Accepted Manuscript

Management of recurrent tonsillitis in children

Diaa El Din El Hennawi, Ahmed Geneid, Salah Zaher, Mohamed

Rifaat

PII: S0196-0709(17)30034-0
DOI: doi: 10.1016/j.amjoto.2017.03.001
Reference: YAJOT 1823
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Received date: 16 January 2017

Please cite this article as: Diaa El Din El Hennawi, Ahmed Geneid, Salah Zaher, Mohamed
Rifaat , Management of recurrent tonsillitis in children. The address for the corresponding
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 ACCEPTED MANUSCRIPT

Title page

Management of recurrent tonsillitis in children.

Diaa El Din El Hennawi1, MD; Ahmed Geneid2, MD, PhD; Salah

Zaher3, MD; Mohamed Rifaat1, MD.

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1
Department of Otorhinolaryngology, Faculty of medicine Suez Canal

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University, Ismailia – Egypt; 2Department of Ear, Nose and throat disorders

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and Phoniatrics-Head and neck surgery, Helsinki, Finland.; 3Department of
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Pediatrics, Faculty of Medicine, Alexandria university; Alexandria, Egypt.
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*Diaa El Din Mohamed El Hennawi.MD

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Professor of Otolaryngology, Faculty of medicine Suez Canal University,

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Ismailia - Egypt.
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dhennawi@yahoo.com
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Tel:+201066685192

*Salah Rafik Zaher, MD

Professor of Pediatrics, Faculty of Medicine ,Alexandria University

Alexandria, Egypt

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Pedotomanager@entnet.org

*Mohamed Rifaat Ahmed ,MD corresponding Author

Assistant professor Otolaryngology, faculty of medicine, Suez Canal

University, Ismailia ,Egypt

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m_rifaat@hotmail.com

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Tel: +201285043825

Fax: +20663415603
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*Ahmed Geneid , MD
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ahmed.geneid@hus.fi
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Department of Ear, Nose and throat disorders and Phoniatrics-Head and

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neck surgery, Helsinki, Finland.

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Conflicts of interests: None

Financial and material support: None

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Level of evidence: 3b

Word count: 2193

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Abstract

Objective: to compare azithromycin (AZT) and benzathine penicillin (BP)

in the treatment of recurrent tonsillitis in children.

Methods: The study comprised of 350 children with recurrent

streptococcal tonsillitis, 284 of whom completed the study and 162 children

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received conventional surgical treatment. The rest of the children, 122, were

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divided randomly into two equal main groups. Group A children received a

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single intramuscular BP (600 000 IU for children ≤ 27 kg and 1 200 000 IU
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for ≥ 27 kg) every two weeks for six months. Group B children received

single oral AZT (250 mg for children ≤ 25 kg and 500 mg for ≥ 25 kg) once
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weekly for six months.

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Results: Both groups showed marked significant reduction in recurrent

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tonsillitis that is comparable to results of tonsillectomy. There were no

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statistical differences between group A and B regarding the recurrence of

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infections and drug safety after six-month follow-up. Group B showed

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better compliance.

Conclusion: AZT proved to be good alternative to BP in the management

of recurrent tonsillitis with results similar to those obtained after

tonsillectomy.

Key words

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chronic tonsillitis - benzathine penicillin - azithromycin

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Introduction

In the present state of medical literature, tonsils are considered as assets to

the immunological system and they are removed or partially excised only

when there is a medical necessity caused by their size, recurrent bacterial

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infections or tumor (1). Recurrent tonsillitis has been defined as four or more

confirmed infection episodes per year with streptococci A-infection

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(2)
diagnosed in one of them . Prevalence is from 11.0-12.3% with marked

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family burden and risk of man serious complication especially in
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(3)
developing countries . Recurrent tonsillitis is usually treated by either
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tonsillectomy or conservative medical treatment when tonsillectomy criteria

are not fulfilled or there is a contraindication for tonsillectomy (4). A review

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by Bruton et al in 2014 found that children with recurrent acute tonsillitis

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have a small benefit from adeno-/tonsillectomy.(5) The procedure will avoid

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only 0.6 episodes of any type of sore throat in the first year after surgery
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compared to non-surgical treatment. The children who had surgery had

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three episodes of sore throat on average compared to 3.6 episodes

experienced by the other children. One of the three episodes is the episode

of pain caused by surgery. It seems that children with the more severe and

frequent tonsillitis are the ones who benefit from surgery in comparison to

the less severely affected children (5).

