key: cord-0831244-0zf9mxpc
authors: Ahmadikia, Kazem; Hashemi, Seyed Jamal; Khodavaisy, Sadegh; Getso, Muhammad Ibrahim; Alijani, Neda; Badali, Hamid; Mirhendi, Hossein; Salehi, Mohammadreza; Tabari, Azin; Mohammadi Ardehali, Mojtaba; Kord, Mohammad; Roilides, Emmanuel; Rezaie, Sassan
title: The double‐edged sword of systemic corticosteroid therapy in viral pneumonia: A case report and comparative review of influenza‐associated mucormycosis versus COVID‐19 associated mucormycosis
date: 2021-03-05
journal: Mycoses
DOI: 10.1111/myc.13256
sha: 6e4d08cd03ecd53221470628ce4c28096c7f57a1
doc_id: 831244
cord_uid: 0zf9mxpc

Acute respiratory distress syndrome is a common complication of severe viral pneumonia, such as influenza and COVID‐19, that requires critical care including ventilatory support, use of corticosteroids and other adjunctive therapies to arrest the attendant massive airways inflammation. Although recommended for the treatment of viral pneumonia, steroid therapy appears to be a double‐edged sword, predisposing patients to secondary bacterial and invasive fungal infections (IFIs) whereby impacting morbidity and mortality. Mucormycosis is a fungal emergency with a highly aggressive tendency for contiguous spread, associated with a poor prognosis if not promptly diagnosed and managed. Classically, uncontrolled diabetes mellitus (DM) and other immunosuppressive conditions including corticosteroid therapy are known risk factors for mucormycosis. Upon the background lung pathology, immune dysfunction and corticosteroid therapy, patients with severe viral pneumonia are likely to develop IFIs like aspergillosis and mucormycosis. Notably, the combination of steroid therapy and DM can augment immunosuppression and hyperglycaemia, increasing the risk of mucormycosis in a susceptible individual. Here, we report a case of sinonasal mucormycosis in a 44‐year‐old woman with hyperglycaemia secondary to poorly controlled diabetes following dexamethasone therapy on a background of influenza pneumonia and review 15 available literatures on reported cases of influenza and COVID‐19 associated mucormycosis.

Viral pneumonia is a worrisome health condition globally; it can be on a seasonal, sporadic, epidemic or even a pandemic scale with life-threatening complications depending on the host's immune status and presence of co-morbid conditions. 1 Notably, influenza and recently coronavirus disease 2019 are especially of specific concern because of the associated severe morbidity, high cost of care and unfavourable clinical outcome. 1, 2 Globally, between 290,000 and 650,000 patients die annually from seasonal influenza 1 and the current COVID-19 pandemic has claimed over 1.5 million lives within 10 months into the pandemic. 2 In patients with severe viral pneumonia, such as influenza and COVID-19, acute respiratory distress syndrome (ARDS) is a common complication that requires intensive care unit (ICU) admission and mechanical ventilation (MV), use of corticosteroids and interleukin antagonists, for example tocilizumab to counter the massive inflammatory airways constriction and subsequent cytokine storm. [3] [4] [5] Importantly, acute viral pneumonia damages alveolar epithelial and endothelial tissues, dysregulates immune system and causes cellular immune dysfunction. [6] [7] [8] Upon the background lung damage, immune dysfunction and corticosteroid therapy in viral pneumonia, invasive fungal infections (IFIs) like aspergillosis and mucormycosis can spontaneously set in. 9, 10 Cases of flu-associated aspergillosis have been evidently highlighted in previous studies 9, 11, 12 ; however, mucormycosis in viral pneumonia cases have been clearly missed or under-reported.

