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Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 16  |  Issue : 5  |  Page : 34-40

Cryptosporidium infection in solid organ transplant recipients in South Asia - Expert group opinion for diagnosis and management


1 Department of Nephrology and Renal Transplantation, Sanjay Gandhi Postgraduate Institute Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Nephrology and Renal Transplant Medicine, Medanta Kidney and Urology Institute, Medanta Medicity, Gurugram, Haryana, India
3 Consultant Nephrology, Sindh Institute of Urology and Transplantation, Karachi, Sindh, Pakistan

Date of Submission01-Sep-2021
Date of Acceptance21-Feb-2022
Date of Web Publication18-Oct-2022

Correspondence Address:
Dr. Narayan Prasad
Department of Nephrology and Renal Transplantation, Sanjay Gandhi Postgraduate Institute Medical Sciences, Lucknow, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_80_21

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  Abstract 


Cryptosporidium is a protozoan ubiquitous in natural water sources worldwide. It is a common intestinal pathogen that frequently causes gastroenteritis syndrome. It is mainly transmitted from person to person via the fecal-oral route, sexual transmission, and possibly through respiratory secretions. After an incubation period of a few days to 2 weeks, it presents as an asymptomatic oocyst passer to clinically evident profuse and prolonged diarrhea, associated with nausea, vomiting, abdominal pain, and fever. The extraintestinal manifestations may occur in the form of respiratory tract disease, pancreatitis, cholangitis, rarely sclerosing cholangitis, and urinary tract infection. Stool microscopy examination for identifying oocysts is the mainstay diagnostic tool. The association with cancer is new evolving paradigm with cryptosporidium infection. Nitazoxanide is the treatment of choice. However, paromomycin in combination with other antiparasitic agents, such as macrolides (azithromycin, spiramycin), and nitazoxanide may be a more effective option in case of no response.

Keywords: Cryptosporidium, diarrheal illness, nitazoxanide, solid organ transplantation


How to cite this article:
Prasad N, Bansal SB, Akhtar SF. Cryptosporidium infection in solid organ transplant recipients in South Asia - Expert group opinion for diagnosis and management. Indian J Transplant 2022;16, Suppl S1:34-40

How to cite this URL:
Prasad N, Bansal SB, Akhtar SF. Cryptosporidium infection in solid organ transplant recipients in South Asia - Expert group opinion for diagnosis and management. Indian J Transplant [serial online] 2022 [cited 2022 Dec 2];16, Suppl S1:34-40. Available from: https://www.ijtonline.in/text.asp?2022/16/5/34/358665




  Introduction Top


Cryptosporidium, an intracellular parasitic protozoan, is a common intestinal pathogen that frequently causes gastroenteritis syndrome.[1],[2] It is ubiquitous in natural water sources throughout the world and is acquired through contaminated food or water, leading to diarrheal illness.[3],[4],[5]


  Epidemiology Top


The exact prevalence and incidence, although unknown, vary according to socioeconomic status in both developed and developing countries. Cryptosporidiosis in solid organ transplant (SOT) recipients is a relatively uncommon illness in the USA and Europe and reported either as case reports or small series.[6],[7],[8],[9],[10] A few case series and epidemiological studies of stool carriage of Cryptosporidium in SOT recipients are reported from endemic areas of the Middle East, India, and South America.[11],[12],[13],[14],[15],[16],[17],[18],[19] However, the prevalence among diarrheal patients is reportedly as high as 12% in developing countries.[20] We observed that cryptosporidiosis accounts for most infectious diarrhea (28.5%) in adult transplant recipients.[21] A Brazilian study[14] reported cryptococcal infection in 35% renal transplant (RT) recipients as compared to 17% in the control population. In comparison, a Turkish study[22] showed 21% in RT recipients than 3% in immunocompetent patients. In pediatric SOT recipients, Cryptosporidium infections account for 18% of infectious diarrhea cases over 3 years and 3.5% in the new recipients.[23] The data reveal that children and immunosuppressed patients are disproportionately affected by cryptosporidium infection.[20]


