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this is the guide for the cohort

https://connect.springerpub.com/highwire_display/entity_view/node/156618/content_details

COHORT DESIGN

Citation:

Study Design:

Level of Evidence:

Introduction/Background Comments/Appraisal

Rationale provided for study

Significance of study provided

Current state of science or evidence clearly articulated

Problem statement or area identified

Research purpose clearly stated

Design Comments/Appraisal

Research question clearly defined and focused

Cohort identified

How was the exposed cohort selected?

Was there clear and defined selection criteria for inclusion of the exposed cohort?

What proportion of eligible subjects were included in exposed cohort?

How was the nonexposed cohort selected?

Was there clear and defined selection criteria for inclusion of the nonexposed cohort?

What proportion of the eligible subjects were included in the nonexposed cohort?

What was the exposure?

Was the exposure specific and measurable?

What was the potential for misclassification of the exposure?

How long was the cohort followed? Was this time period adequate?

Results/Findings Comments/Appraisal

What measures were implemented to reduce attrition? What was the rate of attrition?

Was there a difference in those who were lost to attrition and those who remained in the cohort study?

What were the primary and secondary study outcomes? How were the outcomes measured? Was the measurement valid and reliable?

Any surrogate outcome measures identified? How were the surrogate outcomes measured? Surrogate measurement was valid and reliable?

What was the comparative analysis of the exposed and nonexposed cohort?

Sample size appropriate based on power analysis; rationale for sample size estimation appropriate?

What was the strength of association between the exposure and outcome?

How accurate was the estimate of association between the exposure and outcome (confidence intervals or p-values)?

Bias/Confounders Comments/Appraisal

What was the potential for recall bias? What research strategies were used to reduce recall bias?

Was there potential for selection bias? What strategies were used to reduce selection bias?

Did the researcher identify all potential confounders?

What was the potential for information bias? What strategies were used to reduce information bias?

Was there potential for historical or maturation bias? What strategies were used to reduce historical or maturation bias?

Implications of Findings/Results Comments/Appraisal

What is the potential application of findings to practice?

Were all the clinically important outcomes considered?

How do the study findings fit within the existing state of science and available evidence?

Were the recommendations supported by the study findings?

Strengths Comments/Appraisal

What are the major strengths of the study design?

What are the major weaknesses of the study design?

Limitations Comments/Appraisal

What are the major limitations of the overall study design?

What are the major limitations of the sampling method?

What are the major limitations of the measurement methods?

What are the major limitations of the data management and analysis methods?

Ethical/Legal Comments/Appraisal

Did the research consider human subjects protection?

How were the human subjects rights protected?

Any ethical concerns identified?

Any potential conflicts of interest identified?

Any legal concerns identified?

attached the info the how the cohort should look like , with the info that you have to get it from the pdf.

remember that the way should look like but it is not same because the template change at the end 

Raffetin et al. BMC Infectious Diseases (2023) 23:380
https://doi.org/10.1186/s12879-023-08352-3

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BMC Infectious Diseases

Acceptance of diagnosis and management
satisfaction of patients with “suspected
Lyme borreliosis” after 12 months
in a multidisciplinary reference center:
a prospective cohort study
Alice Raffetin1,2,3*, Amal Chahour1, Julien Schemoul4, Giulia Paoletti5, Zhuoruo He1,6, Elisabeth Baux7,
Solène Patrat‑Delon8, Steve Nguala1, Pauline Caraux‑Paz1, Costanza Puppo9, Pauline Arias1, Yoann Madec10,
Sébastien Gallien1,3,11 and Julie Rivière2

Abstract

Introduction Because patients with a “suspicion of Lyme borreliosis (LB)” may experience medical wandering and
difficult care paths, often due to misinformation, multidisciplinary care centers were started all over Europe a few
years ago. The aim of our study was to prospectively identify the factors associated with the acceptance of diagnosis
and management satisfaction of patients, and to assess the concordance of the medical health assessment between
physicians and patients 12 months after their management at our multidisciplinary center.

Methods We included all adults who were admitted to the Tick‑Borne Diseases Reference Center of Paris and the
Northern Region (TBD‑RC) (2017–2020). A telephone satisfaction survey was conducted 12 months after their first
consultation. It consisted of 5 domains and 13 items rated between 0 (lowest) and 10 (highest grade): (1)Reception;
(2)Care and quality of management; (3)Information/explanations given to the patients; (4)Current medical condition
and acceptance of the final diagnosis; (5)Overall appreciation. Factors associated with diagnosis acceptance and man‑
agement satisfaction at 12 months were identified using logistic regression models. The concordance of the health
status as assessed by doctors and patients was calculated using a Cohen’s kappa test.

Results Of the 569 patients who consulted, 349 (61.3%) answered the questionnaire. Overall appreciation had a
median rating of 9 [8;10] and 280/349 (80.2%) accepted their diagnoses. Patients who were “very satisfied” with their
care paths at TBD‑RC (OR = 4.64;CI95%[1.52–14.16]) had higher odds of diagnosis acceptance. Well‑delivered informa‑
tion was strongly associated with better satisfaction with the management (OR = 23.39;CI95%[3.52–155.54]). The con‑
cordance between patients and physicians to assess their health status 12 months after their management at TBD‑RC
was almost perfect in the groups of those with confirmed and possible LB (κ = 0.99), and moderate in the group with
other diagnoses (κ = 0.43).

*Correspondence:
Alice Raffetin
[email protected]
Full list of author information is available at the end of the article

Page 2 of 13Raffetin et al. BMC Infectious Diseases (2023) 23:380

Conclusion Patients seemed to approve of this multidisciplinary care organization for suspected LB. It helped them
to accept their final diagnoses and enabled a high level of satisfaction with the information given by the doctors,
confirming the importance of shared medical decisions, which may help to reduce health misinformation. This type of
structure may be useful for any disease with a complex and controversial diagnosis.

Key messages

What is already known on this topic?

• Among patients with a suspicion of Lyme borreliosis (LB), less than 15% have confirmed LB, and more than 80%
a differential diagnosis, confirming the need for multidisciplinary structures.

• To our knowledge, there are not any studies about the satisfaction of the patients with these proposed multidis-
ciplinary care paths.

What this study adds?

• Acceptance of diagnosis (80.2%) was associated with satisfaction with the care paths and the current medical
condition of the patients.

• The high satisfaction with the information given by the doctors was a key element of the management satisfac-
tion, confirming the importance of shared medical decisions to meet the patients’ expectancies and reduce mis-
information.

How this study might affect research, practice and policy?

• Provided that this satisfaction survey is externally assessed by additional studies, it could be useful to regularly
assess patients’ satisfaction in the context of multidisciplinary management for suspected LB, and these multi-
disciplinary structures might be generalized for other complex diseases.

Keywords Lyme borreliosis, Multidisciplinary management, Satisfaction, Concordance, Diagnostic acceptance

Introduction
Lyme borreliosis (LB) is the most common tick-borne
disease in Europe and in the USA. It is caused by spiro-
chetes of the Borrelia burgdorferi sensu lato complex [1,
2]. Diagnosis of LB associates an exposure to tick bite, the
presence of specific defined-LB manifestations (the most
frequent being erythema migrans (EM) and Lyme neu-
roborreliosis) and a positive microbiological test (sero-
logical and sometimes PCR tests, save for EM); none of
them alone makes the diagnosis of the infection certain
[3–5]. European guidelines recommend a mono-anti-
biotic therapy for LB treatment. The therapy should be
given for 14 to 28 days according to the infection’s stage
and its clinical manifestation [6, 7]. No studies have yet
proven the clinical benefit of a longer antibiotic treat-
ment [8–12].

