Sickle-cell disease is one of the most common severe monogenic disorders in the world. Haemoglobin polymerisation, leading to erythrocyte rigidity and vaso-occlusion, is central to the pathophysiology of this disease, although the importance of chronic anaemia, haemolysis, and vasculopathy has been established. Clinical management is basic and few treatments have a robust evidence base. One of the main problems of sickle-cell disease in children is the development of cerebrovascular disease and cognitive impairment, and the role of blood transfusion and hydroxycarbamide for prevention of these complications is starting to be understood. Recurrent episodes of vaso-occlusion and inflammation result in progressive damage to most organs, including the brain, kidneys, lungs, bones, and cardiovascular system, which becomes apparent with increasing age. Most people with sickle-cell disease live in Africa, where little is known about this disease; however, we do know that the disorder follows a more severe clinical course in Africa than for the rest of the world and that infectious diseases have a role in causing this increased severity of sickle-cell disease. More work is needed to develop effective treatments that specifically target pathophysiological changes and clinical complications of sickle-cell disease.

https://www.nejm.org/doi/pdf/10.1056/NEJMra1510865

Sickle Cell Disease

Background This study was designed to determine the incidence of thoracic bone infarction in patients with sickle cell diseases who were hospitalized with acute chest or back pain above the diaphragm and to test the hypothesis that incentive spirometry can decrease the incidence of atelectasis and pulmonary infiltrates. Methods We conducted a prospective, randomized trial in 29 patients between 8 and 21 years of age with sickle cell diseases who had 38 episodes of acute chest or back pain above the diaphragm and were hospitalized. Each episode of pain was considered to be an independent event. At each hospitalization, patients with normal or unchanged chest radiographs on admission were randomly assigned to treatment with spirometry or to a control nonspirometry group. Each patient in the spirometry group took 10 maximal inspirations using an incentive spirometer every two hours between 8 a.m. and 10 p.m. and while awake during the night until the chest pain subsided. A second radiograph was obtained thre...

https://www.nejm.org/doi/pdf/10.1056/NEJM199509143331104

Incentive spirometry to prevent acute pulmonary complications in sickle cell diseases.

Background and Methods The management of episodes of severe pain in patients with sickle cell disease is a difficult clinical problem. We studied 36 children and adolescents with sickle cell disease who had 56 acute episodes of severe pain (44 in 27 patients with sickle cell anemia, 8 in 7 patients with sickle cell-hemoglobin C disease, and 4 in 2 patients with sickle cell-β+-thalassemia). The patients were randomly assigned in double-blind fashion to receive an intravenous infusion of either saline placebo or high-dose methylprednisolone (15 mg per kilogram of body weight, to a maximum of 1000 mg) on their admission to the hospital and again 24 hours later. All the patients received intravenous morphine sulfate until severe pain abated and were then given acetaminophen with codeine. Results For all episodes of pain, the duration of inpatient analgesic therapy (intravenous and oral) was significantly shorter for the patients who received methylprednisolone than for those given placebo (mean, 41.3 vs. 71.3...

https://www.nejm.org/doi/pdf/10.1056/NEJM199403173301101

High-dose Intravenous Methylprednisolone Therapy for Pain in Children and Adolescents With Sickle Cell Disease

The phenotypic expression of sickle cell anaemia varies greatly among patients and longitudinally in the same patient. It influences all aspects of the life of affected individuals including social interactions, intimate relationships, family relations, peer interactions, education, employment, spirituality and religiosity. The clinical manifestations of sickle cell anaemia are protean and fall into three major categories: anaemia and its sequelae;pain and related issues; andorgan failure including infection. Recent studies on the pathogenesis of sickle cell anaemia have centred on the sequence of events that occur between polymerisation of deoxy haemoglobin (Hb) S and vaso-occlusion. Cellular dehydration, inflammatory response and reperfusion injury seem to be important pathophysiological mechanisms. Management of sickle cell anaemia continues to be primarily palliative in nature, including supportive, symptomatic and preventative approaches to therapy. Empowerment and education are the major aspects of supportive care. Symptomatic management includes pain management, blood transfusion and treatment of organ failure. Pain managment should follow certain priniciples that include assessment, individualisation of therapy and proper utilisation of opioid and nonopioid analgesics in order to acheive adequate pain relief. Blood selected for transfusion should be leuko-reduced and phenotypically matched for the C, E and Kell antigens. Exchange transfusion is indicated in patients who are transfused chronically in order to prevent or delay the onset of iron-overload. Acute chest syndrome is the most common form of organ failure and its management should be agressive, including adequate ventilation, multiple antibacterials and simple or exchange blood transfusion depending on its severity. Preventitive therapy includes prophylactic penicillin in infants and children, blood transfusion (preferably exchange transfusion) in patients with stroke, and hydroxyurea in patients with frequent acute painful episodes. Bone marrow and cord blood transplantation have been successful modalities of curative therapy in selected children with sickle cell anaemia. Newer approaches to preventative therapy include cellular rehydration with agents that inhibit the Gardos channel or the KCl co-transport channel. Curative gene therapy continues to be investigational at the level of the test tube and transgenic mouse models.

