This post was published to LBPP LIA Cirebon at 9:49:27 04/08/2009
What You need to know about Dengue Fever

Teaching T. Mudwal’s Hypersensitivity Theory Type III
(The Reason Why You Give Corticosteroid in Dengue Hemorrhagic Fever)
I. INTRODUCTION AND EPIDEMIOLOGY
For more than 300 years dengue virus has been a debatable topic of many physicists in the world, since Bylon tried to define the clinical symptoms as the cause of dengue infection in Batavia in 1779. Even until now people still debate about the pathogenesis and the pathophysiology of Dengue fever (it is a controversial topic). The debate of the dengue fever still happens because the number of dengue fever cases is high and so is the number of death caused by dengue fever (even though according to the percentage it is still low). Dissatisfying of the present theory of dengue fever grows higher if the effect of the dengue fever causes misery to the sufferer for all his life, for instance, when he has low thrombosis for the rest of his life (ITP disease). Almost all ITP patients in Indonesia have ever got a dengue fever before. WHO said that the number of dengue case in the world in 2008 is less than 50 million lives in more than 100 countries in the world which are potential to get infected by dengue fever virus. What is interesting from WHO report is that the world health organization is not critical towards the number of dengue cases and mortality report that is given by the countries in the word. Indonesia, for instance, in 2008 reported that the dengue case from 240 million lives, there were only 17.604 cases which are potential to be infected by dengue with 128 mortality. On the other hand, based on the estimation that if there is minimally 5% of the Indonesia population is infected by dengue fever, the number of dengue case are 12 million lives. And if we use the lowest estimation scale of the death case caused by dengue in 2008 as WHO stated which is 0,2% (two of a thousand dengue cases die) so the death case is at least 24.000 people. WHO even did not file a protest at all to the report submitted by Bangladesh which said that the mortality number caused by dengue in Bangladesh in 2008 is 0%. Based on the enormous number of dengue cases as WHO stated and the possibility of having increasingly mortality number, so WHO said Dengue Fever is included as MAJOR PROBLEM DISEASES in the world. And seeing that Indonesia is a country which has the most dengue cases (based on estimation) and dengue is still a controversial issue in all its aspects, it is high time for Indonesian scientists to come forward and speak up and try to overcome these dengue problems based on their researches and their findings.
WHO (2008): – Sick : 50 million people
-+ : 0,2% – 1% (100.000-500.000 lives)
– Endemic (Extraordinary Cases) : + 3% – 5% (300.000-2,5 million lives)
– Population: 2,5 billion lives (> 100 countries in the world)
– Indonesia : Sick : 17.604 cases?
+ : 0,73% (128 patients)?
Indonesia Estimation: – Sick : 5% population 12.000.000 lives
– + : 2 people of Dengue Fever 1000 patients (0,2%)= 24.000(2008)

MAJOR PROBLEM DISEASES IN THE WORLD

World Distribution of Dengue – 2008

PATHOPHYSIOLOGY
+ Reason of therapy
PATHOGENESIS
CONTROVERSIAL Controversial
Why Not?? Steroid is forbidden?
INDONESIA has the HIGHEST Dengue Case in the World
WE HAVE TO BE DARE !
Summary of the Role of Bone Marrow and Thrombolytic Antibody on Adult DF Patients with Thrombocytopenia Research

Foreground
1. DF Pathophysiology  Controversial
2. DF mainly attacks SE Asia and West Pacific Asia and West Pacific
3. Clinical Symptoms are individual
4. Poor Nutrition, Old ageLight Clinical symptoms
5. Generally, secondary infection brings more serious clinical
Symptoms than primary infection
6. Human is not definitive hospes

7. Immunologic Reaction Basis of DF Pathophysiology
8. Target cell of DF virus monocyte, macrophage,
Kupffer cells (not thrombocyte)
9. Immune complex in many body tissues (endothelia, brain, thrombocyte, etc)

10. Free from fever, but thrombocyte keeps decreasing
11. Normal Thrombocyte drops  raises  sharp drops
12. DF Clinical Symptom (+)  IH test positive,
Thrombocyte Antibody positive
13. Thrombolytic transfusion  a waste (isarangkura, tuchinda)
14. Steroid on Shock Children DF is controversial on adult without shock? Steroid affects well
15. DF less than 5 days  thrombocytopenia e.c. bone marrow (BM)
 (BM) statistical analysis vs periphery has not been conducted

