Herregods, 2018

Type of study:

Non-comparative study

Setting and country:

University hospitals, European countries, 2010-2015

Funding and conflicts of interest:

No funding reported, several COI reported (research funding, fees)

Inclusion criteria:

Patients with chronic unexplained cough, minimum recording time of 16 hours, at least four cough bursts throughout the 24-hour

Measurement.

Exclusion criteria:

Alternative diagnosis that could

explain the symptoms, such as asthma, postnasal

drip, or the use of ACE-inhibitors, any upper gastrointestinal surgery

N= 192

Prevalence: N.A.

Age (median (IQR))

 57.5 (48-65) years

Sex (%)

29.7 M / 70.3 F

Number of patients presenting symptoms (%)

Cough

100

Heartburn

39.1

Regurgitation

24.5

Describe index test:

24-hour ambulatory esophageal pH impedance-

pressure monitoring (MII-pH)

off acid suppressive therapy (PPI: 7 days prior to measurements, other drugs: 3 days prior to measurements)

Cut-off point(s):

Symptom association probability (SAP): 95%

Symptom index (SI): ≥50%

Pathological acid exposure time (AET):

Comparator test:

N.A.

Cut-off point(s):

N.A.

Describe reference test:

N.A.

Cut-off point(s):

N.A.

Time between the index test en reference test:

N.A.

For how many participants were no complete outcome data available?

68 patients were excluded

Reasons for incomplete outcome data described?

N=29, < 4 cough bursts, N=2 upper gastrointestinal surgery, N= 14 not stopped PPIs, N=23

technical problems with the catheter/the measurement

lasted less than 16 hours.

Reflux cough episode

SAP (n (%))

49 (25.5)

SI≥50% (n (%))

6 (NR)

Cough reflux episode

SAP (n (%))

46 (24)

SI≥50% (n (%))

2 (NR)

AET >6% (n (%))

41 (21.4)

Authors conclusion

The results of our study indicate that only approximately one quarter of the patients with

chronic unexplained cough has reflux-induced cough,

explaining the observation that the vast majority of

patients with chronic cough does not benefit from

antireflux therapy. In order to identify patients who

are likely to have reflux as a cause of their chronic

cough, it is important to use 24-hour pH-impedance

monitoring combined with objective detection of

cough episodes, e.g. by simultaneous 24-hour ambulatory manometry. This allows for the evaluation of

the temporal association between reflux episodes of all types (acid and weakly acidic) and all cough episodes. Even though the presence of typical GERD symptoms and pathological distal acid exposure time are

associated with an increased chance of having refluxinduced cough, many patients will be missed if these criteria alone are used to identify patients who are likely to respond to treatment.

Remarks

Patients were instructed to push an event marker

on the pH datalogger whenever they experienced a

coughing episode or another symptom (heartburn or

regurgitation) and were instructed to note the nature

of the symptom event and its time of onset in a

specially designed diary. Furthermore they were

instructed to restrict their intake to three meals and

four beverages at standardized times throughout the 24 hours and were told to mark these times down in the diary.

Using acid reflux episodes only:  38(19.8%) patients positive SAP (reflux–cough), 11 patients with false negative result. 32 patients had a positive SAP based on weakly acidic reflux alone.

Using acid reflux episodes only:  30 patients positive SAP (reflux–cough).

18 (9.4%) patients had a positive SAP for both the cough–reflux and reflux–cough sequence.

Sifrim, 2005 (preliminary study, which was followed by study of Blondeau (2007))

Type of study:

Non-comparative study

Setting and country:

University hospital, Belgium

Funding and conflicts of interest:

Non commercial funding, non COI declared

Inclusion criteria:

daily cough of unclear aetiology for at least eight

weeks, no other causes of chronic cough, immunocompetent, normal chest x ray, and no use of ACE inhibitors, no asthma, no postnasal drip syndrome, no previous gastrointestinal surgery or taking medications

known to influence oesophageal function.

Exclusion criteria: see inclusion criteria

N= 28 (22 included in analysis)

Prevalence: N.A.

Age (median (range))

55 (43-81) years

Sex (%)

36.4 M / 54 F

Typical GERD symptoms (%)

36

Describe index test:

24-hour ambulatory esophageal pHimpedance-

pressure monitoring (MII-pH)

off acid suppressive therapy (anti-reflux: 2 weeks prior to measurements, antitussive: on day of measurements)

Cut-off point(s):

Symptom association probability (SAP): 95%

Abnormal AET: pH <4 or decrease of ≤1 pH unit (if already <4)

Comparator test:

N.A.

Cut-off point(s):

N.A.

Describe reference test:

N.A.

