Understanding COVID-19 related multisystem inflammatory syndrome in children

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What is multisystem inflammatory syndrome in children (MIS-C)?

Multisystem inflammatory syndrome in children (MIS-C) is a serious condition in which some parts of the body — such as the heart, blood vessels, kidneys, digestive system, brain, skin or eyes — become inflamed. Inflammation typically includes swelling, often with redness and pain.

Many, but not all, children with MIS-C test negative for a current infection with the virus that causes COVID-19. Yet evidence indicates that many of these children were infected with the COVID-19 virus in the past, as shown by positive antibody test results.

An antibody test with a positive result means that the child’s immune system developed blood proteins (antibodies) that fought the COVID-19 virus.

Sometime this blood test is the only indication that the child was ever infected — meaning the child may have fought the infection without ever having shown signs or symptoms of COVID-19.

Still, some children with MIS-C are currently infected with the virus, usually confirmed by detection of the virus on a swab taken from the back of the nose or throat.

MIS-C shares some of the same signs and symptoms as another condition called Kawasaki disease. Kawasaki disease mainly affects children under 5 years of age. It causes inflammation in the walls of blood vessels, particularly those that supply blood to the heart muscle (coronary arteries). Researchers are working to figure out if the two conditions are related or not.

What are the signs and symptoms of MIS-C?

Signs and symptoms of multisystem inflammatory syndrome in children include those below, though not all children have the same symptoms:

  • Fever that lasts 24 hours or longer
  • Vomiting
  • Diarrhea
  • Pain in the stomach
  • Skin rash
  • Red eyes
  • Redness or swelling of the lips and tongue
  • Feeling unusually tired
  • Redness or swelling of the hands or feet

Emergency warning signs of MIS-C include:

  • Inability to wake up or stay awake
  • Difficulty breathing
  • Chest pain or pressure that doesn’t go away
  • New confusion
  • Bluish lips or face
  • Severe stomach pain

MISC-C and Kawasaki disease

MIS-C appears similar to Kawasaki disease, a rare condition in which children’s hyperactive immune response causes fever, rash and inflammation of blood vessels. Kawasaki disease can cause heart problems and, in rare cases, blood pressure drops that lead to shock.

Inflammation can stretch blood vessel walls, increasing the risk of blood vessels around the heart abnormally bulging or sagging — a condition called coronary vessel aneurysm — that puts them at higher risk of bursting in the future.

In Kawasaki disease, managing blood vessel inflammation reduces the risk of aneurysms, so hopefully this approach can reduce long-term complications in MIS-C.

This Kawasaki-like disease is occurring at up to 30 times the normal frequency in areas hit hard by COVID-19. Most cases have positive or probable exposure to the virus, so researchers are trying to understand if these cases are Kawasaki disease triggered by coronavirus infection, or a new, emerging disease with similar symptoms.

Clinical treatments for Kawasaki disease have been effective, though additional anti-inflammatory drugs are needed more often for MIS-C. Typical Kawasaki disease lasts six to eight weeks, so more time is needed to discern the differences and potential long-term health problems of this new illness.

Because of the common link of immune hyperactivation, this inflammatory syndrome may be related to the cytokine storms or heart problems seen in adults with COVID-19. MIS-C may also be related to the circulatory problems linked to SARS-CoV-2, such as a sudden increase in reddened, painful toes.

The latest clinical results….

Results
Data on 78 patients admitted to PICUs between April 1 and May 10, 2020, and meeting the case definition for PIMS-TS were submitted. Initial presenting features of 29 of these patients have been reported in a recent study16 focusing on the definition of this novel condition (eight of these 29 patients had previously been described in a correspondence article14).

Cardiac features in six patients and renal features in 23 patients have also been presented in single-centre reports.19, 20 Details of presentation, intensive care course, evolution in treatment over time, and longitudinal laboratory data in a national cohort have not been published previously.

