Abstract
Background:
Cryptococcal epidemiology is changing in the modern anti-retroviral era, and immune status informs outcomes. We describe the differences in clinical presentation and mortality of cryptococcosis by immune status in the ART era.
Methods:
We conducted a single-center retrospective cohort study of patients diagnosed with cryptococcosis from 2002 through 2017. Data included demographics, clinical features, diagnostics, and mortality.
Results:
We identified 304 patients with Cryptococcus neoformans infections: 105 (35%) were people living with HIV, 41 (13%) had a history of transplantation, and 158 (52%) were non-HIV non-transplant (NHNT). Age analysis showed people living with HIV were younger (40 years) than transplant (53 years) and NHNT (61 years) (p<0.001). Fevers and headache were more common in people living with HIV (70% and 57%) than in transplant (49% and 29%) and NHNT (49% and 38%) (p=0.003 and p=0.001), respectively. Meningitis was more common in people living with HIV (68%) than in transplant recipients (32%) or NHNT (39%, p< 0.001). Disseminated cryptococcosis was more common in people living with HIV (97%) as compared to transplant (66%) or NHNT (73%) (p<0.001). Time to diagnosis from hospitalization was longer for transplant (median 2 days, IQR+/−9 days) and NHNT patients (median 2 days, IQR+/−7 days) as compared to people living with HIV (median 1 day, IQR+/−2 days) (p=0.003). NHNT patients had a higher risk of 90-day mortality (HR 3.3, 95% CI 1.9–5.8) as compared to people living with HIV.
Conclusions:
The majority of cryptococcosis occurs in NHNT patients. NHNT patients had more localized pulmonary cryptococcosis and significantly higher 90-day mortality. Cryptococcosis in NHNT patients appears to be a distinct entity that needs further study and requires a higher degree of clinical suspicion than it currently receives.
Keywords: Cryptococcus, HIV, Adult, Prognosis, Presentation, Mortality, Transplant
INTRODUCTION:
Opportunistic infections with Cryptococcus neoformans are well characterized in people living with HIV [1–6]. However, in the era of potent antiretroviral therapy (ART), the incidence of cryptococcosis in people living with HIV has decreased considerably in the United States [6]. Less studied populations, including transplant recipients and non-HIV non-transplant (NHNT) patients, now make up an increasing proportion of new cases in the United States [7–11].
The NHNT group encompasses patients with traditional risk factors for cryptococcosis such as malignancy and use of immunosuppressants [12–16], but also includes putatively immunocompetent hosts with no obvious risk factor for cryptococcal infection. Previous studies have suggested that NHNT patients may have a significantly increased mortality compared to people living with HIV or transplant recipients; however the cause of this increased mortality is unclear [7, 8, 17].
The current study was performed to better define clinical presentation, treatment, and mortality of cryptococcosis by patient’s immune status.
METHODS:
Cohort Construction
All patients diagnosed with Cryptococcus neoformans infections at Barnes-Jewish Hospital (BJH), in St. Louis, Missouri, from January 1st 2002 to July 1st 2017 were included. BJH is a 1,315-bed tertiary care academic hospital located in an urban environment with a significant suburban and rural referral base. The study was approved by the Washington University School of Medicine Human Research Protection Office, with a waiver of informed consent.
Cryptococcosis was defined as: 1) positive cryptococcal antigen (CrAg) in blood or cerebrospinal fluid, 2) isolation of Cryptococcus neoformans in any culture or 3) identification by International Classification of Diseases (ICD), 9th (117.5, 321.0) or 10th (B45.1–B45.9) codes for cryptococcal infection using the Barnes Jewish Hospital Medical Informatics database. All cultures at our institution are routinely speciated. No isolates returned as Cryptococcus gattii and this pathogen has never been isolated at our institution. All cases were then confirmed by two independent experts in cryptococcal disease to be true infections by medical record review.
