Introduction

Coccidioidomycosis is a systemic fungal disease caused by dimorphic soil fungi Coccidioides immitis and C posadasii.¹Coccidioides spp. exist almost exclusively in the arid regions of the southwestern United States.¹ Pulmonary coccidioidomycosis is the most common form of disease in dogs.^1,2 Clinical signs of respiratory tract disease of affected dogs can include one or more of cough, wheezing, increased respiratory effort, and cyanosis.^1,2 Treatment recommendations for pulmonary coccidioidomycosis in dogs generally include administration of oral antifungal therapy until there is resolution of clinical signs and thoracic radiographic abnormalities in conjunction with serum anti-Coccidioides immunoglobulin G (IgG) titers of ≤1:4.² Duration of therapy in most dogs ranges from 6–12 mo, but some require protracted therapy.^1,2 Triazoles are prescribed initially with amphotericin B reserved for more severe or refractory cases.³

More aggressive treatment for pulmonary coccidioidomycosis such as lung lobectomy has been described in human literature.^4–6 This is reserved for patients who are refractory to first line therapies, those who develop complications from clinical disease, or who continue to have recurrence of symptoms following discontinuation of antifungals.^4,5 Anecdotal expert opinion suggests that removal of the primary nidus of disease burden can result in a faster resolution of symptoms and prevent the development of potential intrathoracic complications.⁴ The current treatment options for refractory coccidioidomycosis in dogs remain limited to the newer triazoles, including voriconazole and posaconazole, or amphotericin B.^7–9 There is limited information in dogs regarding the utility of lung lobectomy as an adjunctive therapy in dogs with refractory pulmonary coccidioidomycosis. This report describes the successful use of lung lobectomy as an adjunctive treatment in a dog with refractory pulmonary coccidioidomycosis.

Case Description

A 5 yr old, castrated male, border collie mixed-breed dog was presented to a primary care veterinarian in Arizona for evaluation of a 7 day history of cough (day 1). Physical examination findings included a heart rate of 132 beats/min, respiratory rate of 62 breaths/min, and pyrexia at 104.4 °F. Cardiothoracic auscultation revealed increased bronchovesicular sounds in all lung fields with no murmur or arrhythmia. Three-view thoracic radiographs revealed a marked alveolar pulmonary pattern with complete consolidation of the right middle lung lobe with pleural demarcation and superimposition over the cardiac silhouette. There was also a diffuse, mild, bronchointerstitial pulmonary pattern throughout the remainder of the lung lobes (Figures 1A, B). Serum anti-Coccidioides spp. antibody titers were quantified (Immunoglobulin M [IgM] negative, IgG 1:8)^a. A presumptive diagnosis of pulmonary coccidioidomycosis was made, and fluconazole (compounded; 10 mg/kg per os [PO] q 12 hr) was prescribed.

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There was no improvement in clinical signs when the dog was evaluated on day 32. Three-view thoracic radiographs were repeated and were static (Figures 1C, D). Amoxicillin trihydrate/clavulanate potassium^b (16.9 mg/kg PO q 12 hr for 30 days) was added to the treatment regimen because of a concern for a secondary bacterial infection that complicated the expected clinical improvement with antifungal therapy alone.

