ANAESTHESIA, PAIN & INTENSIVE CARE
EDITORIAL VIEW
www.apicareonline.com
Is hemoglobin the missing link in the
pathogenesis of COVID-19?
Amer Majeed, FCARCSI, FRCA, FFICM1,
Matloob Ashraf Shajar, FRCA, FFICM1
ABSTRACT
1
Consultant Anesthesiologist,
King Faisal Specialist Hospital and
Research Centre, Riyadh, (Saudi
Arabia)
Correspondence: Dr
Amer Majeed, Consultant
Anesthesiologist, King Faisal
Specialist Hospital and Research
Centre, Zahrawi St, Al Maather،
Al Maazer, Riyadh 12713, , (Saudi
Arabia),
E-mail: amer.majeed@gmail.com
This editorial considers studies which establish our current understanding of SARSCoV-2 and the indicated direction for treatment of COVID-19 patients and future
research. Recent modelling studies point to the effect of SARS-CoV-2 on hemoglobin
as a key element in understanding the pathogenesis of COVID-19. This would suggest
that the focus of treatment of COVID-19 would need to shift towards maintaining the
oxygen carrying capacity of blood; potentially with blood transfusions and superoxygenation, perhaps including hyperbaric oxygen therapy. Further, early prevention
of thromboembolism, and suppression of the immune response due to hemoglobin
damage, may help contain the clinical course.
Key words: Corona virus disease; COVID-19; SARS-CoV-2; ARDS; Hemoglobin
Received: 4 March 2020;
Reviewed & Accepted: 6
March 2020
Citation: Majeed A, Shajar MA. Is hemoglobin the missing link in the
pathogenesis of COVID-19? Anaesth pain intensive care 2020;24(1):9-12.
DOI: https://doi.org/10.35975/apic.v24i1.1216
INTRODUCTION
On 31st December 2019, Chinese authorities reported
to the World Health Organization (WHO) a cluster
of cases of unexplained pneumonia. On 7th January
2020, these cases were confirmed to have been caused
by a novel coronavirus, later classified as Severe Acute
Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).
The WHO termed the resulting disease coronavirus
disease 2019 (COVID-19) and declared it to be a
pandemic on 12th March 2020. At the time of writing
this editorial, with almost 2 million diagnoses and
0.1 million lives claimed, many healthcare systems
around the world are struggling to cope with the
associated exponential rise in hospitalization. Daily
life has come to a crippling halt in several countries as
worldwide governments attempt to curtail spread of
SARS-CoV-2 using methods such as social distancing,
nationwide lockdowns and curfews. As massive global
research effort continues and new data continue to be
generated, our understanding of COVID-19 evolves
by each passing day.
variants, mainly categorized into types A to C, with
type B mostly endemic in East Asia, and A & C in the
rest of the world.1 Rapidly emerging data from several
centers suggests variation in transmission, virulence,
disease spectrum, and the mortality rate.2,3,4,5,6,7 The
role of angiotensin converting enzyme receptor type
2 (ACE2) as the primary binding site for SARS-CoV-2
for gaining entry into the cell has been elucidated,8
and interestingly, variations in the genetic makeup
of this receptor has been suggested to partially
explain lower susceptibility of some populations to
COVID-19.9
Phylogenetic network analysis of SARS-CoV-2
genomes has demonstrated existence of several mutant
Huang, et al.3 described the chief symptoms of
COVID-19 as: fever (98%), cough (76%), and myalgia
or fatigue (44%). Less common symptoms were
noted to be: sputum production (28%), headache
(8%), hemoptysis (5%), and diarrhea (3%). Dyspnea
developed in 55% of COVID-19 patients; 63% had
lymphopenia. All patients presented with pneumonia
and abnormal findings on chest CT scan. Frequent
complications were noted to include: acute respiratory
distress syndrome (ARDS) (29%), RNAemia (15%),
acute cardiac injury (12%), and secondary infection
(10%). Admission to an ICU was needed by 32% of
COVID-19 patients; 15% of the patients did not
ANAESTH, PAIN & INTENSIVE CARE; VOL 24(1) FEBRUARY 2020
9
Core Research on SARS-CoV-2 and COVID-19:
hemoglobin the missing link
survive. Similar incidences were confirmed in several
studies.4,5
The severity of COVID-19 in confirmed cases ranged
from mild to critical.5 Mild disease was reported in
81% of cases (no or mild pneumonia), severe in 14%
of cases (i.e. with dyspnea, hypoxia, or > 50% lung
involvement on imaging within 24 to 48 h), and
critical in 5% (i.e. with respiratory failure, shock, or
multi-organ dysfunction).
