Hyperbaric oxygen therapy as an adjunctive treatment for COVID-19-associated mucormycosis: a report of two cases. / Oxigenoterapia hiperbárica como tratamiento complementario en mucormicosis asociada con la COVID-19: a propósito de dos casos.

OBJECTIVE.: We present the first two cases reported in Peru of the use of adjuvant hyperbaric oxygen therapy (HBOT) in patients with COVID-19-associated mucormycosis (CAM). The first case is a 41-year-old woman, with pain in the left side of the face and palatine region with purulent rhinorrhea for a month. Only an oroantral fistula was found during physical examination. The second case is a 35-year-old male, with decreased left visual acuity and palatal pain with a fistula, draining purulent secretion for four months. Both patients have history of diabetes, had moderate COVID-19 four months prior to admission, and received corticosteroid therapy for this diagnosis. Tomographic evaluation of both patients showed involvement of the maxillary sinus and surrounding bone tissue; both received diagnostic and therapeutic nasal endoscopy for debridement. Histological analysis showed that the samples were compatible with mucormycosis. The patients underwent debridement and were treated with amphotericin B deoxycholate; however, they presented torpid evolution. Then, HBOT was added and the patients showed an evident improvement after four weeks of treatment with subsequent controls without the presence of mucormycosis. We highlight the favorable evolution of these patients while receiving HBOT as treatment for a disease with high morbimortality, which emerged during the pandemic.

Hyperbaric oxygen treatment: Results in seven patients with severe bacterial postoperative central nervous system infections and refractory mucormycosis.

INTRODUCTION: Resistant bacterial infections following brain and spine surgery and spontaneous mucormycosis with central nervous system (CNS) involvement represent a serious treatment challenge and more efficient therapeutic approaches ought to be considered. Hyperbaric oxygen treatment (HBOT) has shown promise as a complementary therapy. This case series evaluated whether HBOT contributed to infection resolution in seven patients with refractory CNS infectious conditions. METHODS: Clinical results for seven patients referred for HBOT between 2010 to 2018 to treat refractory postoperative brain and spine infections or spontaneously developing mucormycosis were retrospectively analysed. The patients' clinical files and follow-up consultations were reviewed to assess evolution and outcome. RESULTS: Seven patients were referred with a median age of 56 years. The median follow-up was 20 months. Four patients had postoperative infections and three had rhino-orbital-cerebral mucormycosis (ROCM). HBOT was used as an adjunctive treatment to antimicrobial therapy in all patients. Prior to HBOT, all patients had undergone an average of four operations due to infection refractoriness and had completed an average of five months of antimicrobial therapy. After HBOT, infection resolution was obtained in six patients without additional operations, while one patient with ROCM stopped HBOT after the third session due to intolerance. Three patients stopped antimicrobial therapy while four were maintained on prophylactic treatment. CONCLUSIONS: Infection resolution was reached in the six patients that completed HBOT as prescribed. HBOT may serve as an effective complementary treatment in CNS refractory postoperative and spontaneous infections.

Treating mucormycosis using a multimodality approach: a case series.

Most fungal infections found in wounds are secondary or superadded, and are generally benign in their clinical course in healthy individuals, with the exception of mucormycosis. This is a life-threatening infection caused by fungi of the order Mucorales. Primary cutaneous disease may occur following traumatic implantation of spores, or use of contaminated bandages, or as a complication of extensive burns, diabetic acidosis and other specific immunocompromised conditions. The clinical spectrum is highly non-specific and is often triggered by seemingly innocuous trauma. The superficial vesicles or patchy erythema rapidly degrade to haemorrhagic necrosis and rapidly progressive gangrenous lesion. The problem with diagnosing mucormycosis remains, therefore, that the condition has poor clinical indicators and requires reliance on microscopy and fungal culture. Management starts with a clinical suspicion, taking into account the risk factors and lack of response to first-line agents, as well as an aggressive clinical course. Treatment is multimodal, with medical correction of the risk factors and optimisation of limiting factors, such as diabetes, neutropenia and immunosuppressants. Treatment generally involves radical and repetitive surgical debridement, intravenous amphotericin B with monitoring of the nephrotoxicity, along with adjuvant modalities, such as hyperbaric oxygen therapy, colony stimulating factor, interferons gamma and white blood cell transfusion. Successful courses of therapy typically last 4-6 weeks and require cumulative doses that are equivalent to >2g of amphotericin B deoxycholate.

