Infectious Disease Reports 2012; volume 4:e9

Diagnosis and treatment Almost 30 years after its first description,1 HIV still remains a global pandemic, particular- Correspondence: Petros V. Vlastarakos, Lister of HIV-associated ly affecting the countries of sub-Saharan Hospital, Coreys Mill Lane, Stevenage, manifestations Africa, Southeast Asia, and Latin America. HIV Hertfordshire, SG1 4AB, UK. in otolaryngology is an RNA retrovirus which compromises the Tel. +44.1438488837 - Fax: +30.2109714870. , and renders the infected per- E-mail: [email protected] 1 2 son susceptible to opportunistic infections and Emily Iacovou, Petros V. Vlastarakos, Key words: HIV, AIDS, ear, nose, throat, oral. George Papacharalampous,3 malignancy. George Kampessis,4 The incidence of HIV infection in 2009 was Contributions: EI wrote the article; PVV study 2.6 million, whilst the respective prevalence Thomas P. Nikolopoulos5 concept and wrote the article; GP and GK litera- ranged between 31.4-35.3 million people. The ture research and wrote the article; TPN study 1 General Hospital of Larnaca, Cyprus; prevalence of HIV had risen by 27% compared overview and wrote the article. 2Lister Hospital, Stevenage, UK; to the previous decade, although the annual 3Penteli Children’s Hospital, Greece; rate of new cases had been steadily declining Conflict of interest: the authors report no con- flicts of interest. 4Royal Sussex County Hospital, UK; since the late 1990s. In addition, the estimated 5 Atticon University Hospital, Greece number of children living with HIV increased Received for publication: 1 August 2011. to approximately 2.5 million in 2009. Revision received: 9 October 2011. The increased incidence of HIV has resulted Accepted for publication: 28 October 2011. in a greater number of HIV-infected patients presenting to ENT doctors. Indeed, up to 80% This work is licensed under a Creative Commons Attribution NonCommercial 3.0 License (CC BY- Abstract of HIV-infected patients eventually develop NC 3.0). ENT manifestations.2-4 Among the latter, oral Almost 30 years after its first description, disease seems to be the most common, occur- ©Copyright E. Iacovou et al., 2012 HIV still remains a global pandemic. The pres- ring in approximately 40-50% of HIV positive Licensee PAGEPress, Italy ent paper aims to review the current knowl- patients.5 Predisposing factors for HIV-related Infectiousonly Disease Reports 2012; 4:e9 edge on the ear, nose and throat (ENT) mani- ENT conditions include CD4+ cell count of less doi:10.4081/idr.2012.e9 festations of HIV infection, and present the than 200/μL, plasma HIV-RNA levels greater available diagnostic and treatment options. A than 3000 copies/mL, xerostomia, poor oral positive adult patients4,11,12 whereas the respec- literature review was conducted in Medline hygiene, and smoking.6,7 tive percentage in children ranges between and other available database sources. Although ENT manifestations may notuse be Information from related books was also 22.5 and 83.3%.13 diagnostic of HIV infection, they may be heav- included in the data analysis. It is well can present in three forms: ily suggestive of such an infection.8 In addi- acknowledged that up to 80% of HIV-infected pseudomembranous candidiasis, erythema- tion, the occurrence of certain oral manifesta- patients eventually develop ENT manifesta- tous candidiasis, and angular tions in patients with known HIV disease who tions; among which, oral disease appears to be (Figures 1-3).14 Oral pseudomembranous can- are not receiving treatment may be related to the most common. Oro-pharyngeal manifesta- didiasis is the most common fungal infection the progression of the disease.8 Finally, the tions include candidiasis, periodontal and gin- in HIV disease. It has been associated with presence of ENT disease in patients on anti- gival disease, HSV and HPV infection, oral more frequent progression of HIV to AIDS, and retroviral therapy could be the result of an hairy leucoplakia, Kaposi’s sarcoma, and non- also used as a clinical marker to define the increase in the plasma HIV-RNA and suggest Hodgkin’s . ENT manifestations in severity of HIV infection.15 It appears as treatment failure.8-10 In this context, the provi- the neck can present as cervical lym- creamy, white, curd-like plaques on the buccal sion of appropriate care to HIV patients may phadenopathy or parotid gland enlargement. mucosa, , and other oral mucosal sur- require a multi-disciplinary approach. Respective nasal manifestations include faces. The plaques can be wiped away, leaving The aim