Review of Peripheral Blood Eosinophilia: Workup and Differential Diagnosis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

First I want to thank the authors for their large work.

It is a very readable paper. However some of the interesting features of the paper is due to the old and rather obscure references.

An example Is: L 691 statement that “15% of patients with Addisons disease have eosinophilia” with reference to a case report from 1976 that cites a paper from 1948 where 4 of 26 patients with “Addisons disease” . some of whom will probably have had tuberculosis as the primary disease. Referencing as this is not acceptable.

Apart from references that are old and often does not cover the statements – in some of the paragraphs there are a somewhat weird inclusion of case descriptions from published papers (see below).

Eosinophilia is indeed a very difficult topic to cover comprehensively – typically it takes a handful of very skilled clinician from leading institutions, and sometimes a very broad panel of clinicians from different specialities to cover It correctily. - There has recently been published some quite extensive reviews on the subject.

I find it difficult to see if some of the authors are students – quite a few of the authors have not published previously.

Given that Hemato at present is a quite low impact paper, as the paper is readable, as it is indeed a large work that the authors have put into the paper – and that we all like to see junior colleagues merited – it COULD be relevant to publish if it improved to some extent.

If the authors do not resubmit to this paper it could be recommended to focus on a single or a few organsystems.

However it is pertinent that the/one of the senior authors gores through the references and ensures that all statements are valid.

It could be nice to make a statement about the approximate Incidence of eosinophilia in the general population?

 

 

Specific features.

Abstract p12-14 consider rephrasing

L 51 – T1/2 of eosinopohils iss stated to be around 15 hours – one of the two refs they use states 8-18 hours.

L 57-59 delete

L 70-71 Eos counts above 20 should prompt hematological workup – this should indeed be done at much lower counts if not always.

Table 1 – correct statement regarding respiratory diseases.

        Is idiopathic hypereosinophilia a neoplastic process.

Fig 3 I have not reviewed the figure currently

 

L 112-113 consider omitting this

L 122-24 it should be stated that the symptoms can be quite elusive apart from what stated.

L 130-32 I have seen quite a few cases of Wells even though I am not a dermatologist – another case of wrong choice of references – the cited article is from 2012.

L 146-148 Gleich syndrome less than 50 cases?? Same as above.

L 161 “control patients?”  please more than one ref.if you want to give rather prescise incidenses…

L 168 . consider deleting specific autoantibodies…

Fig 4 I have not reviewed the figure

L 235-7 I do not believe that it is a common perception of sputum examniations – although the sensitivity is low – the cytological evaluation of BAL fluids most be about the same lab work (not an expert on this)

L 283 now sputum is described as gold standard – based on a paper from 2014

L 287 hypereosinophilia in 0.3% of asthma cases – seems quite low? ( cf comments to l 866)

L 363 ffff eosniophlic myocarditis --- this is a dysproportinately long description of this rather rare sumptom.

Consider deleting at least l 435-446, l 446 fff should be moved or deleted.

L 598 “autoimmune antibodies”???

L 619-l627 – casuistic info of limited value – and from another group of authors – does not belong in an extensive  review as this.

L 650 too much info on alcohol

L 691 statement that 15% of patients with Addisons disease have eosinophilia with reference to a case report from 1976, that cites a paper from 1948 where 4 of 26 patients with “Addisons disease” . some of whom will probably have had adrenal insuffienency due to TB. This is not acceptable.

L 727 (could be stated that Sheehan´s is postpartum hypopituitarism

L 788-792 rephrase

L 815-827 see comments to l 618 f                                                                                                                                                 

L 833-842 see comments to l 618 f

In general the section of infections should include specific mentioning of schistomiasis – quite a common cause of eosinophilia.

L 857 FIP1L1-PDGFRA mutated patients – the marked male predominance should be mentioned.

L 866-869 another incidence of eosinophilia using the same ref as l 287

L 933 LCH consider mentioning tissue eosinophilia in LCH (previously called eosinophilic granuloma

L 1024 DIHS/DRESS to my understanding it is incorrect that DRESS syndrome has been relabelled DIHS – the terms are used interchangedbly – and DRESS is stille used most commonly (DIHS/DRESS is often used) – again the ref is from 2001.

