This outline is intended to facilitate your preparation for lecture. This web outline will NOT substitute for
regular lecture attendance.
D. Diseases of the Respiratory Tract
System – upper versus lower
Main Diseases & Pathogens of Upper Respiratory Tract (URT)
Defenses of URT– very well defended - multiple defenses - chemical, immunological, and microbial.
Nose
Rhinitis
(cold)
100% viral
Rhinovirus
Coronavirus, Adenovirus
Throat
Pharyngitis
(sore throat)
70% viral
Adenovirus
EBV, Herpes, Coxsackie
S. pyogenes, C. diphtheriae, H. influenzae
30% bacterial
Main Diseases & Pathogens of Lower Resp. Tract (LRT)
Defenses of the LRT – defenses diminish with depth into the lower respiratory system - ciliated epithelial
cells, cough reflex, alveolar macrophages
Trachea
Whooping cough
Influenza
Bronchi
Acute bronchitis
Lungs
Acute infections
Pneumonia
Respiratory Distress
Chronic infections
Tuberculosis
bacterial
viral
Bordetella pertussis
Influenza virus
50% viral
50% bacterial
Adenovirus
Mycoplasma, S. pneumoniae, H. influenzae
bacterial
viral
viral
S. pneumoniae (a.k.a pneumonococcus)
Adenovirus, Influenza virus
Hantavirus, SARS
bacterial
fungal
M. tuberculosis
Aspergillus, Histoplasma
Example of an Acute Lower Respiratory Infection: Influenza
We will talk about:
1. seasonal flu
2. pandemic flu
3. avian flu
Disease - Influenza - “Flu” – for Influenza only, info in blue is what I expect you to master in this course,
rest of the info is to give you a more complete understanding of Influenza.
Agent - Influenza virus (Orthomyxoviridae); enveloped RNA virus
3 strains infect humans (arranged least to most significant)
 Influenza C - Common, but seldom causes disease symptoms
 Influenza B - Often causes sporadic outbreaks of illness, especially in residential communities like
nursing homes.
 Influenza A - Responsible for regular outbreaks, including pandemics. Influenza A viruses also infect
domestic animals (pigs, horses, chickens, ducks) and some wild birds, especially shorebirds and
waterfowl. Influenza A viruses, which cause more severe human illness, are further categorized into
subtypes on the basis of two surface antigens: hemagglutinin (H) and neuraminidase (N). Among all
Influenza viruses (human and animal) there are 14 major H proteins and 9 major N proteins forming
144 different combinations of H+N.
NOMENCLATURE – Influenza viruses are named in the following way
TYPE
of influenza
TOWN
where first
isolated
A
SINGAPORE
NUMBER
YEAR
of isolates of isolation
6
86
TYPE
of H and N
(H1N1)
Virulence
1. kills cells of the trachea (may result in secondary bacterial infections of the respiratory system - acute
ear infections and pneumonia, both due to Streptococcus pneumonia are the most common
complications of influenza infection)
2. makes a protein that inhibits the immune system
1. Seasonal Flu
Transmission
 via respiratory droplets released when an infected person coughs or sneezes.
 enters body thru mucous membranes of eyes, nose, mouth.
 binds to receptors on non-ciliated cells of the respiratory epithelium and then enters those cells via
receptor-mediated pinocytosis
 incubation 1-4 days, average = 2 days.
 contagious from 1 day prior to symptoms (before you know you are sick) and for another 5 days.
Clinical Picture
Uncomplicated influenza illness is characterized by the abrupt onset of constitutional and respiratory
signs and symptoms [Constitutional - fever, myalgia (= body aches), headache, malaise (= overall feeling
of unwell). Respiratory - nonproductive cough, sore throat, and rhinitis].
Influenza illness typically resolves after a limited number of days for the majority of persons, although
cough and malaise can persist for >2 weeks.
The risks for complications, hospitalizations, and deaths from influenza are higher among persons aged
>65 years, young children, and persons of any age with certain underlying health conditions.
Treatment
 Some few, specific anti-viral drugs:
Amantadine and Rimantadine - These drugs inhibit one of the viral matrix proteins that are used to get
viral RNA into the cytoplasm of the target cell. They work against A strains only and resistance to
these drugs evolves quickly.
