King’s Sarcoidosis Questionnaire (KSQ) – Validation study in Serbian speaking population of sarcoidosis patients

Introduction Sarcoidosis is a multiorgan, multisystem chronic disease of unknown etiology and unpredictable course. Health status is reduced in sarcoidosis and assessing it is a difficult multitask effort due to many faces this disease might have. Recently, a new questionnaire for assessing health status in sarcoidosis was developed by a group of authors from England–King’s Sarcoidosis Questionnaire (KSQ). The benefit of KSQ is the ability to develop the best care plan for the patient, as well as to differentiate the efficacy of the administered treatment. Objective The aim of this study was to validate the KSQ in Serbian speaking population of sarcoidosis patients. The test itself is a modular, multi-organ health status measure for patients with sarcoidosis for use in clinic and the evaluation of therapies. The correlation of KSQ with different clinical course of sarcoidosis (acute vs chronic disease) and with the clinical outcome status (COS) in sarcoidosis was also investigated. Methods A total of 159 biopsy positive sarcoidosis patients participated in this study. The average age of the participants was 49.67, majority was female (67.3%) and majority had only pulmonary form of sarcoidosis (71.7%). KSQ ‐ new disease-specific health status instrument, was compared with 5 other already existing instruments already used and validated in sarcoidosis (Saint George Respiratory Questionnaire- SGRQ, Daily Activity List -DAL, Fatigue Assessment Scale- FAS, Medical Research Council dyspnea scale–MRC, Borg Dyspnea Scale and 15D as general questionnaire. Results KSQ has significant correlation with other quality of life questionnaires already used in sarcoidosis. Translated version of KSQ shows significant internal reliability, similar to the original KSQ. Serbian version of KSQ has significant correlation with different clinical course of sarcoidosis and with COS as well. The translated version of KSQ is reliable sarcoidosis specific instrument for assessing health status in these patients.


Funded studies
Enter a statement with the following details:  Pulmonary involvement is present in a vast majority of patients, so the evaluation of pulmonary function tests (PFTs) and chest X ray findings are frequently used in daily practice to assess the disease severity [2].However, these tests often poorly correlate with patients` symptoms.Studies evaluating these problems showed poor agreement between physicians and patients regarding the perceived symptoms of sarcoidosis [3].The gap is even bigger regarding the failure of physicians to evaluate the impact of non-specific features of sarcoidosis related to sensation of fatigue and cognitive function impairments which evidently do occur in sarcoidosis [4,5].
Sarcoidosis usually affects population of working age, who may find very difficult to cope with this disease and its consequent and certainly negative impact on their health status and quality of life.Despite the studies performed with the aim to find out the reliable tools for assessment the disease severity or its progression, up to date there is no reliable tool for assessing the impact of sarcoidosis on patients' health status, and also the impact of therapy with all possible side effects.
Until now the only developed disease-specific questionnaire for measuring the health status in sarcoidosis was the Sarcoidosis Health Questionnaire, created by Christopher Cox and coworkers; it exanimated three domains: Daily Functioning, Physical Functioning, and Emotional Functioning [6].This questionnaire was validated in patients attending a university medical center in the US where 80% of them were African-Americans [6].
Recently new questionnaire for assessing the health status in sarcoidosis was developed by a group of authors from England: The King's Sarcoidosis Questionnaire (KSQ) [7].The KSQ has 5 sections: general health status, lungs, medication, skin and eyes.
The aim of this study was to validate the KSQ in non-English speaking population of sarcoidosis patients.The objective was also to compare the KSQ as disease-specific health status questionnaire with other already used questionnaires in sarcoidosis.

Methods and patients
The cross-sectional study was conducted in the Clinic for Pulmonology of the Clinical Center of Serbia in Belgrade over the period of 6 months.

Patients
We enrolled 159 biopsy positive sarcoidosis patients diagnosed in the Clinic.They all had noncaseating epithelioid cell granulomas on their lung biopsy specimens, without a known cause being identified.All subjects were 18 years old and older, and did not have any associated illnesses that could influence their health status (those with significant comorbidity, like cardiac disorders, were excluded from analysis).Subjects who did not understand the questions from any of the symptoms or health status administered questionnaires were also excluded.All patients were examined during regularly scheduled clinical visits.
Demographic data was collected, with classification of current organ involvement based on the ACCESS study [8].
This study was approved by the institution's ethics committee and all patients consented to participation.
Besides the demographic data, we also collected pulmonary function tests, other, previously validated tests, and the outcome of sarcoidosis.