of the present paper is to review the sinusitis (often due to atypical bacteria), and a red or bleeding underlying surface. The most current knowledge on ENT manifestations of allergic rhinitis. Finally, otological manifesta- common organism involved is albi- HIV infection, and present the available diag- tions include otitis (externa, or media), inner cans; however involvement of non-albicans nostic and treatment options. The implications ear involvement (sensorineural hearingNon-commercial loss, species, such as Candida glabrata and Candida of the early identification of HIV-associated disequilibrium), and facial nerve palsy (up to dubliniensis, has also been described.16,17 ENT disease from a public health perspective 100 times more frequently compared to the Erythematous candidiasis, on the other are also discussed, along with clinical markers general population). Although ENT symptoms hand, presents as a red, flat, subtle on of immune compromise. are not diagnostic of the disease, they might the dorsal surface of the tongue, or on the hard be suggestive of HIV infection, or related to its or soft . The lesion often involves two progression and the respective treatment fail- opposing surfaces, i.e. if a lesion is present on ure. ENT doctors should be aware of the ENT Oro-pharyngeal manifestations the tongue, the palate should be examined for manifestations associated with HIV disease, a matching lesion, etc. Patients usually com- and the respective diagnosis and treatment. A of HIV infection plain of a burning sensation, especially while multi-disciplinary approach may be required to eating spicy or salty food. When the hypophar- provide the appropriate level of care to HIV Oral candidiasis, commonly known as ynx, larynx, or are affected, symp- patients. thrush, is by far the most common oral mani- toms may progress to severe odynophagia and festation of HIV infection. Candidal infection swallowing difficulties. This may be especially can occur in the oropharynx, hypopharynx, and true in children, in which candidal esophagitis larynx, and usually results in severe odynopha- may require hospital admission, and intra- Introduction gia and swallowing difficulties. The prevalence venous administration of amphotericin B.18 of candidiasis varies from 30-90% among HIV Diagnosis is based on the clinical appearance

[page 22] [Infectious Disease Reports 2012; 4:e9] Review of the taking into consideration the history of HIV infection. However, candidiasis can be confirmed in challenging cases from the identification of fungal hyphae or blas- tospores in potassium hydroxide (KOH) prepa- ration.8 Treatment of mild to moderate cases of both erythematous and pseudomembranous can- didiasis includes clotrimazole troches, nystatin oral suspension, and nystatin pastilles, where- as systemic administration of fluconazole, Figure 1. Oral pseudomembranous can- Figure 2. Erythematous candidiasis.8 intraconazole and voriconazole is warranted in didiasis.8 Reproduced with permission Reproduced with permission from IAS- moderate to severe cases (Table 1). from IAS-USA. Top HIV Med 2005;13: USA. Top HIV Med 2005;13:143-8. Voriconazole should be reserved for cases of 143-8. fluconazole resistance, due to more serious iteractions with other drugs.8 Antifungal ther- Periodontal and is fre- apy should last for two weeks to reduce the quently seen in patients with HIV. The preva- colony forming units to the lowest level possi- lence varies between 0-47% in adults19 and 0 to ble and prevent recurrence. 20% in children.20 It most commonly presents presents as erythema, as plaques similar to the ones found in non- and/or fissuring in the corners of the mouth. It HIV populations. may co-exist with erythematous or (Figure 4) pres- pseudomembranous candidiasis, and persist ents as a red band along the gingival margin, for an extensive period of time if left untreat- accompanied by occasional bleeding and dis- 8 ed. Treatment involves the use of a topical comfort. It most frequently appears at the ante- Figure 3. Angular cheilitis. Reproduced rior teeth, but can also extend to the posterior withonly permission from IAS-USA. Top HIV antifungal cream directly applied to the affect- Med 2005;13:143-8. ed areas four times a day for two weeks. teeth. It can also present on attached and non-