16. DF > = 5 days  thrombocytopenia e.c. peripheral process

II. How it works

– The causes of early Thrombocytopenia ( TRO ) ( Cross Sectional Study )
Thrombocytopenia development ( Cohor Study )
STEROID TEST

II.Dengue Fever (DF) Pathogenesis and Pathophysiology
After Dengue virus gets in to the blood stream, then our non specific immune system, which is interferon will quickly react. Interferon is a part of cytokine. Cytosine is peptide, which is produced by Lymphocyte cells, macrophage, and granulocyte and endothelia cells. Interferon function is to simulate the activity of killer cells and natural killer cells to remove unwanted virus directly. Killer cells and natural Killer cells are included in the non-specific immune system. Killer and natural Killer cells are actually lymphocyte cells that are not lymphocyte B or lymphocyte T and their shape are large granules. That is why the cells are also called as large granular lymphocyt or zero cells. Killer cells also have the ability to kill virus that has been in their target cells with ADCC mechanism (antigen depending cytotoxic cell). Other interferon Functions are to induce the surround cells that have been infected by virus virus to be resistant to the virus. Specific Immune will make antibody which will layer the virus (making complex antibody antigen/immune complex) so that it will be easier to be removed by phagocyte cells, in this case especially by macrofrag. On one hand, the immune complex will stimulate the release of complements.These complements that stimulate macrophage to remove the unwanted virus. On the other hand, these complements can also worsen the individu’s condition by releasing, for example, anapylaxin complements (C₃A, C₅A) which causes increasing capillary permeability. It can be worse with the plasma leakage (as the result of the destruction o fimmune complex in blood circulation) will cause a shock to the patients. The viruses which escape from the attack of interferon, natural killer cells, killer cells, antibody and phagocytosis by healthy macrophage (the ones which haven’t been infected by dengue virus) will get in to the target cells. The target cells of dengue virus are monocyte, macrophage, and Kupffer cells (not thrombocyte) which all are our patitentara cells.The virus which succeed to get in to target cells will be destroyed by cytotoxic cells ( Tc Cells) and Killer cellsas it is mentioned before. Here is what makes Dengue virus interesting, they live am ong our soldier cells.And this means there are many of our soldier cells die.The defects and the decreasing number of the cells will cause the immune complex to spread to the whole body including to thrombocyte, then the destruction of tissue, plasma leakage and thrombocytopenia will happen. Thi is the basis why T. Mudwal said that the basis of dengue pathogenesis and pathophysiologyis hypersensitivity type III. Only the people in West Pacific and South East Asia can mainly get dengue fever. Even though it is not impossible with the ability of dengue virus to change its genetic structure and to have genetic structural change on certain people, DF will attackthe world even broader. That is why now we can find many people in America, Europe and Australia get DF, even with a single bite (infeksi primer/IgM positive).

Macrophage cell, etc Tc Cell

Macrophage
Monocyte
Kupffer cell
Interferon Immune complex Lymphocyte B

NK Cell (TNF) LymphocyteTH
ADCC

K Cell (TNF IL 1) Complement Macrophage (IL1 + TNF)

Escaped Virus

Virus in the target cell

Tc Cells ADCC

Complement Activation
can occur
K Cells
Reaction Type II

(IL 1 TNF )

Destruction of Destruction of
Virus + Target Cells Mutan Cells
(IL 1 TNF )

