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Saturday, January 26, 2008

Dogs With Collapsed Trachea; A Recent Study


Pinky and I are really bummed. We had about 5 posts about our dog patient's with the disease of Collapsed Trachea. But when we were putting up our new blog, we had to delete the old one because there was some sort of problem, and we didn't save our posts!

Boo Hoo.

So, we thought we would start again, but this time we are posting some very valuable information about a recent study about dogs that have a Collapsed Trachea.

Read it carefully because what it's saying is that Collapsed Trachea may be a infectious disease and not just a genetic problem.

That's what I say on my website because we help dogs with a Collapsed Trachea by giving herbs that clear toxic heat, with is a heat evil (germ).

Here is the study...I know that any information about this terrible condition is important to dog owners who have this awful problem.

Veterinary Radiology & Ultrasound

Volume 48 Issue 3 Page 199-203, May–June 2007

To cite this article: ANGELA MAROLF, MARGARET BLAIK, ANDREW SPECHT (2007)
A RETROSPECTIVE STUDY OF THE RELATIONSHIP BETWEEN TRACHEAL COLLAPSE AND BRONCHIECTASIS IN DOGS
Veterinary Radiology & Ultrasound 48 (3), 199–203.
doi:10.1111/j.1740-8261.2007.00229.x
Next Article
Full Text
A RETROSPECTIVE STUDY OF THE RELATIONSHIP BETWEEN TRACHEAL COLLAPSE AND BRONCHIECTASIS IN DOGS

* ANGELA MAROLF11Department of Small Animal Clinical Sciences, Veterinary Medical Center, University of Florida, 2015 SW 16th Avenue, PO Box 100102, Gainesville, FL,
* MARGARET BLAIK11Department of Small Animal Clinical Sciences, Veterinary Medical Center, University of Florida, 2015 SW 16th Avenue, PO Box 100102, Gainesville, FL,
* ANDREW SPECHT11Department of Small Animal Clinical Sciences, Veterinary Medical Center, University of Florida, 2015 SW 16th Avenue, PO Box 100102, Gainesville, FL

*
1Department of Small Animal Clinical Sciences, Veterinary Medical Center, University of Florida, 2015 SW 16th Avenue, PO Box 100102, Gainesville, FL

Address correspondence and reprint requests to Dr. Margaret Blaik at the above address. E-mail: blaik@mail.retmed.ufl.edu
Abstract

Tracheal collapse is common in middle age toy and miniature breed dogs. Cartilaginous defects have been identified histologically and are considered a form of chondromalacia. In addition to tracheal cartilaginous changes, concurrent lower airway histologic changes indicative of inflammation have been noted in dogs with tracheal collapse and these changes may lead to concurrent bronchiectasis. The purpose of this study was to investigate the prevalence of bronchiectasis in dogs with a previous radiographic diagnosis of tracheal collapse. The thoracic radiographs of 60 dogs with tracheal collapse were evaluated for evidence of concurrent bronchiectasis. Eighteen of 60 (30%) dogs had evidence of bronchiectasis, and all were cylindrical in morphology. The signalment of affected dogs was similar to that previously reported. The occurrence of bronchiectasis in this group of dogs with tracheal collapse (18 dogs) was six times higher (P<0.05) than the expected prevalence within a random sample population (three dogs). The results of this study provide evidence of a link between tracheal collapse and bronchiectasis. A finding of bronchiectasis with tracheal collapse should encourage further evaluation for chronic lower airway disease in these patients.
Introduction


Tracheal collapse is common in middle age Toy and Miniature breeds with a prevalence of 0.5–2.9%.1–8 Tracheal collapse is characterized by reduction in tracheal diameter due to a wide flaccid dorsal tracheal membrane and weakened cartilaginous rings.1,2,9 Compared with normal cartilage, tracheal cartilage from affected dogs is hypocellular, with decreased amounts of chondroitin sulfate, calcium, glycosaminoglycans, and glycoprotein.2,9 Cartilaginous defects may extend into mainstem bronchi and distal branching segments.3 These changes suggest a form of chondromalacia, but the specific etiology of cartilaginous changes associated with tracheal collapse is unknown. Furthermore, in some breeds such as Miniature and Toy poodles, Pomeranians, Yorkshire Terriers, Maltese, Pugs, and Chihuahuas, tracheochondromalacia may be a specific manifestation of a congenital systemic chondrodystrophy.1–3,5–7,9–11 Other breeds may also have a congenital chondrodysgenesis or may have acquired degeneration of cartilage.2,4

