Professional Documents
Culture Documents
Infections (EC03)
Module: EPM301 Epidemiology of Communicable Diseases
Course: PG Diploma/ MSc Epidemiology
This document contains a copy of the study material located within the computer
assisted learning (CAL) session. The first three columns designate which page,
card and screen position the text refers to.
If you have any questions regarding this document or your course, please
contact DLsupport via DLsupport@lshtm.ac.uk.
Important note: this document does not replace the CAL material found on your
module CDROM. When studying this session, please ensure you work through
the CDROM material first. This document can then be used for revision purposes
to refer back to specific sessions.
These study materials have been prepared by the London School of Hygiene & Tropical Medicine as part of
the PG Diploma/MSc Epidemiology distance learning course. This material is not licensed either for resale
or further copying.
London School of Hygiene & Tropical Medicine September 2013 v2.0
Section 2: Introduction
A fundamental property of most infections/infectious agents is their transmissibility.
Infectious agents are transmitted from one host to another either directly or
indirectly in a wide variety of ways. The efficiency of transmission of an infection
determines population patterns of the infection and disease and has important
implications for disease control.
Several measures have been developed for evaluating the transmission probability of
infectious diseases. In this session we will discuss the history, strengths and
weaknesses of two of the most common measures used: the secondary attack
rate and the reproduction number.
The secondary attack rate is used to calculate the probability that an infectious
disease will be transmitted in a small community such as a household or a school
class.
The secondary attack rate is the proportion of susceptible individuals who have
contact with the primary case and go on to develop the disease as a consequence of
this contact. Note that the secondary attack rate is actually a proportion (risk), not a
true rate.
So, the period from the end of E1 to the end of the combined period (I + E2) is the
period during which any cases occurring amongst the contacts can be attributed to
contact with the primary case.
Interaction: Button: show: output (changes table on RHS)
Similarly, any cases occurring after this time could not have been infected by the
primary case. These are called tertiary cases.
The tertiary cases are excluded from the numerator, as they do not become infected
due to contact with the primary case. However, they should be included as the
denominator as they were susceptible to infection from the primary case.
Interaction: Button: show: output (changes table on RHS)
You must clearly identify the time of onset of each case if you are to distinguish
between primary cases, secondary cases and tertiary cases. It is important to use
a standard manifestation of the disease to identify the date of onset of each case.
In 1948, Hope-Simpson developed the following guidelines for choosing the most
suitable manifestation for measurement:
Interaction: Hyperlink: 1. Obtrusiveness and memorability: output (appears
on RHS)
1. Obtrusiveness and memorability
The manifestation should be
clearly noticeable and be likely
to be remembered to reduce extraneous variability
Interaction: Hyperlink: extraneous variability: output (appears in new
window)
Extraneous variability
Variability not attributable to the biology of the disease, e.g. variability in memory,
reporting, observation etc.
Interaction: Hyperlink: 2. Constancy of presence: output (appears on RHS)
2. Constancy of presence
The manifestation should be present in
the majority of cases of the disease to
reduce the number of false negatives.
(Back to LHS page)
Interaction: Hyperlink: 3. Stability in the cycle of the disease: output (appears
on RHS)
3. Stability in the cycle of the disease
The manifestation should appear at
a stable point in the cycle of the
illness to reduce internal variability.
Interaction: Hyperlink: internal variability: output (appears in new window)
Internal variability
Variability attributable to the biology of the disease.
For example, the onset of jaundice in hepatitis A may appear between 21 and 35
days after infection.
The table below (Hope-Simpson 1948) shows the range of onset times for
different manifestations of measles. Assume that all of these manifestations are
present in a large proportion of cases (guideline 2).
Click on the manifestation below that you would choose in order to measure the time
of onset in a secondary attack rate study.
Hope Simpson himself argued that the time of the fullest rash was the most
noticeable and memorable and used this manifestation in his secondary attack rate
studies.
1. Obtrusiveness and memorability
The manifestation should be
clearly noticeable and be likely
to be remembered to reduce
extraneous variability.
