Introduction
Coccidioidomycosis is a fungal infection caused by the dimorphic soil-borne fungi Coccidioides immitis and Coccidioides posadasii. Both organisms are found in the soil of high desert climate regions, including the southwestern US, Mexico, and Central and South America.1–4 Coccidioidomycosis is highly endemic in Arizona and the south Central Valley of California and can affect both humans and animals.1–5 Infection occurs via inhalation of arthroconidia by the host, resulting in a wide range of disease from subclinical infection to localized pulmonary disease to, in some cases, dissemination and multisystemic disease.1–5
The clinical presentation of dogs with coccidioidomycosis varies, and signs are usually referable to the organs that are affected. Common sites of infection and dissemination include the lungs, tracheobronchial lymph nodes, bones, CNS, heart, and eyes. Treatment usually includes long-term administration of an azole antifungal.1 Fluconazole is often chosen for first-line treatment in dogs owing to its excellent tissue penetration, its relatively low adverse-effect profile, and the availability of affordable generic formulations.4,5 In a study6 of progressive nonmeningeal coccidioidomycosis in humans, fluconazole had a reported response rate of 57% by 12 months, compared with a response rate of 72% with itraconazole. To our knowledge, however, no long-term studies have evaluated and documented the efficacy of fluconazole for the treatment of coccidioidomycosis in dogs. Additionally, evidence-based recommendations regarding the duration of treatment and timing of medication withdrawal are lacking. Clinicians frequently use serial monitoring of serologic test results (IgM and IgG titers) combined with resolution of clinical signs and radiographic and clinicopathologic abnormalities in making decisions regarding treatment duration and discontinuation of treatment. However, this approach is highly clinician dependent, and previous reports1,7 have suggested that serologic titers should not be used as the sole monitoring tool for detecting remission owing to individual variability in titer responses. The purpose of the retrospective study reported here was to document the course and outcome of dogs with coccidioidomycosis treated with fluconazole, as evaluated on the basis of clinical signs, clinicopathologic abnormalities, and serologic test results.
Materials and Methods
Case selection criteria
Medical records of the Midwestern University Companion Animal Clinic (MWU-CAC) in Glendale, Arizona were retrospectively reviewed to identify dogs in which a new diagnosis of coccidioidomycosis had been made between January 1, 2015, and June 1, 2020. Dogs were included in the study only if the diagnosis of coccidioidomycosis had been confirmed at the MWU-CAC through microscopic confirmation of Coccidioides spherules or a combination of appropriate clinical findings, radiographic changes, and clinicopathologic abnormalities. Additionally, dogs were required to meet the following inclusion criteria: positive Coccidioides serologic test results (agar gel immunodiffusion assay), treatment had been initiated with fluconazole, the dog was > 1 year old at the time of diagnosis, and a minimum of 2 recheck examinations after treatment with fluconazole had been started, with the first recheck evaluation occurring within 200 days of starting fluconazole. Dogs were excluded if they received any antifungal treatment other than fluconazole during the study period.
Medical records review
Medical records of dogs included in the study were reviewed, and the following information was recorded: signalment, clinical signs, method of diagnosis, Coccidioides serologic test results (IgM and IgG titers), diagnostic imaging findings, concurrent medications, and fluconazole dosage. Additionally, the following clinicopathologic variables were recorded: total leukocyte, neutrophil, lymphocyte, and monocyte counts; serum globulin concentration; and serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities. Data were recorded at the time of diagnosis (day 0) and at each subsequent recheck visit during the study period. Rechecks were grouped into intervals on the basis of number of days since fluconazole treatment was started, as follows: 1 to 30 days, 31 to 90 days, 91 to 180 days, 181 to 270 days, 271 to 360 days, 361 to 540 days, 541 to 720 days, 721 to 1,080 days, 1,081 to 1,400 days, and > 1,400 days. Owing to the small number of dogs, data for the 1 to 30–day interval and for all intervals after day 720 were not statistically analyzed. Respiratory signs were defined as any of the following: coughing, increased bronchovesicular sounds, dyspnea, labored breathing, and cough elicited with tracheal palpation. A high temperature was defined as a core temperature > 39.4 °C. All radiographs were reviewed by a board-certified veterinary radiologist.
