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Hyperferritinemic Syndromes and Long COVID

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Marilena Stoian

Submitted: 08 November 2025 Reviewed: 30 January 2026 Published: 17 March 2026

DOI: 10.5772/intechopen.1014823

Long COVID - From Pathophysiology to Rehabilitation IntechOpen
Long COVID - From Pathophysiology to Rehabilitation Edited by Sara Palermo

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Long COVID - From Pathophysiology to Rehabilitation [Working Title]

Sara Palermo

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Abstract

Ferritin is a classic iron-binding protein, which is involved in human iron metabolism and possesses important pathogenic roles in the pathophysiology of hyperinflammatory conditions, such as catastrophic antiphospholipid syndrome (cAPS), systemic juvenile idiopathic arthritis (sJIA), adult-onset Still’s disease (AOSD), acquired forms of hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS), and severe COVID-19. According to recent studies, ferritin may also operate as a bioactive mediator or as a signaling molecule, which, consequently, explains the existence of specific receptors expressed by various cells. The concept of “hyperferritinemic syndrome” defines a complex pathophysiological and clinical entity, characterized by a systemic hyperinflammatory state, generally associated with elevated levels of proinflammatory cytokines (hypercytokinemia) and high serum levels of ferritin (hyperferritinemia). Severe forms of coronavirus disease-2019 (COVID-19), in which MAS may frequently develop, have also been linked to the development of a hyperferritinemic syndrome. If ferritin operates as a pathogenic proinflammatory mediator in COVID-19, it seems that certain therapeutic strategies should be performed, such as plasma exchange, which could prove beneficial in severe infection with SARS-CoV-2, as this would decrease the serum levels of both ferritin and proinflammatory cytokines. This review offers several insights into the pathophysiological roles of ferritin in several hyper-inflammatory diseases, particularly in Long COVID, the underlying pathophysiological mechanisms, clinical manifestations, and diagnostic features of somewhat obscure, yet potentially fatal pathological conditions, reunited under the concept of hyperferritinemic syndromes.

Keywords

  • hyperferritinemic syndrome
  • hyperinflammatory state
  • hypercitokinemia
  • immunosupression
  • long COVID

1. Introduction

The spectrum of hyperferritinemic syndromes is currently composed of a relatively small number of rare disorders or diseases, but it should be noted that hyperferritinemia, especially in the context of serum ferritin levels >1000 ng/mL, should raise interest into the clinical and biological investigation of a hyperferritinemic syndrome. The clinician, especially the internist, rheumatologist, infectious disease physician and intensive-care physician, should be aware of the pathophysiological role of ferritin in various inflammatory diseases and clinically and biologically recognize a hyperferritinemic syndrome and its possible causes, through a thorough physical examination of the patient and paraclinical analysis of various biological parameters, such as complete blood count, ESR, CRP and ferritin. Eventhough the pathophysiological roles of ferritin in the context of various rheumatological and/or infectious diseases is yet to be completely clarified, clinical medicine should raise its interest into the diagnostic usefulness of this particular biological parameter, as it has been suggested by multiple studies that it possesses important pathogenic proinflammatory and/or immunosuppressive roles in various inflammatory diseases or syndromes, especially in severe or critically-ill patients.

Ferritin is more than just an iron-storage protein: it is traditionally considered an iron-binding protein, being strongly involved in iron homeostasis and in the physiology of iron metabolism [1], along with other molecules such as transferrin, ferroportin, and hepcidin. This particular molecule, which has been described in all multicellular organisms and synthesized in multiple cells in humans, acts as a buffer against iron deficiency and iron overload, and is also involved in several pathophysiological mechanisms of a wide range of pathological conditions, such as infectious, inflammatory, and neoplastic diseases [2]. Ferritin is found in most tissues as a cytosolic protein, but small amounts are secreted into the serum, where it functions as an iron carrier. Plasma ferritin is also an indirect marker of the total amount of iron stored in the body; hence, serum ferritin is used as a diagnostic test for iron-deficiency anemia and iron overload. Aggregated ferritin transforms into a water-insoluble, crystalline, and amorphous form of storage iron called hemosiderin.

Ferritin is a globular protein complex consisting of 24 protein subunits, forming a hollow spherical nanocage with multiple metal–protein interactions. Ferritin, with iron removed, is called apoferritin.

2. General functional roles of ferritin

Ferritin is a globular protein complex consisting of 24 protein subunits forming a hollow spherical nanocage with multiple metal–protein interactions. Ferritin with iron removed is called apoferritin. Ferritin presents itself either as apoferritin, which is defined as the iron-free ferritin (the protein shell), or as holoferritin [3], which results from the chemical binding of apoferritin to the iron (Fe) element in its +3 oxidation state, known as the ferric cation: Fe3+. Therefore, apoferritin consists of two kinds of polypeptide subunits, called L-subunits or L-ferritin (FTL) and H-subunits or H-ferritin (FTH), respectively [3, 4]. It should be noted that the ratio of FTH to FTL varies widely, depending on the type of tissue in which it is expressed, but also on the functional status of the cell in which ferritin is synthesized; studies have shown that FTL is predominant in tissues such as the liver and spleen, whereas FTH is predominant in the heart and kidneys [4].

According to a study from 2002, the intracellular biosynthesis of ferritin is modulated by various cytokines at different levels: transcriptional, post-transcriptional, and translational, during embryogenesis, cellular differentiation, proliferation, and inflammatory phenomena [5]. The same study has shown that the expression of ferritin may be enhanced by other factors as well, such as increased oxidative stress, the activity of thyroid hormones, various growth factors and secondary messengers, hypoxia-ischemia phenomena and hyperoxia [5].

Each apoferritin molecule has the capacity to bind up to 4,500 Fe3+ [6]. By sequestering iron, ferritin is directly involved in iron homeostasis; through their ferroxidase activity, H-subunits of ferritin transform the toxic ferrous cation (Fe2+) into ferric cation (Fe3+), which is essentially less toxic to the cell [7].

