Potential Harm of Prophylactic Platelet Transfusion in Adult Dengue Patients

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Abstract

Background

Thrombocytopenia is a hallmark of dengue infection, and bleeding is a dreaded complication of dengue fever. Prophylactic platelet transfusion has been used to prevent bleeding in the management of dengue fever, although the evidence for its benefit is lacking. In adult dengue patients with platelet count <20,000/mm ³ without bleeding, we aimed to assess if prophylactic platelet transfusion was effective in reducing clinical bleeding and other outcomes.

Method

We conducted a retrospective non-randomised observational study of dengue patients with platelet count < 20,000/mm ³ without bleeding (except petechiae) admitted to Tan Tock Seng Hospital from January 2005 to December 2008. Baseline characteristics and clinical outcomes were compared between the non-transfused vs. transfused groups. Outcomes studied were clinical bleeding, platelet increment, hospital length of stay, intensive care unit admission and death.

Results

Of the 788 patients included, 486 received prophylactic platelet transfusion. There was no significant difference in the presence of clinical bleeding in the two groups (18.2% in non-transfused group vs. 23.5% in transfused group; P = 0.08). Patients in the transfused group took a median of 1 day longer than the non-transfused group to increase their platelet count to 50,000/mm ³ or more (3 days vs. 2 days, P <0.0001). The median duration of hospital stay in the non-transfused group was 5 days vs. 6 days in the transfused group (P< 0.0001). There was no significant difference in the proportion requiring ICU admission (non-transfused 0.66% vs. transfused 1.23%, P = 0.44) and death (non-transfused 0% vs. transfused 0.2%, P = 0.43).

Conclusion

Platelet transfusion in absence of bleeding in adult dengue with platelet count <20,000/mm ³ did not reduce bleeding or expedite platelet recovery. There was potential harm by slowing recovery of platelet count to >50,000/mm ³ and increasing length of hospitalization.

Author Summary

Thrombocytopenia is one of the most prominent clinical features in dengue infection. This may manifest clinically as bleeding, which carries significant morbidity and mortality. For many years, clinicians have given dengue patients platelet transfusion in a bid to increase their platelet counts to prevent hemorrhagic manifestations. However, this practice has not been proven to reduce the risk of bleeding in dengue. Conversely, transfusion of blood products may be detrimental to patients as it can carry risks of fluid overload, transmission of infectious diseases and transfusion reactions. In this study, the authors found that platelet transfusion in the absence of bleeding in adult dengue patients did not prevent bleeding. Instead, this practice is associated with a slower platelet recovery and increased length of hospitalisation. These findings may contribute to better clinical management of thrombocytopenia in dengue patients and limit the use of these precious blood products.

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Risk factors and clinical features associated with severe dengue infection in adults and children during the 2001 epidemic in Chonburi, Thailand.

Ole Wichmann, Suchat Hongsiriwon, Chureeratana Bowonwatanuwong … (2004)

Dengue haemorrhagic fever (DHF) is an important cause of morbidity in South-east Asia and used to occur almost exclusively in young children. In recent years, there has been a progressive shift in age-distribution towards older children and adults. We investigated an outbreak in 2001 in both children and adults, in an endemic area of Thailand. Retrospective study of 347 patients with serologically confirmed dengue infection admitted to Chonburi Hospital during an epidemic in 2001. A total of 128 (37%) patients had dengue fever (DF) and 219 (63%) had DHF. Patients with DHF were significantly older than patients with DF (11 years vs. 8 years). Clinical bleeding was noted in 124 individuals, both with DF (n = 24) and DHF (n = 100), and significantly more frequently in adults. Twenty-nine (13.2%) of all DHF cases were caused by primary infection. Secondary dengue infection was associated significantly with the development of DHF in children, OR (95% CI) = 3.63 (1.94-6.82), P < 0.0001, but not in adults, OR (95% CI) = 0.6 (0.02-6.04), P = 1. Unusual clinical manifestations were observed in 23 patients: three presented with encephalopathy and 20 with highly elevated liver-enzymes. In the latter group, four patients were icteric and nine had gastrointestinal bleeding. These results indicate that DHF in South-east Asia is common in both children and adults. In dengue-endemic countries, dengue should be considered as a differential diagnosis in patients with clinical gastrointestinal bleeding in association with increased liver enzymes.

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Clinical Features of Dengue in a Large Vietnamese Cohort: Intrinsically Lower Platelet Counts and Greater Risk for Bleeding in Adults than Children

Trung Dinh The, Thao Le Thi Thu, Dung Nguyen Minh … (2012)

