Paediatric actinomycosis: A 16‐year, single‐institution retrospective review of cases

Actinomycosis is a rare subacute to chronic granulomatous infection which can mimic other infectious or malignant diseases. This study examined the epidemiology and treatment outcome of actinomycosis in children.

1 Actinomycosis is a rare subacute to chronic granulomatous infection cause by filamentous Gram-positive anaerobic bacteria. 2 Characteristic features of actinomycosis include chronic infections, localised swelling with suppuration, abscess formation, tissue fibrosis and sinus discharge. 3 Common sites of involvement include the head and neck, thoracic and abdominopelvic region.
What this paper adds 1 In our study, orocervicofacial infection constituted 70% of the cases. 2 All patients were treated with appropriate antibiotics. Majority (90%) of our patients underwent surgical procedures for diagnostic and therapeutic purposes, and overall prognosis was excellent with no mortality. 3 Early diagnosis and appropriate treatment are key to good clinical outcome.
Actinomycosis is a rare subacute to chronic granulomatous infection caused by filamentous Gram-positive anaerobic bacteria from the Actinomyceteceae family. 1,2 Although Actinomyces species are part of the endogenous flora of the oral cavity, gastrointestinal and genitourinary tract, they are rarely identified as pathogens in children, accounting for less than 3% of all reported actinomycosis infection. [2][3][4] Characteristic features of actinomycosis include chronic infections, localised swelling with suppuration, abscess formation, tissue fibrosis and sinus discharge. 1,5 Common sites of involvement include the head and neck, thoracic and abdominopelvic region. 3,6,7 Actinomycosis can affect patients of all ages, with a peak incidence of around 40-50 years. The majority of patients are immunocompetent individuals. Although it is not considered an opportunistic infection, cases have been reported in immunocompromised patients with leukaemia and human immunodeficiency virus infection. 8,9 Preceding risk factors include gingival disease, dental caries, oral trauma and tooth extraction. 2,3 More than 40 Actinomyces species have been identified and the most frequent pathogenic species encountered is Actinomyces israelii. 3,6 Actinomyces spp. has the propensity to develop abscesses that progress to draining sinuses in at least one-third of patients, with characteristic sulphur granules found in the purulent discharge. 1,5 Bacterial cultures and histopathology are the cornerstones of diagnosis. Treatment of actinomycosis often requires both antimicrobial therapy and surgical management. Traditionally, penicillin is the drug of choice, with dosing and duration of therapy based on site and severity of infection. Most experts recommend 4-6 weeks of intravenous antibiotics, followed by 6-12 months of oral therapy. 5,6,10 The aim of this study was to examine the clinical profile, treatment, and outcomes of children with actinomycosis. For the purpose of this case series, we define Actinomyces spp. as those that belonged to the genus Actinomyces before the recent reclassification 11 that created the new genera Schaalia and Winkia, which include Schaalia turicensis, Schaalia odontolytica and Winkia neuii.

Methods
The study was conducted in (KK Women's and Children's Hospital), the largest tertiary paediatric hospital in (Singapore) with approximately 350 beds for paediatric patients. A retrospective medical record review of all children ≤16 years who were diagnosed with actinomycosis and treated at (KK Women's and Children's Hospital) from January 2004 to December 2020 was performed. This retrospective study was approved by the (Singhealth) Centralised Institutional Review Board (CIRB 2018/2205), with a waiver of informed consent for patients recruited before 31/10/2017. Informed consent was obtained from parents/guardians of all recruited subjects from 1/11/2017 as per regulatory requirements. The patients were identified from an inpatient infectious disease clinical database. Patient-specific data pertaining to demographic characteristics, clinical presentation, laboratory and radiological results, treatment, and clinical outcomes were collected from electronic medical chart review.
The diagnosis of actinomycosis was made based on positive culture for Actinomyces species or histological findings consistent with Actinomyces infection from a biopsy specimen. Microbiological confirmation was defined as the presence of non-sporeforming Gram-positive rods on direct examination and slowgrowing organisms in anaerobic culture conditions. Histopathological confirmation was defined as the presence of Gram-positive filamentous organisms with positive periodic acid-Schiff (PAS) stain or Gomori methenamine-silver (GMS) stain, concomitant with sulphur granules. Cases with either culture or histopathological confirmation of actinomycosis were included in this study.
Statistical analyses were done with Microsoft Excel. Categorical data were expressed as numbers and percentages. Continuous data were expressed as median and ranges.

