Dengue

Dengue Bulletin Volume 28 (2004)

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Dengue Haemorrhagic Fever with Encephalopathy/Fatality at PetchabunHospital:
A three-year Prospective Study (1999-2002)

Prasonk Witayathawornwong^#

Department of Paediatrics, Petchabun Hospital, Petchabun Province, Thailand

Introduction

The major pathophysiological hallmarks in dengue haemorrhagic fever (DHF) are leakage and abnormal haemostasis that leads to hypovolemic shock and/or haemorrhage. Generally, vital organs are not primarily involved in DHF but unusual manifestations, mainly the involvement of the central nervous system (CNS) and severe hepatic dysfunction, are increasingly being detected^[1-6]. The incidence of CNS involvement in dengue infection was about
0.88-5.4%^[7-11] first reported in 1976^[12]. Although dengue encephalitis existed as evident from the direct dengue viral invasion^[13-17], the more common conditions were encephalopathy secondary to fluid extravasation, cerebral oedema, hypoperfusion, haemorrhage, hyponatremia, liver failure and renal failure^[2,18-19]. The treatment of DHF with CNS involvement is supportive and symptomatic. Early detection and proper fluid management of DHF should be done to prevent any risk factors.

Materials and methods

There were 1,465 cases of DHF admitted to the Department of Paediatrics, Petchabun Hospital, Petchabun province, Thailand, from 1 May 1999 to 30 April 2002. The diagnosis methods used followed the WHO criteria^[20] and about 82% of cases were serologically confirmed using either enzyme-linked immunosorbent assay or haemagglutination inhibition tests. The treatment consisted of general measures (closely observed vital signs, general appearance and serially recorded haematocrit in 24-48 hours after fever, no medication except antacid for moderate to severe abdominal pain) and fluid therapy (minimal amount to normalize vital signs and haematocrit: 5% dextrose saline for infants, 5% dextrose Ringer acetate for older patients, Dextran-40 in normal saline for impending or fluid overload and fresh whole blood or packed red cells for significant bleeding, platelet concentrate and plasma not used).

Patients with encephalopathy (drowsy, stuporous, comatose and convulsion) were closely observed for blood sugar or dextrostix every six hours. Serum transaminase was done once a day until recovery. Vitamin K₁ and 10% calcium gluconate were administered for three days. Lumbar puncture was performed cautiously if there was no other risk.

The statistical analysis included the percentage, mean, standard deviation and range for demographic data and Student’s t and chi-square tests for comparing non-categorized and categorized variables, respectively.

Results

Of the 1,465 cases of DHF admitted to the Department of Paediatrics, Petchabun Hospital, from 1 May 1999 to 30 April 2002. The male to female ratio was 722:743 (1:1.03). The patients’ age ranged from 80 days to 15 years with the median of 9 years. The highest incidence was in the 5-10-year age group (57%) and the second highest was in the 10-15-year age group (26.2%). Thirty-two patients (2.2%) were under one year of age with the median of 8 months, and all of them except two had primary dengue infection. Eighty-seven per cent of all cases were found in the rainy season during May-October. The patients were from all 11 districts in the Petchabun province, 84% from the central district alone. There were DHF patients from all villages (178) of all the subdistricts (17) of the central district.

There were 34 DHF patients with encephalopathy (2.3%). The male to female ratio was 17:17 (1:1). The median age was 8 years 11 months (range 10 months to 13 years). Thirty patients (88.2%) were older than 5 years. Thirty and four patients developed encephalopathy in the shock and convalescent stages respectively. There were 7, 18 and 9 patients with encephalopathy stage II (drowsy), stage III (stuporous) and stage IV (comatose) respectively. Twenty-eight patients (82.3%) were referred from district hospitals and 17 patients (50%) had a massive fluid overload. Lumbar puncture was performed in 2 non-fatal cases with normal findings. Their serology indicated secondary dengue response.

