Dengue fever in Pakistan: a paradigm shift; changing epidemiology and clinical patterns

Abstract

Dengue fever has huge public health implications and affects over 100 million people
worldwide. This review pictures the current situation of Dengue in Pakistan and presents a
review of published literature. Pakistan has seen recurrent epidemics of Dengue Fever
recently. Unfortunately, these epidemics are becoming more severe in their clinical
manifestation. Pakistan experienced large epidemics of dengue fever during 2008, 2010 and
2011 affecting thousands of people and claiming hundreds of deaths. A comparison of data
during these epidemics indicates a shift from mild to a more severe disease, which could be
interpreted as an epidemiologic transition pattern in the country. Expansion of Dengue in
Pakistan seems to be multifactorial, including the climate change, frequent natural disasters,
vector resistance to insecticides and lack of resources. This highlights the need for rigorous
vector control. Continuing education of primary care physicians is crucial for early
appropriate management to reduce mortality.

Introduction

Dengue fever (DF) is a mosquito-borne viral infection. Given the current estimates of
over 100 million cases worldwide each year and over 2.5 billion individuals at the risk of
infection; it is now considered as one of the most important arthropod-borne diseases from a
public health point of view.1 DF is an illness with profound social, economic and health costs
to society. Dengue virus infection is a risk for anyone living in or travelling to a dengue
endemic region, especially in tropical Asia, Central and South America and the Caribbean
region. Dengue is also one of the most frequent diseases in travellers from endemic areas.
Originally, it was a disease of tropical and sub-tropical areas, but dengue has now become a
worldwide health issue due to the large volume of human travel, which is considered to be
one of the major contributing factors to the geographical spread of dengue virus across the
globe

Dengue emerged as a major public health burden in Southeast Asia after the Second
World War and has now become more concerning with progressively longer, more frequent
and severe epidemics of DF and Dengue hemorrhagic fever (DHF) in this part of the world.2
Although the presence of all four serotypes has been documented, the Indian subcontinent
remains mainly affected by DENV-2 and DENV-3 serotypes.3 Epidemics of dengue in the
Indian subcontinent were rare before the year 2000. However, in last decade, frequent
epidemics have occurred with thousands of reported and unreported DF/DHF cases resulting
in significant morbidity and mortality. Countries that are most adversely affected included
Bangladesh, India, Pakistan and Sri Lanka. The rapidly rising incidence of dengue viral
infection is attributed mainly to the climate change favouring the rapid growth of the vectors
but some authorities suggest the role of some genetic changes in the virus and various other
factors.

In Pakistan, dengue is emerging as a major public health hazard. The situation has
recently become more severe due to increasing number of complicated and uncomplicated
cases on a background of limited resources, poor socioeconomic conditions and lack of
public health awareness. This review aims to give an insight into the historical background
and the current situation of dengue viral infection in Pakistan and an overview of the
published literature.

Dengue epidemics were rare in Pakistan before the turn of the century, but since 2005,
dengue epidemics have become a regular occurrence; usually peaking in July to October. The
monsoon rains hit the region during this part of the year and this season, historically, has
brought mixed fortunes to the people in this area. On one hand, it helps spur the cultivation of
crops which is the main source of income for the people, but at the same time is responsible
for the heavy floods not only leading to the increased growth of the vector but also the spread
of the virus due to the relocation of the people from these floodaffected areas. Pakistan now
suffers from repeated monsoon floods in recent years that might have caused the explosive
increase in DF epidemics in most parts of the country.

In the past 7 years, five major epidemics have been reported affecting thousands of
people claiming hundreds of deaths since then. Unfortunately, due to the lack of
infrastructure and epidemiological data, it is not possible to get the exact number of cases and
mortality data from these epidemics. Most of the information is from the hospital-based
observations or the media reports.

Review Of The Scientific

Literature From Pakistan A decade-wise analysis of the limited published data of

dengue epidemics in Pakistan shows a paradigm shift with gradual increase in the frequency,
incidence and severity of this disease in the clinical practice. Dengue infection was first
documented in Pakistan in 1982. At that time, 12 patients out of a total 174 tested were found
positive for dengue virus; all these samples were collected from the sero-surveys between
1968 and 1978.8 Chan et al.9 documented the first confirmed epidemic of DHF in Karachi in
1994. In the following year, dengue epidemic was reported from the province of Baluchistan
during the investigation of a febrile epidemic at a power plant when 57 out of a total 75
workers were detected positive for immunoglobulin M (IgM) antibodies for at least one
dengue serotype. Qureshi et al. reported 145 cases of dengue from June 1994 to September
1995, which presented in a tertiary care hospital in Karachi. Up until then, the dengue
epidemics were uncommon and happened on a very small scale.

