Upper Respiratory Tract Infections: Colds & Coughs (2024) PDF

Upper Respiratory Tract infections part I: Colds and Coughs Debra Bramblett, PhD Burrell College of Osteopathic Medicine 2024  Describe the manifestations of the common cold and the most common viral causes. Discuss various mechanisms that cold viruses use...

Upper Respiratory Tract infections part I: Colds and Coughs Debra Bramblett, PhD Burrell College of Osteopathic Medicine 2024  Describe the manifestations of the common cold and the most common viral causes. Discuss various mechanisms that cold viruses use to avoid the host defenses. Describe human corona virus and its replication Part I. cycle and the associated disease. Describe the innate immune responses against Learning RNA respiratory virus infections Describe innate immune recognition of ds DNA Objectives viruses such as Adenovirus Recognize the names of the bacteria that are commonly found as normal flora colonizing the mouth, oropharynx and nasopharynx in a healthy individual Describe the most common causes of pharyngitis and their associated syndromes  The common cold Clinical manifestations: Starts with nasal stuffiness, sneezing and headache. Rhinorrhea then occurs with increasing severity General malaise lacrimation, sore throat, slight (low grade) fever. There may be a cough (particularly with viral infections) Most common causes are Rhinovirus and Human Corona virus There are several other viral causes of cold like symptoms : influenza, parainfluenza virus, respiratory syncytial virus (RSV), adenovirus, coxsackie virus human metapneumovirus and bocavirus have also been associated with upper respiratory infections Describe the manifestations of the common cold and the most common viral causes. Comparison of Some Viral Causes of Sore Throat and/or Upper Respiratory Tract Disease Family Name Genome Morphology Receptor Adenoviridae Adenovirus Ds DNA Not Enveloped CAR Icosahedral Orthomyxoviridae Influenza A, B, C ss (-) RNA Enveloped, Sialic Acid segmented Helical nucleocapsid Coronaviridae Coronavirus ss(+) RNA Enveloped ACE2 Angiotensin HCoV-OC43 Helical converting enzyme 2; HCoV-229E APN aminopeptidase N, Sialic acid Paramyxoviridae Parainfluenza ss(-) RNA Enveloped, Sialic acid Subfamily: 1,2,3,4 No segments Helical nucleocapsid Paramyxovirinae Respiratory ss(-) RNA Enveloped, Glycosaminoglycans ( Paramyxoviridae Syncytial virus Helical nucleocapsid GAGs) such as Heparin Subfamily: virus ( RSV) 1 sulfate and chondroitin Pneumovirinae sultfate B Genus Human ss(-) RNA Enveloped, Glycosaminoglycans ( Pneumovirus metapneumovirus virus Helical nucleocapsid GAGs) Picornaviridae Coxsackie A ss(+)RNA No Envelope ICAM-1 or CD55 rhino14_035.0010001.jpg (T=3) Icosahedral Picornaviridae Rhinovirus ss(+)RNA No Envelope ICAM-1 or LDL receptor (T=3) Icosahedral  Pathogenesis of the Common Cold 1. Virus enters by inhalation 2. Infects cells lining nasal passages and the pharynx following attachment to viral receptors such as ICAM-1, aminopeptidase N, (APN) Sialic acid. i. Influenza is known to damage nasal epithelium and ciliated columnar epithelial cells are destroyed and slough off. ii. the nasal epithelium remains intact during rhinovirus infection 3. Inflammatory changes occur with hyperemia, edema and leukocyte inflammation. i. following rhinovirus infection of human epithelial cells in vitro, levels of cytokines increase, and elevated levels of inflammatory mediators and cytokines, including interleukin-1β (IL-1β), IL-6, and IL- 8, have been found in nasal secretions during colds. 4. Production of bradykinin appears to contribute to both sore throat and rhinorrhea. 5. The watery nasal discharge (early phase) is derived from a mix of nasal glandular secretions and plasma transudate. Nasal glands are activated to produce secretions through cholinergic stimulation 6. The nasal congestion (late phase) of the common cold is a result of the dilation of large capacitance veins (sinuses) in the nasal epithelium that can swell and block the nose. 7. The cough associated (later stages) is often a result of irritation of the larynx with mucus. 