Fatal Invasive Candidiasis Diagnosed at Autopsy in a Long-term Hospitalized Patient: A Case Report
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Abstract
Invasive candidiasis is a severe fungal infection caused by Candida species that typically affects immunocompromised individuals. However, emerging evidence shows that even previously immunocompetent patients can develop invasive candidiasis under conditions such as prolonged hospitalization, broad-spectrum antibiotic use, and post-sepsis immunosuppression. We report the case of a 62-year-old male who experienced severe but nonfatal head trauma and required long-term hospitalization for persistent delirium. During his stay, he experienced recurrent febrile episodes that responded poorly to empirical antibacterial treatment. He ultimately deteriorated and died from sepsis. Autopsy revealed disseminated invasive candidiasis with Candida myocarditis, bilateral pulmonary involvement, and renal pyelonephritis, which led to acute renal failure and Candida sepsis. Notably, no antifungal therapy was administered during hospitalization. This case highlights the diagnostic challenges of invasive candidiasis, particularly in patients without classical immunocompromised conditions and in the absence of positive blood cultures for fungal organisms. From a forensic perspective, this case highlights the importance of comprehensive histopathological evaluation of suspected sepsis-related deaths. We emphasize that both clinicians and forensic pathologists must be aware of the risk of fungal infections in long-term hospitalized patients, because prompt diagnosis and appropriate treatment are critical for preventing fatal outcomes.
Introduction
Invasive candidiasis is a fungal infection caused by Candida species and is characterized by the involvement of the bloodstream (candidemia) and/ or deep tissues. Globally, candidemia accounts for an estimated 626,000 cases annually, with mortality rates reaching 90% if untreated [1]. Invasive candidiasis without a positive blood culture is even more prevalent, with approximately 939,000 cases each year and a similarly high mortality rate when not properly managed [1]. While it is typically associated with immunocompromised conditions, such as prolonged hospitalization, use of broad-spectrum antibiotics, or central venous catheters [2-4], emerging evidence highlights that even previously immunocompetent individuals can develop invasive candidiasis, particularly following critical illness, sepsis-induced immunosuppression, or prolonged empirical antibacterial treatment [4].
Clinical suspicion usually arises when patients with symptoms compatible with bacterial infections do not respond to empirical antibiotics and have negative blood cultures for bacterial infection [4]. Without prompt diagnosis and antifungal treatment, invasive candidiasis can rapidly progress to sepsis and eventually death [4]. Although advancements in diagnostic techniques and antifungal therapies have reduced fatal outcomes, such cases remain diagnostically challenging and are rarely encountered in routine autopsy practice.
In this report, we describe a case of fatal Candida sepsis due to invasive candidiasis confirmed at autopsy, aiming to emphasize the importance for forensic pathologists, and where relevant, clinicians, of recognizing the potential for invasive candidiasis even in immunocompetent individuals. We also discuss the pathophysiological progression and clarify the underlying cause of death.
Case Report
A 62-year-old male sustained head trauma after being struck by the opening door of a parked truck and fell while riding a bicycle. His medical history included hypertension, hyperlipidemia, and benign prostatic hyperplasia. Initial imaging at a nearby hospital revealed a skull fracture and a traumatic subarachnoid hemorrhage. Fortunately, the patient regained consciousness after several days in the intensive care unit. Magnetic resonance imaging of the brain revealed multiple parenchymal hemorrhages suggestive of diffuse axonal injury. Although he experienced occasional fever, no pathogens were detected in his blood culture. His general condition stabilized after 1 month of acute-phase treatment, and he was transferred to a long-term care facility for the management of persistent delirium.
