mycoses
Diagnosis,Therapy and Prophylaxis of Fungal Diseases
Original article
Cryptococcosis-related deaths and associated medical conditions in the United States, 2000–2010 Noel C. Barragan,1 Frank Sorvillo2 and Tony Kuo1,2,3 1 Division of Chronic Disease and Injury Prevention, Los Angeles County Department of Public Health, Los Angeles, CA, USA, 2Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, CA, USA and 3Department of Family Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA
Summary
Cryptococcosis is an invasive mycotic infection primarily affecting immunocompromised individuals. The objective of this study was to describe cryptococcosis mortality and associated medical conditions in the US for the period 2000–2010. Cryptococcosis-related deaths were identified from the national multiple-cause-ofdeath dataset. Mortality trends and comparison analyses were performed on overall cases of cryptococcosis and by subset [i.e. clinical manifestations of disease and human immunodeficiency virus (HIV) status]. A matched case–control analysis was also conducted to describe the associations between this disease and comorbid medical conditions. A total of 3210 cryptococcosis-related deaths were identified. Cerebral cryptococcosis was the most commonly reported clinical manifestation of the disease. Approximately one-fifth of the decedents (n = 616) had a co-diagnosis of HIV. Mortality rates were highest among men, blacks, Hispanics, Native Americans and older adults. Poisson regression analysis indicated a 6.52% annual decrease in mortality rates for the study period. HIV (MOR = 35.55, 95% CI 27.95–45.22) and leukaemia (MOR = 16.10, 95% CI 11.24–23.06) were highly associated with cryptococcosisrelated deaths. Cryptococcosis mortality declined significantly during 2000–2010. However, the disease continues to cause appreciable mortality in the US. With the majority of decedents having no HIV co-diagnosis, there is still much to be learned about the epidemiology of this mycosis.
Key words: Cryptococcosis, epidemiology, fungal, infectious, disease, human.
Introduction Cryptococcosis is an invasive mycotic infection which typically affects immunocompromised individuals.1 While estimation of burden for this non-notifiable disease is challenging, the yearly incidence is believed to be between 0.4 and 1.3 cases per 100 000 people in Correspondence: N. C. Barragan, MPH, Division of Chronic Disease and Injury Prevention, Los Angeles County Department of Public Health, 3530 Wilshire Blvd, 8th Floor, Los Angeles, CA 90010, USA. Tel: (213) 427-4408. Fax: (213) 351-2713. E-mail: [email protected] Submitted for publication 16 April 2014 Revised 27 July 2014 Accepted for publication 28 July 2014
© 2014 Blackwell Verlag GmbH
the general US population.2 Cryptococcosis is most often associated with human immunodeficiency virus (HIV) infection and is considered one of the most important fungal diseases in this population.3 The estimated incidence of disease among the HIV-positive population is higher than the general population, at 200–700 cases per 100 000 people.2 While there are dozens of recognised species of Cryptococcus in nature, only two commonly infect humans, Cryptococcus neoformans and Cryptococcus gattii.4 This encapsulated yeast is associated with bird excreta and decaying wood and enters the body through the respiratory route.5,6 The agent can disseminate from the lungs to other tissues through the bloodstream, exhibiting an affinity for brain tissue, commonly leading to cryptococcal meningoencephalitis.7 Serological studies
doi:10.1111/myc.12238
N. C. Barragan et al.
indicate that latent C. neoformans exposure is widespread in humans and symptomatic disease is often a reactivation of latent infection rather than a primary infection.8–10 This pathway to clinical disease often contributes to its underdetection and presents challenges to prevention. Although much has been described about the burden of Cryptococcus infection in the presence of HIV,11 less is known about this infection in other immunocompromised states or among seemingly healthy individuals. To contribute to this gap in the literature, we described and examined the burden of cryptococcosis mortality and associated medical conditions in the US for the period 2000–2010.
Methods The National Vital Statistics System maintained by the National Center for Health Statistics (NCHS) provides multiple-cause-of-death (MCD) data based on recorded death cases in the US. The death certificates in this system include information on sex, race/ethnicity, age and place of residence as well as underlying and associated causes of death as determined by the certifying physician or coroner. Standard collection forms are used in each state and allow persons completing the death certificate to indicate a single underlying cause of death and up to 20 associated causes of death.12 Cryptococcosis-related deaths from 2000 to 2010 were identified for this analysis based on coding from the Tenth Revision of the International Classification of Diseases (ICD-10).13 Death certificates that included any of the following codes as either underlying or associated cause of death were identified as cases: B45.0 (Pulmonary cryptococcosis), B45.1 (Cerebral cryptococcosis), B45.2 (Cutaneous cryptococcosis), B45.3 (Osseous cryptococcosis), B45.7 (Disseminated cryptococcosis), B45.8 (Other forms of cryptococcosis) and B45.9 (Cryptococcosis, unspecified). Case information does not include infecting species, as this is not available in the ICD-10 coding system. Mortality trends and comparison analyses were performed on cases of cryptococcosis as a whole and by subset (i.e. manifestations of the disease and HIV status). Cryptococcosis mortality rates per 100 000 population were generated using bridged-race population estimates provided by NCHS.14 Crude mortality rates and 95% confidence intervals were estimated for sex, age, race/ethnicity, state and census region. Ageadjusted mortality rates (AAMRs) were calculated based on the 2000 US standard population15; ageadjusted rate ratios were also computed. Poisson
2
regression analysis was conducted to model mortality trends over time. Because HIV is an important risk factor for cryptococcosis, a parallel analysis of HIV mortality trends was performed as comparison for the sampled period. Years of potential life lost were calculated by subtracting age at the time of death from 75 (the standard reference for average life expectancy).16 To examine the potential connection between fatal cryptococcosis and other medical conditions listed on the same death certificate, a matched case–control analysis was performed. Five randomly selected nonCryptococcosis-related deaths were selected as controls and were matched to each cryptococcosis case by age group, time period, race/ethnicity and sex. Conditions selected for comparison were those that appeared frequently on death certificates of decedents with cryptococcosis and/or are known to compromise the immune system (e.g. autoimmune/connective tissue disorders, cancer, diabetes, drug and alcohol use and HIV infection); decedents were included in multiple comparison analyses if they were identified as having several comorbid conditions of interest. For these comparison analyses, matched odds ratios and 95% confidence intervals were generated. All statistical analyses were performed using SAS software, version 9.2 (SAS Institute, Cary, NC, USA). Since MCD data are publically available and not individually identifiable, the analysis did not require institutional board review or approval.
