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Vol. 11. Issue 3.
Pages 139-143 (May - June 2015)
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Vol. 11. Issue 3.
Pages 139-143 (May - June 2015)
Brief report
DOI: 10.1016/j.reumae.2014.06.006
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Secondary Macrophage Activation Syndrome Due to Autoimmune, Hematologic, Infectious and Oncologic Diseases. Thirteen Case Series and Review of the Literature
Síndrome de activación macrofágica secundario a enfermedades autoinmunes, hematológicas, infecciosas y oncológicas. Serie de 13 casos clínicos y una revisión bibliográfica
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César Egües Dubuc
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tonoeguesdubuc@hotmail.com

Corresponding author.
, Vicente Aldasoro Cáceres, Miren Uriarte Ecenarro, Nerea Errazquin Aguirre, Iñaki Hernando Rubio, Carlos Francisco Meneses Villalba, Esther Uriarte Itzazelaia, Jorge J. Cancio Fanlo, Olga Maiz Alonso, Joaquin M. Belzunegui Otano
Servicio de Reumatología, Hospital Universitario Donostia, San Sebastián, Spain
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Tables (4)
Table 1. Demographic Characteristics, Etiologies, Triggers, Clinical Course, Treatment and Mortality of Patients With Secondary Macrophage Activation Syndrome.
Table 2. Descriptive Analysis of the Variables of Patients With Macrophage Activation Syndrome Secondary to Autoimmune Diseases.
Table 3. Descriptive Analysis of the Variables of Patients With Macrophage Activation Syndrome Secondary to Hemato-oncological Diseases.
Table 4. Descriptive Analysis of the Variables of Patients With Macrophage Activation Syndrome Secondary to Infectious and Oncological Diseases.
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Abstract
Objective

Describe the demographic characteristics and disorders of patients with diagnosis of macrophage activation syndrome (MAS) in the December 2008–January 2014 period.

Methods

Medical records were reviewed from diagnosis of MAS and after discharge until January 2014. Patients were divided into 4 groups according to the primary disease: autoimmune (AI), hemato-oncologic (HO), infectious (Inf) and oncologic (Onc). The variables were analyzed among the 4 groups and between AI and HO.

Results

Thirteen patients [7 men, with a median of 54 years (32–63)] were studied. The etiologies were: 5 AI, 5 HO, 2 Inf and 1 Onc disease. Hemophagocytic cells were found in the ascitic fluid of one patient. A patient with MAS secondary to IgG4-related disease was found.

Conclusions

Mortality, prognosis and disease progression may be influenced by the delay in diagnosis, treatment initiation and etiology of MAS. HO ill patients had a worse prognosis.

Keywords:
Linfohistiocitocis hemophagocytic
Macrophage activation syndrome
Hemophagocytic syndrome
Hemophagocytosis
Hemophagocytic cells
Resumen
Objetivo

Describir las características demográficas y trastornos de pacientes con diagnóstico de síndrome de activación macrofágica (SAM) en el periodo comprendido entre diciembre de 2008-enero de 2014.

Métodos

Se revisaron las historias clínicas desde el diagnóstico de SAM y tras su alta hospitalaria hasta enero de 2014. Los pacientes se agruparon en 4 grupos: autoinmunes (AI), hemato-oncólogicas (HO), infecciosas (Inf) y oncológicas (Onc). Las variables fueron analizadas entre los 4 grupos y entre AI y HO.

Resultados

Trece pacientes (7 hombres, con una mediana de 54 años [32-63]) se estudiaron. Las etiologías encontradas fueron: 5 AI, 5 HO, 2 Inf y una Onc. Se encontraron células hemofagocíticas en el líquido ascítico en uno de los pacientes. Se encontró un paciente con SAM secundario a enfermedad relacionada con la IgG4.

Conclusiones

La mortalidad, el pronóstico y la evolución de la enfermedad puede verse influida por el retraso en el diagnóstico, el inicio del tratamiento y la etiología del SAM. Los pacientes con enfermedades HO presentaron peor pronóstico.

