INTRODUCTION

Orangutan respiratory disease syndrome (ORDS), first described in the literature in 2021, is defined as a chronic, progressive, self-perpetuating cycle of respiratory infection and inflammation in orangutans (Pongo sp).^24,35 Death ultimately occurs due to loss of respiratory function resulting from chronic structural change. ORDS is a leading cause of death and impacts approximately 20% of the captive orangutan population in North American and European zoos, as well as in multiple orangutan rescue and rehabilitation centers in range countries.^{11,20,22,34,41} The precise pathogenesis is still unknown and the contribution of genetic and/or environmental factors responsible for the susceptibility and chronicity of this disease unique to orangutans have yet to be firmly established.^{5,17,20,37,41}

Historical doctrine suggested that ORDS was initiated from infection in the upper airway which then progressed to the air sac, and finally caused fatal pathology in the lungs and airways.²⁰ However, our previous work demonstrated that while such a progression may occur, disease may begin anywhere in the respiratory tract and progress to affect any combination of regions of the tract.^24,35 Furthermore, previous approaches treated acute respiratory disease, even when recurrent, as isolated cases of airsacculitis, pneumonia or sinusitis.^{6,20,25,39,41} We argue that the acute cases are ‘episodes’, exacerbations of an ongoing, chronic respiratory disease.^23,24,35 Therefore, the treatment needs to address this condition. We defined the start of an exacerbation episode of ORDS as a new appearance of clinical signs that was not observed for at least 2 mon prior to the episode, which persisted and progressed for more than 3 d, and thus warranted the administration of an antibiotic with or without surgical treatment to clear the air sac accumulation of purulent material. An exacerbation was considered resolved when there was no record of the clinical symptom(s) for at least 2 mon. Past work has described the similarities between ORDS and the respiratory aspects of a genetic disorder disease in humans called cystic fibrosis (CF).³⁵–³⁷ We previously showed the positive efficacy of human bronchiectasis-based treatment protocols in early, acute ORDS cases.³⁵ In this case series, we present the positive efficacy of the long-term treatment protocols for ORDS in three chronically affected orangutans with various degrees of lung damage. Our protocol for long-term ORDS treatment consists of chronic combination therapy with low-dose azithromycin, nebulized salbutamol, and nebulized hypertonic saline, as well as an addition of 4 wk oral levofloxacin during an acute exacerbation.

CASE SERIES

Case 1

Case 1 is an adult male Bornean orangutan who was rescued from the wild at 3–4 yr old and has been cared for at the Borneo Orangutan Survival Foundation, Samboja Lestari campus (BOSF-SL) in East Kalimantan, Indonesia, for 24 yr. Case 1 was the most severe in this case series, with chronic disease leading to near end-stage lung pathology prior to the initiation of chronic therapy (Figure 1, top row). The animal had been observed with respiratory symptoms since 2013 at the age of 19 yr old (Table 1), with deep coughing and activity limitation as the most persistent symptoms. This animal had been seen expressing hiding behavior while holding his head with both hands, believed to indicate headache.

Figure 1.

Serial CT Scan images of head, neck, and thorax of Case 1 from 2016 to 2019. The first CT scan in 2016 (top row) showed the baseline condition before the start of ORDS long-term treatment. The right lung was so severely consolidated that it was not visible. The second CT scan in 2017 (middle row), taken after 3 months of long-term treatment, showed a dramatic improvement of the right lung. Bronchiectasis was well observed in both lungs. The third CT scan in 2019 (bottom row), taken after 24 months of long-term treatment, showed that the right lung was relatively unchanged since the previous scan, while there were some improvements on the consolidated area in the left lung.

Table 1.

Demographic and clinical summaries for Cases 1, 2, 3. All are adult male Bornean orangutans housed at the Borneo Orangutan Survival Foundation at Samboja Lestari (BOSF-SL).

Before the initiation of a long-term drug regimen, Case 1 had experienced multiple exacerbations with prolonged respiratory symptoms between 2013 and 2016.   Supplemental Table 1 (Supplemental Table 1 revised.pdf) provides a detailed timeline of symptoms and treatments. In addition to coughing, mucopurulent nasal discharge and air sac purulent material accumulation/drainage were also noted. This animal had five air sac marsupialization surgeries in 4 yr (  Supplemental Table 1 (Supplemental Table 1 revised.pdf)). Following each procedure, the veterinarians conducted additional air sac flushing procedures under general anesthesia every 3–28 d to aid in the clearance of purulent debris.

