Micro 4 goodness me Flashcards
Why do influenza cause respiratory diseases
Influenza virus in humans causes respiratory disease because the virus requires activation by host cell proteases that are only expressed in the respiratory tract
Past influenza pandemics
There have been FOUR big pandemics in the 20th and 21st centuries
o 1918 - Spanish Flu (50 million deaths)
o 1957 - Asian Flu (2 million deaths)
o 1968 - Hong Kong Flu (1 million deaths)
o 2009 - Swine Flu (200,000 deaths)
Features of a pandemic flu virus
- A pandemic virus will have novel antigenicity.
- A pandemic virus will replicate efficiently in human airway.
- A pandemic virus will transmit efficiently between people.
What strains are the influenza vaccinations based on?
3 antigenically different flus tend to affect humans each year
1. Influenza A (H1) (peaks beginning of January)
2. Influenza A (H1N1) (peaks end of December)
3. Influenza B (peaks March)
– Trivalent vaccine in targeted pop’s = purified fraction with HA + NA of inactivated virus
What is the resevoir of influenza A
Natural reservoir of Influenza A is ducks
Human > human transmission of bird flu (H5N1) difficult as virus does not replicate very well at cold temperatures of upper airways (32OC).
Better in deeper lung tissue (still not ideal – 41.5OC) and from here it is difficult to escape.
What is the differenece between antigenic shift and drift
Antigenic Drift = Mutation occur to HA/NA to give new strains of the virus
Antigenic Shift = Complete change of HA/NA
Can only occur with influenza A
There is trading of RNA segments between human and animal strains
What is the role of haemolguttinin in viral pathogenesis
The virus attach to cells via sialic acid receptors. The virus enter the cell in a vesicle called the endosome. The haemaglutinin (HA) protein must be cleaved for the virus to be able to fuse with the endosome membrane and release its genome into the host cells
• Human airway tryptase in the lung lining is capable of cleaving HA, however, this enzyme is not present in other parts of the body
NOTE: there are some mutated forms of influenza which do NOT require HA to be cleaved to be able to enter host cells (this is a particularly virulent form of influenza)
o H5N8 is an example of a very deadly bird flu but it does not cross into humans
What is the significance of PB2 627K
• One of the key factors that allows animal influenza to cross into humans is a mutation in the polymerase protein (PB2 627K)
• The appropriate genes can be incorporated into a virus due to reassortment
o This is when a single cells is infected by both a human virus and a bird virus
o They then shuffle their RNA resulting in the production of a bird virus with the capability of infecting a human
o This is a quick way of acquiring the ability to infect humans and becoming a pandemic
o This is an example of antigenic shift
What happens once the virus breaks free of the endosome membrane?
They enter through endosomes. The acidity of the endosome triggers a fusion event by which it releases its genome into the cell
The genome then travels to the nucleus and takes over host factors to drive transcription and translation
New viral products are produced (proteins and genome)
They will assemble at the surface of the cell and bud off to produce hundreds of copies of the virus
Barriers to viral entry
- Mucus is difficult for viruses to get through
- Human viruses have evolved the ability to chop through the mucus to reach the cells
- They need to be able to recogise sialic acid in order to enter the cell.
- There may be intermediate hosts in whom only a couple of the changes need to be made to be able to infect them (e.g. pigs)
What are the complications of flu?
Secondary bacterial pneumonia/Mutant virus/Co morbidity/Cytokine storm
Antivirals for flu
- Amantadine (Influenza A only) – Targets M2 ion channel. BUT single AA mutation in M2 (S31N) = resistance (now in many ‘flu A strains incl. H1N1)
Therefore not effective against: influenza B, pH1N1 or seasonal H3N2 - Neuraminidase inhibitors: Oseltamivir (Tamiflu), Zanamivir (Relenza), Sialic acid – Effective only if given <48hrs after infection
• Relenza (zanamivir) - inhaled or IV
• Peramivir - IV
HSV Treatment
Encephalitis - Emergency IV aciclovir 10mg/kg tds for 21 days do not wait for test results
Meningitis - self limiting, treat only if IC with IV or 2-3d then oral for 10 days
VZV Treatment
Aciclovir PO/IV. Or valciclovir (prodrug) PO, famcliclovir. 2nd line is foscarnet but toxic. Only treat VZV if: neonatae chickenpox adult chickenpox shingles >50 underlying lung or eye problem
CMV treatment
IV Gancliclovir but BM hepatic and renal toxic so if CI or neurtopenic-»>
Foscarnet
If I/C, 3rd line is cidofovir
CMV strategy for transplant patients
TREAT established disease once it has been developed (high mortality in bone marrow transplant patients)
PROPHYLAXIS for organ TPs with ganciclovir or valganciclovir Side-effects: bone marrow toxicity
PRE-EMPTIVE THERAPY (for bone marrow transplant patients) Starting ganciclovir, valganciclovir or foscarnet when the viral load reaches a certain threshold, monitoring for the appearance of CMV on PCR in the blood.
