Symptomatic treatment of the cough in whooping cough

(Review)

Pillay V, Swingler G

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2003, Issue 4
http://www.thecochranelibrary.com

Symptomatic treatment of the cough in whooping cough (Review)

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Symptomatic treatment of the cough in whooping cough (Review) i

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Symptomatic treatment of the cough in whooping cough

V Pillay, G Swingler

Contact address: Ms Victoria Pillay, Department of Pediatrics and Child Health, School of Child and Adolescent Health, ICH Building,
5th Floor, Red Cross War Memorial Children’s Hospital, Rondebosch, Cape Town, 7700, SOUTH AFRICA. VPillay@hsrc.ac.za.

Editorial group: Cochrane Acute Respiratory Infections Group.

Publication status and date: Unchanged, published in Issue 3, 2008.
Review content assessed as up-to-date: .

Citation: Pillay V, Swingler G. Symptomatic treatment of the cough in whooping cough. Cochrane Database of Systematic Reviews
2003, Issue 4. Art. No.: CD003257. DOI: 10.1002/14651858.CD003257.

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT
Background
Whooping cough is an important cause of childhood morbidity and mortality. There are 20 to 40 million cases of whooping cough
annually world-wide, 90% of which occur in developing countries, resulting in an estimated 200 to 300 000 fatalities each year. Much
of the morbidity is due to the effects of the paroxysmal cough. Corticosteroids, salbutamol (beta 2 - adrenergic stimulant), and pertussis-
specific immunoglobulin have been proposed as standard treatment for the cough. Antihistamines have also been administered. No
systematic review of the effectiveness of any of these interventions or others has been performed.
Objectives
To assess the effectiveness and safety of interventions used to reduce the severity of the coughing paroxysms in whooping cough in
children and adults.
Search strategy
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (issue 2, 2003); MEDLINE (January 1966 to June
2003); EMBASE (1990 to June 2003) and LILACS (1982 to November 2001). We also scanned reference lists of identified trials and
contacted authors of identified trials and relevant pharmaceutical companies.
Selection criteria
Randomised and quasi-randomised controlled trials of any intervention aimed at suppressing the cough in whooping cough; excluding
antibiotics and vaccines.
Data collection and analysis
Two reviewers independently selected studies and extracted data. Our primary outcome was frequency of paroxysms of coughing.
Secondary outcomes were frequency of vomiting, frequency of whoop, frequency of cyanosis, development of serious complications,
mortality from any cause, side effects due to medication, admission to hospital and duration of hospital stay. Disagreements were
resolved by discussion.
Main results
Nine studies satisfied the inclusion criteria but four had insufficient data for meta - analysis of pre-specified outcomes. Studies were small
and poorly reported. The largest study had a sample size of 49 and the smallest study 18. All studies were performed in industrialised
settings.
Symptomatic treatment of the cough in whooping cough (Review) 1
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Eligible studies assessed diphenhyramine, pertussis immunoglobulin, dexamethasone and salbutamol. No statistically significant benefit
was found for any of the interventions. Diphenhydramine did not change coughing spells (mean increase of coughing spells per 24
hours 1.9 with 95%CI - 4.7 to 8.5) and pertussis immunoglobulin no change in hospital stay (0.7 days 95% CI -3.8 to 2.4), and a
mean reduction of 3.1 whoops per 24 hours [95% CI -6.2; 0.02]. Dexamethasone did not show a clear decrease in hospital stay (-3.5
days 95% CI - 15.3 to 8.4) and salbutamol showed no change in coughing paroxysms per 24 hours [-0.22 95% CI - 4.13 to 3.69].

Authors’ conclusions

Insufficient evidence exists to draw conclusions about the effects of any intervention for the cough in whooping cough.

