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\begin{document}

\title{COVID-19 with rapid progression to hypoxemia likely due to imbalance
between ventilation and blood flow: A case report}



\author[1]{Nobuyuki Koriyama}%
\author[1]{Akihiro Moriuchi}%
\author[1]{Kensaku Higashi}%
\author[1]{Tetsuro Kataoka}%
\author[1]{Takuro Arimizu}%
\author[1]{Go Takaguchi}%
\author[1]{Hideki Matsuoka}%
\author[1]{Maki Otsuka}%
\affil[1]{National Hospital Organisation Kagoshima Medical Center}%


\vspace{-1em}



  
  \date{May 15, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
We experienced a case of COVID-19 with hypoxia, which was presumed to be
due to the development of ventilation and blood flow imbalance by
pulmonary intravascular coagulopathy or hypoxic pulmonary
vasoconstriction. Early, short-term combination therapy with remdesivir,
nafamostat mesilate and low-dose dexamethasone was extremely effective.%
\end{abstract}%



\sloppy


\textbf{Case Report}

\textbf{COVID-19 with rapid progression to hypoxemia likely due to
imbalance between ventilation and blood flow: A case report}

Nobuyuki Koriyama MD, PhD\textsuperscript{1}, Akihiro Moriuchi MD,
PhD\textsuperscript{2}, Kensaku Higashi MD\textsuperscript{3}, Tetsuro
Kataoka MD, PhD\textsuperscript{3}, Takuro Arimizu
MD\textsuperscript{4}, Go Takaguchi MD\textsuperscript{4}, Hideki
Matsuoka MD\textsuperscript{4}, Maki Otsuka MD, PhD\textsuperscript{5}

\textsuperscript{1}Department of Diabetes and Endocrine
Medicine,\textsuperscript{2}Gastroenterology,
\textsuperscript{3}Cardiology,\textsuperscript{4}Cerebrovascular
Medicine and\textsuperscript{5}Hematology, National Hospital
Organization Kagoshima Medical Center, 8-1 Shiroyama-cho, Kagoshima
892-0853, Japan

\textbf{Correspondence to:}

Dr. Maki Otsuka

Department of Hematology, National Hospital Organization Kagoshima
Medical Center, 8-1 Shiroyama-cho, Kagoshima 892-0853, Japan

Tel: +81-99-223-1151; Fax: +81-99-226-9246;

E-mail:\emph{otsuka.maki.we@mail.hosp.go.jp}



\textbf{Abstract}

We experienced a case of COVID-19 with hypoxia, which was presumed to be
due to the development of ventilation and blood flow imbalance by
pulmonary intravascular coagulopathy or hypoxic pulmonary
vasoconstriction. Early, short-term combination therapy with remdesivir,
nafamostat mesilate and low-dose dexamethasone was extremely effective.

\textbf{Key words:} COVID-19, hypoxic pulmonary vasoconstriction,
pulmonary intravascular coagulopathy, remdesivir, nafamostat mesilate,
dexamethasone

\textbf{Key Clinical Message:}

Early, short-term combination therapy with remdesivir, nafamostat
mesilate and low-dose dexamethasone was extremely effective for a case
of COVID-19 with hypoxia due to the development of ventilation and blood
flow imbalance.



\textbf{Introduction}

At the end of 2019, an outbreak of atypical pneumonia patients was
reported in Wuhan City, Hubei Province, China. This pneumonia was shown
to be caused by severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) infection and was named coronavirus disease 2019
(COVID-19). To date, the number of infected people globally is about 140
million, and the number of deaths is about 3 million. It is known that
the disease is more likely to become severe in the elderly than in the
young, and the mortality rate of people aged 80 years and over is
extremely high, at 14.8-20.2\% (1,2). It has also been reported that
there is a difference in mortality depending on the presence of
underlying comorbidities, with reported mortality rates of 10.5\% in
patients with cardiovascular disease, 7.3\% in diabetics, 6.3\% in
patients with chronic respiratory disease, and 6.0\% in hypertensive
patients (3).

