COVID-19, Pneumonia & Inflammasomes – The Melatonin Connection

On March 11th, 2020 during a media briefing, the World Health Organizati\aon (WHO) declared COVID-19 a pandemic as confirmed COVID-19 cases outside of China increased 13-fold and the number of countries affected tripled.  On that day, 126,000 people around the world contracted COVID-19, while 122 countries around the world reported COVID-19 infections [3].

Even though cases in China and South Korea have declined dramatically, those in Italy and Iran have been rising relentlessly. Italy has the most cases outside China with roughly 12,462 infections, followed by Iran with 9,000 infections and South Korea with 7,775 (March 11th, 2020).  COVID-19 patients in Italy also have the highest case fatality rate, currently at 6.6% [3].

Unofficial reports from doctors and healthcare workers from COVID-19 frontlines in Italy described most patients displayed symptoms of bilateral interstitial pneumonia that required intubation (invasive ventilation) to assist difficulty in breathing. Even young patients without comorbidities have been observed with severe pneumonia that required intensive care in ICUs [4, 5].

These dramatic and shocking accounts of severe pneumonia in Italians infected by COVID-19 strongly support similar evidence presented by scientists and doctors in China where mortality of critically ill patients with SARS-CoV-2 pneumonia is extremely high. In one study,  86% of ICU patients requiring invasive mechanical ventilation did not survive [6].

In general, patients above 65 years of age with comorbidities and ARDS are at a much higher risk of death.  Acute respiratory distress syndrome (ARDS), or acute lung injury (ALI), is a condition when severe lung failure is marked by acute onset of respiratory failure, accompanied by low arterial oxygen levels.  Most often than not, bilateral opacities in the lungs are also observed in ARDS patients [7].

In one recent cohort study from China, 86% of patients with COVID-19 pneumonia showed typical imaging features of ground-glass opacities (GGO) in their lungs [8]; and 64% had mixed GGO and consolidation [9].  Most shocking of all, 70.2% of patients examined in the study were between the ages of 21 to 50 years [8]. Thus, young patients stricken with bilateral interstitial pneumonia in Italy is not inconsistent with the results of COVID-19 patients observed in China.

Why does SARS-CoV-2, the coronavirus responsible for COVID-19 infection, induce pneumonia in adult patients regardless of age?

COVID-19 Infectiousness & Increased Incidences of Pneumonia

A review of COVID-19 patients between January 12, 2020 to February 6, 2020 who managed to recover from COVID-19 pneumonia, all showed greatest severity of lung disease at approximately 10 days after initial onset of symptoms. The chart below excluded patients with severe pneumonia with symptoms of respiratory distress together with breath rates under 30 per minute, as well as patients who required mechanical ventilation assistance [14].

Distribution and frequency of the major of lung lesions on CT in different stages defined by the time of onset of symptoms.

[Source: Feng Pan, Tianhe Ye et al. Time Course of Lung Changes On Chest CT During Recovery From 2019 Novel Coronavirus (COVID-19) Pneumonia, Radiology Feb 13 2020 ]

By Stage 3, which is day 9 to day 13 after onset of symptoms, 86% of patients with non-severe pneumonia all showed lesions in both  lungs (bilateral). 17% of these patients showed no lesions during Stage 1, from onset of symptoms to the 4th day [14].

However, 81% of critically ill COVID-19 patients would progress to develop life-threatening Acute Respiratory Distress Syndrome (ARDS) [10].  Bilateral interstitial pneumonia will cause progressive scarring of lung tissues in both lungs, eventually reducing the capacity to breathe and the ability to circulate adequate oxygen in the bloodstream [11].  Once ARDS developes, mechanical ventilation assistance is required to faciliate breathing [15].

Coronaviruses are known for causing respiratory diseases with symptoms ranging from common colds to pneumonia [12].  The SARS-CoV or Severe Acute Respiratory Syndrome epidemic of 2003 infected over 8000 people worldwide, with a 10% mortality rate [13].  The closely related MERS-CoV of 2012, also induced acute pneumonia similar to the one caused by SARS-CoV [14].

The current SARS-CoV-2, with 79% similarity to SARS-CoV, also induces pneumonia of varying severity in adult patients regardless of age. However, unlike SARS-CoV that only infected 8,000 people worldwide in 8 months [16], the current SARS-CoV-2, which has been estimated to be up to 1,000 times more infectious than SARS-CoV or other coronaviruses [17, 18], has already infected over 120,000 people worldwide in under three months.

