Diagnostic challenges and implications of a Yellow Fever co-infected with Malaria case in Freetown, Sierra Leone, September 2023: An outbreak investigation

Umaru Sesay^1,2, Adel Hussein Elduma^2,3,&, Hafeez Umar Imam Barrie¹, Henry Bangura², Mohamed Sallieu Bah¹, Monique Aaro Foster⁴, Gebrekrstos Negash Gebru²

 

¹Ministry of Health, Freetown, Sierra Leone, ²Sierra Leone Field Epidemiology Training Program, Freetown, Sierra Leone, ³African Field Epidemiology Network, Freetown, Sierra Leone, ⁴Division of Global Health Protection, United States Centers for Disease Control and Prevention, Freetown, Sierra Leone

 

 

^&Corresponding author
Adel Hussein Elduma, Sierra Leone Field Epidemiology Training Program, National Public Health Agency Freetown City, Sierra Leone.

 

 

 

 

Yellow fever is a zoonotic epidemic-prone disease that is transmitted to humans through bite from infected mosquitos [1, 2]. Yellow fever symptoms included fever, chills, headache, backache, and muscle aches and the incubation period was 3 to 6 days of the infection. Many people infected with yellow fever are asymptomatic, but 12% of people who have symptoms can develop serious illness with a case fatality rate of 67% among the hospitalized cases [3,4].

 

Globally, 34 countries in Africa and 13 countries in Central and South America are either endemic to yellow fever or have at least one region endemic to the disease in 2023 [5]. In Africa, 27 countries are at high risk of yellow fever epidemics. The WHO African Region estimated that between 84,000 to 170,000 severe yellow fever cases and 29,000 to 60,000 deaths are reported annually [6]. Since the yellow fever vaccination initiative was launched, in 2019, vaccination among children 12-23 months in Sierra Leone has been 76% [7]. It is worth mentioning that the yellow vaccine is safe and affordable and a single dose of the vaccine is sufficient to sustain long-life protection against yellow fever infection [6]. Sierra Leone is listed by the World Health Organization (WHO) among the countries with a high risk of yellow fever transmission [8]. Evidence of yellow fever existence was reported in a study conducted in 1975 where people tested positive for the virus by hemagglutination-inhibition and complement fixation tests [9]. In February 2011, the Sierra Leone Ministry of Health notified the WHO of two yellow fever cases in Bonthe District, Southern Province [10]. The yellow fever vaccine was first administered in Sierra Leone in 2003 and was administered to infants at 9 months of age [11]. Until recently, Sierra Leone lacks testing capacity for yellow fever, making it challenging to improve the timely response.

 

In terms of malaria, an estimated 249 million cases and 608,000 deaths were reported in 85 endemic countries in 2022 worldwide [12]. Within the same year, 94% of total malaria cases and 95% of deaths were recorded in Africa, and 78% of the cases were among children under five years old [12]. Nearly half of the deaths were reported in four countries: Nigeria, the Democratic Republic of the Congo, Uganda, and Mozambique (26.8%, 12.3%, 5.1%, and 4.2%, respectively) [12]. To reduce the burden of malaria, countries have implemented indoor residual spraying, decontaminating stagnant water bodies, using bed nets treated with insecticides, and using artemisinin combined therapy as interventions [13]. Despite these interventions, misdiagnosing of febrile illnesses (including yellow fever) for malaria remains persistent, posing a significant public health risk of disease spread [14]. In Sierra Leone, a total of 4 million malaria cases and 11,600 deaths were reported in 2022 [15].

