CLINICAL SCIENCE
Scheimpflug Corneal Densitometry Changes After
Trabeculectomy
Karin R. Pillunat, MD, Johanna Orphal, MD, Maike Haase, MD, Lutz E. Pillunat, MD, PhD, and
Robert Herber, MSc
Purpose: To study the possible changes in Scheimpflug corneal
densitometry 6 months after mitomycin C–augmented trabecu-
lectomy and to compare these measurements with healthy
controls.
Methods: Corneal densitometry was monitored with the Penta-
cam HR3 before and 6 months after first-time uncomplicated
mitomycin C–augmented trabeculectomy in 42 eyes of 42 white
patients with open-angle glaucoma and in 22 healthy age-
matched controls. Preoperative intraocular pressure (IOP), cen-
tral corneal thickness, known duration of the disease, gender, the
type and number of substances, applications and amount of benzalko-
nium chloride per day, and postoperative topical cortisone use
were tested for possible correlations in the trabeculectomy
group.
Results: There was a statistically significant reduction of mean
diurnal IOP from 19.0 6 7.7 to 11.1 6 7.7 mm Hg (P = 0.003)
and the amount of pressure-lowering substances from 3.7 6 1.0 to
0.1 6 0.5 (P , 0.001). Densitometry measurements decreased in
the entire cornea from 25.5 6 5.7 to 23.1 6 5.8 grayscale units
(P = 0.001) with emphasis in the anterior layer. They returned
close to normal 6 months after trabeculectomy and were not
statistically significantly different compared with a healthy con-
trol group (22.8 6 3.4 grayscale unit; P = 0.824). No correlations
could be found with these observations and possible causing factors
studied.
Conclusions: Corneal densitometry, an objective and sensitive
measure of corneal transparency, returned close to normal 6 months
after trabeculectomy. Although the observations cannot be associ-
ated with any causing factor in this study, the significant IOP
reduction and the nearly complete cessation of topical antiglaucom-
atous substances including benzalkonium chloride seem to be the
most plausible reasons for this finding.
Received for publication March 26, 2020; revision received May 21, 2020;
accepted May 25, 2020. Published online ahead of print July 24, 2020.
From the Department of Ophthalmology, Medical Faculty Carl Gustav Carus,
Technische Universität, Dresden, Germany.
The authors have no funding or conflicts of interest to disclose.
Clinical trial registration: NCT02959242.
Correspondence: Karin R. Pillunat, MD, Department of Ophthalmology,
Medical Faculty Carl Gustav Carus, Technische Universität, Fetscher-
strasse 74, 01307 Dresden, Germany (e-mail: karin.pillunat@
uniklinikum-dresden.de).
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Key Words: open-angle glaucoma, trabeculectomy, IOP reduction,
corneal densitometry, antiglaucomatous therapy, benzalkonium
chloride
(Cornea 2021;40:408–414)
C larity or transparency is one of the most important signs
of a healthy cornea. Usually, transparency is clinically
assessed by standard slit-lamp examination, which, however,
represents a rather subjective evaluation. Scheimpflug imaging
and analysis of the anterior segment with the Pentacam HR3 is
one of the methods to simultaneously measure the transmission
of light through the cornea and the amount of backscattered
light. This allows a more reliable, reproducible, and objective
evaluation of corneal transparency. Even clinically clear
corneas have been identified with higher levels of corneal
backscatter,1–3 which might be an indicator for subclinical
structural changes caused by pathological insults.
It is a well-accepted standard that glaucoma patients are
initially treated with topical intraocular pressure (IOP)–lowering
substances. Moreover, there is quite a huge amount of literature
confirming the benefits of IOP lowering to stop or slow down
progression of the disease.4–7 Although IOP reduction is
highest with initial filtration surgery,8 possible complications
associated with glaucoma surgery prevented the breakthrough of
this strategy.
Many patients, however, do not tolerate topical medi-
cation well and develop severe cardiopulmonary side effects9
or ocular surface disease with tear film instability, conjunc-
tival and corneal damage, and progressive ocular discom-
fort.10 Compliance issues11–13 represent another problem with
topical IOP-lowering medications. Whenever medical or laser
treatment seems unlikely to stop progression, or side effects
are severe and compliance is reduced, incisional glaucoma
surgery is recommended.
