ABSTRACT
A 2-year-old boy with severe combined immunodeficiency developed gut
graft-versus-host disease (GVHD) after hematopoietic stem cell
transplantation (HSCT), associated with massive intestinal pneumatosis
(IP), pneumoretroperitoneum (PRP) and pneumomediastinum. His fair
clinical conditions allowed conservative management, with progressive
normalization of imaging findings. The patient did not require surgery
and is alive and in good clinical conditions at follow-up.
In children with GVHD-related IP but good clinical conditions and no
signs of peritonitis, IP, is not a mandatory indication for surgery,
despite its potentially striking imaging features. Conservative
management, with intestinal rest, decompression and antibiotics, often
allows regression of the clinical picture.
INTRODUCTION
Graft-versus-host disease (GVHD, is the most common immunological
complication of allogeneic hematopoietic stem cell transplantation
(HSCT); alloreactive donor T cells recognize recipient’s cells as
non-self, causing direct and indirect damages to different organs. The
most commonly affected organs are the skin, liver and gastrointestinal
tract. (1)
GVHD can be classified, based on type of signs/symptoms, time from HSCT
and immunological feature, as acute or chronic; moreover, overlap forms
rarely occur. Acute GVHD (aGVHD) usually develops 3-5 weeks after
transplantation and can involve the skin, liver, and gastrointestinal
tract (GI). Chronic GVHD (cGVHD) can occur de-novo or following acute
GVHD, arising several months after HSCT and can involve almost any
organ. This complication leads to significant morbidity, reduced quality
of life, and decreased overall survival. In children the rate of cGVHD
tends to be lower (20%–50%) than in adults (60%–70%) (2) and most
commonly involves the skin, eyes, oral cavity, gastrointestinal tract,
liver, and lungs. Less frequently other organs such as the kidneys or
heart may be involved. Manifestations of cGVHD can be of inflammatory
type (erythematous rash, diarrhea, mucositis, pulmonary infiltrates) or
can have fibrotic features (fasciitis, sicca syndrome, esophageal
strictures, sclerotic skin changes and bronchiolitis obliterans).
Rarely, GVHD following hematopoietic stem cell transplantation (HSCT)
presents with intestinal pneumatosis (IP). IP is usually an indication
for surgery. However, it is important to understand when to pursue
conservative management of IP, especially in children with complex
medical problems, such as GVHD, also to avoid unnecessary and
potentially harmful surgery. (3)
We present the case of a child with GVHD following bone marrow
transplantation who developed massive IP with PRP, but no signs of
pneumoperitoneum or peritonitis.
CASE DESCRIPTION
A 2-year-old child with severe combined immunodeficiency underwent HSCT
from an unrelated cord blood unit. Three months later he developed
aGVHD, with acute pancreatitis and severe abdominal pain. Blood tests
showed C-reactive protein (CRP) 11.69 mg/dl (normal <0.5
mg/dl), procalcitonin (PCT) 1.54 ng/ml (normal <0.5 ng/ml),
lipase 1800 IU/L (normal <160 IU/L). Abdominal x-rays and
computed tomography (CT) scan showed marked bowel loops distention,
massive intestinal pneumatosis (IP), pneumoretroperitoneum (PRP) and
pneumomediastinum (Fig. 1). Despite the radiological findings, his
clinical conditions were fair, with abdominal pain and distention but no
signs of peritonitis.
In view of his fair clinical conditions and laparotomy-related risks,
conservative management was carried out, with intestinal rest,
decompression with naso-gastric tube placement, broad-spectrum
antibiotics and tight clinical observation (e.g., abdominal x-rays every
24 hours).
After an initial increase of both IP and PRP, imaging findings
progressively returned to normal within 12 days (Fig. 2). The patient
did not require abdominal surgery and is alive at 6 months of follow-up;
however, despite several line of immunosuppressive therapy he still
presents recurrent flare of GI GVHD.