Due to its high toxicity, iron, after being transported by serum transferrin at the cellular level, once present within the intracellular environment, is biochemically associated with various cytosolic proteins, such as poly-(rC)-binding protein-1 [8], which operates as a cytosolic chaperone involved in the delivery of iron to intracellular ferritin. The biochemical conversion of Fe2+ to Fe3+ is an essential part of iron homeostasis, as it limits the deleterious reaction that may occur between Fe2+ and hydrogen peroxide (H2O2) molecules, known as the Fenton reaction (Figure 1), which may increase the intracellular levels of a highly cytotoxic reactive radical, represented by the hydroxyl radical (HO-) [9].

Figure 1.

The Fenton redox reaction: ferrous iron (fe2+) reacts with hydrogen peroxide (H2O2), resulting in ferric iron (fe3+), hydroxyl radical (OH.), and hydroxide anion (OH-).

Although ferritin is mainly described at the intracellular level, this molecule has also been described in the serum [10]; however, under physiological conditions, its serum levels are clinically insignificant. Elevated serum levels of ferritin, however, may suggest the presence of an underlying pathological condition, such as inflammatory syndromes with multiple etiologies or genetic and transfusion iron-overload diseases [11], hemochromatosis being the most well-studied. According to one source [12], the normal values of serum ferritin, measured in nanograms per milliliter (ng/mL), may vary depending on sex and age (Table 1).

Normal serum ferritin values (ng/mL) Category
24–336 Adult male
24–307 Adult female
25–200 Newborn
200–600 1 month old
50–200 2 to 5 months old
7–140 Children aged 6 months to 15 years old

Table 1.

Normal serum ferritin values (ng/mL).

According to Ten Kate et al., in a study from 2001 regarding iron saturation of serum ferritin in patients diagnosed with AOSD, serum ferritin described in patients with iron-overload-associated conditions may have as little as 2% of the iron content of the intracellular form of ferritin [13]. Interestingly, according to a study from 1979, except for terminal stages of chronic liver disease (for example, end-stage cirrhosis), the increased levels of serum ferritin cannot be associated with cell damage or necrosis, as the usual markers of necrosis, such as cytoplasmic enzymes, are not present in the plasma when serum ferritin levels are increased [14].

In clinical settings, serum ferritin is frequently used in the differential diagnosis of anemia, but also as an essential indicator for multiple pathological conditions, including hereditary hemochromatosis, numerous inflammatory syndromes (infections, autoimmune and autoinflammatory diseases), neurodegenerative diseases, and malignant processes [2, 3, 15], with macrophages being considered the main cellular source of serum ferritin in mice [14, 16–18]. Studies in cellular and molecular biology have shown that the majority of proteins biosynthesized in eukaryotic cells, including ferritin, are secreted into the serum using the classical secretion pathway, which is comprised of the endoplasmic reticulum (ER) and Golgi apparatus [19, 20]. Further studies proved that serum ferritin is mainly secreted by macrophages, its secretion being regulated by at least one non-classical pathway, which uses secretory lysosomes [16] and the interaction with the nuclear receptor coactivator-4 (NCOA4), a selective autophagy receptor, which may also mediate the entry of ferritin into the lysosomes for degradation. Furthermore, it has been proved that NCOA4 has increased intracellular levels when cellular iron levels are decreased, whereas serum ferritin levels are elevated when the systemic levels of iron are high [21, 22]. However, the experimental knockdown of NCOA4 generated the increased secretion of ferritin from monocytic cells and macrophages, suggesting that other secretion pathways, including the ER-Golgi apparatus, may be involved in the cellular secretion process of ferritin; a potential NCOA4-independent secretory autophagy pathway has been described for both ferritin and interleukin-1β (IL-1β) [23] – one of the most important proinflammatory cytokines, along with tumor-necrosis factor-α (TNF-α), IL-6, and type I interferon (IFN).

Serum ferritin is currently considered, along with C-reactive protein, fibrinogen, and procalcitonin, an important acute-phase reactant, its levels being increased during the course of inflammatory processes and reflecting the degree of acute and chronic inflammation in various infectious, rheumatic, hematologic, or malignant diseases, as it was experimentally proved that cultured cells released ferritin into the surrounding environment when grown in the presence of IL-1β and TNF-α [24]. Hepatocytes, Kupffer cells, proximal tubular renal cells, and other tissue macrophages are strongly involved in the secretion of extracellular ferritin [16, 25, 26]. Noteworthy is that some studies suggest that serum ferritin is mainly represented by L-subunits (FTL or L-ferritin) [5, 16, 25], which are N-glycosylated, secondary to a post-translational process that occurs at the level of the Golgi apparatus [27]. Interestingly, the glycosylated fraction of serum ferritin was proved to be approximately 50% under normal conditions, although there are studies that have shown that in patients with AOSD, glycosylated FTL is ≤20% [27–30]. Such decreases in the glycosylation fraction were also described during the course of various hemophagocytic syndromes [31–33], drug-induced hypersensitivity reactions [34, 35] and severe infections [32]. The hypothesized mechanisms underlying the decreased glycosylated fraction of FTL include saturation of the normal glycosylation mechanisms within the cell [28]. Worwood et al. showed in 1979 that hepatic injury and subsequent hepatocytolysis determined decreased glycosylation in the biochemical structure of serum ferritin [36], similar molecular modifications being observed in the setting of tumor lysis syndrome and various hematologic malignancies [37, 38].

As mentioned above, serum ferritin is iron-poor, which suggests that this molecule has a role beyond its involvement in iron sequestration for the plasma variant [39]. Although it is highly unlikely that macrophages are the sole cellular sources of serum ferritin, there is evidence to support their fundamental role in its extracellular secretion; macrophage-mediated ferritin secretion has been proven to be directly connected with various human pathological conditions associated with inflammatory syndromes, as active secretion of ferritin by macrophages was described in the recovered bronchoalveolar lavage fluid during the course of smoking-induced lung inflammation [40]. Moreover, serum levels of CD163 (soluble CD163 or sCD163), an immunological marker of activated macrophages, are correlated with serum levels of ferritin in individuals diagnosed with AOSD and septic shock [41].

Although the exact functions of FTL remain to be established through future thorough investigations, there are studies suggesting that the L-subunits of ferritin have important roles in iron-binding in the plasma, but they may also manifest stimulatory effects on cellular proliferation, independent of iron availability [42].

