key: cord-0963996-30vui3kx
authors: Vos, L.M.; Bruyndonckx, R.; Zuithoff, N.P.A.; Little, P.; Oosterheert, J.J.; Broekhuizen, B.D.L.; Lammens, C.; Loens, K.; Viveen, M.; Butler, C.C.; Crook, D.; Zlateva, K.; Goossens, H.; Claas, E.C.J.; Ieven, M.; Van Loon, A.M.; Verheij, T.J.M.; Coenjaerts, F.E.J.
title: Lower respiratory tract infection in the community: associations between viral aetiology and illness course
date: 2020-03-31
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2020.03.023
sha: 59e5ae00746e86f99465a08a2fcd2e7f5a7ac4fe
doc_id: 963996
cord_uid: 30vui3kx

OBJECTIVES: This study determined associations between respiratory viruses and subsequent illness course in primary care adult patients presenting with acute cough and/or suspected lower respiratory tract infection (LRTI). METHODS: A prospective European primary care study recruited adults with symptoms of lower respiratory tract infection between Nov-Apr 2007-2010. Real-time in-house polymerase chain reaction (PCR) was performed to test for six common respiratory viruses. In this secondary analysis, symptom severity (scored 1=no problem, 2=mild, 3=moderate, 4=severe) and symptom duration were compared between groups with different viral aetiologies using regression and Cox proportional hazard models, respectively. Additionally, associations between baseline viral load (cycle threshold (Ct) value) and illness course were assessed. RESULTS: The PCR tested positive for a common respiratory virus in 1,354 of the 2,957 (45.8%) included patients. The overall mean symptom score at presentation was 2.09 (95%CI 2.07-2.11) and the median duration until resolution of moderately bad or severe symptoms was 8.70 days (interquartile range 4.50-11.00). Patients with influenza virus, human metapneumovirus (hMPV), respiratory syncytial virus (RSV), coronavirus (CoV) or rhinovirus had a significantly higher symptom score than patients with no virus isolated (0.07-0.25 points or 2.3-8.3% higher symptom score). Time to symptom resolution was longer in RSV infections (adjusted hazard ratio (AHR) 0.80, 95%CI 0.65-0.96) and hMPV infections (AHR 0.77, 95%CI 0.62-0.94) than in infections with no virus isolated. Overall, baseline viral load was associated with symptom severity (difference 0.11, 95%CI 0.06-0.16 per 10 cycles decrease in Ct value), but not with symptom duration. CONCLUSIONS: In healthy, working adults from the general community presenting at the general practitioner with acute cough and/or suspected LRTI respiratory viruses other than influenza impose an illness burden comparable to influenza. Hence, the public health focus for viral respiratory tract infections should be broadened.

From the few studies describing the aetiology of acute lower respiratory tract infections (LRTIs) in 62 primary care patients, we know that most LRTIs in the general community are caused by viral 63 pathogens, in particular rhinovirus, influenza virus, coronavirus (CoV), respiratory syncytial virus 64 (RSV), human metapneumovirus (hMPV), and parainfluenza virus (PiV)(1,2). The illness course of LRTIs in adults presenting in this setting -a relatively healthy, working population -is mostly self-66 limiting and complications are rare(3). However, with an average of 3.5 days sick leave per year,

LRTIs cause a substantial socio-economic burden (3, 4) . In adults, influenza virus, bacteria, and 68 viral-bacterial coinfections are assumed to cause the most severe illnesses, with most systemic 69 symptoms, longest illness durations, and most complications(5-7). However, evidence on 70 associations between aetiology and severity are mainly derived from hospital care settings with 71 vulnerable patient populations (8) (9) (10) . In this setting, a focus on pathogens with the highest 72 complication rates is obvious. Quite often, however, this focus is also applied in the general 73 community, with public health interventions as the annual influenza vaccinations targeted at the 74 most vulnerable people with the aim of reducing the risk of complications and death(11). Although 75 data on the impact of respiratory viruses in the primary care setting are limited due to restricted 76 microbial testing and absence of a standardized, validated outcome measure to evaluate illness 77 severity(12), there are studies suggesting that the burden of disease from infections due to 78 respiratory viruses other than influenza -i.p. rhinovirus, coronavirus and RSV -may be greater 79 overall(13). In this study, we aimed to explore the associations between respiratory viral 80 pathogens, including viral load, and illness course in the adult primary care community, thereby 81 opening up possibilities to base the public health focus on the impact of respiratory viruses in 82 primary care, rather than on extrapolated data from hospital settings. This study was conducted in

This prospective study in primary care is part of the GRACE study (Genomics to combat between November 2007 and April 2010 by general practitioners (GPs) from 16 primary care 90 networks in 11 European countries (Supplementary Figure 1) . Patients aged ≥18 years presenting 91 with acute cough (duration of ≤28 days) and/or suspected LRTI, were asked to participate in this 92 study, i.e. to fill out study materials and provide written informed consent(14). Exclusion criteria 93 were pregnancy, breast-feeding, any serious immunocompromised condition and antibiotic use in 94 the previous month (14). About one third of these patients agreed to being randomised to either the 95 intervention (amoxicillin) or placebo arm of the original randomized controlled trial (14). Remaining 96 patients were not randomly assigned, but were included in the observational part of the study(1). In 97 the current study, both trial and observational patients were analysed together, but patients without 98 PCR and/or serology results on viral aetiology (all due to practical reasons) were excluded. Ethical 99 approval was obtained for all participating networks.

