Low interleukin-10 level indicates a good prognosis in Salmonella enterica serovar typhimurium-induced pediatric hemophagocytic lymphohistiocytosis:A case report

BACKGROUND Secondary hemophagocytic lymphohistiocytosis(sHLH)triggered by Salmonella enterica serovar Typhimurium is rare in pediatric patients.There is no consensus on how to treat S.typhimurium-triggered sHLH.CASE SUMMARY A 9-year-old boy with intermittent fever for 3 d presented to our hospital with positive results for S.typhimurium,human rhinovirus,and Mycoplasma pneumoniae infections.At the time of admission to our institution,the patient’s T helper 1/T helper 2 cytokine levels were 326 pg/mL for interleukin 6(IL-6),9.1 pg/mL for IL-10,and 246.7 pg/mL for interferon-gamma(IFN-γ),for which the ratio of IL-10 to IFN-γwas 0.04.In this study,the patient received meropenem,linezolid,and cefoperazone/sulbactam in combination with high-dose methylprednisolone therapy(10 mg/kg/d for 3 d)and antishock supportive treatment twice.After careful evaluation,this patient did not receive HLH chemotherapy and recovered well.CONCLUSION S.Typhimurium infection-triggered sHLH patient had a ratio of IL-10 to IFN-γ≤1.33,an IL-10 concentration≤10.0 pg/mL,and/or an IFN-γconcentration≤225 pg/mL at admission.Early antimicrobial and supportive treatment was sufficient,and the HLH-94/2004 protocol was not necessary under these conditions.

Hemophagocytic lymphohistiocytosis triggered by relapsing polychondritis:A case report

BACKGROUND Hemophagocytic lymphohistiocytosis(HLH)is a rare,life-threatening disorder caused by abnormal histiocytes and T cell activation.In adults,it is predominantly associated with infections,cancers,and autoimmune diseases.Relapsing polychondritis(RP),another rare disease,is diagnosed based on symptoms without specific tests,featuring cartilage inflammation characterized by swelling,redness,and pain,rarely inducing HLH.CASE SUMMARY A 74-year-old woman visited the emergency room with a fever of 38.6℃.Blood tests,cultures,and imaging were performed to evaluate fever.Results showed increased fluorescent antinuclear antibody levels and mild cytopenia,with no other specific findings.Imaging revealed lymph node enlargement was observed;however,biopsy results were inconclusive.Upon re-evaluation of the physical exam,inflammatory signs suggestive of RP were observed in the ears and nose,prompting a tissue biopsy for confirmation.Simultaneously,persistent fever accompanied by cytopenia prompted a bone marrow examination,revealing hemophagocytic cells.After finding no significant results in blood culture,viral markers,and tissue examination of enlarged lymph nodes,HLH was diagnosed by RP.Treatment involved methylprednisolone followed by azathioprine.After two months,bone marrow examination confirmed resolution of hemophagocytosis,with normalization of hyperferritinemia and pancytopenia.CONCLUSION Thorough physical examination enabled diagnosis and treatment of HLH trig gered by RP in patients presenting with fever of unknown origin.

Familial hemophagocytic lymphohistiocytosis type 2 in a female Chinese neonate:A case report and review of the literature

BACKGROUND Familial hemophagocytic lymphohistiocytosis type 2(FHL2)is a rare genetic disorder presenting with fever,hepatosplenomegaly,and pancytopenia secondary to perforin-1(PRF1)mutation.FLH2 has been described in Chinese but usually presents after 1 year old.We describe a female Chinese neonate with FHL2 secondary to compound heterozygous PRF1 mutation with symptom onset before 1 mo old.We review Chinese FHL2 patients in the literature for comparison.CASE SUMMARY A 15-d-old female neonate was referred to our hospital for persistent fever and thrombocytopenia with diffuse petechiae.She was born to a G5P3 mother at 39 wk and 4 d via cesarean section secondary to breech presentation.No resuscitation was required at birth.She was described to be very sleepy with poor appetite since birth.She developed a fever up to 39.5°C at 7 d of life.Leukocytosis,anemia,and thrombocytopenia were detected at a local medical facility CONCLUSION A literature review identified 75 Chinese FHL2 patients,with only five presenting in the first year of life.Missense and frameshift mutations are the most common PRF1 mutations in Chinese,with 24.8%having c.1349C>T followed by 11.6%having c.65delC.The c.658G>C mutation has only been reported once in the literature and our case suggests it can be pathogenic,at least in the presence of another pathogenic mutation such as c.1066C>T.

