Non-Acid GERC: Pathogenesis, Diagnosis and Management

Volume 9, Issue 5, May – 2024 International Journal of Innovative Science and Research Technology
ISSN No:-2456-2165 https://doi.org/10.38124/ijisrt/IJISRT24MAY390
Non-Acid GERC: Pathogenesis,

Diagnosis and Management
Yadav Ambedkar Kumar1; Li Yu*1; Xianghuai Xu*1
1
Department of Pulmonary and Critical Care Medicine,
Tongji Hospital, School of Medicine, Tongji University, No.389, Shanghai 200065, China
Yadav Abishek2; Yadav Dhananjay3;

2 3
Armed Forces Medical College, National Medical College and Teaching Hospital,
Dhaka University, Dhaka, Bangladesh Tribhuwan University, Birgunj, Nepal
*Corresponding Authors: Li Yu and Xianghuai Xu
Abstract:- Total Recent investigations have highlighted I. INTRODUCTION

the pivotal influence of non-acid reflux in the etiology of
chronic cough associated with gastroesophageal reflux During Chronic cough induced by gastroesophageal
disease (GERC). Differentiation between acid and non- reflux, or GERC, stands as a distinct subgroup of
acid GERC is effectively achieved through esophageal pH gastroesophageal reflux disease (GERD) related illnesses,
monitoring, with non-acid reflux drawing attention for its primarily distinguished by persistent coughing and identified
linkage to non-standard symptoms and the intricacies as one of the principal etiology of chronic cough(1). The
involved in its management. categorization of GERC hinges on the pH level of the
refluxate, which delineates between acidic reflux (with a pH
The combination of multi-channel intraluminal of ≤ 4.0) and non-acid reflux (with a pH exceeding 4.0). Non-
impedance with pH monitoring (MII-PH) and its related acid reflux comprises two subtypes: weak acidic reflux,
metrics, including acid exposure time (AET), symptom characterized by a pH greater than 4.0 but less than 7.0, and
association probability (SAP), and symptom index (SI), as weak alkaline reflux, with a pH equal to or higher than 7.0.(2).
well as the quantity, pH, nature of reflux, its spread, and
acid clearance time, alongside innovative measures such In recent years, the role of non-acid reflux in causing
as mean nocturnal baseline impedance (MNBI) and post- GERC has gained increasing recognition(3). However, the
reflux induced peristaltic wave index (PSWPI), is pivotal complexity of nonacid GERC, encompassing its
in precisely delineating reflux patterns and identifying the pathophysiology, diagnostic processes, and treatment options,
temporal connection between non-acid reflux occurrences remains less understood than its acid reflux-induced
and episodes of coughing. The prevailing reliance on counterpart. The proposed mechanisms behind GERC
proton pump inhibitors (PPIs) for treatment has include the potential aspiration of stomach contents into the
encountered constraints in effectively managing non-acid airways or esophageal-triggered bronchial reflexes through
GERC, underscoring the necessity for personalized sensory nerve pathways(4). Additionally, the occurrence of
treatment modalities that confront the unique nonacid GERC may be associated with intermittent relaxation
pathophysiology of non-acid GERC to ameliorate patient of the lower esophageal sphincter and an increased
outcomes. esophageal sensitivity(5). Modern techniques like
Multichannel Intraluminal Impedance-pH (MII-pH)
As research continues to deepen our understanding monitoring have significantly advanced our capability to
and enhance treatment methods for this multifaceted identify and distinguish between acid and nonacid GERC.
condition, the pursuit of effective treatment strategies With MII-pH metrics, such as the DeMeester score, Acid
becomes crucial. Our review aims to delineate the Exposure Time(AET), Symptom Association
spectrum of therapeutic options, advancements in Probability(SAP), symptom index(SI), number of reflux
diagnostics, and an improved grasp of the pathogenesis of episodes, Post-reflux Swallow-induced Peristaltic Wave
non-acid GERD. The focus of this review is to further the Index (PSWPI), and mean nocturnal baseline impedance
advancement of patient care management and to inspire (MNBI), healthcare professionals can now diagnose nonacid
continued research in this intriguing domain of GERC with greater precision. The combined use of the
gastroenterology. PSWPI and AET along with MNBI has been particularly
noted for its diagnostic effectiveness for nonacid GERC.
Keywords:- GERC, GERD, MII-pH Monitoring, Chronic
Cough, MNBI
IJISRT24MAY390 www.ijisrt.com 56
Currently, managing GERC involves dietary and Coughs linked to GER can stem from diverse disease
lifestyle modifications, a range of pharmacological conditions, each characterized by different underlying causes.
treatments, and, when necessary, surgical interventions. Significant aspiration, known as gross or macro aspiration,
Proton pump inhibitors (PPIs) are the most commonly used has been observed in various disorders such as recurrent
medications for this condition(6). However, their aspirational pneumonia, pulmonary abscesses & fibrosis,
effectiveness is primarily observed in patients with acidic obliterative bronchiolitis, and bronchiectasis. Furthermore,
reflux confirmed by MII-pH monitoring. For patients who do micro aspiration has been noted in individuals with conditions
not respond to standard treatments, the emerging role of leading to inflammation of larynx, such as laryngitis,
neuromodulators like baclofen offers new hope. These agents bronchitis, and sinusitis. Nevertheless, some patients
are showing promise in treating nonacid GERC and are experience a chronic persistent cough without other
increasingly becoming a focus of interest among healthcare symptoms related to reflux.(20) and those with bronchial
professionals. asthma have been documented to exhibit vagally mediated
distal esophageal-tracheo-bronchial reflex mechanisms(21).
Although there has been progress in researching nonacid
GERC, a significant gap in our detailed understanding of its The cough associated with GERD does not have specific
pathogenesis, diagnosis, and management still exists. The features or timing that set it apart from coughs due to other
absence of standardized clinical treatment protocols causes(22). It can present either as a productive cough with
continues to be a major challenge, adversely affecting the phlegm, akin to the type seen in chronic bronchitis, or as a dry
patient outcomes. To tackle these existing gaps in knowledge, cough. Night-time occurrences of this cough are relatively
we offer a thorough overview of the current and emerging rare, affecting only a minority of patients(22). Notably, in up
diagnostic tools, treatment options, and potential future to 75% of cases, the cough may arise without any
developments in diagnosing and treating patients with accompanying gastrointestinal symptoms, thus acting as a
nonacid GERC. covert sign of GERD(23).
Alternatively, when assessing chronic cough, it is prudent to
II. THE ASSOCIATION OF CHRONIC COUGH consider GERD as a likely cause, especially in instances
WITH GERD where patients encounter typical gastrointestinal symptoms
like heartburn and regurgitation on a regular basis. This
Many A persistent chronic cough, persisting beyond consideration is further emphasized if chest imaging or the
three weeks in patients who have normal CXR and are not overall clinical presentation is suggestive of a condition that
undergoing treatment with ACE inhibitors, has been the mirrors aspiration syndrome(24). Coughs linked to GERD
subject of extensive studies, particularly in its relationship to can be related to various aspiration syndromes, encompassing
GERD in cough pathogenesis. This type of cough is prevalent, conditions such as Mendelson syndrome, pneumonia, and
affecting an estimated 9% to 33% of the population in both lung abscess.
Europe and the United States(7), imposing a considerable
socioeconomic burden(8). In contrast to Western nations, Although the features and timing of a cough may not
historically, chronic cough among Asians was seldom linked consistently signal GERD as the root cause of chronic
to GERD(9). However, there has been a noticeable rise in coughing, there is a clinical profile that can predict with
chronic cough linked with GERD in Japan (10)and China(11), considerable accuracy (around 91%) whether the patient's
paralleling the increased prevalence of GERD in these cough will respond positively to anti-reflux therapy. This
regions When investigating the causes of chronic cough and remains valid even if the patient does not display any
after excluding other factors like asthma and postnasal drip, gastrointestinal symptoms. Numerous prospective studies
GERD should be taken into account as a potential with pre- and post-intervention comparisons indicate a
aetiology(12). Across several studies, GER has been probable association between chronic cough and GERD.(14,
identified as a contributor to chronic persistent cough in about 15, 22, 25).
38–82% of patients, either independently or alongside
bronchial asthma and postnasal drip(13-18). Over 90% of III. THE OVERVIEW OF NON-ACID GERC
chronic persistent cough cases are attributed to GERD,
bronchial asthma, or postnasal drip, either as separate A. Incidence:
conditions or in combination. Addressing this, the American Recent research recognises the substantial impact of
College of Chest Physicians has endorsed a consensus non-acid reflux on the development of persistent cough(27).
statement, grounded in evidence-based practices, presenting studies suggests that with discontinuation of proton pump
an algorithm to guide the evaluation of chronic cough in inhibitor (PPI) therapy, a significant proportion (37%) of
immunocompetent adults.(19). At the core of this algorithm cases with GERD and a significant majority (80%) of cases
is the guidance that clinicians should first explore postnasal with PPI-treated chronic cough show non-acid reflux(28).
drip as a potential cause when assessing patients with a Among GERC patients who discontinued acid suppression
chronic persistent cough and normal chest X-rays, before therapy, the proportion of reflux types was as follows: 65%
considering bronchial asthma and GERD. This diagnostic acid, 29% weak acid, and 6% weak alkaline(29). An analysis
progression is strategically aimed at isolating the primary of 50 patients undergoing PPI therapy found that 26%
etiology of the cough exhibited a positive symptom index (SI) for non-acid-related
chronic cough. The higher frequency of non-acid-related
persistent cough after PPI treatment may be attributed to the
inhibitory effect of PPIs and the elevated pH caused by the acid GERC. They highlight its critical influence on cough
initial acid reflux. The absence of accurate diagnostic hypersensitivity and the neurogenic inflammation of the
methods may greatly underestimate the actual occurrence of airways that characterizes chronic cough due to non-acid
non-acid GERC. reflux.
B. Clinical Presentation:  Reflux Theory:

