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Keywords:

  • Hemophagocytosis;
  • Hemophagocytic syndrome;
  • Autoimmune disease;
  • Systemic disease

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Objective

To analyze specific clinical findings, underlying disorders, treatments, outcomes, and prognostic factors for reactive hemophagocytic syndrome (RHS) in systemic disease.

Methods

Data were collected using standardized forms as part of a French national survey. Adult cases without an underlying malignancy, diagnosed on bone marrow or lymph node biopsy, were included.

Results

Twenty-six cases (7 men, 19 women, mean age 47.4 ± 17.7 years) were studied. Systemic diseases included systemic lupus erythematosus (n = 14), rheumatoid arthritis (n = 2), adult onset systemic Still's disease (n = 4), polyarteritis nodosa (n = 2), mixed connective tissue disease (n = 1), pulmonary sarcoidosis (n = 1), systemic sclerosis (n = 1), and Sjögren's syndrome (n = 1). RHS occurred in 2 distinct clinical settings in the course of systemic disease. RHS was associated with an active infection in 15 patients (bacterial infections, 10 cases; viral, 3 cases; tuberculosis, 1 case; and aspergillosis, 1 case) and with the onset of a systemic disease alone in 9 cases. Isolated RHS occurred in 2 cases. The overall mortality rate was 38.5%. Two factors were associated with mortality: corticosteroid treatment at the time of RHS diagnosis, and thrombocytopenia (odds ratio = 28, 95% confidence interval = 13.3−238.9).

Conclusions

When RHS occurs in the course of an active systemic disease (situation only reported in cases of systemic lupus or adult Still's disease), immunosuppressive therapy should be used. In contrast, when RHS is present concomitantly with an active infection, immunosuppressive therapy needs to be lowered and antibiotic therapy should be instituted.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Reactive hemophagocytic syndrome (RHS) is characterized by the proliferation of benign hemophagocytic histiocytes in the bone marrow and the mononuclear phagocytic system. Risdall et al first described a group of patients with a distinct clinical syndrome including histiocytic hyperplasia, benign hemophagocytosis, and low blood cell counts (1). Subsequent to Risdall's original description, the full spectrum of RHS and the underlying diseases responsible for it have been recognized. RHS is often described as a complication of hematologic diseases, including acute leukemia, non-Hodgkin's lymphoma, and other illnesses involving immune deficiency [1–3]. Viral, bacterial, fungal, or parasitic infections may also be complicated by RHS (4). In acquired immunodeficiency syndrome, RHS may be associated with the infections that commonly affect patients (e.g., pneumococcal disease, pneumocystosis), Epstein-Barr virus infection, or malignancy (5–8).

RHS occurring in the course of adult systemic disease has rarely been reported. Immunosuppression induced by the systemic disease itself and exacerbated by immunosuppressive therapies may result in RHS, with or without an associated infection. The most frequently reported systemic diseases associated with RHS are systemic lupus erythematosus (SLE) and adult Still's disease (ASD) (9–15). Most previous articles have reported on a single case. Furthermore, the course and treatment of RHS occurring as a complication of systemic diseases has not so far been established clearly in the literature.

The aims of this study were 1) to describe RHS in adult systemic diseases in terms of its clinical manifestations, laboratory features, treatments, and outcomes; 2) to distinguish RHS induced by infection from that complicating the onset of systemic disease; and 3) to analyze the prognostic factors for RHS based on different clinical features and laboratory findings. We collected data on all French RHS cases occurring in the context of adult systemic diseases and put them in perspective with the results of a systematic review of RHS cases reported in the literature.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Data sources.

Clinical data were collected using a structured questionnaire, which was sent by the French National Society of Internal Medicine to all its members in 1999. Cases of RHS were included if they had occurred during the course of adult systemic disease during the 2-year period prior to the study. Of the 338 members questioned, 88% completed the questionnaire, and 21 of them included 1 or 2 cases. The precise number of patients with systemic disease followed by these practitioners during the 2-year collection period was not available.

