Cold and Flu

Acute Respiratory Tract Infections
Except during the neonatal period, acute respiratory tract Infections (ARIs) are the most common causes of both illness and mortality in children under five years of age, with an average of three to six episodes of ARIs per year regardless of where they live or what their family income is (Monto 1974).

In the United States, consumers spend about $2 billion per year for over-the-counter medications for ARI, and the total annual cost of ARI managed in outpatient settings is estimated to be more than $10 billion (Shapiro 1998).


Classification of Acute Respiratory Tract Infections
ARIs are classified as upper respiratory tract infections (URIs) or lower respiratory tract infections (LRIs). The upper respiratory tract consists of the airways from the nostrils to the vocal cords in the larynx, including the paranasal sinuses and the middle ear. The lower respiratory tract covers the continuation of the airways from the trachea and bronchi to the bronchioles and the alveoli in the lungs (Cherian 2006).


Causes of ARIs and Burden of Disease

  1. Upper Respiratory Tract Infections. 
    URIs are the most common infectious illnesses. They include rhinitis, sinusitis, ear infections, acute pharyngitis or tonsillopharyngitis, epiglottitis, and laryngitis — of which ear infections and pharyngitis cause the more severe complications (deafness and acute rheumatic fever, respectively). The vast majority of URIs have a viral etiology. Rhinoviruses account for 25-30% of URIs; respiratory syncytial viruses (RSVs), parainfluenza and influenza viruses, human metapneumovirus, and adenoviruses - for 25-35 %; corona viruses - for 10%; and unidentified viruses for the remainder. Since most URIs are self-limiting, their complications are more important than the infections they cause. Acute viral infections predispose to bacterial infections of the sinuses and the middle ear, and aspiration of infected secretions and cells can result in LRIs (Denny 1995).
  2. Lower Respiratory Tract Infections
    The common LRIs in children and adults are pneumonia and bronchiolitis. Currently, the most common cause of viral LRIs are RSVs. They tend to be highly seasonal, unlike parainfluenza viruses, the next most common cause of viral LRIs (Cherian, 2006).
    Both bacteria and viruses can cause pneumonia. Bacterial pneumonia is often caused by Streptococcus pneumoniae (pneumococcus) or Haemophilus influenzae, mostly type b (Hib), and occasionally by Staphylococcus aureus or other streptococci. Other pathogens, such as Mycoplasma pneumoniae and Chlamydia pneumoniae, cause atypical pneumonias (Cherian, 2006).


Upper respiratory tract infections as a major cause of mild morbidity in adults and children.
URIs are commonly treated in family physicians' practices. Uncomplicated URIs account for 25 million visits to family physicians and about 20 to 22 million days of absence from work or school each year in the United States (Heikkinen 2003).

URI or “the common cold” is a symptom complex usually caused by several virus families. As already mentioned, these are the rhinovirus, coronavirus, parainfluenza virus, RSV, adenovirus, human metapneumovirus and influenza virus. Occasionally, the enterovirus is implicated in summer. Recently, the newly discovered bocavirus has also been linked to URI (Cotton 2008).

Both – the common cold and the flu, are contagious viral infections of the upper respiratory tract and most of the symptoms are similar. But there are key differences in how a cold and a flu initiate and progress. 

What is the difference between the flu and the common cold?

  1. Common cold
    The common cold is one of the most common infectious diseases of humankind. Adults in the United States experience two to four episodes of common cold per year. While the flu is caused by influenza viruses, there are more than 200 distinct viruses that can cause a cold. Among them, rhinoviruses are the cause of more than half of respiratory tract infections (Pratter 2006).

    Bacterial coinfections are very rare. That’s why antibiotic treatment is not required in otherwise healthy young adults with common cold (Mäkelä 1998).  One study reviewed randomized controlled trials (RCTs) from 1966 to 2009 that compared antibiotic therapy with placebo in individuals who had symptoms of acute URI of less than seven days' duration, or acute purulent rhinitis of less than 10 days duration. The authors found insufficient evidence to recommend antibiotics for the treatment of purulent or clear rhinitis in children or adults (Arroll 2005). However, it has been shown that up to 60% of patients with common cold receive an antibiotic, which results in an estimated cost of $37.5 million per year in the United States (Mainous 1996).