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Sirimanna et al reported the usefulness of long-acting penicillin in

(6)
significant reduction of recurrent tonsillitis . However, long acting

penicillin has multiple drawbacks such as hypersensitivity reactions,

anaphylaxis and severe local pain. (7)

Azithromycin (AZT) is an Azalide, a subclass of macrolide antibiotic which

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is widely distributed throughout the body, achieving higher concentrations

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in tonsillar tissues with adequate therapeutic levels during medication with

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minimal side effects. (8) NU
Recurrent tonsillitis always present on a continuum rather than a dichotic
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representation. Children seem to suffer from different grades of recurrent

tonsillitis. The possibility of having other treatment measures than

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tonsillectomy is tempting especially when the child has recurrent tonsillitis

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that falls little short of the criteria for tonsillectomy.(9)

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The aim of the present study was to compare the efficacy of AZT and
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benzathine penicillin (BP)—both administered for six months in the

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management of recurrent tonsillitis—to conventional tonsillectomy.

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Materials and methods

Design, setting and participants

A randomized controlled clinical trial study created in the otolaryngology

department - Suez Canal University Hospital – Ismailia – Egypt and

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Alexandria University Children Hospital –Egypt from March 2005 to May

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2012. The study protocol was approved by the local faculty ethics

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committee and written informed consent was obtained from all patients

relevant.
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Patient eligibility and enrolment
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A total of 350 children with recurrent tonsillitis were included in the study.

Recurrent tonsillitis was defined as four or more episodes of tonsillitis per

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year (for children of either gender) with two of the episodes confirmed to be
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group A streptococcal infection. The enrolled children were aged from five
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to 12. The 350 children enrolled fulfilled the inclusion criteria and did not

have any significant co-morbidities. Significant morbidities included

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rheumatic heart disease, rheumatic fever, marked anesthetic risk, sensitivity

to AZT or BP, the intake of drugs that might interfere with AZT or BP,

hepatic impairment, or long QT syndrome (a prolonged QT interval of more

than 45 msec in ECG).

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Study plan

Children were divided randomly and equally into two groups. Randomization

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was performed prior to study commencement as follows: Opaque envelopes were

numbered sequentially from 1 to 350. A computer-generated table of random numbers was

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used for group assignment; if the last digit of the random number was from 0 to 4,

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assignment was to group 1 (received conventional tonsillectomy), and if the last digit was
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from 5 to 9, assignment was to group 2 (received BP or AZT). Group 2 was randomized

again in similar manner in group A and group B. The assignments were then placed into the
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opaque envelopes and the envelopes sealed. As eligible participants were entered into the

trial, these envelopes were opened in sequential order to give each patient his or her
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random group assignment. The envelopes were opened by the ORL specialist after patient
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consent and just prior to the treatment method.; Group A received medical
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treatment with BP and group B received AZT. Subgroup A children

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received single intramuscular.

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BP (600 000 IU for children ≤ 27 kg and 1 200 000 IU for children ≥ 27

kg) every two weeks for six months. .(10) Subgroup B children received

single oral AZT (250 mg for children ≤ 25 kg and 500 mg for children ≥ 25

kg) once weekly for six months. (11). Children in the AZT subgroup were

subjected to ECG, calculation of the QT interval and liver enzymes before

starting the treatment.

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Out of the 350 children, only 284 managed to complete the study. The

children had a mean age of 7.4 ± 1.6 years.

