Cryptococcal disease remains a major opportunistic infection among people living with HIV (PLWH).1,2 HIV-negative populations have high mortality as well,3 but compared with these populations, PLWH are more likely to have central nervous system (CNS) infections and corresponding symptoms including headaches and altered mental status.3,4 Worldwide, mortality related to cryptococcal meningitis in PLWH has improved with the introduction of effective antiretroviral therapy (ART).5
Despite advances in ART and management of cryptococcosis, mortality among PLWH with cryptococcal meningitis remains high, with most studies evaluating mortality within the first 3 months of diagnosis.3,6–9 Ninety-day mortality in the modern ART era ranges from 13% to 19% in high-resource settings.3,6,9 Risk factors for mortality from these studies have included neurologic deficits, high cerebrospinal fluid (CSF) or serum fungal burden, aged 50 years older, or fluconazole-based treatment.10–13 Although research from sub-Saharan Africa has shown promising long-term survival,14 in the United States, less is known about mortality after 3 months and, therefore, overall mortality in this population.
Other than mortality, cryptococcosis can also have long-lasting effects after diagnosis and treatment. A recent systematic review assessing PLWH and HIV-negative individuals with Cryptococcus neoformans or Cryptococcus gattii meningitis showed that 20%–70% of individuals had long-term neurologic sequelae at 1 year.15
Overall survival rates and risk factors for mortality of PLWH with cryptococcosis in the modern ART era have not been well-established. Evaluating mortality for opportunistic infections in HIV, including Cryptococcus infections, provides insight into PLWH who remain at high risk. In this study, we explore mortality of PLWH with cryptococcosis and aim to better define this population.
All participants diagnosed with HIV and cryptococcosis at Barnes-Jewish Hospital in St. Louis, Missouri, from January 1, 2002, to July 1, 2017, were included. Cryptococcal infection was defined as positive serum or CSF cryptococcal antigen (CrAg), isolation of Cryptococcus species in culture, or identification by the International Classification of Diseases ninth (117.5, 321.0) or 10th (B45.1–B45.9) editions, which were then confirmed through chart review. Localized pulmonary cryptococcosis was defined as cryptococcal infection involving the lung only. CNS infection was defined as a positive CSF CrAg or CSF cultures growing Cryptococcus species. Cryptococcemia was defined as positive bacterial or fungal blood cultures growing Cryptococcus species. Disseminated cryptococcosis was defined as cryptococcal infection involving extrapulmonary sites. All cases were confirmed by the medical record review by investigators.
Outcomes and clinical presentations of PLWH and cryptococcosis were evaluated. Participants were divided into 3 groups: survivors (individuals living at time of analysis), early-mortality (death within 90 days of cryptococcal diagnosis), or late-mortality (death after 90 days of cryptococcal diagnosis) individuals. Patients were further analyzed by the year of their cryptococcal diagnosis, with the cohort split in 2008, at a time where both newer protease inhibitors were available and the year integrase inhibitors were included in the Department of Health and Human Services HIV-1 guidelines from January 29, 2008.16 Before 2008 was designated as the premodern ART era, whereas 2008 and beyond was designated as the modern ART era. Individuals were defined as ART-experienced if they had ever received ART before cryptococcal diagnosis. Viral suppression was defined as HIV-1 viral loads <50 copies/mL. Variables available on this cohort have been previously described8,9 and included demographics, medical history, laboratory and pathology results, treatment, and outcomes, which were obtained by medical record review. Individuals receiving Ryan White, Medicaid, or Medicare were defined as receiving government insurance. Substance abuse was abstracted by the participant report, listed problem in the medical record, or positive drug screen. Psychiatric history before cryptococcosis was abstracted from the medical record. Date of death was abstracted from the electronic medical record and the Social Security Death Index. The Social Security Death Index only includes deaths through 2014. Any dates of death beyond 2014 were obtained from the electronic medical record. Mortality was defined in days after admission until death or the last day of follow-up in our medical record. Cause of death was determined from death summary, which was confirmed by investigators.
