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Available online at www.sciencedirect.com
Review
Mucormycosis in systemic autoimmune diseases Mathieu Royer a , Xavier Puéchal b,c,∗ a
Service de rhumatologie, CHU d’Angers, 49933 Angers cedex 9, France Inserm U1016, CNRS UMR 8104, institut Cochin, Paris, France c National Referral Center for Rare Systemic Autoimmune Diseases hôpital Cochin, Assistance Publique–Hôpitaux de Paris, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France b
a r t i c l e
i n f o
Article history: Accepted 2 January 2014 Available online xxx Keywords: Mucormycosis Opportunistic infections Immunosuppressive drugs Systemic autoimmune diseases
a b s t r a c t Mucormycosis is an emerging infection in systemic autoimmune diseases. All published cases of systemic autoimmune diseases complicated by mucormycosis were reviewed. The clinical features, diagnostic procedures and the main principles of treatment were analyzed. Twenty-four cases of mucormycosis have been reported in systemic auto-immune diseases, of which 83% in systemic lupus erythematosus, all occurring during immunosuppressants. In most cases, the infection was disseminated or rhinocerebral and it had mimicked a flare of the underlying connective tissue disease. A fatal outcome was reported in 58.3% of these patients. In conclusion, mucormycosis often mimics a flare of the underlying systemic disease and is associated with a high mortality rate. Systemic lupus erythematosus is by far the most common associated systemic autoimmune disease. A high degree of awareness is warranted to rapidly rule out infection, of which mucormycosis, in immunocompromised patients with systemic autoimmune disease before a disease flare is conclusively diagnosed. © 2014 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction Mucormycosis is an emerging opportunistic fungal infection for which delayed diagnosis has been associated with high mortality rate [1–3]. Mucormycosis is increasingly recognized in patients with systemic autoimmune diseases while on immunosuppressive drugs, but in most cases, this opportunistic infection is not considered in such patients. As a result, many cases are diagnosed post-mortem. This delay in diagnosis is a major cause of mortality and could be prevented by the correct education of physicians and by increasing their awareness of mucormycosis. We have reviewed all published cases of patients with systemic autoimmune diseases complicated by a mucormycosis. The clinical features were analyzed. We reviewed recommended diagnostic procedures and the main principles of treatment. 2. Methods Published cases of mucormycosis with systemic autoimmune disease were identified by a computerised Medline search of articles published from 1983 to March 2013. The key words
∗ Corresponding author. Centre de référence des maladies systémiques autoimmunes rares, département de médecine interne, hôpital Cochin, université Paris Descartes, Assistance Publique–Hôpitaux de Paris, 27, rue du Faubourg SaintJacques, 75679 Paris cedex 14, France. Tel.: +33 1 58 41 29 71; fax: +33 1 58 41 29 68. E-mail address: [email protected] (X. Puéchal).
used were mucormycosis, zygomycosis, mucorales, fungal infections, opportunistic infections, connective tissue diseases, systemic autoimmune diseases, systemic lupus erythematosus, vasculitis, rheumatoid arthritis, myositis. Only publications in English, French or Spanish were selected for review. We also searched the references of the reports found, to identify additional reports. To be retained for the literature analysis, evidence of mucormycosis had to be documented on conventional diagnostic procedures. We included only those adult cases for which sufficient detail was provided. 3. Results Twenty-four isolated case reports of mucormycosis with systemic autoimmune disease were found [6–28]. The characteristics of these patients are shown in Table 1. Systemic lupus erythematosus (SLE) was by far the most common systemic autoimmune disease, accounting for 83% (20 cases) of the 24 reported cases [6–24]. 3.1. Mucormycosis in systemic lupus erythematosus In SLE, the female predominance (15 F, 5 M) was in agreement with the sex ratio observed in this disease. The infection was disseminated (six cases), cerebral or rhinocerebral (six cases), cutaneous (three cases), respiratory (two cases), digestive (two cases) and renal in one case. All patients were receiving corticosteroid therapy for their autoimmune disease. In addition, patients
1297-319X/$ – see front matter © 2014 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2014.01.002
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Ref
Gender
Age
Systemic auto-immune disease
Mucormycosis clinical form
Diabetes mellitus
Immunosuppressive treatment
Diagnosis
Treatment
Outcome
Arce-Salinas Shenoi Peel Yu
[6] [7] [8] [9]
F M F M
75 14 60 34
SLE SLE SLE SLE
Rhinocerebral Gastric Lungs + hip renal
No Yes Yes ND
CS + AZA CS + CYC + HCQ CS + CYC + cyclosporine CS + CYC + MMF
Amphotericin Amphotericin + micafungine Posaconazole + surgery Amphotericin
Died Recovered Recovered Died
Fujimoto
[10]
F
54
SLE
Cutaneous
Yes
CS
Amphotericin
Died
Alsuwaida Sungkanuparph Liu Hosseini Dickinson Fingerote Bloxham Wong Mok Escobar Coffey
[11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21]
F F F F F M F F F F M
54 20 21 42 36 36 29 21 36 33 29
SLE SLE SLE SLE SLE SLE SLE SLE SLE SLE SLE
No Yes No No Yes No No No Yes No No
CS + CYC CS CS + AZA CS CS CS CS + PE CS + AZA + HCQ CS + CYC CS + CYC CS + AZA
Amphotericin Amphotericin + surgery Fluconazole Amphotericin + surgery Amphotericin + surgery None None None Amphotericin None Amphotericin + surgery
Recovered Recovered Died Died Recovered Died Died Died Died Died Recovered
Figueroa Del Real Del Real Kumar Singh Nogueira
[22] [23] [23] [24] [25] [26]
F M F F F F
15 16 31 28 65 29
SLE SLE SLE SLE RA GPA
Cutaneous Rhinocerebral Disseminated Gastrointestinal Cutaneous Disseminated Disseminated Disseminated Rhinocerebral Cerebral Lungs + Pulmonary artery Rhinocerebral Disseminated Disseminated Rhinocerebral Disseminated Lungs
Biopsy Biopsy Biopsy + arthroscopic Biopsy + urine culture Biopsy + tissue culture Biopsy Biopsy PM Biopsy Biopsy PM PM PM Nasal swab PM Biopsy
ND No Yes No No No
Recovered Died Died Recovered Died Recovered
[27]
M
65
Rhinocerebral
Yes
None
Died
Berenguer
[28]
M
64
ANCA-associated vasculitis undetermined systemic vasculitis
Biopsy PM PM Biopsy PM Broncho alveolar cells culture PM
Amphotericin + surgery None None Amphotericin + surgery Amphotericin Amphotericin + Posaconazole
Royer
CS CS CS CS CS + MTX + ADA CS + CYC + PE; AZA; IFX; RTX CS + CYC
Rhinosinusal
No
ND
Biopsy
Amphotericin + surgery
Recovered
F: female; M: male; SLE: systemic lupus erythematosus; RA: rheumatoid arthritis; GPA: granulomatosis with polyangiitis (Wegener’s); ND: not described; CS: corticosteroids; AZA: azathioprine; CYC: cyclophosphamide; MMF: mycophenolate mofetil; MTX: methotrexate; ADA: adalimumab; HCQ: hydroxychloroquine; IFX: infliximab; RTX: rituximab; PE: plasma exchange; PM: post-mortem.
