Successful posaconazole salvage therapy for rhinocerebral mucormycosis in a child with leukemia. Review of the literature

BackgroundMucormycosis is a fungal infection caused by species of the Mucorales order. These microorganisms are angioinvasive, with rapid disease progression and potentially lethal in its rhinocerebral form.Case reportWe present the case of a 12-year-old female with trisomy 21, acute lymphoblastic leukemia and diabetes, with fever and neutropenia who developed rhinocerebral mucormicosis. After treatment with amphotericin B lipid complex and extensive surgery, disease progressed and posaconazole was added as salvage treatment with full remission of the infection. Four years after diagnosis the patient continues without relapse of mucormycosis or leukemia.ConclusionsThis case highlights the use of posaconazole as either monotherapy or combined therapy. Although it is still debated, it can be considered an option for salvage treatment in children with non-responding mucormycosis, despite lack of standard dosage in pediatric patients.     

Mucormycosis: The hidden and forgotten disease

Mucormycosis is a rare but serious fungal infection caused by a group of moulds called mucormycetes. More attention has recently been paid to it due to its association with coronavirus disease 2019 (COVID-19). Thus, it is important to review the progress of studies on mucormycosis and highlight the important findings in relation to epidemiology, clinical manifestation, major risk factors, diagnostic strategies and management. An electronic literature search was performed in PubMed using the keywords: Rhizopus, Mucorales, mucormycosis, zygomycosis, zygomycetes, COVID-19, the drugs (azoles, posaconazole, isavuconazole, amphotericin B pharmaceutical preparations and caspofungin), combination therapy, diagnosis and clinical manifestations. Studies written in the English language from January 1960 to 2021 were considered for this review article. All search results were reviewed, and the relevance of each article was determined by the authors independently. The review emphasized the fact that the diagnosis of mucormycosis is difficult, it is necessary to have a high index of suspicion to identify it, surgical debridement should be done prior to the dissemination of infection to improve clinical outcomes and identifying underlying risk factors is important for proper treatment. Moreover, antifungal therapeutic options are few with polyenes and their combinations should be appropriate for empirical therapy while posaconazole and isavuconazole are best reserved for de-escalation, refractory cases or patients intolerant to amphotericin B.     

Primary Cutaneous Mucormycosis Presenting as a Giant Plaque: Uncommon Presentation of a Rare Mycosis

Mucormycosis is an uncommon opportunistic fungal infection caused by Zygomycetes. It usually affects immunocompromised, diabetic and trauma patients with infected wounds. We report a case of disseminated infection secondary to facial cutaneous mucormycosis caused by Saksenaea vasiformis in a diabetic patient who had a farming accident causing him severe head injury. The patient was treated with a combination of surgical debridement and antifungal therapy with liposomal amphotericin B, but he had a slow and fatal outcome. In cases of tissue necrosis following trauma involving wound contact with soil (i.e., potential fungal contamination), testing for the presence of Zygomycetes fungi such as S. vasiformis in both immunocompetent and immunocompromised patients is crucial. The reason is that this infection usually has a rapid progression and may be fatal if appropriate treatment is not administered.     

An extensive review on antifungal approaches in the treatment of mucormycosis

During the period of COVID-19, the occurrences of mucormycosis in immunocompromised patients have increased significantly. Mucormycosis (black fungus) is a rare and rapidly progressing fungal infection associated with high mortality and morbidity in India as well as globally. The causative agents for this infection are collectively called mucoromycetes which are the members of the order Mucorales. The diagnosis of the infection needs to be performed as soon as the occurrence of clinical symptoms which differs with types of Mucorales infection. Imaging techniques magnetic resonance imaging or computed tomography scan, culture testing, and microscopy are the approaches for the diagnosis. After the diagnosis of the infection is confirmed, rapid action is needed for the treatment in the form of antifungal therapy or surgery depending upon the severity of the infection. Delaying in treatment declines the chances of survival. In antifungal therapy, there are two approaches first-line therapy (monotherapy) and combination therapy. Amphotericin B ( 1 ) and isavuconazole ( 2 ) are the drugs of choice for first-line therapy in the treatment of mucormycosis. Salvage therapy with posaconazole ( 3 ) and deferasirox ( 4 ) is another approach for patients who are not responsible for any other therapy. Adjunctive therapy is also used in the treatment of mucormycosis along with first-line therapy, which involves hyperbaric oxygen and cytokine therapy. There are some drugs like VT-1161 ( 5 ) and APX001A ( 6 ), Colistin, SCH 42427, and PC1244 that are under clinical trials. Despite all these approaches, none can be 100% successful in giving results. Therefore, new medications with favorable or little side effects are required for the treatment of mucormycosis.     