Categorical variables were analyzed using χ2 and 1-way analysis of variance as appropriate. Continuous variables were analyzed using Mann–Whitney U and Kruskal–Wallis nonparametric testing as appropriate. All-cause mortality was compared with Cox proportional hazards. Logistic regression was completed to evaluate factors for increased mortality. P values of <0.05 were considered statistically significant. Analysis was performed using SPSS [V24] (IBM, Armonk, NY).
Research reported in this publication was supported by the Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from the National Center for Advancing Translational Sciences of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health.
One hundred five PLWH were identified who met the definition for cryptococcosis from January 1, 2002, until the end of the study period on July 1, 2017. Overall mortality at the end of the study period was 47.6% (n = 50) with a median follow-up of 3.7 years [interquartile range (IQR) 1.1; 8.1 years] (Fig. 1A). Overall median survival after diagnosis of cryptococcosis was 244 days (IQR 43, 1167 days). Early mortality, within 90 days of cryptococcal diagnosis, was 16.2% (n = 17) with a median survival of 13.0 days (IQR 2, 43 days). Late mortality, beyond 90 days, was 31.4% (n = 33) with a median survival of 1.9 years (IQR 0.7, 4.3 years). Overall mortality was 20% at 6 months and 27.6% at 1 year. As summarized in Table 1, groups had no significant differences in age, gender, or race (all P's > 0.05).
In early-mortality individuals, 77% (n = 13) had cryptococcosis reported as the cause of death and 12% (n = 2) had an unknown cause of death. In late-mortality individuals, 61% (n = 20) had an unknown cause of death and 21% (n = 7) died of an infectious etiology including cryptococcosis (n = 1, 3%), Clostridium difficile colitis (n = 1, 3%), histoplasmosis (n = 2, 6%), hospital-acquired pneumonia (n = 2, 6%), and varicella-zoster encephalitis (n = 1, 3%). Six individuals (18%) died of noninfectious causes including congestive heart failure (n = 2, 6%), end-stage liver disease complications (n = 1, 3%), gastrointestinal bleed (n = 1, 3%), metastatic melanoma complications (n = 1, 3%), and status epilepticus in an individual with known epilepsy (n = 1, 3%).
The most common site of infection was CNS with 68% (n = 71) of individuals having CNS involvement. (Table 1). Pulmonary involvement was noted in 10% (n = 10). The site of infection was not significantly different between survivors and late-mortality individuals; however, there was a trend of more CNS infections in late-mortality individuals (n = 27, 81%) compared with survivors (n = 36, 66%) (P = 0.099). Presenting symptoms were similar between groups (Table 1). All positive cultures grew C. neoformans with no non-neoformans species identified.
There was no significant difference in the median opening pressure between survivors (36 cm H2O, IQR 18, 45) and those who died (median 28 cm H2O, IQR 20, 40) (P = 0.979). There were no significant differences in the level of serum or CSF CrAg titers at diagnosis between survivors, early-mortality, or late-mortality individuals (P = 0.394). Most participants had serum CrAg titers of 1:16 or higher with no significant differences between groups (P = 0.389). There was no significant difference between completion of lumbar punctures between the premodern ART era (94%) versus the modern era (100%) (P = 0.124).
For participants with CNS involvement (n = 71), over 90% across groups received a formulation of liposomal amphotericin B for treatment with no significant difference between groups (P = 0.611). Of participants with CNS involvement, 64% percent of survivors (n = 23), 50% of early-mortality individuals (n = 4), and 59% of late-mortality individuals (n = 16) received at least 14 days of liposomal amphotericin B (P = 0.756). One-hundred percent of early-mortality individuals (n = 8) with CNS involvement received combination therapy with flucytosine compared with 75% of survivors (n = 27) and 59% of late-mortality individuals (n = 16) (P = 0.066).
