Treatment of Urticaria Caused by Severe Cryptosporidiosis in a 17-Month-Old Child – A Case Report and Review of the Literature

Treatment of Urticaria Caused by Severe Cryptosporidiosis in a 17-Month-Old Child – A Case Report and Review of the Literature | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Treatment of Urticaria Caused by Severe Cryptosporidiosis in a 17-Month-Old Child – A Case Report and Review of the Literature Mehdi Azami, Saeid Amini Rarani, Fatemeh Kiani This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2428867/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Jul, 2023 Read the published version in BMC Infectious Diseases → Version 1 posted 8 You are reading this latest preprint version Abstract Background Cryptosporidium is an intracellular protozoan that causes gastrointestinal symptoms in humans and animals. In immunocompromised patients and children under 5 years of age, the infection is severe and can be life-threatening due to severe diarrhea. Case presentation We report a case of urticaria associated with Cryptosporidium in a 17-month-old female Iranian child. The patient had severe diarrhea, weight loss and urticaria. Since the child's father worked in livestock farming, the hypothesis of parasite transmission from cows or calves to the house and the child was proposed. Several Cryptosporidium oocysts were detected in the modified acid-fast staining of the child's stool sample. The patient was successfully treated with nitazoxanide (100 mg twice daily) and became negative for parasites three days after treatment and one week after discharge from the hospital. Her stool pattern normalized in 1 week and she has had no recurrence after 6 months of follow up. Conclusion A number of parasites are associated with urticaria, but to our knowledge, there is no information on Cryptosporidium -induced urticaria. Therefore, our result may be evidence for the role of this parasite in the development of urticaria. Urticaria Cryptosporidium parasites nitazoxanide Background Cryptosporidiosis is one of the protozoan diseases caused by coccidia of the genus Cryptosporidium . This protozoan was first reported by Tyzzer in 1907 from the stomach glands of a laboratory mouse. Cryptosporidium is one of the most important common intestinal pathogens that has been reported in many organisms and in most parts of the world. The zoonotic role of Cryptosporidium has also made it important in terms of economics and public health [ 1 ]. This disease has been a serious problem in public health and at present it is widely considered as one of the causes of acute infectious gastroenteritis that is self-limiting in individuals with a complete immune system and fatal infection in immunocompromised individuals. About 30 to 50 percent of the deaths of children and infants worldwide are due to cryptosporidiosis [ 2 ]. According to the report of the World Health Organization, about 8 million deaths of children under 5 years of age are related to diarrhea. Sub-Saharan Africa accounts for half of all annual deaths of children under one year of age, and it is estimated that more than 2.9 million cryptosporidiosis infections occur annually in this region [ 3 ]. The routes of Cryptosporidium spp. transmission are waterborne, food-borne, and occasionally person-to-person. Parasites cause weight loss, stunted growth, permanent impact on children's growth and increase in mortality. Acute cryptosporidiosis occurs in the form of severe watery diarrhea, which leads to dehydration, malabsorption and malnutrition. There are various reports of the prevalence of cryptosporidiosis in children in Iran. Previous studies have reported 4.6% prevalence of parasites in children under five years of age in Isfahan city [ 4 ]. The clinical symptoms of cryptosporidiosis are similar in children and adults. These symptoms include watery diarrhea that is sometimes with mucus. Diarrhea may be accompanied by fever, weight loss, nausea, vomiting, and loss of appetite. In severe cases, the parasite can attack the respiratory system, liver, bile ducts, and pancreas [ 1 ]. At present, the effective treatment for cryptosporidiosis is the use of nitazoxanide along with serum therapy. Skin manifestations and urticaria have been reported by some helminth and protozoan parasites [ 5 ]. But so far, there is no report of cryptosporidium parasite skin manifestations. We describe a case of chronic urticaria associated with Cryptosporidium . Case Presentation A 17-month-old female referred to the pediatric clinic of Isfahan Hojjatiyeh hospital due to severe diarrhea with urticaria. He was born in the city of Isfahan and her parents lived in one of the villages around Isfahan. The child's father was a farmer and her mother was a housewife. No similar clinical symptoms were observed in the child's parents. The parents complained about the malaise of their child's, abdominal cramps and diarrhea, which was accompanied by a red rash on the skin. The parents mentioned that the child's symptoms started 20 days ago and visiting