An analysis of reported cases of hemophagocytic lymphohistiocytosis (HLH) after COVID-19 vaccination

Figures & data

Figure 1. PRISMA flow diagram for study selection.

Table 1. Patients from respective case reports included in the analysis.

Author, year	Age; Gender; Region	Vaccine type; Number of doses	Onset of symptoms after vaccination	Fibrinogen (g/L) (2.00–4.00)	Ferritin (μg/L) (11–306)	Triglycerides (mg/dL) (<130)	Soluble CD25/Soluble IL-2 receptor, pg/	Computed tomography (CT)	Clinical examination	Past medical history	Clinical presentation	Treatment	Outcome
Ai S,2021	68; Male; Australia	the ChAdOx1 nCov‐19 vaccine; first dose	18 days	2.3	8498	203.78	733 U/ml	splenomegaly, aortic lymphadenopathy, with no focus of infection	splenomegaly, hyponatremia	hypertension, gout, Bowen’s disease	fever, rigors, lethargy, night sweats	flucloxacillin(IV), gentamicin_x005f_x0002_medication(IV): quinapril, diltiazem, prazosin, hydrochlorothiazide, colchicine, and allopurinol	Not provided
LV Tang，2021	43; Female; China	the inactivated SARS-CoV-2 vaccine; first dose	Not mentioned	1.41	8140.4	215.298	204.99			chronic EBV infection	fever (37.6°C), malaise, vomiting	dexamethasone acetate, glucocorticoid	discharged
Cory P,2021	36; Female; United Kingdom	the ChAdOx1 nCov‐19 vaccine (Oxford – AstraZeneca); first dose	3 days	5.5	12423			Computed tomography of the thorax, abdomen and pelvis revealed gross hepatomegaly, moderate splenomegaly and small bilateral pleural effusions, but no lymphadenopathy. Findings on bedside echocardiography and subsequent cardiac magnetic resonance imaging (MRI) were consistent with constrictive pericarditis. Thoracic ultrasound showed simple bilateral anechoic pleural effusions. MRI of brain and spine were normal.	respiratory rate(32 breaths/minute), oxygen saturation(97%), heart rate(137 beats/minute), blood pressure(104/65 mmHg); mild right upper quadrant abdominal tenderness with hepatomegaly; urine dip was positive for protein, ketones and hemoglobin;electrocardiography – ST elevation in leads V1–2	None	fever (39.9°C), myalgia, sore throat, mild facial swelling, pyrexial, tachycardic,tachypneic, pleuritic pain, a pericardial rub.	antihistamines, antibiotics(IV), piperacillin/tazobactam(IV), analgesia(IV), fluids(IV),methylprednisolone(pulsed IV), prednisolone(Oral),immunoglobulins(IV)	discharged
Beak DW,2021	20; Male; Korea	BNT162b2 mRNA COVID-19 vaccine; first dose	2 days	1.78	6592 ng/mL(22–322)	106		multiple enlarged bilateral lymph nodes, splenomegaly		None	fever (>39°C) and lymphadenopathy,unstable blood pressure with tachycardia,severe myalgia,drowsiness，skin rash,naysea	dexamethasone	discharged
	71; Female; Korea	the ChAdOx1 nCov‐19 vaccine; first dose	7 days	1.68	>16500	501		multiple enlarged lymph nodes, splenomegaly		hypertension	fever,bilateral axillar palpable masses,poor general condition,hypotension,tachycardia,neurologic symptoms,slurred speech,severe motor weakness	dexamethasone, etoposide,apixaban	Not provided
He YF,2022	38; Male; China	Not mentioned; booster shot	28 days	1.83	18669		103,915 U/mL	widespread increased metabolic activity	familial HLH type 3	familial HLH type 3, severe interstitial pneumonia, urticarial vasculitis (UV), erythema annulare centrifugum(EAC)/eosinophilic annular erythema (EAE)	multiple annular to irregular erythema, fever, facial edema, fatigue	antihistamines, glucocorticosteroid, thalidomide, allogeneic bone marrow transplant	Not provided
