Epidemiology and surveillance of fungal infections: an overview David W. Warnock Centers for Disease Control and Prevention Atlanta, Georgia

Healthcare Public Health At this point, it is pertinent to ask: ‘what is public health?’ This is a difficult concept to define, and many well-educated individuals find it difficult to distinguish between clinical medicine and public health. In simple terms, public health can be defined as the prevention of illness in a population. In clinical medicine the focus is on the individual, on the diagnosis of illness, and on its management. In contrast, in public health the focus is – for the most part – on the population, on the prevention of infection, and on its control. We depend on the effectiveness of clinical medicine to cure us when we get sick, but we depend on public health to prevent us from becoming ill. Focus on: individual diagnosis treatment Focus on: - population prevention

The cycle of disease prevention

The cycle of disease prevention

The cycle of disease prevention

The cycle of disease prevention

Public health surveillance ‘The ongoing systematic collection, analysis and interpretation of information about a disease’[1] ‘The reason for collecting, analyzing and disseminating information on a disease is to control that disease’ [2] ‘Collection and analysis should not be allowed to consume resources if action does not follow’ [2] [1] Langmuir N Engl J Med 1963;268:182-92 [2] Foege Int J Epidemiol 1976;5:29-37

The spectrum of public health surveillance Population Data collection Case definition Sentinel surveillance Passive surveillance Syndromic surveillance Population-based surveillance Laboratory-based surveillance Active surveillance

Comparison of surveillance systems Active surveillance Investigator-initiated Dedicated staff needed Extensive case finding performed Extensive clinical and laboratory information Audits performed High cost Passive surveillance Provider-initiated No dedicated staff needed Limited case finding performed Limited clinical and laboratory information No audits performed Lower cost

Number of reported cases of coccidioidomycosis United States, 2007 77 24 3 12 3 72 68 2991 9 4832 23 3 Morbid Mortal Wkly Rep 2007; 56 (no 53) (published July 9, 2009)

Mycotic diseases: passive surveillance Healthcare providers feel no need to report fungal infections since no immediate public health action is required Limitations of current diagnostic tests hinder the development of case definitions As a result these infections are under-diagnosed and under-reported In 2007, CSTE adopted a modified case definition for coccidioidomycosis: a single positive serologic test for IgG is now adequate for definition of a case

Mycotic diseases surveillance: case definitions A standardized case definition is needed to perform reliable surveillance for a disease In some diseases, a positive culture is indicative of colonization rather than infection Consensus case definitions for clinical trial enrollment of immunocompromised patients are too complicated for surveillance and not generalizable to other patient groups

Population-based surveillance Provides the most representative information on a disease in the entire population of a defined geographic location, and specific groups within that population All cases of the disease in the catchment area are identified, but only cases among residents are counted Incidence is calculated as the number of new cases occurring in a defined time period divided by the total population Active population-based surveillance to determine trends in disease incidence is expensive to conduct, and difficult to sustain for long periods

Incidence of Candida bloodstream infections (per 100,000 population) 7.1 1998-2000 7.1 1992-1993 6.0 1998-2001 24.0 1998-2000 25.0 2008-2009 Looking at the distribution of spinach packages with culture-positive spinach samples and the lot code P227, reported by patients, we can see that the packages were distributed across a wide region of the United States. Therefore P 227 could explain cases throughout the wide geographical regions over the course of the outbreak. 8.7 1992-1993 14.0 2008-2009 Diekema et al. 2002; Hajjeh et al. 2004; Kao et al. 1999

Incidence of Cryptococcus gattii infection British Columbia, Canada Average incidence 1999–2006: Vancouver Island: 2.8 cases per 100,000 Mainland: 0.65 cases per 100,000 Cases per 100,000 population Source: BC Centre for Disease Control 2007

Estimated population-based incidence of Candida bloodstream, by race Atlanta, GA, and San Francisco, CA 1992-1993 Cases per 100,000 population Connecticut, and Baltimore, MD 1998-2000 Kao et al. 1999; Hajjeh et al. 2004

Population-based surveillance Cohort studies In cohort studies, the population is defined as a particular group of individuals (e.g. persons with AIDS or transplant recipients) Adequate follow-up is essential to determine the presence or absence of infection and therefore inclusion as a case of disease or non-case These studies are most useful when only a subset of the population is at risk for a particular disease Information is more broadly representative than reports from single centers

12-month cumulative incidence (%) Incidence of invasive fungal infections after stem cell transplant, 2001-2006 (TransNet) 12-month cumulative incidence (%) Kontoyiannis et al. 2009 submitted for publication

12-month cumulative incidence (%) Incidence of invasive aspergillosis after allogeneic stem cell transplant, 2001-2005 (TransNet) Overall incidence: 1.6% 12-month cumulative incidence (%) Transplant center

Sentinel surveillance Conducted at selected medical centers or sites, rather than in the entire population of a geographic location Total burden of disease in the general population cannot be estimated, but useful for diseases where the at-risk population is captured Less expensive and easier to perform than population-based surveillance

Sentinel surveillance Hospital are good sites for sentinel surveillance of invasive fungal infections because good denominators are available Useful for monitoring trends in incidence of particular pathogens and infections, species distribution, and antifungal drug resistance Site selection can be biased, so information may not be representative of the general hospital population