10. Secondary bacterial infections by normal flora can cause secretions to become mucopurulent. If severe, blockage of the sinus ostia or the Eustachian tube occurs, paranasal sinusitis or otitis media results. Symptomatic Treatment for the Common Cold Symptom Etiology Treatment Examples Sore Throat Bradykinin Analgesics, topical NSAIDs anesthetics Acetaminophen Acetaminophen Benzocaine lozenges Rhinorrhea Nasal glandular Anticholinergics Diphenhydramine secretions Doxylamine Ipratropium bromine nasal spray Nasal Engorgement Adrenergic agents Pseudoephedrine obstruction of nasal venous Oxymetazoline nasal spray sinuses  Innate Immune Responses against RNA respiratory Virus infections 1. Pathogen-associated molecular patterns (PAMPs) recognized by pathogen recognition receptors (PRRs): Toll-like receptors (TLRs 3,7,8) expressed by alveolar, interstitial macrophages, DCs, airway epithelial cells, innate lymphocytes and neutrophils. 2. Intracellular receptors (PRRs) such as MDA5, RIG-1, protein kinase R(PKR) recognize viral RNA [dsRNA] an are present in virtually any cell type including the lung. 3. RNA recognition triggers type I and type III interferons (IFNs) and proinflammatory cytokines 4. Signal transduction results in activation of a myriad of interferon stimulated genes (ISGs) to establish the anti-viral state: arrested cell cycle, activation of cell-intrinsic apoptosis and modulation of cell surface to activate NK cells and CTL to kill infected cell. 5. 2’-5’ oligoadenylate synthetase (OAS)/RNase L pathway, which both senses and degrades RNA, making it a potent early inhibitor of viral replication Describe the innate immune responses against RNA respiratory virus infections  Cells possess TLR-independent pathways that respond to viral nucleic acids generated in the cytoplasm by viral replication. As a result, promoters for IFN- /β are induced and released by Antiviral IFN- infected cells. These type I IFNs bind to a common heterodimeric receptor. induced antiviral Intracellular signaling then results in the up regulation of several state hundred Interferon sensitive genes (ISGs) that specify the antiviral state. IRF3 is a key transcriptional factor involved in the signaling pathway leading to establishment of antiviral state in infected cells PKR dsRNA-dependent protein kinase (PKR) is a central component of the interferon antiviral defense pathway. Upon binding dsRNA, PKR undergoes autophosphorylation reactions that activate the kinase. PKR then phosphorylates eIF2α, thus inhibiting protein synthesis in virally-infected cells. PKR and other pathways act to together cause autophagy, sometimes apoptosis or necrotic cell death, preventing further replication of virus. Picornaviridae that cause upper respiratory tract infections Rhinovirus Coxsackie virus A  Review of Picornavirus Characteristics Rhinovirus, Coxsackie virus A and B and many others Virion: Icosahedral with no envelope Genome: (+) ssRNA with a length of 7.0 – 8.5 kb (small) One open reading frame that encodes a single polyprotein comprising structural proteins P1 region and non-structure proteins P2 and P3 regions. Rather than cap dependent initiation of translation , the 5’ end is linked to VPg viral protein. Release of mature and functional proteins is primarily mediated by the viral proteinase 3Cpro and its precursor 3CD Protease 2A IRES Clin Microbiol Revv.26(1); 2013 JanPMC3553670 Picornavirus replication cycle several viral non-structural proteins hijack regulatory mechanisms of host membrane metabolism to induce extensive remodeling of the intracellular membranous structures to form the so- called replication organelles (ROs) where viral RNA replication takes place  Coxsackie A Virus  Family: Picornaviridae, Genus Enterovirus  Structure: Icosahedral and no envelope, stable at pH 3.  