Dengue fever continues to prevail despite all efforts of health-care systems: vector control programs against the mosquito vector Aedes aegypti, repellents and barrier inventions, education, and a vaccine touted with great expectations.

The Dengue vaccine has fallen short of promise: hundreds of adverse effects have been reported, a lack of efficacy to protect against the most frequent viral serotype, together with the threat that vaccine use can increase the severity of subsequent infections. There was much hue-and-cry from public health advocates and health care workers on the DOH’s endorsement of the vaccination campaign for the Sanofi’s vaccine.

In some measures the war being waged against Dengue fever has failed. The Philippine Department of Health-Epidemiology Bureau reported a 41% increase in cases of dengue fever from January 2016 to July 2016 (52,177 cases) compared to the same period in 2015 (36,972). In the same period, dengue related deaths also increased from 129 to 207. (1)

The mosquito vector remains a formidable and resilient foe. Dengue fever continues to threaten with rainy season peaks , heightened with rising urbanization and environmental disruption, unsuitable water storage and sanitation efforts, and the effects of climate change.

Despite the daunting and recurring numbers of annual cases of Dengue fever, most of the cases improve within days—only
1 -2% of cases progress to the more severe conditions called dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). DHF is characterized by decreasing platelet counts that usually start after the the third day. In the DHF group, plasma leakage and severe bleeding may occur resulting in organ failure and death. No specific treatment is available other than supportive care and pain relief. It is from these group that deaths occur.

Thrombocytopenia (low platelet count) in DHF is caused by two virus-induced mechanisms: decreased production and increased peripheral destruction. Bone marrow suppression is attributed to circulating interleukins from a stringent host immune response. (22) Increased peripheral destruction is attributed to the viral effect on the vascular endothelium which induces a spontaneous aggregation of platelets, ending in peripheral platelet lysis. (19)

In vitro studies of C. papaya reported membrane stabilizing properties to protect against stress-induced destruction and possibly prevent platelet lysis. The effect has been attributed to the presence of flavonoids and phenolic compounds. (19) Studies have proposed that quercetin has inhibitory effect against serine protease, particularly Dengue virus serotype 2, preventing viral assembly. (24) (more studies below)

Health Care Challenge in the Boondocks
In the boondocks and the rural areas, because of economic want and reliance on alternative therapies, acute febrile illnesses—whether they turn out to be dengue, trangkaso, or chikungunya—are initially relegated to watchful waiting and home treatment. Home therapy starts with paracetamol, often with a two- or three-day hopeful wait for the fever to resolve or before consultation is sought—a critical time when dengue fever may be starting its progression into the dreaded Dengue Hemorrhagic Fever. In the Tiaong, Quezon area, where the herbal plant tawa-tawa has gained familiarity in the rural grapevine for its use in Dengue fever, some families use the plant on the first or second day of fever.

A fever that persists into the second day might warrant a visit to the albularyo or medico who will do a diagnosis-and- treatment ritual that usually involves a bulong and tawas, to rule out or treat an affliction that might be caused by balis, nuno or dwende. Often, the healer will advise on some herbal therapy or modality: luyang dilaw, massaging of sambong leaves steeped in gas and oil, pounded ikmo leaves applied on the forehead, or even suob. Occasionally, the albularyo might advise on the use of tawa-tawa. It is not uncommon for some to self-medicate with "magasawang-gamot," a one-day combo of an antibiotic,usually amoxicillin, and paracetamol. For children, if the fever is unresolved, a visit to the doctor happens on the second or third day; for older patients, much later. Almost always, only symptomatic treatment is prescribed. Even a hospital visit does not guarantee an admission. There are cases of patients dying after being sent home from a hospital evaluation —dengue infection confirmed only after dying.

Herbal Therapies
In my regular updating of the medicinal plant compilation in StuartXchange, i have run into numerous studies on medicinal plants with anti-dengue properties, anti-dengue replication, beneficial effect on platelet counts, and mosquitocidal studies against Aedes aegypti.

