To provide an overview of the main evidence-based recommendations for the diagnosis of hearing loss in children and adolescents aged 0 to 18 years.Task force members were educated on knowledge synthesis methods, including electronic database search, review and selection of relevant citations, and critical appraisal of selected studies. Articles written in English or Portuguese on childhood hearing loss were eligible for inclusion. The American College of Physicians’ guideline grading system and the American Thyroid Association’s guideline criteria were used for critical appraisal of evidence and recommendations for therapeutic interventions.The evaluation and diagnosis of hearing loss: universal newborn hearing screening, laboratory testing, congenital infections , genetic testing and main syndromes, radiologic imaging studies, vestibular assessment of children with hearing loss, auditory neuropathy spectrum disorder, autism spectrum disorder, and noise-induced hearing loss.Every child with suspected hearing loss has the right to diagnosis and appropriate treatment if necessary. This task force considers 5 essential rights: (1) Otolaryngologist consultation; (2) Speech assessment and therapy; (3) Diagnostic tests; (4) Treatment; (5) Ophthalmologist consultation. Approximately 360 million people (5% of the world’s population) have disabling hearing loss, and nearly 32 million of them are children.The age at which hearing loss is detected has decreased since Universal Newborn Hearing Screening (UNHS) is mandatory in Brazil, in accordance with law number 12,303 of 2010.The World Health Organization (WHO) estimates that approximately 60% of the causes of hearing loss in children are preventable. More than 30% of cases are caused by infections such as rubella, Cytomegalovirus (CMV), mumps, meningitis, measles, and chronic ear infections. Meningitis and rubella together account for more than 19% of cases of childhood hearing loss. Most of these infections can be prevented by vaccination and improved socioeconomic and sanitation conditions. Acute middle ear infections and secretory otitis should be treated immediately with medical or surgical interventions. Perinatal and neonatal complications, such as lack of oxygen, low birth weight, prematurity, and jaundice, account for 17% of cases of childhood hearing loss. Such complications can be avoided by improving mother and child health practices.Since the 1970s in the United States, a multidisciplinary committee named Joint Committee on Infant Hearing (JCIH) has dedicated to detecting risk factors for children to develop hearing loss. There are periodic updates, and the latest statement, issued in 2019, highlighted the following•Neonatal Intensive Care Unit (ICU) for more than 5 days; Hyperbilirubinemia with exchange transfusion regardless of length of ICU stay; Asphyxia or hypoxic-ischemic encephalopathy; Extracorporeal Membrane Oxygenation (ECMO); Microcephaly; Syndromes associated with progressive hearing loss; Congenital or acquired hydrocephalus; Temporal bone abnormalities; In utero infections with syphilis, toxoplasmosis, rubella, CMV, herpes (STORCH), or Zika; Family history of early, progressive, or delayed permanent childhood deafness.•Delayed: Infections that lead to deafness, such as bacterial or viral meningitis and encephalitis ; Chemotherapy; Family suspicion of deafness, speech or language impairment, and developmental delay or regression; Skull or temporal bone trauma.Perinatal or congenital: The JCIH states that children at risk of hearing loss need to be closely monitored, even after undergoing UNHS. This ensures the identification of hearing loss as early as possible and avoids treatment delays.Almost half of hard-of-hearing children will experience hearing deterioration during childhood.For didactic purposes, the main causes of hearing loss in children can be divided into congenital and acquired. The congenital causes include diseases that manifest within the neonatal period (up to 28 days of life) or later (after 28 days of life).The estimated prevalence of congenital profound bilateral hearing loss is 1 in 1000 newborns.Aedes aegypti mosquito and can cross the placental barrier and infect the developing fetus. Congenital Zika Syndrome (CZS) may cause microcephaly, reduced brain parenchyma, and visual and hearing impairment. Approximately 7% of infants with CZS have sensorineural hearing loss.The Zika virus is transmitted by the The incidence of congenital hearing loss is higher in premature children and becomes lower with increasing gestational age and birth weight (1.2% to 7.5% born at 24‒31 weeks and 1.4% to 4.8% with birth weight 750 to 1500 g). Hearing loss affects 1.2% to 7.5% of infants in neonatal ICUs.GJB2, the first gene to be implicated in nonsyndromic human deafness, was discovered in 1997. It is the gene most related to hearing loss. Since then, more than 130 genes and nearly 8000 gene variations have been identified and are associated with severe-to-profound nonsyndromic sensorineural hearing loss. These variations differ significantly based on the ethnic population examined. There are also over 600 clinical syndromes that include deafness. In many of them, deafness is the first clinical feature to manifest.Some syndromes such as coloboma, heart disease, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies/deafness (CHARGE), associated with genetic causes, may also cause hearing loss due to middle or inner ear malformations.Some children may develop deafness after the neonatal period, and this will not be detected by current UNHS. Importantly, a significant number of children who develop prelingual deafness after the neonatal period go undetected by currently implemented UNHS. Dedhia et al.Pendred syndrome is associated with recessive variants in the SLC26A4 gene. It is the most common syndromic form of hereditary sensory hearing loss and is associated with thyroid dysfunction, goiter, Enlarged Vestibular Aqueduct (EVA), and cochlear incomplete partition type II (Mondini deformity).Usher syndrome is also autosomal recessive and has 3 clinical types, associated with at least 9 genes that are differentiated by the severity of hearing loss, vestibular dysfunction, and age at onset of vision loss.Delayed-onset hearing loss may also occur after congenital infections. Historically, prenatal exposure to STORCH agents was a common cause of congenital hearing loss. However, the epidemiology of these agents has changed, and congenital CMV (cCMV) currently is a major cause of delayed-onset hearing loss in many countries. The prevalence of cCMV infection is 0.4% to 2.3% of all newborns. Of infants with confirmed congenital loss, 6% to 7% have cCMV.Hearing loss in children may have multiple etiologies over time, such as temporal bone fractures, infections, exposure to ototoxic drugs, autoimmune diseases, and noise exposure. The estimated prevalence of hearing loss in children up to 18 years of age is 18%.Trauma may cause conductive, mixed, or sensorineural hearing loss, depending on the location and type of temporal bone injury. Up to 82% of children with temporal bone fractures will have hearing loss at presentation; of these cases, 56% will be conductive, 17% will be sensorineural, and 10% will be mixed.Infectious causes of sensory hearing loss include measles, mumps, varicella-zoster virus, Lyme disease, bacterial meningitis, and, rarely, otitis media. Measles and mumps with subsequent hearing loss are more common in unvaccinated children.Streptococcus pneumoniae infections that can cause ossification of the labyrinth. Cochlear implantation is indicated as soon as possible.Hearing loss resulting from bacterial meningitis may be progressive and is more common after The following drugs are known to be ototoxic and cause permanent hearing loss: aminoglycosides, chemotherapy drugs , and loop diuretics. Radiotherapy involving the temporal bones, associated with cisplatin, increases the risk of sensorineural hearing loss, which may manifest a few years after the end of treatment.Autoimmune hearing loss is due to either primary autoimmune dysfunctions in the inner ear or systemic autoimmune diseases such as Cogan syndrome .According to the WHO, 1.1 billion young people are at risk of hearing loss due to prolonged and excessive exposure to loud sounds.The tests used for identifying neonatal hearing loss are transient-evoked and distortion-product Otoacoustic Emissions (OAE) and Auditory Brainstem Response (ABR) . These electrophysiologic tests are suitable for children because they are considered objective and performed under sedation, but their interpretation is examiner dependent. These tests will be described later, when UNHS is discussed.In children aged 7 years or over, subjective tests can be used, such as audiometry. This test is dependent on the child’s response and the examiner’s experience.Hearing loss is defined as compromised ability to hear sounds at thresholds considered normal. For children, an average pure-tone threshold higher than 15 dB HL at 500, 1000, 2000 and 4000 Hz is considered outside the normal reference range. The severity of hearing loss is categorized in This systematic review has the purpose to provide an overview of the evidence-based recommendations for the diagnosis of hearing loss in children and adolescents aged 0 to 18 years.Between April 28 and 29, 2022, a task force consisting of otolaryngologists, otology specialists, Brazilian Society of Otology  directors, and some SBO members met (in person and remotely) to discuss the topic of this guideline. Each participant in this meeting was tasked with giving a 15-min evidence-based lecture on one of the suggested topics. After the lecture, the participants discussed the topic until reaching a consensus. Each author was asked to write a text with the current literature on the topic, based on evidence and containing the elements discussed during the meeting. A rapporteur prepared the final text, which was reviewed by 4 additional coauthors and the Brazilian Journal of Otorhinolaryngology (BJORL) editor.This guideline is not intended to be a substitute for individual professional judgment. Physicians should always act and decide in a way that they believe is best for their patients, regardless of guideline recommendations. They should also operate within their scope of practice and in accordance with their training. The guidelines represent the best judgment of a team of experienced physicians addressing the scientific evidence for a given topic.The grading system of the American College of Physicians (ACP) was used in this guideline, relating to critical appraisal and recommendations on therapeutic interventions47The American Thyroid Association (ATA) created a diagnostic test appraisal system that included consideration of the following methodological elements: consecutive recruitment of patients representative of clinical practice, use of an appropriate reference gold standard, directness of evidence , precision of diagnostic accuracy measures , and consistency of results across studies using the same test that was also used in this guidelineIn the 2019 JCIH statement recommendations,In Brazil, the reality is still far from ideal, despite a 2010 lawUNHS is essential for congenital hearing loss to be detected and rehabilitated as early as possible. Fifty percent of children with hearing loss at birth do not have any risk factors for hearing loss.Screening can be done using 2 methods, OAE or Automated ABR (AABR). Given the very low incidence of auditory neuropathy in children who are not in the ICU, both methods have been shown to be appropriate and are equivalent screening methods for hearing loss identification.A 2-stage UNHS procedure should be conducted. Children who “failed” the first evaluation should undergo a retest, which can be the same as before or another method. It is important that this retest is performed before 1 month of life, preferably before discharge from the maternity hospital if possible, and that there is