CrAg was detected using latex agglutination until April 2016, after which lateral flow assay (LFA) has been used exclusively. Clinical presentations on admission and mortality were compared among people living with HIV, transplant recipients (solid and hematological), and NHNT. In the NHNT group, a subgroup of putatively immunocompetent patients was defined as patients with no documented history of malignancy, chemotherapy, HIV, solid organ or stem-cell transplant, end-stage liver disease, or receiving immunosuppressive drugs. Individuals receiving prednisone at doses of 20 mg daily or more (or equivalent dose of an alternative glucocorticoid) were considered as immunosuppressed.
Variable Definitions
Demographics, predisposing factors, treatment, and mortality were obtained from the Medical Informatics database and from medical record review. Time to diagnosis was defined as the time from admission to the identification of a positive cryptococcal antigen, culture results indicating the presence of Cryptococcus neoformans or encapsulated yeast, or histologic finding of encapsulated yeast. Duration of symptoms was defined as the time from symptom onset (as recorded in the admission and consult notes) to the diagnosis as defined above. Patients who did not receive treatment were reviewed and defined as post-mortem diagnosis, lost to follow-up, and missed diagnosis (patients had evidence of cryptococcal infection but were not diagnosed during evaluation).
Culture site, antigen detection, imaging, and histopathology were used to define site of infection. Localized pulmonary cryptococcosis was defined as cryptococcal infection only involving the lungs. Disseminated cryptococcosis was defined as patients with cryptococcal infection involving extra-pulmonary sites including CNS, cryptococcemia, and cutaneous cryptococcosis. CNS infection was defined as a positive cerebrospinal fluid cryptococcal antigen (CrAg) or cerebrospinal fluid or brain biopsy cultures growing C. neoformans. Cryptococcemia was defined as bacterial or fungal blood cultures with growth of C. neoformans. Skin infections were determined either by presence of skin disease thought to be consistent with cryptococcal skin infection by assessment of the treating physician or by presence of Cryptococcus in culture or histology of skin biopsies.
All-cause mortality was determined by electronic medical record review, supplemented by the Social Security Death Index to account for deaths outside the hospital network. Time of death was defined as number of days from admission until death.
Statistical Analysis
Statistical analysis was performed using SPSS V24 (IBM, Armonk, NY). Fisher’s exact test and Student’s t-test were used for the descriptive statistics and crude mortality. Mann-Whitney U test was used for continuous variables that did not follow a normal distribution. A Cox proportional hazards model was used to compare all-cause mortality among the three groups. For survival analysis, patients were censored at the time of last follow-up, or at 90 days, whichever came first as mortality beyond 90 days was deemed less likely to be related to cryptococcal infection.
RESULTS:
Cohort
Three-hundred and four (304) patients were identified that met the definition for cryptococcosis from January 2002 to June 2017. Of these, 105 (35%) were people living with HIV, 41 (13%) had a history of transplantation, and 158 (52%) were NHNT.
People living with HIV were predominantly African American (76%) compared to NHNT (15%) and transplant (7%). People living with HIV were also younger than NHNT and transplant patients, at 40 vs 53 and 61 years old, respectively (Table 1). Among transplant recipients, transplants consisted of lung (34%), kidney (22%), liver (20%), heart (15%), and hematological stem cell transplants (15%). In people living with HIV, median CD4 count was 15 cells/mm3 (range 0 to 400 cells/mm3).
Table 1.
Baseline characteristics of patients with cryptococcosis (n=304) among three groups (People living with HIV, Transplant and NHNT) 2002–2017.
