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Acute Respiratory Failure in Adult Patients with Dengue Virus Infection

Chin-Chou WangDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China; Department of Respiratory Care, Chang Gung Institute of Technology, Chiayi, Taiwan, Republic of China

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Shih-Feng LiuDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China; Department of Respiratory Care, Chang Gung Institute of Technology, Chiayi, Taiwan, Republic of China

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Shang-Chih LiaoDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China; Department of Respiratory Care, Chang Gung Institute of Technology, Chiayi, Taiwan, Republic of China

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Ing-Kit LeeDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China; Department of Respiratory Care, Chang Gung Institute of Technology, Chiayi, Taiwan, Republic of China

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Jien-Wei LiuDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China; Department of Respiratory Care, Chang Gung Institute of Technology, Chiayi, Taiwan, Republic of China

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An-Shen LinDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China; Department of Respiratory Care, Chang Gung Institute of Technology, Chiayi, Taiwan, Republic of China

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Chao-Chien WuDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China; Department of Respiratory Care, Chang Gung Institute of Technology, Chiayi, Taiwan, Republic of China

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Yu-Hsiu ChungDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China; Department of Respiratory Care, Chang Gung Institute of Technology, Chiayi, Taiwan, Republic of China

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Meng-Chih LinDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China; Department of Respiratory Care, Chang Gung Institute of Technology, Chiayi, Taiwan, Republic of China

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To investigate clinical course and outcome of dengue with acute respiratory failure (ARF), and to identify related risk factors for acquiring ARF in dengue, we retrospectively studied 11 dengue patients with ARF. From June to December 2002, a total of 606 adult patients were diagnosed as having dengue. Eleven (1.8%) of 606 dengue patients had complications of ARF. The main causes of ARF were sepsis (n = 6, 54.5%) and upper gastrointestinal (UGI) bleeding (n = 3, 27.3%). The mortality rate was 72.7% (n = 8). Additionally, univariate analysis showed that age, dyspnea, cough, prothrombin time, activated partial thromboplastin time, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, creatinine, albumin, renal insufficiency, acute renal failure, acute hepatic failure, UGI bleeding, and combination bacterial infection were significantly predictive variables associated with dengue patients with ARF.

INTRODUCTION

As the most important mosquitoborne viral disease affecting humans worldwide, dengue continues to be a major public health issue in tropical and subtropical areas. Dengue, which is caused by dengue virus infection, is endemic in more than 100 countries and causes an estimated 50 million infections annually worldwide.15 Dengue is a febrile illness caused by any one of four serotypes of dengue flavivirus (DEN-1, DEN-2, DEN-3, or DEN-4). Most infections are asymptomatic. Symptomatic dengue virus infection can present with a wide range of clinical manifestations, from a mild febrile illness to life-threatening shock syndrome.611 Dengue is often classified into two nosologic entities: dengue fever (DF) and dengue hemorrhagic fever (DHF). Dengue hemorrhagic fever is the most serious manifestation of dengue virus infection. The clinical presentations, laboratory findings, and serologic analysis of dengue virus infection have been widely reported.1220 However, only one study has investigated dengue patients with acute respiratory failure (ARF) and discussed the effectiveness of oxygen treatment administered by a face mask versus nasal continuous positive airway pressure in pediatric patients with dengue shock syndrome complicated by respiratory failure.17 Otherwise, there is no other published cohort study regarding dengue virus infection with ARF.

During dengue virus infection, dengue virus (or viral antigen) has been detected in pulmonary macrophages and pulmonary endothelial cells. In fatal cases of dengue, histopathologic findings include interstitial inflammation and hemorrhage, alveolar fluid and protein (including fibrin), and lung hemorrhage. Hypoxemia with a widened alveolar-arterial oxygen gradient is common in patients with severe dengue. Non-cardiac pulmonary edema is a common complication of fluid replacement in patients with dengue and profound plasma leakage.15,2124 Nevertheless, the effects of dengue virus infection on the lung are not completely understood and poorly appreciated.

There have been many outbreaks of dengue virus infection in Taiwan.25 A major outbreak of dengue occurred in southern Taiwan in 1987–1988, and a small number of clustered cases with dengue virus infection have since been reported in this area. A large epidemic of dengue caused by the DEN-2 virus occurred between June and December 2002 in southern Taiwan, and a dengue outbreak caused by DEN-1 virus occurred in 1987–1988.2527 More than 5,000 cases of symptomatic dengue were reported during this outbreak.25

From June through December 2002, 661 patients with dengue virus infection were admitted to the Kaohsiung Chang Gung Memorial Hospital, the largest tertiary medical center with a 2,500-bed capacity in southern Taiwan. This study retrospectively analyzed the medical records of these dengue patients. Some of these dengue patients presented with progressive dyspnea and cyanosis and were immediately intubated with mechanical ventilation support. Acute respiratory failure was diagnosed in these dengue patients.

The goal of the present study was to investigate the clinical course and outcome of dengue patients with ARF, and to identify the related risk factors for acquiring ARF in dengue patients. Identification of the causes and related risk factors for acquiring ARF may help clinicians in evaluating the clinical course of dengue virus infection.