DISCUSSION
We report on a child with IP, PRP and pneumomediastinum associated to
GVHD following HSCT.
IP is defined as the presence of gas within the bowel wall. In some
cases, gas may be also observed in the intraperitoneal and
extraperitoneal spaces, and sometimes is accompanied by a local and
systemic inflammatory reaction. It is not a disease per se but a
radiologic and pathologic finding that can be associated with a variety
of disorders, including chronic obstructive pulmonary disease,
gastrointestinal obstruction, bowel ischemia, neonatal necrotizing
enterocolitis, immunodeficiency syndromes, bacterial or viral
infections; moreover, it can occur after surgical procedures as well as
colonoscopies. IP has also been reported in individuals with acquired
immunodeficient states and in those who have undergone bone marrow
transplantation, as a manifestation of GVHD. (4) In patient with GVHD
after HSCT the pathogenesis of this disorder is unclear and probably
multi-factorial. Several elements may be associated with the development
of IP, including pre-transplantation chemotherapy and radiotherapy,
steroid therapy, infectious colitis and septic shock. (5) GI GVHD, leads
to atrophic mucositis with ulcer formation, bacterial and fungal
superinfection, fibrosis and development of malabsorption syndromes.
Damage to the intestinal mucosa, coexisting infection and inflammatory
infiltration with concomitant steroid therapy may predispose to IP.
Lymphocyte depletion induced by prolonged steroid therapy causes an
alteration of lymphoid follicles. This anatomic and functional defects,
associated with the inflammatory process, can produce damage to
muscolaris mucosae and allow the passage of intraluminal bacteria or gas
into the submucosa. (6)
IP may be associated with a heterogeneous clinical picture. In some
cases it is asymptomatic, but in most patients it presents with
abdominal pain, nausea, vomiting and diarrhea. (7) Diagnosis of IP
usually comes from an abdominal X-ray. In selected patients, the
addition of abdominal CT scan may allow the identification of further
signs reflecting the severity of the pathology, such as intestinal wall
thickening, other gas collection (such as PRP in our patient),
pathological bowel wall or soft tissues contrast enhancement, bowel
lumen dilatation, fluid in the peritoneal cavity, gas in the portal
vein. (8) In children also abdominal ultrasound can detect intestinal
penumatosis and other important signs such as bowel distension, bowel
wall thickness, portal venous gas, and free abdominal air as an
abdominal x-ray. Moreover abdominal ultrasound can shows free and focal
fluid collections, the status of peristalsis, and the presence or
absence of bowel wall perfusion using Doppler imaging, with the
advantage of the absence of ionizing radiation. However, the results of
the latter technique are very operator-dependent. (9/10)
In our patient, IP was associated with PRP and pneumomediastinum, but
not pneumoperitoneum (PP) nor clinical manifestations of peritonitis
such as worsening of general conditions, abdominal tenderness, abdominal
wall discoloration. The presentation suggested a confined condition,
that allowed us to undertake conservative management. Generally, in IP
without PP, conservative management, including intravenous antibiotics
and bowel rest for at least 7 days, should be the first-line treatment.
This is especially true in complex patients such as those with GVHD,
where surgical stress may be particularly harmful. Enteral feeding may
be gradually re-introduced when laboratory and imaging findings suggest
regression of the infectious/inflammatory process. Parenteral nutrition
is administered until feeding are fully re-established. (11) Conversely,
in most cases of IP with associated PP, emergency surgery is mandatory,
as the association of PP is often synonymous with intestinal perforation
and peritonitis, which in turn may be the motor for systemic
inflammatory reaction syndrome and multiple organ dysfunction, and PP
associated with IP without peritonitis has been only rarely reported in
the literature. (11/12)
In conclusion, in children with GVHD, IP is a rare complication that may
represent a conundrum for treating physicians and surgeons. Imaging
findings alone may depict a situation that seems more severe than it
really is. If clinical conditions are stable, treatment should be as
conservative as possible. In these complex patients, surgical
exploration should be reserved for those with clinical symptoms of
peritonitis, signs of intestinal perforation or obstruction.