Demographics
There were a total of 10 patients identified during the study period. Of these, seven were female (70%). The median age of presentation was 9.8 years (range 4.7-15.7 years). Patient demographics and clinical profiles are summarised in Tables 1 and 2.     Leukocytosis (+)

Investigations
Six patients (60%) had leukocytosis with neutrophil predominance. Four of these patients had elevated C-reactive protein levels. Half of the patients (n = 5, 50%) had anaemia for their age on their initial full blood count ( Table 2). The majority of patients (n = 8, 80%) underwent imaging studies to further delineate the extent of disease (Figs. 1, 2). Imaging modalities included ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) scans; the majority showed heterogeneous lesions featuring soft-tissue infiltrates with surrounding inflammation.
One patient (case 3) was diagnosed with lung abscess and underwent video-assisted thoracoscopic surgery and right lung lesion wedge resection. Fluid culture yielded mixed growth of anaerobic Gram-negative bacilli and Gram-positive cocci, consisting of Bacteroides, Fusobacterium necrophorum, Streptococcus constellatus and A. israelii. He received 6 days of intravenous clindamycin and ceftriaxone, followed by a course of clindamycin and cefuroxime for 2 weeks. Due to pre-existing amoxicillin

Outcomes
Complications included osteomyelitis (n = 4, 40%), mastoiditis (n = 2, 20%), brain abscess (n = 1, 10%), recurrent neck abscess (n = 1, 10%), thyroid abscess (n = 1, 10%) and lung abscess (n = 1, 10%). One patient (case 6) was diagnosed with right otomastoiditis complicated by periosteal and intracranial abscess. There was a preceding history of right ear cholesteatoma. He presented with 2 weeks of fever and right ear pain. A CT scan of the brain showed right mastoiditis, a sub-periosteal abscess, and an intracranial abscess in the parietal region (Fig. 1). He underwent aspiration of the brain abscess and mastoidectomy. Intra-operative fluid cultures grew A. odontolyticus, along with concomitant organisms, non-haemolytic Streptococcus sp., Pseudomonas aeruginosa, Prevotella oris and Acinetobacter baumannii. He was treated with a combination of intravenous antibiotics at various stages, consisting of ceftriaxone, ampicillin, metronidazole, ceftazidime, vancomycin and piperacillin/tazobactam for a total course of 2 months. Thereafter, he completed a course of amoxicillin/clavulanic acid and ciprofloxacin for another 4 months, with complete resolution and full neurological recovery.
Another patient (case 9) with background of poorly controlled type 1 diabetes mellitus on subcutaneous insulin injection was diagnosed with a right pre-auricular abscess. She presented with right pre-auricular swelling and pain for 1.5 weeks. She underwent incision and drainage of the right pre-auricular abscess. Intra-operative abscess cultures grew A. turicensis and Prevotella buccalis. She was treated with 2 days of empiric antibiotic intravenous cefazolin which was converted to intravenous amoxicillin/ clavulanic acid for 3 days, followed by oral amoxicillin/clavulanic acid. Six weeks into treatment, she developed recurrence of the abscess, for which she underwent a second incision and drainage procedure, with another intra-operative abscess culture revealing A. turicensis. Treatment was continued with oral amoxicillin/ clavulanic acid. Oral clindamycin was added 4 months later in view of recurrence of pus discharge from right pre-auricular area. An initial Gram stain result showed Gram-positive cocci, and the final pus culture showed mixed aerobes and anaerobes. After 1 month, she developed severe diabetic ketoacidosis secondary to dietary indiscretion with inadequate insulin administration and required intensive care unit admission. She received 2 days of Fig. 1 (a) Computed tomography scan of the brain (case 6) showing an extracranial subperiosteal abscess (red arrow) in the region of the right mastoid with a peripherally enhancing hypodense lesion in the right temporal lobe (red dashed arrow). There is resultant mass effect on the right lateral ventricle with midline shift.  intravenous ceftriaxone and metronidazole, which was then converted back to oral amoxicillin/clavulanic acid. She underwent an excision of a right pre-auricular sinus 7 months from her initial diagnosis of a recurrent right pre-auricular abscess. Intra-operative frank pus was noted, and the fluid culture yielded A. turicensis and P. buccalis. The persistent presence of the organisms despite good compliance to oral antibiotics appeared to be related to her inadequate diabetic control; her pre-operative glycaemic control (HBA1C) was 9.0%. Thereafter, she completed another 6 months of oral amoxicillin/clavulanic acid (total of 56 weeks) with complete recovery.
The duration of follow-up of patients was 6 months (range 0-26). Two patients did not attend their scheduled outpatient clinic review. On further checks, they had attended primary care clinics for medical consultations 6-9 years following their initial diagnosis of actinomycosis, and there was no recurrence. All patients had a complete resolution after treatment. There was no reported mortality in our study population.

