short review on management of dengue fever based in WHO, CDC guidelines and novel therapies based on several studies and trials

1. Review on
management
of Dengue
- Dr. Pranab Chhetri

4. WHO stepwise approach
History taking: fever, nausea, vomiting, fluid intake , warning signs?, mental state, dizziness, urinary
output, similar hx in family and neighborhood
Physical examination: hydration state, mental state, hemodynamic status, tachypnea, abdominal
tenderness, hepatomegaly, ascites, pleural effusion, rashes bleeding manifestation, tourniquet test
Investigation: full blood count in first visit, fever with decreasing white cell count is very suggestive
of dengue, rapid rise in hct and fall of platelets is suggestive of plasma leak
In an endemic area fever for 3/more days with low/ decreasing TC, and/ or low platelets, +/-
tourniquet test positive is sufficient to notify the patient as having dengue fever, while lab
confirmation necessary in dengue non-endemic area¹
Treatment: case notification, isolate the patient and the WHO segregates treatment of patients into
3 groups (A,B,C)

5. NS1 antigen 3-7 days²
IgM after 5 days peak by 14 days and
last for 2-3 months²
IgG after IgM disappears and lasts in
low amount life long²

6. Dx: live/travel to endemic area + fever + any 2
(nausea/vomiting, rashes, body pain: headache, joint pain,
retro orbital pain, myalgia, tourniquet test +, leukopenia)³
No warning signs: group A - home/opd based
management
Warning signs or co-existing condition: group B -inpatient
management
Severe dengue: group C - inpatient/ high care
management

7. Group A
Fever- pcm up to 4 doses per day 6 hrs apart/ tepid
sponge bath
Hydration maintain with increase fluid intake such that
there is urine 1’ce every 6 hrs, look for s/o dehydration
Look for danger signs and report to a hospital
immediately
Avoid aspirin, ibuprofen, NSAIDs, as for their
anticoagulant activity
Avoid corticosteroids as they increase the risk of gi bleed

8. Group B
Isotonic Fluid management:¹
5-7 ml /kg/hr for 1-2 hrs
3-5 ml/kg/hr for 2-4 hrs
2-3 ml/kg/hr according to the response
Repeat hct and vitals if no improvement continue 2-3
ml/kg/hr for 2-4 hrs
If hct and vitals deteriorate increase fluid by 5-10
ml/kg/hr for 1-2 hrs and once patient responds taper
accordingly
Maintain UO 0.5 ml/kg/hr
Measure vitals hrly, UO 4-6 hrly, hct 6-12 hrly
Encourage oral fluids and shift IV to oral in 24-48 hrs,
gradual decrease fluid by end of critical phase
Watch out for fluid overload

9. Group C - compensated shock
Isotonic fluid to replace ongoing plasma leak
Goals decrease tachycardia, increase PP, improve
BP and pulse volume, decrease CRT, warm
peripheries and end organ perfusion (alert and
conscious with UP >0.5 ml/kg/hr)
Give 5-10 ml/kg/hr fluid for 1 hr and reassess
vitals, CRT, hct if improving proceed as in B
If not improving 10-20 ml/kg/hr bolus over 1 hr, if
still not improving repeat
If improving give 7-10 ml/kg/hr in 1-2 hrs and
reduce accordingly
If hct is decreasing – BT with WB or PRBC
Aim to stop IV fluid therapy by 48 hrs¹

10. Group C – hypotensive shock
BP low, PP<20mmhg, pulse tachy/low volume, CRT>2
seconds, hct falling/rising
20ml/kg bolus crystalloids/colloids over 15 min then
assess vitals
If patient improves 10 ml/kg for 1 hr the continue as B
with iv fluid resuscitation up to 24-48 hrs
if no improvement give another bolus of colloid 10-20
ml/kg over 15-30min, if patient improves give 7-10 ml/kg
of colloid for 1 -2 hrs then shift to crystalloids as before
If hct falls/ hemorrhagic complication - BT , don’t wait
for low levels of hct
If hct rises- give another bolus of colloid
Monitor vitals and CRT every 15-30 min, hct before and
after boluses till normal , UO every hr till normal then 4-6
hrly, ABG for CO2, lactate every 30 min till normal, blood
sugar and LFT, RFT, coagulation profile accordingly

12. Antimicroboials in dengue
Doxycycline reduces viral plague formation and interacts with the DENV E protein to inhibit a
conformational change ⁴
Virus replication was observed to be significantly reduced in DENV-infected cells after applying
doxycycline
Doxycycline and tetracycline play role in down regulation of pro-inflammatory cytokines (IL6, IL1B,
TNF) such that symptoms improve from the 3rd day of doxycycline administration and to be
continued till day 7
Doxycycline 100 mg BD for 7 days in patients with high risk of complications: decreasing platelets,
TC, hemorrhagic manifestations, plasma leak, positive tourniquet test⁵
Doxycycline and Ribavirin have been known well for the antibiotic and non-antibiotic properties
since its discovery. However, we have found that the novel combination of Doxycycline and Ribavirin
in various dosages exhibited synergistic antiviral effect more particularly against all the serotypes of
Dengue virus⁶
Ivermectin has antiviral and insecticidal effect, endectocides kills a number blood sucking parasites
and also inhibits the development of dengue virus in the survived vectors, reversing the growth
trend of dengue spread ⁷

13. Metformin in dengue:
Replication of dengue virus is restricted by
inhibition of lipid synthesis through AMPK
activation
Immunomodulatory effect: NK cell activation,
reduced T cell exhaustion, enhanced CD8 + T
cell memory shorten viral clearance times ⁸
Specific lipids central to every step in the
replication cycle of the family of viruses
including flaviviradae (DENV, HCV, YFV) during
entry, translation, replication and assemply of
the viral genome