Successful rescue of acute liver failure and hemophagocytic lymphohistiocytosis following varicella infection: A case report and review of literature

Herein we report a case of acute liver failure(ALF) and hemophagocytic lymphohistiocytosis(HLH) induced by varicella infection, successfully rescued by a combination therapy of acyclovir, supportive care, and immunosuppression with dexamethasone and etoposide. A previously healthy 16-year-old boy presented with generalized rash, fever, severe abdominal pain, and abnormal liver function within 4 d. Chickenpox was suspected, and acyclovir and intravenous immunoglobulin were started on admission. However, the patient's condition deteriorated overnight with soaring transaminases, severe coagulopathy and encephalopathy. On the fourth day of admission, pancytopenia emerged, accompanied by hypofibrinogenemia and hyperferritinemia. The patient was diagnosed with ALF. He also met the diagnostic criteria of HLH according to the HLH-2004 guideline. Polymerase chain reaction(PCR) amplifications of varicella-zoster virus(VZV) were positive, confirming that VZV was a causative trigger for ALF and HLH. In view of the devastating immune activation in HLH, immunosuppression therapy with dexamethasone and etoposide was administered, in addition to high dose acyclovir. The patient's symptoms improved dramatically and he finally made a full recovery. To our knowledge, this is only the second report of a successful rescue of ALF associated with HLH, without resorting to liver transplantation. The first case was reported in a neonate infected by herpes simplex virus-1. However, survival data in older children and adults are lacking, most of whom died or underwent liver transplantation. Our report emphasizes the clinical vigilance for the possible presence of HLH, and the necessity of extensive investigation for underlying etiologies in patients presenting with indeterminate ALF. Early initiation of specific therapy targeting the underlying etiology, and watchful immunosuppression such as dexamethasone and etoposide, together with supportive therapy, are of crucial importance in this life-threatening disorder.

Acute liver failure secondary to severe systemic disease from fatal hemophagocytic lymphohistiocytosis:Case report and systematic literature review

AIM To systematically review liver disease associated with hemophagocytic lymphohistiocytosis(HLH),propose reasonable contraindications for liver transplantation for liver failure in HLH,and report an illustrative case.METHODS Systematic review according to PRISMA guidelines of hepatic manifestations of HLH using computerizedliterature search via PubMed of articles published since 1980 with keywords("hemophagocytic lymphohistiocytosis" or "HLH") AND("liver" or "hepatic"). Two authors independently performed literature search and incorporated articles into this review by consensus. Illustrative case report presented based on review of medical chart,and expert re-review of endoscopic photographs,radiologic images,and pathologic slides. RESULTS A 47-year-old Caucasian male,was hospitalized with high-grade pyrexia,rash,total bilirubin = 45 g/dL,moderately elevated hepatic transaminases,ferritin of 3300 ng/dL,leukopenia,and profound neutropenia(absolute neutrophil count < 100 cells/mm3). Viral serologies for hepatitis A,B,and C were negative. Abdominal computed tomography scan and magnetic resonance imaging revealed no hepatic or biliary abnormalities. Pathologic analysis of liver biopsy revealed relatively well-preserved hepatic parenchyma without lymphocytic infiltrates or macrophage invasion,except for sparse,focal hepatocyte necrosis. Bone marrow biopsy and aspirate revealed foamy macrophages engulfing mature and precursor erythrocytes,consistent with HLH. Interleukin-2 receptor(CD25) was highly elevated,confirming diagnosis of HLH according to Histiocytic Society criteria. Patient initially improved after high-dose prednisone therapy. Patient was judged not to be a liver transplant candidate despite model for end stage liver disease(MELD) score = 33 because liver failure was secondary to severe systemic disease from HLH,including septic shock,focal centrilobular hepatocyte necrosis from hypotension,bone marrow failure,and explosive immune activation from HLH. The patient eventually succumbed to overwhelming sepsis,progressive liver failure,and disseminated intravascular coagulopathy. Systematic review reveals liver injury is very common in HLH,and liver failure can sometimes occur. Data on liver transplantation for patients with HLH are very limited,and so far the results have shown a generally much worse prognosis than for other liver transplant indications. Liver transplantation should not be guided solely by MELD score,but should include liver biopsy results and determination whether liver failure is from intrinsic liver injury vs multisystem(extrahepatic) organ failure from HLH.CONCLUSION This case report illustrates that liver transplantation may not be warranted when liver failure associated with HLH is primarily from multisystem failure from HLH. Liver biopsy may be very helpful in determining the severity and pathophysiology of the liver disease.