Results Total sample
A total of 3212 Cryptococcosis-related deaths were identified from 2000 to 2010. Due to missing or invalid data, two cases were excluded. Approximately 35% (n = 1134) indicated cryptococcosis as the underlying cause of death. Males comprised over two-thirds of the cases (71%, n = 2286) and had a higher AAMR than females (Table 1). A majority of deaths were in whites (53%, n = 1709) and blacks (29%, n = 937), and the median age at death was 57.0 years [interquartile range (IQR) = 28]. The highest rates of cryptococcosis mortality were observed in blacks [age-adjusted odds ratio (AOR) = 3.90, 95% confidence interval (95% CI) 3.71–4.09], Hispanics (AOR = 2.08, 95% CI 1.97– 2.20) and Native Americans (AOR = 3.22, 95% CI 3.07–3.39) (referent group: whites; Table 1). Agespecific rates were highest in older age groups (Fig. 1). Cryptococcosis mortality rates and frequency varied by geographical region (Fig. 2). The largest numbers were found in the South (n = 1540) with an AAMR of
© 2014 Blackwell Verlag GmbH
Cryptococcosis-related mortality in the US
Table 1 Cryptococcosis mortality rates and rate ratios per 100 000 population in the United States, 2000–2010.
Frequency2 n = 3210 (%) Sex Female 924 (28.8) Male 2286 (71.2) Race/ethnicity White 1709 (53.2) Hispanic 444 (13.8) Black 937 (29.2) Asian 72 (2.2) Native 48 (1.5) American
Age-adjusted mortality rate (95% CI)
Age-adjusted rate ratio (95% CI)
0.05 (0.05–0.55) 0.15 (0.14–0.16)
1
0.07 0.14 0.26 0.06 0.22
1
(0.06–0.07) (0.13–0.15) (0.24–0.28) (0.04–0.07) (0.15–0.28)
2.88 (2.69–3.08)
2.08 3.90 0.85 3.22
Subset analyses by clinical manifestation (1.97–2.20) (3.71–4.09) (0.79–0.92) (3.07–3.39)
95% CI, 95% confidence interval. 1
Referent group.
2
Do not add up to 100% due to missing data or rounding.
Figure 1 Age-specific cryptococcosis mortality rates per 100 000
population in the United States, 2000–2010.
0.13 per 100 000 population (95% CI 0.12–0.14). The lowest AAMR was found in the Midwest (0.07 per 100 000 population; 95% CI 0.06–0.08), with the overall distribution mirroring HIV mortality rates – i.e. highest in the South and lowest in the Midwest (AAMR of 6.33 per 100 000 population, 95% CI 6.28–6.37 and 2.14 per 100 000 population, 95% CI 2.10–2.17, respectively). The overall annual AAMRs have trended downward during the 11-year study period, declining from 0.13 per 100 000 population in 2000 to 0.07 per 100 000 population in 2010. Poisson regression analysis indicated a decreasing annual per cent rate change of 6.52% (95% CI 7.55–5.48%, P < 0.0001) (Fig. 3). Matched case–control analysis showed a number of medical conditions that were strongly associated with the diagnosis of cryptococcosis on the death certificates (Table 2). HIV [matched odds ratio (MOR) = 35.55, 95% CI 27.95–45.22], leukaemia (MOR = 16.10, 95%
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CI 11.24–23.06), autoimmune disorders (MOR = 6.86, 95% CI 5.40–8.70) and non-Hodgkin’s lymphoma (MOR = 7.18, 95% CI 5.39–9.57) were among the conditions that were strongly associated with cryptococcosis-related deaths. Total years of potential life lost for the decedents with cryptococcosis was estimated to be 60 435 years.
