CONCISE COMMUNICATION

Estimation of the current global burden of

cryptococcal meningitis among persons living with
HIV/AIDS
Benjamin J. Parka, Kathleen A. Wannemuehlerb, Barbara J. Marstonc,
Nelesh Govenderd, Peter G. Pappase and Tom M. Chillera

Objective: Cryptococcal meningitis is one of the most important HIV-related oppor-

tunistic infections, especially in the developing world. In order to help develop global
strategies and priorities for prevention and treatment, it is important to estimate the
burden of cryptococcal meningitis.
Design: Global burden of disease estimation using published studies.
Methods: We used the median incidence rate of available studies in a geographic
region to estimate the region-specific cryptococcal meningitis incidence; this
was multiplied by the 2007 United Nations Programme on HIV/AIDS HIV
population estimate for each region to estimate cryptococcal meningitis cases. To
estimate deaths, we assumed a 9% 3-month case-fatality rate among high-income
regions, a 55% rate among low-income and middle-income regions, and a 70%
rate in sub-Saharan Africa, based on studies published in these areas and expert
opinion.
Results: Published incidence ranged from 0.04 to 12% per year among persons with
HIV. Sub-Saharan Africa had the highest yearly burden estimate (median incidence
3.2%, 720 000 cases; range, 144 000–1.3 million). Median incidence was lowest in
Western and Central Europe and Oceania (
0.1% each). Globally, approximately
957 900 cases (range, 371 700–1 544 000) of cryptococcal meningitis occur each year,
resulting in 624 700 deaths (range, 125 000–1 124 900) by 3 months after infection.
Conclusion: This study, the first attempt to estimate the global burden of cryptococcal
meningitis, finds the number of cases and deaths to be very high, with most occurring in
sub-Saharan Africa. Further work is needed to better define the scope of the problem
and track the epidemiology of this infection, in order to prioritize prevention, diagnosis,
and treatment strategies. ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

AIDS 2009, 23:525–530

Keywords: AIDS, burden, cryptococcal meningitis, cryptococcus,

epidemiology, HIV

a
Mycotic Diseases Branch, bBiostatistics Office, Division of Foodborne, Bacterial, and Mycotic Diseases, cGlobal AIDS Program,
Centers for Disease Control and Prevention, Atlanta, Georgia, USA, dMycology Reference Unit, National Institute for
Communicable Diseases, Johannesburg, South Africa, and eUniversity of Alabama at Birmingham, Birmingham, Alabama, USA.
Correspondence to Dr Benjamin J. Park, 1600 Clifton Road, MS C-09, Atlanta, GA 30333, USA.
Tel: +1 404 639 1619; e-mail: Bpark1@cdc.gov
Received: 23 July 2008; revised: 5 November 2008; accepted: 11 November 2008.