Hemophagocytic lymphohistiocytosis caused by STAT1 gain-offunction mutation is not driven by interferon-γ:A case report

BACKGROUND Hemophagocytic lymphohistiocytosis(HLH)is a life-threatening hyperinflammatory syndrome caused by many genetic defects.STAT1 is a DNAbinding factor that regulates gene transcription.HLH caused by STAT1 gain-offunction(GOF)mutations has rarely been reported and its clinical manifestations and mechanisms are not clearly defined.CASE SUMMARY A 2-year-old boy presented to our hospital with recurrent fever for>20 d.The patient had a personal history of persistent oral candidiasis and inoculation site infection during the past 2 years.Hepatosplenomegaly was noted.Complete blood cell count showed severe anemia,thrombocytopenia and neutropenia.Other laboratory tests showed liver dysfunction,hypertriglyceridemia and decreased fibrinogen.Hemophagocytosis was found in the bone marrow.Chest computed tomography showed a cavitary lesion.Tests for fungal infection were positive.Serum T helper(Th)1/Th2 cytokine determination demonstrated moderately elevated levels of interleukin(IL)-6 and IL-10 with normal interferon(IFN)-γconcentration.Mycobacterium bovis was identified in bronchoalveolar lavage fluid by polymerase chain reaction.Genetic testing identified a heterozygous mutation of c.1154C>T causing a T385M amino acid substitution in STAT1.Despite antibacterial and antifungal therapy,the febrile disease was not controlled.The signs of HLH were relieved after HLH-94 protocol administration,except fever.Fever was not resolved until he received anti-tuberculosis therapy.Hematopoietic stem cell transplantation was refused and the patient died six months later due to severe pneumonia.CONCLUSION Patients with STAT1 GOF mutation have broad clinical manifestations and may develop HLH.This form of HLH presents with normal IFN-γlevel without cytokine storm.

Hemophagocytic lymphohistiocytosis caused by primary Epstein-Barr virus in patient with Crohn's disease

We present a case of a 19-year-old man with a 6-year history of Crohn's disease(CD), previously treated with 6-mercaptopurine, who was admitted to our department for Epstein-Barr virus(EBV) infection and subsequently developed a hemophagocytic lymphohistiocytosis(HLH). HLH is a rare disease which causes phagocytosis of all bone marrow derived cells. It can be a primary form as a autosomic recessive disease, or a secondary form associated with a variety of infections; EBV is the most common, the one with poorer prognosis. The incidence of lymphoproliferative disorders was increased in patients with inflammatory bowel disease(IBD) treated with thiopurines. Specific EBV-related clinical and virological management should be considered when treating a patient with IBD with immunosuppressive therapy. Moreover EBV infection in immunosuppressed patient can occur with more aggressive forms such as encephalitis and diffuse large B cell lymphoma. Our case confirms what is described in the literature; patients with IBD, particularly patients with CD receiving thiopurine therapy, who present 5 d of fever and cervical lymphadenopathy or previous evidence of lymphopenia should be screened for HLH.

