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Obstacles to diagnosis and treatment of Lyme disease in the USA: a qualitative study

Objective For many individuals with Lyme disease, prompt treatment leads to rapid resolution of infection. However, severe complications can occur if treatment is delayed. Our objective was to identify themes around belated diagnosis or treatment of Lyme disease using the General Model of Total Patient Delay (GMTPD). Design We conducted a qualitative interview study using indepth telephone interviews. Setting Participants were patients from a large, integrated health system in the state of Pennsylvania, USA. Participants There were 26 participants. Participants had to have a diagnosis of Lyme disease between 2014 and 2017 and a positive IgG western blot. We used a stratified purposeful sampling design to identify patients with and without late Lyme disease manifestations. To ensure variation in care experiences, we oversampled patients diagnosed outside of primary care. Outcome measures We asked participants about their experience from first Lyme disease symptoms to treatment. We applied an iterative coding process to identify key themes and then synthesised codes into higher order codes representing the GMTPD stages: appraisal delay (symptom to recognition of illness); illness delay (inferring illness to deciding to seek help); behavioural delay (deciding to seek help to the act of seeking help); scheduling delay (seeking help to attending an appointment); and treatment delay (attending appointment to treatment). Results Appraisal delay themes included symptom misattribution, intermittent symptoms and misperceptions about the necessity of a bull’s-eye rash. Health insurance status was a driver of illness and behavioural delays. Scheduling delay was not noted by participants, in part, because 10 of the 26 patients went to urgent care or emergency department settings. Misdiagnoses were more common in these settings, contributing to treatment delay. Conclusion Our study identified potentially modifiable risk factors for belated treatment. Targeting these risk factors may minimise time to treatment and reduce the occurrence of preventable complications.

Johnson et al, Peer J 2014;2:e322). 5. The authors noted that for some patients the impact of LD on work and caregiving persisted after treatment. This raises the question of whether improved diagnosis and access to treatment would have clinical benefit given the limited efficacy of antibiotics currently recommended to treat LD (Stricker & Johnson, Infect Drug Resist 2016:9 215-219). The authors should recognize that use of GMTPD-derived data might not help patients if more effective drugs for LD are not developed and if the limited CDC treatment approach to LD is not expanded. 6. In describing study limitations, the authors should note the small sample size along with the highly selected patient population (see #2 above). A proof-of-concept study using a larger and broader patient sample size is warranted.

GENERAL COMMENTS
This is a very interesting and well conducted piece of research. As the authors state, treatment of Lyme disease is much more effective when received promptly. As such, it is important to understand why diagnosis and treatment are often delayed if we are to address these issues. My main feedback is that it would be useful to highlight as a limitation, the fact that this study was conducted within the American health system. While this is understandable, it does mean that it may not be generalisable to other areas as I suspect different health systems may have other drivers at play. I would also suggest updating the title to: Obstacles to diagnosis and treatment of Lyme disease in the US: A qualitative study.