Table 1. Treatment regimens for HIV-associated ear, nose and throat (ENT) manifestationsuse in adults and children. HIV manifestation Treatment in adults Treatment in children Oral candidiasis Topical agents Topical agents Clotrimazole troches 10 mg: dispense 70, Nystatin 200,000-800,000 U: used qds, or 5 times a day dissolve 1 troche in mouth 5 times a day for 14 days Miconazole 200,000-800,000 U: qds to 5 times a day. Nystatin oral suspension 500,000 U: Swish 5 mL in mouth Oral nystatin 200,000 U: in tablets dissolve as long as possible then swallow (optional), qds for 14 days 1 in the mouth 5 times a day Nystatin pastilles 100,000 U: dispense 56, Systemic agents dissolve 1 in mouth qds for 14 days Fluconazole or ketoconazole 6mg/kg of Systemic agents body weight for 5-7 days Fluconazole 100 mg: dispense 15 tablets, take 2 tablets on day 1, Clotrimazole 10mg bd followed by 1 tablet od for the remainder of the 14-day treatment period Itraconazole oral suspension 10 mg/10 mL: dispense 140 mL, swish and swallow 10 mL per day for 7-14 days. Take medication without food. Voriconazole 200 mg: dispense 14 tablets, take 1 tablet bd for 2 weeks or at least 7 days following resolution of symptoms Angular cheilitis Miconazole cream apply qds for 14 days Miconazole cream apply qds for 14 days KetoconazoleNon-commercial cream apply qds for 14 days Ketoconazole cream apply qds a day for 14 days Necrotizing periodontitis Metronidazole 500 mg: 1 tablet bd for 7-10 days. Metronidazole 15-30 mg/kg/day orally in 3 divided Amoxicillin 500 mg: tds for 7-10 days. doses tds for 7-10 days Clindamycin 150 to 300 mg: qds for 7-10 days. Amoxicillin 40 mg/kg/day in divided doses tds for 7-10 days. into 3 or 4 equal doses for 7-10 days. Clindamycin 8-16 mg/kg/day (4-8 mg/lb/day) divided Oral HSV Acyclovir 800 mg, 5 times a day for 7-10 days Acyclovir 10 mg/kg qds or 5 times per day*. Famciclovir 500 mg tds for 7 days HSV prophylaxis: Acyclovir10 mg/kg bd, or tds Sinusitis CD4>200 cells/mm3 Amoxicillin 40 mg/kg/day tds in divided doses Amoxicillin 1.5-4 g/day Amoxicillin/clavulanate 125/31 tds between 1-6 years, Amoxicillin/clavulanate: 1.75-4/250 g/day 250/62 between 6-12 years Cefuroxime axetil 500 mg bd Cefuroxime axetil 20-30 mg/kg daily given in 2 divided Trimethoprim/sulfamethoxazole:160 mg-800 mg orally bd doses in children >4 weeks of age Telithromycin Trimethoprim/sulfamethoxazole Erythromycin, clarithromycin, azithromycin 6-10 mg/kg/day orally in children >2 months of age CD4<200 cells/mm3 or failure of above therapy Erythromycin, clarithromycin, azithromycin Fluoroquinolone + clindamycin or metronidazole od, once daily, bd, twice daily; tds, every 8 h; qds, every 6 hbd, twice daily; tds, every 8 h. *Severe cases: Acyclovir 10 mg/kg iv tds

[Infectious Disease Reports 2012; 4:e9] [page 23] Review attached gingiva as petechia-like patches. A highly active antiretroviral therapy (HAART most frequently involved, followed by the gingi- fungal etiology has been reported21,22 however therapeutic regimens).38,39 This suggests that a val and buccal mucosa, as well as the dorsum antifungal therapy is not required. Treatment drug or combination of drugs used to treat HIV of the tongue. Kaposi's sarcoma-associated includes debridement by the dentist, mouth may be a risk factor for oral HPV infection.40 herpes was proven to be a co-factor in the rinses with a 0.12% chlorhexidine gluconate The most common HPV subtypes found in the presentation of Kaposi's sarcoma in patients suspension twice daily for two weeks, and oral cavity are subtypes 16 and 18, which may with HIV. Kaposi's sarcoma can be macular, home oral hygiene. be related to oral sexual behavior. The nodular, or raised and ulcerated. The color of In contrast, necrotizing and may be cauliflower-like, spiked, or raised with the lesions can range from red to purple. Early necrotizing periodontitis (Figure 5) can result a flat surface. Treatment involves surgery lesions tend to be red, flat and asymptomatic, in the rapid destruction of soft tissue in the (laser, or cryotherapy) which may need to be with the color becoming darker as the lesion former and hard tissue in the latter condition. repeated due to the frequent recurrence of the ages. As lesions progress, they can become Necrotizing ulcerative periodontitis is a mark- lesions. symptomatic due to trauma or infection. er of severe immune suppression.23 It is char- Kaposi's sarcoma (Figure 9) is still the most of the lesion, usually under local anes- acterized by severe pain (often described by common oral malignancy seen among patients thetic, is necessary for diagnosis. Following patients as deep jaw pain), loosening of the with HIV. The prevalence of oral Kaposi’s sar- the diagnosis of Kaposi's sarcoma, oral teeth, bleeding, fetid odor, ulcerated gingival coma of the mouth varies