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DISCUSSION OF CASES OF DEATH DENGUE HEMORRHAGIC FEVER PATIENTS

T. MUDWAL

Preliminary

Dengue infection is a science that should always be discussed continuously by Indonesian doctors, particularly specialists in internal medicine and especially specialists in internal medicine consultant of infectious tropical diseases. Indonesia potentially is the largest country in the world who can have dengue infection. On the other hand, the therapy given that largely determines recovery or death or a lifetime sequelle (ITP, aplastic anemia, cerebral hemorrhagic stroke ec) depends on the pathogenesis and pathophysiology believed by the doctor are still controversial. Percentage of deaths or sequelle, no matter how small or big remains huge (reaching thousands of people) because dengue infection affectsmillions of people.

Based on how the WHO estimates, 240 million people are potentially exposed to dengue infection in Indonesia (Indonesia Potential Dengue Infected / IDPI) while the estimated annual dengue infection is at least 4.8 million Indonesian (Indonesia Dengue Infection / IDI = 2% IDPI). The  WHO also predicts the number of deaths both in-patient and out-patient ranges from 1-5% of the IDI (4800-24000 people annually). On the other hand, if we dare to say that all patients who suffersfrom lifetime thrombocytopenia (chronic ITP) is caused by dengue infection (due to illness that is most likely to cause thrombocytopenia) then 8435 Indonesian will suffer from ITP, both of which occurred during the childhood or as adults. That number, exclude the number of Indonesian who suffer from the reduction of all blood cell types of either Hb, leucocytes, and platelets (aplastic anemia), which is expected also mainly caused by dengue infection. I proved in 1997, that in DHF patients that come in the hospital with fever before the fifth day, then the hipocelluler state of the bone marrow will occur in 63.6% of patients. And when it comes on a day to 5 s / d day 7, then the bone marrow hipocellularity will occur in 11.8% of patients. If the average is taken then 37.7% of DHF patients will experience hipocelluler state of the bone marrow. Or when multiplied by the number of Indonesian might be infected by dengue infection are 37.7% x4.800.000 = 1.8096 million people. And if just one of 1000 patients who underwent hipocellularity becomes persistent (lifetime of aplastic anemia) then 1810 Indonesianwill incur persistent aplastic anemia each year.

With the continued increase in population, the difficulty of making a good ecosystem, the increase of good transportation system, the ability of dengue virus to alter its genetic material in order to infect humans or otherwise the changing of genetic structure in humans so that it is more succeptableto dengue virus, the possibility of an dengue infection will continue to threaten the Indonesia nation forever.

With the basics in above, I think it is very necessary for all of us to discuss the problem of dengue infection, moreover, deaths thought to be caused by dengue hemorrhagic fever. Death which I think should not happen to a young woman who was admitted to the hospital because of 1 day fever the first (private hospital) and who doesn’t have any other significant clinical symptoms.

Discussion of this paper is apreciated to reach a higher understanding of dengue infection problems and to help the beloved people of Indonesia.

 

 

case

Taken from the national congress abstract PETRI Semarang, 8-10 July 2011

Dengue Shock Syndrome

Case Report

Mirna N Praptini*,Soroy Lardo**, Leonard Nainggolan***

* Department of Internal Medicine Dr Cipto Mangunkusumo Teaching Hospital

Indonesian University School Medicine Jakarta

** Division of Tropical Medicine and Infectious Diseases Department of Internal

Medicine Gatot Soebroto Central Army Hospital

*** Division of Tropical Medicine and Infectious Diseases Department of Internal

Medicine Dr Cipto Mangunkusumo Teaching Hospital-Indonesian University School

Medicine Jakarta

Abstract

Introduction. Increasing morbidity with higher incidence of dengue hemorrhagic fever.

Method. Post hoc analysis in 2 dengue Shock Syndrome (DSS) cases which hospitalized about the same time at Gatot Subroto Central Army Hospital

Result. Hemoconcentrated, at the fifth day of fever, a 22 year-old female and 25 year-old male were diagnosis with DSS. Both patients were intensively monitored. Both overweight, secondary infection, hypoalbuminemia, no hypocholesterolemia, no hypertiglyceride, SGOT/SGPT not more than 3 times normal value in admissions. Both got antibiotic, colloid and crystalloid from the beginning of hospitalization. First patient died with multi organ failure while the second patient survived.

Discussion. The first patient consciousness dropped to soporous, along with pulmonal edema and pleural effusion, breathing failure, DIC, Hb drop to 6 g/dl, acute hepatic failure signed by SGOT increase to 4040, SGPT 920 without icteric and still stable blood pressure. Her thrombocyte goes better but clinically became worst, at 12thday fever she passed away in ICU. The other patient was hospitalized with black diarrhea and good hemodynamic, respiration rate of 28x/min, pulmonary edema and massive pleural effusion. The shock syndrome was due to plasma leak caused by immunology process. The first patient was though to not having adequate therapy from her previous hospital while the second patient was late to diagnose and treat.

Conclusion & Suggestion. Caused by immunological process, plasma leak is specific in DHF and DSS patients. Hypoalbuminemia, high Body Mass Index, and age, was said to be a predictor of DHF while SGOT, cholesterol and triglyceride were not. The grave prognosis DSS could not be predicted while hemorrhage or organ failure had not happened. Diagnosis and management according to WHO guidelines should be carefully applied.

Keywords: Dengue Shock Syndrome (DSS).

