CMR 10 1 19

CLINICAL MICROBIOLOGY REVIEWS, Jan. 1997, p. 19–34 Vol. 10, No.
1
0893-8512/97/$04.0010
Copyright q 1997, American Society for Microbiology
Biology of Isospora spp. from Humans, Nonhuman Primates,

and Domestic Animals
DAVID S. LINDSAY,1* J. P. DUBEY,2 AND BYRON L. BLAGBURN1
Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, Alabama 36849-5519,1 and
Parasite Biology and Epidemiology Laboratory, USDA Agricultural Research Service, Beltsville, Maryland 207052
INTRODUCTION .........................................................................................................................................................19
TAXONOMIC PROBLEMS ........................................................................................................................................20
Isospora hominis.........................................................................................................................................................20
Isospora bigemina.......................................................................................................................................................20
LIFE CYCLE .................................................................................................................................................................21
Ultrastructure............................................................................................................................................................21
Sporogony...................................................................................................................................................................21
Excystation.................................................................................................................................................................21
Endogenous Development ........................................................................................................................................21
Extraintestinal Stages ..............................................................................................................................................21
DEVELOPMENT IN VITRO ......................................................................................................................................23
DIAGNOSIS OF COCCIDIAL INFECTIONS .........................................................................................................23
ISOSPORA INFECTIONS OF HUMANS..................................................................................................................23
ISOSPORA BELLI INFECTIONS...............................................................................................................................23
Life Cycle of I. belli ...................................................................................................................................................25
Intestinal Infections in AIDS Patients...................................................................................................................25
Extraintestinal Infections in AIDS Patients .........................................................................................................26
Infections in Other Immunocompromised Hosts .................................................................................................27
Infections in Immunocompetent Hosts..................................................................................................................27
Microscopic Lesions Due to I. belli ........................................................................................................................27
Diagnosis....................................................................................................................................................................27
Treatment...................................................................................................................................................................27
ISOSPORA INFECTIONS OF NONHUMAN PRIMATES .....................................................................................28
I. arctopitheci Infections............................................................................................................................................28
Diagnosis and Treatment.........................................................................................................................................29
ISOSPORA INFECTIONS OF DOGS AND CATS...................................................................................................29
Infections of Dogs .....................................................................................................................................................29
I. canis infections ..................................................................................................................................................29
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The I. ohioensis complex.......................................................................................................................................29
Infections of Cats......................................................................................................................................................29
I. rivolta infections.................................................................................................................................................29
I. felis infections ....................................................................................................................................................29
Diagnosis....................................................................................................................................................................30
Treatment...................................................................................................................................................................30
ISOSPORA SUIS INFECTIONS OF PIGS ................................................................................................................30
Clinical Signs and Pathogenicity............................................................................................................................30
Immunity....................................................................................................................................................................31
Epidemiology .............................................................................................................................................................31
Diagnosis....................................................................................................................................................................31
Treatment and Control ............................................................................................................................................31
FUTURE DIRECTIONS ..............................................................................................................................................31
REFERENCES ..............................................................................................................................................................31
INTRODUCTION spora but is now used to include Cryptosporidium species, Tox-

oplasma gondii, and other members of the suborder Eimerio-
Isospora species are protozoan parasites that are in the phy- rina. Coccidia have complex life cycles. Members of the genus
lum Apicomplexa. They are members of the group of organ- Isospora can complete their entire life cycle in a single host.
isms referred to as coccidia. The term “coccidia” was once used Several have evolved the ability to use a paratenic host (trans-
to refer primarily to members of the genera Eimeria and Iso- port host) in their developmental cycle.
Coccidia are identified to the species level based on the
* Corresponding author. Mailing address: Department of Pathobi- structure of their sporulated oocyst stage. The size, shape,
ology, College of Veterinary Medicine, 166 Greene Hall, Auburn Uni- color, texture, and type of internal contents are important
versity, Auburn, AL 36849-5519. Phone: (334) 844-2701. Fax: (334) features used in identifying coccidial oocysts. The oocyst stage
844-2652. E-mail: [email protected]. is an environmentally resistant stage which is excreted in the
19
20 LINDSAY ET AL. CLIN. MICROBIOL. REV.
Isospora species can cause serious disease in humans and

nursing pigs. Clinical disease is seldom seen in nonhuman
primates, dogs, or cats. Isospora species do not produce disease
in horses, domestic ruminants, rabbits, or domestic poultry,
and reports of isosporan oocysts in the feces of these hosts
probably represent pseudoparasites that originated in feed
contaminated with wild-bird feces.
TAXONOMIC PROBLEMS
The sporulated oocysts of Isospora species resemble the
sporulated oocysts of the related genera, Toxoplasma, Ham-
mondia, Besnoitia, Frenkelia, and Sarcocystis. This resemblance
led to much confusion during the period from the late 1800s to
the mid-1970s, when the life cycle of these parasites was not
known. We will consider the two most notable examples in
which these problems cause confusion.
Isospora hominis
Human isosporiasis is caused by Isospora belli, which is a true
member of the genus Isospora (187). Many early reports of
human coccidiosis refer to infection with a parasite described
as Isospora hominis. I. hominis is actually a species of Sarco-
cystis, and the name is a synonym for Sarcocystis hominis or S.
suihominis, species acquired by ingesting rare or raw infected
beef or pork, respectively. There is no structural means of
differentiating these two species of Sarcocystis in human fecal
samples or in intestinal biopsy specimens. Intestinal sarcocys-
tosis in humans can be a serious disease (18), unlike in other
animals, which normally show no clinical signs. In many early
reports, it is impossible to determine whether the authors are
describing I. belli or a Sarcocystis species. An example of this
confusion can be found in the pioneering work on coccidiosis,
FIG. 1. Sporulated oocysts of I. belli. (a) Oocyst containing two sporocysts Coccidia and Coccidiosis of Domesticated, Game and Labora-
(arrows). Note the oocyst wall (open arrow), the sporozoites (S) in the sporo- tory Animals and of Man, by E. R. Becker, published in 1934
cysts, and the nucleus of a sporozoite (arrowhead). (b) A Caryospora-like oocyst (7). Becker includes line drawings that demonstrate sporula-
of I. belli containing one sporocyst (arrow). Note the oocyst wall (open arrow), a tion of I. belli but refers to the parasite as I. hominis. The only
sporozoite (S), and sporocyst residuum (R). The oocysts are unstained. Magni-
fication, 31,900. Courtesy of Donald Duszynski, University of New Mexico. way one can be certain if early authors are describing I. belli or

