Opportunistic Coccidiosis in Immunosuppressed Patients: An Overview of Diagnostic Invisibility in Brazil

Opportunistic Coccidiosis in Immunosuppressed Patients: An Overview of Diagnostic Invisibility in Brazil | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 22 July 2025 V1 Latest version Share on Opportunistic Coccidiosis in Immunosuppressed Patients: An Overview of Diagnostic Invisibility in Brazil Authors : Willian Cardoso Ferreira Zorrer 0009-0005-3934-4331 [email protected] , Estefani Rinaldi , Bibiana Rodrigues de Freitas , Pedro Machado Medeiros de Albuquerque , Rodrigo Casquero Cunha , Fabio Raphael Pascotti Bruhn , and rahal.natalia Authors Info & Affiliations https://doi.org/10.22541/au.175315888.85626276/v1 255 views 147 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Opportunistic infections caused by the protozoa Cryptosporidium spp. and Cystoisospora belli represent a challenge for public health, particularly in immunocompromised patients. In Brazil, a country with continental dimensions and socioeconomic diversity, the epidemiology of these intestinal coccidioses is complex and often underestimated. This review article aims to consolidate current knowledge on Cryptosporidium and Cystoisospora infections in immunocompromised individuals within the Brazilian context, addressing clinical manifestations, epidemiology, risk factors, diagnostic methods, treatment options, prevention and control strategies, and challenges related to underreporting. A thorough understanding of these aspects is crucial for improving health policies, optimizing clinical management, and reducing the morbidity and mortality associated with these parasitic diseases. Introduction Intestinal coccidioses, caused by protozoa of the phylum Apicomplexa, such as Cryptosporidium spp. and Cystoisospora belli (formerly known as Isospora belli ), are globally recognized as significant agents of diarrhea, especially in vulnerable populations (1,2) . In immunocompetent individuals, these infections typically present as acute, self-limiting diarrheal episodes. However, in patients with compromised immune systems—such as those living with HIV/AIDS, organ transplant recipients, or individuals undergoing immunosuppressive therapy or chemotherapy—these parasitic infections can lead to severe, chronic, and potentially fatal conditions, characterized by severe dehydration, intestinal malabsorption, and progressive malnutrition (1, 10, 3) . In Brazil, the occurrence of these infections is influenced by a complex interplay of socioeconomic, environmental, and healthcare-related factors. Poor sanitation infrastructure in many regions, contamination of water and food, and proximity to animal reservoirs contribute to the spread of infectious oocysts (4) . Despite their clinical relevance, the true burden of cryptosporidiosis and cystoisosporiasis in immunosuppressed patients in Brazil remains poorly understood, partly due to diagnostic gaps that lead to underreporting. This article reviews the scientific literature on Cryptosporidium spp. and Cystoisospora belli infections in immunosuppressed patients in Brazil, focusing on clinical presentation, epidemiology, risk factors, and challenges in underreporting, aiming to provide an updated epidemiological overview for public health. Etiological Agents and Biological Cycle The genus Cryptosporidium comprises several species, with C. hominis and C. parvum being the most frequently associated with human infections. Transmission occurs through ingestion of sporulated oocysts excreted in the feces of infected hosts, contaminating water, food, or via direct person-to-person or animal-to-person contact (1, 10) . The oocysts are highly resistant to environmental conditions and common disinfectants, such as chlorine. Cystoisospora belli is a monoxenous protozoan, with humans as its only known host. Infection occurs through ingestion of mature oocysts present in water or food contaminated with human feces. The oocysts are excreted immature and require time in the environment to sporulate and become infectious (2) . In both cases, after ingestion, sporozoites are released in the small intestine, invade enterocytes, and initiate cycles of asexual and sexual reproduction, culminating in the formation of new oocysts that are excreted in feces, perpetuating the cycle. In immunosuppressed individuals, replication can be continuous and intense, leading to chronic infection. Epidemiology in Brazil Among Immunosuppressed Patients The epidemiology of cryptosporidiosis and cystoisosporiasis in immunosuppressed patients in Brazil is heterogeneous, underestimated, and lacks comprehensive research. Most available studies focus on patients living with HIV/AIDS, who constitute the highest-risk group. Prevalence and Geographic Distribution Studies conducted in different regions of Brazil show significant variations in the prevalence of these infections. In HIV/AIDS patients, the prevalence of Cryptosporidium spp. can vary considerably. A study in Ribeirão Preto (SP) found a frequency of 6.4% for Cryptosporidium sp. and 4.4% for C. belli in