Reduction in corneal clarity is a sensitive response to
a wide range of corneal insults. Because IOP-lowering
substances and their preservatives are known to irritate the
ocular surface,10 corneal densitometry is a possibility of
assessing and monitoring the cornea’s condition and struc-
tural integrity. Successful trabeculectomy usually allows
a nearly complete reduction of IOP-lowering substances and
their preservatives.
The objective of the present study was, therefore, to
investigate changes of corneal transparency and backscat-
tered light measured with a rotating Scheimpflug imaging
system 6 months after uncomplicated trabeculectomy with
Cornea  Volume 40, Number 4, April 2021
Cornea  Volume 40, Number 4, April 2021
mitomycin C (MMC) and to compare the results with healthy
age-matched controls. Furthermore, to examine clinical and
demographic factors that might be associated with possible
changes.
MATERIALS AND METHODS
In this prospective clinical study, 42 eyes (17 right and
25 left) of 42 white patients with primary open-angle
glaucoma undergoing first time MMC-augmented trabeculec-
tomy were included for analysis as well as 22 healthy controls
matched for age and central corneal thickness (CCT) were
included. Inclusion criteria in the glaucoma group were
patients older than 18 years with clinically normal corneas
showing glaucoma progression after maximal effective med-
ical treatment had failed to control IOP. Exclusion criteria
were patients using contact lenses, suffering from diabetes
mellitus, being treated with corticosteroids, and intraocular
laser therapy or ocular surgery within 6 months before
trabeculectomy. The necessity of more than 1 bleb needling,
more than 1 injection of viscoelastic (Healon GV, AMO
Germany GmbH) to stabilize the anterior chamber in the early
postoperative period, phacoemulsification during the 6-month
follow-up, or insufficient quality of densitometry measure-
ments also led to exclusion.
Healthy controls were recruited from patients scheduled
for phacoemulsification or retinal surgery because of a mac-
ular hole or macular pucker.
All trabeculectomies were performed by either of 2
surgeons (K.R.P. and L.E.P.) using the same standardized
technique, which has been described previously.14,15 After the
preparation of a fornix-based conjunctival flap, two 9 · 4 mm
Merocel sponges soaked with 0.2 mg/mL of MMC 0.02%
were applied below the conjunctiva for 3 minutes. The area
exposed to MMC was irrigated with 10 mL of balanced
salt solution.
Postoperative treatment was also standardized. Patients
received preservative-free topical steroids (dexamethasone;
Dexa EDO; Dr. Mann Pharma GmbH, Germany) 5 times
a day for 4 weeks, with gradual tapering thereafter. Further-
more, preservative-free topical antibiotics (ofloxacin; Floxal
EDO, Dr. Mann Pharma GmbH) were given 3 times a day for
a week and a preservative-free mydriatic (cyclopentolat;
Zyklolat EDO, Dr. Mann Pharma GmbH) twice a day for
a week.
Baseline recordings included age, sex, known duration
of the disease, number of IOP-lowering substances, appli-
cations and the amount of benzalkonium chloride (BAC) per
day, and previous surgeries. A comprehensive ophthalmic
examination included refraction, best spectacle corrected
visual acuity (VA) with Snellen high-contrast VA, slit-lamp
biomicroscopy of the anterior segment, Goldmann applana-
tion tonometry (average of 6 measurements at 1 ,4 , 7 ,10 PM,
at midnight in a supine position, and at 7 AM; Haag-Streit,
Koeniz, Switzerland), gonioscopy, and fundus examination
with a 90-diopter lens. A complete glaucoma workup
included automated perimetry (Swedish interactive thresh-
old algorithm standard 30-2 program; Carl Zeiss Meditec,
Dublin, CA), confocal scanning laser ophthalmoscopy (HRT
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Densitometry Changes After Trabeculectomy
II, Heidelberg Engineering Inc, Heidelberg, Germany), and
scanning laser polarimetry (Nerve Fibre Analyzer GDxPRO,
Carl Zeiss Meditec). Lens thickness (Echograph B-scan-
Cinescan S; Quantel Medical, Clermont-Ferraud, France), if
applicable, was measured with ultrasound and axial length
with optical biometry (IOL-Master; Carl Zeiss Meditec AG,
Jena, Germany). The Pentacam HR 3 (Oculus, Wetzlar,
Germany), a noncontact 3D Scheimpflug imaging system,
was used for objective analysis of the anterior segment and
to evaluate corneal densitometry with the densitometry
analysis software (version 1.21r25) before and 6 months
after uncomplicated trabeculectomy. This software creates
a map of the amount of backscattered light in different
regions and depths of the cornea and allows a full-thickness
evaluation of corneal clarity without any extent of the
duration of the anterior segment examination of 2 seconds.
