Serious viral infections

Influenza

• ssRNA virus from orthomyxovirus family
• Influenza A more severe than B usually
• May present similarly to coronavirus (SARS and MERS)
• Epidemiology
  • Transmitted by aerosolised respiratory secretions, large droplets and fomites
  • Outbreaks spread quickly with children acting as reservoir
  • Mortality mostly in elderly and young infants
  • Occasional mutations and new strains can lead to pandemics with mortality mostly in healthy young adults
• Pathophysiology
  • Incubation 1-4 days
  • Undergo antigenic drift of surface proteins resulting in re-infection of individuals and re-emergence each winter
  • Major antigenic changes (antigenic shift) that can lead to pandemic

influenza

• Primary influenza pneumonia
  • Develops quickly and progresses to ARDS within 24 hours
• Bacterial superinfections are also common, typically S. pneumoniae or S. aureus (incl. CA-MRSA) (S. aureus more severe usually)
• Diagnosis
  • Usually clinical diagnosis with abrupt onset fevers, muscle aches and cough during epidemic
  • Lab confirmation can assist diagnosis and infection control
  • Rapid antigen assays (GeneXpert) identify surface proteins of Influenza A and B (sensitivity variable from 10-80% and specificity 85-95%)
  • PCR is more sensitive and specific but takes much longer

influenza

• High-risk for complications/severe disease
  • <5yo (esp. ATSI) or >65yo
  • Comorbidities (esp. cardiopulmonary)
  • Severe neurological conditions
  • Other chronic illness
  • Immunosuppressed
  • Pregnant patients
  • Patients <19yo receiving long-term aspirin
  • Indigenous >15yo
  • Morbidly obese (BMI >30)
  • NH and long-term care facility residents
  • Down syndrome
  • Homeless

influenza

• Treatment
  • Benefit of neuraminidase inhibitors exists if given within 48 hours of symptom onset and in hospitalised/severe cases beyond this time frame
  • Associated with fewer complications, hospitalisations and deaths in systematic reviews of observational studies (including patients at high risk of complications or severe illness/mortality)
  • Systematic reviews of RCT’s have not shown benefit (largely healthy young adults and therefore underpowered to detect benefit on mortality or hospitalisation)
  • Treatment reduces symptoms by 1 day on average if started within 48 hours (though earlier = greater the time benefit)
  • Potential nausea and vomiting side effects so need to weight risk/benefit
  • Should be used in hospitalised cases or those with risk factors for complications
  • Should also be considered for those with household contacts with increased risk of severe illness/complications and those in institutions to prevent transmission
  • Oseltamivir 75mg BD for 5 days (longer if critically ill)
    • WHO recommends 150mg BD for severe (ventilatory or haemodynamic support) although RCT’s have not shown benefit of this approach

Herpes simplex virus infections

• HSV1
  • dsDNA viruses
  • Usually childhood exposure through non-sexual contact 
  • >85% of population seropositive
  • Most common viral encephalopathy. Mostly age <20 and >50. Mortality >70% if untreated
  • Resides latently in trigeminal ganglion
  • Gains access to brain via trigeminal or olfactory nerves with predilection for medial and inferior temporal lobes
• HSV-2
  • Almost always sexually transmitted
  • Can cause encephalitis in neonates from maternal birth tract. Risk highest if acquired in third trimester
  • Latent in sacral ganglia

Hsv infections

• Clinical features
  • Can be transmitted with overt disease or asymptomatic viral shedding
  • Mostly subclinical
  • Primary infection
    • Typically more widespread mucosal and extramucosal sites with systemic signs and symptoms
    • HSV-1: Gingivostomatitis and pharyngitis
    • HSV-2: Genital ulcers typically (or pharynx)
    • Can present as aseptic meningitis (mostly in women)
    • Topical aciclovir is not effective for primary disease
  • Recurrence (all below HSV-1)
    • Herpes labialis, herpetic whitlow or herpes gladiatorum (skin) or eczema herpeticum
    • Bell Palsy may result from latent HSV-1 in geniculate ganglion
    • Herpes keratitis

HSV infections

• Herpes encephalitis (HSV-1)
  • Acute fever and neurological symptoms
  • Hemiparesis, ALOC, seizures, CN abnormalities, focal seizures, ataxia
  • Many present with altered behaviour
• HSV meningitis (HSV-2)
  • Occurs in up to 25% of primary HSV-2 infections in women
  • Has a benign course (as opposed to encephalitis)
  • Risk of recurrent lymphocytic meningitis (Mollaret syndrome)
• HSV in immunocompromised hosts
  • Widespread dissemination and multiorgan involvement
• Immune-mediated manifestations
  • Erythema multiforme/SJS
  • Haemolytic anaemia
  • Thrombocytopaenia