Epstein–Barr virus-associated hemophagocytic syndrome in a patient with ulcerative colitis during treatment with azathioprine: A case report and review of literature

A 19-year-old female was diagnosed with ulcerative colitis when she presented with persistent melena, and has been treated with 5-aminosalicylic acid for 4 years, with additional azathioprine for 2 years at our hospital. The patient experienced high-grade fevers, chills, and cough fve d prior to presenting to the outpatient unit. At frst, the patient was suspected to have developed neutropenic fever; however, she was diagnosed with Epstein-Barr virus-associated hemophagocytic syndr-ome （EB-VAHS） upon fulfilling the diagnostic criteria after bone marrow aspiration. When patients withinflammatory bowel disease treated with immunomo-dulators, such as thiopurine preparations, develop fever, EB-VAHS should be considered in the differential diagnosis.

Adult onset type 2 familial hemophagocytic lymphohistiocytosis with PRF1 c.65delC/c.163C>T compound heterozygous mutations: A case report

BACKGROUND Familial hemophagocytic lymphohistiocytosis(FHL)is a primary immunodeficiency disease caused by gene defects.The onset of FHL in adolescents and adults may lead clinicians to ignore or even misdiagnose the disease.To the best of our knowledge,this is the first report to detail the clinical features of type 2 FHL(FHL2)with compound heterozygous perforin(PRF1)defects involving the c.163C>T mutation,in addition to correlation analysis and a literature review.CASE SUMMARY We report a case of a 27-year-old male patient with FHL2,who was admitted with a persistent fever and pancytopenia.Through next-generation sequencing technology of hemophagocytic lymphohistiocytosis(HLH)-related genes,we found compound heterozygous mutations of PRF1:c.65delC(p.Pro22Argfs*29)(frameshift mutation,paternal)and c.163C>T(p.Arg55Cys)(missense mutation,maternal).Although he did not receive hematopoietic stem cell transplantation,the patient achieved complete remission after receiving HLH-2004 treatment protocol.To date,the patient has stopped taking drugs for 15 mo,is in a stable condition,and is under follow-up observation.CONCLUSION The delayed onset of FHL2 may be related to the PRF1 mutation type,pathogenic variation pattern,triggering factors,and the temperature sensitivity of some PRF1 mutations.For individual,the detailed reason for the delay in the onset of FHL warrants further investigation.

Diagnostic value of bone marrow cell morphology in visceral leishmaniasis-associated hemophagocytic syndrome:Two case reports

BACKGROUND Visceral leishmaniasis related-hemophagocytic lymphohistiocytosis(VL-HLH)is a hemophagocytic syndrome caused by Leishmania infection.VL-HLH is rare,especially in nonendemic areas where the disease is severe,and mortality rates are high.The key to diagnosing VL-HLH is to find the pathogen;therefore,the Leishmania must be accurately identified for timely clinical treatment.CASE SUMMARY We retrospectively analyzed the clinical data,laboratory examination results,and bone marrow cell morphology of two children with VL-HLH diagnosed via bone marrow cell morphology at Kunming Children’s Hospital of Yunnan,China.Both cases suspected of having malignant tumors at other hospitals and who were unresponsive to treatment were transferred to Kunming Children’s Hospital.They are Han Chinese girls,one was 2 years old and the other one is 9 mo old.They had repeated fevers,pancytopenia,hepatosplenomegaly,hypertriglyceridemia,and hypofibrinogenemia over a long period and met the HLH-2004 criteria.Their HLH genetic test results were negative.Both children underwent chemotherapy as per the HLH-2004 chemotherapy regimen,but it was ineffective and accompanied by serious infections.We found Leishmania amastigotes in their bone marrow via morphological examination of their bone marrow cells,which showed hemophagocytic cells;thus,the children were diagnosed with VL-HLH.After being transferred to a specialty hospital for treatment,the condition was well-controlled.CONCLUSION Morphological examination of bone marrow cells plays an important role in diagnosing VL-HLH.When clinically diagnosing secondary HLH,VL-HLH should be considered in addition to common pathogens,especially in patients for whom HLH-2004 chemotherapy regimens are ineffective.For infants and young children,bone marrow cytology examinations should be performed several times and as early as possible to find the pathogens to reduce potential misdiagnoses.

