MYCOSES 37, 209-2 15 ( 1994) PLCCEPTED: MARCH 24, 1993

CASE REPORTS

Invasive mycotic and actinomycotic oropharyngeal and craniofacial infection in two patients with AIDS

Invasive Pilz- und Strahlenpilzinfektion im Mund-Rachen- Kraniofazialbereic h be i zwei AID S-Patienten

R. Manfredi', A. Mazzoni', 0. Cavicchi3, Donatella Santini4 and F. Chiodo'

Key words. Aspergillosis, candidosis, actinomycosis, oropharynx, craniofacial infection, HIV infection, AIDS.

Schliisselworter. Aspergillose, Candiclose, Aktinomykose, Oropharynx, Kraniofazialberrich, HIV-Infektion, AIDS.

Summary. Two cases of invasive oropharyngeal and craniofacial infection caused Iby fungal and actinomycotic pathogens are described in HIV- infected patients. Two women with a previous diagnosis of AIDS, one with non-Hodgkin's lymphoma and one with Candida oesophagitis, developed a subacute, invasive inflammatory pro- cess characterized by ulcerative necrotizing lesions spreading from the oropharynx up )to the soft and hard palate, maxillary sinuses andl nasal cavity, with extensive soft-tissue necrosis. Although pre- senting with a very similar clinical picture, infec- tion was due to Actinomyces spp. in the first case, while an apparent dual fungal aetiology (Aspergillus J a w s and Candida spp.) was demonstrated in the second patient. Both cases were characterized by remarkable diagnostic difficulties leading to a late final recognition (confirmed by histological exam- ination), and by a partial response to antimicrobial treatment.

Zusammenfassung. Es werden zwei Falle inva- siver oropharyngealer und kraniofazialer Infektio- nen, einmal durch Strahlenpilze, das andere Ma1 durch Pilze bedingt, an HIV-positiven Patienten vorgestellt. Zwei Frauen mit AIDS, Non-Hodgkin- Lymphom sowie Candida-Osophaghs entwickelten

'Istituto Malattie Infettive, %tituto di Microbiologia, 'Istituto di Clinica Otorinolaringoiatrica, 'Istituto di .4natomia Patologica, Universita di Bologna, Bologna, Italy.

Correspondence: Dr Roberto Manfredi, Istituto Malattie Infettive, Universita di Bologna, Via Massarenti, 1 I , 1-401 38 Bologna, Italy.

einen subakuten, invasiventzundlichen ProzeB, charakterisiert durch ulzerierende Nekrosen, die sich vom Oropharynx zum weichen und harten Gaumen, zu den Kieferhohlen und dem Nasen- raum ausbreiteten. Obgleich sich beide Situatio- nen im klinischen Bild stark ahnelten, war der erste ProzeB durch Actinomyces spp., der zweite durch eine Doppelinfektion von Aspergillus j a m s und Cundidu spp. bedingt. In beiden Fallen war die Diagnose schwierig, was zu spater atiologischer Abklarung und zu nur teilweisem Ansprechen auf die antimikrobielle Chemotherapie fuhrte.

Introduction

Actinomycosis is an uncommon human disease, usually presenting as a chronic, localized suppurat- ive infection characterized by indurated infil- tration, followed by abscess formation, tissue fibrosis and draining fistulas, generally involving head and neck (in more than 50% of cases), lungs or the gastrointestinal tract. Micro-organisms belonging to the genus Actinomyces, usually rep- resented in the normal oral flora, may become pathogenic under favourable local circumstances, leading to a slowly progressive granulomatous infection that demonstrates a tendency to spread to contiguous tissue [ 1-91. Fungal micro- organisms such as Candida and Aspergillus are com- monly isolated from the normal oral flora or from the human environment. The impairment of cellu- lar and tissue defence mechanisms and/or other predisposing conditions may allow these species to

210 R. MANFREDI ET AL.

become opportunistic pathogens, usually produc- ing a superficial mucositis (Candida spp.) or a chronic inflammatory granulomatous process (Aspergillus spp.), and rarely deep or disseminated mycotic lesions [ 10-2 11. Here we report two cases of severe oropharyngeal infection due to acti- nomycotic and fungal pathogens presenting with a subacute, invasive course in patients with the acquired immunodeficiency syndrome (AIDS).

