Dear Editor,

The severe form of Coronavirus Disease 2019 (COVID-19) is a systemic disease associated with high mortality rate1,2. Elderly, mainly men with comorbidities, are at increased risk of death. Νevertheless, younger individuals, without underlying diseases, may also develop lethal complications (myocarditis, disseminated intravascular coagulopathy, neurological complications etc.)3,4.

In the ICU of ATTIKON University Hospital (one of the 5 Reference Hospitals for COVID-19 in Athens, Greece), from 5 August to 30 September 2020, 16 (100%) critically ill patients with COVID-19 were admitted (median age 70.5 years, IQR 58–79). The patients were divided into survivors [Group A: 9 (56.3%)] and non-survivors [Group B: 7 (43.7%)](Table1). At the time of ICU admission, the viral load of coronavirus (expressed in Circles trough: Ct) was significantly higher in non-survivors [Group A: 23 (IQR 21–25) vs Group B: 21 (IQR 20–22), p=0.042], while ferritin levels were similar in both groups [Group A: 1290 ng/mL (IQR 550–3572) vs Group B: 980 (IQR 543–3915), p=0.71]. During ICU stay, the viral load remained permanently high in non-survivors [Group A: 32 (IQR 32–37) vs Group B: 22 (IQR 19–24), p=0.001], but it was gradually diminished among survivors [Group A: 39.1% (IQR 30.4–42.9) vs Group B: 0 (IQR -4.8–14.30), p=0.001]. In parallel, ferritin levels were increased by 109.7% (IQR 25.7–382), whatever was higher in non-survivors [Group A: 55.7% (IQR 13.3–85) vs Group B: 486.1% (IQR 137.2–761.9), p=0.007] (Table 1). The HScore, which is an indicator of macrophage activation, was higher in non-survivors [Group A: 54 (IQR 19–70) vs Group B: 87 (IQR 68–99), p=0.048)]. Finally, in this cohort, 9 (56.3%) patients survived and 7 (43.7%) died because of ARDS/Multiple Organ Failure (MOF) (one of the patients developed myocarditis).

Table 1

Demographics, clinical and laboratory data of all patients, survivors and non-survivors (N=16)

ParametersAll patientsSurvivors N=9 (56.3%)Non-survivors N=7 (43.7%)p
Age (years)70.5 (58–79)75 (54–79)67 (62–79)0.92
Gender0.55
Male13 (81.3)8 (88.9)5 (71.4)
Female3 (18.7)1 (11.1)2 (28.6)
Comorbidities
Hypertension12 (8)6 (66.7)6 (85.7)0.59
Cardiovascular disorders7 (43.8)6 (66.7)1 (14.3)0.06
Diabetes II4 (3)1 (11.1)3 (42.9)0.26
COPD4 (25)2 (22.2)2 (28.6)>0.99
Malignancy3 (18.8)1 (11.1)2 (28.6)0.55
Epilepsy2 (12.5)2 (22.2)0 (0)0.48
Obesity1 (6.3)1 (11.1)0 (0)>0.99
Renal failure1 (6.3)0 (0)1 (14.3)0.44
Thrombophilia1 (6.3)1 (11.1)0 (0)>0.99
Admission0.63
Directly from ER6 (37.5)4 (44.4)2 (28.6)
From clinical floor10 (62.5)5 (55.6)5 (71.4)
Time to ICU admission (days)3.5 (0–7)1 (0–7)4 (0–5)0.87
APACHE II admission20 (18.5–21.5)20 (18–21)21 (19–24)0.33
SOFA score13.5 (11.5–15)13 (12–14)15 (11–15)0.23
Ferritin (admission), ng/mL1046.5 (546.5–3748.5)1290 (550–3572)980 (543–3915)0.71
Ferritin (ICU stay), ng/mL2295 (1503.5–6366.5)1735 (1289–4058)2538 (1895–36940)0.19
Ferritin levels increase109.7 (25.7–382)55.7 (13.3–85)486.1 (137.2–761.9)0.007*
Time of highest ferritin levels (day since admission)12.5 (5.5–23.5)10 (5–23)16 (6–24)0.75
Viral load (Ct) admission21.5 (20.5–24)23 (21–25)21 (20–22)0.042*
Viral load (Ct)a29.5 (22–33)32 (32–37)22 (19–24)0.001*
Viral load reduction (Ct) (%)28 (5–39.2)39.1 (30.4–42.9)0 (-4.8–14.3)0.001*
Temperature (℃)a38.1 (37.3–38.9)38 (37.7–38.5)38.4 (36–40.5)0.71
PaO2/FiO2a123.5 (114–159)125 (115–195)122 (53–156)0.56
WBC (x109/L)a14600 (10200–17900)13200 (9300–15900)16900 (11980–27580)0.19
Neutrophils (%)81 (77.5–88)81 (80–83)87 (61–89)0.67
Neutrophils absolute number10380 (7530–14450)10000 (7460–13200)13600 (7600–15100)0.32
Lymphocytes (%)7 (5–12)10 (6–11)6 (5–26)0.75
Lymphocytes absolute number780 (695–1262)770 (640–920)790 (750–1290)0.47
Hba11.3 (9.3–13)11.5 (11–13)11 (8.5–13)0.63
Platelets (x109/L)a258 (224–317)252 (208–318)258 (249–289)0.96
Cytopeniaa5 (31.3)2 (22.2)3 (42.9)0.60
Fibrinogena502.5 (426–775.5)484 (456–782)626 (396–769)0.87
AST (μKat/L)a87 (39.5–244.5)115 (33–168)59 (41–548)0.71
LDHa449.5 (365–627)399 (330–521)596 (378–628)0.19
HS scorea69.5 (50.5–87)54 (19–70)87 (68–99)0.048*
Inotropic agents13 (81.3)6 (66.7)7 (100)0.21
CRRT2 (14.3)1 (11.1)1 (20)>0.99
Length of ICU stay (days)37 (8.5–52.5)52 (29–57)12 (4–45)0.033*

