1) Benign Acute Childhood Myositis (BACM)

The association between viral infections and severe myositis has been recognized for decades. In 1955, Dr. Lundberg observed cases of children in Stockholm, Sweden, who experienced viral prodromal syndromes that subsided within four days, but then soon developed severe myalgias in the calves, rendering them unable to walk [3] [4] . The myalgias typically resolved within three days, leaving the children asymptomatic. Dr. Lundberg later termed this condition as “myalgia cruris epidemica,” now known as benign acute childhood myositis (BACM).

BACM is a rare condition that presents with severe, symmetrical myalgias, predominantly in the calves, leading to difficulty in ambulation following a viral illness. Clinically, affected children typically exhibit a wide-based gait with stiff legs or tiptoe walking [3] [5] [6] . The condition is most commonly associated with influenza A (13%) and influenza B (19%) but has also been linked to coxsackievirus (6%), adenovirus (4%), and echovirus (2%) [3] [5] - [7] . Cases tend to surge during the winter months in the Northern Hemisphere and exhibit a male predominance, with a male-to-female ratio of 2 - 3:1 [3] [5] [7] [8] .

Laboratory findings in BACM are marked by significant elevations in CK levels, often exceeding 20 times the upper limit of normal [3] [5] . Although an intensive diagnostic workup is generally unnecessary, muscle biopsies in select cases have demonstrated variable histopathological findings, ranging from normal morphology to segmental rhabdomyolysis or myositis with moderate necrosis and interstitial inflammation [7] - [9] . BACM has an excellent prognosis, with most children fully recovering with conservative management within a few days to weeks [5] .

2) Post-Viral Myositis (PVM)

Acute viral or post-viral myositis can occur with nearly any virus, although influenza A and B are the most common causes in the United States. Other implicated viruses include enterovirus, herpesvirus, hepatitis, and parvovirus [10] [11] . Clinically, PVM presents with diffuse myalgias, particularly in the limb girdle and paravertebral muscles with minimal muscle weakness [8] . The exact mechanism remains unclear but is hypothesized to involve either direct viral invasion of muscle tissue or molecular mimicry, leading to immune cross-reactivity between viral and muscle proteins.

Norovirus infection typically manifests as acute gastroenteritis. While it is not commonly linked to myositis or myalgias, rare documented cases have been reported. For example, Yamamoto et al. reported BACM secondary to combined rotavirus and norovirus infection in a 2.5-year-old girl [12] . Nishio et al. described a case of rhabdomyolysis linked to norovirus in a 2-year-old Japanese boy [13] .

3) Juvenile Dermatomyositis (JDM)

JDM is a rare autoimmune disease characterized by symmetrical proximal muscle weakness and distinctive skin rashes, often accompanied by systemic involvement [14] - [16] . The annual incidence of JDM is between 1.6 to 4 cases per million children, with a prevalence of 2.5 cases per 100,000 [14] - [16] . It primarily affects children aged 5 to 14 years, with a female predominance (2.3:1) [14] - [17] . The pathophysiology of JDM involves a combination of polygenetic risk factors and environmental triggers leading to immune dysregulation.

The strongest genetic association in both adult and pediatric myositis is within the ancestral haplotype 8.1 region of the human genome [15] [18] [19] . This haplotype includes HLA-A1, HLA-B8, HLA-DR3, and HLA-DQ2, which are prevalent in Caucasians and encompass a significant portion of the major histocompatibility complex on chromosome 6. This region is associated with several autoimmune conditions, including inflammatory myositis, autoimmune liver disease, Sjogren’s syndrome, and myasthenia gravis [19] [20] .

Multiple environmental exposures may trigger immune dysregulation in inflammatory myositis, including ultraviolet exposure, medications, and bacterial and viral infections such as Parvovirus, Coxsackie B virus, Epstein-Barr virus (EBV), polyomavirus and even COVID-19 [15] [21] - [24] . Additionally, inhaled exposures to pollutants, carbon monoxide, smoking, gasoline vapor, and chalk/dust during pregnancy have been implicated in the onset of JDM [15] [22] - [26] .

Greco et al., in 1976, documented a case of post-viral myositis in a 19-year-old female who presented with severe myositis and CPK levels exceeding 2400 U/L, three weeks after experiencing viral symptoms [27] . A muscle biopsy revealed patchy necrosis, while electron microscopy identified numerous virus-like particles within degenerative fibers [27] . These spheroidal structures with spiky surface projections were consistent with myxoviruses, and were absent in normal muscle fibers [27] [28] Although viral cultures from the tissue could not be replicated, these findings suggest that direct viral invasion may result in myositis. Culturing viruses from muscle biopsies remains challenging, largely due to the resistance of mature skeletal muscle to infection. This may explain why children with immature skeletal muscle tissues often present with severe forms of myositis [7] [28] - [31] . However, there are isolated reports of successful viral culture. For instance, Kessler et al. (1980) successfully isolated the influenza A virus from muscle tissue [28] [30] [31] .