The females are more commonly affected than males by Reflux theory is alternatively also known as proximal
either types (acid & non-acid) of GERC(30). Majority of the reflux or micro/major aspiration theory and indicates that
patient with non-acid GERC presents chronic day time dry structural and functional abnormalities in lower esophagus
cough while some of them present with associated postnasal leads to reflux of gastric content in throat as refluxate. There
drip and throat clearing(27, 30). However, the typical are four different mechanism by which reflux occurs:
symptoms of acid reflux are less commonly presented in the transient relaxations of the lower esophageal sphincter
case of non-acid GERC because of the chemical composition (TLESRs), reduced pressure in the LES, LES relaxation
of refluxate which is less likely to cause esophageal related to swallowing, and increased tension during periods
injury(31). The difference between the symptomatic of low LES pressure. Refluxate has the potential to activate
presentation among acidic and non-acidic GERC is due to cough receptors either by directly stimulating them or by
different mechanism of occurrence. Where non-acid GERC is inducing mucus hypersecretion in the lower respiratory tract
occurs due to stimulation of esophageal mechanical receptor, to activate the cough receptors through stimulation of vagal
the acid GERC occurs due to stimulation of esophageal reflex(34).
chemoreceptors(31). However , in the less than 60% of the
cases both types present with typical GERD symptoms which The association of acid reflux to chronic cough is
makes it difficult to differentiate non-acid GERC from acid strongly suggested by many studies as antacid therapy
GERC. significantly improved the cough related symptoms in patient
with acid GERC(35, 36). However, other studies found
C. Pathophysiology: weakly acidic reflux as contributor to GERC pathogenesis as
There are two major pathophysiological mechanism that the acid suppressive therapy did not effectively improve the
contribute to explain the development of GERC(4). The first symptoms in many patients(29, 37, 38). Authors noticed that
one is the reflex theory which encompasses acid and non-acid considerable non-acidic reflux in the proximal esophagus and
reflex. This theory presents a more accurate explanation for larynx among the patients who diagnosed as non-acidic
the majority of non-acid GERC instances and potentially GERC, where non-acidic reflux constituted 73% of the total
underlines fundamental mechanism behind GERC because reflux in the proximal esophagus and 11% in the larynx. In
high reflux is less likely to occur in non-acid GERC. The addition, the cough receptors that were previously activated
second theory to explain the pathophysiology of GERC is the by the vagal reflex are also triggered by reflux. severe gastric
reflux theory which encompasses acid reflux, micro acid reflux causes thicker lower oesophagus, structural and
aspiration and airway reflux. functional defects, and acid reflux into upper oesophagus
which explains the reflux theory mechanism of pathogenesis
 Reflex Theory: of non-acid GERC(34, 39).In a multicenter study on 49
The reflex theory posits that GERC is associated with a patients with reflux associated chronic cough, researchers
heightened cough reflex and the emergence of neurogenic found that largers volume of refluxate and longer period of
inflammation in the airways. This theory suggests that when time of exposure of refluxate to esophagus play a significant
reflux material stimulates the mucosal receptors beneath the role in inducing cough than the acidity of refluxate which
esophagus, it activates a pathway to the cough center, found to be less relevant(40). This also explaines the role of
triggering a bronchial cough response. The mechanism reflux in pathogenesis of Non acid GERC.
involves the discharge of neuropeptides like substance P from
efferent nerves, leading to neurogenic inflammation or the Moreover, Ravelli et al. demonstrated that pulmonary
activation of mast cell neuropeptide receptors. Consequently, aspiration pulmonary aspiration of gastric content is common
inflammatory agents such as trypsin, histamine, and in those patient with unexplained and refractory pulmonary
prostaglandin E2 are released, which then provoke the cough manifestation which suggests the GER could be underlying
receptors and lead to the typical coughing symptoms.(32). cause(41). They also found that a normal intraesophageal PH
Research suggests that nonacidic esophageal reflux induces could not rule out GER in those patients. There is also an
cough by activating mechanical stretch receptors linked to Aδ underlying hypothesis regarding GERC's mechanism which
fibers, whereas acid reflux prompts coughing by stimulating suggests that micro aspiration resulting from proximal as well
the vagus nerve via chemoreceptor transient receptor as gastric reflux directly triggers coughing by irritating the
potential vanilloid type 1 (TRPV1), thereby triggering the respiratory tract which have been explained by Phua et al.
esophago-tracheo-bronchial reflex.(33). Researchers have They stated that patients with cough along with GERD have
noted that the majority of non-acid reflux is weakly acidic and significantly reduced laryngopharyngeal sensitivity (LPS) as
is associated with increased levels of mast cell tryptase (MCT) compared to healthy subjects which might elevate the risk of
and substance P (SP), which are known to heighten cough aspiration and cause pulmonary manifestation(42). There are
sensitivity. (33). These results are consistent with the reflex several other studies which explains the proximal acid reflux
theory, underscoring the role of the weak acid-induced and aspiration of gastric content as the cause of GERC(43-
esophago-tracheo-bronchial reflex in the emergence of non-
45). Moreover, persistent cough appears to protect lung by liquid, which typically has low resistance, flows across an
reducing the level of pepsin in pulmonary tract(46). electrode, the impedance decreases. Additionally, during
hiccups, the low ionic density of air creates a high
