Volume 27, Number 6—June 2021
CME ACTIVITY - Research
HIV Infection as Risk Factor for Death among Hospitalized Persons with Candidemia, South Africa, 2012–2017
We determined the effect of HIV infection on deaths among persons >18 months of age with culture-confirmed candidemia at 29 sentinel hospitals in South Africa during 2012–2017. Of 1,040 case-patients with documented HIV status and in-hospital survival data, 426 (41%) were HIV-seropositive. The in-hospital case-fatality rate was 54% (228/426) for HIV-seropositive participants and 37% (230/614) for HIV-seronegative participants (crude odds ratio [OR] 1.92, 95% CI 1.50–2.47; p<0.001). After adjusting for relevant confounders (n = 907), mortality rates were 1.89 (95% CI 1.38–2.60) times higher among HIV-seropositive participants than HIV-seronegative participants (p<0.001). Compared with HIV-seronegative persons, the stratum-specific adjusted mortality OR was higher among HIV-seropositive persons not managed in intensive care units (OR 2.27, 95% CI 1.47–3.52; p<0.001) than among persons who were (OR 1.56, 95% CI 1.00–2.43; p = 0.05). Outcomes among HIV-seropositive persons with candidemia might be improved with intensive care.
Candida is a common cause of healthcare-associated bloodstream infections in South Africa; the estimated national incidence risk in 2016–2017 was 84 (95% CI 81–86) cases per 100,000 hospital admissions (1). This rate is ≈10-fold higher than that reported in the United States (2). The death rate among patients with Candida bloodstream infections is high and associated with such factors as confirmed or presumed gastrointestinal source of infection, lack of source control, shorter time to positivity of blood cultures, inappropriate or delayed empiric antifungal treatment, lack of consultation with an infectious disease physician, severe sepsis or septic shock, and severity of underlying conditions (3–5). The crude mortality rate associated with candidemia was 43% in South Africa in 2016–2017 (1). In 2 small case series of HIV-seropositive patients with candidemia (Spain, n = 37; Italy, n = 38), the crude mortality rate was ≈60% (6,7). HIV infection may be a risk factor for death among persons with culture-confirmed candidemia. In a 2014 population-based surveillance study in Spain, 16 (2%) of 752 patients with candidemia were HIV-seropositive (8). Although HIV infection was not associated with death on univariable analysis (OR 0.51, 95% CI 0.07–3.93), the study was underpowered. In contrast, in a United States cohort study of 446 adults with candidemia, 22 (5%) were HIV-seropositive, and HIV infection was associated with a 2-fold increased adjusted hazard of 30-day mortality (hazard ratio 2.02, 95% CI 1.11–3.72) (9). This effect of HIV infection on death rates may be mediated by factors related to the host (e.g., neutropenia or neutrophil dysfunction in persons with advanced HIV disease) or the fungal pathogen (infection caused by Candida species other than C. albicans or by >1 Candida spp.) (6,7,10–12). Such an association has not been described in a high HIV prevalence setting. By using data from a 6-year sentinel surveillance study at hospitals in South Africa, we examined the effect of HIV infection on the risk for 30-day mortality among persons with candidemia.
We included persons >18 months of age with an episode of culture-confirmed candidemia identified at 29 sentinel hospitals in South Africa during January 1, 2012–December 31, 2017. The HIV prevalence among inpatients is high at these large urban tertiary-academic or regional acute-care hospitals (e.g., 60% at a Cape Town district hospital in 2012–2013) (13). A case was defined as illness in a person in whom Candida spp. was cultured from blood at a laboratory providing diagnostic pathology services to a sentinel hospital. An episode was defined as a 30-day period from the date of the first positive Candida culture. Any positive blood cultures after this period defined a recurrent episode and thus a new case. We excluded children <18 months of age because we did not have HIV PCR results to confirm an HIV diagnosis for a sufficient number of persons.