Maribavir
- Inhibits viral kinase
- Effective in vitro against CMV and EBV (but no others)
- Does not cause bone or renal toxicity
- On going clinical trials (but they have been disappointing)
EBV MX
In post transplant, pts are at risk of lymphoproliferative disease. (LPD)
• DIAGNOSIS: EBV viral load in blood
• TREATMENT
• Reduce immunosuppression
• Rituximab - anti-CD20 monoclonal antibody
Influenza Treatment
The TWO main surface proteins are haemaglutinin (HA) and neuraminidase (NA)
- HA mediated virus binding and entry into the target cell
- NA allows release of progeny virus particles from the host cell
o NA is the target of the current generation of anti-influenza drugs
o Neuraminidase Inhibitors
• Examples:
• Oselatmivir (Tamiflu) - ORAL
• Zanamivir (Relenza) - Dry Powder
• Effective against influenza A and B
Indicated for all patients who are unwell enough to be admitted to hospital with an influenza virus-related respiratory disease. NEEDS TO BE WITHIN 48 HOURS OF SX ONSET. (36 for zana)
RSV Mx
1st line is outpatient care
If they have asthma, you can give prednisolone
If they are at risk of severe disease in highly seletive situations you can give inhaled ribvarin ±IVIG
IVIG - Derived from pooled donors. Often used as an adjunct to treatment of viral pneumonitis in the immunocompromised
Palivizumab- Monoclonal antibody against RSV
Used prophylactically in the winter months for the prevention of serious lower respiratory tract disease caused by RSV in high risk infants (e.g. preterm, heart or lung disease, SCID)
BK Virus Mx
• Treatment of BK Haemorrhagic Cystitis o Bladder washouts o Reduce immunosuppression o Cidofovir IV • May consider intravesical cidofovir • Treatment of BK Nephropathy o Reduce immunosuppression o IVIG o NOTE: cidofovir cannot be used because it is nephrotoxic
Adenovirus Mx
• Issue in paediatric transplant patients
• Can cause severe multi-organ involvement
• Treatment
o Cidofovir IV
o IVIG
HSV Drug Resistance
o Majority are due to mutation in viral thymidine kinase
o Most of these will show cross-resistance with ganciclovir
o Nearly always occur in immunocompromised patients
o Diagnosed using viral culture and plaque reduction assays (although genotypic assays are also becoming available)
o TREATMENT: foscarnet or cidofovir
CMV Drug resistance
o Most commonly caused by mutations in protein kinase gene (UL97)
o More likely to occur in the context of prolonged therapy in immunocompromised patients
o TREATMENT: foscarnet or cidofovir
How do vaccinations work
- An antigen is delivered by the vaccine which is then taken up by the antigen-presenting cell
- The APC will present the antigen to a naïve T helper cell which becomes activated
- This, in turn, results in activation of B cells
- A proportion of these activated B cells will mature into plasma cells
- The plasma cells will produce antibodies specific for the vaccine antigen
- Antibodies will then bind to the antigen leading to:
o Neutralisation of infectivity
o Antibody-dependent cellular cytotoxicity
NB If an attenuated virus vaccine is used, the T cell response is very important in destroying infected cells
Types of vaccinations
Inactivated
o Whole microorganism is destroyed by heat, chemicals, radiation or antibiotics
o It has no risk of causing infection in the host
o However, it may not produce a very strong or long-lasting immune response
o Examples: Influenza, Polio, Cholera
Live Attenuated
Live organisms are modified to be less virulent. There is a risk of virulence. Avoided in pregnant women/IC pts
E.g. MMR and yellow fever
Toxoid Vaccines- Inactivated toxin components
o Examples:
• Diphtheria
• Tetanus
Subunit
Protein components of the microorganism or synthetic virus-like particles are used
They lack viral genetic material and are unable to replicate e.g. hepB hpv
Conjugate
Poorly immunogenic antigens are paired with a protein that is highly immunogenic (adjuvant) Examples: Hib
Heterotypic
Using pathogens that infect other animals but do NOT cause disease in humans or causes mild disease
o Examples: BCG
- Monovalent = targeting one strain
- Multivalent = targets several strains
Features of Mycobacteria
- Slow growing
- Gram positive, non-motile, rod shaped
- Long-chain fatty (mycolic) acids, complex waxes and glycoproteins in the cell wall
- Acid alcohol fast
o Auramine is usually used as a screening test (burgundy back groun with yellow positive)
ZN is blue background (like primary school photographs) and purple stain
Other non tuberculous mycobacteria
Environmental, no person-person transmission, associated with impaired immunity, poor response to standard anti-TB regimen.
