Long-term impacts of Legionnaires’ disease on health and well-being: rationale, study design and baseline findings of a matched cohort study (LongLEGIO)

Long-term impacts of Legionnaires’ disease on health and well-being: rationale, study design and baseline findings of a matched cohort study (LongLEGIO) | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Long-term impacts of Legionnaires’ disease on health and well-being: rationale, study design and baseline findings of a matched cohort study (LongLEGIO) Melina Bigler , Malina Vaucher , Manuel Wiederkehr , Sophia Brülisauer , Werner C. Albrich , Sarah Dräger , Valentin Gisler , Isabel Akers , Daniel Mäusezahl doi: https://doi.org/10.1101/2024.08.20.24312294 Melina Bigler 1 Swiss Tropical and Public Health Institute , Basel, Switzerland 2 University of Basel , Basel, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site Malina Vaucher 1 Swiss Tropical and Public Health Institute , Basel, Switzerland 2 University of Basel , Basel, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site Manuel Wiederkehr 1 Swiss Tropical and Public Health Institute , Basel, Switzerland 2 University of Basel , Basel, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sophia Brülisauer 3 Cantonal Hospital St. Gallen, Division of Infectious Diseases, Infection Prevention and Travel Medicine Find this author on Google Scholar Find this author on PubMed Search for this author on this site Werner C. Albrich 3 Cantonal Hospital St. Gallen, Division of Infectious Diseases, Infection Prevention and Travel Medicine Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sarah Dräger 4 University Hospital Basel , Switzerland , Division of Internal Medicine 5 University of Basel , Switzerland , Department of Clinical Research Find this author on Google Scholar Find this author on PubMed Search for this author on this site Valentin Gisler 6 Institute for Laboratory Medicine, Cantonal Hospital Aarau , Aarau, Switzerland , Department for Infectious Diseases 7 Department for Infectious Diseases and Infection Prevention, Cantonal Hospital Aarau , Aarau, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site Isabel Akers 8 Spital Limmattal, Zurich-Schlieren , Switzerland , Division of Internal Medicine Find this author on Google Scholar Find this author on PubMed Search for this author on this site Daniel Mäusezahl 1 Swiss Tropical and Public Health Institute , Basel, Switzerland 2 University of Basel , Basel, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: daniel.maeusezahl{at}unibas.ch Abstract Full Text Info/History Metrics Data/Code Preview PDF Abstract Background The long-term effects of Legionnaires’ disease beyond the acute infection and their impact on healthcare utilisation remain poorly understood. We present the rationale and study design of a matched prospective observational cohort study ( LongLEGIO ) aimed at investigating the persistent sequelae on patients’ health, well-being, and health service use following community-acquired Legionnaires’ disease, compared to other bacterial pneumonias that tested negative for Legionella . Methods Patients with Legionnaires’ disease and other bacterial Legionella test-negative pneumonia are recruited from secondary and tertiary care hospitals and matched for sex, age, hospital-level and date of diagnosis. Semi-structured interviews were conducted at baseline (shortly after the pneumonia diagnosis) and at two, six and 12 months following appropriate antibiotic therapy. Baseline assessments capture pre-existing conditions, illness experience, and disease severity, while follow-up assessments evaluate long-term symptoms, healthcare utilisation, quality of life (EQ-5D-5L), and social/work impacts. Data on case management and the disease severity are extracted from patient records. Results A total of 59 patients with community-acquired Legionnaires’ disease and 60 patients with other bacterial Legionella test-negative pneumonia were enrolled. Both cohorts were representative of their respective condition. Key differences between Legionnaires’ disease and non- Legionella bacterial pneumonia patient groups emerged in terms of comorbidities, pneumonia severity, and self-reported quality of life. These differences will be accounted for in future analyses as part of the LongLEGIO study. Conclusions The LongLEGIO study will advance ongoing research on post-acute infection syndromes and provide a robust data foundation for more accurate assessments of the disease burden associated with Legionnaires’ disease. Background Lower respiratory tract infections, including pneumonia, remain a major cause of morbidity and mortality worldwide [ 1 , 2 ] and pose a significant burden on healthcare systems [ 3 , 4 ]. Manifestations of pneumonia can furthermore persist for weeks to months after the acute infection and may lead to additional use of health service [ 5 – 7 ]. Persistent sequelae of pneumonia include respiratory symptoms such as cough or dyspnoea [ 8 ], cardiovascular complications [ 9 ], cognitive impairment [ 10 – 12 ], general fatigue [ 8 , 13 , 14 ], and reduced quality of life [ 15 ]. Moreover, extrapulmonary sequelae often outlast respiratory symptoms [ 5 , 13 , 16 ]. The extent to which such persistent