Hyperinflammatory Syndrome of Unknown Origin Complicated by Shock,DIC,Intracranial Hemorrhage and Spontaneous Splenic Rupture: A Case Report

Abstract

Hyperinflammation syndrome is a life-threatening condition of heterogeneous etiology. Common manifestations include fever, organomegaly, leukopenia or leukocytosis and malaise. We would like to present a rare case of hyperinflammatory syndrome of unknown origin complicated by shock, severe coagulopathy, spontaneous splenic rupture, and intracranial hemorrhage. A 24-year-old man with no past medical history was admitted to intensive care unit presenting with hemodynamic instability, severe acidosis, splenomegaly, bi-cytopenia, with significantly elevated inflammatory markers. Broad spectrum microbiology, hematology and genetic tests were performed to identify a trigger. Due to presence of both sepsis and hemophagocytic lymphohistiocytosis features (HLH), sepsis-HLH overlap syndrome was suspected. Aggressive treatment (broad-spectrum antibiotics, immunomodulation therapy, therapeutic plasma exchange and renal replacement therapy) was instantly initiated. Despite that, shock and profound disseminated intravascular coagulopathy exacerbated. Unexpected splenic rupture and intracranial hemorrhage required urgent surgical intervention, along with amputation of distal foot phalanges due to severe ischemia. Treatment in the intensive care unit lasted 40 days. One year after a discharge from ICU, patient still required neurological rehabilitation and orthopedic treatment. We do hope that this case will make clinicians more aware of HLH and sepsis-HLH overlap syndrome. Further research is required to improve treatment of severe hyperinflammation.

Keywords

hyperinflammation hyperinflammation syndrome hyperferritinemia splenomegaly spontaneous splenic rupture disseminated intravascular coagulation hemophagocytic lymphohistiocytosis sepsis and HLH simultaneously sepsis-HLH overlap syndrome sepsis of unknown origin case report

1. Introduction

Hyperinflammation syndrome of unknown origin represents a complex and challenging clinical scenario in critical care medicine. Due to the wide scope of differential diagnoses, patients presenting with hyperinflammation require thorough and systematic evaluation. One rare but critical cause is Hemophagocytic Lymphohistiocytosis (HLH), a severe and life-threatening disorder characterized by an uncontrolled systemic hyperinflammatory response resulting from impaired immune regulation. A wide variety of trigger mechanisms such as genetics, proliferative process, infections, autoimmune diseases, iatrogenic factors were defined.^1,2 Despite the heterogeneous etiology, HLH leads to the uncontrolled cytokine storm syndrome (CCS) and multiorgan failure. The HLH syndrome could be difficult to recognize due to sepsis-like manifestations. Differential diagnosis in critically ill patients becomes particularly challenging when Hemophagocytic Lymphohistiocytosis (HLH) overlaps with another hyperinflammatory condition, such as in sepsis-HLH overlap syndrome (SHLHOS). We present the case of a young man who developed an overwhelming hyperinflammatory response of unknown origin, ultimately leading to a cascade of fatal complications.

2. Case Report

Patient Information

A 24-year-old man with no relevant past medical history was transferred to the intensive care unit (ICU) from the emergency department due to rapidly progressing respiratory failure and cardiovascular instability, requiring vasopressor support. His presentation was notable for bi-cytopenia (leukopenia and thrombocytopenia). The patient had no recent travel history or known immunosuppression. Symptoms began the evening prior to admission and included high-grade fever, photophobia, abdominal pain, nausea, and generalized weakness.

Clinical Findings, Diagnostics

On admission, the patient was alert (Glasgow Coma Scale 15), with no focal neurological deficits. He exhibited upper abdominal tenderness without peritoneal signs, cold diaphoretic skin, and a prolonged capillary refill time. Initial computed tomography (CT) of the head, chest, abdomen, and pelvis revealed splenohepatomegaly and signs of organ hypoperfusion but no clear source of infection.