14. Other novel therapies
JNJ-A07 developed by Jassen pharmaceuticals has promising results in trials, acts by inhibiting DENV
replication by inhibiting NS4B and NS3 interaction⁹
Mast cell stabilizer: widespread mast cell activation during systemic DENV infection results in
excessive release of vasoactive mast cell mediators that disrupt the endothelium
Eltrombopag a small-molecule thrombopoietin (TPO)-receptor agonist that interacts with human
TPO receptor transmembrane domain of human TPO-receptor & initiates signaling cascades that
induce proliferation & differentiation of megakaryocytes from bone marrow progenitor cells. Used
in ITP, aplastic anemia, HCV induced thrombocytopenia, given to patients with platelets < 50 x
10^9/L¹⁰
The primary outcomes of a clinical trial by S.Chakrabroty, et al showed a 91% patients receiving
eltrombopag exhibited platelet count above the lower normal limit (150 × 109/L) on 7th day¹¹
Eltrombopag can be considered as a therapeutic option to increase the PLT counts in DF and DHF
patients in the management of thrombocytopenia with platelets on day 7above the lower normal
limit (150 × 109/L)¹²

15. Vitamin D3 deficiency increases the risk of acquiring viral infection (influenza, RSV, HIV, DENV).
Some studies also show antiviral action of vitamin D3¹³
Vitamin E has immune enhancing function (both humoral and cellular), antioxidant function and has
been found to increase platelets in dengue patients with thrombocytopenia¹⁴
CPLE (Carica papaya leaf extract) study demonstrates safety and efficacy in increasing platelet
counts ,immunomodulatory and antiviral activity in severe dengue¹⁵

16. Dengvaxia/ CYD-TDV 0.5ml s/c 0/6/12 mths
Quadravalent, live attenuated
Some studies say Dengvaxia can reduce the severity of
Dengue fever in those who have had a prior infection.
However, Dengvaxia may increase the risk of severe
Dengue in those who have not yet been infected.¹⁶
In 2019 FDA approved vaccine Dengvaxia is useful in
preventing dengue in 9-16 y/o people who have
already been infected with dengue but not in
preventing dengue in general population.¹⁷
Developing an antiviral is difficult due to 4 genetically
distinct serotypes that keep evolving as they replicate
Several trials are ongoing

17. Treatment of complication:
Hemorrhagic complication- BT (WB, PRBC, FFP), avoid trauma, avoid IM inj, complete bed rest
Fluid overload- ARDS
Causes hypotonic fluid, rapid iv fluid, iv fluid for more than 48 hrs, BT,
ARDS, pulmonary edema, irreversible shock
Mgmt: O2, furosemide, t/t of hypokalemia, WB if hemorrhage
Hypoglycemia, acid base disorder, electrolyte imbalance managed accordingly
Need of RRT, vasopressors, ventilators might be there

18. Criteria for discharge of patients ¹⁸
Absence of fever for at least 24 hours without the use of anti-fever therapy
No respiratory distress from pleural effusion or ascites
Platelet count > 50,000/ cumm
Minimum of 2 to 3 days after recovery from shock
Return of appetite, Good urine output, Visible clinical improvement

19. Dengue serotypes
Different studies show that DENV2 is a/w more cases of severe dengue
A cross-sectional study by Vincente C.R, et al in Brazil in 2015 showed DENV2 a/w severe dengue
and early detection of the circulating serotype can help prepare to avoid and manage sever dengue
cases
A study by N. Cong, et al in China in 2020 reveled DENV2 had faster replication and more
pathogenicity
A meta-analysis by Kaun-Meg Soo, et al showed that DENV2 and DENV3 were a/w severe dengue in
both SEA and non SEA countries
A cross-sectional study by R. Rauniyar, et al from 2017-2018 in Nepal showed DENV2 to be more
prevalent in Kathmandu and upper hills while DENV1 and DENV3 more prevalent in the Terai belt

20. References:
1. https://www.who.int/publications/i/item/9789241547871
2. Ghai Essential Pediatrics
3. https://www.cdc.gov/dengue/healthcare-providers/treatment.html
4. https://www.ijcp.in/Admin/CMS/PDF/11.%20InternalMedicine_IJCP_JULY_2018.pdf
5. file:///C:/Users/user/Downloads/DOX-Dengue2015.pdf
6. https://actascientific.com/ASMI/pdf/ASMI-05-1005.pdf
7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277121/#:~:text=Because%20of%20the%20antivirus%20and,growing%20trend%20in%20the%20world.
8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539082/
9. https://link.springer.com/article/10.1007/s40506-023-00263-w
10. https://reference.medscape.com/drug/promacta-eltrombopag-342178#10
11. https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(20)30368-0/fulltext#seccesectitle0028
12. https://aimdrjournal.com/wp-content/uploads/2022/04/5.-3.-doctors-journal-32-39.pdf
13. https://journals.sagepub.com/doi/full/10.1177/2058739218791100
14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4228873/
15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029881/#:~:text=This%20study%20demonstrates%20safety%20and,be%20attributed%20to%20CPLE%20trea
tment.
16. https://www.clinicaltrialsarena.com/features/dengue-fever-antivirals-vaccines/
17. https://www.webmd.com/a-to-z-guides/dengue-fever-
reference#:~:text=There%20is%20no%20specific%20medicine,fluids%2C%20and%20see%20your%20doctor.
18. https://dhs.kerala.gov.in/wp-content/uploads/2020/06/ppt2016a.pdf