Opportunistic infections Flashcards
1
Q
When can you stop various maintenance OI treatments?
A
- CMV retinitis/other CMV disease CD4>100 and undetectable 6 months
- Toxo maintenance when CD4>200 and VL<20 for 6 months
- PCP when CD4>200 and 14% for 3 months
- Crypto fluconazole 200mg can stop when CD4>100 and VL<20 for 3 months
- MAC treatment when CD4>100, VL<20 and clinically well for at least 3 months
2
Q
First and second most often occurring cryptococcal serotype in the UK?
A
First: Cryptococcal neoformans grubii (serotype A)
Second: Cryptococcal neoformans gattii
3
Q
Diagnosis of cryptococcal disease
A
- All those with positive serum CrAg should have LP after brain imaging
- A positive CSF Cr-Ag is the most sensitive test
- Must have manometry when do LP
- All those with CD4<200 and symptoms of crypto should have the disease excluded
- A negative test generally excludes disseminated disease although there are isolated reports
- Serum Cr-Ag can be negative in isolated pulmonary disease so MC+S of pulmonary are required to make a diagnosis
- A positive CSF Cr-Ag, indian ink stain of CSF or CSF Cryptococcus culture confirms meningitis
- Blood cultures should always be performed
- If blood or CSF cultures are positive, isolates can be sent for fungal susceptibility testing
4
Q
Poor prognostic markers in cryptococcal meningitis
A
- Blood culture positivity
- Low white blood cells in CSF (<20cells/ml)
- High CSF cryptococcal antigen (>1:1024)
- Confused state
- Raised ICP
5
Q
When might you see a false positive Cr-Ag?
A
In the presence of rheumatoid factor, heterophiles antibodies, anti-idiotypic antibodies or Trichosporon asahii (beigelii) infection
6
Q
Induction therapy for cryptococcal
A
- Liposomal amphotericin B (Ambisome) and flucytosine
- (Addition of flucytosine speeds rate of sterilisation of CSF and reduces rate of relapse in those not on ART, but no impact on mortality)
- Flucytosine associated with haematological toxicity and daily blood counts are required
7
Q
Management of raised ICP
A
If opening pressure >25mmHg then should be reduced to 20mmHg or to 50% of the initial pressure and then repeated daily until stable
8
Q
Maintenance therapy for cryptococcal meningitis and when to stop
A
- After 2 weeks of induction therapy switch to fluconazole 400mg/day for 10 weeks total then reduce to 200mg
- Can stop the 200mg when CD4>100 and VL<20 for 3 months
- (An LP after induction and extension of induction therapy can be considered until CSF cultures are negative e.g. in setting of poor prognostic factors or poor initial response)
- (CSF cryptococcal burden correlates with risk of relapse and mortality)
- Start ART approx 2 weeks after treatment starts, can consider steroids if IRIS
9
Q
Management of cryptococcal disease without CNS involvement:
A
- Always do an LP
- If CSF negative, isolated pulmonary disease can be treated with fluconazole 400mg OD or if more severe then ambisome then secondary prophylaxis
- Same for cryptococcaemia
10
Q
Where do toxo lesion have a predilection for?
