By Lindsey Makratzakis & Craig McConnel, Veterinary Medicine Extension
We have been conducting a study over the past six years evaluating lifetime impacts of dairy calf disease. One of our primary focal points has been clinical respiratory disease and lung consolidation in pre-weaned calves. Several papers have now been published from this study related to peripheral leukocyte gene expression in affected calves (PlosOne 2023; PlosOne 2026), as well as the alignment of clinical signs and consolidation identified through thoracic ultrasonography (AVJ 2023).
Given the longitudinal nature of this project, we have been able to follow individual animals from birth through their 1st, 2nd, and in some cases 3rd or even 4th lactations. Now we are moving forward with analyses of leukocyte gene expression in these cattle during the first two weeks postpartum of their 1st lactation. Fifteen calves with chronic respiratory disease during the pre-weaning period were evaluated as healthy, primiparous transition cows, and our initial assessments have raised some interesting findings.
First a bit of background. Chronic respiratory disease was defined based on having ≥1 lung lobe consolidated for ≥3 consecutive weeks during the pre-weaned period. Eight of the affected 15 calves received antibiotic treatment for respiratory disease during the pre-weaned period, and seven did not. In an effort to establish whether the eight calves that were treated were similar to the seven calves that were not, we evaluated age at onset of consolidation, duration of disease, the thoracic ultrasound score (TUS 0-5), fibrinogen levels, white blood cell counts, the rectal temperature at disease onset and at its highest point. None of the comparisons demonstrated any statistical differences, which means that those calves that were treated with antibiotics appeared to be similar to those that were not for evaluative purposes (Table 1).
Importantly, none of the 15 calves received antibiotics postweaning and all were classified as healthy during weekly evaluations postpartum. In other words, no metritis, pyrexia, mastitis, or other disease states were identified during the first two weeks after their first calving. However, when we compared peripheral leukocyte transcriptomes in those animals postpartum, we found some interesting differences. Keep in mind, the transcriptomic analysis was conducted on samples taken during the first two weeks postpartum and were therefore approximately two years removed from the diagnoses of lung consolidation +/- antibiotic treatment. Those animals that were treated demonstrated gene expression indicating the suppression of antiviral response mechanisms, including a downregulated response to type I interferon. This suggests the potential for increased disease susceptibility.
Admittedly, this is a small sample size and a standalone assessment of something that has numerous potential confounders. Nonetheless, it raises an interesting question regarding the pleiotropic effects of antibiotics. Those are the effects of antibiotic therapy related to biological actions and clinical impacts beyond direct antibacterial killing, including immunomodulation, anti-inflammatory properties, antiviral activity, and microbiome alterations. For example, literature in the human realm has shown that antibiotics exhibit various immunomodulatory effects, including the regulation of pro-inflammatory cytokine production, interaction with Toll-Like Receptors, modulation of the P38/Pmk-1 Pathway, inhibition of Matrix Metalloproteinases, blockade of nitric oxide synthase, and regulation of caspase-induced apoptosis. Additionally, antibiotic-induced alterations to the microbiome are associated with changes in systemic immunity, affecting cellular and humoral responses (Antibiotics 2024). Furthermore, an investigation into how gut commensals modulate systemic immunity and response to viral infection, demonstrated that antibiotic suppression of the gut microbiota reduced systemic tonic type I interferon (IFN-I) and antiviral priming (Immunity 2022).
This is not to suggest that antibiotic therapy should be avoided. There is plenty of evidence demonstrating potential health and welfare benefits of antibiotic use in dairy calves, including a randomized clinical trial to assess the effect of antibiotic therapy on health and growth of pre-weaned dairy calves diagnosed with respiratory disease using respiratory scoring and lung ultrasound (JDS 2020). That study showed that early antibiotic use decreased the progression of consolidation and retreatment risk, while improving pre-weaning growth. However, there remained similar lung pathology during a thoracic ultrasound assessment at weaning. Another more recent paper (JDS 2023) demonstrated that the treatment with two commercial antibiotics reduced clinical and systemic signs of pneumonia and the abundance of pathogenic bacteria in the upper respiratory tract of preweaning dairy calves. However, there was an increase in Mycoplasma MRA observed for one of the antibiotic treatments, demonstrating upper respiratory microbial shifts.
The main takeaway on our end is that there may be long-term, unintended consequences related to antibiotic use in calves. If it is possible to alter the immune trajectory of a transition cow based on pre-weaned treatment choices, then the identification of animals that truly need treatment is paramount. In other words, therapeutic protocols should be based on solid case definitions and thorough outcome assessments. Treating calves with antibiotics may seem like a safe bet across the board but may lead to downstream effects that we are just beginning to truly understand.
Table 1. Pre-weaned calf comparisons| Categories | No Antibiotics | Antibiotics | p - value |
|---|---|---|---|
| Age at Onset (days) | 41.8 ± 4.7 | 42.9 ± 8.6 | 0.95 |
| Duration (weeks) | 5 ± 1.5 | 4.9 ± 1.7 | 0.81 |
| TUS high | 3.8 ± 0.9 | 4 ± 1 | 0.66 |
| Fibrinogen | 612.5 ± 64 | 514.3 ± 177.3 | 0.17 |
| Normal WBC | 7/8 | 4/7 | 0.28 |
| Temp at Onset (⁰F) | 103.6 ± 1.7 | 104.1 ± 1.7 | 0.95 |
| High Temp (⁰F) | 103.9 ± 1.5 | 104.4 ± 1.3 | 0.86 |
Mann–Whitney U (Age at Onset, Duration, TUS high, Fibrinogen, Temp at Onset, High Temp); Fisher’s Exact Test (Normal WBC)