no diagnostic delay in case of new “failed” retests. If the first and second evaluations fail, even in one of the ears, the child should be immediately referred for otolaryngologic evaluation and diagnostic testing.There are, however, important differences between the 2 methods. The OAE test measures the response of the cochlea’s outer hair cells, while the ABR test reflects both cochlear status and auditory neural function that extends beyond the cochlea to the brainstem. However, both have shown to be adequate and equivalent for UNHS, despite having some limitations, such as the influence of responses due to middle ear problems.UNHS may not identify mild losses (less than 25‒40 dB) more often when performed with AABR,In newborns at high risk for hearing loss, as previously described, sensorineural deafness accounts for 2.5% to 10% and conductive hearing loss for 25% to 35%.Hearing screening of newborns with risk factors  should cFor diagnosis, ABR, automated steady-state response, and distortion-product OAE should be performed. When otitis media with effusion is unclear, 1000 Hz impedance meters should be used in children aged 9 months or older.If these newborns are hard of hearing, they should be referred for appropriate rehabilitation, which should be started as soon as possible. This can be done through a Hearing Aid (HA) or Cochlear Implant (CI) so that they experience appropriate hearing and speech development.All children with suspected progressive hearing loss, as in the case of CMV or genetic disorders, require hearing monitoring up to 4 years of age .Newborns who are on mechanical ventilation for more than 5 days receive antibiotic therapy for secondary infection prevention, account for 10% to 15% of all live births, and deserve special attention in neonatal hearing screening.In the pediatric ICU, newborns have several comorbidities such as malformations, severe infections, and low birth weight. Because they are in a noisy environment (incubators), it is difficult to perform the OAE and AABR tests, which delays hearing screening. The diagnosis is frequently delayed or not made.Another important factor for not performing the tests in newborns with risk factors is that neonatal ICU speech therapists often do not specialize in audiology. Furthermore, hospitals rarely have audiologists available on holidays or weekends, which may leave these children unattended in case of hospital discharge. A suggestion to solve this problem is to provide training for intensive care nursing staff or to prepare an on-call schedule for audiologists in maternity hospitals.These children frequently have multiple comorbidities that will be treated after discharge. However, they are often not taken to the office for out-of-hospital hearing screening testing, which causes enormous damage to this population, as they are diagnosed too late, when appropriate auditory rehabilitation is no longer possible.UNHS coverage in Brazil is still very low and has marked regional differences. Measures need to be taken for ensuring nationwide coverage, enabling identification and rehabilitation at an ideal age for children with hearing loss .Regardless of UNHS outcomes, all infants and children should be routinely monitored for hearing, cognitive, and oral language development, as well as for achievement of educational milestones .Training and hiring human resources to perform in-hospital hearing screening is necessary for ensuring that these tests are done before hospital discharge (Insufficient).Checking for screening and retesting at the time of first vaccination is a possible strategy for increasing UNHS coverage, with identification of children who may not have undergone hearing screening at the maternity hospital or who did not return for retesting (Insufficient).Creating a national database with information on tests performed, results, and other data necessary for monitoring and planning actions and adjusting the human, physical, and technological resources for UNHS programs (Insufficient).Creating a UNHS protocol has multiple benefits, including: Identifying newborns at risk of deafness who could benefit from early intervention but are missed by current screening programs; Providing etiologic information as part of screening; Possibly decreasing the number of children who are lost to follow-up; Potentially saving costs by reducing the frequency of later testing.Any screening test must weigh false negatives versus false positives to best serve the screened population. “False positive” may refer to the actual screening device used, but here it refers to the overall result given to parents ‒ “pass” or “refer” ‒ versus the subsequent diagnostic confirmatory physiologic testing, which serves as the “gold standard”. The Positive Predictive Value (PPV) is the probability that individuals who screen positive actually have the disease. An ideal screening test would have a high PPV and a high sensitivity. Although negative predictive value and specificity are also considered in the design of screening tests, a confirmatory or diagnostic test should aim for a high negative predictive value and a high specificity as false negatives are reduced.Once the diagnosis of hearing loss is established, the search for an underlying etiologic diagnosis is recommended. Available guidelines include screening for congenital infections, imaging, and genetic testing.A series of diagnostic laboratory tests that can help determine the cause are shown in Generally, a definitive laboratory diagnosis of congenital rubella infection can only be made within 12 months of birth. Rubella infection may be diagnosed if at least one of the following criteria is met: (1) Positive anti-rubella IgM titer (possibly measured with enzyme immunoassays), (2) Substantial increase in IgG titer 2 to 3 weeks after the acute phase of infection or high titers persisting beyond what can be expected from passive transfer of maternal antibodies, 3) Isolation of rubella virus from cultures of throat, nasal, blood, urine, or Cerebrospinal Fluid (CSF) samples, 4) Polymerase Chain Reaction (PCR) detection of virus in throat swabs, CSF, or surgical specimens .Additional laboratory test results that can confirm the diagnosis of congenital rubella infection are thrombocytopenia, hyperbilirubinemia, and leukopenia. Although congenital rubella infection has become rare in the developed world since the virus was eradicated from the western hemisphere, cases of imported disease are still observed. Furthermore, congenital rubella infection remains endemic in some low-income countries in the developing world and should thus be considered in the diagnostic workup of hearing loss if infection cannot be excluded for historical or epidemiological reasons.cCMV has the highest rate of mother-to-child transmission in humans, with a neonatal prevalence ranging from 0.2%‒2%. Symptoms of congenital infection are intrauterine growth retardation, hepatosplenomegaly, petechial skin rash, retinitis, thrombocytopenia, and hepatitis. Although 80%‒90% of newborns do not show symptoms of cCMV, sensorineural deafness may be present at birth, progress in severity, or develop later. cCMV may lead to a wide spectrum of dysfunctions that, in addition to sensorineural hearing loss, include blindness and neurodevelopmental delay.Foulon et al.Sensorineural hearing loss occurred in 9.9% of asymptomatic children and 33% of symptomatic cases according to a systematic review conducted in 2014.Any newborn with signs of congenital infection should be tested for CMV infection. It is the leading nongenetic cause of congenital hearing loss in high-income countries. This infection should also be considered in children with hearing loss who are healthy and asymptomatic. Other signs and symptoms of CMV infection include microcephaly and jaundice, with sensorineural hearing loss being present in approximately 30% of symptomatic children infected with CMV.cCMV is a challenge for otolaryngologists and pediatricians. The window period for diagnosis is very short, about 2 to 3 weeks after birth. Available tests become undefined after this period. In addition to this difficulty, there is the fact that most patients are asymptomatic. Low clinical suspicion at birth has consequences for delayed diagnosis and interventions.Few Brazilian studies have addressed the topic. Yamamoto et al.The diagnosis of cCMV is based on the identification of viral particles in saliva and urine using a PCR technique in the short window period up to the third week of life,Although described years ago, this method has not reached consensus. For health funding reasons, testing is most often performed in patients considered a target for the disease, such as symptomatic patients with a suggestive clinical status. If screening for cCMV is performed only in this population, the consensus statements point to a significant proportion of asymptomatic patients and patients with cCMV who would miss the chance of being diagnosed early.69According to these consensus statements, in addition to apparent cases, children who fail the UNHS or who present with sensorineural hearing loss of unapparent cause should be tested for cCMV regardless of age.Prenatally, a PCR test for CMV in amniotic fluid can confirm cCMV infection (PPV is close to 100%).In many high-income countries, a blood sample is routinely collected during the first week of life to screen for metabolic, endocrine, and other disorders. If cCMV infection is suspected, in addition to laboratory testing, brain imaging , visual function assessment, and hearing assessment are required. However, cCMV infection is virtually asymptomatic in 90%of newborns. These children generally have fewer neurodevelopmental problems than those who are symptomatic at birth, but 10% will develop substantial sensorineural hearing loss at some point during childhood.Because of the cost of implementing universal screening, low- and middle-income countries do not routinely test newborns. In an SBO discussion forum, medical participants from all Brazilian regions consensually encouraged the practice of universal screening for cCMV. If this is not possible, neonates suspected of having this condition should be tested before discharge.The phenotypes of hearing loss may vary. The most severe forms, characterized as profound bilateral sensorineural hearing loss, seem to occur more often in patients with primary infection, in cases of symptomatic neonates.Children with cCMV and those who failed the second test, in the case of retesting at 30 days, are referred to specialized centers for diagnostic hearing evaluation until the sixth year of life; assessments are performed every 6 months until the third year, and annually thereafter. The diagnostic evaluation consists of audiometry suitable for the child’s neuropsychomotor development. In the case of free-field audiometry, an OAE test is combined so as not to miss patients with unilateral sensorineural hearing loss. In the presence of any abnormality, immittance testing is performed to rule out the conductive causes of hearing loss so common in children. If a diagnosis is made, children are evaluated by click and tone-burst ABR at specific frequencies to reach a conclusion or classification of sensorineural hearing loss.It is important that otolaryngologists and pediatricians are aware of some approaches based on current evidence and consensus statementsCommon findings suggestive of cCMV include CNS malformations, ventriculomegaly, microcephaly, and cortical and periventricular calcifications. Because these changes are present in 80% of patients with sensorineural hearing loss and symptomatic cCMV,Other key assessments are hematology, liver enzyme, bilirubin, and renal function tests, especially when pharmacologic therapy is indicated. These children also require a complete ophthalmologic examination for the diagnosis of congenital cataract and chorioretinitis.Despite the high prevalence and high degree of morbidity, a gold-standard diagnostic test and a definitive