Acute Appendicitis In Leukaemia Patients Undergoing Haematopoietic Stem Cell Transplantation During The Neutropaenic Phase

BACKGROUNDHematopoietic stem cell transplantation(HSCT)is the best treatment for most malignant hematological diseases,some solid tumors and special genetic diseases[1].The hematopoietic/immune system of the recipient was destroyed by mega-dose chemotherapy and radiotherapy,then it would be reconstructed by injecting allogeneic or autologous hematopoietic stem cells(HSCs)or progenitor cells.HSCT includes bone marrow transplantation,umbilical cord blood transplantation and peripheral blood stem cell transplantation according to the HSCs resources.According to the relationship between donors and recipients,HSCT includes auto-transplantation and allo-transplantation.According to the matching of human leukocyte antigen(HLA)of the donors and recipients,HSCT includes the sibling full matched donors,unrelated full matched donors and not all matched donors.HSCT includes myeloablative HSCT and non-myeloablative HSCT according to the intensity of the conditioning regimen.It takes about 2-4 weeks for hematopoiesis reconstruction,while immune reconstruction needs 1-3 years[2].Rapid and stable hematopoiesis reconstruction is the most basic and key step before immune reconstruction.Complications related to hematopoiesis/immune recovery are very common,especially in the neutropenic phase,which are very threatening and very difficult to treat.Neutropenia is quite common,in the "guidelines for clinical application of antimicrobial agents in Chinese patients with neutrophils and fever(2016 Edition)”,neutropenia(also known as agranulocytosis)is defined as absolute count of neutrophile granulocyte in peripheral blood(ANC)<0.5 X 109/L,or probably ANC<0.5 X 109/L for 48 h.Fever is defined as:oral temperature T>38.3 ℃ for once(axillary temperature>38.0℃)or T>38.0℃(axillary temperature of>37.7℃)for more than 1 h.When the patient’s condition is poor or for those the elderly,it always shows no fever or even the hypothermia.The incidence of infection is positively correlated with the temperature degree and duration of agranulocytosis.More than 80%patients with malignant tumors or 10%-50%patients with solid tumor would have infection after they received more than 1 courses of chemotherapy,and it is often accompanied with high mortality rate[3].In a word,the infection is daily issue in front of hematologists and oncologists.After HSCT,better hematopoietic reconstitution and immune reconstruction could promote bone marrow function recovery,shorten the time of agranulocytosis and reduce the incidence of agranulocytosis associated infection.Appendicitis is a rare but life-threatening complication in patients undergoing haematopoietic stem cell transplantation(HSCT).Infectious complications arising from the gastrointestinal tract are common in immunocompromised patients with haematologic malignances[4,5]Serious infection often occurs in neutropaenic patients,especially during HSCT.Acute appendicitis is frequently reported in leukaemia patients after chemotherapy but is rarely reported during HSCT.The Alvarado Scoring System,which is shortened to ASS-MANTRELS,has been used to diagnose acute appendicitis[6].However,acute appendicitis occurred in HSCT patients during the neutropaenic phase.The indexes of Leukocytosis and Shift to the left(LS)of the ASS-MANTRELS were not applicable to these patients.Therefore,a standard criterion applicable for such patients who underwent HSCT was set up.Here,we report 10 cases of acute appendicitis,which were selected from 776 sequential HSCTs.OBJECTIVERetrospect the diagnosis and treatment of complications during the period of hematopoietic stem cell transplantation.Especially study the diagnosis and treatment of appendicitis happened in the neutropenic phase during HSCT.In order to provide better choice for this condition.CONTENT[Methods]Patients who underwent HSCT from 2006 to 2016 in the Hematological Department of Nanfang Hospital were reviewed.The inclusion criteria are as follows:1)upon diagnosis of a malignant haematologic disease,underwent transplant with peripheral blood stem cells(PBSC)only,with bone marrow(BM)only or with both;and 2)acute appendicitis occurred during-10～+60 d.The ASS-MANTRELS was applied to diagnose acute appendicitis,which is characterized by a total score of 10.A score of 5 or 6 is compatible with the diagnosis of acute appendicitis,a score of 7 or 8 indicates probable appendicitis,and a score of 9 or 10 indicates very probable appendicitis.We selected those cases with scores from 5-10.Indicators and measurements of the primary diagnosis,remission condition,underlying disease,conditioning regimen,cell resources,clinical characteristics,routine blood test,ultrasonography,therapy methods and prognosis of acute appendicitis were collected.The relationship between these factors and acute appendicitis was analyzed.