Managing adult-onset Still's disease in pregnancy:A case report

BACKGROUND Adult-onset Still’s disease(AOSD)is a rare systemic inflammatory disorder characterized by fever,arthritis,skin rash,and systemic symptoms.The etiology of AOSD is unknown;however,it is thought to be related to immune dysregulation.Although a rare disease,AOSD can significantly impact reproductive health,particularly during pregnancy.This case study assesses the implications of pregnancy in a patient with AOSD,as well as the potential for heredity of the disease.Neonatal hemophagocytic lympho-histiocytosis(HLH)is a rare and lifethreatening disorder characterized by hyperinflammation and uncontrolled activation of immune cells,leading to multiple organ dysfunction.This case report aimed to introduce neonatal HLH from a mother with AOSD.CASE SUMMARY This case study presents a 29-year-old female with AOSD who became pregnant and gave birth to a premature infant who was diagnosed with neonatal HLH.AOSD can significantly impact pregnancy and childbirth,as it may become more severe during pregnancy,with an increased risk of fetal loss and preterm birth.The management of AOSD during pregnancy involves the use of nonsteroidal anti-inflammatory drugs and glucocorticoids,as well as immunosuppressive agents in severe cases.However,the use of immunosuppressive agents during pregnancy may be associated with potential risks to the fetus.The hereditary implications of AOSD are unclear;however,available evidence suggests that genetic factors may play a role in the disease development.CONCLUSION AOSD can have significant implications for pregnancy and childbirth,including an increased risk of fetal loss and preterm birth.Neonatal HLH,a complication of AOSD in pregnancy,requires prompt diagnosis and management.Women with AOSD who are considering pregnancy should discuss their options with their healthcare provider and develop a management plan that addresses the potential risks to both mother and fetus.

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.

Successful management of infection and macrophage activation syndrome patient using low-dose etoposide:A case report

BACKGROUND Macrophage activation syndrome(MAS),a sub-type of hemophagocytic lymphohistiocytosis(HLH)secondary to autoimmune rheumatic diseases,is a critical and potentially fatal condition characterized by an excessive inflammatory response.Despite the established efficacy of the HLH-2004 guideline in diagnosing and treating HLH over the years,ongoing discussion persists regarding its application,especially for HLH secondary to complicated conditions,such as autoimmune rheumatic diseases combined with severe infection.Etoposide(VP-16),a topoisomerase II inhibitor that effectively induces DNA damage and subsequent apoptosis in hyperactivated immune cells,has been widely used for the treatment of HLH.However,its suppressive effect on immune system may also cause potential exacerbation of infection in autoimmune rheumatic disease-induced HLH patients complicated with severe infection.Therefore,the use of VP-16 in such cases was inconclusive.CASE SUMMARY In this case study,we propose a potentially effective strategy for managing a patient diagnosed with secondary HLH complicated with systemic lupus erythematosus(SLE)and chronic coronavirus disease 2019 infection.Our approach involves early administration of low-dose VP-16(100 mg twice a week,300 mg in total),combined with methylprednisolone,cyclophosphamide,and cyclosporine A.The administration of etoposide effectively led to improvements in various indices of HLH.CONCLUSION Low dose etoposide proves to be an effective approach in alleviating HLH while mitigating the risk of infection.

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.

“Typhoidal Cells”Appear in a Woman with Hemophagocytic Syndrome Secondary To Brucellosis:A Case Report

We report a case of hemophagocytic syndrome(HPS)secondary to brucellosis,in which typhoidal cells were found in bone marrow,suggesting typhoidal cells present not only in Salmonella typhi infections but also in other bacterial infections.Typhoidal cells in bone marrow can be used to quickly identify the presence of bacterial infection pending the results of bone marrow and/or blood cultures.