treatment for cCMV have not yet been established.In cases of moderate-to-severe symptomatic cCMV, relevant consensus statementsThe recommendations of the European consensus statementAlthough not unanimously, pharmacologic intervention was recommended by most European consensus members for patients with asymptomatic or mild forms of cCMV with sensorineural hearing loss at birth or developing later. However, at a subsequent meeting, the experts did not support this approach because there were few studies showing scientific evidence and most of them were not randomized clinical trials. In the absence of evidence, during the SBO discussion forum, we supported the possibility of pharmacologic intervention with the provision of clear information on the uncertain prognosis and potential harm to the child’s health.Since different phenotypes are possible, the choice of auditory rehabilitation method should be individualized and shared with the family of the child with sensorineural hearing loss and cCMV. Most often, a multidisciplinary team is required because different impairments may affect the child’s global development. All forms of auditory rehabilitation can be indicated, and the same patient may need more than one method at different times. Regardless of the method indicated, longitudinal follow-up of the infant with cCMV is important, as it is common for sensorineural hearing loss to progress on the same side or on the opposite side.Several efforts have been made to establish the prognosis of hearing loss progression in patients with cCMV. The belief that only primary gestational infections generate neonates with symptomatic forms and would be responsible for worse hearing outcomes has not been supported in the scientific literature.For clinical practice guidance, the following elements are indicative of worse outcomes of sensorineural hearing loss in cCMV and delayed-onset hearing lossTwo studies evaluated some predictors of good auditory rehabilitation outcomes for patients with CIs.A more detailed analysis of the methodology of these studies shows that the most important covariate possibly affected is the patient’s intellectual quotient, often associated with the amount of CNS imaging abnormalities, which will certainly exert greater influence on patient outcomes during auditory rehabilitation. Conversely, the anatomic site of the lesions and the presence of changes in the temporal and parietal lobes, sites related to the auditory and motor cortical areas of speech, seem to lead to worse outcomes in the follow-up of children with cCMV undergoing auditory rehabilitation with CIs.To date, no vaccines have been approved for marketing in Brazil, but 2 are being tested in the United States in phase II, placebo-controlled, randomized clinical trials. These trials have shown seroconversion in 50% of pregnant women receiving the glycoprotein B vaccine.The consensus statements recommend that pregnant women and mother-and-child health professionals be clearly informed of the forms of transmission and prevention. The measures aim to protect pregnant women from secretions from children under 2 years of age, especially those attending day care centers as they have a prolonged period of transmission and are subject to constant reinfections. Washing hands after diaper changes, avoiding kissing, and not sharing food and cutlery are measures that have been shown to reduce seroconversion in pregnant women.Prevention of fetal infection will only be indicated in cases of contamination confirmed by testing via amniotic fluid between 20 and 21 weeks.Indiscriminate laboratory testing without diagnostic suspicion is not recommended, as it has a low yield (0% to 2%) .Children with sensorineural hearing loss exhibit a 2- to 3-fold increase in the incidence of eye problems, including correctable vision disorders such as astigmatism and refractive errors. Thus, an ophthalmologic evaluation is indicated .Cardiovascular evaluation has a relatively low yield and should be performed if genetic testing or electrocardiography identifies a cardiac abnormality that requires further evaluation. Electrocardiographic changes may be more common among children with unilateral or bilateral sensorineural hearing loss, regardless of the severity of hearing loss .cCMV has been a major challenge for several mother-and-child health professionals, and because its most frequent sequela is sensorineural hearing loss, the otolaryngologist should be directly involved in the multidisciplinary team responsible for the diagnosis and rehabilitation process of children .Because of the different phenotypes of sensorineural hearing loss, a complete protocol including follow-up during the first 6 years of life is suggested, as this will cover delayed-onset losses, which are approximately 1% per year in asymptomatic forms and 4% per year in symptomatic forms .Medical treatment with hyperimmune immunoglobulin, as well as antiviral therapy in intrauterine life, to reduce the risk of fetal contamination and sequelae remains under debate, and only well-founded clinical research protocols should be recommended (Insufficient).Antiviral therapy with the aim of positively impacting the hearing outcome lacks evidence in the literature and is not routinely recommended (Insufficient).Children with profound sensorineural hearing loss caused by cCMV exhibit impaired CI performance compared with those with a CI but without cCMV. Lower CI performance in children with cCMV can be attributed to comorbidities .Currently, there is no vaccine approved for marketing in Brazil, and the educational measures for pregnant women and health professionals regarding prevention of transmission in this population have shown some evidence of efficacy (Insufficient).The otolaryngologist should participate in all stages of the decision-making process for a child with cCMV and sensorineural hearing loss (Insufficient).Identifying the cause is important for the prognosis of hearing loss and language development, as well as for the choice of treatment. Genetic testing should be considered in children with hearing loss of unknown cause. It has a high yield, identifying the condition in 44% of patients with bilateral sensorineural hearing loss.Genetic deafness can be classified by the type of genetic inheritance: Autosomal recessive inheritance is the most common and has the following profile: sensorineural, severe to profound, prelingual. Classified as DFNB; Autosomal dominant inheritance is most commonly characterized as progressive, post lingual, moderate hearing loss. Classified as DFNA; Mitochondrial inheritance is when a man or woman inherits maternal mitochondrial DNA; X-linked inheritance is when a woman, the carrier of the mutation, transmits the gene that manifests only in male family members.To date, 124 genes linked to nonsyndromic hearing loss have been identified, 78 of which are autosomal recessive, 51 are autosomal dominant, and 5 are X-linked.Connexin 26 or GJB2 (Gap Junction Beta-2 protein) was the first gene identified as responsible for nonsyndromic sensorineural hearing loss.There are over 70 different mutations reported. Heterozygous and biallelic mutations make genetic counseling difficult.GJB2 gene mutations account forOne of the most common GJB2 mutations identified worldwide is 35delGOther common GJB2 gene mutations in specific populations include: 167delT ‒ Ashkenazi JewsIt is not easy to determine the frequency of 35delG mutation in Brazil because of the heterogeneity of the population. National studies on deaf patients found quite different results for the presence of this mutation. Oliveira et al.The presence of the heterozygous 35delG mutation, by itself, is not pathogenic, but it can be associated with other compound heterozygous mutations or with the GJB6 gene (DS13S1854 and DS13S1830) and cause hearing loss. In Brazil, the frequency of GJB6 among heterozygotes for the 35delG mutation has varied: 12.5% ,Batissoco et al.3-). It is found in the apical membrane of epithelial cells of the cochlea, endolymphatic sac and duct, and vestibular system, as well as in the thyroid and kidney.This21-exon gene is located on the long arm of chromosome 7. It encodes pendrin, which is a protein expressed in multiple tissues. It is a transmembrane anion exchanger that exchanges mainly Chloride (Cl-), iodide, and bicarbonate , but there are cochlear malformations, especially EVA. In some populations, up to 80% of patients with EVA have an SLC26A4 gene mutation. Thus, the presence of SLC26A4 should be investigated in all individuals with sensorineural hearing loss and inner ear malformations.Approximately 30% of cases of congenital hearing loss are syndromic and occur with structural or functional anomalies of other organs and systems. Genetic factors are poorly understood, although large genome-wide association studies have identified several new disease-associated loci and massive next-generation sequencing may bring additional knowledge to this field. Among the autosomal dominant syndromic causes, Neurofibromatosis type 2 (NF2) is characterized by the development of vestibular schwannomas bilaterally, associated with other meningiomas, optic gliomas, ependymomas, and other spinal tumors. The definitive diagnosis involves bilateral vestibular schwannoma (or family history of NF2), plus one of the following: meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacity and juvenile cortical cataract.98Stickler syndrome is a disorder of collagen connective tissue characterized by congenital vitreous anomaly, early-onset myopia, joint hypermobility, and retinal detachment.CHARGE syndrome, characterized by coloboma, heart defects, choanal atresia, growth retardation, genital hypoplasia, and ear abnormalities, is best evaluated by nasal fiberoptic endoscopy and echocardiography to define these malformations. CT scans show superior semicircular canal aplasia, ossicular abnormalities, and vestibular hypoplasia.99Treacher Collins syndrome is characterized by mandibulofacial dysostosis.Among autosomal recessive syndromes, Pendred syndrome (further described below) is characterized by sensorineural hearing loss, goiter, and defects in iodine metabolism. Imaging evidence of Mondini dysplasia or EVA as well as laboratory tests demonstrating thyroid dysfunction are required for diagnosis.Usher syndrome is characterized by sensorineural hearing loss, vestibular dysfunction, and prepubertal-onset retinitis pigmentosa.Other diseases with later auditory manifestations in the pediatric age group include Alport syndrome . Diagnosis can be made if 4 of the following diagnostic criteria are met: family history of hematuria, high-frequency progressive sensorineural hearing loss, ocular changes including anterior lenticonus and/or macular flecks, and glomerular basement membrane changes.An etiologic investigation for congenital hearing loss should be performed for many reasons. It allows accurate and personalized counseling, provides relief from guilt in some cases, and assists in hearing rehabilitation. Identifying the etiology may help to choose appropriate therapeutic or management options , may identify coexisting medical problems that need to be treated or monitored  and safe preventable risk factors for future hearing deterioration , and may also predict the progression of hearing loss to some extent.Auditory neuropathy is a common finding in Charcot-Marie-Tooth disease, which is the most common inherited neurologic disorder, affecting 1 in 2500 people and being characterized by progressive motor and sensory neuropathy.There are other hereditary progressive motor and sensory neuropathies with auditory neuropathy, such as Friedreich ataxia, with possible spiral ganglion degeneration. Cochlear implantation is likely to have suboptimal postoperative results in these individuals, but it is still a treatment option for deafness.Mohr-Tranebjaerg syndrome (deafness-dystonia syndrome) with optic neuropathy is a progressive genetic neurodegenerative disease characterized by