Key Words: Dengue, platelet, white count

Transcription

1 TREND IN THE CLINICL SYMPTOMS ND HEMTOLOGICL PROFILE OF DENGUE HEMORRHGIC FEVER (DHF) MONG HOSPITLISED PTIENTS IN KUL LUMPUR, USEFUL INDICTOR OF DISESE CTIVITY Saadiah Sulaiman [1], Fatimah Ibrahim [2], Sharifah Ismail [3], Halijah Hassan [4], Mohd, Nasir Taib d, Wan bu akar Wan basb b, Jeffrey bu Hassan [5], Roslina bdul Manap c, Ilinah Ishak c STRCT Objectives: To determine the trend of clinical manifestations of DHF in order to identify useful parameters as indicator or predictor of disease severity Material and Methods: prospective observational study was conducted on one hundred and forty nine adult patients with dengue hemorrhagic fever (DHF) in Hospital Universiti Kebangsaan Malaysia (HUKM) and General Hospital Kuala Lumpur (GHKL) from February 1998 to November The clinical diagnosis of DHF was carried out according to WHO recommendations. The clinical manifestations of dengue infection were observed during the days prior to and after defervescence of fever. Patients were divided into two groups according to the lowest platelet level during the course of disease; i.e. group were mild dengue disease patients with lowest platelet level above 50x109(n=29 patients), and group were severe dengue disease patients with lowest platelet level below 50x109 (n=120 patients), throughout the course of disease. Results: The clinical symptoms and signs of DHF were fever (100%) followed by headache (80.7%) arthralgia (74%), rash (73.3%), myalgia (66.7%), and vomiting (62.7%). In relation to defervescence of fever, during the of course of fever, headache was the earliest symptoms followed by other symptoms, while bleeding symptoms were observed much later, i.e. towards defervescence of fever. Haemorrhagic manifestation was seen in 75 patients (50.9%) manifested as petechial rash, gum bleeding, epistaxis, haematemesis, blood stained saliva, menorrhagia and premature onset menses. ppearance of cutaneous signs such as maculopapular rashes was seen in 30% patient, flushing in 3% of patients and palmar oedema were also noted in 4% of patients. Haematological profile of DHF was analysed and the result showed a trend between the white blood count (WC) and the platelet counts, with the rise of leukocyte counts highly predictive of the rise in platelet counts. In mild disease, the rise in platelet count occurs concurrently with that of total white counts (TWC), but in severe disease, the rise of platelet lags behind the rise in TWC by 24 to 48 hours. The rise of platelet in mild disease occurs early i.e. before defervescence of fever, but in severe disease, the platelet continue to drop until fever defervesce and only rise following that. Conclusions: There are definite trends of symptoms in relation to defeverscence of fever. Headache occurs early and bleeding symptoms occur much later i.e. towards defeversence of fever. The rise of the white blood count is useful indicator for prediction of the rise of platelet and this is a useful index in management of DHF. In mild disease the rise in platelets occurs simultaneously with that of total white count and the rise in platelet occurs early i.e. before defeverscence of fever compared to severe disease where platelet continue to drop until defeversence of fever and only start to rise following that. In severe disease, the rise in platelet is delayed by 24 to 48 hours after the rise in total white count. nother interesting observation is that during the earlier course of fever, following onset of thrombocytopenia, there was transient rise in platelet, which was followed by further drop with platelet, during the course of disease. Key Words: Dengue, platelet, white count INTRODUCTION Dengue fever (DF) has been reported in Malaysia as early as 1902, but dengue infection with haemorrhagic manifestations was reported only in from Penang Island where 62% of cases presented with haemorrhagic signs and 45% of cases had evidence of shock. Since then, DF and DHF have become endemic in Malaysia 2. Dengue and dengue hemorrhagic fever (DHF) are caused by one of four closely related, but antigenically distinctive virus serotypes (DEN 1, DEN 2, DEN 3, and DEN 4) of the genus Flavivirus 3. Recovery from infection by one provides lifelong immunity against that serotype but confers only partial and transient protection against subsequent infection by the other three. Indeed, there is good evidence that sequential infection increases the risk of more serious illness resulting in DHF 4. Infection with dengue viruses produces a spectrum of clinical illness ranging from a non specific viral syndrome to severe and fatal haemorrhagic disease. DF is a severe, flu like illness that affects infants, young children and adults but rarely causes death. The clinical features of dengue fever vary according to the age of the patient. Infants and young children may have a non specific febrile illness accompanied by rash. Older children and adults may have either a mild febrile syndrome or the classical incapacitating disease with abrupt onset of high fever, severe headache, retro orbital pain, muscle and joint pains, and rash 5. DHF, a more severe form of disease characterized by acute fever associated with a hemorrhagic diathesis and tendency to develop shock that can lead to mortality. The common manifestations of mild and moderate DHF cases reported are petechial rash, epistaxis, gum bleeding; while severe cases give rise to blood stained gastric aspirates and haematemesis 6. This paper describes the trend of clinical manifestations of DHF and the haematological findings of 149 hospitalised adult patients in General Hospital (GH), Kuala Lumpur and Hospital Universiti Kebangsaan Malaysia (HUKM). Only patients with DHF grade I and II were recruited into this study from February 1998 to November METHODS One hundred and forty nine patients with DHF, above twelve years old, admitted to General Hospital, Kuala Lumpur (GH) and Hospital Universiti Kebangsaan Malaysia (HUKM) during the year of 1998 and 1999 were studied. Study protocol Clinical data was collected by investigators, who did not interfere with any decision making on the patients. Informed consent was obtained for each patient. Clinical and epidemiological data were recorded by the investigator using standardized questionnaire data collection forms designed for the study. Each patient underwent detailed history taking, physical examinations and blood investigations. The patients underwent a standardized clinical evaluation using questionnaire following admission. Clinical evaluations and haematological investigations were continued until discharge. The criteria for diagnosis of DHF were in accordance with WHO recommendations 6. Patients with symptoms of other causes for fever are excluded. The severity of DHF was classified into grade I to IV. In this classification grade I DHF refers to patients having fever with positive tourniquet test, thrombocytopenia (100,000 cells per mm 3 or less), haemoconcentration (increase in haematocrit by 20% or more relative to baseline value). Grade II DHF is when the patients develope spontaneous bleeding from the skin or other sites in addition to the features manifestated in grade I DHF. Grade III DHF is when the patients have circulatory failure manifested by rapid and weak pulse, narrowing of pulse pressure (20mmHg or less) or hypotension, with the presence of cold clammy skin and restlessness. Grade IV DHF is defined as patients having profound shock with undetectable blood and pulse. lood samples were collected from 149 patients with a clinical diagnosis of DHF. Sera were stored at 20 C for serological tests. Total leukocyte and platelet counts and

