Fetal and Pediatric Pathology, Early Online:1–5, 2012 C Informa Healthcare USA, Inc. Copyright ISSN: 1551-3815 print / 1551-3823 online DOI: 10.3109/15513815.2012.721479
Resistant Invasive Aspergillosis in an Autosomal Recessive Chronic Granulomatous Disease
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Lamia Sfaihi,1 Ines Maaloul,1 Hela Fourati,2 Marie Jose´ Stasia,3 Zeineb Mnif,2 and Mongia Hachicha1 1
Department of Pediatrics, CHU Hedi Chaker, Sfax, Tunisia; 2 Department of Radiology, CHU Hedi Chaker, Sfax, Tunisia; 3 CHU de Grenoble, Chronic Granulomatous Disease Diagnosis and Research Centre, Grenoble, France
Chronic granulomatous disease (CGD) is an inherited immunodeficiency characterized by severe bacterial and fungal infections. Invasive aspergillosis and other rare mold diseases are the leading causes of mortality. We report one case of CGD revealed by retropharyngeal abscess. On evolution, the patient developed an invasive aspergillosis resistant to treatment. Keyswords aspergillosis, child, chronic granulomatous disease
INTRODUCTION Chronic granulomatous disease (CGD) is a rare congenital immunodeficiency syndrome, in which phagocytes lack nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity [1, 2] and as consequence, the patients suffer from recurrent life-threatening bacterial and fungal infections. It is still causes significant morbidity and mortality; and yet no curative treatment is disponible. Recently, bone marrow transplantation has emerged as an important option for patients with CGD [1, 2]. This is a study of a case report of CGD revealed by retropharyngeal abscess, cervical lymphadenitis and recurrent skin abscesses. A review of the literature on this pathology is also presented. CASE REPORT A three-month-old boy, born from consanguineous parents, was admitted in the pediatrics department for fever and cervical lymphadenitis. He had received the Bacille Calmette-Gu´erin and other routine vaccinations. The clinical examination revealed a fever of 38◦ C and painful cervical lymphadenopathy with overlying inflammatory skin. The ultrasound imaging showed a 5 cm retropharyngeal abscess with multiple cervical lymphadenopathy. He underwent a computed tomography that confirmed retropharyngeal abscess which was resolved after drainage and intravenous antibiotics. The biopsy of an adenopathy showed granulomata and the BCG (Bacille Calmette Guerin) infection diagnosis was retained. Microbial swabs grew only klebsiella pneumonia.
Received 13 February 2012; accepted 6 June 2012. Address correspondence to Lamia Sfaihi, Department of Pediatrics, CHU Hedi Chaker, Route el Ain km 0,5, Sfax3029, Tunisia. Email:
[email protected]
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L. Sfaihi et al.
Three months later, he was hospitalized for foot abscesses requiring intravenous antibiotics treatment and surgical incision. Then, he presented an abscess in the arm treated medically and the evolution was suitable. Search for an immunodeficiency began. Results of the nitroblue tetrazolium test of neutrophils with phorbol-myristate acetate (PMA) were abnormal suggesting CGD. The patient and his mother were tested for mutations in CYBA gene. The genomic DNA analysis and RT-PCR (reverse transcription polymerase chain reaction) analysis of the patient showed a homozygous mutation which is a deletion of seven bases GTGCCCG (295-30) in the beginning of exon 5. His mother is heterozygous for this mutation. While the patient received prophylaxis antibiotic (Trimethoprim-sulfamethoxazole and itraconazole), he was hospitalized at the age of 2 years for chronic cough and weight loss. The physical examination revealed growth retardation and bilateral lung sounds. Investigations revealed significantly raised inflammatory markers and a microcytic, hypochromic anemia. The chest radiography showed left upper lobe opacity which was also seen in thoracic computed tomography in association with another one in the lower right lobe (Figure 1). The diagnosis of invasive pulmonary aspergillosis was confirmed by a positive serological test for Aspergillus fumigatus (antibody titers: 1/512). Antifungal therapy was initiated with amphotericin B [1 mg/(kg/day)] for the period of 6 weeks followed by a long-term oral Itraconazole at prophylactic dose. But he was admitted 3 months after because of fever recurrence. The thoracic computed tomography showed the aggravation of radiologic abnormalities and the appearance of osteolytic lesions on the two ribs siding the pulmonary lesion. At the same time, we showed an increase of antibody titers of Aspergillus fumigatus. Therefore, the patient was treated with oral voriconazole (7 mg/kg × 2/day) for 6 months then we decreased the dose to a preventive one (4 mg/kg × 2/day). After this treatment, he presented clinical improvement and a progressive reduction of antibody titers to Aspergillus fumigatus (from 1/512 to 1/2). Fourteen month after, he was admitted for appearance of an anterior thoracic mass with cutaneous fistula. Thoracic computed tomography showed aggravation of the latest pulmonary lesion which extended to the chest wall. The Mycology examination of the pus stemming from the fistula showed an aspergillus fumigatus. Cerebral computed tomography showed three expanding lesions in the fourth ventricular and hydrocephalus (Figure 2]. A combined treatment by intravenous amphotericin B [1 mg/(kg/j)] and oral voriconazole was initiated but evolution was rapid towards a fatal end.