Genome: (+) ssRNA - poly adenylated at the 3’ end and has Vpg covalently linked to 5’ end. Has 3’ and 5’ untranslated regions with an internal ribosome entry site (IRES) in the 5’ UTR  Childhood Diseases: Herpangina, Hand Foot and Mouth disease (A16) Coxsackie A21 and A24 can cause rhinovirus-like symptoms resembling the common cold but is also associated with a maculopapular rash  Interaction with the host: The VP1 protein at the vertices of the virion contains a canyon structure to which the cell receptor binds.  Receptor for Coxsackie A : ICAM-1 expressed on epithelial cells, fibroblasts and endothelial cells; and decay accelerating factor CD55  Transmission: Fecal – oral route ( as are most the Enteroviruses) and by respiratory aerosols  Host cell range: Oropharynx epithelium (replication) Skin following a secondary viremia Rhinovirus is not an Enterovirus but is a Picornavirus rhino14_035.0010001.jpg Family: Picornaviridae Genome Composition: (+) ssRNA Capsid Shape: Icosahedral, no envelope Viral proteins/antigens: More than 100 serotypes P1 region encodes capsid proteins (VP1-4) P2 & P3 regions encode proteins for protein processing (proteases) and genome replication as well as Vpg Receptor(s): ICAM-1, LDL, Sialic Acid Disease: The most common cause of Rhinitis/sore throat Common Cold Host cell range: Highly species specific ( humans), unlike the Enterovirus genus they are unable to replicate in the GI tract. Labile to acid pH and grow best at 33C. Transmission: Direct contact, nasal secretions; Fomites more important than aerosols, acid sensitive and replicate poorly at temperatures above 33C  Rhinovirus: Spread and Evading Host Defenses Spread mainly by coughs and sneezes Rhinovirus replicates best at about 91°F (33C) which is the temperature found in parts of the nose and upper respiratory tract. The release of cytokines during inflammation can promote the spread of the virus by enhancing expression of ICAM-1 viral receptors on the cell surface. Does have antigenic drift (hundreds strains exist) Rhinovirus protease 2A shuts off cap-dependent translation preventing cellular gene expression by cleaving eIF-4G Rhinovirus 2A and 3C cleave IPS-1 (also called MAVS) to stop IFN signaling pathway. Rhinovirus 3C also inhibits apoptosis by cleaving RIPKI. Rhinovirus actually interferes with the production of interferon It seems to interfere with IFN-β gene expression by blocking the activation of the transcriptional regulator IRF-3 Also, protease 2A cleaves nucleoporins, compose the nuclear pore complex, that regulate protein and mRNA trafficking in and out of the nucleus which might interfere with IRF-3 trafficking and activity. Adenovirus Adenovirus Genome is ds DNA Non-enveloped, Icosahedral, capsid virus Adenovirus types 1-7 are respiratory Respiratory Disease: acute febrile pharyngitis, characterized by a cough, sore throat nasal congestion and fever. There are at least 100 serotypes and 49 are human pathogens Viral fibers bind to the adenovirus-coxsackie virus receptor –CAR. These viruses are resistant to drying, detergents, acid, proteases and bile, even mild chlorine treatment. Therefore, it is commonly spread by a fecal/ oral route or by aerosols, by fingers or by fomites and poorly chlorinated swimming pools. Transmission is human to human and there is no animal vector. The histological hallmark of adenovirus infections is a dense central intranuclear inclusion consisting of viral DNA and protein. (Figure) Review of Adenovirus replication 1. Attachment to CAR receptor 2. Endocytosis 3. Lysis of host endosome 4. Microtubular transport to nucleus Premature DNA release can occur in cytoplasm 5. DNA penetration into host nucleus 6. Transcription of early mRNAs 1. Proteins that promote cell growth 2. DNA polymerase mRNA 3. E1A, E1B, expression Stimulation of cell replication and S phase Cell transformation is possible 7. DNA genome replication in permissive cells by viral-encoded DNA polymerase. 