Syndromic approaches to persistent digestive disorders (≥14 days) in resource-constrained settings : aetiology, clinical assessment and differential diagnostics

Background: Gastrointestinal infections are among the leading causes of morbidity worldwide. In contrast to acute diarrhoea, long-lasting digestive disorders can be defined as persistent diarrhoea (≥14 days) and/or persistent abdominal pain (≥14 days). This clinical syndrome is frequently caused by intestinal infections, but its medical importance in the tropics, the range of causative pathogens and the contribution of neglected tropical diseases remain to be elucidated. Currently employed diagnostic tools for the detection of intestinal pathogens frequently lack sensitivity, and there are only few evidence-based recommendations to guide the clinical management of persistent digestive disorders in resource-constrained settings. Rapid diagnostic tests (RDTs) have become available for the diagnosis of various intestinal pathogens and hold promise to be used even in peripheral healthcare centres with only very limited laboratory infrastructure. More recently, multiplex polymerase chain reaction (PCR) assays targeting gastrointestinal pathogens have been developed, but these tests have yet to be systematically evaluated in the tropics. The current Ph.D. thesis was carried out as part of the NIDIAG project, an international research consortium that aims at developing evidence-based diagnosis-treatment algorithms for persistent digestive disorders and other common clinical syndromes in resource-constrained settings of Africa and Asia.
Methods: A systematic review was performed to elucidate the aetiological spectrum of persistent digestive disorders. A study protocol, accompanied by a set of more than 30 standard operating procedures (SOPs), was developed to conduct a multi-country, prospective case-control study to investigate persistent diarrhoea (≥14 days; all individuals aged above 1 year) and persistent abdominal pain (≥14 days; all children and adolescents aged 1-18 years) in Côte d’Ivoire, Indonesia, Mali and Nepal. In the framework of a specific site assessment, a case-control study was performed in Dabou, south Côte d’Ivoire to determine the aetiology and clinical features of persistent diarrhoea. Stool samples were subjected to a host of microscopic techniques, RDTs for Clostridium difficile, Cryptosporidium spp. and Giardia intestinalis, as well as the Luminex® Gastrointestinal Pathogen Panel, a stool-based multiplex PCR. A subsequent study was conducted to assess the diagnostic accuracy of real-time PCR for detection of Strongyloides stercoralis and to compare it to a combination of microscopic methods (Baermann funnel concentration and Koga agar plate). For the first time, a previously validated, urine-based RDT for the diagnosis of Schistosoma mansoni was employed for individual management of patients presenting with digestive disorders to a hospital in Europe.
Results: The systematic review identified more than 40 bacterial, parasitic (helminths and intestinal protozoa) and viral pathogens that may potentially cause persistent diarrhoea and persistent abdominal pain. In a subsequent case-control study in southern Côte d’Ivoire, 20 different intestinal pathogens were detected and >50% of all participants had co-infections. Enterotoxigenic Escherichia coli (32%) and Shigella spp. (20%) were the most prevalent bacterial pathogens, while G. intestinalis (29%) and S. stercoralis (10%) were the predominant intestinal protozoon and helminth species, respectively. With regard to infection status, there were few differences between cases and controls. Most patients with persistent diarrhoea lived in rural areas, but clinical signs and symptoms could not distinguish between specific infections. The protocol for the multi-country NIDIAG study on persistent digestive disorders adopted a case-control approach and regular follow-up visits of symptomatic patients to monitor the clinical response to treatment.
A diagnostic study in south-central Côte d’Ivoire found that the application of a stool-based real-time PCR for S. stercoralis substantially improved the detection rate of this pathogen, leading to a total prevalence of 21.9%, compared to a prevalence of 10.9% according to stool microscopy. C. difficile could also be detected in stool samples from Côte d’Ivoire (5.4% prevalence according to RDT). Non-toxigenic C. difficile strains predominated and their molecular characteristics differed considerably from those observed in other settings. Prolonged storage without properly maintained cold chain only minimally affected the subsequent recovery of C. difficile and its toxins in stool culture.
A point-of-care (POC) test detecting a circulating cathodic antigen (CCA) in urine was successfully utilised to confirm intestinal S. mansoni infection in migrants from Eritrea who presented to a European hospital because of persistent abdominal pain.
Conclusions: Persistent digestive disorders are of considerable public health importance in Côte d’Ivoire and elsewhere, with the majority of cases being detected in rural areas. Many different causative agents may give rise to this syndrome and they can be accurately detected by the application of highly sensitive diagnostic techniques. The diversity of the potentially implicated pathogens underscores the need for a syndromic approach to persistent digestive disorders. RDTs are helpful tools for the detection of specific pathogens and may be implemented as part of diagnostic algorithms in endemic areas and in hospitals providing care for migrants and returning travellers. There is an urgent need to develop a stool-based RDT for S. stercoralis. The high asymptomatic carriage rates of intestinal pathogens call for the inclusion of healthy controls in epidemiological studies to define the specific contribution of each pathogen to the syndrome of persistent digestive disorders. Future studies employing metagenomic approaches will provide further insights into the intestinal microbiome of symptomatic patients and healthy controls.