Cryptococcal meningitis is a serious opportunistic fungal infection which occur most in severe immunocompromised patients caused by pathogenic yeast species of the cryptococcus genus called Cryptococcus neoformans which spreads from the lungs to the brain It is the most common central nervous system (CNS) fungal infection, affecting individual with weaken body immune system The condition is rare in healthy person Immunosupression resulting from HIV, places a patient at risk for infection from different organisms that are other wise relatively mildly hazardaus and that would normally be cleared by a competent immune system, The other oppotunistics diseases includes, -Pneumocystis jirovecii pneumonia -Toxoplasmosis -Cytomegalovirus infections -Tuberculosis -Disseminated mycobacterium avium complex Globally, approximately 957,900 cases of cryptococcal meningitis occur annually, resulting in 624,700 deaths within 3 months of infection in HIV-infected adults and children. Cryptococcal meningitis associated with HIV infection is responsible for more than 600,000 deaths per year worldwide In sub-Saharan Africa, 15%-30% of all patients with AIDS develop cryptococcal disease Mortality rate of is 20%, 55%, 70% in high income , low and middle income and sub- saharan africa countries respectively In Tanzania it accounts btn 13%- 44% of death of HIV infected individual, it is more common in male children than female Risk factors; Advanced HIV /AIDS Cirrhosis Solid organ transplantation Systemic lupus erythematous Advanced Malignant eg leukemia, lyphoma Sarcoidosis Diabetes Long term use of corticosteroid Disseminated Cryptococcus neoformans infection begins in the lungs by inhalation of spores, which in nature are dry, minimally capsulated and easily aerosolized Primary pulmonary infection is self limiting In immunocompitent patients the isolated pulmonary lesion usually heal spontaneously without disseminating even without ant fungal therapy In immunocompromised patients cryptococcus may disseminate frequently through blood stream to other parts of the body but preferentially the central nervous system (brain and meninges) causing cryptococcal meningoencephalitis where by typically manifestating as microscopic multifocal intra cerebral lesions may be evident The infection is more properly characterized as "meningoencephalitis" rather than meningitis since the brain parenchyma is almost always involved on histologic examination Although pulmonary involvement is rarely dangerous , cryptococcal meningitis is life threatening and requires aggressive therapy Focal sites of dissemination may also occur in skin, end of long bone, joints, liver, spleen, kidney, prostate, and other tissues All these cause few or no symptoms but rarely , pyelonephritis with renal pappillary necrosis If tissue involved typically contain cystic masses of yeast with or without inflammatory changes Drugs Amphotericin B Flucytosine and Fluconazole

1. Cryptococcal meningitis
Pendo Chaula
Mmed 3

2. Introduction
• Cryptococcal meningitis is a serious opportunistic fungal infection
which occur most in severe immunocompromised patients caused
by pathogenic yeast species of the cryptococcus genus called
Cryptococcus neoformans which spreads from the lungs to the brain
• It is the most common central nervous system (CNS) fungal infection,
affecting individual with weaken body immune system
• The condition is rare in healthy person

3. • Immunosupression resulting from HIV, places a patient at risk for infection from
different organisms that are other wise relatively mildly hazardaus and that would
normally be cleared by a competent immune system,
• The other oppotunistics diseases includes,
-Pneumocystis jirovecii pneumonia
-Toxoplasmosis
-Cytomegalovirus infections
-Tuberculosis
-Disseminated mycobacterium avium complex
(Tinashe et al.2016)

4. • Globally, cryptococcal meningitis is a leading cause of mortality among
hospitalized adults living with HIV, but is less common among children
living with HIV
• It is most likely to occur in people who have a low CD4 count less
100cells /mm3
• For many years before the development of effective antirectroviral
therapy these infections inflicted significant morbidity and mortality in
patients living with AIDS but has decreased by 90% in US due to effective
use of AR

5. • It can also rarely occur to HIV seronegative children
• Though the condition is uncommon in children, it should be ruled out
when symptoms and/or signs of meningitis are observed or when fever
without a clear source causes severe headache
• Suspect Cryptococcus as a cause in any HIV-infected child with signs
of meningitis, Preventive therapy for cryptococcal antigen–positive
asymptomatic people is a key strategy to prevent cryptococcal
meningitis related mortality
(Topley and Wilson's Microbiology and Microbial Infections, 9th Ed, Edward LA (Ed), Arnold Press, London 1997-) medscape)
(Guo et al. 2016)