    Signs and symptoms of common cold typically occur about one to three days after exposure to a cold-causing virus. They peak around day four, and resolve around day seven. Early signs of common cold include fatigue, nasal stiffness, and a sore throat. When nasal symptoms start, the nose produces clear mucus, but the discharge may later change to yellow or green. Other symptoms include: sneezing, post-nasal drip, coughing, watery eyes, fatigue, body aches, mild headache, low-grade fever (more likely in children). The duration of a cold is usually between 7 and 10 days (Mäkelä 1998).

  2. Influenza
    Influenza is an acute URI caused by influenza virus A or B. It affects patients of all ages, but the highest incidence is in children. Adults older than 65 years and children younger than two years have the highest mortality rates from influenza (Harper 2009).
    Influenza viruses are among the most significant human respiratory pathogens that cause both seasonal, endemic infections and periodic, unpredictable pandemics. The worst pandemic on record, in 1918, killed approximately 50 million people worldwide. Human infections caused by H5N1 highly pathogenic avian influenza viruses have raised concern about the emergence of another pandemic (Taubenberger 2008).

    Up to 50% of the population can be infected in a single pandemic year, and the number of deaths caused by influenza can dramatically exceed what is normally expected. In the elderly, in infants, and in people with chronic diseases, influenza is associated with particularly high mortality (Thompson 2003).

    Influenza is an acute respiratory disease characterized in its full form by the sudden onset of high fever, coryza, cough, headache, prostration, malaise, and inflammation of the upper respiratory tract and trachea. In most cases, lung involvement is not clinically prominent. Acute symptoms and fever often persist for 7 to 10 days. Weakness and fatigue may linger for weeks. Influenza usually occurs in winter outbreaks or epidemics (in temperate climates). People of all ages are afflicted, but the prevalence is greatest in school-age children. Disease severity is greatest in infants, the aged, and those with underlying illnesses. Croup (laryngotracheitis) can be a serious complication in small children (Taubenberger 2008).

    Clinical differentiation between common cold and influenza can be difficult, but there are signs and symptoms that that are more likely for one or the other. These signs and symptoms are summarized in table 1 (cdc.gov).


Table 1: Signs and symptoms of Influenza and common cold (cdc.gov)

Is it a cold or flu?
Signs and symptomsInfluenzaCold
Symptom onsetAbruptGradual
FeverUsualRare
AchesUsualSlight
ChillsFairly commonUncommon
Fatigue, weaknessUsualSometimes
SneezingSometimesCommon
Stuffy noseSometimesCommon
Sore throatSometimesCommon
Chest discomfort, coughCommonMild to moderate
HeadacheCommonRare


How viruses cause disease?
Viruses are very tiny germs. They are made of genetic material inside and of a protein coating on the outside.  Viruses are like hijackers. They invade living, normal cells and use those cells to multiply and produce other viruses like themselves. This can kill, damage, or change the cells, which makes people sick (medlineplus.gov).  The basic process of viral infection and virus replication occurs in 6 main steps (immunology.org):

  1. Adsorption - virus binds to the host cell.
  2. Penetration - virus injects its genome into host cell.
  3. Viral Genome Replication - viral genome replicates using the host's cellular machinery.
  4. Assembly - viral components and enzymes are produced and begin to assemble.
  5. Maturation - viral components assemble and viruses fully develop.
  6. Release - newly produced viruses are expelled from the host cell.

Viral replication is a complex multi-stage process, which can be influenced at different steps.