Palabras clave:
Linfohistiocitocis hemofagocítica
Síndrome de activación macrofágica
Síndrome hemofagocítico
Hemofagocitosis
Células hemofagocíticas
Full Text
Introduction

Macrophage activation syndrome (MAS) is a group of diseases characterized by a severe acute inflammatory syndrome, usually underdiagnosed.1 The usual clinical manifestations are fever, rash, enlarged organs and central nervous system alterations. Laboratory analysis usually shows pancytopenia, hepatitis, coagulopathy, hyperferritinemia and hypertriglyceridemia, and histologically the presence of hemophagocytic cells (HC) on bone marrow (BM), spleen and/or lymph node biopsy.1,2

This disease is caused by proliferation and activation of T cells and macrophages, causing an inflammatory response characterized by hypersecretion of cytokines such as interferon-gamma, tumor necrosis factor alpha, interleukin 1 (IL-1), IL-6, IL-10, IL-12, IL-18, and macrophage colony stimulating factor.1,2 Secondary MAS is the result of an immunological reaction caused by autoimmune disease, infection, exposure to drugs and neoplasms.2,3MAS secondary to autoimmune diseases (AD) has certain differences from the other types such as very high hyperferritinemia, a decrease in erythrocyte sedimentation rate, a mild cytopenia and a more pronounced initial3 coagulopathy. It can occur at any age, but especially at the beginning of juvenile idiopathic arthritis (JIA) and adult Still's disease (ASD), and during the development of systemic lupus erythematosus (SLE). It is estimated to occur in 7% of the patients with JIA, with a mortality rate ranging between 10 and 20%.2–4

In recent years we have witnessed an increased incidence of this disease, probably because before it was underdiagnosed due to lack of knowledge regarding it. It is for this reason that we decided to conduct a review of the cases to date in our hospital.

Objective

To describe the demographic, clinical and laboratory data, treatment strategies, mortality and underlying disorders during hospitalization and after discharge of patients diagnosed with MAS during the period of December 2008–January 2014 in the Hospital Universitario Donostia, Gipuzkoa, Spain.

Materials and Methods

In order to describe the clinical characteristics of patients diagnosed with MAS we reviewed paper and computerized medical records. Following data collection patients were grouped into 4 groups according to the underlying disease: AD, hemato-oncologic (HO), infectious (Inf) and oncologic (Onc).

Nominal variables were diagnosis, possible triggers of MAS and treatments used during admission and currently. Dichotomous variables were gender, fever, organomegaly, hospital mortality after discharge, admission to the intensive care unit (ICU) and recurrence of MAS. Quantitative variables were age, analytical findings, hospital stay in days, days from admission to BM biopsy, days after the BM biopsy until discharge or death of the patient and the evolution time after discharge hospital in months. Quantitative variables with a skewed distribution are represented as median and interquartile range.

Results

13 patients were found 5 with AD, 5 with HO diseases 2, with Inf diseases and one with Onc disease. Table 1 shows demographic characteristics, etiology, possible triggers of MAS, mortality, treatments used during admission and currently as well as clinical outcomes after hospital discharge.

Table 1.

Demographic Characteristics, Etiologies, Triggers, Clinical Course, Treatment and Mortality of Patients With Secondary Macrophage Activation Syndrome.

Id  Etiology and trigger at admissionAge  Gender  Treatments  Death  Clinical course  Current treatments 
SLE onset  Disease itself  57  (1) IG(2) GC(3) CSP  No  Major polyarticular involvement  MTX 7.5mg/week, HCQ200mg/day and MMF500mg/day 
ASD  Pneumococcus, CMV, HSV and parvovirus B19  30  (1) GC(2) CSP  No  In remission  Without treatment since May 2013 
Start of ASD  Disease itself  35  (1) GC(2) CSP(3) Anakinra  No  In remission  Untreated 
SLE onset  Disease itself  16  (1) IG(2) GC(3) CSP(4) Anakinra  No  In remission  HCQ 200mg/day 
Unknown  Unknown  40  (1) GC(2) IG(3) CSP  No  IgG4 associated disease  CSP150mg/day 
Onset of T and B cell NHL  Disease itself  34  (1) Campath-CHOP(2) RTX-CHOP  No  In remission of underlying disease  Without chemo since May 2013 
Acute myeloid leukemia  HLA-compatible BM transplant  65  (1) GC(2) CSP  Yes  Died during admission   
Onset of spleen B cell lymphoma  Disease itself  77  (1) GC(2) IG(3) CSP(4) Anakinra(5) Tocilizumab  Yes  Died during admission   
Onset of extranodal NK cell lymphoma  Epstein Barr  55  (1) GC(2) IG(3) CHOP  Yes  Died during admission   
10  Onset of spleen B cell lymphoma  Disease itself  54  (1) GC(2) CSP93) Anakinra(4) Tocilizumab(5) RTX-CHOP  No  In remission  Without chemo since December 2013 
11  Sepsis due to Campylobacter jejuni  Disease itself  61  (1) IGGC  No  Permanent discharge   
12  HIV C3  Pneumocystis carinii and/or the disease itself  30  (1) GC(2) IG  Yes  Died during admission   
13  Stage IV multiform glioblastoma grade  Chemo with temozolomide  78  (1) IG(2) GC  No  Death due to neoplasia   

