Lecture 32 to 37 Respiratory system Flashcards

1
Q

Single syndrome: multiple etiologies

Ex. Infectious pharyngitis

A
  • Strep. pyogenes or unknown (most common)
  • Rhinovirus, adenovirus, coronavirus, EBV
  • HSV, HPIV, influenza virus Coxsackie virus, etc…
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2
Q

Defenses of respiratory system are often defeated by:

A
  • smoking
  • endotracheal intubation
  • pollution
  • suppression of cough reflex
  • predisposing infection
  • disruption of homeostasis: age, malnutrition, immunosuppression, etc…
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3
Q

Interplay bw a professional and secondary pathogen

Ex. flu & pneumococcal pneumonia

A

Suggested underlying mechanisms

  1. changes to RT
  • epithelial damage
  • airway function altered
  • up-regulation and expsoure of receptors
  1. alteration of innate immune response
  • not limited to flu virus; observed w multiple respiratory viruses with the top ones are:
  • Strep. pneumoniae
  • Staph. aureus
  • Hemophilus influenza
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4
Q

Microflora (URT)

A
  • corynebacterium
  • enterobacteriaceae
  • Staph
  • Strep

Haemophilus

  • Moraxella
  • Mycoplasma
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5
Q

Tranmission & acquisition

A

Exogenous:

  • inhalation of infectious droplets:
    • small droples
    • dried respiratory droplet nuclei w mucin
  • self-inoculation of eyes, etc..
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6
Q

virus persistence on dry inanimate surfaces

A

Survival times

  • adenovirus: 7 d to 3 mo
  • rhinovirus: 2 h to 7 d
  • coronavirus: 3 h; significant w regard to fomite-mediated transmission & survival in dropletss
  • RSV: up to 6 h
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7
Q

Endogenous infections

A
  • Endogenous infectons usually due to microflora
  • situations that can predispose to RT infection
    • nl flora move to unusual location, Ex. smoker, , COPD, CF, asthma, chronic bronchitis, age
  • preceding infection causing damage -> secondary infection
  • aspiration of URT flora, Ex. Enterobacteriaceae into lungs -> aspiration pneumonia
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8
Q

Some pathogens require specialised growth media that is not standard

A
  • Bordetella pertusis: Bordet-Gengou
  • C. diphtheriae: Tinsdale agar
  • (slide 23 for rest)
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9
Q

6 major families of Viral agents of RT infections

A
  1. adenoviruses
  2. rhinoviruses
  3. coronaviruses
  4. HPIV
  5. RSV
  6. influenza viruses
  7. Emerging: non-polio picornaviruses
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10
Q

Some respiratory viruses do NOT exert their main pathology in respiratory tract

A

major examples

  • measles: both rubella & rubeola
  • VZV aka HSV-3
  • smallpox
  • coxsackie virus
  • Norwalk virus
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11
Q

Taxonomy of respiratory infections

A

URT

  • sinusitis
  • rhinitis
  • otolaryngitis
  • laryngitis
  • pharyngitis

LRT

  • bronchitis
  • bronchiolitis
  • pneumonia: community-acquired (acute, subacute, & chronic) and nosocomial (acute)
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12
Q

Viruses directly involved in RTI

A
  • Rhinoviruses: (+) RNA, type of Picorna virus
  • Adenoviruses: linear ds DNA
  • Influenza virus: segmented RNA
  • RSV: (-) RNA
  • Corona virus: (+)
  • HPIV: (-) RNA
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13
Q

Infectious rhinitis: microbial causes

A

Viral agents

  • rhinovirus
  • adenovirus
  • coronavirus
  • Non-polio picorna virus Ex. EV-D 68