| People living with HIV N=105 (%) | Transplant N=41 (%) | NHNT N=158 (%) | p-value | |
|---|---|---|---|---|
| Median age (±IQR), years | 40.0 (13) | 53.0 (17) | 60.5 (22) | <0.001 |
| Male sex | 84 (80) | 25 (61) | 108 (68) | 0.035 |
| Race | <0.001 | |||
| African American | 80 (76) | 3 (7) | 23 (15) | - |
| Non-African American | 25 (24) | 38 (93) | 135 (85) | - |
| Site of infection | ||||
| CNS | 71 (68) | 13 (32) | 62 (39) | <0.001 |
| Pulmonary | 10 (10) | 21 (23) | 60 (38) | <0.001 |
| Bloodstream | 38 (36) | 8 (20) | 43 (26) | 0.098 |
| Other | 2 (2) | 6 (15) | 14 (9) | 0.015 |
| Disseminated disease | 102 (97) | 27 (66) | 115 (73) | <0.001 |
| Positive serum CrAg* | 77 (73) | 17 (41) | 51 (32) | <0.001 |
| Presenting symptoms | ||||
| Fever | 73 (70) | 20 (49) | 78 (49) | 0.003 |
| Fatigue | 81 (77) | 28 (68) | 193 (65) | 0.115 |
| Weight loss | 25 (24) | 8 (20) | 45 (29) | 0.436 |
| Stiff neck | 29 (28) | 5 (12) | 21 (13) | 0.007 |
| Headache | 60 (57) | 12 (29) | 60 (38) | 0.001 |
| AMS | 39 (37) | 12 (29) | 60 (38) | 0.579 |
| Visual changes | 10 (10) | 1 (2) | 8 (5) | 0.190 |
| CN palsy | 3 (3) | 0 (0) | 4 (3) | 0.564 |
| Cough | 21 (20) | 15 (37) | 53 (34) | 0.033 |
| Dyspnea | 19 (18) | 17 (42) | 52 (33) | 0.006 |
| Immunocompetent | 0 (0) | 0 (0) | 62 (39) | <0.001 |
| Cancer (Solid) | 10 (10) | 4 (10) | 36 (23) | 0.008 |
| Cancer (Hematologic) | 0 (0) | 7 (17) | 22 (14) | <0.001 |
| Active chemotherapy | 5 (5) | 6 (15) | 36 (23) | <0.001 |
| End-stage liver disease | 3 (3) | 7 (17) | 27 (17) | 0.001 |
| Immunosuppressant medication | ||||
| Glucocorticoids | 4 (4) | 36 (88) | 23 (15) | <0.001 |
| Biologic | 0 (0) | 2 (5) | 7 (4) | 0.086 |
| Others | 1 (1) | 33 (80) | 16 (10) | <0.001 |
| Duration of Symptoms (median days, ±IQR) | 14.0 (19.8) | 14.0 (29.0) | 19.0 (28.5) | 0.036 |
| Time to Diagnosis from Hospitalization (median days, ±IQR) | 1.0 (2.0) | 2.0 (9.0) | 2.0 (7.0) | 0.003 |
Data are presented as No. (%) unless otherwise indicated. Disseminated disease defined as involvement of CNS, bloodstream, or other non-pulmonary site.
Abbreviations: NHNT, Non-HIV and Non-Transplant; CNS, central nervous system; CrAg, cryptococcal antigen; IQR, Interquartile Range; AMS, Altered Mental Status
Calculated based on patients with disseminated cryptococcosis.
Regarding site of infection, NHNT (27%) and transplant (34%) were more likely to have localized pulmonary cryptococcosis than people living with HIV (3%) (p<0.001) (Table 1). People living with HIV had more CNS infections (68%) as compared to NHNT (39%) and transplant (32%). People living with HIV trended towards more cryptococcemia than transplant and NHNT. People living with HIV were also more likely to have disseminated cryptococcosis (97%) overall as compared to NHNT (73%) and transplant patients (66%) (Table 1).
Within NHNT, 62 patients (39%) were apparently immunocompetent, 38 (23%) patients had a solid organ malignancy, 22 (14%) had a hematologic malignancy, 36 patients (23%) with solid or hematologic malignancy were actively on chemotherapy, 27 patients (17%) had end-stage liver disease, and 23 patients (15%) were receiving glucocorticoids (Table 1). Fourteen NHNT patients (9%) had infections other than pulmonary, bloodstream, or CNS. These included cultures from skin (n=4), urine (n=2), joint aspirates (n=2), ascites (n=2), lymph node biopsy (n=2), bone biopsy (n=1), and ocular fluid (n=1).
