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

DOI: https://doi.org/https://doi.org/10.57187/s.4333

Introduction

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]. Symptoms of pneumonia and overall impaired wellbeing can persist for weeks to months after the acute infection, leading to additional use of health services [4–6]. Persistent sequelae of pneumonia that are reported in the literature include respiratory symptoms such as cough, dyspnoea and chest discomfort [7], cardiovascular complications [8], cognitive impairment [9, 10], general fatigue [7, 11, 12] and reduced quality of life [13]. Notably, extrapulmonary sequelae often outlast the respiratory symptoms [6, 11]. In addition, up to 9% of patients experience recurrent pneumonia within five years of an acute pneumonia episode [14].

Persistent manifestations of pneumonia – particularly non-specific symptoms such as fatigue or cognitive impairment and general reduced wellbeing – are difficult to capture in clinical practice and are often not well documented in medical records [7, 15, 16]. As a result, patient-reported outcome measures (PROMs) collected in prospective studies are important endpoints for assessing recovery from pneumonia [7]. However, most such prospective pneumonia studies do not differentiate between pneumonia-causing pathogens in the analysis but instead stratify for Streptococcus pneumoniae as the most commonly identified cause of community-acquired pneumonia (CAP) [11, 17] or they report persistent symptoms for individual pathogens without comparing findings to pneumonia of other aetiologies [18, 19]. The role of the infecting organism in the persistence of pneumonia symptoms therefore remains poorly understood.

Studying and comparing persistent symptoms of Legionnaires’ disease (LD) with other bacterial pneumonia provides an opportunity to investigate the role of the infection-causing pathogen in persistent pneumonia sequelae. Legionnaires’ disease is caused by the intracellular Gram-negative Legionella bacterium and accounts for about 4–7% of CAP cases in Europe [20]. Legionnaires’ disease often causes severe pneumonia and, in addition to respiratory symptoms, is frequently associated with extrapulmonary manifestations such as confusion, diarrhoea, headache and acute kidney damage [21–23]. The underlying pathophysiological mechanisms of Legionella infections are very similar to those of Coxiella burnetii infections causing Q fever [24, 25]. The long-term health effects of Q fever, particularly chronic fatigue, are well documented in the literature [15].

Despite its potential to cause persistent symptoms and health impairments that might be even more pronounced than for other types of bacterial pneumonia, the chronic impact of Legionnaires’ disease remains little studied. Previous studies have reported persistent fatigue, neurological symptoms such as concentration difficulties and memory loss, muscle weakness and reduced quality of life for up to 17 months after an acute Legionella infection [18, 26]. However, the studies were not specifically designed to compare these symptoms with the persistent manifestations of other types of pneumonia. It therefore remains unclear whether the observed persistent sequelae were due to the underlying Legionella infection or more generally due to the severity of the pneumonia per se. In addition, no study has systematically assessed the use of health services by Legionnaires’ disease patients beyond the acute phase of infection.

Here, we describe the rationale and design of the LongLEGIO study. This prospective study explores the persisting impacts of community-acquired Legionnaires’ disease (CALD) on patients’ health, wellbeing and health service utilisation and compares CALD patients with bacterial community-acquired pneumonia patients who tested negative for Legionella. We will further present the baseline characteristics of the two study cohorts.

Methods

Study design and objectives

The LongLEGIO study is a matched cohort study with the following objectives: (a) To explore CALD patients’ persistent symptoms and general wellbeing and compare them to those of Legionella test-negative bacterial community-acquired pneumonia patients (non-LD CAP), and (b) To describe and compare the care needs and health service utilisation of CALD and non-LD CAP patients during their recovery.

Recruitment and data collection

The LongLEGIO study enrolled CALD and non-LD CAP patients from university and cantonal/regional hospitals in Switzerland. For the recruitment of CALD patients and the collection of baseline data on these patients, the LongLEGIO study builds on a national case-control and molecular source attribution study investigating risk factors and sources of infection for CALD in Switzerland (SwissLEGIO) (figure 1) [27].

Figure 1Recruitment, enrolment and data collection for the community-acquired Legionnaires’ disease (CALD) and Legionella test-negative bacterial community-acquired pneumonia (non-LD CAP) cohorts. Grey: Baseline interviews and data extraction from electronic medical records for CALD patients were done within the context of the SwissLEGIO parent study. Red: LongLEGIO recruitment and data collection for the CALD cohort. Patients were recruited two months after the acute infection from a pool of CALD patients previously included in the SwissLEGIO parent study. Yellow: LongLEGIO recruitment and data collection for the non-LD CAP cohort. Non-LD CAP patients were enrolled from four university and cantonal/regional hospitals shortly after the pneumonia diagnosis. ABT: appropriate antibiotic therapy; CAP: community-acquired pneumonia; LD: Legionnaires’ disease.