Bacterial agents: no significant bacteria

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14
Q

Rhinoviruses

A
  • Sx: common cold, fever is rare in adults
  • virus family: Picornaviridiae
  • Medically signifiicant: Enteroviruses, polioviruses
  • Icosahedral, non-enveloped
  • Pathogenesis:
    • Attachment to ICAM-1 cell receptor via surface clef/canyon
    • viral replication & cell to cell spead
    • cell damange, cilia immoblised, viral shedding
    • Antigenic drift leading to 115 serotypes
  • Epi: all ages, young children more severe, humans sole reservoir
  • Transmisson: direct contact, respiratory droplets, survival time 2h to 7 d
  • Rx: Diversionary care to treat common cold
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15
Q

Adenoviruses

A
  • Sx: pharyngitis, conjunctivitis
  • Family: adenoviridae
  • Genus: Mastadenovirus
  • Replication: Class 1 (nucleus)
  • Etiopath: interference w host immune response
    • E1A*: hijacks cell
      • activates viral gene transcription
      • binds cell growth suppressor: p105Rb promotes transformation
      • deregulates cell growth
      • inhibits activation of interferon response elements
    • E1B: binds p53 & promotes transformation & blocks apoptosis
    • E3: prevents TNF-alpha inflammation
    • fibre protein: enables attachment to host cell receptor
    • receptor varies w viral serotype
      • Serotypes 2 & 5= Coxsackie Adenovirus Receptor (CAR)
      • cell surface glycoprotein belings to IgG superfamily
    • Penton base has toxic activity
      • inhibition of cell mRNA synthesis
      • cell rounding
      • tissue damage
  • Epi: widespread, most infections occur in children
    • can be associated w ocular, respiratory, or GI systems
    • outcomes of adenoviral infection
      • Lytic: ex. mucoepithelial cells
      • Latent: ex. adenoid cells
  • Transmission: swimming pools, aerosols, direct contact, fomites, fingers
    • 7 d to 3 mo survival time
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16
Q

Coronaviruses

A
  • Sx: common cold, SARS
  • Family: Coronaviridiae
  • HCoV-229E, HCoV-OC43, SARS-CoV, MERS-CoV, etc…
  • enveloped, helical nucleocapsid, characteristic fringe=surface/”spike” glycoproteins
  • Genetic material: ss (+) linear RNA
    • class IVb replication
  • Coronavirus S protein: “spike” protein
    • Peplomers: 20 nm projecting surface proteins, define tissue tropism, attach to proteins or carbs, site of main antigenic epitopes: neutralising Ab
  • Etiopath: specifics unclear
    • replication optimal @ 33-34C
    • occurs in ciliated nasal epithelium
    • no good animal model for major CoV types; difficult to isolate & grow
  • Epi: isolated from humans and animals (no cross-infect)
    • total # serotypes undetermined
    • re-infection by same serotype possible
  • Transmission: mostly via droplet; fecal-oral route also possible
    • surival time: 3 h
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17
Q

Infectious pharyngitis: microbial causes

A

Viral agents

  • rhinovirus
  • adenovirus
  • coronavirus

Bacterial agents

  • Strep. pyogenes Group A
  • Strep pneumoniae
  • Corynebacterium diphtheriae

Sx: strep. throat sx, fever, swelling and narrowing, etc…

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18
Q

Strep. pyogenes

A
  • Sx: pharyngitis, strep. throat
  • Group A strep.
  • Pus formation due to leukocidin production

Virulence factors

  • lack catalase (facultative anaerobes)
  • Growth enhanced by CO2
  • nutritionally fastidious
    • nl culture medium=blood agar (BA)
      • yeast extract + peptone +5% blood
      • Beta -> hemolysin enzyme from bacteria to lyse cell membrane so true hemolysis
      • (Alpha-> reduced (not true hemolysis) so green; A disk: Bacitracin inhibits growth of Group A)
      • P disk: inhibits pneumococcus
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19
Q

