Epidemiology, clinical manifestations, and diagnosis of Cystoisospora (Isospora) infections

INTRODUCTION — Cystoisospora belli (formerly known as Isospora belli) is a gastrointestinal protozoan. In patients with acquired immunodeficiency syndrome (AIDS) and other immunodeficiencies, it is an opportunistic pathogen that can cause watery diarrhea and weight loss. Like other enteric pathogens, such as Cryptosporidium and Cyclospora, C. belli is a coccidian, unicellular protozoan parasite that primarily infects the intestinal epithelium [1].

EPIDEMIOLOGY — C. belli is found worldwide, but infections are more common in tropical and subtropical areas [2]. In India, Cystoisospora infections are the most common parasitic cause of diarrhea in patients with human immunodeficiency virus (HIV) [3-5]. Among patients with HIV living in France, Cystoisospora infections were seen more commonly among patients who had emigrated from sub-Saharan Africa [6]. In a study of more than 16,000 patients with HIV living in Los Angeles County between 1985 and 1992, the prevalence of Cystoisospora infections was highest in foreign-born patients, particularly those from Mexico and El Salvador, and among persons of Hispanic ethnicity [7].

Gastrointestinal infections secondary to Cystoisospora are uncommon in the United States and other developed countries but can be acquired by travelers to endemic countries [7-11]. Cystoisospora can also be identified as a copathogen with other enteric organisms, such as Enterocytozoon bieneusi, in geographic regions with high levels of fecal contamination of surface water [12,13].

A history of treatment or prophylaxis with trimethoprim-sulfamethoxazole for Pneumocystis infection in a patient with HIV is associated with a decreased risk of developing cystoisosporiasis [7,14,15].

Cystoisospora has been reported in immunocompetent patients as well as in patients with other cellular immunodeficiencies, such as human T-lymphotropic type 1 infection [16], lymphoblastic leukemia, adult T-cell leukemia, hypogammaglobulinemia, Hodgkin disease, and non-Hodgkin lymphoma [17]. It has also been reported in transplant recipient patients and in individuals taking immunomodulators, such as tumor necrosis factor (TNF) inhibitors [18-20].

TRANSMISSION — Infections are acquired by the ingestion of sporulated oocysts from food or water contaminated with human feces. After ingestion, the parasite invades enterocytes within the small intestine. The parasite completes its life cycle within the human host, and immature oocysts are excreted in the stool 9 to 17 days after infection. Sporulation usually occurs outside the host in the environment after one to two days (range 24 hours to 10 days) [21-23]. However, there are reports of oocyst sporulation in the gut lumen with excretion of partially or fully sporulated oocysts in freshly excreted feces [24].

Sexual transmission via oral-anal contact and person-to-person transmission may be possible but does not appear to be common; in a study of patients with HIV and Cystoisospora infection in Haiti, none of the 170 immunocompetent spouses or siblings cohabitating with the source patients had evidence of infection [8].

CLINICAL MANIFESTATIONS — After an incubation period of approximately 7 to 14 days, the principal manifestation of Cystoisospora infection is a watery, nonbloody diarrheal illness of sudden onset [8]. Commonly seen associated symptoms include malaise, anorexia, abdominal pain, headache, vomiting, and dehydration. Fever may also be present [6]. Patients with steatorrhea secondary to malabsorption may complain of malodorous stool. Cystoisospora infection has also been associated with acalculous cholecystitis in immunocompetent and immunodeficient patients [25,26] and with reactive arthritis in patients with HIV [27].

The clinical course of Cystoisospora infections varies with the immune status of the host. While symptoms are usually self-limited in the immunocompetent host and diarrhea usually resolves after 7 to 10 days [28], cystoisosporiasis is often a chronic, debilitating diarrheal infection in immunocompromised hosts, who may relapse without long-term antibiotic suppression [8,29]. In patients with AIDS, untreated infection is associated with protracted clinical course with severe diarrhea and weight loss, clinically indistinguishable from cryptosporidiosis [8,22]. The secretory stool output can also lead to severe volume loss, renal insufficiency, and electrolyte disturbances [22]. Other immunocompromised patients can also present with severe disease. In one report, a fatal case of Cystoisospora-associated dehydration was described in a patient receiving long-term corticosteroids and methotrexate [30].

Laboratory findings — In contrast to the general rule that protozoan infections do not elicit blood eosinophilia, increases in circulating eosinophils can occur with Cystoisospora infections and are sufficiently common to raise the possibility of this diagnosis.

Secretory diarrhea may lead to hypokalemia, bicarbonate wasting, and increased creatinine secondary to volume loss [22]. Patients with secretory diarrhea usually have elevated stool osmolality and fecal fats noted on special stains (eg, Sudan III stain) consistent with steatorrhea. (See "Approach to the adult patient with suspected malabsorption".)

PATHOLOGY — Cystoisospora infection principally affects the small and large intestines. Histologic alterations in the mucosa include shortened villi, crypt hyperplasia, and increases in infiltrating plasma cells, lymphocytes, and granulocytes. On occasion, organisms have been found at autopsy in extraintestinal sites, including the tracheobronchial lymph nodes, spleen, liver, and biliary tract [31].

