Candida glabrata (Nakaseomyces glabratus) as a component of aspiration pneumonia in a dog with megaesophagus

Abstract

Candida glabrata is a yeast that is a commensal of mucosal surfaces and can cause opportunistic infection in several species. Unlike other Candida species, it is commonly resistant to azoles. Candida pneumonia has been reported in humans, with unclear prevalence, but is very rare in dogs. This report describes an 11-year-old spayed female Dogo Argentino dog with megaesophagus that was managed with mechanical ventilation for aspiration pneumonia. The dog had been treated previously with omeprazole and amoxicillin-clavulanic acid for 2.5 wk. Airway cytology showed inflammation and numerous yeast organisms most consistent with Candida. Therapy with fluconazole was initiated, but the dog’s condition deteriorated and it was euthanized. Candida glabrata and polymicrobial infection were identified on airway culture and postmortem culture of lung tissue. Histologic examination of the lungs showed severe pneumonia with yeast organisms present within macrophages, consistent with infection.

Key clinical message:

Candida should be considered as a possible contributing agent in dogs with aspiration pneumonia, especially those treated with antimicrobials and gastroprotectants.

Fungal pneumonia in dogs is most often caused by endemic mycoses/dimorphic fungi such as blastomycosis or histoplasmosis, and less commonly by aspergillus or other molds (1–4). Candida are normal skin and mucosal fungal flora of humans and veterinary species but may be opportunistic pathogens in the setting of impaired host defenses (5,6). Pneumonia due to Candida has been reported in humans (7–10); however, it is difficult to determine true infection from contamination, and the true prevalence of this condition is debated. Candida pneumonia has been reported rarely in dogs, with most cases of canine Candida pneumonia either due to immunosuppression or as presumptive diagnoses (11,12). Samples isolated from airway lavage may not represent true infection, and definitive diagnosis in these cases is uncertain. Candida glabrata is a common skin and environmental commensal that has been implicated as an opportunist in human infections (13). Candida glabrata is unusual in that it is often resistant to most-used antifungals, including the azoles (14). Although C. glabrata has been renamed Nakaseomyces glabratus, most medical literature largely uses the older term. Therefore, the name “C. glabrata” is used hereafter in this report.

Aspiration pneumonia is a common cause of respiratory distress in dogs (1). Aspiration events can cause sterile pneumonitis or bacterial pneumonia (2). Infectious aspiration pneumonia is more common in humans receiving proton pump inhibitors (3).

This report describes a case of C. glabrata, confirmed via histology, in a dog with acute respiratory distress syndrome undergoing mechanical ventilation for megaesophagus-associated aspiration pneumonia.

CASE DESCRIPTION

An 11-year-old spayed female Dogo Argentino dog with a history of previously diagnosed idiopathic megaesophagus (based on serial radiographs, endoscopy, and exclusion of underlying causes) was presented to a tertiary care facility for treatment of vomiting. She was diagnosed with aspiration pneumonia based on consistent point-of-care ultrasound findings and radiograph changes, fever, and an inflammatory leukogram on complete blood (cell) count (Figure 1). At the time of presentation, the dog had been treated with omeprazole (1 mg/kg, PO, q12h) and amoxicillin-clavulanic acid (12.3 mg/kg, PO, q12h) for 17 d.

FIGURE 1.

A — Lateral radiograph of the thorax of a dog with aspiration pneumonia caused in part by Candida glabrata. B — Postmortem image of the dog’s lungs, showing grossly rubbery and mottled brown-red parenchyma.

The dog was sedated (butorphanol; 0.2 to 0.4 mg/kg, as needed) and given nasal oxygen supplementation (2 to 4 L/min) and ampicillin (22 mg/kg, IV, q6h). Prokinetic therapy was initiated with erythromycin (1 mg/kg, IV, q8h) and metoclopramide (2 mg/kg per day, infusion), and pantoprazole (1 mg/kg, IV, q12h) was continued for esophagitis management. Several more regurgitation episodes occurred overnight and hypoxemia progressed, requiring escalation to high-flow nasal oxygen. Intravenous enrofloxacin (10 mg/kg, q24h) was added.

The dog developed refractory hypoxemia (SpO₂: 88 to 90% at 100% FiO₂ delivered at 70 L/min), marked respiratory effort, and progressive hypercapnia (pCO₂: 72.4 mmHg), necessitating intubation and mechanical ventilation. Point-of-care ultrasonography [microconvex, 8- to 10-mHz probe, scanning bilateral hemithoraces in a modified VetBLUE pattern (FASTVet)] showed bilateral confluent B-lines, primarily ventrally, with right-sided consolidation in the ventral mid-lung field. Sedation was achieved with dexmedetomidine [1 to 2 μg/kg per hour, IV, constant-rate infusion (CRI)], hydromorphone (0.05 mg/kg per hour, IV, CRI), and a continuous infusion of propofol (100 to 200 μg/kg per minute, IV, CRI). Norepinephrine (0.1 to 0.2 μg/kg per minute, IV, CRI) was used to support blood pressure. Ventilation was used in “volume control-assist control” mode with a tidal volume of 7.5 mL/kg, a respiratory rate of 35 brpm, and a positive end expiratory pressure of 6 cmH₂O. Driving pressure was maintained below 15 cmH₂O. The FiO₂ was initially 100% and was titrated down to 60% over the next 12 h.