Mucormycosis-an acute and fatal fungal infection caused by ubiquitous fungal species belonging to Mucorales-is a fungal emergency with a highly aggressive tendency for contiguous spread, associated with a poor prognosis if not accurately and promptly diagnosed and managed. 13 Classically, uncontrolled diabetes mellitus (DM) and other immunosuppressive conditions such as neutropenia and corticosteroid therapy are known risk factors for mucormycosis. 14 The establishment of mucormycosis requires spores inhalation and/or seeding onto the airways or any vulnerable epithelium; germinating into angioinvasive hyphae-utilising host conditions such as hyperglycaemia, ketoacidosis, iron overload and neutropeniacausing endothelial damage, leading to local haemorrhage, thrombosis and necrosis; and eventual dissemination to involve multiple organs. 14, 15 In this study, we present a case of sinonasal mucormycosis in an uncontrolled diabetic patient following dexamethasone therapy on a background influenza pneumonia and provide a review of current literature on influenza and COVID-19 associated mucormycosis (CAM) cases.

A 44-year-old known diabetic woman with a history of poorly controlled diabetes presented to our centre at Shariati Hospital, Tehran, Iran, in February 2020 with a 5-day history of fever, malaise, myalgia, dry cough and partial dyspnoea. She had no history of hypertension, asthma, tuberculosis, heart disease or contact with a confirmed COVID-19 patient. She has been visiting a diabetic clinic, though irregularly, and has been sporadically taking insulin injections whenever she found her blood glucose raised. The dose of insulin injection could not be ascertained. Physical examination revealed a stable patient with mildly laboured breathing and nasal flaring. Her vital signs at presentation were temperature: 37.8°C; blood pressure: 130/80 mm Hg; pulse rate: 92 beats per minute; respiratory rate: 26 breaths per minute; and oxygen saturation: 94% (ambient air).

Her laboratory findings were blood glucose: 230 mg/dL; HbA 1 C: 8%; RT-PCR of upper airways swab specimens (Qiagen) tested positive for influenza and negative for COVID-19. HIV, hepatitis B and C serological tests were all negative. CBC revealed Hb: 14 mg/dL, WBC: 7 × 10 9 /L with 60% neutrophil; CRP and ESR were both elevated. Moreover, her chest computed tomography (CT) demonstrated bilateral multifocal peripherally located patchy ground-glass opacities ( Figure 1 ). Therefore, acute influenza on basis of poorly controlled DM was diagnosed. She received 4 doses of intravenous diabetes following dexamethasone therapy on a background of influenza pneumonia and review 15 available literatures on reported cases of influenza and COVID-19 associated mucormycosis.

corticosteroid therapy, COVID-19, influenza, mucormycosis, viral pneumonia F I G U R E 1 Axial view of chest computed tomography (CT) scan revealing peripheral bilateral ground-glass opacities (IV) dexamethasone (4 mg twice daily) on 2 consecutive days, and her symptoms subsided before she was discharged home on the fourth day of admission.

Twenty days after her discharge, the patient complained of toothache and headache, which was followed by earache, nasal congestion and unilateral facial swelling. Subsequently, the patient visited by a dentist because she thought the facial swelling and pain were due to dental caries. The suspected tooth was evaluated for caries and managed. She was prescribed oral metronidazole, penicillin V and naproxen.

However, the symptoms did not improve. The patient was reassessed, and suspicion of mucormycosis was raised based on relevant clinical symptoms and associated risk factors. Therefore, she was admitted to the infectious disease ward, and empirical treatment with IV liposomal amphotericin B (Ambisome Gilead Co., 3 mg/kg daily, according to local guidelines 13 and experience in our centre) was commenced immediately. The hyperglycaemia was managed with subcutaneous insulin injections titrated against fasting blood glucose levels to maintain a blood sugar level of 150-200 mg/dL. Accordingly, on the second day of admission, an otolaryngologist was consulted and she had functional endoscopic sinus surgery that revealed sinusitis with some partial necrosis in the right maxillary sinus; biopsy was made and the specimens were sent for mycological and pathological examination. CT of paranasal sinuses confirmed the evidence of mucosal thickening in the right maxillary sinus ( Figure 2 ). However, neither palate necrosis nor ptosis and proptosis were noted.