childhood-onset auditory neuropathy, dystonia, and ataxia beginning in the second decade of life, with decreased hearing acuity beginning in the third decade and dementia in the fifth decade of life. Some patients also develop paranoid ideas. It is caused by mutations in the TIMM8A gene, which is an X-linked recessive gene.First described in the literature by Pendred in 1896, this syndrome is characterized by sensorineural hearing loss, inner ear malformations (incomplete partition type II and EVA), and thyroid dysfunction.Audiologic phenotypes may vary, with mild-to-profound, congenital or late-onset hearing loss. Most patients present with severe-to-profound progressive congenital hearing loss, which can be aggravated by traumatic brain injury or barotrauma.Goiter is characteristically multinodular, with onset in the second decade of life. It develops during puberty in 40% of cases and in adulthood in 60%.Two other genes have been described to cause Pendred syndrome, accounting for less than 2% of affected individuals: FOXI1 encoding Forkhead box protein I1 and KCNJ10 encoding the adenosine triphosphate-sensitive potassium channel.Comprehensive genetic testing has become more accessible since the advent of Massively Parallel Sequencing (MPS) based platforms that allow the sequencing of billions of DNA base pairs simultaneously, reducing costs and being suitable for large-scale application.Patients and families should be informed of the ethical and social issues related to genetic testing, including the psychological impact of the diagnosis, implications for family members, and potential employment or insurance discrimination.Authorization and guidance on genetic testing cannot be overlooked. Genetic testing involves not only the patient but also family members, so it must be extremely confidential. Consent for genetic testing in children should be obtained from both parents and, in the case of a positive result, the otolaryngologist should refer the patient to a geneticist for genetic counseling.To define uncertain results, follow-up is recommended because characteristics related to certain mutations may only become apparent as the child grows older, at which time additional testing may be indicated.Considering the frequency of genetic causes in the etiology of hearing loss, whenever the diagnosis is uncertain, it should be checked if all other causes have been ruled out. The American College of Medical Genetics and Genomics (2014)For individuals without physical findings suggestive of syndromic deafness and without medical or neonatal history suggestive of acquired causes, nonsyndromic genes should be investigated – single-gene (GJB2) testing using gene panel tests (Weak recommendation – Moderate level of evidence).Given the high prevalence and costs in Brazil, it is suggested to start investigating the 35delG mutation in GJB2, followed by a gene panel including GJB2 and GJB6 and, if all testing is negative until that moment, large sequencing panels should be used for the different genes involved (Weak recommendation – Moderate level of evidence).Imaging is extremely important for the diagnostic evaluation of pediatric patients. It plays a role in determining the etiology, identifying abnormalities related to hearing loss progression, and surgical planning.The diagnostic yield of imaging studies in the evaluation of children with profound bilateral sensorineural hearing loss ranges from 7% to 74%, with high specificity and high PPV.The imaging modalities of choice for the assessment of pediatric sensorineural hearing loss are high-resolution CT and MRI. CT provides better visualization of bone structures, lower costs, and faster imaging, which makes it easier to use in pediatric patients. However, CT scans expose children to ionizing radiation, and longitudinal studies have shown an increased lifetime risk of developing certain types of cancer.Given the several factors mentioned above, there is considerable variation between clinical practice and institutional protocols in diagnostic methods used.Several studies have demonstrated a correlation between diagnostic yield and hearing loss severity, with an increase of almost 20% in diagnostic yield in severe-to-profound hearing loss compared with mild-to-moderate hearing loss. The diagnostic yield is lower in patients who test positive for mutations in the GJB2 gene, which is the most common cause of nonsyndromic hearing loss.It remains unclear which imaging modality should be ordered, but several studies have reported a higher diagnostic yield with the use of CT than MRI.124The diagnostic yield of CT is estimated at approximately 30% based on systematic reviews. This estimate corresponds to a number needed to image of 4, that is, 4 pediatric patients with congenital bilateral sensorineural hearing need to undergo CT to find a morphologic abnormality. In this same systematic review, CT was able to identify 8.7% more findings than MRI.p = 0.0001).In a multicenter study evaluating the diagnostic yield of CT versus MRI in children with profound bilateral hearing loss, the concordance rate between CT and MRI was 92%, with the diagnostic yield of CT being 7% higher than that of MRI  . MRI is Imaging is essential during the etiologic evaluation of children with bilateral sensorineural hearing loss due to its high diagnostic yield .The choice of imaging modality should consider diagnostic yield, radiation exposure, need for sedation, and cost, but mainly the availability of each modality in each region (Insufficient).The MRI scan, in particular heavily weighted T2 sequences , offer most of the information about cochlear nerve size and integrity, unusual morphologic inner ear anatomy, and intracranial anomalies that might identify the etiology of deafness and possibly affects the cochlear implant process. .Temporal bone CT scan should be considered for children with trauma of temporal bone, craniofacial, and cochlear anomalies at risk of having more surgically challenging anatomy in cochlear implant. .Conductive hearing loss ‒ temporal bone CT scan is the preferred exam. .In humans, the regulation of the body balance occurs through the integration of multiple systems and organs that send information to the CNS , process this information, and send signals and reflexes to control our posture and gait. Among the different sensory systems that contribute to maintaining balance, the following stand out: vision, vestibular system, and proprioception .The vestibular system consists of 3 semicircular canals  and 2 otolith organs (saccule and utricle). Each of these 5 structures has sensory receptors consisting of highly specialized hair cells, with the ampullary cristae located in the ampullae of the semicircular canals, and the utricular and saccular maculae located in the corresponding otolith organs.The vestibular system has a close anatomic relationship with the cochlea, sharing the same bone scaffold and membranous ducts, having similar sensory hair cells, and sharing the same embryonic origin. Thus, disturbances in one system can affect the other system and vice versa.Unlike hearing disorders, which are more easily diagnosed using different methods, vestibular dysfunction is rarely confirmed in early childhood, and, in most cases, it is not even considered by the physicians who first assess the child, such as pediatricians and otolaryngologists. Perhaps the main reason for this is a lack of knowledge of the importance and function of the vestibular system and/or the unavailability of diagnostic methods for pediatric vestibular assessment.135It is important to note that vestibular dysfunction in childhood presents as a delay in some motor development milestones, such as neck control, sitting, crawling, and walking. This makes some children more susceptible to falls and deficits in fine motor skills, thus leading them to avoid, often unconsciously, exposure to more challenging situations involving body balance, such as walking on unstable surfaces . Clear signs, such as the presence of spontaneous nystagmus, are not so common because most patients have bilateral vestibular dysfunction.136There is no doubt that major challenges of vestibular assessment in children with hearing impairment include the methods available for assessing labyrinthine function, their limitations, parameters, and particularities to be performed in this pediatric population.•Clinical Head Impulse Test (cHIT): This test was first described in 1988 by Australian professors Michael Halmagyi and Ian Curthois, and to this day it remains one of the most effective bedside tests to assess vestibular function, although not quantitatively. The test is usually performed with the child sitting on the parents’ lap. While standing in front of the child, the clinician holds the child’s head with both hands and asks the child to maintain gaze on the examiner’s nose. Once a steady gaze has been achieved, the clinician rotates the child’s head with a fast, low-amplitude, high-acceleration head impulse to both sides randomly. Patients with a normal Vestibulo-Ocular Reflex (VOR) can often keep their eyes on the target even under rapid head movement, whereas patients with reduced VOR gains often perform corrective saccades to keep their eyes on the target.•Video Head Impulse Test (vHIT): This test was introduced in the routine practice of vestibular assessment in the last decade. It is an evolution of the bedside cHIT. The vHIT is the only commercially available vestibular assessment method that can evaluate VOR gain in the 3 semicircular canals in the high frequency spectrum, in addition to being able to quantify the level of residual vestibular function. It also has several other advantages over traditional vestibular tests. It is a rapid, highly reproducible, low-cost test that is not uncomfortable for patients.•Vestibular Evoked Myogenic Potentials (VEMP): There are 2 types of VEMPs, cervical VEMP (cVEMP) and ocular VEMP (oVEMP). These tests assess the function of otolith organs . The tests are of vestibular origin, and measurements are most commonly made in the sternocleidomastoid muscle (cVEMP) and in the inferior oblique extraocular muscle (oVEMP). To attain optimal test quality, the patient must contract the muscles measured, which poses a slightly limiting factor in the pediatric population. Child cooperation is mandatory and necessary for a few minutes. The cVEMP can be more easily performed, with electrodes being placed on the sternocleidomastoid muscle, forehead, and suprasternal notch. Because the test requires child cooperation to be performed, most authors consider the cVEMP abnormal if there is no response in at least 3 consecutive attempts. Like vHIT, cVEMP is often used for vestibular assessment in children with hearing loss, and it can be performed successfully in most cases. It is worth mentioning that cVEMP is better tolerated than oVEMP in this specific population.