different doctors, taking antibiotics and prescribed medicines during this period were not effective. The child passed 5 to 6 times a day watery mucous and non-bloody diarrhea. He was examined with moderate dehydration with minor symptoms due to dehydration such as weight loss, deep-set eyes, and pale and lethargic skin. Physical examination of the chest, abdomen, ears and throat was normal, but typical erythematous wheals accompanied by itching and without angioedema were observed on skin. The child had no fever, but presented tachycardia of 127 bpm, a respiratory rate of 20/min, and blood pressure of 85/6.0 mmHg. O 2 saturation on room air was 99%. Her peripheral blood count showed a white blood cell (WBC) count of 11.7×10 3 /mm3, a red blood cell count (RBC) of 4.6×10 6 /mm 3 , hemoglobin of 13.4 g/dL, hematocrit of 41.2%, reticulocytes 1.1% and a platelet count of 541×10 3 / mm 3 . A differential count of WBC revealed the following: neutrophils 49%, lymphocytes 41%, eosinophils 6% and monocytes 4%. The results of biochemical tests were normal. Only a slight amount of hyponatremia (Na: 130.1 mmol/L) and hypokalemia (K: 3.0 mmol/L) was observed. The results of C-reactive protein, erythrocyte sedimentation rate, urine analysis and urine culture, thyroid function tests and thyroid autoantibodies, complement factors C3, C4 and C1 inhibitor, antinuclear autoantibodies (ANA, ENA), serum immunoglobulins, and rheumatoid factor were normal. Slightly IgE level was increased (19 IU/mL, Normal: 0–13 IU/mL). The patient's stool sample was sent to the laboratory for rotavirus-adenovirus antigen, Giardia antigen, Clostridium antigen and fecal bacteria culture and the all results were negative. Routine stool examination for enteric parasites was negative. Modified Ziehl-Nielsen staining of a stool smear showed several Cryptosporidium oocysts. Intravenous fluids with oral paromomycin (30 mg/kg/day) were started for the patient. With the diagnosis of Cryptosporidium , nitazoxanide oral solution (100 mg twice daily) was included in the patient's medication regimen. One day after taking the medicine, the severity of diarrhea decreased, so that after 3 days, the diarrhea was completely cured. At the same time as the frequency of diarrhea decreased, the severity of urticaria also decreased and after 5 days it was generally improved. One week after taking nitazoxanide, the patient was discharged from the hospital with a good general condition. By Modified Ziehl-Nielsen staining method, the presence of Cryptosporidium in the feces was reported negative three days after taking the drug and one week after being discharged from the hospital. Her stool pattern normalized in 1 week and she has had no recurrence after 6 months of follow up. Discussion And Conclusion Cryptosporidium is a zoonosis and intestinal pathogen that infects humans and various animals. The parasite is transmitted through water, food, and feces-contaminated materials, and settles in the epithelial cells of the intestinal region where it reproduces asexually and increases in number. The presence of parasites in the intestine cause's mild to severe gastrointestinal symptoms. The parasite causes severe watery diarrhea that can lead to death in immunocompromised patients and children if left untreated [ 6 ]. A recent study showed, zoonosis transmission of Cryptosporidium species due to contact with cows and calves is prevalent among farm workers and their household members in Isfahan city [ 7 ]. According to the results of this study, most of the people infected with parasites were without diarrhea or clinical symptoms. It is worth discussing this as it probably represents a further risk factor for transmission especially if this was shown to be in young children from which transmission is likely to occur [ 7 ]. In our case, the father of the family was in close contact with cows and calves, and perhaps this factor caused the parasite to be transmitted to the child. Urticaria refers to localized or widespread red edematous papules on the body surface that may last for several weeks. Skin lesions may be accompanied by angioedema, which is characterized by pathological changes in the depth of the dermis and subcutaneous tissue [ 8 ]. Inflammatory mediators released from basophils and mast cells lead to an increase in these skin reactions. About 20% of the general population will develop urticaria at least once in their lifetime. Diagnosing urticaria is easy, but finding its cause is difficult and requires careful examination methods to discover diagnostic clues and rule out serious medical conditions. Several conditions have been found to be related to urticaria symptoms, whereas the term chronic idiopathic urticaria identifies the high percent of conditions in which a pathogenetic factor has not been found [ 9 ]. Identifying the cause of urticaria requires ruling out many other conditions. A special form of urticaria is autoimmune urticaria, in which antibodies are produced against IgE receptors or IgE itself [ 10 ]. Food