Mutated COVID-19, May Foretells

Mankind in a Great Risk in the Future

Ali A. Dawood
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Mutated COVID-19, May Foretells Mankind in a Great Risk in the Future

Ali A. Dawood, Ph.D

PII: S2052-2975(20)30025-1
DOI: https://doi.org/10.1016/j.nmni.2020.100673
Reference: NMNI 100673

To appear in: New Microbes and New Infections

Received Date: 27 March 2020

Accepted Date: 30 March 2020

Please cite this article as: Dawood AA, Mutated COVID-19, May Foretells Mankind in a Great Risk in the
Future, New Microbes and New Infections, https://doi.org/10.1016/j.nmni.2020.100673.

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Mutated COVID-19, May Foretells Mankind in a Great Risk in The
Future
Ali A. Dawood
Ph.D. Microbiology, College of Medicine, University of Mosul, Mosul, Iraq

Abstract:
Corona virus disease 2019 SARS-CoV-2 (COVID-19) is a zoonotic virus causing a variety of
severe of respiratory diseases. SARS-CoV-2 is closest to SARS-CoV and MERS-CoV in
structure. The highly prevalence of COVID-19 is due to the lack onset of symptoms. Our study
aimed to present an overview of the virus in terms of structure, epidemiology, symptoms,
treatment, and prevention. Conduct the differences of whole genome sequence and some viral
proteins to determine the gap and the change alternation of nucleotides and amino acids
sequences. We evaluate 11 complete genome sequence of different coronavirus using BAST and
MAFFT software. We also selected 7 types of structural proteins. We were conclude that
COVID-19 might be created new mutations specifically in glycoproteins hence requires caution
and complete preparation by health authorities.
Keywords: COVID-19, MERS, outbreaks, SARS, zoonotic.
ORCID: 0000-0001-8988-5957, Email: aliadeldawood@gmail.com

Introduction:
The first emerging of novel coronavirus disease 19 was 31th, December 2019 in Wuhan city,
China. COVID-19 is classified the seventh member of the subfamily Orthocoronavirinae under
the family Coronaviridae. The most members of this family are zoonotic viruses that transmitted
to humans via contact with infected animals. Although the bats and snakes are the natural
reservoir of wide coronaviruses, there is no evidence so far that the COVID-19 was originated
and transmitted from the seafood market [1]. Previous study reported that lipid rafts of
coronaviruses have made new strain COVID-19 which is identity 80% to SARS-CoV. Lipid
molecules such as caveolins, clathrins and dynamin have a fundamental role in the
internalization of viruses. Firstly, these molecules are involved in the entry of viruses into host
cells. Second, targeting host lipids is being studied as an antiviral strategy and could have
various applications [2]. COVID-19 seems to need to bind to the ACE-2 receptor on the
membrane host cell to enable it to infect host cell upon coupled with a reliance of serine protease
TMPRSS2. This intracellular protein seems to be a determinant of the virus ability to infect cell
[3].
Mutated COVID-19, May Foretells Mankind in a Great Risk in The
Future

Abstract:
Corona virus disease 2019 SARS-CoV-2 (COVID-19) is a zoonotic virus causing a variety of
severe of respiratory diseases. SARS-CoV-2 is closest to SARS-CoV and MERS-CoV in
structure. The highly prevalence of COVID-19 is due to the lack onset of symptoms. Our study
aimed to present an overview of the virus in terms of structure, epidemiology, symptoms,
treatment, and prevention. Conduct the differences of whole genome sequence and some viral
proteins to determine the gap and the change alternation of nucleotides and amino acids
sequences. We evaluate 11 complete genome sequence of different coronavirus using BAST and
MAFFT software. We also selected 7 types of structural proteins. We were conclude that
COVID-19 might be created new mutations specifically in glycoproteins hence requires caution
and complete preparation by health authorities.
Keywords: COVID-19, MERS, outbreaks, SARS, zoonotic.

Introduction:
The first emerging of novel coronavirus disease 19 was 31th, December 2019 in Wuhan city,
China. COVID-19 is classified the seventh member of the subfamily Orthocoronavirinae under
the family Coronaviridae. The most members of this family are zoonotic viruses that transmitted
to humans via contact with infected animals. Although the bats and snakes are the natural
reservoir of wide coronaviruses, there is no evidence so far that the COVID-19 was originated
and transmitted from the seafood market [1]. Previous study reported that lipid rafts of
coronaviruses have made new strain COVID-19 which is identity 80% to SARS-CoV. Lipid
molecules such as caveolins, clathrins and dynamin have a fundamental role in the
internalization of viruses. Firstly, these molecules are involved in the entry of viruses into host
cells. Second, targeting host lipids is being studied as an antiviral strategy and could have
various applications [2]. COVID-19 seems to need to bind to the ACE-2 receptor on the
membrane host cell to enable it to infect host cell upon coupled with a reliance of serine protease
TMPRSS2. This intracellular protein seems to be a determinant of the virus ability to infect cell
[3].
Prevalence and epidemiology:
Over the past two decades, outbreaks of coronavirus have been observed, the Severe Acute
Respiratory Syndrome (SARS) - COV in 2003 and Middle East Respiratory Syndrome (MERS)
– CoV previously described as a major public health threat. Nowadays, the World Health
Organization considers COVID-19 is more serious and widespread epidemic disease [4]. To
date, it seems that the mortality rate of COVID-19 is lower than the incidence of SARS or
MERS. A significant increase number of COVID-19 cases was observed due to the absence of
emerging pathological symptoms in the virus carriers. For this reason, it may foster the collapse
of local health care [4]. Some countries face an outbreak crisis and try to prevent the spread of
COVID-19 through preventing human gatherings, a curfew is imposed in cities, prevent travel
between countries and close the land borders may reduce the outbreaks.
The main transmission of COVID-19 starts with contacted human to human including relatives
and friends who intimately contacted with patients or incubation carriers. Many studies reported
that coughing and sneezing are the quicker way of the virus dispersion as well as droplet, and
airborne precautions when encountering an infected person [5].
Virus structure:
COVID-19 relates to the betacoronavirus that infects humans and likely developed from bat
origin coronaviruses. Structural analysis shows that COVID-19 probably derives from a bat
SARS-like coronavirus, which has mutated in the spike glycoprotein (protein S) and
nucleocapsid N protein The positive-sense RNA genomes of COVID-19 is differ from SARS-
CoV and MERS-CoV approximately 29.9 kb, 27.9 kb and 30.1 kb, respectively [6]. The
COVID-19 complete genome was annotated to possess 14 open reading frames ORFs encode 27
proteins. Sequence analysis revealed that COVID-19 is identity 80% more than to SARS-CoV
and 50% to the MERS-CoV which originated in bat [7, 8]. In addition to that, spherical external
spike protein displays a characteristic crown shape can be observed under an electron
microscope [9]. Current study, we have compared between novel COVID-19 complete genome
with other related corona virus to provoke the mutation and the gaps. We selected the data from
NCBI and we did the FASTA and BLAST. The comparison between genomes with alignment
has done using MAAFT-7 software. COVID-19 gene bank (MT188341.1), COVID-19
(MT066175.1), bat-SL-CoVZC45 (MG772933.1), SARS-CoV BJ182b (EU371561.1) are
identical alignment in 99%, 89%, and 82% respectively. In figure (1) shows the differences
between 4 complete genomes shows as follow:
GGTATGAGCTATTATTGTAAATCACATAAACCGCCCATTAGTTTTCCATTGTGTGCTAAT 16440
................................A........................... 16494

GGACTACCAACTCAAACTGTTGATTCATCACAGGGCTCAGAATGTGACTATGTCATATTC 17820
...........................................A................ 17874

GGACTTTTTAAAGATTGTAGTAAGGTAATCACTGGGTTACATCCTACACAGGCACCTACA 18060
.....C...................................................... 18114

MT188341.1 + MT066175.1 similarity 99% partial seq.