sequelae of pneumonia are influenced by the infection-causing pathogens is poorly understood. This is because most studies either do not differentiate between different pneumonia-causing pathogens in the analysis or only stratify for Streptococcus pneumonia , the most frequently identified cause of community-acquired pneumonia (CAP) [ 13 , 17 ]. To better understand the impact of specific pathogens on persistent pneumonia manifestations, Legionnaires’ disease (LD) is particularly interesting to study. LD is caused by gram-negative Legionella bacteria and accounts for approximately 4-7% of CAP cases in Europe [ 18 ]. In addition to respiratory symptoms, LD is often associated with extrapulmonary manifestations such as confusion, diarrhoea, headache and acute kidney damage [ 19 – 21 ]. The underlying pathophysiological mechanisms of Legionella infections further closely resemble those of Coxiella burnetii infections causing Q-fever [ 22 , 23 ]. The long-term health effects of Q-fever, particularly chronic fatigue, are well documented in the literature [ 24 ]. In contrast to Q-fever, persistent health impacts of LD remain poorly understood, and studies on this topic are scarce. Lettinga et al. reported that LD patients experienced persistent fatigue, neurological symptoms such as concentration difficulties and memory loss, muscle weakness, and reduced quality of life up to 17 months after acute infection [ 25 ]. However, it remained unclear whether these persistent health impairments were due to the Legionella infection or the severity of the pneumonia. Similarly, another cross-sectional study compared Q-fever and LD patients with healthy subjects from the general population one year after the acute infection. This study also suggested that LD, like Q-fever, can lead to a persistent reduction in quality of life and chronic fatigue [ 26 ]. By design, however, the study did not allow to draw conclusions about the temporal relationship between infection and the presence of the observed health impairments. To date, no study has prospectively compared the persistent health impacts of community-acquired LD (CALD) with the lasting health effects of other bacterial CAP or systematically assessed the use of health services by CALD patients beyond the acute phase of infection. Here, we present the LongLEGIO study and report on the study enrolment. The study explores the persisting impacts of CALD on patients’ health, well-being, and health service use, and compares LD patients with other bacterial CAP patients tested negative for a Legionella infection. Methods Study design and objectives The LongLEGIO study is a matched, prospective observational cohort study. The study enrolled community-acquired Legionnaires’ disease (CALD) and Legionella test-negative bacterial CAP (non-LD bacterial CAP) patients from secondary and tertiary care hospitals in Switzerland. The LongLEGIO study addresses the following objectives: (i) to explore CALD patients’ symptoms and general well-being and compare them to symptoms and the well-being of other non-LD bacterial CAP patients, (ii) to describe and compare the care needs and health service utilisation of CALD and non-LD bacterial CAP patients during the recovery, including their challenges in navigating the health system. Recruitment and data collection For the recruitment and data collection, LongLEGIO builds on an ongoing Swiss national case-control and molecular source attribution study investigating risk factors and infection sources for CALD in Switzerland ( SwissLEGIO ) [ 27 ]. The SwissLEGIO study recruited 204 CALD patients from 20 secondary- and tertiary-care hospitals across Switzerland between August 2021 and March 2024. The 20 university- and cantonal hospitals jointly reported about 45% of all CALD cases that were notified to the Swiss national notification system for infectious diseases during the recruitment period. The LongLEGIO study capitalises on the SwissLEGIO parent study in two ways ( Figure 1 , grey boxes ): First, the LongLEGIO study recruited CALD patients from a pool of LD patients who previously participated in SwissLEGIO . Secondly, the baseline questionnaire and the data extraction from electronic medical records for CALD patients were done as part of the parent study ( Figure 1 ). Download figure Open in new tab Figure 1: Recruitment, enrolment and data collection for the community-acquired Legionnaires’ disease (CALD) and Legionella test-negative bacterial CAP (non-LD bacterial CAP) cohorts. Grey: Baseline interviews and the extraction of data from electronic medical records for CALD patients is done within the context of the SwissLEGIO parent study. Red: Recruitment and data collection for the CALD cohort. Yellow: Recruitment and data collection for the non-LD bacterial CAP cohort. ABT: appropriate antibiotic therapy. Recruitment of community-acquired Legionnaires’ disease (CALD) patients CALD patients, who previously participated in the SwissLEGIO study, were eligible to participate in the LongLEGIO study if they fulfilled the study criteria summarised in Table 1 . Six weeks after CALD patients started appropriate antibiotic therapy 1 , they were invited to participate in the LongLEGIO study by postal mail or e-mail. Written