Table 1 Fifteen studies included in the qualitative synthesis

Agnew et al. [38]

Fortaleza, Brazil

Urban slum

Nested case-control study of a cohort of young children

Cases (diagnosed cryptosporidiosis): 453 ± 49 (15–1167) days

Controls: 436 ± 53 (0–1165) days

Unidentified

43 cases; 43 controls

Age of cases (months): 11 ± 0.9 (range: 3–26)

Age of controls (months): 11 ± 0.9 (4–27)

Cases: 63% boys

Controls: 40% boys

Children who had an episode of symptomatic Cryptosporidium infection had a significantly increased diarrhoeal disease burden (days of diarrhoea/child-year) compared with that for controls both before (39.3 ± 7 vs 21.3 ± 5 days, respectively; P < 0.04) and after (46.1 ± 9 vs 13.9 ± 5 days, respectively; P < 0.04) the diagnosis of Cryptosporidium infection

In the post-Cryptosporidium period, case-children who were < 1 year of age had significantly more episodes of diarrhoea than their controls and significantly more episodes of diarrhoea than in their pre-Cryptosporidium period (data not shown; P ≤ 0.001 and P < 0.05, respectively)

Before Cryptosporidium infection, 8 case-children, who were ≤ 1 year-old and had no diarrhoeal illnesses, had height-for-age Z-scores identical to matched controls. However, after Cryptosporidium infection, these case-children had significant decline in height-for-age Z-scores which were not seen in the matched controls (P < 0.005 for pre-infection vs post-infection case-children)

It is not known whether the increase in post-Cryptosporidium diarrhoeal disease burden was due solely to the impact of infection with Cryptosporidium, or if a similar phenomenon would also be seen with other serious enteric infections (e.g. rotavirus or enteroaggregative Escherichia coli)

Ajjampur et al. [39]

Vellore, South India

Semi-urban slum

Prospective birth cohort study

3 years

Unidentified

40/116 children who consented to take part in the study were identified as having had cryptosporidial diarrhoea, 66 of them had giardial diarrhoea and 22 had both

32 with no documented episodes of cryptosporidial or giardial diarrhoea were also recruited

Mean (± SD) age of the children during assessment was 3.51 ± 0.38 years

Median (IQR) for age at the first documented cryptosporidial episodes were 1.29 (0.81–2.05) years

55.2% males

Children with cryptosporidial diarrhoea had a mean (SD) social quotient (SQ) of 118.70 (35.01) (P = 0.714)

Children with cryptosporidial diarrhoea did not have significantly lower IQ scores than those without a past history of cryptosporidial diarrhoea (mean IQ 100.12, SD 17.28)

In the univariate analysis, a past history of any protozoan diarrhoea, either giardial or cryptosporidial, was not a significant predictor of stunting or being underweight

Cryptosporidial diarrhoea was not associated with poor IQ, SQ or physical growth

Berkman et al. [40]

Lima, Peru

Periurban shanty town

Prospective birth cohort

Follow-up birth to 2 years with cognitive function at 9 years

Unidentified

Cognitive assessment completed in 143 children

77 (54%) had at least one episode of Cryptosporidium infection

Follow-up birth to 2 years with cognitive function at 9 years. Estimated median age at onset of first Cryptosporidium infection was 16.1 months

76 (53%) males

No association between Cryptosporidium infection and cognitive test scores according to the number of episodes, incidence and prevalence, and symptomatic infections

*Carter et al. [21]

UK (Wales)

Sporadic community cases

Prospective case cohort study

12 months

C. parvum (n = 121)

C. hominis (n = 79)

C. parvum and C. hominis (n = 2)

Other species (n = 3)

515 eligible; 205 participated

42 (20%): 6 months-4 years

63 (31%): 5–17 years

100 (49%): 18 years or over

60.6% female at baseline

58.2% female at 3 months

66.3% female at 12 months

12 months follow-up: over a third of cases reported persistent abdominal pain and diarrhoea, 28% reported joint pain and 26% reported fatigue

At both 3 and 12 months, the proportion reporting fatigue and abdominal pain after C. hominis infection was statistically significantly greater than after C. parvum

Overall, 10% of cases had sufficient symptoms to meet IBS diagnostic criteria. A further 27% met all criteria except 6 months’ duration and another 23% had several features of IBS but did not fulfil strict Rome III criteria. There was no significant difference between C. parvum and C. hominis infection with regard to PI-IBS

