Immunology and Infection Flashcards
How is genital herpes diagnosed?
PCR of lesions (negative test does not exclude HSV)
Type specific serology in pregnancy
What are complications of genital herpes?
Aseptic meningitis (HSV2)
Elsberg syndrome (acute urinary retention, constipation and sacral neuralgia)
HSV2 myelo-radiculitis (AIDS)
Bells palsy
HSV encephalitis (HSV1)
Erythema multiforme
Disseminated HSV (pregnancy)
Neonatal herpes
How is genital herpes managed?
First infection:
-Valaciclovir or aciclovir for 7-10 days
-IV if severe
Recurrent episode:
-2-3 days
Suppressive therapy 6-12 months
What is the organism that causes syphyllis?
Treponema pallidum ss pallidum
Corkscrew shaped, motile microaerophillic bacterium
What are the different outcomes of early syphilis and their frequency?
1/3 spontaneously resolve
1/3 infected without clinical disease (latent)
1/3 develop tertiary syphilis
How is neurosyphilis diagnosed?
If neuro signs with positive serology definitive diagnosis is obtained via lumbar puncture
How is syphilis diagnosed?
Screening with serology (enzyme or chemiluminescence immunoassay)
- treponemal (TPPA, TPHA)
- non-treponemal (RPR, VRDL)
Direct dark ground microscopy
Direct fluorescent antigen (DFA)
Treponemal NAAT
How is syphilis treated?
Early: single dose IM benzylpenicillin G or 14 days doxycycline
Late: 3 doses IM benzylpenicillin G or 28 days doxycycline
Neurosyphilis: IV benzylpenicillin 10-14 days or 28 days doxycycline
How are RPR/VRDL used to determine cure or reinfection?
4-fold reduction in RPR = cure
4- fold increase in RPR = reinfection
What diseases do different serovars of Chlamydia trachomatis cause?
A-C: eye disease
D-K: genitourinary disease
L: lymphogranuloma venerum
What is the most common diagnosed bacterial STI?
Chlamydia
How is chlamydia diagnosed?
NAAT from First pass urine, cervical or vulvovaginal swab, rectal or throat swab
How is chlamydia treated?
Doxycycline BD for 7 days
OR azithromycin 1 g stat
Avoid sexual contact for 7 days
What are microbiological features of N gonorrhoeae?
Gram negative diplococci
How is Gonorrhoea diagnosed?
NAAT and culture for susceptibility
How is gonorrhoea treated?
Ceftriaxone + azithromycin
No sexual contact for 7 days
What bacteria commonly cause cellulitis?
Betahaemolytic streptococci cause 70-85% of infections (S dygalactiae, S pyogenes)
S. aureus less common, more likely to cause if pustules
In what population should gram negative cellulitis be suspected?
Immunocompromised host
Cirrhosis
Chronic leg ulceration
Cellulitis of abdominal wall/groin
Marine exposure = Vibrio, Aeromonas
Dog or cat bites = Pasteurella multocida, Capnocytophagia canimorsus
What clinical clues suggest the presence of a necrotising soft tissue infection?
Toxic shock
Systemic unwellness out of proportion
Pain out of proportion
Purplish discolouration
Violaceous bullae
Crepitus
LRINEC score
What is the LRINEC score for necrotising soft tissue infection?
Screen for necrotising soft tissue infection, Score > 6 highly suggestive
CRP < 15 = 0 pts
> 15 = 4 pts,
WCC < 15 = 0 pts
15-25 = 1 pt
>25 = 2 pts
Hb. > 135 = 0 pts
111-135 = 1 pt
<111 = 2 pt
Na > 135 = 0
< 135 = 2
Cr < 141 = 0
> 141 = 2
BSL < 10 = 0
>10 = 1
What organisms commonly cause necrotising soft tissue infections? How does this guide empiric therapy?
Often polymocrobial so need to cover gram +ve, gram -ve and anaerobes
IV clindamycin useful as anti-toxic agent (linezolid is good alternative)
How should necrotising soft tissue infections be managed?
Surgically!
Antibiotic cover
How do penicillins work? What treatment regime influences their efficacy?
Bind to penicillin binding protein in cell wall to inhibit cross-linking of peptidoglycans resulting in cell lysis and bacterial death
Efficacy is proportional to free drug time/MIC = frequent low dose
What are the common organisms that cause diabetic foot infections?
Polymicrobial
Acute infection: S. aureus and Streptococci
Chronic: gram negatives and anaerobes
What are ESBLs, what antibiotics are they resistant to and what organisms express them?
Extended spectrum Beta-lactamases = plasmid mediated expression of extracellular enzyme that hydrolyses the beta-lactam molecule
Confers resistance to all penicillins 1st-3rd generation cephalosporins and aztreonam
Seen in aerobic gram negative bacilli such as E. coli and K. pneumoniae
What is the most common ESBL genotype?
CTX-M (now more common that TEM, SHV)
What is the difference between ESBL and ampC?
ampC is inducible chromosomal gene in ESCAPPM species
Demonstrate similar resistance profile but ampC is not inhibited by clavulanic acid
What antibiotics can be used in ESBL infection?
Sepsis: carbapenems, gentamicin or amikacin
Uncomplicated UTI: nitrofurantoin or trimethoprim if susceptible, fosfomycin, mecillinam
In which groups should treatment of asymptomatic bacteriuria be given?
Pregnant woman
Prior to invasive urological procedure where mucosal bleeding is expected
Is there a role for serology, such as legionella, in the assessment of community acquired pneumonia?
No - unlikely to have generated sufficient antibody response in acute infection to guide management
What is the most common causative organism of community acquired pneumonia?
S. pneumoniae (approx 30%)
What organisms need to be covered with empiric antibiotic therapy for community acquired pneumonia?
S pneumoniae, mycoplasma pneumoniae, S aureus, Legionella, Enterobacteriae, Haemophyllis influenzae
What is the CURB65 score for community acquired pneumonia and how is it interpreted?
Mortality score where 0-1 = low risk, 2 = moderate risk and 3-5 = high risk to inform treatment decision
Confusion
Urea > 7
RR > 30
BP < 90
Age > 65
What is the 30-day mortality for different CURB65 scores and how should they be managed?
0 or 1 = <3%, managed in community with PO amoxicillin
2= 9%, inpatient management with IV therapy with atypical cover (e.g. Amox + doxy)
3-5 = 15-40%, consider ICU with IV therapy including resistant organisms and atypical cover (e.g augmentin + azithromycin)
What MIC is considered resistant with regard to S pneumoniae and penicillins?
> 2 mg/L
What is the rational behind using doxycycline or macrolides (azithromycin) in CAP?
Provide cover for mycoplasma, chlamydophila
Macrolides also provide cover for legionella
What is the rationale for Augementin or ceftriaxone for unwell patients with CAP?
Also provide cover for beta-lactamase producing bacteria such as H. influenzae whilst retaining S pneumoniae cover
What is the resistance mechanism used by MRSA?
Expression of mecA gene that produces PBP2a protein
What are the 4 structural proteins of SARS-CoV2?
Membrane (M)
Spike glycoprotein (S) = target of vaccines
Envelope (E)
Nucleocapsid (N)
Which SARS-CoV2 proteins are targeted by diagnostic tests?
RAT: nucleocapsid antigen
PCR (NAAT): genes for E, N and M, typically CT > 30 not infectious
Antibody: nucleocapsid IgG = prior infection, spike IgG = prior infection or vaccination
What cells does SARS-COV2 infect and how does in gain entry into the cell?
Affects upper and lower respiratory tract epithelial cells
Gains access via cell surface receptors such as ACE2
What are the targets of nirmatrelvir/ritonavir, molnupiravir and remdesivir?
Nirmatrelvir/ritonavir = viral protease
Remdesivir/molnupiravir = RdRP (RNA dependent RNA polymerase)
What type of virus is SARS-CoV2?
Coronavirus: single stranded positive sense RNA virus
What host immune response is recruited to SARS-CoV2 infection?
APCs (DCs) activate antigen specific CD4+ and CD8+ T-cells
Antigen specific B-cells are also recruited and supported by CD4+ T-cells, initially generate low affinity IgM Abs, other B-cells undergo affinity maturation and class switching in lymphoid tissues (nodes and spleen) to produce large amounts high affinity IgG antibodies
Viral clearance requires B and T cell response, T-cell response protects against severe disease (and is the desired outcome fo vaccine therapy)
What mechanisms contribute to severe COVID?
Failure of interferon signalling leads to prolonged viral replication, viraemia and dysregulated hyperinflammatory response
2% men with critical COVID have X-linked recessive TLR7 deficiency
20% >80 with severe COVID have anti-IFN antibodies
What is the key difference between omicron variant and wildtype and delta Variants of SARS-CoV2 virus?
Omicron has greater affinity for upper airway epithelial cells so presents more similarly to other viruses whereas others had greater affinity for lower resp tract.
Omicron less likely to result in hypoxia and hospitalisation
What is the timeline of infection, transmissibility and antibody response to SARS-CoV2 infection?
Incubation 3-7 days
Viral shedding 15-18 days
Virus cleared after 30 days
IgM peak at 20 days
IgG peak at 25 days, lasting up to 4 months
What are mRNA vaccines and their advantages and disadvantages?
Lipid nanoparticles containing mRNA code for an antigen which is synthesised in host cells. This then generates a host immune response to minimise the severity of future infection
Clinically only mRNA vaccine is COVID spike protein, includes anchor so not released in blood and only expressed on cell surface
Advantages:
- highly potent: small amount mRNA generates large amount of protein
- easy to manufacture
Disadvantages:
- mRNA unstable, cold chain must be -70C
- risk of pericarditis/myocarditis
What are protein subunit vaccines, their advantages and disadvantages?
Protein antigen + adjuvant that illicit low grade cellular immune responses
Advantages: good safety profile
Disadvantages:
- low immunogenecity requires adjuvants, often booster doses
- lower ability to produce cellular immune response
- difficulty scaling manufacturing
How do viral vector vaccines work, what are their advantages and disadvantages?