•Caloric test: For many years, this test was considered the gold standard for the assessment of vestibular function. It was first described by Robert Bárány, a Hungarian physician, in the early 20th century. It mainly assesses the function of the lateral semicircular canal in the low frequency spectrum through a nonphysiologic stimulus (irrigation at different temperatures). The caloric test is often performed using a traditional protocol with 4 irrigations at different temperatures in both ears. Traditionally, it is a longer test and somewhat uncomfortable for most patients.Among the various clinically available vestibular assessment methods, it is important to emphasize that all, absolutely all, have some limitations. As mentioned earlier, there are 5 sensory organs in the labyrinth (3 cristae and 2 maculae), and no method can assess all organs at once. Another major limitation of tests of labyrinthine function is the indirect assessment of the vestibular system through reflexes, analyzing both the vestibulo-ocular and vestibulospinal reflexes. That is, they evaluate reflex responses generated by the vestibular system, after a stimulus, and not the labyrinth directly. Another extremely important factor to be considered is that vestibular tests are essentially functional tests and not diagnostic tests. The available tests that are best suited for the assessment of the pediatric population are as follows:In general, most authors agree that performing vestibular tests in children is challenging, although approximately 50% of the children undergoing such tests are able to successfully complete a test battery.Currently, the importance of CI surgery for hearing rehabilitation in children with severe-to-profound bilateral sensorineural hearing loss is unquestionable. This method has advanced in the last 2 decades not only in implant technologies, with increasingly less traumatic electrodes, but also in surgical techniques, which have become minimally invasive, following the concepts of soft surgery. While it is known that CIs can restore hearing, it has also been confirmed histopathologically that CIs can damage several vestibular organs, resulting in poor vestibular function, dizziness, and balance disorders.Most studies aiming to investigate vestibular function in patients before and after CI surgery have been conducted in the adult population, precisely because of the technical difficulties associated with performing vestibular tests in children, as described above. There is still a lack of studies investigating this issue in an exclusively pediatric population. Therefore, the functional and anatomic consequences of CI surgery for children’s vestibular function remains unclear.The advances in CI surgery have led to an increase in sequential bilateral cochlear implantation in children due to the clear advantages of this technique concerning auditory outcomes, such as better development of the auditory cortex, improved sound localization, and significantly better speech production. However, there has been an increased concern about the potential bilateral vestibular consequences that this technique might induce.Pathological studies performed in adults after cochlear implantation have provided increased evidence of endolymphatic hydrops and saccular collapse. Probably for this reason, the cVEMP test appears to be statistically significantly altered in some studies when comparing results before and after surgery.There is a relationship between sensorineural hearing loss and vestibular dysfunction in pediatric patients .There is methodological difficulty in performing vestibular tests in children, as well as in the parameters of normality for such tests in this specific population (Insufficient).Among the various tests, cHIT and vHIT were the best tolerated by pediatric patients .Despite the difficulties in performing vestibular tests, whenever possible, they should be ordered for children who will undergo CI surgery, both unilaterally and in simultaneous or sequential bilateral cases .Children undergoing CI surgery experienced vestibular deterioration postoperatively, especially in cVEMP and caloric test, suggesting that the otolith organs are more affected and that low-frequency tests are more sensitive than high-frequency tests for the analysis of the impact of cochlear implantation on the vestibular system .Auditory Neuropathy Spectrum Disorder (ANSD) is a common cause of hearing loss, affecting 1.2% to 8.4% of those with hearing loss depending on the population.148ANSD often encompasses auditory dyssynchrony and auditory neuropathy, which, in some cases, cannot be distinguished from each other. The site of the injury that causes auditory neuropathy may involve: (1) Presynaptic region, where glutamate is released by hair cells; (2) Synapse, involving postsynaptic excitatory neurotransmitters; (3) Region of onset of postsynaptic excitation  on the terminal dendrite; (4) Region along the spiral ganglion that affects neural signal transmission from the auditory nerve to the brainstem.In cases of auditory neuropathy, inner and outer hair cells, regardless of neural signal transmission, have injuries that result in auditory dyssynchrony. Therefore, individuals typically have deficits in temporal processing of sound that result in impaired speech perception and sound localization.ANSD is caused by both genetic and environmental factors. There are 13 known genes. Environmental causes primarily affect newborns and include hyperbilirubinemia, thiamine deficiency, and hypoxia. ANSD can also be noise-induced or age-related. Spiral ganglion neurons are bipolar and have a cell body located in the cochlear modiolus, peripheral axons distributed along the spiral limbus toward the row of cochlear inner hair cells, and proximal axons that synapse in the midbrain. These neurons are tonotopically organized with the cochlea.Multiple spiral ganglion neuron fibers synapse with each inner hair cell. Their axons are myelinated and project to the brainstem. In response to glutamatergic stimulation at the synapse, EPSPs in the peripheral axon lead to gradual Na+ influx via a large number of channels, which allows temporal encoding of acoustic stimuli.150Genetic lesions that affect the transmission of the auditory signal to the brain lead to a loss of temporal precision and dyssynchrony, with a degraded potential and altered perception and/or difficulty understanding sound, thus leading to deafness due to auditory neuropathy.Synaptopathies can be classified specifically based on the site of synapse injury as presynaptic or postsynaptic. Auditory synaptopathies can be distinguished from auditory neuropathies by electrocochleography. Individuals with synaptopathy appear to have improved adaptation to frequency specific tones, whereas those with neuropathy have low frequency adaptation.Calcium influx at the base of the inner hair cell near the synapse is mediated via the Cav1.3L-type calcium channel, encoded by the CACNA1D gene. Otoferlin, encoded by the OTOF gene, is a protein responsible for regulating the exocytosis of glutamatergic vesicles in the presynaptic region. The vesicular glutamate transporter type 3 (VGLUT3 gene) is responsible for the glutamate uptake at the postsynaptic site.153Mutations in the AIFM1 gene cause neuropathy and are associated with Cowchock syndrome, a neuromuscular disorder associated with deafness and cognitive impairment. It is an X-linked mutation where, in addition to the initial auditory neuropathy, individuals later develop sensory neuropathy with extremity numbness, unsteadiness, and areflexia. It is rare, and to date, there are only 11 reports of AIFM1 mutations causing deafness.The AIFM1 gene encodes apoptosis-inducing factor 1, a flavoprotein located in the mitochondrial intermembrane space within the inner and outer hair cells as well as spiral ganglion neurons. The AIFM1 protein plays a role in oxidative phosphorylation by controlling the production of intracellular free radicals. Some patients with these mutations have cochlear nerve hypoplasia. To date, there are no reports of cochlear implantation in these individuals, but they are expected to have poor outcomes, particularly those with cochlear nerve deficiency.Mutations in the NARS2 gene are autosomal recessive and cause nonsyndromic auditory neuropathy as well as Leigh syndrome, an early-onset progressive neurodegenerative disorder affecting the CNS. The NARS2 gene encodes the mitochondrial asparagine-tRNA ligase protein. The NARS2 protein is expressed in the spiral ganglion and other cells of the organ of Corti.Mutations in the TMPRSS3 gene cause 2 types of autosomal recessive sensorineural hearing loss: severe-to-profound congenital deafness (DFNB10) and progressive postlingual deafness (DFNB8). There are reports of 41 TMPRSS3 mutations identified as causing deafness. This gene encodes the transmembrane serine protease 3 protein, expressed in inner and outer hair cells and in the spiral ganglion.Mutations in the TBC1D24 gene cause hearing loss, genetic epilepsy, onychodystrophy, mental retardation, and seizures. TBC1D24 mutations cause severe-to-profound congenital autosomal recessive nonsyndromic sensorineural hearing loss, in addition to progressive dominant nonsyndromic sensorineural hearing loss. The TBC1D24 gene encodes the Tre2-Bub2-Cdc16 protein expressed in the cilia of inner and outer hair cells and in the spiral ganglion. TBC1D24 mutations cause postsynaptic auditory synaptopathy.Mutations in the DFNB59 gene are the second genetic cause of auditory neuropathy. The protein encoded by DFNB59 is important for the formation of peroxisomes that protect cells from damage during cellular antioxidant response. It is expressed in outer and inner hair cells and spiral ganglion neurons. To date, there are reports of 16 deafness-causing mutations in this gene, 2 of which are related to auditory neuropathy. There are no reports of CI outcomes in individuals with deafness caused by DFNB59 mutations.156The reported incidence of Autism Spectrum Disorder (ASD) has increased dramatically over the past 2 decades, and these trends have led to an increase in the number of referrals to the otolaryngologist for evaluation of individuals with ASD.According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), ASD is characterized as a neurodevelopmental disorder marked by impairment in social interaction, communication, and repetitive/restrictive behaviors.Autism remains a complex diagnosis because of its phenotypic heterogeneity, and its etiology is still debated. Some studies have shown a series of factors involved in the etiology that include genetic, immunological,159The pioneering study on the epidemiology of autism was conducted by Lotter, who reported an incidence of 4.5 diagnosed children per 10,000 in England.In Brazil, there is a lack of studies addressing the epidemiology of ASD nationwide. A study in the state of Santa Catarina found a prevalence of autism of 1.31 per 10,000 population.The increase in the diagnosis of children with ASD, as reported in the literature,169Some warning signs to identify children with ASD are also common to children with hearing loss, such as not looking when called and language impairment. Therefore, since hearing loss may be the cause of language impairment, or it may even co-occur with the diagnosis of ASD,In the literature, there is evidence of abnormal otolaryngologic and audiologic findings in objective and subjectiveAssessing the presence of hearing loss or impairment in individuals with ASD can be an even greater challenge in young children. In this age group, the otolaryngologic and audiologic evaluation involves a battery of physical examination and behavioral, electroacoustic, and electrophysiologic assessments guided by the crosscheck principle, in which possible differential diagnoses are analyzed before the audiologic diagnosis is accepted.OAE, immittance, and ABR testing, which are objective tests commonly recommended and used in clinical otolaryngologic practice, require the child to remain motionless, to wear headphones and have a probe inserted into the external auditory canal, and to have electrodes placed in the head and ears, which often makes assessment difficult in children with ASD.Therefore, objective assessments should be performed during natural sleep, and it is often necessary to schedule one or more visits to complete them; in some cases, they need to be performed with sedation in the operating room. Additionally, in subjective assessments, the child may have interfering behaviors, such as not conditioning to the test, not cooperating with the examiner, paying poor attention to the task, engaging in excessive activity, not tolerating headphones, and being combative toward the examiner.Therefore, otolaryngologic and audiologic assessments in these children may be a difficult task for health professionals and families. It is important to investigate these difficulties in order to propose solutions, guidelines, and improvements in the environment, procedure, and evaluation protocol, minimizing assessment time and the number of sessions and favoring a