A medical Case of Cryptococcal Meningitis involving the Renal side effects of treatment

1. CASE PRESENTATION;
CRYPTOCOCCAL
MENINGITIS
PRESENTER:
17/01/17

2. GENERAL DATA
• Ms XX
• 29 year old female
• Swazi
• Unemployed

3. CHIEF COMPLAINT
21/11/17
•Severe frontal headache, not relieved by analgesia
and vomiting for about 1 week.

4. PRESENT ILLNESS
• Severe frontal headache not relieved by analgesics, accompanied by vomiting and
neck stiffness. In addition, patient has oral thrush.
• RVD positive, but not on treatment, not clear why
• No history of any chronic diseases
• Travel hx: nil
• VITALS;
• T: 36.4
• P: 67
• BP: 125/71
• RBS: 6.6

5. PHYSICAL EXAM
GE;
•Chronically ill-looking, confused with slurred speech
•Dehydrated, Mild pallor
•Oral thrush, Pruritic rash on trunk
•CVS: S1S2-N, no added sounds
•RESP: GAEB
•ABD: SNT, no organomegally

6. • CNS:
• Lethargic, slurred speech, gait disturbance
• Brudzinki’s sign + ..Neck stiffness
• Kernig’s sign +

7. PLAN
• LP; CSF
Crypto Ag, microscopy, India ink, Zeihl-Neelson, culture
• Bloods; FBC, U E & Cr
• Manage as bacterial meningitis
• Trace results in the ward; adjust Rx
• Consult dermatologist in ward

8. OPD PRESCRIPTION 21/11/17
• Rocephin 2g IV stat
• Panado 1g PO TDS x3D

9. LAB FINDINGS 21/11/17TEST RESULT NORMAL RANGE UNITS
WBC 6.28 3.60 – 9.60 x10*3/uL
RBC 4.14 4.20 – 5.40 x10*6/uL
Hb 12.0 12.0 - 15.0 g/dl
MCV 84.7 82.0 – 97.0 FL
Platelet 182 150 – 450 x10*9/l
Creatinine 46 53 - 97 mmol/L
BUN 2.1 2.9 – 9.3 mmol/L
Na 129 136-144 mmol/L
K 3.3 3.5 – 5.5 mmol/L
Ca 2.33 2.10 – 2.55 mmol/L

10. • Plasmodium Falcipurum Ag……. Negative
• VDRL/RPR???

11. CSF findings 21/11/17
MICROSCOPIC;
Clear supernatant appearance
 WBC; 0-2 /HPF
 RBC; 0-3/HPF
INDIA INK; scanty
ZEIHL NEELSON; No AFB seen
GRAM STAIN; Yeast cells <5
CRYPTOCOCCAL antigen; out of stock
CULTURE: pending

12. CSF analysis cont….
component result Normal range units
chloride 125 120 - 130 mmol/L
glucose 2.4 2.2 – 3.9 Mmo/L

13. DIAGNOSIS
• Cryptococcal meningitis
• Oral candidiasis
• Pityriasis rosea
• RVD pre-ART

14. MANAGEMENT
21/11/17
•Amphotericin B 50mg IV in 5% dextrose saline over 4-6 hrs x14D
•IV N/S 1L Q12H
•Nystatin susp 1m QID
•Paracodeine 1G PO TDS
22/11/17
•CTX 960 mg PO BD
•Consult VCT

15. Derma prescription
• Emmulsifying ointment x7D
• 1% hydrocortisone cream BD x7D
• Allergex 4mg nocte x7D

16. 23/11/17
test RESULT NORMAL RANGE UNITS
WBC 3.50 3.60 – 9.60 x10*3/uL
RBC 3.61 4.20 – 5.40 x10*6/uL
Hb 10.4 12.0 - 15.0 g/dl
MCV 83.6 82.0 – 97.0 FL
Plateletes 121 150 – 450 x10*9/l
Creatinine 56 53 - 97 mmol/L
BUN 2.2 2.9 – 9.3 mmol/L
Na 137 136-144 mmol/L
K 2.9 3.5 – 5.5 mmol/L
Ca 2.31 2.10 – 2.55 mmol/L

