Candida and actinomyces

The most common infectious cause of benign acquired TEF is granulomatous infection, most often tuberculosis (Tables 1 and 2) [2, 3, 5–7]. Individual case reports noted 35.5% (n = 11) of fistula cases were attributed to infectious causes, with tuberculosis being the most common (72.7%, n = 8; Table 1). Other less common causes include agents of mucormycosis, herpes simplex infections, and Candida spp. infection, often in the setting of a compromised immune system or diabetes [12–14]. There have only been 12 published cases of TEF caused by Candida (Tables 3 and 4); seven individual reports and two reviews note Candida co-infection with Actinomyces, six of which confirmed the infections by culture (Tables 5 and 6). Candida and Actinomyces species can be found in the oral mucosa, often found in dental plaques and among normal mouth flora, typically causing infection in individuals with impaired mucosal barriers or compromised immune systems [15, 16]. While isolated Candida infections can occur, Actinomyces rarely is the sole culprit of infection, instead, it is often part of a microbial infection in conjunction with other species like Streptococcus, Fusobacterium, or Candida [15, 16]. While there are several reports of Candida and Actinomyces co-infection resulting in esophageal or pulmonary infection, only one noted the formation of a fistula (Table 5) [17]. Like tuberculosis, actinomycosis causes chronic granulomatous inflammation, which may have contributed to the fistula formation in our patient [15, 16]. Actinomyces is a known etiology of mycetoma, chronic granulomatous infections that are classically difficult to treat and require prolonged therapy [8, 9]. These are characterized as either fungal (eumycetoma) or bacterial (actinomycetoma), as in the case of our patient, and classically present with small, painless subcutaneous nodules that develop purulent discharge [8, 9]. Our patient was unusual, not only in the presentation of their actinomycetoma but in its co-infection with Candida and its complication by the formation of a broncholith and subsequent fistula, which, to our knowledge, has not been previously described.

Table 1.

Case reports of documented Bronchial Esophageal Fistula

Grey boxes indicate information not available in the report; ARDS – Acute Respiratory Distress Syndrome; AML – Acute Myeloid Leukemia; AmpB – Amphotericin B; CRT – Chemoradiation Therapy; GSS – Gastrograffin Swallow Study; OTSC – Over-The-Scope Clipping; PNA – Pneumonia; SCC – Squamous Cell Carcinoma; SEMS – Self-Expanding Metallic Stent; VATS – Video-Assisted Thoracic Surgery; LLL – Left Lower Lobe, LMB – Left Main Bronchus, RML – Right Middle Lobe, RLL – Right Lower Lobe; TEF – Tracheoesophageal Fistula; TBF – Tracheobronchial Fistula; BEF – Bronchioesophageal Fistula; EMF – Esophageal-Mediastinal Fistula; EPF – Esophageal-Pulmonary Fistula; GTF – Gastro-Tracheal Fistula; GBF – Gastro-Bronchial Fistula.

Table 2.

Review articles reporting Bronchial Esophageal Fistula

Grey boxes indicate information not available in the report; CRT – Chemoradiation Therapy; EVAC – Endoluminal Vacuum; NHL – Non-Hodgkin Lymphoma; NSCLC – Non-Small Cell Lung Cancer; OTSC – Over-The-Scope Clipping; PNA – Pneumonia; PTX – Pneumothorax; SCC – Squamous Cell Carcinoma; SEMS – Self-Expanding Metallic Stent; RIB – Right Intermediate Bronchus; RMB – Right Main Bronchus; LMB – Left Main Bronchus; TEF – Tracheoesophageal Fistula; TBF – Tracheobronchial Fistula; TPF – Tracheopulmonary Fistula; BEF – Bronchioesophageal Fistula; BPF – Bronchopulmonary Fistula; EPF – Esophageal-Pulmonary Fistula; GTF – Gastro-Tracheal Fistula; GBF – Gastro-Bronchial Fistula; AEF – Aorto-Esophageal Fistula.

Table 3.

Case Reports of documented Candida Fistulas

Grey boxes indicate information not available in the report; AmpB – Amphotericin B; PNA – Pneumonia; PUD – Peptic Ulcer Disease; TEF – Tracheoesophageal Fistula; PEF – Pericardial-Esophageal Fistula; EPF – Esophageal-Pulmonary Fistula; ABF – Aorto-Bronchial Fistula.

Table 4.

Review articles of Candida Fistulas

Grey boxes indicate information not available in the report; CRT – Chemoradiation Therapy; PPI – Proton-Pump Inhibitor; TEF – Tracheoesophageal Fistula; BEF – Bronchioesophageal Fistula.

Table 5.

Case Reports of documented Actinomyces/Candida Co-infection

Grey boxes indicate information not available in the report; AFB – Acid-Fast Bacillus; PCN – Penicillin; PNA – Pneumonia; SCLC – Small Cell Lung Cancer; RML – Right Middle Lobe; RUL – Right Upper Lobe; LML – Left Middle Lobe.

Table 6.

Review articles of Actinomyces/Candida Co-infection

Grey boxes indicate information not available in the report; AmpB – Amphotericin B.

