Artikel 41 – Irrefutable, Pathogenesis and Pathophysiology of Dengue Infection are The Reaction of Hypersensitivity Type III

Irrefutable, Pathogenesis and Pathophysiology of Dengue Infection are

The Reaction of Hypersensitivity Type III


Department of Internal Medicine of Waled Hospital

(Cirebon, West java, Indonesia)

 A. Introduction and Epidemology

The Incidence of dengue infection is growing rapidly in the world in recent decades. Firstly known in 1950, the outbreak of dengue fever was found in the Philippines and Thailand. Nowadays, dengue is most widely found in Asian countries. 2.5 billion people or 2/5 of the world’s population including more than 100 countries around the world are at risk of getting infected by dengue fever (Dengue Potential World Infected / WPDI) (1,2). WHO currently estimates 50 million people (2% WPDI) are infected by dengue hemorrhagic fever worldwide each year (World Dengue Infected / WDI) (1). And an estimated 500,000 people infected with dengue have been treated in hospitals each year (World DHF Hospitalization / WDHI) (1). However, the 2009 data of WHO did not mention the mortality rate (CFR) of dengue worldwide each year. WHO only mentions the death rate could be below 1% or more than 20% depending on the treatment. When we attempt to find it further in the literature, then the obtained mortality rate of dengue each year is in the range between 21000-30000 people per year (2,3,4,5,6,7). Such figures are also recognized by Murray, as he said that death number caused by dengue infection ± 20,000 people, with 75% coming from South East Asia(8). Thus it can be said the mortality rate is approximately 0.05% of dengue infection worldwide (WDI). When compared to the number of hospitalized dengue patients (WDHI), the death rate is equivalent to 5% of WDHI.

The problem is whether the WTO’s reported figures are accurate or not. The predicted number of Morbidity rate (WDI) and mortality rate (CFR) should be higher. The number of patients treated at any hospitals (WDHI) could be even in doubt. For example, the number of hospitalized patients (WDHI) are only 2% of WDI. It means that tens of millions of people suffering from dengue fever are not treated. This happens for example because that person simply complains minor symptoms, which can be self-treated without having to go to the doctor. Or a doctor does not treat dengue patients even it has met the dengue criteria of WHO, 1997, as the physician may diagnose that the patient has only mild complaint (no real bleeding). Or the patients are not treated because the doctor does not think that it is a dengue symptom due to the patient’s platelets that remain above 100,000 / mm3. Diagnosis of Dengue is regarded in significant by the patients with high body temperature remaining less than 7 days as they went to private doctors in endemic areas and the doctor did not perform tourniquet tests. Thus alertness or diagnosis of dengue is lost. Yet, any patient with fever ≤ 7 days in hyperendemic areas, should be carried out tourniquet test. Or patients who have been clear with dengue infection and recommended to be treated by the doctors, refused to be treated because of economic difficulties and so on. All such cases to which I have described contribute to lower the number of patients treated in hospital and will automatically reduce the number of mortality rate of dengue.

The tens of millions of people who are out of hospital treatment, may be dying out side the hospital. While the in-hospital mortality, may not be considered to be caused by dengue since dengue criteria of 1997 cannot be enforced. Hospital reporting system for patients with dengue infection is not perfect yet as well. In such reasons, Jacqueline LDeen et al, doubted the rate of dengue fever reported from the hospital (9).

The exampleof doubts on the accuracy of the dengue reports, is Indonesia. In 2012, Indonesia reported its mortality rate (CFR) is 0.86 which is calculated based on the number of dengue patients which is 45 964 people, and only 408 people died (10). In fact, when calculated with WHO estimation (regardless that the estimation is still below the standard as I have explained above). Then, the approximationof dengue infection rate in Indonesia (IDI) is 2% x Indonesia Potential Dengue Infection (IPDI) = 2% x 240,000,000 = 4,800 000. Of the 4.8 million, it was only 45 964 people were reported as dengue fever patients. And it can almost be ascertained that all these reports are derived from dengue patients who were hospitalized. Or the percentage of the treated patients was only 0.9% of IDI. Thus,as described above, over 99% of people suffering from dengue fever in Indonesia are at stake. And it can also be automatically inferred that the mortality rate below 1% does not describe anything on the success of the treatment and prevention of dengue.