Baseline CD4+ T-cell count at time of cryptococcal diagnosis was similar between survivors (median 26 cells/mm3, IQR 8, 42) and late-mortality individuals (14 cells/mm3, 7, 43) (P = 0.456). There was no significant difference between HIV-1 log RNA levels at time of cryptococcal diagnosis between survivors (median 4.98 log copies/mL, IQR 4.23, 5.31) as compared to late-mortality individuals (median 5.27 log copies/mL, IQR 4.58, 5.79) (P = 0.457). The percentage of individuals prescribed ART before cryptococcosis was similar between groups (44% of survivors, 36% of late-mortality, P = 0.502). For individuals with cryptococcal meningitis, ART was started a median of 27 days after cryptococcal meningitis diagnosis (IQR 0, 76 days). There was no statistically significant association between the timing of starting ART after cryptococcal meningitis and mortality, ART era, or health care status. Most participants were not virally suppressed at the time of cryptococcal diagnosis with no statistical difference between survivors (n = 49, 89%) and late-mortality (n = 28, 85%) groups (P = 0.560) (Table 2).
Late-mortality individuals (n = 32, 97%) were more likely to have known HIV-positive status at time of cryptococcosis diagnosis as compared to survivors (n = 39, 71%) (P = 0.003). The median time from HIV diagnosis to cryptococcosis diagnosis was 5.5 years (IQR 0.5, 13.0) for survivors, 5.0 years (IQR 1.0, 8.0) for early-mortality, and 8.5 years (IQR 3.5, 13.0) for late-mortality (P = 0.383) individuals. At the last observation, survivors had significantly higher rates of HIV viral suppression (n = 34, 62%) than late-mortality individuals (n = 8, 24%) (P = 0.001) (Table 2). Individuals who were not virally suppressed at the last observation had a higher mortality risk than those who were virally suppressed [hazard ratio (HR) 5.5, confidence interval (CI): 2.7 to 11.1, P < 0.001] (Fig. 1B).
Survivors were more likely to have private insurance (n = 19, 35%) than late-mortality PLWH (n = 2, 6%). Late-mortality PLWH were more likely to have government-provided insurance (n = 29, 88%) than survivors (n = 32, 58%) (P = 0.008). Individuals with government-provided insurance had a higher mortality risk than those with private insurance (HR 2.8, CI: 1.1 to 7.2, P = 0.013) (Fig. 1C).
The overall rate of baseline psychiatric diagnosis was 31% (n = 33) without significant difference between survivors and late-mortality individuals (P = 0.728). The overall rate of substance abuse was 49% (n = 51) with rates ranging from 40% to 52% between survivors and late-mortality individuals without significant difference (P = 0.292).
Outcomes in the Modern ART Era
Individuals diagnosed with cryptococcosis in the premodern ART era (n = 56) were compared with those diagnosed during the modern ART era (n = 49). In the premodern ART era, there were significantly fewer survivors (n = 19, 34%) compared with the modern era (n = 36, 74%) (P < 0.001). Premodern ART era individuals had a higher mortality risk compared with modern ART era individuals (HR 2.2, CI: 1.2 to 4.3, P = 0.014) (Fig. 1A). Early-mortality rates were similar between time periods (P = 0.620). There were significantly more late-mortality individuals premodern (n = 27, 48%) compared with modern (n = 6, 12%) (P < 0.001). Both time periods had similar demographics including race and gender (see Supplemental Table 1, Supplemental Digital Content, https://links.lww.com/QAI/B336). Treatment of cryptococcosis including use of liposomal amphotericin B and flucytosine was similar between time periods.
CD4+ T-cell counts at the time of cryptococcal diagnosis were similar between time periods (see Supplemental Table 2, Supplemental Digital Content, https://links.lww.com/QAI/B336). In the premodern era, HIV viral load at time of cryptococcosis diagnosis (5.26 log copies/mL, IQR 4.88, 5.80) was higher than the modern era (4.83 log copies/mL, 4.05, 5.28) (P = 0.011). Viral suppression at time of cryptococcal diagnosis was similar between time periods (P = 0.251). However, viral suppression at death or last observation was significantly higher in the modern ART era (57% vs 29%, P = 0.003).
