Alimentary Pharmacology and Therapeutics

Non-Helicobacter pylori gastritis is common among paediatric

patients with inammatory bowel disease
R. M. Genta*,, & A. Sonnenberg,

*Miraca Life Sciences, Irving, TX,

USA.

University of Texas Southwestern

Medical Center, Dallas, TX, USA.

Dallas VA Medical Center, Dallas,

TX, USA.

Portland VA Medical Center,

Portland, OR, USA.

Oregon Health & Science University,

Portland, OR, USA.

Correspondence to:
Dr A. Sonnenberg, Gastroenterology,
Portland VA Medical Center P3-GI,
3710 SW U.S. Veterans Hospital
Road, Portland, OR 97239, USA.
E-mail: sonnenbe@ohsu.edu

Publication data
Submitted 10 February 2012
First decision 10 March 2012
Resubmitted 11 March 2012
Accepted 15 March 2012
EV Pub Online 9 April 2012

SUMMARY
Background
Helicobacter-negative gastritis and duodenitis occur more often in patients
with inammatory bowel disease (IBD) than in non-IBD controls. Preliminary evidence suggests that they are particularly common among
children.
Aim
To study the age-specic occurrence of gastritis and duodenitis among paediatric IBD patients.
Methods
From a computerised database of surgical pathology reports, we selected
344 IBD patients and 4241 non-IBD controls between the age 0 and
21 years, who underwent colonoscopy and oesophago-gastro-duodenoscopy
with biopsy results from both procedures.
Results
Helicobacter-negative chronic active gastritis was found in 2% of controls
and 20% of IBD patients (Crohns disease (CD) 26%, ulcerative colitis (UC)
13%). Duodenitis was found in 2% of controls and 17% of IBD patients
(Crohns disease 28%, UC 8%). Similar prevalence rates were observed in
male and female patients. The most striking age-specic patterns were seen
in Crohns disease, with chronic active gastritis being highest in the 5
9 years age-group and declining in all subsequent age-groups. The agespecic rise and fall of duodenitis appeared more protracted, reaching a
peak at age 1014 years and then gradually declining.
Conclusions
Helicobacter-negative gastritis and duodenitis occur signicantly more often
in paediatric IBD patients than in non-IBD controls, as well as in adult
IBD patients. Such upper gastrointestinal inammation appears to be particularly common in patients with Crohns disease.
Aliment Pharmacol Ther 2012; 35: 13101316

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Published 2012. This article is a US Government work and is in the public domain in the USA.
doi:10.1111/j.1365-2036.2012.05090.x

Gastritis in paediatric IBD

INTRODUCTION
Inammatory bowel disease (IBD) is associated with the
occurrence of chronic active gastritis unrelated to an
infection with Helicobacter pylori. This type of gastritis is
typically characterised by inltration of the mucosa with
neutrophils, lymphocytes and histiocytes.112 In
instances, when these inammatory inltrates cluster
around groups of few gastric glands, pathologists have
also used the term focally enhanced gastritis,6 although
the less focal form with the general features of H. pylorinegative chronic active gastritis (Hp-negative gastritis) is
probably more common in IBD patients. The Hp-negative gastritis affects 1060% of patients with Crohns disease (CD), and 520% of patients with ulcerative colitis
(UC). By contradistinction, the prevalence of Hp-negative gastritis in the general population is less than 2%.
Some authors have reported an even higher prevalence
of Hp-negative gastritis among paediatric IBD patients,10
although other studies have contested such ndings.13
Using a large national database of pathology reports, in
a previous study, we found Hp-negative gastritis in 17%
of patients with CD and 4% of patients with UC.14
Among paediatric IBD patients, these proportions were
25% and 40% respectively. Our previous study was limited, however, by the relatively small group of 242 paediatric patients, of whom only 26 carried a diagnosis of
IBD. The aim of the present study therefore was to
assemble a much larger group of paediatric patients, who
underwent upper and lower gastrointestinal endoscopy
with biopsies, and to compare the occurrence of various
forms of gastritis among IBD patients and non-IBD controls. We were particularly interested in the age-specic
distribution of Hp-negative chronic active gastritis in the
paediatric population. We hypothesised that the prevalence of Hp-negative chronic active gastritis would be
higher among paediatric IBD cases than among non-IBD
controls, as well as among adult IBD patients.
MATERIALS AND METHODS
Data source
The present study was conducted at the Gastrointestinal
Division of Miraca Life Sciences, a specialised referral
pathology laboratory that receives biopsy specimens from
private outpatient endoscopy centres throughout the
Unites States. The laboratory includes a group of 29
pathologists who share a common approach to biopsy
evaluation. Uniformity among pathologists is maximised
through a standardised approach to specimen handling
and a predetermined set of diagnostic criteria and