TCATCAAACGTTCGGATGCTCGAACTGCACCTCATGGTCATGTTATGGTTGAGCTGGTAG 479
.............T.....C..............C..C...........C..AT.A.... 532

CAGAACTCGAAGGCATTCAGTACGGTCGTAGTGGTGAGACACTTGGTGTCCTTGTCCCTC 539
..........T...........T..........................T.......... 592

ATGTGGGCGAAATACCAGTGGCTTACCGCAAGGTTCTTCTTCGTAAGAACGGTAATAAAG
....A..A..GG.......T........T..A............................ 652
MT188341.1 & MG772933.1 similarity 89% partial seq.
GAAAACTTGTTACT-TTATAT--TGACATTAATGGCAATCTTCATCCA-GATTCTGCCAC 4017
A.T..---......C..G.T.GC...T..C.....T..G...T.-...T......-.AGA 3997

TCTTG-TT--A-GTGACATTGACATCACTTTCTTAAAGAAAGATGCTCCATATATAGTGG 4073
A.A..C..AG.G....-.--..T..GT.....C.TG....G.....A..T..C..G..A. 4054

GTGATGTTGTTCAAGAG-GGTGTTTTAACTGCTGTGGTTATACCTACTAAAAAGGCTGGT 4132
........-A...CT..T....A.A.C...TG...T..A.....CT.C............ 4113

MT188341.1 & EU371561.1 similarity 82% partial seq.

Figure (1): Final alignment between 4 complete genome

According to the alignment analysis, there is a closest similarity between 2 COVID-19 in 99%
compared with other 2 Bat CoV. 7 complete genomes have been alignment for different
coronavirus stains figure (2).

MT066175.1 SARS-CoV-2/NTU01/2020/TWN
MT039873.1 SARS-CoV-2 HZ-1

MN997409.1 SARS-CoV-2/USA-AZ1/2020

MN996532.1 Bat CoV RaTG13

EU371564.1 SARS-CoV -2 BJ182-12

KY938558.1 Bat CoV 16BO133

MN985325.1 SARS-CoV-2/USA-WA1/2020

Figure (2): MAFFT considers similarities in forward strands (red) only, but ignores similarities in reverse strands
(blue), Plot 1/2 alignment MT066175.1 + MT039873.1= 99.7%, plot 1/3: MT066175.1+ MN997409.1=99.7%, plot
1/4 MT066175.1+ MN996532.1= 89%, plot 1/5 MT066175.1+ EU371564.1= 82.4%, plot 1/6 MT066175.1+
KY938558.1= 68%, plot MT066175.1+ MN985325.1= 95%.

Upon to the result above, we revealed that all COVID-19 strains are closest similarity compared
to other strains related to the same family. In other words, we believe that COVID-19 came from
several mutations happened to other members of coronavirus relates to the same infection.
Although genomic analysis does not support the belief that COVID-19 is a laboratory construct,
currently it is impossible to disprove or prove the theories of its origin. To identify the COVID-
19 origin, obtaining virus sequences from immediate animal sources would be the most definite
method.
The first ORF (ORF1a/b) translates two polyproteins, pp1a and pp1ab, and encodes 16 non-
structural proteins (NSP) which takes two-thirds of viral RNA. The remaining ORFs encode
structural proteins including spike (S) glycoprotein, small envelope (E) protein, matrix (M)
protein, and nucleocapsid (N) protein. COVID-19 also possesses accessory proteins that interfere
with the host innate immune response [8].
We have done alignment for different strain of ORF10 COVID-19 GenBank: (QIK50446.1) with
the ORF10 COVID-19 (YP_009725255.1). The result gave similarity 100% without any
mutation in amino acid figure (3).
MGYINVFAFPFTIYSLLLCRMNSRNYIAQVDVVNFNLT 38

...................................... 38

Figure (3): 100% similarity between ORF 10 (QIK50446.1) and (YP_009725255.1).

Nucleocapsid phosphoprotein COVID-19 GenBank: (QIK50445.1) has been aligned with NP

COVID-19 (QIC50514.1) similarity 100%, NP SARS CoV CUHK-L2 (AAS01074.1) similarity
85%, and bat COV HKU5 (QHA24694.1) similarity 61% figure (4). Crystal structure of NP
COVID-19 (6VYO) has been released in 11/3/2020 from RCSB PDB figure (5).
MSDNGPQNQRNAPRITFGGPSDSTGSNQNGERSGARSKQRRPQGLPNNTASWFTALTQHG 60
............................................................ 60
KEDLKFPRGQGVPINTNSSPDDQIGYYRRATRRIRGGDGKMKDLSPRWYFYYLGTGPEAG 120
............................................................ 120
(QIK50445.1) + (QIC50514.1) similarity 100%
GKEDLKFPRGQGVPINTNSSPDDQIGYYRRATRRIRGGDGKMKDLSPRWYFYYLGTGPEA 119
...E.R.............G..............V........E................ 120
GLPYGANKDGIIWVATEGALNTPKDHIGTRNPANNAAIVLQLPQGTTLPKGFYAEGSRGG 179
S.......E..V.....XXXXXXXXXXXXXXXXXXXXXXXX................... 180

(QIK50445.1) + (AAS01074.1) similarity 85%

RATRRIRGGDGKMKDLSPRWYFYYLGTGPEAGLPYGANKDGIIWVATEGALNTPKDHIGT 148
.QD.K.NT.N.-T.P.A.......T......N..FRSV.......HEN..TDA.-SVF.. 136
RNPANNAAIVLQLPQGTTLPKGFYAEGSRGGSQASSRSSSRSRNSSRNSTPGSSRGTSPA 208
.....DP...T.FAP......N.HI..TG.N..S...A....SSR.SSRNGR.NNSSRN. 196
(QIK50445.1) (QHA24694.1) similarity 61%

Figure (4): alignment between (QIK50445.1), (QIC50514.1), (AAS01074.1) and (QHA24694.1).

Figure (5): Crystal structure of NP COVID-19 (6VYO) from RCSB PDB.

ORF7a protein COVID-19 GenBank: (QIK50443.1) has been aligned with NS7a Bat CoV
RaTG13 (QHR63305.1) similarity 99%, hypothetical protein SARS 7 CoV (AFR58706.1)
similarity 89% and putative uncharacterized protein 4 SARS CoV (AAX16199.1) similarity 68%
figure (6).
MKIILFLALITLATCELYHYQECVRGTTVLLKEPCSSGTYEGNSPFHPLADNKFALTCFS 60
.......V.V.................................................. 60
TQFAFACPDGVKHVYQLRARSVSPKLFIRQEEVQELYSPIFLIVAAIVFITLCFTLKRKT 120
...........................................I................ 120
(QIK50443.1) + (QHR63305.1) similarity 99%

MKIILFLALITLATCELYHYQECVRGTTVLLKEPCSSGTYEGNSPFHPLADNKFALTCFS 60
.......T..VFTS.....................P......................T. 60
TQFAFACPDGVKHVYQLRARSVSPKLFIRQEEV-QELYSPIFLIVAAIVFITLCFTLKRK 119
.H.....A..TR.T.........X.........Q......L......L..LI....I... 120
(QIK50443.1) + (AFR58706.1) similarity 89%
MKIILFLALITLATCELYHYQECVRGTTVLLKEPCSSGTYEGNSPFH-PLADNKFALTCF 59
.......T..VFTS.....................P..........AI.CFN.AYYILV. 60
STQFAFACPDGVKHVYQ 76
TRN-----.GSRRTL.. 72
(QIK50443.1) + (AAX16199.1) similarity 68%

Figure (6): alignment between (QIK50443.1), (QHR63305.1), (AFR58706.1) and (AAX16199.1).