Of the 23 National Health Service (NHS) hospital trusts with PICUs in the UK, 15 submitted PIMS-TS data (median three per unit, range 1–24), four reported zero patients, and two were not admitting any children during the study period (having been converted to adult ICUs during the COVID-19 surge).

The two closed units were cardiac units, and their paediatric patients were admitted to neighbouring PICUs. Two PICUs did not share data. The total number of PICU admissions of PIMS-TS cases by week (and the cumulative number of admissions) are shown in figure 1.

The cumulative expected number of admissions derived from historical UK PICANet data for similar inflammatory conditions requiring PICU admission is also shown, showing an increase in cases above the expected number from the week beginning April 20.

Figure thumbnail gr1
Figure 1PIMS-TS admissions per week to UK PICUs, April 1 to May 10, 2020
The cumulative total, and the expected UK cumulative total of similar conditions (Kawasaki disease, toxic shock syndrome, haemophagocytic lymphohistiocytosis, and macrophage activation syndrome) from the previous 5 years are shown. PICU=paediatric intensive care unit. PIMS-TS=paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2.

Characteristics of patients are summarised in table 1. The median age was 11 years (IQR 8–14), and two-thirds of patients were male. Only two patients had major comorbidities, and 61 (78%) had none. Patients from Afro-Caribbean and Asian backgrounds were over-represented.

In the UK the proportion of children aged 10–14 years from an Asian background is 7% and that of children aged 10–14 years from an Afro-Caribbean background is 8%;18 by contrast, 28% of patients in this cohort were Asian and 47% were Afro-Caribbean. Three patients had co-infections, one viral and two bacterial. None was judged to be clinically causative.

Table 1 Demographics and clinical features of 78 patients presenting with PIMS-TS to paediatric intensive care units in the UK

Patients (n=78)
Sex
Female26 (33%)
Male52 (67%)
Age groups
<1 year2 (3%)
1–4 years5 (6%)
5–10 years29 (37%)
11–15 years38 (49%)
16–17 years4 (5%)
Median age, years11 (8–14)
Median observed to expected weight ratio1·22 (1·06–1·41)
Known contact with a COVID-19 case8 (10%)
Comorbidities
None61 (78%)
Usually expected to require primary care15 (19%)
Usually expected to require hospital care2 (3%)
Ethnicity*
Afro-Caribbean37 (47%; 37–58)
Asian22 (28%; 19–39)
White17 (22%; 14–32)
Other2 (3%; 0–9)
SARS-CoV-2 antigen PCR positive17 (22%)
SARS-CoV-2 antigen PCR negative61 (78%)
SARS-CoV-2 IgG serology in PCR positive patients
Positive9/10 (90%)
Negative1/10 (10%)
Not tested7/17 (41%)
SARS-CoV2 IgG serology in PCR negative patients
Positive24/25 (96%)
Negative1/25 (4%)
Not tested36/61 (59%)
PCR negative, serology negative, without known COVID-19 contact (ie, met PIMS-TS criteria, did not meet MIS-C criteria)1/78 (1%)
PCR negative, serology unknown, without known COVID-19 contact (met PIMS-TS criteria, unknown whether would meet MIS-C criteria)32/78 (41%)
Infections with non-SARS-CoV-2 pathogens
None75 (96%)
Bacterial2 (3%)
Viral1 (1%)
Outcome
Discharged from critical care75 (96%)
Still on critical care1 (1%)
Died2 (3%)
Thrombus3 (4%)
Median length of stay, days (n=71)5·0 (3·0–6·5)
Clinical presenting features
Fever78 (100%)
Shock68 (87%)
Vasodilated55 (71%)
Vasoconstricted13 (17%)
Abdominal pain48 (62%)
Diarrhoea50 (64%)
Vomiting49 (63%)
Any abdominal symptom (pain, diarrhoea, or vomiting)70 (90%)
Rash35 (45%)
Conjunctivitis23 (29%)
Data are n (%), n/N (%), or median (IQR), unless otherwise indicated. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. PIMS-TS=paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. MIS-C=multisystem inflammatory syndrome in children.
* Data are n (%; 95% CI).

