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AUTHOR: SEOK WOO YANG, MD & PhD.

CONTACT: Email: soplab@outlook.kr

DATE: 2020.07.30

CONTENT:

 During the early phase of the pandemic COVID-19, I published many therapeutic and preventive suggestions for COVID-19. The predictability of my suggestions are as the followings:

 Above 7 suggestions have been proved. 

 In addition to these, the significance of inherent herpes neuritins in association with COVID-19 will be unraveld in my opinion.

 There are several reports about the skin rash and Kawasaki disease-like symptoms in COVID-19 patients. A majority of these cases may be confirmed as the secondary clinical expression to inherent herpes neuritis.

 In this perspective, inherent herpes neuritis as the side effect of Hydroxychloroquine should be monitered and prepared for its treatment to use Hydroxychloroquine safely.

AUTHOR: SEOK WOO YANG, MD & PhD.

CONTACT: Email: soplab@outlook.kr

DATE: 2020.04.07

CONTENT:

 As of 7th April, in a small city with approximately 160,000 citizens, the confirmed COVID-19 + cases are 50. The mortality rate is 0.

 The patients in my clinic were mainly those with respiratory diseases. There have been no confirmed COVID-19 cases.

 Some patients had fevers. With the therapeutic strategy in line with several previous posts, there have been no confirmed cases of COVID-19 yet. Even several patients with fevers and bronchitis who dropped out of screening hospitals concerning COVID-19 without testing recovered without the aggravation of respiratory diseases. About the reason why they were dropped out of COVID-19 test even with fevers, has not it known.

 The therapeutic drugs administered did NOT include hydroxychloroquine and azithromycin.

 The taken home message is that primary care in the early phase of respiratory diseases amid COVID-19 contagion is a key factor to a key factor to prevent the patients from being vulnerable to COVID-19.

 Early diagnosis, Early treatment!

P.S.

 In some patients with neurologic signs, including headache, alteration of smell and taste and oral mucosa, acyclovir was prescribed simultaneously as I posted.

AUTHOR: SEOK WOO YANG, MD & PhD

CONTACT: soplab@outlook.kr

DATE: 2020.04.03

CONTENT:

 There are many reports about the potential neural damage by COVID-19 coronaviruses in light of SARS coronaviruses. 

 As a cause of the sudden death by COVID-19, the neural injury at the brainstem and brain spread through the olfactory nerve is presumed to play a role in respiratory failure. [1] 

 One interesting fact in the patients with COVID-19 is the loss of smell and taste, about which the author suggested the possibility of provocation of inherent herpes neuritis in the trigeminal ganglion within the brain.[2]

In the endemic area of COVID-19, the author has treated many patients with bronchitis. 

 Among them, some patients had fevers. Interestingly they all had concurrent herpetic mucosal change in their oral pharynx. The herpes mucosal change was various from the overt herpes aphthous minute ulcer to discoloration of the pharynx, the latter of which may be equivocal among physicians. After being treated with acyclovir and antibiotics, acetaminophen, mucolytics, a physiologic dose steroid for bronchitis, the fevers were subsided after 1-day treatment.

 Concerning another cause of sudden death by COVID-19, we need to focus on the possibility of the brainstem injury by inherent herpes neuritis in the brainstem or hypothalamus.[1] 

 But there is no statistical study about the presence of herpes viral infection in the brainstem or hypothalamus as yet. 

  The author experienced some cases with unknown fever, which at last proved to be herpes neuritis probably at the brainstem or/and hypothalamus involved in temperature control. The proof of herpes neuritis was measured by clinical improvement in response to acyclovir, valaciclovir, or famciclovir.  

 Like these cases, if patients have inherent herpes neuritis in the brainstem or hypothalamus and are newly affected with COVID-19, the antiviral immunity may be weakened, the condition of which provokes latent inherent herpes infection and aggravates COVID-19 coronaviral infection in the brainstem or hypothalamus. As a result of this event, the brainstem or hypothalamic injury may be induced and leading to the death of patients.    

 Unfortunately, this hypothesis can not be proved with MRI or blood tests. As the author's clinical experiences for several years, many patients with no abnormality in MRI or blood tests complained of their herpetic symptoms and eventually they were treated and clinically improved by taking in anti-herpetic drugs. 

 With the above facts on the concurrent and inherent herpes neuritis in the brainstem, the author thinks that the early prescription of acyclovir during treating bronchitis in the cases suspicious of COVID-19 may play a role in decreasing the mortality rate in the cases affected with the underlying herpes neuritis in the brainstem. 

P.S.