Corynbacterium diphtheriae

A
  • Sx: severe pharyngitis (diphtheria)
  • 4 biotypes: gravis, mitis, belfanti, and Gram +ve intermedium
  • other non-pathogenic Corynebacteria spp. are members of nl flora in pharynx, nasopharynx, and on skin.
  • other medically-important species:
    • C. jeikeium: associated w bacteraemia, IV cath colonisation
    • C. minutissimum: RTI, wound infections
  • Etiopath:
    • organism is non-invasive and does not enter into blood
    • pharyngitis can be severe enough to block airway -> suffocation
    • main virulence factor= diph. exotoxin
      • genes for toxin acquired via lysogenic conversion.
      • toxin is responsible for local and systemic sx
      • inflammation & formation of pseudomembrane
      • damage to organs
    • Sample & Dx: throat/nasopharyngeal samples
      • screen: CYS Tellurite plate
      • Dx: CYS Tellurite plate + BA (CTBA) -> Tellurite inhibits the growth of most URT bacteria.
      • Immunodiffusion asasy (Elek test): Gold
        • growth = diagonal bands of precipitin = +ve test
      • PCR for tox gene although non-toxigenic strains produce a repressor for gene -> risk of fp
      • methylene blue (very non-specific)
20
Q

Infectious sinusitis & otitis media: microbial causes

A

Viral agents: same as infectious rhinitis

  • rhinovirus
  • adenovirus
  • coronavirus

Bacterial agents

  • Strep. pneumoniae
  • H. influenza
21
Q

Hemophilus influenza

A
  • sx: otitis media, pneumonia, epiglottitis
  • H. influenzae, Gram -ve; pleomorphic, facultative anaerobe
  • nl component of URT flora
  • serotyped according to capsule (a -> f) or described as non-typeable
    • Type b = particularly associated w invasive disease
    • non-typeable strain carried by: 50-80% of people
  • Etiopath:
    • pili
    • non-pilus adhesins Ex. P-2 outer membrane protein; attaches to sialic acid-containing mucin oligosaccharides
    • LPS: impairs ciliary function
    • antiphagocytic capsule composed of polyribose ribitol phosphate (PRP)
    • IgA proteases: > 30 different proteases id
  • Culture & Dx
    • Caogulase: -ve
    • Catalase: +ve
    • Culture: requires chocolate agar w hemin & NAD
      • will not grow on blood agar bc it cannot lyse the RBC to obtain hemin and NAD.
      • is the only haemophilus species that requires both.
22
Q

Infectious bronchitis & bronchiolitis: microbial causes

A

Viral agents

  • influenza virus
  • adenovirus
  • RSV

Bacterial agents

  • Bordetella pertusis
  • Mycoplasma pneumonia
  • Chlamydophilia pneumonia
23
Q

Bordetella pertussis

A
  • Sx: whooping cough (chronic bronchitis)
  • B. pertussis: small, Gram -ve coccobacillus
  • some Bordetella toxins
    • TCT=tracheal cytotoxin
    • PT=Pertussis toxin
    • ACT=adenylate cyclase toxin
    • DNT=demonecrotic toxin
    • LOS
    • Filamentous haemagglutinin (FhA)
  • Etiopath: associated w virulence factors
    • Adhesion: FHA, PT, fimbriae
    • Growth & toxin release: PT, ACT, TCT
    • Local & systemic pathology: TCT, PT, DNT, LOS
  • Whooping cough: stages
    • Incubation: 1 wk
    • Catarrhal sx: common-cold (transient) leading to more serious sx
    • Paroxysmal: inspiratory whoop so severe that the children will vomit
    • Convalescence
  • Culture & ID: nasopharyngeal swab or secretions
    • flexible wire inserted into nasal passage; do not use cotton containing fats which is toxic to Bordetella
    • organism is very susceptible to drying
    • B. pertussis is nutritionally fastidious -> require charcoal blood agar + cephalosporin (Ex. Bordet-Gengou)
    • PCR
  • Prevention: part of DaPT vaccine (aP)
    • Types of vaccines:
      • whole cell (formalin-inactivated)
      • Acellular components, ex. Fha, PT
        • aP= acellular Pertussis
        • lower rate of side effects
24
Q

Human parainfluenza viruses (HPIV)