In the pre-modern era, individuals were less likely to have private insurance (13% vs 35%) and more likely to have government insurance (77% vs 57%) (P = 0.026). Rates of substance abuse and psychiatric illness were similar between time periods. A logistic regression analysis was completed including all factors that reached significance in univariate analysis. Factors that reached significance in the logistic regression included HIV viral load suppressed at the last observation (P = 0.033), insurance provider (P = 0.042), and the ART treatment era (P = 0.002).
Overall mortality of PLWH with cryptococcosis is high, as demonstrated by our cohort. As stated previously, early mortality from cryptococcosis is well-described, but this is one of the first studies in the United States to describe long-term mortality in PLWH with opportunistic infections in the modern ART era. Although the incidence of cryptococcosis in PLWH has decreased,17–19 we noted a continued high overall mortality of nearly 50%. Most of this mortality was seen beyond the first few months after cryptococcal diagnosis. Although the specific cause of death in our cohort, especially after 90 days, was largely unknown because of lack of records, we found some important associations, which may have impacted their risk of death. Notably, individuals who were virally suppressed had better outcomes, outcomes have improved in the modern ART era, and socioeconomic status had a large impact on outcomes.
Although it is known that ART and viral suppression of HIV is key to good outcomes in PLWH,20,21 the contribution of ART in reducing long-term mortality in PLWH with opportunistic infections has not been previously defined. In our cohort, rates of viral suppression at time of cryptococcal diagnosis were low among all individuals. When comparing survivors to late-mortality individuals, many more survivors were virally suppressed at the last observation.
Although not statistically significant, we saw a trend of more CNS infections in late-mortality individuals compared with survivors. Surviving PLWH can have long-term debilitating neurologic sequelae after cryptococcal meningitis. A comparison of 100 PLWH with cryptococcal meningitis and 110 without found up to 41% of individuals had global neurocognitive impairment, 20% severe, after meningitis, which was significantly higher than the nonmeningitis comparison.22 At 1 month, 19% of individuals were unable to track their medications, which may lead to further morbidity related to poorly controlled HIV. Some deficits in neurocognitive function may be reversible. In the study by Montgomery et al,23 asymptomatic CrAg-positive individuals had significant improvement in neurocognitive function, and individuals with cryptococcal meningitis had modest improvements after appropriate treatment. Use of adjunctive dexamethasone for cryptococcal meningitis in PLWH has been associated with an increased neurologic disability at 10 weeks.24 A recent trial in an HIV-negative cohort with cryptococcal meningitis showed that low Montreal Cognitive Assessment Scores was a predictor of poor long-term cognitive function.25 In PLWH, Rhein et al26 noted that those who developed cryptococcal meningitis after being on ART >6 months was a predictor of virologic failure with viral loads >1000 copies/mL. We also noted that individuals diagnosed with cryptococcosis in the modern ART era were more likely to be virally suppressed at the last observation compared with individuals in the pre-modern ART era. This also corresponded with a significantly higher mortality in individuals diagnosed with cryptococcosis in the modern ART era (Fig. 1A).
The mortality difference between premodern and modern ART eras may be due to a number of factors. ART has improved in terms of potency, tolerability, and individuals' access. Modern ART is more potent than ever before and has led to rapid control of HIV in adherent individuals.27,28 Simultaneously, these potent drugs are better tolerated compared with older ART regimens. In the earlier time period, only a small subset of individuals was virally suppressed at their last observation. This was substantially improved in the modern ART era. This indicates that a large portion of late-mortality individuals is related to individuals' HIV control. Despite advances in these areas, however, certain factors including socioeconomic status and psychiatric history can lead to consequential limitations in HIV care.