A
- Multiple, ring enhancing lesions at the grey-white matter interface often basal ganglia or thalamus
- Associated with cerebral oedema and mass effect
- (If CD4 count low, may not have ring enhancement)
- (Single, periventricular lesion suggestive PCNSL)
- (PML tend to involve white matter, rarely contrast enhancing and no mass effect)
- Can also present with signs of a diffuse encephalitis
- Rarely can present as a toxo myelitis, caudal equina syndrome
- Presentations outside CNS include chorioretinitis and pneumonia
11
Q
Diagnosis of toxoplasma:
A
- It is now standard practice to treat a patient with CD4<200 and a brain mass lesion with anti-toxo therapy
- 90% will show good clinical/radiological response within 2 weeks which is good evidence of diagnosis
- CSF PCR for T.Gondii helps establish diagnosis but is only moderately sensitive (sensitivity of 50%, specificity of >94%)
- Do G6PD (although sulphadiazine has been shown to be ok in many that are deficient, but any Hb drop should certainly prompt testing)
12
Q
First line induction therapy for cerebral toxoplasmosis
A
- Sulphadiazine oral
- Pyrimethamine
- Folinic acid
- For 6 weeks
13
Q
Second line toxoplasmosis induction therapy:
A
- Clindamycin, Pyrimethamine, Folinic acid
- Other alternatives include trimethoprim with sulphamethoxazole OR atovaquone with sulphadiazine or pyrimethamine
Give the above for 6 weeks then lower dose for maintenance
Maintenance can be stopped if CD4>200 and VL UD for 6 months
Steroids if symptoms and signs of raised ICP
14
Q
Maintenance therapy for toxoplasmosis
(after 6 weeks induction)
(can be stopped when CD4>200 and VL<20 for 6 months)
A
- Sulphadiazine lower dose
- Pyrimethamine lower dose
- Folinic acid 10mg daily
15
Q
Second line toxoplasmosis maintenance
A
- Clindamycin
- Pyrimethamine
- Folinic acid
16
Q
First and second line primary toxo prophylaxis
A
First line: Cotrimoxazole 480-960mg daily
Second line: Dapsone 50mg daily with pyrimethamine (50mg/weekly) and folinic acid (15mg/weekly)
17
Q
Diagnosis of PML
A
- Lesions are usually bilateral, asymmetric, non enhancing, T2 hyperintense and T1 hypointense
- Restricted to white matter and no oedema
- Sharply demarcated as compared to HIVe
- Pre-ART, JC DNA in CSF had sensitivity of 70-90% and specificity of 92-100% (since introduction ART sensitivity fallen to 50% reflecting reduced viral replication and increased clearance of virus from CSF)
18
Q
Poor prognostic factors in PML
A
- Clinical (older age, brainstem involvement, lowered GCS)
- Viral (high CSF JC VL with delayed clearance with ART)
- Radiological (early brainstem involvement)
- Immunological (CD4<100)
19
Q
Prognosis of PML
A
- Without ART predicted survival of 10% at 1 year
- With ART 50% will survive this long
- Some enter true remission with stabilisation of morbidity and development of atrophy and gliosis on MRI
20
Q
Seropositivity of CMV
A
50-75%
Most MSM
21
Q
Major sites of CMV disease
A
- Retina (accounts for 75%), also GI tract, lung, liver, biliary tract, heart, adrenal glands and nervous system (encephalitis and polyradiculitis)
- Nervous system disease accounts for <1%
22
Q
Diagnosis CMV polyradiculitis
A
- EMG shows axonal neuropathy helping to distinguish from an acute demyelinating polyneuropathy
- (can present as a lumbosacral polyradiculitis with rapidly progressive, painful, bilateral ascending flaccid paralysis)
- Positive CSF PCR >80% sensitive and >90% specific
- Detection of CMV DNA in CSF by PCR correlates well with disease and is not usually due to latent infection, but can also be negative in biopsy proven CMV
