The current knowledge, clinical practice evidence, published guidelines, and journals were collected, investigated, and analyzed by working groups in the workshop. The working group on each sub-topic constructed statements and rationale based on their expertise, and prepared a draft. Midway through the meeting, the working group leader, accompanied by the working group secretary, led the discussion on each statement. Subsequently, the statements were presented to all the key experts present and discussed to meet the standard template. Evidence quality is an objective and reproducible parameter that considers risk of study bias, evidence of possible publication bias, presence of unexplained heterogeneity within experiments, directness of evidence, and accuracy of estimates was evaluated during 2021 until 2022 period (Table 1; Fig. 1).

Table 1  Quality of evidenceFig. 1

Steps for assigning the quality of evidence until grade of recommendation

The grades of recommendation were developed considering the quality of evidence, risks and benefits, as well as the values and preferences of the patients and health practitioners. The grades of recommendation were also developed considering the cost effectiveness, applicability, and general condition of health care centers in Indonesia. The considerations were then discussed and decided into grades of recommendation upon agreement among the experts (Table 2; Fig. 1).

Table 2  Grade of recommendation

The quality of evidence and grades of recommendation were developed in several steps as shown in Fig. 1. All statements and rationales were discussed and agreed upon the meeting. A consensus was achieved when at least 80% of the participants agreed. The final list of statements, grades of recommendation, level of evidence, and rationale was written by the secretary, reviewed by the working group leaders, and summarized in this consensus report.

Dyspepsia

Dyspepsia often explained as chronic pain or disconcert localized to the upper abdomen [4, 12]. In this consensus, we described dyspepsia as any persistent discomfort feeling (e.g., epigastric pain, burning feeling, postprandial fullness, and early satiety) originating from the upper abdomen or GI tract. Dyspepsia can be classified as organic or functional dyspepsia (FD). Organic dyspepsia can be defined as dyspepsia that induced by known etiology that diagnosed after thorough investigation especially concerning structural disease (e.g., endoscopic lesion). The example etiology or risk factor of organic dyspepsia are duodenal or gastric ulcer, erosive gastritis, duodenitis, gastritis, and malignant processes. FD can be defined as dyspepsia with the absence of structural disease after the investigation using imaging, endoscopy, or similar method. The etiology of FD is most likely multifactorial with the exact cause remain unclear. The female sex, rise of age, high socioeconomic status, decreased of urbanization, infection of H. pylori, macro and micronutrient intake in dietary habits, and nonsteroidal anti-inflammatory drug use are risk factor for dyspepsia [1, 13,14,15]. In general, FD can be classified as Postprandial Distress Syndrome (PDS) and Epigastric Pain Syndrome (EPS) (Fig. 2) [1, 12]. PDS primarily involves early satiety or postprandial satiety, and EPS primarily includes epigastralgia or burning [16].

Fig. 2

Algorithm for the diagnosis of uninvestigated dyspepsia

Although it is often benign, especially for FD, dyspepsia has been observed reduce the quality of life. A multi-center Asian study comprising 1115 patients with un-investigated dyspepsia from nine countries including Indonesia revealed that 43% of the patients were shown to have FD [17]. According to data from the Ministry of Health, Republic of Indonesia, dyspepsia was the fifth and sixth most prevalent disease in inpatients and outpatients in Indonesia [18]. The risk factors for patients with dyspepsia such as macronutrient and micronutrient intake in dietary habits in Indonesia may vary among sub-populations [19]. Therefore, determining a guideline for dyspepsia management in daily clinical practice is necessary.