Cut-off point(s):

N.A.

Time between the index test en reference test:

N.A.

For how many participants were no complete outcome data available?

6 patients were excluded

Reasons for incomplete outcome data described?

N=2 continuous intake of proton pump inhibitors; N=1 technical problems in

pH-impedance recording; and N=3 no > 5 cough bursts during the study day

Distal AET (n (%))

10 (45.5) – (6.8% (1.10–19.8%)).

SAP (n (%))

16 (72.7)

Reflux cough episode*

SAP (n (%))

10 (45.6)

Cough reflux episode*

SAP (n (%))

6 (27.3)

* predominantly (more than

50% of (R+S+) intervals)

Authors conclusion

Using ambulatory 24 hour pressure-pH impedance

monitoring, we were able to determine the precise

temporal association between cough and different types of gastro-oesophageal reflux (acid, weakly acidic, and weakly alkaline). Symptom association analysis allowed identification of a subgroup of patients with chronic cough associated with weakly acidic gastro-oesophageal reflux.

Remarks

SAP was positive for any reflux detected by impedance in nine patients, only for acid reflux in five

patients, only for weakly acidic reflux in three patients, and for both acid and weakly acidic reflux in two patients. There was no patient with SAP positive for weakly alkaline reflux

All patients we found ‘‘reflux-cough’’ and ‘‘cough-reflux’’ sequences. Ten SAP positive patients had predominantly (more than 50% of (R+S+) intervals) the sequence ‘‘reflux-cough’’ and were considered to have cough ‘‘induced by’’ reflux.

Patients were encouraged to maintain normal activities,

sleep schedule, and eat their usual meals at their normal

times. Event markers on the pH-impedance data logger

recorded meal times and posture changes. Before the study, patients were instructed to keep a careful diary and trained to use the event marker in the data logger to record cough

episodes and other events.

Blondeau, 2007

Type of study:

Non-comparative cohort

Setting and country: University hospital, Belgium

Funding and conflicts of interest:

Non-commercial funding, one author reported COI

Inclusion criteria:

Daily cough of unclear aetiology for at least eight

weeks, no other causes of chronic cough, if ex smokers: normal pulmonary function, normal chest x ray, and no use of ACE inhibitors, no asthma or eosinophilic bronchitis, no postnasal drip syndrome, no silent sinusitis.

Exclusion criteria: see inclusion criteria

Exclusion criteria:

N=112 (100 analysed, of which 77 off PPI)

Prevalence: NA

Age (median (range))

54 (22-81) years

Sex

33.8 % M /66.2 % F

Typical GERD symptoms (%)

NR

Describe index test:

24-hour ambulatory esophageal pH impedance-

pressure monitoring (MII-pH)

off acid suppressive therapy, time frame NR

Cut-off point(s):

Symptom association probability (SAP): 95%

Symptom index (SI):

Comparator test:

N.A.

Cut-off point(s):

N.A.

Describe reference test:

N.A.

Cut-off point(s):

N.A.

Time between the index test en reference test:

N.A.

For how many participants were no complete outcome data available?

12 were excluded

Reasons for incomplete outcome data described?

N=9 incomplete or defective recording, N=3 <5 cough bursts

Reflux cough episode*

SAP (n (%))

15 (19.5)

Cough reflux episode

SAP (n (%))

NR

AET >6% (n (%))

27 (35.1) - 10% (7.4–16.1)

*only reported for weakly acid reflux and cough

Authors conclusion

A positive association between cough and WA reflux was found in a significant subgroup of

patients with unexplained chronic cough.  Impedance pH- manometry identified patients in whom cough can

be related to reflux that would have been disregarded using the standard diagnostic criteria for acid reflux. Additional pharmacological or surgical outcome studies

are needed to confirm the role of WA reflux in

these patients.

Remarks

The patients were encouraged to maintain normal activities, sleep schedule and eat their usual meals at their normal times. They were asked to remain upright during the day, and lie down only at their usual bedtime. Event markers on the data logger recorded meal times and posture changes. Between meals, patients abstained from snacks, beverages with a pH < 5, and were asked to avoid lozenges and gum chewing.

Before the study, patients were instructed to keep a

careful diary and trained to use a dedicated event

marker in the data logger, to record cough episodes

and other events.

Bogte (2008)

Type of study:

Retrospective study

Setting and country:

University hospital and top clinical hospital, Holland

Funding and conflicts of interest:

Both not reported

Inclusion criteria:

Adult patients

with daily cough of unknown aetiology lasting for at

least 8 weeks, without other causes of chronic cough, no use of ACE inhibitor, no asthma and no postnatal drip syndrome.