I. hominis (Sarcocystis) is to examine the drawings or photomi-
crographs if present. If none are included, a definitive identi-
host feces. Most oocysts are excreted unsporulated and must fication may not be possible.
undergo a developmental period (sporulation) outside the host
before they are sporulated and become infectious. Sporulated Isospora bigemina
oocysts of Isospora species are characterized by having two
sporocysts. Each sporocyst contains four sporozoites (Fig. 1a). In the early and mid-1900s, it was thought that dogs and cats
The sporocyst may or may not have a Stieda body. A Stieda shared the same species of coccidia (7, 8). The name Coccid-
body is a proteinaceous plug found at one end of the sporocyst. ium bigemina had been given by Stiles in 1891 to a parasite
A sub-Stieda body may be present directly beneath the Stieda developing in the lamina propria of a dog (39). The organism
body. Life cycle studies indicate that species of Isospora with a was placed in the genus Isospora in 1906. Based on the location
Stieda body are generally monoxenous and confined to the of the sporocysts, the parasite observed by Stiles was obviously
intestines whereas species that lack a Stieda body often can use a species of Sarcocystis. Wenyon believed that there were two
paratenic hosts, may have latent stages in the host, and may be “races” of I. bigemina that could be differentiated based on size
facultatively heteroxenous. All important and valid species of and called them the large and small races of I. bigemina (188).
Isospora that infect humans, nonhuman primates, dogs, cats, The large race developed in the lamina propria and was ex-
and domesticated mammals lack a Stieda body in their sporo- creted as sporulated oocysts or sporocysts (i.e., a Sarcocystis
cysts. Generic names of Levinia (34) and Cystoisospora (64) species), whereas the small race developed in the epithelial
have been proposed for the Isospora species that utilize cells of the small intestine and was excreted as unsporulated
paratenic hosts, but these generic names have not gained wide- oocysts. It is clear now that the small race of I. bigemina in dogs
spread acceptance. is actually Hammondia heydorni, an obligatorily heteroxenous
About 248 species of Isospora had been described prior to parasite (81). It is impossible to determine what the small race
1986 (95). Most of these species are known only from oocysts of I. bigemina in cats actually was because its oocysts are struc-
found in the feces of the host animal. Until life cycle and turally indistinguishable from those of Toxoplasma gondii,
cross-transmission studies are conducted to determine more Hammondia hammondi, and Besnoitia species. Reports of the
about the biology of these species, the species validity of many large race of I. bigemina in cats, other animals, and humans
of these coccidians is questionable. also actually refer to Sarcocystis species.
VOL. 10, 1997 BIOLOGY OF ISOSPORA SPP. 21
LIFE CYCLE freed from the oocyst wall. Pretreatment of oocysts with so-
dium hypochlorite solution (109, 165) or cystine hydrochloride
Coccidial life cycles are complex, with both exogenous and (128) under CO2 enhances excystation of intact oocysts. Expo-
endogenous cycles present. Paratenic (transport) hosts may sure of oocysts or sporocysts to sodium taurocholate solution
also be employed. (0.75%, wt/vol), bile (5%, vol/vol), or sodium taurocholate
(0.75%, wt/vol) plus trypsin (0.25%, wt/vol) will cause activa-
Ultrastructure tion of sporozoites. If bile is used, the host animal from which
the bile is obtained is of little importance (128). Sporozoites
Transmission electron microscopy has been widely used to become motile within the sporocysts and tumble or glide
examine the developmental stages of coccidial parasites. The around one another. This movement is not continuous but is
entire life cycle of I. suis in pigs has been described by using interrupted by periods of inactivity. Eventually, the sporocyst
TEM, and it was similar to that described for Eimeria species wall opens along four plate-like junctions (148, 165, 166) and
(123). Notable differences are present in the structure of the the sporozoites will exit through the opening that is formed.
sporozoite stages of Isospora and Eimeria species. The sporo- Sporozoites exit oocysts through indentations or fractures that
zoites of mammalian Isospora species contain one or two in- form in one or both ends of the oocyst wall (128, 165).
clusions, termed crystalloid bodies, that are composed of par-
ticles similar in appearance to beta-glycogen particles, whereas
the sporozoites of Eimeria species contain one or two inclu- Endogenous Development
sions, termed refractile bodies, that appear to be protein- The endogenous life cycle of mammalian Isospora species is
aceous. These inclusions are generally lost in the process of somewhat different from that of typical Eimeria species (Fig.
conversion from sporozoite to merozoite stage (59, 122) in vivo 2). Sporozoites enter cells in the intestine but usually do not
but may persist in parasites cultivated in vitro (107). form rounded uninucleate trophozoites. Some sporozoites
and/or merozoites leave the intestine and form dormant cyst
Sporogony stages (hypnozoites) in extraintestinal tissues (31, 40, 149).
Sporogony is the production of infective sporozoites within Intestinal sporozoites may retain their elongate sporozoite
sporocysts inside the oocyst. Sporogony usually occurs outside shape, become binucleate, and divide by endodyogeny to form
the host and is the exogenous phase of the coccidial life cycle. two daughter merozoites. These daughter merozoites divide by
Sporogony is dependent on moisture, temperature, and ade- endodyogeny an indefinite number of times (27, 59, 107, 122,
quate oxygen. Several controlled studies have been conducted 123). For this reason, the number of sequential asexual mer-
on the sporogony of Isospora oocysts from dogs (94, 117), cats ogonous cycles cannot be determined, and developmental
(160), and pigs (108). These studies indicate that temperatures stages are referred to as structural types instead of generations.
greater than 408C or less than 208C inhibit sporulation of the Eventually, multinucleate meronts are formed. These meronts
oocysts. Rapid sporulation (,16 h) of oocysts occurs at 30 or are elongate and retain their merozoite shape. Several meronts
378C. Structural events that occur during sporogony are similar may occur in the same host cell, and, with time, sexual stages
for all species. Oocysts are excreted in the feces, and they are formed. Microgamonts are multinucleate and produce bi-
usually have a contracted sporont. A few oocysts will be ex- flagellated microgametes (60). Macrogamonts lack the highly
creted in the sporoblast stage (two-celled stage). As the nu- eosinophilic wall-forming bodies found in most Eimeria spe-
cleus of the sporont divides, a clear nuclear streak is formed, cies, and the oocyst wall is usually inconspicuous. Microga-
nuclear division occurs, and the sporont divides to form two monts and macrogamonts may coexist in the same host cell.

uninucleate sporoblasts. Nuclear division occurs again, and the The endogenous life cycles in animals that ingest oocysts and
nuclei are visible as clear areas at the poles of the sporoblast. in those that ingest paratenic hosts are similar (35, 38). The
Nuclear pyramids may be seen at the poles of the sporoblasts. prepatent period may be shortened in infections that are ini-
The sporoblasts become elongate and form the sporocyst tiated by consumption of paratenic hosts (35, 38, 43, 65).
stage. Nuclear division occurs again, and the outline of devel-
oping sporozoites soon becomes visible. When the sporozoites Extraintestinal Stages
are fully visible, the oocyst is considered to be sporulated. A
small percentage (,2%) of oocysts are Caryospora-like and Extraintestinal stages occur in the tissues of the definitive
contain one sporocyst which encloses eight sporozoites (96, host in canine and feline Isospora species (31, 40) and I. belli of
108, 121, 193) (Fig. 1b). Heat treatment of unsporulated I. humans (130, 149) (Fig. 3 and 4). Instead of undergoing the
rivolta oocysts at 508C for 5 min increased the numbers of normal developmental cycle in the intestinal tract, some sporo-
Caryospora-like oocysts that were produced after sporulation zoites (merozoites?) leave that site and invade extraintestinal
(121). These Caryospora-like oocysts of I. rivolta were infec- sites in the host. Mesenteric lymph nodes are most often in-
tious for mice (paratenic hosts) and cats. Oocysts collected volved, but other tissues such as the liver, spleen, and tracheo-
from cats inoculated with Caryospora-like oocysts were Isospo- bronchial and mediastinal lymph nodes can be infected. Parasites
ra-like after sporulation, indicating that heat treatment did not are usually found as single organisms resembling sporozoites, but
induce a stable mutation. The biological significance of these some division may occur at these extraintestinal sites, and up to 15
Caryospora-like oocysts is unknown. parasites have been observed in an infected cell (40). The infected
host cells probably are macrophages.
Mice, rats, hamsters, dogs, cats, cattle, sheep, and camels
Excystation
have been shown to be paratenic hosts for several Isospora
Excystation is the process by which sporozoites are released species (31, 40, 42, 55, 65, 78, 82, 154, 192). Sporozoites excyst
from the sporocysts/oocysts. The process is basically the same from oocysts and invade extraintestinal tissues. Mesenteric
for all mammalian Isospora species studied to date (46, 47, 109, lymph nodes are most often infected; other tissues such as the
128, 165, 166) and is similar to what occurs in Sarcocystis spp. spleen, liver, and skeletal muscles are sometimes parasitized.
(15) and T. gondii (22). Studies have been conducted with Parasites are most often found as single organisms; parasite
intact oocysts or with sporocysts that have been mechanically division at these sites has not been confirmed (65). For this
FIG. 2. Developmental stages of I. rivolta in cats and mice. (A, B, G to J, M, and N) Smears fixed in methanol and stained with Giemsa. (C to F) Sections stained
with iron hematoxylin (C, D, F) and by the PAS reaction (E). (K and L) Smears not fixed or stained. (A and C) Division of meronts by endodyogeny (arrow). (B) An
immature meront with four nuclei. (D) Two multinucleated meronts (arrows) in the same parasitophorous vacuole. (E) PAS-positive granules (arrow) in merozoites.
(F) Meronts with different-sized merozoites (arrows). (G) An immature microgamont with many nuclei (arrow). (H) Several mature microgametes (arrow). (I)
Macrogamont with a large nucleus (arrow) and prominent nucleolus. (J) An unsporulated oocyst. (K) Unsporulated oocyst containing a contracted sporont. (L)
Sporulated oocyst containing two sporocysts with sporozoites (arrows). (M) Extraintestinal zoites in the mesenteric lymph node of a cat. One zoite is in a host cell
(arrow), and one has ruptured out of its host cell (arrowhead). (N) Extraintestinal tissue cyst containing a single zoite (arrow) in the mesenteric lymph node of a mouse.
Magnifications, 32,300. Reprinted with permission of the publisher from reference 38.
22
reason, it is more accurate to refer to the host as a paratenic DIAGNOSIS OF COCCIDIAL INFECTIONS
rather than an intermediate host.
Transmission electron microscopy reveals that the sporozo- Coccidia are often members of the normal fauna of animal
ites are inside a parasitophorous vacuole (PV) (14, 42, 129) hosts, and the mere presence of oocysts in the feces is not
(Fig. 3). The appearance of the contents of the PV changes always indicative of clinical infection (103). Demonstration of
during the course of infection. At 1 day postinoculation (p.i.) oocysts in fecal samples is the method of choice for identifying
sporozoites are surrounded by a PV membrane that has a wavy coccidian infections in animals. Fecal flotation in Sheather’s
appearance, and the PV contains numerous vesicles. By 7 days sugar solution (500 g of sugar, 320 ml of water, 6.5 g of phenol)
p.i., there is an electron-dense granular layer immediately be- is most often used, but other flotation solutions such as zinc
neath the PV membrane. Filaments or tubules may also be sulfate or saturated sodium chloride can be used. If large
present in this layer. It is this granular layer that appears as a amounts of fecal fat are present, other concentration tech-
thick wall by light microscopy. Membrane-bound, electron- niques such as formalin-ether or ethyl acetate sedimentation
dense granules, apparently of host cell origin, are present at may be more applicable because of the removal of fecal fat by
the margins of the PV membrane. The sporozoite lies in the the solvents. No special stains are needed to observe the oo-
center of the cyst. Sporozoites increase in size during the cysts. However, special stains are often used to identify human
course of infection and accumulate polysaccharide granules in infections with I. belli.
their cytoplasm. It is because of the presence of these polysac- The diagnosis of coccidiosis in animals is based on clinical
charide (amylopectin?) granules that the sporozoites stain pos- signs (diarrhea), history, evaluation for potential copathogens,
itively in the periodic acid-Schiff (PAS) reaction. The crystal- and demonstration of coccidial oocysts of a pathogenic species
loid bodies of sporozoites remain intact during the course of in the animals’ feces. Knowing the actual numbers of oocysts
the infection. present in the feces is of little help in determining if clinical
Disease does not occur in paratenic hosts (38). Parasites disease is present.
remain viable for at least 23 months in extraintestinal tissues of Demonstration of parasite stages in tissue samples collected
mice (38). When the definitive host ingests a paratenic host, at necropsy in animal infections or in intestinal biopsy speci-
the subsequent prepatent period may be shorter than when mens or samples collected at autopsy in human infections is
infections are initiated by oocysts. The number of oocysts pro- also suitable for obtaining a diagnosis. Special stains are of
duced by the definitive host and the patent period are similar little value in identifying coccidial stages. Familiarity with the
to those in oocyst-induced infections (43). The tissues of paratenic appearance of the stages is far more useful in locating them in
hosts are not infectious for other paratenic hosts (38). histological samples (Fig. 2).
An interesting interaction occurs in mice experimentally in-
fected with I. felis and then challenged with Babesia microti. Mice ISOSPORA INFECTIONS OF HUMANS
infected with I. felis 28 days before infection with B. microti do not
develop B. microti antibodies but are completely resistant to in- I. natalensis has been reported in humans (48), but little is
fection with B. microti (176). Partial resistance to B. microti can be known about this parasite. It was found in the feces of a
achieved by transfer of spleen cells from mice infected with I. felis. 21-year-old patient suffering from amebic dysentery and other
Treatment of I. felis-infected mice with a monoclonal antibody to protozoal and helminth infections. Oocysts of I. natalensis were
L3T41 cells increases their susceptibility to B. microti infection observed on four consecutive days (after the patient had been
(176). These results suggest that cell-mediated immunity is in- treated for amebic dysentery), and the I. natalensis infection
volved in the observed nonspecific resistance. was self-limiting. Infection with this parasite has apparently not

