New diagnostic algorithm may improve PH dengue diagnosis and surveillance – studies suggest
LSHTM Infection Biology Department Head Dr. Martin Lloyd Hibberd giving a brief overview of the dengue virus transmission cycle.

Through the Research and Innovation Office (RIO) of the Research Institute for Tropical Medicine (RITM), London School of Hygiene and Tropical Medicine (LSHTM) Infection Biology Department Head Dr. Martin Lloyd Hibberd shared his analysis of dengue in the Philippines to public health practitioners in the country on 22 August 2022 via Zoom in support of scientifically informed dengue interventions.

The webinar zeroed in on the factors contributing to the local burden of dengue, particularly dengue diagnosis and surveillance.

Dengue surveillance in the Philippines

In the country, the Epidemiology Bureau (EB) of the Department of Health (DOH) conducts passive epidemiological surveillance of dengue through case reporting while RITM performs laboratory epidemiological surveillance.

Data from EB and RITM were used in the studies discussed by Dr. Hibberd. These studies used a new algorithm for dengue diagnosis – the segmentation of suspected dengue cases into active and non-active dengue through use of polymerase chain reaction (PCR) and Immunoglobulin M (IgM) molecular tools. Following this algorithm, those who test positive in the PCR and IgM tests will be either classified as primary or post-primary dengue while those who yield negative results will be classified as either negative or historical dengue. From this, the age of individuals previously infected with dengue before they developed antibody response can be deduced.

“Across the Philippines, from the data that we collected, this came out at 17%. That means each year, 17% of the population as a whole in the Philippines are infected…by the time children are about 10 years old, nearly 70% of them have had a dengue infection,” said Dr. Hibberd about the seroconversion rate – the rate by which the said population has produced antibodies against dengue virus.

Moreover, Dr. Hibberd explained that the seroconversion rate of 17% is also considered as the force of infection (FOI), or how much of the population is being affected and how many true dengue infections are annually occurring. As a result, this allows for a more holistic understanding of the local burden of dengue.

The said algorithm was used for local dengue records from 2014 to 2018 in an effort to better estimate where the dengue cases are occuring. The study was able to establish the link between ordinary dengue or dengue with warning signs and the estimated FOI from the case reports. As for laboratory surveillance data, the study established that there is a good correlation between the age of patients and primary disease which was deduced from the laboratory surveillance data.

Using the same algorithm, Dr. Hibberd also presented the research findings on the estimated annual dengue FOI in the Philippines. The study shows that dengue is prevalent among highly urbanized cities (HUCs).

“When we looked in detail, dengue is very much a disease of the urban cities where mosquitoes like living with humans. We found that across the Philippines, the 33 highly urbanized cities where a lot of the data was coming from, allowed us to get a good estimate of how each of these cities managed to compare with their infection rates one to another,” said Dr. Hibberd.

With this, FOI from the HUCs using laboratory epidemiological surveillance can be cross-checked against the data generated from the case reports. The data to be obtained from here can eventually be used for targeted mosquito vector control interventions.

Challenges in dengue diagnosis

The discussion also touched on the recurring challenge in dengue diagnosis which is the difficulty to confirm the infection as suspected patients seek help late into the viremia – the presence of the dengue virus in the blood. Another difficulty is distinguishing whether a patient has primary infection or post-primary dengue using only one diagnostic tool.

Currently, several diagnostic tools are being implemented for clinical, molecular, and immunological diagnosis. The most common diagnostic tools are PCR and dengue nonstructural protein 1 (NS1) which detect the antigen, and serological IgM and Immunoglobulin G (IgG) tests, which detect antibodies.

The global burden of dengue comprises only an estimate of 96 million reported cases per year, as opposed to the estimated annual record of 294 million unreported cases. Dr. Hibberd reported that through the utilization of specific diagnostic tools, we can further categorize populations affected by dengue. Dr. Hibberd posits that the IgM test may help identify patients with dengue hemorrhagic fever (DHF) and/or dengue shock syndrome (DSS). The PCR test may be specifically used to categorize patients with dengue fever, while the IgG test may be used to help deduce asymptomatic and/or unreported dengue cases, or those individuals have been previously infected with dengue.

When used appropriately, the aforementioned diagnostic tests may decrease the number of unreported cases and therefore result in a more improved estimation of the local dengue burden.

“With IgM and IgG…we can see whether you’ve had dengue historically in the past by measuring your IgG or antibody response over time,” Dr. Hibberd explained.

Dr. Hibberd also suggests that the combination of dengue rapid tests increase probability of dengue confirmation, especially primary and post-primary infection.

Preventing and mitigating dengue

Several strategies may be implemented to combat dengue transmission in the country. Dr. Hibberd recommends the conduct of the following:

  • Case-area targeted interventions (CATI) – for reactive dengue control once hotspot areas have been identified;
  •  Drug prophylaxis – may be considered as this has a more significant impact than mosquito killing;
  • Enrollment of family members in dengue control campaigns – most applicable for household contacts of dengue patients;
  • Mass drug administration – should an effective drug be identified; and
  • Vaccine administration

“Dengue outbreaks can be reduced if we can identify where they are. We can maybe reduce the number of mosquitoes, and prevent those outbreaks from occurring. Or we can do that by looking at the cases and recognizing where those hotspots are. If you want to eradicate, that depends critically on effective coverage – how well can you target the mosquitoes,” emphasized Dr. Hibberd.

Burden of dengue

Dengue infection is a disease caused by four dengue serotypes primarily transmitted by the Aedes aegypti mosquito. With the four dengue serotypes, an individual can be infected with dengue as many as four times in a lifetime.

“As you go through those four infections during your lifetime, you know that the primary one can be quite serious, but the second one is more severe…and the third and fourth or the post-secondary [is] probably less severe,” said Dr. Hibberd. 

Worldwide, dengue cases amount to approximately 390 million per year, in which 100 million are cases presenting with symptoms. 3.6 billion people across the globe are considered to be at risk.

Southeast Asia has recorded the most number of dengue cases in the world by far. In the Philippines, EB recorded 106,630 dengue cases in 2019 alone, which was above the epidemic threshold.

by Anel Azel Dimaano