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Revision Cover Letter
8/10/2014
Dear Dr. IoannisKoutroubakis, editors and reviewers,
Thank you very much for your letter of May 31, 2014. It is with great excitement that
we submit to you a revised version of manuscript “Urticaria due to PEG-3350 and
Electrolytes for Oral Solution in a patient with jejunal nodular lymphoid hyperplasia”
foryour exclusive consideration for publication as a case report in Annals of
Gastroenterology.
Appended to this letter are our point-by-point responses to each of the comments
raised by the reviewers. As you notice, we agree with all the commentsand we have
incorporated the suggested changes into the manuscript. We would like to take this
opportunity to express our sincere thanks to the reviewers for yourgreat deal of
valuableguidance. The comments of the reviewers are highly insightful and enable us to
greatly improve the quality of our manuscript.
Based on the instructions provided in your letter, we have uploaded our revised
manuscript and our reply to the comments under the Editor Decision at the point
"Upload author version" at the journal's website for submission.
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We sincerely hope that the revised manuscript will be approved for publication in Annals
of Gastroenterology.
Thank you very much for your time and consideration! Thank you very much for
considering our research for publication in your journal! Please feel free to contact us
at [email protected].
With best regards,
Hongfeng Zhang, MD, MSc
Department of Medicine,
St. John’s Episcopal Hospital
New York, USA;
Winoah A. Henry, MD
Lea Ann Chen, MD
Mouen A. Khashab, MD
Division of Gastroenterology and Hepatology,
The Johns Hopkins Hospital,
Baltimore, Maryland, USA
Email: [email protected]
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Reply to the reviewer’s comments
Reviewer A:
The authors demonstrated urticaria due to PEG-3350 and electrolytes for oral solution
in a patient with jejunal nodular lymphoid hyperplasia. Zhang and colleagues describe a
30-year-old female who has previously taken a PEG 3350 bowel preparation without
adverse effects, presented for evaluation of chronic diarrhea. As authors suggested, this
is the first case report on the pathological jejunal nodular lymphoid hyperplasia in
association with the GoLYTELY urticarial hypersensitivity. This study is well written and
interesting study. However, there are several problems in this study as described below:
Response:
- Thank you very much for your kind words about our paper. We are delighted to hear
that you think our work is well written and interesting study. In the following sections,
you will find our response to each of your suggestions. We are grateful for your
valuable suggestions.
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Comments to the authors:
(Note: we have started each comment with response in a new page.)
1. The introduction section had not been written very clearly and it appears too short.
This section focused to the aim of the paper.
Response:
- Thank you for the great suggestion. Per your advice, we have now elaborated more
fully on the background and aim of this paper in our introduction section.
The introduction section has been rewritten as follows:
“Polyethylene glycol (PEG) 3350 and Electrolytes for Oral Solution (GoLYTELY®,
Braintree Laboratories, Inc., Braintree, MA) was developed by Davis et al [1] in 1980 to
overcome large fluid and electrolyte shifts seen with other bowel preparations.
GoLYTELY® contains 236 g PEG-3350, 22.74 g of sodium sulfate, 6.74 g sodium
bicarbonate, 5.86 g sodium chloride and 2.97 g potassium chloride. The powder is
dissolved in 4 L of water to form an iso-osmotic solution. The benefit of this lavage
solution is minimal water and electrolyte absorption or secretion across the intestinal
mucosa with sodium sulfate as the predominant salt. Besides the salty taste, the most
common adverse events are mild and include nausea, vomiting, abdominal pain, and
bloating. Rare case reports of urticaria, dermatitis, and anaphylaxis exist and have been
attributed to PEG [2,3] though the mechanism of the GoLYTELY hypersensitivity has not
been explored.
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Nodular lymphoid hyperplasia (NLH) of the small intestine represents a rare disease
that is grossly characterized by the presence of numerous mucosal lymphoproliferative
nodules. It has been suggested that NLH is a risk factor for both intestinal and
extraintestinal lymphoma. There is also an association with immunodeficiency
syndromes and Giardiasis [4]. Its etiology is unknown.
The jejunum differentiates from the rest of the small intestine by its larger diameter,
thicker wall, more plicaecirculares, much longer villi (which largely increase the
absorptive surface area), and the absence of Brunner’s glands or Peyer’s patch.