The diagnosis and the management of LB may be chal-
lenging for several reasons: (i) its wide range of clinical
pictures, sometimes resembling other pathologies; (ii)
the rare sequelae that may occur mainly after late dissem-
inated LB, with most of patients being completely cured

within one month to three years in the most complicated
cases [13–19]; and (iii) the possible presence of subjective
symptoms (asthenia, polyalgia, cognitive complaints) at
all stages of the disease [14, 20], which may persist after
a well-adapted treatment, producing the post-treatment
Lyme disease syndrome (PTLDS) [13, 14, 20, 21], with no
clear guidelines for their management. The causative role
of LB in these subjective symptoms is a source of ques-
tions insofar as these non-specific symptoms may be
encountered in the course of other infectious (Epstein-
Barr-Virus, SARS-CoV-2, etc.) or non-infectious diseases
[22]). In addition, some patients are referred for antibi-
otic therapy for a suspicion of LB, sometimes at their own
request, but are finally diagnosed with other diseases,
mainly rheumatological, neurological, auto-immune or
psychological [23–27].

Therefore, many patients suspected of having LB may
experience diagnosis wandering and difficult care paths,
often due to misinformation. To improve the health
care organization of LB, a French national care plan
for LB was started in 2016 that favored the creation of

Page 3 of 13Raffetin et al. BMC Infectious Diseases (2023) 23:380

multidisciplinary LB centers. These centers are joint
endeavors between departments of infectious diseases,
internal medicine, rheumatology, neurology, algology,
dermatology, psychiatry, microbiology, and physical
rehabilitation to manage patients presenting a suspicion
of LB, in a multidisciplinary approach. There, challenging
cases are discussed in monthly multidisciplinary consul-
tation meetings. One such clinic opened in December
2017 at the General Hospital of Villeneuve-Saint-Georges
in suburban Paris, France. This center was labeled the
Tick-borne Diseases Reference Center (TBD-RC) for
Paris and the Northern region in July 2019 by the French
Ministry of Health, which also established four other
such clinics in France. Teams in other countries have
also initiated such care organizations since 2010 [23–25],
showing a European awareness of the need for the man-
agement of complex LB and its differential diagnoses.
These multidisciplinary experiences have revealed a low
prevalence of confirmed LB (between 10 and 20%), and
the multiplicity of the differential diagnoses [23–27].
We have previously demonstrated that the majority of
patients (80.7%), independently of their final diagno-
ses, had favorable clinical outcomes one year after their
first consultation at TBD-RC of Paris and the Northern
region. However, the opinions of the patients about these
multidisciplinary structures, their diagnosis acceptance,
especially in spite of another diagnosis than LB, and their
own health status assessment after receiving care in this
type of multidisciplinary structure have not been studied
yet [27].

The aims of our study were to analyze the satisfaction
levels of patients experiencing a multidisciplinary man-
agement for suspected LB at TBD-RC of Paris and the
Northern region, to identify the factors associated with
their diagnosis acceptance and their global satisfaction
with the management, and to assess the concordance of
the medical health assessment between the physicians
and the patients 12 months after their first consultation
at TBD-RC.

Methods
We conducted a prospective descriptive and analytic
cohort study, including all adults who consulted at TBD-
RC of Paris and Northern Region for a suspicion of LB,
from 1 December 2017 to 1 December 2020. We followed
the STROBE guidelines [28] (Additional file 1).

Population, setting, and intervention
The care path at TBD-RC was previously described [27]
and is summarized in Fig. 1.

Patients with diagnoses associated with LB were clas-
sified as [13, 29]: confirmed LB (tick exposure, typical
clinical signs and a positive serological test); possible LB

(tick exposure and/or prior erythema migrans, evoca-
tive clinical signs and marked clinical improvement after
21 days of antibiotics); and post-treatment Lyme disease
syndrome (PTLDS) (asthenia/polyalgia/cognitive com-
plaints) or sequelae (objective impairment) after a con-
firmed LB treated as recommended. PTLDS and sequelae
were pooled together as they are both responsible for
persistent symptoms after treatment. Therefore, com-
bining them together was clinically relevant. Moreover,
as sequelae are very rare, the effective would have been
too small to perform statistical tests separately. The other
patients were classified in the group “other diagnoses,”
which were made by a doctor specialized in the field.
A final orientation in the adapted medical department
was offered to every patient, independently of their final
diagnosis.

A telephone-based satisfaction survey was conducted,
independently from the staff consulting at TBD-RC, and
pseudonymized, 12 months after the first consultation at
TBD-RC.

To assess the current health condition of the patients
12 months after their management at TBD-RC, the phy-
sician in charge of the patient had a rating scale between
1 and 5. In the satisfaction survey, patients had a scale
between 0 and 10. The current medical condition cor-
responded to: complete recovery (score 1 for physicians;
score 9–10 in the satisfaction survey for patients), partial
improvement consisting of persistent clinical signs or
symptoms allowing resumption of daily and professional
activities (score 2 for physicians; score 7–8 for patients),
stagnation (score 3 for physicians; score 5–6 for patients),
or deterioration (score 4 for physicians; score 0–4 for
patients).

Patient data and satisfaction survey
Patients’ data were routinely collected in standardized
medical files at the TBD-RC, independently of the study,
to ensure the correct follow-up of the patients.

The satisfaction survey comprised 15 items: 12 items
rated between 0 (lowest grade) and 10 (highest grade), 1
item about the acceptance with 3 categories (yes, no, and
partially), and 2 free-text items. These items covered five
domains: (1) reception; (2) care and quality of manage-
ment (by the medical team, by the paramedical team,
responsiveness and compassion to patients, care path at
TBD-RC); (3) information and explanations given to the
patients; (4) current medical condition after the manage-
ment at the TBD-RC compared to the previous one and
acceptance of the final diagnosis; and (5) overall appreci-
ation (Additional file 2). This questionnaire was inspired
by the MedRisk instrument, and adapted to our setting
(multidisciplinary management for the suspicion of LB)
[30, 31]. It was presented and discussed with patients’

Page 4 of 13Raffetin et al. BMC Infectious Diseases (2023) 23:380

associations involved in LB on the one hand, and in other
diseases such as HIV or diabetes on the other hand, to
check whether this survey was adequate to their expec-
tations. Their suggestions were taken into account to
improve the questionnaire.

Statistical analysis
The four groups of patients classified according to their
final diagnosis as assessed at the TBD-RC of Paris and
the Northern region (i.e. confirmed LB, possible LB,
PTLDS or sequelae, and other diagnosis) were previously
compared according to socio-demographic, clinical, and
microbiological characteristics, and 12-month outcomes
after multidisciplinary care [27]. In the present study,
we compared the satisfaction levels in the four groups of
patients at 12 months after the first consultation at TBD-
RC. Moreover, we focused on the group “other diagno-
ses” to analyze more precisely the results in patients with
a bodily distress syndrome and in patients without a spe-
cific diagnosis, as the diagnostic wandering could remain.

Categorical variables are reported here as proportions
and percentages, and continuous variables as medians
with interquartile ranges (IQR). Categorical variables
were compared by chi-squared or Fischer’s exact test,

as appropriate. Continuous variables were compared
between groups by ANOVA or Kruskal–Wallis test, as
appropriate.

Factors associated with the acceptance of the final diag-
nosis (yes vs partially or no) and those with satisfaction
with the management (yes for a score ≥ 7 and no for a
score < 7) were identified using logistic regression mod-
els. In both analyses, factors associated with the outcome
with a p-value < 0.25 in univariate analysis were consid-
ered in the multivariate model. For the acceptance of the
diagnosis, we chose “care and quality of management by
the medical team” to avoid collinearity with the other
variables and thus make them irrelevant to the multivari-
ate model. For the satisfaction with the management, we
focused on the medical management only, which seemed
more relevant, especially as we then studied the concord-
ance of the health status assessed by doctors and patients.
A stepwise backward procedure was then applied to iden-
tify factors that remained independently associated with
the outcome. Gender and age were forced in the models.

