INTRODUCTION

Non-specific viral febrile illness is a common encounter in an outpatient clinic (Teng et al. 2003). It is an important entity especially in countries where dengue infection is prevalent. This is because one of the common presenting symptoms of dengue infection is non-specific febrile illness (Gibbons and Vaughn 2002). Many clinicians would report and manage a case of acute non-specific viral febrile illness with thrombocytopaenia as dengue infection based on clinical assessment alone (Audit of Dengue notification in Pusat Perubatan Primer HUKM 2004).

However, dengue infection is only one of the many causes of acute febrile thrombocytopaenia. Other causes of febrile thrombocytopaenia include scrub typhus, chikungunya fever, infectious mono-nucleosis, malaria, typhoid fever, leptospirosis  and acute human immuno-deficiency virus conversion disease (Vaughn and Green. 2000). Reporting every case of acute non-specific viral febrile thrombocytopaenia as dengue infection would lead to over reporting. Furthermore, managing all cases of acute non-specific viral febrile illness with thrombocytopaenia as dengue infection may not be appropriate as acute non-dengue viral febrile illness with thrombocytopaenia may differ in their natural history and treatment from dengue infection. Some require less intensive monitoring as in chikungunya fever; some may need antibiotics such as scrub typhus and typhoid fever; some may have other serious outcome such as splenic rupture in infectious mononucleosis and acute human immunodeficiency virus conversion disease. Hence it is important to differentiate patients presenting to the outpatient setting with acute non-dengue febrile thrombocytopaenia from those having dengue infection. Deparis et al in 1998 reported 15.5% of acute non-dengue febrile patients have thrombocytopaenia. There is no published data on the prevalence of such an entity among patients presenting with acute non-specific viral febrile illness. Knowing its prevalence will help us estimate the magnitude of the problem. The objective of this study was to determine the prevalence of non-dengue febrile thrombocytopaenia among febrile patients presenting to the outpatient clinic.

MATERIALS AND METHOD

This was a cross sectional study of a group of patients attending the Primary Care Center of Hospital Universiti Kebangsaan Malaysia (HUKM) and Batu 9 Health Clinic Hulu Langat, from May to November 2003. Consecutive patients who fulfilled the study criteria were invited to participate in the study. The inclusion criteria were age 12 years and above with a history of fever of less than two weeks. Fever was defined as recorded oral temperature of more than 37.5oC. Patients were excluded if there was an apparent localised source of infection e.g. urinary tract infection or acute abdomen. Any illness with pathognomonic clinical features e.g. varicella infection, measles, rubella, scarlet fever and obvious features of dengue haemorrhagic manifestations were also excluded. Consents were taken from all eligible patients before enrolling them into the study.

Full blood count examination was carried out for every patient seen. Patients were assumed to have dengue infection if thrombocytopaenia (platelet count of ≤ 150X109/L) was detected. They were managed as per protocol for management of dengue infection. All the other patients with normal platelet count were called back on day 5 of illness for a repeat full blood count so as not to miss any possibility of thrombocytopaenia. Dengue serology was done for all patients on day five of illness, as early blood sampling of less then day five of illness might yield false negative results. If the patients require admission anytime during the study, the data was than collected from hospital records.

Dengue serology tests were run with PanBio Rapid Immunochromatography method in the virology laboratory, HUKM. The methods, reagents used and interpretation of results were as described by the manufacturer. Primary acute dengue infection is defined as a positive serology test of IgM alone. Secondary infection is defined as a positive IgG with or without a positive IgM. Collectively, both primary and secondary infections constitute acute dengue infection. A negative result is when both IgG and IgM are negative.

Statistical analysis and sample size calculation

Analysis of the data was carried out using SPSS version 11. The denominator is the total number of cases presented as non-specific febrile illness. Calculated minimal sample size of 61 patients was required, based on the estimated prevalence of non-dengue thrombocytopaenia of 20% (95% confidence interval; worst estimated of 10%) among patients presenting with acute non-specific viral febrile illness. Ethics approval was obtained from the research and ethics committee of the Medical Research Center UKM.

RESULTS

153 patients were screened, 49 did not give consent for the study and 17 were excluded for not fulfilling the criteria. Fourteen patients defaulted follow up as they claimed to be well and refused reassessment. Complete data was available for 73 patients. Mean age of the patients in this study was 27.3 years (27.3, SD±11.1). Their baseline characteristics are presented in table 1. Figure 1 summarises the number of patients enrolled in this study. The majority of the patients enrolled were Malay (72.6%).

Thirty five of 73 patients were found to have thrombocytopaenia. Hence, the prevalence of thrombocytopaenia among acute non-specific febrile illness was 47.9%. Among these patients, 40% (14) were serologically negative for dengue infection, and only 60% (21) were diagnosed to have dengue infection. The overall prevalence of acute non-dengue viral thrombocytopaenia among patients presenting with non-specific viral fever is therefore 19.2%.

