Disseminated Fusarium solani infection

Disseminated Fusarium solani infection Susan J. Bushelman, MD, Jeffrey P. Callen, MD, Donna N. Roth, MD, and Lisa M. Cohen, MD Louisville, Kentucky Disseminated fungal infections commonly occur in immunocompromised hosts; Cundida spp. are the most common. Fusarium spp., soil saprophytes once considered pathogenic only in plants, have emerged as serious pathogens in neutropenic patients with malignancies. We describe two patients, one with acute myelogenous leukemia and the other with me&static breast cancer, in whom disseminated Fusarium solani infection developed. Both patients had neutropenia and fever when generalized, tender, erythematous papules developed; most of the papules had black necrotic centers. Despite aggressive therapy with antifungal agents and granulccyte-macrophage colony-stimulating factor, both patients died within 1 month. Disseminated Fusarium infection can be a life-threatening condition in which skin lesions are frequently the initial sign. Early recognition and hematopoietic recovery offer the best chance for survival. (J AM ACAD DERMATOL 1995;32:346-5 1.)

With the increasing use of immunosuppressive and cytotoxic therapies, microbes that only rarely causedhuman infection are now emerging asserious pathogens. Disseminated infection with Fusarium spp.,first reported in 1973,’ is being increasingly reported in the immunocompromised host. Fusarium spp. are ubiquitous soil saprophytes that have been isolated from local infections such as keratitis,213 onychomycosis,4> 5cutaneous infection:> 7arthritis,* peritonitis,9Tlo osteomyelitis,ll* I2 and endophthalmitis.13 We report disseminated Fusarium solani infection in two immunocompromised patients. CASE REPORTS

Case 1 A 34-year-old white man with acute myelogenous leukemia treated with chemotherapy and bone marrow transplantation (BMT) had generalized tender skin lesions that developed in June 1992. Since the initial diagnosis of acute myelogenous leukemia in March 1990 and with each relapse, the patient reported sinus pain and congestion. X-ray films of the sinuses revealed inflammation of the maxillary sinuses without air-fluid levels. The white blood cell count on admission was 1.3 x 109/L. Soon after reinduction chemotherapy with cytosine arabinoside was started, the patient had a temper-

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P. Callen, MD, University Louisville, KY 40292. X/4/56439

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ature of 40.5” C. Empiric therapy with piperacillii, vancomycin, and aztreonam was initiated, but the fever persisted. The white blood cell count reached a nadir of 0.1 x 109/L on the sixth and final day of chemotherapy. Despite amphotericin B therapy (70 mg/day), an eruption developed that started on the patient’s back and be came generalized within 2 days. Examination revealed multiple 8 to 10 mm tender erythematous papules with a black necrotic center on the trunk, face, scalp, extremities, palms, and soles (Fig. 1). The lesions continued to increase in size and number. A biopsy specimen revealed marked epidermal pallor and scattered necrotic keratinocytes. A sparse lymphocytic infiltrate was present throughout the dermis. Numerous septate hyphae were present within and around dermal blood vessels,many of which contained thrombi (Fig. 2). The organisms stained with periodic acid-Schiff stain. Cultures of specimens from the pharynx, skin, and blood grew Fusarium solani. The skin lesions showed no evidence of regression despite treatment with amphotericin B, oral flucytosine, and granulocyte-macrophage colony-stimulating factor. The patient remained neutropenic and died of his disseminated infection 10 days after the onset of the skin eruption.

Case 2 A 49-year-old white woman with breast cancer had a generalized eruption in February 1990. In December 1989 bone and bone marrow metastases developed. The patient was treated with chemotherapy, and neutropenia and persistent fever developed. Despite treatment with broad-spectrum antibiotics and amphotericin B, endophthalmitis and skin lesions developed. The antibiotic regimen included intravitreous and intravenous amphoteri-

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Fig. 1. Multiple patient 1.