 

A study conducted by Rashid Ansumana and colleagues on presumptive self-diagnosis of malaria and other febrile illnesses reported that 59.3% of 910 individuals were presumptively diagnosed with malaria and other febrile diseases by themselves or their family members [16]. This high proportion of self-diagnosis for malaria and other febrile diseases increases the risk of treatment resistance and outbreaks [16, 17]. Although studies [18], [19, 20] have investigated the relationship between malaria and other febrile illnesses, and the diagnostic challenges associated with yellow fever co-infection in Africa; the difficulties clinicians encounter when diagnosing yellow fever cases co-infected with malaria have not been thoroughly investigated, and none has been done in Sierra Leone. This study was conducted to address this knowledge gap. Considering Sierra Leone's fragile health system, it is important to investigate the diagnostic challenges and implications of yellow fever cases co-infected with malaria to prevent disease outbreaks, reduce disease morbidity and fatality, and inform clinical and public health interventions. On September 7, 2023, the District Surveillance Unit of Western-Area-Urban received a notification on a suspected yellow fever case from Connaught Hospital. We investigated the diagnostic challenges of a yellow fever case co-infected with malaria in Freetown, Sierra Leone.

 

 

Study design

 

This is a descriptive case investigation for yellow fever infection in Freetown, Sierra Leone

 

Study setting

 

Western Urban includes the oldest city and national capital Freetown and its surrounding, towns, villages, and landscape. It is Sierra Leone´s major urban, economic, financial, cultural, educational and political center. The city's economy revolves largely around its final natural harbor, which is the largest natural harbor on the continent of Africa. The Freetown peninsula consists of three roughly parallel ranges of highlands that are narrow but extend about 30 km south of Freetown. Tengbeh Town is a largely hilly community in the western part of Freetown overlooking the city.

 

Data collection

 

We interviewed case patients and family relatives and collected data on demographics, clinical, and travel history using the Ministry of Health case investigation form. We reviewed the hospital register and vaccination history. We conducted an active case search in the hospital and the community.

 

Case definition

 

According to the Integrated Disease Surveillance and Response technical guideline, 2019 we defined a suspected case as “any person with acute onset of fever, with jaundice appearing within 14 days of onset of the first symptoms”[21]. Hence, developed a working case definition as any person with acute onset of fever, with jaundice appearing between August 23 to September 7, 2023 within the Tengbeh Town community, Freetown. A probable case was defined as any person suspected of yellow fever and has an epidemiological link to a confirmed case or an outbreak. A confirmed case was defined as any person whose sample tested positive for ELISA IgM and Plaque Reduction Neutralization Test of Yellow fever virus.

 

Laboratory investigation

 

In the course of the investigation, we collected blood samples and sent them to the Central Public Health Reference Laboratory for diagnosis. The sample was shipped to the West Africa Regional Laboratory for yellow fever testing in Senegal for further testing. An Enzyme Linked Immuno Assay kit was used for HBV testing, while the Polymerase Chain Reaction (PCR) test and the YF MAC-HD ELISA KIT manufactured by ATCC (The American Type Culture Collection) was used for the yellow fever testing. According to the World Health Organization (WHO), the turnaround time from sample collection to laboratory testing and dissemination of results of yellow fever cases should be within 48 hours.

 

Contact tracing

 

We define contact as any person who had a direct bite from an infected mosquito between August 23 to September 7, within the Tengbeh Town community, Freetown. We adapted the Ministry of Health line-list form to record all 7 identified contacts (all family members) and followed them up for 14 days. We used the Ministry of Health's yellow fever contact tracing checklist to monitor the contacts daily.

 

Environmental assessment

 

We assessed the general sanitation of the case patient residents/environment, waste collection and disposal site, use of mosquito-treated bed nets, and housing structure.

 

 

This investigation confirmed a yellow fever case co-infected with malaria in Freetown, Western Sierra Leone. Clinicians had difficulty diagnosing the yellow fever case because of the similarity in symptom presentation to malaria and the delay in receiving the yellow fever laboratory test results.

 

Case presentation

 

The case was a 23-year-old male pupil residing in the Tengbeh town community in Freetown. On September 4, 2023, he developed fever, headache, muscle pain, and jaundice and sought medical treatment at 34-Military Hospital where he tested positive for malaria parasite. He was treated with artesunate, ciprofloxacin, and paracetamol. However, his condition worsened on September 7, 2023, prompting him to seek further treatment at Connaught Hospital. There, he was suspected of having a hepatitis B virus (HBV) infection and underwent an abdominopelvic ultrasound scan and serology. The ultrasound scan results were normal, and the HBV test was negative. On the same day, yellow fever was suspected. A blood sample was collected and sent to the laboratory for testing. The sample tested positive for yellow fever using ELISA IgM on November 15, 2023. The patient had no travel or yellow fever vaccination history. No additional cases were found, and no contacts developed symptoms. The patient remains alive but continues to exhibit jaundice symptoms by the time study was conducted.