Laboratory findings on admission revealed bi-cytopenia (WBC 1.83 × 10⁹/L, PLT 9 × 10⁹/L), markedly elevated inflammatory markers (CRP 86.2 mg/L with the range 0-10 mg/l, procalcitonin [PCT] 46.9 ng/mL with the range 0-0,49 ng/ml, ferritin 5,445 µg/L), and severe metabolic acidosis (base excess -16.5 mmol/L, lactate 13.5 mmol/L). Despite early aggressive management, including fluid resuscitation, renal replacement therapy, and empirical broad-spectrum antibiotics (meropenem and vancomycin), the patient’s condition deteriorated rapidly.

Within hours, he developed profound coagulopathy: antithrombin III 35%, platelets <10 × 10⁹/L, hypofibrinogenemia (<30 mg/dL), and APTT beyond the measurable range (>500 s). D-dimer was >10,000 µg/L. International Society on Thrombosis and Haemostasis (ISTH) Criteria for Disseminated Intravascular Coagulation (DIC) score was eight (compatible with overt DIC).³ Thromboelastometry confirmed a severe deficiency of clotting factors (Figure 1.) supporting a diagnosis of fulminant disseminated intravascular coagulation (DIC) with fibrinolytic phenotype. Digital purpura was observed. Transfusions of prothrombin complex concentrate, cryoprecipitate, fibrinogen, and platelet concentrates were administered to facilitate invasive procedures.

Figure 1.

Thromboelastometry of the patient at admission to intensive care unit revaeled profound deficiency of clotting factors

Multi-organ failure progressed with acute liver and kidney injury (anuria, ALT 2005 U/L, AST 1554 U/L, bilirubin 4.51 mg/dL, INR 5.05). Repeat laboratory testing eight hours later showed markedly elevated inflammatory markers: ferritin 10180 µg/L, PCT 172,5 ng/mL, and IL-6 >50,000 pg/mL (above assay detection limit) (Table 1.). The constellation of hyperferritinemia, cytopenia, hypofibrinogenemia, and splenohepatomegaly was strongly suggestive of sepsis-associated hemophagocytic lymphohistiocytosis overlap syndrome (SHLHOS).^4-6 The Hscore scale was calculated to estimate the probability of HLH. At the ICU admission it indicated only a 40–54% probability of HLH (164 points). But repeated evaluation eight hours later, showed an increase up to 70% (179 points).⁷ A co-existence of hemophagocytic syndrome was very possible.

Table 1.

Comparison of Hemophagocytic Lymphohistiocytosis, Systemic Inflammatory Response Syndrome and Sepsis Stages Criteria

Hemophagocytic Lymphohistiocytosis	SIRS and Sepsis Stages
HLH-2024 criteria (≥5)	SIRS
- fever ≥38.5◦ C	-temperature >38°C or <36°C
- fever ≥38.5◦ C	- heart rate > 90/min
- splenomegaly (≥2 cm below the costal margin)	- respiratory rate >20/min or PaCO₂ <32 mmHg
- splenomegaly (≥2 cm below the costal margin)	-WBC >12,000/mm³, <4,000/mm³, or >10% bands
- cytopenias (affecting ≥2/3 lineages in the peripheral blood: hemoglobin <90 g/L; platelets <100 × 109/L; neutrophils <1.0 × 109/L	-WBC >12,000/mm³, <4,000/mm³, or >10% bands
	Sepsis
	- SIRS criteria + suspected or present source of infection
- hypertriglyceridemia and/or hypofibrinogenemia: fasting triglycerides ≥3.0 mmol/L and fibrinogen ≤1.5 g/L	- SIRS criteria + suspected or present source of infection
	Severe Sepsis
	- sepsis criteria
- hemophagocytosis (in bone marrow, spleen, or lymph node)	- lactic acidosis
- ferritin ≥500 μg/L	- SBP <90 or SBP drop ≥40 mm Hg of normal
	Septic Shock
	- severe sepsis with hypotension, despite adequate fluid resuscitation
- sCD25 (ie, soluble interleukin-2 receptor) ≥2400 U/mL
H-score criteria
- temperature ≥38.5^◦C
- organomegaly: hepatomegaly or/and splenomegaly
- number of cytopenias: hemoglobin ≤9.2 g/dL and/or WBC ≤5,000/mm³ and/or platelets ≤110,000/mm³
- ferritin ≥ 2000 ng/mL
- triglycerides ≥ 132,7 mg/dl
- fibrinogen ≤ 250 mg/dL
- AST≥30 U/L
- hemophagocytosis features on bone marrow aspirate

Therapeutic Intervention and Outcomes

High-dose methylprednisolone and intravenous immunoglobulin (IVIG) therapy were initiated. By day 3, the patient required dual vasopressor therapy (norepinephrine and vasopressin) and mechanical ventilation for worsening respiratory failure. Therapeutic plasma exchange (TPE) was initiated. All microbiological cultures remained negative, prompting the addition of empirical antiviral (acyclovir), antifungal (micafungin), and atypical bacterial coverage (clarithromycin and doxycycline).

