Update Management of COVID-19

I Ketut Agus Somia

Division of Tropical and infectious disease

Department of Internal Medicine
Udayana University / Sanglah Hospital
Denpasar Bali Indonesia
Outline
• Clinical symptoms COVID 19 Classification
• Management of COVID 19 in Referral Hospital
• Severity of illness and plan of management
• General management issues
• When to discharge
• COVID-19- specific therapy
• Antiviral
• Indication of antiviral
• Antiviral molecules under trial
• summary
KLASIFIKASI GEJALA INFEKSI COVID-19
Gejala Ringan Gejala Sedang Gejala Berat
Demam >380C Demam >380C Demam >380C yang menetap
Batuk Sesak napas, ISPA berat/ pneumonia berat:
Nyeri Tenggorokan batuk menetap Pasien remaja atau dewasa dengan
Hidung Tersumbat sakit tenggorokan. demam atau dalam pengawasan
Malaise infeksi saluran napas,
(tanpa pneumonia, tanpa ditambah satu dari:
komorbid • frekuensi napas >30 x/menit,
• distress pernapasan berat,
• atau saturasi oksigen (SpO2) < 90%
pada udara kamar
Isolasi diri di rumah Rawat di RS Darurat Rawat di RS Rujukan

PEDOMAN PENCEGAHAN DAN PENGENDALIAN CORONAVIRUS DISEASE (COVID-19). KEMKES RI . REVISI KE-4. 27 Maret 2020
Tatalaksana COVID 19 di Rumah Sakit Rujukan
Terapi Suportif Dini dan Pemantauan
• Terapi suplementasi oksigen segera pada ISPA berat dan distress pernapasan, hipoksemia, atau
syok
• Terapi oksigen dimulai dengan pemberian 5 L/menit dengan nasal kanul dan titrasi
• untuk mencapai target:
• SpO2 ≥90% pada anak dan orang dewasa yang tidak hamil
• SpO2 ≥ 92%-95% pada pasien hamil
• Pemberian cairan konservatif pada pasien dengan ISPA berat tanpa syok.
• antibiotik empirik berdasarkan kemungkinan etiologi.
• Jangan memberikan kortikosteroid sistemik secara rutin untuk pengobatan pneumonia karena
virus atau ARDS di luar uji klinis kecuali terdapat alasan lain.
• Pemantauan ketat pasien dengan gejala klinis yang mengalami perburukan seperti gagal napas,
sepsis
• lakukan intervensi perawatan suportif secepat mungkin
• Pasien yang memiliki komorbid untuk menyesuaikan pengobatan dan penilaian prognosisnya
• Tatalaksana pada pasien hamil, dilakukan terapi suportif dan penyesuaian dengan fisiologi
kehamilan PEDOMAN PENCEGAHAN DAN PENGENDALIAN CORONAVIRUS DISEASE (COVID-19). KEMKES RI . REVISI KE-4. 27 Maret 2020
Severity of illness and plan of management
SEVERITY OF ILLNESS PLAN
Mild illness without any risk factors/ • Outpatient care
Comorbidities • Strict Home Quarantine monitored by
government/health authorities
• Supportive care
• Assess patient’s clinical condition via telephonic
conversation/ using telemedicine facility
Moderate Illness: • Admit in Hospital isolation room
• Dyspnoea • Supportive care
• Hypoeximia • Start empirical antibiotics as per local community
• Infiltrates/ consolidation on chest acquired pneumonia treatment guidelines
xray/ CT scan • Oseltamivir 75/150mg BD
• Consider starting Hydroxychloroquine Or
Lopinavir/Ritonavir (If evident risk factors for
progression of disease are present)
INTERNATIONAL PULMONOLOGIST’S CONSENSUS ON COVID-19
Severity of illness and plan of management
SEVERITY OF ILLNESS PLAN

Critical Illness: • Remdesivir (for compassionate use only)

