Post-infectious fatigue syndrome in dengue infection

Journal of Clinical Virology 38 (2007) 1–6

Post-infectious fatigue syndrome in dengue infection Raymond C.S. Seet a,b,∗ , Amy M.L. Quek b , Erle C.H. Lim a,b a

b

Department of Medicine, Yong Loo Lin School of Medicine, National University Singapore, Singapore Department of Medicine, National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074, Singapore Received 4 July 2006; received in revised form 1 October 2006; accepted 23 October 2006

Abstract Background: Although the acute manifestations of dengue are well known, few studies have assessed the long-term consequences of dengue infection. We prospectively studied the incidence and factors associated with fatigue in a cohort of patients following dengue infection. Methods: We included patients with serologically confirmed dengue infection admitted to the National University Hospital, Singapore, during a dengue outbreak from October–November 2005. The severity of dengue was graded as dengue fever, dengue haemorrhagic fever and dengue shock syndrome. A follow-up telephone interview was performed two months following hospital discharge, where a Fatigue Questionnaire was administered. The presence of significant fatigue was considered as the main outcome measure. Significance was assessed at P < 0.05. Results: One hundred twenty-seven patients, 71 (55.9%) males and 56 (44.1%) females, of mean age 36.06 years (range, 16–70; S.D., 13.722), participated in this study. Twenty-five (19.7%) patients had dengue haemorrhagic fever and the remaining 102 (80.3%) had dengue fever. In multivariate analysis, increased age, female sex, the presence of chills, and the absence of rashes were significantly associated with the development of fatigue post-dengue infection. There was no significant association between fatigue and dengue severity. Conclusions: This observation represents the first systematic evidence that dengue can result in clinical disease beyond the acute phases of infection. Host factors, such as age and sex may be important in the pathogenesis of this clinical entity. © 2006 Elsevier B.V. All rights reserved. Keywords: Dengue; Fatigue; Risk factors; Pathogenesis

1. Introduction Dengue is an important arboviral disease affecting 2.5 million people in more than 100 countries worldwide (Wilder-Smith and Schwartz, 2005). It has been estimated that 2.5 billion people, who live in these populous tropical and subtropical countries where dengue is endemic, are at risk of contracting the disease (Wilder-Smith and Schwartz, 2005). In Singapore, dengue has a year-round transmission with an incidence of 1–4 cases per 10,000. In the past two decades, a surge of outbreaks was observed in 1992, 1998 and 2004. To date, the highest number of cases in Singapore, with a population of four million, was recorded in 2004, with 9459 cases reported. Dengue infection is the ninth most com∗ Corresponding author at: Department of Medicine, National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074, Singapore. Tel.: +65 67722516; fax: +65 67794112. E-mail address: raymond [email protected] (R.C.S. Seet).

1386-6532/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jcv.2006.10.011

mon cause of hospitalization in Singapore, accounting for 8284 hospitalizations in 2004 and 3913 in 2002 (Ministry of Health Singapore, 2005). Dengue results in a spectrum of clinical presentations, from subclinical infection to severe haemorrhagic disease (WHO, 1997). Dengue fever is characterized by sudden onset of high fever, chills, severe headache (mostly frontal or retroocular), skin rash and general malaise which is usually benign and self-limiting (WHO, 1997). Two distinct clinical entities, dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS), have been associated with poorer outcomes (WHO, 1997). Increased systemic vascular leakage and disordered haemostasis are central to the circulatory shock and the shock complications of dengue infections. Haemorrhagic complications of dengue infection include skin and gum bleeding, haemoptysis, haematemesis, epistaxis and intracerebral haemorrhage (WHO, 1997). The mortality rate of DHF and DSS is high, approaching 5% (Wilder-Smith and Schwartz, 2005; Ong et al., in press).