Hsv infections

• Diagnosis
  • PCR swab
  • Temporal lobe lesions on CT/MRI is strongly suggestive of herpes encephalitis
  • EEG: Typical intermittent, high-amplitude slow waves localised to temporal lobes
  • CSF: Lymphocytic pleiocytosis + PCR (94-98% sensitive/specific)
• Prognosis
  • HSV encephalitis – Poor prognostic factors include GCS <=6, focal CNS lesions on CT, increased age and start of antivirals >4 days from onset

Hsv infections

• Treatment of mucocutaneous ulcers
  • HSV encephalitis/disseminated disease/immunocompromised – IV acyclovir 5mg/kg q8h 7-14 days
  • Primary HSV-1 or HSV-2 – Acyclovir 400mg 5 times daily for 7 days or Famciclovir 500mg BD for 7 days
  • Recurrent herpes labialis – Topical aciclovir 5% cream 5 times daily for 5 days
  • Severe recurrences – Oral acyclovir 400mg 5 times daily for 5 days or Famciclovir 1500mg stat (within first 48 hours)
  • Frequent severe recurrence suppression – Acyclovir 400mg BD for 6 months, then reasses

Treatment of genital ulcers

• First episode – Aciclovir 400mg q8h for 5 days
• Episodic therapy – Aciclovir 800mg q8h for 2 days
• Suppressive therapy – Aciclovir 400mg BD for 6 months, then reassess

Varicella zoster virus

• Varicella zoster virus (VZV) causes both chickenpox (Varicella) and herpes zoster (shingles)
• Lifetime incidence of shingles is 10-20% (pre-vaccination) as almost 90% of population is seropositive
• Spreads via respiratory droplets of chickenpox patients or direct contact with vesicle fluid
• Multiplies in regional lymph nodes and then disseminates to nasopharynx and skin
• Contagious until all lesions crusted over
• Remains latent in DRG and reactivates in dermatomes as shingles

VZV

• Chickenpox (Varicella)
  • Non-specific viral prodrome then febrile, vesicular rash
  • Rash occurs as crops (classically papules, vesicles, crusted lesions simultaneously)
  • Mostly torso and face
  • Crust and slough off over 1-2 weeks
  • Immunised patients can develop mild chickenpox
  • Complications
    • Bacterial superinfection (GAS)
    • Progressive varicella with severe skin rash and visceral lung, liver, brain involvement (mostly children with leukaemia/lymphoma)
    • CNS: Cerebellar ataxia, meningitis, meningoencephalitis and vasculopathy
    • Pneumonitis can be severe (especially in pregnant women)

vzv

• Herpes zoster
  • Must have had previous chicken pox
  • Prodrome malaise, headache, photophobia
  • Pain, itching, paraesthesia in dermatomes up to 72 hours prior to rash
  • Maculopapular rash —> vesicular
  • Does not cross midline
  • Mostly chest and face
  • Herpes zoster ophthalmicus can risk vision if ophthalmic branch of trigeminal nerve involved
  • CN VII can be involved causing facial nerve paralysis and herpes zoster oticus (Ramsay Hunt)
  • Post-herpetic neuralgia (pain >30 days) increases with age
  • Immunocompromised hosts can suffer disseminated disease involving more than 3 dermatomes, pneumonitis, hepatitis and encephalitis

vzv

• Diagnosis
  • PCR vesical fluid if unsure from clinical
• Treatment
  • Varicella
    • Supportive care
    • Acyclovir decreases number of lesions and shortens course if started within 24 hours in children but not routinely recommended if otherwise healthy child at low risk of complications
    • High-risk patients should receive acyclovir 20mg/kg PO 5 times daily for 7 days
      • Adults
      • Children >12yo
      • Chronic skin or pulmonary disease
      • Long-term salicylate therapy
      • Immunosuppression
    • If immunocompromised or visceral involvement – Acyclovir 10mg/kg IV q8h for 7-14 days

vzv

• Treatment of Herpes zoster
  • Antivirals reduce duration of rash  and severity of pain with rash
  • Variable efficacy in studies to prevent post-herpetic neuralgia 
  • Antiviral therapy in immunocompromised hosts may reduce risk of disseminated disease
  • Start within 72 hours of rash onset and consider treatment beyond this if new vesicles forming
  • Benefits greater if >50yo
  • Treat immunocompromised hosts nomatter what
  • Aciclovir 800mg PO 5 times daily for 7 days
  • Famciclovir 500mg TDS for 7 days
  • If disseminated: Ayclovir IV 10-12.5mg/kg IV q8h

vzv

• Neuropathic pain
  • Simple analgesia + Prednisolone 50mg daily for 7 days then wean over 14 days
    • Steroids improve quality of life but not rash in the elederly. Often only used in the elderly as are at greater risk of post-herpetic neurlagia
  • Amitryptiline 10-25mg nocte
  • Opioids
• Post-herpetic neuralgia
  • Paracetamol and ice massage
  • Amitryptiline, gabapentin and pregabalin have best evidence
  • TENS
  • Opioids
  • Topical lignocaine or capsaicin