Presentation
Fever was a more common presenting symptoms in people living with HIV (70%) than NHNT (49%) and transplant (49%) (p=0.003). People living with HIV were more likely to present with headache and neck stiffness than transplant and NHNT patients. However, cough and dyspnea were more common in the NHNT (34% and 33%) and transplant (37% and 42%) than people living with HIV (20% and 18%), respectively (Table 1).
Duration of symptoms was longer for NHNT individuals (19.0 days) than people living with HIV (14.0 days) and transplant (14.0 days) (p=0.036). Duration of symptoms did not differ between gender, race, or type of cryptococcal infection (disseminated vs. localized). NHNT patients without altered mental status (AMS) had longer duration of symptoms (22 days) than those with AMS (13 days) (p=0.026). Putatively immunocompetent patients had significantly longer duration of symptoms compared to the rest of the NHNT group (22 vs. 14 days, p=0.015). Time to diagnosis from hospitalization was longer for transplant patients (2.0 days) and NHNT (2.0 days) compared to people living with HIV (1.0 days) (p=0.003).
Laboratory Testing
Overall, people living with HIV were more likely to have a positive serum cryptococcal antigen (74%) as compared to NHNT (35%) and transplant (51%) groups (p<0.001). Very high serum CrAg titers (≥1:1,024) were observed more in people living with HIV than NHNT and transplant. On the contrary, negative serum cryptococcal antigen titers (≤1:8) were seen more frequently in the NHNT and transplant groups than people living with HIV (Table 2). Of patients with disseminated disease, people living with HIV had significantly higher rates of serum CrAg positivity (73%) compared to transplant (41%) and NHNT (32%) (p<0.001).
Table 2.
Review of laboratories of patients with cryptococcosis (n=304) among three groups (People living with HIV, Transplant and NHNT) 2002–2017.
| People living with HIV (N=105) | Transplant (N=41) | NHNT(N=158) | p-value | |
|---|---|---|---|---|
| Positive serum CrAg * | 78 (74) | 21 (51) | 56 (35) | <0.001 |
| Serum CrAg titer * | <0.001 | |||
| 0* | 3 (4) | 10 (32) | 29 (34) | - |
| 1:2–1:8* | 10 (12) | 4 (13) | 7 (8) | - |
| 1:16–1:512* | 35 (43) | 13 (42) | 38 (45) | - |
| ≥l:1024 * | 33 (41) | 4 (13) | 11(13) | - |
| CNS disease | 71 (68) | 13 (32) | 62 (39) | <0.001 |
| Positive CSF CrAg ** | 62 (87) | 13 (100) | 60 (97) | 0.067 |
| Positive CSF culture ** | 62 (87) | 11 (85) | 42 (68) | 0.019 |
| Positive CNS biopsy ** | 1 (1) | 0 (0) | 3 (5) | - |
| Lumbar Puncture Completed | 95 (91) | 29 (71) | 94 (60) | <0.001 |
| Positive CSF CrAg | 62 (59) | 13 (32) | 60 (38) | 0.001 |
| CSF CrAg titer*** | 0.019 | |||
| 0 *** | 20 (24) | 13 (50) | 30 (33) | - |
| 1:2–1:8*** | 11 (13) | 3 (12) | 15 (17) | - |
| 1:16–1:512*** | 20 (24) | 8 (31) | 28 (31) | - |
| ≥l:1024 *** | 31 (38) | 2 (8) | 17 (19) | - |
Calculated based on 197 patients with serum CrAg testing. For people living with HIV (N=81), NHNT (N=85) and Transplant (N=31)
Calculated based on 147 patients with CNS disease. For people living with HIV (N=71), NHNT (N=62) and Transplant (N=13)
Calculated based on 198 patients with cerebrospinal fluid CrAg testing. For people living with HIV (N=82), NHNT (N=90) and Transplant (N=26)
Abbreviations: NHNT, Non-HIV and Non-Transplant; CNS, central nervous system; CrAg, cryptococcal antigen; CSF, cerebrospinal fluid
Similar trends were seen with the cerebrospinal fluid cryptococcal antigen titers. Of patients with cryptococcal meningitis, people living with HIV were more likely to have very high cerebrospinal fluid CrAg titers (≥1:1,024) than NHNT or transplant (Table 2).
