Christina C Chang Global Guideline For The Diagnosis

Review
Global guideline for the diagnosis and management of

cryptococcosis: an initiative of the ECMM and ISHAM in
cooperation with the ASM
Christina C Chang, Thomas S Harrison, Tihana A Bicanic, Methee Chayakulkeeree, Tania C Sorrell, Adilia Warris, Ferry Hagen, Andrej Spec,
Rita Oladele, Nelesh P Govender, Sharon C Chen, Christopher H Mody, Andreas H Groll, Yee-Chun Chen, Michail S Lionakis, Alexandre Alanio,
Elizabeth Castañeda, Jairo Lizarazo, José E Vidal, Takahiro Takazono, Martin Hoenigl, Jan-Willem Alffenaar, Jean-Pierre Gangneux, Rajeev Soman,
Li-Ping Zhu, Alexandro Bonifaz, Joseph N Jarvis, Jeremy N Day, Nikolai Klimko, Jon Salmanton-García, Grégory Jouvion, David B Meya,
David Lawrence, Sebastian Rahn, Felix Bongomin, Brendan J McMullan, Rosanne Sprute, Tinashe K Nyazika, Justin Beardsley, Fabianne Carlesse,
Christopher H Heath, Olusola O Ayanlowo, Olga M Mashedi, Flavio Queiroz-Telles Filho, Mina C Hosseinipour, Atul K Patel, Elvis Temfack,
Nina Singh, Oliver A Cornely, David R Boulware, Olivier Lortholary, Peter G Pappas, John R Perfect
Cryptococcosis is a major worldwide disseminated invasive fungal infection. Cryptococcosis, particularly in its most Lancet Infect Dis 2024
lethal manifestation of cryptococcal meningitis, accounts for substantial mortality and morbidity. The breadth of the Published Online
clinical cryptococcosis syndromes, the different patient types at-risk and affected, and the vastly disparate resource February 9, 2024
https://doi.org/10.1016/
settings where clinicians practice pose a complex array of challenges. Expert contributors from diverse regions of the
S1473-3099(23)00731-4
world have collated data, reviewed the evidence, and provided insightful guideline recommendations for health
Department of Infectious
practitioners across the globe. This guideline offers updated practical guidance and implementable recommendations Diseases, Alfred Hospital,
on the clinical approaches, screening, diagnosis, management, and follow-up care of a patient with cryptococcosis Melbourne, VIC, Australia
and serves as a comprehensive synthesis of current evidence on cryptococcosis. This Review seeks to facilitate optimal (C C Chang PhD); Department of
Infectious Diseases, Central
clinical decision making on cryptococcosis and addresses the myriad of clinical complications by incorporating data
Clinical School, Monash
from historical and contemporary clinical trials. This guideline is grounded on a set of core management principles, University, Melbourne, VIC,
while acknowledging the practical challenges of antifungal access and resource limitations faced by many clinicians Australia (C C Chang); Centre
and patients. More than 70 societies internationally have endorsed the content, structure, evidence, recommendation, for the AIDS Programme of
Research in South Africa,
and pragmatic wisdom of this global cryptococcosis guideline to inform clinicians about the past, present, and future
Durban, South Africa
of care for a patient with cryptococcosis.
Introduction
Cryptococcosis accounts for substantial morbidity and Key points
mortality globally. In 2022, WHO listed Cryptococcus • Accurate delineation of the cryptococcosis clinical syndrome is important as it guides
neoformans as a top fungal priority pathogen.1 antifungal treatment choice and duration; cryptococcosis syndromes are divided into
Cryptococcosis often involves the CNS or the lungs, but CNS, disseminated disease, isolated pulmonary disease, or direct skin inoculation
disseminated disease can affect any organ, yet appear (figure 1)
localised. Despite the knowledge gained and • Liposomal amphotericin B 3–4 mg/kg daily and flucytosine 25 mg/kg four times a day
improvements in clinical outcomes generated by is the most optimal induction therapy option for cryptococcal meningitis,
multiple interventional trials2–7 done primarily in low- disseminated cryptococcosis, and severe isolated pulmonary cryptococcosis in high-
income settings with insufficient resources, mortality income settings
from cryptococcal meningoencephalitis is high, ranging • In low-income settings, patients with HIV-associated cryptococcal meningitis are best
from 24 to 47% at 10 weeks.2,4,7,8 The highest burden of treated with liposomal amphotericin B 10 mg/kg as a single-dose, with 14 days of
disease is in low-income and middle-income countries, flucytosine 25 mg/kg four times a day and fluconazole 1200 mg daily as induction
especially in sub-Saharan Africa,9 where HIV and AIDS therapy; this induction therapy has not been trialled in non-HIV-associated
are the dominant risk factor, although new non-HIV cryptococcal meningitis or other non-CNS cryptococcosis syndromes
immunocompromised risk groups and putatively • Optimise outcomes by providing the most effective antifungal therapy while
immunocompetent individuals are increasingly reported preventing, monitoring, and managing potential toxicity; do not stop or switch to an
in high-income settings with sufficient resources. inferior regimen too early or unnecessarily
Complementary diagnostic and management guidelines • Expect and monitor for clinical relapse and investigate thoroughly for causality; review
for cryptococcosis exist.10–21 This comprehensive manage adherence to antifungal therapy and consider drug–drug interactions; during treatment
ment guideline serves primarily to facilitate clinical follow-up, do not escalate antifungal therapy for persistent blood antigenemia (blood
decision making while also providing an overview of the cryptococcal antigen), persistently positive CSF cryptococcal antigen, visible cryptococci
uncertainties in cryptococcosis management. With in CSF (without culture positivity), or abnormal CSF microscopy or biochemistry, as they
contributors across the globe, this guideline gives voice to are not necessarily indicators of microbiological failure
expertise and challenges from diverse settings in a • Adapt and adopt these ECMM global guidelines to suit local practices, while constantly
globally relevant Review. General principles and treatment advocating for better antifungal access, scrutinising new trial data, and reviewing local
recommendations are provided, and clinicians are urged data to improve patient outcomes
to use careful clinical judgement when formulating
www.thelancet.com/infection Published online February 9, 2024 https://doi.org/10.1016/S1473-3099(23)00731-4 1

Review
Cryptococcal meningitis and CNS cryptococcosis Disseminated Isolated pulmonary cryptococcosis* Direct skin
(non-CNS/ innoculation
non-pulmonary)
cryptococcosis
HIV SOT Non-HIV/ Non-HIV Cryptococcoma Severe †Mild (with or without

non-SOT C gattii cryptococcoma)
Without With
crypto- crypto-
coccoma coccoma
(AIIt) ‡Liposomal amphotericin B 3–4 mg/kg daily and flucytosine 25 mg/kg four times a day in high-income settings or Fluconazole Fluconazole
(AI) §Liposomal amphotericin B 10 mg/kg single dose and 2 weeks of flucytosine 25 mg/kg four times a day and fluconazole 1200 mg daily in low-income 400–800 mg daily 400 mg daily
settings
2 weeks ≥2 weeks ≥2 weeks 4–6 weeks 4–6 weeks 2 weeks 2 weeks 4–6 weeks ¶6–12 months 3–6 months
AI AIIt AIIt BIII BIII BIIu AIIu BIIu BIIu AIII

Consolidation: (AI) fluconazole 400–800 mg daily for 8 weeks
Grades of recommendation
Maintenance: (AIIt) fluconazole 200 mg daily for 12 months A. Strongly recommended

B. Moderately recommended
Figure 1: Recommended first-line antifungal therapy by cryptococcosis syndrome

Grading of recommendation and level of evidence in bolded red letters. Recommendation grading by shading: blue (strongly recommended; A) and yellow (moderately recommend; B). SOT=solid
organ transplantation. C gattii=Cryptococcal gattii. w=weeks. *Isolated Cryptococcal neoformans or Cryptococcal gattii pulmonary cryptococcosis, mild is defined as asymptomatic or mildly symptomatic
patients or with a solitary small nodule (<2 cm); whereas severe is defined as multiple lesions, large lesions (≥2 cm), lobar consolidation, cavitation, multi-lobar involvement, or hypoxaemic. †If the
presence of Cryptococcus spp in respiratory specimens is deemed to be airway colonisation after careful evaluation and no treatment is elected, regular follow-up is recommended, especially in the
setting of future immunosuppression. ‡Strongly preferred in cryptococcal meningitis and CNS cryptococcosis in SOT and non-HIV non-SOT patient populations, disseminated cryptococcosis, and
severe pulmonary cryptococcosis. ‡Has not been directly compared against §. §Has only been trialled in people with cryptococcal meningitis and there are no supporting data of its use in SOT or
non-HIV non-SOT patients or in other cryptococcosis syndromes. ¶Can consider a shorter duration (eg, 3 months) in immunocompetent individuals with mild isolated pulmonary cryptococcosis.
(C C Chang); Institute of treatment plans for the individual patient. See the Yeasts causing cryptococcosis and diagnostic
Infection and Immunity, appendix for more detailed text, tables, and panels methods
St George’s University London,
London, UK
relevant to each section. A summary of the first-line C neoformans species complex is the predominant
(Prof T S Harrison MD, treatment for the different cryptococcosis syndromes is in causative agent of cryptococcosis in people living with
Prof T A Bicanic BMBCh, figure 1.3 An explanation of the evidence grading system HIV, and Cryptococcus gattii species complex more
Prof N P Govender MBBCh); used for the recommendations throughout is in panel 1. commonly causes disease in people who appear
Clinical Academic Group in
Infection and Immunity,
immunocompetent. Although both can cause a similarly
St George’s University Populations at high risk, clinical presentations, broad range of cryptococcosis syndromes, C neoformans
Hospitals NHS Foundation and outcomes has a predilection for CNS disease and C gattii is more
Trust, London, UK Primarily acquired via inhalation but occurring mainly often associated with pulmonary disease and large
(Prof T S Harrison,
Prof T A Bicanic); Medical
upon reactivation after a period of latency, cryptococcosis cryptococcomas.30–32
Research Centre for Medical has protean manifestations, with cryptococcal meningitis Diagnostic methods used to establish the diagnosis,
Mycology, University of Exeter, being the most common severe presentation. Pulmonary extent, severity, and prognosis of cryptococcosis are
Exeter, UK (Prof T S Harrison, cryptococcosis is underdiagnosed and often subclinical. constantly evolving (appendix pp 10, 41). Microscopy
Prof T A Bicanic, Prof A Warris MD,
Prof N P Govender); Division of
Disseminated cryptococcosis can involve any organ of and culture of cerebrospinal fluid (CSF) pellet after
Infectious Diseases and Tropical the body, thus a thorough clinical assessment is required, centrifugation and blood culture, accompanied by CSF
Medicine, Department of even in individuals who appear asymptomatic.24,25 and blood (ie, serum, plasma, or whole blood)
Medicine, Faculty of Medicine
Although classic patient populations at high risk include cryptococcal antigen testing (most commonly by lateral
Siriraj Hospital, Mahidol
University, Bangkok, Thailand people living with HIV and solid organ transplant (SOT) flow assay) and radiological studies, are central to
(Prof M Chayakulkeeree MD); recipients, individuals with other immunosuppressive the diagnosis of cryptococcosis (panel 3; appendix
Sydney Infectious Diseases conditions or receiving immunosuppressant drugs and pp 10, 35, 41).33,34
Institute, University of Sydney,
people putatively immunocompetent are also affected by
Sydney, NSW, Australia
(Prof T C Sorrell MBBS, cryptococcosis (appendix pp 6, 79). Those who survive Screening, primary prophylaxis, and pre-
Prof S C Chen PhD, cryptococcosis report substantial morbidity, ranging emptive therapy
Prof J-W Alffenaar PhD, from 10–70% depending on the disease syndrome and Supportive evidence for cryptococcal screening is limited
J Beardsley PhD); Department of
severity, underlying predisposing conditions of the host, to people living with HIV and depends on blood
Infectious Diseases
(Prof T C Sorrell, Prof S C Chen, and the health-care system in which the patient is cryptococcal antigen by lateral flow assay (panel 4;
J Beardsley), managed26–29 (panel 2; appendix pp 8, 39). appendix p 49).
2 www.thelancet.com/infection Published online February 9, 2024 https://doi.org/10.1016/S1473-3099(23)00731-4

Review
and Department of Pharmacy

Panel 1: Grade of recommendation and level of evidence Panel 2: Recommendations for populations at high risk, (Prof J-W Alffenaar), Westmead
This guideline follows the structure and definitions of clinical presentations, and outcomes Hospital, Westmead, NSW,
Australia; Department of
previous European Confederation of Medical Mycology • (AIII) Cryptococcosis should be considered in any patient Infectious Diseases, Great
guidelines on invasive fungal infections,22,23 which are in presenting with compatible symptoms or microbiology, Ormond Street Hospital,
accordance with the Grading of Recommendations regardless of their immune status. London, UK (Prof A Warris);
Faculty of Science, Institute for
Assessment, Development and Evaluation and Appraisal of • (AIII) Among patients without known predisposition to
Biodiversity and Ecosystem
Guidelines for Research & Evaluation systems, as previously cryptococcosis, exclusion of an underlying Dynamics, University of
described. Strength of recommendation and quality of immunodeficiency (eg, performing HIV serology and CD4 Amsterdam, Amsterdam,
evidence are provided. T-cell count) is recommended Netherlands (Prof F Hagen PhD);
Department of Medical
Grade of recommendation Mycology, Westerdijk Fungal
Biodiversity Institute, Utrecht,
• A: the guideline group strongly supports a
Panel 3: Recommendations for yeast causing Netherlands (Prof F Hagen);
recommendation for use Department of Medical
cryptococcosis and diagnostic methods
• B: the guideline group moderately supports a Microbiology, University
recommendation for use (AIIt) All patients with suspected or confirmed cryptococcosis Medical Center Utrecht,
• C: the guideline group marginally supports a (including cryptococcal antigenemia) require clinical Utrecht, Netherlands
assessment for CNS, pulmonary, and other body site (Prof F Hagen); Division of
recommendation for use Infectious Diseases,
• D: the guideline group supports a recommendation involvement. Department of Medicine,
against use Investigations for disseminated disease should include: Washington University School
of Medicine, St Louis, MO, USA
• Lumbar puncture with measurement of CSF opening
Level of evidence (A Spec PhD); College of
pressure, glucose, protein, cell counts, microscopy, and Medicine, University of Lagos,
• I: evidence from at least one well-designed randomised
culture and quantification of CSF cryptococcal antigen Lagos, Nigeria (R Oladele PhD);
controlled trial (RCT)
• Quantification of blood cryptococcal antigen and cultures Department of Clinical
• II: evidence from at least one well-designed clinical trial, Microbiology and Infectious
of blood, sputum (or other respiratory specimens),
without randomisation; from cohort or case-controlled Diseases, School of Pathology,
or other affected sites Faculty of Health Sciences,
analytic studies (preferably from >1 centre); from multiple
• Brain imaging (preferably MRI) and chest imaging University of the
time series; or from results of uncontrolled experiments Witwatersrand, Johannesburg,
(preferably CT)
• III: evidence from opinions of respected authorities, based South Africa
on clinical experience, descriptive case studies, or reports (Prof N P Govender); Division of
Medical Microbiology, Faculty
of expert committees liposomal amphotericin B compared with amphotericin B
of Health Sciences, University
is long recognised and the accessibility of liposomal of Cape Town, Cape Town,
Added index for source of level II evidence
amphotericin B in high-income settings led to the South Africa
• r: meta-analysis or systematic review of RCT (Prof N P Govender); Centre for
establishment of liposomal amphotericin B 3–4 mg/kg
• t: transferred evidence (ie, results from different patient Infectious Diseases and
daily plus flucytosine 25 mg/kg four times a day for
cohorts or similar immune-status situations) Microbiology Laboratory
2 weeks as the standard. Services, Institute for Clinical
• h: historical control as control group
In low-income settings, challenges with antifungal Pathology and Medical
• u: uncontrolled trials Research, New South Wales
access, adverse effects, and difficulty of monitoring and
• a: for published abstract presented at an international Health Pathology, Westmead,
safely managing 2 weeks of amphotericin B induction
symposium or meeting NSW, Australia (Prof S C Chen);
treatment led to phase 2 studies exploring alternative Department of Microbiology,
regimens. Fluconazole monotherapy, even at doses up Immunology and Infectious
HIV-associated cryptococcal meningitis to 1200 mg daily, was associated with approximately Diseases, Department of
Medicine, Snyder Institute for
Induction therapy 50% mortality at 10 weeks and up to 75% mortality at Chronic Diseases, University of
Multiple studies support the successful combination of 1 year.36–38 An oral combination of fluconazole 1200 mg Calgary, Calgary, AB, Canada
amphotericin B plus flucytosine as the induction daily plus flucytosine 25 mg/kg four times a day was (Prof C H Mody MD); Infectious
treatment of choice in HIV-associated cryptococcal associated with a significant improvement in EFA Disease Research Program
(Prof A H Groll), Center for Bone
meningitis. First trialled by van der Horst and colleagues, compared with fluconazole alone.39 The addition of a Marrow Transplantation
the addition of flucytosine to amphotericin B showed a short, 5–7 day course of amphotericin B at 1 mg/kg daily (Prof A H Groll), and
trend towards improved CSF sterility at 2 weeks and to oral fluconazole or combined oral fluconazole and Department of Pediatric
reduced frequency of relapse.35 In a subsequent trial, this flucytosine showed improved rates of cryptococcal Hematology/Oncology,
University Children’s Hospital,
combination cleared cryptococci (measured as early clearance,40,41 similar to rates observed with 14 days of Münster, Germany;
fungicidal activity [EFA]) more rapidly than either amphotericin B. Department of Internal
amphotericin B alone or amphotericin B plus In the phase 3 ACTA trial conducted in centres in Medicine, National Taiwan
University Hospital and College
fluconazole.5 Importantly, the combination of Africa the oral combination of fluconazole 1200 mg daily
of Medicine, Taipei, Taiwan
amphotericin B 1 mg/kg daily plus flucytosine 25 mg/kg and flucytosine 25 mg/kg four times a day for 2 weeks (Y-C Chen PhD); National
four times a day showed a survival advantage at day 70, was compared with 1 week of amphotericin B 1 mg/kg Institute of Infectious Diseases
compared with amphotericin B alone in the treatment of daily and 2 weeks of amphotericin B 1 mg/kg daily as and Vaccinology, National
Health Research Institutes,
cryptococcal meningitis.2 The nephroprotection of induction therapy, with the amphotericin B groups