Antigen encoding DNA is packages in viral vector which carries it into host cells, where the DNA in translated and transcribed into antigen without being incorporated into host genome
Example is Astrazeneca vaccine for COVID (where chimpanzee adenovirus is used and does not generate immune response to vector)
Advantages:
- robust immune response
- stored at 2-7C
Disadvantages:
- Vaccine induced thrombotic thrombocytopenia (young women)
- Immunity can be developed to viral vector, limiting ability to give repeated doses
What is the influence of SARS-CoV2 vaccination on previously exposed individual? What is the outcome of a booster?
Generates a greater and longer lasting immune response than a COVID-naive individual
Booster generates higher titre antibiodies that last longer
What is the recommended vaccine schedule for SARS-COV2?
Primary course for everyone > 5 years
Booster 6 months after COVID infection or vaccine or 3 months after Evusheld
3rd booster if immunocompromised
What are contraindications to SARS-CoV2 vaccination?
Anaphylaxis to previous dose of vaccine or any component, myo/pericarditis following previous dose
How is COVID treated?
Vaccination = pre exposure prophylaxis
No therapies for post exposure prophylaxis
Mild-moderate (no hypoxia) = aim to prevent severe disease =nirmatrelvir/ritonavir or remdesivir, Inhaled budesonide 2 puffs BD for up to 14 days
Severe COVID (hypoxic) = treatment to improve survival = dexamethasone, baricitinib and tocilizumab. + Remdesivir to reduce length os stay + VTE prophylaxis
Critical COVID (ICU) = treatment to improve survival = dexamethasone, baricitinib and tocilizumab. + Remdesivir to reduce length os stay + VTE prophylaxis
There is no role for Evusheld in current management of COVID as ineffective for later variants
What is paxlovid, its dosage, adverse effects and contraindications?
Combination of Nirmatrelvir (COVID protease inhibitor) + ritonavir (CyP450/CYP3A4 inhibitor that boosts nirmatrelvir) used to treat COVID
Dose:
- eGFR > 60: 300 mg nirmatrelvir + 100 mg ritonvavir BD for 5 days
- eGFR 30-60: 150 mg nirmatrelvir + 1 00 mg ritonavir BD for 5 days
Adverse effects: headache, dygeusia, diarrhoea, vomiting
Contraindications:
- eGFR < 30
-Severe hepatic impairment (Chalres Pugh C)
- Pregnancy
- Drug interactions
What is remdesivir, its dosage, adverse effects and contraindications?
Ribonucleoside analogue that inhibits RNA-dependent RNA polymerase (RdRp
3 day IV course: 200 mg day1, then 100 mg day 2+3 -> for hospitalised and pregnant women
Adverse effects:
- LFT derangement
- renal impairment
- infusion reaction
Contraindications:
- eGFR < 30
- Liver disease
What is the mechanism of severe COVID and what therapies have been demonstrated to improve survival?
Drive by dysregulated immune response to COVID infection in which IL-6 has a central role
Dexamethasone if hypoxic (use prednisolone or hydrocortisone if pregnant due to lower foetal exposure)
Baricitinib
Tocilizumab
What are baricitinib and tocilizumab, when are they indicated in COVID infection and what are their contraindications?
Baricitinib = JAK1/2 inhibitor, given 4 mg OD for 14/7
Tocilizumab = anti-IL6 mAb
Indicated for Severe/critical COVID, often used if not responding to steroid
Both have been shown to reduce mortality and risk of requiring mechanical ventilation
Barictinib can be used in most patients, 50% dose reduced if eGFR 30-60
Tocilizumab, weight based dosing, reserved for pregnant or if eGFR < 30
Contraindications:
- sepsis or severe non-COVID infection
- if already significantly immunosuppressed
What are characteristics of human herpes viruses?
dsDNA genome
Capsid
Tegument = protein layer between nucleocapsid and envelope
Glycoprotein bilayer envelope
What are the different subfamilies of human herpes viruses, their target cells and latency?
Alphaherpesvirinae target mucoepithelial cells are are latent in sensory ganglia. E.g HSV1, HSV2 and VZV
Betaherpesevirinae target white blood cells. E.g CMV latent in monocytes and lymphocytes, Roseolovirus latent in T-cells, leucocytes
Gammaherpesvirinase target lymphocytes and are latent in B-cells. E.g. EBV and KSHV (HHV8)
What are characteristics of CMV infection in an immunocompetent host?
Typically asymptomatic
Fever, lymphadenopathy and lymphocytosis +/- thrombocytopenia and haemolytic anaemia
Rarely pneumonitis, hepatitis, meningoencephalitis and myocarditis
When is CMV transmission the highest in pregnancy? What are common complications
First trimester in primary infection
IUGR, thrombocytopenia, microcephaly, chorioretinitis and sensorineural hearing loss
How does CMV infection manifest in the immunocompromised host?
Rarely asymptomatic
Commonly presents as flu-like illness
Can occur in tissue invasion such as GI tract, hepatitis, pulmonary disease, meningoencephalitis, retinitis (in HIV esp)
What are risk factors for CMV infection in an immunocompromised host?
CMV+ donor with CMV- recipient in solid organ transplant
CMV- donor with CMV+ recipient in HSCT
Immunomodulator therapy
Hypogammaglobulinaemia
What are indirect effects of CMV infection?
Cellular mediated effects such as allograft injury or rejection, EBV-associated PTLD, opporutnistic infection
How is CMV diagnosed in the immunocompetent and immuncompromised host?
Immunocompetent = serology (IgM)
Immuncompromsied = CMV PCR or serum or histopathology of tissue
How is CMV infection treated?
1st line = IV ganciclovir or PO valganciclovir (IV if severely unwell)
2nd line = foscarnet
3rd line = cidofovir or marabivir for resistant or refractory disease
What is the mechanism of action and adverse effects of:
-Ganciclovir/valganciclovir
-foscarnet
-Cidofovir
-Marabivir
- Letermovir
-Ganciclovir/valganciclovir = inhibitor of CMV DNA polymerase, renally dosed, may cause neutropenia
-foscarnet = pyrophosphate analgoue that directly binds to DNA ploymerase, causes nephrotoxicity, electrolyte wasting
-Cidofovir = cytosine analogue, significant toxicity can be mitigated by probenecid
-Marabivir = targets viral UL97 an ATP competitive kinase inhibitor, CYP450-mediated drug interaction
-Letermovir binds CMV terminase complex, not to be used for treatment of CMV, does not cover other herpesviruses, interacts with ciclosporin
What are prophylaxitic strategies for CMV prevention?
Prophylaxis =
- valganciclovir for solid tumours
- letermovir in HSCT as does not induce cytopenias
How is EBV transmitted?
Mainly oral
Can be transmitted via transplant, blood products and possibly in sexual fluids
What is the immunological lifecycle of EBV?
Lytic infection occurs in epithelium of oropharynx where it is shed
Then migrates to B-cells in local lymphoid tissues, where infected memory B-cells proliferate containing cDNA = lytic phase
In immunocompetent host CD4, CD8 and NK-cells bring EBV infection under control. Small pool of memory T-cells persist
How do EBV protein levels correlate to lytic and latent phases of infection?
Lytic: see BZLF1, BRLF1, DNA amplification, viral capsid
Latent: EBNA, LMP and EBER = non-coding RNA
How does EBV serology correlate with EBV infection?
IgM seen 0-10 weeks, peaking 3-6 weeks and then declining
IgG peaks at 5-7 weeks and persists
What is the significance of the LMP-1 gene in EBV?
Lowly immunogeneic and mimics CD40 to promote cell survival and proliferation
Recognised as oncogene in multiple cancers (Burkitts lymphoma, Hodgkins lymphoma, PTLD, nasopharyngeal carcinoma, gastric carcinoma, oral hairy leucoplakia)
What is the role of anti-viral therapy for EBV?
No established role in treatment of infection or prophylaxis
What is PTLD and how is it managed?
Post transplant lymphoproliferative disease, commonly occurring during EBV infection in post transplant period
Managed with reduction in immunosuppression to increase T-cell responses
Can also consider cytoreductive therapy such as rituximab and low dose chemotherapy
What type of virus is varicella zoster, how is it transmitted and what diseases does it cause?
dsDNA
Airborne
Cause chickenpox and herpes zoster
How infectious is varicella zoster and what is the rate of infection in exposed contacts?
Infectious from 48hours pre rash and until 4-5 days post crusting
70-90% household contacts will become infected
What are the clinical features and complciations of chickenpox?
Clinical features:
- viral prodroem: fever, malaise, pharyngitis
- develops itchy vesicular rash in crops over 4 days which crusts over
Complications:
- bacterial skin infection
- encephalitis esp cerebellar ataxia
- pneumonia esp adults
- disseminated varicella in immunosuppressed
How is chickenpox treated in adults?
Given higher rate of complications then treated:
- uncomplicated = oral aciclovir/valaciclovir within 72 hours of rash
- complicated = IV aciclovir
Post exposure prophylaxis in pregnant woman:
- varicella immunoglobulin if < 4 days
- oral aciclovir if > 4 days
- NEVER give varicella vaccine due to risk of congenital disease from live vaccine
What is the natural history of varicella zoster infection?
Control of initial chickenpox
Then latent in dorsal root ganglia
Can reactivate in age as herpese zoster causing rash or neuralgia
What are the key features of herpes zoster and how is it treated?
Painful, unilateral, dermatomal vesicular rash
Treated with valaciclovir or aciclovir
Vaccination as prevention regardless of previous chickenpox or zoster history
What type of virus is measles, its infectivity and the vaccine coverage needed to stop transmission?
Measles morbillivirus = ssRNA
Infectious from 4/7 prior to 4/7 after rash, infectious droplets can stay airborne for up to 2hours
Attack rate = 90%, R0 12-18
Needs 95% vaccine coverage in a community to stop transmission
What are the clinical features of measles?
Incubation period = 6-21 days
Prodrome = 2-4 days
- fever, conjunctivitis, coryza, cough
- koplik spots = white spots on mucosa
Exanthem phase = erythematous blanching macular rash beginning on face then descends
What are complications of measles?
30% affected experience complications and 30% die in developing countries
Pulmonary:
- croup, pneumonia, sinusitis
- bronchiectasis
Neurologic:
-encephalitis
-subacute sclerosisng pan-encephalitis
How is measles treated?