Treatment
Treatment for localized pulmonary disease did not differ between the groups (Supplemental Table 1). Treatment choice and length of therapy in disseminated cryptococcosis patients varied among groups. Amphotericin B as induction therapy trended to be used more frequently in people living with HIV (71%) and transplant patients (74%) than NHNT (57%) (p=0.071). Mean duration of amphotericin induction therapy was similar in all 3 groups (p=0.975). Some patients received Fluconazole as initial therapy, including 21% of people living with HIV, 15% of transplant, and 18% of NHNT patients (p=0.02) (Supplemental Table 2).
Of note, 15% of patients with disseminated cryptococcosis did not receive any therapy following positive CrAg or culture. NHNT patients were more likely to receive no treatment (24%) than people living with HIV (7%) or transplant (8%) patients (p=0.001). Of the 28 NHNT individuals with disseminated infection that were not treated, 15 were diagnosed post-mortem, 10 had evidence of cryptococcosis during admission but per documentation from treating clinicians were not thought to have clinically significant infection, and 3 were diagnosed as an outpatient and lost to follow-up (Supplemental Table 2). Of the 10 patients thought not to have an infection, 3 had low level CrAg titers ≤1:8 which at the time were not felt to be consistent with active infection, 2 had cultures (1 blood, 1 pulmonary) that were thought to be contaminants, 3 had positive cultures that were not recognized by inpatient providers, and 2 had positive cerebrospinal fluid CrAgs but negative cultures and were thought to be false positives.
Mortality
Ninety-day mortality was significantly higher in NHNT (n=65, 41.1%) compared to people living with HIV (n=16, 15.2%) and transplant groups (n=5, 12.2%) (p<0.001). Correspondingly, NHNT patients had a higher risk of 90-day mortality (HR 3.3) as compared to people living with HIV. However, transplant recipients had a risk of 90-day mortality similar to people living with HIV (HR 1.2) (Figure 1, panel A). In disseminated cases, 90-day mortality was higher in NHNT (46%) compared to people living with HIV (15%) or transplant (19%) (p<0.001) (Figure 1, panel B). In contrast, 90-day mortality in patients with localized pulmonary disease did not show statistically significant differences among groups (Figure 1, panels C).
Figure 1:
Kaplan-Meier survival curve of 304 patients with cryptococcosis by underlying condition (People Living with HIV, Non-HIV non-transplant (NHNT), Transplant) from 2002–2017. NHNT patients had the lowest survival among three cohort. Shown are Kaplan–Meier survival estimates for Overall (Panel A), disseminated cryptococcosis (Panel B) and localized pulmonary cryptococcosis (Panel C) over 90-days. Green indicates people living with HIV, Red indicates Transplant recipients, and Blue indicates NHNT patients.
Within the NHNT group, immunocompetent patients had a lower 90-day mortality than immunocompromised patients (HR 0.3, CI 0.1–0.5). The strongest association with increased mortality in the NHNT group was presence of end-stage liver disease (HR 5.7, CI 3.4–9.7). NHNT patients also had higher mortality with disseminated disease vs localized (HR 2.3, CI 1.2–4.4). No significant differences were seen when evaluating use of immunosuppressants, solid and/or hematologic malignancy, gender, or race in the NHNT group (p>0.05).
Patients who received no treatment for their cryptococcal infection had significantly higher mortality than patients who did receive treatment (HR 4.5, CI 2.9–7.1).
Discussion
Improvements in antiretroviral therapy has led to a shift in epidemiology where people living with HIV now comprise a smaller proportion of new cryptococcal infections than previously [7, 8, 17], and both non-HIV immunocompromised and immunocompetent patients are a larger proportion of patients with cryptococcosis than before; however, infections in these populations have been less studied. In our cohort of patients in the era of effective ART, we observed significant differences in the demographics, clinical presentations, and mortality in patients with cryptococcosis among three groups (people living with HIV, transplant, and NHNT). Chiefly, we noted that non-HIV non-transplant individuals were more likely to have limited pulmonary disease, were more likely to have a delay in diagnosis, and had a higher mortality compared to people living with HIV or transplant recipients.
