Invasive fungal disease presenting as septic shock in immunocompromised pediatric and adult patients: summary of reported cases

Abstract

Introduction: Septic shock is a very rare presentation of invasive fungal disease (IFD) in immunocompromised patients. The objective of this paper was to summarize reported cases of pediatric and adult patients with IFD presenting as septic shock in non-Candida infections. Literature data describing etiology, age, and outcome of septic shock as a presentation of IFD, is summarized. Material and methods: The available pediatric data included 23 patients, most of them with underlying non-hematological disease. Results: Only 6/23 (26.1%) were reported to survive this infection. Respective data in adults with invasive fungal disease presenting as septic shock were reported in 28 patients. Most of these patients were treated for acute leukemias (including three patients after hematopoietic cell transplantation); only 5/28 (17.9%) survived the infection. Conclusion: Invasive fungal disease presenting as septic shock in immunocompromised patients is a highly unusual presentation.

Introduction

Patients after allogeneic hematopoietic cell transplantation (allo-HCT) belong to a high-risk group of invasive fungal disease (IFD) [1]. The distribution of pathogens in an allo-HCT setting include aspergillosis in 55–60%, candidiasis in 25–30%, mycormycosis in 7–8%, and rare species e.g. fusariosis, scedosporiosis, geotrichosis in 2–3% [2]. With the widespread introduction of antifungal prophylaxis with azoles, this epidemiology is tending to change, with the rise of rare and sporadic species. No major differences in etiology between children and adults have been reported [3–6], although in one study the incidence of IFD after allo-HCT was significantly higher in children than in adults [6]. Regardless of age, patients in the following groups are considered high-risk for IFD: acute myeloblastic leukemia (AML); recurrent acute leukemia; allogeneic hematopoietic stem cell transplantation; and high risk acute lymphoblastic leukemia (ALL) [4, 5, 7–9]. Coexisting cytomegalovirus replication increases the risk of fungal complications [9].

Clinical symptoms of IFD in immunocompromised patients are dependent on the localization of the infection, which in most cases involves the lungs, abdomen, paranasal sinuses, skin or brain. In most cases, general symptoms occur including fever, followed by other systemic symptoms and laboratory markers of severe infection (e.g. C-reactive protein, procalcitonin). Fungemia or fungal sepsis might occur in a case of bloodstream infection with Candida; nonetheless septic shock is an infrequent presentation [10]. The objective of this paper was to analyze a series of cases of pediatric and adult patients with non-Candida IFD presenting as septic shock.

Material and methods

Studies and case reports regarding non-Candida invasive fungal disease presenting as septic shock in pediatric and adult patients were searched for in ‘PubMed’. Search queries included ‘invasive fungal disease’ OR ‘invasive fungal infection’ AND ‘septic shock’. The following data was retrieved from these reports: number of patients, age, gender, underlying disease, identification of fungal etiology, antifungal therapy, and treatment outcome.

Papers were included into analysis according to the diagnosis made by the respective authors. No additional judgment of sepsis and/or septic shock was made. According to the Third International Consensus Definitions for Sepsis and Septic Shock, sepsis was defined as ‘life-threatening organ dysfunction caused by a dysregulated host response to infection’ [11]. Septic shock was defined as ‘a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone’. Patients with septic shock can be clinically identified by the presence of two factors: the need to use a vasopressor and increased serum lactate concentration despite adequate volume resuscitation [11].

Results

Literature data describing etiology, age and outcome is very limited. The available pediatric data includes 22 patients, most of them with an underlying non-hematological disease (Table I) [12–22]. Only 6/22 (27.3%) are reported to have survived this infection, including 2/4 with acute leukemia. Etiology of the infection was highly variable, however infection with Saprochaete spp. (formerly Geotrichum spp., now proposed as Magnusiomyces spp.) presenting as septic shock was reported in four children, all with acute leukemias. Only two of them survived the infection. IFD-related non-Candida septic shock was reported also in 28 adults (Table II) [21, 23–40]. Among them, high mortality has been observed, with only 5/28 (17.9%) patients survival.

Table I. Literature data on septic shock in children with invasive fungal disease