allergens, drugs, colors, perfumes, insect bites, chemicals and physical sensitivities are other causes of urticaria. The existence of some diseases related to the immune system, viral and bacterial infections are also other causes of urticaria. Although intestinal parasites have been cited as a possible cause of urticaria, only a limited number of documented cases have shown a relationship between parasitic infection and urticaria [ 11 ]. A large number of infections caused by parasitic worms such as Fasciola hepatica , Strongyloides stercoralis , Echinococcus granulosus , filaria, Ascaris lumbricoides , Trichinella spiralis , and Schistosoma sp. have been associated with allergic skin symptoms, and antiparasitic drugs have not been effective in treating urticaria caused by them [ 5 , 11 , 12 ]. The mechanism of urticaria caused by Cryptosporidium , like other enteric pathogens, is not fully understood. The authors hypothesized a pathogenesis similar to that underlying the IgE-mediated allergic response: Cryptosporidium antigens induce specific Th2 clones on lymphocytes, which in turn produce specific cytokines (ILs 3, 4, 5 and 13) and lead to the switch of antibodies and IgE production. This mechanism can be confirmed by performing a skin biopsy and observing the increase in mast cells and mononuclear cells. This reaction will be responsible for increasing the production of histamine and other mediators of early and late inflammatory reaction. The increase of circulating eosinophils in most patients with parasitic infection is another factor related to allergic sensitivity [ 13 ]. A number of antibiotics have been used to treat intestinal cryptosporidiosis. However, most of them cannot kill the organism completely [ 14 ]. Paromomycin is an aminoglycoside that cannot be completely absorbed when taken orally, and as an anti-cryptosporidial drug, it has a high rate of recurrence after treatment [ 15 ]. Perhaps one of the reasons is that paromomycin is placed inside the intestinal tract and has little activity on the intracellular forms of the parasite. Nitazoxanide (Alinia) is a new drug with broad activity against protozoa and intestinal worms. This drug inhibits ferredoxin reductase, which is the main enzyme in the parasite's anaerobic metabolism [ 16 ]. Nitazoxanide has recently been approved by the FDA for the treatment of Giardia and Cryptosporidium in immunocompetent children aged 1 to 12 years. Along with drug treatment, appropriate intravenous nutrition, supportive hydration is necessary due to severe diarrhea. In our case, complete improvement of urticaria was observed using nitazoxanide, a drug that has no anti-allergic and anti-inflammatory effects, without taking any antihistamine. Unfortunately, we do not know the exact mechanism of urticaria caused by Cryptosporidium . Anyway, various reasons have been discussed for the cause of urticaria caused by parasitic infections, such as the role of specific IgE, Th2 cytokine skewing, eosinophil's and coagulation system and finally circulating immune complexes and complement system [ 9 – 12 ]. Our patient was a child with severe diarrhea with typical urticaria. Its cause was determined by an accidental intestinal parasitic infection with Cryptosporidium , which caused an allergic skin reaction. The treatment of parasitic infection led to the disappearance of parasite antigens in feces and the improvement of intestinal symptoms and urticaria. These results may provide evidence for the role of intestinal parasitic infections in the induction of chronic urticaria, especially by Cryptosporidium species. Declarations We have no conflicts of interest to disclose. Acknowledgements The authors warmly thank the child parents for agreeing to submit her case. Author contributions MA collected the data, performed the literature review and wrote the manuscript. SAR took care of the patient. FK performed the laboratory tests and parasite identification. MA and SAR supervised the process of drafting the manuscript and revised all versions. All authors read and approved the final manuscript. Funding This research received no external funding. Availability of data and materials Not applicable. Ethics approval and consent to participate Not applicable. Consent for publication Written informed consent was obtained from the parents of patient for publication of this case report. Competing interests The authors declare that they have no competing interests References Azami M, Hejazi SH, editors. Cryptosporidium and methods of diagnosis. Isfahan University of Medical Sciences, press; 2010. Khan A, Shams S, Khan S, Khan MI, Khan S, Ali A. Evaluation of prevalence and risk factors associated with Cryptosporidium infection in rural population of district Buner, Pakistan. PLoS One. 2019;14(1):e0209188. Walker CL, Rudan I, Liu L, Nair H, Theodoratou E, Bhutta ZA, O'Brien KL, Campbell H, Black RE. Global burden of childhood pneumonia and diarrhoea. Lancet. 