Both FTL and FTH operate on particular cell surface receptors; hepatocytes express receptors which bind both FTL and FTH, while receptors expressed by other tissues show high affinity for FTH [43].

T-cell immunoglobulin and mucin domain-2 (TIM-2), a molecular member of the T-cell TIM gene family involved in the regulation of immune responses, has been described as the receptor for FTH endocytosis, being expressed by B and T cells, hepatocytes, and nephrocytes [26, 44]. Another identified cell surface receptor for ferritin is represented by Scara-5, defined as a scavenger receptor involved in binding various ligands; however, Scara-5, in contrast to TIM-2, mediates the preferential binding of FTL [45].

3. Serum increase of FTH during infectious processes

Studies have proven that the increase in serum ferritin has the ability to limit iron availability to various pathogenic agents during the course of an infectious process [46–48], thus restricting bacterial growth and the progression of the infection. This explains the high mortality rate in individuals diagnosed with a particular infectious disease who are given iron supplementation [49]. Furthermore, it should be noted that in patients who express high pathogen loads, there is a decrease in systemic iron levels, a state defined as hypoferremia, and elevated serum ferritin (hyperferritinemia) [50]. According to a study performed by Alvarez-Hernández et al., the aforementioned biological modifications during infectious processes may be generated experimentally by injection with IL-1α or TNF-α, these proinflammatory cytokines having well-documented effects on macrophage iron uptake, storage, and recirculation [51]. The M1-macrophages, a potent proinflammatory phenotype of macrophages, possess essential roles in this regard. Following their treatment with IFN-γ: the activity of iron-regulatory protein-1 and -2 (IRP-1 and IRP-2, respectively) is decreased, which determines the increase in FTH expression at the intracellular level; there is also an increase in the production of proinflammatory cytokines, such as TNF-α [52, 53]. Similar observations were made by Seifert et al., showing that there is an increase in macrophage biosynthesis of FTH in the presence of non-self agents, which not only limits the availability of iron to the pathogens but also decreases the intensity of local oxidative stress during inflammation [54].

The intracellular mechanisms of ferritin biosynthesis are, as described, responsive to the effects of various proinflammatory cytokines, influencing both the transcriptional and translational phases in different cells, such as hepatocytes, circulating monocytes, and tissue macrophages [25, 55, 56]. Fibroblasts that were exposed to various concentrations of TNF-α and IL-1α were shown to have an increase in FTH expression by influencing the molecular activity of the NF-ҡB signaling pathway [55, 57, 58] while IL-1β induced an increase in the expression of FTH in hepatocytes by binding to an enhancer region 70 bp from the start of the codon [59, 60].

4. The immunomodulatory roles of ferritin

4.1 The proinflammatory activity of ferritin

According to a study published in 2009 by Ruddell et al., which focused on experimentally activated hepatic stellate cells, FTH exhibits important immunoinflammatory properties, similar to those expressed by certain proinflammatory cytokines. FTH interacts with and binds to the TIM-2 receptor, which, at the intracellular level, activates mitogen-activated protein-kinase (MAPK)-induced NF-ҡB through an iron-independent mechanism, leading to an increase in mRNA and protein expression of multiple proinflammatory molecules. These include IL-1β (which was proven to be increased 50-fold), a 100-fold increase in inducible nitric-oxide (NO) synthase (iNOS), and RANTES (Regulated on Activation, Normal T-cell Expressed and Secreted, also known as chemokine C–C motif ligand-5 or CCL-5) – one of the most important proinflammatory chemokines involved in the recruitment of multiple immunoinflammatory cells, such as T-lymphocytes, eosinophils, NK-cells, dendritic cells, and mastocytes [61].

Furthermore, Ruscitti et al. experimentally proved, in a study published in 2020 regarding the pathophysiological involvement of ferritin in AOSD, that FTH increases the expression of NOD (nucleotide-oligomerization domain)-like receptor-3 (NLRP-3), as well as mRNA in macrophages, leading to the increased synthesis and secretion of various potent cytokines, most of which are proinflammatory in nature, such as IL-1β, IL-6, IL-10, IL-12, and TNF-α. It also increased the expression of transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) [62]. Regarding FTL, Ruscitti et al. showed that the L-chains of ferritin have insignificant effects on the expression of proinflammatory cytokines. In fact, according to a study from 2019 published by Zarjou et al., it appears that a compensatory increase in serum FTL, secondary to a decrease in FTH, may have important effects on lowering cytokine levels, which are associated with a reduced mortality rate in sepsis [63]. FTL was proven to induce the inhibition of NF-ҡB intracellular activity, which explains the inhibitory effect of FTL on the expression of proinflammatory mediators in the pathophysiology of sepsis and other hyperinflammatory conditions [63].

It should also be noted that, according to a more recent study from 2022, published by Brands et al., higher serum levels of ferritin correlate with aberrant cytokine responses. Thus, according to the study, patients with serum ferritin levels >500 ng/mL exhibited exaggerated cytokine production, such as IL-8, IL-10, IL-27, and IL-1 receptor antagonist (IL-1RA), but also expressed increased levels of biomarkers indicative of endothelial dysfunction and activation, reflecting the proinflammatory phenotype of endothelial cells: soluble vascular cell adhesion molecule-1 (sVCAM-1), von Willebrand factor, and s-thrombomodulin [64], which could generate a hypercoagulable state.

4.2 The immunosuppressive effects of ferritin

According to several studies, FTH has taken into consideration its immunosuppressive roles. As such, FTH appears to induce the suppression of the delayed type of hypersensitivity, a phenomenon involved in the induction of anergy [65], but also in the inhibition of antibody production by B-cells [66], inhibition of phagocytosis mediated by granulocytes, and in the regulation of granulocyto-monocytopoiesis [67].

Even though the immunosuppressive molecular mechanisms of ferritin currently remain elusive, there are studies which suggest that FTH may operate on particular lymphocyte surface receptors that are yet to be identified [43] or through the down-regulation of CD2, a molecule that operates as a co-factor for lymphocyte stimulation [68]. Furthermore, a study published by Gray et al. in 2001 suggested that ferritin may act as an immunosuppressive agent through its property to determine the secretion of the anti-inflammatory cytokine IL-10 in lymphocytes [69].