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erythematous, tender papules with a black necrotic center on abdomen of

tin B, oral flucytosine, and intravenous vancomycin, imipenem, and acyclovir. Examination disclosed several tender, purpuric nodules of the extremities, many with a vesicular or black necrotic center (Fig. 3). In addition, there were scaly, erythematous plaques on the legs. Multiple new lesions developed during the next 72 hours on the trunk, hands, and face. The cornea contained several small ulcerations. A biopsy specimen revealed septate branching hyphae in thrombosed dermal blood vessels and perivascularly (Fig. 4). These hyphae stained with periodic acid-SchilT stain. Cultures of specimens from the skin, cornea1 ulcer, stool, blood, and central venous catheter tip were positive for F. solani. The patient’s central venous catheter was removed 3 days after the development of skin lesions. Despite a change to the antibiotic regimen and addition of fluconazole and granulocyte-macrophage colony-stimulating factor, she died in March 1990 of complications of fungal septicemia. DISCUSSION Disseminated Fusarium infection in the immunocompromised patient is an increasing cause of morbidity and death, particularly in patients with hematologic malignancies. In a review of the literature, we found 52 reported cases of disseminated Fusarium infection (Table I). 13lo, 14-47These cases meet the criteria for disseminated disease, which is defined as culture-proven involvement of two or more noncontiguous sites.32 Patients with fungemia without organ involvement were not included. Patients with disseminated Fusarium infection usually have chemotherapy-induced neutropenia

Fig. 2. Biopsy specimen from patient 1 revealed numerous septate hyphae within and around thrombosed derma1 blood vesselsunderlying a necrotic epidermis.

and fever that persists despite antibiotic and antifungal therapy. Skin lesions are present in 85% of patients and usually appear early in the course of infection. Typically these lesions are painful, ery-

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Fig. 3. Numerous tender, erythematous to purpuric pap&s crotic center, on upper extremity of patient 2.

and nodules, some with a ne-

Fig. 4. Septate hyphae within and around thrombosed dermal blood vessels seen in a biopsy specimen from patient 2.

thematous, indurated papules and nodules that quickly develop a black necrotic center. The lesions are often disseminated on the trunk and extremities and may involve the scalp, palms, and soles. The clinical features of a patient with disseminated Fusarium infection are similar to those of other fungal infections in the immunocompromised host!* The most common cause of disseminated fungal infection after BMT is infection by Candida spp. Invasive or disseminated Candida infections have been reported in 15% to 25% of BMT pa-

tients.49>5oIn a large seriesof nearly 1200 BMT patients, in 11% a sign&ant non-Candida fungal infection developed.51 Except for Aspergzllus spp., which were isolated in 74% of patients with a disseminated fungal infection, Fusarium spp. were the most commonly isolated organisms (12% of affected patients). Other less common organisms include (in 5% or less)Histoplasma, Mucor, Chrysosporium, Scopulariopsis, and Trichofporon spp. The genus Fusarium includes about 200 species.1 Of these, five have been identtied in disseminated

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infections: F. solani, Fusarium

oxysporum, Fusarium moniliforme, Fusarium proliferatum, and Fusarium anthophilum. F. solani is the most com-