Angioimmunoblastic T-cell lymphoma induced hemophagocytic lymphohistiocytosis and disseminated intravascular coagulopathy: A case report

BACKGROUND Angioimmunoblastic T-cell lymphoma(AITL) is a subtype of peripheral T-cell lymphoma, with heterogenous clinical manifestations and poor prognosis. Here,we report a case of AITL induced hemophagocytic lymphohistiocytosis(HLH)and disseminated intravascular coagulopathy(DIC).CASE SUMMARY An 83-year-old man presented with fever and purpura of both lower limbs for one month. Groin lymph node puncture and flow cytometry indicated a diagnosis of AITL. Bone marrow examination and other laboratory related indexes indicated DIC and HLH. The patient rapidly succumbed to gastrointestinal bleeding and septic shock.CONCLUSION This is the first reported case of AITL induced HLH and DIC. AITL is more aggressive in older adults. In addition to male gender, mediastinal lymphadenopathy, anaemia, and sustained high level of neutrophil-to-lymphocyte ratio may indicate a greater risk of death. Early diagnosis, early detection of severe complications, and prompt and effective treatment are vital.

Fatal hemophagocytic lymphohistiocytosis-induced multiorgan dysfunction secondary to Burkholderia pseudomallei sepsis: A case report

BACKGROUND Burkholderia pseudomallei(B.pseudomallei)is a short,straight,medium-sized Gramnegative bacterium that mostly exists alone,without a capsule or spores,has more than three flagella at one end,and actively moves.B.pseudomallei confers high morbidity and mortality,with frequent granulocytopenia in B.pseudomallei sepsisrelated deaths.However,mortality may be related to hemophagocytic lymphohistiocytosis(HLH)secondary to B.pseudomallei infection.CASE SUMMARY A 12-year-old female was referred from a local hospital to the pediatric intensive care unit with suspected septic shock and fever,cough,dyspnea,and malaise.After admission,supportive symptomatic treatments including fluid resuscitation,anti-infective therapy,mechanical ventilation,and a vasoactive drug maintenance cycle were carefully initiated.The patient became unconscious,her blood pressure could not be maintained even under the exposure of vasoactive drugs,and she experienced cardiorespiratory arrest.The patient died due to ineffective high-quality in-hospital cardiopulmonary resuscitation.A subsequent bone marrow smear examination revealed extensive phagocytosis,and the blood culture was positive for B.pseudomallei.Family history revealed a sibling death from B.pseudomallei sepsis 5 years earlier.CONCLUSION The higher mortality rate in patients with B.pseudomallei sepsis may be related to secondary HLH after infection,wherein multiorgan dysfunction syndrome may be directly related to infection or immune damage caused by secondary HLH.Patients with B.pseudomallei can be asymptomatic and can become an infective source.

Hemophagocytic lymphohistiocytosis after autologous stem cell transplantation in angioimmunoblastic T-cell lymphoma:A case report

BACKGROUND Angioimmunoblastic T-cell lymphoma(AITL), a unique subtype of peripheral Tcell lymphoma, has relatively poor outcomes. High-dose chemotherapy with autologous stem cell transplantation(ASCT) can achieve complete remission and improve outcomes. Unfortunately, subsequent T-cell lymphoma-triggered hemophagocytic lymphohistiocytosis(HLH) has a worse prognosis than B-cell lymphoma-triggered HLH.CASE SUMMARY We here report a 50-year-old woman with AITL who achieved a favorable outcome after developing HLH 2 mo after receiving high-dose chemotherapy/ASCT. The patient was initially admitted to our hospital because of multiple enlarged lymph nodes. The final pathologic diagnosis, made on biopsy of a left axillary lymph node was AITL(Stage Ⅳ, Group A). Four cycles of the following chemotherapy regimen were administered: Cyclophosphamide 1.3 g, doxorubicin 86 mg, and vincristine 2 mg on day 1;prednisone 100 mg on days 1-5;and lenalidomide 25 mg on days 1-14. The interval between each cycle was 21 d. The patient received a conditioning regimen(busulfan, cyclophosphamide, and etoposide) followed by peripheral blood stem cell infusion. Unfortunately, she developed sustained fever and a low platelet count 17 d after ACST, leading to a diagnosis of HLH after ASCT. During treatment, she experienced thrombocytopenia and Pneumocystis carinii pneumonia. The patient was successfully treated with etoposide and glucocorticoids.CONCLUSION It is possible that development of HLH is related to immune reconstitution after ASCT.