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Table 1 Clinical characteristics of 24 patients reported in the literature with systemic autoimmune disease and mucormycosis [6–28].
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received cyclophosphamide or azathioprine in six and four cases, respectively. Additional predisposing factors for opportunistic infection included diabetes mellitus (7/18), hypocomplementemia (7/14), renal damage (12/16), leukopenia (5/10). The mean delay for diagnosis ranged from one to 13 days and in seven cases, diagnosis was done post mortem. In most cases, manifestations of the fungal infection mimicked the symptoms of active SLE and may be particularly misleading. In six cases, mucormycosis was rhinocerebral [6,12,19,20,22,24]. The most common manifestations of the infectious disease, which are also frequently encountered in SLE flare, were headache, facial pain or edema, visual acuity impairment, and in most cases, cranial nerves palsies. In disseminated mucormycosis [13,16–18,23], renal damage was constantly present (acute renal failure, proteinuria) and neurological manifestations were also common (somnolence, disorientation, convulsions, and coma). Other signs could also be misdiagnosed as a lupus flare in these patients: abdominal pain, vomiting, purpura, fever, cough, spontaneous bruising or bleeding. In the two digestive cases [7,14], abdominal pain, cytolysis, emesis were present and may mimic a lupus flare. In one of these patients [14], endoscopic findings led to the diagnosis of ischemic colitis. In the renal case of mucormycosis [9], clinical signs were non-specific: hematuria, proteinuria, acute renal failure. Amphotericin B therapy has been used in most cases. One patient received posaconazole and another patient received fluconazole. In seven cases, surgery was associated with the anti fungal treatment. Among the 20 patients with SLE, 12 (60%) had a fatal outcome. The mean delay between the first clinical signs and death was two months for one patient and less than one month for all other (on average 17 days). All patients with disseminated mucormycosis (6/6) had a fatal outcome versus 3/6 for rhinocerebral mucormycosis and 3/8 in other cases. Among treated patients (n = 14/20), six died (42.8%). When the initial diagnosis was a SLE flare (eight cases), an intensification of immunosuppressive therapy was administered and death occurred in seven cases (87.5%). By contrast, when the initial diagnosis was an infectious complication of immunosuppressive therapy associated with lymphopenia (nine cases), unfavorable outcome (two cases) was less frequent (22.2%). 3.2. Mucormycosis in other systemic autoimmune diseases Despite prevalent use of immunosuppressants, mucormycosis has been infrequently reported in other systemic autoimmune diseases. One non-diabetic patient with rheumatoid arthritis presented a fatal mucormycosis while being treated with the monoclonal anti-TNF agent adalimumab in association with methotrexate [25]. The mucormycosis was disseminated (orbital ischaemia, infarction of anterior and inferior lobes bilaterally, pulmonary peri hilar hazing). The patient died within a few days despite amphotericin B treatment. We have previously reported the case of a diabetes patient suffering from an ANCA associated vasculitis who died of rhinocerebral mucormycosis arteritis, which was diagnosed post-mortem after having mimicked a vasculitis flare [27]. The pathological study confirmed a parietal involvement of the right middle cerebral artery with wall segmental destruction by an abscess, the presence of many hyphae in the media and many mycotic thrombi occluding the wall. Mucormycosis is thus a rare cause of septic arteritis and is able to mimic a vasculitis flare. Two other cases have also been reported in patients with systemic necrotizing vasculitis with a favorable outcome. One had granulomatosis with polyangiitis (Wegener’s) and infection mimicked a pulmonary vasculitis flare (fever, cough, hemoptysis, dyspnea) [26]. The patient recovered after two months of treatment with amphotericin B and posaconazole. Another patient had undetermined systemic vasculitis with
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chronic renal insufficiency [28] and presented a rhinosinusal mucormycosis treated by amphotericin B and surgery with a favourable outcome. Since its presentation may so closely mimic a disease relapse and may be associated with a rise in PR3-ANCA titer [26], some authors have hypothesized that mucormycosis may have been underdiagnosed in patients with vasculitis and that many such cases may have been treated as vasculitis flare and resulted in an unfavorable outcome [26]. 4. Discussion 4.1. Epidemiology Mucormycosis is a rare life-threatening opportunistic infection caused by fungi of the order Mucorales, which are ubiquitous in the environment [1,29,30]. One population-based study estimated the incidence of mucormycosis to be 1.7 cases per million people per year [3]. Mucormycosis is becoming increasingly common in immunocompromised patients [1,3–5,31]. It typically occurs in patients with diabetes mellitus, patients who have received an organ or hematopoietic stem cell transplant, patients with malignancy or with neutropenia [1,3–5,31]. Diabetes is the most common underlying condition [31]. Diabetic patients are particularly vulnerable in the event of poorly controlled diabetes or ketoacidosis [3]. Among 929 reviewed cases of zygomycosis in the literature, Roden et al. [31] showed that diabetic patients, of whom most were type 2 diabetics, represented 36% of the total number of cases. At the onset of mucormycosis, ketoacidosis was found in 48% of patients with type 1 diabetes and in 34% of those with type 2 diabetes. In patients with systemic autoimmune diseases who are often already immunocompromised, immunosuppressive drugs, prolonged high-dose corticosteroid treatment and diabetes favored the occurrence of this opportunistic infection [6–27]. 