A number of studies have investigated the prevalence and epidemiology of cryptosporidiosis in patients with HIV infection. The results of the studies investigating the prevalence of cryptosporidiosis in HIV-positive patients with diarrhea have presented estimates that differ quite markedly from one another, ranging from 0 to 100% with a median of 32% (2
). It is not clear how much these differences may be explained by differences in study design, geographical location, population group, sensitivity of laboratory methods, or stage of disease. Nevertheless, it would appear that the prevalence of carriage Cryptosporidium
spp. oocysts in the absence of diarrhea is very low (5
). There have been rather fewer studies that have attempted to define an overall prevalence in HIV-positive individuals, irrespective of whether they have diarrhea. In Europe, cryptosporidiosis seems to affect about 6.6% of HIV-positive individuals (98
). A slightly earlier U.S. study in Los Angeles found an overall rate of 3.8% of individuals to be positive during the study period (112
The risk of infection increases in more profoundly immunosuppressed persons, as measured by the CD4+
T-lymphocyte counts (93
). Various social and behavioral factors also increase the risk of infection. For example, in a large multicenter European study the risk of cryptosporidiosis was significantly lower for intravenous drug users than for homosexual men (relative risk, 0.34; 95% confidence interval, 0.22 to 0.54) and for women than for men (relative risk, 0.43; 95% confidence interval, 0.21 to 0.87), suggesting that sexual behavior may be an important risk factor (98
). The importance of sexual behavior as a risk factor was also identified in a large U.S. study, where the prevalence of cryptosporidiosis was higher in persons whose suspected HIV exposure category was through sexual contact (3.9%) than among persons in other HIV exposure categories (2.6%; P
< 0.01) and in immigrants from Mexico (5.2%) than in American-born patients (3.8%; P
< 0.01). Blacks (2.7%) were less likely than whites (4.1%) and Latinos (4.2%) to be reported with cryptosporidiosis (P
< 0.001) (112
). In another study, HIV-positive patients who owned dogs (but not other pets) also seem to be at increased risk of infection (odds ratio, 2.19; 95% confidence interval, 0.9 to 5.3; P
= 0.05) (49
Caputo et al. undertook a cross-sectional serological survey of HIV-positive individuals to look for anti-cryposporidial antibodies (19
). They reported that an increased serological response to one or more antigens was related to a number of sexual practices such as having had sex within the past 2 years, having multiple partners during that time, having anal sex, and attending a spa or sauna.
Nosocomial outbreaks of cryptosporidiosis have also been described. For example, an outbreak in a hospital in Copenhagen affected some 18 HIV-positive patients (102
). The source of the outbreak was identified as ice from an ice machine in the ward, contaminated by an incontinent psychotic patient with cryptosporidiosis who was using his hands to pick out ice for cold drinks. More recently, Bruce et al. conducted a retrospective cohort study of transmission between roommates in a hospital setting (15
). They were able to identify 37 HIV-positive patients who had shared a hospital room with 21 Cryptosporidium
-positive index patients and matched them to other HIV-positive individuals with a similar CD4 count but who had not shared a room with a Cryptosporidium
-positive patient. None of the 37 exposed individuals became infected, and one of the unexposed controls became infected, suggesting that person-to-person transmission may not be common. However, extrapolation of this experience to other health care settings with different infection control practices may be difficult.
Molecular epidemiology of Cryptosporidium
isolates has proved useful in determining sources of infection (81
). There have been too few studies on the prevalence of different genotypes of Cryptosporidium
in HIV-infected patients to date to draw firm conclusions. One American study characterized 13 strains from people with AIDS and found that 10 were C. parvum
type 1 (the human type) and 3 were C. parvum
type 2 (the calf type) (130
). A subsequent American study found that 5 of 10 AIDS patients were infected by C. parvum
genotype 1 and 1 was infected by C. parvum
genotype 2 and the remaining isolates were other species (see below) (101
). A study of Cryptosporidium
isolates from HIV-infected patients from Kenya, Switzerland, and the United States found that of 22 isolates examined, 6 were genotype 1, 8 were genotype 2, and 8 were non-parvum
strains, including C. meliagridis
). The genotypes commonly found in humans are C. parvum
genotypes 1 (the human strain) and 2 (the calf strain), although C. meliagridis
and an as yet unnamed dog strain have been described (100
). Although C. parvum
genotype 1 strains seem to predominate in AIDS patients in North America, it is unclear whether this represents increased person-to-person transmission.
