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Case history of a child with sickle cell anemia in India

A three years old male child, native of Jharkhand, Central India presented with mild pallor, icterus, and history of on and off abdominal and joint pains. On examination the child had mild splenomegaly. He had history of two prior hospital admissions. First at the age of 1 year, when he was diagnosed to have pneumonia and second, at the age of 3 years (3 months prior to coming to our institution) for fever, anemia and jaundice. He has had three transfusions till now, last transfusion was 3 months back. There is history of sibling death at 5 years of age due to fever and jaundice.

The hemogram showed anemia with leukocytosis. Red cell morphology (Figure 1) revealed severe anisopoikilocytosis with macrocytes, microcytic hypochromic red cells, target cells, many boat cells, sickled RBCs, polychromatic cells and occasional nucleated RBCs. Results of the automated blood cell counts showed Hb 7.7 g/dl, RBC 2.44 x 109/l, MCV 97.1 fl, MCH 31.4 pg, MCHC 32.3 g/dl, RDW 26.6%. There were occasional nucleated red cells and relative neutrophilia. Further to confirm HbS, a sickling test using freshly prepared 2% sodium meta-bisulphite was performed which was positive (Figure 2).

Hemoglobin HPLC on Bio-Rad Variant 2 showed raised fetal hemoglobin (HbF) and a variant peak in S window (71.9%) at retention time of 4.36 mins. Adult Hb (HbA) of 8.5% was noted (Figure 3). Figure 4 shows Cellulose acetate hemoglobin electrophoresis at alkaline pH (8.6), which showed a prominent band in S/D/G region and a faint band in F region. Investigations of the father showed also showed a variant peak in S window (32.9%) at retention time of 4.36 mins along with HbA (57.1%) on HPLC with Bio-Rad Variant II which is diagnostic of Sickle cell trait (Figure 5).

Sickle cell disease (SCD) is the most common symptomatic hemoglobinopathy caused as a result of inheritance of two copies of the sickle β-globin gene variant (βS). A single nucleotide substitution leading to replacement of glutamic acid by valine at position 6 of the β-globin polypeptide chain leads to formation of HbS which is responsible for disease manifestation.  SCD has a wide geographical distribution throughout major parts of Africa, the Middle East, India and in some regions of Mediterranean countries. In India, it is mainly concentrated in the central region including parts of Madhya Pradesh, Chattisgarh, Orissa, Maharashtra, Gujrat and Jharkhand. HbS has carrier frequencies varying from 5 to 35% and are especially seen amongst the scheduled tribes, scheduled castes and other backward castes.

Sickle cell mutation is believed to be originated five times in history spontaneously. This can be elucidated by five βS-globin haplotypes. These haplotypes include Senegal (SEN), Benin (BEN), Bantu or the Central African Republic (CAR), Cameroon (CAM) and Arab-Indian (ARAB). They enable us to understand the origin, evolution, migration and natural selection of genetic defects. They can be identified by specific restriction sites within the β-globin gene cluster. Different haplotypes are known to have different HbF levels. Senegal and Arab-Indian haplotypes have higher HbF levels when compared to other haplotypes. However, recently a study has investigated the origins of the sickle mutation by using whole-genome-sequence data to conclude that there might be single origin of sickle allele.

LEARNING POINTS

1.    Sickle cell disease (SCD) is the most common symptomatic hemoglobinopathy in the world, largely seen in parts of Africa, the Middle East, India and in some regions of Mediterranean countries.

2.    SCA is a monogenic disorder with an autosomal recessive inheritance. The parents are clinically asymptomatic and have normal blood counts. They are usually diagnosed incidentally or as a result of family studies in SCA patients.

3.    Neonates are asymptomatic due to high HbF, but symptoms begin to appear by six months of age. Many infants present with lethal complications at first presentation. This emphasizes the importance of newborn screening in these susceptible pre-symptomatic cases in endemic regions.

4.    SCA has a variable clinical course amongst different individuals depending upon various genetic determinants like βs haplotype, factors affecting HbF levels and co-inheritance of other disease modifying factors.

5.    Diagnosis mainly relies upon identification of HbS (by any of the following HPLC, Hb Electrophoresis, Iso-electric focusing or sickling test). Once HbS is identified, it has to be validated by alternative method.

6.    Treatment of sickle cell disease generally aims at relieving symptoms and preventing infections, sickle cell crises and long-term complications. Stem cell transplant is the only potential cure available presently.

HPLC pattern of the index case with sickle cell anemia showing HbS and HbF peaks.

Hemoglobin electrophoresis at alkaline pH. Black arrow shows the index case with HbS and HbF bands.

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Jaundice in a Child with Sickle Cell Anemia: A Case Based Approach

• Grand Round
• Published: 09 August 2023
• Volume 91 , pages 73–80, ( 2024 )

Cite this article

• Srinivas Srinidhi Vadlapudi 1 ,
• Anshu Srivastava   ORCID: orcid.org/0000-0003-0902-4140 1 ,
• Praveer Rai 2 ,
• Rajneesh K. Singh 3 ,
• Moinak Sen Sarma 1 ,
• Ujjal Poddar 1 &
• Rajanikant R. Yadav 4  

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Sickle cell anemia (SCA) is an autosomal recessive disorder caused by a mutation in beta globin gene. Hepatobiliary system is affected in 10-40% of patients with SCA and has a multifactorial etiology. The authors present a child with SCA and conjugated hyperbilirubinemia due to biliary obstruction. He underwent endoscopic retrograde cholangiopancreatography (ERCP) and biliary stenting, had complications of post sphincterotomy bleed, retroperitoneal hematoma and post laparoscopic cholecystectomy sepsis with acute sickle hepatic crisis. He was managed successfully and is doing well on follow-up. Here authors discuss a stepwise approach in management of jaundice in a patient with SCA. Patients with SCA are prone to develop vaso-occlusive crisis (VOC) during periods of stress. VOC affects the liver as acute sickle hepatic crisis, acute hepatic sequestration or sickle cell intrahepatic cholestasis and is collectively termed as sickle cell hepatopathy. Hemolysis due to sickling results in cholelithiasis with its associated complications. These patients are vulnerable to viral hepatitis and hemochromatosis due to multiple blood transfusions. There may be a concomitant acute viral hepatitis, drug induced liver injury, Budd-Chiari syndrome or other chronic liver diseases. These conditions have considerable clinical overlap and may coexist, making the evaluation more challenging. Detailed history, examination and investigations are required for differentiation of etiology. Periods of stress must be tackled with proper hydration, oxygen supplementation, maintaining hemoglobin >10 g/dL, and a low hemoglobin S fraction. Patients with SCA and conjugated hyperbilirubinemia are “high-risk” and best managed by a multidisciplinary team. Preventive strategies like timely vaccinations, chelation, etc. must be practised.

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Introduction

Sickle cell anemia (SCA) is an autosomal recessive disorder caused by a mutation in the beta globin gene. Sickle cell disease (SCD) comprises of patients with SCA as well as other compound heterozygotes who have a sickle cell mutation on one beta globin allele and another mutation such as beta thalassemia or Hemoglobin C (HbC) disease on the other. SCA patients usually present with unconjugated hyperbilirubinemia due to hemolysis. However, the hepatobiliary system may be affected in upto ~40% cases, resulting in conjugated hyperbilirubinemia [ 1 ]. Liver related causes account for ~7% of all mortality in patients with SCD [ 2 ]. In this review authors will be highlighting a child of SCA with conjugated hyperbilirubinemia due to biliary obstruction and multiple complications who was managed successfully. The stepwise approach to evaluation and management of jaundice in SCD will be discussed.

Case Report

A 13-y-old boy, a resident of Raipur, Chhattisgarh with no significant family history was diagnosed as a case of SCA in infancy. He was on hydroxyurea and maintained a hemoglobin of 9-10 g/dL. There were no episodes suggestive of sickle cell crisis in the past. He presented to authors with 1 mo history of conjugated hyperbilirubinemia. There was history of pain abdomen in the right upper quadrant at the onset of jaundice which subsided later on. There was no history of pale stools, pruritus, fever or alternative medicine intake. There was no history of hepatic decompensation. On examination he had pallor, deep icterus and a soft non-tender hepatomegaly. The child was hemodynamically stable. The possibilities considered were choledocholithiasis, acute viral hepatitis or acute sickle hepatic crisis.

Basic workup of the patient is shown in Table 1 . At admission, he had leukocytosis (29000/mm 3 , with 75% neutrophils) and mild anemia (9.4 g/dL). His liver function tests revealed deep jaundice (total/direct bilirubin- 55/32 mg/dL), mild elevation of serum transaminases, normal alkaline phosphatase (ALP) and gamma glutamyl transpeptidase (GGT). A normal GGT does not support the possibility of choledocholithiasis. Coagulation profile and renal functions were normal. Serum procalcitonin (PCT) was negative and blood culture sterile.

