Viruses Flashcards
How do arboviruses survive a long time in vector populations?
can be passed from mosquito to its eggs
Diagnostics for arboviruses
PCR - short window of viremia
Serology
What is the natural host for dengue
humans and primates
How many serotypes does dengue have?
4 serotypes
Stages of dengue
Old:
Dengue fever
Dengue haemorrhagic fever
Dengue shock syndrome
New:
Dengue without warning signs
Dengue with warning signs
Severe dengue
Symptoms of dengue
Incubation 5-8 days
“break-bone fever” - fever, headache, retro-orbital pain, arthralgia
haemorrhagic manifestations - petechiae, frank bleeding, rash
other - sore throat, nasal congestion, nausea, vomiting, encephalopathy, hepatomegaly.
“saddleback fever” - re-emergence of fever after 48hrs
Dengue rash appearance
islands of white on a sea of red
Management for dengue
supportive only
With which infection does dengue haemorrhagic fever occur?
2nd infection
(or 1st infection in babies who have maternal antibodies)
Symptoms of dengue haemorrhagic fever
Fever
Narrow pulse pressure
Temperature drop
Marked thrombocytopenia
Can have haemorrhage (not required)
Plasma leakage syndrome
Issues with current dengue vaccine
If patient has had one episode of dengue before, they can be antibody primed to have a reaction (similar to having second infection)
Vaccine ideally needs to be tetravalent.
Currently only recommended in older children (no maternal Abs) and travellers (never had dengue)
What is the natural host for yellow fever
primates
Vector for yellow fever
Aedes Egypti
(Haemagogous in South america)
What is Fagets sign
Heart rate does not rise when temperature rises
Pathogenesis of yellow fever
Replicates initially in dendritic cells
Primary replication is then in APCs
Spread to lymph nodes, liver and spleen
Leads to liver failure and eosinophillic degranulation
Can get shock due to cytokine storm
Symptoms of yellow fever
Stage 1:
Fagets sign
Fever and malaise
Headache, photophobia
Nausea, vomitting, epigastric tenderness
Lumbosacral pain
Conjunctival redness
Stage 2:
Remission
Stage 3:
Day 3-6 of symptoms
fever, nausea, vomitting
jaundice, renal failure
haemorrhage from thrombocytopenia
myocardial injury
shock
Zika type of virus
Flavivirus
Methods of Zika transmission
Mosquito
Sexually
Vertically
Blood transfusion
Zika incubation
2-14 days (though most asymptomatic
Symptoms of Zika
Usually asymptomatic
Low grade fever
macular papular rash
small joint arthralgia
Conjunctivitis
facial swelling
Uveitis
Myocarditis
Pericarditis
Significant symptoms/complications:
- Guillian-Barre Syndrome
- Congenital Zika - zika crosses placenta causing microcephaly, still birth.
What type of virus is JEV
Flavivirus
Complications of JEV
Childhood neurological symptoms and disability
Normal hosts for JEV
Pigs (amplifying) and birds
Humans are dead end hosts
Mosquito that transmits JEV
Culex
Symptoms of JEV
Asymptomatic
Fever
Headache
GI symptoms
Neurological symptoms
Parkinsonian symptoms
Asymmetric limb paralysis
SIADH
Coma
Seizures common in children
JEV findings on MRI-B
Lesions in thalamus and basal ganglia
Chikungunya hosts
Humans
Sylvatic animals
Chikungunya incubation period
1 week
Chikungunya symptoms
Headache
Fever
Rash
myalgia and arthralgia
Chikungunya mosquito
Aedes Egypti
Ebola type of virus
Filovirus (RNA)
CCHF type of virus
Bunya virus (RNA)
Lassa fever type of virus
Arena virus (RNA)
CCHF symptoms
Fever - low grade
Low platelets
Profuse bleeding - with normal obs (platelets <50 = severe) - bleed early, bleed when they still look well.
Malaise
GI symptoms
Severe headache
DIC
Management of CCHF
Supportive management only
Blood products
Can trial ribavirin (SE of haemolytic anaemia)
Favipiravir
Ribavirin should be used as post-exposure prophylaxis!
CCHF vector
Tick bite - multiple types
Needle stick/ IVDU/ Nosocomial
Animal slaughter
CCHF endemic areas
Spain
Turkey
South Asia
Russia
Africa - poorly documented
CCHF incubation
2-21 days
CCHF diagnostics
Serology
PCR
Lassa fever symptoms
CNS infection
Hearing loss (sensory neural)
thrombocytopenia
renal failure
elevated LFTs
Lassa fever location
Nigeria
Sierra leone
Liberia
Only countries in West Africa (where the rat lives)
Vector for lassa fever
multimammate rat - from rats feeding on your food or from rat urine.