CHOP, cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone; CMV, cytomegalovirus; CSP, cyclosporin; ASD, Adult Still's disease; F, female; GC, glucocorticoids; HCQ, hydroxychloroquine; HSV, herpes simplex virus; Id, identification; IG, immunoglobulin SLE, systemic lupus erythematosus; NHL, non Hodgkins lymphoma; M, male; MMF, mycophenolate; MTX, methotrexate; NK, natural killer; Chemo, chemotherapy; RTX, rituximab; HIV, human immunodeficiency virus.

Fever was the only common criterion. Organomegaly (splenomegaly and/or hepatomegaly) was present in all patients except for patient 13. Tables 2–4 show the descriptive analysis of patients with secondary MAS shown by type of disease. Patients 6, 7 and 8 underwent more than one BM biopsy and patient 3 also presented HC and ascites.

Table 2.

Descriptive Analysis of the Variables of Patients With Macrophage Activation Syndrome Secondary to Autoimmune Diseases.

  Median (P25-P75)  Patient 1  Patient 2  Patient 3  Patient 4  Patient 5 
Hospitalization (days)  38 (37–56)  38  10  37  130  56 
Delayed diagnosis (days)  14 (7–18)  14  18  18 
Days recuperating after diagnosis  35 (23–38)  35  23  102  38 
ICU admission  2 (40%)  No  No  No  Yes  Yes 
Follow-up time after discharge (months)  35 (16–42)  31  42  52  16  13 
Hemoglobin (mg/dl)  7.5 (7.3–8.9)  8.9  9.8  7.3  6.1  7.5 
Platelets (/l)  15 000 (8000–72 000)  117 000  8000  5600  72 000  15 000 
Leukocytes (/l)  2340 (1660–3340)  1200  2340  3340  1660  5790 
Neutrophils (/l)  1006 (650–1130)  580  1130  1006  650  3030 
Triglycerides (mg/dl)  417 (412–561)  417  254  604  412  561 
Fibrinogen (mg/dl)  158 (97–287)  No data  212  103  77  513 
Ferritin (ng/ml)  15 300 (2422–15 359)  15 300  2389  175 266  15 359  2422 
Glutamic oxaloacetic transaminase (mg/dl)  512 (395–1080)  1050  395  1318  512  50 
Glutamate-pyruvate transaminase (mg/dl)  566 (199–596)  608  566  596  199  46 
Lactate dehydrogenase (IU/l)  959 (824–993)  824  959  7748  993  564 
Total bilirubin (mg/dl)  1.1 (1.1–5.2)  0,5  1.1  12.7  5.2  1.1 
INR, international normalized ratio  1.5 (1.4–1.7)  1.09  No data  1.55  1.99  1.48 
Total protein (g/dl)  4.5 (4.3–4.9)  5.6  No data  4.4  4.6 
Alkaline phosphatase (mg/dl)  341 (297–407)  275  341  431  297  407 
Table 3.

Descriptive Analysis of the Variables of Patients With Macrophage Activation Syndrome Secondary to Hemato-oncological Diseases.

  No.  Median (P25–P75)  Patient 6  Patient 7  Patient 8  Patient 9  Patient 10 
Hospitalization (days)  No.=5  61 (38–100)  22  100  61  38  248 
Delay in diagnosis (days)  No.=5  14 (9–27)  31  27  14 
Days recuperating after diagnosis  No.=5  30 (16–91)  16  91  30  11  153 
ICU admission  No.=5  4 (80%)  No  Yes  Yes  Yes  Yes 
Follow-up time after discharge (months)  No.=5  14.5 (7.8–21.3)  28 
Hemoglobin (mg/dl)  No.=5  7 (6.6–7.4)  7.4  5.9  7.4  6.6 
Platelets (/l)  No.=5  16 000 (4000–17 000)  22 000  2000  16 000  17 000  4000 
Leukocytes (/l)  No.=5  50 (10–820)  820  50  1300  10 
Neutrophils (/l)  No.=5  0 (0–360)  360  2000 
Triglycerides (mg/dl)  No.=5  382 (340–427)  382  340  227  427  1134 
Fibrinogen (mg/dl)  No.=3  287 (195–4785)  No data  No data  287  103  670 
Ferritin (ng/ml)  No.=4  16 751 (13 246–26 021)  No data  16 796  2868  53 695  16 705 
Glutamic oxaloacetic transaminase (mg/dl)  No.=5  199 (175–277)  86  277  175  199  419 
Glutamate-pyruvate transaminase (mg/dl)  No.=5  147 (108–270)  104  385  270  108  147 
Lactate dehydrogenase (IU/l)  No.=5  1120 (352–1145)  259  352  1120  1145  2490 
Total bilirubin (mg/dl)  No.=5  3.4 (2.5–11.5)  0,8  11.5  2.5  3.4  12.4 
INR, international normalized ratio  No.=5  1.44 (1.3–1.6)  1.32  1.44  4.73  1.05  1.57 
Total protein (g/dl)  No.=5  4.3 (4–4.3)  4.3  3.9  4.7  4.3 
Alkaline phosphatase (mg/dl)  No.=5  262 (231–435)  231  262  142  435  811 
Table 4.