Review
Zhunan, Taiwan (Y-C Chen); populations is contentious. The standard regimen is

Fungal Pathogenesis Section, Panel 4: Recommendations for screening, primary liposomal amphotericin B 3–4 mg/kg daily plus
Laboratory of Clinical prophylaxis, and pre-emptive therapy flucytosine 25 mg/kg four times a day for 2 weeks,
Immunology & Microbiology,
National Institute of Allergy & Adults living with HIV who are antiretroviral therapy (ART)- which is different to the comparators used in the trials.
Infectious Diseases, National naive or after a period of ART discontinuation with less than Retrospective database reviews in the USA showed low
Institutes of Health, Bethesda, 200 CD4 cells per mm³ must have: rates of acute inpatient mortality from cryptococcal
MD, USA (Prof M S Lionakis
• (AI) A lateral flow assay of blood cryptococcal antigen for meningitis (10·5% in HIV-cryptococcal meningitis and
MD); Institut Pasteur, Centre
National de Référence Mycoses the screening of cryptococcosis and the cryptococcal 13·3% in non-HIV cryptococcal meningitis) and a
Invasives et Antifongiques, antigen titre should be measured if positive remarkably low mortality rate at 1 year of 11·6% in the
Groupe de recherche Mycologie • (AIIt) All patients with cryptococcal antigenaemia should past two decades.42,43 The reliance on high-dose
Translationnelle, Département
be carefully assessed and investigated for cryptococcosis fluconazole and flucytosine as the basis of induction
de Mycologie, Université Paris
Cité, Paris, France and treated as appropriate therapy in the AMBITION-cm study might not be
(Prof A Alanio PhD); Laboratoire • (AIIu) In people living with HIV who have asymptomatic pragmatic in high-income settings, where more
de parasitologie-mycologie, cryptococcal antigenaemia but without clinical comorbidities occur, potential drug–drug interactions
AP-HP, Hôpital Saint-Louis,
Université Paris Cité, Paris,
cryptococcosis after thorough investigation (including at need to be carefully considered, and the risk of
France (Prof A Alanio); Instituto least a lumbar puncture), fluconazole 1200 mg daily for hepatotoxicity is less tolerated than in low-income
Nacional de Salud, Bogotá, 2 weeks (when ART can be initiated), followed by settings. In the USA, only a third of patients completed
Colombia (E Castañeda PhD); fluconazole 800 mg daily for 8 weeks, and 200 mg daily the 14 days of flucytosine.44 Although some experts
Department of Internal
Medicine, Hospital
thereafter for 6 months is recommended (guidance support the inclusion of the AMBITION-cm triple
Universitario Erasmo Meoz, might be updated contingent on results of prospective regimen as a primary option in high-income settings,
Faculty of Health, Univesidad trials) other experts call for further comparative trials in high-
de Pamplona, Cúcuta, • (BI) In clinical settings where cryptococcal antigen lateral income settings to assess the regimen’s effect in
Colombia (J Lizarazo MD);
Departmento de Neurologia,
flow antigen screening is not available (despite WHO’s patients with HIV and patients without HIV (in whom
Instituto de Infectologia Emílio strong recommendations), universal primary prophylaxis no supporting data exist). Regardless of the induction
Ribas, São Paulo, Brazil with fluconazole 100 mg daily in people living with HIV in antifungal regimen used, the complications of
(J E Vidal PhD); Departamento
high endemic areas with a CD4 count of less than cryptococcal meningitis, such as increased intracranial
de Moléstias Infecciosas e
Parasitárias, Hospital das 200 cells per mm³ is recommended pressure, require intense clinical monitoring, and most
Clinicas, Faculdade de Medicina In patients without HIV: patients with cryptococcal meningitis require inpatient
da Universidade de São Paulo, care for 1–2 weeks or more.
• (DIIu) Routine blood cryptococcal antigen screening,
São Paulo, Brazil (J E Vidal);
Instituto de Medicina Tropical, primary prophylaxis, and pre-emptive therapy are not Mycological success, defined as cryptococcocal culture
Faculdade de Medicina da recommended negativity (also termed CSF sterility) has been associated
Universidade de São Paulo, São with improved outcomes and reduced clinical relapse.45
Paulo, Brazil (J E Vidal); In people living with HIV and cryptococcal meningitis,
Diseases, Graduate School of
being further randomly assigned to either fluconazole CSF sterility before ART commencement has been
Biomedical Sciences, Nagasaki 1200 mg daily or flucytosine 25 mg/kg four times a day.7 shown to be associated with reduced occurrence of
University, Nagasaki, Japan 1 week of amphotericin B 1 mg/kg daily plus flucytosine neurological deterioration, microbiological relapse, and
(Prof T Takazono PhD); followed by fluconazole 1200 mg daily in the second cryptococcosis-associated immune reconstitution
Department of Respiratory
Medicine, Nagasaki University
week was the best-performing induction group, with inflammatory syndrome (C-IRIS).45 Some treatment
Hospital, Nagasaki, Japan a 24% 10-week mortality rate. This regimen was adopted guidelines advocate performing a lumbar puncture after
(Prof T Takazono); Division of as the preferred 10-week induction regimen by WHO 2 weeks of induction therapy (before changing to
Infectious Diseases, and southern African guidelines until the AMBITION- consolidation therapy) to assess CSF culture sterility as
Translational Medical
Mycology Research Unit,
cm study.16,18 a marker of successful induction.11,15,18,20 Other
European Confederation of In the AMBITION-cm phase 3 study, which had sites guidelines—particularly those focused on low-income
Medical Mycology Excellence across Africa, a single initial 10 mg/kg dose of liposomal settings—do not.10,16
Center for Medical Mycology, amphotericin B with oral fluconazole 1200 mg daily plus
Medical University of Graz,
Graz, Austria
flucytosine 25 mg/kg four times a day for 2 weeks was Consolidation and maintenance therapy
(Prof M Hoenigl MD); compared with the WHO recommendation of 1 week of There have been no trials of consolidation and
BioTechMed, Graz, Austria amphotericin B 1 mg/kg daily plus flucytosine followed maintenance therapy in cryptococcal meningitis within
(Prof M Hoenigl); School of
by 1 week of fluconazole 1200 mg daily.6 This new the past two decades. Two early studies established
Pharmacy, Faculty of Medicine
and Health, University of regimen met non-inferiority criteria (10-week mortality 400 mg daily fluconazole for consolidation therapy.35,46
Sydney, Sydney, NSW, Australia 24·8% vs 28·7%) with similar EFAs and was significantly With the accumulation of safety data of a 800 mg
(Prof J-W Alffenaar); Institute better tolerated. The WHO guidelines now recommend fluconazole daily dose and evidence of a fluconazole dose-
for Health, Environment and
the AMBITION-cm regimen as the preferred antifungal response effect,36,47 this regimen is the preferred
Work Research—Irset, Inserm
UMR_S 1085, University of therapy in people living with HIV and cryptococcal consolidation dose in low-income settings, where
Rennes, Rennes, France meningitis.10 suboptimal antifungal regimens are used.16,18 A gradual
(Prof J-P Gangneux PhD); The applicability of the ACTA and AMBITION-cm rise in median fluconazole minimum inhibitory
Laboratory for Parasitology
trials to high-income settings and in non-HIV concentrations (MICs) in cryptococcal isolates collected

Review
Grades of recommendation
Cryptococcal meningitis in A. Strongly recommended
people with HIV B. Moderately recommended
C. Marginally recommended
D. Recommended against
Induction therapy for 2 weeks
Preferred
(AIIt) Liposomal amphotericin B 3–4 mg/kg daily and
flucytosine 25 mg/kg four times a day in high-income
settings
Or
(AI) A single dose of liposomal amphotericin B
10 mg/kg with 14 days of flucytosine 25 mg/kg
four times a day and fluconazole 1200 mg daily in
low-income settings
(Allt) Proactive intracranial pressure management

with therapeutic lumbar punctures
(CIIu) Consider performing a lumbar puncture at the

end of the second week of induction therapy to check
for CSF sterility
CSF cryptococcocal Yes (CIIu) Consider prolonging

culture positive? induction therapy
No
(AI) Start consolidation therapy: fluconazole

400–800 mg daily for 8 weeks
(AI) Start antiretroviral therapy 4–6 weeks after

cryptococcal meningitis diagnosis and treatment
Recurrent Yes (Allu) Check drug interactions and drug adherence;

symptoms? optimise accordingly
No
(AIIt) Perform CT or MRI brain and lumbar puncture
Start maintenance therapy: fluconazole 200 mg daily for opening pressure, send CSF for analysis and
for 12 months or until immune restoration culture
(BIIu) Cease maintenance therapy after 12 months

of antifungal therapy in patients aviremic on ART Yes No Any Yes (AIII) Treat other causes
CSF cryptococcocal
with CD4 count >100 cells per mm3 Microbiological relapse alternative causes?
culture positive? as appropriate
No
(Alll) Restart maintenance therapy if CD4 count (BIII) Perform antifungal
<100 cells per mm3 susceptibility testing
Probable cryptococcosis-associated immune
reconstitution inflammatory syndrome
(BIII) Restart induction therapy

(AIIu) Continue antifungal therapy
(DI) Do not stop ART
(BIII) Consider prednisolone or dexamethasone

(wean over 4–6 weeks)
Figure 2: Management algorithm for cryptococcal meningitis and cryptococcal meningoencephalitis in people with HIV
ART=antiretroviral therapy. CSF=cerebrospinal fluid.

Review
and Mycology, Centre National

de Référence Mycoses Invasives Panel 5: Ten principles of cryptococcal meningitis management
et Antifongiques LA Asp-C,
University Hospital of Rennes, The key principles in cryptococcal meningitis management are • (BIIu) Perform a scheduled therapeutic lumbar puncture
Rennes, France best read in context (see relevant sections in main text). 48–72 h after initial lumbar puncture or 7 days, regardless of
(Prof J-P Gangneux); Jupiter Although most evidence and recommendations are derived initial opening pressure.
Hospital, Pune, India
(R Soman MD); Deenanath
from cryptococcal meningitis in people living with HIV, many of • (Allt) Persistent raised symptomatic intracranial pressure
Mangeshkar Hospital, Pune, these principles are translatable to non-HIV settings. despite therapeutic lumbar punctures should be managed
India (R Soman); Hinduja by surgical decompression via temporary lumbar drainage,
Hospital, Mumbai, India 1) Selectively screen, risk-stratify, and investigate for
shunting, or ventriculostomy, depending on local expertise
(R Soman); Department of cryptococcosis
Infectious Diseases, Shanghai and resources.
This principle is specific to people with HIV and cryptococcal
Key Laboratory of Infectious
Diseases and Biosafety
meningitis (panel 4). 5) Look for an underlying immunosuppressive state
Emergency Response, National Exploring for an immunosuppressive state—particularly, but
2) Provide best fungicidal induction regimen possible
Medical Center for Infectious not limited to, HIV infection—is important in the management
Diseases, Huashan Hospital, • (AIIt) Liposomal amphotericin B 3–4 mg/kg daily plus
of cryptococcosis.
Fudan University, Shanghai flucytosine 25 mg/kg four times a day for 2 weeks (preferred
• (AIII) Among patients without known predisposition to
China (Prof L-P Zhu PhD); in high-income settings and strongly recommended in SOT
Hospital General de México, cryptococcosis, exclusion of an underlying
and non-HIV non-SOT settings); or (AI) a single dose of
Dermatology Service, immunodeficiency (including performing HIV serology and
Mycology section, Universidad liposomal amphotericin B 10 mg/kg with 14 days of
CD4 T-cell count) is recommended in all patients with
Nacional Autónoma de México, flucytosine 25 mg/kg four times a day and fluconazole
Mexico City, Mexico
cryptococcosis.
1200 mg daily (note: only trialled in people living with HIV
(Prof A Bonifaz PhD); • (BIII) Individuals without a known risk factor for
in low-income settings).
Department of Clinical disseminated cryptococcosis, particularly those with a
Research, Faculty of Infectious • (CIIu) Consider performing a lumbar puncture at the end of
history of other atypical fungal, mycobacterial, or bacterial
and Tropical Diseases, London the first or second week of induction therapy to check for
School of Hygiene and Tropical
infections, should be considered for evaluation of an
CSF sterility before ART commencement.
Medicine, London, UK undiagnosed immunodeficiency, preferably in consultation
• (CIIu) Consider prolonging induction therapy if CSF is
(Prof J N Jarvis PhD, with a clinical immunologist (appendix pp 6, 79).
D Lawrence PhD); Botswana persistently culture positive at 2 weeks.
Harvard AIDS Institute • (BIII) In Cryptococcus gattii CNS infection occurring in non- 6) Provide and ensure adherence to consolidation and
Partnership, Gaborone, HIV patients or CNS cryptococcoma consider extending maintenance therapy
Botswana (Prof J N Jarvis,
D Lawrence); Department of
induction therapy to 4–6 weeks. • Consolidation (8 weeks): (AI) Fluconazole 400–800 mg
Clinical Microbiology and daily. 800 mg is preferred in low-income settings.
3) Monitor for and minimise drug toxic effects
Infection, Royal Devon and • Maintenance (12 months or until immune restoration):
Exeter University Hospital NHS • (AIIu) In-hospital care for the first 1–2 weeks is encouraged
(AIIt) Fluconazole 200 mg daily.
Trust, Exeter, UK to manage the major early complications seen with
(Prof J N Day PhD); Department
• (AIIu) Check for drug–drug interactions and adjust the dose
cryptococcal meningitis management.
of Clinical Mycology, Allergy as necessary.
• (AIIu) The use of amphotericin B and liposomal
and Immunology, I Mechnikov • (AIII) Close therapeutic drug monitoring of tacrolimus,
North Western State Medical amphotericin B should be accompanied by pre-hydration
cyclosporine, and sirolimus levels and dose reduction of
University, Staint Petersburg, and aggressive potassium and magnesium replacement
Russia (Prof N Klimko PhD);
these agents are recommended when azoles are
therapy.
Translational Research, co-administered.73,74
Cologne Excellence Cluster on
• (AIIu) Frequent (at least every alternate day) complete
Cellular Stress Responses in blood counts, renal function tests, and electrolyte 7) Optimal commencement of ART in people with HIV
Aging-Associated Diseases, measurements are recommended to assess for therapy- This principle is specific to people with HIV and cryptococcal
Faculty of Medicine and related nephrotoxicity and bone marrow, fluid, and meningitis.
University Hospital Cologne,
University of Cologne, Cologne,
electrolyte changes. Liver function tests at baseline and at • (DI) Immediate or very early commencement of ART is not
Germany least weekly are recommended. recommended.
(J Salmanton-García PhD, • See appendix pp 16, 30. • If there is inadequate access to antifungal induction therapy,
S Rahn PhD, R Sprute MD, (AI) delay ART for 4–6 weeks.
Prof O A Cornely MD); Center for 4) Manage raised intracranial pressure
Integrated Oncology Aachen
• If there is adequate access to antifungal induction therapy,
• (AIIu) Opening pressure should be measured at every
Bonn Cologne Duesseldorf and (BIIu) consider further individualisation, taking into
lumbar puncture in patients with cryptococcal meningitis.
Excellence Center for Medical consideration resolution of symptoms and signs of
Mycology, Department I of • (Allt) Acute symptomatic elevation of the intracranial
cryptococcal meningitis and intracranial pressure (including
Internal Medicine, Faculty of pressure (≥20 cm of CSF) should be managed by daily
Medicine and University
normalisation of opening pressure), attainment of
therapeutic lumbar punctures (ie, removal of sufficient CSF,
Hospital Cologne, University of CSF cryptococcal sterility, successful identification and
usually around 20–30 mL) to reduce the pressure to 50% of
Cologne, Cologne, Germany management of concurrent co-infections and other
(J Salmanton-García, S Rahn, opening pressure or to a normal pressure of ≤20 cm of CSF
AIDS-defining illnesses, the patient’s readiness for ART, and
R Sprute, Prof Oliver A Cornely); (documented as a closing pressure).
Partner Site Bonn-Cologne, (Continues on next page)
German Centre for Infection