IV. RESPIRATORY TRACT INFLAMMATION resistance to electrical charges, resulting in a significant
AND HYPERSENSITIVITY impedance to gas flow. A pH impedance probe use these
information assess the direction of pill movement in the
Both reflex and reflux theories are linked to pulmonary esophagus lumen and to document the occurrence of
tract inflammation and hypersensitivity, with low forward and backward motion during ingestion and
regurgitation and sustained proximal reflux stimulation regurgitation, respectively(52). The MII-
causing neurogenic inflammation and pharyngeal pH system, when used in combination with pH monitorin
inflammation, respectively. This leads to pulmonary g is not only useful to differentiate the type of reflux i.e.
epithelial damage, exposure of cough receptors, and acid, weak acid & alkaline(53)but also for establishing the
increased respiratory tract sensitivity, potentially play a relationship between reflux occurrence and cough which
significant role in coughing(47, 48). In a study Peterson and are generally not possible with traditional monitoring
colleagues observed an elevated level of SP in sptum in those method. Ambulatory pH-impedance-pressure monitoring,
patients with the dual condition of asthma and acidic GERC, when combined with 24H dynamic manometry, facilitates
as well as those with chronic cough as compared to those with the evaluation of the relational connection between
non-acidic GERC(49). In an another study researchers found different types of reflux( Acid & weak acid) cough. This
that Patients with nonacidic and acidic GERC shown an technique has found a correlation between cough and
increased cough sensitivity and release of Substance P and mildly acidic reflux in patients suffering from chronic
MCT in their airways, suggesting similar mechanisms of cough of unknown aetiology(54-56). There are a number
pathogenesis of both type of GERC(33). Non-acid GERC is of studies have shown that increasing esophageal
seems to be influenced by sensory nerve stimulation, mast impedance monitoring is how essential for effective and
cell activation, and respiratory tract inflammation, with precise identification of non-acid GERC(27, 57,
different molecular mechanisms affecting different clinical 58).However, the MII-pH method requires several
circumstances. adjustments to address the drawbacks such as limited
normal reading range, low sensitivity, and false-negative
 Diagnosis: results. A precise clinical symptoms diary is essential for
Diagnosing GERC is challenging as over 70% of assessing non-acid reflux but many patients fails to
patients do not show typical GER symptoms(26, 50). Hence, maintain a accurate record of their coughing episodes
The American College of Chest Physicians recommends which leads to misdiagnosis. These factors emphasise the
ruling out other possible cause of chronic cough to predict the requirement for further research before adopting this
presence of GERC(26). However, symptoms alone cannot method as standard non-acid GERC diagnostic tool.
distinguish non acid reflux from acidic reflux, thus diagnostic  Associated metrics (MII-pH): pH and impedance
testing require for proper diagnosis of the condition. monitoring are used to measure acid or non-acid exposure
in the esophagus and determine the corelation between
 Monitoring Non-Acid Reflux: symptoms and occurrence of reflux. The two main tools
Traditional 24 hours pH monitoring and endoscopy for this purpose are the symptom index (SI) and symptom
fall short in identifying non-acid reflux associated chronic association probability (SAP) (59). The SI quantifies the
cough, especially in patients with normal esophageal lining proportion of reflux-related symptoms within the
epithelium. Therefore, these methods are not recommended monitoring timeframe, yet it fails to account for the
as primary examinations for such cases. Instead, a range of aggregate count of reflux incidents. Conversely, the SAP
alternative approaches and techniques are now employed to gauges the likelihood that the observed symptom-reflux
detect non-acid GERC which are explained below. correlation is not coincidental, remedying the SI's
oversight by factoring in the overall quantity of reflux
 Multichannel intraluminal impedance pH detection: MII- episodes in its assessment.
pH, a technique first documented by Silny in 1991, had  Symptom associated probability (SAP): SAP is an
been primarily used for monitoring the gas and liquid effective method for identifying the association between
movements within the hollow structures. It works by cough and reflux. It involves creating a dynamic fourfold
measuring the electrical impedance of a catheter equipped table, with each segment of 2 minutes serving as a
with a ring electrode. In this method, a conductive separate calculation interval, to assess various
electrode is inserted into the esophagus through the nasal combinations of symptoms and reflux represented by
passage, allowing the measurement of voltage variations separate square. This approach accounts for both the
between two electrodes. Latest studies have emphasized frequency of reflux and cough symptoms, overcoming the
its effectiveness in detecting both acidic and non-acidic limitations seen with other methods like the SI and
reflux, and also its advanced capability in evaluating the Symptom Sensitivity Index (SSI). The SI and SSI are
symptoms of gastroesophageal reflux disease either focused on specific symptoms or constrained by the
(GERD)(51). It detects the characteristics of the refluxate count of reflux episodes. This comprehensive approach of
that whether they are solid, liquid, gas or mixture. The SAP makes it a frequent choice for diagnosis of non-acid
voltage variations between electrodes also reflects the reflux related chronic cough. SAP scores, calculated using
direction of movement of refluxate. For instance, when a pH measurements, can assess both acidic and nonacidic
reflux. A score above 95% is typically considered positive, exposure of the esophagus to acid and predicting the
indicating a significant non-random correlation between efficacy of PPI therapy. Nowadays, the preference has
