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RACP 2024 > Immunology and Infection > Flashcards

Immunology and Infection Flashcards

1
Q

How is genital herpes diagnosed?

A

PCR of lesions (negative test does not exclude HSV)
Type specific serology in pregnancy

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2
Q

What are complications of genital herpes?

A

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

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3
Q

How is genital herpes managed?

A

First infection:
-Valaciclovir or aciclovir for 7-10 days
-IV if severe

Recurrent episode:
-2-3 days

Suppressive therapy 6-12 months

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4
Q

What is the organism that causes syphyllis?

A

Treponema pallidum ss pallidum
Corkscrew shaped, motile microaerophillic bacterium

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5
Q

What are the different outcomes of early syphilis and their frequency?

A

1/3 spontaneously resolve
1/3 infected without clinical disease (latent)
1/3 develop tertiary syphilis

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6
Q

How is neurosyphilis diagnosed?

A

If neuro signs with positive serology definitive diagnosis is obtained via lumbar puncture

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7
Q

How is syphilis diagnosed?

A

Screening with serology (enzyme or chemiluminescence immunoassay)
- treponemal (TPPA, TPHA)
- non-treponemal (RPR, VRDL)

Direct dark ground microscopy
Direct fluorescent antigen (DFA)
Treponemal NAAT

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8
Q

How is syphilis treated?

A

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

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9
Q

How are RPR/VRDL used to determine cure or reinfection?

A

4-fold reduction in RPR = cure
4- fold increase in RPR = reinfection

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10
Q

What diseases do different serovars of Chlamydia trachomatis cause?

A

A-C: eye disease
D-K: genitourinary disease
L: lymphogranuloma venerum

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11
Q

What is the most common diagnosed bacterial STI?

A

Chlamydia

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12
Q

How is chlamydia diagnosed?

A

NAAT from First pass urine, cervical or vulvovaginal swab, rectal or throat swab

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13
Q

How is chlamydia treated?

A

Doxycycline BD for 7 days
OR azithromycin 1 g stat

Avoid sexual contact for 7 days

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14
Q

What are microbiological features of N gonorrhoeae?

A

Gram negative diplococci

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15
Q

How is Gonorrhoea diagnosed?

A

NAAT and culture for susceptibility

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16
Q

How is gonorrhoea treated?

A

Ceftriaxone + azithromycin
No sexual contact for 7 days

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17
Q

What bacteria commonly cause cellulitis?

A

Betahaemolytic streptococci cause 70-85% of infections (S dygalactiae, S pyogenes)
S. aureus less common, more likely to cause if pustules

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18
Q

In what population should gram negative cellulitis be suspected?

A

Immunocompromised host
Cirrhosis
Chronic leg ulceration
Cellulitis of abdominal wall/groin

Marine exposure = Vibrio, Aeromonas

Dog or cat bites = Pasteurella multocida, Capnocytophagia canimorsus

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19
Q

What clinical clues suggest the presence of a necrotising soft tissue infection?

A

Toxic shock
Systemic unwellness out of proportion
Pain out of proportion
Purplish discolouration
Violaceous bullae
Crepitus
LRINEC score

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20
Q

What is the LRINEC score for necrotising soft tissue infection?

A

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

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21
Q

What organisms commonly cause necrotising soft tissue infections? How does this guide empiric therapy?

A

Often polymocrobial so need to cover gram +ve, gram -ve and anaerobes
IV clindamycin useful as anti-toxic agent (linezolid is good alternative)

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22
Q

How should necrotising soft tissue infections be managed?

A

Surgically!
Antibiotic cover

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23
Q

How do penicillins work? What treatment regime influences their efficacy?

A

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

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24
Q

What are the common organisms that cause diabetic foot infections?

A

Polymicrobial
Acute infection: S. aureus and Streptococci
Chronic: gram negatives and anaerobes

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25
Q

What are ESBLs, what antibiotics are they resistant to and what organisms express them?

A

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

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26
Q

What is the most common ESBL genotype?

A

CTX-M (now more common that TEM, SHV)

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27
Q

What is the difference between ESBL and ampC?

A

ampC is inducible chromosomal gene in ESCAPPM species
Demonstrate similar resistance profile but ampC is not inhibited by clavulanic acid

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28
Q

What antibiotics can be used in ESBL infection?

A

Sepsis: carbapenems, gentamicin or amikacin

Uncomplicated UTI: nitrofurantoin or trimethoprim if susceptible, fosfomycin, mecillinam

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29
Q

In which groups should treatment of asymptomatic bacteriuria be given?

A

Pregnant woman
Prior to invasive urological procedure where mucosal bleeding is expected

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30
Q

Is there a role for serology, such as legionella, in the assessment of community acquired pneumonia?

A

No - unlikely to have generated sufficient antibody response in acute infection to guide management

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31
Q

What is the most common causative organism of community acquired pneumonia?

A

S. pneumoniae (approx 30%)

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32
Q

What organisms need to be covered with empiric antibiotic therapy for community acquired pneumonia?

A

S pneumoniae, mycoplasma pneumoniae, S aureus, Legionella, Enterobacteriae, Haemophyllis influenzae

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33
Q

What is the CURB65 score for community acquired pneumonia and how is it interpreted?

A

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

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34
Q

What is the 30-day mortality for different CURB65 scores and how should they be managed?

A

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)

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35
Q

What MIC is considered resistant with regard to S pneumoniae and penicillins?

A

> 2 mg/L

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36
Q

What is the rational behind using doxycycline or macrolides (azithromycin) in CAP?

A

Provide cover for mycoplasma, chlamydophila
Macrolides also provide cover for legionella

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37
Q

What is the rationale for Augementin or ceftriaxone for unwell patients with CAP?

A

Also provide cover for beta-lactamase producing bacteria such as H. influenzae whilst retaining S pneumoniae cover

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38
Q

What is the resistance mechanism used by MRSA?

A

Expression of mecA gene that produces PBP2a protein

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39
Q

What are the 4 structural proteins of SARS-CoV2?

A

Membrane (M)
Spike glycoprotein (S) = target of vaccines
Envelope (E)
Nucleocapsid (N)

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40
Q

Which SARS-CoV2 proteins are targeted by diagnostic tests?

A

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

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41
Q

What cells does SARS-COV2 infect and how does in gain entry into the cell?

A

Affects upper and lower respiratory tract epithelial cells
Gains access via cell surface receptors such as ACE2

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42
Q

What are the targets of nirmatrelvir/ritonavir, molnupiravir and remdesivir?

A

Nirmatrelvir/ritonavir = viral protease
Remdesivir/molnupiravir = RdRP (RNA dependent RNA polymerase)

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43
Q

What type of virus is SARS-CoV2?

A

Coronavirus: single stranded positive sense RNA virus

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44
Q

What host immune response is recruited to SARS-CoV2 infection?

A

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)

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45
Q

What mechanisms contribute to severe COVID?

A

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

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46
Q

What is the key difference between omicron variant and wildtype and delta Variants of SARS-CoV2 virus?

A

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

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47
Q

What is the timeline of infection, transmissibility and antibody response to SARS-CoV2 infection?

A

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

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48
Q

What are mRNA vaccines and their advantages and disadvantages?

A

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

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49
Q

What are protein subunit vaccines, their advantages and disadvantages?

A

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

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50
Q

How do viral vector vaccines work, what are their advantages and disadvantages?