from 0-12% in Africa hygiene is necessary, and topical injections of papillae, and rapid loss of bone and soft tissue. and 0-38% in USA and Europe.6,41 The oral cav- chemotherapeutic agents, such as vinblastine Intervention is usually intensive curettage and ity is commonly affected and is the first clini- sulfate, or even surgical removal or radiation debridement of all involved tissues, and use of cal site of Kaposi's sarcoma in 20% of cases, therapy can be considered for treatment. topical antiseptic agents, such as 0.12% while it occurs concomitantly with skin and Several surgical techniques have been chlorhexidine gluconate or 10% povidone- visceral involvement in up to 70% of patients.41 described, including cryotherapy and laser iodine lavage. More severe cases should be Within the oral cavity, the hard palate is the therapy.42,43 Systemic chemotherapy should be supplemented by a short course of systemic antimicrobial therapy, usually metronidazole.24 Clindamycin and amoxicillin have also been recommended.25 only Oral infections with virus (HSV) (Figure 6) occur in up to 9% of adults4,11 and 1.3-24% of children with HIV.27-29 Oral HSV presents as a small crop of vesicles which pro- use duce small, painful ulcerations extending onto the adjacent skin, and may coalesce to form giant herpetic lesions. Although their clinical features are similar to non-HIV infected patients, the lesions are often bigger in HIV 8 Figure 4. Linear gingival erythema. 31 patients, recur more frequently, and tend to be Reproduced with permission from IAS- Figure 7. Oral hairy . more persistent. Lesions most commonly USA. Top HIV Med 2005;13:143-8. appear on the , in the mouth, hard palate, and . Although they are typically self-lim- iting, the use of antiviral agents, such as acy- clovir, is sometimes required. HSV ulcers may become chronic in children with severe HIV, and convert into true membranes which may require hospital admission and intravenous administration of acyclovir30 (Table 1). Oral hairy leukoplakia (Figure 7) is a large- ly asymptomatic condition of theNon-commercial tongue caused by the Epstein-Barr virus. It presents as 8 a white corrugated lesion on the lateral bor- Figure 5. Necrotizing ulcerative periodon- Figure 8. Oral HPV lesion. Reproduced titis.8 Reproduced with permission from with permission from IAS-USA. Top HIV ders of the tongue. The lesion cannot be IAS-USA. Top HIV Med 2005;13:143-8. Med 2005;13:143-8. removed by the patient. The prevalence of oral hairy leukoplakia varies from 0.42-38% in HIV- infected adults32-34 to around 2% in children.20 The terminology of this condition arises from the appearance of elongated filiform papillae which can be accompanied by white plaque- like changes. No treatment is required unless cosmetic concerns arise.8 In such cases, good results have been reported with topical appli- cation of trichloracetic or glycolic acid,35 podophyllum resin solution 25%36 and oral acy- clovir.37 Oral human papilloma-virus infection 26 Figure 6. Oral Herpes Simplex virus.26 Figure 9. Kaposi’s sarcoma. (HPV) (Figure 8) has increased in the era of

[page 24] [Infectious Disease Reports 2012; 4:e9] Review reserved for patients with both oral and extra- represent the first clinical manifestation of Sensorineural hearing loss, either unilater- oral Kaposi's sarcoma.44 HIV. Clinical examination should include al or bilateral, occurs in 21-49% of HIV-infect- Non-Hodgkin’s lymphoma (NHL) is the sec- assessment of the characteristics of the mass ed patients.51,59 Most patients show down-slop- ond most common malignant condition associ- (i.e. fixation) and the function of the facial ping hearing loss, usually moderate in the high ated with HIV infection. present nerve. The three common causes of parotid frequencies, whereas speech discrimination is as a focal, ulcerated soft tissue mass on the enlargement in HIV-infected patients are reac- not significantly affected. This type of hearing palate or gingival tissues, which may be red tive of an intraparotid lymph node, loss cannot be easily explained, as a histologi- and inflamed. The lesions can be painful, and benign lymphoepithelial lesions with ductal cal study of the organ of Corti in HIV patients progress rapidly. Suspected lesions are diag- metaplasia, and benign lymphoepithelial did not reveal any abnormality, except from nosed with a biopsy, usually under local anes- cysts.50 Fine-needle aspiration is an effective some cystic changes in the spiral ligament and thetic. Management requires systemically method of distinguishing benign