Cystoisospora/Cystoisosporiasis and Cyclospora/Cyclosporiasis

Cystoisospora and Cyclospora are genera within the Coccidia subclass of protozoans. These single-celled, obligate intracellular parasites cause intestinal infections in humans. Humans are the only host for these species, and they are both transmitted through the fecal–oral route. The symptoms of cystoisosporiasis and cyclosporiasis are watery diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, and fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever. Severe cystoisosporiasis can occur in immunocompromised individuals, particularly those with HIV/ AIDS AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS, and can lead to malabsorption Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion, weight loss, and dehydration Dehydration Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Dehydration is primarily caused by decreased water intake and presents with increased thirst and can progress to altered mental status and low blood pressure if severe. Volume Depletion and Dehydration. Both diseases are self-limited in immunocompetent individuals, though cyclosporiasis has a longer course. Diagnosis is made by identifying the oocysts in stool samples. Antimicrobial therapy, such as trimethoprim Trimethoprim The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and Trimethoprim–sulfamethoxazole, can be used (particularly in immunocompromised individuals).

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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General Characteristics

Basic features of Cystoisospora and Cyclospora

  • Protozoans:
    • Single-celled
    • Obligate intracellular parasites
  • Taxonomy:
    • Class: Conoidasida
    • Subclass: Coccidia

Clinically relevant species

Both organisms cause intestinal disease in humans.

  • Cystoisospora belli (formerly Isospora belli) causes cystoisosporiasis.
  • Cyclospora cayetanensis causes cyclosporiasis.

Epidemiology

Cystoisospora:

  • Occurs worldwide
  • Predominantly seen in tropical and subtropical regions
  • The least common of the intestinal coccidia that infect humans

Cyclospora:

  • Found in developing nations in tropical and subtropical areas:
    • Latin America
    • Egypt
    • Sub-Saharan Africa
    • India
    • Southeast Asia
  • United States: approximately 16,000 cases of foodborne illness each year

Pathogenesis

Host

Both species are found only in humans.

Risk factors

Cystoisospora (severe disease):

  • HIV/ AIDS AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS
  • Lymphoma and leukemia
  • Hypogammaglobulinemia
  • Immunosuppressive therapy
  • Infants and young children

Cyclospora:

  • Endemic areas:
    • Poor sanitation
    • Low socioeconomic status
  • Nonendemic areas:
    • Travelers
    • Import of fresh food from endemic regions
  • Severe disease:
    • Young children
    • Older adults
    • Immunocompromised individuals (e.g., those with HIV/ AIDS AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS)

Transmission

Both species are transmitted via the fecal–oral route (ingestion of contaminated food and water).

Life cycle

Cystoisospora and Cyclospora undergo a similar life cycle:

  • Ingestion of sporulated oocysts from contaminated food or water
  • Sporozoites released in the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine → penetrate intestinal epithelial cells
  • Undergo asexual reproduction → sexual stage begins after invading another cell
  • Fertilization Fertilization To undergo fertilization, the sperm enters the uterus, travels towards the ampulla of the fallopian tube, and encounters the oocyte. The zona pellucida (the outer layer of the oocyte) deteriorates along with the zygote, which travels towards the uterus and eventually forms a blastocyst, allowing for implantation to occur. Fertilization and First Week results in immature oocysts → excreted in the stool
  • Sporulation occurs in the environment

Clinical presentation

Cystoisosporiasis

Cystoisosporiasis has an incubation period of 7–14 days. Presentation of the disease can vary depending on the individual’s immune status.

  • Immunocompetent host:
    • Acute
    • Usually mild and self-limited (usually resolves in 7–10 days)
    • Some hosts are asymptomatic.
    • Diarrhea:
      • Nonbloody
      • Watery
      • Sudden onset 
    • Crampy abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Anorexia
    • Nausea and vomiting 
    • Fever 
    • Malaise
    • Can last for weeks and cause malabsorption Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion and weight loss
  • Immunocompromised host:
    • Chronic, protracted clinical course
    • Severe diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea:
      • Nonbloody
      • May develop steatorrhea 
    • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain 
    • Fever 
    • Malabsorption and weight loss 
    • Dehydration:
      • Renal insufficiency
      • Electrolyte disturbances

Cyclosporiasis

Cyclosporiasis has an incubation period of approximately 7 days. 