been observed since 1953, when it was described. Its oocysts
DEVELOPMENT IN VITRO resemble those of the I. ohioensis complex seen in dogs, I.
rivolta of cats, and I. suis of pigs, but they are slightly larger
Several mammalian Isospora species have been grown in cell (Table 1).
cultures (54, 56, 57, 58, 102, 107). Primary cell cultures from I. chilensis described from humans in South America is not
the host animal generally support the most numerous and most a valid name; it is a species of Sarcocystis. As mentioned above,
chronologically advanced parasite stages. Sporozoites are ob- I. hominis is also no longer considered a valid name because it
tained from excysted oocysts and used as an inoculum. Sporo- too is a species of Sarcocystis.
zoites penetrate host cells and undergo several divisions by Three cases of infection with a coccidian species believed to
endodyogeny. In primary porcine and bovine cell cultures, be an isosporan were reported from humans in Papua New
binucleate meronts and merozoites of I. suis were motile and Guinea (4). The oocysts were excreted unsporulated, were
were observed to exit and enter host cells (102). No noticeable spherical, and measured 8.5 mm in diameter. Sporulation was
ill effects were observed in the host cells. Only I. rivolta and I. slow, taking about 2 weeks, and the final proportion of oocysts
suis have produced multinucleate meronts (with more than two that sporulated was only about 10%. The sporocysts of this
nuclei) in cell cultures, and these meronts did not reach ma- coccidium were illustrated in drawings with no Stieda body, but
turity (54, 102). Sexual stages and oocysts do not develop in cell there appears to be a Stieda body in the photomicrographs that
cultures. Continuous cultivation of an Isospora species has not accompany the description. The parasite is probably a species
been achieved in cell culture. of Cyclospora, a recently recognized coccidial pathogen of hu-
I. felis, I. rivolta, and I. suis will develop from sporozoites to mans that has two sporocysts with Stieda and sub-Stieda bodies
unsporulated oocysts in the chorioallantoic membrane of de- that enclose two sporozoites (144).
veloping chicken embryos (3, 71, 105). Development is usually
limited to the tissues of the chorioallantoic membrane, but ISOSPORA BELLI INFECTIONS
meronts of I. felis have been seen in the livers and intestines of
chicken embryos that have been chemically immunosup- I. belli infections are essentially cosmopolitan in distribution
pressed (71). Although complete development has been ob- but are more common in tropical and subtropical regions,
tained, the in ovo system has not gained widespread use be- especially Haiti, Mexico, Brazil, El Salvador, tropical Africa,
cause few oocysts are obtained and they do not sporulate. the Middle East, and Southeast Asia (53, 88, 164). Pigs, dogs,
24
LINDSAY ET AL.
CLIN. MICROBIOL. REV.

FIG. 3. Stages of I. ohioensis in lymphoid cells of the mesenteric lymph nodes of mice. (A) Zoite in a smear, 4 days after infection. Magnification, 31,650. (B)
Electron micrograph of the crystalloid body 5 days after infection. Note the regular arrangement of units. Magnification, 371,300. (C) Electron micrograph of a zoite
in the region of the nucleus 7 days after infection. The parasitophorous vacuole (PV) is filled nearly completely by granular material (GM). Magnification, 323,800.
(D) Zoite in a smear of mesenteric lymph node, 4 days after infection. Giemsa stain was used. Magnification, 31,650. (E) Electron micrograph of a zoite 14 days after
infection. The PV has an electron-lucent space (ES) and granular material (GM). Magnification, 323,800. Other abbreviations: A, amylopectin; CH, chromatin; CR,
crystalloid body; DK, dark granules; HC, host cell; IT, intravacuolar tubules; LP, limiting membrane of the PV; NH, host cell nucleus; MN, micronemes; PA, zoite;
PE, three-layered pellicle of zoite; R, rhoptries; SL, tissue cyst wall. Reprinted with permission of the publisher from reference 42.
mice, rats, rabbits, guinea pigs, and rhesus monkeys are not lated to travel exposure and/or recent immigration from Latin
suitable definitive hosts (61, 87); however, in one study, patent American countries. Additionally, the use of trimethoprim
infections were reported in two of three gibbons (193). This (TMP)-sulfamethoxazole (SMX) for the treatment or preven-
lack of susceptibility has led some researchers to discount tion of P. carinii pneumonia may effectively prevent the acqui-
animals as reservoirs (90). However, it is not known if these or sition of primary I. belli infection or the recrudescence of
other animals may serve as paratenic hosts for I. belli. The role existing I. belli infection. It was recommended that physicians
of paratenic hosts in the transmission of I. belli needs to be have an increased index of suspicion for I. belli in AIDS pa-
investigated to establish whether modes of transmission other tients with diarrhea who have immigrated from or traveled to
than by contaminated food or water exist. The existence of Latin America, are Hispanics born in the United States, are
paratenic hosts may help explain infections occurring in areas young adults, or have not received prophylaxis with TMP-SMX
where sanitation is adequate. for P. carinii. Additionally, it was suggested that AIDS patients
traveling to Latin America and other developing countries be
Life Cycle of I. belli advised of the potential for food-borne and waterborne acqui-
sition of I. belli infection and consider taking TMP-SMX che-
Oocysts are passed in feces unsporulated or partially sporu- moprophylaxis.
lated (sporoblast stage). They can sporulate in less than 24 h I. belli infection was observed in 20 (15%) of 131 AIDS
(133). Oocysts are elongate and ellipsoidal with slightly ta- patients with opportunistic infections at Port-au-Prince, Haiti
pered ends, or one end may be tapered and the other end blunt (28). Stool samples collected from 170 siblings, friends, and
(Fig. 1; Table 1). The patent period is not known. It may be as sexual partners were negative. No demographic or laboratory
little as 15 days in some patients (127). Chronic infections characteristics distinguished patients with AIDS and I. belli
develop in some patients, and oocysts are excreted for several
from patients with AIDS and other opportunistic infections. In
months to years. In one case, an apparently immunocompetent
another study, three of three patients with I. belli infection
individual had symptoms that were present for 26 years and
were from Haiti and lived in the United States at the time of
had I. belli infection documented on several occasions over a
the study (190).
10-year period.
Nine (19%) of 46 patients from Zaire with chronic diarrhea
All life cycle stages typical of Isospora species have been
and suspected of having AIDS had I. belli (80). Eight of the
observed by light and transmission electron microscopy (16,
nine I. belli-positive patients were later confirmed to have
149, 179). The number of asexual types present has not been
AIDS. I. belli was found in 13 (9.9%) of 81 AIDS patients
determined. If the life cycle is similar to that of other carni-
examined at a reference center in Sao Paulo, Brazil (158).
vore/omnivore Isospora species, the first asexual division would
Stool samples from 81 immunocompetent individuals were
be by endodyogeny. Division by endodyogeny probably occurs