Case reports

Case 1

A 24-year-old woman who had been HIV antibody positive since 1987 (heterosexual contact) and who had non-Hodgkin's lymphoma (diagnosed 10 months before) and herpetic kerato-uveitis (diag- nosed 2 months before) experienced a progressive pharyngeal pain and dysphagia due to a swelling of the left oropharyngeal wall. The swelling was surmounted by an ulcerative necrotizing lesion, associated with inflammatory tumefaction of the homolateral hard and soft palate, as well as an indurated infiltration extending from the left parotid region up to the submaxillary region, with no apparent lymphadenopathy; an evident oropharyngeal candidosis was also present. The patient had undergone tonsillectomy at the age of 7, and no gingivo-dental disease or oropharyngeal interventions were recorded in the weeks pre- ceding hospitalization. On admission, laboratory examinations showed a severe immunosuppression (total WBC count 1980 rnmp3, with 79.4% neutro- phils, 12.1 O/O lymphocytes, CD4+ lymphocytes 11 mm-3); an inflammatory process due to bac- terial or fungal pathogens or a localization of the previously diagnosed lymphoma was initially con- sidered most likely. Candida guilliemondii, Candida glabrata, Staphylococcus aureus and Pseudomonas aerugi- nosa were repeatedly isolated from pharyngeal swabs and biopsy specimens, so that treatment was started with fluconazole (200 mg day-'), cef- triaxone (2 g day-') and netilmicin (300 mg day- I ) . During the following weeks the ulcerative necrotizing process progressively extended through the soft and hard palate; surgical debridement of necrotic tissue led to the formation of a large oronasal fistula. Microscopic and cultural examin- ation of multiple biopsy specimens repeatedly showed a prevalence of necrotic tissue, failing to demonstrate micro-organisms other than Gram- positive cocci, Gram-negative rods and yeasts. Antimicrobial treatment was changed to itracona- zole (400 mg day-') and ceftazidime (3 g day-') plus netilmicin (300mg day-'), with only a

reduction in the inflammatory process involving the oropharynx and the parotid region, with par- tial demarcation of the ulcerative palatal lesion. The necrotizing invasive process progressively extended, in a few weeks, to the rhinopharynx, maxillary sinuses and left nasal cavity, and an indurated, painful mass also appeared at the left mandibular angle. Radiological and computerized tomographic (CT) studies demonstrated a diffuse obliteration of maxillary sinuses with evident involvement of the bone profile on the medial side, associated with multiple low-density regions consistent with phlogistic and necrotic foci involv- ing the left parapharyngeal region and extending up to the left pterygomaxillary fossa, with obliter- ation of the normal tissue planes (Figure 1). The patient, suffering from severe dysphagia with regurgitation of ingesta and rhinolalia, died about 6 months after first admission from respiratory insufficiency due to interstitial pneumonia. Only a histopathological examination performed after the death of our patient on fixed and stored biopsy specimens led to a final diagnosis. Besides large necrotic areas, multiple characteristic granules were detected composed of radiating Gram- positive filamentous bacteria with clubbed ends, diagnostic of Actinomyces infection, without a sig- nificant acute or chronic inflammatory infiltrate (Fig. 2).

Case 2 A 27-year-old woman with a history of intravenous drug abuse and AIDS diagnosed as a result of oesophageal candidosis developed a large param- axillary cellulitis associated with a painful inflam- matory ulcerative lesion of the hard palate, located in the proximity of the second right upper molar tooth. The lesion was initially regarded as an allergic reaction to the injection of local anaes- thetics during dental treatment. The patient, slightly febrile, was severely immunosuppressed (total WBC count 1740 mm-3, neutrophils 72.5%, lymphocytes 19.2%, CD4+ lymphocytes 4 mrnp3). Pharyngeal swabs and tissue samples submitted for microbiological examination showed an appar- ent polymicrobial infection with Aspergillus Jams, Candida albicans, Candida krusei and Streptococcus faec- ium. Histopathological examination of multiple biopsy specimens confirmed the diagnosis, showing large numbers of Candida pseudohyphae and blas- toconidia, together with typical large septate hyphae of aspergdli branching with acute angles; these fungal pathogens have been shown to invade diffusely hard and soft tissue, with extensive necrosis prevailing over reactive inflammatory infiltrate (Fig. 3). The patient initially received

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INVASIVE OROPHARUNGEAL INFECTIONS WITH AIDS 211

Figure 1 Case 1 . Contrast-cnhancrd CT S C . ~ . demonstrating involvement of maxillan. sinuses. nasal c a \ m and surrounding tissues by the invasivc actinomycotic inft-ction. with rvident crosion of honr profiles

jl i

. ".