Pulmonary function tests
On the same day patients completed the KSQ, performed spirometry tests on a pneumotachograph (Jaeger, Germany) with measures expressed as % of the reference values according to the ATS/ERS criteria [9].Pulmonary function measurements included forced expiratory vital capacity (FVC), forced expiratory volume in 1 second (FEV1), peak expiratory flow (PEF).The transfer factor of the lung for carbon monoxide (DLCO) was measured using the single-breath method (Masterlab, Jaeger, Wurzburg, Germany).

Questionnaires used in this study
During the regularly scheduled outpatient clinic visit patients completed King`s Sarcoidosis Questionnaire (KSQ) and also two standardized questionnaires for the measuring of health status: a generic measurethe fifteen-dimensional measure of health-related quality of life (15D) [10] and the Saint George Respiratory Questionnaire (SGRQ) [11].
15D is an instrument for measurement of health-related quality of life [10].It was developed and validated in a large Finnish population.It consists of 15 different and mutually exclusive health dimensions, each represented by one item [12,13].The total questionnaire score ranges between 0 and 1, where 1 signifies the highest level of health status.15D was used in different diseases in many different countries.The Serbian version of 15D was previously used in patients with asthma where it demonstrated good psychometric measurement properties [15].
SGRQ is an instrument that was originally designed to measure the health status of COPD patients [11].Its validity, reliability, and responsiveness were also shown in other pulmonary diseases and sarcoidosis too [15].The questionnaire consists of 50 items with 76 responses, and encompasses three domains of health status: 1) symptoms, focusing on distress because of respiratory symptoms; 2) activities, measuring decreased mobility or physical activity and 3) impacts, measuring the psychosocial influence of disease on the everyday life and patients' well-being.Scores of these domains, as well as the total score, are scaled from 0 to 100, where higher scores represent poorer health status.

Dyspnea questionnaire
Dyspnea was measured by the Modified Medical Research Council (MRC) Dyspnea Scale [16].The MRC scale classifies subjects into one of five categories according to their degree of dyspnea when performing certain activities.Scores range from 0 to 4, with the higher scores indicating more severe dyspnea.

Activities of daily living
The degree of limitation in activities of daily living was evaluated with the List of Daily Activities (DAL), a scale that was originally designed by Stewart and coworkers [17].DAL has 11 items that are related to the usual activities that persons with good health can perform without particular effort.The number of positive responses comprises the DAL score and indicates the degree of impairment.The scale has been used in several studies in patients with chronic pulmonary diseases.DAL has been validated in serbian sarcoidosis patients as well [18,19].

Fatigue measurement
Fatigue Assessment Scale (FAS) was used to assess sensation of fatigue and correlate it with KSQ as a potential measure for fatigue in sarcoidosis.FAS consists of 10 items: five questions reflecting physical fatigue and five questions for mental fatigue.The response scale is a 5-point scale (1 -never to 5 -always).Scores on FAS can range from 10-50.FAS scores < 22 indicate no fatigue.
All questionnaires except FAS, were already used in assessing symptom severity in our population of patients with sarcoidosis [19].However, FAS has been validated in a broad spectrum of fatigue studies in sarcoidosis [4,5].FAS shows good validity and reliability in sarcoidosis patients and measures fatigue as distinct from depression [4,15,20,21].

Clinical outcome of sarcoidosis
The (3 items) and Eye (7 items).The General health status module is intended to be administered to all patients with sarcoidosis.In addition to this, patients also complete organ specific modules if relevant to their condition.
The individual module scores are intended to identify the health domains affected.
The medication module can be used in isolation or combined with overall lung and skin health status questionnaires but not eye health status.
Patients complete the original seven-point Likert scale and scoring is calculated using a reordered scale for appropriate items.The KSQ module and overall (total) scores were transformed to a range of 0-100 [(actual score − lowest possible score/range) ×100], where 100 represents the best health status [7].

