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What diseases are disguised as dengue?
What diseases are disguised as dengue? Po-An Su MD, Che-Kim Tan MD, Chien-Chin Hsu MD, PhD, Kuo-Tai Chen MD PII: DOI: Reference:
S0735-6757(14)00870-5 doi: 10.1016/j.ajem.2014.11.035 YAJEM 54637
To appear in:
American Journal of Emergency Medicine
Received date: Accepted date:
5 November 2014 17 November 2014
Please cite this article as: Su Po-An, Tan Che-Kim, Hsu Chien-Chin, Chen Kuo-Tai, What diseases are disguised as dengue?, American Journal of Emergency Medicine (2014), doi: 10.1016/j.ajem.2014.11.035
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT What diseases are disguised as dengue?
T
Po-An Su MD1, Che-Kim Tan MD2, Chien-Chin Hsu, MD, PhD3,4, Kuo-Tai Chen MD3,5 Division of infection disease, Department of Medicine, Chi-Mei Medical Center
2
Department of Intensive Care Medicine, Chi-Mei Medical Center
RI P
1
Emergency Department, Chi-Mei Medical Center
4
Department of Biotechnology, Southern Tainan University of Technology, Tainan,
MA NU
SC
3
Taiwan
Department of Emergency Medicine, Taipei Medical University, Taipei
ED
5
PT
Address for reprints: Dr. Kuo-Tai Chen Emergency Department, Chi-Mei Medical Center
CE
901 Chung-Hwa Road, Yung Kang, Tainan 710, Taiwan.
AC
Tel: 886-6-2812811 ext. 57196; Fax: 886-6-2816161
E-mail: [email protected]
ACCEPTED MANUSCRIPT Dengue is the most common arthropod-borne viral disease and is prevalent in
T
tropical and subtropical areas. The typical manifestations of dengue include fever,
RI P
headache and myalgia, and these symptoms are commonly present in various
SC
inflammatory and infectious diseases. Therefore, the accurate diagnosis of dengue relies on laboratory studies (1). Currently, capture enzyme-linked immunosorbent
MA NU
assay for dengue immunoglobulin M antibody (dengue IgM) is the most widely applied test. However, dengue IgM antibodies cross-react with other flaviviruses, and a number of non-dengue diseases have been reported to produce positive reactions
ED
in dengue serological tests (1-5). When such non-dengue diseases are mistaken for
PT
dengue, appropriate management of the actual disease is delayed. Therefore, we
CE
conducted the retrospective study to identify the diseases that can present false
AC
positive dengue IgM results.
ACCEPTED MANUSCRIPT We reviewed all emergency department patients who underwent single dengue IgM
T
from April 1, 2010 to May 31, 2011 in the Chi-Mei Medical Center. Among the 292
RI P
reviewed patients, 68 cases exhibited positive results for dengue IgM. The patients
SC
with positive dengue IgM test results underwent further examinations, and the diagnoses of dengue followed the definitions of the World Health Organization (6).
MA NU
The results of further tests yielded 34 dengue patients (dengue group) and 34 uncertain cases. Of the uncertain cases, we were able to identify the actual disease in 10 patients (non-dengue group). We then applied Student’s t-tests to evaluate the
ED
differences in continuous variables between the dengue and non-dengue patients.
PT
The dengue group included 33 adults and 1 child, and the non-dengue group
CE
included 7 adults and 3 children. The adult age distributions were similar between
AC
the dengue and non-dengue patients (dengue vs. non-dengue, 62 vs. 60 years old, respectively, p=0.334). Infectious diseases were present in the majority of the non-dengue group and including urinary tract infection, cholecystitis, perforated peptic ulcer and pediatric tonsillitis. The other non-dengue patients had systemic lupus erythematosus and Kawasaki disease. All of the non-dengue patients and 20 of the dengue patients were admitted. The non-dengue group exhibited longer hospital stays (dengue vs. non-dengue, 6.3 vs. 11.7 days, respectively, p=0.010). Three
ACCEPTED MANUSCRIPT non-dengue patients required intensive care, and surgical interventions were
T
performed in three non-dengue patients (Table).
