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Advances in Experimental Medicine and Biology 1318

Nima Rezaei Editor

Coronavirus
Disease -
COVID-19
Advances in Experimental Medicine
and Biology

Volume 1318

Series Editors
Wim E. Crusio, Institut de Neurosciences Cognitives et Intégratives
d’Aquitaine, CNRS and University of Bordeaux, Pessac Cedex, France
Haidong Dong, Departments of Urology and Immunology, Mayo Clinic,
Rochester, MN, USA
Heinfried H. Radeke, Institute of Pharmacology & Toxicology, Clinic of the
Goethe University Frankfurt Main, Frankfurt am Main, Hessen, Germany
Nima Rezaei, Research Center for Immunodeficiencies, Children’s Medical
Center, Tehran University of Medical Sciences, Tehran, Iran
Junjie Xiao, Cardiac Regeneration and Ageing Lab, Institute of
Cardiovascular Sciences, School of Life Science, Shanghai University,
Shanghai, China
Advances in Experimental Medicine and Biology provides a platform for
scientific contributions in the main disciplines of the biomedicine and the life
sciences. This series publishes thematic volumes on contemporary research in
the areas of microbiology, immunology, neurosciences, biochemistry,
biomedical engineering, genetics, physiology, and cancer research. Covering
emerging topics and techniques in basic and clinical science, it brings together
clinicians and researchers from various fields.
Advances in Experimental Medicine and Biology has been publishing
exceptional works in the field for over 40 years, and is indexed in SCOPUS,
Medline (PubMed), Journal Citation Reports/Science Edition, Science
Citation Index Expanded (SciSearch, Web of Science), EMBASE, BIOSIS,
Reaxys, EMBiology, the Chemical Abstracts Service (CAS), and Pathway
Studio.
2019 Impact Factor: 2.450 5 Year Impact Factor: 2.324

More information about this series at http://www.springer.com/series/5584

Nima Rezaei
Editor

Coronavirus
Disease - COVID-19
Editor
Nima Rezaei MD, PhD
Research Center for Immunodeficiencies,
Children's Medical Center
Tehran University of Medical Sciences
Tehran, Iran

Network of Immunity in Infection,

Malignancy and Autoimmunity (NIIMA)
Universal Scientific Education and Research
Network (USERN)
Tehran, Iran

ISSN 0065-2598     ISSN 2214-8019 (electronic)

Advances in Experimental Medicine and Biology
ISBN 978-3-030-63760-6    ISBN 978-3-030-63761-3 (eBook)
https://doi.org/10.1007/978-3-030-63761-3

© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature
Switzerland AG 2021
This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher,
whether the whole or part of the material is concerned, specifically the rights of translation,
reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any
other physical way, and transmission or information storage and retrieval, electronic adaptation,
computer software, or by similar or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this
publication does not imply, even in the absence of a specific statement, that such names are
exempt from the relevant protective laws and regulations and therefore free for general use.
The publisher, the authors, and the editors are safe to assume that the advice and information in
this book are believed to be true and accurate at the date of publication. Neither the publisher nor
the authors or the editors give a warranty, expressed or implied, with respect to the material
contained herein or for any errors or omissions that may have been made. The publisher remains
neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
This book would not have been possible without the continuous
encouragement of my family.
I wish to dedicate it to my daughters, Ariana and Arnika,
with the hope that we learn enough from today to make a
brighter future for the next generation.
This book is also dedicated to honoring the memory of our
brave fallen doctors and nurses who fought against COVID-19.
Preface

On March 2, 2020, I had an hour-­long meeting with three of my colleagues,

including the head of the hospital, head of infant intensive care unit (ICU),
and the consultant of the hospital, at the head office of the Children’s Medical
Center, the Pediatrics Center of Excellence (Tehran, Iran), to discuss the
novel coronavirus disease 2019 (COVID-­19) outbreak. A few days later, I
realized that all of them were positive for severe acute respiratory syndrome
coronavirus 2 (SARS-­CoV-­2), confirmed by real-­time RT PCR (rRT-­PCR)
assays. Two of them presented with only low-­grade fever and malaise, while
the third one suffered from anosmia in addition to cough and myalgia. So, it
raised several questions in my mind, while I also had some concerns about
being affected by SARS-­CoV-­2, not only because of that meeting with three
physicians who were positive for the virus, but also for meeting and talking

vii
viii Preface

closely with two other faculty members of our hospital, who were both
recently infected by COVID-­19. So, am I positive for COVID-­19? Fortunately,
in the 2 weeks after that meeting and after 8 months of working in the pediat-
ric referral hospital during the pandemic, I had not presented any symptom of
the disease, until October 2020, when I faced headache, backache, chills, and
malaise, which made me to qurantine myself for 18 days. As I was quite sure
about my symptoms, I did not test for SARS-­CoV-­2 during my quarantine.
However, SARS-­CoV-­2 IgG had been incresead slightly, when I got back to
the hospital. So, I am not among more than a hundred million of reported
cases, which might show that the number of COVID-­19 is understimated!
Meanwhile, the global challenges and concerns still remain, while many
questions are yet to be answered! Is being asymptomatic not equal to being
affected? How does the virus spread? Does the outbreak situation change by
weather in different seasons? Who are at a higher risk of infection and mortal-
ity? Are healthy individuals without any underlying disease protected!? How
can we protect ourselves? And the immune system: Friend or Foe?
We, the world outside of China, heard the news of a Chinese city affected
by pneumonia of unknown origin in December 2019. We also saw this city, in
response to the increasing number of patients presented with this unusual
pneumonia, construct a temporary hospital in less than 2 weeks, but did not
realize that this disease could spread far beyond its boundaries, strike near us,
and provide an experience far worse than what happened in the city when
affected the first time. Wuhan was that city, and with the discovery of a coro-
navirus as the pathogen behind that, COVID-­19 was the name assigned to
that unusual pneumonia.
This novel SARS-­CoV-­2 proved to be unique in terms of transmissibility
and mortality. A proof of its being highly contagious is that while we were all
obsessed with the movement of the SARS-­CoV-­2 from Wuhan to all territo-
ries worldwide, it has been very difficult for most of us to track the chrono-
logical order of its global spread after affecting Wuhan. However, its
consequences are hitting us; 5 months have passed since the the World Health
Organization (WHO) declared COVID-­19 a pandemic on March 11, 2020,
while many countries are fighting the first and second wave of the disease. It
should be mentioned that there were only about 100,000 diagnosed cases
within a 3-­month period since the beginning of the outbreak; in the month of
April, about 3 million new cases were reported; now, there are more than 120
million officially reported cases and more than 2.5 million deaths from all
over the world (mid-­March 2021); and it's still unclear when the pandemic
will end! The pandemic has profoundly affected not only human health but
also human behavior and thought. No curative therapy so far! One of my
aforementioned colleagues, who was positive for SARS-­CoV-­2 in March 2020
and cured, faced reinfection 2 months later with positive PCR again! There
are some other reports, especially from healthcare workers who are exhausted
from the continuous long-­term fight against COVID-­19, which shows the
potential risk of reinfection after decreasing the SARS-­CoV-­2 antibody level.
So, how effective will the vaccines be?
It’s about a century since the Spanish influenza pandemic of 1918. How
much does this situation differ from that time? And how much have we
Preface ix

remembered and learned from the pitfalls we had faced? It should also be
mentioned that this novel coronavirus (SARS-­CoV-­2) is the third one in the
twenty-­first century that has brought us outbreaks after severe acute respira-
tory syndrome (SARS) and the Middle East respiratory syndrome (MERS) in
2003 and 2012, respectively, but how much have we prepared ourselves for
this third one? Can we make sure that we will never face such a situation in
the future?
Certain countries, which were at the top of the list of the number of
infected individuals, implemented the policy of closing their borders to
restrict travel from outside. However, they simply forgot the key point that
this virus does not know any border; thus, a borderless solution is needed
when the entire world is affected by such a global challenge! We are all living
on the same Earth, and the world’s complex problem should be considered a
human problem in general; therefore, the solution can’t be country-­based.
Indeed, it's not limited to a specific field of science. Such a complex problem
involves not only medical scientists but also other scientists from formal sci-
ence to physical and chemical science to biological and social science. Thus,
there is a need to work together to solve complex problems, like COVID-­19.
It is now more than a year that the SARS-­CoV-­2 is an inhabitant of the
human heart, lungs, intestines, and brain in an unsatisfactory manner, asking
its origins, evolution, and pathogenesis has become habituated to human
beings, in the hope to hear and learn something for enhancing their prepared-
ness for the next wave of the pandemic and the fourth outbreak of the century.
Inevitably, there have been massive amounts of data published on this curious
subject. In addition to the unexpected rapid flow of publications made avail-
able within only a few months, I have a proof of such curiosity. When I was
preparing the proposal for this book in March when the outbreak just reached
us, I could only collect about ten evidence-­based chapter titles, but since then,
as time passed, there was a lot I had to include in the book. And now that the
book is about to be published, it has more than 50 chapters.
After a rapid introduction to COVID-­19 as a global challenge (Chap. 1),
the book provides general discussions over characteristics, ecology, and evo-
lution of coronaviruses (Chaps. 2 and 3). Then, it goes into the details about
epidemiological (Chaps. 4 and 5), genetic (Chaps. 6 and 7), immunological
(Chaps. 8 and 9), oxidative stress (Chap. 10), and diagnostic and prognostic
(Chaps. 22–24) aspects of COVID-­19. Chap. 11 takes a general view of clini-
cal manifestations of COVID-­19, while Chap. 20 and Chap. 21 link to the
involvement of individual systems. During the COVID-­19 pandemic, pediat-
rics and geriatrics shaped a sharp contrast in terms of disease outcomes, so
Chaps. 12 and 13 separately discuss these specific populations. Pregnant
women and neonates are other populations treated specially under the pan-
demic condition (Chap. 14). The COVID-­19 problem has shown its worst
scenarios in the case of pre-­existing conditions, in particular, cardiovascular
diseases (Chap. 15), hypertension (Chap. 16), and cancer (Chaps. 17 and 18).
Furthermore, it is expected to be complicated if it occurs concurrently with
tropical infections (Chap. 19). The book contains several chapters concerning
the treatment of COVID-­19, ranging from supportive ventilator support and
nutrition therapy to the development of potential virus-­and host-­ based
x Preface

t­ herapies, immune-­based therapies, photobiomodulation, and antiviral photo-

dynamic therapy (Chaps. 25–30). The relations of COVID-­19 to dentistry,
hematology, ophthalmology, and pharmacy lie in Chaps. 33–36, while its
general implications to the healthcare setting take place in Chap. 32. As the
virus is transmitted, misinformation and rumors spread quickly, resulting in
the infodemic (Chap. 37). The book also discusses social issues posed by
COVID-­19 , for example, social isolation, quarantine, lockdown (Chap. 38),
prejudice, and discrimination (Chap. 39), and the resulting consequences on
mental health (Chaps. 40–42), education (Chaps. 43 and 44), tourism indus-
try (Chap. 45), and economy (Chap. 46). It also makes attempts to explain the
bioinformatic approaches (Chap. 47), innovation and ingenuity (Chap. 48),
globalization (Chaps. 49 and 50), social and scientific networking (Chap. 51),
interdisciplinary approaches (Chap. 52), and art integration (Chap. 53) as
solutions to the problems of COVID-­19. Of course, many difficulties remain
to be dissolved, merely as an example of the challenges for vaccine develop-
ment (Chap. 31).
The COVID-­19 Book is the result of the valuable contribution of more
than 200 scientists and clinicians from more than 100 well-­known universi-
ties/institutes worldwide. I would like to hereby acknowledge the expertise of
all contributors for generously devoting their time and considerable effort in
preparing their respective chapters. I would also like to express my gratitude
to Springer Nature for providing me the opportunity to publish the book.
Finally, I hope that this timely book will be comprehensible, cogent, and
of special value for researchers and clinicians who wish to extend their
knowledge on COVID-­19.

Tehran, Iran Nima Rezaei

Your complex pain
is our old pain
Its care could be in our brain
Your sadness
is our loneliness
Its solution should be borderless
This is our world without rain
all alone, full of pain
Uncertain, no gain
If there is no border
the world might have a new order
No complain, no pain…

xi
Acknowledgment

I would like to express my gratitude to the editorial assistant of this book,

Dr. Amene Saghazadeh. Without doubt, the book would not have been com-
pleted without her contribution.