Other studies have suggested that FTH has the ability to interact with the CXC-chemokine receptor-4 (CXCR-4), which inhibits the intracellular activation of MAPK, thus impairing cell proliferation, differentiation, and migration during inflammation [70].

4.2.1 Causal entities of hyperferritinemic syndrome

According to Sandnes et al., in a clinical overview concerning hyperferritinemia, this biological state may be classified based on the iron load status of the organism (Table 2) [6].

Hyperferritinemia without iron overload Hyperferritinemia with or without iron overload Hyperferritinemia with iron overload
Cellular damage Cirrhosis Hereditary hemochromatosis
Inflammatory and infectious conditions: sepsis and septic shock, COVID-19 Alcoholic liver disease (ALD) Dysmetabolic iron overloading syndrome
Immune-mediated syndromes (primary and secondary HLH, AOSD) Non-alcoholic fatty liver disease (NAFLD) Iron-loading anemia (congenital or acquired)
Malignancy: solid and hematological Viral hepatitis B Iatrogenic iron overload (red blood cell transfusion, parenteral iron administration)
Benign hyperferritinemia Viral hepatitis C African iron overload
Gaucher disease Porphyria cutanea tarda Aceruloplasminemia/hypoceruloplasminemia

Table 2.

General classification of hyperferritinemia associated with various underlying pathological conditions (adapted from [6]).

It should be emphasized that, while hyperferritinemia should not be considered a clinical entity in itself and is biologically defined as the mere increased serum levels of ferritin (most frequently, serum ferritin >500 ng/dL) [71], which may or may not be associated with (hyper-)inflammatory conditions, hyperferritinemic syndromes define a group of complex pathophysiological and clinical entities in which hyperferritinemia – the biological hallmark of these conditions – is invariably associated with systemic hyperinflammation and a potentially fatal prognosis. It seems that, in the context of a hyperferritinemic syndrome, ferritin possesses important pathophysiological roles [71], being frequently associated with systemic hyperproduction of cytokines, as mentioned above.

Dramatic elevations of serum ferritin (often elevated above 1,000 ng/dL) [72] have been described in several hyperinflammatory conditions, such as autoimmune (for example, cAPS) and autoinflammatory diseases (particularly sJIA and AOSD), severe COVID-19 and/or multisystem inflammatory syndrome of COVID-19 (MIS) – which could be considered long-COVID or the post-COVID-19 syndrome (PCS) [73, 74], HLH, sepsis and septic shock, as well as cancer, which includes malignant hemopathies but also solid malignant tumors (Table 3) [75].

Diagnostic criteria for HLH – 5 out of 8 criteria required in the diagnosis
Cytopenia: affecting 2 or 3 lineages in peripheral blood: anemia, thrombocytopenia, leukopenia:

  • Hemoglobin <9 g/dL

  • Platelets (thrombocytes) <100,000/µL

  • Neutrophils <1000/µL
Fever: T°C ≥38.5°C
Hypertriglyceridemia; fasting serum triglycerides ≥265 mg/dLHypofibrinogenemia; serum fibrinogen ≤150 mg/dL
Hyperferritinemia; serum ferritin ≥500 ng/mL
Splenomegaly or hepatosplenomegaly
Soluble IL-2 receptor (sIL2R, CD25) >2,400 U/mL
Evidence of hemophagocytosis in bone marrow, spleen, lymph nodes, and/or liver biopsies

Table 3.

Shows the diagnostic criteria for HLH (HLH-2004 criteria).

5. Hemophagocytic lymphohistiocytosis (HLH, hemophagocytic syndrome)

Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome, is a rare, life-threatening hyperinflammatory syndrome characterized by uncontrolled hyperactivation of immune cells, aberrant hyperferritinemia, and gradual multiorgan damage [76]. The main pathogenic features of this pathological condition are the uncontrolled hyperactivity of T-cytotoxic lymphocytes and NK-cells, associated with hyperactivation of tissue macrophages (histiocytes) and systemic hyperproduction of proinflammatory cytokines, a state which has been termed “cytokine storm” or “cytokine release syndrome” (CRS) [76].

In adults, the general clinical features of HLH include high fever, rash, hepatosplenomegaly, lymphadenopathies, bleeding diathesis, sepsis-like syndrome, various degrees of neurological manifestations, and gradual progression toward multiple organ dysfunction syndrome (MODS) [77]. Biologically, patients with HLH generally exhibit high levels of acute phase reactants, such as elevated C-reactive protein and hyperferritinemia, altered liver function, high serum levels of triglycerides (hypertriglyceridemia), hypofibrinogenemia, bi or pancytopenia, elevated serum levels of D-dimers, and lactate dehydrogenase (LDH) [78].

5.1 Etiology

From an etiological perspective, HLH is divided into primary HLH (pHLH) and secondary HLH (sHLH). While pHLH is determined by various mutations in genes expressed by cytotoxic T-cells and NK-cells and clinically manifests mainly during infancy and childhood [79], sHLH may develop in the course of particular underlying pathological conditions, in which there is a violent immune or inflammatory response, such as infections, autoimmune and autoinflammatory diseases, and malignancy (hematological malignancies, solid malignant tumors) (Table 3).

pHLH is determined by genetic mutations in immune cells, with familial HLH (FHL) being considered the main subtype of pHLH [76]. There are currently five identified types of FHL (FHL-1, -2, -3, -4, and -5), with FHL-2 being the most commonly diagnosed type in Japan, according to one study [80]; this subtype has been proven to be caused by a defect in perforin, a cytotoxic molecule secreted by cytotoxic T-lymphocytes and/or NK cells [81]. In contrast to FHL-2, FHL-3, -4, and -5 are determined by genetically induced defects in molecules involved in cytotoxic granule trafficking and the release of perforin toward target cells, such as Munc13-4, syntaxin-11, and Munc18-2 [82, 83, 84]. FHL has been associated with autosomal recessive inheritance, although FHL-5 has been proven to be associated with a single allele mutation in Munc18-2 [85].

sHLH may be induced by multiple pathological conditions, such as infections, rheumatological diseases (autoimmune and autoinflammatory disorders), as well as malignancies (hematological malignancies and solid malignant tumors) [76], and is considered one of the most important hyperferritinemic syndromes. Epidemiological studies have shown that infectious diseases, most frequently viral infections, account for the most commonly encountered causes of sHLH [86–88], whereas solid malignant tumors and malignant hemopathies represent 40 to 70% of sHLH cases in adults, closely followed by systemic autoimmune and autoinflammatory diseases. In all of these cases, taking into consideration that the main pathophysiological mechanism of sHLH is defined by uncontrolled hyperactivity of macrophages (or histiocytes), associated with systemic hyperproduction of proinflammatory cytokines, sHLH is considered synonymous with the concept of macrophage activation syndrome (MAS or MAS-HLH), especially in the context of an underlying rheumatological (autoimmune or autoinflammatory) disease [89].

