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discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/6134092

Dengue outbreak in Karachi, Pakistan, 2006:

experience at a tertiary care center
ARTICLE in TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE NOVEMBER 2007
Impact Factor: 1.84 DOI: 10.1016/j.trstmh.2007.06.016 Source: PubMed

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Aga Khan University Hospital, Karachi

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Transactions of the Royal Society of Tropical Medicine and Hygiene (2007) 101, 11141119

available at www.sciencedirect.com

journal homepage: www.elsevierhealth.com/journals/trst

Dengue outbreak in Karachi, Pakistan, 2006:

experience at a tertiary care center

a
Department of Pathology and Microbiology, The Aga Khan University Hospital, Stadium Road,
P.O. Box 3500, Karachi 74800, Pakistan
b
Department of Medicine, The Aga Khan University Hospital, Stadium Road, Karachi 74800, Pakistan

Received 26 February 2007; received in revised form 25 June 2007; accepted 25 June 2007
Available online 13 August 2007

KEYWORDS
Dengue hemorrhagic
fever;
Abdominal pain;
Hematocrit;
Thrombocytopenia;
Disseminated
intravascular
coagulation;
Pakistan

Summary This is the rst report of the largest epidemic of dengue hemorrhagic fever (DHF)
virus infection (2006) with IgM-conrmed cases from Karachi, Pakistan. Medical records of 172
IgM-positive patients were reviewed retrospectively for demographic, clinical and laboratory
data. Patients were categorized into dengue fever (DF) and DHF according to the WHO severity
grading scale. The mean SD age of the patients was 25.9 12.8 years, 55.8% were males and
the hemoconcentration was recorded in a small number of patients [10 (7.0%)]. Male gender
[odds ratio (OR) = 14.7, P = 0.003), positive history of vomiting (OR = 4.3, P = 0.047), thrombocytopenia at presentation (OR = 225.2, P < 0.001) and monocytosis (OR = 5.8, P = 0.030) were
independently associated with DHF, but not with DF. Five cases (2.9%) had a fatal outcome,
with a male-to-female ratio of 1:4. Three were from a pediatric group (<15 years). Pulmonary
hemorrhages, disseminated intravascular coagulation and cerebral edema preceded death in
these patients. The results have highlighted signicant ndings, such as adult susceptibility to
DHF, pronounced abdominal symptoms and lack of hemoconcentration at time of presentation
in the study population. These ndings may play an important role in the case denitions of
future studies from this part of the world.
2007 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights
reserved.

1. Introduction
Dengue virus is a tropical mosquito-borne avivirus, present
as four antigenically distinct serotypes (DENV-1, -2, -3 and
-4). The virus infects approximately 100 million humans

Corresponding author. Tel.: +92 21 4864530;

fax: +92 21 4934294/4932095.
E-mail address: erum.khan@aku.edu (E. Khan).

each year (Halstead, 2002). The majority of dengue infections cause a moderate-to-mild self-limiting febrile illness
[dengue fever (DF)]; however, some infections lead to
potentially fatal dengue hemorrhagic fever (DHF) and the
more severe dengue shock syndrome (DSS). DHF is the leading cause of hospitalization and death among children in
many countries of Southeast Asia. In recent years, the
disease has become increasingly important in the Pacic
Islands, South America and Asia (WHO, 2007).
In Asia, dengue has made its route geographically from
Southeast Asian countries (Gubler, 1998). In India the rst

0035-9203/$ see front matter 2007 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.trstmh.2007.06.016

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E. Khan a,, J. Siddiqui a, S. Shakoor a, V. Mehraj a, B. Jamil b, R. Hasan a