ORF8 protein COVID-19 GenBank: (QIK50444.1) has been alignment with ORF8 protein
COVID-19 (QHN73801.1) similarity 99%, hypothetical protein Bat SARS CoV Rs806/2006
(ACU31050.1) similarity 76% and hypothetical protein Bat SARS CoV HKU3-8 (ADE34775.1)
similarity 84% figure (7).
MKFLVFLGIITTVAAFHQECSLQSCTQHQPYVVDDPCPIHFYSKWYIRVGARKSAPLIEL 60
............................................................ 60
CVDEAGSKSPIQYIDIGNYTVSCLPFTINCQEPKLGSLVVRCSFYEDFLEYHDVRVVLDF 120
.......................S.................................... 120
(QIK50444.1) + (QHN73801.1) similarity 99%
MKFLVFLGIITTVAAFHQECSLQSCTQHQPYVVDDPCPIHFYSKWYIRVGARKSAPLIEL 60
..L.IVF.LL.P.YCI.K...I.E.CEN...QIE......Y..D.F.KI.S....R.VQ. 60
CVDEAGSKSPIQYIDIGNYTVSCLPFTINCQEPKLGSLVVRCSFYEDFLEYHDVRVVLDF 120
.EGDY.KRI..H.EMF....I..E.LE....A.PV...I....YDY..V.H......... 120
(QIK50444.1) + (ACU31050.1) similarity 76%

GNYTVSCLPFTINCQEPKLGSLVVRCSFYEDFLEYHDVRVVLDFI 121
....I..E.LE....A.PV...I....YDY..V.H.......... 47
(QIK50444.1) + (ADE34775.1) similarity 84%

Figure (7): alignment between (QIK50444.1), (QHN73801.1), (ACU31050.1) and (ADE34775.1).

ORF6 protein COVID-19 GenBank: (QIK50442.1) has been aligned with ORF6 protein COVID-
19 (QIG55989.1) similarity 98%, protein 7 Rhinolophus affinis CoV (AHX37562.1) similarity
88% and NSP 6 SARS CoV ExoN1 (AGT21083.1) similarity 86% figure (8).
MFHLVDFQVTIAEILLIIMRTFKVSIWNLDYIINLIIKNLSKSLTENKYSQLDEEQPMEI 60
.............................................V.............. 60
(QIK50442.1) + (QIG55989.1) similarity 98%

MFHLVDFQVTIAEILLIIMRTFKVSIWNLDYIINLIIKNLSKSLTENKYSQLDEEQPMEI 60
...............I.......IA.....V..SS.VRQ.F.P..KKN..E..D.E.... 60
(QIK50442.1) + (AHX37562.1) similarity 88%
MFHLVDFQVTIAEILLIIMRTFKVSIWNLDYIINLIIKNLSKSLTENKYSQLDEEQPMEI 60
..............SI......RIA.....V..SS.VRQ.L.P..KKN..E..D.E...L 60
(QIK50442.1) (AGT21083.1) similarity 86%

Figure (8): alignment between (QIK50442.1), (QIG55989.1), (AHX37562.1) and (AGT21083.1).

Membrane glycoprotein COVID-19 GenBank: (QIK50441.1) has been aligned with MG

COVID-19 (QIG55988.1) similarity 99%, M protein COVID-19 (APO40582.1) similarity 93%
and membrane glycoprotein Rousettus Bat CoV HKU9 (YP_001039974.1) similarity 61% figure
(9).
MADSNGTITVEELKKLLEQWNLVIGFLFLTWICLLQFAYANRNRFLYIIKLIFLWLLWPV 60
........................................................V... 60
TLACFVLAAVYRINWITGGIAIAMACLVGLMWLSYFIASFRLFARTRSMWSFNPETNILL 120
............................R............................... 120
(QIK50441.1) + (QIG55988.1) similarity 99%
SNGTITVEELKKLLEQWNLVIGFLFLTWICLLQFAYANRNRFLYIIKLIFLWLLWPVTLA 63
E.D....DQ..H.............FA..L......S...........V.......I... 62
CFVLAAVYRINWITGGIAIAMACLVGLMWLSYFIASFRLFARTRSMWSFNPETNILLNVP 123
............A....................V...........W.............. 122
(QIK50441.1) + (APO40582.1) similarity 93%
DSNGTITVEELKKLLEQWNLVIGFLFLTWICLLQFAYANRNRFLYIIKLIFLWLLWPVTL 62
NCTN.VPRP.VIAA.KD..FAVSVIL.FITV...WG.PS.CKPIWV..MFI......LSI 63
ACFVLAAVYRINWITGGIAIAMACLVGLMWLSYFIASFRLFARTRSMWSFNPETNILLNV 122
.AA.F..IHP..SVAF.F...F..IS.I.......S....LC..G.A...M...DM.I.I 123

(QIK50441.1) + (YP_001039974.1) similarity 61%

Figure (9): alignment between (QIK50441.1), (QIG55988.1), (APO40582.1) and (YP_001039974.1).

Envelope protein COVID-19 GenBank: (QIK50440.1) has been aligned with EP COVID-19
(QHZ00381.1) similarity 98%, Chain A, Envelope small membrane protein SARS CoV
(5X29_A) similarity 90% and envelope protein Hypsugo Bat CoV HKU25 (ASL68947.1)
similarity 56% figure (10).
MYSFVSEETGTLIVNSVLLFLAFVVFLLVTLAILTALRLCAYCCNIVNVSLVKPSFYVYS 60
....................................H....................... 60
(QIK50440.1) + (QHZ00381.1) similarity 98%

FVSEETGTLIVNSVLLFLAFVVFLLVTLAILTALRLCAYCCNIVNVSLVKPSFYVYSRVK 63
.Q.M................................A..AA..........TV....... 79
(QIK50440.1) + (5X29_A) similarity 90%
MYSFVSEETGTLIVNSVLLFLAFVVFLLVTLAILTALRLCAYCCNIVNVSLVKPSFYVYS 60
.LP..Q.QI.SF...FFIFTV.CAIT...CM.F...T...MQ.AIG..TL..Q.AI...N 60
(QIK50440.1 (ASL68947.1) similarity 56%

Figure (10): alignment between (QIK50440.1), (QHZ00381.1), (5X29_A) and (ASL68947.1).

