Exploring Potential COPD Immunosuppression Pathways Causing Increased Susceptibility for MAC Infections among COPD Patients

Round 1

Reviewer 1 Report

In the paper under review the authors discuss an important and actual problem - the development of mycobacteriosis of patients with COPD. They have revised a vast amount of relevant publications however the logic of presentation needs to be improved.

The title of the review does not match the content. The main objective of the review is MAC infection in COPD. Introduction should be focused on mycobacterial infection accompanying COPD. Our advice would be combining chapters 3.3 and 3.5 (both chapters are actually devoted to diagnostics). Same goes for chapters from 3.6 to 3.11. The chapters discussing mycobacteriosis pathogenesis should also be combined.

There is no clear conclusion.

 

Author Response

Reviewer#1

1. The title of the review does not match the content. The main objective of the review is MAC infection in COPD.

That is point-on advice. We change the Title to: “Exploring potential COPD immunosuppression pathways causing increased susceptibility for Mycobacterium Avium Complex infection”

1. Introduction should be focused on mycobacterial infection accompanying COPD.

Thank you very much for your insightful advice. Following your advice, we included a section dedicated to COPD and increases prevalence of MAC among the COPD patients in the Introduction:

“Introduction

Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory condition of the pulmonary system that results in obstructive airflow from the lung tissue. Patients with COPD exhibit symptoms of breathing strain, mucus filled sputum, wheezing, chest tightness, fatigue and increased cough. COPD incidence is directly linked to chronic exposure to pulmonary irritants like pollution, particulate matter, and most commonly smoking. COPD is broadly classified into Emphysema and Chronic Bronchitis. Emphysema is a condition where the lung alveoli suffer extensive damage, while Chronic Bronchitis is a long-term inflammation of bronchioles and bronchi that transport air to and from the alveoli. Currently, around 6.6% of the US population or 16.4 million US individuals suffer from COPD. Patients with a history of lung disease like COPD have an increased risk of Mycobacterium Avium Complex (MAC) colonization [2]. In patients with COPD, the risk of contracting a mycobacterial infection is fifteen times higher than that of the general population [24].

Mycobacterium genus was first discovered on March 24, 1882 by Dr. Robert Koch. In the 100 years that followed, other researchers studied MAC and its virulence factors. The most famous species of this genus is Mycobacterium Tuberculosis. However, overall, the mycobacterium genus has more than hundred different species under its umbrella that have been discovered so far. Mycobacterium genus can generally be differentiated into two main classes: tuberculoid-mycobacterium versus Mycobacterium Avium Complex (MAC)[2]. Mycobacterium genus is unique in the way that its cell membrane contains mycolic acid. Most of the mycobacterium are aerobic organisms, which do not produce any spores, are nonmotile and are generally curvilinear to linear shaped [3]. The fact that their cell envelope is composed of lipid-rich material renders them acid-fast. Additionally, mycobacterial peptidoglycan contains lipids in place of proteins and polysaccharides. These properties make the genus neither gram-positive or gram-negative. The cell membrane of mycobacterium is quite similar to cell membranes of other bacteria, but it still differs from them with respect to the presence of lipoarabinomannan (LAM), lipomannan and phosphatidylinositol mannosides [3].

The objective of this review is to synthesize the current literature on Mycobacterium Avium Complex (MAC) susceptibility among COPD patients and discuss some possible physiological and metabolic pathways that result in this increased susceptibility among COPD patients. Additionally, this paper intends to bring light to some key considerations in treatment of patients affected.”

 

1. Our advice would be combining chapters 3.3 and 3.5 (both chapters are actually devoted to diagnostics). Same goes for chapters from 3.6 to 3.11. The chapters discussing mycobacteriosis pathogenesis should also be combined

We very well agree with the advice of the reviewer. We combined chapters 3.3 and 3.5. However, chapters 3.6 to 3.11 were left uncombined to ease the reader’s ability to follow different COPD suppression pathways.

Although we agree with the reviewer that the chapters 3.6 to 3.11 could be combined, we still think leaving them as separate entities, might help readers from all levels of academic training follow the different trains of thoughts about different COPD immunosuppression pathways that result in increased susceptibility for MAC infections.

1. There is no clear conclusion.

After carefully analyzing the conclusion, we agree with the comment of the reviewer. In response to the reviewer’s advice, we placed an emphasis on connecting our conclusion to the thesis. In various parts of the conclusion, there were missing ties to the thesis. In order to solve this issue, we made sure the statements were focused on how COPD contributes to increased susceptibility for MAC infections. Please refer to the edited research paper for the newly written conclusion section that incorporates the thoughtful advice of the reviewer.

