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The Most Common Illness: A Review and Case Study from Harvard Medical School

Harvard Medical Student Review Vol. 2 (Issue 1), pp. 5-18.
The Most Common Illness: A Review and Case Study from Harvard Medical School
J Bradley Segal1,*
1 Harvard Medical School, Boston, MA 02115, USA
Case Study
In August and September of 2014, there was an outbreak
of an acute respiratory infection (ARI) among the first
and second year students at Harvard Medical School and
Harvard School of Dental Medicine. Out of 400
students, 74% (296) completed an anonymous
retrospective survey concerning their recent health. Of
the respondents, 34% of second year (57 of 167) and 25%
of first year (33 of 129) students reported experiencing
an acute illness over the preceding month. 94% (278 of
296) of the recently ill students reported experiencing
one or several ARI symptoms, including nasal
congestion, cough, sore throat, and nasal discharge.
Incidence data were compiled from self-reported dates of
when respondents first began feeling ill (Figure 1).
Behaviors Associated with Infection
The survey also asked respondents five questions
concerning recent social behaviors. Relative risks of
becoming ill were calculated for these dichotomous
behavioral variables, both as a complete cohort and after
stratifying the respondents based on class year (Table 1).
Among both classes, the only two risk factors found to
be significantly associated with becoming ill were
recently going to a party or bar with classmates (RR
1.45, 95% CI 1.000 to 2.104, p = 0.0497) and frequently
or always studying with classmates (RR 1.48, 95% CI
1.010 to 2.188, p = 0.0444). None of the other behaviors
queried significantly altered the risk of contracting an
acute illness.
Kermack and McKendrick’s compartmental
epidemiological model was used to calculate the basic
reproduction number R0 for the outbreak under the
assumption that ill medical students were infected by
their classmates (Kermack and McKendrick, 1991). For
the combined classes, R0 was calculated to be 3.5,
indicating that the average ill student infected 3.5 of his
or her classmates. By way of comparison, estimated R0
for other infectious diseases include 2.7 for the 1918
A/H1N1 influenza pandemic (Mills et al., 2004), 1.5 for
the 2009 H1N1 pandemic (Yang et al., 2009; Fraser et
al, 2009), 3.6 for the 2003 SARS outbreak (Wallinga and
Teunis, 2004), and 1.732.02 for the 2014 Ebola virus
epidemic (WHO Ebola Response Team, 2014).
Behavioral Model of Disease Transmission
The probability of illness transmission is proportional to
the product of the number of contact events sufficient
for transmission between individuals and the per-event
likelihood of transmission. Kermack and McKendrick’s
compartmental model treats populations as homogenous
and combines these two factors into a single parameter
that represents the transmission rate across the
population. This approach is useful for large populations
where following individual interactions are impractical
or when no information on social network structure is
available. While this model can predict the total number
of individuals who will be ill at a given time, it neither
gives any information on how illnesses are dispersed
among subsets of the population norprovides the
opportunity to use behavioral data to predict
This study had both a small population and limited
behavioral data. These allowed for the construction of a
discrete-time Markov model of disease transmission
through the class, wherein probability of a transmission
event between any pair of students was proportional to
the behavioral similarity of the pair. Ideally, such a
behavioral model has the advantages of allowing a better
prediction of the spread of disease prospectively and an
understanding of the specific social interactions that
promote disease transmission retrospectively.
Unfortunately, in the current study, the model informed
Synopsis: The average adult experiences two to five common colds each year. Summed up, people spend more
than a year of life suffering from the illness. This article presents a brief report from an outbreak at Harvard
Medical School followed by a review of what is currently known about the common cold. An emphasis is
placed on illustrative experiments. Despite decades of research, hand washing remains the best method for
preventing infection.
Harvard Medical Student Review Vol. 2 (Issue 1), pp. 5-18.
Figure 1. Incidence from Outbreak at Harvard Medical School
Among the 296 respondents to a retrospective survey, 90 students (30%) reported symptoms of an acute illness over a month-long period.
34% of second-year (57 of 167) and 25% of first-year (33 of 129) medical and dental students reported experiencing an acute illness over
the previous month.
Table 1. The Relative Risks of Contracting an Acute Illness from Various Dichotomous Behaviors
Data were calculated from anonymous surveys to medical and dental students, and relative risks calculated for first- and second-year
classes, as well as in total. Among both classes, going to a bar or party with classmates in the last week and studying with classmates
some or all of the time significantly increased the risk of contracting the illness. For both classes, living in the medical school dorm,
spending more than 30 min a day in the medical education building, or regularly attending lecture did not significantly alter the risk of
becoming ill.
Harvard Medical Student Review Vol. 2 (Issue 1), pp. 5-18.
by social behavior did not predict the spread of illness
any better than Kermack and McKendrick’s
compartmental model. This is likely because the
behavioral survey lacked the granularity to adequately
capture pairwise social interactions. The behavioral
variance calculated from survey responses was small
across the population, and students who reported similar
behaviors may not have preferentially interacted with
one another. In future studies, capturing data more
descriptive of pairwise interactionsfor example, via
construction of a social network wherein network
distances are taken to be the probability of interaction
sufficient for transmissionmay allow this method to be
used to build an informative model of disease spread in
a small population.
Other Considerations
The magnitude of this outbreak was larger than would
be expected based on prior studies of ARI’s among small
communities in relative isolation (Warshauer et al.,
1989; Flynn et al., 1977). The identification of a
pathogen is not required to diagnose the common cold,
but it is possible that the pathogens responsible for this
outbreak were heterogeneous in nature (Heikkinen and
Jarvinen, 2003). While informal studies such as this
may intuitively seem as if they can inform medical
students who wish to avoid catching a cold during the
school year, classic and contemporary research has
unraveled more profound insights into common cold
pathogenesis, transmission, and prevention
How Common is the Cold?
Cohorts of medical students have or likely will
experience occasions when a mysterious ARI rapidly
sweeps through their flu-vaccinated class. The common
cold is a mild ARI characterized by some combination of
malaise, rhinorrhea (nasal discharge), nasal congestion,
headache, cough, sneezing, sore throat, and low-grade
fever (Jackson et al., 1958). While the cold is
unfortunately considered “low yield” for USMLE Step 1
purposes, respiratory infections are the most common
cause of illness in industrialized countries (Denny, 1995)
and are likely the most common cause of illness
worldwide (Papadopoulos, 1999). Adults have two to five
colds per year, totaling in a lifetime to over a year spent
with the disease (Papadopoulos, 1999; Johnston et al.,
1996). Twenty-five million patients in the US visit the
doctor with an ARI chief complaint every year, resulting
in $726 million spent on unnecessary antibiotic
prescriptions (Gonzales et al., 2001). One study found
that 76% of elderly patients with viral common colds
were prescribed antibiotics (Nicholson et al., 1996). The
500 million domestic cases of non-influenza ARI’s
directly cost the US healthcare system $17 billion
annually (Fendrick et al., 2003). By comparison,
influenza has a direct medical cost of $10.4 billion
annually (Molinari et al., 2007). The cold is a significant
source of lost productivity as well (Molinari et al., 2007),
causing adults in the US to miss 20 million days of work
annually (Adams et al., 1996), with indirect costs of
$22.5 billion (Fendrick et al., 2003).
Relevance to Doctors in Training
Given the absence of effective treatments or means of
diagnosis, the common cold remains pertinent to
medical students because unintentionally transmitting
an ARI to any of several vulnerable patient populations
with whom medical students interact can significantly
raise a patient’s risk of death (Meibalane et al., 1977;
Strausbaugh et al., 2003; Malavaud et al., 2001;
Horcajada et al., 2003; Dolan et al., 2012). Infection
with the cold can cause asthma and chronic obstructive
pulmonary disease (COPD) exacerbation, frequently
leading to hospitalization (Nicholson et al., 1993; Mallia
et al., 2011; Teichtahl et al., 1997). For
immunocompromised individuals, the cold can mean
serious complications and possibly death (Ghosh et al.,
1999). Even among elderly patients, a cold lasts twice as
long, has more severe symptoms, and has double the
risk of a lower airway complication such as pneumonia
(Nicholson et al., 1996, 1997).
Despite the prevalence and economic impact of the
disease, the common cold is not proportionally
emphasized in medical education. An understanding of
the cold is needed to refrain from prescribing patient’s
unindicted antibiotics, and, in lieu of effective
treatments, medical providers should know the proven
preventative measures. By understanding the
fundamental features of common cold transmission,
medical students can significantly lower the chances that
they spread the infection (Jefferson et al., 2011). Such an
understanding will contextualize asthmatic and COPD
patients who present in the emergency room short of
breath following an otherwise-harmless cold (Teichtahl
et al., 1997). By learning about the cold, a prudent
student can also minimize his or her own productivity
lost to illness as well. Finally, insights into mankind’s
most common infection can help one understand and
contextualize more malicious infectious diseases.