A

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

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51
Q

What is the influence of SARS-CoV2 vaccination on previously exposed individual? What is the outcome of a booster?

A

Generates a greater and longer lasting immune response than a COVID-naive individual

Booster generates higher titre antibiodies that last longer

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52
Q

What is the recommended vaccine schedule for SARS-COV2?

A

Primary course for everyone > 5 years
Booster 6 months after COVID infection or vaccine or 3 months after Evusheld
3rd booster if immunocompromised

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53
Q

What are contraindications to SARS-CoV2 vaccination?

A

Anaphylaxis to previous dose of vaccine or any component, myo/pericarditis following previous dose

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54
Q

How is COVID treated?

A

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

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55
Q

What is paxlovid, its dosage, adverse effects and contraindications?

A

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

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56
Q

What is remdesivir, its dosage, adverse effects and contraindications?

A

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

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57
Q

What is the mechanism of severe COVID and what therapies have been demonstrated to improve survival?

A

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

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58
Q

What are baricitinib and tocilizumab, when are they indicated in COVID infection and what are their contraindications?

A

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

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59
Q

What are characteristics of human herpes viruses?

A

dsDNA genome
Capsid
Tegument = protein layer between nucleocapsid and envelope
Glycoprotein bilayer envelope

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60
Q

What are the different subfamilies of human herpes viruses, their target cells and latency?

A

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)

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61
Q

What are characteristics of CMV infection in an immunocompetent host?

A

Typically asymptomatic
Fever, lymphadenopathy and lymphocytosis +/- thrombocytopenia and haemolytic anaemia

Rarely pneumonitis, hepatitis, meningoencephalitis and myocarditis

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62
Q

When is CMV transmission the highest in pregnancy? What are common complications

A

First trimester in primary infection

IUGR, thrombocytopenia, microcephaly, chorioretinitis and sensorineural hearing loss

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63
Q

How does CMV infection manifest in the immunocompromised host?

A

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)

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64
Q

What are risk factors for CMV infection in an immunocompromised host?

A

CMV+ donor with CMV- recipient in solid organ transplant
CMV- donor with CMV+ recipient in HSCT
Immunomodulator therapy
Hypogammaglobulinaemia

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65
Q

What are indirect effects of CMV infection?

A

Cellular mediated effects such as allograft injury or rejection, EBV-associated PTLD, opporutnistic infection

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66
Q

How is CMV diagnosed in the immunocompetent and immuncompromised host?

A

Immunocompetent = serology (IgM)

Immuncompromsied = CMV PCR or serum or histopathology of tissue

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67
Q

How is CMV infection treated?

A

1st line = IV ganciclovir or PO valganciclovir (IV if severely unwell)

2nd line = foscarnet

3rd line = cidofovir or marabivir for resistant or refractory disease

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68
Q

What is the mechanism of action and adverse effects of:
-Ganciclovir/valganciclovir
-foscarnet
-Cidofovir
-Marabivir
- Letermovir

A

-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

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69
Q

What are prophylaxitic strategies for CMV prevention?

A

Prophylaxis =
- valganciclovir for solid tumours
- letermovir in HSCT as does not induce cytopenias

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70
Q

How is EBV transmitted?

A

Mainly oral
Can be transmitted via transplant, blood products and possibly in sexual fluids

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71
Q

What is the immunological lifecycle of EBV?

A

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

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72
Q

How do EBV protein levels correlate to lytic and latent phases of infection?

A

Lytic: see BZLF1, BRLF1, DNA amplification, viral capsid

Latent: EBNA, LMP and EBER = non-coding RNA

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73
Q

How does EBV serology correlate with EBV infection?

A

IgM seen 0-10 weeks, peaking 3-6 weeks and then declining
IgG peaks at 5-7 weeks and persists

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74
Q

What is the significance of the LMP-1 gene in EBV?

A

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)

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75
Q

What is the role of anti-viral therapy for EBV?

A

No established role in treatment of infection or prophylaxis

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76
Q

What is PTLD and how is it managed?

A

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

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77
Q

What type of virus is varicella zoster, how is it transmitted and what diseases does it cause?

A

dsDNA
Airborne
Cause chickenpox and herpes zoster

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78
Q

How infectious is varicella zoster and what is the rate of infection in exposed contacts?

A

Infectious from 48hours pre rash and until 4-5 days post crusting
70-90% household contacts will become infected

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79
Q

What are the clinical features and complciations of chickenpox?

A

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

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80
Q

How is chickenpox treated in adults?

A

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

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81
Q

What is the natural history of varicella zoster infection?

A

Control of initial chickenpox
Then latent in dorsal root ganglia
Can reactivate in age as herpese zoster causing rash or neuralgia

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82
Q

What are the key features of herpes zoster and how is it treated?

A

Painful, unilateral, dermatomal vesicular rash
Treated with valaciclovir or aciclovir
Vaccination as prevention regardless of previous chickenpox or zoster history

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83
Q

What type of virus is measles, its infectivity and the vaccine coverage needed to stop transmission?

A

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

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84
Q

What are the clinical features of measles?

A

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

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85
Q

What are complications of measles?

A

30% affected experience complications and 30% die in developing countries

Pulmonary:
- croup, pneumonia, sinusitis
- bronchiectasis

Neurologic:
-encephalitis
-subacute sclerosisng pan-encephalitis

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86
Q

How is measles treated?

A

No specific treatment
Vitamin A in severe measles
Supportive care and treatment of secondary bacterial infection

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87
Q

What conditions may be seen with encephalitis?

A

Meningitis
Myelitis
Radiculitis
Neuritis

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88
Q

What is the diagnostic criteria for encephalitis?

A

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

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89
Q

What are different causes of encephalitis?

A

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

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90
Q

What are common causes of infectious encephalitis in >60 years old?

A

Listeria monocytogenes
HSV
VZV

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91
Q

What are common causes of infectious encephalitis in immunocompromised?

A

HHV6
CMV
EBV
Mealses
VZV
LCMV
Toxoplasma
Cryptococcus
JCV
BKV
Bartonella

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92
Q

What are common causes of infectious encephalitis in different travel locations?

A

-Asia/Pacific: JEV, dengue, malaria, TB
-North America: West nile virus, lacrosse virus, neuroborreliosis, coccidiomycosis
-Africa: malaria, trypanosomiasis, TB

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93
Q

What are common causes of infectious encephalitis associated with animal exposure?

A

-Mosquito: aborovirus, kunjin, JEV, dengue
-Ticks: Rickettsiae
-Bats: rabies
-Monkeys and dogs: rabies

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94
Q

What are common causes of infectious encephalitis associated with rash/unvaccinated?

A

Measles
Mumps
VZV

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95
Q

What are clinical features of HSV encephalitis?

A

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

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96
Q

What is the characteristic MRI finding of HSV encephalitis?

A

asymmetrical abnomrlaities in mesotemporal, orbitofrontal lobes and insular cortex with associated oedema
May also show restricted diffusion or haemorrhage

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97
Q

How is HSV encephalitis treated?

A

IV aciclovir for total 14 days

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98
Q

What are clinical feature of JEV encephalitis?

A

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

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99
Q

How is JEV encephalitis diagnosed and treated?

A

Diagnosed by presence of JEV IgM in serum or CSF

No specific antiviral, managed with supportive care

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100
Q

What is acute disseminated encephalomyelitis (ADEM)?