Narvel H,2022	63; Female; USA	mRNA-1273 vaccine; two doses	4 months	4.46	17899	166	3527	multiple enlarged lymph nodes	afebrile;respiratory rate(21 breaths/minute), heart rate(73 beats/minute), blood pressure(118/67 mmHg), oxygen saturation(Normal);splenomegaly	hypertension, type 2 diabetes, end-stage renal disease on dialysis, heart failure, stroke,coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI)	bilateral leg weakness, left facial droop, fatigue, fever, dry cough, diarrhea, shortness of breath	apixaban, ceftriaxone, azithromycin, immunoglobulin (IV)	discharged
Nasir Saad,2022	46; Male; Pakistan	the BBIP-CorV COVID-19 vaccine; second dose	21 days		7068.1	274			respiratory rate(27 breaths/minute)	None	fever,fatigue,oral ulcers,skin rashes,chills,generalized weakness,reduced appetite,disturbed sleep, weight loss	dexamethasone acetate,dexamethasone	discharged
Shimada Y,2022	85; Female; Japan	BNT162b2 mRNA COVID-19 vaccine; first dose	12 days	5.51	2284.4	83	1450 U/mL	no bilateral lung consolidation, pleural effusion, or splenopmegaly	oxygen saturation(95%), heart rate(90 beats/minute), blood pressure(120/80 mmHg)	hypertension,chronic renal failure	malaise,vomiting, fever (>39°C), fatigue	granulocyte colony-stimulating factor, methylprednisolone	discharged
TingYu Lin,2022	14; Female; China	BNT162b2 mRNA COVID-19 vaccine; first dose	15 days	1.43	4254.2			splenomegaly, enlarged lymph nodes		None	fever, headache, nausea, progressive tachypnea, drowsy consciousness, mottling skin, jaundice, hypotension	IVIG, methylprednisolone(pulse IV),venoarterial extracorporeal membrane oxygenation (VA-ECMO), prednisolone(oral)	discharged
Marie‑Lisa Hieber,2022	24; Female; Germany	BNT162b2 mRNA COVID-19 vaccine; first dose	10 days		138.244			enlarged cervical and supraclavicular lymph nodes	An abdominal ultrasound revealed a splenomegaly	None	fever,unspecifc fatigue,chills,increasing weakness and nausea	intravenous immunoglobulins (IVIGs),dexamethasone, the human interleukin 1 receptor antagonist Anakinra	discharged
Attwell L,2022	60; Male; United Kingdom	BNT162b2 mRNA COVID-19 vaccine; first dose	5 days	0.7	159076	558.18	4833 (0–2500)	bilateral pleural effusions	A repeat transthoracic echocar_x005fdiogram showed severe left ventricular (LV) systolic dysfunction.	tablet-controlled type 2 diabetes mellitus	breathless, fever (>39.3°C) and myalgia	broad spectrum antibiotics, vasopressors,continuous veno-venous haemofiltration (CVVH),methylprednisolone,prednisolone, intra_x005fvenous immunoglobulin and the IL-1receptor antagonist anakinra	improvement,continue to receive treatment
	70; Female; United Kingdom	the ChAdOx1 vaccine; first dose	7 days	0.94	5529		9232 (0–2500)	bilateral patchy infiltrates consistent with an acute pneumonitis.	Transthoracic echocardiogram was normal.Repeat cross_x005fsectional imaging showed progressive bilateral ground-glass opacities. Repeat echocardiogram showed significant deterioration in LV function.	stable JAK2-mutation positive essential throm_x005fbocythaemia, breast cancer in remission and a history of bee sting anaphylaxis	night sweats, breathlessness,myalgia,progressive fevers (39.2°C), cough, weight loss and general malaise	oral antibiotics changed to intravenous antibiotics, vasopres_x005f_x0002_sors，continuous veno-venous haemofiltration (CVVH)，a chest drain,methylprednisolone,prednisolone, intravenous immunoglobulin and the IL-1 receptor antagonist anakinra	died
	30; Male; United Kingdom	the ChAdOx1 vaccine; first dose	8 days	4.17	58255		3575 (0–2500)	bilateral lung consolidation, pleural effusions, a pericardial effusion of 1.5 cm diameter and mild splenomegaly.	Echocardi_x005f_x005f_x005f_x0002_ogram showed mild left ventricular systolic dysfunction.Repeat echocardio_x0002_graph showed deterioration in LV systolic function. A positron emission tomography (PET) CT scan showed intense bone marrow uptake and hypersplenism	anky_x005flosing spondylitis	fever (41.2°C), diarrhea, sore throat,pruritic rash and breathlessness	antibiotic therapy,methylprednisolone,prednisolone	improvement,continue to receive treatment