HIV-positive patients (5). Another study in Rio Grande do Norte, involving hospitalized HIV/AIDS patients, also investigated the frequency of these coccidia, highlighting the lack of data, particularly in the Northeast region (4). A more recent study on the prevalence and genetic characterization of Cryptosporidium spp. and Cystoisospora belli in HIV-infected patients in Brazil observed a significant association between non-adherence to antiretroviral therapy and the presence of these parasites (12). The prevalence of Cystoisospora belli in HIV-positive patients in Brazil also varies, with reported rates ranging from 4.4% to 18% in different studies (6). Seasonality also appears to influence occurrence, with some studies suggesting higher frequencies of Cryptosporidium spp. during rainy months and C. belli during warm and humid months, although both microorganisms can remain viable in the environment for months due to their resistance to environmental conditions (5, 12). Beyond HIV/AIDS patients, other immunosuppressed groups, such as organ transplant recipients and chemotherapy patients, are also at risk, though epidemiological data specific to these groups in Brazil are scarcer. Case reports, such as disseminated cryptosporidiosis in a child undergoing bone marrow transplantation, underscore the importance of these infections in such patients (11) . Risk Factors The primary risk factor for severe and chronic forms of cryptosporidiosis and cystoisosporiasis is immunosuppression, particularly cellular immune deficiency. In HIV/AIDS patients, CD4+ T-cell counts below 200 cells/mm³, and especially under 50–100 cells/mm³, are strongly associated with increased risk of infection and severe disease (4, 10) . Non-adherence or failure of antiretroviral therapy (ART) is another critical factor (12) . Other risk factors include poor socioeconomic and sanitary conditions, as lack of access to basic infrastructure, such as clean water and sanitation, increases exposure to oocysts. Additionally, contact with animals represents an important zoonotic transmission route for Cryptosporidium spp., especially in rural areas or for individuals in close contact with infected livestock or pets. Consumption of contaminated water and food is also relevant, with outbreaks of cryptosporidiosis linked to contaminated public or recreational water supplies documented in other countries—a risk in Brazil due to the oocysts’ resistance to conventional water treatment (11) . Finally, risky sexual practices, such as oral-anal transmission, may occur, particularly for Cryptosporidium spp. (4) . Clinical Presentation in Immunosuppressed Patients In immunosuppressed patients, the clinical presentation of cryptosporidiosis and cystoisosporiasis is typically more severe and prolonged than in immunocompetent individuals. Cryptosporidiosis The predominant manifestation is profuse, watery secretory diarrhea, which may persist for weeks, months, or even years if immunity is not restored. The diarrhea can lead to severe dehydration and electrolyte imbalances; intestinal malabsorption, resulting in significant weight loss and malnutrition; cramping abdominal pain, nausea, vomiting, and low-grade fever (1, 10) . In cases of severe immunosuppression, cryptosporidiosis may disseminate to extraintestinal sites, such as the biliary tract (causing sclerosing cholangitis, acalculous cholecystitis), pancreas (pancreatitis), and respiratory tract (cough, dyspnea) (1, 10) . Cryptosporidium-associated cholangiopathy is a severe complication with a guarded prognosis. Cystoisosporiasis Cystoisosporiasis in immunosuppressed individuals is also characterized by watery diarrhea, intermittent or continuous, often accompanied by abdominal pain, nausea, vomiting, anorexia, fever, and significant weight loss. Malabsorption and steatorrhea are common (3) . Unlike cryptosporidiosis, peripheral eosinophilia may be present in some patients with cystoisosporiasis (2) . Although rare, extraintestinal dissemination of Cystoisospora belli to lymph nodes, liver, and spleen has been described in AIDS patients. The chronicity and severity of symptoms in both infections profoundly impact patients’ quality of life, often necessitating hospitalization and intensive nutritional support. caption \DeclareCaptionFormatnocaption \captionsetupformat=nocaption,aboveskip=0pt,belowskip=0pt \adjustboxsetmax size=0.90.9 \DefineVerbatimEnvironmentHighlightingVerbatimcommandchars= {} Diagnosis The diagnosis of cryptosporidiosis and cystoisosporiasis is not frequent due to high underreporting rates, gaps in patient screening and follow-up, and frequent misclassification as viral gastroenteritis. However, when properly performed, it relies on the detection of oocysts in stool or, in cases of extraintestinal involvement, in biopsy samples or other biological fluids. Traditional Parasitological Methods Light microscopy after specific staining techniques is the most commonly used diagnostic method in routine laboratory practice in Brazil. Modified acid-fast staining techniques, such as the Ziehl-Neelsen (Kinyoun) method, are the most