Review
Research, Cologne, Germany

(Panel 5 continued from previous page) (J Salmanton-García, S Rahn,
R Sprute, Prof Oliver A Cornely);
local experience of cryptococcal meningitis and • (BIII) Antifungal susceptibility testing should be done Histology and Pathology Unit,
cryptococcosis-associated immune reconstitution concurrently on all initial and relapse isolates (if stored and Ecole nationale vétérinaire
inflammatory syndrome (C-IRIS) management (usual range available). An increase in fluconazole minimum inhibitory d’Alfort, Maisons-Alfort,
France (Prof G Jouvion PhD);
is 4–6 weeks). concentration of >2 dilutions is concerning for the potential Dynamyc Team, Université
development of drug resistance. Paris Est Créteil and Ecole
8) Monitor for clinical relapse and investigate causality
• (BIII) Consider recommencing induction therapy with a nationale vétérinaire d’Alfort,
• (AIIt) Investigate thoroughly for causality (ie, CNS and Créteil, France (Prof G Jouvion);
more optimal regimen that is guided by antifungal
non-CNS and infective and non-infective) in cases of Infectious Diseases Institute,
susceptibility testing. School of Medicine, College of
apparent clinical relapse. Investigations should include CT or
Heath Sciences, Makerere
MRI of the brain, lumbar puncture for opening pressure, and 10) Carefully exclude alternative diagnoses before
University, Kampala, Uganda
CSF analyses including microscopy and culture. attributing clinical relapse to C-IRIS (D B Meya PhD); Department of
• (AIIu) Review adherence to antifungal therapy, ART, • (Allt) For patients with suspected paradoxical C-IRIS, Medical Microbiology and
immunosuppressants, and other medications and consider carefully exclude recurrent cryptococcal disease or new Immunology, Faculty of
Medicine, Gulu University,
drug–drug interactions. Perform therapeutic drug infective or non-infective conditions before attributing Gulu, Uganda
monitoring if applicable. Optimise control of underlying symptoms and signs to C-IRIS. Perform a brain MRI and (F Bongomin MMed); Discipline
diseases. lumbar puncture to measure opening pressure and get CSF of Paediatrics, School of Clinical
• (Dllu) The use of follow-up blood or CSF cryptococcal for microbiological, cellular, and biochemical analyses. Medicine, Faculty of Medicine
and Health, University of New
antigen (including monitoring of titres) for clinical decision • (AIIu) Treatment of C-IRIS should include therapeutic South Wales, Sydney, NSW,
making is discouraged. lumbar puncture and symptomatic therapy, such as Australia (B J McMullan PhD);
• (Dllu) Do not escalate antifungal therapy for persistent analgesia, antiemetics, and antiepileptics if appropriate. Department of Infectious
blood antigenemia, persistently positive CSF cryptococcal • (AIII) Continue antifungal therapy. Diseases, Sydney Children’s
Hospital, Randwick, Sydney,
antigen, visible cryptococci in CSF (without culture • (Blll) High-dose prednisolone or prednisone (usually NSW, Australia (B J McMullan);
positivity), or abnormal CSF microscopy or biochemistry. 0·5–1·0 mg/kg daily) or dexamethasone (usually Department of Clinical
These are not necessarily indicators of microbiological 0·2–0·3 mg/kg daily), weaned over 4–6 weeks can be Sciences, Liverpool School of
failure. considered in those with persistent symptoms who are Tropical Medicine, Liverpool,
UK (T K Nyazika); Pediatric
unresponsive to therapeutic lumbar punctures. Rarely, Department, Federal University
9) Evaluate for drug adherence, drug–drug interactions, and
a second steroid course with taper is needed. of São Paulo, São Paulo, Brazil
drug resistance
• (DIII) Do not stop ART. (Prof F Carlesse PhD); Oncology
This principle is specific to people with culture-positive Pediatric Institute-IOP-
(microbiological) persistence or relapse. GRAACC, Federal Univeristy of
São Paulo, São Paulo, Brazil
(Prof F Carlesse); Department of
Microbiology, Fiona Stanley
during initial cryptococcal meningitis presentation have for cryptococcal meningitis treatment in people living Hospital Network, PathWest
been reported in South Africa and Uganda.48,49 Although with HIV are based on the availability of antifungal Laboratory Medicine, Perth,
this evidence could lend support for a higher consolidation drugs. Preferred and alternative strategies are offered in WA, Australia
dose of 800 mg daily of fluconazole in these settings, (figure 3 and figure 4A. (C H Heath MBBS); Department
of Infectious Diseases, Fiona
whether this regimen is required across all patient groups Stanley Hospital, Perth, WA,
and settings is contentious. Widespread fluconazole use Adjunctive therapy Australia (C H Heath); UWA
could also perpetuate further rises in MICs. In the past decade, trials of adjunctive treatment in HIV- Medical School, Internal
Maintenance therapy with fluconazole 200 mg daily associated cryptococcal meningitis have all been shown Medicine, The University of
Western Australia, Perth, WA,
has been shown to be highly effective at preventing to be ineffective, and in some cases harmful. These Australia (C H Heath);
relapse, superior to weekly amphotericin B and include high-dose dexamethasone,75 sertraline,76,77 and Dermatology Unit, Department
itraconazole capsules.50–52 Rarely, triazoles, such as tamoxifen.78 The debate regarding adjunctive exogenous of Medicine, Lagos University
voriconazole,53–60 posaconazole,61–63 or isavuconazole,64,65 interferon(IFN)-γ is unresolved. IFN-γ has been studied Teaching Hospital, University
of Lagos, Lagos, Nigeria
are used as alternatives to fluconazole due to concerns of in two randomised trials of HIV-associated cryptococcal (Prof O O Ayanlowo FWACP);
fluconazole resistance, drug toxicity, or drug–drug meningitis, which suggested faster clearance of yeasts in Centre for Respiratory Diseases
interactions. Notably, none of the newer triazoles have the CSF,79,80 but further studies are needed. There is no Research, Kenya Medical
Research Institute, Nairobi,
been formally trialled in cryptococcosis and none are trial evidence supporting its use in non-HIV-associated
Kenya (O M Mashedi MSc);
readily available in low-income settings (appendix p 30). cryptococcal meningitis (appendix p 65). Department of Public Health,
A low incidence of cryptococcal meningitis relapse is Hospital de Clínicas, Federal
observed after a minimum of 1 year of antifungal therapy Cryptococcal meningitis in SOT recipients University of Paraná, Curitiba,
Brazil
in people living with HIV established on ART, who are Cryptococcosis is the third most common invasive fungal
(F Queiroz-Telles Filho PhD);
virologically suppressed or have a CD4 count more than infection in SOT recipients, with an incidence Department of Medicine,
100 cells/mm³.66–72 of 4·5–33·8%26,28,29 and causing considerable mortality.12 Division of Infectious Diseases,
A management algorithm is described in figure 2 and SOT recipients encompass a third of non-HIV-related University of North Carolina at
Chapel Hill School of Medicine,
key principles are discussed in panel 5. Recommendations cryptococcosis in the USA.81 The majority of cryptococcosis

Review
Antifungal availability
All available *Liposomal amphotericin B 3–4 mg/kg daily †Single dose 10 mg/kg liposomal
and flucytosine 25 mg/kg four times a day amphotericin B with 14 days of flucytosine
for 2 weeks Allt 25 mg/kg four times a day and fluconazole
1200 mg daily AI
No liposomal amphotericin B available Amphotericin B lipid complex 5 mg/kg daily

and flucytosine 25 mg/kg four times a day
for 2 weeks BII
No liposomal amphotericin B or ‡Amphotericin B 0·7–1 mg/kg daily and ‡Amphotericin B 1 mg/kg daily and
amphotericin B lipid complex available flucytosine 25 mg/kg four times a day for flucytosine 25 mg/kg four times a day for one
2 weeks BI week, followed by fluconazole 1200 mg for
one week BI
No flucytosine available Liposomal amphotericin B 3–4 mg/kg daily Amphotericin B lipid complex 5 mg/kg daily †Amphotericin B 0·7–1 mg/kg daily and
and §fluconazole 800–1200 mg daily for and §fluconazole 800–1200 mg daily for §fluconazole 800–1200 mg daily for 2 weeks
2 weeks BIII 2 weeks BIII BI
No ¶polyene antimycotic available Flucytosine 25 mg/kg four times a day and

§fluconazole 800–1200 mg daily for 2 weeks
BI Grades of recommendation
Only fluconazole available §Fluconazole 800–1200 mg daily for 2 weeks A. Strongly recommended
CI B. Moderately recommended
C. Marginally recommended
Figure 3: HIV-cryptococcal meningitis antifungal induction treatment recommendations by antifungal drug availability
Grading of recommendation and level of evidence in bolded red letters. *Has not been compared with †. †Has only been trialled in HIV-cryptococcal meningitis. ‡Amphotericin B: 1 mg/kg showed
earlier fungicidal activity than 0·7 mg/kg, but some institutions use the low dose due to toxicity concerns. §Fluconazole induction doses of up to 1200 mg daily have been trialled but caution is advised;
consider drug–drug interaction and liver toxicity. ¶Polyene antimycotic includes amphotericin B formulations such as conventional deoxycholate amphotericin B, liposomal amphotericin B, and
amphotericin B lipid complex.
Chapel Hill, NC, USA in SOT occurs late (ie, months or years after no single therapeutic regimen or duration that meets all
(Prof M C Hosseinipour MD); transplantation) and is due to reactivated disease; however, patients’ needs, but the therapeutic principles mirror
UNC Project Malawi, Lilongwe,
Malawi (Prof M C Hosseinipour);
acute donor-derived infections have been described.14,82,83 cryptococcal meningitis treatment in high-income
Department of Infectious Anti-rejection drugs vary in their degree of immuno settings, with liposomal amphotericin B 3–4 mg/kg daily
Diseases, Sterling Hospitals, suppression and heart and small bowel transplant and flucytosine 25 mg/kg four times a day as induction
Ahmedabad, India recipients are at the highest cryptococcal meningitis therapy. Induction therapy can be extended in those with
(A K Patel MD); Africa Centers
for Disease Control and
risk.84 CNS and pulmonary cryptococcosis dominate but persistently positive CSF cultures or persistent symptoms
Prevention, Addis Ababa, unusual manifestations, including cutaneous disease85,86 at 2 weeks. In 2022, the combination of liposomal
Ethiopia (E Temfack MD); and pericarditis,87 have been reported. Notably, blood amphotericin B and flucytosine was shown to have a low
Division of Infectious Diseases, cryptococcal antigen can be negative in SOT recipients acute mortality of 6% in a nationwide observational study
Department of Medicine,
University of Pittsburgh,
with cryptococcosis, particularly those with single of non-HIV-associated cryptococcal meningitis in Japan.91
Pittsburgh, PA, USA pulmonary nodules or in lung transplant recipients.88 Figure 4B contains recommendations for treatment in
(Prof N Singh MD); Clinical Trials There are no randomised treatment trials targeted people without HIV or SOT (appendix pp 18, 62).
Centre Cologne, Faculty of specifically at SOT recipients; hence, recommendations
Medicine and University
Hospital Cologne, University of
are extrapolated from evidence in people living with HIV. Pulmonary cryptococcosis
Cologne, Cologne, Germany The use of lipid-formulations in SOT recipients with There are no randomised treatment studies in pulmonary
(Prof Oliver A Cornely); Division CNS cryptococcosis was independently associated with crypto
coccosis. Case series and clinical knowledge
of Infectious Diseases and
reduced mortality compared with amphotericin B.89 The suggest that for patients with cryptococcaemia and
International Medicine,
Department of Medicine, AMBITION-cm regimen has not been studied in evidence of CNS involvement, those with blood
University of Minnesota, non-HIV patients, and the evidence for high dose cryptococcal antigen titres more than 1:512 by latex
Minneapolis, MN, USA fluconazole (with the ensuant potential toxicity and drug– agglutination (or ten-fold higher by lateral flow assay),92 or
(Prof D R Boulware MD);
drug interactions) in this group is absent. A precipitous severe pulmonary disease should be treated as
Université de Paris Cité, APHP,
Service des Maladies reduction in dosing of immunosuppressants, particularly cryptococcal meningitis.33,35,93,94 Patients with mild isolated
Infectieuses et Tropicales, calcineurin inhibitors, can lead to C-IRIS.90 Figure 4B pulmonary disease without cryptococcoma have been
Hôpital Necker-Enfants contains recommendations for treatment in SOT successfully treated with fluconazole monotherapy of
Malades, Centre d’Infectiologie
recipients (appendix p 62).
Necker-Pasteur, Institut
Imagine, Paris, France
(Prof O Lortholary MD); Institut Cryptococcal meningitis in people without HIV
Pasteur, CNRS, Unité de or SOT Figure 4: Antifungal treatment recommendations for cryptococcal
Mycologie Moléculaire, Centre meningitis
The group of people without HIV or SOT is heterogeneous, (A) Recommendations for people with HIV. (B) Recommendations for SOT
National de Référence Mycoses
Invasives et Antifongiques, ranging from apparently healthy people to those with recipients and patients without HIV or SOT. SOT=solid organ transplant.
UMR 2000, Paris, France haematological malignancies or liver cirrhosis. There is CSF=cerebrospinal fluid. TDM=therapeutic drug monitoring.