Four annular zones are thereby analyzed. The central
annular zone reaches from 0 to 2 mm, followed by
concentric zones from 2 to 6 mm, 6 to 10 mm, and 10 to
12 mm from the apex to the periphery of the cornea. Four
corneal layers are analyzed as well, including an anterior
layer (AL; anterior 120 mm), a posterior layer (PL; posterior
60 mm), a central layer (CL; between AL and PL; 120 mm
posterior of the epithelium and 60 mm anterior of the
endothelium), and the total layer (TL; between epithelium
and endothelium). Entire cornea represents all annular zones
and layers. The most peripheral annular zone (10–12 mm)
was not included in the analysis because its reproducibility
has been shown to be weak.16 Moreover, benign corneal
limbal degenerations, which might alter corneal trans-
parency, are quite common in the age group of the study
cohort. Pentacam grayscale units (GSUs) range from 0,
representing maximum corneal transparency, to 100, repre-
senting complete opacity. The built-in Pentacam Nucleus
Staging (PNS) software was used as an objective measure of
nuclear cataracts. The PNS cataract grading score ranges
from 0 to 5, with 5 indicating most advanced nuclear
cataract. An experienced operator performed Pentacam
measurements with uniform dark ambient light conditions at
the same time of day between 9 AM and 12 PM with patients and
controls in a nonmydriatic state.17
Postoperative examinations at the 6-month follow-up
included refraction, best spectacle corrected VA with Snellen
high-contrast VA, slit-lamp examination of the anterior and
posterior segment, Goldmann applanation tonometry (average
of 6 measurements at 1, 4, 7, 10 PM, at midnight in a supine
position, and at 7 AM), and a full glaucoma workup. Any
substances necessary at 6 months postoperatively, as well as
any interventions necessary to keep the filtering bleb function-
ing, were recorded.
The study was approved by the ethics committee of the
Medical Faculty Carl Gustav Carus of the Technische
Universität Dresden, Germany, and followed the tenets of
the Declaration of Helsinki. All participants signed a written
informed consent form.
Based on means and SD of the total layer in a pre-
liminary investigation, a sample size of at least 38 patients
(alpha = 0.05; power = 0.80) was required (G Power 3.1.9.2.
sample size software; University of Duesseldorf, Germany).
www.corneajrnl.com | 409
Pillunat et al
TABLE 1. Demographics of Patients
Age (yr)
Gender male/female (%)
BCVA (LogMar)
Axial length (mm)
Anterior chamber depth (mm)
Anterior chamber volume (mm³)
Anterior chamber angle (°)
Central corneal thickness (mm)
30–2 MD (dB)
30–2 PSD (dB)
Preoperative IOP (mm Hg)
Known duration of glaucoma diseases (yr)
No. of medications/d
Applications/d
BAC %/d
BAC mg/mL/d
BCVA, best corrected visual acuity; MD, mean deviation; PSD, pattern SD.
For data analysis, the SPSS software (version 25; IBM
Statistics, New York, NY) was used. Normal distribution was
tested with the Shapiro–Wilk test and Q-Q plots. Normally
distributed data were expressed as means 6 SD. Linear mixed
models were applied to compare preoperative and post-
operative differences of IOP, number of medications, VA,
and densitometry. Comparison of preoperative and post-
operative densitometry values with healthy controls were
analyzed using the independent t test. The Pearson’s corre-
lation coefficient was used to identify clinical and demo-
graphic factors associated with possible changes in corneal
backscatter. Because of multiple testings, the P value was
adjusted by Bonferroni correction. Therefore, the level of
significance was set to P , 0.004.
FIGURE 1. Box plot of mean diurnal
IOP, mean (X) 6 SD, and median
(quartile 25%, quartile 75%) before
and 6 months after trabeculectomy.
*Marks significance with P , 0.004.