A

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

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101
Q

What is Acute haemorrhagic leuco-encephalopathy (AHLE)?

A

Considered to be severe form of ADEM
More common in adults
50% have preceding infection (most commonly viruses

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102
Q

What is Anti-NMDAR encephalitis and its clinical features?

A

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

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103
Q

How is NMDAR encephalitis diagnosed and treated?

A

CSF positive for anti-NMDAR antibodies

Treated with steroids, IVIg, plasma exchange, treatment of underlying tumour

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104
Q

What are clinical features of anti-LGI1 encephalitis?

A

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

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105
Q

How is anti-LGI1 encephalitis diagnosed and treated?

A

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)

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106
Q

What are clinical features of paraneoplastic encephalitis?

A

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

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107
Q

What auto-antibodies are commonly associated with paraneoplastic autoimmune encephalitis?

A

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

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108
Q

How are paraneoplastic autoimmune encephalopathies treated?

A
  • cancer removal
  • Immunotherapy (IV methylprednisone, IVIg, plasma exchange)
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109
Q

What features of paraneoplastic autoimmune encephalopathies favour good outcomes?

A

Early immunotherapy
Autoantibodies targeting cell-surface antigens

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110
Q

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

A

Normal

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111
Q

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

A

Fungal infection

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112
Q

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

A

Viral

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113
Q

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

A

Bacterial

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114
Q

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

A

TB

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115
Q

What are characteristics MRI findings of HSV and JEV encephalitis?

A

HSV: FLAIR hyperintensity in temporal lobes
JEV; assymetrical increased signal and oedema in thalamus/basal ganglia

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116
Q

What are characteristic EEG findings of HSV and anti-NMDAR encephalitis?

A

HSV: periodic lateralised epileptiform discharges

Anti-NMDAR: rhythmic delta activity at 1-3Hz with superimposed Beats bursts at 20-30Hz

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117
Q

How should acute encephalitis be managed?

A

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

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118
Q

What sites of disease and pathogens are commonly seen in Immunoglobulin or complement deficiencies?

A

Sinuopulmonary, GI, bacteraemia, meningitis

Encapsulated (S. pneumoniae, H influenzae, N meningitidis), Giardia, Cryptosporidia, Campylobacter

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119
Q

What sites of disease and pathogens are commonly seen in granulocyte (neutrophil) deficiencies?

A

Recurrent skin and soft tissue infections, respiratory, Lymphadenitis

Fungal (aspergillus, candida)
Bacterial (pseudomonas, S aureus, S typhi, Nocardia)

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120
Q

What sites of disease and pathogens are commonly seen in cell-mediated immunodeficiencies?

A

Any site

Viruses (CMV, EBV, HSV)
Fungal (PJP, cryptococcus, candida)
Mycobacteria

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121
Q

What sites of disease and pathogens are commonly seen in impaired mucocutaneous barrrier?

A

Skin, line infection, gut translocation (bacteraemia)

Enteric bacteria or skin commensals
Candida
HSV

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122
Q

What pathogens are common causes of infection in TNF-a inhibitor therapy? (infliximab, adalimumab, etanercept)

A

Hepatitis B, HSV
TB, norcardia, listeria
Candida, PJP

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123
Q

What pathogens are common causes of infection in anti-B-cell therapy? (rituximab)

A

Hepatitis B, VZV, HSV
Progressive multifocal leukoencephalopathy (PML, caused by polyomavirus JC)

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124
Q

What are common causes of infection in lymphocyte depleting therapy? (Alemtuzumab = anti-CD52)

A

HSV, VZV, PML, TB, bacterial infections

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125
Q

What are common causes of infection in interleukin pathway inhibitors? (Tocilizumab = anti-IL6, secukinumab = anti-IL17)

A

Increases bacterial infections

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126
Q

What are common causes of infection in JAK inhibitors? (tofacitinib, baracitinib, ruxolitinib)

A

Increase risk of VZV
Increase serious infections
TB

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127
Q

What are common causes of infection in Ibrutinib (bruton’s TKI)?

A

Aspergillus, PJP, Crytpococcus
Respiratory infections

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128
Q

What are common causes of infection in BCR-ABL inhibitors (dasatinib, imatinib)?

A

Hepatitis B, VZV

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128
Q

What are common causes of infection in Idelalisib (PI3KI)?

A

Serious infections increased
PJP
CMV
TB

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129
Q

What are common causes of infection in integrin inhibitors (Natalizumab, vedolizumab)?

A

PML
Respiratory infections
VZV

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130
Q

What are common causes of infection in complement pathway inhibitors (eculizumab)?

A

Neisseria

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131
Q

What infections could be screened for in an immunocompromised individual?

A

HIV, Hep C, Hep B, Syphilis, TB, CMV, HSV, VZV, EBV

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132
Q

What is the screening test for hepatitis B and who should be prescribed prophylaxis?

A

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+

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133
Q

Who should TB be screened for, what test is used and what treatments are available?

A

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

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134
Q

What vaccines are contraindicated in immunocompromised patients?

A

Live vaccines
MMR, oral polio, varicella, zoster, yellow fever, rotavirus

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135
Q

What are common organisms that cause infection in neutropenic fevers?

A

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

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136
Q

What is antibiotics should be used in febrile neutropenia?

A

Cefepime OR piperacillin tazabactam
+ gentamicin if shocked
+ vancomycin if MRSA colonised or clinical line infection

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137
Q

What is the mechanism of action of amphotericin?

A

Binds to ergosterol to affect fungal cell membrane production

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138
Q

What is the mechanism of action of azole anti-fungals?

A

Affect ergosterol synthesis of cell wall via CYP3A4 inhibition

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139
Q

What infections is fluconazole effective for?

A

Candida, cryptococcus, including CNS penetration

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140
Q

What infections is voriconazole indicated for? What special considerations are required?

A

Covers candida and moulds

Cannot be given in ESRF
Due to CYP3A4 polymorphisms requires therapeutic drug monitoring

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141
Q

What infections is posaconazole indicated for?

A

Prophylaxis for candida and moulds

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142
Q

What infections is isavuconazole indicated for?

A

Candida, asperigillus, zygomycosis

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143
Q

What is the mechanism of echioncandin anti fungals (Caspofungin)?

A

Inhibit cell wall synthesis via inhibition of glucan synthase

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144
Q

What infections are echioncandin anti fungals (Caspofungin) indicated for?

A

Invasive candida infections as fungicidal against candida

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145
Q

What infections is amphotericin B indicated for?

A

Any fungal infection as broadest anti-fungal activity

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146
Q

How is an invasive aspergillus infection diagnosed?

A

-Suggestive radiology (chest, sinus, brain)
- identification from tissue or respiratory sample in culture or histology
- galactomannan antigen in serum or BAL

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147
Q

How is aspergillus treated?

A
  • Surgical source control
  • 6-12 weeks of voriconazole or isavuconazole or amphotericin
  • followed by secondary prophylaxis (posaconazole)
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148
Q

What is zygomycosis, how is it diagnosed and treated?

A

Invasive fungal infection due to mucorales species typically affecting lungs or sinus/brain

Diagnosed by microscopy, culture or histology

Treated surgically + amphotericin

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149
Q

In what solid organ transplants is mould/yeast cover routinely given?

A

Lung and liver

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150
Q

In what solid organ transplants is toxoplasmosis cover routinely given?

A

Heart > Lung (co-trimoxazole)

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151
Q

In what solid organ transplants is HBV prophylaxis given?