EBV

• Causes heterophile-positive mononucleosis (Glandular fever)
• Associated with B-cell lymphoma, Hodgkin disease, Burkitt lymphoma and nasopharyngeal carcinoma
• Seen in early childhood and adolescent peaks
• Usually spread from asymptomatic individual via viral shedding in saliva (kissing disease)
• Infects via oropharyngeal epithelium, into bloodstream and into B cells causing increasing in T lymphocytes, enlargement of lymphoid tissue
• In immunocompromised individuals, the B cells continue to proliferate leading to neoplasm

ebv

• Clinical features
  • Infants and young children – Asymptomatic or mild pharyngitis
  • Teenagers – Infectious mononucleosis
    • Fever, lymphadenopathy and pharyngitis
    • Tonsillar exudates are often extensive and may appear necrotic
    • Splenomegaly in 50%
    • Symptoms resolve over 2-3 weeks but severe fatigue can persist for months
    • Morbilliform rash if treated with amoxicillin
  • Complications
    • Meningoencephalitis, GBS, hepatitis, myocarditis, haematological disorders
    • Splenic rupture, CNS complications or airway obstruction are extremely rare
    • Rare chronic form with high viral titre, prolonged illness >=6 months and major organ involvement with poor prognosis
    • Haemolytic anaemia and thrombocytopaenia are rare serious complications

ebv

• Diagnosis
  • If suspected clinically, FBC and monospot
  • Lymphocytosis with >50% lymphoctes and atypical lymphocytes on smear
    • Reactive T cell lymphocytes appear atypical and are also seen in CMV, HIV and viral hepatitis
  • Monospot identifies heterophile antibodies that agglutinate animal erythrocytes (hence cross-species = heterophile) that are made by infected B cells
    • May be negative early in disease course and may need to be repeated
    • Sensitivity reduced in infants and the elderly
    • Particularly important to test pregnant females, as other causes of positive heterophile antibody testing can be teratogenic
• Treatment
  • Rest, analgesia
  • Steroid use is only recommended for severe cases, upper airway obstruction, neurological disease or haemolytic anaemia
  • Acyclovir is only indicated for hairy cell leukoplakia (associated with HIV infection)
  • Avoid contact sports for 4 weeks due to risk of splenic injury

Cmv infection

• Causes primary infection and then recedes into lifelong latency like other herpesviruses
• Transmission requires prolonged contact via sexual, saliva, breastmilk or transplant + transplacental or blood transfusion
• In developed world, primary infection can occur in adulthood – problematic if in pregnancy as teratogenic
  • Risk highest in first trimester
• Organ transplant patients can acquire infection (mostly in first 4 months)
• Pathophysiology
  • Inoculates onto mucosal surface of oropharynx or genitals then disseminates
  • Most infections only mild
  • Primary infection in adolescence or adulthood causes glandular fever-type picture

cmv

• Clinical
  • Primary infection
    • Heterophile-negative IM syndrome with fever, myalgias, lymphocytosis but no exudative pharyngitis
    • Severe disease in non-immunocompromised hosts can involve hepatitis, colitis, GBS, encephalitis and haemolytic anaemia
  • Congenital/neonatal infection
    • Hepatosplenomegaly, jaundice, microcephaly, petachiae, growth retardation
  • Immunocompromised
    • Can be severe and involve any organ
    • Typically begins in transplanted organ and then may disseminate to cause pneumonia, hepatitis and CNS involvement
    • Retinitis is the most common manifestation in HIV with CD4 <50 with painless loss of vision
    • HIV patients also suffer encephalopathy, colitis and peripheral polyradiculopathy
  • Diagnosis
    • Antigen testing, PCR, antibody testing, histology and viral culture all possible
    • Histology shows classic ‘owl’s eye’ large basophilic intranuclear and intracytoplasmic inclusion bodies
  • Treatment
    • Symptomatic therapy for infectious mononucleosis syndrome
    • Antivirals for severe disease or in immunocompromised hosts with IV gancyclovir +- CMV hyperimmune immunoglobulin

arboviruses

• FAR = Fever, arthralgia, rash
  • Chikungunya, Ross River Fever
• CNS = Encephalitis
  • Japanese Encephalitis, Murray Valley Encephalitis
• VHF = Viral haemorrhagic fever
  • Rift valley fever, Crimean-Congo haemorrhagic fever
• Dengue covers all three
• Yellow fever combination FAR and CNS

arboviruses

• Viral haemorrhagic fevers include Dengue, Yellow fever, Chikungunya all spread by Aedes aegypti
• Flaviviruses are the most important subgroup
  • Yellow fever
  • Dengue
  • Japanese encephalitis
  • Murray valley encephalitis
• Alphaviruses
  • Ross river fever
  • Barmah Forest Virus
  • Chikungunya