The first CT scan was conducted in the fourth year of disease progression (October, 2016). The animal was anesthetized using a combination of zoletil (Virbac, Carros 06516, France; 3mg/kg IM), ketamine (Troy Laboratories Pty Ltd, New South Wales 2761, Australia; 4mg/kg IM), and xylazine (Troy Laboratories Pty Ltd, New South Wales 2761, Australia; 0.75mg/kg IM). The animal was intubated and maintained with isoflurane (Piramal Pharma Limited, Telangana State 502321, India) to effect. Intermittent positive pressure ventilation (IPPV) was used as needed to maintain end-tidal CO₂ levels within physiologic range. CT imaging was conducted with the animal in dorsal recumbency. Head, neck, and chest were scanned using a Toshiba Asteion 4 CT scanner, 2009 model CXXG-010A, minimum capacity 135kV, 260mAS (Canon Medical Systems Corporation, Tustin, CA 92780, United States), without contrast. The results showed maxillary and sphenoid sinusitis, bronchiectasis and extensive consolidation in the right lung, and bronchiectasis, consolidation, and abscess in the left lung. Mastoiditis and airsacculitis were not observed. Following short-term treatment with azithromycin 400mg (PT Kimia Farma, Jakarta Pusat 10110, Indonesia) for 3 wk and nebulized salbutamol 2.5mg (GlaxoSmithKline Australia Pty Ltd, Victoria 8003, Australia) q12h using a PARI e-flow nebulizer (PARI Pharma GmbH, Starnberg 82319, Germany) for 8 wk, some improvements of the clinical symptoms were recorded, but the animal still showed heavy breathing and occasional coughing. In August 2017 azithromycin was reinitiated long-term. Evaluation CT scan at month 3 of long-term treatment showed improvement of the right maxillary sinusitis, resolution of sphenoid sinusitis, and improvement of airway disease, pneumonia, and lung consolidation bilaterally. Overall, the visibility of both lungs' structure, especially the right lung, increased dramatically. Following two more exacerbations (at months 7 and 10), nebulized salbutamol and nebulized hypertonic saline 4ml (3% PT. Otsuka Indonesia, Malang 65216, Indonesia, or 7% PARI Respiratory Equipment, Inc., Virginia 23112, USA, depending on availability) q12h were added to the long-term treatment regimen.

Based on the presence of marked right lung bronchiectasis, Case 1 is expected to have lifelong recurrent exacerbations. Consequently, it has experienced a total of five exacerbation episodes during the first five years of chronic therapy. Nevertheless, clear improvement has been noted not only in CT scan assessment, but also in clinical observations (Figures 1 and 2). The last checkup CT scan was conducted 2 yr after the start of chronic treatment and showed unchanged mild maxillary sinusitis and airway disease in both lungs, but improvement in the consolidation of the left lung (Figure 1, bottom row). The exacerbations were significantly milder and shorter compared to the ones before chronic treatment was initiated. Additionally, after chronic therapy began, Case 1 had the longest symptom-free period (17 mon) since the onset of ORDS. The last exacerbation to date was recorded after a temporary supply-related halt of azithromycin during the peak of the COVID-19 pandemic in Indonesia in 2021. As of December, 2022 Case 1 has been on azithromycin, nebulized salbutamol, and nebulized hypertonic saline for 65, 52, and 52 mon, respectively (excluding a 12-wk gap of azithromycin in 2021) and has been symptom-free for 13 mon (  Supplemental Table 1 (Supplemental Table 1 revised.pdf)).

Figure 2.

Color coded timeline of ORDS in Case 1 (top box), Case 2 (middle box), Case 3 (bottom box). Each cell represents one month. As explained in the legend at the bottom of the figure, each color represents either an observed clinical condition, treatment, surgery, or CT scan that occurred/was conducted in that month. This figure shows the period of 2013-2022, however Case 2 had the history of ORDS since 2010, which details can be referred to in the   Supplemental Table 2 (Supplemental Table 2 revised.pdf). The chronic ORDS treatment period is marked by the long continuous rows of red (Azithromycin), orange (nebulized Salbutamol), and beige (nebulized hypertonic saline) cells. Corresponding to the long-term treatment period, it can be observed that there were much fewer blue cells that represented appearance of clinical signs.