The majority of cases (97.5%; n = 3131) had one single cryptococcosis diagnosis listed on the death certificate. Further analysis of this group indicated that cerebral cryptococcosis was the most commonly reported, affecting the majority of decedents (61.9% of cases, n = 1938; 38.3% of them were underlying cause), followed by disseminated (15.6% of total, n = 490; 31.5% of them were underlying cause) and pulmonary (8.0% of total, n = 249; 31.7% of them were underlying cause). Both cutaneous (n = 1) and osseous (n = 0) manifestations were seldom listed as a cause of death. Unclear manifestations included unspecified (13.8% of total, n = 432; 25.5% of them were underlying cause) and other (0.7% of total, n = 21; 23.8% of them were underlying cause). Among those with disseminated or pulmonary diagnosis code, blacks and Native Americans had the highest AAMRs. The median age at death was highest for those with pulmonary cryptococcosis (68 years, IQR = 29 years) and lowest for those with cerebral cryptococcosis (55 years, IQR = 27 years). Poisson regression for the disease manifestations indicated a significant decline in cerebral cryptococcosis of 8.2% per year (95% CI, 9.5% to 6.9%; P < 0.0001); while no significant per cent changes were observed for disseminated and pulmonary cryptococcosis (Fig. 3). Subset analyses by HIV status
Approximately one-fifth of the decedents (n = 616) had a co-diagnosis of HIV, of which less than 2% (n = 9) had cryptococcosis listed as the underlying cause of death. The average age of death among cryptococcosis decedents with HIV co-diagnosis was 42.0 years (IQR = 12), as compared to 62.0 years (IQR = 30) for those without HIV co-diagnosis. Among those with a HIV co-diagnosis on the death certificate, the AAMR was highest among blacks, (0.09 per 100 000 population; 95% CI 0.08–0.10) and Hispanics (0.03 per 100 000 population; 95% CI 0.02–0.04). Among decedents without HIV co-
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Figure 2 Geographic distribution of cryptococcosis age-adjusted mortality rates per 100 000 population, 2000–2010.
diagnosis, AAMRs were highest in blacks (0.17; 95% CI 0.16–0.19) and Native Americans (0.19; 95% CI 0.13–0.25). Geographically, the AAMRs for HIV co-diagnosed cases paralleled the overall group, with the highest rate in the South and the lowest in the Midwest. In comparison, the AAMRs for the non-HIV co-diagnosed cases were highest in the South (0.10 per 100 000; 95% CI 0.10–0.11) and lowest in the Northeast (0.06 per 100 000; 95% CI 0.06–0.07). During the 11-year study period, the AAMRs for cases with HIV as a codiagnosis exhibited a steeper decline (14.9% per year, 17.1–12.7%, P < 0.0001) than for cases without such co-diagnosis (4.5% per year, 5.6–3.3%; P < 0.0001) (Fig. 3).
Discussion Study findings indicate that cryptococcosis mortality has declined significantly but remains an important
4
cause of mortality in the US. Rates were highest among men, blacks, Hispanics, Native Americans and older adults. The YPLL was 60 435 years, suggesting that loss in productivity was likely not trivial. HIV, leukaemia, autoimmune disorders and non-Hodgkin’s lymphoma were among the medical conditions most strongly associated with cryptococcosis-related deaths. Cryptococcosis is well known as an opportunistic mycotic infection in HIV-infected individuals.1 However, the disease is often underappreciated as a cause of severe infection and death in non-HIV-related immunocompromised conditions – e.g. immune suppression from chemotherapy, long-term steroid use related to the treatment of autoimmune/connective tissue disorders and therapy for postsolid organ transplant recipients.1,3,4 This study enumerates the burden of cryptococcosis mortality for the entire US population. It also examines regional variation in cryptococcosis mortality rates and medical conditions associated with this cause of death. Although current literature
© 2014 Blackwell Verlag GmbH
Cryptococcosis-related mortality in the US
All cases*
0.16
Cerebral*
Age-adjusted mortality rate
0.14
Disseminated Pulmonary
0.12
With HIV co-diagnosis* 0.1
Without HIV co-diagnosis*
0.08 0.06 0.04 0.02 0
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Figure 3 Cryptococcosis age-adjusted mortality rates per
100 000 population by clinical manifestation and HIV status. *Statistically significant decline in annual per cent change: all cases 7.0% (95% CI 7.98–5.92%; P < 0.0001); Cerebral cryptococcosis 8.2% (95% CI, 9.46–6.88%; P < 0.0001); cryptococcosis in decedents with a HIV co-diagnosis 14.9% (17.13–12.65%; P < 0.0001); cryptococcosis in decedents without a HIV co-diagnosis 5.1% (6.24–3.92%; P < 0.0001).
suggests a strong association between cryptococcosis and HIV infection, only one-fifth of the decedents in the present MCD analysis listed HIV as a co-diagnosis, highlighting a need for further examination. It should be noted that HIV prevalence is likely underestimated
because certifiers may omit the diagnosis on death certificates due to family preferences and social stigma.17 In addition, there could be a number of decedents with undiagnosed HIV. The dramatic decline of cryptococcosis-related deaths from 2000 to 2010 is likely related to improvements in medical care, especially for the management of HIV infection.3 Such advances as the HAART antiretroviral therapy and more strategic uses of antifungal prophylaxis likely contributed to the decline in mortality frequency and rates.18 The association between cryptococcosis mortality and HIV co-diagnosis was not surprising, but the strong association with other medical conditions such as leukaemia, autoimmune/connective tissue disorders and non-Hodgkin’s lymphoma was somewhat unexpected. In most of these cases, the associated medical condition occurred in decedents without HIV disease. For example, all of the cases of leukaemia in decedents with cryptococcosis had no recorded HIV diagnosis. A similar pattern was observed for cryptococcosis cases with non-Hodgkin’s lymphoma. Limitations
Although the use of population-based MCD data represents an analytic strength, there are several notable limitations. First, misclassification of the causes of death may lead to an underestimation of
Table 2 Medical conditions associated with Cryptococcosis mortality in the United States, 2000–2010.
