Introduction

Iron is an essential element required for survival; however, an excess of this element in the form of iron overload interferes with host immunity and can predispose to infection with siderophilic pathogens. We present a case of fatal gastrointestinal Mucormycosis in a welder with a history of untreated iron overload. Systemic iron overload has been described in the literature in welders, though not extensively. This condition should be considered as a potential host factor in broadening the differential diagnosis in an at-risk patient, such as a welder, who presents with undifferentiated sepsis.

Case Presentation

A 50-year-old Caucasian male with a past medical history of chronic obstructive pulmonary disease and welders’ pneumoconiosis, hypertension, hyperlipidemia, alcohol abuse, and previously confirmed diagnosis of Vibrio parahaemolyticus gastroenteritis 1 year prior was transferred to our facility in August with mixed septic and cardiogenic shock, status post Impella device placement, and complicated by multi-organ failure.

Twenty-five days prior to the presentation, he traveled to Inverness, California, where he consumed raw oysters and subsequently developed self-limited nausea and vomiting within 24 h that resolved spontaneously by the third day. His traveling companions were not affected. Twelve days later (2 weeks prior to admission), he traveled to Chico, California, where he complained of palpitations, shortness of breath, and a painful, red right great toe secondary to what he believed to be a spider bite. According to the patient’s family, he then checked into an urgent care for his toe and was prescribed doxycycline 100 mg oral twice daily, trimethoprim-sulfamethoxazole 800/160 mg one tablet oral twice daily, and valacyclovir 1000 mg oral twice daily.

One week later, he traveled to the coastal city of Fort Bragg, California, where he again consumed raw oysters. He was feeling closer to his usual state of health at that time, aside from his right foot pain. While the patient reported improvement in his great toe pain and swelling on antimicrobials, he was experiencing new pain and swelling in his second toe that spread up his foot and was described as a “blue” discoloration. After returning from this trip 2 days later, he developed nausea, vomiting, and non-bloody diarrhea. His traveling companion did not fall ill. The patient again presented for care, this time to an emergency department, precisely 1 week after his urgent care visit. He complained of worsening painful and swollen toes, fever, and dizziness. He was observed to be slightly tachycardiac with a heart rate of 101 beats per minute and a temperature of 37.7 °C. The exam was notable only for mild redness over the right first toe and distal right second toe with mild streaking of the dorsum of the foot. Radiographs of the foot were normal. The differential at that time included cellulitis, gout, and osteomyelitis, with the working diagnosis being gouty arthritis. He was prescribed a prednisone taper and sent home.

Three days later, he returned to the same emergency department with persistent nausea, vomiting, worsening non-bloody diarrhea, and weakness unresolved by medications. He was found to be febrile to 39.6 °C, tachycardic to 117, hypotensive with a blood pressure of 86/55, and admitted directly to the intensive care unit. Labs were notable for a white blood cell (WBC) count of 28,000 × 10^3/mL, hemoglobin (Hgb) of 14.4 g/dL, hematocrit of 43.1%, platelets of 268 K/mm3, blood urea nitrogen (BUN) of 35 mg/dL, serum creatinine of 2.2 mg/dL, lactate of 3.1 mml/L, and liver function panel (LFT) that was within normal limits. He required pressor support and was started on vancomycin and meropenem. Overnight and into the following morning, he continued to decline with recalcitrant metabolic acidosis and severe sepsis requiring triple pressor support. Within 36 h, he developed multi-organ failure including shock liver and anuric renal failure requiring continuous renal replacement therapy. Chest radiograph showed congestion, and a computed tomography (CT) scan of the abdomen and pelvis showed only mild diverticulosis. A transthoracic echocardiogram showed severe, biventricular failure with an ejection fraction of 30% and new cardiomyopathy which was deemed to be secondary to a non-ischemic cause after further cardiologic investigation. Differentials for cardiomyopathy included infectious vs. iron-overloaded state. Basic rheumatology screening work-up was negative including anti-nuclear antibody and rheumatoid factor. Acute HIV, hepatitis A, B, C, EBV, CMV, and parvovirus B19 antibody were not detected. Coxsackie B virus antibody type 4 was elevated to 1:320, a finding that would, 1 week later, be hypothesized to be the cause of his acute cardiomyopathy. Toxicology and heavy metal screening for arsenic, lead, and mercury were normal. The patient was not a known diabetic and did not use injectable drugs.