17. • A;
Anemia
Hypokalemia
• P;
KCl 600mg PO OD
Fefol 2 tabs BD

18. 30/11/17
test RESULT NORMAL RANGE UNITS
WBC 11.51 3.60 – 9.60 x10*3/uL
RBC 2.84 4.20 – 5.40 x10*6/uL
Hb 8.5 12.0 - 15.0 g/dl
MCV 86.0 82.0 – 97.0 FL
Plateletes 154 150 – 450 x10*9/l
Creatinine 170 53 - 97 mmol/L
BUN 10.7 2.9 – 9.3 mmol/L
Na 136 136-144 mmol/L
K 2.9 3.5 – 5.5 mmol/L
Ca 2.03 2.10 – 2.55 mmol/L
ALP 94 38- 126 U/l
GGT 86 7 - 50 U/l

19. PLAN
• A;
• AKI
• Anemia
• P;
• Hydration: IVI NS 1L 8Hrly
• Repeat bloods on Monday 04/11, FBC, KFT, LFT, electrolytes

20. Patient condition update
• Well oriented
• No neck stiffness
• No headache
• No vomiting
• Jaundice +

21. 04/12/17- Ampho B, D12
test RESULT NORMAL RANGE UNITS
WBC 8.01 3.60 – 9.60 x10*3/uL
RBC 2.49 4.20 – 5.40 x10*6/uL
Hb 7.6 12.0 - 15.0 g/dl
MCV 86.4 82.0 – 97.0 FL
Plateletes 188 150 – 450 x10*9/l
Creatinine 221 53 - 97 mmol/L
BUN 31.1 2.9 – 9.3 mmol/L
Na 124 136-144 mmol/L
K 5.6 3.5 – 5.5 mmol/L
Ca 2.23 2.10 – 2.55 mmol/L
ALP 291 38- 126 U/l
GGT 243 7 - 50 U/l
HBsAg negative

22. DISCUSSION

23. INTRODUCTION
• Although the genus Cryptococcus contains more than 50 species, C
neoformans and C gatti are considered principal pathogens.
• Cryptococcal neoformans is an encapsulated yeast, first described in 1984, by a
pathologist, Busse.
• The most serious infections usually develop in patients with defective cell
mediated-immunity.

24. PATHOGENESIS
• C neoformans can cause an asymptomatic pulmonary infection, followed later by the
development of meningitis.
• Following inhalation through the respiratory tract, the yeast spores are transmitted
into the pulmonary alveoli, where they are phagocytosized by alveolar macrophages.
• If confined to the lungs, it can cause pneumonia, poorly defined mass lesions,
pulmonary nodules, and rarely, pleural effusion.
• The organism disseminates hematogenously and has a propensity to localize to the
central nervous system (CNS).

25. Why the CNS?
• It is uncertain, but a number of hypotheses have been proposed:
• The CSF is a favorable growth medium. In the serum, the organism activates
the alternative complement pathway, but complement activity in the CSF is
very low.
• Dopamine levels in the CNS may promote cryptococcal virulence by serving
as a substrate for melanin production by the organism.
• Production of mannitol by the organism may contribute to brain edema and
inhibit phagocyte function

26. EPIDEMIOLOGY
• GLOBALLY,
• ~957,900 cases of CCM yearly, with more than 600,000 deaths.
• majority among patients with AIDS and a CD4 count <100 cells/microL.
• region with the highest number of estimated cases in 2006 was sub-Saharan
Africa (720,000 cases; range, 144,000 to 1.3 million),
• followed by South and Southeast Asia (120,000 cases; range, 24,000 to
216,000)

27. • MBABANE GOVT HOSP 2016/17
OCT NOV DEC JAN FEB MAR APR MAY JUN JUL AUG SEP
w18 5 4 2 1 0 2 0 1 3 1 2 3
w12 2 1 0 0 1 0 2 1 0 0 2 2

28. DIAGNOSIS
• CCM suspected in patients with advanced HIV infection (CD4 cell count
<100 cells/microL) who have isolated fever and headache.
• Initial evaluation includes a careful history, neurologic exam, and serum
cryptococcal antigen.

29. • LP to obtain CSF
• CSF analysis;
Cryptococal culture - cream-colored mucoid colonies
India ink staining - typical round encapsulated yeast organisms
• Cryptococcal antigen (CrAg) - latex agglutination, sandwich enzyme-linked
immunosorbent assay (ELISA) and lateral flow assay (LFA)

30. MANAGEMENT
• The initial preferred approach to the patient with CCM includes;
induction phase; combination antifungal therapy with
amphotericin B plus flucytosine.
consolidation phase; fluconazole.