In addition to being at increased risk of infection by C. parvum
, patients with AIDS have been reported to be infected with other Cryptosporidium
spp. Xiao et al. found nine non-parvum
species of Cryptosporidium
: C. wrairi
, C. meleagridis
, C. saurophilum
, C. felis
, C. baileyi
, C. muris
, C. andersoni
, C. serpentis
, and C. nasorum
). In the American study mentioned above, 3 of 10 isolates from AIDS patients were C. felis
and 1 was an unnamed Cryptosporidium
sp. similar to one previously isolated from a dog (101
). In the study from Kenya, Switzerland, and the United States, it was found that of 22 isolates examined 6 were C. felis
and 2 were C. meleagridis
). Ditrich et al. reported an infection in a patient which they identified as due to C. baileyi
, normally a parasite of birds (35
). However, this organism was later shown to be antigenically different from C. baileyi
). Recent work in the United Kingdom showed that the feces from six HIV-positive individuals yielded C. parvum
(two patients), C. felis
(two patients), and C. meleagridis
(two patients) (99
; J. McLauchlin, personal communication). In 23 other immunosuppressed patients, of whom 7 were CD40 ligand deficient, 19 had C. parvum
and 4 had C. meleagridis
; of these, 8 had a mixture of genotypes (McLauchlin, personal communication). While isolates of non-parvum
species from humans may be genetically very similar to isolates from animals and birds, there is limited evidence of cross-infectivity (100
). Although it was originally thought that non-parvum
species were restricted to AIDS patients, recent evidence has shown that these species can also infect immunocompetent individuals (22
From the discussion above, it is clear that HIV-positive patients, particularly those with AIDS (as measured by a low CD4 count), are at increased risk of being infected with cryptosporidiosis. This risk is increased when individuals engage in high-risk sexual behavior. The high prevalence of Cryptosporidium
spp. in AIDS patients is probably related to an increased risk of acquiring infection from infected contacts and prolonged excretion, which in turn increases the risk of subsequent transmission. AIDS patients also seem to be more commonly infected with Cryptosporidium
spp. other than C. parvum
than do immunocompetent individuals. In the four studies on isolates from AIDS patients discussed above, a total of 51 isolates were identified of which 14 were non-parvum
(27.5%; 95% confidence interval, 15.9 to 41.7%), considerably higher than found in typing isolates from the general population (89
). This suggests that different risk factors and transmission routes may be involved in non-C. parvum
infections relative to C. parvum
. Immunodeficiency may also alter the host susceptibility to Cryptosporidium
species that are not normally infectious to humans.
Blanshard et al. described the various presentations of cryptosporidiosis in HIV-positive patients in London (13
). In this population, cryptosporidiosis was diagnosed in some 5% of all patients with HIV infection and 21% of patients with AIDS. The authors studied the course of infection in 128 patients. Transient infections were found in 28.7% and were more common in the less strongly immunosuppressed patients. Fulminant disease, the passage of more than 2 liters of stool/day, affected 7.8% of patients but only those with a CD4 count less than 50/mm3
. Chronic disease was present in 59.7% of patients, and 3.9% of infections were asymptomatic. Patients with fulminant disease survived for a median of only 5 weeks, compared with 20 weeks for those with chronic diarrhea and 36 weeks for those with transient infection.
