Koala retrovirus viral load and disease burden in distinct northern and southern koala populations

Koala retrovirus (KoRV) displays features of both an endogenous and exogenous virus and is linked to neoplasia and immunosuppression in koalas. This study explores the apparent differences in the nature and impact of KoRV infection between geographically and genetically separated "northern" and "southern" koala populations, by investigating the disease status, completeness of the KoRV genome and the proviral (DNA) and viral (RNA) loads of 71 northern and 97 southern koalas. All northern animals were positive for all KoRV genes (gag, pro-pol and env) in both DNA and RNA forms, whereas many southern animals were missing one or more KoRV genes. There was a significant relationship between the completeness of the KoRV genome and clinical status in this population. The proviral and viral loads of the northern population were significantly higher than those of the southern population (P

Genetic diversity of Koala retrovirus (KoRV) env gene subtypes: Insights into northern and southern koala populations

Koala retrovirus (KoRV) is a recently endogenised retrovirus associated with neoplasia and immunosuppression in koala populations. The virus is known to display sequence variability and to be present at varying prevalence in different populations, with animals in southern Australia displaying lower prevalence and viral loads than northern animals. This study used a PCR and next generation sequencing strategy to examine the diversity of the KoRV env gene in both proviral DNA and viral RNA forms in two distinct populations representative of the “northern” and “southern” koala genotypes. The current study demonstrated that the full range of KoRV subtypes is present across both populations, and in both healthy and sick animals. KoRV-A was the predominant proviral subtype in both populations, but there was marked diversity of DNA and RNA subtypes within individuals. Many of the northern animals displayed a higher RNA viral diversity than evident in their proviral DNA, indicating relatively higher replication efficiency of non-KoRV-A subtypes. The southern animals displayed a lower absolute copy number of KoRV than the northern animals as reported previously and a higher preponderance of KoRV-A in individual animals. These discrepancies in viral replication and diversity remain unexplained but may indicate relative protection of the southern population from KoRV replication due to either viral or host factors and may represent an important protective effect for the host in KoRV’s ongoing entry into the koala genome

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Health and Diseases of Koalas

The koala (Phascolarctos cinereus) is an arboreal marsupial that is found throughout much of eastern and southeastern Australia, and it relies primarily on eucalypt trees for food, water and shelter [...

Oxalate nephrosis in a population of South Australian koalas (Phascolarctos cinereus).

Renal disease had been reported to occur at high prevalence in the koala population of the Mount Lofty Ranges in South Australia, but the cause was unclear. Kidney crystals consistent with calcium oxalate had been observed in several koalas, suggesting that oxalate nephrosis may occur. The aims of this study were to describe renal pathological changes and confirm oxalate deposition in these koalas and also to investigate possible causes of disease. Oxalate nephrosis was found in 55% of 51 captive and rescued wild koalas from the Mount Lofty population. Renal histopathological changes associated with crystals included intratubular and interstitial inflammation, tubule dilation, glomerular atrophy, tubule loss and cortical fibrosis. Renal insufficiency was confirmed in affected koalas by azotaemia in association with poorly concentrated urine, and decreasing urine specific gravity was significantly associated with increasing severity of histopathological changes. The number of males and females, and captive and rescued wild koalas showing oxalate nephrosis was similar. Age was not found to be a predisposing factor, but many koalas <2 years old were affected. Urinary crystals in all koalas with oxalate nephrosis showed an atypical morphology for calcium oxalate. Hyperoxaluria was also found, suggestive of a primary cause for disease. To investigate whether a dietary cause existed for oxalate nephrosis in koalas, oxalate concentration was measured in juvenile, semi-mature and mature leaves from manna gum (E. viminalis), red gum (E. camaldulensis), SA blue gum (E. leucoxylon) and messmate stringybark (E. obliqua) in spring. Eucalypt leaves were found to be low in oxalate overall (<1% dry weight) with occasional samples that were higher in oxalate. Mount Lofty eucalypts were found to have higher oxalate content overall than those eaten by koalas in Moggill, Queensland, where the prevalence of oxalate nephrosis is lower. To investigate whether endogenous overproduction of oxalate could occur due to an inherited liver enzyme dysfunction, similar to primary hyperoxaluria type I in humans, the activity of alanine: glyoxylate aminotransferase (AGT) was measured in liver samples. Koalas with oxalate nephrosis showed no decrease in AGT activity compared with samples from unaffected Queensland koalas, indicating normal activity of this enzyme. Water content of eucalypt leaves was also measured, since dehydration is a key risk factor for renal calcium oxalate deposition. Mount Lofty eucalypt leaves were found to be lower in moisture in autumn compared with those in Queensland, particularly juvenile and semi-mature leaves of E. obliqua and E. leucoxylon. The pathological, histopathological and clinicopathological description of oxalate nephrosis in koalas provided by this study will assist veterinarians and pathologists in the diagnosis of this disease. Investigation of the pathogenesis of oxalate nephrosis in the Mount Lofty koala population found that neither high eucalypt leaf oxalate or decreased AGT activity were the primary cause. Further research is needed, but based on the low genetic diversity of the Mount Lofty koalas, an inherited pathogenesis of oxalate nephrosis remains likely. To decrease the risk of oxalate nephrosis, water supplementation should be provided for captive and wild Mount Lofty koalas during the hot, dry summer.Thesis (Ph.D.) -- University of Adelaide, School of Medical Sciences, 201