Case 2

Case 2 is an adult male Bornean orangutan who was rescued from the wild as an infant and has been cared for at BOSF-SL for 24 yr (Table 1). This animal was first diagnosed with an episode of an acute respiratory infection in 2010 at the age of 13 yr. The animal experienced 4 more episodes of respiratory infection (  Supplemental Table 2 (Supplemental Table 2 revised.pdf)) before the ORDS diagnosis was established in August 2018 (month 1). From 2010 to July 2018, the animal also had two air sac marsupialization surgeries, followed by the repeated drainage procedures. In contrast with Case 1, Case 2 did not experience prolonged respiratory symptoms; however, the medical history clearly showed that observations of respiratory symptoms increased in frequency over the 2010–2018 period (Figure 2 and   Supplemental Table 2 (Supplemental Table 2 revised.pdf)).

Case 2 had 4 CT scans during the course of his illness. The animal was anesthetized as described for Case 1 and CT imaging was conducted with the animal in dorsal recumbency. The first CT scan, conducted in year 7 after the first respiratory episode, revealed left maxillary sinusitis, left mastoiditis, right lung pneumonia, and bilateral airway disease with bronchial wall thickening and mild bronchiectasis (Figure 3, top row). The regimen for an acute ORDS episode as described in previous work³⁵ was given for 8 wk (  Supplemental Table 2 (Supplemental Table 2 revised.pdf)). An evaluation CT scan conducted eight months later showed resolution of the sinusitis, as well as improvement of the mastoiditis, airway wall thickening, mucus plugging, and pneumonia (Figure 3, row two.)

Figure 3.

Serial CT Scan images of head, neck, and thorax of Case 2 from 2016 to 2019 (top to bottom row). The 2016 and 2017 CT scan results had been published in Sriningsih & Lung et al, 2021³⁵ as a representation of a baseline condition (pre-treatment) and after an acute treatment, respectively. In this manuscript we followed up the case to 2018 scan where it showed re-appearance of bilateral pneumonia (third row), 18 months after completion of the acute treatment. Responding to this, a long-term treatment of azithromycin was initiated. A follow up CT scan in 2019 in month 18 of the treatment again showed improvement in the airway wall thickening and mucus plugging (bottom row).

However, a follow up CT scan conducted a year after the end of treatment revealed persistent airway wall thickening and mild pneumonia (Figure 3, third row), although it was not apparent on clinical observation. In response to another exacerbation, a chronic treatment regimen of azithromycin 400 mg (PT Kimia Farma, Jakarta Pusat 10110, Indonesia) 3x per week was initiated. The added combination of nebulized salbutamol 2.5 mg (GlaxoSmithKline Australia Pty Ltd, Victoria 8003, Australia) q12h and nebulized hypertonic saline 4ml (3% PT, Otsuka Indonesia, Malang 65216, Indonesia, or 7% PARI Respiratory Equipment, Inc., Virginia 23112, USA) q12h was introduced gradually through positive reinforcement training. Following the initiation of chronic therapy, Case 2 was clear from respiratory symptoms for 39 consecutive months. As shown in Table 1 and Figure 2, this prolonged symptom-free period contrasts with the pre-chronic therapy clinical status when the animal experienced an average of four mon per year with visible respiratory symptoms (ranging from 1–8 mon per year).

At the end of December 2022, Case 2 has been on azithromycin, nebulized salbutamol, and nebulized hypertonic saline for 53, 41, and 36 mon respectively (excluding a 12-wk gap of azithromycin in 2021). A final CT scan performed in 2019 showed that the air sacs were clear, with persistence of minimal sinus and airway disease and mild residual infiltrate in the right lower lobe and the mastoid air cells (Figure 3, bottom row). Unfortunately, CT availability ended for all cases in 2019, so no additional CT data is available. Since the initiation of chronic therapy, Case 2 has had only one exacerbation (November 2021), following a temporary 12-week hiatus in azithromycin administration due to the scarcity of the drug during the peak of COVID-19 pandemic in Indonesia in mid-2021.