PLAIN LANGUAGE SUMMARY

No strong evidence exists of any treatment that can relieve the serious cough caused by whooping cough, although there is some
evidence that immunoglobulin might help

Whooping cough (pertussis) is sometimes life-threatening. It is caused by a bacteria that usually affects babies and small children more
severely. Immunisation can prevent it. Babies with whooping cough experience severe bouts of coughing, often leading to vomiting,
malnutrition and dehydration. Treatment with corticosteroids, salbutamol, pertussis specific immunoglobulin (antibodies to increase
the body’s resistance) or antihistamines aims to reduce the cough while the disease runs its course. The review of trials found there is
not enough evidence that these drugs can reduce the cough in whooping cough. Injections of pertussis specific immunoglobulin may
be able to reduce coughs, but more research is needed.

BACKGROUND may lead to malnutrition and dehydration, especially in infants in

Whooping cough (pertussis) is a communicable respiratory disease
(transmitted by coughing and sneezing) (Johnston 2000) caused
by the bacterium Bordetella pertussis (B. pertussis). This disease is
most severe in children, particularly those under the age of 12
months (Johnston 2000). Adults suffer from milder forms of the
disease and the cough is usually less severe (AAP 1997).
Several organisms may cause a similar disease but severe cases are
due to B. pertussis (Hallander 1999). B. pertussis is one of the
major causes of vaccine preventable deaths (WHO 2001). Despite
widespread immunization with pertussis vaccine, there are still
between 20 to 40 million cases of pertussis annually world-wide,
90% of which occur in developing countries, and result in an
estimated 200 to 300,000 fatalities each year (WHO 1999).
The first symptoms of whooping cough are similar to those of
a “common cold,” which are a runny nose, dry cough and mild
fever. After about one to two weeks, coughing begins to occur in
spells (paroxysms) that may last for over a minute. Between cough-
ing (paroxysms), the child may gasp for air with a characteristic
“whooping” sound - although infants may not “whoop” as older
children do. The cough usually lasts at least two weeks and may
persist for more than three months, before gradually improving
(Feigin 1992). Severe coughing paroxysms cause vomiting which
Symptomatic treatment of the cough in whooping cough (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
developing countries (Long 2000). Less common but severe con-
sequences of the cough include cerebral hypoxia, subcutaneous
emphysema or pneumothorax (presence of air in the subcutaneous
tissue or pleural space) and cerebral haemorrhage (Feigin 1992).
Even without severe complications the coughing spasms are very
distressing for the child and parents.
Treatment options depend on the stage of disease. Prevention of
the infection by immunisation against B. pertussis is effective, but
not fully so since some whole cell vaccines display a level of tox-
icity which discourages immunisation (Tinnion 2000). Further-
more immunisation does not confer life long immunity or protect
against other similar organisms. Antibiotic treatment during the
early stage that resembles the common cold is said to shorten the
course of the illness, (but there is no reason to give an antibiotic
for what appears to be just a common cold). Once the cough has
developed antibiotics are said not to change the character of the
cough (Johnston 2000) although they may render the patient non
infectious (Johnston 2000). Therefore treatment of the cough is
symptomatic i.e. treatment aims to reduce the severity of the cough
paroxysms until the disease has run its course (Long 2000).
Corticosteroids, salbutamol (beta 2 -adrenergic stimulant) and
pertussis-specific immunoglobulin have been proposed as standard
treatment for the cough (AAP 1997). Antihistamines have also
2
been administered. Conflicting views have been expressed about
the effectiveness and usefulness of these interventions (Bass 1985;
Hewlett 2000), but no systematic review has been done to assess
the effects of these interventions.