monly isolated speciesin casesof disseminated diseaseand was the causative organism in our two patients. Fusarium spp.grow rapidly in culture. Becauseof the production of diffusible and nondiffusible pigments, the colonies demonstrate a variety of colors including white, pink, lavender, green, purple, red, or brown.26 The organism is identified by its characteristic fusiform or canoe-shaped multiseptate macroconidia, each with a notched basal ce11.41> 43 A biopsy specimen reveals fungal organisms within and around dermal blood vessels, causing thrombosis and often leading to tissue necrosis.302 41 The septate hyphae exhibit repeated branching at angles of 45 degrees to 90 degrees.44These organisms are histologically indistinguishable from Aspergillus, and Acremonium sp~.~~l52 In most cases of local disease, the organism appears to gain entry through a defective barrier that results from trauma. The portal of entry for disseminated Fusarium infection is not well understood but multiple entry siteshave been implicated. In the immunocompromised patient, disseminated diseasemay follow a localized infection.30$4op43The sinuses,28336 lungs,N 41 gastrointestinal tract,10*47 nails 46 skin25 and indwelling venous catheters32 have’been implicated as sourcesof disseminated infection. Fusarium spp. have been described as airborne human pathogens.41 Therefore fungal organisms could enter the sinuses2*or respiratory tract3’ by inhalation. Our first patient reported worsening of sinus symptoms and had a throat culture that grew F. solani. Therefore the sinusesmay have served asthe portal of entry. Indwelling venous catheters may serve as a portal of entry.32 Today catheters are kept in place for longer times, increasing the risk of infection. Furthermore, the risk of infection by this route may be enhanced by the organism’s tropism for silicone rubber catheters.32Our second patient may have been exposed to the organism by this route. Her catheter remained in place for 3 days after the development of skin lesions. In our review of the literature and including our patient, cultures taken from the central venous catheter were positive for Fusarium spp. in only three patients (6%). In a review of 13 casesof disseminated Fusarium infection, one

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Table I. Summary of 52 casesof disseminated Fusarium infection Patient characteristics

(N = 52)

1

N(s)

Male sex 36 (69) Mean age(years) 33.5(range,2-69) Hematologicmalignancyor 44 (85) aplasticanemia Site of involvement (culture-proven) Skin 44 (85) Blood 28 (54) Lung 19(37) Sinus/nasopharynx/larynx 13 (25) Kidney 9 (17) Spleen 7 (13) Gastrointestinaltract or liver 6 (12) Heart 6 (159 Brain 6 (12) 3 (6) Eye Muscle 3 (6) Catheter 3 (6) Fusarium species” F. solani F. oxysporum F. moniliforme F. proliferatum F. anthophilum

Unidentified Death *In one patient,

both F. soluni and

18 (35)

7(13) 5(10) 4w 1 c-4

18(35) 38(73) F. anthophilum were isolated.

patient in whom the central venous catheter was rapidly removed was the sole survivor, despite evidence of disseminated cutaneous infection.32 Another possiblesite of entry is the gastrointestinal tract. loa47 The fungus is ubiquitous in the soil and may be ingested in contaminated foods. The organism may be recovered from stool cultures in some patients as seen in case 2. Historically, eradication of disseminated Fusarium infection has been unsuccessful despite combined modalities, and with few exceptions,death results. In our review of the literature, the mortality rate was greater than 70%. Although in vitro resistance to amphotericin B is usual, clinicolaboratory correlations for fungal sensitivities are lacking, and amphotericin B remains the drug of choice.20> 35The organism is only occasionally susceptibleto the imidazoles and is almost uniformly resistant to rifampin and flucytosine.44The patients with disseminated Fusarium infection have been treated with various combinations of amphotericin B, ketoconazole, miconazole, fluconazole, rifamipin, and 5-fluorocytosine.