Infection-associated Hemophagocytic Syndrome in Critically Ill Patients with COVID-19

Infection-associated hemophagocytic syndrome(IAHS),a severe complication of various infections,is potentially fatal.This study aims to determine whether IAHS occurs in critically ill patients with coronavirus disease 2019(COVID-19).We conducted a retrospective observational study on 268 critically ill patients with COVID-19 between February 1st,2020 and February 26th,2020.Demographics,clinical characteristics,laboratory results,information on concurrent treatments and outcomes were collected.A diagnosis of secondary hemophagocytic lymphohistiocytosis(sHLH)was made when the patients had an HScore greater than 169.Histopathological examinations were performed to confirm the presence of hemophagocytosis.Of 268 critically ill patients with confirmed SARS-CoV-2 infection,17(6.3%)patients had an HScore greater than 169.All the 17 patients with sHLH died.The interval from the onset of symptom of COVID-19 to the time of a diagnosis of sHLH made was 19 days and the interval from the diagnosis of sHLH to death was 4 days.Ten(59%)patients were infected with only SARS-CoV-2.Hemophagocytosis in the spleen and the liver,as well as lymphocyte infiltration in the liver on histopathological examinations,was found in 3 sHLH autopsy patients.Mortality in sHLH patients with COVID-19 is high.And SARS-CoV-2 is a potential trigger for sHLH.Prompt recognition of IAHS in critically ill patients with COVID-19 could be beneficial for improving clinical outcomes.

Hemophagocytic lymphohistiocytosis: Recent progress in the pathogenesis, diagnosis and treatment

Hemophagocytic lymphohistiocytosis(HLH) is a hyperinflammatory syndrome that develops as a primary(familial/hereditary) or secondary(non-familial/hereditary) disease characterized in the majority of the cases by hereditary or acquired impaired cytotoxic T-cell(CTL) and natural killer responses. The molecular mechanisms underlying impaired immune homeostasis have been clarified, particularly for primary diseases. Familial HLH(familial hemophagocytic lymphohistiocytosis type 2-5, Chediak-Higashi syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome type 2) develops due to a defect in lytic granule exocytosis, impairment of(signaling lymphocytic activation molecule)-associated protein, which plays a key role in CTL activity [e.g., X-linked lymphoproliferative syndrome(XLP) 1], or impairment of X-linked inhibitor of apoptosis, a potent regulator of lymphocyte homeostasis(e.g., XLP2). The development of primary HLH is often triggered by infections, but not in all. Secondary HLH develops in association with infection, autoimmune diseases/rheumatological conditions and malignancy. The molecular mechanisms involved in secondary HLH cases remain unknown and the pathophysiology is not the same as primary HLH. For either primary or secondary HLH cases, immunosuppressive therapy should be given to control the hypercytokinemia with steroids, cyclosporine A, or intravenous immune globulin, and if primary HLH is diagnosed, immunochemotherapy with a regimen containing etoposide or anti-thymocyte globulin should be started. Thereafter, allogeneic hematopoietic stem-cell transplantation is recommended for primary HLH or secondary refractory disease(especially EBVHLH).