  • Mostly asymptomatic, especially in immunocompetent individuals
  • Can last weeks to months (if untreated)
  • General symptoms:
    • Diarrhea: 
      • Watery
      • Blood or mucus can occasionally be seen
    • Anorexia
    • Nausea
    • Fatigue
    • Weight loss
    • Bloating and flatulence
    • Low-grade fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever

Diagnosis

Diagnosis of cystoisosporiasis

  • General laboratory findings:
    • Eosinophilia
    • Evidence of dehydration Dehydration Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Dehydration is primarily caused by decreased water intake and presents with increased thirst and can progress to altered mental status and low blood pressure if severe. Volume Depletion and Dehydration:
      • ↓ K
      • ↑ Creatinine
  • Diagnostic testing:
    • Detection of the oocyst in the stool:
      • Thin-walled and ellipsoidal
      • Acid-fast positive
    • PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR) to detect Cystoisospora DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure
    • Intestinal biopsy showing parasites

Diagnosis of cyclosporiasis

  • Detection of the oocyst in the stool: 
    • Modified acid-fast staining: pink or purple, round bodies 
    • Safranin stain: oocysts are red/reddish orange
    • Autofluorescence with fluorescence microscopy
  • PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR) to detect Cyclospora DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure in stool
Cyclospora_cayetanensis

Photomicrograph of Cyclospora cayetanensis oocysts in a stool sample found using a modified acid-fast stain

Image: “Cyclospora cayetanensis” by CDC. License: Public Domain

Management

Cystoisosporiasis management

  • Usually self-limited in immunocompetent individuals
  • Fluid and electrolyte replacement for dehydration Dehydration Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Dehydration is primarily caused by decreased water intake and presents with increased thirst and can progress to altered mental status and low blood pressure if severe. Volume Depletion and Dehydration
  • Nutritional support in cases of malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries
  • Antimicrobial therapy:
    • Indications:
      • Immunocompromised individuals
      • Immunocompetent individuals with persistent symptoms
    • Options:
      • Trimethoprim–sulfamethoxazole (TMP-SMX; 1st-choice)
      • Ciprofloxacin 
      • Pyrimethamine plus leucovorin
      • Nitazoxanide
  • Antiretroviral therapy Antiretroviral therapy Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs for individuals with AIDS AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS
  • Secondary prophylaxis to ↓ risk of relapse in immunocompromised individuals: TMP-SMX

Cyclosporiasis management

Antimicrobials used for the treatment of cyclosporiasis include:

  • TMP-SMX (1st-choice)
  • Nitazoxanide
  • Ciprofloxacin

Differential Diagnosis

  • Microsporidiosis Microsporidiosis Microsporidia are a group of obligate intracellular organisms that were recently reclassified as fungi. The most common species of Microsporidia is Enterocytozoon bieneusi. Microsporidia species are ubiquitous, with a wide range of reservoirs. Immunocompromised individuals (particularly those with AIDS and a CD4 count < 100 cells/µL) most commonly develop symptomatic microsporidiosis. Microsporidia/Microsporidiosis: caused by a group of obligate intracellular spore-forming organisms that were recently reclassified as fungi Fungi A kingdom of eukaryotic, heterotrophic organisms that live parasitically as saprobes, including mushrooms; yeasts; smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi, commonly known as molds, refer to those that grow as multicellular colonies. Mycology: Overview (formerly classified as protozoa). Microsporidia Microsporidia Microsporidia are a group of obligate intracellular organisms that were recently reclassified as fungi. The most common species of Microsporidia is Enterocytozoon bieneusi. Microsporidia species are ubiquitous, with a wide range of reservoirs. Immunocompromised individuals (particularly those with AIDS and a CD4 count < 100 cells/µL) most commonly develop symptomatic microsporidiosis. Microsporidia/Microsporidiosis most commonly affect immunocompromised individuals (particularly those with AIDS AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS) and cause diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea and other disseminated infections. The diagnosis is made by identifying organisms in stool, urine, secretions, or biopsy specimens. Management depends on the species and includes a wide range of antimicrobials.
  • Gastroenteritis Gastroenteritis Gastroenteritis is inflammation of the stomach and intestines, commonly caused by infections from bacteria, viruses, or parasites. Transmission may be foodborne, fecal-oral, or through animal contact. Common clinical features include abdominal pain, diarrhea, vomiting, fever, and dehydration. Gastroenteritis: inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach and intestines, commonly caused by infections from bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview, viruses, or parasites. Common clinical features of gastroenteritis include abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, vomiting, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, and dehydration Dehydration Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Dehydration is primarily caused by decreased water intake and presents with increased thirst and can progress to altered mental status and low blood pressure if severe. Volume Depletion and Dehydration. Diagnostic testing with stool analysis or culture is not always required but can help determine the etiology in certain circumstances. Most cases are self-limited; therefore, the only required treatment is supportive therapy (fluids). 
  • Cryptosporidiosis: infection with Cryptosporidium. Individuals will have watery diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, abdominal cramping, nausea, and fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever that lasts 2–3 weeks, but the infection can be more persistent and severe in immunocompromised individuals. Diagnosis is with identification of the organism in a stool specimen. Cryptosporidiosis is generally self-limited, but it may require nitazoxanide in persistent or severe cases.  
  • Giardiasis Giardiasis Giardiasis is caused by Giardia lamblia (G. lamblia), a flagellated protozoan that can infect the intestinal tract. The hallmark symptom of giardiasis is foul-smelling steatorrhea. Patients who develop chronic infections may experience weight loss, failure to thrive, and vitamin deficiencies as a result of malabsorption. Giardia/Giardiasis: caused by Giardia lamblia Giardia lamblia Giardiasis is caused by Giardia lamblia (G. lamblia), a flagellated protozoan that can infect the intestinal tract. Giardia transmission occurs most commonly through consumption of cysts in contaminated water or through the fecal-oral route. Excystation occurs in the gastrointestinal (GI) tract, and trophozoites attach to the intestinal wall villi and cause malabsorption. Giardia/Giardiasis, a flagellated protozoan that can infect the intestinal tract. The hallmark symptom of giardiasis is foul-smelling steatorrhea. Individuals who develop chronic infections may experience weight loss, failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive, and vitamin deficiencies as a result of malabsorption Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion. The diagnosis is made through detection of Giardia organisms, antigens, or DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure in the stool. Management includes supportive treatment and antimicrobial therapy with metronidazole, tinidazole, or nitazoxanide. 
  • Traveler’s diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea: gastroenteritis that is usually caused by bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview or viruses in the local water, such as enterotoxigenic Escherichia coli Escherichia coli The gram-negative bacterium Escherichia coli is a key component of the human gut microbiota. Most strains of E. coli are avirulent, but occasionally they escape the GI tract, infecting the urinary tract and other sites. Less common strains of E. coli are able to cause disease within the GI tract, most commonly presenting as abdominal pain and diarrhea. Escherichia coli (ETEC) or norovirus Norovirus Norovirus is a nonenveloped, single-stranded, positive-sense RNA virus belonging to the Caliciviridae family. Norovirus infections are transmitted via the fecal-oral route or by aerosols from vomiting. The virus is one of the most common causes of nonbacterial gastroenteritis epidemic worldwide. Symptoms include watery and nonbloody diarrhea, nausea, vomiting, and low-grade fever. Norovirus. Symptoms occur after consumption of contaminated water or food and include watery diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, malaise, and abdominal cramping. The diagnosis is clinical, and the illness is self-limited.

References

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