Taken from e-mail: t.mudwal@yahoo.co.id

Case Illustration

Two cases of dengue shock syndrome at almost the same entry in the Gatot Subroto Army Hospital and treated in the Intermediate Ward and the ICU. The first case is a woman, Ms.Y, 22 years, with a high fever of  5 days before hospital admission (SMRS). The characteristics of viral infection are sudden high fever that is does not decrease with treatment accompanied by headache and bone pain. Patients previously treated in a private hospitals for 5 days and then moved to the Gatot Subroto Army Hospital in the 5 th day since the onset of illness due to insurance problems. During the treatment in the private hospital, the patient’s platelets dropped to just under 100 000 2x without hemoconcentration and clinically significant symptoms, but the patient entered the army hospital in a state of shock, blood pressure 80/60 mmHg and pulse 112x/menit, weak, breathing 24x/menit, temperature of 36 ° C and the first day of menstruation so that the patient was transferred to a ward with a more stringent monitoring, in which the peripheral blood of the patient whenadmitted to Army Hospital was Hb 14.7 g/ dl, Ht 44% (hemoconcentration), 2700 Leukocytes and Platelets 33,000.

Antibodies anti-dengue IgM and IgG was examined on day 5 of fever the result is negative and positive consecutively. Platelets of patient achieving the lowest number 12,000 /mm3 and rise on the fourth day of treatment (day-9). The patients experienced a decrease in consciousness until sopor, along with edema and pleural effusion, respiratory failure, DIC, Hb decreased to 6 g / dl, and acute liver failure which is characterized by an increase until SGOT 4040, SGPT 920 with no clinical jaundice while the blood pressure stabilized at 100/60 mmHg. Patients scheduled for an MRI head with suspected intracranial hemorrhage, and mounted CVP, PRC transfusion, FFP and cryoprecipitate, the administerof antibiotic Meropenem and heparin was given alongside to his DHF therapy, in addition to neurological treatment in the form of mannitol 4x125cc  and citicholin 2×500 mg, whereas pulmonary was not given any therapy . On day 4-of treatment (day-9) platelets of patients actually have started to rise but clinical deterioration until finally on the 7th day of hospitalization (day 12) patients died in the ICU.

The second case is male, Mr. E, 25 years old, with complaints of fever and diarrhea since 4 days SMRS (coincide), with characteristics typical of viral fever that is accompanied by a sudden black stool diarrhea. Since the patient’s stool was black and the patients admittsthe diarrhea amount to 1 cup every 10 minutes with a blood pressure of 120/90 mmHg but rapid pulse 108x/menit, breathing 28x/menit, temperature afebrile, and there is pulmonary edema and massive pleural effusion (decreased vesicular, crackles and wheezing in both lung fields) at admission (day 5), with peripheral blood Hb 14.5 g / dl, Ht 42%, leucocytes 12 100, and platelets 9000, patients admitted to the Intermediate Ward with a diagnosis of DHF grade III with presyok and suspected secondary bacterial infection. Patients was given RL 40 drop/minute, HAES 10 drop/minute, Ceftriaxon 1 x 3 grams and Ranitidine, as well as Ventolin, furosemide, and plans to finish installing CVP although not installed because of clinical improvement. During the treatment the patient’s lowest platelet count was 6,000 on day 5 and on day 8 had increased to 199,000 but the Hb dropped to 9 g / dl and leukocytosis which has now decreased to 7100 but the results of blood gas analysis (BGA) has not been good (pO 2 below 60 mmHg with the mask 8 l / min) on day five of treatment (day 8) despite improved clinical status. On the first day of hospitalization the patient experienced abdominal pain and found the possibility of intra-abdominal hemorrhage on ultrasound (not aspirated) but on day 8 had improved although Hb is not stable yet. The Patientwas given furosemide for his pulmonary edema. On day 13 the patient was transferred to a regular hospital room for improvement clinical status and BGA. Abdominal ultrasound and 3 position abdominal rontgent of the patient indicate the presence of ascites and until the 17 th day of platelets and leukocytes of patients continue to rise until the number 16 200 and 774 000 consecutively, henceforth the patient cannot be discharged.

The similarity of these patients are young, have a pleural effusion due to plasma leakage (data from existing photos day 5 and day-to-4), overweight BMI (24.8 and 24.2 kg/m2), hypoalbuminemia, and no hypercholesterolemia and no hypertrigliseridemia, SGOT / SGPT had not initially increased by more than 3x the normal value, whereas other predictors of DHF such as LDH and CK are not examined. Another resemblancewas the early administration of antibiotics and colloids in addition to crystalloid administration to day 7. While differences in treatment was due to the patients sex, and furosemide was given for treatment of  lung edema in the patient who survived.

Appendix 1. Laboratory recapitulation

RECAPITULATION OF LABORATORY EXAMINATION

Name: Ms. Y (admitted January 4, 2010), RM: 34 25 57

height: 158 cm, weight: 62 kg

 

 

 

 

 

 

Nama: Mr. E (MRS 3 Januari 2010), RM: 34 25 01

Height : 170 cm,  Weight: 70 kg

 

 

 

 

Appendix 2. recapitulation UMU

RECAPITULATION UMU Water Intake and Discharge

Name : Ms.. Y

Age : 22 years

R / UMU balance : balanced

 

 

Name : Mr. E

Age : 25 years

R / UMU balance : balanced

 

 

Case Conclusion

Death of a young woman aged 22 years, overweight at which time in the first hospital (private hospital), only suffered mild clinical symptoms (one day fever before admitted to hospital).

Peripheral blood picture (PBP) Laboratories dated 31-12-09 (a private hospital, the first day of treatment / days of illness)

Hb: 13.4, Ht: 40, LE: 7300, Tr: 176 000, E: 4.4 jt

PBP Laboratories dated 4-1-10 / fifth day of illness / first day of treatment at Army Hospital, (moved due to insurance problems, the first day of menstruation)

Hb: 14.7, Ht: 44, LE: 2700, Tr: 33 000, E: 4.9 million

Blood pressure: 80/60, pulse: 112x/menit, weak      R: 24x/min  t: 36o C

IgG dengue blot +

question

1. Why did the patient suffers from shock? Did hospital I, did not give adequat fluids as claimed in the abstract?

2. Why did the platelets continue to drop and the patient continue to worsen eventhough the patient has entered the fifth day of illness that should have been entered in the healing phase.