Author Response File: Author Response.docx

Reviewer 2 Report

the idea of exploring COPD immunosupression pathways which expose the patients to an increased risk of MAC infection is very interesting and actual

generally the evidence is well summarised and organized, however

1. title does not match the content, the title is supposed to reflect a paper considering the resurgence of MAC and  its grounds which is not the case. so please reformulate the title so that it tells the reader the content is about what make copd patients prone to MAC and why this is an emerging clinical/management problem (if at global level it still remains to be established)
2. if you focus on copd then let it copd be without CF bronchiectasis etc were a separate discussion is needed (also very interesting and rarely tackled)
3.  in the abstract it says it is a research paper. no it is not it is a review
4. MAC  is more common in patients with so called systemic immune suppresion (secondary to therapies, HIV/AIDS). in COPD  there is (to a certain extent) a "local" immunesuppression. So that if you could please find the common denominators for this immunosuppression for the 2 categories, this would add to the rationale of considering MAC in COPD (a short paragraph describing the situation in systemically immunosuppresed, describing the immune impairments exposing them to MAC and identifying the same impairments in copd would be excellent. then in the draft you can leave the elaboration on copd impairments which is very interesting)
5. in the draft you consider MAC as an "immune infection". Please define or clarify

Author Response

Reviewer#2

The idea of exploring COPD immunosuppression pathways which exposes the patients to an increased risk of MAC infection is very interesting and actual..Generally the evidence is well summarised and organized, however

1. Title does not match the content, the title is supposed to reflect a paper considering the resurgence of MAC and  its grounds which is not the case. so please reformulate the title so that it tells the reader the content is about what make copd patients prone to MAC and why this is an emerging clinical/management problem (if at global level it still remains to be established)

We agree with Reviewer 2’s thoughtful idea. The title was changed to “Exploring COPD immunosuppression pathways causing in-creased susceptibility for MAC infections among COPD patients”. Additionally, although we could not get reliable statistics for global extent of the problem, we did manage to get US statistics for the same and included them in the introduction section & chapter 3.2:

Introduction section: “Currently, around 6.6% of the US population or 16.4 million US individuals suffer from COPD. Patients with a history of lung disease like COPD have an increased risk of Myco-bacterium Avium Complex (MAC) colonization”

Chapter 3.2: “The incidence of MAC infections is increasing continuously worldwide. Studies conducted in Belgium [14], Germany[15], South Korea[16], Japan[17], Brazil[18], and more showed the increase in incidence of MAC causing pulmonary disease, specifically MAC in the past 15 years. “

1. If you focus on copd then let it be COPD without CF bronchiectasis etc were a separate discussion is needed (also very interesting and rarely tackled)

We agree that it would be better for the paper to primarily focus on COPD and MAC, instead of talking about Cystic Fibrosis. Therefore, we followed the reviewer’s advice and deleted chapter 3.7 referring to Cystic Fibrosis.

1.  In the abstract it says it is a research paper. no it is not it is a review

We apologize for the mistake. “Research paper” changed to “Review article”. We will pay greater attention next time onwards.

1. MAC  is more common in patients with so-called systemic immune suppression (secondary to therapies, HIV/AIDS). In COPD  there is (to a certain extent) a "local" immunosuppression. So that if you could please find the common denominators for this immunosuppression for the 2 categories, this would add to the rationale of considering MAC in COPD (a short paragraph describing the situation in systemically immunosuppressed, describing the immune impairments exposing them to MAC and identifying the same impairments in copd would be excellent. then in the draft you can leave the elaboration on copd impairments which is very interesting)

Thank you for your great insight. We have added a Chapter 3.12 dedicated to the same:

“3.12 PARALLELS BETWEEN HIV-AIDS PATIENT'S SYSTEMIC IMMUNOSUPPRESSION AND COPD INDUCED LOCALIZED IMMUNOSUPPRESSION

HIV (human immunodeficiency virus) is a virus that attacks the body’s immune system. If HIV is not treated, it can lead to AIDS (acquired immunodeficiency syndrome). HIV primarily attacks the immune system, eventually resulting in a state of immune-system failure, resulting in increased susceptibility in fighting most infectious diseases. HIV preferentially infects CD4 cells in the first few weeks of the infection. CD4 cells play an important role in signalling other immune cells in combating pathogenic microorganisms. Since HIV virus lowers the number of active CD4 cells, the body is not able to muster up a well-coordinated systemic immune response to the infectious pathogen. Consequently, HIV patients are susceptible to MAC infections since there is substantial systemic immunosuppression among HIV-AIDS patients. A parallel to this systemic immunosuppression can be drawn out in COPD patient's localized immunosuppression in the patient's pulmonary tissues. COPD results in systematic destruction of lung tissue, uncoordinated response of cytokines, immunosuppression of innate and adaptive immune cells, redox imbalance in lungs and glutathione deficiency; Overall, resulting in COPD patients' exhibiting a localized immunosuppression in lungs and greater susceptibility to MAC infections.”

1. In the draft you consider MAC as an "immune infection". Please define or clarify

Thank you for your insight in pointing it out. Yes, MAC is not an “immune infection”. Therefore, in the review paper, we made necessary changes wherever MAC was incorrectly referred to as an “immune infection”.

 

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

I recommend the review for publication.

Reviewer 2 Report

ok