Again, Let’s Discuss about DHF Pathogenesis and Pathophysiology (revision)

(The Effect of Rapid Spread of Immune Complexes Vs The Effect of Dengue Virus)


Internal Department Waled Hospital Cirebon, West Java, Indonesia

A. Introduction and Epidemiologist

The incidence of dengue has grown dramatically around the world in recent decades. When firstly recognized in 1950’s dengue epidemic was found in the Philippines and Thailand. Today DHF affects in most Asian countries and the other region. 2.5 billion people/ two fifth of the world’s population or more than 100 countries in the world may be at risk from dengue (World Potential Dengue Infected /WPDI) (1,2). WHO currently estimates that there may be 50 million (2% WPDI) dengue infections worldwide every year/ World Dengue Infection (WDI) (1). And estimated 500.000 people with DHF requires hospitalization every year (World DHF Hospitalization (WDHI)/2% from WDI) (1). Unfortunately the 2009 WHO report, does not mention the number of mortality due to DHF worldwide. WHO only mention the mortality is below 1% or more than 20% depending on the treatment. But based on existing library mortality due to DHF in the world is between 21000-30000 people (2,3,4,5,6,7). Or we can say ±0.05% of the World Dengue Infection (WDI). Or as a benchmark, the number of patients who were hospitalized (WDHI) then the mortality rate = 5% of WDHI.

The problem is whether the figures reported by WHO was quite fair or not. Maybe those numbers could be much higher. For instance the number of DHF patients who were hospitalized or WDHI only amounted to 2% of WDI. This could mean tens of millions of people suffer only mild DHF eg bone pain, chills, nausea stomach are cured by simply taking drugs alone. Or a mild DHF that has been proven according to WHO 1997 criteria but according to the pateint’s doctor he/she does not need to be sent to the hospital. In fact worsening in patients like this can happen very quickly. Or the doctor does not diagnose someone as DHF patients because the thrombocyte does not yet fell below 100.000/m3 (according to WHO criteria 1997). Or doctors in private practice in endemic areas do not make a tourniquet test in patients with fever <7 days, so there is no follow-up to the direction of the DHF. Whereas any fever <7 day should have troniquet test mainly in endemic areas. Or other causes of low WDHI could be refused by DHF patient because there is no money to pay for hospital care (by chance hyperendemic region are not rich countries). Or it could be this low because the WDHI recording and reporting system in hospitals is poor. This often occurs in patients who were treated in hospital, especialy the elderly (> 60 years), who entered not because of fever but because of gastrointestinal complaints, bone pain, headache which turned on while being treated there was continuous platelet decline although later became normal again after discharging from the hospital but was not diagnosed as dengue by doctors (even with the WHO criteria in 2009 these patients cannot be diagnosed as DHF). With reasons like that Jacqeuline L Deen, et al, doubts the numbers of dengue that were reported in hospitals (8). And for reasons like that, a country does not need to be proud of a low mortality rate. Because mortality was ascertained on the basis of the number of dengue deaths that were treated in hospital. With the number of low dengue patients admitted, automatically lowers the number of deaths.

Indonesia in 2008 for example, reported death rates (CFR) 0.73 based on the number of patients with DHF (101,656) and only 737 people died. Clearlythe 101,656 DHF patients reported are hospitalized dengue patients as well as the number of 737 patients who died (9). When calculated with the WHO estimate of logic (which is full of weaknesses such as the criticism above) the number of Indonesian Dengue Infection (IDI) is 2% x Indonesian Potential Dengue Infected (IPDI) = 2% x 240 million = 4.8 million people. Of the 4.8 million people, only 101,656 people were reported as DHF and most likely thefigures of al DHF patients were hospitalized / Indonesia Dengue Hospitalization (IDHI) (only 2.1% of IDI / identical with the WHO estimates WDHI-2% of the WDI). So nearly 98% have unclear fate as described in the criticism WHO WDHI figures. Thus the death rate below 1% does not illustrate the success of treatment and eradication of dengue. Things like this should be realized by other hyperendemic countries such as Thailand (CFR = 0.2%), Myanmar (CFR = 0.7%), East Timor (CFR = 0.56%), Philippines (CFR = 1.5 %), Vietnam (CFR = 0.05%), Malaysia (CFR = 0.07%) (9,10). And the most interesting report was from the State of Bangladesh which reported no death of 1181 found DHF patients (CFR = 0%) (9).

