ORIGINAL ARTICLE MYCOLOGY

Osteomyelitis caused by Aspergillus species: a review of 310 reported

cases

E. Gabrielli1, A. W. Fothergill2, L. Brescini1, D. A. Sutton2, E. Marchionni1, E. Orsetti1, S. Staffolani1, P. Castelli1, R. Gesuita3 and
F. Barchiesi1
1) Clinica Malattie Infettive, Universita Politecnica delle Marche, Ancona, Italy, 2) Fungus Testing Laboratory, University of Texas Health Science Center,
San Antonio, TX, USA and 3) Centro di Epidemiologia Biostatistica e Informatica Medica, Universita Politecnica delle Marche, Ancona, Italy

Abstract

Aspergillus osteomyelitis is a rare infection. We reviewed 310 individual cases reported in the literature from 1936 to 2013. The median age
of patients was 43 years (range, 0–86 years), and 59% were males. Comorbidities associated with this infection included chronic
granulomatous disease (19%), haematological malignancies (11%), transplantation (11%), diabetes (6%), pulmonary disease (4%), steroid
therapy (4%), and human immunodeficiency virus infection (4%). Sites of infection included the spine (49%), base of the skull, paranasal
sinuses and jaw (18%), ribs (9%), long bones (9%), sternum (5%), and chest wall (4%). The most common infecting species were Aspergillus
fumigatus (55%), Aspergillus flavus (12%), and Aspergillus nidulans (7%). Sixty-two per cent of the individual cases were treated with a
combination of an antifungal regimen and surgery. Amphotericin B was the antifungal drug most commonly used, followed by itraconazole
and voriconazole. Several combination or sequential therapies were also used experimentally. The overall crude mortality rate was 25%.

Keywords: Antifungals, aspergillosis, immunosuppressed patients, osteomyelitis, spondylodiscitis

Original Submission: 26 February 2013; Revised Submission: 31 August 2013; Accepted: 31 August 2013
Editor: E. Roilides
Article published online: 15 October 2013
Clin Microbiol Infect 2014; 20: 559–565
doi:10.1111/1469-0691.12389

Corresponding author: F. Barchiesi, Clinica Malattie Infettive, Materials and Methods

Universita Politecnica delle Marche, Azienda
Ospedaliero-Universitaria, Ospedali Riuniti Umberto I-Lancisi-Salesi,
Via Conca 60020, Torrette di Ancona, Ancona, Italy
E-mail: f.barchiesi@univpm.it
Introduction
Aspergillus species have emerged as important causes of
morbidity and mortality in immunocompromised hosts [1,2].
Invasive aspergillosis (IA) can occur in most organs, with the
lung being the main target of this opportunistic infection.
Among the extrapulmonary locations, bone is rarely involved.
Osteomyelitis caused by Aspergillus species is an infection that
is often neglected, and data concerning risk factors, therapies
and outcome are lacking [3–68]. Therefore, in order to
improve our knowledge of this unusual infection, we reviewed
the data presented in the literature concerning this type of IA.
To identify eligible studies for this analysis, four investigators
searched the PubMed database for English language studies
published up to April 2013. The search strategy was based on a
combination of the keywords ‘aspergillus’ AND ‘aspergillosis’
AND ‘osteomyelitis’ AND ‘spondylodiscitis’. All references
cited in these studies were also reviewed to identify additional
studies. Study variables included basic demographics and
clinical and laboratory characteristics, such as underlying
conditions, clinical signs and symptoms, and outcome. We
gave special attention to therapeutic modalities such as surgical
and antifungal treatment, as well as bone imaging techniques
including standard radiology, computed tomography, and
magnetic resonance imaging. Cases were included if they had
biopsy-proven osteomyelitis or imaging suggestive of osteo-
myelitis, and isolation of Aspergillus from cultured bone. If
articular involvement was evident (e.g. isolation of Aspergillus
species from a arthrocentesis) without evidence of bone