Introduction Dengue is emerging as the most important mosquito-borne viral disease in the world. Infection with any of the four dengue viral (DENV) serotypes may result in asymptomatic infection or cause a variety of disease manifestations ranging from non-specific viral illness to a systemic vascular leak syndrome that is typically accompanied by thrombocytopenia, impaired haemostasis and liver dysfunction [1]. Shock due to severe plasma leakage occurs in a proportion of these patients, but other serious complications appear to be rare. The disease has spread rapidly across the tropical and sub-tropical world , with current estimates indicating around 50 million symptomatic infections occur annually [1]. In Southeast Asia, the epicenter of the current pandemic, dengue used to affect children predominantly but recently increasing numbers of young adults have required hospitalization [2], [3], [4]. One plausible explanation for this trend could be a reduction in the force of infection due to socioeconomic development and/or improved vector control such that fewer people are exposed during childhood leaving a larger reservoir of susceptible adults [5]. Alternatively lower birth and death rates in transitioning economies may decrease the flow of susceptible individuals into the population and increase the longevity of immune individuals, increasing the likelihood that an infectious mosquito will feed on an immune individual [6]. Reports describing the clinical picture in adults have only recently started to emerge, and suggest that unusual complications with high mortality such as acute liver failure, encephalopathy, myocarditis and acute renal failure are more common in this group than in children [2], [7]. In one study from Nicaragua signs of vascular leakage, shock and marked thrombocytopenia were seen less commonly with increasing age, although internal haemorrhage occurred more frequently in the adult subjects [8]. In a small prospective study from Sri Lanka, evidence of vascular leakage and shock were also seen more frequently in children compared to adults, although bleeding manifestations were similar [9], while in three small studies from Southeast Asia bleeding manifestations, thrombocytopenia and hepatic dysfunction were seen more commonly in young adults with the frequency of shock similar to the paediatric patient group [2], [3], [10]. Since 2004 we have been conducting large prospective descriptive studies of dengue encompassing the full spectrum of disease presenting to the Hospital for Tropical Diseases (HTD) in Ho Chi Minh City [11], [12], [13]. In this report we aimed to describe the patterns of disease, management strategies, and outcomes, comparing paediatric and adult cases recruited systematically into these studies during specified time-periods. Methods Patients and clinical methods The following groups are eligible for recruitment after written informed consent is obtained from all patients or their parents/guardians: a) children 2–15 years old admitted to the Paediatric Intensive Care Unit (PICU) with clinically suspected dengue and overt complications; b) patients ≥15 years old with suspected dengue admitted to the Adult Intensive Care Unit (AICU) for any reason; c) children 5–15 years old or adults ≥15 years old admitted to the paediatric or adult infection wards with suspected dengue. Ethical approvals are obtained from the Scientific and Ethical Committee of the Hospital for Tropical Diseases and the Oxford University Tropical Research Ethics Committee UK. Eligibility criteria are deliberately broad to allow the study physicians to invite all potential subjects with suspected dengue to participate. However, the PICU is extremely busy and as study enrollment adds to staff workload children are eligible for recruitment only if complications severe enough to warrant intervention develop; patients who are admitted for close observation but receive no specific treatment other than maintenance fluid therapy are not recruited. Secondly, children less than 5 years old have a much lower risk for symptomatic dengue disease than older children, and as the study protocols request daily blood samples we elect not to subject young children admitted to the infection wards with non-severe febrile illness that is unlikely to be dengue, to this discomfort. Demographic information, clinical history and examination details are recorded on specific case report forms (CRFs) and all subjects are seen once daily until discharge by experienced study physicians trained to record all events occurring in the previous 24 hours directly into the CRF. Diagnostic samples for dengue serology/virology are obtained at study enrolment and hospital discharge. Management remains in the hands of the ward clinicians following hospital policies and WHO guidelines. All participants are invited for review several weeks after discharge when a final diagnostic blood sample is obtained. For this comparison we included all patients recruited on the ICUs during the two years between September 2006 and September 2008 and all patients recruited in the infection wards during the year 2007. HTD is the main referral hospital for adults with dengue for southern Vietnam but receives few paediatric referrals. Since referred patients are likely to have more severe disease than direct admissions we considered these two groups separately and structured the comparisons between the age groups to take into account the route of admission. Definitions for all clinical complications assessed are presented in Table 1. 10.1371/journal.pntd.0001679.t001 Table 1 Definitions for complications seen in confirmed dengue cases. Complication Definition Dengue shock syndrome Hypotension for age or narrowing of the pulse pressure ≤20 mm Hg, with impaired peripheral perfusion [1], if considered to be caused by plasma leakage not bleeding, and requiring volume resuscitation Bleeding severity Bleeding severity was coded retrospectively at discharge into four categories [12], [13]:-1. no clinical bleeding detected throughout observation2. minor skin bleeding only (petechiae or bruising at venepuncture sites)3. mild/moderate mucosal bleeding (no intervention required) with or without minor skin bleeding4. severe bleeding - bleeding requiring intervention (eg transfusion, nasal packing), or bleeding into a vital organ (e.g. intracranial bleeding) Fluid overload Respiratory distress due to significant ascites and/or pleural effusions, without evidence of any other respiratory pathology such as pneumonia Encephalopathy Any degree of mental alteration (Glasgow coma score ≤14) Acute liver failure Any degree of mental alteration with increased liver enzymes and a coagulopathy (demonstrated by an international normalized prothrombin ratio ≥1.5) in patients without evidence of pre-existing cirrhosis [25] Severe liver dysfunction Either acute liver failure (as above), or new onset of jaundice with significant increase in transaminase levels (≥300 U/L) considered to be due to dengue, without evidence of any other pathology such as acute viral hepatitis Acute renal failure Increase in serum creatinine at least 3 times baseline, or serum creatinine ≥4 mg/dl with an acute increase of >0.5 mg/dl [26] Laboratory investigations Platelet counts and haematocrit measurements were performed at least once daily on all study patients in the hospital laboratory, with additional haematocrit measurements performed on the ICUs as frequently as required for clinical management. Overall percentage haemoconcentration was calculated as previously described [12], [13]. Liver function tests and coagulation screening tests were only carried out on adults during this time and the findings have been reported elsewhere [13]. Dengue diagnostic capture IgM and IgG ELISA assays were performed using paired enrolment and convalescent specimens and reagents provided by Venture Technologies (Sarawak, Malaysia) [14]. Using the enrolment specimen, DENV RT-PCR was carried out as previously described for a) all paediatric patients (who were generally admitted early) and b) all adult patients enrolled within the first 5 days of illness, and those with negative or inconclusive serology [14]. If both serology and RT-PCR were negative