10.14639/0392-100X-N1436
Objective. Interactions between SARS-CoV-2 and pharyngeal associated lymphoid tissue is thought to influence the manifestations of COVID-19. We aimed to determine whether a previous history of tonsillectomy, as a surrogate indicator of a dysfunctional pharyngeal associated lymphoid tissue, could predict the presentation and course of COVID-19.
Methods. Multicentric cross-sectional observational study involving seven hospitals in Northern and Central Italy. Data on the clinical course and signs and symptoms of the infection were collected from 779 adults who tested positive for SARS-CoV-2, and analysed in relation to previous tonsillectomy, together with demographic and anamnestic data.
Results. Patients with previous tonsillectomy showed a greater risk of fever, temperature higher than 39°C, chills and malaise. No significant differences in hospital admissions were found.
Conclusions. A previous history of tonsillectomy, as a surrogate indicator of immunological dysfunction of the pharyngeal associated lymphoid tissue, could predict a more intense systemic manifestation of COVID-19. These results could provide a simple clinical marker to discriminate suspected carriers and to delineate more precise prognostic models.
text/xml
1827-675X
1436
en
Giancarlo Tirelli
https://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
tonsillectomy
COVID-19 in the tonsillectomised population
Text.Serial.Journal
https://www.actaitalica.it/
41
COVID-19
2021-05-06
2021-01-31
2021-07-08
2021-07-08
197-205
1
Giancarlo Tirelli
2021/05/06
10.14639/0392-100X-N1436
197
Otorhinolaryngology-Head and Neck Surgery Department, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy
1827-675X
tonsillectomy
205
COVID-19 in the tonsillectomised population
https://www.actaitalica.it/article/download/1436/552
41
ACTA OTORHINOLARYNGOLOGICA ITALICA 2021;41:197-205; doi: 10.14639/0392-100X-N1436