4.2. Clinical presentations of mucormycosis Rhinocerebral mucormycosis is the most common form of the infection, accounting one-third of all cases of mucormycosis [3,31]. It is acquired by inhalation of the fungi spores. Symptoms of rhinocerebral mucormycosis are neither pathognomonic nor specific. Nasal obstruction or congestion with noisy breathing, headache, odontalgia, maxillary pain and hyposmia or anosmia may be seen. Necrotic eschars in the nasal cavity, the turbinates or the palate, and necrotic facial lesions correspond to aggressive angioinvasive infections [2,3]. Orbital extension can lead to preseptal and orbital cellulitis, and is associated with chemosis, eyelid edema, proptosis, blurred vision, double vision, worsening ophthalmoplegia and acute vision loss. Intracranial extension is associated with a depressed level of consciousness. Intracranial complications include cavernous and, more rarely, sagittal sinus thrombosis, epidural or subdural abscess formation, cerebral vascular accidents and convulsions [2]. The clinical hallmark of mucormycosis infection is vascular invasion. The organism characteristically invades the walls of adjacent blood vessels, causing thrombosis and infarction or secondary hemorrhages of neighboring tissues. There are sometimes focal areas of granulomatous inflammation [1,32]. When there is extensive central nervous system involvement, the angioinvasive nature of the fungus may result in cavernous sinus thrombosis and internal carotid or middle cerebral artery encasement and thrombosis with extensive resulting cerebral infarctions [3,27]. Contrast-enhanced computed tomography (CT) is useful in defining the extent of rhinocerebral mucormycosis. Such CT scans show the edematous mucosa, fluid filling the ethmoid sinuses, and destruction of periorbital tissues and bone margins [5]. Although
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evidence of infection of orbital soft tissues may be seen on CT scans, magnetic resonance (MR) imaging is more sensitive for this. MR imaging is quite useful in identifying the intradural and intracranial extent of rhinocerebral mucormycosis, cavernous sinus thrombosis, and thrombosis of cavernous portions of the internal carotid artery [5]. Contrast-enhanced MR imaging can also demonstrate perineural spread of the infection. Pulmonary, gastrointestinal, cutaneous and disseminated mucormycosis are less common forms of the infection [5]. Although the clinical manifestations vary, the typical presentation of cutaneous mucormycosis is a necrotic eschar accompanied by surrounding erythema and induration [5]. The symptoms of disseminated mucormycosis vary also widely, reflecting the host as well as the location and degree of vascular invasion and tissue infarction in the affected organs [5]. The organ most commonly associated with dissemination is the lung. The most common site of dissemination is the brain with abscess formation and infarction [3]. Metastatic lesions may also be found in the spleen, liver, heart, skin and other organs [3,5]. 4.3. Differential diagnosis in patients with systemic auto-immune diseases Central nervous system involvement may occur in patients with SLE or ANCA-associated vasculitis. Neurologic manifestations vary according to the cerebral location and the mechanisms involved: cerebral vasculitis, thrombosis, hematoma, pachymeningitis and granulomas in granulomatosis with polyangiitis (Wegener’s) [33]. Focal neurological signs due to cerebrovascular accident are therefore possible. There are no specific diagnostic tests for active cerebral flare and in most cases, confirmatory evidence is not available. Thus, in a suggestive clinical context, the diagnosis of active cerebral manifestations due to the underlying systemic disease relies on excluding other causes. Among these, infection is the most important differential diagnosis to be considered before making a diagnosis and increasing immunosuppressant drug therapy. Among the infections, mucormycosis in its rhinocerebral form can closely mimic a neurological flare of SLE or vasculitis. Clinicians should be especially aware that this differential diagnosis should be considered in a diabetic or immunocompromised patient. 4.4. Diagnosis of mucormycosis Diagnosis of mucormycosis relies upon identification of the fungal agent either by culture or histologically [31]. Mucorales are aerobic fungi that grow in most culture media after two to five days of incubation but it is recommended that the clinical material be inoculated onto Sabouraud dextrose agar and incubated at temperatures of 25 to 55 ◦ C [19,32]. Nevertheless, culturing organisms from a potentially infected tissue is rarely sufficient to establish diagnosis because the causative agent is ubiquitous and a relatively frequent laboratory contaminant. Furthermore, it may be killed as tissue specimens are processed for culture and the organism is rarely isolated from cultures of blood, cerebrospinal fluid, sputum, urine, feces or swabs of infected areas [3]. Thus, the diagnosis should be made by biopsy of infected tissue showing histopathologic evidence of fungal invasion [3]. Blind biopsies of sinus mucosa and/or thickened extraocular muscles are thus warranted to make the diagnosis of rhinocerebral mucormycosis [3]. Direct microscopic examination should demonstrate the characteristic wide, ribbon-like, aseptae hyphal elements that branch at right angles [4,19]. New molecular tools utilizing polymerase chain reaction (PCR) or restriction fragment length polymorphism (RFLP) are being evaluated for the identification of fungi in culture and in tissues to facilitate earlier diagnosis [34].