8. Transcription of late mRNAs 1. Only after DNA replication 2. A Large primary transcript is processed into 18 mRNAs 3. Capsid protein synthesis in cytoplasm 9. Transport of capsid proteins into nucleus 10. Genome is packaged into virions 11. Virions stay in the cell until cell lysis  Immune recognition of Adenovirus, a dsDNA virus I. cGAS/ STING A. The adenovirus DNA genome activates cytoplasmic Cyclic GMO- AMO synthase/stimulator of interferon genes (cGAS/STING) B. IRF-3 mediated IFN and proinflammatory response are stimulated in response to a TLR-independent sensing mechanism involving cGAS-STING. C. cGAS binds the DNA and signals to STING. D. STING then traffics from the ER to an ER-Golgi intermediate compartment and the Golgi apparatus. E. STING recruits and activates the kinase TBK1 which results in phosphorylated IRF3 which dimerizes and then enters the nucleus F. STING also activates the kinase IKK which results in release of NF- kB. G. NF-kB together with IRF3 and other transcription factors to induce the expression of interferons and inflammatory cytokines such as TNF, IL-1β and IL-6. II. IL-1β is induced by the DNA sensor Toll-like receptor 9. NATURE IMMUNOLOGY VOLUME 17 NUMBER 10 OCTOBER 2016  Adenovirus Interferes with host defenses in multiple ways 1. E1A, E1B viral proteins interfere with the antiviral response E1A stimulates cell cycle via Rb sequestration and E2F family transcriptional regulators E1A of adenovirus (AdV) inhibits cGAS/STING E1A blocks IFN signaling and ISG expression by multiple mechanisms E1B blocks apoptosis by repressing p53 activity 2. VA-RNAs Block interferon PKR mediated anti-viral response. Normally in interferon-alerted cells, double stranded viral RNA binds to the cellular protein kinase R (PKR) and activates it. Activated PKR shuts down protein synthesis ending the viral infection. In Adenovirus infected cells, the VA-RNA, which is produced by the virus, acts as a decoy. The VA-RNAs bind to PKR rendering it inactive allowing protein synthesis and virion assembly to continue. 3. Adenovirus Inhibits MHC I expression E3 blocks transport of MHC I to the plasma membrane prevent killing by CTLs Preventing expression of MHC I molecule on the cell surface prevents any antigen presentation. This blocks apoptosis triggered by CD8+ cytotoxic T-cells. NK cells respond to cells that are not expressing appropriate amounts Why is preventing antigen presentation an enigma? of MHCI, leading to infected cell killing anyway Discuss various mechanisms that cold viruses use to avoid the host defenses.  Summary of Adenovirus Respiratory Syndromes Acute Febrile Pharyngitis (Ad 1,2,3,5,7) and Pharyngoconjunctival fever (Ad 3 and Ad7) Occurs in young children under 3 looks like strep. Mild flulike symptoms with nasal congestion, cough, coryza, malaise fever, chills myalgia and headache. Often accompanied by conjunctivitis Acute Respiratory disease (ARD) (Ad4, Ad7) nasal congestion, coryza (nasal discharge), and a cough coupled with fever, chills, malaise, myalgia, and headache. Adenovirus type 4 , type 7 vaccine is approved by the FDA for military populations Military recruits Conjunctivitis and Epidemic Keratoconjuctivitis (Ad3, Ad4, Ad11) Causes follicular conjunctivitis (pinkeye) Mucosa of papebral conjunctiva become pebbled or nodular and inflamed EXTREMELY infectious!!! Spread in aerosols and by the fecal-oral route, by fingers, by fomites ( including towels and medical instruments) and in ponds or poorly chlorinated swimming pools. Associated with close quarters like schools and military barracks  Coronavirus History Isolated in 1930’s as causative agents of Bronchitis in chickens Gastroenteritis in pigs Severe hepatitis and neurological diseases in mice Grouped together in the 1960s based on some common physical characteristics For about 40 years the Coronavirus studies focused on the economically significant respiratory and gastrointestinal diseases in domestic animals and it was recognized that Human coronavirus (HuCov) is responsible for a large fraction of the common cold.  