terminology for biopsy reading. Consensus is maintained

and updated through daily multi-headed microscope
conferences, frequent didactic conferences, a journal
club, a terminology review committee and ongoing comprehensive quality assurance review. The results of all
surgical pathology cases are stored in a single electronic
database. In addition to histopathological ndings, the
database contains the patients demographic characteristics, clinical diagnoses and endoscopic impressions
included with the specimen requisitions.
The study was approved by the Miraca Life Sciences
Institutional Review Board. All data of the study were
collected exclusively by reviewing pre-existing records,
and no direct contact with either patients or providers
was made. No information from any individual patient
was revealed and all patient records were de-identied
before being included in the present analysis. For these
reasons, the study protocol was exempted from the need
for informed consent from its participants.

Patient selection
From a database of 1 272 273 colonoscopies with biopsies between January 2001 and October 2011, we rst
extracted 12 774 procedures among 12 214 unique
patients aged 0 through 21 years. From this population,
we then extracted a subgroup of 1 639 IBD patients with
398 cases of CD, 912 of UC and 329 of indeterminate
colitis (IND). The diagnosis was uncertain or the clinicopathological correlation equivocal in 830 patients, who
were excluded from all further analysis. The remaining
9745 patients were included in the initial non-IBD control group. In a subsequent step, the initial 1639 IBD
patients and the 9745 controls were matched to a database of 978 863 patients, who had an oesophago-gastroduodenoscopy (EGD) with biopsies during the same time
period. A total of 4585 unique patients were found to
have had an EGD (in addition to their colonoscopy), of
whom 344 served ultimately as IBD cases and 4241 as
non-IBD controls. Of the 344 IBD cases, 149 had CD,
120 had UC and 75 had indeterminate colitis.
Histopathological diagnostic criteria
Crohns disease, UC, or IND were diagnosed when a set
of biopsies from a colonoscopy met the histopathological
criteria for IBD as dened by the Working Group of the
North American Society for Pediatric Gastroenterology,
Hepatology and Nutrition, and the Crohns and Colitis
Foundation of America.15 The histological ndings were
correlated with the clinical and endoscopic information
provided to generate the diagnoses of UC, CD or, when

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R. M. Genta and A. Sonnenberg

the histopathology was unequivocally suggestive of IBD,
but the clinical, endoscopic and topographic information
was insufcient, indeterminate colitis.
Gastric biopsy specimens were evaluated according to
the Updated Sydney System.16 Specically, H. pylori gastritis was diagnosed when H. pylori organisms were demonstrated by a specic monoclonal immunochemical
stain (Cell Marque, Rocklin, California, USA), which has
been used in the Miraca laboratory on all gastric biopsy
specimens. Chronic active gastritis with no H. pylori was
diagnosed when the gastric mucosa showed focal or diffuse chronic inammatory inltrates (lymphocytes and
plasma cells), as well as neutrophils, inltrating the surface or foveolar epithelium, but no H. pylori organisms
were detected by the immunohistochemical stain. This
connotation also included what is sometimes referred to
as focally enhanced gastritis, a term now rarely used by
pathologists because in this context, the word enhanced
lacks semantic specicity.
Chronic inactive gastritis was diagnosed when the gastric mucosa showed focal or diffuse chronic inammatory inltrates (lymphocytes and plasma cells) in the
absence of either neutrophilic granulocytes or H. pylori.
Criteria for reactive gastropathy were based on the 2005
denition, which includes various combinations of foveolar hyperplasia, regenerative changes in the surface epithelium, oedema or hyperaemia of the lamina propria,
erosions and smooth muscle proliferation.17 For the purposes of this study, all diagnoses that included the qualiers mild or minimal were not included, as the
interobserver variation is generally unacceptably high in
these cases. Duodenitis was diagnosed when the duodenal mucosa showed active (neutrophilic) inammation in
the epithelium, which may also be eroded, irrespective of
the magnitude of the lymphoplasmocytic inltrates. Gastric foveolar metaplasia, frequently found in the inamed
duodenal mucosa, and sometimes referred to as peptic
duodenitis, was not recorded separately for the purposes
of this analysis.