Case 3

Case 3 is an adult male Bornean orangutan who was rescued from the wild as an infant and has been cared for at BOSF-SL for 23 years. Respiratory symptoms had been observed in Case 3 since 2014 at the age of 16 yr old (Table 1). Before the initiation of the chronic ORDS treatment, Case 3 had experienced three exacerbations and one air sac marsupialization surgery (  Supplemental Table 3 (Supplementary Table 3 revised.pdf) and   Figure 2 (Supplemental Figures revised.pdf)). Similar to Case 2, Case 3's medical history clearly showed progression of frequency of observed respiratory symptoms over the years, and similar to Case 1, Case 3 also had a prolonged episode of respiratory infection lasting 11 mon. The most prominent symptoms were nasal discharge, accumulation of purulent material with drainage from the air sac, and audible breathing.

Case 3 had three CT scans during the course of his illness. For each scan the animal was anesthetized as described for Case 1 and CT imaging was conducted with the animal in dorsal recumbency. The first CT scan was performed at 2.5 yr after onset of respiratory signs (2016) and revealed mild airsacculitis, mild bilateral lower lobe pneumonia, and bilateral mild bronchiectasis with extensive mucus plugging (Figure 4, top row). Images of the mastoid air cells were not available from this scan, so the status of the mastoids is unknown. The antibiotic combination regimen for acute ORDS,³⁵ was given for a total of 12 wk (see   Supplemental Table 3 (Supplementary Table 3 revised.pdf) for detailed timeline and drugs). The animal continued to display clinical symptoms of mucopurulent nasal discharge and heavy breathing, although the follow up CT scan showed resolution of the pneumonia, and improvement in the airway disease. Mild airsacculitis persisted and mastoiditis was noted (Figure 4, middle row).

Figure 4.

Serial CT Scan images of head, neck, and thorax of Case 3 in 2016 (top row), 2017 (middle row), and 2018 (bottom row). The first scan, which was the baseline condition of the animal before treatment, showed bilateral bronchiectasis and mucus plugging. The second scan in 2017 showed resolution of the pneumonia, however the bronchiectasis persisted. Bilateral mastoiditis was also observed. The last scan in 2018, month 13 of the long-term treatment, showed clear lungs with permanent bronchiectasis and persisted mastoiditis.

In late 2017, the long-term drug combination regimen was initiated gradually because it was also necessary to simultaneously begin positive reinforcement training for the animal to comply with the nebulization. First, nebulized salbutamol 2.5mg (GlaxoSmithKline Australia Pty Ltd, Victoria 8003, Australia) q12h began (month 1), followed with oral azithromycin 400 mg (PT Kimia Farma, Jakarta Pusat 10110, Indonesia) q24h 3x/week (Monday, Wednesday, Friday) in month 3, and lastly nebulized hypertonic saline, which has a “salty” taste that may initially impede acceptance (3% PT. Otsuka Indonesia, Malang 65216, Indonesia, or 7% PARI Respiratory Equipment, Inc., Virginia 23112, USA), q12h was added in month 10. Clinical symptoms resolved on month 4, and the animal was symptom-free for the next 25 months, the longest symptom-free period observed since onset of disease (Figure 2). A third CT scan performed in month 13 showed resolution of rhinitis, unchanged bilateral mastoiditis, improved airsacculitis, and marked improvement in airway wall thickening and mucus plugging (Figure 4 bottom row).

During chronic therapy, Case 3 had five more exacerbations in the span of 5 yr, although each episode was significantly shorter than those pre-chronic treatment initiation (  Supplemental Table 3 (Supplementary Table 3 revised.pdf) and   Figure 2 (Supplemental Figures revised.pdf)). Like Cases 1 and 2, Case 3 experienced an exacerbation in month 46 after a temporary halt of azithromycin availability during the COVID-19 peak pandemic in Indonesia in 2021. Further, there was one more mild exacerbation at month 52. As of the end of 2022, Case 3 had been on azithromycin, nebulized salbutamol, and nebulized hypertonic saline for 57, 61, and 52 months respectively and has been symptom free for 9 mon (  Supplemental Table 3 (Supplementary Table 3 revised.pdf)).

DISCUSSION

This case series describes the recurrent and chronic respiratory episodes associated with ORDS in three adult Bornean orangutans (  Supplemental Tables 1 (Supplemental Table 1 revised.pdf),   2 (Supplemental Table 2 revised.pdf), and   3 (Supplementary Table 3 revised.pdf)). These animals are wild-caught orangutans that were confiscated by or dispatched to the BOSF-SL rehabilitation center in East Kalimantan, Indonesia during the 1990s when they were aged between ten months to five years. During their residence at the BOSF center, they have been housed in a variety of enclosures, ranging from group cages with daily access to outdoor forests (forest school), to permanent individual outdoor cages where they are currently housed (  Supplemental Figure 1 (Supplemental Figures revised.pdf)). All orangutans at BOSF-SL are screened for tuberculosis every 1–2 years using a combination of thoracic radiography and submission of bronchoalveolar samples for acid fast staining, mycobacteria culture, and polymerase chain reaction (PCR). All three animals included in this case series have been tuberculosis-free throughout their time at BOSF.

