Anaphylaxis Prediction During Peanut Oral Food Challenge

 MULTIPLE SCLEROSIS: THE IMPACT OF INFECTION ON DISEASE PROGRESSION.

VIRUSES AS A TRIGGERS OF MULTIPLE SCLEROSIS

Historical overview

Viral infections have been emphasized as the underlying etiology of MS since the early discovery of the disease. In 1868, Jean-Martin Charcot described MS for the first time 1 and argued vigorously that pathogenic infections underline the etiology of MS 2. Charcot's argument was inspired by the germ theory advocated by Louis Pasteur and Robert Koch, during the “golden era” of microbiology, which revealed the viral and bacterial origin of numerous known infectious diseases. Known for its antiviral properties, interferon was the first FDA-approved medication for the treatment of MS. In 1993, the FDA approved recombinant interferon beta (IFN β-1b) as the first disease-modifying therapy (DMT) for MS. In 1996, a phase III trial on the intramuscular IFN B-1a demonstrated the positive influence of DMT on the accumulating disability in MS 3.

With Epstein-Barr virus (EBV) on the top of the list, other viruses are investigated for the association with MS including herpesviruses sp., varicella-zoster virus, human endogenous retroviruses, and Torque teno virus. The association between virus infection and demyelinating disease had been postulated 4 based on the isolation of several inclusion bodies related to a papova-like virus from brain cells and urine samples of patients with progressive multifocal leukoencephalopathy (equivalent to MS) 5,6. Poskanzer and colleagues hypothesized that MS was a late manifestation of a common childhood viral infection 7. Over 30 virus antigens had been tested against antibodies in the serum of patients with MS ever since 8. However, Jukka Nikoskelainen failed to find a significant relationship between EBV and MS 9. 

Notwithstanding, more recent studies concluded that EBV seropositivity was found in 100% of the population with MS matched for age and sex 10,11. Furthermore, EBV infection was more likely in adult-onset MS compared to control 12 and other viruses including measles 13. Moreover, it was observed that both IM and MS affect the same young age group and followed the same latitude gradient 13,14. Therefore, EBV is deemed highly correlated with MS. Yet, the cause-effect of EBV and MS is far from consensus. 

In addition to EBV, a human herpesvirus 4, another member of the herpes virus family, human herpesvirus-6 (HHV-6), was correlated with MS. HHV-6 bears clinical similarities to RRMS including phases of latency and reactivation. Moreover, HHV-6 can infect oligodendrocytes and microglia which play a pivotal role in MS pathology15. In the past two decades, the association between HHV-6 and MS has been investigated. Immunoglobulin g (IgG) antibody was found in the CSF sera of patients with DM (39.4%) compared with CSF from patients with other neurological diseases while IgG antibodies specific for EBV and cytomegalovirus (CMV) were detected to a less frequency, 12.1%, and 6.1% respectively 16. Moreover, the HHV-6 genome was significantly detected in the peripheral blood mononuclear cells 17. On the contrary, other studies concluded that herpesvirus DNA was not detected in the CSF or serum of patients with DM 18(p6),19. Therefore, the role of EBV and HHV-6 in the pathogenesis of DM remains to be settled. 

 EPSTEIN BAR VIRUS

The primary EBV infection affects 50% of the population in developed countries and 90-95% of the population worldwide 20,21. Children in the first year of life are rarely infected with EBV. However, children between the first and fifth years of life are the most vulnerable population to EBV infection 22. Another peak of EBV infection appears in the second decade of life in developed countries. On the contrary, young children are the most affected population in the low socio-economic communities 23. Moreover, it was observed that the EBV seroprevalence rate tends to decrease among young age groups projecting a future increase in EBV infection 24,25. 

Notwithstanding, the improvement of economic and sanitary conditions makes EBV infection in early childhood a less common health problem. In the United States (US), the highest incidence of infectious mononucleosis is between 15 to 24 years with 500 new cases/per 100,000 persons per year 26. The prevalence of EBV antibodies was concluded to be declined in US individuals aged 6-19 years from 2003-2004 to 2009-2020 derived from the reduction of the prevalence among non-Hispanic individuals 22. While approximately 30 to 75% of college first-year students were seronegative, about 10 to 20% of susceptible individuals become infected with EBV and 30-50% of them develop infectious mononucleosis 23. 

In Qatar, a national study on healthy blood donors revealed that approximately 98% of the investigated sample were seropositive and around 50% of them had detectable EBV-genome with the predominance of genotype 1 and the Mediterranean strain 27.

In France, it was observed that, over the last two decades, there was a decline in the primary EBV infection as well as seroprevalence 24. On contrary, in England, a recent study showed that 85.3% of the individuals were seropositive to EBV infection with a rapid increase of seropositivity in females more than in males at age of 10-15 years 28. 

The incidence of EBV infections showed no clear annual or seasonal variation and there is no proven predisposition according to gender 23. However, other studies concluded that EBV seroprevalence tends to be higher in females and non-Caucasian ethnic populations 22,26.

Therefore, contrary to the previous estimates, it is noteworthy to highlight that the prevalence of EBV infection, seroprevalence, and infectious mononucleosis is changing dramatically in developed countries due to reasons other than socioeconomic status. 

EPSTEIN BAR VIRUS and B cell Responses

EBV preferentially infects B cells and drives them either to become activated proliferating lymphoblasts or to become resting memory cells where the virus enters into an in-vivo quiescent state. The former drive is implicated in the development of EBV-associated neoplasms (lymphomas and carcinomas) 29 as well as the lethal X-linked lymphoproliferative disease (by inducing mutation of a signal molecule) 30. The later drive is implicated in the pathology of MS 31. 