Nima Rezaei

xiii
Contents

1 Introduction on Coronavirus Disease (COVID-19)

Pandemic: The Global Challenge ��������������������������������������������������   1
Nima Rezaei, Saboura Ashkevarian, Mahsa Keshavarz Fathi,
Sara Hanaei, Zahra Kolahchi, Seyedeh-Sanam Ladi Seyedian,
Elham Rayzan, Mojdeh Sarzaeim, Aida Vahed,
Kawthar Mohamed, Sarah Momtazmanesh, Negar Moradian,
Zahra Rahimi Pirkoohi, Noosha Sameeifar,
Mahsa Yousefpour, Sepideh Sargoli, Saina Adiban,
Aida Vahed, Niloufar Yazdanpanah, Heliya Ziaei,
and Amene Saghazadeh
2 Coronaviruses: What Should We Know About
the Characteristics of Viruses? ������������������������������������������������������ 23
Wei Ji
3 Ecology and Evolution of Betacoronaviruses�������������������������������� 41
Eduardo Rodríguez-Román and Adrian J. Gibbs
4 The Epidemiologic Aspects of COVID-19 Outbreak:
Spreading Beyond Expectations ���������������������������������������������������� 61
Sara Hanaei, Farnam Mohebi, Maziar Moradi-­Lakeh,
Parnian Jabbari, Surinder Kumar Mehta,
Liudmyla S. Kryvenko, Livio Luongo, Loďc Dupré,
and Nima Rezaei
5 The Incubation Period of COVID-­19: Current
Understanding and Modeling Technique�������������������������������������� 81
Char Leung
6 Coronavirus: Pure Infectious Disease or Genetic
Predisposition ���������������������������������������������������������������������������������� 91
Farzaneh Darbeheshti, Hassan Abolhassani,
Mohammad Bashashati, Saeid Ghavami, Sepideh Shahkarami,
Samaneh Zoghi, Sudhir Gupta, Jordan S. Orange,
Hans D. Ochs, and Nima Rezaei
7 Genetic Polymorphisms in the Host and COVID-19
Infection�������������������������������������������������������������������������������������������� 109
Joris R. Delanghe, Marc L. De Buyzere,
and Marijn M. Speeckaert

xv
xvi Contents

8 How COVID-19 Has Globalized: Unknown Origin, Rapid

Transmission, and the Immune System Nourishment������������������ 119
Amene Saghazadeh and Nima Rezaei
9 Potential Antiviral Immune Response Against
COVID-19: Lessons Learned from SARS-CoV���������������������������� 149
Mahzad Akbarpour, Laleh Sharifi, Amir Reza Safdarian,
Pooya Farhangnia, Mahdis Borjkhani, and Nima Rezaei
10 COVID-19 and Cell Stress�������������������������������������������������������������� 169
Abdo A. Elfiky, Ibrahim M. Ibrahim, Fatma G. Amin,
Alaa M. Ismail, and Wael M. Elshemey
11 Clinical Manifestations of COVID-19�������������������������������������������� 179
Mahsa Eskian and Nima Rezaei
12 Pediatrics and COVID-19���������������������������������������������������������������� 197
Tuna Toptan, Sandra Ciesek, and Sebastian Hoehl
13 Geriatrics and COVID-19 �������������������������������������������������������������� 209
Mona Mirbeyk, Amene Saghazadeh, and Nima Rezaei
14 Coronavirus Diseases in Pregnant Women, the Placenta,
Fetus, and Neonate�������������������������������������������������������������������������� 223
David A. Schwartz and Amareen Dhaliwal
15 COVID-19 in Patients with Hypertension ������������������������������������ 243
Thiago Quinaglia, Mahsima Shabani, and Nima Rezaei
16 COVID-19 and Cardiovascular Diseases �������������������������������������� 263
Babak Geraiely, Niloufar Samiei, Parham Sadeghipour,
Azita H. Talasaz, Seyedeh Hamideh Mortazavi, and Roya
Sattarzadeh Badkoubeh
17 How Prevalent Is Cancer in Confirmed Cases
with Coronaviruses and Severe Acute Respiratory
Syndromes?�������������������������������������������������������������������������������������� 293
Maryam Fotouhi, Elham Samami, Sahar Mohseni,
Amir Nasrollahizadeh, Mohammad Haddadi, Mona Mirbeyk,
Amene Saghazadeh, and Nima Rezaei
18 COVID-19 in Patients with Cancer������������������������������������������������ 315
Ali Nowroozi, Sepideh Razi, Kamal Kant Sahu,
Fabio Grizzi, Jann Arends, Mahsa Keshavarz-Fathi,
and Nima Rezaei
19 COVID-19 and Tropical Infection: Complexity
and Concurrence������������������������������������������������������������������������������ 333
Pathum Sookaromdee and Viroj Wiwanitkit
20 Neurologic Manifestations of COVID-19�������������������������������������� 343
Farnaz Delavari, Farnaz Najmi Varzaneh,
and Nima Rezaei
Contents xvii

21 Autoimmune Processes Involved in Organ System Failure

Following Infection with SARS-CoV-2������������������������������������������ 355
Steven E. Kornguth and Robert J. Hawley
22 Clinical and Laboratory Predictors of Severity,
Criticality, and Mortality in COVID-19:
A Multisystem Disease�������������������������������������������������������������������� 369
Bahareh Gholami, Samira Gholami, Amir Hossein Loghman,
Behzad Khodaei, Simin Seyedpour, Nasrin Seyedpour,
Amene Saghazadeh, and Nima Rezaei
23 Diagnostic Tests for COVID-19������������������������������������������������������ 403
Tung Phan and Kristin Nagaro
24 The Role of Medical Imaging in COVID-19���������������������������������� 413
Houman Sotoudeh and Masoumeh Gity
25 Therapeutic Development in COVID-19��������������������������������������� 435
Chan Yang, Yuan Huang, and Shuwen Liu
26 Immune-Based Therapy for COVID-19���������������������������������������� 449
Abdolreza Esmaeilzadeh, Davood Jafari, Safa Tahmasebi,
Reza Elahi, and Elnaz Khosh
27 Ventilatory Support in Patients with COVID-19�������������������������� 469
Paolo Maria Leone, Matteo Siciliano, Jacopo Simonetti,
Angelena Lopez, Tanzira Zaman, Francesco Varone,
and Luca Richeldi
28 Nutrition and Immunity in COVID-19������������������������������������������ 485
Marjan Moallemian Isfahani, Zahra Emam-­Djomeh,
Idupulapati M. Rao, and Nima Rezaei
29 Dietary Supplements for COVID-19���������������������������������������������� 499
Gerard E. Mullin, Berkeley Limektkai, Lin Wang,
Patrick Hanaway, Loren Marks, and Edward Giovannucci
30 Photobiomodulation and Antiviral Photodynamic
Therapy in COVID-­19 Management���������������������������������������������� 517
Reza Fekrazad, Sohrab Asefi, Maryam Pourhajibagher,
Farshid Vahdatinia, Sepehr Fekrazad, Abbas Bahador,
Heidi Abrahamse, and Michael R. Hamblin
31 The COVID-19 Vaccine Landscape������������������������������������������������ 549
Till Koch, Anahita Fathi, and Marylyn M. Addo
32 Prevention of COVID-19: Preventive Strategies
for General Population, Healthcare Setting,
and Various Professions������������������������������������������������������������������ 575
Shirin Moossavi, Kelsey Fehr, Hassan Maleki, Simin
Seyedpour, Mahdis Keshavarz-Fathi, Farhad Tabasi,
Mehrdad Heravi, Rayka Sharifian, Golnaz Shafiei,
Negin Badihian, Roya Kelishadi, Shahrzad Nematollahi,
Majid Almasi, Saskia Popescu, Mahsa Keshavarz-Fathi,
and Nima Rezaei
xviii Contents

33 Pharmacist’s Role and Pharmaceutical Care During

the COVID-­19 Pandemic���������������������������������������������������������������� 605
Pedro Amariles, Mónica Ledezma-Morales,
Andrea Salazar-­Ospina, and Jaime Alejandro Hincapié-García
34 Impact of COVID-19 on Dentistry ������������������������������������������������ 623
Arghavan Tonkaboni, Mohammad Hosein Amirzade-Iranaq,
Heliya Ziaei, and Amber Ather
35 The Implications of COVID-19 to Ophthalmology���������������������� 637
Tracy H. T. Lai, Emily W. H. Tang, and Kenneth K. W. Li
36 Challenges of Cellular Therapy During the COVID-19
Pandemic������������������������������������������������������������������������������������������ 657
Kamal Kant Sahu, Sikander Ailawadhi, Natalie Malvik,
and Jan Cerny
37 COVID-19 Amid Rumors and Conspiracy Theories:
The Interplay Between Local and Global Worlds������������������������ 673
Inayat Ali
38 Exploration of the Epidemiological and Emotional
Impact of Quarantine and Isolation During
the COVID-19 Pandemic���������������������������������������������������������������� 687
Helia Mojtabavi, Nasirudin Javidi, Anne-­Frédérique Naviaux,
Pascal Janne, Maximilien Gourdin, Mahsa Mohammadpour,
Amene Saghazadeh, and Nima Rezaei
39 The Main Sources and Potential Effects
of COVID-19-Related Discrimination�������������������������������������������� 705
Piotr Rzymski, Hanna Mamzer, and Michał Nowicki
40 Potential Mechanisms of COVID-­19-­Related
Psychological Problems and Mental Disorders ���������������������������� 727
Alfred Shaw
41 Mental Health in Health Professionals in the COVID-19
Pandemic������������������������������������������������������������������������������������������ 737
Antonia Bendau, Andreas Ströhle, and Moritz Bruno Petzold
42 Treatment of Patients with Mental Illness Amid
A Global COVID-­19 Pandemic������������������������������������������������������ 759
Ankit Jain, Kamal Kant Sahu, and Paroma Mitra
43 A Shift in Medical Education During the COVID-19
Pandemic������������������������������������������������������������������������������������������ 773
Farida Nentin, Nagaraj Gabbur, and Adi Katz
44 Reopening Schools After a Novel Coronavirus Surge������������������ 785
Dan Li, Elizabeth Z. Lin, Marie A. Brault, Julie Paquette,
Sten H. Vermund, and Krystal J. Godri Pollitt
45 COVID-19 and Its Impact on Tourism Industry�������������������������� 815
Dimitrios G. Lagos, Panoraia Poulaki, and Penny Lambrou
Contents xix

46 COVID-19 and Its Global Economic Impact�������������������������������� 825

Zahra Kolahchi, Manlio De Domenico, Lucina Q. Uddin,
Valentina Cauda, Igor Grossmann, Lucas Lacasa, Giulia
Grancini, Morteza Mahmoudi, and Nima Rezaei
47 Retrieval and Investigation of Data on SARS-CoV-2
and COVID-­19 Using Bioinformatics Approach�������������������������� 839
Muhamad Fahmi, Viol Dhea Kharisma,
Arif Nur Muhammad Ansori, and Masahiro Ito
48 Answering the Challenge of COVID-19 Pandemic
Through Innovation and Ingenuity������������������������������������������������ 859
Kathryn Clare Kelley, Jonathan Kamler, Manish Garg,
and Stanislaw P. Stawicki
49 COVID-19 Pandemic: The Influence of Culture
and Lessons for Collaborative Activities���������������������������������������� 875
Linda Simon Paulo, George M. Bwire, Xingchen Pan,
Tianyue Gao, Amene Saghazadeh, and Chungen Pan
50 A Borderless Solution Is Needed for A Borderless
Complexity, Like COVID-19, the Universal Invader�������������������� 891
Kawthar Mohamed, Rangarirai Makuku,
Eduardo Rodríguez-­Román, Aram Pascal Abu Hejleh,
Musa Joya, Mariya Ivanovska, Sara A. Makka,
Md Shahidul Islam, Nesrine Radwan, Attig-­Bahar Faten,
Chunfeng Xiao, Leander Marquez, and Nima Rezaei
51 Socialization During the COVID-19 Pandemic:
The Role of Social and Scientific Networks During
Social Distancing������������������������������������������������������������������������������ 911
Sara Momtazmanesh, Noosha Samieefar, Lucina Q. Uddin,
Timo Ulrichs, Roya Kelishadi, Vasili Roudenok,
Elif Karakoc-­Aydiner, Deepak B. Salunke, Jan L. Nouwen,
Juan Carlos Aldave Becerra, Duarte Nuno Vieira,
Ekaterini Goudouris, Mahnaz Jamee,
Morteza Abdullatif Khafaie, Morteza Shamsizadeh,
Mohammad Rasoul Golabchi, Alireza Samimiat,
Donya Doostkamel, Alireza Afshar,
Mohammad Amin Khazeei Tabari, Melika Lotfi,
Reza Yari Boroujeni, Niloofar Rambod, Anzhela Stashchak,
Alla Volokha, Dainius Pavalkis, André Pereira,
Amir Hamzah Abdul Latiff, Rauf Baylarov,
Bagher Amirheidari, Mojtaba Hedayati Ch,
Antonio Condino-Neto, and Nima Rezaei
xx Contents

52 Interdisciplinary Approaches to COVID-19���������������������������������� 923

Negar Moradian, Marjan Moallemian, Farnaz Delavari,
Constantine Sedikides, Carlos A. Camargo Jr, Pedro J. Torres,
Armin Sorooshian, Saeid Paktinat Mehdiabadi, Juan J. Nieto,
Stephane Bordas, Hamid Ahmadieh, Mohammad Abdollahi,
Michael R. Hamblin, Frank W. Sellke, Jack Cuzick,
Bozkurt Biykem, Michael Schreiber, Babak Eshrati,
Georg Perry, Ali Montazeri, Ali Akbar Saboury,
Roya Kelishadi, Amirhossein Sahebkar,
Ali A. Moosavi-Movahed, Hassan Vatandoost,
Mofid Gorji-Bandpy, Bahram Mobasher, and Nima Rezaei
53 Health and Art (HEART): Integrating Science
and Art to Fight COVID-19������������������������������������������������������������ 937
Nima Rezaei, Aida Vahed, Heliya Ziaei, Negin Bashari,
Saina Adiban Afkham, Fatemeh Bahrami, Sara Bakhshi,
Alireza Ghanadan, Atlasi Ghanadan, Nastaran Hosseini,
Pariya Kafi, Reihaneh Khalilianfard, Kawthar Mohammed,
Sepideh Sargoli, Kosar Tavasoli, Mahya Zare,
and Amene Saghazadeh
 Introduction on Coronavirus
Disease (COVID-19) Pandemic: 1
The Global Challenge