 

Contact tracing

 

None of the 7 contacts developed signs and symptoms compatible with yellow fever during the 14-day follow-up period.

 

Environmental assessment

 

The case patient resided close to a waste disposal site in a congested area. In front of the veranda, there is a drainage with stagnant water that might be a mosquito breeding ground. No evidence of mosquito bed nights was found.

 

 

The case of the 23-year-old male student from Tengbeh Town community, Freetown, highlights several critical issues in detecting and managing yellow fever in Sierra Leone. The patient initially presented with symptoms such as fever, headache, muscle pain, and jaundice, which are common to multiple infectious diseases. This overlap of symptoms in differentiating yellow fever from other febrile illnesses complicates the diagnostic process, particularly in settings where diseases like malaria and hepatitis B are prevalent. Undifferentiated febrile illness (UFI) is a frequently global medical problem seen in healthcare facilities as stated by Barathan et al study on diagnosis, treatment, and prevention of acute undifferentiated febrile illnesses [22]. Yellow fever and malaria co-infection were reported in a study conducted in Nigeria among febrile patients [23]. A study conducted in Tanzania found that, in addition to yellow fever co-infection, malaria was co-infected with other viral hemorrhagic fevers including Crimean Congo Hemorrhagic Fever and Rift Valley Fever [24]. In a study conducted in Senegal, yellow fever and malaria co-infection was reported among patients with febrile illness [25]. It is necessary for clinicians and health professionals who provide care for patients to pay more attention to the differential diagnosis and consider the possibility of co-infection.

 

Our findings observed an obvious delay in receiving the yellow fever result because the sample was sent to a laboratory outside the country. The delayed suspicion and diagnosis of yellow fever, which was confirmed over two months after the onset of symptoms, underscores the need for heightened clinical awareness and faster diagnostic processes. Studies have shown that acute febrile illnesses have potential causes leading to inaccurate diagnosis [26], for example, Yellow fever shares symptoms with many other acute febrile illnesses, such as malaria, dengue, typhoid, and hepatitis, including fever, headache, muscle pain, and jaundice. This overlap makes it difficult for clinicians to differentiate between these conditions based on symptoms alone [27].

 

Moreover, the fact that no additional cases were found and no contacts developed symptoms suggests that this might have been an isolated case. However, the patient´s prolonged jaundice highlights the severity and potential complications of yellow fever, even in cases that do not result in widespread transmission. The prolonged jaundice may cause liver damage or may lead to other complications like deterioration of brain function and a tendency to bleed [28].

 

The finding that the case had no travel history to a region with an ongoing yellow fever outbreak or contact with a confirmed or suspected case was concerning, suggesting potential community transmission. Sierra Leone has experienced a similar outbreak of febrile illnesses with confirmed or suspected cases having no known travel history or contacts. In Kenema district, for example, a study on late diagnosis of Lassa fever also documented an outbreak of the disease with an unknown sources of infection [17]. The lack of information regarding the source of infection during the investigation limits prevention and control interventions while also increasing the risk of morbidity and mortality, as well as a prolonged outbreak. As a result, a prolonged outbreak will place additional strain on the already overburdened healthcare system, depleting it further.

 

Additionally, this study revealed that the case had no history of yellow fever vaccination which is critical in preventing yellow fever infections [6]. Like many low-income countries, Sierra Leone still faces major challenges in providing and utilizing vaccines to the general public. These challenges include limited vaccine availability and access, inadequate healthcare infrastructure and resources, and a general lack of public awareness regarding the benefits o of routine vaccination uptake, particularly concerning yellow fever. By the end of 2019, 76% of children aged 12 to 23 months had received a yellow fever vaccination, which was less than Sierra Leone's expanded program on immunization (EPI) target of ≥95% [7]. Even though our case involves a young adult, the vaccination rate is lower than the 2019 EPI target which suggests that most people are at risk of getting infected with yellow fever. As a result, the case confirmed during this investigation may have been more vulnerable due to a low vaccination rate.