negative for I. belli. Three (5%) of 60 AIDS patients examined
repeatedly. Endogenous stages are located in enterocytes lin-
in Catalinya, Spain, were positive for I. belli oocysts (155).
ing the villi of the small intestine and rarely in those in the
A pregnant AIDS patient with I. belli diarrhea diagnosed at
large intestine (16, 149, 179). Endogenous stages are seldom
5.5 months of pregnancy delivered a live human immunodefi-
found in other locations such as enterocytes lining the crypts or
in cells in the lamina propria. Extraintestinal infections have ciency virus-positive infant (147). Her sexual partner was also
been observed in AIDS patients (see below) and probably also
occur in immunocompetent patients.
Intestinal Infections in AIDS Patients TABLE 1. Measurements of oocysts of Isospora species

from mammals
Diarrhea produced by I. belli in AIDS patients is often very
fluid and secretory-like and leads to dehydration requiring Dimensions (mm) of:
Species Host
hospitalization. Fever and weight loss are also common find- Oocystsa Sporocystsa
ings. Other opportunistic pathogens are also common in these
patients. Intestinal lesions induced by I. belli and the responses I. belli Humans 23–36 by 12–17 12–14 by 7–9
to chemotherapy are usually similar to those in immunocom- I. natalensis Humans 24–30 by 21–25 17 by 12
petent patients. I. arctopitheci NH primatesb 21–30 by 21–25 13–21 by 10–16
I. callimico NH primates 13–21 by 12–17 10–13 by 7–9
In an extensive 8-year surveillance program of AIDS pa- I. endocallimici NH primates 25–31 by 21–27 15–20 by 10–15
tients in Los Angeles County (164), I. belli was found in 127 I. scorzai NH primates 23 by 20 14 by 9
(1%) of 16,351 patients. The prevalence of infection was high- I. canis Dogs 34–40 by 28–32 18–21 by 15–18
est among foreign-born patients, especially patients from El I. ohioensis Dogs 19–27 by 18–23 15–19 by 10–13
Salvador (7.4%) or Mexico (5.4%) or of other Hispanic eth- I. burrowsi Dogs 17–22 by 16–19 12–16 by 8–11
nicity (2.9%). Patients between the ages of 14 and 24 were I. rivolta Cats 18–28 by 16–23 14–16 by 10–13
more likely to have I. belli infection than were older patients. I. felis Cats 38–51 by 27–39 20–26 by 17–22
Patients with a history of Pneumocystis carinii pneumonia were I. suis Pigs 17–25 by 16–21 11–14 by 8–11
less likely to have I. belli infection. The authors concluded that a
Measurements represent the range unless none was reported.
isosporiasis among AIDS patients in Los Angeles may be re- b
NH primates, nonhuman primates.
positive for I. belli. Treatment with TMP-SMX never elimi-

nated the I. belli infection.
Extraintestinal Infections in AIDS Patients
Two reports of disseminated extraintestinal isosporiasis in

patients with AIDS have been published (130, 149). The first
patient was a 38-year-old white male homosexual who was
examined at the National Institutes of Health, Bethesda, Md.
(149). He initially presented to a local hospital with a history of
progressive dyspnea and fever; he also complained of dyspha-
gia, nausea, vomiting, and brown watery diarrhea (eight or
nine episodes daily). He had lost 20 lb (9.17 kg) in 2 months
(15% of his body weight). P. carinii pneumonia and oropha-
ryngeal candidiasis were noted, and he was treated with TMP-
SMX and pentamidine. His condition improved, and he was
discharged 24 days after admission. He subsequently was re-
admitted complaining of nausea, vomiting, and diarrhea. He
was diagnosed as having Giardia lamblia infection and was FIG. 4. Tissue cysts of I. belli in the spleen of an AIDS patient. A longitudinal
treated with metronidazole. Five months after his initial hos- view and a cross-section of tissue cysts are present. Note the tissue cyst wall
pitalization, he was diagnosed as having I. belli and Entamoeba (arrows) and the nucleus (open arrow) of one zoite. Magnification, 31,000.
histolytica infection. He was treated with TMP-SMX, metroni-
dazole, and diodoquin. Three months later he presented with contained 0.5 liter of serous ascitic fluid. The liver, spleen, and
dyspnea, fever, diarrhea, and generalized wasting. Cytomega- mesenteric lymph nodes were enlarged. The small intestine
lovirus pneumonia was demonstrated at this time. Repeated and colonic mucosa were pale and atrophic, but no ulcerations
stool examinations were negative. He died 2 weeks later. At or perforations were present. No gross lesions were observed
autopsy, the body demonstrated severe cachexia, focally con- in the omentum or other tissues. Examination of samples col-
solidated lungs, multiple small intestinal foci of multifocal er- lected at autopsy revealed stages of I. belli in the intestine,
ythema and hemorrhage, ulcerated cecal lesions up to 5 mm mesenteric and mediastinal lymph nodes, liver, and spleen
across, and enlarged mesenteric, periaortic, and mediastinal (Fig. 4). The extraintestinal stages were always observed as
lymph nodes. Microscopically, disseminated cytomegalovirus single organisms that did not stain with acid-fast stains. The
infection involving the lungs, intestines, adrenal glands, mes- tissue cyst wall was PAS negative, but the enclosed zoite con-
enteric lymph nodes, and, to a lesser extent, liver and pancreas tained PAS-positive granules. The tissue cyst wall did not stain
was observed. Mycobacterium kansasii was cultured from the by the Gomori-Grocott method. Massive infection was ob-
liver and spleen, although no granulomas were observed in served in the lymph nodes in association with plasmacytosis
tissue sections. and some eosinophils but no granulomatous reaction. Parasites
Microscopic findings associated with I. belli infection were were usually grouped in clusters in the paracortical areas or the
observed in the lymph nodes and walls of both the small and lumen of the sinus. Few parasites were observed in Kupffer
large intestines. Marked lymphocytic depletion was observed cells or within macrophages located in portal areas. No in-

