Hearing Impairment in Angolan Children with Acute Bacterial Meningitis With and Without Otitis Media and Otorrhea

Background: Bacterial meningitis (BM) is a common cause of hearing loss in childhood. Our aim was to investigate bacterial etiology, hearing impairment, and outcome in childhood BM with vs. without otitis media (OM) in the resource-poor settings of Angola. Methods: Hearing was tested through brainstem-evoked response audiometry (ABR) in 391 (76%) of 512 children with conrmed BM. The bacteria identied from the ear discharge were compared to those from CSF and the relevance of ndings was examined in terms of hearing among children with or without OM on day 1 and 7 of hospitalization, and at follow-ups of 1, 3 and 6 month(s). Results: No correlation was found in bacteriology between the ear discharge and CSF, and the most common ear pathogens more likely reected chronic than acute middle ear infections. On day 7 in hospital, hearing impairment (>40 dB) was common, regardless of whether concomitant OM or not (in 27% vs. 30%, respectively), whereas on day 7, profound hearing loss (>80 dB) was diagnosed slightly more in children without OM 16% vs. 10% accordingly. Any hearing decit on day 7 was associated with a higher risk of complicated or fatal clinical course (OR 2.76, CI 95% 1.43-5.29, P = .002). Conclusion: No signicant difference prevailed in hearing thresholds between children with or without OM in hospital on day 7 or at later follow-ups. Any hearing impairment on day 7 associated with a higher risk for complicated clinical course or death.


Results
Otoscopy was conducted, and the middle ear status recorded for 512 (out of 723) BM patients. Of these, 450 children (88%) did not have OM (non-OM) while 62 children had OM (39 with otorrhea). The middle ear status remained unexplored if thick wax prevented otoscopy -no suction device for its removal was available. One child diagnosed with dry tympanic membrane perforation was excluded because of no signs of acute infection.
Hearing was successfully tested for 391 of 512 children; this group met the inclusion criteria of this study. Of these children, 342 were non-OM while 49 children had OM. There were 225 boys (58%), the median age was 13 months (range 2 months to 13 years); 183 (47%) were infants (under 12 months).
If ABR was not available for the one month follow-up visit, hearing was tested either by asking questions on 13% (n = 21/168) patients or measured by OAEs on 11% (n = 19/168) patients.

Bacteriology
Bacterial culture results of the ear discharge are found in Table 1, whereas Table 2 projects the discharge cultures against the otorrhea patients' outcomes. The discharge samples were cultured in hospital for only 36% (n = 14 of 39) children who had otorrhea and were positive in 93% of these cases (n = 13 of 14); the one patient with no growth had received prior antibiotics. The most common pathogens were Proteus vulgaris (n = 6, 33%), followed by Pseudomonas aeruginosa (n = 3, 17%), unidenti ed Gram-negative bacilli (n = 3, 17%) and Klebsiella (n = 2, 11%). Enterobacter, Proteus mirabilis and Citrobacter freundii were found in one patient (6%) each. Detection of a single organism was more common 64% (n = 9 of 14) than nding of a mixed/multiple etiology ( Table 2). Single cultures were found for Proteus vulgaris (n = 4), Pseudomonas aeruginosa, Proteus mirabilis, Citrobacter freundii and gram-negative bacilli. Of all pathogens cultured from the ear discharge, 50 % (n = 9/18) were resistant to the antibiotic used for the particular patient. Of the 13 otorrhea patients with positive ear discharge culture, seven (54%) also showed positive CSF culture. These included S. pneumoniae (n = 5, 38%), H. in uenzae (n = 1, 8%), and Proteus (n = 1, 8%), this agent being the only one identi ed in both CSF and ear discharge. Focal neurological signs were diagnosed in 10 (77%) of the 13 children with otorrhea, mainly being the cranial nerves affected with subsequent strabismus, ptosis and facial paresis. One child aged 8 year 7mth was diagnosed with osteomyelitis and mastoiditis. Table 3 presents the results of all the ears´ hearing threshold levels (80 dB, 60 dB and 40 dB) in patients with or without OM, at hospital or at the follow-up visits (1, 3 and 6 months). On day 1, deafness (> 80dB) was diagnosed less often in patients with OM (15%, n = 15/98) than among those with non-OM (25%, n = 170/683) (P = .04). However, on day 7, no difference was found anymore in one-ear deafness (> 80 dB) between patients with OM vs.  Table 3 The hearing thresholds levels of 40 dB, 60 dB, 80 dB and deaf (> 80 dB) tested by ABR in all ears of the children diagnosed with bacterial meningitis with normal middle ear (Non-OM) versus those with concomitant otitis media (OM)* or otorrhea

