4-day-old male Arabian foal (Equus caballus).Foal was weak but ambulatory with expiratory dyspnea and tachypnea since birth and showed an elevated respiratory and cardiac rate and fever. Mucous membranes were hyperemic with multifocal petechiation of the oral mucous membranes and in the inner side of the pinna. The capillary refill time was less than 2 seconds. Pulmonary auscultation revealed snoring, wheezing, and crepitation with a diffuse and moderate alveolar pattern on thoracic radiographs. Supportive care and treatment, including positive pressure ventilation, were pursued without success and the foal was eventually euthanized.
Records indicate the horse to be in good body condition with multifocal petechia of the oral mucous membranes and in the inner aspect of the pinna. Bilaterally, the lung appeared markedly collapsed, were diffusely firm and heavy with an edematous consistency, and a reddish to gray discoloration.
Lung: Affecting all evaluated section there is a severe and diffuse thickening of alveolar septa as a result of moderate to intense hyperplasia of type II pneumocytes and mild septal inflammatory cells mostly lymphocytes, macrophages and neutrophils. In addition, the totality of alveolar, bronchial and bronchiolar lumens are markedly reduced (pulmonary atelectasis) with multifocal aggregates of hypereosinophilic, homogeneous and amorphous material (fibrin) covering the alveolar walls or partially filling the alveolar lumens, and occasionally, bronchial lumens (hyaline membranes). Abundant foamy macrophages with occasional multinucleated cells, neutrophils, cellular and nuclear debris and mild edematous fluid are seen within alveolar lumens admixed with aforementioned hyaline membranes.
Lung: Diffuse severe, subacute interstitial pneumonia with intra-alveolar and intra-bronchiolar hyaline membranes and diffuse severe pulmonary atelectasis.
No clinically significant alterations detected in the blood, including an adequate level of immunoglobulins.
Equine respiratory distress syndrome
findings observed in this case such as the presence of hyaline membranes in
alveolar and occasionally in bronchioles, as well as the severe and diffuse
pulmonary atelectasis and the widespread presence of hyperplastic type II pneumocytes
are compatible with the disease known as Neonatal hyaline membrane disease
also known as Respiratory Distress Syndrome (RDS).
syndrome is well recognized in premature or full-term foals but has not been
further investigated in this species. Affected foals have respiratory distress
from the time of birth, an expiratory grunt or
bark, hypoxemia, heart failure
and/or convulsions and opisthotonos.1 The lungs are diffusely
atelectatic, plum-red, rubbery, and sink or become partially submerged in
formalin.1 Histologically, in addition to the thickened
hypercellular alveolar septa expected in immature lung, hyaline membranes line
collapsed alveoli and sometimes the small bronchioles. Alveoli are edematous,
and cellular debris is occasionally noted.1 Also the pathogenesis is
not well established, is assumed that is occurs because of failure of the
immature type II pneumocytes to secrete functional surfactant or surfactant
dysfunction resulting in increased alveolar surface tension and alveolar and
small bronchioles collapse at the end of expiration.1 The tension
and shear stress imparted on the lung during reinflation of these collapsed
airspaces injures type I pneumocytes and club cells. 1
This condition has been investigated primarily in humans, piglets and calves, but it also has been documented in premature puppies, lambs and primates. A familial form of neonatal respiratory distress is described in piglets with congenital fetal hypothyroidism and possibly hypoadrenocorticism, as thyroid hormone is necessary for maturation of type II pneumocytes. Affected piglets have diffuse alveolar damage with hyaline membranes and bronchiolar necrosis, as well as features suggesting hypothyroidism, including mildly prolonged gestation, fine hair coat, generalized edema, and thyroid follicular hyperplasia with lack of colloid. Other contributing factors in all species are fetal asphyxia, aspiration of meconium in amniotic fluid, reduction in pulmonary arteriolar blood flow, and inhibition of surfactant by fibrinogen, other serum constituents in edema fluid, or by components in aspirated amniotic fluid. A similar condition is prevalent in cloned calves. In this case, the condition has also been associated with abnormalities of surfactant, but have not been adequately investigated in other species of domestic animals.
In humans, RDS is one of the main cause of respiratory distress in the newborn9 and occurs soon after birth, and worsens during the first few hours of life.9,11 Pulmonary edema plays a central role in the pathogenesis of RDS because of the excess lung fluid is attributed to epithelial injury in the airways, decreased concentration of sodium-absorbing channels in the lung epithelium, and a relative oliguria in the first 2 days after birth in premature infants. 9 Symptoms are similar than in domestic animals and include tachypnea, grunting, retractions and cyanosis.7,10 The disease progresses rapidly,5 with increased respiratory effort, intrapulmonary shunting, ventilation perfusion mismatch, and hypoxia with eventual respiratory failure.9,11 The risk of RDS is inversely proportional to gestational age; RDS occurs in approximately 5% of near-term infants, 30% of infants less than 30 weeks gestational age, and 60% of premature infants less than 28 weeks gestational age.9,11 Additional factors associated with development of RDS are male sex in Caucasians, infants born to mothers with diabetes, perinatal asphyxia, hypothermia, multiple gestations, cesarean delivery without labor, prematurity and presence of RDS in a previous sibling.6,9,10,11
The differential diagnosis of interstitial pneumonia in 1- to 4-month-old foals are bacterial or viral infections or treatment with erythromycin or other xenobiotics including 3-methylindole pyrrolizidine alkaloids and pentachlorophenol. Rhodococcus equi, or an aberrant response to that infection, is the main bacterial cause. Respiratory syncytial virus and equid herpesvirus 2 (EHV-2) are documented as the principal viruses for interstitial pneumonias. Other but less frequent causes are endotoxemia and Pneumocystis carinii infection. Because of the presence of severe and diffuse hyperplasia of type II pneumocytes and the multinucleated cells in the lumen of alveolus, we performed immunohistochemistry to eliminate equine herpesvirus infection. No immunopositive cells were seen in any of the sections evaluated.