EBV works through 3 latency transcription patterns to drive the B cell to the resting memory state: the latency I pattern utilizing latency membrane protein (LMP2A) gene expression, the latency II pattern utilizing EB nuclear antigen (EBNA), LMP1, and LMP2A gene expression, and latency III pattern utilizing EBNA1-6, LMP1, and LMP2A-B 32. The latency I pattern keeps the EBV in a non-pathogenic quiescent state inside the memory B-cell. The LMP1 and LMP2A (latency II pattern) provide survival signaling mimicking that of T-cell help and B-cell receptor signaling, thus driving the infected cells to differentiate into memory cells while remaining infected. LMP1 prevents B cells from entering apoptosis and promotes cell proliferation through mimicking CD40 signaling 33. LMP2A is a functional mimic of the BCR thus, rescues the B cells that have no surface immunoglobulin from death 34. Finally, the latency III pattern drives the B cell to become proliferating lymphoblasts, thus potentiating the development of malignancy 35, and EBNA-1 is expressed 36. 

TARGETING EBV

EBV can be targeted at multiple pathways including survival pathways in EBV latency either pre-latency or latency phases, lytic cycle, and EBV-glycoprotein (gp) pathways. In the early pre-latency phase, EBV can be targeted at Zta, Rta, EBNA2, EBNA-LP, or EBHRF1. At the latency phase, the targets include LMP1, 2, or 2B, and EBNA1. Targeting EBV at the lytic cycle can be divided according to the latency phases into immediate, early, and late lytic proteins. Different EBV-gps have been identified as possible targets including gp350, gB, gp42, and gHgL 37. These possible antigens/genes can be possible targets for future EBV vaccines or therapeutic approaches 38–40. 

The type 1 gp350 is implicated in the ability of EBV to enter the host B-cell by binding to CD21 and CD35. Therefore, gp350 has been considered a promising candidate for vaccination against EBV41–43. Other potential targets for EBV vaccination are Zta and Rta immediate EBV proteins encoded by BZLF1 and BRLF1 respectively that are identified by uninhibited CD8+ T-cells 44. 

Recent evidence demonstrated the recognition of CD8+ and CD4+ T-cells of latent proteins EBNA leads to hindering the expression of EBV-infected B-cells, the important contributor to MS pathogenesis 45. Targeting EBV-responsive genes may promote the approach to gene therapy. It was concluded that targeting transcription factor EBNA2 using Bam C promoter derived the expression of a suicide gene and enhanced the antiviral effect of ganciclovir46. Moreover, EBNA1 (present in all EBV-positive cancer cells) represents a promising therapeutic and vaccine target لا47. Another potential target with therapeutic implications is the EBV-primed CD8+ T-cells. Preclinical studies targeting BMLF1 and LMP2 showed a successful reduction in EBV viremia levels 48. Adaptive transfer of latent EBV antigen-specific CD8+ T-cells was proved to be safe and effective 49.

In the wake of understanding the implications of EBV in the pathogenesis of MS, several target proteins and genes have been recognized with promising vaccine and therapeutic potentials. Therefore, it deems important to target EBV antigens/genes for therapeutic purposes against not only MS but lymphoproliferative malignancies as well. 

MS DURING THE COVID-19 PANDEMIC

Infections role in the exacerbation of MS

In the last decade, infection, as a possible etiology for MS, has come to the focus of research. There have been unsettled arguments that the MS course can be affected by the diversity of pathogens that could be involved in disease progression and severity as well as complicating diagnosis and therapy 50. Infections may play a more significant role in the development of MS than they do in the initiation of the disease 51,52. This is supported by the findings of the majority of studies, which found that progressive forms of MS were associated with chronic infections rather than relapsing-remitting forms of MS 53–55.

Moreover, patients with MS are at risk of harboring opportunistic infections that could further complicate the current condition and promote disease progression 56. Patients with MS may have meningitis, peripheral neuropathy, encephalitis, or any other complicated CNS signs and symptoms as a result of a pathogenic infection that might be misinterpreted 57–60. Furthermore, chronic infections add more burden to the therapeutic regimen that depends on multi-modality approaches 56,61. If attention is not paid to the chronic infection, achieving recovery could be a serious challenge. 

It has been reported that nearly 20 different pathogens could be involved in the pathogenesis of MS. however, the causal relationship needs further attention 52,62. The disparity of the results from different laboratories including inter-and intra- laboratory discrepancies may participate to the uncertainty of evidence regarding the involvement of chronic infection in the pathogenesis of MS 50,63.

Gut Virome

The term "gut virome" refers to the compendium of viruses that co-colonize the human gut. These gut virome, in addition to bacteria, are found in significant numbers and is made up of both eukaryotic and prokaryotic viruses. These viruses include those that infect human cells, viruses that infect microorganisms such as bacteria, fungus, and archaea, and plant viruses that reach the gut mostly from the environment and food. Interactions between the gut microbiota and epithelial and immune cells, as well as the regulation of metabolic processes, play a significant role in the development and maintenance of the human immune system, which is essential for maintaining homeostasis 64. Accumulating evidence states that the gut virome plays a key role in disease pathogenesis and therapeutics and can be a promising target for novel therapeutic approaches 65.