Transplant recipients and NHNT patients were more likely to have localized pulmonary cryptococcosis and had more pulmonary symptoms, more often presenting with cough and dyspnea along with isolation of Cryptococcus species from respiratory specimens. Similar trends have been observed in recent studies looking at cryptococcosis in non-HIV patient cohorts [7, 8, 17]. In contrast, people living with HIV predominantly presented with CNS manifestations including fevers, nuchal rigidity, and headache. Consistent with their presenting symptoms, people living with HIV were more likely to have Cryptococcus isolated from the cerebrospinal fluid and more likely to have a positive cerebrospinal fluid cryptococcal antigen with higher titers. Of note, people living with HIV were more likely to undergo a lumbar puncture, possibly due to their presenting symptoms and the known strong association between HIV and cryptococcal meningitis. These findings correlate with other research describing cryptococcosis by immune status [17] and is consistent with the well-described presentations of people living with HIV with cryptococcal infections [1, 2].
Known risk factors for HIV-negative patients for cryptococcosis include solid and hematologic transplantation, immunocompromising medications, and end-stage liver disease, thought to be due to deficiencies in cell-mediated immunity [12–16, 18]. The majority of patients with cryptococcosis in our cohort were NHNT. Previous literature has noted that the NHNT group had significant delays in diagnosis and increased 90-day mortality [7, 17]. In addition to mortality, delays in diagnosis may lead to an increase in non-fatal complications. In our analysis of 90-day mortality, NHNT patients had a significantly higher mortality than people living with HIV and transplant recipients. In localized infection, there was no significant difference between groups, however this may be due to the small sample of patients with localized pulmonary disease. NHNT made up a more significant proportion of our overall cohort (53% compared to 36–38% in other cohorts). Our cohort is more recent which may account for the smaller proportion of people living with HIV, and therefore more NHNT patients, in the modern ART era [7, 17]. Cause of death was not evaluated in this study. Previous research has shown that the vast majority of 90-day mortality in patients diagnosed with cryptococcosis was attributable to the cryptococcal infection (79%) [19].
Higher mortality among NHNT may partly be due to delayed diagnosis. As people living with HIV have well-known presentations, suspicion and diagnosis may be expedited. Transplant and NHNT patients can present non-specifically and in our cohort were more like to present with cough and dyspnea than people living with HIV. A previous study from Taiwan showed increased 90-day mortality and duration of symptoms for HIV-negative patients with cryptococcal meningitis (90-day mortality 30.8%, median duration of symptoms 18 days) compared to people living with HIV (90-day mortality 5.3%, median duration of symptoms 10 days) [20]. In our cohort, NHNT patients did have significantly longer time to diagnosis from onset of symptoms compared to transplant and people living with HIV. Similarly, Bratton et al found that NHNT (mean 44 days) had increased duration of symptoms and mortality, as compared to people living with HIV (mean 19 days) and transplant recipients (mean 24 days) [7].
In previous studies, elevated CrAg has been an important predictor of mortality and poor outcomes in people living with HIV with cryptococcosis [21]. People living with HIV were significantly more likely in our cohort to have serum and cerebrospinal fluid CrAgs ≥1:1024 but had lower mortality compared to NHNT patients. Contributing factors to the higher mortality among NHNT patients may include lack of therapy in patients with disseminated infection (24% in our study). Of those untreated, many were diagnosed post-mortem (13%), but 9% of disseminated cases in NHNT patients were missed despite clinical evidence of infection.