A

In those with HBV positive donor or recipients

152
Q

How should strongyloides infection be treated in solid organ transplant?

A

Ivermectin for Days 1+ 2 +14 to cover all laval forms

153
Q

What type of virus is human monkeypox and how is it transmitted?

A

Orthpoxvirus = brick-like virions
Zoonotic infection, sexual activity MSM

154
Q

What are clinical features of monkeypox?

A

Fever, rash, lymphadenopathy
Incubation period = 4-21 days
Prodrome for 5 days

155
Q

How is monkeypox diagnosed and treated?

A

PCR testing of lesions
Serology can support diagnosis (IgM)
No anti-virals licensed
Pre and post exposure vaccines in Australia

156
Q

What type of virus is Japanese encephalitis virus (JEV) and how is it transmitted?

A

ssRNA
Mosquitos

157
Q

What are clinical features of JEV, how is it diagnosed and treated?

A

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

158
Q

What vaccines are available for JEV and who are they offered to (in Australia)?

A

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

159
Q

What bacteria are AMP-C inducers? What antibiotics should we use for these organisms and why?

A

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

160
Q

What is the shortened 4-month regimen for TB and what evidence supports this?

A

8 weeks rifapentine + isoniazid + pyrazinamide + moxifloxacin the 9 weeks rifapentine + isoniazid + moxifloxacin

161
Q

What are the definitions of MDR-TB, pre-XDR-TB and XDR-TB?

A

MDR-TB = resistant to isoniazid + rifampicin

Pre-XDR-TB = MDR + fluroquinolones resistant

XDR-TB = MDR + fluroquinolones resistant + resistant to Bedaquiline or linezolid

162
Q

What are key features of the 3 types of innate lymphoid cells and what disease processes are they indicated in?

A

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

163
Q

What are components of neutrophil NETs?

A

-Citrullination of histone by enzyme PAD4
- Neutrophil serine protease
- myeloperoxidase and phagocyte oxidase

164
Q

What are the 2 NF-kB pathways?

A

Canonical (classical) activated by PAMPs/DAMPs

Non-canonical (alternative) activated by TNFR superfamily

165
Q

What is the difference between cytokines and chemokines?

A

Cytokines direct growth, maturation and activation of immune cells

Chemokines direct the movement of WBC

166
Q

What are type 1 and type 2 interferons?

A

Type 1 = IFNa and IFNb

Type 2 - IFNg

167
Q

What are the major acute innate cytokines?

A

IL-1, TNFa, IL-6, Il-12, CXCL8, G-CSF, GM-CSF

168
Q

What is the effect of glucocorticoids on cytokines?

A
  • 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
169
Q

What diseases are TNFa targeted therapies used in and what are examples?

A

RA, ankylosing spondylitis, psoriasis, JIA, IBD

mAbs: infiximab, adalimumab, golimumab, centolizumab

Entancercept = recombinant TNFR fused to IgG Fc

170
Q

What diseases are Il-1 targeted therapies used in and what are examples?

A

RA, cryoporin associated periodic syndromes

Anakinra = recombinant IL-1RA

Canakinumab = mAb against IL-1B

171
Q

What diseases are IL-6 targeted therapies used in and what are examples?

A

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

172
Q

What diseases are Il-17A targeted therapies used in and what are examples?

A

Psoriasis, psoriatic arhtropathy, ankylosing spondylitis

IL-17A mAb: secukinumab, ixetizumab

173
Q

What diseases are Il-12/IL-23targeted therapies used in and what are examples?

A

Psoriasis, psoriatic arthropathy, IBD

p40 mAbs; ustekinumab, guselkumab

IgG1k mAb: tidrakizumab, risankizumab

174
Q

What diseases are IL-2 targeted therapies used in and what are examples?

A

Transplant rejection, acute GVHD

IL-2Rc mAb = basiliximab

175
Q

What diseases are IL-10 targeted therapies used in and what are examples?

A

Psoriasis

IL-10 administration

176
Q

What diseases are IL-4/IL-13 targeted therapies used in and what are examples?

A

Atopic dermatitis, asthma, chronic rhinosinusitis

IL-4R mAb: dupilumab

177
Q

What diseases are IL-5 targeted therapies used in and what are examples?

A

Asthma, eosinophilic granulomatosis with polyangitis, hypereosinophilic syndromes

Humanized IL-5 mAb: mepolizumab

IL-5R mAb: benralizumab

178
Q

What is tofacitinib and what disease is it used in?

A

JAK1 + JAK2 inhibitor
Used in RA

179
Q

What are the inheritance patterns of SCID?

A

X-linked
Autosomal recessive

180
Q

What is the most common type of primary immunodeficiency?

A

Antibody disorders
CVID is most common

181
Q

What is common variable immune deficiency?
How is it diagnosed?

A

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

182
Q

How is CVID treated?

A

Immunoglobulin replacement

183
Q

When should an immunodeficiency be suspected?

A

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

184
Q

Which recurrent infections are associated with which immune compartment deficiencies?

A

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

185
Q

How to antibodies protect against infection from encapsulated organisms?

A
  • opsonisation: IgG binding to micro-organism surface triggers phagocytosis by neutrophils and macroophages
  • complement activation via Ab/Ag complex
186
Q

What investigations are used to assess humoral immunity?

A
  • 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

187
Q

How is chronic granulomatous disease treated?

A

-Co trimoxazole and itraconazole prophylaxis
- IFNg (often poorly tolerated)
- anakinara for colitis
- HSCT

188
Q

How is the complement pathway assessed?

A
  • measurement of C3/C4
  • measurement of specific complement factor
  • measurement of regulation proteins (C1 inhibitor, factor H, factor I)
  • haemolytic/ELISA assays (functional MAC)
189
Q

Which complement defects are associated with which infections/autoimmunity?

A

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

190
Q

What are the 3 ways of activating the complement pathway and which factors are involved?

A
  1. Classical: Ab-Ag complexes, typically on pathogen surface, recruit C1g, C1r, C1s, C4, C2
  2. MB-lectin pathway: mannose binding lectin binds mannose on pathogen surface, recruits MBL, MASP-1, MASP-2, C4 and C2
  3. Alternate pathway: pathogen surface recruits C3, factor B and Factor D

All result in C3 convertase

191
Q

What are the late events of the complement pathway?

A

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

192
Q

How are complement deficiencies managed in general?

A

Vaccinations for encapsulated organisms (meningococcus, haemophilus, pneumpcoccus)

193
Q

What clinical features suggest an antibody or combined immune defect?

A
  • Infection in mucosal sites (sinuses, lungs, GIT)
  • Bugs: strep pneumoniae, haemophilus influenzae, giardia, enterovirus, campylobacter, salmonella, shigella
  • autoimmune cytopenias
  • chronic diarrhoea
194
Q

What are the underlying mechanisms of CHAI and LATAIE?

A

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)

195
Q

What is the treatment for CTLA-4 deficiencies?

A

Abatercept = huCTLA-4 linked to modified Fc of IgG

196
Q

What is the inheritance pattern and clinical features of Autoimmune lyphoproliferative syndrome (ALPS)?

A

AD

Lymphadenopathy, splenomegaly, autoimmune haemolytic anaemia/thrombocytopenia, high risk lymphoma

Flow analysis: inceased double negative AB T-cells (up to 40%)

197
Q

What is the inheritance pattern and clinical features of Immune dyregulation polyendocrinopathy enteropathy X-linked (IPEX)?

