40:
566:
782:, which can be used to estimate an individual's risk of HLH. In adults, soluble IL-2 receptor has been found to be a very sensitive marker for HLH, demonstrating 100% sensitivity for ruling out HLH below a cutoff of 2400 U/mL and optimal cutoff for ruling in at 2515 U/mL (sensitivity, 100%; specificity, 72.5%), with 93% specificity at >10 000 U/mL.
513:-dependent cytotoxicity. This inability to remove infected and antigen-presenting cells and terminate the immune response leads to uncontrolled proliferation and activation of the immune system with release of excessive cytokines. These cells then infiltrate organs, releasing more cytokines, which gives the clinical picture. The fever is caused by
143:
The onset of HLH occurs before the age of one year in approximately 70 percent of cases. Familial HLH should be suspected if siblings are diagnosed with HLH or if symptoms recur when therapy has been stopped. Familial HLH is an autosomal recessive disease, hence each sibling of a child with familial
1311:
Bode SF, Ammann S, Al-Herz W, Bataneant M, Dvorak CC, Gehring S, Gennery A, Gilmour KC, Gonzalez-Granado LI, GroĂź-Wieltsch U, Ifversen M, Lingman-Framme J, Matthes-Martin S, Mesters R, Meyts I, van
Montfrans JM, Pachlopnik Schmid J, Pai SY, Soler-Palacin P, Schuermann U, Schuster V, Seidel MG,
777:
Not all five out of eight criteria are required for diagnosis of HLH in adults, and a high index of suspicion is required for diagnosis as delay results in increased mortality. The diagnostic criteria were developed in pediatric populations and have not been validated for adult HLH patients.
833:(type 2). This is a rare autosomal recessive disorder characterized by partial albinism, hepatosplenomegaly, pancytopenia, hepatitis, immunologic abnormalities, and lymphohistiocytosis. Most cases have been diagnosed between 4 months and 7 years of age, with a mean age of about 17 months.
969:
A systematic review recently reported the pooled proportion are fever 97.2%, hepatomegaly 70.2%, splenomegaly 78.4%, thrombocytopenia 90.1%, anemia 76.0%, and serum ferritin ≥500 μg/L 97.1%. The case fatality rate is 14.6% among dengue hemophagocytic lymphohistiocytosis patients.
144:
HLH has a twenty-five–percent chance of developing the disease, a fifty-percent chance of carrying the defective gene (which is very rarely associated with any risk of disease), and a twenty-five–percent chance of not being affected and not carrying the gene defect.
816:
The diagnosis of acquired, or secondary, HLH is usually made in association with infection by viruses, bacteria, fungi, or parasites or in association with lymphoma, autoimmune disease, or metabolic disease. Acquired HLH may have decreased, normal, or increased
856:
HLH is a description of an immunophysiologic state in time. It can be dangerous to infer a genetic impairment of granule-mediated cytotoxicity in patients, especially older children and adults, who meet any of the various criteria for HLH. Thus, like
420:
231:
664:
Secondary haemophagocytic lymphohistiocytosis (acquired haemophagocytic lymphohistiocytosis) occurs after strong immunologic activation, such as that which can occur with systemic infection, immunodeficiency, or underlying malignancy.
1943:
Benson LA, Li H, Henderson LA, Solomon IH, Soldatos A, Murphy J, Bielekova B, Kennedy AL, Rivkin MJ, Davies KJ, Hsu AP, Holland SM, Gahl WA, Sundel RP, Lehmann LE, Lee MA, Alexandrescu S, Degar BA, Duncan CN, Gorman MP (May 2019).
941:
The prognosis is guarded with an overall mortality of 50%. Poor prognostic factors included HLH associated with malignancy, with half the patients dying by 1.4 months compared to 22.8 months for non-tumour associated HLH patients.
508:
The underlying causes, either inherited or acquired, lead to an unchecked immune response when exposed to triggers. Impaired NK-cell cytotoxicity is the hallmark of HLH. All genetic defects for familial HLH are related to
2296:
435:
for four of the causative genes, PRF1 (FHL2), UNC13D (FHL3), STX11 (FHL4), and STXBP2 (FHL5), is available on a clinical basis. Symptoms of FHL are usually evident within the first few months of life and may even develop
198:
The vast majority of patients who meet these criteria will not have a genetic cause of their disease, but rather HLH will be triggered by infection, malignancy, rheumatic disease, and/or certain treatments (as in the
875:
Most patients who meet HLH criteria will have secondary cases. Treatment for these patients should focus on the underlying contributors. Additionally, treatment of the inflammation of HLH itself is often required.
2494:
2479:
668:
Both forms are characterized by the overwhelming activation of normal T lymphocytes and macrophages, invariably leading to clinical and haematologic alterations and death in the absence of treatment.
3277:
624:
level are markedly elevated. In children, a ferritin above 10000 is very sensitive and specific for the diagnosis of HLH, however, the diagnostic utility for ferritin is less for adult HLH patients.
961:
The first case report of HLH was published in 1939 under the term "Histiocytic
Medullary Reticulosis". A second report would come out in 1952 that would rename the disorder that same year.
416:
949:
only). However, long-term remission without the use of cytotoxic and immune-suppressive therapies is unlikely in the majority of adults with HLH and in those with involvement of the
2305:
2847:
3365:
904:
431:
Five genetic subtypes (FHL1, FHL2, FHL3, FHL4, and FHL5) are described, with an estimated overall prevalence of one in 50,000 and equal gender distribution. Molecular
1062:
945:
Secondary HLH in some individuals may be self-limited because patients are able to fully recover after having received only supportive medical treatment (i.e., IV
661:(FHL) or familial erythrophagocytic lymphohistiocytosis, is a heterogeneous autosomal recessive disorder found to be more prevalent with parental consanguinity.
2359:
1520:
Daver N, McClain K, Allen CE, Parikh SA, Otrock Z, Rojas-Hernandez C, Blechacz B, Wang S, Minkov M, Jordan MB, La Rosée P, Kantarjian HM (September 2017).
2840:
1268:
2274:
844:
and haemophagocytic syndrome, with abnormal T-cell and macrophage activation. This type has a grave prognosis if untreated. Type 3 has mutations in
2075:
Fardet, Laurence (September 9, 2014). "Development and
Validation of the HScore, a Score for the Diagnosis of Reactive Hemophagocytic Syndrome".