The most well-known rheumatological diseases that may determine the development of MAS-HLH are systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjӧgren’s syndrome, cAPS, but also sJIA and AOSD [90].

Even though autoimmune and autoinflammatory disorders possess important roles in potentially generating sHLH, studies show that various viral infections are considered the main causes of sHLH, most frequently Epstein-Barr virus (EBV), but also cytomegalovirus (CMV) and herpes-simplex virus (HSV) [91]. One case report also showed that HIV infection may generate HLH [92]. Recent studies suggest that SARS-CoV-2, the causal agent of COVID-19, as well as PCS, may also determine sHLH [93].

5.2 Pathophysiology

Subjects with active HLH exhibit dramatic elevation of various serum proinflammatory cytokines, such as IFN-γ, TNF-α, IL-1β, IL-2, IL-6, IL-12, IL-16, IL-18, and M-CSF, some of which are involved in the development of the clinical manifestations and biological modifications described in HLH, such as altered general state, high fever, vascular leak syndrome, (pan-)cytopenia, elevated serum levels of C-reactive protein (CRP), and hyperferritinemia [94–96]. Given the hyperinflammatory state associated with the dramatic elevation of serum proinflammatory cytokines (hypercytokinemia), this pathobiological phenomenon was termed “cytokine storm” or “cytokine release syndrome” (CRS), considered to be a violent systemic immuno-inflammatory response, which has been proven to be generated by uncontrolled activity of cytotoxic T-lymphocytes and NK-cells, which, in turn, overstimulate the activity of reticuloendothelial macrophages [76]. Subsequently, these histiocytes, once continuously hyperactivated, are involved in the development of hypercytokinemia, as well as hemophagocytosis, which may be described on biopsies from the bone marrow, spleen, lymph nodes, and/or liver in patients with HLH [71]. Regarding hemophagocytosis, this pathophysiological phenomenon defines the engulfment or hyperreactive phagocytosis of erythrocytes, lymphocytes, or other hematopoietic cellular precursors by (hyper-)activated reticuloendothelial macrophages or histiocytes, which may be described within the bone marrow, spleen, lymph nodes, or even liver [97]. This may lead to different forms of cytopenia (anemia, leukopenia/lymphopenia, and/or thrombocytopenia; if all hematopoietic cell lines are affected, the resultant phenomenon is defined as pancytopenia). As it is known, phagocytosis represents an immune process that involves attachment and binding of Fc antibody fragments and C3b complement fractions to particular receptors described on leukocyte membranes, engulfment, and subsequent intracellular fusion of lysosomes with phagocytic vacuoles, followed by cellular biochemical digestion of non-self-molecular elements [97]. Hemophagocytosis should be considered an overactivated form of phagocytosis, in which the increased activity of histiocytes may be described in infections, various inflammatory diseases (such as autoimmune and autoinflammatory conditions), and even in malignancies [98].

Although the precise pathophysiological pathways through which HLH develops and evolves are not well described or understood, recent studies suggest that NK-cells and cytotoxic T-lymphocytes become unable to lyse infected or otherwise activated antigen-presenting cells (APCs). Prolonged interactions between activated lymphocytes and tissue macrophages gradually lead to the amplification of a violent systemic cytokine cascade (cytokine storm syndrome), this loss-of-function of NK cells and cytotoxic T-lymphocytes being further worsened under the influence of the already developed hypercytokinemic state [61, 79].

Currently, it is believed that defects in NK-cell and cytotoxic T-lymphocyte granule-mediated cytotoxicity result in ineffective clearance of infectious agents and/or defective suppression of antigen presentation, which generates persistent antigen exposure and, thus, prolonged activation of T-lymphocytes and interaction with tissue macrophages [99]. Although the exact pathophysiological mechanisms of sHLH are not completely understood, one study showed that HLH-MAS could develop under the influence of persistent activation of Toll-like receptor-9 (TLR-9), as was shown in a murine model [100].

Hence, in HLH, there is a prolonged and exaggerated T-lymphocyte and tissue macrophage interaction and activation, which determines an overwhelming systemic secretion of proinflammatory cytokines, defined as a cytokine storm or cytokine release syndrome, characterized by dramatic serum elevations of immune mediators such as IL-1β, IL-6, TNF-α, IFN-γ, IL-8, IL-12, IL-18, and M-CSF [100]. There is also an uncontrolled proliferation of cytotoxic T-lymphocytes, a dramatic production of IFN-γ, and hyperproliferation of histiocytes, with subsequent invasion of reticuloendothelial organs such as the liver, spleen, bone marrow, and lymph nodes, a phenomenon which explains one of the most important clinical features in HLH: organomegaly, especially hepatosplenomegaly and lymphadenopathies [101]. By invading the bone marrow, hyperreactive histiocytes engulf hematopoietic cellular precursors, which generates hemophagocytosis and subsequent (pan-)cytopenia. These pathophysiological phenomena thus explain the name of this pathological condition.

While IFN-γ has been proven to induce macrophage hyperactivation and stimulate hemophagocytosis, TNF-α is thought to be a fundamental element in the development of hypofibrinogenemia and hypertriglyceridemia [101, 102]. Furthermore, there have been advances in the understanding of the immunosuppressive state in HLH; studies suggest that certain down-regulation of genes involved in the mechanisms of innate and adaptive immunity, with the participation of TLR expression in B and T-lymphocytes, may be a causal factor of this particular pathological state. As such, individuals diagnosed with HLH may express a susceptibility to various infections caused by the aforementioned immunodeficient state [103], which could result in the development of sepsis, septic shock, and MODS.

