Name: Ebrima Sidibeh

Madina Hukah
Muhammad Zia ul Haq

Due: December 7, 2021

GH/EPIDEMIOLOGY 517
Problem 10 – Yellow Fever in Senegal
(You may work alone or in a group of two or three on this problem.)

Note: This last homework case study (#10) on Yellow Fever will be due Tuesday, December 7,
2021 for those who do not have at least 34 points from their past homework case studies.
Our class session on December 7, 2021, will be covering Yellow Fever and serve as a wrap up
for the course. If you are NOT completing the last homework case study (#10) on Yellow
Fever, you MUST attend this last lecture and sign in, otherwise you will be a given a zero for
the case. 

On November 16 (a few years back), an unusual number of patients with fever and
jaundice appeared at Kaffrine Hospital, in Kaffrine, Senegal; many died. Within two days the
agent of this outbreak was determined to be yellow fever virus (YFV). On November 18, an
epidemiological investigation was undertaken. This included active case detection, which started
with the villages from which the cases came, and later was continued in other neighboring
villages in the district. Village chiefs, administrators, and sanitary agents were required to report
ill individuals either meeting the case definition or with febrile illnesses of unclear cause. This
initial investigation found 36 deaths to be attributed to the outbreak, all occurring in children
under 15 years of age.

The only hospital serving this area is in Kaffrine, the major economical and
administrative center of the agriculture district (Figure 1). The town is situated on the main
road, 300km from Dakar. The agricultural district is characterized by Guinean savannah
vegetation, and the Saloum River Valley crosses the area from east to west. Rainfall is
approximately 750 mm/year, with the heaviest precipitation falling between June and November.
Water is widely stored in large clay pots and metal drums. The total population of the district is
about 160,000 inhabitants (from a recent census), and about half the population is under the age
of 15. No urban cases were hospitalized - all hospitalized cases came from villages immediately
surrounding the city. The defined epidemic area had a 20-kilometer radius centered on Kaffrine.

This yellow fever outbreak was the second to occur in Senegal in the past 2 years. The
previous outbreak occurred in Koungheul, a town also in the Saloum River Valley, about 150
kilometers from Kaffrine, in October of the prior year. As a result of the first outbreak, the
second outbreak in Kaffrine was rapidly diagnosed.

An entomological study of mosquitoes was carried out in Kaffrine and the surrounding
villages. Aedes aegypti was the agent most often found in surveys of both adult and larval
stages, and YFV was isolated from this type of mosquito. Other potential vectors (A. furcifer
and A. metallicus) were rare and no YFV was isolated from these species.

In a follow-up study to determine the extent of the outbreak, a total of 449 people
(including all known cases) were examined and tested for immunity to YFV. Samples were
Problem 10: Yellow Fever in Senegal Page 2
obtained from people in each of the villages surrounding Kaffrine. Sampling was based on
randomization involving housing units. Every person in a selected unit was asked to give blood
and to answer questions from a case investigation form (all complied with the requests). A
probable case was defined as a death occurring after a febrile illness lasting two weeks or less,
with jaundice and/or hemorrhagic features. A confirmed case was defined as a person with a
febrile illness and/or jaundice with a positive test for IgM antibody to YFV (a measure of active
or recent infection) or with YF virus isolated from clinical specimens. An asymptomatic case
was defined as someone without signs or symptoms of illness who had a positive test for IgM
antibody to YFV. Those immune (before the outbreak) were defined as persons who had a
positive test for IgG antibody to YFV and a negative test for IgM antibody to YFV.

Thirty-one were confirmed cases and 69 were asymptomatic. Twenty-eight probable

cases were also recorded during the investigation. Table 1 shows the numbers of cases
(confirmed, asymptomatic, and probable) and their location as well as the number of persons
immune before the outbreak (determined by the type of antibody response) by area for the
surrounding villages. Table 2 lists the cases and immunity status by age group.

Assume you are an epidemiologist sent to Senegal from the Institut Pasteur of Senegal to
work up this outbreak. You will have to analyze and interpret the collected data, and plan and
implement control and prevention measures.

Questions
Question 1. What opportunities are there for bias in the definitions used for cases? Briefly
explain your answer.

The method of gathering information about signs and symptoms, as well as whether this
information was collected uniformly for all people suspected of having the condition, were all
factors in determining how to define probable cases. It also depends on the sensitivity and
specificity with which the clinical picture of a fever lasting less than two weeks and
accompanied by jaundice and/or bleeding is used to diagnose yellow fever. Additionally, the
sensitivity and specificity of immunologic testing, as well as virus culture tests, are used to
define a confirmed case.