350 children randomly divided into tonsillectomy and medical treatment

group with 175 in each. Drop out of 13 children in the tonsillectomy group

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and 53 children in the conservative medical treatment one. Tonsillectomy

group was 162 children. Conservative medical treatment group was 122

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children. 61 children in group A that received BP while 61 children in

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group B received AZT. More patients dropped out of the conservative
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medical treatment group. It is postulated that this may be due to some of

them seeking conventional tonsillectomy in the private health care sector or

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due to poor compliance with the conservative medical treatment. Objective

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and outcome measurement assessment

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Data collected included complete medical histories with an emphasis on

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recurrent tonsillitis. Symptoms’ severity was assessed using a visual analog

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scale for symptoms’ severity (with 0 indicating no symptoms and 10

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indicating the most severe symptoms). In addition, a complete ENT and

general physical examination were carried out before the start of the study.

CBC, ASOT, and ESR data were collected from all children at the

beginning of the study and after six months.

The outcomes were assessed through the following measures: 1) Medical

history and clinical evaluation by the end of the trial. 2) ASOT and ESR

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levels were taken before the start of the study and six months after it. 3)

Symptoms’ severity was assessed using the visual analog scale for

symptoms severity as described above. 4) The safety of drugs were assessed

by the detection of adverse effects, which were classified as minor and

accepted adverse effects (GIT upset, dizziness) or major, necessitating the

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exclusion of the child from the study (anaphylaxis, jaundice, a prolonged

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QT interval). 5) Satisfaction assessment was made by asking direct

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questions to the patients, their parents, and the medical staff. Patients’
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satisfaction was classified as a) the patient is comfortable and accepts the

regimen; b) the patient is not comfortable but accepts and continues the
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regimen; c) the patient is not comfortable and does not accept the regimen

and discontinues it (whereupon they were excluded from the study).

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Statistical analysis
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Data collected were processed using SPSS version 18 (SPSS Inc., Chicago,
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IL, USA). Quantitative data were expressed as means ± SD while

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qualitative data were expressed as numbers and percentages. The Student’s

t-test was used to compare the significance of difference for the quantitative

variables that followed a normal distribution.

Ethical considerations

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The study protocol was approved by the faculty’s ethical committee and

written informed consent was obtained from the parents of the children

enrolled in the study after an explanation of the study’s design, and the

benefits and risks associated with the treatment regimen.

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Results
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ASOT and ESR levels.

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The tonsillectomy group had a mean ESR level of 70.3 ± 13.1 ml/h during

the last episode of tonsillitis before tonsillectomy. Six months after the

operation this level dropped to 8.7 ± 1.9 ml/h (P = 0.005). The mean ASOT

for the tonsillectomy group was 436 IU/ml before surgery and declined to

115 IU/ml after six months with statistically significant improvement (P =

0.006).

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The mean ASOT before treatment in group A was 476 IU/ml and 491

IU/ml in group B. After six-months follow-up a statistically significant

reduction in the ASOT in both groups occurred as group A became 126

IU/ml while group B became 141 IU/ml (table 1). There was no

statistically significant difference between the two groups.

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The mean ESR level also showed a statistically significant reduction in its

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values from before treatment to the end of the six-months follow-up (table

1). However, there was no statistically significant difference between

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group A and group B in terms of the improvement degree of the ESR.
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Flow chart of the study, pre- and post-treatment assessments are shown in

figure 1.
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--------------------INSERT FIGURE 1 HERE--------------------

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Severity of symptoms
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The means of the score for the intensity of the symptoms of tonsillitis

before treatment among group A and group B are summarized in table 1.

No statistically significant differences were found between the groups.

Six months after starting the treatment, the means of the scores for the

intensity of the symptoms of tonsillitis in group A group B were

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calculated. There was a marked statistically significant improvement in

both groups from before treatment to the end of the six-months follow-up

(p = 0.03). However, there was no statically significant difference between

the two groups (table 1).

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In terms of the adverse effects encountered in the AZT group, three

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patients had minor adverse reactions e.g. nausea, vomiting, and abdominal

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cramps with diarrhea. ECG was carried out for all the patients as a baseline

and all showed a normal sinus rhythm. In regular ECG follow-ups, 50

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patients (82%) of the AZT group showed QT prolongation and 11 patients
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(18%) showed shortening. The mean of QT rose significantly from 41.6 +

1.7 ms before treatment to 43.8 + 2.9 ms (P =0.007) after. There was no

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statistically significant difference between genders regarding changes in

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QT interval. Also, liver enzymes did not show a significant rise from

before treatment to after treatment, nor was there a difference between

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group A and group B. No serious adverse reactions were reported in either

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group. No patients developed rheumatic activity during the study and

follow-up period.

