SODIUM IODIDE AS A PREVENTIVE STRATEGY FOR RESPIRATORY DISEASE IN PRE-WEANED DAIRY CALVES

• Sponsoring Institution: National Institute of Food and Agriculture
• Project Status: TERMINATED
• Funding Source: ANIMAL HEALTH
• Reporting Frequency: Annual
• Accession No.: 1009815
• Project No.: CALV-AH-346
• Project Start Date: May 31, 2016
• Project End Date: Jun 30, 2017

Project Director
Heller, ME.

Recipient Organization
UNIVERSITY OF CALIFORNIA, DAVIS
410 MRAK HALL
DAVIS,CA 95616-8671

Performing Department
Medicine & Epidemology

Non Technical Summary
Bovine respiratory disease (BRD) is an important cause of animal welfare issues and economic losses in dairy production worldwide. The 2011 NAHMS study found that 18% of pre-weaned heifers are affected by respiratory disease and 16.4% receive antimicrobials. Decreasing pneumonia in pre-weaned heifers would lead to better health and welfare of these animals and reduced antimicrobials usage. NaI is safe, economical and easy to administer. The overall goal of this study is to investigate the potential for NaI in preventing respiratory disease in pre-weaned dairy calves. Two knowledge gaps exist; the kinetics of iodine in airway fluid following oral supplementation of pre-weaned calves, and whether strategically timed NaI supplementation can decrease respiratory disease in a production setting.Scientific evidence of decreased respiratory disease in dairy calves would have positive effects on animal health, economy, antimicrobial stewardship and food safety.

Animal Health Component

100%

Research Effort Categories

Basic

50%

Applied

(N/A)

Developmental

50%

Classification

Knowledge Area (KA)	Subject of Investigation (SOI)	Field of Science (FOS)	Percent
311	3410	1090	80%
315	3410	1090	20%

Knowledge Area
311 - Animal Diseases; 315 - Animal Welfare/Well-Being and Protection;

Subject Of Investigation
3410 - Dairy cattle, live animal;

Field Of Science
1090 - Immunology;

Keywords

bovine respiratory disease

sodium iodide

pre-weaned dairy calves

pneumonia

Goals / Objectives
Problem: Innate airway defenses are crucial to preserving the health of bovine lungs. Stress, coupled with viral infections, compromises natural host defenses and allow bacteria to reach the lower airways and cause pneumonia. Innate defenses include airway mucus and ciliated epithelium, that trap and physically remove pathogens from the respiratory tract, and secreted antimicrobial peptides that neutralize pathogens. An additional mechanism of innate airway defense system has been described in cattle; it consists of lactoperoxidase (LPO), hydrogen peroxide (H2O2), and halide ions [1]. Lactoperoxidase catalyzes the oxidation of halide ions using hydrogen peroxide to form potent antimicrobial products. Typically, thiocyanate serves as the physiologic substrate for this reaction but our recent work has shown potent antiviral and antibacterial properties of hypoiodous acid, the product of iodide ion oxidation by LPO and hydrogen peroxide, in vitro [2-4]. The LPO/H2O2/iodine system could be a powerful preventative strategy to augment innate airway defenses and prevent airway acquired infections. Additional work by our group has shown that oral dosing of adult cattle with Sodium Iodide (NaI) achieves concentrations of Iodide in airway secretions that correspond to effective concentrations in vitro and that these levels persist for at least 72 hours after a single dose [5].The overall goal of this study is to investigate the potential for NaI in preventing respiratory disease in pre-weaned dairy calves. Two knowledge gaps exist; the kinetics of iodine in airway fluid following oral supplementation of pre-ruminant calves, and whether strategically timed NaI supplementation can decrease respiratory disease in a production setting.Justification: BRD is an important cause of animal welfare issues and economic losses in dairy production worldwide. The 2011 NAHMS study found that 18% of pre-weaned heifers are affected by respiratory disease and 16.4% receive antimicrobials. Decreasing pneumonia in pre-weaned heifers would lead to better health and welfare of these animals and reduced antimicrobials usage. NaI is safe, economical and easy to administer. Scientific evidence of decreased respiratory disease in dairy calves would have positive effects on animal health, economy and food safety.HYPOTHESES1. Oral administration of NaI increases levels of iodide in respiratory fluids of pre-weaned dairy calves.2. Oral administration of NaI results in decreased treatments for respiratory disease in pre- weaned dairy calves.SPECIFIC OBJECTIVES1. To determine the kinetics of iodine in airway fluid following oral administration of two different doses of NaI, based on a small population of dairy calves.2. To determine whether calves receiving oral NaI receive significantly fewer treatments for respiratory disease as compared to control calves, and to determine if NaI causes a change in airway pathogen profile.

