Artikel 38 – Controversy of Corticosteroid Research in Dengue Infection

Controversy of Corticosteroid Research in Dengue Infection

Taufiq Muhibbuddin Waly

Waled General Hospital, Cirebon, West Java, Indonesia

 

The debate about application of corticosteroid in Dengue infection has been started for dozens of years. With the minimum of 42 years when Pongpanich et.all tried to evaluate DHF patients using corticosteroid in 1973 [1]. Result of corticosteroid researches for dozens of years generally are not really significant, just as what was stated by Zhang and Cramer  [2]. Not working which means there haven’t been any meaningful difference in result whether we give corticosteroid application or not. Bothways shock is still happening, just as the occurence of severe thrombocytopenia, acites, bleeding and the admitance of DHF patients to ICU. Eventhough high dose corticosteroid is already given to patients even before the 5th day of fever (early stage of Dengue infection).

Same result was also happening  with the research from Oxford university in collaboration with Ho Chi Minh Faculty of Medicine in Vietnam[3]. They also reported that the application of high dose corticosteroid (2 mg/kg of body weight/day, with the maximum amount taken is 60 mg of methylprednisolone/day) taken orally for DHF patients with fever ≤72 hours, the result was corticosteroid wasn’t bringing any benefit for those patients[3]. No benefits because based on shock incidences, ICU admittances, Hematocrit rate, bleeding, platelet rate are not having any meaningful differences between those who had been given with high dose, low dose (0,5 mg/kg of body weight), or no dose at all of corticosteroid.

From that experiment, Hanh Tienh Nguyen et. all also found that patients who is undergoing application of high dose corticosteroid, in their body we can still see cells that are similiar with natural killer and Lymphocyte-T to be around. The same result also happened with cytokine. There’s not any meaningful differences between  patients with high, low or no dose of corticosteroid. So in conclusion, Thi Hanh Tien Nguyen et. all concluded that the application of high dose corticosteroid in DHF patients as a failure in its effect to suppress immune response[4].

Discussion

It was written in refference that the application of high dose corticosteroid for less than 1 week is safe if there’s no gastrointestnal bleeding [5]. It was stated that range of coticosteroid is very wide. We can give up to 1000 mg of methylprednisolone/day or 30 mg/kg of body weight a day in certain cases such as Lupus Nefritis and shock[6,7]. On the other hand, immunosupressive effects of prednisone just like when used to treat autoimmune disease is considered as effectual if prednisone is applied in the dose of 1-2 mg/kg of body weight a day[8]. Or if we convert this dose to methylprednisolone then that means 1,25-2,5 mg/kg of body weight a day. In refference, methylprednisolone is considered to have immunosupressive effects or in high dose level if given in the range of 0,5-1,7 mg/kg of body weight a day[6]. And maximum dose which can be tolerated orally in a day is 80 mg of methylprednisolone a day[6]. On another note, researchers are only brave enough to give methylprednisolone orally with maximum dose of 60 mg a day (immunosupressive/high dose). With range of immunosupressive dose of methylprednisolone can be considered to be very wide (can reach as high as 1000 mg/day)[7], then every research that state high dose methylprednisolone is not giving any meaningful difference in DHF can be considered as a very naive statement. Because they only give the maximum dose of 60 mg of methylprednisolone a day.

If we combine what has been said above with what I have written in “Again Let’s Discuss about Patogenesis and Pathophysiology of DHF[9] then we can conclude that the failure of corticosteroid application in patients with Dengue infection is caused by :

  1. Delayal of corticosteroid application

Corticosteroid is just only given in recovery phase or 5th day of sickness

  1. Application of corticosteroid with weak strength such as hydrocortisone
  2. Corticosteroid application in shock phase or sepsis
  3. Not applying corticosteroid in immunosupressive dose.

 

In researchs where corticosteroids are applied in its stronger variety such as methylprednisolone, the timing of application in early stage of disease (3rd day of fever) and with immunosupressive dose eventhough orally (2 mg/kg of body weight a day). Then failure is caused by :

a. Corticosteroid that were given hadn’t reached immunosupressive level, because the maximum dose was 60 mg/day. From Oxford research we found that from 225 patients all of them were in the age range of 12-15 year old. If Indonesia become the benchmark then the average weight of Indonesian kids are 40 kg. So the dose that should be given in group of high dose methylprednisolone is 80 mg/day. If we take assumption that dose of 2 mg/kg of body weight a day of methylprednisolone as the minimum mark of methylprednisolone that can be considered as having immunosupressive effect then it means that all samples from that research (225 patients), every single one of them didn’t receive methylprednisolone in immunosupressive dose. Futrakul which his research hadn’t been reviewed by Zhang gave good result with the application of 30 mg/kg of body weight of Methylprednisolone in Dengue infection patients who were also accompanied by shock[10]. I myself always give 125 mg of methylprednisolone injection to adult DHF patients with body weight of less than 60 kg. And 250 mg of methylprednisolone to adult DHF patients with body weight >60 kg [11]. Even in severe patients such as those who also have shock I then give 2×250 mg of methylprednisolone injection or 2×500 mg methylprednisolone injection (Think of Possible Existence of Dengue Infection Before You Play Your Surgery Knife/www.dhf-revolutionafankelijkheid.net) [12] . With the failure of reaching immunosupressive dose in that Oxford research in Vietnam then it should be logical if we still saw the appearance of Natural Killer and Lymphocyte-T cell. The same also happen on Cytokine rate which had no meaningful difference in group with high dose, low dose, and no dose of corticsteroid.

b. Included in success of corticoticosteroid therapy is when the rise of platelet count to 100.000 is faster than in patients without corticosteroid therapy. Mine and Hendarsih research are concrete examples[13, 14]. Data of time span of platelet to reach 100.000/mm3 was not included in Oxford and Zhang research. Also noted the phenomenon of reduction in platelet level was not reported in those journals. In my own research, fluctuation of platelet level is fewer in patients that were given high dose of methylprednisolone. This thing will become the 5th point of this discussion.