Discussion
In this study, our aim was to investigate bacterial etiology, hearing impairment, and outcome in childhood BM with vs. without otitis media (OM) in the resource-poor settings of Angola. In our results, hearing de ciency was common, being diagnosed in a third of the children a after a week BM diagnosis. In previous results from this clinical trial data 19 21 . In both study a part of the patient was excluded from the study because of the middle ear disease.
Karppinen et al. results showed that S. pneumoniae was the most common cause of impaired hearing at > 60dB threshold among infants and it caused deafness more often than Hib and N. meningitidis 16 . In our study, there was no difference in hearing between children with or without OM on day 7, or later at the follow-ups of 1, 3 and 6 months. However, any hearing impairment or full deafness a week after the BM diagnosis showed a higher risk for complicated or fatal clinical course.
According to the literature review from Africa, the most common micro-organisms in children causing CSOM are Proteus sp (22-43%), Staphylococcus spp.
(37%), Pseudomonas spp. (13-15%) and S. aureus (5-14%) 22 . We found that the most common pathogen causing otorrhea was Proteus, which is in correspondence with the literature review from Africa 22 . In studies from Kenya for instance, Proteus is frequently detected as the most common agent causing otorrhea among children and young adults 23,24 . In our study, the most common pathogens found in the ear discharge of the children with BM were likely to be related more to chronic than acute middle ear infections.
Barry et al. who found in their study on otogenic intracranial complications that the ear and the CSF specimens only grew the same pathogen in 17% 25 . In line with those ndings, we also found no correlation between the bacteriology of the ear discharge vs. that of CSF. Thus, bacterial OM may occurs coincidentally with BM 25 .
Antibiotics, conjugate vaccines for the three major causes of bacterial meningitis in children aged less than 5 years (HIB, Streptococcus pneumoniae and Neisseria meningitidis), early innovative surgical techniques to treat the complications of OM, an increase in social welfare, and the development of health care systems have resulted in a dramatical reduction of ICC rates in industrialized countries. However, the diagnostics and management of OM still cause ≥ ≥ ≥ major challenges in developing countries, and the growing bacterial resistance to antibiotics is also cause for concern. The prevention of OM, and its complications, remains the most effective way to reduce signi cant morbidity and mortality caused by OM-associated BM in developing countries.
Even if BM is the most common (12-72%) intracranial complication of OM 3-5 , its pathophysiological mechanisms remain poorly understood. Evidently, otogenic meningitis may develop via direct extension through preformed pathways, the mastoid bone, membranous labyrinth, by hematogenous spread 26 or possibly, by passage through the cochlear aqueduct and the internal auditory canal 27 . Interestingly, when in an animal study S. pneumoniae were injected into the middle ear, bacteria were able to spread to the brain tissue without invading the bloodstream 28 . Eavey et al. studied temporal bones of children who had died from meningitis, and concomitant otitis media showed no evidence of a direct expansion or vascular spread 29 . Mastoiditis is a known complication of OM 30,31 , but it is likely to often remain undiagnosed in resource-poor settings, as are also other severe complications such as brain abscess and otitic hydrocephalus, due to unavailability of diagnostic methods such as computed tomography (CT).
In ammatory responses of the inner ear in BM develop due to the spread of infection via the internal auditory canal and/or via cochlear aqueduct. Damage is caused to the intracochlear structures, most importantly the organ of Corti and neural elements -and then hearing is impaired. Suppurative labyrinthitis may result from meningogenic, tympanogenic or hematogenic processes, an example being S. pneumoniae meningitis which rather frequently causes sensorineural hearing loss [11][12][13] .
Hearing impairment (> 40dB) on day 7 was diagnosed in patients with or without OM in 27% and 30%, respectively, which coincides with previous studies 9 . Deafness (> 80 dB) on day 7 was found here in 16% and 10%, respectively, and this nding exceeds the previously reported 2 to 5% frequency of profound hearing loss from developed countries 11,32 . This observation re ects the severity of childhood BM in low-income countries. Labyrinthitis ossi cation (LO) commonly associates with BM 33 . In LO, in ammation of the membranous labyrinth proceeds to brosis and/or rapid neoosteogenesis, which may lead to a partial or total obliteration of the labyrinth´s lumen 34,35 . Since profound hearing loss due to LO can occur within two weeks from the onset of BM, it is imperative that BM patients undergo timely monitoring of their hearing and that imaging is planned if cochlear implantation seems necessary 36,37 .
The use of data from our previous large treatment study 19 is a limitation of this study. However, all data were collected prospectively with speci cally designed forms. This approach ensured the best feasible data collection method in a developing world setting, where there were no suction devices for ear cleaning and no possibility for an ear-, nose-and throat specialist consultation. All maneuvers were performed by skilled pediatricians. Some intracranial complications might have remained undetected because of a lack of diagnostic imaging, and not every child could be tested with ABR. In that situation, hearing was tested by otoacoustic emissions, or by asking questions, which, of course, gave less precise information. Finally, some patients were lost from follow-up due to long distances, poverty, and the isolated location. Despite all these shortcomings, we believe that our ndings are reliable enough to document the frequency of BM-related hearing impairment in Angola.

Conclusion
In this study evaluating hearing impairment in childhood BM in Angola, no signi cant difference in hearing was found in children with or without OM on day 7 or at later follow-ups. Overall, variable hearing loss was detected in a third of patients one week from the BM diagnosis. Any degree of hearing de cit was associated with a higher risk for a complicated clinical course of disease or death. The most common pathogens found in the ear discharge were likely to be related more to chronic than acute middle ear infections. No correlation was observed between the bacteria identi ed from the ear discharge or CSF.
Adequate treatment and timely evaluation of hearing are needed to treat these infections. However, in order to reduce signi cant BM morbidity and mortality in developing countries, vaccinations are of paramount importance. Although unfortunately still at reach of very few children in developing countries, a hearing aid, or cochlear implantation, would mitigate severe or profound hearing loss.

Declarations
Ethics approval and consent to participate ≤ ( ≥