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Cornea  Volume 40, Number 4, April 2021
RESULTS
Demographics of patients are shown in Table 1. Mean
Mean 6 SD
age of the controls was 66 6 8 years (P = 0.384), and mean
68 6 9 CCT was 531.2 6 13.1 mm (P = 0.36).
22 (52)/20 (48) Thirty-three patients (78.6%) had a diagnosis of high
0.21 6 0.37 pressure and 9 (21.4%) of normal pressure open-angle
24.1 6 1.4 glaucoma and had been treated for the disease with topical
3.1 6 0.8 IOP-lowering medications for a mean of 14.3 6 10 years
158.8 6 32.1 before surgery. They used a mean of 3.7 6 1 substances in
34.7 6 6.6 different combinations and application frequencies. Prosta-
525.1 6 29.4 glandins were used in 41 (98%), ß-blockers in 33 (79%),
212.6 6 7 a-agonists in 37 (88%), carboanhydrase inhibitors in 38
8.3 6 4.8 (90%), and pilocarpine in 6 (14%) of the cases. Thirty-six
19.0 6 7.7 patients (85.7%) received IOP-lowering medications pre-
14.3 6 10 served with BAC, and only 6 (14.3%) were treated completely
3.7 6 1 preservative free. IOP was statistically significantly reduced
4.9 6 2 from 19.0 6 7.7 to 11.1 6 7.7 mm Hg (P = 0.003)
0.03 6 0.02 postoperatively (Fig. 1), as well as the need for IOP-lowering
0.3 6 0.2 substances from 3.7 6 1.0 to 0.1 6 0.5 (Fig. 2, P , 0.001).
Corneal densitometry measurements before and after
trabeculectomy and in age-matched healthy controls are
shown in Table 2. Corneal backscatter was reduced in the
entire cornea from 25.5 6 5.7 to 23.1 6 5.8 GSUs (P =
0.001) 6 months after trabeculectomy with emphasis in the
AL (Fig. 3 and Table 2). Densitometry values of the AL and
the entire cornea returned close to normal 6 months
postoperatively and were not statistically significantly
different compared with an age-matched healthy control
group (23.1 6 5.8 vs. 22.8 6 3.4 GSU; P = 0.824) (Fig. 4).
Furthermore, patients with glaucoma showed preoperatively
significantly higher corneal backscatter in the optically
significant 0 to 2 and 2 to 6 mm annular zone of the AL
compared with healthy controls (P = 0.003, Table 2). This
difference was not statistically significant after trabeculec-
tomy anymore (P . 0.004, Table 2). In the entire cornea,
which means all layers and annular zones, preoperative
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Cornea  Volume 40, Number 4, April 2021 Densitometry Changes After Trabeculectomy

FIGURE 2. Bar graph of mean

number of IOP-lowering substances
before and 6 months after trabe-
culectomy. Significance with P ,
0.004.

densitometry was higher compared with the healthy control
group (P = 0.046), which was not statistically significant
after Bonferroni correction anymore.
To find possible correlations, preoperative IOP, CCT,
known duration of the disease, sex, the number of substances,
applications and amount of BAC per day, and postoperative
topical steroid use were tested in the 3 radial zones of the AL
because the greatest differences were seen in the AL (Table 2
and Fig. 3). No significant associations were found for the
parameters investigated (Table 3).
Best spectacle corrected VA with Snellen high-contrast
VA remained stable. It changed insignificantly from 0.21 6
0.37 to 0.23 6 0.33 LogMAR 6 months after trabeculectomy
(P = 0.474).
Thirty-one (74%) patients were phakic and 11
(26%) pseudophakic. Lens status did not change during
follow-up. PNS remained stable in 27 patients (88%). PNS
increased by 2 units in one patient and by one unit in 3
patients. Mean change of PNS was 0.9 6 0.7 to 0.9 6 0.7
(P = 0.818).