timely diagnosis. Moreover, identifying the adversities of audiologic assessment in ASD allows the health professional to interpret the test findings critically, thus helping to rule out or confirm a diagnosis of hearing loss, in addition to making it possible to recognize ASD diagnostic biomarkers.Lotter (1996)United States (CDC), incidence in 11 US states: 2000* 1 in every 150 children; 2021* 1 in every 44 children.Ferreira (2008)Beck (2017)Alves (2018)Protocol for otolaryngologic and audiologic evaluation of children with suspected and/or confirmed autism spectrum disorder in the perception of parents and/or caregiversTo identify factors that can complicate otolaryngologic assessment in ASD.To identify the main hearing tests and evaluation protocols used in this population.To identify the main child behaviors that can interfere with assessment.To characterize the group of children with suspected and/or confirmed ASD who have undergone hearing assessment.Protocol for otolaryngologic evaluation of patients with a presumptive diagnosis of autism spectrum disorder Call center/reception: Proper training of call center staff or care team.Call center/reception: Guidance on conducting the assessments.Child must be asleep during some of the audiologic tests (sleep in the center).Test should be scheduled following the child’s usual bedtime routine.Sleep deprivation; bring the child tired (playing or other activities).Does the child tolerate headphones? (Assess need for desensitization).Is the child afraid of physicians in white coats?Family – Special support from family and friends.Otolaryngologists – Acknowledge the need for different approaches to patients and their families.Audiologists – Acknowledge the need for different approaches to patients and their families.Child must be asleep during electrophysiologic and electroacoustic assessments.Crosscheck principle.Outpatient: Perform meatoscopy; explain the need for a complete hearing assessment and suggest a previous assessment with an otolaryngologist; record behaviors identified during audiometry.Because of the high prevalence of ASD in children with visual impairment or deafness, they should be evaluated for ASD in the presence of visual or hearing impairment.Visual and auditory rehabilitation should be started early, regardless of the degree of impairment; however, success with these devices may vary.Family should always receive guidance, and it is important that patients and family members have real expectations.Hearing loss may be the cause of language impairment, or it may even co-occur with the diagnosis of ASD.Genetic testing in individuals with autism is far from being routinely performed and does not always yield practical results, but the information provided can change the diagnosis and, consequently, the treatment. None of the molecules or syndromes currently linked to ASD has been proven to selectively cause autism. It appears to result in a variety of abnormal neurobehavioral phenotypes, including ASD and nonsyndromic mental retardation. The identification of molecular links between different ASD-related syndromes will lead to the identification of major deregulated signaling pathways in ASD.MED12 (Lujan-Fryns syndrome); Prader-Willi syndrome; Mutations in PTEN ‒ Phosphatase and Tensin ; Rett syndrome; Smith-Lemli-Opitz syndrome; Smith-Magenis syndrome; Sotos syndrome; and Tuberous sclerosis.Selected genetic syndromes that are known etiologies of ASD: 22q11.2 deletion syndrome, including velo-cardio-facial syndrome (Shprintzen); Angelman syndrome; CHARGE syndrome; Cornelia de Lange syndrome; Fragile X syndrome; Mutations in Management of patients with suspected autism spectrum disorder in the office•Otoscopy (conductive component).•Medical team orders the complete auditory test battery: Audiometry or assessment of auditory behavior; Transient-evoked and distortion-product OAE; Immittance testing or impedance audiometry; ABR; Steady-state response; and Tone-burst ABR.Has an otolaryngologist seen the patient?Scheduling team .Tests require specific preparation. An otolaryngologist should see the patient because, if there is any impediment, the tests will not be performed.A number of factors should be considered in the otolaryngologic evaluation of patients with suspected ASD:Ensure an audiologic diagnosis and early rehabilitation before proceeding with any further investigation (Insufficient).Indicate early language stimulation .Evaluate the constantly expanding and evolving list of available laboratory tests in light of the published literature .Recognize the phenotypes of well-described syndromic and metabolic conditions that overlap with ASDs .Define an individualized assessment plan based on medical history and clinical features (Insufficient).The WHO warns that 1.1 billion young people are at risk of hearing loss due to prolonged and excessive exposure to loud sounds.The use of portable music players such as MP3 players, iPods, smartphones, and similar devices has increased worldwide over the past few decades. They can produce sound pressure levels of up to 126 dBA.In fitness sports, the use of loud music is widespread. A study conducted at an aerobics endurance tournament showed music intensity levels ranging from 101 to 119 dB during 120 min of activity.Listening to music during sports activities enhances attention, reduces fatigue, and increases arousal. The more pleasurable a song is, the louder people wish to listen to it.Loud music features 3 main elements of addictive substances, as it causes rapid and intense changes in mood and arousal level, reduces negative mood states, and makes individuals wish to listen to the music again.Niskar et al.A study evaluating 5249 US adolescents aged 12 to 19 years showed that 15.9% had hearing deficits attributable to noise exposure.Exposure to moderate levels of noise, even in the short term, can cause extensive degeneration of inner hair cell synapses, but without hair cell degeneration. Audiometric testing is normal, but when evaluating a large number of noise-exposed people, on average, the thresholds are worse than those of people not exposed to noise.Children and adolescents, even with minimal hearing loss, can have long-term consequences with adverse effects on language development and academic performance. Noise exposure in young people can negatively affect the auditory cortex and increase susceptibility to the effects of aging on hearing.Recreational noise exposure can cause tinnitus and hearing loss in adolescents and young adults .Hearing loss in noise-exposed populations is slow but progressive, despite normal audiometric thresholds in the first few years of exposure .332 Thus, every child with suspected hearing loss has the right to diagnosis and appropriate treatment if necessary. This task force considers 5 essential rights: (1) Otolaryngologist consultation; (2) Speech assessment and therapy; (3) Diagnostic tests; (4) Treatment; (5) Ophthalmologist consultation.The Brazilian Federal Constitution of 1988, in its article 196, defines that health is a right of all and a duty of the State. To achieve this goal, the Brazilian public national health care system  was created in accordance with the guidelines of decentralization, comprehensive care, and popular participation, while respecting the principles of universal care, integrality, and equity.National campaigns should be implemented to raise awareness of the importance of caring for and treating children with hearing loss not just at birth, because many diseases manifest later, as explained in this document. Children at risk of hearing loss with poor school performance or delayed speech development should be evaluated by an otolaryngologist, qualified to assess and indicate the best path to follow.Speech-language pathology assessment plays a critical role in determining treatment and should be performed after evaluation by an otolaryngologist. The speech therapist should be qualified to perform the tests required for each child and, together with the otolaryngologist, indicate the best treatment option for the child.Diagnostic tests are essential to define a child’s hearing impairment. Newborn hearing screening with automated OAE measurements should not be repeated indefinitely. Children who fail the first evaluation should undergo a retest within 30 days. The follow-up for tests should be conducted according to the flowcharts presented in this document.Access to high-quality diagnostic tests is known to be difficult. Therefore, not only the devices required for the tests but also continuing education to audiologists and otolaryngologists should be made available. Children with external auditory canal stenosis or atresia require tests such as bone conduction ABR.Indiscriminate laboratory testing without clinical suspicion is ineffective and has low PPV. Investigation of the most common gene causing deafness, the GJB2 gene, should be offered to families with children diagnosed with profound hearing loss, in addition to imaging (CT or MRI) according to the diagnostic suspicion and reality of each health facility.The authors have no financial relationships relevant to this article to disclose.The authors declare no conflicts of interest.


As biomolecular approaches for hearing restoration in profound sensorineural hearing loss evolve, they will be applied in conjunction with or instead of cochlear implants. An understanding of the current state-of-the-art of this technology, including its advantages, disadvantages, and its potential for delivering and interacting with biomolecular hearing restoration approaches, is helpful for designing modern hearing-restoration strategies. Cochlear implants (CI) have evolved over the last four decades to restore hearing more effectively, in more people, with diverse indications. This evolution has been driven by advances in technology, surgery, and healthcare delivery. Here, we offer a practical treatise on the state of cochlear implantation directed towards developing the next generation of inner ear therapeutics. We aim to capture and distill conversations ongoing in CI research, development, and clinical management. In this review, we discuss successes and physiological constraints of hearing with an implant, common surgical approaches and electrode arrays, new indications and outcome measures for implantation, and barriers to CI utilization. Additionally, we compare cochlear implantation with biomolecular and pharmacological approaches, consider strategies to combine these approaches, and identify unmet medical needs with cochlear implants. The strengths and weaknesses of modern implantation highlighted here can mark opportunities for continued progress or improvement in the design and delivery of the next generation of inner ear therapeutics.  