Treatment of upper respiratory tract infections

  1. Symptomatic treatment
    The most common approach of management of RTIs is relief of symptoms: fever, nasal congestion and cough. Widely used substances for symptom relief are: first generation antihistamines; non-steroid anti-inflammatory drugs (NSAIDs), such as paracetamol and ibuprofen; cough relief products, such as dextromethorphan; expectorants (guaifenesin) and decongestants such as pseudoephedrine and phenylpropanolamine (MMWR 2007). Although they provide symptom relief, there is no conclusive evidence that they shorten the duration of symptoms and illness in general (Schroeder 2004).

  2. Antibiotic treatment
    Antibiotic use in childhood URIs remains debatable since more than 90% of the infections are of viral origin. The reasons behind widespread antibiotic usage include diagnostic uncertainty, socio-cultural and economic pressures, concerns over malpractice litigation and parental expectations of an antibiotic (Pichichero 1999). Antibiotics are overprescribed for URIs and promote antibiotic resistance. However, they have their role in some conditions, such as severe acute rhinosinusitis lasting more than ten days and severe acute otitis media (Dowell 1998).

  3. Antiviral drugs
    There are limited number of substances, which attack the cause of the acute viral infection – the viruses. Unlike the bacterial infections, where there are multiple options for specific treatment, i.e. the antibiotics, the management of the acute respiratory illnesses of viral origin is challenging. The etiologic treatment of the acute viral infections is limited to two groups of antiviral drugs - neuraminidase inhibitors and adamantanes (Cotton 2008).

    Four antiviral drugs are currently available for RTIs, but they are effective only for the treatment or prophylaxis of influenza: adamantanes (amantadine and rimantadine) and the newer class of neuraminidase inhibitors (zanamivir and oseltamivir). Adamantanes or M2 channel blockers are effective only against influenza type A viruses. The M2 proton channel is required for virus replication and maturation. After the virus is taken up into the host cell by endocytosis, the low pH of the endosome activates the M2 channel to allow proton flux from the endosome into the viral interior. This acidification dissociates the viral RNA from its bound matrix proteins and permits release of the viral genetic material to the cytoplasm for replication (Balgi 2013).

    As a class, the neuraminidase inhibitors are effective against all neuraminidase subtypes and, therefore, against all strains of influenza. Neuraminidase inhibitors, zanamivir and oseltamivir, interfere with the release of progeny influenza virus from infected host cells, a process that prevents infection of new host cells and thereby halts the spread of infection in the respiratory tract (Moscona 2005).

    Since replication of influenza virus in the respiratory tract reaches its peak between 24 and 72 hours after the onset of the illness, drugs such as the neuraminidase inhibitors and adamantanes that act at the stage of viral replication must be administered as early as possible (Moscona 2005).

    Unfortunately, antimicrobial resistance (AMR) threatens the effective prevention and treatment of an ever-increasing range of infections caused by bacteria, parasites, viruses and fungi. Antiviral drugs are important for the treatment of epidemic and pandemic influenza, but recent studies have demonstrated that virtually all influenza A viruses circulating in humans were resistant to one category of antiviral drugs – M2 Inhibitors (amantadine and rimantadine). However, the frequency of resistance to the neuraminidase inhibitor oseltamivir remains low (1-2%) (who.int).

  4. New approaches in the management of common cold and influenza 

    Humic acid (HA) complex is an organic substance derived from natural compounds found in humus soil. The molecules are purified from ecologically clean sources. Humic acid interferes with attachment of the virion to the cell surface and inhibits the endonuclease activity of viral RNA polymerase (Lu 2002). With most viruses, the inhibitory effect of HA is directed specifically against an early stage of virus replication – virus attachment to host cells (Klöcking 2005). In a double-blind, randomized study of a Tolpa Torf preparation in patients with recurrent respiratory tract infections, after ingestion of HA for 3 weeks, 70% of the patients were free from infection for the following 3 months, which was statistically significant, as compared to placebo (Jankowski 1993). This result likely reflects the inhibitory activity of humic acid against viruses such as Influenza A, Herpes simplex 1, and Coxsackie A9 (Klöcking 2005).