Being comfortable with the treatment was assessed in both groups on a

single parameter dichotic scale of comfortable vs. uncomfortable. Group A

had a lower level of 36 (59.1%) comfortable patients, versus 25 who

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reported discomfort (40.9%). However, the uncomfortable group continued

the treatment till the end of the year. Satisfaction among group B patients

was significantly higher among 58 patients (95.61%). Only three reported

to be uncomfortable (4.9%) but they also continued the treatment. It is

evident that the AZT patients were more comfortable with the drug than

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the BP patients, with a statically significant difference between both

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groups regarding satisfaction.

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More than 90% of both groups were taking the drug regularly. There was
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no statically significant difference between the groups regarding
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compliance.
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Discussion
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Recurrent tonsillitis is considered to be one of the common reasons for

primary care visits to physicians. Recurrent tonsillitis among children has a

considerable impact on the quality of life, not only due to the effects on

children but also the burden on the parents when their child is suffering.

Tonsillectomy remains a common procedure, especially in western

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(12)
countries . However, a number of immunological studies on the effects

of tonsillectomy point to the importance of a conservative attitude from an

immunological point of view towards adenotonsillectomy (13).

The aim of this study has been to look into alternatives to tonsillectomy,

especially when the tonsillectomy criteria are not fully fulfilled, resources

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are not available or the parents opt for medical treatment. The two

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alternatives were BP and AZT.

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Although intramuscular BP is still the drug of choice for the treatment and
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prevention of recurrent acute rheumatic fever, there are international data

reporting an incidence rate of allergic reactions of about 3.2% with 0.2%

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reporting an anaphylaxic reaction due to monthly BP injections.

Unfortunately, there were three deaths documented in Zimbabwe resulting

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from BP produced by three different manufacturers (14).

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Previous studies have shown that in comparison to oral penicillin,

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intramuscular penicillin has been more effective with rheumatic fever

recurrence and streptococcal throat infections (15).

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Azithromycin which is Azalide antibiotic, has better compliance and is

much easier to take than intramuscular BP.

The present study showed that there is no significant difference between the

group A and B in regard to recurrent tonsillitis after six-months follow-up.

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The ASOT and ESR levels were also reduced to normal and there was no

statistically significant difference between the groups.

AZT has been proven to be very effective in treating group A streptococcal

tonsillopharyngitis when it presents in the acute form (16).

The main concern for using AZT in long treatment has been its possible

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association with increased cardiovascular risk and may lead to

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cardiovascular-related death in high-risk patients. A meta-analysis of

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randomized controlled trials by AlMalki et al., reported AZT safety in
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patients studied in 12 trials included in the meta-analysis from 1990 to 2013
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. Nevertheless, its safety and effectiveness is comparable to Penicillin V
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(18)
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Long-term prophylaxis against streptococcal infections using AZT was

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attempted by Snider et al. in the prophylaxis of children with PANDAS

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(pediatric autoimmune neuropsychiatric disorders associated with

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streptococcal infections). A 12-month trial administration of AZT and

penicillin was done and showed effectiveness in decreasing streptococcal

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infections (19).

The results of this study show the efficacy of AZT in preventing recurrent

tonsillitis and reducing ASOT and ESR levels to a range comparable to

those of BP and tonsillectomy. The children were more comfortable with an

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AZT regimen rather than a BP regimen. Minor adverse reactions were

reported with AZT.

The message of this study is that treatment options other than tonsillectomy

exist for treating recurrent tonsillitis. AZT, which is one of the treatments,

proved to be safe and effective in our study. Further studies should look

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into the possibility of having shorter regimens of AZT when treating

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recurrent tonsillitis.

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Conclusion

The treatment of recurrent tonsillitis is equally effective by treatment with

AZT or BP in comparison to tonsillectomy. AZT was as effective as BP and

tonsillectomy against recurrent tonsillitis after six months of treatment.

