European Journal of General Practice, 2014; 20: 202–208

Original Article

A new diagnostic index for bacterial conjunctivitis in

primary care. A re-derivation study

Henk C. P. M. van Weert, Ellinore Tellegen & Gerben ter Riet

Academic Medical Center, Department of General Practice, University of Amsterdam, Amsterdam, The Netherlands
Eur J Gen Pract Downloaded from informahealthcare.com by Nyu Medical Center on 07/23/15

KEY MESSAGE:

• Only one third of cases of infectious conjunctivitis in primary care has a bacterial origin.
• Discrimination between viral or bacterial origin on clinical grounds is difficult; a simple diagnostic index may help.
• Younger patients and those without glued eyelids are less at risk for a bacterial origin.

ABSTRACT
Background: Eighty per cent of primary care patients with infectious conjunctivitis are treated with antibiotics, although in only
30%, there is a bacterial cause. An accurate diagnostic index to distinguish bacterial from viral conjunctivitis may help reduce unnec-
For personal use only.

essary antibiotics.
Objectives: To validate and, if necessary, improve an existing diagnostic index for bacterial conjunctivitis.
Methods: Non-experimental validation and updating study of an existing diagnostic index in Dutch General Practice. We collected
210 adult patients with incident symptoms suggestive for acute infectious conjunctivitis. GPs completed a standardized questionnaire
and a physical examination of the eye(s) and took a conjunctival sample for culture. Cultures were analysed masked for the GPs’
findings. On bad performance of the existing index on the new patients, we developed a new index combining the dataset on which
the original model had been developed (n ⫽ 176) and the new dataset (n ⫽ 210). Bootstrapped backward variable selection and
shrinkage of regression coefficients was used to protect the new index against bad performance in future patients.
Results: The bacterial culture was positive in 36.3%. The items age and number of glued eyes at awakening were consistent predic-
tors. This model classified 48% (107/386) of patients at a low (⬍ 25%) chance of having a positive culture and 2% as at high (⬎ 70%)
chance.

Conclusion: Correction of a previously derived diagnostic index for bacterial conjunctivitis yielded a simple index, based on history
only. The index is potentially useful to rule out bacterial conjunctivitis in patients below 50 years of age with no history of glued
eyes at awakening. This study underscores the importance of external validation of diagnostic indices.

Keywords: conjunctivitis, diagnostics, diagnostic index, general practice, validation study

INTRODUCTION
In primary care, acute infectious conjunctivitis is pre-
sented by 15 per 1 000 patients annually. Around 30%
of cases are of bacterial origin, but more than 80% of
patients receive antibiotics (1–3). Prescription rates in
general practice have diminished, but over the counter
selling of chloramphenicol eye drops in the UK since
2005 provoked a net increase in the use of topical anti-
biotics by almost 50% (4). Moreover, acute infectious
conjunctivitis of bacterial origin, benefits only marginally
from antibiotic treatment on the short-term (5). Although
the contribution of topical antibiotics to the increase in
antibiotic resistance is difficult to demonstrate, restric-
tion of their use is recommendable (6).
Discrimination between bacterial and other causes
of conjunctivitis on clinical grounds is difficult, and a sys-
tematic literature search showed that diagnostic indica-
tors claiming to be informative were not evidence based
(1–3). General practitioners (GPs) claim that not so much
medical reasons, but rather social factors such as reduc-
ing absence from work or missed school days urge them
to prescribe topical antibiotics (7).
To help reduce the number of unnecessary prescrip-
tions of antibiotics, we previously developed a diagnostic

Correspondence: H. C. P. M. van Weert, Academic Medical Center, Department of General Practice, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam,
The Netherlands. E-mail: h.c.vanweert@amc.uva.nl

(Received 6 July 2012; accepted 20 August 2013)