OBJECTIVES
To assess the effectiveness of interventions to reduce the severity
of the coughing paroxysms in whooping cough in children and
adults.
RESULTS
We were able to extract data for pre-specified outcomes from nine
studies (Table: Characteristics of included studies) but sufficient
data for further analysis from only five of these studies. Data were
presented as means and standard deviations in reporting of those
five studies. For the remainder of the studies (Lucchesi 1949;
Zoumboulakis 1973; Pavesio 1977; Miraglia 1984) we list the
summary statistics reported by the authors for our pre-specified
outcomes (Table 03) as authors either did not respond or were
unable to provide requested data.
Suitable data were available for the following interventions:
(i) Antihistamines versus placebo
Diphenhydramine was the only antihistamine studied. Treatment
was administered at 5mg/kg/day orally in three doses. There was
no statistically significant difference in coughing paroxysms, mean
difference of 1.90 fewer coughs per 24 hours in the placebo group
[95%CI -4.7; 8.7] (Comparison 01). Side effects were not re-
ported.
(ii) Pertussis immunoglobulin versus placebo
Granstrom (Granstrom 1991) conducted a trial assessing the ef-
fect of two forms of immunoglobulins raised respectively by an
investigational monocomponent toxoid pertussis vaccine and a
two component acellular pertussis vaccine. Both treatments were
injected intramuscularly (8 ml). Since no difference was found
between the effects of the two preparations, the results of the two
treatment groups were pooled. There was no statistically signifi-
cant difference in duration of hospital stay, mean decrease of 0.7
days in the treatment group [95 %CI -3.8; 2.4] and a borderline
statistically significant reduction in the mean number of whoops
per day in the immunoglobulin groups as compared to the placebo
group, mean decrease of 3.1 [95% CI -6.2; 0.02] (Comparison
02).
Side effects reported were rash in 4.3% of the treatment group
together with loose stools; and pain and swelling at the injection
site in 5.3% of the placebo group.
(iii) Corticosteroids versus placebo
Symptomatic treatment of the cough in whooping cough (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Roberts (Roberts 1992) assessed the effect of dexamethasone on
the duration of hospital stay. Treatment was administered at
0.3mg/kg for four days. Route of administration was not stated.
There was no statistically significant difference in duration of hos-
pital stay, with a mean decrease of 3.5 days in the dexamethasone
group [95% CI -15.3; 8.4] (Comparison 03). Side effects were
not reported.
(iv) Salbutamol versus placebo
Of two studies of salbutamol with extractable data, one was a cross
over trial (Krantz 1985). Treatment was administered at 0.6mg/
kg/day orally in four doses for two days. There was no statistically
significant difference in coughing paroxysms, mean increase of
0.33 coughs per 24 hours in the salbutamol group [95% CI -5.29;
5.95].
The second study conducted was a similar randomised controlled
trial (Mertsola 1986). Treatment was administered orally at 0.1mg/
kg three times a day for ten days. There was no statistically sig-
nificant difference in coughing paroxysms, mean decrease of 0.7
coughs in the salbutamol group [95% CI -6.2; 4.7].
In both studies, data were reported for each 24 hour period. There
was no evidence of heterogeneity (p = 0.76) between the two stud-
ies. Overall there was no statistically significant difference (p =
0.76) in coughing paroxysms, weighted mean decrease of 0.22
coughs per 24 hours in the salbutamol group [95%CI -4.13; 3.69]
(Comparison 04). Side effects were not reported for either inter-
vention.
DISCUSSION
Studies were generally old and poorly reported. One study was
judged to have had adequate allocation concealment. None of the
trials reported analysis by intention to treat.
We did not pre-specify interventions to be included in the review.
Doing so would have simplified the review at the cost of poten-
tially excluding an effective intervention that could have been over-
looked in current “standard” practice. We did explicitly exclude