Review
A People with HIV

First-line therapies
Induction (2 weeks) Consolidation (8 weeks) Maintenance (12 months or until immune restoration)
(AIIt) Liposomal amphotericin B 3–4 mg/kg daily plus flucytosine (AI) Fluconazole 400–800 mg daily (800 mg preferred in (AIIt) Fluconazole 200 mg daily
25 mg/kg four times a day (preferred in high-income settings); or low-income settings)
(AI) Single dose liposomal amphotericin B 10 mg/kg and 14 days
of flucytosine 25 mg/kg four times a day and fluconazole 1200 mg
daily (recommended in low-income settings)
Alternative therapies
If liposomal amphotericin B is not available: (BIII) Voriconazole 200 mg twice a day (with TDM)
(BIIt) Amphotericin B lipid complex 5 mg/kg daily plus flucytosine
25 mg/kg four times a day
(BIII) Posaconazole 300 mg daily (with TDM)
If liposomal amphotericin B and amphotericin B lipid complex

are not available: (BIII) Isavuconazole 200 mg daily
(BI) Amphotericin B 0·7–1·0 mg/kg daily plus flucytosine 25 mg/kg
four times a day; or
(CIIt) Itraconazole 200 mg twice a day (with TDM)
(BI) Amphotericin B 1 mg/kg daily and 5-flucytosine
25 mg/kg four times a day for 1 week, followed by fluconazole
1200 mg daily for 1 week Comments:
• (AIIu) Opening pressure should be measured at every lumbar puncture in patients with cryptococcal meningitis
• (AIIu) The use of amphotericin B and liposomal amphotericin B should be accompanied by pre-hydration and aggressive
If flucytosine is not available:
potassium and magnesium replacement therapy
(BIII) Liposomal amphotericin B 3–4 mg/kg daily plus fluconazole
• (AIIu) In-hospital care for the first 1–2 weeks is encouraged to manage the early complications of cryptococcal meningitis therapy
800–1200 mg daily;
• (BIII) Monitoring of flucytosine drug concentration is recommended, where available and if timely; particularly with renal
(BIII) Amphotericin B lipid complex 5 mg/kg daily plus fluconazole
dysfunction
800–1200 mg daily; or
• (AIIu) Check for drug–drug interactions and adjust doses as necessary
(BI) Amphotericin B 0·7–1 mg/kg daily plus fluconazole
• (CIIu) Consider performing a lumbar puncture at the end of the first or second week of induction therapy to check for CSF sterility
800–1200 mg daily
before antiretroviral therapy (ART) commencement
• (CIIu) Consider prolonging induction therapy if CSF is persistently culture positive at 2 weeks
If amphotericin B-based therapies are not available: • (CIIt) Adjunctive recombinant interferon-γ might be considered for persistently positive CSF yeast cultures in people with
(BI) Flucytosine 25 mg/kg four times a day and fluconazole HIV-associated cryptococcal meningitis who have evidence of poor inflammatory responses or persistently positive cryptococcal
800–1200 mg daily CSF culture after prolonged antifungal therapy
• (DI) The routine use of high-dose dexamethasone in cryptococcal meningitis is not recommended
• (CIII) A short course of dexamethasone can be considered for specific indications such as symptomatic space-occupying lesions in
If only fluconazole is available: the CNS with surrounding oedema or mass effect and cerebral vasculitis
(CI) Fluconazole 800–1200 mg daily • (BIIu) Cease maintenance therapy after 12 months of antifungal therapy in patients aviraemic on ART with a CD4 count more
than 100 cells per mm³
• (AIII) Restart maintenance therapy if CD4 count drops to less than 100 cells per mm³
B SOT recipients and people without HIV or SOT

First-line therapies
Induction (minimum 2 weeks) Consolidation (8 weeks) Maintenance (12 months)

(AIIt) Liposomal amphotericin B 3–4 mg/kg daily plus flucytosine (AIIt) Fluconazole 400–800 mg daily (AIIt) Fluconazole 200 mg daily
25 mg/kg four times a day
Alternative therapies
If liposomal amphotericin B is not available: (BIII) Voriconazole 200 mg twice a day (with TDM)
(BIIt) Amphotericin B lipid complex 5 mg/kg daily plus
flucytosine 25 mg/kg four times a day
(BIII) Posaconazole 300 mg daily (with TDM)
If liposomal amphotericin B and amphotericin B lipid complex

are not available: (BIII) Isavuconazole 200 mg daily
(BIIt) Amphotericin B 0·7–1·0 mg/kg daily plus flucytosine
25 mg/kg four times a day (CIIt) Itraconazole 200 mg twice a day (with TDM)
If amphotericin B-based therapies are not able to be used: Comments:

(CIIt) flucytosine 25 mg/kg four times a day plus fluconazole • Recommendations in HIV patient population are also applicable
800–1200 mg daily • (AIII) Induction therapy with liposomal amphotericin B and flucytosine should be considered for any disseminated disease or
isolation from a sterile site (even in the absence of CNS manifestations)
Grades of recommendation • (AIII) Close monitoring of tacrolimus, cyclosporine, and sirolimus concentrations (TDM) and dose reduction of these agents are
A. Strongly recommended recommended when azoles are co-administered73,74
B. Moderately recommended • (BIII) Immunosuppressant doses need to be carefully adjusted to allow effective killing of yeasts but should be reduced slowly to
C. Marginally recommended avoid precipitating cryptococcosis-associated immune reconstitution inflammatory syndrome; consider a sequential or stepwise
reduction of immunosuppressants with careful lowering of corticosteroids early and eliminating mycophenolate before
considering reduction of the calcineurin inhibitors because of their direct anticryptococcal activity
• (CIII) In a patient treated for cryptococcosis, retransplantation or a new organ transplant can be considered, provided viable
yeasts have been cleared from CSF and the patient is asymptomatic after receiving 12 months of anticryptococcal treatment

Review
(Prof O Lortholary); Mycoses pressure and do not necessarily indicate direct eye
Study Group Central Unit, Panel 6: Recommendations for pulmonary cryptococcosis involvement. Ocular cryptococcosis can occur98,99 but
Division of Infectious Diseases,
• Stratify treatment by disease severity and presence of is unusual and requires formal ophthalmological
Department of Medicine,
University of Alabama at pulmonary cryptococcoma (appendix pp 22, 67, 84) documentation and management. Isolated skeletal
Birmingham, Birmingham, AL, • Isolated pulmonary cryptococcosis in immunocompetent osteomyelitis is rare and often requires a combined
USA (Prof P G Pappas MD); or immunocompromised host: surgical and medical approach.100–102 Skin lesions might
Division of Infectious Diseases,
• (AIIu) Severe disease: as for CNS disease be polymorphic (panel 7; appendix p 67).
Department of Medicine, Duke
University Medical Center, • (BIIu) Mild disease: fluconazole 400 mg daily for
Durham, NC, USA 6–12 months (range guided by symptom resolution) Specific management issues
(Prof J R Perfect MD); • Pulmonary cryptococcosis with CNS manifestations or Raised intracranial pressure
Department of Molecular
other evidence of dissemination (eg, cryptococcaemia or Increased intracranial pressure has been associated with
Genetics and Microbiology,
Duke University Medical skin lesions) a high burden of cryptococci, leading to both acute and
Center, Durham, NC, USA • (AIIt) as for CNS disease chronic symptoms and signs (eg, visual and hearing loss)
(Prof J R Perfect) • (AIII) If the presence of Cryptococcus spp in respiratory and decreased short-term survival. Clinical experience
Correspondence to: specimen is deemed as airway colonisation after careful has shown that CSF outflow obstruction can be improved
Dr Christina C Chang,
evaluation and no treatment is elected, regular follow-up by removal of CSF; observational studies suggested that
Diseases, Alfred Hospital, is recommended, especially in the setting of future scheduled therapeutic lumbar punctures result in
Melbourne 3181, VIC, Australia immunosuppression substantial improvement in survival, regardless of
christina.chang@monash.edu • Pulmonary cryptococcoma (see cryptococcoma section) opening pressure.103,104 For prolonged control of acute
or increased intracranial pressure, use of lumbar drains in
Prof John R Perfect, Division of cases without hydrocephaly or ventriculostomies in
Infectious Diseases, Department
Panel 7: Recommendations for non-pulmonary non-CNS cases with hydrocephaly might be required.105–107
of Medicine, Duke University
Medical Center, Durham, disease Medical therapies including acetazolamide, mannitol,
NC 27710, USA • (AIIu) The recommendation for cryptococcaemia is to and corticosteroids can be detrimental (panel 8;
john.perfect@duke.edu
treat the same as for CNS disease appendix p 79).108,109
See Online for appendix
• (AIII) The recommendation for primary cutaneous (skin)
cryptococcosis, attributed to direct inoculation without Timing of ART commencement
evidence of dissemination, is fluconazole 400 mg daily for The optimal time to commence ART for HIV infection
3–6 months or until healed during cryptococcosis is controversial. Four randomised
• (BIIu) For all other non-CNS non-pulmonary disseminated trials3,110–112 to find out the optimal timing of ART initiation
disease treat the same as CNS disease in HIV-cryptococcal meningitis co-infection have been
• (BIIu) Cryptococcal eye disease should be managed in done in low-income settings, using induction regimens
collaboration with an ophthalmologist that are not currently preferred, including fluconazole
(800 mg daily) monotherapy,110 amphotericin B 0·7 mg/kg
daily,111 and amphotericin B 0·7–1 mg/kg daily and
400 mg daily.93,95,96 Some clinicians consider watchful- fluconazole 800 mg daily for 2 weeks. These data seem to
waiting and elect not to treat asymptomatic immuno suggest that initiating ART within 2 weeks of cryptococcal
competent people who incidentally culture any meningitis presentation is too early in the setting of
Cryptococcus spp in their sputum and have no radiological suboptimal antifungal therapy, and that delaying ART
features of pulmonary cryptococcosis, as they consider initiation for 4–6 weeks reduces the incidence of C-IRIS
this presentation to be airway colonisation.97 Criteria for and death. CSF sterility before ART commencement
distinguishing colonisation from infection is uncertain might be another factor.45 A retrospective analysis of
(panel 6; appendix pp 22, 67). combined cohorts in high-income settings did not show
higher mortality in those receiving early ART in the first
Non-pulmonary non-CNS disease two weeks of antifungal therapy compared with those
Cryptococcosis can affect any organ following with delayed therapy.113 Early ART in high-income settings
haematogenous dissemination. Clinical presentation of will need careful justification and close monitoring;
non-CNS non-pulmonary disease without fungaemia further randomised studies might be helpful.114
is rare, but possible. The absence of documented There are no studies for timing ART initiation in other
fungaemia does not exclude dissemination. Barring forms of cryptococcosis, those with cryptococcal
direct inoculation into the skin following trauma, extra antigenemia, or those recommencing ART after a period
pulmonary disease is by definition disseminated disease of interruption. Early concerns that potent integrase
and generally requires consideration for aggressive inhibitors pose an increased risk of C-IRIS have been
induction therapy. There are no clinical treatment trials disproven.115 Whether those presenting with cryptococcal
for non-pulmonary non-CNS cryptococcosis. meningitis within 2 weeks of starting ART require
Importantly, visual changes noted in cryptococcal withholding of ART is uncertain (panel 9; appendix
meningitis are frequently related to raised intracranial p 70).116–118

Review
Panel 8: Recommendations for raised intracranial pressure Panel 9: Recommendations for the timing of ART
• (AIIu) Opening pressure should be measured at every commencement
lumbar puncture in patients with cryptococcal meningitis • (DI) Immediate or very early commencement of ART is
• (AIII) A brain CT should be done (if CNS imaging not not recommended.
already done) to exclude CNS outflow obstruction • (AI) If suboptimal antifungal induction therapy is used,
• (Allt) Acute symptomatic elevation of the intracranial delay ART for 4–6 weeks.
pressure (≥20 cm of CSF) should be managed by daily • (BIIu) If optimal antifungal induction therapy was used,
therapeutic lumbar punctures (ie, removal of sufficient consider further individualisation, taking into
CSF, usually around 20–30 mL), to reduce the pressure to consideration resolution of symptoms and signs of
50% of opening pressure or to a normal pressure of cryptococcal meningitis, intracranial pressure (including
≤20 cm of CSF (documented as a closing pressure) normalisation of opening pressure), attainment of CSF
• (BIIu) Perform a scheduled therapeutic lumbar puncture cryptococcal sterility, successful identification,
48–72 h after initial lumbar puncture or 7 days, regardless management of concurrent co-infections and other AIDS-
of initial opening pressure defining illnesses, the patient’s readiness for ART, and
• (Allt) Persistent raised symptomatic intracranial pressure, local experience of cryptococcal meningitis and C-IRIS
despite therapeutic lumbar punctures, should be management (usual range is 4–6 weeks).
managed by surgical decompression via temporary • (CIIt) If possible, ensure CSF is cryptococcal culture
lumbar drainage, shunting, or ventriculostomy, negative before ART commencement.
depending on local expertise and resources • (BIII) For people who have had ART who develop
• (BIII) Consider ventriculoperitoneal (preferential) and cryptococcal meningitis and might need to switch to
lumboperitoneal shunts (alternative) to control both second-line ART or recommence ART, a delay of
acute and chronic hydrocephalus if temporary measures 4–6 weeks is recommended.
are not successful. Ideally, insert shunts after institution • (CIII) Pending further studies, consider withholding ART
of effective antifungal therapy and restarting at 4–6 weeks in those presenting with
cryptococcal meningitis within 2 weeks of starting ART.
• (BIII) Patients with isolated pulmonary cryptococcosis or
Resistance to antifungals those with asymptomatic cryptococcal antigenemia can
Developing secondary resistance to flucytosine is common commence ART earlier (eg, at 2 weeks).
when given as monotherapy, necessitating its use with a
partner drug in cryptococcosis. Acquired resistance to
polyenes, such as amphotericin B, is rare, but the Panel 10: Recommendations for antifungal resistance
emergence of fluconazole resistance is concerning.48,49,119 For those with fluconazole resistance or emerging fluconazole
Fluconazole monotherapy as induction therapy has been resistance:
associated with secondary resistance.120–123 • (BIII) Consider a long (eg, 4 weeks) course of induction
There are no clinical MIC breakpoints for fluconazole treatment with amphotericin B (1 mg/kg daily) or high
against Cryptococcus spp and insufficient data to suggest dose of liposomal amphotericin B (3–6 mg/kg daily)
that high MICs imply worse outcomes. Interpretation of together with flucytosine
epidemiological cutoff values with the Clinical and • (BIII) Consider amphotericin B 1 mg/kg weekly or
Laboratory Standards Institute (CLSI) method for liposomal amphotericin B 3–6 mg/kg weekly as
fluconazole requires accurate species identification. The consolidation or maintenance therapy. Consider daily
epidemiological cutoff values is 8 ug/mL for C neoformans voriconazole, posaconazole, isavuconazole, or
VNI, 16 ug/mL for C gattii VGI, and 32 ug/mL for itraconazole for isolates without evidence of pan-azole
Cryptococcus deuterogattii VGII.124 In principle, a higher resistance, as guided by antifungal susceptibility testing
than two-fold increase in MIC during treatment could • (CIII) If amphotericin B or liposomal amphotericin B are
suggest development of resistance and the need for not available, adding flucytosine to high-dose fluconazole
closer clinical monitoring. There are no European (1200 mg daily) could be considered
Committee on Antimicrobial Susceptibility Testing
(EUCAST) epidemiological cutoff values available for
fluconazole (panel 10; appendix p 72). infective and non-infective (CNS and non-CNS) causes
(figure 2). Cryptococcal antigen persists in the CSF and
Cryptococcal persistence, clinical relapse, and culture- blood, thus it has little clinical utility in distinguishing
positive (microbiological) relapse clinical responders from non-responders.125 Most cases of
Distinguishing clinical relapse from persistent crypto culture-positive (microbiological) relapse occur early and
coccal infection is challenging. Clinical relapse can be due result from inadequate or suboptimal induction therapy
to a microbiological relapse, C-IRIS, raised intracranial or early discontinuation of consolidation or maintenance
pressure (whether related to C-IRIS or not), or other therapy (figure 2; panel 11; appendix p 74).