4.5. Outcome of mucormycosis A high index of suspicion is required to make the diagnosis of rhinocerebral mucormycosis in these patients, as evidenced by the fact that up to half of all cases are diagnosed post-mortem [3], and even 58.3% of the patients with systemic autoimmune disease reported to date in the literature. Delayed diagnosis has been associated with considerably poor outcomes [3]. Indeed, in most cases, the infection is relentlessly progressive and results in death unless treatment is initiated promptly [3]. Survival depends on the clinical form of the infection, the nature of underlying disease and the prompt initiation of treatment [1,3,32]. According to a literature review, the mortality rate is 62% in patients with rhinocerebral infection and 97% (233 of 241 patients) for the subgroup of patients who received no treatment for their infection [31]. 4.6. Treatment of mucormycosis The successful treatment of mucormycosis is based on four principles [1,3,35]: • early diagnosis; • reversal of the underlying predisposing factors, if possible (for example, corticosteroids should be administered at reduced dosages or stopped if at all possible and hyperglycemia and acidemia should be corrected in diabetic ketoacidosis); • urgent surgical debridement of infected and necrotic tissue; • appropriate antifungal therapy. The reference antifungal agent is amphotericin B (amphoB) and the recommended doses are 1 to 1.5 mg/kg/day for amphoB deoxycholate or 3 to 5 mg/kg/day for amphoB in its lipidic form [1,35,36]. The duration of antifungal chemotherapy is not defined but guided by the resolution of all associated symptoms and findings, and maintenance therapy/secondary prophylaxis must be considered in persistently immunocompromised patients [35]. 5. Conclusions In conclusion, mucormycosis is a severe infection, which may occur in diabetic or immunocompromised hosts including patients with connective tissue disease and particularly in SLE patients. The lack of specific clinical features makes it difficult to diagnose. Mucormycosis symptoms often mimic a flare of the underlying systemic disease. Knowledge and awareness of this devastating infection and of its severity are necessary to allow rapid investigations and biopsies to be performed and prevent delays in diagnosis. Although, the mortality rate of rhinocerebral mucormycosis remains high, the infection can be cured when it is diagnosed early and treated with a combination of surgical debridement and amphotericin B treatment. A high degree of awareness is warranted to rule out infection, of which mucormycosis, in immunocompromised patients with systemic autoimmune disease before a disease flare is conclusively diagnosed. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Spellberg B, Walsh TJ, Kontoyiannis DP, et al. Recent advances in the management of mucormycosis: from bench to bedside. Clin Infect Dis 2009;48:1743–51. [2] Mantadakis E, Samonis G. Clinical presentation of zygomycosis. Clin Microbiol Infect 2009;15:15–20.
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[3] Spellberg B, Edwards Jr J, Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation, and management. Clin Microbiol Rev 2005;18:556–69. [4] Lanternier F, Dannaoui E, Morizot G, et al. A global analysis of mucormycosis in France: the RetroZygo Study (2005–2007). Clin Infect Dis 2012;54:S35–43. [5] Petrikkos G, Skiada A, Lortholary O, et al. Epidemiology and clinical manifestations of mucormycosis. Clin Infect Dis 2012;54:S23–34. [6] Arce-Salinas CA, Peres-Silva E. Mucormycosis complications in systemic lupus erythematosus. Lupus 2010;33:115–24. [7] Shenoi S, Emery HM. Successful treatment of invasive gastric mucormycosis in a child with systemic lupus erythematosus. Lupus 2010;19:646–9. [8] Peel T, Daffy J, Thursky K, et al. Posaconazole as first line treatment for disseminated mucormycosis. Mycoses 2008;51:542–5. [9] Yu J, Li RY. Primary renal mucormycosis due to Rhizopus oryzae. Med Mycol 2006;44:461–6. [10] Fujimoto A, Nagao K, Tanaka K, et al. The first case of cutaneous mucormycosis caused by Rhizopus azygosporus. Br J Dermatol 2005;153:428–30. [11] Alsuwaida K. Primary cutaneous mucormycosis complicating the use of adhesive tape to secure the endotracheal tube. Can J Anaesth 2002;49:880–2. [12] Sungkanuparph S, Sathapatayavongs B, Kunachak S, et al. Treatment of invasive fungal sinusitis with liposomal amphotericin B: a report of four cases. J Med Assoc Thai 2001;84:593–601. [13] Liu MF, Chen FF, Hsiue TR, et al. Disseminated mucormycosis simulating cerebrovascular disease and pulmonary alveolar haemorrhage in a patient with systemic lupus erythematosus. Clin Rheumatol 2000;19:311–4. [14] Hosseini M, Lee J. Gastrointestinal mucormycosis mimicking ischemic colitis in a patient with systemic lupus erythematosus. Am J Gastroenterol 1998;93:1360–2. [15] Dickinson M, Kalayanamit T, Yang CA, et al. Cutaneous zygomycosis (mucormycosis) complicating endotracheal intubation: diagnosis and successful treatment. Chest 1998;114:340–2. [16] Fingerote RJ, Seigel S, Atkinson MH, et al. Disseminated mucormycosis associated with systemic lupus erythematosus. J Rheumatol 1990;17:1692–4. [17] Bloxham CA, Carr S, Ryan DW. Disseminated mucormycosis and systemic lupus erythematosus. Intensive Care Med 1990;16:201–7. [18] Wong KL, Tai YT, Loke SL. Disseminated mucormycosis masquerading as cerebral lupus erythematosus. Am J Clin Pathol 1986;86:546–9. [19] Mok CC, Que TL, Tsui EY, et al. Mucormycosis in systemic lupus erythematosus. Semin Arthritis Rheum 2003;33:115–24.