antibiotics (because the issues of the timing of antibiotic adminis-
tration need a different approach). The effectiveness of antibiotics
will require a separate systematic review.
No studies of cough suppressants (e.g. codeine) were identified.
This may be because trials done on cough suppressants are not
necessarily done with reference to whooping cough.
No statistically significant effects were found for any of the inter-
ventions (except a borderline significant effect of perhaps pertussis
immunoglobulin treatment on the mean number of whoops). Per-
tussis immunoglobulin (Granstrom 1991) could plausibly result
in a decrease in the mean number of whoops by anything from
6.22 over 24 hours to an increase of 0.02 over 24 hours.
3
For all the other interventions sample sizes were small and confi-
dence intervals for the mean differences were wide. This indicates
that there is insufficient evidence to reach any conclusion regard-
ing their effectiveness.
The pre-specified sub group and sensitivity analyses were not fea-
sible because of the small number of studies identified.
The studies were done in industrialised countries when pertussis
was still relatively common and the understanding of research
methodology was more elementary than today. This may partially
explain the poor quality and inconclusive nature of the trials. Given
improved research methodology and the fact that the cough in
pertussis remains an important clinical problem, there is a need
for good quality randomised controlled trials of sufficient size to
be conducted, particularly in developing countries.
AUTHORS’ CONCLUSIONS
Implications for practice
Given the uncertain effectiveness and potential side effects of in-
REFERENCES
References to studies included in this review
Danzon 1988 {published data only}
Danzon A, Lacroix J, Infante-Rivard C, Chicoine L.
A double blind clinical trial on diphenhyramine. Acta
Paediatrica Scandinavica 1988;77:614–5.
Granstrom 1991 {published data only}
Granstrom M, Olinder-Nielsen AM, Holmbard P, Mark A,
Hanngren K. Specific immunoglobulin for treatment of
whooping cough. Lancet 1991;338:1230–3.
Krantz 1985 {published data only}
Krantz I, Norrby SR, Trollfors, B. Salbutamol vs placebo for
treatment of pertussis. Pediatric Infectious Diseases Journal
1985;4(6):638–40.
Lucchesi 1949 {published data only}
Lucchesi PF, La Boccetta AC. Whooping cough treated
with pertussis immune serum (human). American Journal of
Diseases of Children 1949;77:15–23.
Mertsola 1986 {published data only}
Merstola J, Viljanen MK, Ruuskanen O. Salbutamol in
the treatment of whooping cough. Scandinavian Journal of
Infectious Disease 1986;18:593–4.
Miraglia 1984 {published data only}
Miraglia del Giudice, Capristo AF, Mirra G, Maiello
N, Coppola T. A controlled double blind study in the
efficacy of chlophedianol - soberol in the treatment of
infantile whooping cough [Studio controllato in doppio
cieco sull‘efficacia del clofedanolo – sobrerolo nella terapia
Symptomatic treatment of the cough in whooping cough (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
terventions for the cough in whooping cough there appears to be
no justification for their use.
Implications for research
Further good quality, well reported randomised controlled trials
of adequate statistical power are required to be done, particularly
in developing countries.
ACKNOWLEDGEMENTS
Dr Thandiwe Sigxaxhe and Dr Merrick Zwarenstein for prelimi-
nary reviewing of the protocol.
Adelaide Morgado, Andy Oxman, Anette Bluemle, Elena Telaro,
Helimamy Moeng, and Jianping Liu for assistance in locating and
translating of foreign language articles in addition to locating au-
thors. Ms Maureen Kirkman from the Pharmaceutical Manufac-
turers Association (South Africa) for providing contacts for phar-
maceutical companies.
della pertose del bambino]. Minerva Pediatrica 1984;36:
1199–206.
Pavesio 1977 {published data only}
Pavesio D, Ponzone A. Salbutamol and pertussis. Lancet
1977;January 15:150–1.
Roberts 1992 {published data only}
Roberts I, Gavin R, Lennon D. Randomized controlled
trial of steriods in treatment of pertussis [letter]. Archives of