2013;381(9875):1405–16. Azami M, Dorostkar Moghadam D. Prevalence of Cryptosporidium in children under 5 years of age, immunocompromised patients and high-risk persons in Isfahan province. Iran South Med J. 2008;11(1):47–54. Kolkhir P, Balakirski G, Merk HF, Olisova O, Maurer M. Chronic spontaneous urticaria and internal parasites–a systematic review. Allergy. 2016;71(3):308–22. Mohaghegh MA, Hejazi SH, Ghomashlooyan M, Kalani H, Mirzaei F, Azami M. Prevalence and clinical features of Cryptosporidium infection in hemodialysis patients. Gastroenterol Hepatol Bed Bench. 2017;10(2):137–42. Izadi M, Jonaidi-Jafari N, Saburi A, Eyni H, Rezaiemanesh MR, Ranjbar R. Cryptosporidiosis in Iranian farm workers and their household members: a hypothesis about possible zoonotic transmission. J Trop Med. 2014; 2014: 405875. doi: 10.1155/2014/405875 Kayiran MA, Akdeniz N. Diagnosis and treatment of urticaria in primary care. North Clin Istanb. 2019;6(1):93–9. Dobrican CT, Muntean IA, Pintea I, Petricău C, Deleanu DM, Filip GA. Immunological signature of chronic spontaneous urticaria. Exp The Med. 2022;23(6):1–7. Cho CB, Stutes SA, Altrich ML, Ardoin SP, Phillips G, Ogbogu PU. Autoantibodies in chronic idiopathic urticaria and nonurticarial systemic autoimmune disorders. Ann Allergy Asthma Immunol. 2013;110(1):29–33. Viñas M, Postigo I, Suñén E, Martínez J. Urticaria and silent parasitism by Ascaridoidea: Component-resolved diagnosis reinforces the significance of this association. PLoS Negl Trop Dis. 2020;14(4):e0008177. 10.1371/journal.pntd.0008177 . Godse K. Can worms cause chronic urticaria? Indian J Dermatol. 2001;51(2):153–4. Ramirez GA, Yacoub MR, Ripa M, Mannina D, Cariddi A, Saporiti N, Ciceri F, Castagna A, Colombo G, Dagna L. Eosinophils from physiology to disease: a comprehensive review. BioMed Res Int. 2018; 2018:9095275. doi: 10.1155/2018/9095275 . Miyamoto Y, Eckmann L. Drug development against the major diarrhea-causing parasites of the small intestine, Cryptosporidium and Giardia . Front Microbiol. 2015;6:1208. 10.3389/fmicb.2015.01208 . Cabada MM, White AC Jr. Treatment of cryptosporidiosis: do we know what we think we know? Curr Opin Infect Dis. 2010;23(5):494–9. Fox LM, Saravolatz LD. Nitazoxanide: a new thiazolide antiparasitic agent. Clin Infect Dis. 2005;40(8):1173–80. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 09 Jul, 2023 Read the published version in BMC Infectious Diseases → Version 1 posted Editorial decision: Major revision 13 Feb, 2023 Reviews received at journal 18 Jan, 2023 Reviewers agreed at journal 12 Jan, 2023 Reviewers invited by journal 11 Jan, 2023 Editor assigned by journal 06 Jan, 2023 Editor invited by journal 06 Jan, 2023 Submission checks completed at journal 06 Jan, 2023 First submitted to journal 30 Dec, 2022 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2428867","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":165501025,"identity":"8684c5b8-ebf9-499e-a42f-dc4607a5a092","order_by":0,"name":"Mehdi Azami","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIiWNgGAWjYFACHgaJBDCDsfEBiMtHipZmAxCXjSgtUBYbmEFQi25778EbDxjs7PmnHW6r/JpjJ8PGwPzw0Q08WszOnEu2SGBIZpa4ndh2W3ZbMtBhbMbGOfi03MgxA/qFmY0BpEVyGzNQCw+bNF4t99+AtNTzyAO1FEtuqydCyw0ekJbDEgZALYwftx0mQsuZHGOLBIPjBoa3E5ulGbcd52FjJuSX42cMb/6oqLaXu53+8OPPbdX2/OzNDx/j0wIBBhCKmQdMElSOBBh/kKJ6FIyCUTAKRgwAAMMVQoWN0hZ2AAAAAElFTkSuQmCC","orcid":"","institution":"Skin Diseases and Leishmaniasis Research Center, Isfahan University of Medical sciences","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Mehdi","middleName":"","lastName":"Azami","suffix":""},{"id":165501026,"identity":"2c7f828b-68a6-441a-a7c4-3d5bba388b96","order_by":1,"name":"Saeid Amini Rarani","email":"","orcid":"","institution":"Nursing and Midwifery Care Research Center, Department of Operating Room, Isfahan University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Saeid","middleName":"Amini","lastName":"Rarani","suffix":""},{"id":165501027,"identity":"0193604f-ecad-4adc-a676-b83e8f13cb1f","order_by":2,"name":"Fatemeh Kiani","email":"","orcid":"","institution":"Department of Medical Parasitology and Microbiology, Hojjatieh Medical Diagnostic Laboratory, Hojjatieh Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Fatemeh","middleName":"","lastName":"Kiani","suffix":""}],"badges":[],"createdAt":"2022-12-30 14:29:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2428867/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2428867/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12879-023-08446-y","type":"published","date":"2023-07-10T01:09:01+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":41742682,"identity":"566003d3-4428-4405-8bcc-008b783fd9f1","added_by":"auto","created_at":"2023-08-18 04:37:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":205248,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2428867/v1/84949a7a-a928-4498-a155-ee951728784d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Treatment of Urticaria Caused by Severe Cryptosporidiosis in a 17-Month-Old Child – A Case Report and Review of the Literature","fulltext":[{"header":"Background","content":"\u003cp\u003eCryptosporidiosis is one of the