Zanamivir (Relenza®) and Oseltamivir (Tamiflu®) - These drugs block the neuraminidase and thus
inhibit release of virus progeny from the infected cell. Spraying zanamivir into the nose or inhaling it
shortens the duration of disease symptoms by one to three days.
 Yearly flu vaccine (see below)
Frequency
20-50% of American population infected and 10-20% ill every year.
Morbidity and Mortality
In US, 114,000 hospitalizations (>57% in people under age 65) and ~40,000 deaths/year – due to
secondary bacterial infections and also primary influenza pneumonia, where the Influenza virus infects
cells of the lungs in addition to the trachea.
***Special topic of importance *** Why is it you can get influenza multiple times? (in theory you are
susceptible every year!)
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Influenza virus is an RNA virus and its genome is made up of 8 RNA segments (a segmented genome
is unusual).
During replication the RNA is copied into RNA by an RNA polymerase. RNA polymerase has no
proof-reading ability; it makes mistakes (i.e., produces mutations).
These mutations cause changes in the surface proteins (the H or the N).
Point mutations = a mutation in the RNA sequence caused by one wrong RNA nucleotide base in the
RNA sequence, will produce a slight, subtle alteration in the surface protein. Antibodies (specific to H
and N surface proteins) that your body produced to fight previous influenza infections do not recognize
these altered surface antigens very well, so your immune response is delayed, you become ill.
This gradual change in the surface protein over time is called antigenic drift  responsible for yearly,
seasonal epidemics.
There are several different types of influenza viruses circulating and different variants within virus types,
and the same type of flu virus does not necessarily circulate each year. A person's immunity to the surface
antigens reduces the likelihood of infection and severity of disease if infection occurs. If someone was
infected with the Fujian strain of Influenza A (H3N2) that predominated last season, they are likely to
have some natural immunity that will give them protection if they are exposed to the Fujian strain or a
closely related H3N2 strain again this season, but no or little immunity to an unrelated strain.
Frequent development of antigenic variants through antigenic drift is the basis for seasonal epidemics and
the reason for the usual incorporation of > 1 new strains in each year's influenza vaccine (see table next
page).
Composition of the Trivalent (= 3 flu strains) Vaccine Last 10 years
Season
H1N1
H3N2
Type B
01–02
A/New Caledonia/99
A/Panama/99
B/Victoria/00
02–03
A/New Caledonia/20/99
A/Moscow/10/99
B/Hong Kong/330/01
03–04
A/New Caledonia/20/99
A/Moscow/10/99
B/Hong Kong/330/01
04–05
A/New Caledonia/20/99
A/Fujian/411/02
B/Shanghai/36/02
05–06
A/New Caledonia/20/99
A/California/7/04
B/Jiangsu/10/03
06-07
A/New Caledonia/20/99
A/Wisconsin//6705
B/Malaysia/2506/04
Influenza A/New Caledonia/99 was discovered and characterized by former CMU student Luke
Daum, who now owns his own company called Longhorn Vaccines and Diagnostics. He is an
international expert on Influenza.
07-08
A/Solomon Islands/3/26
A/Wisconsin/67/05
B/Malaysia/2506/04
08-09
A/Brisbane/59/07
A/Brisbane/10/07
B/Florida/4/06
09-10
A/Brisbane/59/07
A/Brisbane/10/07
B/Brisbane/60/08
10-11
A/California/7/09
A/Perth/16/09
B/Brisbane/60/08
A/California/7/2009 (H1N1) is the pandemic strain that the media called “swine flu”.
The World Health Organization began in February to hold meetings as to what the composition of the
2011-2012 vaccine will be.
FluMist®
On 17 June 2003, the U. S. Food and Drug Administration (FDA) approved FluMist® – a live-virus
vaccine that is given as a spray up the nose.
2. Pandemic Flu
Flu illness that occurs worldwide is referred to as pandemic flu. Pandemic flu occurs when the human
population has no or limited immunity to an influenza virus because either the H or N surface protein is
entirely new. Pandemic strains of influenza are created by a genetic event referred to as recombination.