2 lood samples were collected from 149 patients with a clinical diagnosis of DHF. Sera were stored at 20 C for serological tests. Total leukocyte and platelet counts and haematocrit determination were done using an automated counter, Coulter STKS machine. This machine was calibrated everyday with standardized specimen to ensure the accuracy and precision was within the acceptable range. Serum samples were tested for serological evidence of acute dengue virus infection by IgM capture enzyme linked immunosorbent assay (ELIS) as described by Chungue and Lam (7,8) or using the Panio dengue Duo IgM and IgG rapid strip test. Study design This is an open label observational study. The clinical manifestations and haematological profile of the illness were observed during the days prior to the defervescence of fever. Fever day 0 is defined as the day of defervescence of fever when the fever fell below 37.5 C. Days prior to fever day 0 were designated as fever day 1 (1 day before defervescence of fever), fever day 2(2 day before defervescence of fever) and so on. Days after the defervescence of fever is designated as fever day +1 (1 day after defervescence of fever), fever day +2 (2 days after defervescence of fever) and so on The 149 patients in this study were divided into 2 groups according to their lowest platelet count throughout the course of disease. Group (mild disease activity) is defined as the group of patients whose platelet nadir above 50 x10 9 /L (n = 29). Group (severe disease activity) is defined as the group of patients with platelet nadir below 50 x 10 9 /L (n = 120). Group is the combination of group and group i.e. the combined group. The objective of the group categorization is to find out the specific trend of haematological characteristic of the of severe disease activity group from that of mild disease activity group. Data and Statistical nalysis Data was analysed using SPSS statistical package version for Windows descriptive statistical analysis and the mean value of platelet, haemoglobin and total white cell were plotted. RESULTS ND DISCUSSION Patient demographic data total of 149 patients, 91 (61.1%) male and 58 (38.9%) female were studied. The mean age was 25.9 years. ll patients were in the age range of years. Length of hospital stay ranged from 2 to 20 days, with a mean of 4.5 days. The mean duration of the fever is 9 days. In our study the patients race distribution was 102 (68.4%) Malay, 36 (24.2%) Chinese, 11 (7.4%) Indians, and 4 (2.6%) other races. The race distribution correlates with the racial distribution of the country. Clinical findings Fever was a definite symptom that occurred in all patients. Headache occurred in 80.7% of cases followed by arthralgia, (74%), cutaneous lesion (73.3%), myalgia, (66.7%), vomiting (62.7%) and abdominal pain occurred in 48.7% of cases. in DHF patients. The results are comparable to that of Srichaikul (9) i.e. headache 92.5%, arthralgia 84%, vomiting 57% and abdominal pain 61%. For more details refer to Table 1. Haemorrhagic manifestation was seen in 75 patients (50.9%) manifested as petechial rash, gum bleeding, epistaxis, haematemesis, blood stained saliva, menorrhagia and onset of premature onset. ppearance cutaneous signs such as maculopapular rashes was seen 30% of patients (Srichaikul 18%), flushing in 3% and palmar oedema in 4% of patients. lthough there have been several studies on clinical features of dengue hemorrhagic fever, a thorough MEDLINE search has not revealed any published studies regarding the specific day to day observation of symptoms. In a study conducted by Deparis X et. l 10 observed day to day symptoms were documented in relation to the first day of fever. In our study, the patterns of the clinical features of 149 dengue patients were documented on the first day of admission. History was further taken to determine symptoms in relation to fever and the day of defervesence of fever was taken as reference point. The majority of symptoms had their maximum frequency at fever day 2 except for headache (50%) which peaked at fever day 4. This means that headache precedes all other symptoms like arthralgia, myalgia and vomiting. s headache is about to improve, other symptoms started to peak and progress and then rapidly disappear during defervescence of fever. Most symptoms cleared at fever day +2 (see Figure 1). For bleeding manifestation, epistaxis is the most common bleeding manifestation and peaked at fever day 2. Gum bleeding and bruising peaked at fever day 2 (see Figure 2). Comparing figure 1 and figure 2, we will see that bleeding manifestation lag behind other clinical symptoms. Laboratory investigation Out of 149 patients clinically diagnosed as DHF, 85 (57%) were serologically confirmed. Taking into account of the clinical diagnosis made based on assessment throughout the course of disease (hence excluding other febrile illness of known cause) the positive predictive value of the clinical diagnosis reaches 88.9% 9. The minimum platelet count on the first day of admission was 7x10 9 /L while the maximum reported was 167x10 9 /L. During the course of fever the total white count reaches its nadir before the deferversence of fever and start to rise again. This finding is well described by Srichaikul 9. Table 2 shows the frequency of clinical signs for Group and group that are calculated before and after the deferversence of fever. The variation trend of cumulative symptoms of DHF manifestations, start to decrease before the defervesence of fever (see Table 2). The haematological profiles of DHF are shown in Fig. 3, Fig. 4, and Fig. 5. In group, following the onset of fever, the platelet count starts to fall and become lowest at fever day 1 with mean of x10 9 /L (SD +/ 16.11) and subsequently the platelet and total white blood count ( 3.71x10 9 /L (SD+/ 2.36)) rise concurrently with time as shown in Fig. 3. In Fig. 4, we observed that the platelet count starts to fall following the onset of fever but there is a transient rise of platelet in group which reached peak at day 3 (mean 52.5 x10 9 /L +/ SD 38.79), subsequently the platelet count becomes lowest at day 0 (mean 37.28x10 9 /L, +/ SD 28.04) and started to rise following that. The rise of platelet in Group is lagging by 48 hours compared to that of total white cell count. However, statistical analysis for both group and group using single linear regression to predict platelet change using the change in total white count did not attain statistical significance. The overall platelet count in group became the lowest (mean 43.69x10 9 /L +/ SD 30.85) at the time the fever settled (fever day 0) following which it start to rise. The rise in platelet lagged behind white blood count (mean at day 1, 4.54x10 9 /L +/ SD3.44) by 24 hours as shown in Fig 5. This very interesting observation of the relationship between the trend of total white cell count and platelet could provide guidance in identifying the severe disease from that of the mild disease. In mild disease, the rise in platelet occurs before the defeversence of fever, where as in severe diseases the platelet will continue to drop until

