Abstract
The global incidence of invasive mucormycosis (mucor) infection is on the rise due in part to an increased utilization of immunosuppressive therapies to treat malignancies and autoimmune diseases. While cirrhosis has previously been considered a risk factor for fungal infections, very little is known about the inciting factors precipitating development of isolated cutaneous mucormycosis infection. This form of mucor poses a significant mortality risk despite antifungal and surgical treatments and has been documented in only 5 patients with cirrhosis prior to our case report. This case report presents the sixth documented case of cutaneous mucormycosis in a patient with cirrhosis and explore nosocomial etiologies for its progression to clinically significant infection.
Introduction
Mucormycosis is a fungal infection of the Zygomycete family and order Mucorales. The fungus is found predominantly in soil and decaying matter, and the primary infection route is via spore inhalation. This fungus causes several systemic infections including pulmonary, gastrointestinal, cutaneous, encephalic, and rhinocerebral involvement. 1 Cutaneous mucor is the third most common with rhinocerebral and pulmonary being the 2 most common, respectively.2,3 Overall mortality can range from 25% to 87% depending on the type of infection. 2 Immunocompromised individuals are at the highest risk of infection. The most common risk factors include diabetes mellitus, acquired immunodeficiency syndrome, hematologic malignancy, organ transplant, immunosuppressive therapy, prolonged neutropenia, renal failure, malnutrition, trauma, corticosteroid use, intravenous drug use, iron overload and subsequent treatment with deferoxamine, and burn patients.1,2 The incidence of Mucorales infection is rising globally and it has been postulated this is due to a higher number of individuals who are immunocompromised, from an increasing global incidence of diabetes mellitus or from iatrogenic causes due to treatments of malignancies and autoimmune diseases. 4 Typically, cirrhosis is not considered a major risk factor; however, we postulate cirrhosis should be included as a risk factor for Mucorales infection given that these patients are at an increased risk of acquiring invasive fungal infections. Only 5 case reports of cutaneous mucor in patients with cirrhosis have been published (Table 1). 5 We will present the sixth reported case of cutaneous mucormycosis in a patient with alcoholic cirrhosis.
Case
A 29-year-old female with a history of alcohol use disorder complicated by prior alcoholic pancreatitis presented with tremors, altered mental status, weakness, and jaundice. She was initially admitted to the internal medicine service for sepsis and acute on chronic liver failure. She developed worsening mental status and acute kidney injury necessitating transfer to the medical intensive care unit where she was intubated on arrival. Initial labs in the Medical ICU (MICU) were notable for arterial blood gas (ABG) 7.4/41.9/72/14, creatinine 1.37 mg/dL, blood glucose 154 mg/dL, total bilirubin 13.8 mg/dL, lactate 4.2 mmol/L, hemoglobin 5.4 g/dL, white blood cell count 27.6 × 109/L (Table 2). Her Model for End-Stage Liver Disease-NA score (MELD-Na) at the time of MICU transfer was 29 and Maddrey’s Discriminant Function for alcoholic hepatitis (MDF) was 41.1. Steroids for alcohol hepatitis were initially withheld due to concern for infection, but as she developed shock, she was started on stress dose hydrocortisone. She developed renal failure for which continuous renal replacement therapy (CRRT) was initiated. No infectious etiology was identified, although she completed a few rounds of empiric antibiotics for her shock. Her fungitell was negative. She was extubated after 2 weeks but remained in the MICU as she continued to have waxing and waning vasopressor requirements and remained on CRRT with no signs of renal recovery. She continued to have signs of septic shock with leukocytosis as high as 53 × 109/L and persistent lactate between 3 and 6 mmol/L.
Relevant Laboratory Data During Hospitalization.
Abbreviations: BUN, blood urea nitrogen; AST, aspartate aminotransferase; ALT, alanine aminotransferase.
One week after transferring to the MICU, a rash on the patient’s left upper chest was noted by wound care. This was under an area where an EKG lead was previously applied. When the rash enlarged, dermatology was consulted. They performed a biopsy which resulted 24 hours later with mucormycosis with angioinvasion. Infectious disease and surgery were consulted. She was started on IV liposomal amphotericin and posaconazole. ENT was consulted and did not find any evidence of a fungal sinus infection. Surgery was consulted for debridement and were only able to perform a superficial debridement as they felt an operative debridement carried a prohibitively high morbidity due to her multiorgan failure The extensive surgery would require shoulder disarticulation, an intervention that would not improve quality or quantity of life.