Recombination - Two different Influenza strains with different H and N antigens co-infect the exact same
host cell. During packaging of viral progeny, the 2 strains will exchange an entire segment of RNA, which
will result in a tremendous change in the surface protein. This abrupt change in surface protein is called
antigenic shift responsible for pandemics
Recent flu pandemics
Year
1580
1874
1889-90
1900
1918-20
1933
1940
1957-58
1968-69
1976-77
2009
HN type
Strain
(H3N8)
(H2N2)
(H3N8)
(H1N1)
(H2N2)
(H3N2)
(H1N1)
(H1N1)
Name of pandemic
first Influenza pandemic of recorded history
Asiatic (Russian) Flu pandemic
A/Singapore/57
A/Aichi/68
A/New Jersey/76
A/California/09
”Spanish” Flu pandemic
Influenza viruses were finally discovered
US military began the first Influenza vaccinations
"Asian" Flu pandemic
"Hong Kong" Flu pandemic
"Swine" Flu – turned out to be a false scare
3,900 deaths in U.S. in 1st 6 months.
Since 1977, Influenza A (H1N1) and Influenza A (H3N2) viruses have been in global co-circulation. In
2002, Influenza A (H1N2) viruses that probably emerged after genetic recombination between (H3N2)
and (H1N1), viruses began circulating widely, causing an increase in morbidity and mortality but not a
true pandemic.
3. Avian Influenza (= Bird Flu)
Bird flu is caused by avian influenza viruses. These flu viruses occur naturally among birds. Wild birds
worldwide carry the viruses in their intestines, and among birds the virus is transmitted in the feces, but
avian influenza is usually not fatal to wild birds. However, it is very contagious among birds and can
make some domesticated birds (chickens, ducks, and turkeys) very sick and kill them.
The risk from bird flu is generally low to most people because the viruses occur mainly among birds and
do not usually infect humans. However, during an outbreak of bird flu among poultry (domesticated
chicken, ducks, turkeys), there is a possible risk to people who have contact with infected birds or
surfaces that have been contaminated with excretions from infected birds.
Several cases of human infection with bird flu viruses have occurred since 1997, the most recent outbreak
began in 2003. In October 2003, an epidemic of influenza in chickens began sweeping through several
countries in the Pacific Rim (Vietnam, Thailand, Japan, China, South Korea, Cambodia). The virus is
H5N1. The H5 molecule is common among bird influenza viruses but has not been seen on flu viruses
that cause human epidemics. As a glance at the tables above will show, humans have had long experience
with infections and vaccines by both H1 and H3 flu viruses. But the human population has absolutely no
immunity against any H5 viruses.
Clinical Picture - Symptoms of avian influenza in humans have ranged from typical human influenza-like
symptoms (fever, cough, sore throat, and muscle aches) to eye infections, pneumonia, severe respiratory
diseases (such as acute respiratory distress syndrome), and other severe and life-threatening
complications.
Mortality - currently 63%
Prevention – currently no approved human vaccine although one is in trials and has been found to be
partially protective.
Why are we worried about H5N1? – because of the risk that the virus – if given enough opportunities –
will change into a form that is highly infectious for humans and spreads easily from person to person
causing a pandemic.
Class vote Disease - SARS = Severe Acute Respiratory Syndrome
SARS is a newly emerged disease that was first reported in Asia in February 2003. Over the next few
months, the illness spread to more than two dozen countries in North America, South America, Europe,
and Asia before the SARS global outbreak of 2003 was contained.
Agent - SARS-associated coronavirus (SARS-CoV), a newly evolved Coronavirus.
Transmission - The main way that SARS seems to spread is by close person-to-person contact. The virus
that causes SARS is thought to be transmitted most readily by respiratory droplets (droplet spread)
produced when an infected person coughs or sneezes. Droplet spread can happen when droplets from the
cough or sneeze of an infected person are propelled a short distance (generally up to 3 feet) through the
air and deposited on the mucous membranes of the mouth, nose, or eyes of persons who are nearby. The
virus also can spread when a person touches a surface or object contaminated with infectious droplets and
then touches his or her mouth, nose, or eye(s). In addition, it is possible that the SARS virus might spread
more broadly through the air (airborne spread) or by other ways that are not now known.
Clinical Picture - SARS begins with a high fever (temperature greater than 100.4°F [>38.0°C]). Other
symptoms may include headache, an overall feeling of discomfort, and body aches. Some people also
have mild respiratory symptoms at the outset. About 10-20% of patients have diarrhea. After 2 - 7 days,
SARS patients may develop a dry cough. Most patients develop acute respiratory distress.