Statistical analysis
Data were analyzed with a commercial software program (Prism version 9.0; GraphPad Software). Median and range were used to report nonnormally distributed data. Coccidioides IgG titer and clinicopathologic variables at each recheck interval were compared to baseline values with the Wilcoxon matched-pairs signed rank test. Categorical data were analyzed with the Fisher exact test. For single comparisons, significance was set at values of P < 0.05. However, owing to the number of data points compared over time, a Bonferroni correction was applied for the 6 comparisons (baseline data compared with data for each recheck interval) analyzed, with an adjusted P value cutoff of ≤ 0.0083.
Results
Coccidioidomycosis was diagnosed in 140 dogs examined at the MWU-CAC during the study period. Ninety-one of these dogs did not meet the inclusion criteria and were excluded, leaving 49 dogs in the study. Mixed-breed dogs were most common (16/49) with a total of 21 breeds represented. No other breed was overrepresented, compared with the hospital population. Spayed female dogs comprised 21 of the 49 (42.9%) dogs; 24 (49.0%) dogs were neutered males and 4 (8.2%) were sexually intact males. Median age at diagnosis was 5.9 years (range, 1.0 to 12.1 years), and median weight was 23.0 kg (range, 2.0 to 66.8 kg).
Median IgG titer at diagnosis was 1:32 (range, 1:2 to 1:256), and median IgG titer was significantly decreased, compared with median baseline titer at all recheck intervals after day 90 (Figure 1). Results of IgM testing were positive in 11 of the 49 (22.4%) dogs at diagnosis. The percentage of dogs with positive IgM test results was significantly different from the baseline percentage at all recheck intervals after 90 days, except the 541 to 720–day interval (P = 0.051).
Median IgG titers at the time of diagnosis (baseline) and at various recheck intervals for 49 dogs with coccidioidomycosis that were treated with fluconazole. Error bars represent range. *Significantly different from baseline value.
Citation: Journal of the American Veterinary Medical Association 260, 10; 10.2460/javma.22.01.0006
The most common clinical abnormalities were respiratory signs (28/49), lethargy (28/49), and hyporexia (20/49). Other reported clinical signs included lameness (6/49), vomiting or diarrhea (5/49), peripheral lymphadenopathy (2/49), and an SC mass containing Coccidioides spherules (1/49). One dog had no clinical signs, and the diagnosis was based on positive serologic testing results and clinicopathologic abnormalities suggestive of infection. There was a significant decrease in the percentages of dogs with hyporexia and respiratory signs at all recheck intervals after 90 days (Table 1). The percentage of dogs with lethargy decreased significantly at all recheck intervals. A high temperature was present in 19 of the 49 (38.8%) dogs at the time of diagnosis. The percentage of dogs with a high temperature decreased significantly at all intervals until 270 days, after which time no significant difference was detected.
Frequency (number of dogs) of various clinical abnormalities at the time of diagnosis (baseline) and at various recheck intervals for 49 dogs with coccidioidomycosis that were treated with fluconazole.
| Variable | Baseline (n = 49) | 31–90 days (n = 42) | 91–180 days (n = 37) | 181–270 days (n = 31) | 271–360 days (n = 26) | 361–540 days (n = 23) | 541–720 days (n = 17) |
|---|---|---|---|---|---|---|---|
| Respiratory signs | 28 | 15 | 8a | 2a | 4a | 0a | 1a |
| Lethargy | 28 | 6a | 2a | 1a | 3a | 0a | 1a |
| Hyporexia | 20 | 7 | 2a | 1a | 1a | 0a | 1a |
| High temperature | 19 | 5a | 3a | 2a | 3 | 2 | 1 |
aPercentage of dogs with the sign was significantly (P ≤ 0.0083) different from the baseline percentage.