MATERIALS AND METHODS

This study retrospectively reviewed the medical records of 661 patients diagnosed with dengue virus infection. The quality assurance of diagnostic tests for these 661 dengue patients were confirmed by the Center for Disease Control (Taipei, Taiwan) on the basis of either a positive reverse transcriptase–polymerase chain reaction result, a positive enzyme-linked immunosorbent assay result for specific IgM to dengue virus in serum from patients with acute disease, or a ≥ 4-fold increase in dengue-specific hemagglutination inhibition titers in serum from convalescent patients.28 All 661 dengue patients were infected by with serotype DEN-2 virus.25

Of these 661 patients, 606 adult patients ≥ 18 years of age were included in our study. A dengue patient with ARF was defined as a patient who was immediately intubated with mechanical ventilation support because of failure to respond to 40% oxygen through a nasal cannula as confirmed by 1) hypoxemia (PaO2 < 60 mm of Hg) or hypercapnia (PaCO2 > 50 mm of Hg), 2) bradypnea (respiratory rate < 10/minute) or tachypnea (respiratory rate > 35/min), and 3) severe chest retraction and nasal flaring.29 Patients with dengue and ARF (n = 11) comprised the ARF group. Patients with dengue without ARF comprised the control group (n = 595).

Demographic characteristics and initial clinical manifestations (when these dengue patients were admitted) were obtained from medical records. Initial laboratory data including white blood cell (WBC) count, hematocrit, platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, blood urea nitrogen (BUN), creatinine, and albumin were also obtained from medical records. Abnormal chest radiographs were analyzed by three experienced chest physicians for presence of the following radiographic findings: infiltration only; small pleural effusion (when effusion is < 2 intercostal spaces); moderate pleural effusion (when effusion is 2–4 intercostal spaces); and, massive pleural effusion (when effusion is > 4 intercostal spaces). Data regarding microorganisms growing in culture and antibiotics administered were obtained from medical records.

After illness onset (fever beginning), admitted day (A-day), intubation-day (I-day), weaning-day (W-day), and died-day (D-day) were respectively defined as the day when the patient was admitted, the day when the patient was intubated, the day when the patient was weaned from mechanical ventilation support, and the day when the patient died.

Renal insufficiency was defined as increase in BUN and serum creatinine. Acute renal failure was defined as oliguria with an increase in BUN and serum creatinine. Liver function impairment was defined as increased levels of liver enzymes (AST or ALT). Acute hepatic failure was defined as encephalopathy or jaundice with severe acute liver injury (marked increase in liver enzyme levels) and a defect in synthesis of proteins (prolongation of PT). Information regarding hemorrhage, including upper gastrointestinal (UGI) bleeding, hemorrhagic petechiae/ecchymoses, gum bleeding, oral bleeding, hematuria, hemoptysis, nasal bleeding, vaginal bleeding, conjunctival bleeding, retinal bleeding, and hemoarthritis were obtained from medical records. Combination bacterial infection was defined as when bacterial microorganisms grew in culture.

Statistical analysis.

Data were collected and analyzed with SPSS for Windows version 10.0 (SPSS Inc., Chicago, IL). Some data are presented as summary statistics. Quantitative variables are presented as mean ± SD. Statistical significance of univariate analysis was determined by the Mann-Whitney U test for continuous variables and chi-square test for dichotomous variables. Differences were considered significant when P was < 0.05.

RESULTS

Eleven (1.8%) of 606 adult dengue patients had ARF. The other 595 adult dengue patients without ARF were used as a control group. All 606 dengue patients were Chinese.

Characteristics and clinical course.

Table 1 summarizes the characteristics and clinical course of the 11 adult dengue patients with ARF. The mean age of the 11 patients with ARF, 8 males and 3 females, was 63.09 ± 13.48 years (range = 33–78 years). The mean ± SD A-day was day 2.3 ± 1.0 (range = days 1–4). The main causes of acute respiratory failure were sepsis (6 of 11, 54.5%), hypovolemic shock (3 of 11, 27.3%), neurogenic shock (1 of 11, 9.1%), and bronchospasm (1 of 11, 9.1%).

The three most common associated complications in dengue patients with ARF were UGI bleeding (8 of 11, 72.7%), acute renal failure (7 of 11, 63.6%), and combination bacterial infection (6 of 11, 54.5%). Four dengue patients with ARF had acute hepatic failure (4 of 11, 36.4%), one had diffuse subarachnoid hemorrhage (1 of 11, 9.1%), and 1 had congestive heart failure (1 of 11, 9.1%). All complications regarding acute renal failure and acute hepatic failure were observed before ARF occurred in these patients (seven patients with acute renal or/and acute hepatic failure). Among six dengue patients with combination bacterial infection, positive bacterial cultures and confirmed dengue test results were obtained at the same time in four patients (patients 1, 4, 5, and 11); otherwise, positive bacterial cultures were obtained after the confirmed dengue test result in two other patients (patients 2 and 3). Ten (90.9%) dengue patients with ARF were treated with antibiotic regimens.

