Does PPI Use Increase Pneumonias in Otherwise Healthy Infants?

A recent study (M-L Blank, et al. JPGN 2018; 67: 335-40) showed that proton pump inhibitors (PPIs) do not appear to increase the risk of pneumonia in otherwise healthy infants.

This study used a cohort of 21,991 patients (2005-2012) in New Zealand and examined the use of a PPI (omeprazole, lansoprazole, or pantoprazole) and its association with lower respiratory tract infections (566 validated cases) and 65 cases of radiography-confirmed community acquired pneumonia (CAP).  For each LRTI and each CAP, there were 10 matched controls.

Key findings:

  • Neither current nor recent use of a PPI was associated with an increased risk of CAP or LRTI resulting in hospitalization or death.
  • The matched odds ratio for CAP with current or past use of PPI was 0.88 and for all LRTI cases the matched odds ratio was 1.13.

My take: This study indicates that PPIs are unlikely to contribute to respiratory infections in otherwise healthy infants.  The larger question is how many of these infants really should be receiving PPIs and what other adverse consequences that may occur.

Related blog posts:

Bring Out the Big Guns: Treating Infections with Cirrhosis

A recent study (M Merli et al. Hepatology 2016; 1632-39) indicates that health-care associated infections (HCA) in the setting of cirrhosis respond more favorably to broad-spectrum antibiotics.  In this prospective study of 96 randomized patients, in-hospital mortality was improved in the broad-spectrum group (6%) compared to the standard group (25%).  There was a similar multidrug-resistnace rate (50% broad spectrum compared with 60% in standard group).

Table 1 lists the antibiotic selection.  In the broad spectrum treatment, this almost always included imipenem/cilastin (I/C); with spontaneous bacterial peritonitis (SBP), I/C was combined with vancomycin, and with pneumonia it was combined with both vancomycin and azithromycin.  In contrast, the standard group’s main medication was augmentin (with added azithromycin for pneumonia) or cefotaxime for SBP.

My take: Does this study show that infections in the setting of cirrhosis are becoming more difficult to treat? Probably. How much these findings can be extended to the pediatric population remains uncertain.

Somewhat related topic: Primary prophylaxis of Variceal Bleeding in Children –Summary of the Baveno VI Pediatric Satellite Symposium.  BL Shneider et al. Hepatology 2016; 63: 1368-80. Key point: “there are few pediatric data…therefore, no recommendations for primary prophylaxis with endoscopic variceal ligation, sclerotherapy, or nonspecific beta-blockade in children was proposed.”

Silver Comet Trail

Silver Comet Trail

The Prosecution Rests…PPIs on Trial

For physicians who use proton pump inhibitors in a cavalier manner, a recent review (CM Stark, CM Nylund. J Pediatr 168: 16-22) provides a sobering reassessment of the potential side effects and potential complications of proton pump inhibitors (PPIs).  After finishing the article, the impression left was of a lawyer putting these medications on trial for high crimes and misdemeanors.

Here were the key points:

Infectious disease: PPI-induced hypochloridia is known to alter the gastrointestinal bacteria motif, allowing certain normally absent or depleted pathogenetic microorganisms to survive and proliferate.  This can lead to all of the following:

  • small bowel bacterial overgrowth
  • increased gastrointestinal infections (including Clostridium difficile, Salmonella, Campylobacter, and acute viral gastroenteritis)
  • pneumonia (particularly community acquired pneumonia and hospital acquired pneumonia)
  • upper respiratory infections
  • spontaneous bacterial peritonitis.

The magnitude of these associations is discussed in detail in the review.

Gastrointestinal disease: Use of PPIs has been associated with an increased incidence of the following:

  •  celiac disease which persisted after excluding prescriptions in the year preceding diagnosis (association does not prove causation)
  • benign gastric fundic polyps
  • rebound acid hypersecretion

Malabsorption: PPIs can affect absorption of multiple nutrients, though more studies are needed, particularly in the pediatric age group.