reflux events and symptoms like cough(27). Nevertheless, shifted towards using AET as a more reliable metric,
the Patients suspected of suffering non-acid GERC often owing to concerns about the DeMeester score's
inaccurately record coughs & time during MII-pH inconsistency in repeat assessments(64-66)
monitoring, making it challenging to achieve a diagnostic  Mucosal impedance: In severe reflux disease cases,
SAP score over 95%. While combining a dynamic dynamic impedance measurements can be unreliable
esophageal manometry with daily cough monitoring because low baseline values that complicate interpretation.
could improve accuracy(27, 60), this method is not widely This indicates that GERD might cause long-term changes
yet used in China. Thus, current guidelines suggest in the esophagus, difficult to track with standard
considering an SAP score of 75% or higher as positive. To impedance methods. To overcome this, the Mucosal
validate the effectiveness of such guideline, Xu et al. Impedance (MI) technique was introduced. It utilizes a
examined MII data from 103 patients suspected of having probe inserted through the working channel of an
GERC, which revealed that an SAP of 80% or higher endoscope to directly assess the mucosal impedance(67).
offers a better diagnostic precision for both acidic and  Baseline impedance is an accurate technique for detecting
non-acidic GERC(61). Non-acid GERC has slower nerve GERD and distinguishing its different types. Research by
velocity and symptom onset compared to acid GERC. In Naik et al. in 2019 demonstrated that baseline impedance
a study authors observed that heartburn, cough and acid had a positive predictive value (PPV) of 96% and a
reflux after 2 min post reflux were 80%, 81%, 92% specificity of 95%.(68). However Further research is
respectively in the patients with acid reflux while 54%, required to explore the role of Mucosal Impedance in
56%, 79% respectively in those with non-acid reflux(31). GERC.
Notably SAP calculation, which considers symptoms  Salivary pepsin: Pepsin, a key component of nonacidic
within a 2-minute window post-reflux, may not be gastric juice, is considered to be more damaging to the
suitable for non-acid GERC patients, suggesting the need tissues of the upper respiratory tract than acid. In a
to reassess the suitability of this time frame for calculating comprehensive meta-analysis of research using
SAP in non-acid GERC cases. immunoassay to detect pepsin in saliva and sputum,
 Symptom index (SI): The SI calculates the proportion of Samuels et al. concluded that pepsin testing offers a highly
total coughs occurring within a certain timeframe after precise and noninvasive method for diagnosing
reflux. This period was initially set at 5 minutes but has GERD.(69). This method also proves effective for quick
recently been adjusted to 2 minutes. An SI value screening of the disorder.
exceeding 50% is regarded as positive. In a study authors  Bile reflux: Non-acid reflux includes components like
found that 13 out of 50 cases with non-acid related cough recently consumed food and gas, nonacidic gastric and
had positive SI(31). The SI has a key limitation: it heavily pancreatic secretions, with bile being a primary
focuses on cough symptoms while ignoring the overall constituent. A study by Tack et al. revealed that in a group
count of reflux events. This can result in misleadingly of 65 patients who were still experiencing GERC
negative SI readings for patients with regularly frequent symptoms even after regular PPI therapy, 38% exhibited
reflux but minimal cough symptoms during monitoring, bile acid in their esophagus(70). This suggests a notable
potentially causing misdiagnoses. Moreover, Yang et al. involvement of bile acid in nonacidic GERC cases. The
suggested a diagnostic SI value of ≥45% for acid GERC 24-hour bile reflux monitoring technique is highly
& ≥30% for non-acid after evaluating 118 suspected case beneficial in evaluating GERD with precision. It records
of GERC(62). a range of data, including episodes of bile reflux, the
 Symptom sensitive index (SSI): The SSI measures the duration of prolonged reflux events, the maximum length
proportion of reflux incidents accompanied by cough. A of a reflux episode, and the total time and proportion of
SSI value of 10% or higher deemed positive. However, reflux episodes with an absorption value equal to or
this method heavily relies on the count of reflux episodes, exceeding 0.14. However, while this method excels in
making it less suitable for diagnosing non-acid GERC. identifying and documenting bile acid, it is not capable of
tracking reflux that is weakly acidic or detecting small
 Other Impedance Metrics: amounts of acid in alkaline reflux.
 Post reflux swallow induced peristaltic wave: The PSPW
 DeMeester score & Acid Exposure Time: The DeMeester in pH-impedance studies refers to the subsequent drop in
score (DMS) is a comprehensive metric used to assess impedance within a 30-second span after experiencing
acid exposure during extended pH monitoring, reflux. This occurrence is typically lower in GERD
incorporating elements like acid exposure time (AET). patients than in those without the condition. To determine
AET, represents the total proportion of monitoring the PSPW index, one must divide the total PSPW
duration when esophageal pH remains <4. A suspicion of occurrences by the number of reflux episodes(71-73). The
GERC arises with an AET of 4.8%, and acid GERC is index is useful for assessing the effectiveness of the
considered likely when AET hits 6.2%(62, 63). Values esophagus's primary peristaltic response to reflux, which
that reside within these two limits are deemed as is integral to its capability to perform successive
indeterminate. The DMS, initially a prevalent tool contractions during rapid swallowing. Research has
combining six different parameters to assess acid reflux, revealed that the PSPW index is indicative of diminished
was widely used for identifying possible pathological esophageal chemical clearance in GERD sufferers in
comparison to individuals without GERD. Hence, the LES, a method first proposed by Martinucci et al. To
PSPW index has potential utility as a diagnostic indicator, ensure precision, three 10-minute stable time frames
