Hindawi Publishing Corporation

ISRN Tropical Medicine

Volume 2013, Article ID 139273, 5 pages
http://dx.doi.org/10.1155/2013/139273

Research Article
Does Comorbidity Increase the Risk of Dengue Hemorrhagic
Fever and Dengue Shock Syndrome?

Shahid Mahmood,1 Saadia Hafeez,2 Hiba Nabeel,2 Urooj Zahra,2 and Hammad Nazeer3
1
Department of Community Medicine, Gujranwala Medical College, Gujranwala, Pakistan
2
Fatima Jinnah Medical College, Lahore, Pakistan
3
Department of Infectious Diseases, Shaukat Khanum Memorial Hospital, Lahore, Pakistan

Correspondence should be addressed to Shahid Mahmood; shahidsethi@hotmail.com

Received 18 June 2013; Accepted 24 July 2013

Academic Editors: P. A. Nogueira and M. A. Sosa

Copyright © 2013 Shahid Mahmood et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.

Background. Dengue fever is an emerging public health problem in Pakistan. The aim of this study was to determine the relationship
between comorbid conditions in individuals suffering from dengue fever and the development of dengue hemorrhagic fever or
dengue shock syndrome. Methods. In this age- and sex-matched case control study, total of 132 cases of dengue hemorrhagic
fever/dengue shock syndrome and 249 randomly selected controls were recruited from two major teaching hospitals of Lahore,
Pakistan. A semistructured questionnaire was used to collect data through interview and by reviewing clinical records. SPSS version
18 was utilized for statistical analysis including conditional logistic regression. Results. Odds of developing dengue hemorrhagic
fever (DHF) and dengue shock syndrome (DSS) among diabetics are higher than in controls, but this association was not found
statistically significant (OR. 1.26; 95% CI. 0.78–2.03; 𝑃 = 0.34). Similarly, no association was observed in individuals suffering from
hypertension (OR. 0.93; 95% CI. 0.57–1.49; 𝑃 = 0.76). Odds of developing DHF and DSS were higher for bronchial asthma (adjusted
OR. 1.34) and pulmonary tuberculosis (adjusted OR. 1.41); however P values were insignificant. Conclusion. Presence of diabetes
mellitus, hypertension, ischemic heart disease and bronchial asthma among patients contracted dengue fever will not increase the
risk of dengue hemorrhagic fever and dengue shock syndrome.

1. Background Dengue is endemic in many Southeast Asian countries

and Western pacific region [2]. About 2.5 billion people (40%
Dengue fever is an emerging public health problem prevalent of world’s population) are at risk of dengue transmission.
mostly in tropical and subtropical regions of the world. It The World Health Organization (WHO) estimates that 50 to
is an arbovirus infection transmitted through Aedes aegypti 100 million infections occur yearly, including 500,000 DHF
and Aedes albopictus mosquito species. Four dengue virus cases and 22,000 deaths, mostly among children. Subjects
serotypes (DENV-1, DENV-2, DENV-3, and DENV-4) have who develop DHF have 3–5% chance of death if accompanied
yet been identified and are responsible for most of the by Dengue shock syndrome [2, 3]. In Pakistan, first dengue
clinical manifestations, ranging from asymptomatic disease outbreak was reported in Karachi during 1994 and sporadic
to symptomatic dengue fever (DF) and dengue hemorrhagic cases occurred in coming years. Since environmental condi-
fever (DHF). In majority of patients, infection is self-limiting, tions are conducive to Aedes mosquito breeding in Pakistan,
but in small proportions, the resultant dengue shock syn- therefore dengue virus import through travelling and trade
drome (DSS) may increase morbidity and mortality. Infection completed the disease transmission cycle. Economic and
with one serotype does not give protection against other security related migration 2004 onward introduced the virus
dengue viruses, yet sequential infections increase the risk in Lahore as well. According to Punjab health department,
of developing dengue hemorrhagic fever (DHF) and dengue total of 590339 suspected cases of dengue were reported
shock syndrome (DSS) [1, 2]. in Lahore, out of which 21685 were confirmed by serology.
2 ISRN Tropical Medicine