or inconclusive, assays for non-structural protein 1 (NS1) were performed using Biorad Platelia™ Dengue NS1 Antigen kits following the manufacturer's instructions. Patients were diagnosed to have confirmed dengue if the RT-PCR and/or NS1 results were positive, seroconversion was documented on paired serology, or dengue specific IgM was identified in a patient with a typical clinical syndrome. To define immune-status the ratio of IgM to IgG on or after day 6 of illness was used; a ratio ≥1.78 defined the infection as primary and one ≤1.2 as secondary [15]. Patients with ratios between these values, or in whom the results of enrolment and convalescent specimens differed, were considered unclassifiable. Statistical analysis Data on clinical characteristics and laboratory results were compared between different patient groups using the Chi-square test or Fisher's exact test for categorical variables, and the Mann Whitney test or the Cuzick test for trend for continuous variables. When comparing platelet counts between children and adults we used multiple linear regression to assess the effect of covariates including age-group (age 95% of all such cases) plus a further 19 children who were recruited into the study in the paediatric infection ward and subsequently transferred to PICU with clinical DSS (Figure 1). There were no external referrals from other facilities during the two-year period. Of the 407 children studied, 402 (99%) were confirmed to have dengue, and the remaining 5 had inconclusive results. Immune status could be reliably determined in 325/402 (81%) of cases, of whom 18 children with DSS (6%) had primary infections (DENV-1 = 13; DENV-2 = 1; unknown serotype = 4). 10.1371/journal.pntd.0001679.g001 Figure 1 Profile of patients studied on the intensive care units (Panel A) and the infection wards (Panel B). * These 111 patients were admitted to AICU for close observation but did not go on to develop shock or other complications. Due to workload constraints children admitted to PICU with suspected dengue were only enrolled into the observational study if they developed overt complications. ** Note that these patients were recruited into the study in the infection wards and subsequently transferred to PICU/AICU. During the same two-year period 341 adults admitted to AICU with suspected dengue were also recruited (90% of all suspected dengue admissions to AICU), of whom 315 (92%) were subsequently confirmed to have dengue. Among the remaining 26 patients, 24 had negative dengue diagnostics and/or an alternative final clinical diagnosis (idiopathic thrombocytopenic purpura, septic shock, non-dengue encephalitis, hantavirus infection) and 2 patients had inconclusive dengue diagnostics. Only 186/315 (59%) of the adults with confirmed dengue were admitted directly to HTD with the remaining 129 (41%) being external referrals from other facilities. 110/315 (35%) of the adults studied in AICU had DSS (59 direct admissions and 51 external referrals), 94 (30%) experienced a variety of other complications (47 direct admissions and 47 external referrals), and 111 (35%) were admitted for close observation (79 direct admissions, 31 external referrals, 1 internal referral) but ultimately recovered without developing overt complications (Figure 1). Immune status could be determined in 260/315 (83%) of the patients in AICU, only 16 of whom had primary disease, with only 1 case identified among the patients with shock. Patients with DSS: Table 2 presents a summary of key clinical features, management, and basic laboratory findings, comparing children and adults admitted directly to the two ICUs. Over the two-year period almost 7 times as many children as adults were admitted directly with DSS. The median age for paediatric patients was 9 years. Most adults were in their twenties or early thirties with no patient older than 37 years. Timing of onset of shock was similar in the two groups. Notably a number of patients (12% of children and 15% of adults) were still febrile at the time of onset of shock. Vomiting, abdominal pain and headache were more common among adults at presentation (p = 0.003, p<0.001 and p<0.001 respectively, χ2 test). All adults experienced some clinical bleeding, primarily mild/moderate mucosal bleeding, while one third of children had no bleeding and over 50% manifested only minor skin bleeding during the disease course. Eight children and 3 adults had severe bleeding, all in association with profound shock, and 5 children and 1 adult required blood transfusion. 10.1371/journal.pntd.0001679.t002 Table 2 Key clinical features, therapeutic interventions, and laboratory findings, comparing children and adults with dengue shock syndrome managed in intensive care. Patients with DSS admitted directly p* Referred patients with DSS - Adults only (n = 51) Children (n = 402) Adults (n = 59) Characteristics reported or observed at enrolment ** Age, years 9 (3–14) 19 (15–32) N/A 21 (15–34) Male sex 220 (55) 29 (49) 0.42 20 (39) Day of illness at shock 5 (4–6) 5 (4–6) 0.26 5 (3–6)c Fever ≥38°C at shock 47 (12) 9 (15%) 0.43 - Headache 109 (27) 52 (90)a <0.001 42 (84)a Vomiting 254 (63) 49 (83) 0.003 40 (80)a Abdominal pain 205 (51) 46 (79)a <0.001 40 (82)b Fatigue 362 (90) 58 (98) 0.04 48 (94) Rash 8 (2) 3 (5) 0.16 2 (4)a BP unrecordable or PP≤10 mmHg at shock 60 (15) 11 (19) 0.46 - Summary of clinical features and complications observed during disease course Hepatomegalyδ 365 (91) 43 (73) <0.001 40 (78) Clinical pleural effusion and/or ascites 147 (37) 22 (37) 0.91 26 (51) Overall bleeding severity:- - No bleeding 131 (33)a 0 <0.001*** 0 - Skin bleeding only 207 (52)a 21 (36) 9 (18)a - Mild/Moderate mucosal bleeding 55 (14)a 35 (59) 30 (60)a - Severe bleeding 8 (2)a 3 (5) 11 (22)a Recurrent shock 147 (37)c 5 (8) <0.001 27 (61)d Severe liver dysfunction 0 0 - 2 (4) Acute renal failure 0 0 - 2 (4) Encephalopathy 1 (<1) 1 (2) 0.24 7 (14) Length of hospital stay, days 3 (3–6) 5 (3–8) <0.001 5 (1–16) Death 3 (<1) 1 (2) 0.42 4 (8) Summary of treatment given Total IV fluid given for shock (ml/kg) 114 (70–158)c 75 (45–124) <0.001 91 (41–208)e Colloid used 197 (49)c 8 (14) <0.001 27 (61)d Total colloid volume given (ml/kg) 17 (9–61) 12 (8–24) 0.05 17 (5–57)b Whole blood/packed cells transfusion 5 (1) 1 (2) 0.56 8 (16) Platelet transfusion 0 1 (2) 0.13 7 (14) Inotropes used 19 (5) 1 (2) 0.49 9 (18) Diuretics used 79 (20) 3 (5) 0.006 10 (20) Summary of key laboratory findings Day of illness of maximum haematocrit**** 5 (4–7)b 5 (4–6) 0.18 6 (4–7)a Maximum haematocrit**** 50 (44–56)b 51 (44.5–64.2) N/A 47.4 (38.9–61.1)a Percentage haematocrit change**** § 33 (17–58)f 26 (9–49) <0.001 22 (2–57)a Haematocrit change ≥20%**** 351 (92)f 39 (70) <0.001 20 (53)a Platelet nadir, ×109/L 32 (11–73) 18 (9–49) <0.001 15 (6–43)b Data are presented as number (percentage) for categorical variables and median (90% range) for continuous variables. *: p value for comparisons between children and adults admitted directly with shock (Chi-square test or Fisher's exact test for categorical variables, and Mann Whitney test for continuous variables). **: Age-dependent features such as pulse and respiratory rate are not presented. ***: Overall Chi-square test. ****: Haematocrit values are likely to be affected by severe bleeding during the acute illness, and thus percentage haemoconcentration was not calculated for patients with severe bleeding. For these variables the denominators are 393, 56 and 39 cases in the three patient groups respectively. Absolute values are age-dependent and were not compared statistically. δ: Liver palpable below the costal margin in the mid-clavicular line. §: Percentage change between the maximum recorded haematocrit between days 3 and 8 of illness compared to a baseline value obtained before day 3 of illness or at the follow-up visit. If neither was available the local population mean for age and sex was used as the baseline. Missing data for. a = 1 patient, b = 2 patients, c = 4 patients, d = 7 patients, e = 8 patients, f = 10 patients. Initial shock severity was similar in terms of the proportion with no recordable blood pressure or with very narrow pulse pressure (≤10 mmHg) at presentation. However adults experienced recurrent