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Colds and influenza: A review of diagnosis and conventional, botanical, and nutritional considerations

March 2007
Alternative Medicine Review: a Journal of Clinical Therapeutic 12(1):25-48

Source
PubMed

Authors:

Mario Roxas

Thorne Research

Julie Jurenka

Thorne Research

The common cold is the leading cause of doctor visits in the United States and annually results in 189 million lost school days. In the course of one year the U.S. population contracts approximately 1 billion colds. Influenza infection is still a leading cause of morbidity and mortality, accounting for 20-25 million doctor visits and 36,000 deaths per year in the United States. Conventional therapies for colds and flu focus primarily on temporary symptom relief and include over-the-counter antipyretics, anti-inflammatories, and decongestants. Treatment for influenza also includes prescription antiviral agents and vaccines for prevention. This article reviews the common cold and influenza viruses, presents the conventional treatment options, and highlights select botanicals (Echinacea spp., Sambucus nigra, larch arabinogalactan, Astragalus membranaceous, Baptisia tinctoria, Allium sativa, Panax quinquefolium, Eleutherococcus senticosus, Andrographis paniculata, olive leaf extract, and Isatis tinctoria) and nutritional considerations (vitamins A and C, zinc, high lactoferrin whey protein, N-acetylcysteine, and DHEA) that may help in the prevention and treatment of these conditions.

. A Comparison of Common Cold and Influenza Characteristics

…

. Zinc Lozenges for Treatment of the Common Cold

…

. Zinc Nasal Spray for Treatment of the Common Cold

…

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Content may be subject to copyright.

Content uploaded by Julie Jurenka

Content may be subject to copyright.

Alternative Medicine Review Volume 12, Number 1 2007

Review Article

Page 25

Abstract

The common cold is the leading cause of doctor visits in the

United States and annually results in 189 million lost school

days. In the course of one year the U.S. population contracts

approximately 1 billion colds. Inﬂuenza infection is still a

leading cause of morbidity and mortality, accounting for 20-

25 million doctor visits and 36,000 deaths per year in the

United States. Conventional therapies for colds and ﬂu focus

primarily on temporary symptom relief and include over-the-

counter antipyretics, anti-inﬂammatories, and decongestants.

Treatment for inﬂuenza also includes prescription antiviral

agents and vaccines for prevention. This article reviews the

common cold and inﬂuenza viruses, presents the conventional

treatment options, and highlights select botanicals (Echinacea

spp., Sambucus nigra, larch arabinogalactan, Astragalus

membranaceous, Baptisia tinctoria, Allium sativa, Panax

quinquefolium, Eleutherococcus senticosus, Andrographis

paniculata, olive leaf extract, and Isatis tinctoria) and

nutritional considerations (vitamins A and C, zinc, high

lactoferrin whey protein, N-acetylcysteine, and DHEA) that

may help in the prevention and treatment of these conditions.

(Altern Med Rev 2007;12(1):25-48)

Colds and Inﬂuenza: A Review

of Diagnosis and Conventional,

Botanical, and Nutritional

Considerations

Mario Roxas, ND and Julie Jurenka, MT (ASCP)

Introduction

e common cold, also referred to as acute

viral nasopharyngitis, is a mild, self-limiting infectious

disease that can be caused by more than 100 diﬀerent

viruses. Of these, rhinoviruses and coronaviruses are re-

sponsible for approximately 50-70 percent of all colds.1,2

Colds were known to man even in ancient Egypt where

they were depicted in hieroglyphs. e Greek physician

Hippocrates described the disease as early as the 5th

century BC. In 1914, Walter Kruse, a German profes-

sor, demonstrated that viruses, not bacteria, cause the

common cold,3 but the ﬁnding was not widely accepted

until the 1920s when Alphonse Dochez conﬁrmed it

in chimpanzees and humans. e term “cold” was likely

derived from ancient physicians who described “cold

conditions” and “warm conditions” that were dependent

on or caused by cold or warm environments. In modern

times the misnomer has persisted, possibly due to the

viruses’ eﬀect on thermogenesis. People are thought to

associate the shivering from a viral-induced fever with

shivering from being in a cold climate.4

Although generally benign in symptomol-

ogy, cold viruses are the most common infectious dis-

eases humans contract and result in signiﬁcant costs to

the economy in lost workdays and school attendance.

Adults average 2-4 colds per year and children 6-10,

depending on age and exposure.5 A 2003 study found

common colds resulted in more than 100 million phy-

sician visits annually, at a cost of $7.7 billion. At least

Mario Roxas, ND – Technical Advisor, Thorne Research; Associate Editor,

Alternative Medicine Review; Private practice.

Correspondence address: Thorne Research, PO Box 25, Dover, ID 83825

Email: m.roxas@comcast.net

Julie S. Jurenka, MT (ASCP) – Associate Editor, Alternative Medicine Review;

Technical Assistant, Thorne Research, Inc.

Alternative Medicine Review Volume 12, Number 1 2007

Colds and Inﬂuenza

Page 26

one-third of these patients received an antibiotic, even

though they have no eﬀect on viral infections, not only

adding to the cost but also contributing to the devel-

opment of antibiotic resistance. e study also found

Americans spend nearly $3 billion annually on over-

the-counter drugs that may not provide any symptom

relief. In addition, an estimated 189 million school days

are missed due to colds, which consequently result in

126 million missed workdays by parents who stay home

to care for sick children.6

Inﬂuenza is an acute respiratory illness caused

primarily by the inﬂuenza virus (serotypes A and B).

It occurs worldwide and is responsible for considerable

morbidity and mortality. e ﬁrst report of what was

likely an inﬂuenza epidemic was noted in 1173-1174,7

and the ﬁrst deﬁnitive report occurred in 1694.8 During

the 18th century, data on ﬂu epidemics increased con-

siderably, with comprehensive reports appearing in the

19th century.7,9-11 Inﬂuenza A viruses were ﬁrst isolated

in the laboratory from human specimens in 1933,12

and in 1957 the virus was made available for labora-

tory analysis.13 Subsequent studies have demonstrated

the inﬂuenza virus mutates rapidly (antigenic drift),

creating diﬃculties each year for researchers trying to

develop eﬀective vaccines.14

Inﬂuenza – usually more severe than the com-

mon cold – typically causes fever, headache, muscle

aches, and a more signiﬁcant cough; however, mild cases

of inﬂuenza are similar to colds. Of the two serotypes,

inﬂuenza A occurs more frequently and is more dan-

gerous. Although most epidemics and pandemics are

caused by inﬂuenza A, both A and B serotypes fre-

quently co-circulate during yearly outbreaks. Although

inﬂuenza B is usually less severe, in children the clinical

presentation may be similar to that of inﬂuenza A.15 In-

ﬂuenza-like illness is clinically similar to true inﬂuenza

but is caused by a virus other than inﬂuenza A or B

(e.g., the respiratory syncytial virus).16

In the United States, inﬂuenza epidemics typi-

cally occur during the winter months; the inﬂuenza “sea-

son” stretches from fall to spring in the Northern Hemi-

sphere, with peak activity from December through early

March. Between 1990 and 1999, 36,000 deaths per year

were attributed to inﬂuenza in the United States.17,18

In inﬂuenza epidemic years, 10 percent or more of the

population is typically infected, with about 50 per-

cent of those infected showing symptoms.19 Although

inﬂuenza viruses infect every age group, children have

the highest infection rates. Serious illness and death

rates are highest among the elderly, young children un-

der age two, and those with medical conditions placing

them at increased risk for inﬂuenza complications.17

Because of the potential severity and epidemic/

pandemic possibilities, the Advisory Committee on

Immunization Practices (ACIP) recommends annual

immunizations for persons at high risk for inﬂuenza-

related complications, persons who live with or care for

persons at high risk, and health care workers. e objec-

tive is that immunizations will prevent hospitalization

and/or death and reduce inﬂuenza-related respiratory

illnesses, decrease physician visits among all age groups,

prevent otitis media among children, and decrease work

absenteeism.17

Incidence and Etiopathology

Common Cold

Although acute upper respiratory tract infec-

tions can be attributed to several diﬀerent viral agents,

over 50 percent are caused by rhinoviruses. Coronavi-

ruses account for 10-20 percent, followed by inﬂuenza

viruses (10-15%) and adenoviruses (5%).20,21

Rhinoviruses belong to the Picornaviridae

family, (i.e., “pico” for small and “RNA” because they

are RNA viruses). Other Picornaviridae family mem-

bers include enteroviruses and hepadnaviruses (such

as hepatitis A); there are over 100 diﬀerent rhinovirus

serotypes.20

Rhinovirus infections are typically limited

to the nasopharynx but may also aﬀect the middle

ear and sinuses. Rhinoviruses grow in a fairly narrow

temperature range (33-35° C/91.4-95° F), a range ac-

commodated by the upper respiratory tract. e lower

respiratory tract, however, is warmer and consequently

inhospitable to the virus. Because rhinoviruses cannot

tolerate an acidic environment, the warmer temperature

and acidic environment of the stomach render these vi-

ruses unlikely to cause gastrointestinal infections.

Although rhinovirus infections can occur any-

time, they are more prevalent in the fall and spring;

whereas, coronaviruses seem to occur more often in the

winter and early spring.20 Approximately 70-80 per-

cent of exposed individuals present with symptoms.20

e virus is spread by direct person-to-person contact,

Alternative Medicine Review Volume 12, Number 1 2007

Review Article

Page 27

contact with contaminated surfaces (e.g., telephone re-

ceivers, stair rails, etc.), and inhalation of large-particle

aerosols.

Rhinoviruses bind to intercellular adhesion

molecule 1 (ICAM-1) receptor sites on the epithelium

of the nasopharynx. Typically the infected areas tend to

be isolated, dispersed foci that account for a relatively

small portion of epithelium.22 Infected cells release

interleukin-8 (IL-8), a strong chemo-attractant that

stimulates the release of inﬂammatory mediators, such

as kinins and prostaglandins. Presence of these sub-

stances can increase vasodilation, vascular permeability,

and exocrine gland secretion, ultimately leading to clas-

sic cold symptoms such as nasal congestion, rhinorrhea,

and sneezing. Higher concentration of IL-8 translates

to greater intensity of symptoms.20

Medical evidence suggests that, despite com-

monly held beliefs, exposure to cold temperature or

getting chilled or overheated does not increase suscep-

tibility to infection. Furthermore, upper respiratory

tract abnormalities (e.g., enlarged tonsils or adenoids)

are not thought to place an individual at greater risk of

contracting a cold. However, studies have demonstrated

that psychological stress and allergic conditions aﬀect-

ing the nose and throat inﬂuence susceptibility to infec-

tion.23

Inﬂuenza

Although there are three classiﬁed serotypes

of inﬂuenza viruses (A, B, and C), only the previously

mentioned A and B types are associated with the human

disease most commonly referred to as “the ﬂu.” ese

viruses are divided into various subgroups based on an-

tigenic characteristics. For instance, inﬂuenza A viruses

are typically divided into two general subtypes that cor-

respond to two diﬀerent antigens on the surface of the

virus: hemagglutinin and neuramidase. Hemagglutinin

antigen (HA) is a glycoprotein that allows the virus to

bind to cellular sialic acid and fuse with the host mem-

brane. Neuramidase antigen (NA), on the other hand,

breaks down sialic acid, allowing the virus to disperse

from the infected cell.