The ratio of DF/DHF has not been reported; however it has 2. Methods
been observed that 5–10% of these cases developed DHF,
whereas <5% went to Dengue Shock Syndrome. Death rate In this matched case control study conducted in two major
was reported officially to be less than 1%. More males (68.2%) tertiary care hospitals (Jinnah and Sir Ganga Ram) of Lahore,
in age group 15–45 were affected [2–4]. a total of one hundred and thirty-two cases of dengue hem-
The factors associated with dengue transmission include orrhagic fever and 249 appropriate controls were included.
demographic and societal changes like population growth, These controls were randomly selected from the same health
urbanization, lack of public health awareness, and appro- facilities, as being positive for anti-dengue IgG and were
priate disease reporting. Pathophysiology of severe clinical matched with cases in terms of age (frequency matched
manifestation observed in DHF remains poorly understood, within 5-years group) and sex. The required sample size
though it is believed that secondary infection put the subjects was calculated using WHO software based on book of S.
at great risk of dengue hemorrhagic fever [3]. Dengue shock K. Lwanga and S. Lemeshow taking 5% level of significance
syndrome is the most fatal clinical complication carrying and with 80% power. A case for this study was defined as a
high mortality. Although, more than 90% of dengue fever 15–65 years male or female, who was diagnosed as dengue
cases do not progress to the severe form of disease, there hemorrhagic fever (DHF) by a trained clinician using world
is no effective mechanism to predict the development and health organization (WHO) criteria. Time frame for this
the prognosis of DHF/DSS in these cases. There is no clear study was from September to December 2011. A pretested
understanding why among a big pool of dengue fever cases, semistructured interview form and a checklist for clinical
only small proportion of subject develops DHF/DSS. Under- record review were devised to collect the data. Face to
standing the predictor of DHF/DSS development would face interviews were conducted in hospital settings by the
provide information to identify individuals at higher risk researchers themselves after taking verbal informed consent.
and on the other hand, give sufficient time to clinicians Clinical records were reviewed by medical specialists. All
for reducing dengue related morbidity and mortality [4]. It the responses were first transferred to paper based forms
has been postulated that presence of certain comorbidities followed by its editing and analysis by using SPSS version
like diabetes mellitus, hypertension, chronic renal failure, 18. Numerical data was presented in the form of mean ±
bronchial asthma, and allergies might place some patients SD, whereas categorical data was described using frequencies
at high risk of developing DHF/DSS [5, 6]. Information in and percentages. Difference of means was compared using
this regard is insufficient. However, there is a pathophys- independent t-test while chi-square test and Fisher exact
iological linkage to support this postulation. Endothelial test (where appropriate) were used to compare difference of
changes occurring in diabetes mellitus and allergies might proportions. For ordered categories, chi-square trend was
trigger biological changes resulting in increased capillary used with one degree of freedom. A P-value of less than 0.05
fragility and vessel permeability observed in DHF patients. was considered statistically significant. Odds ratio was used
Exact mechanisms are, though, not clearly understood, as a measure of strength of association between outcome
but it has been suggested that the patients with history of interest and exposures. Crude and adjusted odds ratios
of allergies have constantly activated immune system and along with 95% confidence interval were computed using
there is liberation of proinflammatory cytokines in tissues, conditional logistic regression method. Formal permission
particularly in endothelium [7]. Similarly, in type-2 diabetes was obtained from concerned hospitals and institutional
mellitus, there is an activation of T-lymphocytes and release ethical review committees to conduct this study.
of cytokines like gamma interferon and tumor necrosis factor
alpha, which ultimately increase the capillary fragility and 3. Results
permeability [8]. Similar physiopathological mechanism has
been observed in development of dengue hemorrhagic fever The purpose of this case control study was to test the
and dengue shock syndrome. hypothesis that the subjects suffering from diabetes mellitus,
Only small number of studies have reported relationship cardiovascular diseases, bronchial asthma, tuberculosis, and
between DHF/DSS and selected comorbidities. It has been chronic liver disease have higher odds of developing dengue
observed that individuals with allergies using steroids and hemorrhagic fever and dengue shock syndrome if they
diabetes mellitus were 2.5 times more likely to develop contract dengue virus infection. Of 132 cases, 71 (53.8%) were
DHF [9–11], whereas association with hypertension and males as compared to 158 (63.5%) in controls (Table 1). On the
bronchial asthma was found insignificant. Similarly, in Puerto other hand, 61 (46.2%) and 91 (36.5%) females were included
Rico diabetes mellitus, gastritis, COPD, and hepatitis were among cases and controls, respectively. Difference based on
more prevalent among dengue hemorrhagic patients [12– gender was not statistically significant (𝜒2 = 3.36; 𝑃 = 0.06).
14]. In Pakistan, data on relationship between presence Majority (51.5%) of the cases were aged between 40 and 59
of comorbidities and development of DHF/DSS is scarce. years, whereas proportion of subjects aged 20–39 and more
Current study aims at filling the knowledge gap in this than 60 years were 35 (26.5%) and 26 (19.7%), respectively,
regard. Information thus obtained not only facilitates the (Table 1). Age difference was not found to be statistically
clinicians to identify the subjects at higher risk of devel- significant.
oping DHF/DSS in early stage of disease, but also used Of 132 cases, 57 (43.2%) had diabetes mellitus compared
as an evidence to start an awareness campaign for public to 104 (41.8%) controls, respectively, but this difference
education. between them was not statistically significant (𝑃 = 0.79).
ISRN Tropical Medicine 3

