Kobe J. Med. Sci.,

Vol. 67, No. 1, pp. E7-E9,2021

Markedly Elevated Procalcitonin in Food Protein InducedEnterocolitis Syndrome
ISSEI KONO1,*, MITSUHIRO OKAMOTO1, SHINTARO INOUE1,and YUYA TANAKA2
1

Department of Pediatrics, Hyogo Prefectural Tamba Medical Center, Japan
Department of Allergy, Hyogo Prefectural Kobe Children’s Hospital, Japan*Corresponding author

2

Received 17 November 2020/ Accepted 6 January 2021
Keywords: milk, oral food challenge test, bacterial sepsis, C-reactive protein
Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal foodallergy. Some studies have reported that FPIES was associated with elevated C-reactive protein (CRP).
However, the number of reports on the relationship between FPIES and procalcitonin (PCT) is limited.
This case report highlights the fact that PCT levels can be markedly elevated in patients with acute FPIES.
An 11-month-old girl previously diagnosed with FPIES underwent an oral food challenge test (OFC). Her
serum PCT levels were measured after she developed severe symptoms including fever and shock
following administration of 100mL of formula milk. The PCT levels were extremely elevated but
improved without antibiotics the next day. The fact that serum PCT levels may be significantly elevated inFPIES means that differentiating severe FPIES from sepsis could be more challenging than waspreviously thought.
INTRODUCTION
Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal (GI) foodallergy that typically presents during infancy(7). Acute FPIES causes vomiting, diarrhea, and/or bloody stools.
Furthermore, approximately 15% of patients with acute FPIES present with shock and require aggressive fluid
resuscitation(7). Such patients are often transported to emergency departments and misdiagnosed with sepsis.
The laboratory data findings in acute FPIES are nonspecific. Some studies have reported that FPIES wasassociated with neutrophilia, thrombocytosis, methemoglobinemia, metabolic acidosis, and elevated C-reactive
protein (CRP). However, the number of reports on the relationship between FPIES and procalcitonin (PCT) islimited. Here, we report a case of FPIES in which the patient presented with fever, shock, and highly elevated
PCT levels that were caused by the administration of infant formula milk.
CASE REPORT
A female neonate, who was born at 37 weeks and 5 days of gestation and weighed 3318 g, was administeredformula milk 6 hours after birth. Mildly bloody stools were observed 13 hours after birth. The same formula
milk was continued under close monitoring. The bloody stools subsided temporarily on day 3. On day 9,
however, she again developed bloody stools accompanied by vomiting, weight loss (2976 g on day 9), metabolic
acidosis (venous blood gas: pH 7.264, pCO2 40.7 mmHg, HCO3 18.0 mEq/l), and an elevated CRP (10.2 mg/L).
After the formula milk was changed to an amino-acid-rich elemental diet, Elental® P (EA Pharma, Tokyo, Japan),her symptoms improved. At 2 months of age, she underwent an oral food challenge test (OFC) with 100 mL of
the same formula milk that had caused the original GI symptoms. The result of the OFC was positive, andvomiting was observed 4 hours after ingestion of the formula milk. Since she was in a stable condition aftervomiting, sepsis was not suspected and blood tests were not done. The allergen-specific lymphocyte stimulation
test was positive, and the maximum reaction (count per minute/stimulation index) for lactoferrin and β casein
was 3395/7.45 and 3382/7.42, respectively (control reaction 456). A skin prick test for milk allergens wasnegative. Therefore, she was diagnosed with FPIES due to formula milk. At 11 months of age, she underwent a
second OFC using the same amount of formula milk. After the test, she developed fever, tachycardia, vomiting,diarrhea, pallor, and a mildly reduced level of consciousness. The clinical and laboratory data on the day after
the second OFC test are shown (Table I). Of particular note are the markedly elevated serum PCT levels.
Antibiotics were not prescribed at this point, and after adequate administration of intravenous fluid, her condition
improved the following day.
Written informed consent was obtained from the patient for publication of this case report and accompanying
images.
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I. KONO et al.
Table I

Clinical and laboratory data

23 hours after OFC

38 hours after OFC

Vital signs
Axillary temperature (°C)
Heart rate (bpm)

38.1
187

36.8
118

Complete blood countWhite blood cells (/µL)
Segmented (%Leukocytes)
Stab (%Leukocytes)
Eosinophils (%Leukocytes)
Hemoglobin (g/dL)

14,960
64.5
2.0
2.0
13.5

14,020
36.5
1.5
0.0
10.2

Blood biochemistry
CRP (mg/L)
PCT (ng/mL)
BUN (mg/dL)
Creatinine (mg/dL)

106.3
91.99
56.1
0.54

35.3
39.86
22.4
0.35

Venous blood gas
pHpCO2 (mmHg)
HCO3 (mmol/L)
Methemoglobin (%)