Dengue outbreak in Karachi, Pakistan, 2006

2. Materials and methods

2.1. Location and sampling
The AKUH is a 550-bed tertiary care center located in the
metropolitan city of Karachi, Pakistan. The clinical microbiology laboratory of the AKUH is one of the largest pathology
laboratories in Pakistan and receives samples from both
inpatients and outpatients as well as from clinics and hospitals within the city. Between May and November 2006
a total of 3075 serum samples were received for detection of anti-dengue IgM. Of these, 482 were from patients
admitted with a clinical suspicion of DF or DHF, and 172
were found to be anti-dengue IgM-positive. The medical
records of these 172 patients with conrmed laboratory
diagnosis for dengue virus infection were reviewed retrospectively for demographic, clinical and laboratory data.
Patients were categorized into DF and DHF, according to

the WHO severity grading scale (WHO, 1997). Briey, DF

was dened as an acute febrile illness with two or more of
the following manifestations: headache, retro-orbital pain,
myalgia, arthralgia, rash and leucopenia. DHF was dened
as fever or history of acute fever, lasting 27 d, along with
hemorrhagic tendencies, evidenced by at least one of the
following: positive tourniquet test, petechiae, ecchymoses
or purpura, and bleeding from the mucosa, gastrointestinal
tract, hematemesis or melena. In addition, thrombocytopenia with a platelet count 100 000 cells/mm3 and evidence
of plasma leakage due to increased vascular permeability
were taken into account. These included rise in hematocrit
(greater than 20% above average for age and sex), pleural
effusion and/or ascites. Patients with profound shock along
with other features of DHF were classied as DSS.
Correlations of severity were sought by comparing the
clinical picture, laboratory ndings and requirement for
transfusions during the hospital stay.
The blood indices were initially measured on a continuous scale and nally categorized on the basis of biologically
meaningful cutoffs. Thrombocytopenia was dened as a
platelet count <150 000 cells/mm3 blood. A hematocrit value
>48 was considered raised. Similarly, leucopenia was dened
as a white cell count <4000, neutropenia as neutrophils
<40%, lymphocytosis as lymphocytes >45% and monocytosis as monocytes >10%. Alanine aminotransferase (ALT) was
considered raised if >55 and >33 IU/l for males and females,
respectively. Aspartate aminotransferase (AST) was dened
as raised if >46 and >32 IU/l for males and females, respectively.

2.2. Data management and statistical analysis

The questionnaires were checked and edited for logical
errors and missing information by the trained and experienced medical research ofcer. The data were coded and
entered in EpiData 3.0 (Odense, Denmark) and transferred
to SPSS 14.0 (SPSS Inc., Chicago, IL, USA) for analysis. In
descriptive analysis, the mean and SDs of the continuous
variables and percentages of the categorical variables were
computed. Comparisons between dengue severity groups
(DF and DHF) were made in inferential analysis. Students t
test, univariate logistic regression, 2 test and Fishers exact
test were used for univariate comparisons where appropriate. Logistic regression analysis through the ENTER method
was conducted for multivariable modeling. Odds ratios (ORs)
and their 95% CIs were calculated to assess the strength of
associations. A P-value of <0.05 was considered statistically
signicant.

3. Results
3.1. Epidemiological and demographic ndings
Karachi is located on the eastern coast of the Arabian Sea. It
is the capital of the province of Sindh and the former capital
of Pakistan. Most of the cases were from the east, center and
north of Karachi. Two patients (1.2%) were referred from
other parts of the Sindh province, while two patients were
from Punjab.

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epidemic of dengue was reported in 19631964 (Dar et al.,

2006). Since then, multiple outbreaks have been reported
from different regions of India. New Delhi has a record
of seven outbreaks since 1967 (Gupta et al., 2005). Cocirculation of all four serotypes has been reported from this
region. The last major outbreak reported in Delhi was in
2003, in which DENV-3 was implicated as the major serotype
(Dar et al., 2006). Increased incidence of DHF and DSS seen
in India has been attributed to the sudden dominance of
DENV-3 (Dash et al., 2006). DENV-3 has also caused unexpected epidemics of DHF in Sri Lanka (Messer et al., 2003).
In Pakistan the rst conrmed outbreak of DHF was
reported in 1994 by the Aga Khan University Hospital (AKUH);
the serotype reported was DENV-2 (Chan et al., 1995).
Thereafter, sporadic cases of DHF continued to be documented from different parts of the country. Antibodies
specic to DENV-1 and DENV-2 were found in sera of children
presenting with undifferentiated fever in Karachi (Akram
et al., 1998), indicating that these two dengue serotypes
predominated/prevailed in the 1990s.
During 20052006, however, there was an unprecedented
increase in epidemic DHF activity in the country, with a large
number of cases being reported from Karachi. More than
3640 patients with signs and symptoms suggestive of DF were
admitted to several referral hospitals in the country, including the AKUH. There were 40 deaths, of which 37 were from
the province of Sindh, making it the largest and most severe
outbreak of DF in the country (The News, 2006). Genotyping of selected samples from the early part of the outbreak
(in the autumn of 2005), revealed the presence of DENV-3
(Jamil et al., 2007), and the epidemic was probably a consequence of the introduction of DENV-3 in a population with
prior exposure to DENV-1 and -2, resulting in severe disease
(Jamil et al., 2007).
During the 2006 outbreak, the Clinical Microbiology Laboratory of the AKUH maintained a serum bank of all the
serum samples received for the detection of anti-dengue
IgM. A database of IgM-positive patients admitted to the hospital was established by reviewing the medical records. The
account of clinical and laboratory ndings, along with disease severity, of these IgM-positive patients at the time of
admission to the hospital are discussed here.