common for visualizing Cryptosporidium spp. oocysts (which stain red/pink) and Cystoisospora belli oocysts (which also stain red/pink but are larger and more oval than Cryptosporidium , measuring 20–33 µm in length and 10–19 µm in width) (10) . Safranin-methylene blue is another staining option. Cystoisospora belli oocysts can also be visualized in fresh or Lugol’s iodine preparations but are better identified with permanent stains and exhibit autofluorescence under ultraviolet fluorescence microscopy (2) . The sensitivity of stool parasitological exams can be increased with concentration methods, such as the Ritchie (formalin-ether) or Sheather (sugar flotation) techniques (4) . However, intermittent oocyst shedding, especially in cystoisosporiasis, may require the collection of multiple stool samples. caption \DeclareCaptionFormatnocaption \captionsetupformat=nocaption,aboveskip=0pt,belowskip=0pt \adjustboxsetmax size=0.90.9 \DefineVerbatimEnvironmentHighlightingVerbatimcommandchars= {} Immunological and Molecular Methods Immunological tests, such as enzyme-linked immunosorbent assays (ELISA) and direct immunofluorescence assays (DFA) for detecting Cryptosporidium spp. antigens in stool, offer higher sensitivity and specificity than traditional microscopy and are faster. However, their availability in Brazil’s public health system is limited and rarely utilized. Molecular techniques, such as polymerase chain reaction (PCR), are highly sensitive and specific, allowing not only parasite detection but also species and genotype identification of Cryptosporidium , which is important for epidemiological studies and understanding transmission routes (zoonotic vs. anthroponotic) (8) . Despite their utility, molecular methods are more expensive and complex, typically restricted to research centers and reference laboratories. Diagnostic Challenges in Brazil In Brazil, the diagnosis of coccidioses faces several challenges that significantly contribute to underreporting. Among these obstacles are low clinical suspicion, leading many physicians to not specifically request testing for these parasites. Additionally, there is a lack of standardization and quality control in microscopic exams, resulting in variability in diagnostic quality across laboratories. Limited access to more sensitive tests, such as immunological and molecular methods, particularly in the public healthcare system, further hampers accurate detection. Finally, the need for trained professionals is critical, as correct oocyst identification under microscopy requires considerable expertise. Treatment The management of cryptosporidiosis and cystoisosporiasis in immunosuppressed patients involves supportive measures, specific antimicrobial therapy, and, fundamentally, immune restoration. Cryptosporidiosis Currently, nitazoxanide is the only FDA-approved drug for treating Cryptosporidium-induced diarrhea in immunocompetent individuals and has been used in immunosuppressed patients. In HIV/AIDS patients, nitazoxanide’s efficacy is higher in those with higher CD4+ counts and may help reduce parasite load and symptoms. However, in patients with severe immunosuppression (CD4+ < 50 cells/mm³), parasite eradication becomes difficult without immune recovery (1) . Paromomycin has been used as an alternative but with limited efficacy. Optimization of antiretroviral therapy (ART) is essential in treating cryptosporidiosis in HIV/AIDS patients, as immune recovery typically leads to infection resolution. Cystoisosporiasis The treatment of choice for cystoisosporiasis is sulfamethoxazole-trimethoprim (SMX-TMP) (2, 3) . The response is usually effective, with symptom improvement within days. In HIV/AIDS patients, after acute-phase treatment, secondary prophylaxis (maintenance therapy) with lower SMX-TMP doses is often necessary to prevent relapse, particularly if immunosuppression persists. For patients allergic or intolerant to sulfonamides, alternatives such as pyrimethamine combined with folinic acid or ciprofloxacin may be considered, though ciprofloxacin is generally less effective than SMX-TMP (3) . Supportive Measures In both cases, supportive measures are essential and include oral or intravenous rehydration to correct dehydration and electrolyte imbalances. Adequate nutritional support is also crucial, potentially involving enteral or parenteral nutrition therapy to combat malabsorption and malnutrition. Additionally, antidiarrheal agents, such as loperamide, may be used for symptomatic control, though their use requires caution and medical supervision (6) . Underreporting Underreporting of cryptosporidiosis and cystoisosporiasis in Brazil is a multifactorial problem of great relevance, compromising accurate estimates of disease incidence and, consequently, the planning and implementation of effective control measures (7) . First, the insidious nature of these diseases poses a challenge, as diarrheal episodes are often misattributed to more prevalent or known causes, leading to missed requests for coproparasitological or other diagnostic tests for intestinal coccidia (8) . Another key factor