/pdf/sickle-cell-anaemia-progress-in-pathogenesis-and-treatment-2t2wjaygr0.pdf

Sickle cell anaemia: progress in pathogenesis and treatment.

The first indisputable case of sickle cell disease in the literature was described in a dental student studying in Chicago between 1904 and 1907 (Herrick, 1910). Coming from the north of the island of Grenada in the eastern Caribbean, he was first admitted to the Presbyterian Hospital, Chicago, in late December 1904 and a blood test showed the features characteristic of homozygous sickle cell (SS) disease. It was a happy coincidence that he was under the care of Dr James Herrick (Fig 1) and his intern Dr Ernest Irons because both had an interest in laboratory investigation and Herrick had previously presented a paper on the value of blood examination in reaching a diagnosis (Herrick, 1904±05). The resulting blood test report by Dr Irons described and contained drawings of the abnormal red cells (Fig 2) and the photomicrographs, showing irreversibly sickled cells, leave little doubt that the diagnosis was SS disease. The subsequent history of Dr Walter Clement Noel, that first patient, is described in a fascinating account by Dr Todd Savitt (Savitt & Goldberg, 1989) who found that, on Dr Noel's return to Grenada in 1907, he set-up a dental practice in the capital St. Georges, died from the acute chest syndrome aged 32 years and is buried in the Catholic cemetery at Sauteurs in the north of Grenada (Fig 3). The second case, Ellen Anthony, aged 25 years, had already been under observation in the wards of the University of Virginia Hospital from 1907 and the strange blood film sent to pathologists at Johns Hopkins University Hospital was considered an unusual case of pernicious anaemia (Savitt, 1997). The diagnosis became clear with the publication of Herrick's paper in November, 1910 (Herrick, 1910) and, within 3 months, this second case was reported in February 1911 (Washburn, 1911) (Fig 4). The third case, a woman aged 21 years, reported from Washington University Medical School in 1915 (Cook & Meyer, 1915), raised suspicions of a genetic basis, as three siblings had died from severe anaemia, and blood from both the patient and her asymptomatic father showed a sickling deformity of the red cells on incubation (Emmel, 1917). The fourth case was a 21-year-old black man in the wards of Johns Hopkins Hospital (Mason, 1922). It was Mason who noted the similar features of the first four case reports, he was the first to use the term `sickle cell anaemia' and, finding that the cases were all black, he began the popular misconception that the disease was confined to people of African origin. Genetics of sickle cell disease The discovery by Emmel (1917) of the sickle cell phenomenon in the father of the third case not only suggested a genetic basis for sickle cell disease, but led to a period of confusion in the genetics of the disease. Both Huck (1923) and Sydenstricker et al (1923) noted `latent sicklers' among relatives of patients with the disease, and further analysis of the pedigree of Huck's patients led to the conclusion that the sickle cell phenomenon was inherited as a Mendelian autosomal characteristic (Taliaferro & Huck, 1923). People with positive sickle tests were divided into asymptomatic cases, `latent sicklers', and those with features of the disease, `active sicklers', and it was Dr Lemuel Diggs of Memphis who first clearly distinguished symptomatic cases called sickle cell anaemia from the latent asymptomatic cases which were termed the sickle cell trait (Diggs et al, 1933). Several years were to elapse before the relationship of the trait and the disease was clarified. A review of 32 apparent cases of the disease with data in both parents showed sickling in both parents in 10 cases, in one parent in 15 cases and in neither parent in seven cases (Neel, 1947). Prospective data collection in 29 cases of the disease showed sickling in all 42 parents tested (Neel, 1949), providing strong support for the theory of homozygous inheritance. A Colonial Medical Officer working in Northern Rhodesia (Beet, 1949) reached similar conclusions at the same time with a study of one large family (the Kapokoso-Chuni pedigree). The implication that sickle cell anaemia should occur in all communities in which the sickle cell trait was common and that its frequency would be determined by the prevalence of the trait did not appear to fit the observations from Africa. Despite a sickle cell trait prevalence of 27% in Angola, Texeira (1944) noted the active form of the disease to be `extremely rare' and similar observations were made from East Africa (Lehmann & Milne, 1949; Mackey, 1949; Raper, 1949; Lehmann, 1951), West Africa (Edington, 1954) and Northern Rhodesia (Beet, 1947). In Uganda, Lehmann and Raper (1949, 1956) found a positive sickling test in 45% of one community, from which homozygous inheritance would have predicted that nearly 10% of children had SS disease, yet not a single case was found. The discrepancy led to a hypothesis that some factor inherited from non-black ancestors in America might be necessary for expression of the disease (Raper, 1950). The explanation for this apparent discrepancy gradually emerged. Working with the Jaluo tribe in Kenya, Foy et al (1951) found five cases of sickle cell anaemia among very young children and suggested that cases might be dying at an age before those sampled in surveys. A similar hypothesis

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2141.2001.02557.x

M. J. Gelfand

Papers

Rib infarcts and acute chest syndrome in sickle cell diseases