HLH Syndrome in a Community Hospital: The Challenge of an Early Diagnosis

Figures & data

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Table 1 Patient Data

Patient Number	1	2	3	4	9	10	5	6	7
Sex	F	F	F	M	M	F	F	F	F
Age(Y)	17.25	1.75	1.08	1.75	1.08	0.91	0.83	9.91	0.91
Race	Caucasian	Caucasian	Caucasian	Caucasian	Caucasian	Caucasian	Caucasian	Caucasian	Caucasian
Fever	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Splenomegaly	Yes	No	No	No	Yes	No	No	Yes	No
At least bicytopenia	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
ANC<1000/µL	20	600	700	800	370	200	780	400	5000
Hgb<10/µL	8.8	7	7.5	9.5	7.3	7.6	7.5	9.5	7.8
PLT<100 x 10^3/µL	257	40	200	200	84	56	90	50	52
Triglycerides/fibrinogen	No	Yes	No	Yes	No	Yes	Yes	Yes	Yes
Triglycerides>265mg/dL	100	600	200	115	133	328	480	300	1000
Fibrinogen<150 mg/dL	220	130	150	130	207	135	484	150	145
Ferritin (max)>500 ng/mL	Yes 1000	Yes 8600	Yes 6500	Yes 900	Yes 700	Yes 520	No 480	Yes 7450	Yes 6058
NK Function - Absent or very low	No 16%	Yes 0%	No 18%	No 20%	No 20%	No 20%	Yes 3.6%	No 20%	Yes 1%
Soluble IL2 Receptor (> 2000)	Yes 6000	Yes 5300	Yes 9200	Yes 3700	Yes 11,000	Yes 3000	Yes 4000	Yes 5000	Yes 13,000
Hemophagocytosis	Yes	Yes	Yes	NA	NA	NA	Yes	Yes	No
Total HLH-2004 Criteria	6/8	7/8	5/8	5/8	5/8	5/8	6/8	7/8	6/8
Perforin expression		Normal				Normal		Normal
Liver functions abnormalities	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	Yes
ALT (13–45 U/L)	119	105	167	47	73	90	30	155	31
AST (7–46 U/L)	145	135	484	106	44	146	48	159	86
Bilirubin (0.3–1.2 mg/dL)	18.9*	0.7	1.9	0.2	0.5	0.2	0.4	3.6	0.7
INR (0.8–1.2)	1.65	1.25	1.25	1.04	1.19	1.18	1.27	1.3	1.01
Patient Number	1	2	3	4	9	10	5	6	7
CNS	Normal CT	Normal MRI			Normal CT	Normal MRI			CSF WBC 76 (H) Protein 85 (H)
Markers of inflammation
ESR ≤ 20 mm/hr	NA	8	65	27	NA	NA	47	16	NA
CRP ≤ 0.5 mg/dL	26.5	0.98	2.38	1.2	24.83	2.45	30.7	4.7	36.19
Other organ involvement	MOF*								SVT
Infection	NA*	Adenovirus Type 4 and 7, HHV6	Adenovirus Type 7	Adenovirus Type not known	Streptococcus A	HHV6	Adenovirus Type not known	EBV	Streptococcus group A
Genetic workup**		Normal		Abnormal				Normal
Treatment	HLH-2004 Therapy		Dexamethasone with or without IVIG				IVIG single agent
	Dexamethasone, Etoposide, CSA	Dexamethasone, Etoposide, CSA	IVIG, Dexamethasone	Dexamethasone	IVIG, Dexamethasone	IVIG, Dexamethasone	IVIG	IVIG	IVIG
Length of stay (LOS) days	9	19	22	8	15	8	9	10	16
Alive/Dead	Dead*	Alive	Alive	Alive	Alive	Alive	Alive	Alive	Alive
Follow-up (years)	NA	8.2	8.1	7.3	5.3	5.9	7.1	2.6	6.9
Subsequent admissions	NA		Bronchiolitis obliterans Exacerbation				E.coli UTI
Subsequent major complications	NA		Severe Bronchiolitis obliterans	Mild Bronchiolitis obliterans

Notes: Yellow shades note positive HLH-2004 criteria. *Patient developed pseudomonas sepsis induced multiorgan failure complicating HLH-2004 therapy, with liver failure (bilirubin 18.9), and died day 9. . **Genetic workup included PRF1, UNC13D (Munc13-4), STXBP2 (Munc18-2), STX11, RAB27A and ITK.

Abbreviations: CNS, central nervous system; CSA, cyclosporin A; CT, computerized tomography; HLH, Hemophagocytic Lymphohistiocytosis; MOF, multiorgan failure; IVIG, intravenous gamma globulins; MRI, magnetic resonance imaging; WBC, white blood cell count.

Table 2 Summary Data

n		9
Gender	Male	3 (33%)
	Female	7 (78%)
Race	White - Caucasian	9 (100%)
Age (years)	Median (range)	1.1 (0.8–17.25)
	Average	3.9
HLH 2004 Criteria	≥ 5 of 8	9 (100%)
	Fever	9 (100%)
	Splenomegaly	3 (33%)
	Cytopenia	9 (100%)
	Elevated triglycerides and/or low fibrinogen	6 (66%)
	Elevated ferritin	8 (89%)
	Low/absent NK function	3 (33%)
	Elevated Soluble sIL-2R (CD25)	9 (100%)
	Hemophagocytosis*	5/6 (83.3%)
Other signs	Low Perforin expression	0/3
	Abnormal Genetic evaluation**	1/3
	Liver functions abnormalities	9 (100%)
	CNS Involvement	1 (11%)
Infection	Adenovirus***	4 (44%)
	HHV6***	2 (22%)
	Group A Streptococcus	2 (22%)
	EBV	1 (11%)
Treatment	Dexamethasone, Etoposide, CSA	2 (22%)
	Dexamethasone, IVIG	3 (33%)
	IVIG	3 (33%)
	Dexamethasone	1 (11%)
	HSCT	0 (0%)
Complications	Organ failure 2nd pseudomonas sepsis	1 (11%)
	Adenovirus-related Bronchiolitis Obliterans	2 (22%)
Outcome	Alive	8 (89%)
	Death	1 (11%)
Follow-up	Years, median (range)	7 (2.6–8.2)
Subsequent admissions	Bronchiolitis Obliterans, UTI	2 (22%)
Time Analysis	Length of stay, days, median (range)	10 (8–22)
	Fever Onset to admission, days, median (range)	4 (2–8)
	Fever onset to treatment, days, median (range)	7 (3–10)
	Time to resolution of fever, days median (range)	2 (1–9)

Notes: *Only total 6 bone marrows done, no lymph-node or liver biopsies done. **UNC13D (Munc13-4) with heterozygote loss of exon 31 only in the RNA but not in the DNA, which has unclear significance, and 2 additional heterozygote variants V779M and K867E, predicted to neutral and STXBP2 (Munc18-2) heterozygote variants I526V. ***One patient had both Adenovirus and HHV6. Adenovirus type known for 2 of 4 patients: one patient had type 4 (from throat) and type 7 (from blood); one patient had type 7.