Routine Cryptococcal screening & Treatment in CTCs (1).pptx

Routine Cryptococcal screening & Treatment in
CTCs
MTENGWA DM
BSc in Nursing,DQI fP

Learning modules
Module 1: what is cryptococcus
Module 2: Recognizing signs and symptoms of cryptococcal
disease
Module 3: Diagnosing cryptococcal disease
Module 4: Treating cryptococcal meningitis
Module 5: Preventing cryptococcal meningitis
Module 6: Decision-making guide for cryptococcal screening
Module 7: Your role as a health care provider

Module 1 objectives
• Understand what Cryptococcus is and where it is found in the
environment
• Understand how Cryptococcus infects HIV and AIDS patients
• Understand the high death rates associated with cryptococcal
meningitis

What is Cryptococcus?
• Fungus found in soil
contaminated by bird droppings
• Fungal spores are inhaled from
environment
• The fungus cannot spread from
person to person
Cryptococcus spp.

Cryptococcal infection
• After inhalation, the fungus can cause an
acute lung infection or asymptomatic
• May be dormant in the body for months to
years (latent infection)
• Reactivation of infection can occur in
immunosuppressed people, such HIV/AIDS.
• Adult HIV/AIDS patients with a CD4 count <
100 are at highest risk for reactivation
• Meningitis is the most common presentation

Module 2- Objectives
• Identify the common signs and symptoms of
cryptococcal meningitis
• Recognize other clinical presentations of
cryptococcal disease
• Identify other diseases that may look like
cryptococcal meningitis in HIV/AIDS patients

Module 2: Recognizing signs and symptoms of
• Headache
• Fever
• Change in mental status (ranging from confusion
to lethargy to coma)
• Blurry vision (and other cranial nerve deficits)
• Neck stiffness
• Sensitivity to light
• Nausea and vomiting
• Seizures
• Papilledema

Clinical course of cryptococcal disease
No symptoms or
symptoms of lung infection
• Shortness of breath
• Cough
• Fever
Meningitis
• Headache
• Confusion or coma
• Neck stiffness
• Fever
• Nausea, vomiting
• Sensitivity to light
Infection spreads

Other clinical presentations of cryptococcal
disease
• Lung: Ranges from mild pneumonia to acute
respiratory distress syndrome (ARDS);
Shortness of breath, cough, and fever are the
most common symptoms
• Skin: Papules, pustules, nodules, ulcers are
common skin lesions
• Bone: Most commonly the vertebrae and ribs

Other diseases that may look like cryptococcal
meningitis in persons with HIV/AIDS
• TB meningitis is the most common
• Meningoencephalitis caused by other
organisms (mycobacterial, viral, bacterial)
• Space-occupying lesions (lymphoma,
Toxoplasma gondii, abscess)

Module3: objectives
• Describe the current methods used to
diagnose Cryptococcus infection
• Explain the new dipstick test and the
characteristics of this test
• Understand which test to use when
diagnosing cryptococcal meningitis
• Understand the role of lumbar puncture in
diagnosing cryptococcal meningitis

Current diagnostic methods
• There are several ways to detect Cryptococcus spp.
infections.
• Traditional methods include microscope(Indian Ink),
and growth of the organism in culture.
• Both microscopy and culture are accurate methods
but they are not very sensitive
• In addition, culture results may take days to weeks
to obtain the final results.

Module 3: CrAg testing
• Cryptococcal antigen (CrAg), a chemical marker for
infection, is produced by the fungus Cryptococcus.
• A new antigen detection test, called the Lateral Flow
Assay (LFA), is a rapid dipstick test.
• The test cannot be used to monitor clinical response
to treatment, because serum may remain positive for
CrAg for days to months after successful treatment.
• Antigen can also be detected in CSF and serum
weeks to months before meningitis symptoms
develop

CrAg testing
• Effective: The test is
sensitive, accurate
(>95%), and highly
predictive of who is at
risk for developing
cryptococcal meningitis.
• Simple and quick: The
results of the LFA are
available in 10 minutes.