Zhou, et al. identified laboratory features associated
with adverse outcomes, including: lymphopenia,
raised liver enzymes, lactate dehydrogenase (LDH),
inflammatory markers (e.g. C-reactive protein [CRP],
ferritin), D-dimers (> 1 µg/mL), prothrombin time
(PT), troponin, and creatine phosphokinase (CPK).6
These point to an excessive inflammatory response
in COVID-19 associated with critical and fatal
illnesses.10
Areas requiring further evidence:
Initial reports of harm caused by non-steroidal antiinflammatory drugs (NSAIDs) in COVID-19 led
to recommendations from several bodies to avoid
immunosuppression (e.g. with corticosteroids /
NSAIDs); clinical experience reported by several
centers controverts this recommendation.11 Two
distinct phases of immune response are observed
in this disease. Good state of general health and
appropriate genetic background [e.g. some human
leucocyte antigen (HLA) – types may offer specific
antiviral immunity] may prevent progression from
mild / moderate to severe disease form; the preventive
immune failure plinths viral spread and destruction of
the affected tissues. Inflammation in the lungs is the
main cause of life-threatening respiratory disorders
at the severe stage, and efforts directed at suppressing
inflammation may help to manage the symptoms.12
ARDS consequent upon the lung damage, not less
than the other systems, in these patients has baffled
the intensivists. The near normal respiratory system
compliance in the presence of severe hypoxemia is
not synchronous with the typical ARDS picture.
Gattinoni, et al. in their landmark editorial,7 proposed
two clinical phenotypes; type L (low elastance) and
type H (high elastance). Type L has been found in
70% of patients, and there is dissociation between
their relatively well preserved lung mechanics and
the severity of hypoxemia (high compliance, with
ventilation / perfusion or V/Q mismatch); therefore,
there is a limited response to PEEP. In contrast, type
H (30% of patients) present with a typical ARDS
picture. Progression from type L to H is possible,
and treatment requires adjustment accordingly.
The exact mechanism of the disparity between the
two presentations still remains uncertain; hypoxic
pulmonary vasoconstriction and thromboembolism
10
may explain the L type, whereas inflammatory
lung infiltration augmented by excessive negative
intrathoracic pressure in spontaneously breathing
patient may elucidate the H type.
There are reports of underlying thromboembolic
disease emerging from post-mortem studies.13,14 Microthrombosis leading to the dysregulated pulmonary
perfusion may possibly clarify the V/Q mismatch
and hypoxaemia associated with the phenotype
type L described above. It may also explicate the
conflicting reports about the extent and mechanism
of acute kidney injury,15,16 and acute liver injury.17 The
alarming level of cardiomyopathy, arrhythmias, acute
cardiac injury and shock in COVID-19 may also find
its roots there.4,18,19
ACE2 receptors, which are present in the outer surface
of cells in the lungs, arteries, heart, kidneys, and
intestines, serve as the entry portal of SARS-CoV-2
into cells.8 Ubiquitous presence of these receptors
in these organ systems has been considered as the
key to pathogenesis of COVID-19, but still there are
unanswered questions due to conflicting evidence.
For instance, on one hand, the possible upregulation
of ACE2 leads to an increased risk of infection of
the pulmonary (and possibly other) tissues, and on
the other hand there is evidence to existence of both
cardio protective and pulmonary protective activity
of ACE2.20 Concerns have been raised regarding
concomitant use of ACE1 Inhibitors in COVID-19,
due to the anticipated upregulatory effect on ACE2
receptors, potentiating entry portals for SARS-CoV-2.
However, discontinuing medicated inhibitors in the
patients already taking them has not been supported
by various specialist bodies, due to lack of evidence of
harm, but more so due to reported protective effect of
these agents against lung injury.21,22
COVID-19 and hemoglobin: the missing link?
Interestingly, a study by Wenzhong, et al. could
provide the missing link in the understanding of the
pathogenesis of COVID-19.23 Through conserved
domain analysis, homology modelling, and molecular
docking, they compared the biological roles of certain
proteins of the novel coronavirus. Their results
showed that these proteins, binding to porphyrin,
could attack the 1-beta chain of hemoglobin to
dissociate iron and form porphyrin (hemoglobin
consists of hem and globin; hem is composed of iron
and porphyrin).