1115

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E. Khan et al.
( 12.8) years; 55.8% were males (Table 1). The average
hospital stay of the patients was 3.6 2.4 d.

3.2. Clinical ndings (see Table 1)

Figure 1 Monthly distribution of patients admitted with

dengue virus infection to the Aga Khan University Hospital from
May to November 2006.

Table 1 Descriptive characteristics of patients diagnosed with dengue virus infection admitted to the Aga Khan University
Hospital from May to November 2006
Characteristic
Sociodemographics
Age (years) (mean SD)
Gender (male)
Clinical presentation
Fever
Nausea and/or vomiting
Rash
Abdominal pain
Diarrhea
Body ache
Headache
Cough
Pleural effusion
Ascites
Eye pain
Laboratory ndings
Thrombocytopenia at presentation (n = 161)a
Hemoglobin (low) (n = 146)a
Hematocrit (>48%) (n = 146)a
Leukopenia (n = 155)a
Neutropenia (n = 150)a
Lymphocytosis (n = 149)a
Monocytosis (n = 148)a
Raised ALT (n = 132)a
Raised AST (n = 109)a
Malaria (Giemsa thin smear) (n = 105)a,b
Outcome
Death

DF (%) (n = 44)

DHF (%) (n = 128)

Overall (%) (n = 172)

26.7 12.8
60.9

25.9 12.8
55.8

100.0
52.3
29.5
15.9
15.9
34.1
13.6
4.5
0
0
4.5

97.7
68.0
40.6
33.6
30.5
20.3
5.5
8.6
7.0
3.9
1.6

98.3
64.0
37.8
29.1
26.7
23.8
7.6
7.6
5.2
2.9
2.3

37.5
32.4
0
51.3
12.8
10.5
26.3
40.0
81.8
0

95.9
24.1
9.2
50.0
37.8
28.8
53.6
70.6
95.4
6.3

81.4
26.0
7.0
50.3
31.3
24.2
46.6
63.6
92.7
4.8

2.3

3.1

2.8

23.8 12.6
40.9

DF: dengue fever; DHF: dengue hemorrhagic fever; ALT: alanine aminotransferase; AST: aspartate aminotransferase.
a n = no. of patients tested.
b No. of patients positive for Plasmodium falciparum = 4 and for P. vivax = 1.

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In 2006, the rst case of DHF was admitted in the

month of May. Thereafter, the numbers of cases steadily
increased over the next 5 months. The largest number of
cases was admitted from August to October, and the number of patients decreased during the month of November
(Figure 1). The mean ( SD) age of the patients was 25.9

Fever at time of admission was present in 169 (98.3%) of

the patients; the remaining (1.7%) patients had a history of
fever in the 35 d prior to admission. Gastrointestinal features were most frequent at the time of presentation in both
DF and DHF patients. These included vomiting in 110 (64%),
abdominal pain in 50 (29.1%) and diarrhea in 46 (26.7%).
Body aches were reported by 41 (23.8%). The majority of
these patients had right hypochondrial tenderness on examination. A diffuse erythematous or maculopapular rash, over
the face, upper torso and/or lower limbs was noted in 65
(37.8%) of the patients.
Symptoms such as headache and retro-orbital pain, which
are generally considered cardinal features of DF, were not
very frequently seen in our patient population: 7.6 and 2.3%,
respectively.
The tourniquet test, which is a simple way to detect
capillary fragility and to dene the severity index based