from malig- stria vascularis.54 Possible explanations administered chemotherapy. Many studies nant parotid lumps. The most common FNA include the involvement of either retrocohlear have shown that the CHOP regimen diagnoses include cystic mass or lymphadeni- pathways, or the cochlear nerve itself. Indeed, (cyclophosphamide, doxorubicin, vincristine tis and chronic inflammation.50 and prednisone) can be considered the stan- The treatment of salivary gland enlargement dard approach for patients with aggressive in HIV disease still remains controversial. NHL in the context of HIV infection.45,46 Superficial parotidectomy has been proposed, Surgical debulking may be required for pain but has not yet been widely accepted. relief and improvement of chewing, swallow- Aspiration of the cystic lesions can be of some ing, and speech in large exophytic or peduncu- temporary benefit, and injections of tetracy- lated lesions, whereas radiotherapy may be cline and doxycycline have been shown to be considered for large lesions which cannot be successful, although with limitations due to easily accessed.44 the presence of multiple cysts. Alternatively, external irradiation can be considered (24 Gy in 1.5 Gy daily fractions), with overall accept- only able cosmetic and long-term functional Neck manifestations of HIV results.50,51 infection Figure 10. Right mastoiditis (CT scan-axial projection). The patient underwent corti- use cal mastoidectomy. Cervical lymphadenopathy is the most com- Otological manifestations of mon manifestation of HIV infection in the neck. In addition to reactive lymphadenitis, HIV infection cervical lymphadenopathy may result from tuberculosis, lymphoma, or Kaposi's sarcoma The spectrum of otological manifestations in HIV patients. The term HIV lymphadenopa- in HIV infection is wide. It involves all three thy describes the presence of diffuse lym- parts of the ear (external, middle, inner), with phadenopathy in two or more sites of the neck a cumulative frequency of 20-80% in both for longer than three months.47 This can occur adults and pediatric patients.3,4 in up to 70% of HIV patients within the first Indeed, seborrheic dermatitis has been few months after seroconversion, even before reported in up to 83% of patients, and usually any other symptoms of HIV infection appear. involves the periauricular area.52,53 Otitis The same condition is also seen in children.48 externa, on the other hand, is usually caused The lymph nodes are soft and symmetrical, by Pseudomonas aeruginosa, whilst Candida ranging from 1 to 5 cm in diameter. They are albicans is often the cause of otomycosis. Figure 11. Right mastoiditis (CT scan- coronal projection). The patient under- most frequently observed in the posterior tri- Otalgia is a very frequent symptom in HIV went cortical mastoidectomy. angle.4 The histology is usually Non-commercialsuggestive of patients, which can be attributed to the dispro- reactive follicular hyperplasia. Fine needle portionately severe inflammatory changes in aspiration is indicated in cases of asymmetry, the mastoid air-cells even in otherwise asymp- rapidly enlarged lymph nodes, or any other sus- tomatic carriers.52 Otitis media with effusion picious features. Biopsy under local or general secondary to nasopharyngeal lymphoid hyper- anesthetic may be necessary in cases of high plasia or other nasopharyngeal masses is also suspicion for lymphoma.49 not uncommon in HIV-positive patients.55,56 is also not uncom- ever, Kaposi's sarcoma should be excluded.57 mon in HIV-infected patients. It usually Acute otitis media may also occur, but is usual- involves the parotid glands, tends to be bilater- ly seen in patients with end-stage HIV disease. al, sometimes cystic, and can be accompanied Finally, an increased prevalence of by generalized lymphadenopathy. Typically, the Pneumocystis carinii-infected aural polyps has patient presents with a history of progressive been reported in HIV patients with chronic oti- parotid swelling with minimal tenderness over tis media.4 Treatment in cases of middle ear several months. Salivary gland enlargement infection usually includes broad-spectrum Figure 12. Magnetic resonance imaging occurs in approximately 3 to 30% of adult antibiotics, whereas mastoid exploration may scan of the previous patient. Please note patients infected with HIV,39 and in up to 30% be necessary in cases unresponsive to conser- the difference in the signal on the right of infected children.3 This condition may also vative treatment58 (Figures 10-12). (circle) compared to the left side.