Table 1: Comorbidities in dengue hemorrhagic fever cases in comparison to control population.

Cases (𝑛 = 132) Controls (𝑛 = 249) Total (𝑛 = 381) 𝜒2

Characteristics 𝑃-value
𝑁 % 𝑁 % 𝑁 %
Age (years)
<20 03 2.3 06 2.4 09 2.4
20–39 35 26.5 49 19.7 84 22.0 0.06
7.22
40–59 68 51.5 114 45.8 182 47.8
60+ 26 19.7 80 32.1 106 27.8
Gender
Male 71 53.8 158 63.5 229 60.1
3.36 0.06
Female 61 46.2 91 36.5 152 39.9
Diabetes mellitus
Yes 57 43.2 104 41.8 161 42.3
0.07 0.79
No 75 56.8 145 58.2 220 57.7
Hypertension
Yes 67 50.8 135 54.2 202 53.0
0.41 0.52
No 65 49.2 114 45.8 179 47.0
Ischaemic heart disease
Yes 26 19.7 44 17.7 70 18.4
0.23 0.62
No 106 80.3 205 82.3 311 81.6
Bronchial asthma
Yes 14 10.6 23 9.2 37 9.7
0.18 0.66
No 118 89.4 226 90.8 344 90.3
Chronic liver disease
Yes 12 9.1 27 10.8 39 10.2
0.28 0.59
No 120 90.9 222 89.2 342 89.8
Pulmonary tuberculosis
Yes 10 7.6 13 5.2 23 6.0
0.84 0.35
No 122 92.4 236 94.8 358 94.0
⊢
Column percentages presented.