In addition to tracheal cartilage changes, concurrent small airway and pulmonary parenchymal histologic changes have been identified in dogs. These include epithelial desquamation, submucosal congestion, and submucosal neutrophilic and lymphocytic infiltration.5,6 These histologic changes may indicate common predisposing factors for tracheal collapse and small airway disease. In humans, congenital and acquired forms of tracheomalacia have been described.12–16 Most forms are congenital and occur early in life including Williams–Campbell syndrome, a congenital deficiency of cartilage, Larsen's syndrome, associated with laryngo- and bronchomalacia, and Mounier–Kuhn syndrome, characterized by atrophic or absent elastic fibers and thinning of tracheal muscle.14,17–19 Acquired tracheomalacia is commonly associated with excessive dynamic airway collapse and chronic obstructive pulmonary disease.12,16 Rarely, acquired tracheomalacia is secondary to relapsing polychondritis, characterized by inflammation and destruction of cartilage and other connective tissue.13,20,21 Bronchiectasis, irreversible dilation of diseased bronchi, is reported in congenital and acquired forms of tracheomalacia in humans.16–19,21

As extensive bronchial involvement and small airway disease are components of canine tracheal collapse, concurrent bronchiectasis is possible. Chronic irritation of the tracheal and bronchial epithelium from persistent coughing and airway collapse results in inflammation, epithelial desquamation, and hyperplasia of mucous glands.3,5,6 Together, these pathologic changes hinder mucociliary clearance and provide all of the necessary and classic predisposing factors for development of bronchiectasis.19 Long-standing inflammation of airways leads to destruction of elastic and muscular layers of bronchial walls and, subsequent, bronchial dilation.19

Thoracic radiographs are fundamental in the diagnosis of tracheal collapse and bronchiectasis. In dogs, thoracic radiographs are useful for detection of collapse of the trachea in 60–84% of patients, especially with the use of inspiratory and expiratory projections.3,8,11 However, the esophagus and other overlying structures can make delineation of the trachea at the thoracic inlet difficult.3,22 Fluoroscopy can allow detection of dynamic airway changes and is the diagnostic imaging modality of choice.1,10,8 Bronchoscopy can be used to evaluate the diameter of the trachea and bronchial segments and for grading luminal changes when radiographs or fluoroscopy are inconclusive, but this is associated with anesthetic risks.1,4,8 In humans and animals, thoracic radiographs are a first line diagnostic test for assessment of bronchiectasis, but may be insensitive for detection of early bronchiectatic changes.23,24 The radiographic appearance of bronchiectasis is characterized by nonspecific changes, including bronchial wall thickening and alveolar disease, along with cylindrical and saccular bronchial wall dilation.19,23,24

Coexisting bronchiectasis in patients with tracheal collapse may signal the presence of secondary infection or lower airway inflammation, warranting additional tests and therapy relative to the established treatment for tracheal collapse. The purpose of this study was to investigate the prevalence of concurrent bronchiectasis in dogs with a previous radiographic diagnosis of tracheal collapse.
Materials and Methods


A search for all dogs with a radiographic or fluoroscopic evidence of tracheal collapse diagnoses between January 1, 2005 through March 30, 2006 was performed using the Radiology Information System (RIS) at the University of Florida Veterinary Medical Center. Dogs were selected for study if a radiographic diagnosis of tracheal collapse was reported, and a complete set of radiographs were available (right or left lateral and ventrodorsal or dorsoventral projections).

