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An atypical case of fatal zygomycosis: simultaneous cutaneous and laryngeal infection in a patient with a non-neutropenic solid prostatic tumor.

Abstract

We describe what we believe is the first reported case of simultaneous highly invasive cutaneous and laryngopharyngeal zygomycosis in a non-neutropenic, nondiabetic but immunosuppressed patient with prostate cancer. An invasive fungal process was not suspected until late in the patient's hospital course; when it was, a tracheotomy and direct laryngoscopic biopsies were performed. Unresectable invasive zygomycosis with Rhizopus rhizopodiformis was diagnosed. The patient was managed with liposomal amphotericin B initially and later with palliative medical therapy until he died. This case emphasizes the need for a rapid and specific diagnosis with timely introduction of appropriate antifungal management, particularly now that voriconazole is frequently used as empiric prophylaxis against aspergillosis in high-risk patients.

Introduction

Zygomycosis occurs as an opportunistic infection in immunocompromised and diabetic patients with acidosis, hematologic malignancy, or end-stage renal disease and in those who are taking immunosuppressant therapy after undergoing solid-organ transplantation. Such an infection can occur in the sinocerebral structures, respiratory tract, lungs, and gastrointestinal system, and it can occur as a disseminated illness. Invasive rhinocerebral zygomycosis is a well-known entity; hosts with variable immunologic function (i.e., patients with rheumatologic disease who are treated with steroids) may present with primary cutaneous or invasive zygomycosis.

We describe an atypical case of devastating head and neck zygomycosis. To the best of our knowledge, this is the first reported case of laryngeal zygomycosis in a patient with a non-neutropenic solid tumor and the first reported case of simultaneous laryngeal and cutaneous zygomycosis.

Case report

A 79-year-old man with a history of prostate cancer presented for placement of percutaneous nephrostomy tubes. However, tube placement was complicated by the onset of purulence. He became septic and required fluid resuscitation, and his leukocyte count rose from 7,900 to 33,000/[micro]l. He developed acute renal failure, with a peak serum creatinine level of 2.8 mg/dl and a carbon dioxide (C[O.sub.2]) level of 10 mmol/L. His serum glucose level dropped acutely from 126 to 64 mg/dl. He was not known to be in iron overload; to the contrary, the results of baseline iron studies were low: a serum iron level of 11 [micro]g/dl, 9% saturation, a total iron-binding capacity of 121 [micro]g/dl, and a transferrin level of 97 mg/dl.

The patient's history was significant for a prostatectomy 12 years earlier and urethral obstruction of 8 years' duration. In addition to hormonal ablation, he had received 6 courses of docetaxel (last administered 5 weeks prior to presentation) and 5 months of prednisone dosed at 10 mg daily. It was believed that the patient had continued prednisone therapy right up until presentation. He also had coronary artery disease and congestive heart failure.

[FIGURE 1 OMITTED]

For his current condition, the patient was treated with broad-spectrum antibiotics and vasopressors. Blood cultures yielded Enterobacter cloacae. He developed azotemia and hypoxia secondary to volume overload. He was intubated within 13 hours, and he required central venovenous hemofiltration for volume overload and metabolic acidosis. On day 1 after intubation, a blood gas evaluation revealed a serum pH of 7.28 and a partial C[O.sub.2] (pC[O.sub.2]) level of 32 mm Hg.

On day 7 after intubation, the patient developed multiple erythematous, scaling lesions around his mouth and nose. These lesions were initially thought to be herpetic, and topical acyclovir was administered. Further evaluation of the patient's oropharynx revealed the presence of necrotic annular lesions on the hard and soft palate, on the left nasal ala, beneath the right nostril, and within the right aspect of the columella. Scrapings of the lip lesions and a tracheal aspirate were cultured. Maxillofacial computed tomography (CT) detected no evidence of nasal or sinus disease; thoracic and abdominal CTs demonstrated pulmonary edema and an irregularity of the stomach that raised concerns about a possible mass or ulcerative process. Meanwhile, the patient's renal function improved, and he was extubated on day 9.