23
Q
Treatment of neurological CMV disease
A
- Ganciclovir with or without foscarnet
- ART
- (prophylaxis not required)
24
Q
AIDS defining incidence of bacterial pneumonia
A
2 or more episodes in 12 months
25
Diagnosis of cryptococcal pulmonary disease:
- Usually requires culture of the yeast +/- positive antigen test or staining of the yeast on BAL or pleural fluid
- Giemsa stain or Indian ink would reveal an encapsulated yeast, calcofluor white with fluorescence microscopy
- Culture using blood agar or fungal media such as Sabouraud media
- Biopsy specimens could be stained with fungal stains like Grocott-Gomori methenamine silver
- Blood cultures or serum CrAg frequently positive suggesting disseminated disease, but may be negative
26
Predictive factors for PCP
Not on ART
Oral thrush or OHL
Weight loss
Not taking septrin
Recurrent bacterial pneumonia
High VL
Previous PCP
27
First line treatment of PCP
Severe = PaO2<9.3
- IV high dose septrin 21 days
- Corticosteroids e.g. 5 days 40mg prep BD, then 5 days 40mg OD then 10 days 20mg OD
Mild-moderate
- PO high dose septrin 21 days
Early use CPAP
28
Second line treatment for PCP
Severe disease:
- Clindamycin and primaquine
- Pentamidine
Mild to moderate:
- As above or trimethoprim + dapsone
- Atovaquone
G6PD should be tested before high dose septrin, dapsone or primaquine
29
PCP prophylaxis and when to stop
- Septrin 480mg OD where CD4<200 or <14%, - Stop once over these values for 3 months
- (alternatives include nebulized pentamidine, dapsone plus pyrimethamine)
- If proven PCP at CD4>200, may consider lifelong
30
What trial gave evidence to support early ART in PCP and other OI? (But not Tb)
ACTG 5164
- RCT, randomised to start ART within 2 weeks Vs more like 6 weeks
- More sick were excluded
31
Most likely pathogen for a CAP:
- Similar to general population: Strep pneumoniae and haemophilia influenzae
- Staph aureus has been reported at increased frequency
- Pseudomonas aeruginosa has been noted more at low CD4
- Consider gram negative pathogens if develop in hospitalised setting (e.g. pseudomonas, klebsiella, E-coli, acinetobacter)
- SMART study identified that a structured treatment interruption was associated with increase incidence of bacterial pneumonia
32
Diagnosis of pulmonary cryptococcus neoformans:
- Symptoms and radiology may be indistinguishable from PCP
- Sputum/BAL/pleural fluid could be stained with Giemsa stain, India ink or calcofluor white with fluorescence microscopy
- Cryptococcal antigen can be detected in BAL which is 100% sensitive and 98% specific
- Yeast can be cultured from BAL or biopsy specimens using blood agar or fungal media like Sabouraud media
- Bloods specimens can be stained with E.G. Grocott/Gomori methenamine silver
- Serum CrAG and blood culture frequently positive
33
Side effects of septrin
Rash
Hyperkalaemia
Thrombocytopenia/leukopenia
GI disturbance
Fever
Hepatitis
Anaphylaxis
34
Treatment of pulmonary cryptococcus neoformans
- Ambisome + flucytosine 2 weeks then 400mg fluconazole for 10 weeks total then 200mg until CD4>100 and VL<20 for 3 months
- If LP has excluded CNS disease then could treat with fluconazole 400mg OD for 10 weeks then 200mg
35
Aspergillosis diagnosis:
- Aspergillus spp colonise lung, however if the fungus invades the parenchyma it's called invasive aspergillosis
- Can present insidiously
- Diagnosis combination of radiology and micro: fungal stains such as KOH or Grocott-Gomori methanamine silver