5.3 Clinical features and diagnosis

Patients with HLH exhibit systemic and non-specific clinical manifestations, such as altered general state with high-grade fever associated with shivers, progressive cytopenias (anemia, leukopenia/lymphopenia, thrombocytopenia), and liver dysfunction, which is generally expressed clinically through the presence of jaundice and coagulopathy. Coagulopathy may induce tissue ischemia and necrosis, but variable neurological manifestations are also observed in 30 to 50% of patients with HLH [104], including seizures, altered mental state, brain stem symptoms, and ataxia [105, 106]. This polymorphism of clinical aspects necessitates a differential diagnosis of this hyperinflammatory condition, which should be performed in comparison with severe infections and rheumatological diseases. Noteworthy is the fact that certain modified biological parameters should be taken into consideration, such as elevated serum levels of ferritin; a level >500 µg ferritin/L is considered supportive in the diagnosis of HLH [104], although this value is non-specific and may be present in various febrile diseases. However, dramatically increased levels of serum ferritin, >10,000 µg/L, are considered specific and diagnostic of HLH, with 90% sensitivity and 96% specificity [72]. Other markers also serve as useful elements in the diagnosis of HLH, such as serum elevation of certain proinflammatory cytokines (IFN-γ, IL-10, and especially IL-6) and increased serum levels of soluble CD163 (sCD163), which represents an immunological marker of monocyte/macrophage activation [107, 108].

Table 3: HLH-2004 diagnostic criteria (adapted from [71]).

It appears that the diagnosis of MAS-HLH associated with rheumatological diseases is more challenging, taking into consideration that there is a high rate of overlap between these immunopathological conditions and MAS [109]. Furthermore, serum ferritin levels used in the diagnosis of HLH have proven to be fundamental; serum ferritin levels > 3,000 ng/mL should raise high suspicion of MAS-HLH [72, 110].

6. Catastrophic antiphospholipid syndrome (cAPS)

Catastrophic antiphospholipid syndrome (cAPS) constitutes a severe and rare form of antiphospholipid syndrome (APS), characterized by disseminated thrombotic vascular phenomena at the level of multiple tissues, gradually leading to MODS [111] and affecting < 1% of patients diagnosed with APS. Epidemiological data have shown that cAPS mainly affects women, in 72% of all cases, with a mean age of 39 years [105]. (Figure 2)

Figure 2.

Etiology and general pathophysiological mechanisms in cAPS (adapted from [112]).

From a clinical perspective, patients with cAPS express almost simultaneous multiple organ involvement, most frequently within a week, having positive antiphospholipid antibodies, although the clinical features strongly depend on the type of affected organ and organ systems [105]. These organs and systems include: kidney, manifested by acute kidney injury and renovascular hypertension; skin, manifested by ischemic ulcers, livedo reticularis, and/or gangrene; central nervous system, manifested by ischemic cerebrovascular events or stroke; liver, manifested by ischemic hepatitis; respiratory system, manifested by pulmonary embolism or acute respiratory distress syndrome; heart system, manifested by circulatory myocardial infarction, determined by acute coronary thrombosis. Modified biological parameters may be observed, such as thrombocytopenia, increased serum levels of D-dimers, hyperferritinemia, hemolytic anemia, and increased serum creatinine levels, in the presence of antiphospholipid antibodies. Thrombotic microangiopathy, which is the main pathological finding in APS (and cAPS), is frequently observed on biopsies.

The general diagnostic criteria for cAPS, which require the differential diagnosis and exclusion of other causal entities involved in multiple microthromboses, include:1. multiple organ involvement (more than 3 organs, tissues, systems); 2. synchronous clinical manifestations or clinical onset within a week; 3. pathological evidence of thrombotic microangiopathy on biopsy; 4. positive antiphospholipid antibodies [113]. All four criteria are required for cAPS diagnosis. The pathological conditions considered in the differential diagnosis are disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), heparin-induced thrombocytopenia (HIT), sepsis, various forms of systemic vasculitis, and HELLP syndrome (Hemolysis – Elevated Liver enzymes – Low Platelet count) in pregnant women [113].

Regarding hyperferritinemia, this biological feature was observed in 71% of patients diagnosed with cAPS; approximately one-third of all patients with cAPS exhibit a dramatic increase in serum ferritin levels (>1000 ng/mL) [114].

7. Adult-onset still’s disease (AOSD)

Adult-onset Still’s disease (AOSD) constitutes a rare multisystemic autoinflammatory disorder, clinically characterized by high recurrent fever, evanescent skin rash, lymphadenopathies, polyarthralgia, occasional hepatosplenomegaly, sore throat, and biologically by the existence of high-grade inflammation, with leukocytosis with neutrophilia and hyperferritinemia [115, 116].

7.1 Etiology

7.1.1 Genetic factors

Numerous studies have described a strong association between AOSD and HLA alleles, such as HLA-Bw35, HLA-B17, HLA-B18, HLA-B35, and HLA-DR2, expressed in various ethnic groups [117–120]. Interestingly, polymorphisms in genes involved in the biosynthesis of IL-18, serum amyloid A1, and macrophage inhibitory factor (MIF) have also been described, with these polymorphisms generating the high susceptibility of individuals with AOSD [121–124].

7.1.2 Infectious agents

Clinical observations and multiple studies over the years have proved that various infections, especially viral infections, are potential risk factors and triggers in the development of AOSD, most probably due to the existence of similar clinical manifestations, such as high fever, sore throat, and rash before the onset or relapse of the disease [125, 126]. Some of the viral entities which have been associated with the development of AOSD are rubella virus, measles morbillivirus, mumps virus, EBV, CMV, parvovirus B19, adenovirus, echovirus, human herpes virus-6, influenza virus, and coxsackievirus. It should be noted, however, that some other infectious agents have been described as potential triggers, such as Yersinia enterocolytica, Campylobacter jejuni, Chlamydia trachomatis, Chlamydia pneumoniae, Mycoplasma pneumoniae, and Borrelia burgdorferi [127–132]. Noteworthy is the fact that it appears that CMV infection is strongly associated with the initiation and amplification of the inflammatory response in AOSD [133].