Tracheal collapse was defined by subjective evaluation and objective measurement of tracheal diameter. Objectively, a ratio of tracheal diameter to thoracic inlet width <0.2 was considered narrowed.25,26 Demographic information collected included breed, age, gender, weight, reason for study, and evaluation of tracheal fluoroscopy if available. Locations of tracheal collapse included the caudal cervica regionl, thoracic inlet, and carina/mainstem bronchi. Radiographically, mild, moderate, and severe degrees of tracheal collapse were determined subjectively. However, a modified scale using grades of tracheal collapse observed on bronchoscopy was used, in which mild, moderate, and severe tracheal collapse was characterized by reductions in lumen size of 25%, 50%, >75%, respectively.3,4,8

Bronchiectatic lesions were characterized subjectively as cylindrical or saccular. Cylindrical bronchiectasis refers to dilation of bronchi with failure to taper peripherally. Saccular bronchiectasis refers to dilation of distal bronchi with rounded, cyst-like structures. No objective criteria have been documented regarding presence of bronchiectasis. The distribution of bronchiectatic changes were described as single lobe, multiple lobe (two or three lobes), or generalized (>3 lobes).

All images were digital computed radiographs* evaluated by two authors (AM and MB) at a single workstation.† Features consistent with tracheal collapse and bronchiectasis were assessed and decision reached by consensus. Identification of tracheal collapse and concurrent bronchiectasis was noted. The location and type of bronchiectasis was identified. Additionally, the degree and location of tracheal collapse in patients was evaluated in patients with bronchiectasis.

An exact binomial test was performed to determine if the proportion of bronchiectasis within the dogs with tracheal collapse was higher than what would be expected from a random sample.
Results

Location and Type of Bronchiectasis

Sixty dogs met the inclusion criteria. Bronchiectasis was identified in 18/60 (30%) of dogs. All dogs had cylindrical bronchiectasis (Fig. 1). Single lobe involvement was noted in 8/18 (44%) dogs with five of the eight involving the left or right cranial lung lobes. Multiple lobe involvement was present in 9/18 (50%) dogs, with the right cranial, right middle, right caudal, and left cranial lung lobes identified in equal numbers. A generalized pattern of bronchiectasis was identified in one dog.
Comparison of Bronchiectasis to Degree and Location of Tracheal Collapse

Eleven of 18 dogs (61%) with bronchiectasis had collapse of the cervical trachea. Two dogs (11%) with bronchiectasis had mainstem bronchial collapse. Five of the 18 (28%) dogs with bronchiectasis had radiographic evidence of both caudal cervical and mainstem bronchial collapse. As this was a retrospective study with thoracic radiographs as inclusion criteria, extra thoracic forms of tracheal collapse in the cranial cervical region would not be included in the field of view. So, inspiratory tracheal collapse was not addressed in this study.

Moderate and severe forms of cervical tracheal collapse were identified in 73% (11/15) of cases with bronchiectasis. Both cases of bronchial collapse and concurrent bronchiectasis were moderate to severe. Mild, moderate, and severe forms of tracheal and bronchial collapse were identified in the cases where both were present with concurrent bronchiectasis.

Given the prevalence of bronchiectasis to be 0.05,27 the occurrence of bronchiectasis in 18 dogs in our study is significantly higher (P<0.05) than the expected count of three.
Signalment

Of the 60 dogs with tracheal collapse, 20 breeds were represented (Table 1). The most commonly affected breed was the Yorkshire Terrier (Table 1). Dogs ranged in age from 1 to 16 years with a median age of 9 years. Fifty-four (90%) were small breed dogs (body weight ≤15 kg), and six were large breed dogs (body weight ≥15 kg). Twenty-nine dogs were female (28 neutered), and 31 were male (27 neutered).

Breeds affected with bronchiectasis were Yorkshire Terrier, Chihuahua, Miniature Poodle, Maltese, Pomeranian, Shi Tzu, Italian Greyhound, Beagle, Miniature Pinscher, and mixed breeds, were represented. Yorkshire terriers were most commonly affected (5/18 dogs) but this may be due to their overrepresentation in the study and not necessarily due a true increased incidence. Dogs with bronchiectasis ranged in age from 1 to 14 years with a median age of 9.7 years. XX (94%) were small breed dogs. Nine were female (eight neutered), and nine were male (eight neutered).
Reason for Study

Coughing was the most commonly listed clinical reason x/y dogs (53%) for obtaining thoracic radiographs. Other reported reasons were dyspnea, auscultation of crackles, or evaluation for metastasis or other systemic disease.
Fluoroscopic Evaluation