Based on the analysis of high possibility of mortality and morbidity rates and an even more potential infection as described above, scientists – inhyperendemic countries (Indonesia, Malaysia, Vietnam, Thailand, Myanmar, Cambodia, Philippines, Singapore, India, Pakistan, Sri Lanka , Bangladesh)must discuss the pathogenesis and pathophysiology of DHF, which is still considered controversial (1). Those countries were estimated as 70 % of WDPI/1,8 billion people (1). The importance of reviewing the pathophysiology and pathogenesis of DHF will grow well when we predict that the occurrence of lifetime thrombocytopenia (ITP) can be caused by dengue. Because the disease that is most asossiated with thrombocytopenia in these areas of hyperendemic is dengue. VD Patil and Dinesh reported the occurrence of persistent thrombocytopenia in patients with DHF (11). Likewise with the Uth Karsh Kohli et al (12). On the other hand TM Waly et al have proved the existence of platelet antibodies against dengue patients in 1997 (13). Rahman et al proved again the existence of antibodies in platelets in 2009 (14,15). Even sometimes in treating DHF patients, we found the fragment of anemia aplastic just as reported by Albuquerque et al (16). Based on these facts, the posibillity of treatment of DHF is not just longer to heal but also prevent the patient from experiencing persistent thrombocytopenia or even from the possibility anemia plastic persistent.

B. Pathogenesis and Pathophysiological Conclusions from the Journals of Dengue (17,18,19,20,21,22,23,24,25)

The existence of viremia, is the basis of the occurrence of dengue disease. Viremia will occur due to a storm of cytokines, apoptosis, complement activity all of which will result in tissue damage, bleeding, and leakage of plasma. The ability of the virus itself (depending on its strain) to perform cell destruction and the destruction of immune complex disease also increase the severity of the illness. Viremia will occur when the body does not succeed to make specific antibodies or neutralizing antibodies. Moreover a person can become immune for life, if it has a specific antibody against a strain of dengue virus. But it does not affect specific antibody against another strain of dengue virus. Viral replication in target cells (monocytes, macrophages) will occur when non-neutralizing antibodies are formed. Recurrent viral infections of different types will further facilitate the occurrence of non-neutrilizing antibody. Nevertheless a single first time viral infection (without recurrent infection) can make the occurrence of viremia possible when infected children which been having non-neutralizing antibodies from the mother. Individual nutrition’s status itself is also taking part in DHF severity. That’s the conclusion that we read from the journals of the pathogenesis and pathophysiology of DHF.

From the description above it shows that the basic pathogenesis and pathophysiology of DHF is the occurrence of viremia due to the non-neutralizing antibodies. The problem is what is the meaning of viremia?

Why does virus more easily found when patient only have a light symptom such as fever and have no complication to other organ or having shock (day zero or day 1 of fever). Is it true that success in isolating the virus in biopsy tissues of patients who die due to dengue fever indicate that the virus was indeed capable of damaging tissues? Why are there different individual reaction/ different races against one type of virus? Which is more influential: thevirus type or the frequency of mosquito bites? Why do people with low immunity, such as the elderly (> 60 years) or children with severe malnutrition reacted lighter than those with better immunity or an obese child. Why do people with a particular race are not exposed to dengue, although living in the area of hyperendemic DHF (my experience during 13 years of observing the DHF, has never come across Chinese or the Arabs or the Europeans ethnicorigin eventhough there were many Indonesian who were treated for dengue fever in the area like where I work now or when I worked at Caltex Pacific Indonesia Riau). What exactly is meant by non-neutralizing antibodies and neutralizing antibodies? Patients with free symptoms and will be discharge from the hospital then will have a sudden decreased and rise of platelet count for a long period of time, why?