Recent Advances in the Pathogenesis of Mucormycoses.

PURPOSE: The purposes of this review are to describe the pathogenesis of mucormycosis and to address recent research advances in understanding the mechanisms of fungal invasion and dissemination. METHODS: Studies and reviews published in the PubMed and ClinicalTrials.gov databases until December 2017 that explored or reported recent advances in the understanding of the pathogenesis of mucormycosis were reviewed. FINDINGS: To cause disease, fungal spores need to evade the innate immune system and germinate, leading to angioinvasion and tissue destruction. Recent studies have found that Mucorales are able to downregulate several host defense mechanisms and have identified the specific receptors through which Mucorales attach to the endothelium, facilitating their endocytosis and subsequent angioinvasion. In addition, certain conditions found to act through various mechanisms and pathways in experimental and animal studies, such as hyperglycemia, elevated iron concentrations, and acidosis (particularly diabetic ketoacidosis), increase the virulence of the fungi and enhance their attachment to the endothelium, rendering patients with uncontrolled diabetes and patients with iron overload susceptible to mucormycosis. The role and various antifungal functions of platelets and natural killer cells are highlighted, and the potential contribution of alternative therapies, such as manipulating the innate immune host defenses with granulocyte transfusions or administration of growth factors and using the antifungal effects of calcineurin inhibitors, are presented. Finally, directions and possible implications for future research are provided. IMPLICATIONS: This article provides a comprehensive overview of research advances in the pathogenesis of infections caused by Mucorales and helps future studies develop effective treatment strategies and improve patient outcomes.

Laryngotracheal mucormycosis: Report of a case.

Airway mucormycosis is a deadly opportunistic infection that affects immunocompromised persons, particularly diabetics and those undergoing chemotherapy. Although it is typically a pulmonary or sinonasal infection, mucormycosis can affect the larynx and trachea, with devastating results. We report the case of a 46-year-old man with human immunodeficiency virus infection, hepatitis C infection, neurosyphilis, and recently diagnosed Burkitt lymphoma who presented with dysphonia and stridor after receiving one dose of intrathecal chemotherapy. Flexible laryngoscopy detected the presence of fibrinous material that was obstructing nearly the entire glottis. Surgical debridement revealed a firm mucosal attachment; there was little bleeding when it was removed. After debridement, the patient's dyspnea improved only to recur 2 days later. After an awake tracheotomy, laryngoscopy and bronchoscopy identified necrosis extending from the supraglottic area to the carina tracheae. Biopsies demonstrated hyphal architecture consistent with mucormycosis. Despite continued debridements, the fibrinous material reaccumulated. The patient was placed in hospice care; his airway remained patent, but he died from other causes several weeks after presentation. The management of airway mucormycosis is challenging and complex. Fungal airway infections should be considered in the differential diagnosis of an immunosuppressed patient who presents with dyspnea, dysphonia, and vocal fold immobility. Timely diagnosis and management are critical for a successful outcome, although the prognosis is poor if the infection is widespread, even with the best of efforts.

Bone and joint infections by Mucorales, Scedosporium, Fusarium and even rarer fungi.

Mucorales, Scedosporium and Fusarium species are rarely considered as cause for bone and joint infections. However, these moulds are emerging as important fungal pathogens in immunocompromised and immunocompetent patients. Typical pre-disposing host conditions are immunosuppression and diabetes. Most common causative pathogens are Mucorales followed by Scedosporium and Fusarium. Acremonium and Phialemonium species are rare but some case reports exist. MRI is the gold standard imaging technique. Tissue specimens obtained as aspirates, imaging guided biopsy or open surgery need mycological and histopathological work-up for genus and species identification. Multimodal treatment strategies combine surgical debridement, drainage of joints or abscesses, removal of infected prosthetic joints and systemic antifungals. The treatment of mucormycosis is polyene based and may be combined with either posaconazole or - in rare cases - caspofungin. As Scedosporium species are intrinsically resistant to polyenes and azoles show absence of in vitro activity, voriconazole plus synergistic treatment regimens become the therapeutic standard. In fusariosis, fungal susceptibility is virtually impossible to predict, so that combination treatment of voriconazole and lipid-based amphotericin B should be the first-line strategy while susceptibility results are pending. In the absence of randomized controlled trials, infections due to the above moulds should be registered, e.g. in the registries of the European Confederation of Medical Mycology (ECMM).