Clinical measurements

For the collection of clinical data on the day of presentation (baseline), standardized case report forms (CRFs) were used. GPs completed the CRF on the following 12 symptoms rated by the 104 patients using a 4-point Likert-scale (1=no problem, 2=mild, 3=moderate, 4=severe): cough, At baseline, two nasopharyngeal flocked swabs were taken by trained staff within 24 hours after 116 recruitment and before any antimicrobial treatment had started. Swabs were placed in universal 117 transport medium immediately, frozen locally, and transported on dry ice to the central laboratory performed either as four multiplex and RSV; 

p=0.02) were not detected more frequently in symptomatic patients than in controls, they were not 127 considered pathogenic respiratory viruses and therefore excluded from our analyses(1). A cycle 128 threshold (Ct) value -an inverse, logarithmic, quantitative measurement of viral load -below 45 129 was chosen as cut-off for a positive result. We adjusted our analyses for bacterial infections, which 130 were defined as having at least one of the following pathogens detected in a sputum or 131 nasopharyngeal sample: Streptococcus species, Gram-negative species, or Aspergillus (fungus).

Commensals and Candida species were considered contaminants for which analyses were not 133 adjusted. Microbiologists who determined the results were blinded to clinical information.

Outcome parameters

We focused on two main outcome parameters: symptom severity at presentation and illness 137 duration. Symptom severity was measured as the mean CRF score for all 12 symptoms (scored 1-138 4) at baseline (14, (17) (18) (19) . Illness duration was defined as the duration until absence of any 139 symptoms rated moderately bad or severe (score 3 or above) in the symptom diary following initial

Symptom severity at baseline was analysed with linear regression models and expressed as 146 differences in mean symptom severity with a 95% confidence interval (CI). In an additional step, 

presentation was 2.09 (95%CI 2.07-2.11). Respiratory viruses (1,411) Table 2) . Among patients in 180 whom a virus was detected, a ten cycles lower Ct value -i.e. a higher viral load -measured at 181 presentation, was associated with a 0.11 (95%CI 0.06-0.16) point higher mean symptom severity 182 as compared to patients without detected virus. After stratification for viral aetiology, we only 183 observed an association between viral load and symptom severity for rhinovirus (increase of 0.12 184 per 10 cycles reduction in Ct value, 95%CI 0.04-0.20) and for RSV (increase of 0.16 per 10 cycles symptoms of these viruses (Figure 3) , influenza virus was independently associated with severe generally unwell (OR 2.5, 95%CI 1.8-3.5), and interference with daily activities (OR 2.5, 95%CI 190 1.8-3.5). RSV was associated with severe headache (OR 2.0, 95%CI 1.2-3.5), disturbed sleep (OR 191 1.7, 95%CI 1.1-2.5) and a runny nose (OR 2.9, 95%CI 1.9-4.4). hMPV was associated with severe 192 dyspnoea (OR 2.0, 95%CI 1.0-3.7) and headache (OR 2.0, 95%CI 1.1-3.7). Rhinovirus was 193 associated with severe wheeze (OR 1.6, 95%CI 1.0-2.6), a runny nose (OR 1.6, 95%CI 1.2-2.1) 194 and negatively associated with severe cough (OR 0.8, 95%CI 0.6-0.9). CoV was associated with a 

Finally, a higher viral load was associated with a higher symptom severity at presentation. Looking 266 at specific viruses we only found this association for RSV and rhinovirus, which confirms previous technique, they also rise and drop rapidly and it is known that symptoms mostly follow the viral load(30,31).

In conclusion, in this study among relatively healthy adult patients presenting in a primary care 

Aetiology of lower respiratory tract infection in community: comparative, prospective, population based study of disease burden

Amoxicillin for acute lower-respiratory-tract infection 326 in primary care when pneumonia is not suspected: A 12-country, randomised, placebo-controlled trial

Validation study of a diary for use in acute lower respiratory tract infection

Performance of different mono-and multiplex 24

The preventive effect of vaccine prophylaxis on severe respiratory syncytial 25

Recent vaccine development for human metapneumovirus

Figure 2. Detected viral pathogens in included patients (n=2957) and availability of follow-up data

CoV, coronavirus; hMPV, human metapneumovirus

Parainfluenza virus; RV, rhinovirus; RSV, respiratory syncytial virus

Undet, influenza virus type undetermined

* The following combinations of viral pathogens were found: CoV + RV (n=10), IV + RV (n=8), CoV + hMPV (n=5)

IV + RSV (n=3), CoV + IV (n=2), hMPV + RV (n=2), IV + PiV (n=1), CoV + PiV (n=1), RV + PiV (n=1), RSV + PiV (n=1)

** The following combinations of viral pathogens were found: CoV + RV (n=5), IV + RV (n=3), CoV + IV (n=3), CoV + RSV (n=1), RV + RSV (n=1), IV+ RSV (n=1), RV + PiV (n=1)