Nima Rezaei , Saboura Ashkevarian,

Mahsa Keshavarz Fathi, Sara Hanaei,
Zahra Kolahchi, Seyedeh-Sanam Ladi Seyedian,
Elham Rayzan, Mojdeh Sarzaeim, Aida Vahed,
Kawthar Mohamed, Sarah Momtazmanesh,
Negar Moradian, Zahra Rahimi Pirkoohi,
Noosha Sameeifar, Mahsa Yousefpour,
Sepideh Sargoli, Saina Adiban, Aida Vahed,
Niloufar Yazdanpanah, Heliya Ziaei,
and Amene Saghazadeh

Abstract twenty-first-century medicine, healthcare

systems, education, and the global economy.
By driving the ongoing pandemic of corona- This chapter rapidly reviews the origin,
virus disease 2019 (COVID-19), coronavi- immunopathogenesis, epidemiology, diagno-
ruses have become a significant change in sis, clinical manifestations, and potential

N. Rezaei (*) · M. K. Fathi · S. Hanaei · E. Rayzan ·

S.-S. Ladi Seyedian
M. Sarzaeim · H. Ziaei · A. Saghazadeh
Universal Scientific Education and Research Network
Universal Scientific Education and Research Network
(USERN), Tehran, Iran
(USERN), Tehran, Iran
USC Institute of Urology, USC/Norris
Research Center for Immunodeficiencies, Children’s
Comprehensive Cancer Center, University of
Medical Center, Tehran University of Medical
Southern California, Los Angeles, CA, USA
Sciences, Tehran, Iran
e-mail: [email protected] A. Vahed · M. Yousefpour · S. Sargoli · S. Adiban ·
A. Vahed
S. Ashkevarian
Universal Scientific Education and Research Network
Universal Scientific Education and Research Network
(USERN), Tehran, Iran
(USERN), Tehran, Iran
Z. R. Pirkoohi
Research Institute of Applied Sciences, Academic
Universal Scientific Education and Research Network
Center of Education, Culture and Research (ACECR),
(USERN), Tehran, Iran
Shahid Beheshti University, Tehran, Iran
Shahid Beheshti University, Tehran, Iran
Z. Kolahchi · K. Mohamed · S. Momtazmanesh ·
N. Moradian · N. Yazdanpanah N. Sameeifar
Universal Scientific Education and Research Network Universal Scientific Education and Research Network
(USERN), Tehran, Iran (USERN), Tehran, Iran
School of Medicine, Tehran University of Medical School of Medicine, Shahid Beheshti University of
Sciences, Tehran, Iran Medical Sciences, Tehran, Iran

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 1

N. Rezaei (ed.), Coronavirus Disease - COVID-19, Advances in Experimental Medicine and
Biology 1318, https://doi.org/10.1007/978-3-030-63761-3_1
2 N. Rezaei et al.

therapeutics of COVID-19. It would also features in relation to all the three groups of coro-
explore the effects of the introduction of a naviruses. SARS-CoV is therefore supposed to
single virus, the so-called severe acute respi- be produced by multiple genetic recombination
ratory syndrome coronavirus 2 (SARS-­ events. Subsequently, hCoV-NL63 and hCoV-
CoV-­2), on the public health preparedness HKU1 first occurred in 2004 and 2005, and both
planning. correlated with a form of mild respiratory dis-
ease. hCoVs highly pathogenic to humans con-
Keywords tinued by the outbreak of the Middle East
respiratory syndrome (MERS) with 584 deaths
Borderless · Coronavirus · COVID-19 · and CFR of 36% in 2012. By driving the ongoing
Global · Immune system · Pandemic · pandemic of coronavirus disease 2019 (COVID-
SARS-CoV-2 19), which so far has been the cause of death of
more than 560,000 people worldwide, they have
become a significant change in the twenty-first-
century medicine, healthcare system, education,
1.1 Introduction and economy.

Coronaviruses are enveloped viruses composed

of non-segmented, single-stranded, and positive-­ 1.2 The Source of the Infection
sense RNA, which is the largest genome among
RNA viruses. They belong to the order Phylogenic analyses split coronaviruses into
Nidovirales having the common characteristics: four subgroups: alpha, beta, gamma, and delta.
gene expression through a 3′ nested set of Before the novel coronavirus 2019 appeared, six
multiple subgenomic mRNAs (sg mRNAs), a hCoVs were reported relating to either alpha-
ribosomal frameshifting mechanism for the (HCoV-­ 229E and HCoV-NL63) or
expression, a unique set of enzymatic activities, a betacoronaviruses (HCoV-OC43, HCoV-HKU1,
virion envelope formation, and a multi-span MERS-CoV, and SARS-CoV) (Shereen et al.
membrane protein in the virion. According to 2020). The new HCoV that causes COVID-19
antigenic relationships, 28 species of shares significant similarities with the SARS-
coronaviruses are included in three groups. CoV from the structural and pathological points
Species of group 3 rely on the bird host, while of view and is, therefore, classified as a
species of the other groups occur in mammals, betacoronavirus and called SARS-CoV-2.
including mouse, rat, bat, cow, dog, pig, puffin, HCoVs leading to outbreaks are apparently of
horse, and human (Masters 2006). zoonotic origin circulated in animals before
Human coronaviruses (hCoVs) date back to transmission to humans. SARS-­ CoV-­2 first
the 1960s with the identification of hCoV-229E occurred in late December 2019, in Wuhan,
and hCoV-OC43 from the respiratory tract and China. Notably, evidence shows the existence of
nasopharyngeal wash of patients with the com- SARS-CoV in bats, palm civets, and raccoon
mon cold (Su et al. 2016). They, however, dogs. Also, MERS-CoV occurs in the primary
appeared to be highly pathogenic to humans in host of camels, while bats might transmit it.
the early 2000s, when a virus, SARS-CoV, with Human epidemiological data connects a
the characteristic features of hCoVs caused an relatively high proportion of first- and second-­
outbreak of severe acute respiratory syndrome generation human cases of COVID-19 to the
(SARS) and resulted in 776 deaths with a case Huanan Seafood Wholesale Market in Wuhan
fatality rate (CFR) of 9.6%. Bioinformatics infor- (Huang et al. 2020a). Following whole-genome
mation indicates that SARS-CoV does possess sequencing, which demonstrated 96.2%
nothing new compared to any of the previous similarity, SARS-CoV-2 was proven to be
three groups of coronaviruses, though owning associated with Bat-CoV-RatG13 (SARS-like
1 Introduction on Coronavirus Disease (COVID-19) Pandemic: The Global Challenge 3

bat coronavirus) (Zhou et al. 2020b; Paraskevis polybasic cleavage site, O-linked glycans, and
et al. 2020). Although the primary host had been an SB subunit with higher affinity for binding
indicated, it was imperative to determine the ACE2. These differences may, in part, explain
intermediate hosts between bats and humans to the higher transmission of SARS-CoV-2, which
control the pandemic. Sequence and structural as of July 11, 2020, has infected 12 million
alignment of angiotensin-converting enzyme 2 people worldwide, compared to SARS-CoV
(ACE2) among human, nonhuman primates, with less than 9000 confirmed cases during the
domestic animals, wild animals, and rodents entire outbreak.
indicate that SARS-CoV-2 may not infect The viral infection occurs when the virus acts
chicken, while nonhuman primates may be an on host cells. In the case of SARS-CoV-2, the
intermediate host for transmission (Luan et al. RBD of the spike (S) protein on the viral envelope
2020). Analysis with the binding model of S seems to orchestrate such a mutual action with
protein, receptor-binding domain region (RBD the cell-surface receptor, e.g., ACE2 (Jahanshahlu
region), and ACE2 showed that snakes, and Rezaei 2020b). It requires host proteases for
pangolins, and turtles could serve as possible the cleavage of the S protein into two subunits,
intermediate hosts (Liu et al. 2020b). However, S1 and S2, that undertake the attachment of the
recent studies have demonstrated that it is virus to the membrane and then the fusion of
unlikely for snakes and turtles to be intermediate cellular and viral membranes. Endocytosis is
hosts, and researchers suggested pangolins as another mechanism that contributes to viral
potential targets (Liu et al. 2020a). On a recent internalization, as described for the SARS-CoV
study that isolated coronavirus, they detected (Li et al. 2020b). Whether or not involving
Malayan pangolins to exhibit a high sequence clathrin, endocytosis is accompanied by the
identity (100% in the E gene, 98.2% in the M fusion of membrane with vesicles that transport
gene, 90.4% in the S gene, and 96.7% in the N viral particles and genome followed by the
gene); therefore, it was suggested that SARS- release of the virus into the cell.
CoV-2 could perhaps arise as a result of
recombination between Pangolin-CoV-like 1.3.1.2 Antigen Presentation
virus and Bat-CoV-RatG13-­ like virus (Xiao Self-/nonself-recognition is mastered by the
et al. 2020). major histocompatibility complex (MHC).
Particularly speaking, the presentation of
endogenous antigens to cytotoxic CD8+ T cells is
1.3 Immunopathogenesis mediated by MHC class I, while the presentation
of COVID-19 of exogenous antigens to helper CD4+ T cells is
carried out by MHC class II. Studies have
1.3.1 Virus Entry and Spread associated MHC polymorphisms with a spectrum
of immune-mediated conditions, including aging,
1.3.1.1 T he Virus Binding to Its Cell atopic diseases, autoimmune diseases, and
Receptors neurological diseases. Of interest to here is the
SARS-CoV and SARS-CoV-2 do the action of association of these polymorphisms with
cell entry with a high level of equivalence, infectious diseases, such as human
arising from the same cleavage junctions, the immunodeficiency virus (HIV), hepatitis B virus
highly similar same sequence (96%) of their (HBV), hepatitis C virus (HCV), and tuberculosis,
main protease, a high degree (76%) of similarity which is a potential source of variation in
in the amino acid sequence of their S protein, response to vaccines and, therefore, can help the
similar S2′ cleavage site, and similar residues development of vaccinomics (Saghazadeh and
essential for binding ACE2 (Saghazadeh and Rezaei 2019).
Rezaei 2020b). Compared to that of SARS-CoV, Upon the cell entry of the virus, the presenta-
the S protein of SARS-CoV-2 has acquired a tion of viral antigens by antigen-­presenting cells
4 N. Rezaei et al.

(APCs) leads to the activation of immune vasculitis, interstitial inflammation, and

responses. Less is understood about the mecha- hemorrhage. Of note, tubular cells and podocytes
nism of presentation of SARS-CoV-2, and all our contain clusters of SARS-CoV-2-like particles,
current knowledge is regarding the presentation as demonstrated by electron microscopy.
of SARS-CoV. The presentation of SARS-CoV
involves MHC class I and, to a lesser extent, Liver
MHC class II. As reviewed in (Li et al. 2020b), The liver shows moderate microvesicular steato-
MHC polymorphisms confer susceptibility to sis, mild sinusoidal dilation, and mild portal and
(HLA-B∗4601, HLA-B∗0703, HLA-DR lobular inflammatory activity (Xu et al. 2020;
B1∗1202, and HLA-Cw∗0801) and protection Tian et al. 2020). These changes do not distin-
against (HLA-DR0301, HLA-Cw guish SARS-CoV-2 infection from drug-induced
1502, and HLA-A∗0201) SARS-CoV. It would liver injury.
strengthen the importance of MHC molecules in
the immunopathogenesis of SARS-CoV and pos- Heart
sibly in that of SARS-CoV-2. Interstitial infiltrates of mononuclear cells, mild
focal edema, interstitial fibrosis, and myocardial
1.3.1.3 Pathological Findings hypertrophy might occur in the heart tissue (Xu
Acute respiratory distress syndrome (ARDS) and et al. 2020; Tian et al. 2020).
multiorgan dysfunction syndrome (MODS) are
the most common cause of death in patients with 1.3.2  ole of the Immune System
R
COVID-19. During COVID-19

Lung The respiratory effects of COVID-19 are well-­

Lungs present evidence of acute or organizing known, but COVID-19 can affect other systems,
phase of diffuse alveolar damage (DAD), such as mainly the gastrointestinal system (Gu et al.
desquamation of pneumocytes, hyaline 2020), central nervous system (Saleki et al. 2020;
membrane formation, vascular congestion, Jahanshahlu and Rezaei 2020a), and
pulmonary edema, mononuclear cell infiltrates, cardiovascular system (Zheng et al. 2020b;
and multinucleated syncytial cells (Xu et al. Hessami et al. 2020). Its ability might lie partly in
2020). Consolidation characterized by abundant multiple routes, e.g., fecal-oral transmission,
neutrophilic infiltration may appear as well and airborne transmission, and contact, through
indicates bacterial pneumonia superimposed on which it can spread, and also, partly it can make
SARS-CoV-2 pneumonia (Tian et al. 2020). A in through pulmonary and systemic immune
variety of immune cells expressing CD3, CD4, responses. Research has revealed that an
CD8, CD20, CD79a, CD5, CD38, and CD68 overactivated immune system occurs during
may exist as proven by immunohistochemistry COVID-19 and plays a role in determining the
(Luo et al. 2020). SARS-CoV-2 inclusions in the outcome of the disease (Bahrami et al. 2020;
nucleus and cytoplasm are not visible. Basiri et al. 2020b; Sahu et al. 2020; Yazdanpanah
et al. 2020a; Saghazadeh and Rezaei 2020a;
Kidney Nasab et al. 2020), while inborn errors of
Kidney examination reveals diffuse proximal immunity are not particularly vulnerable to
tubule injury as manifested by brush border loss, COVID-19 and what is likely to happen to high-­
non-isometric vacuolar degeneration, and risk population, i.e., older adults and people with
necrosis (Su et al. 2020). Also, it displays other comorbid conditions (Babaha and Rezaei
hemosiderin granules, pigmented casts, and 2020). Therefore, it seems that the immune
erythrocyte aggregations that may obstruct the system starts attacking the body in response to
flow in the capillaries but lacks any signs of the trigger of COVID-19.
1 Introduction on Coronavirus Disease (COVID-19) Pandemic: The Global Challenge 5