Project Methods
Objective 1: To determine the kinetics of iodine in airway fluid after oral administration of NaI we will enroll 6 pre-weaned calves in a randomized crossover design. They will have baseline airway fluid samples collected prior to receiving a single dose of 10mg/kg or 20mg/kg of NaI in their milk (via bottle). Serial samples of upper airway secretions will be collected 2 hours post administration and every 12 hours after that for 72 hours. If a calf fails to consume their meal, the remainder will be fed via orogastric tube. After a wash out period the groups will be switched and the trial re-run at the new dose. NaI is routinely used in cattle for the treatment of Actinomyces bovis at a dose of 70mg/kg, which causes signs of iodonism in some animals. We chose the low doses for this trial because of its proximity to a human dose (Fischer et al., 2011), and to avoid any signs of toxicity. If calves should fail to generate a sufficient concentration of Iodine in airway fluids in order to inactivate pathogens, the dose will be increased and the experiment repeated. Blood and feces will also be collected at each time point. Samples will be stored at -80°C until evaluated for iodine content by the Michigan State University Diagnostic Center for Population and Animal Health. Peak concentration and half-life of iodine will be evaluated in airway fluids. Animals will also be monitored for any adverse effects of NaI including signs of toxicity (diarrhea, anorexia, hair loss, hypersalivation etc.)Objective 2: Dairy calves at a heifer raising operation will be enrolled at 21 days of age and randomly assigned to treatment or control groups. On this farm, cases of pneumonia start at 3 weeks and peak at 4 weeks with on average 15% of the calves affected. A minimum of 540 animals per group was determined as the necessary sample size needed to detect a reduction of BRD morbidity from 15% to 10% with a confidence level of 95% and a power of 80%. The treatment group will have NaI administered at the optimal dose (as determined in objective 1) in their milk replacer. This ranch utilizes a real-time data collection system (HealthSum) to track illness and treatments in each calf (data entered calf-side by health technicians at each daily check). Data from these calves will be harvested at weaning and analyzed for episodes of respiratory disease signs and treatments as recorded by the technicians. Additionally, deep nasopharyngeal swabs will be collected at the time of enrollment and at one week post treatment in half the animals (every other animal will be selected, due to cost of analysis not all calves can be encorporated), these will provide a survey of viral and bacterial pathogens present in the calves at time of sampling and pre and post samples will be compared to see if treatment altered or eliminated pathogen profiles..Analysis: Results from the dose study will be analyzed by SAS repeated measures analysis using a mixed model to determine area under the curve and peak concentrations. Risk of follow-up treatment will be assessed using logistic regression (SAS) with treatment group being the major explanatory variable and date of enrollment, source, and location on the farm included as covariates.