Point mutations occur in inﬂuenza A and B

viruses, resulting in the frequent emergence of new vi-

ral strains (antigenic drift). Consequently, antibodies

generated to the previous strain have limited protection

against an infection of a new variant, placing the body in

a constant game of “catch-up” with the virus.

Inﬂuenza epidemics are usually associated with

a single serotype. However, it is possible for diﬀerent in-

ﬂuenza viruses to appear sequentially in one location or

to have multiple inﬂuenza strains infect the same area

simultaneously.24 In the United States, an epidemic oc-

curs every 2-3 years, most often caused by inﬂuenza A

viruses.24 Inﬂuenza B viruses typically produce milder

disease and do not undergo antigenic drift as rapidly as

inﬂuenza A viruses.25

Signs and Symptoms

Common Cold

Cold symptoms occur within 1-2 days after

inoculation, and peak 2-4 days later, although some ac-

counts report symptoms presenting less than 24 hours

after exposure.20 Symptoms often start with a tickle or

soreness in the throat, followed by sneezing, runny nose,

nasal congestion, and general malaise. Temperature is

usually normal. Nasal discharge is clear, watery, and can

be quite profuse initially, subsequently turning more

mucoid and purulent. If a cough is present it is gener-

ally mild and may persist up to two weeks. A simple,

uncomplicated cold usually resolves within 10 days.

Inﬂuenza

e incubation period for an inﬂuenza infec-

tion is 1-4 days. Mild cases of the ﬂu present very much

like a common cold (e.g., sore throat, rhinorrhea); mild

conjunctivitis may also occur. However, in a typical ﬂu

presentation an individual rapidly experiences chills and

high fever, prostration, cough, body aches and pains,

headache (particularly behind the eyes), increased sen-

sitivity to light, and generalized malaise. Respiratory

symptoms include sore throat, coryza, and a productive

or non-productive cough. Children may also experience

nausea, vomiting, or abdominal pain; infants may pres-

ent with a sepsis-like syndrome.

Acute symptoms usually subside within 2-3

days, although fever may last up to ﬁve days. e illness

typically resolves after 3-7 days if no complications are

present. However, cough and general malaise can last

for weeks. Table 1 compares the characteristics of inﬂu-

enza and the common cold.

Alternative Medicine Review Volume 12, Number 1 2007

Colds and Inﬂuenza

Page 28

Potential Complications

Common Cold

Although most rhinovirus infections are self-

limiting, they can act as a secondary insult to the upper

respiratory tract in the presence of conditions such as

asthma, cystic ﬁbrosis, chronic bronchitis, or any lower

respiratory tract illness in infants, elderly, smokers, or

immune-compromised patients. e presence of puru-

lent sputum or signiﬁcant lower respiratory tract symp-

toms can be indications of more than a simple rhinovi-

ral infection.

One study of 533 individuals (ages 60-

90) revealed chronic medical conditions increased

the likelihood of lower respiratory complications

from rhinovirus infections by 40 percent. Smokers had

a 47-percent increased risk of developing complica-

tions.26 Diagnosis of bronchitis usually involves pulmo-

nary function tests, chest x-ray, and possibly a sputum

culture.27

Viral pneumonia is another potential com-

plication. Usually the pneumonia is mild and resolves

without treatment within a few weeks, but some cases

are more serious and can require hospitalization. As

with bronchitis, populations at risk for developing se-

vere viral pneumonia are those with impaired immune

systems, chronic medical conditions, impaired lung

function, young children (especially those with heart

defects), and the elderly. Diagnosis of viral pneumonia

Table 1. A Comparison of Common Cold and Inﬂuenza Characteristics

Feature

Etiological Agent

Site of Infection

Symptom Onset

Fever, chills

Headache

General aches, pains

Cough, chest congestion

Sore throat

Runny, stuffy nose

Fatigue, weakness

Extreme exhaustion

Season

Antibiotics helpful?

Colds

>100 viral strains; rhinovirus

most common

Upper respiratory tract

Gradual: 1-3 days

Occasional, low grade (<101˚ F)

Frequent, usually mild

Mild, if any

Mild-to-moderate, with

hacking cough

Common, usually mild

Very common, accompanied by

bouts of sneezing

Mild, if any

Never

Year around, peaks in

winter months

No, unless secondary bacterial

infection develops

Flu

3 strains of influenza virus: influenza

A, B, and C

Entire respiratory system

Sudden: within a few hours

Characteristic, higher (>101˚ F),

lasting 2-4 days

Characteristic, more severe

Characteristic, often severe and

affecting the entire body

Common, may become severe

Sometimes present

Usual, may be severe and last

2-3 weeks

Frequent, usually in early

stages of illness

Most cases between

November and February

No, unless secondary

bacterial infection develops

Alternative Medicine Review Volume 12, Number 1 2007

Review Article

Page 29

may require blood tests, chest x-ray, and possibly naso-

pharyngeal or sputum cultures.27

A viral infection can also travel to the sinus-

es or ears and cause excessive mucus secretion. Sinus

openings or ear canals can become blocked as mucus

accumulates, becoming a breeding ground for bacteria

and other organisms. Even if a bacterial infection does

develop, antibiotics may not speed recovery of an ear

or sinus infection and the infection will usually resolve

on its own. It is estimated 80 percent of children with

otitis media get better without antibiotics.28 ere is

minimal convincing evidence that children prescribed

antibiotics for otitis media have shorter symptom dura-

tion, fewer recurrences, or better long-term outcomes

than those who do not receive antibiotics.29 Despite

this, in the case of ear infections in young children who

are very uncomfortable and crying, physicians will often

prescribe an antibiotic to placate a stressed parent, even

if the physician suspects a viral agent. Unfortunately,

over-prescribing systemic antibiotics (particularly peni-

cillin derivatives such as amoxicillin) has resulted in sig-

niﬁcant antibiotic resistance for the two bacterial patho-

gens most commonly isolated from the nasopharynx of

children with otitis media – Streptococcus pneumoniae

and Haemophilus inﬂuenza.30

Although bacterial sinus infections secondary

to the common cold usually resolve within two weeks

with self-care, antibiotics are often prescribed when a

bacterial infection develops. Diagnosis is typically via

exam of sinuses and ears with a ﬁber-optic scope, sinus

x-rays, or nasal swab cultures.27

Inﬂuenza

In addition to the complications observed with

the common cold, inﬂuenza can on rare occasions re-

sult in encephalitis. When the virus enters the blood-

stream it can localize in the brain, causing inﬂammation

of brain tissue and membranes. In an eﬀort to ﬁght oﬀ

the infection, white blood cells invade the brain tissue,

causing cerebral edema and destruction of nerve cells,

bleeding within the brain, and brain damage. Symp-

toms can include fever, severe headache, neck stiﬀness,

drowsiness, muscle weakness, or seizures.31

Certain population groups have been identi-

ﬁed as high risk for inﬂuenza and its potential compli-

cations. ese groups are considered top priority for

attention when it comes to prophylactic and treatment

measures and are identiﬁed in Table 2.

Diagnosis

Because the signs and symptoms of the com-

mon cold occur so often, most people are familiar with

them and are able to self-diagnose. When a health care

provider is seen, diagnosis will likely be via recent pa-

tient history, ﬁber-optic scope examination of the ear,

nose, and throat, lymph node palpation, and stethoscope

evaluation of the lungs. e provider also determines

whether symptoms of more serious respiratory illnesses

such as pneumonia or bronchitis are present. Although

no laboratory tests are available to detect cold viruses

because of myriad viral agents, throat cultures, blood

tests, or x-rays can rule out a secondary infection.

Inﬂuenza diagnosis based on clinical symptoms

alone can be diﬃcult because infections caused by other

viral agents, including adenovirus, respiratory syncytial

virus, rhinovirus, and parainﬂuenza viruses, can pres-

ent with the same early symptoms. Diagnosis involves

a recent patient history, checking body temperature,

ﬁber-optic examination of ears, nose and throat, and

stethoscopic evaluation of the lungs. During outbreaks

of respiratory illnesses in nursing homes, dormitories,

Table 2. Populations at High Risk for Developing

Inﬂuenza Complications

Adults ≥65 years

Children under age 2 years

Pregnant women

Residents of long-term care facilities

Individuals with cardiovascular disease

Individuals who required regular medical follow-up

or hospitalization during the preceding year due to

chronic metabolic disorders (e.g., diabetes mellitus),

renal dysfunction, hemoglobinopathies, or

immunosuppression (e.g., HIV)

Individuals suffering from any condition that may

compromise respiratory function, the handling of

respiratory secretions, or that can increase the risk

of aspiration

Children and adolescents on long-term aspirin

therapy (due to risk of Reye’s Syndrome)

•

Alternative Medicine Review Volume 12, Number 1 2007

Colds and Inﬂuenza

Page 30

or other closed communities, laboratory testing for in-

ﬂuenza can help conﬁrm inﬂuenza as the cause of the

outbreak.32

Preferred samples for inﬂuenza testing include

nasopharyngeal swab or nasal swab, wash, or aspirate;

sample collection should take place within a few days

of symptom onset. Results from rapid inﬂuenza tests

are available in 30 minutes or less, but viral culture can

take 3-10 days. Most of the rapid tests are >70-percent

sensitive for detecting inﬂuenza and >90-percent spe-

ciﬁc. Viral culture of respiratory samples is the only way

to determine which inﬂuenza A or B strain is causing

illness. Viral culture also allows researchers and epide-

miologists to watch for outbreaks of inﬂuenza and in-

ﬂuenza-like illness in order to develop vaccines for the

coming year.32

Conventional Prevention and Treatment

Over-the-Counter Treatments

Because colds and inﬂuenza are usually self-

limiting, treatment tends to focus on reducing symptom

duration and intensity and minimizing risk of compli-

cations.

For the common cold, a warm and comfort-

able environment and rest and hydration are often all

that is needed. If additional intervention is necessary,

over-the-counter anti-inﬂammatory agents, analgesics,

and nasal/oral decongestants can be used for temporary

symptom relief.

Potential drawbacks do exist to symptom sup-

pression by over-the-counter medications. For instance,

nasal decongestants (e.g., pseudoephedrine, phenyleph-

rine) dry nasal secretions. Although this is the desired

eﬀect, an excessively dry mucosa can increase risk of

infection, not only in the nasopharynx but the sinuses

as well. In addition, when nasal decongestants are used

for an extended period of time (more than ﬁve consecu-

tive days) and then discontinued, a rebound eﬀect of

worsened symptoms can occur due to mucosal depen-

dence on the drug.33 Furthermore, use of decongestants

are contraindicated in patients with cardiovascular dis-

ease, hypertension, diabetes, prostatic hypertrophy, and

thyroid conditions because decongestants can increase

blood pressure, exacerbate thyroid symptoms, and cause

diﬃculty in urination.

Because inﬂuenza is often accompanied by a fe-

ver, an antipyretic (most frequently aspirin or acetamin-

ophen) is often added to over-the-counter analgesics,

antihistamines, and anti-inﬂammatory agents used for

symptom relief. When treating children, however, using

aspirin should be avoided because of concerns linking

its use to Reye’s syndrome.

Fever is an important clinical indicator and is

generally a healthy reaction by the body to combat in-

fection and regain homeostasis. Although a low-grade

fever (37.2-38.3° C/99-101° F) can facilitate healing, fe-

vers are commonly suppressed for the purpose of patient

comfort. Body temperature can rise to 41° C/105.8° F

without harm.34 ere are, however, instances when a

fever can place the patient at risk and use of antipyretics

may be indicated. Several non-pharmacological thera-

pies, such as tepid baths and body sponging, may be

employed as alternatives.

