Preterm Infants with Increased Infections Following Acid Suppression Therapy

A recent study (P Manzoni et al. J Pediatr 2018; 193: 62-7) provide more data on the detrimental effects of gastric acid inhibitors (eg. proton pump inhibitors, histamine-2 receptor antagonists).  This study was a secondary analysis using prospectively collected data from 235 preterm very low birth weight infants. Key findings:

  • “After multivariate analysis, exposure to inhibitors of gastric acidity remained significantly and independently associated with LOS [late-onset sepsis] (OR 1.03); each day of inhibitors of gastric acidity exposure conferred an additional 3.7% odds of developing LOS.”
  • Acid suppression therapy was associated with gram-negative (P<.001) and fungal pathogens (P=.001)
  • The study showed an association between acid blockers and with necrotizing enterocolitis, which was mitigated in those who received bovine lactoferrin

My take (borrowed, in part, from authors): This data “confirm, strengthen, and expand on previous reports describing an association between inhibitors of gastric acidity and infections.”  Thus, the risks of these medications is likely greater than the benefits in the majority of preterm infants.

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Bright Angel Trail

Probiotics Lower Risk of Sepsis in Newborns

Summary of recent study from NPR: Probiotic Bacteria Can Protect Newborns from Deadly Infections

Previous studies have shown that probiotics lower the risk of necrotizing enterocolitis in premature infants.  Now, a study (full text link below) from India examines whether probiotics could lower other infections.

An excerpt:

Feeding babies the microbes dramatically reduces the risk newborns will develop sepsis, scientists report Wednesday in the journal Nature.

Sepsis is a top killer of newborns worldwide. Each year more than 600,000 babies die of the blood infections, which can strike very quickly…

Babies who ate the microbes [Lactobacillus plantarum] for a week — along with some sugars to feed the microbes — had a dramatic reduction in their risk of death and sepsis. They dropped by 40 percent, from 9 percent to 5.4 percent.

But that’s not all. The probiotic also warded off several other types of infections, including those in the lungs. Respiratory infections dropped by about 30 percent…

The only significant side effect seen in the study was abdominal distension, which occurred in six babies. But there were more cases reported in the placebo group than in the group that got the probiotic.

Full text link (thanks to Kipp Ellsworth’s twitter feed for this link): A randomized synbiotic trial to prevent sepsis in newborns in rural India. P Panigrahi et al.

My take: Whether probiotics would be useful broadly in full-term infants in developed countries is uncertain –more studies are needed.

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“ProCESS” for Improvement or Reason for Caution

“There is no such thing as the world of letters apart from the world of men…The scholar without this vision is a pedant.  He mistakes learning for an end in itself, instead of seeing that it is only a weapon in a wise man’s hands.” (Seth Low, 1890 -quoted in NEJM 2014; 370: 1679).

While sepsis, “the syndrome of dysregulated inflammation that occurs with severe infection,” is not frequent among pediatric gastroenterology patients, it does occur. Pediatric GI patients at risk include patients receiving immunosuppression medications, patients with inflammatory bowel disease, and patients with central lines.  So, it is not simply an academic exercise to understand the efforts to improve sepsis treatment. A recent study and related editorials discuss the role for protocols in treating sepsis, and likely have broader implications [NEJM 2014; 370: 173-76 (editorial- ), 1683-93 (article- ), 1750-51 (editorial- )].

Overall, sepsis was reported as the 11th leading cause of death in the U.S. in 2010 and was the single most expensive condition treated in hospitals.  Nevertheless, the diagnosis is in part subjective and these statistics rely on insurance claims.