3 deferversence of fever, following which the platelet starts to rise again. This finding was contrary to analysis of the full blood picture of done by Rebecca 11 that total white cell count did not have a definite pattern, and thus was not a very useful index In mild disease (as in group ), the total white cell count rise earlier fever day 1 and this rise in total white count occurs concurrently with that of platelet. However in the severe disease the total white count reaches its lowest and start to rise, the rise in total white count is only followed by the rise in platelet 48 hours later. Hence, the period of thrombocytopenia is longer in severe disease. This phenomenon may be explained by bone marrow suppression. review conducted by Srichaikul T. et. l 9 has indicated that suppression of haemopoiesis probably begins around 4 5 days after the inoculation of virus by the bites of the infected mosquito during the incubation period (5 8 days). This suppression lasted approximately 7 to 10 days and ended in the acute febrile phase approximately 2 to 3 days before the onset of shock or subsidence of fever 9. This may explain the first platelet trough. Srichaikul further expound that following haemopoeitic suppression, recovery of haemopoeisis with hypercellular marrow and increase in the number of megakaryocytes occur a few days before onset of shock or subsidence of fever and at this point of time our result shows that there is transient of platelet that subsequently start to drop and reached its nadir just before or during the subsidence of fever. With more severe disease more suppression of the bone marrow occurs. However, in severe bone marrow suppression, it is observed the platelet takes longer to rise compared to that of total white count in other words it takes longer to correct the platelet compared to that of total white cells. CONCLUSION There are definite trends of symptoms in relation to defeverscence of fever. Headache occurs early and bleeding symptoms occur much later i.e. towards defeversence of fever. The rise of the white blood count is useful indicator for prediction of the rise of platelet and this is a useful index in management of DHF. In mild disease the rise in platelet occurs simultaneously with that of total white count and the rise in platelet occurs early i.e. before defeverscence of fever compared to severe disease where platelet continue to drop until defeversence of fever and only start to rise following that. In severe disease, the rise in platelet is delayed by 24 to 48 hours after the rise in total white count. Transient rise in platelet during the course of fever is an interesting observation. Possible reason for this is that there maybe two mechanisms of thrombocytopenia i.e. bone suppression that occurs at early stage of disease and platelet consumption that occur later. The weakness of the study is that group only 29 patients, compared to 120 patients for group, not all patients were serologically confirmed. lthough we can see the above trend, the findings were not statistically significant hence further study need to be conducted with greater number of subjects. CKNOWLEDGEMENTS We are indebted to Dr. Mae Lynn Catherine astion, from Universiti Kebangsaan Malaysia for the dengue data collection and the Dean of Universiti Kebangsaaan Malaysia.