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Fatigue is common during the acute stages of dengue infection (Kularatne, 2005; Schwartz et al., 1996; Zhang et al., 2005; Wittesjo et al., 1993) and is defined by the presence of a persistent sense of exhaustion that result in a decreased capacity for physical and mental work (Barofsky and Legro, 1991). A chronic and potentially incapacitating clinical entity, post-infectious fatigue syndrome, has been described in the later phases following an initial recovery of infections, such as infectious mononucleosis, Q fever, Lyme disease and Epstein–Barr virus (Prins et al., 2006). Although the persistence of fatigue following an acute dengue infection has been observed in adults and children (Kularatne, 2005), this phenomenon has not been systematically studied. During an outbreak of dengue infection, we performed a prospective follow-up study to assess the incidence of fatigue in a cohort of hospitalized patients with dengue infection, and to determine the association between postinfectious fatigue and clinical variables, such as demographic characteristics, symptoms, laboratory parameters and dengue severity.

2. Methods 2.1. Setting and patients We included patients with serologically confirmed dengue infection who were admitted to the Department of Medicine, National University Hospital, Singapore, from 1 October to 31 November 2005 during an outbreak of dengue infection. Informed consent was obtained prior to recruitment of patients into the study. During their admission, demographics characteristics and clinical information (symptoms, laboratory parameters and severity of dengue infection) were collected using a standardized questionnaire by trained interviewers (Seet et al., 2005). A follow-up telephone interview was performed 2 months following their discharge from hospital, where a questionnaire was administered to elicit fatigue symptomatology from the onset of dengue infection to two months later. The study protocol was approved by the ethics review committee of our hospital. 2.2. Demographic, clinical information, laboratory parameters We sought to determine if the patients had symptoms of fever, nausea, vomiting, chills, poor appetite, cough, abdominal pain, diarrhea (loose watery stool for more than three times a day), rashes, muscle pain or headaches within 24–48 h of admission. The results of haematologic and biochemical laboratory investigations, performed as part of routine clinical care, were obtained from the case-sheets. They were followed up in the outpatient clinic about 2 weeks from discharge and dengue serology was repeated in patients who had negative IgM to dengue during the hospital admission.

Patients were enrolled in the study if: (1) a diagnosis of dengue infection was confirmed serologically, they were (2) aged 16 years and above or (3) hospitalized. We excluded patients who: (1) had negative serum dengue IgM antibodies, (2) declined a telephone interview 2 months following hospitalisation and (3) did not converse in English. IgM and IgG antibodies to dengue were measured in the acute and convalescent sera using a double-sandwich capture ELISA (Innis et al., 1989). For single serum samples, 40 units of IgM to dengue were considered as evidence of acute dengue infection (Innis et al., 1989). In some patients, dengue virus RNA was performed by reverse transcriptase-nested PCR (Lanciotti et al., 1992). 2.3. Dengue severity The patients were classified and managed using the recommendations of the World Health Organization (WHO) (WHO, 1997). DHF was graded on discharge and was defined as the presence of plasma leakage and thrombocytopaenia, with platelet count <100,000 ␮L−1 (WHO, 1997). The evidence of plasma leakage was defined as a rise of haematocrit >20% from baseline, or from average haematocrit for age and sex of the population, or a drop in haematocrit of >20% after sufficient fluid therapy. Other criteria for plasma leakage were hypoproteinaemia, pleural effusion, and ascites. Haemorrhagic tendencies included a positive tourniquet test, skin bleeding (petechiae, ecchymoses or purpurae), mucosal bleeding (epistaxis, gum bleeding or other sites), haematemesis or malaena. 2.4. Fatigue assessment The presence of significant fatigue was measured by the Fatigue Questionnaire (FQ) (Dittner et al., 2004), administered during a telephone interview 2 months following their hospitalization. The FQ is a validated questionnaire, consisting of 11 items that measure fatigue-related symptoms encompassing the physical and mental dimensions. Physical fatigue corresponds to the subjective feeling of being exhausted and lacking energy, whereas mental fatigue describes the subjective feeling of being mentally exhausted, incorporating items on concentration, memory and speech. The seven items on physical fatigue and the four items on mental fatigue have four response categories (0 = none; 1 = mild; 2 = moderate; 3 = severe) (Table 1). Thus, higher scores imply more fatigue, with a maximum scale score of 33. The scale has good clinical validity in a variety of medical disorders, such as chronic fatigue syndrome, HIV, cancer and multiple sclerosis, in hospital and population-based studies alike (Dittner et al., 2004). By comparing the FQ with the fatigue question in the Revised Clinical Interview Schedule, a relative operating characteristics analysis suggested that a cutoff point of 4 or higher on the dichotomized scale would be the optimum cutoff for a case definition of fatigue (Fukuda