Cases were reported from public-sector and private-sector pathology laboratories. In general, blood cultures were collected if patients had clinical features of sepsis, including tachycardia, tachypnea, increased or subnormal temperature, a change in sensorium, hypotension, or prostration (14). Viable Candida isolates were submitted to a reference laboratory for species-level identification and antifungal susceptibility testing, as previously described (1). Trained nurses or pharmacists identified culture-confirmed cases in the laboratory and interviewed prospectively enrolled participants or their next of kin or reviewed medical charts or electronic laboratory records. Data were collected through a standardized case report form. The main explanatory variable was the participant’s HIV infection status, which was determined during the admission for candidemia. HIV status was self-reported during participant interviews or abstracted from the inpatient chart, a child’s outpatient immunization card, or laboratory records. An in-hospital outcome with a date of outcome was determined at the end of admission to the acute-care hospital or if the participant was transferred to a step-down facility; this outcome was determined at the end of that admission. Outcome was recorded as alive at 30 days for prolonged admissions of >30 days after first positive blood culture. Underlying or immediate cause of death was not recorded. Surveillance officers recorded whether a person had been admitted to the intensive care unit (ICU) at any time during hospitalization, but the specific reason for and dates of ICU admission or discharge were not captured. We calculated a quick Pitt score, an abbreviated version of the Pitt bacteremia score, as the sum of individual scores for body temperature of <35°C (1 point), systolic blood pressure of <90 mm Hg (1 point), cardiac arrest (1 point), mechanical ventilation (1 point ), and altered mental status (1 point) on the day of candidemia diagnosis (15,16).
We used participant identifiers to remove duplicate records. We described the characteristics of the study participants by using descriptive statistics. To determine risk factors for death, we used classical Mantel-Haenszel methods to calculate crude case fatality ratio, odds ratio (OR), and 95% CI for HIV status and each of the potential confounders (Appendix). We did not assume that individual participant-level outcomes were statistically independent in this sentinel surveillance study. We therefore used a random-effects logistic regression analysis to explicitly model between-cluster variation at sentinel sites and simultaneously adjust for participant-level confounders (17) (Appendix). We treated the follow-up period as a fixed 30-day period. We also explored the dose-response effect of HIV on death rates. For this analysis, participants’ HIV infection status was recoded as an ordinal variable: HIV-seronegative, HIV-seropositive without advanced immunosuppression (CD4 count >200 cells/µL), and HIV-seropositive with advanced immunosuppression (CD4 count <200 cells/µL). Before conducting the analysis, we hypothesized that the effect of HIV infection on death rates would differ among participants with candidemia managed in an ICU and those who were not admitted to an ICU; therefore, we considered ICU admission as an effect modifier a priori. We included participants with recorded dates of positive Candida specimen collection and 30-day outcome in a Kaplan-Meier survival analysis. For 67 participants with an outcome date that coincided exactly with the specimen collection date, we recoded their time-to-outcome to 0.5 days. We explored the association between HIV status and ICU admission by classical and multivariable random effects logistic regression analyses as a post-hoc analysis to explore reasons for the main results.
For GERMS-SA surveillance, annual ethics approvals were sought and obtained from several university ethics committees in South Africa. We also obtained approval from the London School of Hygiene and Tropical Medicine Research Ethics Committee.
After deduplication, 8,668 cases were detected by GERMS-SA surveillance during the 6-year period. We excluded 3,643 cases diagnosed at non–sentinel sites and 2,462 cases among infants and children <18 months of age. Of 2,563 cases diagnosed at sentinel sites, a case report form had been completed for 1,846 (72%) (Figure 1). Of those, we retained 1,040 cases with both HIV status and outcome data (56%). We noted differences in age, sex, year of diagnosis, province in which the diagnosis was made, and Candida species among 717 sentinel-site cases with missing case report forms, 806 cases with completed case report forms but missing HIV status or outcome data, and the 1,040 cases included in the final analysis (Appendix Table 1).