Interaction: Hyperlink: extraneous variability.: output (appears in new window)
Extraneous variability
Variability not attributable to the biology of the disease, e.g. variability in memory,
reporting, observation etc.
2. Constancy of presence
The manifestation should be present in
the majority of cases of the disease to
reduce the number of false negatives.
3. Stability in the cycle of the disease
The manifestation should appear at
a stable point in the cycle of the
illness to reduce internal variability.
Interaction: Hyperlink: internal variability: output (appears in new window)
Internal variability
Variability attributable to the biology of the disease.
For example, the onset of jaundice in hepatitis A may appear between 21 and 35
days after infection.
The measles virus is transmitted by droplet spread. The three SAR studies listed
below all calculated a SAR for measles in susceptible children under the age of
14.
School SAR study
Classroom SAR study
Household SAR study
Which study would you expect to have found the highest SAR? Which would you
expect to have found the lowest SAR?
Click and drag boxes from each of the studies in the orange boxes opposite to the
results you would expect.
Interaction: Hyperlink: School SAR study: output (appears in new window)
School secondary attack rate study
Exposure was defined as attending the same school as a primary case.
Interaction: Hyperlink: Classroom SAR study: output (appears in new window)
Classroom secondary attack rate study
Exposure was defined as attending the same school class as a primary case.
Interaction: Hyperlink: Household SAR study: output (appears in new window)
Household secondary attack rate study
Exposure was defined as eating and sleeping in the same house as a primary case.
School secondary
attack rate study
Highest
SAR
Classroom secondary
attack rate study
Intermediate
SAR
Household secondary
attack rate study
Lowest
SAR
This is an example of a study that used the direct method to calculate the
secondary attack rate of meningococcal disease.
Read through the article. While you are reading, answer the questions opposite.
What criteria were used to establish
the onset of each case? Think about
your answer then click below.
Interaction: Button: cloud: output (appears in new window)
In the article, the criterion used to establish the onset of each case is not explicitly
described. As the definition of a secondary case is "...meningococcal disease in a
household member with onset more than 24 hours but less than 31 days after
hospitalisation of the index patient" (p.262), it appears that the time of
hospitalisation was used to date the primary case.
The criterion used to establish the onset of the secondary case appears to be onset
of symptoms (see p262, subheading 'Secondary Attack Rate' paragraph 2). As we
only have detailed information on the time course of onset of symptoms for one
household, it is impossible to judge whether this apparent inconsistency may have
led to an underestimate of the number of co-primary cases and a subsequent
overestimate of secondary cases.
(back to main text)
What estimate of the maximum
infectious period and the minimum and
maximum incubation periods of
meningococcal disease were used in
this study?
Interaction: Button: cloud: output (appears in new window)
The definition of a secondary case used in this study is "meningococcal disease in a
household member with onset more than 24 hours but less than 31 days after
hospitalisation of the index patient" (p.26).
From this, we can assume that the minimum incubation period used in this study
was 24 hours after hospitalisation of the primary case and the combined
maximum infectious period and maximum incubation period was 31days after
hospitalisation of the primary case. The source of these estimates is not given.
(back to main text)
How was the number of exposed
susceptibles determined?
Interaction: Button: cloud: output (appears in new window)
All people who "lived in the same house (or dormitory room) with a patient in the
week prior to the onset of the patient's illness" (p.262) were counted as exposed
susceptibles.
N
_____________
h x (m-1)
where:
This article is an example of a study in which routine surveillance data was used to
estimate the secondary attack rate of meningococcal disease. Read through the
article. While you are reading, answer the questions on the following cards.
1. What was the case definition of meningococcal disease used in this study?
Think about your answer and then click on the button here.
Interaction: Button: cloud: output (appears in new window)
The case definitions used are presented on p. 54 of the article.
Possible case: An illness reported as meningococcal disease by a local physician.
Confirmed case: An illness reported as meningococcal disease by a local physician
in which N. meningitidus was isolated from cerebrospinal fluid, blood or petechial
skin lesions.