A

X-linked

Defect in FoxP3 resulting Treg deficiency

Severe early onset autoimmune enteropathy, T1Dm, eczema, hypothyroidism

198
Q

What is the inheritance pattern and clinical features of Autoimmune polyendocrinopathy cadidiasis ectodermal dysplasia?

A

Defect in AIRE gene, results in inceased expression of self antigens

Autosomal recessive

Hypoparathyroidism, Addison’s disease, chronic mucocutaneous candidiasis, other autoantibodies

199
Q

What are features of Wiskott-Aldrich syndrome?

A

X-linked defect in WASP gene

Triad of eczema, thrombocytopenia, immune dysfunction

200
Q

What is the underlying genetic basis of Ataxia -telangiectasia?

A

Defect in ATM gene affecting DNA repair

201
Q

What infectious susceptibilities are the following innate immunity defects associated with?
- TLR3 deficiency
- CARD9 deficiency
- MSMD
- GATA2

A

-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

202
Q

What is the most common cause of lower limb purpura?

A

Leucoclastic (hypersensitivity vasculitis secondary to furosemide, antibiotics or allopurinol

Distinguished from systemic vasculitis by the presence of haematuria

203
Q

A high level of ANCA directed against PR3 or MPO is associated with which vasculititides?

A

GPA or MPA

204
Q

How quickly should someone with vasculitis respond to treatment?

A

Within days

205
Q

How long should patients treated cyclophosphamide receive haematuria monitoring?

A

Lifelong

206
Q

Which ANCA subset is associated with frequent relapse?

A

PR3-ANCA

207
Q

What are causes of raised ANCA that are not vasculitis?

A

ILD
Bronchiectasis
Cystic fibrosis
IBD
PSC
Drug-induced Lupus
Anti-thyroid drugs (can also cause vasculitis)

208
Q

What are the characteristics, causes and treatment of hypersensitivity (leucoclastic) vasculitis?

A

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

209
Q

What are clinical features of microscopic polyangitis?

A

Palpable purpura + glomerualr haematuria + renal impairment +/- abnormal liver function

p-ANCA with MPO specificitty

210
Q

What clinical features are suggestive of vasculitis?

A
  • palpable purpura
  • multi-organ disease with systemic features
  • pulmonary-renal disease
  • mononeuritis multiplex (only other cause is diabetes)
211
Q

What are the 3 types of small vessel vasculitis?

A

Granulomatous polyangiitis (GPA)
Microscopic polyangiitis (MPA)
Eosinophilic granulomatous polyangiitis (EGPA)

212
Q

When should PR3- and MPO- ANCA be tested directly?

A

Only if small vessel vasculitis is suspected (no role in monitoring)

213
Q

What is the Chapel Hill calssification for vasculitis?

A

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

214
Q

What is Behcet’s disease and how is it treated?

A

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

215
Q

What are the diagnositic features of Takayasu arteritis?

A

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

216
Q

What are the diagnostic criteria of GCA?

A

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

217
Q

How is GCA managed?

A

2 years of steroids 40-60 mg (start pre biopsy)
Low dose aspirin

218
Q

What are clinical features of polyarteritis nodosa?

A

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

219
Q

What is PAN associated ADA2 deficiency and how is it treated?

A

Vascultis associated with single gene mutation in ADA2, AR inheritance

Milder phenotype of polyateritis nodosa

Treated with anti-TNF agents, HSCT

220
Q

What are clinical features of kawasaki disease?

A

Childhood onset with fever > 5days and 4/5 of:
- bilateral conjunctival injection
- oromucosal changes
- erythema of soles, desquatmation
- polymorphous rash
- cervical lymphadenopathy

221
Q

What small vessel vasculitides are ANCA positive?

A

EGPA (50% p-ANCA positive with MPO specificity)
GPA
MPA
Some drug-induced
Some rheumatoid vasculitis

222
Q

Which vasculitides are ANCA negative?

A

Polyarteritis nodosa
Kawasaki disease
Isolated CNS vasculitis
Henoch schonlein purpura
Cryoglobulinaemic vasculitis
Hypersensitivity/leucoclastic vasculitis
Viral vasculitis

223
Q

How is ANCA tested and what is its role?

A
  • screen with indirect immunofluorescence
  • if screen positive then tested for PR3- and MPO- ANCA

Used for diagnosing or excluding small vessel vasculitis

224
Q

What is C-ANCA?

A

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

225
Q

What is p-ANCA?

A

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

226
Q

What is the pathogenesis of ANCA-associated disease?

A

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

227
Q

What other autoantibodies can be present in GPA and MPA?

A

ANA (15%)
Lupus anticoagulant (10%)
Anticardiolipin (10%)
AntiGM (5%)

228
Q

How is limited GPA distinguished from generalised GPA?

A

Do not affect kidneys, but often progress to generalised

229
Q

What A1AT genotypes are associated with developing GPA? Which genotype is the most severe

A

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

230
Q

What are clinical features of GPA?

A

Conjunctival injection
Urinary casts
Alveolar haemorrhage
Air bronchograms
Cavitation
Segmental necrotising GN OR pauci-immune GN

231
Q

How is ANCA vasculitis treated?

A

-induction = Corticosteroids + cyclophosphamide (oral equivalent to IV)
- Maintenance = azathioprine

Can also use methotrexate or azathioprine for induction

232
Q

When is rituximab used in vasculitis?

A

Poorly controlled ANCA- vasculitis

233
Q

What are features of primary pauci immune necrotising GN?

A

Common in elderly
GN only, nil systemic
P-ANCA positive

234
Q

What are features of MPA/PAN overlap syndrome?

A

GN, p-ANCA positive
Often associated with bowel infarction or peripheral neuropathy

235
Q

How are the side effects of treatment for vasculitis minimised?

A

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

236
Q

Through what mechanism can PTU cause ANCA associated vasculitis?

A

PTU accumulated in neutrophils and binds MPO, resulting in a change to its structure and reduced clearance

237
Q

How is drug induced vasculitis treated?

A

Mild = withdraw agent, monitor and steroids for symptom relief

Multi-organ disease: steroids +/- immunosuppression, surveillance for underlying vasculitis

238
Q

What are clinical features of EGPA?

A

Asthma, pulmonary opacities, eosinophilia

Affects skin, nerves, heart, bowel, kidneys

50% p-ANCA positive (MPO)

239
Q

What are the definitions of hypersensitivity and allergy?

A

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

240
Q

What are the two broad types of Allergic hypersensitivity?

A
  1. IgE mediated
    - Atopic
    - Non atopic (insect venom, drugs, other)
  2. Non IgE mediated
    - T-cell
    - Eosinophil
    - IgG mediated
    - other
241
Q

What is atopy?

A

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

242
Q

What are the 4 main types of atopic diseases?

A

Asthma
Allergic rhinits
Atopic eczema
Food allergy

243
Q

What are the two processes in the allergic inflammatory response?

A
  1. 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
  2. Challenge
    - re-exposure to allergen with IgE mediated activation of Mast cells
    - release of immediate vasoactive amines and lipids
    - recruitment of chronic inflammatory cells
244
Q

What are the key cytokines, target cells and host defenses involved in the 4 classes of CD4+ T-cells?

A

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

245
Q

What are the physiological roles of Th2 cells?