Direct and histopathological examinations using 10% potassium hydroxide and haematoxylin and eosin (H&E) staining both showed non-septate, ribbon-like, wide hyphae with right-angle branching, suggestive of mucormycosis ( Figure 3A,B) . Although the culture remained negative probably due to pretreatment, the fresh specimen was subjected to manual DNA extraction, using phenol-chloroformisoamyl extraction after tissue digestion with proteinase K and lysis buffer, 16 followed by semi-nested PCR using Mucorales specific primers (ZM) as previously described by Bialek et al, 17 Subsequently, the treatment with liposomal amphotericin B (Ambisome Gilead Co., 3 mg/kg per day) was continued for 2 weeks.

When the patient's clinical conditions improved, liposomal amphotericin B was terminated at day 18, and the patient was eventually discharged on oral posaconazole (300 mg per day) on the 18th day.

At the last follow-up (8 months later), the patient showed no evidence of mucormycosis.

We conducted a systematic review of the available literature to better characterise the extent of similar previous studies by searching electronic databases including PubMed, Scopus and Google Scholar for studies published in English. The search strategy was conducted using the term "mucormycosis" or "zygomycosis" combined with "influenza" OR "COVID-19" OR "viral pneumonia". 

The database search revealed a total of 17 articles: 10 on influenzaassociated mucormycosis (IAM) and 7 on CAM. Two articles on IAM were excluded based on missing data. The characteristics of the patients included in these studies are summarised in and corticosteroid therapy (IV dexamethasone)(considering the fact that interval of 20 days between dexamethasone therapy and mucormycosis occurrence may be somewhat long to construct an association) were the noticeable risk factors for mucormycosis in the patient.

Similarly, 14/15 (93.3%) of our reviewed cases had at least one underlying condition; DM is the most common underlying disease in 4/8 (50%) and 3/7 (43%) of IAM and CAM, respectively (Table 1) . Exclusively, DM is a major risk factor for mucormycosis. 30 In addition, steroid therapy (such as dexamethasone) can tilt blood glucose levels to hypergly- In terms of severity, on its own, severe pneumonia is a bad prognostic factor and secondary pulmonary IFI increases mortality rates. 10 Our reported case suffered mild/moderate pneumonia, and the sec- CAM appears to be more fatal than IAM, despite an aggressive treatment approach. Comprehensive research is needed to explore other bad prognostic factors in CAM and means of minimising their impact on morbidity and mortality.

The authors declare that they have no conflict of interest. 

The study was approved by the ethical committee of Tehran University of Medical Sciences, Tehran, Iran (IR.TUMS.SPH.

REC.1397.298). To ensure anonymity, details that might disclose the identity of the subject under the study were not included. Written informed consent was obtained from the patient prior to being included in the study.

The data that support the finding of this study have been depos- 

Influenza (seasonal) fact sheet

WHO. Coronavirus disease 2019

Adjuvant corticosteroid treatment in adults with influenza A (H7N9) viral pneumonia

Oropharyngeal candidiasis in hospitalised COVID-19 patients from Iran: species identification and antifungal susceptibility pattern

Surviving sepsis campaign: Guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19)

From virus to inflammation, how influenza promotes lung damage

Influenza virusinduced lung injury: pathogenesis and implications for treatment

Comparison of clinical, para-clinical and laboratory findings in survived and deceased patients with COVID-19: diagnostic role of inflammatory indications in determining the severity of illness

Invasive pulmonary aspergillosis complicating severe influenza: epidemiology, diagnosis and treatment

Invasive fungal infections associated with prior respiratory viral infections in immunocompromised hosts

Influenza-associated aspergillosis in critically-ill patients-a retrospective bicentric cohort study

Influenzaassociated aspergillosis in critically ill patients

Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium

Seminars in respiratory and critical care medicine. © Thieme Medical Publishers

Recent advances in the pathogenesis of mucormycoses

Molecular diagnosis of rhino-orbito-cerebral mucormycosis from fresh tissue samples

