Case Report Phialophora Verrucosa Infection in a BMT Patient
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Bone Marrow Transplantation, (1997) 20, 789–791 1997 Stockton Press All rights reserved 0268–3369/97 $12.00 Case report Phialophora verrucosa infection in a BMT patient TS Lundstrom, MR Fairfax, MC Dugan, JA Vazquez, PH Chandrasekar, E Abella and C Kasten-Sportes Detroit Medical Center, Wayne State University, Detroit, MI, USA Summary: Case report Phialophora is a dematiaceous fungus isolated from soil The patient was a 42-year-old Caucasian female diagnosed and wood. Human infections including chromoblasto- with AML (type M4) in February 1994 with 58% blasts on mycosis, mycotic keratitis, cutaneous infections, and bone marrow biopsy. In March 1994 she received induction prosthetic valve endocarditis have been reported. We therapy with idarubicin and cytarabine (Ara-C). Her course report a case of fatal hemorrhage due to Phialophora was complicated by Pseudomonas aeruginosa bacteremia verrucosa in a patient with prolonged neutropenia and Ludwig’s angina. Consolidation therapy in June 1994 undergoing autologous bone marrow transplant (BMT) with idarubicin and Ara-C was complicated by Stenotro- for acute myelogenous leukemia (AML). Bacterial infec- phomonas maltophilia sternal osteomyelitis which was tions complicated induction and consolidation chemo- treated for 6 weeks with intravenous broad-spectrum anti- therapies. Liposomal amphotericin B (LAMB) was biotics. In September 1994 the patient was in complete given from day +33 to day +72 for febrile neutropenia. remission and hospitalized for autologous BMT. Prepara- Death occurred on day +74 due to tracheal hemorrhage. tive therapy consisted of busulfan and cyclosphosphamide. Autopsy revealed granulation tissue on the posterior She received prophylactic norfloxacin and fluconazole. wall of the trachea with fungal hyphae on histopathol- The BMT course was as follows: on day +2, the patient ogy; the tissue grew Phialophora verrucosa. In vitro sus- developed neutropenia (absolute neutrophil count ,500 ceptibility studies revealed a minimum inhibitory con- cells/mm3). Shortly thereafter, she required total parenteral centration to AmB of 0.1 mg/ml. This represents the first nutrition when severe mucositis developed. Between days reported case of invasive P. verrucosa in a BMT patient +14 and +19, the patient developed Clostridium ramosum leading to fatal hemorrhage, despite large cumulative and Enterococcus faecalis bacteremias requiring broad- doses of LAMB to which the organism remained spectrum antimicrobial therapy. Supraglottic edema requir- susceptible. ing intubation and transfer to the intensive care unit Keywords: Phialophora; fungus; chromoblastomycoses occurred on day +25. At that time, indirect laryngoscopy revealed edema without focal lesions, felt to be secondary to chemotherapy-induced mucositis. An 8 day course of steroids was initiated. On day +33 LAMB (liposomal Phialophora species are ubiquitous dematiaceous fungi that amphotericin B) (Abelcet, Liposome Company, Princeton, can be isolated from soil and wood. P. verrucosa is a well- NJ, USA) was begun empirically at a dose of 5 mg/kg/day known cause of chromoblastomycosis. Several species of for febrile neutropenia despite broad-spectrum antimicro- Phialophora have been reported to cause keratitis and bials. On day +43 the patient required a tracheostomy for cutaneous infections, the majority of which occur following failure to wean from ventilatory support. In addition, oral traumatic inoculation. In addition, a case of prosthetic valve metronidazole was instituted for C. difficile enterocolitis. A endocarditis in a diabetic male has been described, with CAT scan of the thorax was performed in an attempt to associated fungemia. identify an occult infectious focus; this was negative. Back- We present a case of fatal tracheal hemorrhage due to up marrow was infused for failure to engraft. Finally, on invasive P. verrucosa, which, to our knowledge, represents day +64, the patient’s absolute neutrophil count was above the first reported case causing infection in a BMT recipient. 