• Mechanically ventilated • Tocilizumab can be considered (check IL-6 level prior to starting
patient’s Tocilizumab). Especially in patients with evidence of cytokine
• Multi lobar/ bilateral lung release syndrome.
consolidation • Continue IV antibiotics and supportive care
Careful using these drugs in • Rule out ventilator associated pneumonia/ catheter related
patients with multiorgan infections and other secondary bacterial/viral/fungal infections
damage • Always keep in mind the to rule out differentials of non –
resolving pneumonia
• In ventilated patients: follow ARDS NET protocol strategy
• Consider ECMO if need arises
• Refractory or progressive cases in ICU: Interferon beta B1 can
be considered. However it should be combined with an anti-
viral (Lopinavir/Ritonavir) and hydroxychloquine
INTERNATIONAL PULMONOLOGIST’S CONSENSUS ON COVID-19
Laboratory features associated with severe COVID-19
Abnormality Possible threshold
Elevations in:
•D-dimer >1000 ng/mL (normal range: <500 ng/mL)
•CRP >100 mg/L (normal range: <8.0 mg/L)
•LDH >245 units/L (normal range: 110 to 210 units/L)
>2× the upper limit of normal (normal range for troponin T high
•Troponin
sensitivity: females 0 to 9 ng/L; males 0 to 14 ng/L)
>500 mcg/L (normal range: females 10 to 200 mcg/L; males 30 to
•Ferritin
300 mcg/L)
•CPK >2× the upper limit of normal (normal range: 40 to 150 units/L)
Decrease in:
<800/microL (normal range for age ≥21 years: 1800 to
•Absolute lymphocyte count
7700/microL)
Although these laboratory features are associated with severe disease in patients with COVID-
19, they have not been clearly demonstrated to have prognostic value.
the thresholds listed above to identify patients who may be at risk for severe disease
Arthur Y Kim. UpToDate 2020
General management issues
• Infection control
• Empirical treatment for bacterial pneumonia in select patients
• Prevention of venous thromboembolism
• Avoiding nebulized medications
• Limited role of glucocorticoids
• Managing chronic medications
• ACE inhibitors/ARBs
• Statin
• Imunomodulatory agent

Arthur Y Kim. UpToDate 2020

COVID-19-SPECIFIC THERAPY

• Several treatments are being evaluated for COVID-19.

• Although some of these treatments are clinically available for
other indications - their use for COVID-19 remains
investigational.
Figure. Simplified Representation of Severe Acute Respiratory
Syndrome Coronavirus 2 (SARS-CoV-2) Viral Lifecycle and Potential
Drug Targets

ACE2, angiotensin-
converting enzyme 2;

S protein, spike protein;

TMPRSS2, type 2
transmembrane serine
protease

JamesM. Sanders, PhD, PharmD; Marguerite L. Monogue, PharmD; Tomasz

Z. Jodlowski, et all. JAMA. doi:10.1001/jama.2020.6019
 INDICATIONS FOR ANTI-VIRAL THERAPY
• Retrospective data from SARS suggests that earlier treatment (e.g.
within 1-2 days of admission) may be more effective than reserving
therapy until severe organ failures occur (Chan 2003).
• This is consistent with data from influenza that suggests a finite
treatment window occurring relatively early in the disease course.
• The vast majority of patients will do fine without any therapy, so in most cases
there's no need for antiviral therapy.
• However, waiting until patients are severely ill before initiating therapy could
cause us to miss an early treatment window, during which the disease course
is more modifiable.
• Predictors of adverse outcome might be useful in predicting who will do poorly
and thus who might benefit most from early anti-viral therapy, but data is
limited.