Ultrasound doppler of the abdomen revealed gall stones (GS) and dilated common bile duct (CBD, 13 mm) with no features of Budd-Chiari syndrome or chronic liver disease. Magnetic resonance cholangiopancreatography (MRCP) showed a segmental narrowing of the mid CBD over a length of 12 mm with mild proximal dilatation of the CBD and central intrahepatic biliary radical dilatation. However, no filling defect was identified in the CBD. Gall bladder was filled with multiple calculi largest measuring 10 mm in size. Acute viral markers were negative. Sequencing for Gilbert syndrome (UGT1A1 sequencing- TA 7/7 ) was positive.

In view of deep jaundice, neutrophilic leukocytosis and abnormal biliary tree at imaging, a diagnosis of biliary obstruction (choledocholithiasis/ ischemic cholangiopathy) with possible cholangitis was considered. Antibiotics (piperacillin-tazobactum) were started and an endoscopic retrograde cholangiopancreatography (ERCP) was done.

At ERCP, the balloon occlusion cholangiogram showed a dilated proximal CBD (15 mm) with a small filling defect and no stricture. However, on balloon sweep only sludge and no stone was retrieved. A check cholangiogram revealed no filling defect. Endoscopic sphincterotomy (ES) was done and a 10 F X 7 cm double pig tail stent was placed into the right hepatic duct. There were no difficulties or apparent complications noticed during the procedure.

Twenty-four hours post ERCP, the child developed melena, postural hypotension and a significant drop in hemoglobin (9.4 g/dL to 6.4 g/dL). Blood transfusion was given. A side viewing endoscopy (SVE) showed oozing of blood from the apex of sphincterotomy site (Fig. 1 ). Adrenaline injection (1:10000 dilution, in aliquots of 0.5-2 ml) and hemospray application was done and the bleed stopped. However, the child continued to have melena with further drop in hemoglobin to 5.6 g/dL. Computerised tomography (CT) angiography of the abdomen revealed a doubtful arterial blush in the wall of second part of duodenum (suspected pseudoaneurysm/site of active bleed). There was no evidence of perforation in the form of extraluminal air. Digital subtraction angiography (DSA) done after CTA for site of bleed did not identify any abnormality. In view of ongoing bleed, SVE was repeated, which showed continuing oozing from the sphincterotomy site. Hence a 10 mm, 6 cm long fully covered self-expanding metallic stent (FCSEMS, Wallflex, Boston Scientific) was placed. A check SVE done 48 h later showed that there was no further bleed but a bulge in the duodenum near the papilla was seen (?wall hematoma). There was no further drop in hemoglobin. The child remained well with no abdominal pain, fever or peritoneal signs of free perforation.

Side viewing endoscopy showing oozing of blood from the apex of the sphincterotomy site and step-wise management of post endoscopic sphincterotomy bleed

Two weeks later the child started having bilious vomiting. CT abdomen (Fig. 2 a) showed a large collection (5.1 X 14.1 cm) with hyperdense contents tracking along the C loop of duodenum and causing mass effect. There was no perinephric air or extraluminal leak of oral contrast suggestive of duodenal perforation. Hence, the possibility of a retroperitoneal or duodenal wall hematoma was considered. Percutaneous catheter drainage (PCD, size 10 F) of the collection was done which drained hemorrhagic fluid. The child improved (no vomiting or fever and bilirubin decreased from 55 to 20.7 mg/dL). PCD was removed after 2 wk, and the metallic stent in CBD was replaced by a double pig tail plastic (10 F, 5 cm) stent after 1 mo.

Contrast enhanced computerised tomography of abdomen showing ( a) a collection along the C loop of duodenum and compressing it ( Red arrow ). Metallic stent noted in common bile duct and ( b ) a collection in gall bladder fossa ( Black arrow ) and subcutaneous tissue after laparoscopic cholecystectomy

Laparoscopic cholecystectomy (LC) was done six months later. In the immediate post- operative period, he had high grade fever and a small septated collection in gall bladder fossa along with cellulitis at the laparoscopic port site (Fig. 2 b). Abdominal sutures were removed, collection was drained and appropriate antibiotics were given. At this time child had a drop in hemoglobin to 6.5 g/dL and required three units of packed red blood cell transfusion. He recovered within a week and continued to be asymptomatic.

Eighteen days post LC, the double pig tail stent was removed. He is asymptomatic over 16 mo of follow-up, and has had no further sickle cell crisis nor required any further transfusions (Table 1 ).

Most patients with SCD (~90%) present with jaundice [ 3 , 4 ]. However, it is generally unconjugated hyperbilirubinemia secondary to hemolysis of the sickled red blood cells. Hepatobiliary involvement due to multiple etiologies result in conjugated hyperbilirubinemia. The stepwise evaluation and treatment of these cases is detailed in Fig. 3 .

Approach to a case of sickle cell disease with jaundice.  AIH Autoimmune hepatitis, ALF Acute liver failure, ALP Alkaline phosphatase, ALT Alanine aminotransferase, AST Aspartate aminotransferase, CBD Common bile duct, CECT Contrast enhanced computed tomography, DILI Drug-induced liver injury, ERCP Endoscopic retrograde cholangiopancreatography, EUS Endoscopic ultrasound, GGT Gamma glutamyl transpeptidase, IHBRD Intrahepatic biliary radicle dilatation, INR International normalized ratio, MRCP Magnetic resonance cholangiopancreatography, MRI Magnetic resonance imaging, PCT Procalcitonin, UDCA Ursodeoxycholic acid, ULN Upper limit of normal, USG Ultrasonography

Etiology of Conjugated Hyperbilirubinemia and Sickle Cell Hepatopathy

Sickle cell hepatopathy (SCH) encompasses the liver diseases encountered in patients of SCD due to intrahepatic sickling. It includes acute sickle hepatic crisis, acute hepatic sequestration and sickle cell intrahepatic cholestasis [ 5 ]. SCH is precipitated by stress, infections, hypovolemia etc. In patients with SCD admitted with vaso-occlusive crisis, liver is reportedly affected in 10-39% of the cases [ 5 , 6 ]. The degree of sickling increases from mild in acute sickle hepatic crisis to moderately-severe in acute hepatic sequestration and very-severe in sickle cell intrahepatic cholestasis. In the latter two forms of SCH there is sinusoidal dilatation while in sickle cell intrahepatic cholestasis there is also ischemia of the hepatocytes leading to liver failure. The differences between the three forms of SCH are detailed in Table 2 [ 7 , 8 ].

Apart from SCH, there is an increased risk of transfusion related viral hepatitis or iron overload, hemolysis associated cholelithiasis and its complications, acute Budd-Chiari syndrome and ischemic cholangiopathy. In addition, acute viral hepatitis, drug-induced liver injury (DILI), tropical infections etc also occur in these patients, similar to the general population (Table 2 and Fig. 3 ).

As discussed previously the index patient had GS with biliary obstruction. However, due to very high bilirubin authors evaluated and confirmed the presence of concomitant Gilbert syndrome in him. Gilbert syndrome is an autosomal recessive disorder caused by a mutation (increased dinucleotide repeats [TA] 7 or [TA] 8 ) in the promotor region of UGT1A1 which causes decreased production of the enzyme uridine diphosphoglucuronate-glucuronosyltransferase 1A1 that is required for bilirubin conjugation. Patients of SCD with concomitant Gilbert syndrome tend to have higher bilirubin levels and a greater prevalence of GS [ 9 ].

Cholelithiasis in Sickle Cell Disease

Hemolysis of the irreversibly sickled erythrocytes results in unconjugated hyperbilirubinemia. Unconjugated bilirubin precipitates on contact with calcium in the lumen of gall bladder and results in pigment stone formation. The prevalence of GS in SCD increases progressively with age: 14% at the age of 10 y, 36% at 15-18 y, 50% above 22 y of age and 70% above 30 y of age [ 10 ]. In addition, they are more likely to develop symptoms due to GS. In a study, 70% of the patients with SCD and incidentally detected cholelithiasis developed symptoms (biliary colic, acute cholecystitis and/or conjugated jaundice) after a median follow-up of 38 (range: 12-80) mo [ 11 ].

Patients with SCD and GS are also at a higher risk of having choledocholithiasis than the general population with GS (18-30% vs. 5-15%) [ 12 ]. Patients with choledocholithiasis and cholangitis require antibiotics and ERCP for biliary drainage, as done in present case.

Sickle Cell Cholangiopathy (SCC)

SCC is an ischemic cholangiopathy where sickling of erythrocytes in the end arteries of the bile ducts results in hypoxia of bile ducts, which leads to ischemia and stricturing of the bile ducts [ 7 ]. In a series of 616 children with SCD, 0.8% of them had features of SCC [ 1 ]. In another study of patients with SCD and conjugated hyperbilirubinemia, 24.6% of them had SCC [ 13 ]. Treatment of SCC includes ursodeoxycholic acid, endoscopic dilatation of dominant strictures and liver transplantation in advanced cases [ 7 , 14 ]. MRCP, endoscopic ultrasound (EUS) and ERCP will help in evaluation of these cases.