CT scans were conducted on all animals prior to initiation of long-term treatment to confirm both the diagnosis of ORDS and the degree of baseline structural lung damage.¹⁴ Pneumonia and bronchiectasis were confirmed in all three cases. All of them also had airsacculitis, which the authors observed can be missed on CT scan when the flushing procedure has been done shortly before the scan.

ORDS was not recognized as a clinical entity until 2016. Prior to that time, respiratory disease in orangutans was diagnosed and treated as isolated episodes of disease,^6,20,28,35 which was the situation for Cases 1, 2 and 3. Clinical signs recorded in the animals' medical records include coughing, prolonged rhinorrhea with clear to thick nasal discharge, accumulation of purulent material in the air sac, and behavioral signs of headache. These symptoms were often accompanied by systemic signs such as fever, lethargy, and weight loss. Airsacculitis, arguably the most prominent sign of a respiratory infection, was managed with short term (7–21 days) courses of antibiotics and marsupialization surgery to clear the accumulation of purulent material from the sac. Following each marsupialization surgery, periodic air sac flushing was conducted for up to six procedures. These treatments provided only temporary relief and posed significant risk to already compromised animals. Signs predictably reappeared,^20,28 supporting our contention that airsacculitis can present as a sign of the more diffuse and chronic disease process.²⁴

Once bronchiectasis is established in the lungs, human patients experience alternating episodes of stable symptoms and acute exacerbations over their lifetime, with frequency and intensity dependent on baseline severity of disease.² As airway destruction progresses, exacerbations become more frequent and/or severe, ultimately resulting in respiratory failure. The three orangutans in this case series were confirmed to have bronchiectasis and demonstrated comparable symptoms to humans, therefore their therapeutic management was tailored to follow well-established human bronchiectasis protocols.^26,29 The goals of chronic therapy are to reduce the progression of airway destruction by controlling the chronic infection and inflammation.

The combination treatment used in the orangutans of this case series was based on the medical treatment for pancreatic-sufficient CF in humans.³¹ The first component of chronic ORDS treatment^24,29 includes lifelong use of oral azithromycin as an anti-inflammatory^{1,2,7,9,32,33} combined with nebulized salbutamol followed by nebulized hypertonic saline administered twice daily.^12,15,30,42 Per standard CF protocols, long-term azithromycin is effective in humans with bronchiectasis when administered as 250mg PO q24h or 500mg PO 3x/wk. Nebulization of salbutamol is performed to dilate the muscles in the airways in order to prevent bronchospasm during administration of the second nebulized drug,⁴² hypertonic saline, which is used to hydrate the airway mucociliary surface and therefore increase mucus clearance.¹⁵ In this case series, nebulization treatment (  Supplemental Figure 2 (Supplemental Figures revised.pdf)) demonstrated great improvement in relieving the animals' respiratory signs and symptoms. Copious drainage of nasal secretions and productive coughing and sneezing often occur during the nebulization. This drainage presumably relieves sinus pressure and assists with airway clearance. In the authors' experience, the orangutans demonstrate visibly relaxed breathing patterns and improved drainage immediately following nebulization.

The second component of chronic ORDS treatment is the addition of a 4–8 wk course of a broad-spectrum antibiotic administered during an acute exacerbation of clinical disease. Levofloxacin 500 mg PO q24h is a preferred antibiotic to cover for common gram positive and gram negative bacteria associated with these episodes in orangutans.^24,35 Other commonly used antibiotics include doxycycline 100 mg PO q12h, nebulized colistin 77 mg q12h, nebulized tobramycin 160 mg q12h, or meropenem 500 mg IM q12h.