INTERNATIONAL PULMONOLOGIST’S CONSENSUS ON COVID-19

ANTI-VIRAL MOLECULES UNDER TRIAL
(Experimental options)
• Remdisivir
• Lopinavir-ritonavir
• Chloroquine/ hydroxychloroquine
• Favipiravir
• Favipiravir is an RNA polymerase inhibitor that is available in some Asian
countries for treatment of influenza, and it is being evaluated in clinical trials
for treatment of COVID-19 in the United States 1
REMDESIVIR (compassionate use only)
• is a novel nucleotide analogue that has activity against SARS-CoV-2 in
vitro and related coronaviruses (including SARS and MERS-CoV) both
in vitro and in animal studies
• Several randomized trials are underway to evaluate the efficacy of
remdesivir for moderate or severe COVID-19
• Exclusion criteria vary by trials but generally include:
• alanine aminotransferase level >5 times the upper limit of normal,
• chronic kidney disease (creatinine clearance <30 or <50 mL/min, depending
on the trial),
• pregnancy or breastfeeding
• Adult dose: 200mg IV on day 1(loading dose) followed by 100mg IV
OD x 9 days N Engl J Med. 2020 Apr 10. doi: 10.1056/NEJMoa2007016. [Epub ahead of print]
REMDESIVIR (compassionate use only)
• In one multicenter, multinational series, 53 patients with severe
COVID-19 and hypoxia received compassionate-use remdesivir for up
to 10 days and had a median of 18 days of follow-up;
• 68 %  clinical improvement (decreased requirement for oxygen support or
hospital discharge), and 13 percent died.
• Of the 30 patients who were mechanically ventilated at baseline, 17 (57 %)
were extubated
• three of four patients on extracorporeal membrane oxygenation (ECMO) were
taken off it.
• Four patients discontinued remdesivir prematurely for adverse effects
(worsening kidney injury, multiple organ failure, elevated liver enzymes);
• elevated liver enzymes were the most frequent adverse event (23%).
• Data from comparative, randomized trials are needed to define the effect of
remdesivir in COVID-19.
N Engl J Med. 2020 Apr 10. doi: 10.1056/NEJMoa2007016. [Epub ahead of print]
Lopinavir/Ritonavir
• This combined protease inhibitor, which has primarily been used for HIV
infection, has in vitro activity against the SARS-CoV.1
• In a randomized trial of 199 patients with severe COVID-19, the addition of
lopinavir-ritonavir (400/100 mg) twice daily for 14 days to standard care
did not decrease the time to clinical improvement compared with standard
care alone.2
• If lopinavir-ritonavir is used, the patient's HIV status should be known.
• If the patient has HIV, lopinavir-ritonavir should be used as a standard combination
antiretroviral regimen.
• The WHO is launching a trial to further
evaluate remdesivir, hydroxychloroquine/chloroquine, and lopinavir-
ritonavir with and without interferon beta.3
• Dose: Adult: 400/100mg PO Q12h
1. Groneberg DA, Poutanen SM, Low DE, Lode H, Welte T, Zabel P. Lancet Infect Dis. 2005;5(3):147.
2. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, NEJM
3. https://www.sciencemag.org/news/2020/03/who-launches-global-megatrial-four-most-promising-coronavirus-treatments
(Accessed on March 26, 2020).
2. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, NEJM
Lopinavir/Ritonavir
Hydroxychloroquine/chloroquine
• There are insufficient data thus far to know,
whether hydroxychloroquine or chloroquine has a role in treatment of COVID-
19.
• For this reason, strongly recommend that patients should be referred to a clinical trial
whenever possible
• Both chloroquine and hydroxychloroquine have been reported to inhibit SARS-
CoV-2 in vitro, although hydroxychloroquine appears to have more potent
antiviral activity.1
• One unpublished trial comparing two doses of chloroquine for COVID-19 was
stopped early because of a higher mortality rate in the high-dose group,
highlighting the potential for toxicity.2
• unpublished randomized trial of hospitalized patients with mild to moderate
COVID-19, adding hydroxychloroquine to standard of care did not improve the
rate of SARS-CoV-2 clearance or symptomatic improvement by 28 days.3
1. Clin Infect Dis. 2020 Mar 9. pii: ciaa237. doi: 10.1093/cid/ciaa237. [Epub ahead of print]
2. Mayla Gabriela Silva Borba, et all. doi: https://doi.org/10.1101/2020.04.07.20056424
3. Wei Tang, Zhujun Cao, Mingfeng Han, Zhengyan Wang, Junwen Chen. doi: https://doi.org/10.1101/2020.04.10.20060558
 Hydroxychloroquine/chloroquine
• In an open-label study of 36 adults with COVID-19, use of hydroxychloroquine (200 mg three
times per day for 10 days) was associated with a higher rate of undetectable SARS-CoV-2 RNA on
nasopharyngeal specimens at day 6 compared with no specific treatment (70 versus 12.5 %. 1