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[20] Escobar A, Del Brutto OH. Multiple brain abscesses from isolated cerebral mucormycosis. J Neurol Neurosurg Psychiatry 1990;53:431–3. [21] Coffey MJ, Fantone III J, Stiring MC, et al. Pseudoaneurysm of pulmonary artery in mucormycosis. Am Rev Respir Dis 1992;145:1487–90. [22] Figueroa-Damian R, Torres-Gonzales FE. Zygomyocosis in children. Report of two cases. Bol Med Hosp Infant Mex 1993;50:813–8. [23] Del Real MO, Zamora QJ, Abud-Mendoza C, et al. Mucormicosis. Rev Invest Clin 1983;35:237–40. [24] Kumar P, Begum CZ, Thirumaran P, et al. Rhino cerebral mucormycosis in systemic lupus erythematosus. Indian J Dermatol 2013;58:158. [25] Singh P, Taylor SF, Murali R, et al. Disseminated mucormycosis and orbital ischaemia in combination immunosuppression with a tumour necrosis factor alpha inhibitor. Clin Experiment Ophthalmol 2007;35:275–80. [26] Nogueira EL, Ind PW, Friedland JS, et al. Mucormycosis may mimic disease relapse in Wegener’s granulomatosis. J Rheumatol 2010;37:1364–5. [27] Royer M, Cervera P, Kahan A, et al. Mucormycosis cerebral arteritis mimicking a flare in ANCA-associated vasculitis. Lancet Infect Dis 2013;13:182. [28] Berenguer J, Solera J, Moreno S, et al. Mucormycosis. The disease spectrum in 13 patients. Med Clin (Barc) 1990;94:766–72. [29] Richardson M. The ecology of the Zygomycetes and its impact on environmental exposure. Clin Microbiol Infect 2009;15:2–9. [30] Nosari A, Oreste P, Montillo M, et al. Mucormycosis in hematologic malignancies: an emerging fungal infection. Haematologica 2000;85:1068–71. [31] Roden MM, Zaoutis TE, Buchanan WL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis 2005;41: 634–53. [32] Lass-Flörl C. Zygomycosis: conventional laboratory diagnosis. Clin Microbiol Infect 2009;15:60–5. [33] Holle JU, Gross WL. Neurological involvement in Wegener’s granulomatosis. Curr Opin Rheumatol 2011;23:7–11. [34] Dannaoui E. Molecular tools for identification of Zygomycetes and the diagnosis of zygomycosis. Clin Microbiol Infect 2009;15:66–70. [35] Skiada A, Lanternier F, Groll AH, et al. Diagnosis and treatment of mucormycosis in patients with hematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3). Haematologica 2013;98:492–504. [36] Petrikkos GL. Lipid formulations of amphotericin B as first-line treatment of zygomycosis. Clin Microbiol Infect 2009;15:87–92.
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Available online at www.sciencedirect.com
Review
Mucormycosis in systemic autoimmune diseases Mathieu Royer a , Xavier Puéchal b,c,∗ a
Service de rhumatologie, CHU d’Angers, 49933 Angers cedex 9, France Inserm U1016, CNRS UMR 8104, institut Cochin, Paris, France c National Referral Center for Rare Systemic Autoimmune Diseases hôpital Cochin, Assistance Publique–Hôpitaux de Paris, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France b
a r t i c l e
i n f o
Article history: Accepted 2 January 2014 Available online xxx Keywords: Mucormycosis Opportunistic infections Immunosuppressive drugs Systemic autoimmune diseases
a b s t r a c t Mucormycosis is an emerging infection in systemic autoimmune diseases. All published cases of systemic autoimmune diseases complicated by mucormycosis were reviewed. The clinical features, diagnostic procedures and the main principles of treatment were analyzed. Twenty-four cases of mucormycosis have been reported in systemic auto-immune diseases, of which 83% in systemic lupus erythematosus, all occurring during immunosuppressants. In most cases, the infection was disseminated or rhinocerebral and it had mimicked a flare of the underlying connective tissue disease. A fatal outcome was reported in 58.3% of these patients. In conclusion, mucormycosis often mimics a flare of the underlying systemic disease and is associated with a high mortality rate. Systemic lupus erythematosus is by far the most common associated systemic autoimmune disease. A high degree of awareness is warranted to rapidly rule out infection, of which mucormycosis, in immunocompromised patients with systemic autoimmune disease before a disease flare is conclusively diagnosed. © 2014 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction Mucormycosis is an emerging opportunistic fungal infection for which delayed diagnosis has been associated with high mortality rate [1–3]. Mucormycosis is increasingly recognized in patients with systemic autoimmune diseases while on immunosuppressive drugs, but in most cases, this opportunistic infection is not considered in such patients. As a result, many cases are diagnosed post-mortem. This delay in diagnosis is a major cause of mortality and could be prevented by the correct education of physicians and by increasing their awareness of mucormycosis. We have reviewed all published cases of patients with systemic autoimmune diseases complicated by a mucormycosis. The clinical features were analyzed. We reviewed recommended diagnostic procedures and the main principles of treatment. 2. Methods Published cases of mucormycosis with systemic autoimmune disease were identified by a computerised Medline search of articles published from 1983 to March 2013. The key words
∗ Corresponding author. Centre de référence des maladies systémiques autoimmunes rares, département de médecine interne, hôpital Cochin, université Paris Descartes, Assistance Publique–Hôpitaux de Paris, 27, rue du Faubourg SaintJacques, 75679 Paris cedex 14, France. Tel.: +33 1 58 41 29 71; fax: +33 1 58 41 29 68. E-mail address: [email protected] (X. Puéchal).
