Comprehensive Treatment

in Severe COVID-19

Soedarsono
Perhimpunan Dokter Paru Indonesia
Cabang Jawa Timur
 Comprehensive Treatment in Severe
COVID-19

Simptomatic
Pharmacologic
Physic & Psychologic Supportive
“Expert Consensus on Comprehensive Treatment of Coronavirus in Shanghai 2019”
 Outline
• Pharmacologic treatment on COVID-19:
Causal
Immunopathological changes
Complication

Virology
Imunopathogenesis
 VIRAL

HOST

Guo et al. Military

Medical Research (2020) 7:11
Schematic representation of SARS CoV-2
interaction with a target cell.

Cytokine and Growth Factor Reviews 53 (2020) 13–24

 Segmental
bronchopneumonia
Shaded boxes (eg, bacterial and
indicate the influenza) typically
has a different lung
much greater distribution, with
capability for prominent bronchial
immunothromb tree involvement,
osis given the including
alveolar tropism haemorrhagic
of SARS-CoV- destruction of
trachea and large
2. airways,

Lancet Rheumatol 2020;

2: e437–45
The possible pathogenesis of COVID-19

Journal of Thrombosis and Thrombolysis

https://doi.org/10.1007/s11239-020-02129-0
Pulmonary intravascular coagulopathy in COVID-19 pneumonia

Lancet Rheumatol 2020; 2: e437–45

Cardiovascular involvement in COVID-19; key manifestations and
hypothetical mechanisms

T.J. Guzik et al. COVID-19 and the

cardiovascular system: implications
for risk assessment, diagnosis, and
treatment options
 Airway VENTILASI

Alveol

DIFUSI PERFUSI

Kapiler darah
 Airway (HYPO)VENTILASI

Cairan infiltrat
Alveol
PERFUSI

Bood flow HIPOKSEMIA

Kapiler darah
SHUNT UNIT
(PERFUSION WITHOUT VENTILATION)
 Airway VENTILASI

Alveol HYPO
Trombus PERFUSI

Hypo bLood flow

HIPOKSEMIA
Kapiler darah

DEAD SPACE UNIT

(VENTILATION WITH hypo PERFUSION)
COVID-19 can be divided into three phases that correspond to
different clinical stages of the disease

• Stage 1: Asymptomatic state (initial 1–2 days of

infection):
– The inhaled virus SARS-CoV-2 l binds to epithelial cells in
the nasal cavity and starts replicating.
• ACE2 is the main receptor for both SARS-CoV2
– The ciliated cells are primary cells infected in the
conducting airways .
• However, this concept might need some revision, since single-cell
RNA indicates low level of ACE2 expression in conducting airway
cells.
• There is local propagation of the virus but a limited innate immune
response.
– At this stage the virus can be detected by nasal swabs.
• SARS-CoV-2 cycle in
airway epithelial cells
and inflammatory
consequences of viral
infection

Romagnoliet al, PhysiolReviews,

October 2020
• Stage 2: Upper airway and conducting airway
response (next few days)

– The virus propagates and migrates down the

respiratory tract along the conducting airways, and
a more robust innate immune response is
triggered.
• Nasal swabs or sputum should yield the virus (SARS-CoV-2)
• The disease COVID-19 is clinically manifest.

– 80% of the infected patients, the disease will be

mild and mostly restricted to the upper and
conducting airways..
• Stage 3: Hypoxia, ground glass infiltrates, and
progression to ARDS
– about 20% of the infected patients will develop pulmonary
infiltrates and some of these will develop very severe
disease.
• The virus now reaches the gas exchange units of the lung and
infects alveolar type II cells.
• The infected alveolar units tend to be peripheral and subpleural

– The pathological result of COVID-19 is diffuse alveolar

damage with fibrin rich hyaline membranes and a few
multinucleated giant cells.

– The aberrant wound healing may lead to more severe

scarring and fibrosis than other forms of ARDS.
• Recovery will require a vigorous innate and
acquired immune response and epithelial
regeneration

• Elderly individuals are particularly at risk

because of
– diminished immune response
– reduced ability to repair the damaged epithelium.
– reduced mucociliary clearance,
 Key symptoms, and biochemical and radiological
features of the clinical
course of COVID-19.

T.J. Guzik et al. COVID-19 and the

cardiovascular system: implications
for risk assessment, diagnosis, and
treatment options
Progression of the acute disease in 2019 novel
coronavirus disease (COVID-19).

Circulation Research. 2020;126:1443–1455

 Hypercoagulopathy
Immunoparalysis

SARS-
CoV2
Role of IL-6 in respiratory viral infections.

Cytokine and Growth Factor Reviews 53 (2020) 13–24

A: Severe COVID-19
Without Treatment

B: Severe COVID-19

With Treatment
(LMWH & IVIG)
Interim Treatment Guidelines for COVID-19
 Overview of COVID-19, SARS-CoV-2 replication, and
therapeutic targets

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 87 • NUMBER 6 JUNE 2020

Simplified Representation of Severe Acute Respiratory Syndrome Coronavirus 2
(SARS-CoV-2) Viral Lifecycle and Potential Drug Targets

JAMA. 2020;323(18):1824-1836
Int. J. Mol. Sci. 2020, 21, 2657
 VIRAL AND HOST TARGETS
FOR THERAPIES
• There are at least 4 potential therapeutic strategies against
COVID-19, apart from supportive and oxygenation therapies
such as use of ventilators:

1. Direct antiviral drugs against SARSCoV- 2 (eg, remdesivir)

2. Indirect antiviral agents (eg, interferon I, interferon inducers,
and drugs that target host proteins required for infections)
3. Convalescent plasma that contains antibodiesagainst SARS-
CoV-2
4. Drugs that tamp down the pathogenic hyperactiveinfl ammatory
response and cytokinestorm later in disease progression

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 87 • NUMBER 6 JUNE 2020

Potential COVID-19 therapies and their cardiovascular effects

T.J. Guzik et al. COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options
 Ongoing Clinical Trials
• Currently, there is not suficient evidence that any existing antiviral
drugs can eficiently treat COVID-19 pneumonia

• The therapies can be divided into two categories :

– acting on the coronavirus directly,
– inhibiting viral enzyme for genome replication, or by blocking viral
entry to human cells

• The other:
– modulate the human immune system,
– boosting the innate response,
– inhibiting the inflammatory processes that cause lung injury
Int. J. Mol. Sci. 2020, 21, 2657
1) Inhibiting the RNA-dependent RNA polymerase
– Remdesivir
– Favipiravir (Avigan)
2) Inhibiting the Viral Protease
– Ivermectin
– Lopinavir/Ritonavir (Lopivia)
3) Blocking Virus–Cell Membrane Fusion
– Recombinant Human Angiotensin-converting
Enzyme 2 (APN01)
– Hydroxychloroquine
– Arbidol Hydrochloride (Umifenovir)

Int. J. Mol. Sci. 2020, 21, 2657

4) Enhancing the Innate Immune System
– Natural Killer Cells
– Recombinant Interferon
5) Attenuating the Inflammatory
Response
– Intravenous Immunoglobulin (IVIG)
– Blocking the Interleukin (IL)-6 Pathway
– etc
Int. J. Mol. Sci. 2020, 21, 2657
 Therapeutic Strategies for COVID-19





Circulation Research. 2020;126:1443–1455

 Convalescent Plasma for COVID-19

• Covalencent plasma (CP) → passive antibody

therapy → for providing immediate immunity to
susceptible persons
• CP administration reduced viral load and was
safe.
• It is safe in coronavirus infection, the high
mortality of COVID-19, particularly in elderly
and vulnerable persons, or early disease: benefit
> risk.
Glutathione deficiency may contribute to
C O V I D - 19 pathogenesis and outcomes

Polonikov A. ACS Infect. Dis 2020

High Dose for antioxidant effect
Complex
Immune
Dysregulationin
COVID-19
Patients with
Severe
Respiratory
Failure

Giamarellos-
Bourbouliset al.,
2020, CellHost &
Microbe
 theoretical model of disease progression with
potential targeted therapies

Horby PW et al. Effect of Dexamethasone in Hospitalized Patients With COVID-19 – Preliminary Report
• Conclutions:

• Treatment with
dexametaxone at a dose
6 mg once daily for up
to 10 days reduces 28
day mortality
inpatients with
COVID-19 who are
receiving respiratory
support, but no benefit
among patients who did
not require oxygen
All the factors should be considered when
choosing a pharmacologic treatment
VIRAL
BLOCKED

Enhancing the ANTI

Innate Immune COVID-19
System PHARMA-
COAGULANT
GOLOGIC
TREATMENT

CORTICO- Attenuating the

STEROID Inflammatory
Response
GLUTATHION
HIGH DOSE
 Drugs /Agents available

• Obat blokade replikasi Virus (Hidroksiklorokuin,

Lopinavir, Remsedivir, Favipiravir)
• Obat antikoagulan
• Plasma konvalesen
• IL-6 inhibitor
• IVIG
• High Dose Gluthation
• Kortikosteroid (deksametason)
 Obat Blokade Replikasi Virus
• Awal infeksi :
– Terkonfirmasi Covid dengan gejala
– Probable Covid
– Suspek Covid dengan tanda2 gagal napas type 1
• Pasien terkonfirmasi Convid tanpa gejala
(asimtomatik)
– Usia lanjut
– Co morbid : DM, HT, CVD, CKD, perokok, dll
– Obesitas
 Plasma Konvalesen
• Awal infeksi :
– Terkonfirmasi Covid dengan gejala
– Probable Covid
– Suspek Covid dengan tanda2 gagal napas type 1
• Pasien terkonfirmasi Covid tanpa gejala
(asimtomatik)
– Usia lanjut
– Co morbid : DM, HT, CVD, CKD, perokok, dll
– Obesitas
• Awal pulmonary phase
 Obat Antikoagulan
• Awal pulmonary phase
– Gambaran pnemonia (+) pada foto toraks
– Tanpa gambaran pneumonia dengan CRP yang
tinggi
– Tanpa gambaran pneumonia dengan d-Dimer yang
tinggi
– Tanpa gambaran pneumonia dengan sesak atau
hipoksemia
• Sepanjang hyperinflamasi phase
• IL-6 Inhibitor/IVIG
–Pasien probable/ terkonfirmasi
pada awal severe phase
• Deksametason
–Pasien probable/terkonfirmasi
dengan gagal napas
• High Dose Gluthation
–Pasien probable/ terkonfirmasi
pada awal pulmonary phase
 Summary
• Therapy strategy can be divided into two broad categories,
– directly target the virus replication cycle
– immunotherapy approaches boost innate antiviral immune
response or alleviate damage induced by dysregulated
inflammatory responses.
• Until now, the therapeutic strategy is still based on
hypothesis and knowledge of immunopathogenesis
• The drugs/biologic agents used are mostly from existing
drugs/agents
• Timing in giving drugs/agents will determine the outcome