Epstein-Barr virus-induced infection-associated hemophagocytic lymphohistiocytosis with acute liver injury:A case report

BACKGROUND Hemophagocytic lymphohistiocytosis(HLH)is a severe hyperinflammatory reaction,which is rare and life-threatening.According to the pathogen,HLH is divided into genetic and acquired.The most common form of acquired HLH is infection-associated HLH,of which Herpes viruses,particularly Epstein-Barr virus(EBV),are the leading infectious triggers.However,it is difficult to distinguish between simple infection with EBV and EBV-induced infectionassociated HLH since both can destroy the whole-body system,particularly the liver,thereby increasing the difficulty of diagnosis and treatment.CASE SUMMARY This paper elaborates a case about EBV-induced infection-associated HLH and acute liver injury,aiming to propose clinical guides for the early detection and treatment of patients with EBV-induced infection-associated HLH.The patient was categorized as acquired hemophagocytic syndrome in adults.After the ganciclovir antiviral treatment combined with meropenem antibacterial therapy and methylprednisolone inhibition to inflammatory response,gamma globulin enhanced immunotherapy,the patient recovered.CONCLUSION From the diagnosis and treatment of this patient,attention should be paid to routine EBV detection and a further comprehensive understanding of the disease as well as early recognition and early initiation are keys to patients’survival.

Hemophagocytic lymphohistiocytosis with jaundice as first manifestation:A case report

BACKGROUND Hemophagocytic lymphohistiocytosis(HLH)is a rare but life-threatening condition.It is an immune-mediated disease that has a wide range of causes,elicits a hyperinflammatory response,and results in multiple organ damage.Clinical presentations vary,and in some cases,jaundice occurs as the first symptom.CASE SUMMARY We report the case of a 71-year-old female patient who presented with jaundice.She was admitted to our hospital because of the occurrence of“jaundice for half a month”,and upon examination,obstructive jaundice with choledocholithiasis and gallstones was suggested.Cholecystectomy and choledocholithotomy were performed.However,the jaundice did not improve after surgery.We found splenomegaly,cytopenia,hypertriglyceridemia,hypofibrinogenemia,and elevated ferritin.Bone marrow biopsy revealed hemophagocytosis.Later,cardiac arrest occurred when she returned 3 wk after the surgery.We considered that HLH was triggered by septic shock.The patient’s condition deteriorated rapidly,with multiple organ dysfunction and severe gastrointestinal bleeding.Corticosteroid therapy and symptomatic treatment failed to save her life.CONCLUSION Jaundice rarely presents as the first symptom in HLH patients.The HLH in this case was triggered by septic shock with jaundice as the first symptom.Clinicians should try hard to reduce missed diagnoses and misdiagnoses.

Asian variant intravascular large B-cell lymphoma with highly suspected central nervous system involvement:A case report

BACKGROUND Intravascular large B-cell lymphoma(IVLBCL)is a rare subtype of extranodal lymphoma.In particular,the Asian variant of IVLBCL is characterized by hemophagocytic lymphohistiocytosis along with bone marrow involvement.However,central nervous system(CNS)involvement is uncommon in this variant compared to the Western variant.Here,we report a case of typical Asian variant IVLBCL with highly suspected CNS involvement and discuss the nature of the disease and its genetic aberration.CASE SUMMARY A 67-year-old female patient complained of gradually worsening cognitive impairment.While hospitalized,she developed a high fever and showed marked bicytopenia.Intracranial imaging revealed a suspected leptomeningeal disease.Although no malignant cells were found in the cerebrospinal fluid(CSF),the protein and lactate dehydrogenase levels in CSF were increased.Bone marrow examination revealed an increased number of hemophagocytic histiocytes,and 18F-fluorodeoxyglucose(FDG)positron emission tomography with computerized tomography scan revealed increased FDG uptake in both adrenal glands,the liver,and the right ethmoid sinus.A tissue biopsy showed atypical large lymphoid cells with prominent nucleoli in the vessels,and the tumor cells were positive for CD20,BCL2,BCL6,and IRF4/MUM1.In addition,targeted sequencing identified MYD88,TET2,and PIM1 mutations.Consequently,we diagnosed the patient with the Asian variant of IVLBCL with highly suspected CNS involvement.CONCLUSION Suspicion of IVLBCL and immediate diagnosis lead to timely treatment.Moreover,careful CNS examination at diagnosis is recommended.