  • calcium: “there is significant evidence to suggest that PPI use can alter calcium and bone metabolism…associated with an increased risk of hip fractures in older adults….It is reasonable to hypothesize that PPI administration during adolescence and early adulthood could decrease an individual’s peak bone density.”
  • magnesium: PPI have been hypothesized to affect magnesium absorption.  “A study of 366 Canadian patients hospitalized with hypomagnesemia…found PPIs [were] associated with a 43% increased risk of hospitalization.”  More studies are needed to determine the whether this risk is truly significant.
  • iron, vitamin B12, and vitamin C absorption may be affected by PPI use.

Cardiovascular/Renal/Microbiome:

  • Cardiac: In adults, PPI use has been associated with adverse cardiac events.  The pathophysiology could have been pediatric implications.  PPIs can increase asymmetrical dimethylarginine (ADMA) which is an endogenous inhibitor of nitric oxide synthase.
  • Renal: PPIs have been associated with cases of acute interstitial nephritis
  • Microbiome: “PPIs alter the microbiome.”  Decreased diversity of the microbiome has been associated with a large number of medical conditions, including irritable bowel syndrome, inflammatory bowel disease, nonalcoholic fatty liver disease, necrotizing enterocolitis as well as many non-gastrointestinal conditions.  “The temporality of dysbiosis and subsequent disease development has  not been explored fully for most conditions.”

My take: PPIs can be life-saving and disease-altering medications.  At the same time, (per authors) “PPIs should not be prescribed without consideration for all short- and long-term side effects.”

Related blog posts:

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This Webinar Will Review Issues with Regard to Optimal PPI Usage and Includes My Esteemed Colleagues (Dr. Gold and Dr. Garza)

This NASPGHAN Webinar Will Review Issues with Regard to Optimal PPI Usage and Includes My Esteemed Partners (Dr. Gold and Dr. Garza)

If a Guideline Falls in The Woods, and No One Hears It

Two recent articles highlight how ineffective guidelines can be:

  • J Pediatr 2014; 165: 570-6.
  • J Pediatr 2014; 165: 585-91.

In the first retrospective multicenter study, the authors note that hospitals with institutional clinical practice guidelines (CPGs) for bronchiolitis did not have significant reductions in the use of tests and treatments (eg. complete blood count, chest X-ray, bronchodilator use, steroid and antibiotic use).  However, two factors, time that CPG had been in place and ready access to an online written document were associated with a reduction in tests and corticosteroids.

In the second study, a retrospective cohort study of 17,299 cases of uncomplicated pneumonia at 125 hospitals, antibiotic choices rarely coincided with recommended guidelines.  “Ampicillin or penicillin G is strongly recommended for first-line management of uncomplicated pediatric CAP [community acquired pneumonia] in the inpatient setting barring substantial high level penicillin resistance of Streptococcus pneumoniae in the community.” Yet, in this study, about 75% received a third-generation cephalosporin and 5-10% received monotherapy with a macrolide.  The former is generally unnecessary and not advantageous, whereas the latter has a lower efficacy. Less than 1% received a recommended choice.

Bottomline: These studies have obvious implications well beyond bronchiolitis and pneumonia. Experts can agree on plethora of guidelines but they are almost meaningless without efforts to get clinicians to use them.

How Proton Pump Inhibitors Can Cause Infections

In yesterday’s blog, the editorial on “Acid-reducing agents in infants and children: friend or foe?” also commented on an additional study (JAMA Pediatr. 2014. doi: 10.1001/jamapediatrics.2014.696) which addresses the issue of how proton pump inhibitors (PPIs) may contribute to an increased risk of infections.  It is well-known that use of PPIs (and to a lesser extent histamine-2 receptor antagonists) contribute to a significant increased risk of community-acquired pneumonias and gastrointestinal infections (probably including necrotizing enterocolitis in infants).

In this study, (from the editorial) “acid suppression was associated with a positive gastric culture (P =.003) and increased median concentration of gastric bacteria (P<.001). Full-column nonacid reflux was associated with higher concentrations of bacteria in the lung.”