Chest radiographs obtained immediately after the transfer and 1 month later showed no remarkable findings; however, he experienced recurrent episodes of fever throughout most of the hospitalization. Although the attending physician prescribed broad-spectrum antibiotics, such as piperacillin/tazobactam and meropenem, the therapeutic response was transient. Approximately 4 months after the accident and three months post-transfer, the patient developed sepsis accompanied by respiratory distress and died the following day. During his admission to the facility, laboratory tests revealed significant fluctuations in the white blood cell count and persistently elevated C-reactive protein levels. Neither blood cultures nor antibiotic sensitivity tests were performed. The attending physician attributed the cause of death to unspecified sepsis secondary to traumatic subarachnoid hemorrhage.
An autopsy revealed evidence of healed head trauma, including a partially united temporal bone fracture (Fig. 1A) and residual cervical spinal injuries (Fig. 1B). Cerebral contusions in the basal regions of the frontal and temporal lobes had resolved, leaving only a brownish discoloration. Gross examination of other internal organs revealed no remarkable abnormalities. However, microscopic examination of the heart revealed clusters of budding yeast and pseudohyphae accompanied by focal myocardial necrosis and surrounding neutrophilic infiltration, consistent with Candida myocarditis (Fig. 2A, B). In the lungs, multiple blood vessels were filled with inflammatory cells, and widespread Candida clusters were observed in the alveolar walls and perivascular regions (Fig. 3A, B). The kidneys showed diffuse infiltration of inflammatory cells and extensive fungal colonization throughout the cortex and medulla, consistent with Candida pyelonephritis (Fig. 4A, B). The urea nitrogen and creatinine levels were elevated in the vitreous fluid, indicating acute renal failure. Collectively with clinical signs observed prior to his death, including fever over 38°C, hypotension, and tachycardia, the cause of death was determined to be Candida sepsis secondary to disseminated invasive candidiasis, likely aggravated by prolonged hospitalization and lack of antifungal coverage during empirical antibacterial treatment.
Gross findings of the head. (A) A linear fracture of the left temporal bone with partial union is observed. Note that the photograph was taken after craniotomy for brain examination and reconstruction of the skull. (B) Cervical spinal injuries were in the healing process, with residual hemorrhage and disruption of the ligaments.
Microscopic findings of the heart. Multifocal aggregates of budding yeasts and pseudohyphae, consistent with Candida species, were accompanied by neutrophilic infiltration of the myocardium (A, H&E, ×200; B, Gomori methenamine silver stain, ×200).
Microscopic findings of the lungs. Fungal organisms, predominantly budding yeasts, were identified within capillary lumen and alveolar spaces (A, H&E, ×200; B, Gomori methenamine silver stain, ×200).
Microscopic findings of the kidneys. Budding yeasts and pseudohyphae of Candida were surrounded by neutrophilic infiltration within the renal parenchyma. Some glomerular spaces were filled with Candida organisms (A, H&E, ×200; B, Gomori methenamine silver stain, ×200).
Discussion
Candida species are common components of normal human microbiota and can become opportunistic pathogens when host immunity is compromised [5]. Candidiasis encompasses all forms of Candida infection and is frequently diagnosed in individuals with immunocompromised conditions, such as primary immunodeficiency, secondary immunodeficiency like acquired immune deficiency syndrome, diabetes, and long-term hospitalization or antibiotic use, or central venous catheters, providing a direct route for systemic infection during administration of medication or parenteral nutrition [2,3]. In the present case, the deceased appeared to be immunocompetent with only minor medical conditions prior to the accident. However, the patient required prolonged hospitalization with both central venous and urinary catheters in place because of persistent delirium following a traumatic injury. The patient experienced recurrent febrile episodes that prompted repeated courses of empirical broad-spectrum antibacterial therapy. Autopsy, including routine microscopic examination with hematoxylin and eosin (H&E) staining, confirmed that the cause of death was Candida sepsis resulting from disseminated invasive candidiasis.
Candidiasis is broadly categorized into superficial and invasive forms based on the site of infection [6]. Superficial candidiasis involves epithelial surfaces, such as the oral mucosa, skin, esophagus, and vagina. It typically presents as a localized disease and exhibits characteristic clinical findings, allowing diagnosis through physical examination and culture-based methods [7]. In contrast, invasive candidiasis affects the bloodstream or internal organs such as the brain, eyes, heart, and kidneys. This form often manifests with nonspecific systemic symptoms, such as fever, chills, or myalgia, making early diagnosis particularly challenging [3].