Viral Distribution
The common cold does not have a single cause. Rather,
the cold is caused by a host of viruses with strikingly
diverse phylogenetics (Figure 2). Across all age groups,
the most common cause of the cold is the rhinovirus,
accounting for around half of common cold infections
(Monto and Sullivan, 1993). The rhinovirus displays
season-dependent transmission, and during its peak in
autumn, the pathogen causes up to 80% of colds (Arruda
Harvard Medical Student Review Vol. 2 (Issue 1), pp. 5-18.
et al., 1997). Together the coronaviruses, respiratory
syncytial viruses (RSVs), and parainfluenza viruses,
adenoviruses and enteroviruses account for around 35%
of colds (Fendrick et al., 2003). Influenza viruses cause
around 5%15% of colds. Because the common cold is
defined on the basis of its clinical presentation, a mild
influenza infection can accurately be diagnosed as a
cold, meaning that the two infections are not completely
distinct disease entities (Heikkinen and Jarvinen, 2003).
It is suspected that yet-unidentified viruses explain the
remaining 20%30% of the cases of the cold. For
example human metapneumovirus has a worldwide
distribution but was only discovered in children with
the cold in 2001 (van den Hoogen et al., 2001).
Rhinovirus and ICAM-1
As rhinovirus is the most frequent cause of the common
cold (Monto and Sullivan, 1993), the pathogen will be
the primary focus of this review The rhinovirus infects
epithelial cells of the nasopharynx. Viral particles gain
access to the epithelium by the mouth or nose or from
eyes via the lacrimal duct (Hendley, 1999). The eyes and
nose are the most common routes of inoculation
(Hendley et al., 1973). It is known neither how the
rhinovirus gains direct access to cells within the nasal
mucosa nor if the rhinovirus can infiltrate an intact
mucosal membrane (Winther, 2011). 90% of rhinovirus
serotypes enter epithelial cells in the nasopharynx after
binding the surface protein ICAM-1 (Greve et al., 1989).
This receptor is selectively expressed by certain
epithelial cells, with a high concentration among non-
ciliated epithelial cells of the nasopharyngeal tonsil
(adenoid) (Teichtahl et al., 1997). Successful rhinovirus
infection leads to an upregulation of ICAM-1 and
downregulation of an endogenous decoy ICAM-1,
thereby enhancing the viruses’ infectivity (Whiteman et
al., 2003). Rhinovirus can spread from a simple ARI and
infect epithelial cells in the lower airway as well
(Papadopoulos et al., 2000). Subsets of epithelial cells in
the lower airway also express ICAM-1, though at a lower
density than in the upper airway (Mosser et al., 2002).
The optimal temperature for rhinovirus replication is
33°C35°C (Hayden, 2004). In healthy adults, the
nasopharynx temperature is usually 34°C (Keck et al.,
2000). Despite being deeper in the body, areas of the
lower respiratory tract fall within rhinoviruses’
replication range as well. For example, the carina is
33.2°C during normal breathing (Hayden, 2004). Among
infants, rhinovirus is the second most common cause of
pneumonia and bronchiolitis, largely due to its ability to
infect the lower airway (Hayden, 2004).
ICAM-1, Asthma, and Clinical Symptoms
Epithelial ICAM-1 expression is upregulated following
inflammation and mediates subsequent neutrophil
migration (Vejlsgaard et al., 1989; Smith et al., 1988). As
asthma is a disease characterized in part by bronchial
inflammation, patients with asthma tend to have basally
elevated ICAM-1 expression levels in the lower airways
(Wegner et al., 1990). This potentially explains the
strong association between cold infections and acute
asthma exacerbations. Rhinovirus infections in asthma
patients are known to cause morbidity and sometimes
mortality (Johnston et al., 1996). It is estimated that
between 50%80% of asthmatic exacerbations are caused
by the cold (Johnston et al., 1995, 1996). One study
found that 37% of patients who required hospitalization
for an acute asthma attack had a viral ARI (Teichtahl et
al., 1997). Hospital admission is for asthma patients the
strongest predictor of 12-month mortality (Crane et al.,
1992). A laboratory infection of 13 non-asthmatic
volunteers with COPD showed that rhinovirus infection
leads to COPD exacerbation and lower respiratory
symptoms, though the role of ICAM-1 in these patients
is less clear (Mallia et al., 2011).
Interestingly, 25% of patients infected with a cold-
associated virus remain clinically asymptomatic
(Gwaltney and Hayden, 1992). Adults are more likely to
remain asymptomatic during an infection than children
(Peltola et al., 2008). Children also have more severe
colds. Among children, 70% have colds that last at least
10 days (Pappas et al., 2008), as opposed to only 20% of
adults (Gwaltney et al., 1967). It has been proposed that
acquired immunity and variations in ICAM-1 expression
with age may explain why some individuals have active
Caused by Each Type of Virus
The cold is caused by a diverse arrangement of viruses.
Approximately one out of four common colds have an unknown
cause, and there are likely still undiscovered viral pathogens (van
den Hoogen et al., 2001). The numbers shown above change
throughout the year as most of the viruses associated with the
common cold display seasonality. For example in the autumn, the
100 serotypes of the rhinovirus can cause up to 80% of common
colds (Arruda et al., 1997). Data adapted from Heikkinen and
Jarvinen (2003).
Harvard Medical Student Review Vol. 2 (Issue 1), pp. 5-18.
viral infections but remain asymptomatic (Peltola et al.,
2008). One study found that polymorphisms of ICAM-1
were associated with varying susceptibility to common
cold illnesses (Nieters et al., 2001). However, common
cold cases in this study were self-reported, and it is
unclear if individuals with “protective” ICAM-1
genotypes were more likely to resist initial infection of
epithelial cells or if infected individuals were more
likely to remain asymptomatic. Still, ICAM-1 remains a
promising target for future research aimed at preventing
rhinovirus infection.
Clinical Presentation
Because of the variation in clinical symptoms that
patients with a common cold experience, it has not been
possible to develop a pathognomic characterization of
the disease (Eccles, 2005). Diagnosis is made clinically
from reported symptoms with good reliability
(Heikkinen and Jarvinen, 2003). Nine out of ten
patients who diagnose themselves with the cold are
found to have an identifiable virus (Arruda et al., 1997).
Experimentally, there are eight classic symptoms of the
cold: sneezing, malaise, headache, chilliness, nasal
discharge, nasal obstruction, cough, and sore throat
(Jackson et al., 1958). Not all of these are present in
every patient with a cold, and a physical exam may
sometimes reveal conjunctiva injection (bloodshot eyes)
and pharyngeal erythema
Time Course of Symptom Progression
Clinical symptoms tend to occur at overlapping but
consistent time points during the course of an illness
(Figure 3). Though incubation period depends to a large
extent on the type of virus causing the cold (Bradburne
et al., 1967), patients usually begin experiencing their
first symptoms 2472 hr after exposure (Heikkinen and
Jarvinen, 2003). Classically, patients experience a sore
throat 1 to 2 days after exposure, and the percent of
patients experiencing a sore throat quickly dissipates
after day 2 (Tyrrell et al., 1993). Patients then experience
nasal discharge and obstruction between days 2 and 5,
which gives way to cough by about day 6 post-exposure
(Jackson et al., 1958; Tyrrell et al., 1993). On average,
symptoms in healthy adults tend to spontaneously
resolve after 710 days, with the cough generally being
the last symptom to resolve (Heikkinen and Jarvinen,
In contrast, symptoms in elderly patients can take twice
as long to resolve (median 16 days), and the risk of lower
airway involvement is doubled (Nicholson et al., 1996).
Children have the cold for longer as well, with most
cases lasting at least 10 days (Pappas et al., 2008).
Children also tend to have slightly different
symptomatic progression than adults. One study found
88% of children with the cold experienced nasal
congestion and 75% nasal discharge on day 3 of illness
which is similar but more prevalent than in adultsbut
with cough peaking earlier on day 2 and remaining in
half of children through day 8 of illness (Pappas et al.,
Pathogen Identification
When narrowing down a differential diagnosis, the cold
can be distinguished from similar illnesses on a clinical
basis. Simple rhinitis will not present with a sore throat
or cough, and bacterial tonsillitis will not present with a
runny nose or nasal obstruction
diagnosis-and-clinical-features). The cold rarely presents with
a high fever, the presence of which along with cold-like
symptoms is suggestive of the flu. During periods of
high flu activity, the CDC recommends that patients
with this clinical presentation be rapidly triaged to
minimize potential influenza exposure to healthcare
workers and other patients
ettings.htm). Pertussis may initially present as a common
cold would, but coughing will persist for more than 2
weeks, and there may also be apnea or vomiting present
Both the common cold and acute bacterial rhinosinusitis
can present with purulent nasal discharge (thick,
colored) (Wald et al., 1991). Sputum color is indicative of
an inflammatory response but not of any specific
pathogen (Eccles, 2005). Hence when clinically assessing
an ARI, sputum color is a poor prognostic tool for
determining whether antibiotics ought to be prescribed
(Murray et al., 2000). Antibiotic treatment is indicated
when a clinical diagnosis of acute bacterial
rhinosinusitis is made on the basis of severe maxillary
pain in the face or teeth, particularly if the pain is
unilateral, and fever, or rhinosinusitis symptoms and
maxillary pain lasting more than 7 days (Hickner et al.,
2001). However the majority of acute rhinosinusitis cases
that last fewer than 7 days will resolve spontaneously,
and antibiotics ought to be withheld (Hickner et al.,
While the cold-associated viruses can be individually
identified using PCR assays, because the infection is
typically benign and self-limiting, such identification is
not medically indicated. Each family of viruses has
slight variations in its presentation and pathogenesis.
