Factors associated with C ryptosporidium in men who have sex with men: A systematic review

Introduction

Cryptosporidium is an important cause of diarrhoea in humans and animals.^1–3 There are over 20 species of Cryptosporidium; C. parvum and C. hominis are the most common causes of human disease.^1–3 Cryptosporidium are highly infectious, chlorine resistant parasites and transmission is person-to-person, animals-to-person or indirectly through the environment (particularly via water). ³ Cryptosporidium oocysts have been found in many types of water including untreated surface water, filtered swimming pool water, chlorine treated or filtered drinking water. ⁴ Human-to-human transmission occurs directly by the faecal-oral route including sputum and vomit or indirectly by fomites. ² Once ingested, Cryptosporidium oocysts excyst in the gastrointestinal tract and release infective sporozoites which attach to the apical membrane of the host epithelial cell. The sporozoites are then internalised into the cell where they mature and undergo asexual reproduction to produce merozoites which can infect other cells or form gametocytes and progeny oocysts.^2,5 Shedding of oocysts in faeces can lead to autoinfection, heavy persistent infection and transmission. ⁴ The incubation period is normally 7-10 days (longer in immunocompromised hosts). Although infection can be asymptomatic, most immunocompetent patients experience a self-limiting high volume, watery diarrhoea for 2-26 days accompanied by nausea, vomiting, abdominal pain, and fever while immunosuppressed individuals can have life threatening disease including intractable diarrhoea and dehydration.^6,7 Extraintestinal cryptosporidiosis has been reported involving the pancreato-biliary tract (cholangitis) and more rarely the lungs and ear. ²

Since the first cases of human cryptosporidiosis were reported in 1976, Cryptosporidium are now common enteric pathogens, globally.^4,8 The proportion of the general population excreting oocysts is 1%–3% in high-income settings and up to 10% in middle- and low-income settings. Symptomatic cryptosporidiosis is more common in immunocompromised patients, particularly people living with HIV, especially those without access to antiretroviral therapy. ⁹ Acute and chronic infection in children in low income settings associated with malnutrition and high mortality. ¹⁰ Diagnosis is now made by highly sensitive molecular PCR testing but previously relied on microscopy, and immunofluorescence which are less sensitive. ² Despite the magnitude and severity of Cryptosporidium infection, its pathogenesis is poorly understood. ¹¹ There are no effective antimicrobial treatment regimens for cryptosporidiosis; paromomycin, azithromycin and nitazoxanide have been used, but are poorly to moderately effective. ²

People at risk of cryptosporidiosis include household and family contacts, healthcare workers, day care personnel, users of swimming pools, travellers to regions of high endemicity and more recently, sexual partners of infected individuals. ² Sexual transmission of Cryptosporidium spp. has been suggested amongst men who have sex with men (MSM) following reports of outbreaks and from epidemiological studies in high-income settings.^12,13 It is biologically plausible that Cryptosporidium can be sexually transmitted, particularly among MSM due to the infectiousness, mechanisms of transmission and the potential faecal contamination which can occur during sexual activity, particularly oro-anal sex (rimming). ¹³ Recently, there have been significant reported increases in other sexually transmitted enteric pathogens associated with travel, access to testing and diagnostics, and sexual behaviour (e.g. rimming, anal sex, chemsex).^14–16 However, the sexual transmission dynamics of Cryptosporidium remain poorly understood. This review aimed to explore any factors associated with Cryptosporidium in MSM by systematically reviewing the published literature to provide insights for future clinical guidelines and public health strategies.

Methods

Results

The initial search identified 641 citations, 92 duplicate citations were removed, 549 abstracts were screened (484 were excluded), 55 full text manuscripts were assessed for eligibility (51 were excluded), 2 manuscripts were identified from reviewing the reference lists of the eligible manuscripts. In total 6 manuscripts were included in the final review.^{12,13,21–24} (Figure 1) Risk of bias was determined to be low in 2 manuscripts, medium in 2 manuscripts and high in 2 manuscripts. (Supplemental table 1) The manuscripts were from the USA (n = 3), Europe (n = 1) and Australia (n = 2) and were case series (n = 2), cross sectional studies (n = 2) and case control studies (n = 2) published between 1984 and 2021. In total there were 1582 were cases of Cryptosporidium, including 104 who tested Cryptosporidium antibody positive, and 1478 diagnosed by stool specimen microscopy. Four out of the 6 manuscripts were reporting from populations exclusively involving MSM living with HIV (1533 MSM living with HIV with Cryptosporidium).^12,22–24 (Table 1)

OPEN IN VIEWER

Figure 1.

Flow chart of study selection for inclusion in the systematic review.

OPEN IN VIEWER

Table 1.