DOI:10.1097/QAD.0b013e328322ffac

ISSN 0269-9370 Q 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 525
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
526 AIDS 2009, Vol 23 No 4
Introduction
Cryptococcal meningitis, a fungal infection caused by
Cryptococcus spp., is one of the most important HIV-
related opportunistic infections. In countries with a high
HIV/AIDS prevalence, Cryptococcus is one of the most
common causes of meningitis overall, more frequent than
Streptococcus pneumoniae or Neisseria meningitidis [1–7].
Following the introduction of combination antiretroviral
therapy (ART), the incidence of cryptococcosis has
declined substantially in North America and Western
Europe [8–11].
Understanding the burden of cryptococcal disease is parti-
cularly important for public health officials to adequately
plan and prioritize needed resources for disease prevention
and control. To better define the burden of cryptococcal
meningitis, as it relates to other important diseases, and to
understand the need for public health attention to this
infection, we reviewed available epidemiological data and
estimated the global burden of cryptococcal meningitis
among persons living with HIV.
Methods
Cryptococcal meningitis incidence data
We searched the published medical literature in November
2007 for eligible articles, using the search terms ‘HIV’ or
‘AIDS’ and ‘opportunistic infection,’ and limiting to
studies published in English during or after 1996. An
eligible article was one that utilized a prospective or
retrospective cohort study design, was conducted in
relatively varied heathcare settings (e.g., hospitalized and
outpatient), and reported an incidence among persons with
HIVor reported results from which incidence rates among
persons with HIV could be calculated.
Our initial literature search yielded 9032 references. From
these, we identified 19 studies that met our eligibility
criteria [8–10,12–27]. Of the 19 studies, seven were
population-based studies of large geographically defined
areas [8,12,14,15,26,27]. The remaining 12 were
provider-based studies that were not defined by
geography [9,13,16–25].
Eleven studies directly reported an estimated incidence and
in three [9,13,14] the incidence was determined based on
data provided in a figure in the original article. For five
population-based studies [8,10,12,15,27], the number of
cases was reported but the incidence among persons with
HIV was not. For three of these studies [8,12,15], we
calculated the incidence rates in these areas using the
number of cases reported as a numerator and using an
available estimate for the total HIV population as a
denominator. In one of these three [15], this numerator was
the average yearly number of cases during the years of the
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
surveillance, and, for the other two, we used the estimate
for the final year of the study. For denominators, one study
reported an estimate in the text [12], and, in another [15],
we used a national surveillance report [28], and in the third
[8], we used the 2007 United Nations Programme on
HIV/AIDS (UNAIDS) estimate [29]. We excluded the
other two population-based studies [10,27], because we
were unable to determine the HIV population.
Global HIV population data
The global population of persons living with HIV was
taken from the estimate for prevalent cases of HIVamong
adults and children as reported in the 2007 UNAIDS
report (33 200 000 cases) [29,30]. A separate HIV
population estimate was taken for each of the UNAIDS
regions.
Regional and global estimates
We used the median incidence rate from the available
studies of a geographic region, as defined by UNAIDS, to
estimate the region-specific cryptococcal meningitis
incidence. For regions with no available incidence data,
we imputed the rate using the median from a region that
is both geographically proximal and similar in economic
development. Estimates of cryptococcal meningitis
burden for each region i (CMi) were calculated by
multiplying the median incidence rate by the 2007
UNAIDS HIV population estimate for each region [30].
The global burden estimate for cryptococcal meningitis
was defined as the sum of all regional estimates.
The range of cases in each region was calculated as 1
standard deviation (SD) from the regional estimate, in
which the region-specific
pffiffi standard deviation SDi was
defined as SDi ¼ ðĈV  CMi Þ. ĈV was the median
coefficient of variation of available region-specific CVis,
and CMi was the estimate for cryptococcal meningitis
cases in the region i. To determine ĈV, we first calculated
the coefficient of variation (CVi) for each region with at
least two available and differing data points using the
median incidence and a robust estimate of scale based on
the interquartile range. Because region-specific inci-
dences were sparse, we pooled information across regions
to estimate a common measure of variability, the median
coefficient of variation (ĈV). This median coefficient of
variation (ĈV) was then applied to each region to
calculate the region-specific SDi. The estimation of SDi
ignores the variability inherent in the estimate of the HIV
counts. The SD for the global estimate was calculated as
the square root of the sum of the squared SDis.
Estimating case fatality
Because mortality is likely to vary regionally, we estimated
deaths by using case-fatality rates from clinical trials
conducted in developed and less-developed countries
[31,32], by reviewing case series, surveillance reports,
and reports on outcomes of cryptococcal meningitis
[1,5,10,16,26,31,33–39], and by consulting with clinical
 The global burden of cryptococcal meningitis Park et al. 527

Table 1. Estimated cryptococcal meningitis cases and deaths among 10 United Nations Programme on HIV/AIDS global regions by using published incidence rates from studies conducted in those

(125.0–1124.9)
(100.8–907.2)
experts (N.G., P.G.P.) in the care and outcomes of

0.045 (0.009–0.09)
(13.2–118.8)
(range), in 1000s
Estimated deaths

(0.0–0.009)
cryptococcal meningitis. In regions with primarily

(3.0–27.0)

(6.0–53.8)
(0.2–2.2)

(0.7–6.4)
(0.1–1.3)
(0.9–7.8)
developed countries, we assumed a 10-week case-fatality
rate of 9% among infected persons. Case fatality was
estimated to be 55% in regions with primarily less-

1.2

3.6
0.7
4.3
29.9
504.0

66.0
15.0
0.009

624.7
developed countries, excluding sub-Saharan Africa,
where it was estimated to be 70%.

90-day case
fatality (%)
Assumed

ND
9
70
9
9

9
55
55

55

55
55
Results

cryptococcal meningitis
cases (rangea), in 1000s

(144.0–1296.0)

(371.7–1544.0)
Incidence reported in all studies ranged from 0.04 to 12%

(24.0–216.0)
Estimated yearly

(10.9–97.9)
(2.7–24.5)

(5.4–49.0)

(1.3–11.6)
(1.6–14.0)
(1.6–14.1)
per year (Table 1). At least one eligible study was available

(0.0–0.1)

0.5 (0.1–1.0)
from all regions except Eastern Europe and Central Asia;
North Africa and Middle East; and the Caribbean. For

720

0.1

6.5
7.8
7.8
13.6

120
27.2

54.4
957.9
these three regions, incidence rates were imputed: the rate
in Eastern Europe and Central Asia, and North Africa and
Middle East, were assumed to be the same as East Asia

HIV prevalence,
(1.7% per year). The incidence in the Caribbean was

in 1000s
assumed to be the same as Latin America (3.4% per year).