Questionnaire translation process
The original English version of the KSQ was officially translated and adopted into the Serbian language with the assistance of two mother tongue experts who worked independently in the translation from English to Serbian and back translation from Serbian to English.All items from the questionnaire were standardized for validity once again in collaboration with the sarcoidosis experts from the Serbian Association of Sarcoidosis (SAS).
The backward version of the KSQ translation was emailed to the authors of the original KSQ (S Birring and A Patel), so they could give the permission for its use.
The KSQ scores for this study were calculated by the coauthor of the KSQ study, Dr Amit Patel.
After obtaining the final Serbian version, cognitive debriefing was performed; five patients and five physicians were asked if they completely understand the questions from the KSQ.In addition, we asked both doctors and patients to write down their impressions about the new questionnaire.Furthermore, the doctors were asked to give a mark for the questionnaire at the scale from 0-5.
Here are doctors` comments about the KSQ, together with the marks.

Doctors' comments about KSQ:
Milica Kontic, MD, PhD I think that KSQ is clear, specific and very well formulated and that will be understandable to sarcoidosis patients and easy to fill out. (5)

Ana Blanka, MD
I think that questionnaire is very good, because covers all aspects of sarcoidosis.Questions are clear, short and precise which makes this questionnaire understandable and easy to answer.Overview (appearance) is also very clear. (5)

Jasmina Maric Zivkovic, MD, PhD
Symptoms from all sections are comprehensively (overall) presented.The questionnaire its self is very clear.The only remark: I would change is the order of questions in lung, medication and skin section.In medication and lung section the last question should be in the first place.I think that this sarcoidosis questionnaire is very good and useful.It's not very long and our patients shouldn't have any difficulties answering proposed questions. (5)

Snezana Raljevic, MD
Questionnaire consists of 29 questions, divided into 5 subgroups: General health status, lungs, medications, skin, eyes.Questionnaire is short and clear.It wouldn't't take too long for a patient to answer.Questions are understandable to patients and almost all conditions were included that could affect quality of life of sarcoidosis patient.Questions and answers are very well designed so the patients themselves could fill out this questionnaire without any help from investigators.
My opinion is positive for KSQ and I would recommend it for use. (5)

Aleksandra Dudvarski-Ilic, MD, PhD
Questions absolutely reflect the patients' opinion about their disease.Almost all aspects of sarcoidosis are represented in this questionnaire that are important for patients.KSQ ic clear and overview is very good.Some terms in Serbian language could be more adjusted. (4)

Patients about KSQ
Here we also considered patients` medical history , sarcoidosis duration and organ involvement.
Additionally, patients were asked to give a mark for the questionnaire at the scale from 0-5.This questionnaire covers all symptoms of our disease, and I didn't have any difficulties answering these questions.I am also pleased that there are people who are trying to make our disease easier in this way.

Statistical analysis
Descriptive statistics were calculated for the baseline demographic and clinical features.
Continuous variables were presented as means with standard deviations and 95% confidence intervals (CI), while categorical variables are presented with numbers and percentages.
Normality of distribution for continuous variables was tested with mathematical and graphical methods.
Construct validity between the general and organ specific domains of KSQ and the corresponding questionnaires were determined using Spearman's correlation coefficients.
The internal consistency of the Serbian version of KSQ was assessed for multiple item scales by using Cronbach's alpha coefficient (ranges from 0-1, the latter meaning perfect reliability).
Differences between KSQ scores in groups with acute and chronic sarcoidosis were analyzed KSQ organ modules combined with the GHS module all showed a moderate to strong correlation with the SGRQ domains, DAL MRC, FAS and 15D.
Internal reliability for KSQ translated version and original version are showed in Table 2. Cronbach's α coefficients for lungs, skin and eye were higher in translated version of KSQ.Cronbach's α for general health status and medication were lower in Serbian version of KSQ, when compare to original version.
Average age for patients with sarcoidosis was 49.67±11.12and 2/3 were female.The baseline characteristics of the 159 patients who participated in the study are shown in Table 3. Patients with chronic sarcoidosis showed lower KSQ scores in general (Table 4).
Patients with chronic sarcoidosis showed statistically significant lower scores for all KSQ modules except for GHS and medication score.Also, GHS lung score was lower in chronic patients, difference was close to conventional level of significance.
For patients with follow up period more than 5 years, clinical outcome status (COS) was analyzed as they were classified into 9 categories (Table 5).