Both jejunal NLH and GoLYTELY hypersensitivity are extremely rare. We report the first
case of jejunal NLH in association with GoLYTELY hypersensitivity. The potential
pathophysiological etiology of this association is discussed.”
Thank you again for this valuable suggestion.
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2. Please format all the references and article according to the Guide for Authors.
Response:
- We are appreciative of this comment. Per your advice, we have now reformatted all
the references and article according to the Guide for Authors.
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Reviewer B:
Considerations:
(Note: To make the comments easier to identify, we have numbered them. We have
also started each comment with response in a new page.)
1. PEG-3350 would be absorbed in any part of the gut, not only in jejunum. Describing
the timing from the beginning of the intake and the starting of symptoms would be
interesting (page 3, line 11).
Response:
- Thank you for this great suggestion. “Within a few minutes of taking the bowel
preparation” is now added to the manuscript.
The jejunum mainly occupies the left upper and central abdomen. Specialized for the
absorption, the luminal surface of the jejunum is covered with villi which are finger like
projections of mucosa and increase the surface area of tissue available for absorption.
The epithelial cells which line these villi have microvilli.
The jejunum is of great interest to us for its many unique features both anatomically
and histologically. Anatomically the jejunum typically has larger diameter, thicker wall,
more large circular folds (plicaecirculares), and much longer villi (a histologically
identifiable structure) which largely increase the absorptive surface area.
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Histologically the jejunum differentiates from the rest of the small intestine by the
absence of Brunner’s glands (in the duodenum) and Peyer’s patch (in the ileum, which
is manifested as clusters of lymph nodules, and is part of the Gut-Associated Lymphoid
Tissues, or GALT). However, normal jejunum has very few lymphoid tissues.
We think the unique anatomy and histology of the jejunum probably contribute to the
association of GoLYTELY hypersensitivity with jejunal NLH.
Therefore, we have also added “The jejunum differentiates from the rest of the small
intestine by its larger diameter, thicker wall, more plicaecirculares, much longer villi
(which largely increase the absorptive surface area), and the absence of Brunner’s
glands or Peyer’s patch.” to the introduction section, and “The unique anatomy and
histology of the jejunum probably contribute to this association of GoLYTELY
hypersensitivity with jejunal NLH.” to the discussion section.
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2. An etiological cause of the NLH in this case would help to link both NLH and
GoLYTELY hypersensitivity (page 4, line 1).
Response:
- Thank you for this valuable comment. This is exactly what we want to achieve in the
discussion section. In response to the 3rd comment next, we explain why we think that
chronic diarrhea may causeimpaired mucosal barrier. And in response to the 6th
comment later on, we explain that increased mast cells may co-exist with the nodular
lymphoid hyperplasia, according to many literatures. Based on these, we describe an
etiological cause of the NLH which would link both NLH and GoLYTELY
hypersensitivityin this case as follows:
“PEG is used extensively in a wide variety of substances and medications. Although high
molecular weight PEG (>1000 g/mol) solutions are believed to be poorly absorbed, 0.06%
of the mean PEG load was recovered in the urine of normal subjects, and 0.09% was
recovered in patients with inflammatory bowel disease [5]. It was suggested that loss
of mucosal integrity could promote the systemic absorption of PEG-3350 [2]. Chronic
diarrhea is one of the most common gastrointestinal conditions that can impact a
patient's nutritional status due to the remarkably impaired efficiency of the gut to
absorb nutrients and, the patient’s decreased appetite and reduced nutrient intake out
of fear of exacerbating the symptoms; and so chronic diarrhea can cause impaired
normal function of the mucosal recovery and mucosal barrier of the intestine and
therefore lead to increased systemic absorption of PEG-3350 in our patient.
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It should be noted that the mucosal breaks may also be associated with the
pathophysiology of NLH. As the defects in the gastrointestinal mucosal surface caused
by chronic diarrhea in our patient may lead to the chronic antigen exposure, host
immunological stimulation, and the subsequent formation of NLH.