Many Philippine plants have shown potential anti-dengue benefits: (1) Papaya (2) Tawa-Tawa (Gatas-gatas) (3) Morning glory (anti-dengue vector/ADV) (4) Baling-uai (5) Kanapa (6) Dawag (7) Litlit (8) Sinta (9) Kalamansi (10) Ampalaya (11) Luhang dalaga (12) Botong (13) Kamia (14) African tulip tree (15) Palutan (16) Kamote (17) Kintsay (18) Kamatsile (19) Ipil-ipil (20) Pandan-mabango (21) Dama de noche (22) Balatong aso (23) Malayan spurge (24) Tintatintahan (25) Hagonoi-tsina (26) Red ginger (27) Paraiso (28) Palmira (29) Kasuy (30) Hangod (31) Kachumba (32) Anonas.

Of the 32 listed above, two have gained familiarity in the grapevine of alternative pharmacopoeia: tawa-tawa, more familiar to rural folk, and papaya, more extensively studied of the two, but still relatively unknown in the alternative rural health care. Although both have received attention in internet niches of blogs and news releases, little has been done to disseminate the information of potential benefit to the rural areas.

Tawa-tawa
By rural grapevine spread, tawa-tawa has managed to gain stand-by status in the some barangays in the rural areas. However, although supposedly abundant in waste places and open grasslands, it is not easy to find.

While studies have shown many other biologic properties, tawa-tawa has had limited studies for its benefits in Dengue fever. A few studies have been done for its effects platelet count. One study in Sprague-Dawley rats showed a notable increase in platelet count, which was attributed to stimulation of platelet production in the bone marrow. (25) Another study in mice showed no difference in platelet count between treatment and control. (26) In a study of 125 patients with confirmed dengue fever, 75% showed improvement in platelet count, fever, and flu-like symptoms. (27)

Toxicity study
Its safety profile has been studied in animal models. In acute toxicity study, no toxicity was seen at dose of 10 g/kbw, with no sign of acute toxicity at dose below 3000 mg/kg. In subacute toxicity study in rats, the LD50 was estimated at 5000 mg/kg, and long term oral administration for 90 days did not cause sub-chronic toxicity. (28) (29)

Ways to prepare
(1) Boil one plant for i minute in a slow rolling boil; cool. Drink 1 to 1 1/2 glasses every hour for 24 hours.
(2) Boil for 1 minute roots from 6 plants; let cool. Drink 1 to 1 1/2 glasses every hour for 24 hours.
(3) Boil in 1/2 liter of water 100 grams of fresh whole plant for 15 minutes. Cool and filter. Drink 1 glass every hour until fever subsides and fully recovered from the illness.

Papaya
Carica papaya is much more available as backyard or commercial cultivation. It's leaf juice is now being widely used for the treatment of Dengue fever in many countries. Many studies have been done, including three randomized control clinical trials. No significant adverse effects have been reported, with no toxic effects even at higher doses.