Yellow fever

• Mosquito-borne viral haemorrhagic fever with high case-fatality rate
• Endemic to tropical regions of sub-Saharan Africa and South America
• Flavivirus
• Period of infection
  • Flu-like syndrome after 3-6 days incubation
  • Classically red tip of tongue with white middle, relative bradycardia (Faget’s sign) and leukopaenia
• Period of remission
  • Over 48 hours resolution of symptoms
• Period of intoxication
  • 15% of cases have toxic Yellow Fever phase later with classic presentation of with high fever, hepatic dysfunction, renal failure, coagulopathy and shock

Yellow fever

• Mortality of Yellow fever syndrome approaches 50%
• Survivors recover without sequelae
• No specific treatment
• Vaccination is effective

dengue

• ssRNA Flavivirus spread by female Aedes aegypti during the day
• Four serotypes (DEN-1 to 4)
• DEN-2 and DEN-3 are ‘Asian’ and commonly associated with severe disease with secondary dengue infections
• Most cases asymptomatic
• Typically develops 3-14 days after inoculation

dengue

• 3 stages
  • Febrile phase (2-7 days)
    • Viraemic phase with sudden onset high fever, chills, breakbone myalgia, arthralgia, retro-orbital pain and headache
    • On day 2-5 after fever onset, blanching maculopapular rash arises over face, trunk and flexor surfaces lasting 2-3 days
    • Second morbilliform rash can arise 1-2 days after defervescence (spares palms/soles)
  • Critical (plasma-leak) phase
    • Rise in Hct lasting 1-2 days with bleeding risk with thrombocytopaenia and leukopaenia
    • Pleural effusions, ascites, nephropathy and myocardial injury can all arise during this period
  • Recovery phase 
    • Gradual resorption of leaked fluid over 2-3 days
    • Sinus bradycardia and gradual recovery in platelet count and Hct

dengue

• Dengue haemorrhagic fever
  • Most feared which develops in subsequent infection of different serovar
  • Positive tourniquet test, petechiae, bleeding, haematemesis, thrombocytopaenia <100
  • Evidence of increased vascular permeability with rise in HcT >20%, drop in HcT >20% after rehydration, pleural effusion, ascites, hypoalbuminaemia
• Dengue shock syndrome
  • All criteria for Dengue Haemorrhagic Fever + evidence of circulatory failure
  • Rising Hct and continually dropping platelets suggest onset of shock

dengue

• WHO Classification
  • Probable dengue
    • Travel to or live in dengue area
    • Fever and 2 or more of: Nausea, rash, aches, tourniquet positive, leukopaenia, any warning sign
  • Dengue with warning signs
    • Abdo pain/tenderness
    • Persistent vomiting
    • Clinical fluid accumulation
    • Mucosal bleed
    • Lethargy/restlessness
    • Liver enlargement >2cm
    • Increase in Hct with rapid decrease in platelet count
  • Severe dengue
    • Severe plasma leakage – Leading to shock and/or respiratory distress
    • Severe bleeding
    • Severe organ involvement – AST or ALT >= 1000, impaired consciousness or heart and other organ failure

DEngue

• Diagnosis
  • Positive tourniquet test (58% sensitive; 71% specific)
    • 10 or more petechiae in 1 square inch after 2 min BP cuff inflated to mid SBP-DBP
  • Dengue NS1 antigen +- PCR +- serology
    • IgM and IgG only positive after day 5
• Treatment
  • Supportive
  • Avoid antiplatelets, NSAID’s, anticoagulants
  • If no warning signs, passing adequate urine and tolerating oral fluids
    • Outpatient care with GP follow-up every 24-48 hours for warning signs, Hct, Plt counts
  • If comorbidities or social issues treat as inpatient
  • If warning signs, inpatient care
  • Only need platelets for procedures

dengue

• Discharge criteria
  • Absence of fever for 48 hours without antipyretics
  • Improvement in clinical status
    • No evidence of bleeding
    • Normal haemodynamics
    • Good appetite
    • No respiratory distress
    • Normal urine output
  • Rising platelet count
  • Stable Hct without IV fluid administration

Last Updated on October 2, 2020 by Andrew Crofton