Adjunctive therapies have been proposed for use in at least 5 inflammation pathobiology phenotypes in pediatric sepsis-induced multiple organ failure. This article discusses host-pathogen interaction prototypes to facilitate understanding of the rationale for personalized therapy in these phenotypes. The article discusses the literature on adjunctive antiinflammatory and immune modulation therapies that, in addition to traditional organ support and infection source control, might be part of a personalized precision medicine approach to the reversal of each of these inflammatory pathobiology phenotypes.
Key points
- •
Adjunctive therapies are considered by clinicians for use in the management of children with sepsis inflammation pathobiology phenotypes and multiple organ failure (MOF).
- •
A few general themes for the management of pediatric MOF are always pertinent, including the search for and removal of sources of ongoing infection and inflammation, and support of cardiovascular and other organ functions.
- •
Clinicians can also use clinical criteria and confirmatory tests to identify 1 or more of 5 inflammation phenotypes that can be targeted with pathobiology-based adjunctive therapies.
Introduction
Adjunctive therapies are considered by clinicians for use in the management of children with sepsis inflammation pathobiology phenotypes and multiple organ failure (MOF). This article examines host-pathogen interaction models (or prototypes) that provide the rationale for proven, experimental, or proposed inflammation pathobiology phenotype-targeted therapies in pediatric sepsis-induced MOF. A few general themes for the management of pediatric MOF are always pertinent, including the search for and removal of sources of ongoing infection and inflammation, and support of cardiovascular and other organ functions. In addition to this general approach, clinical criteria and confirmatory tests can also be used to identify 1 or more of 5 inflammation phenotypes that can be targeted with pathobiology-based adjunctive therapies ( Table 1 ).
| Phenotype | Clinical Criteria | Biomarker/Prototype | Adjunctive Therapy |
|---|---|---|---|
| Thrombocytopenia-associated MOF | Platelet level <100,000/mm 3 Acute kidney injury Increased LDH level | ADAMTS13<57% Discussed prototypes = purpura fulminans/aHUS |
|
| Immune paralysis–associated MOF | Persistent or secondary infections | Monocyte HLA-DR expression <30% or 8000 molecules Whole-blood ex vivo TNF response to LPS <200 pg/mL Absolute lymphocyte count <1000 mm 3 Discussed prototype = H1N1/MRSA | GM-CSF Immune suppressant withdrawal Restores TNF response to endotoxin |
| Hyperleukocytosis and pulmonary hypertension–associated MOF | Age <6 mo Pulmonary HTN | WBC count >50,000 mm 3 Discussed prototype = critical pertussis | Extracorporeal leukoreduction removes circulating WBCs and decreases pulmonary hypertension |
| Sequential MOF with liver failure | Respiratory distress followed by hepatobiliary dysfunction | s-FasL level >200 pg/mL Discussed prototype = EBV lymphoproliferative disease |
|
| Macrophage activation syndrome | Hepatobiliary dysfunction and disseminated intravascular coagulation | Ferritin level >500 ng/mL Discussed prototype = Viral hemorrhagic fevers | IVIG + steroids + plasma exchange Anakinra Tocilizumab decreases macrophage inflammation |
Thrombocytopenia-Associated Multiple Organ Failure
Thrombocytopenia-associated MOF (TAMOF) centers on endothelial dysfunction, impairment of metalloproteinase activity of ADAMTS13, and consumptive coagulopathy that results in microvascular impairment and organ injury. This article reviews 2 host-pathogen interaction models for TAMOF: (1) Neisseria meningitides –induced purpura fulminans, associated with complement dysfunction, endothelial injury, production of von Willebrand factor (vWF) ultralarge multimers, and intravascular coagulation ( Fig. 1 A ); and (2) atypical hemolytic uremic syndrome (aHUS) as a result of genetic polymorphisms in ADAMTS13 activity or inhibitory complement regulation (see Fig. 1 B). In addition to microbiological source control, both types are amenable to therapeutic plasma exchange, which removes thrombogenic ultralarge vWF multimers and restores ADAMTS13 activity. aHUS is also amenable to biologic terminal complement inhibitors such as eculizumab.
There are also host genetic risk factors for the development of TAMOF, including ADAMTS13 deficiency syndrome (Upshaw-Schulman syndrome, also known as congenital thrombotic thrombocytopenic purpura), and deficiency in complement H. Environmental risk factors include elaboration of inflammatory cytokines resulting in direct endothelial activation or injury, liver failure, and inhibitory ADAMTS13 antibodies as seen in acquired thrombotic microangiopathy. Free hemoglobin resulting from red blood cell hemolysis in TAMOF is a driver for further endothelial and other organ injury. Other sources of pathologic free hemoglobin include any aged blood cells prone to hemolysis on transfusion, cardiopulmonary bypass, extracorporeal membrane oxygenation (ECMO), or continuous renal replacement therapy.
There are several TAMOF-directed adjunctive therapeutic options. In a small, single-center, prospective randomized clinical study, plasma exchange therapy (1.5 volumes on day 1 followed by 1 volume on day 2 through to the end, with the end being determined by return of organ function and platelet count) was associated with removal of ultralarge vWF multimers, restoration of ADAMTS13 functional activity, and improvement in end-organ functional markers. Meta-analyses indicate a mortality benefit with use of plasma exchange therapy in adults. Although the data for use of plasma exchange therapy in critically adult and pediatric intensive care unit (ICU) populations for the indication of sepsis and septic shock are mixed, there is potential benefit in the TAMOF syndrome, based on biological plausibility and a track record of efficacy of its use in microangiopathies. The decision to provide plasma exchange should be based on the clinical condition, including degree of coagulopathy and platelet count. In addition, plasma exchange should be considered in the setting of severe neurologic disease. Evidence for activation of the complement system should also prompt a consideration for plasma exchange therapy. Eculizumab, a C5 terminal complement cleavage inhibitory monoclonal antibody, can be considered in the setting of TAMOF. This therapy has been most extensively studied in the setting of aHUS associated with an ineffective inhibitory complement response, in which eculizumab has been shown to improve renal function, need for renal support, and quality of life among adult patients. Eculizumab has been approved for use in pediatric aHUS. Moreover, earlier administration of the antibody in an aHUS disease course is associated with improved renal recovery.
Immunoparalysis-Associated Multiple Organ Failure
Immunoparalysis-associated MOF centers on impairment of both innate and adaptive immune function with resulting inability for the host to contain a primary or secondary infection. The host-pathogen example used here for this phenotype of MOF is H1N1 influenza A infection with impairment of monocyte function and contraction of adaptive immune populations ( Fig. 2 ). In addition to antiviral and antibacterial therapy to control pathogen burden and removal (when appropriate) of pharmacologic sources of immune suppression, providing granulocyte macrophage colony-stimulating factor (GM-CSF) has been successfully used to reverse innate immune paralysis. Programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade as well as provision of recombinant lymphocyte survival factors such as interleukin (IL)-7 are being evaluated as methods to restore adaptive immune function.