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Table 1 Fatigue Questionnaire

1. Do you have problems with tiredness? 2. Do you have problems starting things? 3. Do you feel weak? 4. Do you make slips of the tongue when speaking? 5. Do you need to rest more? 6. Are you lacking in energy? 7. Do you have difficulty concentrating? 8. How is your memory? 9. Do you feel sleepy or drowsy? 10. Do you have less strength in your muscles? 11. Do you have problems thinking clearly?

None

Mild

Moderate

Severe

0 0 0 0 0 0 0 0 0 0 0

1 1 1 1 1 1 1 1 1 1 1

2 2 2 2 2 2 2 2 2 2 2

3 3 3 3 3 3 3 3 3 3 3

et al., 1994). As no temporal criteria have been applied in the definition of post-infectious fatigue, the follow-up period of 2 months was arbitrarily chosen to reflect significant fatigue post-dengue infection.

Table 2 Demographic characteristics, symptoms and laboratory parameters of study participants (n = 127) Age (mean ± S.D.)

36.06 ± 13.722 years

2.5. Statistical analysis

Sex (%) Male Female

71 (55.9) 56 (4.1)

Race (%) Chinese Malay Indian Others

96 (75.6) 22 (17.3) 6 (4.7) 3 (2.4)

All quantitative data were expressed as the mean ± standard deviation (S.D.). Univariate analysis used Chisquare or Fisher’s exact test for comparisons of qualitative values or the unpaired Student’s t-test for quantitative values. Multivariate analysis used logistic regression. Significant fatigue was a subjective criterion that was compared against demographics, symptoms, laboratory and dengue severity covariates. Significance was assessed at P < 0.05. Adjusted odds ratio (OR) and 95% confidence intervals (CI) were derived from the coefficient of the final multivariate logistic model. All analyses were performed using SPSS 13.0 package (Release 12.0, SPSS Inc., 2003, Chicago, IL).

3. Results 3.1. Demographic variables

Demographic characteristics

Symptoms

Yes (%)

No (%)

Fever Nausea Chills Poor appetite Fatigue Cough Abdominal pain Vomiting Diarrhea Rashes Muscle pain Headaches

119 (93.7) 88 (69.3) 88 (69.3) 113 (89.0) 102 (80.3) 34 (26.8) 38 (29.9) 59 (46.5) 49 (38.6) 64 (50.4) 79 (62.2) 95 (74.8)

8 (6.3) 39 (30.7) 39 (30.7) 14 (11.0) 25 (19.7) 93 (73.2) 89 (70.1) 68 (53.5) 78 (61.4) 63 (49.6) 48 (37.8) 32 (25.2)

Laboratory features

Of the 163 consecutive patients who were evaluated, 36 patients were excluded (25 returned to their country of origin, 6 chose not to participate and 5 lacked an adequate understanding of the English language). A total of 127 patients were enrolled in this study and agreed to be interviewed 2 months following their hospital discharge. Their mean age was 36.06 years (range, 16–70; standard deviation, 13.722), 71 (55.9%) males and 56 (44.1%) females who were of Chinese (n = 96, 75.6%), Malay (n = 22, 17.3%) and Indian (n = 6, 4.7%) ethnicity (Table 2). The response rate of those who had consented to the telephone interview was 100%. 3.2. Clinical and laboratory parameters Fever (93.7%), poor appetite (89.0%), fatigue (80.3%), headaches (74.8%), nausea (69.3%), chills (69.3%), muscle