• but there were substantial methodologic

problems with this study that cast doubt on
the conclusions.2

1. Gautret P, Lagier JC, et all. Int J Antimicrob Agents. 2020;

2. Joint ISAC and Elsevier statement on Gautret et al. paper [PMID 32205204]
https://www.isac.world/news-and-publications/isac-elsevier-statement
Azithromycin and hydroxychloroquine
• Although one study suggested the use of azithromycin in combination
with hydroxychloroquine was associated with more rapid resolution
of virus detection than hydroxychloroquine alone.1
• this result should be interpreted with caution because of the small sample
size, substantial methodologic concerns.2 and unclear biologic plausibility.
• Another small observational study in patients with more severe illness
did not suggest rapid viral RNA clearance with the combination.3
• Both azithromycin and hydroxychloroquine are associated with QTc
prolongation, and combined use may potentiate this adverse effect.4
1. Gautret P, Lagier JC, et all. Int J Antimicrob Agents. 2020;
2. Joint ISAC and Elsevier statement on Gautret et al. paper [PMID 32205204] https://www.isac.world/news-and-publications/isac-elsevier-statement
3. Molina JM, Delaugerre C, Goff JL, et al . Med Mal Infect. 2020 Mar 30. pii: S0399-077X(20)30085-8. doi: 10.1016/j.medmal.2020.03.006. [Epub ahead of print]
4. Arthur Y Kim. UpToDate 2020
Oseltamivir
• Neuraminidase enzyme inhibitor in influenza
• Not seen in SARS CoV2
• No trials on COVID-19
• Many patients with similar presentation of COVID 19 might be
influenza
• Hence better to give the drug to avoid patient worsening due to
influenza
• Dose: 150mg BD x 5 days
Convalescent plasma
• Use of convalescent plasma has been described in case series1
• One case series described administration of plasma from donors who
had completely recovered from COVID-19 to five patients with severe
COVID-19 on mechanical ventilation and persistently high viral titers
despite investigational antiviral treatment.1
• The patients had decreased nasopharyngeal viral load, decreased disease
severity score, and improved oxygenation by 12 days after transfusion
• However, these findings do not establish a causal effect, and the efficacy of
convalescent plasma remains unknown
• Finding appropriate donors and establishing testing to confirm
neutralizing activity of plasma may be logistical challenges.
1. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, Wang F, Li D, Yang M, Xing L, JAMA. 2020 Mar 27. doi: 10.1001/jama.2020.4783. [Epub ahead of print]
IL-6 pathway inhibitors
• Tocilizumab is an interleukin (IL)-6 receptor inhibitor used for
rheumatic diseases and cytokine release syndrome.
• Elevated IL-6 levels have been described in patients with severe
COVID-19, and case reports have described good outcomes with
tocilizumab. 1-3
• systematic evaluation of the clinical impact of tocilizumab on COVID-
19 has not yet been published.
• Treatment guidelines from China's National Health Commission
include the IL-6 inhibitor tocilizumab for patients with severe COVID-
19 and elevated IL-6 levels.4
1. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, HLH Across Speciality Collaboration, UK . Lancet. 2020;395(10229):1033. Epub 2020 Mar 16.
2. Luo P, Liu Y, Qiu L, Liu X, Liu D, Li J. J Med Virol. 2020
3. Michot JM, Albiges L, Chaput N, Saada V, Pommeret F, Griscelli F, Balleyguier C, Besse B, Marabelle A, Netzer F, Merad M, Robert C, Barlesi F, Gachot B, Stoclin A . Ann Oncol. 2020;
4. Arthur Y Kim. UpToDate 2020
WHEN TO DISCHARGE PATIENT

• Resolution of symptoms
• Radiological improvement
• Documented virological clearance in 2 samples at least 24 hours apart

PEDOMAN PENCEGAHAN DAN PENGENDALIAN CORONAVIRUS DISEASE (COVID-19). KEMKES RI . REVISI KE-4. 27 Maret 2020
INTERNATIONAL PULMONOLOGIST’S CONSENSUS ON COVID-19
Summary
• Infection control is an essential component of management of patients with
suspected or documented COVID-19.
• The optimal use of COVID-19-specific therapy is uncertain; no agent has clearly
proven effective.
• For most potential therapies, evidence on their use is low quality.
• For this reason, patients should be referred to clinical trials whenever possible.
• Clinicians should consult their own local protocols for management.
• For patients with nonsevere disease who have no laboratory features associated
with severe disease:
• Supportive care, with close monitoring for disease progression.
• For patients with severe (including critical) disease or with laboratory features
associated with severe disease
• strongly recommend referral to a clinical trial of remdesivir, convalescent
plasma, hydroxychloroquine, or lopinavir – ritonavir (Grade 1C).
• For critically ill patients who have features similar to cytokine release syndrome.
• interleukin (IL)-6 inhibitors have been proposed to disrupt the proinflammatory response.