ISSN 1381-4788 print/ISSN 1751-1402 online © 2014 Informa Healthcare
DOI: 10.3109/13814788.2013.842970

index to estimate the probability of bacterial origin of
conjunctivitis. This index uses ‘number of glued eyes at
awakening,’ ‘itch,’ and ‘history of previous conjunctivitis’
as diagnostic indicators. Using these items, the overall
pre-test probability of 32% of a bacterial conjunctivitis
transformed into post-test probabilities between 4% and
77% (8). An individual patient data meta-analysis of three
previously published primary care trials showed that
patients with ‘purulent discharge’ and ‘mild severity of
redness of the eye’ had significant benefit from antibio-
tics. This analysis, however, included many children less
than five years of age, in whom a bacterial aetiology is
more often present (9).
Since a diagnostic model often performs worse in
populations other than that in which it was derived,
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external validation in another but similar population is
warranted before implementation in clinical practice
(10–15). This paper reports on an attempt to validate
externally our previously developed diagnostic index for
bacterial conjunctivitis and the subsequent re-derivation
of an adapted index.
METHODS
For personal use only.
General design
Originally, the current study was designed as a formal
external validation study of a previously derived diagnos-
tic index for bacterial conjunctivitis. Therefore, it was
executed according to a research protocol very similar to
the previous study (dataset 1, n ⫽ 177) (8). This led to a
dataset (dataset 2, n ⫽ 212) that had the same structure
as the previous one. Data from medical history and phys-
ical examination were modelled against the results of
microbiological cultures (reference standard). The micro-
biologists performing the cultures were not informed
about the results of medical history and physical exami-
nation; GPs did not receive the culture results (double
blinding).
The Ethics Committee of the Academic Medical
Center of Amsterdam exempted this study from formal
approval, as no interference with usual healthcare
occurred.
Participants
General practitioners (GPs). Sixty-two GPs from 22
practices in the Northern and Central parts of the
Netherlands included adult patients with symptoms
suggestive for acute infectious conjunctivitis. Fifteen
GPs had been involved in the previous diagnostic index
derivation study (8).
Patients. Inclusion criteria were: red eye and either dis-
charge or glued eyes at awakening. Exclusion criteria
were: age younger than 18 years; pre-existing symptoms
Diagnostic index for infectious conjunctivitis 203
for longer than seven days; use of systemic or local
antibiotics within the previous two weeks; herpes kera-
titis ever; recent loss of vision, recent eye trauma, or
active infection with chlamydia trachomatis or Neisseria
gonorrhoea. Participants were informed about the study
and gave written informed consent. The inclusion and
exclusion criteria were identical to those of the previous
derivation study.
Data collection
General practitioners (GPs). Between April 2006 and
November 2008 the GPs collected information for each
consecutive patient, presenting with signs of infectious
conjunctivitis.
Medical history. The medical history (questionnaire) con-
tained questions about symptoms (itching, burning, for-
eign body sensation, tears, number of glued eyes at
awakening, and duration of symptoms (days)), a history
of other eye problems (allergic conjunctivitis, hay fever,
pre-existent eye problems, eye surgery and previous
infectious conjunctivitis) and medication.
Physical examination. The eyes were investigated with
regard to the degree of redness of the eye (none, periph-
eral, whole conjunctiva but not pericorneal, or whole
conjunctiva and pericorneal); the presence of periorbital
oedema (absent, present); the kind of discharge (none,
watery, mucous, or purulent); and the number of affected
eyes (one or two).
Microbiological sample. GPs took one conjunctival sam-
ple for bacterial culture of the affected eye. In case of
two affected eyes, the most severely affected eye as
judged by the GP was designated as the study eye. If
two eyes were affected equally severely, the eye which
had shown the first symptoms was taken. After taking
a sample of the conjunctiva of the study eye by rolling
a cotton swab (Laboratory Service Provider, Velsen-
Noord, The Netherlands) across the conjunctiva of the
lower fornix, GPs put the sample in a Stuart transport
medium and sent it the same day by surface mail to the
laboratory for medical microbiology of the Medical Cen-
tre Alkmaar.
Microbiological procedures
At the laboratory, the swabs were inoculated directly
after arrival onto blood agar enriched with 5% sheep
blood, MacConkey agar, and chocolate agar. All media
were made at the laboratory with standard ingredients
(Becton Dickinson, Cockeysville, MD, USA). After stan-
dard inoculation, the blood agar and MacConkey agar
plates were incubated for 48 h at 35°C; the chocolate
plates for 48 h at 35°C, but in a 7% CO2 atmosphere.
 204 H. C. P. M. van Weert et al.
Cultures were analysed daily according to the guide- Table 1. Patient characteristics and pathogen species.
lines of the American Society for Microbiology (16). All
Characteristic Combined data (n ⫽ 386)
pathogens were identified using routine standard bio-
chemical procedures. Suspected colonies were selected Medical history
and further investigated by Gram stain. In case of gram- Age (years) median (IQR) 40 33;55
positive cocci, Gram stain was followed by catalase test, Female (n, %) 238 62
Hay fever (n, %) 67 17
coagulase test or an optochine test. In case of gram-
History of allergic conjunctivitis (n, %) 31 8
negative rods or cocci, sugar tests followed. Actual complaints
Itching (n, %) 184 48
Burning sensation (n, %) 230 60
Statistical methods Foreign body sensation (n, %) 150 39
Bilateral involvement (n, %) 99 26
External validation attempt. As a first step, we applied the
Glued eyes at awakening
regression equation underlying the previously derived None (n, %) 59 15
index for bacterial conjunctivitis in the new dataset 2. We One (n, %) 240 63
assessed discrimination (area under the ROC curve) and Two (n, %) 84 22
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calibration (the extent to which predicted risks are close Physical examination
the observed risks). We used a calibration plot and the Redness
Peripheral only (n, %) 142 37
Hosmer–Lemeshow Chi-square test to investigate calibra- Whole conjunctiva ⫾ pericorneal (n, %) 243 63
tion. However, the validation model performed badly on Secretion
both discrimination and calibration (see Results). None or clear (n, %) 302 79
Mucous or purulent (n, %) 82 21
Re-deriving a new diagnostic index. Since the current Periorbital oedema (n, %) 105 28
(‘validation’) dataset 2 had the same structure as the Culture results
Total number of positive cultures (n, %) 140 36
previous (‘derivation’) dataset 1, we decided to combine Pathogens
datasets 1 and 2 to re-derive a diagnostic index for bac-
For personal use only.