Description of 1,040 Participants Included in the Analysis
Of 1,040 participants, 542 (52%) were men and boys (Table 1). The median age of 1,037 participants with recorded age was 37 years (interquartile range [IQR] 23–52 years). Of 1,035 participants with available date of specimen collection, 288 (28%) had a positive Candida blood culture within 72 hours of hospital admission. Overall, 50% (514/1,023) participants were managed in the ICU during their hospitalization (data on ICU admission were missing for 17 participants). At the time of diagnosis, most (545/1,011, 54%) had a central venous catheter (CVC) in situ, and 24% (245/1,004) were receiving total parenteral nutrition. Of 1,001 participants for whom data was available, 163 (16%) received previous antifungal treatment. A quick Pitt score was calculated for 652/1,040 participants: 319 (49%) had a 0 score, 184 (28%) had a 1 score, 126 (19%) had a 2 score, 20 (3%) had a 3 score, and 3 (1%) had a 4 score (Appendix). Thus, 149/652 (23%) had a quick Pitt score of >2. Of 946 case-patients in which Candida species identification was performed at a diagnostic or reference laboratory, 521 (55%) participants were infected with a Candida species other than C. albicans and the remainder with C. albicans; 33 (3%) case-patients had a mixed Candida infection. Of 1,010 cases, 700 (69%) received systemic antifungal treatment to treat candidemia (participants might have received >1 antifungal agent: fluconazole [n = 503], amphotericin B [n = 265], echinocandin [n = 91], or voriconazole [n = 17]). Of 764 cases with a known Candida species, available antifungal susceptibility data, and applicable Clinical and Laboratory Standards Institute breakpoints (18), 154 (20%) were infected with an antifungal-resistant species. Of these 764, antifungal treatment was recorded for 419, and 9% (38/419) had received inappropriate antifungal treatment. Of 488 cases with recorded information, 361 (74%) had their CVC removed after the candidemia diagnosis. In 4% of patients (45/1,040), evidence of complications of candidemia (deep organ involvement) was indicated in medical charts.
HIV Status and Outcome
Of the 1,040 case-patients, 426 (41%) were HIV-seropositive; we noted several differences in those patients compared with those who were HIV-seronegative (Table 1; Appendix). Among 404 HIV-seropositive persons with available data, 301 (75%) were antiretroviral treatment–experienced. Among 267 participants in whom CD4 count was recorded near the date of the candidemia diagnosis, the median CD4 count was 133 (IQR 42–309) cells/µL; 166/267 (63%) had a CD4 count <200 cells/µL. An additional 35 without a CD4 count had a recorded World Health Organization (WHO) clinical stage of HIV disease. Of these 35 case-patients, illness was WHO stage 3 or 4 in 33 case-patients. Of 141 whose records indicated a recently recorded viral load, 65 (46%) had a viral load of <400 RNA copies/mL. Of the 426 HIV-seropositive persons, 153 (36%) had clinical evidence of HIV-associated wasting. The overall case fatality ratio was 458/1,040 (44%). The case-fatality ratio among HIV-seronegative cases was 37% (230/614) versus 54% (228/426) for HIV-seropositive cases (p<0.001).
Risk Factors for 30-Day Mortality
The crude 30-day case fatality ratio among HIV-seropositive participants was 1.92 (95% CI 1.50–2.47) times higher than among HIV-seronegative participants (p<0.001) (Table 2). After adjusting for sentinel hospital, age, sex, year of diagnosis, ICU admission, receipt of systemic antifungal treatment, and Candida species, the odds of 30-day mortality were still 1.89 (95% CI 1.38–2.60) times higher among HIV-seropositive participants than among HIV-seronegative participants (Table 3); evidence was strong against the null hypothesis (p<0.001). We noted relatively little confounding of the association between HIV status and 30-day mortality by any available explanatory variable. In the final model, differences between hospitals accounted for 3% of the variability in deaths (intracluster correlation coefficient = 0.03; p = 0.003). We found evidence of interaction of HIV status and ICU admission. The stratum-specific mortality OR was larger in the group not managed in an ICU (OR 2.27, 95% CI 1.47–3.52; p<0.001) than those who were admitted to the ICU (OR 1.56, 95% CI 1.00–2.43; p = 0.05), although the 95% CIs overlapped (Table 4). In a dose-response analysis, the adjusted odds of 30-day mortality was 1.90 times higher among HIV-seropositive persons with a CD4 count >200 cells/µL (95% CI 1.13–3.20; p = 0.02) and 2.18 times higher among persons with a CD4 count <200 cells/µL (95% CI 1.39–3.42; p = 0.001) compared with 30-day mortality among HIV-seronegative persons (Appendix Table 4).