In general if a virus goes into our blood, automaticaly the non-specific and specific immune system will react. Reacting with the aim of eradicating the virusbefore it enters the target cells. The failure in blocking virus movement toward target cells will cause the virus to spread widely in the blood (viremia) andsucced in going into the target cells for replication. The virus in the blood will be even more if the virus that has been replicated in target cells goes back into the blood. Interferon, Killer cells, Natural killer cells and antibodies (which try to catch the virus and form an immune complex for more easily phagocytosis by macrophages) are our body’s defense system to prevent the virus from going into the target cells. It is interesting to know that based on the theory adopted today, that the antibodies formed can be neutralizing antibodies that can neutralize the virus movement or non-neutralizing antibodies which cannot neutralize the virus movement but spur the virus to be able to enter into target cells. The immunology of antibodies against virus or other foreign objects cannot be formed if the amount if the virus or alergen is too little or have been destroyed by non-specific immune system or in patients with low immunity / less nutrition (so as not to form antibodies).
When the body has made antibodies then it is definitely sure they are specific antibodies that function to neutralize the virus so they can easily function inthe process of phagocytosis by macrophages. The number of viruses or repeated exposure to alergens will further stimulate the body to create antibodies against the virus or alergen. So there is no such term as non-neutralizing antibodies. Antibodies that exist in our body are IgA, IgG, IgM, IgE, IgD and immunoglobulin super family, which all serve to increase the strength of our defense system. Defense system can be harmful to the body, if there is an overreaction to the virus or a foreign object (hypersensitivity reaction). Excessive body reaction as a reaction to the formation of immune complexes (antigen-antibody complex) cannot be said that the body had been wrong to form antibodies (non-neutralizing antibody formation), an antibody that would spur the virus to enter the target cells to replicate. In such circumstances remain the IgG antibodies produced / IgM which are trying to prevent the movement of dengue viruses by creating an immune complex system which is further phagocyted by macrophages. Because the macrophages system has been infected, it creates a weakness in the macrophage system which makes the immune complex dificult to be phagocyted and thus the imune complex spreads to the whole body tissues. And this high quantity of immune complex will spread and cause a storm of cytokines, complement activation, apoptosis, especialy macrophage system to function again (re-emergence of healthy macrophage system).

Despite severe clinical symptoms so new will happen if the virus strain that infects the return derived from different strains. Antibody someone who had infected a strain of dengue virus, it can recognize other strains of dengue virus (cross reaction), but unable to make specific antibodies (perfect) to bind the other strains of the virus (there is no cross-protective against other strains) (26,27,28). What happens is that there is perfect or antibodies specific fordengue virus that infects the first time (these antibodies do not form immune complex with another viral strain). The occurrence of difference in some epitope / determinant of the virus causing the IgG antibodies formed an imperfect / non-specific. So, in one person there may be found the perfect/specific antibodies and imperfect antibodies/non specific, as evidenced by Russell (the existence of both antibody-neutralizing and non-neutralizing to someone)(29). However, imperfect IgG, still form the immune complex with other viruses (although this bond is not perfect) and remains difficult for virus movement (so not trigger the virus to enter the target cells). With a defect in macrophage systems (the greater this defect because the virus easily break away from its ties with the imperfect IgG), the immune complex that spreads throughout the body then will be destroyed after macrophage system recovers (eg the emergence of healthy macrophages from bone marrow).

Based on the fact that most new people suffer from dengue fever after repeated infection from other types of dengue virus it is clear that the non neutralizing antibodies are identical to the IgG that is not perfect (which occurs due to secondary infection from a different viral strain). While the neutralizing IgG antibodies (which occurs due to primary infection or secondary infection from the same virus) is indentical to the perfect IgG. This understanding accords with what was said by Guzman, that the neutralizing antibody examination is more precise if used for identification of primary viruses (25).