Recruitment of community-acquired Legionnaires’ disease patients

CALD patients were recruited from a representative pool of Legionnaires’ disease patients who participated in the SwissLEGIO study [27]. The SwissLEGIO study recruited 204 CALD patients between August 2021 and March 2024 from 20 university and cantonal hospitals across Switzerland, which jointly reported about 45% of all CALD cases notified to the Swiss health authorities during this period [27]. 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. CALD patients were invited to participate in the LongLEGIO study by post or e-mail. Written informed consent was obtained from all CALD patients prior to the two-month follow-up interview (figure 1).

Recruitment of Legionella test-negative bacterial community-acquired pneumonia patients

Non-LD CAP patients were recruited through one university and three cantonal hospitals. All four hospitals also participated in the SwissLEGIO parent study. During the recruitment period, the hospitals kept track of all community-acquired pneumonia patients with pneumonia of confirmed or clinically suspected bacterial aetiology and who tested negative for Legionella spp. and COVID-19. The recruitment of the non-LD CAP patients occurred as soon as possible after the patients were diagnosed with pneumonia (figure 1).

To ensure comparability, non-LD CAP patients were matched to CALD patients based on sex, age (±5 years), hospital level (university or cantonal hospital) and date of diagnosis (up to +60 days). The recruitment of the non-LD CAP patients was triggered by the enrolment of a CALD patient – eligible for the LongLEGIO study – into the SwissLEGIO parent study. In short, a recruitment request with the match criteria was sent to the four partner hospitals. The eligible non-LD CAP patient with the closest matching diagnosis date was recruited. Eligibility criteria for non-LD 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 CAP patients are followed up over 12 months. Assessments are done at four different time points (figure 1). As soon as possible after the pneumonia diagnosis, a questionnaire-based baseline interview is conducted and additional data are extracted from electronic medical records for the current hospitalisation. Follow-up assessments are conducted at 2, 6 and 12 months after patients have received appropriate antibiotic therapy. All interviews are conducted in person or by a phone/video call.

At baseline, the questionnaire consists of closed and open questions related to patients’ pre-existing comorbidities, their acute illness experience, the perceived disease severity and patients’ health-seeking (table 2). In addition to the baseline interview, information on the patient’s medical history, disease severity, the pneumonia-causing pathogen and the treatment was extracted from electronic medical records.

The follow-up questionnaire focuses on patient-reported outcome measures used in previous studies assessing recovery from pneumonia [7, 13, 33–35] and in studies on Long COVID [36–38]. The questionnaire consists of closed and open questions to investigate (a) the patient’s perceived health, recovery and health-related quality of life (HRQoL) after the acute pneumonia episode, (b) the presence of persistent pneumonia-related symptoms, (c) patients’ (potentially extended) health service utilisation and health-seeking in the informal health sector after hospital discharge, and (d) potential impacts of the infection on patients’ social and work life (table 2).

Statistical analysis

Considering sample size, we assumed a 15% prevalence of symptoms such as fatigue, weakness and a general reduction in quality of life in the non-LD CAP group two months after the acute pneumonia episode. We therefore aimed to recruit and complete the first follow-up interview for 80 CALD patients and 80 non-LD CAP patients to detect a 20% difference between our two cohorts with 80% power and alpha = 0.05. The achieved sample size (59 CALD patients and 60 non-LD CAP patients) is sufficient to provide a power of 70% with alpha = 0.05.

The statistical analyses are being conducted according to the predefined Statistical Analysis Plan (SAP), available in the appendix. In summary, CALD and non-LD CAP patients were characterised at baseline in terms of demographics, illness experience, help-seeking, comorbidities and health-related quality of life. Continuous variables are presented as medians with interquartile ranges (IQRs) and categorical variables as n (%).

To assess long-term effects, we will tabulate the prevalence of symptoms and impairments in the EQ-5D-5L dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) as n (%). EQ-VAS scores will be reported as medians with IQRs at baseline (0 months), 2, 6 and 12 months. We will use bar charts and histograms to present the distribution of symptoms and health-related quality of life measures over time and to visualise differences between cohorts.

To estimate differences in the perceived overall recovery and in the recovery of selected symptoms between CALD and non-LD CAP, we will use non-parametric survival models. Differences in time to recovery between groups will be compared using log-rank tests with survival curves visualised using Kaplan-Meier estimates. Confounders such as selected comorbidities and working status will be accounted for using inverse probability weighting (IPW). Changes in health-related quality of life measures are estimated using a linear or logistic mixed model with a random effect on the individual patient. We will again correct for confounders.