The concordance was calculated using a simple Cohen’s
kappa test (deterioration/stagnation versus partial
improvement/recovery). A sensitivity analysis was per-
formed with a weighted Cohen’s kappa (deterioration,

Fig. 1 Care path of the patients consulting for a suspicion of LB at TBD‑RC. TBD‑RC = Tick‑Borne Disease Reference Center; LB = Lyme borreliosis;
PTLDS = Post‑Treatment Lyme Disease Syndrome

Page 5 of 13Raffetin et al. BMC Infectious Diseases (2023) 23:380

stagnation, partial improvement, and recovery). The
strength of agreement was defined as “slight” for a
Cohen’s kappa between 0 and 0.20, “fair” for one between
0.21 and 0.40, “moderate” for one between 0.41 and 0.60,
“substantial” for one between 0.61 and 0.80, and “almost
perfect” for one between 0.81 and 1.00.

A p-value < 0.05 was defined for statistical significance.
All analyses were performed using Stata version 16 (Col-
lege Station, Texas, USA).

The analyses of the two free-text items will be per-
formed in another study using qualitative methods.

Approval of the ethics committee
The local ethics committee of the University Hospital of
Créteil, France, approved this research (N°2021–02-03).
All the included patients (or their legal guardian(s)) gave
an informed consent to the use of their medical data for
research purposes, prior to their management at TBD-
RC of Paris and the Northern region and to the satis-
faction questionnaire. The research sponsor signed a
commitment to comply with the “Reference Methodol-
ogy MR004” of the French Data Protection Authority
(CNIL, 2,216,096 v 0, December 10, 2019).

Funding
None.

Results
Of 569 patients admitted to the TBD-RC of Paris and the
Northern region between December 2017 and December
2020, 349 (61.3%) answered the satisfaction question-
naire (Fig. 2).

Characteristics of the patients
No statistical difference was found between the charac-
teristics of patients who answered and those who did not
answer the satisfaction questionnaire (Additional file 3).
Characteristics of those who answered the satisfaction
questionnaire are presented in the Table  1. The median
age was 48 years old, and 71.4% of the patients were prac-
ticing forest-based leisure activities. There were statisti-
cally more patients with a history of tick-bite (p = 0.001)
or EM (p < 0.001) in the three groups with a diagnosis
associated with LB. The duration of the symptoms before

the initial consultation at TBD-RC was statistically longer
in patients with another diagnosis (p < 0.001). Of note,
10.3% of the patients self-referred to the center with a
complete medical file but with no letter from a physi-
cian. They were admitted as they were in medical wan-
dering. Most of the patients (66.5%) had symptoms for
more than six months, except in the group of confirmed
LB patients, who had a significantly shorter duration of
symptoms (p < 0.001). Only 31.8% of the patients had a
positive serology in ELISA and Western-Blot, regardless
of the final diagnosis. Most of the patients (65.3%) had
received at least one antibiotic therapy before the first
consultation at TBD-RC and 17.5% had received a non-
recommended one (exceeding eight weeks or associating
different molecules).

Descriptive analyses of the satisfaction survey
The answer rate was not different between the four
groups of patients (p = 0.44). The overall median (IQR)
appreciation score was 9 [8;10] (Table  2). Overall, 276
(79.1%) patients were satisfied with their final diagnosis
(score ≥ 7), 280 (80.2%) accepted their final diagnoses,
296 (84.8%) were satisfied with the management and 310
(88.8%) recommended the TBD-RC (Fig. 3). Scores were
significantly higher among patients with a confirmed LB
than among patients with other diagnoses, except when
it came to the assessment of their health condition. Those
scores did not differ from those of the other groups of
patients (p = 0.18).

The scores evaluating reception, the care, and the qual-
ity of the management provided by the paramedical
team one the one hand and by the medical team on the
other hand, the responsiveness and the compassion to
the patients, the care path at TBD-RC, and the informa-
tion given by the doctor were significantly higher among
patients with a confirmed LB than among patients with
other diagnoses (p = 0.008, p = 0.009, p = 0.001, p = 0.004,
p = 0.005, p < 0.001, respectively).

Patients with a confirmed LB had significantly better
evaluations of their care paths at TBD-RC than patients
with PTLDS/sequelae (p = 0.010). Patients with con-
firmed LB accepted their diagnosis significantly bet-
ter than patients with a possible LB (p = 0.006), PTLDS/
sequelae (p = 0.001), or other diagnoses (p = 0.006).

Fig. 2 Flow chart of the patients who were solicited to answer the satisfaction questionnaire at 12 months

Page 6 of 13Raffetin et al. BMC Infectious Diseases (2023) 23:380

Satisfaction with the final diagnosis and with the global
management were significantly better in patients with
confirmed LB compared to other diagnoses (both
p = 0.004). Patients with confirmed LB recommended
the TBD-RC significantly more than patients with other
diagnoses (p = 0.009).

Moreover, patients oriented in the care paths of
infectious diseases, rheumatology, neurology, internal
medicine, or general practice had a significant better
acceptance of the diagnosis than patients oriented in psy-
chology or psychiatry (p < 0.001), and had a higher level

of satisfaction with the management at TBD-RC than
patients oriented in psychology or psychiatry (p = 0.009).

Among the “other diagnoses” group, we focused on
patients with a bodily distress syndrome who answered
the satisfaction questionnaire (n = 30): 17 (56.7%)
accepted their diagnosis, 6 (20.0%) partially accepted
their diagnosis, and 7 (23.3%) refused the diagnosis;
15 (50.0%) were very satisfied with the management, 4
(13.3%) were satisfied, 9 (30.0%) were moderately satis-
fied and 2 (6.7%) were not satisfied; 18 (60.0%) strongly
recommended the TBD-RC, 6 (20.0%) recommended

Table 1 Comparison of the characteristics of the four groups of patients who answered the satisfaction questionnaire

LB Lyme borreliosis, PTLDS Post-Treatment Lyme Disease Syndrome, IQR Inter quartile range, ELISA Enzyme-Linked Immunosorbent Assay, WB Western-Blot, TBD-RC
Tick-Borne Diseases Reference Center

Characteristics of the patients Total
N = 349 (%)

Confirmed LB
N = 48 (%)

Possible LB
N = 31 (%)

PTLDS or sequelae
N = 34 (%)

Other diagnoses
N = 236 (%)

P value

Age, (years), median [IQR] 48 [35,62] 48 [35,62] 49 [35,62] 48 [35,62] 48 [35,61] 0.242

Male 146 (41.8) 30 (62.5) 16 (51.6) 9 (26.5) 91 (38.6) 0.003

Lifestyle 0.287

Home in a rural area 72 (20.6) 6 (12.5) 10 (32.3) 7 (20.6) 49 (20.8) ‑

Employment in rural areas/forest 17 (4.9) 2 (4.2) 1 (3.2) 0 (0.0) 14 (5.9) ‑

Forest‑based leisure activities 249 (71.4) 40 (83.3) 20 (64.5) 26 (76.5) 163 (69.1) ‑

No exposure 11 (3.2) 0 (0.0) 0 (0.0) 1 (2.9) 10 (4.2) ‑

Past history of tick-bite 234 (67.1) 40 (83.3) 25 (80.7) 28 (82.4) 141 (59.8) 0.001

Past history of erythema migrans 97 (27.9) 29 (60.4) 11 (35.5) 16 (48.5) 41 (17.4) < 0.001

Patients referred by a physician
with a letter

313 (89.7) 46 (95.8) 30 (96.8) 30 (88.2) 207 (87.7) 0.108

General Practitioner 241 (69.1) 31 (64.6) 26 (83.9) 26 (76.5) 158 (67.0)

Specialist physician 59 (16.9) 11 (22.9) 2 (6.5) 4 (11.8) 42 (17.8)

Emergency unit physician 13 (3.7) 4 (8.3) 2 (6.5) 0 (0.0) 7 (3.0)

No letter, patient self‑referral 36 (10.3) 2 (4.2) 1 (3.2) 4 (11.8) 29 (12.3)

Duration (days) of chief complaints prior to
consultation at TBD-RC, median [IQ 25,75]

425.5
[140.5, 1208.5]

406.5
[135, 1171]

422
[139, 1191]

425.5
[144, 1208.5]

532.5
[167.5, 1456.5]

