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DISSEMINATED FUSARIOSIS IN A PEDIATRIC PATIENT WITH ACUTE LYMPHOBLASTIC LEUKEMIA AND PROLONGED FEVER--A CASE REPORT/DISEMINOVANA FUZARIOZA KOD PEDIJATRIJSKOG BOLESNIKA SA AKUTNOM LIMFOBLASTNOM LEUKEMIJOM I PRODUZENOM FEBRILNOSCU--PRIKAZ SLUCAJA.

Introduction

Fusarium species (spp.) are environmental fungi widely distributed in the soil, organic substrates and water. They also cause a broad spectrum of human infections [1].

Infections caused by fungi of Fusarium spp. occur in immunocompromised individuals as a disseminated disease. A high resistance of Fusarium spp. to most antifungal agents leads to mortality rate over 50% among immunocompromised patients [1, 2].

We report a case of a pediatric patient with acute lymphoblastic leukemia (ALL) and prolonged fever due to a disseminated infection with fusarium with unusual properties.

Case Report

A 5-year-old boy was diagnosed with ALL. The previous treatment (induction, consolidation and most of the reinduction chemotherapy) lasted about 9 months and there were no complications or delays.

At the end of the reinduction phase, the boy developed fever and it lasted for the next 15 weeks.

In the beginning, the boy had a fever, but he was in a good condition with normal physical findings. The white blood cells (WBC) count was 2.4 G/l and C-reactive protein (CRP) level was 24 mg/l. Blood, urine and stool cultures were negative. He was initially treated with ceftriaxone and at the same time the reinduction phase was finished.

After that, in the next 4 weeks, the patient presented with high temperature every day (Graph 1), (taken 2 to 3 times per day) associated with malaise, loss of appetite, and occasional vomiting without diarrhea. During the first two weeks he had a nonproductive cough. At the end of the fourth week, decreased breath sounds were noted in the right lung. In this period, the boy had severe granulocytopenia for 3 weeks. The CRP ranged from 96--192 mg/l. Urine analysis, chest X-ray, X-ray of the paranasal sinuses, echocardiography and abdominal ultrasonography (US) revealed no abnormal findings. Repeated blood, urine, and stool cultures were also negative. After 28 days of treatment with broad-spectrum antibiotics and a 10-day course of intravenous fluconazole (FLU), the patient still had daily fevers. Extensive infectious and autoimmune workup was negative and the source of fever was not revealed. Complete remission was confirmed on bone marrow examination. A chest computed tomography (CT) scan (22 (nd) febrile day) revealed multiple lung nodules, 5 mm in diameter (Graph

1). In addition to slightly enlarged liver and spleen, abdominal CT scan showed no abnormalities. Voriconazole (VRC) was initiated. The patient`s WBC stabilized at around 3 G/l, while the CRP was high despite antifungal therapy. A week later, while continuously febrile, the boy stopped coughing. However, he was extremely ill and complained of severe pain in the legs. Ferritin was high (2433 ug/l). In the sixth week, the patient was given a course of parenteral methylprednisolone (1 mg/kg daily) for 2 weeks with VRC concomitantly. On day 2 of steroids, there was a complete defervescence, and the CRP level decreased. During a reduction in the dose of steroids, the boy became febrile once again with an increase in CRP. Anti-Candida and anti-Aspergillus antibodies of the IgM and IgG classes, Aspergillus galactomannan and Candida mannan antigens values were monitored during the illness (Table 1). VRC (used for 30 days) was switched to liposomal amphotericin B (L-AMB) in the 10 (th ) week of illness. The patient remained febrile and exhaustion worsened over the next weeks. Procalcitonin level was high and antibiotic therapy was reintroduced. Abdominal US (52 (nd) febrile day) revealed multiple liver and splenic hypoechoic lesions, 7.5 mm in diameter, associated with hepatosplenomegaly (Graph 1). Repeated abdominal US showed an increase in the size and number of these lesions. A peripheral venous catheter was applied at that point. At week 12 of high temperature, caspofungin (CPFG) was added to L-AMB. At the same time, maintenance therapy for ALL was initiated. As the high temperature was still present, in the 13 (th ) week a diagnostic abdominal laparoscopy was performed. Scattered spots up to 2 mm in diameter were observed macroscopically on the surface of the liver and spleen. The fungi were not detected by direct microscopy in the obtained samples. The sample culture remained positive for Acinetobacter spp. (susceptible to ciprofloxacin only) and Fusarium spp. Histopathology has shown chronic portal and light lobular hepatitis. Our patient received CPFG for 19 days and L-AMB for 45 days. After 38 days of therapy with L-AMB and 3 days with ciprofloxacin (a total of 14 days) the patient became afebrile in the 15 (th) week. Itraconazole (according to the antimycogram) was given during maintenance therapy. The CRP level was still high in the next 2 months (above 50 mg/l). The abdominal US was completely normal after 5 months of treatment with itraconazole. Six years after discontinuation of antifungal therapy, the patient remains in complete remission of his neoplastic disease without signs of clinical infection.