 About which to choose in antiherpetic drugs like acyclovir or famciclovir in the suspicious herpes neuritis in the patients with COVID-19, the author prefers to prescribing acyclovir as a first-line treatment. Famciclovir can be considered when there is no remarkable clinical improvement, even after using acyclovir.

REFERENCE:

[1]  Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play
a role in the respiratory failure of COVID-19 patients. J Med Virol. 2020 Feb 27.

[2] Yang SW. Herpes Neuritis Should Be Checked After Treating With Hydroxychloroquine or Chloroquine: Medical Inference.
https://gracelive.tistory.com/64?category=838022.

AUTHOR: SEOK WOO YANG, MD & PhD.

CONTACT: soplab@outlook.kr

DATE: 2020.03.30

CONTENT:

 On March 30th, FDA approves hydroxychloroquine or chloroquine to be used in treating COVID-19.

 As of today, the main purpose of using hydroxychloroquine and chloroquine is to modulate the cytokine storm and to decrease viral load. 

 There are several reports to favor the use of hydroxychloroquine and chloroquine in COVID-19. But some are skeptical about this theme.

 For example, Guastalegname & Vallone quoted the experimental case of Chikungunya viral infection which is treated with chloroquine. In this experiment, there was a paradoxical effect to show no effect on the acute phase of the disease but the chronic complications of Chikungunya, more frequently in the treated group compared with the control group.

 For this reason, they recommended that clinicians should use hydroxychloroquine and chloroquine cautiously.[1] 

  Coronaviruses and SARS coronaviruses can cause neurologic diseases including loss of smell and taste during a respiratory infection.[2] 

 Among the viruses inherent in human DNA, herpesvirus including simplex and zoster form should be kept in mind after respiratory viral infection.

 Herpesviruses normally reside in the DNA of our cell nucleus and acquire virulent infectivity when our immunity is weakened. 

 Herpesviruses in the trigeminal ganglion of the brain can cause loss of smell and taste like the cases with COVID-19.

 There are several reports that hydroxychloroquine was associated with an increased herpes zoster risk in patients.[3]

 For the above reasons, in the cases of COVID-19 with the administration of hydroxychloroquine and chloroquine, clinicians should check the neurologic diseases by herpes zoster or simplex, such as neural hearing loss, neurogenic dyspnea, etc.  

REFERENCE:

[1] Guastalegname M, Vallone A. Could chloroquine /hydroxychloroquine be harmful
in Coronavirus Disease 2019 (COVID-19) treatment? Clin Infect Dis. 2020 Mar
24:ciaa321.

[2] Bohmwald K, Gálvez NMS, Ríos M, Kalergis AM. Neurologic Alterations Due to
Respiratory Virus Infections. Front Cell Neurosci. 2018 Oct 26;12:386.

[3] Liao TL, Chen YM, Liu HJ, Chen DY. Risk and severity of herpes zoster in
patients with rheumatoid arthritis receiving different immunosuppressive
medications: a case-control study in Asia. BMJ Open. 2017 Jan 5;7(1):e014032.

Living rules to prevent COVID-19

For detailed explanation, refer to category "2019-nCoV, COVID-19" within this blog.

REVIEWER & COMMENTER: SEOK WOO YANG, MD & PhD

CONTACT: E.mail: soplab@outlook.kr

DATE: 2020.03.25

CONTENT:

 Casanova et al demonstrated fecally contaminated liquid droplets of SARS cases are a potential vehicle for contagion besides respiratory droplets. This study reported that SARS coronaviruses remained infectious in water and sewage for days to weeks.[1]

 For this reason, waterborne infection of COVID-19 coronaviruses should be checked meticulously to prevent further spread of COVID-19. 

 In addition to facial masks for blocking respiratory droplets, drinking water should be sterilized. At home, we must boil water or mix bitter herbs or lemons with water before drinking.

 The government should pay attention to sterilize water supply source.

REFERENCE:

Casanova L, Rutala WA, Weber DJ, Sobsey MD. Survival of surrogate
coronaviruses in water. Water Res. 2009 Apr;43(7):1893-8.

AUTHOR: SEOK WOO YANG, MD & PhD

CONTACT: E.mail: soplab@outlook.kr

DATE: 2020.03.22.

CONTENT:

 Besides the acute respiratory distress syndrome in the patients affected by COVID-19, the possibility of subclinical adrenal insufficiency should be considered. When patients are lethargic and dehydrated, intravenous glucose infusion can be considered. But if patients have adrenal insufficiency, intravenous glucose infusion can cause lethal damage, as the following reasons:

 Based on the genetic and clinical similarity of COVID-19 to SARS coronaviruses, the autopsy findings in SARS affected patients are helpful to expect the things to come during the disease progression. 