Statistical analysis
The statistical analysis was carried out using the statistical software of SAS in Cary, NC, USA. The analysis was
focused on the prevalence of the histological diagnoses
among IBD patients. For the age-specic prevalence,
patients were groups into ve age-groups: 04, 59, 10
14, 1519, 2021 years. The cross table wizard of
Access (from Microsoft, Redmond, WA, USA) was used
to extract tables of the six histological diagnoses stratied
by case and control groups, patient age and gender.
The prevalence of each histological diagnosis was compared between IBD case and non-IBD control groups,
using a multivariate logistic regression to adjust for the
varying age and gender distribution of the case and
control groups. The results were expressed as age- and
gender-adjusted odds ratios with their 95% condence
intervals.
RESULTS
Table 1 contains a stratication of the patient population
by diagnosis and histopathological ndings. H. pylori
gastritis was generally uncommon in this population of
paediatric patients, but it was especially uncommon
among all patients with any type of IBD. Hp-negative
chronic active gastritis was 610 times more common in
IBD cases than in non-IBD controls. Chronic inactive
gastritis was also more common in IBD patients than in
controls, but less strikingly so than chronic active gastritis. Reactive gastropathy occurred similarly among IBD
patients and non-IBD controls. Lastly, duodenitis was
found more frequently among patients with all types of
IBD, but particularly among patients with CD. In
Table 2, the frequency of histopathological diagnosis
among cases and control subjects is compared, using
odds ratios and their 95% condence intervals. The difference between IBD cases and non-IBD-controls was
most striking for chronic active gastritis and duodenitis.
Chronic inactive gastritis was found signicantly more
frequently only in all IBD or CD alone.

Table 1 | Prevalence of various types of gastritis and duodenitis in IBD cases and non-IBD controls

Non-IBD controls
All IBD
Crohns disease
Ulcerative colitis
Indeterminate colitis
1312

Helicobacter
pylori gastritis

Chronic active
gastritis

Chronic inactive
gastritis

Reactive
gastropathy

Duodenitis

Total

120 (3%)
5 (1%)
1 (1%)
4 (3%)
0 (0%)

96 (2%)
68 (20%)
39 (26%)
16 (13%)
13 (17%)

407 (10%)
51 (15%)
26 (17%)
15 (13%)
10 (13%)

220 (5%)
18 (5%)
8 (5%)
7 (6%)
3 (4%)

75 (2%)
57 (17%)
42 (28%)
10 (8%)
5 (7%)

4241
344
149
120
75

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Gastritis in paediatric IBD

Table 3 shows the age-specic stratication of the
paediatric IBD population. As one might have expected,
the number of patients increased with increasing age.

Except for the youngest age-group, each age-group was

populated by a fair number of patients. Figure 1 contains
the age-specic prevalence of each gastritis type in non-

Table 2 | Association of histological diagnosis with clinical diagnosis

All IBD
Crohns disease
Ulcerative colitis
Indeterminate colitis

H. pylori gastritis

Chronic active
gastritis

Chronic inactive
gastritis

Reactive
gastropathy

Duodenitis

0.49
0.23
1.12
0.00

10.74
15.09
6.26
8.66

1.71
2.02
1.46
1.55

1.00
1.06
1.10
0.75

10.73
21.03
4.78
3.86

(0.171.09)
(0.011.03)
(0.342.73)
(0.000.00)

(7.6215.07)
(9.8322.86)
(3.4210.81)
(4.4115.89)

(1.232.33)
(1.283.08)
(0.812.47)
(0.742.92)

(0.591.60)
(0.472.05)
(0.462.23)
(0.182.03)

(7.3815.55)
(13.6332.19)
(2.259.19)
(1.329.03)

Odds ratios and their 95% condence interval, adjusted for age and gender.