She underwent aggressive wound care with daily wet to dry dressings, then xeroform to keep from traumatizing the underlying wound bed. At one point during her ICU course, the wound bled significantly and required frequent dressing changes by nursing staff and packing with hemostatic gauze. Bleeding prevented aggressive bedside debridement. She was started on iodosorb (long-acting iodine paste) for better antimicrobial coverage in addition to xeroform gauze which assisted with autolytic debridement of the eschar. The wound began to slowly improve, and she underwent a second bedside debridement with the wound care team. The plan was to transition to amphotericin soaks once the eschar was completely off, but unfortunately, she passed away before this was able to be done due to progressive multiorgan failures without sign of recovery. She survived 2 months after the cutaneous mucor wound was first noticed.
Discussion
Cutaneous mucormycosis is thought to develop when there is a disrupted normal cutaneous barrier, typically because of trauma, leading to the direct inoculation of spores into the skin. 1 It is postulated that in the setting of this skin trauma, any recurring episodes of sepsis, shock, and a need for multiple blood transfusions, create a pseudo immune-deficient state. 4
Cutaneous mucormycosis is classified as either primary or secondary. In primary mucormycosis, direct inoculation leads to skin infection, while in secondary mucormycosis, dissemination from other locations leads to skin involvement. 1 The infection is further categorized into localized, deep, or disseminated. Localized infection involves only the skin and subcutaneous tissue. Deep infection involves the underlying muscle, tendons, or bone. Disseminated disease affects other noncontiguous organs. In the majority of disseminated cases, the portal of entry is the skin and only a small portion of skin involvement occurred due to dissemination from an internal organ. 4 A review on mucor infection showed that the most common sites of cutaneous mucormycosis involvement are the upper and lower extremities though any area of the skin can be affected. The clinical presentation can vary though the most common sign is a black eschar. The majority of cases first present as either a nodule, indurated plaque, targetoid lesion, purpuric lesion, scaly plaque, and ulcer.2,4 Additional signs of sepsis can also be present depending on the underlying immunocompromised state and extent of infection. 4 In our case, the patient was in the medical intensive care unit in multiorgan failure due to acute on chronic liver disease when she developed a small, discolored patch with irregular purple edges. This lesion quickly progressed in size to a large centrally necrotic plaque with a retiform red papular edges.
Importantly, there are reports of nosocomial mucor infection. In one global review of mucor, 15.6% of mucor infections were healthcare-associated presumed to be secondary to adhesive tapes, bandages, intravenous, or arterial catheters. It was noted that mucor can often be found co-infecting surgical wounds as well, either directly or due to dressings. Intramuscular or even subcutaneous injections which can act as skin barrier disruptions were also reported as potential sources of infection by Mucorales. 4 There was noted to be a high rate of mucor infection in burn patients hospitalized in the intensive care units due to their loss of the skin barrier and acquired immune deficiency. 4 In our patient, we postulate an EKG lead may have been the initial insult in disrupting the skin barrier given the initial l hour later diagnosed as cutaneous mucor developed underneath an EKG lead.
Diagnosis of cutaneous mucormycosis is made via combination of histopathology and culture as the clinical features are often nonspecific. Although a black eschar is the most common presentation, it may not always be present and absence of an eschar does not eliminate the diagnosis.2,4 Histology in primary cutaneous mucormycosis shows edema, thrombosis, necrosis, infarctions, as well as an inflammatory reaction. Staining with hematoxylin and eosin, periodic acid-Schiff, or Grocott stains can identify the hyphae. 2 Overall, the diagnosis may be challenging especially in burn patients with atypical wounds thus a high index of suspicion is warranted. 4
Treatment of cutaneous mucormycosis includes the combination of antifungal therapy and surgical debridement.1,2,4 High-dose liposomal amphotericin is the antifungal of choice with azole derivatives as second-line therapy.1,2 The mortality of cutaneous mucormycosis ranges from 25% to 31%. In localized disease, the mortality is lower at 4% to 10% and increases to 26% to 43% in deep infections. In disseminated disease, the mortality can be as high as 83%, though the more recent reports show a mortality of 26% to 50%. 4 A review found a significantly lower mortality when both antifungals and surgery were part of the treatment plan. 4
A meta-analysis showed that the most common risk factors for cutaneous mucormycosis are diabetes and hematological malignancies at 20% and 15.7%, respectively. Approximately 39.6% did not have an underlying disease and 87% of those patients developed cutaneous mucormycosis because of trauma or burns that led to the inoculation of spores into the skin. Cirrhosis was identified as a risk factor in only 1% of the total cases. 4 The incidence of cirrhosis has been increasing with a peak incidence in males between 40-44 and 45-49 years in females. 6 Invasive fungal infections are also becoming more prevalent in patients with liver disease which includes acute liver failure, severe alcohol associated hepatitis, and decompensated cirrhosis. Candida is the most common fungus leading to an invasive infection; however, others such as Cryptococcus, Aspergillus, Pneumocystis, and endemic mycoses are gaining prevalence. 7
