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People who have asthma often ask “Why do I have both asthma and acid reflux”. On the surface, chronic acid reflux (GERD) and asthma appear to be quite separate conditions with little in common.

Asthma is a chronic inflammatory lung disease that causes narrowing of the airways, affecting over 20 million people in the US including up to 6 million children. Symptoms include: wheezing, coughing, difficulty breathing, tightness in the chest and flare-ups associated with allergic reactions or following exercise.

The exact cause of asthma is unknown, but both genetic and environmental factors are thought to be involved. Flare-ups of asthma appear to be allergic in nature as most people with asthma have specific allergies. Allergens that can trigger attacks include cat or dog dander, dust mites, cockroaches, mold and other irritants like cigarette smoke. Asthma diagnosis is made based on a physical exam, breathing tests and a review of one’s medical history.

Chronic acid reflux, often referred to as GERD, which stands for gastroesophageal reflux disease, is a chronic condition caused by the repeated refluxing of stomach contents into the esophagus. Approximately sixty million people in the US suffer with symptoms related caused by acid reflux. The most common symptom is heartburn, described as a burning sensation behind the breastbone. Other reflux symptoms include abdominal pain, cough, sour taste, sore throat, hoarseness, laryngitis, asthma like symptoms (one sign of a possible link) and sinus irritation. Smoking, pregnancy, obesity, hiatal hernia and tight fitting clothes can make symptoms worse.

During acid reflux, the group of muscles at the top of the stomach, called the lower esophageal sphincter (LES), are unable to keep the stomach’s contents from entering the esophagus. The esophagus is not protected by the same mucous layer that coats the inside of the stomach. The result is painful damage to the esophagus. Diagnosis of GERD is generally accomplished by a doctor reviewing a patient’s symptom history in detail including frequency of heartburn, and related symptoms.

If diagnostic tests are required, they may include upper gastrointestinal endoscopy that allows your doctor to look at the lining of your esophagus, stomach and first part of your small intestine using a miniature camera. Damage or irritation to the lining of the esophagus is a common hallmark of GERD. If symptoms persist, additional tests may include manometry to measure how tightly your LES closes as well as 24 hour pH monitoring to measure how much acid is leaking into your esophagus and how long it remains there.

For some time a connection between asthma and acid reflux has been recognized but the reason for the connection has remained a mystery. As many as 80 percent of asthmatics  suffer from abnormal gastroesophageal reflux compared to about 20 – 30 percent of non asthmatics (1, 2). Some asthmatics have GERD with classic symptoms while others shown to have GERD by pH monitoring don’t have classic symptoms and are considered to have “silent GERD” (3). A better understanding of the underlying cause of GERD may shed more light on the connection between this condition and asthma.

What is the true cause of acid reflux?

As a heartburn sufferer myself, I was surprised to find that my symptoms disappeared when I started a carbohydrate restricted diet. I wondered if carbohydrates somehow caused my symptoms and if so, how? I reviewed the leading theory suggesting that certain (trigger) foods, caffeine, or alcohol could relax or weaken the LES muscles and trigger reflux. This concept did not make sense to me and didn’t seem to fit the facts.

As I tried to understand how carbohydrates might trigger reflux and symptoms, I came up with an idea. If some carbohydrates were not fully digested and absorbed in the small intestine, they would be available as food for intestinal bacteria through a process called fermentation. Well fed bacteria make lots of gas. It would be like dropping a Mentos in a bottle of Coke. That much pressure would surely be capable of driving acid reflux into the esophagus and even the lungs. Could bacteria, malabsorbed carbohydrates and fermentation be causing acid reflux and perhaps even asthma?

Bacteria in our gut

The human large intestine contains over 100 trillion microbes belonging to more than 50 genera and over 500 species. These organisms live on nutrients from our diet that we are unable to digest, and in exchange, produce some vitamins and other nutrients that nourish our own cells. Microbes allow us to use food about 30 percent more efficiently and also compete with disease causing germs that might otherwise gain a foothold making us ill. Bacteria outnumber other intestinal microbes by far though some protozoa, fungi and other tiny creatures reside here as well.

While a large diverse population of bacteria is healthy in the large intestine, relatively few bacteria should be present in our small intestine where our own critical nutrient absorption takes place. Normally, the numbers range from zero in the stomach and first part of the small intestine to about one million bacteria per milliliter (mL) in the last part of the small intestine where the large intestine begins. One million bacterial cells is actually a very small amount compared to the trillions in the large intestine.

