[Assessment of MS-Score and HScore in timeliness of diagnosis of macrophage activation syndrome associated with adult-onset Still's disease].

The data of 33 patients with adult-onset still's disease (AOSD)-associated macrophage activation syndrome (MAS) were retrospectively collected from January 2013 to December 2020 in Peking Union Medical College Hospital. Hemophagocytic lymphohistiocytosis (HLH)-2004 criteria, macrophage activation syndrome/juvenile idiopathic arthritis (MS-Score) and hemophagocytic syndrome diagnostic score (HScore) were used to diagnose AOSD-associated MAS, respectively. The time of diagnosis of AOSD-associated MAS by MS-Score was 19.0 (4.5, 31.0) days [M (Q1,Q3)] earlier than by HLH-2004 criteria, and 13.5 (0.5, 21.5) days earlier than by HScore (both P<0.05). The difference was not statistically significant between the time of diagnosis of AOSD-associated MAS by Hscore and by HLH-2004 criteria (P>0.05). There was significant difference among the three criteria (P<0.001). MS-Score can be used to diagnose AOSD-associated MAS earlier than HLH-2004 criteria, while the timeliness of HScore is not certain.

Assessment of the Hemophagocytic Lymphohistiocytosis HScore in Patients With Coronavirus Disease 2019.

The clinical manifestation of moderate to severe coronavirus disease 2019 (COVID-19) has parallels to secondary hemophagocytic lymphohistiocytosis (HLH) both clinically and based on molecular inflammatory response. We found no evidence to support the utility of risk-stratifying COVID-19 patients using risk scoring methodology designed for HLH.

Hemophagocytic Lymphohistiocytosis in a PICU of a Developing Economy: Clinical Profile, Intensive Care Needs, Outcome, and Predictors of Mortality.

OBJECTIVES: To describe the clinical profile, intensive care needs, outcome, and predictors of mortality in critically ill children with hemophagocytic lymphohistiocytosis. DESIGN: Retrospective case series. SETTING: PICU of a tertiary care teaching hospital in North India. PATIENTS: Children 2 months to 12 years old with the diagnosis of hemophagocytic lymphohistiocytosis admitted to PICU from January 2012 to April 2019 (7» yr). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sixty-two children with hemophagocytic lymphohistiocytosis (60 secondary and two primary) were enrolled. The median (interquartile range) age of the study group was 82 months (50.5-124 mo). The median (interquartile range) Pediatric Risk of Mortality III score was 16 (10-23). Majority of hemophagocytic lymphohistiocytosis was infection-associated (n = 51; 82.3%). Among these, scrub typhus accounted for 29% of cases (n = 18), dengue 17.7% (n = 11), bacterial sepsis 14.5% (n = 9), enteric fever 6.5% (n = 4), and other infections 14.5% (n = 9). Systemic-onset juvenile idiopathic arthritis accounted for 9.7% of cases (n = 6) and malignancy for 4.8% patients (n = 3). Majority of cases were treated with steroids (77.4%) and IV immunoglobulin (25.8%). Various complications noted were shock (71%), acute kidney injury (66.1%), acute respiratory distress syndrome (41.9%), disseminated intravascular coagulation (54.8%), CNS dysfunction (54.8%), multiple organ dysfunction syndrome (82.3%), and healthcare-associated infections (14.5%). Intensive care needs for primary illness and/or hemophagocytic lymphohistiocytosis included mechanical ventilation (74.2%); packed RBC (72.3%), fresh frozen plasma (40.3%), and platelet (48.4%) transfusion; vasoactive drugs (71%); and renal replacement therapy (24.2%). The median duration of PICU stay was 5 days (2.5-9.5 d) and mortality was 59.7% (n = 37). On univariate analysis, nonsurvivors had higher Pediatric Risk of Mortality III score; higher proportion of shock, acute kidney injury, acute respiratory distress syndrome, disseminated intravascular coagulation, and multiple organ dysfunction syndrome; the need for blood and blood components, mechanical ventilation, vasoactive drugs, and renal replacement therapy; higher Vasoactive-Inotropic Score; and prolonged duration of mechanical ventilation compared with survivors. CONCLUSIONS: Hemophagocytic lymphohistiocytosis in PICU is commonly secondary to tropical infections and associated with high mortality. Higher severity of illness; shock and multiple organ dysfunction syndrome; need for blood and blood products, mechanical ventilation, vasoactive drugs, and renal replacement therapy; higher Vasoactive-Inotropic Score; and prolonged mechanical ventilation predicted death. Treatment of underlying infection and a less intense immunosuppressive therapy (steroids ± IV immunoglobulin) are suggested options. A high index of suspicion for complicating hemophagocytic lymphohistiocytosis is required in children with prolonged fever, cytopenias, organomegaly, and organ dysfunction not responding to conventional treatment.