3. Actually, how was the prognosis of this patient upon admission ED army hospital, whether the prognosis was good? Bad? Or is it unknown? (up to Almighty God). Because that can only be done based on knowledge learned during the school toward that patient is to overcome the occuring shock, increase alertness and provide rapid treatment if there is bleeding or anything that threatens the lives of these patients. As for the problem of thrombocytopenia, there is no specific therapy (expecting to increase on its own).

And that is what was performed on this patient. On the ninth day of illness or fourth day of treatment at the army hospital, there was a decrease of consciousness (sopor), pleural effusion and pulmonary edema, DIC, decreased Hb up to 6 g / dl and acute liver failure characterized by increased SGOT s / d 4040, SGPT 920 , with no clinical jaundice while blood pressure was stable 100/60 mmHg. Listed CVP, PRC transfusion, FFP, and cryoprecipitate, administration of heparin and antibiotics. Neurologist provide additional drug of mannitol and citicholine. Day 12 or day seven treatment in hospital the patients died in the ICU.

Discussion

Is fluid therapy in these patients is less adequat while being treated in private hospitals? Because we do not know, blood pressure every day during the private hospitalization I / hence used a laboratory benchmark. In the laboratory, a person considered to be dehydrated when:

1. The existence of an increased hematocrit.

Women Ht> 40% men and> 45% (protocol handling DHF from department of health 2003).

As for my own experience based on 15 years observing DPL DHF patients suggested Ht> 45% in Indonesian> 60 years and> 42% in aged <60 years. This also is consistent with the fact that most Hb young Indonesian adults ranging from 12-14 g% and the age old 12-15gr%.

2. The presence of increased Hb levels.

There has been no benchmark for the Indonesian agreed. Based on the information above I propose Hb> 14gr% in Indonesian <60 years and> 15 g% at age> 60 years.

3. Comparison Ht / Hb> 3x.

When viewed laboratories PBP in this patient since the Istday / day IV in private hospitals (31-12-09 s / d 3-1-10) does not sees the rise of hematocrit or hemoglobin or Ht / Hb > 3x. intravascular dehydration was evident on 4-1-10, the day the 5 of illness, when moved to the Gatot Subroto Army Hospital and the patient begins the first day of her period (Hb: 14.7 and Ht: 44 but the Ht / Hb <3x ). Nevertheless the patient arrives in a state of shock (blood pressure 80/60, pulse 112x/menit). Although shock the patient well, compost mentis, R: 24x/menit and no fever. Examination of PBP in the evening at 20.00 showed increasingly clear intravascular dehydration (hb: 15.1, Ht: 46, Ht / Hb> 3x) but the patient was not in a state of shock.

With the circumstances above, it appears that infusion of fluids in a private hospital was adequat. While the lack of fluid in the emergency room at the army hospital due to the possibility of  infusion that was not installed perfectly and because it was the first day of her period. With the administration of adequat fluid was when the patient entered the army hospital emergency room and blood pressure returned to normal, the patient’s problems should be decrease and the patient will continue to improve because shehas entered the fifth day of illness or healing phase. But why more and more patients continue to deteriorate? This is where the role of a doctor’s confidence in the pathophysiology and pathogenesis of DHF, which determines what treatment is given. All theories except the theory T. Mudwal, assume that the virus was culprit of everything. Either because the virus does have the ability to destroy or not by the ability of the virus, but because of viruses from other serotypes that cause the formation of wrong antibodies / non-neutralizing antibody (secondary heterologous infection / ADE). With confidence like that, there was nothing to be done except to keep the patient’s fluid volume and act quickly when there are things that threaten patients’ lives. And that whatwas done and the results are clear. Although most patients survive in that way and only 1-2% are experiencing terrible fate, but still 1-2% is a high amount as had been described before in the introduction. Mortality rate of DHF in women who are menstruating, may be much higher. I myself have experienced such, while still in internship in FK UI in year95. With treatment like that, there happens a speed race between worsening symptoms and therapy to address these symptoms. In Ms.. Y worsening symptoms that occurred were faster and was not resolved with therapy.

T. Mudwal denied pathogenesis, pathophysiological and therapeutic of that way (www.dhf-revolutionafankelijkheid.net). The basis of pathogenesis and pathophysiology of dengue infection is a type III hypersensitivity reactions / immune complex reaction. The life of dengue virus in the cells of our soldiers (monocytes, macrophages, Kupffer cells) will cause paralysis of the army cells hence creating  immune complex (antigen / virus-antibody complexes) which should be destroyed, so it spreads throughout the body. And after our army cells are back on its function or the emergence of a new army cells, the immune complex residing in the tissue is destroyed and automatically these tissues are also damaged either little or a lot. The better sensitivity a person is, such as patients with well-nourished or overnourished-the more severe the clinical manifestations of DHF that happeneds. Sensitivity should be suppressed with immunosuppressive doses of steroids. It should be given as soon as possible after the possibility of dengue infection is diagnosed. WHO criteria of 2009, is better than the 1997 WHO criteria for diagnosis of dengue infection. When these patients on day I, in addition to the fever also had complaints of joint pain, torniquet test +,  the possibility of dengue infection (probable dengue) has to be enforced. And at the time of diagnosis has been established, the same day steroid methyl prednisolone immunoisupressif dose are given immediately. Immunosuppressive doses of steroids can be delayed or not given when the patient entered the fifth day and clearly demonstrated a trend toward improvement (in the healing phase). But if that does not happen immunoisupressif methyl prednisolone dose are still administered, although patients is on day 7.