Discussion
In this retrospective study, we examined the clinical profile, therapeutic interventions, and prognosis of actinomycosis in children. To our knowledge, this is the largest case series of paediatric actinomycosis in a single centre.
Actinomycosis is characterised by a wide range of clinical presentations. Actinomyces species have been known to cause invasive infections via direct extension across tissue planes. Bony extension into the mandible, cervical spine and cranial bones has been described. 5,12 Orocervicofacial actinomycosis is the most common form of infection, usually constituting around 50% of cases, 3,6,13 and the peri-mandibular region is the most common area to be involved. 13,14 In our study, orocervicofacial infection constituted 70% of the cases. In a systemic review by Glass et al., 40% of paediatric actinomycosis involved cervicofacial soft tissue, and 60% had bony involvement, primarily the mandible. 14 Poor oral hygiene and dentition, dental extractions or trauma are risk factors of orocervicofacial infection. 3,[14][15][16] The thoracic form of actinomycosis constitutes around 15% of all cases. 6,10 Pulmonary involvement can arise via local spread from orocervicofacial or abdominal infection, aspiration of oropharyngeal secretions or after oesophageal injury. Risk factors include underlying lung diseases such as bronchiectasis, chronic lung disease and emphysema. 10 In our study, the patient with thoracic actinomycosis presented with chest pain and shortness of breath, in the absence of fever or cough, highlighting the atypical presentation of actinomycosis in children. Identified risk factors were dental caries and gingivitis. Otherwise, he had no underlying chronic lung disease.
Abdominal actinomycosis constitutes about 20% of cases in adults, with pre-disposing factors of gastrointestinal perforation, previous surgery, and neoplasia. 6 In children, there are few case reports of abdominal actinomycosis. Around two-thirds of children with abdominal actinomycosis may present with an abdominal mass, or pain with fever, weight loss and a draining sinus as additional clinical features. 7 About one-fifth of the children in a retrospective study on abdominal actinomycosis had a history of appendicectomy. 7 However, in our study, there were no cases of abdominal actinomycosis.
Actinomyces is a predominant genus of oral microbiota in children. Sarkonen et al. 4 found that at the age of 2 months, onethird of infants were colonised with Actinomyces, predominantly A. odontolyticus. From the age of 1 year onwards, more than 90% of children are colonised with one or more Actinomyces species in their oral cavity. 4 In our study, dental infection (40%) was the most common risk factor, suggesting that improving paediatric oral hygiene and regular dental checks may be important preventive strategies against Actinomyces infection. 17 Actinomyces species are often found as co-pathogens with other bacteria, with the most common co-pathogen being Aggregatibacter actinomycetemcomitans (such as in our case 7). 3 Concomitant organisms were found in 90% of the patients in our study, which is comparable to some adult studies 2,3,18 which report Bacteroides, Fusobacterium, Propionibacterium and Streptococcus species as common co-pathogens. In polymicrobial infections, Actinomyces species were frequently isolated and likely contributed to the pathogenic processes. 2 Depending on the composition of the concomitant synergistic flora, they may be acute, subacute or chronic onset. In the presence of usual aerobes or anaerobic flora, subacute to chronic onset is common. 