By analyzing the series compatibility of the proteins sequences under study, we can confirm that
there is a match between strains of COVID-19. There are obvious differences with respect
compared to other species of coronavirus family. This may indicate that COVID-19 originated
from mutations happened in coronavirus family. In clearer terms, new mutations may be created
as there in a high probability, specifically in glycoproteins.
We are unable to give reasonable explanations for the significant number of amino acid
substitutions between the COVID-19 and SARS-CoV or MERS-CoV due to very limited
knowledge of this novel virus.
Clinical manifestation and symptoms:
The incubation period of the virus may dissimilar accordingly to the age and immune status. As a
general, it has been assumed that incubation period sites between 2-14 days while some cases
observed till 23 days after exposure. The main symptoms can easily seem with elderly aged
above 70 and immunocompromised and diabetic patients. The symptom starts with fever, dry
cough, dyspnea, as well as sore throat, nasal congestion, malaise and bilateral infiltrates may be
seen on chest X-ray, however some cases are detected absence of fever. Clinical features of
COVID-19 include the targeting of the lower airway as evident by upper respiratory tract
symptoms like rhinorrhoea, sneezing, and sore throat which is developed to gastrointestinal
symptoms like diarrhea [10]. Severe cases may present with sepsis, heart attack or even shock.
Conversely, some cases may show mildly ill or asymptomatic altogether.
From WHO records, the period from the symptoms onset and to death of COVID-19 ranged
from 6 - 41 days with a median of 14 days. This period depends on the age and the status of
immune system. It has been shorter with age under 70 years [11].
Preventions:
To prevent spreading virus, managed care of patients with entails early identification. Rapid
isolation, timely establishment of infection prevention and control measures, together with
symptomatic care for patients with mild disease. Supportive treatment for those with severe
COVID-19. Specific attention and spend more efforts to reduce transmission should be presented
to susceptible populations including health care providers, immunocompromised patients,
children, and elderly people [5]. Health care systems around the world must operate with more
than one maximum capacity. It is necessary to cooperate between HCS and WHO to reduce
infection. The use of international media, social media and societal culture by maintaining
personal cleaning, minimizing risk of exposure, avoiding gatherings and preventing all
phenomena that lead to contact between persons [12]. COVID-19 vaccines is under accelerated
development.
The global public health community have to consider the effects of mass gathering cancellations
on the future wellbeing of communities through economic recession as well as through the
spread, or otherwise, of COVID-19 [13].
Diagnosis:
Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) is the most specific and
sensitive assay approved and straightforwardly used by many reference laboratories worldwide.
Other laboratory tests may help assessing disease severity and predicting the risk of evolution
such as cute respiratory distress syndrome (ARDS) disseminated intravascular coagulation (DIC)
and multiorgan failure (MOF). Moreover, C reactive protein (CRP), lactate dehydrogenase
(LDH), erythrocyte sedimentation rate (ESR) and D-dimer, along with diminished concentration
of serum albumin, increased values of LDH, aspartate aminotransferase (AST), alanine
aminotransferase (ALT), total bilirubin, creatinine, cardiac troponins, are used to enhanced and
helpful tests for organs function. Notably, a combined IgM-IgG rapid immunoassay has also
been recently developed as well as elevation of pro-inflammatory cytokines detection kits such
as IL1-β, IL1RA, IL7, IL8, IL9, IL10, basic GCSF, IFNγ, TNFα,and IP10 [14]. A study revealed
that gastrointestinal symptoms with COVID-19 was not associated with viral RNA in the fecal
sample or extended duration of the viral RNA positivity in the feces.
COVID-19 RNA has been isolated from human saliva, nasopharynx and lower respiratory tract.
CT findings and lung abnormalities increased quickly after the onset of symptoms, and followed
by persistence of high levels in extent for a long duration. CT manifestations are important
inspected pattern over time [15]. A study was conducted that there is no evidence that TNF-α
inhibition will increase the risk of COVID-19 outbreaks, specifically [16].
Treatment:
At a moment, there is not yet any approved antiviral treatment for COVID-19. The
implementation of antiviral treatment and prophylaxis has several requirements to dip their risk.
Drugs can be administered shortly after symptom onset to reduce infectiousness and plummeting
viral shedding in the respiratory secretions. Some studied have approved hydroxychloroquine as
antiviral activity in vitro against coronaviruses, and specifically, COVID-19. Remarkably, this
drug was licensed for the chemoprophylaxis and treatment of malaria. Furthermore, drug testing
suggest that prophylaxis with hydroxychloroquine at approved doses may prevent COVID-19
infection and amend viral shedding [17]. Clinical trials of hydroxychloroquine treatment for
COVID-19 pneumonia have showed positive preliminary outcomes in China.
Unfortunately, corticosteroid treatment is commonly used in clinical practice for influenza virus
such as acyclovir, ganciclovir, ribavirin, and methylprednisolone as well as neuraminidase
inhibitors including (peramivir, oseltamivir, and zanamivir,) are invalid for COVID-19 and not
recommended [18].
Conclusions:
Currently, the scientists have made progress in characterizing the new coronavirus, and there are
still many questions that need to be answered. COVID-19 is the greatest biological hazard to
assume the relevance of insidious worldwide threat today. COVID-19 is a highly contagious
during the latency period. It is necessary may adopt and invest more modern technologies both to
facilitate notification, to allow speedier data dissemination and analysis in keeping with the
principles of precision epidemiology.
We suggest that close contact with an infected person is the major factor in disease transmission.
Healthcare workers also have to follow the CDC guidelines and should not attempt to perform
any virus isolation or characterization. The effect of mass gathering cancellations on reducing the
spread of COVID-19 needs to be determined. Current study conducted that any mutation
occurred in the former protein is especially important. There is no evidence that part of COVID-
19 is synthetic.
Declaration of competing interest:
The authors declare no conflicts of interest.

Acknowledgement:
At the end of this study, we would like to inform that all research budgets were self-supporting
without any institute donation.

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Another random document with
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 FIG. 57.

Diagram to represent the Mode of Action of Counter-irritants applied to

the Chest (Lauder Brunton). The irritation of the afferent nerves by the
blister on the chest wall gives rise to a vaso-constrictor reflex in the
vessels of the lung.

Since the vaso-motor nerves are connected almost exclusively with

the dorsal portion of the spinal cord, it is very natural to conclude that
the vaso-motor reflex centres are situated in this region; and the
hypothesis has been advanced by Jacubovitch, and strongly urged
by Gaskell,11 that the cells of the vesicular columns of Clarke, which
are peculiar to this region, are the seat of these reflex mechanisms.
This hypothesis gains some support from the pathology of syringo-
myelia. In this disease the gray matter surrounding the central canal
and the vesicular columns are destroyed. The characteristic
symptoms are vaso-motor and trophic disturbances, consisting of
changes in the vascular tone, changes of local temperature, and
various eruptions, in some cases going on to ulceration in the skin
and mucous membranes. It is, however, undecided whether the
vaso-motor centres of the cord are limited to the columns of Clarke,
or are situated in the gray matter surrounding the central canal, since
both these parts are destroyed in this disease.12 That they are not
located in the anterior or posterior gray cornua is determined by the
fact that diseases limited exclusively to these areas do not cause
vaso-motor disturbances. The situation of the various reflex centres
for the various parts of the body is at different levels of the cord, as
has been determined by the experiments already cited to establish
the level of origin of the vaso-motor nerves. The exact location of the
vaso-constrictor and vaso-dilator reflex centres for definite parts is
yet to be ascertained.
11 Loc. cit.
 12 See Fürstner, Arch. für Psych., xiv. 422.

Vaso-motor Tracts.—These reflex centres are connected with the

medulla by tracts which lie in the lateral columns of the spinal cord,13
although it is not determined in which part of these columns. It is not
possible as yet to separate the constrictors from the dilators in this
tract, nor to determine whether it transmits impulses in both
directions or only from above downward. Nor is the course of
associating fibres between reflex centres at different levels known. In
cases of transverse myelitis the control of the medulla is removed
from the vascular centres below the lesion, and the lack of vascular
tone seen in the paralyzed limbs, together with the susceptibility to
local irritation, is the result of this division of the vaso-motor tracts.
13 “Owsjanikow and Tschirijew,” Bull. de l'Acad. de St. Petersbourg, xviii. 18.

