International Journal of Pediatric Otorhinolaryngology 90 (2016) 231e235

Contents lists available at ScienceDirect

International Journal of Pediatric Otorhinolaryngology

journal homepage: http://www.ijporlonline.com/

Invasive fungal sinusitis in the pediatric population: Systematic

review with quantitative synthesis of the literature
Aaron Smith a, Vikrum Thimmappa a, Brandon Shepherd b, Meredith Ray c,
Anthony Sheyn a, Jerome Thompson a, *
a
Department of Otolaryngology, University of Tennessee Health Science Center, Memphis, TN, USA
b
Department of Otolaryngology, University of Mississippi, Jackson, MS, USA
c
University of Memphis, Department of Biostatistics, Memphis, TN, USA

a r t i c l e i n f o a b s t r a c t

Article history: Background: Invasive fungal sinusitis (IFS) represents an often fatal condition within the pediatric
Received 4 September 2016 population. In an effort to characterize demographics, treatment modalities, and prognostic factors, we
Received in revised form performed a systematic review.
14 September 2016
Methods: We systematically reviewed EMBASE, Medline, TRIPdatabase, SCOPUS and the Cochrane
Accepted 15 September 2016
Available online 17 September 2016
database for invasive fungal nasal and sinus infections limited to individuals <18 years of age. Case series
This paper was presented as a poster pre- including 3 or more patients were included. Demographics, treatment and outcomes were analyzed
sentation at the Combined Otolaryngology using R Gui statistical software.
Spring Meeting American Society of Pedi- Results: Twelve studies met inclusion criteria (103 patients). There was male preponderance of 48.5%
atric Otolaryngology, May 18e22 2016, with median age of 11 years old. Majority of patients had underlying leukemia (44.6%). Aspergillus was
Chicago, IL, USA. the predominant organism (47%). Isolated nasal findings occurred in 14% of patients and nasal findings
occurred in 49% overall. Absolute neutrophil count (ANC) of immunocompromised patients was below
Keywords: 600 in most patients (99%). Average and median length of neutropenia was 2 weeks. All patients were
Invasive fungal sinusitis prescribed amphoterocin with 50% as single medicinal therapy. Surgery occurred in 82.8% of cases. The
Otolaryngology mortality rate was 46%. Univariate analysis identified presenting with facial pain as a negative predictor
Pediatrics
of overall mortality (OR 0.296, 95% CI: 0.104e0.843, p < 0.05).
Immunocompromised
Conclusion: Mortality remains high in pediatric patients with IFS. An ANC of <600 occurred in the
Aspergillus
Mucormycosis majority of immunocompromised patients at a duration of 2 weeks. Presenting with facial pain was a
negative predictor of mortality. Many studies label this condition as invasive fungal sinusitis; however,
approximately one seventh presented with only nasal findings and half overall had nasal involvement.
© 2016 Elsevier Ireland Ltd. All rights reserved.

1. Introduction increased, prevalence remains low; limiting the opportunity for

Advances in pharmacologic therapies for various pediatric dis-
eases have contributed to an increased burden of immunocom-
promised patients. With this increase, the incidence of historically
less common opportunistic infections has also risen [1]. Invasive
fungal sinusitis (IFS) is one such opportunistic infection. IFS is a
serious infection of the nose and paranasal sinuses that often
progresses to fulminant and even deadly disease if not diagnosed
early and treated aggressively. Although the burden of IFS has
* Corresponding author. Department of Otolaryngology, University of Tennessee
Health Science Center, Suite 408, 910 Madison Building, Memphis, TN, USA.
E-mail address: jthomp18@uthsc.edu (J. Thompson).
adequately sized clinical studies. Thus, the majority of the pub-
lished data is presented in small, single center case reports and
series.
The typical presentation of IFS includes a combination of fever,
facial pain, epistasis, nasal congestion, headache, and facial edema.
Concern for IFS should be raised with the acute onset of any of the
above in an immunocompromised patient. Diagnosis begins with
endoscopic examination of nasal and oral cavities for necrotic tis-
sue, indicating hyphal invasion of local vasculature. Biopsy of these
lesions is used to confirm histopathologic diagnosis and speciation
as many fungal species contribute to IFS. However, aspergillus and
zygomycete species are the most commonly implicated. Standard of
care includes aggressive treatment with surgical debridement, IV
antifungal agents, and withdrawal of immunosuppressive agents, if

http://dx.doi.org/10.1016/j.ijporl.2016.09.019
0165-5876/© 2016 Elsevier Ireland Ltd. All rights reserved.