A set of phages in the gut adherent on the mucosal surface of the gut acts as a barrier to prevent the invasion of pathogenic microbes, thus enhancing the innate immunity against the pathogenic luminal bacterial 66. In addition, phages maintain immune homeostasis by controlling the release of cytokines, opsonization, and bacteria recognition by switching on the immune activity of T and B cells 67. Furthermore, the eukaryotic viruses play a crucial role in the augmentation of interferon β production as well as interleukin-15 to protect the host from inflammation, enhance immunity, and maintain homeostasis 65. It was concluded that gut virome is involved in the pathogenesis of inflammatory bowel disease, an autoimmune disorder, with an increase in Caudovirales and a reduction in Microviridae colonization 68,69. In addition, gut virome is attributed to other medical disorders including Clostridioides difficile infection, SARS-CoV-2, obesity, and diabetes 64,66,70. Furthermore, it was found that crAss-like phages were diminished in patients with autoimmune diseases. Several bacteria were identified as targets for the crAss-like phages. Moreover, Faecalibacterium was identified to have a symbiotic relationship with podoviridea which decreases in patients with autoimmune diseases notably systemic lupus erythematosus 71. 

The microbiota interrelationship has been identified in several studies 64,70–73. This bacteriome-virome crosstalk has an immunoprotective role and may cause damage to the CNS. On one hand, microbiota activates host microglia against infection with neurotropic viruses. In preclinical studies, microglia derived from germ-free or antibiotic-treated animals lose the immunoprotective power against viruses 74. On the other hand, dysbiosis following primary CND injury (stroke or trauma) disrupts the gut-brain axis leading to augmentation of secondary brain injury, motor, dysfunction, and cognitive impairment 75. Furthermore, CNS viral infection has been implicated in brain damage including Parkinson’s disease, Alzheimer’s disease, and narcolepsy 74,76,77. In addition, EBV and HHV-6 have been implicated in the development of MS 78.

The mechanism of disruption of the gut-brain axis includes mitigation of tight junction  79 by enteric glial cell activation 80 and systemic toll-like receptor 4 (TLC4) activation leading to gut leakage and dysbiosis-induced neuroinflammation with consequent brain damage 81. CNS resident cells play a crucial role in inducing different pro-inflammatory signatures that serve to recruit virus-specific lymphocytes into the CNS. The invading antigen-specific lymphocytes attempt to eradicate the virus from infected cells without causing irreversible harm to the host – a challenging process the failure of which may lead to permanent brain damage 74.

Viral-induced demyelination animal models in MS 

Viral-induced demyelination in animal models provides distinctive insights into the cellular biology of oligodendroglia involved in the processes of myelin degradation. The viral-induced demyelination animal models demonstrate viral reactivation, viral-induced CNS tissue damage, and latent viral infections. Moreover, such models help to examine the interplay between the immune system and the CNS. Understanding the different mechanisms by which viruses can cause demyelination may provide new insight into the pathophysiology and etiology of demyelination in MS. 

In animal models, viral-induced demyelination is suggested to be due to direct oligodendroglia virus infection, sustained viral infection irrespective of the presence of the causal pathogen resulting in oligodendroglia cell death, and virus-mediated immune response with the release of immune mediators that damage the oligodendroglia and myelin sheath 82. Moreover, the accused virus may process either the glial cells or the myelin to be attacked by the Th1-cell of the host 83. Furthermore, preclinical studies showed that viral antigenic epitope proteins that molecular mimicry to host components may activate the autoreactive T cells 84. Thus, animal models can provide an insight into the diverse mechanisms of viral-induced demyelination. 

Two viruses are used in animal models including mouse hepatitis virus (MHV) and Theiler’s murine encephalomyelitis virus (TMEV). Infection of the mice CNS with these two viruses can demonstrate the impact of the genetic background and the immune response of the host. Cytotoxic T lymphocytes (CTL) that mediate the destruction of infected CNS cells were found to be mitigated in TMEV-infected mice strains progressing to demyelination 85. Therefore, it has been proposed that TMEV-related demyelination is mediated by CD 8+ T cell response 86. Given that the MHC-1 class is essential for CTL activity, the genetic influence underscores the immune response against TMEV persistence 87,88. Moreover, the inflammation and demyelination of the spinal cord shown in histopathological findings were associated with TMEV infection in susceptible mice. Different strains of MHV have been used to produce demyelination in lab mice. Demyelination with axon sparing was noticed in MHV-inoculated mice that keep progressing till the initiation of repair and demyelination of a new focal area 89,90. In chronic demyelination, oligodendroglia undergo necrosis and apoptosis 87,91. To conclude, animal models are a useful strategy to investigate viral-induced demyelination by enteric virome. 

Exacerbation of demyelinating events during COVID-19 pandemic

The COVID-19 pandemic has posed new challenges for the treatment of people with MS. The vulnerability to infection and the side effects of disease-modifying therapies (DMTs) have been identified as potential concerns. The impact of COVID-19 on the clinical progression of MS and the therapeutic strategies was of the utmost concern 92. 

Moreover, there was an apparent discrepancy in recently published guidelines on the use of DMTs due to the dearth of evidence-based information to support their recommendations and the reliance on anecdotal reports 93–95. 