RI P
All of the non-dengue patients and only 2 of the 34 dengue patients had C-reactive
SC
protein (CRP) levels above 15 mg/L (dengue vs. non-dengue, 7 vs. 81, respectively, p=0.000). Compared with the non-dengue patients, the dengue patients exhibited
MA NU
lower white cell counts (dengue vs. non-dengue, 4021 vs. 9430/mm3, respectively, p=0.000) and higher hematocrit levels (dengue vs. non-dengue, 42.1 vs. 37.2 %, respectively, p=0.005). There was no significant difference in platelet counts between
ED
the two groups (dengue vs. non-dengue, 103300 vs. 102700/mm3, respectively,
AC
CE
PT
p=0.920).
ACCEPTED MANUSCRIPT Southern Taiwan is a dengue epidemic area, and emergency physicians are familiar
T
with the manifestations of dengue. Accordingly, febrile patients presenting with
RI P
thrombocytopenia and myalgia typically undergo dengue IgM testing to screen for
SC
dengue.
However, a study of travelers revealed that a single positive IgM is associated with a
MA NU
42.5% false-positive rate, and the authors suggested the use of a more specific diagnostic technique to confirm dengue infection (2). Based on our experience, we found that a single positive dengue IgM provided only 50% specificity for the
ED
diagnosis of dengue, and a significant portion of the misdiagnosed patients (6/10)
PT
required either invasive interventions or immunosuppressive therapy. Additionally, a
CE
retrospective study conducted in Taiwan regarding dengue patients with acute
AC
abdomen revealed that invasive procedures or surgeries increased the requirements of blood transfusion and prolonged hospital stays.(7) Therefore, the early detection of the actual disease and the confirmation of the dengue infection are crucial for suspected patients with positive dengue IgM. Levy et al. performed a study that included 36 dengue patients. These authors found the CRP levels are mildly elevated and seldom exceed 15 mg/L.(8) This finding is in line with our result that the majority of the CRP levels in the dengue patients were below 15 mg/L; the only two cases that exceed this value had CRP levels of 26.5 and
ACCEPTED MANUSCRIPT 28.4 mg/L. Accordingly, a markedly increased CRP level might indicate either a
T
serious infectious or the presence of an inflammatory disease in the involved patient.
RI P
Thrombocytopenia, leucopenia and elevated hematocrit are all common hematologic
SC
abnormalities in dengue patients.(2,6) In our institution, thrombocytopenia and fever are the dominant triggers for physicians to order a dengue IgM. Consequently, the
MA NU
platelet counts of the dengue and non-dengue patients were similar. Leukocytosis is more common than leucopenia in infectious diseases and Kawasaki disease.(9) Regarding the hematocrit level, anemia is typically present in patients with SLE and
ED
Kawasaki disease.(10) Therefore, marked elevations in CRP level, leukocytosis and
PT
low levels of hematocrit are practical markers that should remind physicians to
AC
diseases.
CE
search for either a misdiagnosed illness or the combination of dengue and other
A single dengue IgM does not indicate the diagnosis of dengue infection with certainty. Various infectious and inflammatory diseases can produce positive results. We advocate the performance of an additional confirmatory diagnostic test in suspected cases, particularly those with marked elevations in CRP level, leukocytosis and decreased level of hematocrit.
ACCEPTED MANUSCRIPT References
T
1. Guzman MG, Kouri G. Dengue diagnosis, advances and challenges. Int J Infect Dis.
RI P
2004; 8: 69-80.
SC
2. Wichmann O, Stark K, Shu PY, Niedrig M, Frank C, Huang JH, et al. Clinical features and pitfalls in the laboratory diagnosis of dengue in travelers. BMC Infect Dis.
MA NU
2006; 6: 120.
3. Sopontammarak S, Promphan W, Roymanee S, Phetpisan S. Positive serology for dengue viral infection in pediatric patients with Kawasaki disease in southern
ED
Thailand. Circ J. 2008; 72:1492-4.
PT
4. Santosa A, Poh Z, Teng GG. Delayed diagnosis of systemic lupus erythematosus
CE
due to misinterpretation of dengue serology. Scand J Rheumatol. 2014; 41: 77-9.