COVID-19


COVID-19 in the tonsillectomised population
COVID-19 nella popolazione tonsillectomizzata
Vincenzo Capriotti1*, Francesco Mattioli2*, Francesco Guida1, Alberto Vito Marcuzzo1, Alfredo Lo Manto2,
Andrea Martone2, Giulia Molinari2, Cristoforo Fabbris3, Anna Menegaldo3, Leonardo Calvanese3, Gino Latini4,
Cristina Cingolani4, Paolo Gradoni4, Francesca Boscolo Nata5, Clelia De Sisti6, Vittorio Selle6, Giordano Leone7,
Pietro Indelicato7, Francesco Pilolli8, Niccolò Mevio8, Luca Roncoroni8, Simona Papi9, Marianna Meschiari10,
Riccardo Tominz11, Luca D’Ascanio4, Alberto Dragonetti8, Lucio Torelli12, Loris Trenti13, Giacomo Spinato3,
Paolo Boscolo-Rizzo3, Mario Bussi6, Andrea Cossarizza14, Livio Presutti2, Giancarlo Tirelli1
1
  Otorhinolaryngology-Head and Neck Surgery Department, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy;
2
  Otorhinolaryngology-Head and Neck Surgery Department, University Hospital of Modena, Italy; 3 ENT Clinic and Regional Center
for Head and Neck Cancer, University of Padova Faculty of Medicine and Surgery, Department of Neurosciences, Treviso Regional
Hospital, Treviso, Italy; 4 Institute of Otorhinolaryngology, Department of Head and Neck Surgery, Santa Croce Hospital AORMN,
Fano (PU), Italy; 5 Otorhinolaryngology Unit, Monselice Hospital, Ospedali Riuniti Padova Sud “Madre Teresa di Calcutta”, Monselice
(PD), Italy; 6 Hygiene and Public Health Unit, Department of Prevention, Hospital of Chioggia, AULSS 3 Serenissima, Chioggia (VE),
Italy; 7 Department of Otorhinolaryngology, San Raffaele Hospital, Milano, Italy; 8 Department of Otorhinolaryngology, ASST Grande
Ospedale Metropolitano Niguarda, Milano, Italy; 9 Department of Surgery and Clinical Specialties, University of Modena and Reggio
Emilia, Modena, Italy; 10 Department of Infectious Diseases, Azienda Ospedaliero-Universitaria Policlinico of Modena, University
of Modena and Reggio Emilia Faculty of Medicine and Surgery, Modena, Italy; 11Department of Prevention, Azienda Sanitaria
Universitaria Giuliano Isontina, Trieste, Italy; 12 Department of Medical, Surgical and Health Sciences, University of Trieste, Italy;
13
   Department of General and Digestive Surgery, Colorectal Unit, Bellvitge University Hospital, Barcelona, Spain; 14 Department of
Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy
*
  V. Capriotti and F. Mattioli contributed equally to this work.                              Received: January 31, 2021
                                                                                                    Accepted: March 1, 2021
                                                                                                    Published online: May 6, 2021
SUMMARY
Objective. Interactions between SARS-CoV-2 and pharyngeal associated lymphoid tissue                Correspondence
are thought to influence the manifestations of COVID-19. We aimed to determine whether              Vincenzo Capriotti
a previous history of tonsillectomy, as a surrogate indicator of a dysfunctional pharyngeal         Otorhinolaryngology-Head and Neck Surgery De-
associated lymphoid tissue, could predict the presentation and course of COVID-19.                  partment, Azienda Sanitaria Universitaria Giuliano
                                                                                                    Isontina, strada di Fiume 447, 34149 Trieste, Italy
Methods. Multicentric cross-sectional observational study involving seven hospitals in
                                                                                                    Tel. +39 040 3994736. Fax+39 040 3994180
Northern and Central Italy. Data on the clinical course and signs and symptoms of the in-           E-mail: vince.capriotti@gmail.com
fection were collected from 779 adults who tested positive for SARS-CoV-2, and analysed
in relation to previous tonsillectomy, together with demographic and anamnestic data.               Funding
Results. Patients with previous tonsillectomy showed a greater risk of fever, temperature           None.
higher than 39°C, chills and malaise. No significant differences in hospital admissions were
found.                                                                                              Conflict of interest
Conclusions. A previous history of tonsillectomy, as a surrogate indicator of immunologi-           The Authors declare no conflict of interest.
cal dysfunction of the pharyngeal associated lymphoid tissue, could predict a more intense
systemic manifestation of COVID-19. These results could provide a simple clinical marker
                                                                                                      How to cite this article: Capriotti V, Mat-
to discriminate suspected carriers and to delineate more precise prognostic models.
                                                                                                      tioli F, Guida F, et al. COVID-19 in the
KEY WORDS: COVID-19, SARS-CoV-2, coronavirus, tonsils, tonsillectomy                                  tonsillectomised population. Acta Otorhi-
                                                                                                      nolaryngol Ital 2021;41:197-205. https://doi.
                                                                                                      org/10.14639/0392-100X-N1436
RIASSUNTO
Obiettivo. Si ritiene che le manifestazioni dell’infezione da SARS-CoV-2 siano influenzate          © Società Italiana di Otorinolaringoiatria
dalle interazioni tra il virus e il tessuto linfatico associato alla faringe. Obiettivo di questo   e Chirurgia Cervico-Facciale
studio è determinare se una pregressa tonsillectomia, come indicatore surrogato di disfun-
zione immunologica faringea, possa predire la presentazione e il decorso della COVID-19.                           OPEN ACCESS
Metodi. Studio multicentrico trasversale osservazionale coinvolgente 7 centri italiani. Sono        This is an open access article distributed in accordance with
stati raccolti i dati su decorso, segni e sintomi dell’infezione da 779 adulti positivi al SARS-    the CC-BY-NC-ND (Creative Commons Attribution-Non-
CoV-2, e analizzati in relazione a pregressa tonsillectomia, dati demografici e anamnestici.        Commercial-NoDerivatives 4.0 International) license. The
                                                                                                    article can be used by giving appropriate credit and mentio-
Risultati. I pazienti con pregressa tonsillectomia hanno un maggior rischio di sviluppare
                                                                                                    ning the license, but only for non-commercial purposes and
febbre, raggiungere temperature oltre i 39°C, brividi e malessere generalizzato. Non si             only in the original version. For further information: https://
riscontrano differenze nel tasso di ospedalizzazione.                                               creativecommons.org/licenses/by-nc-nd/4.0/deed.en




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Conclusioni. Il dato anamnestico di pregressa tonsillectomia, come indicatore di disfunzione immunologica faringea, può predire una mani-
festazione sistemica più intensa nei pazienti affetti da COVID-19. Questi risultati possono fornire un marker clinico semplice per discriminare
sospetti portatori del virus e delineare modelli prognostici più accurati.
PAROLE CHIAVE: COVID-19, SARS-CoV-2, coronavirus, tonsille, tonsillectomia



