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\begin{document}

\title{Hearing loss after bacterial meningitis, a retrospective study}



\author[1]{Filip Persson}%
\author[1]{Nora Bjar}%
\author[1]{Ann Hermansson}%
\author[1]{Marie Gisselsson-Solen}%
\affil[1]{Lund Univ Hosp}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\sloppy


\textbf{Key points}

\begin{itemize}
\tightlist
\item
  Meningitis is a life-threatening infection which may develop as a
  complication to acute otitis media
\item
  The most common sequela after meningitis is hearing loss, but risk
  factors for hearing loss have not been studied to any great extent.
\item
  When all cases of meningitis (n=187) occurring in a Swedish county
  during 18 years (2000-2017) were investigated, 71 cases of hearing
  loss were identified, however 68 of the patients had not done a
  hearing test after recovery.
\item
  Hearing loss was significantly more common in adults, occurring in
  45\% in patients aged 21-65 years and in 48\% in patients over the age
  of 65 when assuming that those who had not done a hearing test had
  normal hearing. This corresponded to ORs of 8.0 and 9.8 compared to
  children.
\item
  Concurrent acute otitis media and pneumococcal infection increased the
  odds of hearing loss by 2.1 and 3.6, respectively.
\end{itemize}

\section*{Introduction}

{\label{introduction}}

Meningitis is a life-threatening infection which sometimes occurs as a
complication to acute otitis media (AOM). It is not entirely known what
percentage of bacterial meningitis is of otogenic origin. A Dutch study
found that the most common agents causing community-acquired meningitis
was \emph{Streptococcus pneumoniae} (53\%), and \emph{Neisseria
meningitidis} (37\%), and that concurrent AOM was a risk factor for
negative outcome, indicating the importance of prompt ear examination
(1). A French study of children with bacterial meningitis also
identified \emph{S. pneumoniae} (39\%) and \emph{N. meningitidis} (39\%)
as the most important pathogens(2).

The most common sequela after bacterial meningitis is hearing loss(3).
This is particularly common after pneumococcal meningitis, where as many
as 30\% of patients suffer from hearing loss(3). Some studies have found
lower incidences (7-12\%) of post-meningitis hearing loss in children
compared to adults(4, 5), whereas others have reported similar
incidences(6). Animal research has shown a correlation between
pneumococcal concentration in the middle ear and the development of
hearing loss(7), indicating that early diagnosis of concurrent AOM and
subsequent myringotomy could be beneficial. Swedish meningitis
guidelines include a recommendation to perform otoscopy in all patients
with meningitis, and to follow up patients with audiometry.

The aim of this study was to investigate the incidence of hearing loss
in patients treated for bacterial meningitis in the Swedish county of
Sk\selectlanguage{ngerman}åne (1.4 million inhabitants), between 2000 and 2017 and to
investigate risk factors for hearing loss.

\section*{Materials and methods}

{\label{materials-and-methods}}

In this retrospective, observational study, medical records from all
patients admitted to hospitals in Skåne county with the ICD-code G00
(bacterial meningitis) between 2000 and 2017 were retrieved. Exclusion
criteria were neonatal, viral, fungal or non-infectious meningitis,
borrelia, nosocomial, postoperative, or ventricular shunt-related
infections.

Information about gender, age, otoscopy results, CT/MRI signs of middle
ear infection, microbiological results, subjective hearing loss and
hearing tests were extracted from medical charts. Where pure tone
audiograms were available, pure tone averages (PTA4; defined as the
average of hearing thresholds at 500, 1000, 2000 and 4000 Hz) were
extracted, as was presence of conductive hearing loss (defined as an
air-bone gap of \selectlanguage{english}[?]10 dB on at least two adjacent frequencies). Hearing
loss was defined as PTA4 \selectlanguage{english}[?] 25 on either ear, and further subdivided into
mild (25-40 dB HL), moderate (41-70 dB HL) and severe (\textgreater{}70
dB HL). High frequency hearing was evaluated by calculating the average
hearing thresholds at 6000 and 8000 Hz.

By including data over 18 years in one of the most populous counties in
Sweden, we hoped to be able to estimate the incidence of bacterial
meningitis in Sweden over a long period of time. The proportion of
otogenic meningitis cases, time trends, microbiology and outcomes other
than hearing loss will be reported separately.

The study was approved by the Ethics Review Authority. The STROBE
guideline was used for the preparation of the manuscript.

\emph{Statistical analyses}

Data was analysed using Stata 16.1 (College Station, Tx, USA). The
association between sensorineural hearing loss and possible risk factors
were investigated using uni- and multivariate logistic regression.
Variables showing a substantial association with the outcome in the
univariate analysis were kept in the multivariate analysis. To evaluate
the effect of age, patients were divided into four age groups; children
(0-11 years), teenagers (12-21 years), adults of working age (22-65
years), and elderly (over 65 years).

In a substantial number of patients (n=68), hearing tests were not
performed. In order not to overestimate the prevalence of hearing loss
by only including patients with hearing tests, data for all patients
were used, making the conservative assumption that patients lacking
hearing tests had normal hearing.