    Andrographis is a herb traditionally used in China, India, and Southeast Asia. Recent scientific research indicates that the active constituents in Andrographis, known as andrographolides, block NF-кВ, central transcriptional factor in the host cell, and the assembling of viral particles in new virions (Xia 2004). Controlled clinical trials report its safe and effective use for reducing symptoms of uncomplicated upper respiratory tract infections and the inflammatory symptoms of sinusitis (Gabrielian 2002). The addition of Andrographolide to conventional therapy reduced the occurrence of major complications, the fever clearance time, and the healing time of typical skin or oral mucosa lesions in children with severe hand, foot, and mouth disease (HFMD) (Li 2013).

    Spirulina extract is a nutritional supplement scientifically demonstrated to block viruses from penetrating into cells – including viruses that cause flu. Spirulina extract’s unique benefits and production methods are protected by U.S. and international patents and have been subjected to rigorous scientific studies. In addition to different types of flu viruses, Spirulina extract has also been shown to inhibit a number of other pathogens including several potentially serious intestinal viruses (Enterovirus 71 and Coxsackie virus A162) that may cause illness, paralysis and even death, especially in children (Shih 2003). Calcium Spirulan, a high-molecular weight sulphated polysaccharide inhibits the replication of several enveloped viruses, including Herpes simplex virus type 1, human cytomegalovirus, measles virus, mumps virus, influenza A virus, and HIV-1 (Hayashi 1996). Spirulina extract does not kill viruses. Instead, it protects cells by creating a "viral firewall" that many viruses can’t cross – the inspiration for its name. While Spirulina extract is not intended to treat or prevent illness, just like vitamins, minerals and other nutritional supplements, it helps support the body’s natural defenses (Nielsen 2010; Hirahashi 2002).

    Vitamin C. Based on its immunostimulatory properties, high doses of vitamin C have been postulated to be effective in ameliorating and speeding the recovery from the common cold (Anderson 1975). 

    Zinc. It is well recognized that zinc is an essential trace element, influencing growth and affecting the development and integrity of the immune system. Scientific research has begun to reveal the molecular mechanisms underlying the action of zinc on the immune function. It is clear that this trace element has a broad impact on key immunity mediators, such as enzymes, thymic peptides and cytokines, explaining the paramount importance of zinc's status for the regulation of lymphoid cell activation, proliferation and apoptosis (Dardenne 2002). Zinc contributes to the normal function of the immune system (EFSA 2014) and decreases incidence of infections in elderly people (Prasad 2007).

HIGHLIGHTS

  • Upper respiratory tract infections are the most common infectious diseases of the humankind.
  • The vast majority of URIs have a viral etiology. Bacterial coinfections are rare.
  • There are only two classes of antiviral drugs acting against the causes for URIs of viral origin - Neuraminidase inhibitors and Adamantanes. 
  • Unfortunately, they are effective only against Influenza viruses. About 10% to 15% of common cold in adults are caused by influenza viruses.
  • There are more than 200 distinct viruses that can cause common cold and require aetiologic treatment.
  • There are some substances of natural origin with well documented scientific data on inhibition of viral replication, such as humic acid, andrographolide and spirulina. They can support health and contribute to fast recovery from RTIs.