in the lymph nodes, and foci of granuloma-like histiocytic pro- volvement of the biliary system was noted. A moderate steato-
liferation were seen in the mesenteric, periaortic, and medias- sis and cholestasis was also observed. The spleen had I. belli
tinal lymph nodes. Intracellular zoites were observed in the tissue cysts in the red and white pulp; the cysts were associated
cytoplasm of histiocytes. The parasites were surrounded by a with congestion and atrophy of the white pulp.
thick eosinophilic cyst wall in hematoxylin-and-eosin-stained Notable differences in the light microscopic findings in these
sections. The cyst wall was PAS positive. Most of the infected two patients are the presence of more than one zoite within a
cells contained only one zoite; however, some contained two or tissue cyst observed in the first patient and the lack of PAS
three. Examination of the intestinal tissues demonstrated in- reactivity of the tissue cyst wall in the second. Additionally, no
traepithelial asexual and sexual stages of I. belli and occasion- granulomatous reaction was observed in the lymph nodes in
ally merozoites that appeared to be in cells in the lamina the second patient. It was believed that the concurrent cyto-
propria. Numerous I. belli oocysts were observed in scrapings megalovirus infection helped lead to dissemination of the parasite
obtained from the intestine. in the first patient. However, cytomegalovirus or other intestinal
The second case was observed in a 30-year-old black woman pathogens were not documented in the second patient.
who was a native of Burkina Faso but had lived in France for Transmission electron microscopy was used to examine por-
2 years (130). She initially presented with fever, diarrhea, and tions of lymph nodes in both patients, and the findings were
weight loss. She was found to have esophageal candidiasis and similar. The zoites were in a PV within the cytoplasm of his-
I. belli infection. The I. belli infection was treated with TMP- tiocytes. Organelles typical of coccidial sporozoites/merozoites
SMX (200 mg/day), and the diarrhea resolved within a week. with a crystalloid body and polysaccharide granules were
She was placed on maintenance therapy of 100 mg of TMP- present. An electron-dense granular layer was seen immedi-
SMX daily but suffered eight episodes of recurrent infection ately beneath the PV membrane. This layer probably com-
diagnosed by stool examination or duodenal biopsy over the posed the tissue cyst wall observed by light microscopy. The
next 3 years. Examination of the biopsy specimens demon- ultrastructural features of these tissue cysts observed in the
strated severe villous atrophy and meronts, gamonts, and oo- lymph nodes of humans are similar to the tissue cysts observed
cysts of I. belli within enterocytes. Gamonts and merozoite-like in mice inoculated with I. felis and I. ohioensis.
stages were observed in the lamina propria. No other patho- A recent study (23) examined the submicroscopic appear-
gens were observed in the biopsy specimens. An autopsy con- ance of I. belli infection in a 30-year-old white female intrave-
ducted after her death revealed cachexia. The abdominal cavity nous drug user from Italy who had AIDS. Her symptoms were
watery, nonbloody diarrhea and fever. She was treated with sponse to surgical, dietary, or antibiotic treatments was
TMP-SMX, and her diarrhea stopped in 2 days. No other observed. An 18-month-old female in Thailand was admitted
clinical data were presented. Ultrastructural examination of to hospital with severe dehydration, inappetence, and weak-
small intestinal biopsy specimens taken at the duodenojejunal ness (178). She had four or five diarrhetic bowel movements
junction demonstrated trophozoites, merozoites, meronts, and daily. She responded to treatment with electrolytes and TMP-
macrogamonts in epithelial cells. Occasionally, merozoites SMX, and her diarrhea ceased within 5 days.
were observed in the intestinal lumen, in the lamina propria,
and within lymphatic channels. The demonstration of merozo- Microscopic Lesions Due to I. belli
ites in lymphatic channels documents a means of their dissem-
ination to lymph nodes and to other tissues. The authors con- The main microscopic changes are villous atrophy and crypt
sidered that their findings of extracellular merozoites might hyperplasia (16, 149, 179). Eosinophils may be present in the
indicate that I. belli is not strictly an intracellular parasite. This lamina propria in large numbers approaching those seen in
consideration is erroneous, because it is well documented that eosinophilic enteritis. Plasma cells, lymphocytes, and polymor-
motile stages of Isospora can leave host cells and invade new phonuclear leukocytes (PMNs) are present in increased num-
host cells (110). This movement is a normal part of the life bers. The lymphatics may be dilated.
cycle, and these fortuitous observations of extracellular stages
are not indicative of extended extracellular survival by these Diagnosis
forms of the parasite. It is interesting that the photomicro- The Sheather sugar flotation method is an excellent method
graph of a merozoite in a lymphatic channel (Fig. 6 in refer- for detecting oocysts of I. belli (26, 115). The unsporulated
ence 23) appears to be a tissue cyst. The merozoite is sur- oocysts of I. belli are readily visible unstained by light micros-
rounded by electron-dense material identical to that seen in copy. Oocysts are in a slightly higher plane of focus than other
tissue cysts in lymph nodes. parasite cysts or ova (49). Flotation methods are superior to
Asexual and sexual stages and oocysts of I. belli have been direct fecal smears for detecting oocysts (53). Sedimentation
observed in the bile duct epithelium of an AIDS patient with concentration methods are also more sensitive than direct
acalculous cholecystitis (8a). No lymph nodes were examined smears. Charcot-Leyden crystals may (70, 88, 131, 162) or may
in this patient, and the relationship between bile duct infec- not (163) be present in stool samples that contain I. belli
tions and disseminated infections with tissue cysts is presently oocysts.
not known. Stained fecal smears made from concentrated samples may
aid in the detection of I. belli oocysts (17, 92, 115, 137, 145).
Infections in Other Immunocompromised Hosts The modified acid-fast stain produces pink-staining oocysts
Clinical disease in I. belli infections is usually more severe in that contain bright red sporonts or sporoblasts (137). Oocysts
immunocompromised patients than in immunocompetent pa- stained by the auramine-rhodamine procedure fluoresce bright
tients. I. belli has been observed in patients with concurrent yellow (115). When the Giemsa stain is used, both the oocysts
Hodgkin’s disease (16), non-Hodgkin’s lymphoproliferative and sporoblasts stain pale blue. The heated safranin-methylene
disease (72), human T-cell leukemia virus type 1-associated blue technique produces oocysts that are orange-red (17). The
adult T-cell leukemia (68), and acute lymphoblastic leukemia trichrome stain is of little use (92).
(189). These patients respond to specific anti-I. belli treatment Duodenal aspirates (100, 179), the duodenal string test
(see below). (190), and small intestinal biopsies (179) are also useful in
It was suggested in one report that treatment with pred- suspected cases in which oocysts are not found in stool sam-

nisolone (60 mg/day for 13 days) led to transient immunosup- ples. I. belli oocysts are observed in duodenal aspirates and in
pression and severe I. belli infection in one patient (134). The mucus collected in the string test. Developmental stages of I.
patient recovered without specific treatment. belli can be identified in enterocytes in small intestinal biopsy
specimens. Some biopsy samples may be negative for develop-
Infections in Immunocompetent Hosts mental stages but contain characteristic lesions. Likewise, oo-
cysts may be present in stool samples from some biopsy-neg-
I. belli causes serious and sometimes fatal disease in immu- ative patients (63). Routine histological staining methods are
nocompetent humans. Symptoms of I. belli infection include satisfactory for demonstrating parasite stages. Many of the
diarrhea, steatorrhea, headache, fever, malaise, abdominal parasites will be in vacuoles, making them readily identifiable.
pain, vomiting, dehydration, and weight loss (16, 75, 85, 98, I. belli can cause disease with relatively few stages of the par-
179). Blood is not usually present in the feces. Eosinophilia is asite present and can be missed on small intestinal biopsy.
observed in some patients. The disease is often chronic, with
parasites present in the feces or biopsy specimens for several
Treatment
months to years. Recurrences are common.
Experimental infections demonstrate that fever begins 8 Many agents have been used to treat I. belli infections. Com-
days after ingestion of oocysts and lasts for about 8 days (120). binations of protozoal dihydrofolate reductase/thymidylate
Nonbloody diarrhea begins 7 to 9 days after ingestion of oo- synthase inhibitors (TMP or pyrimethamine) with sulfon-
cysts. The prepatent period is 10 to 11 days, and oocysts are amides (SMX, sulfadiazine, or sulfadioxine) have generally
excreted for 32 to 38 days. No oocysts were excreted when one proven effective. Treatment with TMP-SMX has been used
volunteer attempted to reinfect himself 33 days after ingestion most often (23, 28, 62, 88, 92, 147, 178, 189). One study exam-
of oocysts, indicating that immunity had developed. ined the TMP-SMX treatment of a group of 32 Haitian AIDS
Disease is more severe in infants (98) and young children patients. The patients ranged in age from 24 to 55 years old.
(178) than in adults. A 6-month-old male infant in California They had a history of chronic intermittent diarrhea with a
had I. belli infection that terminated fatally after 30 weeks of mean duration of 7.9 months (range, 2 to 26 months). The
continuous total parental nutrition (98). The disease was char- diarrhea was liquid, and 2 to 10 stools were excreted a day. The
acterized by severe diarrhea (1 to 3 liters daily) due to cholera- patients also had a history of diffuse, crampy abdominal pain,
like hypersecretion of intraluminal fluid. Little clinical re- nausea, and intermittent fever. Of the 32 patients, 28 required
oral or intravenous rehydration before or during the first 3 of diclazuril orally for 7 days. Oocysts were eliminated from the
days of the study. The patients were treated with oral TMP stools by 2 to 3 days. Diarrhea completely stopped in four of
(160 mg)-SMX (800 mg) four times a day for 10 days. Diarrhea the eight patients, but severe diarrhea persisted in one patient.
and abdominal pain stopped 1 to 6 days (mean, 2.5 days) after Oocysts were present in the stools of one of three patients
treatment. All stool samples examined after the end of treat- examined more than 1 month later. Diarrhea and oocyst ex-
ment were negative. At the end of the study, the prophylaxis of cretion recurred at 47 days after treatment.
I. belli infection was examined in these patients. Ten patients
received placebo orally three times a week, 10 received TMP ISOSPORA INFECTIONS OF NONHUMAN PRIMATES
(160 mg)-SMX (800 mg) orally three times a week, and 12
received pyrimethamine (25 mg)-sulfadioxine (500 mg) orally Little is known about the coccidial infections of nonhuman
once a week. Of the 10 patients given placebo, 5 developed primates. Most of the Isospora species recorded are known
recurrent I. belli infection in 1 to 3.5 months and were re- only by their oocyst structure (Table 1).
treated with TMP-SMX for 10 days with favorable outcomes. I. callimico was isolated from the feces of a Goeldi’s mar-
None of the patients given pyrimethamine-sulfadioxine had moset (Callimico goeldi) at a laboratory animal facility in Bal-
relapses, and 1 of the patients given TMP-SMX developed an timore, Md. (Table 1) (84). The oocysts were excreted for 7
asymptomatic I. belli infection. Severe pruritus developed in 1 days and sporulated in 2 days.
patient in each drug treatment group, resulting in the termi- I. endocallimici was isolated from the feces of five Goeldi’s
nation of treatment. marmosets from the Tulane University Delta Regional Pri-
Pyrimethamine-sulfadoxine has been used less frequently mate Research Center in Louisiana (Table 1) (46). Two of the
than TMP-SMX but also gives prompt clinical response and animals were born at the center, and three were exported from
eliminates the parasite when used (70, 133). Pyrimethamine- Peru. No transmission or life cycle studies have been con-
sulfadiazine is also effective in treating I. belli infection (132, ducted with these species.
179). Pyrimethamine used alone is also effective in patients I. scorzai was isolated from the feces of a Uakari monkey
with sulfonamide allergies (186). (Cacajao rubicundus) that was housed in the London Zoo, and
Macrolide antibiotics have marginal efficacy in treating I. the parasite was transmitted to another monkey, Cebus nigrivit-
belli enteritis. Sirimamycin given at 1.5 g twice daily initially tatus (2). The life cycle of I. scorzai is not known. Experimen-
provided clinical improvement in a Haitian AIDS patient who tally inoculated kittens did not excrete oocysts.
did not respond to TMP-SMX, furazolidone, or tetracycline I. cebi was isolated from the feces of a Cebus albifrons from
treatments for I. belli enteritis (66). The response to treatment the Alto Magdalena region of Colombia (119). The sporocysts
lasted about a month, and then the patient relapsed. A treat- of this species have Stieda bodies, indicating that it is a pseu-
ment course with pyrimethamine-sulfadiazine was initiated af- doparasite of avian origin. A similar Isospora species was iso-
ter the relapse, but little improvement was observed. Roxithro- lated from the feces of a Bonnet monkey (Macaca radiata) at
mycin (2.5 mg/kg every 12 h) was used successfully to treat an the Delhi Zoo in India but was not named (9).
African AIDS patient who was suffering from chronic I. belli- Isospora paponis was isolated from Chacma baboons (Papio
induced diarrhea that did not respond to TMP-SMX or py- ursinus) (125). Oocysts sporulated endogenously in the small
rimethamine treatments (136). Roxithromycin was given orally intestines, indicating that this is a Sarcocystis species. Addition-
for 15 days, and the diarrhea became intermittent and less ally, sporulated oocysts of this species have been seen in the
severe. Although diarrhea requiring hospitalization occurred skeletal muscles of Chacma baboons (126). Chimpanzees (Pan
twice during the 2 months after treatment, no I. belli oocysts troglodytes) can also serve as definitive hosts for Sarcocystis