Assessment of the HScore for reactive haemophagocytic syndrome in patients with rheumatic diseases.

OBJECTIVES: Reactive haemophagocytic syndrome (RHS) is a hyperinflammatory disorder often occurring in the background of several disorders such as infections, malignancies, and rheumatic diseases. Recently, a score known as the HScore was developed for the diagnosis of RHS. In the original study, most of the patients had underlying haematological malignancy or infection and the best cut-off value for the HScore was 169 (sensitivity 93%; specificity 86%). In this study we aimed to analyse the performance of the HScore in rheumatic disease-related RHS. METHOD: The patients with rheumatic disorders evaluated in the Departments of Rheumatology and Paediatric Rheumatology at Hacettepe University, Ankara, Turkey between 2002 and 2014 were reviewed retrospectively. The first group (n = 30) consisted of patients with RHS; the control group (n = 64) included patients with active rheumatic diseases without RHS. RESULTS: In the RHS group, 14 (46.7%) had adult-onset Still's disease (AOSD), 10 (33.3%) systemic juvenile idiopathic arthritis (SJIA), and six (20%) systemic lupus erythematosus (SLE). The control group (n = 64) consisted of 32 (50%) AOSD, 13 (20.3%) SJIA, and 19 (29.7%) SLE patients. Applying the HScore to the RHS patients, the best cut-off value was 190.5 with a sensitivity of 96.7% and specificity of 98.4%. When we excluded the patients from the control group who had not had bone marrow aspiration (n = 23), the same cut-off (190.5) performed best (sensitivity 96.7%; specificity 97.6%). Applying the 2004 haemophagocytic lymphohistiocytosis (HLH-2004) criteria gave a sensitivity of 56.6% and a specificity of 100% in the whole study group. CONCLUSIONS: In our study, a cut-off value for the HScore different from the original study performed better. Further studies are warranted to determine optimum cut-off values in different studies.

'Bedside assessment' of acute hantavirus infections and their possible classification into the spectrum of haemophagocytic syndromes.

Hantavirus infections, recently renamed 'hantavirus fever' (HTVF), belong to the most common but also most underestimated zoonoses in the world. A small number of reports described the so-called 'lipid paradox' in HTVF, i.e. the striking contrast between a very low serum total cholesterol and/or high-density lipoprotein cholesterol (HDLc), and a paradoxical concomitant hypertriglyceridaemia. In a prospective study, with patients being their own control after illness, we wanted to verify if this quick and easy 'bedside test' was robust enough to warrant a preliminary diagnosis of acute kidney injury (AKI) caused by HTVF. The study cohort consisted of 58 Belgian cases (mean age 44 years), admitted with varying degrees of AKI and of thrombocytopaenia, both characteristic for presumptive HTVF. All cases were sero-confirmed as having acute HTVF. At or shortly after hospital admission, a significant (p < 0.001) decrease of total cholesterol and HDLc was found in comparison with normalised levels in the same cohort, quantified a few days after spontaneous AKI recovery. Conversely, fasting triglyceride levels during HTVF infection were significantly (p < 0.001) higher during illness than after recovery. This 'lipid paradox' was most outspoken in severe HTVF cases, often accompanying, or even predicting, major kidney or lung complications. Thus, this 'bedside assessment' seems to hold even promise for presumptive diagnosis of more severe so-called 'hantavirus cardio-pulmonary syndrome' (HCPS) cases, mostly described hitherto in the New World. In more severe AKI cases, the mean total cholesterol was significantly lower (p = 0.02) than in milder cases, i.e. cases with peak serum creatinine levels of < 1.5 mg/dL. Thrombocytopaenia, generally accepted as the severity index in HTVF, appeared, moreover, significantly correlated with serum levels of total cholesterol (R = 0.52, p < 0.001) and with serum levels of HDLc (R = 0.45, p < 0.01). A link with the novel clinical entity of haemophagocytic syndromes, also characterised by manifest hypertriglyceridaemia, is discussed.

Diagnostic utility of bone marrow examination for the assessment of patients with fever of unknown origin: a 10-year single-centre experience.