Based on belief like this, we reject theory which states that sickness in baby <4 months old is because of non-neutralizing antibody that is inheritef from mother’s side. Non-neutralizing antibody in individual will only last temporarily when the person is sick. The formation of non-neutralizing antibody or imperfect immunoglobulin because the person is too sensitive so the immature plasma cell will form weak antibody and this in turn will cause weak bond between antigen and antibody complex.

Occurrence of immature plasma cell is proven by findings of blue lymphocyte plasma in patients with DHF. Because of that, this non-neutralizing antibody or imperfect immunoglobulin will disappear after the sickness is over and the one that’s left is only neutralizing antibody. This neutralizing antibody is the one which is inherited by baby <4 months old. So, antibody dependent enhancement theory which states that sickness in baby <4months old because of  that non-neutralizing antibody can’t be kept.

However we must admit that neutralizing antibody from mother can also ignite DHF reaction in baby <4months old. But this kind of thing is rarery happens. even if it happens it will only gives light clinical symptoms. The reason of this is in baby less than 4 months old have immunoglobulin from mother that lives in endemic area usually already contain neutralizing antibody from several kinds of other Dengue virus. So that reactions happen in baby <4months old are usually light or the occurrence is very rare. IgM will only be made if the baby is already 4 months old and IgG after the beby is 6 months old. Conclusion from above is if the baby is less than 4 months or more than 4 monts old is having DHF, still the basic of that sickness is hypersensitivity type III as already stated above. Sensitivity is inherited genetic condition. Other than information stated above, antibody dependent enhancement theory can also be rejected simply because that theory can’t describe why a person whom his mother has never had DHF infection in her whole life (for example, white people who live in Dengue hyper endemic area such as South East Asia). Surprisingly her child can still be infected by Dengue. Is hypersensitivity type III theory can answer this problem? Other problem is if Hypersensitivity type III theory is the basic of pathogenesis and pathophysiology of DHF, why we rarely see people hospitalized dengue infection in 2nd, 3rd or 4th time ?

Primary infection can make hypersensitivity type III (spread immune complexes to the whole body), if the antigen in large amounts or had to be superantigen. Primary infection usualy gives light clinical symptoms compared to secondary infection. Because the numbers of IgM immune complex which are spread are much less compare than if there is immune complex with IgG. This case based on fact that IgG is the greatest amount of immunoglobulin in blood (75% of total immunoglobulin). Besides the changes of antigen, the genetic changes of the individual who is suffering from DHFcan cause a primary infection also. Whereas lack of DHF patients hospitalized more than once, because of our antibody system has been much faster toform antibodies and catch the virus, before entering into the target cells. Or because many strains of the virus, are known by the antibodies system of that person. For example at the time of first infection by dengue virus 3, the person is not suffering from DHF, just suffered DHF after infection with dengue virus 4. So the person will become infected again with dengue virus when he is infected by DHF virus 1 and 2. Although the clinical symptoms that occur will be much lighter, due to the large amount of epitope or the properties of dengue viruses 1 and 2 are recognized by our antibody system, although not entirely (the person is not hospitalized / iceberg phenomenon/light clinical symptoms). From the description above it is clear to us that non-neutralizing antibodies are mainly IgG but also IgM, but this antibody are only last temporarily, while the patient is having dengue attack or several days after attack. Where as neutralizing antibodies is IgM and IgG but finnaly only IgG remains and this is permanent.

Of the many cases of severe DHF after infection recurrent / repeatedly bitten by the mosquito Aedes aegypti (secondary infection) and from the discovery of DHF complication in all body tissues (endothelium, liver, kidney, pancreas, bone marrow, eyes, heart, nerves, platelets, brain etc.) (33,34), that occur in a very quick tempo then type III hypersensitivity reactions (immune complex reaction) is a more precise basis of pathogenesis and pathophysiology of DHF. This is the basis of Hurricane cytokines, apoptosis, plasma leakage that causes bleeding tissue damage and shock in DHF. The occurrence of immune complex which circulating in DHF patient blood, can be proven by Ruangjirachuporn et al in 80% of patient from 80 children that suffering DHF disease (22). 20% amount that can’t be proven is patients who are having primary infection and the patient itself come before they suffering the 5th day of their fever (IgM still hasn’t been formed/immune complex not yet happening).