shock much less frequently than did children, indicated by the need for colloid resuscitation in only 8 (14%) adults as compared to 197 (49%) children (p<0.001, χ2 test). Adults were usually successfully managed with smaller volumes of fluid than children. Approximately one third of all patients developed clinically detectable pleural effusions or ascites, but only 3 (5%) of adults compared to 79 (20%) of children required diuretics. Three children (2 prolonged shock and severe bleeding, 1 prolonged shock with encephalopathy) and 1 adult (prolonged shock with encephalopathy) died despite full supportive care. All others made a full recovery. Data for the 51 externally referred adults with DSS are also presented in Table 2 and clearly demonstrate that these patients were more severely ill than those admitted directly to AICU. Almost 60% of this group experienced recurrent shock and 11 patients (22%) developed severe bleeding. Clinical pleural effusions and ascites were common with 12/51 (24%) developing respiratory distress. Five patients required assisted ventilation (4 with fluid overload, and 1 with encephalopathy and pneumonia), while the remainder were managed successfully with oxygen and diuretics. Two patients had severe liver dysfunction demonstrated by jaundice and very high transaminase levels, and another two patients developed acute renal failure likely due to prolonged shock. A total of 7/51 (14%) of these externally referred adults became encephalopathic, 5 in association with severe bleeding. Four (8%) of the 51 patients died - 3 due to severe bleeding and fluid overload and 1 due to encephalopathy. Patients with other notable complications without shock: Among the 94 patients admitted to AICU without DSS but with other notable complications, the clinical pattern was similar among direct admissions and external referrals, although the latter group tended to be more severely ill. There were 28/47 externally referred patients (60%) with severe bleeding (among them 3 cases with acute liver failure, 1 case with severe liver dysfunction, 2 cases with encephalopathy and intracranial bleeding demonstrated on CT scan, 1 case with a bleeding peptic ulcer, and the remaining 21 cases with no underlying cause detected), 14 patients (30%) with mucosal bleeding that settled without intervention, 2 patients with severe liver dysfunction but only skin or mild mucosal bleeding, and 1 case each with isolated encephalopathy, haemoglobinuria, and profound thrombocytopenia. Among the 47 direct admissions, there were 12 patients (26%) with severe bleeding (among them 2 cases with associated liver and renal failure, and 1 case with a bleeding peptic ulcer), 27 patients (57%) with mucosal bleeding that settled, 3 patients with syncope, 2 patients with haemoglobinuria and 1 case each with isolated encephalopathy, severe liver dysfunction, and profound thrombocytopenia. One of the externally referred patients with acute liver failure and severe bleeding died, but the remaining patients recovered. Patients admitted for observation: A total of 111 patients were admitted to AICU for close observation, of whom 64 (58%) had transiently narrowed pulse pressure without evidence of impaired peripheral perfusion. None of these patients went on to develop clear signs of shock and all were discharged well without specific interventions other than maintenance fluid therapy. This group of adults appears to be of intermediate severity, with median platelet nadirs and percentage haemoconcentration significantly more abnormal than those of the adults managed on the infection wards but significantly less deranged compared to the adults admitted directly to AICU with DSS (data not shown). Although 270 children with suspected dengue were admitted to PICU for close observation during the same period, none developed shock or any other complications and thus were not recruited, as per the PICU research protocol. Clinical description of patients managed throughout on the infection wards During 2007 we recruited 559 children with suspected dengue (approximately 25% of all such children as judged from the ward discharge records) and 398 adults with suspected dengue (approximately 10% of all such adults) admitted to the paediatric or adult infection wards at HTD. Of the 559 children, 498 (89%) were confirmed to have dengue, with immune status determined in 419 (84%), 130 primary and 289 secondary infections. Nineteen of these children (4%) developed DSS in hospital (see ICU section) and another 7 children were transferred to PICU for observation but did not develop shock. Of the 398 adults, 333 (84%) had dengue confirmed, among whom immune status was determined in 266 (80%), 30 primary and 236 secondary infections. Within the dengue-confirmed group 286 adults had been admitted directly to HTD while 47 were external referrals. Only 1 adult was transferred to AICU, a patient with known hyperthyroidism who developed rapid atrial fibrillation that responded to conventional treatment. Table 3 presents the clinical features and key laboratory findings, comparing the 472 children and 285 adults admitted and managed throughout on the infection wards (hereafter referred to as uncomplicated dengue cases), with findings for the externally referred adults presented separately. Significantly more males than females were recruited in the paediatric ward. This was consistent with the observed male/female ratio observed among all admissions to that ward, but was not apparent in the male/female ratio for PICU admissions. Children were admitted to hospital approximately one day earlier than adults. However, adults were generally more symptomatic than children – most notably 70% complained of muscle pain compared to only 19% of children (p<0.001, χ2 test). Bleeding also occurred more frequently in adults. Almost half the children had no bleeding and minor mucosal bleeding was noted in only 10%, primarily epistaxis, compared to 46% of adults with mainly gum or minor upper gastrointestinal bleeding. In contrast more than 60% of children received some maintenance fluid therapy compared to 29% of the adults, either because of vomiting or high fever with inadequate oral intake. 10.1371/journal.pntd.0001679.t003 Table 3 Key clinical features, therapeutic interventions, and laboratory findings, comparing children and adults with uncomplicated dengue managed on the infection wards. Patients with uncomplicated dengue admitted directly p* Referred patients with uncomplicated dengue Adults only (n = 47) Children (n = 472) Adults (n = 285) Characteristics reported or observed at enrolment ** Age, years 12 (7–14) 22 (15–34) N/A 21 (16–39) Male sex 303 (64) 132 (46) <0.001 25 (53) Day of illness 3 (2–5) 4 (2–6) <0.001 4 (2–6) Headache 325 (69) 260 (93)d <0.001 44 (94) Fatigue 424 (90) 255 (94)f 0.07 39 (83) Muscle pain 90 (19) 190 (70)f <0.001 33 (70) Cough 76 (16) 66 (24)c 0.01 17 (36) Vomiting 174 (37) 140 (50)b <0.001 28 (60) Diarrhoea 53 (11) 103 (37)d <0.001 15 (32) Abdominal pain 96 (20) 112 (41)e <0.001 22 (47) Rash 33 (7)a 37 (13) 0.006 4 (9) Hepatomegalyδ 27 (6) 21 (7)a 0.36 7 (15) Summary of subsequent disease course Day of illness at defervescenceξ 6 (4–8)a 6 (4–8)c 0.35 6 (4–9) Overall bleeding severity:- - No bleeding 216 (46)a 46 (16) <0.001*** 3 (6) - Skin bleeding only 209 (44)a 107 (38) 13 (28) - Mild/Moderate mucosal bleeding 46 (10)a 132 (46) 31 (66) Length of hospital stay, days 5 (3–7) 5 (2–7) 0.04 5 (3–8) Summary of treatment given Any maintenance IV fluid given 292 (62) 84 (29) <0.001 16 (34)**** Summary of key laboratory findings Day of illness of maximum haematocrit 6 (3–8)a 6 (4–8)c 0.003 6 (4–8) Maximum haematocrit 43.9 (38.3–53.5)a 44.9 (38.8–53.9)c N/A 45.1 (39.2–56.2) Percentage haematocrit change§ 14 (−2–37)a 10 (−3–32)c <0.001 11 (−3–46) Haematocrit change ≥ 20% 143 (30)a 49 (18)c <0.001 9 (19) Platelet nadir, ×109/L 80 (30–178)a 42 (12–117)c <0.001 40 (10–134) Data are presented as number (percentage) for categorical variables and median (90% range) for continuous variables. *: p value for comparison between children and adults with uncomplicated dengue admitted directly (Chi-square test or Fisher's exact test for categorical variables, and Mann Whitney test for