Key points:

  • Policymakers in New York require hospitals to adopt sepsis protocols (“Rory’s regulations”) following the death of a 12 year-old boy who died from unrecognized sepsis.  Other agencies, like the National Quality Forum (NQF), have recommended this as well. The Centers for Medicare and Medicaid is considering whether to adopt the NQF metric.
  • The ProCESS (Protocolized Care for Early Septic Shock) study (31 centers) enrolled 1341 patients (average age 61 years) into 3 randomized separate arms: protocol-based goal-directed therapy bundle, protocol-based standard therapy, and usual care. Conclusion: protocol-based resuscitation did not improve outcomes.
  • Sepsis mandates are not without risks.  Overdiagnosis can lead to unwarranted antibiotics, excessive testing, excessive blood transfusions, diversion of scarce ICU resources, and complications from central line placement.
  • Two more multicenter studies are underway (ARISE and ProMISE) which will further determine the utility of protocoled sepsis care

While the ProCESS trial did not identify improvements in protocol-driven care, most patients (76%) in all three groups received antimicrobials by the time of randomization (mean of ~3 hours).  Thus, early recognition of sepsis with treatment, particularly antibiotics and volume resuscitation, remain critical.  The editorial (pg 1750) imparts some useful advice from Machiavelli: “the physicians say it happens in hectic fever, that in the beginning of the malady it is easy to cure but difficult to detect, but in the course of time, not having been either detected or treated in the beginning, it becomes easy to detect but difficult to cure.”

Neutrophil function as a biomarker for Acute Liver Failure

More data on impaired neutrophil function in acute liver failure (ALF) and subacute liver failure (SALF) is available (Hepatology 2013; 57: 1142-52).

This study examined 15 ALF patients and 10 SALF patients in a cross-sectional case-control cohort design who were admitted to the liver ICU at King’s College Hospital between 2008-2010.  The median age for the ALF group was 33 and for the SALF group it was 52.5.  Ultimately 10 survived without liver transplantation; the remainder either died or underwent liver transplantation.

Neutrophil function was assessed on admission and then serially every 3-4 days in several ways; these assays were compared with 6 septic controls and 11 healthy controls.  Phagocytic activity was measured with a “Phagotest,” which quantifies opsonization of labeled E. coli. Oxidative burst was measured with the “Burtest,” which determines the percentage of phagocytic cells that produce a reactive oxygen species.  Other tests examined neutrophil phenotype and cytokine measurements (TNF-α, IL-1β, IL-6, CXC8/IL-8, IL-10, and IL-17).

Key findings:

  • Impaired neutrophil phagocytic activity in both ALF and SALF cohort on admission predicted non survival without liver transplant (p=0.01).
  • Neutrophil expression of CD-16 was significantly reduced in ALF cohort on day 1 (p<0.001).

Take-home message:

This study demonstrates specific defects in neutrophil function in ALF/SALF that are similar to impaired bactericidal function in severe sepsis.  Neutrophil function assays, while not available at the bedside at this time, are important biomarkers in ALF/SALF for increased susceptibility for sepsis and death.

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Hepcidin for sepsis recognition

While this blog has discussed hepcidin’s essential role in iron homeostasis (see below), it performs well as a marker of sepsis as it is also an acute phase reactant (J Pediatr 2012; 162: 67-71).

Hepcidin is known to contribute to host defense by depriving microbes of access to iron and through direct antimicrobial properties.  In this study, the authors compared the performance of hepcidin to C-reactive protein (CRP) from the serum of 44 infants with late-onset sepsis.  Specimens were obtained in the acute and convalescent periods.


  • Hepcidin levels were increased 4-fold in infants with sepsis compared without infants who were not septic (P<.0001).  Levels returned to normal following therapy.
  • Hepcidin levels >92.2 ng/mL correctly identified 91% of all infants (PPV 100%, NPV 87%, specificity 100%, sensitivity 76%)
  • Models combining hepcidin with CRP did not perform better than hepcidin alone.
  • Hepcidin values were comparable to CRP, and possibly more useful.  The authors stated that a CRP value of >7.95 mg/dL had a PPV of 89%, NPV 74%, specificity of 96%, and sensitivity of 47%.
  • Hepcidin has been reported to peak at 6 hours after interleukin-6 injection in humans whereas CRP peaks 24-48 hours after an inflammatory stimulus.

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