  Transmission and Pathogenesis of Cryptosporidium Top


The life cycle of cryptosporidium is shown in [Figure 1]. Cryptosporidium is transmitted from person to person mainly via the fecal-oral route, sexual transmission, and possibly through respiratory secretions.[24],[25],[26],[27],[28],[29],[30] Outbreaks of cryptosporidiosis have been described in daycare canters,[31],[32] in association with animal petting farms,[33],[34] and contaminated drinking as well as recreational water use.[35],[36] Children, residents, and travelers to endemic areas and intestinal graft recipients carry a higher risk of cryptosporidium infection.[11],[14],[37],[38],[39]
Figure 1: Life cycles of cryptosporidium in brief. The Sporulated oocysts are excreted by the infected host mainly through faeces (step 1) and the cysts are used as diagnostic material as well. Transmission of Cryptosporidium spp. occurs mainly through ingestion of fecally contaminated water, food or following direct contact with infected animals or people or possibly sometimes through inhalation (step 2); and following ingestion by a host, excystation occurs (step-3), leading to infection. Finally, the sporozoites are released and infect the epithelial cells. The thick wall oocyst are excreted and thin walled oocyst cause autoinfection (the figure has been adopted from https://www.cdc.gov/dpdx/cryptosporidiosis/index.html

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Infectivity depends on the number of oocysts and species and subtypes of cryptosporidium.[40],[41] Cryptosporidium parvum (C. parvum) and Cryptosporidium hominis (C. hominis) account for >90% of the human cases.[28],[42],[43] The parasite binds to the apical surface of the intestinal epithelium and promotes its reproduction. All the life stages of cryptosporidium are observed in the microvillus border of epithelial cells and within the bronchial mucus glands in case of respiratory tract infection.[44]

It inflicts direct injury to the epithelial cells and produces a local inflammatory response by activating the immune system and the release of pro-inflammatory cytokines. It leads to impairment of the absorption and secretory function of the intestine.[1],[45]

Toll-like receptors (TLR2 and TLR4) present on intestinal epithelial cells play an important part in initiating immune activation following mucosal injury by the parasite.[46],[47],[48] The activation of TLRs leads to cytokine release (IL-12, IL-15, IL-18, TNF-α, and IFN-α/β), followed by recruitment of other cells of the innate immune response such as NK cells, macrophages, and dendritic cells. The production of I IFN-γ and IL-8 by these cells, is responsible for further activation of the innate and adaptive immune systems. The effect of these leads to crypt cell hyperplasia, villous atrophy, and blunting and killing of infected cells.[49],[50],[51]

The role of the T-cell function and IFN-γ is supported by severe and prolonged cryptosporidiosis in patients with acquired immunodeficiency syndrome (AIDS) and CD4 count <50 cells/mm3, and improvement of the symptoms after the introduction of highly active antiretroviral therapy.[52],[53],[54]


  Clinical Features Top


The incubation period of cryptosporidium ranges from a few days to 2 weeks. The clinical presentation may vary from asymptomatic oocyst passers to clinically evident profuse and prolonged diarrhea, associated with nausea, vomiting, abdominal pain, and fever.[1],[12],[22],[53],[54],[55],[56],[57],[58],[59] It may manifest with other nonspecific symptoms such as generalized weakness, myalgia, anorexia, and headache.[1],[3],[5],[60] Persistently irregular bowel can lead to dehydration and wasting, leading to increased morbidity.[23],[55],[60] Dehydration, hypotension, and sometimes tacrolimus toxicity may lead to acute kidney injury.[7],[8],[9],[16],[22],[55],[60],[61],[62],[63],[64] [Box 1].




  Extraintestinal Manifestations Top


The extraintestinal atypical manifestations may occur in the form of respiratory tract disease,[28],[65],[66],[67],[68] pancreatitis, cholangitis, rarely sclerosing cholangitis,[2],[57],[59],[61],[69],[70],[71],[72] and urinary tract infection.[73] It is usually observed in immunocompromised SOT patients and AIDS patients.[71],[72],[73],[74]

Respiratory cryptosporidiosis may present with upper or lower respiratory tract involvement. It manifests with nasal discharge, voice change, cough, dyspnea, and hypoxemia.[65],[66],[67],[68] Infection of the biliary tree could act like an extraintestinal reservoir. It may be responsible for relapses if not treated with drugs that have biliary excretion.[2],[75] Relapse rates in cryptosporidiosis are high (up to 40%–60%) due to incomplete eradication of the oocysts, especially from the biliary tree, possibly due to inadequate intestinal drug levels in patients with severe diarrhea.[57],[58] The cryptosporidiosis illness is typically self-limited in immunocompetent hosts and may have protracted courses in immunocompromised patients in AIDS patients, transplant recipients on immunosuppression, and hypogammaglobulinemia.[7],[25],[37],[55],[59],[62],[73]


  Diagnosis Top


Stool microscopy examination for identifying oocysts is the mainstay diagnostic tool for cryptosporidium infection.[75],[76],[77],[78],[79],[80] However, it has low sensitivity if the concentration of oocysts is low. The size of oocysts (usually 3–7 μm) may be misdiagnosed as a yeast infection. Modified staining with Ziehl–Neelsen or fluorescent techniques such as auramine-rhodamine improves the detection.[75],[76]