500 cells/mm3 (duration of neutropenia 65 days). Repeat laryngoscopy was done on day +68. Findings included bilateral vocal cord paralysis with tracheal edema and ery- thema, and a black eschar at the site of impingement of the tracheal balloon, which was felt to be traumatic in nature. The following day the patient was again noted to be febrile Correspondence: Dr T Lundstrom, 4160 John R, Suite 2140, Wayne State and bacteremic with E. faecalis. On day +72, LAMB was University, Detroit, MI 48201, USA Presented in abstract form at Infectious Diseases Society of America, San discontinued after a cumulative dose of 14 782 mg. Two Francisco, California, October 1995 days later the patient expired due to profuse tracheal Received 21 January 1997; accepted 30 June 1997 hemorrhage. Phialophora verrucosa in BMT TS Lundstrom et al 790 At autopsy, a 4.5 × 3 × 3 cm protuberant mass was ident- ified inside the trachea beneath the tracheostomy and at the site of the endotracheal tube balloon. This mass consisted of dark red granulation tissue with a fresh blood clot on the surface, from which blood could be expressed. A large amount of fresh blood was also present in the trachea, bron- chi, pulmonary alveoli, esophagus and stomach. Micro- scopic examination of the polypoid tracheal mass showed necrotic granulation tissue composed of numerous small to medium caliber blood vessels, some with thicker walls and dilated lumens. There were innumerable fungal hyphae growing within the vessels and extending into the surround- ing interstitium. These fungal hyphae were of uniform diameter with intertwined branches and numerous septae (Figure 1). There were no fungal hyphae demonstrated in the lung tissue itself. Examination of the bone marrow showed engraftment of the myeloid and erythroid precur- sors with hypocellularity. No megakaryocytes were seen. There was no evidence of residual leukemia in the bone marrow or other organs. Homogenized tissue samples from the tracheal mass and the lung parenchyma were stained with calcofluor white and cultured for fungi using standard methods. No fungal elements were seen in either tissue preparation received in microbiology, although histologic sections of the tracheal lesion revealed fungal hyphae. After 2 weeks of incubation at 30°C, both specimens grew rare velvety black colonies with black reverses both on Sabouraud dextrose agar and Mycocel agar (Difco, Ann Arbor, MI, USA). Scotch tape Figure 2 Slide culture of tracheal isolate on Saboraud dextrose agar preparations did not maintain structures for identification, stained with Lactophenol cotton blue 22 days after subculture demon- so slide cultures were inoculated on the same media. The strates phialide with vase-shaped collarette of P. verrucosa. (Line is 10 hyphae were smooth-walled, septate and brown. Pale brown mm.) phialides with vase-shaped colarettes developed after 3 weeks in slide culture. These produced oval to cylindrical conidia which accumulated at the tips (Figure 2), pathogno- The MIC for amphotericin B and 5-FC was defined as 1 monic for P. verrucosa. the lowest concentration that inhibited 90–100% of the vis- In vitro susceptibilities for amphotericin B, itraconazole, ible growth. The MIC for the azoles was defined as the fluconazole and 5-FC against the P. verrucosa isolate were lowest concentration that inhibited 80% of visible growth. determined using the NCCLS M27-P standards in a broth The MICs were determined in duplicate for the isolates macrodilution method for filamentous fungi.2 using the broth macrodilution technique. Prior to MIC test- ing, the isolates were passaged three times on Sabouraud dextrose agar to ensure stability and viability. Prior to the second MIC determination, the isolates were again pass- aged twice to ensure stability of the MIC. P. verrucosa ATCC 28181 was used as the control strain. The P. verrucosa strain recovered at autopsy remained susceptible to amphotericin B with an MIC of 0.1 mg/ml (Table 1). Table 1 In vitro antifungal susceptibility results for P verrucosa MIC (48 h) mg/ml Drug ATCC 28181 Patient isolate Amphotericin B 0.2 0.1 Figure 1 Section of the tracheal mass (Gomori methenamine silver stain) Fluconazole 10 10 showing small vessels and vascular buds filled with masses of fungal Itraconazole 0.39 0.78 hyphae which penetrate through the walls and into the surrounding 5-FC .20 .20 necrotic tissue. Phialophora verrucosa in BMT TS Lundstrom et al 791 Discussion cular obstruction by the fungal hyphae can lead to extensive tissue necrosis, possibly decreasing the penetration of anti- Infections with Phialophora species have been described fungals to the affected area. Finally, although the Phialo- in normal hosts. P. verrucosa is one of the etiologic agents phora remained susceptible to amphotericin B in vitro, this of chromoblastomycosis. Cutaneous infections3,4 due to P. may not correlate with in vivo activity. richardsiae are also well described. Keratitis has also been In conclusion, Phialophora species must be added to the described due to P. mutabilis.5 These cases were treated growing list of opportunistic fungal pathogens described in with topical clotrimazole for cutaneous disease and keto- BMT patients. Moreover, one must be aware that this infec- conazole for keratomycosis, with good results. tion may develop despite prophylactic azole administration, There has also been a single fatal case of endocarditis and may have a fatal outcome despite engraftment and of a native aortic and a porcine mitral valve