Kaplan-Meier Survival Analysis
An outcome date was available for 1,023 participants. Overall, 44% (452/1,023) died within 30 days. The Kaplan-Meier survival curves diverged for HIV-seropositive and HIV-seronegative persons within 3 days of candidemia diagnosis and then remained roughly parallel until day 30 (Figure 2). Evidence was strong against the hypothesis that survival experience did not differ by HIV status (p<0.001).
Association of HIV Status and ICU Admission
Among 1,023 participants, a lower proportion (175/422, 41%) of HIV-seropositive persons than HIV-seronegative persons (339/601, 56%) were admitted to the ICU (crude OR 0.55, 95% CI 0.42–0.71; p<0.001). After adjustment for sentinel site, age, sex, and quick Pitt score category (n = 583) (Appendix Table 5), HIV-seropositive participants were 60% less likely to be admitted to the ICU than HIV-seronegative participants (OR 0.40, 95% CI 0.25–0.64; p<0.001). Among HIV-seropositive participants, a similar proportion with and without advanced HIV disease were admitted to the ICU (72/166 [43%] vs. 39/99 [39%]; p = 0.53). A similar proportion of HIV-seropositive participants receiving and not receiving antiretroviral treatment were admitted to ICU (116/299 [39%] vs. 50/101 [50%]; p = 0.06).
In this surveillance study of hospitalized persons with candidemia in South Africa, the prevalence of HIV infection was 41% (95% CI 38%–44%). The 30-day mortality rate was almost twice as high among HIV-seropositive persons as among HIV-seronegative persons (OR 1.89, 95% CI 1.38–2.60; p<0.001), after adjusting for relevant confounders. The effect of HIV infection on death rates was estimated to be stronger among those not managed in an ICU than those who were, though the 95% CIs overlapped. HIV-seropositive persons also had a substantially lower risk for ICU treatment during their admission than those who were HIV-seronegative.
The overall crude mortality rate associated with candidemia of 44% (95% CI 41%–47%) reported in this study is higher than that reported in resource-rich settings (19), possibly owing to differences in our hospitalized cohort. The overall median age was lower, a large proportion were critically ill, and amphotericin B deoxycholate and azoles were the mainstay of treatment, whereas few patients received echinocandins. In our large study, we found a crude mortality rate among HIV-seropositive patients of 54%, which is comparable to the 60% mortality rate reported in 2 case series (6,7). Our main results are consistent with a United States cohort study that found that HIV infection was associated with a 2-fold increased adjusted hazard of 30-day mortality (9). We believe that this association between HIV and death among persons with candidemia is biologically plausible. First, the mechanism for an increased risk for death among HIV-seropositive persons may operate at the individual level. Despite a large proportion having received previous antiretroviral treatment, the median CD4 count among hospitalized HIV-seropositive participants with candidemia in this study was 133 cells/µL, and almost two thirds had advanced HIV disease (defined by the WHO as a CD4 count of <200 cells/µL) (20). This finding is consistent with reports of virologic failure and treatment interruption among an increasing proportion of HIV-seropositive patients at acute-care hospitals in South Africa (21). Many persons with advanced HIV disease have neutropenia or neutrophil defects (10,11). This innate immune defect may be a consequence of abnormal progenitor stem cell growth, a deficiency of granulocyte colony-stimulating factor, bone marrow infiltration by opportunistic infectious agents or malignant cells, treatment with particular medicines, or autoimmune phenomena (10). The alteration in the innate immune response may then reduce the clearance of Candida from the bloodstream, despite appropriate antifungal treatment. People with advanced HIV disease might also have been admitted primarily for management of disseminated tuberculosis, cryptococcal disease, or Pneumocystis pneumonia, which are associated with high death rates (20). In addition, more than one third of HIV-seropositive participants in this study were recorded to have evidence of HIV-associated wasting. Patients with a poorer nutritional state or loss of lean body mass have worse outcomes (22).