Nine of 60 (15%) dogs underwent radiography had digital fluoroscopy. In all dogs fluoroscopy confirmed the radiographic diagnosis. Three dogs had dynamic mainstem bronchial collapse not apparent radiographically.
Discussion


The signalment, breed distribution, and clinical signs of dogs in this study are similar to those previously reported for other dogs with tracheal collapse.1–5,7,10,11,22

Tracheal collapse and bronchiectasis were identified in 30% of dogs, which is significantly higher than would be expected in a random sample. In this study, 42 dogs had radiographic evidence of tracheal collapse without bronchiectasis while radiographs of the remaining 18 dogs were characterized by both conditions. An additional nine dogs with bronchiectasis, without concurrent tracheal collapse, were identified in the database during the same time period, confirming the paucity of dogs with this radiographic diagnosis. This provides circumstantial evidence for a link between tracheal collapse and bronchiectasis. However a definitive the relationship, if any, between tracheal collapse and bronchiectasis has not been determined. The majority of dogs with bronchiectasis in our study had moderate to severe tracheal and/or mainstem bronchial collapse.

A multifactorial etiology of tracheal collapse seems plausible.1,11,22 A functional tendency to tracheal collapse may be congenital in origin. However, exposure to aggravating factors, which exacerbate these tracheal cartilaginous changes, may lead to progressive cartilaginous degeneration until the patient develops clinical signs related to the tracheal collapse.5,11 This theory is supported by the breed predisposition and middle age presentation of dogs with tracheal collapse. These initiating factors could also contribute to the development of bronchiectasis through chronic airway inflammation. Decreased mucociliary clearance due to the congenital cartilaginous defects would augment the classic pathway for bronchiectasis and contribute to irreversible dilation of affected bronchi. Previously implicated initiating factors include inhalation of allergens or other irritating substances, congestive heart failure, obesity, and excessive barking.5,11 It is also possible that chronic lower airway disease may exacerbate tracheal collapse due to increased expiratory pressures.

The majority of affected lung lobes in the single bronchiectatic distribution group were either the left or right cranial lung lobe, which is consistent with the previously reported distribution of bronchiectasis.27 This distribution is likely due to the ventral position of these bronchi which allows gravity to compound the already compromised mucociliary clearance mechanisms.27 A multiple lobe distribution likely reflects progression of the overall condition through extension of inflammation to other bronchi.

In humans, acquired forms of central airway collapse can be associated with chronic obstructive pulmonary disease and have similar clinical findings as canine patients.13,16 Congenital forms of chondromalacia are associated with disorganized, hypocellular cartilage and/or atrophy or absence of elastic fibers in trachealis muscles.14,15,17,18 The apparent breed predisposition combined with the histochemical changes in dogs with tracheal collapse correspond to changes noted in the chondrodystrophic mice models in human chondromalacia suggesting a congenital component to the canine tracheal collapse syndrome.9,28

Bronchiectasis has been described as a rare concurrent condition with congenital and acquired forms of chondromalacia in people.13,17,21 In previous reports, bronchiectasis was diagnosed in 22–27% of human patients.13,21 In a prior retrospective study, 9/27 dogs with bronchiectasis had concurrent tracheal collapse.27 Similarly, 18/60 dogs had bronchiectasis and tracheal collapse in our study.

In human patients, inspiratory vs. expiratory computed tomography (CT) is gaining acceptance as a noninvasive way to detect expiratory tracheal collapse, other tracheal changes, concurrent lower airway and lung conditions such as bronchiectasis and emphysema.12,16,17 The sensitivity of CT has been reported at 80–88% for diagnosis of tracheal collapse when compared to bronchoscopy.12,21 Additional benefits of thoracic CT in diagnosis of tracheal collapse include evaluation of airways too small for bronchoscopy, pulmonary parenchymal changes, and tracheal or bronchial calcifications.12,21 The major CT criterion for diagnosis of tracheal collapse is reduction of tracheal lumen ≥50% at expiration or during coughing.12 Intubation and general anesthesia are the major disadvantages of inspiratory vs. expiratory CT in dogs. With short-acting injectable anesthetics and multislice CT scanners, diagnostic quality inspiratory vs. expiratory CT examinations may be possible in dogs.

