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Epidemiology of Infectious Diseases

Catherine Diamond MD MPH UCI Infectious Diseases & Epidemiology Divisions (714) 456-7612 diamondc@uci.edu

Surveillance

Routine collection, analysis & reporting of data monitoring morbidity & mortality trends for public health purposes Active: agency actively contacts hospitals/MDs on a regular basis to find cases Passive: agency receives reports from hospitals/MDS Sentinel systems: certain MDs or hospitals report designated cases in order to catch trends early

Trends

Secular trend: a change in the prevalence of infection over years, usually due to better living conditions, better hygiene & vaccination, e.g. decrease in TB in US Seasonal trend: refers to changes in the prevalence of infection occurring over the year, e.g. influenza outbreaks. Changes of temperature, crowding, humidity may play a role

Endemic vs. Epidemic vs. Pandemic

Endemic infection-infection or disease that occurs regularly at low to moderate frequency Epidemics occur when there are sudden increases in frequency in frequency above endemic levels Pandemics are global epidemics, an epidemic occurring over a wide area & usually affecting a large portion of the population. The size of outbreaks is dependent on factors such as the ratio of susceptible to immune subjects, period of infectivity, population density etc

What is an Outbreak?

The occurrence of cases of an illness clearly in excess of expectancy Usually compare current number of cases with the number over a comparable period sometime in the past an increase in the number of cases over past experience for a given population, time & place Must take into account seasonal variations in disease incidence for diseases such as influenza

Three Common Conditions for the Occurrence of an Epidemic or Outbreak


1.

2.

3.

The introduction a new pathogen, or the increased amount of or change in virulence of a known pathogen from an infected human, animal, bird or arthropod vector or from air, water, food, soil, drug or other environmental source An adequate number of exposed & susceptible persons An effective means of transmission between the source of the pathogen & the susceptible persons

Why Should We Study Outbreak Investigations?

Outbreaks are important public health events Outbreaks are experiments of nature & allow the opportunity to learn more about the natural history of disease Outbreaks represent breakdowns in public health You might end up investigating an outbreak someday Outbreaks are real life examples of practical applications of epidemiologic methods Outbreaks are interesting

What Are the Steps in a Outbreak Investigation?


1.
2. 3.

4.
5. 6.

Verify the diagnosis Confirm the existence of an outbreak Identify & count cases (establish case definition) Orient data in terms of time, place & person Formulate & test hypotheses Identify & implement control measures

Steps in an Outbreak Investigation

Different investigators may have slightly different lists of steps The logistics of preparing for an outbreak investigation could be considered as one of the steps The steps are not necessarily carried out exactly in the order listed

Step 1: Verify the Diagnosis

Is it an epidemic? Be certain it is real & not a false alarm ( pseudoepidemic) In hospital setting, pseudoepidemics may be due to false positive diagnosis resulting from contamination e.g. environmental contamination of specimens during laboratory processing In contrast, there may also be artifactual clustering of real cases, e.g. change in reporting due to change in diagnostic methods, new physician/clinic in town, changes in local/national awareness. HIV/AIDS examples

Step 2: Confirm the Existence of an Outbreak

Compare the magnitude of the current problem with baseline Problems with determining baselines
Lack of data Varying or no case definition Incomplete reporting, lack of surveillance

Step 3: Identify & Count Cases

Case definition usually specifies a person with: Some set of symptoms or signs or laboratory diagnosis Occurring in some time period In some specific setting Remember spectrum of disease (you may want to include asymptomatic/subclinical cases since information about them may be crucial to investigation)

Secondary Cases

Consider whether you want to include secondary cases. Secondary cases are persons who were infected as a result of exposure to a primary case E.g. in a food borne outbreak of E coli 0157: H7 primary cases were infected by consumption of contaminated hamburger & secondary cases would be infected through exposure to a primary case (e.g. in a day care) These secondary cases were not exposed to the source of the outbreak & their inclusion in the risk factor analysis would tend to bias toward the null In many cases it is desirable to look for secondary cases & collect information on them but not include them in the primary analysis