1.3.2.1 Antiviral Immune Dysfunction supposition is supported by the biomarkers of

When a pathogen invades the body, innate CSS that hitherto have been associated with the
immune receptors initiate a cascade of immune severity of COVID-19, including inflammatory
responses through recognition of pathogen-­ markers (CRP and procalcitonin), tissue injury
associated molecular patterns (PAMPs). Type I markers (LDH, AST, ALT), cytokines and
interferon (IFN) responses are an essential chemokines (IL6, I1B, IFNY, IL2Ra), fibrin
element of antiviral immunity and success in the degradation products (D-dimer, fibrinogen), and
control of viral replication (Saghazadeh and macrophage activation markers (ferritin)
Rezaei 2017). Both SARS-CoV and MERS- (Henderson et al. 2020).
CoV possess structural and nonstructural
proteins that prevent these responses from being
generated by either directly or indirectly 1.4 Epidemiology
interfering with IFN signaling pathways
(Prompetchara et al. 2020). Inhibition of type I 1.4.1  Historical Review of SARS
A
IFN responses in the early phase of infection Pandemic
leads to progression to severe infection, and this
may be true for SARS-CoV-2. Also, antiviral In late 2002, an emerging infectious disease-­
immunity depends on the effector functions of causing pneumonia was introduced to the world.
cytotoxic lymphocytes, e.g., cytotoxic T In March 2003, a CoV was identified as the
lymphocytes (CTLs) and natural killer (NK) causative agent, and a month later (April 16,
cells. In people with COVID-19, CTLs and NK 2003), the WHO verified that SARS-CoV was
cells not only are reduced in number but also are the definitive origin of the disease. SARS is
functionally exhausted as indicated by the defined as a respiratory infection with a history of
increased expression of exhaustion markers high fever, cough, and dyspnea and may lead to
NKG2A on NK cells and PD-1 and Tim-3 on T respiratory distress syndrome. The WHO reported
cells (Diao et al. 2020; Zheng et al. 2020a; Fathi the outbreak on February 11, 2003, when the
and Rezaei 2020). confirmed cases exceeded 300, and declared the
disease as a global alert on March 12, 2003. The
1.3.2.2 Cytokine Storm first case was reported from China in November
Cytokine storm syndromes (CSS) refer to con- 2002, and then in February 2003, the virus spread
ditions associated with the maladaptive release to Hong Kong, Singapore, Toronto, and Hanoi. It
of cytokines (Ye et al. 2020), including malig- was found that on February 21, 2003, an infected
nancy, ARDS, cytokine release syndrome, physician transported the infection to Hong
familial hemophagocytic lymphohistiocytosis, Kong. In the hotel he was staying in, transmission
systemic juvenile idiopathic arthritis, and to other guests occurred and subsequently
macrophage activation syndrome. In particular, contributed to other countries’ involvement
the cytokine storm might occur in infections (Cherry 2004; Skowronski et al. 2005). It seems
with the influenza virus and Epstein-Barr virus. that SARS-CoV, a beta genera virus, had an
Disease progression in patients with COVID-19 animal reservoir, an Asian civet cat. The
is accompanied by immune dysregulation, and transmission was mainly via human to human
this is not restricted to the antiviral immune contact with respiratory droplets, and most
dysfunction mentioned above but extended to happened in markets. The Chinese government’s
pro-inflammatory cytokine upregulation (Rokni nontransparency resulted in a global epidemic.
et al. 2020). The latter, along with multiorgan SARS diagnosis is based on clinical manifes-
involvement, are the main characteristics of tations and laboratory findings. Dynamic changes
cytokine storm syndrome, which are seen in in chest X-rays are compatible with the infection
severe COVID-19. For this, severe COVID-19 is stages. Contact with confirmed cases and travel
supposed to be a cytokine storm syndrome. The to endemic areas are clues in diagnosis. The treat-
6 N. Rezaei et al.

ment was mainly supportive, but some drugs 1.4.2.1 Epidemiological Characteristics
showed clinical improvements like lopinavir, By July 12, 2020, COVID-19 has affected around
ritonavir, and remdesivir (Peeri et al. 2020). 13 million people worldwide. A systematic
However, no specific drug or vaccine was devel- review (Park et al. 2020) summarizes the main
oped. The WHO measures were limited to tradi- epidemiological characteristics of COVID-19 as
tional epidemic controlling tools. follows: the basic reproduction number, 1.9–6.5;
Patients were mostly from healthcare provid- the incubation period, 4–6 days; and the case
ers, and most transmissions happened in the hos- fatality rate outside of China, 0.3–1.4%.
pital setting (Skowronski et al. 2005). Many
medical procedures, like intubation, which 1.4.2.2 Routes of Transmission
exposed them to respiratory discharge, put them The transmission of SARS-CoV-2 is mainly
at risk of infection (Peeri et al. 2020). The dependent on respiratory droplets, followed by
disease also had a tremendous psychological aerosols. Other routes that possibly mediate the
impact on the healthcare staff. Confronting with virus transmission include the eye-nose and
a disease with unknown origin made immense fecal-oral transmission routes.
distress (Sim and Chua 2004). During the
pandemic, governments dealt with significant 1.4.2.3 The Spectrum of Infection
economic challenges. Quarantine limited the The spectrum of clinical severity covers both
trading to essential everyday needs, and the asymptomatic and symptomatic individuals. A
tourism industry was among the most affected symptomatic infection might cause either mild to
industries (Fan 2003). moderate symptoms of infection, severe infection
The pandemic peak was the last week of May that requires hospital admission, a critical
2003. Finally, the epidemic led to more than infection that requires intensive care unit (ICU)
8000 infected cases with about 10% mortality admission, or even death. Among symptomatic
rate, and 29 countries were affected. Presumably, individuals, about 20% develop severe to critical
the last patients were infected in July 2003, and infection, and the remainders are diagnosed as
the disease was controlled after 7 months mild to moderate infection. Very concerning is
(Cherry 2004). Up to now, no other cases of that current data, though not sufficient for
SARS infection have been reported (Peeri et al. calculation of the role of asymptomatic
2020). individuals in the transmission of infection,
clearly reveals that the challenge of containing
the infection largely lies not in detecting
1.4.2 The Current State of COVID-19 asymptomatic cases but who can carry high
concentrations of the live SARS-CoV-2 in the
Undoubtedly, the eyes can easily judge how pow- absence of symptoms. Reports provide different
erful the global influence of the COVID-19 out- estimations of the ratio of asymptomatic
break is, starting from December 2019 in Wuhan, individuals, ranging from 30% to more than 50%
China, spreading across countries worldwide in a (Nishiura et al. 2020; Gandhi et al. 2020).
few months, and turning into a pandemic (Hanaei
and Rezaei 2020; Jabbari et al. 2020). However, 1.4.2.4 High-Risk Population
the measurement of such an influence is neces- Adults aged 70 and above, male sex, and preex-
sary for controlling the present pandemic and isting medical conditions, e.g., cancer, diabe-
also would help in being prepared for its next tes, cardiovascular disease, chronic respiratory
waves. When defining the epidemiology of an disease, and hypertension, are the factors
epidemic, different factors matter, e.g., the num- known to be associated with death from
ber of infected people, the transmissibility of the COVID-19 (Ahmadi et al. 2020; Hessami et al.
infection, and the spectrum of clinical severity 2020; Basiri et al. 2020b; Shamshirian and
(Lipsitch et al. 2020). Rezaei 2020). Moreover, reports have indicated
1 Introduction on Coronavirus Disease (COVID-19) Pandemic: The Global Challenge 7

that the mortality of COVID-19 is not equal in 1.5.1.2 Serologic Diagnosis

different ethnicities. Accordingly, in the USA, Serologic tests are comparatively easier to per-
most of the deceased patients were Blacks or form, requiring less technical expertise and
indigenous Americans. Even after age adjust- equipment compared to nucleic acid detection
ment, the mortality rates of Blacks and indige- (Rashid et al. 2020). Samples are the blood that is
nous Americans were 3.8 and 3.2 times as high collected in tubes, which poses a less potential
as Whites, respectively. On the other hand, the risk to the staff handling the samples. The use of
mortality of other races came after these two serologic methods requires appropriate
(https://www.apmresearchlab.org/covid/ interpretations of the results and understanding
deaths-­by-­race). of the strengths and limitations of such tests.
There is much to determine the value of
serological testing in COVID-19 diagnosis and
1.5 Diagnosis and Clinical monitoring. More comprehensive evaluations of
Manifestations of COVID-19 the performance of serologic tests are rapidly
underway. Considerations for the use of serologic
1.5.1 Diagnosis methods for COVID-19 require the correct and
appropriate interpretations of the results and
Diagnosis of COVID-19 is mainly based on epi- understanding the strengths and limitations of
demiological history, clinical manifestations, and such tests (Rashid et al. 2020).
some auxiliary examinations, such as nucleic
acid detection, computed tomography (CT) scan, 1.5.1.3 Imaging
immune identification technology, and blood Some patients with positive chest CT findings
culture (Li et al. 2020b). Recent outbreaks with may present with negative results of RT-PCR for
RNA viruses have presented great difficulties SARS-CoV-2 (Xie et al. 2020a). It has been
with diagnosis (Basiri et al. 2020a). It was suggested that CT could play a role in the
particularly the case during the 2015–2016 COVID-19 case ascertainment. CT abnormalities
pandemic of Zika virus (ZIKV) due to low viral might predate RT-PCR positivity in symptomatic
titers and transient infection (Faye et al. 2008). patients and those without symptoms, which
subsequently tested positive by RT-PCR (Hessami
1.5.1.1 Nucleic Acid Test et al. 2020; Corman et al. 2020).
The two commonly used nucleic acid detection
technologies for SARS-CoV-2 are real-time
quantitative polymerase chain reaction 1.5.2 Clinical Manifestations
(RT-qPCR) and high-throughput sequencing. The
reliable identification method for SARS-CoV-2 Even though coronaviruses usually have mild
is virus blood culture and high-throughput symptoms in human beings, betacoronaviruses
sequencing of the whole genome (Li et al. 2020b). such as SARS- and MERS-CoV can cause severe
Diagnosis by screening and confirmation steps forms associated with high mortality rates (Peeri
by the molecular method have been designed and et al. 2020; Sabino-Silva et al. 2020). SARS-­
validated with the use of synthetic nucleic acid CoV-­ 2, which is responsible for the recent
technology. It was followed by the development outbreak, is an emerging betacoronavirus that has
of numerous nucleic acid assays (Corman et al. clinical manifestations with various severity in
2020). Diagnosis of suspected cases is confirmed five stages, from asymptomatic infection to
by RNA assays with real-time PCR, using critical form (Bulut and Kato 2020; Verity et al.
respiratory samples. RNA-based molecular tests 2020; Lotfi and Rezaei 2020). Although the
require to set up facilities and instruments, with global concern about this viral infection has been
appropriate biosafety measures, and skilled increased obviously due to the high
laboratory technicians at a high cost. transmissibility of the disease, it has a relatively
8 N. Rezaei et al.