Common presenting features were fever, shock (usually vasodilated), abdominal pain, diarrhoea, and vomiting (table 1). 70 (90%) of 78 patients presented with at least one abdominal symptom. Rash was seen in 35 (45%) patients) and conjunctivitis in 23 (29%). Of 35 patients tested for SARS-CoV-2 IgG serology, 33 were positive, and one of the two negative serology patients was PCR positive.

Of the 78 patients in our cohort, 45 (58%) also met all criteria for a MIS-C diagnosis; of the remaining 33 patients, one would definitely not have met MIS-C criteria and 32 did not have a serology test and therefore their MIS-C status could not be determined (appendix).

Longitudinal data for the first 4 days of admission are presented in table 2. Data were available for all 78 patients on day 1, and for 36 patients throughout the first 4 days, as we only included data for patients still on intensive care.

Patients presented with elevated C-reactive protein, D-dimer, and ferritin, troponin, and lymphopenia. Longitudinal data over the first 4 days of admission showed a reduction in C-reactive protein, D-dimer, and ferritin concentrations towards normal levels.

The neutrophil count was stable, although raised, and creatinine and alanine aminotransferase concentrations remained normal. The lymphocyte count increased and the median rose above 1·0 × 109 cells by day 3. The troponin concentration increased over the first 4 days of admission.

Table 2 Laboratory results for the first 4 days of PICU admission

Reference rangesDay 1 (n=78)Day 2 (n=44)Day 3 (n=43)Day 4 (n=36)
Neutrophil count (× 109 cells per L)2·0–7·512·3 (10·7–22·9)13·2 (9·2–17·6)13·0 (8·9–19·4)11·9 (7·2–20·0)
Lymphocyte count (× 109 cells per L)1·5–4·00·7 (0·4–1·1)0·9 (0·7–1·6)1·2 (0·9–1·7)1·8 (1·0–2·3)
Platelet count (× 109 cells per L)150–400125 (75–178)179 (115–272)187 (109–293)201 (100–358)
C-reactive protein (mg/L)<5264 (192–316)233 (143–308)191 (77–283)96 (39–197)
D-dimer (μg/L)<5004030 (2349–7422)2293 (1319–4638)3503 (1902–5291)1659 (646–3792)
Ferritin (μg/L)12–2001042 (538–1746)1152 (473–1529)842 (495–1422)757 (484–1198)
Troponin (ng/L)<10157 (43–810)232 (70–829)355 (66–2252)358 (30–3015)
Creatinine (μmol/L)60–12075 (46–103)54 (41–77)48 (34–67)49 (32–64)
ALT (IU/L)10–5050 (30–93)51 (27–77)43 (30–68)51 (35–71)
Data are median (IQR). PICU=paediatric intensive care unit. ALT=alanine aminotransferase.

Historical data on the incidence of PICU admissions for the four similar inflammatory conditions (Kawasaki disease, toxic shock syndrome, haemophagocytic lymphohistiocytosis, and macrophage activation syndrome) between 2015 and 2019 showed that the average number of admissions to all UK PICUs combined for the four inflammatory conditions was one admission (95% CI 0·8–1·22) per week, and the annual total number of admissions ranged from 44 to 67.

Over the past 5 years, the highest number of total national admissions was for toxic shock syndrome (n=119) and for haemophagocytic lymphohistiocytosis and macrophage activation syndrome (n=114); Kawasaki disease was less common (30–40 admissions in total; exact numbers were not available due to the small numbers). Full details are provided in the appendix.

During the study period, the average number of weekly admissions for PIMS-TS to UK PICUs was 14 (at least 11 times greater than expected for similar conditions), peaking at 32 (at least a 26-fold increase).Critical care interventions, treatments, and outcomes are shown in table 3.