used were mucormycosis, zygomycosis, mucorales, fungal infections, opportunistic infections, connective tissue diseases, systemic autoimmune diseases, systemic lupus erythematosus, vasculitis, rheumatoid arthritis, myositis. Only publications in English, French or Spanish were selected for review. We also searched the references of the reports found, to identify additional reports. To be retained for the literature analysis, evidence of mucormycosis had to be documented on conventional diagnostic procedures. We included only those adult cases for which sufficient detail was provided. 3. Results Twenty-four isolated case reports of mucormycosis with systemic autoimmune disease were found [6–28]. The characteristics of these patients are shown in Table 1. Systemic lupus erythematosus (SLE) was by far the most common systemic autoimmune disease, accounting for 83% (20 cases) of the 24 reported cases [6–24]. 3.1. Mucormycosis in systemic lupus erythematosus In SLE, the female predominance (15 F, 5 M) was in agreement with the sex ratio observed in this disease. The infection was disseminated (six cases), cerebral or rhinocerebral (six cases), cutaneous (three cases), respiratory (two cases), digestive (two cases) and renal in one case. All patients were receiving corticosteroid therapy for their autoimmune disease. In addition, patients
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Ref
Gender
Age
Systemic auto-immune disease
Mucormycosis clinical form
Diabetes mellitus
Immunosuppressive treatment
Diagnosis
Treatment
Outcome
Arce-Salinas Shenoi Peel Yu
[6] [7] [8] [9]
F M F M
75 14 60 34
SLE SLE SLE SLE
Rhinocerebral Gastric Lungs + hip renal
No Yes Yes ND
CS + AZA CS + CYC + HCQ CS + CYC + cyclosporine CS + CYC + MMF
Amphotericin Amphotericin + micafungine Posaconazole + surgery Amphotericin
Died Recovered Recovered Died
Fujimoto
[10]
F
54
SLE
Cutaneous
Yes
CS
Amphotericin
Died
Alsuwaida Sungkanuparph Liu Hosseini Dickinson Fingerote Bloxham Wong Mok Escobar Coffey
[11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21]
F F F F F M F F F F M
54 20 21 42 36 36 29 21 36 33 29
SLE SLE SLE SLE SLE SLE SLE SLE SLE SLE SLE
No Yes No No Yes No No No Yes No No
CS + CYC CS CS + AZA CS CS CS CS + PE CS + AZA + HCQ CS + CYC CS + CYC CS + AZA
Amphotericin Amphotericin + surgery Fluconazole Amphotericin + surgery Amphotericin + surgery None None None Amphotericin None Amphotericin + surgery
Recovered Recovered Died Died Recovered Died Died Died Died Died Recovered
Figueroa Del Real Del Real Kumar Singh Nogueira
[22] [23] [23] [24] [25] [26]
F M F F F F
15 16 31 28 65 29
SLE SLE SLE SLE RA GPA
Cutaneous Rhinocerebral Disseminated Gastrointestinal Cutaneous Disseminated Disseminated Disseminated Rhinocerebral Cerebral Lungs + Pulmonary artery Rhinocerebral Disseminated Disseminated Rhinocerebral Disseminated Lungs
Biopsy Biopsy Biopsy + arthroscopic Biopsy + urine culture Biopsy + tissue culture Biopsy Biopsy PM Biopsy Biopsy PM PM PM Nasal swab PM Biopsy
ND No Yes No No No
Recovered Died Died Recovered Died Recovered
[27]
M
65
Rhinocerebral
Yes
None
Died
Berenguer
[28]
M
64
ANCA-associated vasculitis undetermined systemic vasculitis
Biopsy PM PM Biopsy PM Broncho alveolar cells culture PM
Amphotericin + surgery None None Amphotericin + surgery Amphotericin Amphotericin + Posaconazole
Royer
CS CS CS CS CS + MTX + ADA CS + CYC + PE; AZA; IFX; RTX CS + CYC
Rhinosinusal
No
ND
Biopsy
Amphotericin + surgery
Recovered
F: female; M: male; SLE: systemic lupus erythematosus; RA: rheumatoid arthritis; GPA: granulomatosis with polyangiitis (Wegener’s); ND: not described; CS: corticosteroids; AZA: azathioprine; CYC: cyclophosphamide; MMF: mycophenolate mofetil; MTX: methotrexate; ADA: adalimumab; HCQ: hydroxychloroquine; IFX: infliximab; RTX: rituximab; PE: plasma exchange; PM: post-mortem.
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Table 1 Clinical characteristics of 24 patients reported in the literature with systemic autoimmune disease and mucormycosis [6–28].