Thoracic radiography was performed in 21 of the 49 dogs at the time of diagnosis. Radiographic findings included tracheobronchial lymphadenopathy (9/21), an alveolar pulmonary pattern (6/21), a pulmonary mass (2/21), a bronchointerstitial pulmonary pattern (3/21), and pleural effusion (1/21). In 3 dogs, thoracic radiographs were normal. More than 1 radiographic abnormality was present in 5 of the 21 dogs.
A CBC and serum biochemistry profile were performed in 45 of the 49 dogs at the time of diagnosis. Hyperglobulinemia was the most common abnormality reported, occurring in 37 of the 45 (82.2%) dogs. Both median globulin concentration and the frequency of hyperglobulinemia decreased significantly at all recheck intervals (Table 2). Leukocytosis was reported in 21 of the 45 (46.7%) dogs at diagnosis, with 27 of 45 (60%) and 26 of 45 (57.8%) dogs having monocytosis and neutrophilia, respectively. Median WBC, neutrophil, and monocyte counts were significantly decreased from baseline at all recheck intervals. The frequency of leukocytosis was decreased at all recheck intervals, median neutrophil count was significantly decreased at all recheck intervals beginning at 91 to 180 days after initiation of treatment, and median monocyte count was decreased beginning at the 181 to 270–day recheck interval.
Median clinicopathologic values at the time of diagnosis (baseline) and at various recheck intervals for 49 dogs with coccidioidomycosis that were treated with fluconazole.
| Variable | Baseline (n = 45) | 31–90 days (n = 30) | 91–180 days (n = 24) | 181–270 days (n = 19) | 271–360 days (n = 18) | 361–540 days (n = 16) | 541–720 days (n = 14) |
|---|---|---|---|---|---|---|---|
| WBCs (cells/μL) | 14,900 | 12,550a | 9,500a | 9,000a | 9,050a | 8,650a | 10,050a |
| Neutrophils (cells/μL) | 11,200 | 9,050a | 6,870a | 6,375a | 6,198a | 6,052a | 6,981a |
| Monocytes (cells/μL) | 928 | 803a | 475a | 480a | 391a | 392a | 448a |
| Globulin (g/dL) | 4.2 | 3.5a | 3.3a | 3.2a | 3.0a | 3.1a | 3.3a |
| ALT (U/L) | 28.5 | 43.5a | 55.0a | 63.0a | 63.0 | 60.0a | 61.5 |
| ALP (U/L) | 68.0 | 103.5a | 95.0 | 82.0 | 123.5 | 70.5 | 80.5 |
ALP = Alkaline phosphatase. ALT = Alanine aminotransferase.
aMedian value was significantly (P ≤ 0.0083) different from baseline value.
Median ALT activity at diagnosis was 28.5 U/L (range, 14 to 462 U/L). Median ALT activity was significantly higher than baseline at all intervals except the 271 to 360–day and 541 to 720–day recheck intervals (P = 0.02 and 0.04, respectively). However, median ALT activity was not above the upper reference limit at any time. High ALT activity was documented in 16 of the 49 (32.7%) dogs at some point after treatment with fluconazole was started, whereas only 1 of the 45 (2.2%) dogs had a high ALT activity at diagnosis. The percentage of dogs with a high ALT activity was significantly higher than at baseline at the 361 to 540–day and 541 to 720–day recheck intervals, but not at any other time point. Median ALP activity at diagnosis was 68 U/L (range, 11 to 1,442 U/L). No significant difference from baseline in either median ALP activity or in the percentage of dogs with a high ALP activity was observed at any time point.