Medical condition1 Autoimmune and connective tissue disorders Cancer (all types) Cancer of bone marrow Cancer, non-Hodgkin’s lymphoma Leukaemia Cardiovascular disease Chronic renal failure Diabetes Drug and alcohol use Human immunodeficiency virus (HIV)
Cryptococcosis -related deaths2 (n = 3210), n (%) 165 (5.1) 506 116 119 126 801 368 259 156 616
(15.8) (3.6) (3.7) (3.9) (24.9) (11.5) (8.1) (4.9) (19.3)
Matched control deaths2 (n = 16 050), n (%) 128 (0.8) 2910 234 88 41 6723 990 1323 902 143
(18.1) (1.5) (0.6) (0.3) (41.9) (6.2) (8.2) (5.6) (0.9)
Matched odds ratio (95% CI) 6.86* (5.40–8.70) 0.84* (0.75–0.93) 2.53* (2.02–3.17) 7.18* (5.39–9.57) 16.10* (11.24–23.06) 0.45* (0.41–0.49) 1.97* (1.74–2.24) 0.98 (0.85–1.12) 0.86 (0.72–1.02) 35.55* (27.95–45.22)
95% CI, 95% confidence interval. 1 ICD-10 codes: autoimmune and connective tissue disorders (M06, M32, D86, G70, L93, M3, M353); all cancer (C34, C90 C61, C50, C18, C79 C71, C78, C80, C22, C64, C46, C85, D46, C81, D70, C92, C83, D47, C84, C88, C91, C95); cancer of bone marrow (D46, C81, D70, C92, C83, D47, C84, C88, C95); non-Hodgkin’s lymphoma (C85); Leukaemia (C91); cardiovascular disease (I46, I25, I10, I50, I64, I48, I21, I42, I49, I12, I51, I11, I70, I73); chronic renal failure (N03, N18, N19); Diabetes (E10, E11, E14); drug and alcohol (F17, K70, F10, F19, T40); HIV (B23, B20, B22, R75). 2
Do not add to 100% due to the possibility of a decedent having multiple conditions.
*
Statistically significant.
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cryptococcosis-related deaths and inaccurate reporting of disease manifestation. Second, census data often contain errors in the population estimates, which can potentially distort the calculated mortality rates. Finally, differentiation of C. neoformans and C.gatti in the MCD dataset was not possible in the analysis, limiting the interpretation of the mortality patterns. In light of the emergence of C. gatti as an important infectious agent in the Pacific Northwest, this differentiation could have led to a better understanding of the epidemiology of this yeast.19
Conclusions In spite of an overall decline in AAMRs for cryptococcosis during the 11-year study period from 2000 to 2010, this mycosis remains an important cause of death in the US. With a large proportion of cases without HIV co-diagnoses, there is still much to be learned regarding the epidemiology of cryptococcosis as an opportunistic infection.
3
4
5 6
7 8
9
10
11
12
Acknowledgements The authors thank Patricia L. Cummings and Rebecca K. Butler for their technical assistance and contributions to this article.
13
14
Conflict of interest 15
All authors reported no conflicts of interest and have no financial disclosures.
References 1
2
6
Mitchell T, Perfect J. Cryptococcosis in the era of AIDS-100 years after the discovery of Cryptococcus neoformans. Clin Microbiol Rev 1995; 8: 515–48. Centers for Disease Control and Prevention National Center for Emerging and Zoonotic Infections Diseases, Division of Foodborne, Waterborne, and Environmental Diseases. Fungal diseases: Cryptococcosis statistics. [WWW document] Updated February 13, 2014. URL
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17 18
19
http://www.cdc.gov/fungal/diseases/cryptococcosis-neoformans/statistics.html. [Accessed on 19 July 2014]. Mirza S, Phelan M, Rimland D et al. The changing epidemiology of cryptococcosis: an update from population-based active surveillance in 2 large metropolitan areas, 1992–2000. Clin Infect Dis 2003; 36: 789–94. Dixit A, Carroll S, Quershi S. Cryptococcus gatti: an emerging cause of fungal disease in North America. Interdiscip Perspect Infect Dis 2009; 2009: 840452. doi:10.1155/2009/840452. Bicanic T, Harrison T. Cryptococcal meningitis. Br Med Bull 2004; 72: 99–118. Passoni L. Wood, animals and human beings as reservoirs for human Cryptococcus neoformans infection. Forum Micologico 1999; 16: 77–81. Buchanan K, Murphy J. What makes Cryptococcus neoformans a pathogen? Emerg Infect Dis 1998; 4: 71–83. Saha DC, Goldman DL, Shao X et al. Serologic evidence for reactivation of cryptococcosis in solid-organ transplant recipients. Clin Vaccine Immunol 2007; 14: 1550–4. Goldman DL, Khine H, Abadi J et al. Serologic evidence for Cryptococcus neoformans infection in early childhood. Pediatrics 2001; 107: E66. Chen L, Goldman D, Doering T, Pirofski L, Casadevall A. Antibody response to Cryptococcus neoformans proteins in rodents and humans. Infect Immun 1999; 67: 2218–24. Park B, Wannemuehler K, Marston B, Govender N, Pappas P, Chiller T. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS 2009; 23: 525–30. Division of Vital Statistics, National Center for Health Statistics, Centers for Disease Control and Prevention, Unites States Department of Health and Human Services. National Vital Statistics System. [WWW document] URL http://wonder.cdc.gov/wonder/help/mcd.html [accessed on 3 January 2013]. World Health Organization. International Statistical Classification of Diseases and Related Health Problems- 10th Revision, edition 2010, 4th edn. Malta: World Health Organization, 2011. National Center for Health Statistics. U.S. Census populations with bridged race categories. [WWW document] 2012. URL http://www. cdc.gov/nchs/nvss/bridged_race.htm [accessed on 3 January 2013]. Anderson R, Rosenberg H. Age standardization of death rates implementation of the year 2000 standard. Nat Vital Stat Rep 1998; 47: 1–20. National Center for Health Statistics. Health, United States, 2010: With Special Feature on Death and Dying. Hyattsville, MD: National Center for Health Statistics, 2011. King M. AIDS on the death certificate: the final stigma. BMJ 1989; 298: 734–6. Masur H, Kaplan J, Holmes K. Guidelines for preventing opportunistic infections among HIV-infected persons -2002. MMWR Recomm Rep 2002; 51: 1–46. Harris J, Galanis E, Lockhart S. Cryptococcus gatti infections and virulence. Curr Fungal Infect Rep 2014; 8: 81–89.
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Diagnosis,Therapy and Prophylaxis of Fungal Diseases
Original article
Cryptococcosis-related deaths and associated medical conditions in the United States, 2000–2010 Noel C. Barragan,1 Frank Sorvillo2 and Tony Kuo1,2,3 1 Division of Chronic Disease and Injury Prevention, Los Angeles County Department of Public Health, Los Angeles, CA, USA, 2Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, CA, USA and 3Department of Family Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA
Summary
Cryptococcosis is an invasive mycotic infection primarily affecting immunocompromised individuals. The objective of this study was to describe cryptococcosis mortality and associated medical conditions in the US for the period 2000–2010. Cryptococcosis-related deaths were identified from the national multiple-cause-ofdeath dataset. Mortality trends and comparison analyses were performed on overall cases of cryptococcosis and by subset [i.e. clinical manifestations of disease and human immunodeficiency virus (HIV) status]. A matched case–control analysis was also conducted to describe the associations between this disease and comorbid medical conditions. A total of 3210 cryptococcosis-related deaths were identified. Cerebral cryptococcosis was the most commonly reported clinical manifestation of the disease. Approximately one-fifth of the decedents (n = 616) had a co-diagnosis of HIV. Mortality rates were highest among men, blacks, Hispanics, Native Americans and older adults. Poisson regression analysis indicated a 6.52% annual decrease in mortality rates for the study period. HIV (MOR = 35.55, 95% CI 27.95–45.22) and leukaemia (MOR = 16.10, 95% CI 11.24–23.06) were highly associated with cryptococcosisrelated deaths. Cryptococcosis mortality declined significantly during 2000–2010. However, the disease continues to cause appreciable mortality in the US. With the majority of decedents having no HIV co-diagnosis, there is still much to be learned about the epidemiology of this mycosis.
Key words: Cryptococcosis, epidemiology, fungal, infectious, disease, human.
Introduction Cryptococcosis is an invasive mycotic infection which typically affects immunocompromised individuals.1 While estimation of burden for this non-notifiable disease is challenging, the yearly incidence is believed to be between 0.4 and 1.3 cases per 100 000 people in Correspondence: N. C. Barragan, MPH, Division of Chronic Disease and Injury Prevention, Los Angeles County Department of Public Health, 3530 Wilshire Blvd, 8th Floor, Los Angeles, CA 90010, USA. Tel: (213) 427-4408. Fax: (213) 351-2713. E-mail: [email protected] Submitted for publication 16 April 2014 Revised 27 July 2014 Accepted for publication 28 July 2014
© 2014 Blackwell Verlag GmbH
the general US population.2 Cryptococcosis is most often associated with human immunodeficiency virus (HIV) infection and is considered one of the most important fungal diseases in this population.3 The estimated incidence of disease among the HIV-positive population is higher than the general population, at 200–700 cases per 100 000 people.2 While there are dozens of recognised species of Cryptococcus in nature, only two commonly infect humans, Cryptococcus neoformans and Cryptococcus gattii.4 This encapsulated yeast is associated with bird excreta and decaying wood and enters the body through the respiratory route.5,6 The agent can disseminate from the lungs to other tissues through the bloodstream, exhibiting an affinity for brain tissue, commonly leading to cryptococcal meningoencephalitis.7 Serological studies
doi:10.1111/myc.12238
N. C. Barragan et al.
indicate that latent C. neoformans exposure is widespread in humans and symptomatic disease is often a reactivation of latent infection rather than a primary infection.8–10 This pathway to clinical disease often contributes to its underdetection and presents challenges to prevention. Although much has been described about the burden of Cryptococcus infection in the presence of HIV,11 less is known about this infection in other immunocompromised states or among seemingly healthy individuals. To contribute to this gap in the literature, we described and examined the burden of cryptococcosis mortality and associated medical conditions in the US for the period 2000–2010.