5. The time span of platelet level in order to increase to 100.000/mm3 and fewer cases of fluctuation of platelet count should be the main point in determining successful therapy of high dose corticosteroid application

6. It should be remembered that high dose corticosteroid level may vary between each individuals. If with dose of 1×125 mg of methylprednisolone injection platelet count still on decrease, maybe the immunosupressive dose is not yet reached in this patient. Dose can be increased to 2×125 mg and so on[15]. With this kind of concept, we can understand the failure of Shashidhara, et al.  They only dare to give dexametason 20mg/day (its equal with 106mg metilprednisolon/day). In that research there was no mentioned of which day these corticosteroid application was given. Corticosteroid that was given before the fifth day of sickness will give better effect[11,13].

Conclusion

From above discussion we can conclude that researchs of corticosteroid application are not easy to be done properly. There should always be courage and consistency in giving patients with 2 mg/kg of body weight a day or giving patients with very large dose of corticosteroid in the form of injection. Eventhough it should be like that, the dose that we consider as immunosupressive may not prove to have immunosupressive effect in certain individuals. If those researchs are not meant to be done or we are afraid to do such research then it should be logical that we must back to discuss patogenesis and patophysiology of Dengue that is proven to be close to the truth. Because the difference in therapy of doctor and Rasputin or Jesus is the patogenesis and patophysiology of disease itself and not the  recovery of the patient. With the agreement of patogenesis and patophysiology of Dengue infected patient, it can be hoped that diagnosis and therapy of Dengue infected patiens are not changing throughout time just like what’s happening now (1997,2009,2011,??). Those things will only make doctors throughout the world confused.

I claim that patogenesis and patophysiology of Dengue infection is Hypersensitivity type III theory. The occurance of imperfect antibody (non-neutralizing antibody), imperfect plasma cell (blue lymphosite cell), the worsening of disease after formation of immune complex, rapid spread of immune complex throughout body, South East Asian people that contributed to 70% of World Potential Dengue Infected[16], the weaker immunity the less severe clinical symptoms of Dengue infection, the finding of platelet antibody in Dengue infection. For me all of them clearly shows the involvement of Hypersensitivity type III reaction (Again, Leet’s Discuss About Patogenesis and Patophysiology of DHF)[9].

 

References

  1. Pongpanich B, et al. Studies on dengue hemorrhagic fever. Clinical study: an evaluation of steroids as a threatment. J Med Assoc Thai 1973, 56:6-14. Google Scholar.
  2. Zhang F, Kramer CV. Corticosteroid for dengue infection (Review). The Cochrane Collaboration
  3. Dong T. H. Tam, et al. Effect of Short Course Oral Corticosteroid Therapy in Early Dengue Infection in Vietnamese Patients: A Randomized, Placebo-Controlled Trial. Oxford University Press on behalf of the Infectious Diseases Society of America
  4. Thi Hanh Tien Nguyen, et al. Corticosteroids for Dengue – Why Don’t They Work?. 2013
  5. Boumpas DT, et al. Glucocorticoid therapy for immune-mediated diseases. Basic and clinical correlates. Ann Intern Med 1993; 119:1198-1208.
  6. com. Methylprednisolone Dosage.
  7. Aditi Singha, Arvind Bagga. Pulse Steroid Therapy. Indian Journal of Pediatrics, Volume 75 – October, 2008.
  8. Bruce M. Hall, et al. Corticosteroids in autoimmune diseases.

Aust Prescr 1999;22:9-11

  1. Taufiq M Waly. Again, Let’s Discuss About DHF Pathogenesis and Pathophysiology. from www.dhf-revolutionafankelijkheid.net.
  2. Futrakul P, et al. Hemodinamic response to high dose methylpredisolone and mannitol in severe Dengue-shock patients unresponsive to fluid replacement. South East Asian J Trop Med Pub Hlth 1987;18:373-9.
  3. Mudwal. The Summary of T. Mudwal Type III Hypersensitivity And Application Of The Theory. www.dhf-revolutionafankelijkheid.net.
  4. Mudwal. Think Possible Existence of Dengue Infection Before you Play the Surgery Knife. www.dhf-revolutionafankelijkheid.net.
  5. Wally T M, et al: The role of platelet antibody and bone marrow in adult Dengue hemorrhagic fever with thrombocytopenia. Med J Indones 1998; 7 : 242-8.
  6. Hendarsih E: The role of methylpredisolone on platelet amount in DHF patient (thesis). Padjajaran University, Bandung, 2004.
  7. K.C Shashidhara, K.A Sudharshan Murthy, H. Basavana Gowdappa, Abhijith Bhograj: Effect of High Dose of Steroid on Plateletcount in Acute Stage of Dengue Fever with Thrombocytopenia. 2013
  8. Dengue guidelines for diagnosis treatment, prevention and control. A joint publication of the WHO and the special programme for research and training in tropical disease, 2009.

 

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