Table 6 Summary of recommendations

Key points

- Macrophage activation syndrome (MAS) is an acute, severe, and potentially lethal complication of several inflammatory diseases but seems particularly linked to both systemic juvenile idiopathic arthritis (sJIA) as well as in those with adult-onset Still disease.

- MAS is classified among the secondary causes of hemophagocytic lymphohistiocytosis (sHLH). Other secondary HLH causes are infections and tumors and as a side effect of some drugs as aspirin, NSAIDs, etc.

- MAS may be the first presentation of some patients with sJIA or lupus.

- Several factors could trigger MAS incidence as a flare of the underlying disease and complicated infections.

- Standardized diagnostic and treatment guidelines for MAS are currently lacking.

- Up till now, there are no international guidelines or recommendations for the management of MAS.

1

A

8.39 ± 1.7

95.65

H

The target of therapy is to reach:

▪ Fever < 38.5°C

▪ No organomegaly

▪ No cytopenia

▪ A significant drop in serum ferritin ( best is <2000 ng/mL)

▪ Triglycerides < 1.5 mmol/L

▪ Aspartate aminotransferase < 30 IU/L

▪ Fibrinogen > 2.5 g/L

▪ No hemophagocytosis in bone marrow (when feasible)

2

B

8.62 ± 1.6

95.65

H

 1-a

Prevention

- MAS is not a preventable condition but lowering its incidence may be through good control of the underlying disease with optimum management and follow-up for laboratory markers. Poor disease control may be suggestive of MAS development.

- Close follow-up of patients with inflammatory rheumatic diseases particularly those with past history of MAS, may help in preventing severe attacks.

2

B

8.52 ± 0.69

91.3

H

 1-b

First line of management

- An early diagnosis and prompt aggressive initial treatment are both key factors for a favorable outcome.

- The first line of treatment is parenteral administration of high doses or pulsed corticosteroids in dose 30 mg/kg/d (maximum 1g) for 3 to 5 consecutive days, followed by 0.2:0.5 mg/d oral corticosteroids.

1

A

8.26 ± 1.7

95.65

H

 1-c

Monitoring and follow-up (clinical and lab)

Clinically: improving the overall status of the patient (e.g., conscious level) and absence of fever, improvement of clinical signs of systemic affection, petechial rashes as well as organomegaly.

Lab: elevation of platelets, WBCs, and serum fibrinogen. Lowering levels of AST, ferritin, and triglycerides.

Assessment of inciting factors:

- Changes in the treatment regimen of JIA may be a provoking factor, so it is important to revise and reverse any recent alteration of medical therapy.

- Infection may be a provoking factor; therefore, clinical manifestations suggestive of infection and positive cultures are helpful to confirm the diagnosis.

- Neurological manifestations may require further investigations, e.g., MRA and MRV (to exclude vasculitis) and in some cases may require admission and proper monitoring in ICU.

3

B

8.13 ± 1.6

95.65

H

 1-d

Define resistant/irresponsive and severe cases of MAS

- Resistant/irresponsive cases: cases refractory to conventional therapy with high-dose steroids.

- Severely ill patients: patients with multiorgan failure.

1

A

8.26 ± 1.8

95.65

H

 1-e

Management of resisted and severe cases

- In resisted cases: using of IVIG especially if associated with infection (2 g/kg/day, single continuous infusion).

- For severely ill children: IL-1 receptor blockade (anakinra) (daily sc injection of 1–2 mg/kg/dose) has been remarkably effective when conventional therapy failed.

- Human anti-IL-1β monoclonal antibody, canakinumab, has been reported to be successful in the treatment of MAS-associated sJIA (≥2 years and weight ≥7.5 kg: 4 mg/kg SC q month; not to exceed 300 mg/dose).

- For severely resistant cases: (tocilizumab): recombinant, humanized IL-6 receptor monoclonal antibody with good response. <30) kg: 12 mg/kg IV, ≥30kg: 8 mg/kg) once IV infuse over 60 min.

- Cyclosporin A was found to be effective in severe or corticosteroid-resistant MAS as IV or in an oral dose of 1.25 mg/kg PO BID (max 4mg/kg/d).

- Cyclosporin A can be given as monotherapy, but in most patients, it is used as part of a combinational regimen with corticosteroids.

- Etoposide can be used as salvage therapy in resisted cases not responding to other therapies

- JAK inhibitors have promising experimental results for future expanded use in MAS management.

- Anti-thymocyte globulin (ATG) can be used as salvage therapy for MAS but it is associated with high rates of infection; its safety and efficacy are not established in children.

3

B

8.56 ± 1.6

91.3

H

 2-a

Key points

- Coronavirus disease 2019 (COVID-19) in children is usually mild. However, in rare cases, children can be severely affected, and clinical manifestations may differ from adults.

- Multisystem inflammatory syndrome in children (MIS-C) is an uncommon complication of COVID-19 that has a presentation similar to Kawasaki disease (KD), MAS, or toxic shock syndrome.

- MIS-C should be suspected in a child with COVID-19 infection, particularly if presented with fever > 38 °C (100.4 °F) and at least two of the following suggestive clinical features: rash, gastrointestinal symptoms, edema of hands/feet, oral mucosa changes, conjunctivitis, lymphadenopathy, and neurologic symptoms.

- The clinical presentation of MIS-C may include persistent fevers, gastrointestinal symptoms (abdominal pain, vomiting, and diarrhea), cardiovascular and respiratory affection, rash, and conjunctivitis. Patients typically present with 3 to 5 days of fever, followed by the development of shock and/or multisystem involvement.

- Laboratory findings include lymphocytopenia, elevated inflammatory markers (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], D-dimer), and elevated cardiac markers (troponin, brain natriuretic peptide [BNP]).

- MAS is one of the presentations of MISC with evidence of hemophagocytosis in the bone marrow.

4

D

8.28 ± 1.5

91.3

H

 2-b

Management strategy

- Supportive care must be agreed with the experts who should take care of these patients, including pediatric ICU, pediatric infectious diseases, immunology, and rheumatology teams.

- Vital signs, hydration, electrolytes, and metabolic status must be carefully monitored; fluid resuscitation, inotropic support, respiratory support, and, in rare cases, extracorporeal membrane oxygenation (ECMO) can be used in case of deterioration.

- Patients with shock should be treated with volume expansion using Plasma-Lyte or Ringers lactate, vasoactive medications as epinephrine and norepinephrine are preferred. Use of antithrombotic therapy may be needed depending on the patient presentation and investigations (pediatric hematology consultation is advised in such cases).

- Use of intravenous immunoglobulin (IVIG) 2g/kg, steroids, aspirin, and anticoagulation treatment is recommended at the same dosages that are usually administered to children with KD.

- IL-1 receptor antagonist (anakinra), an IL-6 inhibitor (tocilizumab), and a chimeric IgG1κ monoclonal antibody specific for human TNFα (infliximab) could be used.

- Whenever applicable, treat the associated bacterial infections.

4

D

8.24 ± 1.6

91.3

H