On average, the three animals in this series have been on oral azithromycin for 56.3 mon (50–62 mon), on salbutamol/albuterol nebulization for 51.3 mon (41–61 mon), and on hypertonic saline nebulization for 46.7 mon (36–52 mon). Prior to the chronic ORDS treatment, the orangutans in this case series experienced years in which they were more often sick than not (Figure 2 and Table 1). For example, in the years 2013, 2015, and 2017, Case 1 had 7-9 mon each year when he suffered from respiratory infection symptoms (Figure 2). This exacerbation frequency and duration is in contrast with the animal's disease state after chronic ORDS treatment in which he was observed to manifest symptoms for 0–3 mon per year from 2018 to 2022. In fact, following the initiation of chronic ORDS treatment, the three animals experienced an average of 1.1 mon per year of exacerbation periods compared to an average of 5.4 mon prior to initiation of chronic therapy.

Based on numerous positive clinical trials and meta-analyses demonstrating efficacy, the use of azithromycin in chronic treatment to decrease the frequency of exacerbation in human cystic fibrosis and non-CF bronchiectasis is now considered standard of care.^{3,9,19,21,32,33,38,40} The anti-inflammatory effect of azithromycin is far more important that its antibiotic modality.⁹ Although some clinicians have expressed concern about its chronic use promoting the development of antibiotic resistance, multiple studies on the use of chronic azithromycin have not demonstrated clinically important resistance.^8,16,27,40

CT scan following long-term treatment showed improvement throughout the respiratory tract in all three orangutans as expected. Given the animals' severe baseline disease, chronic structural pulmonary changes remain notable despite ongoing therapy. Once structural damage to the airway walls is at an advanced stage, such as was seen in Case 1, the damage is likely irreversible (Figure 1). Recent studies in human patients have shown, however, that when airway disease is identified in the early stages, the damage is potentially reversible.^10,13,18 This possibility highlights the importance of early detection and effective treatment of ORDS, in hopes of altering the course of disease and halting the progression of structural change. Case 1 demonstrates that airways with severe permanent damage can still receive great benefit of chronic therapy and that the patient can experience greatly improved quality and length of life.

Previous literature and historical doctrine hypothesize that chronic respiratory disease in orangutans is initiated from an airborne upper respiratory tract infection which then seeds the air sac and finally the lungs.²⁰ However, Case 3 in this series had normal sinus imaging on initial CT scan, but nonetheless had airsacculitis and lower airway disease including chronic pneumonia and bronchiectasis (Figure 4). This case and several others in the authors' experience demonstrate that the ORDS initial symptoms and infection can begin in and migrate to any area of the respiratory tract in any order.^24,35

Previous study suggests that Bornean orangutans are more likely to be affected by ORDS than Sumatran orangutans.⁴¹ Anecdotally, it seems true in the population of orangutans in rescue centers in Indonesia where there are more ORDS cases reported in centers in Borneo than in Sumatra. However, this interpretation could be biased by the fact that there are less orangutan centers in Sumatra than in Borneo. Investigations into specific genetic mutations is ongoing.³⁷

This case series provides the strongest evidence that when left untreated, respiratory infection in orangutans may progress from mild symptoms (chronic nasal discharge or occasional cough) to a severe, life-threatening condition (bronchiectasis and pneumonia). Often runny noses are managed as chronic allergies when they actually represent a visible sign of underlying disease. Because disease progression is quite slow, affected animals could be in a negative welfare state for extended periods, from years to decades. Thus, consistent with our previous observations, CT scan is critical in diagnosing ORDS as well as for monitoring the progress of the disease.^4,24 Even with unrecognized or minimal clinical symptoms, all three animals in this case series were shown to have clinically important abnormalities in their mid and lower respiratory tract ranging from airway wall thickening and mucus plugging to bronchiectasis, pneumonia, and airsacculitis. Critically, if CT scan had not been available, the severity of each animal's disease would have been under-recognized. These “silent cases” likely demonstrate the animals' chronic adaptation to their slowly progressive respiratory deterioration over years.

In conclusion, acute episodes of respiratory illness in orangutans that have previously been treated as isolated incidents should be approached differently. More recent data suggests that a notable proportion of orangutans experience acute exacerbations that represent an escalation of a chronic respiratory condition. This case series describes improvements in ORDS cases that were treated with the chronic therapies used in humans with CF. However, our understanding of ORDS is still evolving and future refinements of these recommendations for prevention and treatment are likely over time, as more animals are studied over longer time periods. To ensure the health and future existence of this critically endangered species, continued research on the etiology, predisposing factors, and management of ORDS in captive orangutans is critical.