AC
5. Arya SC, Agarwal N. Dengue and concurrent urinary infection in a tertiary care hospital in Delhi. Trans R Soc Trop Med Hyg. 2009; 103: 642-3. 6. World Health Organization. Dengue hemorrhagic fever: diagnosis, treatment, prevention and control. 2nd ed. Geneva: World Health Organization, 1997. 7. Khor BS, Liu JW, Lee IK, Yang KD. Dengue hemorrhagic fever patients with acute abdomen: clinical experience of 14 cases. Am J Trop Med Hyg. 2006; 74: 901-4. 8. Levy A, Valero N, Espina LM, Anez G, Arias J, Mosquera J. Increment of interleukin 6, tumor necrosis factor alpha, nitric oxide, C-reactive protein and apoptosis in
ACCEPTED MANUSCRIPT dengue. Trans R Soc Trop Med Hyg. 2010; 104: 16-23.
T
9. Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, et al.
RI P
Diagnosis, treatment, and long-term management of Kawasaki disease: a
SC
statement for health progessionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the
MA NU
Young, American Heart Association. Pediatrics. 2004; 114: 1708-33. 10. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis,
AC
CE
PT
ED
Rheum. 1982; 25: 1271-7.
ACCEPTED MANUSCRIPT Table. Ages, genders, accurate diagnoses and requirements for invasive procedures and intensive care units among the non-dengue patients.
F (55) M (67)
M (72)
PT
F (85)
ED
M (72)
(Escherichia coli) Pyelonephritis, Bacteremia (Escherichia coli) Pyelonephritis, Bacteremia
CE
(Escherichia coli) Urinary tract infection
M (8)
Kawasaki disease
F (3)
Tonsillitis
M (4)
Tonsillitis
AC
M (32)
Pediatric (3)
T
Intensive care unit
7 days
Surgery for perforated gastric ulcer
MA NU
Perforated gastric ulcer Cholecystitis, Bacteremia
Invasive procedures
RI P
Systemic lupus erythematosus Systemic lupus erythematosus
F (48)
Adult (7)
Diagnosis
SC
Gender (age)
Cholecystectomy
12 days
Nephrectomy
4 days
S0735-6757(14)00870-5 doi: 10.1016/j.ajem.2014.11.035 YAJEM 54637
To appear in:
American Journal of Emergency Medicine
Received date: Accepted date:
5 November 2014 17 November 2014
Please cite this article as: Su Po-An, Tan Che-Kim, Hsu Chien-Chin, Chen Kuo-Tai, What diseases are disguised as dengue?, American Journal of Emergency Medicine (2014), doi: 10.1016/j.ajem.2014.11.035
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT What diseases are disguised as dengue?
T
Po-An Su MD1, Che-Kim Tan MD2, Chien-Chin Hsu, MD, PhD3,4, Kuo-Tai Chen MD3,5 Division of infection disease, Department of Medicine, Chi-Mei Medical Center
2
Department of Intensive Care Medicine, Chi-Mei Medical Center
RI P
1
Emergency Department, Chi-Mei Medical Center
4
Department of Biotechnology, Southern Tainan University of Technology, Tainan,
MA NU
SC
3
Taiwan
Department of Emergency Medicine, Taipei Medical University, Taipei
ED
5
PT
Address for reprints: Dr. Kuo-Tai Chen Emergency Department, Chi-Mei Medical Center
CE
901 Chung-Hwa Road, Yung Kang, Tainan 710, Taiwan.
AC
Tel: 886-6-2812811 ext. 57196; Fax: 886-6-2816161
E-mail: [email protected]
ACCEPTED MANUSCRIPT Dengue is the most common arthropod-borne viral disease and is prevalent in
T
tropical and subtropical areas. The typical manifestations of dengue include fever,
RI P
headache and myalgia, and these symptoms are commonly present in various
SC
inflammatory and infectious diseases. Therefore, the accurate diagnosis of dengue relies on laboratory studies (1). Currently, capture enzyme-linked immunosorbent
MA NU
assay for dengue immunoglobulin M antibody (dengue IgM) is the most widely applied test. However, dengue IgM antibodies cross-react with other flaviviruses, and a number of non-dengue diseases have been reported to produce positive reactions
ED
in dengue serological tests (1-5). When such non-dengue diseases are mistaken for
PT
dengue, appropriate management of the actual disease is delayed. Therefore, we
CE
conducted the retrospective study to identify the diseases that can present false
AC
positive dengue IgM results.