No specific treatment
Vitamin A in severe measles
Supportive care and treatment of secondary bacterial infection
What conditions may be seen with encephalitis?
Meningitis
Myelitis
Radiculitis
Neuritis
What is the diagnostic criteria for encephalitis?
Major (essential) =Altered mental status lasting > 24 hours without other cause found
Minor (>3 confirmed, > 2 probable):
- fever >38 within 72 hours before or after presentation
- generalised or partial seizure not attributable to pre exisiting seizure
- new onset focal neurology
- CSF WCC > 5
-neuroimaging suggestive of encephalitis
-EEG consistent with encephalitis
What are different causes of encephalitis?
Infectious:
- viral = most common (enterovirus overall most common, HSV1 most common for severe)
- bacterial
- fungal
- parasites
- para/post infectious: ADEM, AHLE
Non-infectious:
- anti-NMDR
- anti-LGI1
- anti-Caspr2
- paraneoplastic limbic
What are common causes of infectious encephalitis in >60 years old?
Listeria monocytogenes
HSV
VZV
What are common causes of infectious encephalitis in immunocompromised?
HHV6
CMV
EBV
Mealses
VZV
LCMV
Toxoplasma
Cryptococcus
JCV
BKV
Bartonella
What are common causes of infectious encephalitis in different travel locations?
-Asia/Pacific: JEV, dengue, malaria, TB
-North America: West nile virus, lacrosse virus, neuroborreliosis, coccidiomycosis
-Africa: malaria, trypanosomiasis, TB
What are common causes of infectious encephalitis associated with animal exposure?
-Mosquito: aborovirus, kunjin, JEV, dengue
-Ticks: Rickettsiae
-Bats: rabies
-Monkeys and dogs: rabies
What are common causes of infectious encephalitis associated with rash/unvaccinated?
Measles
Mumps
VZV
What are clinical features of HSV encephalitis?
Bimodal onset: early childhood or >50
Affects anterior and medial temporal lobe, inferior frontal lobe, thalamus and insular cortex
Presents with headache, fever, confusion and altered behaviour
CSF demonstrates raised WCC, positive for HSV (typically HSV1) with peak virus days 3-7
What is the characteristic MRI finding of HSV encephalitis?
asymmetrical abnomrlaities in mesotemporal, orbitofrontal lobes and insular cortex with associated oedema
May also show restricted diffusion or haemorrhage
How is HSV encephalitis treated?
IV aciclovir for total 14 days
What are clinical feature of JEV encephalitis?
RNA flavivirus typically affecting children
5-15 day incubation period with fever, headache, myalgia and/or rash
Then develop seizures, parkinsonian features, altered consciousness, possible motor weakness
50% have raised opening pressures
How is JEV encephalitis diagnosed and treated?
Diagnosed by presence of JEV IgM in serum or CSF
No specific antiviral, managed with supportive care
What is acute disseminated encephalomyelitis (ADEM)?
Immune mediated demyelinating disorder
Features:
- acute polyfocal neurological deficits
- encephalopathy
- neuroimaging demonstrates multifocal demyelination
- rare in adults
- typically monophasic (cf MS)
- seen post infection or vaccination
What is Acute haemorrhagic leuco-encephalopathy (AHLE)?
Considered to be severe form of ADEM
More common in adults
50% have preceding infection (most commonly viruses
What is Anti-NMDAR encephalitis and its clinical features?
Antibodies present in CSF against GluN1 subunit of NMDAR
Associated with ovarian teratomas and HSV-encephalitis
More common in woman (8:2)
Median onset is 21 years old
In children presents with seizures, abnormal movement, irritability
In adults presents with abnormal behaviour, reduced LOC, characteristic movement disorders (facial dyskinesia, stereotyped movement disorder)
5% develop demyelinating disorder
How is NMDAR encephalitis diagnosed and treated?
CSF positive for anti-NMDAR antibodies
Treated with steroids, IVIg, plasma exchange, treatment of underlying tumour
What are clinical features of anti-LGI1 encephalitis?
Caused by antibodies against LGI1 protein which is associated with voltage-gagted potassium channels
Gradual onset, peaks in age 60s
Involves temporal lobe: epilepsy, amnesia
Associated with hyponatraemia, faciobrachial dystonic seizure (quick movement os unilateral face and leg)
Not typically associated with tumours
How is anti-LGI1 encephalitis diagnosed and treated?
Diagnosed by presence of anti-LGI1 antibodies in CSF
MRI may show hippocampal T2 hyperintensity, mesial temporal sclerosis
Treated with immunotherapy (IV methylprednisone, IVIg, plasma exchange)
What are clinical features of paraneoplastic encephalitis?
Most commonly involves limbic structures (lateral to thalamus, between cortex + brainstem) = short term memory impairment, behavioural change, altered mental state, seizure
Most commonly seen bilaterally on neuroimaging, often does not involve mesial temporal lobes
What auto-antibodies are commonly associated with paraneoplastic autoimmune encephalitis?
Intracellular neuronal antigens:
- antibodies to ANNA-1/Hu & ANNA-3 = SCLC
-antibodies to LUZP4 =Germ cell tumours
-antibodies to Ma2/Ta = testicular, lung
Extracellular neuronal antigens:
- antibodies to AMPAR = SCLC, thymoma
- antibodies to GABABR = SCLC
- antibodies to mGLUR5 = hodgkins
How are paraneoplastic autoimmune encephalopathies treated?
- cancer removal
- Immunotherapy (IV methylprednisone, IVIg, plasma exchange)
What features of paraneoplastic autoimmune encephalopathies favour good outcomes?
Early immunotherapy
Autoantibodies targeting cell-surface antigens
What is the diagnosis of the following CSF parameters?
- Opening pressure < 25 cmH20
- Cell count < 5
- Cell differential showing lymphocyte predominance, no neutrophils or RBCs
- CSF: plasma glucose > 0.5
- Protein < 0.5
Normal
What is the diagnosis of the following CSF parameters?
- Opening pressure very high
- Cell count 5 -1000
- Cell differential showing lymphocyte predominance
- CSF: plasma glucose >0.5
- Protein 0.2-5.0
Fungal infection
What is the diagnosis of the following CSF parameters?
- Opening pressure normal to high
- Cell count 5 - 1000
- Cell differential showing lymphocyte predominance
- CSF: plasma glucose > 0.5
- Protein 0.5 -1
Viral
What is the diagnosis of the following CSF parameters?
- Opening pressure high
- Cell count 100 - 50,000
- Cell differential showing neutrophil predominance
- CSF: plasma glucose low <0.4
- Protein >1.0
Bacterial
What is the diagnosis of the following CSF parameters?
- Opening pressure high
- Cell count 5 - 500
- Cell differential showing lymphocyte predominance
- CSF: plasma glucose Very low < 0.3
- Protein 1.0-5
TB
What are characteristics MRI findings of HSV and JEV encephalitis?
HSV: FLAIR hyperintensity in temporal lobes
JEV; assymetrical increased signal and oedema in thalamus/basal ganglia
What are characteristic EEG findings of HSV and anti-NMDAR encephalitis?
HSV: periodic lateralised epileptiform discharges
Anti-NMDAR: rhythmic delta activity at 1-3Hz with superimposed Beats bursts at 20-30Hz
How should acute encephalitis be managed?
Start aciclovir +/- empiric antibiotics immediately
Perform LP, noting CSF PCR can be falsely negative in first 72 hours
If infectious cause excluded then consider steroids while awaiting antibodies
What sites of disease and pathogens are commonly seen in Immunoglobulin or complement deficiencies?
Sinuopulmonary, GI, bacteraemia, meningitis
Encapsulated (S. pneumoniae, H influenzae, N meningitidis), Giardia, Cryptosporidia, Campylobacter
What sites of disease and pathogens are commonly seen in granulocyte (neutrophil) deficiencies?
Recurrent skin and soft tissue infections, respiratory, Lymphadenitis
Fungal (aspergillus, candida)
Bacterial (pseudomonas, S aureus, S typhi, Nocardia)
What sites of disease and pathogens are commonly seen in cell-mediated immunodeficiencies?
Any site
Viruses (CMV, EBV, HSV)
Fungal (PJP, cryptococcus, candida)
Mycobacteria
What sites of disease and pathogens are commonly seen in impaired mucocutaneous barrrier?
Skin, line infection, gut translocation (bacteraemia)
Enteric bacteria or skin commensals
Candida
HSV
What pathogens are common causes of infection in TNF-a inhibitor therapy? (infliximab, adalimumab, etanercept)
Hepatitis B, HSV
TB, norcardia, listeria
Candida, PJP
What pathogens are common causes of infection in anti-B-cell therapy? (rituximab)
Hepatitis B, VZV, HSV
Progressive multifocal leukoencephalopathy (PML, caused by polyomavirus JC)
What are common causes of infection in lymphocyte depleting therapy? (Alemtuzumab = anti-CD52)
HSV, VZV, PML, TB, bacterial infections
What are common causes of infection in interleukin pathway inhibitors? (Tocilizumab = anti-IL6, secukinumab = anti-IL17)
Increases bacterial infections
What are common causes of infection in JAK inhibitors? (tofacitinib, baracitinib, ruxolitinib)
Increase risk of VZV
Increase serious infections
TB
What are common causes of infection in Ibrutinib (bruton’s TKI)?
Aspergillus, PJP, Crytpococcus
Respiratory infections
What are common causes of infection in BCR-ABL inhibitors (dasatinib, imatinib)?
Hepatitis B, VZV
What are common causes of infection in Idelalisib (PI3KI)?
Serious infections increased
PJP
CMV
TB
What are common causes of infection in integrin inhibitors (Natalizumab, vedolizumab)?
PML
Respiratory infections
VZV
What are common causes of infection in complement pathway inhibitors (eculizumab)?
Neisseria
What infections could be screened for in an immunocompromised individual?
HIV, Hep C, Hep B, Syphilis, TB, CMV, HSV, VZV, EBV
What is the screening test for hepatitis B and who should be prescribed prophylaxis?