Question 2. List two possible reasons why this outbreak is not occurring in urban Kaffrine.
Briefly explain your choices.

1) Transmission began in nearby villages, and by the time the outbreak was discovered, it
had not reached the city.
2) In the urban population, background immunity was higher, possibly due to immunization
or earlier exposure to the virus, and this level was strong enough to prevent transmission

Question 3. What do you think would account for the difference in the measures of occurrence
between age groups? Briefly explain your answer, showing all calculations supporting your
answer. [Hint: calculate at least two different rates]
Problem 10: Yellow Fever in Senegal Page 3

Age in Years Samples Yellow Immune Attack Ratio Incidence Ratio (95%
Fever Before (95% CI) CI)
Cases Outbreak
0-9 143 53 42 52.5 (42.3-62.5) 37.1(29.1-45.5)
10-19 115 36 54 59.0 (45.7-71.4) 31.3(23-40.6)
 20 191 11 175 68.8 (41.3-89) 5.8 (2.9-10.1)
Total 449 100 271 56.2 (48.6-63.6) 22.3 (18.5-26.4)

The incidence ratios dropped as age increases, with only a few cases among those aged 20 and
up. This trend is statistically significant, with a p-value of < 0.0001.  The attack ratios (cases per
100 non-immune population) did appear to rise with age, but they were not statistically different
with a p-value < 0.41.

Age in Years Samples Immune Before Percent Immune

Outbreak Before Outbreak
0-9 143 42 29.4
10-19 115 54 47
 20 191 175 91.6
Total 449 271 60.4

Immunity levels grew dramatically with age group prior to the pandemic. Since they had not
lived through past outbreaks or been exposed to endemic yellow fever, young people in this area
were substantially less likely than older people to be immune to yellow fever. This also explains
why all the people who died as a result of the outbreak were children. The density of mosquitos
and human immunological responses play a role in resurgent yellow fever epidemics. Despite the
fact that this community had a high overall rate of immunity (60.4 percent), "herd immunity"
was insufficient to protect these people from an epidemic. Unprotected children in Africa are at
the greatest danger of contracting yellow fever and dying as a result.

Question 4. What do you think are the reservoir and source in this outbreak? [Hint: which of
the three types of epidemic pattern is involved? (see additional information)] Briefly explain
your answers.

Yellow fever is transmitted to monkeys in tropical rainforests by a variety of wild mosquitoes

other than Aedes aegypti. The virus can then be passed on to other mosquitoes that feed on the
affected monkeys. Humans entering the forest are bitten by infected wild mosquitoes, resulting
in occasional occurrences of yellow fever. Young males working in the forest make up most of
the cases (e.g., logging). The virus can sometimes spread beyond the person who is infected. As
a result, the reservoir consists of monkeys, humans, and mosquitoes. Mosquitoes are the source
and inoculation by bite is the mode of acquisition. Based on the data provided and because of the
domestic vector Aedes aegypti and the possibility of human-to-human transmission, the
Problem 10: Yellow Fever in Senegal Page 4
epidemic pattern appears to resemble that of an urban epidemic. However, because the outbreak
occurred in rural regions, the authors classified it as an intermediate outbreak, and they believe
they discovered it during the second phase of the cycle, when Aedes aegypti transmission was
most prevalent. 

Question 5.
a) What immediate control measures, if any, would you take at this time?

We would commence by trying to reduce the number of mosquitoes for immediate control. To
achieve this, the number of mosquito breeding sites, stagnant water should be removed as much
as possible. Insecticides should be used to treat any stagnant areas that cannot be eliminated.
Local leaders should be called upon to aid in the process of identifying everyone who may have
contracted the disease as soon as possible. The use of screened sleeping areas (mosquito bed
nets) for mosquito protection may also be advised.

b) What measures, if any, would you suggest to prevent future outbreaks? Briefly explain your
answers.

I would strongly suggest vaccination campaigns, which are the most effective way to avoid
future epidemics. This can be done, along with a 10-year booster vaccine to be administered
following the initial shot. The authors concluded that a large vaccination effort launched in 1993
could have prevented the outbreak in Senegal. However, the yellow fever vaccine has been
linked to major side effects. Hence, there is some dispute about whether it is better to immunize
regularly or to organize mass vaccination campaigns when the disease strikes.

Question 6. Due to recent media attention, there is public concern that yellow fever may spread
from this outbreak to the United States. Your supervisors would like you to address this issue.
Write a brief memo in response.

