Developmental lung disease with associated pulmonary hypertension in a Sphynx kitten

Abstract

Case summary

This case report describes the clinical presentation, diagnostic findings and clinicopathologic features consistent with developmental lung disease (DLD) and pulmonary hypertension (PH) in a 3-month-old Sphynx Munchkin kitten. The kitten was originally referred for episodes of respiratory distress that was unresponsive to medical management, consisting of diuretics, antibiotics and corticosteroids. Echocardiography was consistent with a high probability of PH of a non-cardiac etiology. Baseline blood work, thoracic radiographs, thoracic CT with triphasic angiography and a bronchoalveolar lavage were performed. Thoracic CT revealed diffuse ground-glass opacity with bronchiolectasis and distention of the pulmonary artery and branches. The bronchoalveolar lavage identified an equal distribution of non-degenerative neutrophils and macrophages, with erythrophagocytosis and no overt neoplastic cells or infectious organisms identified. The kitten was humanely euthanized due to the lack of an identifiable treatable etiology and poor prognosis. Histopathological findings were most consistent with DLD with diffuse acinar underdevelopment and vascular changes including pulmonary capillary hemangiomatosis. These findings have not been previously reported in the feline DLD literature.

Relevance and novel information

There is a paucity of literature describing DLD and its potential to cause PH in cats. A comprehensive diagnostic evaluation, ultimately including histologic examination, is needed to reach a diagnosis of DLD. The presence of PH in a young kitten without any identifiable primary cardiac or respiratory cause, pulmonary thromboembolism or cardiac parasites should lead to a DLD being considered.

Case description

A 3-month-old, 0.68 kg, male intact Sphynx Munchkin kitten presented to the University of Missouri Veterinary Health Center for progressive respiratory distress. Prior history included adoption from a breeder with no known health screening or genetic testing for the sire and dam. No information was available about the clinical status of other littermates. Since adoption, the kitten had displayed intermittent tachypnea and open-mouth breathing, which self-resolved with restricted activity, but were concerning enough to lead to a local emergency clinic visit on the night of the adoption. Initial diagnostics at this clinic included an unremarkable blood gas analysis and an abnormal rapid test for feline N-terminal pro-B-type natriuretic peptide. Furosemide was prescribed (3 mg/kg PO q12h). The following day, a complete blood count showed an inflammatory leukogram and mild reticulocytosis. Amoxicillin-clavulanic acid (11.4 mg/kg PO q12h) and prednisolone (0.7 mg/kg PO q12h for 1 day, tapered over 3 days) were prescribed 6 days later with no clinical response. The kitten had received one dose of selamectin and sarolaner topical solution, was up to date on vaccines and did not have outdoor access.

At 12 days after adoption, the kitten was brought to the University of Missouri. The kitten was quiet, alert and responsive, normothermic (101.6°F [38.67°C]), tachycardic (268 beats/min) and tachypneic (60 breaths/min), with pale pink mucous membranes and abdominal distention without a fluid wave. The kitten was open-mouth breathing with increased bronchovesicular sounds bilaterally and a paradoxical breathing pattern. Point-of-care ultrasound revealed B lines bilaterally within the lungs (not further quantified) with no ascites. The kitten was stabilized with oxygen supplementation. Referral thoracic radiographs were reviewed, which revealed cardiomegaly with a vertebral heart score of 8.75 ¹ and occasional patchy areas of increased opacity over a diffuse unstructured interstitial lung pattern and a prominent main pulmonary artery (Figure 1). Echocardiography, performed after administration of butorphanol (0.2 mg/kg IV), showed normal left atrial size (left atrium:aorta ratio 1.41, left atrial diameter in the right parasternal long axis 10.1 mm [reference interval (RI) <12.5]) ² and the low end of normal left ventricular dimensions (left ventricular internal diameter at end diastole 9.2 mm [RI 8.2–14.3]) ² with subjective right atrial and right ventricular dilation, right ventricular concentric hypertrophy (see videos 1 and 2 in the supplementary material), interventricular septal flattening and pulmonary artery dilation with decreased right pulmonary artery distensibility index (24.1% [RI in dogs >30]), ³ consistent with a high probability of pulmonary hypertension (PH) (Figure 2). The tricuspid regurgitant profile was incomplete, preventing estimation of pulmonary artery systolic pressure. There were no congenital cardiac defects.