were observed in stool samples. species, and reports of Isospora sporocysts in their feces actu-
Treatment with anti-giardial agents such as metronidazole, ally describe Sarcocystis sporocysts.
tinidazole, quinacrine, and furazolidone is probably of little
value (19, 175, 179, 186). However, some cases of apparently I. arctopitheci Infections
successful treatment with metronidazole have been reported
(62, 72). I. arctopitheci has been studied more than the other coccidia
Administration of the antimalarial compounds primaquine of nonhuman primates (76–78, 140). Hendricks conducted
phosphate and chloroquine phosphate gave temporary relief of cross-transmission studies with this parasite and claimed to
chronic I. belli infection in an immunocompetent patient after have successfully transmitted it to members of six genera of
a 2-week treatment course (179). Intestinal biopsy specimens New World nonhuman primates, four families of carnivores,
and duodenal aspirates were negative. The patient relapsed in and one marsupial species (77). This is an unusually large and
1 month, and biopsy and aspirate specimens were positive for diverse definitive host range, and further experimental studies
I. belli. are needed to confirm or deny these initial findings.
Veterinary anticoccidial drugs have been used with some The endogenous life cycle of I. arctopitheci occurs in the
success in treating I. belli infections in humans. Amprolium was small intestine (140). Developmental stages are located in en-
used in an AIDS patient in the Netherlands who was suffering terocytes on the distal two-thirds of the villi, and parasite
from severe diarrhea (181) and for whom treatment with py- densities are greatest in the jejunum. Asexual multiplication
rimethamine-sulfadiazine was stopped because of pancytope- was found to be exclusively by endodyogeny, and eosinophilic
nia. Spiramycin had been only partially effective. Amprolium bodies were present in gamonts (140). The prepatent period
was given orally beginning at 10 mg/kg and increasing to 90 was about 7 days, but the patent period was not reported.
mg/kg. The frequency of diarrhea lessened after 6 days of Extraintestinal stages were not seen in the definitive host.
treatment. Amprolium treatment was stopped on day 7 be- Experimental studies indicate that I. arctopitheci can be
cause of polyneuropathy but was reinitiated on day 20 at a pathogenic (140). Of 13 titi marmosets (Saguinus geoffroyi), 4
reduced dose of 30 mg/kg. The stool became normal by day 28 died after being inoculated with 1 3 105 to 2 3 105 oocysts. No
of treatment, and no oocysts were present after day 35. Dicla- clinical signs were seen in marmosets that died 3 and 5 days p.i.
zuril was used in a trial to treat eight AIDS patients with I. belli Bloody diarrhea was seen in two marmosets that died 7 days
diarrhea in Kinshasa, Zaire (89). Each patient received 200 mg p.i. All nine other marmosets remained normal. The micro-
scopic lesions observed were necrosis of apical enterocytes enterocytes, and cryptitis. Dogs developed an immunity that
with exposure of the lamina propria. lasted for about 2 months.
I. burrowsi develops in enterocytes and cells in the lamina
Diagnosis and Treatment propria in the posterior small intestine (180). Two asexual
types are present. Division by endodyogeny has not been re-
Diagnosis is made by finding the characteristic oocysts (Ta- corded but probably occurs. The prepatent period is 6 days,
ble 1) in fecal samples. Fecal flotation with Sheather’s sugar and oocysts are excreted for 9 to 15 days.
solution is recommended as a reliable and sensitive technique. I. neorivolta develops in cells in the lamina propria in the
Sedimentation or other concentration techniques are also ad- posterior small intestine (41). Four asexual types are recog-
equate. nized, and division by endodyogeny is observed. The prepatent
Most Isospora infections in nonhuman primates are subclin- period is 6 days, and oocysts are excreted for 13 to 23 days.
ical. We are unaware of any reports on the treatment of Iso- Little is known about the pathogenesis of I. burrowsi or I.
spora infections in nonhuman primates. Agents used in hu- neorivolta infection in dogs. Neither caused disease in experi-
mans or veterinary products may be of some value. mental infections of dogs (41, 116, 180).
Because the significance of diarrhea caused by coccidia in
ISOSPORA INFECTIONS OF DOGS AND CATS dogs is unclear, the treatment of the condition is also unclear.
Suspected clinical cases can be treated with a variety of drugs
Infections of Dogs used alone or in combination (see below).
Several species of Isospora infect dogs (Table 1). Cats are Infections of Cats
not the definitive hosts for Isospora species found in dogs (32).
Young dogs are more likely to be infected, and surveys indicate I. rivolta and I. felis infect cats. Dogs do not serve as defin-
that 3 to 38% of dogs are positive for coccidial oocysts (91). itive hosts for these species (159). Both feline Isospora species
Stray dogs are more likely to be infected than are dogs with have extraintestinal stages in the feline definitive host and in a
owners because stray dogs must hunt for food and therefore variety of paratenic hosts. From 3 to 36% of cats examined
have more exposure to infected paratenic hosts. excrete oocysts (91). Stray cats are more likely to excrete oo-
It is unclear if coccidiosis is a serious problem in dogs (103, cysts. Coccidiosis in cats is not thought to be a common prob-
146). Diarrhea associated with the presence of coccidial oo- lem (191) and is usually seen only in naturally infected kittens
cysts in young dogs occurs, but the clinical significance is not in which other disease-causing agents may be present. The
established because of the possibility of concurrent bacterial or drugs used to treat dogs are used to treat kittens.
viral infections. Published reports of naturally occurring canine I. rivolta infections. I. rivolta develops in enterocytes in the
coccidiosis are few (24, 44, 141), and further studies on natural small intestine (38). Three structural types of asexual stages
cases are needed before firm conclusions can be made. Experi- are present. The first asexual division is by endodyogeny. The
mental infections have not usually been associated with disease. prepatent period is 4 to 7 days, and oocysts are excreted for
I. canis infections. I. canis has the largest oocysts of the more than 14 days.
canine Isospora species and is the only species that can be Experimentally, I. rivolta can cause disease in newborn kit-
diagnosed by microscopical examination of oocysts (Table 1). tens (38). Diarrhea occurs 3 to 4 days after administration of
I. canis develops in cells in the lamina propria of the posterior 1 3 105 or 1 3 106 sporocysts. Microscopic changes consist of
small intestine (93). Three asexual types are present, and the congestion, erosion of enterocytes, villous atrophy, and crypti-