Reference

2http://www.who.int/mediacentre/factsheets/fs194/en/
Arroll B, Kenealy T. Antibiotics for the common cold and acute purulent rhinitis. Cochrane Database Syst Rev. 2005;(3):CD000247
Balgi AD, Wang J, Cheng DYH, Ma C, Pfeifer TA, Shimizu Y, et al. (2013) Inhibitors of the Influenza A Virus M2 Proton Channel Discovered Using a High-Throughput Yeast Growth Restoration Assay. PLoS ONE 8(2): e55271.
Cherian T, Chow J, et al. Acute Respiratory Infections in Children. In: Jamison DT, Breman JG, Measham AR, et al., editors. Disease Control Priorities in Developing Countries. 2nd edition. Washington (DC): The International Bank for Reconstruction and Development / The World Bank; 2006. Chapter 25.
Cotton, Mf et al. “Management of upper respiratory tract infections in children” South African family practice : official journal of the South African Academy of Family Practice/Primary Care vol. 50,2 (2008): 6-12.
Denny F. W. Jr. The Clinical Impact of Human Respiratory Virus Infections. American Journal of Respiratory and Critical Care Medicine. 1995;152(4, part 2):S4–12
Dowell SF, Schwartz B, Phillips WR. Appropriate use of antibiotics for URIs in children: Part II. Cough, pharyngitis and the common cold. The Pediatric URI Consensus Team. Am Fam Physician. 1998;58(6):1335–1342. 1345.
Gabrielian ES et al., “A Double Blind, Placebo-Controlled Study of Andrographis Paniculata Fixed Combination Kan Jang in the Treatment of Acute Upper Respiratory Tract Infections Including Sinusitis.,” Phytomedicine : International Journal of Phytotherapy and Phytopharmacology 9, no. 7 (October 2002): 589–97.
Gabrielian ES, Shukarian AK, Goukasova GI, et al. A double blind, placebo-controlled study of Andrographis paniculata fixed combination Kan Jang in the treatment of acute upper respiratory tract infections including sinusitis. E S Gabrielian et al., “A Double Blind, Placebo-Controlled Study of Andrographis Paniculata Fixed Combination Kan Jang in the Treatment of Acute Upper Respiratory Tract Infections Including Sinusitis.,” Phytomedicine : International Journal of Phytotherapy and Phytopharmacology 9, no. 7 (October 2002): 589–97.
Harper SA, Bradley JS, Englund JA, et al.; Expert Panel of the Infectious Diseases Society of America. Seasonal influenza in adults and children—diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(8):1003–1032.
Hayashi T, Hayashi K, Maeda M, Kojima I. Calcium spirulan, an inhibitor of enveloped virus replication, from a blue-green  alga Spirulina platensis. J Nat Prod. 1996;59(1):83-87.
Heikkinen T, Järvinen A. The common cold. Lancet. 2003;361(9351):51–59
Hirahashi T, Matsumoto M, Hazeki K, Saeki Y, Ui M, Seya T. Activation of the human innate immune system by Spirulina: augmentation of interferon production and NK cytotoxicity by oral administration of hot water extract of Spirulina platensis. Tomohiro Hirahashi et al., “Activation of the Human Innate Immune System by Spirulina: Augmentation of Interferon Production and NK Cytotoxicity by Oral Administration of Hot Water Extract of Spirulina Platensis.,” International Immunopharmacology 2, no. 4 (March 2002): 423–34. Int Immunopharmacol. 2002;2(4):423-434
https://medlineplus.gov/viralinfections.html
https://www.cdc.gov/flu/about/qa/coldflu.htm
https://www.immunology.org/public-information/bitesized-immunology/pathogens-and-disease/virus-replication
Jankowski A, Nienartowicz B, Polanska B, Lewandowicz-Uszynska A. A randomised, double-blind study on the efficacy of Tolpa Torf Preparation (TTP)  in the treatment of recurrent respiratory tract infections. Arch Immunol Ther Exp (Warsz). 1993;41(1):95-97
Klöcking R, Helbig B. Humic Substances, Medical Aspects and Applications of. In: Biopolymers Online. Wiley-VCH Verlag GmbH & Co. KGaA; 2005.