Such cases should also be realized by dengue hyperendemic countries such as Thailand (CFR = 0.47%), Myanmar (CFR = 0.4%), Malaysia (CFR = 0.2%), Singapore (0, 7%) (10). Philippines (0.56%) (11). The most interesting part is the report from Brunei Darussalam that say that there is no dengue deaths of 436 cases (12). Similarly thing that has also been reported by the state of Bangladesh. Where Bangladesh reported that no one had died from 1181 patients diagnosed with dengue (CFR = 0%) (13).

From the above descriptions, it is clear for us that the mortality and morbidity rate, or CFR in dengue hyperendemic countries does not actually show the CFR of dengue infection. Since the reported CFR is derived only from the number of hospitalized patients. Therefore, the experts of dengue from hyper-endemic countries such as Indonesia, Malaysia, Vietnam, Thailand, Myanmar, Cambodia, the Philippines, Singapore, India, Pakistan, Sri Lanka, Bangladesh re-discuss the pathogenesis and pathophysiology of dengue, which is still considered to be controversial (1). Hyperendemic countries are estimated to contribute to 70% of WPDI/1.8 billion people (1).

The importance of revisiting the pathophysiology and pathogenesis of dengue fever will also likely lead to a decline of patients with lifetime thrombocytopenia or aplastic anemia. Because,in hyperendemic areas, dengue is often the major cause of thrombocytopenia. VD and Dinesh Patil had reported persistent thrombocytopenia in dengue patients (14). Uth Karsh Kohli et al (15)also reported the same. On the other hand TM Waly has proved the existence of platelet antibodies in patients with dengue in 1997 (16). Later, Rahman proved  the possibility of platelet antibodies in patients with dengue in 2009 (17,18). While Alburqueque reported aplastic anemia in patients with dengue(19).

 B. Pathogenesis and pathophysiology of Dengue Fever (conclusions from journals on dengue fever (20, 21, 22, 23, 24, 25, 26, 27, 28)

The existence of viremia is the basis of the occurrence of dengue fever. Viremia results in complement activity, a cytokine storm, apoptosis, where itwill subsequently lead to tissue damage, bleeding and leakage of plasma. The ability of the virus itself (depending on strain) to damage cell and destroy the immune complex contributes to the severity of the disease. Viremia will occur when the body does not succeed in forming specific antibodies or neutralizing antibodies. A person can become immune for life, if it has a specific antibody against a strain of dengue virus. However, it is not able to provide immunity against the other strains of the dengue virus. Dengue virus replication occurs in its target cells (monocytes, macrophages, and Kupffer cells). Viral replication in target cells will happen when non-neutralizing antibodies are formed. The recurring dengue infection occurred from different strains of dengue virus will further facilitate the occurrence of non-neutralizing antibodies. However, even the first dengue infection without recurring infection can also cause viremia. This is due to the non-neutralizing antibodies from the mother. But, dengue infection recurring from the other types or secondary infections occur more easily and cause more severe symptoms than the primary infection. Nutritional status of a patient can also worsen dengue disease.

From the above conclusions, it appears that the basis for the occurrence of dengue fever and what makes it worsedepends on viremia. On the other side,another theory from T.Mudwal as he said that a person’s hypersensitivity can be exposed to dengue. Where hypersensitivity reactions are the responsibility of hypersensitivity type III/ hypersensitivity reactions of immune complex (29).

 C. Discussion

 Being a Healthy or sick individual, as we know, it is the interaction between the human immune system with the environment and agents (bacteria / virus / antigen). In order for the humans to stay healthy, the immune system should be good, the environment must persistently support the immune system, and antigen, as well as all its supporting factors, should be eliminated.

However, apart from the classical theory of occurrence of illness in humans as described above, humans can also become ill if their immune systems are too reactive (hypersensitive). Where, in such circumstances, the immune system provide an overreaction to the particular agent/microorganisms. So it’s not the immune system that make a person sick, but the errors in respondingthe agents getting into the body that is responsible for the occurrence of the illness.

Based on the readings on pathogenesis and pathophysiology, dengue infection as has been noted above, basically, there are 3 theories on pathogenesis and pathophysiology.

  1. Theory of virus virulence

The virulence of the virus is the cause of everything. The virus is considered vicious if he is able to replicate, induce apoptosis and the release of cytokines, and increase the activity of the complement. Where everything will subsequently lead to tissue damage. Along with this basic theory, then it arises terms for ferocious Dengue virus, for Indonesia, it dengue virus type 3, type 2 for Thailand, and type 4 for Mexico, Puerto Rico, and El Salvador. Dengue virus type 1 in Indonesia and Thailand

Based on this theory,fluid administration and strict observation is the main therapy for patients infected by dengue.