informed consent was obtained for all CALD patients prior to the two-month follow-up interview ( Figure 1 ). View this table: View inline View popup Download powerpoint Table 1: Eligibility criteria for CALD patients and non-LD bacterial CAP patients’ participation in the LongLEGIO study Recruitment of Legionella test-negative bacterial CAP (non-LD bacterial CAP) patients Legionella test-negative bacterial CAP (non-LD bacterial CAP) patients were recruited through three cantonal (secondary hospitals) and one university hospital (tertiary hospital). All three hospitals also participate in the SwissLEGIO parent study. During the recruitment period, all hospitals kept track of all bacterial CAP patients who tested negative for Legionella and COVID-19 and who were treated with a full course of antibiotics for pneumonia. 2 The recruitment of non-LD bacterial CAP patients occurred shortly after the patients were diagnosed with pneumonia ( Figure 1 ). Non-LD bacterial CAP patients were matched to CALD patients based on sex, age (+/- 5 years), hospital level (university vs. cantonal hospitals), and date of diagnosis (+ 60 days). The recruitment of the non-LD bacterial CAP patients was triggered by the enrolment of a CALD patient – eligible for the LongLEGIO study – into the SwissLEGIO study. In short, the study team sent a recruitment request with the matching criteria to one of the partner hospitals. The hospital then recruited the eligible non-LD bacterial CAP patient with the closest date of a matching diagnosis. Eligibility criteria for non-LD bacterial CAP patients are summarised in Table 1 . Written informed consent was obtained prior to the baseline interview. Data collection For the LongLEGIO study, the two cohorts of CALD patients and non-LD bacterial CAP patients are followed up over 12 months. Assessments are done at four different time points ( Figure 1 ): Shortly after the pneumonia diagnosis, a semi-structured baseline interview is conducted and additional data is extracted from electronic medical records for the current hospitalisation. Follow-up assessments in the form of semi-structured interviews are afterwards conducted at two, six and twelve months after patients started appropriate antibiotic therapy 3 - 4 . All interviews are either conducted in person or over the phone/ by video calls. At baseline, the questionnaire consists of structured and open questions related to patients’ pre-existing co-morbidities, their acute illness experience, the perceived disease severity and patients’ health-seeking ( Table 2 , Questionnaire ). In addition to the baseline interview, information on the patient’s medical history, disease severity, information on the pneumonia causing pathogen, the clinical case management and prescribed antibiotics were extracted from electronic medical records. View this table: View inline View popup Download powerpoint Table 2: Content of the LongLEGIO questionnaire The follow-up questionnaires consist of structured and open questions to investigate (i) the patient’s perceived health, recovery, and health-related quality of life after the acute pneumonia, (ii) the presence of persistent pneumonia-related symptoms, (ii) patients’ (potentially extended) health service utilisation and health seeking in the informal health sector after the hospital discharge, and (iv) potential impacts of the infection on patients’ social and work life ( Table 2 ). The design of the follow-up questionnaires was informed by the Explanatory Model Interview Catalogue (EMIC) [ 34 ], by research on the long-term recovery from pneumonia [ 8 , 15 , 35 – 37 ] and by research on Long-COVID [ 38 – 40 ]. Statistical analysis CALD patients and non-LD bacterial CAP patients are characterised in terms of demographics, illness experience, help-seeking, comorbidities and health-related quality of life (HRQoL). Continuous variables are presented as medians (IQRs), and categorical variables as n (%). To compare persistent symptoms, additional healthcare consultations after discharge, and changes in HRQoL scores over time (two, six and 12 months) within each cohort, we will be use the McNemar’s chi-square test or the Wilcoxon signed-rank test as appropriate. For comparisons between groups at each time point, we will use the Chi-square test or Fisher’s exact test for categorical variables, and the t-test or Mann-Whitney U test for continuous variables, as appropriate. The association between CALD and long-term symptoms will be evaluated by multivariable logistic regression, adjusting for potential confounders such as age, gender, smoking status, comorbidities, and severity of pneumonia. Given the large proportion of elderly participants, a subgroup analysis will be conducted for patients aged 65 and older. Only participants who completed at least the first follow-up interview will be included in the analysis. If possible, multiple imputation for missing variables and a sensitivity analysis using complete-case analysis is foreseen. Statistical analysis will be conducted using the statistical software R Version 4.3.2 (R Core Team, Vienna, Austria). Data management Data are collected on standardised electronic Case Report Form (eCRF) using the data collection software Open Data Kit (ODK, getodk.org ). Forms are encrypted and all patient-identifying information is removed. Individual forms are linked through unique subject IDs. Automated validations are implemented in the eCRF to check for data completeness and plausibility. In addition, submitted forms are continuously checked for plausibility and accuracy, and source data verification is performed. Data is stored on a secured network drive accessible only to authorised study personnel. The network drive is backed up regularly, according to our internal institutional policy. Study population Sample size and enrolment The recruitment timelines and the sample size for the LongLEGIO study were bound to the enrolment of CALD patients in the SwissLEGIO parent study. Overall, 86 CALD patients and 110 non-LD bacterial CAP patients were invited to participate in the LongLEGIO study between June 2023 and June 2024. In total, 59 CALD patients (enrolment rate of 69%) and 60 non-LD bacterial CAP patients (enrolment rate of 55%) agreed to participate. There were no differences in age, gender and ICU admission rates between participants and non-participants among CALD patients, and in gender and ICU admission rates among the patients with non-LD bacterial CAP ( Table S1 , Supplementary material ). There was a statistically significant difference in age between participants and non-participants among the non-LD bacterial CAP patients (69 vs. 77, p=0.016). With 59 CALD patients and 60 non-LD bacterial CAP patients enrolled in the LongLEGIO study, the sample size was sufficient to provide a power of 78% with alpha=0.05 to detect a 20% difference between our two cohorts. Given that the majority of patients in both groups were over 50 years old, we assumed for our power calculation a 10% prevalence of non-specific symptoms—such as fatigue, weakness, and a general reduction in quality of life—that were not clearly attributable to either CALD or bacterial CAP. Baseline characteristics The baseline characteristics for the CALD and the non-LD bacterial CAP cohorts are summarised in Table 3 . The median age for both cohorts is 69 years; males comprised 59.3% among CALD and 63.3% among non-LD bacterial CAP patients. Both cohorts have a similar comorbidity burden as measured by the Charlson Comorbidity Index (CCI). Non-LD bacterial CAP patients, however, were more likely to suffer from chronic obstructive pulmonary disease (20% vs 10.2%), malignancies (31.7% vs 13.6%), and were more likely immunosuppressed (23.3% vs 13.6%). On the contrary, more CALD than non-LD bacterial CAP patients suffered from chronic kidney failure (15.3% vs 8.3%). Patients in both cohorts exhibited a similar health-seeking behaviour prior to the hospital visit with the majority of patients initially consulting a GP. CALD patients were more frequently pre-treated with antibiotics (28.3% vs 15.3%). View this table: View inline View popup Table 3: Baseline characteristics of 119 Legionnaires’ disease patients (CALD) and non-LD bacterial community-acquired pneumonia patients (CAP) During the acute phase of their pneumonia, non-LD bacterial CAP patients more frequently reported respiratory symptoms including cough (80% vs 66.7%), shortness of breath (78% vs 66.1%), and chest pain (49.1% vs 35.1%). On the contrary, CALD patients reported more frequently extrapulmonary symptoms such as fever (89.3% vs 76.3%), muscle aches (51.8% vs 25.9%), headaches (47.3% vs 28.1%) and nausea or emesis (11.9% vs 3.3%). The ICU admission rate and the proportion of patients who needed mechanical ventilation was higher for CALD than for non-LD bacterial CAP patients (13.6% vs 8.3% and 6.8% vs 1.8%, respectively). Finally, participants were asked to report on their perceived quality of life prior to experiencing first pneumonia symptoms ( Table S2 , Supplementary material ). Generally; non-LD bacterial CAP patients reported lower quality of life scores compared to CALD patients. Differences were particularly pronounced for the EQ-5D-5L dimensions of mobility, daily activity and pain/discomfort. Discussion Persistent manifestations of CALD beyond the acute infection and its impact on healthcare utilisation remain poorly understood. We present the rationale and study design of a prospective, matched cohort study to investigate persistent sequelae of CALD and compare them to manifestations of persistent pneumonia among non-LD bacterial CAP patients. Previous studies examining the persistent sequelae of CAP have rarely stratified their analysis by the different pneumonia-causing pathogens [ 9 – 12 , 14 , 15 ]. Among those that have, the focus was on Streptococcus pneumonia [ 13 , 17 ]. This limited stratification was mainly due to sample size limitations and lack of information on the CAP-causing pathogen in these studies. In contrast, studies focusing specifically on persistent sequelae of Legionella infections never included pneumonia patients as a comparison group. To our knowledge, the LongLEGIO study is the first to systematically compare the persistent health effects of CALD with the persistent manifestations of non-CALD bacterial CAP, going beyond a survival analysis based on mortality data [ 41 ]. Such a comparison is crucial to contextualise the frequency of observed health and well-being