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.

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.

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.

Postpartum hemophagocytic lymphohistiocytosis:A case report

BACKGROUND Postpartum hemophagocytic lymphohistiocytosis(HLH)is a rare disease with unclear pathophysiology.It is a secondary HLH diagnosed using the pediatric diagnostic criteria;however,the clinical diagnosis of postpartum HLH remains challenging.Hence,HLH may remain undiagnosed,leading to poor patient prognosis.Therefore,improvements in the accuracy of postpartum HLH diagnoses and treatments are necessary.CASE SUMMARY We report the case of a 40-year-old female with postpartum HLH.The patient attended the postpartum care center for 3 wk after giving birth and underwent needle aspiration due to thyroid gland enlargement 11 d before an emergency department visit precipitated by fever and abdominal pain.Since no abnormal emergency room findings were noted,the patient was discharged with a prescription for broad-spectrum antibiotics.Three days later,she returned to the emergency room in a hemodynamically unstable state and was admitted to the intensive care unit with suspected sepsis or hematologic disease.The patient was treated,without effect,for sepsis using broad-spectrum antibiotics,and for suspected hematologic disease with steroid therapy.However,she died due to rapidly worsening symptoms.CONCLUSION Rapid recognition and appropriate treatment of postpartum HLH are needed to improve the prognosis.

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.

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 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.

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.

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 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.

Intensive care unit complications and outcomes of adult patients with hemophagocytic lymphohistiocytosis: A retrospective study of 16 cases

AIM To study the management, complications and outcomes of adult patients admitted with hemophagocytic lymphohistiocytosis(HLH) in the intensive care unit(ICU).METHODS We performed a retrospective observational study of adult patients with the diagnosis of "HLH" admitted to the two academic medical ICUs of Baylor College of Medicine between 01/01/2013 to 06/30/2017. HLH was diagnosed using the HLH-2004 criteria proposed by the Histiocyte Society.RESULTS Sixteen adult cases of HLH were admitted to the medical ICUs over 4 years.Median age of presentation was 49 years and 10(63%) were males. Median Sequential Organ Failure Assessment(SOFA) score at the time of ICU admission was 10. Median ICU length of stay(LOS) was 11.5 d and median hospital LOS was 29 d. Septic shock and acute respiratory failure accounted for majority of diagnoses necessitating ICU admission. Septic shock was the most common ICU complication seen in(88%) patients, followed by acute kidney injury(81%) and acute respiratory failure requiring mechanical ventilation(75%). Nine patients(56%) developed disseminated intravascular coagulation and eight(50%) had acute liver failure. 10 episodes of clinically significant bleeding were observed.Multi system organ failure was the most common cause of death seen in 12(75%)patients. The 30 d mortality was 37%(6 cases) and 90 d mortality was 81%(13 cases). There was no difference in mortality based on age(above or less than 50 years), SOFA score on ICU admission(more than or less than 10),immunosuppression, time to diagnose HLH or direct ICU admission versus floor transfer.CONCLUSION HLH is a devastating disease associated with poor outcomes in ICU. Intensivists need to have a high degree of clinical suspicion for HLH in patients with septic shock/multi system organ failure and progressive bi/pancytopenia who are not responding to standard management in ICU.

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.

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.

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).

Haemophagocytic lymphohistiocytosis secondary to Plasmodium falciparum malaria: Case report and review of the literature

Rationale:Haemophagocytic lymphohistiocytosis is a rare complication of malaria,which is often misdiagnosed.Patient concerns:A 30-year-old male was admitted to our department for persistent fever,which began after returning from a stay in Guinea-Conakry.The laboratory investigations revealed a pancytopenia and an elevated C-reactive protein.Peripheral smear examination showed Plasmodium falciparum,therefore confirming the diagnosis of malaria.The laboratory tests showed a worsening pancytopenia.Bone marrow aspiration and biopsy revealed images of hemophagocytosis.Diagnosis:The diagnosis of haemophagocytic lymphohistiocytosis complicating malaria infection was established.Interventions:The patient was treated with artemether-lumefantrine.No immunosuppressant treatment was delivered to the patient.He received antipyretic and antimalarial treatment only.Outcomes and lessons:We report a case of haemophagocytic lymphohistiocytosis trigged by malaria infection and we review all reported cases secondary to Plasmodium falciparum malaria by searching PubMed publications till October 2019.Haemophagocytic lymphohistiocytos secondary to malaria should be suspected even in non-severe cases of malaria.

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.

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.