Haematologic parameters White cell count (×109 L−1 ) Haemoglobin (g/dL) Hematocrit (%) Platelet (×109 L−1 ) Biochemistry parameters Sodium (mmol/L) Potassium (mmol/L) Urea (mmol/L) Creatinine (mmol/L) Albumin (mmol/L) Total bilirubin (IU/L) Aspartate transaminase (IU/L) Alkaline transaminase (IU/L) Alkaline phosphatase (IU/L) Lactate dehydrogenase (mmol/L) Prothrombin time (s) Activated thromboplastin time (s)

Mean + standard deviation

Normal ranges

3.080 14.509 43.091 67.84

± ± ± ±

1.6164 2.0229 4.7595 30.280

4.0–11.0 13.1–17.3 39.9–51.9 130–400

135.68 3.71 3.83 78.48 39.04 10.64 187.03 107.01 71.09 1060.48

± ± ± ± ± ± ± ± ± ±

2.985 0.488 1.607 33.170 4.079 7.933 413.917 138.023 55.706 990.832

135–150 3.5–5.0 2.5–7.5 65–125 38–48 5–30 10–50 10–70 40–130 300–700

13.66 ± 1.587 40.02 ± 6.648

9.8–13.3 26.3–36.1

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pain (62.2%) and rashes (50.4%) were amongst the common symptoms amongst the study participants. Mean (standard deviation) white cell count was 3.080 × 109 L−1 (1.6164), haemoglobin 14.509 g/dL (2.0229), haematocrit 43.091% (4.7595), platelet count 67.84 × 109 L−1 (30.280), sodium 135.68 mmol/L (2.985), potassium 3.71 mmol/L (0.488), urea 3.83 mmol/L (1.607), creatinine 78.48 mmol/L (33.170), albumin 39.04 mmol/L (4.079), total bilirubin 10.64 IU/L (7.933), aspartate transaminase 187.03 IU/L (413.917),

alkaline transaminase 107.01 IU/L (138.023), alkaline phosphatase 71.09 IU/L (55.706), lactate dehydrogenase 1060.48 IU/L (990.832), prothrombin time 13.66 s (1.587) and activated thromboplastin time 40.02 s (6.648) (Table 2). 3.3. Dengue severity and virological features Twenty-five (19.7%) patients were diagnosed with dengue haemorrhagic fever and the remaining 102 (80.3%) had

Table 3 Summary of demographic, symptoms and laboratory parameters of patients with significant fatigue following dengue infection Fatigue

Demographic characteristics Age (mean ± S.D.)†

Race Chinese Malay Indian Others Symptoms Fever Nausea Chills† Poor appetite Fatigue Cough Abdominal pain Vomiting Diarrhea Rashes† Muscle pain Headaches

Odds ratio (95% confidence interval)

0.006

1.118 (1.033–1.209)

Yes (%) (n = 31)

No (%) (n = 96)

39.00 ± 13.051

35.11 ± 13.865

14 (45.2%) 17 (54.8%)

57 (59.4%) 39 (40.6%)

20 (64.5%) 6 (19.4%%) 2 (6.5%) 3 (9.7%)

76 (79.2%) 16 (16.7%) 4 (4.2%) 0

27 (87.1%) 24 (77.4%) 25 (80.6%) 28 (90.3%) 24 (77.4%) 7 (22.6%) 8 (25.8%) 15 (48.4%) 14 (45.2%) 18 (58.1%) 20 (64.5%) 24 (77.4%)

92 (95.8%) 64 (66.7%) 63 (65.6%) 85 (86.5%) 78 (81.3%) 27 (28.1%) 30 (31.3%) 44 (45.8%) 35 (36.5%) 46 (47.9%) 59 (61.5%) 71 (74.0%)