Direct immunofluorescence is now a commonly used method. The enzyme-linked immunosorbent assay kits are available with sensitivities ranging from 66% to 100% with excellent specificity.[29],[77],[78],[79],[80] Immunochromatographic tests are rapid but have lower sensitivity for species other than C. parvum or C. hominins.[81],[82]

Multiplex polymerase chain reaction test that can detect different gastrointestinal pathogens, including viruses, parasites, and bacteria, are now available in many laboratories, including ours.[83],[84] It has high sensitivity and carries a high cost.[40],[41],[60],[85]

Intestinal biopsy and tissue histopathology is a useful method for diagnosis if indicated.

Parasites are seen within the lumen or on lining epithelial surfaces. It is particularly crucial for intestine transplant recipients when diarrhea persists, despite negative stool examination.[7],[86],[87] Sputum and other respiratory samples may also be examined with the same methods in the scenario of respiratory infections.[65],[66],[67]


  Treatment Top


The stepwise treatment approach is shown in [Figure 2].
Figure 2: Stepwise approach and treatment of cryptosporidium infection

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  General Management Top


Oral or intravenous rehydration depending on the severity of dehydration is the mainstay of management. A lactose-free diet may be preferred as cryptosporidium may destroy mature epithelial cells lining the villi resulting in loss of enzymes such as lactase. Antimotility agents should only be used if other causes of diarrhea such as Clostridium difficile or dysentery are ruled-out.


  Modulation of Immunosuppression Top


The next step of management in SOT recipients is optimizing immunosuppression as severity is linked with the degree of immunosuppression.[12],[21],[22],[25],[87],[88] The reduction of immunosuppression may result in the clearance of parasites.[59]

Mycophenolate may induce diarrhea. However, it carries some antiparasitic activity against cryptosporidium by inhibiting folate metabolism.[55] Cryptosporidium induced diarrhea may also result in increased tacrolimus toxicity. It occurs because of a combination of factors, including reduced cytochrome 3A activity during inflammation,[25],[89] reduced P-glycoprotein activity of intestinal cells and increased absorption, and possible interaction with other drugs that may result in acute kidney injury as well.[4],[5],[25],[37],[55],[89]

In the cases of nonresponsiveness, partial response to the antimicrobials, relapse, or in the presence of other opportunistic infections, we suggest reducing the degree of overall immunosuppression and to switch mycophenolate to Azathioprine, and in case of concomitant tacrolimus toxicity, switching tacrolimus to cyclosporine may be considered.[21]


  Antiparasitic Agents Top


The stepwise protocol for the approach and treatment is shown in [Figure 1]. Antiparasitic drugs such as nitazoxanide, paromomycin, or azithromycin are commonly used drugs. However, nitazoxanide is an approved drug for treating cryptosporidiosis by the FDA; yet, it has no significant drug-drug interactions. It does not require dose adjustments in renal or hepatic failure.[90] Nitazoxanide has been effective in 3 randomized clinical trials among immunocompetent adults and children, showing a reduction in diarrhea duration and eradication of cysts from stool.[91],[92] Its effectiveness in immunocompromised patients has been variable, with some clinical trials showing positive results, whereas, in other trials, the drug was no better than placebo. The recommended nitazoxanide dose in SOT recipients is 500 mg twice daily for 14 days;[25] however, data from randomized trials in SOT recipients is lacking, and longer therapy courses are sometimes employed.[3],[4],[8]

Paromomycin, a nonabsorbable aminoglycoside, has limited activity against the parasite, and it requires a higher concentration to inhibit parasitic activity.[93] Paromomycin in combination with other antiparasitic agents such as azithromycin and Nitazoxanide may be a more effective option.[7],[11],[13],[14],[16],[22],[37],[56],[58],[62],[63],[94]

Macrolide antibiotics such as azithromycin, clarithromycin, or spiramycin also have activity against cryptosporidium.[90] It reduces the duration of symptoms and oocyst shedding in a clinical trial of treating children with cryptosporidiosis.[95],[96] However, these findings were not consistent in the subsequent randomized trial.[96] Successful use of spiramycin and azithromycin alone or in combination therapy with paromomycin or nitazoxanide in SOT patients has been described.[7],[13],[37],[56],[58],[63]

Several clinical trials and case series studied the use of azithromycin in immunocompetent and immunocompromised patients with cancer and HIV infection. However, it showed mixed results in clinical response, including duration of symptoms and oocyst shedding.[97],[98],[99],[100] Drug interaction of macrolides with tacrolimus or cyclosporine must be considered before prolonged use of macrolides.