Staphylococcus aureus (n, %) 41 29

terial conjunctivitis, now built on a more robust dataset. Streptococcus pneumoniae (n, %) 44 31
Had the external validation of the previously derived Haemophilus influenzae (n, %) 18 13
index been satisfactory in terms of discrimination and Othera (n, %) 39 27
Total pathogens (n, %) 142 100
calibration, combining the datasets and re-deriving a
new model would not have been necessary. IQR denotes interquartile range (25th and 75th centile, respectively).
aOthers include: Pseudomonas spp., Moraxella catarrhalis, other

Data preparation. Available were two datasets of 177 (set
1) and 212 (set 2) patients, respectively. In dataset 1, one
patient was excluded because she scored negative on
‘redness of the eye,’ which was an inclusion criterion. In
dataset 2, one 15 year-old patient had been inadvertently
admitted and was analysed since the 18 year cut-off had
no biological rationale for this study. Finally, two patients
from dataset 2 were excluded because a bacterial culture
result was missing. This left 176 (dataset 1) and 210
(dataset 2) patients for analysis (n ⫽ 386; Table 1).
Collapsing variable categories. The type of redness was
documented as ‘mild’ (peripheral only); ‘moderate’
(complete conjunctiva, but not pericorneal); ‘severe’
(complete conjunctiva). However, the moderate and
severe categories were associated with a positive culture
equally strongly. Therefore, we modelled redness as
‘peripheral’ versus ‘moderate/severe’. Similarly, for
secretion the original categories of ‘none’ (n ⫽ 3), ‘clear,’
‘mucous,’ and ‘purulent ’ were recoded as ‘none/clear ’
versus ‘mucous/purulent.’
Variable selection. In three separate analyses, we used
backward elimination for variable selection starting with
a model including all variables and eliminating those
Streptococcus spp.
whose associations were weaker than P ⫽ 0.05, 0.10 and
0.157, respectively to assess the stability of the selected
model across these thresholds (17). For each threshold,
1 000 bootstrap samples were drawn, and the frequency
with which a variable was selected into the model
(bootstrap inclusion fraction (BIF) was counted (Supple-
mentary Appendix Table 1. available at http://www.
informahealthcare.com/doi/abs/10.3109/13814788.
2013.842970). To enhance parsimony of the final model,
we predefined a threshold for inclusion of predictor vari-
ables into the definitive model of 2/3, that is, 670 selec-
tions out of 1 000. To enhance clinical applicability, we
first let the selection procedure select indicators that a
physician may collect without actually seeing the patient.
In a second step, we assessed the added value of indica-
tors that necessitate visual inspection of the eye(s) by a
medically trained person, namely, redness, secretion,
and oedema. We plotted the shrunk predicted probabil-
ities and their 95% CIs to enhance valid application of
the diagnostic model in practice.
Parameter-wise shrinkage. The main reasons to com-
bine both available datasets were: (a) the larger size