Progress 05/31/16 to 06/30/17

Outputs
Target Audience:Project results presented to at Conference for Research workers in animal disease, an international conference for veterinary immunologists, infectious disease experts and epidemiologists. Project presented to veterinary internal medicine community at annual American College of Internal Medicine meeting. Due to nature of the results, they were not disseminated to animal industry representatives or contacts. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?This project provided valuable research training for a large animal internal medicine resident, who had very little research experience prior to this project and has since gone on to pursue a PhD in livestock population health. How have the results been disseminated to communities of interest?Results disseminated to veterinary communities of interest (veterinary infectious disease and immunology researchers as well as large animal internists) through conference presentations. Due to results being negative, and possibly having this treatment be detrimental to calves on farm, the resutls were not disseminated widely to producers or industry representatives. What do you plan to do during the next reporting period to accomplish the goals? Nothing Reported

Impacts
What was accomplished under these goals? Objective 1 was achieved for one dose of NaI, which achieved sufficient levels, therefore the experiment was not repeated at a higher dose as was planned. Objective 2 was partially achieved; a large on-farm trial was performed and showed that treated calves had higher respriatory disease occurance than non-treated. Airway pathogen profile was obtained for a small subset of animals and was not significantly different, however a large scale sampling was to be funded by a different source of funding which fell through due to external factors.

Publications

• Type: Conference Papers and Presentations Status: Published Year Published: 2018 Citation: Sodium Iodide as a Preventative Strategy Against Respiratory Disease in Pre-Weaned Dairy Calves (Abstract F11) Lisa Gamsjaeger1; Gary McArthur2; Meera Heller1; Brian Vander Ley3 1University of California-Davis, Davis, CA, USA; 2Swinging Udders Veterinary Clinic, Elk Grove, CA, USA; 3University of Nebraska-Lincoln, Clay Center, NE, USA Bovine Respiratory Disease (BRD) remains a major economic problem in the dairy industry and the aim of preventing disease as well as reducing antimicrobial use warrants evaluation of potential alternatives. The LPO/H2O2/I- system is able to inactivate common bacterial and viral BRD pathogens in vitro. Administration of oral sodium iodide (NaI) significantly increases the I- concentration of respiratory fluids in pre- weaned dairy calves, suggesting potential as a preventative strategy against respiratory disease. The objective of this study was to evaluate the effect of orally administered NaI on BRD treatment frequency and weaning weights of pre-weaned dairy calves. 427 female pre-weaned dairy calves, aged 18 (�2) days and housed in individual hutches on a ranch in central California, were used for this study. The calves were divided into treatment (20 mg/kg NaI orally on day 0 and day 4) and control groups (no treatment). A subset of calves of both groups (70 treatment calves and 70 control calves) were given respiratory and ultrasound scores on day 0 (baseline) and day 7. Medical treatments were recorded for the entire study period and all calves were weighed at weaning. Ultrasound scores, change in ultrasound scores from baseline and respiratory scores of treatment calves on day 7 were significantly higher (p=0.001, p=0.0127 and p=0.0243, respectively) than those of control calves. In addition to having higher respiratory and ultrasound scores, treatment calves had higher odds of being treated for respiratory disease (OR 2.04, p=0.0003) than controls. Despite these apparent increases in respiratory disease in the treatment group, average daily gain and weaning weights did not differ between groups. The findings of this study do not support the use of oral NaI as a preventative strategy against respiratory disease in pre-weaned dairy calves.
• Type: Conference Papers and Presentations Status: Published Year Published: 2017 Citation: 206 - Evaluation of iodide supplementation to decrease respiratory disease in pre-weaned dairy calves M.C. Heller1, L. Gamsjaeger2. 1Veterinary Medicine and Epidemiology, University of California Davis, Davis, CA, USA, 2Veterinary Medicine Teaching Hospital, University of California Davis, Davis, CA, USA. [e-mail] Session: Respiratory Disease in Cattle, Room 8, 12/5/2017 9:45 AM Innate airway defenses are crucial to preserving the health of bovine lungs. Stress, coupled with viral infections, compromises natural host defenses and allow bacteria to reach the lower airways and cause pneumonia. Innate defenses include airway mucus and ciliated epithelium, that trap and physically remove pathogens from the respiratory tract, and secreted antimicrobial peptides that neutralize pathogens. Augmenting innate mucosal defense mechanisms with iodine is effective at killing bovine bacterial and viral respiratory pathogens in vitro. The overall goal of this study was to determine whether NaI treatment could diminish respiratory disease or decrease antimicrobial treatments in pre-weaned dairy calves. Pre-weaned dairy calves (n=428) at a mixed source calf ranch were and randomly assigned to treatment or control groups at 20 (�2) days of age. The treatment group was administered NaI orally at Day 0 and Day 4. Calves received a respiratory score and lung ultrasound score at enrollment and at Day 7. Illness, treatment data and weaning weights were harvested from an on-farm real-time data collection system (HealthSum). Contrary to expectations, treated calves had worse respiratory and ultrasound scores on Day 7, and slightly more treatment events over the study period. Differences between groups were small but statistically significant. We hypothesize that iodide may have unintended effects on normal respiratory flora, creating more advantageous conditions for pathogens.

