INT J TUBERC LUNG DIS 20(5):685–688
Q 2016 The Union
http://dx.doi.org/10.5588/ijtld.15.0653
Efficacy of zinc sulphate on in-hospital outcome of community-
acquired pneumonia in people aged 50 years and over
S. Sharafi,* A. Allami†
*Qazvin University of Medical Sciences, †Department of Infectious Diseases, Faculty of Medicine, Boalisina
Hospital, Qazvin, Iran
S E T T I N G : Some studies have reported a beneficial effect
of zinc sulphate in children with community-acquired
pneumonia (CAP).
O B J E C T I V E : To evaluate the effect of adjuvant zinc
therapy in adult hospitalised CAP patients aged 750
years on standard antibiotic treatment.
M E T H O D S : In a randomised double-blind placebo-
controlled clinical trial, 91 hospitalised patients diag-
nosed with CAP using standard clinical and radiological
criteria were randomised to receive 220 mg (110 mg
twice daily) zinc sulphate for 4 days or placebo, in
addition to antibiotics. The primary endpoint was length
of hospital stay, and secondary endpoints were time to
normalisation of oxygen saturation, respiratory rate and
COMMUNITY-ACQUIRED PNEUMONIA (CAP)
is a leading cause of morbidity and mortality
worldwide, particularly among the elderly.1 Despite
improvements in antibiotic treatment, no significant
progress has been made.2 Convalescence from pneu-
monia among the elderly takes longer, and complica-
tions and death are also more frequent, than in
younger adults.3,4 Additional therapeutic interven-
tions in addition to antibiotics may help improve
outcomes in patients with CAP.
Zinc is an essential micronutrient that is critical for
normal immune functions. All types of immune cells
show decreased function after zinc depletion.5
Particularly in the elderly, zinc deficiency has been
indicated as a risk factor for immune deficiency and
susceptibility to infection.6,7
Most studies in adults have assessed the relation-
ship between zinc deficiency and the risk of
pneumonia and the preventive effects of zinc
supplementation.8 In several other studies, the
effects of zinc supplementation in critically ill
patients in the intensive care unit (ICU) have been
discussed;9 however, no article on the effect of zinc
supplementation on the treatment of pneumonia in
adults was found in our literature review. Earlier
Correspondence to: A Allami, Department of Infectious Diseases, Faculty of Medicine, Qazvin University of Medical
Sciences, Boalisina Hospital, Qazvin, Iran. e-mail: allami9@yahoo.com
Article submitted 1 August 2015. Final version accepted 9 November 2015.
SUMMARY
temperature. Disease severity was scored using CURB-
65 (mental Confusion, Urea .20 mg/dl, Respiratory
rate 730/min, low Blood pressure and age 765 years)
R E S U LT S : The results did not show significant differ-
ences in length of hospital stay, time to normalisation of
respiratory rate and oxygen saturation between patients
in the zinc sulphate and placebo groups (P ¼ 0.18, 0.65
and 0.26, respectively).
C O N C L U S I O N : A short course of zinc supplementation
does not improve outcome in hospitalised patients aged
750 years with CAP. In this setting, it should not be
recommended as routine adjunctive treatment.
K E Y W O R D S : pneumonia; zinc; adult; therapy; com-
munity-acquired infections
studies have reported a beneficial effect of zinc
sulphate on clinical outcomes in children with
pneumonia.7,10
Our hypothesis was that adjunctive treatment
with zinc sulphate in addition to antibiotic treatment
may improve outcomes in adult patients with CAP.
We conducted a clinical randomised placebo-con-
trolled trial in hospitalised patients with CAP. The
primary endpoint was length of hospital stay (LOS).
Secondary end points were defervescence, time to
normalisation of respiratory rate and duration of
hypoxaemia.