Hemophagocytic lymphohistiocytosis secondary to composite lymphoma:Two case reports

BACKGROUND Hemophagocytic lymphohistiocytosis(HLH)is a rare and life-threatening disease caused by inherited pathogenic mutations and acquired dysregulations of the immune system.Composite lymphoma is defined as two or more morphologically and immunophenotypically distinct lymphomas that occur in a single patient.Here,we report two cases of HLH secondary to composite lymphoma with mixed lineage features of T-and B-cell marker expression both in the bone marrow and lymph nodes in adult patients.CASE SUMMARY Two patients were diagnosed with HLH based on the occurrence of fever,pancytopenia,lymphadenopathy,splenomegaly,hemophagocytosis and hyperferritinemia.Immunohistochemical staining of the axillary lymph node and bone marrow in case 1 showed typical features of combined B-cell and T-cell lymphoma.In addition,a lymph node gene study revealed rearrangement of the T-cell receptor chain and the immunoglobulin gene.Morphology and immunohistochemistry studies of a lymph node biopsy in case 2 showed typical features of T cell lymphoma,but immunophenotyping by flow cytometry analysis of bone marrow aspirate showed B cell lymphoma involvement.The patients were treated with high-dose methylprednisolone combined with etoposide to control aggressive HLH progression.The patients also received immunochemotherapy with the R-CHOP(rituximab,cyclophosphamide,doxorubicin,vincristine,and prednisone)regimen immediately after diagnosis.Both patients presented with highly aggressive lymphoma,and died of severe infection or uncontrolled HLH.CONCLUSION We present two rare cases with overwhelming hemophagocytosis along with composite T-and B-cell lymphoma,which posed a diagnostic dilemma.HLH caused by composite lymphoma was characterized by poor clinical outcomes.

Clinical and Biological Significance of Clonal Macrophage Detection in Hemophagocytic Syndrome

Summary: By using the method of clonal analysis the evidence to prove that Hemophagocytic syndrome (HPS) is reactive or malignant was investigated to probe into the pathogenesis of HPS and its relations with clinical prognosis. The macrophages abnormally proliferated in bone marrow were isolated. Electrophoresis analysis was made after DNA extraction, enzyme restriction of human ardrogen receptor (HUMARA) genetic locus, and PCR amplification. In the 9 specimens, clonal proliferation was found in 2 cases and nonclonal proliferation in 7. Among the 7 cases of nonclonal proliferation, 3 were voluntarily discharged without clinical outcome, 2 cases fully recovered after 2-3 week treatment of large dose gamma globulin intravenous drip and hormone therapy, 1 case died at the 43th day after the hormone and anti-infection therapy, and one case was found to have granular leukoblast in peripheral blood after 3 weeks and diagnosed as having M2a after bone puncture. For the two patients with clonal proliferation, one obtained remission after chemotherapy and the other was died after 32 days without chemotherapy. It was concluded that there do exist clonal or malignant proliferation in HPS, so not every case is reactive.

Unusual presentation of systemic lupus erythematosus as hemophagocytic lymphohistiocytosis in a female patient: A case report

BACKGROUND Hemophagocytic lymphohistiocytosis(HLH) is a rare life-threatening disorder,often resulting in the immune-mediated injury of multiple organ systems,including primary HLH and secondary HLH(sHLH). Among them, sHLH results from infections, malignant, or autoimmune conditions, which have quite poor outcomes even with aggressive management and are more common in adults.CASE SUMMARY We report a rare case of a 36-year-old female manifested with sHLH on background with systemic lupus erythematosus(SLE). During hospitalization, the patient was characterized by recurrent high-grade fever, petechiae and ecchymoses of abdominal skin, and pulmonary infection. Whole exon gene sequencing revealed decreased activity of natural killer cells. She received systematic treatment with Methylprednisolone, Etoposide, and anti-infective drugs. Intravenous immunoglobulin and plasmapheresis were applied when the condition was extremely acute and progressive. The patient recovered and did not present any relapse of the HLH for one year of follow-up.CONCLUSION The case showed sHLH, thrombotic microvascular, and infection in the whole course of the disease, which was rarely reported by now. The treatment of the patient emphasizes that early recognition and treatment of sHLH in SLE patients was of utmost importance to improve the prognosis and survival rate of patients.