Human Coronaviruses Genome Composition: ss (+) RNA, non segmented Shape: Spherical or pleomorphic virion with petal shaped spikes, helical nucleocapsid Major Viral proteins /antigens: E1 (matrix) , E2 (S spike), E3 (Hemagglutinin/Neuraminidase), L, N Enveloped Receptor(s): glycoproteins on epithelial cell surface varies depending on type: ACE Angiotensin converting enzyme 2; APN aminopeptidase N, Sialic acid Classification: Family Coronaviridae subfamily Coronavirinae Four Genera: Alpha, Beta, Gamma and Delta Seven human Coronaviruses that cause respiratory disease in humans. Alphacoronavirus- HCoV-229E and HCoV-NL63 Betacoronavirus HCoV-OC43, HCoV-HKU1, SARS-CoV, MersCoV and SARS-CoV2  Disease: HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1 are the low-risk members of this family Human and the reason for some common colds. Coronavirus Interaction with the host: Non-lytic, released by exocytosis Disease Host cell range reflects a strict species specificity of vs each strain but readily mutate, possibly resulting in cross species infection. Zoonotic Zoonotic forms: SARS-CoV, SARS-CoV2 and MERS-CoV Coronavirus Severe lower respiratory disease disease Transmission: aerosols and large droplets and fecal oral transmission  Coronaviriae is a genetically diverse family currently groups into four genogroups (alpha, beta, gamma and delta). Coronavirus (CoV) The replication of viral genomic RNA is inherently error – prone leading to the production of many species. Genogroups MERS and SARS are both part of the Beta genogroup Most CoV strains have restricted host range but the zoonotic CoVs have the ability to jump into new host species by acquiring mutations  Fung TS, Liu DX. Human Coronavirus: Host- FYI Pathogen Interaction. Annu Rev Microbiol. 2019 Sep 8;73:529-557. doi: 10.1146/annurev-micro-020518-115759. Epub 2019 Jun 21. PMID: 31226023.  1. HCov Replication 1. Attachment (S1) to ACE2 or APN 2. Entry/fusion from endosomes (S2) 3. Translation of a) NS proteins (pp1a, pp1ab) that rearrange 2. cell membranes to form double membrane vesicles where viral replication takes place. 3. b) RNA polymerase (RDRP) 9. 5. c) Proteases (PLPpro and Mpro) 8. 4. Formation of replication membranes 5. Genome transcription and replication 6. 6. Sub-genomic RNAs encode structural proteins 4. 7. Translation of sub-genomic RNAs for 7. structural protein synthesis 8. Virion assembly in the ER followed by budding into the Golgi 9. and release via secretory pathway.  Coronaviruses circumvent the innate immune response in multiple ways: 1. “trojan-horse”: infect antigen-presenting cells to spread to infect other cells. 2. Viral proteases 3CLpro and PLpro cleave NF-ĸB essential modulator (NEMO) to attenuate the IFN response PLpro has the additional function of stripping ubiquitin and ISG15 from host-cell proteins to aid coronaviruses in their evasion of the host innate immune responses. 3. Replication organelle (RO) formation Hijacks the host endoplasmic reticulum (ER) membrane and construct a ‘shelter’ where the viral components can escape cytosolic PRR sensing. 4. Modification at 5’end with 2’-O methylation. removal of the 5′-ppp moiety from viral RNAs, a molecular signature of RIG-I ligand 5. Inhibition of multiple IFN signaling cascades Proteins that bind to IRF3 and prevent the phosphorylation, dimerization, and nuclear translocation of IRF3, resulting in the suppression of the IFN signaling pathway. 