I,

Figure 2. Case 1 . Photomicrograph of somr actinomyotic cgrgranules: a central dense mass is surrounded by radiating filamentous bacteria. A large number of Gram-positivc bacilli are visible in the backrround, with no evidencr of tissue reaction. Scrtion stained with Gram (original magnification, x 400).

itraconazole (400 mg day - I ) , clindamycin (1.8 g day-'), piperacillin (4 g day- I ) and netilmicin (300 mg day- ') plus anti-inflammatory treatment. Although oedema and swelling of the inflam- matory paramaxillary mass were reduced, the ulcerative necrotizing palatal lesion progressively extended, producing a large oronasal fistula and spreading through the right nasal cavity and maxil- lary sinuses (Figure 4). Antimicrobial treatment was subsequently modified, including fluconazole (400 mg day-'), amphotericin B (1 mg kg-' day-') and pefloxacine (800 mg day-'), followed

by intraconazole 11400 mg day- I ) and piperacillin (6 g day-'); surgical debridement removed nec- rotic tissue from the nasal cavity and maxillary sinuses, obliterated with friable, greyish-yellowish material. A radiological and CT examination con- firmed the presence of an inflammatory process extending from the right parapharyngeal wall through nasal coanas (with necrosis of inferior and middle turbinate bones), ethmoidal and sphenoidal cells, and from the right maxillary sinus up to the floor of the right orbit, without regard to tissue planes. After an 8-week follow-up, a partial

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212 R. MANFREDI ET AL.

Figure 3. Case 2. Light micrograph showing the association of Aspergillus spp. and Cundida spp. in the same lesion. Large numbers of Cundida blastoconidia with initial budding of pseudohyphae can be seen together with some large septate hyphae of aspergdli, in absence of tissue reaction. Section stained with periodic acid-Schiff (PAS) (original magnification, x 1000).

Figure 4. Case 2. Ulcerative necrotizing lesion of the hard and soft palate, producing a large oronasal fistula.

demarcation of lesions was obtained, with a reduction of inflammatory process; the patient presented rhinolalia and severe regurgitation of ingesta, so that nasogastric feeding was started. Our patient died 3 months after admission from fulminant Pseudomonar aeruginosa septicaemia; nec- ropsy examination was not performed.

Discussion

The clinical picture described in our patients was characterized by a subacute, invasive course lead-

ing to extensive soft-tissue necrosis with bone involvement and craniofacial spread (as docu- mented by CT evaluation), showing a very similar course in both cases, apparently unrelated to the specific microbial aetiology (actinomycotic in the first patient, fungal in the second). Furthermore, both cases presented remarkable diagnostic prob- lems causing a late final recognition, with partial and unsatisfactory response to antimicrobial treatment.

Actinomyces spp. are normal inhabitants of the oropharyngeal cavity. As common commensals, they usually exhibit low pathogenity, producing a

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INVASIVE OROPHARYNGEAI. INFECTIONS WITH AIDS 213

granulomatous infkction only when the organism gains entrance to deeper tissues through a break in the mucous membranes, often supported by dental disease, minor oral trauma, surgery, poor oral hygiene or chronic sinusitis [ 1-9, 221. As far as we know, only seven cases of actinoniycosis have been reported in patients with HIV infection. The first report by Yeager et al. [23] in 1986 described a case of extensive cervkofacial actino- mycosis with bone involvement, secondary to tooth extraction. Subsequent reports concerned dis- seminated cutaneous abscesses [24], pulmonary involvement [25], cervical localization [ 261, oral infection by Actinomyces naeslundii discovered after tooth extraction [27] and two cases of perianal and anorectal involvement [28, 291. Actinomycosis is usually not considered an opportunistic infec- tion. Although immunodeficiency resulting from HIV infection may increase susceptibility to this disease and support a morr severe and progressive course, there has been no increase in the incidence of actinomycosis among AIDS patients, and actinomycosis associated with HIV infection remains an extremely rare finding [23-- 291. However, since some studies have :shown a signifi- cantly increased frequency of Actinomyces infection in patients with cancer and other immunocom- promised patients [3, 5, 61, it remains unclear whether HIV infection plays a contributory or merely coincidental role in the development of actinomycosis. In fact, like other micro-organisms, Actinomyces is a bacterial pathogen whose contain- ment primarily relies on an intact T-cell and monocyte-macrophage function, by formation of a granulomatous reaction 17, 91.

Aspergillus spp. infection is being recognized with increasing frequency among immunosuppressed patients, especially when neutropenia is present [5, 14, 15, 17-19]. During recent years, invasive aspergillosis has presented as an ernerging disease in AIDS patients, probably because of the increas- ing incidence of neutropenia, owing to prolonged survival and widespread use of potentially myelo- toxic drugs (such as aritiretroviral agents, some antimicrobial and antiviral drugs, chemotherapy for AIDS-related malignancies). Visceral disease usually becomes evident with pulmonary localiz- ation, followed by brain. heart and kidney involve- ment [5, 10-14, 17, 301. Invasive maxillary and rhinosinusal infection without lung involvement is more frequently seen in tropical regions (probably related to climatic and hygienic conditions sup- porting fungal growth) [ 17, 3 I] , whereas it is rarely found in association with cancer [ 14,-.l7, 19, 20, 32, 331 and still less frequently in patients with AIDS (only three cases described up to now [ 10, 12, 301). Pharyngeal and rhinosinu:ial aspergillosis

includes a sprctrum of diseases ranging from a non-invasive, granulomatous form (more fre- quently seen in endemic regions and in immuno- competent subjects) to an aggressive type, usually found in immunocompromised patients. The majority of cases of invasive disease are produced by Aspergillusj~ivus (the same species isolated in our patient); because of its potent toxin production, this fungal pathogen expresses a relevant destruc- tive potential, by entering blood vessels and precip- itating thromboernbolism and tissue necrosis [ 15, 161.