About 17 fatal cases (1.6% of total DHF cases, male:female = 8:9 , median age 8 years and 4 months, range 10 months to 12 years) had the median duration of 13 hours for deaths (range 1-26 hours, mean±SD = 13.4±8.4 hours). Sixteen of the 17 cases (94.1%) were dead within 24 hours. Profound shock and massive gastrointestinal haemorrhage since admission were detected in all patients. Hepatic failure, comatose stage and massive fluid overload were detected since admission in 12 (70.6%), 9 (52.9%) and 7 (41.1%) cases respectively. There was no history of taking acetaminophen more than 60 mg per kg/day. Aspirin and non-steroidal anti-inflammatory drug (NSAID), Ibuprofen, were taken by each patient for many days during the febrile stage. Convulsion was detected in 4 cases (Tables 1 and 2).

Table 1. Clinical manifestations of 17 fatal cases

TDF = total duration of fever; DI = duration of illness
GIH = gastrointestinal haemorrhage; S = shock stage; kg = kilograms
^1,2 = first, second degree protein energy malnutrition
* or prior medications especially excessive fluid replacement
ARDS = Adult respiratory distress syndrome
DIC = Disseminated intravascular coagulation
NSAID = Non-steroidal anti inflammatory drug
L/S = liver/spleen

Table 2. Laboratory investigations of 17 fatal cases

* normal (10-14)/(23-35) sec
h = hours, m = minutes
SDI = secondary dengue infection

There were 17 non-fatal cases (male:female = 9:8, median age = 9 years, range = 3-12 years). Massive gastrointestinal haemorrhage, shock and massive fluid overload were detected since admission in 11 (64.7%), 13 (grade 3-9, grade 4-4, 76.4%) and 10 (58.8%) cases respectively. There were 5 cases with acute renal failure and one with liver failure since admission. Fifteen of the 17 cases were referred from district hospitals. Haemodialysis and plasmapheresis were done in 3 renal failure cases and 2 cases with only supportive treatment. All 17 cases recovered completely without neurological sequelae. The average (mean ± SD) hospitalization duration and recovery period from encephalopathy were 8.3 ± 5.31 days and 5.1 ± 3.7 days respectively (Tables 3, 4).

Table 3. Clinical manifestations of 17 non-fatal encephalopathy cases

^1,2 = first, second degree protein energy malnutrition
ARF = acute renal failure; ARDS = Adult respiratory distress syndrome
GIH = gastrointestinal haemorrhage; JP = just palpable

Table 4. Laboratory investigations of 17 non-fatal encephalopathy cases

* normal: (10-14 )/(23-35 ) sec
** duration in hospital/consciousness change (days)

A comparison between the clinical manifestations and laboratory investigations of the fatal and non-fatal cases, usual manifestations and encephalopathy cases are shown in Tables 5, 6 and 7 respectively.

Table 5. Comparison between clinical manifestations and laboratory investigations of fatal and non-fatal cases

* mean (standard deviation, SD)
** minimum value
PT=Prothrombin time
PTT=Partial thromboplastin time

Table 6. Comparison between clinical manifestations of usual manifestations and encephalopathy cases

only non fatal cases

Table 7. Comparison between laboratory investigations of usual and encephalopathy cases

* mean (standard deviation, SD)