Review
C-IRIS
Panel 11: Recommendations for cryptococcal persistence, clinical relapse, and C-IRIS has been described in people with HIV usually
culture-positive (microbiological) relapse between 2 weeks and 3 months after commencement of
• (AIIt) Think broadly and investigate thoroughly for causality (CNS or non-CNS and ART. Patients develop exaggerated symptoms and signs
infective or non-infective) in cases of apparent clinical relapse; investigations should or atypical inflammation, reminiscent of a paradoxical
include brain CT or MRI, lumbar puncture for opening pressure, and CSF analyses, recurrence,126,127 but C-IRIS can also occur in the setting of
including microscopy and culture immune recovery or withdrawal of immunosuppressants.
• (AIIu) Review adherence to antifungal therapy, ART, immunosuppressants, and other It has also been observed in seemingly immunocompetent
medications and consider drug–drug interactions; perform therapeutic drug individuals, including in C gattii infections, as a post-
monitoring if applicable. Optimise control of underlying diseases infectious inflammatory immune response syndrome
• (CIII) Consider escalating antifungal therapy while awaiting CSF results (and (PIIRS).90,128 There is no diagnostic biomarker for C-IRIS.
de-escalate if culture-negative) It is diagnosed by diagnosis of exclusion (figure 2).
• (Dllu) The use of follow-up blood or CSF cryptococcal antigen (including monitoring There have been no therapeutic trials in C-IRIS.
of titres) for clinical decision making is discouraged Management strategies include therapeutic lumbar
• (Dllu) Do not escalate antifungal therapy for persistent blood antigenemia, puncture and symptomatic therapies. In severe C-IRIS,
persistently positive CSF cryptococcal antigen, visible cryptococci in CSF (without corticosteroids are commonly used to dampen
culture positivity), or abnormal CSF microscopy or biochemistry; these are not inflammation, although their efficacy has not been
necessarily indicators of microbiological failure rigorously examined in clinical trials. In steroid-refractory
For culture-positive (microbiological) persistent or relapsed infection (figure 1): C-IRIS, there are case reports on the use of tumour
• (BIII) Antifungal susceptibility testing should be done concurrently on all initial and necrosis factor-α blockers, such as adalimumab129–132 or
relapse isolates (if stored and available); an increase in fluconazole MIC of more than thalidomide,133–135 with mixed success. Corticosteroids can
two dilutions is considered concerning for the potential development of drug also be beneficial in PIIRS (panel 12; appendix p 76).136
resistance
• (BIII) Consider reinduction with a more optimal regimen (guided by antifungal C gattii
susceptibility testing) About 50–70% of C gattii infections occur in putatively
immunocompetent hosts,137–139 compared with 2–30% in
people with HIV.140–144 Autoantibodies to granulocyte-
macrophage colony-stimulating factor and idiopathic
Panel 12: Recommendations for C-IRIS CD4 lymphopenia are reported risk factors.137,145–147 Notably,
• (Allt) For patients with suspected paradoxical C-IRIS, carefully exclude recurrent not all commercial lateral flow assays are able to detect
cryptococcal disease or new infective or non-infective conditions before attributing C gattii disease.148 Antifungal agents used for treatment
symptoms and signs to C-IRIS; perform a brain MRI and lumbar puncture to measure are the same as for C neoformans.30,32,141 However,
opening pressure and get CSF for microbiological and biochemical analyses 4–6 weeks of induction therapy might be required in
• (AIIu) Treatment of C-IRIS should include therapeutic lumbar puncture and some cases of non-HIV-associated meningitis with
symptomatic therapy, such as analgesia, antiemetics, and antiepileptics, if appropriate C gattii (panel 13; appendix p 81).149
• (AIII) Continue antifungal therapy
• (Blll) High-dose prednisolone or prednisone (usually 0·5–1·0 mg/kg daily) or Cryptococcomas
dexamethasone (usually 0·2–0·3 mg/kg daily), weaned over 4–6 weeks, can be Cryptococcomas occur predominantly in the lungs and
considered in those with persistent symptoms who are unresponsive to therapeutic brain and are more frequent in C gattii infection.140,150
lumbar punctures; rarely a second steroid course with taper is needed CNS cryptococcomas can manifest as neurological
• (DIII) Do not stop ART deficits or raised intracranial pressure,140 which requires
• (BIII) Cases of steroid-refractory or recurrent C-IRIS should be discussed with experts in urgent management. Corticosteroids and surgical
the field resection can be of value.149,151,152 Radiological lesions can
• (BIIu) Steroids could be considered for PIIRS persist indefinitely despite clinical and microbiological
cure (panel 14; appendix p 84).32,153 Recommendations for
cryptococcomas are in.
Panel 13: Recommendations for C gatti Non-C neoformans and non-C gattii strains of
In C gattii CNS disease: cryptococcus
• (AIII) Treat the same as C neoformans CNS infection There are individual case reports and small case series
• (BIII) In non-HIV patients, consider extending induction of non-C neoformans and non-C gattii cryptococcus
therapy to 4–6 weeks infections, predominantly in immunosuppressed patients.
• (AIII) Early CSF shunting is indicated for obstructive Papiliotrema laurentii (previously Cryptococcus laurentii)154
chronic hydrocephalus and Naganishia albida (previously Cryptococcus albidus)155
Treatment of C gattii lung disease is summarised in the account for about 80% of the invasive infections in this
appendix (p 17). group and usually involve the skin, lungs, bloodstream, or
CNS.156 Colonisation, especially of the skin, respiratory, and

Review
Panel 14: Recommendations for cryptococcomas Panel 15: Recommendations for non-C neoformans and non-C gattii strains of
• (AIII) Perform a biopsy or aspirate to exclude a secondary cryptococcus
pathogen or an underlying tumour in non-responding • (AIII) As non-C neoformans and non-C gattii Cryptococcus spp are rarely pathogenic,
cryptococcomas (particularly in immunosuppressed careful assessment of the laboratory identification and clinical context is required to
patients) ascertain clinical significance
• (BIII) Consider surgical resection for accessible brain • (CIII) For CNS or disseminated disease, treat the same as C neoformans CNS infection
lesions more than 3 cm, lesions at risk of compressing
critical structures, or large lesions not responding to
therapy Panel 16: Recommendations for cryptococcosis in pregnancy
• (DIII) During follow-up, do not prolong or escalate • (AIII) Use liposomal amphotericin B or amphotericin B in induction, consolidation,
therapy for persistent radiological findings in the absence and maintenance therapy and for the treatment of isolated cryptococcal antigenemia
of new or worsening symptoms or signs • (DII) Avoid the use of flucytosine and fluconazole in pregnancy, particularly in the first
For CNS cryptococcoma: trimester; their use in the second and third trimester requires careful individualised
• (BIII) Consider prolonging CNS antifungal induction risk–benefit assessment
therapy to 4–6 weeks • (BIII) Fluconazole can be used after delivery despite its excretion into breastmilk
• (BIII) Consider corticosteroids for large cryptococcomas • (AIII) Apply clinical judgement when considering initiation of antifungal therapy and
with surrounding mass effect or if neurological symptoms duration of therapy, factoring in trimester of pregnancy and severity of illness
and cerebral imaging signs worsen despite a good • (Clll) For asymptomatic cryptococcal antigen in pregnancy, consider intermittent
microbiological response polyene therapy, especially in the first trimester
The appendix (pp 22, 84) summarises treatment of lung
cryptococcoma.
Panel 17: Recommendations for paediatric cryptococcosis
For the treatment of CNS or disseminated disease:
gastrointestinal tracts must be distinguished from true • (AIIt) Induction: amphotericin B 1 mg/kg daily or liposomal amphotericin B 3–4 mg/kg
disease. In some cases, the laboratory might misidentify daily plus flucytosine (100– 150 mg/kg daily in 4 divided doses) for 2 weeks
another yeast as P laurentii or N albida on the basis of non- • (AIIt) Consolidation: fluconazole 12 mg/kg (maximum 800 mg) daily for 8 weeks
definitive commercial identification methods.157 Elevated • Maintenance: fluconazole 6 mg/kg daily (maximum 800 mg) for 6–12 months
MICs against flucytosine, fluconazole, and other azoles for • (AIIt) Should be provided for people who live with HIV and are
some isolates have been documented but are of uncertain immunocompromised
clinical significance (panel 15; appendix p 85).158,159 • (BIIt) Can be provided for people who are immunocompetent
• (AIII) For the treatment of severe isolated pulmonary diseases: treat the same as CNS
Pregnancy disease
The majority of cases of cryptococcosis in pregnancy occur • (AIII) Treatment of mild isolated pulmonary disease: fluconazole 12 mg/kg daily
in the third trimester or postpartum.160,161 Maternal mortality (maximum 800 mg) for 6–12 months
from disseminated cryptococcosis is approximately 25%, • (AIII) Screening is recommended for children older than 10 years living with HIV in
and less than 50% of women carry their pregnancy to high disease prevalence areas
term.161 Extensive clinical experience suggests that
amphotericin B and liposomal amphotericin B are safe
during pregnancy (Category B drug), and thus are the Conclusions
cornerstone of treatment.161,162 Flucytosine is rated by the Cryptococcosis and its management is complex and
USA Food and Drug Administration as a Category C drug challenging. Adherence to clinical practice guidelines can
because of its direct effects on RNA and DNA metabolism. improve outcomes.44,175 Although there has been substantial
Fluconazole is a Category D drug due to its increased risk development of evidence from randomised controlled
of musculoskeletal malformations, tetralogy of Fallot, trials over the past 20 years, there are considerable unmet
and spontaneous abortions (panel 16; appendix p 86).163–167 needs (appendix pp 23, 91). Addressing these challenges is
particularly crucial in low-income settings, where the
Paediatrics burden of disease is high and access to antifungal therapy
There is a clear need for paediatric-specific studies in is inadequate. Equally, more clinical research needs to be
cryptococcosis. CNS disease seems to predominate in done in high-income settings, where host risk profiles are
paediatrics, but non-CNS disease is probably under- changing and an increasing array of presentations of
reported.168–174 Clinical efficacy trials and studies to cryptococcosis are being recognised, necessitating more
validate diagnostic tests and therapies for cryptococcosis nuanced and individualised treatment plans.
in children are scarce. Recommendations are extra Contributors
polated from studies in adult populations. Dosing of JRP guided the structure, content, and development of the guideline.
antifungal agents needs particular attention for the OAC contributed to the conceptual planning, management, and
supervision of the project. CCC and JRP coordinated the work of the
paediatric patient (panel 17; appendix p 87).

