Helicobacter pylori infection and extragastric disorders in children: A critical update

Table 1 Association between Helicobacter pylori and iron stores in children: clinical and intervention studies

Study and study design	Study population	H. pyloridetection	Intervention	Outcome: evaluation	Outcome: results
Choe et al[18] 1999, South Korea; Randomized double-blind, placebo-controlled trial	22 children with IDA and H. pylori infection	EGDS	Group A (n = 8): 2-wk triple eradication therapy and 10-wk oral ferrous sulfate; Group B (n = 5): 2-wk triple eradication therapy and10-wk placebo iron; Group C (n = 7): 2-wk placebo eradication therapy and 10-wk oral ferrous sulfate	Follow-up of 18 children (group A, n = 6; group B, n = 5; group C, n = 7): changes in iron, Hb, SF, TIBC at 4 and 8 wk after the end of eradication therapy	At 8 wk, Hb significantly increased in all groups. No significant changes in iron, TIBC and SF occurred in any group
Choe et al[56] 2000, South Korea; Open therapeutic trial	13 adolescents with sideropenic refractory anemia and H. pylori antral gastritis	EGDS	All 13 children received 2-wk triple eradication therapy and 6-wk oral ferrous sulfate	Follow-up of 11 adolescents: changes in Hb and SF 4 wk after the end of eradication therapy	At 4 wk Hb and SF significantly increased
Choe et al[17] 2001, South Korea; Open therapeutic trial	21 adolescent athletes with IDA and H. pylori infection	EGDS	12 received 2-wk triple eradication therapy; 9 received 10-wk oral ferrous sulfate	Follow-up of 21 adolescents: changes in iron, Hb, SF, TIBC 10 wk after the start of either therapy	Hb, iron, SF increased significantly only in the athletes who received eradication therapy
Kurekci et al[62] 2005, Turkey; Clinical trial	140 H. pylori-infected children	SAT,14C UBT	All 140 children (18 with IDA, 36 with ID, 86 controls) received 2-wk triple eradication therapy	Follow-up of 140 children: changes in Hb,SF, and MCV 4 wk after completion of eradication therapy	SF significantly increased in all groups; Hb and MCV values significantly increased only in IDA group
Mahalanabis et al[63] 2005, India; Randomized double-blind, placebo-controlled trial	169 asymptomatic children: 85 H. pylori–positive, 84 H. pylori -negative	13C UBT	86 (42 H. pylori-positive, 44 H. pylori–negative) received 8-wk ferrous fumarate; 83 (43 H. pylori-positive, 40 H. pylori–negative) received 8-wk placebo	Follow-up of 84 iron supplemented (42 H. pylori -positive and 42–negative) and 83 placebo children (43 H. pylori-positive and 40 –negative): changes in Hb, Ht, and SF after 8 wk of iron supplementation or placebo	In iron-supplemented group, SF improved in both H. pylori-positive and –negative children, while Hb and Ht significantly increased only in those H.pylori-negative; In the placebo group, no significant changes in Hb, Ht, and SF occurred regardless of H. pylori status
Gessner et al[67] 2006, Alaska; Randomized controlled household open trial	219 children with ID and H. pylori infection	13C UBT	106 (intervention group) received 2-wk triple eradication therapy and 6-wk iron sulfate; 113 (control group) received 6-wk iron sulfate	In intervention group, 104, 94 and 94 children were, respectively, assessed 2, 8 and 14 mo after treatment initiation for ID and anemia; In control group, 110, 109 and 107 children were, respectively, assessed 2, 8 and 14 mo after completion of iron supplementation for ID and anemia	At 14 mo, 65% and 72% of children in the intervention and control groups had, respectively, ID [AAR, 0.90 (95% CI,0.74-1.1)]; and 22% and 14% of children in the intervention and control groups had, respectively, anemia [AAR, 1.6 (95% CI, 0.86-2.9)].Results were similar when children were compared by H. pylori infection status