Mast cells (MCs) are concentrated in the areas of lymphoid storage and their
proliferation dependents on T-cell growth factor. MCs are also the major modulator of
the lymphoid cell immune function and regulate the proliferation of the lymphoid cell
[6]. Lee et al [7] reported that intestinal lymphoid cells could differentiate into MCs.
However, MCs are difficult to identify via standard hematoxylin and eosin staining. They
can be seen when stained with metachromatic dyes such as toluidine blue or Giemsa
stain. It is believed that many patients with mast cell–associated diseases may be
missed if these dyes are not used. We certainly missed the opportunity to repeat the
jejunal mucosa biopsy with these unique dyes in our patient. However, Nicolov et al [8]
found there were extremely increased numbers of mucosal mast cells in the jejunal NLH.
We hypothesize that in the jejunal NLH, the concentrated lymphoid cells associated
cytokines and the increased mast cells associated IgE responses contribute to the
hypersensitivity reaction to an unusual antigen, such as GoLYTELY. The unique
anatomy and histology of the jejunum probably also contribute to this association of
GoLYTELY hypersensitivity with jejunalNLH.”
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We hope our revised discussion now more clearly develops the linkages to which you
refer.
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3. Page 5, lines 10-13: “It should be noted that the mucosal breaks may also be
associated with the pathophysiology of NLH. As the defects in the gastrointestinal
mucosal surface caused by chronic diarrhea in our patient may lead to chronic antigen
exposure, host immunological stimulation, and the subsequent formation of NLH.”
There is no evidence of the impaired mucosa in this case, because etiology of chronic
diarrhea is not specified.
Response:
-Thank you for this great comment. In order to have evidence for the impaired mucosa
in our patient, we did a thorough search for the literatures on the relationship of the
impaired mucosa and the chronic diarrhea. We realize diarrhea results when the
remarkable efficiency of the gut for absorbing nutrients is impaired. And chronic
diarrhea is one of the most common gastrointestinal conditions that can impact a
patient's nutritional status. [Gorospe EC, Oxentenko AS.Nutritional consequences of
chronic diarrhoea.Best Pract Res ClinGastroenterol 2012;26:663-75]
In addition, diarrhea directly cause decreased appetite and reduced nutrient intake out
of fear of exacerbating the symptoms. Chronic diarrhea may also cause acidosis,
hypokalemia and dehydration.
All these factors of chronic diarrhea can interfere with the normal function of mucosal
barrier and mucosal recovery, and therefore impair the intestinal mucosa.
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Different method was used to test the intestinal permeability including the lactulose:
mannitol test, which may be conducted in the future research.
As such, we added the following sentence to the first paragraph of the discussion
section:
“It was suggested that loss of mucosal integrity could promote the systemic absorption
of PEG-3350 [2]. Chronic diarrhea is one of the most common gastrointestinal
conditions that can impact a patient's nutritional status due to the remarkably impaired
efficiency of the gut to absorb nutrients and, the patient’s decreased appetite and
reduced nutrient intake out of fear of exacerbating the symptoms; and so chronic
diarrhea can cause impaired normal function of the mucosal recovery and mucosal
barrier of the intestine and therefore lead to increased systemic absorption of PEG-3350
in our patient.”
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4. NLH’s histological structure differs from Inflammatory Bowel Disease (page 5, line 7).
Response:
- We agree that NLH’s histological structure differs from that of Inflammatory Bowel
Disease. The connection between Inflammatory Bowel Disease and our patient’s NLH is
the impaired mucosal barrier which may lead to increased systemic absorption of PEG3350. While Inflammatory Bowel Disease is associated with the breaks in the mucosal
barrier, our patient’s chronic diarrhea was also associated with impaired mucosal barrier,
as explained in the response to the 3rdcomment earlier.
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5. This sentence could be better expressed: “The advantage of this lavage is negligible
net water and sodium shift…” (page 4, line 13).
Response:
-Thank you for this great suggestion. This sentence has now been changed as follows:
“The benefit of this lavage solution is minimal water and electrolyte absorption or
secretion across the intestinal mucosa with sodium sulfate as the predominant salt.”
We feel the revised sentence is expressed more clearly.
Please note: the paragraph containing this sentence has been moved to the beginning
of the introduction section.