415:) are associated with, and thought to be triggered or promoted by, EBV infection. These cases of HLH are classified as belonging to the class of
1216:
Giang HT, Banno K, Minh LH, Trinh LT, Loc LT, Eltobgy A, Tai LL, Khan A, Tuan NH, Reda Y, Samsom M, Nam NT, Huy NT, Hirayama K (November 2018).
2833:
2745:
2671:
1314:"The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis"
1463:
Braga Neto, Manuel B.; Badley, Andrew D.; Parikh, Sameer A.; Graham, Rondell P.; Kamath, Patrick S. (2022-02-03). Solomon, Caren G. (ed.).
326:
1995:"Hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis: a journey of a thousand miles begins with a single (big) step"
872:
has collected the published consensus management documents for the many contexts in which HLH occurs and they host full-text versions.
2661:
1839:"Evaluation of the role of secretory sphingomyelinase and bioactive sphingolipids as biomarkers in hemophagocytic lymphohistiocytosis"
210:
Primary HLH is caused by high-penetrance variants in genes associated with the syndrome, and thus is part of the phenotype of several
3445:
2265:"Press Announcements – FDA approves first treatment specifically for patients with rare and life-threatening type of immune disease"
1312:
Speckmann C, Stepensky P, Sykora KW, Tesi B, Vraetz T, Waruiru C, Bryceson YT, Moshous D, Lehmberg K, Jordan MB, Ehl S (July 2015).
1178:
Esteban, Ysabella M.; de Jong, Jill L. O.; Tesher, Melissa S. (1 August 2017). "An
Overview of Hemophagocytic Lymphohistiocytosis".
1218:"Dengue hemophagocytic syndrome: A systematic review and meta-analysis on epidemiology, clinical signs, outcomes, and risk factors"
682:
1. A molecular diagnosis consistent with HLH. These include the identification of pathologic mutations of PRF1, UNC13D, or STX11.
2625:
806:
984:
412:
3440:
2793:
2218:
Machowicz R, Janka G, Wiktor-Jedrzejczak W (March 2017). "Similar but not the same: Differential diagnosis of HLH and sepsis".
862:
3420:
3319:
2965:
799:
1363:
Mehta, Puja; McAuley, Daniel F.; Brown, Michael; Sanchez, Emilie; Tattersall, Rachel S.; Manson, Jessica J. (2020-03-28).
1054:
140:
HLH as defined by the HLH-04 criteria (see below) is a descriptive diagnosis. Its individual components are non-specific.
2509:
2298:
Clinical
Commissioning Policy: Anakinra for Haemophagocytic Lymphohistiocytosis (HLH) for adults and children in all ages
923:
Clinical
Commissioning Policy: Anakinra for Haemophagocytic Lymphohistiocytosis (HLH) for adults and children in all ages
440:. However, symptomatic presentation throughout childhood and even into young adulthood has been observed in some cases.
2943:
2856:
2754:
2798:
2735:
2725:
2682:
930:
861:, one must simultaneously manage both the acute physiologic changes associated with HLH (like systemic inflammation,
500:
Nearly half of the cases of type 2 familial hemophagocytic lymphohistiocytosis are due to bi-allelic PRF1 mutations.
2825:
1749:
Allen, Carl (June 2008). "Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis".
404:
causes such as bone marrow or other organ transplantations; chemotherapy; or therapy with immunosuppressing agents.
2990:
2764:
1627:
Zhang, Kejian; Filopovich, Alexandra H.; Johnson, Judith; Marsh, Rebecca A.; Villanueva, Joyce (January 17, 2013).
357:
112:
seen more often in children than in adults. It is a life-threatening disease of severe hyperinflammation caused by
2909:
1885:
2915:
3333:
791:
617:
330:
322:
2331:
3208:
3180:
3004:
2901:
2720:
2643:
1656:
671:
A subtype of primary HLH where the inflammation is limited to the central nervous system has been described.
338:
1266:
Wysocki CA (December 2017). "Comparing hemophagocytic lymphohistiocytosis in pediatric and adult patients".
2269:
2264:
1010:
879:
While optimal treatment of HLH is still being debated, current treatment regimes usually involve high dose
365:
334:
113:
2860:
2705:
2618:
2077:
1751:
407:
About 33% of all HLH cases, ~75% of Asian HLH cases, and nearly 100% of HLH cases caused by mutations in
1136:"How can an internal medicine specialist save a patient with hemophagocytic lymphohistiocytosis (HLH)?"
493:
307:
151:. Therefore, HLH should be included in the differential diagnosis of intensive care unit patients with
3401:
3053:
2814:
2656:
369:
211:
200:
39:
3349:
2710:
2695:
2529:
1889:
795:
315:
836:
Three types of
Griscelli syndrome are recognised: type 1 has neurologic symptoms and mutations in
565:
2788:
2775:
1577:
848:
and is characterized by partial albinism. This type does not pose a threat to those so affected.
3450:
3236:
2715:
2666:
2611:
2381:
Scott, Ronald Bodley; Robb-Smith, A.H.T. (July 22, 1939). "Histiocytic
Medullary Reticulosis".
950:
542:
373:
311:
187:
703:
Decreased blood cell counts affecting at least two of three lineages in the peripheral blood:
2750:
2730:
550:
125:
2171:"Autoimmune lymphoproliferative syndrome misdiagnosed as hemophagocytic lymphohistiocytosis"
706:
Haemoglobin <9 g/100 ml (in infants <4 weeks: haemoglobin <10 g/100 ml) (
3018:
2758:
2648:
729:
346:
109:
97:
1522:"A consensus review on malignancy-associated hemophagocytic lymphohistiocytosis in adults"
840:. Prognosis depends on the severity of neurologic manifestations. Type 2 has mutations in
8:
2783:
2687:
2498:
858:
760:
223:
215:
774:
In addition, in the case of familial HLH, no evidence of malignancy should be apparent.