Diagnosis and evaluation of patients with dyspepsia Statement 1

The diagnosis of ‘FD’ can be made if the patients mentioned to have a syndrome; however, the upper GI endoscopy or imaging investigation do not show any structural abnormality that can explain the symptoms (unexplained after a routine clinical evaluation). The syndrome is a group of patient’s complaints with one or more the following symptoms, which have been present within the past 3 months in at least 6 months from the previous onset: epigastric pain, burning feeling, uncomfortably postprandial satiety, and early or quick satiety. The diagnosis of ‘organic dyspepsia’ can be made by clinicians if the patients mentioned the syndrome and the upper GI endoscopy or imaging investigation clearly show any structural abnormality that may explain the symptoms. The diagnosis of ‘un-investigated dyspepsia’ can be made if the patients experience any persistent discomfort feeling as likely to be the dyspepsia syndrome in the upper abdomen; however, the upper GI endoscopy or imaging investigation has yet to be done.

Grade of recommendation: Strong.

Level of evidence: High.

Rationale:

Dyspepsia described as chronic pain or disconcert localized to the upper abdomen [4, 12]. Patient with single or multiple symptoms related with gastroduodenal abnormalities (e.g., epigastric pain and burning, postprandial satiation, early satiety, etc.) according to Rome III and IV criteria Indigestion is diagnosed. However, these criteria remain somewhat vague and can be difficult to interpret for patients and physicians. The British Gastroenterology Society defines dyspepsia as a group of upper gastrointestinal symptoms lasting more than 4 weeks [20]. Dyspepsia due to structural abnormalities or another specific etiology can be classified as organic dyspepsia while dyspepsia with unclear etiology can be likely classified as FD [21].

FD describe as disease with one or more gastroduodenal manifestations based on Rome IV criteria. The signs included postprandial satiety, early satiety, sensation of epigastric pain and burning, with no evidence of structural disease (including upper endoscopy). According Rome III criteria, a diagnosis of FD can be made without requiring a minimum frequency of occurrence. Criteria are met if symptoms persist for at least 3 months in his 6 months prior to diagnosis. Likely no signs of structural disease to explain symptoms [12, 22,23,24,25]. Of note, multiple organic, systemic, or metabolic disorders of and medications that can cause symptoms resembling organic dyspepsia and should be considered withdrawn from FD diagnosis. The differential diagnosis of FD includes for example: gastritis, peptic ulcer disease (PUD), GI and hepatobiliary cancers, parasitic infections, H. pylori infections, celiac disease, gastroparesis, small intestinal bacterial overgrowth, irritable bowel syndrome, chronic pancreatic disorders, hyper- and hypothyroidism, acute cholecystitis, chronic renal failure, electrolyte imbalances, and medications [17, 21].

Statement 2

The alarm symptoms of dyspepsia are still beneficial in Indonesia. Thus, health practitioners should understand and apply observation of the alarm symptoms of dyspepsia during clinical practice. Patients with the alarm symptoms should prompt referral for the upper endoscopy investigation.

Grade of recommendation: Strong.

Level of evidence: High.

Rationale:

The alarm symptoms of dyspepsia involve weight loss (unintended weight loss), continuous dysphagia, constant vomiting, gastrointestinal bleeding, anemia, fever, mass in the upper abdomen, family history of stomach cancer, and age 50 years [1, 26]. As many as 13% and 4% of patients with alarm symptoms who underwent endoscopy were diagnosed with clinically significant peptic ulcer disease and gastric cancer, respectively [26]. Patients with the alarm symptoms in Indonesia may not because of H. pylori infection since the prevalence of this bacterium infection is low in general population. This condition may lead to more serious differential diagnosis during the etiology analysis. Therefore, even though there only 313 hospitals in Indonesia have gastrointestinal endoscopy systems with most of them in mainland Java [18], patients with the alarm symptoms should referred to the health care centers (hospital) where the endoscopy investigation could be performed [26, 27]. Careful observation and management should be performed by monitoring the patients’ health condition according to the patient’s and health care centers’ situation. The health practitioners should be wary of the new onset of dyspepsia and alarm symptoms in the above patients [1].