0.277 0.277 0.034 0.538 0.450 0.146 0.257 0.750 0.059 0.026 0.477 0.320

0.310 (0.037–2.561) 0.310 (0.037–2.561) 6.904 (1.157–41.202) 0.465 (0.041–5.324) 0.795 (0.635–0.925) 3.467 (0.648–18.558) 2.593 (0.498–13.496) 0.737 (0.113–4.819) 0.193 (0.035–1.068) 0.113 (0.017–0.774) 1.905 (0.323–11.237) 0.387 (0.060–2.512)

3.101 ± 1.5836 14.568 ± 1.9090 43.241 ± 4.2707 67.25 ± 29.490

0.367 0.689 0.267 0.146

1.284 (0.746–2.210) 0.858 (0.405–1.816) 1.235 (0.851–1.793) 1.022 (0.992–1.053)

Sex† Male Female

P-value

0.015 1.000 9.687 (1.546–60.684) 0.178

Laboratory features (mean ± standard deviation) Hematologic parameters White cell count (×109 L−1 ) 3.015 ± 1.7398 Haemoglobin (g/dL) 14.326 ± 2.3667 Hematocrit (%) 42.626 ± 6.0902 Platelet (×109 L−1 ) 69.68 ± 33.050 Biochemistry parameters Sodium (mmol/L) Potassium (mmol/L) Urea (mmol/L) Creatinine (mmol/L) Albumin (mmol/L) Total bilirubin (IU/L) Aspartate transaminase (IU/L) Alkaline transaminase (IU/L) Alkaline phosphatase (IU/L) Lactate dehydrogenase (mmol/L)

135.32 ± 3.156 3.69 ± 0.624 3.70 ± 1.957 80.29 ± 56.333 38.84 ± 3.891 11.03 ± 10.002 276.42 ± 766.775 124.48 ± 223.164 79.97 ± 78.385 1268.94 ± 1693.677

135.80 ± 2.935 3.72 ± 0.437 3.87 ± 1.483 77.88 ± 21.021 39.11 ± 4.157 10.51 ± 7.181 157.55 ± 187.710 101.24 ± 95.916 68.16 ± 46.050 991.73 ± 603.656

0.311 0.576 0.066 0.227 0.091 0.211 0.313 0.697 0.717 0.515

0.850 (0.620–1.164) 0.618 (0.114–3.341) 0.445 (0.187–1.055) 1.026 (0.984–1.069) 1.234 (0.967–1.576) 0.936 (0.844–1.038) 1.004 (0.996–1.013) 0.997 (0.980–1.013) 0.995 (0.966–1.024) 0.999 (0.997–1.001)

Prothrombin time (s) Activated thromboplastin time (s)

13.98 ± 1.031 42.12 ± 9.467

13.56 ± 1.722 39.32 ± 5.294

0.577 0.322

1.170 (0.674–2.031) 1.084 (0.924–1.273)

7 (22.6%)

18 (18.8%)

0.855

0.851 (0.151–4.783)

Dengue severity Dengue haemorrhagic fever †

P < 0.05, by logistic regression analysis.

R.C.S. Seet et al. / Journal of Clinical Virology 38 (2007) 1–6

dengue fever. DEN-1 was isolated from the serum of 20 patients, DEN-3 in six patients and DEN-4 in one patient. None had received blood transfusion products during their acute hospitalization. 3.4. Fatigue assessment Significant fatigue was present in 31 (24.4%) patients. The relationships between the demographic features, symptoms, laboratory features and dengue severity characteristics, and the presence of significant fatigue are shown in Table 3. None of the patients had any symptoms of infection from the onset of dengue infection to the interview. In multivariate analysis, increased age (OR 1.118, 95% CI 1.033–1.209), female sex (OR 9.687, 95% CI 1.546–60.684), the presence of chills (OR 6.904, 95% CI 1.157–41.202) and the absence of rashes (OR 38.462, 95% CI 1.292–58.824) were significantly associated with the development of fatigue, post-dengue infection. There was no significant association between haematologic and biochemical parameters, and dengue severity.