Yellow fever has a short incubation period of generally three to six days. However, it is usually
not lethal and can be misdiagnosed as a variety of different illnesses. It's easy to spread in
metropolitan areas, especially when there are a lot of mosquitos. With current air travel, a person
may contract this sickness in a city like Kaffrine, then board an airplane and be in any city in the
world the next day. With the reintroduction of Aedes aegypti mosquitoes in numerous cities
across the Western Hemisphere, conditions are more favorable than ever for outbreaks.
Despite this, the majority of the world's endemic regions are located between tropical areas of
Africa and Central and South America. So, while it's possible that this illness would spread from
Africa to the West and become endemic there, the chances of it reaching the United States are
small.
Problem 10: Yellow Fever in Senegal Page 5

*****************************************************************************
Table 1: Distribution of Yellow Fever Virus immunity before the outbreak, by villages

Confirmed Asymptomatic Total Probable Immune Before

Sites Samples Cases Cases Cases* Cases Outbreak**
Kaffrine Hospital 12 9 0 9 5 3
Dougounbene 167 16 21 37 4 100
Katiawane 78 4 12 16 9 50
Lanta 67 1 8 9 1 40
M’Bollop 42 1 9 10 9 27
Nianghene 83 0 19 19 0 51
Total 449 31 69 100 28 271

* Confirmed plus asymptomatic cases

** those who tested positive for IgG antibody to Yellow Fever Virus (YFV) and negative for IgM antibody
to YFV among the persons sampled

Table 2: Yellow Fever cases and Yellow Fever immunity before the outbreak, by age group

Immune before
Age (years) Samples outbreak* Yellow Fever Cases*
0-9 143 42 53
10-19 115 54 36
20 191 175 11
Total 449 271 100
* see Table 1

Figure 1: Map of Epidemic Region

Problem 10: Yellow Fever in Senegal Page 6

Background Material on ARBOVIRUSES

Read Heymann section on Arboviruses; Nelson Chapter 25 (not all sections relevant)

Additional Information
I. Vectors and Arboviruses
A. Some organisms require another living being to facilitate their spread from host to host.
This accomplice, called a vector, often is an insect. Frequently, the vector bites an
infected animal, human, etc. and ingests some of its blood. It then bites a second animal,
human, etc. and deposits some of the organism-infested blood from the first. Sometimes
insect vectors themselves are carried by other vectors. For example, rodents can directly
harbor pathogens, but they also can serve as the hosts for passage of fleas, ticks, etc. in
which the human pathogen resides. The same is true for snails. Thus, a host/victim's
contact with infecting organisms and vectors will be an important part of determining
whether it will become infected.
1. Arthropods are especially frequent vector carriers of organisms to humans
a. Bilaterally symmetrical invertebrates – segmented bodies, rigid exoskeleton, and
skeleton that is molted periodically, and several pairs of jointed appendages
b. One of the largest animal phyla, with more than a million described species and
estimates of 25 million undescribed ones

B. Arthropod-borne viruses (Arboviruses) – viruses that are maintained in nature through

biological transmission between susceptible vertebrate hosts by blood-feeding arthropods
(primarily mosquitoes and ticks).
1. Defined on an epidemiologic basis. Thus, any virus is an arbovirus if it multiplies in one
or more arthropods and if it is biologically transmitted to vertebrates with sufficient
frequency by the arthropods to make this an important means of virus survival.
Problem 10: Yellow Fever in Senegal Page 7
2. Epidemiologic classification of ALL viruses (Source: Blacklow chapter in Gorbach ID
textbook, 3rd Edition)
a. Enteric viruses – normally acquired by ingestion (fecal-oral route) and localize to the
intestinal tract
b. Respiratory viruses – usually acquired by inhalation or by fomites that are brought to
the respiratory tract (by hand to nose or hand to mouth or hand to eye, etc.), and
localize to the respiratory tract
c. Oncogenic viruses – acquired by close contact or injection and typically become
persistent and may progress to malignancy
d. Arboviruses (Arthropod-Borne) – replicate in arthropods that feed on the blood of
humans. Major infection problem in humans is meningitis and encephalitis.

C. All arboviral encephalitides are zoonotic, being maintained in complex life cycles
involving a nonhuman primary vertebrate host and a primary arthropod vector. These
cycles usually remain undetected until humans encroach on a natural focus, or the virus
escapes this focus via a secondary vector or vertebrate host as the result of some ecologic
change.