Studies
• Increased Platelet Count / Leaf Extract: Study showed fresh Carica papaya leaf extract significantly increased the platelet and RBC counts in test groups compared to control. Identification of active constituents is paramount for its potential as medication to boost thrombopoiesis and erythropoiesis in humans and animals where those cell lineages have been compromised. (9) Open-labeled, randomized controlled trial investigated the platelet increasing property of C. papaya leaf extract in patients with thrombocytopenia associated with dengue. Results showed the leaf extract significantly increased the platelet count (p<0.003) over the therapy duration. (10) An observational, prospective, uncontrolled, open label, single center study investigated the effect of papaya leaves extract capsules in acute febrile illness with thrombocytopenia in 80 patients. Results showed significant increased in platelet count (p<0.05) and maintained stability of hematocrit level. Findings suggest acceleration of platelet count increase and shortening of hospitalization time. (11)
• Effect on Thrombocyte Count in Dengue / Leaves / A Case Report: Study investigated the role of Carica papaya leaves in Dengue Fever. Toxicity study (acute, sub-acute, and chronic toxicity) on Sprague Dawley rats showed leaf juice was safe for oral consumption. In a study on a 45-year old man showed a dramatic increase in thrombocyte count from 28,000 to 1,138,000 within 5 days of administration. The report was supported by another study in which the PTAFR gene, which is known to be responsible for increased platelet production and aggregation, increased 13.42-folds among patients who consumed papaya juice. Besides increasing thrombocyte count, the anti-hemolytic action of leaves could have potential therapeutic benefit. (12) (13)
• Activity Against Dengue Fever / Leaves: Study investigated the potential of Carica papaya leaves extracts against Dengue fever in a 45 year old patient bitten by carrier mosquitoes. Extract was prepared in 25 cc of aqueous extract of leaves administered twice daily for five consecutive days. Rechecking of blood samples showed an increase in platelet count, white blood cells, and neutrophils. Results suggest potential activity against Dengue fever. (14)
• Acceleration of Platelet Count Increase in Dengue: Study investigated the platelet increasing property of leaf juice in patients with dengue fever. In an open-labeled randomized controlled trial of 228 patients with dengue fever (DF) and dengue hemorrhagic fever (DHF), study showed a significant increase in mean platelet count in the intervention group in both DF and DHF patients. (15)
• Salutary Effects of Leaf Extract in Dengue Fever Patients: Pilot study showed the effects of papaya leaf juice in dengue patients in elevating total WBC counts, platelet counts and recovery without hospital admission. Typically, platelet count drops in dengue after the first three days of fever, gradually increasing after the 7th day or decreasing further along with other clotting facts to develop into the dengue hemorrhagic state. In this study, the platelet count increased in all 12 patients with two doses of papaya leaf juice. (See Uses/Dengue for preparation of leaf juice) (16)
• Guidelines in Use of Papaya Leaf Extract in Dengue: Study provides background and guidelines on the use of papaya leaf extract concomitant with other anti-dengue therapies. Three randomized control clinical trials have reported no significant adverse effects even at higher doses. Use of leaf extract have shown benefits in reduction of duration of fever, illness, hospital days, and prevention of conversion of dengue to Dengue hemorrhagic fever. (see below for preparations) (6)
• Effect on Platelet Count in Thrombocytopenia of Dengue Fever / Decreased Platelet Transfusion / Leaves: Study evaluated the effect of C. papaya leaf extract on platelet count of dengue fever patients. Results showed increase in platelet count in dengue fever without any side effects and prevented the complication of thrombocytopenia. (20)
• Review: Papaya Extract to Treat Dengue: A Novel Therapeutic Option?: Studies indicated that the juice of leaves of C. papaya helped increase the platelets in Dengue patients. Review includes 7 studies from the past 10 years: one animal study, one case report, threes case series and two randomized trials. Although the studies and case reports in literature lack adequate information, they raise the possibility that papaya leaf extract can be an important treatment option in the future. Review suggests large scale studies to establish the usefulness or ineffectiveness of this natural product for dengue treatment. (19)
• Efficacy and Safety of Leaf Extract in Dengue / Review and Meta-Analysis: Review looked at randomized controlled trials related to efficacy and safety. Primary endpoint was mortality, and secondary endpoints were increase in platelet count, hospitalization days, and Grade 3 and 4 adverse events. Papaya leaf extract was found to be associated with increase in platelet count and decrease in hospitalization days. Mortality and adverse events could not be pooled. Meta-analysis concludes that C. papaya leaf extract can be considered a potential candidate for increase in platelet count in patients with Dengue. However, large clinical trials are needed to provide high-quality evidence before a decision related to extract use is made. (21)

Toxicity Studies and Concerns
• Toxicity studies have been done on papaya leaves and leaf juice. Acute, sub-acute, and chronic toxicity studies on Sprague-Dawley rats showed the leaf juice to be safe for oral consumption. (46) A repeated dose 28-day oral toxicity study of a leaf extract at a dose up to 14 times levels used in traditional medicine in Malaysia showed a safety profile. (74)
• Cyanogenic concern: Concerns have been raised about papaya being weakly cyanogenic, i.e., producing a small amount of hydrogen cyanide (0.02 mg of cyanide in four papaya leaves, with the amount decreasing as the leaves mature). Dr. Noor Hisham of the Malaysia Health Ministry said that the lowest cyanide to endanger humans is one mg per kg body weight (a 60 kg man requires 12,000 papaya leaves to induce poisoning). The Malaysian IMR (Institute of Medical Research) conducted a safety study using the highest dosage of 2,000 mg per kg body weight in laboratory animals. (5)
• Use in Pregnancy: Papaya leaf juice is not advised in pregnant women who contract dengue. The papain in papaya is a potent potent proteolytic enzyme found abundantly in seeds, leaves, and fruit and has been reported to cause miscarriages and be unsafe to the unborn baby.