Methods The National Vital Statistics System maintained by the National Center for Health Statistics (NCHS) provides multiple-cause-of-death (MCD) data based on recorded death cases in the US. The death certificates in this system include information on sex, race/ethnicity, age and place of residence as well as underlying and associated causes of death as determined by the certifying physician or coroner. Standard collection forms are used in each state and allow persons completing the death certificate to indicate a single underlying cause of death and up to 20 associated causes of death.12 Cryptococcosis-related deaths from 2000 to 2010 were identified for this analysis based on coding from the Tenth Revision of the International Classification of Diseases (ICD-10).13 Death certificates that included any of the following codes as either underlying or associated cause of death were identified as cases: B45.0 (Pulmonary cryptococcosis), B45.1 (Cerebral cryptococcosis), B45.2 (Cutaneous cryptococcosis), B45.3 (Osseous cryptococcosis), B45.7 (Disseminated cryptococcosis), B45.8 (Other forms of cryptococcosis) and B45.9 (Cryptococcosis, unspecified). Case information does not include infecting species, as this is not available in the ICD-10 coding system. Mortality trends and comparison analyses were performed on cases of cryptococcosis as a whole and by subset (i.e. manifestations of the disease and HIV status). Cryptococcosis mortality rates per 100 000 population were generated using bridged-race population estimates provided by NCHS.14 Crude mortality rates and 95% confidence intervals were estimated for sex, age, race/ethnicity, state and census region. Ageadjusted mortality rates (AAMRs) were calculated based on the 2000 US standard population15; ageadjusted rate ratios were also computed. Poisson
2
regression analysis was conducted to model mortality trends over time. Because HIV is an important risk factor for cryptococcosis, a parallel analysis of HIV mortality trends was performed as comparison for the sampled period. Years of potential life lost were calculated by subtracting age at the time of death from 75 (the standard reference for average life expectancy).16 To examine the potential connection between fatal cryptococcosis and other medical conditions listed on the same death certificate, a matched case–control analysis was performed. Five randomly selected nonCryptococcosis-related deaths were selected as controls and were matched to each cryptococcosis case by age group, time period, race/ethnicity and sex. Conditions selected for comparison were those that appeared frequently on death certificates of decedents with cryptococcosis and/or are known to compromise the immune system (e.g. autoimmune/connective tissue disorders, cancer, diabetes, drug and alcohol use and HIV infection); decedents were included in multiple comparison analyses if they were identified as having several comorbid conditions of interest. For these comparison analyses, matched odds ratios and 95% confidence intervals were generated. All statistical analyses were performed using SAS software, version 9.2 (SAS Institute, Cary, NC, USA). Since MCD data are publically available and not individually identifiable, the analysis did not require institutional board review or approval.
Results Total sample
A total of 3212 Cryptococcosis-related deaths were identified from 2000 to 2010. Due to missing or invalid data, two cases were excluded. Approximately 35% (n = 1134) indicated cryptococcosis as the underlying cause of death. Males comprised over two-thirds of the cases (71%, n = 2286) and had a higher AAMR than females (Table 1). A majority of deaths were in whites (53%, n = 1709) and blacks (29%, n = 937), and the median age at death was 57.0 years [interquartile range (IQR) = 28]. The highest rates of cryptococcosis mortality were observed in blacks [age-adjusted odds ratio (AOR) = 3.90, 95% confidence interval (95% CI) 3.71–4.09], Hispanics (AOR = 2.08, 95% CI 1.97– 2.20) and Native Americans (AOR = 3.22, 95% CI 3.07–3.39) (referent group: whites; Table 1). Agespecific rates were highest in older age groups (Fig. 1). Cryptococcosis mortality rates and frequency varied by geographical region (Fig. 2). The largest numbers were found in the South (n = 1540) with an AAMR of
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Cryptococcosis-related mortality in the US
Table 1 Cryptococcosis mortality rates and rate ratios per 100 000 population in the United States, 2000–2010.
Frequency2 n = 3210 (%) Sex Female 924 (28.8) Male 2286 (71.2) Race/ethnicity White 1709 (53.2) Hispanic 444 (13.8) Black 937 (29.2) Asian 72 (2.2) Native 48 (1.5) American
Age-adjusted mortality rate (95% CI)
Age-adjusted rate ratio (95% CI)
0.05 (0.05–0.55) 0.15 (0.14–0.16)
1
0.07 0.14 0.26 0.06 0.22
1
(0.06–0.07) (0.13–0.15) (0.24–0.28) (0.04–0.07) (0.15–0.28)
2.88 (2.69–3.08)
2.08 3.90 0.85 3.22
Subset analyses by clinical manifestation (1.97–2.20) (3.71–4.09) (0.79–0.92) (3.07–3.39)
95% CI, 95% confidence interval. 1
Referent group.
2
Do not add up to 100% due to missing data or rounding.
Figure 1 Age-specific cryptococcosis mortality rates per 100 000
population in the United States, 2000–2010.
