Cytokine storm syndromes (CSS) are a group of disorders representing a variety of inflammatory causes. The clinical presentations of all CSS can be strikingly similar, creating diagnostic uncertainty. However, clinicians should avoid the temptation to treat all CSS equally, because their inciting inflammatory insults vary widely. Failure to identify and address this underlying trigger results in delayed, inoptimal, or potentially harmful consequences. This review places the hemophagocytic syndromes hemophagocytic lymphohistiocytosis and macrophage activation syndrome within a conceptual model of CSS and provides a logical framework for diagnosis and treatment of CSS of suspected rheumatic origin.
Objectives
After reading this article, the reader should be able to:
- 1.
Identify clinical similarities and differences between the variety of cytokine storm syndromes
- 2.
Describe the clinical and immunologic hallmarks of macrophage activation syndrome and hemophagocytic lymphohistiocytosis
- 3.
Describe a pathoetiologic framework for understanding cytokine storm syndromes.
The final common pathway
History
In the days before germ theory, the term sepsis (from the Greek sepo , “I rot”) was applied to all states of uncontrolled inflammation. Today, sepsis is reserved to refer to overwhelming inflammation in the context of a systemic infection (although even this definition can be ambiguous). The term cytokine storm syndrome (CSS) was developed to accommodate the observation that multiple inflammatory causes can result in a disease that appears similar to sepsis. The unifying feature of CSS is a clinical and laboratory phenotype suggestive of massive inflammation, progressing to multiple organ dysfunction syndrome (MODS) and eventually death, a final common pathway.
Examination and Laboratory Findings
The clinical constituents of this pathway can include fever, tachycardia, tachypnea, hypotension, malaise, generalized swelling, altered mental status, diffuse lymphoadenopathy, organomegaly (particularly of the liver and spleen), and often erythematous or purpuric rash. In response to the desire by intensive care practitioners to standardize hemodynamic management of CSS, criteria for systemic inflammatory response syndrome (SIRS) were proposed in 1992 and have been amended several times, notably to accommodate pediatric practice ( Table 1 ).
| SIRS | |
|---|---|
| Presence of at least 2 of the following 4 criteria Must include abnormal temperature or leukocyte count | |
| Core temperature | >38.5°C or <36°C |
| Abnormal heart rate | >2SD more than normal for age a or |
| unexplained persistent increase over 0.5-h to 4-h period, or | |
| for children <1 year old: heart rate <10th percentile for age a or | |
| unexplained persistent heart rate depression over a 0.5-h period | |
| Respiratory rate | >2SD more than normal for age or |
| acute requirement for mechanical ventilation | |
| Leukocyte count | Increased or depressed b for age or |
| >10% immature neutrophils | |
a Not explained by external stimuli or drugs.
CSS also have several common laboratory abnormalities. Hematologic parameters like leukocytosis or thrombocytosis can indicate the acute phase response. Alternatively, increased cell counts can decrease precipitously as a feature of nearly all CSS, suggesting consumption. Clinicians can also take advantage of a host of nonspecific acute phase reactants, including erythrocyte sedimentation rate (ESR), C-reactive protein, procalcitonin, serum amyloid A, ferritin, and fibrinogen among others. Akin to acute cytopenias, an acute decrease in ESR and fibrinogen is most associated with macrophage activation syndrome (MAS), but can be seen in any CSS and often suggests active disseminated intravascular coagulopathy (DIC). Screens for coagulopathy such as fibrin split products and d-dimer are often increased in CSS even in the absence of overt DIC, suggesting subclinical endothelial activation. Likewise, hypoalbuminemia is frequently observed and likely represents systemic capillary leak. Routine testing often reflects various organs in distress, including the liver, pancreas, and kidneys. Such tests are rarely capable of distinguishing direct inflammatory damage from that induced by insufficient oxygen delivery.
