Successful treatment of vertebral osteomyelitis due to Aspergillus flavus in an immunocompetent patient
- 1 University of New South Wales, Prince of Wales Clinical School, Randwick, New South Wales, Australia
- 2 Infectious Diseases, Prince of Wales Hospital and Community Health Services, Randwick, New South Wales, Australia
- Correspondence to Dr Myong Gyu Joshua Kim; myonggyu.kim@health.nsw.gov.au
Abstract
Aspergillus osteomyelitis (AO) is a rare and often lethal opportunistic infection in predominantly immunocompromised patients. Treatment has shifted from amphotericin therapy to voriconazole monotherapy due to increased effectiveness and less toxicity. We report a case of an immunocompetent woman with vertebral osteomyelitis due to Aspergillus flavus who was successfully treated with surgery (requiring hardware implantation) and monotherapy posaconazole (following intolerance and hepatitis due to voriconazole). She remained well at follow-up post cessation of 12 months of antifungal therapy. We provide an updated literature review examining the role of azole monotherapy as the gold standard of treatment for AO.
Background
Aspergillus sp are ubiquitous and commonly found in the upper respiratory tract. Invasive aspergillus is most common in the respiratory system and rare in the bone and central nervous system. While aspergillus infection in the immunocompromised is well documented in the literature, it is rare to cause problems in immunocompetent patients. Aspergillus osteomyelitis (AO) is a relatively rare condition associated with high morbidity and mortality.1
As the presentation is non-specific with often negative blood cultures, the diagnosis is frequently delayed that can lead to unnecessary complications.2 Diagnosis of this infection can be troublesome as small amounts of specimen collected can miss the organism and fail to grow in fungal culture or identify the hyphae. PCR assay is a highly sensitive method to diagnose Aspergillus infection,3 4 however, currently takes an extended period of time to process in most laboratories. Voriconazole has replaced amphotericin as the main treatment of Aspergillus.5 6
A review of AO from January 2014 to January 2022 identified 25 published case reports. Case series revealed surgical debridement if possible along with azole therapy provided the best outcomes. Here, we present a case of aspergillus fumigatus vertebral osteomyelitis successfully managed with surgery (requiring internal fixation) and posaconazole monotherapy. We then provide an updated literature review over the last 8 years with a focus on therapy and outcomes.
Case presentation
A woman in her early 60s was referred by her general practitioner with worsening cervical neck pain for 3 months warranting investigation with a CT scan reporting extensive endplate bony erosions at cervical vertebrae (C)2 and C3 suggestive of infective discitis (figure 1). She was usually fit and well, with a previous history of a thyroid carcinoma which was resected then treated with radioactive iodine. She had no other medical history which was of concern for an immunosuppressed condition. The patient had no fevers or weight loss and was neurologically intact on examination. Initial laboratory findings showed a C reactive protein (CRP) of 30 mg/L and white blood cell count (WBC) of 12.16×109/L (neutrophils 9.2×109/L). Radiography of the chest showed no active lung lesion. An MRI with gadolinium (figure 2) confirmed the CT findings with increased signal on the short tau inversion recovery sequence with enhancement post gadolinium in the C2 and C3 vertebral body. This was followed by a CT-guided fine needle biopsy of the vertebral disc. The bacterial, fungal and acid-fast bacilli cultures were negative and the 16S RNA PCR and 18S RNA PCR were being processed in the interim. The patient was started taking cefazolin following the biopsy and planned for 6 weeks of outpatient intravenous antibiotics following her discharge.
CT of the spine as outpatient. Extensive endplate bony erosions at C2 and C3.
MRI of the spine on admission. Short tau inversion recovery sequence with enhancement post gadolinium in the C2 and C3 vertebral body.
However, the patient’s symptoms worsened and she represented 10 days later. A repeat CT and MRI scan demonstrated progression of the discitis at C2–C3, with complete collapse of the anterior C3 vertebral body (figure 3). There was a small epidural abscess extending from mid C2–C4, and moderate bilateral neural foraminal stenosis at C3–C4. Subsequently, vancomycin was added to the cefazolin and the patient underwent emergency surgery (cervical spine anterior corpectomy and posterior cervical stabilisation and fusion). The following day, the 18S RNA PCR identified Aspergillus flavus from the biopsy last admission and the patient was loaded with voriconazole. The intraoperative specimens later cultured A. flavus confirming the culprit organism and the cefazolin and vancomycin was ceased. The postoperative period was complicated by dysphagia requiring temporary nasogastric feeding and severe pain, which was managed by the acute pain service. The patient had an unremarkable CT of the chest, abdomen and pelvis and an ophthalmology review to exclude metastatic fungal infection. After being cleared back to a full diet, she was discharged home on oral voriconazole.