[Infectious Disease Reports 2012; 4:e9] [page 25] Review

HIV was shown to induce neuropathological Table 2. Prevalence of HIV-associated ear, nose and throat (ENT) manifestation in adults and changes and damage to the central nervous children. system, particularly subcortical demyelination, Common HIV-associated Prevalence Prevalence in a large percentage of infected individuals, ENT manifestations in adults in children even in the absence of gross neurological man- ifestations.60 Other causes of sensorineural Oral manifestations hearing loss such as neoplasms, and ototoxic Oral candidiasis 30-90% 22.5-83.3% agents should also be excluded. If the hearing Periodontal and gingival disease ≤4% ≤20% Herpes Simplex virus infection 9% 1.3-24% loss affects the patient’s everyday listening ≤ Oral hairy leukoplakia 0.42-38% 2% activities and quality of life, the provision of Neck manifestations digital hearing aids should be considered. Cervical lymphadenopathy ≤70% ≤70% HIV patients also tend to experience signifi- Parotid gland enlargement 3-30% ≤30% cant disequilibrium, which is also often clini- Nasal manifestations cally attributed to central nervous system Allergic rhinitis ≤70% n.r. pathology. However, inner ear abnormalities Sinusitis 30-68% 24% have also been reported (i.e. sub-epithelial ele- Otological manifestations vation of the neurosensory of the Otitis externa 5% 4% saccule and utricle, inflammatory endolym- Otitis media 13% 46% phatic precipitations) and may also be impor- SNHL 21-49% n.r. tant in the pathogenesis of vertigo in these Facial nerve palsy 4.1% n.r. patients.54 n.r., not reported; SNHL, sensorineural hearing loss. Finally, unilateral and bilateral facial nerve palsy is a condition that occurs with a 100-fold greater frequency in the HIV infected popula- intranasally-administered steroids, in patients lococci, and anaerobic species. Appropriate tion (4.1% vs 0.04%)60-62 (Table 2). Facial nerve receiving ritonavir-containing antiretroviral oral only treatment in these cases includes the neuropathy can occur at any stage of the HIV regimens72 (Table 3). Budesonide is preferred combination of fluoroquinolone and clin- infection. It may precede the appearance of over fluticasone, due to the significantly longer damycin or metronidazole. The combination of HIV antibodies, and seems to occur more fre- half-life of the latter, whereas montelukast can two antimicrobial agents with activity against 71 quently in HIV carriers than patients with full- be successfully used. H1-antihistamines can Pseudomonas aeruginosa was shown to blown AIDS.62-64 Peripheral facial nerve neu- also be considered in patients with HIV.74,75useimprove mortality in patients with HIV with ropathy is usually self-limiting, and may either In addition to compromised immunity, Pseudomonas infection, compared with be idiopathic, or due to herpes virus infection impaired mucocilliary clearance has also been monotherapy.77 Patients with persisting symp- (Ramsey Hunt syndrome).65 Treatment reported, and can be held accountable for the toms require nasal endoscopy with culture of includes acyclovir 800mg five times daily for high prevalence of rhinosinusitis in HIV the obtained swabs, and a CT scan of the seven days, and administration of pred- patients.67 There is no difference in bacteriolo- sinuses, with the view of performing endo- nisolone 30 mg once daily for five days, with gy compared with the general population, scopic drainage; intravenous antibiotics can tapering of the starting dose in three-day inter- including Streptococcus pneumoniae, also be used.78,79 Patients with no improvement vals. Facial nerve palsy can also be seen in end- Haemophilus influenzae, Moraxella after maximal medical treatment can be con- stage patients either as an isolated entity, or as catarrhalis, and Streptococcus viridans in sidered candidates for functional endoscopic part of multiple cranial nerve involvement. acute episodes, whereas Staphylococcus sinus surgery, especially when anatomic varia- However, it is usually secondary to opportunis- aureus, Staphylococcus epidermidis, and anaer- tions of the nasal and paranasal cavities which 80 tic infections or intracranial tumors.66 obes are seen in chronic cases. However, atyp- predispose to sinus disease are present. ical bacteria can also play