Discussion
Invasive CNS mucormycosis (CNS-M) is a rare but often deadly invasive
fungal infection in the pediatric population (4)(5). The acute and
rapidly progressive evolution generally causes unfavorable outcomes with
very high mortality rates of up to 65% despite appropriate treatment
(5).
CNS-M can manifest in three distinct clinical forms: as rhinocerebral
mucormycosis (RCM), disseminated mucormycosis with CNS involvement, or
as ICM(6). The latter is the least frequent form, accounting for only
8% of CNS-M cases (7, 8)
Isolated cerebral mucormycosis has been described in the literature as
having an exceedingly poor prognosis(7, 9-11){Kerezoudis, 2019
#143;Kerezoudis, 2019 #143}. The pooled mortality rate in a
meta-analysis by the Mayo clinic was noted at 65%in adults(12),
Rhizopus has been shown to be the most common isolated organism
(59%)(13). Cases of isolated cerebral mucormycosis usually involve the
basal ganglia or thalamus(7). Lesions are usually deep-seated with
common basal ganglia involvement which is thought to be due to seeding
from the middle cerebral artery, especially in intravenous drug
users(6). However, interestingly, it has been shown that in
immunocompromised patients, cortical lesions are more common like our
case(6, 14)
Our case outlines the major obstacles in diagnosis of ICM as the
clinical symptoms were initially fairly subtle, conventional stains and
cultures were negative, and obtaining a CNS biopsy specimen is not
always feasible in vulnerable populations such as pediatric cancer
patients (9). There are currently no clinically available circulating
biomarkers of mucormycosis (9). Serum tests such as the 1,3-β-D-glucan
assay and the aspergillus galactomannan assay are typically negative in
invasive mucormycosis (10). Therefore, definitive diagnosis requires
microbiological analysis of tissue obtained by biopsy or surgical
debridement (11), high degree of clinical suspicion and prompt
intervention (9, 12). The inclusion of PCR based testing for infectious
organisms was critical in this cryptogenic presentation as the first
finding to indicate the correct diagnosis(11, 15).
There are limited prospective clinical data on optimal therapies for
CNS-M in children(10, 12, 16). A combined medical and surgical approach
has repeatedly been shown to lead to the best outcomes(17), though
aggressive surgical debridement is not always feasible depending on
location of the infection, such as the CNS, where severe sequelae may
result from attempting to surgically remove all fungal disease(12, 18).
It has been widely accepted that early and aggressive surgical
debridement in rhinosinus mucormycosis is essential to survival but this
has not been established for isolated cerebral mucormycosis(13). Some
studies have shown decreased mortality with stereotactic
aspiration/debridement, but others have shown no differences in
outcome(14). In our case, an aggressive debridement of all
radiologically involved tissue would have conferred a neurological
deficit that was not acceptable to the patient or family. The positive
outcome in this case from a more limited debridement in combination with
a salvage medical regimen supports a measured approach(15, 18).
Until recently, amphotericin B and the triazole antifungals
(Posaconazole and ISAV) were the only systemic antifungals available
with good activity against Mucorales species (18, 19). Posaconazole has
been used in invasive mucormycosis in adults and adolescents as salvage
therapy; however, CNS penetration has been reported to be poor (20), and
Posaconazole monotherapy in CNS-M has not been adequately studied(20).
Furthermore, there are concerns about the oral bioavailability of
Posaconazole oral suspension in younger children who can’t swallow the
extended-release tablet(21).