6. Epidemiology
Globally, approximately 957,900 cases of cryptococcal meningitis occur
annually, resulting in 624,700 deaths within 3 months of infection in
HIV-infected adults and children.
Cryptococcal meningitis associated with HIV infection is responsible
for more than 600,000 deaths per year worldwide
In sub-Saharan Africa, 15%-30% of all patients with AIDS develop
cryptococcal disease
Mortality rate of is 20%, 55%, 70% in high income , low and middle
income and sub- saharan africa countries respectively
In Tanzania it accounts btn 13%- 44% of death of HIV infected
individual, it is more common in male children than female
 ( Wajanga et al .2011)

7. The risks factors ( immunosuppressive
conditions
• Advanced HIV /AIDS
• Cirrhosis
• Solid organ transplantation
• Systemic lupus erythematous
• Advanced Malignant eg leukemia, lyphoma
• Sarcoidosis
• Diabetes
• Long term use of corticosteroid
(Andres F. Henao-Martinez et all, 2016)

8. Pathogenesis
• Disseminated Cryptococcus neoformans infection begins in the lungs
by inhalation of spores, which in nature are dry, minimally capsulated
and easily aerosolized
• Primary pulmonary infection is self limiting
• In immunocompitent patients the isolated pulmonary lesion usually
heal spontaneously without disseminating even without ant fungal
therapy

9. • In immunocompromised patients cryptococcus may disseminate frequently
through blood stream to other parts of the body but preferentially the
central nervous system (brain and meninges) causing cryptococcal
meningoencephalitis where by typically manifestating as microscopic
multifocal intra cerebral lesions may be evident
• The infection is more properly characterized as "meningoencephalitis"
rather than meningitis since the brain parenchyma is almost always
involved on histologic examination
• Although pulmonary involvement is rarely dangerous , cryptococcal
meningitis is life threatening and requires aggressive therapy

10. • Focal sites of dissemination may also occur in skin, end of long bone,
joints, liver, spleen, kidney, prostate, and other tissues
• All these cause few or no symptoms but rarely , pyelonephritis with
renal pappillary necrosis
• If tissue involved typically contain cystic masses of yeast but acute
inflammatory changes are minimal or absent

12. Transmission
• The directly inhaling of spores( soil particles contaminated by bird –
pigeon droppings) from the environment
• The infection cannot spread from person to person

13. Signs and symptoms
• The presentation in cryptococcosis varies with the site of infection and the
patient’s immune status
• The symptoms developed gradually within a few days to weeks of
exposure to lungs
immunocompetent patients(pulmonary)
• Cough (54%)
• Cough with the production of scant mucoid sputum (32%)
• Pleuritic chest pain (46%)
• Low-grade fever, dyspnea, weight loss
• Malaise (less common)

14. Hiv-infected patients (Pulmonary)
• Fever (84%)
• Cough (63%)
• Dyspnea (50%)
• Headache (41%)
• Weight loss (47%)
Other possible findings in pulmonary infection are as follows
• Pleuritic pain
• Hemoptysis
• Rales or pleural rub
• Acute respiratory distress syndrome (ARDS

15. Meningitis and meningoencephalitis ( CNS)
Common symptoms are as follows
• Headache
• Confusion
• Lethargy
• Obtundation
• Coma
• Normal or mildly elevated temperature
• Nausea and vomiting (with increased intracranial pressure)
• Fever and stiff neck (with an aggressive inflammatory response; (Less
common)
• Blurred vision, photophobia, and diplopia
• Hearing defects, seizures, ataxia, aphasia, and choreo athetoid
movements

16. Skin and cutenous tissue
Cutaneous manifestations (10-15% of cases) are as follows
• Papules, pustules, nodules, ulcers, or draining sinuses
• Umbilicated papules in patients with AIDS.
• Cellulitis with necrotizing vasculitis in organ transplant recipients

17. Other less common forms of cryptococcosis
• Optic neuritis or endophthalmitis
• Myocarditis
• Chorioretinitis
• Hepatitis
• Peritonitis
• Renal abscess
• Myositis
• Adrenal involvement
(Medscape updated may 2021)

18. Differential diagnosis
• Pyogenic, Nocardial Or Aspergillus Abscess.
• Bacteria Meningitis
• Mycobacterial Tb Infection
• Histoplasma Capsulatum
• Acanthamoeba Infection
• Neuro syphylis
• Lymphomas
• Lymphatic Meningitis
• Meningeal Metastases
• Intracranial Haemorrhage

19. Complication
• Seizure disorder
• Hearing loss
• Repeated
• Brain damage or atropy
• hydrocephalus.
• Meningeal enhancement and local lesion
• Coma.
• Repeated cryptococcal infection
Guo et al, 2016)