For example, one study found that 40% of patients with
PCR-confirmed rhinovirus infections initially presented
with a sore throat, but only 25% of rhinovirus-negative
patients had this initial presentation (Arruda et al.,
1997). However, accurately differentiating the common
Harvard Medical Student Review Vol. 2 (Issue 1), pp. 5-18.
cold-associated viruses on a clinical basis alone is not
possible (Nicholson et al., 1997; Arruda et al., 1997;
Kirkpatrick, 1996).
Role of the Immune Response
The rhinoviruses do not directly cause observable
damage to host tissue (Winther et al., 1984a, 1986). The
only observable change under histology is an increased
number of polymorphonuclear leukocytes in the nasal
mucosa following infection (Winther et al., 1984b).
Because epithelial cells are left unscathed, it is believed
that cold symptoms are caused completely or to a
significant extent by an immune response and are not a
direct result of viral pathogenesis (Hendley, 1999). The
immune response, mediated by signaling molecules
released directly or indirection from infected epithelial
cells, results in bradykinin release, which is associated
with increased vascular permeability of the venous
sinuses, thereby causing the cold’s hallmark symptoms
of nasal discharge and congestion (Proud et al., 1990).
Applying bradykinin in the noses of healthy volunteers
mimics these symptoms of the cold (Proud et al., 1988)
and occurs in a dose-dependent fashion (Doyle et al.,
1990). A handful of other pro-inflammatory cytokines
and chemokines explain the other common cold
symptoms such as sneezing, headache, fever, and
malaise (Kirchberger et al., 2007). The culpability of the
immune response in causing the common cold
symptoms have earned it the nickname the, “cytokine
disease” (Kirchberger et al., 2007).
Because the inflammatory response to the cold causes
infected epithelial cells to undergo apoptosis and
subsequent extrusion, it has been proposed that the
immune response limits local viral spread (Winther,
2011). Hence, a therapeutic intervention that restricts
the immune response for the purposes of symptom
suppression may theoretically exacerbate an infection or
prolong viral shedding
infections). However, this remains incompletely
understoodfor unknown reasons, application of nitric
oxide both tapers the immune response to a cold and
results in faster rhinovirus clearance (Proud, 2005). This
Figure 3. Clinical Symptoms of the Cold Tend to Change over the Course of the Illness
The symptoms of the cold tend to present and resolve in a predictable pattern. Often an ill-defined headache and malaise are the first symptoms
patients notice. Most patients experience a sore throat by day 2 post-exposure. This gives way to nasal discharge and nasal obstruction. A cough
is usually the last symptom to appear and often persists past the resolution of the other symptoms to around day 7 to 10 post-exposure (data not
shown; Heikkinen and Jarvinen, 2003). Diagnostically this information has limited utility because the exact clinical course differs for every
patient (Kirkpatrick, 1996). Results adapted from Jackson et al. (1958).
Harvard Medical Student Review Vol. 2 (Issue 1), pp. 5-18.
is an area of research that may yield new therapeutic
targets for common cold treatment.
The Cold in Immunocompromised Patients
Studies of the common cold among patients with
impaired immune systems allude to the complexity of
the immune system’s role in rhinovirus infection. In one
study of 22 severely myelosuppressed,
immunocompromised adults who contracted rhinovirus,
33% of the patients developed a fatal pneumonia at an
average of 12 days after the onset of cold symptoms
(Ghosh et al., 1999). A more recent study found similar
rates of rhinovirus pneumonia among
immunosuppressed patients (Jacobs et al., 2013). While
60% of these patients also had a bacterial, viral or fungal
co-infection, rhinovirus was the sole detectable pathogen
in 40% of the patients with pneumonia (Jacobs et al.,
2013). In a study of the first 100 days after hematopoietic
cell transplantation, immunosuppressed patients did
become symptomatic following rhinovirus or coronavirus
infection (Milano et al., 2010). Of these, around 15% of
patients continued to shed virus for 3 months or more,
but 13% of patients had detectable viral particles and
never reported developing clinical symptoms. Another
small prospective surveillance study following
hematopoietic cell transplantation found that pediatric
patients with a rhinovirus infection were more likely to
remain asymptomatic and shed viral particles then
develop clinical symptoms (Srinivasan et al., 2013). Two
patients in this study asymptomatically shed rhinovirus
for 14 and 34 days before developing symptoms. Another
study found that among immunosuppressed adult lung
transplant recipients, higher rhinovirus titer was
associated with clinical symptoms of the cold, while
patients with lower viral loads had clinical symptoms far
less frequently (Gerna et al., 2009).
There are limited data on common cold infections
among immunocompromised individuals, but the
available studies demonstrate that an intact immune
system is required to minimize the risk of morbidity and
mortality from the cold. Interestingly,
immunocompromised patients can still show the signs
and symptoms characteristic of an immune response to a
cold infection. These patients may not be any more
likely to remain asymptomatic than healthy adults with
active rhinovirus infections (Gwaltney and Hayden,
1992; Peltola et al., 2008), but in some
immunocompromised individuals there is a prolonged
latent asymptotic phase before the patients mount an
immune response. It can also take months for these
patients to successfully extinguish a cold infection.
Hand Contact and Fomites
The classic means by which the cold is transmitted is
self-inoculation from a healthy individual’s own
fingertips (Hendley et al., 1973). Usually a person will
contaminate his or her fingers and spread the virus by
touching his or her own eyes or nose, which gives the
virus access to the nasal mucosa (see “Causes” above).
Cold viruses find their way onto hands from either
direct contact with someone actively shedding the
virussuch as a handshakeor indirectly from contact
with an infected environmental surface. A study using
PCR in hotel rooms found that ill individuals shed viral
particles on 33%60% of commonly touched fomites like
door handles, TV remotes, and light switches (Winther
et al., 2007). Rhinoviruses can survive on environmental
surfaces for several hours (Gwaltney et al., 1982). Even
though viral titer drops by an order of magnitude when
a droplet containing active virus dries out, viral traces
that are undetectable via tissue culture can still cause an
infection (Winther, 2011).
One study in a pediatric ward found that wearing plastic
goggles that covered the eyes and nose when holding
infants with an ARI decreased infections by 43% among
infants and 34% among healthcare workers (Gala et al.,
1986). Another study found that 0 of 14 adult
participants seated near but physically separated from
infants with RSVs became ill, 4 of 10 adults who
touched the infants became ill, and 5 of 7 adults who
held and played with the infants fell ill (Hall et al.,
1981). These results reinforce the conclusion that when
caring for someone with the cold, preventing self-
inoculation from hand-eye or hand-nose contact is
essential for avoiding infection of oneself and others.
Saliva is a poor conduit for viral transmission90% of
people with a cold have undetectable levels of virus in
their mouth (Kirkpatrick, 1996). Infection that results
from kissing a person with the cold is considered a rare
occurrence, likely because of the low titer of virus in
saliva and because inoculation of pharyngeal mucosa
rarely causes infection (Hendley et al., 1973; D’Alessio et
al., 1976).
Aerosolized Droplets
Infections caused by aerosolized droplets have been
documented, but this is not considered a significant
route of transmission (Winther, 2011). Many studies
have demonstrated that touching a person with the cold
leads to infection far more frequently than physical
proximity to a sick individual alone. It has been
proposed that perhaps the recirculation of air may
increase the chances of cold transmission by raising the
Harvard Medical Student Review Vol. 2 (Issue 1), pp. 5-18.
risk of exposure to aerosolized droplets. To test this
hypothesis, researchers compared the incidence of colds
1-week post-airplane flight for 1,100 travelers. Half the
passengers flew on planes that recirculated cabin air and
the other half flew on planes with fresh air ventilation.
The researchers found the recirculation of air in the
context of commercial flights had no significant effect
on cold transmission (Zitter et al., 2002). However, it
should be noted that this finding is at odds with data
from military barracks, where living in a closed-
ventilation barracks was found to raise the relative risk
of catching a ARI by 1.5 (95% CI 1.46 1.56) (Brundage
et al., 1988).