3 Actinomycosis has been referred to as the 'masquerader' of the head and neck with significant diagnostic challenges due to an insidious natural history and lack of acute inflammatory features. 18 Bonnefond et al. highlighted that diagnosis may often be delayed, with the median duration from symptom onset to diagnosis of 1 month. 19 In our study, the median duration from admission to diagnosis was 6 days. Early diagnosis was achieved likely due to sampling obtained through surgical procedures for microbiological and histological confirmation. Commonly reported symptoms include fever and chronic soft tissue swellings, consistent with the clinical presentation of the children in our study. These soft tissue swellings may develop a firm consistency over time, mimicking malignancy. Of note, one differentiating feature from malignant lesions is that regional lymphadenopathy is often a late finding. 16,19 Microbiological identification is the gold standard for diagnosis, but isolation of Actinomyces species is usually achieved in fewer than 50% of cases. 19 Presence of Gram-positive filamentous organisms and sulphur granules is supportive of the diagnosis. However, sulphur granules are not specific to actinomycosis and can be present in nocardiosis, chromomycosis and botryomycosis. 20 Special stains like PAS or GMS can be useful to demonstrate the filamentous branching bacteria (Fig. 3a,b).
Successful treatment of actinomycosis often involves a combination of surgical and antimicrobial treatment, tailored to individual patients. 4,6 Actinomyces species are uniformly susceptible to penicillin and most other beta-lactam antibiotics, carbapenems and vancomycin. 4,21 Traditionally, high-dose parenteral penicillin for 4-6 weeks followed by 2-12 months of oral penicillin V has been recommended. 4,6,22 Doxycycline, clindamycin and erythromycin are suitable alternatives for patients with penicillin allergy. 22 In contrast to other anaerobic infections, metronidazole has minimal in-vitro activity towards Actinomyces spp. and should not be used as monotherapy. 4,6,23 Antimicrobial therapy is tailored to the patient, based on the site of infection and the presence of concomitant organisms. A treatment regimen consisting of a beta-lactam and a betalactamase inhibitor, such as clavulanate or tazobactam, would provide additional cover against Staphylococcus aureus, Enterobacteriaceae and Gram-negative anaerobes. In our study, the majority of patients (90%) underwent surgical procedures for diagnostic and therapeutic purposes. The median duration of intravenous antibiotic in our cohort was 5 days before conversion to oral antibiotics.
Our study has some limitations due to its retrospective design and small sample size. Although the small number of patients limits the generalizability of the results, these findings are comparable to similar studies done in adults 3,13,19 and case reports of paediatric actinomycosis. [14][15][16] As the incidence of actinomycosis is low in children, multi-centre studies may be required to further investigate the utility of shorter antibiotic regimens.
The overall prognosis of the patients in our study was excellent, with no mortality. Early diagnosis and appropriate treatment are key to good clinical outcome.

Conclusions
Actinomycosis, a rare clinical entity in children, poses a diagnostic challenge due to its insidious clinical course and broad differential diagnoses at presentation. This study highlights the distinct and varied clinical manifestations and the high complication rate of actinomycosis in children, and we recommend a high index of suspicion for early diagnosis and treatment. With appropriate surgical intervention and antimicrobial therapy, the prognosis appears excellent and relapses are rare.