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Infections and the Common Inherited Hemoglobin Disorders
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SECTION 6 International Medicine: Major Tropical Syndromes: Systemic Infections
Infections and the Common Inherited Hemoglobin Disorders THOMAS N. WILLIAMS | DAVID J. WEATHERALL
KEY CONCEPTS • The inherited hemoglobin disorders are the commonest monogenic diseases. Between 300 000 and 400 000 babies are born with them each year. Eighty percent of births are in low- or middle-income countries (LMIC). • The frequency of these diseases is likely to increase significantly in the future. • All these diseases are associated with increased susceptibility to a wide range of infections. • The diagnosis of infection is often complicated by underlying complications of the hemoglobin disorder. • Blood-borne infection is still a major risk, particularly in LMIC. • Because the pattern of infection varies between different types of hemoglobin disorders, an accurate diagnosis of the particular disorder is a vital part of the management of episodes of infection.
Classification and Epidemiology CLASSIFICATION Different forms of hemoglobin (Hb) are produced in embryonic, fetal and adult life, each consisting of pairs of different globin chains. Adult hemoglobin consists of a major component HbA (α2β2) and a minor fraction HbA2 (α2δ2). In fetal life the major hemoglobin is HbF (α2γ2). The inherited disorders of hemoglobin are classified into two major groups (Box 122-1). First there are the structural hemoglobin variants. Although there are many hundreds of these variants, only three reach extremely high frequencies: Hbs S, C and E. The clinical manifestations of Hbs S and C are related to abnormal structure-function mecha-
BOX 122-1 A CLASSIFICATION OF THE COMMON INHERITED HEMOGLOBIN DISORDERS Structural Hemoglobin Variants • HbS • HbC • HbE • Many rarer forms Thalassemias • α-thalassemia • α+-thalassemia • α0-thalassemia • β-thalassemia • β+-thalassemia • β0-thalassemia • δβ-thalassemia Common Compound Heterozygotes • HbS β-thalassemia • HbE β-thalassemia • HbSC disease • α+/α0-thalassemia
nisms, while those of HbE result from its reduced rate of synthesis. Second are the thalassemias, which result from many different mutations that reduce the synthesis of the α- or β-globin chains.1 As shown in Box 122-1 the compound heterozygous inheritance of both structural variants and β-thalassemia, notably HbS β-thalassemia and HbE β-thalassemia, are of considerable clinical importance; globally, HbE β-thalassemia accounts for about 50% of severe cases of β-thalassemia.
EPIDEMIOLOGY The global distribution of Hbs S and E and of the different forms of thalassemia are shown in Figures 122-1 to 122-3 and the reasons for the remarkably high frequency of these diseases are summarized in Box 122-2. Natural selection is of key importance.2 Carriers for the sickle cell, mild forms of α-thalassemia and HbC genes show significant protection against Plasmodium falciparum malaria. There is increasing evidence that the same applies to carriers for HbE or β-thalassemia. The complex mechanisms for this protection are not yet fully understood. It has been found recently that there is complex interplay between these protective mechanisms. For instance, although carriers of the sickle cell and mild α-thalassemia genes are protected against malaria, those that inherit both these genes lose their protection completely.3 Such complex epistatic interactions will undoubtedly be found for other genetic polymorphisms of this type. Other factors that maintain the high frequency of the hemoglobin disorders include a high level of consanguinity in many of the affected populations, the epidemiological transition whereby improvements in public health allow more affected babies to survive to present for treatment, and emigration from high-frequency countries to richerresourced countries where treatment is available for these disorders.
Pathogenesis and Pathology The increased susceptibility to certain forms of infection in patients with inherited disorders of hemoglobin is best understood by first considering their molecular pathology.
SICKLE CELL ANEMIA AND ITS VARIANTS The substitution of valine for glutamic acid at position 6 in the β-globin chain of HbS leads to deformity of the red cells at relatively low oxygen tensions.4 The characteristic sickle shape reflects polymerization of the globin chains and leads to a variable degree of vasoocclusion. The latter results in reperfusion injury characterized by excessive oxidant generation and activation of the endothelium of small vessels with diminished nitric oxide availability. Vascular occlusion leads to widespread complications including early splenic atrophy,
BOX 122-2 FACTORS RESPONSIBLE FOR THE HIGH LEVEL OF INHERITED HEMOGLOBIN DISORDERS • • • • •
Natural selection High frequency of consanguinity Epidemiological transition Population migration Increasing population size
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The global distribution of hemoglobins S and E
HbE
HbS
Figure 122-1 The global distribution of hemoglobins S (HbS) and E (HbE). The patchy distribution of HbS in the New World as a result of emigration from Africa is not shown. (From Weatherall D.J., Clegg J.B.: The thalassaemia syndromes, 4th ed. Oxford: Blackwell Science; 2001. Used with permission.)
infarction of bone marrow leading to painful crises, chronic leg ulcers, vascular complications of the brain, and many other forms of tissue damage. The deformity of the red cells is associated with a hemolytic anemia of varying severity. By far the most important factor in proneness to infection based on the pathophysiology of sickle cell disease is the very early loss of splenic function due to damage to the spleen by the deformed sickle cells.5 Susceptibility to invasive pneumococcal infection is the major cause of early death in babies and young children. There may also be increased proneness to other infections, notably Haemophilus influenzae type B (Hib). The increased frequency of Salmonella osteomyelitis results from infection of the marrow and overlying bone infarcts that occur during painful crises. While there is no evidence of increased susceptibility to viral infections, the aplastic crises that tend to occur in small epidemics are undoubtedly due to parvovirus infection.6 In infections of this type in patients with sickle cell anemia, because of the extremely shortened lifespan of their red cells, profound anemia develops over a very short period. They are also prone to severe complications of influenza, including the precipitation of painful crises.7 The hemolytic anemia results in increased bilirubin production with a high frequency of gallstone formation and associated infection of the gallbladder. There is a high frequency of the genetic mutation that results in Gilbert’s syndrome in those of African origin and those affected are even more prone to this complication.8
THE THALASSEMIAS
The α-thalassemias result from deletions or point mutations in one or both of the linked pairs of α-globin genes (αα/αα).1 They are divided into the α+- and α0-thalassemias. In the former a single α gene is lost by deletion or its function is suppressed by a point mutation, the so-called non-deletion (ND) form (-α/αα, αNDα/αα). Although these are the commonest genetic disorders they are not associated with severe anemia. The α0-thalassemias are characterized by deletion of both of the linked pairs of α-globin genes (–/αα). In the compound heterozygous state for α0-and α+-thalassemia (-α/–) there is significant