732:(fasting, greater than or equal to 265 mg/100 ml) and/or decreased amounts of
298:
to attack EBV-infected cells. Malignant disorders associated with secondary HLH include
3152:
3111:
3091:
3075:
2442:
2417:
2195:
2170:
2146:
2121:
2102:
1970:
1945:
1863:
1838:
1776:
1685:
1660:
1601:
1572:
1548:
1521:
1502:
1489:
1464:
1440:
1415:
1391:
1364:
1340:
1313:
1293:
1245:
1217:
1111:
1084:
1031:
1005:
869:
830:
613:
186:. Laboratory findings may include elevated triglyceride levels, low fibrinogen levels,
171:
2503:
2394:
1381:
2855:
2540:
2447:
2398:
2351:
2235:
2231:
2200:
2151:
2137:
2094:
2057:
2016:
1975:
1925:
1868:
1819:
1768:
1731:
1690:
1638:
1606:
1553:
1506:
1494:
1445:
1396:
1345:
1285:
1237:
1195:
1157:
1116:
1036:
554:
510:
361:
160:
156:
63:
2106:
1780:
1297:
1249:
3337:
3261:
2740:
2437:
2429:
2390:
2343:
2332:"Prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis"
2227:
2190:
2182:
2141:
2133:
2086:
2047:
2006:
1965:
1957:
1915:
1858:
1850:
1809:
1760:
1721:
1680:
1672:
1596:
1586:
1543:
1535:
1526:
1484:
1476:
1435:
1427:
1386:
1376:
1335:
1327:
1277:
1229:
1187:
1147:
1106:
1096:
1026:
1018:
714:
639:
602:
598:
534:
353:
342:
219:
2580:
2252:
914:(proprietary name Gamifant) for the treatment of pediatric and adult primary HLH.
3034:
2534:
2347:
2052:
2035:
1961:
1814:
1800:
1795:
1331:
1281:
1191:
578:
432:
377:
303:
299:
175:
3379:
3252:
2545:
946:
892:
880:
148:
129:
51:
2591:
2488:
1920:
1903:
1628:
1101:
1085:"Your critical care patient may have HLH (hemophagocytic lymphohistiocytosis)"
3434:
3097:
2634:
1591:
1318:
979:
910:
On 20 November 2018, the FDA approved the anti-IFN-gamma monoclonal antibody
646:
530:
518:
514:
295:
2122:"Soluble interleukin-2 receptor is a sensitive diagnostic test in adult HLH"
605:. The liver function tests are usually elevated. A low level of the protein
3127:
3105:
2451:
2433:
2355:
2239:
2204:
2186:
2155:
2098:
2061:
2020:
1979:
1929:
1872:
1823:
1796:"Marked hyperferritinemia does not predict for HLH in the adult population"
1772:
1735:
1694:
1642:
1610:
1557:
1498:
1480:
1449:
1400:
1349:
1289:
1241:
1199:
1161:
1120:
1083:
Machowicz, Rafal; Janka, Gritta; Wiktor-Jedrzejczak, Wieslaw (2016-01-01).
1040:
1022:
896:
845:
809:. As a syndrome of intense inflammation it needs to be differentiated from
698:
586:
235:
132:
syndromes. There are inherited and non-inherited (acquired) causes of HLH.
55:
2402:
1431:
3164:
2586:
2011:
1994:
1661:"Human perforin mutations and susceptibility to multiple primary cancers"
1633:
918:
900:
888:
770:(soluble IL-2 receptor) >2400 U/ml (or per local reference laboratory)
746:
721:
570:
2471:
1902:
Ponnatt, Tanya Sajan; Lilley, Cullen M.; Mirza, Kamran M. (2021-08-04).
1152:
1135:
865:, hepatitis, etc.) and look deeply for various underlying contributors.
290:
Secondary HLH (sHLH) is associated with, and thought to be promoted by,
3327:
3313:
2879:
1676:
1539:
1414:
Fajgenbaum, David C.; June, Carl H. (2020-12-03). Longo, Dan L. (ed.).
911:
754:
733:
628:
594:
574:
401:
397:
291:
272:
204:
159:. Patients in the earlier stages of HLH are frequently hospitalized at
121:
117:
81:
72:
68:
47:
2090:
1854:
1764:
1726:
1709:
3395:
2895:
2575:
2551:
2169:
Rudman
Spergel A, Walkovich K, Price S, et al. (November 2013).
2036:"How I treat hemophagocytic lymphohistiocytosis in the adult patient"
1233:
884:
779:
537:. TNF-alpha and TNF-gamma may also lead to inhibition of lipoprotein
526:
522:
152:
3303:
3220:
2875:
1365:"COVID-19: consider cytokine storm syndromes and immunosuppression"
1055:"Familial hemophagocytic lymphohistiocytosis: MedlinePlus Genetics"
926:
739:
621:
546:
462:
443:
The five subtypes of FHL are each associated with a specific gene:
389:
385:
381:
294:
and non-malignant diseases that likewise weaken the ability of the
260:
227:
179:
2556:
805:
Other conditions that may be confused with this condition include
321:
In rheumatic diseases, this syndrome is more often referred to as
3192:
3174:
818:
632:
606:
2603:
2523:
2520:
2517:
2514:
2217:
1082:
3373:
3359:
3271:
3230:
3136:
3069:
2937:
2483:
1708:
Usmani, G. Naheed; Woda, Bruce A.; Newburger, Peter E. (2013).
841:
810:
750:
707:
590:
538:
488:
470:
264:
252:
248:
240:
1837:
Jenkins RW, Clarke CJ, Lucas JT, et al. (November 2013).
798:
that present with hemophagocytic lymphohistiocytosis, such as
778:
Attempts to improve diagnosis of HLH have included use of the
3285:
3202:
3146:
3012:
2998:
2984:
2927:
837:
790:
The differential diagnosis of HLH includes secondary HLH and
692:
479:
449:
393:
283:
268:
244:
214:. The most common and best studied causes of Primary HLH are
167:
2168:
1462:
695:(defined as a temperature >100.3 °F, >38 °C)
3047:
2959:
2889:
1946:"Pediatric CNS-isolated hemophagocytic lymphohistiocytosis"
1626:
1573:"Epstein–Barr Virus and Hemophagocytic Lymphohistiocytosis"
767:
457:
276:
256:
183:
2416:
Farquhar, James W.; Claireaux, Albert E. (December 1952).