ACCEPTED MANUSCRIPT We reviewed all emergency department patients who underwent single dengue IgM
T
from April 1, 2010 to May 31, 2011 in the Chi-Mei Medical Center. Among the 292
RI P
reviewed patients, 68 cases exhibited positive results for dengue IgM. The patients
SC
with positive dengue IgM test results underwent further examinations, and the diagnoses of dengue followed the definitions of the World Health Organization (6).
MA NU
The results of further tests yielded 34 dengue patients (dengue group) and 34 uncertain cases. Of the uncertain cases, we were able to identify the actual disease in 10 patients (non-dengue group). We then applied Student’s t-tests to evaluate the
ED
differences in continuous variables between the dengue and non-dengue patients.
PT
The dengue group included 33 adults and 1 child, and the non-dengue group
CE
included 7 adults and 3 children. The adult age distributions were similar between
AC
the dengue and non-dengue patients (dengue vs. non-dengue, 62 vs. 60 years old, respectively, p=0.334). Infectious diseases were present in the majority of the non-dengue group and including urinary tract infection, cholecystitis, perforated peptic ulcer and pediatric tonsillitis. The other non-dengue patients had systemic lupus erythematosus and Kawasaki disease. All of the non-dengue patients and 20 of the dengue patients were admitted. The non-dengue group exhibited longer hospital stays (dengue vs. non-dengue, 6.3 vs. 11.7 days, respectively, p=0.010). Three
ACCEPTED MANUSCRIPT non-dengue patients required intensive care, and surgical interventions were
T
performed in three non-dengue patients (Table).
RI P
All of the non-dengue patients and only 2 of the 34 dengue patients had C-reactive
SC
protein (CRP) levels above 15 mg/L (dengue vs. non-dengue, 7 vs. 81, respectively, p=0.000). Compared with the non-dengue patients, the dengue patients exhibited
MA NU
lower white cell counts (dengue vs. non-dengue, 4021 vs. 9430/mm3, respectively, p=0.000) and higher hematocrit levels (dengue vs. non-dengue, 42.1 vs. 37.2 %, respectively, p=0.005). There was no significant difference in platelet counts between
ED
the two groups (dengue vs. non-dengue, 103300 vs. 102700/mm3, respectively,
AC
CE
PT
p=0.920).
ACCEPTED MANUSCRIPT Southern Taiwan is a dengue epidemic area, and emergency physicians are familiar
T
with the manifestations of dengue. Accordingly, febrile patients presenting with
RI P
thrombocytopenia and myalgia typically undergo dengue IgM testing to screen for
SC
dengue.
However, a study of travelers revealed that a single positive IgM is associated with a
MA NU
42.5% false-positive rate, and the authors suggested the use of a more specific diagnostic technique to confirm dengue infection (2). Based on our experience, we found that a single positive dengue IgM provided only 50% specificity for the
ED
diagnosis of dengue, and a significant portion of the misdiagnosed patients (6/10)
PT
required either invasive interventions or immunosuppressive therapy. Additionally, a
CE
retrospective study conducted in Taiwan regarding dengue patients with acute
AC
abdomen revealed that invasive procedures or surgeries increased the requirements of blood transfusion and prolonged hospital stays.(7) Therefore, the early detection of the actual disease and the confirmation of the dengue infection are crucial for suspected patients with positive dengue IgM. Levy et al. performed a study that included 36 dengue patients. These authors found the CRP levels are mildly elevated and seldom exceed 15 mg/L.(8) This finding is in line with our result that the majority of the CRP levels in the dengue patients were below 15 mg/L; the only two cases that exceed this value had CRP levels of 26.5 and
ACCEPTED MANUSCRIPT 28.4 mg/L. Accordingly, a markedly increased CRP level might indicate either a
T
serious infectious or the presence of an inflammatory disease in the involved patient.