The Elusive Hemophagocyte
Hemophagocytes are activated macrophages seen histologically to be have engulfed other hematopoietic elements (erythrocytes, leukocytes, or platelets ( Fig. 1 )). Hemophagocytes are the pathologic hallmark of hemophagocytic lymphohistiocytosis (HLH) and MAS. However, hemophagocytes are not essential to the diagnosis of HLH and can be seen in juvenile patients with arthritis without overt MAS. In addition, hemophagocytes are found commonly in a host of other inflammatory states including sepsis and after bone marrow transplant. Whether hemophagocytes are inflammatory, antiinflammatory, or serve different roles in differing diseases is a matter of ongoing study.
The final common pathway
History
In the days before germ theory, the term sepsis (from the Greek sepo , “I rot”) was applied to all states of uncontrolled inflammation. Today, sepsis is reserved to refer to overwhelming inflammation in the context of a systemic infection (although even this definition can be ambiguous). The term cytokine storm syndrome (CSS) was developed to accommodate the observation that multiple inflammatory causes can result in a disease that appears similar to sepsis. The unifying feature of CSS is a clinical and laboratory phenotype suggestive of massive inflammation, progressing to multiple organ dysfunction syndrome (MODS) and eventually death, a final common pathway.
Examination and Laboratory Findings
The clinical constituents of this pathway can include fever, tachycardia, tachypnea, hypotension, malaise, generalized swelling, altered mental status, diffuse lymphoadenopathy, organomegaly (particularly of the liver and spleen), and often erythematous or purpuric rash. In response to the desire by intensive care practitioners to standardize hemodynamic management of CSS, criteria for systemic inflammatory response syndrome (SIRS) were proposed in 1992 and have been amended several times, notably to accommodate pediatric practice ( Table 1 ).
| SIRS | |
|---|---|
| Presence of at least 2 of the following 4 criteria Must include abnormal temperature or leukocyte count | |
| Core temperature | >38.5°C or <36°C |
| Abnormal heart rate | >2SD more than normal for age a or |
| unexplained persistent increase over 0.5-h to 4-h period, or | |
| for children <1 year old: heart rate <10th percentile for age a or | |
| unexplained persistent heart rate depression over a 0.5-h period | |
| Respiratory rate | >2SD more than normal for age or |
| acute requirement for mechanical ventilation | |
| Leukocyte count | Increased or depressed b for age or |
| >10% immature neutrophils | |
a Not explained by external stimuli or drugs.
CSS also have several common laboratory abnormalities. Hematologic parameters like leukocytosis or thrombocytosis can indicate the acute phase response. Alternatively, increased cell counts can decrease precipitously as a feature of nearly all CSS, suggesting consumption. Clinicians can also take advantage of a host of nonspecific acute phase reactants, including erythrocyte sedimentation rate (ESR), C-reactive protein, procalcitonin, serum amyloid A, ferritin, and fibrinogen among others. Akin to acute cytopenias, an acute decrease in ESR and fibrinogen is most associated with macrophage activation syndrome (MAS), but can be seen in any CSS and often suggests active disseminated intravascular coagulopathy (DIC). Screens for coagulopathy such as fibrin split products and d-dimer are often increased in CSS even in the absence of overt DIC, suggesting subclinical endothelial activation. Likewise, hypoalbuminemia is frequently observed and likely represents systemic capillary leak. Routine testing often reflects various organs in distress, including the liver, pancreas, and kidneys. Such tests are rarely capable of distinguishing direct inflammatory damage from that induced by insufficient oxygen delivery.
The Elusive Hemophagocyte
Hemophagocytes are activated macrophages seen histologically to be have engulfed other hematopoietic elements (erythrocytes, leukocytes, or platelets ( Fig. 1 )). Hemophagocytes are the pathologic hallmark of hemophagocytic lymphohistiocytosis (HLH) and MAS. However, hemophagocytes are not essential to the diagnosis of HLH and can be seen in juvenile patients with arthritis without overt MAS. In addition, hemophagocytes are found commonly in a host of other inflammatory states including sepsis and after bone marrow transplant. Whether hemophagocytes are inflammatory, antiinflammatory, or serve different roles in differing diseases is a matter of ongoing study.