PCR based identification and discrimination of agents of mucormycosis and aspergillosis in paraffin wax embedded tissue

Secondary bacterial infections in patients with viral pneumonia

Opportunistic fungal infections in the epidemic area of COVID-19: a clinical and diagnostic perspective from Iran

Prevalence of putative invasive pulmonary aspergillosis in critically ill patients with COVID-19

Invasive pulmonary fusariosis in an immunocompetent critically ill patient with severe COVID-19

Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study

COVID-19, superinfections and antimicrobial development: What can we expect?

Fungal co-infection in COVID-19 patients: Should we be concerned?

Global epidemiology of mucormycosis

Invasive fungal diseases during COVID-19: we should be prepared

A case of invasive pulmonary mucormycosis resulting from short courses of corticosteroids in a well-controlled diabetic patient

Incidence of co-infections and superinfections in hospitalized patients with COVID-19: a retrospective cohort study

Population-based analysis of invasive fungal infections

Corticosteroids as adjunctive therapy in the treatment of influenza: an updated cochrane systematic review and meta-analysis

Study on invasive aspergillosis using galactomannan enzyme immunoassay and determining antifungal drug susceptibility among hospitalized patients with hematologic malignancies or candidates for organ transplantation

Diabetes mellitus as the major risk factor for mucormycosis in Mexico: epidemiology, diagnosis, and outcomes of reported cases

Steroid-induced hyperglycemia: An underdiagnosed problem or clinical inertia? A narrative review

Novel perspectives on mucormycosis: pathophysiology, presentation, and management

Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study

COVID-19 infection may cause ketosis and ketoacidosis

Epidemiology of mucormycosis: review of 18 cases in a tertiary care hospital

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion

Early, low-dose and short-term application of corticosteroid treatment in patients with severe COVID-19 pneumonia: single-center experience from Wuhan, China. medRxiv

Mortality of critically ill patients with severe influenza starting four years after the 2009 pandemic

COVID-19 associated pulmonary aspergillosis

Disease entities in mucormycosis

Combination polyenecaspofungin treatment of rhino-orbital-cerebral mucormycosis

Mucormycosis in haematological patients: case report and results of prospective study in Saint Petersburg

Diagnosis and treatment of mucormycosis in patients with hematological malignancies

Emergent aerosols generating procedures in oral & maxillofacial surgery in Covid-19 pandemic

Pulmonary mucormycosis in a patient with acute liver failure: a case report and systematic review of the literature

Tracheal, laryngeal and pulmonary mucormycosis followed by organizing pneumonia in a patient with adult onset still's disease

Disseminated Mucormycosis with Positive Aspergillus Galactomannan. Case Reports in Infectious Diseases

Surgical emergencies confounded by H1N1 influenza infection-a plea for concern

592: rapidly progressive invasive pulmonary mucormycosis in the setting of severe diabetic ketoacidosis

Tracheal mucormycosis pneumonia: a rare clinical presentation

Rhino-orbital mucormycosis associated with COVID-19

Mucormycosis with orbital compartment syndrome in a patient with COVID-19

Histopathological findings and viral tropism in UK patients with severe fatal COVID-19: a postmortem study

Bronchopleural fistula development in the setting of novel therapies for acute respiratory distress syndrome in SARS-CoV-2 pneumonia

Rare and fatal gastrointestinal mucormycosis (Zygomycosis) in a COVID-19 patient: a case report

Acute invasive rhinoorbital mucormycosis in a patient with COVID-19-associated acute respiratory distress syndrome

A challenging complication following SARS-CoV-2 infection: a case of pulmonary mucormycosis

How to cite this article

The double-edged sword of systemic corticosteroid therapy in viral pneumonia: A case report and comparative review of influenza-associated mucormycosis versus COVID-19 associated mucormycosis