Module 3: diagnosing cryptococcal disease
• Patients with signs and
symptoms of meningitis,
also evidence of
anywhere in the body need
to be evaluated for
• CSF should be collected by
performing a lumbar
puncture.
• LP pic

Module 3: diagnosing Cryptococcal disease
• Three tests should be performed on CSF to
detect Cryptococcus:
1. India Ink stain
2. Cryptococcal antigen detection test
3. Fungal culture.
• At least one of these tests should be positive
in order to confirm the diagnosis of
Cryptococcal meningitis.

Lumbar puncture
• Before performing a lumbar puncture, ensure
that there are no focal neurologic deficits.
• If there are, perform a head CT first to rule out
a space-occupying lesion.
• Where CT scans are not available, you may
consider proceeding without imaging, but this
decision should be discussed with a senior
clinician, weighing potential risks and benefits.

Lumbar puncture……..
• When performing a lumbar puncture, always
record the opening pressure (normal: <20
cmH2O)
• CSF analysis should include the following;
1. Microscopy (cell count, Gram stain, India Ink
stain)
2. Chemistry (protein, glucose),
3. Bacterial culture
4. Tests for Cryptococcus (CrAg, fungal culture)

Differential DDx
• Other common causes of meningitis in
HIV/AIDS patients should be ruled out,
therefore, consider ordering
1. adenine deaminase (ADA) and
2. mycobacterial smear and culture
(tuberculosis),
3. TPHA (syphilitic meningitis)
4. Toxoplasma antibodies (IgG, IgM
toxoplasmosis).

How to diagnose non-meningeal cryptococcal
disease
• If non-meningeal cryptococcal disease is
suspected, an antigen detection test, India Ink
stain, or culture of the relevant clinical
specimen may be useful (for example, a skin
biopsy or sputum sample).
• Any patient with a positive test needs to be
evaluated with a lumbar puncture for

Module 4: Treating Cryptococcal Meningitis
Training objectives
• Describe the current treatment for adult cryptococcal
meningitis
• Understand the importance of managing intracranial
pressure
• Describe common side effects from fluconazole
therapy
• Describe important fluconazole drug interactions
• Define immune reconstitution inflammatory
syndrome (IRIS)

Module 4: the current treatment for adult
• Treatment of adult cryptococcal meningitis
consists of three phases:
1. induction, given to rapidly clear the organism
from the body
2. Consolidation, given to ensure that the
organism is completely eradicated
3. Maintenance, is given to prevent recurrence
of disease after treatment; this phase is also
known as secondary prophylaxis.

Induction phase (2weeks) Consolidation phase
(8weeks)
Maintenance phase
Amphotericin B
0.7mg/kg/day IV + 5
Flucytosine 100mg/kg/day
administered orally for
1week + Fluconazole
1.2g /day for 1 week
Fluconazole 400-800mg/
day for 8 weeks or until CSF
is sterile
Fluconazole 200mg per day
For 1 year on ART and CD4 ≥ 200
if viral load monitoring not
available, or CD4 ≥ 100 and a
suppressed viral load
Note:
It is recommended to initiate ART 5 weeks after initiation
of Cryptococcal meningitis treatment in ART naïve patient
to prevent IRIS and mortality

Minimum package for amphotericin B toxicity
prevention, monitoring and management
Pre-emptive hydration and electrolyte supplementation
Adults
1 liter of normal saline solution with KCL 20 mmol over 2-4 hours
before each controlled infusion of amphotericin B (with 1liter of
5% dextrose) plus one to two 8mEq KCL tablets orally twice daily.
Note:
• An additional one 8mEq KCL tablet twice daily may be added
during the second week.
• If available, magnesium supplementation should also be
provided (two tablets 250mg of magnesium trisilicate twice
daily)

Adolescents and Children
• Up to 1liter of normal saline solution 20 mmol of KCL
at 10-15 ml/kg over 2-4 hours before each controlled
infusion of amphotericin B.
• If saline is unavailable, give other intravenous
rehydration solutions that contain potassium eg.
Darrow’s or Ringer’s Lactate solutions.
• Potassium replacement should not be given to
patients with pre-existing renal impairment or
hyperkalemia.