In our cohort, in addition to modern ART and improved viral suppression, we found that outcomes of PLWH with cryptococcosis are also largely affected by insurance coverage, which is likely to be a surrogate for socioeconomic status. Previous studies have linked insurance status to socioeconomic status, finding that over 60% of uninsured families are low income.29 We saw negative outcomes in individuals who were uninsured or had government-provided insurance compared with PLWH with private insurance. Type of insurance has been previously implicated in limited access to case management and mental health.30
In our cohort, rates of clinically diagnosed psychiatric illness were high (31% overall). Previous research in PLWH has shown rates of depression at 22%–50%.30 Psychiatric illness has also been closely associated with substance abuse in PLWH.31 Our cohort had an overall substance abuse history of 48%, similar to previous studies showing rates of 40%–74% in PLWH.30 The combination of possible neurologic and psychiatric complications after meningitis and additional insults from substance abuse may have led difficulty navigating the health care system or maintaining adherence to ART.
Additional risk factors for late-mortality individuals have been previously described. Compared with our cohort, these typically have followed patients for ≤1 year and have had smaller cohorts. A Thai study found altered mental status at the initial presentation, and elevated CSF fungal burdens were linked to increased mortality at 1 year (odds ratio 5.27 and 7.08, respectively).32 Day et al33 found similar associations in individuals with an elevated CSF fungal burden or Glasgow Coma Scale less than 15. We found no such associations in altered mental status or any other presenting symptoms in our cohort. Fungal burdens were elevated across all groups without a significant difference. Other associations with long-term mortality after cryptococcal meningitis included depressed CD 4+ T-cell count and advanced age at time of cryptococcal diagnosis.34,35 We did not find any association between age or CD4+ T-cell count at presentation in our cohort. At 6 months, Day et al reported >50% mortality; at 1 year, Chaiwarith et al and Mathiesen et al reported 52% and 56% mortality, respectively.32,33,35 Comparatively, we noted lower mortality rates of 20% at 6 months and 27.6% at 1 year. The relatively higher mortality noted in other cohorts may be secondary to being conducted in resource-limited settings,32,33 trialing of liposomal amphotericin monotherapy, or because the other cohorts were conducted with premodern ART that may have been harder to obtain and tolerate. Conversely, previous studies have shown a drop-off in mortality after 6 months with appropriate treatment in both high-resource and low-resource settings.15 Leveling off of mortality has been linked to appropriate combination therapy for cryptococcal meningitis with amphotericin and flucytosine and the addition of antiretrovirals.33,36 The majority of PLWH (76.2%) in our cohort with cryptococcal meningitis were appropriately treated with combination therapy, and there were no differences between the groups. However, despite appropriate induction and maintenance therapy, mortality after 3 months remained elevated, only starting to plateau after 3 years.
Limitations of this study include being performed at a single, academic tertiary referral center. Our medical center is located in the Midwest United States, which may not generalize to other health care settings. When comparing long-term follow-up between time periods, there may be a length-time bias that can overestimate survival. However, despite this potential bias, mortality remained high in this cohort. When comparing survivors to mortality groups, there may be survivorship bias, which can overestimate differences between groups. This retrospective study may also be limited due to errors of omission from lack of documentation or loss of old records, including the lack of cause of death in many of the late-mortality individuals.
In conclusion, mortality of PLWH after cryptococcosis remains high, especially among individuals who are not virologically suppressed and have surrogate markers for low socioeconomic status. Whether their increased mortality is secondary to previous behaviors (eg, nonadherence) or psychiatric and neurologic changes after cryptococcal meningitis is unknown. Control of HIV strongly impacts outcomes although these outcomes significantly improved since 2008 in our cohort, possibly due to improved HIV treatment options with modern ART. PLWH with predictors for long-term mortality after cryptococcosis should be followed closely and their risk factors addressed because their mortality risk remains elevated well beyond the initial 90 days after cryptococcosis diagnosis. Given the low rates of viral suppression, efforts should focus on ART adherence and addressing socioeconomic factors to help mitigate their increased mortality risk.
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