Introduction                                                             tonsillitis that do not benefit from medical therapy alone 10.
                                                                         It has long been debated if tonsillectomy might interfere
Coronavirus disease 2019 (COVID-19), caused by the
                                                                         with host immune response and susceptibility to airborne
severe acute respiratory syndrome coronavirus 2 (SARS-
                                                                         infections. The first studies appeared in the early 1970s,
CoV-2), has shown a wide variety of manifestations, rang-
                                                                         when Ogra showed a reduced level of IgA in nasopharyn-
ing from asymptomatic infection to critical respiratory
                                                                         geal secretions and a diminished local immune response
failure 1,2. Fever, cough, shortness of breath and sudden
                                                                         to oral poliovirus vaccine in children who had undergone
onset of smell and taste deficiency are frequently reported,
                                                                         adeno-tonsillectomy 11. Since then, several reports have
alongside gastrointestinal disturbances and non-specific
                                                                         been published, with non-univocal conclusions: if removal
complaints such as myalgia and malaise 1. Various risk fac-
tors have been debated to influence symptom severity and                 of the palatine tonsils alone does not seem to considerably
prognosis, such as sex, coexisting chronic disorders and                 influence humoral and cellular systemic immunity 12, their
tobacco use; however, the interindividual variability and                importance in both promoting and effecting the local in-
susceptibility are not fully understood 3,4.                             flammatory response and production of antibody-secreting
The role of the pharyngeal microenvironment in the trans-                cells is better outlined, with the latter spreading throughout
mission, modulation, and clinical progression of SARS-                   the upper airway mucosa and memory cells migrating to
CoV-2 infection has been receiving growing attention 5.                  regional and distant lymph nodes and secondary lymphoid
SARS-CoV-2 is known to enter the host mucosa via the an-                 organs 13. This key role decreases with age, but residual ac-
giotensin converting enzyme 2 6, which it uses to colonise               tivity has been found in patients older than 80 years; chron-
the upper airway tract in addition to other target organs 7.             ic and recurrent inflammation are crucial in accelerating the
The pharyngeal surfaces of the upper airways are charac-                 decay of immune function 8.
terised by secondary lymphoid organs and mucosal-asso-                   If the role of pharyngeal microenvironment in COVID-19
ciated lymphoid tissue (MALT), which form a morpho-                      pathophysiology and course is of great research interest, its
functional immunologic unit known as “Waldeyer’s ring”.                  usefulness in daily practice requires clinical markers that
Waldeyer’s ring is a key structure in stimulating locore-                could provide information on its status. In the hypothesis
gional immune response and tolerance towards infec-                      that a previous tonsillectomy could reflect a locoregional
tive stimuli. In this lymphoid tissue, foreign antigens are              chronic inflammatory state as a result of an impaired im-
processed and presented to naïve lymphocytes through a                   munological Waldeyer’s ring activity, we wanted to assess
complex network involving dendritic, T-helper and B-cells,               its possible role as a predictor of interindividual variability
eventually forming high affinity colonies that differentiate             in host response to SARS-CoV-2 infection.
in activated plasma cells and memory cells. This process
leads to specific IgA production, which can be found all                 Materials and methods
along the upper airway tract mucosa and secretions; on the
other hand, the memory B-cells generated migrate to other                Study design
lymphoid organs, such as the spleen and local and distant                We conducted this multicentric observational cross-sec-
lymph nodes 8.                                                           tional study at 7 centres from Northern and Central Italy,
An intrinsic incapability to elicit and regulate an appropri-            areas with a high prevalence of confirmed cases at the time
ate immune response is thought to be a key element in the                of the study (University Hospital of Trieste; University
pathogenesis of recurrent tonsillitis; the resulting chronic             Hospital of Modena; Treviso Regional Hospital; IRCCS
inflammatory state further jeopardises the mutual interac-               San Raffaele Scientific Institute, Milan; Niguarda Hospital,
tion between the locoregional immune cells and with for-                 Milan; Hospital of Chioggia; Hospital of Fano) 14.
eign pathogens, leading to a vicious cycle that ends with                The study was approved by the Ethics Committee of the
failure to form an effective barrier against infective agents 9.         Friuli Venezia Giulia Region on June 16th, 2020 (CEUR-
Tonsillectomy represents one of the most frequently per-                 2020-Os-156), and informed consent was obtained verbally
formed operations by otolaryngologists and surgeons, and                 for telephone interviews. The authors received no funding
constitutes the mainstay treatment for chronic or recurrent              for the study.