Peripheral ischemia worsened, likely due to the combined effects of vasopressor therapy, hypoperfusion, and DIC, ultimately resulting in partial bilateral distal foot phalanges amputations within three weeks.

On day 9, the CT evaluation was performed, due to unexpected drop of haemoglobin in arterial blood gas (ABG). Imaging showed spontaneous splenic rupture with intra-abdominal hemorrhage, which required emergent laparotomy and splenectomy with blood transfusions. Histopathology showed: (1) subtotal necrosis of the splenic pulp with diffuse hemorrhage, (2) sinus histiocytosis in a mesenteric lymph node, and (3) extensive hepatic necrosis (∼90%) consistent with hypoperfusion injury (Figure 2).

Figure 2.

Serial changes in laboratory markers relevant to the diagnosis of haemophagocytic syndrome during the first eight days of hospitalization

In the following days serial head CT scans revealed a left frontal intracerebral hemorrhage with mass effect, correlating with clinical signs of right-sided hemiplegia and impaired responsiveness. On day 15, decompressive craniectomy was performed. The patient gradually improved with persistent right hemiplegia and partial aphasia.

The ICU stay lasted 40 days. All notable incidents are presented at the timeline (Figure 3). During hospitalization the patient required intensive rehabilitation, psychological, psychiatric, and clinical speech therapist support. He was discharged from the hospital to the neurorehabilitation center with hemiplegia and aphasia features.

Figure 3.

The timeline of notable events over the hospitalization

Despite extensive diagnostic workup and interdisciplinary evaluation, no definitive trigger for the overwhelming hyperinflammatory response could be identified (Figure 4).

Figure 4.

Investigations undertaken for differential diagnosis of hyperinflammatory syndrome

ED – emergency department, ICU – intensive care unit, RRT – renal replacement therapy, NA – noradrenaline, HNIG – human normal immunoglobulin, TPE - total plasma exchange.

Follow up Nine months after ICU discharge, the patient continues to require neurological and orthopaedic care, along with intensive rehabilitation. The neurological recovery is improving. He is currently awaiting the implantation of prosthetic devices.

3. Discussion

An excessive hyperinflammatory process is a frequent phenomenon in critically ill patients.^8,9 A wide variety of trigger factors ie: infections, cancers, autoimmune disorders, genetic defects as well as iatrogenic factors are related with severe dysregulation of immune homeostasis.¹⁰ Progressing multiorgan failure induced by a cytokine storm demands quick and accurate differential diagnosis. The identification of pathologic trigger, targeted treatment and organ sustained are crucial to reduce fatal outcomes. An initial clinical management based upon signs and symptoms is complicated when features of different syndromes mimics (sepsis and HLH), or overlaps – like in SHLHOS.^5,11,12 Severe HLH and septic stages (sepsis/septic shock) are both conditions with dysregulated immune response and familiar, nonspecific signs and symptoms (Tab.1.).^12,13 However, they differ in pathophysiological mechanism and inflammatory cytokine profile.¹⁴ Therefore, the strategies of HLH and sepsis treatment are significantly different.^11,15,16

According to Sepsis-3 criteria, sepsis is a life-threatening condition of concurrent infection and organ dysfunction due to dysregulated host response to infection.¹³ It can evolve into more severe septic shock.¹⁷ Throughout the years it is still leading cause of mortality among critically ill patients worldwide. First consensual definition was established in 1991, and first guidelines were released in 2004. Actual recommendations of Surviving Sepsis Campaign were published in 2021.^13,17,18

HLH is a rare, life-threatening disorder characterized by uncontrolled systemic hyperinflammatory response, often followed by multiorgan failure. First description was published in 1939 by Oxford’s doctors Ronald Bodley Scott and A.H.T. Robb-Smith, as histiocytic medullary reticulosis.^19,20 The actual HLH name appeared nearly 45 years later, when Janka proposed it in 1983.^21,22 The HLH condition is usually as primary (familial, genetic) - more common in infants and young children, and secondary (acquired, triggered by infections, tumors, autoimmune diseases, or immune checkpoint inhibitors) – common in adolescents and adults (Table 2).¹⁴

Table 2.