7.325
30.3
15.3
2.4

7.425
30.5
19.7
0.7

Stool test
Fecal occult blood

Positive

Stool antigen test
Rotavirus
Adenovirus
Norovirus

Negative
Negative
Negative

Bacteriological examination
Blood culture

NegativeDISCUSSION
This case suggests that serum PCT may be markedly elevated in FPIES. Unlike IgE-related food allergies,
FPIES can be accompanied by fever and elevated CRP. Fever is observed in 13% of FPIES patients at initialpresentation(7). Moreover, 61.1% and 33.3% of FPIES cases show increased CRP and CRP levels >20 mg/L,
respectively(4). Additionally, elevated CRP levels were observed in FPIES patients who presented with fever(4).
Fever and elevated CRP levels often indicate infection and sepsis, which is one of the main differential
diagnoses of FPIES. PCT, on the other hand, has been proposed as a more characteristic marker of systemic
inflammation than CRP(8). However, there have been only two international reports on FPIES with elevated
PCT till date(2,9). In this clinical case, the PCT levels observed were much higher than those reported in thosestudies (3.84 ng/mL and 15.58 ng/mL)(2,9). Differentiating severe FPIES from sepsis could be more challenging
than was previously thought, in other words, patients with FPIES who present with fever and a high PCT are
more likely to be misdiagnosed with sepsis.
It is unclear how FPIES leads to elevated PCT levels. A recent paper reported that interleukin-6 (IL-6) waselevated 6 hours after ingesting allergenic food in patients with FPIES(1). PCT levels increase in the presence ofpro-inflammatory cytokines, such as IL-1, IL-6, or tumor necrosis factor α. This is most likely due to inhibitionof PCT proteolysis(5). These cytokines are also involved with raised CRP levels and CRP levels are known to beelevated in FPIES. A similar mechanism is presumably responsible for the increase in PCT levels. On the otherE8

HIGH PCT IN FPIES
hand, PCT is reported to be more accurate for the diagnosis of sepsis than CRP(10). However, it should be notedthat no matter how high the PCT is, there are cases of non-sepsis, as in this case.
In this case, serum PCT levels were not taken prior to the OFC due to the infant being in good generalcondition at the time. The PCT levels were confirmed as decreased on the second day after the OFC without
antibiotics. From this clinical course, it is almost certain that the increase in PCT value was due to the formulamilk.
A variety of protocols for FPIES-related OFCs have been published(7). The current consensus is toadminister the challenge food at a dose of 0.06 to 0.6 g (usually 0.3 g) of the food protein per kilogram of bodyweight. Although low dose OFCs are safer, patients have to undergo repeated OFCs, which increases hospitalvisits. In this case, due to family circumstances, the patient's parents opted for a single high dose OFC. Througha process of fully informed consent and shared decision-making, a dose of 0.6 g of milk protein per kilogram ofbody weight (100mL of formula milk) was chosen for the first OFC. There is data that suggests that in patientswith milk-induced FPIES, 60% develop tolerance by 1 year of age(3). For this reason, the same amount offormula milk (100mL) was prepared for the second OFC. As a result, both doses were near the upper limit of therecommended dosage range. According to Japanese FPIES consensus recommendations, performing serial OFCs
daily over the course of two weeks with a starting milk load of 0.5 mL/kg and increasing gradually to 20 mL/kg
is thought to be safer than a single high dose OFC(6). It is possible that this patient’s severe reaction may havebeen prevented using this low dose OFC strategy.
In conclusion, PCT may be highly elevated in patients with FPIES. It is difficult to distinguish FPIES fromsepsis by examining laboratory data alone, and FPIES should be considered as a differential diagnosis in patientswith markedly elevated PCT levels.
ACKNOWLEDGMENTS
None of the authors has any conflicts of interest or any financial ties to disclose.
The authors would like to thank Noel Hauser, Hyogo Prefectural Tamba Medical Center, for providing
constructive advice and Editage (www.editage.com) for English language editing.
REFERENCES
1.

Doi, M., Matsubara, Y., Iwakoshi., N., and Furuichi, Y. 2019. Food protein-induced enterocolitis
syndrome caused by egg yolk in an infant. Pediatr Int 61: 411-31.
2. Jędrzejczyk, M., Bartnik, K., Funkowicz, M., and Toporowska-Kowalska, E. 2020. Locust bean gum
induced FPIES in infant. J Investig Allergol Clin Immunol 30: 197-9.
3. Katz, Y., Goldberg, M.R., Rajuan, N., Cohen, A., and Leshno, M. 2011. The prevalence and natural
course of food protein-induced enterocolitis syndrome to cow's milk: a large-scale, prospective
population-based study. J Allergy Clin Immunol 127: 647-53.
4. Kimura, M., Ito, Y., Tokunaga, F., Meguro, T., Shimomura, M., Morishita, H., et al. 2016. Increased
C-reactive protein and fever in Japanese infants with food protein-induced enterocolitis syndrome. Pediatr
Int 58: 826-30.
5. Maruna, P., Nedelníková, K., and Gürlich, R. 2000. Physiology and Genetics of Procalcitonin. Physiol
Res 49 Suppl 1: S57-61.
6. Nomura, I. principal investigator. 2017. Consensus Recommendations for diagnosis and treatment ofNon-IgE mediated Gastrointestinal Food Allergy in Neonates and Infants (Internet). Setagaya: NationalCenter for Child Health and Development (cited 2017 Nov 11). Available from:https://www.ncchd.go.jp/hospital/sickness/allergy/shokakan_shishin20171111.pdf.
7. Nowak-Wegrzyn, A., Chehade, M., Groetch, M.E., Spergel, J.M., Wood, R.A., Allen, K., et al. 2017.
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis
syndrome: Executive summary-Workgroup Report of the Adverse Reactions to Foods Committee,
American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol 139: 1111-26.e4.
8. Pontrelli, G., De Crescenzo, F., Buzzetti, R., Jenkner, A., Balduzzi, S., Calò Carducci, F., et al.
2017.
Accuracy of serum procalcitonin for the diagnosis of sepsis in neonates and children with systemic
inflammatory syndrome: a meta-analysis. BMC Infect Dis 17: 302.
9. Ribeiro, A., Moreira, D., Costa, C., Pinto, and Pais, I. 2018. Food protein-induced enterocolitis
syndrome: a challenging diagnosis. BMJ Case Rep 2018: bcr2017222822.
10. Liu, Y., Hou, J., Li, Q., Chen, K., Wang, S., and Wang, J. 2016. Biomarkers for diagnosis of sepsis inpatients with systemic inflammatory response syndrome: a systematic review and meta-analysis.
Springerplus 5: 2091.

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