It has been recognized that COVID-19 illness exhibits three grades of increasing severity, which correspond with distinct clinical findings, response to therapy, and clinical outcome: stage 1 (mild) early infeccion, stage II (moderate)—pulmonary involvement (IIa) without hypoxia and (IIb) with hypoxia, and stage III (severe)— systemic hyperinflammation.[9] In this last phase the markers of systemic inflammation seem to be elevated such as IL-2, IL-6, IL-7, granulocyte colony- stimulating factor, macrophage inflammatory protein 1-a, TNF-α, CRP, ferritin, and D- dimer characterizing patients with more severe disease.[3, 4, 9]
Clinical and laboratory parameters in the COVID-19 are similar with MAS. Laboratory parameters including highly elevated CRP and hyperferritinemia, the latter of which may play a complex role in disease, are key to the diagnosis of MAS and are elevated in many severe COVID-19 pneumonia cases. Other features including coagulopathy and abnormal liver function may be evident suggesting that a subgroup of COVID-19 pneumonia cases also have MAS, without having organomegaly. In common with the disseminated intravascular coagulation (DIC) associated with MAS, there is evidence of D-dimer level elevation in COVID-19 pneumonia which might represent an extension of this novel virally induced hyper-inflammatory pulmonary immunopathology to the adjacent microcirculation with extensive secondary fibrinolytic activation.[6]
“MAS like-syndrome” can occur in patients at this advanced stage of the disease, thus all patients with severe COVID-19 they should be screened for MAS with laboratory tests should be interpreted looking for tendencies to increase ferritin, decreased platelets, and undoubtedly an important clue to MAS is the reduction of erythrocyte sedimentation rate in the face of acute anemia and infection. The interpretation of laboratory signs is essential to alert the possibility of MAS associated.[10]
The HScore [11] can be applied to identify the subgroup of patients most likely to have MAS for whom immunosuppression could be instituted and thus improve mortality. However, it is important to highlight that for the realization and validation of this score, most of the infections included were due to bacteria or mycobacteria, and therefore it may not be appropriate to apply this score to COVID-19 infections.
In a retrospective study of fatal cases of COVID-19 in two hospitals in Wuhan, the majority of patients died from multiple organ failure. Of the 85 patients, 58 (68.2%) had one or more comorbidities. The majority were men (72.9%) aged ≥ 65 years (61.2%). The most common cause of death in 81/85 patients was respiratory failure (46, 91%), followed by septic shock (19, 75%), multiple organ failure (13, 16.05%) and cardiac arrest (7, 8.64%). Chest computed tomography was performed on 80 patients, 76.3% having multiple ground-glass opacities. Among the laboratory characteristics, the most frequent were leukocytosis, neutrophilia, thrombocytopenia, eosinopenia, in addition to increased CRP, D-dimer, fibrinogen and DHL. It is possible that some patient developed “MAS like-syndrome”, but this diagnosis was not mentioned, pointing out that 33% of the patients received intravenous infusions of immunoglobulin.[12]
Therefore, the overlapping cytokine profiles between severe ARDS and MAS may limit the utility of cytokine profiling in the differentiation between both conditions and many of the laboratory changes reported in COVID- 19 could predominantly reflect ARDS. COVID-19 severe pneumonia may represent a novel viral MAS-like immunopathology, where hyper-inflammation may be key to virus control in the faceof disabled type-1 interferon responses. Furthermore, the recognition of MAS is problematic in COVID-19 pneumonia cases with the severe inflammation emanating from the pulmonary compartment mimicking MAS, but the lack of other classical systemic clinical features making MAS presentation atypical and diagnosis more difficult.[6]
For the treatment of MAS, we have as therapeutic options oral or pulse steroids, intravenous immunoglobulin, selective blocking of IL-6 and IL-1β, in addition to JAK inhibitors.[5, 8, 10]
In the case report of this patient, as he is elderly, with multiple comorbidities that could predispose the possibility of secondary bacterial infection, we opted in addition to coverage with antibiotics, started IVIg and corticosteroids. This strategy has already by Hutchinson et al [13] that suggested immediate use of IVIg 2g/kg associated with intravenous methylprednisolone (1g from 3 to 5 days). As our patient is diabetic, we chose to make 1g of methylprednisolone only on the first day, and 250 mg on the next two days, always reevaluating the need or not to increase the dose through the results of laboratory tests and clinical signs, and it was not necessary increase as we could demonstrate.
IVIg is a pooled preparation of normal immunoglobulin IgG obtained from several thousand healthy donors [14] and has an important role in the treatment of MAS and serves to reduce inflammation by several mechanisms, including reducing complement activation and cytokine inhibition.[15, 16] It may also have the additional benefit of counteracting some of the immune deficiency brought about by other drugs and the disease state. However, there are potential side effects of IVIg,[17] and as we have shown in the clinical case, the flow of the infusion should be done with caution, starting with 25ml/h and gradually increasing according to the patient's tolerability. IVIg has been also reported as a treatment key for severe cases of COVID-19 in previous studies.
Corticosteroids are a fundamental part of the treatment of MAS. In rheumatologic practice, there is a tendency to give pulsed intravenous methylprednisolone at the outset [18]. Meanwhile, in adult haematology practice, dexamethasone is used.[19] In the treatment of severe pneumonia, whether by COVID-19 or not, the use of corticosteroids is well established. However, whether with methylprednisolone,[20, 21] or with dexamethasone,[22] the doses for adjuvant treatment in severe viral pneumonia are lower, since they respond well to low doses of corticosteroids. The problem here is to draw attention to cases in which macrophage inflammation presents itself systematically as MAS, and in these cases, low doses of corticosteroids will not be enough.