Overall, 36 (46%) of 78 children were invasively ventilated, and three (4%) required extracorporeal membrane oxygenation. A variety of therapies were given, with 59 (76%) of 78 patients receiving intravenous immunoglobulin and 57 (73%) requiring steroids. 17 (22%) of 78 patients received biologic immunomodulation agents (eight received anakinra, seven received infliximab, three received tocilizumab, and one received rituximab; and two patients received two biologics).

One child was treated with an antiviral therapy (remdesivir). Treatments were varied and inconsistent; however, over the study period, the proportion of patients being given each therapy increased over time (figure 2).

The proportion of patients receiving vasoactive infusions remained constant (five [83%] of six in week 3, 17 [81%] of 21 in week 4, 27 [84%] of 32 in week 5, and 14 [82%] of 17 in week 6), but the proportion of patients on invasive ventilation dropped from five (83%) of six in week 3 to two (12%) of 17 by week 6.

Three (4%) patients had significant thrombi, with no pulmonary emboli. Seven (9%) patients received therapeutic anticoagulation (table 3), either due to thrombi or due to concerns about diffuse microthrombi.

Table 3 Interventions for patients with PIMS-TS admitted to paediatric intensive care units

Patients (n=78)
Highest level of respiratory support
No respiratory support12 (15%)
Oxygen only12 (15%)
High flow nasal cannula therapy13 (17%)
Non-invasive ventilation5 (6%)
Invasive mechanical ventilation36 (46%)
Extracorporeal membrane oxygenation3 (4%)
Cardiovascular support
Fluid bolus72 (92%)
Inotropic or vasoactive infusion65 (83%)
Renal replacement therapy1 (1%)
Drug therapies
Antibiotics78 (100%)
Steroids57 (73%)
Intravenous immunoglobulin59 (76%)
Immunomodulation with biologic agents*17 (22%)
Anakinra8 (10%)
Infliximab7 (9%)
Tocilizumab3 (4%)
Rituximab1 (1%)
Aspirin or other antiplatelet therapy45 (58%)
Anticoagulation
Prophylactic32 (41%)
Therapeutic7 (9%)
Antiviral therapy (remdesivir)1 (1%)
Figure thumbnail gr2
Figure 2Number of patients with PIMS-TS admitted to UK paediatric intensive care units, and percentage receiving individual treatments over time
Weeks with fewer than three patients were excluded. Biologic refers to any of anakinra, infliximab, tocilizumab, or retiximab. PIMS-TS=paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2.

A third (28 [36%] of 78) of patients were found to have coronary artery abnormalities on echocardiography during PICU admission. 18 had evidence of aneurysms and ten had coronary arteries that were characterised as unusually echogenic.

There were no obvious differences in the demographics, presenting features, or level of invasive therapies between patients with any coronary artery abnormality and those with normal coronary arteries, or those who were invasively ventilated and those who were not (table 4).

Table 4 Comparison of key demographic characteristics, laboratory tests, therapies, and other presenting features in patients with or without any coronary abnormalities, and those who were invasively ventilated and those who were not

Any coronary artery abnormality (n=28)No coronary artery abnormality (n=50)Invasively ventilated (n=36)Not invasively ventilated (n=42)
Median age, years11 (7–13)11 (8–14)10 (8–13)11 (6–14)
Male sex16 (57%)34 (68%)23 (64%)29 (69%)
Non-white23 (82%)38 (76%)29 (81%)32 (76%)
Highest CRP (mg/L)227 (166–292)283 (206–328)294 (225–355)227 (179–298)
Lowest platelet count (× 109 cells per L)143 (95–164)150 (83–197)125 (81–168)151 (96–185)
Lowest lymphocyte count (× 109 cells per L)0·70 (0·4–1·2)0·72 (0·5–1·0)0·74 (0·5–51·0)0·70 (0·4–1·1)
Highest ferritin (μg/L)1205 (536–2468)1156 (563–1803)1205 (653–2124)858 (449–1506)
Highest troponin (ng/L)187 (49–574)120 (21–818)253 (68–892)147 (45–809)
Highest D-dimers (ng/L)4990 (2425–7691)4080 (2538–7537)4897 (3350–9420)3660 (2021–6409)
Rash11 (39%)22 (44%)15 (42%)20 (48%)
Conjunctivitis9 (32%)13 (26%)8 (22%)15 (36%)
Shock26 (93%)42 (84%)30 (83%)38 (90%)
Data are n (%) or median (IQR). CRP=C-reactive protein. NA=not applicable.

