir hosts and serve as ongoing sources of infection.15
Clinical features
Clinical disease usually manifests 2 to 6 months after initial infection, but the organism may remain dormant for many years.15 Patients without preexisting immunity usually present with acute onset of high fever, chills, and malaise. In comparison, patients in Leishmania-endemic regions have some degree of immunity and commonly present with subacute or chronic disease, manifested by an insidious onset of fever, weight loss, weakness, and failure to thrive.6,15 Hepatosplenomegaly is present and may be massive in both acute and subacute/chronic disease.15 Secondary bacterial infections including pneumonia and tuberculosis are important contributions to overall mortality with visceral leishmaniasis. Cirrhosis is uncommon.15 Patients with HIV or those receiving immunosuppressive medications are at increased risk of severe disease and disease relapse.1,15 Visceral leishmaniasis is now recognized as an important opportunistic infection of late-stage HIV, with high coinfection rates reported from Ethiopia, India, and Brazil.1
Recognition of visceral leishmaniasis requires a high index of suspicion, particularly since latent infection may only become clinically apparent years after initial infection, or when patient immunity is compromised. Common laboratory findings in visceral leishmaniasis are normocytic anemia, leukopenia, thrombocytopenia, polyclonal hypergammaglobulinemia, and elevated erythrocyte sedimentation
rate. Liver transaminases are often mildly elevated, but serum bilirubin is usually within normal limits.15 Definitive diagnosis is made through visualization of amastigotes in tissue aspirates or biopsies and by culture or molecular testing of involved tissues.6,16 Testing for antiparasitic antibodies or parasite antigens can also be performed. Microscopic examination of bone marrow smears has an estimated 60% to 80% sensitivity for diagnosis of visceral leishmaniasis, whereas the sensitivity of examining a splenic aspirate exceeds 95%. Splenic aspirate is rarely performed in nonendemic settings because of the risk of fatal hemorrhage but is a widely used and relatively safe procedure when performed by experienced practitioners.17 Parasites are less commonly seen in the liver, lymph nodes, and buffy coat of peripheral blood.16
rate. Liver transaminases are often mildly elevated, but serum bilirubin is usually within normal limits.15 Definitive diagnosis is made through visualization of amastigotes in tissue aspirates or biopsies and by culture or molecular testing of involved tissues.6,16 Testing for antiparasitic antibodies or parasite antigens can also be performed. Microscopic examination of bone marrow smears has an estimated 60% to 80% sensitivity for diagnosis of visceral leishmaniasis, whereas the sensitivity of examining a splenic aspirate exceeds 95%. Splenic aspirate is rarely performed in nonendemic settings because of the risk of fatal hemorrhage but is a widely used and relatively safe procedure when performed by experienced practitioners.17 Parasites are less commonly seen in the liver, lymph nodes, and buffy coat of peripheral blood.16
In the United States, bone marrow examination is commonly paired with culture, serology, and molecular analysis at the CDC. It is important to contact the CDC before obtaining a biopsy so that they can provide a collection instructions and a kit for specimen transport to their laboratories; further information is available at http://www.cdc.gov/parasites/leishmaniasis/health_professionals/.
Imaging
Ultrasonography and CT usually reveal an enlarged liver and spleen. While the spleen enlarges at a relatively constant rate (approximately 1 inch/month) until it fills the abdomen, the liver undergoes less predictable enlargement and may even be normal in size.11
Gross findings
The liver is generally enlarged and has a smooth capsule.18 The cut surface may be firm with a nodular appearance in cases with significant fibrosis.