20. Diagnosis
Diagnosis based on
• Proper history taking and physical examination
• Blood: Fungal culture, cryptococcal serology, and cryptococcal
antigen testing
• Cerebrospinal fluid: India ink smear, fungal culture, and cryptococcal
antigen testing
• Urine and sputum cultures, even if renal or pulmonary disease is not
clinically evident
• Cutaneous lesions: Biopsy with fungal stains and cultures
• In AIDS patients with cryptococcal pneumonia, culture of
bronchoalveolar lavage washings

21. -Chest x- ray
• radiographic findings in patients who are asymptomatic and
immunocompetent may include the following:
• Patchy pneumonitis
• Granulomas ranging from 2-7 cm
• Miliary disease similar to that in tuberculosis
-CT and MRI –PRIOR performing lumber puncture
• To patients who present with focal neurologic deficits or a history
compatible with slowly progressive meningitis
• If a mass lesion is identified, do not perform a lumbar puncture to
obtain spinal fluid; rather, consult a neurosurgeon for an alternative
procedure.

22. The criteria for diagnosis
-The definitive diagnosis is determined if at least one of the following
• Positive culture of cryptococcus from cerebral spinal fluid
• the positive india ink smear of CSF centrifuged sediment for
cryptococcus
• Positive cryptococcal antigen findings in the CSF and OR in the
blood

23. 9. Treatment
• Although current HAART regimens have substantially and dramatically
decreased AIDS-related OIs and deaths, prevention and management
of OIs remain critical components of care for HIV-infected children
• The management of cryptococcal meningitis should be done in
phases as per guideline
-Induction phase
-Consolidation phase
-Maintanance phase
(Mahsa Abassi et al.2016)

24. Common antifungal used
• Amphotericin B
• Flucytosine
• fluconazole

25. Induction phase
• Goal is rapid sterilization of CSF
• The drugs to treat cryptocaccal meningitis are given in form of
combination therapy.
-Treat with amphotericin B 0.7 -1.0mg/ kg per day intravenously in
14 days.
• Then in combination with.
-Flucytosine 100mg /kg/day divided into 4 doses orally per day for 7
days followed by 2mg/kg/day up to the maximum dose of 800mg
daily.

26. In the absence of flucytosine or costly , the altenaltive therapy should
be Amphotericin B 0.7-1 mg /kg/day i/v for 14 days (if liposomal
amphotericin B is available give 3-6mg /kg i/v for 10days) and
fluconazole 6-12mg/kg i/v/oral once daily for 14 days.

27. Consolidation phase
Fluconazole 400mg -800mg for 8weeks based on patient response to
induction phase
Start 2weeks after of induction therapy
It can be used until documentation of CSF sterility and ART initiation
It decreases the risk of persistent infection, disease relapse or IRIS
however The guideline support the use of long duration of high dose
fluconazole through the consolidation phase for about 3-4 month

28. Maintanance phase
After successful induction and consolidation therapy the culture
negative patients should be placed on fluconazole 6mg /kg ( maximum
200mg/day) for yrs
Discontinue maintanance treatment if;
CD4 ≥ 100 with undetected < 50copies viral load
CD4 ≥ 200 if viral load monitoring not available
It recommended to initate ART 5 weeks after initiation of cryptococcal
meningitis treatment to prevent IRIS and reduce mortality

29. Amphotericin B has better efficacy but had substantial toxicity
• Kidney Damage( Reversible)
• Muscle and joint pain
• Anaemia
• Hypokalaemia and hypomagnesamia hypokalaemia- require
electrolyte monitoring and supplentation to prevent life threatening
hypotension
• Thrombophlebitis and peripheral venous thrombosis
• Fever
• Rigors
• Nausea and vomiting

30. Prognosis
• The disease is the infrequent disease with high fatality rate in children
if not diagnosed and treated quickly
• The factors related to poor prognosis in are;
-Cerebral hernia
-Hydrocephalus
-Consciousness disorder
-Visual impairments
-intracranial pressure more than 300mmH2o in CSF

31. Prevention
• Targeted screening aproach because the C. Neofomans is able
to live in the body undetected especial when immune system is
weaker than normal
• Cryptococcal antigen screening-
-simple blood test is used to both adult, adolescent and children as
per WHO guideline to identify the risk of cryptococcal meningitis
development during the management of people with advanced
HIV infection
-Able to detect cryptococcal antigen in serum a median of 22 days
before symptoms of meningitis develop( silent cryptococcal
meningitis)
-Helping to reduce HIV related mortality globally and Africa in
particular.

32. • Use of primary Antifungal prophylaxis is recommended in patients with
advanced HIV infection
• Fluconazole
• Itraconazole
(Richard Ssekitoleko et al 2014)
Proper HIV counseling and testing
Early Initiation of ART to all clients tested positive for HIV( test and treat)
Early diagnosis and treatment of the disease to prevent disease
complication.