Complications of ERCP in SCD and Post Sphincterotomy Bleed

Biliary obstruction and cholangitis is a significant stress for patients with SCD and it can precipitate SCH and increase the risk of complications during interventions. The index child had post-sphincterotomy bleed which first required adrenaline injection and hemospray followed by placement of FCSEMS to control the bleed.

Post endoscopic sphincterotomy (ES) bleed complicates 0.3-9.6% of ERCP procedures [ 15 ]. Other complications being post ERCP pancreatitis (3.5-9.7%), cholangitis (0.5-3%), bleeding (0.3-9.6%), duodenal perforation (0.08-0.6%) and sedation related events (upto 24.6%) [ 15 ].

The index child had delayed (occurs after the procedure is completed) and severe bleed as it resulted in prolonged hospitalisation (>10 d) including ICU stay (>1 d) [ 15 ]. Post-procedure at the time of bleed, authors noted that the child had mild coagulopathy (INR- 1.7), most likely due to sickle cell crisis precipitated by the stress of ERCP and acute cholangitis.

Stepwise management of post-ES bleed has been detailed in Fig. 1 [ 15 ]. Initial moderate-severe bleed and serum bilirubin >10 mg/dL are independent risk factors for rebleed [ 16 ]. Both of which were present in index patient. Although a sickle cell crisis can complicate the outcome of invasive procedures like ERCP, in a series of 240 ERCP procedures done in 224 patients, only 4 (1.7%) had mild post ES bleed and 8 (3.3%) had mild acute pancreatitis [ 13 ]. Hence, ERCP is safe if done only when indicated and by experts.

The index child also had a retroperitoneal hematoma which was symptomatic with bilious vomiting and required percutaneous drainage. The differentials being a retroperitoneal or a duodenal wall hematoma. These two entities are sometimes difficult to differentiate, especially when large as in present case. The absence of clinical and imaging evidence of perforation (extraluminal air or oral contrast), tracking of the hematoma along the C loop of the duodenum, and the timing of hematoma formation favour the possibility of duodenal wall hematoma. The duodenum is a likely location for hematoma formation due to its fixed, retroperitoneal nature, rich submucosal arterial supply and formation of a closed loop between pylorus and ligament of Treitz. Trauma due to the endoscope or instruments can result in rupture of the vessels [ 17 , 18 , 19 ].

However, one cannot exclude totally the possibility of a small duodenal perforation which got sealed by the FCSEMS placed for the management of the post ES-bleed [ 20 ].

Fortunately, the management of both these conditions is similar and requires drainage (percutaneous or surgical) when symptomatic as was done in index patient [ 17 , 18 , 21 ].

Controversies in Management of Patients with Sickle Cell Disease

Laparoscopic cholecystectomy (Elective vs. emergent; Symptomatic vs. asymptomatic)

Although the index patient had symptomatic cholelithiasis which requires cholecystectomy, there is an ongoing debate whether to subject the asymptomatic GS patients to an elective cholecystectomy or wait for symptoms to develop and then perform the same. Elective LC may be preferred as the symptoms of biliary complications may overlap with that of vaso-occlusive crisis or a vaso-occlusive crisis may be triggered because of cholangitis, resulting in a more complicated situation. On the other hand, surgery in an asymptomatic patient is an additional stress and risks the development of a vaso-occlusive crisis.

Curro et al. found that patients of SCD undergoing LC when asymptomatic (n = 16) had a shorter post-operative stay (3 vs. 7.4 d, p  = 0.001) and fewer complications (12.5% vs. 80%, p  = 0.03) as compared to patients who were symptomatic (n = 10) at the time of LC [ 11 ]. Al-Mulhim et al. also showed a higher need of conversion to open cholecystectomy (9.5% vs. 12%) and greater number of complications (0 vs. 18%) in symptomatic patients [ 22 ]. However, Muroni et al. found that although elective LC patients fared better, there was no significant difference in number of complications (11.5% vs. 22.5%), need for conversion to open cholecystectomy (2% vs. 10%) and duration of hospital stay (5.8 vs. 7.96 d, p  = 0.56) among patients undergoing LC with incidentally detected GS (n = 52) vs. those with symptomatic GS (n = 51) [ 23 ].

Goodwin et al. (n = 191) compared sickle cell patients undergoing elective asymptomatic vs. elective symptomatic vs. emergent cholecystectomy and found that the length of hospital stay was lesser in patients undergoing elective cholecystectomy in asymptomatic patients (2.9 vs. 4.5 vs. 7.2 d, p  = 0.02) [ 24 ]. Al-Salem et al. (n = 87) compared LC with open cholecystectomy (OC) and found lower complication rate (7.7% vs. 22.9%) and hospital stay (4.5 vs. 7.5 d, p <0.001) in the LC group [ 25 ]. None of the studies have reported mortality due to surgery.

In view of these findings, most centres practice elective LC when GS are identified on screening even if asymptomatic.

Role of ERCP in patients with cholelithiasis with or without choledocholithiasis

In the era of OC, intraoperative cholangiogram (IOC) to look for CBD stones used to be done routinely. CBD exploration was done in patients with IOC suggestive of CBD stones. However, at present in the era of LC and easy availability of ERCP, IOC is used sparingly. Issa et al. had shown that among 242 ERCP procedures in patients with SCD, CBD stones were detected in 88 (39.3%) including 18 (18.6%) cases with normal CBD on ultrasound and conjugated hyperbilirubinemia. Therefore, USG is not a good modality for evaluation of CBD stones in these cases [ 12 , 13 ]. They opined that ERCP should be performed prior to cholecystectomy if the patient with SCD has CBD stones on imaging, complications like acute cholangitis or pancreatitis, deep jaundice (bilirubin >50 mg/L) or elevated alkaline phosphatase. In patients of SCD with cholelithiasis and conjugated hyperbilirubinemia, it may be better to perform an MRCP or EUS to identify CBD stones [ 12 , 13 ]. This will help to better select patients for ERCP and decrease the rate of negative ERCP.

Post LC, the index child developed a significant fall in hemoglobin along with a collection in gall bladder fossa and port site cellulitis. Even though there was no documented conjugated hyperbilirubinemia, a significant fall in hemoglobin is likely due to sickle cell crisis due to the stress of surgery and infection.

The present patient highlights two important aspects of managing children with SCD and jaundice. One is that these patients are prone to unexpected complications and need a multidisciplinary team of interventional radiologist, endoscopist, surgeon and hepatologist for a good outcome. Second that these patients may have multiple factors contributing to the conjugated hyperbilirubinemia at the same time which are difficult to differentiate like biliary obstruction causing infection and also precipitating SCH. This calls for extreme vigilance while managing these “high-risk” individuals.

Preventive Strategies for Patients with Sickle Cell Disease

Patients with SCD encounter transfusion related viral hepatitis (hepatitis B and C) or iron overload. Regular screening for hepatitis B, C, HIV and signs of iron overload (serum ferritin, MRI liver and heart in cases with suspected iron-overload) must be done [ 26 , 27 , 28 ]. Hepatitis A and B vaccine should be given. As patients are at risk of auto-splenectomy they must be vaccinated against capsulated organisms ( Pneumococcus, meningococcus and Haemophilus influenza B ) and influenza (yearly vaccine). Iron overload can occur even in transfusion independent patients as they undergo continuous hemolysis. Adequate chelation must be offered as and when required.

These patients need screening for GS, and elective cholecystectomy before development of GS related complications. Invasive procedures like liver biopsy should be avoided as much as possible, especially in emergency setting. A study reported a mortality of 28% and hemorrhagic complications in 36% after liver biopsy. These patients were in sickle cell crisis at the time of biopsy which predisposed them to an adverse outcome [ 29 ].

To prevent sickle cell crisis, a HbS of at least <50% and preferably <30% and Hb >10 g/dL should be maintained by use of hydroxyurea, packed red cell transfusion or exchange transfusion [ 8 , 11 , 30 ]. Stressful conditions/infections should be avoided and if present, treated urgently by hydration, antipyretics and antibiotics.

The patients and parents need to be educated about their disease, need of regular follow-up and urgent medical attention during illness.

In conclusion, hepatobiliary involvement is an important problem in patients with SCD with a multifactorial etiology. Targeted step-wise management by experts results in a good outcome.

Allali S, de Montalembert M, Brousse V, et al. Hepatobiliary complications in children with sickle cell disease: a retrospective review of medical records from 616 patients. J Clin Med. 2019;8:1481–96.

Article   PubMed   PubMed Central   CAS   Google Scholar  

Kyrana E, Rees D, Lacaille F, et al. Clinical management of sickle cell liver disease in children and young adults. Arch Dis Child. 2021;106:315–20.