Downloaded for Mahasiswa KTI UKDW (mhsktiukdw01@gmail.com) at Universitas Kristen Duta Wacana from ClinicalKey.com by Elsevier on February 07, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
232 A. Smith et al. / International Journal of Pediatric Otorhinolaryngology 90 (2016) 231e235

applicable, is necessary for improved outcomes. Despite these ef-
forts, reported mortality rates are between 33 and 100% in certain
immunocompromised populations [2]. An understanding of prog-
nostic factors for survival might improve the care given to these
patients and thus result in better outcomes.
Recently, Turner, et al. performed a systematic review of adult
IFS literature. Their review, composed of 52 case studies and over
800 patients, reported relevant statistical data on presentation,
treatment, and outcomes [3]. Our study aims to perform a similar
systematic review focusing specifically on outcomes in the pedi-
atric population (see Fig. 1).
2. Methods
A systematic review of the literature was performed by
querying the EMBASE, Medline (via PubMed), TRIPdatabase,
SCOPUS, and Cochrane databases from the date of database
inception to 10/20/2014. The review aimed to identify case reports
or case series of invasive fungal sinusitis infections in individuals
younger than 18 years of age. Only case series with 3 or more
patients met inclusion criteria. Articles not published in the En-
glish language, Cadaveric studies, and other non-human studies
were all excluded. The following search criteria were used:
“invasive sinusitis”; “invasive rhinosinusitis” alone AND: “pedi-
atric”; “invasive fungal sinusitis” alone AND: “pediatric”,
”children”, “BMT”, “cancer”, “immunocompromised”, “immuno-
competent”, “leukemia”, “malignancy”, “transplant”; “invasive
fungal rhinosinusitis” alone AND: “pediatric”, ”children”, “BMT”,
“cancer”, “immunocompromised”, “immunocompetent”, “leuke-
mia”, “malignancy”, “transplant”.
Two authors (AS, VT) independently reviewed the titles and
abstracts of retrieved articles for selection. The full texts of these
articles were then screened by each author to ensure appropriate
inclusion criteria were met. Of the articles included in the analysis,
some reported mixed pediatric and adult patients. In these reports,
patient data was individually extracted without including the adult
data. Any discrepancies were reconciled by discussion. De-
mographics, treatment, and outcomes were compiled into a data-
base where they were analyzed as a single cohort using chi square,
Student T-test, and univariate logistic regression. All statistical
analysis was conducted in R Gui statistical software.
3. Results
This systematic review produced 1294 articles in the identifi-
cation phase. After removal of duplicates, this number became
1041. Initial screening of abstracts resulted in 331 articles and after
evaluation of inclusion and exclusion criteria 44 articles underwent
full-text review. Ultimately, 12 articles met study criteria and were
evaluated for quantitative analysis [1,4e14].

Fig. 1. PRISMA Diagram, delineating systematic evaluation and decision for inclusion. Final number included 12 of the initial 1294 identified articles.

Downloaded for Mahasiswa KTI UKDW (mhsktiukdw01@gmail.com) at Universitas Kristen Duta Wacana from ClinicalKey.com by Elsevier on February 07, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
 A. Smith et al. / International Journal of Pediatric Otorhinolaryngology 90 (2016) 231e235 233

These studies were all level 4 evidence based upon the Oxford
Center for Evidence Based Medicine definition.
A total of 103 patients were included in the analysis. A male Table 1
preponderance of 48.5% was noted. Median age was 11 years old. Patient demographics of those with Invasive Fungal Sinusitis (IFS).

Acute lymphoid leukemia made up the majority of immuno- Number Frequency

compromised states (44.6%) with aspergillus as the predominant Total cases 103 e
causative organism (47%, Fig. 2). Aspergillus did not favor one Mean age 11.33 e
underlying leukemia (ALL vs AML, chi square p < 0.88) Absolute Gender
neutrophil count (ANC) was below 600 in most immunocom- Male 50 48.5%
Female 34 33.0%
promised patients (99%). One study had 5 immunocompetent
Unspecified 19 18.4%
patients without specific laboratory values available [13]. Average Underlying disease
and median length of neutropenia was 2 weeks. Isolated nasal ALL 46 44.6%
findings occurred in 14% of patients with nasal findings occurring AML 31 30.1%
Aplastic anemia 5 4.9%
in 49% overall. Amphoterocin was prescribed in all cases with
Burkitt's lymphoma 2 1.9%
50% as single medicinal therapy. Surgery occurred in 82.8% of Other/unspecified 19 18.5%
cases. Overall mortality was 46% (Tables 1 and 2). Outcome
Univariate logistic regression was applied to model the Survived 55 53.9%
probability of death given the potential predictors: gender, Deceased 47 46.0%

diagnosis, presenting symptoms (Table 3), infecting organism,

surgery, type of surgery, antibiotics, antibiotics with GCSF, and
sinonasal site of infection. Only the presenting symptom of pain CI: 0.104e0.843, p < 0.05). No other variables were predictors of
proved a significant predictor of overall mortality (OR 0.296, 95% overall mortality (p-values > 0.05) (see Table 3).

