Post by Nadica (She/Her) on Nov 22, 2024 3:44:10 GMT
Could the next “disease X” be a pandemic of virus-induced encephalitis? What should our first medical response be? - Published Nov 19, 2024
Disclaimer
As a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also.
1- Introduction
In February 2018, the World Health Organization (WHO) designated an unknown potential epidemic disease as “Disease X”, placing it at the bottom of its shortlist of potentially fatal diseases that pose the greatest public health risk. This was a call to action for the world to prepare for the unknown. Shortly after, in November 2019, Coronavirus disease 2019 (COVID-19) emerged as the first Disease X the world witnessed. Unfortunately, we were ill-prepared and millions of lives were lost, mostly and paradoxically in the highly developed countries equipped with the best medical resources. Moreover, COVID-19 remains a persistent public health challenge, resulting in tragic losses, primarily in the developed countries. This is mainly attributed to the continuous evolution of SARS-CoV-2 variants and subvariants with immune-evasive properties e.g. the KP.3 and XEC subvariants. Interestingly, in March 2024, the WHO wisely launched a new network dedicated to early and accurate detection of SARS-CoV-2, MERS-CoV and novel coronaviruses of public health importance.
Despite COVID-19 being the first Disease X, similar and potentially more catastrophic pandemics are expected in both the short and long terms. Interestingly, on August 14, the WHO director-general declared a recent Mpox outbreak with the new Mpox virus strain that emerged last year, clade 1b, in Africa as a public health emergency of international concern and if there’s one lesson to be learned from COVID-19, it would be not to underestimate even a trivial threat and to maintain utmost vigilance. This article aims to discuss some important potential global public health threats while considering the worst case scenario of a pandemic of virus-induced encephalitis.
2- The current potential pandemics
The world has recently experienced an unprecedented spread of dengue virus disease beyond historical transmission areas, such as in Europe. This is largely attributed to climate change and/or evolutionary viral mutations, with global cases rising close to record highs. Similarly, due to global warming, experts have raised concerns about the potential transmission of the tick-borne severe viral Crimean-Congo hemorrhagic fever to the UK and other previously unaffected non-African countries .
Moreover, it’s important to note that fruit bats are known to be the reservoir of two other prioritized potentially epidemic/pandemic viral hemorrhagic diseases; Ebola virus disease and Marburg disease. Currently, both are endemic in some African countries only, but due to climate variations, the endemic settings could change and the threat could spread to areas beyond historical transmission.
Furthermore, the world could encounter unexpected infections if pteropid bat species which are the reservoir host of Nipah virus and/or the natural mosquito habitat involved in the pathogenesis of Rift Valley Fever were similarly affected. Notably, both infections are also among the mentioned list prioritized by the WHO.
3- The unseen potential of bioterrorism-induced pandemics
Recently, a preprint presented alarming results from gain-of-function research, raising global concerns that one of the SARS-related coronaviruses could potentially cause a new airborne pandemic. These researchers demonstrated the ability of the SARS-CoV-2 related pangolin coronavirus GX_P2V (short_3UTR) to cause a 100% mortality rate while using a human ACE2 transgenic mice experimental model. GX_P2V (short_3UTR) induced fatal encephalopathy, as shown by shrunken neurons in that research.
From my perspective, it’s important to be vigilant and globally prepared for a potential pandemic of virus-induced encephalitis as the worst case scenario in order to avoid huge losses as encountered during COVID-19 pandemic. This could arise from various sources including zoonotic spillover from virulent natural evolution, rogue or accidental break during gain-of- function laboratory research leading to more virulent versions of viruses such as herpes simplex,West Nile, SARS-CoV-2 as attempted in the aforementioned preprint, or even as a result of premeditated bioterrorism.
Notably, regardless of its wide distribution and its assumed acquired general immunity, Herpes Simplex Virus type 1 is the most frequently detected viral agent in samples derived from American and European viral encephalitis patients when compared to other family viruses including SARS-CoV-2. It’s important to also consider genetically modified Rabies and/or other neurotropic viruses in simulation of worst case scenarios as billions of people are considered vulnerable. Nevertheless, the public health stakeholders should not be surprised nor panicked, but rather prepared as it’s almost inevitable that the human race will have to confront such serious challenges at some point in our history. It’s our duty to anticipate the worst and prepare ourselves as best we can. Remarkably, one common factor that ties together most, if not all, of the mentioned diseases is the lack of specific, effective and safe pharmacotherapy.