Delahoy et al. [41]

Kenya

Rural community

Prospective, age-stratified, health facility-based matched case-control study of children with MSD

~ 60 days (acceptable range 50–90 days)

Unidentified

Among the 1778 MSD case children enrolled, Cryptosporidium was identified in 195 cases (11.0%)

46%: 0–11 months

27%: 12–23 months

25%: 24–59 months

56% male

At follow-up, Cryptosporidium- positive cases had increased odds of being stunted (adjusted odds ratio, aOR: 1.65, 95% CI: 1.06–2.57), underweight (aOR: 2.08, 95% CI: 1.34–3.22), or wasted (aOR: 2.04, 95% CI: 1.21–3.43), and had significantly larger negative changes in height- and weight-for-age z-scores from enrollment

Guerrant et al. [42]

Fortaleza, Brazil

Urban slum

Prospective cohort study

6–9 years

Unidentified

26 children; 9 Cryptosporidium infections (6 with diarrhoea, 3 without diarrhoea)

26 children (12 boys and 14 girls)

Age range: 6.5–9 years

Cryptosporidium infections (seen in 9/26 children) in the first 2 years of life were correlated with a 2-fold increase in episodes of diarrhoea at 0–2 years of age (P = 0.017, by 2-sample t-test)

Fitness scores in children with early childhood Cryptosporidium were 10% lower than in controls (9.0 vs 10.0; P = 0.008, by 2-sample t-test)

Adjusting for Cryptosporidium removed both the significance of the correlation between diarrhoea and fitness and between Cryptosporidium and fitness

*Hunter et al. [15]

UK (Northwest of England and Wales)

Sporadic community cases and controls

Case-control study

2 months

C. parvum (n = 50)

C. hominis (n = 61)

Unidentified (n = 124)

235 case patients; 232 control subjects

Age range: 0–89 years

Control subjects were significantly older than case patients (χ² = 8.574, P = 0.0034)

49% of case patients and 46% of control subjects were male

40% of case patients reported recurrence of intestinal symptoms after resolution of the acute stage of illness

Reports of joint pain (odds ratio, OR: 2.8), eye pains (OR: 2.44), recurrent headache (OR: 2.10), dizzy spells (OR: 1.69), and fatigue (OR: 3.0) were significantly more common in case patients than in control subjects, but only in people who had experienced C. hominis infection

*Igloi et al. [15]

Netherlands

Sporadic community cases and controls

Case-crossover and cryptosporidiosis case control study

4 months

C. parvum (n = 216)

C. hominis (n = 92)

308 cases

Median age: 26 years (range: 1–80)

58% were female

Compared to before illness, cases were significantly more likely to report dizziness (OR: 2.25), headache (OR: 2.15), fatigue (OR: 2.04), weight loss (OR: 1.82), diarrhoea (OR: 1.50), abdominal pain (OR: 1.38) or joint pain (OR: 1.84). However, symptoms of joint pain and headache occurred among cases after illness at a rate that was not significantly different from that observed in the general population

There were no significant differences in post-infection symptom occurrence between C. hominis and C. parvum

*Insulander et al. [19]

Stockholm County, Sweden

Sporadic community cases

Prospective cryptosporidiosis case cohort study

25–36 months

C. parvum (n = 111)

C. hominis (n = 65)

Other species (n = 17)

271 cases

Median age: 32 years (range: 1–73 years)

126 male and 145 female

After 25–36 months follow-up: 15% reported intermittent diarrhoea (8/53), 9% reported abdominal pain (5/53), 8% reported myalgia/arthralgia (4/53), 4% reported fatigue (2/53)

There was no difference in frequency of persisting symptoms between patients infected with C. parvum or C. hominis

Korpe et al. [43]

Bangladesh

Peri-urban slum

Prospective birth cohort study

2 years

C. hominis (n = 220)

C. parvum (n = 8)

C. parvum and C. hominis (n = 5)

Other species (n = 5)

Unidentified (n = 154)

392 children

Birth to 24 months of age

55% male

Children with Cryptosporidium spp. infection had a greater than 2-fold increased risk of severe stunting at age two compared to uninfected children (OR: 2.69, 95% CI 1.17–6.15, P = 0.019) independent of sex, income, maternal body-mass index, maternal education and weight for age adjusted z-score (WAZ) at birth