- Galactomannan test is an enzyme linked assay that detects a cell wall constituent of Aspergillus - false positives can occur e..g in those receiving tazocin
36
Treatment of aspergillosis:
Voriconazole
Ambisome alternative
Caspofungin if significant renal or liver disease
37
Diagnosis and treatment of CMV pneumonia
- Requires biopsy showing intranuclear viral inclusion or positive immunostaining for CMV antigens plus a compatible syndrome and no alternative cause
- Treatment:
- Gancliclovir 21 days
- Foscarnet or cidofovir are alternatives
38
First line treatment for oral and oesophageal candida
- Oral: fluconazole 100-200mg/day for 7-14 days
- Oesophageal: 200-400mg/day 14-21 days
Caspofungin or ambisome alternatives
Alternatives for oral candida:
- Nystatin 100,000 units/ml, amphotericin lozenges, clotrimazole pessaries etc
39
Treatment of CMV oesophagitis or colitis
- IV gancliclovir
- Oral valganciclovir alternative
40
Treatment of HSV oesophagitis
- Aciclovir IV followed by valaciclovir or famciclocvir oral for total for 14 days
41
Who with bacterial diarrhoea should get Abx
If CD4<200, or if C diff
42
Treatment of microsporidium
- ART
- If E. intestinalis then albendazole
43
Treatment of entamoeba histolytica
- Metronidazole high dose 10 days then paromomycin (for luminal infection)
- (or diloxanide furoate)
44
Strogyloides stercoralis treatment
- Ivermectin
- (alternative albendazole)
45
Schistosoma treatment
- Praziquantel
46
Stool investigation to look for Microsporidia
- Examination of 3 stools with chromotrope and chemofluorescent stains
47
Treatment of CMV retinitis
- If peripheral disease only then oral valganciclovir 900mg BD induction for 2 weeks, (ganciclovir/foscarnet/cidofovir alternatives)
- If zone 1 or 2 (more central) part of retina involved then may use adjunctive intraocular ganciclovir or foscarnet
- Continue valgan 900mg OD until CD4>100
NB all CMV therapies can cause cytopenias, renal toxicity and electrolyte disturbance
48
Treatment of Chagas disease
Benznidazole
49
Anti-fungals in pregnancy
- Aim for topical treatment where possible e.g. PV clotrimazole or PO nystatin, avoid fluconazole certainly in first trimester,
- Ambisome can be used in most cases instead
- Caspofungin and voriconazole never
50
Treatment of varicella zoster virus
- Primary varicella (chickenpox): IV acyclovir or oral if CD4 ok and uncomplicated disease
- Zoster: start treatment as soon as possible and continue for at least 7 days until lesions dried
- >Localised dermatomal zoster: oral acyclovir 800mg 5x day
- > Severe cutaneous or disseminated or CNS disease admit for IV acyclovir 10-14 days
- > if resistance or failing then IV foscarnet
51
Which of HSV1 or HSV2 more likely to cause meningitis?
- HSV1 more likely encephalitis
- HSV2 more likely meningitis
- > CSF HSV DNA very sensitive and specific although may get false negative in first 72 hours
52
Treatment of HSV encephalitis
Acyclovir IV
53
Diagnosis of MAC
- Culture in blood or from bone marrow aspirate
- Preferred culture method on solid media e.g. Lowenstein-Jenson, middlebrow
- May see acid fast organisms before cultures are back
54
Treatment of MAC
- Macrolide and ethambutol with or without rifabutin (given when marked symptoms or advanced immunosuppression)
- Clarithromycin better (max 500mg BD) than azithro however azithro has fewer DDI and better tolerated
55
How long to continue MAC treatment?
- Stable on ART with low VL, CD4>100 for at least 3 months and clinical response (asymptomatic and negative blood cultures) for at least 3 motnhs
56
If patient not responding to MAC treatment in 4-8 weeks what to do?