an important role Furthermore, surgical management is and need to be considered in the treatment of required in cases of invasive fungal sinusitis, these patients, especially in cases of decreased with debridement of infected bone and tissue, Nasal manifestations of HIV CD4 count (i.e. Alternaria alternata, correction of the conditions that predispose to Non-commercialAspergillus, Pseudallescheria boydii, infection, and antifungal medication. The use infection Cryptococcus, Candida albicans, of liposomal amphotericin B which shows Acanthamoeba castellani, Microsporidian, and increased cure rates and decreased drug toxic- Nasal manifestations are not uncommon Legionella pneumophila).67 ity, compared with conventional amphotericin among HIV patients. Indeed, rhinosinusitis Standard outpatient medical therapy with B therapy, should be preferred.77 Washings seems to occur with a prevalence of 11-70% in oral antibiotics for three weeks and nasal with solutions containing amphotericine-B different studies.67-70 decongestants are often sufficient. In chronic and water for injection may also prove useful.81 Although cellular immunity is compromised cases, treatment should last 4-6 weeks.76 Oral in AIDS, studies have shown excessive produc- antibiotics in cases of acute infection include tion of IgE, which can be suggestive of allergic amoxicillin (standard or high doses), co-amox- rhinitis (in the absence of active parasitic iclav (standard or high doses), or cefuroxime. Conclusions infections). Sample et al.71 reported a 2-fold Trimethoprim/sulfamethoxazole or macrolides increase in the incidence of allergic symptoms can be used in β-lactam-allergic patients, but HIV is a global pandemic that affects mil- in HIV-infected men, which may reach 87% failure rates are higher. If the response to lions of adults and children in the developed after the infection. Patients typically present antibiotic therapy is partial, or when the CD4 and developing countries. The prevalence of with clear rhinorrhea and nasal congestion. count is less than 200 cells per mm3, and in HIV has risen by 27% compared to the previous Treatment is challenging, due to the risk of cases of chronic infection, the coverage should decade, although the annual rate of new cases iatrogenic Cushing’s syndrome from the be broadened to include pseudomonas, staphy-

[page 26] [Infectious Disease Reports 2012; 4:e9] Review had been steadily declining since the late used in the treatment of mild to moderate This requires oral hygiene and topical injec- 1990s. cases, whereas systemic administration of flu- tions of chemotherapeutic agents; surgical Up to 80% of HIV-infected patients eventual- conazole, intraconazole and voriconazole is removal or radiation therapy can also be con- ly develop ENT manifestations. Among ENT warranted in moderate to severe cases. Oral sidered for treatment. manifestations, oral disease seems to be the HPV infection has also increased in the era of HIV lymphadenopathy may be the result of most common, occurring in approximately 40- HAART therapeutic regimens, suggesting that reactive lymphadenitis, tuberculosis, lym- 50% of HIV positive patients. Oral candidiasis a drug or combination of drugs used to treat phoma, or Kaposi's sarcoma, and is the most is by far the most common oral manifestation HIV may be a risk factor for the former. common manifestation of HIV infection in the of HIV infection. Clotrimazole troches, nystatin Kaposi's sarcoma is still the most common oral neck. Salivary gland disease is also not uncom- oral suspension, and nystatin pastilles can be malignancy seen among patients with HIV. mon, but its treatment still remains controver-