SARS-CoV-2 has a positive-sense, single-stranded RNA genome, and binds
to angiotensin-converting enzyme 2 (ACE2) receptors present on the cell
surface with a coronal spike protein on its surface envelope. By doing
so, it invades the cell by endocytosis due to membrane fusion, leading
to viral amplification (4). ACE2 receptors are known to be widely
expressed in nerve cells, olfactory nerve epithelium, the tongue,
intestinal epithelial cells, vascular endothelial cells, etc., in
addition to alveolar type II epithelial cells (5,6). Therefore,
SARS-CoV-2 causes not only severe pneumonia and fatal acute respiratory
distress syndrome, but also multifaceted disorders of many cells,
tissues, and organs (7).

In COVID-19 pneumonia, cases of severe hypoxemia in the early stage (8)
and cases of sudden deterioration in respiratory status due to silent
hypoxia leading to death (9) have been reported. It is speculated that
major changes in one of the following factors: 1) thrombosis due to
impaired blood coagulation, 2) disordered hypoxic pulmonary
vasoconstriction (HPV) (10,11), and 3) imbalance between ventilation and
blood flow in healthy lungs, or relatively small changes in these
factors occurring at the same time (11) are responsible for the disease
severity in such cases.

Here, we report a case of COVID-19 who showed progressive silent
hypoxemia that was presumed to be due to an imbalance between
ventilation and blood flow, but with only mild pneumonia visualized on
computed tomography (CT), in whom early multidrug therapy was effective.

\textbf{Case Report}

The patient was a 70-year-old Japanese man (172.0 cm tall, weighing 68.0
kg, body mass index 23.0 kg/m\textsuperscript{2}) who had smoked 20
cigarettes a day for 47 years until 5 years ago. He was under treatment
and follow-up for essential hypertension, dyslipidemia and chronic
kidney disease, and his blood pressure and lipid levels were well
controlled with administration of 40 mg of olmesartan medoxomil (Olm)
and 5 mg of atorvastatin calcium hydrate. His renal function was stable.
The patient presented with nasal discharge, malaise and a mild cough,
and tested positive for SARS-CoV-2 by the polymerase chain reaction
(PCR) test, three days after coming in extended contact with a colleague
who was also diagnosed with SARS-CoV-2. Since he had many risk factors
for disease aggravation, he was urgently admitted to our hospital (Day
1) the day after symptom onset and confirmation of the diagnosis.

At admission, his body temperature was 36.4 \selectlanguage{ngerman}°C, blood pressure was
185/72 mmHg, pulse was 86 beats/min, respiratory rate was 20 beats/min
and peripheral oxygen saturation on pulse oximetry
(SpO\textsubscript{2}) was 97.0\%. Laboratory findings at this time
showed lymphocyte depletion and coagulation abnormalities {[}lymphocytes
8.5\%, fibrinogen 518 mg/dL, fibrinogen degradation products 5.26 \selectlanguage{greek}μ\selectlanguage{english}g/mL
and D-dimer (D-D) 1.68 \selectlanguage{greek}μ\selectlanguage{english}g/mL{]} (Table 1). In addition, iron deficiency
anemia was observed (he was scheduled for close examination of the
gastrointestinal tract after COVID-19 was cured), and it was difficult
to evaluate the ferritin level (Table 1). CT showed emphysematous
changes in the lung field and ground-glass-like shadows with unclear
borders below the dorsal pleura of the upper right lobe (Figure 1a).