In this case even if the hospital I, no steroids was given, the doctors at the Army Hospital should have given steroids /immunoisupressif dose methylprednisolone, the fact that the platelet count fell to 12,000 on 4-1-10 at 20.00 from the amount of 33 000 on 4-1-10 morning. This indicates that the process of healing has not occurred and the threat of the spread of immune complex to all body tissues and destruction of the immune complex, which resulted in damage to body tissues is still happening. If necessary the dose of methyl prednisolone must be  raised again on 5-1-10, because platelets dropped again to 15 000 (see application theory HS type III in www.dhf-revolutionafankelijkheid.net). Platelets <20000, said in the library, is a risk factor for the occurrence of spontaneous bleeding tissues including spontaneous cerebral hemorrhage. Giving platelets from outside or platelet transfusions, have been demonstrated to be proven useless. I once had proven that a patient with platelet 7000, on day 8 of illness, the bone marrow was hipercellular and the number of megakariocyte aregreatly increased. This means the supply of platelets from the plants is abundantwhen in the state of severe thrombocytopenia (platelet count <20000). The bone Marrow are ready to supply 200.000-300.000 platelets/mm3 into the blood circulation ifin the state of severe thrombocytopenia. So if the platelets from ourselves are being destroyed let alone if we give platelets from the outside. The presence of platelet antibodies is said to be the cause, as I proved in 97 and reinforced by Andika Rahman et al of hematology FK UI in 2009. This platelet antibodies will persist causing lifetime thrombocytopenia. On the other hand, platelet in the DHFdo not function the same as normal platelet. This is due to immune complexes that attach to the platelets, but has not yet distort the shape of the platelets so it is still counted in laboratory tests. In patients with minor trauma such as rubbing the nose can cause bleeding despite normal platelet number. Even if having normal menstruation still requires a normal amount and function of platelet as well as other clotting factors, both at the beginning of menses (bleeding) and at the end of menses (the end of the blood). If there is interference with the function or a very low platelet count, bleeding in theory would be more. The menstruation blood will reduce the number of platelets because it used to reduce menstrual bleeding. Presence of fallingHb on 6-01-10/the 7thday illness / day 3 treatment at the army hospital / day 3 of menstruation from 8.4 to 13.4 (PBP laboratory day I in private hospitals) most likely originated from menstrual blood discharge even if the patient stated it was few. As with the falling Hb on 10-1-10/the 11th day of illness / day 7 of treatment at the army hospital / one day before the patient died on 11-1-10 (based on the last email of dr. Myrna) to 6, 0 gr% because of the presence of DIC which cause extensive bleeding due to the extent of damage to the capillary walls and clotting factor disorders caused severe liver function disorders. So at the beginning of menstruationin date 4-1-10 it should have been given drugs to pause and prevent the reduction of the decreasing number of platelets. Providing immunosuppressive doses of methyl prednisolone is also to stop the activationkinin system and prevent reactivation of  that kinin system (patients in shock again). Seeingat the time of entry in the ED Army Hospital, intravascular dehydration occurred only slightly (14gr% Hb and Ht> 42% but the Ht / Hb was> 3x), menstrual bleeding was not so much (as evidenced not an absolute decline in Hb was 14.7 g% ) it is most likely due to shock in this patient because of kinin system activation.

The more the increase in platelet counts to> 50 000 since day 7 of illness / day 4 in RSPAD care /8-1-09 whereas when patients experienced a decrease in consciousness showed cerebral hemorrhage that occurred not because of bleeding due to thrombocytopenia, but because of an immune complex that has spread to the brain and then destroyed, causing brain damage and also possible brain hemorrhage. Unfortunately, there was no CT scans in this patient. The menstruation did stopped on day 5 at the army hospital care / day 8 sakit/9-1-09 (BB messenger from dr. Myrna) and the platelets also continued to increase (95 000 platelets on 9-1-09). But all the complication due to the spread of immune complex has occurred. In the end, the platelets fell again to 48,000 on the day of the patient’s death in 11-1-09. And finally the death of this patient was because of brain stem death or because of the spread of immune complex to the myocardium, causing extensive damage to heart muscle.

I myself have ± 6 times gotten a case like this, and everyone of them survived with administrating high doses of methyl prednisolone / immunosuppressive drugs as early as possible and stop menstruating drug (primolut n 1×1). There was one person who died, but that’s when I was in internship at FK UI in the year 95, where the treatment is done by default as the case of nn. Y. Administration of high-dose methyl prednisolone should also be accompanied with the provision of total pump inhibitors and anti-emetic drugs. Indeed, the cost becomes more expensive, but if the theory of HS type III is the most rational theory, the life-saving and the avoidance of squelle are preferred rather than cost, and each patient has the right to obtain this information no matter if the patient is a Jamkesmas patient (national Insured). To ensure there is no squelle, patients were advised to go home after a day 4 of illness, when the hemodynamic are stable, no fever and platelets of the patients> 100.000/mm3. Discharging patients which solely rely on stable hemodynamic, no fever and platelets> 50 000 without a care in day the fever was(the protocol department of health 2003) contains a risk for the occurrence of death in the home and lifetime squelle. Everything I said above is also my comments on the study of Padjajaran Medical Faculty (Tariff Magnitude of Dengue Patients Managed in Hasan Sadikin Hospital as Compared to INA-Drg’s and Description of Its Components).