Repeated MRI of the spine. Progression of the discitis at C2–C3, with complete collapse of the anterior C3 vertebral body.
Outcome and follow-up
Outpatient voriconazole therapy was complicated by blurred vision but resolved spontaneously in a few days. Multiple voriconazole dosing adjustments were needed due to liver function test derangement and subtherapeutic levels. Following an readmission for possible drug induced hepatitis, the antifungal regime was switched to posaconazole monotherapy at the 5-month mark. The patient tolerated posaconazole with minimal side effects and therapeutic levels. A repeat MRI in 6 months showed interval resolution of the postsurgical and infective changes without evidence of residual infection. She completed 12 months of treatment in total and the posaconazole was ceased after review.
She remained well on follow-up 12 months later post cessation of treatment.
Discussion
AO is an infrequent but important pathology to identify early on, which is classically associated in the immunocompromised patients. Vertebral bodies appear to be the most frequent site for aspergillus infections in the bone.7 One possible source of exposure for our patient was that she was an avid gardener and did report regular rose thorn prick injuries, thus possibly leading to haematogenous spread of disease.
It is important to highlight the clinical symptoms of AO are not specific. Back pain, weight loss and possible neurological involvement are also manifestations of bacterial vertebral osteomyelitis.8 Similarly, the CRP and WBC are sometimes in the normal range or only mildly elevated. Imaging modalities can aid in the diagnosis of fungal osteomyelitis, however, have their own limitations. Non-pyogenic spondylitis such as fungal infection and tuberculosis typically preserve disk morphology.9 In our patient, the MRI demonstrated endplate bony erosion and eventually near complete destruction and collapse of the cervical vertebral body, which is more characteristic of a pyogenic source of infection.
The gold standard for diagnosis of invasive aspergillosis requires a tissue specimen demonstrating hyphae and a positive culture for Aspergillus sp.10 The diagnosis can also be confirmed with positive cultures from a typically sterile site such as bone or cerebrospinal fluid. As our patient was not immunocompromised, we did not initially suspect atypical or rarer causes of osteomyelitis thus deemed a core biopsy as an appropriate investigation for diagnostics. We acknowledge biopsy sensitivity can vary due to various reasons including sampling error and operator proficiency. While there was no growth in the initial fungal culture, we note the PCR assay from the same sample detected Aspergillus sp, culminating in initiation of antifungal treatment. The use of PCR as an early diagnostic marker for invasive aspergillosis has increased, but largely in the context of immunocompromised patients with haematological malignancy, and thus warrants further study.11
Voriconazole has replaced amphotericin for the first line treatment for invasive aspergillosis. Our patient
was managed on voriconazole for a period of 5 months before being transitioned to posaconazole due to liver function derangement. Besides the afore-mentioned adverse effect, this patient represents a case of severe vertebral AO with a favourable outcome with surgery and extended posaconazole monotherapy treatment due to retained infected prosthesis.
We performed a literature search using PubMed with the terms ‘aspergillus’, ‘Aspergillosis’ and ‘osteomyelitis’. We found 25 other published cases of AO from January 2014 to January 2022, which were accessible, in English and included antifungal treatment details (table 1).
Aspergillus osteomyelitis case reports published 2014–2022
| Case (Ref) | Age/sex | Comorbidities | Bone involved | Species | Surgical treatment | Antifungal treatment | Duration of treatment | Outcome |
| 114 | 68/M | Diabetes | Necrotising otitis externa with temporozygomatic involvement | Flavus | Yes | Voriconazole | 3 months | Alive |
| 215 | 64/M | Diabetes | Clivus | Not stated | Yes | Voriconazole | 2 months | Alive |
| 316 | 51/M | Nil | Ribs | Flavus | Yes | Voriconazole | 4 months | Alive |
| 416 | 40/M | Nil | Ribs | Flavus | Yes | Voriconazole | 3 months | Alive |
| 517 | 52/M | Recent cardiac transplant | Scapula | Fumigatus | Yes | Voriconazole | 12 months | Alive |
| 618 | 28/F | Complement deficiency | Skull | Fumigatus | Yes | Itraconazole | 13 months | Died |
| 719 | 12/M | Stem cell transplant | Thoracolumbar spondylodiscitis | Terreus | Yes | Voriconazole | 23 months | Alive |
| 820 | 53/M | Nil | Vertebral | Not stated | Yes | Voriconazole | 3 months and ongoing | Alive |
| 921 | 23/M | Chronic granulomatous disease | Vertebral | Udagawae | Yes | Posaconazole and micafungin | 6 months | Alive |
| 1022 | 9/M | Chronic granulomatous disease | Rib | Nidulans | Yes | Voriconazole | 3 months | Alive |
| 1123 | 29/M | Human immunodeficiency syndrome | Vertebral | Not stated | No | Itraconazole | 3 months | Died |