In clinical practice, empirical antibiotic therapy is often initiated under the presumption of a bacterial infection. However, prolonged use of broad-spectrum antibiotics can disrupt the normal bacterial flora, leading to dysbiosis and fungal overgrowth [8]. Additionally, even previously immunocompetent individuals can develop post-sepsis immunosuppression, rendering them vulnerable to opportunistic pathogens [9]. When invasive candidiasis is not promptly identified and treated, it may progress to Candida sepsis and ultimately death [10,11].
The diagnosis of invasive candidiasis relies on microbiological confirmation, most commonly through blood cultures or tissue biopsy, guiding the initiation of systemic antifungal therapies, such as echinocandins, including caspofungin [12,13]. However, invasive candidiasis can occur without candidemia, either because of the low sensitivity of fungal blood cultures or restriction of infection to deep tissue compartments [10]. In such cases, the absence of microbiological evidence delays appropriate antifungal treatment, and continued empirical antibiotic use can further promote fungal overgrowth, increasing the risk of Candida sepsis and fatal outcomes [10,13].
Notably, the numbers of deaths attributable to candidemia and invasive candidiasis without positive blood culture results differ markedly. Annual deaths from candidemia are estimated to be approximately 165,000, whereas invasive candidiasis without positive blood cultures accounts for an estimated 482,000 deaths. Given that the mortality rate among treated patients is similar in both groups, the discrepancy in total deaths is assumed to be largely due to differences in diagnostic and treatment rates. Specifically, the ratio of treated to untreated patients, based on annual incidence, is approximately 9:1 for candidemia but only 1:5 for invasive candidiasis without positive blood cultures [1].
Previous studies have reported cases of fatal invasive candidiasis associated with prolonged hospitalization in immunocompetent individuals. Jackson et al. described a case of Candida pneumonia in a healthy male patient [14]. The patient developed symptoms of pneumonia following treatment for acute myocardial infarction. Antibacterial therapy was initiated after blood cultures revealed Staphylococcus epidermidis. Although his condition improved slightly with antibacterial treatment, he developed sepsis and died on the 26th day of admission. Autopsy revealed hepatic changes and disseminated intravascular coagulation consistent with sepsis along with pathological evidence of Candida pneumonia. Mathai et al. reported a case of renal candidiasis in an immunocompetent male who stayed at the hospital for 4 months after a head injury in a traffic accident, which resulted in obstruction of the collecting system [15]. These cases, including the present one, underscore that prolonged hospitalization itself, through factors such as antibiotic-induced dysbiosis, invasive medical devices, and post-sepsis immune suppression, can create conditions favorable for invasive fungal infections, even in patients without prior immunodeficiency. Failure to recognize these risk factors can result in delayed diagnosis, inappropriate treatment, and ultimately, fatal outcomes.
From a forensic standpoint, this case highlights the importance of considering invasive fungal infection as a potential cause of death in long-term hospitalized patients, even in the absence of overt immunosuppression. Comprehensive postmortem diagnostic approaches, including histopathological examination, are essential in cases where the clinical cause of death is nonspecific or unclear, as they can uncover underlying fungal dissemination and provide critical insights for accurate identification of the cause of death and clinical decisions.
In conclusion, this case emphasizes the importance of recognizing the risk of invasive candidiasis in immunocompetent individuals undergoing prolonged hospitalization. Clinicians and forensic pathologists should be aware of the risk of fungal infections, especially when antibacterial treatments fail and microbiological evidence is limited, to improve diagnostic accuracy and prevent fatal outcomes.
Notes
Conflicts of Interest
Moon-Young Kim, contributing editor of the Korean Journal of Legal Medicine, was not involved in the editorial evaluation or decision to publish this article. The remaining authors declare no conflicts of interest.