Introduction

Mucormycosis is an invasive fungal infection caused by the Mucorales order of Zygomycetes, causing high burden of in-hospital mortality [1]. Although these infections are uncommon, increasing number of cases is being recognized in immunocompromised states. The common predisposing factors for mucormycosis include uncontrolled diabetes, high dose glucocorticoids, neutropenia, organ transplant recipients, iron overload states, and recently COVID-19 infection in India [2, 3].

Infections are a major cause of morbidity and mortality in SLE, although the prevalence of invasive fungal infections is low in these patients [4]. Immune dysregulation and the use of immunosuppressive drugs predispose these patients to invasive fungal infections [5]. Data on mucormycosis in SLE is sparse, and there are only 2 cases reported so far of pulmonary mucormycosis (PM) in patients with SLE.

We describe a case with active lupus and PM who was successfully managed with conventional amphotericin B. In addition, we also present the data available so far on mucormycosis in SLE.

Case report

A 20-year-old lady presented with 6 months history of low-grade fever, oral ulcers, alopecia, inflammatory polyarthralgia of small joints of hand, anaemia requiring blood transfusions, and pedal oedema which had recently progressed to anasarca. There was no history of photosensitivity or malar rash. She also had progressive proximal muscle weakness over the past 3 months. Twenty days ago, she had two episodes of generalized tonic–clonic seizures and history of irrelevant talk. Physical examination revealed normal sensorium and orientation, blood pressure of 120/80 mmHg, pallor, anasarca, ulcers over palate and buccal mucosa, diffuse hair thinning, and boggy swelling of bilateral proximal interphalangeal joints. Cardiovascular, respiratory, and abdominal examination was unremarkable. She had grade 2 power in the shoulder and pelvic girdle and grade 3 at the knee and elbows and grade 4 at the wrist and ankle joint. Deep tendon reflexes and sensory system examination were normal.

Laboratory evaluation showed haemoglobin of 9.9 g%, platelet count of 27,000/cu.mm, creatinine 1.1 mg/dl, lactate dehydrogenase 338 U/L, creatinine phosphokinase 27 U/L, Alanine and aspartate aminotransferase 58 U/L, and 20 U/L, respectively. Anti-nuclear antibody (ANA) was positive with homogenous pattern, anti-ds-DNA antibody levels were > 300 IU, and in addition, she had anti-histone, anti-nucleosome, anti-Ro, and anti-La antibodies. Her IgG and IgM anticardiolipin (aCL) antibody titres were 25 GPL (normal: 3–18 GPL) and > 100 MPL (normal: 3–18 MPL), respectively, with negative beta2-glycoprotein antibody. Her complement levels were C3: 12 mg/dl (normal: 60–120 mg/dl), and C4: 2 mg/dl (normal: 15–40 mg/dl). Urinalysis showed proteinuria 3 + with active urine sediments and 24-h urinary protein of 2.7 g. Cerebrospinal fluid examination and MRI head were normal.

A diagnosis of SLE with Lupus nephritis and neuropsychiatric lupus was made. She was treated with daily intravenous pulse of 250 mg methylprednisolone (MPS) for 3 days followed by prednisolone 1 mg/kg body weight. She also received intravenous cyclophosphamide (CYC) induction 750 mg/m2 body surface area (750 mg). With this and supportive care, her anasarca and muscle weakness improved.

A few days later, she developed breathlessness and tachycardia, with presence of coarse crepitations in right infra-scapular and infra-axillary regions. ECG showed sinus tachycardia. Chest X-ray showed new onset consolidation in right lower zone, following which antibiotics (intravenous piperacillin-tazobactam and oral azithromycin) were started and prednisolone was tapered to 0.25 mg/kg. She had no fever, cough, or expectoration. A day later, she has sudden onset of hoarseness of voice and video-laryngoscopy showed evidence of subglottic narrowing.