Source	Age	Primary disease	Etiology	Treatment	Outcome
Zeng et al., 2021 [12]	Median age 22 months; age range: 3–44 months in 12 children	Various	Talaromyces marneffei	Amphotericin B 7/11 Itraconazole 2/11 Fluconazole 2/11 Voriconazole 3/11 Caspofungin 3/11	Died 9/12 Cured 3/12
Romanio et al., 2017 [13]	1-year-old boy	Down’s syndrome in postoperative period of congenital cardiac disease correction	Saccharomyces cerevisiae	Amphotericin B	Alive
Watson et al., 2016 [14]	12-year-old girl	Juvenile idiopathic arthritis	Blastomyces	Amphotericin B, adjunctive inhaled amphotericin; liposomal amphotericin B was changed to amphotericin B lipid complex	Died
El Dib et al., 2014 [15]	5-year-old boy		Coccidioidomycosis	Patient died before receiving required antifungal therapy	Died
Cavalcante et al., 2014 [16]	10-year-old girl	JSLE	Cryptococcus neoformans	Amphotericin B (liposomal) (3 mg/kg)	Died
França et al., 2012 [17]	14-year-old girl	JSLE	Histoplasma capsulatum	Amphotericin B (liposomal) (1 mg/kg)	Died
Pereira et al., 2004 [18]	2-year-old girl	Lymphoproliferative syndrome	Paracoccidioides brasiliensis	Intravenous sulfamethoxazole-trimethoprim (10 mg/kg trimethoprim)	Died
Hsu et al., 1998 [19]	23-month-old boy	AML	Trichosporon beigelii	Amphotericin B	Died
Wee et al., 2019 [20]	13-year-old boy	ALL	Saprochaete clavata	Amphotericin B and voriconazole (10 weeks)	Alive
	17-year-old boy	AML	Saprochaete clavata	Amphotericin B (60 mg/d)	Died
Parahym et al., 2015 [21]	15-year-old boy	AML	Saprochaete capitata	Caspofungin, amphotericin B (lipid) (5 mg/kg) (24 days), and voriconazole (400 mg/d)	Alive
Trabelsi et al., 2015 [22]	17-year-old boy	AML	Saprochaete capitata	Amphotericin B (60 mg/d)	Died

ALL — acute lymphoblastic leukemia; AML — acute myeloid leukemia; JSLE — juvenile systemic lupus erythematosus

Table II. Literature data on septic shock in adults with invasive fungal disease

Source	Age	Primary disease	Etiology	Treatment	Outcome
Caldas et al., 2022 [23]	43-year-old woman	Crohn’s disease on treatment with infliximab and azathioprine	Saprochaete clavata, Legionella pneumo­phila serogroup 1	Amphotericin B (liposomal)	Died
Duarte et al., 2021 [24]	66-year-old woman	AML	Saprochaete capitata	Amphotericin B (liposomal) and flucytosine	Died
Lo Cascio et al., 2020 [25]	20-year-old woman	ALL	Saprochaete clavata	Caspofungin	Died
Buchta et al., 2019 [26]	Patient 1 — 45-year-old man Patient 2 — 61-year-old woman Patient 3 — 58-year-old woman Patient 4 — 50-year-old woman Patient 5 — 66-year-old woman	1 — AML after allo-HCT 2 — AML 3 — AML after allo-HCT 4 — AML after auto-HCT 5 — DLBCL	1 — Saprochaete clavata 2 — Saprochaete clavata 3 — Saprochaete clavata 4 — Saprochaete clavate (+ Candida albicans were cultivated from nasopharyngeal swab) 5 — Saprochaete clavata + Candida glabrata	1 — amphotericin B (1 mg/kg) 2 — amphotericin B (1 mg/kg), amphotericin B (lipid) (5 mg/kg) 3 — amphotericin B (0.7–1 mg/kg), amphotericin B (lipid) (5 mg/kg), voriconazole (2 × 200 mg) 4 — amphotericin B (0.7–1 mg/kg) 5 — micafungin (100 mg), voriconazole (2 × 200 mg)	1 — died 2 — survived (but died from early relapse of AML later) 3 — died 4 — died 5 — died
Ben Neji et al., 2019 [27]	39-year-old man	AML	Saprochaete capitata	Amphotericin B (deoxycholate)	Died
Alobaid et al., 2019 [28]	67-year-old woman	Diabetes, hypertension, ischemic heart disease, left ventricular failure, peripheral vascular disease, bronchial asthma and obstructive sleep apnea	Saprochaete capitata	No antifungal therapy	Died
Bansal et al., 2018 [29]	29-year-old woman	AML	Saprochaete capitata	Amphotericin B (liposomal)	Died
Hajar et al., 2018 [30]	82-year-old man	Kidney transplant recipient	Saprochaete capitata	Amphotericin B (liposomal)	Died
Pamidimukkala et al., 2017 [31]	48-year-old woman	Biphenotypic acute leukemia	Saprochaete capitata concomitant Enterococcus gallinarum		Died
Fernández-Ruiz et al., 2017 [32]	55-year-old man	Refractory acute leukemia	Saprochaete capitata	Amphotericin B and voriconazole	Died
Del Principe et al., 2016 [33]	50-year-old woman	Mantle cell lymphoma	Saprochaete clavate	Amphotericin B (liposomal) (3 mg/kg), 47 days	Died on day 60 from chemotherapy initiation because of lymphoma progression
Subramanya Supram et al., 2016 [34]	Patient 1 — 77-year-old woman Patient 2 — 80-year-old man	Patient 1 — hypertension, Alzheimer’s disease Patient 2 — COPD, hypertension	Patient 1 — Saprochaete capitata + + Flavobacter spp. (endotracheal aspirate) Patient 2 — Saprochaete capitata	Patient 1 — no antifungal therapy Patient 2 — fluconazole (400 mg/day for 4 days)	Patient 1 — died Patient 2 — died
Trabelsi et al., 2015 [22]	Patient 1 — 25-year-old woman Patient 2 — 57-year-old man	AML	Saprochaete capitata	Patient 1 — amphotericin B (60 mg/d) Patient 2 — amphotericin B (80 mg/d) + voriconazole (2 × 200 mg)	Patient 1 — died Patient 2 — died
Picard et al., 2014 [35]	Patient 1 — 46-year-old woman Patient 2 — 70-year-old man Patient 3 — 63-year-old woman	AML	Saprochaete clavata	Patient 1 — amphotericin B (liposomal) and voriconazole Patient 2 — caspofungin Patient 3 — amphotericin B (liposomal) and voriconazole	Patient 1 — survived septic shock, died because of hemorrhage Patient 2 — died Patient 3 — died
García-Ruiz et al., 2013 [36]	55-year-old man	ALL	Saprochaete capitata	Amphotericin B (liposomal) (4 mg/kg/d) + voriconazole	Died
Saghrouni et al., 2012 [37]	47-year-old man	AML	Saprochaete capitata	Amphotericin B (1 mg/kg) for 14 days followed by voriconazole 2 × 200 mg	Died
Avelar Rodriguez et al., 2017 [38]	28-year-old man	Cocaine abuse and Child-Pugh class C alcoholic liver cirrhosis	Rhinocerebral mucormycosis, Candida glabrata	Amphotericin B (liposomal) 3 mg/kg	Died
Fernández- -Ruiz et al., 2017 [32]	56-year-old man	Solid cancer, abdominal surgery, prolonged ICU stay	Wickerhamomyces anomalus	Amphotericin B for 9 days followed by fluconazole for 5 days)	Alive
Taniguchi et al., 2009 [39]	18-year-old man	Mitochondrial encephalomyopathy accompanied by refractory anemia and chronic renal failure	Lecythophora mutabilis	Micafungin 5 mg/kg, amphotericin B (liposomal) (3 mg/kg)	Died
Hennequin et al., 2000 [40]	47-year-oldman	Adenocarcinoma of lower esophagus	Saccharomyces boulardii	Fluconazole (100 mg/d) initiated on day 35 for six weeks	Alive