Secondary Hemophagocytic Lymphohistiocytosis - Triggers and Associated Diseases

Malignancy	Congenital immunodeficiency syndromes
-Hematologic: Lymphoma, Leukemia	- severe combined immunodeficiency,
- Solid	- severe combined immunodeficiency,
- Solid	- DiGeorge syndrome,
Autoimmune diseases	- Wiskott–Aldrich syndrome,
- Systemic lupus erythematosus - Adult-onset Still’s disease - Rheumatoid arthritis - Vasculitis - Inflammatory bowel disease	- Wiskott–Aldrich syndrome,
	- ataxia–telangiectasia
	- dyskeratosis congenita
Infections (commonly associated)	Transplantation
- Viruses: EBV, CMV, herpes viruses, HIV, Viral hepatitis, Influenza, Human Parvovirus B19 - Bacteria: Mycobacterium tuberculosis, Rickettsia spp, Staphylococcus spp, E. coli	- Kidney,
	- Bone marrow transplant
	Other
- Fungi: Histoplasma	Other
- Fungi: Histoplasma	- Drugs
- Parasites: Toxoplasma spp, Babesia spp, Plasmodium spp, Leishmania spp	- Drugs
	- Surgery or biopsies
	- Vaccination or acute injuries
	- Diabetes or chronic liver disease
	- Pregnancy
	Idiopathic or unknown

Epidemiology of HLH is difficult to estimate, due to sophisticated diagnostic, misclassification and limited adult HLH data.²³ In 2023, the USA retrospective cohort study was published, which identified 16,136 adult HLH non-elective admissions between 2006-2019.²⁴ Two peaks of morbidity were observed among young adults (16-30 years) and older adults (56-70 years). In-hospital mortality reached 18,4%. A trigger or an associated condition was unidentified in 35,8% of patients. Poor prognosis, variations across age, sex, race groups and underlying causes were also noted.²⁴

The underlying defect in HLH subtypes is an impaired down-regulation activity of Natural-Killer (NK) cells and cytotoxic T cells with prolonged macrophages activity in a result. Hence, the level of circulating immune complexes and antibodies arises, the vicious proinflammatory cytokinemia perpetuating.^25-27 Recently, HLH-related cytokines and factors ie: IFN-γ, Janus kinase-signal transducer and activator of transcription (JAK-STAT), IL-6, TNF-α, IL-1, IL-18, CD52, CD20 and programmed cell death protein 1 (PD-1), have been better-described.²⁷ Hopefully, it may improve treatment strategies in the future.^27-29

Diagnosis of HLH is based upon revised HLH-2024 criteria.³⁰ Recognizing 5 of 7 below criteria need to be fulfilled: fever ≥38.5◦ C, splenomegaly (≥2 cm below the costal margin), cytopenias (≥2/3 lineages in the peripheral blood with hemoglobin <90 g/L, platelets <100 × 10^9/L; neutrophils <1.0 × 10^9/L), hypertriglyceridemia ≥3.0 mmol/L and/or hypofibrinogenemia ≤1.5 g/L, ferritin ≥500 μg/L, sCD25 (ie, soluble interleukin-2 receptor) ≥2400 U/mL and/or hemophagocytosis in bone marrow, spleen, or lymph node.³¹ However, abovementioned abnormalities could be observed also in early sepsis.