RHS was diagnosed in cases of otherwise unexplained cytopenia involving at least 2 cell lines and identifiable hemophagocytic histiocytes (16). Only cases of RHS confirmed by bone marrow (biopsy or aspirate), liver, or lymph node biopsies were included. In the bone marrow, the degree of hemophagocytic reaction was quantified in terms of the percentage of hemophagocytic cells (2). Patients with an ongoing malignancy were not included. Immunophenotyping with monoclonal antibodies was not available for all patients and did not constitute a criterion for inclusion.

Systemic disease was defined according to international criteria (17–22). Systemic disease was preferred to autoimmune disease so that other diseases that could also be complicated by RHS, including sarcoidosis and vasculitis, would not be excluded. Clinical and laboratory data, as well as the course and treatment of the systemic disease, were recorded. The following data were recorded for each case: the patient's age at the time of RHS diagnosis, the patient's sex and medical history, clinical and laboratory data, course and treatment of RHS including the outcome (survived, died from RHS, died of another condition). For peripheral blood counts and biochemistry, nadir or peak values were recorded. Coagulopathy was defined when hypofibrinogenemia or elevated fibrinogen degradation products were present. Hemolysis was diagnosed when low haptoglobin and high bilirubin levels were observed. Immunosuppressive therapies were classified as corticosteroids alone, immunosuppressants alone (azathioprine, cyclophosphamide, methotrexate), or immunosuppressants and corticosteroids in combination. We separated the treatments for systemic diseases given prior to RHS from the treatment of RHS.

Based on a review of the literature, 2 sets of trigger factors that may have caused RHS in patients with underlying systemic disease were defined: infections and the onset of underlying systemic disease. Diagnosis of an active infection was established by positive cultures from body fluids or organs, positive IgM serology, or positive polymerase chain reaction for a particular organism. The onset of systemic disease was defined if the set of clinical and biological abnormalities specific to the disease were observed.

At the same time, a systematic review was made of the published cases of RHS occurring in the course of systemic disease. The Medline database was searched using a strategy that included the following medical subject headings: “hemophagocytosis,” “hemophagocytic histiocytosis,” or “macrophage activating or activated syndrome;” the subheadings were “systemic disease,” “lupus,” or “autoimmune disease.” This screening was supplemented by a manual search of all references in the articles. Only well-described cases were included.

Statistic analysis.

Wilcoxon and Fischer's exact tests were used, as appropriate, to analyze continuous and categorical variables. Statistical significance was set at P < 0.05. Data were not further explored using logistic regression models due a lack of power. Associations were expressed using odds ratios (ORs) with 95% confidence intervals (95% CIs). The SAS for Windows (SAS Institute, Cary, NC) version 8.0 software package was used for statistical analyses.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Clinical features.

The clinical characteristics of the 26 patients presenting with RHS in the course of systemic disease are shown in Table 1. The mean age at the time of RHS diagnosis was 47.4 ± 17.7 years (range 17–73 years). The systemic diseases included SLE in 14 cases, rheumatoid arthritis (RA) in 2 cases, ASD in 4 cases, polyarteritis nodosa in 2 cases, and 1 case each of mixed connective tissue disease, pulmonary sarcoidosis, systemic sclerosis, and Sjögren's syndrome.

Table 1. Clinical characteristics of 26 patients with reactive hemophagocytic syndrome and systemic disease*
Clinical symptoms of RHSTrigger factor of RHS
Patient no.AgeSexSystemic diseaseFever >38°CLymphadenopathySplenomegalyHepatomegalySkin lesions
  • *

    RHS = reactive hemophagocytic syndrome; F = female; RA = rheumatoid arthritis; SS = primitive Sjögren's syndrome; M = male; ASD = adult Still's disease; SLE = systemic lupus erythematosus; MCTD = mixed connective tissue disease; PAN = polyarteritis nodosa.

  • Trigger factors are onset of systemic disease, infection, both, or no circumstance.