0.13 per 100 000 population (95% CI 0.12–0.14). The lowest AAMR was found in the Midwest (0.07 per 100 000 population; 95% CI 0.06–0.08), with the overall distribution mirroring HIV mortality rates – i.e. highest in the South and lowest in the Midwest (AAMR of 6.33 per 100 000 population, 95% CI 6.28–6.37 and 2.14 per 100 000 population, 95% CI 2.10–2.17, respectively). The overall annual AAMRs have trended downward during the 11-year study period, declining from 0.13 per 100 000 population in 2000 to 0.07 per 100 000 population in 2010. Poisson regression analysis indicated a decreasing annual per cent rate change of 6.52% (95% CI 7.55–5.48%, P < 0.0001) (Fig. 3). Matched case–control analysis showed a number of medical conditions that were strongly associated with the diagnosis of cryptococcosis on the death certificates (Table 2). HIV [matched odds ratio (MOR) = 35.55, 95% CI 27.95–45.22], leukaemia (MOR = 16.10, 95%
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CI 11.24–23.06), autoimmune disorders (MOR = 6.86, 95% CI 5.40–8.70) and non-Hodgkin’s lymphoma (MOR = 7.18, 95% CI 5.39–9.57) were among the conditions that were strongly associated with cryptococcosis-related deaths. Total years of potential life lost for the decedents with cryptococcosis was estimated to be 60 435 years.
The majority of cases (97.5%; n = 3131) had one single cryptococcosis diagnosis listed on the death certificate. Further analysis of this group indicated that cerebral cryptococcosis was the most commonly reported, affecting the majority of decedents (61.9% of cases, n = 1938; 38.3% of them were underlying cause), followed by disseminated (15.6% of total, n = 490; 31.5% of them were underlying cause) and pulmonary (8.0% of total, n = 249; 31.7% of them were underlying cause). Both cutaneous (n = 1) and osseous (n = 0) manifestations were seldom listed as a cause of death. Unclear manifestations included unspecified (13.8% of total, n = 432; 25.5% of them were underlying cause) and other (0.7% of total, n = 21; 23.8% of them were underlying cause). Among those with disseminated or pulmonary diagnosis code, blacks and Native Americans had the highest AAMRs. The median age at death was highest for those with pulmonary cryptococcosis (68 years, IQR = 29 years) and lowest for those with cerebral cryptococcosis (55 years, IQR = 27 years). Poisson regression for the disease manifestations indicated a significant decline in cerebral cryptococcosis of 8.2% per year (95% CI, 9.5% to 6.9%; P < 0.0001); while no significant per cent changes were observed for disseminated and pulmonary cryptococcosis (Fig. 3). Subset analyses by HIV status
Approximately one-fifth of the decedents (n = 616) had a co-diagnosis of HIV, of which less than 2% (n = 9) had cryptococcosis listed as the underlying cause of death. The average age of death among cryptococcosis decedents with HIV co-diagnosis was 42.0 years (IQR = 12), as compared to 62.0 years (IQR = 30) for those without HIV co-diagnosis. Among those with a HIV co-diagnosis on the death certificate, the AAMR was highest among blacks, (0.09 per 100 000 population; 95% CI 0.08–0.10) and Hispanics (0.03 per 100 000 population; 95% CI 0.02–0.04). Among decedents without HIV co-
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Figure 2 Geographic distribution of cryptococcosis age-adjusted mortality rates per 100 000 population, 2000–2010.
diagnosis, AAMRs were highest in blacks (0.17; 95% CI 0.16–0.19) and Native Americans (0.19; 95% CI 0.13–0.25). Geographically, the AAMRs for HIV co-diagnosed cases paralleled the overall group, with the highest rate in the South and the lowest in the Midwest. In comparison, the AAMRs for the non-HIV co-diagnosed cases were highest in the South (0.10 per 100 000; 95% CI 0.10–0.11) and lowest in the Northeast (0.06 per 100 000; 95% CI 0.06–0.07). During the 11-year study period, the AAMRs for cases with HIV as a codiagnosis exhibited a steeper decline (14.9% per year, 17.1–12.7%, P < 0.0001) than for cases without such co-diagnosis (4.5% per year, 5.6–3.3%; P < 0.0001) (Fig. 3).
Discussion Study findings indicate that cryptococcosis mortality has declined significantly but remains an important
4
cause of mortality in the US. Rates were highest among men, blacks, Hispanics, Native Americans and older adults. The YPLL was 60 435 years, suggesting that loss in productivity was likely not trivial. HIV, leukaemia, autoimmune disorders and non-Hodgkin’s lymphoma were among the medical conditions most strongly associated with cryptococcosis-related deaths. Cryptococcosis is well known as an opportunistic mycotic infection in HIV-infected individuals.1 However, the disease is often underappreciated as a cause of severe infection and death in non-HIV-related immunocompromised conditions – e.g. immune suppression from chemotherapy, long-term steroid use related to the treatment of autoimmune/connective tissue disorders and therapy for postsolid organ transplant recipients.1,3,4 This study enumerates the burden of cryptococcosis mortality for the entire US population. It also examines regional variation in cryptococcosis mortality rates and medical conditions associated with this cause of death. Although current literature
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Cryptococcosis-related mortality in the US
All cases*
0.16
Cerebral*
Age-adjusted mortality rate
0.14
Disseminated Pulmonary
0.12
With HIV co-diagnosis* 0.1
Without HIV co-diagnosis*
0.08 0.06 0.04 0.02 0
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Figure 3 Cryptococcosis age-adjusted mortality rates per
100 000 population by clinical manifestation and HIV status. *Statistically significant decline in annual per cent change: all cases 7.0% (95% CI 7.98–5.92%; P < 0.0001); Cerebral cryptococcosis 8.2% (95% CI, 9.46–6.88%; P < 0.0001); cryptococcosis in decedents with a HIV co-diagnosis 14.9% (17.13–12.65%; P < 0.0001); cryptococcosis in decedents without a HIV co-diagnosis 5.1% (6.24–3.92%; P < 0.0001).
