Table 2.

Reported therapies for MODS subtypes

Subtype	Treatment	Study Population	Design	Study	Outcome
Immune paralysis	Immune suppressant Withdrawal			Case reports	Infection and MODS resolution
	GM-CSF 66,118,120	Children with ≥ 3 organ failure and ex vivo TNF response < 168 pg/mL; N = 14; GM-CSF N =7, Standard N = 7	Randomized Controlled Trial	Prospective Single Center66	GM-CSF reversed immune paralysis, and reduced the onset of nosocomial infection from 8 infections in 7 patients with placebo patients with GM-CSF (p < 0.05).
		Adults with septic shock/severe sepsis/MODS and Immune paralysis defined by low monocyte HLA-DR expression N = 38; GM-CSF N = 19, placebo N = 19	Randomized Placebo Controlled Trial	Prospective Multiple Center Study118	GM-CSF reversed immune paralysis, increased ventilator free days and improved Physiologic Severity/MODS Score (p < 0.05).
	Interferon gamma154	Intubated adults with severe multiple trauma and immune paralysis N=21; Inhaled Interferon gamma N = 11, Inhaled placebo N = 10	Randomized Placebo Controlled Trial	Prospective Single Center Study154	Inhaled Interferon gamma reduced ventilator associated pneumonia (p< 0.5) and restored alveolar macrophage HLA-DR expression
Thrombocytopenia Associated MOF	Plasma Exchange 30,31,48,49,155	Pediatric TAMOF N =42 15 plasma exchange; 27 standard care	Cohort Study Plasma Exchange vs Standard Therapy	Prospective Multiple Center Analysis49	28 day Mortality decreased from 70.4% to 26.7%; Multivariate analysis found improved survival controlling for PRISM, OFI, PELOD, neurologic failure (p = 0.048).
		Pediatric TAMOF N=10; plasma exchange N = 5; standard therapy N = 5	Randomized Controlled Trial Plasma Exchange vs Standard Therapy	Prospective Single Center30	Plasma exchange restored organ function, improved ADAMTS13 levels, and reduced 28 day mortality from 80% to 0% (p < 0.05)
		Adult TAMOF N = 37; Plasma infusion N = 22, Plasma exchange N = 15	Randomized Trial Plasma Infusion Vs Plasma Exchange	Prospective Single Center155	Plasma exchange reduced hospital mortality from 32% to 0% (p < 0.001)
		Adult TAMOF N=102; Plasma infusion N = 51, Plasma Exchange N = 51	Randomized Trial Plasma Infusion vs Plasma Exchange	Prospective Multiple Center31	Plasma exchange Reduced hospital mortality from 16% to 4% (p = 0.035); and 6 month mortality from 37% to 22% (p = 0.035)
	C5a antibody (Ecullizumab)42–47	Two small Phase II trials; age > 12 years with atypical Hemolytic Uremic Syndrome	Open Label Single Arm; Year Long Treatment	Prospective Multiple Center42	Improved renal function over time and loss of plasma exchange dependence led to FDA approval as orphan drug
		Case series N=3 of children with HUS- STEC-related MODS treated with plasma exchange/ Eculizumab rescue	Open Label Single Arm Two Week Treatment	Retro- spective Single Center Case Series47	Improved MODS resolution and renal function thought to be temporally related to Eculizumab
Sequential MOF	Rituximab156,157	Phase II trial of N = 43 adults with PTLD unresponsive to holding immune suppression subsequently treated with Rituximab	Open Label Single Arm	Prospective Multiple Center Study156	86% survival at 80 days; 62% survival at 1 year
		Phase II trial of adding Rituximab to low dose chemotherapy N = 55 in children with PTLD already receiving low dose cytoxan and prednisone	Open Label Single Arm	Prospective Multiple Center Study157	83% survival at 4.8 years
	Antivirals/IVIG/ Methylprednisone			Case reports	Infection and MODS resolution
	HLH protocol158	Case series treated with HLH-94 protocol	Registry, Open label Single Arm	Retro- spective, Multiple Center158	5 year probability of survival is 54%
Macrophage Activation Syndrome	Methylprednisone/ IVIG / Plasma Exchange69	Pediatric secondary hemophagocytic lymphohistiocytosis /sepsis/multiple organ dysfunction syndrome/macro- phage activation syndrome N = 23; HLH chemotherapy protocol N =6, IVIG / Methylprednisone N = 17	Cluster Randomized Trial Comparing HLH Protocol With Plasma Exchange To IVIG/ Methyl- Prednisone With Plasma Exchange	Prospective Multiple Center Analysis69	Plasma exchange and treatment with IVIG/Methyl- prednisone reduced hospital mortality from 50% to 0% (p = 0.002).
	IRAP70,159	Adult MODS with disseminated intravascular coagulation and hepatobiliary dysfunction	Randomized Double Blinded Placebo Controlled Trial	Post Hoc Multiple Center Analysis159	28 day mortality decreased from 64.7% to 34.6% hazard ratio 0.28 [95% Confidence Interval I 0.11–0.0071] p = 0.007
		Pediatric secondary hemophagocytic lymphohistiocytosis /sepsis/multiple organ dysfunction syndrome/macro- phage activation syndrome treated with IRAP N=8	Case series	Post-Hoc Single Center70	Considered to be temporally related to improvement of MODS. Hospital survival 100%.
	Tocilizumab71,160	Pediatric patients with cytokine releasing syndrome after CART treated with tocilizumab N = 13	Case series	Post-Hoc Single Center160	Considered to be temporally related to improvement of MODS

MODS- Multiple Organ Dysfunction Syndrome, GM-CSF- Granulocyte Macrophage Colony Stimulating Factor, N – number of patients, HLA-DR – Human leukocyte antigen DR, TAMOF – Thrombocytopenia associated Multiple Organ Failure, PRISM – Pediatric Risk of Mortality, OFI – Organ Failure Index, C5a – Complement component 5a, HUS-STEC – Hemolytic Uremic Syndrome-Shiga Toxin producing Escherichia Coli, FDA – Food and Drug Administration, PTLD – Post Transplant Lympho Proliferative Disease, IVIG – Intra Venous Immune Globulin , HLH – Hemophagocytic Lympho Histiocytosis, IRAP – Interleukin 1 receptor antagonist protein, CART – Chimeric Antigen Receptor T cell therapy