Evolving Case Definitions

Patients may not have laboratory tests because the tests are expensive, difficult to obtain or clinically not necessary Early on, investigators use a loose case definition which includes confirmed, probable & even possible cases Later a tighter case definition may increase the ability to detect a true association Ideally your case definition will include most if not all of the actual cases & very few or no false positive cases

Definite vs. Probable vs. Possible Cases

Definite case: laboratory confirmation E.g. E coli 0157:H7 isolated from stool culture in a resident of the county with onset of symptoms during a specified time period Probable case: typical clinical features without laboratory confirmation Bloody diarrhea with same person, place & time restrictions Possible case: fewer of the typical clinical features Abdominal cramps & diarrhea with the same person, place & time restrictions

Identify Cases
1. Conduct a systematic search a. Cast a wide net regarding geography & population b. The original cases may or may not be representative of the true extent of the problem 2. Use multiple sources which may include a. Medical systems: hospitals, laboratories, physician's office, clinics b. Surveillance data c. Media/press announcements d. Special surveys e.g. if outbreak involved a defined population such as persons on a cruise ship you could survey that entire population

Step 4: Orient Data in Terms of Time, Place & Person

Characterize the cases in terms of time, place & person:


Time: draw epidemic curves Place: construct spot maps Person: compare groups

Time & Outbreaks: The Epidemic Curve

An epidemic curve is a graph of the distribution of cases according to time of onset. From the curve you can tell: Where you are in the time course of an epidemic (e.g. beginning, middle, end) From the pattern of the curve, you may be able to draw inferences about the mode of spread of the causative agent ( e.g. personto-person, common source)

Common Source or Point Outbreaks

Common source or point outbreaks refer to the exposure of a susceptible population to a common source of a pathogen often at the same time, such as at a church picnic or neighborhood restaurant These most frequently result in a short, sharp epidemic curve with cases clustered around single defined peak value. If the agent is transmissible to other by person to person contact then secondary peaks may occur

Common Source or Point Outbreaks

For a common source exposure, if you have identified the disease & know its usual incubation period (the time interval between exposure to an infectious agent & the appearance of the first signs or symptoms of disease) , you can estimate a probable time period of exposure & use that information to focus your investigation The minimum incubation time should correspond to the interval between exposure & the first case The average incubation period should correspond to the interval between exposure & the peak of the outbreak or the time occurrence of the median case

Types of Epidemic Curves

The commercial distribution of food through many states or a chain of stores has created a new form of common source epidemic in which the time & pattern of delivery, purchase & consumption in a local area define the nature of the epidemic If exposure occurs over different times, the epidemic curve can spread out continuously

Figure 1. Outbreak-Associated Confirmed Cases of S. enteritidis Infection in Minnesota in September and October 1994, According to the Date of Onset. One hundred fifty cases were reported.

Propagative Epidemic Curves


Propagative or progressive epidemic curves result from epidemics involving the spread of a pathogen from one susceptible individual to another e.g. measles, influenzafrequently occur in propagative epidemics Curve with some clusters of irregular peaks & somewhat spread out is consistent with person to person spread Mixed epidemics involve both a single, common exposure to an infectious agent & secondary propagative spread to other individuals e.g. many food borne pathogens (Salmonella, Hepatitis A) & airborne organisms (TB) Mixed type of curves such as a single large peak followed by successive smaller peaks may be seen when a common source outbreak occurs followed by secondary person to person spread

Place of Outbreak: Spot Maps

Demonstrate geographic extent of the problem Demonstrate cluster or pattern illustrating where cases live, work or may have been exposed Most famous example of a spot map is John Snows spot map of the distribution of cholera cases around the Broad Street pump

Distribution of Cholera Deaths in Golden Square Area of London August-September 1848

Characterize Cases

Characterize the cases completely & systematically by developing a questionnaire before the patients are contacted. Collect: Identifying information: Name, address, telephone number Demographic information: Age, sex, race, occupation Clinical information: symptoms, date of onset, medical evaluation Risk factor information: depends on the disease being investigated

