Korean Journal of
Veterinary Service

Interstitial lung disease (ILD) encompasses a diverse group of non-infectious, non-neoplastic disorders affecting lung parenchyma, exhibiting similar symptoms, diagnostic imaging patterns, and clinical manifestations (Reinero and Cohn, 2007; Reinero, 2019a). Drug-induced interstitial lung disease (DILD), a subset of ILD caused by drug exposure, is primarily associated with chemotherapeutic agents and accounts for 23% to 51% of documented cases in human medicine (Skeoch et al, 2018). The pathophysiology of DILD remains unclear but is thought to result from increased pulmonary capillary permeability due to various underlying mechanisms.

An 11-year-old, 7 kg neutered male Dachshund presented to the Jeju National University College of Veterinary Medicine Teaching Hospital with acute onset dyspnea following a subcutaneous (SC) injection of cytosine arabinoside (CA). The patient was previously diagnosed with meningoencephalitis of unknown origin (MUO) via two magnetic resonance imaging (MRI) scans conducted 8 weeks apart and cerebrospinal fluid analysis. The treatment regimen included prednisolone (1 mg/kg q 12 h PO) and CA SC protocol (50 mg/m² SC q 12 h, 4 times at 3-week intervals) as immunosuppressive agents, along with levetiracetam (30 mg/kg q 8 h PO), potassium bromide (10 mg/kg q 12 h PO), and gabapentin (10 mg/kg q 12 h PO) as anticonvulsants.

The patient developed acute respiratory symptoms after the ninth CA protocol, worsening over 5 days, prompting early re-presentation (Supplementary video 1). Physical examination revealed tachycardia (heart rate 150 per minute) without murmur, tachypnea (respiratory rate 60 per minute), and labored respiratory effort. Neurologic exams showed no deterioration (absent menace OS, general postural reflex deficit in the left hind limbs). The patient was depressed but conscious with normal mentation. Thoracic radiographs revealed bilateral diffuse interstitial to alveolar pulmonary opacities, right-sided cardiomegaly, and mild bulging of the main pulmonary artery, which were not detected 240 days ago (Fig. 1). Echocardiography revealed tricuspid regurgitation velocity (TRV) of 3.4 m/s in the left apical 4-chamber view, measured by pulse wave Doppler, suggesting right-sided heart enlargement. No evidence of mitral valve degeneration or left-sided heart failure was observed. Laboratory investigations, including complete blood count (CBC), serum chemistry, and venous blood gas analysis, were performed. CBC revealed mild regenerative anemia. Venous blood gas analysis showed hyperlactatemia (5.6 mmol/L, reference interval 0.3∼2.5 mmol/L). Other values were within reference intervals or not remarkable. Peripheral blood smear showed a few nucleated or hyperchromatic erythrocytes without marked left shift or toxic change. Additional tests, including polymerase chain reaction (PCR) for Babesia genus and a canine pancreatic-specific lipase (cPL) colorimetric assay kit test (SNAP® cPL^TM, IDEXX Laboratories, Inc.; North Grafton, MA, USA), were conducted due to the patient’s previous history of babesiosis and pancreatitis. PCR for Babesia was negative, but the cPL kit test was consistent with pancreatitis. Laboratory findings are listed in Table 1.

Table 1 . Laboratory findings on Day 0.