protozoan diseases caused by coccidia of the genus \u003cem\u003eCryptosporidium\u003c/em\u003e. This protozoan was first reported by Tyzzer in 1907 from the stomach glands of a laboratory mouse. \u003cem\u003eCryptosporidium\u003c/em\u003e is one of the most important common intestinal pathogens that has been reported in many organisms and in most parts of the world. The zoonotic role of \u003cem\u003eCryptosporidium\u003c/em\u003e has also made it important in terms of economics and public health [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis disease has been a serious problem in public health and at present it is widely considered as one of the causes of acute infectious gastroenteritis that is self-limiting in individuals with a complete immune system and fatal infection in immunocompromised individuals.\u003c/p\u003e \u003cp\u003eAbout 30 to 50 percent of the deaths of children and infants worldwide are due to cryptosporidiosis [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. According to the report of the World Health Organization, about 8\u0026nbsp;million deaths of children under 5 years of age are related to diarrhea. Sub-Saharan Africa accounts for half of all annual deaths of children under one year of age, and it is estimated that more than 2.9\u0026nbsp;million cryptosporidiosis infections occur annually in this region [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The routes of \u003cem\u003eCryptosporidium\u003c/em\u003e spp. transmission are waterborne, food-borne, and occasionally person-to-person. Parasites cause weight loss, stunted growth, permanent impact on children's growth and increase in mortality. Acute cryptosporidiosis occurs in the form of severe watery diarrhea, which leads to dehydration, malabsorption and malnutrition. There are various reports of the prevalence of cryptosporidiosis in children in Iran. Previous studies have reported 4.6% prevalence of parasites in children under five years of age in Isfahan city [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe clinical symptoms of cryptosporidiosis are similar in children and adults. These symptoms include watery diarrhea that is sometimes with mucus. Diarrhea may be accompanied by fever, weight loss, nausea, vomiting, and loss of appetite. In severe cases, the parasite can attack the respiratory system, liver, bile ducts, and pancreas [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. At present, the effective treatment for cryptosporidiosis is the use of nitazoxanide along with serum therapy.\u003c/p\u003e \u003cp\u003eSkin manifestations and urticaria have been reported by some helminth and protozoan parasites [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. But so far, there is no report of \u003cem\u003ecryptosporidium\u003c/em\u003e parasite skin manifestations. We describe a case of chronic urticaria associated with \u003cem\u003eCryptosporidium\u003c/em\u003e.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 17-month-old female referred to the pediatric clinic of Isfahan Hojjatiyeh hospital due to severe diarrhea with urticaria. He was born in the city of Isfahan and her parents lived in one of the villages around Isfahan. The child's father was a farmer and her mother was a housewife. No similar clinical symptoms were observed in the child's parents. The parents complained about the malaise of their child's, abdominal cramps and diarrhea, which was accompanied by a red rash on the skin. The parents mentioned that the child's symptoms started 20 days ago and visiting different doctors, taking antibiotics and prescribed medicines during this period were not effective. The child passed 5 to 6 times a day watery mucous and non-bloody diarrhea. He was examined with moderate dehydration with minor symptoms due to dehydration such as weight loss, deep-set eyes, and pale and lethargic skin. Physical examination of the chest, abdomen, ears and throat was normal, but typical erythematous wheals accompanied by itching and without angioedema were observed on skin. The child had no fever, but presented tachycardia of 127 bpm, a respiratory rate of 20/min, and blood pressure of 85/6.0 mmHg. O\u003csub\u003e2\u003c/sub\u003e saturation on room air was 99%.\u003c/p\u003e \u003cp\u003eHer peripheral blood count showed a white blood cell (WBC) count of 11.7\u0026times;10\u003csup\u003e3\u003c/sup\u003e/mm3, a red blood cell count (RBC) of 4.6\u0026times;10\u003csup\u003e6\u003c/sup\u003e/mm\u003csup\u003e3\u003c/sup\u003e, hemoglobin of 13.4 g/dL, hematocrit of 41.2%, reticulocytes 1.1% and a platelet count of 541\u0026times;10\u003csup\u003e3\u003c/sup\u003e/ mm\u003csup\u003e3\u003c/sup\u003e. A differential count of WBC revealed the following: neutrophils 49%, lymphocytes 41%, eosinophils 6% and monocytes 4%. The results of biochemical tests were normal. Only a slight amount of hyponatremia (Na: 130.1 mmol/L) and hypokalemia (K: 3.0 mmol/L) was observed. The results of C-reactive protein, erythrocyte sedimentation rate, urine analysis and urine culture, thyroid