4- The potential role of early immune-modulatory treatment
Notably, it has been emphasized that the world must emerge from COVID-19 with a determination to better prepare, learning from its failures, for future pandemics. Unfortunately, as a global community, we still seem least prepared and our African COVID-19 approach, which has resulted in the lowest COVID-19 mortality rates worldwide, when compared to the population, even among the elderly and patients with multiple comorbidities could help us in this regard. Interestingly, if we exclude South Africa, which has entirely adopted the Western approach, with COVID-19 deaths exceeding the all other African countries combined, the morality paradox becomes even more evident. This argument could also explain why South African researchers emphasize the underestimated COVID mortality while ignoring that this underestimation, by at least 35%, is global, not just in Africa. From my perspective, a fair assessment of this paradox should consider our African early immune-modulatory treatment as implemented in the Egyptian Kelleni’s protocol, which has successfully saved patients of all ages and with various co-morbidities throughout COVID-19 pandemic and other virus-induced outbreaks, including influenza and respiratory syncytial viruses.
Notably, several viral infections, including the influenza virus, share common immune-inflammatory pathways that can lead to a cytokine storm in severe cases. This was the basis addressed by the drugs used in Kelleni’s immune-modulatory protocol as well as other suggested drugs Therefore, from both a pharmacological and clinical perspective, we suggest that the immune-modulatory early treatment approach remains our best weapon if and when unexpected virus-induced pandemics strike the world once again, as happened with COVID-19.
In the event of a virus-induced pandemic, early immune-modulatory treatment Could be our most valuable tool, especially in the early response phase. Notably, nitazoxanide, an integral component of Kelleni’s protocol, has been shown to be beneficial while assessing virus-induced encephalopathy in experimental live virus and cell-based assays. It has also been shown to be clinically effective in immune-modulatory treatment for an immune-compromised patient suffering from progressive encephalitis.
5- Conclusion
Finally, it’s highly recommended that some of the global resources dedicated to antiviral research be redirected towards promoting research in immunopharmacology. This field of clinical pharmacology could provide incredible solutions not only for infectious diseases but also for what we re-propose to call “immune system dysrhythmia” or “immune system dyssynergia” to describe the disrupted and uncoordinated immune homeostasis which is, from a pathophysiological standpoint, a hallmark of various medical conditions lacking optimal therapy including viral encephalitis.
Disclaimer
As a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also.
1- Introduction
In February 2018, the World Health Organization (WHO) designated an unknown potential epidemic disease as “Disease X”, placing it at the bottom of its shortlist of potentially fatal diseases that pose the greatest public health risk. This was a call to action for the world to prepare for the unknown. Shortly after, in November 2019, Coronavirus disease 2019 (COVID-19) emerged as the first Disease X the world witnessed. Unfortunately, we were ill-prepared and millions of lives were lost, mostly and paradoxically in the highly developed countries equipped with the best medical resources. Moreover, COVID-19 remains a persistent public health challenge, resulting in tragic losses, primarily in the developed countries. This is mainly attributed to the continuous evolution of SARS-CoV-2 variants and subvariants with immune-evasive properties e.g. the KP.3 and XEC subvariants. Interestingly, in March 2024, the WHO wisely launched a new network dedicated to early and accurate detection of SARS-CoV-2, MERS-CoV and novel coronaviruses of public health importance.
Despite COVID-19 being the first Disease X, similar and potentially more catastrophic pandemics are expected in both the short and long terms. Interestingly, on August 14, the WHO director-general declared a recent Mpox outbreak with the new Mpox virus strain that emerged last year, clade 1b, in Africa as a public health emergency of international concern and if there’s one lesson to be learned from COVID-19, it would be not to underestimate even a trivial threat and to maintain utmost vigilance. This article aims to discuss some important potential global public health threats while considering the worst case scenario of a pandemic of virus-induced encephalitis.
2- The current potential pandemics
The world has recently experienced an unprecedented spread of dengue virus disease beyond historical transmission areas, such as in Europe. This is largely attributed to climate change and/or evolutionary viral mutations, with global cases rising close to record highs. Similarly, due to global warming, experts have raised concerns about the potential transmission of the tick-borne severe viral Crimean-Congo hemorrhagic fever to the UK and other previously unaffected non-African countries .
Moreover, it’s important to note that fruit bats are known to be the reservoir of two other prioritized potentially epidemic/pandemic viral hemorrhagic diseases; Ebola virus disease and Marburg disease. Currently, both are endemic in some African countries only, but due to climate variations, the endemic settings could change and the threat could spread to areas beyond historical transmission.