REVIEWER 1
The study enrolled 26 patients who were interviewed by telephone and told that their responses would not impact their medical care and "would be kept confidential". Was informed consent obtained in writing from these patients using an IRB-approved consent form?
Geisinger's Institutional Review Board determined that the study posed minimal risk of harm to participants. They waived the requirement of written consent and approved a verbal consent process that would take place on the phone before the start of the telephone interview. We added a sentence in the Data Collection section (page 6) that notes the waiver of written consent.
Patients were selected based on a clinical diagnosis of LD and an IgG Western blot test "meeting CDC criteria of five or more positive bands". Thus these patients were highly selected based on stringent diagnostic criteria that may not apply to most LD patients (Cook & Puri, Int J Gen Med. 2017;10:113-123). This fact should be stated in the Discussion.
On page 17 of the Discussion, we added a sentence regarding the limitations of our eligibility criteria, noting that patients with early Lyme disease will not test positive using the IgG Western blot test.
Eleven patients reported joint pain, but it is unclear whether any patient had frank arthritis. In a similar vein, only three patients (11.5%) had a "bullseye" rash and almost two-thirds had no rash at all, while only 2 patients (7.7%) had Bell's palsy. Thus a major problem with LD diagnosis is the lack of classic "hard" symptoms required for recognition of the disease according to CDC criteria. This lack of consistent symptomatology points to the need to change clinical criteria for LD diagnosis, and hopefully the use of GMTPD-derived data should influence the CDC to recognize the variable nature of LD symptoms. To this end, the "other" initial symptoms recalled by 34.6% of patients (Table 1) should be listed.
We updated Table 1 to describe the other initial symptoms reported by patients in footnote #2. Originally, joint swelling was included in the "other" category. In the revised manuscript we modified the "joint pain" category to include joint swelling. Thus, joint swelling was removed from the "other" category and added to the updated "joint pain/swelling" category.
The authors state that more information is needed to give a better picture of the "individual and population-level burden" of LD. The burden of LD has been examined in recent "big data" studies that should be referenced ( In the Discussion section on page 16, we added a sentence referencing the articles that have studied activity limitations and productivity in Lyme disease. The authors noted that for some patients the impact of LD on work and caregiving persisted after treatment. This raises the question of whether improved diagnosis and access to treatment would have clinical benefit given the limited efficacy of antibiotics currently recommended to treat LD (Stricker & Johnson, Infect Drug Resist 2016:9 215-219). The authors should recognize that use of GMTPD-derived data might not help patients if more effective drugs for LD are not developed and if the limited CDC treatment approach to LD is not expanded.
While our paper notes that some of the participants reported that Lyme disease symptoms impacted their work even after treatment, these participants reported receiving antibiotics at late stages in their disease. We cannot conclude from our study that patients would have had persistent symptoms after treatment if they had been treated earlier in their disease. Thus, our findings do not call into question the effectiveness of timely administration of antibiotic treatment for Lyme disease.
In describing study limitations, the authors should note the small sample size along with the highly selected patient population (see #2 above). A proof-of-concept study using a larger and broader patient sample size is warranted.
In the discussion section on page 17, we added a sentence regarding the limitations of our eligibility criteria. We also added this limitation to the "Strengths and limitations of this study" on page 3. We revised our last sentence in the manuscript to note that a future study should be large and include patients across the full spectrum of Lyme disease.
Abstract: Since recent "big data" studies suggest that up to two-thirds of LD patients may have persistent symptoms despite treatment (see Adrion et al. reference), the word "most" should be changed to "many".
We have changed the word "most" to "many" in the abstract.

Page 3: "conducted"
On page 3 under "Strengths and limitations of this study" we changed the word "conduct" to "conducted." Page 12: "presenteeism" ("presentism" means something else) On page 12, we changed the word "presentism" to "presenteeism." In table 2, we removed the word "disease" from the phrase "…told disease me I had bursitis…" REVIEWER 2 My main feedback is that it would be useful to highlight as a limitation, the fact that this study was conducted within the American health system. While this is understandable, it does mean that it may not be generalisable to other areas as I suspect different health systems may have other drivers at play. I would also suggest updating the title to: Obstacles to diagnosis and treatment of Lyme disease in the US: A qualitative study.
In the Discussion section on page 17, we added a sentence noting that findings may not be generalizable outside of the United States. We also added this limitation to the "Strengths and limitations of this study" on page 3. We modified the title to the suggested title: Obstacles to diagnosis and treatment of Lyme disease in the US: A qualitative study.