Ten days later (day 42), the dog was presented to the Pet Emergency and Referral Center for evaluation of a worsened cough. On physical examination, the dog was pyrexic at 104.7 °F with a consistent, dry, nonproductive cough and increased effort on expiration. The heart and respiratory rates were 120 beats/min and 40 breaths/min, respectively. Thoracic auscultation revealed increased bronchovesicular sounds bilaterally and crackles in the left lung fields. Initial diagnostic testing included a complete blood count (CBC) and serum biochemical profile before general anesthesia for a thoracic computed tomography (CT), tracheobronchoscopy, and bronchoalveolar lavage. A CBC revealed a mild leukocytosis (22.74 × 10³/uL; reference interval 5.05–16.76 × 10³/uL) characterized by a mature neutrophilia (18.71 × 10³/uL; reference interval 2.95–11.64 × 10³/uL) and monocytosis (2.16 × 10³/uL; reference interval 0.16–1.12 × 10³/uL), and a mild nonregenerative anemia (hematocrit test 34.7%; reference interval 37.3–61.7%; reticulocyte hemoglobin 21.2 pg; reference interval 22.3–29.6 pg). Serum biochemistry identified a mild hyperglobulinemia (4.6 g/dL; reference interval 2.5–4.5 g/dL). Thoracic CT^c with a manual inspiratory breath hold and single-phase angiography was performed followed by tracheobronchoscopy. There was marked gravity-dependent pulmonary consolidation and attenuation of the right middle lung lobe (Figure 2). Similar, less severe gravity-dependent consolidation and attenuation of the caudal part of the left cranial lung lobe was also evident. Adjacent to the regions of pulmonary consolidation was a mixture of mosaic and ground-glass pulmonary attenuations. There were also multifocal, small, contrast-enhancing, nodular attenuations throughout the left and right caudal and cranial lung lobes. Marked enlargement of the tracheobronchial lymph nodes with compression of the principal bronchi of the left and right caudal lung lobes was evident along with enlargement of the cranial mediastinal lymph nodes. Endoscopic examination disclosed hyperemia of the trachea with collapse of the left mainstem bronchus and narrowing of the right mainstem bronchus. A large amount of yellow-tinged fluid occluded the right middle lung lobe. Bronchoalveolar lavage was performed, and cytological examination of the fluid sample identified marked neutrophilic inflammation characterized by mildly degenerate neutrophils in addition to fewer macrophages and small lymphocytes. Rare large round spherule-like structures were noted to have a thick wall with a stippled internal appearance most consistent with Coccidioides spp. spherules. Antifungal treatment was changed to itraconazole (US Food and Drug Administration (FDA)-approved generic capsules; 5.8 mg/kg PO q 12 hr with food) along with a tapering course of prednisone (0.93 mg/kg PO q 24 hr for 5 days; then 0.6 mg/kg PO q 24 hr for 10 days).

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The dog was presented for a recheck evaluation on day 83, and the cough had worsened, approximately 2 wk after prednisone was discontinued. On physical examination, the dog was pyrexic at 103.7 °F and had bilateral green mucoid ocular discharge with a heart rate of 110 beats/min and a respiratory rate of 60 breaths/min recorded. Thoracic auscultation revealed increased bronchovesicular sounds with occasional cough. Repeat thoracic radiographs were recommended but were declined by the owner. Medications at the time of discharge included itraconazole and SAMe/Silybin at unchanged dosages. Prednisone (0.56 mg/kg PO q 24 hr) was also reinstituted in an effort to ameliorate clinical signs.

The dog was presented on day 118 for a planned examination. The dog was doing well at home, and the cough had resolved. Physical examination findings included a temperature of 103.2 °F, a heart rate of 90 beats/min, and a respiratory rate of 60 breaths/min. Coccidioides spp. antibody serology was repeated (IgM positive; IgG 1:16). Thoracic radiographs were performed and revealed unchanged consolidation of the right middle lung lobe with a mild, diffuse bronchointerstitial pattern evident in the remainder of the lung lobes (Supplemental Figure 1 A–C). A serum biochemical profile revealed a moderate increase in alkaline phosphate (717 U/L; reference interval 23–212 U/L). Medications continued at the time of discharge included itraconazole and prednisone at unchanged dosages in conjunction with S-adenosylmethionine (SAMe)/Silybin (Denamarin, Nutramax Laboratories Inc, Lancaster, South Carolina) (425 mg, PO, q 24 hr). On day 145, the dog was evaluated, and the cough remained resolved. Physical examination findings included a temperature of 102.3 °F, a heart rate of 130 beats/min, and a respiratory rate of 70 breaths/min. Itraconazole blood levels^d were performed given the lack of expected clinicopathologic and radiographic improvement and continued dependency on prednisone for control of coughing. Itraconazole levels were within the therapeutic range (3.1 μg/dL; reference interval 2–7 μg/dL). The treatment plan was altered to replace itraconazole with fluconazole (FDA-approved generic; 9.8 mg/kg PO q 12 hr). The addition of amphotericin B or one of the newer oral azoles such as posaconazole or voriconazole were discussed but declined by the owner, and a right middle lung lobectomy was pursued instead. Other medications at the time of discharge included SAMe/Silybin and prednisone (unchanged doses).

Approximately 5.5 mo after initial diagnosis (day 160), the dog underwent a right thoracotomy. A right lateral thoracotomy approach was made for removal of the right middle lung lobe. There were numerous fibrous adhesions between the right middle lung lobe and adjacent lung lobes. Additional fibrous adhesions within the pleural space with associated vascular supply also required breakdown for successful removal. The right middle lung lobe was abnormal on gross examination because it had numerous miliary-nodular lesions that were red, and the lung was firm. The surgery concluded without complication, and the dog was discharged 2 days later with the following medications: fluconazole (unchanged dose), prednisone (0.46 mg/kg PO q 24 hr for 10 days; then 0.23 mg/kg PO q 24 hr for 5 days), SAMe/Silybin (unchanged dose), and gabapentin (9.3 mg/kg PO q 8 hr for 10 days).