lies in diagnostic limitations. As previously discussed, the heavy reliance on traditional microscopic methods—which require not only adequate equipment but also high expertise—combined with limited availability and access to more sensitive and specific diagnostic tests, such as molecular assays, in many regions of the country, significantly contributes to underdiagnosis and, consequently, underreporting (9) . Moreover, the lack of awareness and low clinical suspicion among healthcare professionals regarding the importance of actively investigating these infections, especially in at-risk groups beyond those with advanced HIV/AIDS—such as transplant recipients, oncology patients, or those on other immunosuppressive therapies—constitutes a significant barrier (10) . Additionally, the fragility of the epidemiological surveillance system for these specific parasitic diseases is a concern. Although AIDS is a notifiable condition, associated opportunistic infections, including cryptosporidiosis and cystoisosporiasis, are not always reported systematically, uniformly, or in detail. Notably, there is no specific, nationally unified epidemiological surveillance system for these coccidiosis that comprehensively covers all immunosuppressed patient profiles (11) . Finally, the scarcity of robust prevalence studies with national or even regional coverage hinders the construction of a reliable epidemiological overview. Many available surveys are geographically localized or focus on very specific populations, as demonstrated by Moura (4) and other isolated studies like Ferreira & Almeida (10) , preventing generalization of data to the rest of the country. In this context, overcoming underreporting of cryptosporidiosis and cystoisosporiasis in Brazil requires a multifaceted and coordinated approach. Such an approach must include strengthening epidemiological surveillance systems, improving reporting workflows; enhancing laboratory capacity and quality, including expanded access to more accurate diagnostic methods; continuous training and awareness-raising for healthcare professionals to improve suspicion and investigation; and the effective routine inclusion of these parasites in the diagnostic workup for chronic or persistent diarrhea, particularly in all immunosuppressed patient groups (12) . Prevention and Control Prevention and control of cryptosporidiosis and cystoisosporiasis in immunosuppressed patients require an integrated approach, with a primary focus on optimizing host immunity, especially in HIV/AIDS patients through effective antiretroviral therapy (ART). Chemoprophylaxis with sulfamethoxazole-trimethoprim (SMX-TMP), indicated for other conditions, may offer additional protection against cystoisosporiasis in severely immunosuppressed individuals. Concurrently, rigorous personal and food hygiene measures are essential, including frequent handwashing, consumption of treated water—noting Cryptosporidium’s resistance to routine chlorination—and properly cleaned and cooked foods, as well as careful handling of animals to mitigate zoonotic transmission. At the community level, investment in basic sanitation and sewage treatment is critical to reduce environmental contamination by oocysts. Health education, targeting immunosuppressed patients and their caregivers on risks and preventive practices, complements these strategies. In Brazil, although ministerial guidelines exist for managing opportunistic infections in HIV/AIDS patients, the effective implementation of environmental control measures and universal access to accurate diagnostics remain significant challenges. caption \DeclareCaptionFormatnocaption \captionsetupformat=nocaption,aboveskip=0pt,belowskip=0pt \adjustboxsetmax size=0.90.9 \DefineVerbatimEnvironmentHighlightingVerbatimcommandchars= {} Socioeconomic Impact The socioeconomic impact of cryptosporidiosis and cystoisosporiasis in immunosuppressed patients in Brazil is considerable, though often underestimated due to underreporting. This impact manifests through high direct costs to the healthcare system, including expenses related to consultations, tests, medications, and prolonged hospitalizations, as well as significant indirect costs from lost productivity and premature mortality. Additionally, chronic diarrhea and associated symptoms severely compromise patients’ and their families’ quality of life. Outbreaks, particularly waterborne cryptosporidiosis, can also incur high costs for epidemiological investigations and emergency control measures. Thus, reducing the burden of these diseases through effective prevention and control strategies represents substantial potential savings for Brazil’s healthcare system and society at large. Current Challenges and Strategic Actions for the Future Infections caused by Cryptosporidium spp. and Cystoisospora belli remain a significant challenge for the health of immunosuppressed patients in Brazil, often resulting in severe and debilitating clinical presentations. The true epidemiological scale of these parasitic diseases remains partially understood, a direct reflection of underreporting