Study of homeopathic drug Veratrum viride for the prevention of ARDS in COVID-19

Study of homeopathic drug Veratrum viride for the prevention of ARDS in COVID-19 by activation of cholinergic anti-inflammatory pathway

ABSTRACT-

Background-In the current pandemic of COVID-19, the main complication seen in majority of patients is ARDS and respiratory failure. Cytokine storm is playing major role in the hyper inflammatory lung pathology. ‘Cholinergic anti-inflammatory pathway’ is neglected for years in immune modulation to control cytokine storm through activation of vagus nerve. Materials and Methods- A literature search was conducted using various bibliographic databases like PubMed etc, Google search engine to collect all relevant research and review articles about COVID-19 patholphysiology. Homeopathic materia medica books from different authors were reviewed for Veratrum viride. Repertorisation of most common pathological general symptoms seen in COVID-19 cases was done by Complete Repertory 2015. Conclusion-The scientific co-relation between patho-physiolgy of COVID-19 pneumonia and ARDS with homeopathic drug picture of Veratrum viride shows the importance of role of Veratrum viride in addressing cytokine storm by activation of Cholinergic Anti-inflammatory pathway for prevention of ARDS and death.

Keywords- Veratrum viride, COVID-19, prevention, ARDS, cholinergic anti-inflammatory pathway.

Abbreviations- COVID-19 (coronavirus disease 2019), ARDS (acute respiratory distress syndrome), VG (vagal ganglia) DRG (dorsal root ganglia), IL (interleukin), TNF (tumour necrosis factor), ACE2 (angiotensin converting enzyme2), SARS (severe acute respiratory syndrome), ANS (autonomic nervous system), SNS (sympathetic nervous system), PNS (parasympathetic nervous system), ACh (acetylcholine), NTS (nucleus tractus solitarius).

INTRODUCTION-

The most common complication of COVID-19 is rapidly progressing pneumonia and ARDS and is major cause of mortality. The bilateral lung involvement with ground glass opacity at the periphery of lungs is typical of COVID-19. ⁽¹⁾ Cytokine storm is considered to be one of the major causes of ARDS and multiple-organ failure and disease aggravation. ⁽²⁾ Effectively suppressing the cytokine storm is an important way to prevent the deterioration of patients with COVID-19 infection and save the patient’s lives.

OBJECTIVE OF THE STUDY-

The main objective of the study was to correlate the pathophysiological phenomena of the COVID-19 pneumonia with Veratrum viride and to describe the role of Veratrum viride in addressing cytokine storm of COVID-19 through cholinergic anti-inflammatory pathway.

MATERIALS AND METHODS- 

A literature search was conducted using various bibliographic databases like pubmed, google search engine to collect all relevant research and review articles about COVID-19 cases and patho-physiolical phenomena not only related to the COVID-19 lung pathology but also for the brain stem involvement in COVID-19. Database search was done for role of nervous system in controlling immunological responses and especially for cytokine storm. Homeopathic data was collected from the different homeopathic materia medica books and was related to Veratrum viride only. The repertorization was done by Complete Repertory 2015 and based on only pathological general symptom of COVID-19. Analysis of all the studies was done to correlate the relation between COVID-19 pathophysiology and the Veratrum viride materia medica.