impairments in CALD patients against the background occurrence in a suitable control group. It will further allow us to investigate the extent to which the persistence of health impairments of CAP is reflected in the tropism and pathogenic mechanisms of the causative pathogen. Ultimately, this may improve our understanding of the underlying pathogenesis of persistent pneumonia manifestations and post-acute infection syndromes [ 24 , 42 ]. The LongLEGIO study focuses on patient-reported outcome measures (PROMS), as opposed to selecting mortality or hospital readmission rates as primary outcome measures, which has been the focus of previous studies on Legionella [ 41 , 43 ]. PROMS provide robust measures of persistent symptoms and functional impairments that patients experience [ 8 ]. Persistent symptoms and functional impairments, as measured by PROMS, are also one of the main reasons for additional GP consultations and emergency department visits after the acute phase of pneumonia [ 6 , 7 ]. PROMS, however, are usually not well documented in medical records and hence can only be adequately captured by applying prospective study designs [ 42 ]. The LongLEGIO study is also the first study to assess the healthcare utilisation of CALD patients beyond the acute infection and to explore its association with persistent sequelae of CALD. As the COVID-19 pandemic and the advent of Long COVID have clearly demonstrated, post-acute infection syndromes can contribute significantly to the disease burden of infectious diseases [ 39 , 42 ]. However, to date, estimates of the burden of LD do not take into account persistent health impairment and the associated increased medical expenditure [ 44 , 45 ]. By providing insights into both, the presence of persistent health and well-being impairment and additional healthcare utilisation after the acute infection, the LongLEGIO study will generate data to facilitate a better estimation of the disease burden of LD in the future. This, in turn, may help public health specialists and physicians to better plan and anticipate the health care resources needed for the holistic treatment of CALD. Enrolment for the LongLEGIO study was completed in June 2024. A total of 59 CALD patients and 60 non-LD bacterial CAP patients have been enrolled. Our non-LD bacterial CAP and CALD patient cohorts are representative for the two patient populations. Similar to previous studies comparing characteristics of CALD and non-LD bacterial CAP patients, LD patients were more likely to suffer from extrapulmonary symptoms, were more frequently pre-treated with antibiotics prior to hospital admission and were more often admitted to the ICU [ 21 , 46 , 47 ]. Non-LD bacterial CAP patients, on the other hand, were more likely to suffer from chronic obstructive pulmonary disease and malignancies, which is also consistent with findings from previous research [ 20 ]. Finally, we also observed differences in the self-reported quality of life scores (lower scores were reported by non-LD bacterial CAP patients). Both, comorbidities and pneumonia severity may influence the long-term health outcomes after pneumonia [ 5 , 6 , 13 , 16 ]. We will, therefore, correct for these differences in our analyses. For the self-reported quality of life score, each patient will serve as their own control and relative rather than absolute changes in reported scores from the pre-pneumonia baseline score will be assessed. The LongLEGIO study has limitations. Despite its prospective nature, the study may be subject to recall bias, especially between the six- and 12-month follow-up periods. We try to mitigate this recall bias by specifically probing for both, intermittent and current symptoms. In addition, interviewers are instructed to systematically probe for all the symptoms and health service consultations that were reported by the patient in previous interviews. Finally, and despite the integration of the LongEGIO study into the national SwissLEGIO parent study, our sample size for CALD remains relatively small. It is, therefore, possible that we underestimate functional impairments that are relatively rare although we are confident to fully capture the common persistent sequelae of CALD. In summary, the LongLEGIO study explores and compares persistent health and well-being impacts of CALD and non-LD bacterial CAP in two representative cohorts. The study aims to contribute to ongoing research on post-acute infection syndromes, a phenomenon long recognized and well-documented for conditions like Q-fever but often challenging to capture in daily medical practice [ 24 ]. As the recent COVID pandemic has shown, more research on persistent health impairments after acute infections is highly needed as they represent a significant burden for patients and healthcare systems. Data Availability All data produced in the present work are contained in the manuscript. Ethical considerations Ethical approval for the study was obtained from the Ethics Commission of Northwestern and Central Switzerland (EKNZ, 2023-00639). This study is conducted in accordance with the principles of Good Epidemiological Practice and the Declaration of Helsinki. Data are stored in concordance with Swiss data protection laws. Written informed