Descriptive Analysis of the Variables of Patients With Macrophage Activation Syndrome Secondary to Infectious and Oncological Diseases.

  Patient 11  Patient 12  Patient 13 
Hospitalization (days)  17  31  30 
Delay in diagnosis (days)  12  18  15 
Days recuperating after diagnosis  13  15 
ICU admission  No  No  No 
Follow-up time after discharge (months)  27 
Hemoglobin (mg/dl)  7.3  7.8  8.6 
Platelets (/l)  10 000  9000  5000 
Leukocytes (/l)  3090  1010  480 
Neutrophils (/l)  2320  230 
Triglycerides (mg/dl)  274  471  149 
Fibrinogen (mg/dl)  No data  214  117 
Ferritin (ng/ml)  9.755  10 938  No data 
Glutamic oxaloacetic transaminase (mg/dl)  23  134  54 
Glutamate-pyruvate transaminase (mg/dl)  32  234  88 
Lactate dehydrogenase (IU/l)  752  44  426 
Total bilirubin (mg/dl)  1.6  1.7  3.7 
INR, international normalized ratio  1.38  1.11  1.88 
Total protein (g/dl)  5.4  5.6  3.1 
Alkaline phosphatase (mg/dl)  172  73  68 

With regard to treatment strategies, all patients received glucocorticoids (GC), 8 patients (3 AD and 2 HO, 2 Inf and 1 Onc) received immunoglobulin (IG), 8 patients (5 AD and 3 HO) received cyclosporine (CSP), 4 patients (2 AD and 2 HO) received anakinra, 2 patients (2 HO) tocilizumab and chemotherapy. All patients received broad spectrum antibiotics, except patient 11. Most patients received maintenance therapy and transfusions of red blood cells and platelets, colony stimulating factor, erythropoietin and vasopressors. Patient 5 required three hemodialysis sessions during hospitalization due to fluid overload, and clinicians, during admission, did not reach a definite etiologic diagnosis but seven months after discharge identified it as an IgG4-related disease.

Patients 7, 8 and 9 died during admission with a diagnosis of multiple organ dysfunction syndrome (MODS) and patient 12 presented massive hemoptysis; 13 patients died after discharge due to their underlying disease. Five patients were admitted to the ICU, all for MODS. Patients 4 and 7 had 2 admissions to the ICU each, with the second admission diagnosis being, in patient 7, MODS and sepsis as well as bacterial peritonitis in patient 4 due to Pseudomonas aeruginosa, Enterococcus faecallis and Bacteroides fragillis, requiring up to 4 surgical cavity lavages. No patient had a recurrence of MAS after discharge.

Discussion

The main diseases related to MAS in our study were AD and HO, these being the most frequent. With respect to AD, we found 3 patients who started with MAS and one that presented the ethological diagnosis after hospital discharge, which was associated with IgG4 disease, the first case reported of this association with MAS.

In a series of 18 patients in the US, one case was found after bone marrow transplantation.4,5 In a series of 58 patients with HIV in France, other infectious agents were described, including HIV, acting as triggers of MAS.6MAS cases secondary to Pneumocystis jirovecii have been reported in patients with HO disease and not in HIV.9 Patient 12 could be the first case of MAS secondary to P. jirovecii in a patient with HIV, although HIV could also be the cause of MAS.

The most common bacteria related to MAS are Salmonella, Tuberculosis and Pseudomonas,5 and within the Enterobacteriaceae isolated cases of Serratia, Klebsiella and Campylobacter have been reported.7–9 In 2001, the first described case of MAS secondary to Campylobacter fetus was reported in a patient with acquired immunodeficiency syndrome. Patient 11 is the first case of MAS secondary to Campylobacter jejuni.