Source …. The Lancet

History….

When the COVID-19 pandemic was first reported in Asia and initially spread throughout the globe, paediatricians were grateful that children seemed to be only mildly symptomatic with the infection in most cases.

Then, an alarming warning came from the National Health Service in England in April 2020 about cases of older school-aged children and adolescents presenting with fever, hypotension, severe abdominal pain and cardiac dysfunction who tested positive for SARS-CoV-2 infection either by nasopharyngeal RT-PCR assay or by antibody testing.

These children had laboratory findings of cytokine storm, including high serum IL-6 levels, and generally required inotropic support to increase cardiac output with rare need for extracorporeal membrane oxygenation.

Almost all of these children no longer required intensive care after only a few days and completely recovered, although rare deaths resulted from complications of extracorporeal membrane oxygenation.

Case series of children presenting with this condition have now been reported from the UK1, Italy2, Spain3, France and Switzerland4, and the United States5. The Centers for Disease Control and Prevention (CDC) has developed a case definition for use in the United States and has termed the condition multisystem inflammatory syndrome in children (MIS-C).

Physicians have noted some clinical similarities between MIS-C and Kawasaki disease (KD), a febrile illness of young childhood involving inflammation of the blood vessels that can result in coronary artery aneurysms.

KD is presently of unknown aetiology, although substantial recent progress supports a presently unidentified ubiquitous virus as the cause6. Patients with MIS-C may have some of the clinical features of KD, including fever, dilation of conjunctival blood vessels, rash and redness of the oropharynx.

However, these clinical signs can be observed in many infectious diseases in childhood and are not specific for any one diagnosis. The question has therefore arisen as to whether MIS-C and KD are the same entity.

The epidemiology of KD has been virtually identical in all countries in the world for the past 50 years or more, with 80% of cases occurring in children <5 years of age and with a peak incidence at ~10 months of age.

This is in marked contrast to the epidemiology of MIS-C, which affects older children and adolescents. Various characteristic laboratory findings in MIS-C, such as leukopenia and extremely high levels of ventricular natriuretic peptide (a marker of heart failure), are not features of KD.

Asian children have the highest rate of KD in the world, whereas children of African descent seem to be at particular risk of developing MIS-C1. No cases of MIS-C have been reported in China and Japan7. It is clear that the epidemiology of the two conditions is quite dissimilar and, therefore, it is important to avoid jumping to conclusions regarding a similar aetiology.

Because of the overlapping clinical features and the lack of a diagnostic test for either KD or MIS-C, distinguishing the two conditions in an individual patient can be difficult. Several groups have reported the rare occurrence of coronary aneurysms in children with MIS-C1,2, but it is unclear whether MIS-C can result in this complication, or whether these children actually had KD.

If SARS-CoV-2 infection can result in coronary aneurysms in childhood, it would be the first virus to be proven to do so. More often, mild transient dilation of the coronary arteries is reported in MIS-C, as occurs in another paediatric condition that is also associated with high serum IL-6 levels, systemic onset juvenile idiopathic arthritis.

Although SARS-CoV-2 has not been definitively proven as the cause of MIS-C, the fact that MIS-C appeared during outbreaks of COVID-19 in Europe and the United States is highly suggestive.