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6. Page 5, line 13-14: “There are extremely increased numbers of mucosal mast cells in
the jejunal NLH”. This statement is based on a unique case record in literature;
however in other publication (Webster et al) no excess infiltration with inflammatory
cells was described.
Recommended bibliography:
Webster AD, Kenwright S, Ballard J, Shiner M, Slavin G, Levi AJ, Loewi G, Asherson GL.
Nodular lymphoid hyperplasia of the bowel in primary hypogammaglobulinaemia: study
of in vivo and in vitro lymphocyte function. Gut. 1977 May;18(5):364-72.
Response:
-We are very appreciative of this comment. We have done a complete search for the
literatures regarding the relationship of the lymphoid cell congregates and mast cells.
We also went through the contents of the mentioned publication by Webster et al.
We agree there is only one case record in literature on extremely increased number of
mucosal mast cells in the jejunal NLH. However, there are many literatures
demonstrating evidences of tight spatial interactions between mast cells and lymphoid
cells.
Mast cells are concentrated in the areas of lymphoid storage; they are dependent upon
T-cell growth factor for their proliferation. On the other hand, mast cells are the major
modulator of the lymphoid cell immune function and regulate the proliferation of the
lymphoid cell. [Khan MM, Strober S, Melmon KL. Regulatory effects of mast cells on
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lymphoid cells: the role of histamine type 1 receptors in the interaction between mast
cells, helper T cells and natural suppressor cells. Cell Immunol 1986;103:41-53.]
The evidence of a tight spatial interaction between mast cells and B lymphocytes in
secondary lymphoid organs, along with the data regarding the abundance of mast cells
in several B-cell lymphoproliferative disorders and investigation on mast cells has
showed that mast cells enhance the proliferation and differentiation of B cells. [Merluzzi
S, Frossi B, Gri G, Parusso S, Tripodo C, Pucillo C. Mast cells enhance proliferation of B
lymphocytes and drive their differentiation toward IgA-secreting plasma cells. Blood
2010;115:2810-2817.]
Small intestinal innate lymphoid cells could differentiate into mast cells. Intestinal mast
cell progenitors could function as innate lymphoid cells. [Lee Y, Kumagai Y, Jang MS, et
al. Intestinal Lin- c-Kit+ NKp46- CD4- population strongly produces IL-22 upon IL-1β
stimulation. J Immunol 2013;190:5296-5305.
Increased numbers of lymphoid follicles and aggregates, increased number of mast cells
were the statistically significant key findings in lymphocytic follicles and aggregates
colitis. [Shah N, Thakkar B, Shen E, Loh M, Chong PY, Gan WH, Tu TM, Shen L, Soong
R, Salto-Tellez M. Lymphocytic follicles and aggregates are a determinant of mucosal
damage and duration of diarrhea. Arch Pathol Lab Med 2013;137:83-89.]
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We think the reason why there is only one case record in literature on extremely
increased number of mucosal mast cells in the jejunal NLH is because mast cells are
difficult to identify in a biopsy via standard hematoxylin and eosin staining. [Ramsay DB,
Stephen S, Borum M, Voltaggio L, Doman DB. Mast cells in gastrointestinal
disease.GastroenterolHepatol (NY) 2010;6:772–777.]
Mast cells are shown to a better advantage when stained with metachromatic dyes such
as toluidine blue which renders the histamine granules a striking purple and all other
non-metachromatic tissue blue, and Giemsa staining. Mast cells can also be selectively
stained by the astra blue technique, and evaluated with immunohistochemical analysis
for CD117 and mast-cell tryptase.
It has been believed that many patients with mast cell–associated diseases may be
missed if these dyes are not used. [Ramsay DB, Stephen S, Borum M, Voltaggio L,
Doman DB. Mast cells in gastrointestinal disease.GastroenterolHepatol (NY)2010;6:772–
777.]
Webster et al described “the lamina propria and villi away from the nodules appeared
normal and there was no excess infiltration with inflammatory cells”. [Webster AD,
Kenwright S, Ballard J, Shiner M, Slavin G, Levi AJ, Loewi G, Asherson GL. Nodular
lymphoid hyperplasia of the bowel in primary hypogammaglobulinaemia: study of in
vivo and in vitro lymphocyte function. Gut 1977 May;18(5):364-72.] This description
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was based on the view from the dissecting microscope. However, mast cell can only be
seen with selective stain such as Toluidine blue or Giemsa.