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References

1- sharma k, kumar d.

Ligation versus bipolar diathermy for hemostasis in tonsillectomy: a

comparative study. Indian J Otolaryngol Head Neck Surg. 2011

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Jan;63(1):15-9.

2- Alho OP , Koivunen P, Penna T, Teppo H, Koskela M, Luotonen J.

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Tonsillectomy versus watchful waiting in recurrent streptococcal

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5;334(7600):939. Epub 2007 Mar 8.
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3- Kvestad E, Kvaerner K, Roysamb E, Tambs K, Harris J, Magnus P.

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(Online). 2014 Jul 22;2014.

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5- Burton MJ , Glasziou PP, Chong LY, Venekamp RP. Tonsillectomy

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6- Sirimanna KS , Madden GJ, Miles SM. The use of long-acting

penicillin in the prophylaxis of recurrent tonsillitis. J Otolaryngol.

1990 Oct;19(5):343-4.

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7- Brunton L L, Parker K L.penicillin ,cephalosporin and other beta

lactam inhibitor antibiotics, Goodman and goldman pharmacol

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8- Lister PJ, Balechandran T, Ridgway GL, Robinson AJ. Comparison

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9- Zielnik-Jurkiewicz B , Jurkiewicz D. Implication of immunological

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abnormalities after adenotonsillotomy. Int J Pediatr
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10- Broderick MP , Hansen CJ, Russell KL, Kaplan EL, Blumer

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JL, Faix DJ..

Serum penicillin G levels are lower than expected in adults within tw

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o weeks of administration of 1.2million units. PLoS

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One. 2011;6(10):e25308.
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11- Gopal R1, Harikrishnan S, Sivasankaran S, Ajithkumar

VK, Titus T, Tharakan JM..

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r. Indian Heart J. 2012 Jan-Feb;64(1):12-5.

12- Van Staaji BK, van den Akker EH, Rovers MM , Hordijk GJ,

Hoes AW, Schilder AG. Effectiveness of adenotonsillectomy in

children with mild symptoms of throat infections or adenotonsillar

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hypertrophy: open, randomised controlled trial. Clin Otolaryngol

2005; 30: 60–3.

13- Brandtzaeg P. Immunology of tonsils and adenoids: everything

the ENT surgeon needs to know. Int J Pediatr Otorhinolaryngol. Dec

2003;67 Suppl 1:S69-76.

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14- Wyber R , Zühlke L , Carapetis J .

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The case for global investment in rheumatic heart-disease control.

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Bull World Health Organ. 2014 Oct 1;92(10):768-70.
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15- manyemba j , mayosi bm.intramuscular penicillin is more

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fever--a systematic review. s afr med j. 2003 mar;93(3):212-8.

16- Casey JR , Pichichero ME. Higher dosages of azithromycin are

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1;57(7):788-92.

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Tables

Table (1): The mean degree of the ASOT in both groups after treatment.

Group Before After

treatment treatment

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Mean SD Mean SD

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ASOT A 476 18 126* 14

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B 491
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ESR A 68.7 9.7 9.4* 3.2

B 71.2 12.3 10.2* 2.8

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Dysphagia A 8.1 1.5 5.3 1.8

B 8.7 1.1 4.9 1.4

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Fever A 9.3 1.1 4.3 0.9

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B 8.9 2.3 4.1 1.2

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Arthralgia A 7.2 0.9 3.9 1.8

B 7.9 1.4 3.6 0.9

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Body ache A 8.7 1.4 3.7 1.1

B 8.1 0.8 3.2 1.7

*P = 0.005, n= 61 for group A and B

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Figure 1

350 children, randomly

divided into tonsillectomy
and medical treatment
groups with 175 children in
each.
13 children dropped out of

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the tonsillectomy group and
53 children dropped out of
the conservative medical

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treatment group.
Pre-treatmet
assessment

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Conservative medical
Tonsillectomy group: 162
treatment group: 122
children
children
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61 children in group B 61 children in group A

receieved AZT received BP
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Post-treatment
assessment, 6 months
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after tonsillectomy or
start of medical
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treatment
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AC

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