of the combined dataset is likely to make the deriva-
tion of the new model more reliable; and (b) the larger
size also enabled us to check the functional form of
age (the only indicator that may be modelled not
using dummy variables) more robustly (17). To coun-
teract over-optimism of the model, the regression
coefficients of the final logistic model were made
smaller using ‘parameter-wise shrinkage.’ This tech-
nique shrinks strong predictors less than weak ones
since the likelihood of selecting a weaker predictor is
more prone to chance than selecting a strong one
(18). The regression coefficients were multiplied (and
attenuated) by these factors and their standard errors
re-calculated.
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Diagnostic index for infectious conjunctivitis 205
Patient and pathogen characteristics of the combined
dataset (n ⫽ 386)
Patient characteristics of the combined dataset are pre-
sented in Table 1. The overall prevalence of a positive
bacterial culture was 36.2% (140/386). The most preva-
lent pathogens were Streptococcus pneumonia (44/140
positive cultures; 31%) and Staphylococcus aureus
(41/140 positive cultures; 29%).
Re-deriving a new diagnostic index using the combined
dataset (n ⫽ 386)
Table 2 shows the distributions of the candidate indica-
tors stratified by culture result and their univariable
odds ratios. (Supplementary Appendix Table 1. available

RESULTS
External validation attempt of the previously derived
index (n ⫽ 210)
Application of the existing diagnostic index to the newly
collected dataset 2 (external validation; n ⫽ 210) clearly
showed over-optimism of the index (data not shown).
The AUC-ROC, as the overall measure of discrimination,
fell from 0.72 to 0.58, while calibration proved particu-
For personal use only.
at http://www.informahealthcare.com/doi/abs/10.3109/
13814788.2013.842970) shows how stable indicators
were selected across 1 000 bootstrap samples at alpha
levels of variable selection of 5%, 10%, and 15.7%.
‘History of glued eyes at awakening ’ and ‘age’ were
consistently selected for inclusion. The bootstrap inclu-
sion fraction for ‘type of redness’ exceeded our 670/
1 000 threshold at alpha levels of 10% and 15.7%, but
not of 5%. Calibration was reduced by adding ‘type of
redness’ (Hosmer–Lemeshow P ⫽ 0.756 down to

larly bad with a Hosmer–Lemeshow P-value ⬍ 0.0001. P ⫽ 0.235) and we, therefore, omitted this indicator
Therefore, datasets 1 and 2 were combined to a more (Figure 1). The shrinkage factors for the two coefficients
robust dataset to re-derive a diagnostic index for bacte- of the dummies for ‘glued eyes’ and the coefficient for
rial conjunctivitis. ‘age’ were 0.814, 0.892 and 0.929, respectively.

Table 2. Index tests and their univariable odds ratios for the combined dataset (n ⫽ 386). Values are numbers
(%), unless stated otherwise.

Positive Negative
culture culture Odds ratio
140 (36) 246 (64) (95% CI)