(back to main text)
2. What was the definition of a secondary case used in this study?
Think about your answer and then click on the button here.
Interaction: Button: cloud: output (appears in new window)
The secondary case definition is also presented on p. 54 of the article.
Secondary case: ' A case of meningococcal disease in a patient's contact with onset
less than 60 days after the onset of the primary case'.
Which of the reasons shown opposite could explain this difference in the
household secondary attack rate for meningococcal disease obtained in the two
studies?
Click 'true' or 'false' for each reason. The tabs will change colour accordingly green
for true, red for false.
Interaction: Tabs: 1 : output (appears in new window)
The secondary attack rate of meningococcal disease in Belgium from 1971 to 1976
may have been genuinely higher than the secondary attack rate in the United States
from November 1973 to March 1974.
Interaction: Button: true: output (appears in new window)
That's correct. The secondary attack rate is not fixed for a specific disease, but varies
according to a number of different circumstances. The secondary attack rate of
meningococcal disease is known to be much higher in epidemic periods than in nonepidemic periods. The US study was deliberately carried out during a non-epidemic
period. The Belgium study was carried out over a much longer time period (4 years)
and may have included epidemic periods. Other factors that can influence the
secondary attack rate are the age and sex of exposed individuals, and factors that
influence how often cases and susceptibles make contact, such as crowding and
social structure.
Interaction: Button: false: output (appears in new window)
In fact this is true. The secondary attack rate is not fixed for a specific disease, but
varies according to a number of different circumstances. The secondary attack rate
of meningococcal disease is known to be much higher in epidemic periods than in
non-epidemic periods. The US study was deliberately carried out during a nonepidemic period. The Belgium study was carried out over a much longer time period
(4 years) and may have included epidemic periods. Other factors that can influence
the secondary attack rate are the age and sex of exposed individuals, and factors
that influence how often cases and susceptibles make contact, such as crowding and
social structure.
(back to main text)
Interaction: Tabs: 2 : output (appears in new window)
The possible classification of co-primary cases as secondary cases in the De Wals
study may have led to an overestimation of the household secondary attack rate in
this study.
Interaction: Button: true: output (appears in new window)
That's correct. Table II on p.56 of the De Wals article shows that 30% of the
secondary cases for whom time interval data was available occurred ~< day after
the primary case. These cases would probably have been considered to be coprimary cases by the Meningococcal Study Group. However, the lack of a clear
statement about which manifestation was used to date the onset of the cases in both
studies makes it difficult to judge the exact impact of this difference.
Interaction: Button: false: output (appears in new window)
In fact this is true. Table II on p.56 of the De Wals article shows that 30% of the
secondary cases for whom time interval data was available occurred ~< day after
the primary case. These cases would probably have been considered to be coprimary cases by the Meningococcal Study Group. However, the lack of a clear
statement about which manifestation was used to date the onset of the cases in
both studies makes it difficult to judge the exact impact of this difference.
(back to main text)
Interaction: Tabs: 3 : output (appears in new window)
The method used to estimate the number of susceptible household contacts in the
study by De Wals may have led to an overestimation of the household secondary
attack rate in this study.
The study found a secondary attack rate of 0% in parents, siblings and other
domestic contacts and 23% in sexual contacts. This study, along with other
evidence, suggests that the sexual route is the most important route for the
transmission of hepatitis B virus from an acute primary case within the household.
On the basis of these data, which of the following transmission routes is likely to
have been the most important?
Interaction: Button: Hint: output (appears in new window)
Hint
Calculate the SAR for children in the same class as the primary case and children
who share the same toilet facilities as the primary case.
(back to main text)
Interaction: Hotspot: droplet spread: output (appears in new window)
SAR among children in the same class as a primary case = 4 / 27 = 15%
SAR among children who used the same toilet facilities as a primary case = 33 / 75
= 44%
If droplet spread were the most important transmission route, we would expect the
SAR among children in the same class as a primary case to be higher than the SAR
in children who used the same toilet facilities as a primary case. Please try again.