Among these 11 patients, 6 (54.5%) of 11 had pleural effusions (3 with small pleural effusions, 1 with a moderate effusion, and 2 with massive effusions) in chest radiographs, 3 (27.3%) of 11 had infiltrations, and 2 (18.2%) of 11 had no effusions at the onset of ARF. Diagnostic thoracentesis was performed in patient 5 and 6 and the characteristics were transudative. During intubation process, blood secretion was observed only in patient 4.

The mean ± SD I-day was day 3.8 ± 1.5; four (36.4%) patients failed on day 2, 2 (18.2%) on day 4, 4 (36.4%) on day 5, and 1 (9.1%) on day 6. Three (27.3%) of the 11 dengue patients with ARF survived (W-day = 14, 65, and 2, respectively) and 8 (72.7%) died (mean ± SD D-day = 3.8 ± 1.5, range = days 2–19).

Comparison of characteristics and underlying diseases.

Table 2 shows comparisons of characteristics and underlying diseases in adult dengue patients with ARF and without ARF. No significant differences were observed between the two groups for A-day and sex ratio. However, age (P = 0.005) was significantly different between the ARF group and the control group. There were significant differences between the two groups for hypertension (P = 0.036), Chronic obstructive pulmonary disease (P = 0.039), stroke (P = 0.049), and end stage renal disease (P = 0.010).

Comparison of initial symptoms/signs and initial laboratory findings.

Table 3 shows a summary of initial symptoms/signs for adult dengue patients with ARF and without ARF. In addition to fever, the most common clinical presentations for dengue patients with ARF were abdominal pain, bone pain, myalgia, and cough, which accounted for 54.5%, 45.5%, 45.5%, and 45.5%, respectively, of the presentations. Initial symptoms and signs of both groups were also compared. There were significant differences for cough (P = 0.016) and dyspnea (P = 0.001) between the two groups.

Table 4 shows a summary of initial laboratory findings for adult dengue patients with ARF and without ARF and comparisons of initial laboratory findings between these two groups. No significant differences were observed between the two groups for WBC count, hematocrit, platelet count, ALP, and total bilirubin. However, age (P = 0.005), PT (P < 0.001), APTT (P = 0.001), AST (P = 0.015), ALT (P = 0.042), BUN (P = 0.007), creatinine (P = 0.002), and albumin (P < 0.001) were significantly different between the two groups.

Comparison of associated clinical courses.

Table 5 shows comparisons of associated clinical courses between the ARF group and the control group. There were significant differences between both groups for renal insufficiency (P < 0.001), acute renal failure (P < 0.001), acute hepatic failure (P < 0.001), hemorrhage (P < 0.001), UGI bleeding (P < 0.001), and combination bacterial infection (P < 0.001).

DISCUSSION

This retrospective study showed that 1.8% of adult dengue patients had ARF. The mortality rate (72.7%) for these 11 adult dengue patients with ARF was high. Dengue patients with ARF have seldom been discussed,15,30 and only one cohort study has been published.17 This could result in a lack of widespread awareness of ARF in dengue patients. Consequently, clinicians are likely not aware of the potential for ARF when treating dengue patients at high risk for ARF; this study provides relatively rare data regarding a series of dengue patients with ARF.

Dengue hemorrhagic fever is the most serious manifestation of dengue. The cardinal features that distinguish DHF from classic dengue are increased vascular permeability (plasma leakage syndrome), marked thrombocytopenia (< 100,000/μL) associated with bleeding and hepatomegaly and/or abnormal liver function.28 In this study, all 11 dengue patients with ARF also had DHF. Plasma leakage syndrome is the most specific and life-threatening feature of DHF.4,31 Plasma leakage syndrome and extreme decreases in platelet counts associated with bleeding frequently occur between three and seven days after illness onset. In this study, all 11 dengue patients with ARF were intubated 2–6 days after illness onset. This finding is similar to the clinical course regarding plasma leakage syndrome in dengue patients with DHF.

In our study, combination bacterial infection was significantly different between both groups; 22 dengue patients were had combination bacterial infections (6 with ARF and 16 without ARF). Among the 22 dengue patients, positive bacterial cultures and confirmed dengue test results were generated at the same time in 18 patients (4 with ARF and 14 without ARF). Because of pathologic results obtained at the same time, it is difficult to distinguish which one is primary infection or secondary infection. Thus, dengue with concomitant bacterial infection was reported in these 18 patients. Otherwise, positive bacterial cultures were obtained after confirmed dengue test results in the other 4 patients (2 with ARF and 2 without ARF); the combination bacterial infection may be a secondary infection in these 4 dengue patients.