\textbf{Results}

Initially, 556 patients were identified. After applying exclusion
criteria, 187 patients remained (Figure 1), 106 of whom were men. The
age distribution is shown in Table 1. Hearing tests were available in
119 cases, 107 of which were pure tone audiometries. Hearing loss was
diagnosed in 81 patients, in 13 cases unilaterally, and was more common
in adults and elderly (Table 1). Three patients had bilateral severe
hearing loss, and an additional 13 had unilateral severe hearing loss.
Of the 105 patients where data for 6 and 8 kHz were available, hearing
thresholds \textgreater{}40 dB on these frequencies occurred frequently
in adult patients, however, never in children or teenagers (Table1). The
most commonly identified bacteria were \emph{S. pneumoniae} (58\%)
and\emph{N. meningitidis} (12\%) (Table 2).

In the univariate analysis, there was no evidence of a correlation
between gender and hearing loss, however, there was strong evidence of
adult and elderly patients having greatly increased odds of hearing loss
(OR=7.3, p=0.01 and OR=8.4, p=0.007).

There was also evidence that patients with pneumococcal infection had
increased odds of hearing loss (OR=4.1, p\textless{}0.001). On the other
hand, patients with meningococcal infections had decreased odds of
hearing loss (OR=0.2, p=0.009). There was also evidence for an
association between hearing loss and concurrent AOM (OR=3.3,
p\textless{}0.001).

Age, concurrent AOM and presence of \emph{S. pneumoniae} /\emph{N.
meningitidis} was kept in the multivariate analysis (Table 3). There was
still strong evidence that age was a risk factor for hearing loss.
Patients with concurrent AOM had twice the odds of hearing loss, and for
those with pneumococcal infection, the odds increased 3.6-fold. In the
multivariate analysis, no association was seen between meningococcal
infection and hearing loss.

\par\null

\textbf{Discussion}

In this retrospective study, which comprised data from an entire Swedish
county during 18 years, post-meningitis hearing loss was associated with
age, pneumococcal infection and concurrent AOM. Despite recommendations
in the national guidelines, more

than a third of patients had not done a hearing test after recovery.

The main outcome in this study was post-meningitis hearing loss. Even
when we assumed that patients lacking audiometry had normal hearing, as
many as 43\% had hearing loss. This is a higher prevalence than the 30\%
wich has been described previously(3). This might, in part, be explained
by different definitions of hearing loss, and by some patients in the
present study having had previously undiagnosed hearing loss. The
conservative assumption that patients lacking audiometries had normal
hearing should at least not lead to an over-estimation of the prevalence
of hearing loss, and it seems reasonable to suppose that patients who
complained about hearing loss in the recovery period should have been
tested.

An obvious finding in this study was the increased risk for adults and
elderly of developing hearing loss. Age \textgreater{}70 years has
previously been associated with an ``unfavourable outcome''(8), Since
most patients in this study had not tested their hearing prior to their
meningitis, the finding might, at least partly, be explained by the fact
that the prevalence of hearing loss increases with age. Some patients
might therefore have had previously undiagnosed presbyacusis. This risk
should partly be alleviated by our assumption that all patients in whom
hearing tests were missing had normal hearing. Missing audiometries were
not less common among the older age group (data not shown).

The correlation between AOM and hearing loss seems to have been partly
confounded by pneumococcal infection, since it decreased in the
multivariate analysis, however, the odds of hearing loss was still twice
as high among patients with AOM in the multivariate analysis. A Dutch
study also found that the odds of hearing loss increased by 2.6 in
patients with concurrent AOM (9).

\emph{S. pneumoniae} -- a common otopathogen - increased the odds of
hearing loss almost four-fold after controlling for other risk factors.
That patients with pneumococcal meningitis are more likely to develop
long-term hearing loss has been noticed in a previous meta-analysis as
well as in a retrospective review on children(3, 10). The negative
association between meningococcal infection and hearing loss in the
univariate analysis was not present in the multivariate analysis,
indicating the former results were confounded by age, meningococcal
infections being almost exclusively found among children and teenagers
(data not shown).

This study has several limitations, one of which is the retrospective
design, meaning that many patients did not undergo hearing tests. In
addition, most patients had not done hearing tests before their
meningitis, so there was no way of knowing for certain that the hearing
loss was caused by the meningitis. The design also means that
microbiological PCR tests and serotyping were not performed.

A strength of the study is that it encompasses a whole county of Sweden
during a period of 18 years, implying that the results should be
generalisable.

Better knowledge of risk factors for post-meningitis hearing loss can
hopefully result in better compliance with existing guidelines, leading
to more patients undergoing otoscopy when admitted to hospital with
bacterial meningitis, and more patients being followed up audiologically
after recovery. As discussed above, early diagnosis of concurrent AOM,
and subsequent myringotomy might decrease the risk of developing hearing
loss.