Statement 3

Endoscopy investigation is suggested to exclude upper GI neoplasia or other organic diseases in dyspeptic patients with aged 50 years or greater, dyspepsia patients with the alarm symptoms, and/or patients presenting with symptoms that are non-responsive to the initial treatment.

Grade of recommendation: Conditional.

Level of evidence: Moderate.

Rationale:

Gastric cancer is the fifth highest incidence among cancers worldwide and as the fourth most prevalent cause of cancer-related death globally (1) and frequently presents with dyspepsia. In Indonesia, the new case and risk of gastric cancer is low (19th rank in new case of cancer) (2); however, some ethnic groups had severe gastric mucosal disease as a hallmark of high-risk populations (3). Endoscopy is not widely available in all areas in Indonesia; thus, stratifying the risk by the alarm symptoms is necessary to increase the cancer detection rate (4).

Management of dyspepsia Statement 4

Patients with dyspepsia should undergo initial treatment with empirical proton pump inhibitor (PPI) therapy with or without a prokinetic if there is no alarm symptom.

Grade of recommendation: Strong.

Level of evidence: High.

Rationale:

PPI therapy is superior to placebo or antacid therapy in treating dyspepsia. The test and treat strategy may be cost-effective when applied to the regions in Indonesia with high prevalence of H. pylori infection (please refer to H. pylori infection consensus section). Exercise-promoting therapy should be used with caution and at the lowest effective dose (e.g., metoclopramide for < 12 weeks, domperidone doses ≤ 30 mg daily) (Fig. 3) [4, 6].

Fig. 3

Algorithm for the management of dyspepsia

Statement 5

After H. pylori eradication, FD patients with any dyspepsia symptom should be treated with a PPI.

Grade of recommendation: Conditional.

Level of evidence: Medium.

Rationale:

Symptoms that might appear after H. pylori eradication may vary among heartburn, epigastric pain, nausea, or other symptoms [28]. PPI therapy has a statistically significant impact on dyspepsia symptoms with a number needed to treat (NNT) of 10 (95% CI: 7–20). Overall, 69.6% patients of PPI group had persistent dyspeptic symptoms in comparison with 75.2% control group [6]. However, if PPI therapy is observed to no longer beneficial, it should be stopped and evaluated [4].

Statement 6

Tricyclic antidepressants (TCAs) and prokinetics can be considered as an optional therapy for patients with FD in whom treatment with PPIs failed. An evaluation or re-evaluation of H. pylori infection status should be conducted for such patients.

Grade of recommendation: Conditional.

Level of evidence: Moderate.

Rationale:

Based on the excellent evidence for TCAs in this indication, TCAs should be administered before prokinetic drugs to treat FD. TCAs have been shown to be highly effective in treating patients with FD [29]. TCAs are commonly associated with adverse events (constipation, dry mouth, urinary retention, and somnolence) [6, 10, 29]. Evaluation or re-evaluation of the H. pylori infection status should be conducted as there is still a possibility of recurrence or recrudescence even after eradication therapy, which can cause the symptoms to persist [26, 30]. In addition, a recent meta-analysis study showed that TCAs, but not Selective Serotonin Reuptake Inhibitors (SSRIs), are efficacious in the treatment of FD, but antidepressants were also associated with a higher incidence of adverse events than placebo [29].

Statement 7

Psychological therapies should be considered for FD patients with no response prior to drug therapy.

Grade of recommendation: Conditional.

Level of evidence: Low.

Rationale:

A review that involved a total of 12 Randomized Controlled Trials (RCT) in FD patients showed that psychological therapies will give significant benefit over the control group. Studies suggested that psychological therapies have a significant benefit of reducing dyspepsia symptoms (RR = 0.53; 95% CI: 0.44–0.65) with an NNT of 3 (95% CI: 3–4). The most common approaches included cognitive behavioral therapy or other various forms of psychotherapy. Although a dramatic effect was observed with regard to the reduction of dyspepsia symptoms, the quality of the data is very low [6]. Future RCT-based study in Indonesia is needed to provide more evidence of psychological therapies benefits towards FD patients.