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received cyclophosphamide or azathioprine in six and four cases, respectively. Additional predisposing factors for opportunistic infection included diabetes mellitus (7/18), hypocomplementemia (7/14), renal damage (12/16), leukopenia (5/10). The mean delay for diagnosis ranged from one to 13 days and in seven cases, diagnosis was done post mortem. In most cases, manifestations of the fungal infection mimicked the symptoms of active SLE and may be particularly misleading. In six cases, mucormycosis was rhinocerebral [6,12,19,20,22,24]. The most common manifestations of the infectious disease, which are also frequently encountered in SLE flare, were headache, facial pain or edema, visual acuity impairment, and in most cases, cranial nerves palsies. In disseminated mucormycosis [13,16–18,23], renal damage was constantly present (acute renal failure, proteinuria) and neurological manifestations were also common (somnolence, disorientation, convulsions, and coma). Other signs could also be misdiagnosed as a lupus flare in these patients: abdominal pain, vomiting, purpura, fever, cough, spontaneous bruising or bleeding. In the two digestive cases [7,14], abdominal pain, cytolysis, emesis were present and may mimic a lupus flare. In one of these patients [14], endoscopic findings led to the diagnosis of ischemic colitis. In the renal case of mucormycosis [9], clinical signs were non-specific: hematuria, proteinuria, acute renal failure. Amphotericin B therapy has been used in most cases. One patient received posaconazole and another patient received fluconazole. In seven cases, surgery was associated with the anti fungal treatment. Among the 20 patients with SLE, 12 (60%) had a fatal outcome. The mean delay between the first clinical signs and death was two months for one patient and less than one month for all other (on average 17 days). All patients with disseminated mucormycosis (6/6) had a fatal outcome versus 3/6 for rhinocerebral mucormycosis and 3/8 in other cases. Among treated patients (n = 14/20), six died (42.8%). When the initial diagnosis was a SLE flare (eight cases), an intensification of immunosuppressive therapy was administered and death occurred in seven cases (87.5%). By contrast, when the initial diagnosis was an infectious complication of immunosuppressive therapy associated with lymphopenia (nine cases), unfavorable outcome (two cases) was less frequent (22.2%). 3.2. Mucormycosis in other systemic autoimmune diseases Despite prevalent use of immunosuppressants, mucormycosis has been infrequently reported in other systemic autoimmune diseases. One non-diabetic patient with rheumatoid arthritis presented a fatal mucormycosis while being treated with the monoclonal anti-TNF agent adalimumab in association with methotrexate [25]. The mucormycosis was disseminated (orbital ischaemia, infarction of anterior and inferior lobes bilaterally, pulmonary peri hilar hazing). The patient died within a few days despite amphotericin B treatment. We have previously reported the case of a diabetes patient suffering from an ANCA associated vasculitis who died of rhinocerebral mucormycosis arteritis, which was diagnosed post-mortem after having mimicked a vasculitis flare [27]. The pathological study confirmed a parietal involvement of the right middle cerebral artery with wall segmental destruction by an abscess, the presence of many hyphae in the media and many mycotic thrombi occluding the wall. Mucormycosis is thus a rare cause of septic arteritis and is able to mimic a vasculitis flare. Two other cases have also been reported in patients with systemic necrotizing vasculitis with a favorable outcome. One had granulomatosis with polyangiitis (Wegener’s) and infection mimicked a pulmonary vasculitis flare (fever, cough, hemoptysis, dyspnea) [26]. The patient recovered after two months of treatment with amphotericin B and posaconazole. Another patient had undetermined systemic vasculitis with
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chronic renal insufficiency [28] and presented a rhinosinusal mucormycosis treated by amphotericin B and surgery with a favourable outcome. Since its presentation may so closely mimic a disease relapse and may be associated with a rise in PR3-ANCA titer [26], some authors have hypothesized that mucormycosis may have been underdiagnosed in patients with vasculitis and that many such cases may have been treated as vasculitis flare and resulted in an unfavorable outcome [26]. 4. Discussion 4.1. Epidemiology Mucormycosis is a rare life-threatening opportunistic infection caused by fungi of the order Mucorales, which are ubiquitous in the environment [1,29,30]. One population-based study estimated the incidence of mucormycosis to be 1.7 cases per million people per year [3]. Mucormycosis is becoming increasingly common in immunocompromised patients [1,3–5,31]. It typically occurs in patients with diabetes mellitus, patients who have received an organ or hematopoietic stem cell transplant, patients with malignancy or with neutropenia [1,3–5,31]. Diabetes is the most common underlying condition [31]. Diabetic patients are particularly vulnerable in the event of poorly controlled diabetes or ketoacidosis [3]. Among 929 reviewed cases of zygomycosis in the literature, Roden et al. [31] showed that diabetic patients, of whom most were type 2 diabetics, represented 36% of the total number of cases. At the onset of mucormycosis, ketoacidosis was found in 48% of patients with type 1 diabetes and in 34% of those with type 2 diabetes. In patients with systemic autoimmune diseases who are often already immunocompromised, immunosuppressive drugs, prolonged high-dose corticosteroid treatment and diabetes favored the occurrence of this opportunistic infection [6–27]. 4.2. Clinical presentations of mucormycosis Rhinocerebral mucormycosis is the most common form of the infection, accounting one-third of all cases of mucormycosis [3,31]. It is acquired by inhalation of the fungi spores. Symptoms of rhinocerebral mucormycosis are neither pathognomonic nor specific. Nasal obstruction or congestion with noisy breathing, headache, odontalgia, maxillary pain and hyposmia or anosmia may be seen. Necrotic eschars in the nasal cavity, the turbinates or the palate, and necrotic facial lesions correspond to aggressive angioinvasive infections [2,3]. Orbital extension can lead to preseptal and orbital cellulitis, and is associated with chemosis, eyelid edema, proptosis, blurred vision, double vision, worsening ophthalmoplegia and acute vision loss. Intracranial extension is associated with a depressed level of consciousness. Intracranial complications include cavernous and, more rarely, sagittal sinus thrombosis, epidural or subdural abscess formation, cerebral vascular accidents and convulsions [2]. The clinical hallmark of mucormycosis infection is vascular invasion. The organism characteristically invades the walls of adjacent blood vessels, causing thrombosis and infarction or secondary hemorrhages of neighboring tissues. There are sometimes focal areas of granulomatous inflammation [1,32]. When there is extensive central nervous system involvement, the angioinvasive nature of the fungus may result in cavernous sinus thrombosis and internal carotid or middle cerebral artery encasement and thrombosis with extensive resulting cerebral infarctions [3,27]. Contrast-enhanced computed tomography (CT) is useful in defining the extent of rhinocerebral mucormycosis. Such CT scans show the edematous mucosa, fluid filling the ethmoid sinuses, and destruction of periorbital tissues and bone margins [5]. Although