Although, odds of developing dengue hemorrhagic fever (adjusted OR. 1.34) and pulmonary tuberculosis (adjusted
(DHF) and dengue shock syndrome (DSS) among diabetics OR. 1.41); however, this pattern could not be generalized as
are higher than in controls (Table 2), but this association wide confidence intervals at 95% were observed (0.57–3.43
was not statistically significant (OR. 1.26; 95% CI. 0.78– for TB and 0.62–2.88 for asthma) with insignificant 𝑃-values
2.03; 𝑃 = 0.34). Furthermore, even duration of suffering (Table 2). In addition, duration of illnesses was not found to
from diabetes mellitus either in cases or among controls will be statistically significant with these comorbidities (𝑃 = 0.40
not increase the odds of developing sever forms of dengue for bronchial asthma and 𝑃 = 0.36 for tuberculosis).
illness. Similarly, no association was observed in individuals
suffering from hypertension (OR. 0.93; 95% CI. 0.57–1.49;
𝑃 = 0.76). Nevertheless, participants with ischaemic heart 4. Discussion
disease though had higher odds (adjusted OR. 1.52) but wide
confidence interval at 95% level of significance (CI. 0.85–2.73; Dengue infection has emerged as an important public health
𝑃 = 0.15) shows that this pattern has been observed merely issue in Pakistan. Recent outbreak in Lahore during 2011
by chance (Table 2). No significant association was also found has demonstrated the fatal nature of this arbovirus infection.
among cases of DHF and DSS with Chronic liver disease Large proportion of dengue seropositive patients developed
(𝜒2 = 0.28 at 1 df; 𝑃 = 0.59). severe manifestations of disease like dengue hemorrhagic
Regarding respiratory tract health issues, it was found fever (DHF) and dengue shock syndrome (DSS) and more
that among cases of DHF, only 12 (9.1%) and 14 (10.6%) were than three hundred precious lives lost. Since pathophysiology
suffering from pulmonary tuberculosis and bronchial asthma of this disease is still poorly understood and there is no
compared to 5.2% and 9.2%, respectively. Although, odds of mechanism to predict or identify which case would develop
developing DHF and DSS were higher for bronchial asthma DHF and DSS, therefore there evidence should be gathered
4 ISRN Tropical Medicine

Table 2: Risk of dengue hemorrhagic fever (DHF) in relation to existing comorbidities (𝑛 = 381).

Unadjusted estimates Adjusted estimates∗

Comorbidity
OR. 95% CI. 𝑃 OR. 95% CI. 𝑃
Diabetes mellitus
No 1 Reference 1 Reference
Yes 1.05 0.69–1.62 0.79 1.26 0.78–2.03 0.34
Hypertension
No 1 Reference 1 Reference
Yes 0.87 0.57–1.32 0.52 0.93 0.57–1.49 0.76
Ischaemic heart disease (IHD)
No 1 Reference 1 Reference
Yes 1.14 0.66–1.95 0.62 1.52 0.85–2.73 0.15
Bronchial asthma
No 1 Reference 1 Reference
Yes 1.16 0.57–2.34 0.66 1.34 0.62–2.88 0.44
Pulmonary tuberculosis
No 1 Reference 1 Reference
Yes 1.48 0.63–3.49 0.36 1.41 0.57–3.43 0.44
Duration of diabetes Mellitus
<5 years 1 Reference 1 Reference
5–10 years 1.25 0.56–2.80 0.57 2.76 0.77–9.84 0.11
>10 years 1.44 0.58–3.59 0.42 1.86 0.55–6.26 0.31
Duration of hypertension
<5 years 1 Reference 1 Reference
5–10 years 0.98 0.46–2.07 0.96 0.92 0.29–2.91 0.89
>10 years 1.25 0.42–3.56 0.71 0.73 0.14–3.66 0.70
∗
Adjusted for age, sex, and duration of illness.