4 Table 1. Symptoms and signs recorded for hospitalised patients with dengue haemorrhagic fever. No of cases / 149 (100%) 121 (80.7%) 111 (74.0%) 110 (73.3 %) 100 (66.7 %) 94 (62.7%) 75 (50.9 %) 73 (48.7%) 51 (34.0%) 38 (25.3%) Clinical Features Fever Headache rthralgia Rash Myalgia Vomiting leedingtendency bdominal pain Retro orbital pain Sore throat

5 Table 2. Daily variations of the clinical symptoms of DHF signs relation to defeverscence of fever SYMPTOMS / GROUP DY 6 DY 5 DY 4 DY 3 DY 2 DY 1 DY 0 DY 1 DY 2 DY 3 Headache rthralgia Myalgia Vomiting bdominal pain Taste aberration Weakness of lower limb Sore throat Loss of appetite Diarrhoea Maculopapular rash Petechial rash Gum bleeding Epistaxis lood stained saliva Flushed face Malaena Haemoptysis Female menorrhagia Haematemesis Palmar oedema ruising Nausea Female premature menses

6 Figure 1. Distribution of the common clinical symptoms in relation to deferverscence of fever RT=rthalgia, MY=Myalgia, HE=Headache, VOM=Vomiting, TS=Taste aberration, DI=Diarrhoea and SOR=Sore throat

7 Figure 2. Distribution of the bleeding symptoms in relation to deferverscence of fever EPI= Epistaxis, GUM= Gum leeding, HTM= Haematemesis, RU=ruising, FEM= Female Menorrhagia, FEP= Female Premature Menses

8 Fig. 3. Group Dengue patients Haematological profile with platelet nadir greater than 50 x10 9 /L. Legend abreactions TWCmean= Mean value of total white blood count. TWCmed = Median value of total white blood count. Hbmean = Mean value of Haemoglobin. Hbmed = Median value of Haemoglobin. PLTmean = Mean value of Platelet. PLTmed = Median value of Platelet. PCVmean = Mean value of Packed cell value. PCVmed = Median value of packed cell value.