Viral Shedding and Contagiousness
Viral shedding peaks 4872 hr after infection (Hendley
and Gwaltney, 2004). In one study, 24 married couples
were monitored after a spouse was inoculated with
rhinovirus. The researchers found that the risk factors
for successful pathogen transmission were high viral
load, moderate symptoms, and time spent with spouse
(D’Alessio et al., 1976). This finding indicated that viral
spread depends on peak viral load coinciding with the
presence of only mild symptoms. Hence, most
transmissions of the cold tend to occur within the first 5
days after exposure. Even though symptoms usually
taper off after 57 days, viral shedding continues for up
to 2 weeks after infection, meaning a recently ill person
can still unknowingly spread the cold (Winther et al.,
Several distinct families of viruses cause the cold (Monto
and Sullivan, 1993). Even among the most common
cause of the cold, the rhinovirus, there are over 100
virus serotypes, thus far thwarting vaccination efforts
(Heikkinen and Jarvinen, 2003). Targeted therapies
might still be possible, since many pathogeneses share
common pathways. For example, upregulating a decoy
form of ICAM-1—the surface protein that 90% of
rhinoviruses use to gain entry into epithelial cells
decreases rhinovirus infectivity in vitro (Whiteman et
al., 2003). The recent discovery of conserved motifs
among broad serotypes of rhinovirus may also
potentially yield targets for drug development (Poland
and Barry, 2009; Palmenberg et al., 2009). Non-vaccine
strategies have been the primary area of research in cold
prevention research.
Pharmaceutical Prophylaxis
Importation into a household by school-aged children is
a common route of cold transmission to adults (Monto
and Sullivan, 1993). Hence, one preventative strategy is
to take aggressive measures that stop the infection of
family members when one member of a household
catches the cold.
Prophylactic pharmaceutical agents demonstrated to
prevent cold infections exist, but these still carry
unpalatable side effects. For example in one study,
whenever a participant developed a cold, his or her
family would begin a 7-day prophylactic course of
intranasal interferon (Douglas et al., 1986). The
treatment reduced ARI illnesses among family members
by 41%, but each course of treatment had around a 12%
risk of intranasal bleeding. Intranasal interferon was
particularly efficacious for rhinovirus infections,
decreasing infections by 86%. However, it is not possible
to clinically determine if a cold is caused by rhinovirus
as opposed to another viral pathogen, limiting the utility
of the observed efficacy (Nicholson et al., 1997 ;Arruda
et al., 1997; Kirkpatrick, 1996). Additionally, interferon
use led to a concerning leukocyte accumulation in the
mucosa (Hayden et al., 1987). Other antiviral
chemotherapies (e.g., ICAM-1 blocker, capsid binding
agents, and protease inhibitors) have similarly failed to
show a promising risk to benefit ratio (Winther, 2011).
Weather and Isolation
Contrary to popular belief, there is no demonstrated
association between being in cold weather and common
cold susceptibility. Newcomers and long-time workers at
a remote research base in Antarctica were found to be
equally susceptible to catching the cold (Warshauer et
al., 1989). While a medical school class’ isolation might
seem protective, another Antarctica study of ARI’s
during a period of absolute isolation found that a
respiratory infection present at the beginning of
isolation persisted throughout the 6 months of winter
isolation (Flynn et al., 1977).
Vitamin C
Another popular means of cold prevention, vitamin C
supplementation, was examined in a meta-analysis of 29
trials (Hemila and Chalker, 2013). Together the studies
include 10,708 participants from the general public and
show vitamin C supplementation does not decrease
common cold incidence, either when taken regularly or
in large prophylactic doses (RR 0.97, 95% CI 0.94 to
1.00) (Hemila and Chalker, 2013). Because vitamin C
does not reduce cold incidence in the general public, the
authors suggested that routine vitamin C
supplementation “is not justified.” While regular
supplementation of vitamin C was associated with an 8%
reduction of symptom duration in adults and 14%
reduction in children, given the wide variation of cold
presentations (Monto and Sullivan, 1993), it is possible
that this statistical finding is entirely sub-clinical and is
not relevant for a population-wide recommendation.
Additionally, it was found that mega-doses of vitamin C
Harvard Medical Student Review Vol. 2 (Issue 1), pp. 5-18.
after the onset of clinical symptoms had no effect on
illness duration or symptom intensity.
Curiously, five studies of 598 extreme athletes under
conditions of intense but brief physical stress
individuals at a ski camp (Ritzel, 1961), runners in an
ultra-marathon (Peters et al., 1993), etc.receive a clear
and consistently positive benefit from vitamin C
supplementation (Hemila and Chalker, 2013). For
example, in one study half of the Canadian military
recruits taking part in arctic training exercises were
given a daily placebo and the other half were given daily
vitamin C (Sabiston and Radomski, 1974). To minimize
bias, the supplemented group was only revealed to both
participants and researchers at the end of the study
through the measurement of intravenous ascorbate
levels. Among 112 men, 25% taking the placebo and only
10% receiving vitamin C caught the cold. The five
studies show that vitamin C supplementation under
conditions of acute physical stress cuts the incidence of
cold infections by half (RR 0.48, 95% CI 0.35 to 0.64)
(Hemila and Chalker, 2013). Two other randomized
controlled trials found that individuals under conditions
of prolonged physical stressmarine recruits at boot
camp and competitive adolescent swimmersreceived no
benefit from vitamin C in terms of cold prevention (Pitt
and Costrini, 1979; Constantini et al., 2011). This
perhaps indicates that the supplementation with vitamin
C has a substantial benefit, but only under conditions of
acute physical stress (Hemila and Chalker, 2013).
Hence, aside for a narrow subset of
extreme athletes, vitamin C has no
demonstrated therapeutic benefit. Yet,
even if it will not help treat or prevent
the cold, especially given the low risk
and cost of vitamin C, supplementation
does not hurt.
Surgical Masks
While masks can prevent cold
transmission in hospital wards
especially when they prevent self-
inoculation by covering the eyes and
nose (Gala et al., 1986)surgical masks
have not yet been demonstrated to be
effective in more general contexts. One
prospective study found that wearing a
surgical mask has no effect on
likelihood of catching a cold, but it did
significantly make a mask-wearing
participant more likely to experience
headaches (Jacobs et al., 2009). Yet it is
worth noting that this 77-day study
with 32 participants was underpowered
and would only have detected an
absolute risk reduction of 60% from
wearing a mask. Unfortunately, other
drastic or novel approaches have not yet shown great
promise either (Jefferson et al., 2011). For example, use
of tissue paper with virucidal properties did not
effectively reduce the frequency of colds (Farr et al.,
Social Networks
Contemporary studies into the social component of
disease transmission have utilized quirky features of
social networks to successfully prevent the spread of
infectious diseases and computer viruses. For example,
the targeted vaccination of “central” individuals who
have the most connections in a social network can raise
population immunity (Pastor-Satorras and Vespignani,
2002; Cohen et al., 2003). Because central individuals
have more connections in a social network, they are
likely to spread a disease to more people and become
infected earlier in an outbreak. Another feature of social
networks is the so-called “friendship paradox,” which is
the observation that your friends have more friends than
you door that your friends are likely more central than
you are. Researchers used this during a flu outbreak at
Harvard College and found that if random volunteers
nominated a friend, because that friend was more likely
to be a central individualand hence more likely to get
sick earlier in an outbreakmonitoring the nominated,
central friends for signs of the flu significantly improved
early flu detection (Figure 4) (Christakis and Fowler,
2010). At this time, however, a study utilizing social
Figure 4. Early Infection of Central Individuals in an Outbreak
Your friends tend to be more centrally located in social networks than you are. Hence in the
conditions of social spreading, “central” individuals in a social network pick up infections
earlier than random individuals. Researchers were able to use this feature of social networks
in real-time to detect an influenza outbreak significantly earlier than traditional
surveillance methods (Christakis and Fowler, 2010). Theoretical results adapted from
Christakis and Fowler (2010).
Harvard Medical Student Review Vol. 2 (Issue 1), pp. 5-18.
network structure for early detection or prevention has
not been attempted for the common cold.
Hand WashingThe Punch Line
What do we have to prevent the cold, then? The answer
can be gleaned from a classic experiment in 1980 in
which one group of random volunteers dipped their
fingers in dilute iodine solutionit was known to have
virucidal properties (Hendley et al., 1978)and were
compared to volunteers who dipped their hands into
water that was died to look and smell like iodine
(Gwaltney et al., 1980). Immediately after drying their
hands, volunteers made hand contact with rhinovirus-
positive donors who had just picked their noses (“The
donors contaminated their hands with nasal secretions
by finger-to-nose contact”), and 15 min later, volunteers
touched their own eyes and noses. This was repeated for
3 days. None of the eight iodine-exposed volunteers
became infected, while all seven controls became ill (p <
0.001). Unfortunately, routine iodine use is impractical
given that many patients do like having iodine-stained
Subsequent randomized controlled trials demonstrated
that good hand hygiene leads to a 20% decrease in cold
incidence (Carabin et al., 1999; Ladegaard and Stage,
1999). One crossover study found that giving children
hand-sanitizer to compliment normal hand washing
resulted in a 50% decline in ARI incidence (Dyer et al.,
2000). A meta-analysis of 67 studies on preventing ARI
transmission concurred hygienic measures are the most
effective measure to prevent ARI infection (Jefferson et
al., 2011).