Cochlear implants (CIs) are prostheses that electrically stimulate the cochlear nerve to restore not only sound perception, but speech understanding in people with profound sensorineural hearing loss. CIs use a battery-powered sound processor worn at ear level to transmit electrical signals to an electrode array that has been surgically implanted in the inner ear. The first generation of implants was approved by the FDA in 1984. These devices used a single electrode that allowed recipients to perceive the presence or absence of sound, while variably restoring some speech understanding ,3. The FPatients who undergo implantation today do so under a growing number of indications and use devices with a tonotopic array of as many as 24 electrodes. These modern CIs promote language acquisition, literacy, and academic performance in pre-lingually deaf children ,6, whileWhile CI devices are a successful treatment option for many hearing-impaired individuals, several challenges related to their delivery, use, and access remain. Overcoming these challenges has fueled the investigation and development of biomolecular and pharmacologic therapeutic approaches using gene augmentation, gene-editing, antisense, and other small molecules ,21,22,23As these new therapies continue their development and optimization towards translation into hearing impaired patients, we review the current clinical management with CIs. Here, we describe hearing with an implant and detail common surgical approaches and electrode arrays, new indications and outcome measures for implantation, and barriers to CI utilization. Finally, we discuss unmet medical needs for individuals being treated with CIs, and the opportunities for improvement with biomolecular and pharmacological approaches.CIs are designed to restore speech perception for people with sensorineural hearing loss. They do not, however, replicate our hearing apparatus. Instead, CIs meet their purpose by layering an array of discrete electrodes covering the frequency range of human speech into the tonotopic infrastructure upon which we also rely to localize sound and hear music. Unsurprisingly, the extent to which CIs can process complex stimuli such as these is limited.CIs cover a narrower range of frequencies than the cochlea , and they do so less accurately. Individual electrodes stimulate broad swaths of territory along the basilar membrane, often falling short of the apical turn ,41. As aCIs also struggle to encode the temporal cues we use to perceive pitch in music, localize sounds, and hear speech in background noise. CIs cannot phase lock as our cochlea does . MoreoveAlong with deciphering speech from background noise, it is with this FSP information that we detect the lower-frequency, bass components of music . A CI usNovel brain-imaging and sound-processing techniques have allowed us to identify cochlear stimulation and auditory training strategies that may improve music appreciation among this population ,57,58,59In addition to FSP, there are a variety of other strategies designed to improve the sound quality a CI user can experience when listening to music by stimulating more territory along the basilar membrane. Measuring the extent to which a stimulus must be altered to generate perceived differences in sound quality among CI users , researcModern cochlear implantation is a relatively routine and safe procedure. Nonetheless, operations can generate trauma, inflammation, fibrosis, obstructive hydrops, or synaptic changes in the inner ear that can manifest as residual hearing loss and vertigo ,65,66,67For patients who have some residual hearing, threshold shifts are almost inevitable after implantation . Today, Electrode arrays are most commonly implanted via the transmastoid facial recess approach with RW or cochleostomy insertion . Some ceThe RW itself presents a reliable landmark for a surgeon placing an electrode array , and RW RW approaches are perhaps especially suited to placing shorter electrode arrays, such as those used for patients with substantial residual low frequency hearing. They are doubly favorable here, as histopathologic evidence indicates cochleostomies can seed an ossification process causing endolymphatic hydrops that characteristically costs a patient the low frequency hearing the operation aims to preserve, while treating their hearing loss . These fThe design of a CI’s electrode array also impacts hearing preservation after implantation. The two major categories of array are straight lateral wall (LW) and curved peri-modiolar (PM) . PM arraPure hybrid implants have electrodes that are roughly a third the length of typical arrays. There are also longer, short-LW arrays that offer slightly more coverage in the cochlea, while appearing to preserve hearing in the lower frequencies , though The growing use of cone beam CT imaging has allowed for intraoperative and postoperative evaluation of electrode placement. CT scans can show electrode dislocation, tip fold-over, and mispositioning. This allows for real time visualization of the electrode and revision of the insertion at the time of initial surgery . When coBone-conduction hearing aids (BCHA) and contralateral routing of signals (CROS) hearing aids have long been employed for patients with profound unilateral hearing losses (UHL) who pursue care . These dCIs present a means of restoring these binaural cues in patients with UHL, and in 2019, the Food and Drug Administration (FDA) expanded CI indications to include “patients 5 years and older with single sided deafness (SSD) and asymmetric hearing loss (AHL) who have profound sensorineural hearing loss in the ear to be implanted and normal hearing or mild to moderate sensorineural hearing loss in the other ear” . The approval followed the proliferation of evidence that adults with acquired UHL can access binaural hearing benefits in localization and masked speech perception, sometimes within months of implantation ,94,95. ISome of the data that contributed to the approval of CIs for SSD came from studies of implantation as a treatment for tinnitus ,99,100. Studies in the SSD setting were initiated by the observation that tinnitus suppression was a common side effect of treatment among people who underwent implantation for bilateral hearing losses . These tSSD trials of implantation for tinnitus have their own limitations. Patients can be neither randomized nor blinded. The most ubiquitous outcome measures for tinnitus , while nPatients who already use a CI and experience tinnitus rely on a combination of patient education, sound retraining therapy, and cognitive behavioral therapy, which are common strategies for other patients reporting tinnitus . While hBilateral profound hearing loss in the high frequencies prevents people from understanding speech, especially in noisy conditions, even if their low frequency hearing remains intact. Until recently, patients with profound high frequency losses and significant residual low frequency hearing were left to contend with the most socially isolating outcomes of their loss, without a solution . ImportaIn 2014, the FDA approved a hybrid device with the function of a hearing aid and a cochlear implant with a shorter electrode array that stimulates just the high frequency, basal turn of the cochlea . These dBy the time of their approval, these devices were not themselves new ,116. HowExperience with these devices has demonstrated that people can integrate acoustic and electrical signals, and hybrid implants effectively restore the consonant recognition necessary for users to unlock their residual lower frequency hearing ,122,123.Prolonged hearing preservation is possible among hybrid CI users; there is evidence of significant preservation 15 years after implantation . NonetheDespite the efficacy of hybrid implants and the potential for patients to integrate acoustic and electric signals in the same ear, a host of case series, cohort studies, and retrospective reviews have reported patients who initially use hybrid devices frequently move to rely solely on electrical stimulation ,128,129.Auditory brainstem implants (ABI) are analogous to CIs, save that their electrodes are on a flat mesh rather than a wire array, and they stimulate the cochlear nucleus in the lateral recess of the fourth ventricle in the brainstem. These devices were pioneered for patients with Neurofibromatosis type 2 (NF2), where they are used after bilateral acoustic neuromas or treatments thereof cause profound hearing loss . UnfortuIn managing NF2, physicians take every measure to preserve the cochlear nerve to the extent that the patient could still benefit from a CI, rather than an ABI. Surgeons have simultaneously resected acoustic neuromas while placing CIs for 30 years . Until 2Unlike NF2, which causes tumor-related cochlear nerve loss, cochlear nerve aplasia is a potentially treatable cause of deafness in children. Colletti et al. have consistently reported excellent results and even open set discrimination in children who use ABIs for cochlear nerve aplasia . Hearing loss is a significant, but modifiable risk factor for cognitive decline . HearingNaturally, CIs are being used and studied in older adults with hearing loss with increased frequency. Trials of older adults with and without cognitive impairment undergoing implantation report that the devices are safe to use and improve patients’ speech understanding and quality of life ,142. WhiCritical to the ongoing use of these devices in older populations is the finding that age and overall health do not appear to appreciably change a patient’s risk for CI-related complications . NonetheThe success of a CI is typically evaluated based on a user’s ability to recognize speech in quiet and noisy conditions. However, these performance indicators do not reflect users’ self-perceived communication abilities or the CI’s impact on their quality of life . PreviouThe arrival of these instruments is well-timed. They are the most psychometrically sound instruments we have for CI users and can therefore help clinicians interrogate the real-world value of ongoing iterative changes in implantation techniques and technology ,151. GivInvestigations into patients who do not receive the expected benefit from cochlear implantation have expanded our understanding of how genetic factors influence auditory outcomes. Notably, CI recipients with genetic derangements of spiral ganglion function perform lower on speech perception tests than patients whose mutations disrupt the organ of Corti . MiyagawIn a 2018 survey of 81 neurotologists, 78% reported that they had performed an off-label implantation in the previous 2 years . RespondThe FDA approved a device for children starting at 9 months of age for the first time in 2020 ,159. ThiWhile regulatory approvals and off-label uses for CIs proliferate, an insidious set of socioeconomic barriers also prevents patients in need of accessing implantation. In the United States (US), it is estimated that less than 10% of adult and 50% of pediatric candidates utilize CIs ,164,165.In the US, children and adults accessing their care via Medicaid who qualify for CI candidacy do not experience the same outcomes as those who are covered by private payers ,171. ThiThe care pathway for patients with private insurance is different, but not necessarily more straightforward. Private payers commonly disregard not only published scientific evidence, but also clinical practice guidelines, and inconsistently acknowledge common CI indications. It is not uncommon for a private payer to refuse to cover implantations for children under a year of age and those with SSD . Basic research on the feasibility of an Optical Cochlear Implant (oCI) using photonic stimulation of the hair cells or spiral ganglion cells rather than electrical current as used in the current Electrical Cochlear Implant (eCI) suggests a theoretical possibility of improving the dynamic range of current eCI stimulation strategies (which could enhance understanding in background sound and music appreciation) and more focused neural stimulation than eCI . Recent reviews provide an excellent summary of the major issues related to oCI ,177. Two basic strategies are under investigation: Infrared Neural Stimulation (INS), which encodes sound by creating heat with an implanted laser to initiate neural stimulation; and Optogenetic Stimulation, which expresses photosensitive ion channels to neurons. Despite the potential, investigators have several significant obstacles to overcome. With INS, the challenge of balancing the heat generation to create enough to stimulate without damaging the cells is formidable. There is still controversy as to whether or not such INS stimulation is producing direct neural stimulation from the localized thermal effect or if there is an optoacoustic event stimulating surviving neurons from the stress-relaxation waves following confined heating within the cochlea in animal experiments . With OpThe placement of the CI electrode array within the scala tympani necessarily disrupts the microenvironment of that delicate inner ear structure. A silicone carrier delivers the electrodes from the receiver–stimulator to the cochlea. Recent developments have allowed special grafting and coating of