METHODS
Patients
Patients were prospectively enrolled between Sep-
tember 2013 and October 2014 at the two university
medical centres (teaching hospitals) of Boalisina and
Velayat, Iran. Patients were considered eligible if they
met the following criteria: 1) provided written
informed consent; 2) clinical symptoms suggestive
of CAP: cough (with or without sputum), fever
(.38.58C), pleuritic chest pain or dyspnoea; 3) new
consolidations on chest radiograph; and 4) age 750
686 The International Journal of Tuberculosis and Lung Disease
years. Patients were excluded from the study if one of
the following criteria applied: presence of severe
immunosuppression (e.g., use of immunosuppres-
sants), malignancy, LOS .25 days, any likely
infection other than CAP, pneumonia that developed
within 8 days of hospital discharge and indications
that the patients was unable and/or unlikely to
comprehend and/or follow the protocol. Subgroup
analysis of patients with severe CAP (CURB-65
[mental Confusion, Urea .20 mg/dl, Respiratory
rate 730/min low Blood pressure [diastolic blood
pressure 660 mm Hg or systolic blood pressure ,90
mm Hg] and age 765 years] score 72) was
planned.11,12
Study design
Patients were double-blinded and randomised to
receive 110 mg of zinc sulphate (25 mg of zinc) twice
daily or matching placebo for a total of 4 days,
administered in the same way as the antibiotics
(intravenous or oral). This usually comprised a b-
lactamase stable b-lactam in combination with a
macrolide. The zinc sulphate was formulated and
manufactured as capsules by Alhavi Pharmaceutical
Company, Tehran, Iran, and packaged in a strip of 10
capsules. The back of the strip was labelled with an
identification number.
Randomisation was conducted by drawing pieces
of paper from an opaque bag. The allocation
sequence was kept in a safe place throughout the
course of the study. Researchers, patients and other
health care workers were blinded to the group to
which the subject was assigned (no a priori knowl-
edge of group assignment, i.e., allocation conceal-
ment). All patients were treated with empirical
antimicrobial agents according to national guide-
lines.13 The duration of antibiotic treatment was left
entirely to the discretion of the medical team in
charge, as was the decision whether or not to switch
from intravenous to oral treatment. To avoid
exaggerated estimates of treatment effect, baseline
and follow-up clinical and paraclinical data measure-
ment and recording were performed by nurses with
adequate experience. No criteria were imposed for
hospital discharge, and the investigators did not
influence decisions concerning discharge.
The modified British Thoracic Society assessment
tool was used for severity assessment;11 the assess-
ment tool relies on four easily measurable clinical
features, and was developed mainly as a means of
identifying patients with severe CAP at high risk of
mortality. A CURB-65 severity score was calculated,
and one point given for each feature present (range 0–
4 points).14 The presence of two or more of the
features mentioned predicted mortality if the overall
sensitivity and specificity was around 80%.15 The
CURB-65 score was categorised as ,2 or 72, a score
of 72 being taken to identify patients with severe
CAP. Defervescence was defined as temperature
,37.58C.12 All patients were observed and subse-
quently asked about adverse events, such as vomiting,
after zinc or placebo administration. Renal function
assessment was performed on presentation. Oxygen
saturation .92% was considered normal (breathing
room air).
Statistical analysis
A sample size was calculated based on published data
of an earlier trial,16 in which 64 of a total of 122
patients with CAP received a zinc supplement along
with antibiotic treatment. We calculated that 45
patients were needed in both arms to detect a mean
difference of 2 days LOS between zinc sulphate and
placebo treatment, with a power of 80% and an alpha
level of 0.05. The data were summarised as frequencies
or percentages for categorical variables, and as means
and standard deviations or medians and interquartile
ranges if distribution was skewed. We compared
continuous variables (age, LOS, defervescence, time
to normalisation of respiratory rate and hypoxaemia)
using the Mann-Whitney test and proportions (CURB-
65 and sex) using the v2 test or Fisher’s exact test. P ,
0.05 was considered statistically significant. The
Statistical Package for Social Sciences software,
version 19.0 (SPSSw, Armonk, NY, USA) was used
for data management and statistical analysis.