low mortality rate compared to previous Potential neurological manifestations have

coronaviruses (Petrosillo et al. 2020). Most cases been reported in COVID-19 patients, such as
are categorized in the mild to the moderate dizziness, acute cerebrovascular diseases,
classification of the disease, while a low number unstable walking, malaise, and impaired
of patients develop a severe or critical form of the consciousness (Wang et al. 2020b).
disease. The disease may be asymptomatic up to Keratoconjunctivitis is another infrequent clinical
14 days and even more up to 24 days in some symptom that might appear as an initial clinical
cases (Ather et al. 2020; Peng et al. 2020); but the symptom in COVID-19 patients (Cheema et al.
mean incubation period reported for this viral 2020).
infection is 5.2 days, which is relatively similar to
SARS and MERS (Bulut and Kato 2020).
Therefore, patients who have an asymptomatic 1.6 Potential Therapeutics
form of the infection and also patients during the for COVID-19
asymptomatic incubation period can be carriers
and transmit the disease without awareness. The 1.6.1 Interferon-Alpha
most common symptoms of this viral infection and Interferon-Beta
are fever, followed by dry cough, fatigue, and
shortness of breath (Hu et al. 2020). Among Both interferon-alpha (IFN-α) and interferon-­
upper airway manifestations, pharyngodynia, beta (IFN-β) have been shown to affect
nasal congestion, and rhinorrhea are more coronaviruses, especially MERS-CoV.
common (Lovato and de Filippis 2020). In more Although most in vitro studies and animal stud-
severe cases, viral pneumonia can cause ARDS, ies reported controversial effects of IFN-α and
and also these patients can have major IFN-β against the SARS-CoV-2, some publica-
complications such as acute cardiac injury (ACI), tions have shown promising results of IFN-α
acute kidney injury (AKI), and shock (Hu et al. and IFN-β in combination with ribavirin and/or
2020). In a study of 1590 patients with COVID-­19, lopinavir/ritonavir (Sanders et al. 2020).
these comorbid conditions resulted in poorer According to the study by Ivan Fan-Ngai Hung
clinical outcomes, especially in the presence of et al., in patients with mild to moderate COVID-
more than one comorbidity (Guan et al. 2020a). 19 infection, the early triple antiviral therapy
Epidemiological studies reveal that a higher (ribavirin and lopinavir/ritonavir) with IFN-
mortality rate occurs in geriatric patients and β-1b was safer than using the lopinavir/ritonavir
patients who have preexisting comorbid alone and had better results in palliating the
conditions and that the median survival time symptoms, reducing the duration of
might be reduced to 5 days in old patients (Bulut hospitalization, and SARS-CoV-2 viral
and Kato 2020). shedding (Hung et al. 2020). Therefore, IFN-β
Other less prevalent clinical manifestations might be a good choice in combination with
include headache, diarrhea, nausea, vomiting, other antivirals, but further research is needed
myalgia, and arthralgia (Guan et al. 2020b; to confirm its actual effects.
Huang et al. 2020b). In the mild form of the
disease, alterations in the sense of smell and taste
are commonly reported by the patients, and the 1.6.2 Antivirals
clinicians should consider these symptoms as
initial apparent symptoms of the disease (Spinato In combat with a newly emerged disease that
et al. 2020). Most of the patients have alterations does not have any specific known treatment,
in their chest CT. Bilateral ground-glass opacities the tendency is to use the most probably potent
(GGO), especially in the periphery of the lungs, available drugs on patients due to the time-­
are a common finding among most of the patients consuming process of de novo drug discovery.
due to pneumonia (Han et al. 2020). This process is named drug repurposing or
1 Introduction on Coronavirus Disease (COVID-19) Pandemic: The Global Challenge 9

drug repositioning that is defined as using an 1.6.3 Convalescent Plasma and IVIG
approved drug for a new disease that is not on
its indication list. Considering the matter of In urgent conditions such as outbreaks when
time in the current pandemic condition, the there is no approved medication, the last hope of
best way to find potential candidates for repur- increasing the survival of the patients is to use
posing method might be computational or in convalescent plasma or immunoglobulins
silico approach. After a drug is proposed by (Pourahmad et al. 2020). It is usually performed
computational methods, the next step is to by taking the plasma of a survived patient, which
investigate the efficacy of that candidate by contains several types of immunoglobulins, and
in vitro studies. If the candidate got approval in injecting it into patients that represent severe
this level, it could enter the observational stud- forms of the disease. This method might be useful
ies or clinical trials, in which the latter is the if it was used within 48 h of the ICU admission of
most valid and reliable method to confirm a the patient. Many positive changes might occur,
drug candidate. such as reducing the need for mechanical
Table 1.1 provides a summary of the drugs ventilation, reducing the length of hospital stay,
most frequently entered into clinical trials. and recovery promotion (Chen et al. 2020; Xie
Chloroquine and hydroxychloroquine are of the et al. 2020b).
very first proposed candidates that entered the
trials. However, the computational methods have
not reported any specific target for them. 1.6.4 Monoclonal Antibodies
Lopinavir and ritonavir gain a low score in
computational methods in addition to the fact that Monoclonal antibodies are produced by one spe-
in observational studies and clinical trials, no cific clone of B cells. Therefore, they have a
specific benefit more than standard care was monovalent affinity and only identify one epitope
reported. Ribavirin is another candidate that is of an antigen. While most of the literature
acceptable by computational methods by regarding the treatment of the COVID-19
targeting two components of COVID-19, but due infection with monoclonal antibodies is related to
to its toxicity and high dose requirement, it might the previous knowledge of SARS and MERS,
not be the right choice. Although remdesivir was some studies express the effectiveness of
a promising candidate in both computational and anti-IL-6 antibodies against the COVID-19
in vitro studies, the overall number of cases is not infection. Tocilizumab is an IL-6 receptor
enough to statistically confirm its effectiveness. antagonist that lowered the use of oxygen
Favipiravir has the same condition as remdesivir, supplement in 75% of patients in a study
but the reports of its effectiveness are on moderate conducted in China. Another relevant monoclonal
cases of the disease, and there is not enough antibody is sarilumab, in which its efficacy is not
evidence for its effect on more severe cases. The approved yet, and it is in phase II/III clinical trial
other potential candidate to mention is atazanavir, (Lu et al. 2020).
which has successfully targeted six components
of COVID-19 in computational methods.
Furthermore, besides its positive results in 1.6.5 Corticosteroids
in vitro studies in decreasing viral replication, it
is reported that atazanavir has some anti-­ When an enhanced immune response arises, it
inflammatory effects because it diminishes the causes several injuries to the body, and the use of
IL-6 and TNF-α secretion from infected corticosteroids lies in reducing these injuries.
monocytes. However, there is no ongoing clinical However, the corticosteroids might cause some
trial on this potential candidate. side effects like lowering the pace of the viral
10 N. Rezaei et al.

Table 1.1 Antivirals repurposed by computational methods

Observational/clinical
Antivirals Computational methods In vitro studies studies
Chloroquine/ - No specific target, the Inhibiting the glycosylation No clear benefit was
hydroxychloroquine probability of targeting of host receptors, proteolytic present, and some side
3CLpro, PLP, Nsp3b, Nsp3c, processing, and endosomal effects like ventricular
and E-channel acidification, therefore, the arrhythmias are reported
- The effectiveness of the viral entry prevention (Mehra et al. 2020)
drugs that have no specific (Sanders et al. 2020)
targets is controversial, and
they are not recommended
Lopinavir/ritonavir - Low docking scores 3CLpro inhibition in other No benefit was present
- The failure of the coronavirus strains (Sanders apart from standard care
drug-target interaction et al. 2020) (Cao et al. 2020).
according to molecular
dynamics simulation
Ribavirin Targets PLP and RdRp Inhibiting viral replication in Due to its toxicity and high
high concentrations only dose requirement, this drug
(Sanders et al. 2020) has less chance in the
treatment of COVID-19
(Sanders et al. 2020)
Remdesivir Targeting 3CLpro and RdRp In vitro activity against Reported good
several Coronaviridae, effectiveness against the
including SARS-CoV-2 with COVID-19 infection, but
an EC50 value of 0.77 Μm more studies are needed to
(Sanders et al. 2020) statistically confirm its
effectiveness (Wang et al.
2020)
Favipiravir Targeting RdRp Having an EC50 of - Useful in the clinical
61.88 μM/L against recovery of moderate cases
SARS-CoV-2 in Vero E6 cells at day 7, more RCTs are
(Sanders et al. 2020) needed to confirm further
the results (Sanders et al.
2020)
- Median viral clearance
time (4 days) and chest
image improvement rate
(91.43%) (Lu et al. 2020)
Atazanavir Targeting 3CLpro, RdRp, - Diminished viral replication No trial was found
helicase, 3′to5′exonuclease, in the human epithelial
2′-O-ribose pulmonary cells infected with
methyltransferase, and COVID-19 (Fintelman-­
EndoRNAse Rodrigues et al. 2020)
- Diminished secretion of
IL-6 and TNF-alpha in
SARS-CoV-2-infected human
monocytes (Fintelman-­
Rodrigues et al. 2020)
Mohamed et al. (2020b)

clearance and, consequently, lengthening the 1.6.6 Vaccine Development

disease period. The use of the corticosteroids in
the treatment of COVID-19 is controversial, and Vaccine development (for both therapeutic and
almost all studies do not recommend it (Sanders preventive purposes) is a long time-consuming
et al. 2020). process that needs to become faster during
1 Introduction on Coronavirus Disease (COVID-19) Pandemic: The Global Challenge 11

epidemics. The COVID-19 vaccine candidates ple, infections and organ failure, as well as to
that have entered the clinical trials are DNA-­ other conditions that increase the risk of under-
based, RNA-based, live attenuated virus, and nutrition like aging (Hirbod-Mobarakeh et al.
inactivated virus vaccine platforms as of writing 2014). Besides, micronutrients, e.g., trace ele-
this manuscript (Craven 2020, 28 May). RNA-­ ments and vitamins, crucially contribute to the
based and DNA-based vaccine development regulation of immune responses, interestingly
platforms and recombinant-subunit developing antiviral immune responses (Mahmoudi and
platforms have a potential faster process than Rezaei 2019). Nutritional therapy is, therefore, of
other platforms. The potential fast speed of RNA high priority during the pandemic of COVID-19,
and DNA vaccines is because the development causing an acute respiratory infection associated
process of these vaccines does not require with fever and multiorgan failure. In particular, it
fermentation or culture. Furthermore, next-­ might be beneficial to older people with preexist-
generation sequencing and reverse genetics are ing chronic conditions, who are considered as the
considered as tools that can accelerate the vaccine most susceptible vulnerable to COVID-19 and
development process in the time of epidemics. adverse outcomes.
However, there are more challenges in developing Other efforts to combat COVID-19 occur in
a vaccine for COVID-19 itself. For example, multiple disciplines of immunotherapy (Fathi
whether to use a full-length spike protein or RBD and Rezaei 2020; Lotfi et al. 2020), regenerative
as the target has remained an unsolved issue medicine (Basiri et al. 2020b), medical biotech-
(Sharifkashani et al. 2020). Furthermore, nology (Rezaei 2020b), picotechnology (Rabiee
regarding the recent vaccine candidates’ et al. 2020), and telemedicine (Moazzami et al.
preclinical studies, it has been observed that the 2020). However, the quality of clinical studies
candidates can intensify the pulmonary damage does not meet the requirements (Rzymski et al.
both directly and as a consequence of the surge in 2020). The observation of the same phenotype of
the level of antibodies (Lurie et al. 2020). By disease in family members and individuals with
considering these obstacles in this way, the idea specific genetic defects might establish a genetic
of vaccine repurposing might help to speed up basis of disease that would deserve the attention
this process. As an illustration, the Bacillus of clinical pharmacists (Yousefzadegan and
Calmette-Guerin (BCG) live-attenuated vaccine Rezaei 2020; Darbeheshti and Rezaei 2020).
is one of the first candidates proposed to be
effective against COVID-19, and some clinical
trials are underway to investigate its effectiveness 1.7  OVID19 Pandemic: Global
C
(medicine 2020a, b). Challenges, Prevention,
and Preparedness
for the Next Pandemic
1.6.7 Nutrition
The primary prevention steps included isolation
As new trends in the diet have emerged, so have of confirmed cases, quarantine of suspected indi-
the new trends in noncommunicable diseases. viduals, and traveler screening. Scientific collab-
Nutrition therapy and its immunomodulatory orations facilitated the identification of the virus,
effects have been a topic of crucial importance in and the genome was sequenced in mid-­ April
the context of chronic diseases that lack a specific 2003 (Skowronski et al. 2005). The genome
treatment, including cardiovascular diseases, sequencing gave on to the development of sophis-
cancer, and metabolic disorders. The importance ticated diagnosis tests and targets for medication
of nutrition therapy extends to acute conditions and vaccine (Chow et al. 2003).
that increase nutritional requirements, for exam-
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noble allies that struggled on with us, without one token of
resistance.
Fulano suffered least. He turned his brave eye back, and
beckoned me with his ear to listen, while he seemed to say: “See,
this is my Endurance! I hold my Power ready still to show.”
And he curved his proud neck, shook his mane like a banner, and
galloped the grandest of all.
We came to a broad strip of sand, the dry bed of a mountain-
torrent. The trail followed up this disappointing path. Heavy
ploughing for the tired horses! How would they bear the rough work
down the ravine yet to come?
Suddenly our leader pulled up and sprang from the saddle.
“Look!” he cried, “how those fellows spent their time, and saved
ours. Thank Heaven for this! We shall save her, surely, now.”
It was water! No need to go back to Pindar to know that it was
“the Best.”
They had dug a pit deep in the thirsty sand, and found a lurking
river buried there. Nature never questioned what manner of men
they were that sought. Murderers flying from vengeance and
planning now another villain outrage,—still impartial Nature did not
change her laws for them. Sunshine, air, water, life,—these boons of
hers,—she gave them freely. That higher boon of death, if they were
to receive, it must be from some other power, greater than the
undiscriminating force of Nature.
Good luck and good omen, this well of water in the sand! It
proved that our chase had suffered as we, and had been delayed as
we. Before they had dared to pause and waste priceless moments
here, their horses must have been drooping terribly. The pit was
nearly five feet deep. A good hour’s work, and no less, had dug it
with such tools as they could bring. I almost laughed to think of the
two, slowly bailing out the sliding sand with a tin plate, perhaps, and
a frying-pan, while a score of miles away upon the desert we three
were riding hard upon their tracks to follow them the fleeter for this
refreshment they had left. “Sic vos non vobis!” I was ready to say
triumphantly; but then I remembered the third figure in their group,
—a woman, like a Sibyl, growing calmer as her peril grew, and
succor seemed to withdraw. And the pang of this picture crushed
back into my heart any thoughts but a mad anxiety and a frenzy to
be driving on.
We drank thankfully of this well by the wayside. No gentle beauty
hereabouts to enchant us to delay. No grand old tree, the shelter
and the landmark of the fountain, proclaiming an oasis near. Nothing
but bare, hot sand. But the water was pure, cool, and bright. It had
come underground from the Sierra, and still remembered its parent
snows. We drank and were grateful, almost to the point of pity. Had
we been but avengers, like Armstrong, my friend and I could
wellnigh have felt mercy here, and turned back pardoning. But
rescue was more imperative than vengeance. Our business tortured
us, as with the fanged scourge of Tisiphone, while we dallied. We
grudged these moments of refreshment. Before night fell down the
west, and night was soon to be climbing up the east, we must
overtake,—and then?
I wiped the dust and spume away from Fulano’s nostrils and
breathed him a moment. Then I let him drain deep, delicious
draughts from the stirrup-cup. He whinnied thanks and undying
fealty,—my noble comrade! He drank like a reveller. When I mounted
again, he gave a jubilant curvet and bound. My weight was a feather
to him. All those leagues of our hard, hot gallop were nothing.
The brown Sierra here was close at hand. Its glittering, icy
summits, above the dark and sheeny walls, far above the black
phalanxes of clambering pines, stooped forward and hung over us as
we rode. We were now at the foot of the range, where it dipped
suddenly down upon the plain. The gap, our goal all day, opened
before us, grand and terrible. Some giant force had clutched the
mountains, and riven them narrowly apart. The wild defile gaped,
and then wound away and closed, lost between its mighty walls, a
thousand feet high, and bearing two brother pyramids of purple cliffs
aloft far above the snow line. A fearful portal into a scene of the
throes and agonies of earth! and my excited eyes seemed to read,
gilded over its entrance, in the dead gold of that hazy October
sunshine, words from Dante’s inscription,—
“Per me si va tra la perduta gente;
Lasciate ogni speranza voi, ch’ entrate!”
“Here we are,” said Brent, speaking hardly above his breath. “This
is Luggernel Alley at last, thank God! In an hour, if the horses hold
out, we shall be at the Springs; that is, if we can go through this
breakneck gorge at the same pace. My horse began to flinch a little
before the water. Perhaps that will set him up. How are yours?”
“Fulano asserts that he has not begun to show himself yet. I may
have to carry you en croupe, before we are done.”
Armstrong said nothing, but pointed impatiently down the defile.
The gaunt white horse moved on quicker at this gesture. He seemed
a tireless machine, not flesh and blood,—a being like his master,
living and acting by the force of a purpose alone.
Our chief led the way into the cañon.
 CHAPTER XX.

