Toxoplasmosis, cryptosporidiosis, and isosporiasis in HIV-negative immunocompromised patients: A single-centre study, Ottawa, Ontario, Canada

Abstract

Background

Historically, patients with HIV have been at the highest risk of infection with opportunistic protozoans such as Toxoplasma, Cryptosporidium, and Isospora. Among patients with HIV who are compliant with antiretroviral therapy, the likelihood of acquiring an opportunistic infection is low. The risk of infection is harder to mitigate in the growing number of HIV-negative immunodeficient patients, such as people with hematological malignancies or those who are post-transplantation.

Methods

We conducted a retrospective case series of patients with documented Toxoplasma infections between 2008 and 2017 and with Cryptosporidium and Isospora infections between 2014 and 2017 at the Ottawa Hospital.

Results

During the study period, there were 10 confirmed cases of toxoplasmosis, 20 cases of cryptosporidiosis, and 2 cases of isosporiasis. Cryptosporidiosis (95%) and toxoplasmosis (60%) occurred more frequently among HIV-negative patients, whereas isosporiasis cases were limited to HIV-positive patients. Among patients with cryptosporidiosis, the most common underlying cause of immunosuppression in HIV-negative individuals was solid organ transplantation (15.79%), followed by diabetes (10.53%), end-stage renal disease (5.26%), and hematologic malignancy (5.26%). Seventy percent of patients had no known cause of immunosuppression. The most common underlying condition associated with toxoplasmosis was hematological malignancy (50%), followed by solid organ transplantation (33.33%), and solid tumours (16.66%).

Conclusions

This study’s results suggest that Cryptosporidium infections are more common among immunocompetent patients in Ottawa, whereas Toxoplasma infections are more common among HIV-negative patients with acquired immunodeficiencies. As the demographics of immunocompromised individuals continue to evolve, screening for protozoal infections in high-risk populations may become clinically important.

Infections with opportunistic protozoans such as Toxoplasma, Cryptosporidium, and Isospora can cause serious morbidity and mortality. Cryptosporidium and Isospora are enteric protozoans that usually cause diarrheal illness and are transmitted via a fecal–oral route (1). Toxoplasma is a protozoan that can cause various systemic illnesses but is most commonly associated with encephalitis and chorioretinitis (2). In immunocompetent individuals, infections with Toxoplasma, Cryptosporidium, and Isospora usually have a subclinical presentation and are self-limited (1, 3, 4). In immunocompromised individuals, opportunistic protozoans result in more severe disease (5, 6). Most studies describing the impact of opportunistic protozoans in immunocompromised hosts have been limited to patients with HIV (5, 6).

Among patients with HIV, the severity of infection with opportunistic protozoans correlates with lower CD4 lymphocyte counts (7). In countries in which antiretroviral treatment is easily accessible, rates of acute opportunistic illnesses have decreased among patients who are adherent to therapy (8, 9). However, the demographics of immunocompromised individuals are changing with new indications for immunosuppressive treatments, broader organ transplant criteria, and increasing life expectancy for people with chronic diseases (10).

The incidence of infection with opportunistic protozoans among HIV-negative immunocompromised patients is poorly documented (11, 12). Some studies show that solid organ transplantation and hematologic malignancies have become the most common underlying conditions for patients with toxoplasmosis and cryptosporidiosis (11, 13). Here, we review and describe cases with toxoplasmosis, cryptosporidiosis, and isosporiasis identified in recent years in Ottawa to understand the need for improvement in preventive measures.

Materials and Methods

Study design

This study was conducted using a hospital-based retrospective case series of patients who had infection with Toxoplasma, Cryptosporidium, or Isospora. Records from the Ottawa Hospital Data Warehouse were screened from January 2008 to December 2017 for patients suspected to have an infection with Toxoplasma and from January 2014 to December 2017 for patients suspected to have an infection with Cryptosporidium or Isospora. We were unable to obtain an accurate list of patients with positive Cryptosporidium or Isospora from 2008 to 2013 because of changes in the laboratory coding system. The Ottawa Hospital is a tertiary care centre in Ottawa and includes a catchment area for referrals from Eastern Ontario and parts of Northern Ontario. Complex care, chemotherapy, and transplantation in this region occur at the Ottawa Hospital. Currently at the Ottawa Hospital, approximately 200 hematopoietic stem cell transplants and 80–100 renal transplants are performed yearly. Patients with non-renal transplants are repatriated back to the Ottawa Hospital after transplant. The rate of HIV in Ottawa has remained stable, with approximately 60 new cases per year (14). All new cases are referred to an HIV clinic, where they are evaluated for initiation of antiretroviral therapy and assessed for opportunistic infections if symptoms of concern are present. For this study, the date of infection was defined as the first date that clinical disease was confirmed with positive PCR, culture, pathology, or stool tests for ova and parasites. A thorough review of each patient’s relevant medical records was conducted to review all laboratory results and physician notes during and around the time of the patient’s presentation to our tertiary care centre for medical consultation. CT reviewed the medical records to elucidate patients’ clinical symptoms at the time of presentation. Patient outcomes were recorded, along with HIV status, immunosuppression, and comorbidities. Mortality as documented by a death certificate in the patient’s chart was recorded up to 12 months from the time of diagnosis.