Klöcking R, Helbig B. Humic Substances, Medical Aspects and Applications of. In: Biopolymers Online. Wiley-VCH Verlag GmbH & Co. KGaA; 2005.
Li X, Zhang C, Shi Q, et al. Improving the efficacy of conventional therapy by adding andrographolide sulfonate in the treatment of severe hand, foot, and mouth disease: a randomized controlled trial. Evid Based Complement Alternat Med. 2013;2013:316250.
Lu FJ, Tseng SN, Li ML, Shih SR. In vitro anti-influenza virus activity of synthetic humate analogues derived from protocatechuic acid. Arch Virol. 2002;147(2):273-284
Mainous, A. G., III, W. J. Hueston, and J. R. Clak. 1996. Antibiotics and upper respiratory infection: do some folks think there is a cure for the common cold? J. Fam. Pract. 42:357–361.
Mäkelä  MJ et al., “Viruses and Bacteria in the Etiology of the Common Cold,” Journal of Clinical Microbiology 36, no. 2 (February 13, 1998): 539–42.
MMWR. Infant deaths associated with cough and cold medications – two states, 2005. 2007 January 12; 2007.
Monto A. S., Ullman B. M. Acute Respiratory Illness in an American Community: The Tecumseh Study. Journal of the American Medical Association. 1974;227(2):164–69.
Moscona A, “Neuraminidase Inhibitors for Influenza,” New England Journal of Medicine 353, no. 13 (September 29, 2005): 1363–73.
Nielsen CH, Balachandran P, Christensen O, et al. Enhancement of natural killer cell activity in healthy subjects by Immulina(R), a Spirulina extract enriched for Braun-type lipoproteins. Claus Henrik Nielsen et al., “Enhancement of Natural Killer Cell Activity in Healthy Subjects by Immulina(R), a Spirulina Extract Enriched for Braun-Type Lipoproteins.,” Planta Medica 76, no. 16 (November 2010): 1802–8.
Pichichero ME. Understanding antibiotic overuse for respiratory tract infections in children. Pediatrics. 1999;104(6):1384–1388.
Pratter MR, “Cough and the Common Cold,” CHEST 129, no. 1 (January 1, 2006): 72S–74S.
Schroeder K, Fahey T. Over-the-counter medications for acute cough in children and adults in ambulatory settings. Cochrane Database Syst Rev. 2004;4:CD001831
Shapiro ED , “Epidemiology of Acute Respiratory Infections,” Seminars in Pediatric Infectious Diseases 9, no. 1 (1998): 31–36.
Shih S-R, Tsai K-N, Li Y-S, Chueh C-C, Chan E-C. Inhibition of enterovirus 71-induced apoptosis by allophycocyanin isolated from a blue-green alga Spirulina platensis. Shin-Ru Shih et al., “Inhibition of Enterovirus 71-Induced Apoptosis by Allophycocyanin Isolated from a Blue-Green Alga Spirulina Platensis.,” Journal of Medical Virology 70, no. 1 (May 2003): 119–25.
Taubenberger, Jeffery K and David M Morens. “The pathology of influenza virus infections” Annual review of pathology vol. 3 (2008): 499-522.
Taubenberger, Jeffery K., and David M. Morens. “The Pathology of Influenza Virus Infections.” Annual review of pathology 3 (2008): 499–522. PMC. Web. 3 Oct. 2018.
Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289:179–86.
Xia Y-F, Ye B-Q, Li Y-D, et al. Andrographolide attenuates inflammation by inhibition of NF-kappa B activation through covalent modification of reduced cysteine 62 of p50. J Immunol. 2004;173(6):4207-4217.
Anderson TW, Beaton GH, Corey P, et al: Winter illness and vitamin C: the effect of relatively low doses. Can Med Assoc J 1975; 112: 823 – 826.
Dardenne M. Zinc and immune function. 13Eur J Clin Nutr. 2002;56 Suppl 3:S20-S23.
EFSA Panel on Dietetic Products N and A (NDA). Scientific Opinion on the substantiation of a health claim related to zinc and normal function of the immune system pursuant to Article 14 of Regulation. EFSA J. 2014;12(1924):1-9.
Prasad AS, Beck FWJ, Bao B, et al. Zinc supplementation decreases incidence of infections in the elderly: effect of  zinc on generation of cytokines and oxidative stress. Am J Clin Nutr. 2007;85(3):837-844

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