Healthcare utilisation – including visits to general practitioners, specialist physicians, emergency departments and rehospitalisations – will be analysed across the entire follow-up period and within each follow-up interval. We will assess both the proportion of patients consulting healthcare services at least once for any reason and the proportion of patients consulting healthcare services specifically due to pneumonia after hospital discharge. Additionally, we will report the absolute number of consultations.

Only participants who completed at least the first follow-up interview will be included in the analysis. Missing data will be imputed using logical rules. No further imputation for missing values is foreseen.

All analyses will be conducted using R (version 4.4.1; R Core Team, Vienna, Austria).

Data management

Data are collected on standardised electronic Case Report Forms (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 identification. Automated validations are implemented in the eCRF to check for data completeness and plausibility and submitted forms are continuously checked for plausibility and accuracy. Data are stored on a secured network drive accessible only to authorised study personnel.

Ethical considerations

Ethical approval for the study was obtained from the Ethics Commission of Northwestern and Central Switzerland (EKNZ 2023-00639) and the boards of the participating hospitals. 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.

Study population

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 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 CAP patients (enrolment rate of 55%) agreed to participate. There were no significant differences in age, sex and ICU admission rates between participants and non-participants among CALD patients, and in sex and ICU admission rates among the patients with non-LD CAP (appendix table S1). There was a difference in age between participants and non-participants among the non-LD CAP patients (69 years vs 77 years).

Baseline characteristics

The baseline characteristics are summarised in table 3. The median age for both cohorts is 69 years; males comprised 59.3% of CALD and 63.3% of non-LD CAP patients. Both cohorts have a similar comorbidity burden as measured by the Charlson Comorbidity Index. Non-LD CAP patients, however, were more likely to have chronic obstructive pulmonary disease (COPD) (20.0% vs 11.9%), malignancies (33.3% vs 13.6%) and were more likely immunocompromised (25.0% vs 13.6%). In contrast, more CALD than non-LD CAP patients had chronic kidney failure (15.3% vs 10.0%). Patients in both cohorts exhibited similar health-seeking behaviour prior to the hospital visit with the majority of patients initially consulting a general practitioner. CALD patients were more frequently pre-treated with antibiotics (30.4% vs 15.3%).

During the acute phase of their pneumonia, non-LD CAP patients more frequently reported respiratory symptoms including cough (80.0% vs 66.7%), shortness of breath (78.0% vs 66.1%) and chest pain (49.1% vs 35.1%). On the contrary, CALD patients reported more frequent 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 invasive ventilation were higher for CALD than for non-LD CAP patients (13.6% vs 8.3% and 6.8% vs 1.8%, respectively).

Finally, participants were asked to report on their perceived health-related quality of life prior to the onset of pneumonia symptoms. We used the standardised EQ-5D-5L questionnaire which measures health-related quality of life across five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression). In addition, patients are also asked to rate their overall health on a scale from 0 (lowest possible score) to 100 (EQ-VAS score) [29]. In general, non-LD CAP patients reported lower EQ-VAS scores compared to CALD patients. Differences in the reported health-related quality of life were observed for the dimensions mobility, daily activity and pain/discomfort (table 3, appendix table S2).

For non-LD CAP patients, Streptococcus pneumoniae and Haemophilus influenzae were each identified as the causative pathogen in 10.0% of the patients. Mycoplasma pneumoniae was the causative pathogen in 5.0% of patients. Viral-bacterial pneumonia with bacterial superinfection was recorded for 3.3% of non-LD CAP patients. No pathogen was detected in 73.3% of non-LD CAP patients (appendix table S2).

Discussion

Acute infections can cause persistent health problems. Although post-acute infection syndromes have been recognised for some time, they have often been neglected and underreported, with few exceptions like Q fever [15]. The COVID-19 pandemic, however, brought renewed attention to this issue, when long-term health and wellbeing impairments were observed in a significant subset of patients months or even years after the acute SARS-CoV-2 infection [36–38]. Similarly, persistent health impairments have been reported for community-acquired pneumonia [8–13, 17]. However, the role of the infection-causing pathogen in the persistence of community-acquired pneumonia symptoms and sequelae in general remains unclear, and data on the long-term health effects of Legionnaires’ disease are scarce. Here, we described the rationale and design of a matched cohort study to investigate persistent sequelae of community-acquired Legionnaires’ disease (CALD) and compare them with manifestations of persistent pneumonia in non-LD CAP patients. We also presented the baseline characteristics of our two study cohorts, which are representative of their respective patient populations.