especially in the absence of other impedance-pH around 1 a.m., 2 a.m., and 3 a.m. are chosen for
assessment data(71, 74). measurement(79). During these periods, the patient is in a
 Number of reflux event: Standard metrics for MII-PH supine position, ideally without any swallowing, reflux
testing, such as AET, DMS, SAP, and SI, are widely events, artifacts, or significant pH changes. The average
recommended for the assessment of GERC(4, 26, 75). BI for each of these intervals is computed using
Despite their widespread use, these metrics are not specialized software. The average of these BI values then
without limitations. AET and DMS, for instance, merely provides the MNBI, effectively reflecting the BI over a
gauge the severity of acid reflux events. Moreover, the six-hour night-time duration. This methodology has
effectiveness of SAP and SI may be reduced due to flaws gained widespread acceptance in many studies. However,
in their algorithms and the possibility of inadequate variations exist in some research, such as using the
patient compliance. To address these issues in diagnosis, impedance channel at 5cm above the LES or calculating
a new objective benchmark has been introduced for more an average MNBI value from the distal four channels (Z3–
accurate identification of GERD. Under the guidance of Z6) (80-83).
The Lyon GERD Consensus, exceeding 80 reflux  Baseline impedance measurements serve as indicators of
episodes in a 24-hour span is classified as abnormal, while the esophageal mucosa's permeability, a phenomenon
a count below 40 is considered to be within the documented in animal studies and among healthy human
physiological norm for diagnosing GERD(66). subjects. Notably, lower impedance values have been
 The technique of impedance-pH monitoring stands as a observed in cases of both erosive and non-erosive
dependable approach for quantifying reflux episodes, a GERD(84, 85). Decreased baseline esophageal mucosal
variable that is notably stable and not significantly altered impedance is linked to alterations in the intercellular
by the use of proton pump inhibitors (PPIs)(76). This spaces and tight junctions, and these changes are often
makes it a valuable adjunctive assessment, especially associated with the manifestation of reflux symptoms(86-
when findings from AET are inconclusive. Contemporary 88).
studies underscore the diagnostic importance of  MNBI serves as an impedance-based diagnostic tool that
quantifying reflux episodes for the assessment of both records readings during sleep, thus avoiding the daytime
acid and non-acid GERC. Specifically, diagnosing non- interference of swallowing 108. Studies have
acid GERC is effectively accomplished by recording demonstrated that low MNBI readings can effectively
upwards of 58 non-acid reflux episodes, whether as a distinguish between several gastrointestinal conditions,
stand-alone measure or combined with additional MII-PH such as different forms of esophagitis, cough-associated
indices(77). Crossing the threshold of 58 non-acidic symptoms, non-erosive reflux disease (NERD), as well as
reflux episodes and a rate of non-acid reflux higher than discerning functional heartburn from GERD/NERD in
68.18% provides clinicians with a robust indicator for the comparison with healthy subjects(71-73). A reduced
early identification of non-acid GERC. This criterion is MNBI suggests a deterioration in the esophageal mucosal
emerging as one of the most definitive and objective barrier and has proven to improve the diagnostic accuracy
measures within MII-PH evaluation, offering significant of impedance-pH tests for patients with uncertain GERD
diagnostic merit for GERC, with increasing specificity for diagnoses. Furthermore, MNBI is valuable alongside Acid
nonacidic variants. Nevertheless, there is a need for Exposure Time (AET) to monitor a patient's reaction to
further investigative work to validate the exactness and treatments for reflux(74).
consistency of this measure against traditional diagnostic
modalities.  Monitoring cough:
 Mean nocturnal base line impedance: The Acid Exposure Monitoring cough patterns plays a crucial role in
Time (AET) is considered a critical measure for detecting diagnosing GERC since the assessment of SAP and SI relies
abnormal reflux, yet it's noteworthy that nearly a third of on the documentation of cough incidents by the patient,
reflux esophagitis patients may present with AET within typically noted in a diary or similar record-keeping tool. Such
normal limits(78). To overcome the limitations of AET, records are vital for identifying the correlation between reflux
additional parameters such as Mean Nocturnal Baseline events and coughing, aiding in the effective diagnosis and
Impedance (MNBI) have been developed. These management of GERC.
parameters are instrumental in examining chemical
clearance processes and determining the health and  Diary cough occurrence recording: A cough diary is a
function of the esophageal lining. They not only improve personal record in which individuals track occurrences of
the accuracy of impedance-pH testing in distinguishing their coughs within a set timeframe, often over a 24-hour
acid from non-acid GERC but also have the potential to cycle. The data noted is based on personal observation,
identify those with non-acid GERC who could benefit which can result in missing or incorrectly logged details.
from established anti-reflux therapies(71). In MII-pH As a result, SAP determined from these diaries may not
monitoring, there are six impedance channels (Z1–Z6) be entirely precise. Studies suggest that the frequency of
strategically placed at intervals of 17, 15, 9, 7, 5, and 3cm coughs recorded by patients typically represents just 40%
above the LES. The established protocol for measuring of the true number of episodes. Furthermore, recorded
MNBI in this procedure calculates the baseline impedance instances of coughing are typically noted to have an
(BI) specifically at the channel situated 3cm above the estimated duration of about 30 seconds. Additionally, the
presence of a chronic cough might itself trigger GER,  Diagnostic Standard:

adding complexity to establishing a clear causal The updated 2021 Chinese cough guidelines set forth
relationship between the two conditions. In a study by the diagnostic criteria for coughs linked to GERD (94). This
Wunderlich and Murray, it was found that only about one- encompasses: (I) a chronic cough that may present with or
third of cough episodes had a positive association with without classic reflux symptoms like heartburn and
GER as determined by the symptom association regurgitation; (II) the detection of abnormal acid or non-acid
probability metric(89). Despite these limitations, reflux through esophageal monitoring, indicated by an AET
clinicians are still advised to recommend the keeping of a exceeding 6% or a SAP of 95% or higher; and (III) a
cough diary record for patients. significant reduction or complete resolution of cough
 24H cough monitoring: Twenty-four-hour cough symptoms following anti-reflux therapy. Yet, the application
monitoring provides a more accurate assessment of cough of these diagnostic criteria is confined to a select number of
severity compared to individual cough scores or quality of specialized cough research centers in China. This restriction
life evaluations. Currently, devices developed for cough stems mainly from the resource-intensive nature of
monitoring, which continue to be refined, fall into two esophageal impedance-pH monitoring, an essential element
categories: single-element and multi-element. Devices of the diagnostic procedure, which is costly and requires
with single-element design predominantly employ voice significant time to perform. At our cough clinic, we undertake
detection technology. (90-92). Conversely, multi-element esophageal impedance-pH monitoring for about 70% of
devices not only record audio but also incorporate patients presumed to have GERD-related cough to
additional metrics like respiratory inductive substantiate their diagnosis.(11, 95).
plethysmography. (93). Currently, the application of
cough monitoring in clinical setting within China is not
yet a standard practice.
Table 1: Diagnostic Standard of Non-Acid GERC