suggests a strong association between cryptococcosis and HIV infection, only one-fifth of the decedents in the present MCD analysis listed HIV as a co-diagnosis, highlighting a need for further examination. It should be noted that HIV prevalence is likely underestimated
because certifiers may omit the diagnosis on death certificates due to family preferences and social stigma.17 In addition, there could be a number of decedents with undiagnosed HIV. The dramatic decline of cryptococcosis-related deaths from 2000 to 2010 is likely related to improvements in medical care, especially for the management of HIV infection.3 Such advances as the HAART antiretroviral therapy and more strategic uses of antifungal prophylaxis likely contributed to the decline in mortality frequency and rates.18 The association between cryptococcosis mortality and HIV co-diagnosis was not surprising, but the strong association with other medical conditions such as leukaemia, autoimmune/connective tissue disorders and non-Hodgkin’s lymphoma was somewhat unexpected. In most of these cases, the associated medical condition occurred in decedents without HIV disease. For example, all of the cases of leukaemia in decedents with cryptococcosis had no recorded HIV diagnosis. A similar pattern was observed for cryptococcosis cases with non-Hodgkin’s lymphoma. Limitations
Although the use of population-based MCD data represents an analytic strength, there are several notable limitations. First, misclassification of the causes of death may lead to an underestimation of
Table 2 Medical conditions associated with Cryptococcosis mortality in the United States, 2000–2010.
Medical condition1 Autoimmune and connective tissue disorders Cancer (all types) Cancer of bone marrow Cancer, non-Hodgkin’s lymphoma Leukaemia Cardiovascular disease Chronic renal failure Diabetes Drug and alcohol use Human immunodeficiency virus (HIV)
Cryptococcosis -related deaths2 (n = 3210), n (%) 165 (5.1) 506 116 119 126 801 368 259 156 616
(15.8) (3.6) (3.7) (3.9) (24.9) (11.5) (8.1) (4.9) (19.3)
Matched control deaths2 (n = 16 050), n (%) 128 (0.8) 2910 234 88 41 6723 990 1323 902 143
(18.1) (1.5) (0.6) (0.3) (41.9) (6.2) (8.2) (5.6) (0.9)
Matched odds ratio (95% CI) 6.86* (5.40–8.70) 0.84* (0.75–0.93) 2.53* (2.02–3.17) 7.18* (5.39–9.57) 16.10* (11.24–23.06) 0.45* (0.41–0.49) 1.97* (1.74–2.24) 0.98 (0.85–1.12) 0.86 (0.72–1.02) 35.55* (27.95–45.22)
95% CI, 95% confidence interval. 1 ICD-10 codes: autoimmune and connective tissue disorders (M06, M32, D86, G70, L93, M3, M353); all cancer (C34, C90 C61, C50, C18, C79 C71, C78, C80, C22, C64, C46, C85, D46, C81, D70, C92, C83, D47, C84, C88, C91, C95); cancer of bone marrow (D46, C81, D70, C92, C83, D47, C84, C88, C95); non-Hodgkin’s lymphoma (C85); Leukaemia (C91); cardiovascular disease (I46, I25, I10, I50, I64, I48, I21, I42, I49, I12, I51, I11, I70, I73); chronic renal failure (N03, N18, N19); Diabetes (E10, E11, E14); drug and alcohol (F17, K70, F10, F19, T40); HIV (B23, B20, B22, R75). 2
Do not add to 100% due to the possibility of a decedent having multiple conditions.
*
Statistically significant.
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cryptococcosis-related deaths and inaccurate reporting of disease manifestation. Second, census data often contain errors in the population estimates, which can potentially distort the calculated mortality rates. Finally, differentiation of C. neoformans and C.gatti in the MCD dataset was not possible in the analysis, limiting the interpretation of the mortality patterns. In light of the emergence of C. gatti as an important infectious agent in the Pacific Northwest, this differentiation could have led to a better understanding of the epidemiology of this yeast.19
Conclusions In spite of an overall decline in AAMRs for cryptococcosis during the 11-year study period from 2000 to 2010, this mycosis remains an important cause of death in the US. With a large proportion of cases without HIV co-diagnoses, there is still much to be learned regarding the epidemiology of cryptococcosis as an opportunistic infection.
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Acknowledgements The authors thank Patricia L. Cummings and Rebecca K. Butler for their technical assistance and contributions to this article.
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Conflict of interest 15
All authors reported no conflicts of interest and have no financial disclosures.
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