Pathophysiology of lung in COVID-19 –

COVID-19-related severe respiratory distress is manifested by relatively well-preserved lung mechanics, despite the severity of hypoxemia, characterized by high respiratory compliance, high shunt fraction. The pathology in these cases differs from the diffuse alveolar damage and hyaline membrane formation which are hallmarks of typical ARDS. ⁽³⁾ The primary cause of death was respiratory failure with exudative diffuse alveolar damage with massive capillary congestion often accompanied by microthrombi despite anticoagulation. ⁽⁴⁾ Vascular enlargement is rarely reported in usual ARDS, yet was seen in most cases of COVID-19 ARDS. ⁽⁵⁾ Perfusion abnormalities, combined with the pulmonary vascular dilation is observed, are suggestive of intrapulmonary shunting toward areas where gas exchange is impaired, resulting in a worsening ventilation–perfusion mismatch and clinical hypoxia. ⁽⁶⁾ The pulmonary abnormalities in COVID-19 patients appear largely restricted to the alveolar capillaries, i.e., more of a thrombotic microvascular injury with few signs of viral cytopathic or fibroproliferative changes. ⁽³⁾ Local endothelial cell dysfunction in the pulmonary microvasculature is likely to play an important role in the thromboinflammatory processes that ultimately result in COVID-19 vasculopathy. ⁽⁷⁾ In lung autopsy reports upon macroscopic examination, the lungs of all patients were heavy, congested, and oedematous, with patchy involvement and diffuse alveolar damage. ⁽⁸⁾ Some COVID-19 cases shows an overproduction of early response proinflammatory cytokines such as interleukin (IL)-6, IL-1, and TNFα, leads to a cytokine storm. This hyperinflammatory state can cause lung injury, including damage to the microvasculature and endothelial dysfunction. Early intervention aimed at reducing inflammation might help prevent thrombosis. ⁽⁹⁾

Neurogenic Inflammation of lungs-

Neurogenic inflammation refers to the inflammation that is produced through the release of substances from the nervous system—in particular, from small-diameter primary afferent fibers. ⁽¹⁰⁾ The respiratory tract (higher and lower) is densely populated by sensory afferents originating from neurons in the vagal ganglia (VG) and dorsal root ganglia (DRG). . The crosstalk between nerve fibers and immune cells is critical in mediating inflammation of the airway following exposure to allergens or viral infection. Activation of these nerve fibre releases of several pro-inflammatory molecules, including substance P and cytokines such as IL-6. Pro-inflammatory substances have reported to be up regulated in COVID-19 cases and reflect the severity of the disease. ⁽¹¹⁾ Postganglionic sympathetic neuron may also play a role in neurogenic inflammation suggesting that there is a vagal mechanism affecting neurogenic inflammation. ⁽¹²⁾

Brain Stem Affection in COVID-19 –

Most of the patients of COVID-19 admitted could not breathe spontaneously. Some patients with COVID-19 also showed neurologic signs, such as headache, nausea, and vomiting. Increasing evidence shows that corona viruses are not always confined to the respiratory tract but may also invade the central nervous system inducing neurological diseases. ⁽¹³⁾ Respiratory distress is not only the result of pulmonary inflammatory structural damage, but also due to the damage caused by the virus in the respiratory centers of the brain. ⁽¹⁴⁾ As with other respiratory viruses, SARS-COV-2 may enter the central nervous system through the hematogenous or retrograde neuronal route by taking the path of the olfactory nerve. The latter can be supported by the fact that some patients are having smell impairment. ⁽¹⁵⁾ . Neurotropism could also occur at the level of the vagus nerve that terminates in the dorsal vagal complex in the brainstem. Many recently published papers reported ability of SARS-CoV-2 to attack human brain and also the eventuality of the involvement of the brain in the physiopathology of SARS-Cov-2. ⁽¹⁶⁾ COVID-19 was detected in the cerebrospinal fluid. There are ACE2 receptors in the rostral ventrolateral medulla in the brain. ACE2 converts angiotensin II to angiotensin 1–7.  An increase in the angiotensin 1–7 level in the brain activates the sympathetic nervous system which leads to systemic vaso-constriction and increase arterial blood pressure. Thus raised sympathetic activity leads to myocardial injury and ARDS by pulmonary capillary leakage. ⁽¹⁷⁾

Autonomic neural regulation of immunity-

The central nervous system regulates innate immune responses through hormonal and neuronal routes. The neuro-endocrine stress response and the sympathetic and parasympathetic nervous systems generally inhibit innate immune responses at systemic and regional levels, whereas the peripheral nervous system tends to amplify local innate immune responses. ⁽¹⁸⁾ The autonomic nervous system (ANS), composed of two primary branches, the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS), plays a critical role in regulating processes required for maintaining physiological homeostasis and responding to acute stressors. ⁽¹⁹⁾ About 75% of parasympathetic nerves fibers arise from the tenth cranial nerve, the vagus nerve. ⁽²⁰⁾ The ‘cytokine theory of disease’ states that an overproduction of cytokines can cause the clinical manifestations of disease. The ‘inflammatory reflex’ is a physiological pathway in which the autonomic nervous system detects the presence of inflammatory stimuli and modulates cytokine production. Afferent signals to the brain are transmitted via the vagus nerve, which activates a reflex response that culminates in efferent vagus nerve signaling. Termed the ‘cholinergic anti-inflammatory pathway’, efferent activity in the vagus nerve releases acetylcholine (ACh) in the vicinity of macrophages within the reticulo-endothelial system. ACh can interact specifically with macrophage alpha7 subunits of nicotinic ACh receptors, leading to cellular deactivation and inhibition of cytokine release. ⁽²¹⁾