In their result “table 1 Relationship between serum, salivary, and jejunal juice
immunoglobulins and cells with intracytoplasmic immunoglobulin in jejunal biopsies of
patients with and without biopsy and radiographic evidence of nodular lymphoid
hyperplasia”, the table showed the absence of immunoglobulin staining cells with
fluorescein and peroxidase labelled antisera, which was not the same as the absence of
the inflammatory cells.
The electron micrographs of Webster et al’s paper have shown “unusual cell containing
phagocytosed material” “within the nodule” “with a chromatin arrangement” of “the
nuclei” “resembling that of macrophages”. However, after a thorough search on the
electron micrographs of mast cells and macrophages in the literatures[Iwamoto T,
Smelser GK. Electron microscope studies on the mast cells and blood and lymphatic
capillaries of the human corneal limbus. Invest Ophthalmol1965;4:815-834.], we think
those macrophage-resembling cells may well be the mast cells.
Therefore, we added the following paragraph as the 3rd paragraph of the discussion
section:
“Mast cells (MCs) are concentrated in the areas of lymphoid storage and their
proliferation dependents on T-cell growth factor. MCs are also the major modulator of
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the lymphoid cell immune function and regulate the proliferation of the lymphoid cell
[6]. Lee et al [7] reported that intestinal lymphoid cells could differentiate into MCs.
However, MCs are difficult to identify via standard hematoxylin and eosin staining. They
can be seen when stained with metachromatic dyes such as toluidine blue or Giemsa
stain. It is believed that many patients with mast cell–associated diseases may be
missed if these dyes are not used. We certainly missed the opportunity to repeat the
jejunal mucosa biopsy with these unique dyes in our patient. However, Nicolov et al [8]
found there were extremely increased numbers of mucosal mast cells in the jejunal
NLH.”
We think the revised discussion is more interesting and balanced.
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7. Page 5, line 15: “We hypothesize that in the jejunal NLH, the concentrated lymphoid
cells associated cytokines and the extremely increased mast cells associated IgE
responses contribute to the hypersensitivity reaction to an unusual antigen”: histological
findings of mucosal biopsy should have been better described to accept this statement.
Were there increased mast cells in the biopsy of the case?
Response:
-Thank you for this insightful comment.
As we explained in the response to the 6thcomment:
Mast cells are difficult to identify in a biopsy via standard hematoxylin and eosin
staining. [Ramsay DB, Stephen S, Borum M, Voltaggio L, Doman DB. Mast cells in
gastrointestinal disease.GastroenterolHepatol (NY) 2010;6:772–777.]
Mast cells are shown to a better advantage when stained with metachromatic dyes such
as toluidine blue which renders the histamine granules a striking purple and all other
non-metachromatic tissue blue, and Giemsa staining. The mast cells can also be
selectively stained by the astra blue technique, and evaluated with
immunohistochemical analysis for CD117 and mast-cell tryptase.
It has been believed that many patients with mast cell–induced diseases may be missed
if these stains are not used. [Ramsay DB, Stephen S, Borum M, Voltaggio L, Doman DB.
Mast cells in gastrointestinal disease.GastroenterolHepatol (NY) 2010;6:772–777.]
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Our patient’s jejunal biopsy was processed using the standard H & E stain. We missed
the opportunity to repeat the jejunal mucosa biopsy with toluidine blue or Giemsa stain.
In our response to the 6th comment, we elaborated on the close associations of mast
cells with lymphoid cells based on many literatures. Asthe proliferation of mast cells and
lymphoid cells are closely related, our patient’s jejunal nodular lymphoid hyperplasia
may co-exist with increased mast cells.
However, our histological study of the biopsy with different dyes is obviously limited,
and further experiments with the biopsy specimen or repeat biopsy with additional
staining specific for mast cells are needed before this statement has a strong base on
our histological findings. As such, we now acknowledge this realty as a limitation of our
work.
