state of the art review
How we prevent and manage infection in sickle cell disease Amy Sobota,1,2 Vishakha Sabharwal,1,2 Gwendoline Fonebi1,3 and Martin Steinberg1,3 1
Boston University School of Medicine, 2Department of Pediatrics, Boston Medical Center, and 3Department of Medicine, Boston Medical Center, Boston, MA, USA
Summary Sickle cell disease (SCD) affects approximately 100 000 people in the US, 12 500 in the UK, and millions worldwide. SCD is typified by painful vaso-occlusive episodes, haemolytic anaemia and organ damage. A secondary complication is infection, which can be bacterial, fungal or viral. Universal newborn screening, routine use of penicillin prophylaxis, availability of conjugated vaccines against S. pneumoniae and comprehensive care programmes instituted during the past few decades in industrialized countries have dramatically reduced childhood mortality and improved life expectancy. Yet patients with SCD remain at increased risk of infection. Unfortunately, the treatment of most bacterial infections that are common in SCD is not based on the results of randomized controlled clinical trials. In their absence, treatment decisions are based on consensus guidelines, clinical experience or adapting treatment applied in other diseases. This leads to wide variation in treatment among institutions and even between treating physicians in a single institution. Prevention of infection, when possible, is most important and we focus on prevention through targeted prophylaxis and vaccination. We will share our management strategies for managing the more common infections in SCD and provide the rationale for our recommendations. Keywords: bacteraemia, vaccination, S. pneumoniae, acute chest syndrome. Sickle cell disease (SCD) affects approximately 100 000 people in the US, 12 500 in the UK, similar numbers in France and millions in Africa, the Mediterranean basin, the Middle East, India and Brazil. The numbers of those affected is likely to grow.(Hassell, 2010; Piel et al, 2013a,b) SCD is typified by painful vaso-occlusive episodes, haemolytic anaemia and organ damage as an end result of deoxyHbS polymerization.(Steinberg et al, 2009) A secondary complication is infection, which can be bacterial, fungal or viral. Universal
Correspondence: Amy Sobota, MD MPH, 850 Harrison Avenue Yawkey Ambulatory Care Center 4S-11, Boston, MA 02118, USA. Email: [email protected]
ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 757–767
newborn screening, routine use of penicillin prophylaxis, availability of conjugated vaccines against S. pneumoniae and comprehensive care programmes instituted during the past few decades in industrialized countries have dramatically reduced childhood mortality and improved life expectancy.(Hassell, 2010; Quinn et al, 2010) However, patients with SCD remain at increased risk of infection. Unfortunately the treatment of most bacterial infections that are common in SCD is not based on the results of randomized controlled clinical trials. In their absence treatment decisions are based on consensus guidelines, clinical experience or adapting treatment applied in other diseases. This leads to wide variation in treatment among institutions and even between treating physicians in a single institution. Prevention of infection is the goal, when possible. This review focuses on prevention through targeted antibiotic prophylaxis and vaccination. We will also share our management strategies for managing the more common infections in SCD and provide the rationale for our recommendations.
Malaria The high incidence of the sickle cell trait is a result of the selective pressure of endemic falciparum malaria. Trait carriers have reduced parasite density and less severe malaria.(Aidoo et al, 2002; Goncalves et al, 2014) Given the strong protective effect of HbS it is possible that homozygotes for the HBB E6V mutation (HbS homozygotes) have a greater degree of protection than trait carriers [discussed in by McAuley et al (2010)]. Although there was no evidence that patients with SCD had an increased risk for developing uncomplicated or complicated malaria, when malaria was present the mortality rate was higher compared with the general population. This suggested the important role of effective malaria prophylaxis for individuals with SCD. However, other than insecticide-impregnated netting, the choice of a suitable antimalarial has been difficult.( McAuley et al, 2010; Makani et al, 2013) Half of the children with SCD who contract malaria have acute painful episodes and severe haemolytic anaemia requiring transfusion.(Aloni et al, 2013) Other evidence suggests that malaria is an important cause of death in SCD in patients outside the hospital.(Makani et al, 2010) Readers are directed to a current review for further data on First published online 27 May 2015 doi: 10.1111/bjh.13526
Review reducing morbidity from malaria in SCD. (Aneni et al, 2013).
Human immunodeficiency virus (HIV) HIV and SCD often coexist in the same populations due to overlap of endemic regions [World Health Organization (WHO) 2006; Owusu et al, 2015]. HIV-infected children with SCD have more complicated hospitalizations.(Kourtis et al, 2007) HIV infection also increases the risk of sepsis. One study showed that HIV infection was less common in SCD than controls.(Nouraie et al, 2012) This led to the speculation that SCD might make it more difficult to become infected with HIV or alter the progression of HIV infection. It was suggested that when HIV and SCD coexist, host factors, such as asplenia, might retard HIV progression.(Bagasra et al, 1998) Additionally, hydroxycarbamide (hydroxyurea), the major drug treatment for SCD, has activity in HIV infection and is synergistic with some reverse transcriptase inhibitors.(Lori & Lisziewicz, 2000) HIV infection has also been associated with haemolytic anaemia, pulmonary hypertension and osteonecrosis, all common complications of SCD. Blood transfusions, especially in areas of the developing world, are an additional risk factor for transmission of infection in SCD. (Diarra et al, 2013).