Ethics
This trial was registered with the Iranian Registry
of Clinical Trials website (registration ID
IRCT2015013120882N1). The study protocol
was approved by the medical ethics committee of
Qazvih University of Medical Sciences.
RESULTS
In this study, of 120 hospitalised patients diagnosed
with CAP who met the inclusion criteria, 29 were
unwilling to continue the study. The remaining 91
patients were randomised, and two patients, one in
each group, were excluded due to LOS .25 days. Data
from a final 89 randomised patients were analysed. The
mean age was 73.8 6 12.2 years; 51 (57.3%) patients
were male (Table 1). Patients with severe CAP were
evenly distributed among the two groups (CURB-65
score 72; 23 [51.1%] vs. 20 [45.4%] patients, P ¼
0.593). Other clinical and paraclinical features (Glas-
gow coma scale, oxygen saturation, white blood count,
erythrocyte sedimentation rate, platelet count and
sodium) were not significantly different between the
two groups. The results of the Mann-Whitney U-test
did not show significant differences in LOS, time to
normalisation of hypoxaemia and tachypnoea between
patients in the zinc sulphate and the placebo groups
(Table 2). We found a significant difference in time to
defervescence among the two study groups, although
 Zinc and in-hospital outcome of CAP 687

Table 1 Baseline characteristics and CURB-65 severity score in the zinc and placebo groups
Zinc group Placebo group
(n ¼ 45) (n ¼ 44) Total
Characteristics n (%) n (%) n (%) P value
Male sex 28 (63.6) 23 (51.1) 51 (57.3) 0.343*
Age, years, mean 6 SD 72.9 6 13.0 74.8 6 11.3 73.8 6 12.2 0.579†
Age 50–64 years 12 (26.7) 9 (20.5) 21 (23.6) 0.490*
Age 765 years 33 (73.3) 35 (79.5) 68 (76.4)
Comorbid illnesses
Hypertension 15 (33.3) 17 (38.6) 32 (36.0) 0.602*
Hyperlipidaemia 8 (17.8) 6 (13.6) 14 (15.7) 0.592*
Diabetes mellitus 9 (20.0) 6 (13.6) 15 (16.9) 0.423*
Ischaemic heart disease or
congestive heart failure 10 (22.2) 12 (27.3) 22 (24.7) 0.581*
Neurological dysfunction 7 (15.6) 16 (36.4) 23 (25.8) 0.025*‡
Pulmonary 7 (15.6) 5 (11.4) 12 (13.5) 0.563*
Other 8 (17.8) 6 (13.6) 14 (15.7) 0.592*
Risk class (CURB-65)
0 4 (8.9) 3 (6.8) 7 (7.9) 0.912*
1 18 (40.0) 21 (47.7) 39 (43.8)
2 17 (37.8) 13 (29.5) 30 (33.7)
3 5 (11.1) 6 (13.6) 11 (12.4)
4 1 (2.2) 1 (2.3) 2 (2.2)
Severe CAP 23 (51.1) 20 (45.4) 43 (48.3) 0.593*
Temperature on admission,
8C, mean 6 SD 38.3 6 0.9 37.8 6 0.9 38.0 6 0.9 0.013‡
* v2 test.
†
Mann-Whitney U-test.
‡
Significant.
CURB-65 ¼ mental Confusion, Urea .20 mg/dl, Respiratory rate 730/min, low Blood pressure (diastolic blood pressure
660 mm Hg or systolic blood pressure ,90 mm Hg), age 765 years; CAP ¼ community-acquired pneumonia.