Dengue outbreak in Karachi, Pakistan, 2006

on WHO criteria was not performed in any of our patients,
mainly because of the presence of other suggestive clinical
and laboratory features on presentation and excessive clinical workload both in the inpatient and outpatient settings.
The severity classication based on this test, therefore,
could not be ascertained. Other criteria of DHF, such as gum
bleeding and hematemesis were seen in 10 (5.8%) patients,
followed by epistaxis (nasal bleed) in 6 (3.5%) and subconjunctival bleed in 4 (2.3%) patients. Other signs of plasma
leakage, such as pleural effusion and ascites, were present
in 5.2 and 2.9% of patients, respectively.

3.3. Laboratory ndings (see Table 1)

3.3.2. Hemoglobin and hematocrit

Hemoconcentration was recorded in a small number of
patients (n = 10, 7.0%), and all of these patients were classied into the DHF category. Anemia was present in 26% of
the patients.
3.3.3. Lymphocytes/granulocytes
Leucopenia is one of the dening features of DF and DHF. The
mean leukocyte count at the time of presentation remained
low-to-normal (4.9 cells/mm3 ), and leucopenia was noted
in 50.3% of patients, with a minimum count recorded of
0.9 cells/mm3 . Similarly, the mean values for the neutrophil
and lymphocyte counts remained within the normal range
(50.5 and 35.5%, respectively). Lymphocytosis, neutropenia and monocytosis were noted in 24.2, 31.3 and 46.6% of
patients, respectively, at the time of admission.
3.3.4. Liver enzymes
The majority of patients presented with signicantly elevated liver enzymes ALT and AST. The mean value for ALT
was 145.5 IU/l ( SD 210), while that for AST was 273.0 IU/L
( SD 303).
3.3.5. Comparative analysis to assess the factors
associated with disease severity
In the absence of the tourniquet test, patients could not be
categorized into different severity grades of DHF. Patients
were broadly grouped into DHF based on the presence of
petechiae, ecchymoses or purpura. In addition, patients
with bleeding from mucosa, hematemesis or melena and
thrombocytopenia with platelet count 100 000 cells/mm3
were categorized as DHF.
Of 172 conrmed patients, 128 (74.4%) met the criteria
of DHF at time of admission. One patient with DHF on presentation later developed DSS. The male-to-female ratio in
DF was 1.0:0.7; in DHF it was 1.6:1.0. The mean age of the
DF and DHF patients was 23.8 and 26.7 years, respectively.
The youngest DHF patient was 9 months old.
Factors signicantly associated with disease severity in
univariate analysis were male gender, positive history of
abdominal pain, thrombocytopenia at presentation, monocytosis, lymphocytosis, neutropenia, raised ALT, raised AST

Table 2 Univariate analysis of factors associated with

dengue hemorrhagic fever (DHF) in comparison to dengue
fever (DF) among patients diagnosed with dengue virus infection admitted to the Aga Khan University Hospital from May
to November 2006
Characteristic

ORa

Gender (male)
Abdominal pain
Vomiting
Thrombocytopenia at
presentation
Monocytosis
Lymphocytosis
Neutropenia
Raised ALT
Raised AST
Length of hospital
stay (d)

2.3
2.7
1.9
38.7

(1.14.5)
(1.16.5)
(0.93.9)
(12.9116.2)

0.021
0.026
0.061
<0.001

3.2
3.4
4.1
3.6
4.6
1.3

(1.47.3)
(1.110.5)
(1.511.4)
(1.58.4)
(1.120.2)
(1.11.5)

0.004
0.023
0.004
0.002
0.029
0.020

(95% CI)

P-valueb

Note: analyzed by Students t test, univariate logistic regression

and 2 or Fishers exact test, as appropriate.
ALT: alanine aminotransferase; AST: aspartate aminotransferase.
a Odds ratio for DHF vs. DF.
b P < 0.05 considered statistically signicant.