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Patients                                                         sion according to previous history of tonsillectomy. Patient
Adults (≥ 18 years) assessed at the participant hospitals        characteristics hypothesised to influence outcomes, togeth-
between February 25th and May 20th, 2020, were included          er with previous tonsillectomy, were included in multivari-
if they tested positive for SARS-CoV-2 RNA by polymer-           ate analysis.
ase chain reaction on nasopharyngeal and throat swabs
performed according to the World Health Organization             Sample size calculation
recommendation 15. Criteria for exclusion were a diagno-         Sample size was determined considering patients with a
sis of cognitive impairment reported by the patient or a         previous tonsillectomy as the case group and fever as the
caregiver, and inability to answer one or more questions         event, assuming that fever is highly common among pa-
in the questionnaire.                                            tients with COVID-19 and, being a sign rather than a symp-
                                                                 tom, is less prone to patient subjective interpretation. Given
Data collection                                                  a population with a supposed prevalence of 25% of tonsil-
Data were collected from clinical charts compiled dur-           lectomies, hypothesising a prevalence of fever of 70% in
ing hospitalisation, during evaluation in the emergency          the group who had undergone tonsillectomy and of 60%
room, at the moment of the pharyngeal swab testing and           in the group who had not, it was necessary to enroll 585
updated with subsequent telephonic monitoring, which             patients, with α = 5% and power (1– b) = 95%.
was active during the state of emergency for the treated-
at-home patients and performed by trained medical per-           Statistical analysis
sonnel. Any missing information was eventually filled in
                                                                 Continuous variables were expressed as means and stand-
by trained medical personnel who recalled the patients,
                                                                 ard deviation or medians and interquartile ranges (IQR),
assessing missing demographic and anamnestic data and
                                                                 according to data distribution determined with the Shapiro-
possible common signs and symptoms of COVID-19 that
                                                                 Wilk test. Categorical variables were summarised as counts
were not reported or updated in the charts. The examined
                                                                 and percentages. No imputation was made for missing data.
items were arbitrarily chosen based on the most frequent
                                                                 In univariate analysis, Fisher’s exact test was performed for
COVID-19-associated comorbidities, signs and symptoms,
as reported by the literature at the time of the study design.   categorical variables, whereas the Mann-Whitney U test
Patients were considered affected by a coexisting disorder       was performed for continuous variables. Logistic regres-
if they had been previously diagnosed and if (one of the fol-    sion was performed in multivariate analysis; results of mul-
lowing): i) required or had required pharmacological thera-      tivariate analysis are reported as odds ratio (OR) and 95%
py; ii) led to a hospital admission; iii) treated with surgery   confidence interval (95% CI).
or with chemotherapy, radiotherapy, biological therapy, or       P values < 0.05 (two-sided) were considered statistically
other oncological therapies.                                     significant. Statistical analyses were performed using SPSS
Signs and symptoms were classified as COVID-19-related           Version 26 (IBM Corp., Armonk, NY, USA).
if they appeared de novo or as a worsening of a chronic
symptom within a period of 14 days before or after the pos-      Results
itive result of the microbiological test. Those who did not
develop new signs, symptoms, or worsening of a chronic           Patients
symptom within this period were classed as “asympto-             We recruited 779 patients. Table I shows the distribution
matic”. Interviews were conducted at least 20 days after         of patient characteristics in detail, overall and in relation to
the microbiological test in order to reduce the risk of false    previous tonsillectomy. Median age was 50.0 ± 20.1 years,
asymptomatic cases in pre-symptomatic patients.                  and 54.2% of patients were female. Active smokers ac-
                                                                 counted for 10.5%, and former smokers and non-smokers
Outcomes                                                         for 21.6% and 67.9%, respectively. About one-third of the
The primary outcome was to determine differences in              population had at least one comorbidity (38.5%), with a
the prevalence of the investigated signs and symptoms            higher prevalence of chronic cardiovascular disease or hy-
among patients who had undergone tonsillectomy and               pertension (15.9%) and obesity (13.9%).
patients who had not. Risk to develop a sign or a symp-          Tonsillectomy had been performed on 27.3% of patients.
tom according to previous history of tonsillectomy was           Tonsillectomised patients appeared to be older and with a
assessed in the multivariate analysis, together with pa-         higher prevalence of associated disorders than the non-ton-
tient characteristics.                                           sillectomised subgroup. No difference in sex distribution
Secondary outcome was risk estimation of hospital admis-         was recorded among the two groups.



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Table I. Clinical characteristics of study patients.
 Characteristic                                                       All patients                                 Tonsillectomy
                                                                        n = 779                          Yes                            No                               p
                                                                                                       n = 213                        n = 566
 Age - median (IQR)                                                   50.0 (20.1)                    55.2 (14.0)                    48.0 (19.2)                     < 0.001***
 Sex
   Male sex                                                            357 (45.8)                    106 (49.8)                     251 (44.3)                         0.20
   Female sex                                                          422 (54.2)                    107 (50.2)                     315 (55.7)
 Smoking history
   Current                                                              82 (10.5)                     21 (9.9)                       61 (10.8)                        0.79
   Former                                                              168 (21.6)                     47 (22.1)                     121 (21.4)                        0.85
   Never                                                               529 (67.9)                    145 (68.1)                     384 (67.8)                       > 0.99
 Current alcohol consumption                                           267 (34.3)                     77 (36.2)                     190 (33.6)                        0.50
 Presence of any allergy                                               271 (34.8)                     77 (36.2)                     194 (34.3)                        0.67
 BMI – median (IQR)                                                    25.0 (5.3)                    25.1 (5.6)                     24.9 (5.2)                        0.13
 Any coexisting disorder                                               300 (38.5)                    106 (49.8)                     194 (34.3)                      < 0.001***
   Obesity                                                             108 (13.9)                    36 (16.9)                      72 (12.7)                         0.13
   Chronic pneumopathy                                                  36 (4.6)                      13 (6.1)                       23 (4.1)                         0.25
   Chronic cardiovascular disease or hypertension                      124 (15.9)                    50 (23.5)                      74 (13.1)                        0.001***
   Diabetes                                                             44 (5.6)                      21 (9.9)                       23 (4.1)                        0.003**
   Immunodeficiency                                                      3 (0.4)                       1 (0.5)                        2 (0.4)                        > 0.99
   Autoimmune disease                                                   60 (7.7)                      18 (8.5)                       42 (7.4)                         0.65
   Chronic renal disease                                                11 (1.4)                       5 (2.3)                        6 (1.1)                         0.18
   Hepatopathy                                                          24 (3.1)                      10 (4.7)                       14 (2.5)                         0.16
   Cancer (current or previous)                                         21 (2.7)                       6 (2.8)                       15 (2.7)                        > 0.99
Column percentages are reported in brackets for categorical variables. p-values refer to the univariate analysis (Fisher’s exact test, Mann-Whitney’s U test). IQR: interquartile range.
BMI: body mass index. * = p < 0.05. ** = p < 0.01. *** = p < 0.001.