consent was obtained from all study participants prior to enrolment. Funding This LongLEGIO study received no extra funding. The parent SwissLEGIO project is funded by the Swiss Federal Office of Public Health (grant nr: 142004673). Conflict of Interests The authors declare that they have no conflict of interests. Supplementary material View this table: View inline View popup Download powerpoint Table S1: Baseline characteristics of 86 Legionnaires’ disease patients (CALD) and 110 non-LD bacterial community-acquired pneumonia patients (CAP) invited to participate in the LongLEGIO study between June 2023 and June 2024 View this table: View inline View popup Table S2: Supplementary baseline characteristics of 119 Legionnaires’ disease patients (CALD) and non-LD bacterial community-acquired pneumonia patients (CAP) Acknowledgements We thank Jan Hattendorf for his valuable advice on the design and development of the protocol. At the Federal Office of Public Health, we acknowledge the various initial inputs and exchanges surrounding this study with Ornella Luminati, Monica Wymann and Mirjam Mäusezahl-Feuz. We thank Chiara Strozzi and the Kompetenzzentrum für Ausbruchs-untersuchungen (KEA) at Swiss TPH for their support in the final data collection phase. Footnotes ↵ 1 Defined as the prescription of macrolides, quinolones or doxycycline. All these antibiotics exhibit intracellular activity and hence, activity against Legionella . [ 22 , 28 ] ↵ 2 Defined as empiric or targeted treatment for bacterial pneumonia according to Swiss National Pneumonia guidelines and for at least 3 days. [ 29 ] ↵ 3 For CALD patients, this was defined as the prescription of macrolides, quinolones or doxycycline. [ 22 , 28 ] ↵ 4 For non-LD bacterial CAP patients, this was defined as the prescription of beta-lactams, macrolides, quinolones or tetracyclines for patients with pneumonia of unclear aetiology OR pathogen-specific antibiotics if aetiology was known. [ 29 ] References 1. ↵ Bender RG , Sirota SB , Swetschinski LR , et al. Global, regional, and national incidence and mortality burden of non-COVID-19 lower respiratory infections and aetiologies, 1990– 2021: a systematic analysis from the Global Burden of Disease Study 2021 . The Lancet Infectious Diseases 2024 . 2. ↵ World Health Organization . Global Health Estimates . https://www.who.int/data/global-health-estimates . Date last updated: August 15 2024. Date last accessed: August 15 2024 . 3. ↵ Tsoumani E , Carter JA , Salomonsson S , et al. Clinical, economic, and humanistic burden of community acquired pneumonia in Europe: a systematic literature review . Expert Review of Vaccines , 2023 : 22 ( 1 ): 876 – 884 . OpenUrl 4. ↵ Welte T , Torres A , Nathwani D . Clinical and economic burden of community-acquired pneumonia among adults in Europe . Thorax 2012 : 67 ( 1 ): 71 – 79 . OpenUrl Abstract / FREE Full Text 5. ↵ Aliberti S , Dela Cruz CS , Amati F , et al. Community-acquired pneumonia . Lancet 2021 : 398 ( 10303 ): 906 – 919 . OpenUrl 6. ↵ Adamuz J , Viasus D , Camprecios-Rodriguez P , et al. A prospective cohort study of healthcare visits and rehospitalizations after discharge of patients with community-acquired pneumonia . Respirology 2011 : 16 ( 7 ): 1119 – 1126 . OpenUrl PubMed 7. ↵ Daniel P , Bewick T , McKeever TM , et al. Healthcare reconsultation in working-age adults following hospitalisation for community-acquired pneumonia . Clinical Medicine 2018 : 18 ( 1 ): 41 – 46 . OpenUrl Abstract / FREE Full Text 8. ↵ Pick HJ , Bolton CE , Lim WS , et al. Patient-reported outcome measures in the recovery of adults hospitalised with community-acquired pneumonia: a systematic review . The European Respiratory Journal 2019 : 53 ( 3 ). 9. ↵ Corrales-Medina VF , Alvarez KN , Weissfeld LA , et al. Association Between Hospitalization for Pneumonia and Subsequent Risk of Cardiovascular Disease . JAMA 2015 : 313 ( 3 ): 264 – 274 . OpenUrl CrossRef PubMed 10. ↵ Davydow DS , Hough CL , Levine DA , et al. Functional Disability, Cognitive Impairment, and Depression After Hospitalization for Pneumonia . The American Journal of Medicine 2013 : 126 ( 7 ): 615 – 624.e615 . OpenUrl CrossRef PubMed 11. Chalitsios CV , Baskaran V , Harwood RH , et al. Incidence of cognitive impairment and dementia after hospitalisation for pneumonia: a UK population-based matched cohort study . ERJ Open Research , 2023 : 9 ( 3 ). 12. ↵ Girard TD , Self WH , Edwards KM , et al. Long-Term Cognitive Impairment after Hospitalization for Community-Acquired Pneumonia: a Prospective Cohort Study . Journal of General Internal Medicine 2018 : 33 ( 6 ): 929 – 935 . OpenUrl 13. ↵ El Moussaoui R , Opmeer BC , de Borgie CA , et al. Long-term symptom recovery and health-related quality of life in patients with mild-to-moderate-severe community-acquired pneumonia . Chest 2006 : 130 ( 4 ): 1165 – 1172 . OpenUrl CrossRef PubMed Web of Science 14. ↵ Metlay JP , Fine MJ , Schulz R , et al. Measuring symptomatic and functional recovery in patients with community-acquired pneumonia . Journal of General Internal Medicine 1997 : 12 ( 7 ): 423 – 430 . OpenUrl CrossRef PubMed Web of Science 15. ↵ Glick HA , Miyazaki T , Hirano K , et al. One-Year Quality of Life Post-Pneumonia Diagnosis in Japanese Adults . Clinical Infectious Diseases 2021 : 73 ( 2 ): 283 – 290 . OpenUrl 16. ↵ Waterer G . Recovery from community acquired pneumonia: the view from the top of the iceberg . European Respiratory Journal 2017 : 49 ( 6 ). 