Medical history
Mean age in years (SD) 49 (17) 41 (15) 1.03 (1.01–1.04)
Female 92 (66) 146 (60) 1.31 (0.85–2.03)
Hay fever 23 (17) 44 (18) 0.91 (0.52–1.58)
History of allergic conjunctivitis 12 (9) 19 (8) 1.11 (0.52–2.36)
History of conjunctivitis 34 (24) 62 (25) 0.94 (0.58–1.52)
Actual complaints
Itching 63 (45) 121 (49) 0.85 (0.56–1.28)
Burning sensation 85 (61) 145 (59) 1.08 (0.70–1.64)
Foreign body sensation 57 (41) 93 (38) 1.13 (0.74–1.73)
Bilateral involvement 53 (38) 46 (19) 2.62 (1.64–4.19)
Glued eyes at awakening
None 10 (7) 51 (21) Reference
One 81 (58) 159 (65) 2.83 (1.33–6.04)
Two 51 (36) 35 (14) 7.78 (3.39–17.87)
Physical examination
Redness
Peripheral only 42 (30) 100 (41) Reference
Whole conjunctiva ⫾ pericorneal 97 (70) 146 (59) 1.58 (1.02–2.46)
Secretion
None or clear 110 (79) 192 (79) Reference
Mucous or purulent 30 (21) 52 (21) 1.00 (0.61–1.67)
Periorbital oedema 37 (27) 68 (28) 0.92 (0.57–1.47)
 206 H. C. P. M. van Weert et al.

(a) 0.8 (b) 0.8

0.6 0.6
Observed (proportion)

Observed (proportion)
0.4 0.4

0.2 0.2

P = 0.756 P = 0.235
0 0
0 0.2 0.4 0.6 0.8 0 0.2 0.4 0.6 0.8
Predicted (proportion) Predicted (proportion)
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Figure 1. (Hosmer–Lemeshow) Calibration plots showing how the diagnostic probabilities of a positive bacterial culture predicted by the models
correspond with the observed probabilities in ten groups of about equal size. (a) Model including age and the number of glued eyes at
awakening derived on combined data (n ⫽ 386). (b) Model including age, the number of glued eyes at awakening and type of redness. Note
how discrepancies between predicted and observed probabilities increased, particularly in the highest four deciles, compared to the left graph.
The P-value for the fit has decreased from 0.756 to 0.235, indicating overall worse calibration.

The final model with ‘number of glued eyes at a validation cohort exist: inadequate development of the
awakening ’ and ‘age’ classified 47% (183/386) of index and major differences between the derivation and
patients at low risk (⬍ 25%) of having a positive cul- validation population.
For personal use only.

ture and 2% (7/386) at high risk (⬎ 70%). Figure 2
facilitates the clinical interpretation of the re-derived
index for bacterial conjunctivitis using ‘age’ and ‘his-
tory of glued eyes at awakening ’ as the only diagnos-
tic indicators.
DISCUSSION
Main findings
A previously derived index for bacterial conjunctivitis
proved not to validate well in an independent dataset
with a comparable patient mix as in the derivation study.
In the current study among adults with signs of acute
infectious conjunctivitis, a positive bacterial culture was
present in 36%. The number of glued eyes at awakening
and age were consistently associated with a positive cul-
ture result. Adding type of redness of the eye to this
model contributed little to the discriminative capacity,
but reduced calibration.
Strengths and limitations
Lack of external validation is probably one of the reasons
of the failure to translate research into health practice
(14,16). We started the current study with the aim of
performing an external validation study of the previously
derived and published index for bacterial conjunctivitis
(8), but performance of this index in the new (validation)
population was not satisfactory. In general, two main
reasons for worse performance of a diagnostic index in
Our previous study—in retrospect—was of limited
size, had relatively few events and the model was devel-
oped without adequate internal validation methods (8).
Our validation cohort (dataset 2), however, comprised a
similar case-mix (in an exclusion criteria), the same mea-
surements and outcome-parameters, and (partly) the
same participating GPs. Combination of both datasets,
therefore, offered the opportunity to update the existing
index in a cohort of sufficient size and with more patients
having bacterial infection. We now used the bootstrap
resampling technique as a robust method of internal
validation. We, therefore, think that our new index is
more robust than the previously published index. This
new index is simple and practicable, but doctors and
pharmacists should, as always, be aware of several limi-
tations. We excluded patients with symptoms of other
(more severe) eye diseases. In particular keratitis and
iritis might be overlooked by lay personnel; these patients
generally present with pain and photophobia. Signs and
symptoms, which are strong predictors but (very) sel-
dom occur, will not be selected in our model, as is the
case in most diagnostic models.
Comparison with existing literature
This study confirms that only about 30% of patients
with conjunctivitis seen by a GP might have a bacterial
infection. We found glued eyes (as reported by patients
and as a proxy for purulent discharge) and age as
predictors for a bacterial origin of a present infectious
conjunctivitis.
 Diagnostic index for infectious conjunctivitis 207