Slow growing backteria (x3)
1. M. Avium-intracellulare complex
-Pulmonary manifestation in normal people, e.g. pharyngitis, may invade bronchial tree esp if underlying lung disease e.g. bronchiectasis.
-Immuncompromised - Disseminated infection
-AIDS – Disseminated multibacillary infection, Mycobacteraemia (consider in HIV pts with londstanding diarrhoea)
- M. Marinarum (fish tank granuloma)
- Single or clusters of papules/plaques
- Swimming pool/aquarium owners - M. Ulcerans (Buruli Ulcer) – insect transmission; tropics/Aus
- Early – painless nodule
- Usually slowly progressive leading to ulceration, scarring + contractures
- Seldom fatal, hideous deformity
RAPID GROWING - causes skin and soft tissue infections
• Mycobacterium abscessus
• Mycobacterium chelonae
• Mycobacterium fortuitum
What is the ungrouped mycobacterium
LEPROSY- skin and neuronal based disease
Spectrum
Mycobacterium leprae
• TWO types:
1. Paucibacillary tuberculoid (people lose digits)
• Few skin lesions
• Robust T cell response that causes peripheral neuropathy
- Multibacillary lepromatous
• Abundance of bacilli
• Multiple skin lesions
• Poor T cell response - this then causes the facies
‘Shaved’ eyebrow (madarosis), thickened peripheral nerves
TB Transmission
o Droplet/airborne o Suspended in air o Reaches the lower airway macrophages o Infectious dose is 1-10 bacilli o Air remains infectious for 30 mins
Extrapulmonary TB
- Lymphadenitis -Pericarditis -Abdominal [peritonitis, ileitis]
- Genito-urinary, renal, testicular
- Misc: skin, liver etc Increased risk in HIV coinfection
Where s pulmonary TB?
o Causes caseating granulomata
o This can be found in the lung parenchyma and mediastinal lymph nodes
o Commonly found in the upper lobes
what is the gold standard for TB diagnosis
• Culture o Gold standard o Can be done with solid or liquid systems o Takes up to 6 weeks o Further testing for culture isolates
How can we check if you’re immune to TB?
Tuberculin Skin Test (TST)
o Looks for previous exposure to Mycobacteria
o 2 units of tuberculin are injected intradermally
o It is examined after 48-72 hrs looking for a reaction
o It is a delayed-type hypersensitivity reaction
o This cross-reacts with BCG so can confuse the interpretation
o POOR sensitivity: HIV, age, immunosuppression, Overwhelming TB
IGRAs
o Detection of antigen-specific IFN-gamma production
o Examples: ELISpot and Quantiferon
o NO cross-reaction with BCG
o Cannot distinguish latent and active TB
o Issues with sensitivity and specificity
TB Tx and its side effects
o 3 or 4 drugs for 2 months
o Then rifampicin + isoniazid for 4 months
o 10 months of treatment needed for CNS TB
o Cure rate = 90%
Rifampicin • Raised transaminases • Induces CYP450 • Orange secretions Isoniazid • Peripheral neuropathy (give with pyridoxine) • Hepatotoxicity Pyrazinamide • Hepatotoxicity Ethambutol • Visual disturbance
TB resistance
o Quinolones + aminoglycosides + para-aminosalicylic acid (PAS) + cycloserine + ethionamide
o Current WHO recommendations state that 7 drugs should be used for 9-12 months
What else should you be wary of in TB treatment?