17. ↵ Kruckow KL , Zhao K , Bowdish DME , et al. Acute organ injury and long-term sequelae of severe pneumococcal infections . Pneumonia 2023 : 15 ( 1 ): 5 . OpenUrl 18. ↵ Graham FF , Finn N , White P , et al. Global Perspective of Legionella Infection in Community-Acquired Pneumonia: A Systematic Review and Meta-Analysis of Observational Studies . International Journal of Environmental Research and Public Health 2022 : 19 ( 3 ): 1907 . OpenUrl 19. ↵ Roed T , Schonheyder HC , Nielsen H . Predictors of positive or negative legionella urinary antigen test in community-acquired pneumonia . Infectious disease 2015 : 47 ( 7 ): 484 – 490 . OpenUrl 20. ↵ Viasus D , Di Yacovo S , Garcia-Vidal C , et al. Community-acquired Legionella pneumophila pneumonia: a single-center experience with 214 hospitalized sporadic cases over 15 years . Medicine 2013 : 92 ( 1 ): 51 – 60 . OpenUrl CrossRef PubMed Web of Science 21. ↵ Allgaier J , Lagu T , Haessler S , et al. Risk Factors, Management, and Outcomes of Legionella Pneumonia in a Large, Nationally Representative Sample . Chest 2021 : 159 ( 5 ): 1782 – 1792 . OpenUrl 22. ↵ Cunha BA , Burillo A , Bouza E . Legionnaires’ disease . Lancet 2016 : 387 ( 10016 ): 376 – 385 . OpenUrl CrossRef PubMed 23. ↵ Raoult D , Marrie T , Mege J . Natural history and pathophysiology of Q fever . The Lancet Infectious Diseases 2005 : 5 ( 4 ): 219 – 226 . OpenUrl CrossRef PubMed Web of Science 24. ↵ Choutka J , Jansari V , Hornig M , et al. Unexplained post-acute infection syndromes . Nature Medicine 2022 : 28 ( 5 ): 911 – 923 . OpenUrl CrossRef PubMed 25. ↵ Lettinga KD , Verbon A , Nieuwkerk PT , et al. Health-related quality of life and posttraumatic stress disorder among survivors of an outbreak of Legionnaires disease . Clinical Infectious Diseases 2002 : 35 ( 1 ): 11 – 17 . OpenUrl CrossRef PubMed Web of Science 26. ↵ van Loenhout JA , van Tiel HH , van den Heuvel J , et al. Serious long-term health consequences of Q-fever and Legionnaires’ disease . The Journal of Infection 2014 : 68 ( 6 ): 527 – 533 . OpenUrl CrossRef PubMed Web of Science 27. ↵ Fischer FB , Bigler M , Mäusezahl D , et al. Legionnaires’ disease in Switzerland: rationale and study protocol of a prospective national case-control and molecular source attribution study (SwissLEGIO) . Infection 2023 . 28. ↵ Ewig S , Kolditz M , Pletz M , et al. Management of Adult Community-Acquired Pneumonia and Prevention - Update 2021 - Guideline of the German Respiratory Society (DGP), the Paul-Ehrlich-Society for Chemotherapy (PEG), the German Society for Infectious Diseases (DGI), the German Society of Medical Intensive Care and Emergency Medicine (DGIIN), the German Viological Society (DGV), the Competence Network CAPNETZ, the German College of General Practitioneers and Family Physicians (DEGAM), the German Society for Geriatric Medicine (DGG), the German Palliative Society (DGP), the Austrian Society of Pneumology Society (ÖGP), the Austrian Society for Infectious and Tropical Diseases (ÖGIT), the Swiss Respiratory Society (SGP) and the Swiss Society for Infectious Diseases Society (SSI) . Pneumologie 2021 : 75 ( 9 ): 665 – 729 . OpenUrl 29. ↵ Schweizerische Gesellschaft für Infektiologie. Pneumonie / Ambulant-erworbene Pneumonie CAP . https://ssi.guidelines.ch/guideline/3007/de . Date last updated: May 15 2024. Date last accessed: August 15 2024 . 30. Herdman M , Gudex C , Lloyd A , et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L) . Quality of Life Research , 2011 : 20 ( 10 ): 1727 – 1736 . OpenUrl CrossRef PubMed Web of Science 31. World Health Organization . Regional Office for Europe. Wellbeing measures in primary health care/the DepCare Project: report on a WHO meeting: Stockholm, Sweden, 12– 13 February 1998 . Copenhagen: World Health Organization. Regional Office for Europe 1998 . 32. Mahler DA , Wells CK . Evaluation of clinical methods for rating dyspnea . Chest 1988 : 93 ( 3 ): 580 – 586 . OpenUrl CrossRef PubMed Web of Science 33. Michielsen HJ , De Vries J , Van Heck GL . Psychometric qualities of a brief self-rated fatigue measure: The Fatigue Assessment Scale . Journal of Psychosomatic Research , 2003 : 54 ( 4 ): 345 – 352 . OpenUrl CrossRef PubMed Web of Science 34. ↵ Weiss MG . Explanatory Model Interview Catalogue (EMIC): Framework for Comparative Study of Illness . Transcultural Psychiatry 1997 : 34 : 235 – 263 . OpenUrl CrossRef 35. ↵ El Moussaoui R , Opmeer BC , Bossuyt PM , et al. Development and validation of a short questionnaire in community acquired pneumonia . Thorax 2004 : 59 ( 7 ): 591 – 595 . OpenUrl Abstract / FREE Full Text 36. Wyrwich KW , Yu H , Sato R , et al. Observational longitudinal study of symptom burden and time for recovery from community-acquired pneumonia reported by older adults surveyed nationwide using the CAP Burden of Illness Questionnaire . Patient Related Outcome Measures 2015 : 6 : 215 – 223 . OpenUrl 37. ↵ Lamping DL , Schroter S , Marquis P , et al. The community-acquired pneumonia symptom questionnaire: a new, patient-based outcome