Since 2005, the country has seen a recurring trend of larger epidemics of dengue viral
infection in various regions on an annual basis. During 2006, the first epidemic of DF was
reported from Punjab and since then DF has become a recurring nightmare in the province.
The official figures based on the hospital records report that there were 113 confirmed cases
of dengue viral infection during the 2006 epidemic, while 232 cases were reported in the year
2007. Three deaths occurred in the whole of Punjab due to complicated dengue infection
during 2007. The increasing trend in the incidence of DF continued and during 2008, 1,407
cases were reported from all over Punjab including nine deaths due to complicated dengue
infection.2 During 2009, 2010 and then in 2011, Pakistan experienced very large epidemics
of DF. The epidemic during 2010 affected more than 5,000 people resulting in 31 deaths
from the province of Sindh. Official figures for the epidemic during 2011 reported 16,580
confirmed cases of dengue viral infection and 257 deaths in the city of Lahore only and
nearly 5,000 cases and 60 deaths reported from the rest of the country. We suspect that this
may reflect an under reporting due to the lack of resources and poor reporting system from
the other parts of the country and the actual figures might be much higher across the country.

Multiple serotypes have been reported from various parts of the country by different
researchers (Table 1). Dengue viruses type 1 and 2 isolated from children in Karachi in 1997
were identified via serological studies. Jamil et al. reported DEN-3 infection for the first time
during the 2005 epidemic of DHF in Karachi. Pakistan experienced a larger epidemic of DF
during 2006 when Khan et al. reported co-circulation of dengue serotype 2 and 3 in Karachi.
Humayun et al. reported cases with dengue infection during the 2008 epidemic in Lahore and
also revealed the prevalence of three different dengue serotypes circulating in this region for
the first time in Pakistan. Out of 17 samples checked via real-time polymerase chain reaction
(PCR), ten patients had DEN-4, five had DEN-2 and two had DEN-3 infection. Later on,
Fatima et al. Found the presence of DEN-2 and DEN-3 by doing the serotypic and genotypic
analysis of dengue virus from three small epidemics in Lahore from 2007 to 2009. Koo et al.
in 2013 confirmed the findings reported by Humayun et al.2 in 2008 when they analysed sera
obtained from 200 dengue-suspected patients from various epidemics between 2006 and
2011. Out of the 94 confirmed cases, they were able to isolate three different dengue
serotypes including DENV-2, DENV-3 and DENV-4.

Small hospital-based studies from all over the country have reported different aspects
of major individual epidemics, but there is paucity of data looking at the prevalence of
dengue infection in Pakistan. Siddiqui et al. Retrospectively analysed blood for dengue IgM
on samples obtained during a communitybased surveillance for febrile illnesses in Karachi
from 1999 and 2001 and the incidence of DF was estimated to be 185/100,000/year.
Interestingly there was no reported epidemic of Dengue during that period.

As mentioned earlier, most of the studies published from Pakistan are limited and
hence may not reflect the magnitude of problem in the community. From the available data, it
is quite obvious that the hemorrhagic complications are more frequently seen with the
involvement of multi-system in patients admitted in the hospitals. However, we tried to
explain the situation in the community by the pyramid model. At the base of the pyramid,
most of the cases are asymptomatic, followed in reducing frequency by symptomatic DF,
DHF and the dengue shock syndrome (DSS). Based on the higher number of complicated
cases admitted to the hospital, with DHF and DSS reflecting the tip of the iceberg, one can
postulate that the base formed by undifferentiated fever may be very large, and thus the
prevalence of dengue in the community would be very high. We therefore believe that
Dengue viral infection has changed its paradigm from a mild febrile illness to a more severe
form of the disease with more frequent hemorrhagic manifestations and hospital admissions
due to complicated dengue viral infection.
 Unfortunately, many of the factors contributing to dengue epidemics, from poor
hygiene and sanitation to climate change, are risk factors common to most infectious
diseases. Demographic and social changes, as well as a lack of effective mosquito control,
have facilitated the spread of Aedes aegypti in Pakistan. The increasing incidence of dengue
suggests that the current vector control measures are ineffective. There is no effective vaccine
or direct therapy available against the dengue virus, so vector control is the main approach for
control and prevention. Although insecticide spraying has been used extensively, larval
source reduction (eliminating or cleaning water-filled containers that can harbour Aedes
Aegypti larvae) is considered the most effective way of controlling the mosquito populations.
Although the difficulty to implement integrated strategies for mosquito control in the region
remains the major factor in the ineffective vector control, it is also thought that mosquitoes in
Pakistan are developing resistance to insecticide when Khan et al.19 reported a moderate to
high level of resistance to agrochemicals in Pakistani field populations to Aedes albopictus,
which is one of the vectors for DF. Although the geographic extent of this resistance was
unknown, if this proves to be a widespread issue across the country, the vector control will be
a very difficult challenge.