1310:
417:
Epstein–Barr virus–associated lymphoproliferative diseases
16:
Immune disorder in the blood leading to hyperinflammation
1942:
1362:
688:
2. Fulfillment of five out of the eight criteria below:
238:. These mutations include those in the following genes:
226:
use to kill targeted cells, such as those infected with
1519:
147:
Patients with HLH, especially when untreated, may need
2461:
1177:
1710:"Advances in understanding the pathogenesis of HLH"
1707:
1215:
679:The current (2008) diagnostic criteria for HLH are
1901:
1836:
1655:
1269:Current Opinion in Allergy and Clinical Immunology
2415:
3432:
1992:
1659:, Thia KY, Andrews M, et al. (April 2013).
1134:Machowicz, Rafal; Basak, Grzegorz (2020-03-05).
985:X-linked lymphoproliferative disease § XLP2
2380:
2253:https://www.histiocytesociety.org/HLH-Consensus
1908:Archives of Pathology & Laboratory Medicine
1173:
1171:
903:have also been used. Other medications include
216:loss of function, (i.e. inactivating) mutations
190:, and elevated ferritin levels (among others).
1413:
1261:
1259:
1133:
2841:
2746:Hereditary progressive mucinous histiocytosis
2672:Congenital self-healing reticulohistiocytosis
2619:
2211:
1629:"Familial Hemophagocytic Lymphohistiocytosis"
736:in the blood (≤ 150 mg/100 ml)
589:—including a decreased number of circulating
1564:
1513:
1168:
659:familial haemophagocytic lymphohistiocytosis
2592:Familial Hemophagocytic Lymphohistiocytosis
2294:
1830:
1649:
1304:
1256:
413:X-linked lymphoproliferative disease type 1
2848:
2834:
2626:
2612:
2162:
1986:
1936:
1622:
1620:
38:
2441:
2194:
2145:
2051:
2010:
1993:Jordan MB, Filipovich AH (October 2008).
1969:
1919:
1888:at the U.S. National Library of Medicine
1862:
1813:
1725:
1684:
1600:
1590:
1547:
1488:
1439:
1390:
1380:
1339:
1211:
1209:
1151:
1110:
1100:
1030:
829:A major differential diagnosis of HLH is
785:
180:yellow discoloration of the skin and eyes
2288:
1006:"Hemophagocytic syndromes and infection"
564:
2220:Critical Reviews in Oncology/Hematology
1617:
1265:
807:autoimmune lymphoproliferative syndrome
3433:
3320:Congenital generalized lipodystrophy 3
2794:Interdigitating dendritic cell sarcoma
2418:"Familial Haemophagocytic Reticulosis"
2329:
2119:
2074:
2033:
1793:
1206:
1003:
933:) to be used in the treatment of HLH.
813:, which may be extremely challenging.
674:
2829:
2607:
2362:from the original on October 18, 2021
1748:
1570:
824:
400:. Secondary HLH may also result from
135:
3292:Hemophagocytic lymphohistiocytosis 4
1904:"Hemophagocytic Lymphohistiocytosis"
1140:Polish Archives of Internal Medicine
800:X-linked lymphoproliferative disease
529:is due to the suppressive effect on
352:Secondary HLH also occurs rarely in
331:adult onset forms of Still's disease
323:macrophage activation syndrome (MAS)
1886:Lymphohistiocytosis,+Hemophagocytic
172:enlargement of the liver and spleen
94:haemophagocytic lymphohistiocytosis
13:
2944:Cranio-lenticulo-sutural dysplasia
2857:Inherited disorders of trafficking
2755:Multicentric reticulohistiocytosis
2701:Hemophagocytic lymphohistiocytosis
730:High blood levels of triglycerides
503:
86:hemophagocytic lymphohistiocytosis
25:Hemophagocytic lymphohistiocytosis
14:
3462:
3334:Limb-girdle muscular dystrophy 2B
2799:Follicular dendritic cell sarcoma
2736:Progressive nodular histiocytosis
2726:Generalized eruptive histiocytoma
2683:non-Langerhans cell histiocytosis
2633:
931:interleukin 1 receptor antagonist
652:
376:); and infections caused by EBV,
128:. It is classified as one of the
3446:Diseases of immune dysregulation
3209:Hereditary spastic paraplegia 10
2991:X-linked intellectual disability
2765:Indeterminate cell histiocytosis
2422:Archives of Disease in Childhood
2232:10.1016/j.critrevonc.2017.03.023
2138:10.1182/bloodadvances.2017012310
1950:Neurol Neuroimmunol Neuroinflamm
1794:Schram, Alison (March 5, 2015).
587:decreased numbers of blood cells
585:The blood count typically shows
545:. Activated macrophages secrete
358:severe combined immunodeficiency
218:in genes that code for proteins
3181:Hereditary spastic paraplegia 4
2662:Hand–Schüller–Christian disease
2409:
2374:
2323:
2277:from the original on 2019-04-23
2257:
2246:
2113:
2068:
2027:
1895:
1879:
1787:
1742:
1701:
1469:New England Journal of Medicine
1456:
1420:New England Journal of Medicine
1407:
1065:from the original on 2021-01-25
212:inborn errors of immunity (IEI)
2120:Hayden, Anna (December 2017).
2034:Schram, Alison (May 7, 2015).
1714:British Journal of Haematology
1356:
1127:
1076:
1047:
997:
792:macrophage-activation syndrome
618:erythrocyte sedimentation rate
325:and occurs most frequently in
166:HLH clinically manifests with
1:
3441:Autosomal recessive disorders
2721:Benign cephalic histiocytosis
2644:Langerhans cell histiocytosis
2395:10.1016/S0140-6736(00)61951-7
2330:Parikh, Sameer (April 2014).
1382:10.1016/S0140-6736(20)30628-0
990:
631:level is usually low and the
339:juvenile idiopathic arthritis
124:that secrete high amounts of
3421:vesicular transport proteins
2861:vesicular transport proteins
2348:10.1016/j.mayocp.2013.12.012
2295:NHS England (October 2021).
2270:Food and Drug Administration
2078:Arthritis & Rheumatology
2053:10.1182/blood-2015-01-551622
1962:10.1212/NXI.0000000000000560
1815:10.1182/blood-2014-10-602607
1752:Pediatric Blood & Cancer
1332:10.3324/haematol.2014.121608
1282:10.1097/ACI.0000000000000405
1192:10.3928/19382359-20170717-01
953:(brain and/or spinal cord).