If the condition becomes less common as the pandemic ceases, it will further support an association. However, many questions remain. Why was this condition not observed in China, where the virus was first reported?

Is it such a rare condition that it is observed only in nations with a very large number of cases of COVID-19 (such as the United States, Spain, Italy, France and the UK) but not in nations with fewer cases (such as Japan and China)?

Or has the virus changed in some way over time that has resulted in a change of its pathogenicity? Or has some other policy in individual countries affected the prevalence of MIS-C (for example, childhood administration of BCG vaccine)? Data are presently lacking to answer these important questions.

If MIS-C is indeed related to infection with SARS-CoV-2, the pathophysiological mechanism of disease is unclear. Some have proposed that the condition is not the result of acute viral infection but is a post-infectious phenomenon related to IgG antibody-mediated enhancement of disease.

This hypothesis seems to have emerged for two main reasons. First, MIS-C cases have lagged in time compared with the peak of SARS-CoV-2 infection in at least some countries. However, as children likely acquire the virus from their parents because of stay-at-home restrictions, a lag from the peak of cases in adults could be expected.

Second, children with MIS-C more often test positive for antibody to SARS-CoV-2 than for virus using nasopharyngeal RT-PCR assay.

However, children with MIS-C have a predominantly gastrointestinal presentation of their illness with few, if any, respiratory symptoms in most cases. Therefore, the virus may be primarily replicating in the gastrointestinal tract; enterocytes have been shown to be readily infected by SARS-CoV-2 (REF.8), and patients with MIS-C who have undergone exploratory laparotomy have been found to have mesenteric adenitis, supporting gastrointestinal infection4. Stool RT-PCR assays for the virus are not widely clinically available and have not been reported for children with MIS-C.

Moreover, the presence of antibody to SARS-CoV-2 does not itself imply a post-infectious process, because antibodies may arise during the second week of infection. Furthermore, there is a lack of information regarding the specificity of the antibody assays carried out in patients with MIS-C, which can be widely variable.

As SARS-CoV-2 infection spreads through a community, resulting in asymptomatic or mildly symptomatic infection in the majority of children, positive antibody tests will become increasingly common, and childhood controls will be necessary to establish an association between SARS-CoV-2 and a particular disease.

Of interest, worsening of illness has so far not been an apparent clinical problem in patients with COVID-19 who are treated with convalescent plasma, as one might expect if antibody-mediated enhancement is an important mechanism for the development of severe COVID-19 complications.

One compelling alternative hypothesis for the marked cytokine storm experienced by children with MIS-C derives from the well-known ability of coronaviruses to block type I and type III interferon responses9, with the potential outcome of delayed cytokine storm in patients with immune responses that cannot control viral replication well or in those with initially high SARS-CoV-2 viral load9,10 (Fig. 1).

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Fig. 1
Pathogenesis of multisystem inflammatory syndrome in children: a hypothesis.
The timing of the interferon (IFN) response to SARS-CoV-2 infection can vary with viral load and genetic differences in host response. When viral load is low, IFN responses are engaged and contribute to viral clearance, resulting in mild infection. When viral load is high and/or genetic factors slow antiviral responses, virus replication can delay the IFN response and cytokine storm can result before adaptive responses clear the virus, resulting in severe disease including multisystem inflammatory syndrome in children (MIS-C). Adapted with permission from REF.9, Elsevier.

The CDC case definition of MIS-C is extremely broad and would be met in many children with acute COVID-19, KD, other viral infection, systemic onset juvenile idiopathic arthritis, and many other infectious and inflammatory conditions of childhood.

Such a broad case definition will likely complicate the identification of the true spectrum and potential complications of MIS-C. It is likely that focusing on patients with the initially described presentations of shock, severe abdominal pain and myocardial dysfunction will be most informative in urgently needed research studies to understand the pathophysiology and clinical outcomes of MIS-C.


References

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