CO INFECTION WITH HIV!
Diagnostic Challenges
o Clinical presentation is less likely to be classical
o Symptoms and signs might be absent if low CD4+
o More likely to have extra-pulmonary manifestations (i.e. normal CXR)
o Smear microscopy and culture is less sensitive
o Tuberculin skin test is more likely to be negative
o Low sensitivity of IGRAs
• Treatment Challenges
o Timing of treatment initiation
o Drug interactions
o Overlapping toxicity
o Duration of treatment (adherence)
o Healthcare resources
Worm classification
o Cestodes (tape worms) • Hydatid disease • Pork/beef/fish tapeworms (pork = Taenia solium, cows = teania salingatum)
o Trematodes (flukes)
• Less common
• Can affect lung, liver or intestines
• Schistosomiasis is an example
o Nematodes (roundworms)
• Hookworms
• Ascaris
• Strongyloides
Cestodes
Hydatid disease = dogs are definitive host. Problem occurs when humans eat infected dog poo and the worms think we are the intermediate host and lays eggs in our liver.
Praziquantel to treat the worm
Cyst removal may require surgery and are difficult to treat. Aspiration of cyst can work but can cause anaphylaxis if spills.
Cysticercosis - dying worms cause trouble
Give: Albendazole, praziquantel and steroids
Pork/beef cestodes
• Humans are the definitive host for these tapeworms
•Within the human, the adult tapeworm will lay eggs in the GI tract >The eggs will be excreted in the stools (look like 2cm, white wriggly things)
•These will then be eaten by pigs and cows
•Within these intermediate hosts, the egg will hatch, the larvae come out, they burrow through the intestine into the tissues where they form a cyst
•The cyst will contain a small tapeworm
•Humans will then eat the beef or pork, the cysts will open, releasing the tapeworm
•The tapeworms will then mature in the gut
You can’t get cystericosis from undercooked meat, just from eating food with infected human stool
Schistosomiasis
Contamination: humans come into contact with contaminated water, schisto burry through and settle down in the venules of the bladder or gut. They have sex and pump out loads of eggs. Damage is caused by the laying of eggs and migration of eggs (who are motile) through the bladder to be urinated/pooed out. They then find a body of water where they hatch into miracidia. Invade and mature in snail. Snail releases infectious cercariae -> look for human foot.
Eggs on their way out burry through tissue and can get stuck e.g. in the bladder wall. The eggs are also carcinogenic -> bladder cancer
In the gut, they are less damaging and not carcinogenic. But, retrograde passage of eggs into the liver causes cirrhosis e.g. oesophageal varices and portal HTN (however, synthetic function is preserved)
Diagnosis: Microscopy, Serology, Biopsy
• Urine: S. haematobium
• Stool: S. mansoni, S. japonicum
Treatment- Praziquantel
• Prevention
o Difficult to interrupt their lifecycle
o Can kill the snails, kill the reeds or kill the worms
o Advise people to stop swimming in rivers
Summary
o Ask about exposure (has to be outside of UK)
o Determine which samples need to be sent
o Check for end organ disease (bladder and liver)
o Empirical treatment may occasionally be needed
PUO definition
- Fever of 38.3 or more
- Present for more than 3 weeks
- Spent 3d in hospitla or 3 OP evaluations
Possible causes:
1) Infections
2) Neoplasms
3) Connective tissue diseases
4) Misc. Conditions (Abscesses, Endocarditis, Tuberculosis, Complicated UTIs), 5) Undiagnosed conditions
Types of PUO
Healthcare PUO
- More than 24 hours in hospital
- Causes: Surgery, devices, drugs (vanco, penicllins, seroternergic), LRTI (incl. ventilator-associated in ITU), C. diff colitis, Immobilisation
HIV PUO
Seroconversion, TB, Kaposi’s sarcoma, Bacterial, Disseminated MAI, PCP, CMV, Cryptococcus, Toxoplasmosis, Lymphoma Histoplasmosis, Drug fever etc
Neutropenic PUO
Chemotherapy, Haematological malignancies. Look for conditions that require neutrophils (eg fungal [aspergillus], bacterial sepsis), Mycobacteria, GVHD, Drug fever
How to investigate PUO
All the bedside examinations
HIV test
EBV and CMV serology (monospot diagnoses both, NB IgM is more useful than IgG because knowing whether they had an infection in the past won’t help diagnosis now)
Extra test: CK, ANA, ANCA, RhF, Ferritin, Abdo imaging
PET CT - using FDG (Fluro-D Glucose) as it accumulates in cells with an increased rate of glycolysis (highlights activated leucocytes and allows metabolic correlation to anatomical scan). Shows vascular infection/inflammation
But caution in those with poor glucose control.