to screen patient at early stage for monitoring and early hypertension and ischemic heart disease, we did not find
intervention. This study was initiated on a premise that any association and these findings were consistent with
certain comorbidities might increase the risk of developing studies in Brazil and Puerto Rico [12]. Duration of illness in
dengue hemorrhagic fever (DHF) and dengue shock syn- case of diabetes mellitus was significant (OR. = 2.76 for 5–
drome (DSS). This premise was based on clinical observations 10 years of illness), yet no such relationship was observed
communicated by clinicians at various forums. In order to for hypertension. Although, no statistical association was
test this hypothesis, patients of DHF/DSS were compared observed between chronic lung issues like tuberculosis and
with those who only had dengue fever for presence of bronchial asthma, however, other studies did found positive
comorbidities like cardiovascular diseases, diabetes mellitus, relationship between allergies and DHF [11]. We cannot
chronic liver disease, chronic lung disorders and allergies. comment on this issue as none of our participant reported
We did not find any statistical association with these comor- history of allergies; nevertheless considering close association
bidities, though unadjusted estimates suggest that individuals between allergies and bronchial asthma, such link cannot be
suffering from diabetes mellitus and ischemic heart diseases ignored.
have higher odds of developing DHF than the control Results of this study should be interpreted consider-
population. Similar observation was also reported by Riaz et ing its retrospective nature, issues related to incomplete
al. [10] that the diabetics were at higher risk of DHF than clinical data available, and relatively small control popula-
the control population. Similarly, of the 170 cases of DHF tion for comparison. Moreover, results may lack external
and 1175 controls in their study, Figueiredo et al. [11] found validity since the cases were recruited mainly from three
that individuals who reported allergies and taking steroids; major hospitals in Lahore and did not include patients
those who had diabetes were 2.5 times at higher risk of in private clinics. Considering the strong evidence pro-
developing DHF. Adjusted odds ratio in the mentioned study vided by studies in Brazil and Puerto Rico [12] about
for diabetes was 2.75 (95% CI. 1.12–6.73) and that for allergies relationship between comorbidities and development of
was 1.29 (95% CI. 0.87–1.89). In contrast, though adjusted dengue hemorrhagic fever, we suggest a followup study with
odds ratio in our case was 1.26; however wide confidence larger comparison group in order to screen those dengue
interval (0.78–2.03) and insignificant P-value indicates the cases with tendency to progress to dengue hemorrhagic
effect of smaller sample size used in our study. As regards fever.
ISRN Tropical Medicine 5

5. Conclusion [8] J. G. Rigau-Pérez and M. K. Laufer, “Dengue-related deaths in

Puerto Rico, 1992–1996: diagnosis and clinical alarm signals,”
This is probably the first study in Pakistan to investigate the Clinical Infectious Diseases, vol. 42, no. 9, pp. 1241–1246, 2006.
relationship between dengue hemorrhagic fever and selected [9] O. Parkash, A. Almas, S. W. Jafri, S. Hamid, J. Akhtar, and H.
comorbid conditions. We did not find any statistical associ- Alishah, “Severity of acute hepatitis and its outcome in patients
ation between dengue hemorrhagic fever and dengue shock with dengue fever in a tertiary care hospital Karachi, Pakistan
syndrome with diabetes mellitus, hypertension, bronchial (South Asia),” BMC Gastroenterology, vol. 10, no. 2, article 43,
asthma, chronic lung disease, and chronic liver diseases. 2010.
[10] M. M. Riaz, K. Mumtaz, M. S. Khan et al., “Outbreak of dengue
fever in Karachi 2006: a clinical perspective,” Journal of the
Conflict of Interests Pakistan Medical Association, vol. 59, no. 6, pp. 339–344, 2009.
[11] M. A. A. Figueiredo, L. C. Rodrigues, M. L. Barreto et al.,
The authors declare no competing interests. There was no
“Allergies and diabetes as risk factors for dengue hemorrhagic
external funding involved for any part of this study. fever: results of a case control study,” PLoS Neglected Tropical
Diseases, vol. 4, no. 6, article e699, 2010.
Authors’ Contribution [12] J. G. Rigau-Pérez and M. K. Laufer, “Dengue-related deaths in
Puerto Rico, 1992–1996: diagnosis and clinical alarm signals,”
Shahid Mahmood contributed in study conception, design, Clinical Infectious Diseases, vol. 42, no. 9, pp. 1241–1246, 2006.
data analysis and interpretation, and drafting the paper. [13] World Health Organization, “Impact of dengue,” 2008,
Saadia Hafeez helped in study design, data collection, and http://www.who.int/csr/disease/dengue/impact/en/index.html.
drafting the paper. Hiba Nabeel participated in data col- [14] World Health Organization, “Comprehensive guidelines for
lection, data management, and drafting tables. Urooj Zahra prevention and control of Dengue and Dengue haemorrhagic
helped in data collection, paper revision, and final drafting. fever- Revised and expanded edition, 2011,” SEARO technical
Hammad Nazeer helped in study design, interpretation of publication series No. 60, http://www.searo.who.int/entity/vec-
results, and revision of the paper. All the authors read and tor borne tropical diseases/documents/SEAROTPS60/en/in-
approved the final manuscript for publication. dex.html.