Discussion of Case II

In case II were seen again that the patients who should have been entered in the healing phase (day 5 ill) still did not yet entered the phase of healing (still very low platelet counts and the presence of pulmonary edema). This shows again that patients with excellent nutrition / overweight /good immunity will provide a greater clinical symptoms. It is interesting to me when prof. Tuti Parwati et al from Udayana Medical Faculty claim to found a dengue infection in patients with poor immunity of HIV patients with very low CD4 counts (23 cells/mm3)(Case Report : Dengue Manifestation in AIDS Patient). Based on an abstract Petri congress in July 2011, dengue infection in patients is caused by the leakage of plasma, with (+) IgG and IgM dengue blot. Whereas plasma leakage of someone who is poor immunity or malnurished, is not a sign that the person is infected with dengue virus. Plasma leakage with minimal manifestations torniquet test +, is common in people with malnutrition and often infected with various diseases (such as HIV) that cause fragility of capillary walls. People like that are also easy to suffer from plasma leakage with severe manifestations such as pulmonary edema, pleural edema, ascites, etc.. Hipoalbumin can also cause such symptoms. While IgG and IgM are positive in this patient, I do not think it is from a new dengue virus infection, but because at least of a dengue virus-infected 2-3 months earlier. Positive IgM on one dengue virus infection (eg virus A) will persist for 2-3 months. IgM itself is formed 5 days after a person is exposed to that dengue virus infection. While IgG against the virus A would be positive on day 14 if virus A is the first dengue virus to enter the blood vessels of this patient. Or on day 2 if the dengue virus infection is from another serotypes of dengue virus infection or if it entered for the 2nd or 3rdtime in the patient’s blood vessels. IgG will last a lifetime. So the imonuglobulin that was detected positive in that patient maybe from a virus that was 2-3 months prior to admission Sanglah Hospital, Denpasar. And at that time CD4 should have a detected greater than 200 cells/mm3, such as patients with dengue infection found in Cuba, Brazil and Singapore. It turned out that in the abstract that the CD4 found in the patient 1 month before entering Sanglah Hospital, Denpasar was 272 cells/mm3. To find out if there is dengue virus in HIV patients it is more precise to examine using NS1 antigen. The failure of HIV patients to make dengue virus antibodies will causes dengue virus to be detected on the first up to 7 days of illness. In people without HIV,NS1 antigen is only good if used for diagnosis of DHF on the first day of illness if its is a secondary infection, or before day 5 when it is a primary infection (Again Let’s Discuss about DHF pathogenesis and pathophysiology in www.dhf-revolutionafankelijkheid.net).

With no formation of antibodies against dengue virus in HIV patients thus immune complex and the spread of immune complex automatically does not occur. And clinical symptoms of dengue infection in HIV patients will automatically be mild or with no symptoms at all. The existence of fever in HIV patients found in Sanglah Hospital, will most probably not due to the effects of dengue infection, but maybe due to other infections (because of very low CD4 count at that time).

The success of NS1 antigen in patients with DHF as claimed Andalas Medical Faculty, (as written in the conclusion abstract) should be criticized. Based on what I said above, data on how many secondary infection (IgG positive) and how much primary infection (IgM positive)should the researched. If the patients studied was primarily a primary infection (IgM positive) then naturaly the NS1 antigen will give a good results because the study is the DHF patients with fever of 3 days. This is my commentary to Andalas Medical Faculty on the research of NS1 antigen (Diagnosis of Dengue Virus Infection Using NS1 antigen Detection in Human Serum).

Another case that indicates a lack of understanding in the sense of positive IgM can also be seen at the case reports conducted Sumatera Utara Medical Faculty Tarigan Affandi et al. Where do they keep asking why IgM remained positive after 17 days of treatment. (Coincidence Severe Malaria and DHF A Case Report). The analysis of that case is that if indeed there is a positive IgM on day 7 of treatment, whereas at the time of entry the IgM was negative but IgG was positive, then the likelihood of the patient hospitalized in Adam Malik, Medan after 8-day of fever in that hospital (Malaria) was infected by dengue infection from a different serotype of dengue virus on the 2nd day of hospital care. So the positive IgG at the start of hospitalization only indicates that the patient had been infected with dengue virus before entering the hospital. Hence the diagnosis of this patient is malaria patient affected by other types of dengue infections in the hospital after being treated for 2 days. And IgM remained positive unquestionable because it will remain positive up to ± 2-3 months. (Coincidence Severe Malaria and DHF a Case Report)

Back to the discussion of  the 2nd, I thank Allah, God of the Universe because

1. Proper fluid management, so that pulmonary edema did not gain weight and can be maintained stable hemodynamics.

2. The spread of severe immune complex so it is not found the existence of cerebral disorder, extensive DIC and severe liver dysfunction. Clearly the fate of these patients is better than the first patient no matter how both were obese and equally did not get steroids. Or it can be said equally were both obese however, the individual sensitivity of the dengue virus is not necessarily the same. That might explains why loss of consciousness or other disturbances in this patient does not occur.

3. No occurrence of spontaneous bleeding in this patient is because no matter how far down the platelet count was 20 000 mm 3 for days. The platelets in this patient finally rose> 20 000 mm3 after day 5 of hospital care or 9day of illness.

4. The reactive thrombocytosis which amounted to 774,000, based BB messenger from dr. Myrna, is  said to have been decline.

How does the handling this case in my opinion or based on type III hypersensitivity reaction?

Patients get sick on day 5, obesity, intravascular dehydration still occurred (Hb> 14.5 g%), the platelet count is still very dangerous (9000/mm3) there is a presence of pulmonary edema, the patient actually has not entered in the healing phase. Giving careful fluid (colloid 24 hours per kolf) and injection of furosemide 1×40 mg or 1×80 mg if systolic> 100 mm Hg. The problem is whether to use immunosuppressive doses of methyl prednisolone? It is necessary, because in this patient the healing phase has not yet occurred. Immunosuppressive doses of steroids will have an effect.