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Clinical Microbiology and Infection ª2013 European Society of Clinical Microbiology and Infectious Diseases
560 Clinical Microbiology and Infection, Volume 20 Number 6, June 2014
involvement, the case was excluded from this analysis. The
variables collected were analysed as a function of outcome by
performing a t-test for independent samples when appropriate
(e.g. age) or the Fisher exact test for categorical variables. A
model of logistic regression was also utilized to evaluate the
effect of the factors analysed on the healing of osteomyelitis
caused by Aspergillus species. All factors that were statistically
significant in the univariate analysis and those with significant
clinical relevance were included. A p-value of <0.05 was
considered to be statistically significant.
Results
A total of 310 individual cases of osteomyelitis caused by
Aspergillus species described between 1936 and 2013 were
identified. An additional 51 cases found in the literature
published during the same time period were excluded from the
present analysis, because they did not fulfil the study definition
criteria. An increase in the number of reports over time was
noted (Fig. 1). Fifty-nine per cent of the patients were male.
The median age was 43 years (range, 0–86 years).
The comorbidities identified for Aspergillus osteomyelitis
included chronic granulomatous disease (CGD) (19%), hae-
matological malignancies (11%), transplantation (11%), diabetes
(6%), surgery, trauma and fractures (6%), human immunode-
ficiency virus infection (4%), steroid therapy (4%), pulmonary
disease (4%), previous Aspergillus infection (4%), intravenous
drug use (3%), otitis and sinusitis (3%), and cancer (1%).
Among cancer patients, 50% had lung cancer, 25% breast
cancer, and 25% vertebral condrosarcoma. Some patients had
multiple comorbidities, and in 36 patients (12%) comorbidities
were not reported (Fig. 2a). The most common sites of
infection included the spine (49%) (20% thoracic, 20% lumbar
140
120
100
No. of cases
80
60
40
20
Time (decade)
*For the 2000s, 20 cases diagnosed after the year 2010 are included.
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Clinical Microbiology and Infection ª2013 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20, 559–565
CMI
and sacral, and 3% cervical), base of the skull, paranasal sinuses
and jaw (18%), ribs (9%), long bones (9%), sternum (5%), chest
wall (4%), hand or foot bones (3%), and hips (2%) (Fig. 2b).
Aspergillus species were isolated from 278 individual cases.
In four patients, multiple species were isolated, and in 61
patients the Aspergillus species was not specified. The most
common infecting Aspergillus species were Aspergillus fumigatus
(55%), Aspergillus flavus (12%), and Aspergillus nidulans (6.7%).
Less frequently isolated species included Aspergillus terreus
(2.3%), Aspergillus niger (2.3%), Aspergillus versicolor (0.7%), and
Aspergillus flaviparus (0.3%) (Fig. 2c). Although a given species
of Aspergillus was not associated with a particular risk factor,
there was a trend towards a high prevalence of A. flavus in
diabetic patients (25% of patients with osteomyelitis caused by
A. flavus were diabetic). There were significant differences
between the paediatric/young (≤18 years) and adult
(>18 years) populations concerning risk factors, and the
localization and distribution of Aspergillus species. In particular,
CGD was found in 75% and 4% of the paediatric and the adult
populations, respectively (p 0.0001). Conversely, transplanta-
tion and diabetes were both significantly more frequent in
adults (19% vs, 1.5%, p 0.0001; and 11% vs. 1.5%, p 0.009).
Chest wall involvement and long bone involvement were
significantly more frequent in the paediatric/young population
than in the adult population (40% vs. 16%, p 0.0001; and 17%
vs. 8%, p 0.04). Finally, Aspergillus species other than A. fumig-
atus were significantly more frequent in the paediatric/young
population than in the adult population (32% vs. 20%, p 0.04).
Along with non-specific and systemic symptoms (e.g. fever,
asthenia, and weight loss), local symptoms related to the
specific site of infection were often reported. Most commonly,
local pain and hyposthenia or loss of organ function for
systems innervated by the compressed nerve (e.g. cranial
nerve palsy, paraplegia, and incontinence) were reported. Of
FIG. 1. Number of osteomyelitis cases
caused by Aspergillus species over a period
of eight decades.
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FIG. 2. Risk factors (A), localization (B)
and distribution of Aspergillus species (C)
in patients with Aspergillus osteomyelitis.
CGD, chronic granulomatous disease;
HIV, human immunodeficiency virus;
IDU, intravenous drug use.
the 310 cases reviewed, 193 (62%) were treated with a
combination of an antifungal regimen and surgery, 80 (26%)
were treated with an antifungal regimen alone, and nine (3%)
were only treated surgically. In 14 cases, the drug used was not
specified. For the remaining 28 patients, treatment was either
not specified or not given (only six patients). Monotherapy was
used in 53% of treated patients, and combination (two to four
drugs) or sequential therapies were used in the remaining
cases. Amphotericin B was the drug most frequently used,
either in monotherapy or in combination regimens (205
individual cases (92 monotherapy, 113 combination/sequential
Clinical Microbiology and Infection ª2013 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20, 559–565
Gabrielli et al. Osteomyelitis caused by Aspergillus spp. 561
regimen)), followed by itraconazole (89 individual cases (16
monotherapy, 73 combination/sequential regimen)), and vo-
riconazole (57 individual cases (29 monotherapy, 28 combina-
tion/sequential regimen)) (Fig. 3). The formulation of
amphotericin B was specified in only 43 cases: deoxycholate
in 12 cases, and liposomal derivative in 31 cases. There were
122 cases reported after the year 2000, which was the year in
which voriconazole was first used against Aspergillus infections.
Amphotericin B (alone or in combination) was used in 64
cases (52%), and voriconazole (alone or in combination) was
used in 55 cases (45%). The outcome of infection was reported
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250 TABLE 1. Distribution of patient characteristics according