Sepsis (6 of 11, 54.5%) was the major main cause of ARF in the 11 dengue patients. Among these six dengue patients, four had concomitant bacterial infection (Klebsiella pneumoniae was isolated from blood culture and cerebrospiral fluid culture in patient 1, Corynebacterium from blood culture and urine culture in patient 4, K. pneumoniae from blood culture in patient 5, and Corynebacterium from blood culture and sputum culture in patient 11) (Table 1). Two other patients had only dengue (patients 8 and 10), Although plasma leakage syndrome and hemorrhagic presentation were the cardinal features for dengue patients with DHF, this study indicated that combination bacterial infection (especially concomitant bacterial infection) played an important role in the progression to ARF in dengue patients. Whether the cause of morbidity is due to dengue, concomitant bacterial infection, or both requires further investigation.

Hemorrhage is a major problem and contributes to a worsening morbidity and mortality in dengue patients.31 The pathogenesis of hemorrhage may be multifactorial and encompass vasculopathy, platelet deficiency and dysfunction, and blood coagulation defects.32 Of the dengue patients with DHF, severity of hemorrhagic manifestations varied markedly with spontaneous petechiae, hematemesis, metrorrhagia, melana, and epistaxis.4,10,31 The severe thrombocytopenia and toxic hemorrhagic stage develops 3–5 days after illness onset.12,33 Additionally, most UGI bleeding occurred on day 4 after illness onset.14,33 Among the 606 dengue patients, different types of hemorrhage were observed in 348 patients during their course of dengue. Table 6 shows the distribution of different types of hemorrhage in both groups. Gum bleeding and hemorrhagic petechiae were the major types of hemorrhage observed in our study. Among these different types of hemorrhage, a significant difference was observed only for UGI bleeding between both groups. Thus, UGI bleeding is a major factor regarding hemorrhage in dengue patients.

In this study, hypovolemic shock in three patients was caused by UGI bleeding and neurogenic shock in one patient was caused by diffuse subarachnoid hemorrhage, which was an infrequently reported cause. Hemorrhage was observed before ARF in these 4 dengue patients. However, there were three patients with UGI bleeding after ARF. Hemorrhage, especially UGI bleeding, was also an important cause of ARF in this study. During hemorrhaging, patients received blood transfusions with concentrated platelets, packed red blood cells, and fresh-frozen plasma to correct bleeding, anemia, and hypovolemic shock. Close monitoring of vital signs and hematocrit levels to assess the severity of hemorrhage are required to reduce morbidity and mortality.34

In our study, different factors that contributed to ARF were obtained from medical records. Because of clinical presentation with fever, confirmed pathology reports, and no evidence regarding other causes, sepsis was the cause of treatment failure in six patients. Sepsis was caused by dengue virus infection in patients 8 and 10; however, it was difficult to determine the primary cause of ARF in 4 other dengue patients with concomitant bacterial infection (patients 1, 4, 5, and 11). Because of massive bleeding and low wedge pressure, hypovolemic shock caused by UGI bleeding was the main cause of ARF in 3 patients (patients 2, 7, and 9). Because of clinical presentations with seizure and conscious loss and radiographic proof of diffuse subarachnoid hemorrhage, subarachnoid hemorrhage was the main cause of ARF in patient 6. Because of diffuse wheezing and hypercapnia without metabolic acidosis in arterial blood gas, bronchospasm was the main cause of ARF in patient 3.

In this study, there was a significant difference in albumin levels between the ARF group and the control group. Plasma leakage syndrome is the most specific and life-threatening feature of DHF.4,31 One of the cardinal features that distinguish DHF from classic dengue is plasma leakage syndrome. Among these 606 dengue patients (348 with DHF and 258 with DF), there was a significant difference in albumin levels between the DHF group and the DF group (Table 7). Thus, the albumin level may be a surrogate indicator of severe plasma leakage.

In the 11 patients with ARF, bloody secretion was observed only in patient 4. Thus, pulmonary hemorrhage was excluded as a factor for ARF in the other 10 patients. Because plasma leakage syndrome is the most specific and life-threatening feature of DHF,4,31 infiltration and pleural effusion were probably caused by plasma leakage syndrome.21,22 Since this was a retrospective study and diagnostic thoracentesis was not performed in all patients with pleural effusion, the actual incidence of hemorrhagic pleural effusion needs further evaluation.

In dengue patients, plasma leakage is important and should be managed aggressively to prevent or reverse hypovolemic shock.24 Non-cardiac pulmonary edema is a common complication of fluid replacement in patients with dengue and profound plasma leakage.24 Whether fluid replacement is a factor that leads to or contributes to ARF in these dengue patients needs further evaluation. Among the 606 dengue patients, 256 patients (6 with ARF group and 250 in the control group) had been treated with aggressive fluid replacement (at least 2,000 mL of intravenous fluid within 24 hours of admission or before the onset of ARF). There was no significant difference in aggressive fluid replacement between the two groups (Table 8). Thus, aggressive fluid replacement was not a factor that contributed to ARF in our study.

The renal condition of dengue patients was another important factor in the development of ARF. There were significant differences between both groups for BUN, creatinine, renal insufficiency, and acute renal failure. All episodes of acute renal failure were observed before ARF occurred in our study. Acute renal failure may result from excessive plasma leakage or a massive active hemorrhage.35,36 Although acute renal failure is rare in dengue patients, it seems to progress to ARF when complicated by other factors.