Second, an increased risk for death may be a consequence of differential treatment practices at the sentinel hospitals for HIV-seronegative and HIV-seropositive persons. We found that HIV-seropositive persons were 60% less likely to have received intensive care during their hospitalization. Several studies in Italy have documented the large proportion of patients who are managed for candidemia in general medical wards (23–25). In addition, the adjusted effect of HIV infection on 30-day mortality rates was stronger among participants who were not managed in an ICU during their hospital stay. This finding suggests that intensive care and monitoring of patients with candidemia, including those who are HIV-seropositive, might reduce mortality rates. However, in a resource-limited setting, the number of ICU beds is restricted. The criteria for admission to a public-sector ICU in South Africa includes an assessment of the severity of the acute or underlying illness and whether organ dysfunction can realistically be reversed. These criteria apply equally to those with and without HIV infection, according to a survey of critical care physicians in South Africa, although no data exist on the proportion of HIV-seropositive persons who were eligible for ICU admission but were not referred or were turned down (26,27). Among HIV-seropositive participants in our study, similar proportions of persons with advanced HIV disease who were receiving antiretroviral treatment were or were not admitted to ICU, suggesting that these factors were not the sole criteria for admission.
We confirmed several well-described risk factors for death among patients with candidemia, including inappropriate or no antifungal treatment, ICU admission, increased age, and a quick Pitt score of >2 (28). Removal of a CVC following diagnosis of candidemia was protective against death. A limitation of this study is that it was a secondary data analysis and was not specifically designed or powered to answer whether HIV infection was associated with death among patients with candidemia. However, the study was conducted in a high HIV prevalence setting, our sample size was large, and we found strong and consistent evidence against the null hypothesis after adjustment for confounding. Selection bias was a limitation because we excluded 60% of cases diagnosed at sentinel hospitals for whom data for the main exposure and outcome variables were missing. We also found differences among those who were included and excluded from the analysis. For instance, we included a larger proportion of cases among adults 18–44 years of age, cases caused by C. albicans, and cases from outside Gauteng Province in the analysis (Appendix). Data were also missing for confounder variables, and we excluded several potentially critical confounders from the main multivariable analysis. However, including these variables in a smaller dataset for multivariable analysis did not change the point estimate for the main exposure effect, although the 95% CI was wider (Appendix Table 3). In ≈20% of cases, HIV status was self-reported by participant or next-of-kin interview if a clear record of HIV status was not in the chart. If HIV-seropositive persons underreported their actual infection status, it might have weakened the association with death demonstrated in this study. Because we were unable to adjust for unmeasured factors, such as the presence or severity of diagnosed or undiagnosed underlying conditions, residual confounding is also possible. We conducted this study in an upper middle-income country, and participants were recruited at urban sentinel hospitals with ICU facilities; therefore, the results might not apply to all hospital populations. Cause of death was not recorded, and we were thus unable to estimate the number of deaths directly attributable to candidemia among either HIV-seropositive or HIV-seronegative participants. We excluded children <18 months of age from this analysis and cannot comment on whether HIV exposure or infection is associated with death in this population.
A key strength of this study was that it was nested within a large active surveillance system; laboratory audits were conducted to ensure that all culture-confirmed cases were captured. The main outcome measure was in-hospital death, a clear endpoint that was unlikely to have been misclassified. Given that most persons with HIV infection live in sub-Saharan Africa and the risk for healthcare-associated infections, including those caused by antimicrobial-resistant fungi, is becoming increasingly critical in this region (1,29–31), our findings might have broader implications than similar studies and are an essential addition to the literature.
In conclusion, we found that the overall crude mortality rate associated with candidemia was high, and HIV-seropositive persons were at ≈2-fold increased adjusted risk for all-cause in-hospital death, compared with their HIV-seronegative counterparts. This effect on mortality rates was weakened among those admitted to the ICU, though HIV-seropositive persons were substantially less likely to have received intensive care. We recommend a high index of suspicion for candidemia among admitted HIV-seropositive persons, regardless of the presence of classical risk factors. We further recommend that HIV-seropositive persons with suspected candidemia rapidly begin appropriate early antifungal treatment, that they be investigated to identify an infection source and control measures instituted, and that they should be considered for intensive care and monitoring to reduce deaths. Where feasible, consultation with an infectious disease specialist would enable this level of care.
This work was supported in its entirety by the National Institute for Communicable Diseases, a Division of the National Health Laboratory Service, Johannesburg, South Africa.