Fig 5. Reused from a reference the authors did not contribute to. Line 4 in the figure – the second panel could be deleted . Line 5 tryptase occurs two times.

L 1143 it is correct the patients with IgG4RD quite often have eosinophilia – and It is probably an overlooked cause of eosinophilia  Luke Chen´s group have done some work on this.

 

 

Author Response

Dear Reviewer 1,

Thank you kindly for your extensive notes regarding our manuscript. We have taken all comments into consideration and made appropriate changes based on your recommendations. Regarding your question of authors, I myself am a senior resident in internal medicine and Samir Dalia, MD is an attending in hematology/oncology. The remainder of the authors are students. We hope the changes are to your liking and have addressed your concerns. Older references were updated or omitted in favor of newer references and changes were made to the figures as needed. We have reworked our Figure 5 to ensure it is a unique work and will therefore not require special permission to publish.

Please see the attachment. Responses are made via bullet points. If there are any additional questions, please do not hesitate to reach out.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This is a very extensive manuscript, that systematically recapitulates the state of the art in the diagnostic workout of a large set of diseases presenting eosinophilia as a prominent feature. It is very well-written, and backed by a long list of references, which will be useful for the practitioner interested in any of these numerous conditions. It is clearly organized, and covers many diseases which would not be deemed primarily hematological. The paper also includes flow charts which may prove useful in clinical settings. As someone who has had a long career in research on eosinophils and eosinophilia - dating back to the early 1980s - I was pleasantly surprised by the sections dealing with eosinophilia in infection, allergy, and mutation (HES). They are updated with much exciting information on the possible connections of eosinophils and mycobacterial or viral infections. Other current issues that are appropriately reviewed include the possible contribution of eosinophils to cancer biology, which has sparked interest among investigators for an even longer period. I think this will be a very useful addition to the literature on eosinophils in clinical medicine, even though it avoids discussion of the underlying cellular and molecular mechanisms which are shared by these heterogeneous conditions.

 

In my reading of this extensive manuscript, I was positively impressed by the accuracy and clarity of most statements. In a few cases, however, I came across statements that are either vague or misleading, as follows:

 

“Therefore, when formulating an infectious cause of eosinophilia, it is essential to obtain a detailed travel history, possible exposure to contaminated food or water, insect bites, sexual contacts, patient demographics, accompanying symptoms and the relative degree of the eosinophilia.” In this case, it is unclear to me why sexual contacts are relevant to the understanding of infectious eosinophilia. For most parasitic infections, a history of sexual contacts is not essential for the diagnosis. Perhaps the authors were thinking of HIV infections?

 

“Physical exam findings that constitute infectious eosinophilia include lymphadenopathy, hepatomegaly, splenomegaly, mucocutaneous lesions or skin necrosis and gastrointestinal complaints.” I don’t understand this statement. These physical exam findings do NOT “constitute infectious eosinophilia”, although they may be present in patients who are suspected of presenting eosinophilia due to an undiagnosed infection. Please correct or clarify.

 

“Pathologically, this (Ommen’s) disease presents with absence of B cells and oligoclonal autoreactive T cells which leads to eosinophilia and elevated IgE.” Given that IgE is produced by B cells, elevated IgE can only be found when B cells are present, so some clarification is needed - how can B cells be present in the absence of B cells?”

 

“It has been suggested that eosinophils are activated by irradiation, secondary to an enrichment of genes involved in eosinophil regulation, differentiation, survival, chemoattraction and expression.” This statement seems to be referring to “an enrichment in expression (or in products) of genes involved in eosinophil regulatio, survival, and chemoattraction,” This is NOT an enrichment of these genes, but an enrichment of their products. Please correct or clarify.

Comments on the Quality of English Language

A few queries that require correction and/or refining the language used in the text are included in my comments to authors. They should be addressed in a revised manuscript.

Author Response

Dear Reviewer 2,

Thank you for your support of our manuscript and the remarks you have given us for improvement. We are pleased to present an updated manuscript integrating your recommendations. We have clarified some confusing statements and updated some of the comments. 

Please see the attachment. Responses are made via bullet points. If there are any additional questions, please do not hesitate to reach out.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I find the paper is improved and acceptable for publishing in the current form

Reviewer 2 Report

Comments and Suggestions for Authors

The modifications made in the manuscript were satisfactory. I have no more queries.