Cardiac magnetic resonance imaging or endomyocardial biopsy was then considered. As these procedures were not performed on the premises, the patient was transferred to our facility. In preparing the patient for transport via airlift, he became acutely unresponsive and was found to be in pulseless electrical activity arrest on the flight pad. During the code blue, chest compressions were initiated, and one round of epinephrine was administered after which a return of spontaneous circulation was achieved. The patient was transported back to the catheterization lab emergently where an Impella device was placed. After 72 h in the cardiac intensive care unit, the patient was transferred to our facility.

At the time of arrival, WBC was 18,000 × 10^3/mL, Hgb 9.6 g/dL, hematocrit 29.1%, platelets 79 K/mm3, BUN 53 mg/dL, serum creatinine 4.7 mg/dL, and an LFT panel showed an AST of 22,669 U/L, ALT 5678 U/L, total bilirubin 9.5 mg/dL, and alkaline phosphatase of 43 U/L. Vital signs were notable for the temperature of 38.9 °C, blood pressure of 86/64, pulse of 101, respiratory rate of 14, and oxygen saturation of 97% on mechanical ventilation. APACHE II score was thirty points. Upon initial examination, he was critically ill, intubated, and mechanically ventilated requiring vasopressor support and continuous renal replacement therapy. Jaundice and icteric sclera were appreciated. Examination of his lower extremities revealed purple discoloration of the right first and second toes, with diffuse, delayed capillary refill. Vancomycin and meropenem were continued, and doxycycline was added. Chest radiograph revealed an enlarged heart, retrocardiac airspace opacity, and appropriate lines and tubes. A CT scan of the abdomen and pelvis revealed scant bilateral pleural effusion with bibasilar atelectasis and cardiomegaly. On hospital day two, a transesophageal echocardiogram revealed an ejection fraction of 40% and a small pericardial effusion with no evidence of endocarditis. Infectious disease was consulted for mixed shock and query of Vibrio vulnificus or parahaemolyticus infection as no cause for the sepsis had thus far been elucidated despite extensive work-up with imaging and cultures. Recommendations included continuing antimicrobials and awaiting additional infectious work-up, in addition to obtaining a gastrointestinal polymerase chain reaction panel and stool culture, both of which resulted as negative. Listeriosis was also considered on the differential but was not recovered. Gastroenterology consultation determined that the transaminitis was secondary to a combination of shock liver, possible undiagnosed infection, possible thrombus, or Wilson’s disease, though the latter two were ruled out by imaging and laboratory evaluation, respectively.

Over the next 3 days, the patient remained critically ill but stable. His feet were noted to have black, mottled toes with bullae formation primarily on the right foot with progression to the soles (Fig. 1). Vascular surgery consultation recommended an ankle-brachial index which revealed normal arterial perfusion to the bilateral lower extremities with severe inframalleolar disease bilaterally. The working diagnosis was vasopressor-induced ischemia with or without embolization secondary to the Impella device, which was removed on hospital day four. The infectious work-up was repeated with blood, urine, and respiratory cultures via mini-bronchoalveolar lavage. By hospital day five, inotropic and vasopressor support were weaned off, the patient was extubated, and vancomycin was stopped while meropenem was changed to ceftriaxone for empiric treatment of Vibriosis in addition to the doxycycline. The infectious disease team also recommended aspiration of the bullous lesion from the patient’s right foot for microbiologic evaluation which yielded a negative gram stain and culture. The patient remained well and improved slightly each day over the next 4 days.

Fig. 1
figure 1

Purple discoloration of the right foot with multiple bullae (top). Mottled right foot with pale, dusky right first, and second toes (bottom)