Article   PubMed   Google Scholar  

Aloni MN, Tshimanga BK, Ekulu PM, Ehungu JLG, Ngiyulu RM. Malaria, clinical features and acute crisis in children suffering from sickle cell disease in resource-limited settings: a retrospective description of 90 cases. Pathog Glob Health. 2013;107:198–201.

Article   PubMed   PubMed Central   Google Scholar  

Yadav R, Lazarus M, Ghanghoria P, et al. Sickle cell disease in Madhya Pradesh, Central India: a comparison of clinical profile of sickle cell homozygote vs. sickle-beta thalassaemia individuals. Hematology. 2016;21:558–63.

Article   PubMed   CAS   Google Scholar  

Shah R, Taborda C, Chawla S. Acute and chronic hepatobiliary manifestations of sickle cell disease: a review. World J Gastrointest Pathophysiol. 2017;8:108–16.

Koskinas J, Manesis EK, Zacharakis GH, Galiatsatos N, Sevastos N, Archimandritis AJ. Liver involvement in acute vaso-occlusive crisis of sickle cell disease: prevalence and predisposing factors. Scand J Gastroenterol. 2007;42:499–507.

Lacaille F, Allali S, de Montalembert M. The liver in sickle cell disease. J Pediatr Gastroenterol Nutr. 2021;72:5–10.

Ahn H, Li CS, Wang W. Sickle cell hepatopathy: clinical presentation, treatment, and outcome in pediatric and adult patients. Pediatr Blood Cancer. 2005;45:184–90.

Batista JVGF, Arcanjo GS, Batista THC, et al. Influence of UGT1A1 promoter polymorphism, α-thalassemia and β s haplotype in bilirubin levels and cholelithiasis in a large sickle cell anemia cohort. Ann Hematol. 2021;100:903–11.

Suell MN, Horton TM, Dishop MK, Mahoney DH, Olutoye OO, Mueller BU. Outcomes for children with gallbladder abnormalities and sickle cell disease. J Pediatr. 2004;145:617–21.

Curro G, Meo A, Ippolito D, Pusiol A, Cucinotta E. Asymptomatic cholelithiasis in children with sickle cell disease: early or delayed cholecystectomy? Ann Surg. 2007;245:126–9.

Issa H. Role of ERCP in the era of laparoscopic cholecystectomy for the evaluation of choledocholithiasis in sickle cell anemia. World J Gastroenterol. 2011;17:1844–7.

Issa H, Al-Haddad A, Al-Salem A. Sickle cell cholangiopathy: an endoscopic retrograde cholangiopancreatography evaluation. World J Gastroenterol. 2009;15:5316–20.

Ahmed M, Dick M, Mieli-Vergani G, Harrison P, Karani J, Dhawan A. Ischaemic cholangiopathy and sickle cell disease. Eur J Pediatr. 2006;165:112–3.

Dumonceau JM, Kapral C, Aabakken L, et al. ERCP-related adverse events: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2020;52:127–49.

Lee MH, Tsou YK, Lin CH, et al. Predictors of re-bleeding after endoscopic hemostasis for delayed post-endoscopic sphincterotomy bleeding. World J Gastroenterol. 2016;22:3196–201.

Samra M, Al-Mouradi T, Berkelhammer C. Gastric outlet obstruction due to intramural duodenal hematoma after endoscopic biopsy: possible therapeutic role of endoscopic dilation. Case Rep Gastroenterol. 2018;12:692–8.

Pan YM. Endoscopic drainage for duodenal hematoma following endoscopic retrograde cholangiopancreatography: a case report. World J Gastroenterol. 2013;19:2118–21.

Weiss E, Tadley M, Leung PS, Kaplan M. Ruptured dissecting intramural duodenal hematoma following endoscopic retrograde cholangiopancreatography. ACG Case Rep J. 2017;4:e70-2.

Kumbhari V, Sinha A, Reddy A, et al. Algorithm for the management of ERCP-related perforations. Gastrointest Endosc. 2016;83:934–43.

Theopistos V, Theocharis G, Konstantakis C, et al. Non-operative management of type 2 ERCP-Related retroperitoneal duodenal perforations: a 9-year experience from a single center. Gastroenterol Res. 2018;11:207–12.

Article   Google Scholar  

Al-Mulhim A, Abdulatif M, Ali A. Laparoscopic cholecystectomy in children with sickle cell disease. Saudi J Gastroenterol. 2006;12:130–4.

Muroni M, Loi V, Lionnet F, Girot R, Houry S. Prophylactic laparoscopic cholecystectomy in adult sickle cell disease patients with cholelithiasis: a prospective cohort study. Int J Surg. 2015;22:62–6.

Goodwin EF, Partain PI, Lebensburger JD, Fineberg NS, Howard TH. Elective cholecystectomy reduces morbidity of cholelithiasis in pediatric sickle cell disease. Pediatr Blood Cancer. 2017;64:113–20.

Al-Salem AH, Issa H. Laparoscopic cholecystectomy in children with sickle cell anemia and the role of ERCP. Surg Laparosc Endosc Percutan Tech. 2012;22:139–42.

Ebert EC, Nagar M, Hagspiel KD. Gastrointestinal and hepatic complications of sickle cell disease. Clin Gastroenterol Hepatol. 2010;8:483–9.

Theocharidou E, Suddle AR. The liver in sickle cell disease. Clin Liver Dis. 2019;23:177–89.

Praharaj DL, Anand AC. Sickle hepatopathy. J Clin Exp Hepatol. 2021;11:82–96.

Zakaria N, Knisely A, Portmann B, et al. Acute sickle cell hepatopathy represents a potential contraindication for percutaneous liver biopsy. Blood. 2003;101:101–3.

Kliegman R, Behman RE, Nelson WE. Nelson Textbook of Pediatrics. 20th ed. Philadelphia: Elsevier; 2016.

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Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

Srinivas Srinidhi Vadlapudi, Anshu Srivastava, Moinak Sen Sarma & Ujjal Poddar

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SSV contributed to acquisition, analysis and interpretation of the data and drafting the article; AS conceptualized and designed the study and contributed to acquisition, analysis and interpretation of the data and co-drafting the article; PR contributed to acquisition, analysis and interpretation of the data, co-drafting the article; RKS, MSS, UP and RRY contributed to acquisition, analysis and interpretation of the data and critical revisions of the manuscript. All the authors approved the final version of the manuscript. AS will act as the guarantor for this manuscript. 

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Vadlapudi, S.S., Srivastava, A., Rai, P. et al. Jaundice in a Child with Sickle Cell Anemia: A Case Based Approach. Indian J Pediatr 91 , 73–80 (2024). https://doi.org/10.1007/s12098-023-04747-x

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Issue Date : January 2024

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Case Study: Sickle Cell Disease A 25-Year-Old in Transition

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A 25-year-old woman with a history of sickle cell disease (SCD) presents to the clinic for follow-up after a hospitalization for a vaso-occlusive pain crisis complicated by influenza A. She has a history of an acute ischemic stroke at age 5 years and has received monthly, simple red cell transfusions since the stroke. Her last transfusion was approximately four months prior. She is taking deferasirox 20 mg/kg daily but occasionally misses doses.

Laboratory results show the following:

Which of the following is the next best step in diagnosis

• Restart scheduled red blood cell transfusions
• Start prophylactic penicillin
• Discontinue transfusions and start hydroxyurea
• Order transcranial doppler ultrasonography (TCD) to assess risk of stroke
• Increase dose of deferasirox to 25 mg/kg/day

Explanation

The incidence of primary stroke in children with SCD is 0.6 to 0.8 events per 100 patient-years, with a cumulative incidence of 7.8 percent by age 14 years in the Jamaican cohort and 11 percent by age 20 years in the U.S. Cooperative Study of Sickle Cell Disease. Once stroke has occurred, the incidence of recurrent (secondary) stroke ranges from 47 to 93 percent in patients not started on regular transfusions. The Stroke Prevention Trial in SCD (STOP) randomized 130 high-risk children with SCD to either transfusion therapy (to maintain HbS 30%) or observation. These high-risk children had an increased blood flow in the internal carotid or middle cerebral artery by TCD. This study showed a 92 percent reduction in incidence of first stroke in transfused high-risk patients. A follow-up study, STOP2, randomly assigned 72 children whose TCD had normalized after 30 months of transfusion therapy to either ongoing or discontinued transfusions. The study was closed early due to a significant increase in abnormal TCD velocity and stroke risk for those who halted transfusion therapy.

The multicenter phase III TWiTCH trial evaluated children with SCA and abnormal TCD velocities without a history of stroke on chronic transfusions. Data showed that hydroxyurea at maximal tolerated dose was noninferior to chronic transfusions for maintaining TCD velocities as primary stroke prophylaxis (choice C). This patient has a history of ischemic stroke, so the results of TWiTCH do not apply to her.