ISAV, a second-generation triazole, was approved for the treatment of
invasive aspergillosis (IA) or invasive mucormycosis(22). There is
limited information on the CNS penetration of ISAV, however, a few
studies demonstrated efficacy with ISAV treatment for CNS infections
caused by a wide range of different fungi(9, 23). More recently, ISAV
was assessed prospectively in a single-arm study of patients with
mucormycosis and other rare fungal infections (the VITAL trial) (16,
24). In this study, ISAV showed promising results against mucormycosis
with efficacy and outcomes similar to amphotericin B, these results turn
light in horizon for ISAV not only as salvage but also as first-line
agent of mucormycosis treatment(22). VITAL trial didn’t look
specifically effectiveness of ISAV in CNS-M, but 29% of cases had CNS
involvement. Meanwhile, the pediatric dosing regimen of this drug has
not been established. Desai et al. extrapolated an adult population
pharmacokinetic model to determine the appropriate dose of ISAV for
children(16). Accordingly, our patient received 10mg/kg of the prodrug
isavuconazonium sulfate (equivalent to 5.4mg/kg of isavuconazole) every
8 hours for the first 2 days and once daily thereafter. Duration of
therapy is always a question. Although our patient achieved radiographic
resolution(10), we would continue ISAV suppressive treatment until the
patient completes chemotherapy, is no longer in an immunosuppressive
state and has reconstitution of the immune system.
In summary, our case is noteworthy in highlighting several challenges
encountered in the diagnostics and management of ICM with eventually
successful salvage treatment with monotherapy ISAV with complete
clinical and radiologic responses. We hope that our case adds to the
growing evidence supporting of ISAV as well-tolerated, safe, and
efficacious therapy in ICM and promising therapy for salvage treatment
and could be hope in horizon in children with ICM. The availability of
an IV and oral of ISAV makes an attractive oral step-down therapy for
with invasive or disseminated mucormycosis. Prospective clinical trials
are needed to evaluate the established pediatric dose, safety, and
efficacy of ISAV in children and its role as first-line treatment for
ICM.
Reference List
1. Locatelli F, Zugmaier G, Rizzari C, Morris JD, Gruhn B, Klingebiel T,
et al. Effect of Blinatumomab vs Chemotherapy on Event-Free Survival
Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic
Leukemia: A Randomized Clinical Trial. JAMA. 2021;325(9):843-54.
2. Chamilos G, Marom EM, Lewis RE, Lionakis MS, Kontoyiannis DP.
Predictors of pulmonary zygomycosis versus invasive pulmonary
aspergillosis in patients with cancer. Clin Infect Dis. 2005;41(1):60-6.
3. Walsh TJ, Goodman JL, Pappas P, Bekersky I, Buell DN, Roden M, et al.
Safety, tolerance, and pharmacokinetics of high-dose liposomal
amphotericin B (AmBisome) in patients infected with Aspergillus species
and other filamentous fungi: maximum tolerated dose study. Antimicrob
Agents Chemother. 2001;45(12):3487-96.
4. Jeha S, Pei D, Choi J, Cheng C, Sandlund JT, Coustan-Smith E, et al.
Improved CNS Control of Childhood Acute Lymphoblastic Leukemia Without
Cranial Irradiation: St Jude Total Therapy Study 16. J Clin Oncol.
2019;37(35):3377-91.
5. Tissot F, Agrawal S, Pagano L, Petrikkos G, Groll AH, Skiada A, et
al. ECIL-6 guidelines for the treatment of invasive candidiasis,
aspergillosis and mucormycosis in leukemia and hematopoietic stem cell
transplant patients. Haematologica. 2017;102(3):433-44.
6. Nagy-Agren SE, Chu P, Smith GJ, Waskin HA, Altice FL. Zygomycosis
(mucormycosis) and HIV infection: report of three cases and review. J
Acquir Immune Defic Syndr Hum Retrovirol. 1995;10(4):441-9.
7. Siddiqi SU, Freedman JD. Isolated central nervous system
mucormycosis. South Med J. 1994;87(10):997-1000.
8. Sun YQ, Liu ZY, Huang XJ, Yan CH, Xu LP, Zhang XH, et al. A
Retrospective Study of Central Nervous System Invasive Fungal Disease
after Allogeneic Stem Cell Transplantation: Risk Factors, Clinical
Characteristics, and Outcomes. Biol Blood Marrow Transplant.
2017;23(7):1158-64.