Table 3. Interactions between commonly administered ear, nose and throat medications and antiretroviral drugs.73 ENT medication Interaction with antiretroviral drug/potential clinical effects Management Itraconazole Inhibition of CYP450 3A4 If co-administration with darunavir is required, Increased darunavir and itraconazole effects when itraconazole is combined the dose of itraconazole should not exceed 200 mg daily with darunavir (darunavir also inhibits CYP450 3A4) Administer itraconazole capsules at least 2 h after Decreased itraconazole effects when combined with didanosine, didanosine tablets/suspension (decreased gastric acidity from the antacid buffer contained within didanosine Do not co-administer with efavirenz tablets/suspension resulting in decreased itraconazole absorption) Decrease indinavir to 600 mg tds Decreased itraconazole effects when combined with efavirenz (efavirenz induces CYP450 3A4) Do not exceed itraconazole 200 mg bd Increased indinavir effects when combined with indinavir (due to CYP450 3A4 inhibition) Manufacturer recommends against using high doses of Increased lopinavir/ritonavir and itraconazole effects when combined with lopinavir/ritonavir itraconazole (including drops) with lopinavir/ritonavir (lopinavir/ritonavir also inhibits CYP450 3A4) (200 mg daily) Increased ritonavir effects when combined with ritonavir (due to CYP450 3A4 inhibition) Doseonly adjustment when combined with Increased saquinavir and itraconazole effects when combined with saquinavir ritanovir is not established (saquinavir also inhibits CYP450 3A4) Consider reducing itraconazole to 100 mg bd when combined with saquinavir Voriconazole Inhibition of CYP450 3A4 Do not co-administer with atazanavir/ darunavir Decreased yoriconazole effects when combined with atazanavir/ darunavir useNo dose adjustment is necessary when combined (due to possible induction of CYP450) with etravirine Possibly increased etravirine effects when combined with etravirine: Do not co-administer with lopinavir/ritonavir (due to CYP450 3A4 inhibition) Avoid co-administration with ritonavir Decreased voriconazole levels when combined with lopinavir/ritonavir Do not co-administer with efavirenz at standard doses; (due to possible induction of CYP450 by ritonavir) increase voriconazole to 400 mg bd, and decrease Decreased voriconazole effects when combined with ritonavir efavirenz to 300 mg QHS (due to induction of CYP450 3A4) Decreased voriconazole effects and increased efavirenz effects when combined with efavirenz (efavirenz induces CYP450 3A4) Fluconazole Inhibition of CYP450 3A4 No dose adjustment necessary Increased etravirine, nevirapine, saquinavir, tipranavir, effects Ketoconazole Inhibition of CYP450 3A4 Dose adjustment when combined with darunavir Increased darunavir and ketoconazole effects when ketoconazole is combined is not established with darunavir (darunavir also inhibits CYP450 3A4) If co-administration is required, the dose Increased delavirdine effects when combined with delavirdine of ketoconazole should not exceed 200 mg daily (due to CYP450 3A4 inhibition) No dose adjustment necessary when combined When combinedNon-commercial with didanosine, possibly decreased didanosine effects with delavirdine (decreased gastric acidity from the antacid buffer contained within didanosine Consider didanosine EC tablets/suspension resulting in decreased ketoconazole absorption) Administer ketoconazole at least 2 h Decreased ketoconazole effects when combined with efavirenz prior to didanosine tablets/suspension (efavirenz induces CYP450 3A4) Do not co-administer with efavirenz Increased indinavir effects when combined with indinavir Consider decreasing indinavir to 600 mg tds (due to CYP450 3A4 inhibition) Manufacturer recommends against using high When combined with lopinavir/ritonavir, increased ketoconazole effects, doses of ketoconazole (including drops) with and decreased lopinavir/ritonavir effects lopinavir/ritonavir (200 mg daily) Increased maraviroc effects when combined with maraviroc Reduce maraviroc dose to 150 mg bd when used (due to CYP450 3A4 inhibition) with ketoconazol Increased nelfinavir effects when combined with nelfinavir No dose adjustment necessary when (due to CYP450 3A4 inhibition) combined with nelfinavir Decreased ketoconazole effects when combined with nevirapine Do not co-administer with nevirapine (nevirapine induces CYP450 3A4) No dose adjustment necessary when combined Decreased ketoconazole effects when combined with rilpivirine with rilpivirine, but monitoring for potential failure Increased ritonavir/ saquinavir effects when combined with ritonavir/ of antifungal therapy is required saquinavir (due to CYP450 3A4 inhibition) Dose adjustment when combined with ritonavir/ saquinavir is not established CYP450, cytochrome P450 enzyme complex-family 3-subfamily A-polypeptide 4; bd, twice daily; tds, every 8 h; QHS, at bedtime.

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