Incidence of Candida bloodstream infections (per 10,000 hospital admissions) Sweden 3.2 Canada 4.0 France 2.0 United States 8.0 Spain 5.3 Italy 3.8 Brazil 24.9 Australia 2.1 Almirante et al. 2005; Colombo et al. 2005; Chen et al. 2006; Hajjeh et al. 2004; Laupland et al. 2005; Tortorano et al. 2004;

Administrative data as sources of information Hospital discharge and death records, based on ICD codes, are widely available, and permit application of common definitions to similar data from different institutions, Use of these data minimizes ascertainment bias when investigators use diverse methods for case finding Helpful for investigating long-term trends in disease incidence rates Limitations include diagnostic errors, inconsistent disease coding, and undetected duplicate reporting of cases

Chang et al. Infect Control Hosp Epidemiology 2008; 29: 25-30 Comparison of the use of administrative data with an active system for surveillance of invasive aspergillosis in a single hospital, 2001-2005 64 of 1736 transplant recipients had ICD-9 codes consistent with IA, triggering medical record review; 3 cases detected by other methods 48 of 67 patients reviewed had other or no infections, or had insufficient evidence to be classed as proven or probable IA 14 of 19 patients reviewed and classed as having IA identified by both methods; 3 identified by active surveillance only; 2 identified by ICD-9 code only Chang et al. Infect Control Hosp Epidemiology 2008; 29: 25-30

Bitar et al. Emerg Infect Dis 2009; 15: 1395-1401 Incidence of zygomycosis in France based on analysis of hospital records,1997-2006 Cases per 100,000 population Bitar et al. Emerg Infect Dis 2009; 15: 1395-1401

Disease registries as sources of information Provide useful information about clinical details of rare fungal infections, or infections occurring in special hosts, such as transplant recipients Limited value for public health surveillance because meaningful and appropriate denominator data are not available Subject to ascertainment bias: variable participation or case finding leads to unrepresentative results Should not be interpreted as being representative of broader populations

FoodNet Foodborne Diseases Active Surveillance Network Established in 1996 as a collaboration among CDC, USDA, FDA, and state health departments Conducts population-based, active surveillance for laboratory-confirmed infections caused by 9 pathogens commonly transmitted through food Campylobacter spp., Listeria monocytogenes, Salmonella spp., Shigella spp., STEC O157, Vibrio spp., Yersinia enterocolitica, Cryptosporidium spp., Cyclospora spp. 2009 : 10 sites, 45 million persons, 15% of population

FoodNet trends: E. coli O157 infections Incidence per 100,000 population 1.30 National objective 0.90 Make y axis horizontal. Looks better with white background. Healthy People 2010 Objective: 1.0 illness per 100,000 persons

Estimating the burden of disease Most surveillance systems do not capture the total burden of disease in a population This is because the reporting of a case depends on a number of steps: the patient must visit a doctor; the doctor must collect a sample; the sample must be tested; the pathogen must be identified; and the test result must be notified The proportion of cases that are detected and reported differs from disease to disease

Food-related illness and death in the United States ‘Foodborne diseases cause 76 million illnesses, 325,000 hospitalizations, and 5000 deaths in the United States each year’ This article had been cited on 2350 occasions through 9.21.09 Mead et al. Emerg Infect Dis 1999;5:607-25

Estimating the global burden of HIV-associated cryptococcosis Literature search for studies reporting estimates of incidence among HIV populations since 1996 Median incidence for each UNAIDS geographic region multiplied by the HIV population to estimate number of cases To estimate number of deaths, assumed a 3-month case fatality rate 9% in high-income regions 55% in low- and middle-income regions 70% in Sub-Saharan Africa Park et al. AIDS 2009; 23: 525-30

Estimated annual cases of HIV-associated cryptococcosis Eastern Europe & Central Asia 27,200 Western & Central Europe 500 North America 7,800 East Asia 13,600 North Africa & Middle East 6,500 Caribbean 7,800 South & South-East Asia 120,000 Sub-Saharan Africa 720,000 Latin America 54,400 Oceania 100 Global total: 957,900 cases (range: 371,700 – 1,544,000) Park et al. AIDS 2009; 23: 525-30

Estimated annual deaths from HIV-associated cryptococcosis Eastern Europe & Central Asia 15,000 Western & Central Europe 45 North America 700 East Asia 1,200 North Africa & Middle East 3,600 Caribbean 4,300 South & South-East Asia 66,000 Sub-Saharan Africa 504,000 Latin America 29,900 Oceania 10 Global total: 624,700 deaths (range: 125,000 – 1,124,900) Park et al. AIDS 2009; 23: 525-30

Estimated deaths in Sub-Saharan Africa from cryptococcosis and other infectious diseases* WHO estimates * Excluding HIV AIDS

In conclusion: Similar burden of disease estimates need to be developed for other fungal infections These estimates would allow for comparison with other diseases These estimates would help set public health and healthcare priorities, and determine resource allocations

Thank you for your attention The findings and conclusions in this presentation are those of the author and do not necessarily represent the views of the Centers for Disease Control and Prevention