Bone marrow (BM) examination is included in the diagnostic algorithm of fever of unknown origin (FUO), although its role is not clearly determined. The purpose of this study was to assess the role of BM studies in patients with FUO. We retrospectively reviewed 45 consecutive patients (25% human immunodeficiency virus-positive) with FUO who underwent a BM study in the University Hospital of Salamanca from 2000 to 2010. We analysed the diagnostic role of BM smears, multiparameter flow cytometry analysis, histology and microbiological cultures. Five patients (11%) were finally diagnosed by BM study (three had an infectious disease and two were found to have haematological malignancies), all of whom were immunocompetent patients. Histology was the most useful study (diagnosis was obtained in 4/5 patients), while BM cultures did not establish the final diagnosis in any patient. Flow cytometry established the diagnosis in one patient, although this patient was also diagnosed by histology. In conclusion, BM study is useful for establishing the aetiology of FUO. BM biopsy for histological examination should be always mandatory if a BM examination is performed.

Marrow assessment for hemophagocytic lymphohistiocytosis demonstrates poor correlation with disease probability.

OBJECTIVES: To evaluate the amount of hemophagocytosis in 64 marrow core biopsy specimens and aspirates from 58 patients with clinical suspicion for secondary hemophagocytic lymphohistiocytosis (HLH) or reported findings of hemophagocytosis. METHODS: A review of medical records assigned patients to a low-risk (45 patients) or high-risk (13 patients) HLH group, and association with histologic findings was examined using the Fisher exact test. RESULTS: The amount of hemophagocytosis in aspirate or the core biopsy specimen did not correlate with disease probability (P = .17 and P = .63, respectively). Of the clinical/laboratory criteria assessed, the most significant correlations with HLH were highly elevated ferritin (P = .01), cytopenias (P = .02), and fever (P = .009). CONCLUSIONS: Our findings indicated that marrow histologic findings alone do not reliably predict the probability of HLH, and an isolated finding of hemophagocytosis, even when present in a high amount, lacks specificity for HLH.

A clinicopathological analysis of 26 patients with infection-associated haemophagocytic lymphohistiocytosis and the importance of bone marrow phagocytosis for the early initiation of immunomodulatory treatment.

OBJECTIVE: To analyse the clinicopathological presentation, outcome and importance of bone marrow haemophagocytosis in patients with infection-associated haemophagocytic lymphohistiocytosis (IA-HLH) in a tertiary care hospital in Northern India. STUDY DESIGN: Between January 2007 and December 2009, 26 consecutive patients meeting the diagnostic criteria for IA-HLH, based on the HLH2004 protocol of the Histiocyte Society, were followed up for between 12 and 34 months (median 20 months). RESULTS: IA-HLH was diagnosed in three of the five patients who died 5-6 weeks after the onset of the illness, whereas diagnosis in the remaining group was made a median of 2 weeks after the onset of the illness. The predominant presenting features were fever (100%), hepatomegaly (69%), splenomegaly (58%) and anaemia (96%). All patients showed >3% haemophagocytosis on bone marrow studies-in four cases after serial aspiration/biopsies. Twenty-one (80.8%) cases were non-fatal and five (19.2%) patients died. The non-fatal cases included eight (38.1%) cases of viral infection, seven (33.3%) bacterial infections, two (9.6%) fungal and four (19.0%) protozoal infections; whereas four (80%) bacterial infections and one (20%) viral infection were associated with the fatal cases. The mean of the nadir blood counts of white blood cells, absolute neutrophil counts and platelets; the mean of all the peak biochemical parameters of liver function tests, lactate dehydrogenase and ferritin and the lowest fibrinogen values before treatment, differed significantly (p<0.05) between the non-fatal and the fatal group, being worse in the latter. CONCLUSIONS: IA-HLH is important because it can obscure the typical clinical features of the underlying primary disease, thus delaying the diagnosis and having a negative effect on the outcome. Although bone marrow haemophagocytosis is not a mandatory diagnostic criterion, we found it to be a useful tool together with biochemical parameters for early recognition of HLH, especially in developing countries lacking molecular and flow laboratories. The severity of pancytopenia and derangement in biochemical markers were significantly higher in the patients who died.