Invasive fungal disease of the sinus and orbit: a comparison between mucormycosis and Aspergillus.

BACKGROUND/AIMS: Invasive fungal infections of the head and neck are rare life-threatening infections where prompt diagnosis and intervention is critical for survival. The aim of this study is to determine the clinical characteristics and outcomes of invasive fungal disease of the sinus and orbit, and to compare mucormycosis and Aspergillus infection. METHODS: A retrospective review was conducted from a single tertiary care eye and ear hospital over 20 years (1994-2014). Twenty-four patients with a confirmed pathological diagnosis of invasive fungal disease of the sinus and/or orbit were identified and their medical records were reviewed. The main outcome measures were type of fungus, location of disease, mortality and visual outcome. RESULTS: Patients with orbital involvement had a higher mortality and higher likelihood of mucormycosis infection compared with those with sinus-only disease (78.6% vs 20%, p=0.01; 86% vs 30%, p=0.01, respectively). Patients with mucormycosis had a higher mortality (71%) than patients with Aspergillus (29%); however, this was not statistically significant (p=0.16). All patients with orbital involvement and/or mucormycosis infections were immunosuppressed or had inadequately controlled diabetes, and had a cranial neuropathy or ocular motility dysfunction. All five post-transplant patients with orbital infections died, while the two transplant patients with sinus infections survived. CONCLUSIONS: Patients with orbital fungal infections are more likely to be infected with mucormycosis compared with Aspergillus and have a higher mortality compared with infections sparing the orbit. History of transplant portends a dismal prognosis in orbital infections. Invasive fungal disease should be considered in any immunocompromised patient presenting with a new cranial neuropathy or ocular motility abnormality.

Management of rhino-orbital mucormycosis.

Mucormycosis is an uncommon acute invasive fungal infection that affects immunocompromised patients. It progresses rapidly and has poor prognosis if diagnosed late. Early detection, control of the underlying condition with aggressive surgical debridement, administration of systemic and local antifungal therapies, hyperbaric oxygen as adjunctive treatment improves prognosis and survivability.

To exenterate or not? An unusual case of pediatric rhinocerebral mucormycosis.

Rhinocerebral mucormycosis (RM) is a rare, potentially lethal fungal infection. Traditional teaching encourages aggressive surgical resection until viable bleeding tissue is encountered, often leading to orbital exenteration, skull base resection, and cerebral debridement, in addition to systemic antifungal therapy. We present a 2-year-old male with acute lymphocytic leukemia undergoing chemotherapy presenting with RM and unilateral orbital and intracranial involvement. After aggressive sinonasal debridement, systemic antifungal and hyperbaric oxygen therapies, he recovered without need for further aggressive tissue resection. We report the successful management of invasive orbital and intracranial RM without orbital exenteration or cerebral debridement.

Cutaneous mucormycosis of the upper extremity in an immunocompetent host: case report.

Cutaneous mucormycosis, a relatively common infection in immunocompromised patients, remains rare in the immunocompetent patient outside the setting of major trauma. We report a case of an immunocompetent patient who developed left upper extremity Rhizopus infection following arterial puncture. Treatment included surgical debridement, liposomal amphotericin B, and hyperbaric oxygen wound therapy; the patient recovered fully. A review of the literature of cases of upper extremity Mucor infection is included for context. We feel that a high degree of suspicion for Mucor infection is warranted in patients with the described risk factors who do not respond to first-line antibiotics.

Pulmonary mucormycosis.

Mucormycosis (formerly zygomycosis) is a life-threatening opportunistic mycosis that infects a broad range of hosts with qualitative or quantitative defects in innate immunity, including patients with severe neutropenia, recipients of corticosteroids or other immunosuppressive medications, poorly controlled diabetes mellitus, and those with iron overload states. Mucormycosis has recently emerged as breakthrough sinopulmonary infection in hematologic patients and recipients of transplantation being on antifungal prophylaxis with Aspergillus-active antifungals that lack activity against Mucorales. Unlike pulmonary aspergillosis, the prognosis and outcome of pulmonary mucormycosis have not improved significantly over the last decade, mainly because of difficulties in early diagnosis and the limited activity of current antifungal agents against Mucorales. Recent evidence suggests a critical role for iron metabolism and fungal-endothelial cell interactions in pathogenesis of mucormycosis, and holds promise for development of novel therapeutic strategies. Currently, prompt initiation of antifungal therapy with a lipid amphotericin B-based regimen, reversal of underlying host factors, and aggressive surgical approach offers the best chances for survival of patients infected with this devastating mycosis.