4000
1600

1300

1600
22 500

75
800

760

380

230

33 200
Using these rates, we estimated 957 900 (range, 371 700–
1.54 million) cryptococcal meningitis cases occurred in
2006 (Table 1). The region with the highest number of
of variation
estimated cases was sub-Saharan Africa (720 000 cases; Coefficient

(CVi)

0.90

0.74

0.64

1.73
ND
ND

ND

ND

ND
ND
ND
range, 144 000–1.3 million), followed by South and
South-east Asia (120 000 cases; range, 24 000–216 000).
Oceania (100 cases), Western and Central Europe (500
incidence
Median
yearly

cases), North Africa and Middle East (6500 cases), and

0.07
1.7c

3.4c

ND
3.2
1.7
0.1
3.0

1.7
0.6

3.4

Range calculation for region i based on the equation SDi ¼ ðĈV  CMi, in which ĈV ¼ 0:8:
North America (7800 cases) were the regions with

Data presented as incidence [reference number of study from which value was obtained].
the fewest.
12.0 [19]
ND
ND
ND

ND

ND

ND

ND
ND
ND

ND
On the basis of these estimates and the estimates of case
e

fatality outlined above, approximately 624 725 deaths

Reported yearly incidence, by study (%)d

(range, 124 956–1,124 494) were associated with crypto-

0.5b [12]

coccal meningitis (Table 1); Oceania is estimated to have

ND
ND
ND
ND

ND

ND

ND
ND
ND
ND
d

had the fewest (nine deaths), whereas sub-Saharan Africa

had the most (504 000; range, 100 800–907 200). When
comparing the estimate of deaths in sub-Saharan Africa
0.1 [26]

1.7 [24]

0.1 [14]
ND
ND

ND

ND

ND

ND
ND
ND

with other diseases excluding HIV, deaths associated with

c

cryptococcal meningitis are higher than tuberculosis

(350 000) and approach the number related to childhood-
0.04b [8]
3.2 [21]
1.7 [22]

3.0 [18]

1.5 [23]

cluster diseases (pertussis, poliomyelitis, diphtheria,

ND

ND

ND
ND
ND
b

measles, and tetanus, 530 000 deaths combined),

diarrheal diseases (708 000), and malaria (1.1 million)
No data available; incidence assumed.
0.1b [15]

(Fig. 1) [40].
4.0 [16]
1.7 [17]

4.7 [20]

0.1 [13]

3.4 [25]
0.6 [9]

Calculated based on available data.

ND

ND

ND

ND
a

North Africa and Middle East

Discussion
South and South-east Asia

On the basis of review of available epidemiological data, we

Eastern Europe and
Sub-Saharan Africa

Central Europe

estimate a very substantial global burden of cryptococcal

North America
Central Asia

Latin America

meningitis, both in terms of numbers of infections and

Western and

Caribbean

associated deaths. These estimates will be useful for public

East Asia
regions.

Oceania
Region

Global

health officials in designing and prioritizing efforts to

prevent, diagnose, and treat cryptococcal disease.
b

d
a

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
528 AIDS 2009, Vol 23 No 4

1 200 000

1000 000

800 000

600 000

400 000

200 000

0
ia

es

is

IV

es

ns

e
tis
se

si

os

gu
os
ar

is
as

as

io
co

gi
iti
a

pr
al

en
tit
ul

ct
ng

in
se

se

se

at
oc
M

Le
pa
rc

fe
en

D
ep
i
di

di

di
ud
oc

be

in
e
m
H

H
al

er

er
pt

cl
Tu

e
oe

od
st

ex

st
ry

pt
lu

lu
C
rrh

at
ry
s
-c

-c
D

m
-c
ia

od

al
ST

ne
on
D

ic
ho

op

al
ld

in
Tr
hi

st
C

te
In
Fig. 1. Comparison of deaths in sub-Saharan Africa due to HIV-related cryptococcosis, as estimated in present study, and
common infectious diseases excluding HIV, as estimated by World Health Organization. STD, sexually transmitted disease.