< 0.001

Patient’s chief complaint < 0.001

Erythema migrans 10 (2.9) 6 (12.5) 0 (0.0) 1 (2.9) 3 (1.3)

Clinical signs/symptoms evoking early dissemi‑
nated LB (< 6 months)

100 (28.7) 27 (56.3) 12 (38.7) 10 (29.4) 51 (21.6)

Clinical signs/symptoms evoking late dissemi‑
nated LB (> 6 months)

232 (66.5) 15 (31.3) 19 (61.3) 23 (67.7) 175 (74.2)

Questions after a tick‑bite 4 (1.2) 0 (0.0) 0 (0.0) 0 (0.0) 4 (1.7)

Positive serological test with no clinical signs 3 (0.9) 0 (0.0) 0 (0.0) 0 (0.0) 3 (1.3)

Serological test < 0.001

IgM and/or IgG positive in ELISA and WB 111 (31.8) 33 (68.8) 12 (38.7) 19 (55.9) 47 (19.9)

IgG positive in ELISA only 46 (13.2) 5 (10.4) 8 (25.8) 5 (14.7) 28 (11.9)

IgM and IgG negative in ELISA 163 (46.7) 7 (14.6) 11 (35.5) 10 (29.4) 135 (57.2)

No serology (suspicion of erythema migrans) 26 (7.5) 3 (6.3) 0 (0.0) 0 (0.0) 23 (9.8)

Antibiotic therapy prescribed before TBD-RC 228 (65.3) 36 (75.0) 16 (51.6) 34 (100.0) 142 (60.2) < 0.001

Antibiotic therapy > 4 weeks 71 (20.3) 12 (25.0) 2 (6.5) 14 (41.2) 43 (18.2) 0.003

Non‑recommended treatments (> 8 weeks of
antibiotics and/or associated antimicrobials)

61 (17.5) 6 (12.5) 0 (0.0) 10 (29.4) 45 (19.1) 0.011

Page 7 of 13Raffetin et al. BMC Infectious Diseases (2023) 23:380

TBD-RC, 4 (13.3%) had no opinion, and 2 (6.7%) did not
recommend TBD-RC.

Finally, we also focused on patients with no specific
diagnosis at the end of the investigations at the TBD-RC
(n = 17): 16 (94.1%) accepted their diagnosis and 1 (5.9%)
did not; 15 (88.2%) were very satisfied with the manage-
ment at TBD-RC, 1 (5.9%) was satisfied and 1 (5.9%) was
moderately satisfied; 15 (88.2%) strongly recommended
the TBD-RC, 1 (5.9%) recommended TBD-RC and 1
(5.9%) did not.

Factors associated with the diagnostic acceptance
and the management satisfaction at 12 months
In the multivariate analysis (Additional file  4), patients
“very satisfied” with their care paths at TBD-RC had
higher odds (OR = 4.64, 95% confidence interval (CI)
[1.52–14.16]) of diagnosis acceptance compared to
patients only “satisfied.” Patients with a possible LB had
lower odds of diagnosis acceptance compared to patients
with other diagnoses (OR = 0.23, 95%CI [0.07–0.77]).
Patients “moderately satisfied” with the care and the
management of the doctors at TBD-RC had lower odds
of diagnosis acceptance compared to satisfied patients

(OR = 0.05, 95%CI [0.01–0.32]). Patients assessing their
current medical state compared to the previous one as
“stagnation” had lower odds of diagnosis acceptance
compared to patients describing a “partial improvement”
(OR = 0.16, 95%CI [0.06–0.42]).

In the multivariate analysis about management sat-
isfaction (Additional file  5), patients over 48  years
had marginally significant higher odds of satisfaction
with management (OR = 31.98, 95%CI [1.79–571.74],
p = 0.051) than patients under 35. Patients “very satisfied”
with the information given by the doctors had higher
odds of satisfaction with management than “satisfied”
patients (OR = 23.39, 95%CI [3.52–155.54]). Patients
who were moderately satisfied with their care and man-
agement by the medical team had lower odds of satisfac-
tion with management (OR = 0.01, 95%CI [0.00–0.10])
such as patients moderately satisfied with the care paths
(OR = 0.01, 95%CI [0.00–0.08]), compared to satisfied
patients. Gender, final diagnosis, responsiveness, and
compassion to patients were not associated with sat-
isfaction with management. Notably, in the univariate
analysis, a first line of antibiotics prescribed at the TBD-
RC was significantly associated with a better satisfaction

Table 2 Comparative results of the satisfaction questionnaire between the 4 groups of patients at 12 months

LB Lyme borreliosis, PTLDS Post-Treatment Lyme Disease Syndrome, TBD-RC Tick-Borne Diseases Reference Center

Domains and Items rated from 0 (worst) to
10 (best)
Median, [25;75]

Total
N = 349 (%)

Confirmed LB
N = 48 (%)

Possible LB
N = 31 (%)

PTLDS or Sequelae
N = 34 (%)

Other Diagnoses
N = 236 (%)

P-Value

Domain 1: Reception
Satisfaction of the reception by the secretary 9 [8;10] 9 [8;10] 9 [8;9] 8 [8;9] 8 [8;10] 0.017

Domain 2: Care and quality of management
By the paramedical team 9 [8;10] 9 [9;10] 9 [8;9] 8 [7;9] 9 [8;10] 0.007

By the medical team 9 [8;10] 10 [9;10] 9 [9;10] 9 [8;10] 9 [8;10] 0.011

Responsiveness and compassion to patients 9 [8;10] 10 [9;10] 9 [9;10] 9 [8;10] 9 [8;10] 0.023

Care‑path at TBD‑RC 9 [8;10] 9 [8;10] 9 [8;10] 8 [7;10] 9 [8;10] 0.020

Domain 3: Information and explanations given to the patients
By the secretary 9 [8;10] 9 [8;10] 9 [8;10] 8 [7;10] 8 [8;10] 0.003

By the paramedical team 9 [8;10] 9 [9;10] 9 [8;9] 8 [7;9] 9 [8;10] 0.004

By the medical team 9 [8;10] 10 [9;10] 9 [9;10] 9 [8;10] 9 [8;10] < 0.001

Domain 4: Current medical condition
Current condition after the management at
the TBD-RC compared to the previous one

8 [7;9] 8.5 [8;9] 8 [7;9] 8 [7;9] 8 [7;9] 0.185

Acceptance of the final diagnosis 0.020

Yes 280/349 (80.2) 47/48 (97.9) 24/31 (77.4) 24/34 (70.6) 185/236 (78.4)

No 29/349 (8.3) 1/48 (2.1) 1/31 (3.2) 4/34 (11.8) 23/236 (9.8)

Partially 40/349 (11.5) 0/48 (0.0) 6/31 (19.4) 6/34 (17.7) 28/236 (11.9)

Domain 5: Overall appreciation
Satisfaction of the final diagnosis 9 [8;10] 10 [9;10] 9 [8;10] 9 [8;10] 9 [6;10] 0.031

Satisfaction of global management 9 [8;10] 10 [9;10] 9 [9;10] 9 [8;10] 9 [8;10] 0.025

Recommendation of the TBD‑RC to your sur‑
roundings

9 [8;10] 10 [9;10] 9 [9;10] 9 [8;10] 9 [8;10] 0.041

Page 8 of 13Raffetin et al. BMC Infectious Diseases (2023) 23:380

with management compared to that of patients who had
received a previous one (OR = 2.59, 95%CI [1.17–5.71],
p = 0.011). However, a second line of antibiotics pre-
scribed at TBD-RC was not associated with a better satis-
faction (p = 0.124).