continuous variables). **: Age-dependent features such as pulse and respiratory rate are not presented. ***: Overall Chi-square test. ****: no information available prior to HTD admission. δ: Liver palpable below the costal margin in the mid-clavicular line. ξ: Day of defervescence was defined as the first day that the temperature dropped to 37.5°C and remained at or below this level subsequently. §: Definition for percentage haematocrit change as in Table 2. Missing data for. a = 1 patient, b = 3 patients, c = 5 patients, d = 6 patients, e = 9 patients, f = 13 patients. Key laboratory findings (Tables 2 and 3) Normal haematocrit values are age-dependent, but the median maximum values recorded during the acute illness were similar, indicating greater increases in children than adults. Percentage haemoconcentration was also greater in children than adults in both the DSS and the uncomplicated dengue groups (both p<0.001, Mann Whitney test), and consequently the proportion of children with ≥20% haemoconcentration was also greater than among the adults (both p<0.001, χ2 test). The median day of illness on which the maximum HCT occurred was slightly later (day6) in the uncomplicated dengue patients than those with DSS (day 5). The platelet nadir occurred on day 6 of illness in both age-groups, with levels generally lower in those with shock than with uncomplicated dengue (Figure 2). Only 8 adults with shock - 4 with severe bleeding, and 4 with counts below 20×109/L who required invasive procedures - and a further 13 adults with severe bleeding without shock, received platelet transfusions in addition to other blood products. No paediatric patient received a platelet transfusion. Considering patients directly admitted with shock, daily platelet counts were consistently lower among adults than children during the acute illness (p<0.001 for all daily comparisons between days 4–8, Mann Whitney test), although no difference was apparent at the follow-up visit. Among direct admissions with uncomplicated dengue, thrombocytopenia was consistently more severe in adults than children between days 2–10 of illness, and the adults' platelet counts were also significantly lower when reassessed at the follow-up visit after recovery (all p<0.01, Mann Whitney test). Multiple linear regression indicated that serotype had no significant effect on the platelet nadir (p = 0.53 for patients with uncomplicated dengue, p = 0.12 for patients with shock), but that there was an association with immune status i.e. secondary infection was an independent predictor of a lower platelet nadir (estimated effect size −22.0×109/L (95% CI: −30.6 to −13.4), p<0.001 in the uncomplicated dengue group, and −13.2×109/L (95% CI: −23.8 to −2.7), p = 0.01 in patients with shock). In addition, age-group had a pronounced effect on the platelet nadir (estimated effect of age ≥15 years was −35.5×109/L (95% CI: −43.0 to −27.9), p<0.001 in patients with uncomplicated dengue, and −6.7×109/L (95% CI: −13.2 to −0.2), p = 0.04 in patients with shock). Notably, age also significantly affected the platelet count at follow-up in the uncomplicated dengue group, with a larger effect size compared to that observed during the acute illness; the estimated effect of age ≥15 years (assessed by multiple linear regression adjusted for serotype and immune status) on follow-up platelet values was −41.7×109/L (95% CI: −64.1 to −19.4), p<0.001. This relationship was not apparent for follow-up platelet values in the DSS group (estimated effect of age ≥15 years −6.5×109/L (95% CI: −40.1 to 27.2), p = 0.7). 10.1371/journal.pntd.0001679.g002 Figure 2 Daily platelet counts in children and adults with dengue. Box and whisker plots showing daily platelet counts during the course of illness and at follow-up for children and adults admitted directly to the relevant ICU with shock (Panel A), and for children and adults with uncomplicated dengue admitted directly to and managed throughout on the relevant infection wards (Panel B). Mean +/− SD day of illness at follow up for patients with DSS was 40+/−3 for children and 31+/−12 for adults, and for patients with uncomplicated dengue was 39+/−3 for children and 29+/−13 for adults. Boxes represent the median and interquartile values. Open circles indicate outlying/extreme values. The total number of patients included in each group each day is indicated on the X axis. The Mann-Whitney test was used to compare the daily platelet counts between children and adults, *** p<0.001 and ** p<0.01. We also found significant correlations between lower platelet counts and the overall severity of bleeding graded at discharge. Figure 3 presents the lowest platelet counts recorded during specified time-periods during the illness course according to bleeding severity, for the children and adults separately. The majority of patients who developed mucosal bleeding were adults, with the onset usually between days 4–6 of illness. To assess relationships between platelet counts and onset of mucosal bleeding in more detail in this group, we compared the most recent counts measured prior to development of any mucosal bleeding (≤24 hours) with counts measured at the same time in the disease evolution for patients who never developed mucosal bleeding (Figure 4); the counts were significantly lower in those who developed mucosal bleeding on days 5 and 6 of illness (p = 0.03 and p<0.001, respectively) and borderline significant for day 4 (p = 0.06, all Mann-Whitney test). 10.1371/journal.pntd.0001679.g003 Figure 3 Associations between platelet counts and bleeding severity in children and adults with dengue. Box and whisker plots showing associations between the lowest platelet counts observed in specific time-periods (early febrile – days 1–3, critical – days 4–6 and convalescent periods – day 7–10) during the illness course and at the follow up visit, and the overall bleeding severity for all children (Panel A) and adults (Panel B) admitted directly to the hospital. Boxes represent the median and interquartile values. Open circles indicate outlying/extreme values. The total number of patients included in each group each time-period is indicated on the X axis. The Cuzick test for trend was used to compare the lowest platelet counts across the overall bleeding score in each time-period, *** p<0.001 and ** p<0.01. 10.1371/journal.pntd.0001679.g004 Figure 4 Platelet counts by day of illness for adults who did or did not develop mucosal bleeding. Box and whisker plots showing platelet counts on days 4, 5 and 6 of illness comparing adults who developed mucosal bleeding during the subsequent 24 hour period to adults who never developed mucosal bleeding throughout the illness course. Boxes represent the median and interquartile values. Open circles indicate outlying/extreme values. The total number of patients included in each group each day is indicated on the X axis. Patients in whom mucosal bleeding developed prior to admission to HTD are not included. The Mann-Whitney test was used to compare the platelet counts between the two groups on each day. *** p<0.001 and * p<0.05. Discussion The availability of detailed prospectively-collected observational data on a large number of dengue patients admitted to a single institution in an endemic region permitted this examination of the clinical patterns of dengue disease by age. We found that although the overall clinical picture was similar in children and adults some clear differences were apparent, particularly in the pattern of complications seen. Admission with shock and development of recurrent shock were more common in children than adults, and plasma leakage was more profound. In contrast bleeding manifestations and organ involvement were more common and more severe in adults. Thrombocytopenia was also more severe in adults, but this likely reflects similar disease-associated effects superimposed on intrinsically lower normal platelet values in adults compared to children. Health-seeking behavior and local admission policies and referral systems may influence observed disease patterns, particularly in a hospitalized population. For example the male excess among children with uncomplicated dengue has been documented previously and may reflect parental