III. Various DF Pathophysiology and Pathogenesis Theories
Based on the scheme, comes the various kinds of theories of dengue fever pathogenesis dan patophysiology.
Virus Virulency Theory
Secondary Heterologous / Infection Enhancing
Antibody of Halstead
Immunopathology Theory
APOPTOSIS Theory
Antigen Antibody Theory
Mediator Theory
Endotoxin Theory
T. Mudwal’s HYPERSENSITIVITY Theory TYPE III
A. Virus Virulence Theory
Virus Virulency is the cause of everything. There are four kinds of cerotype of dengue virus, they are dengue virus 1,2,3,4. The Theory stated that it is the vicious virus that causes the tissue damage, plasma leakage, thrombocytopenia and many more. As in Indonesia the dengue virus 3 that is belived to be the most vicious. In Thailand, it is dengue virus 2 and in the Philiphinnes, it is dengue virus 3 dan 4.
The weaknesses of the theory are:
1. It often occurs that the infection by the considered vicious virus, but only with a single bite (igM +) gives clinically lighter symptoms than by the less vicious virus in several bites even though with different virus cerotype.
2. It is often found that patients who is theoretically have low immune, like poor nutrition, old age gives away lighter clinical symptoms, although they were infected by considered vicious dengue virus in several times, even from different cerotypes. In reality we rarely find old age patient (> 60 years) has serious clinical DF symptoms
3. People in certain race could not be infected by Dengue virus although they live in endemic area that has many Aedes Aegypty mosquitos. Therefore this theory can not explain why dengue fever only mainly attacks people in South East Asia and West Pasifik and not people in America, Europe and Australia.
B. Halstead’s Secondary Heterologous Infection / Infection Enhancing Antibody Theory
The Theory was created byHalstead in 1970s. The basis of the theory is that someone can be infected by dengue fever if he was infected at least twice from different types (creating non neutralizing antibodi). Non-neutralizing Antibodi will cause the virus to easily get in to target cells and there will be immune complex spread. And if he is infected by the virus only once, he will not suffer from dengue fever because what will happen is the creation of neutralizing antibodi. Neutralizing antibodi is actually IgM, while non neutralizing antibody is IgG. It It seem that Halstead in 70s noticed that all dengue patients has positive IgG, while those who had negative IgGdid not suffer from dengue fever. This is the theory that many people follow now.
The weaknesses of the theory are:
1. Theoritically the creation of antibody is actually to make phagocytosis easily happens from macrophage cells. That is why it is weird if after lgG antibody is created, the virus can get in to the target cells and replicated. The term neutralizing and non-neutralizing does not exist in alergy textbook and immunology. Although we want to say that after the creation of lgG, Dengue fever disease will get more serious, it is caused by the disfunction of macrophage cells because of infected by the virus. As the result immune complex will spread to the whole body and wide spread of tissue damage and shock will happen.The widespread tissue damage is caused by the emerging of new macrophage cellsthat haven’t been infected by dengue virus which will remove the unwanted entire immune complex (identical with hypersensitivity theory type III T.Mudwal said)
2. Halstead could not answer why there are many people get infected by Dengue fever virus even it is only bitten once (positive IgM, negative IgG). To try to answer this, Halstead said that to have someone could get infected by dengue fever depended on his genetic (it is not necessary to be bitten twice or more by Aedes Agypti mosquitos that carries dengue virus fromdifferent cerotype). So, indirectly Halstead theory of secondary heterologous infection is not valid. According to T.Mudwal what halstead meant by genetic is whether someone is sensitive towords dengue virus. What strange is, until now almost all medicine faculties in the world teach that someone can be infected by dengeue fever if secondary heterologous infection of Halstead happens
Two different types of virus Non Neutralizing
Antibody Sick
Virus 1

Non Neutralizing Antibody
Not Spreading

Virus II
(Different type of Virus)