7.2 Pathophysiology: AOSD-associated MAS, cytokine storm, and the pathogenic role of ferritin

AOSD is currently considered a classic hyperferritinemic syndrome, characterized by the existence of a cytokine storm, this pathophysiological phenomenon being involved in the activation and amplification of systemic inflammation [116, 124, 125]. The major pathogenic role in AOSD is possessed by reticuloendothelial macrophages and neutrophils, along with NK-cells and T-lymphocytes, all of these immune cellular elements being involved in the hyperactivated inflammatory response [125].

Individuals with AOSD generally express hyperactivation of tissue macrophages (hyperactivation of the reticulohistiocytic system or MAS), a pathogenic phenomenon biologically reflected in the elevated levels of various biomarkers, including MIF and IFN-γ [134, 135]. It has been suggested that the continuous hyperactivation of histiocytes is a direct result of their persistent molecular interaction with either pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) [136, 137]. The pathogenic role of several DAMPs has been well described in the pathophysiology of AOSD; these include high mobility group box-1, advanced glycation-end (AGE) products, S100 proteins, soluble CD163, MIF, as well as neutrophil extracellular traps (NETs) [137], all of these elements being involved in the hyperactivation of macrophages through their molecular and functional interaction with TLR, leading to the activation of several intracellular signaling systems, including NLRP3 inflammasomes. NLRP3 inflammasomes, once activated, are involved in the upregulation of caspase-1, leading to the proteolytic cleavage of two fundamental cytokines: IL-1β and IL-18, which results in the production of their mature functional forms [136, 138, 139]. The extracellular secretion of IL-1β and IL-18 further determines the immune cells to secrete large amounts of serum proinflammatory cytokines, including IL-6, IL-8, IL-17, TNF-α, but also IL-1β and IL-18 themselves [136, 138, 140].

Regarding ferritin, this particular molecule is produced, as mentioned, by multiple cellular types, including macrophages, hepatocytes, and liver histiocytes (Kupffer cells) [141], and may operate as a proinflammatory cytokine [61]. From a pathogenic perspective, ferritin may activate an iron-independent intracellular molecular cascade, which determines the activation of a complex system known as phosphatidylinositol-3-kinase – nuclear factor kappa-B (PI3K-NF-ҡB); once activated intracellularly, this system amplifies the expression of various proinflammatory molecular mediators, such as IL-1β, iNOS, RANTES, inhibitor of NF-ҡB, and intracellular adhesion molecule-1 in hepatic stellate cells (Ito cells) [61]. It should also be noted that ferritin itself is molecularly regulated by various cytokines, including IL-1β [59, 142]. Although more studies should be performed, it is currently believed that ferritin possesses essential roles in the initiation and amplification of systemic inflammation in AOSD, operating even as an oxygen radical donor [143].

Other pathophysiological mechanisms in AOSD have been described as well, such as neutrophil activation associated with increased NETs formation, NK-cells deficiency and T-lymphocytes imbalance [144].

7.3 Clinical features and diagnosis

Patients with AOSD generally exhibit several frequently encountered clinical manifestations, such as high recurrent fever, arthritis and/or polyarthralgia (this may induce frequent confusion with rheumatoid arthritis, which explains the necessity of a thorough differential diagnosis), evanescent skin rash, sore throat, odynophagia, myalgia, myositis, lymphadenopathies, and hepatosplenomegaly. Additionally, some patients may also exhibit other associated yet more severe manifestations, including pericarditis, myocarditis, pleuritis, and/or hepatitis [144]. Occasionally, individuals with AOSD may develop life-threatening systemic complications, such as pulmonary hypertension, fulminant hepatitis, heart failure, ARDS, DIC, and thrombotic microangiopathy [116, 126, 145].

Among laboratory findings, CRP and erythrocyte sedimentation rate (ESR) are almost always constantly elevated [71]. Very high serum levels of ferritin are closely related to the disease activity and are associated with recurrent flares, clinical and biological manifestations of MAS, as well as with poor prognosis [146–148]. It appears that dramatic elevations of serum ferritin higher than five times the upper limit of normal values, if combined with a decrease in the proportion in the glycosylated fraction of ferritin (<20%), increase the specificity of AOSD to 93% [116, 145, 146]. Furthermore, significant leukocytosis, with > 15,000 leukocytes/mm3, may be described, being associated with neutrophilic predominance [71].

The most frequently used diagnostic criteria for AOSD are the Yamaguchi criteria: fever > 39 °C for more than 1 week; arthralgia or arthritis for more than 2 weeks; typical salmon evanescent skin rash; leukocytosis > 10,000/mm3 with > 80% polymorphonuclear cells; hepato-splenomegaly; negative serum levels of anti-nuclear antibodies or rheumatoid factor; altered liver function tests; recent onset of lymphadenopathies; sore throat.

Serum proinflammatory cytokine levels, such as IL-1β, IL-6, IL-18, TNF-α, and IFN-γ, are dramatically increased in AOSD and are generally associated with the activity of the disease [133, 149, 150]. Clinical and biological observations have shown that, among these proinflammatory cytokines, IL-18 is considered to be an essential biomarker in the diagnosis of AOSD [151, 152]. Studies have shown that increased levels of serum IL-18 are associated with hepatitis, steroid dependence, and inflammatory pattern [152, 153], while increased serum levels of IL-1β have been associated with systemic pattern, and increased serum levels of IL-6 are associated with the existence of arthritis [150, 154].

8. Septic shock

Sepsis is defined as a life-threatening multiple organ dysfunction induced by the host’s violent systemic immune response to various disseminated infections, according to the International Consensus Definitions for Sepsis and Septic Shock [155]. It is well-known that the immune reaction to different infections causes the systemic hyperproduction of both proinflammatory and anti-inflammatory cytokines, generating variable degrees of systemic inflammatory response syndrome (SIRS) and compensatory anti-inflammatory response syndrome (CARS).

During the course of the infectious process, activated macrophages hyperproduce serum ferritin after being stimulated by IL-1β and TNF-α, with NF-ҡB being the main intracellular signaling system involved [156]. Intuitively, further immune dysregulation and systemic inflammation are expected, as serum ferritin levels above 4,420 ng/mL generate the systemic increase of IL-6, IL-18, IFN-γ, and sCD163, indicative of an exaggerated proinflammatory response [157], which most probably generates a vicious proinflammatory cycle, aggravating the condition.