Interaction: Hotspot: faecal oral spread: output (appears in new window)
Correct
SAR among children in the same class as a primary case = 4 / 27 = 15%
SAR among children who used the same toilet facilities as a primary case = 33 / 75
= 44%
As the SAR in children who used the same toilet facilities as a primary case was
higher than the SAR among children in the same class as a primary case, faecal-oral
spread was probably the most important transmission route.
Kemper (1980) and Longini et al (1982). These methods are beyond the scope of
this course.
secondary cases / total no. exposed susceptibles. So, this would in fact lead to an
overestimation of the denominator and an *underestimation* of the SAR
Interaction: Hotspot: This would lead to an underestimation of the SAR. output
(appears in new window)
That's correct. A large proportion of asymptomatic infections before the onset of the
study would lead to an overestimation of the number of persons who are susceptible.
SAR = no. secondary cases/total no. exposed susceptibles. So, this would lead to an
overestimation of the denominator and an underestimation if the SAR.
SAR = 1 / 4 = 25%
Interaction: Tabs: Question 2 : output
Question 2
What is the susceptible-exposure attack rate in this household? Give your answer
as a percentage.
Susceptible-exposure
Interaction: Calculation: attack rate = % output (appears in new window)
Correct response:
That's correct. In this household there were 3 transmissions as a result of 10
exposures, so the susceptible-exposure attack rate is 30%.
Incorrect response:
Sorry, that's not right. In this household there were 3 transmissions as a result of 10
exposures, so the susceptible-exposure attack rate is 30%.
Interaction: Tabs: Question 3 : output
Suppose that E is actually immune to infection, and has been misclassified as
susceptible. Will this error have a greater impact on the SAR or the susceptibleexposure attack rate?
Interaction: Hotspot: Greater impact on SAR output (appears in new window)
In fact, if E is actually immune the true SAR would be 1/3 = 33% and the true
susceptible-exposure attack rate would be 3/6 = 50%. Overestimation of
susceptibles has a greater impact on the susceptible-exposure attack rate because
the 'false susceptibles' are repeatedly counted in denominator.
Interaction: Hotspot: The R0 for measles would probably be higher in a rural area
output (appears in new window)
In fact, an infective case is likely to make more contacts in an urban area than in a
rural area, so R0 is likely to be higher. Studies in the USA have estimated a R0 of
12.2 in urban Baltimore and a R0 of 5.4 in rural Kansas.
Interaction: Hotspot: The R0 for measles would probably be the same in both
areas output (appears in new window)
In fact, an infective case is likely to make more contacts in an urban area than in a
rural area, so R0 is likely to be higher. Studies in the USA have estimated a R0 of
R0 = v d
The vectorial capacity is defined as the average number of potentially infective
bites that will ultimately be delivered by all the vectors feeding on a single host in
one day. It is a function of the density of the vector population, its propensity to
feed on the host species in question and its life expectancy.
Interaction: Hyperlink: vectors: output (appears in new window)
Vector
A living carrier, such as an insect, that transports an infectious agent from an
infected individual to a susceptible individual.
If all other factors were unchanged, how would you expect the R0 to change during
the season of low mosquito density?
Choose from one of the answers opposite.
Interaction: Hotspot: The R0 of malaria would probably increase output (appears in
new window)
In fact, if the mosquito density were to decrease the vectorial capacity would
decrease and R0 would decrease.
Interaction: Hotspot: The R0 of malaria would probably decrease output (appears
in new window)
That's correct, if the mosquito density were to decrease the vectorial capacity would
decrease and R0 would decrease.
Interaction: Hotspot: The R0 of malaria would probably stay the same output
(appears in new window)
In fact, if the mosquito density were to decrease the vectorial capacity would
decrease and R0 would decrease.