Fig. 2. Breakdown of causative organisms of Invasive Fungal Sinustis (IFS). Aspergillus was the predominant causative fungal organism, present in 47% of cases.

Downloaded for Mahasiswa KTI UKDW (mhsktiukdw01@gmail.com) at Universitas Kristen Duta Wacana from ClinicalKey.com by Elsevier on February 07, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
234 A. Smith et al. / International Journal of Pediatric Otorhinolaryngology 90 (2016) 231e235

Table 2 than other symptoms. Further, the clinician may have a higher in-
Disease characteristics and treatment modalities. dex of suspicion of an underlying invasive process if this symptom
Number Frequency is present. The combined effect of the above may provide more
Absolute neutrophil count (n ¼ 91)
expedient and aggressive care for the patient, both in terms of
>600 1 1.1% underlying disease as well as fungal infection, leading to improved
<600 90 98.9% overall survival.
This entity is often referred to only identifying the involve-
Days neutropenic (n ¼ 39) ment of the sinuses; however, we note almost half of those
Average length of time: 18 d
afflicted had nasal cavity involvement. This distinction is
Location of symptoms (n ¼ 57)
important since the first site of identification is oftentimes
Nasal cavity only 8 14.0% within the nasal cavity [3]. We propose renaming to fungal
Paranasal sinuses only 29 50.9% invasive rhinosinus disease (FIRD). Little data exists reporting
Both 20 35.1% survival prior to the advent of intranasal surgery. The overall
Surgery (n ¼ 64) mortality rate remains high today, but may have been higher
Surgical debridment 53 82.8% prior to surgical intervention.
No debridement 11 17.2%

Medicinal therapy (n ¼ 64)

5. Conclusion
Amphotericin only 32 50.0%
Combined therapy 32 50.0% Many studies label this condition as invasive fungal sinusitis;
however, approximately one seventh presented with only nasal
findings and half overall had nasal involvement. IFS is unlikely
Table 3 in those with an ANC >600, which is why a return to immuno-
Univariate odds ratios modeling the probability of overall mortality based upon competency plays such an important role in treatment, along
presenting symptoms given symptoms. Presenting with facial pain proved to be the with medical and surgical options. Further, duration of
only negative predictor of overall mortality (p < 0.05, bold indicates significance).
neutropenia lasting 2 weeks or more was most commonly
Presenting symptoma Odds ratio (95% confidence interval) P-value encountered. Mortality of this clinical entity remains high
Multiple symptoms 0.41 (0.13, 1.28) 0.1258 despite advances in medical and surgical therapy. Presenting
Fever 0.7 (0.26, 1.91) 0.4858 with facial pain was a negative predictor of mortality. Further
Orbital involvement 1.62 (0.46, 5.76) 0.4529 evaluation is needed to understand additional predictive factors
Facial pain 0.296 (0.10, 0.84) 0.0226 for survival.
Edema 0.73 (0.27, 2.03) 0.5522
Rhinorrhea 0.48 (0.15, 1.51) 0.2111
Obstruction congestions 0.31 (0.09, 1.11) 0.0710 Disclosures
Headache 1.07 (0.2, 5.73) 0.9379
a
All other variables from the univariate analysis were insignificant at the None.
alpha ¼ 0.05 level and therefore odds ratios not reported. Bolded values are sta-
tistically significant.
Acknowledgements