A Case of Rhinoorbital Mucormycosis in a Leukemic Patient with a Literature Review from Turkey

Mucormycosis (Zygomycosis) is a rare, invasive, opportunistic fungal infection of the paranasal sinuses, caused by a fungus of the order Mucorales. We report a case of rhinoorbital mucormycosis caused by Rhizopus oryzae in an acute lymphoblastic leukemia patient and review the 79 Mucormycosis cases reported in the last decade from Turkey. In our case, the diagnosis was made with endoscopic appearance, computerized tomography of the paranasal sinuses, and culture of the surgical materials. Following aggressive surgical debridement and parenteral amphotericin B therapy, the patient recovered completely. In Turkish literature, rhinocerebral manifestations were the most common form of the mucormycosis (64 cases), followed by pulmonary form (6 cases). The most common risk factor was hematologic malignancies (32 cases) and diabetes mellitus (32 cases), similar to those reported from the rest of the world. The etiologic agents responsible for the review cases were Rhizopus sp., Mucor spp., Rhizomucor spp., Rhizopus oryzae, Mucor circinelloides, and Lichtheimia corymbifera. Although various treatment modalities were used, amphotericin B was the mainstay of therapy. Mortality rate was found to be 49.4% in review cases. It seems that strong clinical suspicion and early diagnosis, along with aggressive antifungal therapy and endoscopic sinus surgery, have great importance for better prognosis in mucormycosis.     

Medical and Adjunctive Treatment of Mucormycosis in Children: Scientific Rationale and Analysis of Cases Reported in the Literature

Mucormycosis is associated with significant morbidity and mortality in both children and adults. Studies have shown an increase in the incidence of mucormycosis, particularly among hematopoietic stem cell transplant (HSCT) recipients, patients with hematologic malignancies, and those with diabetic ketoacidosis. The infection typically presents as soft tissue, rhinoorbitocerebral, pulmonary, or disseminated disease and is characterized by rapid clinical progression and high mortality rates. Treatment with amphotericin B lipid formulations in combination with surgery offers the best option for treatment and survival; posaconazole, a relatively new antifungal triazole, is increasingly used for consolidation or salvage therapy. Because of the poor prognosis of zygomycosis, particularly in immunocompromised cancer patients, adjunctive treatments such as hyperbaric oxygen therapy, use of immunomodulatory cytokines, and in vivo iron chelation continue to be explored. Thus far, it is unclear how these adjunctive treatments can be harnessed to impact outcomes and which patients may benefit from them.     

Posaconazole Salvage Treatment for Invasive Fungal Infection

Invasive fungal infection (IFI) is an important cause of morbidity and mortality. Posaconazole is a second generation triazole with a broad spectrum, and it may be suitable for salvage antifungal treatment although posaconazole is not usually considered to be as first-line antifungal therapy for IFI. The purpose of this study was to assess the utility of posaconazole salvage treatment for IFI. We conducted a retrospective review of patients with salvage antifungal treatment with posaconazole for IFI at our institution between December 2007 and July 2012. A total of ten patients received posaconazole salvage IFI. Etiology of IFI was consisting of mucormycosis (four patients), Paecilomyces variotii (one patient), and unspecified IFI etiology (five patients). Causes of posaconazole treatment were following; intolerance of previous antifungal therapy in five patients, refractory IFI on previous antifungal therapy in four patients, and both intolerance of previous antifungal therapy and refractory IFI on previous antifungal therapy in one patient. Duration of posaconazole salvage treatment ranged from 15 to 355 days with median 47 days. The overall successful posaconazole salvage treatment response rate was 80.0 % (8 of 10 patients). There were three patients who died during the study period. However, only one death was attributed to the progression of IFI. Two patients discontinued posaconazole due to adverse events. Posaconazole salvage treatment was effective antifungal therapy for IFI. Further studies are needed to define the optimal therapeutic strategy.     