Aggressive natural killer cell leukemia with skin manifestation associated with hemophagocytic lymphohistiocytosis:A case report

BACKGROUND Aggressive natural killer cell leukemia(ANKL)is a rare natural killer cell neoplasm characterized by systemic infiltration of Epstein–Barr virus and rapidly progressive clinical course.ANKL can be accompanied with hemophagocytic lymphohistiocytosis(HLH).Here,we report a case of ANKL with rare skin lesions as an earlier manifestation,accompanied with HLH,and review the literature in terms of etiology,clinical manifestation,diagnosis and treatment.CASE SUMMARY A 30-year-old woman from Northwest China presented with the clinical characteristics of jaundice,fever,erythema,splenomegaly,progressive hemocytopenia,liver failure,quantities of abnormal cells in bone marrow,and associated HLH.The immunophenotypes of abnormal cells were positive for CD2,cCD3,CD7,CD56,CD38 and negative for sCD3,CD8 and CD117.The diagnosis of ANKL complicated with HLH was confirmed.Following the initial diagnosis and supplementary treatment,the patient received chemotherapy with VDLP regimen(vincristine,daunorubicin,L-asparaginase and prednisone).However,the patient had severe adverse reactions and complication such as severe hematochezia,neutropenia,and multiple organ dysfunction syndrome,and died a few days later.CONCLUSION This is the first reported case of ANKL with rare skin lesions as an earlier manifestation and associated with HLH.

Successful treatment of adult-onset still disease caused by pulmonary infection-associated hemophagocytic lymphohistiocytosis: A case report

BACKGROUND Adult-onset still disease(AOSD) and hemophagocytic syndrome(HPS) are two inflammatory diseases with very similar clinical manifestations. HPS is one of the most serious complications of AOSD and its risk of death is very high. It is difficult to identify HPS early in patients with AOSD, but early identification and proper treatment directly affects the prognosis.CASE SUMMARY A 39-year-old male showed a high spiking fever and myalgia. Laboratory data revealed elevated white blood cell, serum ferritin, and neutrophil percentage.However, his fever failed to relieve after a clear diagnosis of AOSD caused by pulmonary infection and treatment by antibiotics and corticosteroids;further laboratory data showed elevated serum ferritin, C-reactive protein, erythrocyte sedimentation rate and triglyceride, as well as liver abnormalities. Bone marrow smear showed hemophagocytosis. Secondary HPS was definitely diagnosed. The high fever disappeared and the laboratory findings returned to normal values after treatment by high-dose intravenous methylprednisolone and methotrexate.CONCLUSION For AOSD patients with high suspicion of HPS, active examination needs to be considered for early diagnosis, and timely using of adequate amount of corticosteroids is the key to reducing risk of HPS death.

Unexpected Occurrence of Fetal Hemophagocytic Syndrome in a Patient with Hereditary Diffuse Leukoencephalopathy with Spheroids