Diagnostic Criteria for Nonacid GERC Description
Cough characteristics Persistent chronic cough lasting for 8 weeks or longer, with possible
accompanying symptoms such as acid reflux, heartburn, chest pain, etc.
MII-pH Monitoring Abnormal nonacid reflux is determined by MII-pH monitoring when the DMS is
below 14.72, the SAP for nonacid reflux is 95% or higher, the AET is 6% or less,
and the total number of reflux episodes surpasses 58..
Response to Treatment A complete resolution or substantial improvement in cough (indicated by a
decrease in cough symptom score by more than 50%) following a structured anti-
reflux therapy regimen.
Exclusion of Other Causes Confirmation that other potential causes of chronic cough have been investigated
and ruled out.
 Management: potential benefits. They can thicken the stomach's fluid

content, which may help prevent reflux. Additionally, they
 Acid Suppression and Alginates Therapy: have the ability to neutralize substances that aren't acidic,
PPI are effective in reducing non-acid reflux and related such as pepsin and bile salts, and they can create a barrier
damage, promoting mucosal healing, and lowering airway above the layer of stomach acid(98, 99). In a study of 25
sensitivity (30). However, the medical consensus generally patients with non-acid reflux who were not responding to PPI
does not recommend PPIs as a primary treatment for non-acid alone, it was found that the addition of alginate to their
GERC. Tutuian et al. conducted a study and found 26% of treatment led to a median improvement of 75% in their
patients on PPI experienced non-acid GERC, a lower symptoms. The overall efficacy of this combined treatment
percentage than those without PPI(96). Studies in our approach was 92%, underscoring the effectiveness of using
department revealed that PPI in combination with prokinetics both PPI and alginate in managing non-acid reflux(99).
can achieve a satisfactory therapeutic goal in patients with Nonetheless, in contrast to earlier reports, certain studies
non-acid GERC (30). Additionally, augmentation of acid indicate that alginate compounds are more effective in
suppression therapy might be effective in increasing the pH reducing acidic reflux rather than nonacidic reflux. This was
during reflux incidents, consequently decreasing the demonstrated in research involving a new alginate, which did
occurrence of acid reflux events. In a study with a small not show a significant reduction in non-acid reflux incidents,
cohort of 12 patients suffering from nonacidic reflux, an yet proved to be effective in reducing acidic reflux
improvement in symptoms was observed in half of the episodes(100). Additionally, In a concise crossover research,
patients following a doubling of their proton pump inhibitor the impact of a regular antacid and a combination of alginate-
(PPI) dosage(97). antacid on acid exposure after meals was compared and they
found the alginate-antacid mix was more effective at reducing
Alongside the option of increasing the dosage of PPI, acid exposure following meals than the antacid alone. Despite
treatments based on alginate serve as another method for this, the study noted no notable difference in the overall
controlling acid. Alginate compounds come with a range of frequency of reflux incidents, which included both acid and
non-acid reflux(101).
One might contend that alginate therapy, by thickening the majority of the patients mainly had non-acidic reflux, but
the consistency of gastric contents, could potentially decrease the study didn't conduct any follow-up to determine long-
the volume of reflux despite not lessening the number of term results. Further investigations are required to better
reflux episodes. This hypothesis warrants further exploration understand the role of baclofen in treating extra-esophageal
for confirmation. Clinically, alginates are widely utilized, symptoms and to verify its sustained effectiveness in
supported by patient-reported advantages and a well- alleviating symptoms(109). In a randomized trial with 234
documented safety profile. However, definitive proof participants, the effectiveness of baclofen and gabapentin in
substantiating the efficacy of alginates in managing non-acid treating GERC, particularly those resistant to PPI and
reflux is currently insufficient. domperidone, was assessed. The study found that both
medications had comparable effectiveness, with success rates
 Prokinetics: of 53.0% for baclofen and 57.3% for gabapentin. The role of
Prokinetics are drugs that augment gastrointestinal non-acid reflux in these outcomes is unclear, as the study did
motility by increasing the affinity of M receptors to not specifically focus on this aspect. However, given the lack
acetylcholine, resulting in enhanced gastric and esophageal of response to PPIs in all patients, non-acid reflux might have
motility. Additionally, they mitigate the effects of reflux been a contributing factor. Additional research is required to
material on the lower esophagus and decrease the amount and more precisely understand the effects of baclofen and
frequency of nonacidic reflux(102). In a meta-analysis of 12 gabapentin on GERD-related coughs and to clarify the role of
RCTs involving over 2000 participants, Ren et al. non-acid reflux in these treatments(110).
investigated the supplementary effects of prokinetics on
GERD patients unresponsive to PPI therapy. The analysis In clinical practice, the prescribing of baclofen is
showed that prokinetic agents reduced the frequency of reflux frequently limited due to its potential side effects. Common
events, yet the esophageal acid exposure time did not change. adverse reactions includes dizziness, tiredness, headaches,
Patients experienced an improvement in overall quality of life; and gastrointestinal issues. Informing patients about these
however, there was no significant enhancement in clinical potential side effects is a regular part of the prescribing
symptoms or in the GERD-typical findings observed during process. Attempts to create other GABA-B agonists with
endoscopy. As anticipated, side effects were more common fewer side effects have mostly ceased because of their
among those treated with prokinetics.(103). insufficient effectiveness.
 TLESR Inhibitors: Buspirone, a serotonin receptor agonist specifically on