Safe and successful endoarterial infusion of liposomal amphotericin B in treatment of mucormycosis

Mucormycosis is a rare invasive mycotic infection treated by antifungini or amphotericin B. We describe the case of a patient with septic fever and a necrotic lesion, with phlegmon of medial left thigh. Surgery was performed to drain the abscess content and to remove the necrotic tissue; mucormycosis was diagnosized by histological and culture tests and treated by intravenous amphotericin B. Since the lesion worsened, liposomal amphotericin B was directly infused into the left common iliac artery, with progressive improvement, and treatment was continued until complete recovery. Therefore, the endoarterial infusion of liposomal amphotericin B was a safe and successful treatment of advanced lesions of mucormycosis. In such lesions, intravenous general antibiotic administration probably is not sufficient to reach the whole infected area.     

Pulmonary Mucormycosis due to Lichtheimia ramosa in a Patient with HIV Infection

Mucormycosis is increasingly common in patients with risk factors such as diabetes mellitus, neutropenia, and corticosteroid therapy. However, mucormycosis seems to be less common in patients with human immunodeficiency virus (HIV) infection compared to patients with other risk factors. Despite their lower virulence, Lichtheimia species should be regarded as emerging pathogens among Mucoralean fungi. We report a fatal case of pulmonary mucormycosis due to Lichtheimia ramosa in a 52-year-old man with an end-stage HIV infection. He had a cachectic appearance and his CD4 count was 8 cells/mm³. The fungal infection was diagnosed based on a positive sputum culture with histopathologic confirmation. The fungus was resistant to caspofungin, anidulafungin, and voriconazole [minimum inhibitory concentration (MCI) >32 µg/ml], whereas the E test MIC values of itraconazole, posaconazole, and amphotericin B were 0.38, 0.38, and 0.5 µg/ml, respectively. Although intravenous drug use is the main risk factor for the development of mucormycosis in HIV-infected patients, it may also develop in patients with low CD4 count, opportunistic infections and/or additional diseases, such as Kaposi’s sarcoma or severe immunodeficiency, as in our case.     

Primary cutaneous mucormycosis in an immunocompetent host

Mucormycosis in immunocompetent hosts is rare, and is often related to trauma. We report a case of primary cutaneous mucormycosis in a 26 year old immunocompetent female due to Mucor species. A combination of Amphotericin B and surgical debridement completely eradicated the infection.     

Características clínicas y evolución de los pacientes diagnosticados de mucormicosis en un hospital de tercer nivel (2012-2016)

Background

The most common presentation of mucormycosis in the past was the nasosinusal involvement in patients with diabetic ketoacidosis. However, in the last few years, new groups of patients with risk of mucormycosis have emerged.

Isavuconazole in a Successful Combination Treatment of Disseminated Mucormycosis in a Child with Acute Lymphoblastic Leukaemia and Generalized Haemochromatosis: A Case Report and Review of the Literature

Invasive mucormycosis in immunocompromised children is a life-threatening fungal infection. We report a case of a 7-year-old girl treated for acute lymphoblastic leukaemia complicated by disseminated mucormycosis during induction therapy. Microscopic examination of surgically removed lung tissue revealed wide, pauci-septate hyphae suggesting a Mucorales infection. This diagnosis was confirmed immunohistochemically and by PCR analysis followed by a final identification of Cunninghamella sp. The patient was treated successfully with surgical debridement and antifungal combination therapy with amphotericin B, caspofungin and isavuconazole. The use of isavuconazole in a child was not previously reported. Additionally, case reports concerning pulmonary mucormycoses in paediatric population published after 2010 were reviewed. Nineteen out of 26 identified patients suffered from haematological diseases. Reported mortality reached 38.5%. By the fact of rising morbidity, unsatisfactory results of treatment and remaining high mortality of mucormycoses in immunocompromised patients, new therapeutic options are warrant. Isavuconazole, with its broad-spectrum activity, good safety profile and favourable pharmacokinetics, is a promising drug. However, further studies are necessary to confirm positive impact of isavuconazole on mucormycosis treatment in children.