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Becausemost patients have neutropenia, and becauseclinical improvement depends on the recovery of a normal white blood cell count, granulocyte transfusions have also been used and were given to 14 of the 52 patients with disseminated infection. Similarly, granulocyte-macrophage colony-stimulating factor, another therapy of questionable benefit, was used in our patients. Although there have been two reported casesof disseminated Fusarium infection in nonimmunocompromised patients,34T47 severe neutropenia appears to be the major risk factor for the development of invasive and disseminated fungal infections in the majority of patients.48Likewise, recovery of normal neutrophil function is necessaryfor the resolution of infection.44 Despite the use of antifungal drugs, patients with neutrophil recovery are more likely to survive than those with persistent severe neutropenia.44 REFERENCES 1. Cho CT, Vats TS, Lowrnan JT, et al. Fusarium solani infection during treatmentfor acute leukemia.J Pediatr 1973;83:1028-31. 2. NaumannG, GreenWR, ZimmermanLE. Mycotic keratosis.A histopathologic studyof 73cases.Am J Ophthalmol 1967;64:668-82. 3. ZapaterRC, ArrecheaA. Mycotic keratitisby Fusarium; a reviewandreport of two cases.Ophthahnologica1975; 17&l-12. 4. ZaiasN. Superficialwhite onychomycosis. Sabouraudia 1966;5:99-103. 5. DisalvoAF, FicklingAM. A caseof non-dermatophytic toe onychomycosis causedby Fusarium oxysporum. Arch Dermatol1980;116:699-700. 6. Ooi SP,ChenTT, HuangTH, et al. Granulomaannulare like skinlesiondueto Fusarium roseurn’ therapywith ketoconazole.Arch Derrnatol1987;123:167-8. 7. BenjaminRP, CallawayJL, ConantNF. Facialgranuloma associatedwith Fusarium infection. Arch Dermatol 1970;101:598-600. 8. JackieC, LeekJC, OlsonDA, et al. Septicarthritisdueto Fusarium solani. J Rheumatol1983;10:151-3. 9. Kerr CM, PerfectJR, Jorgensen JH, et al. Fungalperitonitisin patientsoncontinuousambulatoryperitonealdialysis.Ann Intern Med 1983;99:334-7. 10. RipponJW, LarsonRA, RosenthalDM, et al. Disseminatedcutaneous andperitonealhyalohyphomycosis caused by Fusarium species: threecasesandreviewof the literature. Mycopathologia1988;101:105-11. 11. Page JC, FriedlanderG, Dockery GL. Post-operative Fusarium osteomyelitis. J Foot Surg 1982;21:174-6. 12. BourguignonRL, WalshAF, Flynn JC, et al. Fusarium speciesosteomyelitis. J BoneJointSurgAm 1976;58:722-3. 13. Mohr JA, NicholsNB, JonesJH, et al. Fungalendophthahnitis.SouthMed J 1973;66:685-8. 14. AbramowsyCR, QuinnD, BradfordWD, et al. Systemic infectionbyFusarium in a burnedchild.Theemergence of a saprophyticstrain.J Pediatr1974;84:561-4.

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15. Gutman L, Chou SM, PoreRS. Fusariosis, myasthenic syndromeandaplasticanemia.Neurology1975;25:922-6. 16. Young NA, Kwon-ChungKJ, KubotaTT, et al. Disseminated infectionby Fusarium moniliforme during treatment for malignantlymphoma.J Clin Microbial 1978; 7:589-94. 17. Mutton KJ, LucasTJ, HarknessJL. Disseminated Fusarium infection.Med J Aust 1980;2:624-5. 18. WheelerMS, McGinnisMR, SchellWA, et al. Fusarium infectioninburnedpatients.Am J ClinPathol1981;75:30411. 19. SteinbergGK, Britt RH, EnzmannDR, et al. Fusarium brainabscess. Casereport.J Neurosurg1983;58:598-601. 20. BlazarBR, Hurd DD, SnoverDC, etal. InvasiveFusarium infectionsin bonemarrowtransplantrecipients.Am J Med 1984;77:645-5 1. 21. ChaulkCP, SmithPW, FeaglerJR, et al. Fungemiadueto Fusarium solani in animmunocompromised child.Pediatr Infect Dis 1986;5:363-6. 22. MatsudaT, MatsumotoT. Disseminated hyalohyphomycosisin a leukemicpatient. Arch Dermatol 1986;122: 1171-5. 23. JuneCH, Beatty PG, ShulmanHM, et al. Disseminated Fusarium moniliforme infection after allogenicmarrow transplantation.SouthMed J 1986;79:513-5. 24. Karp JE, Mertz WG. Associationof reducedtotal iron bindingcapacityandfungalinfectionsin leukemicgranulocytopenicpatients.J Clin Oncol 1986;4:216-20. 25. AnaissieE, Kantarjian H, JonesP, et al. Fusarium. A newlyrecognizedpathogenin immunosuppressed patients. Cancer1986;57:2141-5. 26. VegliaKS, Marks VJ. Fusarium asa pathogen:a casereport of Fusarium sepsis andreviewof theliterature.J AM ACAD DERMATOL 1987;16:260-3.