Data analysis

Descriptive analysis was conducted for each variable. Data were reported using both the raw number of patients and as a percentage of the total number of patients.

Ethical approval

This study was reviewed and approved by the Ottawa Hospital Research Ethics Board. The protocol identification number was 20170859-01H. Informed consent was waived because of the retrospective case series design.

Results

We identified 10 patients with Toxoplasma, 20 with Cryptosporidium, and 2 with Isospora infections. Among the 10 patients with toxoplasmosis, 2 had positive PCR tests from samples of aqueous humour, 1 was positive in blood alone, and the remaining 7 had positive cerebrospinal fluid or brain tissue samples. The diagnoses of cryptosporidiosis and isosporiasis were made by means of a positive stool test for ova and parasites. Patients diagnosed with a Toxoplasma or Cryptosporidium infection were divided into groups on the basis of the comorbidity that was felt to be a risk factor for infection (Table 1).

Table 1:

Characteristics of 30 patients diagnosed with infections caused by Toxoplasma or Cryptosporidium

Characteristic	No. (%)*
	Toxoplasma; n = 10	Cryptosporidium; n = 20
Age, y, median (range)	58.5 (35–79)	42 (16–68)
Sex
Male	5 (50)	13 (65)
Female	5 (50)	7 (35)
HIV status
Positive	4 (40)	1 (5)
Treated and compliant	0 (0)	0 (0)
Untreated	4 (100)	1 (100)
Negative	6 (60)	19 (95)
Cause of immunosuppression in HIV-negative patients†
Hematologic malignancy	3 (50)	1 (5.26)
Bone marrow transplantation	0 (0)	0 (0)
Solid tumour	1 (16.66)	0 (0)
Solid organ transplantation
Kidney	1 (16.66)	2 (10.53)
Heart	1 (16.66)	1 (5.26)
Other comorbidities
End-stage renal disease	1 (16.66)	1 (5.26)
Type 2 diabetes mellitus	0 (0)	3 (15.79)
Cirrhosis	0 (0)	0 (0)
Age >75 y at diagnosis	3 (50)	0 (0)
No immunosuppression or major comorbidity	0 (0)	14 (70)
Mortality at 12 mo
HIV-positive patients	0 (0)	0 (0)
HIV-negative patients	2 (33.33)	1 (5.26)

*Unless otherwise specified

† Total is >100% because some patients had more than one cause for immunosuppression

Of the 10 patients with toxoplasmosis, 5 (50%) were male and 5 (50%) were female. The median age at the time of infection was 58.5 years (range 35–79). Four patients (40%) were HIV-positive. Of HIV-negative patients with toxoplasmosis, 3 (50%) had a hematologic malignancy, 1 (16.66%) had a solid tumour, and 2 (33.33%) had a solid organ transplant.

Among HIV-positive patients, toxoplasmosis rates appeared to remain stable between 2008 and 2017. The number of cases of toxoplasmosis among HIV-negative patients increased from 1 (16.66%) in 2008–2012 to 5 (83.33%) in 2013–2017 (Figure 1). Mortality at 12 months was noted for 2 (33.33%) HIV-negative immunosuppressed patients with toxoplasmosis. Causes of death were due to multi-organ failure, transplant rejection, and multiple opportunistic infections, including cytomegalovirus pneumonitis, adenovirus hepatitis, and post-transplant lymphoproliferative disease.

Figure 1:

Number of patients with Toxoplasma infections diagnosed between 2008 and 2017

Of the 20 patients with cryptosporidiosis, 13 (65%) were male and 7 (35%) were female. The median age at the time of infection was 42 years (range 18–68). One patient (5%) was HIV-positive. For HIV-negative patients with cryptosporidiosis, 1 (5.26%) had a hematologic malignancy, none had a solid tumour, and 3 (15.79%) had a solid organ transplant. Fourteen (70%) HIV-negative patients with cryptosporidiosis had no documented immunosuppression or comorbidity (Table 1). Over the study period, rates of Cryptosporidium infection varied over time with no definite trend. Mortality at 12 months was noted for 1 (5.26%) HIV-negative immunosuppressed patient with cryptosporidiosis secondary to septic shock with respiratory failure. Mortality at 12 months was unknown for 6 immunocompetent patients with Cryptosporidium.

Two patients were identified with isosporiasis, both of whom were HIV-positive with no other known causes of immunosuppression. There was no associated mortality within 12 months of the date of infection for either.