Fresh Leaf Juice Preparations
• A: (1) Use fresh healthy mature leaves from a fruit-bearing tree. Some suggest use of younger leaves at the lower part of the tree. (2) Wash thoroughly with running tap water and chop into small pieces, excluding the main stem. (3) Put 50 grams of chopped leaves in a mortar and pestle. Add 50 cc of boiled cool water and 25 grams of sugar. (4) Pound for 15 to 30 minutes into a uniform pulp. (5) Squeeze by hand to extract the leaf extract. Take 30 cc (2 tablespoons) 3x daily before meals for adults, 5-10 cc three times daily for children, until recovery. Because of its bitter taste, sips of cold water is suggested after drinking of the leaf extract. (6) Author suggests refrigerator storage of the preparation for 24 hours. (4)
• B: (1) This method suggests the use of ten fresh papaya leaves—one leaf is estimated to yield a tablespoonful of leaf juice. (2) De-vein the leaves Discard the long stems and central veins. (3) Chop leaves into small pieces and place in blender with enough water to make a liquid paste. (4) Strain the fluid and discard the pulp. (5) Take 2 tablespoon of leaf juice every three hours for 2-3 days, or for one week, if symptoms persist. (18)
• C. Decoction: (1) Wash and partly dry some medium-size papaya leaves. (2) Separate from long stems and central veins. (3) Cut into small pieces. (4) Place in a sauce pan with 2 liters of water. (5) Bring to a boil and simmer until the water is reduced by half. (6) Strain the liquid and place decoction in glass containers. (7) Add sugar to taste. Drink half a glass every six hours. (8) May be stored for up to 5 days, but preferably used as fresh as possible.
• D. Juiced: (1) Put the cleaned leaves through the juicer to extract the juice. (2) Store the juice in the fridge to consume within 4 or 5 days.
• D. Blend: (1) Crush 10 leaves and put in a blender with a cup of pure drinking water. (2) Blend the leaves. (3) Strain out the juice using a cheese cloth. (4) Use a tablespoon one to twice daily.

The Alternative Treatment Potential
The Case for Use Papaya Leaf Juice in Suspected Dengue Fever
Results of studies and clinical research support the initiation of papaya leaf extract concurrently with the usual dengue management. The use of the leaf extract has shown the potential to increase platelet counts and decrease the need for platelet transfusions. Dr. Sanath Hettiges in his journal publication "Guidelines in Using Carica Papaya Leaf Extract for Dengue Fever Patients" advocates for the use of papaya leaf extract from the first day of Dengue fever in addition to the supportive management after the diagnosis is established by Dengue antigen testing. (6)

Alas, in the Philippines, for many of the poor in the boondocks and remote rural areas, the first day or two of a febrile illness are often consigned to hopeful waiting and home therapies, seeking consultations with albularyos, hilots, and medicos two or three days later when the fever fails to resolve.

For many of the poor in the boondocks and the remote rural areas, where the early days of febrile illness are often consigned to hopeful waiting and home therapies, albularyos, hilots, and medicos, I suggest the use of papaya leaf juice as empirical addition to the treatment of acute febrile conditions, and to continue its use until the fever subsides, even without the benefits of viral testing. The clinical studies and its safety profile are compelling and should justify its use. Early use may prevent the progression of some cases of Dengue fever to the dreaded Dengue Hemorrhagic Fever, possibly avoid hospitalization and the need for platelet transfusions, and actually save lives. Yes, I can hear the hue and cry, the chorus of "Horrors!" from the traditionalists.

Other uses and formulations
A simple web search for "papaya-dengue" will yield dozens of blogs, articles, and news releases. A search for "carica papaya for dengue treatment" likewise yields dozens of medicinal studies. What surprises is how papaya leaf extract has failed to catch on in the rural grapevine of alternative therapies for dengue, the way tawa-tawa—although relatively underused—has become the familiar anti-dengue plant.