Personal Characteristics & Outbreaks

The case group must be thoroughly described in terms of age, race, sex, occupation, diagnosis & other factors Rates are then calculated to identify high risk groups E.g. age, sex (HIV), occupation (HCW)

Step 5: Formulate & Test Hypotheses

Generate hypotheses to explain outbreak Usually conduct a case control or cohort study Consider evidence for causation

Cohort vs. Case Control Study Design

In cohort study, you have knowledge of entire population (e.g. can count how many individuals were exposed and how many were infected)

Can compare attack rate in the exposed and unexposed Can calculate RR (incidence in exposed/incidence in unexposed)

But often only have information regarding some of the population and then need to use a case control design

Can compare proportion of cases and proportion of controls eating food item Can calculate OR (AD/ BC)

Coccidiodomycosis Outbreak Following Northridge Earthquake

39% of cases vs. 17% of controls reported physically being in a dust cloud OR 3.0 (95% CI 1.6-54). Duration of time spent in dust cloud correlates with OR:
0 minutes OR 1.0 1-15 minutes OR 1.7 16-30 minutes OR 3.0 >30 minutes OR 5.2

Causation

Strength of the association. The stronger the association, the more likely it is real Consistency with other studies. A consistent finding is more plausible Exposure precedes disease Dose-response effect (not mandatory but adds credibility) Biologic plausibility Removal of agent decreases or eliminates disease

Attack Rate

Attack rate is an incidence rate

Used when occurrence of disease among a population at risk increases greatly over short period of time, often related to a specific exposure The disease rapidly follows the exposure during a fixed time period Often used for food borne illness

Attack rate=

ill X 100 during a time period (ill + well)

Secondary Attack Rate

Secondary attack rate yields an index of the spread of disease within a household or similar circumscribed unit The secondary attack rate is used to measure infectivity: the capacity of the agent to enter & multiply in a susceptible host & thus produce infection or disease

Case Fatality Rate

Case fatality rate: the number of deaths caused by a disease among people who have the disease An index of the deadliness of a particular disease CFR= # of deaths due to disease X X 100 # of cases due to disease X

Step 6: Implementing Control & Prevention Measures

Eliminating or treating the source-e.g. removing an infected foodhandler from work & treating appropriately Cohorting patients- a common approach in hospitals, childcare & other institutional setting Preventing further exposures-e.g. as in the HIV/AIDS epidemic through educational efforts to change knowledge & behaviors Protecting the population at risk- e.g. through vaccination System changes. For example, changing the method by which meat inspection is conducted to decrease the risk of contamination with E coli 0157:H7

Use of Molecular Subtyping in Infectious Disease in Infectious Disease Outbreak


Molecular subtyping of patient & source outbreaks has become an increasingly important part of outbreak investigations Many methods of subtyping including pulsed field gel electrophoresis (PFGE) & restriction fragment length polymorphism (RFLP) Within a species of infectious agents, there are multiple strains with different genetic compositions. Subtyping techniques attempt to determine the degree of genetic relatedness of different isolates Outbreaks are nearly always caused by a single strain of the causative organism & thus termed clonal Subtyping of isolates can be used to determine whether the isolated involved are closely related & are therefore likely to be associated with a common source The results of subtyping can be applied to the case definition Subtyping is usually not immediately available & thus is not used in the initial case definition but may be incorporated in later analysis

Case Scenario

You are the county epidemiologist in a county on the Pennsylvania/Ohio border Between November 13 & December 3, 26 cases of hepatitis are reported to your county health department Although you just started working there, this seems like a lot to you! You decide to investigate

Step 1: Verify the Diagnosis

How would you verify the diagnosis of Hepatitis A?