Previous studies on persistent sequelae of community-acquired pneumonia have rarely stratified analyses by the different pneumonia-causing pathogens [8–10, 12, 13]. Of those that have, the focus has been on Streptococcus pneumoniae [11, 17]. This limited stratification was mainly due to sample size limitations and a lack of information on the community-acquired pneumonia-causing pathogens. In contrast, studies examining persistent sequelae of Legionella infections did not include pneumonia patients as a comparison group [18, 26]. To our knowledge, the LongLEGIO study is the first study that systematically compares the persistent health effects of CALD with the persistent manifestations of non-LD CAP, going beyond a survival analysis based on mortality data [39]. Such a comparison is crucial to contextualise the frequency of observed health and wellbeing impairments in CALD patients against the background occurrence in a suitable control group. Moreover, this approach will allow us to explore how the persistence of community-acquired pneumonia-related health impairments is linked to the pathogenic mechanisms of the causative bacteria. Ultimately, this may improve our understanding of the underlying pathogenesis of persistent pneumonia manifestations and post-acute infection syndromes [15, 16].

The LongLEGIO study prioritised patient-reported outcome measures, rather than focusing on mortality or hospital readmission rates which have been the primary outcomes in previous large studies on Legionella that relied on medical record data [39, 40]. Such patient-reported outcome measures provide robust measures of persistent symptoms and functional impairments that patients experience [7]. Persistent symptoms and functional impairments, as measured by patient-reported outcome measures, are also one of the main reasons for additional general practitioner consultations and emergency department visits after the acute phase of pneumonia [4, 5]. Patient-reported outcome measures, however, are usually not well documented in medical records and hence can only be adequately captured by applying prospective study designs [15, 16].

The LongLEGIO study is also the first study to assess healthcare utilisation among CALD patients beyond the acute infection and its association with persistent sequelae of CALD. As demonstrated by the COVID-19 pandemic and the rise of Long COVID, post-acute infection syndromes can significantly contribute to the burden of infectious diseases [16, 37]. However, current estimates of the burden of Legionnaires’ disease do not account for persistent health impairment or the resulting increased medical costs [41, 42]. By examining both persistent sequelae of CALD and additional healthcare utilisation after the acute infection, the LongLEGIO study will provide data for a better disease burden estimate for Legionnaires’ disease in the future. This, in turn, may help public health specialists and physicians to plan and anticipate the health care resources needed for the holistic treatment of CALD beyond the acute phase of the disease.

A total of 59 CALD patients and 60 non-LD CAP patients were enrolled between June 2023 and June 2024. Our non-LD CAP and CALD patient cohorts appear representative of the two patient populations. Similarly to what is reported in previous studies, Legionnaires’ disease patients were more likely to suffer from extrapulmonary symptoms, were more frequently pre-treated with antibiotics before hospital admission and were more often admitted to the ICU [21–23, 43]. Non-LD CAP patients, on the other hand, were more likely to suffer from chronic obstructive pulmonary disease, immunosuppression and malignancies, which is also consistent with findings from previous research [23, 43]. Finally, we also observed differences in the self-reported quality of life scores (lower scores were reported by non-LD CAP patients). Both comorbidities and pneumonia severity may influence the long-term health outcomes after pneumonia [4, 6, 11]. We will therefore correct for these differences in our future analyses of long-term outcomes. For the self-reported quality of life score, each patient will serve as their control and relative rather than absolute changes in reported scores from the pre-pneumonia baseline score will be assessed and compared between groups.

The LongLEGIO study has limitations. First, the study may be subject to recall bias, especially between the 6- and 12-month follow-up points. 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. Second, despite the integration of the LongLEGIO 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 of fully capturing the common persistent sequelae of CALD. Finally, the study compared only patients surviving hospitalisation, restricting the population of CALD and non-LD CAP.

In summary, the LongLEGIO study explores and compares persistent health and wellbeing impacts of CALD and non-LD CAP in two representative cohorts. The study aims to contribute to ongoing research on post-acute infection syndromes, a phenomenon long recognised and well-documented for conditions like Q fever but often challenging to capture in daily medical practice [15]. Here, we presented the rationale and study design of the LongLEGIO study and characterised the two study cohorts. Results of the long-term follow-up of these two cohorts will be reported in subsequent publications.

Availability of data and material

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Acknowledgments

We thank Jan Hattendorf for his advice on the design and development of the study protocol. At the Federal Office of Public Health, we would like to thank Ornella Luminati and Monica Wymann for the exchanges surrounding this study. We thank Katia Sidler and Sereina Livia Müller for their assistance with patient recruitment at the University Hospital of Basel. We thank Chiara Strozzi, Florian Zacher, Helena Greter, Cornelia Speich and Céline Fürer for their support in the data collection.

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Appendix

The appendix is available in the pdf version of the article at https://doi.org/10.57187/s.4333.