The right middle lung lobe was fixed in 10% neutral-buffered formalin followed by routine processing and paraffin-embedding and submitted for histopathology. The right middle lung lobe architecture was obliterated by combinations of fibrosis, type 2 pneumocyte hyperplasia, hemorrhage, and chronic-active mixed inflammation, often organized as pyogranulomas and granulomas that occasionally contained central fungal organisms. The organisms were spherical, had a 3 μm refractile capsule, a diameter of up to 34 μm, and contained granular to vacuolated basophilic material or rarely, were packed with 1–2 μm round spheres (endospores), which are findings most consistent with spherules of Coccidioides spp. (Supplemental Figure 2). Airways were mostly preserved but collapsed, distorted, and hyperplastic. There was extensive pleural fibrosis with regionally entrapped adipocytes (fibrous adhesions) and edematous fibrovascular proliferation.

The dog was evaluated 2 wk after surgery (day 174) for suture removal. The dog was reported to be doing well with no coughing. Prednisone was discontinued, as scheduled, the day before the visit. Physical examination revealed a temperature of 102.6 °F, a heart rate of 120 beats/min, and a respiratory rate of 50 breaths/min. Thoracic auscultation was unremarkable, and the right lateral thoracic incision was healed. Medications at the time of discharge included fluconazole and SAMe/Silybin at unchanged dosages. Three months after surgery (day 250), the dog was presented for a recheck examination at which time the following diagnostic tests were performed: thoracic radiographs, Coccidioides antibody serology, and a serum chemistry panel. The dog was reported to be doing well at home with no coughing. There were no abnormalities on physical examination. Radiographs revealed mild bronchial thickening evident in the perihilar region with no other abnormalities noted (Supplemental Figure 1 D–F). Serum anti-Coccidioides IgG titer remained positive at 1:4, and IgM was negative. The biochemical panel was unremarkable. At the time of discharge, the dog was continued on fluconazole and SAMe/Silybin at unchanged dosages.

A final recheck evaluation occurred on day 364 for a repeat thoracic CT, CBC, serum biochemical profile, and Coccidioides spp. antibody serology. The dog remained subclinical, which prompted the owner to decrease the fluconazole (9.3 mg/kg q 24 hr) without veterinary consultation approximately 2 mo before. The physical examination remained unremarkable. There were no clinically relevant abnormalities on the CBC or the serum biochemical profile. Thoracic CT revealed three, small, solitary nodules located in the mid caudal aspect of the accessory lung lobe, mid-left caudal subsegment of the cranial lung lobe, and left caudal lung lobe (Supplemental Figure 3). Serum anti-Coccidioides IgG titer remained positive at 1:2, and IgM was negative. Fluconazole was discontinued given the complete resolution of clinical signs, low serum IgG titer, and near normal thoracic imaging results with the exception of changes that are typical following a lung lobectomy. The previously prescribed SAMe/Silybin was also discontinued. At the time of writing, a phone update revealed that the dog remained subclinical 90 days following discontinuation of fluconazole.

Discussion

This report describes lung lobectomy as an adjunctive treatment for pulmonary coccidioidomycosis in a dog. Surgical management has previously been described in dogs with either extensive bony lesions or involvement of the pericardium.² In humans, it is estimated that 5–10% of Coccidioides spp. infections result in ongoing pulmonary complications, such as nodules and cavitations.⁴ This has led to various recommendations of when to consider surgical intervention in patients with symptomatic persistent nodular or cavitary pulmonary coccidioidomycosis. The recent guidelines for the treatment of coccidioidomycosis developed by the Infectious Diseases Society of America Working Group recommends that patients with cavitary pulmonary coccidioidomycosis consider surgical intervention when after 2 yr of antifungal therapy symptoms persist or recur whenever antifungal treatment is discontinued.⁵ The Jaroszewski et al. study recommends that patients with nodular or cavitary coccidioidomycosis consider surgical intervention if after at least 3 mo of antifungal therapy symptoms persist or if there is either progressive or refractory disease.⁴

The dog in this report was treated with either fluconazole or itraconazole for a total duration of approximately 5.5 mo without expected clinical, clinicopathologic, or thoracic radiographic improvement. In humans with pulmonary coccidioidomycosis, the median time to see ≥50% improvement in symptoms after initiation of antifungal therapy is approximately 90 days.¹⁰ To the authors’ knowledge, there have been no prospective studies in dogs with pulmonary coccidioidomycosis that have investigated the time to significant clinical improvement after initiation of oral antifungal therapy. However, in the authors’ experience, noticeable improvement in clinical signs without the aid of glucocorticoids are noted within approximately 1–2 mo of initiating therapy with first line oral antifungal medications in dogs. One explanation for the lack of improvement despite appropriate antifungal therapy in the dog reported, here, is that there was an extensive fungal burden localized to a single lung lobe. Dogs with coccidioidomycosis that have entire lung lobes affected can be challenging to manage with oral antifungals. It is possible that there is impaired delivery, penetration, or both of a large granuloma (i.e., large consolidated lung lobe) with standard oral antifungal medications.