Two days later, the patient developed intermittent fever and a necrotic-appearing eschar on the skin and vermillion of the lips and similar lesions on the palate mucosa (figure 1). Mild biphasic stridor was noted. Flexible fiberoptic laryngoscopy revealed mucosal edema, erythema, and abundant thick, black crusting in the hypopharynx, supraglottis, and visible glottis. The left vocal fold was paretic. Cultures of the tracheal aspirate material taken 5 days earlier and of the lip taken 1 day earlier grew a zygomycetous fungus. Based on the appearance of the patient's skin and oropharyngeal lesions and the culture results, we initiated therapy with liposomal amphotericin B (5 mg/kg).

The next day, new perioral lesions were noted. An awake tracheotomy, direct laryngoscopy, bronchoscopy, and directed biopsies were performed to establish the extent of disease. The results of frozen-section analysis of the biopsies of the lip, soft palate, and larynx were all consistent with zygomycosis. Specifically, permanent sections confirmed the presence of broad-branching, nonseptate hyphae with extensive tissue necrosis and ulceration, as seen with invasive disease (figure 2). The tracheobronchial mucosa appeared normal on bronchoscopy. Resection of the lip and laryngeal lesions was not feasible in view of the extent of involvement at multiple sites in the upper aerodigestive tract. Although the abdominal CT had indicated possible involvement of the stomach, no further evaluation was performed.

On postoperative day 2, the patient experienced progressive respiratory failure despite supportive therapy and an increase in the dosage of liposomal amphotericin B to 7.5 mg/kg (cumulative dose: 3.0 g). His family elected not to advance his level of care, and the patient died shortly thereafter. The family declined an autopsy.

Four cultures were positive for a zygomycetous fungus that was subsequently identified as Rhizopus rhizopodiformis. The culture findings on the tracheal aspirate did not raise any alarm until the cultures from the lip scrapings were reported as positive for the same organism. Two days after the initiation ofliposomal amphotericin B, the tracheal cultures revealed the persistence of the organism.

[FIGURE 2 OMITTED]

Discussion

Invasive zygomycosis is a well-defined clinical syndrome associated with fungi in the genera Rhizopus, Mucor, Absidia, Rhizomucor, and Cunninghamella. The infection in our patient was caused by R rhizopodiformis, ubiquitous environmental fungi that may be the source of nosocomial outbreaks secondary to environmental contamination. The clinical presentations of infection by fungi of these genera are consistently the same.

In 1978, Keys et al published a classic report of nosocomial Rhizopus infection in immunocompromised hosts, including neonates who had been exposed to an adhesive tape (Elastoplast) used to secure endotracheal tubes. (1) The following year, Everett et al reviewed cases of localized postoperative Rhizopus wound infections that were traced to the use of Elastoplast bandages contaminated with Rhizopus. (2) These examples support the recommendation that we must speciate the pathogen in order to monitor for potential nosocomial outbreaks. While cases of primary cutaneous zygomycosis (1-4) and primary tracheal zygomycosis (5-7) have been reported, to the best of our knowledge, ours is the first reported case of both cutaneous and extensive transglottic zygomycosis.

We hypothesize that the cutaneous infection occurred first. As was the case in some of the earlier reports, our patient's dermatologic infection might have been caused by contaminated endotracheal tape; even though the chronology of our cultures did not support this, it is possible that the early skin lesions were not prominent. If the cutaneous infection did indeed manifest first, it then spread to involve the aerodigestive tract. In terms of its clinical course, the infection became aggressive at the time antifungal therapy was initiated, as new cutaneous lesions were noted within 24 hours after the patient's initial evaluation by the infectious disease consultants. The patient was not neutropenic, and he had no history of diabetes, but he had recently received chemotherapy, including a low-dose corticosteroid for prostate cancer. The combination o frecent chemotherapy, his azotemia, (8) and his metabolic acidosis (9) likely predisposed him to invasive zygomycosis.

A striking feature of this case was the duration of smoldering subclinical infection, as the patient's endotracheal cultures grew the filamentous organism at least 5 days before he experienced clinical decline. In 2000, Kontoyiannis et al suggested that a respiratory culture positive for a zygomycete was typically associated with a steady decline to rapid death. (10)

Successful treatment of tracheal zygomycosis requires surgical debridement with parenteral antifungal therapy. (5,7) There is a single report of cutaneous zygomycosis treated without surgical debridement of lesions, (4) but invasive disease requires early recognition, surgical debridement, and liposomal amphotericin B or posaconazole. Fluconazole, voriconazole, and the echinocandins have no therapeutic activity against fungi of the order Mucorales.