Figure 1.

Right lateral and ventrodorsal thoracic radiography in a 3-month-old, male intact Sphynx Munchkin kitten. (a) Right lateral radiographic projection revealing increased height (h) and width (w) of the cardiac silhouette with a vertebral heart score of 8.75. A diffuse unstructured interstitial pattern (solid white arrows) is seen throughout with occasional irregular areas of alveolar pattern (black solid arrows). The abdomen is pendulous with decreased serosal detail (triangle). (b) Ventrodorsal projection showing cardiomegaly (w) and pulmonary trunk enlargement (clear arrow). L = left side of the patient

Figure 2.

Two-dimensional echocardiographic images of a 3-month-old, male intact Sphynx Munchkin kitten. (a) Right parasternal short-axis view of the heart base with normal left atrial size. (b) Right parasternal four chamber long-axis view showing right atrial dilation and right ventricular concentric hypertrophy. Ao = aorta; LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle

The kitten remained severely oxygen dependent, and therefore received oxygen supplementation while in hospital, including before and after thoracic CT, and a blind bronchoalveolar lavage. Paired ventilator-assisted inspiratory and expiratory breath-hold CT with triphasic angiography revealed diffuse ground-glass opacity (GGO), with multifocal regions of complete opacification in the right cranial, right middle and both subsegments of the left cranial lung lobe (Figure 3). Left lungs were less well inflated than right lungs. There was traction bronchiectasis/bronchiolectasis and peribronchovascular/peribronchiolovascular thickening with a patchy reticular pattern and parenchymal bands. The lobar main pulmonary arteries and branches were larger than the corresponding veins, although the pulmonary artery to vertebral height of the sixth vertebral body ratio was not greater than reported for prepubertal cats (Figure 4). ⁴ The pulmonary trunk:aorta ratio was 1.9, consistent with CT support for PH in dogs. ⁵ The angiogram (soft tissue window) showed no filling defects in the vessels; however, there was subtle support of mosaic perfusion. Bronchoalveolar lavage revealed a total nucleated cell count of 2010 cells/µl with 47% non-degenerate neutrophils and 47% macrophages (RI 200–400 cells/µl; 65–80% macrophages, <10% eosinophils, <10% lymphocytes and <7% neutrophils),^6–8 the latter containing hemosiderin and occasionally displaying erythrophagocytosis. No infectious organisms or neoplastic cells were observed. With the young age at onset of clinical signs, lack of primary cardiac or other identifiable respiratory disease, developmental lung disease (DLD) was strongly suspected.

Figure 3.

Dorsal minimum intensity projection (MinIP) CT images comparing (a) a 3-month-old, male intact Sphynx Munchkin kitten with alveolar capillary hemangiomatosis and pulmonary hypertension secondary to a suspect developmental lung disease to (b) a 9-month-old, male castrated domestic shorthair cat with absence of CT lung parenchymal abnormalities. MinIP allows a visual assessment of the difference between air in the airways (ie, endobronchial) and the lung parenchyma, and highlights subsegmental airways that may not be otherwise depicted on a transverse image. (a) MinIP accentuates the difference between the diffuse ground-glass opacity of the lung parenchyma, and the airway lumen (arrows), whereas the difference between (b) the lung parenchyma and endobronchial lumen is normal (arrows)

Figure 4.

CT images of a 3-month-old, male intact Sphynx Munchkin kitten with alveolar capillary hemangiomatosis and pulmonary hypertension secondary to a suspect developmental lung disease. (a–c) Transverse images show multifocal areas of complete opacification (solid black arrows), diffuse ground-glass opacity (circle), parenchymal band (curved white arrow) and traction bronchiectasis (solid white arrows). (d) Dorsal 10 mm thickness maximum intensity projection shows caudal lobar pulmonary arteries (solid black arrows) being larger than the corresponding caudal lobar pulmonary veins (clear arrows)