Concordance of the medical health assessment
between the physicians and the patients 12 months
after the management at TBD-RC
The Cohen’s kappa value in all the patients demonstrated
a moderate agreement (κ = 0.41) between the doctor and
the patient health assessment at 12  months after their
management at TBD-RC (Table 3 and Fig. 4). Nonethe-
less, there was no difference between the doctor and the
patient health assessment in patients with confirmed
LB or possible LB, with a Cohen’s kappa value show-
ing an almost perfect agreement in patients with possi-
ble LB (κ = 0.99). In patients with PTLDS/sequelae, the
agreement was fair (κ = 0.36), and in patients with other
diagnoses it was moderate (κ = 0.43). The differences in
agreement were always in the same direction: patients
assessed their health status more severely than physicians
did (Table 3). There was no difference in the results of the
simple Cohen’s kappa and of the weighted Cohen’s kappa.

Moreover, despite moderate agreement in patients
with other diagnoses regarding their orientation in the
adapted department, there was not any statistical differ-
ence between the medical and the patients’ assessments
of the patients’ health statuses (p = 0.083).

Discussion
Summary of the principal findings
To our knowledge, this is the first study assessing the
diagnostic acceptance and the satisfaction of patients
undergoing multidisciplinary management of sus-
pected LB. We recorded a very good overall appreciation
(median of 9/10 [8;10]) from the patients who consulted
at the TBD-RC of Paris and the Northern Region. Over-
all, 79.1% (n = 276/349) of them were satisfied with the
final diagnosis, 80.2% (n = 280/349) accepted their diag-
nosis, 84.8% (n = 296/349) were satisfied with the man-
agement and 88.8% (n = 310/349) recommended the
TBD-RC to others. As expected, patients with confirmed
LB showed significantly higher satisfaction level than
patients with other diagnoses. Patients with a high satis-
faction with the care paths at TBD-RC were four times
more likely to accept their diagnosis. The high satisfac-
tion of the information given by the doctors was the

Fig. 3 Comparative results of the overall appreciation between the 4 groups of patients at 12 months

Page 9 of 13Raffetin et al. BMC Infectious Diseases (2023) 23:380

main factor positively associated with satisfaction with
the management. The concordance between patients and
physicians to assess their health status 12  months after
their first consultation at TBD-RC was almost perfect
in patients with confirmed and possible LB, fair in those
with PTLDS/sequelae and moderate in those with other
diagnoses.

Strengths and weaknesses of the study
Our data should help other physicians involved in LB
management and its differential diagnoses to better
understand the expectations of patients and to improve
their care paths. The comparison of the current medi-
cal condition assessed by patients or by physicians at
12  months after their management at TBD-RC also
highlights the differences between “disease” and “illness”
and might enable a better assessment of the latter in the
future, leading to a better patient-centered care. Moreo-
ver, we obtained a high answer rate (61.3%), enhanc-
ing the power of the analyses, probably due to the three

systematic reminders, and to the brevity of the question-
naire (2–5 min), which was highlighted by patients as a
condition to answer.

The main limitation is that we used a non-previously
validated satisfaction questionnaire for the management
of LB in a monocenter study. Nonetheless, we assume
that this point represents also a strength, as ours is the
first study assessing this topic with a questionnaire
drawn up by a dedicated and multidisciplinary team,
by patients, and by patients’ associations to fulfill their
expectations. We assume an innovative use of this survey.
A multicenter validation of this questionnaire in other
TBD-RC in France and in Europe could enable research-
ers to assess its external validity and its reproducibility in
other settings.

Strengths and weaknesses in relation to other studies
To our knowledge, the satisfaction of patients with a
suspicion of LB had not been assessed before this study.
Some studies have already been published and found
similar results for other diseases (cancer, diabetes, etc.)

Table 3 Concordance of the medical health assessment between the physicians and the patients at 12 months

NA Not adapted, Cohen’s kappa could not be performed because of too close values but there was no statistical differences (almost perfect accordance), LB Lyme
borreliosis, PTLDS Post-Treatment Lyme Disease Syndrome

Current medical condition of the patients at M12 after
TBD-RC, compared to the previous medical condition

Assessed by the patient Assessed by the
physician

P-value Cohen’s Kappa

Of all the patients < 0.001 0.41

Deterioration (score 0–4)
Or Stagnation (score 5–6)

63/345 (18.3) 48/345 (13.9)

Partial improvement (score 7–8)
Or Recovery (score 9–10)

282/345 (81.7) 297/345 (86.1)

Of patients with a confirmed LB 0.831 NA

Deterioration (score 0–4)
Or Stagnation (score 5–6)

2/47 (4.3) 1/47 (2.1)

Partial improvement (score 7–8)
Or Recovery (score 9–10)

45/47 (95.7) 46/47 (97.9)

Of patients with a possible LB 0.739 0.99

Deterioration (score 0–4)
Or Stagnation (score 5–6)

1/31 (3.2) 3/31 (9.7)

Partial improvement (score 7–8)
Or Recovery (score 9–10)

30/31 (96.8) 28/31 (90.3)

Of patients with PTLDS/sequelae 0.022 0.36

Deterioration (score 0–4)
Or Stagnation (score 5–6)

6/33 (18.2) 3/33 (9.1)

Partial improvement (score 7–8)
Or Recovery (score 9–10)

27/33 (81.8) 30/33 (90.9)

Of patients with other diagnoses < 0.001 0.43

Deterioration (score 0–4)
Or Stagnation (score 5–6)

54/234 (23.1) 41/234 (17.5)

Partial improvement (score 7–8)
Or Recovery (score 9–10)

180/234 (76.9) 193/234 (82.5)

Page 10 of 13Raffetin et al. BMC Infectious Diseases (2023) 23:380

or for specific settings (private care structures, rural hos-
pitals, etc.) [32–35]. A study exploring the satisfaction of
patients with health care in Chinese public hospitals
in urban and rural areas demonstrated that the most
important factors were the professional competence,
communication/information, caring attitude, emotional
support, and the environment/facilities [32]. Moreover, for
the elderly care in private structures, satisfaction with
care has come to play a crucial role. Kazemi et al. iden-
tified that supportive leadership was positively associ-
ated with satisfaction with care, as it enabled the job
satisfaction of the workers and therefore a higher qual-
ity of the care delivered to the patients [33]. In addition,
Moreno et al. showed that the satisfaction of patients
with cancer care was associated with a high percep-
tion of their quality of life, and with a good commu-
nication with their care provider, as in our study [34].
In the future, we could implement our satisfaction
survey with a question about the quality of life of the
patients.

Meaning of the study and implication for practice
and for policy makers
Diagnostic certainty as an element of diagnostic acceptance
and concordance? Not only and not necessarily
Patients with a possible LB had lower odds of accepting
their final diagnosis compared to other diagnoses. The
word “possible” introduces the notion of uncertainty,
leading to a possible doubt about the final diagnosis.
Actually, due to uncertainty, auto-diagnosis could be
elaborated and shaped by patients’ emotions, representa-
tions and experiences of the disease. Consequently, “dis-
ease” (doctor’s point of view), “sickness” (societal point of
view) and “illness” (patient’s point of view) can coexist,
according to the different points of view [36]. Nonethe-
less, this point is balanced by the high satisfaction with
the management at TBD-RC reported by patients with a
possible LB, and by the results among patients with no
specific diagnosis who reported a high acceptance of the
absence of specific diagnosis and a high satisfaction with
the global management at TBD-RC.

Fig. 4 Comparison of the medical health assessment between the physicians and the patients at 12 months

Page 11 of 13Raffetin et al. BMC Infectious Diseases (2023) 23:380

A favorable clinical outcome as element of agreement
between doctors and patients
Despite the lower odds of diagnostic acceptance in
patients with possible LB, patients with confirmed and
possible LB had an almost perfect strength of concord-
ance with the doctor’s health state evaluation after one
year of management at TBD-RC. The better clinical out-
comes of these two groups of patients (91.6% and 90.7%
of patients with a favorable outcome, respectively) [27]
seems to draw these two evaluations closer, by bring-
ing together the “disease,” the “sickness” and the “ill-
ness” independently of the degree of subjectivity of the
patients. A favorable outcome should also restore con-
fidence in the health care system and free oneself from
misconceptions.