1. Preventing the spread of immune complex in all body tissues such as in the case of I (Nn.Y) simply we can estimate the presence of immune complexes that spread into the tissues of the body by looking at the low value of lymphocyte count in dengue infection. I said that in the heat of patients with lymphocyte count <20%, dengue infection should be suspected as the cause until proven otherwise. (Application of theories of HS type III in www.dhf-revolutionafankelijkheid.net). The amount of immune complex that spreads rapidly to the network, will lead to naive lymphocytes in the circulation, go to school / maturation into bone marrow and thymus. I said the febris patient with lymphocyte count <20%, it must be suspected there will be dengue infection as the cause until there will be clearly proven not the dengue viral itself as the cause . The quickly wide spread of immune complex to the tissue will cause naive lymphocyte in circulation go to school or having maturation in thymus and bone marrow. The effect of this process lymphocyte count in circulation will be low. What I said was apparently supported by the research of FK UGM which states that in severe DHF (grade III-IV) CD4 and CD8 counts are lower than mild dengue and dengue fever (The Difference of circulating lymphocyte Value in Classification of Hemorrhagic Fever)

2. Prevention of shock due the activation of kinin system.

The activation of kinin system, can occur from minor bleeding (eg bleeding manifestations which occur on + torniquet tes only) and when this happens it  can lead to a great increase in permeability caused by mast cell degranulation. This reaction is the same as anaphylactic reactions, but because there is no IgE reaction it is said to have an anofilaktoid reaction. The activation of kinin system is also able to stimulate C3 and C5a which can also lead to the increased of capillary permeability. I had an experiences like this, where patients were diagnosed with probable dengue but suffered from shock many times on the first day of treatment, although the platelet count was> 150,000 mm3. Manifestations of bleeding in the patient was only positive torniquet test (read applications in the theory of HS type III www.dhf-revolutionafankelijkheid.net). The value of vascular endothelial growth factor measured will be higher if there is damage to the capillary walls. Therefore it is logical if patient that are infected with dengue virus will show a significant increase in VEGF values than healthy people / without damage to capillary walls, as were patients with dengue infection without warning sign or probable dengue will show a higher VEGF values than patients with VEGF with warning sign. The few samples in warning sign group which having mucosal bleeding for example, nose bleed and gum bleed and as addition the few sample with positive rumple leed compared to the sample amount of patients without warning sign with positive rumple leed causing the low VEGF count in with warning sign group compared to without warning sign/probable dengue. Or we can say positive rumple leed will affect more compared to thrombocyte amount or even the increase value of hematocryte in the increasing of VEGF value. The shock that triggered by minimal bleeding or positive rumple leed without other bleeding (the activation of kinin system like what I have been described above) causing VEGF severe dengue value not different significantly with non severe dengue VEGF especially in without warnig sign/probable dengue group. Or we can say, the shock that happened in severe dengue group almost all of them have positive rumple leed examination. Or not the massive bleeding is the cause of shock in severe dengue group. Based on that condition, it is logical to say possitve rumple leed can become a sign of dengue with warning sign not like what happen now, whereas positive rumple leed is used as a sign dengue infection without warning sign (WHO 2009 dengue criteria diagnosis). That is my comment toward the research on VEGF value in dengue infection that has been done by Dipenogoro Medical Faculty (Comparison of Vascular Endothelial Growth Factor/ VEGF Level between Dengue Virus Infected Patient with and without Warning Signs in Dr. Kariadi Hospital, Semarang).

3. The fear of prolonged thrombocytopenia (persistence platelet antibody in a long time).

To further establish whether the patient is not yet in the healing phase double-check the DPL. If the DPL platelets did not increase to> 30.000/mm3, then immediately methyl prednisolone is given together with the total pump inhibitors and anti-emesis. The contra-indications of methyl prednisolone is erosive gastritis. Black stool, must be proved by digital rectal examination (rectal toucher / RT). If RT is negative, or yellow then give immunosuppressive doses of methyl prednisoslon evenif the patient  complain of syndrome dyspepsia. Experience shows that the administration of immunosuppressive doses of methyl prednisolone together with the total pump inhibitors and anti-emesis relieve the syndrome dyspeptic complaints. This is expected because the reduction of immune complex that spreads to the stomach. (See application HS type III theory in www.dhf-revolutionafankelijkheid.net)

 

 

CONCLUSION

We have discussed two interesting cases of dengue infection and also comments on some research done about the problem of dengue infection. It is now up to us all, whether stay on the existing pathogenesis and pathophysiology and still provide conservative therapies such as now, or switch to theHS type III reaction as the basis of pathogenesis and pathophysiology of dengue and then provide therapy as I have suggested in the application of HS type III reactions on my site www.dhf-revolutionafankelijkheid.net .

HS type IIIreaction as the basis for pathogenesis and pathophysiology of dengue infection do not need to  be proven anymore. Because it is a conclusion or the resultant outcome of all studies ever conducted against dengue or dengue virus infection in 40 years.

In the end the truth is a matter that can not be refuted by common sense that would automatically force a clean conscience to acknowledge that fact.

Wassalam,

T. Mudwal

 

Appendix 1

Diagnosis of Dengue Virus Infection using NS1 Antigen Detection in Human Serum

Idriani H, Ahmad, A, Acang N

Subdivision Tropical Infection Medical Faculty of Andalas University

Abstract
Background. Dengue is associated with explosive urban epidemics and has become a major public health problem in many tropical developing countries, including Indonesia. The laboratory diagnosis of dengue can be carried out using several approaches, however sensitive and specific assays usefeul to diagnose in the dengue are desirable. The flavivirus non-structural protein NS1, a highly conserved and secreted glycoprotein, is candidate protein for diagnosis of dengue.
Methods. We tested 50 serum samples from patients with acute infection of hemorrhagic fever disease during the first three days after the onset of the symptoms. Of these, 50 were from patients with acute infection of one of the four dengue serotypes, detected by RT-PCR.
Results. The sensitivity of dengue NS1 Ag ELISA on acute serum samples (n=50) was 98%, specificity 100%. Positive predictive value 100%, Negative predictive value 88% and accuracy 98%.
Conclusion. Our findings support the use of diagnostic tools based on the NS1 antigen detection for the diagnosis of acute DENV infection. The Elissa NS1 Ag test for DENV infection was highly sensitive and specific, and would therefore be a suitable first-line test.
Keywords : dengue hemorrhagic fever, RT-PCR, NS1, ELISA