HBsAg, anti-HBcAb, anti-HBsAb + HBV DNA if HBsAg or anti-c positive
Tenofovir or entecavir should be prescribed to - those who are HbsAg+
-HSCT or those receiving rituximab with antiHBcAb+
Who should TB be screened for, what test is used and what treatments are available?
Screened for those with exposures prior to starting immunosuppresive therapy
With Quantiferon or Mantoux
If positive then then to rule out active TB
Treatment dictated by drug interactions and risk of hepatoxicity
What vaccines are contraindicated in immunocompromised patients?
Live vaccines
MMR, oral polio, varicella, zoster, yellow fever, rotavirus
What are common organisms that cause infection in neutropenic fevers?
74% Gram negative:
- E coli (most common of gram-)
- Enterobacter cloacae
- Klebsiella
- Pseudomonas
- Acinetobacter (least common of gram-)
19% gram positive:
- Strep > enterococcus > S aureus
Rarer: anaerobes, polymicrobial, fungal
What is antibiotics should be used in febrile neutropenia?
Cefepime OR piperacillin tazabactam
+ gentamicin if shocked
+ vancomycin if MRSA colonised or clinical line infection
What is the mechanism of action of amphotericin?
Binds to ergosterol to affect fungal cell membrane production
What is the mechanism of action of azole anti-fungals?
Affect ergosterol synthesis of cell wall via CYP3A4 inhibition
What infections is fluconazole effective for?
Candida, cryptococcus, including CNS penetration
What infections is voriconazole indicated for? What special considerations are required?
Covers candida and moulds
Cannot be given in ESRF
Due to CYP3A4 polymorphisms requires therapeutic drug monitoring
What infections is posaconazole indicated for?
Prophylaxis for candida and moulds
What infections is isavuconazole indicated for?
Candida, asperigillus, zygomycosis
What is the mechanism of echioncandin anti fungals (Caspofungin)?
Inhibit cell wall synthesis via inhibition of glucan synthase
What infections are echioncandin anti fungals (Caspofungin) indicated for?
Invasive candida infections as fungicidal against candida
What infections is amphotericin B indicated for?
Any fungal infection as broadest anti-fungal activity
How is an invasive aspergillus infection diagnosed?
-Suggestive radiology (chest, sinus, brain)
- identification from tissue or respiratory sample in culture or histology
- galactomannan antigen in serum or BAL
How is aspergillus treated?
- Surgical source control
- 6-12 weeks of voriconazole or isavuconazole or amphotericin
- followed by secondary prophylaxis (posaconazole)
What is zygomycosis, how is it diagnosed and treated?
Invasive fungal infection due to mucorales species typically affecting lungs or sinus/brain
Diagnosed by microscopy, culture or histology
Treated surgically + amphotericin
In what solid organ transplants is mould/yeast cover routinely given?
Lung and liver
In what solid organ transplants is toxoplasmosis cover routinely given?
Heart > Lung (co-trimoxazole)
In what solid organ transplants is HBV prophylaxis given?
In those with HBV positive donor or recipients
How should strongyloides infection be treated in solid organ transplant?
Ivermectin for Days 1+ 2 +14 to cover all laval forms
What type of virus is human monkeypox and how is it transmitted?
Orthpoxvirus = brick-like virions
Zoonotic infection, sexual activity MSM
What are clinical features of monkeypox?
Fever, rash, lymphadenopathy
Incubation period = 4-21 days
Prodrome for 5 days
How is monkeypox diagnosed and treated?
PCR testing of lesions
Serology can support diagnosis (IgM)
No anti-virals licensed
Pre and post exposure vaccines in Australia
What type of virus is Japanese encephalitis virus (JEV) and how is it transmitted?
ssRNA
Mosquitos
What are clinical features of JEV, how is it diagnosed and treated?
Most asymptomatic
Otherwise non-specific viral illness followed by altered mental state and neuro deficits
Serum or CSF IgM, rarely detect virus
MRI changes in thalamus, basal ganglia, midbrain, pons and medulla
Treatment is supportive
What vaccines are available for JEV and who are they offered to (in Australia)?
Single dose live vaccine = Imojev, or 2 dose inactivated vaccine = JEspect
People exposed to piggeries or pork abattoir
People who work with mosquitos
Lab workers who may be exposed
What bacteria are AMP-C inducers? What antibiotics should we use for these organisms and why?
HECKYes (replaces ESCAPPM)
Halfnia alvei
Enterobacter cloacae
Citrobacter freundii
Klebsiella aerogenese
Yersinia enterolitica
Cefepime and meropenem as both weak inducers and poor substrates of AMP-C
What is the shortened 4-month regimen for TB and what evidence supports this?
8 weeks rifapentine + isoniazid + pyrazinamide + moxifloxacin the 9 weeks rifapentine + isoniazid + moxifloxacin
What are the definitions of MDR-TB, pre-XDR-TB and XDR-TB?
MDR-TB = resistant to isoniazid + rifampicin
Pre-XDR-TB = MDR + fluroquinolones resistant
XDR-TB = MDR + fluroquinolones resistant + resistant to Bedaquiline or linezolid
What are key features of the 3 types of innate lymphoid cells and what disease processes are they indicated in?
None have antigen receptors - respond to cytokines
ILC 1: express Tbet, respond to viral infections and produce IFNg and TNF, may drive IBD, RA
ILC2: express GATA3,respond to parasitic infection, produce Th2 cytokines and may drive allergy/asthma
ILC3: express RORgt, respond to bacterial infection, produce IL-17 and IL-22, and may have a role in IBD, MS, psoriasis
What are components of neutrophil NETs?
-Citrullination of histone by enzyme PAD4
- Neutrophil serine protease
- myeloperoxidase and phagocyte oxidase
What are the 2 NF-kB pathways?
Canonical (classical) activated by PAMPs/DAMPs
Non-canonical (alternative) activated by TNFR superfamily
What is the difference between cytokines and chemokines?
Cytokines direct growth, maturation and activation of immune cells
Chemokines direct the movement of WBC
What are type 1 and type 2 interferons?
Type 1 = IFNa and IFNb
Type 2 - IFNg
What are the major acute innate cytokines?
IL-1, TNFa, IL-6, Il-12, CXCL8, G-CSF, GM-CSF
What is the effect of glucocorticoids on cytokines?
- Target transcription factors to reduce transcription of inflammatory cytokines
- attenuate TNFa and IL1B
- reduce circulating T-cells and inhinit IL-2
- attenuate monocyte IL-12 resulting in shift towards Th2
What diseases are TNFa targeted therapies used in and what are examples?
RA, ankylosing spondylitis, psoriasis, JIA, IBD
mAbs: infiximab, adalimumab, golimumab, centolizumab
Entancercept = recombinant TNFR fused to IgG Fc
What diseases are Il-1 targeted therapies used in and what are examples?
RA, cryoporin associated periodic syndromes
Anakinra = recombinant IL-1RA
Canakinumab = mAb against IL-1B
What diseases are IL-6 targeted therapies used in and what are examples?
RA, juvenile RA, castelman’s disease, giant cell arteritis, cytokine release syndrome, COVID-19
IL-6R mAb: tocilizumab, sarilumab
Chimeric IL-6 mAb: siltuximab
Humanised IL-6 mAb: sirukumab
What diseases are Il-17A targeted therapies used in and what are examples?
Psoriasis, psoriatic arhtropathy, ankylosing spondylitis
IL-17A mAb: secukinumab, ixetizumab
What diseases are Il-12/IL-23targeted therapies used in and what are examples?
Psoriasis, psoriatic arthropathy, IBD
p40 mAbs; ustekinumab, guselkumab
IgG1k mAb: tidrakizumab, risankizumab
What diseases are IL-2 targeted therapies used in and what are examples?
Transplant rejection, acute GVHD
IL-2Rc mAb = basiliximab
What diseases are IL-10 targeted therapies used in and what are examples?
Psoriasis
IL-10 administration
What diseases are IL-4/IL-13 targeted therapies used in and what are examples?
Atopic dermatitis, asthma, chronic rhinosinusitis
IL-4R mAb: dupilumab
What diseases are IL-5 targeted therapies used in and what are examples?
Asthma, eosinophilic granulomatosis with polyangitis, hypereosinophilic syndromes
Humanized IL-5 mAb: mepolizumab
IL-5R mAb: benralizumab
What is tofacitinib and what disease is it used in?
JAK1 + JAK2 inhibitor
Used in RA
What are the inheritance patterns of SCID?
X-linked
Autosomal recessive
What is the most common type of primary immunodeficiency?
Antibody disorders
CVID is most common
What is common variable immune deficiency?
How is it diagnosed?
Collection of genetically heterogenous cause of hypogammaglobulinaemia resulting in recurrent infections
Diagnosed by severely reduced IgG +/- low IgA and/or low IgM
Confirmed by absence of antibody response to vaccination
Need to exclude other causes for hypogammaglobulinaemia
How is CVID treated?
Immunoglobulin replacement
When should an immunodeficiency be suspected?
Severe infections
Unusual infections
Persistent infections (warts, diarrhoea, chronic candida)
Recurrent infections (sino-pulmonary, herpes, HPV)
Malignancies (rare, multiple)
Autoimmune disease (atypical presentation)
Not gaining weight
Which recurrent infections are associated with which immune compartment deficiencies?
Bacterial = antibody
Fungal/viral/HPV = T-cell
Staphylococcal/fungal = phagocytic
Encapsulated organisms (Streptococcus agalactiae, Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Escherichia coli, Salmonella species, Klebsiella, and Pseudomonas aeruginos) = complement, spleen
How to antibodies protect against infection from encapsulated organisms?
- opsonisation: IgG binding to micro-organism surface triggers phagocytosis by neutrophils and macroophages
- complement activation via Ab/Ag complex
What investigations are used to assess humoral immunity?
- Serum IgG, IgA, IgM +/- IgE levels +/- IgG subclasses
- lymphocyte count and subsets
-rule out secondary causes of low IgG- serum and urine protein + albumin (low IgG +/- IgA but preserved IgM in GIT or renal losses)
- haematologic malignancy
- assess antibody function 4 weeks post vaccination, normal >1 g/L or 4x increase
Can also test specific antibody responses, lymphocyte proliferation and bone marrow aspirates
How is chronic granulomatous disease treated?