TTE - if you’re considering infective endocarditis
Empirical treatment should be started after taking samples for culture UNLESS patient is unstable. Try to identify source as this will tell you the most likely pathogens to treat with antibiotics.
Very high Ferritin is indicative of what
Very high ferritin is classically associated with:
• Adult-onset Stills disease
• Macrophage activation syndrome - present with salmon pink rash and arthralgia can have abn LFTs.
Significant overlap with some infective causes (it is an acute phase protein)
When to treat PUO?
If clinical signs of SEPSIS - haemodynamic compromise in the context of fever and possible infection = START ANTIBIOTICS IMMEDIATELY
What is IGRA?
o Interferon-gamma release assay
o Limited sensitivity and specificity for active TB
o This is a test for latent TB (this is the case in about 1/3 of people)
o This is NOT particularly useful in someone with PUO because you don’t know if they have latent TB or not
o It can be -ve in ~ 10-20% of people with active TB
o It is not a great test
o TST - useful in diagnosing sarcoid disease
Where are ticks likely to bite?
They jump onto leg and crawl upwards up till waistband.
Indications for emergency treatment in PUO?
Infective Endocarditis - TTE Disseminated TB - Milliary, pericardial and meningeal TB CNS TB GCA
GCA
- Headache±jaw claudication and raised ESR (but not needed for diagnosis)
- Cx is visual changes tongue necrosis (so it won’t need to present with these)
Age > 50
Ix: Biopsy gold standard
Malignant causes of PUO
• Lymphoma
o Especially non-Hodgkin’s
o Often advanced disease with aggressive subtypes
o Raised LDH, weight loss, hepatosplenomegaly, lymph nodes
• Leukaemia
o Bone marrow biopsy
• Renal cell carcinoma
o 20% will present with a fever
• HCC or metastases to the liver
• Often identified on axial imaging (so the patient may not reach the criteria for PUO)
Infectious causes of PUO
- Viral (EBV, CMV, HIV)
- Bacterial (Mycobacteria, Typhoid, Zoonoses)
- Parasitic (Malaria, Entamoeba, Schisto and Toxo)
- Fungal (Cryptococcus and Histoplasmosis)
Inflammatory causes of PUO
o Younger = Adult onset Stills
o Older = GCA
o Involve a rheumatologist
Helminths
3 main types (5 total) Hookworm- transdermal Ascaris lumbricoides - ingested with food Trichuris Trichuria - ingested with food Strongyloides stercoralis - transdermal
Ascaris Lumbricoides
o You eat the eggs which migrate around your body and eventually hatch
o Once hatched, it will move to the intestines and mature into an adult worm
o It will remain in the intestines and lay eggs which will be excreted through the faeces
(Gastric washings of the ascriasis case)
Strongyloides
o Causes damage by: • Hyperinfection • Larva currens (itchy rash) • Malabsorption • Usually ASYMPTOMATIC o Treatment • Ivermectin - Can be found on perianal skin
A 61-year-old man is seen in the diabetic foot clinic because of a chronic ulcer on his left leg. The ulcer has been present for the past 5 months and is well demarcated with no sensation at the base of the ulcer. He has grown the same bacteria from swabs taken from the ulcer multiple times
Pseudomonas is a common cause of chronic wound infection
Malaria PC vs Dengue Pc
Dengue:
- Saddleback fever
- Retroorbital headache
- 50% erythrodermic rash
- Hepatitis, bleeding, encephalitis myocarditis
- haemorrhagic fever/shock (IF PREVIOUSLY INFECTED)
- Conjunctival injection
Malaria:
o Fevers - cyclical or continuous with spikes
o Malaria paroxysm - chills, high fever, sweats
o SEVERE malaria
• High parasitaemia or schizont
• Altered consciousness with/without seizures
• ARDS
• Circulatory collapse
• Metabolic acidosis
• Renal failure, haemoglobinuria (blackwater fever)
• Hepatic failure
• Coagulopathy +/- DIC
• Severe anaemia
• Hypoglycaemia
• In other words, this is end-organ damage resulting from malaria
Vectors and organisms in dengue vs malaria
Dengue is caused by flavivirus carried by the aedes mosquito.