COVID-19 Upper Respiratory Tract Viral Load is 1000 Times HIGHER Than SARS (2003)

Due to the high mutation rate of the spike protein in SARS-CoV-2 [19], the virus is showing a pattern of higher infectiousness.  A study released by scientists in Germany on March 8th, 2020 found that this coronavirus is not only infecting lower respiratory tracts as seen in early January when COVID-19 patients in China examined displayed no obvious symptoms of rhinorrhoea (runny nose), sneezing, or sore throat, but all had pneumonia with abnormal chest CTs and 29% of those early patients examined developed ARDS (acute respiratory distress syndrome) [20].

The subjects from the German study were all young to middle-aged professionals without significant underlying disease, some had no comorbidity.  All cases were tested when symptoms were still mild, including fever, cough, rhinitis, sinusitis diarrhea. One subject had no symptoms at all. Upon taking throat swabs from these patients upon onset of symptoms, all results from day 1 to day 5 tested positive for COVID-19.  The high viral load from these early throat swabs indicated potential viral replication in upper respiratory tract tissues. This means that there is actually ACTIVE VIRAL replication of SARS-CoV-2 in the throat during the first 5 days after symptoms onset [21].

The positive early throat swabs contrasts starkly to SARS, where only 39% of nasal or nasopharyngeal swab samples tested positive in patients infected by SARS in 2003, Hong Kong [22].  The difference in viral loads detected between these two coronavirus ‘cousins’ are quite staggering. In Sars-CoV, it took 7 to 10 days after onet to reach peak RNA concentration. Whereas SARS-CoV-2 reached peak RNA concentration by only the 5th day.  In addition, the number of SARS-CoV-2 viral copies obtained per swab was ONE THOUSAND TIMES higher than those of SARS-CoV in 2003!  [22. 23, 24]

SARS-CoV-2 Spike Protein Furin Cleavage Site – The Reason For COVID-19 High Infectivity and Pathogenicity?

On March 11th, 2020, Wenling Wang et al. released an alarming paper detailing the results of 1070 specimens collected from 205 COVID-10 patients.  The mean age of patients was 44 years, between the ages of 5 to 67 years. 68% of the patients were male. The study specimens were collected from three hospitals in the Hubei and Shandong provinces and Beijing, China, during the period from January 1 through February 17, 2020 [25].

The team led by Wang collected pharyngeal (throat) swabs from patients 1 to 3 days after hospital admission.  Other samples from blood, sputum, feces, urine and nose were collected throughout the illness. 19% of the patients were in critical condition and required mechanical ventilation. These patients were sampled by bronchoalveolar lavage fluid and fibrobronchoscope brush biopsy [25].  What Wenling Wang et al. discovered supported the findings of the German team, led by Roman Wölfel [21].

The highest viral load was found in specimens from bronchoalveolar lavage fluid (93%), followed by sputum (72%), nasal (63%) fibrobronchoscope brush biopsy (46%), pharyngeal swabs (32%), feces (29%), and blood (1%). Interestingly, none of the 72 urine specimens tested positive for the coronavirus [25].

The team of German scientists led by Wölfel et al. proposed the hypothesis that the extension of tropism of the coronavirus is due to the furin cleavage site in the spike protein of SARS-CoV-2.  This cleavage site is not present in SARS-CoV [17, 18] The presence of furins on almost all cell surfaces allow a dramatically increased ability to fuse to host cells, facilitating viral entry even in cells that have low expressions of the ACE2 receptor [26].

The furin cleavage allows efficient virus entry into basically all cell types, making the COVID-19 easily transmissible at rates up to 1,000 times greater than the virulent SARS coronavirus [18]. This is possibly the reason why SARS (2003) infected only 8,000 people worldwide and COVID-19 infected over 120,000 people in one third of the time, even though both coronaviruses cause pneumonia of varying severity.

Cleavage specificity can dictate the tropism and virulence of the virus. The fact that COVID-19 has cleavage sites for furin enzymes renders this virus to be highly pathogenic, with the capacity to replicate in MULTIPLE tissues and organs due to how furins are utilized and distributed in the human body [27].

Furin-like cleavage in human coronaviruses have been associated with the development of neurological diseases where the invasiveness and efficient establishment of lower pathogenicity can result in persistent infection of the central nervous system [28].  Thus it was not a surprise when in early March of 2020, doctors from Beijing Ditan Hospital affiliated to Capital Medical University, a designated institution for COVID-19 treatment, showed for the first time that COVID-19 can attack the human central nervous system, causing symptoms of encephalitis [29].

The presence of furin enzymes on all cell surfaces cleaves and activates the SARS-CoV-2 in a wide range of tissues and organs. Activated SARS-CoV-2 then unleashes NLRP3 inflammasomes, initiating a flurry of immune reactions that can result in deadly cytokine storms. ….