FIGURE 1. a. Frontal chest radiograph shows hazy airspace consolidation in the left lung with air bronchogram. Enlargement of soft tissues and interruption of the costal third anterior arc. b. Consolidation in the left upper lobe with chest wall invasion. A small consolidation in the middle lobe. Fetal and Pediatric Pathology
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Resistant Invasive Aspergillosis in an Autosomal Recessive CGD
FIGURE 2. a. Axial SE T1 image shows a hypo-intense mass in the posterior fossa within the fourth venticle. b. Coronal SE T2 image shows hyper-intense mass, hydrocephalus. c. Post contrast axial SE T1 image shows extra-axial masses in the cerebello-pontine angle cisterns, in the supra-sellar cistern and an important enhancement in the fourth venticle mass. Note the meningeal marked enhancement. d. Post contrast axial SE T1 image reveals intense meningeal enhancement in the inter peduncular cistern, subarachnoid mass markedly enhanced e. Post contrast coronal SE T1 image shows bilateral cavernous sinus masses. f. Post contrast coronal SE T1 image shows enhancement of the cerebellum tentorium.
DISCUSSION CGD is a rare inherited disorder of phagocytic cells that affects from 200 000 to 450 000 live births. It is inherited in a heterogeneous manner, with five distinct genetic mutations identified up to now [3]. Most commonly encountered is the X-linked form of the disease which accounts for around two thirds of the cases and is responsible for the increased incidence of the disease in male children. The remaining one third of the cases is inherited in an autosomal recessive way like that in our patient who had a CYBA gene mutation that was previously found in other patients [3]. CDG normally manifests within the early months or years of life [1]. According to an Italian study achieved recently and including a large cohort of patients [60], the mean age of the onset of symptoms was 1 year (the median was 7.5 months) and the age of diagnosis was significantly lower in the X recessive group compared with the autosomal recessive group [4]. Our patient developed the first symptoms at the early age of 3 months. CGD patients are vulnerable to organisms that are positive catalyses and thus destroy hydrogen peroxide. These organisms include Staphylococcus spp., Serratia, Nocardia, mycobacteria and Aspergillus spp.; Penicillium, Paecilomyces, Acremonium, Rhizopus spp. and dematiaceous moulds are isolated less frequently [1]. C Informa Healthcare USA, Inc. Copyright
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Aspergillus spp., especially A. fumigatus, has become one of the prevailing causes of infections in CGD patients causing 80%–90% of cases of invasive aspergillosis in immune compromised patients [1]. Aspergillosis is also the most common cause of mortality in patients with CGD and is responsible for over one third of deaths. The fungal infection can affect the pulmonary tract, the brain and the bones causing osteomyelitis. In our case, the pulmonary aspergillosis was diagnosed at the age of 2 years; although he was under prophylactic treatment by trimethoprim/sulfamethoxazole and itraconazole [5, 6]. The lung was the most common site of the disease, and Aspergillus species was responsible for approximately 40% of the culture-positive cases. The role for serology, such as the b-D-glucan and galactomannan assays, are undefined in CGD patients, but when results are positive, these assays might be helpful to follow up in some cases [7]. Antibacterial (trimethoprim/sulfamethoxazole) and antifungal (itraconazole) prophylaxis has significantly reduced the rates and severity of infections in patients with CGD, but breakthrough infections still occur as in our case [8, 9]. In fact our patient developed a pulmonary aspergillosis despite the beginning of the antimicrobial prophylaxis treatment 18 month earlier. In spite of significant advances in the management of fungal infections in immune compromised patients, invasive aspergillosis remains an important life-threatening complication and one of the most refractory fungal infections [10]. In fact, our patient developed disseminated and refractory aspergillosis despite suitable curative treatment by amphotericin B and voriconazole. CONCLUSION In conclusion, this study shows that fungal infections especially due to Aspergillus are one of the most frequent causes of morbidity and mortality in CGD patients. The management is still difficult because of the resistance of some species such as Aspergillus. Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article. REFERENCES [1] Winkelstein JA, Marino MC, Johnston RB Jr, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore) 79:155–169, 2000. [2] Stasia MJ, Li XJ. Genetic and immunopathology of chronic granulomatous disease. Semin Immunopathol 30(3):209–235, 2008. [3] Roos D, Kuhns DB, Maddalena A, et al. Hematologically important mutations: the autosomal recessive forms of chronic granulomatous disease (second update). Blood Cells Mol Dis 44:291–299, 2010. [4] Baldassare M, Rondelli R, Soresina A. et al. Clinical features, long term follow-up and outcome of a large cohort of patients with chronic granulomatous disease: an Italian multicenter study. Clin Immunol 126(2):155–164, 2008. [5] Patel N, Krai T, Perry D, et al. Recurrent deep cervical abscesses in chronic granulomatous disease: a case report and review of the literature. Int J Pediatr Otorhinolaryngol Extra 6(4): 378–381, 2011. [6] Roxo P Jr, Pa dua de Menezes U, Condino-Neto A, et al. Unusual presentation of brain aspergillosis in chronic granulomatous disease. Pediatr Neurol 43:442–444, 2010. [7] Martire B, Rondelli R, Soresina A, et al. Clinical features, long-term follow-up and outcome of a large cohort of patients with Chronic Granulomatous Disease: an Italian multicenter study. Clin Immunol 126:155–164, 2008. Fetal and Pediatric Pathology
Resistant Invasive Aspergillosis in an Autosomal Recessive CGD
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[8] Seger RA. Modern management of chronic granulomatous disease. Br J Haematol 2008;140:255–266. [9] Gallin JI, Alling DW, Malech HL, et al. Itraconazole to prevent fungal infections in chronic granulomatous disease. N Engl J Med 348:2416–422, 2003. [10] Alsultan A, Willians MS, Lubner S, et al. Brief report: chronic granulomatous disease presenting with disseminated intracranial aspergillosis. Pediatr Blood Cancer 47:107–110, 2006.
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