-Co trimoxazole and itraconazole prophylaxis
- IFNg (often poorly tolerated)
- anakinara for colitis
- HSCT
How is the complement pathway assessed?
- measurement of C3/C4
- measurement of specific complement factor
- measurement of regulation proteins (C1 inhibitor, factor H, factor I)
- haemolytic/ELISA assays (functional MAC)
Which complement defects are associated with which infections/autoimmunity?
SLE = C1, C4 and C2 (failure to clear self antigen)
Recurrent sinopulmonary. = C2
Recurrent or severe infections = C3
Neisseria meningitidis, sepsis, gonococcal arthritis = C5-C9
Neisseria and bacterial = factor B, properdin and factor D
What are the 3 ways of activating the complement pathway and which factors are involved?
- Classical: Ab-Ag complexes, typically on pathogen surface, recruit C1g, C1r, C1s, C4, C2
- MB-lectin pathway: mannose binding lectin binds mannose on pathogen surface, recruits MBL, MASP-1, MASP-2, C4 and C2
- Alternate pathway: pathogen surface recruits C3, factor B and Factor D
All result in C3 convertase
What are the late events of the complement pathway?
C3 convertase leads to:
- C3a and C5a: peptide mediators of inflamation and phagocyte recruitment
- C3b
1. binds complement receptors on phagocytes resulting in opsonosation of pathogens and removal of immune complexes
2. Activates terminal complement components (C5b, C6, C7, C8, C9) resulting in MAC which lyse pathogens and cells
How are complement deficiencies managed in general?
Vaccinations for encapsulated organisms (meningococcus, haemophilus, pneumpcoccus)
What clinical features suggest an antibody or combined immune defect?
- Infection in mucosal sites (sinuses, lungs, GIT)
- Bugs: strep pneumoniae, haemophilus influenzae, giardia, enterovirus, campylobacter, salmonella, shigella
- autoimmune cytopenias
- chronic diarrhoea
What are the underlying mechanisms of CHAI and LATAIE?
CHAI = CTLA-4 haplo-insufficinecy autoimmunity and immunodeficiency = loss of function in CTLA-4
LATAIE = LRBA deficiency with autoantibodies, regulatory T (Treg) cell defects, autoimmune infiltration, and enteropathy = loss of function in LRBA (chaperone molecule which allows CTLA-4 to be moved to cell surface)
What is the treatment for CTLA-4 deficiencies?
Abatercept = huCTLA-4 linked to modified Fc of IgG
What is the inheritance pattern and clinical features of Autoimmune lyphoproliferative syndrome (ALPS)?
AD
Lymphadenopathy, splenomegaly, autoimmune haemolytic anaemia/thrombocytopenia, high risk lymphoma
Flow analysis: inceased double negative AB T-cells (up to 40%)
What is the inheritance pattern and clinical features of Immune dyregulation polyendocrinopathy enteropathy X-linked (IPEX)?
X-linked
Defect in FoxP3 resulting Treg deficiency
Severe early onset autoimmune enteropathy, T1Dm, eczema, hypothyroidism
What is the inheritance pattern and clinical features of Autoimmune polyendocrinopathy cadidiasis ectodermal dysplasia?
Defect in AIRE gene, results in inceased expression of self antigens
Autosomal recessive
Hypoparathyroidism, Addison’s disease, chronic mucocutaneous candidiasis, other autoantibodies
What are features of Wiskott-Aldrich syndrome?
X-linked defect in WASP gene
Triad of eczema, thrombocytopenia, immune dysfunction
What is the underlying genetic basis of Ataxia -telangiectasia?
Defect in ATM gene affecting DNA repair
What infectious susceptibilities are the following innate immunity defects associated with?
- TLR3 deficiency
- CARD9 deficiency
- MSMD
- GATA2
-TLR3 = herpes simplex encephalitis
- CARD9 = invasive fungal disease
- MSMD = mendelian susceptibility to mycobacterial disease (IL-12/IL-13rb1 deficiency, STAT1 deficiency, IFNGR and IFNG autoantibodies)
- GATA2 = Monocytopenia + disseminated MAC
What is the most common cause of lower limb purpura?
Leucoclastic (hypersensitivity vasculitis secondary to furosemide, antibiotics or allopurinol
Distinguished from systemic vasculitis by the presence of haematuria
A high level of ANCA directed against PR3 or MPO is associated with which vasculititides?
GPA or MPA
How quickly should someone with vasculitis respond to treatment?
Within days
How long should patients treated cyclophosphamide receive haematuria monitoring?
Lifelong
Which ANCA subset is associated with frequent relapse?
PR3-ANCA
What are causes of raised ANCA that are not vasculitis?
ILD
Bronchiectasis
Cystic fibrosis
IBD
PSC
Drug-induced Lupus
Anti-thyroid drugs (can also cause vasculitis)
What are the characteristics, causes and treatment of hypersensitivity (leucoclastic) vasculitis?
3 out of 5 of:
- Age > 16
- Temporal relationship with drug
- maculopapular rash
- skin biopsy demonstrating perivascular neutrophils
NO SYSTEMIC FEATURES
Commonly caused by :
- sulfonamides (frusemide, thiazide)
- penicillins
- cephalosporins
- allopurinol
- phenytoin
Treated by drug cessation
What are clinical features of microscopic polyangitis?
Palpable purpura + glomerualr haematuria + renal impairment +/- abnormal liver function
p-ANCA with MPO specificitty
What clinical features are suggestive of vasculitis?
- palpable purpura
- multi-organ disease with systemic features
- pulmonary-renal disease
- mononeuritis multiplex (only other cause is diabetes)
What are the 3 types of small vessel vasculitis?
Granulomatous polyangiitis (GPA)
Microscopic polyangiitis (MPA)
Eosinophilic granulomatous polyangiitis (EGPA)
When should PR3- and MPO- ANCA be tested directly?
Only if small vessel vasculitis is suspected (no role in monitoring)
What is the Chapel Hill calssification for vasculitis?
Based on vessel size - cannot classify all vasculitidies
Large vessel = GCA, takayasu
Medium vessel = polyarteritis nodosa, Kawasaki disease, isolated CNS vasculitis
Small vessel
1. ANCA-associated = no immune complexes = MPA, EGPA, GPA
2. Immune-complex:
Cryoglobulinaemic vasculitis
IgA vasculitis (henloch-schonlein)
Hypocomplementemic urticarial vasculitis (Anti-C1q)
Anti-GBM
What is Behcet’s disease and how is it treated?
Autoinflammatory disease of arteries and vein of all sizes
Associated with Turkish population
Need apthous ulcers x 3 in 12 months PLUS 2/4 of:
- occular inflammation
- genital ulcers
- pathergy reaction
- skin lesions: pustules, erythema nodosum
Rx: colchicine, steroids, consider VTE prophylaxis
What are the diagnositic features of Takayasu arteritis?
3/6 of:
- age < 40
- caludication of extremities
- decreased pulsation in one or both brachial arteries
- SBP difference >10 between arms
- bruit over 1 or both subclavian arteries or abdominal aorta
What are the diagnostic criteria of GCA?
Age at onset > 50
No systemic involvement including eyes
3 of 11:
- localised headache of new onset
- sudden onset visual change
- PMR (2 pt)
- jaw claudication
- tender or decreased pulse of temporal artery (2 pt)
- ESR > 50
- biopsy with necrotising arteritis (2 pt)
- unexplained fever, anaemia
How is GCA managed?
2 years of steroids 40-60 mg (start pre biopsy)
Low dose aspirin
What are clinical features of polyarteritis nodosa?
Affects medium sized vessels esp visceral
Common at bifurcations and microanuerysms
Can result in infarction of spleen, bowel, kidney
Associated with peripheral neuropathy and HepB
ANCA negative (in overlap syndorme with MPA ANCA is positive)
Often good response to steroids, relapse uncommon
Not associated with GN, lung haemorrhage or fever
What is PAN associated ADA2 deficiency and how is it treated?
Vascultis associated with single gene mutation in ADA2, AR inheritance
Milder phenotype of polyateritis nodosa
Treated with anti-TNF agents, HSCT
What are clinical features of kawasaki disease?
Childhood onset with fever > 5days and 4/5 of:
- bilateral conjunctival injection
- oromucosal changes
- erythema of soles, desquatmation
- polymorphous rash
- cervical lymphadenopathy
What small vessel vasculitides are ANCA positive?
EGPA (50% p-ANCA positive with MPO specificity)
GPA
MPA
Some drug-induced
Some rheumatoid vasculitis
Which vasculitides are ANCA negative?
Polyarteritis nodosa
Kawasaki disease
Isolated CNS vasculitis
Henoch schonlein purpura
Cryoglobulinaemic vasculitis
Hypersensitivity/leucoclastic vasculitis
Viral vasculitis
How is ANCA tested and what is its role?
- screen with indirect immunofluorescence
- if screen positive then tested for PR3- and MPO- ANCA
Used for diagnosing or excluding small vessel vasculitis
What is C-ANCA?
Cytoplasmic granular fluorescence with central attenuation on immunofluorescence
Directed against PR3, common in upper resp tract disease
Typical pattern common in EGPA (90%), MPA (30%)
Atypical pattern seen in autoantibodies against bactericidal permeability-increasing protein, common in pseudomonas colonised CF
What is p-ANCA?
Immunofluorescence of peri-nuclear with nuclear extension
Directed against MPO = GN, haematuria
MPA (70%), GPA (10%)
Note atypical p-ANCA is directed against other antigens and seen in IBD
What is the pathogenesis of ANCA-associated disease?
Infections induce neutrophils to express ANCA antigens on surface
PMNs activated by binding of self ANCA FAb and Fc to FcgR
PMN degranulates (recruit complement) and release NETs (thrombotic), PR3 and MPO bind and activate endothelium
ANCA also induce granuloma via monocyte acgtivation
ANCA prevent A1AT mopping up PR3
What other autoantibodies can be present in GPA and MPA?
ANA (15%)
Lupus anticoagulant (10%)
Anticardiolipin (10%)
AntiGM (5%)
How is limited GPA distinguished from generalised GPA?