Appendix  2

Tariff Magnitude of Dengue Patients Managed in Hasan Sadikin Hospital as Compared to INA-Drg’s and description of Its Components

Misriani, Bachti Alisjahbana, Elsa Pudji Setiawati, Uun Sumardi, Yovita Hartantri, Hadi Jusuf

1Department of Internal Medicine, Hasan Sadikin Hospital/Padjajaran University-Bandung. 2Department of Public Health, Medical Faculty, Padjajaran University, Bandung

Introduction. Dengue is an important public health issue because its high incidence and thus become the most frequent cause of young productive adult. In the INA-DRG standard document, the Indonesian Government has allocated funds for reimbursement of tariff for managing dengue cases in hospitals. This study asses what is the magnitude of the tariff imposed by our dengue patients, compared to INA-DRG and describe the most dominant component of the tariff.
Methodology. The study is an evaluation of consecutively hospitalized dengue fever and dengue hemorrhagic fever cases in the 3rd class ward of Hasan Sadikin Hospital. Data of all the tariffs needed to care of patient were collected from secondary data (medical records) and interview with the patients. These data further were presented descriptively, classified into several components and compared with the INA-DRG standard.
Results. A total of 70 dengue patient, (35 dengue fever and 35 dengue hemorrhagic fever) were included in the study. The median age of patients was 21 (range 14-56 years) and 62,9% were male. Patients came to hospitals with median fever days of 4 days (range 3-6 days), with length of hospital stay median of 5 days (range 2-6 days). Complications are more common in dengue hemorrhagic fever than dengue fever (p 0,0006). Magnitude of tariff of dengue fever cases were median of Rp. 1,215,700, – (range of Rp. 593,100 to Rp. 1,672,250) and for dengue hemorrhagic fever median of Rp. 1,235,000, – (range Rp. 612.00to 1.563.800). These were not significantly different (p 0,233). Variation occurs mostly because of different days duration of hospitalization. These tariffs of was lower than INA-DRG’s by 1.233.002 rupiah in dengue fever and 1.199.802 rupiah in Dengue Hemorrhagic fever. The largest component of tariff is treatment room rate (53,7%), laboratory examination (31,7%), medicines (12,1%) and emergency (2,6%).
Conclusion. There was no different in the tariff for management of dengue fever and dengue hemorrhagic in hospital, and these tariff is 50% (1.219.000 rupiah) lower than INA-DRG. The biggest component of the tariff is the room tariff. Because there still an execess in the funds allocated, we recommend to put USG examination to determine plasma leakage as a standard for dengue patient.
Key words : dengue, tariff treatment, Clinical pathway, INA-DRG

Appendix  3

Comparison of Vascular Endothelial Growth Factor (VEGF) Level between Dengue Virus Infected Patients with and without Warning Signs in Dr. Kariadi Hospital, Semarang

Nur Farhanah, Krisna Tsaniadi, Muhammad Hussein Gasem

1Division of Infectious Diseases-Tropmed, Department of Medicine, Dr. Kariadi Hospital

2Faculty of Medicine Dipenogoro University (FMDU), Semarang, Indonesia

Background. Vascular Endothelial Growth Factor (VEGF) is a glycoprotein that plays important role in angiogenesis and vascular permeability. In patients with dengue virus infection (DVI), the diminished count as well as the function of platelets are the prominent clinical features. Those are divided, by the latest WHO 2009 classification, into clinical spectrum of non –severe dengue (with or without warning signs) and severe dengue. A previous study has demonstrated an elevated level of VEGF-A, the most potent permeability-enhancing cytokine in Dengue Hemorrhagic Fever (DHF). The role of VEGF in causing plasma leakage in different clinical spectrum of dengue is, however, still unclear.
Subject and Method. This observational study was conducted in Dr. Kariadi Hospital, Semarang during the period September 2009-August 2010. Plasma samples from 30 patients with DVI, confirmed by serological test and 10 patients without any clinical disease as control were tested for VEGF level using ELISA kits. The samples were divided into non-severe and severe dengue by presence of shock. The non severe group was also divided into with and without clinical signs by the evidence of plasma leakage, hemoconcentration, hypoalbuminemia, and bleeding symptoms.
Results: In this study, the DVI group (n=30) was classified into group of non severe dengue (n=27), including those with warning sign and without warning sign(n=13, n=14, respectively), with 10 samples In the control group. The average age of the patients was 21 years old (range=14-58 yrs), 16 males (53%).
The mean level of VEGF in all patients with DVI, both non severe and severe was (35,54 pg/ml), were significantly higher that those in control group, (7,98) (p=0,000). The mean level of VEGF in non severe (37,02) pg/ml) group was higher that those in severe (22,18 pg/ml) but statistically not significant (p=0,277). Additionally the mean level of VEGF in non severe with warning sign (28.89 pg/ml) group was significantly lower that those without warning sign (44.58 pg/ml) (p=0,032).
Conclusion. In this study, there were significant elevated VEGF level in DV1 patients compared with control group. The VEGF level was significantly lower in non severe dengue with warning sign compared with those without warning sign. Further investigation in the course of VEGF and platelet count during dengue virus infection is needed.
Objectives. To know thee level of VEGF in each different dengue clinical spectrum.
Keywords: Dengue WHO 2009 classification, warning signs, VEGF.
Appendix  4

The Difference of Circulating Lymphocyte Value in Classification of Dengue

Anna Anggraini, Soebagyo Loehoeri, Donni Priambodo, Rizka Humardewayanti, Yanri Wijayanti

Department of Internal Medicine, Faculty of Medicine Gadjahmada University- Dr. Sardjito Central General Hospital, Yogyakarta.