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evidence of infection of orbital soft tissues may be seen on CT scans, magnetic resonance (MR) imaging is more sensitive for this. MR imaging is quite useful in identifying the intradural and intracranial extent of rhinocerebral mucormycosis, cavernous sinus thrombosis, and thrombosis of cavernous portions of the internal carotid artery [5]. Contrast-enhanced MR imaging can also demonstrate perineural spread of the infection. Pulmonary, gastrointestinal, cutaneous and disseminated mucormycosis are less common forms of the infection [5]. Although the clinical manifestations vary, the typical presentation of cutaneous mucormycosis is a necrotic eschar accompanied by surrounding erythema and induration [5]. The symptoms of disseminated mucormycosis vary also widely, reflecting the host as well as the location and degree of vascular invasion and tissue infarction in the affected organs [5]. The organ most commonly associated with dissemination is the lung. The most common site of dissemination is the brain with abscess formation and infarction [3]. Metastatic lesions may also be found in the spleen, liver, heart, skin and other organs [3,5]. 4.3. Differential diagnosis in patients with systemic auto-immune diseases Central nervous system involvement may occur in patients with SLE or ANCA-associated vasculitis. Neurologic manifestations vary according to the cerebral location and the mechanisms involved: cerebral vasculitis, thrombosis, hematoma, pachymeningitis and granulomas in granulomatosis with polyangiitis (Wegener’s) [33]. Focal neurological signs due to cerebrovascular accident are therefore possible. There are no specific diagnostic tests for active cerebral flare and in most cases, confirmatory evidence is not available. Thus, in a suggestive clinical context, the diagnosis of active cerebral manifestations due to the underlying systemic disease relies on excluding other causes. Among these, infection is the most important differential diagnosis to be considered before making a diagnosis and increasing immunosuppressant drug therapy. Among the infections, mucormycosis in its rhinocerebral form can closely mimic a neurological flare of SLE or vasculitis. Clinicians should be especially aware that this differential diagnosis should be considered in a diabetic or immunocompromised patient. 4.4. Diagnosis of mucormycosis Diagnosis of mucormycosis relies upon identification of the fungal agent either by culture or histologically [31]. Mucorales are aerobic fungi that grow in most culture media after two to five days of incubation but it is recommended that the clinical material be inoculated onto Sabouraud dextrose agar and incubated at temperatures of 25 to 55 ◦ C [19,32]. Nevertheless, culturing organisms from a potentially infected tissue is rarely sufficient to establish diagnosis because the causative agent is ubiquitous and a relatively frequent laboratory contaminant. Furthermore, it may be killed as tissue specimens are processed for culture and the organism is rarely isolated from cultures of blood, cerebrospinal fluid, sputum, urine, feces or swabs of infected areas [3]. Thus, the diagnosis should be made by biopsy of infected tissue showing histopathologic evidence of fungal invasion [3]. Blind biopsies of sinus mucosa and/or thickened extraocular muscles are thus warranted to make the diagnosis of rhinocerebral mucormycosis [3]. Direct microscopic examination should demonstrate the characteristic wide, ribbon-like, aseptae hyphal elements that branch at right angles [4,19]. New molecular tools utilizing polymerase chain reaction (PCR) or restriction fragment length polymorphism (RFLP) are being evaluated for the identification of fungi in culture and in tissues to facilitate earlier diagnosis [34].
4.5. Outcome of mucormycosis A high index of suspicion is required to make the diagnosis of rhinocerebral mucormycosis in these patients, as evidenced by the fact that up to half of all cases are diagnosed post-mortem [3], and even 58.3% of the patients with systemic autoimmune disease reported to date in the literature. Delayed diagnosis has been associated with considerably poor outcomes [3]. Indeed, in most cases, the infection is relentlessly progressive and results in death unless treatment is initiated promptly [3]. Survival depends on the clinical form of the infection, the nature of underlying disease and the prompt initiation of treatment [1,3,32]. According to a literature review, the mortality rate is 62% in patients with rhinocerebral infection and 97% (233 of 241 patients) for the subgroup of patients who received no treatment for their infection [31]. 4.6. Treatment of mucormycosis The successful treatment of mucormycosis is based on four principles [1,3,35]: • early diagnosis; • reversal of the underlying predisposing factors, if possible (for example, corticosteroids should be administered at reduced dosages or stopped if at all possible and hyperglycemia and acidemia should be corrected in diabetic ketoacidosis); • urgent surgical debridement of infected and necrotic tissue; • appropriate antifungal therapy. The reference antifungal agent is amphotericin B (amphoB) and the recommended doses are 1 to 1.5 mg/kg/day for amphoB deoxycholate or 3 to 5 mg/kg/day for amphoB in its lipidic form [1,35,36]. The duration of antifungal chemotherapy is not defined but guided by the resolution of all associated symptoms and findings, and maintenance therapy/secondary prophylaxis must be considered in persistently immunocompromised patients [35]. 5. Conclusions In conclusion, mucormycosis is a severe infection, which may occur in diabetic or immunocompromised hosts including patients with connective tissue disease and particularly in SLE patients. The lack of specific clinical features makes it difficult to diagnose. Mucormycosis symptoms often mimic a flare of the underlying systemic disease. Knowledge and awareness of this devastating infection and of its severity are necessary to allow rapid investigations and biopsies to be performed and prevent delays in diagnosis. Although, the mortality rate of rhinocerebral mucormycosis remains high, the infection can be cured when it is diagnosed early and treated with a combination of surgical debridement and amphotericin B treatment. A high degree of awareness is warranted to rule out infection, of which mucormycosis, in immunocompromised patients with systemic autoimmune disease before a disease flare is conclusively diagnosed. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Spellberg B, Walsh TJ, Kontoyiannis DP, et al. Recent advances in the management of mucormycosis: from bench to bedside. Clin Infect Dis 2009;48:1743–51. [2] Mantadakis E, Samonis G. Clinical presentation of zygomycosis. Clin Microbiol Infect 2009;15:15–20.
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