A total of 55 of the 661 dengue patients admitted to our hospital during this outbreak were children. However, no children with dengue had ARF. Age was significantly different in both groups in our study. Age has been identified as a risk factor for mortality in dengue patients.37,38 Typically, age-associated co-morbidities and decreased immunity are a potential risk factor for active infection in elderly patients.39

Multiple organ failure was another important factor in the 11 dengue patients with ARF. Seven patients with ARF had complicated acute renal failure and/or acute hepatic failure. All episodes of acute renal failure and acute hepatic failure were observed before respiratory failure occurred. Furthermore, all four patients with both acute renal failure and acute hepatic failure died; only one of the other three patients with only acute renal failure died. Thus, we conclude that the combination of acute renal failure and hepatic failure is a high risk factor for mortality in dengue patients.

This retrospective study had several limitations. First, it was conducted at a single medical center, and the patient population may be biased by patient selection and referred pattern. Second, this study was a retrospective survey, which used incomplete data for some patients and did not control for laboratory examinations and the clinical courses of all dengue patients. Thus, prospective investigations should be conducted. Despite these limitations, this study provides relatively rare data regarding a series of dengue patients with ARF.

In conclusion, the main causes of ARF were sepsis and UGI bleeding. Age; initial presentations of dyspnea and cough; PT, APTT, AST ALT, BUN, creatinine, and albumin; and associated clinical courses of renal insufficiency, acute renal failure, acute hepatic failure, UGI bleeding, and combination bacterial infection were significantly predictive variables associated with dengue patients with ARF. Acute respiratory failure is a rare complication in adult dengue patients but has a high mortality rate. Physicians should be aware of the risk factors for ARF and pay more attention to those patients with multiple high risk factors for this condition.

Table 1

Characteristics and clinical course of 11 adult dengue patients with acute respiratory failure*