Disease in Childhood 1992;11(11):982–3.
Zoumboulakis 1973 {published data only}
Zoumboulakis D, Anagnostakis D, Albanis V, Matsaniotis
N. Steriods in treatment of pertussis: A controlled clinical
trial. Archives of Disease in Childhood 1973;48:51–4.
References to studies excluded from this review
Ames 1953
Ames RG, Cohen SM, Fischer AE, Kohn J, McPherson AZ,
Marlow J, et al.Comparison of the therapeutic efficacy of
four agents in pertussis. Pediatrics 1953;11:323–37.
Badr-El-Din 1976
Badr-el-din MK, Aref GH, Kassem AS, Abdel-Moneim
MA, Abbassy A Amr. A beta - adrenergic stimulant,
salbutamol, in the treatment of pertussis. Journal of Tropical
Medicine and Hygiene 1976;79(10):218–9.
Balagtas 1971
Balagtas RC, Nelson KE, Levin S, Gotoff SP. Treatment
of pertussis with pertussis immunoglobulin. Journal of
Pediatrics 1971;79(2):203–8.
4
Brunskill 1986
Brunskill A, Langdon D. Salbutamol and pertussis [letter].
Lancet 1986;2(August):282.
Bruss 1999
Bruss JB, Malley R, Halperin S, Dobson S, Dhalla M,
Mciver J, et al.Treatment of severe pertussis: a study of
the safety and pharmacology of intravenous pertussis
immunoglobulin. Pediatric Infectious Disease Journal 1999;
18:505–11.
Chandra 1972
Chandra H, Karan S, Mathur YC. Evaluation of
betamethasone and isoniazid along with chloramphenicol
in the management of whooping cough. Indian Pediatrics
1972;2:70.
Lewis 1984
Lewis D. Double blind controlled trial in the treatment
of whooping cough using drosera. Midlands Homoeopathy
Research Group Newsletter 1984;11:49–58.
Pavesio 1979
Pavesio D, Mora P, Levi P. Preliminary results with
salbutamol in the treatment of petussis. Minerva Pediatrica
1979;31(11):901–905.
Additional references
AAP 1997
American Academy of Pediatrics. Pertussis. In: Peter G
editor(s). Red Book: Report of the Committee on Infectious
Diseases. 24th Edition. Elke Grove Village: American
Academy of Pediatrics, 1997:394.
Bass 1985
Bass JW. Pertussis: Current status of prevention and
treatment. Pediatric Infectoius Disease Journal 1985;4:
614–9.
SOURCES OF SUPPORT
External sources of support
• University of Cape Town SOUTH AFRICA
• Department of Arts, Culture, Technology and Science SOUTH AFRICA
Symptomatic treatment of the cough in whooping cough (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Feigin 1992
Feigin RD, Cherry JD. Pertussis. In: Bralow L editor
(s). Textbook of Pediatric Infectious Diseases. 3. Vol. 2,
Pennsylvania: WB Saunders Company, 1992:1211–2.
Hallander 1999
Hallander HO, Gnarpe J, Gnarpe H, Olin P. Bordetella
pertussis, Bordetella parapertussis, Mycoplasma
pneumoniae, Chlamydia pneumoniae and persistent cough
in children. Scandinavian Journal of Infectious Diseases 1999;
31(3):281–6. [MEDLINE: 99409784].
Hewlett 2000
Hewlett EL. Bordetella Species. Mandell: Principles and
practice of infectious diseases. 5. Churchhill Livingstone,
2000:2419.
Johnston 2000
Johnston RB Jr. Whooping Cough. In: Goldman, Bennet
editor(s). Cecil Textbook of Medicine. 21st Edition. WB
Saunders, 2000:1666.
Long 2000
Long SS. Pertussis (Bordetella pertussis and B. parapertussis).
Behrman: Nelson Textbook of Pediatrics. 16th Edition. WB
Saunders, 2000:840–1.
Tinnion 2000
Tinnion ON, Hanlon M. Acellular vaccines for preventing
whooping cough in children. The Cochrane Library
2001, Issue 1.Art. No.: CD001478. DOI: 10.1002/
14651858.CD001478.pub2.
WHO 1999
WHO position paper. Pertussis Vaccines. Weekly
Epidemiological Record 1999;74(18):137–42.
WHO 2001
World Health Organisation. Mental Health: New
understanding, new hope. www.who.int/whr/2001/main/
en/pdf/annex2.en.pdf (accessed 7 June 2002) 2001.
∗
Indicates the major publication for the study
5
Internal sources of support
• South African Cochrane Centre SOUTH AFRICA

INDEX TERMS

Medical Subject Headings (MeSH)

Albuterol [therapeutic use]; Dexamethasone [therapeutic use]; Diphenhydramine [therapeutic use]; Histamine H1 Antagonists [ther-
apeutic use]; Immunoglobulins [therapeutic use]; Randomized Controlled Trials as Topic; Whooping Cough [∗ drug therapy]

MeSH check words

Adult; Child; Humans

Symptomatic treatment of the cough in whooping cough (Review) 6

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.