Antiviral Agents

Antiviral drugs limit the ability of the inﬂu-

enza virus to infect respiratory epithelial cells and can

oﬀer modest symptomatic relief. Although treatment

is generally recommended for high-risk patients who

develop inﬂuenza-like symptoms, there is no evidence

these drugs decrease the risk of serious complications in

these patients.24,35 Furthermore, they must be adminis-

tered within 48 hours of symptom onset to be eﬀective.

Although antiviral medications can be used to prevent

inﬂuenza infection, immunization is the preferred mea-

sure for prophylaxis in the conventional medical model.

In the United States, four antiviral agents are available

for use against inﬂuenza: amantadine (Symmetrel®),

rimantadine (Flumadine®), zanamivir (Relenza®), and

oseltamivir (Tamiﬂu®).

Amantadine and Rimantadine

Amantadine and rimantadine reduce the dura-

tion of uncomplicated inﬂuenza A infection by inhibit-

ing virus penetration or uncoating. Adamantine deriva-

tives were the ﬁrst eﬀective antiviral agents for treatment

of inﬂuenza. Although some reports claim amantadine

or rimantadine can prevent 70-90 percent of inﬂuenza

A illness, the drugs must be taken from 10 days to six

weeks for eﬀectiveness,36 and are not eﬀective against

inﬂuenza B infections.

Alternative Medicine Review Volume 12, Number 1 2007

Review Article

Page 31

Resistance to amantadine and rimantadine

can develop rapidly, rendering the drugs ineﬀective.

Approximately 30 percent of treated individuals start

shedding resistant variants 2-5 days after beginning

treatment.36 Although the drug resistance that develops

during treatment does not aﬀect the eﬃcacy of treat-

ment for the patient, it can result in transmission of a

resistant virus to contacts.21 To reduce the potential for

drug resistance, treatment should be stopped after 3-5

days (or 1-2 days after symptoms resolve).

Side eﬀects such as nervousness and/or insom-

nia occur in 10 percent of individuals receiving aman-

tadine and two percent receiving rimantadine, and are

more prominent in the elderly and in those with CNS

disease or impaired renal function. Other possible ad-

verse eﬀects include anorexia, nausea, and constipa-

tion.24 In patients with impaired renal function, dosage

is decreased according to creatinine clearance. Rimanta-

dine dosage should not exceed 100 mg/day in patients

with hepatic dysfunction.

Zanamivir and Oseltamivir

Zanamivir and oseltamivir are newer anti-in-

ﬂuenza drugs that can reduce the duration of uncom-

plicated inﬂuenza A and B infections. ese drugs are

neuramidase inhibitors, meaning they essentially block

the activity of the neuramidase enzyme on the surface of

the inﬂuenza virus, consequently preventing the spread

of the virus to uninfected cells.

Drug resistance with neuramidase inhibitors is

also a concern, although not to the same extent as the

adamantine derivatives. Fewer adverse side eﬀects are

associated with neuramidase inhibitors compared to

the adamantine counterparts. Clinical trials on zana-

mivir and oseltamivir show headache and gastrointes-

tinal disturbance to be the most common side eﬀects

(oseltamivir produced occasional nausea and vomiting),

with occurrence comparable to that of placebo.37-40 Al-

though neuramidase inhibitors work on both inﬂuenza

A and B and are associated with fewer side eﬀects, they

are signiﬁcantly more expensive than adamantine de-

rivatives. Because zanamivir is only available as an orally

inhaled powder, it can cause bronchospasm and should

be avoided in patients with underlying reactive airway

disease.24,36,41

Inﬂuenza Vaccinations

Although antiviral medications oﬀer preven-

tive support, conventional medicine regards vaccination

as the standard of care for preventing inﬂuenza and its

complications.25

Vaccines are typically modiﬁed each year to

include the most prevalent strains from the previous

season: usually two inﬂuenza A viruses (e.g., H3N2

and H1N1) and one B virus, as the vaccine is only eﬀec-

tive against three particular strains in any given season.

When the vaccine contains the same hemagglutinin an-

tigen and/or neuramidase antigen as the strains in the

community, vaccination can decrease infections by 70-

90 percent in healthy adults under age 65.24 ere are,

however, several hundred strains of inﬂuenza circulat-

ing at any time, and healthy adults are not the popula-

tion in most need of vaccination.

Interestingly, vaccines appear to be less eﬀec-

tive in institutionalized elderly patients. According to

the Centers for Disease Control (CDC), even when the

match between the vaccine and the circulating virus is

close, the eﬃcacy rate of the ﬂu vaccination drops to

30-40 percent for institutionalized individuals over age

65.32

A report on the inﬂuenza vaccination eﬀect on

seasonal mortality in the elderly revealed that, although

in the United States the number of individuals age 65

and older getting ﬂu vaccinations increased from 15-50

percent before 1980 to 65 percent in 2001, the actual

rate of ﬂu-related deaths did not decline.42

Vaccine-induced immunity decreases with an-

tigenic drift; therefore, prior vaccinations provide less

or no protection as the viruses mutate. Furthermore,

vaccination oﬀers no protection against antigenic shift,

which occurs when two diﬀerent strains of inﬂuenza

combine to form a new subtype having a mixture of the

surface antigens of the two original strains.

Two forms of inﬂuenza vaccines are available

for administration, an inactivated inﬂuenza vaccine and

a live attenuated inﬂuenza vaccine (LAIV), both of

which are antigenically equivalent to the annually rec-

ommended strains. Because both vaccines use inﬂuenza

viruses initially grown in embryonated hens eggs, they

may contain trace amounts of residual egg protein and

are contraindicated in patients with a history of anaphy-

lactic reactions to chicken or egg protein.24,25

Alternative Medicine Review Volume 12, Number 1 2007

Colds and Inﬂuenza

Page 32

Although inactivated inﬂuenza vaccines con-

taining killed viruses do not produce signs or symptoms

of inﬂuenza virus infection, LAIV has the potential to

produce mild ﬂu-like signs or symptoms. In the United

States, the LAIV is administered intranasally to healthy

individuals, ages 5-50 years. e vaccine should not be

given to patients in high-risk groups, pregnant women,

household contacts of immune-deﬁcient patients, or

children receiving chronic aspirin therapy. Children,

ages 5-8 years, not previously vaccinated with the LAIV,

should receive a second dose at least six weeks after the

ﬁrst dose.

e most common adverse eﬀects associated

with ﬂu vaccines range from localized pain at the injec-

tion site (for the inactivated vaccine) to rhinorrhea, fe-

ver, fatigue, painful joints, and headache.24,25,43 Guillain-

Barre syndrome has been reported as a possible serious

adverse eﬀect occurring within two weeks of vaccina-

tion.43 Although some studies assess the risk at 10 cases

per million persons vaccinated,44 it is recommended

that individuals with a history of Guillain-Barre syn-

drome not be vaccinated.32

In an interesting blend of conventional treat-

ment and alternative therapies, a small randomized,

controlled, eight-week study was conducted on 41 adult

participants exploring the alterations in brain and im-

mune function produced by mindfulness meditation.

Brain activity was measured before, immediately after,

and four months after an eight-week clinical training

program in mindfulness meditation. At the end of the

eight-week period, subjects in both the experimental

and control groups were inoculated with inﬂuenza vac-

cine. Results of the study revealed signiﬁcant increases

in left-sided anterior brain activation and antibody ti-

ters to the inﬂuenza vaccine in meditators versus non-

meditators, indicating meditation might improve one’s

response to ﬂu vaccines.45

Alternative Treatments for Cold and Flu

Nutritional Considerations

Vitamin C

Since the 1940s, numerous studies have sug-

gested high doses of vitamin C both prevent and reduce

the eﬀects of the common cold. And, ever since Linus

Pauling – a highly respected, two-time Nobel prize

winner – advocated large doses of vitamin C in his 1970

bestseller, Vitamin C and the Common Cold, interest in

vitamin C for treating colds and other viruses has sky-

rocketed.

A meta-analysis of 29 controlled trials investi-

gated the beneﬁts of ≥200 mg vitamin C daily for the

common cold in 11,077 subjects.46 e meta-analysis

revealed vitamin C prophylaxis does appear to reduce

the duration and severity of colds, but not the incidence.

However, regarding incidence, in a subgroup of six

studies in which subjects were under signiﬁcant physi-

cal stress from exercise training in cold northern cli-

mates (soldiers, skiers, or marathon runners), subjects

on vitamin C prophylaxis demonstrated a 50-percent

reduction in incidence of the common cold.47 e 29-

trial meta-analysis also examined the eﬀect of vitamin

C prophylaxis on cold duration (n=9,676 colds). Doses

of ≥200 mg daily shortened cold duration in children

by 14 percent and eight percent in adults. e eﬀect of

prophylactic vitamin C on cold severity was examined

in several of the trials, (7,045 respiratory episodes) and

those taking vitamin C experienced slightly fewer “at

home” days than those not taking vitamin C, suggesting

a less severe infection.46 Table 3 summarizes the preven-

tion studies from this meta-analysis for which full text

was available.

e meta-analysis also evaluated the eﬃcacy

of vitamin C taken at the onset of cold symptoms (for

treatment rather than prevention) and found no statis-

tically signiﬁcant beneﬁt in cold duration or severity,46

with the exception of one large trial that reported a

reduction in duration with 8 g vitamin C at symptom

onset.55 Table 4 summarizes the treatment studies from

this meta-analysis for which full text was available.

Alternative Medicine Review Volume 12, Number 1 2007

Review Article

Page 33

Table 3. Summary of Vitamin C Studies for Prevention of the Common Cold48-65

1942

1944

1956

1961

1972

1973

1974

1975

1976

1977

1979

1981

1998

Cowan

Dahlberg

Franz

Ritzel

Anderson

Charleston

Wilson

Anderson

Coulehan

Carson

Karlowski

Coulehan

Elwood

Ludvigsson

Miller

Pitt

Carr

Himmelstein

363 college students

2,525 Army

personnel

89 medical students

& nurses

279 children at ski

school

818 adults

90 adults

421 boarding-school

children

2,349 adults

641 Navaho children

263 adults

190 adults

868 Navaho children

688 adults

615 school children

44 twin children

674 Marines

95 pairs of adult &

adolescent twins

92 marathon runners

& sedentary controls

SBC

RCT

SBC

RCT

2 years

57 days

3 months

2 weeks

3 months

15 weeks

9 months

3 months

14 weeks

40 days

9 months

15-18 weeks

100 days

3 months

5 months

8 weeks

100 days

2 months

200 mg daily

200 mg daily for 24

days, then 50 mg daily

205 mg daily

1 g daily

4 g daily for 3 days,

then 1 g daily

1 g daily

200 mg daily

250 mg-2 g daily; 3

dosage arms

1-2 g daily; 2 dosage

arms

1 g daily

3 g daily

1 g daily

500 mg-1 g daily;

3 dosage arms

2 g daily

1,070 mg daily

1 g daily

Duration of Trial Year Authors Subjects Type of Study Dosage

incidence

incidence, duration

incidence

incidence, duration

incidence, duration,

severity

incidence, duration

duration, severity

incidence, duration,

severity

incidence, duration

incidence

duration

incidence, duration

incidence, duration,

severity

duration, severity

incidence, duration,

severity

incidence, duration,

severity

incidence, duration,

severity

Outcome Measured

No effect on incidence

No effect on incidence or duration

No effect on incidence

Decreased incidence; no effect on

duration

Significantly decreased incidence and

severity

Decreased incidence; slightly decreased

duration

Decreased severity in girls only

No effect on incidence; small effect on

duration and severity

No effect on incidence; shortened

duration

No effect on incidence

Slightly decreased duration

No effect on incidence; shortened

duration

Slight decrease in incidence and duration

No effect on incidence; shortened

duration and severity

Significantly decreased duration in a

subgroup; no effect overall

No effect on incidence or duration;

possible decrease in severity

Significantly decreased incidence,

duration, and severity

No benefit on any parameter in marathon

runners

Outcome

* Trials shown are those for which full text was available in English. Several other trials were included in the Douglas meta-analysis.