Cutaneous and Respiratory Lesions in Bushfire-Affected Koalas

In the wake of increasingly frequent bushfires emerging as a threat to wildlife worldwide, koalas have notably been the most rescued species in Australia. However, our understanding of burns and their severity in koalas is limited; hence, this study investigated the histopathological features and depth of burns in koala skin, as well as the presence of smoke-induced respiratory tract damage. In four bushfire-affected koalas that had been euthanised on welfare grounds, skin burns in various body regions were scored based on clinical appearance as superficial, partial thickness, or full thickness. Histological sections of affected regions of skin were assessed as Grades I–IV and showed that furred regions on the ear margins and dorsum were histologically more severe, at Grade III, compared with the clinical score. There was a similar finding for footpad burns, which were the most common body region affected. In the respiratory tract, pulmonary oedema and congestion were evident in all koalas. Overall, the results highlight that cutaneous burn lesions on furred and palmar/plantar surfaces can have higher severity based on the burn depth than is clinically apparent. Therefore, there is a need to consider this when developing treatment plans and establishing prognosis for burnt koalas at triage, as well as that a high likelihood of pulmonary oedema exists

Prevalence and clinical significance of koala retrovirus in two South Australian koala (Phascolarctos cinereus) populations

Purpose. Koala retrovirus (KoRV-A) is 100 % prevalent in northern Australian (Queensland and New South Wales) koala populations, where KoRV-B has been associated with Chlamydia pecorum disease and the development of lymphosarcoma. In southern populations (Victoria and South Australia), KoRV-A is less prevalent and KoRV-B has not been detected in Victoria, while the current prevalence in South Australian populations is unknown but is thought to be low. This study aimed to determine (i) the prevalence of KoRV in the two largest South Australian koala populations [Kangaroo Island (KI) and Mount Lofty Ranges (MLR)], (ii) KoRV subtype and (iii) if an association between KoRV and C. pecorum exists.Methodology. Wild koalas were sampled in KI (n = 170) between 2014 and 2017 and in MLR (n = 75) in 2016. Clinical examinations were performed, with blood collected for KoRV detection and typing by PCR.Results. KoRV prevalence was 42.4 % [72/170, 95 % confidence interval (CI): 34.9-49.8 %] in KI and 65.3 % (49/ 75, 95 % CI: 54.6-76.1 %) in MLR. Only KoRV-A, and not KoRV-B, was detected in both populations. In MLR, there was no statistical association between KoRV and C. pecorum infection (P = 0.740), or KoRV and C. pecorum disease status (P=0.274), although KoRV-infected koalas were more likely to present with overt C. pecorum disease than subclinical infection (odds ratio: 3.15, 95 % CI: 0.91-5.39).Conclusion. KoRV-A is a prevalent pathogen in wild South Australian koala populations. Future studies should continue to investigate KoRV and C. pecorum associations, as the relationship is likely to be complex and to differ between the northern and southern populations

An Analysis of Demographic and Triage Assessment Findings in Bushfire-Affected Koalas (Phascolarctos cinereus) on Kangaroo Island, South Australia, 2019–2020

In the 2019–2020 Australian bushfires, Kangaroo Island, South Australia, experienced catastrophic bushfires that burnt approximately half the island, with an estimated 80% of the koala population lost. During and after the event, rescued koalas were triaged at a designated facility and a range of initial data were recorded including rescue location and date, sex, estimation of age, body condition and hydration, and assessment of burn severity (n = 304 records available). Koalas were presented to the triage facility over a span of 10 weeks, with 50.2% during the first 14 days of the bushfire response, the majority of which were rescued from regions of lower fire severity. Burns were observed in 67.4% of koalas, with the majority (60.9%) classified as superficial burns, primarily affecting the limbs and face. Poor body condition was recorded in 74.6% of burnt koalas and dehydration in 77.1%. Negative final outcomes (death or euthanasia, at triage or at a later date) occurred in 45.6% of koalas and were significantly associated with higher mean burn score, maximum burn severity, number of body regions burnt, poor body condition score, and dehydration severity. The findings of this retrospective study may assist clinicians in the field with decision making when triaging koalas in future fire rescue efforts