Discussion

Fusarium spp. are widespread in nature. This genus of fungal opportunists was first identified in 1958. Among immunocompromised patients, Fusarium spp. are second to Aspergillus spp. as the most common cause of invasive fungal infections [1, 3]. Only a few species cause disease in humans, most often F. solani complex, F. oxysporum complex and F. fujikuroi complex [1].

Disseminated fusariosis occurs only in conditions associated with immunosuppression and some risk factors. Our patient had most of them: acute leukemia, previous treatment with high doses of dexamethasone, prolonged and severe neutropenia and extended antibiotic treatment [4, 5].

The typical clinical presentation is neutropenic fever in patients with myalgia and sudden appearance of erythematous papular or nodal painful skin lesions with central necrosis. Cutaneous lesions were not observed in our patient, although they are seen in approximately 85% of patients with early stage disseminated fusarium infections [6]. Pneumonia may be the only manifestation of the disease or part of a disseminated disease. It is very similar to invasive pulmonary aspergillosis with angioinvasion, lung infarction and characteristic nodules with or without the halo sign [6, 7]. The clinical signs of hepatosplenic disease typically develop after neutrophil recovery [7].

Despite broad-spectrum antibiotic therapy, refractory fever, nausea, myalgia, pulmonary symptoms with pulmonary infiltrates, liver and spleen involvement indicated an invasive fungal infection.

Standard diagnostic procedures for fungal infections include microscopic examination of liquid and solid diagnostic specimens, blood cultures and all clinical cultures, non-culture assays for fungal antigens and imaging studies [8].

Direct microscopic examination of biological samples is the fastest way for obtaining the diagnosis [6]. The sensitivity of blood culture to detect fungemia ranges between 21 and 71% for Candida, but it is very low for the infection caused by Aspergillus spp. [9]. Our patient did not have positive blood cultures, although they are often positive with the infections caused by Fusarium spp.

Fusarium spp. may contaminate laboratory specimens. The growth of fusarium from non-sterile samples in high risk patients should be interpreted as a probable infection until proven otherwise [6]. Liver culture from our patient was positive for Acinetobacter and Fussarium spp. The genus Acinetobacter is a major cause of nosocomial infections. Its ability to develop multidrug resistance and to persist in any environmental conditions makes infections by Acinetobacter very dangerous [10]. Our patient received antibiotics from all groups except fluoroquinolones. In this case, Acinetobacter was susceptible to ciprofloxacin only.

Identification of the genus Fusarium is not difficult. However, species identification requires molecular methods (matrix-assisted laser desorption ionization-time of flight mass spectrometry, multiplex PCR assay) [2, 6].