Actinomycetoma and broncholithiasis

Broncholithiasis is caused by calcification of material that enters the tracheobronchial tree, often due to granulomatous infection material that migrates from surrounding lymphatic structures [4, 5]. This can result in airway obstruction and inflammation, and while most often asymptomatic, they can be complicated by recurrent pneumonia and TEF formation [4, 5]. In fact, it was found that the most common infectious causes were fungal and mycobacterial infections, with Histoplasma being the most common etiology in the United States and other less common pathogens being tuberculosis, Actinomyces, and Aspergillus [4]. Despite the association with actinomycosis, there has not been a reported case of the formation of an actinomycetoma with Candida co-infection further complicated by broncholithiasis and TEF, representing a novel presentation for this pathology.

Diagnosis of TEF

Currently, there are no formal guidelines to establish or confirm the diagnosis of TEF. However, most experts agree that either esophagography or endoscopy is necessary to diagnosis and assist with pre-operative planning [2, 18]. The diagnosis of TEF is most often made using a combination of upper endoscopy and bronchoscopy. The literature review noted that 67.7% (n = 21) of patients were initially evaluated with CT, followed by bronchoscopy (41.9%, n = 13) and an esophagogastroduodenoscopy (EGD; 35.5%, n = 11; Table 1) [1, 2, 18]. CT initially only revealed a broncholith in our patient, but follow-up upper endoscopy revealed a fistulous communication between the right mainstem bronchus and the esophagus (Fig. 2a and b). While not necessary, radiographic imaging with chest radiography is often obtained in the setting of aspiration pneumonia or other symptoms suggestive of consolidation, and this may show non-specific signs of aspiration-related changes, lung masses, or widening of the mediastinum in the setting of granulomatous disease [1–3, 18]. CT imaging of the chest may be used to evaluate for signs of fistula or abnormalities in the mediastinum or aerodigestive tract; currently, there is a lack of data regarding the sensitivity, specificity, or predictive values of CT imaging in patients with known TEF [2]. CT imaging is useful, however, and plays a crucial role in diagnosing broncholithiasis, as it can give information on the location and degree of obstruction. While CT has good sensitivity for the early detection of bone involvement in those with more classic mycetoma of the lower extremity, in those cases, it is less frequently used as part of the routine diagnostic work-up in favor of culture and histology [4, 8]. In our patient, non-contrast CT of the chest revealed a broncholith within the right mainstream bronchus with evidence of post-obstructive atelectasis in the right lower lobe (Fig. 2).

Treatment of infections in TEF

While treatment of TEFs is often aimed at treating the fistulous communication, concomitant efforts need to be made to treat the underlying cause. Although infectious causes of benign acquired TEF are not uncommon, the treatment and diagnosis are not well described. The most commonly described infectious cause of TEF was tuberculosis infection, which, once confirmed as secondary to infection with Mycobacterium tuberculosis, is typically treated with surgical repair and prolonged courses of combination antibiotics [2, 5–7, 19]. Other infectious causes that have been recently described include mucormycosis infection treated with liposomal amphotericin B and a case of silicotuberculosis infection [5, 17]. Broncholithiasis is managed surgically or conservatively based on patient symptoms and extent of disease, with definitive management consisting of bronchoscopic extraction or pulmonary resection of the affected lobe [4, 5]. Unlike broncholithiasis, surgical treatment alone of mycetoma is rarely successful, but does play a role in fungal disease [8]. The pharmacologic treatments vary based on the infectious agent; fungal mycetoma (eumycetoma) often requires combined surgical excision followed by prolonged therapy with itraconazole for 1–2 years as first-line therapy, whereas actinomycetomas are often amenable to antibiotic therapy alone [8]. Antimicrobial treatment options for actinomycetoma often include use of penicillins, aminoglycosides, trimethoprim-sulfamethoxazole, or dapsone alone or in combination with one another, partially depending on the organisms determined to be driving the process [8]. A commonly used regimen in our review was use of IV penicillin for Actinomyces involvement, with oral fluconazole when there is concern for fungal coinfection. A period of more intensive treatment can then be followed by oral amoxicillin (Table 5).

Although reported as an infectious cause of benign acquired TEF, there are currently no concise guidelines on treatment for patients with TEF secondary to Candida infection. Of the cases that noted fistulas attributed to Candida infection, 15 reported treatment, and of those, eight were treated with combined surgery and medical therapy (44.4%) with an associated 25% mortality. Another four cases were treated with medical therapy alone (22.2%), with an associated 50% mortality and three patients were treated with surgery alone (16.7%), associated with a 100% mortality (Table 3). Of those that received medical therapy, the most commonly given antimicrobial agent was fluconazole (n = 8) followed by amphotericin B (n = 4), consistent with other reports [20]. To date, complications following treatment for infectious causes of fistulae have not been reported (Table 4). Only one reported case of an Actinomyces and Candida co-infection that resulted in a fistula has been reported; treatment was a combination of vancomycin, voriconazole, piperacillin-tazobactam, and liposomal amphotericin B and was complicated by Mucorales and Rhizopus infection, resulting in necrotizing pneumonia [17]. Our patient's definitive therapy was a combination of amoxicillin-clavulanate and fluconazole for six months based on the Actinomyces and Candida co-infection; a wedge resection and flap reconstruction was also completed without any perioperative morbidity. Follow-up esophagography suggested no leak from the fistula site, and all symptoms have resolved.