The median initial daily dosage of fluconazole was 19.7 mg/kg/d (range, 9.9 to 23.9 mg/kg/d), with the daily dose most commonly divided into twice daily administration. Commercial pharmacy–grade fluconazole was prescribed to 24 of the 49 (49.0%) dogs, whereas a compounded product was prescribed to 25 (51.0%) dogs. Fluconazole administration was discontinued in 24 of the 49 dogs over the course of the study period. The median duration of fluconazole treatment was 298.5 days (range, 130 to 1,000 days) for the dogs in which treatment was discontinued. Three dogs had fluconazole administration restarted after it was initially discontinued; this reinstitution of treatment was not included in treatment duration data. One of these dogs had fluconazole administration discontinued after 200 days of treatment, but it was restarted 78 days later when the dog presented with a mass on the antebrachium, in which Coccidioides spherules were documented. This dog was distinct from the dog with spherules noted on initial presentation and was subsequently lost to follow-up after restarting fluconazole. Although neither of the 2 remaining dogs had clinical signs of coccidioidomycosis, fluconazole was restarted owing to an increase in the IgG titer after treatment discontinuation. One dog had a negative titer test at treatment cessation, with a titer of 1:4 measured 171 days after discontinuation of fluconazole. The second dog had a titer of 1:4 at treatment discontinuation with a titer of 1:8 documented 476 days later. Both dogs had monocytosis at the time fluconazole was reinstituted, and 1 dog also had hyperglobulinemia.
Adjunctive treatments included predominantly anti-inflammatory and analgesic medications administered for variable durations. A tapering course of prednisone was started at the time of diagnosis for 10 of the 49 (20.4%) dogs, and 9 of the 49 (18.4%) dogs were treated with NSAIDs. Other adjunctive treatments such as antimicrobials and opioid medications were prescribed at the discretion of the attending clinician.
Discussion
To our knowledge, the present study was the first to document the long-term response to fluconazole treatment in dogs with coccidioidomycosis. The median treatment duration was 298.5 days, although the duration of treatment varied widely among dogs (range, 130 to 1,000 days). This variability in treatment duration reflected the wide variety of clinical manifestations and differing severity of disease between individual dogs. It has been suggested that treatment of coccidioidomycosis should continue for at least 6 to 12 months and until the IgG titer is ≤ 1:2.4,8 However, to the authors’ knowledge, no controlled studies have been performed to determine the optimal treatment duration for coccidioidomycosis in dogs or to evaluate whether longer treatment durations are required for disseminated infections. A recent study9 evaluating the use of posaconazole for disseminated coccidioidomycosis in 8 dogs demonstrated clinical improvement in all 8 dogs and remission in 6 of the 8 dogs with a median treatment duration of 18 months. Whether shorter treatment durations can be considered for localized infections in dogs is currently unknown. Ideally, dogs in our study would have been divided into groups on the basis of whether the disease was localized or disseminated, but this separation was not possible owing to the retrospective nature of the study and the fact that diagnostic investigation to confirm dissemination was not performed in all cases.
Three dogs in our study had fluconazole restarted owing to relapse, although in only 1 of these dogs was recurrence of Coccidioides infection confirmed via cytologic visualization of spherules. In the other 2 dogs, the decision to reinstitute treatment was based on increasing IgG titers with associated clinicopathologic abnormalities suggestive of coccidioidomycosis. Neither dog displayed signs consistent with coccidioidomycosis, so whether the titer increase in these dogs represented a true relapse remains unclear, especially given that additional diagnostic investigation was not performed in either of these dogs. Twenty-three of the 47 (47%) dogs were either lost to follow-up or still receiving fluconazole at the end of the study period. No recheck evaluation after fluconazole discontinuation was required for inclusion in this study. Additionally, it is unknown whether any of the dogs lost to follow-up relapsed at some point; therefore, the true frequency of relapse in our study cannot be conclusively determined. The dog in our study with documented relapse had negative Coccidioides IgM and IgG test results before discontinuation of fluconazole 200 days after starting treatment. In humans, relapse rates of 15% to 39% have been reported following azole therapy.6,10–12 Whether the relapse frequency is similar in dogs remains unknown, and prospective studies should aim to clarify the frequency of relapse after fluconazole treatment in dogs. Additionally, although no dog in our study was documented to have died of coccidioidomycosis, it is possible that some of the dogs that were lost to follow-up either died or were euthanized owing to progressive disease or that more severe cases were euthanized soon after diagnosis and were excluded from this study because of insufficient follow-up.