31. MONITORING
• During therapy, patients should be monitored for recurrence of clinical
symptoms that may suggest
increased intracranial pressure,
relapse of infection (from lack of adherence or drug resistance),
 adverse events related to antifungal therapy, and
immune recovery syndromes secondary to antiretroviral therapy (ART).

32. Intracranial pressure
• frequent monitoring is needed for individuals with evidence of increased ICP
(defined as ICP>20 cmH2O) and persistent symptoms.
• Some individuals are asymptomatic, therefore, difficult to assess clinically.
• ICP should be measured at the time of initial LP, if the patient has persistant
symptoms, and when repeat fungal cultures are obtained after 2 weeks of induction
therapy.
• LP, which leads to transient improvement in ICP, can be life-saving.

34. Drug resistance testing
• resistance considered if the CSF has not been sterilized after two weeks, or if
a patient has relapsing infection.
• A cryptococcal isolate be evaluated for changes in the minimum inhibitory
concentration (MIC) against the antifungal agent that is being administered.
• a threefold increase in MIC from the pre-treatment isolate to the on-
treatment isolate would suggest emerging drug resistance.
• An absolute MIC of >16 mcg/mL for fluconazole or >32 mcg/mL for
flucytosine for a single isolate may also be suggestive of drug resistance

35. Adverse events
• Amphotericin B deoxycholate is frequently associated with
electrolyte disturbances,
anemia, renal insufficiency, and
 infusion site reactions, such as drug fever and rigors.
• daily monitoring of serum creatinine and electrolytes
• Some require significant amounts of K and/or Mg supplementation during
therapy and hydration with NS during amphotericin B infusions.

36. • Flucytosine is mainly associated with gastrointestinal intolerance.
Laboratory abnormalities include elevations in aminotransferases, anemia,
leukopenia, and thrombocytopenia.
• Fluconazole is generally well tolerated; patients occasionally may develop
rash or abnormal aminotransferases.

37. Sterilization of cerebrospinal fluid
• LP is repeated for fungal culture after two weeks of induction antifungal
therapy to confirm sterilization of the cerebrospinal fluid (CSF), even among
patients who have clinically improved.
• The opening pressure should also be measured at that time

39. Lipid based Ampho B
• UWHC guidelines; The newer lipid-based formulations of amphotericin B
are less likely to cause elevations in serum creatinine than conventional
amphotericin B deoxycholate (AmB).
• Available studies indicate comparable efficacy.
• The lipid-based formulations are usually used as second-line agents because
they are much more expensive than the conventional formulation.

42. TAKE HOME MESSAGE
• Patients with advanced HIV infection (CD4 cell count <100 cells/microL) who have
isolated fever and headache; suspect CCM.
• LP and CSF analysis to confirm diagnosis. Serum latex agglutination may also be used
• Monitoring of patient symptoms and drug adverse effects is very crucial during
management.
• Lipid based Ampho B formulations have comparable efficacy with less side effects…but
expensive.
• Combination of Ampho B with flucytosine leads to faster and increased sterilization of
CSF from crypto Ag.

44. REFERENCES
• Cox, G M and Perfect, J R, 2017. Clinical management and monitoring during antifungal therapy of the
HIV-infected patient with cryptococcal meningoencephalitis. Extracted from UpTodate, 10/12/17.
• Goshman, L. 2009. UWHC Guidelines For the Use Of Lipid-Based Amphotericin B Products In Adults
and Children. Guidelines developed by UWHC Center for Drug Policy (CDP)
• Rolfes MA, et. al. 2015. The effect of therapeautic lumber puncture on acute mortality from cryptococcal
meningitis. Clin infection 2014, 59 1607-14.
• Sloan D, Dlamini S, Paul N, Dedicoat M. 2008. Treatment of acute cryptococcal meningitis in HIV
infected adults, with an emphasis on resource-limited settings. Cochrane Database of Systematic Reviews
2008, Issue 4. Art. No.: CD005647. DOI: 10.1002/14651858.CD005647.pub2.
• Viviani ET. AL., 1994. Lipid-based amphotericin B in the treatment of cryptococcosis. Springer Link. 22:
137.https://doi.org/10.1007/BF01739025