  1. Theory of virus virulence combined with the errors of the immune system response during the dengue virus enters the body

The body can overcome dengue infection, even if it’s considered the most virulent one, as long as no non-neutralizing antibodies is not formed. Non-neutralizing antibodies are immediately formed when the body is infected with dengue virus of a different serotype (Secondary Heterologous Infection Theory). So,this theory implies that there is no term for virulent or not virulent dengue virus. All dengue virus is virulent when it manages to enter the target cells, replicates and in creasesits strength in the target cell and then again into the blood. The Non-neutralizing antibody spurs viral entry into target cells.

So based on this theory, when someone is infected with the virus of a kind,even if it’s considered the most virulent one, either once or again and again, that person will never get infected by dengue fever (creating lifelong immunity against that virus/ forming lifelong neutralizing antibodies against the virus of a kind). However, the immunity against the virus also simultaneously triggers the formation of non-neutralizing antibodies when the body is possessed by dengue virus from another type. This theory is nowworld widely used.

Based on this theory,the main therapy for someone infected by dengue is the same as the theory of virus virulence that is fluid administration and close observation.

  1. The Errors of individual immune response are the main basis of dengue illness (Theory of Hypersensitivity type III, by T. Mudwal,

Mudwal proposes the theory on the following basis:

a. Not all people or races can be affected by dengue

Dengue fever mainly in South-East Asia and Western Pacific (although,nowadays, it has struck nearly 100 countries in the world and infected a variety of races). His observations for 20 years against dengue fever patients, showed that the Arab ethnic, Chinese, White, are very rarely affected by dengue, even during extraordinary cases. his observations while working at the Cipto Mangunkusumo Hospital (RSCM), Pacific Caltec, Riau and his present job,  are the basis for statement that in addition to the fact that there are on this earth as it is written in journals.

b. Poor immunity, low symptoms

If we used a benchmark that severe dengue is someone with a history of fever ≤ 7 days, presence of shock, shortness of breath, hepatosplenomegaly, severe bleeding /DIC and platelets ≤ 20.000/mm3, then roughly calculation there are more common in people with good nutrition, have a good immune system rather than a person with malnutrition or those with age> 60 years, which is roughly with a bad immune system. It is difficult for a HIV patient who clearly have a poor immunity to be infected by dengue. Dengue fever can only infect  HIV patient when CD4 count is above 200 cel/mm3. Or the immune system are still pretty good.

c. The spread of immune complex in body tissue has been proven

Ruangjirachuporn said that in almost 80% of 80 children suffering from dengue fever, immune complexes were found in many tissues of the body (31). Extensive tissue damage due to dengue such as endothelial damage, liver, kidney, bone marrow, pancreas, eyes, liver, nerves, brain, etc., has been reported once (32,33). Therefore,T.Mudwal said the destruction of the immune complex is the basis for the destruction of tissue (not by the virulence of the virus itself). So, on that basis, we cannot assert that the discovery of the virus in biopsy tissue of people who have died from dengue, suggesting that the ability of the virus that makes such damage.

 d. Theoretically, Viremia of dengue virus does not cause a cytokine storm

Viremia in dengue infection, occurrs on day 0 or day 1 of fever (NS-I antigen can be positive up to 100%). But, Viremia occurs in mild clinical symptoms only. A heavy clinical symptom occurs after the antibodies are formed (immune complex/complex antigen-antibody are formed). Theoretically, the body’s reaction to the virus, without being bound antibody is lighter than the virus that has bound the antibodies. It is because the reaction does not activate the complement C1, C2, C4 (34,35,36). So that the cytokine storm is not likely to happen if the virus does not bind to the antibodies. Cytokine storm occurs only when immune complex exists and it is large in number and spreads throughout the body. This reinforces point C above.

e. The presence of non-neutralizing antibodies and blue plasma lymphocytes is a clear symptom of hypersensitivity