Intra-abdominal Rhizopus microsporus infection successfully treated by combined aggressive surgical, antifungal, and iron chelating therapy.

SUMMARY: Zygomycetes are widely distributed in the environment as inhabitants of soil and decaying matter. On rare occasions, these organisms can cause invasive infections in immunocompromised hosts. As zygomycetes are resistant to most conventional antifungal agents, its infection is often fatal. We report 2 cases of unusual intra-abdominal Rhizopus microsporus infection in children with acute leukemia as a result of an unprecedented outbreak due to oral intake of contaminated allopurinol tablets and ready-to-eat food items. Among the 2 patients, one of them survived after aggressive combined surgical, antifungal (AmBisome, Caspofungin, and Posaconazole) and iron chelation therapy.

Cutaneous mucormycosis: report of five cases and review of the literature.

Mucormycosis is a highly aggressive fungal infection caused by Zygomycetes, from the order of Mucorales. This infection commonly presents an aggressive and rapid course and typically affects immunocompromised patients. Mucormycosis can manifest in different clinical patterns and locations. Although the correct diagnosis is often difficult, an early identification is essential for patient survival. Several clinical forms of mucormycosis are recognised. Cutaneous mucormycosis is less common than other clinical forms, but potentially lethal if treatment is not rapid. Tissue examination by histopathology and culture confirms the fungal infection. Standard treatment includes antifungal therapies associated with surgical debridement. We report five different cases of cutaneous mucormycosis treated in our institution and the management carried out in each case.

Hyperbaric oxygen therapy and the eye.

Hyperbaric oxygen therapy (HBOT) is a primary or adjunctive therapy for a variety of medical disorders including some involving the eye. This paper is the first comprehensive review of HBOT for ocular indications. The authors recommend the following as ocular indications for HBOT: decompression sickness or arterial gas embolism with visual signs or symptoms, central retinal artery occlusion, ocular and periocular gas gangrene, cerebro-rhino-orbital mucormycosis, periocular necrotizing fasciitis, carbon monoxide poisoning with visual sequelae, radiation optic neuropathy, radiation or mitomycin C-induced scleral necrosis, and periorbital reconstructive surgery. Other ocular disorders that may benefit from HBOT include selected cases of ischemic optic neuropathy, ischemic central retinal vein occlusion, branch retinal artery occlusion with central vision loss, ischemic branch retinal vein occlusion, cystoid macular edema associated with retinal venous occlusion, post-surgical inflammation, or intrinsic inflammatory disorders, periocular brown recluse spider envenomation, ocular quinine toxicity, Purtscher's retinopathy, radiation retinopathy, anterior segment ischemia, retinal detachment in sickle cell disease, refractory actinomycotiC lacrimal canaliculitis, pyoderma gangrenosum of the orbit and refractory pseudomonas keratitis. Visual function should be monitored as clinically indicated before, during, and after therapy when HBOT is undertaken to treat vision loss. Visual acuity alone is not an adequate measure of visual function to monitor the efficacy of HBOT in this setting. Ocular examinations should also include automated perimetry to evaluate the central 30 degrees of visual field at appropriate intervals. Interpretation of the literature on the efficacy of HBOT in treating ocular disorders is complicated by several factors: frequent failure to include visual field examination as an outcome measure, failure to adequately address the interval from symptom onset to initiation of HBOT, and lack of evidence for optimal treatment regimens for essentially all ocular indications. Because some ocular disorders require rapid administration of HBOT to restore vision, patients with acute vision loss should be considered emergent when they present. Visual acuity should be checked immediately, including vision with pinhole correction. If the patient meets the criteria for emergent HBOT outlined in the paper, normobaric oxygen should be started at the highest inspired oxygen fraction possible until arrangements can be made for HBOT.