function tests and thyroid autoantibodies, complement factors C3, C4 and C1 inhibitor, antinuclear autoantibodies (ANA, ENA), serum immunoglobulins, and rheumatoid factor were normal. Slightly IgE level was increased (19 IU/mL, Normal: 0\u0026ndash;13 IU/mL). The patient's stool sample was sent to the laboratory for rotavirus-adenovirus antigen, \u003cem\u003eGiardia\u003c/em\u003e antigen, \u003cem\u003eClostridium\u003c/em\u003e antigen and fecal bacteria culture and the all results were negative. Routine stool examination for enteric parasites was negative. Modified Ziehl-Nielsen staining of a stool smear showed several \u003cem\u003eCryptosporidium\u003c/em\u003e oocysts. Intravenous fluids with oral paromomycin (30 mg/kg/day) were started for the patient. With the diagnosis of \u003cem\u003eCryptosporidium\u003c/em\u003e, nitazoxanide oral solution (100 mg twice daily) was included in the patient's medication regimen. One day after taking the medicine, the severity of diarrhea decreased, so that after 3 days, the diarrhea was completely cured. At the same time as the frequency of diarrhea decreased, the severity of urticaria also decreased and after 5 days it was generally improved. One week after taking nitazoxanide, the patient was discharged from the hospital with a good general condition.\u003c/p\u003e \u003cp\u003eBy Modified Ziehl-Nielsen staining method, the presence of \u003cem\u003eCryptosporidium\u003c/em\u003e in the feces was reported negative three days after taking the drug and one week after being discharged from the hospital. Her stool pattern normalized in 1 week and she has had no recurrence after 6 months of follow up.\u003c/p\u003e"},{"header":"Discussion And Conclusion","content":"\u003cp\u003e \u003cem\u003eCryptosporidium\u003c/em\u003e is a zoonosis and intestinal pathogen that infects humans and various animals. The parasite is transmitted through water, food, and feces-contaminated materials, and settles in the epithelial cells of the intestinal region where it reproduces asexually and increases in number. The presence of parasites in the intestine cause's mild to severe gastrointestinal symptoms. The parasite causes severe watery diarrhea that can lead to death in immunocompromised patients and children if left untreated [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. A recent study showed, zoonosis transmission of \u003cem\u003eCryptosporidium\u003c/em\u003e species due to contact with cows and calves is prevalent among farm workers and their household members in Isfahan city [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. According to the results of this study, most of the people infected with parasites were without diarrhea or clinical symptoms. It is worth discussing this as it probably represents a further risk factor for transmission especially if this was shown to be in young children from which transmission is likely to occur [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In our case, the father of the family was in close contact with cows and calves, and perhaps this factor caused the parasite to be transmitted to the child.\u003c/p\u003e \u003cp\u003eUrticaria refers to localized or widespread red edematous papules on the body surface that may last for several weeks. Skin lesions may be accompanied by angioedema, which is characterized by pathological changes in the depth of the dermis and subcutaneous tissue [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Inflammatory mediators released from basophils and mast cells lead to an increase in these skin reactions. About 20% of the general population will develop urticaria at least once in their lifetime. Diagnosing urticaria is easy, but finding its cause is difficult and requires careful examination methods to discover diagnostic clues and rule out serious medical conditions. Several conditions have been found to be related to urticaria symptoms, whereas the term chronic idiopathic urticaria identifies the high percent of conditions in which a pathogenetic factor has not been found [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Identifying the cause of urticaria requires ruling out many other conditions. A special form of urticaria is autoimmune urticaria, in which antibodies are produced against IgE receptors or IgE itself [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Food allergens, drugs, colors, perfumes, insect bites, chemicals and physical sensitivities are other causes of urticaria. The existence of some diseases related to the immune system, viral and bacterial infections are also other causes of urticaria. Although intestinal parasites have been cited as a possible cause of urticaria, only a limited number of documented cases have shown a relationship between parasitic infection and urticaria [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. A large number of infections caused by parasitic worms such as \u003cem\u003eFasciola hepatica\u003c/em\u003e, \u003cem\u003eStrongyloides stercoralis\u003c/em\u003e, \u003cem\u003eEchinococcus