there was an imbalance between the two groups with Reduction in LOS is an important goal in the
respect to mean rate of fever on admission (P ¼ 0.018). treatment of patients with CAP. Zinc supplementa-
Two patients developed hospital-acquired pneu- tion did not lead to shorter LOS in our study. A
monia, and were treated in the ICU (one patient in similar negative result was found in young children
each group). Other patients in the zinc sulphate group hospitalised for pneumonia in a developing country.17
and in the placebo group did not have any treatment- Zinc deficiency appears to be widespread in
related adverse events. developing countries,18 and zinc supplementation
might therefore be effective for the prevention of
upper respiratory infection and diarrhoea, and as
DISCUSSION adjunct treatment for diarrhoea in malnourished
children.7,10 Several clinical trials conducted in devel-
This was a randomised double-blinded placebo
oping countries, especially in the past decades, have
controlled trial of the use of zinc sulphate in
suggested that preventive zinc supplementation reduc-
hospitalised adult patients with CAP for adjuvant es mortality and morbidity among children due to
therapy. Although a trend towards improved clinical pneumonia19,20 and, if given with empiric antimicro-
outcomes was observed in the zinc group, these bial treatment, it can significantly reduce the time to
differences were not statistically significant at day 5. normalisation of respiratory rate, hypoxia and LOS in
young children with pneumonia;3 however, the most
Table 2 Length of hospital stay and time to normalisation of recent trials have shown that zinc may not favourably
parameters of disease severity among adults with community- influence clinical outcomes in children hospitalised for
acquired pneumonia
pneumonia.16,21–23 A systematic review of current
Zinc group Placebo group randomised trials in critical care showed that evidence
Outcomes median [IQR] median [IQR] P value*
for recommending the routine use of high-dose zinc
Length of hospital stay 6 [5–10] 8 [6–11] 0.176 was inadequate.24 Another study showed that serum
Time to normalisation
of respiratory rate 1 [0–1] 1 [0–2] 0.256
zinc levels on the initiation of ventilation had no
Time to normalisation predictive value for 30-day mortality, ventilatory
of fever 6 [0–36] 6 [0–15] 0.043† support time or ICU LOS.9 Although inadequate
Time to normalisation
of hypoxaemia 0 [0–1] 0 [0–1] 0.647 stores of zinc might be a risk factor for pneumonia in
the elderly,25 zinc administration as an adjunctive to
* Mann-Whitney U-test.
†
Significant.
antibiotics does not seem to improve outcomes of
IQR ¼ interquartile range. pneumonia in adults. Improved nutrition in developing
688 The International Journal of Tuberculosis and Lung Disease
countries may reduce the prevalence of zinc deficiency.
Further research in representative settings is required
to help clarify conflicting results.
In line with our study findings, a recent study found
no evidence of increased risk for nosocomial infec-
tions in patients treated with zinc sulphate. Zinc
supplementation may even be associated with a
reduction in nosocomial pneumonia in patients.26
Adverse events related to treatment with zinc
sulphate in our study were low and did not differ
from placebo. Adverse effects such as decrease in
immunity and high-density lipoprotein cholesterol
levels, anaemia, copper deficiency and possible
genitourinary complications were reported with
long-term and high-dose zinc consumption; however,
at recommended dosages, zinc is well-tolerated.10
Some limitations may apply to our study. A
potential limitation of the present study was that
the prevalence of zinc deficiency in our study
population was not directly assessed. We used zinc
sulphate in a twice-daily dosage, which may not be
sufficient for establishing effective serum levels over a
24 h period; this limits the comparison with studies
using zinc sulphate thrice daily.
In conclusion, zinc sulphate at 110 mg twice daily for
4 days did not improve clinical outcomes in hospital-
ised patients with CAP aged 750 years. Because of a
lack of significant clinical benefit, zinc sulphate should
not be recommended as routine adjunct treatment in
CAP, and further research in representative settings is
required to help clarify the role of zinc in the treatment
of severe pneumonia in adults.
Acknowledgements
The study was sponsored by a grant by Qazvin University of
Medical Sciences, Qazvin. The authors would like to thank the
medical and nursing staff at the Boalisina and Velayat Medical
Centres who participated in the study.
