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Case Presentation. 42 yo African female admitted to HCM with papular rash x 3 monthsBegan on back, then spread to involve face and extremities (UE>LE) 2 months prior to admission pruritisAlso had headache at the time of initial presentationAdmitted to HC Machava when Sx first began and was follo
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2. Learning Objectives To discuss the challenges of managing cryptococcal disease in Mozambique and other resource limited settings
To discuss strategies for prevention of severe cryptococcal disease in areas of high disease burden (such as sub-Saharan Africa)
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3. Case Presentation 42 yo African female admitted to HCM with papular rash x 3 months
Began on back, then spread to involve face and extremities (UE>LE) 2 months prior to admission
+pruritis
Also had headache at the time of initial presentation
Admitted to HC Machava when Sx first began and was followed in Dermatology clinic there.
Also developed shortness of breath with dry cough 2 days prior to admission
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4. Additional Information HIV+, on ART x 3 months (?regimen)
CD4 count unavailable (followed at outside hospital)
No previous history of skin rash
Family/social history, medication list, and allergies not obtained in ED when family members were present.
ROS: No fevers, nausea, vomiting, or diarrhea; had been unable to walk prior to presentation
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5. Physical Examination T 37.2°C, HR 80, RR 40, BP 120/80, SpO2 not done
ill-appearing, tachypneic, prostrate
oral thrush
mild nuchal rigidity
scattered rales & rhonchi on pulmonary exam
Neuro exam limited due to altered mental status, normal strength, 1+ DTR’s bilaterally, negative Babinski, pupils equal and reactive
Skin: diffuse papular and vesicular lesions involving back, chest, extremities (palms and soles spared), and face; perineal region also spared
Many lesions were umbilicated
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10. Laboratory Data FBC
WBC 7.10 x 103/µL
89%N, 7%L, 3%M, 1%E
Hgb 10 gm/dL
Hct 28.4%
MCV 85 fL
Plt 228 x 103/mcL
ESR 130 mm/hr
Chemistries
Na 130, K 4.6, normal glucose
AST 60, ALT 24, ALP 201, GGT 223, LDH 625, tbili 9.1 µmol/L (normal), TP 75 gm/L (65-81 ), alb 24 gm/L (35-50)
BUN 10.5 mmol/L
Normal 2.5-6.4
Creatinine 98.4 µmol/L
Normal 53-115
Malaria smear negative
RPR NR
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11. CSF Studies Opening pressure not grossly elevated, but equipment to measure was not available.
Clear, colorless fluid
TP 0.38 grams/L (normal), glucose 50 mg/dL (normal), Cl 129 mmol/L (normal)
No cells were observed
Gram stain negative; culture sent
India ink positive, CRAG negative
VDRL negative
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12. Chest X-ray 12
13. A diagnostic procedure had been performed prior to patient’s admission.. 13
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16. How do you interpret this patient’s CSF results? A) The India ink was falsely positive, and the patient does not have cryptococcal meningitis.
B) The CSF CRAG was falsely negative, and the patient has cryptococcal meningitis.
C) A laboratory error likely occurred, and this CRAG result was for a different patient.
D) The positive India ink is likely due to contamination from the patient’s skin lesions during the lumbar puncture.
E) None of the above (other) 16
17. How would you treat this patient? A) Treat for disseminated cryptococcosis, bacterial pneumonia, and Pneumocystis (including steroids if indicated).
B) Treat for disseminated cryptococcosis, bacterial pneumonia, and Pneumocystis (without steroids even if indicated).
C) Treat for disseminated cryptococcosis and bacterial pneumonia.
D) Treat for disseminated cryptococcosis and continue ARV’s.
E) Other 17
18. Hospital Course Initially started on ceftriaxone, hydrated with NS, and given paracetamol prn
Started on oral fluconazole (600 mg BID) when results returned on HD2
Switched to amphotericin B on HD3
Died on HD3 (?cause)
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19. Additional Information Skin biopsy was performed on 05/08/2010.
Results were available on 16/08/2010.
Patient was admitted to HCM on 09/09/2010.
Patient was on no antifungal treatment at the time of hospital admission. 19
20. Cryptococcal Disease in Africa Sub-Saharan Africa has the highest burden of cryptococcal disease worldwide.
Median incidence of 3.2% among all HIV+ individuals
720,000 cases annually
High mortality rates (20-50%) even with ART
Most cases reported with CD4=100 in ART-naïve pts or as “unmasking” of undiagnosed infection in setting of ART 20 Meya et al, CID 2010;51(4):448-455
21. Strategies to Prevent CM-related Mortality Earlier HIV diagnosis and ART initiation prior to AIDS
Primary fluconazole prophylaxis in patients with AIDS
Screening and treatment for occult cryptococcemia 21 Meya DB et al, CID 2010;51(4):448-55
22. CRYPTOPRO Study 1,519 ART-naïve patients in eastern Uganda randomized to receive fluconazole 200 mg 3x/week or placebo
All had CD4<200, those with + serum CRAG excluded
Primary outcomes:
Invasive cryptococcal disease
All-cause mortality
Subjects enrolled in ART program (median time to ART 11 weeks, IQR 7-17)
Similar baseline characteristics (median CD4 111, 65% female)
22 Parkes-Ratansh R et al, 16th Annual CROI, Abstract 32
23. Cryptococcal Events 23 Parkes-Ratansh R et al, 16th Annual CROI, Abstract 32
24. All-Cause Mortality 24 Parkes-Ratansh R et al, 16th Annual CROI, Abstract 32
25. Summary of Results 25 Parkes-Ratansh R et al, 16th Annual CROI, Abstract 32
26. CRAG Screening Prior to ART Antigenemia is detectable for a median of 22 days prior to onset of symptoms in pts with cryptococcal disease.