A HORSE.
Yes, John Brent, you were right when you called Luggernel Alley a
wonder of our continent.
I remember it now,—I only saw it then;—for those strong scenes
of nature assault the soul whether it will or no, fight in against
affirmative or negative resistance, and bide their time to be admitted
as dominant over the imagination. It seemed to me then that I was
not noticing how grand the precipices, how stupendous the
cleavages, how rich and gleaming the rock faces in Luggernel Alley.
My business was not to stare about, but to look sharp and ride hard;
and I did it.
Yet now I can remember, distinct as if I beheld it, every stride of
that pass; and everywhere, as I recall foot after foot of that fierce
chasm, I see three men with set faces,—one deathly pale and
wearing a bloody turban,—all galloping steadily on, on an errand to
save and to slay.
Terrible riding it was! A pavement of slippery, sheeny rock; great
beds of loose stones; barricades of mighty boulders, where a cliff
had fallen an æon ago, before the days of the road-maker race;
crevices where an unwary foot might catch; wide rifts where a shaky
horse might fall, or a timid horseman drag him down. Terrible riding!
A pass where a calm traveller would go quietly picking his steps,
thankful if each hour counted him a safe mile.
Terrible riding! Madness to go as we went! Horse and man, any
moment either might shatter every limb. But man and horse neither
can know what he can do, until he has dared and done. On we
went, with the old frenzy growing tenser. Heart almost broken with
eagerness.
No whipping or spurring. Our horses were a part of ourselves.
While we could go, they would go. Since the water, they were full of
leap again. Down in the shady Alley, too, evening had come before
its time. Noon’s packing of hot air had been dislodged by a mountain
breeze drawing through. Horses and men were braced and cheered
to their work; and in such riding as that, the man and the horse
must think together and move together,—eye and hand of the rider
must choose and command, as bravely as the horse executes. The
blue sky was overhead, the red sun upon the castellated walls a
thousand feet above us, the purpling chasm opened before. It was
late, these were the last moments. But we should save the lady yet.
“Yes,” our hearts shouted to us, “we shall save her yet.”
An arroyo, the channel of a dry torrent, followed the pass. It had
made its way as water does, not straightway, but by that potent
feminine method of passing under the frowning front of an obstacle,
and leaving the dull rock staring there, while the wild creature it
would have held is gliding away down the valley. This zigzag channel
baffled us; we must leap it without check wherever it crossed our
path. Every second now was worth a century. Here was the sign of
horses, passed but now. We could not choose ground. We must take
our leaps on that cruel rock wherever they offered.
Poor Pumps!
He had carried his master so nobly! There were so few miles to
do! He had chased so well; he merited to be in at the death.
Brent lifted him at a leap across the arroyo.
Poor Pumps!
His hind feet slipped on the time-smoothed rock. He fell short. He
plunged down a dozen feet among the rough boulders of the
torrent-bed. Brent was out of the saddle almost before he struck,
raising him.
No, he would never rise again. Both his fore-legs were broken at
the knee. He rested there, kneeling on the rocks where he fell.
Brent groaned. The horse screamed horribly, horribly,—there is no
more agonized sound,—and the scream went echoing high up the
cliffs where the red sunlight rested.
It costs a loving master much to butcher his brave and trusty
horse, the half of his knightly self; but it costs him more to hear him
shriek in such misery. Brent drew his pistol to put poor Pumps out of
pain.
Armstrong sprang down and caught his hand.
“Stop!” he said in his hoarse whisper.
He had hardly spoken, since we started. My nerves were so
strained, that this mere ghost of a sound rang through me like a
death yell, a grisly cry of merciless and exultant vengeance. I
seemed to hear its echoes, rising up and swelling in a flood of thick
uproar, until they burst over the summit of the pass and were
wasted in the crannies of the towering mountain-flanks above.
“Stop!” whispered Armstrong. “No shooting! They’ll hear. The
knife!”
He held out his knife to my friend.
Brent hesitated one heart-beat. Could he stain his hand with his
faithful servant’s blood?
Pumps screamed again.
Armstrong snatched the knife and drew it across the throat of the
crippled horse.
Poor Pumps! He sank and died without a moan. Noble martyr in
the old, heroic cause.
 I caught the knife from Armstrong. I cut the thong of my girth.
The heavy California saddle, with its macheers and roll of blankets,
fell to the ground. I cut off my spurs. They had never yet touched
Fulano’s flanks. He stood beside me quiet, but trembling to be off.
“Now Brent! up behind me!” I whispered,—for the awe of death
was upon us.
I mounted. Brent sprang up behind. I ride light for a tall man.
Brent is the slightest body of an athlete I ever saw.
Fulano stood steady till we were firm in our seats.
Then he tore down the defile.
Here was that vast reserve of power; here the tireless spirit; here
the hoof striking true as a thunderbolt, where the brave eye saw
footing; here that writhing agony of speed; here the great promise
fulfilled, the great heart thrilling to mine, the grand body living to
the beating heart. Noble Fulano!
I rode with a snaffle. I left it hanging loose. I did not check or
guide him. He saw all. He knew all. All was his doing.
We sat firm, clinging as we could, as we must. Fulano dashed
along the resounding pass.
Armstrong pressed after,—the gaunt white horse struggled to
emulate his leader. Presently we lost them behind the curves of the
Alley. No other horse that ever lived could have held with the black
in that headlong gallop to save.
Over the slippery rocks, over the sheeny pavement, plunging
through the loose stones, staggering over the barricades, leaping the
arroyo, down, up, on, always on,—on went the horse, we clinging as
we might.
It seemed one beat of time, it seemed an eternity, when between
the ring of the hoofs I heard Brent whisper in my ear.
“We are there.”
 The crags flung apart, right and left. I saw a sylvan glade. I saw
the gleam of gushing water.
Fulano dashed on, uncontrollable!
There they were,—the Murderers.
Arrived but one moment!
The lady still bound to that pack-mule branded A. & A.
Murker just beginning to unsaddle.
Larrap not dismounted, in chase of the other animals as they
strayed to graze.
The men heard the tramp and saw us, as we sprang into the
glade.
Both my hands were at the bridle.
Brent, grasping my waist with one arm, was awkward with his
pistol.
Murker saw us first. He snatched his six-shooter and fired.
Brent shook with a spasm. His pistol arm dropped.
Before the murderer could cock again, Fulano was upon him!
He was ridden down. He was beaten, trampled down upon the
grass,—crushed, abolished.
We disentangled ourselves from the mêlée.
Where was the other?
The coward, without firing a shot, was spurring Armstrong’s
Flathead horse blindly up the cañon, whence we had issued.
We turned to Murker.
Fulano was up again, and stood there shuddering. But the man?
A hoof had battered in the top of his skull; blood was gushing
from his mouth; his ribs were broken; all his body was a trodden,
massacred carcass.
He breathed once, as we lifted him.
Then a tranquil, childlike look stole over his face,—that well-
known look of the weary body, thankful that the turbulent soul has
gone. Murker was dead.
Fulano, and not we, had been executioner. His was the stain of
blood.
 CHAPTER XXI.