Posaconazole, a new broad-spectrum triazole, and terbinafine, an allylamine antifungal, have in vitro activity against these fungi. The activity of posaconazole against zygomycosis varies in animal models; R rhizopodiformis is susceptible to posaconazole in a dose-dependent fashion. (11) The successful use of posaconazole against zygomycetes has been described only in case reports. (12) This drug was used as successful salvage therapy in a solid-organ transplant recipient with zygomycosis who did not respond to therapy with amphotericin B. (13) Speciation is important in order to determine the efficacy of the newer antifungals against the range of zygomycete genera and species.

Until recently, no microbiologic techniques were available to facilitate the prompt diagnosis of zygomycosis. But today, the development of a multiplex polymerase chain reaction assay (PCR) (14) and PCR-based restriction fragment length polymorphism (15) to identify pathogenic Rhizopus species in human tissue offers hope that rapid diagnosis--and hence better survival--may be possible.

Our case highlights the importance of the prompt recognition of the patient's perioral and lip lesions as suspicious for zygomycosis. Early therapy with liposomal amphotericin B or posaconazole and surgical debridement might have altered the course of infection. Accurate diagnosis is dependent on culture or histopathology from biopsy, as zygomycosis must be distinguished from other hyphal fungal infections (e.g., aspergillosis). It is imperative that clinicians have a high index of suspicion and the ability to recognize the early signs of cutaneous zygomycosis, even in the absence of diabetic ketoacidosis or overt immunosuppression. Growth of a filamentous organism from endotracheal aspirate or sputum in an intubated patient also warrants further prompt investigation.

The etiology of invasive fungal infections in hospitalized immunocompromised patients is evolving. Because aspergillosis is still the most common filamentous fungal infection, voriconazole recently replaced amphotericin B as the first-line treatment for febrile neutropenia and as empiric therapy in tertiary care centers. Since then, however, an increase in the incidence of zygomycosis has been reported. The switch to voriconazole has been implicated, because this drug does not have activity against the zygomycetes. (16-18)

Describing their prospective study of 27 patients with hematologic malignancies with and without a history of stem-cell transplant, Kontoyiannis et al recently reported that the use of voriconazole prophylaxis and the presence of sinusitis were strongly associated with zygomycosis on multivariate analysis when patients with zygomycosis were compared with those with aspergillosis (odds ratio: 76.72; 95% confidence interval: 6.48 to 908.15; p = 0.001). (19) Of 20 cases speciated by morphology and sequencing identification, there were 14 cases of definite and 1 probable Rhizopus, 4 cases of Mucor, and 1 case of Cunningharnella; this distribution implies a lack of voriconazole activity in the entire group.

Overall, there appeared to be a trend toward an increase in the incidence of zygomycosis in the 1990s in cancer centers before the routine use of voriconazole. (20) This trend may continue with the development of new antifungal drugs.

References

(1.) Keys TA, Haldorson AM, Rhodes KH, et al. Nosocomial outbreak of Rhizopus infections associated with Elastoplast wound dressings--Minnesota. MMWR Morb Mortal Wkly Rep 1978;27(5): 33-4.

(2.) Everett ED, Pearson S, Rogers W. Rhizopus surgical wound infection associated with elasticized adhesive tape dressings. Arch Surg 1979;114(6):738-9.

(3.) Dickinson M, Kalayanamit T, Yang CA, et al. Cutaneous zygomycosis (mucormycosis) complicating endotracheal intubation: Diagnosis and successful treatment. Chest 1998;114(1):340-2.

(4.) Kerrayem A. Primary cutaneous mucormycosis complicating the use of adhesive tape to secure the endotracheal tube. Can J Anesth 2002;49:880-2.

(5.) Schwartz JR, Nagle MG, Elkins RC, Mohr JA. Mucormycosis of the trachea: An unusual case of acute upper airway obstruction. Chest 1982;81(5):653-4.

(6.) Andrews DR, Allan A, Larbalestier RI. Tracheal mucormycosis. Ann Thorac Surg 1997;63(1):230-2.

(7.) Wolf O, Gil Z, Leider-Trejo L, et al.Tracheal mucormycosis presented as an intraluminal soft tissue mass. Head Neck 2004;26(6):541-3.