Initial improvement was noted in oxygenation (SpO₂: 95 to 98% at 40 to 60% FiO₂), PvCO₂ (consistently < 50 mmHg), and lung surface pathology on point-of-care ultrasonography (reduction in the number of B-lines and size of consolidated areas). Approximately 36 h after initiation of ventilation, the dog’s condition began to worsen; higher FiO₂s were required to maintain oxygenation and positive end expiratory pressure was escalated. Marked ventilator asynchrony occurred, requiring paralysis with cisatracurium (0.1 mg/kg, IV, administered twice). Thoracic radiographs were reevaluated and showed a marked, multilobar, alveolar pulmonary pattern, markedly progressive relative to the prior radiographs and consistent with severe aspiration pneumonia exacerbated by atelectasis.

Due to increased airway resistance, difficulty attaining tidal volumes, and a “sawtooth” appearance to ventilator loops, airway suction was applied through the endotracheal tube. This was done by passing a new, sterile suction catheter attached to a disposable aspirating tube (Argyle Luki Aspirating Tube; Cardinal Health, Dublin, Ohio, USA) into the endotracheal tube after disconnection from the ventilator, returning ~15 mL of foul-smelling brown fluid. Cytology was carried out in-house and showed septic suppurative inflammation with structures suspicious for yeast (Figure 2). Samples were sent for review by a clinical pathologist and for aerobic and anaerobic culture.

FIGURE 2.

Photomicrographs showing the cytology of fluid suctioned from the airway of a dog. Stain: modified Wright-Giemsa; magnification: 100× objective. Note the thin-walled, round to oblong, basophilic structures consistent with yeast (arrows), confirmed by culture to be Candida glabrata.

The pathologist reported marked neutrophilic inflammation with numerous yeast organisms, each ranging from 3 to 10 μm in diameter with a clear capsule and narrow-based budding, most consistent with Candida spp.

Based on these findings, treatment with fluconazole (5 mg/kg, IV, q12h) was initiated. Overnight, the dog became progressively hypotensive and developed oliguria and hyperkalemia. Therapy with furosemide increased urine output and improved hyperkalemia. Despite continued therapy, the dog’s condition continued to deteriorate, with multiorgan dysfunction, new onset azotemia and hyperkalemia, oligoanuria, and arrythmias. The dog also required increasing ventilator support. Based on these changes, euthanasia was elected by the owners on the following morning.

Culture results received post-mortem showed growth of C. glabrata (3+), methicillin-resistant Staphylococcus pseudintermedius (2+), Enterococcus faecium (2+), Escherichia coli (1 colony), and Clostridium butyricum (1+).

Postmortem examination was completed by a Board-certified anatomic pathologist and resident. Approximately 90% of the lungs appeared grossly rubbery and mottled brown-red (Figure 1). Histopathologic assessment of the lungs showed a hypercellular pulmonary parenchyma; within ~60% of the alveoli were innumerable neutrophils that were frequently degenerate, fibrin that was occasionally enmeshed with pyknotic cellular debris, and rare, 10- to 30-micrometer-diameter foci of mineral. Occasional macrophages contained degenerate neutrophils within the cytoplasm. Terminal bronchioles commonly contained inflammatory cells, fibrin, and necrotic debris, and had lost epithelial lining cells. Within the hypercellular regions were rare, 3- to 7-micrometer-diameter, round to ovoid yeast organisms with occasional, narrow-based budding that were only identifiable with Gomori methenamine silver (GMS) staining (Figure 3). These yeast organisms were occasionally located within the cytoplasm of macrophages. Occasional, small- to medium-caliber blood vessels were variably occluded by thrombi.

FIGURE 3.

Photomicrographs of a section of lung obtained post-mortem from a dog with Candida glabrata pneumonia. A — Hypercellular pulmonary parenchyma with intra-alveolar neutrophils, fibrin, and rare 10- to 30-micrometer-diameter foci of mineral; and terminal bronchioles containing inflammatory cells and necrotic debris. Stain: Hematoxylin and eosin; magnification: 10×. B — Rare, 3- to 7-micrometer-diameter, round to ovoid yeast organisms with occasional narrow-based budding. Stain: Gomori methenamine silver (GMS); magnification: 60×.