Step 1: Verify the Diagnosis

Review clinical & laboratory features of the cases to determine if they are consistent with the diagnosis of hepatitis A

HEPATITIS A CLINICAL FEATURES


Jaundice by

age group:
Rare complications:

<6 yrs 6-14 yrs >14 yrs

<10% 40%-50% 70%-80%

Fulminant hepatitis Cholestatic hepatitis Relapsing hepatitis Average 30 days Range 15-50 days None

Incubation period: Chronic sequelae:

EVENTS IN HEPATITIS A VIRUS INFECTION


Clinical illness

Infection

ALT IgM IgG

Response

Viremia

HAV in stool

10

11

12

13

Week

Step 2: Confirm the Existence of an Outbreak

How would you confirm the existence of an outbreak?

Step 2: Confirm the Existence of an Outbreak

Compare the number of cases against historical numbers Between November 13 & December 3, 26 cases of Hepatitis A were reported to the county health department compared with 1 case in the previous 4 months FYI in Orange County in 2002, there were 91 reported cases of hepatitis A (3.1 cases per 100,000 population)

Step 3: Identify & Count Cases

What would be your case definition? How would you identify cases? Would you include secondary cases?

ACUTE HEPATITIS A CASE DEFINITION FOR SURVEILLANCE

Clinical criteria An acute illness with: discrete onset of symptoms (e.g. fatigue, abdominal pain, loss of appetite, intermittent nausea, vomiting), & jaundice or elevated serum aminotransferase levels
Laboratory criteria IgM antibody to hepatitis A virus (anti-HAV) positive Case Classification

Confirmed. A case that meets the clinical case definition & is laboratory confirmed or a case that meets the clinical case definition & occurs in a person who has an epidemiologic link with a person who has laboratory-confirmed hepatitis A (i.e., household or sexual contact with an infected person during the 15-50 days before the onset of symptoms)

Step 3: Identify & Count Cases

Case definition: defined as a person with discrete symptom onset between November 13 & December 4 in association with the presence of IgM antibody to HAV in your county

Step 3: Identify & Count Cases

Identify cases:

State health department requests counties to immediately report all HAV cases The county contacts all county physicians, hospitals, laboratories & neighboring county & state health departments to rapidly report cases Advertisements/media/signs

Secondary cases might bias toward the null; could collect early on but might not include in analysis

Step 4: Orient Data in Terms of Time, Place & Person

What would the epidemic curve look like? What would a spot map look like? Are there specific demographic or other characteristics of the cases?

Step 4: Orient Data in Terms of Time, Place & Person

A spot map would likely show more cases in the geographic area nearest the restaurant Presumably cases would reflect the demographics of restaurant goers, patients with symptomatic hepatitis A & residents of the county

22 (51%) were male Median age 34 years (range 5-66) All were white 14 (33%) hospitalized No travel, injection drug use or malemale sex

Step 5: Formulate & Test Hypotheses

What do you hypothesize is the cause of the outbreak? How would you collect data to prove this hypothesis? How would you analyze data to validate your hypothesis?

Step 5: Formulate & Test Hypotheses

Infected food product vs. infected employee The CDC Viral Hepatitis Surveillance Program Questionnaire Case control study Genetic relatedness of hepatitis A sequence.

Food Item

Case

Control

OR

Green Onions
Diced Tomatoes

38/40 (95)
12/38 (31)

30/60 (50%)
8/64 (13)

12.7 (2.6-60.1)
3.0 (1.1-8.4)

With green onions Without green onions Honey Mustard Sauce With green onions
Without green onions

8/40 (20)
5/39 (13) 7/39 (18) 4/40 (10) 3/38 (8)

3/64 (5)
5/64 (8) 3/64 (5) 1/64 (2) 2/64 (3)

4.8 (1.1-22.4)
1.9 (0.5-6.9) 6.4 (1.3-31.8) 8.0 (0.9-71.6) 2.9 (0.5-17.5)