\textbf{Conclusion}

This study showed that the incidence of hearing loss after bacterial
meningitis was strongly associated with age, but also with concurrent
acute otitis media and \emph{S. pneumoniae} infection. In an on-going
prospective study on the same population, we hope to be able to confirm
the findings more robustly.

\section*{References}

{\label{references}}

1. van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB,
Vermeulen M. Clinical features and prognostic factors in adults with
bacterial meningitis. N Engl J Med. 2004;351(18):1849-59.

2. Bargui F, D'Agostino I, Mariani-Kurkdjian P, Alberti C, Doit C,
Bellier N, et al. Factors influencing neurological outcome of children
with bacterial meningitis at the emergency department. Eur J Pediatr.
2012;171(9):1365-71.

3. Edmond K, Clark A, Korczak VS, Sanderson C, Griffiths UK, Rudan I.
Global and regional risk of disabling sequelae from bacterial
meningitis: a systematic review and meta-analysis. Lancet Infect Dis.
2010;10(5):317-28.

4. Chandran A, Herbert H, Misurski D, Santosham M. Long-term sequelae of
childhood bacterial meningitis: an underappreciated problem. Pediatr
Infect Dis J. 2011;30(1):3-6.

5. Richardson MP, Reid A, Tarlow MJ, Rudd PT. Hearing loss during
bacterial meningitis. Archives of Disease in Childhood. 1997;76(2):134.

6. Kutz JW, Simon LM, Chennupati SK, Giannoni CM, Manolidis S. Clinical
predictors for hearing loss in children with bacterial meningitis. Arch
Otolaryngol Head Neck Surg. 2006;132(9):941-5.

7. Perny M, Roccio M, Grandgirard D, Solyga M, Senn P, Leib SL. The
Severity of Infection Determines the Localization of Damage and Extent
of Sensorineural Hearing Loss in Experimental Pneumococcal Meningitis. J
Neurosci. 2016;36(29):7740-9.

8. Tubiana S, Varon E, Biron C, Ploy MC, Mourvillier B, Taha MK, et al.
Community-acquired bacterial meningitis in adults: in-hospital
prognosis, long-term disability and determinants of outcome in a
multicentre prospective cohort. Clin Microbiol Infect.
2020;26(9):1192-200.

9. Heckenberg SG, Brouwer MC, van der Ende A, Hensen EF, van de Beek D.
Hearing loss in adults surviving pneumococcal meningitis is associated
with otitis and pneumococcal serotype. Clin Microbiol Infect.
2012;18(9):849-55.

10. Woolley AL, Kirk KA, Neumann AM, Jr., McWilliams SM, Murray J,
Freind D, et al. Risk factors for hearing loss from meningitis in
children: the Children's Hospital experience. Arch Otolaryngol Head Neck
Surg. 1999;125(5):509-14.



\section*{Tables and figures}

{\label{tables-and-figures}}

\textbf{Hosted file}

\verb`image1.emf`  available at \url{https://authorea.com/users/737566/articles/712443-hearing-loss-after-bacterial-meningitis-a-retrospective-study}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{Bacterium} & \textbf{Patients (\%)}\tabularnewline
\midrule
\endhead
S. pneumoniae & 108 (58)\tabularnewline
N. meningitidis & 23 (12)\tabularnewline
S. pyogenes & 6 (3)\tabularnewline
S. aureus & 7 (4)\tabularnewline
Listeria monocytogenes & 5 (3)\tabularnewline
H. influenzae type B & 8 (4)\tabularnewline
Group B streptococci & 3 (2)\tabularnewline
Other & 8 (4)\tabularnewline
No growth & 19 (10)\tabularnewline
\bottomrule
\end{longtable}

Table 2. Bacteriological findings\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& Odds Ratio & 95\%CI & p\tabularnewline
0-11 years & ref & - & -\tabularnewline
12-21 years & 0.7 & 0.05-9.9 & 0.8\tabularnewline
22-65 years & 8.0 & 1.7-38.4 & 0.009\tabularnewline
65+ years & 9.8 & 2.0-47.9 & 0.005\tabularnewline
AOM & 2.1 & 1.04-4.4 & 0.040\tabularnewline
\emph{S. pneumoniae} & 3.6 & 1.7-7.8 & 0.001\tabularnewline
\emph{N. meningitidis} & 1.8 & 0.4-8.9 & 0.5\tabularnewline
\bottomrule
\end{longtable}

Table 3. Correlation between risk factors and the development of
sensorineural hearing loss after bacterial meningitis, multivariate
logistic regression with adjustments for agegroup, AOM and
pneumococcal/meningococcal infection.

Figure 1. Patient flow chart\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Table-1-meningitis-hearingloss/Table-1-meningitis-hearingloss}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Table-2-meningitis-hearingloss/Table-2-meningitis-hearingloss}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Table-3-meningitis-hearingloss/Table-3-meningitis-hearingloss}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1-Meningitis-hearingloss/Figure-1-Meningitis-hearingloss}

\end{center}
\end{figure}

\selectlanguage{english}
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