Background. In investigaton of subpopulations of lymphocytes in DHF patients, it was found that the percentage T lymphocytes decreased, whereas that of B lymphocyte increased. The decrease in circulating lymphocytes may relate to the high level of cellular activation. It is possible that in dengue, antigen-specific T cells and other activated cells migrate to tissues such as lymph nodes, spleen and liver to clear dengue virus-infected cells and that these cells then undergo apoptosis at these distant sites. Absolute CD4 T cell, CD8 T cell value were decreased in patients with DHF compared those with DF. The aim of this study is to found out the difference of circulating lymphocyte value in classification of dengue.
Method. A retrospective study from medical record registry in Dr. Sardjito Central General Hospital, Yogyakarta. Data retrieved from medical records of subjects who were diagnosed with DF or DHF during the period of January to December 2009 . Subjects who were suffered from co-infections, had immune suppression drugs or chemotheraphy, underwent radiation were excluded from the study.
Results. This study obtained 141 subjects. Fifty four percent (54%) of patients were male, the mean age was 24, 6±8,6 years old. The details of the case were as follow : 30 DF, 65 grade I DHF, 28 grade II DHF, 16 grade III DHF, 2 grade IV DHF. The log mean value of lymphocyte of group I (DF), group III (consist of DHF I, DHF III), group III (consist of DHF III, DHF IV) were 3.102±220 cells/mm3, 3.023±247 cells/mm3, 2.717±139 cells/mm3 (mean±SD) group I, group III compared to group group II (p<0,01 ; p<0,01 respectively). Otherwise there was not statistically significant difference between group II compared to group I (p<0,1).
Conclusion. The mean value of lymphocyte of group III (DHF III, DHD IV) was lower than group I (DF) and group II (DHF I, DHF II).
Keywords : dengue, lymphocyte value.

Appendix  5

Coincidence Severe Malaria and DHF A Case Report

Afandi Tarigan, Endang Sembiring, Saut Marpaung Fransciscus Ginting, Tambar Kembaren, Armon Rahimi, Yosia Ginting

Division of Tropical and Infectious Diseases, Department of Internal Medicine Medical Faculty University of Sumatera Utara / Adam Malik Hospital Medan

Abstract
Background. Indonesia is an endemic area of malaria and dengue hemorrhagic fever (DHF) infections. Although the coincidence of malaria and Dengue hemorrhagic fever (DHF) infections. Although the coincidence of malaria and DHF is rare but it can happen anytime and detoriate patient’s condition, but with a good management can ensure high rates toward the diseases. Antibody response to DHF infection differs according to the immune status of the host. IgM antibodies are the first immunoglobulin isotype to appear. These antibodies are detectable in 50% of patients by days 3-5 after onset of illness, increasing to 80% by day 5 and 99% by day 10.
Casereport. A man 48 years old, come with complaints of fever since 8 days ago, chills, sweating, nausea, vomiting and a history of traveled to endemic area of malaria. Vital signs: apathy, blood pressure :100/70 mmHg, pulse rate :96x/I, resipatory rate :22x/I, temperature : 38o C, icteric (+). Laboratories : hemoglobin 18,9 gr/dl, direct bilirubin 3,12 mg/dl, AST 159 U/L, ALT 130U/L, blood glucose level 76 mg/dl, PT 18,4”, INR 1,44, APTT 44,3”, TT 20,5”, K+ 4,1 mmol/L, Na+ 138 mmol/L, Cl- 109 mmol/L, HbsAg (-), IgG Anti Dengue (+), IgM anti Dengue (-), Plasmodium falciparum (+), the density of malaria (+4). Patient was discharge after 7 days of hospitalized with plasmodium falciparum (-), and IgM anti-dengue was (+) reevaluated after 17 days of treatment. Patients was treated with infusion of Ringer Lactate., Artemether on the 1st day : 160mg/i.m. (on the left and right thigh), and 80 mg/i.m (2nd day – 4th day), Artesunate 500 mg (two times a day 1000 mg), 200 mg of Amodiaquine (two times a day), Primaquine 45 mg (single dose) on 1st day and 500 mg Systenol (three times a day).
Conclusion. We report a case severe malaria with DHF, when IgM anti-dengue was (+) after 17 days of treatment.
Keywords: Severe malaria, Dengue Hemorrhagic Fever, Anti-dengue IgG (+), Anti-dengue IgM (+)

Appendix  6

Case Report : Dengue Manifestation in AIDS Patient

Agus Lastya, Susila Utama, Agus Somia, Tuti Parwati Merati

Tropical and Infectious Disease Division, Internal Medicine Dept. Medical Faculty Udayana Univ./Sanglah Hospital Denpasar

Abstract
Introduction. AIDS and Dengue are an infectious disease with high incidence. Manifestation of Dengue infection is rare in AIDS patients, but it has been reported in Cuba, Brazil and Singapore with CD4 count above 200 cell/mm3.
FirstCase. Male, 31 yo, homosexual. AIDS was diagnosed for one year. On CD4 2 cell/mm3, HAART was started. Four months after initiating HAART, patient suffering for Toxoplasmosis cerebral as IRIS with CD4 is 23 cell/mm3. Two month later, patient was admitted to hospital with fever and haematemesis. On follow up we found plasma leakage and positive for Dengue serological test in both IgM and IgG.
SecondCase. Male, 25 yo, multipartner, AIDS diagnosed for two years . HAART was started on CD$ 81 cell/mm3. Eleven months later, patient was admitted to hospital with fever. On follow up we found positive Dengue serological test for IgM. One month before dengue infection, CD4 was 272 cell/mm3.
Summary. This report showed that Dengue in AIDS is possible by the role of immune system dysregulation, as well as improvement of inflammatory response by HAART therapy.
Keywords: Dengue, AIDS, CD4.

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