Do not affect kidneys, but often progress to generalised
What A1AT genotypes are associated with developing GPA? Which genotype is the most severe
MS, MZ, SS and ZZ genotypes
All result in uninhibited PR3 which is more immunogenic
Z genotype most severe + most organs involved + more progressive, has least A1AT so more PR3
What are clinical features of GPA?
Conjunctival injection
Urinary casts
Alveolar haemorrhage
Air bronchograms
Cavitation
Segmental necrotising GN OR pauci-immune GN
How is ANCA vasculitis treated?
-induction = Corticosteroids + cyclophosphamide (oral equivalent to IV)
- Maintenance = azathioprine
Can also use methotrexate or azathioprine for induction
When is rituximab used in vasculitis?
Poorly controlled ANCA- vasculitis
What are features of primary pauci immune necrotising GN?
Common in elderly
GN only, nil systemic
P-ANCA positive
What are features of MPA/PAN overlap syndrome?
GN, p-ANCA positive
Often associated with bowel infarction or peripheral neuropathy
How are the side effects of treatment for vasculitis minimised?
Immunosupressants:
- shortest possible course
- oral cyclophosphamide in the morning
- fertility preservation (zoladex, gamete harvest, IVF)
- minimise sun exposure in azathioprine
Infections:
- co-trimoxazole 2x/week as prophylaxis
- pentamidine Q6 weekly for pneumocystis
Steroids:
- PPI cover
- bone protection
Through what mechanism can PTU cause ANCA associated vasculitis?
PTU accumulated in neutrophils and binds MPO, resulting in a change to its structure and reduced clearance
How is drug induced vasculitis treated?
Mild = withdraw agent, monitor and steroids for symptom relief
Multi-organ disease: steroids +/- immunosuppression, surveillance for underlying vasculitis
What are clinical features of EGPA?
Asthma, pulmonary opacities, eosinophilia
Affects skin, nerves, heart, bowel, kidneys
50% p-ANCA positive (MPO)
What are the definitions of hypersensitivity and allergy?
Hypersensitivity = objectively reproducible symptoms or signs, initiated by exposure to a defined stimulus at a dose tolerated by normal subjects
Allergy = hypersensitivity reaction initiated by immunologic mechanisms
What are the two broad types of Allergic hypersensitivity?
- IgE mediated
- Atopic
- Non atopic (insect venom, drugs, other) - Non IgE mediated
- T-cell
- Eosinophil
- IgG mediated
- other
What is atopy?
Immunological reaction where IgE is readily produced in response to ordinary exposure (skin, ingestion, inhalation) to common allergens of subjects environment
Not all atopy is an allergic disease state, not all IgE -mediated disease is atopy
What are the 4 main types of atopic diseases?
Asthma
Allergic rhinits
Atopic eczema
Food allergy
What are the two processes in the allergic inflammatory response?
- Sensitisation
- allergen is processed and presented on MHCII to Th cells
- results in IgE class switching and production by B-cells/plasma cells
- IgE binds tissue mast cells - Challenge
- re-exposure to allergen with IgE mediated activation of Mast cells
- release of immediate vasoactive amines and lipids
- recruitment of chronic inflammatory cells
What are the key cytokines, target cells and host defenses involved in the 4 classes of CD4+ T-cells?
Th1: IFNg, macrophages, intracellular pathogens
Th2: IL-4, IL-5, IL-13, eosinophils, parasites
Th17: IL-17, IL-22, neutrophils, extracellular pthaogens
TFh: IL-21, B-cells, extracellular pathogens
What are the physiological roles of Th2 cells?
Tissue homeostasis and repair
Barrier immunity: elimination of microbes at epithelial barriers
What are characteristics of IgE?
- 2 light + 2 heavy chains
- Fc attaches to receptor on effector cells
- Fab binds allergen
- short serum half life approx 2 days
- rapidly binds receptors on inflammatory cells (majority of IgE is bound to cells)
How does IgE activate Mast cells?
Via cross-linking of 2 or more adjacent IgE molecules on FcRI
What Mast cell mediators are released on Mast cell activation?
Preformed:
- histamine
- heparin
- tryptase
- chymase
Synthesise:
- prostaglandins
- leukotrienes
- cytokine: IL-4 + IL-13 (IgE class switching), IL-5 + GM-CSF (eosinophil recruitment), TNFa
What cytokines are involved in eosinophil development?
IL-3 for initial commitment
IL-5 and GM-CSF for maturation and priming
What mechanisms are implicated in successful allergen immunotherapy?
Generate CD4+CD25+ Tregs producing IL-10 and TGF-b, which promote IgG and IgG4 production by B-cells, where IgG inhibits IgE-Allergen binding (by competing for allergen biding)
What immune cells and factors result in allergy?
APC presents allergen to Th2 cell, produces:
- IL-4 which promotes IgE
- IL-5 which recruits eosinophils
What are the 3 stages of allergen specific immunotherapy?
- Hours to days: basophil and mast cell desensitisation
- Days to weeks: increased Tregs
- Weeks to months/years: regulation of B-cells and antibodies
How long does it take to generate long term tolerance to an allergen with immunotherapy?
3 years
What are the two major types of asthma and their key features?
T2 high:
-Mast cells, Th2, NKT, ILC2s promoting eosinophils and/or IgE
T2 low:
- neutrophils, ILC1/3, Th1, Th17 resulting in low IgE and no eosinophils
What are the two major types of adverse drug reaction?
- Type A = pharmacological (80%)
- side effects
- toxicity
- secondary indirect effects
- drug interactions - Type B = hypersensitivity (10-15%)
- immune mediated = allergic (5-10%)
- Non immune mediated = non allergic (5-10%)
What are the different mechanisms of immune mediated drug reactions and their characeteristics?
IgE mediated (<10%):
- immediate (< 1 hour)
- urticaria, angioedema, bronchospasm, anaphylaxis
T-cell mediated (most common):
- non immediate (> 1 hour)
- Maculopapular, morbilliform, SJS
Others:
- immune complex
- cytotoxic
What are key features of an allergic drug hypersensitivity?
- cannot occur on first exposure (need previous exposure for sensitisation)
- usually occur on first dose of subsequent course
- features of IgE mediated or T-cell mediated reaction
Which drugs can anaphylaxis independent of IgE?
Immunologic:
- Radio-contrast
- NSAIDs
- dextrans (iron)
- mAbs
Non immunologic:
- physical
- ethanol
- opioids
What are the different types of immune hypersensitivity, their reactants and effector cells?
Type I:
- IgE
- Mast cell
- asthma, anaphylaxis
Type II:
- IgG
- FcR+ cells (phagocytes, NK cells)
- Eg haemolytic anaemia, thrombocytopenia
Type III:
- IgG
- FcR+ cells, complement
- serum sickness
Type IVa:
- IFNg, TNFa (Th1)
- macrophages
- tuberculin reaction, contact dermatitis
Type IVb:
- IL-5, IL-4/IL-13 (Th2)
- eosinophils
- chronic asthma
Type IVc:
- Perforin/granzyme B (CTL)
- T-cells
- contact dermatitis, hepatitis
Type IVd:
- CXCL8, GM-CSF
- Neutrophils
- AGEP, behcet’s
What is the mechanism of reaction assessed for with skin testing?
IgE mediated reactions
What is the mechanism of action of immediate hypersensitivity to beta lactams?
Antibody against beta lactam ring
(note can also have antibody against side chain)
What are the 3 mechanisms of delayed hypersensitivity to drugs?
TCR binding to
- hapten = protein or peptide linked to active part of drug
- prohapten = metabolised drug is binds to proteins
- direct binding of drug to TCR (p-i concept, pharmacological interaction)
What is the underlying immune reactions in:
- amoxil bullous rash
- Maculopapular exanthem
- Acute generalised exanthematous pustulosis (AGEP)
amoxil bullous rash
- CD8+T-cells direct killing keratinocytes
Maculopapular exanthem
- CD4+ secrete IL-5 and TNFa to kill MHCII+ keratinocytes
AGEP
- CD4 and CD8 activity via GM-CSF and IL-8
How should drug allergies be managed?
- Low probability = re challenge to eliminate suspicion
- Immediate probability
- avoid drug if non essential
- if testing negative or unavailable re-challenge, if positive challenge the desensitise, if negative challenge then use
- if testing positive then desensitise - High probability
- avoid drug if non essential or severe reaction (SJS)
- if essential but non-severe reaction then desensitise
What are the different mechanisms of anaphylaxis?
- Allergic:
- IgE, FceRI mediated
- Other: blood products, immune aggregates, drugs - Idiopathic
- Non-allergic:
- physical: exercise, cold
- Other: drugs
What is the clinical definitions of anaphylaxis?
- Skin symptoms or swollen lips AND 1 of:
- difficulty breathing
- low BP (SBP <100 or 30% decrease) - Exposure to suspected allergen AND 2 of:
- skin symptoms or swollen lips
- difficulty breathing
- reduced BP
- GI symptoms - Exposure to known allergen with low BP
How is anaphylaxis managed?
0.5 mg IM adrenaline (0.5 mL 1:1000)
Oxygen
Fluid resuscitation
What is the most specific test for anaphylaxis?
Serum tryptase taken within 2 hours of event
What is the most common cause of gastroenteritis?
Norovirus
What GI pathogens are associated with the following foods:
- Beef
- Pork
- Shellfish
- unpasteurised dairy
- Beef: STEC, C. perfringens
- Pork: Yersinia
- Shellfish: Vibrio parahaemolyticus, norovirus
- unpasteurised dairy: non-typhoidal salmonella, Campylobacter, Yersinia, S. aureus endotoxin
What organisms that cause diarrhoea are associated with the following:
- reactive arthritis
- Guillain-Barre syndrome
- Haemolytic uraemic syndrome
- Aortitis
- Liver abscess
- reactive arthritis: campylobacter, salmonella, shigella, yersinia
- Guillain-Barre syndrome: campylobacter
- Haemolytic uraemic syndrome: shiga-toxin producing E coli (STEC)
- Aortitis: salmonella
- Liver abscess: entamoeba histolytica
How are giardia and entamoeba histolytica diarrhoea treated?