These findings were interpreted as severe neutrophilic and histiocytic pneumonia with intralesional yeast. Other postmortem findings included acute renal tubular necrosis, adrenal medullary infarction, hepatic nodular hyperplasia, parathyroid hyperplasia, and thyroid atrophy. Cultures of lung samples collected post-mortem (~12 to 14 h after euthanasia) grew C. glabrata (2+), Staphylococcus pseudintermedius (2+), Enterococcus faecium (2+), Enterobacter hormaechei (2+), and Bacteroides thetaiotaomicron (2+). Sensitivity testing is not routinely provided on postmortem cultures at our institution.

DISCUSSION

Opportunistic, non-albicans Candida infections are an increasingly common cause of morbidity and mortality in human patients (6,11,12,15–25). Of the reported canine cases of candidiasis, 2 involved C. glabrata specifically (17,22). In humans, C. glabrata has been identified in several case reports of pneumonia, often as a result of immunosuppression or chronic lung disease but sometimes in those without predisposing factors (13,26–28). In several such cases, the diagnosis was presumptive due to a lack of histologic confirmation and was based on response to therapy, clinical signs, and cytologic findings in sputum on bronchoalveolar lavage samples. This demonstrates the inconsistency and difficulty in interpreting growth or detection of Candida.

Other species of Candida have also been reported to cause disease in dogs. Candida was associated with urinary infections (17,18), joint infection (19), mastitis (20), stomatitis (21), peritonitis (22), cerebral infections (23), and disseminated disease (20,24). Candida has rarely been proposed as a component of canine pneumonia, especially with histologic confirmation (11,12,25).

It can be difficult to determine if Candida in biological samples represents infection, colonization, or contamination, as Candida can be present in fluids and on surfaces of normal individuals. In general, the presence of organisms within white blood cells suggests a pathological process, as it implies an active immune response against the organism. In humans, the standard for determination of Candida pneumonia is histologic demonstration of the organisms within lung tissue, which confirms tissue invasion or immune response against the organism (8). In the present case, Candida was noted histologically within pulmonary macrophages, suggesting a pathological process and not solely contamination. Unclear, however, were the relative contributions of fungal and bacterial elements to the dog’s clinical signs and whether the severity of disease could be explained by bacterial infection alone.

In this case, the prior use of antibiotics (29) and a proton pump inhibitor (30) were likely predisposing factors. A recent publication described esophageal candidiasis caused by Candida albicans in 2 dogs with megaesophagus (31). If esophageal candida overgrowth was also present in the dog described herein, aspiration may have contributed to pulmonary infection. We suspect that, during an aspiration event, this yeast entered the respiratory tract and contributed to pneumonia, though several bacterial species likely played equal or greater roles.

Several bacterial species were isolated on antemortem cultures of an airway lavage sample and postmortem cultures of pulmonary parenchyma. This is common in aspiration pneumonia, in which a mixed flora is often present (1). Differences in the bacteria recovered from the 2 samples may have been due to contamination (of either sample), differences in bacterial populations in different locations (airway versus parenchyma), or changes in bacteria present over time (though the time from initial culture to death was only 24 h). Two species of clinical relevance (Staphylococcus pseudintermedius and Enterococcus faecium) grew on both samples, suggesting these were not contaminants; it is thus unlikely that Candida alone was responsible for clinical signs, but it likely played a role in polymicrobial infection. Important for this report, C. glabrata was also present in both samples and was seen intracellularly.

The timeline of events in this case was not consistent with ventilator-associated pneumonia, which is defined as infection that develops after at least 48 h of mechanical ventilation (32). This dog was at risk for aspiration pneumonia due to the presence of megaesophagus, and sedation for mechanical ventilation may have resulted in a reduced ability to protect airways and a higher risk of aspiration. Although intubation with cuff inflation and regular mouth care were provided, continued aspiration of esophageal material remained a risk.

Fluconazole is generally an effective antifungal drug for systemic candidiasis caused by most species in humans and was chosen in this case due to its availability as an IV injection and relative affordability. Clinical decompensation and euthanasia occurred before culture results were available. Therefore, the species was not known when treatment was initiated. However, C. glabrata was reported to have a higher rate of triazole resistance than other species (33). It is possible that fluconazole resistance was present in this isolate, and substitution with an echinocandin may have been indicated (14,34). The decision for euthanasia was based on acute kidney injury and progressive multiorgan dysfunction rather than lack of fluconazole efficacy. Given the timeline of events, we suspect that alternative antifungal therapy would not have resulted in improvement rapidly enough to change the clinical course.

This report serves as a description of Candida as a component of aspiration pneumonia in a dog. Although this dog had several predisposing factors for Candida overgrowth, there was no identified cause for immunodeficiency, though this does not exclude it as a possible contributing factor. In dogs with identified risk factors or lack of response to expected therapies, investigation for Candida infection via airway sampling may be reasonable, and if detected may not be simply a contaminant. If C. glabrata is detected, it may be reasonable to consider echinocandin therapy.