No.Age, SexConfirmed test resultInitial laboratory data (A-day)Underlying diseaseAssociated complicationChest radiograph presentationAntibiotic treatmentI-dayMain cause of failureOutcome (W-day or D-day)
* A-day = the day, when the patient was admitted, after the onset of illness; I-day = the day, when the patient was intubated, after the onset of illness; W-day = the day, when the mechanical ventilation was weaning, after the onset of illness; D-day = the day, when the patient was dead, after the onset of illness; (Day no.) = the day, when the study was generated or the clinical presentation was observed, after the onset of illness; WBC = white blood cell (×103/μL; normal range M 3.9–10.6, F3.5–11); Hct = hematocrit (%; normal range M 41–53, F 36–46); COPD = chronic obstructive pulmonary disease; Platelet = (×104/μL; normal range 15–40); PT = prothrombin time (sec normal range 10–14); HTN = hypertension; B/C = blood culture; CSF/C = cerebrospinal fluid culture; APTT = activated partial thromboplastin time (sec; normal range 24.6–33.8); AST = aspartate aminotransferase (U/L; normal range 0–37); ALT = alanine aminotransferase (U/L normal range: 0–40); BIL = total bilirubin (mg/dL; normal range 0.2–1.4); ALB = albumin (gm/dL; normal range 3.0–5.0); Cr = creatinine (mg/dL; normal range 0.4–1.4); UGI bleeding = upper gastrointestinal bleeding; Tip/C = central line tip culture; BUN = blood urea nitrogen (mg/dL; normal range 7–20); U/C = urine culture; PCR = reverse transcriptase–polymerase chain reaction; ESRD = end stage renal disease; SAH = subarachnoid hemorrhage; CAD = coronary artery disease; DM = diabetes mellitus; ALP = alkaline phosphatase; BPH = benign prostatic hyperplasia.
170, MIgG(+)
 IgM(+)
 (day 1)WBC = 2.80, Hct = 28.6
 Platelet = 3.0, PT = 11.4
 APTT = 47.8, AST = 1,430
 ALT = 929, BIL = 5.3
 ALB = 1.8, Cr = 2.1
 (day 1)COPD
 HTNBacterial meningitis (day 1)
 (B/C,CSF/C: Klebsiella pneumoniae)Pleural effusion (day 1)
 (Bilateral moderate)Ceftriaxone
 GentamicinDay 2SepsisDied
 (D-day = 2)
267, MIgG(+)
 IgM(+)
 (day 3)WBC = 4.20, Hct = 42.0
 Platelet = 8.7, PT = 12.6
 APTT = 52.9, AST = 842
 ALT = 637, ALB = 1.9
 BUN = 112, Cr = 3.2
 (day 3)Stroke
 HTNUGI bleeding (day 3)
 Acute renal failure (day 3)
 Central line infection (day 11)
 (Tip/C: Pseudomonas aeruginosa)
 Urinary tract infection (day 12)
 U/C: acinetobacter baumannii)Normal (day 6)
 Normal (day 11)Maxipime
 TeicoplaninDay 6Hypovolemic shock
 (due to UGI bleeding)Survived
 (W-day = 14)
375, FIgG(+)
 IgM(+)
 (day 2)WBC = 2.80, Hct = 35.8
 Platelet = 9.0, PT = 11.4
 APTT = 48.7, AST = 58
 ALT = 46, ALB = 2.4
 Cr = 0.6 (day 2)COPD
 Stroke
 HTNCongestive heart failure (day 2)
 Pneumonia (day 7)
 (S/C: Klebsiella pneumoniae)
 Urinary tract infection (day 13)
 (U/C: Citrobacter diversus)Pul congestion (day 2)
 Mild infiltration (day 4)
 (Right lower lobe)Clindamycin
 Piperacillin
 AmikacinDay 4Bronchospasm
 (due to COPD)Survived
 (W-day = 65)
446, FPCR(+)
 (day 2)WBC = 6.90, Hct = 27.3
 Platelet = 3.0, PT = 11.5
 APTT = 53.0, AST = 3,423
 ALT = 1,100, ALB = 2.5
 BUN = 37, Cr = 4.2 (day 2)ESRD
 Hepatitis B
 HTNAcute renal failure (day 2)
 Urinary tract infection (day 2)
 (B/C, U/C: Corynebacterium)
 UGI bleeding (day 4)Normal (day 2)
 Pleural effusion (day 5)
 (Bilateral small)AugmentinDay 5SepsisDied
 (D-day = 6)
559, MIgG(+)
 IgM(+)
 (day 3)WBC = 2.40, Hct = 36.8
 Platelet = 2.9, PT = 11.2
 APTT = 46.8, AST = 31
 ALT = 30, ALB = 2.8
 (day 3)Lung cancer
 COPD
 Bacteremia (day 3) (B/C: Klebsiella pneumoniae)Pleural effusion (day 3)
 (Right massive)
 Pleural effusion (day 5)
 (Right moderate)Piperacillin
 GentamicinDay 5SepsisDied
 (D-day = 19)
633, MIgG(+)
 IgM(+)
 (day 3)WBC = 3.30, Hct = 37.3
 Platelet = 1.8, PT = 12.3
 APTT = 57.6, AST = 6,010
 ALT = 4,510, ALB = 3.0
 BUN = 17, CR = 1.7
 (day = 3)UrolithiasisAcute hepatic failure (day 3)
 Acute renal failure (day 4)
 Diffuse SAH (day 5)
 UGI bleeding (day 6)Pleural effusion (day 3)
 (Right massive)
 Pleural effusion (day 5)
 (Right massive)Ceftazidime
 AmikacinDay 5Neurogenic shock (due to diffuse SAH)Died
 (D-day = 8)
757, FPCR(+)
 (day 2)WBC = 4.00, Hct = 25.3
 Platelet = 2.1, PT = 10.8
 APTT = 36.6, AST = 64
 ALT = 33, ALB = 2.6
 (day = 2)HyperlipidemiaUGI bleeding (day 2)Pleural effusion (day 2)
 (Bilateral small)NoneDay 2Hypovolemic shock
 (due to UGI bleeding)Died
 (D-day = 2)
869, MPCR(+)
 (day 1)WBC = 13.00, Hct = 34.4
 Platelet = 10.1, PT = 11.8
 APTT = 50.8, AST = 88
 ALT = 76, ALB = 2.5
 (day 1)ESRD
 CAD
 DMAcute renal failure
 (day 1)
 UGI bleeding (day 4)Pleural effusion (day 1)
 (Right small)Piperacillin
 AmikacinDay 2SepsisSurvived
 (W-day = 6)
978, MPCR(+)
 (day 4)WBC = 3.70, Hct = 40.9
 Platelet = 1.5, PT = 14.2
 APTT = 68.0, AST = 672
 ALT = 542, ALP = 78
 ALB = 3.3, Cr = 1.7
 (day 4)NoneUGI bleeding (day 4)
 Acute renal failure (day 4)
 Acute hepatic failure (day 4)Normal (day 4)CeftriaxoneDay 4Hypovolemic shock
 (due to UGI bleeding)Died
 (D-day = 5)
1072, MPCR(+)
 (day 3)WBC = 10.00, Hct = 40.8
 Platelet = 2.5, PT = 11.6
 APTT = 41.9, AST = 144
 BUN = 38. Cr = 1.6
 (day 3)BPHAcute renal failure (day 4)
 UGI bleeding (day 5)
 Acute hepatic failure (day 5)Mild infiltration (day 3)
 (Right lower lobe)
 Mild infitration (day 5)
 (Right lower lobe)Augmentin
 Amikacin
 CeftazidimeDay 5SepsisDied
 (D-day = 7)
1168, MIgG(+)
 IgM(+)
 (day 1)WBC = 10.30, Hct = 30.8
 Platelet = 9.4, PT = 12.9
 APTT = 54.8, AST = 143
 ALT = 69, BIL = 1.8
 ALB = 3.0
 (day 1)Stroke
 DM
 HTNAcute renal failure (day 1) Acute hepatic failure (day 1)
 Pneumonia (day 2)
 (B/C, S/C: Corynebacterium)
 UGI bleeding (day 12)Moderate infiltration (day 1)
 (Right lower lobe)Meropenum
 VancomycinDay 2SepsisDied
 (D-day = 18)
Table 2