Metronidazole (+ paromomycin for entamoeba)
How is norovirus spread?
Faecal-oral, droplets, fomites, cotaminated environment
What is the duration of antibiotics for joint infections?
- small joints of the hand = 2/52
- large joint = 4-6/52
- prosthesis = 6/52 minimum
According to the PIANO study, what are organisms that cause early and late prosthetic joint infections?
Early = gram negative (E coli) and enterococci
Late = S. aureus, beta haemolytic strep
What process gives rise to winter influenza epidemics?
Antigenic drift of haemagglutinin (is key mediator of immunity)
What process gives rise to influenza A pandemics?
Antigenic shift = abrupt change in neuraminidase or haemagglutinin
(Flu B can’t because there is only one type of haemagglutinin and one type of neuraminidase)
What is the mechanism of action of oseltamivir?
Neuraminidase inhibitor, prevents viral particle budding
What is the most common cause of fever in returned traveller from:
- subsaharan africa
- south east asia
- latin america
- south central asia
- subsaharan africa: malaria
- south east asia: dengue
- latin america: dengue
- south central asia: enetric fever
What are common causes of fever in returned traveller with following incubation periods:
- acute (<10 days)
- intermediate (10-21 days)
- chronic (> 21 days)
- acute (<10 days): dengue, influenza, zika
- intermediate (10-21 days): malaria, viral haemorrhagic fever, typhoid
- chronic (> 21 days): malaria, hepatitis, TB
What are live vaccines available in Australia and New Zealand?
MMR
Yellow fever
BCG
Varicella/Zoster
Oral polio
Orochol berna (cholera)
IMOJEV (JE)
Oral typhoid
What is malaria?
Parasitic amoeba that infects erythrocytes:
-P. falciparum
-P. vivax
-P. malariae
-P. knowlesi
What is the lifecycle of a malaria parasite?
- female mosquite injects sporozoites when bites
- Migrate to liver and replicate
- Rupture into blood stream and infect red cells
- Replicate in red cells and rupture
- Gametocytes ingested by mosquito when feeding
- complete lifecycle in mosquito gut before migrating to salivary glands for infection
What is the role of thick and thin films in malaria diagnosis?
Thick = screening
Thin = assess density and species
How is severe malaria defined? What parasites causes this and how is it treated?
End organ dysfunction or high parasitaemia (>10%)
Caused by P. falciparum (also P. vivax and knowlesi)
IV artemisinin (artesunate) (rapid parasite clearance and low resistance rates)
Which malaria parasites have dormant stages and how should they be treated?
P. vivax and P. ovale
Primaquine for 7-14 days (need G6PD screening)
What is the most sensitive culture site for enteric fever?
Bone marrow
What is the empiric treatment for enteric fever?
Azithromycin or ceftriaxone
(consider meropenem if acquired in Pakistan)
What family do the following arboviruses belong to:
- dengue
- zika
- chikungunya
- dengue: flavivirus
- zika: flavivirus
- chikungunya: alphavirus
What mosquitos transmit:
- malaria
- dengue
- zika
- chikungunya
- malaria: Anopheles
- dengue: Aedes
- zika: Aedes
- chikungunya: Aedes
What are the 3 phases of dengue fever?
- Febrile:
headache, fever, myalgia
Most proceed to recovery - Critical:
Increased capillary permeability and fragility = effusions, thrombocytopenia and coagulopathy - Recovery:
Dengue rash
Fatigue
What is antibody dependent enhancement with regard to dengue?
When an immune response generated (non neutralising antibodies) to a new serotype following previous serotype infection results in increased viral replication and increased cytokines -> higher risk of severe dengue
When can PCR and NS1 rapid antigen testing be used to detect dengue?
First 5 days of illness
What travel illness presents with symmetrical small joint polyarthropathy?
chikungunya
When can chikungunya be detected by PCR?
first week
What travel illness causes non-purulent conjunctivitis and mild oedema of hands and feet?
Zika
What does HIV require to infect a cell?
CD4 (T-cell, monocyte, macrophage, DC, microglial) AND
CCR5 (early infection)
CXCR4 (late infection)
Where does the reservoir of HIV that presents cure persist?
Resting memory T-cells (latent infection)
Where is the body does early HIV infection occur?
Lymph systems of GIT
What is the HIV lifecycle in a cell?
HIV gp120 trimer binds CD4 resulting in conformational change where gp41 stalks docks with cell membrane which results in contact of viral and cell membrane, allowing fusion and viral contents (nucleocapsid, RNA and enzymes) to enter the cell
This is mediated by CCR5 in early stage
In cytoplasm nucleocapsid is digested by host cell enzymes. Viral RNA is turned into DNA by reverse transcriptase enzyme
RNAseH separates HIV DNA and HIV RNA
In the cell nucleus viral DNA is integrated into host cell chromosome by integrase enzyme
In host choromosome when neighbouring genes are active, HIV DNA is transcribed into HIV mRNA and translated into HIV proteins end enzymes
These are bundled up into virion which buds off the host cell. After this a protease enzyme cleaves viral proteins into active enzymes
What cells do HIV replicate in?
Active immune cells (not active or resting cells)
What is the main way that the body tries to control HIV infection?
CTL killing of infected cells via HIV antigen expression on MHC-I
Why are T-cells depleted in HIV?
- early loss of T-cells during maturation due to infection
- chronic inflammation suppresses production
What genetic factors are associated with slow HIV progression?
- HLAB57, HLAB27
- CCR5 depletion
Why doesn’t the human immune system make effective neutralising antibodies against HIV?
- diversity in gp120 epitopes/antigens (between strains)
- important gp120 epitopes are hidden (glycosylated)
- human immune system has a preference for non-binding gp120 epitopes
- HIV surface has a low concentration of gp120 and antibodies are unable to cross-link
What are broadly neutralising antibodies in HIV infection?
Large variable chains that bind to multiple gp120 sites that prevent gp120 binding cell
When do the following need to be monitored on HIV treatment?
- CD4 count
- HIV viral load
- Genotype resistance
- CD4 count: baseline, until returns to normal, re-check if viral load not controlled
- HIV viral load: baseline, after treatment started (8-12 weeks), regular monitoring
- Genotype resistance: baseline, if persistent viraemia
What is the mechanism of action of nucleoside inhibitors (NRTIs) and examples?
Bind to viral reverse transcriptase at deoxynucleotide binding site, blocking DNA synthesis.
Zidovudine (T), lamivudine (C), emtricitabone (C), abacavir (G), tenofovir(A)
Which nucleoside inhibitors have a low barrier to resistance?
Lamivudine, emtricitabine (so need to be used as combo drugs)
What are common side effects of the following nucleoside inhibitors?
Zidovudine
Abacavir
Tenofovir disoproxil fumarate
Tenofovir alafenamide
Zidovudine
- lipodystrophy
- metabolic toxicity
- GI upset
Abacavir
- hypersensitivity (needs HLA-B57*01 testing
Tenofovir disoproxil fumarate
- nephrotoxic (tubular wasting)
- reduced bone density
Tenofovir alafenamide
- less nephrotoxic
- weight gain
- dyslipidaemia
Which NRTIs also provide treatment for hepatitis B co-infection?
Tenofovir
(Not Lamivudine or emtricitabine due to resistance)
What are non-nucleoside reverse transcriptase inhibitors (NNRTIs) and some examples?
Bind to reverse transcriptase but not at deoxynucleosdie binding sites, altering enzyme conformation and block DNA synthesis
Nevirapine, efavirenz, rilpiverine, delaverdine, etravirine, doravirine
What are common side effects of the following non nucleoside inhibitors?
Nevirapine
Efavirenz
Rilpiverine
Delaverdine
Etravirine
Nevirapine
- hypersensitivity incl fatal hepatitis (stop if rash)
Efavirenz
- sedation, insomnia, vivid dreams
- rash (continue)
- LFT derangement
- dyslipidaemia
Rilpiverine
- prolong Qtc
Delaverdine
- rash (Continue)
- headache
Etravirine
- rash (Continue)
- GI side effects
What is the mechanism of action of protease inhibitors to treat HIV and examples?
Block viral protease preventing maturation of virus during and after budding of virion leading to production of defective virus.
Ritonavir, lopinavir, atazanavir, darunavir
What are common side effects of protease inhibitors used to treat HIV? side effects for:
- ritnoavir
- lopinavir
- atazanavir
- darunavir
- GI upset
- dyslipidaemia
- impaired glucose tolerance
- lipodystrophy
ritnoavir:
- poorly tolerated, used to boost other protease inhibitors
- CYP3A4 interactions
lopinavir:
- needs BD dosing
atazanavir:
- elevated bilirubin
- rarely renal stones
darunavir:
- rash (continue)
What is the mechanism of action of integrase inhibitors and examples?
Inhibit viral integrase preventing integration of viral DNA into host DNA. Particularly rapid reduction in viral load
Raltegravir, elvitegravir dolutegravir, bictegravir
What are common side effects of the following integrase inhibitors:
Raltegravir
Elvitegravir
Dolutegravir
Bictegravir
All have small risk of neural tube defects
Raltegravir
- raised CK, rhabdo
Elvitegravir
- CYP3A4 inhibitor cobicistat in formula
Dolutegravir
- headache
- depression/anxiety
- insomnia
Bictegravir
- headache
- GI upset
- avoid dofetilide (anti-arrhythmic)
What is the mechanism of action for the following HIV drugs?
Enfuviritide
Maraviroc
Enfuviritide
- prevents fusion of viral and cell membrane
Maraviroc
- prevents binding to CCR5 co-receptor
What are the preferred starting regimens for HIV?
- Integrase inhibitor + 2 NRTI
- Bictegravir/tenofovir alafenamide/emtracitabine
- Dolutegravir/abacavir/lamivudine
- Dolutegravir+ tenofovir/emtracitabine
- Raltegravir + tenofovir/emtracitabine - INSTI + 1 NRTI if no resistance and no HBV
- Protease inhibitor + 2 NRTI if planning to conceive (avoid integrase inhibitor)
What time-frame should post-exposure prophylaxis be given for HIV? What is it’s duration?