Microscopic findings
The predominant microscopic finding is Leishmania amastigotes within macrophages (Fig. 9.5). Amastigotes are 2 to 5 µm in diameter and have a small nucleus and rod-shaped kinetoplast. These important morphologic features are difficult to appreciate in formalin-fixed tissues, but are often more apparent on air-dried aspirates and smears (Fig. 9.6). Other histologic findings include sinusoidal enlargement, lymphoplasmacytic inflammation in the lobules and portal tracts, nonnecrotizing granulomatous inflammation, ballooning degeneration of hepatocytes, and focal cellular necrosis. Diffuse fibrosis (so-called “Roger cirrhosis”) has also been described, particularly from cases of visceral leishmaniasis in India.15,18,19
 Figure 9.5 Visceral Leishmaniasis of the liver, in which small intracellular objects are seen within Kupffer cells (arrows, H&E, 400 ×; inset 1,000 ×). It is challenging to make out the characteristic features in formalin-fixed paraffin-embedded sections. |
 Figure 9.6 Giemsa-stained air-dried preparation of a liver aspirate showing a macrophage containing numerous Leishmania sp. amastigotes (1,000 ×). Each amastigote contains a small oval-to-round nucleus and a rod-shaped kinetoplast (arrows). |
Special stains and immunohistochemistry
Although amastigotes are readily apparent using H&E, the characteristic nucleus and kinetoplast may be difficult to identify, thus raising the possibility of other small intracellular organisms such as yeasts. Gomori methenamine-silver (GMS) is useful for differentiating amastigotes from yeasts since they are GMS negative, whereas the Brown and Hopps tissue Gram stain and combined H&E/Jones silver stain are useful for highlighting the kinetoplast. Other stains such as periodic acid-Schiff (PAS), Giemsa, and Wilder reticulum stain offer no additional diagnostic advantage.
Molecular findings
Molecular amplification and sequencing methods are commonly used at specialized reference centers such as the CDC for detection and species identification. These methods are best performed on fresh tissue and culture isolates, but may also be performed on formalin-fixed paraffin-embedded tissues.
Differential diagnosis
The primary clinical differential diagnosis for patients with fever and recent travel to a Leishmania-endemic setting includes malaria, typhoid, and tuberculosis.17 On microscopic examination, the differential diagnosis includes other small intracellular objects such as Histoplasma capsulatum (also found inside of histiocytes), Toxoplasma gondii, and Trypanosoma cruzi. As mentioned earlier, yeasts are GMS positive whereas amastigotes are GMS negative. Toxoplasma gondii can infect any nucleated cell and appears as tissue cysts and tachyzoites. The tachyzoites are 2 to 5 µm in size and may have a similar appearance to Leishmania amastigotes (Fig. 9.7), but can be differentiated by their arc shape (not always seen in tissue sections) and lack of a kinetoplast. Commercially available T. gondii immunohistochemistry may also be helpful. Leishmania spp. amastigotes are indistinguishable from amastigotes of Trypanosoma cruzi, but the latter are rarely seen in the liver and generally form larger collections of amastigotes. Clinical correlation is useful for differentiating infection with the two parasites.
 Figure 9.7 Toxoplasmosis in a liver biopsy demonstrating collections of intracellular and extracellular tachyzoites within the liver parenchyma (arrow, H&E, 400 ×). On higher magnification (inset, bottom right, 1,000×), the oval-to-arc shape of the tachzyoites can be appreciated. Because of their small size, the organisms are best highlighted using T. gondii immunohistochemistry (inset, above right, 1,000×). |
Prognosis and treatment
Visceral leishmaniasis is a potentially fatal disease that should be treated promptly. Treatment options are potentially toxic and availability may be limited; therefore treatment should be provided by an infectious disease physician or other specialist. The conventional therapy is a pentavalent antimonial compound (e.g., Pentostam), which is available through the CDC to U.S. physicians.14 Parental liposomal amphotericin B and miltefosine are additional options. Antiretroviral therapy should be considered for HIV coinfected patients since it improves survival and decreases the risk of relapse.6
Plasmodium falciparum (malaria)
Definition, etiology, and pathogenesis
Malaria is caused primarily by four species in the genus Plasmodium: P. falciparum, P. vivax, P. ovale, and P. malariae.20 Of these, Plasmodium falciparum is the deadliest species to cause human malaria and is found in the tropics and subtropics worldwide. The WHO estimates that 3.2 billion individuals are at risk of infection worldwide.21 In 2015, there were approximately 214 million cases and over 400,000 deaths.21 The highest morbidity and mortality is in nonimmune individuals (e.g., travelers) and children under the age of 5 years who live in endemic areas (primarily Sub-Saharan Africa).