Medullary Centres.—It has been stated already that a general vaso-

motor centre with both constrictor and dilator powers is situated in
the medulla. This lies in two divisions on each side of the middle line,
in or just beneath the floor of the fourth ventricle, from the calamus
scriptorius up to the level of the sixth nerve-nucleus. Each division
governs the vascular tone of its own side of the body,14 and lesions
in its region in man produce unilateral vaso-motor symptoms.15 This
centre can be excited to reflex action by strong irritation locally or
through the blood, in which case a general constriction or dilatation
of the vessels of the entire body will ensue. It seems probable,
however, that the general centre in the medulla is made up of a
number of special centres, each of which governs a definite set of
organs. The vascular tone of the thoracic and abdominal viscera is
certainly regulated by a series of such centres. Brown-Séquard and
Schiff have produced hemorrhages in the lungs, pleura, stomach,
intestines, and kidneys at different times by destructive lesions of the
medulla, and the well-known experiments of Bernard, in which by
puncture of the medulla local hyperæmia of the liver or kidneys was
caused, producing glycosuria or polyuria, confirm this view. Lesions
of these parts in man produce similar effects. Charcot has shown
that in cerebral hemorrhage ecchymoses may be found in the
stomach, pleura, and endocardium, and that pneumonia is especially
frequent upon the paralyzed side. De Jonge16 has been able to
collect thirteen cases of diabetes mellitus in which a lesion of the
medulla (hemorrhage or tumor) was found after death; and Flatten17
has proven the existence of similar lesions in diabetes insipidus. The
connection of these centres with the liver and kidneys has been
traced elsewhere.18 The medulla contains a special centre for the
vaso-motor nerves of the abdomen, which are in the domain of the
splanchnic nerves. This centre is excited reflexly by impulses
reaching it through the depressor nerve of Cyon from the heart; so
that when that organ is overburdened it may be relieved by a fall of
arterial pressure produced by dilatation of the abdominal vessels.
Whether the connection of the medulla with the centres in the
semilunar ganglion which preside directly over these vessels is
made by way of the spinal cord or by way of the pneumogastric
nerve is still undetermined, though the researches of Gaskell favor
the former view. Gastric and intestinal disturbances are certainly
produced by nervous lesions in the medulla, but whether they are
due to vascular changes is uncertain. The vomiting of mucus and
blood, and the large watery evacuations which accompany mental
shock or anxiety, as well as the polyuria associated with mental
effort, have been ascribed to irritation of local centres in the medulla
governing the gastro-intestinal and urinary organs by impulses
received from the cortex above. The spleen is under the control of
vaso-motor centres, since section of the splenic branches of the
semilunar ganglia will produce a great enlargement of the organ, and
irritation of the cut end of these branches will produce contraction.19
The medulla also contains a vaso-dilator centre for the erectile
tissues of the genital organs, irritation of which by mental action or
local disease causes impulses to pass to the nervi erigentes by way
of the spinal cord, resulting in a flow of blood to the parts. Although a
centre has been thought to exist controlling the circulation in the
lungs, whose paralysis has been supposed to explain the occurrence
of sudden pulmonary œdema without other known cause, no definite
facts regarding it are known. That the action of the heart is under the
control of the medulla is a fact too well known to require more than a
mention. The physiology of the nervous control of the heart cannot
be discussed here.
14 Owsjanikow, Arbeiten aus d. Physiol. Instit. zu Leipzig, 1871.

15 M. A. Starr, “Sensory Tract in Central Nervous System,” Journ. Nerv. and Ment.
Dis., July, 1884, pp. 396-398.

16 Arch. f. Psych., xiii.

17 Ibid.

18 See Tyson, “Diabetes Mellitus,” Pepper's System of Medicine, Vol. I. p. 195; Edes,
“Diabetes Insipidus,” ibid., Vol. IV. p. 30.

19 Tarchanoff, Pflüger's Arch., viii. p. 97; Ross, Diseases of the Nervous System, vol.
i. p. 225.

While these medullary centres are certainly influenced by impulses

reaching them from the cerebral hemispheres, as is evident from the
vaso-motor symptoms produced by mental action—e.g. pallor from
fright, blushing, etc.—it is impossible to state in what portion of the
hemispheres in man the higher vaso-motor centres lie. Eulenburg
and Landois locate them in the motor area in animals.20 They are
certainly beyond control of the will, and are wholly reflex in their
action, a purely mental act in this case being the excitant of a purely
physical result.21
20 Arch. f. Path. Anat., Bd. lxviii. p. 245.

21 In addition to the articles already cited the reader is referred to Landois's

Physiology, to Duval's article, “Vaso-moteurs,” in the Dictionnaire de Médecine et de
Chirurgie, vol. xxxviii. (1885), for a summary of vaso-motor physiology, and to
Gerhardt's “Ueber Angio-neurosen,” Volkmann's Sammlung klin. Vorträge, No. 209.
Gaskell's researches, published in the Journal of Physiology, are the most recent and
satisfactory.
PATHOGENESIS.—From this review of the physiology of the vaso-motor
system it becomes evident that disturbances of vascular tone may
be produced by many different causes acting upon many various
parts. They may be due to local affections of the part in which the
symptoms are present, as in the case of erythema22 after burns or
frost-bite, or congestion of any organ after injury. They may be due
to affections of the vaso-motor nerves passing to the part affected,
as in the case of vascular changes due to peripheral nerve lesions.23
They may be due to affections of the sympathetic ganglia connected
with the part affected, as in the case of migraine,24 sudden flushing
of one ear, certain cases of polyuria,25 and Basedow's disease.26
They may be due to lesions in the spinal cord affecting the vaso-
motor centres27 or compressing the nerve-roots on their way to and
from the sympathetic ganglia,28 as is the case in the various forms of
myelitis and in Raynaud's disease or symmetrical gangrene, and in
meningitis, tumors of the cord, or Pott's disease. They may also be
caused by such conditions in the cord as cut off the vaso-motor
centres from the medullary centres, such as transverse myelitis from
compression or traumatism.29 They may be due to lesions of the
medulla oblongata,30 as is seen in some cases of polyuria and
glycosuria,31 and in cases of universal erythema32 following acute
fevers. They may be due to diseases of the cerebral hemispheres,
as is evident from the vaso-motor symptoms occurring in hemiplegia
and hysteria. Finally, they may be of a reflex origin, dependent upon
some obscure source of irritation in a part quite distant from the
region in which the symptoms appear.33
22 Vol. IV. p. 511.

23 Vol. V., “Neuritis.”

24 Vol. V., “Migraine.”

25 Vol. IV., “Polyuria.”

26 Vol. III. p. 761.

27 Vol. V., “Syringo-myelitis.”

 28 Vol. V., “Meningitis Spinalis.”

29 Vol. V., “Transverse Myelitis.”

30 Vol. V., “Medulla.”

31 Vol. I., “Diabetes Mellitus.”

32 Vol. IV. p. 512.

33 Vol. V. p. 205.

The DIAGNOSIS of the seat of the lesion in many cases of vaso-motor

neurosis may be made if the organ or the exact limitation of the area
affected be ascertained, and the history of the case, together with
the concurrent symptoms of other kinds, be considered. In some
cases no organic cause can be found, and in these a reflex cause
should be diligently searched for.

SYMPTOMS.—A vaso-motor affection may manifest itself either by a

spasm or a paralysis of the vessels. In angiospasm the part affected
becomes pale, and irritation no longer causes a vaso-motor reflex. It
looks shrunken, and if the skin over it is loose it may be thrown into
folds or shrivelled, presenting the appearance seen in the hands
after long immersion in hot water. The lack of blood in the part
arrests the processes of metabolism which are normally constant,
and if the condition continues this may result in such a disturbance of
nutrition that ulceration, or even gangrene, may ensue. The local
anæmia, combined with the cessation of metabolism, produces a fall
of temperature in the affected part, which is then more easily
affected by the temperature of the air than in a normal state, so that
exposure to cold is very liable to cause freezing. These conditions
necessarily produce an impairment of function, so that if the affection
is located in the extremities, as the fingers, they are soon rendered
useless. The term digiti mortui has been applied to this state. In the
surface of the body angiospasm causes cutis anserina, pallor,
numbness, tingling, slight anæsthesia, and analgesia. If it occurs in a
limb, the finer motions are imperfectly performed, and in time the
nutrition of the muscles may be so impaired as to produce atrophy
and paresis. It may even lead to gangrene. Nothnagel has
recorded34 five cases of sciatica in which the pain produced a reflex
spasm of the vessels of the leg, which, persisting, resulted in partial
paralysis, atrophy, lowering of temperature, pallor, and sensory
disturbances. Ross mentions35 the sudden appearance of
circumscribed patches on the hands and forearms of washerwomen,
in which there is a pallor, coldness, and partial anæsthesia. These
may be limited to the distribution of a single nerve, and may be
accompanied by trophic affections.
34 Arch. f. Psych., v.

35 Vol. I. p. 221.

Spasm of the veins may occur as well as of the arteries,36 or

independently of them. In the latter case the blood will not pass out
of the capillaries. The part will then be blue, swollen, œdematous,
and painful; the temperature will be lowered by increased radiation of
heat, and all the sensations and functions be impaired in greater or
less degree. If this continues, nutrition may suffer, and in the end
gangrene develop, which will take its course and lead to the throwing
off of the part. Grainger Stewart has described such a condition
occurring in both hands and feet.37 It may be likened to a severe
form of Raynaud's disease.
36 Weiss, “Symmetrische Gangrän,” Wiener Klinik, 1882.