(8.) Deshpande DH, Desai AP. Cerebral mucormycosis in cases of renal failure. Neurol India 1976;24(1):20-3.

(9.) Artis WM, Fountain JA, Delcher HD, Jones HE. A mechanism of susceptibility to mucormycosis in diabetic ketoacidosis: Transferrin and iron availability. Diabetes 1982;31(12):1109-14.

(10.) Kontoyiannis DP, Wessel VC, Bodey GP, Rolston KV. Zygomycosis in the 1990s in a tertiary-care cancer center. Clin Infect Dis 2000; 30(6):851-6.

(11.) Dannaoui E, Meis JF, Loebenberg D, Verweij PE. Activity of posaconazole in treatment of experimental disseminated zygomycosis. Antimicrob Agents Chemother 2003;47(11):3647-50.

(12.) Greenberg RN, Scott LJ, Vaughn HH, Ribes JA. Zygomycosis (mucormycosis): Emerging clinical importance and new treatments. Curr Opin Infect Dis 2004;17(6):517-25.

(13.) Tobon AM, Arango M, Fernandez D, Restrepo A. Mucormycosis (zygomycosis) in a heart-kidney transplant recipient: Recovery after posaconazole therapy. Clin Infect Dis 2003;36(11):1488-91.

(14.) Nagao K, Ota T, Tanikawa A, et al. Genetic identification and detection of human pathogenic Rhizopusspecies, a major mucormycosis agent, by multiplex PCR based on internal transcribed spacer region of rRNA gene. J Dermatol Sci 2005;39(1):23-31.

(15.) Larche J, Machouart M, Burton K, et al. Diagnosis of cutaneous mucormycosis due to Rhizopus microsporus by an innovative PCR-restriction fragment-length polymorphism method. Clin Infect Dis 2005;41(9):1362-5.

(16.) Marty FM, Cosimi LA, Baden LR. Breakthrough zygomycosis after voriconazole treatment in recipients of hematopoietic stem-cell transplants. N Engl J Med 2004;350(9):950-2.

(17.) Siwek GT, Dodgson Kh de Magalhaes-Silverman M, et al. Invasive zygomycosis in hematopoietic stem cell transplant recipients receiving voriconazole prophylaxis. Clin Infect Dis 2004;39(4):584-7.

(18.) Oren I. Breakthrough zygomycosis during empirical voriconazole therapy in febrile patients with neutropenia. Clin Infect Dis 2005; 40(5):770-1.

(19.) Kontoyiannis DP, Lionakis MS, Lewis RE, et al. Zygomycosis in a tertiary-care cancer center in the era of Aspergillus-active antifungal therapy: A case-control observational study of 27 recent cases. J Infect Dis 2005;191(8):1350-60.

(20.) Kauffman CA. Zygomycosis: Reemergence of an old pathogen. Clin Infect Dis 2004;59(4):588-90.

Kristine E. Johnson, MD; Kevin Leahy, MD, PhD; Christopher Owens, MD; Joel N. Blankson, MD, PhD; William G. Merz, PhD; Bradley J. Goldstein, MD, PhD

From the Division of Infectious Diseases, Department of Medicine (Dr. Johnson and Dr. Blankson), Department of Otolaryngology-Head and Neck Surgery (Dr. Leahy and Dr. Goldstein), and Department of Pathology (Dr. Owens and Dr. Merz), Johns Hopkins Medical Institutions, Baltimore.

Reprint requests: Kristine E. Johnson, MD, 1830 E. Monument St., Room 401, Baltimore, MD 21205-2100. Phone: (410) 614-7037; fax (410) 955-7889; e-mail: kjohns87@jhmi.edu
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Title Annotation:ORIGINAL ARTICLE
Comment:An atypical case of fatal zygomycosis: simultaneous cutaneous and laryngeal infection in a patient with a non-neutropenic solid prostatic tumor.(ORIGINAL ARTICLE)
Author:Johnson, Kristine E.; Leahy, Kevin; Owens, Christopher; Blankson, Joel N.; Merz, William G.; Goldste
Publication:Ear, Nose and Throat Journal
Geographic Code:1U5MD
Date:Mar 1, 2008
Words:2512
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