Non Neutralizing Antibody
Spreading

C. Apoptosis Theory
This theory stated that the seriousness of dengue fever is caused by the death of cells physiologically as the result of various stimuli released by cytoxic lymphocyte. The damage of target cells, endotel cells, thrombocyte cells, etc are neither because of the virus that live in the target cells nor because of consuming alien substance by macrophage(phagocyte activity) in immune complex that attached to those cells, but because of the programmed cells to die by themselves since the virus stimulate cytoxic lymphocyte cells to secrete granzyme and fragmentine that will code death.
The weakness of the theory:
The theory does not discuss about the spread of immune complex that has obviously been proven by researchers and ignore the abilty of phagocyte cells to destroy the immune complex. In general, this theory is so similar to the virus virulency theory, that its weaknesses are the same as the virus virulency theory.
D. Immunopathologic Theory
The theory stated that if someone is infected by dengue virus, there will be only two possibilities that he will be immune or get sick
The weakness of the Theory:
It is too simple or bogus.
E. Mediator/Cytosine Theory
The basis of the theory derives from dengue fever is the secrete of Cytosine
The weakness of the theory:
This theory is too simple.
F. Thrombocyte Endotelia Theory
The seriousness of dengue fever is determined by whether there is damage in the thrombocyte and endotel.
The weakness of the theory:
It is too simple.
G. Endotoxin Theory
Endotoxin from colon bacteria holds an important role in the seriousness of dengue fever clinical symptoms.This is because endotoxin will activate Cytosine cascade, especially tumor necrosing factor (TNF) and interleukin 1 (IL 1). On shock dengue feverthere is 75% endotoxin, while on non shock DF there is 60% endotoxin. On acute digestive canal bleeding, it is found that the endoxin rate is higher than less acute digestive canal, although on both case the number of thrombocyte is the same. Endotoxin from colon bakteriacan get in to blood circulation, that is because colon bacteria translocation occurs in blood circulation caused by the damage of colon lumens.
The weaknesses of the theory are:
1. Is the measured endotoxin as effective as endotoxin in the circulation? Because as it is known, the effect ofendotoxin in the circulation can be reduced by the body by binding those endotoxins with proyein plasma as in transferin ADP and other proteins. In that research, during the endotoxin examination PCA (precloric acid) which contain NaOH is given so that the plasma proteins bind with the endotoxin get lose and it caused the measured endotoxin was high. Besides, the endotoxin effectscan be weakened or even neutralized by antibody.
2. The increasing TNF, IL1, IL6, may not be the result of the endotoxin effects (the result of tissue damage) but may be because of complex antibody virus that activate the lymphocyte T (IL1 ↑, IL6 ↑) and activate macrophage (TNF ↑)
3. Having the same thrombocyte but the bleeding occurred on higher endotoxin may not be caused by the endotoxin or the thrombocyte, since it is only one of the factors that can cause bleeding risks.
4. The theory does not explain benign pathogenesis and pathophysiolgy of dengue fever (they haven’t destroy colon mucus). For your consideration, in RSCM it has been proven that when the mortality number and the morbidity number are not different means more to the cancer patients with high sepsis and endotoxin rather than cancer patients with low sepsis and endotoxin.
H. T.Mudwal’s Hipersensitivity type III Theory
The basis of hypesensitivity reaction type III is the spreading of immune complex to the whole body casued by phagocyte/macrophage cells disfunction. The Immune complex that has spreaded to the tissue and circulation can be destroyed by other phagocyte cells, in this case by macrophage that hasn’t been infected by virus or certain germs (healthy phagocyte). This can be seen, for example by streptococcus type A infection that can cause inflammation and heart, joints and kidney damage. In Hipersensitivity tipe III reaction, autoimmune can happen which is the body reaction to destroy itself. This is possible because in every human there are autoreactive lymphocyte which tends to haveautoimmune reaction. The one which acts as reactive lypocyte is T Helper lymphocyte. That auto immune does not happen to human is because there is a homeostasis immune regulator mechanism. T suppressors Lymphocytet will suppres autoreactive lymphocyte not to have auto immune reaction. Immune complex which attached to cells or certain tissue is a strong stimulus for autoreactive lymphocyte to have auto immune.
T.Mudwal said that tha basis of Dengue Fever pathogenesis dan pathophysiology is hypersensitivity reaction type III based on the following reasons:
1. Not all people or race will be infected by dengue fever. Dengue Fever mainly attacks South East Asia and West Pacific regions. This means individu’s genetic and sensitivity has more role than the viciousness of the virus.
2. It is rare to find that old age patients (>60 years) who suffer serious dengue fever. This shows that the less someone’s immune, the least sensitive he is.
3. In general, secondary infections or repeated mosquitos bites show more severe clinical symptom than primary infection or single mosquito bite. This shows that it needs time for antibody to form and to have antigen-antibody reaction.
4. It is proven that the spreading of complex immune to the whole body occurs; such as to the wall of blood vein, thrombocyte, pancreas, kidney, liver and etc.
5. It is concedted that the living and breeding dengue virus cells within our soldier cells (monocyte, thrombocyte, Kupffer cells). Thrombocyte is not the target of dengue virus.
6. It is found that autoimmune reaction (positive thrombocyte antibody) on DF patients in 62% research samples which proved that according to thrombocyte antibody laboratorium result and there were patients who haod experience sharp increase and decrease of the thrombocyte number several times although their bone marrow megacariocyte at the time were normal. Sharp increase and decrease of the thrombocyte number show that thrombocyte antibody can be positive and negative quickly and repeatedly.
7. It is proven that giving thrombocyte transfusion does not give increasing number significantly, even in some patients there were some drastic decreasing number of thrombocyte.
8. Giving steroid dosage of immunosuppressive, in this case metilprednisolone, brings good result especially if it is given to dengue fever patients 1mg/kg weight/day)
When patients are diagnosed to be infected by dengue fever, allimmunologic reaction has occured. IMMUNOSUPPRESIVE STEROID DOSAGE PREVENTS THE PROLONGED IMMUNOLOGIC REACTION.