Tonsillectomy and SARS-CoV-2 infection                                                         0.41-1.13, p = 0.14), sore throat (OR 1.60, 95% CI 0.98-2.62,
The distribution of the examined signs and symptoms ac-                                        p = 0.06), myalgia (OR 0.93, 95% CI 0.61-1.43, p = 0.76),
cording to previous tonsillectomy and related univariate                                       dizziness (OR 1.12, 95% CI 0.57-2.21, p = 0.75), headache
analysis are summarised in Table II. Tonsillectomised pa-                                      (OR 1.12, 95% CI 0.73-1.72, p = 0.60), nausea (OR 0.62,
tients showed a significantly higher prevalence of fever,                                      95% CI 0.33-1.14, p = 0.12), diarrhoea (OR 1.16, 95% CI
temperature greater than 39°C and shortness of breath, with                                    0.75-1.80, p = 0.51). Odds to have an asymptomatic course
a lower rate of nasal congestion and myalgia compared to                                       did not differ between tonsillectomised and non-tonsillecto-
patients who did not undergo tonsillectomy.                                                    mised patients (OR 1.26, 95% CI 0.53-3.00, p = 0.60).
Table III summarises the results of multivariate analysis,
showing the signs and symptoms at augmented risk to be                                         Tonsillectomy and risk of hospitalisation
developed in case of previous tonsillectomy. Patients with                                     While previous tonsillectomy was more prevalent among
a previous history of tonsillectomy showed greater risk to                                     patients admitted to hospital, tonsillectomised patients did
report fever and to reach temperatures higher than 39°C.                                       not show an increased risk for admission at the multivariate
An increased risk for chills and malaise was also observed.                                    analysis (Tab. IV).
The association with nasal congestion was lost.
Tonsillectomised patients did not show an increased risk to
                                                                                               Discussion
develop the other investigated signs and symptoms: cough
(OR 1.06, 95% CI 0.69-1.63, p = 0.78), shortness of breath                                     In our study, we wanted to explore the possibility that a
(OR 1.35, 95% CI 0.86-2.11, p = 0.19, confusion (OR 1.58,                                      previous tonsillectomy, as an indicator of chronic tonsillitis
95% CI 0.87-2.90, p = 0.14), rhinorrhoea (OR 0.99, 95%                                         and possibly of immunological dysfunction of the Waldey-
CI 0.58-1.70, p = 0.98), nasal congestion (OR 0.68, 95% CI                                     er’s ring, could reflect the underlying characteristic of the



200
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Table II. Distribution of COVID-19-related signs and symptoms.
 Signs and symptoms                                       All patients                                             Tonsillectomy
                                                                        n = 779                          Yes                            No                                p
                                                                                                       n = 213                        n = 566
 Asymptomatic                                                            46 (5.9)                       13 (6.1)                       33 (5.8)                        0.87
 Fever                                                                 508 (65.2)                     156 (73.2)                     352 (62.2)                       0.004**
 T > 39°C                                                               82 (10.5)                      36 (16.9)                       46 (8.1)                       0.001**
 Cough                                                                 411 (52.8)                     113 (53.1)                     298 (52.7)                        0.94
 Shortness of breath                                                   239 (30.7)                     80 (37.6)                      159 (28.1)                        0.01*
 Chills                                                                255 (32.7)                      76 (35.7)                     179 (31.6)                        0.30
 Malaise                                                               423 (54.3)                     124 (58.2)                     299 (52.8)                        0.20
 Confusion                                                              89 (11.4)                     30 (14.1)                       59 (10.4)                        0.17
 Rhinorrhoea                                                           150 (19.3)                     37 (17.4)                      113 (20.0)                        0.48
 Nasal congestion                                                      193 (24.8)                     40 (18.8)                      153 (27.0)                        0.02*
 Sore throat                                                           180 (23.1)                      53 (24.9)                     127 (22.4)                        0.51
 Myalgia                                                               385 (49.4)                     92 (43.2)                      293 (51.8)                        0.04*
 Dizziness                                                              78 (10.0)                       19 (8.9)                      59 (10.4)                        0.59
 Headache                                                              343 (44.0)                      87 (40.8)                     256 (45.2)                        0.29
 Nausea                                                                126 (16.2)                     29 (13.6)                       97 (17.1)                        0.28
 Diarrhoea                                                             260 (33.4)                     77 (36.2)                      183 (32.3)                        0.35
 Smell disturbance                                                     446 (57.3)                     113 (53.1)                     333 (58.8)                        0.17
 Taste disturbance                                                     446 (57.3)                     113 (53.1)                     333 (58.8)                        0.17
Column percentages are reported in brackets for categorical variables. p-values refer to the univariate analysis (Fisher’s exact test). * = p < 0.05. ** = p < 0.01. *** = p < 0.001.