As discussed throughout this review, many of the most
illustrative studies of the common cold rely on despotic
study protocols. Some studies leveraged drastic
geographical conditionsat Antarctic research bases and
military exercises on the Northern frontierto study the
cold in isolation (Warshauer et al., 1989; Flynn et al.,
1977; Sabiston and Radomski, 1974). Other researchers
intentionally infected healthy volunteers with the cold,
ranging from the infection of married people to study
risk factors associated with transmission (D’Alessio et
al., 1976) to infecting COPD patients simply to prove
that the cold causes COPD exacerbation (Mallia et al.,
2011). Such measures were not utilized for the purposes
of the brief case study of the outbreak at Harvard
Medical School. Good-hearted volunteers and the self-
limited nature of the cold have made it possible for
researchers to illuminate the pathogenesis,
transmissions, and prevention of mankind’s most
common ailment.
The case study from Harvard Medical School revealed
two risk factors significantly associated with contracting
an ARI. However, the gross social patterns of behavior
elucidated in the study did not capture unique social
interactions with the granularity needed to prospectively
predict the spread of disease or retrospectively describe
the specific social interactions that tended to promote
disease transmission. Disease transmission in social
networks is an unexplored area of research in common
cold transmission, and the methods discussed above
have implications for preventing and detecting outbreaks
among small semi-isolated communities such as
universities, hospital wards, military bases, and
retirement communities. Such prevention efforts are
especially important given that in this outbreak ill
students each infected 3.5 of their colleagues.
Thus far, good hand hygiene is the best method of
preventing common cold transmission, especially when
around children (Jefferson et al., 2011). A survey of the
literature supports this intuitive conclusionself-
inoculation from one’s fingers through the eyes or nose
is the most frequent means by which the cold is
transmitted (Hendley et al., 1973). Saliva and aerosolized
droplets rarely cause infections (Winther, 2011;
Kirkpatrick, 1996; D’Alessio et al., 1976). Yet infectious
viral particles can persist on hands and commonly used
fomites for hours (Winther et al., 2007; Gwaltney et al.,
1982). Peak viral shedding coincides with early cold
symptoms such as rhinorrhea (Jackson et al., 1958;
Hendley and Gwaltney, 2004). Cold symptoms are
completely attributable to our immune response
(Hendley, 1999). Children tend to have more colds per
year than adults (Pappas et al., 2008) and are frequently
responsible for exposing family members to the
numerous cold pathogens (Monto and Sullivan, 1993).
Annually, the cold accrues more direct medical costs
than influenza and is the number one reason for missed
work and school (Fendrick et al., 2003; Molinari et al.,
2007). There are no effective treatments for the cold
adults-treatment-and-prevention). This makes prevention
especially important for vulnerable populations such as
asthmatic, COPD, elderly, and immunocompromised
patients (Nicholson et al., 1996; Mallia et al., 2011;
Teichtahl et al., 1997; Ghosh et al., 1999). Alas, as a
prevention strategy, hand washing is almost
disappointingly simple. But given hand washing’s safety
(consider nose bleeds from intranasal interferon)
(Douglas et al., 1986; Hayden et al., 1987), ease (consider
surgical masks in public) (Jacobs et al., 2009), and
efficacy (consider vitamin C) (Hemila and Chalker,
2013), perhaps a simple solution is not a bad thing for
such a common problem.
The author would like to thank Annie Morgan for
essential help with data analysis for the case study at
Harvard Medical School, and extends aHi nother warm
thank you to the HMSR staff for their patience with this
Harvard Medical Student Review Vol. 2 (Issue 1), pp. 5-18.
manuscript. The author has no conflicts of interest to
Adams PF, Hendershot GE, Marano MA. Current
estimates from the National Health Interview Survey,
(1996). Vital and health statistics Series 10. Data from
the National Health Survey 1999, 1–203.
Arruda, E., Pitkaranta, A., Witek, T.J., Jr., Doyle, C.A.,
and Hayden, F.G. (1997). Frequency and natural history
of rhinovirus infections in adults during autumn. J.
Clin. Microbiol. 35, 28642868.
Sabiston, B.H., and Radomski, M.W. (1974). Health
Problems and Vitamin C in Canadian Northern
Military Operations. Defence and Civil Institute of
Environmental Medicine Report 74-R-1012.
Bradburne, A.F., Bynoe, M.L., and Tyrrell, D.A. (1967).
Effects of a “new” human respiratory virus in
volunteers. BMJ 3, 767769.
Brundage, J.F., Scott, R.M., Lednar, W.M., Smith,
D.W., and Miller, R.N. (1988). Building-associated risk
of febrile acute respiratory diseases in Army trainees.
JAMA 259, 21082112.
Carabin, H., Gyorkos, T.W., Soto, J.C., Joseph, L.,
Payment, P., and Collet, J.P. (1999). Effectiveness of a
training program in reducing infections in toddlers
attending day care centers. Epidemiology 10, 219227.
Christakis, N.A., and Fowler, J.H. (2010). Social
network sensors for early detection of contagious
outbreaks. PLoS ONE 5, e12948.
Cohen, R., Havlin, S., and Ben-Avraham, D. (2003).
Efficient immunization strategies for computer networks
and populations. Phys. Rev. Lett. 91, 247901.
Constantini, N.W., Dubnov-Raz, G., Eyal, B.B., Berry,
E.M., Cohen, A.H., and Hemila, H. (2011). The effect of
vitamin C on upper respiratory infections in adolescent
swimmers: a randomized trial. Eur. J. Pediatr. 170, 59
Crane, J., Pearce, N., Burgess, C., Woodman, K.,
Robson, B., and Beasley, R. (1992). Markers of risk of
asthma death or readmission in the 12 months following
a hospital admission for asthma. Int. J. Epidemiol. 21,
D’Alessio, D.J., Peterson, J.A., Dick, C.R., and Dick,
E.C. (1976). Transmission of experimental rhinovirus
colds in volunteer married couples. J. Infect. Dis. 133,
Denny, F.W., Jr. (1995). The clinical impact of human
respiratory virus infections. Am. J. Respir. Crit. Care
Med. 152, S4S12.
Dolan, G.P., Harris, R.C., Clarkson, M., et al. (2012).
Vaccination of health care workers to protect patients at
increased risk for acute respiratory disease. Emerg.
Infect. Dis. 18, 12251234.
Douglas, R.M., Moore, B.W., Miles, H.B., et al. (1986).
Prophylactic efficacy of intranasal alpha 2-interferon
against rhinovirus infections in the family setting. N.
Engl. J. Med. 314, 6570.
Doyle, W.J., Boehm, S., and Skoner, D.P. (1990).
Physiologic responses to intranasal dose-response
challenges with histamine, methacholine, bradykinin,
and prostaglandin in adult volunteers with and without
nasal allergy. J. Allergy Clin. Immunol. 86, 924935.
Dyer, D.L., Shinder, A., and Shinder, F. (2000).
Alcohol-free instant hand sanitizer reduces elementary
school illness absenteeism. Fam. Med. 32, 633638.
Eccles, R. (2005). Understanding the symptoms of the
common cold and influenza. Lancet Infect. Dis. 5, 718
Farr, B.M., Hendley, J.O., Kaiser, D.L., and Gwaltney,
J.M. (1988). Two randomized controlled trials of
virucidal nasal tissues in the prevention of natural upper
respiratory infections. Am. J. Epidemiol. 128, 11621172.
Fendrick, A.M., Monto, A.S., Nightengale, B., and
Sarnes, M. (2003). The economic burden of non-
influenza-related viral respiratory tract infection in the
United States. Arch. Intern. Med. 163, 487494.
Fraser, C., Donnelly, C.A., Cauchemez, S., et al. (2009).
Pandemic potential of a strain of influenza A (H1N1):
early findings. Science 324, 15571561.
Gala, C.L., Hall, C.B., Schnabel, K.C., et al. (1986). The
use of eye-nose goggles to control nosocomial respiratory
syncytial virus infection. JAMA 256, 27062708.
Gerna, G., Piralla, A., Rovida, F., et al. (2009).
Correlation of rhinovirus load in the respiratory tract
and clinical symptoms in hospitalized immunocompetent
and immunocompromised patients. J. Med. Virol. 81,
Ghosh, S., Champlin, R., Couch, R., et al. (1999).
Rhinovirus infections in myelosuppressed adult blood
and marrow transplant recipients. Clinical infectious
diseases: an official publication of the Infectious
Diseases Society of America 29, 528532.
Gonzales, R., Malone, D.C., Maselli, J.H., and Sande,
M.A (2001). Excessive antibiotic use for acute respiratory
infections in the United States. Clinical infectious
diseases: an official publication of the Infectious
Diseases Society of America 33, 757762.