CONFLICT OF INTEREST STATEMENT
All the authors declare that they have no conflict of interest.
REFERENCES:
- Ji-Hye Lee, Gye-Yeon Lim, Soo Ah Im, Nak-Gyun Chung, Seung-Tae Hahn.
Gastrointestinal Complications Following Hematopoietic Stem Cell
Transplantation in Children. Korean J Radiol 2008; 9:449-457
- Kristin Baird, Kenneth Cooke, Kirk R. Schultz. Chronic Graft-Versus-
Host Disease (GVHD) in Children. Pediatr Clin N Am 2010; 57:297–322
- Andrew D. Jones, Richard Maziarz, Jason Gilster, John Domreis,
Clifford W. Deveney, Brett C. Sheppard. Surgical complications of bone
marrow transplantation. The American Journal of Surgery 2003;
185:481–484
- P.N. Khalil, S. Huber-Wagner, R. Ladurner, A. Kleespies, M. Siebeck,
W. Mutschler, K. Hallfeldt, K.G. Kanz. Natural history, clinical
pattern, and surgical considerations of pneumatosis intestinalis. Eur
J Med Res 2009; 14: 231-239
- Deborah L. Day, Norma K.C. Ramsay, Janis Gissel Letourneau.
Pneumatosis Intestinalis After Bone Marrow Transplantation. AJR 1988;
151:8-87
- C Zu ̵̈lke, S Ulbrich, C Graeb, J Hahn, M Strotzer, E Holler, and K-W
Jauch. Acute pneumatosis cystoides intestinalis following allogeneic
transplantation the surgeon’s dilemma. Bone Marrow Transplantation
2002; 29:795–798
- Newman JA, Candfield S, Howlett D, McKenzie P, Sahu S.
Graft-versus-host disease. BMJ Case Reports 2010; 10:1136
- Katarzyna Laskowska, Małgorzata Burzyńska-Makuch, Anna Krenska, Sylwia
Kołtan, Małgorzata Chrupek, Elżbieta Nawrocka, Władysław Lasek,
Zbigniew Serafin. Pneumatosis cystoides interstitialis: A complication
of graft-versus-host disease. A report of two cases. Pol J Radiol
2012; 77:60-63
- Takahiro Hosokawa, Yoshitake Yamada, Yutaka Tanami et al. Predictors
of prognosis in children with portal venous gas detected by
ultrasound. Med Ultrason 2019; 21:30-36
- Shuai Chen, Yuanjun Hu, Qinghua Liu et al. Application of abdominal
sonography in diagnosis of infants with necrotizing enterocolitis.
Medicine 2019; 98:28
- N. Ade-Ajayi, P. Veys, M. Stanton, D.P. Drake, A. Pierro. Conservative
management of pneumatosis intestinalis and pneumoperitoneum following
bone-marrow transplantation. Pediatr Surg Int 2002; 18:692–695
- Takanashi M, Hibi S, Todo S, Sawada T, Tsunamoto K, Imashuku S.
Pneumatosis cystoides intestinalis with abdominal free air in a
2-year-old girl after allogeneic bone marrow transplantation. Pediatr
Hematol Oncol 1998; 15:81–84
LEGENDS:
Figure 1: a: abdominal x-rays showing IP; b: coronal CT scan with PRP
(arrows); c: sagittal CT scan showing pneumomediastinum (arrow head),
PRP (arrow) and IP (empty arrows).
Figure 2: consecutive abdominal x-rays (a: day 1; b: day 3; c: day 5; d:
day 11) showing progressive reduction of intestinal pneumatosis.
Clinical conditions remained fair during all period.
ethics statement
The patient involved in this case was appropriately consented for this
publication using the institution’s policy for media consent.