Of the remaining 38 patients with the normal platelet count, three were tested positive for dengue serology. Therefore, total number of dengue infection was 24 and hence the prevalence of dengue infection among patients presenting with non-specific viral fever was 32.9%.

DISCUSSION

This study confirmed that thrombo-cytopaenia is common among adult patients with non-specific febrile illness. About half of them (47.9%) had thrombocytopaenia. A significant proportion of patients with thrombocytopaenia (40%) were serologically negative for dengue infection. Hence, equating all patients with thrombocytopaenia as having dengue infection may lead to over diagnosis. However, one has to be cautious when interpreting this data. Panbio Rapid Immunochromatography test kit was used as a gold standard for diagnosis in this study. Serologically negative result for dengue does not rule out dengue infection. Antigen detection by polymerase chain reaction, viral culture or paired serology should be used as the gold standard for diagnosis (WHO 1997).Therefore, even though Panbio Rapid Immunochromato-graphy test kit has very good sensitivity and specificity, false positive and negative test results do occur. In reference to a local study by Lam et al., the false negative rate of this Panbio Rapid test was 0% (sensitivity of 100%) and the false positive rate was 11% (specificity of 89%) (Lam and Devine 1998). Whereas, Vaughn et al. demonstrated that 80% of dengue patients would show a diagnostic level of secondary dengue infection by day 1 of defervescence using haemagglunition-inhibition test (HAI, in detecting IgG) which gave a false negative of 20%. Day of defervescence was defined as the day when the temperature dropped below 38oC which commonly occurs around day 5 to 7 of illness (Vaughn et al. 1997). In the present study, the false negative rate for serological diagnosis using Panbio Rapid Immunochromatography test was probably less then 20%. Considering the rate of false negative as 20%, there would still be 11 patients (33.3%) with seronegative results and the prevalence of acute non-dengue viral thrombocytopaenia among patients presenting with non-specific viral fever would therefore be 15.1%.

Deparis et al reported that 15.5% of acute non-dengue febrile patients have thrombocytopaenia (Deparis et al. 1998). However, patients from this study were among those suspected to have dengue infection, and not all patients with acute non-specific febrile illness were from an outpatient setting. From this data, it is evident that non-dengue thrombo-cytopaenia is a significant entity that should be differentiated with dengue infection. It is important to differentiate between these two groups, as acute non-dengue febrile thrombocytopaenia might be different in their natural history from those with dengue infection. At present, all patients with acute non-specific febrile illness and thrombo-cytopaenia are assumed to have dengue fever, and they are managed as such. This may not be the appropriate management as the other causes of febrile thrombo-cytopaenia require different management strategies.

In this study, data were collected prospectively in order to standardise data collection and to minimise incomplete data. The patients selected were all from outpatient clinic with non-specific viral febrile illness and the result confirmed that dengue infection indeed is a common problem among them during the non-epidemic season, whereby the prevalence was 32.9%. The prevalence of dengue infection is consistent with that of other studies, where dengue infection is endemic, ranging from 21%-35% (Trofa et al. 1997, Deparis et al. 1998, Akram et al. 1998, Kalayanarooj et al. 1998). However, 32.8% of the patients eligible for this study were unwilling to participate. They were probably suffering from a milder form of non-dengue viral fever. Hence, the true prevalence might be lower then 32.9%. During an epidemic episode, the prevalence might increase up to as high as 90% (Teerakut et al. 1990).There is no published data on the prevalence of dengue infection among patients presenting with undifferentiated fever from Malaysia. Chin et. al. in 1993 reported 69.4% and 85.7% of clinically diagnosed dengue fever and dengue haemorrhagic fever respectively were serologically positive. However, these were among patients with clinically diagnosed dengue infection and not all patients with undifferentiated fever (Chin et al. 1993).

CONCLUSION

Non-dengue febrile thrombocytopaenia is a significant entity among adult patients with acute non-specific febrile illness. 19.5% of these patients had non-dengue febrile thrombocytopaenia and 40% of thrombocytopaenic febrile patients were seronegative for dengue infection. It may not be appropriate to manage them as dengue infection because the course of the illness may differ significantly from dengue infection. A future study on this group of patients is needed in order to gain better understanding of its aetiological agents, natural history and hence guide us on the appropriate management.

ACKNOWLEDGEMENTS

We are grateful to Dr. Leelavathy, Dr. Hazizi, Dr. Aida, Dr. Wasilah, Dr. Nor Azila, M/A Azhar and Fairul for their participation in collection of data. I would like to thank all the laboratory assistants from Batu 9 Health Clinic and Primary Care Clinic Hospital Universiti Kebangsaan Malaysia Bandar Tasik Selatan, who helped with the laboratory tests