The pathophysiology of dermatomyositis is multifaceted, with one of the crucial pathways involving interferon signaling [4] [26] [32] [33] . Interferons are released in response to pathogen-associated molecular patterns (PAMPs) that recognize viral proteins or genetic material. PAMPs bind to toll-like receptors (TLR), initiating downstream signaling cascades that result in increased production of type 1 interferons [4] [26] [32] - [34] . Additionally, TLR-independent pathways, including RIG-1, MDA-5, and STING, promote interferon production via mitochondrial antiviral signaling proteins (MAVS) [4] [26] [32] [33] . In JDM, plasmacytoid dendritic cells (pDCs) in perifascicular and perivascular regions produce large quantities of interferons. These interferons bind to interferon receptors (IFNAR), leading to the upregulation of interferon-stimulated genes (ISGs) [4] [32] [33] .

ISGs subsequently release multiple cytokines and chemokines, including CXCL 9, CXCL 10, and CXCL 11 [4] [16] [32] - [34] . These chemokines bind to the CXCR 3 receptor, facilitating the migration of T cells, NK cells, and macrophages [32] [33] .

Finally, the adaptive immune system also plays a significant role in dermatomyositis, as demonstrated by the presence of T and B cells in muscle biopsies. T-cells amplify innate immune responses by recruiting neutrophils and macrophages, whereas B-cells contribute to the development of high-affinity myositis-specific antibodies [33] .

The histopathological features of muscle biopsies in viral myositis differ significantly from those observed in inflammatory myositis. Bove et al. analyzed muscle biopsies from 12 children and reported patchy necrosis with minimal inflammatory infiltration [35] . Similarly, Agyeman et al. identified muscle degeneration and necrosis with minimal inflammation in 28 out of 35 cases [9] . While large-scale studies are lacking, these findings suggest that muscle necrosis, rather than inflammation, is the predominant histopathological feature in viral myositis. This contrasts sharply with dermatomyositis, where tissue biopsies consistently demonstrate pronounced inflammation with CD4⁺ and B cells within the perivascular and perimysial regions, leading to perimysial atrophy [15] [16] .

Histopathological changes in skin biopsies, such as vacuolated interface dermatitis, are highly associated with dermatomyositis, though they are not exclusive diagnostic findings. Wolstencroft et al. examined 228 skin biopsies from dermatomyositis patients and observed a strong association with several histopathological changes, including perivascular inflammation (85%), mucin deposition (81%), basal vacuolization (75%), and dyskeratotic keratinocytes (74%) [36] [37] . Over 90% of the biopsies exhibited at least one of these findings [37] . However, interface dermatitis is not unique to dermatomyositis; as it can also occur in systemic lupus erythematosus, viral exanthems, drug reactions, erythema multiforme, and graft-versus-host disease [38] [39] . Therefore, the pathological findings of interface dermatitis must always be interpreted in the appropriate clinical context to ensure accurate diagnosis.

MRI plays a pivotal role in the diagnostic evaluation of myositis, aiding in distinguishing patterns associated with various etiologies. It is particularly useful for identifying areas most likely to yield diagnostic results on muscle biopsy. In viral myositis, MRI often reveals diffuse muscle involvement characterized by focal or patchy edema, but without muscle atrophy or fatty infiltration [40] . In JDM, MRI findings vary with the disease phase. During the acute phase, symmetric muscle edema is typically observed in the proximal extremities, which may also involve fascial and subcutaneous soft tissues [40] . In the chronic phase, MRI commonly demonstrates muscle atrophy with fatty replacement and calcinosis [40] .

Virus-induced myositis is a clinical diagnosis typically characterized by the abrupt onset of symptoms following a viral infection. In contrast, the diagnosis of dermatomyositis can be more challenging and is often guided by established classification criteria. The initial criteria for inflammatory myositis were proposed by Peter and Bohan in 1975, encompassing symmetric proximal muscle weakness, laboratory evidence of muscle damage, histopathological evidence of myositis, myopathic changes on EMG, and the presence of a typical rash consistent with dermatomyositis [15] [16] . Since then, advances in the identification of muscle-specific antibodies have significantly refined the diagnostic process. The 2017 EULAR/ACR classification criteria incorporate these antibodies and introduce a scoring system with a sensitivity of 93% and specificity of 88% for diagnoses supported by muscle biopsy. When a biopsy is not feasible, the sensitivity is 87%, and the specificity is 82% [41] . A total score of 5.5 without a biopsy or 6.7 with a biopsy indicates probable myositis, while scores of 7.5 without biopsy or 8.7 with biopsy indicate definitive myositis [41] .

Characteristic skin manifestations in dermatomyositis include heliotrope rash, Gottron’s papules, and Gottron’s sign [42] - [44] . These cutaneous findings can often precede the onset of myositis by several months [45] . While the 2017 EULAR criteria include major cutaneous manifestations, minor criteria such as the V-sign, shawl sign, and holster sign are also frequently observed [36] . Recognizing both major and minor skin changes is crucial for timely diagnosis. Amyopathic dermatomyositis, which lacks significant muscle involvement, poses diagnostic challenges and can be easily confused with lupus erythematosus. Da Silvia et al. reported that 37% of patients with dermatomyositis were initially misdiagnosed with cutaneous or systemic lupus erythematosus [43] [46] .