and length of hospital stay in days (Table 2). The signicant associations of male gender, positive history of
vomiting, thrombocytopenia at presentation and monocytosis were further conrmed by multivariate analysis (data not
shown).
Forty patients (23.3%) with DHF required platelet transfusions because of severe thrombocytopenia (platelet count
<20 000/mm3 ). Normal saline infusions were also more commonly used in patients with DHF (37.5%) compared with
those with DF (20.5%).
A total of ve cases (2.9%) had a fatal outcome. One
patient with DF died of causes unrelated to dengue infection, while four died of complications of DHF. The majority of
the patients who died were females (n = 4). Three were from
the pediatric group (<15 years of age). Pulmonary hemorrhages, disseminated intravascular coagulation and cerebral
edema were identied as possible causes of death. As autopsies are not routinely performed in our study area because
of religious and cultural beliefs, the exact cause(s) of death
could only be surmised from antemortem diagnosis based
on radiological examination (X-rays, computed tomography
scans) and laboratory tests.

4. Discussion
Unprecedented population growth and unplanned urbanization are the two main factors that have led to the emergence
of dengue virus infection in tropical developing countries
(Gubler, 1998). Karachi, the metropolitan city of Pakistan,
is also facing a similar crisis.
Karachi experienced the rst major outbreak of DHF in
1994, and since then DF has been recognized as one of the
causes of fever in the area (Akram et al., 1998; Paul et al.,
1998; Qureshi et al., 1997), with few cases of DHF and very
few deaths directly attributable to DHF/DSS. The majority of

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3.3.1. Platelets
Thrombocytopenia with an overall mean platelet count of
85.5 cells/mm3 was noted in 81.4% of patients. The lowest
platelet count was 5 cells/mm3 .

1117

1118

form of bleeding or liver function abnormalities (Rama

Krishna et al., 2006). Liver injury from dengue virus is
mediated by its direct infection of hepatocytes and Kupffer cells (Ling et al., 2007). Liver involvement is usually
associated with severe complications such as gastrointestinal bleeding, secondary to the associated coagulation
defects (Wichmann et al., 2004). Abdominal pain with vomiting and right hypochondrial tenderness were signicant
ndings in our patients with DHF. This is important, as
other infectious causes such as enteric fever, Hepatitis A,
meningitis and enteroviral infections are common in Pakistan and may lead to delay in diagnosis. Our ndings
suggest that DHF should be included in the differential diagnosis of patients with fever and gastrointestinal
symptoms.
The primary pathophysiologic abnormality seen in DHF
and DSS is an acute increase in vascular permeability that
leads to leakage of plasma into the extravascular compartments, resulting in hemoconcentration and decreased blood
pressure (Gubler, 1998). Plasma volume studies have shown
a reduction of more than 20% in severe cases. In our study,
hemoconcentration by denition was documented in a few
patients only. This is a very important nding, as raised
hematocrit is one of the dening characteristics of DHF,
based on WHO criteria, and an elevated hematocrit value is
used for case denition in eld studies during outbreak situations. Iron deciency anemia and hemoglobinopathies are
major problems in Pakistan. About 5% of the Pakistani population carries the -thalassemia trait (Ahmed et al., 2002).
Our patients may have had a low baseline hematocrit, leading to relative hemoconcentration. The role of these factors
leading to low hematocrit levels in the presence of DHF without overt hemorrhage in our study population needs further
studies.
The spectrum of other hematologic ndings, such as leucopenia, thrombocytopenia, lymphocytosis and raised ALT
levels, is comparable to those of other epidemics reported
from Southeast Asia [Taiwan (Wichmann et al., 2004), India
(Dash et al., 2006) and Bangladesh (Islam et al., 2006)].
We observed a signicant independent association of
male gender and vomiting (P < 0.05) with DHF. Although
genetic studies are desirable to assess the signicance of the
association of DHF with males in Karachi, it is our opinion
that the uneven male-to-female ratio in our patient population is a reection of the social bias of male gender in our
society. Failure to seek medical attention for females in the
family (adults as well as children) in a timely manner may
have led to high mortality in females.
The cause of death in most patients was pulmonary hemorrhages and respiratory failure. One of the adult patients
died from secondary cerebral edema. Although more cases
of DHF were seen in adults, the disease was severe, with a
fatal outcome, in children.
In conclusion, despite the limitation in terms of patient
population (not all infected patients were included) and
study design (retrospective review), the results of our study
have highlighted signicant ndings, such as adult susceptibility to DHF, pronounced abdominal symptoms and lack of
hemoconcentration at the time of presentation in our study
population. These are important observations and should be
taken into account in the case denitions of future studies
from Pakistan.

