State-of-the-Art lecture: Interstitial lung diseases in dogs and cats
STATE OF THE ART: INTERSTITIAL LUNG DISEASES IN DOGS AND CATS
Carol R. Reinero, DVM, DACVIM (Small Animal Internal Medicine), PhD
University of Missouri
Columbia, MO, USA
Interstitial lung diseases (ILDs) encompass a wide variety of non-infectious and non-neoplastic inflammatory lung diseases. The term “interstitial” in ILD is misleading, because these diverse pulmonary disorders involve changes to the distal lung parenchyma including airways, pulmonary parenchyma, blood vessels and/or the pleura. A more accurate description sometimes used in the human literature is diffuse parenchymal lung diseases (DPLDs). Globally, interstitial lung diseases comprise many distinct syndromes with over 200 described in humans. They are grouped together based on similarities in clinical signs, imaging features, and physiologic and pathologic manifestations. Interstitial lung diseases are still considered rare and poorly characterized in veterinary medicine, in large part due to the need for lung tissue for histopathologic examination, expertise in respiratory pathology, and a multidisciplinary approach involving clinicians, radiologists and pathologists. In this lecture, based on a review of the literature and clinical case examples, recognized interstitial lung diseases in dogs and cats will be presented along with a comparison to related syndromes in humans.
ARE INTERSTITIAL LUNG DISEASES RARE?
In dogs and cats very few ILDs are recognized which is in stark contrast to human medicine in which over a couple hundred ILDs that have been characterized. Interstitial lung diseases are probably not as rare as we think in dogs and cats, despite infrequent diagnosis. There are several reasons for this. First, interstitial lung diseases are challenging to diagnose with histologic examination required for confirmation. Lung biopsy in a patient with respiratory compromise is not a trivial procedure. It is expensive, associated with some morbidity and occasional mortality. In dogs or cats that die from interstitial lung disease, necropsy is often not pursued. Even if histopathology is performed, a definitive diagnosis may not be reached for many interstitial lung diseases because as a whole they are poorly characterized. This in turn leads to frustration by clinicans (“why did I recommend getting lung tissue if I didn’t get an answer”) and owners (“why did I spend all that money and put my dog or cat at risk for a test that was inconclusive”). This may lead to bias in the future where clinicians then fail to advocate strongly for histopathologic examination. A second reason why there is so little known about veterinary interstitial lung diseases is the lack of routine multidisciplinary collaboration between clinicians, radiologists and pathologists to help characterize these disorders and explain discrepancies from each individuals’ perspective. Veterinary pathologists cannot work in a bubble, but must talk to clinicians to help understand what compromises a clinical syndrome. If no lesions to explain the histologic results can be found, it is worth discussing distribution of lesions with a radiologist as recuts of a different section of tissue may provide answers. As another example, pathology reports commonly use the term “histiocytic pneumonia” which may accurately describe the findings under a microscope. However, there is no specific clinical syndrome of a histiocytic pneumonia, so to a clinician this is an unsatisfactory answer. Histiocytes could be present secondary to infection, neoplasia or as part of an interstitial lung disease and diagnosis does not end with the histologic description of “histiocytic pneumonia”. After discussion with the clinician, the pathologist should be able to apply special stains to help identify certain microorganism or to do immunohistochemistry to help determine if the histiocytes represent a histiocytic sarcoma. A third reason we lack concrete knowledge about interstitial lung diseases is that there has been a tendency to assume interstitial and alveolar radiographic patterns correlate with a histologic diagnosis of disease confined to the interstitium or alveoli and that no further testing is needed. While radiographs are a reasonable first screening test, they are not a sensitive modality and certainly not to correlate pathology accurately on a histologic level. With the advent of computed tomography, accuracy of thoracic imaging has dramatically improved and computed tomographic patterns of disease now have more meaning.
TYPES OF INTERSTITIAL LUNG DISEASE
Interstitial Lung Disease in Humans
There is no single classification scheme for interstitial lung disease in humans, in part because of the sheer numbers of disorders, overlap in features between diseases and constant improvements in diagnostic capabilities. Idiopathic interstitial pneumonias (IIPs) comprise a large and important number of interstitial lung diseases. They have been subdivided into idiopathic pulmonary fibrosis (IPF), idiopathic non-specific interstitial pneumonia (iNSIP), respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia, cryptogenic organizing pneumonia (COP), acute interstitial pneumonia (AIP), a group of rare IIPs and unclassifiable IIPs.