172FRA++Both
246FSS+++Infection alone
332MASD++++Onset alone
427FSLE++Onset alone
548FSLE+++Both
663FASD++Infection alone
748FMCTD+Infection alone
853FSLE++Infection alone
967FRAInfection alone
1026MSLE+++Infection alone
1163MSLE+Infection alone
1260FSLEOnset alone
1320FSLEOnset alone
1462FSystemic sclerosisInfection alone
1573FSarcoidosis+++No
1638FSLE++++Both
1720FSLE +polymyositis++Both
1862FSLE +myasthenia+Onset alone
1934FSLE+++No
2059MPANBoth
2134FSLE++Onset alone
2237FSLE++Both
2317FSLE+++Onset alone
2441MASD++Onset alone
2572MASD+Onset alone
2660MPAN++Infection alone

In 8 cases, RHS and systemic disease were diagnosed simultaneously, whereas in other cases, RHS-complicated systemic disease had been evolving for an average of 76.6 months. Laboratory data at the time of RHS are reported in Table 2. Anemia (hemoglobin < 11.5 gm/dl), neutropenia (<1.5 × 109/liter), lymphopenia (<1.0 × 109/liter), and thrombocytopenia (<150 × 109/liter) occurred in 85%, 46%, 91%, and 77% of cases, respectively. All patients had depression of at least 2 cell lines. C-reactive protein levels were lower than 10 mg/liter in 18% of the cases. The erythrocyte sedimentation rate was normal (lower than 15 mm/hour) in 13% of the cases. Coagulopathy was present in 4 cases. Data on ferritin concentrations were available for 16 cases, and the ferritin concentration was higher than 1,000 μg/liter in 69% of the cases. Mean ferritin levels reached 83.345 ± 94.574 μg/liter in cases of ASD. Triglyceride levels were available for 20 patients and were elevated in 60% of cases. Aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase (LDH) levels were elevated in 65%, 69%, and 76% of the cases, respectively. Mean serum albumin levels were 30 ± 6 gm/liter. Hemolysis was reported in 3 cases. Schizocytes were never reported.

Table 2. Factors associated with mortality in cases of reactive hemophagocytic syndrome in patients with systemic disease (quantitative factors)*
 Mean ± SDAlive (n = 16) Mean ± SDDead (n = 10) Mean ± SDP
  • *

    NS = not significant; AST = aspartate aminotransferase; ALT = alanine aminotransferase; LDH = lactate dehydrogenase.

Age (years)47.4 ± 17.742.5 ± 17.655.1 ± 15.8NS
Hemoglobin (gm/dl)8.7 ± 2.49.2 ± 2.67.9 ± 2.0NS
Neutrophils (× 109/liter)2.4 ± 1.91.9 ± 1.83.9 ± 5.4NS
Lymphocytes (× 109/liter)0.54 ± 0.410.63 ± 0.410.36 ± 0.33NS
Platelets (× 109/liter)95 ± 12137 ± 13943 ± 540.002
AST (IU/liter)286 ± 661171 ± 190472 ± 1045NS
ALT (IU/liter)284 ± 847122 ± 106544 ± 1361NS
LDH (U/liter)1,735 ± 1,6931,427 ± 1,0682,300 ± 2,512NS
Triglycerides (gm/liter)3.19 ± 3.03.5 ± 3.13.2 ± 3.1NS
Ferritine (μg/liter)41,512 ± 78,46514,313 ± 29,25790,493 ± 121,753NS
Erythrocyte sedimentation rate (mm/hour)65 ± 4454.4 ± 4183.5 ± 46NS
C-reactive protein (mg/liter)111 ± 10893 ± 108146 ± 139NS

RHS was diagnosed from bone marrow analysis in 25 cases and from lymph node biopsy alone in only 1 case. Seven patients underwent bone marrow aspirates only, with RHS being detected in each case. Of the 18 patients who underwent both bone marrow biopsy and aspirate, 5 had positive aspirates but a negative biopsy, 5 had negative aspirates but a positive biopsy, and 8 had both positive biopsy and aspirate results. Two patients underwent both lymph node and bone marrow biopsies; in 1 case, the lymph node biopsy confirmed the RHS diagnosed from the bone marrow biopsy while in the other, the lymph node biopsy was normal. Only 3 patients exhibited hemophagocytic cell infiltration of more than 5% in the bone marrow.