The number of bacteria in the upper digestive system is controlled by the constant movement of food, acid produced by the stomach, bile, intestinal immunity and the production of mucin that make it difficult for bacteria to adhere to the intestinal surface. Importantly, our efficient digestive process normally limits the amount of nutrients available for bacterial growth. When this balance is disrupted, resident bacteria can rapidly overgrow in the small intestine.

The term Small Intestinal Bacterial Overgrowth (SIBO), refers to bacteria, mostly from the large intestine, invading and overpopulating the small intestine. SIBO is defined as having greater than 100,000 bacteria per milliliter in the upper part of the small intestine. Despite the many defenses the body has to prevent overgrowth, SIBO is common and continues to be linked to a growing number of disorders such as irritable bowel syndrome (IBS), Crohn’s and celiac disease and cystic fibrosis.

When SIBO occurs, normally harmless bacteria overgrow and produce lots of gas (carbon dioxide, hydrogen and methane). If too much gas is produced but not dissipated by intestinal absorption or metabolism by gas consuming bacteria, it can create pressure in the small intestine and stomach that actually drives the reflux of stomach contents past the LES into the esophagus. People with weakened or defective LES muscles will be more susceptible to reflux because less gas pressure will be required to push open the LES.

Can fermentation create enough gas pressure to cause acid reflux? I believe it can. Years ago, as a research scientist, I routinely grew bacterial cultures often working with intestinal strains of bacteria. The growth media contained carbohydrate (typically glucose) because gut bacteria prefer to consume carbohydrates for energy. I was amazed at the amount of gas that most strains could produce. As little as thirty grams (the weight of six nickels) of carbohydrate can give rise to ten liters of hydrogen gas. So much (flammable) gas can be produced by intestinal bacteria that there have been well documented cases of explosions during intestinal surgery (4,5).

The following nine points of evidence convinced me that carbohydrate malabsorption coupled with SIBO may be the ultimate cause acid reflux and perhaps a factor in asthma:

  • Management of dietary carbohydrates improves reflux symptoms and reduces esophageal acid exposure. (6,7,8). I believe reducing carbs is an effective treatment because intestinal bacteria are denied fuel which limits their growth and ability to produce gas.
  • Treatment of GERD patients with the antibiotic erythromycin decreases gastro esophageal reflux and increases apparent LES pressure (9,10). The authors suggested that erythromycin had increased the lower esophageal sphincter (LES) pressure in the these patients. But how can an antibiotic tighten these muscles? LES pressure is measured by inserting a tube through the LES that detects how tightly the LES closes. In this case the LES appeared be closing more tightly after treatment with erythromycin. Possibly, the authors failed to recognize the growth inhibiting effect of erythromycin on intestinal bacteria and how that would limit reflux causing gas. What appears to the authors as “strengthening the defective LES in GERD patients” is, in my opinion, a decrease in intragastric (stomach) gas pressure because erythromycin is inhibiting the intestinal microbes that were producing the gas in the first place. The LES appears to exhibit increased pressure but the effect is actually caused by a decrease in intragastric pressure that no longer pushes as hard on the LES.
  • Consumption of the carbohydrate fructose oligosaccharide (FOS), which is indigestible by humans, but fermented by gut bacteria produces intestinal gas and increases the number of reflux episodes and symptoms of relfux (11). The authors noted an increase in something called transient lower esophageal sphincter relaxations (TLESRs). In other words, the LES opened more as if it was relaxing. I believe these “Lower esophageal sphincter relaxations” described by the authors actually represent the LES being “forced” open by gas pressure. Consuming FOS ensures 100% malabsorption. The fermentation of FOS by gut microbes makes enough gas to pressurize the small intestine and stomach and force open the LES causing reflux and heartburn in susceptible people.
  • In GERD patients, reflux was associated with an increase in intra-abdominal (gas) pressure and belching (12,13). The increase in intra-abdominal gas pressure and belching is consistent with the idea that gas produced in the small intestine from carbohydrate fermentation can create gas pressure in the stomach and cause belching as the gas escapes into the esophagus. The only difference between belching and acid reflux is that the gas pushes stomach contents into the esophagus in the later case and escapes on its own in the former.
  • Cystic fibrosis (CF) patients have a very high (up to 80%) prevalence for GERD and exhibit well documented carbohydrate malabsorption and bacterial overgrowth associated with pancreatic digestive enzyme deficiency due to blockage of pancreatic ducts with thick mucus (14,15,16). After studying the connection between GERD and CF as well as the details of carbohydrate malabsorption in CF, I am convinced that pancreatic enzyme insufficiency leads to malabsorption, SIBO and the reflux-related symptoms so prevalent in cystic patients.
  • The prevalence of GERD in IBS patients (39%) and IBS in GERD patients (49%) is much higher than the prevalence of GERD (19%) or IBS (12%) in the general population indicating a relationship between the two conditions (17). IBS has been clearly linked to small intestinal bacterial overgrowth via hydrogen breath testing and, like GERD, has been treated successfully with carbohydrate restriction as well as antibiotics (18,19,20,21,22). This evidence is consistent with SIBO playing a role in both conditions.
  • Half of GERD patients taking PPI drugs showed evidence of SIBO by glucose breath testing compared to only 25% of IBS patients not taking PPIs. Eighty-seven to ninety percent of SIBO-positive patients (with GERD or IBS) showed improvement after antibiotic treatment (23). I believe the SIBO-positive results in both groups would have been higher if the study employed the lactulose breath test instead of the glucose breath test. Lactulose is not digested or absorbed in the small intestine and can detect bacteria (fermenting the lactulose and producing hydrogen) throughout the entire length of the small intestine. Glucose is rapidly absorbed in the first part of the small intestine and will only detect bacteria if they are present in this region. Dr. Pimentel found that 78 percent of IBS patients tested at the Cedars-Sinai Medical Center had SIBO as indicated by a positive lactulose breath test (18).
  • GERD is associated with obesity and carbohydrate restriction improved symptoms and reduced esophageal acid exposure in obese patients regardless of weight loss (24,25,26). Obese people consume more food, especially carbohydrates, which I believe can lead to “volume based” malabsorption causing SIBO and reflux.
  • A significant number of GERD patients report new symptoms following fundoplication surgery that include excessive gas (abdominal gas and flatulence), bloating, diarrhea and abdominal pain (27, 28,29). The procedure is aimed at preventing reflux, but the side effects are indicative of trapped stomach and intestinal gas as would be expected with malabsorption and SIBO.