The Stroke with Transfusions Changing to Hydroxyurea (SWiTCH) study was designed as a phase III multicenter trial to determine the efficacy of hydroxyurea/phlebotomy, compared with transfusions/chelation for children with SCA, stroke, and iron overload in secondary stroke prophylaxis. The primary endpoint was a composite of noninferiority for stroke prevention and superiority for reduction of liver iron content. The trial was terminated at the first scheduled interim analysis for futility for the composite endpoint, which required superiority of phlebotomy over iron chelation for reducing excess iron stores. The incidence of stroke on the hydroxyurea plus phlebotomy arm was higher (7 of 67 patients; 10.4%) than in the transfusion plus chelation arm (1 of 66 patients; 1.5%). These results, though not powered for inferiority, showed a trend towars increased stroke risk with transition to hydroxyurea. In patients with prior stroke, cessation of transfusion therapy is currently not recommended.

Whether chronic transfusion therapy can be stopped after a longer period of transfusions in a patient with a prior stroke remains unclear even though risk of recurrent stroke remains high in adolescence and young adulthood. In patients older than 16 years, TCD velocity criteria to determine stroke risk is not reliable (choice D).

In the Prophylaxis with Oral Penicillin in Children with Sickle Cell Anemia trial, children with SCA were randomly assigned to receive oral prophylactic penicillin or placebo PROPS 1986 ). The trial ended eight months early after the occurrence of 15 cases of pneumococcal sepsis, 13 in the placebo group and two in the penicillin group, showing an 84 percent reduction in pneumococcal sepsis with penicillin prophylaxis. The follow-up study, PROPS II, did not show an increased risk in pneumococcal infections with discontinuation of prophylactic penicillin after age 5 years. Therefore, prophylactic penicillin is not recommended in adults with SCA (choice B).

The trajectory of ferritin in this patient has not been established and an increase in oral iron chelation is not indicated at this time.

Case Study submitted by Marquita Nelson, MD, of University of Chicago, Chicago, IL.

• Hirst C, Owusu-Ofori S Prophylactic antibiotics for preventing pneumococcal infection in children with sickle cell disease . Cochrane Database Syst Rev. 2014 6:CD003427.
• Valadi N, Silva GS, Bowman LS, et al Transcranial Doppler ultrasonography in adults with sickle cell disease . Neurology. 2006 22:572-574.
• Ware RE, Davis BR, Schultz WH, et al Stroke with transfusions changing to hydroxyurea (SWiTCH) . Blood. 2012 119:3925-3932.
• Kumar N, Gross JB Jr, Ahlskog JE TCD with transfusions changing to hydroxyurea (TWiTCH): hydroxyurea therapy as an alternative to transfusions for primary stroke prevention in children with sickle cell anemia . Blood. 2015 126:3.

American Society of Hematology. (1). Case Study: Sickle Cell Disease A 25-Year-Old in Transition. Retrieved from https://www.hematology.org/education/trainees/fellows/case-studies/sickle-cell-disease-a-25-year-old-in-transition .

American Society of Hematology. "Case Study: Sickle Cell Disease A 25-Year-Old in Transition." Hematology.org. https://www.hematology.org/education/trainees/fellows/case-studies/sickle-cell-disease-a-25-year-old-in-transition (label-accessed August 13, 2024).

"American Society of Hematology." Case Study: Sickle Cell Disease A 25-Year-Old in Transition, 13 Aug. 2024 , https://www.hematology.org/education/trainees/fellows/case-studies/sickle-cell-disease-a-25-year-old-in-transition .

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Improving Preventive Care for Children With Sickle Cell Anemia: A Quality Improvement Initiative

Michael d. cabana.

From the * Department of Pediatrics, University of California, San Francisco (UCSF), San Francisco, Calif.;

† Epidemiology & Biostatistics, University of California, San Francisco (UCSF), San Francisco, Calif.;

‡ the Institute for Health Policy Studies, University of California, San Francisco (UCSF), San Francisco, Calif.;

§ Children’s Hospital at Montefiore, Bronx, N.Y.;

¶ The Albert Einstein College of Medicine, Bronx, N.Y.;

Marsha J. Treadwell

∥ UCSF Benioff Children’s Hospital, Oakland, Calif.;

Peggy Stemmler

** FrameShift Group, Phoenix, Ariz.;

Michael Rowland

M. a. bender.

†† Department of Pediatrics, University of Washington, Seattle, Wash.;

‡‡ Seattle Children’s Hospital; Seattle, Wash.;

Neha Bhasin

§§ Department of Pediatrics, University of Arizona, Tucson, Ariz.;

Jong H. Chung

¶¶ Department of Pediatrics, University of California, Davis, Sacramento, Calif.;

Kathryn Hassell

∥∥ Department of Internal Medicine, University of Colorado, Aurora, Colo.;

N. F. Nik Abdul Rashid

*** Cure 4 The Kids Foundation, Las Vegas, Nev.; and

Trisha E. Wong

††† Departments of Pediatrics and Pathology, Oregon Health & Science University, Portland, Oreg.

Naomi S. Bardach

Associated data.

Supplemental Digital Content is available in the text.

Introduction:

Sickle cell disease is a complex chronic disorder associated with increased morbidity and early mortality. The Pediatric Quality Measures Program has developed new sickle cell-specific quality measures focused on hydroxyurea (HU) counseling and annual transcranial Doppler (TCD) screening; however, these measures have not been used in a clinical setting to inform quality improvement (QI) efforts.

From 2017 to 2018, 9 sickle cell subspecialty clinics from the Pacific Sickle Cell Regional Collaborative conducted a year-long QI collaborative focused on improving the percentage of patients with HU counseling and TCD screening based on the new quality measures. After an initial kick-off meeting, the 9 sites participated in monthly conference calls. We used run charts annotated with plan-do-study-act cycle activities to track each site’s monthly progress and the overall mean percentage for the entire collaborative.

There was an overall improvement in the aggregate HU counseling from 85% to 98% ( P < 0.01). For TCD screening, referral frequency changed from 85% to 90% ( P = 0.76). For both measures, the variation in frequencies decreased over the year.

Conclusion:

Over 1 year, we found that a regional QI collaborative increased HU counseling. Although referral for TCD screening increased, there was no overall change in TCD completion. Overall, this QI report’s findings can help clinicians adopt and implement these quality measures to improve outcomes in children.

INTRODUCTION

Sickle cell disease includes a group of inherited, chronic disorders [including sickle cell anemia (SCA—HbSS, HbSβ 0 thalassemia), HbSC, HbSβ+-thalassemia] which are associated with increased morbidity and early mortality. 1 There are evidence-based interventions that can improve pediatric outcomes. For example, hydroxyurea (HU) therapy can decrease complications related to SCA, such as pain, acute chest syndrome and anemia. 2 Annual transcranial Doppler (TCD) ultrasound screening for children with SCA, when coupled with chronic transfusion therapy for those at highest risk, can decrease the incidence of stroke. 3

Despite evidence-based recommendations for the management of SCA, 4 there are gaps in current care. For example, based on Medicaid administrative data from 6 states, only 18% of children with SCA were noted to have consistent HU therapy, based on prescription refill records. 5 Also, annual TCD screening rates for children with SCA are estimated to range from only 22% to 44%. 6

To improve the quality of pediatric SCA care, the Pediatric Quality Measures Program has developed 2 new quality measures for SCA that focus on (1) counseling regarding the benefits and risks of HU, and (2) annual TCD screening. 7 Though the American Academy of Pediatrics recommends that the new pediatric quality measures “are useful for local quality improvement (QI) activities as well as for reporting to state and federal agencies and other regulatory bodies,” 8 there are limited data about the usability of these new measures. Our objective was to examine if a multi-state QI collaborative composed of sickle cell subspecialty clinics could utilize these new PQMP quality measures for SCA care.

The Pacific Sickle Cell Regional Collaborative (PSCRC) includes 15 clinical sites in the Western United States. It is 1 of 5 regional collaboratives funded by the Department of Health and Human Services Health Resources and Services Administration Sickle Cell Disease Treatment Demonstration Program. 9 PSCRC sites include community hospitals and clinics, academic medical centers, and federally qualified health centers.

PSCRC leadership includes clinicians with regional collaboration experience to standardize, improve, and refine sickle cell disease care. Previous projects include tracking barriers to HU uptake, developing HU educational materials, and creating state action plans to improve sickle cell disease care. PSCRC site leads present lectures and clinical case presentations on monthly telementoring videoconferences, aligned with the Extension for Community Healthcare Outcomes Project model that brings best-practice care to underserved areas. 10

The existing collaborative structures provided a venue for the QI collaborative work to test the SCA measures usability. The QI collaborative started with a 1-day in-person meeting. It continued for a year, with monthly conference calls, plan-do-study-act (PDSA) cycles, and data collection every other month.

