Surgical Complications of Typhoid Fever: First National Typhoid Conference in Niamey, Niger

Introduction

Typhoid fever is a bacterial infection caused by Salmonella enterica serovar Typhi ( S. Typhi) that disproportionately impacts the economically disadvantaged. The Global Burden of Disease Study estimates more than seven million cases of typhoid fever and more than 93,000 resulting deaths globally in 2021. ¹ Typhoid fever and specifically TIP, a late complication of untreated typhoid fever, can be financially catastrophic for families and complications can be difficult to manage.

Patients with TIP often present after about two weeks of initial symptoms, characteristically fever and diffuse abdominal pain. Although clinical signs and symptoms are typically non-specific, the operative finding of at least one oval-shaped perforation on the anti-mesenteric side of the bowel is pathognomonic of TIP and allows surgeons to diagnose typhoid in the operating room. Perforations and pre-perforations occur most commonly in the distal ileum but can occur anywhere in the small intestine or colon. Typhoid may also affect the gallbladder and lead to inflammation and necrosis. TIP remains a major cause of morbidity and mortality in sub-Saharan Africa, with an estimated case fatality rate of 20% overall and up to 30% in children. ²

In 2018, the World Health Organization (WHO) recommended programmatic use of typhoid vaccines for the control of typhoid fever. Typhoid conjugate vaccines (TCVs) should be prioritized in countries with the highest burden of disease and/or antimicrobial resistant S. Typhi. ³ It remains challenging for many countries to introduce this critical vaccine given competing health priorities and the difficulty in estimating the true burden of disease. Diagnosing typhoid fever is complicated due to the non-specificity of symptoms and limited diagnostics in many typhoid endemic countries. Using TIP as a surrogate indicator for typhoid could fill a much-needed disease burden gap that would allow governments to make decisions on TCV introduction for the most marginalized children in rural and remote areas without blood culture capability.

Justification and meeting goals

Niger, a Francophone country in West Africa, has a population of more than 24 million people. The gross domestic product of Niger is approximately $14.92 billion USD, with an average household income of 338,000 West African CFA franc (approximately $554 USD based on 2024 currency conversion rates) per household. ⁴ Currently, typhoid fever is estimated to impact 333 per 100,000 persons each year in Niger, although many believe this is a large underestimate. ⁵ Surgeons across Niger consistently report high levels of ileal perforations that overwhelm operating rooms and hospitals during the peak typhoid season and are presumed to be typhoid-related. Although there is growing concern within the Nigerien surgical community regarding TIP, access to published data from Niger, like many Francophone African countries, remains limited often due to French publications in local journals, or journals not well-known to non-Nigeriens and Westerners. ^{6, 7}

On July 22, 2023, surgeons from across Niger, along with local and international typhoid experts and representatives from the Ministry of Health including the Director of Immunizations, Dr. Assan Abdoul Nasser, convened in Niamey, Niger for the first National Typhoid Conference ( Table 1).

With three safe and effective TCVs prequalified and two eligible for introduction support from Gavi, the Vaccine Alliance (Gavi), surgeons came together to share data and experiences to inform country and regional decision-making on TCV introduction. The meeting goals were to share data regarding typhoid burden and complications in Niger, especially those requiring surgical intervention, and to improve care for patients with typhoid and develop strategies to advocate for TCV introduction in Niger.

Diagnosis and management of typhoid fever in Niger

While blood culture diagnosis is the gold standard for diagnosis of typhoid fever, many low- and middle-income countries face resource limitations and lack the laboratory capacity and capability to diagnose typhoid using this mechanism. Other diagnostics, such as the Widal test, are often inaccurate. As a result, typhoid is often underreported and/or treatment is incorrect, which leads to an increase in severe clinical outcomes. New cost-effective rapid diagnostics are in development but require further testing in endemic settings.

At the Niger meeting, Dr. Mahamadou Doutchi outlined general trends in the diagnosis and treatment of patients with suspected typhoid fever in Niger. Due to the non-specific symptoms of typhoid fever, along with similar seasonal patterns to malaria, many patients are initially treated for malaria, and some will additionally receive antibiotics, oral ciprofloxacin being the most prescribed in the outpatient setting. Many patients worsen and develop abdominal pain, leading to hospitalization and surgery. Only in the operating room, where pathognomonic findings for TIP are found, do many patients receive a definitive diagnosis of typhoid fever. As a result, typhoid fever is commonly referred to as a “surgical disease” in Niger.

Once admitted, patients will generally receive intravenous antibiotics, most commonly a combination of ceftriaxone and metronidazole. A patient’s hospital course can vary due to complications.

Regional burden of typhoid intestinal perforation: Maradi, Niamey, Tahoua, Zinder

There are eight distinct administrative regions in Niger: Agadez, Diffa, Dosso, Maradi, Niamey, Tahoua, Tillabéry, and Zinder ( Figure 1). Information from four of these regions was presented at the conference. Each region was represented by practicing surgeons from their region at the conference, but not all regions came with a presentation.