Monitoring
• Serum potassium and creatinine (baseline and twice
weekly), especially in the second week of amphotericin
B administration.
• Hemoglobin (baseline and weekly).
• Careful attention to fluid monitoring of intake and
output, and daily weight.

Management
• If significant hypokalemia (K <3.3mmol/l), increase potassium
supplementation to two KCL ampules (40 mmol), or one or
two 8mEq KCL tablets three times daily. Monitor potassium
daily.
• If hypokalemia remains uncorrected, double magnesium oral
supplementation.
• If creatinine increases by >2 fold from baseline value, either
temporary omission of an amphotericin B dose, or increase
pre-hydration to one liter 8 hourly. Once improved, restart at
0.7 mg/kg/day and consider alternate day amphotericin B.
• If creatinine remains elevated, discontinue amphotericin and
continue with fluconazole at 1200 mg/day. Monitor creatinine
daily

Managing intracranial pressure
• Intracranial pressure (ICP) is elevated in most
patients with cryptococcal meningitis and, if left
untreated, can lead to death.
• ICP should be measured at the time of lumbar
puncture using a manometer
• If opening pressure is >20 cm H20, remove 10-30 ml
CSF to reduce pressure by at least 50% or to <20 cm
H20

Managing ICP…………
• Remove not more than 30mls of CSF per day
when managing increased intracranial
pressure.
• If there is persistent pressure elevation >25
cm of water and symptoms of meningitis,
repeat lumbar puncture daily until the CSF
pressure and symptoms have been stabilized
for >2 days

Cryptococcal antigen screening when
CD4+ T-lymphocyte count <100 cells/µl
Initiate ART
No fluconazole
§
A lumbar puncture may be considered if
available.
†
Special situations include:
 Prior cryptococcal meningitis
 Pregnancy or breastfeeding
mothers
 Clinical liver disease
*
Symptomatic for meningitis if either of
the following is present:
1. Headache
2. Confusion
Start fluconazole 1200 mg daily and refer
immediately for lumbar puncture
Lumbar puncture (+)
POSITIVE
NEGATIVE
 Contact patient for urgent follow-up
 Screen for symptoms of meningitis*
 Check for special situations†
Symptomatic Asymptomatic§
Fluconazole 800 mg daily for
2 weeks then 400mg for 2weeks
as outpatient
Amphotericin B 0.7mg/kg/day IV + 5
Flucytosine 100mg/kg/day orally for
1week + Fluconazole 1.2g /day for 1
week followed by 800mg daily for
8weeks
Fluconazole 200 mg daily
Continue fluconazole for minimum of 1 year in total and discontinue
when patient has had two CD4 counts >200 taken at least 6 months
apart
Lumbar puncture (-)
Start ART after 2 weeks of antifungal
therapy
Start ART after 5 weeks of antifungal
therapy
.
CrAg screening and treatment algorithm

Patients who require special attention
1. Patients with prior cryptococcal meningitis
 Do not need to be routinely screened
 Ensure that they received adequate maintenance therapy for prior
episode of meningitis
 If new symptoms, need to be evaluated for relapse and/or IRIS
(Immune Reconstitution Inflammatory Syndrome)
2. Pregnancy or breastfeeding mothers
 Fluconazole can cause damage to the fetus
 Any woman of childbearing age who tests positive for cryptococcal
antigen should receive a pregnancy test
 If the patient is pregnant or breastfeeding, consultation with an
experienced medical practitioner is required
 Women of childbearing age who start taking fluconazole should avoid
getting pregnant while on this medication. They should be counselled
on using appropriate birth control
Module 5

Side effects of fluconazole therapy
Fluconazole is an oral medication with several
possible side effects including:
• Diarrhea, nausea, abdominal pain
• Headache, dizziness
• Rash
• Liver toxicity
• Teratogenicity (can cause damage to fetus,
especially during the 1st trimester)

Fluconazole drug interactions
Fluconazole can interact with other medications
• Patients on nevirapine should be monitored
closely for signs of liver toxicity because
combination use with fluconazole increases
nevirapine levels.
• Concomitant use of rifampicin and fluconazole
decreases levels of fluconazole in the blood.