 

Implications of study findings

 

Like other febrile diseases, yellow fever presents a serious public health threat in Sierra Leone when cases are not detected in time. Since the primary source of the infection was unknown, effective public health and clinical interventions to control and prevent yellow fever recurrence may have been compromised. With limited healthcare infrastructure, a yellow fever outbreak not only creates a double workload for healthcare workers, but also increases government healthcare spending, disrupts routine activities, and increases morbidity and mortality. A multi-pronged approach is required to address the critical challenges faced in diagnosing a yellow fever case co-infected with malaria. Stakeholders should increase capacity-building opportunities for clinicians to enhance the prompt detection of yellow fever cases and other febrile illnesses. Stakeholders through the National Public Health Agency should solicit support from partners to establish a yellow fever testing laboratory to increase the turnaround time. Surveillance for yellow fever and other febrile illnesses should be heightened in hospitals. Tools including case definition, sample collection forms, and case-based forms should be made available at all times. Stakeholders should intensify community awareness programs on early healthcare-seeking behavior for yellow fever and other febrile diseases.

 

Strengths and limitations

 

The study provides the first comprehensive investigation of a yellow fever case co-infected with malaria in Sierra Leone. Additionally, the study provided useful information for implementing public health and clinical interventions to prevent the recurrence of yellow fever outbreaks. Despite this strength, we acknowledge some limitations of this study. First, the lack of a yellow fever laboratory testing facility affected the timely diagnosis and implementation of targeted interventions. However, we followed the Ministry of Health's standard operating procedure to isolate the case and identify contacts. Second, the information obtained from the case, relatives, and healthcare workers during the investigation may have been prone to recall bias. We collected exposure data from the case-patient register to reduce the recall bias. Finally, the limited contacts identified during the investigation could have led to missed cases. Finally, this investigation did not conduct an active case search in school, possibly limiting the possibility of detecting additional cases, identifying contacts, and potential breeding sites of mosquitoes.

 

 

The Yellow fever case study highlights the significant diagnostic challenges in differentiating yellow fever from other febrile disease. The overlap of symptoms for febrile illnesses like malaria, hepatitis B, and Yellow fever complicates the clinical diagnosis. The delay in obtaining yellow fever test results due to external laboratory processing highlights the need for MoH and partners to improve local diagnostic capabilities to reduce delays in diagnosing yellow fever and other febrile illnesses. Lack of evidence of mosquito-treated bed net use and presence of stagnant water in the case patient´s home surroundings could have potentially served as a mosquito breeding site, possibly exposing the case patient to yellow fever infection and malaria. Stakeholders are recommended to increase efforts to optimize the uptake of routine yellow fever vaccines. Funding should be provided to the district health management structures to enhance immunization supply and utilization efforts including providing incentives to healthcare workers to enhancing outreach services.

 

Public health actions taken

 

We sensitized community residents on regular use of insecticide-treated bed nets, early healthcare seeking with febrile illnesses, and improved environmental cleaning. Additionally, we orientated healthcare workers on the case definition of yellow fever and clinical case management of yellow fever cases.

 

 

The authors declare no competing interests.

 

 

Conceptualization and design: Umaru Sesay, Adel Hussein Elduma, Data Collection: Hafiz Umar Imam Barrie, Analysis, and Interpretation: Umaru Sesay, Adel Hussein Elduma, Drafting of the original draft: Umaru Sesay and Adel Hussein Elduma, Review of Manuscript: Umaru Sesay, Adel Hussein Elduma, Hafiz Umar Imam Barrie, Henry Bangura, Mohamed Sallieu Bah, Gebrekrstos Negash Gebru. The final approval was made by all authors.

 

 

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