The aberrant control of immune responses in MS was concluded to have no notable impact on host defense against infectious pathogens 96. Early findings revealed that the risk of infection and related morbidity from COVID-19 in patients with MS is nearly approximate to that of the general population 97. In an observational cohort study, the Expanded Disability Status Scale (EDSS), age, and obesity were identified as independent risk factors for severe COVID-19; COVID-19 severity was not correlated with DMTs therapy 98. It was documented that the probability of death from COVID-19 for patients with MS was estimated to be less than 1% 99, which, optimistically, was within the range of worldwide mortality statistics averaging approximately 3% in the general population 100. Therefore, it can be inferred that the established risk factors in the general population also apply to those with multiple sclerosis.

Notwithstanding,  it was reported that the frequency of infections is higher in patients with MS compared with the general population 101 along with the increased risk of hospitalization and significantly increased mortality 102  Even further, infections may produce relapses in MS, which may cause lasting disability 103. Crucially, infections are well-known consequences of various DMTs in patients with MS in the context of COVID-19 104,105. 

Regarding demyelination, several research studies reported diverse neurological features in patients with COVID-19 that are characterized by demyelination. The exact etiology of COVID-19-associated demyelination remains to be elucidated 106. Although demyelination has been reported with MERS-COV and SARS-CoV-1 107, there is a paucity of data concerning SARS-CoV-2 108. A recent study concluded that SARS-CoV-2 can cross the blood-brain barrier and induce demyelination in the CNS 109. The demyelination in the context of COVID-19 was reported to mimic commonly the manifestations of encephalitis-encephalomyelitis (91%) and MS, NMOSD, and MOGAD to a lesser extent 108.

TRENDS IN MS RESEARCH

MRI Imaging of chronic active inflammation in MS

There is no doubt that histopathology is the golden standard to detect chronic active MS lesions 110 that impact mainly the white matter (WM) and are more common in PMS 111. Chronic active lesions have a rim of iron-laden activated microglia and/or macrophages encircling an inactive core with an intact blood-brain barrier (BBB), implying a segregated chronic inflammatory pathophysiology 112. 

There has been a substantial improvement in neuroimaging strategies for detecting in-vivo MS lesions. The susceptibility-based high- and ultra-high field MRI scan with dynamic contrast (using gadolinium) enhancement can detect the iron-rim lesions as paramagnetic hypodensity more accurately in clinically isolated syndrome (CIS), RRMS, and PMS 113,114. Given the diminish of iron-rim lesions over time, quantitative susceptibility mapping has been developed to localize and quantify the iron-rim lesions precisely 115. Furthermore, MRI was concluded to be able to detect leptomeningeal inflammation as a contributor to MS Pathology 116

Moreover, positron emission tomography (PET) has been applied to study MS chronic active inflammatory lesions with the use of microglia- and macrophages-specific radiotracers. The implication of PET with radiotracers can be of diagnostic, therapeutic, and prognostic value in the detection of inflammation 117. With the inclusion of PET as an imaging strategy, the biochemical activities may be detected accurately and noninvasively, with promising guidance to more appropriate therapy.  Detailed information about molecular biology can be provided early enough before the development of the anatomic changes, thus allowing close monitoring of MS progression and consequently therapeutic management. These major neuroinflammatory elements have been characterized as targets for PET imaging including astrogliosis, cytokines levels, and specific proteins 118.   

Sodium (23Na) MRI is a recent cutting edge in the detection of chronic active lesions in patients with MS.  it was concluded that high sodium values in chronic active MS inflammatory lesions were proposed to be a significant indicator of progressive lesions 119. Moreover, a recent study presumed that a reduction of the apparent diffusion coefficient indicates an early stage of disease progression 120. Further studies concurred with the previous findings. A recent study concluded that relaxation weighted 23Na MRI and Na-density MRI could explicate the molecular pathological changes in MS 121.

Role of RNA sequencing to understand MS

Thanks to single-cell RNA sequencing (scRNA) and single-nucleus RNA (snRNA) sequencing (RNA-seq), our knowledge of the molecular alterations of neurodegenerative diseases has evolved. The next-generation RNA-seq has changed our knowledge of the molecular genesis of human illness. The bulk population sequencing measures average transcript expression, however, cell-to-cell gene expression variability data was lacking 122. Therefore, RNA-seq has been developed to overcome this shortcoming 123. Attempts to give insight into cell type-specific mechanisms of MS lesions have been made in recent transcriptional studies. 

Given the heterogenicity of the MS cortical and subcortical areas, changes in cell type-specific gene expression were detected involving aggressive cellular oxidative stress and loss of CUX2-expressing excitatory neurons of the upper layer (L2-L3) in demyelination and partially remyelinated cortical lesions in patients with MS 124. The association of these findings with the underlying meningeal inflammation with consequent B-cell infiltration raises the potential benefits of B-cell depleting therapy 125. Moreover, the use of snRNA-seq unveiled transcriptional changes in several myelin genes in oligodendrocytes and apparently normal white matter (WM) in patients with MS 126. MS-associated transcriptional changes were demonstrated in blood and CSF with more gene differentiation expression in blood than in CSF 127. In addition, snRNA-seq identified transcriptomic alterations related to astrocyte-specific Sphk1/2 with therapeutic implications 128.

On the other hand, scRNA-seq can identify unusual cell populations, gene regulatory linkages, and cell lineage development 122. ScRNA-seq expression analysis identifies various myeloid cell types in the CSF of patients with neuroinflammation. Detection of microglia in CSF was made by the expression of a specific surface protein 129. Moreover, scRNA-seq was used to characterize the diversity of astrocytes and their regulation 130. 