Colony stimulating factor-1 receptor (CSF1R) plays important roles in the differentiation and proliferation of macrophage and microglia in systemic organs and the brain. A genetic defect in CSF1R causes hereditary diffuse leukoencephalopathy with spheroids (HDLS). HDLS mainly affects the cerebral white matter and shows pre-senile cognitive decline, motor disturbance, and epilepsy. However, systemic manifestations outside the brain have not yet been described in patients with HDLS. Here, we report the case of a 41-year-old man with HDLS carrying the p. K793T mutation in CSF1R, who unexpectedly died of sepsis and hemophagocytic syndrome shortly after the onset of HDLS. The fetal sequence of sepsis and hemophagocytic syndrome was triggered by enterocolitis. An autopsy revealed that focal inflammation in the intestine had almost resolved. Most strikingly, massive infiltration of cluster of differentiation (CD) 68- and CD163-immunopositive macrophages with hemophagocytosis was observed in the bone marrow, spleen, and liver. Less abundant infiltration of CD68- and CD204-immunopositive macrophages without hemophagocytosis was also seen in the lung and intestine. At present, the pathogenetic link between CSF1R mutation and hemophagocytic syndrome in this patient is unclear. Our case, however, clearly shows that even in patients with HDLS, aberrant activation of functional macrophages can be induced under certain conditions in visceral organs.

Hemophagocytic lymphohistiocytosis complicated by polyserositis:A case report

BACKGROUND Hemophagocytic lymphohistiocytosis(HLH)is a rare group of disorders of immune dysregulation characterized by clinical symptoms of severe inflammation.There are basically two types of clinical scenarios:Familial HLH and sporadic HLH.It is thought that the syndrome is implicated in the development of infections,malignancies,and autoimmune diseases.HLH,whether primary or secondary,is characterized by activated macrophages in hematopoietic organs,hepatosplenomegaly,cytopenia,and fever;however,HLH complicated with polyserositis(PS)has never been reported.CASE SUMMARY We present a case of fever in a 46-year-old previously healthy Chinese woman complicated by pericardial,pleural,and abdomen effusions.She had no contact with sick individuals,recent travel,illicit drug use,or new sexual contacts.She did not consume alcohol or tobacco and lacked a family history of other diseases.Antibiotics were prescribed for suspected infection,and acute liver injury subsequently occurred.Contrast-enhanced computed tomography showed mild pericardial effusion,pleural effusion,hepatosplenomegaly,and a large amount of ascites.A full blood count revealed leukopenia and thrombocytopenia.Increased ferritin and triglyceride levels were observed.The test for Epstein-Barr(EB)virus DNA was positive.This suggests that EB virus replication and EB virus infection existed.Additional studies showed hemophagocytosis in bone marrow biopsy specimens.The patient’s condition progressed rapidly.After providing symptomatic support treatment,eliminating immune stimuli,and administering comprehensive cyclosporine and dexamethasone treatment,the patient’s condition continued to progress,and the patient’s family members decided to stop treatment;the patient subsequently died.CONCLUSION This case shows the significance of considering HLH as part of the evaluation of unexplained fever and PS of unknown origin.

Systemic autoimmune abnormalities complicated by cytomegalovirus-induced hemophagocytic lymphohistiocytosis:A case report

BACKGROUND Hemophagocytic lymphohistiocytosis(HLH)is a rare but life-threatening disorder,characterized by a hyperimmune response.The mortality is high despite progress being made in the diagnosis and treatment of the disease.HLH is traditionally divided into primary(familial or genetic)and secondary(reactive)according to the etiology.Secondary HLH(sHLH),more common in adults,is often associated with underlying conditions including severe infections,malignancies,autoimmune diseases,or other etiologies.CASE SUMMARY The case involves a 31-year-old woman,presented with a high persistent fever,rash,and splenomegaly.She met the diagnostic criteria of the HLH-2004 guideline and thus was diagnosed with HLH,with positive anti-nuclear antibody(ANA)and positive cytomegalovirus(CMV)-DNA.The patient responded well to a combination of immunomodulatory,chemotherapy,and supportive treatments.When her PCR evaluation for CMV turned negative,her serum ferritin also dropped significantly.Her clinical symptoms improved dramatically,and except for ANA,the abnormal laboratory findings associated with HLH returned to normal.Our previous study has shown that the median overall survival of HLH patients is only 6 mo;however,our patient has been cured and has not presented with any relapse of the disease for 6 years.CONCLUSION This case emphasizes that thorough early removal of the CMV infection is significant for the prognosis of this HLH patient.