imbalance of globin-chain synthesis with the production of excess β-chains which form unstable tetramers called HbH. HbH disease is characterized by a hemolytic anemia of varying severity associated with splenomegaly. The homozygous state for α0-thalassemia (–/–) causes stillbirth. The β-thalassemias result from many different mutations of the β-globin genes (β/β) which result in a variable degree of suppression of globin-chain production leading to an excess of α-chains that precipitate and cause severe damage to the red cell precursors and red cells in the circulation.9 Depending at least in part on the severity of the β-globin gene mutation these conditions vary in their phenotype from β-thalassemia major, which requires lifelong transfusion, to a milder form of the disease called β-thalassemia intermedia. HbE thalassemia shows a wide range of phenotypic expression, from a transfusiondependent disorder like thalassemia major to a condition that is associated with normal growth and development, albeit at a relatively low hemoglobin level.10 Inadequately transfused patients with severe β-thalassemia, as well as profound anemia, develop skeletal deformities due to bone marrow expansion, progressive splenomegaly, defective growth and development, and a wide range of other complications. In well-transfused patients iron loading, both from transfused blood and due to increased iron absorption, is an important complication that has to be dealt with by the administration of chelating agents. The common symptomatic form of α-thalassemia, HbH disease, also shows wide phenotypic diversity depending, at least in part, on the molecular forms of α-thalassemia that have been inherited. Like HbE β-thalassemia, at one end of the spectrum it is a transfusiondependent disorder, mainly due to relatively severe hemolysis. The pattern of infection in the severe β-thalassemias is different to that in sickle cell anemia in many respects.11 Before the days when adequate transfusion levels were achieved, progressive splenomegaly was extremely common, necessitating splenectomy. At that time there was an extremely high rate of infection after splenectomy, particularly in children aged less than 5 years. Although the situation has improved
Chapter 122 Infections and the Common Inherited Hemoglobin Disorders
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The global distribution of the different forms of α-thalassemia
--MED –α 3.7 I αTα
1 – 15%
--SEA 5 – 15% –α 3.7 I –α 4.2 α Tα 60% (–α 3.7) αTα 5 – 40% (–α 3.7 I) α Tα
α+-thalassemia
5 – 80% 40 – 80% (–α 3.7 I) (–α 3.7 II) (–α 4.2)
–α 4.2 –α 3.7 III αTα
α0-thalassemia
Figure 122-2 The global distribution of the different forms of α-thalassemia. The main forms of the disease that are shown are the carrier states for α+-thalassemia and its different forms, -α3.7 I, -α3.7 II, -α3.7 III. The common forms of α0-thalassemia, –αSEA and –αMED are also shown. The very high, if approximate, gene frequencies are also shown, indicating that this is the commonest genetic disease globally. (From Weatherall D.J., Clegg JB.: The thalassaemia syndromes, 4th ed. Oxford: Blackwell Science; 2001. Used with permission.)
considerably following the administration of adequate transfusion and the use of iron chelating agents, progressive splenomegaly is still seen quite often and a significant number of splenectomies are still carried out with the risk of infection with similar organisms to those that occur in sickle cell anemia. Patients with β-thalassemia are also prone to a wide range of other infections.1 Because of transfusion dependence blood-borne infections are still common, notably hepatitis B and C and human immunodeficiency viruses (HIVs). Malaria is also an important blood-borne infection in some of the developing countries in the tropics. The only pathogens that have been shown quite unequivocally to occur with an increased frequency in iron-loaded patients with β-thalassemia are those of the Yersinia genus, which normally have a low rate of pathogenicity and an unusually high requirement for iron. They do not secrete sideropores but have receptors for ferrioxamine and become pathogenic in the presence of iron which is bound to the widely used chelating agent desferrioxamine.11 There have been many reports of severe infections with this organism in patients with severe β-thalassemia. Reports have also documented the occurrence of severe, invasive fungal infections, in particular mucormycosis, in multiplytransfused patients with β-thalassemia, although the mechanism underlying this susceptibility is unclear. Patients with sickle cell anemia, while they are less prone to malaria, have severe complications and a high mortality risk if they are infected.12 There is strong evidence that in the case of Plasmodium vivax malaria carriers for α-thalassemia and patients with HbE β-thalassemia are more susceptible than normal
individuals. This probably reflects the fact that the receptor for P. vivax is the Duffy antigen which is expressed at a higher level on relatively young red cells, which are present in all the hemoglobin disorders.
PREVENTION Marked reduction in the births of babies with serious forms of β-thalassemia and to a lesser extent with sickle cell anemia have been achieved in many countries. Programs of this type rely on intensive public education about the nature of the inherited hemoglobin disorders, prenatal screening of parents to detect those at risk for having an infected child, prenatal diagnosis by analysis of DNA obtained by chorionic villus sampling, and termination of pregnancy in cases in which the genotype is that of sickle cell anemia or a severe form of thalassemia.1 In many of the higher-income countries in which prenatal diagnosis for sickle cell anemia is not yet widely applied, screening of newborn babies at risk is now carried out, either by the use of hemoglobin electrophoresis or high performance liquid chromatography (HPLC) analysis. Early administration of prophylactic penicillin has been shown to deliver a remarkable reduction in early deaths from infection.13 Recent studies in Africa suggest that early deaths are associated with similar organisms to those in the higher-income countries and the development of neonatal diagnosis and prophylaxis of this type is likely to have a major effect in reducing early death rates.14 Vaccination with pneumococcal, Hib and meningococcal vaccines are also being incorporated into these regimens. In the case of the severe forms of
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The world distribution of the β-thalassemias IVS-I-110G→A COD 39 C→T IVS-I-6 T→C IVS-I-1-G→A IVS-II-745 C→G COD 6-A
IVS-I-110G→A COD 39 C→T IVS-II-1 G→A IVS-I-5 G→C COD 8-AA COD 44-C
COD 41/42-TTCT COD 17 A→T IVS-II-654 C→T –28 A→G COD 26 G→A(HbE) IVS-I-5 G→C COD 19 A→G –29 A →G –88 C→T IVS-I-5 G→C COD 8/9 + G IVS-I-1 G→T 619 bp DEL COD 26 G→A(HbE)
Figure 122-3 The world distribution of the β-thalassemias. The remarkable diversity of the different mutations that are involved in β-thalassemia in different ethnic groups are indicated. Those in boxes are the milder β-thalassemia mutations that occur in different populations, particularly in West Africa. (From Weatherall D.J., Clegg J.B.: The thalassaemia syndromes, 4th ed. Oxford: Blackwell Science; 2001. Used with permission.)
α- or β-thalassemia similar regimens are only indicated in those who have undergone splenectomy, regardless of their age. Other important preventive measures for reducing the frequency of infectious complications include prophylaxis for blood-borne infection and malaria. Although the former is particularly relevant to those with transfusion-dependent forms of thalassemia it is becoming important in those with sickle cell anemia because increasing numbers are being placed on regular transfusion, particularly to reduce the frequency of neurological complications. The organisms of particular importance are hepatitis B and C viruses, HIV and malaria. Although donor screening programs have had a major effect in reducing the frequency of blood-borne infections of this type, they still remain a considerable problem in many low- and middle-income countries. Malaria prophylaxis and the use of bednets are vital in countries with a high rate of malaria transmission.
CLINICAL FEATURES The clinical findings of infection in patients with inherited hemoglobin disorders are particularly complex because they are often associated with symptoms and signs of complications of the underlying disorder.
Sickle Cell Anemia and its Variants15 The particularly high frequency of pneumococcal infection in early childhood is, unless protective action has been taken, a very common cause of mortality. Major episodes usually occur in children under 2 years of age and the disease usually has a rapid onset characterized by fever, convulsions and early coma. The condition may progress rapidly
as a form of severe sepsis associated with shock and features of the Waterhouse–Friederichsen syndrome. Hemorrhagic features of disseminated intravascular coagulation may also occur. In other cases the clinical picture is dominated by the signs of bacterial meningitis or pneumonia. Osteomyelitis, usually due to Salmonella infection, is characterized by localized and persistent bone pain and extreme tenderness on palpation. Aplastic crises are characterized by symptoms of infection associated with those of sudden and profound anemia. The acute chest syndrome is characterized by shortness of breath, collapse and severe hypoxia, as demonstrated by pulse oximetry and blood gas analysis. Malarial infection is often associated with profound anemia.