Variables	Result	Reference interval (unit)
CBC
Red blood cell count	4.61	5.65∼8.87 (10×12/L)
Hematocrit	30.3	37.3∼61.7 (%)
Hemoglobin	10.9	13.1∼20.5 (g/dL)
Reticulocytes	59	10∼110 (10×3/μL)
White blood cell count	20.43	5.05∼16.76 (10×9/L)
Neutrophils	18.06	2.95∼11.64 (10×3/μL)
Lymphocytes	1.55	1.05∼5.1 (10×3/μL)
Monocytes	0.79	0.16∼1.12 (10×3/μL)
Eosinophils	0.01	0.06∼1.23 (10×3/μL)
Basophils	0.02	0∼0.1 (10×3/μL)
Platelets	119	148∼484 (10×9/L)
Serum chemistry
Creatinine	1.8	0.5∼1.8 (mg/dL)
BUN	65	7∼27 (mg/dL)
BUN/CREA	36	-
Phosphate	6.7	2.5∼6.8 (mg/dL)
Calcium	10	7.9∼12 (mg/dL)
ALT	184	10∼125 (U/L)
AST	43	0∼50 (U/L)
ALP	589	23∼212 (U/L)
GGT	33	0∼11 (U/L)
Bilirubin-Total	0.4	0∼0.9 (mg/dL)
CRP	0.9	0.1∼1 (mg/dL)
Venous blood gas analysis
pH	7.403	7.31∼7.46
Na	145.8	145∼151 (mmol/L)
K	4.61	3.9∼5.1 (mmol/L)
Cl	130.1	110∼119 (mmol/L)
iCa	1.31	1.16∼1.4 (mmol/L)
Lactate	5.6	0.3∼2.5 (mmol/L)

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; BUN/CREA, blood urea nitrogen : creatinine ratio; CRP, C-reactive protein; GGT, gamma-glutamyl transferase; iCa, ionized calcium..

Figure 1. Thoracic radiographs of this case. (A) At day 0, bilateral, diffuse interstitial to alveolar pattern observed. (B) Formal thoracic radiographs (240 days ago) did not show any abnormal pulmonary patterns.

Based on the clinical and pathological findings, the tentative diagnosis included ILD caused by CA, non-cardiogenic pulmonary edema (NCPE) induced by acute pancreatitis, and aspiration pneumonia. CA-induced ILD was prioritized due to the onset coinciding with administration, while other potential causes were deemed unlikely. Pancreatitis-induced NCPE was deprioritized as the patient showed no distinct symptoms relating to pancreatitis, implying that cytokine release was insufficient to provoke distant organ failure. Aspiration pneumonia was also considered unlikely due to the absence of antecedents such as vomiting. The elevation of TRV on echocardiogram was considered irrelevant, likely a transient effect of labored respiration.

The treatment on day 0 focused on symptomatic therapy and withdrawal of CA. As exclusion of infectious pneumonia and pancreatitis was inconclusive, amoxicillin-clavulanic acid (AMC, 17 mg/kg PO q 12 h) was prescribed. SC fluids (0.9% normal saline 70 ml SC q 24 h) were added for supportive therapy for pancreatitis, and oxygen supplementation was occasionally provided at home. Pulmonary infiltration improved from day 1 after discontinuation of CA and continued to improve (Fig. 2). However, dyspnea was not completely resolved despite radiographic improvement. Pulmonary hypertension (PH) secondary to DILD was suspected based on previous echocardiographic findings. Consequently, oral sildenafil (2 mg/kg q 8-12 h) was initiated on day 8. Five days later, the patient’s dyspnea improved further, indicating a favorable response to sildenafil without adverse effects (Supplementary video 2). By day 112, the patient exhibited no respiratory symptoms. Echocardiographic re-examination showed improved parameters, including PA/Ao ratio (0.8) and TRV (2.2 m/s), leading to the discontinuation of sildenafil. The patient’s respiratory status remained stable until the one-month follow-up. There was no relapse of seizures or deterioration of neurologic signs following substitution of the CA SC protocol with oral mycophenolate mofetil (12 mg/kg PO q 12 h).

Figure 2. Changes shown in ventrodorsal thoracic radiographs. (A) At day 0, bilateral, diffuse interstitial to alveolar pattern observed. (B) Following discontinuation of CA, there was a notable decrease in the opacity within the general lung field at Day 5. (C) At Day 22, after 2 weeks of sildenafil administration, additional improvement of lung opacity was observed.