Cholinergic anti-inflammatory pathway in immunomodulation-

 Vagotomy without stimulation significantly increased peak serum TNF levels as compared to sham operated controls. Stimulation of vagus nerve signals was shown to significantly inhibit TNF release in animals receiving lethal amounts of endotoxin ⁽²²⁾ The pulmonary parasympathetic inflammatory reflex may consist of three components: 1).The afferent arc residing in the distal airway or alveolus 2).The NTS information-integrating center in the brain stem 3).The efferent arc innervating the distal lung epithelial cells. Vagus nerve endings are reported to innervate the distal airway of the lung, possibly in the alveoli where varieties of sensors in the vagal afferent arc are located. Via this apparatus, mechanical, chemical, biological, and other stimuli in the alveoli can be sensed. Sensory neurons can recognize different pathogens. The information is transmitted via the afferent arm to NTS, a processing center, which is capable of differentiating types of infection, inflammation, or challenges. After processing, the active potentials are remitted from NTS to the alveoli via the vagal efferent arc. The vagal nerve endings could synthesize and release ACh, which in turn activates α7 nAChR in the proinflammatory cells (example: macrophages and neutrophils) or epithelial cells to regulate the production of proinflammatory cytokines. ⁽²³⁾ The efferent arm of the inflammatory reflex, termed as the “cholinergic antiinflammatory pathway”, is a highly robust mechanism for cytokine control and thereby can prevent tissue injury and death.

Study of Veratrum  viride materia medica–

The Veratrum alkaloids, which are chemically similar to steroids, include protoveratrine, veratridine and jervine. Of these alkaloids veratridine is the most potent. ⁽²⁵⁾ Veratrum viride in small doses has a selective action on the afferent (pulmonary) nerve-endings of the vagus and has also a direct action on the medullary centres leading to vaso-constriction and to paralysis of respiration. ⁽²⁶⁾

Site of action of Veratrum viride – cerebrospinal nervous system, especially pneumogastric nerve (vagus nerve), vasomotors, medulla, cranium, capillaries, arteries. ⁽²⁷⁾

Kind of action – The most of the action of Veratrum viride is spent upon the medulla oblongata causing Paralysis of its functions.. The medulla is the center that controls respiration and death takes place due to paralysis of the respiratory muscles. No remedy in the materia medica produces sudden and intense congestion and inflammation of the lungs as is caused by Veratrum viride, through its paralytic influence upon the motor filaments of the pneumogastric nerve. .  In one experiment (by Dr Burt) cats and dogs killed with the Veratrum viride all had inflammation of the lungs of the most marked character. The microscope revealed intense congestion and a large number of the capillary vessels ruptured together with the pressure and rupture of the capillaries, ends in hyperaemic congestion, or inflammation. Sections of the lungs were so completely hepatised, that, when thrown into the water, they immediately sank to the bottom of the vessel. ⁽²⁸⁾ Veratrum viride is indicated in frankly developed pneumonia. ⁽²⁹⁾ Violent Congestive Conditions; Active hyperemia especially cerebral – congestion of the base of brain and of upper portion of spinal cord therefore it interferes with function of pneumogastric nerves. ⁽³⁰⁾ Veratrum viride, by affecting the pneumogastric nerve (vagus), and by paralyzing its functions, produces congestion and inflammation in every organ and tissue to which it is distributed. ⁽³¹⁾ It is an invaluable remedy in those violent congestions which precede pneumonia. It may even abort the whole disease. It is also indicated when the engorgement is so profound as to threaten the death of the patient. It is indicated before hepatization has taken place. ⁽³²⁾ E. B. Nash quoted that- “It was claimed that if we could control the quickened circulation so as to decrease the amount of blood forced into the congested lung, that you thereby gave the lung a chance to free itself of the existing engorgement. It looked plausible, and certainly in many cases remarkable cures were effected, and that in a short time”. ⁽³³⁾