and the heterogeneity of available studies (7) . To advance the fight against these parasitoses in the Brazilian context, the implementation of coordinated and strategic actions is imperative. This includes, fundamentally, strengthening epidemiological surveillance by establishing more efficient and comprehensive reporting systems and substantially improving national diagnostic capacity. Such improvement involves not only expanding access to more sensitive and specific methods in the public healthcare network but also ensuring continuous training for laboratory professionals, as advocated by health guidelines (9) . Parallelly, fostering research is crucial, encouraging multicenter epidemiological studies with standardized methodologies to more accurately characterize the prevalence, distribution, and risk factors associated with these infections across diverse immunosuppressed groups and regions of the country, including investigations into the genetic diversity of circulating Cryptosporidium species, as highlighted in regional studies (10) . Continuous health education, aimed at both training professionals for improved clinical suspicion and management (10) and guiding patients on preventive measures, is another essential pillar. Additionally, effective public policies promoting consistent investments in basic sanitation and ensuring water supply quality are indispensable. Finally, while immune restoration is a key component of treatment, the search for more effective and safer antiparasitic agents for severely immunosuppressed patients must remain a priority in clinical research. An integrated and synergistic approach to these multiple fronts is essential to effectively reduce the morbidity and mortality associated with cryptosporidiosis and cystoisosporiasis in immunosuppressed patients in Brazil. Such efforts would not only improve the quality of life for these individuals but also alleviate the considerable burden these infections place on the healthcare system (11) . Referências 1. Bonsere WCP, Mioranza SL, Fariña LO, Santos KC, Ayala TS. Surtos de criptosporidiose em humanos: uma revisão sistemática. Rev Bras Meio Ambiente. 2020;8(2). 2. Noor MA, et al. Cystoisospora belli infection: a mini review. Asian Pac J Trop Biomed. 2019;9(5):181-6. 3. Cunha GV, Paz LB, Azenha EM, Junior RS, Albernaz DAS. Principais protozoários entéricos oportunistas associados à AIDS: Cryptosporidium parvum, Isospora belli, Cyclospora cayetanensis e Microsporidia. Rev Aten Saúde. 2018;16(55):99-107. 4. Moura LNS, et al. Frequência de Cryptosporidium spp. e Cystoisospora spp. em pacientes HIV/AIDS internados no Hospital Giselda Trigueiro, Natal/RN [Trabalho de Conclusão de Curso]. Natal: Universidade Federal do Rio Grande do Norte; 2017. 5. Instituto Adolfo Lutz. Frequência de Cryptosporidium sp e Isospora belli em pacientes soropositivos para o HIV na região de Ribeirão Preto, SP. Rev Inst Adolfo Lutz. 2000;60(1):45-9. 6. Assis DC, et al. Prevalence and genetic characterization of Cryptosporidium spp. and Cystoisospora belli in HIV-infected patients. Rev Inst Med Trop Sao Paulo. 2013;55(3):149-54. 7. Santos FP, Lima CA. Desafios da vigilância de coccidioses intestinais no Brasil. Rev Bras Epidemiol. 2021;24:e210034. 8. Oliveira Filho AN, Barreto MS, Gomes TA. Etiologia e diagnóstico diferencial de diarreias persistentes em pacientes imunocomprometidos. J Bras Patol Med Lab. 2019;55(3):280-95. 9. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Guia de vigilância em saúde. 6ª ed. Brasília: Ministério da Saúde; 2022. 10. Ferreira JC, Almeida RP. Conhecimento e práticas de médicos da atenção primária sobre o manejo de enteroparasitoses oportunistas. Cad Saude Publica. 2020;36(5):e00123419. 11. Teixeira MG, Costa MCN, Carmo EH. Vigilância epidemiológica no Brasil: avanços e desafios. Cien Saude Colet. 2018;23(6):1823-30. 12. Sociedade Brasileira de Infectologia. Recomendações para o manejo de infecções oportunistas em pacientes com HIV/AIDS. São Paulo: SBI; 2023. Information & Authors Information Version history V1 Version 1 22 July 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords coccidiosis cryptosporidiosis disease immunodeficiency isospora parasite Authors Affiliations Willian Cardoso Ferreira Zorrer 0009-0005-3934-4331 [email protected] Universidade Federal de Pelotas View all articles by this author Estefani Rinaldi Universidade Federal de Pelotas View all articles by this author Bibiana Rodrigues de Freitas Universidade Federal de Pelotas View all articles by this author Pedro Machado Medeiros de Albuquerque Universidade Federal de Pelotas View all articles by this author Rodrigo Casquero Cunha Universidade Federal de Pelotas View all articles by this author Fabio Raphael Pascotti Bruhn Universidade Federal de Pelotas View all articles by this author rahal.natalia View all articles by this author Metrics & Citations Metrics Article Usage 255 views 147 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Willian Cardoso Ferreira Zorrer, Estefani Rinaldi, Bibiana Rodrigues de Freitas, et al. 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