The lack of an identifiable treatable etiology and the severe clinical signs supported a grave prognosis. Humane euthanasia was elected and necropsy allowed. Histopathologic examination of the lung showed marked, diffuse acinar underdevelopment with large peripheral air spaces having markedly enlarged alveoli. Bronchi identified as having cartilage in the wall were subjectively far too small for the level of branching. Bronchiolectasis (dilation of the small airways) was noted with extension to the pleural surface. There was a decreased number of small bronchioles in all lung lobes, and there were engorged alveolar capillaries with multifocal alveolar capillary hemangiomatosis and double capillaries (Figure 5). Right ventricular hypertrophy (4 mm thickness grossly), secondary to increased pulmonary arterial pressures, was noted. A hypercoagulable state was considered unlikely as no pulmonary arterial thrombi were noted on CT angiography or histologic examination.

Figure 5.

Lung histopathology images of a 3-month-old, male intact Sphynx Munchkin kitten. (a) Low magnification showing the lung alveolar parenchyma. There are double capillaries adjacent to the alveolar walls and evidence of hemangiomatosis. (b) High magnification showing double capillaries with hemosiderophages (small arrows) suggestive of prior hemorrhage within the lung

Discussion

Developmental lung disease encompasses a poorly characterized spectrum of abnormal development and growth of the airways, alveoli and vasculature (alone or in combination), as was shown in this kitten with underdeveloped pulmonary acini leading to PH. Intra-acinar vessels are associated with respiratory bronchioles, alveolar ducts and alveolar walls; ⁹ thus, diffuse underdevelopment of pulmonary acini is speculated to lead to increased pulmonary vascular resistance and ultimately PH. PH is not a disease per se, but a consequence of a variety of cardiac, respiratory and vascular disorders, with cats having six proposed classes ¹⁰ based on the canine PH consensus statement. ¹¹ This includes the following: (1) pulmonary arterial hypertension (PAH; including a subdivision encompassing the clinical syndrome of pulmonary capillary hemangiomatosis [PCH]); (2) left-sided cardiac disease; (3) respiratory disease and hypoxia (including a subdivision encompassing DLD); (4) pulmonary emboli/thrombi/thromboembolic disease; (5) parasitic disease; and (6) multifactorial or unclear mechanisms. The classification scheme helps provide clarity in etiology with respect to recommended diagnostic testing, treatment and prognosis. PCH has rarely been reported in cats,^12,13 and when it is the primary process driving PH, it is classified as subgroup 1 within the first major category of PH (ie, group 1 PAH).^10,11 However, PCH as a histologic descriptor/pathologic process (rather than as a primary clinical syndrome) may also occur secondary to disorders causing chronic volume overload, as has recently been reported in dogs and cats with left-sided heart disease. ¹⁴ Based on the kitten described in this report, we speculate that histologic changes consistent with PCH may also occur secondary to DLD, which falls within the category of group 3 PH. Diagnosis of DLD is challenging ante mortem, with advanced respiratory diagnostics primarily serving to rule in or out other respiratory, cardiac and vascular disorders. Histopathology currently represents the only definitive means of diagnosis in cats.

In humans, DLD encompasses a broad spectrum of pulmonary developmental malformations, including acinar dysplasia, congenital alveolar dysplasia and alveolar capillary dysplasia, among others. ¹⁵ These types of DLD appear to be clinically similar. Preliminary diagnostic investigations, such as thoracic radiography or CT, may reduce the likelihood of other cardiovascular and respiratory disorders but are not specific for DLD. Definitive diagnosis requires histological examination of lung biopsy specimens and recognition of characteristic patterns. ¹⁵