Risk associations with Cryptosporidium in men who have sex with men.

Study	Study characteristics	Population	Study design	Diagnostics	Risk factors with cryptosporidium in MSM
Soave et al., 1984, USA 21	MSM attending New York clinics, USA.	N = 6, MSM	Case series	Microscopy	Drugs: 3/6 recreational drug use
					HIV: 4/6 living with HIV, 5/6 previous Treponema pallidum, 4/6 previous Entamoeba histolytica
Pedersen et al., 1996, Europe 22	6548 patients living with HIV from 17 European countries.	161/3964 MSM living with HIV diagnosed with Cryptosporidium	Cross-sectional	Microscopy	MSM living with HIV with Cryptosporidium more likely to be younger in age (<30 years, p < 0.001), diagnosed in 1989 (p < 0.001) and in Southern part of Europe (p < 0.001) compared to IDU. MSM were more (RR = 1) likely to develop cryptosporidiosis during HIV follow up compared with IDUs (RR = 0.34 [CI = 0.22-0.54] and people in other risk category (RR = 0.56 [CI = 0.33-0.97)
Caputo et al., 1999, Australia 23	MSM living with HIV attending Hospital and 2 community clinics in Melbourne.	104/236 MSM living with HIV had positive antibody to Cryptosporidium	Cross-sectional	Serology	Factors associated with increased serological response (27-kDa): Younger MSM [<35 OR = 1, (reference), >45 OR = 0.5 (CI = 0.2-0.9)
					Sexually active in past 2 years (OR = 2.3, CI = 1.0-5.6, p = 0.03)
					Having had >10 sexual partners during the past two years (OR = 3.0, CI = 1.2-7.6, p = 0.04)
					Attending a spa or sauna 1-5 times (OR = 1.9, CI = 1.0-3.8, p = <0.05)
Hellard et al., 2003, Australia 13	MSM attending sexual health clinics in Melbourne and Sydney.	10 cases, 24 controls (7/10 cases and 16/24 controls living with HIV)	Case-control	Microscopy	Having more than one sexual partner in the past month (OR = 6.67, CI = 1.15-38.60, p = 0.034).
Danila et al., 2014, USA 12	Public health laboratory reporting, Minneapolis-St Paul.	8 MSM living with HIV, median age 40. All had same subtype: IfA12G1R2	Case series	Microscopy	Identifying as African American (5/8, 63%) compared with 4% for all other Cryptosporidium cases reported in 2013
Khalakdina et al., 2021, USA 24	California HIV/AIDS reporting system registry, CDC USA.	1293 cases and 84490 control MSM living with HIV diagnosed with Cryptosporidium. (As AIDS defining illness)	Case-control	Microscopy	Ethnicity: African American/African American IDU MSM less likely to have cryptosporidium (OR = 0.6 [0.5-0.7]/OR = 0.6 [0.6-1.0]) compared with white male non IDU MSM. Heterosexuals living with HIV significantly less likely to have cryptosporidium than MSM living with HIV (multivariate OR = 0.5 [0.4-0.7]

IDU = injecting drug user, MSM = men who have sex with men, CI = confidence interval, RR = relative risk, OR = odds ratio

We have identified the following demographic factors associated with Cryptosporidium in MSM: living with HIV [in studies involving both MSM living with HIV and HIV negative MSM], younger age [<30 years old], geographical areas [Southern Europe v Northern Europe] and previous sexually transmitted infections namely Treponema pallidum and Entamoeba histolytica.^21–23 We also identified the following behavioural factors associated with Cryptosporidium in MSM: recreational drug use, having more than 10 sexual partners in the past 2 years, and attending sex on premises venues with a spa/sauna between 1 and 5 times in past 2 years^13,21,23 (Table 2) We discovered conflicting evidence on ethnicity: one 2014 study from the US suggested that African American MSM were more likely to have Cryptosporidium and another 2021 US study suggested that African American MSM and African American MSM who inject drugs were less likely to have Cryptosporidium than white male non-injecting drug users.^12,24

OPEN IN VIEWER

Table 2.

Associations with Cryptosporidium in men who have sex with men.

Demographic	Living with HIV
	Younger age
	Geography; Southern v Northern Europe
	Ethnicity: African American in USA
Behavioural	Previous Treponema pallidum
	Previous Entamoeba histolytica
	Recreational drug use
	10+ sexual partners in the past 2 years
	Attending sex on premises with spa/sauna 1-5x in  2 years

Discussion

To our knowledge, this is the first systematic review of Cryptosporidium in MSM. The extent and dynamics of sexual transmission of Cryptosporidium in MSM remains unclear, however although limited by only six manuscripts, we have identified some potential demographic and behavioural factors that may be associated with the sexual transmission of Cryptosporidium in MSM.