Discussion

DHF patients from all the 11 districts in the Petchabun province were included in this study. The minors were referred from 10 other districts. The adults were from the 178 villages in all 17 subdistricts of the central district. This epidemic was similar to the previous dengue epidemic in 1997^[22]. This data implied that the dengue virus had spread nationwide. The percentage of DHF patients with CNS involvement in this study was 2.3%, the same as in the previous study^[22] as well as in other studies^[7-11].Female patients were reported to be more severely affected and accounted for more fatalities than male patients but without any significant difference^[18,23-25].In this study, the number of both sexes was equal and both had usual manifestations and encephalopathy cases. Young patients, especially those less than 1 year of age, had the tendency to be more severely and fatally affected^[18,23-25].Age itself was not a risk factor of disease severity in this study. Although there was one fatal case aged 10 months (10 RM), 85% of those who died were older than 5 years. Most of the DHF/DSS patients were well-nourished but patients with CNS involvement were more undernourished without significant difference^[24,26]. In this study, patients with usual manifestations and encephalopathy were underweight^[21] by about 50% and 35.3% respectively. Patients with encephalopathy were mainly in stage III^[7,8,18,27] (88.2%) initially developed in shock stage (52.9%), more than in febrile or convalescent stage^[7,9,28]. Seizure in DHF with encephalopathy had been reported in about 18.8-100%^{[7-9,13,18,24,27,29,30]}. In this study seizure was detected in 4 out of 34 patients (11.7%). Two patients (1NW, 7UA), under 5 years, developed seizure in afebrile stage, indicating that the seizure might have had a specific primary cause^[10].However, some children had possible confounding factors such as hyponatremia (3 patients, 1NW, 4KB, 7UA), hypoglycemia (15TW), and liver failure (3 patients, 1NW, 7UA, 15TW). Other factors could be a history of previous febrile seizure, co-infection^[10] and drug ingestion.

The causes or factors contributing to CNS manifestations included the following: direct CNS infection – a rare entity, CNS bleeding^[6,18] and severe hepatic dysfunction. Lumbar puncture was done in only two patients (5CP, 15KN) in the convalescent stage with normal findings. Direct CNS infection could not be evaluated in this study. There was massive gastrointestinal haemorrhage in 28 out of 34 cases (82.3%). Acute liver failure could be the direct or indirect cause of encephalopathy^[31,32] and an important cause of death in DHF^[33]. Twelve of the 17 fatal cases (70.5%) had this severe condition. Severe hepatic dysfunction could be due to profound shock, massive gastrointestinal haemorrhage or immune complex mechanism^[34]. The liver pathology in profound shock stage might be centrilobular hepatocellular necrosis^[35] or extensive necrosis of hepatocytes usually in a massive or submassive distribution^[33]. Massive gastrointestinal haemorrhage might cause hepatic dysfunction and vice versa. Immune complexes, detected in 80% of DHF patients^[36], might be deposited in hepatocytes and then destroyed as in hepatitis B virus infection^[34]. Excessive use of hepatotoxic drugs such as acetaminophen, an antiemetic drug, might interfere with liver function. There was no history of excessive use of such drugs in this study. Two fatal cases with liver failure and massive gastrointestinal haemorrhage had taken aspirin (3TR) and non-steroidal anti-inflammatory drug, Ibuprofen (7UA), for many days during the febrile stage. Both drugs aggravated the gastrointestinal haemorrhage and aspirin could have induced Reye syndrome^[37].

Thalassemia, of which two cases with a large liver and spleen were included in this study (4KB, 12WL), was a risk factor for hepatic failure^[18]. Acute renal failure (ARF) was a rare complication of DHF but could occur in severe cases with prolonged shock, DIC and also hepatorenal syndrome^[37]. There were five patients with ARF in this study. All of them recovered completely, three (6WD, 8SSr, 14SL) with haemodialysis and plasmapheresis and two (1YB, 9SN) with only supportive and symptomatic therapy. Hyponatremia was a factor in CNS involvement. Serum sodium of encephalopathy patients in this study was slightly low. It was due to excessive hypotonic solution replacement. The risk factors of encephalopathy in this study were profound shock, massive gastrointestinal haemorrhage, excessive fluid overload and severe hepatic dysfunction. Among the fatal and non-fatal encephalopathy cases, laboratory investigations except for coagulogram, were not significantly different. But fatal cases had more severe shock conditions, gastrointestinal haemorrhage and onset and depth of encephalopathy (Table 5).

Conclusion

In conclusion, encephalopathy in DHF was a severe complication with high mortality, although neurological sequelae in recovered patients were rare. Prevention should be attempted by early diagnosis and proper management of fluid therapy.

Acknowledgements

The author thanks officials of the Regional Medical Science Centre, Phitsanuloke, Thailand, for DHF serology testing and all nursing staff and workers of the Paediatrics Department of Petchabun Hospital for taking good care of the patients.

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