Myopathies associated with Streptococcus equi equi infection

Strangles caused by Streptococcus equi equi (S. equi) infection is an all too common and vexing problem for the equine industry. In some outbreaks, up to 20% of cases develop complications such as guttural pouch empyema, purpura haemorrhagica (PH) and bastard strangles (Sweeney et al., 1987). In the Hepworth-Warren et al. (2024), case report in the current issue, complications of an initially silent S. equi infection included PH characterised by fever, hyporexia, lethargy, petechia and limb oedema as well as additional features of rapid onset gluteal and lumbar muscle atrophy. The latent S. equi became apparent after signs of PH in the form of submandibular lymphadenopathy and guttural pouch empyema. The case highlights the importance of a thorough history to detect exposure to strangles and highlights additional complications of S. equi infection that are unique to Quarter Horse-related breeds (Quarter Horses, Paints, Appaloosas and their crosses). With PH, petechia, ecchymosis, hypoalbuminaemia and limb oedema occur because of the deposition of IgA or IGM + streptococcal M protein (SEM) immune complexes in vessel walls that together with complement produce necrotising vascular neutrophilic infiltrates and extravasation of fluid (Galan & Timoney, 1985). PH in the Hepworth-Warren case was confirmed by the presence of mild leukocytoclastic vasculitis in skin biopsies and an SEM titre of 1:1600 which is not as high as typically seen with PH (>1:1600). Treatment with antibiotics and corticosteroids was successful in resolving the clinical signs of PH. Fortunately, this horse was not affected by a potentially fatal complication of infarctive PH. Infarctive PH becomes a differential diagnosis if serum creatine kinase (CK) activity is markedly elevated (>35,000 U/L) and horses are painful with firm swollen areas in pectoral, abdominal and crus muscles, muscles that are compressed when horses are lying down (Kaese et al., 2005). PH was unlikely in the Hepworth-Warren case as these signs were not present and CK was only elevated to 3563 U/L. Aggressive and prolonged corticosteroid treatment is essential in cases of infarctive PH to prevent fatal infarction of the gastrointestinal tract, lungs and other tissues (Kaese et al., 2005). Quarter Horse-related breeds are particularly susceptible to complications from S. equi infection because of a genetic proclivity for myosin heavy chain myopathy (MYHM) caused by an E321G mutation in the myosin heavy chain 1 gene (MYH1) encoding type 2X myosin (Finno et al., 2018). In approximately 40% of cases of MYHM, a history of exposure to S. equi, other infectious diseases or vaccination with S. equi or influenza/rhinopneumonitis precedes clinical signs (Hunyadi et al., 2017; Lewis et al., 2007). In 60% of cases, however, the reason why horses develop MYHM is unknown leaving owners and veterinarians frustrated. Both horses heterozygous and homozygous for the MYH1 mutation develop MYHM with clinical signs being more severe and difficult to manage in homozygotes (Valberg et al., 2022). The Hepworth-Warren Quarter Horse was heterozygous for the MYH1 mutation and only 20% of heterozygotes are reported to develop clinical signs of MYHM (Valberg et al., 2022). The reason why some heterozygotes do not develop disease is not known but could be the result of disease exposure, environment and the horse's genetic background. In the general Quarter Horse population, 7% of horses are heterozygous and a smaller percentage homozygous for the MYH1 mutation. Reining horses have the highest prevalence of the MYH1 mutation at 24% (heterozygous) followed by working cow (17%) and halter (16%) performance horses (Gianino et al., 2019). The clinical disease caused by the MYH1 mutation was initially called immune-mediated myositis, however, the overarching term myosin heavy chain myopathy (MYHM) was later adapted because of additional syndromes associated with the MYH1 mutation. In addition to IMM as described in the Hepworth-Warren case, calciphylaxis and nonexertional rhabdomyolysis (nER) are also associated with this mutation. Horses with MYHM may present with one of these disorders or a combination of nER progressing to IMM or IMM progressing to calciphylaxis. Immune-mediated myositis usually develops in horses <8 years of age or >16 years of age and is characterised by rapid profound atrophy of gluteal and epaxial muscle initially concurrent with moderate serum CK and AST elevations (often <20,000 U/L) (Lewis et al., 2007). The Hepworth-Warren 2-year-old Quarter Horse was quite typical in this regard presenting with rapid muscle atrophy and modest elevations of serum CK activity. In the early phase of gluteal and epaxial muscle atrophy, CD4+, and to a lesser extent, CD8+ and CD20+ lymphocytes infiltrate type 2X muscle fibres and cuff small blood vessels (Durward-Akhurst et al., 2016). Because locomotor muscles in Quarter Horses consist of >50% fast contracting anaerobic type 2X fibres, gross atrophy becomes readily apparent. The Hepworth-Warren case was diagnosed with IMM based on genetic testing for the MYH1 mutation. With the advent of genetic testing, a muscle biopsy of