LUGGERNEL SPRINGS.
“I am shot,” gasped Brent, and sank down fainting.
Which first? the lady, or my friend, slain perhaps for her sake?
“Her! see to her!” he moaned.
I unbound her from the saddle. I could not utter a word for pity.
She essayed to speak; but her lips only moved. She could not
change her look. So many hours hardening herself to repel, she
could not soften yet, even to accept my offices with a smile of
gratitude. She was cruelly cramped by her lashings to the rough
pack-saddle, rudely cushioned with blankets. But the horror had not
maddened her; the torture had not broken her; the dread of worse
had not slain her. She was still unblenching and indomitable. And still
she seemed to rule her fate with quiet, steady eyes,—gray eyes with
violet lights.
I carried her a few steps to the side of a jubilant fountain lifting
beneath a rock, and left her there to Nature, kindliest leech.
Then I took a cup of that brilliant water to my friend, my brother.
“I can die now,” he said feebly.
“There is no death in you. You have won the right to live. Keep a
brave heart. Drink!”
And in that exquisite spot, that fair glade of the sparkling
fountains, I gave the noble fellow long draughts of sweet
refreshment. The rescued lady trailed herself across the grass and
knelt beside us. My horse, still heaving with his honorable gallop,
drooped his head over the group. A picture to be remembered!
Who says that knighthood is no more? Who says the days of
chivalry are past? Who says it, is a losel.
Brent was roughly, but not dangerously, shot along the arm. The
bullet had ploughed an ugly path along the muscles of the fore-arm
and upper-arm, and was lodged in the shoulder. A bad wound; but
no bones broken. If he could but have rest and peace and surgery!
But if not, after the fever of our day, after the wearing anguish of
our doubtful gallop; if not?—
Ellen Clitheroe revived in a moment, when she saw another
needed her care. Woman’s gentle duty of nurse found her ready for
its offices. My blundering good-will gave place willingly to her fine-
fingered skilfulness. She forgot her own weariness, while she was
magnetizing away the pangs of the wounded man by her delicate
touch.
He looked at me, and smiled with total content.
“My father?” asked the lady, faintly, as if she dreaded the answer.
“Safe!” said I. “Free from the Mormons. He is waiting for you with
a friend.”
Her tears began to flow. She was busy bandaging the wound. All
was silent about us, except the pleasant gurgle of the fountains,
when we heard a shot up the defile.
The sharp sound of a pistol-shot came leaping down the narrow
chasm, flying before the pursuit of its own thundering echoes. Those
grand old walls of the Alley, facing each other there for the shade
and sunshine of long, peaceful æons, gilded by the glow of
countless summers, splashed with the gray of antique lichens on
their purple fronts, draped for unnumbered Octobers with the scarlet
wreaths of frost-ripened trailers,—those solemn walls standing there
in old silence, unbroken save by the uproar of winter floods, or by
the humming flight of summer winds, or the louder march of
tempests crowding on,—those silent walls, written close with the
record of God’s handiwork in the long cycles of creation, lifted up
their indignant voices when the shot within proclaimed to them the
undying warfare of man with man, and, roaring after, they hurled
that murderous noise forth from their presence. The quick report
sprang out from the chasm into the quiet glade, where the lady
knelt, busy with offices of mercy, and there it lost its vengeful tone,
and was blended with the rumble of the mingled rivulets of the
springs. The thundering echoes paused within, slowly proclaiming
quiet up from crag to crag, until one after another they whispered
themselves to silence. No sound remained, save the rumble of the
stream, as it flowed away down the opening valley into the haze,
violet under gold, of that warm October sunset.
I sprang up when I heard the shot, and stood on the alert. There
were two up the Alley; which, after the shot, was living, and which
dead?
Not many moments had passed, when I heard hoofs coming, and
Armstrong rode into view. The gaunt white horse galloped with the
long, careless fling I had noticed all day. He moved machine-like, as
if without choice or volition of his own, a horse commissioned to
carry a Fate. Larrap’s stolen horse trotted along by his old master.
Armstrong glanced at Murker’s body lying there, a battered mass.
“Both!” he whispered. “The other was sent right into my hands to
be put to death. I knew all the time it would be sent to me to do
killing. He was spurring up the Alley on my own horse. He snapped
at me. My pistol did not know how to snap. See here!”
And he showed me, hanging from his saddle horn, that loathliest
of all objects a man’s eyes ever lighted upon, a fresh scalp. It
sickened me.
“Shame!” said I. “Do you call yourself a man, to bring such a
thing into a lady’s presence?”
“It was rather mean to take the fellow’s hair,” says Armstrong. “I
don’t believe brother Bill would have did it. But I felt orful ugly, when
I saw that fat, low-lived devil, and thought of my brother, a big, hul-
hearted man as never gave a bad word to nobody, and never held
on to a dollar or a slug when ayry man wanted it more ’n him.
Come, I’ll throw the nasty thing away, if you say so.”
“Help me drag off this corpse, and we’ll bury man and scalp
together,” I said.
We buried him at the gate of the Alley, under a great cairn of
stones.
“God forgive them both,” said I, as I flung the last stone, “that
they were brutes, and not men.”
“Brutes they was, stranger,” says Armstrong, “but these things is
ordered somehow. I allow your pardener and you is glad to get that
gal out of a Mormon camp, ef it did cost him a horse and both on
you an all day’s tremble. Men don’t ride so hard, and look so wolfish,
as you two men have did, onless their heart is into it.”
“It is, indeed, strange,” said I, rather thinking aloud than
addressing my companion, “that this brute force should have
achieved for us by outrage what love failed in. Fate seems to have
played Brute against Brute, that Love might step between and claim
the victory. The lady is safe; but the lover may have won her life and
lost his own.”
“Look here, stranger,” says Armstrong, “part of this is yourn,”
pointing to the money-belt, which, with the dead man’s knife and
pistol, he had taken from the corpse. “Halves of this and the other
fellow’s plunder belongs to your party.”
I suppose I looked disgusted; yet I have seen gentle ladies
wearing boastfully brooches that their favorite heroes had taken
from Christian men dead on the field at Inkermann, and shawls of
the loot of Delhi cover many shoulders that would shudder over a
dead worm.
“I’m not squimmidge,” said Armstrong. “It’s my own and my
brother’s money in them belts. I’ll count that out, and then, ef you
wont take your part, I’ll pass it over to the gal’s father. I allowed
from signs ther was, that that thar boss Mormon had about tuk the
old man’s pile. Most likely these shiners they won last night is some
of the very sufferins Sizzum got from him. It’s right he should hev
’em back.”
I acknowledged the justice of this restitution.
“Now,” said Armstrong again, “you want to stay by your friend
and the gal, so I’ll take one of the pack mules and fetch your two
saddles along before dark lights down. It was too bad to lose that
iron gray; but there’s more ’n two horses into the hide of that black
of yourn. He was the best man of the lot for the goin’, the savin’, and
the killin’. Stranger, I’ve ben byin’ and sellin’ and breedin’ kettrypids
ever since I was raised myself; but I allow I never seed a horse till I
seed him lunge off with you two on his back.”
Armstrong rode up the Alley again. Another man he was since his
commission of vengeance had been accomplished. In those lawless
wilds, vendetta takes the place of justice, becomes justice indeed.
Armstrong, now that his stern duty was done, was again the kindly,
simple fellow nature made him, the type of a class between pioneer
and settler, and a strong, brave, effective class it is. It was the
education, in youth, in the sturdy habits of this class, that made our
Washington the manly chief he was.
I returned to my friends by the Springs.
Emerging from the austere grandeur of the Alley, dim with the
shadows of twilight, the scene without was doubly sweet and almost
domestic. The springs, four or five in number, and one carrying with
it a thread of hot steam, sprang vigorously out along the bold edges
of the cliffs. All the ground was verdure,—green, tender, and
brilliant, a feast to the eyes after long staring over sere deserts. The
wild creatures that came there every day for refreshment, and
perhaps for intoxication in the aerated tipple of the Champagne
Spring, kept the grass grazed short as the turf of a park. Two great
spruce-trees, each with one foot under the rocks, and one edging
fountainward, stood, pillar under pyramid. Some wreaths of drooping
creepers, floating from the crags, had caught and clung, and so
gone winding among the dark foliage of the twin trees; and now
their leaves, ripened by autumn, shook amid the dusky green like an
alighting of orioles. Except for the spruces posted against the cliffs,
the grassy area of an acre about the springs was clear of other
growth than grass. Below, the rivulet disappeared in a green thicket,
and farther down were large cottonwoods, and one tall stranger
tree, the feminine presence of a drooping elm, as much unlooked-for
here as the sweet, delicate woman whom strange chances had
brought to dignify and grace the spot. This stranger elm filled my
heart with infinite tender memories of home, and of those early
boyish days when Brent and I lay under the Berkeley College elms,
or strayed beneath the elm-built arches up and down the avenues of
that fair city clustered round the College. In those bright days,
before sorrow came to him, or to me my harsh necessity, we two in
brotherhood had trained each other to high thoughts of courtesy and
love,—a dreamed-of love for large heroic souls of women, when our
time of full-completed worthiness should come. And his time had
come. And yet it might be that the wounded knight would never
know his lady, as much loving as beloved; it might be that he would
never find a sweeter soothing in her touch, than the mere touch of
gratitude and common charity; it might be that he would fever away
his beautiful life with the fever of his wound, and never feel the holy
quiet of a lover’s joy when the full bliss of love returned is his.
I gave a few moments to the horses and mules. They were still to
be unsaddled. Healthy Fulano had found his own way to water, and
now was feasting on the crisp, short grass along the outlet of the
Champagne Spring, tickling his nose with the bubbles of gas as they
sped by. Sup, Fulano! This spot was worth the gallop to see Sup,
Fulano, the brave, and may no stain of this day’s righteous death-
doing rest upon your guiltless life!
Brent was lying under the spruces, drowsing with fatigue,
reaction, and loss of blood. Miss Clitheroe sat by watching him.
These fine beings have an exquisitely tenacious vitality. The
happiness of release had suddenly kindled all her life again. As she
rose to meet me, there was light in her eyes and color in her cheeks.
Her whole soul leaped up and spoke its large gratitude in a smile.
“My dear friend,” she said; and then, with sudden tearfulness,
“God be thanked for your heroism!”
“God be thanked!” I repeated. “We have been strangely selected
and sent,—you from England, my friend and I, and my horse, the
hero of the day, from the Pacific,—to interfere here in each other’s
lives.”
“It would seem romance, but for the sharp terror of this day,
coming after the long agony of my journey with my poor, errant
father.”
“A sharp terror, indeed!”
“But only terror!” and a glow of maidenly thankfulness passed
over her face. “Except one moment of rough usage, when I slipped
away my gag and screamed as they carried me off, those men were
considerate to me. They never halted except to dig a well in the
sand of a riverbed. I learned from their talk that they had made an
attempt to steal your horses in the night, and, failing, dreaded lest
you, and especially Mr. Brent, would follow them close. So they rode
hard. They supposed that, when I was found missing, whoever went
in pursuit, and you they always feared, would lose time along the
emigrant road, searching eastward.”
“We might have done so; but we had ourselves ridden off that
way in despair of aiding you,”—and I gave her a sketch of the events
of the morning.
“It was the hope of succor from you that sustained me. After
what your friend said to me last evening, I knew he could not
abandon me, if he had power to act.” And she looked very tenderly
at the sleeper,—a look to repay him for a thousand wounds.
“Did you find my glove?” she asked.
 “He has it. That token assured us. Ah! you should have seen that
dear wounded boy, our leader, when he knew we were not astray.”
I continued my story of our pursuit,—the lulling beat of the
stream undertoning my words in the still twilight. When I came to
that last wild burst of Fulano, and told how his heroic charge had
fulfilled his faithful ardor of the day, she sprang up, thrilled out of all
weariness, and ran to the noble fellow, where he was taking his
dainty banquet by the brookside.
She flung her arms around his neck and rested her head upon his
shoulder. Locks of her black hair, escaping into curls, mingled with
his mane.
Presently Miss Clitheroe seemed to feel a maidenly consciousness
that her caresses of the horse might remind the horse’s master that
he was not unworthy of a like reward. She returned to my friend. He
was stirring a little in pain. She busied herself about him tenderly,
and yet with a certain distance of manner, building a wall of delicate
decorum between him and herself. Indeed, from the beginning of
our acquaintance yesterday, and now in this meeting of to-day, she
had drawn apart from Brent, and frankly approached me. Her fine
instinct knew the brother from the lover.
Armstrong presently rode out again.
When he saw his brother’s sorrel horse feeding with the others,
he wept like a child.
We two, the lady and I, were greatly touched.
“I’ve got a daughter myself, to home to the Umpqua,” said
Armstrong, turning to Miss Clitheroe; “jest about your settin’ up, and
jest about as many corn shuckins old. Ellen is her name.”
“Ellen is my name.”
“That’s pretty” (pooty he pronounced it). “Well, I’ll stand father to
you, just as ef you was my own gal. I know what a gal in trouble
wants more ’n young fellows can.”
 Ellen Clitheroe gave her hand to Armstrong in frank acceptance of
his offer. He became the paternal element in our party,—he
protecting her and she humanizing him.
We lighted our camp-fire and supped heartily. Except for Brent’s
uneasy stir and unwilling moans, we might have forgotten the
deadly business of that day.
We made the wounded man comfortable as might be with
blankets, under the sheltering spruces. After all, if he must be hurt,
he could not have fallen upon a better hospital than the pure open
air of this beautiful shelter; and surely nowhere was a gentler nurse
than his.
Armstrong and I built the lady a bower, a little lodge of bushes
from the thicket.
Then he and I kept watch and watch beneath the starlight.
Sleeping or waking, our souls and our bodies thanked God for this
peace of a peaceful night, after the terror and tramp and battle of
that trembling day.
 CHAPTER XXII.