Bioinformatics and MS

Providing customized medical care for patients with MS has been an evolving challenge. In-between visits clinical MS activities and progression may pass unnoticed. Subtle but significant symptoms of relapses are either under-reported or failed to be recalled during the clinical visits 131. Moreover, some MS-related disabilities such as memory, linguistic, and verbal problems may be ignored based on the subjective reporting of the patient 132. Biased clinical assessment may hinder making informed treatment decisions concerning the inclusion of the appropriate medication on time. Given the qualitative nature of MRI assessment, radiologist-dependent reports are subject to discrepancies and contradictories 133. 

Therefore, digital tools may provide a method for standardization of MS care and minimize the subjective bias to a great extent. The advancement of digital health solutions is quite encouraging. The digital tools can empower healthcare professionals with on-time forwarding of the information of patients and on-time access to patients with serious symptoms or inquiries 134. 

Moreover, telemonitoring applications allow for a continuous flow of the patient’s data for adequate monitoring of symptoms and disease progression 135. Thus, under-reporting of serious events is mitigated, and the in-between visits gap is ameliorated 136. Timely assessment of disease progression and new symptom development as well as the development of medication side effects help to customize medication prescriptions with increasing compliance. Furthermore, digital tools may enhance self-assessment and direct contact with medical care without unnecessary delay 137. 

On the other hand, artificial intelligence (AI) can provide unbiased quantification of MRI scans. Several software tools have been developed recently to overcome the subjective bias of MRI reporting 138. However, fewer than 6% of the most recent studies on medical deep learning algorithms included validation using external data from a third party 139.

A cutting-edge platform has been available with CE marked and FDA approval mHealth applications. The MS management platform is composed of a smartphone and website application with a healthcare professional portal for patient outcomes including validated symptoms, disabilities, cognitions, and feeling fatigued. In addition, the platform is provided with a clinical brain MRI quantification. In a clinical study, the platform for MS management was proved sensitive to subclinical and clinical variabilities of MS subtypes 140. A smartphone application has been developed to collect self-reported data concerning fatigue and other symptoms using the Outcomes Measurement Information System (PROMIS) in patients with MS 141.

Diversity and inclusion in clinical research in MS

The fundamental purpose of human research is to obtain generalizable conclusions concerning safety and efficacy. The homogeneity of participants causes bias in data analysis and hence, generalizability is doubtful. The National Institutes of Health (NIH) Revitalization Act, 1993, directed the NIH to institute guidelines stressing the inclusion of the disadvantaged and minorities including females in clinical research 142. 

Black and Hispanic populations suffering from MS had poorer disease courses and outcomes than their White population counterparts 143. The non-white MS patients are more likely to be influenced by socioeconomic determinants disparities in research, healthcare, and consequently devastating outcomes. Several research studies concluded that race and ethnicity are undermined in MS DMT trials. In the USA, only 5% of participants in a trial are African Americans or of African origin and 1% are of Hispanic ethnicity compared to 13-18% of the population in the USA respectively 144,145. Moreover, race and ethnic representation are ignored on manufacturer websites 143. Available data showed that non-White MS patients are significantly underrepresented in phase III trials 146. Quotas, recruited number targets, are proposed as a solution to increase the number of non-White, the disadvantaged target population in MS clinical trials 147.

A patient cohort consisting of a heterogeneous population contributes to the expansion of the existing knowledge base on the MS process. Therefore, better therapeutic choices can be based on informed decisions rather than insufficient data or intuition. Moreover, during the early stages of the drug development process, heterogeneous cohort studies help in identifying particular effectiveness and safety parameters. Consequently, the availability of this information is crucial for patients, together with their healthcare participants, to make informed decisions about their care 148.

VIRAL COMPLICATIONS OF DMTS

Mitigating Risks of DMTs-1

The recently developed DMTs with high efficacy have strong immunosuppressive and immunomodulatory features. Therefore, mitigation of the risk of viral infection (the concern of this review) is of utmost importance. Risk mitigating strategies include meticulous patient selection, screening protocol before the initiation of DMTs, and vaccination against the possible viral infection in immunocompromised patients. Furthermore, antivirus prophylaxis regimens are recommended in some contexts. Viral markers are available to detect viral infection before starting DMTs, however, some viruses are dominant and reactivated only when the immune system is incapacitated. Therefore, medical history of previous exposure to certain virus infections or receiving therapy for these viruses should not be ignored.

Screening for hepatitis B (HBsAg), hepatitis C (anti-HBcAb), varicella-Zoster virus (VZV) (VZV IgG Ab), John Cunningham virus (JCV) (JCV Ab), HIV (variable tests), and SARS-CoV-2 (PCR and Spike protein) is highly recommended before starting DMTs including anti-CD20, S1P modulators, cladribine, natalizumab, alemtuzumab 56. Vaccination against the virus (or viruses) of concern should be directed mainly against the high-risk groups. For instance, hepatitis B vaccination should be given to unvaccinated patients (seronegative) and those at risk of infection including the risk of sexual contact, intravenous drug abusers (users), and healthcare professionals in contact with hepatitis B patients or their body fluids, and travelers to endemic regions 149. Hepatitis B seropositive patients should receive antivirus prophylaxis therapy under the supervision of a professional hepatologist 150. It is worth noting that live attenuated vaccines should be avoided concerning VZV and SARS-CoV-2. Therefore, shingrix and gene-based should be considered in MS patients who are going to receive anti-CD20 therapy to protect against VZV and SARS-CoV-2 respectively 151–153. Patients on alemtuzumab should receive anti-herpes prophylaxis therapy 154. In addition, those at risk of SARS-CoV-2 infection should be given recommendations to avoid viral transmission including avoiding crowding and poorly ventilated closed spaces, mask-wearing, and social distancing 92.