936:
851:
560:
335:systemic lupus erythematosus
7:
3005:Hermansky–Pudlak syndrome 2
973:
964:
657:Primary HLH, also known as
601:. The bone marrow may show
569:Light microscopic image of
426:
10:
3467:
956:
796:primary immunodeficiencies
494:Syntaxin binding protein 2
354:immunodeficiency disorders
308:acute lymphocytic leukemia
114:uncontrolled proliferation
3416:
3402:Distal muscular dystrophy
3390:
3348:
3302:
3260:
3251:
3219:
3191:
3163:
3135:
3126:
3086:
3064:
3042:
3033:
2976:
2954:
2926:
2902:Hermansky–Pudlak syndrome
2874:
2867:
2807:
2773:
2680:
2641:
2566:
2465:
1921:10.5858/arpa.2020-0802-RA
1102:10.1186/s13054-016-1369-3
1004:Fisman, David N. (2000).
905:cytokine targeted therapy
745:Haemophagocytosis in the
699:Enlargement of the spleen
645:Bone marrow biopsy shows
201:cytokine release syndrome
193:
62:
46:
37:
29:
24:
3350:Vacuolar protein sorting
3237:Spinocerebellar ataxia 5
2916:Chédiak–Higashi syndrome
2696:Juvenile xanthogranuloma
1890:Medical Subject Headings
1592:10.3389/fimmu.2017.01902
929:(a modified recombinant
720:Neutrophils <1Ă—10/L (
713:Platelets <100Ă—10/L (
609:in the blood is common.
366:Wiskott–Aldrich syndrome
316:myelodysplastic syndrome
106:haemophagocytic syndrome
2789:Langerhans cell sarcoma
2776:malignant histiocytosis
2706:Erdheim-Chester disease
2336:Mayo Clinic Proceedings
1578:Frontiers in Immunology
1465:"Calm before the Storm"
2716:Sea-blue histiocytosis
2667:Eosinophilic granuloma
2434:10.1136/adc.27.136.519
2187:10.1542/peds.2012-2748
1999:Bone Marrow Transplant
1481:10.1056/NEJMcps2111163
1023:10.3201/eid0606.000608
951:central nervous system
786:Differential diagnosis
582:
543:triglyceride synthesis
374:dyskeratosis congenita
337:. It occurs rarely in
312:acute myeloid leukemia
126:inflammatory cytokines
2815:Rosai–Dorfman disease
2751:Reticulohistiocytosis
2731:Xanthoma disseminatum
2657:Letterer–Siwe disease
1432:10.1056/NEJMra2026131
1011:Emerging Infect. Dis.
568:
551:plasminogen activator
370:ataxia–telangiectasia
3153:Griscelli syndrome 1
3112:Griscelli syndrome 3
3076:Griscelli syndrome 2
2759:Reticulohistiocytoma
2711:Niemann–Pick disease
2649:X-type histiocytosis
2012:10.1038/bmt.2008.232
577:containing numerous
347:rheumatoid arthritis
176:enlarged lymph nodes
110:hematologic disorder
54:within macrophages.
2784:Histiocytic sarcoma
2688:Non-X histiocytosis
1153:10.20452/pamw.15226
761:natural killer cell
675:Diagnostic criteria
635:level is elevated.
3338:Long QT syndrome 9
2567:External resources
2311:on 13 October 2021
1677:10.4161/onci.24185
1540:10.1002/cncr.30826
870:Histiocyte Society
868:The International
831:Griscelli syndrome
825:Griscelli syndrome
614:C reactive protein
583:
581:in their cytoplasm
327:the juvenile onset
232:Epstein-Barr virus
136:Signs and symptoms
3428:
3427:
3412:
3411:
3247:
3246:
3122:
3121:
3029:
3028:
2868:Vesicle formation
2823:
2822:
2601:
2600:
2091:10.1002/art.38690
1855:10.1002/ajh.23535
1765:10.1002/pbc.21423
1727:10.1111/bjh.12293
1571:Marsh RA (2017).
1375:(10229): 1033–4.
595:white blood cells
555:hyperfibrinolysis
533:by TNF-alpha and
362:DiGeorge syndrome
220:cytotoxic T cells
205:CART cell therapy
161:internal medicine
157:hyperferritinemia
149:intensive therapy
108:, is an uncommon
92:), also known as
78:
77:
19:Medical condition
3458:
3262:Synaptic vesicle
3258:
3257:
3133:
3132:
3040:
3039:
2872:
2871:
2850:
2843:
2836:
2827:
2826:
2741:Papular xanthoma
2628:
2621:
2614:
2605:
2604:
2463:
2462:
2456:
2455:
2445:
2428:(136): 519–525.
2413:
2407:
2406:
2378:
2372:
2371:
2369:
2367:
2327:
2321:
2320:
2318:
2316:
2310:
2304:. Archived from
2303:
2292:
2286:
2285:
2283:
2282:
2261:
2255:
2250:
2244:
2243:
2215:
2209:
2208:
2198:
2166:
2160:
2159:
2149:
2117:
2111:
2110:
2072:
2066:
2065:
2055:
2031:
2025:
2024:
2014:
1990:
1984:
1983:
1973:
1940:
1934:
1933:
1923:
1899:
1893:
1883:
1877:
1876:
1866:
1834:
1828:
1827:
1817:
1791:
1785:
1784:
1746:
1740:
1739:
1729:
1705:
1699:
1698:
1688:
1653:
1647:
1646:
1624:
1615:
1614:
1604:
1594:
1568:
1562:
1561:
1551:
1517:
1511:
1510:
1492:
1460:
1454:
1453:
1443:
1416:"Cytokine Storm"
1411:
1405:
1404:
1394:
1384:
1360:
1354:
1353:
1343:
1308:
1302:
1301:
1263:
1254:
1253:
1234:10.1002/rmv.2005
1213:
1204:
1203:
1180:Pediatric Annals
1175:
1166:
1165:
1155:
1131:
1125:
1124:
1114:
1104:
1080:
1074:
1073:
1071:
1070:
1051:
1045:
1044:
1034:
1001:
917:In October 2021
742:≥ 500 ng/ml
715:thrombocytopenia
640:sphingomyelinase
603:hemophagocytosis
573:showing stromal
343:Kawasaki disease
203:associated with
98:British spelling
42:
22:
21:
3466:
3465:
3461:
3460:
3459:
3457:
3456:
3455:
3431:
3430:
3429:
3424:
3408:
3386:
3344:
3298:
3278:CEDNIK syndrome
3243:
3215:
3187:
3159:
3118:
3082:
3060:
3025:
2972:
2950:
2922:
2863:
2854:
2824:
2819:
2803:
2769:
2686:
2676:
2647:
2637:
2632:
2602:
2597:
2596:
2562:
2561:
2474:
2460:
2459:
2414:
2410:
2389:(6047): 194–8.