the epaxial or gluteal muscles is rarely used in practice because of the invasiveness of a biopsy and the temporal presence of lymphocytic infiltrates (S. Valberg, personal observation). The aetiology of IMM has been proposed to be a loss of self-tolerance to type 2X myosin (Durward-Akhurst et al., 2016; Finno et al., 2018). Like the central nervous system, skeletal muscle presents very few major histocompatibility complexes on the cell membrane (Durward-Akhurst et al., 2016). It is possible that irritating vaccines, trauma or abscesses expose the altered myosin protein to the immune system resulting in autoimmune destruction of type 2X fibres. The amino acid sequence of SEM overlaps that of type 2X myosin creating the possibility that antigenic mimicry is an instigator of disease (Finno et al., 2018). The mainstay of treatment for IMM is corticosteroids tapered each week for over 1 month and this approach worked well in the Hepworth-Warren case (Lewis et al., 2007). Recurrence of atrophy in susceptible horses occurs in about 40% of cases, particularly homozygotes requiring repeated bouts of corticosteroid treatment (Lewis et al., 2007; Valberg et al., 2022). Preventing exposure to respiratory infections where possible, spacing out vaccines to prevent a surge of inflammatory cytokines, avoiding immune stimulants and monitoring closely to institute treatment early if recurring signs of atrophy develop can help avoid episodes of atrophy. Systemic calcinosis or calciphylaxis is a rare sequelae to IMM in young (less than 9 years of age) horses with the MYH1 mutation. Severe atrophy is followed by diverse organ failure due to systemic dystrophic calcification. A high product of serum calcium multiplied by serum phosphorus (>65 mg/dL) is common in calciphylaxis and this was not present in the Hepworth-Warren case (Sponseller et al., 2022; Tan et al., 2010). The histopathologic findings in muscle biopsies resemble those of IMM, however, multinucleated giant cells are consistently present and dystrophic calcification of muscle fibres is also evident (Tan et al., 2010). Systemic tissue calcification is often fatal and at postmortem, dystrophic calcification is evident in one or all of the following tissues skeletal and cardiac muscle, pulmonary alveoli, renal tubules and tunica intima of blood vessels (Tan et al., 2010). The osteoclastogenic effects of inflammatory cytokines are well documented in a variety of inflammatory conditions in humans (Redlich & Smolen, 2012). In one recent case, corticosteroids, calcium chelation with sodium thiosulfate and aluminium hydroxide administration were successful in treating a homozygous MYHM calciphylaxis case (Sponseller et al., 2022). Sixty-seven per cent of nER cases in Quarter Horse-related breeds were associated with the MYH1 mutation of which 75% were homozygotes and 25% heterozygotes (Valberg et al., 2018). Severe, generalised muscle degeneration occurs with serum CK and AST in the hundreds of thousands, much higher than that reported for the Hepworth-Warren case. Triggering factors include infection with S. equi, Anaplasma phagocytophilum, Corynebacterium pseudotuberculosis and other infectious agents but often the trigger is unknown. Muscle atrophy may or may not occur within a few weeks of onset of nER (Valberg et al., 2018). Muscle biopsies of gluteal or epaxial muscles show acute muscle degeneration, glycogen depletion in large muscle fibres and, unlike IMM, <18% of horses have lymphocytic infiltrates in muscle fibres (Valberg et al., 2018). This suggests an alternate aetiology to immune-mediated muscle fibre destruction. The MYH1 mutation appears to enhance the calcium sensitivity of muscle fibres which could result in a hyper-contractile state where muscles are more likely to contract and fail to relax triggering myodegeneration (Ochala et al., 2021). Dantrolene, which slows the release of calcium from the sarcoplasmic reticulum, can be a beneficial adjunct to the treatment of nER (S. Valberg, personal observation). Routine genetic testing for the MYH1 mutation will make owners conscious of the likelihood that MYHM may develop and help them institute veterinary treatments early in the course of disease. Veterinary awareness of the various sequella to S. equi infections, especially in Quarter Horse-related breeds, will lead to early and effective treatment targeted at both the infectious and autoimmune aetiology of clinical signs. MYHM is unique in that it is the first mutation described in the type 2X myosin MYH1 gene across species and the first myosin mutation associated with an immune-mediated disease and with rhabdomyolysis. Coding sequences for myosin are highly conserved across species highlighting the importance of a conserved protein structure for function of this large locomotor protein. Continued research may further highlight the mechanisms by which altering one amino acid in the myosin globular head can cause such a diverse range of clinical signs. No funding. Having retired from Michigan State University, S. Valberg runs the Valberg Neuromuscular Diagnostic Laboratory which reviews muscle biopsy samples from horses with suspected muscle diseases. Not required for this clinical commentary.