Aresolised when sweeping
incubation for lassa fever
and viral shedding period
1-3 weeks
continues for shed for 3 months in the semen
Treatment for Lassa fever
Ribavirin
Ebola symptoms
Stage 1:
Conjunctivitis
Fever
Lethargy
Stage 2:
Severe GI symptoms - massive diarrhoeal and vomiting losses.
Severe lethargy
Electrolyte imbalance
Stage 3: 33%
coagulopathy
ESRF
encephalopathy
seizures
hypoglycaemia
long term - cataracts
Post exposure prophylaxis for Ebola
Ribavirin
monoclonal antibodies
Treatment for Ebola
supportive management
antibiotics - risk of gut bacterial translocation
Antivirals - remdesevir
monoclonal antibodies
Investigations for Ebola
PCR
Lateral flow test
Pre-exposure management for Ebola
Vaccine available!
Highly effective
Methods of contact tracing for ebola
- History based contact tracing
- gene sequencing based contact tracing.
Rabies virus and epidemiology/transmission
Family Rhabdoviridae, genus lyssavirus
Dog, fox, raccoon bat
Similar diseases → european bat lyssavirus, australian bat lyssavirus
Long incubation period → weeks to months (can even be years)
Spreads from bite site to brain, then spreads outward to skin, saliva etc.
Route of inoculation - broken skin, mucous membranes, transplants.
Rabies symptoms
Encephalopathy (fluctuant)
Confusion, agitation, aggression
Flaccid paralysis
Autonomic stimulation - salivation, frothing
Hydrophobia
Aerophobia
Muscle spasms
30% is paralytic rabies - paralysis, loss of reflexes, fasiculations, sphincter dysfunction
Diagnosis for rabies
Sample at hair follicle - usually back of neck
Management of rabies
no cure once symptomatic
Sedatives
Barrier nursing
Vaccinate those exposed
Depending on category can choose vaccine vs vaccine + immunoglobulin. (animal derived)
Wash wound
Dont suture
Which diseases increase the risk of HIV transmission
Trichomoniasis
HSV2
Schistosoma haematobrium
(diseases causing breaks in urogenital area)
What are the stages of the HIV viral cycle
- Binding: GP120 binds to CD4 receptor on host cell - Co-receptor CCR5 or CXCR4 must also bind to allow entry (depends on the type of HIV as to which one it can bind with)
- Fusion - Fusion occurs with the viral envelope and cell membrane
- Reverse transcription - Reverse transcriptase enzyme creates DNA from RNA
- Integration- The integrase enzyme integrates the viral DNA into host DNA.
- Transcription and translation then occurs to create new viral proteins
- The new viral proteins leave the host cell by budding, using host cell wall as its envelope
- Protease enzyme cleaves the long chain proteins into its active components - HIV is now active to infect another CD4 cell.
Cell target for HIV
CD4 cell with GP120 receptor and CCR5 co-receptor (or CXCR4)
In what ways is viral load and CD4 count used in monitoring
viral load - indicates treatment response
CD4 - indicates disease stage
what is the HIV ‘set point’
Where HIV viral load reaches equilibrium with CD8 –> HIV will eventually escape this set point, but can last years
Protective mutations in HIV
delta 32 mutation
HLA-B57
HIV testing
High resource/ inpatient:
CD4 count
HIV viral load
Low resource/ self test:
- 4th Generation p24 antigen ELISA (detects within 14 days)
- Rapid diagnostic tests
- immunochromatography
- immunofiltration (INSTI) - (only useful in HIV1 types M,O)
Oraquick - HIV self test (better in high prevalence than high incidence)
Alere Ag/Ab combo test
Recommended HIV drug regime
2x NRTI + 3rd agent (INSTI or NNRTI)
List of NRTIs and their side effects
1st drugs:
TDF - GI symptoms, hypophosphatemia, osteoporosis, renal impairment
TAF - GI symptoms, hypophosphatemia, osteoporosis, renal impairment (all less than TDF)
Zidovudine - Anaemia, nausea, lipodystrophy, muscle pain
Abacavir - HLA-B5701 hypersensitivity, rash, nausea, flu-like symptoms.
2nd drugs:
Lamivudine - Peripheral neuropathy, Hair loss, Insomnia, Lactic acidosis.
Emtricitabine - GI symptoms, Hyperglycaemia, Hypertriglyceridemia, Itch, Skin darkening.
List of NNRTIs and their side effects
Efavirenz - Rash, Hepatotoxicity, Insomnia, Depression
High drug interactions, CYP2B6 G516T genotype affects plasma concentrations.