In this era of pioneering microbiome research, it is not surprising that chronic changes in gastric acid production could cause these results.  This is something to consider when calculating risks and benefits, particularly in situations where the benefits are quite minimal.

Here’s the abstract:

Importance  The use of acid suppression has been associated with an increased risk of upper and lower respiratory tract infections in the outpatient setting but the mechanism behind this increased risk is unknown. We hypothesize that this infection risk results from gastric bacterial overgrowth with subsequent seeding of the lungs.

Objectives  To determine if acid-suppression use results in gastric bacterial overgrowth, if there are changes in lung microflora associated with the use of acid suppression, and if changes in lung microflora are related to full-column nonacid gastroesophageal reflux.

Design, Setting, and Participants  A 5-year prospective cohort study at a tertiary care center where children ages 1 to 18 years were undergoing bronchoscopy and endoscopy for the evaluation of chronic cough. Acid-suppression use was assessed through questionnaires with confirmation using an electronic medical record review.

Main Outcomes and Measures  Our primary outcome was to compare differences in concentration and prevalence of gastric and lung bacteria between patients who were and were not receiving acid-suppression therapy. We compared medians using the Wilcoxon signed rank test and determined prevalence ratios using asymptotic standard errors and 95% confidence intervals. We determined correlations between continuous variables using Pearson correlation coefficients and compared categorical variables using the Fisher exact test.

Results  Forty-six percent of patients taking acid-suppression medication had gastric bacterial growth compared with 18% of untreated patients (P = .003). Staphylococcus (prevalence ratio, 12.75 [95% CI, 1.72-94.36]), Streptococcus (prevalence ratio, 6.91 [95% CI, 1.64-29.02]), Veillonella (prevalence ratio, 9.56 [95% CI, 1.26-72.67]), Dermabacter (prevalence ratio, 4.78 [95% CI, 1.09-21.02]), and Rothia (prevalence ratio, 6.38 [95% CI, 1.50-27.02]) were found more commonly in the gastric fluid of treated patients. The median bacterial concentration was higher in treated patients than in untreated patients (P = .001). There was no difference in the prevalence (P > .23) of different bacterial genera or the median concentration of total bacteria (P = .85) in the lungs between treated and untreated patients. There were significant positive correlations between proximal nonacid reflux burden and lung concentrations of Bacillus (r = 0.47, P = .005), Dermabacter (r = 0.37, P = .008), Lactobacillus (r = 0.45, P = .001), Peptostreptococcus (r = 0.37,P = .008), and Capnocytophagia (r = 0.37, P = .008).

Conclusions and Relevance  Acid-suppression use results in gastric bacterial overgrowth of genera including Staphylococcus and Streptococcus. Full-column nonacid reflux is associated with greater concentrations of bacteria in the lung. Additional studies are needed to determine if acid suppression–related microflora changes predict clinical infection risk; these results suggest that acid suppression use may need to be limited in patients at risk for infections.

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Diseases peculiar to children

In celebration of NEJM’s 200th anniversary, a special series of articles is being published.  A recent one, titled “What we don’t see” makes some useful observations about the history and trajectory of the field of pediatrics (NEJM 2012; 366: 1328-34).

According to the author, most physicians did not consider children as a distinct medical population in the early part of the 19th century.

  • In 1789 Benjamin Rush at the Univ of Pennsylvania gave lectures called “diseases peculiar to children.”
  • William Osler introduced the term “pediatrics” in 1880.
  • While advances in genetics, surgery, neonatology, oncology, and many other disciplines have been very important, infectious diseases have remained the predominant cause of childhood death both in the past and currently.
  • In 2008, causes of childhood death worldwide:  pneumonia 19%, diarrhea 15%, malaria 8%, other infections 26%.  Diarrhea and pneumonia each killed more than 1 million children.
  • Neonatal deaths comprised 41% of all deaths in the first 5 years of life.