2379:
2375:
2365:
2363:
2328:
2324:
2314:
2312:
2308:
2301:
2293:
2289:
2280:
2278:
2263:
2262:
2258:
2251:
2247:
2216:
2212:
2167:
2163:
2132:(26): 2529–34.
2118:
2114:
2073:
2069:
2046:(19): 2908–14.
2032:
2028:
1991:
1987:
1941:
1937:
1900:
1896:
1884:
1880:
1849:(11): E265–72.
1835:
1831:
1808:(10): 1548–52.
1792:
1788:
1747:
1743:
1706:
1702:
1654:
1650:
1625:
1618:
1569:
1565:
1534:(17): 3229–40.
1518:
1514:
1461:
1457:
1426:(23): 2255–73.
1412:
1408:
1361:
1357:
1309:
1305:
1264:
1257:
1214:
1207:
1176:
1169:
1132:
1128:
1081:
1077:
1068:
1066:
1059:medlineplus.gov
1053:
1052:
1048:
1002:
998:
993:
976:
967:
959:
939:
881:corticosteroids
854:
827:
788:
677:
655:
591:red blood cells
579:red blood cells
563:
506:
504:Pathophysiology
433:genetic testing
429:
378:cytomegalovirus
304:B-cell lymphoma
300:T-cell lymphoma
196:
138:
52:red blood cells
20:
17:
12:
11:
5:
3464:
3454:
3453:
3448:
3443:
3426:
3425:
3417:
3414:
3413:
3410:
3409:
3407:
3406:
3405:
3404:
3391:
3388:
3387:
3385:
3384:
3383:
3382:
3380:Cohen syndrome
3370:
3369:
3368:
3355:
3353:
3346:
3345:
3343:
3342:
3341:
3340:
3324:
3323:
3322:
3309:
3307:
3300:
3299:
3297:
3296:
3295:
3294:
3282:
3281:
3280:
3267:
3265:
3255:
3253:Vesicle fusion
3249:
3248:
3245:
3244:
3242:
3241:
3240:
3239:
3226:
3224:
3217:
3216:
3214:
3213:
3212:
3211:
3198:
3196:
3189:
3188:
3186:
3185:
3184:
3183:
3170:
3168:
3161:
3160:
3158:
3157:
3156:
3155:
3142:
3140:
3130:
3124:
3123:
3120:
3119:
3117:
3116:
3115:
3114:
3102:
3101:
3100:
3087:
3084:
3083:
3081:
3080:
3079:
3078:
3065:
3062:
3061:
3059:
3058:
3057:
3056:
3043:
3037:
3031:
3030:
3027:
3026:
3024:
3023:
3022:
3021:
3009:
3008:
3007:
2995:
2994:
2993:
2980:
2978:
2974:
2973:
2971:
2970:
2969:
2968:
2955:
2952:
2951:
2949:
2948:
2947:
2946:
2933:
2931:
2924:
2923:
2921:
2920:
2919:
2918:
2906:
2905:
2904:
2885:
2883:
2869:
2865:
2864:
2853:
2852:
2845:
2838:
2830:
2821:
2820:
2818:
2817:
2811:
2809:
2805:
2804:
2802:
2801:
2796:
2791:
2786:
2780:
2778:
2771:
2770:
2768:
2767:
2762:
2748:
2743:
2738:
2733:
2728:
2723:
2718:
2713:
2708:
2703:
2698:
2692:
2690:
2678:
2677:
2675:
2674:
2669:
2664:
2659:
2653:
2651:
2639:
2638:
2631:
2630:
2623:
2616:
2608:
2599:
2598:
2595:
2594:
2583:
2571:
2570:
2568:
2564:
2563:
2560:
2559:
2548:
2537:
2526:
2506:
2491:
2475:
2470:
2469:
2467:
2466:Classification
2458:
2457:
2408:
2373:
2342:(4): 484–492.
2322:
2287:
2273:. 2019-03-06.
2256:
2245:
2210:
2181:(5): e1440–4.
2161:
2126:Blood Advances
2112:
2085:(9): 2613–20.
2067:
2026:
1985:
1935:
1914:(4): 507–519.
1894:
1878:
1843:Am. J. Hematol
1829:
1786:
1759:(6): 1227–35.
1741:
1720:(5): 609–622.
1700:
1665:Oncoimmunology
1648:
1616:
1563:
1512:
1475:(5): 479–485.
1455:
1406:
1355:
1303:
1276:(6): 405–413.
1255:
1205:
1186:(8): e309–13.
1167:
1126:
1075:
1046:
995:
994:
992:
989:
988:
987:
982:
975:
972:
966:
963:
958:
955:
947:immunoglobulin
938:
935:
895:is also used.