RI P
Thrombocytopenia, leucopenia and elevated hematocrit are all common hematologic
SC
abnormalities in dengue patients.(2,6) In our institution, thrombocytopenia and fever are the dominant triggers for physicians to order a dengue IgM. Consequently, the
MA NU
platelet counts of the dengue and non-dengue patients were similar. Leukocytosis is more common than leucopenia in infectious diseases and Kawasaki disease.(9) Regarding the hematocrit level, anemia is typically present in patients with SLE and
ED
Kawasaki disease.(10) Therefore, marked elevations in CRP level, leukocytosis and
PT
low levels of hematocrit are practical markers that should remind physicians to
AC
diseases.
CE
search for either a misdiagnosed illness or the combination of dengue and other
A single dengue IgM does not indicate the diagnosis of dengue infection with certainty. Various infectious and inflammatory diseases can produce positive results. We advocate the performance of an additional confirmatory diagnostic test in suspected cases, particularly those with marked elevations in CRP level, leukocytosis and decreased level of hematocrit.
ACCEPTED MANUSCRIPT References
T
1. Guzman MG, Kouri G. Dengue diagnosis, advances and challenges. Int J Infect Dis.
RI P
2004; 8: 69-80.
SC
2. Wichmann O, Stark K, Shu PY, Niedrig M, Frank C, Huang JH, et al. Clinical features and pitfalls in the laboratory diagnosis of dengue in travelers. BMC Infect Dis.
MA NU
2006; 6: 120.
3. Sopontammarak S, Promphan W, Roymanee S, Phetpisan S. Positive serology for dengue viral infection in pediatric patients with Kawasaki disease in southern
ED
Thailand. Circ J. 2008; 72:1492-4.
PT
4. Santosa A, Poh Z, Teng GG. Delayed diagnosis of systemic lupus erythematosus
CE
due to misinterpretation of dengue serology. Scand J Rheumatol. 2014; 41: 77-9.
AC
5. Arya SC, Agarwal N. Dengue and concurrent urinary infection in a tertiary care hospital in Delhi. Trans R Soc Trop Med Hyg. 2009; 103: 642-3. 6. World Health Organization. Dengue hemorrhagic fever: diagnosis, treatment, prevention and control. 2nd ed. Geneva: World Health Organization, 1997. 7. Khor BS, Liu JW, Lee IK, Yang KD. Dengue hemorrhagic fever patients with acute abdomen: clinical experience of 14 cases. Am J Trop Med Hyg. 2006; 74: 901-4. 8. Levy A, Valero N, Espina LM, Anez G, Arias J, Mosquera J. Increment of interleukin 6, tumor necrosis factor alpha, nitric oxide, C-reactive protein and apoptosis in
ACCEPTED MANUSCRIPT dengue. Trans R Soc Trop Med Hyg. 2010; 104: 16-23.
T
9. Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, et al.
RI P
Diagnosis, treatment, and long-term management of Kawasaki disease: a
SC
statement for health progessionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the
MA NU
Young, American Heart Association. Pediatrics. 2004; 114: 1708-33. 10. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis,
AC
CE
PT
ED
Rheum. 1982; 25: 1271-7.
ACCEPTED MANUSCRIPT Table. Ages, genders, accurate diagnoses and requirements for invasive procedures and intensive care units among the non-dengue patients.
F (55) M (67)
M (72)
PT
F (85)
ED
M (72)
(Escherichia coli) Pyelonephritis, Bacteremia (Escherichia coli) Pyelonephritis, Bacteremia
CE
(Escherichia coli) Urinary tract infection
M (8)
Kawasaki disease
F (3)
Tonsillitis
M (4)
Tonsillitis
AC
M (32)
Pediatric (3)
T
Intensive care unit
7 days
Surgery for perforated gastric ulcer
MA NU
Perforated gastric ulcer Cholecystitis, Bacteremia
Invasive procedures
RI P
Systemic lupus erythematosus Systemic lupus erythematosus
F (48)
Adult (7)
Diagnosis
SC
Gender (age)
Cholecystectomy
12 days
Nephrectomy
4 days