Rilpiverine - Rash, Insomnia, headache, depression. Hypertriglyceridemia. Must be taken with food.
List of INSTIs and their side effects
Dolutegravir - Rash, insomnia, depression, GI effects, weight gain.
Bictegravir -
List of PIs and their side effects
Lopinavir - GI side effects, headache, pancreatitis, hypertriglyceridemia, hyperglycaemia, arrhythmia.
Atazanavir - GI side effects, headache, jaundice, renal stones, arrhythmia.
Definition of virological failure of HIV treatment and management
viral load >1000 on 2 separate occasions with good adherence.
Make switch within class - Tenofovir/ABC to Zidovudine or other way
Continue Lamivudine or Emtricitabine (forces virus to maintain a certain resistance gene which has a big impact on fitness)
Change 3rd drug from NNRTI to dolutegravir or dolutegravir to PI.
(keep lamivudine/emtricitabine as it increases viral fitness cost)
When does U=U not apply?
breast feeding
What HIV regimen should be used in Hep B co-infection
Tenofovir regimen
When should ART be delayed
CNS TB or cryptococcal meningitis
Which ART drug class has the highest barrier to resistance
Protease inhibitors
Important interactions with HIV drugs
Tacrolimus (CYP3A4 interactions)
Dolutegravir and metformin
Rilpiverine and PPI’s
Protease inhibitors and TB drugs
What is the biggest cause of HIV drug resistance?
Non-compliance
What happens to HIV virus once drugs that it has formed resistance to are removed
Reverts to wild-type virus for improved fitness - but archives resistance genes so will recur faster if re-exposed.
HIV drugs with low RAM barriers and high RAM barriers (RAM = resistance associated mutation)
Low RAMs = Lamivudine, Emtricitabine, Efavirenz
High RAMs = PIs, Dolutegravir
When should a HIV drug not be used based on population data?
If that population has >10% resistance to a specific drug
When should first viral load be checked after commencement of ART?
6 months - this is how long ART takes to have full effect (may take up to 9 months.
Methods of HIV resistance testing
- Genotype testing
- pol gene
- integrase gene (for INSTI)
Note - there are many quasi species that develop in an infection - Sanger sequencing can only detect a resistance mutation if it is present in >20% of quasi species.
2, Phenotype testing
- serial dilutions with ART
Method of naming gene mutations
original peptide - position number - new peptide
Why should ART be switched early if resistance is noted?
Because resistance genes accumulate over time - with higher accumulation you risk class resistance developing.
How does HIV get to the lymph nodes + infect more CD4 cells.
picked up in periphery by dendritic cell (also has CCR5) and taken to LN.
Infected cells die via pyroptosis which attracts more inflammatory cells to the site.
Why does immunity drop in HIV prior to CD4 count?
Due to early effect on mucosal CD4 cells not picked up on serum samples
Difference in TB presentation in HIV+ patients
Less likely to form granulomas
More likely to see widespread necrosis
What are the 2 types of IRIS
Unmasking - signs and symptoms of a disease develop after ART.
Paradoxical - OI is improving with treatment - ART is commenced and there is then a clinical deterioration in that disease.
Management of newly diagnosed HIV without signs of TB
6 months isoniazid prophylaxis
Best HIV drug (3rd) to use alongside TB drugs
Efavirenz (NNRTI)
Prophylaxis for HIV based on CD4 counts
<250
Coccidioidomycosis (in endemic areas only) with fluconazole.
<200
- PJP with Bactrim
<150
- Histoplasmosis (in endemic areas only) with itraconazole
<100
Toxoplasmosis with Bactrim
Cryptococcus - screen and treat
<50
MAC - no treatment required if starting ART
Pathogens causing CNS disease in HIV
TB
Toxoplasmosis
Cryptococcus
CMV
HSV
Malaria
JEV
JC virus (causes PML)
Chagas
Causes of stroke in HIV
HIV associated vasculopathy
Vasculitis
aneurysm formation
accelerated atherosclerosis
opportunistic infections
neoplasia
endocarditis septic emboli
Mycotic anurysm
IHD
HIV associated cardiac dysfunction
coagulopathy/hyperviscosity
HIV effect in paediatrics
impaired brain growth/atrophy
developmental decline
motor language tone dysfunction
Stages of HAND (HIV associated neurocognitive disorder)
For hand must have deficits in 2 cognitive domains
- Asymptomatic neurocognitive impairment (ANI)
- mild deficit in 2+ domains but no functional impairment - Mild neurocognitive impairment (MNI)
- mild/mod deficit in 2+ domains with mild functional impairment - HIV associated dementia
- severe deficit in 2+ domains with severe functional impairment
HIV drug with best CNS penetration
Zidovudine
Dolutegravir
Nevirapine
Management of babies born to HIV+ mothers
Need 6 months Isoniazid prophylaxis
Testing at 6 weeks, 9 months, 18 months.