893:immunoglobulin
891:. Intravenous
853:
850:
826:
823:
787:
784:
772:
771:
764:
759:Low or absent
757:
743:
737:
727:
726:
725:
718:
711:
701:
696:
676:
673:
654:
653:Classification
651:
562:
559:
505:
502:
498:
497:
484:
475:
466:
453:
428:
425:
195:
192:
137:
134:
130:cytokine storm
102:hemophagocytic
76:
75:
66:
60:
59:
44:
43:
35:
34:
31:
27:
26:
18:
15:
9:
6:
4:
3:
2:
3463:
3452:
3451:Histiocytosis
3449:
3447:
3444:
3442:
3439:
3438:
3436:
3423:
3422:
3415:
3403:
3400:
3399:
3398:
3397:
3393:
3392:
3389:
3381:
3378:
3377:
3376:
3375:
3371:
3367:
3364:
3363:
3362:
3361:
3357:
3356:
3354:
3351:
3347:
3339:
3335:
3332:
3331:
3330:
3329:
3325:
3321:
3318:
3317:
3316:
3315:
3311:
3310:
3308:
3305:
3301:
3293:
3290:
3289:
3288:
3287:
3283:
3279:
3276:
3275:
3274:
3273:
3269:
3268:
3266:
3263:
3259:
3256:
3254:
3250:
3238:
3235:
3234:
3233:
3232:
3228:
3227:
3225:
3222:
3218:
3210:
3207:
3206:
3205:
3204:
3200:
3199:
3197:
3194:
3190:
3182:
3179:
3178:
3177:
3176:
3172:
3171:
3169:
3166:
3162:
3154:
3151:
3150:
3149:
3148:
3144:
3143:
3141:
3138:
3134:
3131:
3129:
3125:
3113:
3110:
3109:
3108:
3107:
3103:
3099:
3098:Choroideremia
3096:
3095:
3094:
3093:
3089:
3088:
3085:
3077:
3074:
3073:
3072:
3071:
3067:
3066:
3063:
3055:
3052:
3051:
3050:
3049:
3045:
3044:
3041:
3038:
3036:
3032:
3020:
3017:
3016:
3015:
3014:
3010:
3006:
3003:
3002:
3001:
3000:
2996:
2992:
2989:
2988:
2987:
2986:
2982:
2981:
2979:
2975:
2967:
2964:
2963:
2962:
2961:
2957:
2956:
2953:
2945:
2942:
2941:
2940:
2939:
2935:
2934:
2932:
2929:
2925:
2917:
2914:
2913:
2912:
2911:
2907:
2903:
2900:
2899:
2898:
2897:
2892:
2891:
2887:
2886:
2884:
2881:
2877:
2873:
2870:
2866:
2862:
2858:
2851:
2846:
2844:
2839:
2837:
2832:
2831:
2828:
2816:
2813:
2812:
2810:
2806:
2800:
2797:
2795:
2792:
2790:
2787:
2785:
2782:
2781:
2779:
2777:
2772:
2766:
2763:
2760:
2756:
2752:
2749:
2747:
2744:
2742:
2739:
2737:
2734:
2732:
2729:
2727:
2724:
2722:
2719:
2717:
2714:
2712:
2709:
2707:
2704:
2702:
2699:
2697:
2694:
2693:
2691:
2689:
2684:
2679:
2673:
2670:
2668:
2665:
2663:
2660:
2658:
2655:
2654:
2652:
2650:
2645:
2640:
2636:
2635:Histiocytosis
2629:
2624:
2622:
2617:
2615:
2610:
2609:
2606:
2593:
2589:
2588:
2584:
2582:
2578:
2577:
2573:
2572:
2569:
2565:
2558:
2554:
2553:
2549:
2547:
2543:
2542:
2538:
2536:
2532:
2531:
2527:
2525:
2522:
2519:
2516:
2512:
2511:
2507:
2505:
2501:
2500:
2496:
2492:
2490:
2486:
2485:
2481:
2477:
2476:
2473:
2468:
2464:
2453:
2449:
2444:
2439:
2435:
2431:
2427:
2423:
2419:
2412:
2404:
2400:
2396:
2392:
2388:
2384:
2377:
2361:
2357:
2353:
2349:
2345:
2341:
2337:
2333:
2326:
2307:
2300:
2299:
2291:
2276:
2272:
2271:
2266:
2260:
2254:
2249:
2241:
2237:
2233:
2229:
2225:
2221:
2214:
2206:
2202:
2197:
2192:
2188:
2184:
2180:
2176:
2172:
2165:
2157:
2153:
2148:
2143:
2139:
2135:
2131:
2127:
2123:
2116:
2108:
2104:
2100:
2096:
2092:
2088:
2084:
2080:
2079:
2071:
2063:
2059:
2054:
2049:
2045:
2041:
2037:
2030:
2022:
2018:
2013:
2008:
2004:
2000:
1996:
1989:
1981:
1977:
1972:
1967:
1963:
1959:
1955:
1951:
1947:
1939:
1931:
1927:
1922:
1917:
1913:
1909:
1905:
1898:
1891:
1887:
1882:
1874:
1870:
1865:
1860:
1856:
1852:
1848:
1844:
1840:
1833:
1825:
1821:
1816:
1811:
1807:
1803:
1802:
1797:
1790:
1782:
1778:
1774:
1770:
1766:
1762:
1758:
1754:
1753:
1745:
1737:
1733:
1728:
1723:
1719:
1715:
1711:
1704:
1696:
1692:
1687:
1682:
1678:
1674:
1671:(4): e24185.
1670:
1666:
1662:
1658:
1652:
1644:
1640:
1636:
1635:
1630:
1623:
1621:
1612:
1608:
1603:
1598:
1593:
1588:
1584:
1580:
1579:
1574:
1567:
1559:
1555:
1550:
1545:
1541:
1537:
1533:
1529:
1528:
1523:
1516:
1508:
1504:
1500:
1496:
1491:
1486:
1482:
1478:
1474:
1470:
1466:
1459:
1451:
1447:
1442:
1437:
1433:
1429:
1425:
1421:
1417:
1410:
1402:
1398:
1393:
1388:
1383:
1378:
1374:
1370:
1366:
1359:
1351:
1347:
1342:
1337:
1333:
1329:
1326:(7): 978–88.
1325:
1321:
1320:
1319:Haematologica
1315:
1307:
1299:
1295:
1291:
1287:
1283:
1279:
1275:
1271:
1270:
1262:
1260:
1251:
1247:
1243:
1239:
1235:
1231:
1227:
1223:
1222:Rev Med Virol
1219:
1212:
1210:
1201:
1197:
1193:
1189:
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1089:Critical Care
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344:
340:
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319:
317:
313:
309:
305:
301:
297:
296:immune system
293:
288:
286:
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280:
278:
274:
270:
266:
262:
258:
254:
250:
246:
242:
237:
234:(EBV) or the
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229:
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221:
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208:
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191:
189:
188:transaminitis
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3128:Cytoskeleton
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2366:December 14,
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2039:
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1949:
1938:
1911:
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1897:
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1143:
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1067:. Retrieved
1058:
1049:
1017:(6): 601–8.