There are many pathways that increase the risk of developing an invasive fungal infection in patients with liver disease including host immune dysfunction, barrier failures, malnutrition, and alterations in the microbiome. Prolonged hospitalization is a risk factor although interestingly a stay in the intensive care unit is only a risk factor for alcohol related hepatitis. Dysfunction of the immune system occurs through several mechanisms. Cirrhotic livers don’t produce as much immunoglobulin and complement which in turn leads to decreased opsonization by macrophages. Additionally, neutrophil function is decreased. Patients with severe alcoholic hepatitis may have underlying cirrhosis; however, a mechanism is also present in patients with only severe alcoholic hepatitis that leads to immune dysfunction. It has been shown that patients with severe alcoholic hepatitis have elevated IL-10 levels which lead to reduced antimicrobial activity. The use of steroids in these patients is also another mechanism of immune suppression. Disruption of the intestinal microbiome with overgrowth of Candida species in patients with cirrhosis leads to disruption of the intestinal barrier and translocation of bacteria as well as fungi. Finally, there is underlying malnutrition and sarcopenia that further weakens the immune system. 7
To date that we are aware of, there are only 5 known cases of cutaneous mucormycosis in patients with cirrhosis and the mortality was 100%. Of those 5 patients with cirrhosis and cutaneous mucor, 3 had infections in the upper extremities which were thought to have originated from previous injection sites, a line site, or an infected dressing. 5 Our case would be the fourth reported upper extremity cutaneous mucor which is consistent with the review that suggests the upper extremity was the most common location for cutaneous mucor infection.
Concerningly, the incidence of mucormycosis has been increasing globally. The most recent surge occurred after the COVID19 pandemic which was likely secondary to the number of immunocompromised patients affected by this virus as well as the use of corticosteroids therapy. 3 Other suggested etiologies are the more prevalent use of prophylactic voriconazole in neutropenic patients which can be selective for a higher incidence of mucor infections. 8 Given mucor spores are ubiquitous in soil, compost piles, fruits, and decaying organic material, any event (natural disasters or iatrogenic) that can disrupt these spores may lead to mucor inoculation. It has been reported that there are higher rates of mucor infection in combat-related trauma as well. 4
Conclusion
Our case is only the sixth known reported case of cutaneous mucor in a patient with cirrhosis. Patients with cirrhosis are at a high risk of invasive fungal infections which include mucormycosis due to their underlying immune dysfunction. Cutaneous mucormycosis is the third most common type of infection and has a variable clinical presentation. Given the increasing global incidence of this very pathogenic and highly fatal infection, we must keep a higher index of suspicion for this disease as earlier detection may lead to improved patient outcomes.
We must consider cirrhosis a risk factor in the development of cutaneous mucor and expeditious diagnosis with early initiation of intravenous antifungal therapy and surgery (if feasible) is required, although still portends a high mortality. The use of azole impregnated dressings has not been well studied though further investigation into this potential concomitant treatment should be considered. We must try to minimize skin barrier disruptions in the upper extremities as this is the most commonly reported site of cutaneous mucor infection. We acknowledge this may not always be feasible in the MICU where multiple interventions are required (Figures 1 and 2).
Progression of cutaneous mucormycosis wound on left chest and left upper arm. (A) Initial wound. (B) Six days after wound was first detected. (C) Postsuperficial surgical debridement. (D) Significant bleeding from the wound requiring frequent hemostatic gauze packing. (E) Eschar formation. (F) After bedside debridement of remaining eschar.
(A) Low-power microphotograph displaying full thickness skin showing areas of necrosis in subcutaneous tissue (arrow heads). Original magnification ×20, hematoxylin and eosin stain. (B) High-power microphotograph showing ribbon-like hyphae measuring 5 to 20 μm in diameter (arrows) within necrotic subcutaneous tissue (arrow heads). Original magnification ×200 magnification, hematoxylin and eosin stain. (C, D) Microphotograph highlighting ribbon-like/pauci-septate hyphae (arrows), consistent with Mucorales. Original magnification ×200 and ×400, GMS special stain.
Footnotes
Acknowledgements
None.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval
Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent
Informed consent for patient information to be published in this article was not obtained because the patient is deceased.
Prior Presentation of Abstract Statement
None.