A
  • Sx: croup; bronchitis
  • Virus family: paramyxoviridae (-ve) ss RNA
  • Subfamily: paramyxovirniae & pneumoviriniae
    • Genera: HPIV 1 &3 (respirovirus), HPIV-2, HPIV-4 (Mumps), morbillivirus (measles), megamyxovirus, Hendra virus, Nipah virus
    • Genus: RSV, mPV
  • Enveloped, linear ss (-) sense RNA virus
  • Glycoprotein with Hemagglutinin-Neuraminidase (HN)
  • Fusion factor (F)
  • ​Etiopath:
    • Transmission: inhalation of large-droplet aerosols
    • Fusion factor (F) involved in viral entry
    • Release of nucleocapsid into cytoplasm occurs following fusion of viral and host cell envelope.
    • Virulence factors (below) inhibit IFN-alpha & beta production and signaling pathways.
    • Inflammation and mucosal edema can lead to narrowing of airway and stridor.
  • Virulence factors
    • P/F proteins: immune evasion
    • F proteins (fusion proteins): role in syncytium formation
    • HN protein: structural Hemagglutinin & Neuraminidase
    • L protein: multifunction polymerase
    • M protein: matrix structural protein
    • P/F protein (non-structural protein): role in evasion of immune response by blocking IFN expression & signalling
25
Influenza
* orthomyxo virus (-) ss RNA * TBC sialic acid Adults Sx: * rapid: onset after short incubation of 1 to 4 d * sudden: malaise and headachle lasting a few h * abrupt: rise of fever, chills, severe muscle aches. Loss of appetite, non-productive cough lasting 3 to 8 d * recovery: complete in 7 to 10 d * Pt contagious before sx appear (end of 1st d) for next 7 d * risk of secondary infection highest in time from 6 to 12 d after infection Children's Sx: * same as those in adults, PLUS * high fever * G.I. sx: vomiting, ab pain * earache (otitis media) * muscle pain and sometimes swelling * febrile convulsions (rare but occurs in children \< 3 y) Complications * primary viral pneumonias * secondary bacterial pneumonias * muscle inflammation: cardiac involvement * rare neuro syndromes: Guillain-Barre, encephalitis, Reye's syndrome in Children (made worse by aspirin and aspirin containin drugs) Types * Type B: found only in humans; less severe than type A; 2 valences against B (Victoria-like & Yamagata-like) * Type C: cause mild illness in humans & do not cause epidemics, pandemics. * Type A: disease of birds -\> all 15 H and 9 N types Virulence factors: Matrix protein (M1), NA, HA, ion channel M2 protein (type A only), RNA segments (below) * 8 segments: Influenza A & B * 7 segments: Influenza C * M1 & M2 proteins common to all A viruses * - caveat: hidden from immune system Influenza virus increases the susceptibility of the lower respiratory tract to bacterial invasion by destroying cilated cells. Entry of influenza into cell * Stage 1: attachment * Stage 2: Entry & Fusion w endosomal vesicle (not cell membrane) * Stage 3: Uncoating
26
Subgrouping of Influenza A: Hemagglutinin
* Rod-shaped * Hemagglutinin is **Major Ag** against which neutralizing Ab are directed * **highly variable**: responsible for evolution of new strains * **4 HA subtypes** described in humans: HA1-3, HA5 * carried out by **cell proteases** * **Note: **HA spikes extend like a spring bringing viral and cell envelope together * Receptor Mediated Endocytosis (RME) involving sialyloligosaccharide on cell membrane bring Both NA & HA intracell so neutralising Ab cannot reach.
27
Subgrouping of Influenza A: Sialidase enzyme
* A type of sialidase enzyme: removes terminal sialic acid residues from glycoproteins and glycolipids * Functions/roles * enables release of newly formed budding virus from host cells * helps virus move thru mucin layer * 2 subtypes: N1 and N2
28
Influenza Etiopath
Etiopath: - aerosol droplets - contacts respiratory epithelium of middle RT. - desquamation of cells - triggers T-cell response - interferon response - leading to 2o endogenous infections from several microbes causing pneumonia