 In the autopsy of SARS cases, the adrenal glands in patients revealed necrosis, infiltration of monocytes and lymphocytes loaded with SARS coronaviruses within vessels, and thrombosis in small veins.[1][2]

 With this finding, we can infer the possibility of adrenal insufficiency.

 In patients with adrenal insufficiency who have not received glucocorticoids, glucose infusion may cause high fever ("glucose fever") followed by collapse and death. Presumably, the glucose is metabolized, and the water dilutes the plasma, and the resultant osmotic gradient between the plasma and the cells causes the cells of the thermoregulatory centers in the hypothalamus to swell to such an extent that their function is disrupted.[3]

 The author infers that the neuropathologic change of glucose fever may be similar to that of central pontine myelinolysis after too rapid medical correction of sodium deficiency (hyponatremia). Hyponatremia is often accompanied by adrenal insufficiency. Central pontine myelinolysis causes damage to myelin and neuron in the brainstem, especially pons and even extrapontine brain tissue.

 On this point, intravenous fluid therapy in COVID-19 patients, subclinical hyponatremia conditions should be also considered.  

 The brain tissues infected with SARS coronaviruses are supposed to be susceptible to this hypothetical neural damage. 

 Gu J et al summarized many reports about observations of the central nervous system affected with SARS-coronaviruses, as follows: 

 RT-PCR has detected SARS-CoV genomic sequences in cerebral spinal fluid and in brain tissue specimens. The virus has been successfully isolated from brain tissue. Edema and focal degeneration of neurons have been observed in the brains of SARS autopsies. IHC(immunohistochemical stain), in situ hybridization, and EM(electron microscopy) have confirmed viral infection of neurons. Gliocytes have also been found infected by SARS-coronaviruses.[4]

 With the above reasons, the possibility of adrenal insufficiency and related neurologic damage can be applied to the cases with COVID-19.

 For this reason, when patients with COVID-19 are lethargic and dehydrated, intravenous fluid therapy should be done without glucose except for overt hypoglycemic conditions and without rapid correction of hyponatremia. 

 To correct the adrenal insufficiency, the physiologic dose of steroids should be prescribed in the early phase of COVID-19. This may be also beneficial to prevent acute respiratory distress syndrome in COVID-19, for alveolar macrophages induce cytokine-related inflammatory responses that can be lessened by steroids. 

P.S.

 The physiologic dose of steroids the author recommends is methylprednisolone 1mg #2 (0.5mg intake two times) per day at a 60kg weighted person.

REFERENCE:

[1] Ding YQ, Wang HJ, Shen H, Li ZG, Geng J, Han HX, Cai JJ, Li X, Kang W, Weng DS, Lu YD, Wu DH, He L, Yao KT. The clinical pathology of severe acute respiratory syndrome (SARS): a report from China. J Pathol. 2003;200:282–289.

[2] Gu J, Gong EC, Zhang B, Zheng J, Gao ZF, Zhong YF, Zou WZ, Zhan J, Wang SL, Xie ZG, Zhuang H, Wu BQ, Zhong HH, Shao HQ, Fang WG, Gao DX, Pei F, Li XW, He ZP, Xu DZ, Shi XY, Anderson VM, Leong ASY. Multiple organ infection and the pathogenesis of SARS. J Exp Med. 2005;202:415–424.

[4] Gu J, Korteweg C. Pathology and Pathogenesis of Severe Acute Respiratory Syndrome. Am J Pathol. 2007 Apr; 170(4): 1136–1147.

[3] Ganong WF. Chapter 20. The Adrenal Medulla & Adrenal Cortex, In Review of Medical Physiology, 22nd ed. Appleton & Lange, 2005, p 370.

AUTHOR: SEOK WOO YANG, MD & PhD.

CONTACT: E.mail; soplab@outlook.kr

DATE: 2020.03.19

CONTENT:

 Conventional coronavirus is known as an ss(single-stranded) RNA virus. Its incubation period is 2 ~ 5 days, whereas novel coronavirus is 4 ~ 14 days and SARS one is 2 ~ 7 days. 

 As supportive evidence of the incubation period of novel coronavirus longer than that of SARS coronavirus, there was a report three persons recovered from COVID-19 still had positive RT-PCR results for novel coronaviruses, even without symptoms and contagion into nearby family members.[1] 

 Its clinical implication has not been solved. 

 Despite novel coronaviruses are similar to SARS ones, why is the incubation period of novel coronaviruses longer than SARS ones? 

 What are the factors to explain the above phenomena?