The Thalassemias11 The symptoms and signs of patients who have developed severe pneumococcal or related infections after splenectomy are similar to those described above with sickle cell anemia and splenic malfunction. However, patients with severe forms of thalassemia are prone to a wide variety of infections that are often the presenting feature. The clinical picture is characterized by fever, malaise, a worsening of the anemia and, sometimes, increasing splenomegaly. The infections that are caused by Yersinia spp. in iron-loaded patients receiving the chelating agent desferrioxamine are usually characterized by severe abdominal pain, diarrhea, vomiting, fever and a sore throat. Occasionally there may be an associated development of an acute abdomen due to rupture of the bowel. Blood-borne infections with hepatitis B or C viruses may later be associated with the clinical picture of chronic viral hepatitis, often complicated by associated liver damage due to excess iron.
Chapter 122 Infections and the Common Inherited Hemoglobin Disorders
Figure 122-4 A chronic ulcer on the ankle of a patient with β-thalassemia. (From Weatherall D.J., Clegg J.B.: The thalassaemia syndromes, 4th ed. Oxford: Blackwell Science; 2001. Used with permission.)
Chronic leg ulcers, which usually are found on the medial side of the legs just above the ankle, are characterized by persistent pain; in those that become secondarily infected there is usually a purulent discharge (Figure 122-4).
DIAGNOSIS For the diagnosis of the infectious complications of the hemoglobin disorders it is important first to identify the particular disease involved. In sickle cell anemia and its related disorders the diagnosis can be easily achieved by hemoglobin electrophoresis or HPLC analysis. It is very important to also check the parents for the presence of the carrier state for either HbS or a related variant.15 In the β-thalassemias the diagnosis is most easily made by HPLC analysis, which shows high levels of HbF and much reduced or absent levels of HbA.1 Similarly, in HbE β-thalassemia the pattern is characterized by a predominance of HbE with varying levels of HbF, but no HbA. Again it is vital to check the parents; in the β-thalassemias both of them have a raised level of HbA2 while in HbE β-thalassemia one parent has a raised level of HbA2 and the other HbA with approximately 20–30% of HbE. These diagnoses are most easily carried out by HPLC analysis. The more severe form of α-thalassemia, HbH disease, is identified by the presence of variable amounts of HbH associated with HbA and normal or reduced levels of HbA2, again easily identifiable by HPLC analysis.1 These definitive diagnostic tests must be accompanied by detailed hematological studies.1,15 Sickle cell disease is characterized by a variable degree of anemia and the peripheral blood film often shows sickled erythrocytes; the reticulocyte count is always elevated. In all forms of β-thalassemia there is a variable degree of anemia associated with characteristic morphological changes of the red cells which show microcytosis and hypochromia with a varying percentage of target cells. In those with hemoglobin H disease, as well as it showing similar morphological changes of their red cells and a raised reticulocyte count, the presence of HbH can be demonstrated by incubating the
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red cells with brilliant cresyl blue dye followed by a search for red cell inclusion bodies produced by the precipitation of HbH. An accurate diagnosis of the form of hemoglobin disorder and knowledge of the common infectious complications in the different varieties provides a valuable background to the diagnostic tests required for infectious episodes.16,17 In cases of severe pneumococcal sepsis or related infections in babies and young children with defective splenic function in sickle cell anemia, or in those with severe βthalassemia who have been splenectomized, urgent blood cultures are required. In cases in which the physical examination has suggested the possibility of pneumonia or meningitis urgent radiological investigation or lumbar puncture are also indicated. The diagnosis of aplastic crisis in sickle cell anemia due to parvovirus infection can be made on the hematological findings, which show a profound drop in the hemoglobin level associated with the absence of reticulocytes in the peripheral blood; the bone marrow shows marked hypoplasia of the red cell progenitors. In patients with sickle cell anemia and severe bone pain the distinction between Salmonella osteomyelitis and an infarct may be extremely difficult. Radiological studies may not be helpful but the addition of ultrasonography may be helpful in confirming a subperiosteal collection and in guiding aspiration to distinguish between collections of blood or pus.18 The diagnosis is usually confirmed by culture of aspirates. The diagnosis of blood-borne infections in the hemoglobin disorders requires analysis for the different hepatitis viruses, HIV and, in endemic areas, malarial parasites in the peripheral blood. The presence of chronic leg ulcers requires careful culture of the lesions to identify possible secondary infection. The diagnosis of Yersinia infections that mainly affect iron-loaded patients with β-thalassemia requires the assessment of the body iron load by measurement of the serum ferritin level or, better, using hepatic MRI measurements. Appropriate blood cultures are also required. The most difficult differential diagnosis in infectious complications is between pneumonia and pulmonary infarction in the acute chest syndrome in sickle cell anemia.15 Both conditions are associated with pulmonary infiltrates on the chest radiograph. Arterial blood gases may be reduced in both conditions, although the degree of hypoxia is often out of proportion to the consolidation, particularly in cases of pulmonary infarction. The occurrence of fat embolism as the cause of the condition can sometimes be diagnosed by the demonstration of fat-laden macrophages obtained by bronchial lavage.
TREATMENT The acute infections that occur at a particularly high frequency in babies and children with sickle cell anemia during the early years of life, and those that follow splenectomy at any age in patients with severe forms of thalassemia, are treated using similar principles. These infections are medical emergencies requiring a rapid clinical evaluation, blood and urine culture, a complete blood count and a chest radiograph. Those that are severely anemic require immediate cross-match for early transfusion. Although until fairly recently it has been common practice to treat these young children with large doses of penicillin, because of the occurrence of at least partial penicillin resistance and the possibility that other organisms than the pneumococcus may be involved, it is now advised that broad-spectrum antibiotics should be administered intravenously, ceftriaxone for example.19 If penicillin-resistant pneumococcal infection is suspected on epidemiological grounds then a second agent, either vancomycin or rifampin, should be added. Other supportive measures include adequate oxygenation, fluid replacement, the administration of plasma and platelets in cases associated with intravascular coagulation, and the control of convulsions with appropriate anticonvulsant agents. The principles of management of acute infections of this type, or other severe infections, in patients with β-thalassemia who have undergone splenectomy are similar.20 The management of other infectious complications of sickle cell anemia is more straightforward. Following the diagnosis of an aplastic crisis the patient should receive regular blood transfusion to maintain the hemoglobin at its usual steady-state level. Since spontaneous
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recovery usually takes several weeks it is very important that these patients are followed up at regular intervals. The management of Salmonella osteomyelitis requires therapy for at least 4–6 weeks. Chloramphenicol or ampicillin have been widely used for the management of this condition although more recently cefotaxime or ceftriaxone are also proving valuable, particularly in cases where the infection has become disseminated. The chronic leg ulcers that are common in both sickle cell anemia and severe β-thalassemia are best managed with thorough and regular wound toilet, culture and the use of appropriate antibiotics if the lesion has become infected. In cases in which healing does not occur after a reasonable time of conservative management, skin grafts may be required.15,21 The infections that occur with Yersinia spp. are mainly restricted to patients with severe thalassemia on regular transfusion and iron
chelation, although they may occur more commonly in association with sickle cell anemia now that high level transfusion is becoming more common. The iron chelation drug desferrioxamine should be stopped, stool cultures examined for Yersinia spp. and antibiotic treatment administered with either an aminoglycoside or co-trimoxazole. The blood-borne and bone marrow transplant infections that occur in all forms of severe hemoglobin disorders, which are now becoming much less common due to adequate donor screening programs, require appropriate management of the different forms of viral hepatitis, HIV, malaria22 and other viral infections. References available online at expertconsult.com.