Giovanni Caocci,2021	38; Female; Italy	BNT162b2 mRNA COVID-19 vaccine; second dose	21 days		500	225	2.610 U/mL (223–710)	multiple enlarged tender lymph nodes		None	fever (40°C),chills,fatigue, diffuse cutaneous eruption of erythematous papules	methylprednisolone, prednisone	discharged
Hee WonPark,2022	21; Male; South Korea	BNT162b2 mRNA COVID-19 vaccine; second dose	14 days	1.3	23639		5776 U/mL	splenomegaly, hepatosplenomegaly	erythematous rash, icteric conjunctivae, normocellular marrow with sub_x005fstantial histiocytosis, active hemophagocytosis	None	general weakness,fever (39.5°C), myalgia,skin rash	steroid pulse, TazoperanTM, piperacillin and tazobactam(IV), methylprednisolone(IV), dexamethasone	discharged
Rehmat Ullah Awan,MD,2022	33; Male; USA	BNT162b2 mRNA COVID-19 vaccine; second dose	3 days	8.1 × 10^−5	>26000	738	49421.8		splenomegaly	hyperlipidemia,seasonal allergies	fever,chillsrash,malaise,jaundice,headaches,intermittent fevers (38.9°C),body aches,weight loss,arthralgias	prednisolone,prednisone,methylprednisolone, anakinra,intravenous immunoglobulin,etoposide, dexamethasone	multiorgan failure,then comfort care
Vernon Wu,2022	60; Male; USA	BNT162b2 mRNA COVID-19 vaccine; first dose	6 days	2.91	1365		33903.1		lymphadenopathy,Splenomegaly	Barrett’s esophagus	slurred speech, fevers(38.3°C),night sweats, loss of appetite, malaise, weight loss, delirium, non-ambulatory	prednisone,etoposide,dexamethasone	discharged
	32; Female; USA	BNT162b2 mRNA COVID-19 vaccine; second dose	52 days		68212		14 130.2		lymphadenopathy,Splenomegaly	None	arthralgias, fevers(40.8°C), myalgias, shortness of breath, weakness	prednisone,etoposide,dexamethasone,emapalumab-lzsg	discharged
Sassi, M 2021	85; Male; Tunisia	BNT162b2 mRNA COVID-19 vaccine; first dose	Shortly after vaccination	4.3	378					None	anorexia, asthenia, pruritus	Not mentioned	Not provided
Joseph M. Rocco，2022	52; Male; USA	BNT162b2 mRNA COVID-19 vaccine; first dose	1 day	1.05	8130	650	25603		Splenomegaly,EBV viremia	viral syndrome	fever(39.5°C), abdominal pain,acute liver injury, hypotension	Dexamethasone, etoposide	died
	53; Male; USA	BNT162b2 mRNA COVID-19 vaccine	4 days	4.35	75249	263	18100		Hepatomegaly,EBV viremia,Pseudomonas bacteremia and autoimmune hemolytic anemia	interstitial lung disease	fever(39.6°C), worsening hypoxia	Dexamethasone, IVIG, anakinra	discharged
	57; Male; USA	mRNA-1273 vaccine	12 days	<0.35	>15000	142	2473		Kaposi sarcoma herpesvirus viremia,decompensated heart failure	heart failure and well-controlled HIV	malaise nausea(30.2°C),hypotension	Methylprednisolone	died
	55; Female; USA	BNT162b2 mRNA COVID-19 vaccine	3 days	5.61	7724	106	4907		Hepatosplenomegaly	None	fever(40.1°C),cytopenia,hyperferritinemia	Ketorolac, anakinra (not tolerated)	Alive(pending chemotherapy, transplantation)
	48; Female; USA	mRNA-1273 vaccine	8 days	5.27	285	138		worsening mediastinal lymphadenopathy		HIV	fevers(39.4°C), cough,pleuritic chest pain	Prednisone, infliximab	Alive (remains on treatment for IRIS)

Figure 2. Ruxolitinib was bound to IL-2 Rα by molecular docking. (a) mode of binding of ruxolitinib to IL-2 Rα. (b) two-dimensional interaction between ruxolitinib and IL-2 Rα, circles represent amino acid residues, numbers inside are amino acid abbreviations and numbers, lines represent interactions, colors represent interaction types, and numbers on lines represent distances. (c) 3D structure of ruxolitinib binding to IL-2 Rα.