Sarker et al[66] 2008, Bangladesh; Randomized double-blind, placebo controlled trial	200 asymptomatic children with H. pylori infection and IDA (n = 141) or ID (n = 59); 60 uninfected children with IDA (n = 49) or ID (n = 11)	13C UBT	Regimen 1 (n = 50): 2-wk triple eradication therapy and 90-d ferrous sulfate; Regimen 2 (n = 50): 2-wk triple eradication therapy and 90-d placebo iron; Regimen 3 (n = 49): 2-wk placebo eradication therapy and 90-d ferrous sulfate;Regimen 4 (n = 51): 2-wk placebo eradication therapy and 90-d placebo iron; Uninfected controls: 90-d iron therapy alone	Follow-up of 190 infected (regimen 1, n = 47; regimen 2, n = 49; regimen 3, n = 45; regimen 4, n = 49) and 55 uninfected children: changes in Hb, SF and sTfR 3 mo after the initiation of therapy	Improvements in Hb, SF and sTfR were significantly greater in children who received iron therapy (regimens 1 and 3; negative control group) compared with the 2 other groups who did not receive iron (regimens 2 and 4);No differences in Hb, SF and sTfR values between children who remained positive and those who eradicated H. pylori
Fagan et al[68] 2009, Alaska; Randomized controlled household open trial	219 children with ID and H. pylori infection	13C UBT	106 (intervention group) received 2-wk triple eradication therapy and 6-wk iron sulfate; 113 (control group) received 6-wk iron sulfate	In intervention group, 104, 94, 94 and 85 children were, respectively, assessed 2, 8,14 and 40 mo after treatment initiation for ID and anemia; In control group, 110, 109,107 and 91 children were, respectively, assessed 2, 8 ,14 and 40 mo after completion of iron supplementation for ID and anemia	Control and intervention groups had similar temporal trends regarding ID,anemia, and IDA.When groups were compared according to H. pylori infection status at 40 mo, children without H. pylori demonstrated better resolution of outcomes
Duque et al[65] 2010, Mexico; Randomized placebo- controlled trial	69 children with ID/anemia: 33 H. pylori-infected in whom the organism was eradicated; 36 uninfected children	13C UBT	After completion of eradication, 17 received 12-wk ferrous sulfate, 16 children 12-wk placebo iron; Uninfected controls: 12-wk ferrous sulfate	Follow-up of 33 H. pylori-infected children in whom the organism was eradicated, and 36 uninfected children: changes in Hb and SF after completion of the 12- wk regimen	Compared to uninfected iron-supplemented controls, only children who eradicated H. pylori and received iron supplementation showed an increased Hb concentration. A significant SF increase occurred only in uninfected iron-supplemented controls compared to placebo group
Cardenas et al[44] 2011, Texas- United States; Randomized double-blind, placebo-controlled trial	110 asymptomatic children with H. pylori-infection	IgG antibodies, 13C UBT	32 received both quadruple sequential therapy and 6-wk iron supplementation; 29 quadruple eradication only; 23 iron supplementation only; 26 placebo only	Intent-to-treat (n = 110) and per protocol (n = 90) analyses:changes in Hb,SF, and TrS at 8 mo from baseline	Intent-to-treat and per-protocol analyses revealed no differences across study arms in changes of iron stores. However, children who eradicated the infection had a statistically significant larger increase in SF than children who remained infected
Xia et al[64] 2012, China; Randomized double-blind, controlled trial	80 adolescents with IDA and H. pylori infection	IgG antibodies, SAT	37 (intervention group) received 2-wk triple eradication therapy and 12-wk iron supplementation; 43 (control group) received 12-wk iron supplementation alone	Follow-up of 74 children: changes in Hb, SF, and sTfR 3 mo after completion of the 12-wk regimen	Hb and SF values were increased only in the intervention group. sTfR was significantly decreased in both the intervention and control groups