Just like Halstead, the antibodies are not capable of forming neutralizing antibodies (non-neutralizing antibodies are formed). But T. Mudwaldoes not address it as non-neutralizing antibodies. T. Mudwal said it was imperfect Ig G / IgM (because immunologically, our immunoglobulin is IgA, IgE, IgD, IgM, IgG). The formation of imperfect Ig G / IgMis because of our body’s sensitivity against dengue antigen, so that young plasma cells are also to make antibodies. As a consequence, the Ig G / IgM were not perfectly formed, then the virus managed to escape from the bonds of Ig G / IgM and enter the target cells. So the imperfect Ig G / IgM does not occur to spur the virus to enter the target cells, as proposed by Halstead. The bond of antigens and antibodies still persist, but it is weak. The presence of this hypersensitivity confirmed with the discovery of the cells of blue plasma lymphocyte (LPB) in patients with dengue fever. Only dengue can cause the visibility of LPB cells in acute moment (<7 days of illness). In fact, there are studies that say, LPB is present in 98% of patients with dengue(37). For healthy people, LPB is not visible at all (zero%).

f. The evidence of the immunosuppressive doses of corticosteroids in patients with dengue fever

Another fact proving that the hypersensitivity is the cause of dengue is the successful administration of drugs to suppress hypersensitivity (corticosteroid in immunosuppressivedose) as it is carried by Waly et al (FK UI 1997) (12), Hendarsih et al (38) (FK UNPAD 2004 ), and Futrakul et al (Thailand 1987) (39).

The failure of steroid administration is due to its adminsitration after 4 days of illness or steroid administrationin weak dose (hydrocortisone) and not in a large dose (immunosuppressive). The administration of steroids during shock condition and of the hydrocortisone group does not give any effect (40,41,42,43). At DSS, fluid resuscitation is more urgent than steroid administration. The failure of high dose Corticosteroid application (2mg/Kg of Body Weight/d) in fever < 5 days (early stage of dengue infection), just like what had been done by Oxford Medical Faculty in Collaboration with Ho Chi Minh Medical Faculty Vietname (44), Caused

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 of Methylprednisolone in Dengue infection patients who were also accompanied by shock. 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. 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/ . 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 corticosteroid(46).

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. Data of time span of platelet to reach 100.000/mm3was 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. So 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. From all of the reason above 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.

Being afraid of the side effects of corticosteroids cannot be a reason to reject the theory of Hypersensitivity type III as the basis for pathogenesis and pathophysiology of Dengue. Based on the literature, large doses of corticosteroid administration are safe as long as no gastrointestinal bleeding (47). Nevertheless, acid pump inhibitors and anti-emesis may be considered in the administration of high doses of corticosteroids. T.Mudwal suggests to give minimally methyl prednisolone ≥1,5 mg / kg / day as immunosuppressivedose.

g. Positive Platlet Antibody is Found

The belief of the type III hypersensitivity theory as a basis pathophysiology and pathogenesis of DHF are getting stronger with the acquisition of a positive auto immune reaction against platelets (positive platelet antibody). This is possible because in humans the auto reactive lymphocytes that tend to hold an autoimmune reaction (30,31). T- Helper lymphocytes act as an autoreactive lymphocyte. There is no occurrence of autoimmune reactions in humans due to the imunoregulator homeostasis mechanism. Lymphocyte T suppressor will suppress auto reactive lymphocytes to not hold auto immune reaction. Immune complex attached to a particular cell or tissue is a strong stimulus for auto reactive lymphocytes to enter into the autoimmune reaction. The existence of patients who shows a sharp decline and then followed by a sharp increase of the number of platelets quickly show the existence of positive platelet antibodies and rapidly becomes negative again due to the body’s efforts in maintaining homeostasis imunoregulator (30,31). So is the failure of platelet transfusion in patients with DHF, mainly due to the positive antibody thrombocyte. What is feared is the presence of persistence antibody for life, thus causing prolonged thrombocytopenia.

Immune Complex deployment and its Destruction According T.Mudwal

Because the target cells of dengue virus are our soldier cells (monocytes, macrophages and Kupffer cells), the immune complexes formed, both between perfectIg G / IgM with the antigen and a small portion of imperfect Ig G / IgM with antigen, failed to be destroyed by our soldier cells so that the it spread throughout the body (the capillary walls, thrombocytes, bone marrow, liver, spleen, brain, liver, eyes, and so on). The return of our soldier cells in normal function or the arrival of the soldiers from their headquarters in normal bone marrow causes the destruction of the immune complexes. Dengue severity depends on the location and the number of immune complexes that are destroyed. The elaboration of points at of, stated above, T.Mudwal said that the individual hypersensitivity is the cause of dengue. As the devastation is caused by the formation, dissemination and destruction of immune complex, the hypersensitivity reaction that occurs is a type III hypersensitivity reaction or reaction complex immune. On that basis viremia, or the virus virulence, is not the thing to be afraid of, but the spread of immune complexes throughout the body tissueis what should really be feared (rapid spread of immune complexes are more dangerous than dengue virus virulence).