All patients at risk of HIV should be screened for a history of sexually transmitted infection, contact with a high-risk partner, and intravenous drug abuse (or use). Because HIV depletes CD4+ lymphocytes, HIV testing should be carried out before starting CD4 depleting medications including alemtuzumab and cladribine 155,156.

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection that impacts the cerebral tissues. PML is caused by JCV that flourishes in immunodeficient patients. Screening is recommended for JCV antibodies before starting DMTs, especially natalizumab. The incidence of PML increases among JCV seropositive patients receiving natalizumab 157. 

Mitigating Risks of DMTs-2

MRI plays a significant role in the risk mitigation of DMTs in the context of viral infection. Patients with MS who receive natalizumab for more than 18 months should go for MRI monitoring is found to be JCV seropositive 158 every 6 months 159. MRI proved a useful tool in this subset of patients to detect PML cerebral lesions in asymptomatic PML 160. Ocrelizumab was found to be a significant alternative 161. Similarly, patients receiving cladribine should have a baseline MRI within 3 months of starting the medications to exclude PML lesions 56. In case PML-suggestive symptoms emerge, the baseline imaging will serve as a valuable point of comparison 162,163. The herebefore recommendations are sound for DMTs with a possible risk of PML 159. 

A case study revealed enteroviral meningoencephalitis in one child and an adult receiving the anti-CD20 monoclonal antibody rituximab for immune thrombocytopenia and relapsed B cell lymphoma respectively. An MRI revealed the presence of myelitis and asymmetrical enhancement of the right parietal meninges after gadolinium enhancement 164. Therefore, Enteroviral Meningoencephalitis is a significant complication of anti-CD20 therapy that should be of concern in patients with MS receiving rituximab 165. The prescription of DMTs during the COVID-19 pandemic was and is still a matter of debate. A recent study concluded that MRI can detect MS disease progression in patients receiving extended interval dosing of ocrelizumab as a potential risk mitigation strategy during the COVID-19 pandemic 166. 

Progressive Multifocal Leukoencephalopathy

Patients who receive a limited number of DMTs for the treatment of MS are at an increased risk of developing a rare but fatal disease known as progressive multifocal leukoencephalopathy (PML). PML is caused by a JCV infection in the brain. The only effective treatment is restoring the disturbed immune system. This is typically accomplished in a patient diagnosed with MS by removing the offending therapeutic agent e.g., natalizumab 161,162. In addition, the patient can be treated with highly active antiretroviral therapies 167 or PD1 receptor inhibitors 168 in the case of HIV-associated PML.

JCV is a primate polyomavirus with dsDNA enclosed in a capsid without a lipoprotein envelope. The route of transmission is not clear, however, based on antibody testing, JCV is widespread worldwide. In immunodeficiency patients, infection with JCV results in viral replication and mutation to a neurotropic virus strain 169. Then, the mutated virus disseminates to the brain and actively replicates within oligodendrocytes leading to cell death 170. Consequently, areas of demyelination appear giving rise to the symptoms and MRI features characterizing PML.

The control of JCV depends largely on the competent response of T lymphocytes including CD4+ and CD8+ T-cells. Active CD4+ T-cells produce interferon-γ (IFN γ) and IL-4 that play a significant role in clearing JCV and protecting against the development of PML 171,172. Furthermore, the CSF of patients newly diagnosed with PML included increased amounts of IL-10 indicating the presence of aberrant CD4+ T cells, thus increasing the risk factor for developing PML 173. Moreover, natalizumab-treated patients showed the inability of CD8+ T-cells to migrate into the CNS 174. CD8+ T-cells were found at the margins of the cerebral lesions exhibiting granzyme B polymerization suggesting the cytotoxic role of CD8+ T-cells against JCV 175. A key chemokine receptor, CCR5, that is involved in CNS viral responses, was found on CD8+ T-cells 176. T-cell exhaustion is another factor of concern in the immunopathogenesis of PML. T-cell exhaustion is characterized by the upregulation of programmed cell death protein (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) 177. Thus, immune responses to pathogens are reduced 178. T-cell exhaustion was reported in PML patients 179 and MS patients receiving dimethyl fumarate 180. 

Several treatment modalities have been developed to overcome lymphocyte surveillance. The trials of immune checkpoint inhibitors to improve JCV-specific immunity showed promising outcomes 181. Anti-PD1 therapies e.g., nivolumab or pembrolizumab showed JCV-specific CD4+ and CD8+ T-cells resulting in the removal of the virus from the CSF 182,183. Several factors influence the efficacy of anti-PD1 therapies including the number of JCV-specific T cells 184 and the severity of exhaustion of CD8+ T-cells 185. Other cutting-edge PML treatment approaches include interleukins, JCV/BKV specific cells transfer, plasma exchanges, CCR5 agonists, granulocyte-colony–stimulating factor (GCSF) 170,176,177,186.

The integrated RNA-Seq interpretation system (IRIS)

Recently, RNA sequencing methods, with their high-throughput yields, have allowed a proliferation of genomic and transcriptome research, however, they have created a challenge with large amounts of data. The complexity of organizing, analyzing, and interpreting these data has increased as a direct consequence of the exponential expansion in the amount of sequencing data. Consequently, there is a significant need for user-friendly software applications and websites that are capable of running bioinformatics tools. The recent advances in sequencing have brought large omics data for better comprehending complex biological systems. 