There are few case reports of congenital lung disorders in cats. One report documented severe PH in a 1-year-old cat with DLD, with CT showing severe generalized cardiomegaly, diffuse GGO, parenchymal bands and subpleural interstitial thickening associated with mild bronchiolectasis. ¹⁶ A lung biopsy was consistent with a developmental abnormality of pulmonary parenchyma. Shortly thereafter, the cat was euthanized, and histopathology showed diffuse markedly enlarged alveolar spaces, alveolar hemorrhage and alveolar parenchymal enlargement suggestive of DLD. ¹⁶ Other reports of DLD include a retrospective analysis of cats and dogs with lobar emphysema and a high suspicion of congenital bronchial cartilage defects, ¹⁷ a 2-month-old kitten with suspected congenital lobar emphysema and concomitant hiatal hernia ¹⁸ and a 5-month-old Ragdoll with suspected congenital lobar emphysema. ¹⁹ Additional reports describe bronchial dysgenesis leading to lobar emphysema in a cat ²⁰ and suspected bronchopulmonary dysplasia resulting in pulmonary bulla, subsequent rupture and spontaneous pneumothorax in a cat. ²¹ None of these case reports assessed for PH.

The clinical syndrome of PCH has been described in two cats.^12,13 In one cat with comorbid hypertrophic cardiomyopathy, PCH was confirmed as the primary process causing PH (group 1, PAH). ¹² In the other cat, hypertrophic cardiomyopathy was considered a significant contributor to death; however, it remains unclear whether histologic evidence of PCH was secondary to left-sided heart failure (group 2, left-sided cardiac disease), as has recently been proposed, ¹⁴ or whether PCH represented a comorbid primary disease process (group 6, PH with multifactorial mechanisms). The kitten in this report exhibited multifocal alveolar capillary engorgement, with many alveoli containing double capillaries within the septa (Figure 5), consistent with PCH. Given the widespread and marked diffuse acinar underdevelopment, including underdevelopment of the acinar vasculature, the authors suspect that the histologic lesions of PCH were secondary to DLD (group 3, PH secondary to respiratory disease or hypoxia) rather than representing a primary vascular disorder (group 1, PAH). For classification as group 1 PCH, histologic evidence of anomalous pulmonary capillary proliferation should constitute the sole clinically relevant pathologic process.

When PH is identified, diagnostic tests should focus on elucidating the underlying cause of both the clinical signs and PH. Diagnosis of PAH (group 1 PH) relies on excluding all other causes of PH that could account for the histologic vascular lesions. Thus, given the histologic evidence of DLD, the microscopic lesions of PCH were considered most likely secondary to developmental vascular anomalies, and group 1 disorders were ruled out. Echocardiography confirmed a high probability of PH and excluded primary left-sided cardiac disease or other congenital cardiac disorders (group 2 PH) as causes of the kitten’s clinical signs. A fecal analysis was not performed because the kitten did not defecate while in hospital; however, the kitten had no outdoor access to snails or slugs, and no lungworms were noted histologically, so Aelurostrongylus abstrusus infection was considered unlikely. No other infectious organisms or neoplastic cells were identified on bronchoalveolar lavage. Diffuse GGO within the lungs on CT raised suspicion of a primary respiratory etiology (group 3 PH), which was ultimately confirmed histologically as DLD characterized by diffuse acinar underdevelopment, large peripheral air spaces and vascular changes including PCH. A thrombotic or embolic etiology (group 4 PH) was considered less likely owing to the absence of an identifiable underlying hypercoagulable state. Perfusion defects identified during the arterial phase of CT in the lung window could have been compatible with small to medium vessel clots, among other vascular abnormalities; however, no clots were noted on histologic examination. Cardiac parasites (group 5 PH) were considered unlikely based on the kitten’s young age and the lack of supportive cytologic and histologic findings. No multifactorial or unclear causes (group 6 PH) were identified following comprehensive evaluation.

Conclusions

As illustrated by this case report, DLD can cause PH in cats. A comprehensive diagnostic approach incorporating signalment, clinical signs, routine and advanced imaging modalities (radiography, echocardiography and CT), cytology and ultimately histology was required for a definitive diagnosis of DLD and PH. Although the disease was severe and ultimately untreatable in the kitten described here, further studies are required to expand current knowledge regarding the histopathological features and potential treatment options for cats with DLD and PH.

Supplemental Material

Video 1. Right parasternal short-axis cine loop of the heart base depicting a dilated right branch of the main pulmonary artery. There is a decreased right pulmonary artery distensibility index of 24.1%

Video 2. Right parasternal short-axis cine loop of the left ventricle and right ventricle depicting normal left ventricular dimensions and right ventricular dilation.