Side effects of amphotericin B therapy
• Amphotericin B is an intravenous medication
with many potentially serious side effects.
• It should only be given in settings where side
effects and response to therapy can be closely
monitored.
• Serious side effects of amphotericin B therapy
include acute infusion reactions, renal toxicity,
and electrolyte abnormalities

Amphotericin drug interaction
• Amphotericin B and tenofovir have shared
renal toxicity
• If renal impairment develops consider
switching TDF to an alternative NRTIs

Immune reconstitution inflammatory syndrome
(IRIS)
• Clinical worsening or new presentation of cryptococcal
disease after starting ART is called cryptococcal immune
reconstitution inflammatory syndrome (IRIS).
• There are two types of IRIS: unmasking and paradoxical.
Unmasking IRIS refers to a new diagnosis of cryptococcal
disease after ART is started.
• Paradoxical IRIS refers to worsening of known existing
cryptococcal disease or recurrence of previously treated
cryptococcal disease.
• IRIS generally occurs in the first weeks to months after ART is
started, but can occasionally occur later

Factors favoring dx of CM IRIS
• Temporal association between starting ART and
clinical presentation (median 1 month post ART)
• Evidence of rapid immune restoration (sharp rise of
CD4 count from baseline)
• Clinical features (new or increased lymphadenopathy
or cytology CSF WBC)
• Because IRIS can be life-threatening, it is currently
recommended that ART-naïve patients diagnosed
with cryptococcal meningitis should receive some
anti-fungal therapy before ART is started.

Module 5: Preventing Cryptococcal Meningitis
Learning objectives
• Describe the importance of preventing
• Understand the advantages and disadvantages
of primary prophylaxis
• Describe the rationale behind cryptococcal
screening

Importance of preventing CM
• cryptococcal disease is common among
HIV/AIDS patients and is responsible for a
large number of deaths
• Cryptococcal meningitis may account for 20%
of early deaths among patients starting ART.
• In resource limited settings, lack of diagnostic
tools can lead to a delay in identifying
• Late diagnosis leads to poor treatment
outcome

Cryptococcal screening
• Cryptococcal screening is another strategy to
prevent deaths from cryptococcal meningitis
• Antigen test can detect CrAg in serum a
median 22 days (range 5-234) before
symptoms of meningitis develop1
• Highly predictive of who is at risk for
developing cryptococcal meningitis
• Possible to identify early cryptococcal disease,
prevent progression to meningitis through
early treatment

• Patients with low CD4 count can be screened
for CrAg (pin prick blood) and treated with
pre-emptive fluconazole if positive
• This process minimizes unnecessary
treatment for patients who are at lower risk of
getting sick from cryptococcus
• This decreases costs and concerns about drug
resistance, side effects, and safety.

1. Identify patients at risk (CD4 <100)
2. Test for cryptococcal antigenemia before
symptom onset
3. Treat with oral fluconazole
4. Prevent cryptococcal meningitis deaths
Treatment
+Serum CrAg
but no
symptoms
Meningitis
1. French et al., AIDS 2002
Module 4

Screen & treat saves lives
28% ↓ in all-cause mortality
Mfinanga S, et al. Lancet 2015
Module 4

WHO Recommendation for Screening
WHO Rapid Advice Guidelines on Cryptococcal Meningitis, 2016.
Module 4

Module 6: Decision-Making Guide for
Cryptococcal Screening
Learning objectives
• Use the decision-making guide to manage an
adult patient with a positive screening
cryptococcal antigen test
• Understand how cryptococcal screening fits
into routine HIV care

Decision-making guide (1)
• When you order a CD4 count test, the
laboratory should automatically perform a
cryptococcal antigen test on all patients
whose CD4 count is ?<100.
• A patient with a positive cryptococcal antigen
test should be contacted urgently to return to
the clinic for follow-up
• It is important to keep a detailed record of
patients’ contact information.