The presence of many immune complexes is able trigger chaos in our immune system. It may happen that the cells of the body that should not be destroyed, will also be destroyed. At the highest level, this autoimmune reaction can occur in many organs or SLE occurs. If the self-tolerance mechanisms can control this, the autoimmune reaction is completed or the person is becoming normal. But if not, then autoimmune reactions may occur lifetime as ITP, SLE, chronic hepatitis autoimmune, rheumatoidarthritis, etc. (34,35,36). The knowledge of this theory would answer that the cause Evan syndrome or HELLP syndrome may also be of dengue virus infection as well. If to mention the syndrome, it is likely like cases occurred in the United States, Europe, or Australia. But for dengue hyper endemic country like Indonesia, it is very possible all disruption is caused by dengue infection. Another thing to keep in mind is that even the recovery of damaged organs after being infected may occur imperfectly. Aplastic anemia, stroke, visual impairment due to retinal damage, etc., may occur.

Based on the above description,severe dengue reaction will occur if there are many incoming antigens, many imperfect antibodies, many invalid dengue-infected macrophages, as well as the location and the number of immune complexes which are destroyed. Virus infection in small number or virus of a kind usually does not cause the reactionsof HypersensitivityType III. Or it could also give a reaction but usually mild (fever, headache, muscle pains, vision problems, etc.). However, it could also provide a severe reaction as described above, or there are many antigens or it is super antigen in nature. Or the people are too sensitive that they produce many IgM or there is genetic mutations either from the virus or the individuals. There are some differences between the theory of T. Mudwal and Haslstead. when Halstead said that one kind of viral infection for the first time will result in lifelong immunity then T. Mudwal say no. There is no lifelong immunity in people hypersensitive. The reaction depends on what has been described above. This was the true foundation of T. Mudwal to say why the primary infection may provide clinical symptoms. One thing that is difficult to answer by Halstead so that he proposes antibody dependent enhancement theory to explain why the primary infection can cause clinical symptoms. According to this theory is the primary infection occurs to someone because he gets the non-neutralizing antibodies from his mother. So if there is an infection of dengue virus of a different type as what was on his mother, then he can be infected by dengue. Meanwhile, according to T. Mudwal, children of 0-4 months are going to get the antibodies from the mother in accordance with what virus has infected the mother. But after that because of his genetic itself, then it forms sensitive IgM. After six months, the sensitive IgG is dormed. Thus antibodies of dengue virus received from the child’s mother, only last for about 6-9 months. For then sick of the child for dengue IgM and IgGis due to the sensitivity of the children themselves. The sensitivity is genetic.

The second infection of dengue virus occurred in small quantities and with the same virus, it may usually not trigger a reaction, but there may not trigger immunity lifelong. However in case of virus infection occur for second time in a different type of virus, although in small amount, it is more dangerous than the same virus infection in large numbers (as Theory Halstead). This is because different viruses will provide stronger stimulus to the immune response errors than the same virus. But if the virus is infected again by the third or fourth (other dengue virus) then the reaction will happen lighter because some of the properties of the virus has been recognized by our immune system (because both are dengue viruses).

Initially, dengue virus did not infect humans but only monkeys or apes (48). If today, a lot of dengue virus causing illness in humans in this world, it is because the human hypersensitivity or the genetic mutation of the virus or the genetic mutation of the human himself or the movement of the people (transportation, urbanization, etc.)

D. Scheme

1. The scheme of the theory of Hipersensitifity Tipe III

 The scheme of the theory of Hipersensitifity Tipe III

 2. The Scheme of Plasma Leakage and Shock (Hypersensitivity type II theory)

Plasma leakage and shock

3. Thrombocytopenia Pathogenesis (Hypersensitifity type III theory)

The Scheme of Plasma Leakage and Shock


Pathogenesis and pathophysiology is the basis of doctor’s treatment. That is what distinguishes between doctors and non-doctors in providing treatment. It is not a matter of patient cured or not, which makes a person awarded the title of doctor.

There has 3 main basic theories discussed and explained. The theory of pathogenesis and pathophysiology of dengue infection. The virus virulence theory, the theory of secondary heterologous infection and antibody dependent enhancement by Halstead and Hypersensitivity Type III theory by T.Mudwal. It depends on us intellectuals to carefully select it. True intellectual is never afraid of anything, as long as it is not against his conscience.

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