Information, a key for the management satisfaction
The subjectivity of patients and their experiences of the
disease have an important place in diagnosis acceptance,
which follows the five well-known steps: the initial shock,
the denial, the rebellion, the negotiation, the reflection
and finally the acceptance [37]. Although information
was well delivered, it was not associated with diagnosis
acceptance by patients, probably because of their own
experiences and their own “grief circles.” Other sources
of information, such as media or the surroundings, can
play a role in the construction of disease perception and
representation. However, well-delivered information was
strongly associated with better satisfaction with manage-
ment, showing that the doctor-patient relationship is at
the forefront of the care experience, and emphasizing the
importance of the shared medical decision, as already
demonstrated in other studies [32, 38]. Indeed, the time
spent with the patient to share information and listen to
them to meet their expectations may help to reduce med-
ical wandering and health misinformation.

Multidisciplinary management to improve the satisfaction
with global management
The high overall satisfaction with case management by a
multidisciplinary team has been shown in our study, such
as in other studies. Implementation of a pain manage-
ment strategy in a trauma center in Australia involving
a dedicated and multidisciplinary team led to improve-
ments in communication about pain with the trauma
patients and increased the patients’ pain satisfaction
score [39]. This corroborates our results showing that the
information was strongly associated with a better satis-
faction, probably due to the fact that the TBD-RC had
a dedicated and very specialized team. Moreover, in a
multidisciplinary colorectal and uro-gynecology service
in Ireland, seeing many specialists at the same place was

associated with a high satisfaction of the patients and
higher physician confidence [40].

Unanswered questions and future research
More studies in other settings are warranted to assess
these preliminary findings and the external validity of the
satisfaction questionnaire used for LB. Studies in the field
of social sciences and anthropology would be comple-
mentary, improving comprehension of the expectations
of the patients, of their possible ensuing paradoxes, and
of their points of satisfaction and dissatisfaction. They
would also help to better understand the origins of mis-
information that may have led to medical wandering and
then to dissatisfaction of the TBC-RC. The type of sat-
isfaction questionnaire we used in our center could be
implemented after these warranted studies.

Conclusion
Patients seemed to approve of this new multidiscipli-
nary care organization for suspected LB, as in TBD-RC,
showing high satisfaction with the diagnostic and thera-
peutic management. The final diagnostic acceptance was
associated with the satisfaction with the proposed care
paths and the current medical condition of the patients.
The high satisfaction with the information given by the
doctors was a key element of the satisfaction with the
management, confirming the importance of the doctor-
patient relationship and of the shared medical decision
(time spent with patient to share information and to lis-
ten to them to meet their expectancies). This may help to
reduce health misinformation.

The agreement between patients and physicians to
assess their health status 12 months after their manage-
ment at TBD-RC was almost perfect for patients with
confirmed and possible LB, suggesting that a favorable
clinical outcome allows for bringing these two evalua-
tions closer, independently of the degree of subjectivity of
the patients and of their degree of misconceptions.

Multidisciplinary structures may be useful for any complex
diagnosis, such as LB, to help to reduce medical wandering
and the negative impact of health misinformation.

Supplementary Information
The online version contains supplementary material available at https:// doi.
org/ 10. 1186/ s12879‑ 023‑ 08352‑3.

Additional file 1: Supplementary file 1. STROBE Statement—Checklist
of items that should be included in reports of cohort studies.

Additional file 2. Satisfaction survey.

Additional file 3: Supplementary file 2. Comparison of the epidemio‑
logical characteristics of the patients who answered or not to the satisfac‑
tion survey, consulting the TBD‑RC of Paris and the Northern region.

Page 12 of 13Raffetin et al. BMC Infectious Diseases (2023) 23:380

Additional file 4. Multivariate analyses of the associated factors with the
diagnostic acceptance versus no acceptance at 12 months.

Additional file 5. Multivariate analyses of the associated factors with the
management satisfaction versus no satisfaction at 12 months.

Acknowledgements
We are grateful to the following persons for their contribution and support to
the TBD‑RC and this study. The Tick‑Borne Diseases Reference Center of Paris
and the Northern Region Working Group : Anna Belkacem, Fernanda Medina,
Audrey Barrelet, Agathe Bounhiol, Kevin Diallo, Danielle Jaafar, Claudine Badr,
Soline de Monteynard: Department of Infectious Diseases; Romain Jouenne,
Emmanuel Dossou: Department of Internal Medicine; Stéphanie Emilie, Chris‑
tine Shenouda: Department of Rheumatology; Catherine Fabre, Lydie Lim,
Navaneethan Nindulan: Department of Neurology; Sylvie Le Berre, Corinne
Canu, Vincent Robin: Department of Algology; Sophie Dellion, Floriane Kouby:
Department of Dermatology; Jonas Bantsimba: Department of Geriatrics;
Jacques Breuil, Eric Hernandez, Camille Corlouer, Laurence Ghisalberti: Depart‑
ment of Microbiology; Eric Meinadier, Arthur Lefort: Department of Physical
Rehabilitation; Aurélie Garraffo, Anne Chace, Emilie Georget, Anaïs Chosidow:
Department of Pediatrics; Ilia Pustilnicov, Arnaud Bimier: Department of Health
Economics. We are grateful to the French Ministry of Health, which has pro‑
vided an annual budget allowance for the development of the TBD‑RC since
July 2019, and to the Regional Health Agency of Paris region who created a
position for an infectious diseases physician to work at the TBD‑RC in 2020.

Potential conflicts of interests
None.

Authors’ contributions
Conceptualization: A.R., J.S., A.C., S.N.; methodology: A.R., Y.M., J.R., S.G.; valida‑
tion: A.R., J.R., S.G.; formal analysis: A.R., J.R., Z.H., S.N.; Investigation: A.R., A.C.,
J.S., P.C.‑P., G.P.; writing—original draft preparation: A.R., S.G., J.R.; writing—
review and editing: A.R., A.C.,J.R., S.G., J.S., P.C.‑P., G.P., S.P.‑D., E.B., Y.M., Z.H., S.N.,
P.A.; visualization: A.R., A.C.,J.R., S.G., J.S., P.C.‑P., G.P., S.P.‑D., E.B., Y.M., Z.H., S.N.,
P.A.; supervision: J.R., S.G. All authors have read and agreed to the published
version of the manuscript. The corresponding author attests that all listed
authors meet authorship criteria and that no others meeting the criteria have
been omitted.

Funding
None.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from
the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate
The local ethics committee of the University Hospital of Créteil, France,
approved this research (N°2021–02‑03). All the included patients (or their
legal guardians) gave an informed consent to the use of their medical data
for research purposes, prior to their management at TBD‑RC of Paris and the
Northern region and to the satisfaction questionnaire. The research sponsor
signed a commitment to comply with the “Reference Methodology MR004” of
the French Data Protection Authority (CNIL, 2216096 v 0, December 10, 2019).
All methods were carried out in accordance with the Declaration of Helsinki.

Consent for publication
Not applicable.

Competing interests
The authors declare no competing interests.

Author details
1 Department of Infectious Diseases, Tick‑Borne Diseases Reference Center
of Paris and the Northern Region, General Hospital of Villeneuve‑Saint‑
Georges, Villeneuve‑Saint‑Georges, France. 2 EpiMAI Research Unity, Laboratory

of Animal Health, Ecole Nationale Vétérinaire d’Alfort, Anses‑National
Veterinaty School of Alfort, Maison‑Alfort, France. 3 DYNAMIC Research Unity,
UPEC‑Anses, Créteil, France. 4 Department of Rheumatology, Tick‑Borne
Diseases Reference Center of Paris and the Northern Region, General
Hospital of Villeneuve‑Saint‑Georges, Villeneuve‑Saint‑Georges, France.
5 Department of Psychiatry, Tick‑Borne Diseases Reference Center of Paris
and the Northern Region, General Hospital of Villeneuve‑Saint‑Georges, Ville‑
neuve‑Saint‑Georges, France. 6 Department of Public Health, University of Paris
Saclay, Saclay, France. 7 Department of Infectious Diseases, Tick‑Borne Diseases
Reference Center of the Eastern Region, Brabois Hospital, University Hospital
of Nancy, Nancy, France. 8 Department of Infectious Diseases, Tick‑Borne Dis‑
eases Reference Center of the Western Region, University Hospital of Rennes,
Rennes, France. 9 Department of Psychology, Lumière University Lyon II, UMR
1296, Lyon, France. 10 Epidemiology of Emerging Diseases Unit, Institut Pasteur,
University of Paris, Paris, France. 11 Department of Infectious Diseases, UH Henri
Mondor, Créteil, France.