D. Many arboviruses have a variety of different vertebrate hosts and some are transmitted by
more than one vector (so modeling is complicated!)
1. The reservoir varies for many of the viruses; certain species of smaller vertebrates with
high population replacement rates, such as birds and rodents, generally serve as hosts. In
some instances, larger mammals can be involved. Reptiles, amphibians, and bats have
been suspected of serving as overwintering hosts for a few of these viruses.
2. Most of these viruses cause infections in animals, and humans are accidental hosts of no
particular importance in the maintenance of the virus or its natural history. About 100
arboviruses are known to infect humans and most of these are known to cause clinical
disease. Many of these are encountered in tropical and semitropical countries.
3. Where mobility of the patient is a requirement for transmission, (direct contact), it is to
the organism's benefit to keep the organism living as long as possible. By contrast,
vector-borne infections may be more virulent, as their need to keep their hosts alive may
be less pressing.
a. Example - arboviral infections represent dead-end variations not essential to the life
cycle - survival of the human is of no import to the organism, so adaptation to the host
is unimportant

E. The term arbovirus has no taxonomic significance. More than 300 different infectious
agents have been identified that fit this definition. Many have similar physical and
chemical properties and can be placed within families. Immunologic properties are used
to cluster the individual viruses
1. Antigenic relationships, morphology and replication mechanisms now are used to
classify the viruses into families and genera, of which Togaviruses (Alpha viruses) and
Flaviviruses are the best known and of greatest clinical importance.
Alpha viruses are mosquito-borne, while Flaviviruses may be carried not only by
mosquitoes but also by other arthropods (e.g., ticks, sandflies, gnats). The vector is
unknown at present for some of the arboviruses. Note that not all viruses in these
families are arboviruses.
2. Originally virus names were derived from the disease descriptions (e.g., dengue -
'breakbone fever", bluetongue, yellow fever). Later, geography in combination with
Problem 10: Yellow Fever in Senegal Page 8
disease syndrome was favored (e.g., Venezuelan equine encephalomyelitis, Colorado
tick fever, West Nile fever). Others were defined by their location of first discovery, as
no clinical syndromes were known for them at the time (e.g. Ross River)
Prominent today (Nelson pgs. 826-52)
 Dengue virus (see Wilder-Smith. Dengue. Lancet 2019);
 West Nile virus;
 Western Equine Encephalomyelitis virus; Eastern Equine Encephalomyelitis virus;
St. Louis Encephalitis virus; Murray Valley Encephalitis virus;
 Japanese B Encephalitis virus;
 Chikungunya virus (Wahid et al. IJID 2017);
 Yellow Fever Virus – see references below
 Zika virus – a recent arbovirus to cause epidemics (see Perspective by Fauci and
Morens, NEJM 2016;374:601-4).

F. Most of the arboviruses have been associated with less severe illness, perhaps fever alone
or fever with rash or fever and headache or fever and especially severe myalgia (e.g.,
dengue). These agents still can cause quite memorable clinical illness, even though they
are likely to resolve without sequelae. Likewise, some of the viruses that can cause
severe disease usually will cause milder symptoms, or perhaps none at all.
a. More attention usually is given to the viruses like Yellow Fever Virus that cause
relatively severe diseases: fevers associated with hemorrhage, frequently quite severe
and fatal; fever with infection or inflammation of the brain tissue (encephalitis),
which can be fatal as well; fever associated with inflammation of the meningeal
covering of the brain and spinal cord (meningitis), which is less often fatal).
b. Clinical syndromes produced by the arboviruses share the common features of fever
and muscle ache (myalgia). Beyond that, the same virus often causes a variety of
patterns in different patients. The situation is even more complicated because a wide
variety of viruses can cause the same clinical syndrome. Thus, clinical features are
not frequently useful in determining the likely etiology. Instead, epidemiologic
features and laboratory testing are the major means of recognition.

G. Specific diagnosis of arboviral disease depends on isolation of the virus (performed only
at a small number of specialized laboratories) or detection of immunologic response (the
more usual method used).
1. Materials for virus isolation should be kept chilled or frozen at temperatures of at least
-60 degrees C if shipment for testing involves shipment for great distances.
2. For many arboviruses, antibody (IgM) is often detectable by the end of the first week of
the infection and falls rapidly thereafter, so acute specimens of blood for serologic
testing should be obtained as early as possible after infection, to help demonstrate a rise
or fall in antibody titer between acute and convalescent specimens. Other types of
antibody (e.g., IgG) may persist for many years after the time that infection occurs.
The optimal method for serologic testing varies from virus to virus, although
hemagglutination inhibition (HI), complement fixation (CF), fluorescent antibody (FA),
enzyme linked immunosorbent assay (ELISA) methods have been employed frequently
(see Heymann and Nelson references above)
3. In many parts of the world malaria is the first thought in acute illness of the type
produced by arboviruses, and the ability to determine whether malaria is present is a
major factor in correct handling of epidemics in these geographic areas (although, of
course, both illnesses can occur at the same time in the same person).
Problem 10: Yellow Fever in Senegal Page 9

H. Control of Mosquito-Borne Infections

1) Personal protective measures - include reducing time outdoors wearing long pants and
long-sleeved shirts and applying mosquito repellent to exposed skin areas.
2) Public health measures to reduce the population of infected mosquitoes - often include
use of insecticides to kill juvenile (larvae) and adult mosquitoes, or eliminate breeding
grounds.