A

Tissue homeostasis and repair

Barrier immunity: elimination of microbes at epithelial barriers

246
Q

What are characteristics of IgE?

A
  • 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)
247
Q

How does IgE activate Mast cells?

A

Via cross-linking of 2 or more adjacent IgE molecules on FcRI

248
Q

What Mast cell mediators are released on Mast cell activation?

A

Preformed:
- histamine
- heparin
- tryptase
- chymase

Synthesise:
- prostaglandins
- leukotrienes
- cytokine: IL-4 + IL-13 (IgE class switching), IL-5 + GM-CSF (eosinophil recruitment), TNFa

249
Q

What cytokines are involved in eosinophil development?

A

IL-3 for initial commitment
IL-5 and GM-CSF for maturation and priming

250
Q

What mechanisms are implicated in successful allergen immunotherapy?

A

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)

251
Q

What immune cells and factors result in allergy?

A

APC presents allergen to Th2 cell, produces:
- IL-4 which promotes IgE
- IL-5 which recruits eosinophils

252
Q

What are the 3 stages of allergen specific immunotherapy?

A
  1. Hours to days: basophil and mast cell desensitisation
  2. Days to weeks: increased Tregs
  3. Weeks to months/years: regulation of B-cells and antibodies
253
Q

How long does it take to generate long term tolerance to an allergen with immunotherapy?

A

3 years

254
Q

What are the two major types of asthma and their key features?

A

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

255
Q

What are the two major types of adverse drug reaction?

A
  1. Type A = pharmacological (80%)
    - side effects
    - toxicity
    - secondary indirect effects
    - drug interactions
  2. Type B = hypersensitivity (10-15%)
    - immune mediated = allergic (5-10%)
    - Non immune mediated = non allergic (5-10%)
256
Q

What are the different mechanisms of immune mediated drug reactions and their characeteristics?

A

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

257
Q

What are key features of an allergic drug hypersensitivity?

A
  • 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
258
Q

Which drugs can anaphylaxis independent of IgE?

A

Immunologic:
- Radio-contrast
- NSAIDs
- dextrans (iron)
- mAbs

Non immunologic:
- physical
- ethanol
- opioids

259
Q

What are the different types of immune hypersensitivity, their reactants and effector cells?

A

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

260
Q

What is the mechanism of reaction assessed for with skin testing?

A

IgE mediated reactions

261
Q

What is the mechanism of action of immediate hypersensitivity to beta lactams?

A

Antibody against beta lactam ring
(note can also have antibody against side chain)

262
Q

What are the 3 mechanisms of delayed hypersensitivity to drugs?

A

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)

263
Q

What is the underlying immune reactions in:
- amoxil bullous rash
- Maculopapular exanthem
- Acute generalised exanthematous pustulosis (AGEP)

A

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

264
Q

How should drug allergies be managed?

A
  1. Low probability = re challenge to eliminate suspicion
  2. 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
  3. High probability
    - avoid drug if non essential or severe reaction (SJS)
    - if essential but non-severe reaction then desensitise
265
Q

What are the different mechanisms of anaphylaxis?

A
  1. Allergic:
    - IgE, FceRI mediated
    - Other: blood products, immune aggregates, drugs
  2. Idiopathic
  3. Non-allergic:
    - physical: exercise, cold
    - Other: drugs
266
Q

What is the clinical definitions of anaphylaxis?

A
  1. Skin symptoms or swollen lips AND 1 of:
    - difficulty breathing
    - low BP (SBP <100 or 30% decrease)
  2. Exposure to suspected allergen AND 2 of:
    - skin symptoms or swollen lips
    - difficulty breathing
    - reduced BP
    - GI symptoms
  3. Exposure to known allergen with low BP
267
Q

How is anaphylaxis managed?

A

0.5 mg IM adrenaline (0.5 mL 1:1000)
Oxygen
Fluid resuscitation

268
Q

What is the most specific test for anaphylaxis?

A

Serum tryptase taken within 2 hours of event

269
Q

What is the most common cause of gastroenteritis?

A

Norovirus

270
Q

What GI pathogens are associated with the following foods:
- Beef
- Pork
- Shellfish
- unpasteurised dairy

A
  • Beef: STEC, C. perfringens
  • Pork: Yersinia
  • Shellfish: Vibrio parahaemolyticus, norovirus
  • unpasteurised dairy: non-typhoidal salmonella, Campylobacter, Yersinia, S. aureus endotoxin
271
Q

What organisms that cause diarrhoea are associated with the following:
- reactive arthritis
- Guillain-Barre syndrome
- Haemolytic uraemic syndrome
- Aortitis
- Liver abscess

A
  • 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
272
Q

How are giardia and entamoeba histolytica diarrhoea treated?

A

Metronidazole (+ paromomycin for entamoeba)

273
Q

How is norovirus spread?

A

Faecal-oral, droplets, fomites, cotaminated environment

274
Q

What is the duration of antibiotics for joint infections?

A
  • small joints of the hand = 2/52
  • large joint = 4-6/52
  • prosthesis = 6/52 minimum
275
Q

According to the PIANO study, what are organisms that cause early and late prosthetic joint infections?

A

Early = gram negative (E coli) and enterococci
Late = S. aureus, beta haemolytic strep

276
Q

What process gives rise to winter influenza epidemics?

A

Antigenic drift of haemagglutinin (is key mediator of immunity)

277
Q

What process gives rise to influenza A pandemics?

A

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)

278
Q

What is the mechanism of action of oseltamivir?

A

Neuraminidase inhibitor, prevents viral particle budding

279
Q

What is the most common cause of fever in returned traveller from:
- subsaharan africa
- south east asia
- latin america
- south central asia

A
  • subsaharan africa: malaria
  • south east asia: dengue
  • latin america: dengue
  • south central asia: enetric fever
280
Q

What are common causes of fever in returned traveller with following incubation periods:
- acute (<10 days)
- intermediate (10-21 days)
- chronic (> 21 days)

A
  • acute (<10 days): dengue, influenza, zika
  • intermediate (10-21 days): malaria, viral haemorrhagic fever, typhoid
  • chronic (> 21 days): malaria, hepatitis, TB
281
Q

What are live vaccines available in Australia and New Zealand?

A

MMR
Yellow fever
BCG
Varicella/Zoster
Oral polio
Orochol berna (cholera)
IMOJEV (JE)
Oral typhoid

282
Q

What is malaria?

A

Parasitic amoeba that infects erythrocytes:
-P. falciparum
-P. vivax
-P. malariae
-P. knowlesi

283
Q

What is the lifecycle of a malaria parasite?

A
  1. female mosquite injects sporozoites when bites
  2. Migrate to liver and replicate
  3. Rupture into blood stream and infect red cells
  4. Replicate in red cells and rupture
  5. Gametocytes ingested by mosquito when feeding
  6. complete lifecycle in mosquito gut before migrating to salivary glands for infection
284
Q

What is the role of thick and thin films in malaria diagnosis?

A

Thick = screening
Thin = assess density and species

285
Q

How is severe malaria defined? What parasites causes this and how is it treated?

A

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)

286
Q

Which malaria parasites have dormant stages and how should they be treated?

A

P. vivax and P. ovale

Primaquine for 7-14 days (need G6PD screening)

287
Q

What is the most sensitive culture site for enteric fever?

A

Bone marrow

288
Q

What is the empiric treatment for enteric fever?