29
Antigenic drift vs. shift
* Shift: A * Drifts: ABC
30
Infuenza epi
* Type B is as severe as A but not as common (epi less sevre) * Only A has animal reservoir and cause pandemics * Types A & B can cause epidemics
31
Subacute LRT Infection aka Walking Pneumonias or Atypical pneumonias
Prokaryotes * mycoplasma sp. - mycoplasma = walking pneumonia; most common cause of walking pneumonia; kids under 5; crowded institutions - no quick, simple or cheap etiologic lab dx * Chlamydia sp. * Chlamydophilia -\> walking pneumonia * C. psittaci -\> parrot fever causing pneumonia, post-strep rheumatic fever, and giant cell myocarditis * Legionella sp. C. pneumoniae & mycoplasma infections present w same RT sx Eukaryotes * usually fungi; Respiratory fungi in middle US (appalachians) * Histoplasma sp. * Blastomyces sp. * Coccidiodes sp. * Candida sp. Broad-spectrum antibiotics do not treat walking pneumonia effectively
32
Streptococcus pneumoniae
* All strep are aerotolerant anaerobes (facultative) -\> can survive reduced O2 levels -\> deep in RT - part of nl flora - cause of lobar pneumonia * Clinical sx: pneumonia, sinusitis, otitis media * S. pneumoniae on blood agar * Note alpha-hemolysis = strep * p disk=optochin antibiotic inhibits pneumococcus * Epi: commonest cause of community acquired pneumonia * part of nasopharyngeal flora * no animal or env. reservoir -\> humans are the reservoir * Tranmission: * Exogenous: person to person via droplets * Endogenous: if there is predisposing condition such as influenza
33
Pathogenesis of pneumococcal pneumonia
* capsule * IgA protease * pneumolysin * autolysin * transformation Prevention: polyvalent capsular polysaccharide vaccine ex. pneumovax, pnu-immune * immunises against 23 of the most common serotypes * indicated for protection of high risk individuals such as young and elderly and those w: chronic disease, HIV, alcoholism * also: 7-valent conjugated vaccine: T-cell dependent response
34
Properties of pneumolysin
* inhibits ciliated epithelial cell activity * cytotoxic for alveolar and endothelial cells * causes inflammation * decr. PMN effectiveness
35
Infectious pneumonia: microbial causes
Viral agents * influenza virus * adenovirus * RSV * SARS * Metapneumovirus * Bunyavirus Bacterial agents * strep. pneumonia * mycoplasma pneumonia * Legionella pneuphilia * chlamydia pneumonia * Ricketssia sp. * Coxiella burnetti * Pseudomonas sp. * bacillus anthracis * mycobacterium tb
36
Klebsiella pneumonia
* Sx: bronchopneumonia, lung abscesses, common in alcoholics and addicts * Enterobacteriaeceae, Gram -ve bacillus, large capsule (mucoid apperance) * part of microbial flora: nl in GIT * 2 high affinity iron uptake systms: aerobactin & enterochelin * necrosis of lung tissue due in part to LPS * can cause severe and destructive nosocomial pneumonia -\> **red currant jelly sputum & putrid odour**
37
Features of necrotizing pneumonia
* lung abscesses/aspiration pneumonia * \>1 area of lung parenchyma replaced by cavities filled w debris. * large % of cases are polymicrobial (\>1 species) -\> putrid odour to breath & sputum * range of microrganism in addition K. pneumoniae can include: * S. aureus * anaerobes and microaerophiles from nl mouth flora * microaerophiles on outside use up O2; anerobes grow on inside
38
Legionella pneumophilia
* Sx: Legionnaire's disease (pneumonia), pontiac fever (self-limiting) Family: Legionellaceae * single genus: Legionella * Gram -ve rods, motile, non-spore forming * 49 species, 70 serogroups * \>80% of all infections due to L. pneumophilia sergroup 1 * can be associated w epidemics * uptake is via phagocytosis; prevent fusion of phagosome-lysosome. * much of damage = host inflammatory response. * virulence factors * intracell growth * endotoxin * extracell protease * Epi: expsure = inhalation of contaminated aerosols * person to person transmission = rare * can survive ~50C for \> 30 min. * Does not take saffranin couterstain so is invisible under gram stain -\> silver stain * *