Members of GERMS-SA: John Black, Shareef Abrahams, Vanessa Pearce (Eastern Cape Province); Anwar Hoosen, Vicky Kleinhans, Masego Moncho (Free State Province); Alan Karstaedt, Caroline Maluleka, Charl Verwey, Charles Feldman, David Moore, Gary Reubenson, Khine Swe Swe Han, Jeannette Wadula, Jeremy Nel, Kathy Lindeque, Maphoshane Nchabeleng, Nazlee Samodien, Nicolette du Plessis, Nontombi Mbelle, Nontuthuko Maningi, Norma Bosman, Ranmini Kularatne, Sharona Seetharam, Teena Thomas, Theunis Avenant, Trusha Nana, Vindana Chibabhai (Gauteng Province); Adhil Maharj, Asmeeta Burra, Fathima Naby, Halima Dawood, Jade Mogamberry, Koleka Mlisana, Lisha Sookan, Praksha Ramjathan, Prasha Mahabeer, Romola Naidoo, Sumayya Haffejee, Yacoob Coovadia Khine Swe Swe Han, Nomonde Dlamini, Surendra Sirkar (KwaZulu-Natal Province); Ken Hamese, Ngoaka Sibiya, Ruth Lekalakala (Limpopo Province); Greta Hoyland, Jacob Lebudi (Mpumalanga Province); Pieter Jooste (Northern Cape Province); Ebrahim Variava, Erna du Plessis (North West Province); Andrew Whitelaw, Kessendri Reddy, Mark Nicol, Preneshni Naicker, Colleen Bamford (Western Cape Province); Adrian Brink, Ebrahim Hoosien, Elizabeth Prentice, Inge Zietsman, Maria Botha, Peter Smith, Terry Marshall, Xoliswa Poswa (Ampath laboratories); Chetna Govind, Juanita Smit, Keshree Pillay, Sharona Seetharam, Suzy Budavari, Victoria Howell (Lancet laboratories); Carel Haumann, Catherine Samuel, Marthinus Senekal (PathCare laboratories); Andries Dreyer, Khatija Ahmed, Louis Marcus, Warren Lowman (Vermaak and Vennote laboratories); Angeliki Messina, Dena van den Bergh, and Karin Swart (Netcare hospital group); Ananta Nanoo, Andries Dreyer, Anne von Gottberg, Anthony Smith, Arvinda Sooka, Cecilia Miller, Charlotte Sriruttan, Cheryl Cohen, Chikwe Ihekweazu, Claire von Mollendorf, Desiree du Plessis, Erika van Schalkwyk, Farzana Ismail, Frans Radebe, Genevie Ntshoe, Gillian Hunt, Hlengani Mathema, Husna Ismail, Jacqueline Weyer, Jackie Kleynhans, Jenny Rossouw, John Frean, Joy Ebonwu, Judith Mwansa-Kambafwile, Karen Keddy, Kerrigan McCarthy, Liliwe Shuping, Linda de Gouveia, Linda Erasmus, Lucille Blumberg, Marshagne Smith, Martha Makgoba, Motshabi Modise, Nazir Ismail, Nelesh Govender, Neo Legare, Nicola Page, Ntsieni Ramalwa, Nuraan Paulse, Phumeza Vazi, Olga Perovic, Penny Crowther-Gibson, Portia Mutevedzi, Riyadh Manesen, Ranmini Kularatne, Ruth Mpembe, Sarona Lengana, Shabir Madhi, Shaheed Vally Omar, Sibongile Walaza, Sonwabo Lindani, Sunnieboy Njikho, Susan Meiring, Thejane Motladiile, Tiisetso Lebaka, Vanessa Quan, Verushka Chetty, Serisha Naicker, Tsidiso Maphanga, Mabatho Mhlanga, Thokozile Gloria Zulu, Ernest Tsotetsi, Phelly Matlapeng, Siphiwe Kutta, Lerato Qoza, Sydney Mogokotleng, Mbali Dube, and Amanda Shilubane (National Institute for Communicable Diseases).
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Original Publication Date: May 19, 2021
1Members of GERMS-SA are listed at the end of this article.