Combination
to the outcome of Aspergillus osteomyelitisa
200
No. of treatments

Monotherapy Positive Negative

150 outcome outcome
(n = 190) (n = 77) pb

100 Age 165c 70

Median in years (SD) 40.4 (22.1) 37.5 (26.9) 0.391
Gender 160 68
50 Males, no. (%) 115 (71.9) 50 (73.5) 0.740
Localization 187 77
0 Spine, no. (%) 94 (50.2) 40 (51.9) 0.681
Skull, no. (%) 37 (19.7) 16 (20.7) 0.508
Other bones, no. (%) 56 (29.9) 21 (27.2) 0.771
Isolates 163 65
A. fumigatus, no. (%) 112 (68.7) 44 (67.7) 1
Aspergillus species other 51 (31.2) 21 (32.3) 0.871
than A. fumigatus, no. (%)
Risk factors 185 71
FIG. 3. Antifungal drugs used for the treatment of Aspergillus CGD, no. (%) 40 (21.6) 20 (28.1) 0.402
Transplantation, no. (%)d 26 (14) 13 (18.3) 0.434
osteomyelitis. Haematological 22 (11.8) 11 (15.4) 0.406
malignancies, no. (%)e
Diabetes, no. (%) 19 (10.1) 6 (8.4) 0.815
Previous Aspergillus 23 (12.4) 10 (14) 0.836
for 266 patients. For 44 patients, the outcome was not infection, no. (%)
Previous surgery, no. (%)f 30 (16.2) 2 (2.8) 0.002
mentioned. A positive outcome (cure/improvement) was HIV infection, no. (%) 8 (4.3) 5 (7.0) 0.526
Steroid use, no. (%) 9 (4.9) 8 (11.2) 0.093
reported for 189 patients (71%), and a negative outcome IDU, no. (%) 11 (5.9) 0 (0) 0.037
Pulmonary disease, no. (%)g 14 (7.6) 4 (5.6) 0.786
(death/worsening/chronicity of infection) was reported for 77 Ear or sinus infection, no. (%) 15 (8.1) 5 (7.0) 1
Other causes, no. (%)h 12 (6.4) 7 (10) 0.428
patients (29%). Among the 122 cases reported after the year Treatment
2000, the outcome was known for 109. Eighty patients (73%) Antifungal treatment  184 (97.3) 68 (88) 0.001
surgical debridement (%)i
had a positive outcome, and 29 patients (27%) had a negative Antifungal treatment + 117 (61.9) 45 (58.4) 0.398
surgical debridement (%)j
outcome. Among the 188 cases reported before the year
CGD, chronic granulomatous disease; HIV, human immunodeficiency virus; IDU,
2000, the outcome was known for 158 patients. One hundred intravenous drug use; SD, standard deviation.
a
The outcome of osteomyelitis was reported in 267 of 310 individual cases;
and ten patients (70%) had a positive outcome, and 48 patients positive outcome (cure/improvement) was described in 190 cases, and negative
outcome (death/worsening/chronicity of infection) was described in 77 cases.
(30%) had a negative outcome. Overall, positive, negative and b
The t-test was used for independent variables (e.g. age), and the Fisher exact test
was used for categorical variables. A p-value of <0.05 was considered to be
unknown outcomes were seen, respectively, in 64%, 28% and statistically significant.
c
8% of patients treated with amphotericin B, in 77%, 22% and Numbers in bold type indicate the patients for which a given characteristic was
reported and considered for statistical analysis.
1% of those treated with itraconazole, and in 73%, 26% and 2%
d
Solid organ transplantation included: kidney, heart, liver, lung, kidney + pancreas,
and heart + lung.
e
of those treated with voriconazole. Many of the patients Haematological malignancies included: lymphoma, acute and chronic leukaemia,
myelodysplasia, aplastic anaemia, haematopoietic stem cell transplantation, and
considered were receiving adjunctive therapies that might haemophilia.
f
This category included patients who had undergone surgery at the site of infection
either hinder (e.g. immunosuppressive agents) or promote by Aspergillus, or patients who had trauma or fractures at the site of infection or
had undergone orthopaedic surgery.
(e.g. immune-stimulating factors) the resolution of the infec- g
Pulmonary diseases included: pulmonary tuberculosis, silicosis, the presence of
bronchiectasis, and chronic obstructive pulmonary disease. Patients with carci-
tion. In particular, many CGD patients were treated with noma of the lung were also included in this category.
h
supportive therapies such as interferon-c, granulocyte col- The following factors were included in this category: malnutrition, advanced age,
alcoholism, viral hepatitis, liver cirrhosis, Down’s syndrome, chronic renal failure,
ony-stimulating factor, granulocyte–macrophage colony-stim- dialysis, and ulcerative colitis.
i
All treated patients, regardless of the addition of surgery, were included in this group.
j
ulating factor, or white blood cell transfusion, which might Only patients treated with antifungal therapy plus surgery were included in this
group.
interact synergistically with antifungal therapy [69]. In the
univariate analysis, a significantly greater proportion of
subjects with a favourable outcome underwent surgery (for the univariate analysis and those with significant clinical
trauma or fractures) prior to the development of infection by relevance were included. The factors included in the final
Aspergillus (p 0.002). Additionally, a significantly greater pro- analysis are those that yielded the best regression model.
portion of subjects with a favourable outcome received Again, previous surgery (p 0.028) and antifungal treatment
antifungal therapy (p 0.001). When, from among this group (p 0.043) were both associated with a better outcome.
of patients, those who had been treated with the combination Additionally, localization of the infection in the vertebrae or
of antifungal and surgery were considered separately, the in bones other than the skull significantly decreased the
difference was not statistically significant (p 0.398). Similarly, chances of recovery. The effect of these factors is present, but
for other variables, there were no statistically significant an estimate of its size is not accurate, as shown by the large
differences between the two groups (Table 1). In the multi- width of the CIs at 95% of the OR (Table 2). The overall crude
variate analysis, all factors that were statistically significant in mortality was calculated to be 25%.

