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Teaching T. Mudwal’s Hypersensitivity Type III Theory

(The Reason Why You Give Corticosteroid in Dengue Hemorrhagic Fever)

 

I. INTRODUCTION AND EPIDEMIOLOGY

For more than 200 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 DHF (it is a controversial topic). The debate of the DHF still happens because the number of DHF cases is high and so is the number of death caused by DHF (even though according to the percentage it is low). Dissatisfying of the present theory of DHF grows higher if the effect of the DHF causes misery to the sufferer for all his life, for instance, when he has low thrombocyte for the rest of his life (ITP diseases). Almost all ITP patients in Indonesia have ever got a DHF before. WHO said that the number of DHF 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 DHF (2,5 billion people). What is interesting from WHO report is that the world health organization is not critical towards the number of DHF cases and mortality report that is given by the countries in the world. Indonesia, for instance, in 2008 reported that the dengue hemorrhagic fever case from 240 million lives which are potential to be infected there were only 17.604 cases by DHF with 128 mortality number. On the other hand, based on the estimation that if there is minimally 5% of the Indonesia population is infected by DHF, the number of DHF case are 12 million lives. And if we use the lowest estimation scale of the death case caused by DHF in 2008 as WHO stated which is 0,2% (two of a thousand DHF 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 DHF 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 DHF is included as MAJOR PROBLEM DISEASES in the world. And seeing that Indonesia is a country which has the most DHF cases (based on estimation) and DHF 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 DHF 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 DHF 1000 patients (0,2%)= 24.000(2008)

 

MAJOR PROBLEM DISEASES IN THE WORLD

II.Dengue Hemorrhagic Fever (DHF) 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. Cytokine 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 fagocyt 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 phagocyte activity 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 soedier cells.The virus which succeed to get in to target cells will be destroyed by cytotoxic cells ( Tc Cells) and Killer cells as it is mentioned before. Here is what makes Dengue virus interesting, they live among 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. The destruction of tissue, plasma leakage and thrombocytopenia will happen. This 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, DHF will attackthe world even broader. That is why now we can find many people in America, Europe and Australia get DHF, even with a single bite (primer infection/IgM positive).

III. Various DHF Pathofisiology and Pathogenesis Theories

based on the scheme, comes the various kinds of theories of DHF pathogenesis dan pathophysiology.

Virus Virulency Theory

secondary Heterolegous/ Infection Enhaching

Antybody of Halstead

Immunopathology Theory

APOPTOSIS Theory

Antigen Antibody Theory

Mediator Theory

Endotoxin Theory

T. Mudwal’s HYPERSENSITIVITY TYPE III Theory

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

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/Cytokine Theory

The basis of the theory derives from dengue fever is the secrete of Cytokine

The weakness of the theory:

This theory is too simple.

F. Thrombocyte Endotelial Theory

The seriousness of DHF 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 Cytokine cascade, especially tumor necrosing factor (TNF) and interleukin 1 (IL 1). On shock DHF there is 75% endotoxin, while on non shock DHF 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 protein 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 ligh 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 high endotoxin rather than cancer patients with low sepsis and low 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 cell). 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 DHF pathogenesis dan pathophysiology is hypersensitivity reaction type III based on the following reasons:

1. Not all people or race will be infected by DHF. DHF 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, macrofag, Kupffer cells). Thrombocyte is not the target of dengue virus.

6. It is found that autoimmune reaction (positive thrombocyte antibody) on DHF 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 curent show that thrombocyte antibody can be positive and negative quickly and repeatedly.

7. It is proven that giving thrombocyte transfusion does not give increasing countof thrombocyt 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 DHF patients <(less than) 5 days. On DHF ≥ 5 days lowery too fast on thrombocyte count does not happen. If the viciousness of the virus is the cause, giving immunosupressif metilprednisolone will bring negative result to the patients.

Frequent comments on this theory are the number of samples that are checked is so few (29 patients). T.Mudwal responded that the statistical calculation (likelihood ratio) will also give the same result if it is conducted in big amount of samples (P= 0,01850). And this, for example, is proven with research about the existence of thrombocyte antibody which was conducted by UI Medicine Faculty, Hematology department in cooperation with Eiykman Institution in 2008. The result was thrombocyte antibody was proven to be positive on 29 patients (70%) from the dengue fever samples which they analyzed (13th Congress of the European Hematology Association, June 12-15 2008). Actually without conducting repeated research, T.Mudwal research is scientifically still rational and stronger because it is proven in the research. The 2 most followed theories are virulency and Halstead’s secondary infection theories actually does not conduct any research or any simple research.Virulency theory is only observing dengue fever patients with serious clinical symptomsand isolate the virus in the patients. Halstead theory is also not too far different, which only discovers that patients who suffer from dengue fever are almost entirely had positive igG that what he said as non-neutralizing antibody.

 

IV. Metilprednisolone imunosuppresive Effects towards Dengue Hemorrhagic Fever pathogenesis and pathophysiology

There will be pressure on the whole immune system that fights dengue virus.

The Scheme of metilprednisolone imunosuppresive effecttowards DHF pathogenesis and pathophysiology

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