An integrated RNA-Seq interpretation system (IRIS) is a web service that can analyze scRNA-seq data and extracts useful information. IRIS3 has been developed with 20 capabilities, which makes it easier for researchers to analyze scRNA-seq data 187.

A regulon, a group of genes that work together as a single unit, is usually controlled by the same repressor or activator gene. Therefore, the ability to detect active regulons in a certain cell type is called cell-type-specific regulons (CTSR). CTSR provides the researchers with a unique possibility to find key regulators and target genes that cause a certain complex disease. Hence, IRIS has been developed to figure out how to find CTSRs from single-cell RNA-Seq (scRNA-Seq) data.

RNA-Seq data is useful for predicting how gene regulatory networks would behave under different situations or cell types. RNA-seq generates genome-scale gene expression profiles that may be evaluated utilizing correlation, co-expression, clustering, and differential gene expression.  IRIS for expression data analysis (EDA) and functional gene modules (FGM) have developed utilizing R packages (edgeR, DESeq2, and limma) for differential gene expression analysis and investigation of interactive networks and complex biological processes respectively 188,189.

Differential gene expression (DGE) analysis is the most common computational method to look at expression data to find out the specific characteristics at the sample or cell level 190. Although, there are diverse computational methods, differentially expressed genes (DEGs) are genes that are expressed differently in two or more conditions. Therefore, DEGs can help researchers find a way to connect differences in gene expression levels with differences in phenotype. However, there are still many problems and constraints, such as problems with experimental design, the need for fully-integrated discovery-driven analyses and DGE tools, and the lack of functionalities and interactivity, especially in demonstrating the results 191.

Therefore, IRIS-DGE has been developed to address these challenges constructively. IRIS-DEG is an easy-to-use, interactive platform for in-depth analyzing gene expression data and yielding interactive summaries quickly. IRIS-EDA is unique in giving the user a more complete and multi-level platform for analysis with high efficacy and flexibility. IRIS-DEG is capable of single-cell and bulk RNA-Seq analysis; GEO submission, discovery-driven, and DGE analyses, experimental design approach through integrated DGE analysis tools, and interactive visualizations 189.

On the other hand, the QUBIC2 tool can find biologically important biclusters on 10X scRNA-Seq data and be used to identify cell type-specific regulons (Xie et al., 2020), which show regulatory signals and the genes they control in a certain cell type 187(p3). Using a left-truncated mixture Gaussian model 193, QUBIC2 finds biclusters, which are groups of genes that are expressed and regulated at the same time. This is called a functional gene module (FGM) (Xie et al., 2020). From scRNA-Seq data, studying FGM can help us understand how genes talk to each other and how complex biological processes work. 

Notwithstanding, QUBIC2 was only available as a C programming language implementation and could only be used for a few downstream analysis functions. The success of the comprehensive web server-based RNA-Seq interpretation system 189, encouraged the creation of an R package called IRIS-FGM to help researchers use scRNA-seq data FGMs studies 188.  

INCLUSIVE AND ACCESSIBLE INNOVATIONS FOR MS CARE 

The role of diet in modifying the course of MS

The role of nutritional determinants in MS pathogenesis is still unknown. No dietary pattern has been related to the impact of nutritional intervention on inflammatory states in MS patients 194. It is recommended that saturated fatty acids (SFA) of animal origin should be reduced to control the inflammatory process in MS 195. Moreover, there is a growing interest in the low-fat diet and polyunsaturated fatty acid (PUFA) supplementation due to the promising effect on MS disease progression 196–198. Heavyweight before the age of 20 has shown a significant correlation with the risk of MS. Furthermore, the correlation between vitamin D insufficiency 194 and MS highlights the latitude gradient in MS prevalence 199. In addition, the involvement of oxidative stress in the inflammatory process raised the interest in dietary antioxidants 200,201. Therefore, dietary habits that help mitigate the severity and progression of MS should be considered complementary to pharmacological treatment 202.  

The effect of metabolic factors on the inflammatory process is one of several theoretical pathways that attempt to explain the impact of diet on MS pathology 203. The metabolites that arise from the diet either directly or by gut microbiota share common mechanisms of action including G-protein coupled receptor (GPR) signaling (GPCRs), an epigenetic mechanism for gene expression, and transcription factors 204. It was observed that specific GPRs recognize omega-3 fatty acids (FA), tryptophan metabolites, and short-chain FA (SCFA) 205–207. GPCRs signal leads to downstream inhibition of NF-kB among other anti-inflammatory factors 204. 

Moreover, butyrate, for example, is a natural inhibition of histone deacetylases (HDAC). Acting epigenetically, HDAC acetylates histones resulting in transcription activation with an anti-inflammatory downstream effect involving Foxp3 expression on Treg cells 208. Last but not least, aryl hydrocarbon receptor (AhR) activation is associated with a diverse range of anti-inflammatory effects on the immune system. In patients with MS, metabolites e.g., tryptophan and flavonoids activate AhR on astrocytes in the brain leading to focal cerebral effects 209.