Review
authors. TAB, CCC, MC, FH, TSH, OL, RO, JRP, TCS, AS, and MH reports receipt of an European and Developing Countries Clinical
AW contributed to the coordination of data collection, data visualisation, Trials Partnership. JNJ reports support from the National Institute for
and participants’ contributions and communication and wrote the first Health Research; grants from European and Developing Countries
manuscript draft. All authors contributed towards the literature review, Clinical Trials Partnership, joint global health trials (Wellcome Trust,
collection and preparation of data, creation of tabled recommendations, MRC, and UK aid) and CDC; speaker fees from Gilead Sciences;
and critical review of the manuscript. participation on a data safety and monitoring board for the HARVEST,
ARTIST, CASTLE, and ACACIA trials. GJ reports travel support to attend
Declaration of interests
a meeting at ISHAM. NK was a speaker and advisor for Gilead Sciences,
AA reports grants from the Agence Nationale de la Recherche; serving as
Merck/MSD, and Pfizer and a speaker for Astellas. MSL reports support
a consultant to Gilead Sciences; receiving speaking honoraria from
from the Division of Intramural Research, National Institute of Allergy
Gilead Sciences and PR Edition; travel support from Gilead sciences and
and Infectious Diseases (NIAID), and National Institutes of Health
Pfizer; and patents with the Institut Pasteur. J-WA reports grants or
(NIH). OL reports receipt of consulting fees and honoraria from Gilead
contracts from WHO (fungal priority pathogens list) and receipt of
Science and patents with INSERM APHP. OMM reports travel support
equipment and materials from the Westmead Hospital Foundation.
for ISHAM meeting in India and being the country ambassador for
JB reports support from the Australian National Health and Medical
Kenya for ISHAM. BJM reports being chair of the Australia and New
Research Council and receipt of honoraria from Gilead. TAB reports a
Zealand Paediatric Infectious Diseases Group. DBM reports leadership
personal research fellowship from Gilead Sciences; investigator-led
role in the Crypto Meningitis advocacy group. RO reports receiving
research grant from Pfizer; lecture honoraria and participation in
research and educational grant funding from Gilead Sciences, CDC
advisory boards for Gilead Sciences, Mundipharma, and Pfizer; and
Atlanta, and Pfizer Specialties and travel support from the CDC
participation in the Trial Steering Committee for a phase 2 trial of
foundation. PGP reports grants from Mayne, Astellas, Scynexis, and
inhaled opelconazole (Pulmocide). FC reports speaker honoraria from,
Cidara and receipt of consulting fees from F2G and Cidara. AKP reports
and being part of, an advisory board for Pfizer and United Medical.
speaker honoraria for Gilead Science, Pfizer India, and Intas
CCC reports receipt of an Early Career Fellowship from the Australian
pharmaceutical. JRP reports grants from NIH, Appili, and Sfunga;
National Health and Medical Research Foundation, receipt of a speaker
royalties from Up-To-Date; and participation on a data safety monitoring
travel support for IDweek 2024, being a principal investigator in an early
board or advisory board from Pulmocide, EFFECT trial, and IMPRINT
phase clinical trial unit, and was a recipient of the Australian National
trial. FQ-TF reports receipt of speaker honoraria from Pfizer and United
Health and Medical Research Council Early Career Fellowship
Medical, travel support and laboratory diagnostic kits from IMMY, and
(APP 1092160). MC reports grants from Cidara, F2G, Pfizer, and Janssen;
leadership roles in Infocus Latin America. JS-G reports speaker
receipt of honoraria from Pfizerm MSD and Gilead; and travel support
honoraria from Gilead and Pfizer and is on an advisory committee for
from Pfizer. SCC reports untied educational grants from MSD Australia
Pfizer. AS reports grants from Astellas and receiving consulting fees
and F2G and is on the antifungal advisory boards of MSD Australia,
from Scynexis. RSp has received speaker honoraria from Pfizer and
Gilead Sciences, and F2G. OAC reports grants or contracts from BMBF,
reports being chair of Young European Confederation of Medical
Cidara, EU-DG RTD (101037867), F2G, Gilead, MedPace, MSD,
Mycology. TT reports receipt of honoraria from Pfizer, MSD, Asahikasei
Mundipharma, Octapharma, Pfizer, and Scynexis; consulting fees from
pharma, and Sumitomo pharma. AW reports a grant from UK Research
AbbVie, AiCuris, Biocon, Cidara, Gilead, IQVIA, Janssen, Matinas,
and Innovation; receipt of consultant fees from Gilead and
MedPace, Menarini, Moderna, Molecular Partners, MSG-ERC, Noxxon,
MundiPharma; speaker fees from F2G and Gilead; and participation as a
Octapharma, Pfizer, PSI, Scynexis, and Seres; honoraria for lectures from
data safety monitoring board member for the RECOVERY trial.
Abbott, AbbVie, Al-Jazeera Pharmaceuticals, Hikma, Gilead, Grupo
All declarations are outside the submitted work. All other authors declare
Biotoscana/United Medical/Knight, MedScape, MedUpdate, Merck/
no competing interests.
MSD, Noscendo, Pfizer, Shionogi, and streamedup!; payment for expert
testimony from Cidara; participation on a data safety monitoring board Acknowledgments
or advisory board from Boston Strategic Partners, Cidara, IQVIA, This work was supported in part by the Division of Intramural
Janssen, MedPace, PSI, Pulmocide, Shionogi, and The Prime Meridian Research of National Institute of Allergy and Infectious Diseases and
Group; a patent at the German Patent and Trade Mark Office the National Institutes of Health. We thank the many reviewers from
(DE 10 2021 113 007·7); stocks from CoRe Consulting and EasyRadiology; the 75 international societies (appendix p 32)who provided helpful and
other interests from Wiley; support from the German Federal Ministry of constructive advice on the guidelines during the public consultation
Research and Education; and funding by the Deutsche process and thank Andreas Mazzella for assistance with figure 2.
Forschungsgemeinschaft under Germany’s Excellence Strategy (Cologne
References
Cluster of Excellence on Cellular Stress Responses in Aging-associated
1 WHO. WHO fungal priority pathogens list to guide research,
Diseases, EXC 2030—390661388). J-PG reports speaker honoraria from development and public health action. Geneva: World Health
Gilead, MundiPharma, and Pfizer. NPG reports grants from National Organization, 2022.
Institutes of Health (USA), National Institute of Health and Care 2 Day JN, Chau TTH, Wolbers M, et al. Combination antifungal
Research (UK), Medical Research Council (MRC; UK), Centers for therapy for cryptococcal meningitis. N Engl J Med 2013; 368: 1291–302.
Disease Control and Prevention (CDC; USA), and National Health 3 Boulware DR, Meya DB, Muzoora C, et al. Timing of antiretroviral
Laboratory Service Research Trust (South Africa); participation in the therapy after diagnosis of cryptococcal meningitis. N Engl J Med
ACACIA trial as part of the data safety monitoring board, project 2014; 370: 2487–98.
committee of DREAMM, project advisory committee for 5FC Crypto, and 4 Beardsley J, Wolbers M, Kibengo FM, et al. Adjunctive
leadership roles in the Federation of Infectious Diseases Societies of dexamethasone in HIV-associated cryptococcal meningitis.
Southern Africa. AHG reports grants from Gilead Sciences; personal fees N Engl J Med 2016; 374: 542–54.
from Amplyx, Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp & 5 Brouwer AE, Rajanuwong A, Chierakul W, et al. Combination
Dohme, Mundipharma, Pfizer, and Scynexis; speaker honoraria from antifungal therapies for HIV-associated cryptococcal meningitis:
Gilead Sciences and MSD; and participation in an advisory board for a randomised trial. Lancet 2004; 363: 1764–67.
Astellas, Mundipharma, Partner Therapeutics, and Pfizer. FH reports 6 Jarvis JN, Lawrence DS, Meya DB, et al. Single-dose liposomal
grants from Health Holland and European Society for Clinical amphotericin B treatment for cryptococcal meningitis. N Engl J Med
Microbiology and Infectious Diseases; leadership roles as treasurer of the 2022; 386: 1109–20.
Netherlands Society for Medical Mycology, Chair of the Division 7 Molloy SF, Kanyama C, Heyderman RS, et al. Antifungal
Microbial Genomics of the Royal Netherlands Society for Microbiology, combinations for treatment of cryptococcal meningitis in Africa.
Vice-President International Society for Human and Animal Mycology N Engl J Med 2018; 378: 1004–17.
(ISHAM); and receipt of evaluation kits from Bruker and Pathonostics. 8 Bicanic T, Wood R, Meintjes G, et al. High-dose amphotericin B with
TSH reports receipt of an investigator award from Gilead Sciences, flucytosine for the treatment of cryptococcal meningitis in HIV-
honoraria from Pfizer and Gilead Sciences, and participation in a data infected patients: a randomized trial. Clin Infect Dis 2008;
47: 123–30.
safety monitoring board or advisory board for Viamet and F2G.

Review
9 Rajasingham R, Govender NP, Jordan A, et al. The global burden of 28 George IA, Spec A, Powderly WG, Santos CAQ. Comparative
HIV-associated cryptococcal infection in adults in 2020: a modelling epidemiology and outcomes of human immunodeficiency virus
analysis. Lancet Infect Dis 2022; 22: 1748–55. (HIV), non-HIV non-transplant, and solid organ transplant
10 WHO. Guidelines for diagnosing, preventing and managing associated cryptococcosis: a population-based study. Clin Infect Dis
cryptococcal disease among adults, adolescents and children living 2018; 66: 608–11.
with HIV. Geneva: World Health Organization, 2022. 29 Hevey MA, George IA, Raval K, Powderly WG, Spec A. Presentation
11 Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice and mortality of cryptococcal infection varies by predisposing
guidelines for the management of cryptococcal disease: 2010 update illness: a retrospective cohort study. Am J Med 2019; 132: 977–83.
by the infectious diseases society of America. Clin Infect Dis 2010; 30 Baddley JW, Chen SC, Huisingh C, et al. MSG07: an international
50: 291–322. cohort study comparing epidemiology and outcomes of patients
12 Baddley JW, Forrest GN. Cryptococcosis in solid organ with Cryptococcus neoformans or Cryptococcus gattii infections.
transplantation—guidelines from the American Society of Clin Infect Dis 2021; 73: 1133–41.
Transplantation Infectious Diseases Community of Practice. 31 Ngamskulrungroj P, Chang Y, Sionov E, Kwon-Chung KJ.
Clin Transplant 2019; 33: e13543. The primary target organ of Cryptococcus gattii is different from that of
13 Schmidt-Hieber M, Silling G, Schalk E, et al. CNS infections in Cryptococcus neoformans in a murine model. MBio 2012; 3: e00103–12.
patients with hematological disorders (including allogeneic stem- 32 Mitchell DH, Sorrell TC, Allworth AM, et al. Cryptococcal disease of
cell transplantation)—guidelines of the Infectious Diseases the CNS in immunocompetent hosts: influence of cryptococcal
Working Party (AGIHO) of the German Society of Hematology and variety on clinical manifestations and outcome. Clin Infect Dis 1995;
Medical Oncology (DGHO). Ann Oncol 2016; 27: 1207–25. 20: 611–16.
14 Singh N, Huprikar S, Burdette SD, Morris MI, Blair JE, Wheat LJ. 33 Charlier C, Dromer F, Lévêque C, et al. Cryptococcal
Donor-derived fungal infections in organ transplant recipients: neuroradiological lesions correlate with severity during cryptococcal
guidelines of the American Society of Transplantation, infectious meningoencephalitis in HIV-positive patients in the HAART era.
diseases community of practice. Am J Transplant 2012; 12: 2414–28. PLoS One 2008; 3: e1950.
15 Chang CC, Hall V, Cooper C, et al. Consensus guidelines for the 34 Tien RD, Chu PK, Hesselink JR, Duberg A, Wiley C. Intracranial
diagnosis and management of cryptococcosis and rare yeast cryptococcosis in immunocompromised patients: CT and
infections in the haematology/oncology setting, 2021. Intern Med J MR findings in 29 cases. AJNR Am J Neuroradiol 1991; 12: 283–89.
2021; 51 (suppl 7): 118–42. 35 van der Horst CM, Saag MS, Cloud GA, et al. Treatment of
16 Govender NP, Meintjes G, Mangena P, et al. Southern African HIV cryptococcal meningitis associated with the acquired
Clinicians Society guideline for the prevention, diagnosis and immunodeficiency syndrome. N Engl J Med 1997; 337: 15–21.
management of cryptococcal disease among HIV-infected persons: 36 Longley N, Muzoora C, Taseera K, et al. Dose response effect of
2019 update. South Afr J HIV Med 2019; 20: 1030. high-dose fluconazole for HIV-associated cryptococcal meningitis in
17 No authors listed. Guidelines for the prevention and treatment of southwestern Uganda. Clin Infect Dis 2008; 47: 1556–61.
opportunistic infections in adults and adolescents with HIV: 37 Gaskell KM, Rothe C, Gnanadurai R, et al. A prospective study of
recommendations from the Centers for Disease Control and mortality from cryptococcal meningitis following treatment
Prevention, the National Institutes of Health, and the HIV induction with 1200 mg oral fluconazole in Blantyre, Malawi.
Medicine Association of the Infectious Diseases Society of America. PLoS One 2014; 9: e110285.
July 1, 2021. https://clinicalinfo.hiv.gov/en/guidelines/adult-and- 38 Rothe C, Sloan DJ, Goodson P, et al. A prospective longitudinal
adolescent-opportunistic-infection/cryptococcosis?view=full study of the clinical outcomes from cryptococcal meningitis
(accessed May 30, 2022). following treatment induction with 800 mg oral fluconazole in
18 WHO. Guidelines on the diagnosis, prevention and management of Blantyre, Malawi. PLoS One 2013; 8: e67311.
cryptococcal disease in HIV-infected adults, adolescents and 39 Nussbaum JC, Jackson A, Namarika D, et al. Combination
children: supplement to the 2016 consolidated guidelines on the use flucytosine and high-dose fluconazole compared with fluconazole
of antiretroviral drugs for treating and preventing HIV infection. monotherapy for the treatment of cryptococcal meningitis:
Geneva: World Health Organization, 2018. a randomized trial in Malawi. Clin Infect Dis 2010; 50: 338–44.
19 Kung HC, Huang PY, Chen WT, et al. 2016 guidelines for the use of 40 Muzoora CK, Kabanda T, Ortu G, et al. Short course amphotericin
antifungal agents in patients with invasive fungal diseases in B with high dose fluconazole for HIV-associated cryptococcal
Taiwan. J Microbiol Immunol Infect 2018; 51: 1–17. meningitis. J Infect 2012; 64: 76–81.
20 European AIDS Clinical Society. Cryptococcosis. October 2021. 41 Jackson AT, Nussbaum JC, Phulusa J, et al. A phase 2 randomized
https://eacs.sanfordguide.com/ois/cryptococcosis (accessed controlled trial adding oral flucytosine to high-dose fluconazole,
Aug 18, 2022). with short-course amphotericin B, for cryptococcal meningitis.
21 Izumikawa K, Kakeya H, Sakai F, et al. Executive summary of AIDS 2012; 26: 1363–70.
JSMM clinical practice guidelines for diagnosis and treatment of 42 Charalambous LT, Premji A, Tybout C, et al. Prevalence, healthcare
cryptococcosis 2019. Med Mycol J 2020; 61: 61–89. resource utilization and overall burden of fungal meningitis in the
22 Cornely OA, Alastruey-Izquierdo A, Arenz D, et al. Global guideline United States. J Med Microbiol 2018; 67: 215–27.
for the diagnosis and management of mucormycosis: an initiative 43 Pyrgos V, Seitz AE, Steiner CA, Prevots DR, Williamson PR.
of the European Confederation of Medical Mycology in cooperation Epidemiology of cryptococcal meningitis in the US: 1997–2009.
with the Mycoses Study Group Education and Research PLoS One 2013; 8: e56269.
Consortium. Lancet Infect Dis 2019; 19: e405–21.
44 Bratton EW, El Husseini N, Chastain CA, et al. Approaches to
23 Chen SC, Perfect J, Colombo AL, et al. Global guideline for the antifungal therapies and their effectiveness among patients with
diagnosis and management of rare yeast infections: an initiative of cryptococcosis. Antimicrob Agents Chemother 2013; 57: 2485–95.
the ECMM in cooperation with ISHAM and ASM. Lancet Infect Dis
45 Chang CC, Dorasamy AA, Gosnell BI, et al. Clinical and
2021; 21: e375–86.
mycological predictors of cryptococcosis-associated immune
24 Huang SH, Chuang YC, Lee YC, et al. Lumbar puncture for reconstitution inflammatory syndrome. AIDS 2013; 27: 2089–99.
non-HIV-infected non-transplant patients with cryptococcosis:
46 Mootsikapun P, Chetchotisakd P, Anunnatsiri S,
should it be mandatory for all? PLoS One 2019; 14: e0221657.
Choksawadphinyo K. The efficacy of fluconazole 600 mg/day versus
25 Baddley JW, Perfect JR, Oster RA, et al. Pulmonary cryptococcosis in itraconazole 600 mg/day as consolidation therapy of cryptococcal
patients without HIV infection: factors associated with disseminated meningitis in AIDS patients. J Med Assoc Thai 2003; 86: 293–98.
disease. Eur J Clin Microbiol Infect Dis 2008; 27: 937–43.
47 Hope W, Stone NRH, Johnson A, et al. Fluconazole monotherapy is
26 Brizendine KD, Baddley JW, Pappas PG. Predictors of mortality and a suboptimal option for initial treatment of cryptococcal meningitis
differences in clinical features among patients with cryptococcosis because of emergence of resistance. MBio 2019; 10: e02575–19.
according to immune status. PLoS One 2013; 8: e60431.
48 Naicker SD, Mpembe RS, Maphanga TG, et al. Decreasing
27 Rajasingham R, Smith RM, Park BJ, et al. Global burden of disease fluconazole susceptibility of clinical South African Cryptococcus
of HIV-associated cryptococcal meningitis: an updated analysis. neoformans isolates over a decade. PLoS Negl Trop Dis 2020;
Lancet Infect Dis 2017; 17: 873–81. 14: e0008137.