Another explanation for the lack of response might have been associated with the fungal infection being resistant to both fluconazole and itraconazole. A fungal culture and susceptibility panel would have been useful in making that determination and could have been considered in our case when the bronchoalveolar lavage sample was obtained. The initial use of compounded fluconazole in this case might have delayed clinical and radiographic improvement. Compounded formulations of oral antifungals have poor bioavailability in both dogs and cats.^11–14 Specifically, compounded formulations of fluconazole should be avoided because of poor bioavailability, lack of consistency with quality control, and potential lack of stability.^13,14 The dog reported herein was only treated with compounded fluconazole for the first 41 days of treatment, and we would have expected to have seen more progress with an FDA-approved generic formulation of itraconazole over the next 104 days.

Fluconazole is the most common first line oral treatment followed by itraconazole in dogs with coccidioidomycosis.^1,7 The newer azoles such as voriconazole and posaconazole have been described in the human literature for refractory cases, but there is limited information of their use in dogs with refractory coccidioidomycosis.^3,7–9 It is unknown whether the use of one of the newer azoles or amphotericin B would have resulted in clinical resolution, but they were declined by the owner. In lieu of owner consent to pursue one of these other antifungal treatment regimens and a lack of expected improvement after more than 5 mo of therapy, a lung lobectomy was offered as an adjunctive treatment option to debulk the burden of disease.

The dog reported here was administered prednisone at anti-inflammatory dosages for an extended period of time to mitigate clinical signs because the dog was severely affected. There were several attempts to discontinue prednisone, but this resulted in a resurgence of clinical signs on each occasion. Eventually, the owner refused to discontinue prednisone because of a concern for severe relapse in clinical signs. Therefore, it remains unknown if the sustained improvement in clinical signs on day 118 was associated with the anti-inflammatory effects of prednisone or a delayed response to oral antifungal therapy. Gross and histopathological examination of the right middle lung lobe revealed evidence of intralesional spherules and severe architectural changes supporting the likelihood that the clinical improvement was related to prednisone rather than antifungal medications. Short-term administration (e.g., 14–21 days) of corticosteroids are often prescribed in the acute phase of pulmonary coccidioidomycosis at anti-inflammatory dosages to mitigate clinical signs in moderately to severely affected dogs but can be detrimental if administered long term.^15,16

Duration of antifungals for treatment of pulmonary coccidioidomycosis varies by clinician preference because there are no clear guidelines in dogs on when to discontinue therapy. A previous review article suggested continuing antifungal therapy for a minimum of 6–12 mo.¹ Another commonly used approach is to discontinue medications 3 mo after a combination of negative anti-Coccidioides spp. antibody test results and resolution of clinical signs and thoracic imaging abnormalities. However, many dogs with coccidioidomycosis never achieve negative antibody serology results, and thus some clinicians discontinue therapy after resolution of clinical signs and thoracic imaging abnormalities in conjunction with low anti-Coccidioides spp. IgG antibody titer results (i.e., ≤1:4). Pulmonary coccidioidomycosis in humans is typically treated for a minimum of 3–6 mo; however, there is a wide spectrum of reported treatment durations that vary on a case-by-case basis.^4,8,17 For example, the median duration of antifungal therapy in one study was 8.5 wk (range 1.5–28 wk).¹⁰ The dog presented herein received antifungal therapy for approximately 12 mo. Fluconazole was administered for 6 mo after the lung lobectomy, and the discontinuation of therapy was based on the resolution of clinical signs, thoracic imaging findings, and low IgG titers.

Conclusion

This case report describes the successful treatment outcome in a dog with severe Coccidioides spp. pneumonia following lung lobectomy and oral antifungal therapy. Future studies are warranted to determine the clinical benefit of adjunctive lung lobectomy in dogs with coccidioidomycosis who have large fungal burdens localized to a single lung lobe and are refractory to standard first-line oral antifungal therapies.