Yellow Fever (read Nelson pages 843-845, and relevant sections of Heymann)
The following web sites contain additional information about yellow fever:
http://www.cdc.gov/yellowfever/
http://www.who.int/mediacentre/factsheets/fs100/en/index.html
Recent review: Bifani et al. Curr Treat Options Infect Dis. July 2020

Yellow Fever is an acute infectious viral disease of short duration and varying severity.
Mild cases are characterized by sudden onset, fever, chills, headache, backache, generalized
muscle pain, nausea and vomiting. Moderate cases are characterized by jaundice, albuminuria
(protein in the urine), and leukopenia (low white blood cell count). Most infections resolve at
this stage. In severe cases, the disease manifests into hemorrhagic symptoms, including heavy
nose bleeding, gingival bleeding, hematemesis (vomiting blood), and can lead to liver and renal
failure. While 20-50% of all jaundiced cases are fatal, the overall case-fatality rate is generally
less than 5%. Outbreaks still occur – for example, Brazil 2016-2019: Figeurido et al. Viruses
2020; Angola 2015-2016: Grobbelaar et al. EID 2016.
The incubation period for Yellow Fever is generally three to six days. The blood of
infected persons is infectious before the onset of symptoms and for the first three to five days of
illness. Incubation period in A. aegypti is generally nine to twelve days. Once mosquitoes are
infectious, they remain so for life. Recovery from yellow fever is followed by lifelong
immunity. A vaccine for YFV is available, with antibodies appearing within 7 to 10 days of
immunization, and protection is considered to last for life (updated recommendations from the
previous guidance for a 10-year booster.)
Recent outbreaks in Angola and the Democratic Republic of the Congo led to shortages
of vaccine. A strategy to combat this shortage has been fractional dosing of vaccine—giving ½
or 1/5th of the usual dose, depending on the formulation of the vaccine. This is part of an
emergency response. The duration of protection when less than a full dose is administered is
unclear.
There are three epidemic patterns of YFV transmission. The first is sylvatic, or wild,
transmission. These epidemics only involve wild non-human vertebrates and vectors. The
second is urban transmission. Urban epidemics result from man-to-man transmission via the
domestic vector Aedes aegypti and occur within populated areas. The third pattern is
intermediate transmission. Intermediate epidemics are the most common in rural areas. They
consist of two successive phases: transmission by wild mosquitoes (A. furcifer, A. taylori, A.
luteocephalus) and relay by a domestic vector: A. aegypti, which in turn infects humans. Vertical
transmission also can occur.
Surveillance for yellow fever is conducted by national authorities - suspect cases are
identified and have a blood specimen taken. Initial laboratory confirmation is generally
accomplished by testing of serum for virus-specific IgM antibodies within countries where
facilities are available to conduct the test. However, specimens having an IgM-positive result at
national level are then to be forwarded to the Institute Pasteur in Dakar, Senegal, which serves as
the regional laboratory for confirmation of yellow fever diagnoses. This 2nd level of
Problem 10: Yellow Fever in Senegal Page 10
confirmation allows specimens to undergo a comprehensive testing algorithm including: 1.
Differential IgM serology for additional flaviviruses; 2. Plaque reduction neutralization testing
(PRNT); and 3. Virus isolation. Case definitions and the laboratory confirmation algorithm were
revised in 2010 in recognition of the fact that multiple flaviviruses (that is, dengue fever,
chikungunya [an Alphavirus], West Nile virus, Rift Valley fever [a Phlebovirus, family
Bunyaviridae], CCHF [a Nairovirus, family Bunyaviridae] co-circulate in yellow fever endemic
areas and pose diagnostic challenges for conventional IgM immunoassays due to serological
cross-reactivity.

For further reading:

 WHO has issued a plan for elimination of Yellow Fever--see Eliminate Yellow fever
Epidemics (EYE): a global strategy, 2017–2026. See:
https://apps.who.int/iris/bitstream/handle/10665/272408/9789241513661-eng.pdf

 Travelers returning to North America from endemic areas may bring YF with them – see
https://www.cdc.gov/mmwr/volumes/66/wr/mm6634a5.htm