It remains controversial whether Cryptosporidium is sexually transmitted as there is a paucity of empirical data, however there is plausibility (transmission dynamics) and similar organisms have become sexually transmissible in MSM including Giardia duodenalis and Entamoeba histolytica.^25,26 During the early years of the HIV epidemic, Cryptosporidium was a frequent cause of morbidity and mortality associated with severe immunosuppression, however the data from this review suggests that MSM were more affected by Cryptosporidium compared to other risk groups which suggests some sexual transmission.^22,24 Similar to outbreaks of Shigella spp. and Entamoeba histolytica seen in MSM, there appears to be some geographic variation independent of testing location which either is representative of specific sexual networks and behaviours, or the inter-relationship between food/water transmission with sexual transmission.^15,22,26 Although it isn’t clear why, this review suggests that younger MSM are more likely to acquire Cryptosporidium than older MSM which is in contrast to sexually transmitted Entamoeba histolytica in MSM.^27–29 However, human volunteer and serological surveys have suggested that individuals with pre-existing antibodies to Cryptosporidium may be partially protected and experience less diarrhoea on subsequent challenge which may be why some older MSM are protected. ³⁰ The geographic and ethnicity differences described in this review may also be related to wider health inequalities seen particularly in neglected diseases including sexually transmitted infections (STIs) and sexually transmitted enteric infections and we cannot easily explain the discrepancy identified in ethnicity in this review.^12,24 It is likely that any ethnicity association in the context of African-American people living in the United States will be confounded by other social determinants of health including access to healthcare, and therefore any geographic and ethnicity associations will be nuanced and complex. Furthermore, given the paucity of comparative data on sexually transmitted Cryptosporidium in MSM, an appropriate control for any comparative study will be challenging, hence conflicting results.^12,24 Current or previous STIs including sexually transmissible enteric infections with Cryptosporidium in MSM provide some crude empirical evidence for sexual transmission and this has been described in other infections (Shigella flexneri, S. sonnei, Entamoeba histolytica) suggesting that all MSM with Cryptosporidium should also be offered comprehensive testing for STIs.^{14,15,21,26,28,29,31–33} Chemsex and other recreational drug use behaviours are associated with sexually transmitted infections and sexually transmitted enteric infections and serve as evidence of sexual transmission of Cryptosporidium in sexual networks of MSM engaging in chemsex or generalised recreational drug use.^{15,21,33–35} The associations of more than 10 sexual partners in the past 2 years and visiting sex on premises venues is similar to other sexually transmitted enteric infections including Shigella sonnei and Shigella flexneri and Entamoeba histolytica, and is likely to represent possible sexual transmission of Cryptosporidium within specific sexual networks of MSM. ^{13,15,23,27,32,35–38}

There are several limitations to this systematic review making overall interpretation of the data challenging. There were only 6 manuscripts eligible for this review which included 2 case series which were considered to have high risk of bias. There is likely to be significant reporting bias and the studies included were highly heterogenous in design including quality, population sampling, data collection and microbiology. Most of the studies included were from clinical samples rather than population studies which may affect overall representation. Furthermore, any associations or lack of associations in this narrative review should be interpreted with caution due to the nature of the manuscripts in the review. Most of the manuscripts in this review did not assess MSM with Cryptosporidium for other sexually transmitted infections or sexually transmissible enteric infections and these pathogens are often asymptomatic.^39,40 There are now data suggesting that MSM with enteric pathogens should be tested for asymptomatic STIs. ¹⁴ There will be significant reporting bias as most MSM with Cryptosporidium either don’t have any formal microbiology samples taken and or a sexual history to ascertain transmission risk. Many MSM may not be able to disclose their sexual behaviour, recreational drug use or other behaviours due to stigma. We were only able to include manuscripts in English and accept that most Cryptosporidium transmission occurs in non-English speaking parts of the world.

MSM continue to experience endemic and significant outbreaks of STIs including T. pallidum, Shigella spp. and more recently Mpox and it is not inconceivable that we will observe future outbreaks of Cryptosporidium in MSM. ⁴¹ To some extent sexually transmitted infections in particular sexually transmissible enteric infections remain neglected diseases and MSM globally experience significant inequalities including access to healthcare. There are a paucity of data confirming the sexual transmission of Cryptosporidium in MSM, but we have been able to identify some factors which may be associated with sexual transmission. This review suggests that clinicians should consider testing for Cryptosporidium in MSM presenting with diarrhoea to support individual management and public health surveillance. Furthermore, these data suggest that MSM with enteric pathogens should be tested for all STIs. ¹⁴ These data are useful to support future outbreaks of Cryptosporidium in MSM as will provide some insight for public health interventions.

Supplemental Material