H. pylori: Helicobacter pylori; IDA: Iron deficiency anemia; EGDS: Esophagogastroduodenoscopy; Hb: Hemoglobin; TIBC: Total iron-binding capacity; SF: Serum ferritin; SAT: Stool antigen test; UBT: Urea breath test; ID: Iron deficiency; MCV: Erythrocyte mean corpuscular volume; Ht: Hematocrit; ARR: Adjusted relative risk; sTfR: Serum transferrin receptor; TrS: Transferrin saturation.

Table 2 Baseline clinical features of children with chronic idiopathic thrombocytopenic purpura

Study	No. of patients	Male/female	Disease duration	Concomitanttherapy1	Diagnosis ofH. pyloriinfection	No. of infected children	No. of infected untreated children	Age of infected children, yr		Age of uninfectedchildren, yr	PLT count (× 109/L) among treatedH. pylori-positive/No. of children	PLT count (× 109/L) amongH. pylori-negative/No. of children	PLT count (× 109/L) among untreatedH. pylori-positive/No. of children
Jaing et al[95] 2003, Taiwan	22	13/9	29 ± 26 mo	13/22	Stool antigen	9	0	5 (1-13.5)		8.7 (1.8-17.3)	< 50/9	50-99/3 < 50/10	-
Rajantie et al[96] 2003, Finland	17	7/10	3.9 (0.6-14.5) yr	NR	H. pylori antibodies and/or 13C UBT	0	0		3.82 (0.3-14.3)		-	-	-
Hayashi et al[97] 2005, Japan	10	6/4	4.2 ± 3.2 yr	NR	Stool antigen and/or 13C UBT	2	1	9 (7-11)		9 (4-14)	50-99/1	50-99/4 < 50/4	< 50/1
Yetgin et al[98] 2005, Turkey	35	NR	≥ 2 yr	NR	H. pylori antibodies and/or histology/13C UBT	11	0	NR	NR	NR	< 50/11	< 50/24	-
Loffredo et al[99] 2007, Italy	39	13/26	> 6 mo	-	H. pylori antibodies, 13C UBT, or stool antigen	8	0		112 (4.4-17)		< 100/8	< 100/31	-
Neefjes et al[100] 2007, Netherlands	47	18/29	> 1 yr	-	Stool antigen	3	0		≤ 162		< 100/3	< 100/44	-
Wu et al[101] 2007, Taiwan	32	18/14	NR	32/32	Stool antigen	6	6	5.13 (1.9-9.8)		4.13 (0.2-13.5)	-	8.8 ± 11.3/26	5.5 ± 4.7/6
Bisogno et al[102] 2008, Italy	24	9/15	1.2 (0.6-24) yr	-	Stool antigen, 13C UBT	8	0	13.2 (4.6-25.1)	12.52 (2-25.1)	10.8 (2-16.5)	< 50/8	50-99/3 < 50/13	-
Hamidieh et al[103] 2008, Iran	31	14/17	2.3 ± 1.7 yr	NR	13C UBT	4	0		8.923 (3.5-14)		100/1 < 50/3	NR	-
Treepongkaruna et al[105] 2009, Thailand	16	7/9	1.2-9.5 yr	9/16	13C UBT	164	9	7.4 -16.5			23 (3.0-84.0)/7	-	34 (3.0-86.0)/9
Ferrara et al 2009[104], Italy	24	14/10	1.8 (1.3-2.3) yr	-	Stool antigen	8	0	7.5 (6.7-10.2)		7.8 (5.4-10.7)	29.8 ± 3.8/8	33.5 ± 3.8/16	-
Russo et al 2011[106], Italy	37	12/25	> 1 yr	-	Stool antigen	374	-	12.3 ± 4.3513.6 ± 2.96	-	-	26.5 ± 22.3/33527.7 ± 22.3/46	-	-

Results are given as mean plus or minus standard deviation, or as median (range), unless otherwise noted.

¹Concomitant therapy included steroids or other immunosuppressive therapies;

²Age of all patients;

³Mean (range);

⁴This series included only infected patients;

⁵Children with successful eradication;

⁶Children with unsuccessful eradication. PLT: Platelet; H. pylori: Helicobacter pylori; NR: Not reported.

Table 3 Follow-up and platelet response to Helicobacter pylori eradication therapy among children with chronic idiopathic thrombocytopenic purpura

Study	Follow-up	Bacterialeradication	PLT count (× 109/L) among treatedH. pylori-positive with eradication success/No. of children	PLT count (× 109/L) among treatedH. pylori-positive with eradication failure/No. of children	PLT count (× 109/L) among untreatedH. pylori-positive/No. of children	PLT count (× 109/L) amongH. pylori-negative/No. of children
Jaing et al[95] 2003, Taiwan	6 mo	9/9	> 150/2	-	-	50-99/4
			100-150/2			< 50/9
			50-99/1
			< 50/4
Hayashi et al[97] 2005, Japan	1 yr	1/1	> 150/1	-	NR	> 100/2
						NR/6
Yetgin et al[98] 2005, Turkey	1 yr	9/11	< 50/9	< 50/2	-	NR
Loffredo et al[99] 2007, Italy	1 yr	7/8	NA	NA	-	< 100/31
Neefjes et al[100] 2007, Netherlands	6-9 mo	3/3	≥ 100/3	-	-	51 ± 39.6/30
Wu et al[101] 2007, Taiwan	NR	-	-	-	88.2 ± 89.5/61	64.9 ± 75.8/161
						132.7 ± 74.7/92
Bisogno et al[102] 2008, Italy	6-50 mo	8/8	> 150/3	-	-	> 100/3
			< 50/5			50-99/8
						< 50/5
Hamidieh et al[103] 2008, Iran	6-11 mo	4/4	50-99/2	-	-	NR
			< 50/2
Treepongkaruna et al[105] 2009, Thailand	6 mo	7/7	> 100/1	-	> 100/1	-
			< 100/6		< 100/7
Ferrara et al[104] 2009, Italy	1 yr	8/8	≥ 150/6	-	-	50-99/7
			100-149/2			< 50/9
Russo et al[106] 2011, Italy	1 yr	33/37	> 150/7	< 50/4	-	-
			50-149/6
			< 50/20

Results are given as mean plus or minus standard deviation, or as median (range), unless otherwise noted.

¹On therapy with high-dose methylprednisolone;

²On therapy with intravenous immunoglobulin. PLT: Platelet; H. pylori: Helicobacter pylori; NR: Not reported.