Figure 1. Map of the eight administrative districts of Niger; gray represents the regions with presentations in this summary.

This map is a modified version of Niger Regions.png from Wikimedia Commons ( this file), licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license.

Typhoid conjugate vaccines

Although typhoid vaccines have long been used by travelers and certain military personnel, as presented by Professor Brah Souleymane, they have yet to become accessible to the local Nigerien people. ¹¹ Fortunately, TCVs hold promise for use in typhoid-endemic countries like Niger and have the potential to overcome many of the challenges that impeded uptake of earlier vaccines. In addition to being safe and effective, TCVs provide strong protection for at least four years, ¹² only require one dose, are safe for children as young as six months, and can be administered in combination with other vaccines. ^{13, 14} Three African countries, Liberia, Zimbabwe, and Malawi, have introduced TCV through campaigns, followed by routine immunization, ¹² and Burkina Faso is slated to introduce in late 2024. Other countries in Africa and Asia are in the planning phases of TCV applications and introduction.

In the keynote presentation, Dr. Kathleen Neuzil described the continued endemicity of typhoid. Although it has been virtually eliminated from most high-income countries, typhoid remains a significant disease amongst poor and marginalized children with limited access to healthcare. Control of enteric diseases, including typhoid, faces unprecedented challenges due to competing health priorities, increasing political conflicts, economic stress on families and governments, climate change and extreme weather events, and antimicrobial resistance. Recently, fluoroquinolone resistance was identified in Niger through a surveillance study on pediatric TIP patients in Maradi. All isolated typhoid specimens demonstrated fluoroquinolone resistance, concerning in an area where ciprofloxacin remains the first line choice of antibiotic for treatment of febrile children in the outpatient setting. The high numbers of TIP throughout the country and the presence of fluoroquinolone-resistant strains both provide compelling reasons to introduce TCV in Niger.

Dr. Lassane Kabore summarized support for the introduction of TCV. Gavi has pledged to fully fund a one-time single dose catch up campaign for all children up to 15 years of age. Additionally, the organization will co-finance introduction in routine immunization schedules, with each vaccine costing an estimated $0.20 USD (121 CFA with current 2024 exchange rates), with operational grants available for introduction costs. To further emphasize the TCV benefit, a video was shown highlighting the effects of typhoid in children in rural villages in Niger and emphasizing the nominal cost of the vaccine in comparison to the cost of the often multiple surgeries and the subsequent management of disease morbidity, including ostomy care.

Conclusions

At the first National Typhoid Conference in Niamey, Niger, surgeons from four regions of Niger shared local data that demonstrated TIP remains a major cause of emergency surgery and mortality throughout the country. Across most studies, TIP was responsible for 38 to 65% of acute peritonitis. Additionally, TIP most frequently occurred in patients under 15 years of age and those who reside in rural regions where healthcare is difficult to access. Surgical treatment of TIP depends on severity of disease, particularly number of perforations and location of these perforations. Management can include primary repair, small bowel resection with primary anastomosis, or bowel resection with creation of an ileostomy. Late presentations of TIP often require ileostomy creation which translates to difficulties with management, higher morbidity, and additional costs. Mortality rates associated with TIP remain high, ranging from 11 to 14%, although this is lower than previous case fatality estimates in sub-Saharan African countries. While numbers were small, women of childbearing age had the highest mortality rate amongst all populations presented. In addition to the medical morbidity of TIP, patients and their families also face social hardships secondary to stigma around ostomies and financial hardships due to the high cost of hospitalization and subsequent treatment. In Niger, surgeons provide a unique and important perspective in raising awareness on typhoid and its complications.

As evident by the alarming amount of TIP, the lack of blood culture surveillance in most of Niger should not imply that there is no typhoid fever. While more feasible diagnostics are essential, children should not be denied safe and effective vaccines while such diagnostics are in development and/or blood culture capability is expanded. Thus, countries need to be innovative and flexible in defining disease burden. Additionally, the recent identification of fluoroquinolone-resistant S. typhi in Niger is particularly alarming and could lead to catastrophic consequences if not quickly addressed. TCVs offer a single dose, safe, well-tolerated, and cost-effective option. In Niger, TCV could be included as a component of multi-antigen campaigns – for example, with pentavalent meningitis vaccines, yellow fever vaccines, or measles vaccines. Improvements in water, sanitation, and hygiene (WASH) are essential and must not be forgotten. Vaccines and WASH go hand-in-hand to provide short- and long-term tools to prevent and control typhoid. At the first National Typhoid conference in Niger, clinicians and policymakers have come together to take on typhoid and begin to make it a disease of the past.

Disclaimer

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