granulosus\u003c/em\u003e, filaria, \u003cem\u003eAscaris lumbricoides\u003c/em\u003e, \u003cem\u003eTrichinella spiralis\u003c/em\u003e, and \u003cem\u003eSchistosoma\u003c/em\u003e sp. have been associated with allergic skin symptoms, and antiparasitic drugs have not been effective in treating urticaria caused by them [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe mechanism of urticaria caused by \u003cem\u003eCryptosporidium\u003c/em\u003e, like other enteric pathogens, is not fully understood. The authors hypothesized a pathogenesis similar to that underlying the IgE-mediated allergic response: \u003cem\u003eCryptosporidium\u003c/em\u003e antigens induce specific Th2 clones on lymphocytes, which in turn produce specific cytokines (ILs 3, 4, 5 and 13) and lead to the switch of antibodies and IgE production. This mechanism can be confirmed by performing a skin biopsy and observing the increase in mast cells and mononuclear cells. This reaction will be responsible for increasing the production of histamine and other mediators of early and late inflammatory reaction.\u003c/p\u003e \u003cp\u003eThe increase of circulating eosinophils in most patients with parasitic infection is another factor related to allergic sensitivity [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA number of antibiotics have been used to treat intestinal cryptosporidiosis. However, most of them cannot kill the organism completely [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Paromomycin is an aminoglycoside that cannot be completely absorbed when taken orally, and as an anti-cryptosporidial drug, it has a high rate of recurrence after treatment [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Perhaps one of the reasons is that paromomycin is placed inside the intestinal tract and has little activity on the intracellular forms of the parasite. Nitazoxanide (Alinia) is a new drug with broad activity against protozoa and intestinal worms. This drug inhibits ferredoxin reductase, which is the main enzyme in the parasite's anaerobic metabolism [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Nitazoxanide has recently been approved by the FDA for the treatment of \u003cem\u003eGiardia\u003c/em\u003e and \u003cem\u003eCryptosporidium\u003c/em\u003e in immunocompetent children aged 1 to 12 years. Along with drug treatment, appropriate intravenous nutrition, supportive hydration is necessary due to severe diarrhea. In our case, complete improvement of urticaria was observed using nitazoxanide, a drug that has no anti-allergic and anti-inflammatory effects, without taking any antihistamine. Unfortunately, we do not know the exact mechanism of urticaria caused by \u003cem\u003eCryptosporidium\u003c/em\u003e. Anyway, various reasons have been discussed for the cause of urticaria caused by parasitic infections, such as the role of specific IgE, Th2 cytokine skewing, eosinophil's and coagulation system and finally circulating immune complexes and complement system [\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur patient was a child with severe diarrhea with typical urticaria. Its cause was determined by an accidental intestinal parasitic infection with \u003cem\u003eCryptosporidium\u003c/em\u003e, which caused an allergic skin reaction. The treatment of parasitic infection led to the disappearance of parasite antigens in feces and the improvement of intestinal symptoms and urticaria. These results may provide evidence for the role of intestinal parasitic infections in the induction of chronic urticaria, especially by \u003cem\u003eCryptosporidium\u003c/em\u003e species.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eWe have no conflicts of interest to disclose. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors warmly thank the child parents for agreeing to submit her case.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMA collected the data, performed the literature review and wrote the manuscript. SAR took care of the patient. FK performed the laboratory tests and parasite identification. MA and SAR supervised the process of drafting the manuscript and revised all versions. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the parents of patient for publication of this case report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAzami M, Hejazi SH, editors. \u003cem\u003eCryptosporidium\u003c/em\u003e and methods of diagnosis. Isfahan University of Medical Sciences, press; 2010.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhan A, Shams S, Khan S, Khan MI, Khan S, Ali A. Evaluation of prevalence and risk factors associated with \u003cem\u003eCryptosporidium\u003c/em\u003e infection in rural population of district Buner, Pakistan. PLoS One. 2019;14(1):e0209188.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalker CL, Rudan I, Liu L, Nair H, Theodoratou E, Bhutta ZA, O'Brien KL, Campbell H, Black RE. Global burden of childhood pneumonia and diarrhoea. Lancet. 