KEY REFERENCES Kato G.J., Gladwin M.T.: Mechanisms and clinical complications of hemolysis in sickle cell disease and thalassemia. In: Steinberg M.H., Forget B.G., Higgs D.R., et al., eds. Disorders of hemoglobin. 2nd ed. Cambridge: Cambridge University Press; 2009:201-224. Kitchen A.D., John A.J.B.: Transfusion borne infections. In: Murphy M.E., Pamphilon D.H., eds. Practical transfusion medicine. 2nd ed. Oxford: Blackwell; 2005:208-228. Olivieri N.F., Weatherall D.J.: Clinical aspects of beta thalassemia and related disorders. In: Steinberg M.H., Forget B.G., Higgs D.R., et al., eds. Disorders of hemoglobin. 2nd ed. Cambridge: Cambridge University Press; 2009: 357-416.
Pearson H.A., Gallagher D., Chilcote R., et al.: Developmental pattern of splenic dysfunction in sickle cell disorders. Pediatrics 1985; 76(3):392-397. Serjeant G.R.: Sickle cell disease. 2nd ed. New York: Oxford University Press; 1992. Thein S.L., Wood W.G.: The molecular basis of β-thalassemia, δβ-thalassemia, and hereditary persistence of fetal hemoglobin. In: Steinberg M.H., Forget B.G., Higgs D.R., et al., eds. Disorders of hemoglobin. 2nd ed. Cambridge: Cambridge University Press; 2009:323356. Weatherall D.J., Clegg J.B.: The thalassaemia syndromes. 4th ed. Oxford: Blackwell Science; 2001.
Williams T.N., Obaro S.K.: Sickle cell disease and malaria morbidity: a tale with two tails. Trends Parasitol 2011; 27(7):315-320. Williams T.N., Uyoga S., Macharia A., et al.: Bacteraemia in Kenyan children with sickle-cell anaemia: a retrospective cohort and case-control study. Lancet 2009; 374(9698): 1364-1370. Williams T.N., Weatherall D.J.: World distribution, population genetics, and health burden of the hemoglobinopathies. Cold Spring Harb Perspect Med 2012; 2:a011692.
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REFERENCES 1. Weatherall D.J., Clegg J.B.: The thalassaemia syndromes. 4th ed. Oxford: Blackwell Science; 2001. 2. Williams T.N., Weatherall D.J.: World distribution, population genetics, and health burden of the hemoglobinopathies. Cold Spring Harb Perspect Med 2012; 2:a011692. 3. Williams T.N., Mwangi T.W., Wambua S., et al.: Negative epistasis between the malaria-protective effects of alpha+-thalassemia and the sickle cell trait. Nat Genet 2005; 37(11):1253-1257. 4. Kato G.J., Gladwin M.T.: Mechanisms and clinical complications of hemolysis in sickle cell disease and thalassemia. In: Steinberg M.H., Forget B.G., Higgs D.R., et al., eds. Disorders of hemoglobin. 2nd ed. Cambridge: Cambridge University Press; 2009:201-224. 5. Pearson H.A., Gallagher D., Chilcote R., et al.: Developmental pattern of splenic dysfunction in sickle cell disorders. Pediatrics 1985; 76(3):392-397. 6. Serjeant G.R., Serjeant B.E., Thomas P.W., et al.: Human parvovirus infection in homozygous sickle cell disease. Lancet 1993; 341(8855):1237-1240. 7. Bundy D.G., Strouse J.J., Casella J.F., et al.: Burden of influenza-related hospitalizations among children with sickle cell disease. Pediatrics 2010; 125(2):234-243. 8. Haverfield E.V., McKenzie C.A., Forrester T., et al.: UGT1A1 variation and gallstone formation in sickle cell disease. Blood 2005; 105(3):968-972.
9. Thein S.L., Wood W.G.: The molecular basis of β-thalassemia, δβ-thalassemia, and hereditary persistence of fetal hemoglobin. In: Steinberg M.H., Forget B.G., Higgs D.R., et al., eds. Disorders of hemoglobin. 2nd ed. Cambridge: Cambridge University Press; 2009:323-356. 10. Olivieri N.F., Muraca G.M., O’Donnell A., et al.: Studies in haemoglobin E beta-thalassaemia. Br J Haematol 2008; 141(3):388-397. 11. Olivieri N.F., Weatherall D.J.: Clinical aspects of beta thalassemia and related disorders. In: Steinberg M.H., Forget B.G., Higgs D.R., et al., eds. Disorders of hemoglobin. 2nd ed. Cambridge: Cambridge University Press; 2009:357-416. 12. Williams T.N., Obaro S.K.: Sickle cell disease and malaria morbidity: a tale with two tails. Trends Parasitol 2011; 27(7):315-320. 13. Gaston M.H., Verter J.I., Woods G., et al.: Prophylaxis with oral penicillin in children with sickle cell anemia: a randomized trial. N Engl J Med 1986; 314(25):15931599. 14. Williams T.N., Uyoga S., Macharia A., et al.: Bacteraemia in Kenyan children with sickle-cell anaemia: a retrospective cohort and case-control study. Lancet 2009; 374(9698):1364-1370. 15. Serjeant G.R.: Sickle cell disease. 2nd ed. New York: Oxford University Press; 1992.
16. Akuse R.M.: Variation in the pattern of bacterial infection in patients with sickle cell disease requiring admission. J Trop Pediatr 1996; 42(6):318-323. 17. Okuonghae H.O., Nwankwo M.U., Offor E.C.: Pattern of bacteraemia in febrile children with sickle cell anaemia. Ann Trop Paediatr 1993; 13(1):55-64. 18. Rifai A., Nyman R.: Scintigraphy and ultrasonography in differentiating osteomyelitis from bone infarction in sickle cell disease. Acta Radiol 1997; 38(1):139-143. 19. Wilimas J.A., Flynn P.M., Harris S., et al.: A randomized study of outpatient treatment with ceftriaxone for selected febrile children with sickle cell disease. N Engl J Med 1993; 329(7):472-476. 20. Vento S., Cainelli F., Cesario F.: Infections and thalassaemia. Lancet Infect Dis 2006; 6(4):226-233. 21. Serjeant G.R.: Leg ulceration in sickle cell anemia. Arch Intern Med 1974; 133(4):690-694. 22. Kitchen A.D., John A.J.B.: Transfusion borne infections. In: Murphy M.E., Pamphilon D.H., eds. Practical transfusion medicine. 2nd ed. Oxford: Blackwell; 2005: 208-228.