The connection between gut and lungs

Normally, stomach acid forms a barrier between bacteria in your intestines and your esophagus, lungs and sinuses because bacteria are killed by stomach acid. Acid reflux can surpass this protective mechanism, especially if stomach acid is neutralized. When acid neutralizing drugs are used (PPIs, H2 blockers and even antacids), bacteria from the intestines are more likely to overgrow and survive in the small intestine and stomach. Reflux can cause these bacteria to enter the esophagus and potentially the lungs and sinuses. People on acid blocking meds are more susceptible to respiratory infections most likely from bacteria originating in their own intestines.

This connection has been proven in a large study linking acid reducing medications to pneumonia. A study of more than 364,000 people led by Robert J.F. Laheij at the University Medical Center St. Radboud in Nijmegen , the Netherlands , found that the risk of pneumonia was almost double for people taking proton-pump inhibitors for prolonged periods compared to people not taking such drugs (41). The increased risk of respiratory infection was also seen in children taking acid reducing medication (42).

As further proof of the connection between reflux and lung problems, Belgium researchers found that the potent antibiotic azithromycin reduced gastroesophageal reflux as well as esophageal acid exposure and the concentration of bile acids in fluid removed from the lungs of lung transplant patients (43). Similar to the erythromycin studies cited above, the authors did not consider that the profound effect might be due to the antibiotic treatment inhibiting gut microorganisms. In this case, stomach acid and bile were being refluxed not only into the esophagus, but directly into the lungs. Azithromycin treatment helped prevent reflux into the esophagus and lungs likely via its effect on SIBO inhibition. The results were quite beneficial for the patients.

Asthma and GERD

In an attempt to understand the connection between GERD and asthma, large multicenter studies were conducted to determine if treatment of GERD with potent PPI drugs would reduce asthma symptoms and improve lung function in poorly controlled asthmatics that had GERD or silent GERD. Studies with the PPI drugs lansoprazole and esomeprazole were conducted to determine if the treatment of GERD with these drugs would have a positive impact on asthma. In each case, the drugs did not improve asthma symptoms or lung function (44,45).

The study employing esomeprazole (Nexium), called the SARA study (for study of acid reflux and asthma), concluded that “gastroesophageal reflux is not a likely cause of poorly controlled asthma”. The authors reasoning was that Nexium “treated the GERD” and the asthma did not improve, therefore GERD can’t be a cause of asthma. It should come as no surprise that I disagree with this conclusion and find myself surprised that no one caught the flaw in this logic.