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CMI
TABLE 2. Multivariate model of risk factors for outcome
among patients with Aspergillus osteomyelitis
Variable OR (95% CI)
Previous surgery 5.29 (1.49–33.78)
Antifungal therapy 4.59 (1.11–23.37)
Localization
Spine 0.27 (0.08–0.83)
Skull 0.29 (0.07–1.02)
Other bones 0.30 (0.1–0.85)
Discussion
Although osteomyelitis represents a rare form of IA, its crude
mortality was found to be not negligible, at 25%. It is
interesting to note that, when the bone infection was related
to a possible external insult (e.g. surgery for previous trauma
or fractures), the outcome was significantly more favourable
than in other circumstances where the patient was more likely
to be compromised (e.g. CGD, haematological malignancies,
and transplantation). This highlights how, even for this rare
clinical form, the host plays a crucial role in the evolution of
the infection. Importantly, we found a significantly higher
proportion of patients receiving antifungal therapy who had a
positive outcome. In contrast, the combination of surgery and
antifungal therapy did not significantly influence the outcome.
Although this finding seems to contradict the beneficial effect
of antifungal therapy as described above, one might speculate
that patients treated with the combination of drugs and
surgery were those who were most clinically compromised,
and that even such aggressive therapy could not yield a
positive outcome. These data gleened from the literature also
indicate how, for this type of infection, the choice of
treatment is highly variable. As expected, amphotericin B
was the drug most commonly used in the treatment of
Aspergillus osteomyelitis, followed by two azoles: itraconazole
and voriconazole. Echinocandins were only rarely used. The
Infectious Diseases Society of America guidelines recommend
either amphotericin or voriconazole for the treatment of
Aspergillus osteomyelitis, whereas the British Infection Society
recommends amphotericin in combination with flucytosine for
the treatment of serious Aspergillus osteomyelitis and recom-
mends itraconazole for the treatment of stable patients [2,63].
Both itraconazole and voriconazole are less toxic than
amphotericin B; also, they can be administered orally, and
achieve bone concentrations above the typical MIC for
Aspergillus [70,71]. It must be noted that A. flavus was the
second most often encountered species of Aspergillus in this
series of patients (12%). This species, along with A. terreus and
A. nidulans, is often reported to be less susceptible to
amphotericin B than other species [72–74]. This finding,
Clinical Microbiology and Infection ª2013 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20, 559–565
Gabrielli et al. Osteomyelitis caused by Aspergillus spp. 563
coupled with the fact that the polyene is still the drug most
commonly used, at least in the induction phase, stresses the
p importance of definitive identification of the fungus.
In conclusion, this study is the largest published review of
0.028
0.043 Aspergillus osteomyelitis in the literature to date, and provides
0.028 useful information about this uncommon infection by under-
0.062
0.028 lining its epidemiology, treatments, and outcomes. Taking into
account the fact that this is a retrospective, multisource case
review study, the possibility of a reporting bias cannot be
eliminated. This is because articles showing a more favourable
outcome were published, and this could result in an under-
estimation of the total number of osteomyelitis cases caused
by Aspergillus species in patients who had an unfavourable
outcome.
Transparency Declaration
The Authors declare no conflicts of interest.
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ª2013 The Authors