Table 3 | Age-specic prevalence of various types of gastritis and duodenitis in IBD

Helicobacter
pylori gastritis

Chronic active
gastritis

Chronic inactive
gastritis

Reactive
gastropathy

Duodenitis

Total

04
59
1014
1519
2021
Total

0 (0%)
0 (0%)
0 (0%)
2 (1%)
3 (3%)
5 (1%)

1 (33%)
9 (53%)
17 (35%)
25 (15%)
16 (14%)
68 (20%)

0 (0%)
1 (6%)
9 (19%)
28 (17%)
13 (11%)
51 (15%)

0 (0%)
0 (0%)
3 (6%)
6 (4%)
9 (8%)
18 (5%)

0 (0%)
3 (18%)
10 (21%)
30 (19%)
14 (12%)
57 (17%)

3
17
48
162
114
344

Gastritis prevalence (%)

Age-group

60

Controls

CAG
40

40
DUO

20

20

CIG

RG
Hp

0
04

Gastritis prevalence (%)

CD

60

59

IND

60

04

1014 1519 2021

60

40

40

20

20

59

1014 1519 2021

UC

0
04

59

1014 1519 2021

Age group

04

59

1014 1519 2021

Age group

Figure 1 | Age-specic prevalence of Helicobacter pylori-negative chronic active gastritis (CAG), chronic inactive
gastritis (CIG), reactive gastropathy (RG), duodenitis (DUO), and H. pylori-positive gastritis (Hp) in non-IBD controls,
patients with Crohns disease (CD), indeterminate colitis (IND) and ulcerative colitis (UC).
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R. M. Genta and A. Sonnenberg

Gastritis prevalence (%)

80

80
F-IBD

60
40

40

20

20

M-IBD

CAG

DUO

CIG

RG
Hp

0
04

59

1014 1519 2021

80
Gastritis prevalence (%)

60

04

59

1014 1519 2021

80
M-Controls

F-Controls
60

60

40

40

20

20
0

0
04

59

1014 1519 2021

Age group

04

59

1014 1519 2021

Age group

Figure 2 | Age-specic prevalence of Helicobacter pylori-negative chronic active gastritis (CAG), chronic inactive
gastritis (CIG), reactive gastropathy (RG), duodenitis (DUO), and H. pylori-positive gastritis (Hp) in female (F) and
male (M) non-IBD controls, as well as female and male IBD patients.

IBD controls, as well as in patients with CD, indeterminate colitis, and UC. The most striking patterns were
seen in CD with chronic active gastritis being highest in
the 59 years age-group and declining in all subsequent
age-groups. Compared with chronic active gastritis, the
age-specic rise and fall of duodenitis appeared more
protracted, reaching a peak at age 1014 years and then
gradually declining. Compared with non-IBD controls,
the age-specic prevalences of chronic active gastritis
and duodenitis in UC patients were both elevated. Compared with CD, however, this elevation in UC was less
dramatic and characterised by a gradual rise rather than
a sharp rise and subsequent fall. Stratied by gender, the
age-specic prevalence of gastritis and duodenitis showed
similar patterns among male and female paediatric
patients. In both gender groups alike, chronic active gastritis and duodenitis were more common among IBD
cases than among non-IBD controls (Figure 2).