SECTION 6 International Medicine: Major Tropical Syndromes: Systemic Infections
Infections and the Common Inherited Hemoglobin Disorders THOMAS N. WILLIAMS | DAVID J. WEATHERALL
KEY CONCEPTS • The inherited hemoglobin disorders are the commonest monogenic diseases. Between 300 000 and 400 000 babies are born with them each year. Eighty percent of births are in low- or middle-income countries (LMIC). • The frequency of these diseases is likely to increase significantly in the future. • All these diseases are associated with increased susceptibility to a wide range of infections. • The diagnosis of infection is often complicated by underlying complications of the hemoglobin disorder. • Blood-borne infection is still a major risk, particularly in LMIC. • Because the pattern of infection varies between different types of hemoglobin disorders, an accurate diagnosis of the particular disorder is a vital part of the management of episodes of infection.
Classification and Epidemiology CLASSIFICATION Different forms of hemoglobin (Hb) are produced in embryonic, fetal and adult life, each consisting of pairs of different globin chains. Adult hemoglobin consists of a major component HbA (α2β2) and a minor fraction HbA2 (α2δ2). In fetal life the major hemoglobin is HbF (α2γ2). The inherited disorders of hemoglobin are classified into two major groups (Box 122-1). First there are the structural hemoglobin variants. Although there are many hundreds of these variants, only three reach extremely high frequencies: Hbs S, C and E. The clinical manifestations of Hbs S and C are related to abnormal structure-function mecha-
BOX 122-1 A CLASSIFICATION OF THE COMMON INHERITED HEMOGLOBIN DISORDERS Structural Hemoglobin Variants • HbS • HbC • HbE • Many rarer forms Thalassemias • α-thalassemia • α+-thalassemia • α0-thalassemia • β-thalassemia • β+-thalassemia • β0-thalassemia • δβ-thalassemia Common Compound Heterozygotes • HbS β-thalassemia • HbE β-thalassemia • HbSC disease • α+/α0-thalassemia
nisms, while those of HbE result from its reduced rate of synthesis. Second are the thalassemias, which result from many different mutations that reduce the synthesis of the α- or β-globin chains.1 As shown in Box 122-1 the compound heterozygous inheritance of both structural variants and β-thalassemia, notably HbS β-thalassemia and HbE β-thalassemia, are of considerable clinical importance; globally, HbE β-thalassemia accounts for about 50% of severe cases of β-thalassemia.
EPIDEMIOLOGY The global distribution of Hbs S and E and of the different forms of thalassemia are shown in Figures 122-1 to 122-3 and the reasons for the remarkably high frequency of these diseases are summarized in Box 122-2. Natural selection is of key importance.2 Carriers for the sickle cell, mild forms of α-thalassemia and HbC genes show significant protection against Plasmodium falciparum malaria. There is increasing evidence that the same applies to carriers for HbE or β-thalassemia. The complex mechanisms for this protection are not yet fully understood. It has been found recently that there is complex interplay between these protective mechanisms. For instance, although carriers of the sickle cell and mild α-thalassemia genes are protected against malaria, those that inherit both these genes lose their protection completely.3 Such complex epistatic interactions will undoubtedly be found for other genetic polymorphisms of this type. Other factors that maintain the high frequency of the hemoglobin disorders include a high level of consanguinity in many of the affected populations, the epidemiological transition whereby improvements in public health allow more affected babies to survive to present for treatment, and emigration from high-frequency countries to richerresourced countries where treatment is available for these disorders.
Pathogenesis and Pathology The increased susceptibility to certain forms of infection in patients with inherited disorders of hemoglobin is best understood by first considering their molecular pathology.
SICKLE CELL ANEMIA AND ITS VARIANTS The substitution of valine for glutamic acid at position 6 in the β-globin chain of HbS leads to deformity of the red cells at relatively low oxygen tensions.4 The characteristic sickle shape reflects polymerization of the globin chains and leads to a variable degree of vasoocclusion. The latter results in reperfusion injury characterized by excessive oxidant generation and activation of the endothelium of small vessels with diminished nitric oxide availability. Vascular occlusion leads to widespread complications including early splenic atrophy,
BOX 122-2 FACTORS RESPONSIBLE FOR THE HIGH LEVEL OF INHERITED HEMOGLOBIN DISORDERS • • • • •
Natural selection High frequency of consanguinity Epidemiological transition Population migration Increasing population size
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The global distribution of hemoglobins S and E
HbE
HbS
Figure 122-1 The global distribution of hemoglobins S (HbS) and E (HbE). The patchy distribution of HbS in the New World as a result of emigration from Africa is not shown. (From Weatherall D.J., Clegg J.B.: The thalassaemia syndromes, 4th ed. Oxford: Blackwell Science; 2001. Used with permission.)
infarction of bone marrow leading to painful crises, chronic leg ulcers, vascular complications of the brain, and many other forms of tissue damage. The deformity of the red cells is associated with a hemolytic anemia of varying severity. By far the most important factor in proneness to infection based on the pathophysiology of sickle cell disease is the very early loss of splenic function due to damage to the spleen by the deformed sickle cells.5 Susceptibility to invasive pneumococcal infection is the major cause of early death in babies and young children. There may also be increased proneness to other infections, notably Haemophilus influenzae type B (Hib). The increased frequency of Salmonella osteomyelitis results from infection of the marrow and overlying bone infarcts that occur during painful crises. While there is no evidence of increased susceptibility to viral infections, the aplastic crises that tend to occur in small epidemics are undoubtedly due to parvovirus infection.6 In infections of this type in patients with sickle cell anemia, because of the extremely shortened lifespan of their red cells, profound anemia develops over a very short period. They are also prone to severe complications of influenza, including the precipitation of painful crises.7 The hemolytic anemia results in increased bilirubin production with a high frequency of gallstone formation and associated infection of the gallbladder. There is a high frequency of the genetic mutation that results in Gilbert’s syndrome in those of African origin and those affected are even more prone to this complication.8
THE THALASSEMIAS
The α-thalassemias result from deletions or point mutations in one or both of the linked pairs of α-globin genes (αα/αα).1 They are divided into the α+- and α0-thalassemias. In the former a single α gene is lost by deletion or its function is suppressed by a point mutation, the so-called non-deletion (ND) form (-α/αα, αNDα/αα). Although these are the commonest genetic disorders they are not associated with severe anemia. The α0-thalassemias are characterized by deletion of both of the linked pairs of α-globin genes (–/αα). In the compound heterozygous state for α0-and α+-thalassemia (-α/–) there is significant
imbalance of globin-chain synthesis with the production of excess β-chains which form unstable tetramers called HbH. HbH disease is characterized by a hemolytic anemia of varying severity associated with splenomegaly. The homozygous state for α0-thalassemia (–/–) causes stillbirth. The β-thalassemias result from many different mutations of the β-globin genes (β/β) which result in a variable degree of suppression of globin-chain production leading to an excess of α-chains that precipitate and cause severe damage to the red cell precursors and red cells in the circulation.9 Depending at least in part on the severity of the β-globin gene mutation these conditions vary in their phenotype from β-thalassemia major, which requires lifelong transfusion, to a milder form of the disease called β-thalassemia intermedia. HbE thalassemia shows a wide range of phenotypic expression, from a transfusiondependent disorder like thalassemia major to a condition that is associated with normal growth and development, albeit at a relatively low hemoglobin level.10 Inadequately transfused patients with severe β-thalassemia, as well as profound anemia, develop skeletal deformities due to bone marrow expansion, progressive splenomegaly, defective growth and development, and a wide range of other complications. In well-transfused patients iron loading, both from transfused blood and due to increased iron absorption, is an important complication that has to be dealt with by the administration of chelating agents. The common symptomatic form of α-thalassemia, HbH disease, also shows wide phenotypic diversity depending, at least in part, on the molecular forms of α-thalassemia that have been inherited. Like HbE β-thalassemia, at one end of the spectrum it is a transfusiondependent disorder, mainly due to relatively severe hemolysis. The pattern of infection in the severe β-thalassemias is different to that in sickle cell anemia in many respects.11 Before the days when adequate transfusion levels were achieved, progressive splenomegaly was extremely common, necessitating splenectomy. At that time there was an extremely high rate of infection after splenectomy, particularly in children aged less than 5 years. Although the situation has improved
Chapter 122 Infections and the Common Inherited Hemoglobin Disorders
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The global distribution of the different forms of α-thalassemia
--MED –α 3.7 I αTα
1 – 15%
--SEA 5 – 15% –α 3.7 I –α 4.2 α Tα 60% (–α 3.7) αTα 5 – 40% (–α 3.7 I) α Tα
α+-thalassemia
5 – 80% 40 – 80% (–α 3.7 I) (–α 3.7 II) (–α 4.2)
–α 4.2 –α 3.7 III αTα
α0-thalassemia
Figure 122-2 The global distribution of the different forms of α-thalassemia. The main forms of the disease that are shown are the carrier states for α+-thalassemia and its different forms, -α3.7 I, -α3.7 II, -α3.7 III. The common forms of α0-thalassemia, –αSEA and –αMED are also shown. The very high, if approximate, gene frequencies are also shown, indicating that this is the commonest genetic disease globally. (From Weatherall D.J., Clegg JB.: The thalassaemia syndromes, 4th ed. Oxford: Blackwell Science; 2001. Used with permission.)