The flaw is making the assumption that Nexium (or any other acid reducing drug) eliminates any threat from GERD. There is no evidence I am aware of that shows that Nexium and other PPI drugs stop reflux. The drugs simply shut down the production of stomach acid. The above studies suggest that acid alone is not the cause of difficult to treat asthma. But uncontrolled reflux ensures that digestive enzymes, bile and bacteria continue to insult the esophagus, lungs and sinuses. One or more of these substances likely plays a role in the continued exacerbation of asthma even when patients are given PPI drugs. Prolonged use of PPI drugs may actually make things worse by blocking the production of stomach acid that prevents gut bacteria from entering the esophagus, lungs and sinuses.

But what would happen if you could stop all reflux, not just neutralize stomach acid? Would that help people with asthma and GERD? This idea has actually been tested. Fundoplication operations dramatically reduce reflux itself. And it turns out that fundoplication operations dramatically improve asthma symptoms. And, this results in a significant reduction in medicine usage.

[30],[31] This suggests to me that something in refluxate other than acid exacerbates asthma. Regardless of whether the trigger is bile, bacteria or enzymes, stopping reflux (not neutralizing stomach acid) is a viable strategy to improve asthma in people with GERD. Acid reflux may even be an etiological cause of asthma.

Research led by Sebastian Johnston at Imperial College London points to bacteria as one likely suspect in the exacerbation of asthma. The team treated 278 adults diagnosed with asthma with either placebo or telithromycin, an antibiotic used to treat bacterial pneumonia. Treatment was initiated within 24 hours after an acute exacerbation of asthma requiring short-term medical care (46). The results of the study showed the group treated with the antibiotic had a significant improvement in symptoms. Though the other endpoint -peak expiratory flow in the morning at home – was not significantly different, the researchers concluded that there was evidence of the benefit of telithromycin in patients with acute exacerbations of asthma. They also noted that the mechanisms of benefit remain unclear. The contribution of gut bacteria via reflux appears to be the most promising candidate to explain these findings.

What should reflux sufferers and asthmatics do?

Clearly GERD and asthma are very different and complex conditions that share a link. People undergoing treatment for either condition should not make any immediate changes before consulting their own healthcare provider. Your own health care provider may offer diagnostic tests to determine if you suffer from various types of carbohydrate malabsoption such as lactose or fructose intolerance. Some health care providers provide screening for SIBO itself. If you, or someone you know have asthma which is not well controlled, I suggest talking to your doctor about initiating one of my diets that control acid reflux (clinical research studies support both approaches).

One approach is an overall low carbohydrate diet described in my book Heartburn Cured. The other approach documented in my new book, Fast Tract Digestion Heartburn limits only difficult to digest carbohydrates. Are you ready to put the Fast Tract Diet into action? Try the Fast Tract Diet Mobile App.

If you are taking PPI drugs, I recommend talking to your doctor about tapering off these drugs over a period of two to three weeks. I do not recommend people with SIBO undergo antibiotic treatments without first trying to control the overgrowth of bacteria by the two approaches described above. Based on the rational presented in this article, controlling SIBO and GERD by general or selective carbohydrate restriction should dramatically improve the symptoms and severity of asthma, but only clinical testing can provide the proof.

References

1. Sontag SJ, O’Connell S, Khandelwal S, Miller T, Nemchausky B, Schnell TG, Serlovsky R. Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy. Gastroenterology. 1990 Sep;99(3):613-20. A Bediwy, M Elkholy, M Al-Biltagi, H Amer, and E Farid. Induced Sputum Substance P in Children with Difficult-to-Treat Bronchial Asthma and Gastroesophageal Reflux: Effect of Esomeprazole Therapy. Int J Pediatr. 2011; 2011: 967460.

2. Leggett JJ, Johnston BT, Mills M, Gamble J, Heaney LG. Prevalence of gastroesophageal reflux in difficult asthma: relationship to asthma outcome. Chest. 2005 Apr;127(4):1227-31.

3. Parsons JP, Mastronarde JG. Gastroesophageal reflux disease and asthma. Curr Opin Pulm Med. 2010 Jan;16(1):60-3.

4. Dener IA, Demirci C. Explosion during diathermy gastrotomy in a patient with carcinoma of the antrum. Int J Clin Pract. 2003 Oct; 57(8):737-8.