A

Azithromycin or ceftriaxone
(consider meropenem if acquired in Pakistan)

289
Q

What family do the following arboviruses belong to:
- dengue
- zika
- chikungunya

A
  • dengue: flavivirus
  • zika: flavivirus
  • chikungunya: alphavirus
290
Q

What mosquitos transmit:
- malaria
- dengue
- zika
- chikungunya

A
  • malaria: Anopheles
  • dengue: Aedes
  • zika: Aedes
  • chikungunya: Aedes
291
Q

What are the 3 phases of dengue fever?

A
  1. Febrile:
    headache, fever, myalgia
    Most proceed to recovery
  2. Critical:
    Increased capillary permeability and fragility = effusions, thrombocytopenia and coagulopathy
  3. Recovery:
    Dengue rash
    Fatigue
292
Q

What is antibody dependent enhancement with regard to dengue?

A

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

293
Q

When can PCR and NS1 rapid antigen testing be used to detect dengue?

A

First 5 days of illness

294
Q

What travel illness presents with symmetrical small joint polyarthropathy?

A

chikungunya

295
Q

When can chikungunya be detected by PCR?

A

first week

296
Q

What travel illness causes non-purulent conjunctivitis and mild oedema of hands and feet?

A

Zika

297
Q

What does HIV require to infect a cell?

A

CD4 (T-cell, monocyte, macrophage, DC, microglial) AND
CCR5 (early infection)
CXCR4 (late infection)

298
Q

Where does the reservoir of HIV that presents cure persist?

A

Resting memory T-cells (latent infection)

299
Q

Where is the body does early HIV infection occur?

A

Lymph systems of GIT

300
Q

What is the HIV lifecycle in a cell?

A

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

301
Q

What cells do HIV replicate in?

A

Active immune cells (not active or resting cells)

302
Q

What is the main way that the body tries to control HIV infection?

A

CTL killing of infected cells via HIV antigen expression on MHC-I

302
Q

Why are T-cells depleted in HIV?

A
  • early loss of T-cells during maturation due to infection
  • chronic inflammation suppresses production
303
Q

What genetic factors are associated with slow HIV progression?

A
  • HLAB57, HLAB27
  • CCR5 depletion
304
Q

Why doesn’t the human immune system make effective neutralising antibodies against HIV?

A
  • 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
305
Q

What are broadly neutralising antibodies in HIV infection?

A

Large variable chains that bind to multiple gp120 sites that prevent gp120 binding cell

306
Q

When do the following need to be monitored on HIV treatment?
- CD4 count
- HIV viral load
- Genotype resistance

A
  • 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
307
Q

What is the mechanism of action of nucleoside inhibitors (NRTIs) and examples?

A

Bind to viral reverse transcriptase at deoxynucleotide binding site, blocking DNA synthesis.

Zidovudine (T), lamivudine (C), emtricitabone (C), abacavir (G), tenofovir(A)

308
Q

Which nucleoside inhibitors have a low barrier to resistance?

A

Lamivudine, emtricitabine (so need to be used as combo drugs)

309
Q

What are common side effects of the following nucleoside inhibitors?
Zidovudine
Abacavir
Tenofovir disoproxil fumarate
Tenofovir alafenamide

A

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

310
Q

Which NRTIs also provide treatment for hepatitis B co-infection?

A

Tenofovir
(Not Lamivudine or emtricitabine due to resistance)

311
Q

What are non-nucleoside reverse transcriptase inhibitors (NNRTIs) and some examples?

A

Bind to reverse transcriptase but not at deoxynucleosdie binding sites, altering enzyme conformation and block DNA synthesis

Nevirapine, efavirenz, rilpiverine, delaverdine, etravirine, doravirine

312
Q

What are common side effects of the following non nucleoside inhibitors?
Nevirapine
Efavirenz
Rilpiverine
Delaverdine
Etravirine

A

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

313
Q

What is the mechanism of action of protease inhibitors to treat HIV and examples?

A

Block viral protease preventing maturation of virus during and after budding of virion leading to production of defective virus.

Ritonavir, lopinavir, atazanavir, darunavir

314
Q

What are common side effects of protease inhibitors used to treat HIV? side effects for:
- ritnoavir
- lopinavir
- atazanavir
- darunavir

A
  • 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)

315
Q

What is the mechanism of action of integrase inhibitors and examples?

A

Inhibit viral integrase preventing integration of viral DNA into host DNA. Particularly rapid reduction in viral load

Raltegravir, elvitegravir dolutegravir, bictegravir

316
Q

What are common side effects of the following integrase inhibitors:
Raltegravir
Elvitegravir
Dolutegravir
Bictegravir

A

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)

317
Q

What is the mechanism of action for the following HIV drugs?
Enfuviritide
Maraviroc

A

Enfuviritide
- prevents fusion of viral and cell membrane

Maraviroc
- prevents binding to CCR5 co-receptor

318
Q

What are the preferred starting regimens for HIV?

A
  1. Integrase inhibitor + 2 NRTI
    - Bictegravir/tenofovir alafenamide/emtracitabine
    - Dolutegravir/abacavir/lamivudine
    - Dolutegravir+ tenofovir/emtracitabine
    - Raltegravir + tenofovir/emtracitabine
  2. INSTI + 1 NRTI if no resistance and no HBV
  3. Protease inhibitor + 2 NRTI if planning to conceive (avoid integrase inhibitor)
319
Q

What time-frame should post-exposure prophylaxis be given for HIV? What is it’s duration?

A

Within 72 hours of exposure
Taken for 28 days

320
Q

What PEP should be used for non-occupational exposure to known HIV positive source for:
- detectable or unknown viral load
- undetectable viral load

A

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

321
Q

What PEP should be used for occupational exposure to known HIV positive source for:
- detectable or unknown viral load
- undetectable viral load

A

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)

322
Q

What PEP should be used for non-occupational exposure to unknown HIV status source?

A

2 drugs only if high risk activity or from high prevalent community
(tenofovir + lamivudine OR emtracitabine)

323
Q

What is the recommended regimen for HIV PrEP?

A

Tenofovir + emtricitabine OD

324
Q

How is pneumocystis jirovecii pneumonia diagnosed?

A

PCR of induced sputum (needs high pre test probability due to colonisation)

325
Q

How is pneumocystis jirovecii pneumonia treated?

A

co-trimoxazole (10 mg/kg/day) + steroids for hypoxia

326
Q

When is PJP prophylaxis indicated for HIV?

A

Primary: CD4 < 200
Secondary: following PJP episode until immune recovery

(co-trim 480 mg OD)

327
Q

How does cryptococcal infection present in HIV?

A

Meningo-encephalitis due to C. neoformans (yeast)
presents with headahce and fever +/- behaviour or confusion. Meningism = late sign

328
Q

What are LP/CSF features of cryptococcal CNS infections?

A
  • raised opening pressure
  • Normal CSF or raised WCC and protein, low glucose
  • halo around organism with indian ink stain
  • Cryptococcal antigen positive
329
Q

How is cryptococcal CNS infection treated?

A
  • LP +/- shunt to relive pressure
  • amphotericin + flucytosine induction
  • cosnolidation with 8 weeks fluconazole and then maintenance therapy until immune reconstitution
330
Q

What is the most common CNS infection in patients with advanced HIV not on treatment or prophylaxis?

A

Toxoplasmosis
(can reactivate at counts < 100)

331
Q

Is brain biopsy required to start treatment for toxoplasmosis?