Of the IIPs, IPF is the most common. With substantial multidisciplinary collaboration, a diagnostic algorithm frequently negating the need for lung biopsy has been developed in human patients. Key to diagnosis of IPF is recognition of a “usual interstitial pattern” on high resolution computed tomography that closely correlates with a usual interstitial pattern on histology. Importantly, other interstitial lung diseases that may mimic IPF must be ruled out with historical questions, physical examination findings and other relevant diagnostic tests. The presence of fibrosis alone does not make a diagnosis of IPF, as is often incorrectly presumed in veterinary medicine (see below).
It is somewhat confusing that there is both a histologic pattern of NSIP as well as a clinical disease syndrome of NSIP. The histologic pattern can either be idiopathic with no underlying cause identified (falling into the category of IIPs) or be secondary to many other disorders, including familial fibrosis, drug toxicity, collagen vascular disorders and hypersensitivity pneumonitis, among others.
Respiratory bronchiolitis-interstitial lung disease and the majority of cases of desquamative interstitial pneumonia are considered smoking-related diseases. They represent a spectrum of injury induced by cigarette smoking. This is important as smoking cessation represents a key part of therapy. Prognosis in general for respiratory bronchiolitis-interstitial lung disease is good; prognosis for desquamative interstitial pneumonia is more varied with severe respiratory impairment and death as possible sequelae.
Cryptogenic organizing pneumonia is the idiopathic form of a syndrome previously referred to as bronchiolitis obliterans with organizing pneumonia. The small airways damaged from an insult develop inflammation and plugging, leading to a downstream organizing pneumonia. Organizing pneumonia, like NSIP, is also a histologic pattern of disease as well as a distinct clinical syndrome secondary to known (infection, drugs, radiation, neoplasia, transplantation, aspiration, etc) and unknown (COP) etiologies.
Acute interstitial pneumonia, sometimes referred to as idiopathic adult respiratory distress syndrome (ARDS) presents as acute respiratory failure with diffuse bilateral infiltrates on lung imaging. Additionally, patients lack an inciting cause, have prior radiographs failing to document respiratory disease and have histologic evidence of “diffuse alveolar damage”, the characteristic histologic lesion seen with ARDS. Mortality is high, with mechanical ventilation being an important tenant of therapy.
A discussion of the other human ILDs is well beyond the scope of this lecture; the emphasis will switch to ILDs recognized in dogs and cats or syndromes which likely exist but have not yet been well documented.
Interstitial lung disease in dogs and cats
One of the most commonly diagnosed ILDs in dogs and cat is IPF. A variety of injuries to alveolar epithelial or capillary endothelial cells can lead to inflammation, and as part of the reparative process, may share a common pathway culminating in pulmonary fibrosis. In veterinary medicine, the presence of an unknown cause of pulmonary fibrosis, even if severe, does not alone fit the diagnostic criteria for human IPF. As described above, human IPF has several important defining criteria including a UIP histologic pattern. Even the West Highland White terrier, the poster child for canine IPF, does not have the analogous disease to humans: while there is no doubt they have a familial fibrotic lung disease, it is not the same as human IPF. In fact, one report suggests its histologic appearance more closely resembles NSIP than UIP. Although histologic lesions noted in a series of cats with “IPF” showed resemblance to human IPF, a more thorough evaluation for other known causes that could terminate in fibrosis should be attempted. This is important because end stage pulmonary fibrosis has no effective treatment; however, if underlying inflammatory disease, inhalational injury, drugs, infection, etc. is aggressively treated early, progression to fibrosis may be slowed or halted. Intervening before development of end stage lung will have better success that attempting to find a viable treatment in a lung obliterated with scar tissue. To underscore the myriad numbers and types of diseases and triggers for pulmonary fibrosis (each with different time courses for progression, responses to treatment, and likely prognosis), the term fibrotic lung disease or fibrotic ILD is proposed to replace IPF in veterinary medicine. Known causes of fibrotic lung disease in dogs and cats include drugs (e.g., chemotherapeutics), toxins (e.g., paraquat), genetics (West Highland White terrier, Dalmatian)
Still termed bronchiolitis obliterans with organizing pneumonia in the veterinary literature, idiopathic cryptogenic organizing pneumonia (COP) has been described in both dogs and cats. Most disease is diffuse, but solitary lesions mimicking a lung neoplasm has been seen by the author. In comparison to fibrotic lung disease, COP appears to be very steroid-responsive. Diagnosis is made through antemortem lung biopsy. Delay in diagnosis and subsequent therapy can be life-threatening. Immunosuppressive doses of steroids and sometimes other immunosuppressants with a slow taper has been curative in the author’s experience. However, rapid tapering or insufficient immunosuppression may lead to clinical relapses.