Rifabutin is also effective against Cryptosporidium.[101] However, the drug interaction resulting in a reduced level of tacrolimus and cyclosporine again raises a concern on using this drug in organ recipients. Rifaximin has also been shown to be active in vitro. Although Tacrolimus levels are not affected by rifaximin, the elevation of rifaximin levels may occur because of P-glycoprotein inhibition.

Because individual drugs lack full activity against the parasite, the use of combination therapy may be a more attractive option. Current guidelines recommend starting with nitazoxanide alone as preferred therapy, although combination therapy is an alternative option.[25] In our own study, we observed a higher response rate (85.7% vs. 38.46%), stool clearances (95% vs. 61.5%), and a lower relapse rate (9.5% vs. 15.3%) of combination therapy of Nitazoxide plus fluoroquinolones compared to nitazoxanide alone.[21]

If the biliary tract is the reservoir of infection in immunocompromised patients, then paromomycin-like medicines should be avoided. This drug is not absorbed and may lead to relapses. Drugs with biliary excretion, such as nitazoxanide, should be preferred in these patients.[2],[70] Relapse rates in cryptosporidiosis are high (up to 40%–60%) due to the Incomplete eradication of the oocysts, especially from the biliary tree, and possibly due to inadequate intestinal drug levels in patients with severe diarrhea.[57],[58] Acalculous cholecystitis may require cholecystectomy. Sclerosing cholangitis may need endoscopic retrograde pancreatography with possible papillotomy and stenting, along with antiparasitic drugs.[94]


  Prevention Top


SOT recipients should avoid drinking untreated wells, streams, and lake water. Cryptosporidium oocysts are resistant to chlorine disinfection and survive for days in treated recreational water despite adequate chlorination.[24],[102] SOT recipients should avoid swimming in unclean streams or lakes. Although no pieces of evidence are available, particular precautions will be required if recipients move to an endemic zone of infection.

Drinking water should either municipal treated properly, filtered by <1 μm filters, or bottled water. SOT recipients should avoid contacting patients with diarrhea. Handwashing is strongly encouraged for everyone, including other family members. Contaminated surfaces should be cleaned with running water and soap.[25],[103]


  Future Perspectives Top


Passive immunity enhancement

Hyperimmune colostrum (oral bovine immunoglobulin [IgG]) and monoclonal or polyclonal antibodies may reduce oocyst excretion and clinical symptoms.[104],[105] However, they sometimes may increase diarrhea. These agents with antiparasitic agents may be a strategy to consider in refractory immunocompromised individuals.[105] The decline in infection rate with age indicates the acquisition of immunity[29],[52] against the parasite, although such a protective immune response is not well studied.[29],[68] Rechallenge of infection in healthy volunteers showed that after the second re-challenge, diarrhea episodes were similar, but clinical severity was milder and fewer subjects were shedding oocysts.[106] Both IgG and immunoglobulins A antibodies increased after exposure; however, there was no correlation with infection.[106]

Newer antiparasitic agents

In-depth studies of genomes of C. parvum and C. hominis open the pathways of the invention of many newer antiparasitic drugs. They are targeted against calcium-dependent protein kinases, hexokinase, lactate dehydrogenase, and inosine-5-monophosphate dehydrogenase. A few fatty acyl-CoA binding inhibitors and microtubule formation inhibitors are also being studied. It may be a therapeutic agent against this infection in the future.[87],[107]

Vaccine development

Vaccine prevention remains a goal of any infection, producing morbidity and mortality. A vaccine was investigated in a mouse model.[108] There are several challenges of vaccine development for cryptosporidium, particularly in clinical practice.[109] The two most common species causing human disease, C. parvum, and C. hominis, share >95% of their genome, so it may be possible to have one vaccine for both species. Several parasitic antigens such as gp15 and gp40 have been evaluated in vaccine development. Both elicit an immune response and production of interferon-gamma by mononuclear cells in patients previously infected with cryptosporidium. A vaccine trial in Bangladesh using IgA against gp15 showed the antibody was not species-specific and resulted in a shorter illness duration.[87]

A recombinant DNA vaccine using Vaccinia, Salmonella, or Lactobacillus as DNA vectors has also been under investigation.[87] However, the efficacy of these vaccines still needs to be proven first in immunocompetent and subsequently in immunocompromised individuals.

Association with cancer

There are emerging controversies about cryptosporidium as the cause and consequences of cancer. Nevertheless, a meta-analysis recently reported a positive association between Cryptosporidium infection and cancer in general and colorectal cancer in particular.[110],[111] Immunocompromised people may have a higher risk of developing malignancy induced by this parasite, especially if immunosuppression is more severe.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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