first asexual division is probably by endodyogeny. The tis. No disease was seen in 10- to 13-week-old kittens inocu-
prepatent period is 9 days. The length of the patent period has lated with up to 105 oocysts. Cats develop immunity to infec-
not been determined. tion, but it is not complete because some oocysts are shed after
Disease was not produced in 25 6-week-old or 6 8-week-old challenge (38).
pups inoculated with 1 3 105 to 1.5 3 105 I. canis oocysts (93). I. felis infections. I. felis develops in enterocytes in the small
Solid immunity follows primary infection, and no oocysts are intestine and occasionally the cecum (161). Three structural
discharged after challenge (6). It has been suggested that the types of asexual stages are recognized. The first asexual divi-
stress of weaning and shipping may enhance I. canis infections sion is by endodyogeny. The prepatent period is 7 to 11 days,
(93). This suggestion needs further investigation because these and oocysts are excreted for about 11 days.
outbreaks of coccidially associated diarrhea may be related to Experimental studies indicate that I. felis is not pathogenic
a decrease in immunity and reactivation of latent extraintesti- for cats over 1 month of age (83, 161). Few signs of disease are
nal stages with subsequent intestinal infection and clinical signs seen in 6- to 13-week-old cats given 1 3 105 to 1.5 3 105
of disease. oocysts. Mild microscopic changes consisting of congestion,
The I. ohioensis complex. Three Isospora species having erosion of superficial enterocytes, and neutrophil infiltration
smaller oocysts than I. canis can be found in dogs: I. ohioensis, may be seen. Four-week-old kittens are the most susceptible,
I. burrowsi (Table 1), and I. neorivolta. Because they cannot be and enteritis, emaciation, and death can occur after inocula-
separated based on oocyst structure and because I. ohioensis tion of 105 oocysts (1).
was the first named, these oocysts are often referred to as I. Cats develop immunity to I. felis, because after infection,
ohioensis-like (44) or members of the I. ohioensis complex. they have no or decreased oocyst production when challenged
I. ohioensis develops in enterocytes in the small intestine, with I. felis oocysts. Studies indicate that cats infected naturally
cecum, and colon of dogs (35). Two asexual types are recog- with I. felis develop lower antibody titers than do those exper-
nized, and division by endodyogeny is observed. The prepatent imentally inoculated with I. felis (142). If these cats are chal-
period is 5 days, and the length of the patent period is not lenged with Toxoplasma gondii, they will develop an antibody
known. The parasite can cause disease in experimentally in- titer to T. gondii and demonstrate an anamnestic response to I.
fected 7-day-old pups but not weaned pups or young dogs (36). felis antigen. A 22-kDa peptide on sporozoites is the major I.
Diarrhea was the major clinical sign seen in the 7-day-old pups. felis protein antigen recognized by immune feline serum (143).
Microscopic changes were villous atrophy, necrosis of apical Peptides of 22, 45, 58, and 62 kDa on T. gondii tachyzoites or
sporozoites are recognized by I. felis immune feline serum. suis is ubiquitous where pigs are farrowed in confinement (21,
Absorption of I. felis immune serum with these T. gondii stages 25, 31, 51, 99, 139, 152, 156, 157) and is responsible for 15 to
removes reactivity of the 45-, 58-, and 62-kDa peptides, imply- 20% of the cases of piglet diarrhea seen at diagnostic labora-
ing that the 22-kDa peptide is specific to I. felis. tories in the United States, Canada, and other countries. Out-
I. felis and T. gondii have evolved an unusual relationship in breaks of coccidiosis occur year-round. I. suis can be seen in
the feline definitive host (20, 33, 37). Cats that have previously nursing piglets suffering from other neonatal diarrheal dis-
recovered from a T. gondii infection will reexcrete T. gondii eases, and it increases the severity of disease caused by these
oocysts if they receive a primary challenge with I. felis oocysts. agents (135, 150, 151, 171).
Cats that have a primary I. felis infection followed by a primary Infected piglets develop diarrhea at 7 to 14 days of age. The
T. gondii infection develop strong immunity to T. gondii and diarrhea is yellowish to gray and initially pasty but becomes
will not reexcrete T. gondii oocysts if challenged with I. felis fluid after 2 to 3 days; blood is never present if I. suis is the only
oocysts. The biological significance or mechanism of this rela- infectious agent. If blood is present, other agents are involved
tionship is unknown. as primary or copathogens. Piglets become covered with diar-
rhetic feces, causing them to stay damp and smell like soured
Diagnosis milk. They become lethargic but continue to nurse. Infections
fail to respond to commonly used antibiotics. Piglets within a
Fecal flotation with Sheather’s sugar solution is the recom- litter and all litters in the farrowing house are not equally
mended method. It is important to examine stools for bacterial affected by coccidiosis. Morbidity is high, and mortality is mod-
and viral agents that cause disease in these animals because erate. Microscopic changes consist of villous atrophy, villous
coccidiosis is usually asymptomatic. Dogs are coprophagic and fusion, necrotic enteritis, and crypt hyperplasia (52, 74, 173,
often will have oocysts from other animal feces in their sam- 183). Experimental studies indicate that the development of
ples. It is important to recognize these pseudoparasites. The clinical disease and microscopic lesions are dependent upon
most common of these are Eimeria species from ruminants, the number of oocysts inoculated and the age at which piglets
rabbits, or rodents. These oocysts will not be in the two-celled are inoculated (13, 86, 112, 153, 172, 173). Doses of 5 3 104
stage as is common for Isospora species. They often will have oocysts or less generally produce diarrhea but no mortality in
ornamentations, such as micropyle caps or dark thick walls, young (1- to 3-day-old) piglets, doses of 7 3 104 to 3 3 105
that are not found on Isospora oocysts. Isospora oocysts that oocysts cause low to moderate mortality, and doses of 4 3 105
contain sporocysts with Stieda bodies are also pseudoparasites. or greater cause high mortality in young piglets. Weight gains
Cats may also have coccidial pseudoparasites in their feces of infected piglets are depressed (111).
from the ingestion of prey. There is some evidence that I. suis may cause postweaning
diarrhea in 5- to 6-week-old piglets (138), with diarrhea begin-
Treatment ning 4 to 7 days after the piglets are weaned. Morbidity is 80 to
Sulfadimethoxine given at 50 mg/kg orally once a day for 10 90%, but mortality is very low.
to 14 days will eliminate oocyst excretion in most dogs and cats Endogenous stages are found throughout the small intestine
(104, 191). The combination of ormetoprim (11 mg/kg) and and occasionally in the cecum and colon (73, 113, 123, 173).
sulfadimethoxine (55 mg/kg) given orally for up to 23 days has Parasite densities are highest in the jejunum and ileum. De-
been used effectively in dogs (45). Amprolium given orally velopmental stages are found in enterocytes. Two types of
once a day at 300 to 400 mg/kg for 5 days or 110 to 220 mg/kg meronts are produced (113). Type 1 meronts are binucleate
for 7 to 12 days is effective in treating coccidiosis in dogs. Other and divide by endodyogeny (122, 123), whereas type 2 meronts