Comparisons of characteristics and underlying diseases in adult dengue patients with ARF (ARF group) and without ART (control group)*

ARF group (n = 11)Control group (n = 595)P
* ARF = acute respiratory failure; A-day = day when the patient was admitted after the onset of illness; IQR = interquartile range (25th, 75th percentile); COPD = chronic obstructive pulmonary disease; ESRD = end stage renal disease. Significant P values are in bold.
Mean ± SD A-day (day)2.3 ± 1.0
 Median = 2
 IQR = (1, 3)3.1 ± 1.5
 Median = 3
 IQR = (2, 4)0.082
Sex (M/F)8/3260/3350.068
Mean ± SD age (years)63.09 ± 13.48
 Median = 68
 IQR = (57, 72)50.48 ± 15.69
 Median = 53
 IQR = (39, 63)0.005
Diabetes mellitus (%)2 (18.2)59 (9.9)0.305
Hypertension (%)5 (45.5)107 (18.0)0.036
COPD (%)3 (27.3)41 (6.9)0.039
Stroke (%)3 (27.3)45 (7.6)0.049
ESRD (%)2 (18.2)7 (1.2)0.010
Malignancy (%)1 (9.1)15 (2.5)0.257
Table 3

Comparisons of initial symptoms/signs in adult dengue patients with ART (ART group) and without ARF (control group)*

Initial symptom/signARF group n = 11Control group n = 595P
* An individual patient might have more than one symptom and/or sign. ARF = acute respiratory failure. Significant P values are in bold.
Fever10 (90.9%)566 (95.1%)0.431
Petechiae4 (36.4%)213 (35.8%)1.000
Bone pain5 (45.5%)265 (44.5%)1.000
Myalgia5 (45.5%)165 (27.7%)0.193
Headache3 (27.3%)194 (32.6%)1.000
Gum bleeding0 (0%)58 (9.7%)0.612
Chest pain2 (18.2%)28 (4.7%)0.099
Cough5 (45.5%)150 (25.2%)0.016
Dyspnea4 (45.5%)24 (4.0%)0.001
Hemoptysis1 (9.1%)22 (3.7%)0.349
Abdomen pain6 (54.5%)197 (33.1%)0.194
Vomiting4 (36.4%)144 (24.2%)0.476
Diarrhea0 (0%)78 (13.1%)0.375
Tarry stool2 (18.2%)26 (4.4%)0.088
Hematemesis1 (9.1%)6 (1.0%)0.121
Table 4

Comparisons of initial laboratory findings in adult dengue patients between with ARF (ARF group) and without ARF (control group)*

ARF group (n = sample size)Control group (n = sample size)P
* Values are the mean ± SD. ARF = acute respiratory failure; WBC = white blood cells; IQR = interquartile range (25th, 75th percentile); PT = prothrombin time; APTT = activated partial thromboplastin time; AST = aspartate aminotransferase; ALT = alanine aminotransferase; ALP = alkaline phosphatase; BUN = blood urea nitrogen. Significant P values are in bold.
WBC (× 103/μL)5.76 ± 3.70
 Median = 4.0
 IQR = (2.8, 10.0)
 (n = 11)4.57 ± 2.52
 Median = 4.0
 IQR = (2.8, 5.7)
 (n = 544)0.406
Hematocrit (%)34.54 ± 5.80
 Median = 35.8
 IQR = (28.6, 40.8)
 (n = 11)38.67 ± 14.52
 Median = 38.1
 IQR = (34.5, 41.5)
 (n = 544)0.073
Platelets (× 104/μL)4.91 ± 3.53
 Median = 3.0
 IQR = (2.1, 9.0)
 (n = 11)8.26 ± 6.03
 Median = 8.0
 IQR = (2.8, 12.3)
 (n = 547)0.092
PT (sec)11.97 ± 0.97
 Median = 11.6
 IQR = (11.4, 12.6)
 (n = 11)10.81 ± 1.42
 Median = 10.5
 IQR = (10.1, 11.1)
 (n = 223)< 0.001
APTT (sec)50.81 ± 8.23
 Median = 50.8
 IQR = (46.8, 54.8)
 (n = 11)42.10 ± 8.88
 Median = 40.8
 IQR = 36, 45.65)
 (n = 228)0.001
AST (U/L)1173.18 ± 1896.31
 Median = 144
 IQR = (64, 1430)
 (n = 11)144.74 ± 351.336
 Median = 82
 IQR = (45, 145)
 (n = 403)0.015
ALT (U/L)730.82 ± 1313.65
 Median = 76
 IQR = (46, 929)
 (n = 11)101.03 ± 156.78
 Median = 58
 IQR = (36, 105.5)
 (n = 240)0.042
ALP (U/L)78
 Median = 78
 IQR = (78, 78)
 (n = 1)93.67 ± 75.78
 Median = 71
 IQR = (54.5, 110.5)
 (n = 57)0.742
Total bilirubin (mg/dL)3.55 ± 2.47
 Median = 3.55
 IQR = (1.8, 5.3)
 (n = 2)1.27 ± 0.76
 Median = 1.10
 IQR = (0.7, 1.58)
 (n = 40)0.051
BUN (mg/dL)51.00 ± 41.80
 Median = 37.5
 IQR = (22, 93.5)
 (n = 4)18.09 ± 18.41
 Median = 14.0
 IQR = (11, 19)
 (n = 86)0.007
Creatinine (mg/dL)2.16 ± 1.18
 Median = 1.7
 IQR = (1.6, 3.2)
 (n = 7)1.05 ± 0.51
 Median = 1.0
 IQR = (0.8, 1.2)
 (n = 361)0.002
Albumin (g/dL)2.66 ± 0.53
 Median = 2.60
 IQR = (2.4, 3.0)
 (n = 11)3.34 ± 0.49
 Median = 3.30
 IQR = (3.0, 3.63)
 (n = 146)< 0.001
Table 5