39
Pseudomonas spp.
* Gram -ve rods, strictly **aerobic,** * highly motile w multiple flagella, versatile metabolism * opportunist ubiqitous in fresh water sources * Catalase + * Oxidase + * encapsulated * thrives in aquatic environment * non-hemolytic; produces very mucoid colonies on conventional agar * some strains produce pigments: **Pyocyanin, pyoverdin/Fluorescein** giving a **green colour** to colourles media; **smells like Grapes!** **Etiopath:** * Toxin inactivates E2-F by ribosylation (same as Diphtheria toxin) **Sx​** * only weakly pathogenic to persons w normal innate acquired immunity; most common infection is **Otitis Externa** (Swimmer's ear) * Dangerous for persons w structural defects in body defenses. * burn victims * CF: causing necrotising bronchial pneumonia * pseudomonas aeruginosa & Burkholderia cepacia are now considered CF pathogens * often fatal nosocomial infection * osteomyelitis in diabetics & IV drug users * nosocomial UTI * Eccthyma gangrenosum: black necrotic lesions on skin Rx: * Pipericidin * Fluoroquinolones for UTI * Aminoglycosides
40
Mycobacterium tuberculosis
* grow in long parallel chains "cords" * aerobic * non-spore forming * resist drying but still sensitive to heat * unusual cell wall -\> does not take up Gram stain -\> afb stain - killed by gentle heating -\> pasteurization * Cell wall structure: * mycolic acid = straight chain hydrocarbon = wax * Lipoarabinomannan (LAM) = inactivates macrophages and scavenge free radicals * grows slowly in lab: 2 to 8 wk * Etiopath: intracell survival in alveolar macrophages * prevent oxidative burst & inhibit phagosome-lysosome fusion -\> role of sulfolipids * resist lysosomal enzymes, reactive O2 species * escape phagosome * LAM & mycolic acids * secrete siderophores: exochelins Tb & AIDS * resistance to Tb largely dependent on subset of CD4+ helper T cells that produce alpha-interferon * normally: enhance antimicrobial activity of macrophages * in active AIDS, total population of CD4+ helper T cells reduced. Culture & Dx of M. tb * M. Tb is hydrophobic so grows on top of agar instead of inside agar; requirees * Lowenstein-Jensen agar * Oleic acid - albumin broth * Also Z-N & R-A stains
41
MTb Rx
* multiple combination therapy * antimycotic agents include: 1st line: * isoniazid * rifampin * streptomycin * ethambutol 2nd line: * para-aminosalicyclic acid * cycloserine * fluoroquinolones Prevention * prophylactic antimycotics * BCG (Bacillus Calmette-Guerin) vaccine * attenuated M. bovis strain
42
TB Drug resistance
* MDR-TB: resistant to both isoniazid (INH) and rifampin * XDR-TB: MDR + resistant to any fluoroquinoloine + 1 of 3 following injectable drugs: amikacin, capreomycin, kanamycin * TDR-TB: XDR-TB that is completely resistant to all tested drugs (preliminary definition)
43
Teleomorphs vs. Anamorphs
* Teleomorph = recognized sexually reproducing form of fungs * Anamoprhin = asexually reproducing form; usually ill-defined * Ex. Ajellomyces capsulatus & dermatitidis
44
Blastomyces dermatitidis
* 2 presentations: 1. pulmonary & 2. extrapulmonary disseminated * Epi * similar to that of histoplasmosis * found in decaying organic matter * outbreaks associated w contact w soil * most infections: N. America
45
Coccidiodes imitidis
* most virulent of all human mycotic pathogs; expsoure is through inhalation of arthroconidia (endospores) from soil * Spherule protects spores from phagocytosis (fig. below) * mostly in desert areas of US but not exclusive (SW USA, Arizona, Cali), N. Mexico, S. & Central America * Self-limited flu-like illnesses