2013;381(9875):1405\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAzami M, Dorostkar Moghadam D. Prevalence of \u003cem\u003eCryptosporidium\u003c/em\u003e in children under 5 years of age, immunocompromised patients and high-risk persons in Isfahan province. Iran South Med J. 2008;11(1):47\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKolkhir P, Balakirski G, Merk HF, Olisova O, Maurer M. Chronic spontaneous urticaria and internal parasites\u0026ndash;a systematic review. Allergy. 2016;71(3):308\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMohaghegh MA, Hejazi SH, Ghomashlooyan M, Kalani H, Mirzaei F, Azami M. Prevalence and clinical features of \u003cem\u003eCryptosporidium\u003c/em\u003e infection in hemodialysis patients. Gastroenterol Hepatol Bed Bench. 2017;10(2):137\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIzadi M, Jonaidi-Jafari N, Saburi A, Eyni H, Rezaiemanesh MR, Ranjbar R. Cryptosporidiosis in Iranian farm workers and their household members: a hypothesis about possible zoonotic transmission. 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Eosinophils from physiology to disease: a comprehensive review. BioMed Res Int. 2018; 2018:9095275. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1155/2018/9095275\u003c/span\u003e\u003cspan address=\"10.1155/2018/9095275\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiyamoto Y, Eckmann L. Drug development against the major diarrhea-causing parasites of the small intestine, \u003cem\u003eCryptosporidium\u003c/em\u003e and \u003cem\u003eGiardia\u003c/em\u003e. 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Clin Infect Dis. 2005;40(8):1173\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Urticaria, Cryptosporidium, parasites, nitazoxanide","lastPublishedDoi":"10.21203/rs.3.rs-2428867/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2428867/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\n\u003cp\u003e\u003cem\u003eCryptosporidium\u003c/em\u003e is an intracellular protozoan that causes gastrointestinal symptoms in humans and animals. In immunocompromised patients and children under 5 years of age, the infection is severe and can be life-threatening due to severe diarrhea.\u003c/p\u003e\n\u003ch2\u003eCase presentation\u003c/h2\u003e\n\u003cp\u003eWe report a case of urticaria associated with \u003cem\u003eCryptosporidium\u003c/em\u003e in a 17-month-old female Iranian child. The patient had severe diarrhea, weight loss and urticaria. Since the child's father worked in livestock farming, the hypothesis of parasite transmission from cows or calves to the house and the child was proposed. Several \u003cem\u003eCryptosporidium\u003c/em\u003e oocysts were detected in the modified acid-fast staining of the child's stool sample. The patient was successfully treated with nitazoxanide (100 mg twice daily) and became negative for parasites three days after treatment and one week after discharge from the hospital. Her stool pattern normalized in 1 week and she has had no recurrence after 6 months of follow up.\u003c/p\u003e\n\u003ch2\u003eConclusion\u003c/h2\u003e\n\u003cp\u003eA number of parasites are associated with urticaria, but to our knowledge, there is no information on \u003cem\u003eCryptosporidium\u003c/em\u003e-induced urticaria. Therefore, our result may be evidence for the role of this parasite in the development of urticaria.\u003c/p\u003e","manuscriptTitle":"Treatment of Urticaria Caused by Severe Cryptosporidiosis in a 17-Month-Old Child – A Case Report and Review of the Literature","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-01-09 08:31:55","doi":"10.21203/rs.3.rs-2428867/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2023-02-13T07:13:54+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-01-18T08:51:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"60d09d3e-0a6a-4415-8df0-7ca75327fcc9","date":"2023-01-12T10:56:57+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-01-11T08:18:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-01-06T07:57:08+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2023-01-06T07:43:34+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-01-06T07:37:32+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2022-12-30T14:23:03+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b37718d2-3ec3-46f3-8d6e-c26a9f869566","owner":[],"postedDate":"January 9th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-08-18T04:13:55+00:00","versionOfRecord":{"articleIdentity":"rs-2428867","link":"https://doi.org/10.1186/s12879-023-08446-y","journal":{"identity":"bmc-infectious-diseases","isVorOnly":false,"title":"BMC Infectious Diseases"},"publishedOn":"2023-07-10 01:09:01","publishedOnDateReadable":"July 10th, 2023"},"versionCreatedAt":"2023-01-09 08:31:55","video":"","vorDoi":"10.1186/s12879-023-08446-y","vorDoiUrl":"https://doi.org/10.1186/s12879-023-08446-y","workflowStages":[]},"version":"v1","identity":"rs-2428867","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2428867","identity":"rs-2428867","version":["v1"]},"buildId":"-HB7Z8yhvgn0wM9Nzuekk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}