Although no decrease in SpO\textsubscript{2} was observed,
administration of favipiravir (Fav) 3600 mg daily was started from the
evening of the same day, due to the presence of mild pneumonia as seen
on CT and the presence of multiple comorbidities. In addition, since
SpO\textsubscript{2} was lower than at night, 1 L/min oxygen
administration via a nasal cannula was also started. Weakness and a
decreased level of consciousness (tendency to somnolence) appeared from
the early morning of Day 2, but a neurologist ruled out a stroke. Since
somnolence and weakness were considered as side effects of Fav, the drug
was discontinued on the evening of Day 2, and his symptoms improved by
the morning of Day 3. Thereafter, since his temperature increased again,
the frequency of administration of acetaminophen 500 mg was increased
from 0 to 3 times a day. In addition, his CRP level increased and
SpO\textsubscript{2} decreased, requiring an increase in oxygen flow
rate from 1 to 3 L/min by nasal cannula. CT performed on Day 4 showed
slight deterioration in the pneumonia (Figure 1b). Therefore, 200 mg of
remdesivir (Rem) was administered on Day 4, with 100 mg daily being
administered from Day 5 until Day 10, for a total of 7 days (Figure 2a).
On Day 7, blood gas data under administration of 4 L/min oxygen by nasal
cannula (Figure 2b) showed that the alveolar-arterial oxygen difference
(A-aDO\textsubscript{2}) had increased to 122.1 mmHg (Table 2),
indicating an imbalance between ventilation and blood flow. However, no
pulmonary hypertension was observed on electrocardiogram or
echocardiography. Furthermore, since a tendency of increasing D-D levels
was also observed (Figure 2d), the combination of nafamostat mesilate
(Naf) 100 mg daily by continuous intravenous infusion and dexamethasone
(Dex) 6 mg daily was administered for 4 days from Day 7 (Figure 2a). The
treatment was remarkably effective, resulting in fever reduction and a
decrease in CRP and D-D levels (Figure 2a, c and d). On Day 10, oxygen
administration could be discontinued, and at the same time (Figure 2b),
his blood pressure control improved (Figure 2e). By Day 13,
A-aDO\textsubscript{2} had also significantly improved to 33.2 mmHg
without supplementary oxygen (Table 2), and CT showed a tendency for
improvement in pneumonia (Figure 1c).

For blood pressure control during the course of his hospitalization,
continuous intravenous infusion of pernidipine (4-9 mg/hr) was performed
for 2 days when oral intake was difficult due to the decreased
consciousness level, and from day 4, Olm 40 mg and nifedipine 20 mg were
administered in combination. With the treatment of COVID-19, his blood
pressure gradually stabilized, and the dose of nifedipine was reduced
from Day 14 to 10 mg, and nifedipine was discontinued from Day 19
(Figure 2).

It took some more time for SpO\textsubscript{2} to stabilize, but it
eventually improved and the patient was discharged on Day 21 (Figure 2).

\textbf{Discussion}

Cases of COVID-19 often develop ischemic stroke, ischemic heart disease
and venous thromboembolism. It has been reported that elevated D-D is a
predictor of COVID-19 mortality (12), and that thrombi are frequently
observed in pulmonary microarteries and pulmonary veins in autopsy cases
(13). McGonagle et al. distinguished macrothrombosis and widespread
microthrombosis in the lung from disseminated intravascular coagulation
(DIC) and called it pulmonary intravascular coagulopathy (PIC) (14).
Causes of the blood coagulation disorders in COVID-19 include
hyperformation of neutrophil extracellular traps due to inappropriate
release of nuclear chromatin from activated neutrophils that migrated
and accumulated at the infected site, and subsequent platelet
aggregation by their supplementation/activation (15,16). Furthermore, it
is known that elevation of Von Willebrand factor (vWF), which is derived
from macrophages and \emph{monospheres} or is activated by inflammatory
cytokines (Interleukin-6, Tumor necrosis factor-\selectlanguage{greek}α, \selectlanguage{english}etc.),
coagulation-inducing factors such as factors VII and VIII, and
plasminogen activator inhibitor-I which suppresses urokinase-type or
tissue plasminogen activator (15,17), are involved in the pathogenesis.
On the other hand, it has been reported that vWF and P-selectin are
released into the blood due to activation and damage of vascular
endothelial cells, or that the loss of thrombomodulin, which is the
center of the fibrinolytic system, causes microvascular thrombosis (18).
Downregulation of ACE2 by SARS-CoV-2 binding inhibits the conversion of
angiotensin II (AII) to angiotensin 1-7 (AT\textsubscript{1-7}),
resulting in an imbalance in the renin-angiotensin system. Reportedly,
this results in further damage to vascular endothelial cells by AII,
inflammation, promotion of oxidation, vasoconstriction, and coagulopathy
mediated by an increase in plasminogen activator inhibitor-I (19-21). In
this case, the patient's blood pressure, which was largely stable at the
time of admission, was subsequently elevated. It has been suggested that
Olm increases ACE2 and AT\textsubscript{1-7}, which binds to the Mas
receptor to lower blood pressure and protect organs (22). Due to the
fact that blood pressure control was stabilized by the treatment of
COVID-19 (Figure 2e), we speculated that the ACE2 consumption by
SARS-CoV-2 might have made achievement of the antihypertensive effect of
Olm via the Mas receptor difficult. On the other hand, the fact that
blood pressure control was stabilized by the treatment of COVID-19 might
suggest that direct vascular endothelial damage due to SARS-CoV-2 was
progressing. In addition to the above-mentioned coagulopathy, the
patient developed HPV disorder (9,10), which, we speculated, together
with emphysematous changes in the lungs, rapidly caused imbalance
between ventilation and blood flow.