considerably following the administration of adequate transfusion and the use of iron chelating agents, progressive splenomegaly is still seen quite often and a significant number of splenectomies are still carried out with the risk of infection with similar organisms to those that occur in sickle cell anemia. Patients with β-thalassemia are also prone to a wide range of other infections.1 Because of transfusion dependence blood-borne infections are still common, notably hepatitis B and C and human immunodeficiency viruses (HIVs). Malaria is also an important blood-borne infection in some of the developing countries in the tropics. The only pathogens that have been shown quite unequivocally to occur with an increased frequency in iron-loaded patients with β-thalassemia are those of the Yersinia genus, which normally have a low rate of pathogenicity and an unusually high requirement for iron. They do not secrete sideropores but have receptors for ferrioxamine and become pathogenic in the presence of iron which is bound to the widely used chelating agent desferrioxamine.11 There have been many reports of severe infections with this organism in patients with severe β-thalassemia. Reports have also documented the occurrence of severe, invasive fungal infections, in particular mucormycosis, in multiplytransfused patients with β-thalassemia, although the mechanism underlying this susceptibility is unclear. Patients with sickle cell anemia, while they are less prone to malaria, have severe complications and a high mortality risk if they are infected.12 There is strong evidence that in the case of Plasmodium vivax malaria carriers for α-thalassemia and patients with HbE β-thalassemia are more susceptible than normal
individuals. This probably reflects the fact that the receptor for P. vivax is the Duffy antigen which is expressed at a higher level on relatively young red cells, which are present in all the hemoglobin disorders.
PREVENTION Marked reduction in the births of babies with serious forms of β-thalassemia and to a lesser extent with sickle cell anemia have been achieved in many countries. Programs of this type rely on intensive public education about the nature of the inherited hemoglobin disorders, prenatal screening of parents to detect those at risk for having an infected child, prenatal diagnosis by analysis of DNA obtained by chorionic villus sampling, and termination of pregnancy in cases in which the genotype is that of sickle cell anemia or a severe form of thalassemia.1 In many of the higher-income countries in which prenatal diagnosis for sickle cell anemia is not yet widely applied, screening of newborn babies at risk is now carried out, either by the use of hemoglobin electrophoresis or high performance liquid chromatography (HPLC) analysis. Early administration of prophylactic penicillin has been shown to deliver a remarkable reduction in early deaths from infection.13 Recent studies in Africa suggest that early deaths are associated with similar organisms to those in the higher-income countries and the development of neonatal diagnosis and prophylaxis of this type is likely to have a major effect in reducing early death rates.14 Vaccination with pneumococcal, Hib and meningococcal vaccines are also being incorporated into these regimens. In the case of the severe forms of
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The world distribution of the β-thalassemias IVS-I-110G→A COD 39 C→T IVS-I-6 T→C IVS-I-1-G→A IVS-II-745 C→G COD 6-A
IVS-I-110G→A COD 39 C→T IVS-II-1 G→A IVS-I-5 G→C COD 8-AA COD 44-C
COD 41/42-TTCT COD 17 A→T IVS-II-654 C→T –28 A→G COD 26 G→A(HbE) IVS-I-5 G→C COD 19 A→G –29 A →G –88 C→T IVS-I-5 G→C COD 8/9 + G IVS-I-1 G→T 619 bp DEL COD 26 G→A(HbE)
Figure 122-3 The world distribution of the β-thalassemias. The remarkable diversity of the different mutations that are involved in β-thalassemia in different ethnic groups are indicated. Those in boxes are the milder β-thalassemia mutations that occur in different populations, particularly in West Africa. (From Weatherall D.J., Clegg J.B.: The thalassaemia syndromes, 4th ed. Oxford: Blackwell Science; 2001. Used with permission.)
α- or β-thalassemia similar regimens are only indicated in those who have undergone splenectomy, regardless of their age. Other important preventive measures for reducing the frequency of infectious complications include prophylaxis for blood-borne infection and malaria. Although the former is particularly relevant to those with transfusion-dependent forms of thalassemia it is becoming important in those with sickle cell anemia because increasing numbers are being placed on regular transfusion, particularly to reduce the frequency of neurological complications. The organisms of particular importance are hepatitis B and C viruses, HIV and malaria. Although donor screening programs have had a major effect in reducing the frequency of blood-borne infections of this type, they still remain a considerable problem in many low- and middle-income countries. Malaria prophylaxis and the use of bednets are vital in countries with a high rate of malaria transmission.
CLINICAL FEATURES The clinical findings of infection in patients with inherited hemoglobin disorders are particularly complex because they are often associated with symptoms and signs of complications of the underlying disorder.
Sickle Cell Anemia and its Variants15 The particularly high frequency of pneumococcal infection in early childhood is, unless protective action has been taken, a very common cause of mortality. Major episodes usually occur in children under 2 years of age and the disease usually has a rapid onset characterized by fever, convulsions and early coma. The condition may progress rapidly
as a form of severe sepsis associated with shock and features of the Waterhouse–Friederichsen syndrome. Hemorrhagic features of disseminated intravascular coagulation may also occur. In other cases the clinical picture is dominated by the signs of bacterial meningitis or pneumonia. Osteomyelitis, usually due to Salmonella infection, is characterized by localized and persistent bone pain and extreme tenderness on palpation. Aplastic crises are characterized by symptoms of infection associated with those of sudden and profound anemia. The acute chest syndrome is characterized by shortness of breath, collapse and severe hypoxia, as demonstrated by pulse oximetry and blood gas analysis. Malarial infection is often associated with profound anemia.