Received: 21 November 2022 Accepted: 26 May 2023

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  • Acceptance of diagnosis and management satisfaction of patients with “suspected Lyme borreliosis” after 12 months in a multidisciplinary reference center: a prospective cohort study
    • Abstract
      • Introduction
      • Methods
      • Results
      • Conclusion
    • Key messages
    • Introduction
    • Methods
      • Population, setting, and intervention
      • Patient data and satisfaction survey
      • Statistical analysis
      • Approval of the ethics committee
      • Funding
    • Results
      • Characteristics of the patients
      • Descriptive analyses of the satisfaction survey
      • Factors associated with the diagnostic acceptance and the management satisfaction at 12 months
      • Concordance of the medical health assessment between the physicians and the patients 12 months after the management at TBD-RC
    • Discussion
      • Summary of the principal findings
      • Strengths and weaknesses of the study
      • Strengths and weaknesses in relation to other studies
      • Meaning of the study and implication for practice and for policy makers
        • Diagnostic certainty as an element of diagnostic acceptance and concordance? Not only and not necessarily
        • A favorable clinical outcome as element of agreement between doctors and patients
        • Information, a key for the management satisfaction
        • Multidisciplinary management to improve the satisfaction with global management
      • Unanswered questions and future research
    • Conclusion
    • Anchor 31
    • Acknowledgements
    • References

2

Epidemiological Research Study Review No. 1

SARS-CoV-2 Infection & Pulmonary Tuberculosis in Children and Adolescents: A Case-Control Study

PMHNP Post-Master

NGR5674-Population Health, Epidemiology, & Statistical Problems

Professor Diane Gullett, RN, PhD, MSN, MPH

July 9, 2023

Epidemiological Research Study Review No. 1

The purpose of the review of “SARS-CoV-2 infection and pulmonary tuberculosis in children and adolescents: A case-control study” (2023) using a critical appraisal tool is to analyze the assertiveness of the study and research through a structured checklist that make an evaluation of the methodology against the set of criteria to provide theoretical and clinical quality. The present review covers the analytical appropriateness of the design and results evaluation.

Citation

Swanepoel, J., van der Zalm, M.M., Preiser, W. et al. (2023). SARS-CoV-2 infection and pulmonary tuberculosis in children and adolescents: a case-control study
. BMC Infect Dis,
23, 442.
https://doi.org/10.1186/s12879-023-08412-8

Study Design: Observational unmatched case-control study

Level of Evidence: IV

Introduction/Background


Rationale Provided for Study

As a result of the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-Cov-2) pandemic, it is possible that the risk of exposure to the disease can influence in the increase of the occurrence of infection with Tuberculosis (TB) in children and adolescents not only due to the physiologic affectation but also as a consequence of the exposure and the fragmentation of the medical/clinical services. The study pursues to determine if an exposure is associated with such outcome.


Significance of Study Provided

As both diseases are influenced by bio-social determinants where exist probable directional consequences in the risk factors and the incidence of morbidity and mortality, the study is focused on determining whether an association exists between previous SARS-CoV-2 infection and odds of TB to establish a clinical understanding between such relationship.


Current State of Science or Evidence clearly Articulated

The research with emphasis on the correlation between exposure to SARS-CoV-2 and TB has not completely understood and investigated. Not only SARS-CoV-2 is a novel disease which health implications at the long-term demand new study but also TB for child and adolescent has remained as an area neglected by research and programmatic prioritization. Only one cohort study and one clinical study (from same population) have provided some findings which take both different conclusions about the clinical evidence of the immune response in terms of association from the exposure between both diseases.


Problem Statement/Area Identified

According to the authors, “the association between pulmonary TB and past SARS-CoV-2 infection remains understudied.” (Swanepoel, Van Der Zalm, & Preiser et. al., 2023). The reduction of immune responses either due to the infection processes or the effect of pharmacological and/or clinical interventions in combination with risk factors to disease infection reveals that “hyperinflammatory environment, induced by SARS-CoV-2 infection, could potentially accelerate TB disease progression.” (Swanepoel et. al., 2023).


Research Purpose

The purpose has been established as “to determine whether an association exists between previous SARS-CoV-2 infection and odds of pulmonary TB disease in children and adolescents from a high TB burden setting” (Swanepoel et. al., 2023)., including the evaluation of autoimmune response through IgG measures, and the odds of pulmonary TB disease.

Design


Research Question

The research question for the current study is not stated even thought the dissertation seeks for the exploration and explanatory findings that correlate and demonstrate the relationship between the exposure of SARS-CoV-2 infection as risk factor for complication of TB. In this form, the implicit research question pursues the accuracy of relation in terms of infection rather than to establish any prognosis, diagnostic, or treatment. As TB can have a long latency period between an exposure and outcome, the intention for a precise research question to match the study design is placed on the attribute of interest and a single outcome.


Cases

The cases have been clearly defined from previous census of a cohort study in a region and group (Umoya and Teen TB) from the period of one year (November 1st, 2020 to November 1st, 2021). The case definition has been established as “primary diagnosis of newly diagnosed pulmonary TB, with or without HIV co-infection, was made in a hospital or clinic and patients were within the first 14 days since diagnosis.” (Swanepoel et. al., 2023). In this way the cases were based on the prevalence according that the cases consider new and preexisting within the population at the specific time rather than the choice of new cases (incident). For the study, the overall cases are referred, however, from the incidence of TB in the region at 681/100,000 (2015) (Swanepoel et. al., 2023).

Teen TB

Umoya

Combined

Cases n (%)

Controls n (%)

Cases n (%)

Controls n (%)

Cases n (%)

Controls n (%)

Overall

50

51

14

48

64

99

From the same population, once the groups have been defined, the cases (and controls) are evaluated using the inclusion and exclusion factors. The sample considered one-hundred-and-one adolescents and 86 children. Among the 86 eligible participants from the Umoya study, 24 children were excluded while the remaining from the total 163 individuals (sixty-four individuals with pulmonary TB and 99 individuals without pulmonary TB were included. were gathered from the Teen TB study. In terms of proportion from the population, it is not provided a data which serve to conclude the real equivalence but referred those cases where pulled from the system which deliver health services to 30% of the regional population (Swanepoel et. al., 2023).


Controls

Controls have been established as “individuals younger than 20 years of age from similar epidemiological contexts as TB cases who were evaluated closely and found to not have current TB disease” (Swanepoel et. al., 2023). The number of controls also was redefined under the inclusion and exclusion functions and estimated according to similar range to compare with the cases. They were pooled from similar populations and gathered from the same studies as the cases. The proportion of controls are not defined in the relation to the control in an explicit method; however, the independence from the risk factor of exposure seems like the controls have been sampled in a way that their independent of the exposure, from their selection, have not been more (or less) likely if they have the exposure of interest.


Exposures

The exposure to has been ascertained by the detection of quantitative SARS-CoV-2 anti-spike immunoglobulin G (IgG) which means that the individuals have been exposed in the last 14 days to SARS-CoV-2. The results of such exposure to the risk factor are supposed to increase the likelihood of allowing the transition from latent to active TB. The measure is developed through serological assay according to the manufacturer’s protocols (tests) and blinded to clinical characteristics where values≥50 and <50 were defined as positive and negative respectively (Swanepoel et. al., 2023). However, exposure can be linked to facts of misclassification due to the potentiality of other viral infections such as Human Immunodeficiency Virus (HIV), influenza, and measles to an increased risk of TB disease in same population by inducing immunosuppression. The exposure determination is similar for cases and controls considering person, time, and place.