5. Bigard M-A, Gaucher P, Lassalle C. Fatal colonic explosion during colonoscopic polypectomy. Gastroenterology 1979; 77: 1307-1310.

6. Yancy WS Jr, Provenzale D, Westman EC. Improvement of gastroesophageal reflux disease after initiation of a low-carbohydrate diet: five brief cased reports. Altern Ther health med. 2001. Nov-Dec; 7(6):120,116-119.

7. Austin GL, Thiny MT , Westman EC, Yancy WS Jr, Shaheen NJ . A very low-carbohydrate diet improves gastroesophageal reflux and its symptoms. Dig Dis Sci. 2006 Aug;51(8):1307-12.

8. Eades M. Protein Power. 1996 Bantam Books.

9. Pennathur A, Tran A, Cioppi M, Fayad J, Sieren GL, Little AG. Erythromycin strengthens the defective lower esophageal sphincter in patients with gastroesophageal reflux disease. Am J Surg. 1994 Jan;167(1):169-173.

10. Pehl C, Pfeiffer A, Wendl B, Stellwag B, Kaess H. Effect of erythromycin on postprandial gastroesophageal reflux in reflux esophagitis. Dis Esophagus. 1997 Jan;10(1):34-37.

11. Piche T, des Varannes SB, Sacher-Huvelin S, Holst JJ, Cuber JC, Galmiche JP. Colonic fermentation influences lower esophageal sphincter function in gastroesophageal reflux disease. Gastroenterology. 2003 Apr;124(4):894-902.

12. Dodds WJ, Dent J, Hogan WK, Helm JF, Hauser R, Patel GK, Egide MS, Mechanisms of gastroesophageal reflux in patients with reflux esophagitis. N. Engl J Med. 1982. Dec 16;307(25):1547-52.

13. Lin M, Triadafilopoulos G. Belching: dyspepsia or gastroesophageal reflux disease? Am J Gastroenterol. 2003 Oct;98(10):2139-45.

14. Ledson MJ, Tran J, Walshaw MJ. Prevalence and mechanisms of gastro-oesophageal reflux in adult cystic fibrosis patients. J R Soc Med. 1998 Jan;91(1):7-9.

15. Vic P, Tassin E, Turck D, Gottrand F, Launay V, Farriaux JP. Frequency of gastroesophageal reflux in infants and in young children with cystic fibrosis. Arch Pediatr. 1995 Aug;2(8):742-6.

16. Fridge JL, Conrad C, Gerson L, Castillo RO, Cox K. Risk factors for small bowel bacterial overgrowth in cystic fibrosis. J Pediatr Gastroenterol Nutr. 2007 Feb;44(2):212-8.

17. Nastaskin I, Mehdikhani E, Conklin J, Park S, Pimentel M. Studying the overlap between IBS and GERD: a systematic review of the literature. Dig Dis Sci. 2006. Dec;51(12):2113-20.

18. Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol. 2000;95:3503-6.

19. Austin GL, Dalton CB, Hu Y, Morris CB, Hankins J, Weinland SR, Westman EC, Yancy WS Jr, Drossman DA. A very low-carbohydrate diet improves symptoms and quality of life in diarrhea-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol. 2009 Jun;7(6):706-708.

20. Majewski M, Reddymasu SC, Sostarich S, Foran P, McCallum RW. Efficacy of rifaximin, a non absorbed oral antibiotic, in the treatment of small intestinal bacterial overgrowth. Am J Med Sci. 2007 May;333(5):266-70.

21. Pimentel M. Review of rifaximin as treatment for SIBO and IBS. Expert Opin Investig Drugs. 2009 Mar;18(3):349-58.

22. Yang J, Lee HR, Low K, Chatterjee S, Pimentel M. Rifaximin versus other antibiotics in the primary treatment and retreatment of bacterial overgrowth in IBS. Dig Dis Sci. 2008 Jan;53(1):169-74.

23. Lombardo L, Foti M, Ruggia O, Chiecchio A. Increased incidence of small intestinal bacterial overgrowth during proton pump inhibitor therapy. Clin Gastroenterol Hepatol. 2010 Jun;8(6):504-8.

24. Hagen J, Deitel M, Khanna RK, Ilves R. Gastroesophageal reflux in the massively obese. Int. Surg. 1987 Jan-Mar;72(1):1-3.

25. Fisher BL, Pennathur A, Mutnick JL, Little AG. Obesity correlates with gastroesophageal reflux. Dig Dis Sci. 1999 Nov;44(11):2290-4.