[Results]From 2006 to 2016,776 sequential patients underwent HSCT in the laminar air flow ward(LAFW).Ten of these patients experienced acute appendicitis(7 males)during-1 d～+7 d,with the rate of occurrence of 1.29%.The neutrophil count had a mean value of 0.06(0.01-0.40)×109/L,revealed agranulocytosis in all of the patients.The median age of these patients was 18.5 years(range:10-39 years).Seven patients had ALL and 3 others had CML(CML-BC,CP).Two patients remained in non-remission after chemotherapy,and 8 patients achieved complete remission(CR).All of the patients underwent allo-HSCT,and seven patients received different A/B/O blood type cell resources.Five patients received a conditioning regimen of IDA(45 mg/m2)+TBI(4.5 Gy×2 d)+CY(120 mg/kg)+VP-16(30 mg/kg),1 patient received a conditioning regimen of IDA(45 mg/m2)+TBI(7 Gy×1 d)+CY(120 mg/kg)+VP-16(30 mg/kg),and 4 other patients received a conditioning regimen of TBI(4.5 Gy×2 d)+CY(120 mg/kg)+Ara-c(10 g)+VP-16(30 mg/kg),Flu(30 mg/m2·d×5 d)+Ara-c(10 g)+TBI(4.5 Gy×2 d)+CY(120 mg/kg)+VP-16(15 mg/kg),Bu(3.2 mg/kg·d×4 d)+Cy(120 mg/kg)and Bu(3.2 mg/kg·d×3 d)+CY(120 mg/kg)+ Ara-c(4 g/m2).Amongst these patients,5 patients received cells from sibling full matched donors(HLA 10/10),2 patients received cells from unrelated full matched donors(HLA 10/10),2 patients had haploid donors(HLA 10/10),and 1 patient had a haploid donor with 1 antigen mismatched(HLA 9/10).Eight patients received PBSC,and 2 others received both PBSC and BM.Ten patients were treated with an anti-fungal preventative,antiviral drugs,and anti-bacterial treatment with broad-spectrum antibiotic treatment,such as imipenem cilastatin,teicoplanin,sulfamethoxazole,etimicin,levofloxacin,and others.In our study,acute appendicitis occurred at the median time of+4 d(range:-1 d to+7 d).The main clinical manifestations were fever,anorexia,nausea,vomiting,right lower quadrant abdominal tenderness and migratory pain.All 10 of the HSCT patients acquired acute appendicitis during the neutropenic phase,so the laboratory index including L(Leukocytosis)and S(Shift to the left)of the ASS-MANTRELS were not applicable for these patients,and their initial scores ranged from 5 to 7.It seems that the ASS-MANTRELS was not sensitive to such a situation since the occurrence of appendicitis is higher in patients who underwent HSCT according to clinical experience.In 8 patients who had ultrasonography performed,6 showed thickening of the appendix wall and fat stranding.Considering the sensitivity and specificity,we defined the positive ultrasound result as a score of 2 and the negative result as 0.The new scoring system could be named ASS-MANTREU.Ten patients received nonsurgical approaches,including bowel rest,total parental nutrition and broad-spectrum antibiotic therapy combined with two or three antibiotics,together with water electrolyte balance maintenance treatment and supportive care.The abdominal ultrasound was indicated as negative when it was rechecked after the signs and symptoms of acute appendicitis disappeared.During the follow-up period of 24 m,8 patients did not show relapse,1 patient died from gastrointestinal bleeding 2 m later without recurrence of appendicitis,and only 1 patient relapsed,which occurred 1 y later,but it was resolved by appendectomy(with the pathological result of gangrenous appendicitis).The average incidence rate of acute appendicitis is 0.1%in the general population.When leukaemia patients undergo transplantation,the risks of infection are much higher,especially during the neutropaenic phase.In most medical institutions throughout the world,the diagnosis of acute appendicitis follows the criteria of the ASS-MANTRELS,and while some also use ultrasound or computerized tomography,there are no available diagnostic criteria for patients undergoing HSCT.In this study,in such HSCT patients for whom the LS of the ASS-MANTRELS were applicable,the level of evidence for diagnosis would be upgraded when the ultrasonography index was added to the ASS-MANTRELS scoring system.CT is not convenient for such HSCT patients,ultrasonography could be a convenient and operable index for such patients.In conclusion,acute appendicitis occurring during the neutropaenic phase of HSCT can be diagnosed according to the Modified Appendicitis Scoring System(ASS-MANTREU),and the scoring system is also applicable for the long-time neutropaenic patients.[Conclusions]Acute appendicitis occurring during the neutropenic phase of HSCT can be better diagnosed according to the Appendicitis Scoring System(ASS-MANTREU)and can be resolved by conservative treatment with broad-spectrum antibiotics.