Comparisons of associated clinical courses in adult dengue patients with ARF (ARF group) and without ARF (control group)*

ARF groupControl groupP
* ARF = acute respiratory failure; UGI bleeding = upper gatrointestinal bleeding. Significant P values are in bold.
Renal insufficiency9 (81.8%)
 (n = 11)59 (16.2%)
 (n = 365)< 0.001
Acute renal failure7 (63.6%)
 (n = 11)0 (0%)
 (n = 595)< 0.001
Liver function impairment11 (100%)
 (n = 11)332 (79.8%)
 (n = 416)0.132
Acute hepatic failure4 (36.4%)
 (n = 11)2 (0.3%)
 (n = 595)< 0.001
Hemorrhage11 (100%)
 (n = 11)337 (56.5%)
 (n = 595)0.003
UGI bleeding8 (72.7%)
 (n = 11)54 (9.1%)
 (n = 595)< 0.001
Combination bacterial infection6 (54.5%)
 (n = 11)16 (2.7%)
 (n = 595)< 0.001
Table 6

Distributions of different types of hemorrhage in dengue patients with ARF (ARF group) and without ARF (control group)*

ARF group (n = 11)Control group (n = 595)P
* An individual patient might have more than one hemorrhage presentation. ARF = acute respiratory failure; UGI bleeding = upper gastrointestinal bleeding. Significant P value is in bold.
UGI bleeding8 (72.7%)54 (9.1%)< 0.001
Hemorrhagic petechiae/ecchymoses3 (27.3%)120 (20.2%)0.473
Gum bleeding3 (27.3%)113 (19.0%)0.448
Oral bleeding2 (18.2%)30 (5.0%)0.110
Nasal bleeding1 (9.1%)22 (3.7%)0.349
Hemoptysis1 (9.1%)23 (3.9%)0.361
Hematuria2 (18.2%)46 (7.7%)0.214
Vaginal bleeding1 (9.1%)8 (1.3%)0.153
Retinal bleeding0 (0%)2 (0.3%)1.000
Conjunctival bleeding0 (0%)3 (0.5%)1.000
Hemoarthritis0 (0%)1 (0.2%)1.000
Subarachnoid hemorrhage0 (0%)1 (0.2%)1.000
Table 7

Comparisons of albumin in 606 dengue patients with dengue hemorrhage fever (DHF group) and with dengue fever (DF group)*

DHF group (n = 122)DF group (n = 35)P
* Values are mean ± SD. Significant P value is in bold.
Albumin (g/dL)3.26 ± 0.523.47 ± 0.480.011
Table 8

Comparisons of fluid replacement in dengue patients with ARF (ARF group) and without ARF (control group)*

ARF group (n = 11)Control group (n = 595)P
* ARF = acute respiratory failure.
With fluid replacement6 (54.5%)250 (42.0%)0.540

*

Address correspondence to Meng-Chih Lin, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China and Department of Respiratory Care, Chang Gung Institute of Technology, Chia-Yi, Taiwan, 123 Dabi Road, Niaosung Shiang, Kaohsiung, Taiwan, Republic of China. E-mail: mengchih@adm.cgmh.org.tw

Authors’ addresses: Chin-Chou Wang, Shih-Feng Liu, An-Shen Lin, Chao-Chien Wu, Yu-Hsiu Chung, and Meng-Chih Lin, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China. Shang-Chih Liao, Division of Nephrology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China. Ing-Kit Lee and Jien-Wei Liu, Division of Infectious Disease, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China.

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Author Notes

Reprint requests: Meng-Chih Lin, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China and Department of Respiratory Care, Chang Gung Institute of Technology, Chiayi, Taiwan, 123 Dabi Road, Niaosung Shiang, Kaohsiung, Taiwan, Republic of China, Telephone: 886-7-731-7123 extension 8199, Fax: 886-7-732-2402, E-mail: mengchih@adm.cgmh.org.tw.
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