26. Austin GL, Thiny MT , Westman EC, Yancy WS Jr, Shaheen NJ . A very low-carbohydrate diet improves gastroesophageal reflux and its symptoms. Dig Dis Sci. 2006 Aug;51(8):1307-12.

27. Vakil N, Shaw M, Kirby R. Clinical effectiveness of laparoscopic fundoplication in a US community. Am J Med. 2003 Jan;114(1):1-5.

28. Klaus A, Hinder RA, DeVault KR, Achem SR. Bowel dysfunction after laparoscopic anti reflux surgery: incidence, severity, and clinical course. Am J Med. 2003 Jan;114(1):6-9.

29. Beldi G, Gláttli A. Long-term gastrointestinal symptoms after laparoscopic nissen fundoplication. Surg Laparosc Endosc Percutan Tech. 2002 Oct;12(5):316-9.

30. Hirschowitz BI, Worthington J, Mohnen J. Vitamin B12 deficiency in hypersecretors during long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther. 2008. Jun 1;27(11):1110-21.

31. Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B12). Ann Intern Med. 1994 Feb 1;120(3):211-5.

32. Yang YX, Lewis JD, Epstein S, Metz DC . Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006 Dec 27;296(24):2947-53.

33. Targownik LE , Lix LM , Metge CJ , Prior HJ , Leung S , Leslie WD . Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ. 2008 Aug 12;179(4):319-26.

34. Patel TA, Abraham P, Ashar VJ, Bhatia SJ, Anklesaria PS. Gastric bacterial overgrowth accompanies profound acid suppression. Indian J Gastroenterol. 1995 Oct;14(4):134-6.

35. Fried M, Siegrist H, Frei R, Froehlich F, Duroux P, Thorens J, Blum A, Bille J, Gonvers JJ, Gyr C. Duodenal bacterial overgrowth during treatment in outpatients with omeprazole. Gut 1994; 35:23-26.

36. Shindo K, Machida M, Fukumura M, Koide K, Yamazaki R. Omeprazole induces altered bile acid metabolism. Gut. 1998 Feb;42(2):266-71.

37. Theisen J, Nehra D, Citron D, Johansson J, Hagen JA, Crookes PF, DeMeester SR, Bremner CG, DeMeester TR, Peters JH. Suppression of gastric acid secretion in patients with gastroesophageal reflux disease results in gastric bacterial overgrowth and deconjugation of bile acids. J Gastrointest. Surg. 2000 Jan-Feb;4(1):50-4.

38. Lombardo L, Foti M, Ruggia O, Chiecchio A. Increased incidence of small intestinal bacterial overgrowth during Proton Pump Inhibitor therapy. Clin Gastroenterol Hepatol. 2010 Jun;8(6):504-8.

39. Fossmark R , Johnsen G , Johanessen E , Waldum HL . Rebound acid hypersecretion after long-term inhibition of gastric acid secretion. Aliment Pharmacol Ther. 2005 Jan 15;21(2):149-54.

40. Reimer C, Søndergaard B, Hilsted L, Bytzer P. Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology. 2009 Jul;137(1):80-7.

41. Laheij RJ , Sturkenboom MC , Hassing RJ , Dieleman J , Stricker BH , Jansen JB . Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA. 2004 Oct 27;292(16):1955-60.

42. Canani RB, Cirillo P, Roggero P, Romano C, Malamisura B, Terrin G, et al. Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children. Pediatrics 2006;117:e817-20.

43. Mertens V, Blondeau K, Pauwels A, Farre R, Vanaudenaerde B, Vos R, Verleden G, Van Raemdonck DE, Dupont LJ, Sifrim D. Azithromycin reduces gastroesophageal reflux and aspiration in lung transplant recipients. Dig Dis Sci. 2009 May;54(5):972-9.

44. Littner MR, Leung FW, Ballard ED 2nd, Huang B, Samra NK Effects of 24 weeks of therapy on asthma symptoms, exacerbations, quality of life, and pulmonary function in adult asthmatic patients with acid reflux symptoms. Chest. 2005 Sep;128(3):1128-35.

45. Mastronarde JG, Anthonisen NR, Castro M, Holbrook JT, Leone FT, Teague WG, Wise RA. Efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med. 2009 Apr 9;360(15):1487-99.

46. Johnston SL, Blasi F, Black PN, Martin RJ, Farrell DJ, Nieman RB; TELICAST Investigators. The effect of telithromycin in acute exacerbations of asthma. N Engl J Med. 2006 Apr 13;354(15):1589-600.