- Construct a new regimen out of e.g. rifabutin, linezolid, oflox, levoflox, moxiflox, amikacin
- Most would continue ethabutol as it facilitates the penetration of other agents into the mycobacteria
57
MAC prophylaxis
- Consider if CD4<50
- Azithromycin 1250mg weekly (can stop when VL<20 and CD>50 for at least 3 months)
58
Mycobacterium kansasii treatment
- Rifamycin is key (rifampicin or rifabutin) then ethambutol, isoniazide + pyridoxine
- RIE
59
Diagnosis of malaria
- Thick film to diagnose malaria and estimate % parasitaemia
- Thin film- for speciation
- +/- rapid diagnostic antigen test
60
Treatment of uncomplicated falciparum malaria
- Artemether-lumefantrine (Riamet) (PIs might decrease levels but can still give)
- Alternatives include quinine with doxy or quinine with clinda
61
Treatment of severe falciparum malaria
- IV artesunate first line
- IV quinine 2nd line (QT prolongation, ECG before, ideally on monitor, monitor BM carefully too)
- In pregnancy IV artesunate not recommended in frist trimester, might go for quinine and clindamycin
62
Treatment of leishmaniasis
- Visceral leish: ambisome
- Cutaneous: local infiltration of sodium stibogluconate or systemic
63
Treatment of penicillosis
(septate yeast forms, red colour, SouthEast asia and China)
- Ambisome 2 weeks then intraconazole 10 weeks then maintenance
64
Do ODG in suspected oesophageal candida in the following sitautions:
- No oral lesion
- Not responding to treatment
- Alternative condition suspected
65
Most common forms of candida causing infection
Candida albicans 62-68%
Candida glabrata 17-21%
Candida dublinessis 6-12%
Glabrata should be treated with alternative to fluconazole unless susceptibility shown
Candida Auris new cause of inherently multi drug resistant
66
First line treatment for oral and oesophageal candida
Oral: fluconazole 100-200mg 7-14, chlorhexidine mouthwash and removal of biofilms
- Topical e.g. nystatin has slower clearance of yeast, higher relapse rate and reduced tolerability, might use in pregnancy
Oesophageal: fluconazole 200-400mg 14-21 days depending on severity
- Intraconazole an option but fluconazole better short term response and fewer DDI
- Aim to stop PPIs with fluconazole
- Itraconazole should not be given with enzyme inducers
67
Monitoring with azoles
- Other that fluconazole 100mg OD or less, all require regular LFT monitoring e.g. in the first week then monthly or bimonthly
- Avoid itraconazole in heart failure
- If fluconazole not working can try itraconazole/voriconaozle/posiconazonole, if not working or intolerant can try e.g. caspofungin, ambisome etc.
68
Monitoring with azoles
- Other that fluconazole 100mg OD or less, all require regular LFT monitoring e.g. in the first week then monthly or bimonthly
- Avoid itraconazole in heart failure
- If fluconazole not working can try itraconazole/voriconaozle/posiconazonole (need TDM with these), if not working or intolerant can try e.g. caspofungin, ambisome etc.
69
Treatment of vulvovaginal candida due to non-albicans candida with reduced fluconazole suscepbibillity e.g. C.glabrata
Nystatin pessaries or 5-flucytosine, amphotericin pessaries or topical boric acid
70
Management of latent Tb
- Test with IGRA those from medium (40-150/100,000 person years) and high incidence countries (>151/100,000 person years)
- Exclude active Tb first
- Repeat in 4 weeks if indeterminate
- Don't test if Hx of Tb
- Treat with 6 months isoniazid + pyridoxine
- OR 3 months Rifampicin + isoniazid +pyridoxine
71
Tb treatment if on a PI
Replace rifampicin with rifabutin
72
When to start ART in active Tb
- If CD4<50 start as soon as possible within 2 weeks
- if CD4>200 benefit of early ART less clear, could wait until induction (2 months) over
- Don't start early if TBM
- SAPIT + CAMELIA: early ART (within 2 weeks or so) where CD4< 50- less death
- In SAPIT, deferral of ART to 4 weeks post ART in those with higher CD4 reduced risk of IRIS without increasing AIDS or death
73
What ART with Tb treatment?
- Truvada + EFV is first line in those taking rifampicin
- RAL 800mg BD or DTG 50mg BD can be used, continue BD for 2 weeks after stopping rifampicin
- Aim to avoid kivexa as ABC hypersensitivity may confuse the picture
- Rilpivirine should not be given with rifamycins
- Do not use cobi with rifamycins as no data, if ritonavir boosted PI use rifabutin
- Do not use doravirine with rifampicin, can do 100mg BD doravirine with rifabutin continuing 2 weeks after stop rifabutin
- Don't use fixed combinations with TAF or BIC, or dual therapy or injectables until further data
74
IGRA Vs tuberculin skin test
- Both less likely to be positive in presence of advanced immunosuppresion, but IGRA less affected
- IGRA not affected by prior BCG vaccination but tuberculin skin test is
- IGRA do not require follow up visit to read the result like tuberculin skin test
- Both may be negative early in the window perio
75
What mutation do Xpert MTB/RIF look for fo rapid identification or rifampicin resistance?