Dyspepsia patients with COVID-19 Statement 8

Patients’ dyspepsia with COVID-19 should be carefully evaluated whether the etiology of dyspepsia is because of the viral infection or there is another etiology.

Grade of recommendation: Conditional.

Level of evidence: High.

Rationale:

COVID-19 can have GI manifestations, including symptoms related to dyspepsia, during or post the disease process. The symptoms such as nausea and mild and transient vomiting might cause by a gastrointestinal response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or to antiviral medication [31]. Some of the GI manifestations could also be a predictor of worse prognoses of COVID-19 [26]. Specific to the upper GI, this might be due to direct pathological pathways since viral nucleocapsid proteins were detected in the cytoplasm of the stomach cells [32,33,34]. In Indonesia, several studies reported that dyspepsia may occur during or post COVID-19 infection [35, 36]. Not only dyspepsia but other severe conditions induced by organic dyspepsia might also occur. For example, in other countries, it was reported that approximately 4% of patients with SARS-CoV-2 pneumonia had gastrointestinal bleeding [37]. Thus, the etiology of dyspepsia in patients with COVID-19 should be evaluated carefully. The evaluation should begin with the profound anamnesis to dispose any other possible differential diagnosis.

Statement 9

When the onset of dyspepsia occurs likely together with the first onset of COVID-19 symptoms and most of differential diagnosis for ‘organic dyspepsia’ can be eliminated, the clinicians should consider the diagnosis as ‘organic dyspepsia et causa COVID-19’.

Grade of recommendation: Strong.

Level of evidence: High.

Rationale:

Generally, the diagnosis of dyspepsia in COVID-19 patients is the same as the diagnosis of dyspepsia in general (Statement 1). There is no clear difference in treatment or diagnosis of dyspepsia between patients who test positive or negative for COVID-19. Diagnosis and management should be done with caution, but as a mandatory standard he should ensure certain protection through the use of PPE [38]. The clinical and procedural guidelines provided by the experts should be implemented thoroughly, especially while carrying out invasive management such as endoscopy [39]. The health practitioners should use personal protective equipment (PPE) to prevent infection with the virus.

Statement 10

The clinicians should carefully determine the management therapy for dyspepsia patients with COVID-19 in order to get the best therapeutic option with less side effect to the upper GI tract.

Grade of recommendation: Conditional.

Level of evidence: Low.

Rationale:

Management of patients with dyspepsia and COVID-19 is the same as management of patients with systemic dyspepsia (Statement 4). Several risk factors lead to damage to the gastric mucosa from stress in COVID-19 patients, especially in critically ill patients. These include mechanical ventilation, hypoxia, multiple organ failure, psychological stress, and acute respiratory distress syndrome. Theoretically, the COVID-19 patients, especially during their critical condition, should have a higher incidence of stress-induced gastric mucosal damage. PPIs can be used as an option to prevent stress-induced gastritis erosion in COVID-19 patients with such risk factors. Additionally, enteral nutrition and mucosal protectants help protect the gastrointestinal mucosa. Other recommended treatments, such as antipyretic, liver support, management of drug-related adverse events, and psychotherapeutic support, may also be provided as needed. Metoclopramide, domperidone, or 5-hydroxytryptamine receptor antagonists are preferred treatment options for nausea and vomiting [31].