Contrast-enhanced computed tomography (CECT) scan of neck and chest revealed mass-like consolidation in the right lower lobe with central ground glass opacities intermingled with small cavities and intersecting reticular strands suggestive of Bird’s nest sign. Multiple variable-sized random nodules were seen scattered in bilateral upper lobes (right more than left), with many of them showing central cavitation and peripheral ground glass halo (Fig. 1a). No obvious bronchial wall thickening was seen. Based on these imaging findings in a background of ongoing immunosuppression, a diagnosis of invasive fungal infection (IFI) was made, mucormycosis being the most likely aetiology. The rest of the upper airway showed no abnormality. The paranasal sinuses were normal.

Fig. 1
figure 1

CECT Chest. a CECT chest at presentation. Axial section of upper chest reveals multiple nodules with central cavitation in right upper lobe (white arrowhead). Lung window and mediastinal window images at mid and lower levels reveal Bird’s nest sign (yellow arrowheads) suggestive of invasive fungal infection. b. Post treatment HRCT chest. Axial sections of right lung at upper, mid and lower levels reveal reduction in size and number of cavitary lesions in right upper lobe (white arrowhead) and resolution of the mass-like consolidation in the right lower lobe with a residual thin-walled cavity (yellow arrowheads)

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With subglottic stenosis and multiple cavitary lesions in the lung, a possibility of coexisting small vessel vasculitis was also considered; however, ANCAs were negative. Hoarseness of voice subsided within 2 days of its onset with ongoing prednisolone therapy. Throat and nasal swab for COVID-19 RTPCR was negative. Laboratory assessment showed no evidence of sepsis. Bronchoalveolar lavage aspirate (BAL) on KOH wet mount preparation showed plenty of broad aseptate right angled branching fungal hyphae classical of Mucorales fungi (Fig. 2a). This was confirmed on fungal culture with a confluent growth of Rhizopus microsporus. Serological assay for Aspergillus, galactomannan, β-D-glucan, and quantitative PCR in serum or tissue sample was not done. There was no evidence of neutropenia or elevated blood sugar during the hospital stay.

Fig. 2
figure 2

Microbiological identification of mucormycosis. Lactophenol cotton blue mount (LPCB) of culture shows sporangiospores in pairs terminating in Sporangium with subspherical columella containing brownish sporangiospores with primitive rhizoids. The isolate was identified as Rhizopus microsporus

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With the diagnosis of PM, she was treated with conventional amphotericin B (AmB) at 1 mg/kg body weight every 24 h with monitoring of renal functions and electrolytes. The serial HRCT chest (on day 15 of amphotericin B dose and subsequently after completing 1 g of cumulative amphotericin B) showed resolution of the mass-like consolidation in the right lower lobe and a residual thin-walled cavity was seen. The satellite lesions in upper lobes significantly reduced in size and number (Fig. 1b). She remained afebrile with no breathlessness and improvement in chest findings. On discharge, she was given oral posaconazole and low dose oral prednisolone with hydroxychloroquine. Patient continued to have proteinuria without active urine sediments on follow-up. In view of bland proteinuria and recent history of PM, she was treated with angiotensin receptor blockers and tacrolimus. Presently, she is asymptomatic with only minimal residual muscle weakness in proximal muscles.

Methods

A literature review was undertaken in MEDLINE and Google scholar. Any cases of mucormycosis in SLE were sought in MEDLINE using the search string {(“mucor”[MeSH Terms] OR “mucor”[All fields] OR “mucormycosis”[MeSH Terms] OR “mucormycosis”[All fields] OR “zygomycetes”[All fields] OR “rhizopus”[MeSH Terms] or “rhizopus”[All fields]) AND (“lupus” OR “SLE”)}. A total of 46 articles were retrieved in MEDLINE and 11 is Google scholar. Articles without a full text or those not in English were excluded. A total of 8 cases of disseminated mucormycosis were identified with available clinical details. In addition, 1 case each of disseminated mucormycosis was reported as treatment-related adverse event in a trial of myeloablative stem cell transplant in SLE by Burt RK [6] and an autopsy series of SLE by Jindal B [7].