Harvard Medical Student Review Vol. 2 (Issue 1), pp. 5-18.
Greve, J.M., Davis, G., Meyer, A.M., et al. (1989). The
major human rhinovirus receptor is ICAM-1. Cell 56,
Gwaltney, J.M., Jr., and Hayden, F.G. (1992).
Psychological stress and the common cold. N. Engl. J.
Med. 326, 644645, author reply 56.
Gwaltney, J.M., Jr., and Hendley, J.O. (1982).
Transmission of experimental rhinovirus infection by
contaminated surfaces. Am. J. Epidemiol. 116, 828833.
Gwaltney, J.M., Jr., Hendley, J.O., Simon, G., and
Jordan, W.S., Jr. (1967). Rhinovirus infections in an
industrial population. II. Characteristics of illness and
antibody response. JAMA 202, 494500.
Gwaltney, J.M., Jr., Moskalski, P.B., and Hendley, J.O.
(1980). Interruption of experimental rhinovirus
transmission. J. Infect. Dis. 142, 811815.
Hall, C.B., and Douglas, R.G., Jr. (1981). Modes of
transmission of respiratory syncytial virus. J. Pediatr. 99,
Hayden, F.G. (2004). Rhinovirus and the lower
respiratory tract. Rev. Med. Virol. 14, 1731.</jrn>
Hayden, F.G., Winther, B., Donowitz, G.R., Mills, S.E.,
and Innes, D.J. (1987). Human nasal mucosal responses
to topically applied recombinant leukocyte A interferon.
J. Infect. Dis. 156, 6472.</jrn>
Heikkinen, T., and Jarvinen, A. (2003). The common
cold. Lancet 361, 5159.</jrn>
Hemila, H., and Chalker, E. (2013). Vitamin C for
preventing and treating the common cold. Cochrane
Database Syst. Rev. 1, Cd000980.</jrn>
Hendley, J.O. (1999). Clinical virology of rhinoviruses.
Adv. Virus Res. 54, 453466.</jrn>
Hendley, J.O., and Gwaltney, J.M., Jr. (2004). Viral
titers in nasal lining fluid compared to viral titers in
nasal washes during experimental rhinovirus infection.
J. Clin. Virol. 30, 326328.
Hendley, J.O., Wenzel, R.P., and Gwaltney, J.M., Jr.
(1973). Transmission of rhinovirus colds by self-
inoculation. N. Engl. J. Med. 288, 13611364.
Hendley, J.O., Mika, L.A., and Gwaltney, J.M., Jr.
(1978). Evaluation of virucidal compounds for
inactivation of rhinovirus on hands. Antimicrob. Agents
Chemother. 14, 690694.
Hickner, J.M., Bartlett, J.G., Besser, R.E., Gonzales, R.,
Hoffman, J.R., and Sande, M.A. (2001). Principles of
appropriate antibiotic use for acute rhinosinusitis in
adults: background. Ann. Emerg. Med. 37, 703710.
Horcajada, J.P., Pumarola, T., Martinez, J.A., et al.
(2003). A nosocomial outbreak of influenza during a
period without influenza epidemic activity. Eur. Respir.
J. 21, 303307.
Jackson, G.G., Dowling, H.F., Spiesman, I.G., and
Boand, A.V. (1958). Transmission of the common cold to
volunteers under controlled conditions. I. The common
cold as a clinical entity. AMA Arch. Intern. Med. 101,
Jacobs, J.L., Ohde, S., Takahashi, O., Tokuda, Y.,
Omata, F., and Fukui, T. (2009). Use of surgical face
masks to reduce the incidence of the common cold
among health care workers in Japan: a randomized
controlled trial. Am. J. Infect. Control 37, 417419.
Jacobs, S.E., Soave, R., Shore, T.B., et al. (2013). Human
rhinovirus infections of the lower respiratory tract in
hematopoietic stem cell transplant recipients. Transpl.
Infect. Dis. 15, 474486.
Jefferson, T., Del Mar, C.B., Dooley, L., et al. (2011).
Physical interventions to interrupt or reduce the spread
of respiratory viruses. Cochrane Database Syst. Rev.
Johnston, S.L., Pattemore, P.K., Sanderson, G., et al.
(1995). Community study of role of viral infections in
exacerbations of asthma in 9-11 year old children. BMJ
310, 12251229.
Johnston, S.L., Pattemore, P.K., Sanderson, G., et al.
(1996). The relationship between upper respiratory
infections and hospital admissions for asthma: a time-
trend analysis. Am. J. Respir. Crit. Care Med. 154, 654
Keck, T., Leiacker, R., Riechelmann, H., and Rettinger,
G. (2000). Temperature profile in the nasal cavity.
Laryngoscope 110, 651654.
Kermack, W.O., and McKendrick, A.G. (1991).
Contributions to the mathematical theory of epidemics
I. 1927. Bull. Math. Biol. 53, 3355.
Kirchberger, S., Majdic, O., and Stockl, J. (2007).
Modulation of the immune system by human
rhinoviruses. Int. Arch. Allergy Immunol. 142, 110.
Kirkpatrick, G.L. (1996). The common cold. Prim. Care
23, 657675.
Ladegaard, M.B., and Stage, V. (1999). Ugeskr. Laeger
161, 43964400.
Malavaud, S., Malavaud, B., Sandres, K., et al. (2001).
Nosocomial outbreak of influenza virus A (H3N2)
infection in a solid organ transplant department.
Transplantation 72, 535537.
Harvard Medical Student Review Vol. 2 (Issue 1), pp. 5-18.
Mallia, P., Message, S.D., Gielen, V., et al. (2011).
Experimental rhinovirus infection as a human model of
chronic obstructive pulmonary disease exacerbation. Am.
J. Respir. Crit. Care Med. 183, 734742.
Meibalane, R., Sedmak, G.V., Sasidharan, P., Garg, P.,
and Grausz, J.P. (1977). Outbreak of influenza in a
neonatal intensive care unit. J. Pediatr. 91, 974976.
Milano, F., Campbell, A.P., Guthrie, K.A., et al. (2010).
Human rhinovirus and coronavirus detection among
allogeneic hematopoietic stem cell transplantation
recipients. Blood 115, 20882094.
Mills, C.E., Robins, J.M., and Lipsitch, M. (2004).
Transmissibility of 1918 pandemic influenza. Nature
432, 904906.
Molinari, N.A., Ortega-Sanchez, I.R., Messonnier, M.L.,
et al. (2007). The annual impact of seasonal influenza in
the US: measuring disease burden and costs. Vaccine 25,
Monto, A.S., and Sullivan, K.M. (1993). Acute
respiratory illness in the community. Frequency of
illness and the agents involved. Epidemiol. Infect. 110,
Mosser, A.G., Brockman-Schneider, R., Amineva, S., et
al. (2002). Similar frequency of rhinovirus-infectible
cells in upper and lower airway epithelium. J. Infect.
Dis. 185, 734743.
Murray, S., Del Mar, C., and O’Rourke, P. (2000).
Predictors of an antibiotic prescription by GPs for
respiratory tract infections: a pilot. Fam. Pract. 17, 386
Nicholson, K.G., Kent, J., and Ireland, D.C. (1993).
Respiratory viruses and exacerbations of asthma in
adults. BMJ 307, 982986.
Nicholson, K.G., Kent, J., Hammersley, V., and Cancio,
E. (1996). Risk factors for lower respiratory
complications of rhinovirus infections in elderly people
living in the community: prospective cohort study. BMJ
313, 11191123.
Nicholson, K.G., Kent, J., Hammersley, V., and Cancio,
E. (1997). Acute viral infections of upper respiratory tract
in elderly people living in the community: comparative,
prospective, population based study of disease burden.
BMJ 315, 10601064.
Nieters, A., Brems, S., and Becker, N. (2001). Cross-
sectional study on cytokine polymorphisms, cytokine
production after T-cell stimulation and clinical
parameters in a random sample of a German population.
Hum. Genet. 108, 241248.
Palmenberg, A.C., Spiro, D., Kuzmickas, R., et al.
(2009). Sequencing and analyses of all known human
rhinovirus genomes reveal structure and evolution.
Science 324, 5559.
Papadopoulos, N.G. (1999). JSRIZA, Banatvala J,
Pattison J. Principles and practice of clinical virology,
Fourth Edition (Chichester, UK: John Wiley & Sons).
Papadopoulos, N.G., Bates, P.J., Bardin, P.G., et al.
(2000). Rhinoviruses infect the lower airways. J. Infect.
Dis. 181, 18751884.
Pappas, D.E., Hendley, J.O., Hayden, F.G., and
Winther, B. (2008). Symptom profile of common colds
in school-aged children. Pediatr. Infect. Dis. J. 27, 811.
Pastor-Satorras, R., and Vespignani, A. (2002).
Immunization of complex networks. Phys. Rev. E Stat.
Nonlin. Soft Matter Phys. 65, 036104.
