Opportunistic infections Flashcards
When can you stop various maintenance OI treatments?
- 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
First and second most often occurring cryptococcal serotype in the UK?
First: Cryptococcal neoformans grubii (serotype A)
Second: Cryptococcal neoformans gattii
Diagnosis of cryptococcal disease
- 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
Poor prognostic markers in cryptococcal meningitis
- Blood culture positivity
- Low white blood cells in CSF (<20cells/ml)
- High CSF cryptococcal antigen (>1:1024)
- Confused state
- Raised ICP
When might you see a false positive Cr-Ag?
In the presence of rheumatoid factor, heterophiles antibodies, anti-idiotypic antibodies or Trichosporon asahii (beigelii) infection
Induction therapy for cryptococcal
- 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
Management of raised ICP
If opening pressure >25mmHg then should be reduced to 20mmHg or to 50% of the initial pressure and then repeated daily until stable
Maintenance therapy for cryptococcal meningitis and when to stop
- 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
Management of cryptococcal disease without CNS involvement:
- 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
Where do toxo lesion have a predilection for?
- 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
Diagnosis of toxoplasma:
- 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)
First line induction therapy for cerebral toxoplasmosis
- Sulphadiazine oral
- Pyrimethamine
- Folinic acid
- For 6 weeks
Second line toxoplasmosis induction therapy:
- 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
Maintenance therapy for toxoplasmosis
(after 6 weeks induction)
(can be stopped when CD4>200 and VL<20 for 6 months)
- Sulphadiazine lower dose
- Pyrimethamine lower dose
- Folinic acid 10mg daily
Second line toxoplasmosis maintenance
- Clindamycin
- Pyrimethamine
- Folinic acid
First and second line primary toxo prophylaxis
First line: Cotrimoxazole 480-960mg daily
Second line: Dapsone 50mg daily with pyrimethamine (50mg/weekly) and folinic acid (15mg/weekly)
Diagnosis of PML
- 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)
Poor prognostic factors in PML
- Clinical (older age, brainstem involvement, lowered GCS)
- Viral (high CSF JC VL with delayed clearance with ART)
- Radiological (early brainstem involvement)
- Immunological (CD4<100)
Prognosis of PML
- 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
Seropositivity of CMV
50-75%
Most MSM
Major sites of CMV disease
- 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%
Diagnosis CMV polyradiculitis
- 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
Treatment of neurological CMV disease
- Ganciclovir with or without foscarnet
- ART
- (prophylaxis not required)
AIDS defining incidence of bacterial pneumonia
2 or more episodes in 12 months
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
Predictive factors for PCP
Not on ART
Oral thrush or OHL
Weight loss
Not taking septrin
Recurrent bacterial pneumonia
High VL
Previous PCP
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
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
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
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
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
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
Side effects of septrin
Rash
Hyperkalaemia
Thrombocytopenia/leukopenia
GI disturbance
Fever
Hepatitis
Anaphylaxis
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
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
Treatment of aspergillosis:
Voriconazole
Ambisome alternative
Caspofungin if significant renal or liver disease