4. Discussion
IFS is a serious infection of the nose and paranasal sinuses
that often progresses to fulminant and even deadly disease if not
diagnosed early and treated aggressively with surgical debride-
ment, IV antifungal agents, and improved immunocopetency.
Despite these efforts, reported mortality rates are between 33
and 100% in certain immunocompromised populations. In a pe-
diatric population, review of the literature shows neutropenia
from an underlying malignancy with an ANC <600 is the most
frequent setting of IFS, particularly, if present for more than 2
weeks prior to onset of invasive fungal disease.
In contrast to the adult IFS review, adults often have
concomitant diabetes which is a predictor of survival; children
more oftentimes are immunosuppresed secondary to underlying
malignancy or treatment for that malignancy. The overall goal in
treating these infections is to treat the underlying immunosu-
pression; for diabetics, they most often present with diabetic
ketoacidosis which is a reversible condition within days while
pediatric malignancies and their treatment commonly have
prolonged courses of neutropenia that will only increase with
time.
Our discovery of facial pain as a negative predictive factor for
overall mortality may be explained by this symptom occurring
early in the disease course. This symptom may be more noticeable
to the patient and expressed to the treating physician more readily
None.
References
[1] B.K. Lansford, C.M. Bower, R.W. Seibert, Invasive fungal sinusitis in the
immunocompromised pediatric patient, Ear Nose Throat J. 74 (1995)
566e573.
[2] C.A. Kennedy, G.L. Adams, J.P. Neglia, G.S. Giebink, Impact of surgical treat-
ment on paranasal fungal infections in bone marrow transplant patients,
Otolaryngol. Head. Neck Surg. 116 (1997) 610e616.
[3] J.H. Turner, E. Soudry, J.V. Nayak, P.H. Hwang, Survival outcomes in acute
invasive fungal sinusitis: a systematic review and quantitative synthesis of
published evidence, Laryngoscope 123 (2013) 1112e1118.
[4] F. Ardeshirpour, L.A. Bohm, K.K. Belani, S.F. Sencer, T.A. Lander, J.D. Sidman,
Surgery for pediatric invasive fungal sinonasal disease, Laryngoscope 124
(2014) 1008e1012.
[5] S.S. Choi, G.J. Milmoe, P.A. Dinndorf, R.R. Quinones, Invasive Aspergillus
sinusitis in pediatric bone marrow transplant patients. Evaluation and man-
agement, Arch. Otolaryngol. Head. Neck Surg. 121 (1995) 1188e1192.
[6] P.C. Iwen, M.E. Rupp, S.H. Hinrichs, Invasive mold sinusitis: 17 cases in
immunocompromised patients and review of the literature, Clin. Infect. Dis.
24 (1997) 1178e1184.
[7] K.T. Kavanagh, W.T. Hughes, D.M. Parham, L.R. Chanin, Fungal sinusitis in
immunocompromised children with neoplasms, Ann. Otol. Rhinol. Laryngol.
100 (1991) 331e336.
[8] H.P. Lai, Y.C. Chen, L.Y. Chang, et al., Invasive fungal infection in children with
persistent febrile neutropenia, J. Formos. Med. Assoc. 104 (2005) 174e179.
[9] E.A. Lueg, R.H. Ballagh, V. Forte, Analysis of the recent cluster of invasive
fungal sinusitis at the Toronto Hospital for Sick Children, J. Otolaryngol. 25
(1996) 366e370.
[10] P.S. Malhotra, D. Danahey, J. Sidman, Bilateral lateral rhinotomy incisions for
medial maxillectomies in the management of pediatric invasive fungal
sinusitis, Laryngoscope 111 (2001) 1960e1963.
[11] T.J. McGill, G. Simpson, G.B. Healy, Fulminant aspergillosis of the nose and
paranasal sinuses: a new clinical entity, Laryngoscope 90 (1980) 748e754.

Downloaded for Mahasiswa KTI UKDW (mhsktiukdw01@gmail.com) at Universitas Kristen Duta Wacana from ClinicalKey.com by Elsevier on February 07, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
 A. Smith et al. / International Journal of Pediatric Otorhinolaryngology 90 (2016) 231e235 235

[12] A.H. Park, H.R. Muntz, M.E. Smith, Z. Afify, T. Pysher, A. Pavia, Pediatric
invasive fungal rhinosinusitis in immunocompromised children with cancer,
Otolaryngol. Head. Neck Surg. 133 (2005) 411e416.
[13] A.A. Siddiqui, A.A. Shah, S.H. Bashir, Craniocerebral aspergillosis of sinonasal
origin in immunocompetent patients: clinical spectrum and outcome in 25
cases, Neurosurgery 55 (2004) 602e611 discussion 611e603.
[14] O. Tarkan, B. Karagun, S. Ozdemir, et al., Endonasal treatment of acute invasive
fungal rhinosinusitis in immunocompromised pediatric hematology-oncology
patients, Int. J. Pediatr. Otorhinolaryngol. 76 (2012) 1458e1464.

Downloaded for Mahasiswa KTI UKDW (mhsktiukdw01@gmail.com) at Universitas Kristen Duta Wacana from ClinicalKey.com by Elsevier on February 07, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.