Zigomicetos y zigomicosis en la era de las nuevas terapias antifúngicas / Zygomycetes and zygomycosis in the new era of antifungal therapies

La zigomicosis o mucormicosis es la tercera infección fúngica invasora tras la candidiasis y la aspergilosis. Tradicionalmente se ha consideradouna enfermedad de adquisición comunitaria, pero se está convirtiendo en una infección de frecuente adquisición nosocomial. En los últimosaños, numerosos estudios en instituciones aisladas apuntan a un aumento del número de casos de zigomicosis invasora a raíz de las nuevasterapias antifúngicas e inmunosupresoras, y al aumento de la población inmunodeprimida. Por otro lado, el diagnóstico de la zigomicosismuchas veces es complicado, sobre todo en las formas pulmonares y diseminadas. Uno de los principales problemas que presenta el aislamientode zigomicetos de muestras clínicas en el laboratorio de microbiología es que con frecuencia los resultados tienen una difícil interpretación.Además, el aumento del número de micosis invasoras por hongos resistentes a los antifúngicos ha llevado al desarrollo de nuevasmoléculas con actividad antifúngica y diferentes perfiles de actividad frente a los zigomicetos(AU)

Zygomycosis or mucormycosis is the third most invasive fungal infection after candidiasis and aspergillosis. Traditionally, it has been considereda community-acquired disease, but it is becoming a frequent nosocomial-acquired disease. Recently, several publications from differentinstitutions have reported an increase in the number of cases of invasive zygomycosis as a result of the new antifungal and immunosuppresivetherapies and the emerging immunocompromised population. In addition, the diagnosis of zygomycosis is elusive, mainly in pulmonaryand disseminated forms. One of the main limitations in isolating Zygomycetes from clinical samples is the interpretation of results. The increasingnumber of invasive fungal infections caused by multiresistant fungi has led to the development of new antifungal drugs with variableactivity against Zygomycetes(AU)

Hyperbaric oxygen in the treatment of invasive fungal infections: a single-center experience.

BACKGROUND: Invasive fungal infections by Mucorales or Aspergillus spp. are lethal infections in immune compromised patients. For these infections a multimodal approach is required. One potential tool for treating these infections is hyperbaric oxygen. OBJECTIVES: To evaluate the clinical course and utility of hyperbaric oxygen in patients with invasive fungal infections by Mucorales or Aspergillus spp. METHODS: We conducted a retrospective chart review of 14 patients treated with HBO as part of their multimodal therapy over a 12 year period. RESULTS: Most patients had significant immune suppression due to either drug treatment or their underlying disorder. Thirteen of the 14 underwent surgery as part of the treatment and all were receiving antifungal therapy while treated with the hyperbaric oxygen. The number of HBO sessions ranged between 1 and 44. Seven of the patients survived the infection. No patient developed complications due to HBO therapy. CONCLUSIONS: HBO is a potentially significant adjunct in the treatment of invasive fungal infections. Evidence on its usefulness as a standard of care in these infections is still lacking. Since it will be difficult to generate conclusive data regarding the importance of HBO in these infections, the value of HBO in these patients should be considered on an individual basis.

Mucormycosis--early diagnosis and treatment.

OBJECTIVE: The aim of this retrospective study was to analyse the data of patients with rhino-orbital-cerebral mucormycosis for predisposing factors, diagnosis, treatment and survival rate. The role of frozen section in early diagnosis and use of nasal endoscopy in diagnosis, treatment and follow-up of patients has also been examined. DESIGN: Retrospective case series. SETTING: University Teaching Hospital. METHODS: The case notes of 9 patients with diagnosis of mucormycosis who presented from 1973 to 2001 were examined. The data for predisposing factors, signs/symptoms, histological diagnosis, radiological intervention, medical and surgical treatment and final outcome was analysed. RESULTS: There were 9 patients with mucormycoses. Early diagnosis was made by endoscopic examination and frozen section in 5 patients, which was later confirmed by histology. Treatment included parental and/or local amphotericin, hyperbaric oxygen and debridement either by endoscopic or external approach, with or without orbital exenteration. This resulted in an overall survival of 5 patients. CONCLUSION: Frozen section diagnosis allows for early therapy since successful treatment depends on systemic amphotericin, surgical debridement and treatment of underlying predisposing factors. Nasal endoscopy is useful in diagnosis, endoscopic debridement and follow up of patients.