4. Discussion Post-infectious fatigue was observed in approximately 25% of hospitalized patients with dengue infection. Important risk factors for the development of fatigue included older age, female sex, the presence of chills and the absence of rashes. The incidence of fatigue following dengue infection, however, is lower when compared to those following the Epstein–Barr virus (38–40%) (White et al., 2001; Buchwald et al., 2000) and Q-fever (31%) (Ayres et al., 1998). Although disabling long-term outcomes, such as transverse myelitis (Seet et al., 2006) and Guillain–Barre syndrome (Patey et al., 1993) have been previously reported in case reports, this study represents the first systematic evidence that dengue can result in clinical disease beyond the acute phases of infection. The pathogenesis of post-infectious fatigue is likely multifactorial and may result from a combination of pathogenic effects produced by the virus and the immune response of the host to the virus. In dengue infection, aberrations in the immune response is thought to trigger a complex series of immune responses, followed by transient aberration in the immune response resulting in an inversion of the CD4/CD8 ratio and an overproduction of cytokines, such as C3a and C5a that result in an immune-mediated damage to the endothelial cells (Guzman and Kouri, 2002). This may prompt a complex interaction of the immune, endocrine, musculoskeletal and neurological systems, possibly through the hypothalamic–pituitary–adrenal axis and the autonomic nervous system, to result in the clinical phenomenon of fatigue following dengue infection (Ader et al., 1991). A higher frequency of post-infectious fatigue in older patients and females suggest that host factors are important in the pathogenesis of post-infectious fatigue in dengue infection. Certain attributes, such as reproductive function

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(Harlow et al., 1998), genetic constitution (Prins et al., 2006) and psychosomatic handling of stress (Deale et al., 1998), may underlie the predisposition to fatigue in females. The significance of chills and the absence of rashes as predictors of fatigue are not certain. The relative importance of host genetic factors is also suggested by the different susceptibility to dengue haemorrhagic (DHF) in the various racial and sex groups (Halstead, 1988). Recent studies on the different HLA associations in DHF lend support to the importance of the host factor in modulating the effects of dengue infection (Stephens et al., 2002; LaFleur et al., 2002; Zivna et al., 2002). In contrast, the lack of association between the severity of dengue infection and post-infectious fatigue in the current study suggest that viral factors may be less important in the pathogenesis of fatigue. Our study has several limitations. First, only hospitalized patients with symptomatic infections were recruited and those with asymptomatic infections who do not require hospitalization were not studied. Further population-based studies should be performed to determine the burden of disease within the community. Second, although our patients had serological confirmation of dengue infection, the possibility of a concurrent co-infection that may have ameliorated or aggravated fatigue could not be excluded. Third, the premorbid psychological make-up of the patients, which may influence the perception of fatigue, was not included in this study. These limitations, however, should be set against the strengths of the prospective study design and high rates of follow-up. We describe a syndrome of post-infectious fatigue that occurred in the later stages of dengue infection and provide evidence that dengue can result in clinical disease beyond the acute phases of infection. The association of age and female sex, but not dengue severity, with the development of fatigue suggests that host factors are important in the pathogenesis of post-infectious fatigue in dengue infection. The mechanisms for fatigue following dengue infection are not known and may be explained by the immune alterations that are triggered by the dengue virus. Further studies are needed to better understand this clinical entity. Conflict of interest statement We declare that we have no conflict of interest. Acknowledgements We thank Adeline Chow, Guo Yaling, Dr. Goh Khean Teik, the medical and nursing staff of the National University Hospital, Singapore, for their contributions to this study. Contributors: Raymond C.S. Seet took part in study conception and design, interpretation of results, drafted the initial manuscript and revision for important content. Amy M.L. Quek participated in the study design, acquisition and interpretation of results, and revision for important content. Erle

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C.H. Lim contributed to the study design, interpretation of results, and revision for important content.

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