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On hospital day ten, he became acutely encephalopathic with worsening vital signs and developed acute right upper quadrant pain with three episodes of melena. He underwent urgent esophagogastroduodenoscopy (EGD) secondary to an acute decrease in hematocrit and platelets. The EGD revealed severe esophagitis and stress ulcers. Biopsies were not obtained due to the thrombocytopenia. Of note, a heparin-induced thrombocytopenia enzyme-linked immunosorbent assay resulted as positive. By the following day, the patient developed severe abdominal pain again, and this time repeat CT imaging of the abdomen and pelvis revealed severe colitis with pneumatosis coli, acute pancreatitis, splenic infarcts, and increased bilateral lower lobe opacities. Antibiotics were broadened to piperacillin-tazobactam and vancomycin. General surgery was consulted who recommended emergent exploratory laparotomy which the patient underwent. The exploration revealed transmural necrosis of the cecum, appendix, small bowel, and omentum. Four samples were sent for culture and pathologic evaluation. Ascitic fluid cultures revealed Bacteroides and Parabacteroides species. Post-operatively, the patient required increasing vasopressor support due to refractory hypotension. Meropenem was substituted for piperacillin-tazobactam. The patient would return to the operating room 2 days later on hospital day twelve, and again on hospital day thirteen. Each trip to the operating room revealed new and worsening areas of bowel and omental necrosis and ischemia requiring resection. On hospital day fourteen, surgical pathology of tissue samples from three of three sites showed angio-invasive and tissue-invasive fungal organisms. Liposomal amphotericin and micafungin were initiated. The patient was again taken to the operating room for a fourth time where he was found to have grossly visible, extensive tissue necrosis of most abdominal contents and organs consistent with an invasive fungal infection (Fig. 2). Intraoperative consultation with an additional general surgeon and an infectious disease specialist determined that the tremendous extent of disease would require resection incompatible with life. Multidisciplinary discussions concluded with the recommendation to transition the patient to comfort care. The patient’s family agreed, and he expired several hours later. Post-mortem culture results revealed the presence of Rhizopus microsporus and Clavispora lusitaniae. Posthumously, it was discovered that the patient had a past diagnosis of systemic iron overload previously determined to be secondary to his twenty-year profession as a welder.

Fig. 2
figure 2

Intra-operative findings included extensive tissue necrosis consistent with invasive fungal infection

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Discussion

Iron is an essential element for almost all living organisms, including many human pathogens through multiple innate host defenses that restrict iron from pathogenic organisms [1, 2]. During normal iron homeostasis, the majority of iron is sequestered intracellularly within hemoglobin, and free extracellular iron is scarce with extracellular iron bound by transferrin [2]. During infection, additional mechanisms are activated to restrict iron from pathogens, most of which are facilitated by hepcidin. These include iron-sequestering proteins on mucosal surfaces, iron depletion from the extracellular fluid, prevention of non-transferrin-bound iron generation, and iron transport out of phagocytic vacuoles [1, 2]. Iron overload disorders interfere with these host responses and predispose the host to infection.

Numerous organisms are known to have increased virulence in the setting of excess iron, including bacteria, fungi, viruses, and protozoa [3]. Commonly reported siderophilic bacteria include Vibrio species (particularly Vibrio vulnificus), Yersinia enterocolitica, Listeria monocytogenes, and Escherichia coli [1, 3,4,5,6,7]. Within the kingdom fungi, Mucorales species are most commonly reported as opportunistic infections in iron-overloaded states, though Aspergillus species are also known to display increased pathogenicity [3, 8,9,10,11]. The mechanisms by which each organism overcomes the host’s iron-restricting defenses are varied and unique, including siderophore-mediated iron uptake, heme uptake, and transferrin receptors, among others [2].

In this case of presumed Vibriosis and disseminated gastrointestinal Mucormycosis in a welder, we suspect that total body iron overload predisposed the patient to overwhelming infection with siderophilic pathogen(s). While welding has been associated with pulmonary hemosiderosis, total body iron overload in welders is less well characterized, though there is an association described between high airborne iron levels and excess body iron in welders [12], in addition to several case reports in the literature of systemic iron overload in welders [13, 14]. A clear limitation of this case report is the lack of confirmation of acute iron overload. Posthumously, it was discovered that the patient did indeed have a history of systemic iron overload though historical details regarding his diagnosis are lacking. During both hospitalizations, ferritin, transferrin saturation, and iron levels were not evaluated. Gastrointestinal tract Mucormycosis is rarely reported and purportedly related to disseminated disease [15]. This entity accounts for 7% of all cases with a substantial mortality rate approaching 85% [16]. When it does present clinically, a common manifestation is an upper gastrointestinal bleed that frequently evades definitive diagnosis until postmortem examination [15]. The patient did not have known malignancy, organ transplantation, poorly controlled diabetes, or long-term steroid use, though he did receive corticosteroids both as an outpatient and during admission prior to the diagnosis being discovered. The primary site of entry for Mucormycosis was not definitively established; however, we postulate that the patients initial toe infection may have been undiagnosed primary cutaneous Mucormycoses that eventually progressed to widely disseminated infection. Known risk factors that may have contributed to this dissemination include receipt of corticosteroids, refractory metabolic acidosis, and untreated, iron overload state as prior history would support. Despite these limitations, the case illustrates the risk of infection with siderophilic pathogens in a patient with known or suspected systemic iron overload. Thus, careful consideration of such pathogens should be given to at-risk patients who fail to improve with conventional diagnostics and therapeutics.