As expected, both IgG titers and the percentage of dogs with positive IgM titer results decreased significantly over time after fluconazole treatment was started. The median IgG titer was significantly decreased from baseline at all recheck intervals beginning 91 to 180 days after starting treatment. The most common clinical signs at diagnosis were respiratory abnormalities, lethargy, and hyporexia. The frequency of all 3 clinical signs decreased significantly over time, with lethargy decreasing as soon as the 31 to 90–day recheck interval and respiratory signs and hyporexia decreasing in frequency beginning at the 91 to 180–day recheck interval. Although none of these clinical signs can be definitively attributed to coccidioidomycosis, their presence combined with clinicopathologic and radiographic changes at the time of diagnosis, the noted resolution associated with treatment, and the persistence of this improvement over time were highly suggestive. To the authors’ knowledge, the duration of treatment required before a decrease in titer or improvement in clinical signs can be expected has not been reported previously.
The percentage of dogs with a positive IgM titer test result was not significantly different from baseline until after 90 days of treatment, with 4 of 20 (20%) dogs having a positive IgM titer test at the 31 to 90–day recheck interval. A previous study7 also documented positive IgM titer test results in 2 chronically infected dogs, and the authors hypothesized that persistent IgM titers could have represented disseminated infection. In some human cases, high IgM titers have been found to persist for years and have been suggested to have a role in predicting severity of disease.13,14 Whether the same may hold true for dogs is unclear from the data available and is an area that should be considered for future study.
Resolution of hyperglobulinemia and leukocytosis tended to occur concurrently with improvements in serologic titers and clinical signs. The most common clinicopathologic abnormalities identified in our study were hyperglobulinemia, monocytosis, and neutrophilia. Both the median globulin concentration and the percentage of dogs with hyperglobulinemia were significantly decreased from baseline at every recheck interval beginning 31 to 90 days after starting fluconazole. The frequencies of neutrophilia and leukocytosis were significantly decreased from baseline beginning at the 91 to 180–day recheck interval, and the frequency of monocytosis was significantly decreased starting at the 181 to 270–day recheck interval. Decreases continued to be significant for all of these parameters at each interval with the exception of the 541 to 720–day recheck interval, at which time the frequency of leukocytosis was not significantly different from the baseline frequency. Together, these data suggest that improvement in both clinical signs and clinicopathologic abnormalities may take > 6 months and that clinicians should not assume a lack of therapeutic efficacy if complete resolution of signs is not noted within the first 90 days of treatment.
The percentage of dogs with an ALT activity above the upper reference limit was significantly higher, compared with the baseline percentage, at the 361 to 540–day and 541 to 720–day recheck intervals but not at any other time point. Fluconazole is generally considered less hepatotoxic than other azole derivatives, as > 70% is excreted through the urine and it is not eliminated through the cytochrome P450 system.15 A study16 comparing the efficacy of fluconazole with itraconazole for treatment of blastomycosis in dogs reported 3 of 18 fluconazole-treated dogs with high ALT activity. No dogs showed clinical signs of hepatotoxicosis, and all 3 dogs with high ALT activity continued to receive fluconazole.16 The frequency of high ALT activity was slightly higher in our study, with 16 of the 49 (32.7%) dogs having a high ALT activity at some point after starting treatment with fluconazole. The reason for this discrepancy is unclear, although it is worth noting that the median dosage of fluconazole used to treat coccidioidomycosis was nearly twice the median dosage used in the previous study (19.7 mg/kg/d, compared with 10.4 mg/kg/d).16 It is unknown whether the higher dosage of fluconazole used in our study could have impacted the number of dogs with high ALT activity. Similar to the previous study, no dog in our study had fluconazole discontinued as a result of hepatotoxicosis. However, because no dogs in our study had hepatic biopsy performed during the study period, we cannot rule out the possibility of primary liver abnormalities contributing to the high ALT activity in some of these dogs.