SBC = Single-blind, randomized, controlled

RCT = Double-blind, randomized, controlled

Alternative Medicine Review Volume 12, Number 1 2007

Colds and Inﬂuenza

Page 34

Cold incidence: Among all trials

included in the meta-analysis (29 total

with 11,077 participants) the pooled

relative risk (RR) of developing

a cold while taking prophylactic

vitamin C was 0.96 (95% CI 0.92-

1.00) – not a signiﬁcant diﬀerence

when compared to placebo. However,

in a subgroup of six trials involving

642 soldiers, skiers, and marathon

runners exercising in cold climates,

individuals on vitamin C prophylaxis

had only a 50-percent chance of

developing a cold compared to

subjects exercising in cold climates

and not taking vitamin C (pooled

RR: 0.50).

Cold duration: In trial comparisons

involving 9,676 respiratory episodes,

adults on vitamin C prophylaxis

experienced an eight-percent

reduction in cold duration compared

to placebo, while children on

prophylaxis experienced a 15-percent

reduction in cold duration compared

to placebo.

Cold severity: Pooled analysis of

trial comparisons involving 7,045

respiratory episodes among adults

and children revealed a modest, yet

statistically signiﬁcant, decrease in

cold severity in those taking vitamin

C prophylaxis. e main outcomes

measured were missed school or

work days and mean symptom

severity score. However, results were

inconsistent and parameters used

to measure severity varied greatly

among the trials.

Table 4. Summary of Vitamin C Studies for Treatment of the Common Cold

55,58,66-70

e following is a summary of meta-

analysis conclusions.46

Prophylaxis trials (vitamin C given to prevent

colds):

Alternative Medicine Review Volume 12, Number 1 2007

Review Article

Page 35

One drawback to trials using high-dose vitamin

C is that gastrointestinal side eﬀects make it diﬃcult to

keep the trials double-blind. Consequently, any eﬀective

trial using therapeutic doses of 2-10 g daily is met with

skepticism by the conventional medical community.71

Some of the studies in the meta-analysis showing little

or no eﬀect used vitamin C dosages considered “small”

by vitamin C advocates (100-500 mg per day).

Another factor is the plasma half-life of high-

dose vitamin C, which is approximately 30 minutes.72

is suggests most studies are methodologically ﬂawed

because vitamin C, when not dosed frequently enough,

would be expected to show only minimal beneﬁt. e

Vitamin C Foundation (formed by a group of highly-

regarded physicians and researchers specializing in or-

thomolecular medicine and headed by Abram Hoﬀer,

MD, PhD) recommends very high doses of vitamin C

for the common cold – an initial dosage of up to 8 g

every 20-30 minutes.73 Unfortunately, oral doses of this

magnitude are not feasible for most people due to gas-

trointestinal symptoms, with supplementation often be-

ing discontinued. Vitamin C supplementation in large,

divided doses over several days is likely to be the most

eﬀective at alleviating symptoms or shortening cold du-

ration.

In the case of inﬂuenza, few clinical trials have

examined the eﬃcacy of vitamin C. In a controlled trial

of 226 patients with inﬂuenza A, 114 patients received

300 mg vitamin C daily, while 112 patients served as

controls; outcomes measured were development of

pneumonia and duration of hospital stay. Pneumonia

was reported in two cases in the treatment group and

10 in the control group, while hospital stays for inﬂu-

enza or related complications averaged nine days in the

vitamin C group and 12 days in the control group.74

A two-year, controlled trial of 715 students

(ages 18-32) examined the eﬀect of high-dose vitamin

C in preventing and relieving the symptoms of viral-in-

duced respiratory infections (colds and ﬂu). In the con-

trol group of 463 students, those reporting symptoms

were treated with decongestants and pain relievers. e

252 students in the treatment group were divided into

those reporting symptoms and those who were asymp-

tomatic. Symptomatic individuals were given hourly

doses of 1 g vitamin C for the ﬁrst six hours, and then 1 g

three times daily until symptoms subsided; asymptom-

atic students received 1 g three times daily throughout

the test period. In the test group, vitamin C administra-

tion resulted in an 85-percent decrease in cold and ﬂu

symptoms compared to the control group. e results

of this study are diﬃcult to interpret, however, as the

study period was not clearly deﬁned and data did not

separate the incidence of colds versus the ﬂu.75

Zinc

Zinc plays an important role in maintaining

healthy immune function. Human studies have ob-

served even a mild zinc deﬁciency can elicit changes in

immune status, such as defective natural killer (NK)

cell function, decreased interleukin-2 production, and

anergy.76

Zinc supplementation has long been considered

an eﬀective means of reducing the duration of the com-

mon cold. In a randomized study, 200 healthy children

were assigned to receive either oral zinc sulfate (15 mg

elemental zinc) or placebo daily for seven months, with

an increase to 15 mg twice daily at the onset of a cold.

e mean number of colds in the zinc group was sta-

tistically signiﬁcantly fewer than the placebo group (1.2

versus 1.7 colds per child, respectively; p=0.003), while

mean cold-related school absences was 0.9 days for the

zinc group versus 1.3 days in the placebo group.77

Several trials have examined the use of zinc

lozenges for colds, with mixed results (Table 5).78-84 One

placebo-controlled, seven-day study observed 65 indi-

viduals who took either a loading dose of 46 mg zinc

(two zinc gluconate lozenges) followed by 23 mg zinc

(one lozenge) or placebo every two wakeful hours until

symptoms were absent for six hours. After seven days

86 percent of the zinc group were symptom-free com-

pared to 46 percent of the placebo group (p=0.0005).78

Cold duration: In an analysis of seven trials

involving 3,294 respiratory episodes, vitamin

C provided no signiﬁcant beneﬁt to duration

of cold symptoms compared to placebo.

Cold severity: No statistically signiﬁcant eﬀect

of vitamin C on cold severity was observed in

treatment groups compared to placebo when

four trials involving 2,753 respiratory episodes

were analyzed.

erapeutic trials (vitamin C given at onset of a cold):

Alternative Medicine Review Volume 12, Number 1 2007

Colds and Inﬂuenza

Page 36

Table 5. Zinc Lozenges for Treatment of the Common Cold

Kurugol Z, et al.

(2006)

McElroy BH,

Miller SP (2003)

McElroy BH,

Miller SP (2002)

Prasad AS, et al.

(2000)

Turner RB,

Cetnarowski WE

(2000)

Macknin ML, et

al. (1998)

Eby GA, et al.

(1984)

200 (n=100 in tx

group) school-age

children

134 (n=134 in tx

group) school-age

children; retro. data

used as placebo

496 (n=119 in tx

group) school-age

children

48 (n=25 in tx

group) adults

273 (n=204 in tx

groups)* adults w/

induced colds

281 (n=208 in tx

groups)** adults

w/ natural colds

249 (n=124 in tx

groups) school-age

children

65 (n=37 in tx

group) adults and

school-age children

zinc sulfate syrup

zinc gluconate

glycine lozenges

zinc gluconate

glycine lozenges

zinc acetate

lozenges

zinc gluconate

glycine lozenges;

zinc acetate

lozenges (two

different potencies)

zinc gluconate

glycine lozenges;

zinc acetate

lozenges (two

different potencies)

zinc gluconate

glycine lozenges

zinc gluconate

glycine lozenges

15 mg daily prophylactic; 15 mg twice

daily after onset of cold and until

symptoms resolved

13.3 mg (1 lozenge) daily as a prophylactic

measure; 53.2 mg (4 lozenges) daily at

onset of cold signs and/or until symptoms

resolved

13.3 mg (1 lozenge) daily as a prophylactic

measure

12.8 mg (1 lozenge) every 2-3 hours

13.3 mg (1 zinc gluconate lozenge) x 6/d

(n=69);

11.5 mg (1 zinc acetate lozenge) x 6/d

(n=70);

5 mg (1 zinc acetate lozenge) x 6/d (n=65)

*n=69+70+65=204

13.3 mg (1 zinc gluconate lozenge) x 6/d

(n=68);

11.5 mg (1 zinc acetate lozenge) x 6/d

(n=68);

5 mg (1 zinc acetate lozenge) x 6/d (n=72)

** n=68+68+72=208

10 mg (1 lozenge) three times daily during

school hours; Children grades 1-6: 20 mg

(2 lozenges) on school nights and 100 mg

(5 lozenges) per day on weekends Children

grades 7-12: 30 mg (3 lozenges) on school

nights and 110 mg (6 lozenges) per day on

weekends

46 mg (2 lozenges) loading dose followed

by 23 mg (1 lozenge) every 2 wakeful

hours until symptoms absent for 6 hours

7 months

10/2001-05/2002;

pre-1999 records used as

placebo data

review of cases from

01/1998-08/2001

Initiated within 24 hours

of onset and continued

until symptoms resolved

From onset of cold up to

14 days

From onset of cold up to

14 days

From within 24 hours of

onset of cold until

symptoms absent for 6

hours

7 days

Mean no. colds per child:

1.2 (Z) vs 1.7 (P); (p=0.003)

Mean no. cold-related absences per child:

0.9 days (Z) vs 1.3 days (P); (p=0.04)

Shorter duration of cold symptoms in zinc group vs

placebo; (p<0.0001)

Mean no. of colds per child:

1.28 (±1.03) (Z) vs 1.7 (±1.9) (P); (p<0.05)

Mean duration (days) of cold per child:

6.9 (±3.1) (Z) vs 9.1 (±3.5) (P); (p=0.001)

Median no. of colds per year:

0.0 vs 1.3; (p<0.001)

Mean duration (in days) of cold:

4.5 (±1.6) (Z) vs 8.1 (±1.8) (P); (p<0.01)

Median duration (in days) of cold:

zinc gluconate lozenges: 2.5 (Z) vs 3.5 (P); (p=0.035)

zinc acetate lozenges: Neither potency had any

significant effect.

Effect on severity of cold:

No difference between zinc preparations and placebo

Effect on duration or severity of cold: No difference

between zinc preparations and placebo

No significant difference between zinc group and

placebo

After 7 days, 86% of zinc group were asymptomatic

vs 46% of placebo group; (p=0.0005). Zinc lozenge

shortened the duration of cold by 7 days.

Study Length

Study (year) Sample Size Zinc Form Dosage of Zinc Findings

One study involving 48 adults found zinc acetate loz-

enges (12.8 mg zinc per lozenge) taken every 2-3 hours

while awake reduced the duration of cold symptoms

compared to placebo (4.5 versus 8.1 days).84

In a seven-month, phase IV trial, 134 school

children were given 13.3 mg zinc (one zinc gluconate

lozenge) daily as a preventive and 53.2 mg zinc (four zinc

gluconate lozenges) daily at cold onset until symptoms

resolved. Previously collected data was used as a control.