patient pharyngeal MALT and related COVID-19 manifes-                                           frequently infected palatine tonsils compared to healthy
tations.                                                                                        controls, such as a different composition of the antigen-
In our population, tonsillectomised patients showed an in-                                      presenting cell (APC) population, a reduced capability in
creased risk of developing fever and temperatures higher                                        regulating the inflammatory response and decreased IgA
than 39°C, along with malaise and chills. It is plausible that                                  and IgM production 13.
malaise and chills were consequences of the fever and its                                       Frequently infected tonsils show an abnormal distribution
intensity, reflecting a more intense systemic involvement.                                      of activated dendritic cells (DCs), the most efficient APC,
Patients with previous history of tonsillectomy were older                                      which appear superficially concentrated on the lympho-ep-
and with more coexisting disorders than those who did not                                       ithelium in addition to the interfollicular T-cell areas: this
receive the operation. However, even accounting for these                                       suggests an increased production of inflammatory media-
possible confounding factors in the multivariate logistic                                       tors and chemotactic dysregulation 16-18. DCs also medi-
regression, tonsillectomised patients still showed a greater                                    ate B-/T-cell interaction, which results in the selection
risk to express a more intense systemic response to the vi-                                     of specific activated B-cells, memory B-cells and anti-
rus. In the multivariate analysis, p-values associated with                                     inflammatory T-cell-derived cytokines such as IL-10 19:
augmented risk to develop fever and temperatures higher                                         impairment of the role of DC could undermine these es-
than 39°C were far below the value of 0.05 set for signifi-                                     sential immune functions in patients with chronic tonsil-
cance (p = 0.003 and p < 0.001, respectively), bypassing                                        litis 13.
the possible over-powering effect of our large sample and                                       Moreover, tonsils subjected to chronic inflammation show
giving strength to our hypothesis.                                                              a reduced production of anti-inflammatory cytokines and a
As mentioned above, tonsillectomy itself is probably an in-                                     lowered tolerance to viral infections compared to isolated
dicator rather than the cause of a decreased Waldeyer’s ring                                    hyperplasia. In a study by Mikola et al., tonsillar mRNA
immune function; its activity of defense and inflammatory                                       expression of IL-37, a fundamental inhibitor of innate im-
regulation is furtherly worsened by chronic infections that                                     munity and inflammatory cytokines, appeared to be di-
eventually lead to a vicious cycle and to surgical removal 8.                                   minished in the chronic tonsillitis group when adjusted for
Significant differences have been demonstrated between                                          age 20. Additionally, B-regulatory cells suppress effector