The foremost medication being researched for its impact the 5-HT1A receptor in the fundus and esophagus,
on the lower esophageal sphincter (LES) is baclofen, which demonstrates promise in enhancing the tone of the lower
activates gamma-aminobutyric B receptors. Its action esophageal sphincter (LES) and in improving fundic
reduces the occurrence of transient LES relaxations and accommodation, which might raise the reflex threshold(111).
strengthens its the basal tone, both key factors in the Notably, in a study with scleroderma patients, buspirone
therapeutic approach to GERD(104). A meta-analysis of 9 increased LES pressure and reduced heartburn and
RCTs evaluated baclofen's role as a GABAB receptor agonist regurgitation symptoms(112). Similar outcomes were seen in
in the management of GERD. The analysis determined that healthy individuals(113). However, these effects were not
baclofen notably decreased AET, reduced the frequency of replicated in a randomized trial involving patients with
reflux episodes, and lowered the rate of transient LES ineffective esophageal motility. Further investigations are
relaxations (TLESRs), all without an uptick in adverse necessary to better understand buspirone's impact and its
effects(105) . A RCT independently found that that baclofen possible role in treating esophageal disorders.
was effective in reducing both acid as well as non-acid reflux,
in addition to improving GERD-related symptoms(106).  Surgical Therapy to Reduce Reflux Burden:
Furthermore, a crossover trial investigated the use of baclofen Surgical procedures are meticulously crafted to fortify
as a supplementary treatment to PPI in GERD patients and the lower esophageal sphincter for individuals grappling with
found a marked decrease in non-acid reflux occurrences, but GERD, with the objective of reinstating a robust barrier
no significant change was seen in acid reflux incidents, and between the stomach and the lower esophagus, thereby
there was no clear symptomatic improvement too, which may reducing or eradicating reflux occurrences. Conventional
be attributed to the limited range of assessed symptoms(107). surgical methods include Nissen fundoplication, a thorough
A new RCT has shown that baclofen, may be effective in wrapping technique suitable for patients with regular
managing rumination syndrome, presumably by affecting the esophageal motility, and partial fundoplication for those with
LES(108). In light of this evidence, it appears reasonable to compromised esophageal motility. Another option is
use baclofen as a treatment option for non-acid reflux. endoscopic radiofrequency ablation, a procedure utilizing
Nonetheless, additional research, particularly on its efficacy heat generated by electrodes to alter esophageal tissues,
in symptom relief, is necessary. aiming to alleviate symptoms.(114).
The research on the effects of baclofen on extra- Numerous investigations have delved into non-acidic
esophageal symptoms remains limited. A recent open-label reflux, particularly in patients who exhibit resistance to
study examined the efficacy of combining baclofen with PPI, proton pump inhibitors. In a noteworthy study, 19 individuals
finding improvements in various symptoms and cumulative who remained unresponsive to PPIs underwent
reflux symptom scores over three months periods. Initially, fundoplication. Among them, 14 exhibited a positive
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Non-Acid GERC: Pathogenesis, Diagnosis and Management

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Volume 9, Issue 5, May – 2024 International Journal of Innovative Science and Research Technology

ISSN No:-2456-2165 https://doi.org/10.38124/ijisrt/IJISRT24MAY390

Non-Acid GERC: Pathogenesis,

Yadav Abishek2; Yadav Dhananjay3;

*Corresponding Authors: Li Yu and Xianghuai Xu

Abstract:- Total Recent investigations have highlighted I. INTRODUCTION

B. Clinical Presentation:  Reflux Theory:

presence of a chronic cough might itself trigger GER,  Diagnostic Standard:

Table 1: Diagnostic Standard of Non-Acid GERC

 Management: potential benefits. They can thicken the stomach's fluid

 TLESR Inhibitors: Buspirone, a serotonin receptor agonist specifically on

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