Treatment - The treatment of coronavirus-associated SARS has been evolving and so far there is no
consensus on an optimal regimen.
Mortality - A total of 8,098 people worldwide became sick with SARS during the 2003 outbreak. Of
these, 774 died (= 9.6%). In the United States, only eight people had laboratory evidence of SARS-CoV
infection and there were no deaths.
There is no known transmission of SARS anywhere in the world. The most recent case was in China in
April, 2004. However, SARS is not declared eradicated and is present in its natural animal reservoirs and
has the potential to return to the human population in the future.
FYI - Example of a Chronic Lower Respiratory Infection
Disease – Tuberculosis (TB)
 Ancient disease of humans
 The bacteria usually attack the lungs. But, TB bacteria can attack any part of the body such as the
kidney, spine, and brain.
 Today, one of leading infectious killers world wide
 The leading cause of death in women
 Orphans more children than any other infectious disease
Agent - Mycobacterium tuberculosis (GPR, obligate aerobe, obligate pathogen, very slow growing).
Virulence factors – none – provokes an ineffective and inappropriate and harmful immune response.
Transmission
 only people with active, clinical cases are infectious.
 via respiratory droplets when infectious people cough, sneeze, talk or spit.
 present is smallest respiratory droplets
 inhaled directly into lungs
Clinical picture
Slow progression, gradual loss of lung function, “consumption”.
Case History
A 23-year-old female college student presents to the Student Health Services with a three-month history
of fatigue, weight loss, fever, and night sweats. She has a cough that is worsening and has recently
produced blood-stained sputum.
Examination
On examination she is thin. Her temperature is 37.8C, and she is dyspnoeic at rest. Chest auscultation is
consistent with right apical consolidation.
Chest radiograph
Right apical shadowing
Diagnosis of TB
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skin test
x-ray
acid-fast stain of sputum
Treatment
Very long term antibiotic therapy
Frequency
 1/3 of the world pop. is infected; someone in the world is newly infected every second. Left
untreated, each person with active TB disease will infect between 10 and 15 people a year.
 5-10% of people who are infected with TB (but who are not infected with HIV) become sick or
infectious at some time during their life.
 2 mil. deaths/yr
 10 -15 mil. U.S. infected, about 10,000 new infections/yr.
Prevention
avoid exposure to infectious persons. Prophylactic antibiotic therapy.
HIV and TB
HIV and TB form a lethal combination, each speeding the other's progress. HIV weakens the immune
system. Someone who is HIV-positive and infected with TB is many times more likely to become sick
with TB than someone infected with TB who is HIV-negative. TB is a leading cause of death among
people who are HIV-positive. It accounts for about 13% of AIDS deaths worldwide. In Africa, HIV is the
single most important factor determining the increased incidence of TB in the past 10 years.
FYI diseases of Upper Respiratory Tract
1. Strep throat = streptococcal pharyngitis
 Streptococcus pyogenes
 Transmitted in respiratory droplets
 Enters thru the oropharynx (mouth/throat)
 Infects mucosa of oropahrynx
Clinical Picture
Txt
Penicillin (oral for 10 days)
Resistance to erythromycin & tetracycline is increasing
During winter months up to 16% of school children carry S. pyogenes
Goals of treatment
1. Hasten recovery
2. Prevent spread
3. Prevent complications
Complications
1. Peritonsillar abscesses
2. Ear and sinus infections
3. Scarlet fever (toxin encoded by lysogenic phage – but a different lysogenic phage than that responsible for
flesh-eating strep)
4. Acute Rheumatic Fever (ARF)
5. Rheumatic heart disease
6. Acute Glomerulonephritis (AGN)
Treatment failure
70% stop by 6 days
80% stop by 9 days
2. Infectious mononucleosis = mono = kissing disease
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Epstein-Barr Virus (EBV) – Herpesvirus, member of the Herpesviridae family.
Persistent (permanent) infection
Is transmitted in saliva
Enters thru the oropharynx (mouth/throat)
Infects the cells of the salivary glands
Also infects epithelial cells and white blood cells (WBC = immune cells)
Causes inflammation of lymphatic tissue