Within 72 hours of exposure
Taken for 28 days
What PEP should be used for non-occupational exposure to known HIV positive source for:
- detectable or unknown viral load
- undetectable viral load
Detectable or unknown viral load = 3 drugs
(tenofovir
AND lamivudine OR emtracitabine
AND dolutegravir OD OR raltegravir BD OR rilpirivine OD)
Undetectable viral load: no PEP
What PEP should be used for occupational exposure to known HIV positive source for:
- detectable or unknown viral load
- undetectable viral load
Detectable or unknown viral load = 3 drugs
(tenofovir
AND lamivudine OR emtracitabine
AND dolutegravir OD OR raltegravir BD OR rilpirivine OD)
Undetectable viral load = 2 drugs (tenofovir + lamivudine OR emtracitabine)
What PEP should be used for non-occupational exposure to unknown HIV status source?
2 drugs only if high risk activity or from high prevalent community
(tenofovir + lamivudine OR emtracitabine)
What is the recommended regimen for HIV PrEP?
Tenofovir + emtricitabine OD
How is pneumocystis jirovecii pneumonia diagnosed?
PCR of induced sputum (needs high pre test probability due to colonisation)
How is pneumocystis jirovecii pneumonia treated?
co-trimoxazole (10 mg/kg/day) + steroids for hypoxia
When is PJP prophylaxis indicated for HIV?
Primary: CD4 < 200
Secondary: following PJP episode until immune recovery
(co-trim 480 mg OD)
How does cryptococcal infection present in HIV?
Meningo-encephalitis due to C. neoformans (yeast)
presents with headahce and fever +/- behaviour or confusion. Meningism = late sign
What are LP/CSF features of cryptococcal CNS infections?
- raised opening pressure
- Normal CSF or raised WCC and protein, low glucose
- halo around organism with indian ink stain
- Cryptococcal antigen positive
How is cryptococcal CNS infection treated?
- LP +/- shunt to relive pressure
- amphotericin + flucytosine induction
- cosnolidation with 8 weeks fluconazole and then maintenance therapy until immune reconstitution
What is the most common CNS infection in patients with advanced HIV not on treatment or prophylaxis?
Toxoplasmosis
(can reactivate at counts < 100)
Is brain biopsy required to start treatment for toxoplasmosis?
No
When should anti-retroviral treatment be started for HIV?
within 14 days of diagnosis except where risk of immune reconstitution inflammatory syndrome:
- 6 weeks after cryptococcal meningitis
- CNS TB
What is the most common cause of infective endocarditis?
S. aureus
What is the mechanism of synergy between amoxicillin and gentamicin for E. faecalis infective endocarditis?
Increased uptake of aminoglycoside binding by bacterium when the cell wall is altered by beta lactam
What is the mechanism of synergy between amoxicillin and cefotaxime for E. faecalis infective endocarditis?
Differential saturation of E. faecalis penicillin binding proteins
What is recommended treatment of E. faecalis endocarditis?
Amoxicillin AND gentamicin OR Ceftriaxone
How frequently should blood cultures be taken in S. aureus bacteraemia?
Every 24-48 h until cleared
What is standard treatment for complicated and uncomplicated MSSA bacteraemia?
Flucloxacillin or cefazolin
Uncomplicated: 14 days
Complicated: 28 days
What are the 5 most common bacterial causes of meningitis in adults?
- Strep pneumoniae (most common)
- N meningitidis
- H influenzae
- Group B strep
- Listeria mononcytogenes (esp > 65)
What CSF features support a diagnosis of bacterial meningitis?
- opening pressure > 20
- Protein > 1
- CSF: blood glucose ration < 0.5
- WCC > 1000 (10% cases are < 100)
- Neutrophil predominant (not in Listeria)
How is bacterial meningitis managed?
- dexamethasone 10 mg IV Q6H for 4 days, stopped if pneumococcal excluded
- ceftriaxone +/- benzyl penicillin if at risk of listeria
- vancomycin if high risk for pneumococcal (gram positive diplococci)
What are suitable alternatives to ceftriaxone and benzylpenicillin for baterial meningitis?
Ceftriaxone = moxifloxacin
Benzylpenicillin = co-trimoxazole
How long do N meningitidis+ patients need to be in droplet iso for?
24 hours post antibiotic administration
What is post exposure prophylaxis for N meningitidis meningitis?
Given to household contacts and healthcare workers who have performed airway management without a mask
Rifampicin BD 4 doses
Ciprofloxacin 500 mg stat
Ceftriaxone 250 mg IM stat (pregnancy)
Why does splenectomy leave patients susceptible to encapsulated bacteria?
Encapsulated bacteria are unable to bind complement, only mechanism of clearance is by spleen
How is asplenism diagnosed on blood film?
Howell-Jolly body (nuclear remnants) = round, dark stain peripherally in red blood cells
What encapsulated organisms can cause overwhelming infection in hypo-/asplenism?
- Strep pneumoniae
- Haemophilus infleunzae type b
- N. meningitidis
What prophylaxis is given post splenectomy?
Daily amoxicillin for 3 years
Back pocket script for amoxicillin
Are live vaccines safe in asplenism?
Yes
What is the structure of a pneumococcal vaccine?
polysaccharide molecule conjugated to a protein carrier
What vaccinations should asplenic patients receive?
- Pneumococcal vaccine:
- PCV13 x1 (before PPV)
- PPV 23 x3 over 5 years
1-2 weeks pre splenectomy or 1 week post - Meningococcal vaccine
- Hib vaccine as adult x1(unless fully vaccinated as child)
- Annual influenza
What is the most common meningococcal serotype in Aus/NZ?
B
What is the mechanism of action of the following anti-fungals?
- azoles
- polyenes (amphotericin B)
- echinocandins (caspofungin)
azoles inhibit lanosterol 14-a-demethlase involved in ergosterol synthesis, impairing wall synthesis
polyenes (amphotericin B) bind to sterols in cell membrane increasing permeability
echinocandins (caspofungin) inhibit wall synthesis via inhibition of 1,3-beta-D-glucan synthesis
What is the mechanism of drug interaction with azoles?
Inhibit CYP450
What is the key limitation of echocandins (caspofungin) in the treatment of candida infections?
Minimal CNS penetration
What drugs interact with echinocandins (caspofungin)?
Cyclosporin
Tacrolimus
Rifampicin
Phenytoin
Carbamazepine
What is empiric treatment of candidaemia?
Caspofungin, stepped down to fluconaxzole if susceptible and blood cultures cleared
What is the clinical significance of Candida auris?
Often resistant to echocandins and amphotericin B
Still treat with echocandins as first line
What is the mechanism of resistance of MRSA?
mecA gene carried on mobile genetic element (staphylococcal cassette chromosome SCCmec)
mecA encodes PBP2a which is a transpeptidase with poor affinity to beta lactams
What antibiotics are effective for MRSA?
- Vancomycin (glycopeptide, cell wall)
- teicoplanin (glycopeptide, cell wall)
- daptomycin (affects cell membrane, poor CNS)
- ceftaroline (high affinity for PBP2a)
- Quinupristin-dalfopristin (50s ribosome, bacteriocidal)
- Linezolid (50s ribosome, bacteriostatic, bone marrow suppression)
- clindamycin (50s ribosome, bacteriostatic)
- co-trim (sulfa = competes with PABA, trim blocks dihydrofolate reductase, together block 2 steps in nucleic acid and protein synthesis bacteriostatic)
What is the mechanism of resistance VRSA?
Acquisition of plasmid containing vanA gene from resistant enterococci, which alters peptidoglycan terminus( D-Ala to D-Lac) to prevent binding
What antibiotics are enterococci intrinsically resistant to?
- cephalosporins
- macrolides
- glycopeptides
- tetracyclines
- fluroquinolones
(E. faecalis is sensitive to amoxicillin, but E. faecium is not)
What is the difference between VanA and VanB resistance?
VanB is susceptible to teicoplanin
What antibiotics can be used for VRE?
- linezolid
- daptomycin
- tigecycline
- quinupristin-dalfopristin
What is the mechanism of acquisition of ESBL genes?
Transferred on plasmids
What are ESCAPPM organisms?
Organisms that carry an inducible cephalosporinase on Chromosomal AmpC
Enterobacter
Serriatia
Citrobacter freundii
Acinetobacter (aeromonas)
Proteus (not mirabilis)
Providencia
Morganella morganii
What antibiotics can be used for ESCAPPM organisms?
- carbapenems (ertapenem not fo acinetobacter)
- piperacillin-tazabactam
What are mechanisms of carbapenem resistance?
Efflux pumps
Porin mutations
Carbapenemase:
- KPC
- NDM
- IMP
- VIM
- OXA-48
- OXA-181
What antibiotics can be used for carbapenem-resistant organisms?
Combo therapy:
- colistin (bacterial cell membrane)
- tigecycline (30s ribosome, bacteriostatic)
- amikacin (aminoglycoside 30s ribosome)
How is TB spread?
Droplets
What proportion of latent TB reactivate?
10%
Is there cross-reactivity of the TB IGRA to BCG and NTM?
No
How does MTB appear under microscopy with acid-fast stain?
Thin curved rod
Ziehl-Neelsen = red
Auramine = yellow/orange
What is the gold standard for TB diagnosis and susceptibility testing?
Culture (liquid = 6 weeks, solid = 8 weeks)
What is treatment for latent TB?
9 months isoniazid
OR
4 months rifampicin
How is active TB treated?
2 months: (RHEZ)
- rifampicin (R)
- isoniazid (H)
- ethambutol (E)
- pyrazinamide (Z)
Then 4 months (RH)
(new evidence showing 8 weeks rifapentine +H+Z+moxi then 9 weeks rifapentine + H+ moxi non inferior)
What are common adverse drug reaction for the following anti-TB drugs?
- Rifampicin
- isoniazid
- ethambutol
- Pyrazinamide
Rifampicin:
- drug interactions (pgp inducer, inducer CYP450)
- hepatitis
- hypersensitivity
Isoniazid:
- hepatitis
- rash
- peripheral neuropathy
Ethambutol:
- optic neuropathy
Pyrazinamide:
- hepatitis
- skin
- polyarthralgia
- gout