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Table III. COVID-19-related signs and symptoms affected by history of previous tonsillectomy.
 Characteristic                             Fever                         T > 39°C                                           Chills                            Malaise
 Tonsillectomy                                  2.06           0.003**             3.68          < 0.001***           1.71              0.02*             1.71             0.02*
                                            (1.27-3.33)                        (2.04-6.63)                        (1.10-2.65)                         (1.10-2.65)
 Age                                            1.00             0.68              1.00              0.64             0.99              0.83              0.99              0.35
                                            (0.99-1.01)                        (0.98-1.02)                        (0.98-1.01)                         (0.98-1.01)
 Female sex                                     0.47          < 0.001***           0.52             0.02*             1.29              0.80              1.29              0.13
                                            (0.34-0.67)                        (0.30-0.89)                        (0.93-1.78)                         (0.93-1.78)
 Smoking history                                               0.001**                               0.72                             0.007*                              0.006*
   Current                                      0.39          < 0.001***           0.92              0.86              0.46           0.002**             0.46            0.002**
                                            (0.24-0.63)                        (0.39-2.17)                         (0.28-0.76)                        (0.28-0.76)
    Former                                      0.96             0.85              1.24              0.46              1.07             0.73              1.07              0.73
                                            (0.65-1.43)                        (0.70-2.20)                         (0.74-1.55)                        (0.74-1.55)
 Alcohol consumption                            0.93             0.69              0.87              0.62              1.70             0.72              1.70            0.002**
                                            (0.65-1.43)                        (0.51-1.49)                         (1.22-2.38)                        (1.22-2.38)
 Allergies                                      1.20             0.27              1.22              0.44              1.06             0.55              1.06              0.71
                                            (0.87-1.67)                        (0.73-2.03)                         (0.78-1.45)                        (0.78-1.45)
 Body mass index                                1.00             0.92              1.01              0.79              0.99             0.85              0.99              0.68
                                            (0.95-1.05)                        (0.93-1.10)                         (0.94-1.04)                        (0.94-1.04)
 Any coexisting disorder                        0.82             0.53              1.53              0.30              0.95             0.58              0.95              0.86
                                            (0.45-1.51)                        (0.68-3.43)                         (0.54-1.68)                        (0.54-1.68)
    Obesity                                     1.29             0.51              1.30              0.61              1.69             0.96              1.69              0.14
                                            (0.61-2.71)                        (0.48-3.55)                         (0.84-3.41)                        (0.84-3.41)
    Pneumopathy                                 0.84             0.66              0.83              0.75              0.64             0.39              0.64              0.25
                                            (0.38-1.85)                        (0.26-2.64)                         (0.29-1.38)                        (0.29-1.38)
    Cardiovascular disease or                   1.35             0.32              0.97              0.94              0.98             0.60              0.98              0.94
    hypertension                            (0.74-2.44)                        (0.46-2.03)                         (0.57-1.69)                        (0.57-1.69)
    Diabetes                                    1.10             0.82              1.49              0.39              2.48             0.61              2.48             0.02*
                                            (0.49-2.46)                        (0.60-3.68)                         (1.13-5.45)                        (1.13-5.45)
    Immunodeficiency                            0.60             0.70              0.00            > 0.99              1.16             0.60              1.16              0.91
                                            (0.04-8.37)                          (0.00 - .)                       (0.08-16.74)                       (0.08-16.74)
    Autoimmune disease                          1.43             0.33              0.98              0.97              0.87             0.49              0.87              0.68
                                            (0.70-2.93)                        (0.37-2.59)                         (0.45-1.69)                        (0.45-1.69)
    Renal disease                               1.25             0.78              0.65              0.70              2.36             0.19              2.36              0.31
                                            (0.27-5.78)                        (0.07-5.80)                        (0.45-12.52)                       (0.45-12.52)
    Hepatopathy                                 3.52             0.05              2.15              0.16              1.24             0.19              1.24              0.65
                                           (0.99-12.55)                        (0.75-6.18)                         (0.49-3.12)                        (0.49-3.12)
    Cancer (current or previous)                1.22             0.71              1.57              0.52              2.03             0.94              2.03              0.18
                                            (0.44-3.39)                        (0.40-6.28)                         (0.73-5.63)                        (0.73-5.63)
Results of the multivariate logistic regression. Odds ratio (95% confidence interval) and p-values for each variable are reported. * = p < 0.05. ** = p < 0.01. *** = p < 0.001.



T-cells and other lymphocytes via production of IL-10, IL-                                    tonsils in mediating the production of secretive antibodies
35 and TGF-β, and they are involved in supporting immu-                                       and local clearance of the virus 23.
nological tolerance. These cells are distributed among all                                    All these features, together with the components of the in-
human lymphoid tissues, including the palatine and naso-                                      nate immunity hosted by pharyngeal MALT, are involved
pharyngeal tonsils 21.                                                                        in the response against viruses and have a role in the inter-
Finally, the impaired secretion of IgM and IgA finds its                                      individual variability of the manifestation and transmission
molecular counterpart in a reduced cytoplasmatic expres-                                      of COVID-19 5, as our findings appear to support.
sion of the J-chain, a peptide implied in the formation of                                    For what concerns the severity and clinical course of the
the cited polymeric immunoglobulins, among youngsters                                         disease, assuming hospital admission as a surrogate indi-
with recurrent tonsillitis 22. In the possibility of routine ap-                              cator of severity, no significant differences emerged be-
plication of a rapid salivary SARS-CoV-2 screening test,                                      tween tonsillectomised and non-tonsillectomised patients.
it might be necessary to take into account the role of the                                    This finding, representing the secondary outcome of our



202
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Table IV. Distribution of patient characteristics according to clinical course and risk of hospital admission.
 Characteristic                                  Treated at home          Admitted to hospital Univariate analysis                                  Multivariate analysis