As mentioned, the pathophysiology of DILD remains unclear. Proposed hypotheses include direct cytotoxic effects on pulmonary epithelium and endothelium, immune-mediated responses involving the release of pro-inflammatory cytokines and chemokines, and oxidative stress through the production of reactive oxygen species (Matsuno, 2012). Given its heterogeneous nature and overlapping characteristics with other lung diseases, making a definitive diagnosis can be challenging, and no standardized diagnostic approach has been established. Therefore, confirming exposure to known risk factors and excluding other possible diagnoses is emphasized (Skeoch et al, 2018; Conte et al, 2022).

In veterinary medicine, bleomycin, lomustine (CCNU), vincristine, and cisplatin have been identified as potential causative agents of DILD or drug-induced non-cardiogenic pulmonary edema (NCPE) among commonly used chemotherapeutics in dogs and cats (Fleischman et al, 1971; Knapp et al, 1987; Van Meervenne et al, 2008; Balakrishnan et al, 2017). Previously, cytosine arabinoside (CA) was presumed not to induce lung toxicity in dogs until a 2016 case report described such adverse events (Hart and Waddell, 2016). Since then, CA-induced pulmonary toxicity in dogs has been recognized as a potential risk factor for ILDs or NCPE (Reinero, 2019b; Unger and Martin, 2023). In this report, we suspect CA-induced DILD with secondary pulmonary hypertension (PH), based on other possible diagnoses being considered unlikely and the onset of dyspnea coinciding with CA administration.

This case study illustrates the occurrence of PH, suspected to be a consequence of DILD, and its successful management with sildenafil. PH is a recognized complication of ILD, diagnosed by echocardiographic findings and clinical signs indicative of PH, and phosphodiesterase-5 inhibitors (PDE5Is) such as sildenafil are known to be effective symptomatic treatments (Reinero et al, 2020). Sildenafil is not indicated as a first-line treatment in PH secondary to ILD or other respiratory diseases in human medicine, but several studies have reported its efficacy in dogs with group 3 PH, including ILD (Kellihan et al, 2015; Köster and Kirberger, 2016; Johnson and Stern, 2019; Fabyan et al, 2023). Thus, the current consensus statement recommends sildenafil therapy for group 3 PH patients (Reinero et al, 2020). In this case, PH was suspected based on echocardiographic evidence combined with the presence of respiratory effort. Consequently, sildenafil was prescribed, and the patient responded well to the therapy, further supporting the diagnosis. The relation between PH development and DILD was suspected due to the temporal association and absence of other suspected underlying mechanisms.

The patient exhibited a resolution of secondary PH and a degree of remission of DILD. Rather than being a primary clinical condition, PH is an abnormal hemodynamic state comorbid with underlying disorders. Therefore, resolution of PH can be expected with control of the underlying disease (Reinero et al, 2020). Given that adverse drug reactions were considered the primary etiology, along with the acute onset of the condition, it was anticipated that pulmonary damage would recover with cessation of the drug. As the patient remained asymptomatic after discontinuation of sildenafil, it was presumed that recovery did occur, and resolution of PH followed as the underlying cause was remediated. Furthermore, this observation supports the association between ILD and the development of PH.

In this case, computed tomography, pulmonary function tests, and histopathological examinations were not performed (Fabyan et al, 2023). However, given the observed improvement following discontinuation of CA without additional intervention, the chronological relevance with CA administration and symptom onset, and the absence of other pulmonary diseases likely to induce the patient’s condition, we suspect this case represents a rare instance of CA-induced ILD, despite the aforementioned limitations.

This case report is the first to document secondary PH in a patient with suspected CA-induced ILD, achieving remission as the patient remained asymptomatic following discontinuation of sildenafil.

The online version contains supplementary material available at https://doi.org/10.7853/kjvs.2024.47.2.95.

This study was supported by the National Research Foundation (NRF) of Korea grant funded by the Korea government (MSIT) (RS-2023-00252033).

The dog described in this report was a client-owned patient presented for care at the veterinary medical teaching hospital of Jeju National University. Informed owner consent was received for any possible research use of all diagnostic samples acquired from the dog.

No potential conflict of interest relevant to this article was reported.