CT is the imaging modality of choice for diagnosis of bronchiectasis in people.19,23,24 CT is reported to have between 84–90% sensitivity for diagnosing bronchiectasis.19,24 It is possible with the increased sensitivity of CT, that more dogs in our study would have had bronchiectatic changes than were found radiographically.

The overall etiology of tracheal collapse in dogs is unclear; however, a multifactorial condition is most likely. It remains to be determined if chronic inflammation leads to chondromalacia and, occasionally, bronchiectasis, or if congenital factors play the primary role in the manifestation of this condition. Bronchiectasis is considered uncommon in dogs, but the results of this study warrant further investigation into the link between tracheal collapse and bronchiectasis. A finding of bronchiectasis should also prompt consideration of other concurrent lower airway disease. Further evaluation of these patients to search for chronic lower airway disease may be indicated as treatment may change based on evidence of lower airway inflammation or infection.

There is no known common denominator between dogs which have both tracheal collapse and bronchiectasis and dogs which have only tracheal collapse or bronchiectasis. Future studies investigating the presence of coinciding lower airway inflammation or infection in dogs with tracheal collapse and bronchiectasis are necessary. Additionally, research into possible genetic and nongenetic links in these dogs would help elucidate the underlying etiology of tracheal collapse and bronchiectasis

A shortcoming of this study is that no control group, without evidence of tracheal collapse, of normal dogs or dogs with lower airway disease, was included for comparison. Additionally, the evaluators were aware of the diagnosis of tracheal collapse which may have contributed to bias. Although these limitations are present, they should not affect the overall intent of the study, which was to determine whether tracheal collapse and bronchiectasis were found in the same patient.
Footnotes

*Kodak© CR 800/900 Series, Eastman Kodak Co., Health Imaging Group, Rochester, NY.

†Kodak© DX Workstation System 5, Eastman Kodak Co., Health Imaging Group, Rochester, NY.
ACKNOWLEDGEMENTS


The authors would like to thank Dr. Nicole Gibson for her assistance with the statistical analysis of the data.
REFERENCES