RHS trigger factors.

The clinical settings of RHS (onset of systemic disease, infection, or both) are shown in Table 1.

Active infection was reported in 15 cases of RHS; in 9 of these, infection occurred alone while in the other 6, infection was associated with the onset of systemic disease. Bacterial infection was present in 10 cases (septicemia, 3 cases; pneumonia, 5 cases; and kidney infection, 2 cases). Viral infection was diagnosed in 3 cases (varicella-zoster virus in 1 case, parvovirus B19 in 1 case, and Epstein-Barr virus in 1 case). Aspergillosis and tuberculosis were each observed in 1 case.

In 9 cases, the onset of systemic disease alone and RHS occurred simultaneously. In 2 cases, no underlying disorder was identified.

The frequency of trigger factors, i.e., onset of systemic disease versus infection, differed significantly between 2 groups of systemic diseases: in SLE and ASD, disease onset was more frequently associated with RHS (disease onset, 72%; infection, 44%); whereas in other systemic diseases, infection was more frequently associated with RHS (disease onset, 25%; infection, 88%; P = 0.03).

At the time of RHS diagnosis, 8 patients were receiving immunosuppressive therapy: corticosteroids alone in 15 cases, and corticosteroids together with other immunosuppressive drugs in 3 cases (methotrexate, 1 case; azathioprine, 1 case; cyclophosphamide, 1 case). In 6 of these cases, immunosuppressive therapy had been increased (increased corticosteroid regimen in 4 cases, immunosuppressant added to corticosteroids in 2 cases) the month before RHS, following onset of the systemic disease.

Treatment of RHS.

Antibiotics were administered in all cases of bacterial or mycobacterial infection (11 cases). Antiviral therapy with acyclovir was given in 3 cases. The patient with aspergillosis was treated with amphotericin B.

The treatment administered for RHS was corticosteroids alone in 19 cases (increased oral intake or methylprednisolone pulse), and immunosuppressive therapy (cyclophosphamide) in addition to corticosteroids in 3 cases. Intravenous immunoglobulins were given in 2 cases of SLE, 1 of which was associated with infection, and in 1 case of ASD. In 1 case, no treatment was given for RHS.

Outcome.

Ten patients died (38.4%): 4 cases as a direct result of RHS, 3 cases due to infection, and 3 cases due multiple organ failure. In the other cases, remission was observed, but a relapse occurred in 5 cases (SLE, 4 cases; ASD, 1 case). Relapses were always seen to be associated with the onset of systemic disease, on average 6 months after the first episode of RHS. In 1 case, the relapse occurred after 5 years of followup.

Factors that were significantly associated with mortality were an absence of lymphadenopathy (P = 0.014), thrombocytopenia (<50 × 109/liter; P = 0.002), immunosuppressive therapies given at the time of RHS diagnosis (P = 0.009), or corticosteroids alone (P = 0.014) (Table 3). The corresponding odds ratios were as follows: OR = 15, 95% CI 1.5–149.7 for both lymphadenopathies and corticosteroid therapy given prior to RHS; OR = 28, 95% CI 13.3–238.9 for thrombocytopenia. Treatments given for RHS (immunosuppressants or corticosteroids) were not associated with a lower risk of mortality.

Table 3. Factors associated with mortality in reactive hemophagocytic syndrome (RHS) occurring in the course of patients with systemic disease (qualitative factors)
 Alive (n = 16) no. (%)Dead (n = 10) no. (%)P
Sex (female) (n = 19)12 (63)7 (37)ns
Fever (n = 20)12 (60)8 (40)ns
Adenomegaly (n = 11)10 (91)1 (9)0.014
Hepatomegaly (n = 6)2 (33)4 (67)ns
Splenomegaly (n = 7)4 (57)3 (43)ns
Disseminated intravascular coagulation (n = 3)1 (33)2 (67)ns
Percent hemophagocytic cells > 5%0 (0)3 (100)ns
Presence of infection (n = 15)7 (46)8 (54)ns
Onset of systemic disease (n = 15)11 (73)4 (27)ns
Patients with systemic lupus erythematosus (n = 14)11 (79)3 (21)ns
Treatment given at diagnosis of RHS8 (45)10 (55)0.009
 Corticosteroids or immunosuppressors (n = 18)   
 Corticosteroids alone (n = 15)6 (40)9 (60)0.014
Treatment of RHS (corticosteroids or cyclophosphamide) (n = 22)12 (55)10 (45)ns