TABLE 2. Scheimpflug Densitometry Measuring Corneal Backscatter Before and After Trabeculectomy and in Healthy Age-
Matched Controls
Preoperative Postoperative Healthy controls
P† to Preoperative P‡ to Postoperative
Layer Annulus (mm) GSU Mean 6 SD GSU Mean 6 SD P* GSU Mean 6 SD Glaucoma Glaucoma
AL; 0–120 mm 0–2 30.5 6 8.2 26.7 6 7.4 , 0.001 25.0 6 2.3 0.003 0.299
2–6 28.8 6 7.9 24.9 6 6.8 , 0.001 23.4 6 2.1 0.003 0.318
6–10 37.5 6 10.2 33.9 6 9.9 , 0.001 33.4 6 9.1 0.119 0.844
CL 0–2 18.6 6 4.4 18.2 6 5.4 0.523 15.8 6 1.2 0,005 0.045
2–6 17.8 6 3.8 17.2 6 4.2 0.279 15.2 6 1.2 0.003 0.033
6–10 26.3 6 6.8 24.9 6 7.0 0.080 24.5 6 6.3 0.307 0.823
PL; posterior 60 mm 0–2 13.8 6 3.9 13.3 6 4.6 0.289 12.6 6 1.8 0.177 0.496
2–6 13.8 6 3.6 13.1 6 3.9 0.075 12.8 6 1.6 0.221 0.731
6–10 21.6 6 6.7 20.2 6 6.9 0.020 21.8 6 4.1 0.899 0.323
TL 0–2 21.0 6 5.0 19.4 6 5.5 0.010 17.8 6 1.2 0.005 0.184
2–6 20.1 6 4.7 18.4 6 4.8 0.004 17.1 6 1.1 0.005 0.216
6–10 28.5 6 7.6 26.4 6 7.7 0.011 26.6 6 6.2 0.317 0.917
Entire cornea 25.5 6 5.7 23.1 6 5.8 0.001 22.8 6 3.4 0.046 0.824
Bold type signifies P , 0.004.
*P value: comparison between densitometry pre- and postoperative tested by linear mixed models.
†P value: comparison between healthy controls and preoperative glaucoma patients, tested by independent t test.
‡P value: comparison between healthy controls and postoperative glaucoma patients, tested by independent t test. Due to multiple testing, the P-value was adjusted by Bonferroni
correction.

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Pillunat et al
FIGURE 3. Areas of the densitometry map (gray color), where GSU (grayscale units) changed significantly.
DISCUSSION
In this study, Scheimpflug corneal densitometry mon-
itored with the Pentacam HR3 densitometry module was
used to examine the amount of corneal backscattered light,
before and 6 months after uncomplicated MMC-augmented
trabeculectomy and compared with an age-matched healthy
control group. A statistically significant reduction of densitom-
etry measurements in the entire cornea with emphasis in the
AL, which turned close to normal after surgery, was seen.
The normal cornea scatters light mainly in the AL (air/
tear film/cornea interface), followed by the CL and PL.16,18 An
explanation for this finding might be that deeper layers of
corneal lamellae are more strictly organized than more
superficial layers.19 Light scattering increases if the space
between collagen fibrils becomes less regular. Furthermore,
keratocytes, which have the highest density in the anterior
FIGURE 4. Densitometry (GSU; grayscale units) in the entire
cornea before and after trabeculectomy and in healthy con-
trols. *Marks significance with P , 0.004.
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Cornea  Volume 40, Number 4, April 2021
stroma,20 are an important source of light scatter.21 Disruption
of the uniform spacing between collagen lamellae or a change
of keratocyte shape under stress induce an increase in corneal
backscatter. Keratocytes in a wounded area for example, as
well as increased space between the collagen lamellae in
corneal edema, increase backscatter and corneal opacification
because of changes in the refractive index.22 Pentacam
densitometry has been used to objectively monitor the progress
or response to therapy of corneal infections.23 Furthermore,
Koc et al2 presented evidence that increasing corneal back-
scatter may be a sensitive method to identify subclinical
keratoconus, even earlier than topographic, topometric, and
tomographic analyses. This might allow the hypothesis that
corneal densitometry is a very sensitive indicator of corneal
structural integrity, of corneal health or disease.3,24 One
explanation of the current findings might be a better endothelial
cell and metabolic pump function at lower IOP levels, thereby
normalizing corneal hydration, keratocyte activity, and corneal
transparency. A study investigating the effect of topical
prostaglandins on corneal clarity found statistically signifi-
cantly reduced corneal densitometry measurements starting at 3
months after initiating IOP-lowering treatment.25 Another
possibility might be that chronic and long-term topical IOP-
lowering medication stimulates keratocyte proliferation and
activity, which leads to a decreased cellular transparency21 and
an increased stromal reflectivity especially in the anterior
stromal layer, which was shown by in vivo confocal mico-
scopy.26 Keratocytes are the major cell type of the stroma and
responsible for providing the extracellular matrix and main-
taining stromal homeostasis. Most of these corneal keratocytes
are located in the anterior stroma.20 Under normal conditions,
keratocytes are transparent except for the nuclei,21 when
studied with in vivo confocal microscopy.27 Although we did
not find any correlations with possible causing factors, it seems
plausible that after nearly complete cessation of chronic topical
therapy with IOP-lowering substances and the complete cessa-
tion of exposure to preservatives, the cornea recovers.