The Thalassemias11 The symptoms and signs of patients who have developed severe pneumococcal or related infections after splenectomy are similar to those described above with sickle cell anemia and splenic malfunction. However, patients with severe forms of thalassemia are prone to a wide variety of infections that are often the presenting feature. The clinical picture is characterized by fever, malaise, a worsening of the anemia and, sometimes, increasing splenomegaly. The infections that are caused by Yersinia spp. in iron-loaded patients receiving the chelating agent desferrioxamine are usually characterized by severe abdominal pain, diarrhea, vomiting, fever and a sore throat. Occasionally there may be an associated development of an acute abdomen due to rupture of the bowel. Blood-borne infections with hepatitis B or C viruses may later be associated with the clinical picture of chronic viral hepatitis, often complicated by associated liver damage due to excess iron.
Chapter 122 Infections and the Common Inherited Hemoglobin Disorders
Figure 122-4 A chronic ulcer on the ankle of a patient with β-thalassemia. (From Weatherall D.J., Clegg J.B.: The thalassaemia syndromes, 4th ed. Oxford: Blackwell Science; 2001. Used with permission.)
Chronic leg ulcers, which usually are found on the medial side of the legs just above the ankle, are characterized by persistent pain; in those that become secondarily infected there is usually a purulent discharge (Figure 122-4).
DIAGNOSIS For the diagnosis of the infectious complications of the hemoglobin disorders it is important first to identify the particular disease involved. In sickle cell anemia and its related disorders the diagnosis can be easily achieved by hemoglobin electrophoresis or HPLC analysis. It is very important to also check the parents for the presence of the carrier state for either HbS or a related variant.15 In the β-thalassemias the diagnosis is most easily made by HPLC analysis, which shows high levels of HbF and much reduced or absent levels of HbA.1 Similarly, in HbE β-thalassemia the pattern is characterized by a predominance of HbE with varying levels of HbF, but no HbA. Again it is vital to check the parents; in the β-thalassemias both of them have a raised level of HbA2 while in HbE β-thalassemia one parent has a raised level of HbA2 and the other HbA with approximately 20–30% of HbE. These diagnoses are most easily carried out by HPLC analysis. The more severe form of α-thalassemia, HbH disease, is identified by the presence of variable amounts of HbH associated with HbA and normal or reduced levels of HbA2, again easily identifiable by HPLC analysis.1 These definitive diagnostic tests must be accompanied by detailed hematological studies.1,15 Sickle cell disease is characterized by a variable degree of anemia and the peripheral blood film often shows sickled erythrocytes; the reticulocyte count is always elevated. In all forms of β-thalassemia there is a variable degree of anemia associated with characteristic morphological changes of the red cells which show microcytosis and hypochromia with a varying percentage of target cells. In those with hemoglobin H disease, as well as it showing similar morphological changes of their red cells and a raised reticulocyte count, the presence of HbH can be demonstrated by incubating the
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red cells with brilliant cresyl blue dye followed by a search for red cell inclusion bodies produced by the precipitation of HbH. An accurate diagnosis of the form of hemoglobin disorder and knowledge of the common infectious complications in the different varieties provides a valuable background to the diagnostic tests required for infectious episodes.16,17 In cases of severe pneumococcal sepsis or related infections in babies and young children with defective splenic function in sickle cell anemia, or in those with severe βthalassemia who have been splenectomized, urgent blood cultures are required. In cases in which the physical examination has suggested the possibility of pneumonia or meningitis urgent radiological investigation or lumbar puncture are also indicated. The diagnosis of aplastic crisis in sickle cell anemia due to parvovirus infection can be made on the hematological findings, which show a profound drop in the hemoglobin level associated with the absence of reticulocytes in the peripheral blood; the bone marrow shows marked hypoplasia of the red cell progenitors. In patients with sickle cell anemia and severe bone pain the distinction between Salmonella osteomyelitis and an infarct may be extremely difficult. Radiological studies may not be helpful but the addition of ultrasonography may be helpful in confirming a subperiosteal collection and in guiding aspiration to distinguish between collections of blood or pus.18 The diagnosis is usually confirmed by culture of aspirates. The diagnosis of blood-borne infections in the hemoglobin disorders requires analysis for the different hepatitis viruses, HIV and, in endemic areas, malarial parasites in the peripheral blood. The presence of chronic leg ulcers requires careful culture of the lesions to identify possible secondary infection. The diagnosis of Yersinia infections that mainly affect iron-loaded patients with β-thalassemia requires the assessment of the body iron load by measurement of the serum ferritin level or, better, using hepatic MRI measurements. Appropriate blood cultures are also required. The most difficult differential diagnosis in infectious complications is between pneumonia and pulmonary infarction in the acute chest syndrome in sickle cell anemia.15 Both conditions are associated with pulmonary infiltrates on the chest radiograph. Arterial blood gases may be reduced in both conditions, although the degree of hypoxia is often out of proportion to the consolidation, particularly in cases of pulmonary infarction. The occurrence of fat embolism as the cause of the condition can sometimes be diagnosed by the demonstration of fat-laden macrophages obtained by bronchial lavage.
TREATMENT The acute infections that occur at a particularly high frequency in babies and children with sickle cell anemia during the early years of life, and those that follow splenectomy at any age in patients with severe forms of thalassemia, are treated using similar principles. These infections are medical emergencies requiring a rapid clinical evaluation, blood and urine culture, a complete blood count and a chest radiograph. Those that are severely anemic require immediate cross-match for early transfusion. Although until fairly recently it has been common practice to treat these young children with large doses of penicillin, because of the occurrence of at least partial penicillin resistance and the possibility that other organisms than the pneumococcus may be involved, it is now advised that broad-spectrum antibiotics should be administered intravenously, ceftriaxone for example.19 If penicillin-resistant pneumococcal infection is suspected on epidemiological grounds then a second agent, either vancomycin or rifampin, should be added. Other supportive measures include adequate oxygenation, fluid replacement, the administration of plasma and platelets in cases associated with intravascular coagulation, and the control of convulsions with appropriate anticonvulsant agents. The principles of management of acute infections of this type, or other severe infections, in patients with β-thalassemia who have undergone splenectomy are similar.20 The management of other infectious complications of sickle cell anemia is more straightforward. Following the diagnosis of an aplastic crisis the patient should receive regular blood transfusion to maintain the hemoglobin at its usual steady-state level. Since spontaneous
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recovery usually takes several weeks it is very important that these patients are followed up at regular intervals. The management of Salmonella osteomyelitis requires therapy for at least 4–6 weeks. Chloramphenicol or ampicillin have been widely used for the management of this condition although more recently cefotaxime or ceftriaxone are also proving valuable, particularly in cases where the infection has become disseminated. The chronic leg ulcers that are common in both sickle cell anemia and severe β-thalassemia are best managed with thorough and regular wound toilet, culture and the use of appropriate antibiotics if the lesion has become infected. In cases in which healing does not occur after a reasonable time of conservative management, skin grafts may be required.15,21 The infections that occur with Yersinia spp. are mainly restricted to patients with severe thalassemia on regular transfusion and iron
chelation, although they may occur more commonly in association with sickle cell anemia now that high level transfusion is becoming more common. The iron chelation drug desferrioxamine should be stopped, stool cultures examined for Yersinia spp. and antibiotic treatment administered with either an aminoglycoside or co-trimoxazole. The blood-borne and bone marrow transplant infections that occur in all forms of severe hemoglobin disorders, which are now becoming much less common due to adequate donor screening programs, require appropriate management of the different forms of viral hepatitis, HIV, malaria22 and other viral infections. References available online at expertconsult.com.