Decision-making guide (2)
• The patient should be assessed for symptoms
of meningitis and for special situations
• If the patient has any symptom of meningitis
will need a lumbar puncture.
• Patients with a LP that shows Cryptococcus in
the spinal fluid will need to be hospitalized for
two weeks of amphotericin B therapy

CrAg screening decision making

Patients with previous history of cryptococcal
meningitis
• Patients with a previous history of CM do not need to be
routinely screened.
• If the patient has new symptoms of meningitis, he/ she will
need to be evaluated for relapse disease and/or IRIS.
• If the patient does not have new symptoms, ensure that the
patient has received or is receiving adequate maintenance
therapy (fluconazole 200 mg until CD4 count >200 cells/µl on
ART and for a minimum of 12 months total) after being
treated with induction and consolidation therapy.

Patients on tuberculosis medications
• TB medications (including INH) and fluconazole can
be started at the same time.
• Because both fluconazole and TB medications can
damage the liver, these patients should preferably be
started on an efavirenz-based ART regimen.
• Patients should be monitored closely for signs of liver
damage and if present, then liver function tests
should be ordered

Pregnancy or breastfeeding mothers
• Fluconazole can be harmful to a fetus, all women of
childbearing age should have a pregnancy test.
• The risks, benefits and alternatives to fluconazole treatment
should be discussed with the patient.
• Mothers who are breastfeeding also require risk-benefit
assessment as fluconazole can be transmitted through breast
milk to the infant.
• Women of childbearing age who are not yet pregnant and are
starting fluconazole should be advised to avoid becoming
pregnant during treatment

Children
• Screening is not recommended for children as
CM is less common in this group.
• All children who are serum CrAg-positive
should be referred for lumbar puncture (LP).
• Children with a positive LP should be managed
according to WHO 2016 guideline

What should I do if a lumbar puncture cannot
be performed?
1. If a lumbar puncture is contraindicated but the patient is
symptomatic and has a positive serum CrAg test, the patient
should be treated with amphotericin B.
2. If a lumbar puncture cannot be performed because resources
are not available, the patient should be transferred to the
nearest facility where such services are available.
3. If a lumbar puncture cannot be performed because the
patient refuses the procedure, every effort at proper patient
education and discussion of risk and benefits should be made. If
the patient still refuses, he or she will need to be treated like a
patient for whom a lumbar puncture is contraindicated

How does screening fit into routine HIV care
• Like co-trimoxazole prophylaxis and isoniazid
preventive therapy (IPT), cryptococcal
screening and treatment of antigenemia with
oral fluconazole should be part of an
integrated care and treatment strategy for
HIV/AIDS patients.

Module 7: Your Role as a Health Care Provider
Learning objectives
• Understand what you can do as a health care
provider as part of the screening program for
cryptococcal antigen
• Be able to counsel your patients on
fluconazole adherence

What you can do as a health care provider
• Save lives by screening your patients and treating them with
oral fluconazole before symptoms of cryptococcal meningitis
develop.
• Counsel your patients on fluconazole adherence.
• Provide regular feedback to coordinators regarding the
program’s operation so that they can make improvements.
• Build awareness of cryptococcal meningitis by teaching other
health care providers about this screening strategy.

How to counsel your patients
• Patients should understand that cryptococcal
antigenaemia can be deadly if it is not treated
• Emphasize the importance of taking
fluconazole, even if the patient does not have
any symptoms
• patients should understand how many
fluconazole pills to take.

Routine Cryptococcal screening & Treatment in CTCs (1).pptx

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