health-seeking behavior [4], [16]. HTD admits around 8–10,000 patients with suspected dengue annually. Although it functions as the main provider of inpatient care for local adults with dengue as well as being a referral centre for severe adult disease, local children may be taken preferentially to one of two paediatric hospitals in the city and HTD receives few regional paediatric referrals. Therefore we focused the main analysis on direct admissions from the local area in order to better reflect patterns of symptomatic disease by age. Our findings support the generally accepted view that severe vascular leakage is more common in children [8], [17]. Age is known to influence intrinsic vascular permeability, with children demonstrating a lower threshold for leakage than adults [18]. Similarly, homeostatic mechanisms aimed at minimizing cardiovascular decompensation in the face of increased permeability are less well developed in children. However it is important to note that the population affected by dengue in Vietnam, a hyper-endemic country, is relatively young - the oldest patient in the study was 57 years old and the oldest DSS case was 37 years old. Secondary infection is well recognised as a risk factor for severe disease; 6% of the paediatric shock cases had primary infections compared to 30% of the uncomplicated paediatric cases, while only 6% of adults overall had primary disease with a single patient (aged 18 years) identified among the shock cases. Reports from Taiwan and Singapore, where endemicity is lower than Vietnam and secondary infections likely to occur later in life, indicate that infections occurring in elderly patients with co-morbidities are at greater risk for severe complications and death [19], [20]. Skin and mild to moderate mucosal bleeding were significantly more common in adults, and severe bleeding in the absence of DSS occurred only in adults. Although we cannot exclude the possibility that some local children with severe bleeding without shock were admitted to one of the two paediatric hospitals, informal communication with both centres indicates this presentation to be rare. In the majority of the adults manifesting severe bleeding without shock few specific antecedents (such as peptic ulcer disease) could be identified. Coagulation abnormalities for the adult patients have been reported previously [13], showing a general pattern of prolonged partial thromboplastin times with reduced plasma fibrinogen levels, but little change in the prothombin time or evidence of procoagulant activation. This pattern of abnormalities has also been described among children with dengue, with increasingly severe abnormalities seen in association with more severe vascular leakage [12], [21], and the evidence to date suggests that a typical “dengue coagulopathy” occurs alongside the well-recognized thrombocytopenia. Since coagulation tests were not performed systematically in the children involved in this analysis no direct comparisons by age were possible, but we were able to demonstrate that thrombocytopenia was more marked in adults than children; we documented significantly lower platelet counts in the adults throughout the evolution of the disease, with clear associations with the overall severity of both leakage and bleeding. The development of bleeding events across the spectrum from mild skin bleeding to severe mucosal bleeding probably reflects a combination of dengue-induced abnormalities on a background of characteristics intrinsic to the individual; thus it is unlikely that the lower platelet counts in adults are directly responsible for the greater risk for bleeding per se in this group. The multiple linear regression analysis indicated that the platelet/age-group effect cannot be explained solely by the fact that adults had more secondary infections than children – adult age-group was an independent predictor of lower platelet counts for both severity groups during the acute illness and for the uncomplicated dengue patients at follow-up. The absence of an apparent effect at follow-up in the DSS patients may be explained by differences in the timing of these visits. Most adults attended for review about 4 weeks from illness onset, at a time when rebound thrombocytosis was likely still to be a factor, while children generally returned for review 1–2 weeks later (Figure 2). Rebound thrombocytosis is normally proportionate to the severity of preceding thrombocytopenia and may have confounded the age effect in the DSS patients. In support of this, follow-up platelet counts were significantly higher in adults with DSS compared to adults with uncomplicated dengue, (measured on average 29 days from illness onset), while no difference was seen in the follow-up platelet counts in the respective paediatric patient groups, (measured on average 40 days from illness onset, data not shown). Few data are available on platelet changes with age, but one European study that examined platelet counts in 500 healthy subjects also demonstrated a progressive decline in platelet numbers during childhood, leveling off at 18 years [22]. We also found that children were generally less symptomatic than adults in the febrile phase of uncomplicated dengue, although they were more than twice as likely to receive maintenance intravenous fluid therapy. Comparisons of management strategies between the groups are complicated by the fact that both general and dengue-specific fluid management guidelines are tailored to expected age-related requirements. However the favourable outcome in most cases, together with the fact that significantly greater haemoconcentration was demonstrated in the children despite their receiving considerably more fluid therapy overall than the adults, indicates that the interventions were likely proportionate to need. Over the years considerable experience has accumulated regarding fluid management of children with dengue, but as epidemiological patterns begin to change and more adults present with severe and complicated disease, it is crucial that suitable fluid management algorithms are developed that are relevant to the age-groups at risk. Additionally, given that profound but frequently asymptomatic thrombocytopenia is almost universal in adults with dengue, the lack of practical guidelines on the use of blood products needs to be addressed. Prophylactic platelet transfusions are becoming almost routine in some dengue-endemic countries, using arbitrary thresholds without evidence of benefit [23], [24]. Among this cohort of 1528 confirmed-dengue cases (of whom only 9 patients died) prophylactic platelet transfusions were given to just 4 patients, all of whom had profound thrombocytopenia and required invasive procedures, in addition to a total of 17 patients who had severe bleeding. In view of the associated clinical risks and the financial cost of prophylactic platelet transfusions it is essential that formal research studies are carried out before this becomes established as the standard of care. In summary, in this large study comparing the clinical features of dengue between adults and children we have demonstrated that the complications experienced by the two groups tend to reflect age-related physiological norms. Children, who have intrinsically higher microvascular permeability tend to develop vascular leakage and DSS, while adults tend to experience bleeding complications or severe organ impairment. The higher frequency and greater severity of bleeding manifestations in adults is likely to be driven by a variety of factors including a) intrinsically lower baseline platelet counts b) a greater likelihood of experiencing a secondary rather than a primary infection and c) a greater propensity to have underlying chronic diseases that might predispose the subject to bleeding. Knowledge of the patterns of disease in different age-groups is helpful firstly to facilitate development of suitable management guidelines. Secondly, as dengue spreads to new geographical locations and the epidemiological picture diversifies, it is crucial that changing patterns of disease are recognized and global trends identified. Supporting Information Checklist S1 STROBE checklist. (DOC) Click here for additional data file.