The attack would result in a drop in hemoglobin
available to carry oxygen and also shift the oxygen
dissociation curve and reduce the oxygen affinity
with hemoglobin (thus producing a picture similar
to methemoglobinemia, or carbon monoxide
poisoning). The lung cells would have extremely
intense inflammatory response and poisoning due
to the ensuing inability to exchange carbon dioxide
ANAESTH, PAIN & INTENSIVE CARE; VOL 24(1) FEBRUARY 2020
editorial view
and oxygen efficiently, which eventually would result
in ground-glass appearance on lung images. The
mechanism would also interfere with the normal
hem anabolic pathway of the human body and would
result in human disease.
According to the validation analysis of these findings,
chloroquine could prevent SARS-CoV-2 proteins
from attacking hem and forming porphyrin, and
also inhibit their ability to bind to porphyrins to a
certain extent, effectively relieving the symptoms of
respiratory distress. Favipiravir could also inhibit
some of these proteins from binding to porphyrin,
thus preventing the virus from entering host cells and
catching free porphyrins.
CONCLUSION
In summary, majority of the patients progressing to
the severe form of COVID-19 present with hypoxia
with well-preserved lung mechanics, but ARDS
like picture on chest imaging. They may require
unconventional therapeutic interventions, different
from the classic ARDS management, thus avoiding
the use of high PEEP or PEEP/FiO2 scale, and shift
focus of treatment towards oxygenation, reducing
the V/Q mismatch (prone positioning, partial anti
coagulation, inhaled prostaglandins, nitric oxide),
and maintaining the oxygen carrying capacity of
blood (blood transfusions, super-oxygenation).
Corticosteroids, judicious fluid management, and
prevention of barotrauma, may slow progression of
the disease to classic ARDS. In deed there is a great
potential of further research in this direction, and
we might have to wait for a solid evidence-based
management protocol.
Conflict of interest: None declared by the author
REFERENCES
1.
2.
3.
4.
5.
Forster P, Forsterd L, Renfrew C,
Forsterc M. Phylogenetic network
analysis of SARS-CoV-2 genomes.
Proc Natl Acad Sci U S A. 2020 Apr 8.
pii: 202004999. [PubMed] [Free Full
Text] DOI: 10.1073/pnas.2004999117
Tang X, Wu C, Li X, Song Y, Yao X, Wu
X, et al. On the origin and continuing
evolution of SARS-CoV-2. Natl Sci Rev.
2020 Mar 3 [PubMed] DOI: 10.1093/
nsr/nwaa036
Huang C, Wang Y, Li X, Ren L, Zhao
J, Hu Y, et al. Clinical features of
patients infected with 2019 novel
coronavirus in Wuhan, China.
Lancet.
2020;395(10223):497506. [PubMed] DOI: https://doi.
org/10.1016/S0140-6736(20)301835
Wang D, Hu B, Hu C, Zhu F, Liu X,
Zhang J, et al. Clinical Characteristics
of 138 Hospitalized Patients With
2019 Novel Coronavirus-Infected
Pneumonia in Wuhan, China. JAMA,
2020 Feb 7. [PubMed] [Free Full Text]
DOI: 10.1001/jama.2020.1585
Wu Z, McGoogan JM. Characteristics
of and Important Lessons from
the Coronavirus Disease 2019
(COVID-19) Outbreak in China:
Summary of a Report of 72 314 Cases
6.
7.
8.
9.
from the Chinese Center for Disease
Control and Prevention. JAMA, 2020
Feb 24. [PubMed] [Free Full Text]
DOI: 10.1001/jama.2020.2648.
Zhou F, Yu T, Du R, et al. Clinical course
and risk factors for mortality of adult
inpatients with COVID-19 in Wuhan,
China: a retrospective cohort study.
Lancet. 2020; 395(10229):1054.
[PubMed]
[Free
Full
Text]
DOI: 10.1001/jama.2020.2648
Gattinoni L, Chiumello D, Caironi
P, Busana M, Romitti F, Brazzi L, et
al. COVID-19 pneumonia: different
respiratory treatment for different
phenotypes? Intensive Care Med.
2020. (in press) [Free Full Text]
DOI: 10.1007/s00134-020-06033-2
Zhou P, Yang X-L, Wang X-G, Hu
B, Zhang L, Zhang W, et al. A
pneumonia outbreak associated
with a new coronavirus of
probable bat origin. Nature. 2020
Mar;579(7798):270-273. [PubMed]
[Free Full Text] DOI: 10.1038/s41586020-2012-7.
Hussain M, Jabeen N, Raza F, Shabbir
S, Baig AA, Amanullah A, et al.
Structural Variations in Human ACE2
may Influence its Binding with SARSCoV-2 Spike Protein. J Med Virol.