rpoB
76
Sensitivity and specificity or Xpert MTB/RIF
- In smear positive Tb 98-99% sensitive and specific
- However in smear negative Tb more like 67% sensitive
(Newer Xpert MTB/RIF Ultra has improved sensitivity but lower specificity)
(WGS requires a culture isolate, Xpert don't)
77
Diagnosis of Tb meningitis
- CSF usually lymphocytic, low glucose, high protein, can be accelular in advanced disease
- Gold standard is Mt by culture, but limited sensitivity
- Staining for AFB has low sensitivity, so use large volumes, Xpert MTB/RIF Ultra better however negative still doesn't exclude
- ADA can be useful but not standardised so not recommended
Do MRI
78
Diagnosis of pleural Tb
- Pleural fluid PCR has low sensitivity for diagnosis of pleural Tb, same with culture
- Even if not obvious cough or parenchymal disease do induced sputum or BAL for culture
- Medical thoracoscopy may be useful
- ADA may be useful, if lymphocyte predominant exudative effusion with raised ADA -> high probability of Tb
79
Tb mimics on histopathology
Histoplasmosis (always do fungal stain), sarcoidosis, nocardiosis, leishmaniasis, tumour, vasculitis, brucellosis, meliondosis
80
What should you consider if smear positive for AFB with negative molecular tests for TB, whilst awaiting cultures?
Consider covering for MAC too by using rifabutin instead of rifampicin and adding cali or azithromycin to regimen until cultures available
81
Tb treatment interruptions
- During intensive phase if <14 days just complete, but if >14 days start again
- During continuation phase varies, but if received less than 80% doses and lapse >3 months restart from beginning with intensive
82
Investigations and monitoring in Tb treatment
- At start of treatment do HIV VL, CD4, ALT/AST, Bili, ALP, creatinine, platelets, hep B and C, Snellen and Ishihara plates
- Liver check at 2 weeks then 2-4 weekly
83
Definition of treatment failure in Tb
- Smear or culture positive at 5 months
- Usually an adherence issue
84
What to give for isolated isoniazid resistance?
Rifampicin, ethambutol, pyrazinamide and levofloxacin (moxiflox and rifampicin DDI)
85
Definition of MDR and XDR
MDR is at least isoniazid and rifampicin resistance (1.5% in UK), if also fluoroquinolone and injectables (e.g. amikacin) resistant then XDR
(get specialist input, an all oral regimen might be constructed with bedaquilline, don't give if QT interval>500ms
86
Example of fluoroquinolone
Moxiflox
Levoflox
Ciproflox
(Tendon pain)
87
Rifamycins and steroid
- Increase steroid dose 50% with rifampicin
- Increase steroid dose 33% with rifabutin
88
Rifampicin and methadone
- Rifampicin will reduce levels of methadone and could cause symptomatic withdrawal, equally when rifampicin stopped could get methadone side effects
- No issue with rifabutin
89
Definition of DILI
- AST/ALT X3 upper limit of normal if symptomatic
- AST/ALT X5 upper limit of normal if asymptomatic
90
What to do if DILI
- Consider stopping all potentially liver toxic drugs: rifampicin, isoniazid, pyrazinamide, septrin, some ART
- Aim to continue Tb treatment with liver friendly regimen such as ethambutol, streptomycin, amikacin, levoflox (not moxiflox)
- Monitor LFTs regularly
- Once ALT/AST drops to <2x upper limit normal can re-introduce a first line regimen with a reintroduction regimen
- If initial reaction was life threatening, use different drugs
91
If have pre-existing liver disease, which Tb drug to stop first if DILI?
Pyrazinamide
If don't already have liver disease ?isoniazid
92
Most likely cause of rash with Tb treatment?
- Ethambutol
- If no mucosal involvement, treat symptomatically, if widespread of worsening stop all drugs and use reintroduction regimen