                                                            n (%) =                      n (%) =                          p                    OR (95% CI)                   p
                                                           668 (85.8)                   111 (14.2)
 Age                                                       48.0 (19.0)                 62.3 (19.1)                   < 0.001***             1.07 (1.05-1.09)            < 0.001***
 Sex
   Male                                                    283 (42.4)                   74 (66.7)                    < 0.001***             2.33 (1.37-3.98)              0.002**
   Female                                                  385 (57.6)                   37 (33.3)                                                  Ref                       -
 Smoking history                                                                                                                                    -                      0.01*
   Current                                                  79 (11.8)                    3 (2.7)                      0.002**               0.26 (0.07-0.92)               0.04*
   Former                                                  126 (18.9)                   42 (37.8)                    < 0.001***             1.62 (0.97-2.69)               0.07
   Never                                                   463 (69.3)                   66 (59.5)                      0.05                        Ref                       -
 Current alcohol consumption                               208 (31.1)                   59 (53.2)                    < 0.001***             1.37 (0.83-2.24)               0.22
 Presence of any allergy                                   243 (36.4)                   28 (25.2)                      0.02*                0.68 (0.40-1.14)               0.15
 BMI                                                       24.7 (5.2)                   26.8 (5.2)                   < 0.001***             1.01 (0.93-1.10)               0.78
 Any coexisting disorder                                   232 (34.7)                   68 (61.3)                    < 0.001***             2.43 (1.12-5.29)               0.03*
   Obesity                                                  85 (12.7)                   23 (20.7)                      0.04*                1.07 (0.40-2.87)               0.89
   Chronic pneumopathy                                       29 (4.3)                    7 (6.3)                       0.33                 1.10 (0.38-3.18)               0.86
   Chronic cardiovascular disease or                        96 (14.4)                   28 (25.2)                     0.007**               0.42 (0.21-0.85)               0.02*
   hypertension
   Diabetes                                                 33 (4.9)                    11 (9.9)                       0.05                  0.47 (0.19-1.20)              0.12
   Immunodeficiency                                          3 (0.4)                    0 (0.0%)                       1.00                    0.00 (0.00-.)              > 0.99
   Autoimmune disease                                       51 (7.6)                     9 (8.1)                       0.85                  1.03 (0.40-2.61)              0.96
   Chronic renal disease                                     6 (0.9)                     5 (4.5)                       0.01*                4.99 (1.05-23.83)              0.04*
   Hepatopathy                                              18 (2.7)                     6 (5.4)                       0.14                  0.79 (0.25-2.54)              0.69
   Cancer (current or previous)                             12 (1.8)                     9 (8.1)                      0.001**                1.50 (0.48-4.71)              0.49
 Tonsillectomy                                             171 (25.6)                   42 (37.8)                      0.01*                 1.38 (0.75-2.53)              0.30
Counts (column percentages) are reported in brackets for categorical variables, medians (interquartile range) are reported for continuous variables. Results of the univariate (Fisher’s
exact test, Mann-Whitney’s U test) and multivariate (logistic regression) analysis are reported, with related p-values. BMI: Body Mass Index. OR: odds ratio. 95% CI: 95% confidence
interval. * = p < 0.05. ** = p < 0.01. *** = p < 0.001.



work, may have been partially biased by the impossibility                                      ment of the pharyngeal lymphoid tissues led to both chronic
to retrieve accurate data from those who died, as well as                                      tonsillitis and tonsillectomy in the past, and now the same
the lack of other surrogate indicators such as hospitalisa-                                    dysfunction could be responsible for an altered response
tion time, complication rate and the small percentage of                                       to SARS-CoV-2. An uncontrolled inflammatory reaction
asymptomatic subjects. A more inclusive cohort account-                                        to the virus, mediated by a dysfunctional Waldeyer’s ring,
ing for all the above-mentioned biases and possible in-                                        could have led to fever, higher temperatures and associated
dicators of severity and complications may be necessary                                        symptoms. From this perspective, previous tonsillectomy
to specifically clarify the possible role of Waldeyer’s ring                                   as an indicator of an impaired immunological activity of
status on the global severity and clinical course of the dis-                                  pharyngeal MALT could be regarded as a predictor of an
ease.                                                                                          altered host response to SARS-CoV-2 infection. Vice-ver-
Our results seem to corroborate a potentially independ-                                        sa, people with a functional Waldeyer’s ring could develop
ent role of pharyngeal-associated lymphoid organs in the                                       more subtle and less intense symptoms, possibly leading to
host response to SARS-CoV-2 infection. The fundamental                                         lack of identification of viral carriers.
importance of these organs in patrolling the upper airways                                     As tonsillectomy is frequently performed and has a high
against SARS-CoV-2 and other infective agents has been                                         prevalence in general population, this anamnestic informa-
widely recognised 5. The higher prevalence of systemic                                         tion may take on potential relevance in the context of the
signs and symptoms in the tonsillectomised patients in our                                     COVID-19 pandemic 10. If these findings are confirmed
cohort can be explained hypothesising that intrinsic impair-                                   by further studies, investigating history of previous tonsil-



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V. Capriotti et al.




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