ANAESTH, PAIN & INTENSIVE CARE; VOL 24(1) FEBRUARY 2020
2020 Apr 6. DOI: 10.1002/jmv.25832.
10. Mehta P, McAuley DF, Brown M,
Sanchez E, Tattersall RS, Manson JJ, et
al. COVID-19: consider cytokine storm
syndromes and immunosuppression.
Lancet.
2020;395(10229):10331034. [PubMed] [Free Full Text] DOI:
10.1016/S0140-6736(20)30628-0
11. Russell B, Moss C, Rigg A,
Van Hemelrijck M. COVID-19
and treatment with NSAIDs and
corticosteroids: should we be
limiting their use in the clinical
setting?
Ecancermedicalscience.
2020;14:1023.
Published
2020
Mar 30. [PubMed] [Free Full Text]
DOI: 10.3332/ecancer.2020.1023
12. Shi Y, Wang, Y, Shao C, Huang J,
Gan J, Huang X, et al. COVID-19
infection: the perspectives on immune
responses. Cell Death Differ. 2020 Mar
23. [PubMed] DOI: 10.1038/s41418020-0530-3
13. Danzi GB, Loffi M, Galeazzi G, Gherbesi
E. Acute pulmonary embolism and
COVID-19 pneumonia: a random
association? Eur Heart J. 2020 Mar
30. [PubMed] DOI: 10.1093/eurheartj/
ehaa254
14. Xie Y, Wang X, Yang P, Zhang S.
COVID-19 Complicated by Acute
11
hemoglobin the missing link
Pulmonary Embolism. Radiology:
Cardiothoracic Imaging 2020 Mar
16; 2(2):e200067. [Free Full Text]
DOI: 10.1148/ryct.2020200067
15. Wang L, Li X, Chen H, Yan S, Li D,
Li Y, et al. Coronavirus Disease 19
Infection Does Not Result in Acute
Kidney Injury: An Analysis of 116
Hospitalized Patients from Wuhan,
China. Am J Nephrol. 2020 Mar
31:1-6. [PubMed] [Free Full Text]
DOI: 10.1159/000507471
16. Pan X, Xu D, Zhang H, Zhou W, Wang
LH, Cui XG. Identification of a potential
mechanism of acute kidney injury
during the COVID-19 outbreak: a study
based on single-cell transcriptome
analysis. Intensive Care Med. 2020
Mar 31. [PubMed] [Free Full Text]
DOI: 10.1007/s00134-020-06026-1
17. Zhang C, Shi L, Wang FS. Liver
injury in COVID-19: management
and challenges. Lancet Gastroenterol
Hepatol.
2020;5(5):428-430.
[PubMed] [Free Full Text] DOI: 10.1016/
S2468-1253(20)30057-1
18. Shi S, Qin M, Shen B, Cai Y, Liu T,
Yang F, et al. Association of cardiac
injury with mortality in hospitalized
patients with COVID-19 in Wuhan,
China. JAMA Cardiol. 2020 Mar
25. [PubMed] [Free Full Text]
DOI: 10.1001/jamacardio.2020.0950
19. Arentz M, Yim E, Klaff L, Lokhandwala
S, Riedo FX, Chong M, et al.
Characteristics and Outcomes of 21
Critically Ill Patients With COVID-19
in Washington State. JAMA. 2020
Mar 19. [PubMed] [Free Full Text]
DOI: 10.1001/jama.2020.4326
20. Caldeira D, Alarcão J, Vaz-Carneiro A,
Costa J. Risk of pneumonia associated
with use of angiotensin converting
enzyme inhibitors and angiotensin
receptor blockers: systematic review
and meta-analysis. BMJ. 2012 Jul
11;345:e4260 [PubMed] [Free Full
Text] DOI: 10.1136/bmj.e4260.
21. HFSA/ACC/AHA Statement Addresses
Concerns Re: Using RAAS Antagonists
in COVID-19. American College of
Cardiology (ACC). Accessed on:
8th April 2020. Available at: https://
professional.heart.org/professional/
ScienceNews/UCM_505836_
HFSAACCAHA-statementaddresses-concerns-re-using-RAASantagonists-in-COVID-19.jsp
22. Guo J, Huang Z, Lin L, Lv
J. Coronavirus disease 2019 and
cardiovascular disease: a viewpoint on
the potential influence of angiotensinconverting enzyme inhibitors/
12
ANAESTH, PAIN & INTENSIVE CARE; VOL 24(1) FEBRUARY 2020