9 Fig. 4. Group Dengue patients Haematological profile with platelet nadir below than 50 x10 9 /L. Legend abreactions TWCmean= Mean value of total white blood count. TWCmed = Median value of total white blood count. Hbmean = Mean value of Haemoglobin. Hbmed = Median value of Haemoglobin. PLTmean = Mean value of Platelet. PLTmed = Median value of Platelet. PCVmean = Mean value of Packed cell value. PCVmed = Median value of packed cell value. Fig. 5. Group for 149 Dengue patients haematological profile. Legend abreactions TWCmean= Mean value of total white blood count. TWCmed = Median value of total white blood count. Hbmean = Mean value of Haemoglobin. Hbmed = Median value of Haemoglobin. PLTmean = Mean value of Platelet. PLTmed = Median value of Platelet.

10 PCVmean = Mean value of Packed cell value. PCVmed = Median value of packed cell value. REFERENCES 1. Rudnick,., Tan, E.E., Lucas, J.K. & Omar, M. (1965). Mosquito borne Haemorrhagic Fever in Malaya. ritish Medical Journal, 1, Gordon, S.C.E. (1986). Dengue: n Introduction. In: Dengue Fever Studies in Malaysia. Rudnick,. & Lim, T.W. (Editors), ulletin No. 23, Kuala Lumpur: Institute for Medical Research Malaysia, pp Gubler, D. J. & Kuno, G. (1997). Dengue and Dengue Hemorrhagic Fever: its history and resurgence as a global public health problem. In: Dengue and Dengue Hemorrhagic Fever, Gubler, D. J., and Kuno, G. (Editors), UK: C International, pp Vaughn, D. W., Green, S., Kalayanarooj, S., Innis,., Nimmannitya, S., Suntauakorn, S., Rothman,. L., Ennis, F. & Nisalak,. (1997). Dengue in Early Febrile Phase: Viremia and ntibody Responses. The Journal of Infectious Diseases, 176, World Health Organization Geneva. (1997). Dengue haemorrhagic fever: Diagnosis, treatment, prevention and control, 2 nd edition. Geneva: World Health Organization, pp George, R. & Duraisamy, G. (1981). leeding Manifestations of Dengue Haemorrhagic Fever in Malaysia. cta Tropica, 38, Chungue, E., outin, J. P. & Roux, J. (1989). ntibody capture ELIS for IgM antibody titration in sera for dengue serodiagnosis and surveillance. Research in Virology, 140, Lam, S.K., Devi, S. and Pang, T. (1987). Detection of specific IgM in Dengue infection. Southeast sian Journal of Tropical Medicine Public Health, 18, Tanomsri Srichaikul MD, MSc. and Suchitra Nimmannitya MD, MPH. Haematology in dengue and dengue haemorrhagic fever, ailliére s Clinical Haematology, Vol 13, No 2, pp , X.Deparis,. Murgue, C. Roche, O. Cassar and E. Chungue, Changing clinical and biological I manifestations of dengue during the dengue 2 epidemic in French Polynesia in 1996/97 description and analysis in a prospective study, Tropical Medicine and International Health, Vol 3 No 11 pp Nov Rebecca George, Clinical features and management of dengue haemorrhagic fever in Malaysia, ulletin No. 23. Institute for medical research Malaysia 1986: page [1] Damansara Specialist Hospital (Previously attached to Faculty of Medicine, Universiti Kebangsaan Malaysia). Correspondence to: Dr Saadiah Sulaiman 125 Jalan Jaya andar Tun Razak Cheras Kuala Lumpur, Malaysia < Saadiahazim@yahoo.co.uk> [2] Faculty of Engineering(Department of iomedical Engineering), University of Malaya, 50603, Kuala Lumpur, Malaysia. [3] Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia [4] Faculty of Electrical Engineering, Universiti Teknologi MR, Shah lam, Selangor, Malaysia [5] zzahrah Specialist Center, angi, Selangor, Malaysia