The most common radiographic lesion identified on thoracic radiographs in the present study was tracheobronchial lymphadenopathy, which was identified in 9 of 21 (42%) dogs. The frequency of tracheobronchial lymphadenopathy in our study was slightly less than what has previously been reported, with Johnson et al7 reporting tracheobronchial lymphadenopathy in 10 of 19 (52.6%) dogs with coccidioidomycosis. The reason for this difference is unclear, but it may simply reflect differences in the 2 populations studied. In an endemic region, the presence of tracheobronchial lymphadenopathy has been shown to be highly specific for positive Coccidioides serologic test results,17 but it is important to note that while common, tracheobronchial lymphadenopathy was observed in less than half of the cases for which thoracic radiographs were available in our study. There was a wide variety of other radiographic findings associated with coccidioidomycosis in our study, consistent with prior reports.1,4,7 This finding should serve as a reminder that clinicians evaluating dogs for respiratory signs in endemic areas should not rule out coccidioidomycosis as a differential diagnosis on the basis of a lack of radiographically apparent tracheobronchial lymphadenopathy.
Although the percentage of dogs with respiratory signs in our study was significantly reduced at all recheck intervals beyond 90 days of fluconazole treatment, we were unable to draw firm conclusions regarding the duration of time needed for radiographic lesions to resolve because of a lack of consistent recheck imaging in many cases. Although it is standard at our practice to recommend follow-up thoracic imaging 90 to 120 days after initiation of treatment, many owners elect to forego imaging at this interval owing to cost and the improvement in clinical signs.
Our study had several limitations. Owing to the retrospective nature of the study, fluconazole formulation and dosage, duration of treatment, recheck intervals, and adjunctive treatments were not standardized, preventing definitive recommendations regarding treatment. After the initial visit, we noted a significant decrease in the percentage of dogs with a high temperature until recheck visits > 270 days after initiation of treatment. Although we suspect that at least in some dogs, a high temperature at later recheck visits was most likely the result of hyperthermia secondary to excitement or anxiety during the visit, the retrospective nature of the study makes this finding speculative. Dogs received either pharmacy grade or compounded fluconazole at the discretion of the attending clinician. Because recheck intervals were not standardized, not every dog was reexamined at every interval. Therefore, it is possible that changes could have been detected earlier in some dogs. A prospective study using more consistent and precise recheck intervals along with standardized repeated diagnostic imaging and clinicopathologic testing may allow for better and more accurate detection of changes over time. The clinical importance of the percentage of dogs with high ALT activity over the course of the study is unclear, and because liver biopsy was not performed in any dog, it is unknown whether these changes could be related to fluconazole use. Additionally, serologic titers were measured at 1 of 2 commercial laboratories at the discretion of the attending clinician, and not every dog was rechecked consistently at the same laboratory. Whether this could have resulted in a different titer result for any of the dogs in our study is not known. Finally, because many dogs were lost to follow-up and dogs with fewer than 2 recheck examinations were excluded from analysis, it is possible that the frequencies of relapse and mortality were underestimated.
Our data demonstrated that oral administration of fluconazole is highly effective for treatment of coccidioidomycosis in dogs. Dogs in our study showed resolution of commonly seen clinicopathologic abnormalities along with a concurrent decrease in antibody titer and improvement in clinical signs beyond 90 days of treatment. Because markers of improvement may require 90 days or longer to resolve, clinicians should recognize that a lack of response to fluconazole treatment during the first 90 days should not be interpreted as therapeutic failure. Prospective studies are needed to allow for more definitive recommendations regarding optimal fluconazole dosage, duration of treatment, and frequency of relapse.
Acknowledgments
No third-party funding or support was received in connection with this study or the writing or publication of the manuscript. The authors declare that there were no conflicts of interest.
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