CONCENTRATION OF HEPATITIS A VIRUS IN VARIOUS BODY FLUIDS


Feces

Body Fluids

Serum Saliva

Urine

100
Source:

102

104

106

108

1010

Infectious Doses per mL


Viral Hepatitis and Liver Disease 1984;9-22 J Infect Dis 1989;160:887-890

HEPATITIS A VIRUS TRANSMISSION


Close personal contact (e.g., household contact, sex contact, child day-care centers) Contaminated food, water (e.g., infected food handlers) Blood exposure (rare) (e.g., injection drug use, rarely by transfusion)

No risk factor identified for 40%-50% of cases

GLOBAL PATTERNS OF HEPATITIS A VIRUS TRANSMISSION


Endemicit y Hig h Moderate Diseas e Rate Low to high High Peak Age of Infection Early childhood Late childhood/ young adults Young adults Adult s Transmission Patterns Person to person; outbreaks uncommon Person to person; food & waterborne outbreaks Person to person; food & waterborne outbreaks Travelers; outbreaks uncommon

Low Very low

Low

Very low

RISK FACTORS ASSOCIATED WITH REPORTED HEPATITIS A, 1990-2000, UNITED STATES


Sexual or Household Contact 14% Unknown 46% International travel 5% Men who have sex with men 10% Injection drug use 6% Other Contact 8% Contact of daycare child/employee 6% Child/employee in day-care 2% Food- or waterborne outbreak 4%

Source: NNDSS/VHSP

Cause of the HAV Epidemic

Green onions grown & processed in Mexico then shipped on ice to US restaurant where they are chopped and placed raw in giant vats of mild salsa Possible contact with HAV-infected workers especially children working in the field during green onion harvesting/preparation Possible contact with HAV-contaminated water during irrigation, rinsing, icing

Step 6 Implementing Control & Prevention Measures

What control measures would you implement? How would you prevent future cases?

Step 6 Implementing Control & Prevention Measures

Control

Immunoglobulin Close restaurant

Prevention

Vaccination Public health announcements to avoid raw green onions Agricultural quality control

Water quality for irrigation Provide sanitary facilities for field workers Child-care for field workers Prevent HAV transmission

PREVENTING HEPATITIS A

Hygiene (e.g., hand washing) Sanitation (e.g., clean water sources) Hepatitis A vaccine (pre-exposure) Immune globulin (pre- & post-exposure)

HEPATITIS A PREVENTION IMMUNE GLOBULIN

Pre-exposure travelers to intermediate & high HAV-endemic regions Post-exposure (within 14 days) Routine household & other intimate contacts Selected situations institutions (e.g., day-care centers) common source exposure (e.g., food prepared by infected food handler)

HEPATITIS A VACCINES
Highly immunogenic 97%-100% of children, adolescents, & adults

have protective levels of antibody within 1 month of receiving first dose; essentially 100% have protective levels after second dose
Highly efficacious In published studies, 94%-100% of children

protected against clinical hepatitis A after equivalent of one dose

Hepatitis A Incidence, United States, 1980-2002*


1995 vaccine licensure

16
Cases/100,000

1996 ACIP recommendations 1999 ACIP recommendations

12 8
2002 rate* = 2.9

4 0
1980 '85 1990 '95 2000

*2002 rate provisional

Year

1987-97 average incidence

Hepatitis A Incidence
NYC DC

2002 incidence

rate per 100,000

0-4 >=20

5-9

10-19

NYC

Rate per 100,000 > = 20 10 - 19 5-9 0-4

DC

rate per 100,000

0-4 >=20

5-9

10-19

Conclusion

Step 1: Verify the diagnosis Step 2: Confirm the existence of an outbreak Step 3: Identify & count cases Step 4: Orient data in terms of time, place & person Step 5: Formulate & test hypothesis Step 6: Implementing control & prevention measures

Acknowledgements

Lisa Jackson, MD MPH University of Washington for lecture outline HAV slides from CDC website www.cdc.gov Dentinger et. al. An Outbreak of Hepatitis A Associated with Green Onions. J. Infect Dis 2001; 183: 1273-6. CDC. Hepatitis A Outbreak Associated with Green Onions at a RestaurantMonaca, PA, 2003. MMWR 2003; 52: 1155-1157.