ALL — acute lymphoblastic leukemia; allo-HCT — allogeneic hematopoietic cell transplantatin; AML — aute myeloid leukemia; auto-HCT — autologous hematopoietic cell transplantatin; COPD — chronic obstructive pulmonary disease; DLBCL — diffuse large B-cell lymphoma; ICU — intensive care unit

Discussion

Invasive fungal infections represent a serious medical problem worldwide and are a major cause of morbidity and mortality in patients with hematological malignancies. Other immunocompromised patients are also at high risk of IFD mainly because of the increased use of immunosuppressive and cytotoxic therapies, as well as improved diagnostic techniques. Candida and Aspergillus spp. are major causative agents.

However, with the new prevention strategies, new species are increasingly being reported as agents of bloodstream infections (BSI) or disseminated fungal disease. While Candida spp. is the most common etiology of fungal BSI and septic shock, such presentation is rare in case of other fungal pathogens.

Septic shock is the most dangerous presentation of infection, bringing the risk of poor prognosis. In this paper, we have searched for patients with non-Candida invasive fungal infection presenting as septic shock. We have found a limited number of reports, both in children and adults.

Septic shock is always a medical emergency. It requires the immediate administration of antimicrobials. Usually, bacterial etiology is suspected and adequate empirical treatment broadly covering the most probable pathogens is promptly started. In immunocompromised patients, in the presence of severe infection with symptoms of septic shock, atypical agents including fungal etiology should also be considered. One should also be aware of mixed etiology of septic shock in patients.

The most striking finding of our analysis is the low survival of patients, as only 26.1% of children and 17.9% of adults survived fungal infection with septic shock. Even with the long time period of inclusion, this survival rate was low in comparison with the outcome of IFD seen in leukemic patients both in the first [3, 41] and second [42, 43] decades of this century.

Immunocompromised patients, especially those with hematological malignancy who develop septic shock caused by fungal infection, are at very high risk of mortality. There are two options to improve therapeutic effect. Firstly, starting the empirical antifungal therapy as soon as possible is essential to increase the chance of survival in these patients. Secondly, it is recommended that early source control, including catheter removal, is a key factor influencing the outcome of leukemic or transplant patients with septic shock or sepsis of fungal etiology [4, 8].

The limitation of this study was the heterogenous population in terms of primary diagnosis, primary treatment, and etiology of fungal infection. We also limited the analysis to non-Candida etiology, because the symptoms of sepsis are relatively more frequent in Candida bloodstream infection.

Conclusion

Septic shock is a very rare presentation of fungal infection in immunocompromised patients, but the mortality is very high both in children and adults.

Authors’ contributions

KC, JS — design of study. RD, MRP, KC — provision of clinical data. All authors — analysis of clinical data. TS, JS — literature search and analysis of data. TS, JS — writing manuscript. All authors — critical revision and final approval.

Conflict of interest

The authors declare no conflict of interest.

Financial support

None.

Ethics

The work described in this article has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans; EU Directive 2010/63/EU for animal experiments and uniform requirements for manuscripts submitted to biomedical journals.