1014:
1009:
999:
968:
960:
944:
940:
922:
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909:
897:Methotrexate
878:
874:
867:
855:
846:melanophilin
835:
828:
815:
804:
789:
776:
773:
687:
684:
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469:
456:
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442:
437:
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289:
282:
239:
236:Dengue virus
209:
197:
165:
146:
142:
139:
105:
101:
93:
89:
85:
79:
3165:Microtubule
2587:GeneReviews
1956:(3): e560.
1634:GeneReviews
925:, allowing
919:NHS England
901:vincristine
889:cyclosporin
755:lymph nodes
747:bone marrow
722:neutropenia
575:macrophages
571:bone marrow
553:leading to
419:and termed
341:, juvenile
122:macrophages
118:lymphocytes
30:Other names
3435:Categories
2880:Melanosome
2541:DiseasesDB
2383:The Lancet
2315:14 October
2281:2018-11-20
2175:Pediatrics
1657:Trapani JA
1645:. NBK1444.
1369:The Lancet
1095:(1): 215.
1069:2021-01-24
991:References
921:published
912:emapalumab
821:activity.
734:fibrinogen
629:fibrinogen
627:The serum
612:The serum
474:(Munc13-4)
402:iatrogenic
398:SARS-CoV-2
116:of benign
82:hematology
73:immunology
69:Hematology
48:Micrograph
3419:See also
2808:Ungrouped
2576:eMedicine
2557:234437005
2552:SNOMED CT
1507:246488008
937:Prognosis
885:etoposide
852:Treatment
794:or other
599:platelets
561:Diagnosis
535:TNF-gamma
527:cytopenia
523:TNF-alpha
496:)/UNC18-2
292:malignant
230:like the
228:pathogens
153:cytopenia
64:Specialty
3304:Caveolae
3221:Spectrin
2966:CDOG IIE
2876:Lysosome
2774:WHO-III/
2452:13008468
2360:Archived
2356:24581757
2275:Archived
2240:28477737
2226:: 1–12.
2205:24101757
2156:29296904
2107:43419202
2099:24782338
2062:25758828
2021:18679369
1980:31044148
1930:34347856
1873:23828274
1824:25573993
1781:25546028
1773:18085676
1736:23577835
1695:23734337
1643:20301617
1611:29358936
1585:: 1902.
1558:28621800
1499:35108473
1450:33264547
1401:32192578
1350:26022711
1298:11439142
1290:28957822
1250:52002485
1242:30109914
1200:28806468
1162:32134401
1121:27389585
1063:Archived
1041:11076718
974:See also
965:Research
927:Anakinra
766:Soluble
763:activity
740:Ferritin
622:ferritin
547:ferritin
463:Perforin
438:in utero
427:Genetics
421:EBV+ HLH
390:protozoa
386:bacteria
382:HIV/AIDS
356:such as
224:NK cells
182:, and a
50:showing
3193:Kinesin
2681:WHO-II/
2581:ped/745
2535:D051359
2443:1988563
2403:6131175
2196:3813387
2147:5728644
1971:6467688
1864:4348111
1686:3654607
1602:5766650
1549:5568927
1490:8830531
1441:7727315
1392:7270045
1341:4486233
1112:4937543
1032:2640913
957:History
819:NK cell
633:D-dimer
607:albumin
511:granule
333:and in
163:wards.
100:), and
3374:VPS13B
3360:VPS33B
3272:SNAP29
3231:SPTBN2
3137:Myosin
3070:RAB27A
2938:SEC23A
2642:WHO-I/
2524:603552
2521:608898
2518:603553
2515:267700
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2440:
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1968:
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1871:
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780:HScore
751:spleen
708:anemia
620:, and
597:, and
539:lipase
525:; the
489:STXBP2
486:FHL5:
477:FHL4:
471:UNC13D
468:FHL3:
455:FHL2:
447:FHL1:
409:SH2D1A
372:, and
345:, and
314:, and
265:SH2D1A
253:STXBP2
249:RAB27A
241:UNC13D
194:Causes
3286:STX11
3203:KIF5A
3147:MYO5A
3019:CPSQ3
3013:AP4M1
2999:AP3B1
2985:AP1S2
2928:COPII
2546:31418
2504:288.4
2489:D76.1
2309:(PDF)
2302:(PDF)
2103:S2CID
2040:Blood
1801:Blood
1777:S2CID
1503:S2CID
1294:S2CID
1246:S2CID
859:shock
838:MYO5A
693:Fever
480:STX11
450:HPLH1
411:(see
394:fungi
284:MAGT1
269:BIRC4
245:STX11
168:fever
3396:DYSF
3328:CAV3
3314:CAV1
3175:SPG4
3106:MLPH
3054:BBS3
3048:ARL6
2977:APC:
2960:COG7
2910:LYST
2896:HPS7
2890:HPS1
2530:MeSH
2510:OMIM
2499:9-CM
2448:PMID
2399:PMID
2368:2015
2352:PMID
2317:2021
2236:PMID
2201:PMID
2152:PMID
2095:PMID
2058:PMID
2017:PMID
1976:PMID
1926:PMID
1869:PMID
1820:PMID
1769:PMID
1732:PMID
1691:PMID
1639:PMID
1607:PMID
1554:PMID
1495:PMID
1446:PMID
1397:PMID
1346:PMID
1286:PMID
1238:PMID
1196:PMID
1158:PMID
1117:PMID
1037:PMID
899:and
887:and
768:CD25
638:The
549:and
521:and
519:IL-6
515:IL-1
458:PRF1
396:and
329:and
281:and
277:CD27
261:PRF1
257:LYST
222:and
184:rash
155:and
120:and
3092:CHM
3035:Rab
2495:ICD
2480:ICD
2438:PMC
2430:doi
2391:doi
2387:234
2344:doi
2228:doi
2224:114
2191:PMC
2183:doi
2179:132
2142:PMC
2134:doi
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2048:doi
2044:125
2007:doi
1966:PMC
1958:doi
1916:doi
1912:146
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1722:doi
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1019:doi
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