The NHNT group is heterogeneous and includes both immunocompetent and immunocompromised individuals. Previous research has shown that NHNT individuals may also have more medical co-morbidities than people living with HIV or transplant recipients [8]. Previous estimates state that within cryptococcosis cohorts, about 17–22% are putatively immunocompetent [22, 23]. In our cohort, the most common group in NHNT consisted of patients with no known underlying risk for immunocompromise. Within our sub-group analysis of NHNT patients, immunocompetent patients did have a significantly lower 90-day mortality compared to NHNT patients with known immunocompromise. Within the NHNT group, patients with end-stage liver disease (HR 5.7, CI 3.4–9.7) and those with disseminated cryptococcosis (HR 2.3, CI 1.2–4.4) had increased mortality. Other factors, including malignancy or immunosuppressant use were not associated with increased mortality. A cohort in the U.S. compared phenotypically normal patients compared to immunocompromised and found that after people living with HIV and transplant recipients, cancer (12%) and chronic glucocorticoids (10%) were the most common causes for immunocompromise [24]. The immunocompetent patients in this cohort were less likely to have bloodstream involvement and had significantly increased mean time to diagnosis (81 days vs 34 days) [24]. We similarly saw increased duration of symptoms prior to diagnosis (mean 60.0 vs 27.2 days) in our NHNT immunocompetent patients.
Limitations of this study include being performed at a single medical center and the potential misclassification of the extent of the disease that is inherent to retrospective studies. Given the nature of cryptococcosis, we are limited by likely missing a number of asymptomatic cases and those that were never diagnosed prior to discharge or mortality resulting in selection bias. Retrospective cohorts can also have omission errors from lack of documentation. Certain data points, including duration of symptoms, are limited by patient report. Referral bias is also a possible limitation given this study was conducted at a large tertiary referral center.
In conclusion, the changing management of immunocompromised patients has prompted a shift in epidemiology of cryptococcosis from people living with HIV and transplants, who have well-described presentations and clinical course, to patients with less traditional or unknown risk factors. Among them, the NHNT group, showed the highest mortality although the etiology for this remains unclear. Further study of this diverse group may help identify predictors of risk and mortality, as well as optimal treatment approaches.
Supplementary Material
Supplemental Table 1. Initial therapy choice and duration in patients with localized pulmonary cryptococcosis (n=60) (2002–2017).
Data are presented as No. (%) unless otherwise indicated. Missed diagnosis defined as evidence of cryptococcal infection during evaluation by clinician without subsequent treatment.
Abbreviations: NHNT, Non-HIV and Non-Transplant; 5-FC, Flucytosine. IQR, Interquartile Range
Supplemental Table 2. Initial therapy choice and duration in patients with disseminated cryptococcosis (n=244) (2002–2017).
Data are presented as No. (%) unless otherwise indicated. Missed diagnosis defined as evidence of cryptococcal infection during evaluation by clinician without subsequent treatment.
Abbreviations: NHNT, Non-HIV and Non-Transplant; 5-FC, Flucytosine. IQR, Interquartile Range
Acknowledgments
Funding Source:
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 (NCATS) of the National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH.
Conflicts of Interest:
Dr. Powderly reports grant support from Merck Labs and consulting work with Merck Labs and Gilead. Dr. Spec reports grant support and consulting work with Astellas, consulting work with Viamet, and consulting work with Minnetronix.
Footnotes
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Associated Data
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Supplementary Materials
Supplemental Table 1. Initial therapy choice and duration in patients with localized pulmonary cryptococcosis (n=60) (2002–2017).
Data are presented as No. (%) unless otherwise indicated. Missed diagnosis defined as evidence of cryptococcal infection during evaluation by clinician without subsequent treatment.
Abbreviations: NHNT, Non-HIV and Non-Transplant; 5-FC, Flucytosine. IQR, Interquartile Range
Supplemental Table 2. Initial therapy choice and duration in patients with disseminated cryptococcosis (n=244) (2002–2017).
Data are presented as No. (%) unless otherwise indicated. Missed diagnosis defined as evidence of cryptococcal infection during evaluation by clinician without subsequent treatment.
Abbreviations: NHNT, Non-HIV and Non-Transplant; 5-FC, Flucytosine. IQR, Interquartile Range