Average cold duration of the zinc group was 6.9±3.1

days versus 9.0±3.5 days for the control group.80

Several studies have concluded, however, that

zinc lozenges fare no better than placebo.81-83 One study

involving two arms (273 adults with induced colds;

281 adults with natural colds) examined the eﬀects of

zinc gluconate (13.3 mg zinc) or zinc acetate (5 or 11.5

mg zinc) lozenges compared to placebo. e treatment

groups took six lozenges daily of their respective prepa-

ration from cold onset until symptoms resolved, for a

maximum of 14 days. e subjects with induced colds

Alternative Medicine Review Volume 12, Number 1 2007

Review Article

Page 37

taking zinc gluconate demonstrated a median duration

of illness of 2.5 days compared to 3.5 days in the pla-

cebo group (p=0.35); no signiﬁcant change was noted

in symptom severity compared to placebo. e zinc ac-

etate group yielded no signiﬁcant change in cold dura-

tion or symptom severity compared to placebo. In the

experimental arm involving subjects with natural colds,

none of the zinc groups yielded any signiﬁcant change

in duration of cold and/or severity of symptoms com-

pared to placebo.82

In another study, the eﬃcacy of zinc gluconate

lozenges (10 mg zinc per lozenge) compared to placebo

was examined in 249 school children. Lozenges were

dosed at one lozenge ﬁve times daily (grades 1-6) or six

times daily (grades 7-12) from cold onset until symp-

toms were absent for six hours. No signiﬁcant diﬀeren-

ces were noted between the zinc and placebo groups.83

A meta-analysis of the eﬀect of zinc gluconate

lozenges for the common cold analyzed eight random-

ized, clinical trials. Although the researchers cited limi-

tations to their analysis (e.g., dependence on the validity

of the studies and the fact that their analysis was limited

to a single variable [presence of “any” cold symptom af-

ter seven days of treatment]), the authors found weak

evidence for the eﬃcacy of zinc gluconate lozenges in

reducing cold duration.81

Diﬀerences in zinc preparations, including form

(zinc gluconate versus zinc acetate), amount (elemental

zinc per lozenge; ranges from 5-23 mg), and composi-

tion of the lozenge have been identiﬁed as possible ex-

planations why study results are inconsistent.79,85

Intranasal zinc preparations are often sold as

over-the-counter cold remedies. However, studies have

not shown this route of administration to be as eﬀec-

tive as lozenges. Two placebo-controlled trials found in-

tranasal zinc gluconate slightly reduced the duration of

cold symptoms.86,87 In one study, 78 adults took 2.1 mg

zinc daily (one spray in each nostril four times daily) or

placebo for 10 days from cold onset. Mean duration of

cold was 4.3 days in the zinc group versus six days in the

placebo group (p=0.002).86 Similarly, another study ob-

served 213 adults taking either 2.1 mg zinc (one spray

in each nostril every four hours) or placebo from cold

onset until symptoms resolved. Duration of cold was

2.3 days in the zinc group versus nine days in the pla-

cebo group (p<0.05).87

ese ﬁndings contrast with two other placebo-

controlled studies that found no beneﬁt from zinc nasal

spray.88,89 One study followed 91 individuals with in-

duced colds using either zinc gluconate nasal spray (one

spray in each nostril ﬁve times daily) or placebo for three

days before the challenge and six days after.88 e sec-

ond study involved 160 adult participants taking 0.044

mg zinc (zinc sulfate nasal spray) or placebo daily from

cold onset until symptoms resolved or up to 14 days.89

In both cases, the respective researchers concluded that

changes in cold duration or symptom severity were no

diﬀerent between the zinc and placebo groups. Table 6

summarizes the studies of zinc nasal spray.

In an interesting footnote, several cases report

individuals experiencing loss of the sense of smell (an-

osmia) after using intranasal zinc as a cold remedy.90

Zinc at doses of 30 mg and above can cause

stomach upset, nausea, and/or vomiting, which can be

reduced when taken with food. Prolonged excessive zinc

intake can result in copper deﬁciency, as documented in

a case of zinc gluconate supplementation at 850-1,000

mg per day for one year. Signs and symptoms included

fatigue, dyspnea on exertion, anemia, neutropenia, pal-

lor, and orthostatic pulse changes.91

Vitamin A

Clinical trials examining vitamin A to boost

immunity and treat respiratory infections have yielded

conﬂicting results. e majority of studies have been

conducted in children malnourished, underweight,

and/or deﬁcient in vitamin A. No consistent beneﬁt has

been observed in healthy children or adults with viral-

induced respiratory infection.92,93 One study analyzed

the eﬀect of 50,000-100,000 IU vitamin A given as a

single dose to children under age ﬁve years with pneu-

monia, a potential cold/ﬂu complication. No signiﬁcant

diﬀerences were reported between the treatment and

placebo groups with respect to duration of respiratory

symptoms.94

N-acetylcysteine

N-acetylcysteine (NAC), an ester of the amino

acid L-cysteine, is a potent antioxidant.95 It has been

used for over 30 years to treat bronchitis and other

lung conditions due to its expectorant and mucolytic

properties.96,97 In a 1988 randomized controlled trial,

Alternative Medicine Review Volume 12, Number 1 2007

Colds and Inﬂuenza

Page 38

91 patients with chronic bronchitis were given 300 mg

NAC or placebo twice daily for six months. Over the

four winter months, subjects in the NAC group expe-

rienced a 65-percent reduction in sick leave days from

bronchitis exacerbation (173 days versus 456 days in

the placebo group), indicating less severe infection in

the NAC group.98

A larger trial involving 262 elderly subjects

investigated the eﬀect of oral NAC prophylaxis on

the occurrence and severity of inﬂuenza-like episodes

and inﬂuenza A infection during the cold and ﬂu sea-

son. Subjects received 600-mg NAC tablets or placebo

twice daily for six months. Over the six-month period,

the number of subjects with inﬂuenza-like episodes in

the NAC group averaged 29 percent, compared to 51

percent in the placebo group. In regard to severity of

inﬂuenza-like episodes, 72 percent of those in the NAC

group who became ill reported mild episodes, 26 percent

reported moderate episodes, and two percent reported

severe episodes. In the placebo group 48 percent re-

ported mild episodes, 47 percent moderate episodes,

and six percent severe episodes, indicating that a greater

percent of the placebo group experienced a severe infec-

tion. Of the 262 subjects in the study, 65 became in-

fected with inﬂuenza A virus. Although infection rates

between placebo and NAC groups were similar, only 25

percent of the NAC group who became infected with

inﬂuenza A was symptomatic compared to 79 percent

in the placebo group.99

Dehydroepiandrosterone (DHEA)

Inﬂuenza is particularly dangerous to older

people with weakened immune systems. Age-associ-

ated DHEA deﬁciency may be partially responsible for

an age-related decline in immune function.100,101 One

study demonstrated a metabolite of DHEA enhanced

Table 6. Zinc Nasal Spray for Treatment of the Common Cold

Mossad SB

(2003)

Belongia EA,

et al. (2001)

Turner RB

(2001)

Hirt M, et al.

(2000)

78 (n=40 in tx

group) adults

160 (n=81 in tx

group) adults

91 (n=41 in tx

group) adults w/

induced colds

213 (n=108 in tx

group) (adults)

zinc gluconate

nasal spray

(33mmol/L)

zinc sulfate nasal

spray

zinc gluconate

nasal spray

(33mmol/L)

zinc gluconate

nasal spray

(33 mmol/L)

2.1 mg/day (1 spray

in each nostril

4x/day)

0.044 mg/day (2

sprays in each

nostril 4x/day)

2.1 mg/day (1 spray

in each nostril q4h

5x/day)

2.1 mg/day (1 spray

in each nostril q4h)

Initiated 24-48 hrs

from onset of cold

until symptoms

resolved or up to 10

days

Initiated at onset of

cold until

symptoms resolved

or up to 14 days

Initiated 3 days

before viral

challenge and for 6

days after

Initiated within 24

hrs from onset of

cold until

symptoms resolved

Mean duration (in days) of cold:

4.3 (Z) vs 6 (P); (p = 0.002)

Signicant reduction of total

symptom scores started from

second day of the study;

Adverse eects (mainly nasal

stinging) similarly reported in both

zinc and placebo groups

Eect on duration or severity of

cold: No dierence between zinc

preparations and placebo

No eect on total symptom score,

rhinorrhea, nasal obstruction, or

proportion of infected volunteers

who developed colds compared to

placebo

Shorter time to resolution of

symptoms in zinc group vs

placebo: 2.3 days (Z) vs 9.0 days

(P); p<0.05

Study Length

Study (year) Sample Size Zinc Form Dosage of Zinc Findings

Alternative Medicine Review Volume 12, Number 1 2007

Review Article

Page 39

T-helper cell activation and protected mice from a le-

thal inﬂuenza virus infection.102 Other studies have

shown DHEA and its metabolites have powerful im-

mune-enhancing and antiviral eﬀects.103-105 In elderly

men, administration of 50 mg DHEA daily resulted

in signiﬁcant increases in number of monocytes and

B-lymphocytes, a 62-percent increase in B-cell activ-

ity, a 40-percent increase in T-cell activity, and signiﬁ-

cant increases in both NK-cell numbers and activity.101

DHEA may be a hormone to consider for prevention

of colds and ﬂu, particularly in the elderly; most studies

of DHEA for immune enhancement in the elderly used

50 mg daily.

High Lactoferrin Whey Protein

Whey protein supplementation appears to en-

hance the immune system,106 scavenge free radicals,107

and exhibit antimicrobial activity.108 Lactoferrin is a

peptide fraction of whey with documented antibacteri-

al, antimycotic, antiviral,109 and immune-modulating ef-

fects. Studies have shown lactoferrin is an iron-binding

protein110 that is present in exocrine secretions, includ-

ing tears, nasal exudates, saliva, and bronchial mucus.111

Lactoferrin is also a major constituent of circulating

polymorphonuclear neutrophils (PMNs)112 and is re-

leased on degranulation in septic areas.113

To date, no clinical trials have been conducted

on the use of high lactoferrin whey protein to prevent

or treat colds or ﬂu, but because of its demonstrated

antiviral, antibacterial, and anti-inﬂammatory proper-

ties, it may be of beneﬁt in alleviating the symptoms

or complications of these viral infections. e primary

function of lactoferrin is to scavenge free iron in ﬂuids

and inﬂamed areas,114 suppressing free radical-mediated

damage and decreasing the availability of the metal to

invade microbial and neoplastic cells. Lactoferrin has

also been shown to bind to viral receptor sites and in-

hibit in vitro growth of several viruses, including HIV,

Herpes simplex 1 and 2, hepatitis C, and human cyto-

megalovirus.112

Botanicals for the Prevention and

Treatment of Colds and Flu

Echinacea (Echinacea spp)

Various species of Echinacea have been iden-

tiﬁed for generations by traditional herbalists as in-

valuable medicinal plants.115,116 Although traditional

herbalists used Echinacea for various conditions, from

alopecia to cancer, its modern application is primarily

for immune support. Today, Echinacea is arguably the

most recognized herbal supplement for prevention and

treatment of colds and ﬂu. Despite this long history in

traditional herbal medicine, or perhaps because of it,

Echinacea has come under much scientiﬁc scrutiny to

determine its eﬀectiveness for colds and ﬂu.