measure to evaluate symptoms in patients with community-acquired pneumonia . Chest 2002 : 122 ( 3 ): 920 – 929 . OpenUrl CrossRef PubMed Web of Science 38. ↵ Horn A , Krist L , Lieb W , et al. Long-term health sequelae and quality of life at least 6 months after infection with SARS-CoV-2: design and rationale of the COVIDOM-study as part of the NAPKON population-based cohort platform (POP) . Infection 2021 : 49 ( 6 ): 1277 – 1287 . OpenUrl 39. ↵ Menges D , Ballouz T , Anagnostopoulos A , et al. Burden of post-COVID-19 syndrome and implications for healthcare service planning: A population-based cohort study . PLoS One 2021 : 16 ( 7 ): e0254523 . OpenUrl CrossRef PubMed 40. ↵ Zhang H , Huang C , Gu X , et al. 3-year outcomes of discharged survivors of COVID-19 following the SARS-CoV-2 omicron (B.1.1.529) wave in 2022 in China: a longitudinal cohort study . The Lancet Respiratory Medicine 2024 : 12 ( 1 ): 55 – 66 . OpenUrl 41. ↵ Serrano L , Ruiz LA , Perez-Fernandez S , et al. Short- and long-term prognosis of patients with community-acquired Legionella or pneumococcal pneumonia diagnosed by urinary antigen testing . International Journal of Infectious Diseases 2023 : 134 : 106 – 113 . OpenUrl 42. ↵ Davis HE , McCorkell L , Vogel JM , et al. Long COVID: major findings, mechanisms and recommendations . Nature reviews Microbiology 2023 : 21 ( 3 ): 133 – 146 . OpenUrl CrossRef PubMed 43. ↵ Gamage SD , Ross N , Kralovic SM , et al. Health after Legionnaires’ disease: A description of hospitalizations up to 5 years after Legionella pneumonia . PLoS One 2021 : 16 ( 1 ): e0245262 . OpenUrl 44. ↵ Cassini A , Colzani E , Pini A , et al. Impact of infectious diseases on population health using incidence-based disability-adjusted life years (DALYs): results from the Burden of Communicable Diseases in Europe study, European Union and European Economic Area countries, 2009 to 2013 . Eurosurveillance 2018 : 23 ( 16 ). 45. ↵ Collier S , Deng L , Adam E , et al. Estimate of Burden and Direct Healthcare Cost of Infectious Waterborne Disease in the United States . Emerging Infectious Disease 2021 : 27 ( 1 ): 140 . OpenUrl 46. ↵ Fiumefreddo R , Zaborsky R , Haeuptle J , et al. Clinical predictors for Legionella in patients presenting with community-acquired pneumonia to the emergency department . BMC Pulmonary Medicine 2009 : 9 ( 1 ): 4 . OpenUrl 47. ↵ Viasus D , Gaia V , Manzur-Barbur C , et al. Legionnaires’ Disease: Update on Diagnosis and Treatment . Infectious Diseases and Therapy 2022 : 11 ( 3 ): 973 – 986 . OpenUrl View the discussion thread. Back to top Previous Next Posted August 21, 2024. Download PDF Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Long-term impacts of Legionnaires’ disease on health and well-being: rationale, study design and baseline findings of a matched cohort study (LongLEGIO) Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Long-term impacts of Legionnaires’ disease on health and well-being: rationale, study design and baseline findings of a matched cohort study (LongLEGIO) Melina Bigler , Malina Vaucher , Manuel Wiederkehr , Sophia Brülisauer , Werner C. Albrich , Sarah Dräger , Valentin Gisler , Isabel Akers , Daniel Mäusezahl medRxiv 2024.08.20.24312294; doi: https://doi.org/10.1101/2024.08.20.24312294 Share This Article: Copy Citation Tools Long-term impacts of Legionnaires’ disease on health and well-being: rationale, study design and baseline findings of a matched cohort study (LongLEGIO) Melina Bigler , Malina Vaucher , Manuel Wiederkehr , Sophia Brülisauer , Werner C. Albrich , Sarah Dräger , Valentin Gisler , Isabel Akers , Daniel Mäusezahl medRxiv 2024.08.20.24312294; doi: https://doi.org/10.1101/2024.08.20.24312294 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Epidemiology Subject Areas All Articles Addiction Medicine (573) Allergy and Immunology (865) Anesthesia (302) Cardiovascular Medicine (4453) Dentistry and Oral Medicine (444) Dermatology (383) Emergency Medicine (609) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1515) Epidemiology (15242) Forensic Medicine (30) Gastroenterology (1131) Genetic and Genomic Medicine (6615) Geriatric Medicine (669) Health Economics (1001) Health Informatics (4552) Health Policy (1372) Health Systems and Quality Improvement (1614) Hematology (543) HIV/AIDS (1270) Infectious Diseases (except HIV/AIDS) (15929) Intensive Care and Critical Care Medicine (1106) Medical Education (624) Medical Ethics (147) Nephrology (670) Neurology (6625) Nursing (346) Nutrition (999) Obstetrics and Gynecology (1148) Occupational and Environmental Health (957) Oncology (3344) Ophthalmology (979) Orthopedics (369) Otolaryngology (421) Pain Medicine (436) Palliative Medicine (130) Pathology (665) Pediatrics (1696) Pharmacology and Therapeutics (693) Primary Care Research (714) Psychiatry and Clinical Psychology (5461) Public and Global Health (9252) Radiology and Imaging (2207) Rehabilitation Medicine and Physical Therapy (1371) Respiratory Medicine (1197) Rheumatology (597) Sexual and Reproductive Health (715) Sports Medicine (530) Surgery (714) Toxicology (99) Transplantation (289) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a02d0de8dc338650',t:'MTc3OTk2OTE1OA=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();