The role of exercise in modifying the course of MS

In MS, patients typically reduce their physical activity out of fear of aggravating their symptoms, which may lead to reconditioning. There is an increasing belief that regular exercise training is a viable strategy for minimizing the reconditioning process and attaining an ideal level of patient activities and functions as well as improving the physical and mental symptoms without provoking the severity of illness symptoms or relapse. Participation in therapeutic exercise might notably and significantly improve several aspects of their cardiorespiratory fitness (aerobic fitness), muscular strength, flexibility, balance, tiredness, cognition, quality of life (QoL), and respiratory function. 

Practicing aerobic training, patients with MS uses multiple muscles against low burden 210,211. Several studies found that aerobic training of low to moderate intensity is safe and tolerable as well as effective in augmenting cardiovascular fitness and QoL patients with EDSS less than 7 212,213. Patients with mild or moderate physical impairment may increase their aerobic fitness and experience less tiredness with low to moderate intensity aerobic exercise training. Exercise reduces long-term inactivity that increases tiredness and the risk of incapacitation 212,214. There is evidence to support the benefit of exercise in alleviating tiredness through enhancing the hypothalamic-pituitary-adrenal axis 215. Moreover, strength training was concluded to improve leg strength, mobility, and fatiguability 216 as well as fostering reliable recovery in knee extensor and plantar flexor muscle forces and hence, walking 217.  

Patients with MS may adjust well to resistance exercise, which may improve tiredness, fatigue, and mobility. Weight machines are preferred over free weight and home-based exercise programs 218. The performance of resistant training should be supervised by experienced staff for safety and the attainment of benefits 218,219. Furthermore, muscle stretching and other flexibility exercises may reduce spasticity and avoid future unpleasant spasms and contractures 210,211. Balance exercises reduce the risk of falling and improve balance. Flexibility exercises were concluded to minimize spasticity, augment joint movement, and improve posture and balance 220. Stretching should precede and follow the sessions involving the upper and lower body muscle groups 221.

There are broad recommendations for exercise in the MS population. The tailored exercise program should be intended to treat the primary complaint of the patient, as well as increase strength, endurance, balance, and coordination 222. 

Use of artificial intelligence and MRI for MS Care: How does this improve care and accessibility?

MRI  is necessary for diagnosis, prediction of disease stage, and prognosis of the early stages of MS that might be misdiagnosed owing to the quasi-clinical presentation 223. Although cerebral lesions on MR images are a significant imaging biomarker for the diagnosis of MS detection of MR lesions is complex, time-consuming, and relies on radiologist expertise. Therefore, artificial intelligence (AI) has a place in modern medicine for punctual detection and thus, therapeutic decision-making in the context of MS 224.

Identification of white matter lesions in 3D MRI is crucial for appropriate diagnosis and thus, therapy in patients with MS. However, it is rather difficult, complex, and time-consuming to recognize early MS and assess its development. Machine learning (ML) system has been proved effective in the identification of early MS development. The utilization of convolutional neural networks (CNN), transfer learning, and softMax software proved superior to enhancing the efficacy of MRI in the detection of MS lesions, and prediction of the course of illness with an impressive accuracy rate of nearly 98.8% 225,226. Moreover, the U-net is another typical DL architecture in MS image processing featuring a fully CNN with contraction and expansion pathways for segmentation 227. An automatic segmentation approach with gadolinium-enhancing new T2 is found to be a fundamental biomarker in the detection of MS disease progression irrespective of the paucity of symptoms 228. Furthermore, patients with RMS can be accurately detected (89%) by the application of the SVM ML model 229.

In conclusion, the critical first step toward precision medicine is the identification of disease phenotypes based on the underlying processes based on biology rather than clinical criteria. Therefore, informed decisions can select individuals who will benefit from the medicine of concern. AI and ML use multidimensional data to find groups of people with similar characteristics and comparable pathobiological processes rather than shared clinical symptoms. The various models of AI and ML provide promising and the field of early diagnosis and consequently, therapeutic decision-making.

The inequities and disparities among the disadvantaged.

Structural and social determinants of health create and sustain health inequalities in the context of neurological diseases. These determinants include interpersonal intolerance, institutional constraints contributing to discriminatory access to care, and close community factors such as socioeconomic status, marginalization, and availability of nutritious food. Interventions to increase neurologic health equality need multi-leveled approaches to address these interrelated determinants that create and sustain uneven health quality and equity in the context of MS in particular 230. 

Recent findings emphasize the higher incidence of MS among African Americans than Hispanics and Asians who are less likely to get MS than European whites 231,232. Moreover, MS mortality patterns show racial/ethnic and age differences, indicating an uneven illness burden. Disparities in health along with inequalities in genetic, environmental, and societal features may contribute to illness variability and endophenotypes 233. In the USA, African Americans suffer from health disparities being a minority. Health disparities are avoidable differences in MS morbidity, burden, and mortality that disproportionately impact some groups despite sharing similar disease features. Therefore, the combination of health inequality and disparities regarding access or availability of health facilities, services, and care at any social and institutional level influences the clinical diversity of disease severity and progression 234. Moreover, poor access to health care facilities and illiteracy with the prescribed DMTs were concluded to participate in health disparities among African Americans 235. 

Nurses’ home visits were suggested as a solution to provide healthcare to the disadvantaged. This approach was suggested to be effective in mitigating the socioeconomic determinants of health. Nurses’ home-visit interventions enable patients with MS at risk for health inequalities to evade harm, keep healthy, and regulate current symptoms 234. Therefore, research that incorporates the healthcare system, provider-patient intercommunication, the requirements of patients and their community, disease perceptions, and the expectations of the disadvantaged would promote a more inclusive manner of evaluating MS outcomes 236.

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