Review
49 Smith KD, Achan B, Hullsiek KH, et al. Increased antifungal drug 68 Martínez E, García-Viejo MA, Marcos MA, et al. Discontinuation of
resistance in clinical isolates of Cryptococcus neoformans in Uganda. secondary prophylaxis for cryptococcal meningitis in HIV-infected
Antimicrob Agents Chemother 2015; 59: 7197–204. patients responding to highly active antiretroviral therapy. AIDS
50 Saag MS, Cloud GA, Graybill JR, et al. A comparison of itraconazole 2000; 14: 2615–17.
versus fluconazole as maintenance therapy for AIDS-associated 69 Mussini C, Pezzotti P, Miró JM, et al. Discontinuation of
cryptococcal meningitis. Clin Infect Dis 1999; 28: 291–96. maintenance therapy for cryptococcal meningitis in patients with
51 Bozzette SA, Larsen RA, Chiu J, et al. A placebo-controlled trial of AIDS treated with highly active antiretroviral therapy:
maintenance therapy with fluconazole after treatment of an international observational study. Clin Infect Dis 2004;
cryptococcal meningitis in the acquired immunodeficiency 38: 565–71.
syndrome. N Engl J Med 1991; 324: 580–84. 70 Vibhagool A, Sungkanuparph S, Mootsikapun P, et al.
52 Powderly WG, Saag MS, Cloud GA, et al. A controlled trial of Discontinuation of secondary prophylaxis for cryptococcal
fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in human immunodeficiency virus-infected patients
meningitis in patients with the acquired immunodeficiency treated with highly active antiretroviral therapy: a prospective,
syndrome. N Engl J Med 1992; 326: 793–98. multicenter, randomized study. Clin Infect Dis 2003; 36: 1329–31.
53 Bandettini R, Castagnola E, Calvillo M, et al. Voriconazole for 71 Sheng WH, Hung CC, Chen MY, Hsieh SM, Chang SC.
cryptococcal meningitis in children with leukemia or receiving Successful discontinuation of fluconazole as secondary
allogeneic hemopoietic stem cell transplant. J Chemother 2009; prophylaxis for cryptococcosis in AIDS patients responding to
21: 108–09. highly active antiretroviral therapy. Int J STD AIDS 2002;
54 Carbonara S, Regazzi M, Ciracì E, et al. Long-term efficacy and 13: 702–05.
safety of TDM-assisted combination of voriconazole plus efavirenz 72 Lortholary O, Poizat G, Zeller V, et al. Long-term outcome of
in an AIDS patient with cryptococcosis and liver cirrhosis. AIDS-associated cryptococcosis in the era of combination
Ann Pharmacother 2009; 43: 978–84. antiretroviral therapy. AIDS 2006; 20: 2183–91.
55 Gamaletsou MN, Sipsas NV, Kontoyiannis DP, et al. Successful 73 Dodds-Ashley E. Management of drug and food interactions with
salvage therapy of refractory HIV-related cryptococcal meningitis azole antifungal agents in transplant recipients. Pharmacotherapy
with the combination of liposomal amphotericin B, voriconazole, 2010; 30: 842–54.
and recombinant interferon-γ. Diagn Microbiol Infect Dis 2012; 74 Glotzbecker B, Duncan C, Alyea E 3rd, Campbell B, Soiffer R.
74: 409–11. Important drug interactions in hematopoietic stem cell
56 Nierenberg NE, Thompson GR 3rd, Lewis JS 2nd, Hogan BK, transplantation: what every physician should know.
Patterson TF. Voriconazole use and pharmacokinetics in combination Biol Blood Marrow Transplant 2012; 18: 989–1006.
with interferon-gamma for refractory cryptococcal meningitis in 75 Beardsley J, Wolbers M, Day JN. Dexamethasone in cryptococcal
a patient receiving low-dose ritonavir. Med Mycol 2010; 48: 532–36. meningitis. N Engl J Med 2016; 375: 189–90.
57 Perfect JR, Marr KA, Walsh TJ, et al. Voriconazole treatment for 76 Rhein J, Huppler Hullsiek K, Tugume L, et al. Adjunctive sertraline
less-common, emerging, or refractory fungal infections. for HIV-associated cryptococcal meningitis: a randomised, placebo-
Clin Infect Dis 2003; 36: 1122–31. controlled, double-blind phase 3 trial. Lancet Infect Dis 2019;
58 Loyse A, Wilson D, Meintjes G, et al. Comparison of the early 19: 843–51.
fungicidal activity of high-dose fluconazole, voriconazole, and 77 Villanueva-Lozano H, Treviño-Rangel RJ, González GM, et al.
flucytosine as second-line drugs given in combination with Clinical evaluation of the antifungal effect of sertraline in the
amphotericin B for the treatment of HIV-associated cryptococcal treatment of cryptococcal meningitis in HIV patients: a single
meningitis. Clin Infect Dis 2012; 54: 121–28. Mexican center experience. Infection 2018; 46: 25–30.
59 Sabbatani S, Manfredi R, Pavoni M, Consales A, Chiodo F. 78 Ngan NTT, Thanh Hoang Le N, Vi Vi NN, et al. An open label
Voriconazole proves effective in long-term treatment of a cerebral randomized controlled trial of tamoxifen combined with
cryptococcoma in a chronic nephropathic HIV-negative patient, amphotericin B and fluconazole for cryptococcal meningitis. eLife
after fluconazole failure. Mycopathologia 2004; 158: 165–71. 2021; 10: 10.
60 Yao Y, Zhang JT, Yan B, et al. Voriconazole: a novel treatment 79 Pappas PG, Bustamante B, Ticona E, et al. Recombinant interferon-
option for cryptococcal meningitis. Infect Dis (Lond) 2015; gamma 1b as adjunctive therapy for AIDS-related acute cryptococcal
47: 694–700. meningitis. J Infect Dis 2004; 189: 2185–91.
61 Espinel-Ingroff A, Aller AI, Canton E, et al. Cryptococcus 80 Jarvis JN, Meintjes G, Rebe K, et al. Adjunctive interferon-γ
neoformans–Cryptococcus gattii species complex: an international immunotherapy for the treatment of HIV-associated cryptococcal
study of wild-type susceptibility endpoint distributions and meningitis: a randomized controlled trial. AIDS 2012; 26: 1105–13.
epidemiological cutoff values for fluconazole, itraconazole, 81 Marr KA, Sun Y, Spec A, et al. A multicenter, longitudinal cohort
posaconazole, and voriconazole. Antimicrob Agents Chemother 2012; study of cryptococcosis in human immunodeficiency virus-
56: 5898–906. negative people in the United States. Clin Infect Dis 2020;
62 Esposito V, Viglietti R, Gargiulo M, et al. Successful treatment of 70: 252–61.
cryptococcal meningitis with a combination of liposomal 82 Sun HY, Alexander BD, Lortholary O, et al. Unrecognized
amphotericin B, flucytosine and posaconazole: two case reports. pretransplant and donor-derived cryptococcal disease in organ
In Vivo 2009; 23: 465–68. transplant recipients. Clin Infect Dis 2010; 51: 1062–69.
63 Pitisuttithum P, Negroni R, Graybill JR, et al. Activity of 83 Santos DWCL, Hagen F, Meis JF, et al. Donor-Derived
posaconazole in the treatment of central nervous system fungal Transmission of Cryptococcus gattii sensu lato in Kidney Transplant
infections. J Antimicrob Chemother 2005; 56: 745–55. Recipients. Emerg Infect Dis 2020; 26: 1329–31.
64 Schwartz S, Cornely OA, Hamed K, et al. Isavuconazole for the 84 Wu G, Vilchez RA, Eidelman B, Fung J, Kormos R, Kusne S.
treatment of patients with invasive fungal diseases involving the Cryptococcal meningitis: an analysis among 5521 consecutive
central nervous system. Med Mycol 2020; 58: 417–24. organ transplant recipients. Transpl Infect Dis 2002; 4: 183–88.
65 Thompson GR 3rd, Rendon A, Ribeiro Dos Santos R, et al. 85 Sun HY, Alexander BD, Lortholary O, et al. Cutaneous
Isavuconazole treatment of cryptococcosis and dimorphic mycoses. cryptococcosis in solid organ transplant recipients. Med Mycol 2010;
Clin Infect Dis 2016; 63: 356–62. 48: 785–91.
66 Aberg JA, Price RW, Heeren DM, Bredt B. A pilot study of the 86 Osawa R, Alexander BD, Lortholary O, et al. Identifying predictors
discontinuation of antifungal therapy for disseminated cryptococcal of central nervous system disease in solid organ transplant
disease in patients with acquired immunodeficiency syndrome, recipients with cryptococcosis. Transplantation 2010; 89: 69–74.
following immunologic response to antiretroviral therapy. 87 El Helou G, Hellinger W. Cryptococcus neoformans pericarditis in
J Infect Dis 2002; 185: 1179–82. a lung transplant recipient: case report, literature review and pearls.
67 Kirk O, Reiss P, Uberti-Foppa C, et al. Safe interruption of Transpl Infect Dis 2019; 21: e13137.
maintenance therapy against previous infection with four common 88 Singh N, Alexander BD, Lortholary O, et al. Pulmonary
HIV-associated opportunistic pathogens during potent antiretroviral cryptococcosis in solid organ transplant recipients: clinical relevance
therapy. Ann Intern Med 2002; 137: 239–50. of serum cryptococcal antigen. Clin Infect Dis 2008; 46: e12–18.

Review
89 Sun HY, Alexander BD, Lortholary O, et al. Lipid formulations of 112 Zhao T, Xu XL, Lu YQ, et al. The effect of early vs deferred
amphotericin B significantly improve outcome in solid organ antiretroviral therapy initiation in HIV-infected patients with
transplant recipients with central nervous system cryptococcosis. cryptococcal meningitis: a multicenter prospective randomized
Clin Infect Dis 2009; 49: 1721–28. controlled analysis in China. Front Med (Lausanne) 2021; 8: 779181.
90 Sun HY, Alexander BD, Huprikar S, et al. Predictors of immune 113 Ingle SM, Miro JM, May MT, et al. Early antiretroviral therapy not
reconstitution syndrome in organ transplant recipients with associated with higher cryptococcal meningitis mortality in people
cryptococcosis: implications for the management of with human immunodeficiency virus in high-income countries:
immunosuppression. Clin Infect Dis 2015; 60: 36–44. an international collaborative cohort study. Clin Infect Dis 2023;
91 Takazono T, Hidaka Y, Morimoto S, et al. Comparison of 77: 64–73.
liposomal amphotericin B alone and in combination with 114 Boulware DR, Jarvis JN. Timing of antiretroviral therapy in
flucytosine in the treatment of non-HIV cryptococcal cryptococcal meningitis: what we can (and cannot) learn from
meningitis: a nationwide observational study. Mycoses 2022; observational data. Clin Infect Dis 2023; 77: 74–76.
65: 897–902. 115 Kityo C, Szubert AJ, Siika A, et al. Raltegravir-intensified initial
92 Aissaoui N, Benhadid-Brahmi Y, Sturny-Leclère A, et al. antiretroviral therapy in advanced HIV disease in Africa:
Investigation of CryptoPS LFA-positive sera in patients at risk of a randomised controlled trial. PLoS Med 2018; 15: e1002706.
cryptococcosis. Med Mycol 2022; 60: myac078. 116 Rhein J, Hullsiek KH, Evans EE, et al. Detrimental outcomes of
93 Pappas PG, Perfect JR, Cloud GA, et al. Cryptococcosis in human unmasking cryptococcal meningitis with recent ART initiation.
immunodeficiency virus-negative patients in the era of effective Open Forum Infect Dis 2018; 5: ofy122.
azole therapy. Clin Infect Dis 2001; 33: 690–99. 117 Kalata N, Ellis J, Kanyama C, et al. Short-term mortality outcomes
94 Vilchez RA, Linden P, Lacomis J, Costello P, Fung J, Kusne S. Acute of HIV-associated cryptococcal meningitis in antiretroviral therapy-
respiratory failure associated with pulmonary cryptococcosis in naïve and therapy-experienced patients in sub-Saharan Africa.
non-aids patients. Chest 2001; 119: 1865–69. Open Forum Infect Dis 2021; 8: ofab397.
95 Nadrous HF, Antonios VS, Terrell CL, Ryu JH. Pulmonary 118 Alufandika M, Lawrence DS, Boyer-Chammard T, et al. A pragmatic
cryptococcosis in nonimmunocompromised patients. Chest 2003; approach to managing antiretroviral therapy-experienced patients
124: 2143–47. diagnosed with HIV-associated cryptococcal meningitis: impact of
96 Skolnik K, Huston S, Mody CH. Cryptococcal lung infections. antiretroviral therapy adherence and duration. AIDS 2020;
Clin Chest Med 2017; 38: 451–64. 34: 1425–28.
97 Shirley RM, Baddley JW. Cryptococcal lung disease. 119 Chen YC, Chang TY, Liu JW, et al. Increasing trend of fluconazole-
Curr Opin Pulm Med 2009; 15: 254–60. non-susceptible Cryptococcus neoformans in patients with invasive
98 Avendaño J, Tanishima T, Kuwabara T. Ocular cryptococcosis. cryptococcosis: a 12-year longitudinal study. BMC Infect Dis 2015;
Am J Ophthalmol 1978; 86: 110–13. 15: 277.
99 Wong BJ, Rao NA, Ameri H. Optical coherence tomography 120 Bicanic T, Harrison T, Niepieklo A, Dyakopu N, Meintjes G.
imaging of presumed Cryptococcus neoformans infection localized to Symptomatic relapse of HIV-associated cryptococcal meningitis after
the retina. J Curr Ophthalmol 2019; 31: 353–56. initial fluconazole monotherapy: the role of fluconazole resistance
and immune reconstitution. Clin Infect Dis 2006; 43: 1069–73.
100 Wood L, Miedzinski L. Skeletal cryptococcosis: case report and
review of the literature. Can J Infect Dis 1996; 7: 125–32. 121 Van Wyk M, Govender NP, Mitchell TG, Litvintseva AP,
GERMS-SA. Multilocus sequence typing of serially collected isolates
101 Medaris LA, Ponce B, Hyde Z, et al. Cryptococcal osteomyelitis:
of Cryptococcus from HIV-infected patients in South Africa.
a report of five cases and a review of the recent literature. Mycoses
J Clin Microbiol 2014; 52: 1921–31.
2016; 59: 334–42.
122 Stone NR, Rhodes J, Fisher MC, et al. Dynamic ploidy changes
102 Zhou HX, Lu L, Chu T, et al. Skeletal cryptococcosis from 1977
drive fluconazole resistance in human cryptococcal meningitis.
to 2013. Front Microbiol 2015; 5: 740.
J Clin Invest 2019; 129: 999–1014.
103 Rolfes MA, Hullsiek KH, Rhein J, et al. The effect of therapeutic
123 Bongomin F, Oladele RO, Gago S, Moore CB, Richardson MD.
lumbar punctures on acute mortality from cryptococcal meningitis.
A systematic review of fluconazole resistance in clinical isolates of
Clin Infect Dis 2014; 59: 1607–14.
Cryptococcus species. Mycoses 2018; 61: 290–97.
104 Kagimu E, Engen N, Ssebambulidde K, et al. Therapeutic lumbar
124 Procop GW, Dufresne PJ, Berkow E, et al. Epidemiological cutoff
punctures in human immunodeficiency virus-associated
values for antifungal susceptibility testing. 4th ed. Berwyn, PA:
cryptococcal meningitis: should opening pressure direct
Institute and Laboratory Standards, 2022.
management? Open Forum Infect Dis 2022; 9: ofac416.
125 Aberg JA, Watson J, Segal M, Chang LW. Clinical utility of
105 Cherian J, Atmar RL, Gopinath SP. Shunting in cryptococcal
monitoring serum cryptococcal antigen (sCRAG) titers in patients
meningitis. J Neurosurg 2016; 125: 177–86.
with AIDS-related cryptococcal disease. HIV Clin Trials 2000; 1: 1–6.
106 Manosuthi W, Sungkanuparph S, Chottanapund S, et al. Temporary
126 French MA. HIV/AIDS: immune reconstitution inflammatory
external lumbar drainage for reducing elevated intracranial
syndrome: a reappraisal. Clin Infect Dis 2009; 48: 101–07.
pressure in HIV-infected patients with cryptococcal meningitis.
Int J STD AIDS 2008; 19: 268–71. 127 Haddow LJ, Colebunders R, Meintjes G, et al. Cryptococcal immune
reconstitution inflammatory syndrome in HIV-1-infected
107 Zhang Q, Li H, Zhang K, et al. Lumbar drainage for the
individuals: proposed clinical case definitions. Lancet Infect Dis
treatment of refractory intracranial hypertension in HIV-
2010; 10: 791–802.
negative cryptococcal meningitis. Future Microbiol 2019;
14: 859–66. 128 Panackal AA, Wuest SC, Lin YC, et al. Paradoxical immune responses
in non-HIV cryptococcal meningitis. PLoS Pathog 2015; 11: e1004884.
108 Newton PN, Thai H, Tip NQ, et al. A randomized, double-blind,
placebo-controlled trial of acetazolamide for the treatment of 129 Deshayes S, Bouvier N, Chatelet V, et al. Severe cryptococcal-
elevated intracranial pressure in cryptococcal meningitis. associated neurological immune reconstitution inflammatory
Clin Infect Dis 2002; 35: 769–72. syndrome in a renal transplant recipient treated with adalimumab.
Transpl Infect Dis 2016; 18: 461–65.
109 Hu Z, Yang Y, Cheng J, Cheng C, Chi Y, Wei H. The use of
mannitol in HIV-infected patients with symptomatic cryptococcal 130 Scemla A, Gerber S, Duquesne A, et al. Dramatic improvement of
meningitis. Drug Discov Ther 2017; 10: 329–33. severe cryptococcosis-induced immune reconstitution syndrome
with adalimumab in a renal transplant recipient. Am J Transplant
110 Makadzange AT, Ndhlovu CE, Takarinda K, et al. Early versus
2015; 15: 560–64.
delayed initiation of antiretroviral therapy for concurrent HIV
infection and cryptococcal meningitis in sub-saharan Africa. 131 Gaube G, De Castro N, Gueguen A, et al. Treatment with
Clin Infect Dis 2010; 50: 1532–38. adalimumab for severe immune reconstitution inflammatory
syndrome in an HIV-infected patient presenting with cryptococcal
111 Bisson GP, Molefi M, Bellamy S, et al. Early versus delayed
meningitis. Med Mal Infect 2016; 46: 154–56.
antiretroviral therapy and cerebrospinal fluid fungal clearance in
adults with HIV and cryptococcal meningitis. Clin Infect Dis 2013; 132 Sitapati AM, Kao CL, Cachay ER, Masoumi H, Wallis RS,
56: 1165–73. Mathews WC. Treatment of HIV-related inflammatory cerebral
cryptococcoma with adalimumab. Clin Infect Dis 2010; 50: e7–10.