 In SARS, viral shedding is the nonlytic release of the vast majority of mature virions into the extracellular space via the Golgi apparatus from the ER.[2].  If novel coronavirus behaves in this way, the incubation period may be similar to that of SARS coronavirus.

 If so, there must be the other pathway for viral shedding and replication to be continued except for the extracellular space, namely the intracellular space.  

 Which compartment of the intracellular space is probably suitable for viral shedding and replication?

 The author supposes that the isolated hidden place for introverted viral shedding into the cell may be an intranuclear space, for the vast majority of viral release happens on the extracellular cytoplasmic border, as aforementioned.

 The author infers the answer from the point that the main target cell organelle by novel coronavirus is endoplasmic-reticulum(ER).    

 Among four main proteins in coronaviruses, N protein forms a complex by binding to genomic RNA and M protein triggers the formation of interacting virions in this endoplasmic reticulum-Golgi apparatus intermediate compartment(ERGIC) with this complex.[3][4]

 The characteristic electron microscopic findings of the alveolar epithelial cells in SARS cases are markedly dilated rough endoplasmic reticulum(RER) and smooth endoplasmic reticulum(SER).[5]

 Uniquely, there was a comment on the membranous inclusion bodies in some nuclei.[5]

 Considering the genetic & electron microscopic similarity of novel coronavirus to SARS coronavirus, the chance for nuclear inclusions to occur is high. 

 About the structure of nuclear inclusions, the reference journal did not include the related figure, and we can not clearly describe the electron microscopic feature to explain viral shedding into the intra-nuclear space.

 Instead, the electron microscopic finding of nuclear inclusions in the cells may be an alternative tool to explain why nuclear inclusions in novel coronaviral infected cells can be a hidden reservoir for persistent viral replication. 

 About the detailed structure of nuclear inclusion, that in pituitary adenoma may be appropriate for a comparable explanation. 

 The nuclear inclusion in pituitary adenoma is composed of the ER-rich cytoplasm within the cell nucleus.

 Yang et al(2003) analyzed the genesis of nuclear inclusion as the result of intracytoplasmic invagination into the nucleus. [6]  

 A part of the outline of the nuclear inclusion is composed of a double-layered membrane at the locus between the nucleus and the cytoplasm. Its origin can not be proved to be from whether ER or nuclear membrane.

 The point is that nuclear inclusion includes ER-rich cytoplasmic components, which is continuous with the ER on the cytoplasmic side.

 The author thinks that this nuclear inclusion with ER-rich cytoplasmic component can be a reservoir for persistent viral replication even during viral release into the extracellular space and cell division. 

 Despite the detrimental cytolytic cytotoxicity in COVID-19 cases, the presence of the long incubation period of novel coronaviruses can be explained by this hypothesis.

 Hence, further research for novel coronaviruses should be performed to investigate the presence of nuclear inclusions in COVID-19 cases.

P.S. 

 If nuclear inclusions in COVID-19 cases will be found, please correspond to me about the next step for therapeutic strategy.   

REFERENCE:

[1] Lan L, Xu D, Ye G, et al. Positive RT-PCR Test Results in Patients Recovered From COVID-19. JAMA. Published online February 27, 2020.

[2] Denison MR. CORONAVIRUS RESEARCH: KEYS TO DIAGNOSIS, TREATMENT, AND PREVENTION OF SARS. In: Institute of Medicine (US) Forum on Microbial Threats; Knobler S, Mahmoud A, Lemon S, et al., editors. Learning from SARS: Preparing for the Next Disease Outbreak: Workshop Summary. Washington (DC): National Academies Press (US); 2004.

[3] de Haan CA, Masters PS, Lili Kuo, Harry Vennema, Peter JM, Rottier. Coronavirus particle assembly: primary structure requirements of the membrane protein. J Virol. 1998; 72: 6838-6850. 

[4] Escors D, Ortego J, Enjuanes L. The membrane M protein of the transmissible gastroenteritis coronavirus binds to the internal core through the carboxy-terminus. Adv Exp Med Biol. 2001; 494: 589-593. 

[5] Ding Y, Wang H, Shen H, Li Z, Geng J, Han H, Cai J, Li X, Kang W, Weng D, Lu Y, Wu D, He L, Yao K. The clinical pathology of severe acute respiratory syndrome (SARS): a report from China. J Pathol. 2003 Jul;200(3):282-9.(PDF free download)

[6] Yang SW, Yang KM, Kang Hy, Kim TS. Intranuclear cytoplasmic pseudoinclusions in pituitary adenomas. Yonsei Med J. 2003 Oct 30;44(5):816-20.(PDF free download)