6. CoVs encode endonuclease activity. Though counter-intuitive for an RNA virus, the virus destroys its own RNA at certain locations or in certain stages of the infection to avoid the triggering of the RNA sensing and virus-destroying machineries Pharyngitis  Normal flora Colonizing the Mouth, Oropharynx and Nasopharynx The most common oral microbes (Mouth) Actinomyces- Gram positive, Facultatively Anaerobic but grow best under Anaerobic conditions Peptostreptococcus- Gram positive coccus (anaerobic) Streptococcus mutans -Gram positive coccus (facultative anaerobe) Members of the viridans Streptococci Streptococcus sp Gram positive coccus ( facultative anaerobe) Haemophilus sp Gram negative short rod (facultative anaerobe) Neisseria sp -Gram negative diplococcus, aerobic Bacteroides sp Gram negative rod (obligate anaerobe) Fusobacterium -Gram negative fusiform, (anaerobe) Prevotella - Gram negative rod (anaerobe) Veillonella -Gram negative coccus (anaerobic) In the mouth, Aerobes are ten to one-hundred fold less in number than the anaerobes in the mouth, nasopharynx and oropharynx although both are present. Objective: Recognize the names of the bacteria that are commonly found as normal flora colonizing the mouth, oropharynx and n asopharynx in a healthy individual.  Though in close proximity, the nasal cavity and the oropharynx vary in the flora composition NASAL CAVITY OROPHARYNX Staphylococcus aureus (facultative Streptococcus species predominate anaerobe) Streptococcus pneumoniae (facultative anaerobe) But can vary between individuals with either Streptococcus pyogenes (facultative anaerobe) S. aureus or S. epidermidis being carried most. Staphylococcus aureus (to a lesser extent) Staphylococcus epidermidis (facultative Neisseria meningitidis (gram -, aerobic) anaerobe) Neisseria flavescens (gram -, aerobic) Corynebacterium sp. (aerobic) Haemophilus influenzae (gram -, facultative Most common in the nares anaerobic ) Propionibacterium (anaerobic) Moraxella catarrhalis (gram -, aerobic) The nasal microbiota is more similar to the skin. There are predominantly aerobes and many more species Skin has a wide variety of microenvironments that compose the oropharynx than the nasal cavity and Gram vary in conditions including the nasal cavity. negative. Higher temp, lower pH,  Pharyngitis Symptoms: Fever, sore throat, edema and hyperemia of the tonsils Generally, a benign self-limited process Etiologies: Majority of sore throats are viral: Adenovirus and Rhinovirus are frequently identified as most prevalent. Viruses associate with other syndromes together with the sore throat Symptoms that indicate viral and not bacterial pharyngitis include conjunctivitis, cough, coryza, hoarseness, diarrhea and discreet ulcerative lesions. Some sore throats are bacterial Streptococcus pyogenes (GAS) is the bacterial cause of greatest concern due to association with rheumatic fever. Group C and G streptococci are commonly found as normal microbiota in the human pharynx; however, they have also become increasingly recognized as potential causes of pharyngitis. Other bacteria: Arcanobacterium haemolyticum, Corynebacterium diphtheriae, Non-toxigenic strains of C. diphtheriae, Neisseria gonorrheae, Mycoplasma pneumoniae, Chlamydia pneumoniae Describe the most common causes of pharyngitis and their associated syndromes  Streptococcus pyogenes (GAS)- Review Slide Strep Throat Gram positive: stain purple Cocci in chains Surface antigens Lancefield group A “GAS” Other antigenic components: LTA, M protein , fimbrial proteins, fibronectin-binding proteins F, cell bound streptokinase. Other external components: Hyaluronic acid capsule Pilli/fimbriae Biochemical characteristics: Catalase (-), facultative anaerobic, β- hemolytic, Small Colonies with large zone of hemolysis; bacitracin sensitive Virulence Factors: C5a peptidase, Streptococcal pyrogenic exotoxins: Spe A, SpeB, Spe C, Spe F; Streptolysin S & O, Streptokinase A & B, Dnases, Diseases Associated Hyaluronidase Strep throat, sinusitis, otitis, pneumonia, necrotizing fasciitis, Impetigo, erysipelas, cellulitis  Streptococcus