Review
133 Brunel AS, Reynes J, Tuaillon E, et al. Thalidomide for steroid- 155 Choe YJ, Blatt DB, Yalcindag A, Geffert SF, Bobenchik AM,
dependent immune reconstitution inflammatory syndromes during Michelow IC. Cryptococcus albidus fungemia in an
AIDS. AIDS 2012; 26: 2110–12. immunosuppressed child: case report and systematic literature
134 Lortholary O, Fontanet A, Mémain N, Martin A, Sitbon K, review. J Pediatric Infect Dis Soc 2020; 9: 100–05.
Dromer F. Incidence and risk factors of immune reconstitution 156 Khawcharoenporn T, Apisarnthanarak A, Mundy LM.
inflammatory syndrome complicating HIV-associated Non-neoformans cryptococcal infections: a systematic review.
cryptococcosis in France. AIDS 2005; 19: 1043–49. Infection 2007; 35: 51–58.
135 Somerville LK, Henderson AP, Chen SC, Kok J. Successful 157 Xiao M, Fan X, Chen XX, et al. Misidentification of a rare species,
treatment of Cryptococcus neoformans immune reconstitution Cryptococcus laurentii, by commonly used commercial biochemical
inflammatory syndrome in an immunocompetent host using methods and matrix-assisted laser desorption ionization-time of
thalidomide. Med Mycol Case Rep 2014; 7: 12–14. flight mass spectrometry systems: challenges for clinical mycology
136 Anjum S, Dean O, Kosa P, et al. Outcomes in previously healthy laboratories. J Clin Microbiol 2016; 54: 226–29.
cryptococcal meningoencephalitis patients treated with pulse taper 158 Arendrup MC, Boekhout T, Akova M, Meis JF, Cornely OA,
corticosteroids for post-infectious inflammatory syndrome. Lortholary O. ESCMID and ECMM joint clinical guidelines for the
Clin Infect Dis 2021; 73: e2789–98. diagnosis and management of rare invasive yeast infections.
137 Chen SC, Slavin MA, Heath CH, et al. Clinical manifestations of Clin Microbiol Infect 2014; 20 (suppl 3): 76–98.
Cryptococcus gattii infection: determinants of neurological sequelae 159 Oliveira LSS, Pinto LM, de Medeiros MAP, et al. Comparison of
and death. Clin Infect Dis 2012; 55: 789–98. Cryptococcus gattii/neoformans species complex to related
138 Chen SC, Meyer W, Sorrell TC. Cryptococcus gattii infections. genera (Papiliotrema and Naganishia) reveal variances in virulence
Clin Microbiol Rev 2014; 27: 980–1024. associated factors and antifungal susceptibility.
139 Harris JR, Galanis E, Lockhart SR. Cryptococcus gattii infections and Front Cell Infect Microbiol 2021; 11: 642658.
virulence. Curr Fungal Infect Rep 2014; 8: 81–89. 160 Ely EW, Peacock JE Jr, Haponik EF, Washburn RG. Cryptococcal
140 Chen S, Sorrell T, Nimmo G, et al. Epidemiology and host- pneumonia complicating pregnancy. Medicine (Baltimore) 1998;
dependent and variety-dependent characteristics of infection due to 77: 153–67.
Cryptococcus neoformans in Australia and New Zealand. 161 Pastick KA, Nalintya E, Tugume L, et al. Cryptococcosis in pregnancy
Clin Infect Dis 2000; 31: 499–508. and the postpartum period: case series and systematic review with
141 Morgan J, McCarthy KM, Gould S, et al. Cryptococcus gattii recommendations for management. Med Mycol 2020; 58: 282–92.
infection: characteristics and epidemiology of cases identified in 162 Bright PD, Lupiya D, van Oosterhout JJ, Chen A, Harrison TS,
a South African province with high HIV seroprevalence, 2002–04. Chan AK. The treatment of a pregnant HIV positive patient with
Clin Infect Dis 2006; 43: 1077–80. cryptococcal meningitis in Malawi—case report and review of
142 Litvintseva AP, Thakur R, Reller LB, Mitchell TG. Prevalence of treatment options. Med Mycol Case Rep 2017; 19: 9–12.
clinical isolates of Cryptococcus gattii serotype C among patients 163 Pursley TJ, Blomquist IK, Abraham J, Andersen HF, Bartley JA.
with AIDS in sub-Saharan Africa. J Infect Dis 2005; 192: 888–92. Fluconazole-induced congenital anomalies in three infants.
143 Nyazika TK, Hagen F, Meis JF, Robertson VJ. Cryptococcus Clin Infect Dis 1996; 22: 336–40.
tetragattii as a major cause of cryptococcal meningitis among 164 Mastroiacovo P, Mazzone T, Botto LD, et al. Prospective assessment
HIV-infected individuals in Harare, Zimbabwe. J Infect 2016; of pregnancy outcomes after first-trimester exposure to fluconazole.
72: 745–52. Am J Obstet Gynecol 1996; 175: 1645–50.
144 Steele KT, Thakur R, Nthobatsang R, Steenhoff AP, Bisson GP. 165 Zhu Y, Bateman BT, Gray KJ, et al. Oral fluconazole use in the first
In-hospital mortality of HIV-infected cryptococcal meningitis trimester and risk of congenital malformations: population based
patients with C gattii and C neoformans infection in Gaborone, cohort study. BMJ 2020; 369: m1494.
Botswana. Med Mycol 2010; 48: 1112–15. 166 Mølgaard-Nielsen D, Svanström H, Melbye M, Hviid A, Pasternak B.
145 Saijo T, Chen J, Chen SC, et al. Anti-granulocyte-macrophage Association between use of oral fluconazole during pregnancy and
colony-stimulating factor autoantibodies are a risk factor for central risk of spontaneous abortion and stillbirth. JAMA 2016; 315: 58–67.
nervous system infection by Cryptococcus gattii in otherwise 167 Mølgaard-Nielsen D, Pasternak B, Hviid A. Use of oral fluconazole
immunocompetent patients. MBio 2014; 5: e00912–14. during pregnancy and the risk of birth defects. N Engl J Med 2013;
146 Yang DH, England MR, Salvator H, et al. Cryptococcus gattii species 369: 830–39.
complex as an opportunistic pathogen: underlying medical 168 Lenz D, Held J, Goerke S, et al. Primary cutaneous cryptococcosis
conditions associated with the infection. MBio 2021; 12: e0270821. in an eight-year-old immunocompetent child: how to treat?
147 Viola GM, Malek AE, Rosen LB, et al. Disseminated cryptococcosis Klin Padiatr 2015; 227: 41–44.
and anti-granulocyte-macrophage colony-stimulating factor 169 Molina-Leyva A, Ruiz-Carrascosa JC, Leyva-Garcia A,
autoantibodies: an underappreciated association. Mycoses 2021; Husein-Elahmed H. Cutaneous Cryptococcus laurentii infection in
64: 576–82. an immunocompetent child. Int J Infect Dis 2013; 17: e1232–33.
148 Shi D, Haas PJ, Boekhout T, Hahn RC, Hagen F. Neglecting genetic 170 Sweeney DA, Caserta MT, Korones DN, Casadevall A, Goldman DL.
diversity hinders timely diagnosis of Cryptococcus infections. A ten-year-old boy with a pulmonary nodule secondary to
J Clin Microbiol 2021; 59: e02837–20. Cryptococcus neoformans: case report and review of the literature.
149 Chen SC, Korman TM, Slavin MA, et al. Antifungal therapy and Pediatr Infect Dis J 2003; 22: 1089–93.
management of complications of cryptococcosis due to Cryptococcus 171 Ramdial PK, Sing Y, Deonarain J, Bhimma R, Chotey N, Sewram V.
gattii. Clin Infect Dis 2013; 57: 543–51. Pediatric renal cryptococcosis: novel manifestations in the acquired
150 Phillips P, Galanis E, MacDougall L, et al. Longitudinal clinical immunodeficiency syndrome era. Int J Surg Pathol 2011; 19: 386–92.
findings and outcome among patients with Cryptococcus gattii 172 Lizarazo J, Escandón P, Agudelo CI, Castañeda E. Cryptococcosis in
infection in British Columbia. Clin Infect Dis 2015; 60: 1368–76. Colombian children and literature review. Mem Inst Oswaldo Cruz
151 Phillips P, Chapman K, Sharp M, et al. Dexamethasone in 2014; 109: 797–804.
Cryptococcus gattii central nervous system infection. Clin Infect Dis 173 Gao LW, Jiao AX, Wu XR, et al. Clinical characteristics of
2009; 49: 591–95. disseminated cryptococcosis in previously healthy children in
152 Fujita NK, Reynard M, Sapico FL, Guze LB, Edwards JE Jr. China. BMC Infect Dis 2017; 17: 359.
Cryptococcal intracerebral mass lesions: the role of computed 174 Joshi NS, Fisher BT, Prasad PA, Zaoutis TE. Epidemiology of
tomography and nonsurgical management. Ann Intern Med 1981; cryptococcal infection in hospitalized children. Pediatr Infect Dis J
94: 382–88. 2010; 29: e91–95.
153 Hospenthal DR, Bennett JE. Persistence of cryptococcomas on 175 Gassiep I, Douglas J, Emeto TI, Crawley K, Playford EG.
neuroimaging. Clin Infect Dis 2000; 31: 1303–06. Cryptococcal infections over a 15 year period at a tertiary facility &
154 Kordossis T, Avlami A, Velegraki A, et al. First report of impact of guideline management. Mycoses 2018; 61: 633–38.
Cryptococcus laurentii meningitis and a fatal case of Cryptococcus
albidus cryptococcaemia in AIDS patients. Med Mycol 1998; Copyright © 2024 Elsevier Ltd. All rights reserved.
36: 335–39.

Christina C Chang Global Guideline For The Diagnosis

Uploaded by

Copyright:

Available Formats

Christina C Chang Global Guideline For The Diagnosis

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Christina C Chang Global Guideline For The Diagnosis

Uploaded by

Copyright:

Available Formats

Review

Global guideline for the diagnosis and management of

www.thelancet.com/infection Published online February 9, 2024 https://doi.org/10.1016/S1473-3099(23)00731-4 1

HIV SOT Non-HIV/ Non-HIV Cryptococcoma Severe †Mild (with or without

AI AIIt AIIt BIII BIII BIIu AIIu BIIu BIIu AIII

Maintenance: (AIIt) fluconazole 200 mg daily for 12 months A. Strongly recommended

Figure 1: Recommended first-line antifungal therapy by cryptococcosis syndrome

2 www.thelancet.com/infection Published online February 9, 2024 https://doi.org/10.1016/S1473-3099(23)00731-4

and Department of Pharmacy

www.thelancet.com/infection Published online February 9, 2024 https://doi.org/10.1016/S1473-3099(23)00731-4 3

Zhunan, Taiwan (Y-C Chen); populations is contentious. The standard regimen is

4 www.thelancet.com/infection Published online February 9, 2024 https://doi.org/10.1016/S1473-3099(23)00731-4

(Allt) Proactive intracranial pressure management

(CIIu) Consider performing a lumbar puncture at the

CSF cryptococcocal Yes (CIIu) Consider prolonging

(AI) Start consolidation therapy: fluconazole

(AI) Start antiretroviral therapy 4–6 weeks after

Recurrent Yes (Allu) Check drug interactions and drug adherence;

(BIIu) Cease maintenance therapy after 12 months

(BIII) Restart induction therapy

(DI) Do not stop ART

(BIII) Consider prednisolone or dexamethasone

www.thelancet.com/infection Published online February 9, 2024 https://doi.org/10.1016/S1473-3099(23)00731-4 5

and Mycology, Centre National

6 www.thelancet.com/infection Published online February 9, 2024 https://doi.org/10.1016/S1473-3099(23)00731-4

Research, Cologne, Germany

www.thelancet.com/infection Published online February 9, 2024 https://doi.org/10.1016/S1473-3099(23)00731-4 7

No liposomal amphotericin B available Amphotericin B lipid complex 5 mg/kg daily

No ¶polyene antimycotic available Flucytosine 25 mg/kg four times a day and

8 www.thelancet.com/infection Published online February 9, 2024 https://doi.org/10.1016/S1473-3099(23)00731-4

A People with HIV

If liposomal amphotericin B and amphotericin B lipid complex

B SOT recipients and people without HIV or SOT

Induction (minimum 2 weeks) Consolidation (8 weeks) Maintenance (12 months)

If liposomal amphotericin B and amphotericin B lipid complex

If amphotericin B-based therapies are not able to be used: Comments:

www.thelancet.com/infection Published online February 9, 2024 https://doi.org/10.1016/S1473-3099(23)00731-4 9

10 www.thelancet.com/infection Published online February 9, 2024 https://doi.org/10.1016/S1473-3099(23)00731-4

www.thelancet.com/infection Published online February 9, 2024 https://doi.org/10.1016/S1473-3099(23)00731-4 11

12 www.thelancet.com/infection Published online February 9, 2024 https://doi.org/10.1016/S1473-3099(23)00731-4

www.thelancet.com/infection Published online February 9, 2024 https://doi.org/10.1016/S1473-3099(23)00731-4 13

14 www.thelancet.com/infection Published online February 9, 2024 https://doi.org/10.1016/S1473-3099(23)00731-4

www.thelancet.com/infection Published online February 9, 2024 https://doi.org/10.1016/S1473-3099(23)00731-4 15

16 www.thelancet.com/infection Published online February 9, 2024 https://doi.org/10.1016/S1473-3099(23)00731-4

www.thelancet.com/infection Published online February 9, 2024 https://doi.org/10.1016/S1473-3099(23)00731-4 17

18 www.thelancet.com/infection Published online February 9, 2024 https://doi.org/10.1016/S1473-3099(23)00731-4

You might also like

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.