9. Marchesi F, Girmenia C, Goffredo BM, Salvatorelli E, Romano A,
Mengarelli A, et al. Isavuconazole: Case Report and Pharmacokinetic
Considerations. Chemotherapy. 2018;63(5):253-6.
10. Francis JR, Villanueva P, Bryant P, Blyth CC. Mucormycosis in
Children: Review and Recommendations for Management. J Pediatric Infect
Dis Soc. 2018;7(2):159-64.
11. Dadwal SS, Kontoyiannis DP. Recent advances in the molecular
diagnosis of mucormycosis. Expert Rev Mol Diagn. 2018;18(10):845-54.
12. Kerezoudis P, Watts CR, Bydon M, Dababneh AS, Deyo CN, Frye JM, et
al. Diagnosis and Treatment of Isolated Cerebral Mucormycosis:
Patient-Level Data Meta-Analysis and Mayo Clinic Experience. World
Neurosurg. 2019;123:425-34 e5.
13. Paramythiotou E, Frantzeskaki F, Flevari A, Armaganidis A,
Dimopoulos G. Invasive fungal infections in the ICU: how to approach,
how to treat. Molecules. 2014;19(1):1085-119.
14. Weprin BE, Hall WA, Goodman J, Adams GL. Long-term survival in
rhinocerebral mucormycosis. Case report. J Neurosurg. 1998;88(3):570-5.
15. Millon L, Scherer E, Rocchi S, Bellanger AP. Molecular Strategies to
Diagnose Mucormycosis. J Fungi (Basel). 2019;5(1).
16. Steinbach WJ. Latest Thoughts on Treating Pediatric Mucormycosis. J
Pediatric Infect Dis Soc. 2020;9(5):640-4.
17. Antoniadi K, Iosifidis E, Vasileiou E, Tsipou C, Lialias I,
Papakonstantinou E, et al. Invasive Mucormycosis in Children With
Malignancies: Report From the Infection Working Group of the Hellenic
Society of Pediatric Hematology-Oncology. J Pediatr Hematol Oncol.
2021;43(5):176-9.
18. Kontoyiannis DP, Lewis RE. How I treat mucormycosis. Blood.
2011;118(5):1216-24.
19. Schelenz S, Barnes RA, Barton RC, Cleverley JR, Lucas SB, Kibbler
CC, et al. British Society for Medical Mycology best practice
recommendations for the diagnosis of serious fungal diseases. Lancet
Infect Dis. 2015;15(4):461-74.
20. Reinwald M, Uharek L, Lampe D, Grobosch T, Thiel E, Schwartz S.
Limited penetration of posaconazole into cerebrospinal fluid in an
allogeneic stem cell recipient with invasive pulmonary aspergillosis.
Bone Marrow Transplant. 2009;44(4):269-70.
21. Jancel T, Shaw PA, Hallahan CW, Kim T, Freeman AF, Holland SM, et
al. Therapeutic drug monitoring of posaconazole oral suspension in
paediatric patients younger than 13 years of age: a retrospective
analysis and literature review. J Clin Pharm Ther. 2017;42(1):75-9.
22. Ashkenazi-Hoffnung L, Bilavsky E, Levy I, Grisaru G, Sadot E,
Ben-Ami R, et al. Isavuconazole As Successful Salvage Therapy for
Mucormycosis in Pediatric Patients. Pediatr Infect Dis J.
2020;39(8):718-24.
23. Schwartz S, Cornely OA, Hamed K, Marty FM, Maertens J, Rahav G, et
al. Isavuconazole for the treatment of patients with invasive fungal
diseases involving the central nervous system. Med Mycol.
2020;58(4):417-24.
24. Marty FM, Ostrosky-Zeichner L, Cornely OA, Mullane KM, Perfect JR,
Thompson GR, 3rd, et al. Isavuconazole treatment for mucormycosis: a
single-arm open-label trial and case-control analysis. Lancet Infect
Dis. 2016;16(7):828-37.