*Lilja et al. [20]

Ostersund, Sweden

Outbreak cohort and controls

Case-control study

28 months

C. hominis

215 cases; 344 non-cases

Median age of cases: 41 (range: 3–79) years

Median age of non-cases: 56 (range: 3–95) years

57% of cases and 55% of controls were women

48% of cases reported symptoms at follow-up, most commonly headache, fatigue, abdominal pain, and nausea

Compared to non-cases, the cases were more likely to report watery diarrhoea, abdominal pain, stiff joints, joint pain, joint discomfort, fatigue, nausea, and headache at follow-up after adjusting for age and sex

The likelihood of cases reporting symptoms at follow-up differed between age groups: joint pain (OR: 13.2, 95% CI: 2.8–61.9) and nausea (OR: 2.7, 95% CI: 1.2–6.0) were associated only with the 16–40-year age group; diarrhoea (OR: 3.9, 95% CI: 1.1–14.3) was associated only with the > 65-year age group; and headache (OR: 4.0, 95% CI: 1.3–13.1) was associated only with the 6–15-year-old age group

Phillips et al. [44]

London, UK

Sporadic urban community and traveller community cases

Retrospective cohort

Variable

Unidentified

123 children

Not specified

50% of children excreting only Cryptosporidium had diarrhoea lasting over 21 days; in 8% of cases diarrhoea continued for over 6 months. 23% of cases had weight below the third centile and a further 9% had failure to thrive. Most cases (63%) of chronic diarrhoea occurred in the first two years of life. A mild to moderate enteropathy was present in all 9 children undergoing a small intestinal biopsy and 7 showed the presence of Cryptosporidium adhering to villous epithelium. All patients eventually recovered spontaneously

Although a greater proportion of patients with mixed infections had weight below the 3rd percentile (8/21) this was not significantly different to those with Cryptosporidium alone (11/61)

*Rehn et al. [17]

Ostersund and Skelleftea, Sweden

Community outbreak cases and controls

Case-control study

11 months

C. hominis

Östersund: 872 (310 cases)

Skellefteå: 743 (149 cases)

Östersund: Median age of cases: 32 years (range: 1–93)

Skellefteå: Median age of cases: 34 years (range: 2–92)

Östersund: 310 (38%) cases, 138 (45 %) were male

Skellefteå study: 149 (22%) cases, 73 (49 %) were

Outbreak cases were more likely to report diarrhoea (Östersund OR: 3.3, 95% CI: 2.0–5.3. Skellefteå OR: 3.6, 95% CI: 2.0–6.6), watery diarrhoea (Östersund OR: 3.4, 95% CI: 1.9–6.3. Skellefteå OR: 2.8, 95% CI: 1.5–5.1) abdominal pain (Östersund OR: 2.1, 95% CI: 1.4–3.3, Skellefteå OR: 2.7, 95% CI: 1.5–4.6) and joint pain (Östersund OR: 2.0, 95% CI: 1.2–3.3, Skellefteå OR: 2.0, 95% CI: 1.1–3.6) at follow-up compared to non-cases

*Stiff et al. [18]

UK (mainly northern England)

Community outbreak cases

Prospective cohort study

12 months

C. parvum

197 invited; 54 took part

Mean age: 41.8 years

14 males and 40 females

12 months follow up: participants self-reported weight loss (31%), abdominal pain (38%), diarrhoea (33%), eye pain (9 %), joint pain (33 %), fatigue (22 %) and symptoms consistent with irritable bowel syndrome (IBS) (28 %). Two people were medically diagnosed with IBS

*Widerstrom et al. [4]

Östersund, Sweden

Community outbreak cases and controls

Case-control study

2 months

C. hominis

1524 eligible; 1044 (69.2%) responded

Median age: 44 years (range: 0–98 years)

481 male (46.1%) and 563 female (53.9%)

Most common symptoms among case-patients were episodes of diarrhoea > 3 times daily (89.0%), watery diarrhoea (84.3%), abdominal cramps (78.8%), fatigue (73.1%), nausea (63.9%), and headache (57.1%)

Muscle or joint aches, which were reported less frequently in Östersund than in other studies

The median duration of diarrhoea, the level of attack rates in different age groups, and recurrence rate of diarrhoea corresponded to findings in other outbreaks