Table 1 summarizes disseminated and pulmonary mucormycosis cases reported in literature [8,9,10,11,12,13,14,15].

Table 1 Patient and disease characteristics of the cases reported in literature
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Discussion

The present case highlights the importance of early diagnosis using radiology and BAL in PM as that can result in favourable outcome. Though infections are an important cause of hospitalization in patients with SLE, invasive fungal infections (IFI) are uncommon in SLE. However, IFI do occur due to use of immunosuppressive therapy and have an in-hospital mortality of more than 50% [16]. In a retrospective study from South China, of 45 patients of SLE with IFI, Aspergillus (44.4%) and Cryptococcus (51.1%) were the commonly identified species. Patients with active lupus nephritis developed more IFI with higher mortality rates being noted (20%) [4]. Another study from Taiwan compared a large cohort of SLE (24,541 patients) with age-matched non-SLE diseased controls (245,410 subjects); incidence rate of IFI among patient of lupus was 20.83 per 10,000 person-years compared to 1.88 per 10,000 person-year in non-SLE diseased controls [17].

In our case, an HRCT done early in the disease course was suggestive of mass-like consolidation with central ground glass opacity giving a ‘reverse halo sign’. Also, the central low attenuation areas showed intersecting reticular lines and small cavities typical of ‘Bird’s nest sign’. Multiple randomly distributed macronodules with peripheral ‘halo sign’ and central cavitation were also seen. These findings are typically seen in invasive fungal infections. Among the common invasive fungal infections encountered in a background of immunosuppression, PM and invasive pulmonary Aspergillosis (IPA) can show these findings; however, the presence of Bird’s nest sign, reverse halo sign, absence of bronchial wall thickening, and random rather than peri-bronchial distribution of nodules were findings which favoured a diagnosis of mucormycosis more than Aspergillosis [18]. A definite diagnosis of PM was established by BAL which on microbiological assessment revealed broad aseptate right angled branching hyphae of mucormycetes [19].

The reversed halo sign on imaging is not specific for fungal infections but in severely immunocompromised patients, this sign is suggestive of invasive fungal infection; halo sign has been reported in 19–94% of patients with PM [20, 21]. Other common imaging findings in PM include areas of wedge-shaped or mass-like consolidations and nodules with cavitation. Consolidations crossing the fissures, invasion of the chest wall, and pulmonary arteries are more common with PM than IPA. Pulmonary artery pseudoaneurysms may also be seen in PM [22]. Though radiological signs are not definitive for the diagnosis, guidelines for screening of fungal infection in immunosuppressed patients recommend early HRCT in those with a clinical suspicion [23]. Even when radiology is suggestive, a definitive mycological diagnosis should be made as mucormycosis is susceptible to only AmB, posaconazole, and isavuconazole [24].

Early diagnosis and initiation of treatment are important. Correctable risk factors, mainly the control of blood glucose, tapering dose of steroids, and discontinuation of other immunosuppressive drugs should be addressed. Although conventional AmB has been the cornerstone of treatment for Mucorales [25], but over a decade, lipid formulation of AmB is recommended due to better tissue penetration and less nephrotoxicity [26]. Our patient received conventional AmB due to affordability issues and responded well to treatment; therefore, in a resource poor country, considering early treatment with conventional AmB can bring favourable outcomes. Treatment is recommended till the near normalization of radiographic abnormalities and negativity of cultures [27]. Since the patients with SLE require immunosuppressive agents for their disease to be in remission, long-term therapy is indicated in these patients with posaconazole having a potent activity against Mucorales and being available in oral preparation [28]. Using adjunctive treatment like interferon gamma and/or granulocyte macrophage colony stimulating factor, hyperbaric oxygen requires more data [29].

Conclusion

Pulmonary mucormycosis is well described in patients with uncontrolled diabetes, neutropenia, and organ-transplant recipients but it is not well reported in SLE. In patients with high index of suspicion, early imaging can guide in initial diagnosis followed by confirmation with culture or histopathology. Early and aggressive treatment even with conventional AmB can lead to good outcome.