Therefore, in the 3rdparagraph of the discussion section, we added the following
sentences:
“Mast cells (MCs) are concentrated in the areas of lymphoid storage and their
proliferation dependents on T-cell growth factor. MCs are also the major modulator of
the lymphoid cell immune function and regulate the proliferation of the lymphoid cell
[6]. Lee et al [7] reported that intestinal lymphoid cells could differentiate into MCs.
However, MCs are difficult to identify via standard hematoxylin and eosin staining. They
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can be seen when stained with metachromatic dyes such as toluidine blue or Giemsa
stain. It is believed that many patients with mast cell–associated diseases may be
missed if these dyes are not used. We certainly missed the opportunity to repeat the
jejunal mucosa biopsy with these unique dyes in our patient. However, Nicolov et al [8]
found there were extremely increased numbers of mucosal mast cells in the jejunal
NLH.”
We hope you find our approach acceptable.
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8. Page 5, line 19-20: “In addition, Kokkonen et al [8] reported an association between
NLH of the duodenum, terminal ileum or colon and food allergy in children”. Food
allergy differs from PEG-3350 hypersensitivity so Kokkonen’s work should not be
mentioned in this report.
Response:
-Thank you for this insightful suggestion. Per your advice, we have now eliminated this
sentence and the corresponding reference.
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9. Page 6, line 11-12: “…because GoLYTELY hypersensitivity can potentially be severe”.
Reference bibliography of severe cases of GoLYTELY hypersensitivity is needed to
support this affirmation.
Response:
-Thank you for this great suggestion. We have now added two references of severe
cases of GoLYTELY hypersensitivity to the manuscript:
[2][Shah S, Prematta T, Adkinson NF, Ishmael FT. Hypersensitivity to Polyethylene
Glycols. Journal of Clinical Pharma 2013;53:352-355.]
Shah et alreported hypersensitivity reaction of flushing, diffuse hives, shortness of
breath, tachycardia, light headedness, brief loss of consciousness, wheezing and
hypotension in a 52 year old white man a few minutes after ingestionGoLYTELY.
[3] [Savitz JA, Durning SJ. A Rare Case of Anaphylaxis to Bowel Prep: A Case Report
and Review of the Literature. Mil Med 2011;176:944-945.]
Savitz and Durning reported a biphasic anaphylaxis reaction of a 33 year old female to
PEG solution with urticaria, facial flushing, dyspnea, chest tightness, throat closure
sensation, light headedness and tongue swelling.
We hope you find our references are now effectively used.
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10. Page 6, line 13: “Increased caution should be warranted in cases where defects in
mucosal integrity are suspected”. This conclusion would be right if impaired mucosal
would have been better evidenced in this case report.
Response:
- Thank you for raising this important point.
As mentioned in our response to the 3rdcomment:
In order to have evidence for the impaired mucosa in our patient, we did a thorough
search for literatures on the relationship between impaired mucosa and chronic diarrhea.
And we realize that diarrhea results when the remarkable efficiency of the gut for
absorbing nutrients is impaired. And chronic diarrhea is one of the most common
gastrointestinal conditions that can impact a patient's nutritional status. [Gorospe EC,
Oxentenko AS.Nutritional consequences of chronic diarrhoea.Best Pract Res
ClinGastroenterol 2012;26:663-675.]
In addition, diarrhea directly cause decreased appetite and reduced nutrient intake out
of fear of exacerbating the symptoms. Chronic diarrhea may also cause acidosis,
hypokalemia and dehydration.
All these factors of chronic diarrhea can interfere with the normal function of mucosal
barrier and mucosal recovery, and therefore impair the intestinal mucosa.
27
Different method was used to test the intestinal permeability including the lactulose:
mannitol test, which may be conducted in the future research.
As such, we added the following sentence to the first paragraph of the discussion
section:
“It was suggested that loss of mucosal integrity could promote the systemic absorption
of PEG-3350 [2]. Chronic diarrhea is one of the most common gastrointestinal
conditions that can impact a patient's nutritional status due to the remarkably impaired
efficiency of the gut to absorb nutrients and, the patient’s decreased appetite and
reduced nutrient intake out of fear of exacerbating the symptoms; and so chronic
diarrhea can cause impaired normal function of the mucosal recovery and mucosal
barrier of the intestine and therefore lead to increased systemic absorption of PEG-3350
in our patient.”
Again, we appreciate all your insightful comments.