In this case, CT suggested pneumonia, which had multiple aggravating
factors. Therefore, administration of Fav was started immediately after
admission (Figure 2a). Fav selectively inhibits RNA-dependent RNA
polymerase (RdRp) by its metabolization and conversion to the active
form favipiravir-ribofuranosyl triphosphate by an intracellular enzyme,
which is recognized as a substrate for RdRp by RNA viruses (23). After
the commencement of Fav treatment, the patient exhibited weakness and
decrease in consciousness (tendency to somnolence), which improved after
discontinuation of Fav. Chen et al. reported that 4.31\% of patients
receiving Fav had a psychiatric reaction (24), suggesting that these
symptoms in our patient were likely to have been side effects of Fav.
Subsequently, since fever persisted and the patient's
SpO\textsubscript{2} progressively decreased (Figure 2b), Rem was
started on Day 4 (Figure 2a). Reportedly, Rem is phosphorylated in cells
to a nucleic acid analog (triphosphate type remdesivir), which, like
Fav, binds to RdRp and selectively inhibits it, thereby suppressing the
growth of RNA viruses (23,25). Its effectiveness against SARS-CoV-2 by
this mechanism has also been reported (25-27). However, although CT
suggested only slight exacerbation of pneumonia, our patient's fever
persisted, SpO\textsubscript{2} decreased, and CRP and D-D levels tended
to increase even after the start of Rem (Figure 2a-d ). Therefore, Naf
100 mg and Dex 6 mg were also used from Day 8 (Figure 2a). Naf
suppresses transmembrane protease serine 2 (TMPRSS2), an enzyme that
cleaves and activates the spike protein, and blocks the invasion of
SARS-CoV-2 into host cells (23,28). It is used for the treatment of DIC
and acute pancreatitis because it binds to the active center (serine) of
enzymes, such as thrombin, XIIa, Xa, VIIa, kallikrein, plasmin and
trypsin, and suppresses the coagulation/fibrinolytic system. Doi et al.
have reported the efficacy of Naf 0.2 mg/kg/hr in combination with Fav
for COVID-19 when administered as a continuous intravenous infusion for
an average of 14 days (29), but the optimal administration method has
not yet been established. We were able to confirm a decrease in D-D
levels after 4 days of administration of Naf with Rem at approximately
the smallest dose (0.07 mg/kg/hr) used in DIC (Figure 2d). Preliminary
results from a large randomized controlled trial conducted in the United
Kingdom showed that once-daily administration of 6 mg Dex for up to 10
days resulted in a 35\% reduction in mortality in patients with COVID-19
receiving invasive mechanical ventilation (30). On the other hand, the
mortality rate in patients treated with Dex who received only oxygen
support without invasive ventilatory management reduced by 20\% (30).
Corticosteroids (CS) are known to bind to cytoplasmic CS receptors and
translocate to the nucleus, reducing the activity of pro-inflammatory
transcription factors, such as nuclear factor of \selectlanguage{greek}κ\selectlanguage{english}B and activator
protein-1, and to regulate transcription of anti-inflammatory genes
(31). As a result, they reduce a number of inflammatory mediators
involved in excessive cytokine responses (cytokine storms), although
their effect on COVID-19 remains controversial (32,33). Even in the
large-scale randomized controlled trial mentioned above, no benefit of
Dex administration to a group of patients with independent ventilation
was recognized (31). Since CS affects the function of many immune cells
and suppresses both innate and acquired immunity, smaller doses and
shorter treatment durations are recommended (34). For this reason, we
administered Dex 6 mg once daily for 4 days using a decrease in CRP as
an indicator of response to therapy, which proved to be successful
(Figure 2a). Asakura et al. have demonstrated the concept of antiviral,
anticytokine and anticoagulant combination therapy according to the
stage of COVID-19 (35). In our case, the combination therapy was
extremely effective within a short period of time, confirming its
importance in the treatment of COVID-19.