(a) No glued eye(s) (b) One glued eye

15 25 35 45 55 65 75 85 95 15 25 35 45 55 65 75 85 95

100 100 100 100

80 80 80 80

Probability (%)
Probability (%)

60 60 60 60

40 40 40 40

20 20 20 20

0 0 0 0
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15 25 35 45 55 65 75 85 95 15 25 35 45 55 65 75 85 95
Age (years) Age (years)

(c) Two glued eyes

15 25 35 45 55 65 75 85 95

100 100

80 80
Probability (%)

60 60
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40 40

20 20

0 0
15 25 35 45 55 65 75 85 95
Age (years)

Figure 2. Diagnostic probabilities of a positive bacterial culture as a function of age and the number of glued eyes at awakening in patients presenting
to a general practitioner with symptoms of conjunctivitis. Diagnostic probabilities (prevalence) and 95% confidence limits of a positive bacterial
culture as depending on age for patients with symptoms suggestive of acute conjunctivitis and who report to have no (a), one (b), or two (c) glued
eyes at awakening. Probabilities and their 95% confidence limits were calculated after (parameterwise) shrinkage of the regression coefficients for
age and the number of glued eyes at awakening to enhance application of the model to external populations.

In clinically diagnosed acute bacterial conjunctivitis in effect on decision making in practice. Infectious conjunc-
adults, topical antibiotics might improve the five-day tivitis, however, mostly is a self-limiting disease and in
remission rate by 31%, in comparison with placebo (18). general antibiotic treatment has only small benefits (9).
A recent meta-analysis showed that patients with mild Application of our model might serve as a starting point
severity of redness of the eye and purulent discharge for future trials, investigating the benefits of such treat-
might profit from topical antibiotics (9). Purulent discharge ment, as it will enrich the included population and thus
probably is the cause of the eyelid(s) being glued. enhance contrasts between intervention and placebo
groups.
Implications for future research
Implications for practice
This study confirms the necessity to validate diagnostic
indices in comparable, but other patients as those, in Topical antibiotics generate side effects. In the Netherlands,
whom the derivation of the index took place. an increasing in-vitro resistance (61%) against the most
Strictly speaking, this new index therefore, needs used ocular antibiotic (fusidic acid) is seen (18). Prescribing
external validation to guarantee absence of over or and delivering (unnecessary) antibiotic treatment also
under fitting and a management study to determine its generates costs. In the UK, about 4 million preparations
 208 H. C. P. M. van Weert et al.
for topical antibiotic treatment of the eye are issued annu-
ally while 74% of cases with acute infectious conjunctivitis
recover within seven days without treatment (9).
Our new index has the advantage that it may be used
by lay personnel, including pharmacists. Using this
model, it is possible to classify around 48% of patients
with signs of infectious conjunctivitis below 25% chance
of a positive culture. As antibiotic eye preparations
nowadays are available without prescription in many
European countries, our model might help doctors
and pharmacists to persuade patients to refrain from
antibiotic treatment. Patients with a conjunctivitis, but
without glued eyes are at low risk of a bacterial origin
(Figure 2, maximum risk ⬍ 40%). For those younger than
25 years, the risk is lower than 10%. By contrast, in
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patients with two glued eyes and older than 65 years of
age the risk is over 70% (Figure 2).
In conclusion, when adult patients present with
infectious conjunctivitis a simple diagnostic index might
help reduce the number of antibiotic treatments, as ben-
efits are small and half of the patients can be explained
that they have a small chance of any profit, as their com-
plaints probably will not be caused by a bacterial infec-
tion. Formally, however, a validation study still is
necessary and the impact of applying this index on health
For personal use only.
care needs to be assessed.
ACKNOWLEDGEMENTS
The authors thank the participating general practitioners
and their patients for making this study possible and
their willingness to invest their time in a study from
which they did not have any direct advantage.
FUNDING
This study was supported by a grant of ZonMW, The
Netherlands Organization for Health Research and
Development. No 42000024.
Declaration of interest: The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of the paper.
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