Acknowledgments
The authors are grateful to all subjects and their relatives
for sparing precious time for interview and allowing review
of clinical records. The authors also would like to thank
the cooperation and facilitation of all the medical and
paramedical staff of Sir Ganga Ram and Jinnah Hospitals.

References
[1] World Health Organization, Dengue and Dengue Haemmor-
rhagic Fever, World Health Organization, Geneva, Switzerland,
2012.
[2] Centers for Disease Control (CDC), “Epidemiology of Dengue
fever,” 2012, http://www.cdc.gov/dengue/epidemiology/index
.html.
[3] M. Malik, “Dengue prevention, control and management,”
in International Conference in Lahore Pakistan on Dengue
Prevention and Management, 2012.
[4] J. A. Potts and A. L. Rothman, “Clinical and laboratory features
that distinguish dengue from other febrile illnesses in endemic
populations,” Tropical Medicine and International Health, vol.
13, no. 11, pp. 1328–1340, 2008.
[5] D. J. Gubler, “Epidemic dengue/dengue hemorrhagic fever as a
public health, social and economic problem in the 21st century,”
Trends in Microbiology, vol. 10, no. 2, pp. 100–103, 2002.
[6] L. Thomas, Y. Brouste, F. Najioullah et al., “Predictors of severe
manifestations in a cohort of adult dengue patients,” Journal of
Clinical Virology, vol. 48, no. 2, pp. 96–99, 2010.
[7] G. N. Malavige, P. K. Ranatunga, V. G. N. S. Velathanthiri et al.,
“Patterns of disease in Sri Lankan dengue patients,” Archives of
Disease in Childhood, vol. 91, no. 5, pp. 396–400, 2006.
 MEDIATORS of

INFLAMMATION

The Scientific Gastroenterology Journal of

World Journal
Hindawi Publishing Corporation
Research and Practice
Hindawi Publishing Corporation
Hindawi Publishing Corporation
Diabetes Research
Hindawi Publishing Corporation
Disease Markers
Hindawi Publishing Corporation
http://www.hindawi.com Volume 2014
http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Journal of International Journal of

Immunology Research
Hindawi Publishing Corporation
Endocrinology
Hindawi Publishing Corporation
http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Submit your manuscripts at

http://www.hindawi.com

BioMed
PPAR Research
Hindawi Publishing Corporation
Research International
Hindawi Publishing Corporation
http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Journal of
Obesity

Evidence-Based
Journal of Stem Cells Complementary and Journal of
Ophthalmology
Hindawi Publishing Corporation
International
Hindawi Publishing Corporation
Alternative Medicine
Hindawi Publishing Corporation Hindawi Publishing Corporation
Oncology
Hindawi Publishing Corporation
http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Parkinson’s
Disease

Computational and
Mathematical Methods
in Medicine
Behavioural
Neurology
AIDS
Research and Treatment
Oxidative Medicine and
Cellular Longevity
Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation
http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014