Regarding MAS secondary to chemotherapy, cases have been rarely described. In 2012 a patient with neuroblastoma was associated to MAS after starting chemotherapy.10 Patient 13 is probably the first case of MAS secondary to chemotherapy with temozolomide, although MAS could also be attributed to the tumor itself, albeit less likely.

None of the patients underwent quantification of natural killer cells and sIL-2 receptor because these tests are not performed in our hospital. These tests are not available in all hospitals, and when performed, the results are often slow to come. It is for this and the high mortality related to MAS that these tests should not be decisive for the diagnosis, let alone onset of treatment, provided there is a high suspicion of MAS.1,10,11

In patient 3, HC were found in ascites. There are some reports in the literature of HC in pathological body fluids. The first case of HC in ascites was described in 2007 in a patient with liver cirrhosis and Escherichia coli, with another in 2008 in a patient after a cholecystectomy.12,13 In the pleural fluid 2 cases induced by EBV have been described.14,15 In 2007, the first case of HC in the cerebrospinal fluid in a patient with visceral leishmaniasis was described.16 This could lead us to the conclusion that HC could be found in any pathological body fluid before undertaking a BM biopsy, or when faced with inconclusive biopsies; this is another element to consider for the diagnosis.

A relationship was noted between more hospital days from admission to the BM biopsy and the onset of treatment with greater mortality, especially in patients with HO diseases. The main cause of mortality was MODS, although patients were treated with broad spectrum antibiotics, antifungals and antiretroviral drugs. This suggests that mortality is mainly due to MAS and not to a possible associated infection.

The goal of treatment is to stop the inflammatory process. Initial treatments are GC such as methylprednisolone or dexamethasone in children because they easily cross the blood brain barrier. IGs are another option when suspecting a viral infection and in severe cases where no expected response to GC is expected. GC should be reduced slowly and progressively in order to avoid reactivation.1 In refractory cases or reactivation, CSP doses between 2 and 8mg/kg/day could be associated. Biological treatments are used when GC and/or synthetic immunosuppressive drugs have not been effective. Receptor inhibitors of TNF, IL-1 and IL-6 are an option; these should be used with caution and monitoring of side effects or complications such as infections. Rituximab has proven effective in patients with MAS secondary to SLE.3,17 Anakinra is effective in MAS secondary to systemic JIA; it also shows an advantage over other biological treatments, and it is a drug with a short half-life.2 We must also remember that there have been reports of MAS secondary to biological treatment.5

Other measures to consider during immunosuppressive therapy are gastric protection, cotrimoxazole prophylaxis, oral antifungal drugs and evaluating the use of antiretrovirals.1 The onset of antibiotic therapy is controversial and depends on several factors such as comorbidities. In reactivation cases, broad-spectrum antibiotics should be employed, although some authors recommend their use at the start of immunosuppressive treatment.1

The objective of this study was to collect and analyze the experience in our hospital, and thus provide information for future work. We can see that MAS could be suspected in patients with prolonged fever unresponsive to broad-spectrum antibiotics and be accompanied by organomegaly, cytopenias, coagulopathy and hepatitis. The early diagnosis and initiation of treatment may improve the prognosis, and compliance with all diagnostic criteria should not be strictly necessary for initiating treatment, due to the diseases’ high mortality.

Conclusions

Mortality, prognosis and disease progression may be influenced by delay in diagnosis, treatment initiation and etiology of MAS. HC may be present not only in the bone marrow, lymph nodes and spleen, but also in other pathological body liquids, such as ascites. The secondary MAS hemato-oncological diseases presented worse prognosis.

Ethical ResponsibilitiesProtection of people and animals

The authors declare that this research did not perform experiments on humans or animals.

Confidentiality of data

The authors declare that they have followed the protocols of their workplace regarding the publication of data from patients, and all patients included in the study have received sufficient information and gave written informed consent to participate in the study.

Right to privacy and informed consent

The authors state that no patient data appear in this article.

Conflict of Interest

The authors have no conflict of interest to state.

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Please cite this article as: Egües Dubuc C, Aldasoro Cáceres V, Uriarte Ecenarro M, Errazquin Aguirre N, Hernando Rubio I, Meneses Villalba CF, et al. Síndrome de activación macrofágica secundario a enfermedades autoinmunes, hematológicas, infecciosas y oncológicas. Serie de 13 casos clínicos y una revisión bibliográfica. Reumatol Clin. 2015;11:139–143.

Copyright © 2014. Elsevier España, S.L.U.. All rights reserved
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