Diﬀerent species of Echinacea demonstrate

immuno-supportive properties. Both Echinacea pur-

purea and Echinacea angustifolia appear to activate non-

speciﬁc cellular and humoral immunity and the comple-

ment system.117-121 Polysaccharides from E. purpurea

have been shown in vitro to preferentially stimulate the

mononuclear immune system and release of interleu-

kin-1 (IL-1).117 Similarly, in vitro studies on arabinoga-

lactans from E. purpurea have been observed to induce a

dose-dependent release of tumor necrosis factor-alpha

(TNF-α) from peritoneal macrophages.117 In another

study, glycoproteins known as arabinogalactan-proteins

isolated from E. pallida demonstrated marked immuno-

modulatory eﬀects by stimulating IgM production and

proliferation of lymphocytes in mice.122

A randomized, double-blind, placebo-

controlled trial observed 48 adult female participants

over a period of four weeks to determine the immuno-

logical activity of various Echinacea preparations and

larch arabinogalactan versus placebo.123 Of the various

preparations used in the study, complement properdin

(a protein in serum used as a marker for assessing im-

mune response) increased by 21 percent over placebo in

participants taking a combination extract of E. purpurea

and E. angustifolia and by 18 percent in subjects taking

a combination of E. purpurea, E. angustifolia, and larch

arabinogalactan. e other forms did not provoke a sig-

niﬁcant response.

Clinical studies have shown mixed results re-

garding Echinacea’s eﬀect on reduction and duration of

symptoms associated with common cold, inﬂuenza, and

other acute respiratory infections. One randomized,

double-blind, placebo-controlled study involving 282

Alternative Medicine Review Volume 12, Number 1 2007

Colds and Inﬂuenza

Page 40

adults examined the eﬀect of an Echinacea formulation

(0.25 mg/mL alkamides, 2.5 mg/mL chicoric acid, and

25 mg/mL polysaccharides=1 unit) or placebo for sev-

en days from cold onset. e dosage was 10 units on the

ﬁrst day of cold symptoms, followed by four units per

day for the next seven days. Total daily symptom sever-

ity scores, recorded on a 10-point scale (0=minimum;

9=maximum), were 23.1-percent lower in the Echina-

cea group compared to placebo (p<0.01).124

In a related placebo-controlled trial on 150

adults using the same Echinacea formula (dosage=eight

5-mL units on the ﬁrst day and three units daily on subse-

quent days for the next seven days), researchers observed

decreased daily symptom scores and increases in the num-

ber of total white blood cells, monocytes, neutrophils, and

NK cells in the Echinacea group versus placebo.125

In another placebo-controlled, blinded study

assessing changes in cold duration, 80 adult participants

were randomly assigned to take E. purpurea herb extract

or placebo at the onset of cold symptoms until symp-

toms subsided. e median duration of illness was six

days in the Echinacea group compared to nine days in

the placebo group (p=0.0112).126

Conversely, some studies have reported no sta-

tistically signiﬁcant improvement from Echinacea for

the common cold.127-130 For example, in a randomized,

double-blind, placebo-controlled trial, 148 college stu-

dents were given an encapsulated mixture of unreﬁned

E. purpurea herb (25%) and root (25%) and E. angus-

tifolia root (50%) or placebo; 1 g doses were taken six

times on the ﬁrst day of a cold and three times daily on

each subsequent day for a maximum of 10 days. ere

were no signiﬁcant diﬀerences in severity or duration of

symptoms between the Echinacea and placebo groups.131

In another placebo-controlled trial, 128 adults were ad-

ministered 100 mg E. purpurea or placebo three times

daily until cold symptoms were relieved, up to a maxi-

mum of 14 days, with no statistical diﬀerence observed

between the two groups.130

ere is a clear controversy within the estab-

lished scientiﬁc community regarding the eﬃcacy of

Echinacea. Diﬀerences in study results might be associ-

ated with the preparation used in a given study (E. pur-

purea, E. angustifolia, or E. pallida, or a combination),

the part of the plant used, and the method of extraction.

Nevertheless, there is suﬃcient evidence to warrant fur-

ther investigation of Echinacea for immune support.

Elderberry (Sambucus nigra)

Sambucus nigra is a member of the Caprifolia-

ceae or honeysuckle family. Extracts of the berries are

used primarily as antiviral agents for colds, inﬂuenza,

and Herpes virus infections. Research demonstrates

Sambucus nigra possesses immune-modulating and an-

tioxidant properties.132,133 Constituents of the berries

include the ﬂavonoids quercetin and rutin, anthocya-

nins identiﬁed as cyanidin-3-glucoside and cyanidin-3-

sambubioside,134 the hemagglutinin protein Sambucus

nigra agglutinin III (SNA-III),135 cyanogenic glycosides

including sambunigrin,136,137 viburnic acid, and vitamins

A and C.133

e antiviral properties of elderberry were

ﬁrst studied by Mumcuoglu, an Israeli virologist, who

demonstrated elderberry constituents neutralize the

activity of the hemagglutinin spikes found on the sur-

face of several viruses, including inﬂuenza A and B and

the Herpes virus. When these hemagglutinin spikes are

deactivated, the viruses can no longer pierce cell walls

or enter the cell and replicate.138 Elderberry extracts

also exert an immune-modulating eﬀect by enhanced

cytokine production, which activates phagocytes and

facilitates movement to inﬂamed tissues.139 Elderberry

anthocyanin ﬂavonoids also possess signiﬁcant antioxi-

dant potential.140 Although no clinical trials have been

conducted, the German Commission E reports that

constituents of Sambucus provide eﬀective relief for

colds, fevers, and catarrh.141 Anecdotal reports indicate

elderberry extracts can shorten the duration or lessen

the severity of the common cold, particularly when used

in combination with vitamin C and zinc.

Two randomized, double-blind, placebo-con-

trolled studies demonstrate the elderberry extract,

Sambucol, eﬀectively inhibits both inﬂuenza A and B

strains when given orally to patients in the ﬁrst 48 hours

of inﬂuenza symptoms. In one study, 27 individuals (23

with laboratory conﬁrmation of inﬂuenza B) experienc-

ing typical early ﬂu symptoms were given Sambucol

(n=15) or placebo (n=12) daily for three days – two ta-

blespoons (30 mL) for children or four tablespoons (60

mL) for adults – and symptoms were monitored for six

days. Serum from all subjects was analyzed for antibod-

ies to inﬂuenza A and B at the initial dose and during

the convalescent phase. While diﬀerences in antibody

titers between the two groups did not reach statistical

Alternative Medicine Review Volume 12, Number 1 2007

Review Article

Page 41

signiﬁcance, a trend in favor of the treatment group was

observed. Clinically however, signiﬁcant improvement

in ﬂu symptoms was observed in 14 of 15 subjects in

the treatment group two days after initial dosing, with

complete symptom resolution in 13 of 15 subjects af-

ter three days. In the placebo group, complete symptom

resolution was only achieved by 4 of 12 subjects within

three days and 5 of 12 subjects after ﬁve days.142

In a second study, 60 patients (ages 18-54

years) experiencing early inﬂuenza symptoms were

given 15 mL (1 tablespoon) Sambucol or placebo syrup

four times daily for ﬁve days; symptoms were monitored

for eight days. In the treatment group, the majority of

patients reported “pronounced improvement” after an

average of 3-4 days, while the placebo group required

7-8 days to reach the same level of improvement.143

Garlic (Allium sativa)

Although clinical research examining garlic’s

eﬀect on colds and ﬂu is minimal, one study did evalu-

ate an allicin-containing garlic supplement on cold inci-

dence and duration in 146 volunteers. Subjects received

one capsule daily for 12 weeks between November and

February, and symptoms were assessed via a symptom

diary using a ﬁve-point scale. In the garlic-supplemented

group, 24 colds were reported compared to 65 in the

placebo group; the treatment group experience shorter

duration of cold symptoms compared to placebo – 1.5

versus 5.0 days, respectively.144

Panax quinquefolium

Panax quinquefolium (North American

ginseng) has been shown in controlled trials to reduce

the incidence, duration, and severity of colds and ﬂu in

both ill and healthy individuals. A four-month study

that commenced at the beginning of cold and ﬂu season

evaluated 323 healthy adults (ages 18-65 years) with a

history of at least two colds the previous year. ose in

the treatment group received two 200-mg capsules daily

of a standardized extract of P. quinquefolium containing

80-percent poly-furanosyl-pyranosyl-saccharides, while

the placebo group received 200 mg rice powder (encap-

sulated) twice daily. Outcomes measured were number

of colds, symptom severity, and total number of symp-

tomatic days. In patients taking the ginseng extract the

mean number of reported colds was reduced by 9.2

percent, and the risk of developing a cold was reduced

by 12.8 percent compared to the placebo group. In ad-

dition, the ginseng group reported a 31-percent lower

symptom score (severity) and 34.5-percent fewer symp-

tom days (duration) than the placebo group.145

In a second study using a proprietary extract

containing highly concentrated poly-furanosyl-pyrano-

syl-saccharides, 43 community-dwelling elderly adults

were given 200-mg capsules of the extract or placebo

twice daily for four months. One month into the study,

all participants received an inﬂuenza vaccination. Dur-

ing the ﬁrst two months, incidence and duration of re-

spiratory infections did not diﬀer signiﬁcantly between

the two groups. During the last two months, however,

32 percent of subjects taking the herbal formula report-

ed an upper respiratory tract infection compared to 62

percent in the placebo group. In addition, the treatment

group reported average symptom duration of 5.6 days

compared to 12.6 days in the placebo group.146

A Combination of Eleutherococcus senticosus and

Andrographis paniculata

A combination of Eleutherococcus senticosus and

Andrographis paniculata was found eﬀective for inﬂu-

enza infections. e combination formula, also known

as Kan Jang®, was studied in a pilot trial involving 540

adults with inﬂuenza. Subjects (n=71) were given two

tablets containing standardized extracts of Androgra-

phis (88.8 mg) and Eleutherococcus (10.0 mg) three

times daily for 3-5 days, while individuals using con-

ventional antiviral medications (n=469) – amantadine

or other physician-preferred medication – served as the

control group. Primary outcome measures were severity

of disease (measured by development of complications)

and disease duration (measured by number of days on

sick leave). In the herbal formula group, 30.1 percent

progressed to complicated inﬂuenza compared to 67.8

percent in the control group. Likewise, those in the

herbal group experienced a shorter duration of symp-

toms (approximately 6-7 days) compared to 9-10 days

in the control group.147

A second phase of the trial, involving 66 inﬂu-

enza patients (n=31 herbal treatment; n=35 controls

[conventional treatment]) using the same protocol, re-

vealed comparable results. Days on sick leave were sig-

niﬁcantly fewer in the herbal group (7.2 days) than in

Alternative Medicine Review Volume 12, Number 1 2007

Colds and Inﬂuenza

Page 42

the control group (9.2 days). In addition, 31.4 percent

of patients in the herbal-treatment group developed

post-inﬂuenza complications, while that rate more than

doubled to 71.0 percent in the control group. ese

studies appear to indicate Kan Jang extract is an eﬀec-

tive herbal therapy that may be superior to conventional

antiviral medications for reducing severity and duration

of inﬂuenza infections.147

Larch Arabinogalactans

Larch arabinogalactans, polysaccharides de-

rived from the wood of Larix occidentalis (Western

larch), stimulate the immune system by activating

phagocytosis and potentiating the eﬀect of the reticu-

loendothelial system. Because of these properties, larch

arabinogalactans may be an eﬀective adjunct for the

treatment of colds and ﬂu.148,149

Recurrent otitis media is common in pediatric

populations and a frequent complication of colds. Im-

proving immune system function might lead to a de-

crease in both frequency and severity of this common

complication. Research has demonstrated larch and

other arabinogalactans enhance the immune response

to bacterial infection via stimulation of phagocytosis,

competitive binding of bacterial ﬁmbriae, or bacterial

opsonization. D’Adamo reports a decrease in occur-

rence and severity of otitis media in pediatric patients

supplemented prophylactically with larch arabinogalac-

tan.148 Larch arabinogalactan’s mild taste and excellent

solubility in water and juice make it a relatively easy

therapeutic tool to employ in pediatric populations.148

Olive Leaf Extract

Constituents of the olive tree, Olea europaea,

have been studied and utilized in folk medicine for

centuries. Olive leaf extract, derived from the leaves of

the olive tree, contains phenolic compounds, speciﬁ-

cally oleuropein, that have demonstrated potent anti-

microbial, antioxidant, and anti-inﬂammatory activity.