37 Grainger Stewart, An Introduction to the Study of Nervous Diseases, p. 138.

Angio-paralysis is more frequent than angiospasm, and may be due

either to paralysis of the vaso-constrictors or to excitement of the
vaso-dilators. It shows itself by a bright-red or mottled appearance of
the skin, and increase of local temperature, and more rapid
processes of nutrition, together with an increase of secretion if the
part is a gland or a mucous membrane, and an increase of sweat if it
is the skin. In the latter case an increased sensitiveness to changes
of temperature, a subjective sensation of heat, and hyperæsthesia
and hyperalgesia may occur. The hyperæsthesia on the paralyzed
side which is present in hemiparaplegia spinalis is ascribed to the
vaso-motor paralysis. But these symptoms soon give place to others.
The dilatation of the vessels, which at first caused an increased flow
of blood to the part, produces a slowing of the blood-current in the
part, just as a river runs less rapidly where it becomes wider. The
slowing of the current in the skin allows of a more complete cooling
of the part as the radiation of heat and the evaporation of moisture
are increased, and the slowness of the renewal of blood impairs the
processes of nutrition, so that to the first stage of redness, heat, and
increased metabolism there ensues a stage of blueness, cold, and
defective nutrition, and the function of the part may be impaired. In
this stage it usually presents a mottled appearance, and may be
slightly swollen and œdematous, and the continued increase of
perspiration gives it a clammy coldness to the touch. In all of these
conditions severe pain, sometimes of a burning character, is a very
distressing symptom (causalgia). These conditions are seen in
peripheral nerve-lesions, and give rise to the appearances which
have been so admirably described by Weir Mitchell.38
38 Injuries of Nerves.

A peculiar combination of symptoms may be mentioned here, to

which Weir Mitchell has given the name of erythromelalgia.39 This
disease begins with tenderness and pain in the soles of the feet,
which are soon followed by a marked distension of the capillary
vessels. The congestion is attended by a sensation of burning pain
similar to that produced by a blister. The surface is at first of a dull
dusky-red color; later it appears purple. The redness is not uniformly
distributed over the sole, but occurs in patches of irregular shape,
being especially frequent over prominent parts exposed to pressure
and friction, and the attacks seem to be brought on by long standing
or walking. At first there is a rise of temperature in the affected
surface, the arteries pulsate visibly, the veins are swollen, and there
may be some œdema. Later, the foot is cold and pale. Sensations of
touch and temperature are normal, but the part is so extremely
tender that walking is impossible. There is no paralysis. One or both
feet may be affected, but the patches of redness are rarely
symmetrical. The hands are occasionally affected. The condition
may occur in paroxysms or may remain for some time. It resists all
known methods of treatment, although applications of cold relieve
the burning pain to some extent and the tenderness enforces rest.
39 Amer. Journ. of the Med. Sci., July, 1878.

With angio-paralysis may be classed the taches cérébrales of

Trousseau no longer considered diagnostic of meningitis, but
denoting a weakened condition of vaso-constrictor action in the local
ganglia of the vessel-wall which may occur upon local irritation of the
skin in any severe disease affecting the nutrition of the general
nervous system.

Actual rupture of the capillaries in the course of vaso-motor diseases

is rarely observed, although the stigmata appearing in hysterical and
cataleptic patients may be ascribed to this cause. In this connection
tabetic ecchymoses may be mentioned, which appear suddenly
without local injury, and resemble an ordinary bruise, running a
similar course. They occur only in the course of locomotor ataxia.40
40 Straus, Arch. de Neurologie, tome i. p. 536.

In addition to these forms of vaso-motor affections there is a

condition of instability of vascular tone which manifests itself by
sudden transient changes in the circulation of various organs. This is
a functional affection, usually due to malnutrition. It is seen in many
cases of neurasthenia and hysteria, and manifests itself by sudden
flushes or pallor, alternations of heat and cold, local sweating,
attacks of mental confusion, and inability to use any organ
continuously from disturbance of the power of the vaso-dilators to
maintain a condition of functional hyperæmia.41 Little is actually
known about the causes of this state of the vascular system,
although much has been written about it. (For a fuller description the
article on Neurasthenia may be consulted.)
41 Anjel, Arch. für Psychiatrie, xv. 618.
Many functional derangements of the internal viscera have been
ascribed to such vaso-motor instability with more or less probability,42
but hypothesis of this kind, however plausible, is evidently beyond
confirmation. It is especially in affections of this kind that causes of
reflex irritation are to be carefully sought. Cutaneous angio-
neuroses, such as have just been described, may affect any part of
the body. They usually appear suddenly, producing much discomfort
and an impairment of function in the part if it is an extremity. They
disappear as rapidly as they come. The duration of such attacks
varies from a few minutes to several days. They are very liable to
recur. If it is the vessels under the control of the cervical sympathetic
which are affected, the symptoms will be those of migraine or of
lesion of the ganglia.43 If it is the vessels in the extremities which are
involved, the condition of digiti mortui or erythromelalgia or
symmetrical gangrene44 may be produced.
42 Fox, The Influence of the Sympathetic System in Disease, London, 1885.

43 See p. 1263.

44 See p. 1257.

A singular epidemic occurred in France in 1828 and 1830 which was

termed acrodynia. Many persons were suddenly seized with vomiting
and purging, and soon after the onset the extremities became red or
mottled in blotches, swollen and œdematous, and hot, painful, and
tender. The attacks lasted from a few days to two months, and
during this time the skin became thick and hard, the muscles weak
and subject to spasms, and the general health was impaired.
Relapses occurred in many cases, but all finally recovered, and
hence the exact nature of the disease was not ascertained.

COURSE.—In any case of vaso-motor neurosis the course of the

disease and its termination will depend chiefly upon its cause. If the
cause is some permanent lesion of the nervous system, the
condition will remain, and in this case the termination will depend
upon the severity of the symptoms. Angiospasm may be so severe
as to lead to gangrene ana the separation of the part affected, or
may be so slight as to cause only subjective discomfort and a little
pallor. Angio-paralysis may lead to an extreme degree of congestion,
which is attended by heat and pain at first, later by paræsthesia and
coolness, with increased liability of the part to be affected by
changes in the surrounding air. This stage is succeeded by one of
less marked dilatation of the vessels and a spontaneous partial
recovery, although the more moderate symptoms may continue
indefinitely and seriously impair the function of the part. If the cause
is a temporary derangement of function in the vascular mechanism,
is reflex irritation which can be removed, or is a curable organic
disease, the symptoms will subside rapidly or gradually and perfect
recovery may follow. If the condition is one of irritability in the vaso-
motor centres, producing alternations of flashing or pallor, such as is
observed in nervous exhaustion, it may recur irregularly for a
considerable length of time until the causative condition can be
removed.

PROGNOSIS.—The prognosis must be determined in each case by a

consideration of the cause of the affection, of the nature of the
symptoms, of the severity of the disease, and of the possibility of
success in both symptomatic and causative treatment. In the angio-
paralytic cases an eventual spontaneous relief from much of the
discomfort may be promised, although the duration of the symptoms
cannot be predicted.

TREATMENT.—Treatment must be directed primarily to removing or

diminishing the severity of the cause. A review of the section on
Pathogenesis will indicate how wide a field this may include, and the
reader must be referred to the special articles which are alluded to in
that place for therapeutic measures. Special diligence is to be shown
in searching for a source of reflex irritation. When the cause cannot
be reached, and when the symptoms are of such severity as to
demand immediate attention, treatment may be directed to them.

In all conditions of vaso-motor disease it is important to shield the

part from external injury; for if the vessels are dilated they are liable
to rupture, and any abrasion of the surface may produce serious
inflammation and ulceration; and if the vessels are contracted any
injury will be repaired slowly and imperfectly on account of the
anæmia, and may even hasten the approach of gangrene.