If baby is positive:
Cotrimoxazole prophylaxis from 4 weeks - 18 months
ART:
Neonate - Zidovidine + Lamivudine + Raltegravir
Child - Abacavir + Lamivudine + Dolutegravir
Should breastfeeding be recommended in HIV positive mothers
high income - no, bottle feed to reduce risk
LMIC - yes. as risk of water contamination is greater
Causes of diarrhoea in HIV
- Seroconversion illness
- Infections
- ART side effects
- HIV enteropathy
Treatment of infective diarrhoea in HIV
Depending on suspected cause:
- Bactrim
- Metronidazole
- Albendazole
Treatment of HSV in pregnancy
Aciclovir 400mg
If acquired in 3rd trimester - suppress until delivery
If before the 3rd trimester - suppress from 32 weeks.
Hepatitis A virus type and incubation
single strand RNA virus
2-4 weeks
Hepatitis A transmission
faecal-oral route
Highest risk areas for symptomatic Hep A
transition areas - in endemic areas infection occurs in children who have less severe symptoms.
Hep A symptoms
hepatitis and jaundice
rare - myocarditis, GBS, AKI
Hep A diagnostics
Serology
Hep A RNA detection in stool
Prevention and management of Hep A
Self limiting –> supportive care only
Hep A vaccine - 2 doses 6 months apart - gives 10 years protection.
When to use:
- travel vaccine
- population vaccine in transition areas
- post exposure
Hep B virus type
double stranded circular DNA virus
How does Hep B enter cell
NTCP receptor
How does Hep B increase risk of malignancy
integrates into p53 preferentially (a tumor suppressor gene) → increases malignancy risk.
How does Hep B evade the immune system?
Overloads the immune system by releasing large volumes of non-functional virus (surface antigen only) → creates eventual down-regulation of the immune system.
Hep B vaccination schedule
4 doses: 24hrs, 6,10,14 weeks
Management of Hep B in pregnancy
If viral load >200,000 - give tenofovir
+ give baby Hep B immunoglobulin at birth
What are the stages if Hep B infection, and in which stages should treatment be given?
Immune tolerance - dont treat
Immune clearance - treat - elevated LFTs
Immune control - dont treat
Immune escape - treat - elevated LFTs
Hep B treatment
Tenofovir or entecavir
Hep D virus type
small RNA virus
dependant on Hep B for replication
Hep D investigations
ELISA
Hep D RNA PCR
Hep D treatment
Interferon alpha
Hep C virus type
single strand RNA virus
Who to treat with Hep C
Everyone! It is curable. No persistance
Hep C treatment
Need to use drug combinations for treatment due to high risk of resistance
NS3B, NS4A, NS5A, NS5B
(often sofosbuvir combinations)
Issues with Hepatitis and HIV co-infection
HIV increases the rate of hepatitis hepatic fibrosis
Increased risk of ART causing hepatotoxicity
HIV leads to decreased CD4 cells in gut mucosa leading to increased bacterial translocation - increases work for liver and causes fibrosis.
Hep E virus type
single strand RNA
Hep E incubation transmission and clinical relevance
Incubation- 4 weeks, self limiting after 4 weeks
water outbreaks, faecal oral route.
90% of cases are asymptomatic
rare extra hepatic manifestations
increases risk of still births
Hep E treatment
Ribavirin
+/- Interferon alpha
mechanism of Covid-19 lung disease
In Covid there is diffuse alveolar damage with severe endothelial injury and microthrombi
= immune mediated thrombotic microangiopathy
Covid-19 management
B - breathing - give O2 if sats low
A - antivirals (mild - paxlovid, molnuperavir mod/sev- remdesivir)
S - steroids
I - IL6 - Tocilizumab
C - clotting - clexane
Monkey pox virus type and clades
Variola virus
Clade 1 (Africa) and Clade 2 (USA)
Clade 2b is current outbreak
Monkeypox transmission
direct, sexual, respiratory (close range), transplacental, fomites
Symptoms of Monkey pox
Papules or macular rash
Starts on trunk or point of inoculation - includes palms and soles
Mucosal lesions
Clade 1 (Africa) - all lesions at same stage, many lesions
Clade 2 (USA)- lesions at different stages, fewer lesions
Clade 2b - polymorphic rash, few lesions, sometimes anogenital only, lymphadenopathy in 50%
Reservoir of infection in Monkey pox
Likely to be rodents
(humans and primates are hosts)