1.
Padrid P, Amis TC. Chronic tracheobronchial disease in the dog. VCNA 1992;22:1203–1229.
2.
Dallman MJ, McClure RC, Brown EM. Normal and collapsed trachea in the dog: scanning electron microscopy study. Am J Vet Res 1985;46:2110–2115.
Medline, ISI
3.
Johnson L. Tracheal collapse: diagnosis and medical and surgical treatment. Vet Clin North Am 2000;30:1253–1266.
4.
Johnson LR, McKiernan BC. Diagnosis and medical management of tracheal collapse. Sem Vet Med Surg 1995;10:101–108.
5.
Suter PF, Lord PF. Thoracic Radiography: a textbook atlas of thoracic diseases of the dog and cat.
Switzerland
: Wettswill, 1984.
6.
Done SH, Drew RA. Observations on the pathology of tracheal collapse in dogs. J Small Anim Pract 1976;17:783–791.
Medline, ISI
7.
Spaulding GL. Medical management considerations for upper airway disease. Prob in Vet Med 1992;4:419–428.
Medline
8.
Tangner CH, Hobson HP. A retrospective study of 20 surgically managed cases of collapsed trachea. Vet Surg 1982;11:146–149.
ISI
9.
Dallman MJ, McClure RC, Brown EM. Histochemical study of normal and collapsed tracheas in dogs. Am J Vet Res 1988;49:2117–2124.
Medline, ISI
10.
O'Brien JA, Buchanan JW, Kelly DF. Tracheal collapse in the dog. J Am Vet Radiol Soc 1966;7:12–19.
Synergy
11.
White RA, Williams JM. Tracheal collapse in the dog—is there really a role for surgery? A survery of 100 cases. J Small Anim Pract 1994;35:191–196.
ISI
12.
Baroni RH, Ashiku S, et al. Dynamic CT evaluation of the central airways in patients undergoing tracheoplasty for tracheobronchomalacia. AJR 2005;184:1444–1449.
Medline, ISI
13.
Behar JV, Choi YW, Hartman TA, et al. Relapsing polychondritis affecting the lower respiratory tract. AJR 2002;178:173–177.
Medline, ISI
14.
Hoeve HJ, Joosten KF, Bogers AJ, et al. Malformation and stenosis of the cricoid cartilage in association with Larsen's syndrome. Laryngoscope 1997;107:792–794.
CrossRef, Medline, ISI
15.
McNamara VM, Crabbe DC. Tracheomalacia. Paed Respir Rev 2004;5:147–154.
CrossRef, Medline
16.
Wright CD, Grillo HC, Hammoud ZT, et al. Tracheoplasty for expiratory collapse of central airways. Ann Thorac Surg 2005;80:259–266.
CrossRef, Medline, ISI
17.
George J, Jain R, Tariq SM. CT bronchoscopy in the diagnosis of Williams–Campbell syndrome. Respirology 2006;11:117–119.
Synergy, Medline, ISI
18.
Schoor JV, Joos G, et al. Tracheobronchomegaly—the Mounier–Kuhn syndrome: report of two cases and review of the literature. Eur Respir J 1991;4:11202–11206.
19.
Luce JM. Bronchiectasis. In: Murray JF, Nadel JA. (eds): Textbook of respiratory medicine, 2nd ed.
Philadelphia
: WB Saunders Co, 1994;1398–1417.
20.
Staats BA, Utz JP, Michet CJ. Relapsing polychondritis. Sem in Resp Crit Care Med 2002;22:145–154.
CrossRef
21.
Tillie-Leblond I, Wallaert B, Leblond D, et al. Respiratory involvement in relapsing polychondritis: clinical, functional, endoscopic, and radiographic evaluations. Medicine 1998;77:168–176.
CrossRef, Medline, ISI
22.
Mason RA, Johnson LR. Tracheal collapse. In: King LG. (ed): Textbook of respiratory disease in dogs and cats, 1st ed.
St. Louis
: Saunders, 2004;346–355.
23.
Hansell DM. Bronchiectasis. Radiol Clin North Am 1998;36:107–128.
CrossRef, Medline, ISI
24.
Kumar NA, Binh N, Maki D. Bronchiectasis: current clinical and imaging concepts. Semin Roentgenol 2001;36:41–40.
CrossRef, Medline, ISI
25.
Harvey CE, Fink EU. Tracheal Diameter: analysis of radiographic measurements in brachycephalic and nonbrachycephalic dogs. J Am Anim Hosp Assoc 1982;18:570–576.
ISI
26.
Huber ML, Henderson RA, Finn-Bonder S, et al. Assessment of current techniques for determining tracheal luminal stenosis in dogs. Am J Vet Res 1997;58:1051–1054.
Medline, ISI
27.
Hawkins EC, Basseches J, Berry CR, et al. Demographic, clinical, and radiographic features of bronchiectasis in dogs: 316 cases (1988–2000). J Am Vet Med Assoc 2003;223:1628–1635.
CrossRef, Medline
28.
Houghton MJ, Carey JC, Seegmiller RE. Pulmonary hypoplasia in mice homozygous for the cartilage matrix deficiency (cmd) gene: a model for a human congenital disorder. Ped Pathology 1989;9:501–512.
Medline
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* CHRISTOPHER R. LAMB. (2007) LE





Pinky
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2 comments:

Briarwood Pups said...

How do I find out more about the herbs that you have used to help with collapsed trachea. This condition is in one of my dogs that if I had to categorize would have met the TCM description for wood, with excessive heat. She was highly vaccinated and fed Kibbles N Bits for 2 years before we got her. With higher quality kibble and then raw diet and supplements and some detox, we've seen drastic improvement, but in the past year she has developed a cough which was diagnosed as collapsed trachea. Am researching solutions for her. Thanks

Unknown said...

I believe one of my dogs has a collapsed trachea as well. She has had a progressively worsening cough over the last few months, and it seems with cases like her, the prognosis does not appear good. This type of problem appears to run in her family, but will still need to confirm with a vet. It would be great to have other options besides surgery, especially if multifactor origin is involved.