A second study from London investigated the outcome in 38 HIV-positive patients with cryptosporidiosis (80
). Of these 38 patients, only 11 (29%) experienced a clinical remission. Remission had a major impact on survival. The patients who experienced remission had a median survival time of 66 weeks compared to only 11.5 weeks for the nonremission group (P
= 0.001). The median lymphocyte count of the remission group was significantly higher than that of the nonremission group (1,100 × 106
and 550 × 106
/liter, respectively; P
A few years later, U.S. workers also described four clinical syndromes, similar to but slightly different from those found by the British group: chronic diarrhea (affecting 36% of patients), cholera-like disease (33%), transient diarrhea (15%), and relapsing illness (15%) (75
). Infected patients had a significantly shorter duration of survival from the time of diagnosis than did Cryptosporidium
-negative AIDS patients (240 and 666 days, respectively; P
= 0.0004). Survival was independent of sex, race, or injection drug use. Interestingly, antiretroviral use was protective against disease (odds ratios, 0.072; P
Italian workers investigated the particular outcome of Cryptosporidium
infection in children with HIV infection (53
). A total of 35 children were examined every 2 months and, if found to have diarrhea were tested for Cryptosporidium
; 5 (14%) were positive, 4 of whom recovered spontaneously. All five positive patients had AIDS. Diarrhea in those found to be Cryptosporidium
positive was much more protracted than in those with diarrhea due to other causes.
One study has shown that prognosis is independently related to two factors measured at the time of Cryptosporidium
diagnosis: CD4 count of ≤53 cells/mm3
versus >53 cells/mm3
(relative hazard, 6.18; 95% CI, 2.99 to 12.76) and hematocrit of ≤37% versus >37% (relative hazard, 2.27; 95% CI, 1.22 to 4.22) (29
). The median survival in the subgroup with a CD4 count of >53 and hematocrit of >37% was 1,119 days compared to only 204 days in the subgroup with a CD4 count of <53 and hematocrit of <37%. This study also showed that an initial AIDS-defining diagnosis of cryptosporidiosis was a poor prognostic factor compared to other possible diagnoses (relative hazard of death, 2.01; 95% CI, 1.38 to 2.93).
One aspect of chronic cryptosporidiosis in patients with AIDS is the large weight loss that many experience. One study from France reported that the severity of weight loss in such patients is independently associated with levels of nutrient intake (P
< 0.005) and high stool frequency (P
< 0.01) but not with nutrient malabsorption (12
As well as developing a more severe form of typical gastrointestinal disease, people with HIV infection can develop atypical disease presentations, affecting body systems not usually affected in immunocompetent individuals. Some of these unusual presentations are discussed below.
Atypical gastrointestinal disease.
In a review of the literature published in 1997, the authors were able to identify only 16 cases of gastric cryptosporidiosis (127
). Despite this, gastric involvement is probably more common than was previously realized, but detection is difficult because diagnosis requires upper gastrointestinal tract endoscopy. In an endoscopic study of 71 patients with AIDS and chronic diarrheal illness or other gastrointestinal disorders of unexplained origin, 24 individuals were positive for cryptosporidiosis. Of these 24 patients, 16 (67%) had parasites in the gastric epithelium (104
). Few of the patients reported any symptoms that could be correlated with this gastritis, and the authors concluded that there was no clear correlation between gastric colonization and related clinical and pathological features. One particularly problematic complication of gastric involvement is antral narrowing and gastric outlet obstruction (21
). Such gastric outlet obstruction can lead to nausea and vomiting and eventually may cause a severe reduction in nutrient intake.
A further unusual complication of cryptosporidiosis in AIDS patients is pneumatosis cystoides intestinalis (30
). Pneumatosis cystoides intestinalis is characterized by the presence of thin-walled, gas-containing cysts in the intestinal wall. Sometimes these cysts can rupture, resulting in a pneumoretroperitoneum and pneumomediastinum.
There is a case report of cryptosporidiosis affecting the esophagus in a 2-year-old child and resulting in vomiting and dysphagia (64
). Finally, there is also a case report of Cryptosporidium
infection causing appendicitis (96
). The diagnosis was confirmed histologically after an appendectomy was performed.
Biliary tract disease.