     

Coronavirus Disease (Covid-19) Associated Mucormycosis (CAM): Case Report and Systematic Review of Literature

Severe coronavirus disease (COVID-19) is currently managed with systemic glucocorticoids. Opportunistic fungal infections are of concern in such patients. While COVID-19 associated pulmonary aspergillosis is increasingly recognized, mucormycosis is rare. We describe a case of probable pulmonary mucormycosis in a 55-year-old man with diabetes, end-stage kidney disease, and COVID-19. The index case was diagnosed with pulmonary mucormycosis 21 days following admission for severe COVID-19. He received 5 g of liposomal amphotericin B and was discharged after 54 days from the hospital. We also performed a systematic review of the literature and identified seven additional cases of COVID-19 associated mucormycosis (CAM). Of the eight cases included in our review, diabetes mellitus was the most common risk factor. Three subjects had no risk factor other than glucocorticoids for COVID-19. Mucormycosis usually developed 10–14 days after hospitalization. All except the index case died. In two subjects, CAM was diagnosed postmortem. Mucormycosis is an uncommon but serious infection that complicates the course of severe COVID-19. Subjects with diabetes mellitus and multiple risk factors may be at a higher risk for developing mucormycosis. Concurrent glucocorticoid therapy probably heightens the risk of mucormycosis. A high index of suspicion and aggressive management is required to improve outcomes.

     

急性淋巴细胞白血病患者侵袭性头状地霉感染1例及文献回顾

目的:通过报道1例急性淋巴细胞白血病患者侵袭性头状地霉感染的临床资料,并结合文献探讨头状地霉感染的临床特点、有效的诊断及治疗方法。方法:报道国内首例急性淋巴细胞白血病患者化疗后骨髓抑制期感染头状地霉病例,并对该病的诊断及治疗等进行系统文献回顾。结果:该白血病患者经血培养证实为头状地霉感染,并累及肺脏、肝脏和皮肤,治疗过程中先后采用卡泊芬净、脂质体两性霉素B和脂质体两性霉素B联合伏立康唑等治疗,虽然脂质体两性霉素B联合伏立康唑治疗患者体温正常,临床症状稍有改善,但是患者在化疗后40天放弃治疗并死于心肺功能衰竭。结论:头状地霉感染的发病率低,临床症状不够典型,诊断困难,预后差。根据患者的临床表现,结合血培养、GM实验、G实验和CT扫描等检查,可有助于诊断。头状地霉感染尚无非常有效的治疗方式,采用脂质体两性霉素B或两性霉素B联合伏立康唑或其他新的抗真菌药物可能获得一定的疗效,早期诊断、早期联合治疗和患者早期脱离粒缺状态是治疗成功的关键。     

Primary Cutaneous Mucormycosis in a Patient with Burn Wounds Due to Lichtheimia ramosa

Mucormycosis is usually an invasive mycotic disease caused by fungi in the class mucormycetes. Here we report a case of cutaneous mucormycosis due to Lichtheimia ramosa in a 20-year-old female patient with burn injuries. She was admitted to the hospital with accidental flame burns covering 60 % total burn surface area. After 15 days of admission to hospital, the burn wound showed features of fungal infection. Culture showed white cottony growth belonging to the Mucorales order. Morphological identification confirmed it as L. ramosa. She was managed surgically and medically with the help of amphotericin B. Patient survived due to prompt diagnosis and appropriate medical and surgical treatment. Early diagnosis is critical in prevention of morbidity and mortality associated with the disease. Fungal infection in burn wounds can be difficult to diagnose and manage.     

Mucormycosis in Mainland China: A Systematic Review of Case Reports

Mycopathologia - Mucormycosis is a lethal fungal infection with increasing incidence. The epidemiology of mucormycosis in current mainland China has not been fully elucidated. To investigate the...     