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.

Next-generation sequencing technology for diagnosis and efficacy evaluation of a patient with visceral leishmaniasis: A case report

BACKGROUND Visceral leishmaniasis(VL)is a parasitic disease caused by Leishmania and transmitted by infected sand flies.VL has a low incidence in China,and its clinical presentation is complex and atypical.This disease is easily misdiagnosed and can become life-threatening within a short period of time.Therefore,early,rapid and accurate diagnosis and treatment of the disease are essential.CASE SUMMARY A 25-year-old male patient presented with the clinical manifestations of irregular fever,hepatosplenomegaly,increased polyclonal globulin,and pancytopenia.The first bone marrow puncture biopsy did not provide a clear diagnosis.In order to relieve the pressure and discomfort of the organs caused by the enlarged spleen and to confirm the diagnosis,splenectomy was performed,and hemophagocytic syndrome was diagnosed by pathological examination of the spleen biopsy.Following bone marrow and spleen pathological re-diagnosis and metagenomic next-generation sequencing(mNGS)technology detection,the patient was finally diagnosed with VL.After treatment with liposomal amphotericin B,the body temperature quickly returned to normal and the hemocytes recovered gradually.Post-treatment re-examination of the bone marrow puncture and mNGS data showed that Leishmania was not detected.CONCLUSION As a fast and accurate detection method,mNGS can diagnose and evaluate the efficacy of treatment in suspicious cases of leishmaniasis.

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.

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.

Inherited Genetic Susceptibility to Nonimmunosuppressed Epstein-Barr Virus-associated T/NK-cell Lymphoproliferative Diseases in Chinese Patients

Epstein-Barr virus(EBV)T/NK-cell lymphoproliferative diseases are characterized by clonal expansion of EBV-infected T or NK cells,including chronic active EBV infection of T/NK-cell type(CAEBVT/NK),EBV-associated hemophagocytic lymphohistiocytosis(EBV HLH),extranodal NK/T-cell lymphoma of nasal type(ENKTL),and aggressive NK-cell leukemia(ANKL).However,the role of inherited genetic variants to EBV+T/NK-LPDs susceptibility is still unknown.A total of 171 nonimmunosuppressed patients with EBV T/NK-LPDs and 104 healthy donors were retrospectively collected and a targeted sequencing study covering 15 genes associated with lymphocyte cytotoxicity was performed.The 94 gene variants,mostly located in UNCI 3D,LYST,ITK,and PRF1 genes were detected,and mutations covered 28/50(56.00%)of CAEBV-T/NK,31/51(60.78%)of EBV HLH,13/28(46.42%)of ENKTL,and 13/48(27.09%)of ANKL.Most mutations represented monoallelic and missense.Three-year overall survival rate of patients with CAEBV-T/NK and EBV+HLH was significantly lower in patients with germline mutations than in those without germline mutations(P=0.0284,P=0.0137).Our study provided novel insights into understanding a spectrum of nonimmunosuppressed EBV*T/NK-LPDs with respect to genetic defects associated with lymphocyte cytotoxicity and reminded us that the gene sequencing may be an auxiliary test for diagnosis and risk stratification of EBV+T/NK-LPDs.

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.