Immunosuppressive Steroid Dosage effects

Virus

Macrophage
Monocyte
Kupffer cells
The Virus succeeded directly get in to the target cells (Monocyte, Macrophage, Kupffer cells), but the number of dead monocyte, macrophage, and Kupffer cells decreasing. This is because these cells fail to approach dengue virus so that dengue virus is hard to get into the cells. If dengue virus can get in to its target cells, the virus will still be dead. Not because of the phagocyte from Tc cells or killer cells (where both can get suppressed as the effect of high metilprednisolone dosage) but because of the millium of the target virus cells (human macrophage/monocyte/Kupffeir cells) but not the millium that is good for the development of the virus rather than if the virus live within the its target cells inside horse or monkey’s body (human is not definitive hospes for dengue fever). So, obviously the destructive effect of immune complex which spreads to someone does not occur.

V. Metilprednisolone immunosuppresive Effect on Prolonged thrombocytopenia.
METILPREDNISOLONE IMMUNOSUPPRESIVE EFFECT
ON PROLONGED THROMBOCYTOPENIA.
FEVER 5 hari → the thrombocytopenia length slightly increases, but sharp drop of the number of thrombocy does not occur and the chance of prolonged or lifetime thrombocytopenia (ITP) decreases.
SHARP DROPS OF THROMBOCYTE NUMBER ON SOME DF PATIENTS GRAPH.

5 things that cause failure in giving steroid on DF, they are:
1. The Dosage used is not immunosuppressive dosage and the steroid type given is notstrong steroid but weak steroid like hidrocortison.
2. Steroid given is late, such as the patient has shocked or DF > 5 days.
3. Steroid must not be given to patient who is proven having gastrointestinal bleeding (melena).
4. The effect of Steroid will lessen if it is given to DF patient ≥ 5 days with thrombocyte antibodi (-).
5. There is hidden bleeding such as hematuria or menstruation.
VI. Vaccination Problems on DF
Vaccination

Non Sesitive Patient (igG-, igM-) Danger on
(America, Europe, Australia) beginning phase of vaccination

Vaccination

igG+ / igM+ Futile

Sensitive Patient
igG- / igM- Can be good/bad

The danger on beginning phase means that it will make it easier to have sensitivity reaction on the individu so that he will suffer DF, while on the next phase the chaosness in our immune system will lessen. The lessen chaosness in immune system, for example; the speed of non specific and specific immune system in destroying virus will be faster and stronger. It also occurs that the speed of the creation of new macrophage will be faster. The chaos of autoreactive lymphocyte which induces to have antibody thrombocyte does not occur. However, the early light clinical symptoms, such as headache, bone pain, soreness, and high temperature can occur. That is why DF desease is an iceberg phenomenon illness, in which top is the patients whose thrombocyte are lower than or equal to 100.000/mm3 so that they are diagnosed with DF.
For Indonesia vaccination is futile, because Aedes Aegypty mosquitos with their dengue virus are found all over the region in Indonesia
VII. The Cause of Thrombocytopenia Problems on DF
THE CAUSE OF THROMBOCYTOPENIA PROBLEMS ON DF
(Thrombocyte<150.000/mm³)

Destroyed Thrombocyte

Complex Immune blood vein wall
(Virus and antibody)

-Macrophage DIC/Comsumtive Coagulopathi
-Endotoxin?

B. Complex Immune Attached to thrombocyte Phagocytosis
(Virus and antibody)

The creation of antibody thrombocyte destroyed in circulation
+
Destroyed in tissue (RES activity Lymph and liver)

Does Virus directly destroy thrombocyte? Only proven INVITRO(Funahara)
Rejected by Hypersensitivity type III
Decreasing Thrombocyte Production

Complex Immune Bone Marrow Megacariocyte ↓↓
(Virus and antibody)

-Thrombocytopenia caused by decreasing thrombocyte production as a result of bone marrow megacarocyte pressure is only proven on having fever < 5 days and only factor number 4 statistically after the destruction of immune complex which attach to thrombocyte in the circulation, thrombocyte antibody, and uncompensated DIC. Before hypersensitivity theory type III was found, DF experts still concede that thrombocytopenia < 5 days occurs because of bone marrow megacarocyte pressure. T.Mudwal denied this because he did bone marrow biopsy directly and that instant after had been diagnosed on patients who really proven to be infected by DF and later on had statistical counting (multiple regression analysis) to other factors that also had roles in thrombocytopenia. While in the old theory bone marrow biopsy was done on DF patients who were not certain to have dengue fever and there was no multiple regression analysis conducted towards other factors which have roles in thrombocytopenia. T.Mudwal was the first in the world to truly had biopsy on bone marrow of DF adult patients who were proven to have dengue fever (Positive DF clinical symptoms as WHO, positive Panbio test, positive IH test or positive presumtive).