Detectable in 11% of patients >100 days prior to symptoms
Is this an opportunity to test and start antifungal therapy prior to initiation of ART in patients with low CD4 counts? 26 French N et al, AIDS 2002;16:1031-8
27. CRAG Screening in RSA CohortJarvis JN et al, CID 2009;48:856-62 Retrospective analysis of well-characterized clinical cohort in Cape Town of patients started on ART according to WHO 2002 guidelines
CRAG testing on blood plasma samples collected prior to and (for subset) 16 weeks after ART initiation
Meridian Cryptococcal Latex Agglutination System used, validated for BP specimens
Primary Endpoints:
Antigenemia (=1:2) at baseline
Microbiologically confirmed cryptococcal meningitis in first year of follow-up 27
28. Baseline Characteristics and Outcomes (all patients) 28
29. Baseline Characteristics and Outcomes (CD4=100) 29
30. Antigenemia and Clinical Outcomes CRAG+ patients had much higher mortality risk than CRAG- patients during 1-year follow-up, regardless of history of disease
14/41(34%) CRAG+ vs. 64/574(11%), p<0.001
Adjusted hazard ratio 3.2 (95%CI 1.5-6.6, p<0.01)
Mortality risk strongly associated with antigen titer. 30 Jarvis JN et al, CID 2009;48:856-62
31. 31 Jarvis JN et al, CID 2009;48:856-62
32. What about screening and treatment? Cost-effectiveness analysis of CRAG screening of patients with CD4=100 at time of ART initiation in Uganda (Meya DB et al, CID 2010;51(4):448-55)
Data analyzed from prospective cohort of 609 patients
Initiated on ART if CD4=200 or WHO Stage IV
d4T or AZT/3TC/NVP or EFV; all received CTZ
Qualitative serum CRAG performed in all (Wampole Laboratories)
Median follow-up period: 3.9 years (min. 2.5)
17 pts with prior known history of cryptococcosis were excluded. 32
33. Model Characteristics 2010 cost of CRAG testing at this center was US$16.75
NHLS cost US$5.61
Cost of fluconazole not included in model
Average anti-fungal use was less in screened/treated group than in untreated group
33 Meya DB et al, CID 2010;51(4):448-55
34. Results Of 295 patients with CD4=100 and no prior history of CM, 26 were CRAG+ (8.8%, 95%CI 5.8-12.6%)
21 given fluconazole (200-400 mg x 2-4 wks)
Mortality rate of 42% (11/26, 95%CI 23-63%) in CRAG+
6(29%) of fluconazole-treated pts (3 from CM)
5(100%) of ART-only group died within 2 months of ART (2 from CM) 34 Meya DB et al, CID 2010;51(4):448-55
35. Cost-effectiveness Analysis(for CRAG+, CD4=100, no prior Hx CM) Number needed to test to detect 1 CRAG+ person = 11.3 (95%CI 7.9-17.1)
Number needed to screen & treat to prevent 1 death = 15.9 (95%CI 11.1-24)
Cost to detect 1 asymptomatic person = US$190 (95%CI $132-$286)
Cost to save 1 life within first month of ART with preemptive Tx = US$266 (95%CI $185-$402) 35 Meya DB et al, CID 2010;51(4):448-55
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37. Issues to Consider Cost of implementing new preventive measures in already overburdened health care systems
Risk of selecting for fluconazole resistance (Cryptococcus, Candida species)
Dose of fluconazole for preemptive treatment
In which asymptomatic patients with antigenemia should LP be done to rule out meningeal involvement? 37
38. Points for Discussion What is the best way to decrease the burden of severe cryptococcal disease in sub-Saharan Africa?
What is the best way to prevent complications of cryptococcal meningitis in areas where manometers to measure CSF opening pressure are not available? 38
39. Based on currently available data, what is the best approach for the prevention of severe cryptococcal disease in patients starting ART areas of high disease burden? A) CRAG screening of patients with CD4=100 and treatment with fluconazole (200-400 mg) in CRAG+.
B) CRAG screening of patients with CD4=100 and treatment with fluconazole (800 mg) in CRAG+.
C) Prophylactic fluconazole (200-400 mg) for all patients with CD4=200.
D) Prophylactic fluconazole (800 mg) for all patients with CD4=200.
E) CRAG screening of patients with CD4=200 and treatment with fluconazole (200-400 mg) in CRAG+.
F) CRAG screening of patients with CD4=200 and treatment with fluconazole (800 mg) in CRAG+.
G) None of the above (Other) 39
40. Obrigado pela atenção!Thank you for your attention! 40