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

RHS is a frequently fatal condition that is generally associated with lymphoma or an infectious disease. It has rarely been described in the course of systemic diseases. In the largest published studies of RHS, systemic disease was found to be the underlying disorder in 2–5% of RHS cases (Table 4). RHS may occur as a rare but serious complication of systemic diseases; it has been reported in 6 of 250 (2.4%) cases of SLE (14) and in 1 of 23 (4%) cases of ASD (23).

Table 4. Cases of reactive hemophagocytic syndrome complicating adult systemic diseases in largest series of the literature
Authors (ref)Systemic disease (no.)Cases of reactive hemophagocytic syndrome, no.Mortality, no. (%)
Kaito et al (25)Systemic lupus erythematosus (1), adult Still's disease (1)3420 (59)
Sailler et al (27)Systemic lupus erythematosus (3)9949 (49)
Tsuda (2)Systemic lupus erythematosus (1), dermatomyositis (1)235 (22)
Wong and Chan (3)Systemic lupus erythematosus (2)4018 (45)
Albert et al (24)Systemic lupus erythematosus (2)4728 (62)
Risdall et al (1)Systemic lupus erythematosus (1)195 (26)
Reiner et al (26)Systemic lupus erythematosus (2), rheumatoid arthritis (1), polymyalgia rheumatica (1)237 (30)
Total16285132 (46)

We report on 26 cases of RHS occurring in the course of systemic disease. The clinical and biologic features did not differ greatly from the classic description of RHS reported in previous studies (1, 2, 24–27). We show that the respective incidences of fever, hepatomegaly, splenomegaly, and lymphadenopathy were lower in our patients than in previous reports of RHS (24). One explanation for these findings is that the retrospective inclusion criteria used in our study may have selected clinically attenuated cases of RHS.

Our Medline search identified 40 well-documented cases of RHS occurring in the course of systemic disease. We found 19 cases of SLE (2, 12, 14, 26, 28–30), 9 cases of ASD (9–11, 13, 15, 31, 32), 5 cases of RA (26, 33–36), 1 case of Crohn's disease (26), 1 case of polymyalgia rheumatica (26), 2 cases of sarcoidosis (26, 37), 1 case of dermatomyositis (38), 1 case of systemic sclerosis (39), and 1 case of mixed connective tissue disease (39). The average age of the patients was 49.9 ± 15.0 years and the sex ratio was 30 women to 10 men. In the 27 cases where detailed data were available, RHS and the systemic disease appeared simultaneously on 11 occasions (the time elapsing being less than 1 month). In the other cases, systemic disease had been present for an average of 37 months before RHS was diagnosed. Ferritin concentrations were higher than 1,000 μg/liter in 13 cases and normal in 2 other cases (results only available for 15 cases). Higher ferritin levels were observed in cases of ASD (the mean ferritin concentration in ASD being 22,500 ± 2,790 μg/liter). Coagulopathy was observed in only 2 cases (results available for 21 cases). The clinical and biologic features of our patients did not differ from the RHS cases associated with systemic disease that had previously been reported in the literature (Table 5).

Table 5. Comparison between 26 cases of reactive hemophagocytic syndrome in systemic disease and 40 isolated, well-documented cases of the literature
 French cases (n = 26)Literature cases (n = 40)
Age, mean ± SD, years47.4 ± 17.749.9 ± 15.0
Sex ratio, F:M19:730:10
Systemic lupus erythematosus, %5447
Onset of systemic disease, %5870
Infection, %5847
Dead, %3830

This is the largest study to date on RHS occurring in the course of systemic disease, and it suggests that it is more common than previously recognized and represented in the literature. SLE and ASD predominated among the systemic diseases complicated by RHS.