The worldwide number of infections and deaths due to
cryptococcal meningitis appear similar to those for
diseases that have received greater public health attention.
In sub-Saharan Africa, deaths due to cryptococcal
meningitis (530 000) may be more frequent than
tuberculosis (350 000) [40].
Our estimates of global disease burden are limited by the
number of available studies in the literature and by the
limitations of the original studies themselves. Provider-
based cohort studies may not be representative of the
region as a whole, and larger, population-based studies
may be limited by incomplete follow-up or case
ascertainment. For example, in one of the population-
based studies from South Africa, the incidence was much
lower than other studies from sub-Saharan Africa, likely
due to incomplete case ascertainment [26].
We assumed case-fatality rates based on reviewing reports
from clinical trials, surveillance studies, and expert
opinion. Despite these assumptions, we feel that the
number of deaths is fairly accurate, particularly in sub-
Saharan Africa, as our estimate is consistent with what
would be calculated from HIV cohort and natural history
studies. These studies report that 13–44% of HIV/AIDS
deaths are due to Cryptococcus [16,38,41]. If 2094 996
HIV/ AIDS deaths occur annually in sub-Saharan Africa
[40], then annual Cryptococcus-related deaths should range
from 272 349 to 921 798.
likely to be stable or even increasing, due to the evolution
of the HIV epidemic in many of these areas, expanding
access to ART is not likely to impact the global burden of
cryptococcal disease soon. In fact, rates of cryptococcal
meningitis in South Africa have actually increased since
the introduction of antiretroviral therapy [42], thereby
emphasizing the growing and future need for attention to
this problem.
In many of the developing countries in sub-Saharan
Africa and South and South-east Asia, the capacity to
perform the complicated management of severe crypto-
coccal meningitis is limited [43]. An important step in
reducing the impact of this infection undoubtedly is the
marked expansion of ARV access therapy for HIV, as risk
of cryptococcal disease is substantially reduced among
persons receiving these treatments. However, because the
numbers of people with advanced immunosuppression
from HIV and cryptococcal disease will continue to
remain high despite expanded access to antiretroviral
therapy, specific public health efforts are needed.
One such effort should be the expansion of laboratory
diagnostic capacity for cryptococcal meningitis, such as
India ink staining of cerebral spinal fluid, and the
cryptococcal antigen latex agglutination test, which is
simple to use, has high sensitivity and specificity [44],
and requires little training for the proper use and
interpretation.

Many of the incidence estimates used here were Prevention of disease is the ultimate public health goal in
determined prior to the current effort to provide wide the approach to cryptococcal meningitis, though this may
access to antiretroviral treatment. However, as the be difficult to achieve. Although most clinical trials did
number of persons still needing antiretroviral drugs is not show a survival benefit [45–48], additional clinical

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 The global burden of cryptococcal meningitis Park et al.
trials are warranted, especially in sub-Saharan Africa,
where the incidence of cryptococcal meningitis is high
and outcomes of infection are poor. Another strategy that
warrants further investigation is screening for early
cryptococcal disease with the serum cryptococcal antigen
test. Nonmeningeal cryptococcal infection often pre-
cedes meningitis but is underrecognized or misdiagnosed
[16,35,49–51]. Early detection and treatment of asymp-
tomatic or latent cryptococcal infection may allow for
fluconazole to be used as the first-line therapy, a much less
expensive and highly available option.
Our findings underscore the tremendous burden of
cryptococcal meningitis, as well as the critical need for a
better understanding of its epidemiology in developing
countries with large numbers of persons living with
HIV/AIDS. A focused effort to improve diagnostic
capacity, expand treatment options, and identify effective
measures for prevention of cryptococcal disease is
urgently needed.
Acknowledgements
The findings and conclusions in this presentation/report
are those of the author(s) and do not necessarily represent
the official position of the Centers for Disease Control
and Prevention.
This information is distributed solely for the purpose of
predissemination peer review under applicable infor-
mation quality guidelines. It has not been formally
disseminated by the Centers for Disease Control and
Prevention. It does not represent and should not be
construed to represent any agency determination
or policy.
Funding source: This study was conducted while being
employed by the US Government; no external funds
were used for this study.
P.G.P. has received a research grant, is a member of
speakers’ bureau, and is an ad hoc advisor (Pfizer, Merck,
Astellas) and has received a research grant and is an ad hoc
advisor (Schering-Plough).
B.J.P., K.A.W., B.J. M., N.G., T.M.C. have no conflicts
of interest.
Conception and design were done by B.J.P., K.A.W.,
B.J.M., N.G., P.G.P., T.M.C.
Acquisition of data was done by B.J.P., K.A.W.
Analysis and interpretation of data was done by B.J.P.,
K.A.W., B.J.M., N.G., P.G.P., T.M.C.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
529
Drafting of manuscript was done by B.J.P., K.A.W.,
B.J.M., T.M.C.
Critical review of manuscript was done by B.J.P., K.A.W.,
B.J.M., N.G., P.G.P., T.M.C.
Statistical analysis was done by B.J.P., K.A.W.
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