Why not viremia (virus without antibodies attachment) which stimulate the cytokine storm? Dengue virus which are found in huge quantities in the blood without immunoglobulin attachment (not forming immune complex) will only stimulate a weak complement activation (lectin route / alternate route) and will not stimulate the release of the cytokine storm. The activation of complement is formed through the lectin / alternative, not through C1, C2 and C4 (30,31). Where we know C1 carry’s the function to increase the permeability of the capillary, C2 for activating Kinin, while C4 function as an opsonin (32). With no active C1, C2 and C4, few of our soldiers cells (macrophages, lymphocytes, granular cells, endothelial cells), will not manage to go close and destroy the dengue virus, thus cytokines that are released are few or in other words no cytokine storm. While the virus is in the target cells can only be destroyed by cytotoxic lymphocyte cells with ADCC mechanism (even in this situation cytokine storm does not occur because the complement activity did not go via C1, C2 and C4), with this reason, it is clear to us that the virus without attached antibodies will not produce Cytokine storm, or just give only mild symptoms of the virus. So fever in the state of viremia may not exist or only mild heat alone due to low cytokine production, resulting in low arachidonic acid releasefrom hypothalamic. With reasons like that, we now know why viremia occurrs in day zero or day 1 in secondary infections, where immunoglobulin / immune complex has not happened / just a little. This thing is based on NS1 antigen examination that showing the result as 100% positive at the zero day of fever in DHF patients (without considering if it is the primary/secondary infection) (4). But if it is tested on secondary infection only, the positivity is only 68,8% (6). The result of this significant reduction is because patients come to the doctor after the 1st day of fever (almost no free virus left/almost al virus already attached by immune complexes). With that kind of reason it seems logic that primary infection gives a very high positivity 97,4%. Kumarasamy V et al, doing this research on 224 people that having fever problem and it is positively proven caused by DHF (6). What happened with virus isolation? Sumarmo found the faster patient come to hospital to do virus islotaion (≤3 days), so the success rate will be higher. Because at that time antibodies that formed in the body still low (35). For this reason also, it is more obvious to us that a great many clinical symptoms does not occur at the time of viremia but at the time of destructions of imune complexes when the macrophages system has returned healthy. Similarly, for reasons like this we can understand why the primary infection gives lighter clinical features compared with secondary infection. Halstead found that there is no primary infection on Thailand children that suffering DHF faling down to shock (17).

What about the malignancy of a virus? The destruction of tissues is not because the activation of complement / cytokine storm of immune complex that spreads, but because the virus is malignant and can damage the tissue, platelets, endothelial cells programmed for apoptosis and so on.
Viruses which are capable of such and in a large number (viremia) provide clinical symptoms of becoming severe DHF. In reality, Dengue viruses which are capable of destroying tissues are unknown. In Indonesia Dengue virus which is considered to be malignant is Dengue-3 virus, dengue-2 virus in Thailand, in the Mexico, Puerto Rico, El Savador dengue-4 virus (3). It often happens to people with low immunity, such as the elderly (> 60 years) and children who are malnourished that provide mild clinical symptoms, although the infection by dengue virus is considered to be malignant. Dengue virus infection which is considered to be malignant but one bite only (primary infection +) gives a lighter clinical symptoms compared to Dengue infection whichis not considered malignant with a few more bites (secondary infection +). People from certain races do not suffer from dengue fever, despite living in endemic areas during outbreaks. Thus the discovery of dengue virus in the body tissues in biopsies of patients who died of dengue, it’s not certain that the virus is the cause of tissues damage. Because, as being told back then, virus that’s not attached by immune complex will only give light clinical symptoms. With already being proven that immune complexes which circulating in blood of DHF patient, so immune complex is also located on those tissues (22). The destruction of immune complex itself is the factor that causing tissue from being damaging (not because of malignancy virus).