| 124 | 53/M | Nil | Vertebral | Not stated | Yes | Amphotericin B | Not stated | Alive |
| 1324 | 62/F | Diabetes | Maxillary | Not stated | Yes | Amphotericin B and voriconazole | 3 months | Alive |
| 1425 | 4/F | Chronic granulomatous disease | Ribs | Fumigatus | Yes | Amphotericin and voriconazole | 2 months | Died |
| 1526 | 70/M | Coronary artery bypass graft surgery, diabetes | Rib | Flavus | Yes | Voriconazole | 6 months | Alive |
| 1627 | 20/M | Recurrent pulmonary tuberculosis | Vertebral | Terreus | Yes | Voriconazole then caspofungin | 3 months | Alive |
| 1728 | 65/M | Recent cardiac transplant | Sternal | Fumigatus | Yes | Voriconazole then isavuconazole | 12 months | Alive |
| 1829 | 61/M | Nil | Sphenoid sinus | Fumigatus | Yes | Voriconazole then posaconzole | 12 months | Alive |
| 1930 | 77/M | Rheumatoid arthritis | Sternal | Fumigatus | Yes | Voriconazole | 4 months | Died |
| 2031 | 68/M | Diabetes | Temporozygomatic | Flavus | Yes | Voriconazole | 3 months | Alive |
| 2132 | 65/F | Coronary artery bypass graft surgery, diabetes | Sternal | Fumigatus | Yes | Voriconazole then isavuconazole | 12 months | Alive |
| 2233 | 59/F | Diabetes | Sphenoid and clivus | Not stated | Yes | Voriconazole | 3 months | Alive |
| 2334 | 43/M | Nil | Vertebral | Not stated | Yes | Voriconazole | 3 months | Alive |
| 2417 | 52/M | Cardiac transplant | Scapula | Fumigatus | Yes | Voriconazole | 24 months | Alive |
| 2535 | 6/M | Chronic granulomatous disease | Neurocranium (skull) | Fumigatus | No | Voriconazole then itraconazole | 18 months and ongoing | Alive |
Analysis of these cases revealed an overall mortality of 16% (4/25), which was similar to the rate of 25% found in the previous review of 310 cases up to 2013.12 Of note, only two patients did not have surgical intervention in our review and one patient died 3 months later and the other one received 18 months of antifungal treatment and ongoing prophylaxis. This is in comparison to the 33% of patients in the 2014 review who did not have surgery. In contrast to the 2014 review where amphotericin B was the most frequently used antifungal either in monotherapy or combination treatment (66%), we noted a shift towards treatment with voriconazole in monotherapy or combination treatment (76%). This is likely attributed to the changes in first line recommendations for invasive aspergillosis with Segal and Walsh6 and Herbrecht et al. 5 In recent years, there appears to be increasing evidence that posaconazole is suitable as an alternative treatment for invasive aspergillosis.13 Our patient tolerated posaconazole well with minimal adverse effects. Only 6 of the 25 cases were immunocompetent with no other comorbidities.
Vertebral osteomyelitis caused by aspergillus infection is very uncommon. Early detection of the pathogen is important for the proper management of the patient. This can be difficult to achieve in healthy individuals with non-specific symptoms and obscure imaging findings. We conclude that posaconazole therapy can likely be a suitable alternative treatment for Aspergillus infection with retained hardware.
Patient’s perspective
I wish that my fungus disease had been recognised earlier as I was in extreme pain prior to the operation to the point where I considered ending my own life. However, I am very grateful to the team that helped get me better and although I don’t think I will be the same again I am doing the things I like and enjoying life. If my story helps in any way for other people getting earlier treatment I would be happy. Thank you again.
Learning points
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Aspergillus osteomyelitis is a rare and often lethal opportunistic infection in predominantly immunocompromised patients.
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Early diagnosis is crucial to avoid unnecessary complications and it is important to consider testing with 18S RNA PCR.
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Our case was successfully managed with surgery and voriconazole monotherapy, followed by extended posaconazole treatment to treat infected retained hardware.
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A review of the published literature suggests that surgery and voriconazole monotherapy appears to be the best standard of practice to date.
Ethics statements
Patient consent for publication
Footnotes
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Contributors MGJK was the primary author who drafted the manuscript including the literature review. KO was the senior author responsible for the conception of the manuscript and the revision of the manuscript.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
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Author note Each author certifies that this material has not been and will not be submitted to or published in any other publication.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
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