Next, the management therapy (e.g., antiviral and vitamin including their dose) should be chosen carefully in order to get the best option with less side effect to the upper GI tract. The 4th Edition of Indonesian COVID-19 Management Guideline (published in 2022) stated that antiviral drugs including Favipiravir, Redesivir, Molnupiravir, and Nirmatrelvir/Ritonavir with several doses’ regimen can be used as the treatment for COVID-19 infection [40]. According to The Indonesian Food and Drug Authority and previous studies, while all these drugs potentially induce upper GI tract symptoms such as nausea, vomiting, and abdominal pain, certain drug reported to have lower side effect compared to other [41,42,43]. Single drug regimen and lower dose regimen are desirable to reduce the risk of nausea, vomiting, and abdominal pain. Combination between drugs should be assessed carefully. For example, previous studies showed that GI adverse events were more commonly found in patients with LPV/r (a Lopinavir-Ritonavir recombinant therapy) compared to any other regimen therapy. Compared to LPV/r, single regimen of Favipiravir showed a lower side effect of nausea, vomiting, and abdominal pain, thus it might better to use Favipiravir only than LPV/r in dyspepsia patients if there is no special reason to use LPV/r regimen [41]. Further study needs to be governed in order to understand best regimen option for COVID-19 patient with dyspepsia in Indonesia.

Helicobacter pylori infection

The H. pylori infection rate in Indonesia is low compared to other Asian countries [44, 45]. A preliminary study showed that of 267 patients have symptoms of dyspepsia from the five largest islands in Indonesia, 22.1% (59/267) of patients were positive for H. pylori infection based on the criteria of a minimum of one positive test result from the four diagnostic test methods: culture, histological, immunohistochemistry (IHC), and rapid urease test (CLO test, Kimberly-Clark, USA) [46]. Furthermore, a prospective study including 1053 patients from 19 cities across Sumatra, Java, Borneo, Bali, Sulawesi, Timor, and Papua Island confirmed this low prevalence (10.1%) in the general populations, even though some populations tend to have higher prevalence compared to others [47]. Source of drinking water, age, and religion, were risk factors for H. pylori infection; however, only ethnicity could be considered as an independent risk factor for H. pylori infection in Indonesia [48]. Future studies on a larger study population are needed to achieve an accurate representative number of the Indonesian population. Nevertheless, since different islands and cities have different prevalence of H. pylori infection (Table 3), management consensus of H. pylori infections remains desirable.

Table 3 Prevalence of H. pylori infection in Indonesia [46, 55, 81]Epidemiology and disease-related H. pylori Statement 11

Improvement of sanitary and hygiene conditions (e.g., source of drinking water) is important and need to be governed to minimize the prevalence of H. pylori in Indonesia. The knowledge regarding sanitary and hygiene should be propagating to every elements of communities as part of main health promotion programs especially by primary health care units.

Grade of recommendation: Strong.

Level of evidence: High.

Rationale:

Sanitary and hygienic conditions especially the drinking water sources are known risk factors for H. pylori infection and are associated with poor household hygiene when contracting this infection. A study in Indonesia, where data were adjusted for age and sex, found that people who used tap water as their drinking water source had significantly lower infections than those who drew water from a well/river [46, 49, 50].

Statement 12

H. pylori infection is still a risk factor for dyspepsia and other gastroduodenal diseases including in the low infection prevalence area.

Grade of recommendation: Not applicable.

Level of evidence: High.

Rationale:

H. pylori infection was shown to be more common in patients with dyspepsia than in asymptomatic controls or patients with gastric ulcer, gastric cancer, and duodenal ulcer. Disease symptoms reflect the pattern and degree of gastritis or gastric atrophy. Even in areas with low prevalence of H. pylori infection, the clinicians still can find patients with H. pylori-positive (e.g. Surabaya where the Chinese ethnicity tend to have positive results of H. pylori infection compared to Javanese) [51]. H. pylori positive patients showed more severe disease compared with H. pylori-negative patients by histopathological examination [51]. Thus, regardless of where the patients were from, if the patients have H. pylori infection, eradication therapy must be initiated. In addition, other factors such as diet/nutrition pattern need to be monitored since they have an effect on dyspepsia and other gastroduodenal diseases [1, 7, 15, 52].

Statement 13

The low gastric cancer incidence in Indonesia not only due to low H. pylori infection prevalence.

Grade of recommendation: Not applicable.

Level of evidence: High.