R = R0 x
NB: Note that to generate this formula, we assume that all individuals in the
population mix at random. However, this assumption is not always true. The
estimation of R for population in which individuals do not mix at random is discussed
R0 = 1 / x
Interaction: Button: example: output (appears in new window)
Example
In 1950, a study collected data on the age-specific prevalence of antibodies to type 2
poliovirus in an unimmunised urban population in Miami. Fine and Carneiro (1999)
used this data, along with data on the age-demographic structure of Miami from
1950 1955, to estimate that 25% of this population were susceptible to poliovirus
type 2. They used this figure to estimate a R0 of 4 for poliovirus type 2 in this
population.
x=a/L
NB: This formula works for populations with a rectangular age distribution, i.e. in
which the mortality rate is low and fairly homogeneous across age groups, and the
life expectancy is high. This is observed mostly in several high-income countries.
For population with an exponential age distribution like many low and middle-income
countries (i.e. shorter life expectancy, high mortality rates, hence high proportions of
young age groups, and low proportions of older age groups), the following formula
can be used:
X = 1/(1+L/A)1 + a/L
Suppose that this is a stable population in which births exactly balance deaths. No
one in this population has been vaccinated against measles.
If the incidence and prevalence of measles in this population is stable, what is the
R0 for measles to one decimal place?
R0 = calc 1
It is important to be aware that this method can only be used if the population mixes
together homogeneously and there are no age-related differences in the
transmission rate.
Interaction: Calculation: R0 = calc 1 output (appears in new window)
Correct response:
That's correct. If the incidence and prevalence of measles in this population is
stable, then
R = 1, and
R0 = L / a = 60 / 7 = 8.6
Incorrect response:
Remember that if the incidence and prevalence of measles in this population is
stable, then
R = 1, and R0 = 1/ x.
If x = a / L, then
R0 = L / a = 60 / 7 = 8.6
If R ~< 1, then, on average, each case will produce less than one infective
secondary case.
Show Button
In this case, the incidence of the disease will decrease, and the disease will
eventually be eliminated from the population.
Interaction: Button: cloud: output (appears in new window)
Vaccination programmes
Vaccination can reduce transmission of infection by reducing the proportion of
susceptibles in a population (x) and increasing the proportion immune (1 x).
The proportion of the population immune to infection is called the herd immunity
(HI).
The higher the herd immunity, the less likely an infected case is to make contact
with a susceptible and transmit the infection. At a certain threshold, called the
herd immunity threshold, each case will only be able to transmit the infection to
one other case.
The herd immunity threshold (HIT) is thus the proportion of the population that
need to be immune (1 x) for the disease to become stable (R = 1).
threshold):
HIT
= 1 (1 / R0)
= (R0 1) / R0
Example
If R0 for measles is 9, then you can calculate the proportion of the population that
would have to be immune to measles if any major outbreaks are to be avoided, as
follows:
HIT = (R0 1) / R0 = 8 / 9 = 0.89
So more than 89% of the population would have to be immune to measles if major
outbreaks are to be avoided.
Assume again that R0 for measles is 9. If you had a vaccine that provided
complete and lifelong immunity, you would have to immunise at least 89% of the
population to prevent any major measles outbreaks. This ignores any immunity in
the population from previous infection.
The proportion of the population that would have to be vaccinated to make R0 ~<
1 increases if the vaccine does not provide full immunity to all those vaccinated.
is a 2.5% chance that R0 ~> 2.67, and so we would expect R0 to be less than 2.67
on 97.5% of occasions.
Therefore we calculate the HIT at the 95% upper confidence limit in order to
answer the question. When R0 is 2.67, the HIT is:
HIT = 1 (1 / 2.67) = 1 0.37 = 63%.
transmission probability per contact (p) and the duration of infectiousness (d).
R0 = c p d
It follows that you can use data on the effects of a public health intervention on
any one of these factors to help predict the impact the intervention will have on R0
and thus the potential for transmission in a population.
How short would the average infectious period have to be to eventually eliminate
tuberculosis from this population? Enter your answer to the nearest number of
whole weeks.
An average case of TB would have to be infectious for less than Calc 1 weeks.
Interaction: Calculation: Calc 1 output (appears in new window)
Correct response:
That's correct. If R0 = 6 then the period of infectiousness would have to reduce more
than sixfold, from 52 weeks to 8 weeks, to produce R ~< 1.