pyogenes (GAS) Pathogenesis Protein/Structure Actions Review M protein Fimbriae with M-like protein adheres to host Colonization/ F protein Binds to fibronectin in the pharyngeal epithelium Slide Adhesion Lipoteichoic acid Contributes to adherence Hyaluronic capsule Poorly immunogenic; blocks opsonization by complement; shields bacterium from phagocytosis because it tears away when grabbed Evading Immune M protein M binds factor H which degrades complement factor C3b system Avoids adaptive immune system by antigenic variation or phase variation; C5a peptidase Prevents active recruitment of phagocytic cells to the site of infection. Remember products of the complement pathway (C3a and C5a) also attract neutrophils to the site of infection. Streptolysin O and S Kill phagocytes and other blood cells (erythrocytes, leukocytes, and platelets) Avoids Killing by phagocytosis by causing release of lysosomal contents Streptokinase A and B Activate a host-blood factor plasminogen by cleavage. This dissolves blood clots Hyaluronidase breaks down hyaluronic acid located between cells allowing for penetration and spread of bacteria ( it causes disruption of connective tissues and fibrin) Invasion Dnase B Reduces viscosity of abscess material and facilitates spread. Streptococcal pyrogenic Spe A, SpeB, Spe C, Spe F are super-antigens ; Cause the release of large amounts of interleukins (cytokine exotoxins storm) IL-1, TNF, IL-2 and life-threatening immune responses: Toxic Shock Syndrome, necrotizing fasciitis and Scarlet fever are examples of super antigen action.  Notes on other bacteria that cause sore throat Group C and Group G streptococci have increasing been identified in cases of pharyngitis. Group C and G are now grouped together as S. dysgalactiae subs. dysgalactieae Fusobacterium necrophorum (Gram negative, rods, anaerobe) is increasing recognized as pharyngitis that progresses to peritonsillar abscess in young people Arcanobacterium haemolyticum (a Gram-positive rod) has been recognized as a cause for over 20 years. Over half of those affected present with a scarlatiniform macular rash. Mostly seen in young adults. Pharyngeal involvement during a N. gonorrheae (Gram negative diplococci) infection can be asymptomatic or mild but a thorough history should be taken of young adults with pharyngitis who are sexually active and at risk for sexually transmitted disease. Corynebacterium diphtheriae (gram positive pleomorphic rods) is rare in developed countries due to vaccination but sore throat is one the most common presentations. Other Viral causes of Associated Syndrome Pharyngitis Rhinovirus Common cold Coronavirus HuCoVs Common cold Adenovirus (1-7) Pharyngoconjunctival fever and acute respiratory diseases Herpes simplex viruses 1 and 2 Gingivostomatitis Influenza A, B Influenza Parainfluenza 1,2,3,4 Common cold and Croup Respiratory Syncytial virus (RSV) 1 Cold, Bronchiolitis and Croup Epstein-Barr virus Infectious Mononucleosis Coxsackie A Herpangina and hand-foot and mouth disease Cytomegalovirus (CMV) CMV mononucleosis Human immunodeficiency virus Primary HIV infection (HIV)  Notes on viral causes of Pharyngitis Pharyngitis occurs as part of the classic symptoms of infectious mononucleosis (IM) caused by EBV or CMV Primary HIV infection occurring in the first 5-29 days of infection can include fever pharyngitis and lymphadenopathy resembling IM. Enteroviral infections causing pharyngitis and URTI occur mostly in summer and fall and cause 8-29% of cases mild pharyngitis without lymphadenopathy or exudate. Pharyngitis associated with specific enteroviral syndromes include Hand foot and mouth and herpangina. Adenovirus causes about 25% of pharyngitis in children. Pharyngoconjunctival fever and swimming Primary HSV-1 infection causes gingivostomatitis in children whereas pharyngitis is seen in adolescent and young adults can be due to both HSV-1 and HSV-2.