Causes
An analysis of the underlying pathoetiology of all CSS supports this simple but essential postulate: cytokine storm results from excessive proinflammatory stimuli, inadequate regulation of inflammation, or elements of both. Proinflammatory stimuli can include antigens, superantigens (compounds that trigger nonspecific but massive activation of T-cell receptors), adjuvants (such as toll-like receptor [TLR] ligands; for an excellent review of TLRs in infection and autoimmunity see Ref. ), allergens (antigens triggering an allergic response), and proinflammatory cytokines themselves. Antiinflammatory mechanisms can be humoral or cellular and seek to dampen or terminate a proinflammatory pathway. Table 2 provides several examples of both proinflammatory stimuli and antiinflammatory mechanisms. Defects leading to excessive proinflammatory or inadequate antiinflammatory responses can be host-derived or environmental.
| Proinflammatory Agents | |
|---|---|
| Antigens | Antibody or B-cell receptor epitopes Peptides presented on MHC |
| Adjuvants | TLR ligands LPS, bacterial DNA, dsRNA, flagellin, etc Other PRR ligands Microbial nucleic acids Inflammasome triggers Uric acid crystals, hyperglycemia, ATP |
| Cytokines/chemokines | IL-1β, IL-6, IL-12, IL-18, TNFα, IFNγ,… |
| Antiinflammatory Agents | |
|---|---|
| Cells | Regulatory T cells Alternatively activated macrophages B10 B cells |
| Cytokines | IL-10, TGFβ, IL-1ra |
| Molecules | Antimicrobial peptides |
Host Factors
Conventional immunodeficiencies
Because sepsis is common among otherwise immunologically normal hosts, it is easy to forget that there are likely hundreds of genetic and epigenetic risk factors for the development of sepsis. Patients with immunodeficiencies should be considered at risk for CSS by virtue of their inability to effectively clear the proinflammatory elements of an infection. Persistent infection provides a rich source of both antigen and adjuvant, which, as the infection worsens, can quickly overwhelm the ability of the body to regulate inflammation.
The primary immunodeficiencies encompass defects in both innate and adaptive immunity and include entities such as severe combined immunodeficiency (SCID), X-linked agammaglobulinemia, common variable immunodeficiency, chronic granulomatous disease, and complement component deficiencies (see http://www.immunodeficiencysearch.com/ for a thorough, searchable review of immunodeficiency syndromes ). Other host-derived immunodeficiency states such as extremes of age and malnutrition can contribute to the inability to effectively clear inflammatory stimuli.
Familial HLH
Familial HLH (fHLH) is a CSS usually occurring in younger children who present with immense inflammation, pancytopenias, and other features of the final common pathway. Such patients’ disease is usually triggered by viral infection, and patients are unable to effectively clear the virus. fHLH, by definition, occurs in individuals with little to no ability of their natural killer (NK) cells and cytotoxic T cells to kill targeted cells. The genetic defects associated with fHLH all relate to the packaging, exocytosis, or function of cytotoxic granules ( Table 3 ), with perforin gene defects being the most common and best studied. Similar to patients with SCID, children with fHLH eventually succumb to their illness without allogeneic bone marrow transplantation. Animal models of HLH suggest that uncontrolled activation of cytotoxic T cells by antigen-presenting cells (APCs) drives the disease, with interferon-γ (IFN-γ) being the primary pathogenic cytokine. Other inflammatory pathways are also involved in these models, as recently illustrated by the crucial role of MyD88 in disease development. MyD88 is a critical signaling molecule downstream of interleukin 1 (IL-1) receptor and TLR signaling, and as discussed later, may provide some common inflammatory link to MAS.
| FHLH2 | FHLH3 | FHLH4 | FHLH5 | GS2 | CHS | HPSII | |
|---|---|---|---|---|---|---|---|
| Gene | PRF1 | UNC13D | STX11 | STXBP2 | RAB27A | CHSI/LYST | AP3BI |
| Protein/function | Perforin/pore-forming protein | Munc12–14/priming factor | Syntaxin11/membrane fusion | Munc18-2/membrane fusion | Rab27a/tethering | Lyst/lysosomal fission-protein sorting | Ap3β1/sorting of lysosomal protein |
| Murine model | Prf1−/− | Jinx | None | None | Ashen | Beige | Pearl |
| HLH | + | + | + | + | + | + | 1 case report |
| Cytotoxic activity | − | − | ± | ± | − | − | − |
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