Transmission to humans occurs primarily through the bite of an infected female Anopheles mosquito. Less commonly, the organism is transmitted through congenital infection and blood transfusion.6,20 Mosquitoes inject the infective form of the parasite (the sporozoite) into the blood while feeding, and this form travels to the liver to undergo a short-term asexual reproductive phase in hepatocytes.6 Within 7 to 10 days, parasites are then released into the blood stream to infect and replicate within erythrocytes. With P. ovale and P. vivax infection, some parasites also remain behind in the liver in a dormant phase called a hypnozoite, which can reactivate months to years later.6 Within erythrocytes, parasites feed on the host’s hemoglobin and form hemozoin as a waste product. After 48 to 72 hours of replication, the infected erythrocyte bursts and newly formed parasites are released into the blood to infect new erythrocytes.6US Some parasites also form gametocytes, which are the infective stage for the mosquito; the parasite life cycle continues when gametocytes are taken up by a female Anopheles during a blood meal.6
There are several reasons why Plasmodium falciparum is responsible for the greatest burden of human morbidity and mortality. Unlike the other species, it is capable of infecting all stages of erythrocytes and
can therefore reach very high levels of parasitemia. Furthermore, P. falciparum-infected erythrocytes will adhere to other erythrocytes (i.e., cytoadherence) and sequester in the microcirculation, resulting in blood-flow sludging and hypoxia. Cytoadherence and sequestration does not occur with other Plasmodium species.
can therefore reach very high levels of parasitemia. Furthermore, P. falciparum-infected erythrocytes will adhere to other erythrocytes (i.e., cytoadherence) and sequester in the microcirculation, resulting in blood-flow sludging and hypoxia. Cytoadherence and sequestration does not occur with other Plasmodium species.
Clinical features
Clinical symptoms typically appear 2 to 3 days after parasites are released from the liver into the peripheral blood (total time: 9 to 13 days after infection). The clinical manifestations may mimic many other infections and therefore malaria must be considered in the differential in patients with recent exposure to malaria-endemic areas. The classical feature is the fever paroxysm, characterized by abrupt onset of chills, followed by fever, and then sweats.6,20 Each species is associated with a characteristic fever cycle (e.g., every 48 hours or less with P. falciparum infection) that peaks with erythrocyte rupture and release of pyrogens into the blood, although this is not reliably seen. Other symptoms include myalgia, headache, anorexia, nausea, vomiting, diarrhea, and shortness of breath.20 Falciparum malaria commonly presents with gastrointestinal symptoms and progresses to high fever, hepatic tenderness, hepatomegaly, jaundice, and splenic tenderness with ongoing erythrocyte rupture and sequestration of infected cells in visceral capillaries.22 Complications of falciparum malaria include hypotension, pulmonary edema, hypoglycemia, disseminated intravascular coagulopathy, glomerulonephritis, mental status alterations, seizures, and death. Adverse fetal outcomes are also seen in pregnancy.22 Laboratory testing commonly reveals anemia and elevated bilirubin and transaminases.
Definitive diagnosis is usually made by detecting intact parasites, or their DNA in peripheral blood. Microscopic examination of Giemsa-stained thin and thick blood films is considered the gold standard diagnostic test and allows for calculation of percent parasitemia.20 Commercially available rapid diagnostic tests are also commonly used for detection of Plasmodium antigens in peripheral blood, but are less sensitive than blood film examination, particularly for non-falciparum species and low levels of parasitemia. Finally, nucleic acid amplification tests such as polymerase chain reaction (PCR) generally offer increased sensitivity over blood films and are useful for detecting low-level parasitemia and mixed infections. However, they are not widely available and limited to specialized research facilities and reference labs. Serologic testing is used primarily for blood donor screening and has no role for diagnosis of acute infection.20
Gross findings
The spleen is commonly enlarged, particularly in patients with repeated or long-standing infections, and perisplenic fibrosis and adhesions may be present.11 There is variable liver enlargement, and the parenchyma may have a diffuse slate-gray discoloration because of hemozoin pigment accumulation in Kupffer cells.22 Patients with chronic falciparum malaria may have a lobular pattern of pigmentation because of hemozoin deposition in portal tracts.