Isavuconazole and Liposomal Amphotericin B as Successful Combination Therapy of Refractory Invasive Candidiasis in a Liver Transplant Recipient: A Case Report and Literature Review

Invasive fungal infections in liver transplant recipients are associated with elevated morbidity and mortality and pose a challenge to the treating physicians. Despite of lacking clinical data, the use of antifungal combination therapy is often considered to improve response rates in an immunocompromised patient population. We herein report a case of refractory invasive candidiasis in a liver transplant recipient treated successfully with a combination of isavuconazole und high-dose liposomal amphotericin B. The antimycotic combination treatment was able to clear a bloodstream infection with C. glabrata and led to regression of bilomas among tolerable side effects. The use of the above-mentioned antifungal combination therapy in a liver transplant recipient has not been reported previously. This case highlights the efficacy and safety of antifungal combination therapy in immunocompromised patients with refractory invasive candidiasis.

     

Alteration of liver glycopatterns during cirrhosis and tumor progression induced by HBV

The incidence of hepatocellular carcinoma (HCC) is closely correlated with hepatitis B virus (HBV)-induced liver cirrhosis. Structural changes in the glycans of serum and tissue proteins are reliable indicators of liver damage. However, little is known about the alteration of liver glycopatterns during cirrhosis and tumor progression induced by HBV infection. This study compared the differential expression of liver glycopatterns in 7 sets of normal pericarcinomatous tissues (PCTs), cirrhotic, and tumor tissues from patients with liver cirrhosis and HCC induced by HBV using lectin microarrays. Fluorescence-based lectin histochemistry and lectin blotting were further utilized to validate and assess the expression and distribution of certain glycans in 9 sets of corresponding liver tissue sections. Eight lectins (e.g., Jacalin and AAL) revealed significant difference in cirrhotic tissues versus PCTs. Eleven lectins (e.g., EEL and SJA) showed significant alteration during cirrhotic and tumor progression. The expression of Galα1-3(Fucα1-2)Gal (EEL) and fucosyltransferase 1 was mainly increasing in the cytoplasm of hepatocytes during PCTs-cirrhotic-tumor tissues progression, while the expression of T antigen (ACA and PNA) was decreased sharply in cytoplasm of tumor hepatocytes. Understanding the precision alteration of liver glycopatterns related to the development of hepatitis, cirrhosis, and tumor induced by HBV infection may help elucidate the molecular mechanisms underlying the progression of chronic liver diseases and develop new antineoplastic therapeutic strategies.     

Nosocomial Rhinocerebral Mucormycosis: Two Cases with a Temporal Relationship

Mucormycosis is an unusual fungal infection that usually affects immunosuppressed patients. Small outbreaks of mucormycosis have been previously reported. We present two clinical cases of fatal rhinocerebral mucormycosis with a close temporal relationship between them and a possible nosocomial transmission: case 1 was a 75-year-old male with diabetes and COPD, treated with antibiotics and systemic corticosteroids, who developed rhinocerebral mucormycosis. Case 2 was an 88-year-old woman who was treated with systemic antibiotics and corticosteroids and developed the same infection after insertion of a nasogastric tube. Both patients concurred at the same time in our hospital, and healthcare staff was common to both of them. These cases, along with previously reported cases, highlight that, although infrequent, transmission of the fungus in the hospital environment is a real possibility that should be taken into account in order to initiate contact and air isolation precautions that could avoid nosocomial transmission of this infection.     

Detection of antibodies against Fasciola hepatica in cirrhotic patients from Peru

The prevalence of Fasciola hepatica infection, in endemic countries, in patients with established cirrhosis is unknown. We hypothesized that, in endemic countries, the presence of fascioliasis may be detected in a serum pool of cirrhotic patients. Forty-four previously stored serum samples of patients with established liver cirrhosis, in the Hospital Nacional Cayetano Heredia in Lima, Peru, were collected from 1998 to 2003 and assessed for hepatitis B, C and fascioliasis antibodies (Fas2 ELISA). Hepatitis B surface antigen (HBsAg) was positive in 8.8% (n = 34), hepatitis B core antibody (anti-HBc) in 32.5% (n = 34), hepatitis C antibodies (anti-HCV) in 9.1% (n = 33), and 9.1% (n = 44) were Fas2 ELISA positive. This disease is an example of an emerging tropical infection which can be present in chronic liver diseases, requiring greater clinician awareness especially in endemic rural areas. Further clinical studies are warranted.