Remarkable advances in the early detection of invasive fungal infections have been made by the development of non-culture assays for fungal antigens [8]. Routine antigen detection with the Aspergillus galactomannan index (GMI) enzyme-linked immunosorbent assay (ELISA) test should be considered in high-risk patients. Positive GMI tests should be interpreted as indicative of invasive aspergillosis or invasive fusariosis [6]. Cross-reactivity has been observed for a number of other fungi including Fusarium species and some beta-lactam antibiotics. Serial GM assessments can also be used to monitor the effectiveness of antifungal therapy [9]. Routine Candida antibody and antigen testing and routine testing for Aspergillus antibodies are not recommended for patients with hemato-oncological malignancies [7]. In our patient, positive test for mannan and GMI, as well as antibodies to Candida and Aspergillus were probably due to cross-reactivity.

Our patient developed a disseminated fusarium infection. He received a broad spectrum of antibiotics and FLU first. After detection of pulmonary nodes he received an empiric treatment with VRC and later L-AMB for suspected aspergillosis. In the meantime, the cough has stopped. Chest X-ray findings were still normal. Due to suspicion of hemophagocytic lymphohistiocytosis, he received a short course of corticosteroids. Later, CPFG was added due to positive anticandida antibody and mannan antigen. Considering that the infection spread to the liver and spleen, both fusarium and acinetobacter were isolated from the liver sample. The fungigram revealed that the pathogenic agent was resistant to antifungal polyene, FLU, VRC and was sensitive to itraconazole, which is inconsistent with literature data.

This boy was our first patient with a disseminated fusarium infection. At that time, the Fusarium spp. was detected in the hospital water system and in hospital air samples.

Conclusion

A timely diagnosis of invasive fungal disease in children is a big challenge. Over the past decade, survival from invasive fusariosis has increased. This is most likely the result of much more frequent use of voriconazole or combined antifungal therapy, although European Guidelines recommend only one week of combination therapy.

References

(1.) Al-Hatmi AMS, Bonifaz A, Ranque S, Sybren de Hoog G, Verweij PE, Meis J F. Current antifungal treatment of fusariosis. Int J Antimicrob Agents. 2018;51(3):326-32.

(2.) Lainhart W. Fusarium spp., a genus of common plant pathogens that can cause devastating, opportunistic human disease. Clin Microbiol Newsl. 2018;40(1):1-5.

(3.) Horn DL, Freifeld AG, Schuster MG, Azie NE, Franks B, Kauffman CA. Treatment and outcomes of invasive fusariosis: review of 65 cases from the PATH Alliance[R]registry. Mycoses. 2014;57(11):652-8.

(4.) Pagano1 L, Busca A, Candoni A, Cattaneo C, Cesaro S, Fanci R, et al. Risk stratification for invasive fungal infections in patients with hematological malignancies: SEIFEM recommendations. Blood Rev. 2016;31(2):17-29.

(5.) Kassar O, Charfi M, Trabelsi H, Hammami R, Elloumi M. Fusarium solani endocarditis in an acute leukemia patient. Med Mal Infect. 2016;46(1):57-9.

(6.) Nucci F, Nouer SA, Capone D, Anaissie E, Nucci M. Fusariosis. Semin Respir Crit Care Med. 2015;36(5):706-14.

(7.) Ruhnke M, Bohme A, Buchheidt D, Cornely O, Donhuijsen K, Einsele H, et al. Diagnosis of invasive fungal infections in hematology and oncology - guidelines from the Infectious Diseases Working Party in Haematology and Oncology of the German Society for Haematology and Oncology (AGIHO). Ann Oncol. 2012;23(4):823-33.

(8.) Groll AH, Castagnola E, Cesaro S, Dalle JH, Engelhard D, Hope W, et al. Fourth European Conference on Infections in Leukaemia (ECIL-4): guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or allogeneic haemopoietic stem-cell transplantation. Lancet Oncol. 2014;15(8):e327-40.

(9.) Warris A, Lehrnbecher T. Progress in the diagnosis of invasive fungal disease in children. Curr Fungal Infect Rep. 2017;11(2):35-44.