Cholangitis, and particularly sclerosing cholangitis, is an important complication of AIDS. Although not appearing to adversely affect survival, the disease can be a cause of significant pain (43
). Of 20 patients suffering from cholangitis in a British study, 13 had cryptosporidiosis. In a Spanish study of 43 AIDS patients with chronic diarrhea due to Cryptosporidium
infection, 8 patients (18.6%) were reported to have Cryptosporidium
infection of the common bile duct (71
Following the waterborne outbreak of cryptosporidiosis in Milwaukee, Vakil et al. reported that of 82 patients, believed to have become infected at the time of the outbreak, 24 (29.3%) reported biliary symptoms (126
). The presence of biliary symptoms was a strong indicator of the prognosis since 83% of patients with symptoms died within the following year compared to only 48% of those without. In our view, it is doubtful that this difference was due directly to the biliary involvement but is more likely to reflect the point that more severely immunocompromised persons are more likely to experience biliary involvement.
A series of 15 autopsies on patients with AIDS and cryptosporidiosis showed that five had evidence of infection of the pancreas (50
). Histological changes were generally mild and were limited to hyperplastic squamous metaplasia. Three people with AIDS presented with acute or chronic pancreatitis related to cryptosporidiosis (17
). All three patients had abdominal pain resistant to analgesics, increased serum amylase levels, and abnormalities at both sonography and computed tomography. Endoscopic retrograde cholangiopancreotography revealed papillary stenosis in all three patients. It is difficult to assess the impact of cryptosporidiosis-related pancreatic disease. Certainly, the first study does not suggest significant morbidity due to Cryptosporidium
in the pancreas.
Respiratory tract disease.
In the study from Spain mentioned above, 7 of 43 patients (16.3%) with chronic diarrhea due to Cryptosporidium
oocysts detectable in the sputum (71
). Of these seven patients, five had respiratory symptoms and an abnormal chest radiograph; Mycobacterium tuberculosis
was isolated in two of the five, and M. avium
was isolated in another two. The remaining two patients had no respiratory symptoms and normal chest radiographs. An additional case series of five patients with respiratory cryptosporidiosis, all of whom had respiratory symptoms, was reported from Spain (27
). Again, another respiratory pathogen was isolated in four patients (M. tuberculosis
in two, M. fortuitum
one, cytomegalovirus and Pneumocystis carinii
in one). This latter group also reviewed literature published to that point and were able to identify some 57 patients with respiratory cryptosporidiosis, 40 of whom had another pathogen detected. Given the difficulty in diagnosing many respiratory pathogens, it is not clear to us how relevant respiratory disease secondary to cryptosporidiosis is in the prognosis of and symptoms associated with AIDS. Neither of the papers discussed above can be taken to show that cryptosporidiosis causes respiratory disease.
Dunand et al. reported on 5 of their own cases and reviewed 14 other cases of parasitic sinusitis in HIV-positive patients from the literature (37
). Symptoms often included fever and chills in addition to local tenderness and discharge. Although the prognosis was frequently poor, this was due to other complications of HIV infection.
There have been a large number of studies aimed at developing a satisfactory therapy for cryptosporidiosis, particularly in patients with AIDS. Although several agents have been found to have some activity (most notably macrolides such as spiramycin and clarithromycin, the aminoglycoside paromomycin, and ionophores such as Lasalocid and maduramycin), results have been mixed (52
). In part because of the failure of other therapeutic approaches, there have been several attempts at passive antibody-based immunotherapy for cryptosporidial infections (32
). These have also had limited success. One therapeutic intervention that has a dramatic effect on cryptosporidiosis in AIDS patients is antiretroviral therapy leading to recovery of the CD4 count. In one study of two patients with cryptosporidiosis, both were free from the parasite within 24 weeks after starting antiretroviral therapy (44
). This finding was confirmed in another, larger study, where all patients taken antiretroviral agents showed clinical recovery (74
). Two patients subsequently relapsed after the therapy, was stopped. The authors noted that resolution of the diarrhea seemed to be related to an increased CD4+
cell count rather than to the viral load. Furthermore, at least one clinic has noted a decrease in problems related to cryptosporidiosis in their AIDS patients since the onset of the widespread use of protease inhibitors (68
); and eradication of infection in people on highly active antiretroviral therapy has also been observed (87
). These findings give further support to the observation that it is cellular immunity that is of paramount importance in clearing Cryptosporidium