KEY REFERENCES Kato G.J., Gladwin M.T.: Mechanisms and clinical complications of hemolysis in sickle cell disease and thalassemia. In: Steinberg M.H., Forget B.G., Higgs D.R., et al., eds. Disorders of hemoglobin. 2nd ed. Cambridge: Cambridge University Press; 2009:201-224. Kitchen A.D., John A.J.B.: Transfusion borne infections. In: Murphy M.E., Pamphilon D.H., eds. Practical transfusion medicine. 2nd ed. Oxford: Blackwell; 2005:208-228. Olivieri N.F., Weatherall D.J.: Clinical aspects of beta thalassemia and related disorders. In: Steinberg M.H., Forget B.G., Higgs D.R., et al., eds. Disorders of hemoglobin. 2nd ed. Cambridge: Cambridge University Press; 2009: 357-416.
Pearson H.A., Gallagher D., Chilcote R., et al.: Developmental pattern of splenic dysfunction in sickle cell disorders. Pediatrics 1985; 76(3):392-397. Serjeant G.R.: Sickle cell disease. 2nd ed. New York: Oxford University Press; 1992. Thein S.L., Wood W.G.: The molecular basis of β-thalassemia, δβ-thalassemia, and hereditary persistence of fetal hemoglobin. In: Steinberg M.H., Forget B.G., Higgs D.R., et al., eds. Disorders of hemoglobin. 2nd ed. Cambridge: Cambridge University Press; 2009:323356. Weatherall D.J., Clegg J.B.: The thalassaemia syndromes. 4th ed. Oxford: Blackwell Science; 2001.
Williams T.N., Obaro S.K.: Sickle cell disease and malaria morbidity: a tale with two tails. Trends Parasitol 2011; 27(7):315-320. Williams T.N., Uyoga S., Macharia A., et al.: Bacteraemia in Kenyan children with sickle-cell anaemia: a retrospective cohort and case-control study. Lancet 2009; 374(9698): 1364-1370. Williams T.N., Weatherall D.J.: World distribution, population genetics, and health burden of the hemoglobinopathies. Cold Spring Harb Perspect Med 2012; 2:a011692.
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REFERENCES 1. Weatherall D.J., Clegg J.B.: The thalassaemia syndromes. 4th ed. Oxford: Blackwell Science; 2001. 2. Williams T.N., Weatherall D.J.: World distribution, population genetics, and health burden of the hemoglobinopathies. Cold Spring Harb Perspect Med 2012; 2:a011692. 3. Williams T.N., Mwangi T.W., Wambua S., et al.: Negative epistasis between the malaria-protective effects of alpha+-thalassemia and the sickle cell trait. Nat Genet 2005; 37(11):1253-1257. 4. Kato G.J., Gladwin M.T.: Mechanisms and clinical complications of hemolysis in sickle cell disease and thalassemia. In: Steinberg M.H., Forget B.G., Higgs D.R., et al., eds. Disorders of hemoglobin. 2nd ed. Cambridge: Cambridge University Press; 2009:201-224. 5. Pearson H.A., Gallagher D., Chilcote R., et al.: Developmental pattern of splenic dysfunction in sickle cell disorders. Pediatrics 1985; 76(3):392-397. 6. Serjeant G.R., Serjeant B.E., Thomas P.W., et al.: Human parvovirus infection in homozygous sickle cell disease. Lancet 1993; 341(8855):1237-1240. 7. Bundy D.G., Strouse J.J., Casella J.F., et al.: Burden of influenza-related hospitalizations among children with sickle cell disease. Pediatrics 2010; 125(2):234-243. 8. Haverfield E.V., McKenzie C.A., Forrester T., et al.: UGT1A1 variation and gallstone formation in sickle cell disease. Blood 2005; 105(3):968-972.
9. Thein S.L., Wood W.G.: The molecular basis of β-thalassemia, δβ-thalassemia, and hereditary persistence of fetal hemoglobin. In: Steinberg M.H., Forget B.G., Higgs D.R., et al., eds. Disorders of hemoglobin. 2nd ed. Cambridge: Cambridge University Press; 2009:323-356. 10. Olivieri N.F., Muraca G.M., O’Donnell A., et al.: Studies in haemoglobin E beta-thalassaemia. Br J Haematol 2008; 141(3):388-397. 11. Olivieri N.F., Weatherall D.J.: Clinical aspects of beta thalassemia and related disorders. In: Steinberg M.H., Forget B.G., Higgs D.R., et al., eds. Disorders of hemoglobin. 2nd ed. Cambridge: Cambridge University Press; 2009:357-416. 12. Williams T.N., Obaro S.K.: Sickle cell disease and malaria morbidity: a tale with two tails. Trends Parasitol 2011; 27(7):315-320. 13. Gaston M.H., Verter J.I., Woods G., et al.: Prophylaxis with oral penicillin in children with sickle cell anemia: a randomized trial. N Engl J Med 1986; 314(25):15931599. 14. Williams T.N., Uyoga S., Macharia A., et al.: Bacteraemia in Kenyan children with sickle-cell anaemia: a retrospective cohort and case-control study. Lancet 2009; 374(9698):1364-1370. 15. Serjeant G.R.: Sickle cell disease. 2nd ed. New York: Oxford University Press; 1992.
16. Akuse R.M.: Variation in the pattern of bacterial infection in patients with sickle cell disease requiring admission. J Trop Pediatr 1996; 42(6):318-323. 17. Okuonghae H.O., Nwankwo M.U., Offor E.C.: Pattern of bacteraemia in febrile children with sickle cell anaemia. Ann Trop Paediatr 1993; 13(1):55-64. 18. Rifai A., Nyman R.: Scintigraphy and ultrasonography in differentiating osteomyelitis from bone infarction in sickle cell disease. Acta Radiol 1997; 38(1):139-143. 19. Wilimas J.A., Flynn P.M., Harris S., et al.: A randomized study of outpatient treatment with ceftriaxone for selected febrile children with sickle cell disease. N Engl J Med 1993; 329(7):472-476. 20. Vento S., Cainelli F., Cesario F.: Infections and thalassaemia. Lancet Infect Dis 2006; 6(4):226-233. 21. Serjeant G.R.: Leg ulceration in sickle cell anemia. Arch Intern Med 1974; 133(4):690-694. 22. Kitchen A.D., John A.J.B.: Transfusion borne infections. In: Murphy M.E., Pamphilon D.H., eds. Practical transfusion medicine. 2nd ed. Oxford: Blackwell; 2005: 208-228.