RHS involves the proliferation of benign hemophagocytic histiocytes in the bone marrow and reticuloendothelial system. We showed that bone marrow aspirate was insufficient to obtain a diagnosis of RHS. Both bone marrow aspirate and biopsy are required, since some patients had a normal aspirate and a pathologic biopsy, whereas others had a normal biopsy and pathologic aspirate.

It appears that RHS may be associated with several different clinical settings, including infection, the onset of a systemic disease, or both.

In published cases of RHS occurring in patients with systemic disease, RHS was associated with the onset of disease and infection in 70% and 47% of cases, respectively (calculated from the data available on 34 cases).

An important finding in our study was that in SLE and ASD, the onset of disease alone seemed more likely to induce RHS. In cases of SLE and ASD, RHS was found to be associated with the onset of the disease in 72% of the cases. In contrast, with the other systemic diseases, infection was always present when RHS appeared. In the case of patients with RA, polyarteritis nodosa, systemic sclerosis, mixed tissue connective disease, or sarcoidosis, onset of the systemic disease alone was never found to be responsible for RHS.

This difference in the trigger disorders associated with RHS suggests that in SLE or ASD, infection and the disease should be treated together, whereas in other systemic diseases, infection should be treated and the immunosuppressive treatment of the underlying disease decreased.

In previous studies, the overall mortality associated with RHS was reported to be 46% (range 22–60%); however, these studies did not report specific mortality associated with RHS occurring in course of systemic diseases (Table 4). The prognostic factors associated with mortality due to RHS were studied in 34 patients (25), in whom the case fatality rate was 59%. In this study, factors associated with a higher risk of mortality were low hemoglobin levels, a low platelet count, high alkaline phosphatase, high bilirubin, high ferritin concentrations, and older age.

Our data suggest that the prognostic factors for RHS in systemic disease were thrombocytopenia, absence of lymphadenopathy, and the presence of corticosteroid therapy. SLE was not associated with a more favorable prognosis. Other factors, including the ferritin and LDH concentrations, were not significantly correlated with prognosis. However, it should be noted that because of the number of patients available, we had limited power to detect any significant associations.

The treatment strategies for RHS are not well established. The clinical setting and a set of prognostic factors need to be considered when choosing the optimum treatment strategy. In particular, when RHS is associated with an active infection occurring in an immunocompromised patient, the infection should be treated promptly and the immunosuppressive therapies decreased as much as possible. The majority of our patients were receiving immunosuppressive therapy when RHS occurred. In systemic diseases other than SLE and ASD, infection was the main factor for RHS, and onset of the disease alone was never associated with RHS. Therefore, treatment with antiinfectious agents and a reduction in immunosuppressive therapies should systematically be ensured in cases of RHS associated with RA, polyarteritis nodosa, mixed connective tissue disease, systemic sclerosis, or sarcoidosis. On the other hand, when RHS is associated with a systemic disease alone (a situation observed only in SLE and ASD), immunosuppressive therapy should probably be increased. In cases where both infection and ongoing systemic disease are associated with RHS, intravenous immunoglobulins in addition to antiinfectious agents may be considered. Immunoglobulin therapy has been shown to improve the outcome of a few pediatric cases of RHS (37, 40–42). Most of these patients were immunocompromised. In these cases, a clinical improvement was observed within 24–72 hours (42). Immunoglobulins may control both the viral replication and lymphohistiocytic dysregulation induced by infection. Only a prospective study will be able to determine the efficacy of combined therapy using antiinfectious agents and immunoglobulins in RHS. More generally, further studies are required to confirm the value of the treatment strategies proposed herewith for RHS associated with systemic disease.

RHS occurring in the course of systemic disease is an infrequent but important clinical entity in terms of patient prognosis. Physicians must keep the symptoms of RHS in mind, particularly because it is difficult to distinguish RHS symptoms from those of several systemic diseases. The treatment of RHS is an urgent matter and the optimum treatment strategy will depend on the underlying disorder: infection or the onset of systemic disease. In SLE and ASD, onset of the disease may be the only factor triggering RHS, whereas in other systemic diseases, infection (secondary to immunosuppression) is always present.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES
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