Perfect rest, bandaging with cotton, and even the application of a

light splint to the extremities will be advisable in cases of
angiospasm. It is desirable to retain the animal heat, inasmuch as its
supply is deficient. In angio-paralysis rest in a somewhat elevated
position and applications of mild evaporating lotions are indicated in
the early stage; later, the limb may be bandaged. It is not advisable
to attempt by tight bandaging to counteract the effect of the vascular
paralysis, for the nutrition of the limb is liable to suffer and gangrene
may be induced.

Massage of a part affected with vaso-motor symptoms is of great

service, since the circulation can be increased in the veins, and thus
indirectly in the capillaries, and the nutrition of the part can thus be
favored. It is more efficacious in angio-paralysis than in angiospasm.
Too rough rubbing is of course to be avoided, lest the skin be injured.
All counter-irritation is to be strictly forbidden.

Electricity has been used with varying results. According to Erb,45

moderate faradic applications contract the vessels; strong faradic
applications, especially with the brush, dilate the vessels. The
galvanic current at first contracts the vessels, but this is followed by
a secondary dilatation, which will be greater and occur more rapidly
the stronger the current used.46 Cathodal closures contract the
vessels; the anodal continuous current dilates them widely. Stabile
continuous currents through a nerve dilate the vessels which the
nerve supplies. Inasmuch as vaso-constrictors and vaso-dilators
pass together in many nerves, and are found together in all parts, it
is impossible to apply electricity to either alone. In those cases,
therefore, in which it has been ascertained which set of vaso-motors
is affected, it is not always possible to produce a direct effect upon
that set by electrical treatment. Erb recommends, in conditions of
vaso-motor spasm a trial of the galvanic current, the cathode on an
indifferent point, the anode being applied over the vaso-motor
centres governing the part, and also over the area of the body which
is affected, and held there while a moderate continuous current is
passing, interruptions being avoided; or, the cathode being placed on
the neck, the anode may be applied to the nerves passing to the
affected part; or a strong continuous current may be sent through the
nerve, its direction being changed several times during a moderately
long application. Finally, the faradic brush applied to the part or a
strong faradic current sent through its nerve may relax the spasm. In
any case, all these methods should be tried before electrical
treatment is abandoned.
45 Electrothérapie, 562.

46 To this statement Lauder Brunton assents—Pharmacology, p. 250.

In vaso-motor paralysis other methods are used. The cathode is

placed on the part congested, and a weak galvanic current is
employed with frequent interruptions or even with changes of the
pole; or the cathode may be moved about upon the reddened skin
while a mild continuous current is passing. A very weak faradic
current with wet electrodes, or even a weak faradic current applied
with a brush, may be of service. Here, again, various methods may
be tried.

If the extremities are affected, it may be well to immerse them in a

basin of water which is connected with one pole of the battery, and
the current directed in the manner just described, according to the
case. It must be confessed that no definite results can be predicted
from the use of electricity in these cases, and much more experience
is needed before definite rules can be laid down. The records show
that in apparently similar cases opposite methods of application have
produced favorable effects, while in other cases all methods have
failed. Too much reliance should not be placed in electrical
treatment. Erythromelalgia is an obstinate affection, and
symptomatic treatment, directed chiefly to quieting the pain by opium
and allaying the sensation of burning by cool baths, must be resorted
to.
Internal remedies may be tried appropriate to the condition present.
In angiospasm nitrite of amyl inhaled, or nitro-glycerin 1/100 gr. t. i. d.,
may give considerable relief, although both of these drugs are to be
used with caution. Chloral hydrate is also of some service, and
where the patient is in pain and suffers from insomnia this may fulfil
several indications. In angio-paralysis ergot has been used with
advantage. Oxygen inhalations are of service. Chloride of potassium
may also be tried. It is evident, however, that such remedies, acting
as they do upon the general arterial system, are not to be depended
upon in the treatment of local conditions, since they have no
selective action upon the affected part. The majority of the drugs
known as sedatives and antispasmodics have been used in these
conditions, but the records of individual cases show that they are not
of much avail. Theoretical therapeutic measures based upon
experimentation on animals have been fully discussed by Lauder
Brunton,47 but practical experience has not yet been sufficiently
extensive to warrant any further statements.
47 Pharmacology, Therapeutics, and Materia Medica, pp. 229-360. Lea Bros., 1886.

Symmetrical Gangrene.

SYNONYMS.—Local asphyxia, Asphyxie locale, Raynaud's disease;

Symmetrische Gangrän.

DEFINITION.—Symmetrical gangrene is an affection of the nervous

system characterized by arterial or venous spasm appearing in
symmetrical parts of the body, especially in the phalanges of all the
extremities, which may result in trophic changes or in gangrene.
There are various stages in the disease, which have given rise to the
various names by which it is known. The stage of local syncope, in
which there occurs a moderate contraction of the arterioles and
consequent pallor of the part, may be followed by a stage of local
asphyxia, in which the complete contraction of the arterioles cuts off
entirely the supply of arterial blood, and the regurgitation of venous
blood produces cyanosis of the part; and this, if continued, may
result in the gangrene of the part, which is then thrown off. Instead of
a condition of local asphyxia, there may be a spasm of the smaller
veins, resulting in a local erythema, which may go on to capillary
stasis and then to gangrene. The spasm of the vessels may cease at
any stage as suddenly as it began; and if this occurs in the first or
second stage, no gangrene results.

HISTORY.—While isolated cases of this affection had been recorded

as curiosities during the past two centuries,48 the disease was first
studied with care by Raynaud in his Thèse de Paris in 1862. He
collected twenty-eight cases which had been described with
accuracy or had been personally observed in the hospitals of Paris,
and after a thorough analysis of the symptoms defined the disease
as “a neurosis characterized by an exaggeration of the excito-motor
power of the cord presiding over the vaso-motor nerves.” He called
particular attention to the condition of spasm in the vessels, and
proposed the name asphyxie locale to designate the peculiar
appearance of the parts affected. He also noticed the resulting
gangrene as a new variety of gangrene, not dependent upon
embolism or upon changes of an atheromatous nature in the coats of
the vessels.
48 Schrader, 1629; Hertius, 1685; Bouquet, 1808; Moulin, 1830; Racle, 1859—cited in
full by Weiss, “Symmetrische Gangrän,” Wiener Klinik, 1882.

The condition was at once recognized by others, and several cases

had been reported prior to 1873, when Raynaud published a more
complete article on the subject in the Dictionnaire de Médecine et de
Chirurgie under the title gangrene symmétrique; in 1874 he recorded
five new cases in the Archives générales de Médecine, vol. i. pp. 5
and 189.

The disease, having been thus established as a definite nervous

affection, began to be noticed in other countries than France; and
Billroth in Vienna,49 Weir Mitchell,50 Mills,51 A. McL. Hamilton,52 and J.
C. Warren53 in this country, and many other careful observers,
published cases, together with more or less complete articles upon
the disease. In 1882, Weiss produced a monograph54 upon the
subject containing references to all the cases which had appeared;
and this is still the most complete article to be found, although the
essay of R. Lauer55 and the discussion of the disease by the Berlin
Medical Society,56 as well as the short articles of Schulz57 and Lutz,58
deserve mention, for they contain additional observations of cases
and numerous facts not to be found elsewhere.
49 Wiener Med. Wochensch., 1878, No. 23.

50 Amer. Journ. of the Med. Sci., 1878, July.

51 Ibid., 1878, Oct.

52 N. Y. Med. Journ., 1874, Oct.

53 Boston Surg. and Med. Journ., 1879, No. 3.

54 Weiss, Wiener Klinik, 1882, “Symmetrische Gangrän;” also Zeitschrift für Prac.
Heilkunde, 1882.

55 Inaug. Dissert., Strasburg, 1884.

56 Zeitschrift für klin. Med., vi. p. 277, 1883.

57 Deut. Arch. f. klin. Med., xxxv. 183, 1884.

58 Bäyr. ärzt Intell. Blatt, 1884, xxxi. 24.

SYMPTOMS.—The disease begins suddenly in all cases, and the

constitutional symptoms are less prominent than the local ones. In
some cases there are noticed a certain degree of mental
disturbance, a condition of depression with a tendency to sigh and
cry without cause, disturbed sleep with unpleasant dreams,
irritability, and headache. A loss of appetite and disorders of
digestion may follow, and then the local symptoms appear. In other
cases, which seem to be the majority, the local condition develops
without any such premonitory disturbances of the nervous and
digestive systems, although these may ensue. The local symptoms
first noticed may be paræsthesiæ or pain in all the extremities,
usually limited to the tips of the fingers and the toes. These are
continuous and severe, and are immediately followed (and
occasionally preceded) by an appearance of ischæmia or of
cyanosis or of erythema, in the order of frequency named.