Repertory chart-

For repertorisation, the most common pathological general symptoms of COVID-19 were taken into consideration. (Repertorisation chart: Figure 1)

Discussion of Veratrum viride in co-relationship with COVID-19-

PRINCIPLE of homoeopathy is LIKE CURE LIKES; i.e. The drug that can produce some set of symptoms (Toxicological symptoms) in a normal individual; in homoeopathic potency is capable of removing that set of symptoms in the diseased person. So, toxicological poisoning of the drug gives us location of action and kind of action of that drug. Location of the homeopathic drug, kind of action and range of the action of the drug must be similar to the pathology or disease process.

The complication in COVID 19 patients is due to excessive vigorous response given by the immune system to the antigen (virus) i.e. Cytokine storm. Interestingly, Veratrum viride is the only remedy in the repertory for bilateral pneumonia. Bilateral pneumonia is atypical pneumonia and especially seen in many viral infection and it is due to the severe immunological response given by the body to antigen or virus. In homeopathic materia medica, Veratrum viride is indicated for STHENIC INFLAMMATION where the meaning of sthenic is active and vigorous. That also indicates the role of Veratrum viride in severe immunological reactions like cytokine storm. Repertorisation of the most common pathological general symptoms and the location of pathology in COVID-19 cases are also indicating towards the Veratrum-viride as a important totality. Brain stem is also an important site of infection because many patients show symptoms of loss of taste and loss of smell even before development of lower respiratory symptoms. Veratrum viride has action on the brain stem, medulla and capillaries. In COVID-19 we can see all these sites are important location of pathology. Even in COVID-19 ARDS, the lung capillaries are the main site of inflammation and rupture and thrombosis is seen. Though Veratrum viride is not in the repertory under thrombosis, Veratrum viride is given there in inflammation of small vessels and capillaries. Inflammation in small capillaries can always lead to thrombosis and necrosis. The typical lung autopsy findings of the Veratrum viride poisoned animals are also matching with the COVID-19 lung autopsy findings, where there is rupture of pulmonary capillaries, thrombus and lot of mucus. The role of Autonomic Neural control on immunity through ‘inflammatory reflex’ is also very important. If we can stimulate the vagus nerve then through its parasympathetic activation it is capable to control the cytokine storm. So its role in immunomodulation by ‘cholinergic anti-inflammatory pathway’ can be a life saving deal in cytokine storm. As discussed earlier by applying homeopathic law ‘like cure likes’, we can say that “if Veratrum viride in  toxic doses can produce severe inflammatory storm  by inhibiting the vagus nerve, then Veratrum viride in Homeopathic Potency can stimulate the vagus nerve and by activating ‘cholinergic anti-inflammatory pathway’ aborts cytokine storm” 

CONCLUSION-

From all above the discussion, one can conclude that Veratrum viride can be an important remedy in the current Pandemic of COVID 19 in congestive stage of bilateral frankly developed pneumonia due to cytokine storm and can prevent further complications like ARDS and death. From all the data reviewed we can hypothesize that, Veratrum viride in Homeopathic potency is capable of stimulating ‘CHOLINERGIC ANTI- INFLAMMATORY PATHWAY’ which is a ‘missing link’ for years in the management of inflammatory processes like cytokine storm. In the future, case control study of Veratrum viride in COVID-19 pneumonia should be done. Thus with proper experimentation and documentation Homeopathic Remedy Veratrum viride could be not only seen as alternative medicine but could be used as main stream remedy in COVID-19 pneumonia.

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About Author:

Dr Nilesh Suresh Pendurkar

B.H.M.S. PG HOM(London),

Director, Aarogya Homeopathic Clinic, Bazarpeth, Kanakavli, Dist- Sindhudurg, Maharashtra