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Predictive value of simple clinical and laboratory variables for dengue hemorrhagic fever in adults.

Vernon J. Lee, David C B Lye, Yan. Sun … (2008)

Singapore experienced its worst dengue outbreak in 30 years in 2004, with 9459 notified cases, of which 83% were hospitalized. To determine predictors of dengue hemorrhagic fever (DHF) upon first presentation to hospital to aid clinicians in determining need for admission. We conducted a retrospective cohort study on dengue patients in Tan Tock Seng Hospital, Singapore in 2004, with patients categorized into dengue fever (DF) and DHF. Demographic, clinical, and laboratory variables upon first presentation were compared to determine the likelihood of developing DHF. There were 1973 dengue patients-118 (6.0%) were DHF, of which 82 (4.2%) developed DHF during hospitalization. From the multivariate analysis, patients with bleeding had an odds of developing DHF 237.6 times that of DF, a unit decrease in total protein (g/L) had an odds of 1.28 times, a unit increase in blood urea (mmol/L) had an odds of 1.31 times, and a unit decrease in lymphocyte proportion had an odds of 1.08 times. The model had a sensitivity of 97.6%, specificity of 60.2%, and may reduce 1118 (56.7%) dengue admissions. A few easily available clinical and laboratory results may assist clinicians in determining dengue admissions.