9. Severe COVID-19

The hallmark of severe COVID-19 is represented by a hyperinflammatory immune response characterized by dramatic serum elevations of IL-1β, IL-1RA, and TNF-α. It is well known that critically ill patients exhibit neutrophilia, lymphopenia, and very increased levels of IL-6 [158], which suggests the existence of a CRS or MAS, similar to sHLH or AOSD. In severe COVID-19, the mechanism involves a delayed IFN response mediated by multiple structural and non-structural proteins associated with SARS-CoV-2, this phenomenon further orchestrating immune reactions and interfering with T-lymphocytes, generating T-cell apoptosis. It is also described as a heavy accumulation of monocyte-macrophages, as well as neutrophils, in the pulmonary parenchyma following coronaviral infection, these immune cellular elements being important sources of proinflammatory cytokines and chemokines [159].

Mehta et al. proposed that COVID-19 may be an important member of the hyperferritinemic syndromes, as CRS characterizes the severe forms of the disease in a similar manner to sHLH or AOSD [160]. It seems that highly increased serum levels of ferritin are an essential biological tool in the diagnosis of COVID-19 severity, while also suggesting a worse prognosis, in which case hyperferritinemia is virally driven [161]. Ferritin is most probably operating as a proinflammatory cytokine – whose secretion is induced by various proinflammatory cytokines – in severe COVID-19, in a similar or identical manner to AOSD, leading to a “MAS-like syndrome” in severe COVID-19.

Several studies focused on autopsy findings in COVID-19 patients; macroscopic features in autopsies included pleurisy, pericarditis, lung consolidation, and pulmonary edema [162], whilst microscopic findings described diffuse alveolar damage associated with heavy inflammatory infiltrates constituted mainly by monocyte-macrophages, with minimal lymphocyte infiltration, but with the presence of multinucleated giant cells [163, 164]. It should be noted that similar pathological findings – pleurisy and pericarditis, have also been described in patients with AOSD and MAS [165, 166].

Currently, there are studies that describe common pathophysiological phenomena between severe COVID-19 and AOSD, as the COVID-19-associated hyperinflammatory state resembles the hyperinflammatory state associated with AOSD [125]. According to a study by Fung S. Y. et al. regarding IL-1β, SARS-CoV-2 has been shown to possess the pathogenic property of upregulating the intracellular activity of the inflammasome, which generates the hyperproduction of IL-1β, a pathophysiological feature also described in AOSD [167].

Macrophages, as it was shown, are involved in the hyperproduction of proinflammatory cytokines and might also be involved in the hyperproduction of serum ferritin [3]. As described in the present review, ferritin biosynthesis may be induced by proinflammatory cytokines, including IL-6 [3]. This aspect is noteworthy, as serum levels of IL-6 may be dramatically increased in severe COVID-19, with this proinflammatory cytokine being used as a useful parameter associated with COVID-19 severity [168].

If ferritin operates as a pathogenic proinflammatory mediator in COVID-19, it seems that certain therapeutic strategies should be implemented, such as plasma exchange, which could prove beneficial in severe infection with SARS-CoV-2, as this would decrease the serum levels of both ferritin and proinflammatory cytokines [169].

10. Emotional stress and the risk of anxiety or depression in patients with hyperferritinemic syndromes or Long COVID

In hyperferritinemic syndromes and Long COVID, the emotional symptoms are linked to complex biological factors (like iron accumulation or inflammation) as well as the psychosocial burden of chronic illness. In hyperferritinemic syndromes, conditions involving iron overload, such as hereditary hemochromatosis (HC), can lead to mental health issues through several mechanisms:

  • Direct neurological impact: Excess iron can accumulate in brain tissues, specifically the basal ganglia, potentially damaging neurons, disrupting neurotransmitter function (e.g., dopamine, serotonin), and causing oxidative stress.

  • Common symptoms: Anxiety, depression, mood swings, irritability, brain fog, and chronic fatigue are recognized symptoms of HC.

  • Impact on quality of life: The physical symptoms of HC (joint pain, fatigue, liver issues) and the management of the condition can also contribute to psychological distress.

  • Treatment effects: While iron depletion therapy can prevent or reverse organ damage, a study found that mental health issues may persist even after iron levels are managed.

  • Comorbidities: Active adult-onset Still’s disease (AOSD), another condition characterized by high ferritin, has also been linked to anxiety and depression, which negatively impact the patient’s quality of life.

In Long COVID, anxiety and depression are among the most common neuropsychiatric symptoms reported. The link is considered to be multidimensional:

  • Biopsychosocial effects: The mental health impact stems from a combination of the direct biological effects of the virus and the psychological consequences of the illness, such as social isolation, financial insecurity, and caregiver burnout.

  • Neuroinflammation: The SARS-CoV-2 virus can trigger inflammation in the brain or cause inflammatory molecules from the body to cross the blood-brain barrier. This neuroinflammation can damage brain cells and alter mood-regulating neurocircuitry and neurotransmitter metabolism, contributing to anxiety and depression.

  • Altered iron homeostasis: One study found that altered iron homeostasis and unresolved inflammation were strong early indicators of persistent symptoms in Long COVID patients, linking iron dysregulation to ongoing health issues.

  • Pre-existing risk factors: Individuals with pre-existing mental health conditions or prior psychological distress are at a higher risk of developing Long COVID.

  • Symptom burden: The persistence of physical symptoms (fatigue, breathlessness, etc.) is strongly correlated with higher levels of anxiety and depression.

In both hyperferritinemic syndromes and Long COVID, emotional stress, anxiety, and depression are significant concerns. The mechanisms involve both the direct physiological effects of the underlying conditions (iron accumulation or inflammation) and the broader psychological and social challenges associated with managing a chronic or prolonged illness. That is why a multidisciplinary approach is necessary to ensure good physical and psychological functionality for patients with Long COVID and hyperferritinemic syndromes.

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Submitted: 08 November 2025 Reviewed: 30 January 2026 Published: 17 March 2026

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