Progress 05/31/16 to 09/30/16

Outputs
Target Audience: Nothing Reported Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?This project is the major research project for Lisa Gamsjaeger, who is undergoing her residency training in large animal internal medicine at UC Davis. This project also involved veterinary students who obtained experience in physical examinations, respiratory scoring, and (blood, nasal secretions, nasophyaryngeal swab) sample collection in calves. How have the results been disseminated to communities of interest? Nothing Reported What do you plan to do during the next reporting period to accomplish the goals?Continue to analyze data, and publish results. Present findings at scientific meetings (UC Davis House Officer Seminar Day, Conference for Research Workers in Animal Disease)

Impacts
What was accomplished under these goals? Specific Objective 1 Augmenting innate mucosal defense mechanisms with iodine is effective at killing bovine bacterial and viral respiratory pathogens in vitro. The objective of this study was to determine the kinetics of iodine in nasal secretions following oral administration of 20mg/kg inorganic iodine, to assess the feasibility of using this innate defense mechanism to prevent respiratory disease in vivo. Design - Prospective clinical study Animals - 7 female pre-weaned Holstein Friesian calves of similar age were used for this study. Procedures - Calves suckled 20mg/kg of NaI added to their milk, after baseline samples (blood and nasal secretions) were collected. Consecutive samples were then obtained at 1,3,6,12,48 and 72 hours post-administration. Samples were submitted to a diagnostic lab for analysis of iodine concentration. Results - Iodine concentrations were significantly elevated in nasal secretions (P=0.0017) and serum (P<0.0001) over baseline levels at all timepoints sampled. Serum levels peaked at 6 hours (mean 17,188ng/ml, and nasal fluid concentrations at 12 hours (mean 56,383ng/ml). No adverse effects were noticed in any of the calves. Conclusion - This study shows that oral administration of NaI increases iodine concentrations in airway fluids of pre-weaned dairy calves, above effective concentrations in vitro, and could augment upper respiratory defense mechanisms. Further studies are needed to determine if sodium iodide is effective as a preventive strategy for respiratory disease in pre-weaned dairy calves. Specific Objective 2 To determine whether calves receiving oral NaI receive significantly fewer treatments for respiratory disease as compared to control calves, and to determine if NaI causes a change in airway pathogen profile. Design: Prospective Clinical Trial Animals: 400 Pre-weaned dairy calves Procedures: Calves were randomly assigned to treatment or control group. Treated calves received two doses of 20mg/ml NaI orally 4 days apart starting at 18+/-2 days of age. Disease and treatment data entered daily via a hand held tablet device for each calf. Treatment and disease data were harvested at weaning, along with weaning weights for each calf. A subset of calves in each group received respriatory scores based on the Wisconsin Respiratory Scoring chart, and a lung ultrasound score at the initiation of the study and one week post initiation. Results: Data has been collected, analysis is pending. Conclusion: Pending analysis of results.

Publications