The reduction of backscatter of light and improvement of
transparency mainly in the anterior section of the cornea might
be an indirect proof for a “healthier” cornea after IOP-lowering
surgery. At lower IOP levels, the pump function of the corneal
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Cornea  Volume 40, Number 4, April 2021 Densitometry Changes After Trabeculectomy

TABLE 3. Correlation Between Preoperative and Postoperative Changes of Corneal Densitometry Values and Different Baseline
Factors in the Anterior Layer and the Entire Cornea
Preoperative
Preoperative No. of Preoperative Preoperative Preoperative Known Duration Postoperative
IOP Substances Applications Per Day BAC Per Day CCT of Disease Topical Steroids
AL: 0–2 mm annulus
r 20.181 0.121 0.145 0.205 20.130 20.098 20.175
P 0.271 0.445 0.367 0.193 0.411 0.537 0.268
AL: 2–6 mm annulus
r 20.233 0.088 0.100 0.200 20.191 20.178 20.144
P 0.153 0.581 0.533 0.204 0.224 0.260 0.364
AL: 6–10 mm annulus
r 20.145 0.044 0.107 0.163 20.112 20.086 20.198
P 0.377 0.783 0.506 0.303 0.479 0.589 0.209
Entire cornea
r 20.112 0.078 20.142 0.196 20.036 0.044 20.240
P 0.497 0.623 0.384 0.214 0.823 0.782 0.125
r, Pearson's correlation coefficient; significance P , 0.004.

endothelium improves. Moreover, topical IOP lowering is
rendered unnecessary and eliminates the cumulative toxic
effect of the active compounds and BAC.28 It is likely that
the refractive index changes in a “healing” cornea.
VA remained stable 6 months after uncomplicated
trabeculectomy. However, routine VA examinations with
Snellen high-contrast VA may not reveal a better visual
quality caused by decreased light backscattering. Although
high-contrast VA remained stable, low-contrast VA might
have shown a positive impact on VA.29 There is significant
literature on VA loss after trabeculectomy, often implicating
cataract formation,30,31 which was not seen in the current
study. One reason might be that cataracts were mild before
surgery and another that the follow-up of 6 months might be
too short for cataracts to progress.
It is one of the limitations of the study that low-contrast
VA testing, which might have picked up small changes in
VA, was not performed. Furthermore, we did not ask for or
assess the quality of vision such as blurring, contrast
sensitivity, or glare. Another limitation is that endothelial
cell counts were not assessed in all patients. In the 11 cases
with preoperative and postoperative endothelial cell counts
(CEM-530 Specular Microscope; Nidek, Japan), they
changed insignificantly from 2091 6 344 to 2056 6 340
cells/mm2 (P = 0.64). In addition, the time course of change
in Pentacam corneal densitometry cannot be addressed
because we only examined corneal densitometry before and
6 months after trabeculectomy. In vivo confocal microscopy
would be a good method to detect changes in number of
keratocytes located in the anterior stroma. This should be
addressed in a future study. Finally, the cohort might have not
been large enough to find correlations with possible causing
factors.
Assessing Scheimpflug corneal densitometry or trans-
parency and its changes might be a sensitive and objective
method to evaluate the overall “health” or structural integrity
of the cornea. Corneal densitometry in the AL returned close
to normal 6 months after trabeculectomy. Although the
observations could not be associated with any causing factor
in this study, the significant drop in IOP and the complete
cessation of topical antiglaucomatous medications including
BAC seem to be the most plausible reasons for this finding.
This indicates, on one hand, that corneal changes caused by
higher IOP, and glaucoma medication and its preservatives
are probably reversible. On the other hand, the results give
evidence of the benefit of earlier glaucoma surgery in the
course of the disease.
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