(1) The fingers may look pale and dead, presenting the appearance
of the so-called digiti mortui, and may be cold, painful, and
anæsthetic. If this condition is moderate in degree, a certain amount
of blood will continue to flow through the contracted arterioles, and
then it corresponds to the description given by Raynaud of syncope
locale. If it is extreme, the part may be wholly deprived of arterial
blood, and then a true local asphyxia is present. In this stage the
patients usually suffer considerably, although some do not complain
of pain until the next stage. The ischæmia is attended with an
impairment of sensation to touch, temperature, and pain, and finer
motions become clumsy on account of the subjective numbness and
actual anæsthesia. At the same time, the fingers look shrunken, the
skin being thrown into folds, as if the hand had been soaked in hot
water, or they may appear as if frozen, the skin being hard and
immovable.59 The secretion of perspiration may be increased, and
the fingers feel damp as well as cold, or it may be suspended. The
local temperature is lowered. If the part is cut, little or no blood will
flow. At this stage the arterial spasm may suddenly relax and the part
return gradually to its normal condition, the cessation of the
constriction of the arteries and the return of blood being usually
accompanied by burning pain, which may last for some hours. The
duration of such an attack may vary from a few moments to several
days. If it continues longer, this stage is usually succeeded by the
second stage, of cyanosis.
59 Finlayson, Medical Chronicle, 1885, No. 4.

(2) The stage of cyanosis results from one of two conditions: either
the arterial spasm is so complete that no blood passes into the part,
in which case venous blood from lack of vis a tergo or in response to
gravitation regurgitates into the capillaries, distending them and
producing a state of blueness; or a venous spasm occurs, preventing
the exit of blood from the part, which then becomes actively
congested, and the blood in the capillaries, from want of renewal,
soon becomes venous and produces the cyanotic appearance. The
stage of ischæmia may be so short that it is hardly noticed, so that
the patient's attention is first attracted by the swollen, blue, and
extremely painful condition. The skin may be stretched, the tissue
infiltrated with products of exudation, which can be pressed out, as
can also the venous blood, and the surface may itch as well as be
painful. Anæsthesia is rarely present in this stage, and there may
even be hyperæsthesia. The part is cool from the increased radiation
of heat and cessation of the processes of metabolism, the local
temperature being lowered. The small vessels on the surface will be
visibly injected, and capillary ecchymoses may rarely be seen. There
is less liability to difficulty in movement in this stage than in the
former one, as the sensations of the part are not benumbed, but if
present it is due to the swelling. This condition, like that in the former
stage, may cease suddenly, the recovery of the normal appearance
being, as a rule, slower than after a simple ischæmia. The duration
of this stage has varied from a few seconds to several days. It is
usually followed by gangrene.

(3) The condition of local erythema is described here because it may

lead to gangrene, and has therefore been considered by Weiss as
one of the early stages of the disease. As a rule, however, it is not
followed by the death of the part, and the affection in these cases is
probably one of erythromelalgia rather than of symmetrical
gangrene. Like the stage of ischæmia, the stage of erythema may
appear suddenly. The part presents a bright-red or a mottled
appearance—is hot and swollen, and painful. The vessels are visibly
injected, the local temperature is raised, the secretion of sweat may
or may not be increased, and the patient feels a burning sensation
rather than pain. Hyperæsthesia to touch and temperature and pain
is usually present, or the sensations are normal. The blood can be
pressed out, but returns immediately. In this condition of hyperæmia
slight injuries lead frequently to an inflammatory process, ulcers may
form in the pulps of the fingers or around the nails, and the eschars
may appear dark and even gangrenous; or an actual condition of
gangrene may appear in the tips of the fingers, the exact method of
its occurrence being a matter of dispute. The erythematous condition
is much more likely to be permanent than are the other stages of the
disease—another fact which has led to some hesitation in
considering it a true stage. This condition of erythema may be due to
a paralysis of the vaso-constrictors, the converse of the spasm
occurring in ischæmia. It has also been ascribed to an irritation of the
vaso-dilators; and this appears to be the more probable hypothesis.

(4) The stage of gangrene is always preceded by that of cyanosis,

and the death of the tissue is due to the arrest of nutrition
consequent upon a stasis of the blood. It is not necessary to invoke
the injury of trophic nerves to explain its appearance. In the tips of
the cyanotic fingers, on their palmar surface, beneath the epidermis,
a small blister appears, filled with a dark serous fluid or with pus or
blood. This soon ruptures, and a dark dry scab forms, beneath which
an ulceration may go on destroying the corium, but not penetrating
deeper. In the majority of cases the gangrene is limited to a small
area of the pulps of the fingers, and only involves the superficial
layers of the corium. The gangrenous spot is surrounded by a purple
margin. When the sphacelus has separated a scar remains which is
frequently insensitive. In other cases when the sphacelus is thrown
off it leaves a deep ulcer, which may look as if the lost tissue had
been cut out with a punch, and this gradually granulates and heals.
In still other cases the entire skin of the terminal phalanx may
become black and dry, presenting a true gangrenous appearance.
Then a line of demarcation is formed, usually at the junction of the
terminal with the middle phalanx; separation of the gangrenous part
occurs, and a stump is left covered with thin, glossy skin. This
extensive gangrene, involving an entire phalanx, is the exception
rather than the rule.

While the gangrenous process is in progress in the tip of the finger

the nails cease to grow, and may become bulbous and rigid; the
epidermis elsewhere may become dry and desquamate, and
ulceration around the root of the nail may take place. With the
completion of the stage of gangrene, which may last from one to five
weeks according to its extent, the local symptoms terminate.

It is the symmetrical distribution of the local symptoms just

enumerated which is the peculiar characteristic of the disease. The
fingers of both hands, the toes of both feet, symmetrically situated
spots upon the back, trunk, thighs, legs, forearms, and arms (in the
order of frequency named), are affected either singly or in
combination. In the majority of cases fingers and toes are affected
together, and a few spots are seen on the trunk. In many cases the
toes escape. In a large number of cases the face has been affected,
spots of cyanosis appearing on the nose or ears or lips. As a rule,
the stage of gangrene only ensues in the tips of the extremities, but
a few cases are recorded in which little areas of skin elsewhere have
passed through all the stages of the disease. Pigmentation occurs in
spots upon the body when the process does not go on to gangrene.

Among the rare symptoms which have occurred in some cases are
great impairment of temperature, pain, and electric sensations in the
affected extremities; swelling, pain, redness about, and effusion into,
the joints; considerable loss of motion in the muscles of the hands
and feet, with diminution of electric excitability, but no qualitative
change; and oculo-pupillary changes ascribed to an irritation of the
cervical sympathetic fibres at their origin in the spinal cord.

In addition to the constitutional symptoms mentioned, which may

usher in the disease and may continue during its course, there have
been observed temporary albuminuria, glycosuria, and hæmaturia.
Fever never occurs as a symptom of the disease, and if present
must be ascribed to some other condition. The special senses have
been affected in a few cases. In one case a spastic contraction of
the retinal arteries alternated with attacks of ischæmia in the
extremities.60 The intellect is usually unaffected, but Weiss observed
a case in which transient aphasia occurred, which he attributes to
local spasm in the arteries of the cortex. The patient could find words
only after long thought, and spoke slowly and with difficulty.
60 Raynaud, Arch. gén. de méd., 1874, p. 11; Galezowski examined the discs.