Distinguishing between sepsis and HLH is highly difficult as none of them have pathognomonic biomarker. Diagnostic complications might be met, as a source of hyperinflammation remained unknown. Unfortunately, the culture negative sepsis is the most common type of sepsis among septic patients.^32-34 The most supportive parameter may be extreme hyperferritinemia, which is the most characteristic feature of HLH, but not a specific one. There is no a consensual threshold for extreme hyperferritinemia, ranges vary between studies.³⁵ Important difference is that the ferritin concentration in sepsis and septic shock does not reach values as high as in HLH. The ferritin values characteristic for HLH are often >7000 to 10 000 µg/L.^12,36,37 Another useful diagnostic tool in clinical practice is the H-score for Reactive Hemophagocytic Syndrome. Analyses reported that both the H-score and HLH-2004 criteria have good diagnostic accuracy in critically ill adults.¹⁴ The best prediction accuracy for a HLH diagnosis was found for 4 HLH- 2004 criteria (95.0% sensitivity and 93.6% specificity) and HScore cutoff of 168 (100% sensitivity and 94.1% specificity).^7,38

The HLH treatment depends on the underlying causes and should be tailored promptly after confirmation of the diagnosis.¹² A promising diagnostic marker CD38high/HLA-DR+ CD8+ T cells, has been described recently. Its increased frequency in flow cytometric assessment appeared to be optimal factor to identify active HLH from early sepsis. A threshold of >7% CD38high/HLA-DR+ cells among CD8+ T cells resulted in 100% sensitivity and 89% specificity in distinguish HLH from early sepsis patients.^16,39,40

Our patient presented both features of severe septic shock and HLH, so the SHLHOS diagnosis was taken under consideration (Tab. 1). The diagnostic path chosen at patient’s admission is presented at the flowchart (Figure 5.). Although initial diagnostic did not confirm co-existence of sepsis and HLH, a double-aim treatment was implemented, due to further patient deteriorating. Despite the aggressive, intensive therapy and broad-spectrum antimicrobial treatment, the early empiric immunomodulation was applied due to fulminant, progressing multiorgan failure. Recommendations strongly suggest early use of glucocorticoids, the recombinant IL-1 receptor antagonist anakinra, and/or the intravenous immunoglobulin at the early stages of suspected HLH.⁴¹ A spontaneous spleen rupture (SSR) and an intracranial hemorrhage were complications related to the hyperinflammatory syndromes. SSR also known as nontraumatic or atraumatic splenic rupture, is rare but described entity. Is associated with infections, malignancies or inflammatory conditions. In our case, combination of severe shock (general hypoperfusion), extreme inflammatory response (massive antigenic activation, extremely high leukocytosis - leukostasis) and microthrombi (due to profound DIC) made spleen highly fragile and more susceptible to self-damage.⁴² The combination of overwhelming cytokine storm, coagulopathy and low platelet counts is a high-risk factor for spontaneous hemorrhages in critically ill patients with severe hyperinflammation.¹⁵

Figure 5.

Diagnostic pathway at admission when sepsis-HLH overlap syndrome was suspected

SHLHOS – sepsis-HLH overlap syndrome. TG – triglyceride. AST – aspartate aminotransferase.

The final outcomes of extensive microbiological, haematological, and genetic investigations were negative (Figure 4). The underlying cause of the severe hyperinflammatory response remains unidentified. Nevertheless, the implementation of a dual, empirical treatment strategy likely contributed to the patient’s survival and favourable clinical trajectory.^24,26

4. Conclusions

The HLH and sepsis may have similar acute manifestations but required a different treatment approach. A management of HLH, and other hyperinflammatory syndromes, should include three major compounds: immunomodulatory treatment to prevent organ damage, actively search for underlying causes and treat a possible trigger factor of immune dysregulation.³¹ Further research is required to improve treatment of severe hyperinflammation. Novel targeted therapies should concentrate on reducing an excessive activation of key role cytokines and signaling pathways, hence increase survival rate.²⁷

Supplemental Material

Supplemental Material - Hyperinflammatory Syndrome of Unknown Origin Complicated by Shock, DIC, Intracranial Hemorrhage and Spontaneous Splenic Rupture: A Case Report

Supplemental Material for Hyperinflammatory Syndrome of Unknown Origin Complicated by Shock, DIC, Intracranial Hemorrhage and Spontaneous Splenic Rupture: A Case Report by Zofia Serafinowicz, Jarosław Gadomski, Paweł Andruszkiewicz and Mateusz Zawadka in Clinical Medicine Insights: Case Reports.

Footnotes

ORCID iD

Mateusz Zawadka

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Supplemental material

Supplemental material for this article is available online.

Appendix

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