agents such as furazolidone, quinacrine, and metronidazole are multinucleate. Both types of meronts are motile and can
probably are of little clinical value. actively exit and penetrate host cells (110). The prepatent
period is 4 to 5 days, and the patent period is 2 weeks or longer.
Several peaks in oocyst numbers can occur during the patent
ISOSPORA SUIS INFECTIONS OF PIGS period (21, 73, 184). Extraintestinal stages of I. suis have not
The actual number of valid species of coccidia that infect been found by microscopic examination of tissues from in-
swine is unknown because most are known only from the fected piglets or in experimentally inoculated mice (73, 123,
sporulated-oocyst stage. Levine and Ivens list 13 named species 148, 170). Oral feeding of mouse or pig tissues was inconclusive
of Eimeria and 3 species of Isospora isolated from swine (97). in one study (170). Transmission occurred following intraper-
I. suis, I. almataensis, and I. neyrai are the species of Isospora itoneal inoculation of intestinal lymph node homogenates or
isolated from swine. I. almataensis and I. neyrai are known only homogenates of pooled spleen and liver from pigs inoculated 1
from oocysts in the feces. I. almataensis is most probably a or 2 days previously with large numbers (5 3 107 and 1 3 107
combination of a bird Isospora sp. and I. suis. oocysts, respectively) of I. suis oocysts (73). The prepatent
Biester and Murray described I. suis from pigs in 1934 (10– period was 10 to 12 days in the recipient pigs.
12). However, it was not recognized as a major cause of disease The role of viral and bacterial copathogens with I. suis has
in nursing piglets until the early 1970s (167, 171). This probably been examined experimentally (5, 185). The responses of gno-
reflects the modernization of the swine production industry tobiotic and conventional pigs to I. suis and rotavirus coinfec-
and the use of confinement facilities for the farrowing (birth- tion are similar (185). The degree of observed clinical disease
ing) of piglets. is more severe when the pathogens are administered concur-
rently than when either is given singly. Both the virus and the
parasite develop preferentially in the enterocytes of the central
Clinical Signs and Pathogenicity
and distal portion of the villi in the small intestine, and com-
Coccidiosis in pigs is a severe disease of nursing piglets (52, petition for a suitable host cell is believed to be the cause of the
168). I. suis is the cause of neonatal porcine coccidiosis (167). observed increase in clinical disease and microscopic lesions.
There are no reports of coccidiosis caused by I. almataensis or An established I. suis infection will interfere with the estab-
I. neyrai. Eimeria species do not cause clinical coccidiosis in lishment of a Salmonella typhimurium infection (5). The in-
nursing pigs (106). Neonatal porcine coccidiosis caused by I. creased gut motility and destruction of host cells probably
interfere with the ability of the bacterium to colonize the in- The presence of paired merozoites indicative of division by
testinal mucosa. endodyogeny is characteristic for I. suis in pigs (101). Histo-
logical sections taken from the jejunum or ileum also contain
Immunity developmental stages in the enterocytes.
Piglets that recover from I. suis infection exhibit a strong
Treatment and Control
degree of resistance to reinfection. No clinical signs develop
after challenge, and few or no oocysts are excreted in the feces Anticoccidial treatment of piglets has generally proven un-
(174). Colostral antibodies against I. suis do not protect piglets rewarding. Nursing piglets do not eat or drink enough to make
from developing clinical coccidiosis (177). Antibody levels in antibiotics added to feed or water useful. Catching each piglet
serum peak about 1 week after primary infection, and a sec- for dosing is time-consuming and labor-intensive and probably
ondary antibody response occurs following challenge infection. practical only on small farms. Controlled studies indicate that
Serum antibodies against I. suis do not recognize sporozoites amprolium, monensin, and furazolidone are not effective in
of Eimeria debliecki, E. neodebliecki, E. scabra, or E. porci in an preventing coccidiosis in nursing piglets (29, 67). Toltrazuril
indirect fluorescent-antibody test. Lymphocyte migration inhi- does show promise as an effective means of preventing coccidiosis
bition responses of pigs that are immune to I. suis are signifi- in nursing piglets (30). When 20 to 30 mg of toltrazuril/kg was
cantly lower than those of controls when soluble or particulate given orally as a single dose to 3- to 6-day-old piglets, coccidiosis
I. suis sporozoite antigens are used. Polymorphonuclear leu- was reduced from 71 to 22%. The severity of diarrhea and oocyst
kocyte (PMN) chemotactic factors were generated by lympho- excretion was reduced in toltrazuril-treated piglets.
cytes from piglets inoculated with I. suis and incubated with Lasalocid and halofuginone have been evaluated in early-
soluble or particulate sporozoite antigens. Lymphocytes from weaned pigs experimentally infected with I. suis (118, 124).
control pigs did not produce chemotactic factors for PMNs Lasalocid given at 150 mg/kg of feed prevented weight loss in
after incubation with I. suis sporozoite antigens, and the anti- pigs but did not prevent oocyst excretion. These pigs developed
gens alone were not chemotactic for PMNs. strong immunity to reinfection. Halofuginone given at 6 mg/kg
of feed inhibited oocyst production but caused reduced weight
Epidemiology gains due to poor feed intake. The halofuginone-treated pigs
did not develop strong immunity to challenge infection.
The epidemiology of neonatal porcine isosporiasis is puz- Improved sanitation is the best means of controlling neona-
zling. Sows are often infected with Eimeria species, but the tal coccidiosis (50). Feeding anticoccidial agents to sows is not
prevalence of I. suis is usually less than 5% (50, 69, 114, 182). recommended because they are not the source of fecal oocysts
The sow is a logical source of infection for newborn piglets, but for their nursing piglets. Commercially available disinfectants
studies conducted in the United States have failed to demon- do not inhibit the development of I. suis oocysts when used at
strate I. suis oocysts in a significant number of sows (50, 114, the concentrations recommended by the manufacturers (169).
168). I. suis oocysts were not found in the feces of 77 sows Once the oocysts sporulate, they are even more resistant to
examined from 7 farms with a problem of neonatal coccidiosis disinfectants. Steam cleaning is effective in killing sporulated
caused by I. suis, and only 1 of 172 sows examined from 27 and unsporulated oocysts and is an effective means of decreas-
farms without a history of neonatal coccidiosis was positive ing piglet exposure to infective I. suis oocysts. Additional pre-
(114). Eimeria oocysts were found in 91% of these sows. In ventive measures are for farm workers to limit their access to
another study, sows from two farms with neonatal coccidiosis infected piglets to prevent crate-to-crate spread of infection via
in piglets were examined on a daily basis for about 1 week prior their boots. Also, flies and other insects should be controlled to

to farrowing, at farrowing, and for about 2 weeks postfarrowing prevent them from mechanically carrying oocysts from crate to
(168). I. suis oocysts were not found in these sows; however, crate. Supportive measures such as providing water or electro-
piglets nursing from these sows developed coccidiosis and ex- lyte solutions in piglet waters may be of value in preventing
creted I. suis oocysts at 4 to 8 days of age. Microscopic exam- dehydration in clinically infected piglets.
ination of milk samples and placentas from these sows were
negative for parasites. Once I. suis is established on a farm, it
is probably maintained by infection of piglets from the con- FUTURE DIRECTIONS
taminated farrowing crate. Future studies on human I. belli infections need to examine
the latent tissue cyst stage of the parasite. It is most probably
Diagnosis responsible for the recrudescence of clinical disease which is
observed in AIDS and other patients. It is obvious that the
Diagnosis is based on a clinical history suggestive of coccid-
tissue cyst stage is not killed by treatment with TMP-SMX. An
iosis and the demonstration of I. suis oocysts in fecal samples
in vitro culture system needs to be developed to examine po-
or the demonstration of developmental stages in mucosal
tential anticoccidial agents against I. belli and to study tissue
smears or histological sections obtained from necropsy speci-
cyst biology. Experimental inoculation of rodents with I. belli
mens (101). Samples for oocyst identification should be taken
oocysts needs to be examined to determine whether latent
from pigs that have had diarrhea for 2 days or more because
infections develop in these animals. If rodents are found to be
clinical signs often appear before oocysts are excreted in the
paratenic hosts, potentially other food animals may also be
feces (173). Pasty fecal samples are likely to contain more
capable of transmitting the infection.
oocysts than are liquid samples. Fecal fat makes identification
Additional studies on dog and cat Isospora spp. should be
of oocysts in Sheather’s sugar flotation preparations difficult. A
conducted to determine if these coccidia are truly pathogenic
solution of saturated sodium chloride and glucose has been
in them. Studies with neonatal porcine coccidiosis should focus
recommended as an alternative flotation medium (79).
on identifying effective treatments and vaccines.
The use of mucosal imprints stained with any Giemsa-type
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CLINICAL MICROBIOLOGY REVIEWS, Jan. 1997, p. 19–34 Vol. 10, No.

Biology of Isospora spp. from Humans, Nonhuman Primates,

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INTRODUCTION spora but is now used to include Cryptosporidium species, Tox-

Isospora species can cause serious disease in humans and

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Intestinal Infections in AIDS Patients TABLE 1. Measurements of oocysts of Isospora species

positive for I. belli. Treatment with TMP-SMX never elimi-

Extraintestinal Infections in AIDS Patients

Two reports of disseminated extraintestinal isosporiasis in

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