There are no fatalities recorded for infected COVID-19 patients under the age of nine. The fatality rate increases linearly with age. The highest rate of fatality is seen in patients aged 80 and above [71].   Experts have yet to answer the question as to why COVID-19 is sparing young children [72].

While you ponder over this puzzle, take a look at this chart, which mirrors the above table but in REVERSE:

[Source: Grivas TB, Savvidou OD. Melatonin the “light of night” in human biology and adolescent idiopathic scoliosis. Scoliosis. 2007;2:6. Published 2007 Apr 4. doi:10.1186/1748-7161-2-6]

What does this chart measure?  An ancient and powerful molecule that everyone is familiar with – melatonin.  What does melatonin have to do with SARS-CoV-2?

Melatonin Inhibits NLRP3 Inflammasomes

Melatonin is well known for its chronobiotic effects, regulating biological functions tied to circadian rhythms.  Numerous studies have revealed that melatonin exerts effects beyond the control of circadian oscillators. The NLRP3 inflammasome is now recognized as a target for melatonin!

The fact that the pro-inflammatory cytokine storm effects are induced by the activation of NLRP3 inflammasomes, the ability of melatonin to INHIBIT NLRP3 inflammasome elevates this powerful molecule to a truly unique position in the fight against COVID-19.  This also means that if a patient, regardless of age, has adequate melatonin, the infectiousness of COVID-19 will be greatly reduced, and the chances of developing ARDS/ALI significantly diminished.

Melatonin is the reason why children under the age of 9 seldom exhibit severe symptoms. In fact, children may exhibit mild or even no symptoms at all, even though they have been infected by SARS-CoV-2 [73].  How significant is the difference in melatonin production between children, adults and the elderly?

For most people, peak melatonin production is between the hours of 2 am to 3 am.  The maximum melatonin levels measured in healthy adults between the ages of 65 to 70 years appeared to be around 49.3 picograms/ml (pg/ml).  Adults more than 75 years of age only have maximum production levels of 27.8 pg/ml [74].

Young children, on the other hand, have extremely high melatonin levels, compared to adults.  The maximum levels recorded for children showed a decline as age increased. Children between the ages of 1 to 5 had peak melatonin at 325 pg/ml, while those between the ages of 5 to 11 already declined to 133 pg/ml [76].

Compared to healthy adult seniors, a young child can easily have TEN TIMES the amount of peak melatonin levels.  But even then, the actual physiological concentration is extremely low. How much is one picogram, exactly?

To give you some perspective, most melatonin supplements are around 3 to 5 mg per capsule or tablet.  One milligram equals 1,000,000,000 picograms. That is why the physiological dosage generally recommended for melatonin supplementation is around 0.3 milligram [75].

The fact that young children have such high melatonin levels explains why they show very mild symptoms after COVID-19 infections. …

Melatonin secretion in the third trimester of pregnancy is more than doubled compared to the first trimester.

[Source: Voiculescu SE, Zygouropoulos N, Zahiu CD, Zagrean AM. Role of melatonin in embryo fetal development. J Med Life. 2014;7(4):488–492.]

However, if you noticed in the earlier chart showing melatonin levels during various ages, you will notice that infants younger than three months have very little melatonin [76].  Yet studies from China showed that infants under one year of age who were infected by COVID-19 did not exhibit any severe symptoms [90]. Why?

Nitric Oxide and Ascorbic Acid Inhibits NLRP3 Inflammasomes

Nitric oxide produced in nasal passages is possibly part of the defense system against bacterial and viral infections [91].  Newborns have been found to have an extremely high level of nitric oxide in their barely developed paranasal sinuses. The levels of nitric oxide in nasal passages of infants matched those found in adults [92].

In rodent sepsis models, nitric oxide was demonstrated to inhibit NLRP3 activation [93].   Ascorbic acid, in addition to supporting the production of nitric oxide [97], can act on multiple levels, reducing oxidative stress, regulating hypoxia signaling, mitochondrial membrane potential, furin expression, and modulation of immune defenses to stem the progression of cytokine storms [94, 95, 96].

Ascorbic acid can dose-dependently inhibit NLRP3 Inflammasomes both in vitro and in vivo, decreasing IL-1β secretion, without inducing any cytotoxic effects nor cell death [98].

Thus, the combined use of melatonin and ascorbic acid may prove to be most effective in the treatment for COVID-19 patients, especially those with cardiovascular and hypertension comorbidities.  …

Water fluoridation inhibits melatonin production:

Water Fluoridation Increases Suggestibility

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