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the patients were diagnosed on the basis of clinical features

compatible with DF and DHF, with only a few laboratoryconrmed cases (Qureshi et al., 1997). This is the rst report
of the largest epidemic of DHF with IgM-conrmed cases
from Karachi, Pakistan.
Analysis of monthly dengue cases showed peak incidence
from August to October 2006. This pattern is consistent with
reports from other endemic countries (Gupta et al., 2006;
Islam et al., 2006; Lai et al., 2004) and correlates well with
the hot summer and monsoon season, which provide ideal
breeding conditions for Aedes aegypti.
DHF is considered primarily to be a disease of children
under the age of 15 years and is a leading cause of hospitalization of young children in Southeast Asia (Gubler, 1998). In
our study, 83.6% of adult patients presented to the hospital
with signs and symptoms compatible with DHF. A similar age
distribution was also noted during the 19941995 outbreak
in Karachi. This observation is consistent with reports from
other endemic countries. A 3-year study from India showed
a maximum number of cases between the ages of 21 and
30 years (Gupta et al., 2006). In the 2001 outbreak in Kaohsiung city in Taiwan, the mean age of the patients with DHF
was 55 years (Lai et al., 2004). Similarly in Singapore, young
adults were predominantly affected by DHF in the 2005 outbreak (Low et al., 2006).
Hyperendemicity (co-circulation of more then one
serotype) and/or introduction of a new virulent serotype in
the community perhaps render the adult population more
susceptible to a severe form of the disease. The population of Karachi has had a prior encounter with DENV-1 and
2 (Akram et al., 1998). Serum samples from our patients
with suspected DHF/DSS in the early part of this epidemic
(autumn of 2005) revealed DENV-3 as the cause of the DHF
(Jamil et al., 2007).
The DENV-3 serotype has recently been reported as the
cause of severe DHF outbreaks in India, Bangladesh and Sri
Lanka and has emerged as the predominant serotype in the
region (Gupta et al., 2006; Islam et al., 2006; Malavige et al.,
2006). In the Americas DENV-3 has been responsible for many
severe outbreaks. In Nicaragua in 1994 the introduction of
DENV-3 was associated with a countrywide epidemic of DF
and DHF. Similarly, the introduction of DENV-3 in Mexico in
1995 coincided with an increase in the number of DHF cases
(Uzcategui et al., 2003).
Comparison of genomic sequences of global dengue
viruses has revealed subtype 3 to be emerging throughout
endemic countries such as India, Mozambique, Somalia, Sri
Lanka and Brazil (Gupta et al., 2006). DENV-3 has never been
documented in Pakistani patients before. Pakistani strains
of DENV-3 have been found to be genetically related to the
Indian strains of DENV-3 isolated from Delhi in 2004 (Jamil
et al., 2007). The shift in the age distribution of DHF in
our study population is consistent with observations in other
studies conducted in other endemic regions and is perhaps
due to the introduction of a new serotype of dengue (DENV3) in Karachi. Further studies are required to conrm this
association.
Although abdominal pain and vomiting have been found
to be prominent presenting symptoms (Anuradha et al.,
1998), the exact mechanism underlying gastrointestinal
symptoms in dengue virus infections is not fully known.
Gastrointestinal manifestations of DF are mainly in the

E. Khan et al.

Dengue outbreak in Karachi, Pakistan, 2006

Authors contributions: EK, RH and BJ contributed to
the conception and design of the study; EK, JS and VM
designed the study protocol; JS and SS collected and analyzed the data; VM analyzed and helped in interpretation
of the results, along with data management; EK drafted the
manuscript; RH and BJ critically reviewed the manuscript
for intellectual content. All authors read and approved the
nal manuscript. EK and RH are guarantors of the paper.
Funding: This work was supported in part through a grant
from the Joint Pakistan-US Academic and Research Program
Higher Education Commission/ Ministry of Science and Technology, Islamabad, Pakistan and USAID Islamabad, Pakistan.
Conicts of interest: None declared.

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