Lung: Pneumonia, bronchointerstitial, necrotizing, diffuse, moderate, subacute with type II pneumocyte hyperplasia and marked atelectasis.
Pulmonary surfactant is not only important for initial
inflation of the lung, but for reinflation of the lung after end expiration as
well. It is 80-90% by weight composed of lipid with approximately 70% of this
in the form of dipalmitoylphosphtidylcholine.5 Surfactant lipids are
produced by Type II alveolar cells. This product, combined with surfactant proteins
(SP) A-D, (produced by club cells) provide the reduction in surface tension
required, but surfactant actually performs more functions in the lung.5
Surfactant proteins are also known as collectins, and are part of the innate
immune system.5 Bacteria, viruses and some fungi have surface
receptors for the lectin domains on the hydrophobic SPs A and D, allowing these
proteins to participate in clearance activities for the pathogens. In
addition, SP A and D also acts as immunomudulators, inhibiting allergen-induced
lymphoproliferation, dendridic cell matureation, and eosinophil release of
In 1929, German scientist Kurt von Neergaard performed the first investigations on surface tension in atelectatic porcine lungs, noting the intense pressures required to inflate the lungs for the first time, similar to a babyâs first breath.3 Fifteen years later, Dr. Peter Gruenwald, a New York pathologist, unaware of von Neergaardâs experiments, repeated them on the lungs of stillborn infants, noting that the resistance to inflation appeared to be the result in increased surface tension. In the early 1950s, three independent researchers in different countries (one of whom, John Clements, worked at the US Army Chemical Center in Edgewood, Maryland) independently identified surfactant while studying the effects of nerve gas on the lungs.3
A research fellow, at the Harvard School of Medicine, Dr.
Mary Avery, hearing of Clementâs research, visited him to learn about this new
surface film in the lung and devised a way to measure it in lung extracts
from babies dying soon after birth. Her publication,
Surface properties in
relation to atelectasis and hyaline membrane disease in 1959, noted that
it took 30 dynes of pressure to inflate the lungs of babies with hyaline
membrane disease versus only 8 dynes in babies dying of other causes. One of
the most high-profile infant deaths attributable to respiratory distress
syndrome was Patrick Bouvier Kennedy, last child of John F. Kennedy and
Jacqueline Kennedy, who died 39 hours after birth. 3
1972 proved to be a banner year for treatment of neonatal hyaline membrane disease the discovery by Howie et al. that the administration of corticosteroids to mothers at risk for preterm birth reduced preterm rates of RDS by stimulating surfactant synthesis.4 Finally, in the early 1980âs , independent testing with modified bovine and porcine surfactants showed great promise, with five different formulations being put into clinical trials: 1) old synthetic or protein free, 2) natural minced lung extracts, 3) natural lung lavage extracts, 4) natural amniotic fluid extracts, and 5) synthetic protein analogues.4 Today, prophylactic treatment with natural surfactants has been considered to decrease RDS by up to 50% and overall, neonatal mortality in the US by 6%.4
The moderator started off the conference with an admonition
to residents to review pulmonary slides (of which todayâs conference has four)
on a consistent basis, as well as reviewing the important segments of the lung
that bear review on each slide. He then reviewed five basic categories of
pneumonia - bronchopneumonia, interstitial, bronchointerstitial, embolic, and granulomatous,
and defined his rare usage of the simple term
pneumonia as a morphologic
diagnosis (when the precise location of the inflammation cannot be localized to
a particular segment).
This case generated spirited debate, and at the end of the discussion, we could not definitely identify equine respiratory disease as the cause of the histologic changes in this slide. While there was polymerized fibrin within alveoli, participants did not appreciate hyaline membrane formation. In addition, the distributed sections contained significant necrosis within terminal bronchioles, which was not described by the contributor. While these are non-specific findings, they are also reminiscent of the well-known entity of interstitial and bronchointerstitial pneumonia seen in foals from 1 week to 9 months, for which a single definitive cause has not been established.1 As mentioned by the contributor, possible causes for this syndrome includes viruses (RSV and EHV-2, aberrant responses to Rhodococcus equi or other common bacterial pathogens, surfactant dysfunction secondary to production of phospholipase A2 by alveolar macrophages, hyperthermia, or a variety of xenobiotics or toxins.
This slide was also reviewed by Dr. Kurt Williams, a subject matter expert in veterinary pulmonary pathology from Michigan State University. He agreed with our premise that the level of fibrin within the alveoli is not of the severity that one would expect with hyaline membrane disease and neonatal distress syndrome, but observed other changes in this particular slide that suggest a vascular reason for the notable changes. In this particular slide, there is significant increase in fibrous connective tissue of the pulmonary arterioles and "onion skinning" which suggests pulmonary hypertension. In addition, there is significant venous remodeling suggesting venous hypertension as well. Venous hypertension leads to an increase in pressure in pulmonary capillary pressure, which leads to the diffuse alveolar damage and fibrin exudation seen in this slide. In a young foal, this condition may result from significant cardiac disease, which was not described by the contributor. Intravascular pulmonary shunting might also result in concurrent arterial and venous hypertension. This was a very interesting case which answer lay beyond microscopic evaluation of the histologic specimen.
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8. McKenzie III HC. Disorder of foals. In: Reed SM, Bayly WM, Sellon DC ed. Equine Internal Medicine. 4th ed. St. Louis, MO: Elsevier; 2018: 1387-1391.
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