Cundidu spp. are considered one of the major opportunistic pathogens in immunocompromised patients with impairment of cellular and tissue defence mechanisms 114, 181. However, they are only rarely found as a cause of invasive sinusitis or noma-like ulcerative lesions spreading from the oropharyngeal cavity to contiguous tissues, with extensive tissue infarction and necrosis and bone erosion [21, 34, 351.

Early diagnosis of these microbial diseases may be extremely difficult in the immunocompromised host since micro-organisms such as Actinomyces or Aspergillus often cannot be isolated in clinical speci- mens until late in the course of disease. In patients with HIV infection, differential diagnofis of ulcer- ative oropharyngeal lesions may include bacterial or fungal infections, viral (cytomegalovirus, herpes simplex virus) lesions or severe aphthous ulcers, while an invasive inflammatory cancrum oris-like process may be attributed to lymphoma, oral or maxillary carcinoma, Kaposi's sarcoma, bacterial abscess, Vincent's disease, candidosis, aspergillosis, mucormycosis or other rare opportunistic infec- tions [34-411. In most cases, the best approach to a final diagnosis is a combination of histopatholog- ical examination and culture of biopsy specimens, especially when infection involves the oropharyn- geal cavity, where colonization must be dis- tinguished froni invasive infection [ l 1, 14, 181.

Actinomyces infection is relatively rare and infrequently suspected by physicians, as its clinical presentation is often consistent with other infec- tious or neoplastic diseases. Moreover, the chances of obtaining an early laboratory identification are restricted by stringent transport and culture requirements, overgrowth of associated micro- organisms and the susceptibility of Actinomyces spp. to a wide spectrum of commonly used antibiotics. All these factors may contribute to delayed or missed diagnosis [ 1, 3, 4, 7, 9, 221. Although we could not identify Actinomyces through culture tech- niques in our first patient, unequivocal histopathol- ogical diagnosis was established on finding typical bacterial granules in the affected tissue.

O n the other hand. isolation of Candida and

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214 R. MANFREDI ET AL.

Aspergillus spp. from mucous surfaces is not a reliable diagnostic clue, since fungal colonization is enhanced in AIDS and other immunocom- promised patients [ l l , 14, 16, 18, 36, 371. In the second patient, culture results were confirmed by histological findings, demonstrating both Aspergillus and Candida micro-organisms diffusely invading tissue. The association of these two different oppor- tunistic fungi (Aspergillus and Candida) in the same lesion, with both micro-organisms apparently play- ing a pathogenic role and possibly responsible for the atypical aggressive course of infection, has previously been described once [42].

In both our cases, early aetiological diagnosis could have been further hampered by the absence of a granulomatous reaction (probably because of the prevalence of necrosis and the severe underlying immunodeficiency and neutropenia of patients) and the concurrent isolation of other micro-organisms from the site of infection (Candida spp., Staphylococcus aureus and Pseudomonas aeruginosa in the first case, Streptococcus faecium in the second patient), later regarded as saprophyte or concur- rent organisms, according to histopathological findings.

Finally, antimicrobial treatment did little to modify the progressive clinical course of infection in our patients. Although penicillin G (usually considered as the drug of choice for actinomycosis) was not used in our first patient, many antibiotics potentially effective on Actinomyces spp. (p-lactam antibiotics, clindamycin, quinolones) were admin- istered at full doses for a very long period, obtaining only a slowing of progression and a partial demarcation of the invasive process. Also, in the second case, antifungal agents (itraconazole, fluconazole, amphotericin B) obtained only a par- tial and unsatisfactory clinical response. The severe HIV-related immunodeficiency may play a sig- nificant role, supporting a more aggressive course of infection and conditioning an apparent failure of treatment. Surgical debridement, performed in both our patients, is not unanimously rec- ommended in the treatment of immunocom- promised patients with invasive oropharyngeal and craniofacial opportunistic infections [4, 16, 19, 27, 351.

In conclusion, the possibility of invasive infec- tion by Actinomyces, Aspergillus and Candida, although representing an infrequent clinical entity, should be carefully considered in the differential diagnosis of the wide variety of diseases involving the oro- pharyngeal tract and craniofacial region in HIV- infected patients. These infectious complications are potentially severe, and remarkable problems are encountered in establishing prompt diagnosis and an effective treatment.

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