Case Identification

Clinic staff at each site used manual chart reviews every 2 months to generate data on performance for both measures for children with SCA based on provider documentation. For the HU measure, participating clinics identified patients 9 months and older with SCA seen in the clinic during the previous 2 months. For the TCD measure, participating clinics identified children with SCA 2–15 years of age seen during the preceding 2 months. Participating clinicians collected data on the percentage of eligible children who had received anticipatory guidance regarding the risks and benefits of treatment with HU within the last 12 months. Also, each site collected data on the percentage of children referred for TCD and the percentage of children who had documentation of a completed TCD within the last 12 months in the medical record.

If a patient was currently prescribed HU, “counseling” was defined as a documented discussion of the risks and benefits of continued therapy, reviewing labs and discussing the results with the patient, a parent or guardian, or any other family member, and/or reviewing the patient’s adherence. If a patient was not currently prescribed HU, “counseling” was defined as a discussion of the rationale for HU treatment with the patient, a parent or guardian, or any other family member, and/or a review of the patient’s rationale for declining HU and/or a review of the patient’s medical reasons for ineligibility.

TCD referral for screening (“TCD referral”) was defined as any documentation by a healthcare provider of patient referral for TCD screening to decrease stroke risk. Completed TCD screening (“TCD completion”) was defined as documentation of TCD screening results noted in the patient’s medical record.

Interventions

We used the Model for Improvement as the QI framework for the project. 11 Participating PSCRC practices were asked to identify a team from their practice. Practice teams typically included 1 or more clinicians, an office manager, and clinic staff (medical assistant or RN). Four sites included a family partner (eg, parent of a child in the practice with SCA). The family partner provided additional ideas from a family perspective for clinic interventions, particularly concerning educational materials.

In August 2017, we conducted an 8-hour face-to-face QI kick-off meeting over 2 days within the PSCRC annual meeting in Sacramento, CA. This initial meeting included a review of SCA care evidence, goals of clinical QI measures, a practical review of QI theory and methods, and a review of baseline data that was collected on current performance on HU counseling and TCD referral measures. During the meeting, based on baseline data, the collaborative team members developed specific collaborative goals to increase the percentage of patients meeting the measures. Each site also developed a PDSA cycle for a test of change tailored to their site. Some PDSA cycles attempted to address the specific clinic characteristics (eg, availability of radiology and staffing), changes in staff workflow, or interventions to modify patient behavior (eg, patient reminders).

From August 2017 to September 2018, teams at each site conducted a minimum of at least 3 PDSA cycles, with most completing at least 6 cycles (one every 2 months). Every other month, teams at each site collected data on at least 10 patients or all patients if the volume was less than 10, via manual chart review as described above. Some patients were evaluated more than once if they had multiple visits in the same year. During the 12-month intervention period, the PSCRC collaborative conducted ten 1-hour webinar conferences that occurred approximately once per month. The webinars were hosted by a moderator who was familiar with QI techniques. During the monthly webinars, the collaborative members reviewed individual site data and overall collaborative performance. Leaders at each of the sites shared their lessons learned from their PDSA cycles and were encouraged to apply lessons learned at other sites to their sites, as applicable. 12

We used run charts (percentage of charts with documented TCD referral and HU counseling within the last 12 months), annotated with PDSA cycle activities, to track the results monthly for each site, and the mean percentage for the entire collaborative. We tracked the range of frequencies reported by the sites every other month.

Based on consensus and a review of baseline data, the collaborative participants felt that achieving benchmarks of 90% of patients with documented for HU counseling and 90% for TCD referral within the last 12 months would be a clinically significant goal. Since referral does not always guarantee that a test will be completed, we also collected data on TCD completion percentage documented in the medical record.

Due to the small number of patients at many sites, reflecting the low prevalence of SCA in any given geographical area, we did not collect monthly data, nor were we able to construct statistical process control charts. However, we used chi-square and Fisher Exact tests to compare the percentage of patients counseled for HU, referred for TCD screening, and completed TCD screening at the baseline and final cycle.

Maintenance of Certification credit was provided to qualified participants who completed the QI collaborative requirements. The Institutional Review Boards at the University of California, San Francisco, and at the Albert Einstein College of Medicine approved this project.

Participation

From August 2017 to July 2018, 9 PSCRC clinics participated in the QI collaborative (Table ​ (Table1). 1 ). Of the 9 clinics, 3 clinics treated only adult patients, 5 treated only pediatric patients, and 1 treated both adult and pediatric patients. Since HU counseling recommendations applied to adult and pediatric patients, all 3 adult-only clinics focused on the HU counseling measure and only supplied data regarding HU counseling frequencies. All 6 of the pediatric clinics provided data on both HU counseling and TCD referral.

Participating Clinics

Peds indicates pediatric.

*Based on 2016–2018 data. Pediatric volumes reflects patients 0–19 years of age. Adult volumes reflect patients greater than 19 years old for clinics that include both adult and pediatric patients. All clinics were subspecialty clinics in hematology.

PDSA Cycles to Improve HU Counseling

For the HU measure, there was an overall improvement in the aggregate data. At baseline, 85% of patients had documented HU counseling in the last 12 months. The counseling percentage gradually increased each cycle to 98% ( P < 0.01 for comparison of beginning to the end of the collaborative performance). Also, there was more consistency in reporting over time. The reported clinic counseling percentages varied by 60 points (40%–100%) at the beginning of the intervention to a range of 10% age points (90%–100%) at the end. Individually, 4 clinics showed an improvement, 3 showed no improvement, and 2 showed a decline in the percentage of patients with a history of HU counseling. In the 2 clinics with a decline, both had a baseline counseling rate of 100% that declined to 90%.

Figure ​ Figure1 1 shows the changes in the HU counseling percentage and ranges with the different PDSA interventions initiated by the sites. The individual clinics tested various interventions throughout the year. Many clinics first implemented the changes with only one provider or panel of patients before expanding the interventions or training other providers.

Changes in HU counseling with PDSA interventions initiated. Numbers in parentheses indicate the number of clinics that attempted the intervention during the cycle.

Several different interventions focused on the use of the electronic medical record (EMR). For example, several clinics had EMRs that allowed clinicians to modify an individual patient’s problem list. One intervention was to add “HU counseling” to the patient problem list to remind clinicians to counsel about HU. In 1 case, the clinic incorporated a standard order set for HU counseling into the EMR. Another clinic implemented an order set in the EMR to coordinate HU counseling with other clinic personnel.

Because the EMR could also be modified to create a standardized set of extended text for clinical documentation, this provided the impetus for clinicians to create HU counseling documentation which could be easily imported into a note, using an abbreviated word or phrase (eg, a “dot phrase” in the EPIC EHR; Epic Systems, Verona, Wis.). Early on, the QI collaborative developed a consensus on what constituted adequate counseling in specific circumstances (eg, initial counseling of HU, discussion of HU for patients who have previously declined HU) and standard language to describe HU counseling ( See Appendix 1, Supplemental Digital Content 1, http://links.lww.com/PQ9/A231 ). The development of this dot-phrase created standardization of practice and documentation. It increased the ease of medical record review. Multiple clinics applied this intervention during the year.

Finally, many clinics were already utilizing patient education information and brochures to facilitate the discussion of different topics. One clinic initiated the development of an HU patient information brochure for use in HU counseling.

PDSA Cycles to Improve TCD Referral Frequency

At baseline, for the TCD referral measure, 85% of patients had been referred for TCD screening in the last 12-month period. This percentage e fluctuated over the 12-month intervention period, from a low of 80% to a high of 97%, with a final mean of 90% ( P = 0.75). As with HU counseling, more consistency was observed with the range of reported percentages. The range of values decreased from 40% age points (60%–100%) to 20% age points (80%–100%) at the end of the intervention period. Individually, 3 clinics showed an improvement; 1 showed no improvement, and 2 showed a temporary improvement and then a decline in the frequency of TCD referral.

Figure ​ Figure2 2 shows the changes in the percentages of patients referred for TCD in the last 12-month period and reported ranges with the different PDSA interventions initiated by the sites. Several interventions focused on reminders for scheduling the TCD test. Initially, these interventions focused on reminding the patient’s family via telephone 1 week before the clinic visit to schedule a TCD test before the clinic visit. However, over the year, these interventions evolved to clinics assisting patients in scheduling the TCD test at the end of the visit, to clinic staff scheduling the TCD test on behalf of the patient. Towards the latter part of the intervention year, clinic nurses and scheduling staff in 2 clinics began tracking patients with overdue TCD test and addressing follow-up issues. In 1 clinic, the physician and an RN navigator would discuss which patients needed reminders and referrals for TCD testing in the coming month. Besides, 1 clinic provided additional training to clinic staff regarding the need for TCD testing and the testing interval. Reminders were also directed at physicians. One site modified the EMR by adding “TCD screening” and due date to the patient problem list to remind clinicians to discuss and order TCD testing.