Microscopic findings
The most common microscopic findings in the liver and other organs are vascular congestion and malaria pigment (hemozoin)-laden erythrocytes and phagocytes within capillaries (Fig. 9.8). Hemozoin appears as granular clumps of variably sized brown-black pigment that is birefringent using polarized light.22,23 Intraerythrocytic parasites may also be seen; on H&E, they appear as faintly staining, blue-gray, spherical masses measuring 2 to 4 µm, with one or more associated pigment clumps.22 The infected erythrocytes are often nearly depleted of hemoglobin and are very pale. A study of autopsy-diagnosed malaria deaths detected involvement of the liver in 78% of cases, whereas involvement of the brain, spleen, lungs, and myocardium were seen in 100%, 67%, 56%, and 43% of cases, respectively.24
Differential diagnosis
The clinical differential diagnosis of malaria is broad and includes other febrile illnesses such as bacteremia,
dengue, African trypanosomiasis, and cholera. In histologic sections, the primary differential is formalin pigment, which has a similar appearance to hemozoin pigment. Formalin pigment may deposit in congested tissues, especially when phosphate-buffered neutral formalin is not used. Like hemozoin, it appears as granular brown-black clumps and is birefringent with polarized light. However, it is usually extracellular and commonly rod-shaped, whereas hemozoin is intracellular, associated with intraerythrocytic parasites, and spherical.
dengue, African trypanosomiasis, and cholera. In histologic sections, the primary differential is formalin pigment, which has a similar appearance to hemozoin pigment. Formalin pigment may deposit in congested tissues, especially when phosphate-buffered neutral formalin is not used. Like hemozoin, it appears as granular brown-black clumps and is birefringent with polarized light. However, it is usually extracellular and commonly rod-shaped, whereas hemozoin is intracellular, associated with intraerythrocytic parasites, and spherical.
 Figure 9.8 Liver biopsy in a fatal case of malaria due to Plasmodium falciparum (H&E, 400 ×). Evidence of the parasites is seen primarily as hemozoin pigment (inset, 1,000×) within erythrocytes and Kupffer cells (arrow). Faintly staining blue-gray intraerythrocytic parasites may also be seen (arrow head). |
Prognosis and treatment
Malaria is a potentially life-threatening disease, and treatment should be begun promptly.20 When diagnosed early, the prognosis is very good, but untreated P. falciparum is associated with high mortality. Treatment varies by the infecting species, the region where infection was acquired, percent parasitemia, clinical status (including comorbidities and pregnacy), and drug allergies.6,20 Most P. falciparum worldwide is resistant to chloroquine, and therefore other drugs such as atovaqunone-proguanil (Malarone), artemether-lumefantrine (Coartem), quinine, and mefloquine must be used.14 Although uncomplicated P. falciparum disease can be treated with oral agents, severe malaria is usually treated with parenteral quinine, quinidine, or artimisinin agents.14 Exchange transfusion may be considered for patients with percent parasitemia of 10% or higher although it is no longer recommended by the CDC.20 Primaquine is added to treatment regiments for P. ovale and P. vivax malaria to eradicate the dormant hypnozoite stage in the liver.14
Cryptosporidium species (cryptosporidiosis)
Definition, etiology, and pathogenesis
Cryptosporidium are small intracellular apicomplexan parasites that infect the intestinal and biliary epithelium of humans and a wide array of other animals.6 They were previously classified as coccidia along with Cyclospora cayetanensis and Cystoisospora (Isospora) belli, but are now known to be more closely related to the gregarines, which are parasites of invertebrates.25 Nearly 20 Cryptosporidium species have been reported to infect humans. The two most common species are C. hominis (a human/anthroponotic parasite) and C. parvum (a zoonotic parasite).25
Cryptosporidium is found worldwide and causes human disease in both tropical and temperate climates. There are an estimated 750,000 cases of cryptosporidiosis each year in the United States alone, with the vast majority thought to be undiagnosed or unreported.25 Transmission is through the fecal-oral route. Humans become infected through ingestion (and possibly inhalation) of infective oocysts in contaminated food or drinking and recreational water sources, as well as through direct contact with infected humans or animals.25 Many outbreaks in the United States have been associated with swimming pools, waterparks, day care centers, petting zoos, and faulty municipal water supplies.25 Patients with AIDS and other immunocompromised states are at increased risk for acquiring infection and developing prolonged or severe disease.
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