Oleuropein and derivatives such as elenolic acid have

been shown to be eﬀective in in vitro and animal studies

against numerous microorganisms, including retrovi-

ruses, coxsackie viruses,150 inﬂuenza, and parainﬂuenza

3,150,151 as well as some bacteria.152 Research suggests

that olive leaf constituents interact with the protein of

virus particles and reduce the infectivity and inhibit rep-

lication of viruses known to cause colds, inﬂuenza, and

lower respiratory infection.150,151,153 Olive leaf extract

has also been shown to stimulate phagocytosis, thereby

enhancing the immune response to viral infection. An-

ecdotal reports indicate olive leaf extract taken at the

onset of cold or ﬂu symptoms prevents or shortens the

duration of the disease. For viral sore throats, gargling

with olive leaf tea may alleviate symptoms, possibly by

decreasing inﬂammation and viral infectivity.

Astragalus (Astragalus membranaceus)

Astragalus membranaceus has traditionally been

used as a tonic and treatment for colds and ﬂu, either

alone or in conjunction with other herbs.154 Astraga-

lus is rich in polysaccharides, ﬂavonoids, multiple trace

minerals, and amino acids, all of which contribute to its

immuno-supportive properties. Animal studies demon-

strated oral administration of Astragalus root extract to

mice infected with Japanese encephalitis virus increased

survival rates by 30-40 percent compared to 20 percent

in the untreated control group.155 e researchers attri-

bute this to increased phagocytic activity.

In a small, double-blind, placebo-controlled

trial participants took oral extracts of Echinacea pur-

purea, Astragalus membranaceus, or Glycyrrhiza glabra

singly, a combination of the three herbs, or placebo

twice daily for seven days, to determine whether intake

of the herbal tinctures (singly and/or in combination)

stimulated activation and/or proliferation of immune

cells. Of the herbs tested, Astragalus demonstrated the

strongest activation and proliferation of immune cells,

particularly CD8 and CD4 T-cells, compared to place-

bo. Furthermore, the combination herbal formula dem-

onstrated an additive eﬀect regarding activation, but not

proliferation, of T-cells.156

Baptisia (Baptisia tinctoria) in Combination with

other Herbs

A randomized, double-blind, placebo-con-

trolled trial of 238 subjects with acute cold symptoms

demonstrated that a formula of Baptisia tinctoria root

(30 mg), Echinacea purpurea root (22.5 mg), and uja

occidentalis leaf (6 mg) three times daily for 7-9 days

signiﬁcantly reduced intensity and duration of symp-

toms compared to placebo. In subjects who suﬀered

from moderate-symptom intensity at baseline, at least

50-percent improvement by day 5 was experienced in

Alternative Medicine Review Volume 12, Number 1 2007

Review Article

Page 43

55.3 percent of the treatment group compared to 27.3

percent of the placebo group (p=0.017).157 erapeu-

tic beneﬁt of the herbal formula was noted on day 2,

reached signiﬁcance (p=0.05) on day 4, and continued

to improve until the end of the treatment.157

Isatis (Isatis tinctoria; Isatis indigotica)

Both the leaf and root of Isatis have been used

for centuries in traditional medicine for the treatment

of various infections, including upper respiratory in-

fections, inﬂuenza, encephalitis, and gastroenteritis.158

Isatis is listed in both old and new Chinese pharma-

copoeias, and is considered an eﬀective antipyretic and

anti-inﬂammatory.159 e antimicrobial action of the

root is similar in action to berberine.159 In vitro and hu-

man studies from China have shown Isatis root extract

to be antibacterial, antiviral, and antiparasitic.158

Animal studies indicate Isatis polysaccharide

increases total white blood cell and lymphocyte counts

in peripheral blood, and antagonizes the immuno-sup-

pressive actions induced by hydrocortisone, indicating

Isatis is capable of increasing humoral and cellular im-

mune function.160

Conclusion

Common cold viruses and inﬂuenza infections

are leading causes of doctor visits in the United States,

aﬄicting a signiﬁcant portion of the population. e

common cold, although relatively mild in symptomolo-

gy and severity, accounts for a signiﬁcant number of lost

work or school days. Inﬂuenza, although considered a

preventable disease, accounts for 36,000 deaths annu-

ally in the United States. Although vaccinations and an-

tiviral drugs can be helpful in prevention and treatment

of inﬂuenza, their scope and eﬀectiveness are limited.

Consequently, most conventional interventions for colds

and ﬂu involve symptomatic relief with over-the-coun-

ter medications. Natural therapeutics in the form of nu-

tritional supplementation and immune-stimulating and

antiviral botanicals can support the body’s natural de-

fenses, potentially decreasing the incidence of colds and

ﬂu, shortening the duration and decreasing the intensity

of symptoms, and preventing complications.

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Potential Role of Vitamins and Zinc on Acute Respiratory Infections Including Covid-19

Article

Full-text available

May 2021

Background. Vitamin C, E, D, A, zinc are considered to be essential in preventing and treating of acute respiratory infections (ARI) including COVID-19. Methods. We reviewed published studies evaluating the potential roles of these vitamin and zinc for ARIs and COVID-19 using Medline database, medRxiv, and bibliographic references. Results. Vitamins C, D, and E did not reduce incidence of common cold in general, but vitamin C reduced by half in population with physical and environment stresses. Vitamins C and E shortened duration and reduced severity of common cold. A large-dose vitamin A had no effect on recovery from pneumonia. Zinc improved clinical deterioration and pneumonia duration in under five. The effect on preventing COVID-19 morbidity and related-death was lacking. Conclusions. Although the effects of vitamins and zinc on ARIs including COVID-19 were inconclusive, taking these for a short period during pandemic may be beneficial when there is risks of deficiency.

Medicinal Plants and Isolated Molecules Demonstrating Immunomodulation Activity as Potential Alternative Therapies for Viral Diseases Including COVID-19

Article

Full-text available

May 2021

Plants have been extensively studied since ancient times and numerous important chemical constituents with tremendous therapeutic potential are identified. Attacks of microorganisms including viruses and bacteria can be counteracted with an efficient immune system and therefore, stimulation of body’s defense mechanism against infections has been proven to be an effective approach. Polysaccharides, terpenoids, flavonoids, alkaloids, glycosides, and lactones are the important phytochemicals, reported to be primarily responsible for immunomodulation activity of the plants. These phytochemicals may act as lead molecules for the development of safe and effective immunomodulators as potential remedies for the prevention and cure of viral diseases. Natural products are known to primarily modulate the immune system in nonspecific ways. A number of plant-based principles have been identified and isolated with potential immunomodulation activity which justify their use in traditional folklore medicine and can form the basis of further specified research. The aim of the current review is to describe and highlight the immunomodulation potential of certain plants along with their bioactive chemical constituents. Relevant literatures of recent years were searched from commonly employed scientific databases on the basis of their ethnopharmacological use. Most of the plants displaying considerable immunomodulation activity are summarized along with their possible mechanisms. These discussions shall hopefully elicit the attention of researchers and encourage further studies on these plant-based immunomodulation products as potential therapy for the management of infectious diseases, including viral ones such as COVID-19.

Progression and Trends in Virus from Influenza A to COVID-19: An Overview of Recent Studies

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Full-text available

Jun 2021

Influenza is a highly known contagious viral infection that has been responsible for the death of many people in history with pandemics. These pandemics have been occurring every 10 to 30 years in the last century. The most recent global pandemic prior to COVID-19 was the 2009 influenza A (H1N1) pandemic. A decade ago, the H1N1 virus caused 12,500 deaths in just 19 months globally. Now, again, the world has been challenged with another pandemic. Since December 2019, the first case of a novel coronavirus (COVID-19) infection was detected in Wuhan. This infection has risen rapidly throughout the world; even the World Health Organization (WHO) announced COVID-19 as a worldwide emergency to ensure human health and public safety. This review article aims to discuss important issues relating to COVID-19, including clinical, epidemiological, and pathological features of COVID-19 and recent progress in diagnosis and treatment approaches for the COVID-19 infection. We also highlight key similarities and differences between COVID-19 and influenza A to ensure the theoretical and practical details of COVID-19.

Possible therapeutic effects of Nigella sativa and its thymoquinone on COVID-19

Article

Full-text available

Jan 2021
PHARM BIOL

Context COVID-19 is a novel coronavirus that causes a severe infection in the respiratory system. Nigella sativa L. (Ranunculaceae) is an annual flowering plant used traditionally as a natural food supplement and multipurpose medicinal agent. Objective The possible beneficial effects of N. sativa, and its constituent, thymoquinone (TQ) on COVID-19 were reviewed. Methods The key words including, COVID-19, N. sativa, thymoquinone, antiviral effects, anti-inflammatory and immunomodulatory effects in different databases such as Web of Science (ISI), PubMed, Scopus, and Google Scholar were searched from 1990 up to February 2021. Results The current literature review showed that N. sativa and TQ reduced the level of pro-inflammatory mediators including, IL-2, IL-4, IL-6, and IL-12, while enhancing IFN-γ. Nigella sativa and TQ increased the serum levels of IgG1 and IgG2a, and improved pulmonary function tests in restrictive respiratory disorders. Discussion and conclusions These preliminary data of molecular docking, animal, and clinical studies propose N. sativa and TQ might have beneficial effects on the treatment or control of COVID-19 due to antiviral, anti-inflammatory and immunomodulatory properties as well as bronchodilatory effects. The efficacy of N. sativa and TQ on infected patients with COVID-19 in randomize clinical trials will be suggested.

