Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Jun 15;64(suppl_3):S205-S212.
doi: 10.1093/cid/cix076.

Should Controls With Respiratory Symptoms Be Excluded From Case-Control Studies of Pneumonia Etiology? Reflections From the PERCH Study

Melissa M Higdon  1 , Laura L Hammitt  1   2 , Maria Deloria Knoll  1 , Henry C Baggett  3   4 , W Abdullah Brooks  5   6 , Stephen R C Howie  7   8   9 , Karen L Kotloff  10 , Orin S Levine  1   11 , Shabir A Madhi  12   13 , David R Murdoch  14   15 , J Anthony G Scott  2   16 , Donald M Thea  17 , Amanda J Driscoll  1 , Ruth A Karron  18 , Daniel E Park  1   19 , Christine Prosperi  1 , Scott L Zeger  20 , Katherine L O'Brien  1 , Daniel R Feikin  1   21 ; PERCH Study Group
Collaborators, Affiliations
Review

Should Controls With Respiratory Symptoms Be Excluded From Case-Control Studies of Pneumonia Etiology? Reflections From the PERCH Study

Melissa M Higdon et al. Clin Infect Dis. .

Abstract

Many pneumonia etiology case-control studies exclude controls with respiratory illness from enrollment or analyses. Herein we argue that selecting controls regardless of respiratory symptoms provides the least biased estimates of pneumonia etiology. We review 3 reasons investigators may choose to exclude controls with respiratory symptoms in light of epidemiologic principles of control selection and present data from the Pneumonia Etiology Research for Child Health (PERCH) study where relevant to assess their validity. We conclude that exclusion of controls with respiratory symptoms will result in biased estimates of etiology. Randomly selected community controls, with or without respiratory symptoms, as long as they do not meet the criteria for case-defining pneumonia, are most representative of the general population from which cases arose and the least subject to selection bias.

Keywords: PERCH; control selection; pneumonia etiology; respiratory symptoms; selection bias..

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
A, Distribution of respiratory symptoms among human immunodeficiency virus (HIV)–negative controls in the Pneumonia Etiology Research for Child Health (PERCH) Study. *Observed or reported. Clinical history recorded information on presence/absence of runny nose, cough, fever, ear discharge, difficulty breathing, wheeze, and sore throat as reported by guardian or study staff; clinical examination included assessment of cough, respiratory rate, and temperature by trained examiner. Tachypnea was defined as a respiratory rate ≥60 breaths per minute on clinical examination for children 1–2 months of age, ≥50 for children 2–11 months, and ≥40 for children 12–59 months. Fever on clinical examination was defined as temperature ≥38°C. B, Number of symptoms present among 1683 HIV-negative controls with any respiratory symptom. Respiratory symptoms (observed or reported) include runny nose, cough, tachypnea, fever, ear discharge, difficulty breathing, wheeze, and sore throat.
Figure 2.
Figure 2.
Depiction of realistic, hypothetical cohort in which pathogen X causes pneumonia solely through upper respiratory tract infection (URTI): comparison of a case-control study enrolling controls with and without URTI to a case-control study enrolling only controls without URTI. *The proportion of children that go on to develop URTI. **The proportion of children that go on to develop pneumonia.
Figure 3.
Figure 3.
Rhinovirus nasopharyngeal/oropharyngeal (NP/OP) polymerase chain reaction (PCR) prevalence among chest radiograph (CXR)–positive cases and controls with and without symptoms of respiratory illness by site. CXR-positive was defined as the presence of alveolar consolidation and/or other infiltrate on CXR. Respiratory symptoms include runny nose, cough, tachypnea, fever, ear discharge, difficulty breathing, wheeze, and sore throat. *χ2 test comparing controls with vs without respiratory symptoms yielded P < .05.
See this image and copyright information in PMC

References

    1. Madhi SA, Groome MJ, Zar HJ, et al. Effectiveness of pneumococcal conjugate vaccine against presumed bacterial pneumonia hospitalisation in HIV-uninfected South African children: a case-control study. Thorax 2015; 70:1149–55. - PubMed
    1. Deloria-Knoll M, Feikin DR, Scott JA, et al. ; Pneumonia Methods Working Group Identification and selection of cases and controls in the Pneumonia Etiology Research for Child Health project. Clin Infect Dis 2012; 54suppl 2:S117–23. - PMC - PubMed
    1. Deceuninck G, De Wals P, Boulianne N, De Serres G. Effectiveness of pneumococcal conjugate vaccine using a 2 + 1 infant schedule in Quebec, Canada. Pediatr Infect Dis J 2010; 29:546–9. - PubMed
    1. Pilishvili T, Chernyshova L, Bondarenko A, et al. Evaluation of the effectiveness of Haemophilus influenzae type b conjugate vaccine introduction against radiologically-confirmed hospitalized pneumonia in young children in Ukraine. J Pediatr 2013; 163(1 suppl):S12–8. - PubMed
    1. de la Hoz F, Higuera AB, Di Fabio JL, et al. Effectiveness of Haemophilus influenzae type b vaccination against bacterial pneumonia in Colombia. Vaccine 2004; 23:36–42. - PubMed