Conflicts of interest: none declared.
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C A D R E : Certaines études ont mis en évidence un effet
bénéfique du sulfate de zinc chez les enfants atteints de
pneumonie communautaire (CAP).
O B J E C T I F : Evaluer l’effet d’un traitement adjuvant par
zinc chez des patients adultes de 750 ans, hospitalisés
avec une CAP et recevant un traitement antibiotique
standard.
M É T H O D E S : Essai clinique randomis é en double
aveugle contre placebo. Quatre-vingt onze patients
hospitalisés avec un diagnostic de CAP selon des
critères cliniques et radiologiques standard ont été
randomisés pour recevoir 220 mg (110 mg deux fois
par jour) de sulfate de zinc pendant 4 jours ou un
placebo, en plus des antibiotiques. Le paramètre
principal a été la durée de séjour à l’hôpital et les
paramètres secondaires ont été le délai de normalisation
M A R C O D E R E F E R E N C I A: Algunos estudios han
indicado un efecto favorable del sulfato de zinc en el
tratamiento de los niños con diagnóstico de neumonı́a de
origen extrahospitalario (CAP).
O B J E T I V O S: Evaluar el efecto del tratamiento
complementario con sulfato de zinc en pacientes
adultos, a partir de los 50 años, hospitalizados por
CAP, que estaban recibiendo un tratamiento antibiótico
corriente.
M É T O D O S: Fue este un estudio clı́nico controlado con
placebo, aleatorizado y con diseño de doble anonimato.
Noventa y un pacientes hospitalizados con diagnóstico
de CAP, según los criterios clı́nicos y radiográficos
corrientes, se dividieron de manera aleatoria en dos
grupos para recibir 220 mg de sulfato de zinc (110 mg
dos veces al dı́a) o placebo durante 4 dı́as, al mismo
tiempo que los antibióticos. El principal criterio de
valoración fue la duración de la hospitalización y los
criterios secundarios fueron la normalización de la
Zinc and in-hospital outcome of CAP i
RESUME
de la saturation en oxygène, de la fréquence respiratoire
et de la température. La gravité de la maladie a été
estimée selon l’échelle CURB-65 (Confusion, Urée .7
mmol/l, débit Respiratoire 730/min, tension artérielle
Basse and âge 765 ans).
R É S U LT A T S : Les résultats n’ont pas mis en évidence de
différence significative en termes de séjour hospitalier, de
délai de normalisation de la fréquence respiratoire et de
la saturation en oxygène entre les patients sous sulfate de
zinc et le groupe placebo (P ¼ 0,18, 0,65 et 0,26
respectivement).
C O N C L U S I O N : Une supplémentation brève en zinc
n’améliore pas l’ état des patients de 750 ans,
hospitalisés pour CAP et dans ce contexte il ne devrait
pas être recommandé comme traitement adjuvant de
routine.
RESUMEN
saturación de oxı́geno, la frecuencia respiratoria y la
temperatura. Se calificó la gravedad de la enfermedad
mediante la escala CURB-65 (Confusión, Úrea .7
mmol/l, frecuencia Respiratoria 730/min, tensión
arterial Baja y edad 765 años).
R E S U LT A D O S: Los resultados no pusieron en evidencia
diferencias significativas en la duraci ón de la
hospitalizaci ón (P ¼ 0,18), el lapso hasta la
normalización de la frecuencia respiratoria (P ¼ 0,65)
o la saturación de oxı́geno (P ¼ 0,26) entre los pacientes
que recibieron sulfato de zinc y el grupo que recibió
placebo.
C O N C L U S I Ó N: Un ciclo corto de tratamiento
complementario con sulfato de zinc no mejoró el
desenlace clı́nico de los pacientes de edad de 750 años
hospitalizados por CAP en este entorno. No se deberı́a
recomendar este tratamiento complementario en la
práctica corriente.