Grindelia squarrosa Extract and Grindelic Acid Modulate Pro-inflammatory Functions of Respiratory Epithelium and Human Macrophages

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Full-text available

Jan 2021

Aim of the study: Both nasal and bronchial epithelial cells have evolved sophisticated mechanisms involved in cellular response to bacterial infection. Recognition of pathogens by TLR receptors activate the NF-κB transcription factor, and lead to production of wide spectrum of cytokines (TNF-α, IL-1β, IL-6 and IL-8). Released by epithelium proinflammatory cytokines intensify migration of macrophages to damaged tissues and modulate their pro-inflammatory functions. Based on traditional use of G. squarrosa aerial parts we hypothesized that successful treatment of cold-related diseases may arise from modulation of the pro-inflammatory functions of respiratory epithelium and human monocytes/macrophages. The biological activity of G. squarrosa extract and grindelic acid were compared with clarithromycin and budesonide used as positive controls. Methods: The expression of surface receptors (TLR-4, IL-10) and expression of adhesive molecules (ICAM-1, VCAM-1, E-selectin) was analyzed with flow cytometry. The macrophage attachment to the epithelial cells was assessed fluorimetrically. The p65 NF-κB concentration and cytokine production was measured spectrophotometrically using enzyme-linked immunosorbent assay. Antibacterial activity was examined by the standard disc-diffusion method and serial dilution method according to CLSI guidelines. Results: G. squarrosa extract and grindelic acid had no antimicrobial effect. However, we noticed significant modulation of pro-inflammatory functions of LPS-stimulated nasal and bronchial epithelium. G. squarrosa extract treatment resulted in decrease of TLR-4 expression and p65 NF-κB concentration and inhibition of cytokines synthesis (IL-8, TNF-α, IL-1β and IL-6) in both cellular models. Additionally, G. squarrosa extract slightly modulated ICAM-1 expression affecting on attachment of macrophages to epithelium. Only G. squarrosa extract was able to stimulate the anti-inflammatory functions of macrophages by inducing TGF-β release and IL-10 receptor surface expression. Grindelic acid, identified as a dominant compound in the plant extract, modulated pro-inflammatory functions of epithelium and macrophages slightly. Conclusion: The obtained results support traditional use of Grindelia squarrosa preparations for a treatment cold-associated diseases symptoms. In our opinion, the observed biological effect of extract may be a consequence of synergistic effect of all compounds present in the extract.

Effects of a Combination of Elderberry and Reishi Extracts on the Duration and Severity of Respiratory Tract Infections in Elderly Subjects: A Randomized Controlled Trial

Article

Full-text available

Nov 2020

Elderly people are particularly vulnerable to respiratory tract infections, so natural strategies to ameliorate the duration and severity of these infections are of great interest in this population. The objective of this study is to evaluate the efficacy of the consumption of a combination of elderberry and reishi extracts on the incidence, severity, and duration of respiratory tract infections in a group of healthy elderly volunteers. A randomized, double-blind, placebo-controlled pilot study was performed during the winter season. A group of 60 nursing home residents ≥65 years of age was randomly assigned to receive a combination of 1.5 g of elderberry +0.5 g of reishi or a placebo daily for 14 weeks. Data about the health conditions of the volunteers were evaluated and recorded by a medical doctor every 2 weeks. The incidence of respiratory infections was similar in both groups. However, volunteers in the extract group presented a significantly lower duration of common cold events (2.5 vs. 4.8 days, p = 0.033).and a significantly lower probability of having a high severity influenza-like illness event (p = 0.039). Moreover, the incidence of sleep disturbances was significantly lower in the extract group (p = 0.049). Therefore, the administration of a combination of elderberry and reishi extracts to the elderly population during the winter season might be used as a natural strategy to reduce the duration and severity of respiratory tract infections.

The Possible Therapeutic Effects of Some Medicinal Plants for Chronic Cough in Children

Article

Full-text available

Oct 2020
EVID-BASED COMPL ALT

The use of plants or their isolated bioactive components for the prevention and treatment of various disorders has been developed. Here, we aim to identify effective medicinal plants for relief of cough and respiratory symptoms in children. The data of this review article were obtained from published articles in scientific databases, including PubMed, Google Scholar, and Scopus, until December 2019. The keywords, including "Zataria multiflora Boiss."OR "Portulaca oleracea L."OR "Ferula assa-foetida L."OR "Nigella sativa L."AND "respiratory symptoms"OR "airway inflammation"OR "smooth muscle relaxant effects,"were searched individually or combined. The mentioned medicinal plants decreased total white blood cell (WBC), neutrophils, and eosinophils counts of blood and lung lavage in animal model-induced respiratory disorders. These plants also have protective effects on serum immunoglobulin, antibody titer, eosinophil count, and proinflammatory cytokines. Evidence from the studies indicated that the abovementioned medicinal plants have smooth muscle relaxant properties (bronchodilator effects) via stimulation of β-adrenoceptor or inhibition of muscarinic receptors (in vitro) and also improved the pulmonary function test in clinical settings. These medicinal plants are safe and easy to use. Based on the anti-inflammatory, anti-antispasmodic, and immunomodulatory effects, the clinical benefit may be assumed, therefore considering a place for these medicinal plants in relieve of chronic cough and symptoms of children's allergy, asthma, and common cold.

Rhinitis, rhinosinusutus and phytotherapy

Article

May 2021

V. V. Shilenkova

Acute rhinitis and acute rhinosinusitis (ARS) have viral etiology in the most of cases, and their therapy is aimed at alleviating clinical symptoms and preventing new episodes. The indications for antibiotic therapy are severe bacterial ARS, ARS with complications, and recurrent bacterial ARS. Such a categorical approach is due to the increase of antibiotic resistance, which leads to the popularization of efficient phytotherapy. Modern herbal medical products comply with general recommendation and standards of efficacy, safety and quality, and their effectiveness has been proven in clinical trials along with synthetic drugs. In acute upper respiratory tract infections, herbal medical drugs stimulate the immune system, relieve clinical symptoms, and improve the patient’s quality of life. A significant emphasis in phytotherapy is given to complex drugs synthesized on the basis of phytoneering. One of such remedies is the herbal medicinal product containing the different parts of 5 medicinal herbs: Gentian root (Gentianae radix), Primrose flowers (with calyx) (Primulae flos (cum calycibus)), Common sorrel herb (Rumicis herba), Elder flowers (Sambuci flos) and Vervain herb (Verbenae herba). This herbal medicinal product shows secretolytic, secretomotor, antiinflammatory, antiviral and mild antibacterial farmacological effects. The article provides an analysis of studies in vitro and in vivo proving the anti-inflammatory effect of Sinupret®, its potentiating effect on nasal mucosa mucociliary transport as well as efficacy and safety in patients with rhinosinusitis.

306-Data

Article

Apr 2021

Muhammad Akram

Important antihistaminic plants and their potential role in health

Chapter

Mar 2021

Allergic diseases such as allergic asthma, hay fever, dermatitis, food, and drug allergies have increased tremendously in the last decade with increased morbidity. The current antihistaminic drugs have some limitations in terms of safety and efficacy. Most of the allergic conditions are chronic and long-term therapy is essential. Therefore, most allergic patients seek better alternatives to synthetic antihistaminic agents. Several plants and their derived natural products have been reported as effective, safe, and cheap antiallergic agents. Additionally, several plant-derived formulas have reached the clinical trials as safe antiallergic, with similar mechanisms to synthetics drugs. In this chapter, we highlighted the relevant use of plants from folk medicine or scientific-based evidence for natural antiallergic drugs. Special emphasis is given on the natural compounds with reported antiallergic activity.

The Pharmacology of Chinese Herbs

Book

Jul 1998

Kee Huang

The common cold

Article

Jan 1995

Gwaltney, J.M., Jr

Antiinflammatory activities of lactoferrin

Conference Paper

Oct 2001
J AM COLL NUTR

Orla M. Conneely

Lactoferrin is a non-heme iron binding glycoprotein produced during lactation and by epithelial cells at mucosal surfaces. The protein is a prominent component of the first line of mammalian host defense and its expression is upregulated in response to inflammatory stimuli. In this paper, the antibacterial and immune modulatory properties of lactoferrin that contribute to host defense are reviewed. In addition, the results of recent preclinical and clinical studies demonstrating that lactoferrin acts as an inhibitor of dermal inflammatory cytokine production are summarized. The results indicate that lactoferrin may act as a potent anti-inflammatory protein at local sites of inflammation including the respiratory and gastrointestinal tracts.

Zinc: Health effects and research priorities for the 1990s

Article

Jun 1994
ENVIRON HEALTH PERSP

This review critically summarizes the literature on the spectrum of health effects of zinc status, ranging from symptoms of zinc deficiency to excess exposure. Studies on zinc intake are reviewed in relation to optimum requirements as a function of age and sex. Current knowledge on the biochemical properties of zinc which are critical to the essential role of this metal in biological systems is summarized. Dietary and physiological factors influencing the bioavailability and utilization of zinc are considered with special attention to interactions with iron and copper status. The effects of zinc deficiency and toxicity are reviewed with respect to specific organs, immunological and reproductive function, and genotoxicity and carcinogenicity. Finally, key questions are identified where research is needed, such as the risks to human health of altered environmental distribution of zinc, assessment of zinc status in humans, effects of zinc status in relation to other essential metals on immune function, reproduction, neurological function, and the cardiovascular system, and mechanistic studies to further elucidate the biological effects of zinc at the molecular level.

Larch arabinogalactan

Article

Jan 1996

P. D'Adamo

The immune system in health and disease

Article

Jan 1999
IMMUNOBIOLOGY

Encyclopedia of Natural Medicine

Article

Jan 1997

Antimicrobial activity of lactoferrin: Mechanisms and possible clinical applications

Article

Jan 2005

Lactoferrin (Lf) is an iron binding multifunctional glycoprotein that is present in several mucosal secretions like milk, tears and saliva. Lf is also an abundant component of the specific granules of neutrophils and can be released into the serum upon neutrophil degranulation. One of the functions of this protein is the transport of metals, but it is also an important component of the non-specific immune system. Human and bovine Lfs display a broad antimicrobial spectrum against Gram positive and Gram negative bacteria, fungi and several viruses. While the iron-binding properties were originally believed to be solely responsible for the host defense properties ascribed to lactoferrin, it is now known that other mechanisms contribute to the antimicrobial role of this glycoprotein. This review gives an overview of the knowledge of these mechanisms and the potential clinical applications of Lf against infections.

Echinacea purpurea Therapy for the Treatment of the Common Cold

Article

Jun 2004
ARCH INTERN MED

Background Echinacea purpurea stimulates the immune response and is promoted to reduce symptom severity and the duration of upper respiratory tract infections. We sought to determine the efficacy of a standardized preparation of E purpurea in reducing symptom severity and duration of the common cold.Methods A randomized, double-blind, placebo-controlled design was used. Patients received either 100 mg of E purpurea (freeze-dried pressed juice from the aerial portion of the plant) or a lactose placebo 3 times daily until cold symptoms were relieved or until the end of 14 days, whichever came first. Symptoms (sneezing, nasal discharge, nasal congestion, headache, sore or scratchy throat, hoarseness, muscle aches, and cough) were scored subjectively by the patient and recorded daily in a diary. Kaplan-Meier curves were used to estimate the survival function of time to resolution in each group. The Wilcoxon rank sum test was used to compare time to resolution between the 2 groups.Results One hundred twenty-eight patients were enrolled within 24 hours of cold symptom onset. Group demographic distribution was comparable for sex, age, time from symptom onset to enrollment in the study, average number of colds per year, and smoking history. No statistically significant difference was observed between treatment groups for either total symptom scores (P range, .29-.90) or mean individual symptom scores (P range, .09-.93). The time to resolution of symptoms was not statistically different (P = .73).Conclusions Some studies have concluded that Echinacea effectively reduces the symptoms and duration of the common cold. We were unable to replicate such findings. Further studies using different preparations and dosages of E purpurea are necessary to validate previous claims.

Ascorbic acid for the common cold. A prophylactic and therapeutic trial

Article

Mar 1975
J Am Med Assoc

Thomas R. Karlowski

Colds and influenza: A review of diagnosis and conventional, botanical, and nutritional considerations

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