27. Okuda C, Ito M, Sato Y, et al. Disseminated cutaneous Fusarium infectionwith vascularinvasionin a leukemic patient.J Med Vet Mycol 1987;25:177-86. 28. AnaissieE, KantarjianH, RoJ, et al. Theemergingroleof Fusarium infectionsin patientswith cancer.Medicine (Baltimore)1988;67:77-83. 29. SummerbellRC, Richardson SE, KaneJ. Fusarium proliferatum as an agent of disseminated infection in an imrnunosuppressed patient.J Clin Microbial 1988;26: 82-7. 30. Merz WG, Karp JE, HoaglandM, et al. Diagnosisand successful treatmentof Fusariosis in thecompromised host. J Infect Dis 1988;158:1046-55. 31. Venditti M, Micozzi A, GentileG, et al. InvasiveFusarium solani infections in patientswith acuteleukemia.RevInfect Dis 1988;10:653-60. 32. RichardsonSE, BannatyneRM, SummerbellRC, et al. Disseminated Fusarial infectionin the immunocompromisedhost.Rev Infect Dis 1988;10:1171-81. 33. Mowbray DN, PallerAS, NelsonPE,et al. Disseminated Fusarium solani infectionwith cutaneous nodules in abone marrowtransplantpatient. Int J Dermatol1988;27:698701. 34. SturmAW, GraveW, KweeWS. Disseminated Fusarium oxysporum infection in patient with heatstroke.Lancet 1989;1:968. 35. Minor RL Jr, Pfaller MA, Gingrich RD, et al. DisseminatedFusarium infectionsin patientsfollowingbonemarrow transplantation.Bone Marrow Transplant 1989; 4:653-8. 36. BarriosNJ, Kirkpatrick DV, MurcianoA, et al. Successful treatmentof disseminated Fusarium infectionin anim-

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munocompromised child. Am J Pediatr Hematol Oncol 1990;12:319-24. 37. Schneller FRG, Gulati SC, Cunningham IB, et al. Fusurium infectionsin patientswith hematologic malignancies. Leuk Res1990;14:961-6. 38. LupinettiFM, Giller RH, Trigg ME. Operativetreatment of Fusarium fungalinfectionin the lung.Ann ThoracSurg 1990;49:991-2. 39. HelmTN, LongworthDL, Hall GS,et al. Casereportand review of resolvedfusariosis.J AM ACAD DERMATOL 1990;23:393-8. 40. ViscoliC, CastagnolaE, Moroni C, et al. Infectionwith Fusarium species in two childrenwith neuroblastoma. Eur J Clin Microbial Infect Dis 1990;9:773-6. 41. El-Am AS. Disseminated infectioncausedby Fhsarium solani in a patientwith aplasticanemia.N Y StateJ Med 1990;90:60910. 42. RobertsonMJ, SocinskiMA, SoiiferRJ, et al. Successful treatmentof disseminated Fusurium infectionafter autologousbonemarrowtransplantationfor acutemyeloidleukemia.BoneMarrow Transplant1991;8:143-5. 43. AgamanolisDP, KalwinskyDK, Krill CE Jr, et al. Fusarium meningoencephalitis in a child with acuteleukemia. Neuropediatrics1991;22:110-2. 44. GamisAS, GudnasonT, GiebinkGS, et a1.Disseminated infection with Fusarium in recipientsof bonemarrow transplants.Rev Infect Dis 1991;13:1077-X8.

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