Peltola, V., Waris, M., Osterback, R., Susi, P.,
Ruuskanen, O., and Hyypia, T. (2008). Rhinovirus
transmission within families with children: incidence of
symptomatic and asymptomatic infections. J. Infect. Dis.
197, 382389.
Peters, E.M., Goetzsche, J.M., Grobbelaar, B., and
Noakes, T.D. (1993). Vitamin C supplementation reduces
the incidence of postrace symptoms of upper-respiratory-
tract infection in ultramarathon runners. Am. J. Clin.
Nutr. 57, 170174.
Pitt, H.A., and Costrini, A.M. (1979). Vitamin C
prophylaxis in marine recruits. JAMA 241, 908911.
Poland, G.A., and Barry, M.A. (2009). Common cold,
uncommon variation. N. Engl. J. Med. 360, 22452246.
Proud, D. (2005). Nitric oxide and the common cold.
Curr. Opin. Allergy Clin. Immunol. 5, 3742.
Proud, D., Reynolds, C.J., Lacapra, S., Kagey-Sobotka,
A., Lichtenstein, L.M., and Naclerio, R.M. (1988). Nasal
provocation with bradykinin induces symptoms of
rhinitis and a sore throat. Am. Rev. Respir. Dis. 137,
Proud, D., Naclerio, R.M., Gwaltney, J.M., and
Hendley, J.O. (1990). Kinins are generated in nasal
secretions during natural rhinovirus colds. J. Infect. Dis.
161, 120123.
Ritzel, G. (1961). Helv. Med. Acta 28, 6368.
Smith, C.W., Rothlein, R., Hughes, B.J., et al. (1988).
Recognition of an endothelial determinant for CD 18-
dependent human neutrophil adherence and
transendothelial migration. J. Clin. Invest. 82, 1746
Srinivasan, A., Flynn, P., Gu, Z., et al. (2013). Detection
of respiratory viruses in asymptomatic children
Harvard Medical Student Review Vol. 2 (Issue 1), pp. 5-18.
undergoing allogeneic hematopoietic cell
transplantation. Pediatr. Blood Cancer 60, 149151.
Strausbaugh, L.J., Sukumar, S.R., and Joseph, C.L.
(2003). Infectious disease outbreaks in nursing homes:
an unappreciated hazard for frail elderly persons. Clin.
Infect. Dis. 36, 870876.
Teichtahl, H., Buckmaster, N., and Pertnikovs, E.
(1997). The incidence of respiratory tract infection in
adults requiring hospitalization for asthma. Chest 112,
Flynn, T.C., Fusch, L.W., and Dick, E.C. (1977). Colds
and immunity in the 77 winter personnel at McMurdo
Station and Scott Base, 1976. Antartic Journal
Tyrrell, D.A., Cohen, S., and Schlarb, J.E. (1993). Signs
and symptoms in common colds. Epidemiol. Infect. 111,
van den Hoogen, B.G., de Jong, J.C., Groen, J., et al.
(2001). A newly discovered human pneumovirus isolated
from young children with respiratory tract disease. Nat.
Med. 7, 719724.
Vejlsgaard, G.L., Ralfkiaer, E., Avnstorp, C., Czajkowski,
M., Marlin, S.D., and Rothlein, R. (1989). Kinetics and
characterization of intercellular adhesion molecule-1
(ICAM-1) expression on keratinocytes in various
inflammatory skin lesions and malignant cutaneous
lymphomas. J. Am. Acad. Dermatol. 20, 782790.
Wald, E.R. (1991). Purulent nasal discharge. Pediatr.
Infect. Dis. J. 10, 329333.
Wallinga, J., and Teunis, P. (2004). Different epidemic
curves for severe acute respiratory syndrome reveal
similar impacts of control measures. Am. J. Epidemiol.
160, 509516.
Warshauer, D.M., Dick, E.C., Mandel, A.D., Flynn,
T.C., and Jerde, R.S. (1989). Rhinovirus infections in an
isolated antarctic station. Transmission of the viruses
and susceptibility of the population. Am. J. Epidemiol.
129, 319340.
Wegner, C.D., Gundel, R.H., Reilly, P., Haynes, N.,
Letts, L.G., and Rothlein, R. (1990). Intercellular
adhesion molecule-1 (ICAM-1) in the pathogenesis of
asthma. Science 247, 456459.
Whiteman, S.C., Bianco, A., Knight, R.A., and Spiteri,
M.A. (2003). Human rhinovirus selectively modulates
membranous and soluble forms of its intercellular
adhesion molecule-1 (ICAM-1) receptor to promote
epithelial cell infectivity. J. Biol. Chem. 278, 11954
WHO Ebola Response Team (2014). Ebola virus disease
in West Africathe first 9 months of the epidemic and
forward projections. N. Engl. J. Med. 371, 14811495.
Winther, B. (2011). Rhinovirus infections in the upper
airway. Proc. Am. Thorac. Soc. 8, 7989.
Winther, B., Brofeldt, S., Christensen, B., and Mygind,
N. (1984a). Light and scanning electron microscopy of
nasal biopsy material from patients with naturally
acquired common colds. Acta Otolaryngol. 97, 309318.
Winther, B., Farr, B., Turner, R.B., Hendley, J.O.,
Gwaltney, J.M., Jr., and Mygind, N. (1984b).
Histopathologic examination and enumeration of
polymorphonuclear leukocytes in the nasal mucosa
during experimental rhinovirus colds. Acta Otolaryngol.
Suppl. 413, 1924.
Winther, B., Gwaltney, J.M., Jr., Mygind, N., Turner,
R.B., and Hendley, J.O. (1986). Sites of rhinovirus
recovery after point inoculation of the upper airway.
JAMA 256, 17631767.
Winther, B., McCue, K., Ashe, K., Rubino, J.R., and
Hendley, J.O. (2007). Environmental contamination
with rhinovirus and transfer to fingers of healthy
individuals by daily life activity. J. Med. Virol. 79, 1606
Yang, Y., Sugimoto, J.D., Halloran, M.E., et al. (2009).
The transmissibility and control of pandemic influenza
A (H1N1) virus. Science 326, 729733.
Zitter, J.N., Mazonson, P.D., Miller, D.P., Hulley, S.B.,
and Balmes, J.R. (2002). Aircraft cabin air recirculation
and symptoms of the common cold. JAMA 288, 483
... It has been determined that up to 40%-80% of cases of colds are caused by rhinoviruses, followed by coronavirus, influenza virus, respiratory syncytial virus, parainfluenza virus, adenovirus, and enterovirus [14]. Moreover, approximately 25% of the cases of the common cold are caused by unknown viruses [15], while 5% to 15% are caused by influenza viruses [16]. It has also been shown that the kinds of viruses related to the common cold change throughout the year [14]. ...
... On average, in healthy adults, symptoms tend to spontaneously resolve after 7 to 10 days, with cough generally being the last symptom to resolve [14], [17]. High fever is rarely experienced compared with the typical symptoms of influenza [16]. ...
... Given that vaccination has no effect on preventing infection, the most common method of cold prevention in the world is handwashing [16], [3]. Alcohol hand sanitizers are effective against influenza, but not rhinoviruses [25]. ...
Conference Paper
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More than 200 virus strains have been implicated in common colds, thereby thwarting vaccination efforts. However, the most common causes of colds are human rhinoviruses, which infect the epithelial cells of the nasopharynx. Moreover, after decades of research, the best documented method of preventing infection remains to be handwashing. However, stopping people from inadvertently touching or rubbing one’s nose and eyes is difficult, and the effectiveness of preventing such habits has not been validated. Here, we reported the results of a randomized controlled trial (n = 120) performed over 50 days. We examined the effectiveness of using smartwatches equipped with a sensor and a vibration alert, as well as the self-checking of behavior, in preventing subjects from touching their nose or eyes. Participants were randomly assigned to either the smartwatch group or the handwashing group (control). Subjects in the handwashing group were requested to wash their hands after going out, whereas subjects in the smartwatch group were requested to wash their hands and in addition wear a smartwatch that vibrates to remind them not to excessively touch their nose or eyes. The daily frequency of nose and eye touching was also recorded by the smartwatches. The first incidence of an upper respiratory tract infection (URTI) was the primary endpoint. In the smartwatch group, compared with the control group, the incidence of URTIs was significantly lower by 53% (p < 0.05) and was associated with a decrease in the mean frequency of nose or eye touching (p < 0.05).