Values are expressed as number (%) or median (IQR). IQR: interquartile range. Patients presented more than one comorbidity. AST: Aspartate Aminotransferase. APACHE II: Acute Physiology And Chronic Health Evaluation II. COPD: Chronic Obstructive Pulmonary Disease. CRRT: Continuous Renal Replacement Treatment. HS score: hemophagocytic syndrome. LDH: Lactate Dehydrogenase. SOFA: Sequential Organ Failure Assessment. WBC: White Blood Cells count.

a On day of highest ferritin levels.

* p<0.05 statistically significant.

A consistent proportion of COVID-19 patients will develop acute respiratory distress syndrome (ARDS) related to increased production of cytokines (the so-called cytokine storm) and a small subset secondary haemophagocytic lymphohistiocytosis (sHLH), a T-cell driven hyperinflammatory, ‘hyperferritinemic syndrome’5. These are the two main causes of mortality in the severe form of COVID-19. The sHLH development reflects the ability of coronavirus to bind TLRs and to activate inflammasome through IL-1β release, but the relationship is not clear since many COVID-19 patients, even with bad prognosis, do not meet the classification criteria of HScore (Table 2)6,7. In light of the absence of highly increased HScore, ferritin remains high and reveals constant macrophage activation albeit not to such an extent as to be the full-blown sHLH8-10. In our cohort, high viral load and ferritin levels have been observed in non-survivors indicating a relation between the activity of the disease and the outcome of the patients. A future research perspective could be focused on the following three questions: a) ‘Is COVID-19 a hyperferritinemic syndrome without being full-blown sHLH?’; b) ‘Is there a need to revalidate sHLH and HScore cut-off limits in these patients?’; and c) ‘When in the course of the COVID-19 infection may the clinicians consider starting immunomodulatory treatment?’.

Table 2

Haemophagocytic lymphohistiocytosis (HLH)-2004 diagnostic criteria11 and HScore (HS)12

HScore
ParameterNumber of points
Temperature (℃)
<38.40
38.4-39. 433
>39.449
Organomegaly
None0
Hepatomegaly or splenomegaly23
Hepatomegaly and splenomegaly38
Number of cytopenias
One lineage0
Two lineages24
Three lineages34
Triglycerides (mmol/L)
<1.50
1.5–4.044
>4.064
Fibrinogen (g/L)
>2.50
≤2.530
Ferritin (ng/mL)
<2.0000
2.000-6.00035
>6.00050
Serum Aspartate aminotransferase (IU/L)
<300
>3019
Haemophagocytosis on bone marrow aspirate
No0
Yes35
Known immunosuppression
No0
Yes18
A.A molecular diagnosis consistent with HLH
B.Al least five of the following criteria should be met
1. Fever
2. Splenomegaly
3. Cytopenia (affecting ≥2 or 3 lineages in the peripheral blood
 Haemoglobin <90 g/L (in infants < 4 weeks haemoglobin <100 g/L)
 Platelets <100 x 109/L
 Neutrophils <1.0 x 109/L
4. Hypertriglyceridaemia and / or hypofibrinogenaemia
 Fasting triglycerides ≥3.0 mmol/L
 Fibrinogen ≤1.5 g/L
5. Hemophagocytosis in bone marrow or spleen or lymh nodes. No evidence of malignancy
6. Low or no NK cell activity (according to local laboratory reference)
7. Ferritin ≥500 mg/L
8. sCD25 ≥2400 U/mL

[i] HScore: HS >169 is 93% sensitive and 86% specific for HLH. NK: natural killer. sCD25: soluble CD25.

Figure 1
http://www.pneumon.org/f/fulltexts/135958/PNE-34-1-g001_min.jpg
Figure 2
http://www.pneumon.org/f/fulltexts/135958/PNE-34-1-g002_min.jpg
Figure 3
http://www.pneumon.org/f/fulltexts/135958/PNE-34-1-g003_min.jpg