materials onto the silicone electrode carrier. Materials which reduce friction and insertion trauma have already been implemented in animal models with some success . The preDevelopment of coating materials not only allows for atraumatic electrode insertion, but may also enable the delivery of drugs and other biologically active compounds directly to the inner ear. Animal studies evaluating the safety of steroid-eluting electrode arrays are well underway. The ability to deliver steroids to the scala tympani provides an exciting opportunity to further advance acoustic hearing preservation and reduce vertigo in the setting of cochlear implantation . FinallyIntraoperative facial nerve monitoring has long been the practice for CI surgeons to preserve facial motor function during the delicate surgical procedure. Within the last decade, there have been significant developments of additional intraoperative monitoring procedures to evaluate the electrode insertion process and final placement prior to closure. Impedance measurements and neural response telemetry can be obtained after electrode placement and prior to closure to partially evaluate device integrity and placement.To further preserve acoustic hearing in patients undergoing CI, new intraoperative monitoring techniques have been developed to evaluate cochlear trauma and direct the surgeon to more gentle insertion. While a full discussion of these techniques is beyond the scope of this manuscript, intraoperative electrocochleography measures electrical potentials generated within the cochlea and can be used to evaluate preservation of function during insertion. The results of large reviews on the efficacy of this type of monitoring in the clinical setting are largely mixed . More reThere is a heterogeneous community of people who understand deafness not as a disability, but as a cultural characteristic to be embraced as part of an individual’s identity. Voices from this community are a constant and impactful presence in conversations that establish the goals of early childhood interventions for hearing loss, deaf education, and the experience of deafness. We are not attempting to write on behalf of the people in this community, nor to summarize what is a lived-in spectrum of deeply held beliefs about cochlear implantation. Similarly, we do not speculate as to their positions about forthcoming inner ear therapeutics. Our purpose here is to call attention to a constituency who will be a part of the coming conversations about interventions making their way into and beyond clinical trials. Themes from the conversations that define the CI space can inform the development and evaluation of an oncoming wave of inner ear therapeutics. CIs are the standard we have in treating so many of the conditions for which there are inner ear therapeutics in pre-clinical and clinical pipelines . UnderstA small molecule, gene, or antisense therapy designed to preserve or restore hearing could avert surgical implantation entirely, or postpone it. Alternatively, if these treatments selectively restore hearing in some frequencies, they may create a novel use case for combination therapy. Preclinical studies using gene and antisense therapies show impressive rescue of low- and mid-frequency sensitivity, demonstrating that these drugs can reach the cochlear apex ,37,38,39This review features the ongoing improvements in CIs and the major shortcomings in CI outcomes for listening in background sound, music appreciation, surgical and post-surgical complications, and the age of implantation limiting the therapeutic window that highlight the unmet medical needs for individuals with a hearing impairment. Gene and antisense therapies aim to reach all defective hair cells along the basilar membrane and, in doing so, may improve hearing in noisy environments and the appreciation for music. Several delivery routes to the inner ear have been investigated, including topical-tympanic membrane application (antisense), trans-tympanic injection , intracochlear injection via RW injection or cochleostomy (gene and antisense), and intralabyrinthine injection via the utricle or canalostomy ,26. The Recipients of new inner ear therapeutics may still benefit from the speech and auditory training that have been honed over decades with CI users. As we have learned with cochlear implantation, rehabilitation and hearing therapy is a significant component of therapeutic success beyond just providing sensory input. Patients pursuing new therapies will likely need to confront a set of economic and social barriers that overlaps those facing CI candidates. These and other tensions encountered over decades of implantation and use can direct opportunities to address unmet medical needs as we develop a new standard of care for people with hearing loss.


Coronavirus disease 2019 (COVID-19)-associated mucormycosis (CAM) is responsible for a high mortality rate due to its unique and severe host-pathogen interactions. Critically ill or immunocompromised COVID-19 patients are more prone to suffer from aggressive mycoses. Probable victims include those with uncontrolled diabetes mellitus (DM), metabolic acidosis, prolonged neutropenia, increased ferritin levels, hypoxia, and prolonged hospitalization with/without mechanical ventilators and corticosteroids administration. The current review aims to outline the journey of patients with CAM as well as the advantages and disadvantages of the currently available diagnostic techniques. It also discussed the current status of treatment options and caveats in the management of mucormycosis. Multidisciplinary team, early diagnosis, controlling the predisposing condition(s), complete surgical debridement, effective antifungal therapies , and implementing antifungal stewardship programs are imperative in CAM cases. Rhizopus oryzae (R. oryzae) fungus accounts for nearly 60% of mucormycosis in humans around the world, being responsible for 90% of the rhino-orbital-cerebral mucormycosis (ROCM) type [Lichtheimia, Apophysomyces, Cunninghamella, Rhizomucor, and Mucor species are less common types [R. oryzae, Lichtheimia, Rhizomucor, and Mortierella spp. can infect patients with diabetic ketoacidosis (DKA) or other types of acidosis. With their distinctive host-pathogen interactions, Mucorales evade the host immune system and facilitate disease progression regardless of treatment, increasing the mortality rate [Mucormycosis leads to poor survival rates regardless of the notable understanding of its pathophysiology, enhanced diagnostic tools, and different treatment options , 2. MucoCM) type . Lichtheon types . Mucoralon types . For insity rate .According to the World Health Organization (WHO) statistics, mucormycosis occurs with a global incidence rate of 0.005-1.7 per million population with a case fatality rate of 46%. In India and China, the incidence of mucormycosis predominantly increases among patients with uncontrolled diabetes mellitus (DM) –12. In Iet al. have confirmed the diagnosis of mucormycosis in 95% of COVID-19 patients, whereas 80% had DM, and about 76% received corticosteroids [et al. also reported that 57% of patients had uncontrolled DM while 18% had DKA in the 2019 nationwide multicenter study of 388 suspected or confirmed cases of mucormycosis in India before COVID-19 [et al. highlighted that COVID-19-associated mucormycosis (CAM) is more serious than influenza-associated mucormycosis, irrespective of an intense therapeutic approach [Recent global medical reports have documented that the rate of mucormycosis increases in COVID-19 patients and the cases are suffering from significantly poor prognoses . In a resteroids , 19. Forsteroids . Prakashapproach . The preThe nonspecific and confusing clinical presentation of mucormycosis remains burdensome, making its diagnosis and treatment more difficult . MucormyRapid diagnosis is usually deterred due to the relative lack of specific agents that detect mucormycosis in the cerebrospinal fluid . In addiet al. suggested to assess the risk factors, clinical settings, forms of invasive mycosis, advantages and limitations of diagnostic techniques, and demand for individualized or standard treatment options in patients with COVID-19 [Patients with COVID-19 exhibit ROCM as the most common clinical presentation seen worldwide in clinical microbiology , 23. ThrCOVID-19 .Table 1TDepending on the involved organ, ROCM ranges from a limited invasion to sinonasal tissue and rhino-orbital disease to a diffuse rhino-orbital-cerebral (ROC) disease that involves CNS . For insin-situ identification methods or culture of specimens are highly advocated to diagnose tissue mucormycosis [The United States Food and Drug Administration (FDA) has not yet approved serological assays that identify Mucorales compared to Aspergillus galactomannan index and β1,3-D-glucan (BDG) assays that can diagnose IA and other hyalohyphomycetes , 38. Dirrmycosis .et al. suggested that PCR should be restricted to tissues showing Mucorales hyphae upon staining to avoid the false positive results [Stains of fixed sections showing invasive nonpigmented hyphae, such as periodic acid-Schiff, hematoxylin-eosin, and Grocott-Gomori’s methenamine-silver stain, are confirmatory of mucormycosis . Moreove results .Lateral flow immunoassay (LFIA) is an essential serological assay for large-scale screening of immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), being used for national and regional seroprevalence surveys in Europe and the USA , 42. LFIThe PCR of fresh tissues is highly sensitive and specific with PCR-restriction fragment length polymorphism that confirms the diagnosis to the genus or species level. The European Confederation of Medical Mycology (ECMM) states that the fresh tissue is more advantageous than those embedded in paraffin because formalin damages DNA . HoweverThe PCR of blood/serum samples can early identify circulating fungal DNA, help follow up and assess treatment response, and indicate angioinvasive disease. However, low quantities of fungal DNA, heterogeneity of internal transcribed spacer regions, and lack of both comprehensive database and species-specific probes provide false negative result. False positive results occurring due to amplification of DNA contaminating the sample are less likely compared to other samples –59.Although investigators have evaluated numerous therapeutic regimens, mainly systemic glucocorticoids are proven to improve survival in hypoxemic COVID-19 patients . Recogniγ and/or granulocyte-macrophage colony-stimulating factor might improve the immune system against certain Mucorales in vitro [Upon suspicion of mucormycosis, the ECMM and Mycoses Study Group Education and Research Consortium (MSG-ERC) in 2019 strongly recommended an appropriate imaging, followed by an immediate complete surgical intervention whenever possible, and systemic antifungal drugs. Surgical debridement for both necrotic tissue and neighboring healthy-looking infected tissues should be aggressive when needed. Surgery is helpful in soft tissue and ROC infections, and it may be valuable in a single localized pulmonary lesion. Table in vitro , 70.TablCunninghamella and Apophysomyces isolates. A minimum inhibitory concentration (MIC) of ≤0.5 μg/mL amphotericin B significantly resulted in better outcomes over six weeks in humans [R. oryzae in infected mice [Among other antifungal therapies, amphotericin B possesses the highest activity except for some n humans . Moreoven humans . Similarn humans –76. For ted mice . Oral foted mice , 78, a nMultidisciplinary team preparedness, early diagnosis, controlling the predisposing condition(s), applying complete surgical debridement, using systemic and local antifungal therapies, and implementing antifungal stewardship programs are imperative for CAM patients. Further research is mandatory to explore other noxious prognostic factors in COVID-19 associated mucormycosis and methods to reduce their influence on morbidity and mortality along with finding more effective medications.