A

No

332
Q

When should anti-retroviral treatment be started for HIV?

A

within 14 days of diagnosis except where risk of immune reconstitution inflammatory syndrome:
- 6 weeks after cryptococcal meningitis
- CNS TB

333
Q

What is the most common cause of infective endocarditis?

A

S. aureus

334
Q

What is the mechanism of synergy between amoxicillin and gentamicin for E. faecalis infective endocarditis?

A

Increased uptake of aminoglycoside binding by bacterium when the cell wall is altered by beta lactam

335
Q

What is the mechanism of synergy between amoxicillin and cefotaxime for E. faecalis infective endocarditis?

A

Differential saturation of E. faecalis penicillin binding proteins

336
Q

What is recommended treatment of E. faecalis endocarditis?

A

Amoxicillin AND gentamicin OR Ceftriaxone

337
Q

How frequently should blood cultures be taken in S. aureus bacteraemia?

A

Every 24-48 h until cleared

338
Q

What is standard treatment for complicated and uncomplicated MSSA bacteraemia?

A

Flucloxacillin or cefazolin
Uncomplicated: 14 days
Complicated: 28 days

339
Q

What are the 5 most common bacterial causes of meningitis in adults?

A
  • Strep pneumoniae (most common)
  • N meningitidis
  • H influenzae
  • Group B strep
  • Listeria mononcytogenes (esp > 65)
340
Q

What CSF features support a diagnosis of bacterial meningitis?

A
  • opening pressure > 20
  • Protein > 1
  • CSF: blood glucose ration < 0.5
  • WCC > 1000 (10% cases are < 100)
  • Neutrophil predominant (not in Listeria)
341
Q

How is bacterial meningitis managed?

A
  • 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)
342
Q

What are suitable alternatives to ceftriaxone and benzylpenicillin for baterial meningitis?

A

Ceftriaxone = moxifloxacin
Benzylpenicillin = co-trimoxazole

343
Q

How long do N meningitidis+ patients need to be in droplet iso for?

A

24 hours post antibiotic administration

344
Q

What is post exposure prophylaxis for N meningitidis meningitis?

A

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)

345
Q

Why does splenectomy leave patients susceptible to encapsulated bacteria?

A

Encapsulated bacteria are unable to bind complement, only mechanism of clearance is by spleen

346
Q

How is asplenism diagnosed on blood film?

A

Howell-Jolly body (nuclear remnants) = round, dark stain peripherally in red blood cells

347
Q

What encapsulated organisms can cause overwhelming infection in hypo-/asplenism?

A
  • Strep pneumoniae
  • Haemophilus infleunzae type b
  • N. meningitidis
348
Q

What prophylaxis is given post splenectomy?

A

Daily amoxicillin for 3 years
Back pocket script for amoxicillin

349
Q

Are live vaccines safe in asplenism?

A

Yes

350
Q

What is the structure of a pneumococcal vaccine?

A

polysaccharide molecule conjugated to a protein carrier

351
Q

What vaccinations should asplenic patients receive?

A
  1. Pneumococcal vaccine:
    - PCV13 x1 (before PPV)
    - PPV 23 x3 over 5 years
    1-2 weeks pre splenectomy or 1 week post
  2. Meningococcal vaccine
  3. Hib vaccine as adult x1(unless fully vaccinated as child)
  4. Annual influenza
352
Q

What is the most common meningococcal serotype in Aus/NZ?

A

B

353
Q

What is the mechanism of action of the following anti-fungals?
- azoles
- polyenes (amphotericin B)
- echinocandins (caspofungin)

A

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

354
Q

What is the mechanism of drug interaction with azoles?

A

Inhibit CYP450

355
Q

What is the key limitation of echocandins (caspofungin) in the treatment of candida infections?

A

Minimal CNS penetration

356
Q

What drugs interact with echinocandins (caspofungin)?

A

Cyclosporin
Tacrolimus
Rifampicin
Phenytoin
Carbamazepine

357
Q

What is empiric treatment of candidaemia?

A

Caspofungin, stepped down to fluconaxzole if susceptible and blood cultures cleared

358
Q

What is the clinical significance of Candida auris?

A

Often resistant to echocandins and amphotericin B

Still treat with echocandins as first line

359
Q

What is the mechanism of resistance of MRSA?

A

mecA gene carried on mobile genetic element (staphylococcal cassette chromosome SCCmec)

mecA encodes PBP2a which is a transpeptidase with poor affinity to beta lactams

360
Q

What antibiotics are effective for MRSA?

A
  • 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)
361
Q

What is the mechanism of resistance VRSA?

A

Acquisition of plasmid containing vanA gene from resistant enterococci, which alters peptidoglycan terminus( D-Ala to D-Lac) to prevent binding

362
Q

What antibiotics are enterococci intrinsically resistant to?

A
  • cephalosporins
  • macrolides
  • glycopeptides
  • tetracyclines
  • fluroquinolones

(E. faecalis is sensitive to amoxicillin, but E. faecium is not)

363
Q

What is the difference between VanA and VanB resistance?

A

VanB is susceptible to teicoplanin

364
Q

What antibiotics can be used for VRE?

A
  • linezolid
  • daptomycin
  • tigecycline
  • quinupristin-dalfopristin
365
Q

What is the mechanism of acquisition of ESBL genes?

A

Transferred on plasmids

366
Q

What are ESCAPPM organisms?

A

Organisms that carry an inducible cephalosporinase on Chromosomal AmpC

Enterobacter
Serriatia
Citrobacter freundii
Acinetobacter (aeromonas)
Proteus (not mirabilis)
Providencia
Morganella morganii

367
Q

What antibiotics can be used for ESCAPPM organisms?

A
  • carbapenems (ertapenem not fo acinetobacter)
  • piperacillin-tazabactam
368
Q

What are mechanisms of carbapenem resistance?

A

Efflux pumps
Porin mutations
Carbapenemase:
- KPC
- NDM
- IMP
- VIM
- OXA-48
- OXA-181

369
Q

What antibiotics can be used for carbapenem-resistant organisms?

A

Combo therapy:
- colistin (bacterial cell membrane)
- tigecycline (30s ribosome, bacteriostatic)
- amikacin (aminoglycoside 30s ribosome)

370
Q

How is TB spread?

A

Droplets

371
Q

What proportion of latent TB reactivate?

A

10%

372
Q

Is there cross-reactivity of the TB IGRA to BCG and NTM?

A

No

373
Q

How does MTB appear under microscopy with acid-fast stain?

A

Thin curved rod
Ziehl-Neelsen = red
Auramine = yellow/orange

374
Q

What is the gold standard for TB diagnosis and susceptibility testing?

A

Culture (liquid = 6 weeks, solid = 8 weeks)

375
Q

What is treatment for latent TB?

A

9 months isoniazid
OR
4 months rifampicin

376
Q

How is active TB treated?

A

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)

377
Q

What are common adverse drug reaction for the following anti-TB drugs?
- Rifampicin
- isoniazid
- ethambutol
- Pyrazinamide

A

Rifampicin:
- drug interactions (pgp inducer, inducer CYP450)
- hepatitis
- hypersensitivity

Isoniazid:
- hepatitis
- rash
- peripheral neuropathy

Ethambutol:
- optic neuropathy

Pyrazinamide:
- hepatitis
- skin
- polyarthralgia
- gout

RACP 2024 (15 decks)

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