Hypersensitivity pneumonitis, also known as extrinsic allergic alveolitis in humans, is caused by diffuse small airway and pulmonary parenchymal inflammation from repetitive inhalation of small particulate environmental antigens. The closest disease in the veterinary literature resembling the human syndrome is inhalation of puffball mushroom spores in dogs. However, inhalation of puffball mushroom spores usually occurs as a single massive inhalation of these antigens, compared to human disease triggered by repetitive exposure to mushrooms. Although there are many other antigens capable of inducing hypersensitivity pneumonitis in humans, no other spontaneous examples of this disease have been reported in dogs or cats.
Pulmonary alveolar proteinosis, described in dogs and a cat, is a rare disorder resulting from flooding of the alveoli with surfactant. Thoracic radiographs generally display diffuse interstitial to alveolar patterns, and diagnosis can be made via the opaque, milky BAL fluid showing PAS positive macrophages and lipid on cytology. Lung lavage was successfully used to treat a dog with this condition.
Pulmonary alveolar microlithiasis is classified as an interstitial lung disease. Small calculi accumulate in alveolar spaces for unknown reasons in small animals; this disease must be distinguished from metastatic and dystrophic calcification and from broncholithiasis. In many cases, animals are asymptomatic and thoracic radiographs pick up mineralized densities as an incidental finding.
The pneumoconiosis represent a similar group of diseases sharing in common environmental exposure to mineral dusts and fibers. Anthracosis, a mild form of pneumoconiosis, occurs with chronic exposure to smoke, coal dust or air pollution and has been linked to lung cancer in dogs. Silicosis in and asbestosis has been reported rarely in dogs. There are a couple of unique features of pneumoconiosis compared to other ILDs: first, they are preventable and second, by employing avoidance strategies in ongoing disease, improvements may be noted clinically.
Lipid (or lipoid) pneumonia comes in two forms: exogenous from accidental inhalation of animal, vegetable or mineral sources of lipid and endogenous in response to accumulation of lipids after injury to type II pneumocytes. Both forms have been described in dogs and cats. Exogenous lipid pneumonia most commonly occurs after administration of mineral oil for constipation or hairballs. Endogenous lipid pneumonia in cats tends to occur secondary to obstructive pulmonary disease. In dogs, endogenous lipid pneumonia has been associated with mycobacterial pneumonia and rarely in tandem with other respiratory diseases (with unclear cause and effect).
Other interstitial lung diseases poorly characterized on the veterinary side include pulmonary hyalinosis; diffuse alveolar hemorrhage; ILDs from drugs, biologics and radiation; lymphocytic interstitial pneumonia, granulomatosis with polyangiitis (Wegener’s granulomatosis); and histiocytic disorders.
CLINICAL APPROACH TO CANINE ILDs
In this lecture, using case based examples, clinical and pathologic features of interstitial lung diseases (ILDs)/diffuse parenchymal lung diseases (DPLDs) in dogs and cats will be described. Emphasis will be placed on the diagnostic evaluation, paying special attention to interpretation of imaging findings and discrimination of these disorders from others.
1. Reinero, C. Interstitial lung diseases in dogs and cats part I: The idiopathic interstitial pneumonias. Vet J 2019;243:48-54.
2. Reinero, C. Interstitial lung diseases in dogs and cats part II: Known cause and other discrete forms. Vet J 2019;243:55-64.