Discussion
Sarcoidosis is multiorgan, multisystem disease affecting patients` health in many different ways.The relationship between HS and sarcoidosis was first examined in 1997 [23].Since that time until now authors have been trying to find out the best measure considering patients quality of life and /or health status [24].
Health status is reduced in sarcoidosis and assessing it is a difficult multitask effort due to many faces the disease might have.The clinical course of sarcoidosis is unpredictable.More than 90% of sarcoidosis patients have lung disease.However, other organs like the lymph nodes, skin, and eyes are frequently involved.Patients with pulmonary sarcoidosis are often presented with respiratory symptoms while other general symptoms such as fever, anorexia, weight loss, pain and fatigue are present as well.All of the above is disabling for the patient and cause an impaired quality of life.
Disease specific sarcoidosis questionnaires seem to be insufficient.The insufficiency first refers to non-English speaking populations; translation and validation studies for their use in other populations are lacking.
The first disease-specific sarcoidosis questionnaire (SHQ) was published in 2003.However, the development and validation study was performed in predominantly (80%) African-American patients [15].Since that time the first translation-validation study of SHQ in different patients' population was published in 2012 performed in New Zealand [32].
However, the New Zealand patient population is also English-speaking population, although the languages do differ.
There is yet another obstacle in conducting health status studies in non-English speaking populations.The translation-validation process in these countries is one more step to perform, and this is extremely important for all further steps.
In general, health status is a broad concept that is influenced by numerous factors including even extra pulmonary problems.In this study KSQ translated version shows significant correlation with other HS questionnaires already used in sarcoidosis, i.e., SGRQ and 15D (Table 1).
In this study we wanted to evaluate the new sarcoidosis specific questionnaire, first validated in UK patients' population in 2012 [7].After performing the translation process further analyses showed that the translated version of the KSQ showed high internal reliability, similar to the original KSQ version (Table 2).
Patients with chronic sarcoidosis (112 pts) had in general lower KSQ scores.Significantly lower scores in chronic sarcoidosis were: lung score, skin and eye score; also, GHS Eye score, GHS Lung, Skin score and GHS Lung Skin Medication (Table 4).
For patients with follow up period more than 5 years, clinical outcome status (COS) was analyzed as they were classified into 9 categories (Table 5).
In the light of the COS categories, that incorporates many components of sarcoidosis out of which the current or past need for systemic therapy, it was not surprising to realize that KSQ Medication score correlated with the COS categories; the correlation was negative with p=0.002 (Table 6) In a validation study performed by authors from New Zealand, SHQ scores correlated poorly with lung function parameters [32].In our study KSQ scores significantly correlated with lung function parameters (considering both spirometry and diffusing capacity).This is in tune with lung involvement of the disease and consecutive airway obstruction findings in sarcoidosis (Table 6).
The fact that sarcoidosis involves lung parenchyma, thus affecting blood-gas exchange on the basic levels of lung parenchyma explains good correlation and the advantage of KSQ and its translation version in discovering this fundamental lesion leading to diffusing capacity impairments.
KSQ translated version showed significant correlation with MRC scores, the finding that is even more significant when considering that the MRC addresses the level of activities that leads to dyspnea [34].
The DAL measures the ability to perform various daily activities such as eating, dressing, bathing, using the lavatory, walking, going to the market and climbing the stairs.
The correlation of KSQ translated version with this activity questionnaire is statistically significant in all KSQ domains.Fatigue is a common symptom of sarcoidosis and measuring it is a unique task when speaking about quality of life and /or health status in this patient` population.It is an outstanding advantage of KSQ that can reliably measure this sensation.
However, in our opinion further studies are necessary to distinguish the components of fatigue (mental or physical) in correlation with KSQ.
KSQ has been validated in both German and Dutch languages [35,36].
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clinical outcome of sarcoidosis is quite variable.Several scoring systems have been used to assess the level of disease and clinical outcome.WASOG (World Association of Sarcoidosis and other Granulomatous diseases) task force was to define clinical phenotypes of disease based on clinical outcome in sarcoidosis patients (COS).To determine COS category, it is mandatory that the patients are followed up for five years after the diagnosis was established [22].The components of sarcoidosis were incorporated into the final nine COS categories, including the following: the current or past need for systemic therapy, the resolution of the disease, and current status of the condition.The estimated COS categories are: Resolved: COS 1-Never treated, COS 2-No therapy > One year; Minimal Disease: COS 3 -Never treated, COS 4 -No therapy > One year; Persistent sarcoidosis with no current therapy: COS 5-Never treated, COS 6 -No therapy > One year; Persistent sarcoidosis with current therapy: No worsening prior year: COS 7-Asymptomatic, COS 8-Symptomatic, Persistent sarcoidosis with current therapy: COS 9 -Worsening in prior year KSQ Questionnaire King's Sarcoidosis Questionnaire (KSQ) is a modular multi-organ health status measure for patients with sarcoidosis for use in clinic and the evaluation of therapies.It consists of five modules: General health status-GHS (10 items), Lung (6 items), Medication (3 items), Skin