DISCUSSION
The present study was undertaken to analyse the agespecic prevalence of gastritis among paediatric IBD
patients. The study conrmed our initial hypothesis that
non-Hp gastritis would be more common among IBD
patients than among non-IBD controls, as well as among
1314

adult IBD patients. The occurrence of inammatory inltrates into the upper gastrointestinal mucosa in IBD was
particularly common with respect to chronic active gastritis and duodenitis and, to a lesser degree, chronic
inactive gastritis. The rise in chronic active gastritis and
duodenitis affected mostly the age-groups 59 and 10
14 years. All these ndings were more pronounced in
CD than UC. They occurred similarly in male and
female IBD patients.
The strength of this study relates to its relatively large
patient population that allowed us to stratify the data by
IBD type, age-group and gender. Except for the youngest
age-group 04, all other age-groups were represented by
a fair number of patients. All diagnoses were made by
surgical pathologists with subspecialty training in gastrointestinal pathology. It would have been difcult or even
impossible to extract similarly detailed information about
gastrointestinal histopathology from any other data
source. These strengths need to be contrasted with several potential limitations. As the analysis relied on a
database of surgical pathology, little additional demographic data were available concerning socio-economic
status or ethnicity. Similarly, we had little information
about the natural history of the disease, such as age at
onset, severity, extent of intestinal manifestation, or types

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Gastritis in paediatric IBD

of therapy. To be included into the study, a patient had
to undergo colonoscopy as well as EGD. We may have
missed CD patients with involvement of the small intestine only. Although UC was more common, in general,
patients with CD were more likely to be subjected to an
EGD plus colonoscopy.
The occurrence of chronic active gastritis and duodenitis is a remarkable feature of IBD. It is presently
unknown, however, what these ndings mean with
respect to the aetiology and pathophysiology of the disease. It is unclear, for instance, whether these inammatory lesions of the upper gastrointestinal mucosa
represent a similar expression the same disease process
that affects the distal parts of the intestine, albeit at a
lower level of disease activity. They could also reect on
the altered immune status of IBD patients or their generally increased susceptibility for superimposed gastrointestinal infections. Lastly, it remains unclear why chronic
active gastritis and duodenitis occur more frequently in
paediatric than adult IBD. Is this a reection on differences in the immune response of children as compared
with adults, or are children generally more exposed to
enteric infections? Chronic active gastritis and duodenitis
could also be more common in children because in the
paediatric population, the biopsies are generally taken
closer to the time of disease onset. In this regard, young
age would only serve as a proxy epidemiological parameter for temporal proximity to the time of disease onset.
The general prevalence of H. pylori shows a clear-cut
age-dependent rise. The infection rate has steadily
declined during the past decades.18 It was not surprising
therefore to nd a relatively low prevalence of H. pylori
gastritis in our paediatric population. In multiple previous studies, H. pylori has been found to infect IBD
patients less frequently than non-IBD controls.19 We
found a similar pattern in our study population,

although the difference between the two groups failed to

reach statistical signicance. In general, there seems to
exist some striking and yet unexplained epidemiological
similarity between IBD and peptic ulcer disease (PUD).
On the one hand, there is an inverse relationship
between the infection with H. pylori and the occurrence
of IBD as opposed to the strong (and causal) relationship between H. pylori and the occurrence of PUD. On
the other hand, IBD and PUD seem to be both associated with their own type of gastritis. H. pylori-positive
chronic active gastritis frequently coincides with PUD,
whereas H. pylori-negative gastritis appears to frequently
occur in IBD, especially among young patients. Both diseases are also characterised by similar geographical variations within the United States, as well as throughout the
world.20 Lastly, the time trends of PUD and IBD are
both shaped by similar and unusual birth-cohort patterns.21, 22 Obviously, such similarities could represent
just a coincidence or a reection of some shared risk factors, but there is also the possibility that these similarities could eventually open a window to shed some new
light on the yet-unknown aetiology of IBD.
In conclusion, the present study shows that both gastritis and duodenitis occur signicantly more often in
paediatric IBD patients than in non-IBD controls, as well
as in adult IBD patients. Upper gastrointestinal inammation appears to be particularly common in patients
with CD. The occurrence of such changes could potentially provide a new avenue to study the pathophysiology
of IBD.

ACKNOWLEDGEMENTS
Declaration of personal interests: Robert M. Genta is
employed by Miraca Life Sciences, Irving, TX, USA. Amnon Sonnenberg is supported by a grant from Takeda
Pharmaceuticals. Declaration of funding interests: None.

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Aliment Pharmacol Ther 2012; 35: 1310-1316

Published 2012. This article is a US Government work and is in the public domain in the USA.