Exclusion criteria:

See inclusion criteria

N=58 (55 analysed)

Prevalence: NA

Median age (range)

53 (18-73)

Sex: 38.2% M / 61.8% F

Typical GERD symptoms (%)

NR

Describe index test:

24-hour ambulatory esophageal pH + manometry

monitoring (in subgroup of patients simultaneous ambulatory monitoring of pressure was performed to record cough episodes)

off acid suppressive therapy (PPI: 5 days prior to measurements, other drugs: 5 days prior to measurements)

Cut-off point(s):

Symptom association probability (SAP): 95%

Symptom index (SI): ≥50%

Pathological AET: total time with pH

below 4 exceeded 6.0%, in upright position when the

reflux exceeded 9% and in supine position when the

reflux exceeded 3%

Comparator test:

N.A.

Cut-off point(s):

N.A.

Describe reference test:

N.A.

Cut-off point(s):

N.A.

Time between the index test en reference test:

N.A.

For how many participants were no complete outcome data available?

3 were excluded

Reasons for incomplete outcome data described?

N=2 PPI use, N=1 technical error

Reflux cough episode

SAP (n (%))

11 (29.7)

SI≥50% (n (%))

6 (16.2)

Cough reflux episode

SAP (n (%))

5 (13.5)

SI≥50% (n (%))

0

AET >6% (n (%))

23 (41.8)

Authors conclusion

This study has shown that 24-h pHmonitoring with symptom association analysis has a

relatively high diagnostic yield in the evaluation of

patients with chronic cough. Half of the patients

with a positive refluxcough association suggesting

reflux-induced cough have physiological oesophageal

acid exposure. When available, the additional

use of 24-h oesophageal manometry is advisable

since this leads to better detection of the coughing

episodes.

Remarks

Patients were encouraged to keep a normal daily

routine, and no restrictions were imposed on the

type of food or beverage intake.

Smith (2010)

Type of study:

Non-comparative cohort

Setting and country:

University hospital, UK

Funding and conflicts of interest:

Several authors reported COI (financial support, fees), non-commercial funding

Inclusion criteria:

Nonsmokers

(and exsmokers of >6 months) with normal

chest radiographs, suffering from chronic cough (duration

≥8 weeks).

Exclusion criteria:

ACE inhibitors, opiates (or other antitussive agents),

with a recent respiratory tract infection, or

with significant medical comorbidities

N= 78 (71 analysed)

Prevalence: NA

Median age (IQR):

59 (51-64)

Sex: 33.8% M /66.2 % F

Typical GERD symptoms

NR

Describe index test:

24-hour ambulatory esophageal pH impedance-

pressure monitoring (MII-pH) + cough monitoring using recording device and microphone

off acid suppressive therapy (PPI: 2 weeks prior to measurements, other drugs: 2 weeks prior to measurements)

Cut-off point(s):

Symptom association probability (SAP): 95%

Comparator test:

N.A.

Cut-off point(s):

N.A.

Describe reference test:

N.A.

Cut-off point(s):

N.A.

Time between the index test en reference test:

N.A.

For how many participants were no complete outcome data available?

7 were excluded

Reasons for incomplete outcome data described?

NR

Reflux cough episode

SAP (n (%))

34 (47.9)

Cough reflux episode

SAP (n (%)) – 2 minute window

40 (56.3)

SAP (n (%)) – 10 seconds window

17 (23.9)

Authors conclusion

Using novel ambulatory acoustic cough

monitoring with simultaneous impedance/pH recordings, we have shown that, irrespective of possible underlying cause, reflux can temporally associate with cough. The lack of association with degree/proximal extent of

reflux and erosive disease, but link to increased cough

reflex sensitivity, suggests that a sensitized central mechanism may be facilitating reflux-induced cough and cough-induced reflux. Furthermore, the presence of a similar incidence of cough preceding reflux points to the

possible existence of a self-perpetuating cycle maintaining chronic cough. In addition, these results may partly explain the poor efficacy of traditional drugs, such as those targeting gastric acidity in the treatment of chronic

cough.

Remarks

For the 2-minute window, 71.8% of subjects had

reflux-cough and/or cough-reflux associations, with

32.4% exhibiting both processes.