Age 31 ,
sarcoidosis duration: 1-year, Current therapy: Prednisone I think that this questionnaire includes most of the problems that sarcoidosis patients encounter.It's very clear and easy to answer.(5) I.Dj/ Age 50, sarcoidosis duration: 1-year, Current therapy: No ) S.D/Age74, sarcoidosis duration: 8 years, Current therapy: Prednisone+ Methotrexate I have read this questionnaire very carefully and I think that includes a lot of symptoms that are related to sarcoidosis.(5) S. P/Age 56, sarcoidosis duration: 4 years, Current therapy: No I think that based on my course of the disease this questionnaire covered the essence of sarcoidosis and all the symptoms and conditions sarcoidosis patient can experience.(5)D.J/Age 42, sarcoidosis duration: 5 years, Current therapy: Prednisone+ Methotrexate Questions are precise, but I had hard time answering them.I believe the main lack of this questionnaire is that questions only consider 2-week period.I believe so, because while I am in a hospital, I rest all day and my symptoms are less there comparing when I am at home and having all my daily routine activities.I think real answers could be given when I am in my everyday environment.

Table 1 .
Correlation between KSQ scoreswith COS score, other questionnaires scores and lung functions were calculated using Pearson (or Spearman) correlation coefficient as appropriate.The level of significance was set at 0.05.Statistical analysis was performed using the IBM SPSS 21 (Chicago, IL, 2012) package.Correlation between KSQ modules and SGRQ domains, DAL MRC, FAS and 15D scores were mostly moderate to strong, negative and statistically significant, except for medication and skin score.The correlations between the KSQ GHS and lung domain and all questionnaires (SGRQ domains, using Students t-test (or Mann Whitney test) as appropriate.DAL MRC, FAS and 15D) were negative, moderate to strong (r= -0.523 to -0.751).KSQ medication and skin score showed a negative, weak to moderate correlation with SGRQ domains, DAL MRC, FAS and 15D (r= -0.175 to -0.350).The Eyes module showed a negative, moderate to strong correlation with the other questionnaires (r=-0.382 to -0.574).

Table 6 .
There was no statistically significant correlation between FVC and KSQ modules.FEV 1 correlate positive statistically significant only with lung score.Positive, statistically significant correlation was observed between PEF and DLco with GHS, Lung, Eye, GHS Lung, GHS Skin score, GHS Eye, GHS Lung Skin, GHS Lung Medication, GHS Skin Medication and GHS Lung Skin Medication score.Statistically significant negative correlation between COS score and KSQ lung, GSH Lung, GSH S, GSH LM, GSH SM, GSH LMS were observed.Negative, moderate statistically significant correlation was observed between COS score and medication score.Correlation between COS and GSH score was negative and close to conventional level of significance.There was no statistically significant correlation between skin, eyes, GHS Eye and COS score.

Table 1 .
[36]authors from the Netherlands have shown good internal consistency for all KSQ, and intraclass correlation coefficients and Bland-Altman plots showed good repeatability of the KSQ, therefore the test was successfully validated for Dutch language[35].The German version required the reduction of models, from original 29 to 24, in order to fulfil the requirements of the Rasch model; however, the original 29 version can still be used to compare data to international version[36].Both versions have not been compared to other, previously validated, questionaries, same as the Serbian version.Correlation between KSQ scores and other questionnaires

Table 2 .
Internal reliability for KSQ translated version

Table 3 .
Baseline characteristics of the study participants

Table 6 .
Correlation between lung function parameters, clinical outcome of sarcoidosis and