CHAMPAGNE.
How soundly I slept, in my sleeping hours, after our great victory,
—Courage over Space, Hope over Time, Love over Brutality, the
Heavenly Powers over the Demon Forces!
I sprang up, after my last morning slumber, with vitality enough
for my wounded friend and myself. I felt that I could carry double
responsibility, as Fulano had carried double weight. God has given
me the blessing of a great, vigorous life. My body has always been a
perfect machine for my mind’s work, such as that may be; and never
a better machine, with every valve, crank, joint, and journal in good
order, than on that dawn at Luggernel Springs.
If I had not awaked alive from top to toe, from tip to tip, from
end to end, alive in muscle, nerve, and brain, the Luggernel
Champagne Spring would have put life into me.
Champagne of Rheims and Epernay! Bah!
Avaunt, Veuve Clicquot, thou elderly Hebe! Avaunt, with thy
besugared, begassed, bedevilled, becorked, bewired, poptious
manufacture! Some day, at a dull dinner-party, I will think of thee
and poison myself with thy poison, that I may become deaf to the
voice of the vulgar woman to whom some fatal hostess may consign
me. But now let no thought of Champagne, even of that which the
Veuve may keep for her moment most lacrymose of “veuvage,”
interfere with my remembrance of the Luggernel Spring.
 Champagne to that! More justly a Satyr to Hyperion; a stage-
moon to Luna herself; an Old-World peach to a peach of New
Jersey; a Democratic Platform to the Declaration of Independence; a
pinching, varnished boot to a winged sandal of Mercury; Faustina to
Charlotte Corday; a senatorial speech to a speech of Wendell
Phillips; anything crude, base, and sham to anything fine, fresh, and
true.
Ah, poor Kissingen! Alas, unfragrant Sharon! Alack, stale
Saratoga! Ichabod! Adieu to you all when the world knows the
virtues of Luggernel!
But never when the O-fartunatus-nimium world has come into
this new portion of its heritage,—never when Luggernel is renowned
and fashion blooms about its brim,—never when gentlemen of the
creamiest cream in the next half-century offer to ladies as creamy
beakers bubbling full of that hypernectareous tipple,—never will any
finer body or fairer soul of a woman be seen there about than her
whom I served that morning. And, indeed, among the heroic
gentlemen of the riper time to come, I cannot dream that any will
surpass in all the virtues and courtesies of the cavalier my friend
John Brent, now dismounted and lying there wounded and patient.
Oranges before breakfast are good. There be who on awakening
gasp for the cocktail. And others, who, fuddled last night, are limp in
their lazy beds, till soda-water lends them its fizzle. Eye-openers
these of moderate calibre. But, with all the vigorous vitality I have
claimed, perhaps I might still have remembered yesterday with its
Gallop of Three, its suspense, its eager dash and its certainty, and
remembered them with new anxieties for to-day, except for my
morning draught of exhilaration from the unbottled, unmixed
sources of Luggernel. Thanks La Grenouille, rover of the wilderness,
for thy froggish instinct and this blissful discovery!
I stooped and lapped. Long ago Gideon Barakson recognized the
thorough-going braves because they took their water by the
throatful, not by the palmful. And when I had lapped enough, and
let the great bubbles of laughing gas burst in my face, I took a
beaker,—to be sure it was battered tin, and had hung at the belt of a
dastard,—a beaker of that “cordial julep” to my friend. He was
awake and looking about him, seeking for some one.
“Come to your gruel, old fellow!” said I.
He drank the airy water and sat up revived.
“It is like swallowing the first sunbeam on the crown of a snow-
peak,” he said.
Miss Clitheroe dawned upon us with this. She came forth from her
lodge, fresh and full of cheer.
Brent stopped looking about for some one. The One had entered
upon the scene.
I dipped for her also that poetry in a tin pot.
“This,” said she, “is finer balm than the enchanted cup of Comus;
never did lips touch a draught
‘To life so friendly, or so cool to thirst.’
To-day my life is worthy of this nepenthe. My dear friend, this is the
first night of peaceful, hopeful rest I have had, since my poor father
was betrayed into his delusion. Thank you and God for it!”
And again her eyes filled with happy tears, and she knelt by her
patient. While she was tenderly and deftly renewing the bandages,
Armstrong stood by, and inspected the wound in silence. Presently
he walked off and called me to help him with our camp-fire.
“Pretty well ploughed up, that arm of his’n,” said he.
“I have seen amputation performed for less.”
“Then I’m dum glad there’s no sawbones about. I don’t believe
Nater means a man’s leg or arm to go, until she breaks the solid
bone, so that it ain’t to be sot nohow. But what do you allow to do?
Lamm ahead or squat here?”
 “You are the oldest; you have most experience; I will take your
advice.”
“October is sweet as the smile of a gal when she hears that her
man has made fifteen hundred dollars off the purceeds of a half-acre
of onions, to the mines; but these yer fall storms is reg’lar Injuns;
they light down ’thout sendin’ on handbills. We ought to be p’intin’
for home if we can.”
“But Brent’s wound! Can he travel?”
“Now, about that wound, there’s two ways of lookin’ at it. We ken
stop here, or we ken poot for Laramie. I allow that it oughter take
that arm of his’n a month to make itself right. Now in a month ther’ll
be p’r’aps three feet of snow whar we stand.”
“We must go on.”
“Besides, lookerhere! Accordin’ to me the feelin’s mean suthin’,
when a man’s got any. He’ll be all the time worryin’ about the gal till
he gets her to her father. It’s my judgment she’d better never see
the old man agin; but I wouldn’t want my Ellen to quit me, of I was
an unhealthy gonoph like him. Daughters ought to stick closer ’n
twitch-grass to their fathers, and sons to their mothers, and she ain’t
one to knock off lovin’ anybody she’s guv herself to love. No, she’s
one of the stiddy kind,—stiddy as the stars. He knows that, that
there pardener of yourn knows it, and his feelin’s won’t give his arm
no rest until she’s got the old man to take care of and follow off on
his next streak. So we must poot for Laramie, live or die. Thar’ll be a
doctor there. Ef we ken find the way, it shouldn’t take us more ’n ten
days. I’ll poot him on Bill’s sorrel, jest as gentle a horse as Bill was
that rode him, and we’ll see ef we hain’t worked out the bad luck
out of all of us, for one while.”
Armstrong’s opinion was only my own, expressed Oregonly. We
went on preparing breakfast.
“That there A. & A. mule,” says Armstrong, “was Bill’s and mine,
and this stuff in the packs was ours. I don’t know what the fellers
did with the two mean mustangs they was ridin’ when they found us
fust on Bear River,—used ’em up, I reckon.”
Here Brent hailed us cheerily.
“Look alive there, you two cooks! We idlers here want to be
travelling.”
“I told you so,” said Armstrong. “He understands this business
jest as well as we do. He’ll go till he draps. Thar’s grit into him, ef I
know grit.”
Yes; but when I saw him sit still with his back against the spruce-
tree, and remembered his exuberant life of other days, I desponded.
He soon took occasion to speak to me apart.
“Dick,” said he, “you see how it is. I am not good for much. If we
were alone, you and I might settle here for a month or so, and write
‘Bubbles from the Brünnen.’ But there is a lady in the case. It is plain
where she belongs. I know every inch of the way to Laramie. I can
take you through in a week”—he paused and quavered a little, as he
continued—“if I live. But don’t look so anxious. I shall.”
“It would be stupid for you to die now, John Brent the Lover, with
the obstacles cut away and an heroic basis of operations.”
“A wounded man, perhaps a dying man, has no business with
love. I will never present her my services and ask pay. But, Dick, if I
should wear out, you will know what to say to her for me.”
At this she joined us, her face so illumined with resolution and
hope that we both kindled. All doubt skulked away from her
presence. Brent was nerved to rise and walk a few steps to the
camp-fire, supported by her arm and mine.
Armstrong had breakfast ready, such as it was. And really, the
brace of wood grouse he had shot that morning, not a hundred
yards from camp, were not unworthy of a lady’s table, though they
had never made journey in a crowded box, over a slow railroad,
from Chicago to New York, in a January thaw, and then been bought
at half price of a street pedler, a few hours before they dropped to
pieces.
We grouped to depart.
“I shall remember all this for scores of sketches,” said Miss
Clitheroe.
And indeed there was material. The rocks behind threading away
and narrowing into the dim gorge of the Alley; the rushing fountains,
one with its cloud of steam; the two great spruces; the greensward;
the thickets; and above them a far-away glimpse of a world, all run
to top and flinging itself up into heaven, a tumult of crag and
pinnacle. So much for the scenery. And for personages, there was
Armstrong, with his head turbaned, saddling the white machine; the
two mules, packed and taking their last nibbles of verdure; Miss
Clitheroe, in her round hat and with a green blanket rigged as riding-
skirt, mounted upon the sturdy roan; Brent resting on my shoulder,
and stepping on my knee, as he climbed painfully to his seat on the
tall sorrel; Don Fulano waiting, proud and eager. And just as we
were starting, a stone fell from overhead into the water; and looking
up, we saw a bighorn studying us from the crags, wishing, no doubt,
that his monster horns were ears to comprehend our dialect.
I gave the party their stirrup-cup from the Champagne Spring.
The waters gurgled adieu. Rich sunrise was upon the purple gates of
the pass. We struck a trail through the thicket.
Good bye to the Luggernel Springs and Luggernel Alley! to that
scene of tragedy and tragedy escaped!
 CHAPTER XXIII.

AN IDYL OF THE ROCKYS.

I shall make short work of our journey to Laramie.
We bent northeastwardly by ways known to our leader,—alas!
leader no more. He could guide, but no more gallop in front and
beckon on the cavalcade.
It was a grand journey. A wild one, and rough for a lady. But this
lady was made of other stuff than the mistresses of lapdogs.
We crossed the backbone of the continent, climbing up the clefts
between the ragged vertebræ, and over the top of that meandering
spine, fleshed with great grassy mounds; then plunging down again
among the rifts and glens.
A brilliant quartette ours would have been, but for my friend’s
wound. Four people, all with fresh souls and large and peculiar
experience.
Except for my friend’s wound!
My friend, closer than a brother, how I felt for him every mile of
that stern journey! He never complained. Only once he said to me,
“Bodily agony has something to teach, I find, as well as mental.”
Never one word of his suffering, except that. He wore slowly
away. Every day he grew a little weaker in body; but every day the
strong spirit lifted the body to its work. He must live to be our guide,
that he felt. He must be cheerful, gay even, lest the lady he had
saved should too bitterly feel that her safety was daily paid for by his
increasing agony. Every day that ichor of love baptized him with new
life. He breathed love and was strong. But it was love confined to his
own consciousness. Wounded, and dying perhaps, unless his life
could beat time by a day or an hour, he would not throw any share
of his suffering on another, on her, by calling for the sympathy which
a woman gives to her lover.
Did she love him? Ah! that is the ancient riddle. Only the Sphinx
herself can answer. Those fair faces of women, with their tender
smiles, their quick blushes, their starting tears, still wear a mask
until the moment comes for unmasking. If she did not love him,—
this man of all men most lovable, this feminine soul in the body of a
hero, this man who had spilled his blood for her, whose whole
history had trained him for those crowning hours of a chivalric life
when the lover led our Gallop of Three; if she did not love him, she
must be, I thought, some bloodless creature of a type other than
human, an angel and no woman, a creature not yet truly embodied
into the body of love we seemed to behold.
She was sweetly tender to him; but that the wound, received for
her sake, merited; that was hardly more than the gracious
thankfulness she lavished upon us all. What an exquisite woman!
How calmly she took her place, lofty and serene, above all the
cloudy atmosphere of such a bewildering life as hers had been! How
large and deep and mature the charity she had drawn, even so
young, from the strange contrasts of her history! How her keen
observation of a woman of genius had grasped and stored away the
diamond, or the dust of diamond, in every drift across her life!
She grew more beautiful daily. Those weary days when, mile after
dreary mile, the listless march of the Mormon caravan bore her
farther and farther away into hopeless exile, were gone forever. She
breathed ruddy hope now. Before, she had filtered hope from every
breath and only taken the thin diet of pale endurance. All future
possibility of trial, after her great escape, seemed nothing. She was
confident of Brent’s instant recovery, with repose, and a surgeon
more skilful than she, at Fort Laramie. She was sure that now her
father’s wandering life was over, and that he would let her find him a
home and win him a living in some quiet region of America, where
all his sickly fancies would pass away, and his old age would glide
serenely.
It would be long, too long, for the movement of this history,
should I attempt to detail the talks and minor adventures of that trip
by which the character of all my companions became better known
to me.
For the wounded man’s sake we made lengthened rests at
noonday, and camped with the earliest coming of twilight. Those
were the moonlight nights of brilliant October. How strange and
solemn and shadowy the mountains rose about our bivouacs! It was
the poetry of camp life, and to every scene by a fountain, by a
torrent, in a wild dell, on a mountain meadow with a vision of a
snow-peak watching us all the starry night and passing through
rosiness into splendor at sunrise,—to every scene, stern or fair, our
comrade gave the poetry of a woman’s presence and a woman’s fine
perception of the minuter charm of nature.
And then—think of it!—she had a genius for cookery. I have
known this same power in other fine poetic and artistic beings. She
had a genius for imaginative cookery,—a rich inheritance from her
father’s days of poverty and coal-mining. She insisted upon her
share of camp-duty; and her great gray eyes were often to be seen
gravely fixed upon a frying-pan, or watching a roasting bird, as it
twirled slowly before the fire, with a strip of pork featly disposed
overhead to baste that succulent revolver; while Brent, poor fellow,
lay upon the grass, wrapped in blankets, slowly accumulating force
for the next day’s journey, and watched her with wonderment and
delight that she could condescend to be a household goddess.
“Ther ain’t her ikwill to be scared up,” would Armstrong say on
these occasions. “I’m gittin’ idees to make my Ellen the head woman
on all the Umpqua. I wish I had her along; for she’s a doughcyle gal,
and takes nat’ral to pooty notions in thinkin’ and behavior and fixin’
up things ginerally.”
 Armstrong became more and more the paternal element in our
party. Memory of the Ellen on the Umpqua made him fatherly
thoughtful for the Ellen here, a wanderer across the Rocky
Mountains. And she returned more than he gave, in the sweet
civilizing despotism of a lady. That grizzly turban presently
disappeared from his head. Decorous bandages replaced it. With
that token went from him the sternness. He was a frank, honest,
kindly fellow, shrewd and unflinching, but one who would never
have lifted his hand against a human being except for that great,
solemn duty of an exterminating vengeance. That done, he was his
genial self again. We never tired of his tales of plains and Oregon
life, told in his own vivid dialect. He was the patriarchal pioneer, a
man with the personal freedom of a nomad, and the unschooled
wisdom of a founder of states in the wilderness. A mighty hunter,
too, was Armstrong. No day passed that we did not bag an antelope,
a deer, or a big-horn. It was the very land of Cocaigne for game. The
creatures were so hospitable that it hardly seemed proper gratitude
to kill them; even that great brown she-bear, who one night “popped
her head into the shop,” and, muttering something which in the
Bruin lingo may have been, “What! no soap!” smote Armstrong with
a paw which years of sucking had not made tender.
Except for Brent’s wound, we four might have had a joyous
journey, full of the true savor of brave travel. But that ghastly,
murderous hurt of his needed most skilful surgery, and needed most
of all repose with a mind at peace. He did not mend; but all the
while
“The breath
Of her sweet tendance hovering over him
Filled all the genial courses of his blood
With deeper and with ever deeper love.”
But he did not mend. He wasted daily. His sleeps became deathly
trances. We could not wear him out with haste. Brave heart! he bore
up like a brave.
 And at last one noon we drew out of the Black Hills, and saw
before us, across the spurs of Laramie Peak, the broad plain of Fort
Laramie.
Brent revived. We rode steadily. Just before sunset, we pulled up
at our goal.
 CHAPTER XXIV.

DRAPETOMANIA.
For the last hour I had ridden close to Brent. I saw that it was
almost up with him. He swayed in his saddle. His eye was glazed
and dull. But he kept his look fixed on the little group of Laramie
Barracks, and let his horse carry him.
I lifted up my heart in prayer that this noble life might not be
quenched. He must not die now that he was enlarged and sanctified
by truest love.
At last we struck open country. Bill Armstrong’s sorrel took a
cradling lope; we rode through a camp of Sioux “tepees,” like so
many great white foolscaps; we turned the angle of a great white
wooden building, and halted. I sprang from Fulano, Brent quietly
drooped down into my arms.
“Just in time,” said a cheerful, manly voice at my ear.
“I hope so,” said I. “Is it Captain Ruby?”
“Yes. We’ll take him into my bed. Dr. Pathie, here’s a patient for
you.”
We carried Brent in. As we crossed the veranda, I saw Miss
Clitheroe’s meeting with her father. He received her almost peevishly.
We laid the wounded man in Ruby’s hospital bed. Evidently a fine
fellow, Ruby; and, what was to the point, fond of John Brent.
Dr. Pathie shook his head.
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