Changes in TCD Screening with PDSA Interventions Initiated. Numbers in parentheses indicate the number of clinics that attempted the intervention during the cycle.

One site had the capability and staff to conduct TCD testing as part of its routine clinical service (Fig. ​ (Fig.3). 3 ). During the first PDSA cycle, this clinic re-organized the visit workflow to begin with the TCD test. In the second PDSA cycle, this clinic added a second ultrasound TCD technician to the clinic staff to decrease missed screenings if the sole technician was not available. Towards the end of the intervention period, the clinic noted that patients were not obtaining TCD screening within 1 year. As a result, clinic visits only for TCD testing were initiated. These “short interval” visits ensured that TCD testing could occur within a 1-year interval. Both the frequency of referrals for TCD and the completion of TCDs increased in this clinic.

Run chart for the clinic with “in-house” TCD showing changes in TCD screening and completion.

Although the mean percentage of patients with documented TCD referrals increased, there was no change in the mean percentage of patients with a completed TCD screening documented in the medical record for the collaborative (Fig. ​ (Fig.4). 4 ). The baseline percentage of TCD completion documented in the medical record was 82%, fluctuated from 70% to 90% during the year, and ended at 82% ( P = 1.00). The range of completed TCD percentages decreased from 60% age points (40%–100%) to 20% age points (70%–90%). Individually, 4 clinics showed an improvement, 1 showed no improvement, and 1 showed an overall decline in the percentage of documented completed TCD screening. For the single clinic with TCD testing capability, the percentage of documented completed TCD screening increased from 80% to 90% during the intervention period (Fig. ​ (Fig.3 3 ).

Mean percentage of TCD referral and TCD completion for collaborative.

Although sickle cell disease is the most common inherited blood disorder in the United States, few pediatric practice collaboratives focus exclusively on this condition. We found that a regional collaborative was able to improve the likelihood of HU counseling with SCA over 1 year. There was a change in aggregate HU counseling from 85% to 98%. However, for TCD referral, there was no statistically significant increase (85%–90%). Also, there was no change in the frequency of completed TCD testing documented in the medical record, which remained 82%.

There were variations of 3 successful interventions (eg, standardized documentation, EMR reminders or prompts, education materials) that were applied using PDSA cycles to improve HU counseling. Interventions focused on leveraging the EMR to remind clinicians to counsel about HU therapy and refer for TCD. EMR prompts have been used as reminders to enhance clinical practice for ordering vaccinations, screening tests, and referrals. Investment in EMR-based reminders may result in sustainable interventions. 13 – 15

Another EMR intervention was to standardize the documentation of HU counseling. However, 1 issue with the HU counseling quality measure is that the definition of counseling can differ from clinician to clinician and by the patient situation. Clinical practice guidelines for the management of sickle cell disease state that clinicians should “educate” about HU therapy; however, the guidelines provide little detail about what should be discussed. 4 At the start of the collaborative, the PSCRC developed a consensus regarding what constituted counseling based on different clinical situations. For example, the topics discussed during annual HU counseling may differ for a patient who is initially learning about HU versus a patient who continues to take HU; it may also differ by the patient’s age and sex. The collaborative structure facilitated achieving group consensus through monthly calls and clinicians testing the use of dot phrases in interval months.

To help sustain HU counseling, the standardization of HU documentation can help clinicians more quickly communicate the HU counseling status and what topics have already been discussed. Similarly, placement of HU counseling in a prominent place in the EMR can serve as a reminder and make the HU counseling documentation routine.

We noted that many interventions for TCD screening focused not on physician TCD referral, but also on facilitating patient adherence for TCD completion. For instance, interventions to improve TCD completion were initially designed to remind patients who were already scheduled for the clinic to set up their TCD testing individually. Later interventions focused on the clinic staff monitoring, of which patients needed TCD testing with active staff reminders for patient follow-up. Over the year, the interventions evolved from patient reminders to systems to track and engage patients.

There was a discordance in the percentage of patients referred for TCD compared to patients with a completed TCD. In most situations, patients with SCA need to go to a different clinical site or building for TCD testing. Few pediatric hematologists have on-site TCD available at the clinic. This situation adds further patient burden and time away from work. A national survey on TCD screening also noted that the distance to travel for testing was a barrier to completing TCD screening. 16 Successful TCD screening requires multi-disciplinary care, which can be difficult to coordinate across different settings.

The one high-volume clinic in the collaborative with TCD testing available in the clinic improved TCD testing completion frequency. This experience supports having in-clinic access to TCD as a method to improve screening rates. This approach could potentially be used in other settings to justify the expense associated with this additional resource. For lower volume clinics, this approach may not be sustainable and may be more challenging to justify. These clinics may need to partner with health plans to coordinate a population health management and preventive care approach for children with sickle cell disease. The additional expenses would need to be balanced by the savings in costs and quality of life through stroke episodes averted through TCD screening. However, this is an area for additional research.

Limitations

It is difficult to compare the frequency of HU counseling and TCD referral with other published reports. For this QI report, we only included children seen in the clinic in the last 2 months versus including every child followed at each of the centers in our denominators. This difference likely explains why there was such a high proportion of children at baseline who had been offered HU and referred for a TCD compared to other studies. 5 , 6

The PSCRC is a unique collaborative; however, the providers work in clinical sites that provide general pediatric hematology care, similar to clinics in large medical centers throughout the United States. The overall baseline performance of the PSCRC was higher than other clinics, based on other published reports. 5 , 6 There may have been a “ceiling effect,” as the performance approached 100%. For example, several clinics already had high HU counseling levels, and the 2 sites that declined went from 100% to 90%. The overall effect of the different interventions may be more significant in other settings with lower baseline performance. Alternatively, the success may have been due to the characteristics of these high-performing clinics. Overall, the general strategies, such as reminder systems, staff engagement, and patient engagement, can be applied in any setting. For clinics that see lower volumes of patients with SCA, some interventions, such as additional staff for in-clinic TCD screening, may not be cost-effective.

The HU measure focused on documentation of provider counseling. Although this can be measured quantitatively, the measure does not assess counseling effectiveness, patient understanding, or patient adherence. Further work is needed to understand better how to measure and improve these subsequent facets of SCA care. Finally, the outcomes were based on medical record audit and were not externally validated by administrative claims data or by parent-report of actual physician counseling. However, data from the medical record are sufficient to assess the success of small tests of change through PDSA cycles. 11

CONCLUSIONS

Both HU counseling and TCD screening strategies are highlighted in current practice guideline recommendations for SCA. We found that these quality measures can be used in QI initiatives in clinics that care for children with SCA. However, we did not see a significant change in TCD referral or TCD completion frequency. The limited ability of the clinics without TCD testing within the clinic to improve on the TCD completion measure suggests that TCD testing completion as a quality measure may be more appropriate at a health plan level. Overall, this QI report’s findings can help clinicians adopt and implement these quality measures to improve sickle cell disease outcomes in children.

The authors have no financial interest to declare in relation to the content of this article.

ACKNOWLEDGEMENTS

This work was funded by the Agency for Health Care Research & Quality (AHRQ) (U18HS025297) and the Health Resources and Services Administration (U1EMC27862).

Supplementary Material

Published online December 28, 2020

Supplemental digital content is available for this article. Clickable URL citations appear in the text.

Selections from this manuscript were presented at the Pediatric Academic Societies Meeting, April 27, 2019, Baltimore, MD.

To cite: Cabana MD, Marsh A, Treadwell M, Stemmler P, Rowland M, Bender MA, Bhasin N, Chung JH, Hassell K, Nik Abdul Rashid NF, Wong TE, Bardach NS. Improving Preventive Care for Children With Sickle Cell Anemia: A Quality Improvement Initiative. Pediatr Qual Saf 2021;6:e379.

Sickle Cell Disease: Case Study with Clinico-Pathological Aspect

G. K. Sawke¹ and C. B. S. Dangi²

¹Department of Pathology, People’s College of Medical Sciences and Research Centre, Bhopal India.

²Human Genetic Lab. CSRD, People’s Group, Bhanpur Road, Bhopal India.

Corresponding Author E-mail: [email protected]

Sickle cell disease is an autosomal recessive inherited disorder of red blood cells. It has also been called a ‘molecular’ disease because it results from the mutation of one aminoacid in haemoglobin molecule. This article reports a case of homozygous sickle cell disease in an adolescent patients with complications. It also advocates for further study on various clinicopathological aspects of the disease and urge for alertness on the part of health care professionals regarding a holistic approach to the management.

Sickle cell disease(SCD); Autosomal; Haemoglobin.  