In some countries, papaya leaf juice has caught on as alternative treatment for Dengue, Chikungunya, and Zika. India, Sri Lanka, Malaysia, and have done studies on the use of papaya leaf juice for dengue fever. The leaf juice has also been used as a natural spray to kill Aedes aegypti mosquitoes, and although toxic to mosquito larvae it is considered safe to use around people. In India and Indonesia, papaya leaf extracts are available in capsule and tincture forms. (18)

Papaya is ubiquitous, much more available than tawa-tawa. Many studies have already suggested potential benefits for Dengue fever treatment, and possibly, for other mosquito borne viral diseases, and most importantly, besides its potential benefit for the dreaded decreases in platelet count and progression to DHF, it boasts of an equally compelling safety profile.

A volume of work has already been done on papaya leaf extract: studies on Dengue treatment, platelet benefits, formulations, vector control, and other clinical applications (antihelmintic, antioxidant, antiulcer, anticancer, hypoglycemic, antimalarial, hypotensive, etc.) It is quite possible papaya leaf juice will prove to be effective as empiric prophylactic therapy for dengue and other diseases.

Equally surprising as how little is known of papaya leaf extract in the rural grapevine of alternative therapies, is why—in the absence of any specific anti-viral therapy for Dengue fever, the predictable statistics of death and morbidity, and despite the accumulation of studies on its benefits—the papaya leaf extract has not found a place in the treatment recommendations of traditional health care.

While we benefit greatly from already available volume of information on papaya leaf extract, the Philippines can contribute clinical studies that could further add to the evidence of efficacy. Papaya leaf extract should be evaluated for affordable and alternative formulations with longer shelf-life and easy accessibility for future use, with guidelines for use and home preparation methods disseminated through the barangay health care system.

Studies have shown that papaya leaf juice has worked benefits in cases of dengue, and, possibly, saved lives. While there is no certainty that it will work on everyone, for a disease that continues to escape the science of cure and prevention, that burdens humanity with predictable deaths and morbidity, there is no reason to deny papaya leaf juice a place in the prevention and treatment of suspected dengue fever.

(1)
Dengue fever cases rise int the Philippines / July 2016 InterHealth Worldwide /
(2)
Dengue Situation Update 504, 15 November 2016 / WHO
(3)
Dengue cases rise by 36% nationwide, say DOH / Tina G. Santos /Philippine Daily Inquirer, July 26, 2016
(4)
Clinical Review: Dengue fever / Senanayake A M Kularatne / BMJ 2015;351:h4661 / doi: https://doi.org/10.1136/bmj.h4661 / Cite this as: BMJ 2015;351:h4661
(5)
Papaya leaf juice hikes platelet count, being studied as cure to dengue: Malaysia health exec / Philippine News Agency / Bernama / Feb 1, 2016
(6)
Guidelines in using carica papaya leaf extract for Dengue fever patients / Senanayake A M Kularatne / BMJ 2015;351:h4661 / doi: https://doi.org/10.1136/bmj.h4661
(7)
Papaya / StuartXchange
(8)
Tawa-tawa /StuartXchange
(9)
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(10)
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(11)
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(12)
Effects of papaya leaves on thrombocyte counts in dengue - a case report / Osama Siddique, Ayesha Sundus and Mohammad Faisal Ibrahim / Journal of Pakistan Medical Association
(13)
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(14)
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(15)
Carica papaya Leaves Juice Significantly Accelerates the Rate of Increase in Platelet Count among Patients with Dengue Fever and Dengue Haemorrhagic Fever / Soobitha Subenthiran, Tan Chwee Choon, Kee Chee Cheong, Ravindran Thayan, Mok Boon Teck, Prem Kumar Muniandy, Adlin Afzan, Noor Rain Abdullah, and Zakiah Ismail / Evidence-Based Complementary and Alternative Medicine, Volume 2013 (2013) / http://dx.doi.org/10.1155/2013/616737
(16)
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(17)
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(19)
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(20)
Effect of Carica papaya Leaf Extract Capsule on Platelet Count in Patients of Dengue Fever with Thrombocytopenia / Ajeet Kumar Gadhwal, BS Ankit, Chitresh Chahar, Pankaj Tantia, P Sirohi, RP Agrawal / Journal of the Association of Physicians of India, Vol 64, June 2016
(21)
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(23)
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(24)
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(26)
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