DIAGNOSIS — The diagnosis of Cystoisospora infection is usually made by detecting oocysts in the feces. However, oocysts are often excreted intermittently and may be sparse, which can make diagnosis difficult [32]. When seen, oocysts of Cystoisospora are thin walled and ellipsoidal in form. They are usually 23 to 36 micrometers by 12 to 17 micrometers.

In cases of heavy infection, oocysts can be seen on a simple wet mount of stool. However, as with Cryptosporidia and Cyclospora, Cystoisospora usually cannot be detected by routine stool ova and parasite examinations. Thus, acid-fast staining [8] or specific fluorescent techniques [33,34] must be requested when Cystoisospora infection is suspected [1,22,35]. Polymerase chain reaction (PCR) assays have been developed for detecting Cystoisospora deoxyribonucleic acid (DNA) in fecal samples, but they are not widely available, particularly in under-resourced settings [13,36,37]. In one study, genotyping of Cystoisospora using melting curve analysis after real-time PCR suggested two distinct genotypes [38].

If the stool examination is not diagnostic, parasites may also be detected in duodenal aspirates or within intestinal biopsy tissue examined under light microscopy; morphologically, Cystoisospora resembles Cyclospora on histologic sections [39]. (See 'Differential diagnosis' below.)

DIFFERENTIAL DIAGNOSIS — Other enteric pathogens to consider in the patient with severe watery diarrhea include Cryptosporidia, Cyclospora, Giardia, Campylobacter, Cholera, Shigella, and Salmonella. In an immunocompromised patient, cytomegalovirus (CMV) and Enterocytozoon bieneusi should also be considered.

Cholera is usually not confused with the other pathogens because of its rapid onset and epidemiology (ie, massive outbreaks in areas of poor sanitation). Salmonella, Shigella and Entamoeba histolytica may sometimes be distinguished by their association with bloody diarrhea. A history of recent antibiotic exposure would suggest Clostridioides difficile. Giardia is a small bowel pathogen associated with significant flatus and upper gastrointestinal symptoms without blood in the stool. Viral pathogens, such as rotavirus and Norwalk can also cause watery diarrhea, but are self-limited, even in the immunocompromised host.

Cryptosporidium infection is difficult to distinguish clinically from Cystoisospora, but on microscopic examination, the latter parasites have a smaller round morphology with a size of approximately 4 to 6 micrometers; each parasite also contains four sporozoites [8].

Noninfectious causes of severe diarrhea include inflammatory bowel disease, celiac disease, pancreatic insufficiency, motility disorders, neuroendocrine tumors, villous adenoma, niacin deficiency, and laxative abuse. (See appropriate topic reviews.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute diarrhea in adults" and "Society guideline links: Opportunistic infections in adults with HIV".)

SUMMARY AND RECOMMENDATIONS

●Definition – Cystoisospora belli (formerly known as Isospora belli) is an opportunistic protozoan pathogen, which can cause self-limited watery diarrhea in immunocompetent patients and severe debilitating chronic diarrhea with wasting in patients with AIDS. (See 'Introduction' above.)

●Epidemiology – Cystoisospora belli is found worldwide, but infections are more common in tropical and subtropical areas. The main risk factor for chronic infectious diarrhea secondary to Cystoisospora infection in a patient with HIV is immunosuppression (CD4 cell count <50 cells/microL). (See 'Epidemiology' above.)

●Transmission – Infections are acquired by the ingestion of sporulated oocysts from food or water contaminated with human feces. (See 'Transmission' above.)

●Clinical manifestations

•The principal manifestation of Cystoisospora infection is a watery, nonbloody diarrheal illness of sudden onset. Commonly seen associated symptoms include malaise, anorexia, abdominal pain, headache, vomiting, and dehydration. (See 'Clinical manifestations' above.)

•The clinical course of Cystoisospora infections varies with the immune status of the host. While symptoms are usually self-limited in the immunocompetent host, cystoisosporiasis is often a chronic, debilitating diarrheal infection in immunocompromised hosts, who may relapse without long-term antibiotic suppression. (See 'Clinical manifestations' above.)

●Laboratory findings – Secretory diarrhea may lead to hypokalemia, bicarbonate wasting, and increased creatinine secondary to volume loss. (See 'Laboratory findings' above.)

●Pathology – Cystoisospora infection principally affects the small and large intestines. Histologic alterations in the mucosa include shortened villi, crypt hyperplasia, and increases in infiltrating plasma cells, lymphocytes, and granulocytes. (See 'Pathology' above.)

●Diagnosis – The diagnosis of Cystoisospora infection is usually made by detecting oocysts in the feces, usually with the aid of special staining techniques such as acid-fast staining or immunofluorescence. Multiple stool samples may be required. Polymerase chain reaction (PCR) assays have also been developed. (See 'Diagnosis' above.)

●Differential diagnosis – Other enteric pathogens to consider in the patient with severe watery diarrhea include Cryptosporidia, Cyclospora, Giardia, Campylobacter, Salmonella, and Enterocytozoon bieneusi. (See 'Differential diagnosis' above.)