Sampling, Variables, & Level of Significance

The sampling in size is proper for evaluation and contrast against previous studies (cohorts) and for the microbiologic confirmation of pulmonary TB disease against healthy individuals exposed to an infectious case of pulmonary TB in their household. With 164 individuals among cases and control, the sampling satisfies the normal distribution. The samples utilized baseline clinical data collected from the participants, but serum samples are collected as part of the biorepository and stored for later analysis. Nevertheless, the study considers a variable which is not included in the research criteria according to the HIV status of case, control, and environment (with or without HIV co-infection). P value from a likelihood ratio test for trend with a significance level of 95% (Swanepoel et. al., 2023).


Data Management

Data was analyzed using STATA (version 17, College Station, TX, USA). The information was processed under the descriptive analysis to characterize the study population, comparing the case and control groups to identify differences between groups with respect to potential confounders. Univariable logistic regression was performed to calculate unadjusted odds ratios (ORs) and accompanying 95% confidence intervals (CIs) for each covariable. A Mann-Whitney U-test was developed to assess whether the distribution of SARS-CoV-2 IgG

values differed between case and control groups. The analysis plan was established to find any association because of the risk factors combining dataset and different combination of controls (Swanepoel et. al., 2023).

Results/Findings


Comparison of Cases vs Controls

The statistical procedures calculate the relationship between exposures and the likelihood of becoming ill in a given patient with exposure to SARS-CoV-2. Both, cases and controls, are pulled from the same population where bio-social descriptors entail a mixed ancestry, age group, sex, household size, socioeconomic environment, risks of exposure, and comorbidities with diseases (HIV). However, the study recognizes that in the comparison between cases and controls, the outcome comparison was not possible to adjust for sex (differences) or HIV status due to the small number of cases in the model of statistical inference by estimating the distribution of log-transformed viral-specific IgG response values (Swanepoel et. al., 2023). The particular control recruitment functions is different for one group (Teen TB) based on they were recruited to the study later than cases.


Confounders Distribution/Adjustments

The researchers recognize that there is also a risk of residual confounding in this study. SARS-CoV-2 and TB. Potential confounders such as sex and HIV status could not be included in the model examining the association between SARS-CoV-2 IgG due to the small number of IgG seropositive individuals with TB disease. The matching of cases and controls on key confounders such as age and sex were not possible to be estimated during the analysis and no adjustment were developed to measure confounding variables (with the exception of age), making difficulty to determine if both are equally distributed between cases and controls (Swanepoel et. al., 2023).


Sample Size, Power Analysis, & Strength of Association

Based on the sample size, there was no significant difference in the odds of pulmonary TB disease between those with SARS-CoV-2 IgG serology, SARS-CoV-2 IgG for seropositive and seronegative, and seropositive cases and controls median IgG value in the combined dataset. Statistical power in the hypothesis test, as the probability that the test will detect an effect, was determined at p-value of 0.04, 0.09, 0.21, and 0.18 for each sensitivity analysis respectively and in relation with the odds ratios estimated using unconditional logistic regression (Swanepoel et. al., 2023). The study was inadequately powered to investigate the main study associations.


Accuracy

The accuracy of the estimation through the association between the exposure and outcome was establishes for the unadjusted at 95% CI in each group and combined at 0.14, 0.54, and 0.36 while after the adjusted OR with same significance it remains at 0.81 with combined at 0.9 (Swanepoel et. al., 2023). This represents an issue to validate the correlation from exposure to development of the disease (from latent to active). A case-control study can help to test a hypothesis about the link between a risk factor and an outcome, it is not as powerful as other types of study in confirming a causal relationship.

Bias/Confounders

The researchers were unable to identify all potentially critical confounders, referring that many potential confounders that need to be considered when investigating associations between these two infections. They also pointed out that the risk of selection bias and residual confounding in the study were high due to the biases associated with the types of controls selected. Using inclusion/exclusion criteria was not enough to influence over the appropriate data collection method (selection bias), regardless the data was integrated from cohort studies. Particular assertion is taken from symptomatic controls in the incidence of hospital admission, which increases the risk of acquiring SARS-CoV-2 (information bias) (Swanepoel et. al., 2023).

Implications of Findings/Results

Once the datasets were combined and adjusted for age group, sex, and household size, there was not possible to find evidence of a relationship between previous SARS-CoV-2 infection and pulmonary TB disease. However, by using IgG antibody response, it appears that serological response to SARS-CoV-2 amongst cases with serological evidence of previous infection demonstrated an increased odds of pulmonary TB disease. The potential application, in addition to be the first study in the region which evaluate relationship between risk factors of SARS-CoV-2 and TB, is the generalization of these findings as references in others high TB-burden settings, and how the virulence, dysregulation of immunological responses, and severity of new SARS-CoV-2 infections can increase the risk factor for progression to TB disease or increases susceptibility to infection (Swanepoel et. al., 2023). The researchers´ recommendations not only emphasizes the growing body of knowledge on the association between two infections but adds with the finding the necessity to generalizable same type of study to more settings.

Strengths

A strength of the study includes the use of a serology testing strategy that allows for the interpretation of an exposure-outcome temporal association but has the weakness of evaluation of serum samples from individuals with TB who were within the first 14-day since diagnosis which affect and reduce the chance of detecting IgG antibodies against SARS-CoV-2

acquired after the diagnosis of pulmonary TB disease was made. Another strength is the inclusion of more controls than TB cases from the same cohort study (Swanepoel et. al., 2023).

Limitations

Based on researchers´ analysis, they determine that the study was inadequately powered to investigate the associations, influence probably by the interference of random errors. The Teen TB and Umoya studies provided different control groups, including the ineffective background frequency selection for SARS-CoV-2 IgG seropositivity samples which differ between the control groups and the general population (as the proportion could not be defined). Moreover, the matching of cases and controls on key confounders such as age and sex were not possible evaluated (Swanepoel et. al., 2023). For the data management and analysis methods, the sampling differs in some controls from the Teen TB group in place and time, leading to the occurrence of bias, including the facts that IgG ranges for the cases cannot be generalized due to the differences in SARS-CoV-2 transmission dynamics.

Ethical/Legal

The research accomplishes to follow the Declaration of Helsinki and South African Guidelines for Good Clinical Practice. Ethical approval for the project was obtained from several institutions according to the Committee´s approval and protocols. For samples access, all parents/legal guardians/participants in the studies provided written informed consent for their data and samples, establishing protection of individual´s rights. It was not necessary to receive approval for consent for publication and the authors does reveal any competing interests. The research provides human subject protection during for communication with cases and controls, but it does not address the healthcare orientation for those who tested positive for active TB.

Reflection

The case-control study is fair in the provision of scientific merit for a research report but has a poor applicability to clinical decision making. The study was unable to demonstrate convincing evidence of relationship between the exposure to SARS-CoV-2 for development of active tuberculosis. Several flags were detected in the revision of cases and controls groups, statistical inferences in the tabulation, power analysis, confounders, and bias. It is recognized as the first epidemiologic study which evaluates the relationship between both diseases. Then, the analysis can be conceptualized as being undertaken on a reconstructed source population from which cases and controls stem as well as the matching between the exposure-outcome distribution.


References

Mhaskar, R., Emmanuel, P., & Mishra, S. et. al. (2009). Critical appraisal skills are essential to informed decision-making.
Indian J Sex Transm Dis AIDS. 30(2):112-9. doi: 10.4103/0253-7184.62770.

Porche, D. J. (2023). Epidemiology for the Advanced Practice Nurse: A Population Health Perspective. Appendix E: 327-328

Swanepoel, J., Van Der Zalm, M. M., & Preiser, W. et. al. (2023). SARS-CoV-2 infection and pulmonary tuberculosis in children and adolescents: a case-control study.
BMC Infectious Diseases, 23(1). https://doi.org/10.1186/s12879-023-08412-8

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