Li, 2021

Type of study:

Non-comparative cohort

Setting and country:

Respiratory clinic, China

Funding and conflicts of interest:

No COI reported, Non-commercial funding

Inclusion criteria:

chronic cough with co-existing typical reflux related

symptoms such as regurgitation and heartburn; potential GERC was considered when the other common causes of chronic cough including cough variant asthma, upper airway cough syndrome, eosinophilic

bronchitis were excluded after a sequential

laboratory workup according to an established algorithm,  concomitant GERC was suspected when the therapy pointed to the current cause of chronic cough could not resolve cough completely

Exclusion criteria:

refusal or intolerance

to MII-pH; women in pregnancy or lactation

N= 175 (158 analysed)

Prevalence: NA

Mean age ± SD: 44.3 + 14.6

Sex: 44.3% M /55.7 % F

Typical GERD symptoms

All patients

Describe index test:

24-hour ambulatory esophageal pH impedance-

pressure monitoring (MII-pH)

off acid suppressive therapy (PPI: 7 days prior to measurements, other drugs: 7 days prior to measurements)

Cut-off point(s):

Symptom association probability (SAP): 95%

AET: >6%

Comparator test:

N.A.

Cut-off point(s):

N.A.

Describe reference test:

N.A.

Cut-off point(s):

N.A.

Time between the index test en reference test:

N.A.

For how many participants were no complete outcome data available?

17 were excluded

Reasons for incomplete outcome data described?

N=7 declined, N=8 failed MII-pH, N=2 lost to follow up

SAP only (n (%))

Acid reflux

10 (6.3)

Non-acid reflux

30 (4.7)

AET >6%  only (n (%))

69 (43.7)

SAP and AET (n (%))

25 (18.6)

Authors conclusion

MII-pH is a more reliable and sensitive test currently available for identification of GERC, and can recognize non-acid GERC failing to

be detected by 24-h esophageal pH monitoring. It improves the diagnostic yield of GERC and is gradually replacing 24-h esophageal pH monitoring for the identification of GERC in clinical practice. However, MII-pH has its inherent limitations similar to 24-h esophageal pH monitoring with suboptimal diagnostic efficacy. For the suspected GERC patients with a negative MII-pH, the implementation of empirical

anti-reflux is a remedy to avoid the misdiagnosis and

under- diagnosis of GERC.

Remarks

The patients were instructed to maintain their usual lifestyle, and keep a diary to

record the timing of the start and end of meals, changes in position and symptoms.

Zhang, 2023

Type of study:

Non-comparative cohort

Setting and country:

Respiratory clinic, China

Funding and conflicts of interest:

Non-commercial funding, no COI reported

Inclusion criteria:

Aged between 18 and 70 years old;  cough lasting for >8 weeks, with concomitant other reflux-related symptoms such as regurgitation and heartburn; other possible causes of chronic cough including cough variant asthma, upper airway cough syndrome, and eosinophilic bronchitis were excluded after a sequential laboratory work-up; and successful MII-pH.

Exclusion criteria:

other co-existing causes of chronic cough;  neither cough events nor other reflux-related symptoms were reported, or fewer than four cough events were recorded during MII-pH; or patients had incomplete clinical information or were lost to follow-up.

N= 213 (105 analysed)

Prevalence: NA

Mean age ± SD:

46.0±14.9

Sex: 42.9% M / 57.1% F

Typical GERD symptoms

All patients

Describe index test:

24-hour ambulatory esophageal pH impedance-

pressure monitoring (MII-pH)

off acid suppressive therapy (PPI: 7 days prior to measurements, other drugs: 7 days prior to measurements)

Cut-off point(s):

Symptom association probability (SAP): 95%

AET: >6%

Comparator test^[1]:

N.A.

Cut-off point(s):

N.A.

Describe reference test^[2]:

N.A.

Cut-off point(s):

N.A.

Time between the index test en reference test:

N.A.

For how many participants were no complete outcome data available?

89 were excluded

Reasons for incomplete outcome data described?

N=69 alone cough reported, N=12 <4 cough bursts, N=10 no symptom recording, N=7 only other reflux related symptoms without cough bursts during MII-pH, N=5 incomplete MII-pH recording, N=3 no completion of anti-reflux therapy and N=2 loss to follow-up

Cough episodes - SAP (n (%))*

36 (34.3)

Total episodes - SAP (n (%))**

25 (23.8)

*only reviewing the recordings of cough episodes (not the other reflux-related symptoms such as regurgitation and heartburn)

** involved the total symptoms (cough and all the other reflux-related symptoms).

Authors conclusion

C-SAP was superior to T-SAP for the identification of GERC, especially non-acid GERC in that it had higher sensitivity and a similar high specificity. C-SAP may therefore improve the diagnostic yield of GERC, even though its efficacy was suboptimal.

Remarks

The patients were instructed to maintain their normal daily life and push an event marker on the digital data logger whenever cough or other reflux-related symptoms occurred. They were also asked to keep a journal to record the timing of meals, recumbent position, and symptom episodes in detail. These data were used to check the appropriate use of the event button and distinguish the type of symptoms.