GENERAL COMMENTS
Overall the authors have done a good job of responding to the reviewer comments. Two issues remain: 1. It has been shown that CDC Western blot criteria detect only 64% of patients with "convalescent" Lyme disease who are tested at least 4-6 weeks after infection (Cook & Puri, Int J Gen Med. 2017;10:113-123). Thus the problem is not just insensitivity of early Lyme disease testing alluded to by the authors, and this broader test problem should be pointed out in the Discussion on pg 17 since it significantly impacts the diagnosis of the disease. The reference should also be included in the report.
2. Table 1 is confusing because "Other" symptoms are listed under both "First symptom recalled" and "Symptom that triggered first contact with medical provider". Although the current footnote #2 refers to the former category, both categories have the same number of patients (but with slightly different percentages for some reason), so are these in fact the same patients? The footnote should specify how many patients had each symptom, and listing "no symptoms" as a symptom is an oxymoron. Please correct the Table. VERSION 2 -AUTHOR RESPONSE

Reviewer: 1
Overall the authors have done a good job of responding to the reviewer comments. Two issues remain: It has been shown that CDC Western blot criteria detect only 64% of patients with "convalescent" Lyme disease who are tested at least 4-6 weeks after infection (Cook & Puri, Int J Gen Med. 2017;10:113-123). Thus the problem is not just insensitivity of early Lyme disease testing alluded to by the authors, and this broader test problem should be pointed out in the Discussion on pg 17 since it significantly impacts the diagnosis of the disease. The reference should also be included in the report.
On page 17 we have updated the discussion to reflect that CDC Western blot criteria can result in false negative results at all stages of Lyme disease. We cited two references to support this change.
We updated the reference section to add these references.
2. Table 1 is confusing because "Other" symptoms are listed under both "First symptom recalled" and "Symptom that triggered first contact with medical provider". Although the current footnote #2 refers to the former category, both categories have the same number of patients (but with slightly different percentages for some reason), so are these in fact the same patients? The footnote should specify how many patients had each symptom, and listing "no symptoms" as a symptom is an oxymoron. Please correct the Table. We have updated table 1 to provide a list of "other" symptoms that triggered the first contact with a medical provider (footnote #3.) Upon review of the data, we determined that the number of "other" responses should be changed from 8 to 7 and that the number of reports of rash should be changed from 4 to 5. We updated the results section of the manuscript (page 8) to reflect these changes.
We updated footnote #2 to change "no symptoms" to "none reported." Additional changes: 1. In the revised manuscript we reformatted the references as requested. 2. We have addressed Rachel Herman's contributions within the manuscript and in ScholarOne. 3. Per the formatting requirements for BMJ Open, we embedded tables 1 and 2 into the body of the revised manuscript. 4. Per the formatting requirements for BMJ Open, we added the city/state of authors on the title page and added the word count to the revised manuscript.

REVIEWER
Raphael Stricker, MD Union Square Medical Associates, USA REVIEW RETURNED 29-Apr-2018 Table 1 is still problematic with regard to Footnotes 2 and 3. For Footnote 2, Bell's palsy should be listed as a Lyme symptom in the Table (as opposed to "Other") since it is listed in the Table as a Lyme symptom in the next two categories. And it is still illogical for a list of "other symptoms" to include "none reported". If a symptom was not reported, it cannot be recalled. As for Footnote 3, "incidental finding" is not a symptom. The authors should specify what the "incidental finding" was.

VERSION 3 -AUTHOR RESPONSE
Reviewer 1 Table 1 is still problematic with regard to Footnotes 2 and 3. For Footnote 2, Bell's palsy should be listed as a Lyme symptom in the Table (as opposed to "Other") since it is listed in the Table as a Lyme symptom in the next two categories. And it is still illogical for a list of "other symptoms" to include "none reported". If a symptom was not reported, it cannot be recalled. As for Footnote 3, "incidental finding" is not a symptom. The authors should specify what the "incidental finding" was.
In our revised manuscript, we updated table 1 in the following ways: -We moved Bell's palsy from the footnote to the body of the table.
-We removed "none reported" from the 'other symptoms" category by creating a separate row for patients who reported no symptoms.
-We removed "incidental findings" from the "other symptoms" category by creating a separate row for patients in whom Lyme disease was discovered during a clinic visit for another condition. We noted that the clinician found a rash during the clinic visit.