The limitations of our report are that we did not confirm the
histopathology of the lung and that since this was a case report, we
cannot confirm that our therapy would be effective in all cases.

\textbf{Conclusion}

In COVID-19 patients with multiple comorbidities who have hypoxemia and
coagulation abnormalities that are disproportionate to the severity of
pneumonia on CT, there is a high possibility that ventilation and blood
flow imbalance due to PIC or HPV disorder has occurred. We believe it is
important to commence antiviral and anticoagulant therapy as soon as
possible, followed by use of a low dose of Dex for a short period to
control cytokine hyperreactivity.

\textbf{Acknowledgements}

We also thank the patient for her permission to publish this manuscript.
Furthermore, we thank medical editing services on Forte, Inc.

\textbf{Conflict of Interest}

None declared

\textbf{Author contributions}

N.K., A.M., K.H., T.K., T.A., G.T., H.M., and M.O. attended to the
patient; N.K. wrote the manuscript; M.O. supervised management of the
case and contributed to writing and editing the manuscript. All authors
have read and approved the final manuscript.

\textbf{Ethics statement, consent for publication}

Patient consent was obtained from the patient for publication of this
case report and any accompanying images.

\textbf{Availability of data and material}

Not applicable.



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\textbf{Figure Legends}

\textbf{Figure 1} Chest computed tomography images

a: Image taken on Day 1 showing emphysematous changes in the lung field
and ground-glass-like shadows with unclear borders below the dorsal
pleura of the upper right lobe. b: Image taken on Day 7 showing slight
exacerbation of the ground-glass shadows. C: Image taken on Day 13
showing improvement in the ground-glass shadows.

\textbf{Figure 2} Clinical course of the patient

a: The black dots indicate changes in body temperature and dotted lines
indicate respiratory rate. The white inverted triangle indicates 3600 mg
favipiravir administration. The long downward-pointing black arrow
indicates administration of 200 mg remdesivir, and the short
downward-pointing black arrows indicate administration of 100 mg
remdesivir. The horizontal white bars indicate continuous intravenous
infusion of nafamostat mesilate 0.07 mg/kg/hr. The black inverted
triangles indicate administration of 6 mg dexamethasone. b: The
transition of SpO\textsubscript{2}. The horizontal black bars indicate
the flow rate of oxygen administered via a nasal cannula. The white
circles indicate the day when CT was performed, and the black stars
indicate the days when confirmatory blood gas analyses were performed.
c: The transition of C-reactive protein (CRP) level. d: The transition
of D-dimer (D-D) levels. e: The transition of systolic blood pressure at
the top and diastolic blood pressure at the bottom part of the graph.
The horizontal light-gray bar indicates administration of olmesartan,
the moderately-dark gray bar indicates continuous intravenous infusion
of pernidipine, and the dark gray bar indicates administration of
nifedipine.

BP, blood pressure; BT, body temperature; CRP, C-reactive protein; D-D,
D-dimer; RR, respiratory rate; SpO\textsubscript{2}, peripheral oxygen
saturation on pulse oximetry.

\textbf{Hosted file}

\verb`Figure1.pptx`  available at \url{https://authorea.com/users/424553/articles/529626-covid-19-with-rapid-progression-to-hypoxemia-likely-due-to-imbalance-between-ventilation-and-blood-flow-a-case-report}

\textbf{Hosted file}

\verb`Figure2.pptx`  available at \url{https://authorea.com/users/424553/articles/529626-covid-19-with-rapid-progression-to-hypoxemia-likely-due-to-imbalance-between-ventilation-and-blood-flow-a-case-report}

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