Another potential cause for increasing dengue epidemics may be climate change with
global warming. This is also supported by the fact that dengue has always hit the country
hard after the monsoon rainy season. Dengue transmission increases with increasing
atmospheric temperature and humidity, since higher temperatures and moisture optimise
mosquito breeding. Pakistan, due to its geographic location, agricultural dependence and
recurrent floods is at the high risk of climate change and is among the top 16 ‘most
vulnerable nations’ for climate change as per the Climate Change Vulnerability Index (CCVI)
over next 30 years.

The current armed conflicts and recurrent natural disasters including floods and
earthquakes in Pakistan may also have been the important contributory factor of the disease.
The plains of Punjab provide a home to millions of internally displaced refugees who moved
away from the war-torn northeastern and tribal regions, bringing with them an increase in
infectious disease. Furthermore, war itself is known to be one of the most potent fomenters of
infectious disease: Studies have shown that ‘complex emergencies’ can cause a several-fold
increase in infection rates. We suggest that the recent increase in severe cases in Pakistan is
due to individuals now experiencing secondary infections with a different serotype as it is
well known that secondary infection with a heterologous serotype confers increased risk of
severe disease.2 Many experts also believe that different dengue serotypes, and even strains
of the same serotype, differ in their potential to cause severe disease.26 Some studies have
shown associations of DENV-227 and DENV-328 with increased risk of hospitalisation and
severe disease possibly due to some genetic mutation making the virus more virulent. Since
DENV-2 and DENV-3 remain the dominant serotypes of dengue virus epidemics in Pakistan,
the presence of multiple serotypes during an epidemic could explain the increasing number of
dengue-infected cases developing DHF and DSS and hence increased mortality in Pakistan.
However, because of small sample sizes and lack of all four serotypes during the same
epidemic, there is no clear consensus on the association of severity of the disease with a
specific serotype. Also, the association of the disease severity with a specific serotype has not
been reported from Pakistan. Pakistan, so patients presenting with symptoms likely to be DF
are managed appropriately. The development of a protocol to be followed by healthcare
workers means that standardised care can be provided across the board. Strategies to mobilise
and deploy staff need to also be in place by the Pakistani government. As one of the
challenges in Pakistan, especially in rural areas, is access to healthcare, it becomes even more
important for a nationwide strategy in place where populations based in rural areas can
receive effective treatment. It is essential to harness the power and potential of social media
and generic media. However, the challenge remains with high levels of illiteracy in regards to
how much information would be absorbed in the more rural areas.

The most obvious future direction lies in grasping the true extent of the disease. Most
of the published studies focus entirely on data from large urban populations. This does not
give us a true picture of the actual burden of the disease. We can certainly postulate from the
data available but a more detailed epidemiological study and the use of electronic record
systems of the patient would give accurate information and help direct scarce sources
appropriately.

Strategies must be put in place to address a DF epidemic when it occurs such as

nationalised proformas with management plans, distribution of equipment needed for
diagnosis and treatment on a nationwide level and recruiting and deploying staff
appropriately at times of epidemic. Resources also need to be assigned to monitoring DF
levels at times when there isn’t an epidemic; study and understanding of epidemic patterns
can also help direct resources and mobilise staff and equipment appropriately.

Vector control is the key and the measures to control the vector need to be
implemented strictly and monitored closely. The prevention strategies recommended by the
World Health Organisation (WHO) focus mainly on vector control. Although this will be the
main stay of preventive measures, due to the political and sectarian violence in Pakistan, it
will be difficult to implement permanent or indeed well-funded programmes. Certainly, to
improve vector control, the country would benefit from improved water systems, but this
could prove to be a sizable task. Other larger issues also lie in improving street cleaning and
improved collection of household waste. Immediate or simpler options could lie in changing
trading legislation such as ensuring all water containers are sold with watertight lids.

Conclusion

Dengue is now endemic throughout the country. Reasons for the currently observed frequent
and severe epidemics are multifactorial. They may include climate change, circulations of
multiple dengue serotypes, virus evolutions and socio-economic factors. There is no antiviral
therapy or vaccination available for dengue at this time, so the early detection and early
supportive management is the key to avoid deaths due to complicated infection. Because of
the limited therapeutic options, effective vector control methods are the only effective ways
to reduce the risks of future epidemic. We also recommend the need for improved
infrastructure of healthcare system that would help to estimate the true burden of dengue
disease across the country. We also suggest that regular surveillance of resistance to
insecticides should first be part of the focus. Moreover, public awareness about dengue and
the cooperation with public health campaigns are the recommended strategies for controlling
dengue vectors and to reduce risks to humans as well as environmental health