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Kristy O. Murray: Role: Editor

Journal

Journal ID (nlm-ta): PLoS Negl Trop Dis

Journal ID (iso-abbrev): PLoS Negl Trop Dis

Journal ID (publisher-id): plos

Journal ID (pmc): plosntds

Title: PLoS Neglected Tropical Diseases

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Print): 1935-2727

ISSN (Electronic): 1935-2735

Publication date (Electronic): 25 March 2016

Publication date Collection: March 2016

Volume: 10

Issue: 3

Electronic Location Identifier: e0004576

Affiliations

[1 ]Communicable Disease Center, Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore

[2 ]Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Baylor College of Medicine, UNITED STATES

Author notes

The authors have declared that no competing interests exist.

Conceived and designed the experiments: DCL YSL. Performed the experiments: TLT DCL YSL. Analyzed the data: JGXW THL DCL YSL LKL. Contributed reagents/materials/analysis tools: JGXW LKL. Wrote the paper: THL ELN DCL JGXW.

* E-mail: tau_hong_lee@ 123456ttsh.com.sg

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Publisher ID: PNTD-D-15-01334

DOI: 10.1371/journal.pntd.0004576

PMC ID: 4807876

PubMed ID: 27015272

SO-VID: de99c433-3037-4b79-b949-6b714b145a04

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This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 11 August 2015

Date accepted : 3 March 2016

Page count

Figures: 2, Tables: 3, Pages: 10

Funding

This study was supported by STOP Dengue Translational Clinical Research programme, funded by the National Research Foundation through the National Medical Research Council, Singapore (Grant number NMRC/TCR/005/2008). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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ScienceOpen disciplines: Infectious disease & Microbiology

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ScienceOpen disciplines: Infectious disease & Microbiology

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Potential Harm of Prophylactic Platelet Transfusion in Adult Dengue Patients

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Risk factors and clinical features associated with severe dengue infection in adults and children during the 2001 epidemic in Chonburi, Thailand.

Clinical Features of Dengue in a Large Vietnamese Cohort: Intrinsically Lower Platelet Counts and Greater Risk for Bleeding in Adults than Children

Predictive value of simple clinical and laboratory variables for dengue hemorrhagic fever in adults.

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