Malaria is caused by falciparum carried by the anopheles mosquito.
o Plasmodium falciparum (Invades erythrocytes of all ages, Can be life-threatening, Can be drug-resistant)
o Plasmodium vivax
o Plasmodium ovale
o Plasmodium malariae
o Plasmodium knowlesi - Behaves like falciparum
Ix of Dengue vs Plasmodium
Dengue can do serology from day 5, if not PCR
Malaria
THREE thick and thin blood smears (Field’s or Giemsa stain)
• THICK: screen for parasites (sensitive)
• Thin: identify species and quantify parasitaemia
• Quantifying involves looking at the proportion of red cells that are parasitised
• NOTE: > 2% is considered high
o Malaria antigen detection tests (rapid antigen test)
Mx of dengue vs malaria
Mx of dengue is supportive
Malaria:
Treatment - Non-Falciparum Malaria
o Chloroquine - 3 days
o Primaquine - 30 mg for 14 days
(IMPORTANT: need to screen for G6PD deficiency before starting primaquine because it can cause haemolysis. Primaquine is effective in the hypnozoite stage (liver stage) )
o Complications in non-Falciparum malaria are very rare, but splenic rupture is well recorded
Treatment - Mild Falciparum Malaria
If not vomiting, parasitaemia < 2% and ambulant
1. Oral malarone (atovaquone and proguanil)
• 4 tablets daily with food for 3 days
2. Artermisinin combination therapy (ACT)
• E.g. Riamet/Co-artem - artemisinin + lumefantrine
3. Oral quinine 600 mg tds Then doxycycline 100 mg OD for 1 week. This is NOT used very frequently
Treatment - SEVERE Falciparum Malaria o ABC approach o Correct hypoglycaemia o Cautious hydration (avoid overload) o Organ support is necessary o IV Artesunate in preference to IV quinine o Daily parasitaemia monitoring o Follow on with oral antimalarials o Artesunate is the TREATMENT OF CHOICE for severe malaria
Quinine side effects
- Quinine side-effects:
- Cinchonism (technical term for quinine overdose)
- Tinnitus
- Dizziness
- Nausea and vomiting
- Arrhythmias
- Hyperinsulinaemia (worsens hypoglycaemia)
Faget sign
Faget sign — sometimes called sphygmothermic dissociation — is the unusual pairing of fever with bradycardia (slow pulse) or normal/ only slightly raised pulse relative to the systemic distress. It is a sign of: Yellow fever Typhoid fever Brain abscess Tularaemia Brucellosis Colorado tick fever Some pneumonias - Legionella pneumonia and Mycoplasma pneumonia
PC: Fever, sweats, dry cough, constipation (with diarrhoea beforehand)
O/E: 39C, HS I + II (Gallop rhythm),
CXR clear
ECG Peaked p waves
Vaccinations up to date for travel hx
Diagnosis and management? and complications
Typhoid fever
- Dry cough, constipation -> salmonella typhi/paratyphi
- sphygmothermic dissociation
- Other PC: Rose spots (Rare), splenomegaly
- The vaccine is only partially protective against S. typhi and offers NO protection against S. paratyphi
- Incubation: 7-18 days (can be up to 60 days)
- Cx
o GI bleeding
o Perforation
o Encephalopathy
- Treatment
o Empirical ceftriaxone (2 g IV OD)
o Azithromycin PO 500 mg BD 7 days