Patients who were HIV-positive had no mortality noted at 12 months regardless of the type of protozoal co-infection. None of the patients with HIV co-infections in this study were compliant or actively being treated with antiretroviral therapy at the time of diagnosis with a protozoal infection.

Discussion

In this study, we reviewed recent cases of toxoplasmosis, cryptosporidiosis, and isoporiasis in our academic centre to determine key populations presenting with opportunistic protozoal infections. Among the three protozoal infections, we found that cryptosporidiosis (n = 20) was the most common infection, followed by toxoplasmosis (n = 10) and isosporiasis (n = 2). Cryptosporidiosis and toxoplasmosis occurred more frequently in HIV-negative than HIV-positive patients, whereas the two isosporiasis cases were limited to HIV-positive patients.

Only 5% (1/20) of patients with cryptosporidiosis in our study were HIV-positive. Our finding is similar to recent literature identifying Cryptosporidium to be an important cause of chronic diarrhea in HIV-negative patients with chronic renal failure or diabetes, and, in particular, after renal transplantation (15–19). In addition, among the remaining HIV-negative patients in our study, 73.68% had no known cause of immunosuppression. Similar findings were found in a study that reported Cryptosporidium rates as high as 55% among immunocompetent patients presenting with acute diarrhea (4). This is in keeping with previous studies suggesting that Cryptosporidium may be a relatively common cause of self-limited, non-viral diarrhea among immunocompetent patients (4, 20–22). It is important to note that cryptosporidiosis in advanced HIV infection is chronic in nature as compared with acute diarrheal illness in immunocompetent hosts. It is possible that infection with Cryptosporidium among our immunocompetent patients caused acute diarrheal illness rather than chronic diarrheal illness; however, we were not able to be certain of this because of limited follow-up data. Despite Cryptosporidium being more common among immunocompetent patients in our study, among immunocompromised patients, it remained more frequent in those without HIV.

Moreover, our data show that the largest proportion of patients diagnosed with toxoplasmosis were HIV-negative (6/10; 60%). Patients with hematological malignancies followed by recipients of solid organ transplantation were at highest risk for toxoplasmosis. The lower rates of toxoplasmosis among patients after bone marrow transplantation and patients who were HIV-positive may be due to the use of trimethoprim–sulfamethoxazole as prophylaxis against Pneumocystis jirovecii. Our results are consistent with those of a recent study that shows a higher frequency of toxoplasmosis among HIV-negative immunocompromised patients than among those infected with HIV (13). In addition, we noted a rising trend in toxoplasmosis rates among HIV-negative patients over time. The timeline of increased toxoplasmosis among HIV-negative immunocompromised patients is in line with broader indications for immunosuppressive treatments and organ transplant criteria in the past few years (10). Our data suggest that HIV-negative immunosuppressed patients represent a subgroup at risk for toxoplasmosis and may be at higher risk of mortality from this infection than HIV-positive patients. Similar findings were found in the United States, where a decline in toxoplasmosis mortality was observed among HIV-positive patients but not among infected patients without an HIV co-diagnosis (23).

In this study, we noted only two patients with Isospora infections, likely because Isospora has a distribution that is limited mainly to tropical regions in developing countries (1). Both patients in our study were HIV-positive and not on highly active antiretroviral therapy at the time of infection. Their HIV diagnosis was their only known cause of immunosuppression. It is unclear whether these two patients had any recent travel history to regions in which Isospora is endemic. Because of the limited data in this study, it is uncertain whether isosporiasis is more common among non-controlled HIV-positive patients (24).

Data from this study are from a single centre, which limits generalizability. However, the Ottawa Hospital has a patient demographic similar to that of other tertiary hospitals in Canada, and it is a referral centre for the region, providing complex care and transplantation services. Although our sample size is small, we have captured all cases of Cryptosporidiosis, Toxoplasmosis, and Isosporiasis at our centre by PCR, pathology reports, and stool test for ova and parasites. It is possible that patients with mild, self-limited disease who did not present to the Ottawa Hospital, or who were not tested for these opportunistic infections, may have been omitted from our analyses.

Despite these limitations, our data show that HIV-negative immunosuppressed patients are also at risk for protozoal infections, in particular Toxoplasmosis. In addition, mortality status 12 months post-infection was not captured for six patients, and as such, it is possible that the mortality rate reported in our study is underestimated, representing a limitation of our study. As the demographics of immunocompromised individuals continue to evolve with newer indications for immunosuppressive treatments and a rising number of transplants, considering protozoal infections in the differential diagnosis is clinically important.

Ethics approval:

This study was reviewed and approved by the Ottawa Hospital Research Ethics Board. The protocol identification number was 20170859-01H.

Informed consent:

Informed consent was waived because of the retrospective case series design.

Funding:

No funding was received for this article.

Disclosures:

The authors have nothing to disclose.

Peer Review:

This manuscript has been peer reviewed.