(10.) Almasaudi SB. Acinetobacter spp. as nosocomial pathogens: epidemiology and resistance features. Saudi J Biol Sci. 2018;25(3):586-96.

Rad je primljen 9. VI 2018.

Recenziran 19. VII 2018.

Prihvacen za stampu 7. VIII 2018.

BIBLID.0025-8105:(2018):LXXI:9-10:314-318.

Institute for Child and Youth Health Care of Vojvodina, Novi Sad

Department of Hematology and Oncology (1)

University of Novi Sad, Faculty of Medicine, Novi Sad (2)

Natasa KACANSKI (1), Branislava RADISIC (1) and Jovanka KOLAROVIC (1,2)

Corresponding Author: Prof. dr Jovanka Kolarovic, Institut za zdravstvenu zastitu dece i omladine Vojvodine, 21000 Novi Sad, Hajduk Veljkova 10, E-mail: jovanka.kolarovic@mf.uns.ac.rs

https://doi.org/10.2298/MPNS1810316K
Table 1. Fungal biomarkers during and after the fever
Tabela 1. Gljivicni biomarkeri tokom i nakon febrilnosti

Elisa immunodiffusion assay        week 7      week 10      week 13
Elisa imunodifuzijski test         7. nedelja  10. nedelja  13. nedelja

anti-Candida IgM antibody          > 500       440          > 500
anti-Candida IgM antitela
anti-Candida IgG antibody            300       330            225
anti-Candida IgG antitetela
Candida mannan antigen                 0,34      0,94           1,28
Candida mannan antigen
anti-Aspergillus IgM antibody        112       130            200
anti-Aspergillus IgM antitela
anti-Aspergillus IgG antibody        390       310            280
anti-Aspergillus IgG antitela
Aspergillus galactomannan antigen      0,25      3,33           0,3
Aspergillus galactomannan antigen

Elisa immunodiffusion assay        week 25
Elisa imunodifuzijski test          25. nedelja

anti-Candida IgM antibody          420
anti-Candida IgM antitela
anti-Candida IgG antibody          230
anti-Candida IgG antitetela
Candida mannan antigen               0,4
Candida mannan antigen
anti-Aspergillus IgM antibody       66
anti-Aspergillus IgM antitela
anti-Aspergillus IgG antibody      450
anti-Aspergillus IgG antitela
Aspergillus galactomannan antigen    0,28
Aspergillus galactomannan antigen

Elisa immunodiffusion assay        reference values

Elisa imunodifuzijski test         referentne vrednosti
anti-Candida IgM antibody          [greater than or equal to] 80 U/ml
                                   positive
anti-Candida IgM antitela          [greater than or equal to] 80 U/ml
                                   pozitivan
anti-Candida IgG antibody          [greater than or equal to] 100 U/ml
                                   positive
anti-Candida IgG antitetela        [greater than or equal to] 100 U/ml
                                   pozitivan
Candida mannan antigen             index [greater than or equal to] 0,5
                                   positive
Candida mannan antigen             indeks [greater than or equal to] 0,5
                                   pozitivan
anti-Aspergillus IgM antibody      [greater than or equal to] 70 U/ml
                                   positive
anti-Aspergillus IgM antitela      [greater than or equal to]70 U/ml
                                   pozitivan
anti-Aspergillus IgG antibody      [greater than or equal to] 70 U/ml
                                   positive
anti-Aspergillus IgG antitela      [greater than or equal to] 70 U/ml
                                   pozitivan
Aspergillus galactomannan antigen  index [greater than or equal to] 0,5
                                   positive
Aspergillus galactomannan antigen  indeks [greater than or equal to] 0,5
                                   pozitivan
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Title Annotation:CASE REPORTS/PRIKAZI SLUCAJEVA
Author:Kacanski, Natasa; Radisic, Branislava; Kolarovic, Jovanka
Publication:Medicinski Pregled
Date:Sep 1, 2018
Words:2260
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