Serum ferritin is a cost-effective laboratory marker for hemophagocytic lymphohistiocytosis in the developing world.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease in children and presents many diagnostic difficulties. Without prompt intervention, the disease typically runs a rapidly fatal course. Diagnostic criteria were proposed by the Histiocyte Society in 1991 and have since been modified. Included in these criteria is a ferritin level >500 mcg/L. Although not diagnostic, a high ferritin level is highly suggestive of HLH. Serum ferritin assays are more accessible and cost-effective compared with other biochemical markers, particularly in resource-limited settings. Fifteen patients with HLH were treated at Red Cross War Memorial Children's Hospital between 1991 and 2010. Hyperferritinemia was a consistently reliable finding (93%) compared with either serum fibrinogen or triglycerides, which were elevated in only half of the patients. It is our contention that analysis of a complete blood count and serum ferritin (in addition to clinical criteria and tissue examination of marrow and/or cerebrospinal fluid) is probably the single most cost-effective and clinically helpful means to make the diagnosis of HLH when laboratory access is limited.

Clinical assessment of Mycoplasma pneumoniae-associated hemophagocytic lymphohistiocytosis.

BACKGROUND: Mycoplasma pneumoniae has been reported to be an etiologic pathogen of infection-associated hemophagocytic lymphohistiocytosis (HLH), but few case reports have been available to date. METHODS: The clinical features of four childhood cases of M. pneumoniae-associated hemophagocytic lymphohistiocytosis (Mp-HLH) were retrospectively assessed to obtain data that might be useful for early diagnosis and effective management. The previous English-language literature pertaining to Mp-HLH was also reviewed. RESULTS: The patients were two boys and two girls, aged between 1 and 11 years of age. One patient was demonstrated to have concurrent infection with rubella. All the patients had typical radiographic features of M. pneumoniae pneumonia, and one patient also had encephalopathy as a complication. All the children underwent bone marrow examination because of antibiotic-refractory fever, mild hepatosplenomegaly, cytopenia, hyperferritinemia and elevated levels of urine beta2-microglobulin. Cytopenia and hepatosplenomegaly in the present patients were relatively mild as compared to those in cases of other infection-associated HLH such as Epstein-Barr virus infection-associated HLH. Treatment with corticosteroids resulted in prompt and complete resolution in two cases, and i.v. high-dose gammaglobulin therapy achieved a complete response in another child. Spontaneous resolution under treatment with antibiotics alone was observed in one case. CONCLUSION: Although Mp-HLH is a rare complication of M. pneumoniae infection, it should always be considered in patients with antibiotic-refractory M. pneumoniae infections with cytopenia. Mp-HLH might be effectively treated by corticosteroids or high-dose gammaglobulin. To clarify the diverse clinical manifestations of M. pneumoniae infections, immunological interactions between M. pneumoniae and the host immune system should be further investigated.

A direct immunoassay assessment of streptavidin- and N-hydroxysuccinimide-modified biochips in validation of serological TNFalpha responses in hemophagocytic lymphohistiocytosis.

The authors report 2 biochip platforms on gold manufactured by either nanoscale biotinylated self-assembled architectures to streptavidin surface or proteins containing free NH(2) groups to N-hydroxysuccinimide (NHS)-activated surfaces and investigated the potential application of tumor necrosis factor-alpha (TNFalpha) serodiagnosis of hemophagocytic lymphohistiocytosis (HLH). Interactions of TNFalpha antigen and TNFalpha antibody on the biochips were optimized using an indirect immunofluorescence method. Variation coefficients were 1.87% to 4.56% on the streptavidin biochip and 5.03% to 8.64% on the NHS biochip. The correlation coefficients (r) in TNFalpha and TNFalpha antibody assays in HLH patients between the 2 biochip formats were 0.9623 and 0.9386 and the concordance frequencies were 92.2% and 96.1%, respectively. To detect plasma TNFalpha-receptor complexes (TNFR1 and R2) in HLH, a biochip assay strategy was developed. Plasma levels of TNFalpha, TNFalpha antibody, and TNFalpha-receptor complexes (TNFR1 and R2) were detected in plasmas from 42 HLH cases using streptavidin biochips. Frequencies of the biomarkers in the plasmas were 40.5% (17/42) for TNFalpha, 30.9% (13/42) for TNFalpha antibody, 28.6% (12/42) for TNFalpha-receptor 1 complex, and 26.1% (11/42) for TNFalpha-receptor 2 complex, respectively. The streptavidin biochip format was more sensitive than the NHS surface and was demonstrated to be a valuable tool to identify individual biomarker molecules and molecular complexes in sera and cell lysates and to track therapeutic progress of patients.