Hemophagocytic lymph histiocytosis (HLH): etiologies, pathogenesis, treatment, and outcomes in critically ill patients: a review article and literature to review

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S. no	Author	Topic	Outcome
1.	Athale J. [1]	Challenges in Identifying Hemophagocytic Lymphohistiocytosis in the ICU	In the ICU, patients with an HLH diagnosis have a 10-fold higher serum ferritin than those with other diagnosis concerning elevated ferritin values, confirms that HLH patients with elevated ferritin levels have poor prognosis
2.	Dao D, et al. [7]	Etiologies and Clinical Outcomes of Patients with Secondary Hemophagocytic Lympho-histiocytosis at a Tertiary PICU	Causative factors for secondary HLH included cytomegalovirus-EBV coinfections (60%), EBV sole infections (20%), cytomegalovirus sole infections (16%) and one unknown cause (4%). 14 (56%) of the 25 patients survived. C Reactive Protein and mean PELOD-2 Score were significantly higher in fatal versus nonfatal cases which confirmed that C Reactive protein if elevated worsen the prognosis.
3.	Gregory J, et al. [13]	Outcomes Analysis of Children Diagnosed with Hemophagocytic Lympho-histiocytosis in the PICU	67% of the 33 patients had secondary HLH, 21% had primary HLH, and 12% had HLH of an unidentified cause. 1-year post hospital discharge survival rate was 58%. This study showed that HLH patients with increase ICU stay or increase length of hospital stay had more probability to die in the first year post discharge from the hospital
4.	Knaak C, et al. [6]	Treatment and Mortality of Hemophagocytic Lympho-histiocytosis in Critically Ill adult Patients: A Systematic Review with Pooled Analysis	Infections were reported most frequently as triggers for secondary HLH across all continents (49.9%), followed by malignancies (28.0%), autoimmune diseases (12.1%) unknown triggers (9.4%), and drugs (0.6%). Highest mortality was seen in the subset with unidentified cause of HLH syndrome. HLH patients treated with IVIG showed improved mortality while those on cyclosporine had increased mortality as it causes suppression of the immune system
5.	Meena NK, et al. [14]	The Performance of Diagnostic Criteria for Hemophagocytic Lymphohistiocytosis in Critically Ill Patients	2 of the 10 patients diagnosed with HLH survived overall. Individually, 5 of the 6 criteria had very high sensitivity values; The fulfilment of any 5 of the 6 criteria had a statistically significant specificity of 97.2%. The criteria of bi-cytopenia had statistically significant sensitivity and specificity. A cut point of ferritin of 1197 ng/mL was a good indicator of HLH with a specificity of 70.0% and a sensitivity of 90.0%. A cutoff of 143.5 of the H-Score with a specificity and sensitivity of 90% was assessed as optimum.
6.	Wohlfarth P, et al. [15]	Interleukin 1 Receptor Antagonist Anakinra, Intravenous Immunoglobulin, and Corticosteroids in the Management of Critically Ill Adult Patients with Hemophagocytic Lympho-histiocytosis	A median decline of 2.5 (1–4) and 3.5 (1–6) points in the SOFA scores of 6 of the 8 patients could be appreciated at 1 and 2 weeks after the initiation of anakinra therapy, respectively, indicating an improvement in organ dysfunction. Among the treatment options, early initiation of Anakinra therapy plays a vital role in decreasing hospital stay of HLH patients
7.	Wohlfarth P, et al. [15]	Prognostic Factors and Long-term Outcome in 52 Turkish Children with Hemophagocytic Lymphohistiocytosis	Of the 52 critically ill pediatric patients, 28 (54%) had primary HLH and 24 (46%) had secondary HLH. Overall, 58% patients survived. Primary HLH correlated with a significantly higher mortality rate of 66% than secondary HLH with a mortality rate of 16%. Which concludes that as secondary HLH usually have a cause, starting early treatment to treat the inciting factor lead to decrease in mortality of HLH patients
8.	Knaak C, et al. [3]	Hemophagocytic Lymphohistiocytosis in Critically Ill Patients	An overall mortality of 60% was seen. The trigger associated with highest mortality was that of malignancy (71.4%) and the trigger associated with lowest mortality was that of autoimmune disease (44.4%). Maximum SOFA score significantly correlated with 30-day mortality. Aspartate aminotransferase levels were also significantly higher in non-survivors.

Athale J. Challenges in identifying hemophagocytic lymphohistiocytosis in the icu. Crit Care Med. 2020;48(4):599–600.

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Dao D, Xoay TD, Galeano BK, et al. Etiologies and clinical outcomes of patients with secondary hemophagocytic lymphohistiocytosis at a tertiary picu. Pediatr Crit Care Med. 2019;20(7):e311- e318.

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Gregory J, Greenberg J, Basu S. Outcomes analysis of children diagnosed with hemophagocytic lymphohistiocytosis in the picu. Pediatr Crit Care Med. 2019;20(4):e185–e190.

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Knaak C, Schuster FS, Nyvlt P, et al. Treatment and mortality of hemophagocytic lymphohistiocytosis in adult critically ill patients: a systematic review with pooled analysis. Crit Care Med. 2020;48(11):e1137–e1146.

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Meena NK, Sinokrot O, Duggal A, et al. The performance of diagnostic criteria for hemophagocytic lymphohistiocytosis in critically ill patients. J Intensive Care Med. 2019 March 12:088506661983713. Published online. DOI: https://doi.org/10.1177/0885066619837139.

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Wohlfarth P, Agis H, Gualdoni GA, et al. Interleukin 1 receptor antagonist anakinra, intravenous immunoglobulin, and corticosteroids in the management of critically ill adult patients with hemophagocytic lymphohistiocytosis. J Intensive Care Med. 2019;34(9):723–731.

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Knaak C, Schuster FS, Spies C, et al. Hemophagocytic lymphohistiocytosis in critically ill patients. Shock. 2020;53(6):701–709.

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