Furthermore, the world could encounter unexpected infections if pteropid bat species which are the reservoir host of Nipah virus and/or the natural mosquito habitat involved in the pathogenesis of Rift Valley Fever were similarly affected. Notably, both infections are also among the mentioned list prioritized by the WHO.
3- The unseen potential of bioterrorism-induced pandemics
Recently, a preprint presented alarming results from gain-of-function research, raising global concerns that one of the SARS-related coronaviruses could potentially cause a new airborne pandemic. These researchers demonstrated the ability of the SARS-CoV-2 related pangolin coronavirus GX_P2V (short_3UTR) to cause a 100% mortality rate while using a human ACE2 transgenic mice experimental model. GX_P2V (short_3UTR) induced fatal encephalopathy, as shown by shrunken neurons in that research.
From my perspective, it’s important to be vigilant and globally prepared for a potential pandemic of virus-induced encephalitis as the worst case scenario in order to avoid huge losses as encountered during COVID-19 pandemic. This could arise from various sources including zoonotic spillover from virulent natural evolution, rogue or accidental break during gain-of- function laboratory research leading to more virulent versions of viruses such as herpes simplex,West Nile, SARS-CoV-2 as attempted in the aforementioned preprint, or even as a result of premeditated bioterrorism.
Notably, regardless of its wide distribution and its assumed acquired general immunity, Herpes Simplex Virus type 1 is the most frequently detected viral agent in samples derived from American and European viral encephalitis patients when compared to other family viruses including SARS-CoV-2. It’s important to also consider genetically modified Rabies and/or other neurotropic viruses in simulation of worst case scenarios as billions of people are considered vulnerable. Nevertheless, the public health stakeholders should not be surprised nor panicked, but rather prepared as it’s almost inevitable that the human race will have to confront such serious challenges at some point in our history. It’s our duty to anticipate the worst and prepare ourselves as best we can. Remarkably, one common factor that ties together most, if not all, of the mentioned diseases is the lack of specific, effective and safe pharmacotherapy.
4- The potential role of early immune-modulatory treatment
Notably, it has been emphasized that the world must emerge from COVID-19 with a determination to better prepare, learning from its failures, for future pandemics. Unfortunately, as a global community, we still seem least prepared and our African COVID-19 approach, which has resulted in the lowest COVID-19 mortality rates worldwide, when compared to the population, even among the elderly and patients with multiple comorbidities could help us in this regard. Interestingly, if we exclude South Africa, which has entirely adopted the Western approach, with COVID-19 deaths exceeding the all other African countries combined, the morality paradox becomes even more evident. This argument could also explain why South African researchers emphasize the underestimated COVID mortality while ignoring that this underestimation, by at least 35%, is global, not just in Africa. From my perspective, a fair assessment of this paradox should consider our African early immune-modulatory treatment as implemented in the Egyptian Kelleni’s protocol, which has successfully saved patients of all ages and with various co-morbidities throughout COVID-19 pandemic and other virus-induced outbreaks, including influenza and respiratory syncytial viruses.
Notably, several viral infections, including the influenza virus, share common immune-inflammatory pathways that can lead to a cytokine storm in severe cases. This was the basis addressed by the drugs used in Kelleni’s immune-modulatory protocol as well as other suggested drugs Therefore, from both a pharmacological and clinical perspective, we suggest that the immune-modulatory early treatment approach remains our best weapon if and when unexpected virus-induced pandemics strike the world once again, as happened with COVID-19.
In the event of a virus-induced pandemic, early immune-modulatory treatment Could be our most valuable tool, especially in the early response phase. Notably, nitazoxanide, an integral component of Kelleni’s protocol, has been shown to be beneficial while assessing virus-induced encephalopathy in experimental live virus and cell-based assays. It has also been shown to be clinically effective in immune-modulatory treatment for an immune-compromised patient suffering from progressive encephalitis.
5- Conclusion
Finally, it’s highly recommended that some of the global resources dedicated to antiviral research be redirected towards promoting research in immunopharmacology. This field of clinical pharmacology could provide incredible solutions not only for infectious diseases but also for what we re-propose to call “immune system dysrhythmia” or “immune system dyssynergia” to describe the disrupted and uncoordinated immune homeostasis which is, from a pathophysiological standpoint, a hallmark of various medical conditions lacking optimal therapy including viral encephalitis.