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.

If indeed type- III hypersensitivity is the basis of pathogenesis and pathophysiology of DHF, why did many corticosteroids treatment failed? Why are there a lot of white people and the rest of the world affected by DHF when logicaly they are not sensitive? The failure of corticosteroids is because most researchon corticosteroid is given in a late or after fever of more than 4 days. The steroids which were given were not powerful enough such as methylprednisolone and the dosage is not immunosuppressive. Even studies that gave the corticosteroids in patients who had shock used steroid such as hydrocortisone (36,37,38,39). In DSS, fluid resustitation is more beneficial than corticosteroids. However there is one study (Futrakul et al) that gives methylprednisolone dose of 30 mg / kg 2 times daily with good results (40). Waly et al (1997) found that giving corticosteroids after day -4 fever did not give significant results in preventing the decrease in platelet counts. Hendarsih (2004) also got the same result as Waly et al (41). But if we being given Corticosteroids before 5th the result has significant(13,41). Corticosteroids that are given in patients with dengue fever after 4 days of fever is given only when there is suspicion for the presence of positive antibody platelet a presence of a sharp decline the number of platelet, in convalescence stadium of DHF (>5 day ill). The success of immunosuppressive doses of corticosteroids in DHF with fever before 5 days, further down the significance that the Dengue virus which has the ability to destroy tissue cells (13,41). It also proves that the spread and destruction of immune complexes were the cause severe clinical symptoms in DHF patients. Immunosuppressive doses of steroids prevent the formation, dissemination and destruction of immune complex is occurring on a massive scale.

T Mudwal suggests giving methylprednisolone ≥ 1.5 mg / kg / day as the dose of immunosuppressive (42). The fear of side effects in corticosteroid cannot be a reason to reject type-III hypersensitivity theory as the basis of pathogenesis and pathophysiology of DHF. There should be a way to find a drug that can be immunosuppressive and safe. Giving high doses of corticosteroid within a maximum of 1 week, say the literature, does not provide any side effects as long as there is no gastrointestinal bleeding (43). Acid pump inhibitors and anti-emesis may be considered in the delivery of high doses corticosteroid.

While the spread of dengue worldwide or the start infection in certain races by dengue, other than due to the spread of the mosquito Aedes aegypti, the spread of people from hyperendemic area to another part of the world that are not endemic area is also caused by genetic changes of the dengue virus or genetic changes of individual, so it is more susceptible to dengue.

D. SCHEME pathogenesis of DHF, the pathogenesis of thrombocytopenia and the pathogenesis of plasma leakage / Shock

Pathogenesis of DHF (Hypersensitivity type III theory)

Plasma Leakage and Shock (Hypersensitivity type III theory)

Thrombocytopenia Pathogenesis (Hypersensitivity type III theory)



It has been discussed that the destruction of immune complex which rapidly spread throughout the body / tissues plays a bigger role than the effects of viremia and its malignancy. This means the type- III hypersensitivity should be considered as the basis for pathogenesis and pathophysiology of DHF. It is expected that anything which has not been clear about the DHF can be clear. So there should no longer be among us who will say that DHF is a cursefrom God or devil disease (7).

In addition to the eradication of the vector mosquito Aedes aegypti, a more serious attention should be given early in patients with DHF. It is necessary to take the decision to give high dose steroids. Thus the expected deaths from dengue, both treated in hospital or outside hospital will be lower, as well as the length of the stay in hospital. Cases of prolonged thrombocytopenia even cases of aplastic anemia can be decreased.

Thanks for his discussion :

Primal Sudjana MD, (Head of Internal Department Padjadjaran University) Bandung, West Java, Indonesia.

Hadi Yusuf MD, (Staff of Tropical Disease Division, Internal Department Padjadjaran University) Bandung, West Java, Indonesia.

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