Infection is the major trigger of hemophagocytic syndrome in adult patients treated with biological therapies.
BACKGROUND
Hemophagocytic syndromes (hemophagocytic lymphohistiocytosis, HLH) are characterized by a wide range of etiologies, symptoms, and outcomes, but have a common etiopathogenic pathway leading to organ damage: an excessive inflammatory response. Biological therapies have been proposed as a therapeutic option for refractory HLH, but have also been related to the development of HLH in severe immunosuppressed patients.


OBJECTIVE
The purpose of this study was to analyze the clinical characteristics and outcomes of adult patients who developed HLH after receiving biological therapies.


RESULTS
We identified 30 patients (29 from the PubMed search and one unpublished case), including 19 women and 11 men, with a mean age of 46.5 years. Underlying diseases consisted of rheumatologic/autoimmune diseases in 24 patients and hematological neoplasia in the remaining 6. Biological agents received before the development of HLH were mainly anti-TNF agents (n = 19). Search for microorganisms confirmed systemic infection in 20 (67%) patients, including Mycobacterium tuberculosis (n = 5), cytomegalovirus (CMV) (n = 4), Epstein-Barr virus (EBV) (n = 3), Histoplasma capsulatum (n = 3), Escherichia coli (n = 2), Staphylococcus aureus, Leishmania amastigotes and Brucella melitensis (n = 1, respectively); viral infections were mainly reported in inflammatory bowel disease (IBD) patients. Patients with infections had more frequently received previous immunosuppressive therapies (p = 0.036) and had lower leukocyte counts (p = 0.020) in comparison with patients without associated infections. The outcome was described in 29 patients. After a mean follow-up of 6.3 months, 8 patients died (28%) and 6 had received anti-TNF agents. There was a high mortality rate in patients aged >65 years and those with tuberculosis (62% and 60%, respectively).


CONCLUSIONS
In patients receiving biological therapies who develop HLH, searching for a concomitant infectious process is mandatory, and specific surveillance for EBV/CMV infections (in patients with IBD) and for bacteria, including mycobacteria (in elderly patients receiving anti-TNF therapy), is recommended.
Josep Font Laboratory of Autoimmune Diseases, CELLEX-Institut d׳Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Department of Systemic Autoimmune Diseases, Hospital Clínic, Barcelona, Spain.
Pilar
P
Brito-Zerón
Department of Internal Medicine, Hospital Clínic, Barcelona, Spain.
Xavier
X
Bosch
Department of Internal Medicine, Hospital do Meixoeiro, Vigo, Spain.
Marta
M
Pérez-de-Lis
Department of Internal Medicine, Hospital do Meixoeiro, Vigo, Spain.
Roberto
R
Pérez-Álvarez
Department of Internal Medicine, Hospital Ramón y Cajal, Madrid, Spain.
Guadalupe
G
Fraile
Josep Font Laboratory of Autoimmune Diseases, CELLEX-Institut d׳Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Hoda
H
Gheitasi
Josep Font Laboratory of Autoimmune Diseases, CELLEX-Institut d׳Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Soledad
S
Retamozo
Josep Font Laboratory of Autoimmune Diseases, CELLEX-Institut d׳Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Albert
A
Bové
Department of Internal Medicine, Hospital Clínic, Barcelona, Spain.
Ester
E
Monclús
Department of Internal Medicine, Hospital Clínic, Barcelona, Spain.
Ona
O
Escoda
Department of Infectious Diseases (ICMiD), Hospital Clínic, Barcelona, Spain.
Asunción
A
Moreno
Department of Haematology, Hospital Clínic, Barcelona, Spain.
Armando
A
López-Guillermo
Lupus Research Unit, The Rayne Institute, St Thomas׳ Hospital, King׳s College University, London, UK.
Munther A
MA
Khamashta
Josep Font Laboratory of Autoimmune Diseases, CELLEX-Institut d׳Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Department of Systemic Autoimmune Diseases, Hospital Clínic, Barcelona, Spain. Electronic address: mramos@clinic.ub.es.
Manuel
M
Ramos-Casals
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001327:Autoimmune Diseases / Q000188:drug therapy*; D001688:Biological Products / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000009:adverse effects* / Q000627:therapeutic use; D007239:Infections / Q000150:complications*; D051359:Lymphohistiocytosis, Hemophagocytic / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D012216:Rheumatic Diseases / Q000188:drug therapy*; D012307:Risk Factors; D055815:Young Adult
D018501:Antirheumatic Agents; D001688:Biological Products; D007155:Immunologic Factors
Anti-TNF; Biological therapy; Hemophagocytic syndrome; Mortality; Tuberculosis