Introduction

Sickle cell disease (SCD) is an hereditary hemolytic anemia . People with sickle cell disease have red blood cells that contain mostly hemoglobin S, an abnormal type of hemoglobin. Hemoglobin – is the main substance of the red blood cell. It helps red blood cells carry oxygen from the air in our lungs to all parts of the body. Normal red blood cells contain hemoglobin A. Hemoglobin S and hemoglobin C are abnormal types of hemoglobin. Normal red blood cells are soft ,round and biconcave and can squeeze through tiny blood vessels. The basic molecular lesion in Hb S is the single point mutation in one aminoacid out of 146 in haemoglobin molecule. There is substitution of valine for glutamic acid at six residue position of beta globin .

Sickle-cell anaemia is the name of a specific form of sickle-cell disease in which there is homozygosity for the mutation that causes HbS. Sickle-cell anaemia is also referred to as “HbSS”, “SS disease”, “haemoglobin S” or permutations thereof. In heterozygous people, who have only one sickle gene and one normal adult hemoglobin gene, it is referred to as “HbAS” or “sickle cell trait”. Other, rarer forms of sickle-cell disease include sickle-haemoglobin C disease (HbSC), sickle beta-plus-thalassaemia (HbS/β + ) and sickle beta-zero-thalassaemia (HbS/β 0 ). These other forms of sickle-cell disease are compound heterozygous states in which the person has only one copy of the mutation that causes HbS and one copy of another abnormal haemoglobin allele.

An 11 years girl patient refered to Centre for Scientific Research and  Development(CSRD) of people’s group for advance haematology investigations.

Patient has significant skeletomuscular pain off and on, abdominal discomfort with pain and fever off and on. She was recently operated for cholecystectomy for gallstones.There was history of hip surgery nine years ago. No history of jaundice, or any other chronic illness was present. On examination pallor++, and mild spleenomagaly was found.

Patient’s investigation profile revealed Haemoglobin 7 gms%, Total WBC count within normal limits,differential WBC count ;neutrophilia, haematocrit 20.7%, RBCs indices within normal limits except RDW 15%. Normal platelets count and coagulation profile. Serum Iron studies and Vitamin B12 & Red cell folate were within normal range.Coomb’s test, G6PD, and Malaria antigen tests were negative. Liver function tests show mild increase in total and indirect bilirubin . Blood glucose, urea, serum creatinin, electrolytes were normal.

Patient’s abdominal ultrasonography report shows cholelithiesis and mild spleenomagaly.

In CSRD patient’s blood samples were investigated for haemoglobin electrophoresis (HPLC). Haemoglobin chromatography revealed high value of fetal haemoglobin(Hb F)-30.7% (normal <1.5%), low value of haemoglobin adult(Hb A) 3.4% (normal range 83.24-90.79%), and very high concentration of haemoglobin sickle(Hb S) 62.9% which is normally absent.  With these findings diagnosis of Haemoglobin ‘S’ homozygous state was considered and haemoglobin electrophoresis (HPLC) of parents and siblings were advised.

Following the patients tests, her parents and brother’s investigations performed. Both the parents and brother’s reports showed haemoglobin S heterozygous state. Patient was advised to consult haematologist in tertiary care hospital for advance treatment and management .

If one parent has sickle-cell anaemia (SS) and the other has sickle-cell trait (AS), there is a 50% chance of a child’s having sickle-cell disease (SS) and a 50% chance of a child’s having sickle-cell trait (AS). When both parents have sickle-cell trait (AS), a child has a 25% chance (1 of 4) of sickle-cell disease (SS). In our case both the parents are haemoglobin S heterozygous(AS),hence the patient is (SS) and her brother is (AS).

Clinical expression of the patients with sickle cell disease(SCD) is variable. Some patients need a lot of care while others need only routine check-ups.

The new therapies for treating SCD, hydroxyurea, a ribonuclease   reductase inhibitor, is most promising. Hydroxyurea was initially developed because of its ability to increase fetal haemoglobin production, but it has other beneficial effects too. Other new therapies being evaluated include butyrates and decitabine.[8] Bone marrow transplantation of children has shown cure in some patients. [9] Both bone marrow transplantation and hydroxyurea therapy are expensive modalities.

Finding financial resources for such expensive therapies for SCD have been difficult, especially in developing countries like India. For the optimal management of SCD patients, a comprehensive care centre with multidisciplinary team is required. Early diagnosis of patients by screening programme is very important. Diagnosed patients should be referred to centre for periodic evaluation. Parents should be given genetic counseling and support. Presently patient is maintaining normal routine  life with  proper clinical management.

• Platt OS, Brambilla DJ, Rosse WF, et al. “Mortality in sickle cell disease. Life expectancy and risk factors for early death”.1994; N. Engl. J. Med. 330 (23): 1639–44
•   National Institute of (2002) The management of sickle cell disease. NIH publication No. 02-2117.
• Stuart MJ, Setty BN. Acute chest syndrome of sickle cell disease:new light on an old problem. Curr Opin Hematol 2001;8(2):111-22.
• Hagar RW, Vichinsky EP. Major changes in sickle cell disease. Adv Pediatr 2000;47:249-72.
• Ohene-Frempong K. Stroke in sickle cell disease: demographic, clinical, and therapeutic considerations. Semin Hematol 1991;28:213-9.
•  Hord J, Byrd R, Stowe L. Streptococcus pneumoniae sepsis and meningitis during the penicillin prophylaxis era in children with sickle cell disease. J Pediatr Hematol Oncol 2002;24:470-2.
•  Vichinsky E, ed. Transfusion-related iron over load in sickle cell anaemia. Seminars in hematology, ed. NS Young and Beris. Vol 38(No 1,Suppl1:1-5, 14-23.Philadelphia PA:Harcourt Health Sciences, 2001.
•  Vichinsky EP. New therapies in sickle cell disease. Lancet 2002;360:629-31.
•  Walters MC, Storb R, Patience M, Leisenring W, Taylor T, Sanders JE, et al. Impact of bone marrow transplantation for symptomatic sickle cell disease: an interim report. Multicenter  investigation of bone marrow transplantation for sickle cell disease. Blood 2000;95:1918-24.

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Prevalence, patterns, and factors associated with abnormal lung function among children with sickle cell disease in Uganda: a cross-sectional study

Affiliations.

• 1 Department of Paediatrics and Child Health, St. Mary's Hospital Lacor, Gulu, Uganda.
• 2 Uganda Cancer Institute, Mulago National Referral Hospital, Kampala, Uganda.
• 3 Department of Medical Microbiology and Immunology, Faculty of Medicine, Gulu University, Gulu, Uganda.
• 4 Department of Planning, Kwania District Local Government, Kwania, Uganda.
• 5 College of Health Sciences, Makerere University Lung Institute, Makerere University Kampala, Kampala, Uganda.
• 6 College of Health Sciences, Makerere University Lung Institute, Makerere University Kampala, Kampala, Uganda. [email protected].
• 7 Department of Paediatrics and Child Health, Mulago National Referral Hospital, Kampala, Uganda.
• PMID: 39127673
• PMCID: PMC11316324
• DOI: 10.1186/s12887-024-04988-5

Background: Pulmonary complications are common among children with sickle cell disease (SCD). However, there is little literature on associated lung function abnormalities in Uganda. We aimed to determine the prevalence, patterns, and factors associated with abnormal lung function among children with SCD in a tertiary care hospital in Uganda.

Method: A cross-sectional study was conducted among children aged 6 to 18 years at the SCD clinic (SCC) of Mulago National Super-Specialized Hospital between January 2020 and April 2021. Data on sociodemographic and clinical characteristics was collected using a standardized questionnaire. Laboratory investigations, including a complete blood count and serum lactate dehydrogenase (LDH), were done. Spirometry was performed following the ATS/ERS standards. Multivariable modified Poisson regression analysis was performed to determine factors associated with abnormal lung function.

Results: A total of 332 participants were enrolled. The mean age was 11.7 ± 3.4 years, and 184 (55.4%) were female. Overall, 126 (37.9%) participants had abnormal lung function: 67/126 (53.2%) restrictive, 57/126 (45.2%) obstructive, and 2/126 (1.6%) mixed-ventilatory patterns. Factors associated with abnormal lung function were; serum LDH level > 600UL (aIRR: 1.89 95% CI: 1.2 - 7.4, p = 0.049), a history of acute chest syndrome (aIRR: 1.55, 95% CI: 1.06-2.25, p = 0.024), wasting (aIRR: 1.33, 95%CI: 1.02 - 1.72, p = 0.032), and use of charcoal for household cooking (aIRR: 1.49, 95% CI: 1.03-2.15, p = 0.035).

Conclusion: More than one-third of children with SCD in Uganda have lung function abnormalities. Strategies to improve nutrition, reduce exposure to charcoal smoke, and monitoring serum LDH levels may be important in preventing or managing abnormal lung function in this population. The identification of reversible and irreversible airway obstruction in children with sickle cell disease also highlights the need for targeted interventions to address these specific patterns of abnormal lung function.

Keywords: Children; Lung function; Sickle cell disease; Uganda.

© 2024. The Author(s).

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Conflict of interest statement

The authors declare no competing interests.

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