Incorrect response:
In fact, if R0 = 6 then the period of infectiousness would have to reduce more than
An infectious agent that does not reproduce directly within the definitive host, e.g.
most parasitic helminths and arthropods.
To reflect this, the basic reproduction number is defined as the expected number of
mature female offspring that one female parasite will produce in her lifetime. This
is similar to the initial demographic concept of the net reproduction rate.
average female worm in her lifetime. As these worms could be in one host or in
several, this does not tell us how many secondary hosts are infected.
female worm produces in her lifetime. As these worms could be in one host or in
several, this does not tell us how many secondary hosts are infected.
(back to main text)
A female worm produces an average of
4 mature female worms in her
lifetime.
However, you should not always assume that transmissibility is constant for all
individuals within a population. There are many examples of particular individuals
who are exceptionally efficient transmitters of infection. Such individuals are
sometimes called 'superspreaders'. Superspreaders may arise for biological or social
reasons.
Interaction: Button: example: output (appears in new window)
Example
Typhoid fever is a disease caused by the bacterium Salmonella typhi. See
http://www.cdc.gov/nczved/divisions/dfbmd/diseases/typhoid_fever / for details on
the clinical presentation and epidemiology of typhoid fever. Chronic typhoid carriers
excrete S.typhi in the stools over a period of many years. The chronic carrier state is
often acquired in middle age. There are important examples of food handlers who
have been chronic typhoid carriers and have been exceptionally efficient transmitters
of S.typhi.
(back to main text)
Interaction: Hyperlink: 2. Assumption of homogeneous mixing: output
(appears in new window)
Assumption of homogeneous mixing
The R depends on the assumption that there is random mixing within the
population and that there is an equal chance of an infective case making contact
with a susceptible person or an immune person.
However, most human populations do not mix randomly. People tend to form
groups who mix more with their own members than with other groups.
Non-homogenous mixing patterns can have a significant impact on transmission
within a population.
N
_______
h x (m 1)
where:
h = number of households with a primary case
m = mean number of people per household
N = total number of secondary cases
Why calculate a SAR?
The SAR can be used to:
help elucidate the transmission routes
of an infectious agent
help determine which control measures
may reduce transmission
help measure post-licensure vaccine
efficacy.
Assumptions in calculating a SAR
1. The SAR assumes that each secondary
case is derived from a single primary
case within the household.
2. Most SAR studies assume that all
cases of successful transmission of
infection are symptomatic.
3. Most SAR studies assume that all
individuals in the denominator are
equally susceptible.
R0 = c p d
The net reproduction number
The net reproduction number (sometimes called the effective reproduction number)
R is the average number of secondary infective cases produced by each primary
case in a population where not all the individuals are susceptible.
If all the individuals in a population mix together at random, so that infectious cases
are as likely to make contact with susceptibles as with immunes, then R is the
product of R0 times the proportion of the population that are susceptible (x):
R = R0 x
How to calculate R0: direct estimation
Method 1
In theory, it should be possible to measure R0 directly by counting the number of
infective secondary cases that are produced after a primary case of infection is
introduced into a totally susceptible population.
Method 2
R0 = c p d
So, if you have data on c, p and d, you can calculate R0.
How to calculate R0: indirect estimation
In equilibrium conditions where the average incidence and prevalence of the
disease is stable,
R0 = 1 / x
If, in addition, all of these are true:
The disease results in life-long immunity
The population is stable (with births
exactly balancing deaths)
No one has been vaccinated against the
disease, then:
R0 = L / a
L = average life-expectancy in the population
a = average age of infection
NB: As discussed in EC03, this formula applies to populations with a rectangular
age distribution.
Uses of the reproduction number
The reproduction number is a central concept for understanding the population
biology of an infectious agent in a host population. You can use the reproduction
number to help predict the effects of public health interventions on the
transmission of an infectious agent in a population.
produced by a single primary infective case. However, you should not always
assume that transmissibility is constant for all individuals within a population.