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Background: On March 23, 2014, the World Health Organization (WHO) was notified of an outbreak of Ebola virus disease (EVD) in Guinea. On August 8, the WHO declared the epidemic to be a "public health emergency of international concern." Methods: By September 14, 2014, a total of 4507 probable and confirmed cases, including 2296 deaths from EVD (Zaire species) had been reported from five countries in West Africa--Guinea, Liberia, Nigeria, Senegal, and Sierra Leone. We analyzed a detailed subset of data on 3343 confirmed and 667 probable Ebola cases collected in Guinea, Liberia, Nigeria, and Sierra Leone as of September 14. Results: The majority of patients are 15 to 44 years of age (49.9% male), and we estimate that the case fatality rate is 70.8% (95% confidence interval [CI], 69 to 73) among persons with known clinical outcome of infection. The course of infection, including signs and symptoms, incubation period (11.4 days), and serial interval (15.3 days), is similar to that reported in previous outbreaks of EVD. On the basis of the initial periods of exponential growth, the estimated basic reproduction numbers (R0 ) are 1.71 (95% CI, 1.44 to 2.01) for Guinea, 1.83 (95% CI, 1.72 to 1.94) for Liberia, and 2.02 (95% CI, 1.79 to 2.26) for Sierra Leone. The estimated current reproduction numbers (R) are 1.81 (95% CI, 1.60 to 2.03) for Guinea, 1.51 (95% CI, 1.41 to 1.60) for Liberia, and 1.38 (95% CI, 1.27 to 1.51) for Sierra Leone; the corresponding doubling times are 15.7 days (95% CI, 12.9 to 20.3) for Guinea, 23.6 days (95% CI, 20.2 to 28.2) for Liberia, and 30.2 days (95% CI, 23.6 to 42.3) for Sierra Leone. Assuming no change in the control measures for this epidemic, by November 2, 2014, the cumulative reported numbers of confirmed and probable cases are predicted to be 5740 in Guinea, 9890 in Liberia, and 5000 in Sierra Leone, exceeding 20,000 in total. Conclusions: These data indicate that without drastic improvements in control measures, the numbers of cases of and deaths from EVD are expected to continue increasing from hundreds to thousands per week in the coming months.
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Health care workers (HCWs) may transmit respiratory infection to patients. We assessed evidence for the effectiveness of vaccinating HCWs to provide indirect protection for patients at risk for severe or complicated disease after acute respiratory infection. We searched electronic health care databases and sources of gray literature by using a predefined strategy. Risk for bias was assessed by using validated tools, and results were synthesized by using a narrative approach. Seventeen of the 12,352 identified citations met the full inclusion criteria, and 3 additional articles were identified from reference or citation tracking. All considered influenza vaccination of HCWs, and most were conducted in long-term residential care settings. Consistency in the direction of effect was observed across several different outcome measures, suggesting a likely protective effect for patients in residential care settings. However, evidence was insufficient for us to confidently extrapolate this to other at-risk patient groups.
We have shown that viruses are associated with 80 to 85% of asthma exacerbations in school-age children in the community. We hypothesize that viral infections are also associated with severe attacks of asthma precipitating hospital admissions. To investigate this, we conducted a time-trend analysis comparing the seasonal patterns of respiratory infections and hospital admissions for asthma in adults and children. During a 1-yr study in the Southampton area of the United Kingdom, 108 school-age children monitored upper and lower respiratory symptoms and took peak expiratory flow rate (PEFR) recordings. From children reporting a symptomatic episode or a decrease in PEFR. samples were taken for detection of viruses and atypical bacteria. A total of 232 respiratory viruses and four atypical bacteria were detected. The half-monthly rates of upper respiratory infection were compared with the half-monthly rates for hospital admissions for asthma (International Classification of Diseases [ICD] code 493) for the same time period for the hospitals serving the areas from which the cohort of schoolchildren was drawn. The relationships of upper respiratory infections and hospital admissions for asthma with school attendance were studied. Strong correlations were found between the seasonal patterns of upper respiratory infections and hospital admissions for asthma (r = 0.72; p < 0.0001). This relationship was stronger for pediatric (r = 0.68; p < 0.0001) than for adult admissions (r = 0.53; p < 0.01). Upper respiratory infections and admissions for asthma were more frequent during periods of school attendance (87% of pediatric and 84% of total admissions), than during school holiday periods (p < 0.001). These relationships remained significant when allowance was made for linear trend and seasonal variation using multiple regression analysis (p < 0.01). Not surprisingly, school attendance, because it is a major factor in respiratory virus transmission, was found to be a major confounding variable in children. This study demonstrates that upper respiratory viral infections are strongly associated in time with hospital admissions for asthma in children and adults. Rhinoviruses were the major pathogen implicated, and the majority of viral infections and asthma admissions occurred during school attendance. Comments. The relationship between rhinovirus infection and hospitalization for asthma was strongest in children. Intuitively. I think we all know that "URI'S" are associated with asthmatic attacks in children, but this paper proves the point.
Human rhinoviruses (HRVs) are a common cause of upper respiratory infection (URI) in hematopoietic stem cell transplant (HSCT) recipients; yet, their role in lower respiratory illness is not well understood. We performed a retrospective chart review of HSCT recipients with HRV infection from the time molecular detection methods were implemented at our institution in 2008. Factors associated with proven or possible HRV pneumonia at the first HRV detection were evaluated by univariate and multivariate analysis. We then characterized all episodes of proven and possible HRV pneumonia from the initial HRV infection through a 1-year follow-up period. Between 2008 and 2011, 63 HSCT recipients had ≥1 documented HRV infections. At first HRV detection, 36 (57%) patients had HRV URI and 27 (43%) had proven or possible HRV pneumonia; in multivariate analysis, hypoalbuminemia (odds ratio [OR] 9.5, 95% confidence interval [CI] 1.3-71.7; P = 0.03) and isolation of respiratory co-pathogen(s) (OR 24.2, 95% CI 2.0-288.4; P = 0.01) were independently associated with pneumonia. During the study period, 22 patients had 25 episodes of proven HRV pneumonia. Fever (60%), cough (92%), sputum production (61%), and dyspnea (60%) were common symptoms. Fifteen (60%) episodes demonstrated bacterial (n = 7), fungal (n = 5), or viral (n = 3) co-infection. Among the remaining 10 (40%) cases of HRV monoinfection, patients' oxygen saturations ranged from 80% to 97% on ambient air, and computed tomography scans showed peribronchiolar, patchy, ground glass infiltrates. HRV pneumonia is relatively common after HSCT and frequently accompanied by bacterial co-infection. As use of molecular assays for respiratory viral diagnosis becomes widespread, HRV will be increasingly recognized as a significant cause of pneumonia in immunocompromised hosts.
Rhinovirus illness in young adults was characterized by rhinorrhea, nasal obstruction, sneezing, and pharyngeal discomfort. Length of illness ranged from 1 to 33 days, with a median of 7.42 days; one fourth of the illnesses lasted two weeks. Nasal symptoms, hoarseness, and cough occurred more frequently with confirmed rhinovirus common colds than with illnesses from which rhinoviruses were not cultured. Significant neutralizing antibody responses were measured in 77% of 77 paired serum specimens from patients with rhinovirus illness; only 5% had homologous titers of 8 or more in the acute phase of illness. The findings support other data indicating that serum neutralizing antibody develops following the majority of rhinovirus illnesses and is important in preventing symptomatic rhinovirus infection.
Detection of respiratory viruses by molecular methods, in children without respiratory symptoms undergoing hematopoietic cell transplantation (HCT), has not been well described. A prospective study of 33 asymptomatic children detected respiratory viruses in 8 of 33 (24%) patients before HCT. Human rhinovirus (HRV) was detected in five patients, and human adenovirus (hADV) in three patients. Two additional patients shed HRV, and one shed human coronavirus (hCoV), post-HCT. Two patients had co-infections. Of the 11 asymptomatic patients where respiratory virus was detected, 3 (27%) later developed an upper respiratory tract infection, from the same virus. Pediatr Blood Cancer © 2012 Wiley Periodicals, Inc.
We investigated, in a random sample of a German population, the association of polymorphisms in the genes encoding the cytokines interleukin 2 (IL-2), interleukin 4 receptor (IL-4R), interleukin 6 (IL-6), interleukin 10, interferon gamma (IFNG), tumor necrosis factor (TNF) and intercellular adhesion molecule 1 (ICAM-1) with (1) secreted levels of the respective proteins after T-cell stimulation and (2) data on selected diseases obtained from a questionnaire. The scope of this investigation was to further the understanding of the genetic background of allergies and common colds and the observed heterogeneity of many immune responses in the human population. In contrast to previous reports that showed associations of promoter polymorphisms of cytokine genes with the production of the corresponding protein, we did not find associations with protein release after T-cell stimulation in vitro. Among the correlations with the clinical parameters, we observed an increased risk of allergies (odds ratio, OR=4.1; confidence interval, CI: 1.6-10.4), particularly hay fever (OR=5.6, CI: 1.8-17.1) in individuals homozygous for IFNG 13 CA-repeats. In combination with the TNF wildtype, the risk for hay fever increased to OR=8.4 (CI: 2.7-25.6). Furthermore, individuals with a combination of IL2, IL6 and ICAM-1 polymorphisms tended to have higher frequencies of reported common colds than individuals with the alternate genotypes. As these are results of an explorative investigation, these findings require confirmation in material from a different source. If confirmed, these relationships could contribute to a better characterisation of the genetic component of allergies.