Diagnostic Algorithm

Based on the comprehensive literature review and the current management practices of benign acquired TEF, a diagnostic algorithm is proposed to assist in better diagnose those with relevant symptoms and history (Fig. 5). Once diagnostic imaging confirms the presence of a TEF, the anatomy should be further evaluated with esophageal and bronchial endoscopic visualization. Endoscopic evaluation allows for visualization and characterization of the fistula, can be used to dislodge debris obstructing the fistula site and assist in obtaining crucial biopsies of the lesion to help determine the underlying etiology of the TEF, guiding its treatment [1, 2, 4, 9, 10, 17, 18].

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Diagnostic algorithm

¹Risk factors include history of esophageal or bronchial malignancy, prior surgery or stenting, HIV/AIDS, TB, prior radiation

²Symptoms suggestive of TEF or EBF include cough (56%), aspiration (37%), fever (25%), dysphagia (19%), PNA (5%), hemoptysis (5%), or worsening of cough with swallowing liquids and solids 87% (Ono's Sign)

³Imaging includes Esophagography (1^st line), barium preferred over gastrograffin (70% accurate), CT is preferred in those that cannot swallow, those that are ventilated or intubated that present with continued air-leaks despite well-inflated cuff, abdominal bloating, loss of tidal volume or worsening oxygenation

⁴Positive imaging should be followed up with Endoscopy or Bronchoscopy (flexible or rigid), as both will directly visualize lesion, evaluate location and size of lesion and can be used to get biopsy

⁵Symptoms suggestive of infectious etiology include additional symptoms of weight loss, night sweats or infection refractory to standard therapy

⁶Common infectious causes include tuberculosis, mucormycosis, histoplasmosis, syphilis, aspergillosis, each with specific biopsy findings, risk factors and treatments

Citation: European Journal of Microbiology and Immunology 14, 3; 10.1556/1886.2024.00043

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Traditionally, TEF is repaired with an endoscopic approach, preferable to open surgical approaches, as endoscopy has a much lower risk of fistula complications [1, 3, 21]. Benign TEFs are often amenable to definitive surgical intervention compared to those with TEF secondary to malignancy, which often have multiple comorbidities that make them poor surgical candidates [1–3]. The primary endoscopic technique is esophageal or airway stenting, using self-expanding plastic stents that primarily serve as a bridge to definitive surgical repair, especially in those with concomitant tracheal stenosis in order to maintain airway patency [1, 12, 18, 22, 23]. Stenting can also be used in those with benign TEF that are not surgical candidates, opting for a single stent in those with distal fistula sites, or dual stenting those with more proximal or mid-esophagus fistulae [1, 12, 18, 22, 24–26]. Although self-expanding metallic stents (SEMS) are usually preferred for those with malignant fistulae, there is a growing body of evidence that prefers fully covered SEMS in those with complicated benign TEFs or those who are not surgical candidates [1, 12, 18, 22, 24, 26]. Definitive surgical correction involves division and closure of the TEF in conjunction with airway restoration using a muscle flap interposition based on the defect's size and absence of airway stenosis [1, 12, 27, 28]. Differences in single vs. double-layer closure techniques and in the tissue used to close the defects have been reported; intercostal muscles and latissimus dorsi muscle flaps are the most commonly used [1, 12, 27, 28]. Due to the complexity and associated comorbidities, patients with acquired TEFs often receive stenting and surgical repair. However, surgical management for tracheal and esophageal defects remains controversial [2, 3, 12, 27, 28]. Stent placement has been shown to prevent aspiration pneumonia, and often, oral intake can be resumed after complete surgical closure of the fistula. However, most patients require nutritional support via gastrostomy, jejunostomy, or parenteral nutrition [3, 18, 22]. Furthermore, there are reported complications of endoscopic stenting, the most common being stent migration, bleeding, perforation, and, paradoxically, the formation of new TEFs [3, 18, 22]. Of the 31 individual cases of fistula reviewed, 32.3% were secondary to surgery or stenting (Table 1). Although considered a definitive treatment, fistula recurrence often complicates surgical repair, and can have an operative mortality rate reported as high as 11% from post-op emphysema, pneumonia, and hemorrhage [3, 26–28].

Overall, TEF should be suspected in patients with known risk factors or symptoms, such as recurrent bronchitis or pneumonia, or persistent coughing following nutritional intake. Management by a multidisciplinary team is essential and includes imaging and endoscopic findings for diagnosis, histologic analysis for differentiation between malignant and benign entities, evaluation of infectious etiologies and appropriate treatments for optimal outcomes. Fungal or bacterial infections causing benign TEF, while uncommon but not rare, need to be considered in diagnosis and treated quickly and appropriately for optimal outcomes.