Other viral diseases The incidence of hepatitis C and hepatitis B is highly dependent on the safety of the blood supply. It has been recommended that screening for hepatitis C be done in multiply transfused patients, which include most patients with SCD, and that screening be offered to all adults born between 1945 and 1965. B19 human parvovirus causes transient erythroid aplasia that is clinically evident in patients with haemolytic anaemia. It is the major cause of acute aplastic episodes in SCD (Serjeant et al, 1993) and has also been associated with acute chest syndrome (ACS), splenic and hepatic sequestration, bone marrow necrosis, painful episodes and cerebrovascular disease (including stroke, silent infarct and seizures). (Wierenga et al, 2001; Smith-Whitley et al, 2004; Dowling et al, 2012) When acute anaemia from transient erythroid aplasia causes cardiovascular compromise, transfusions might be necessary. High titres of IgG anti-B19 parvovirus antibodies suggest past infection and lasting protection; with acute infection, the IgM titre increases. A safe and effective vaccine has yet to be marketed. Individuals with SCD are at high risk for complications from influenza.(Strouse et al, 2010) Children with SCD are hospitalized for influenza at a rate 56-times that of children without SCD.(Bundy et al, 2010).
Risk of bacterial infection Bacterial infections are a major cause of morbidity and mortality in SCD.(Adamkiewicz et al, 2003) This increased sus758
ceptibility is mainly a result of impaired splenic function, however other factors, such as defects in complement activation, micronutrient deficiencies, tissue ischemia and inflammation also contribute.(Booth et al, 2010) S. pneumoniae, H. influenzae type b, and non-typhi Salmonella species, have been identified as important causes of infection in SCD. Other bacteria associated with frequent infections in SCD include Mycoplasma and C. pneumoniae, which cause pneumonia, ACS and Yersinia enterocolitis. Substantial improvements in prognosis have followed the introduction of penicillin prophylaxis and immunization with conjugate vaccines directed against S. pneumoniae and H. influenzae type b. The rate of invasive S. pneumoniae disease among children with SCD aged 20 years.(Castro et al, 1994) As increasing numbers of patients of all ages in developed countries now receive hydroxycarbamide, the incidence of ACS is likely to have fallen as this drug decreases its incidence by up to 40%.(Charache et al, 1996). ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 757–767
Osteomyelitis/Septic arthritis An increased risk of osteomyelitis in SCD is attributed to splenic dysfunction, sickle cell-induced damage to bone and bone marrow and, perhaps, bowel ischaemia. Vaso-occlusion may lead to infarction of the gut, permitting invasion by Salmonella and other enteric organisms. Reduced function of the liver and spleen, together with interference with reticuloendothelial system function due to erythrophagocytosis, suppresses clearing of these organisms from the blood stream. The expanded bone marrow with sluggish flow leads to an ischemic focus for Salmonella localization. Most Salmonella infections in SCD involve long bones and joints, can be symmetrical and occur most frequently in early childhood.( Epps et al, 1991; Chambers et al, 2000) SCD has classically been associated with Salmonella abscesses of the spleen, but more recent series noted a predominance of Staphylococcal infection associated with this condition.(Neonato et al, 2000) In 299 HbS homozygotes the prevalence of osteomyelitis was 12%.(Neonato et al, 2000) In a small study, HLA class II DRB1* 15 had a protective effect against infectious complications, including osteomyelitis, whereas patients with HLA class II DQB1* 03 were more susceptible to serious infections.(Tamouza et al, 2002) A mechanism for this possible association was not proposed. Associations of the HLA locus with many different infections might be a result of modulation of the immune response although the bulk of genes associated with infection are outside of this locus.(Hill, 1998). The most common sites of osteomyelitis tend to be previous areas of infarcted bone or bone marrow.( Barrett-Connor, 1971; Bennett & Namnyak, 1990; Anand & Glatt, 1994) In a retrospective study, the prevalence of septic arthritis in 2000 adult patients was 03% compared with 7% cases of osteomyelitis.(Hernigou et al, 2010). Causative pathogens. In the general population S. aureus is the most common pathogen causing osteomyelitis. In SCD, Salmonella species, other Gram-negative pathogens and S. aureus were the most common isolates in adults.(Burnett et al, 1998; Sadat-Ali, 1998) Salmonella bacteraemia, whose incidence peaks in children aged between 2 and 10 years, is associated with a 77% incidence of osteomyelitis.(Zarkowsky et al, 1986) Multiple sites are often involved. S. aureus is also a common pathogen in both osteomyelitis and septic arthritis.( Sankaran-Kutty et al, 1988; Thanni, 2006; Hernigou et al, 2010). Diagnosis. Diagnosing osteomyelitis and septic arthritis in individuals with SCDs can be challenging, as the clinical findings can be similar to those of vaso-occlusive episodes. Magnetic resonance imaging and bone scintigram can sometimes help identify foci of infection. In a multivariate analysis, children with proven osteomyelitis had limb swelling and more days of pain and fever preceding the diagnosis when ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 757–767
compared with controls with uncomplicated vaso-occlusive episodes.(Berger et al, 2009) Bone biopsy or aspiration of a suspected infection site is the gold standard for diagnosis, despite substantial false negative rates. Treatment. In the absence of randomized controlled trials evidence is lacking about best practices.(Marti-Carvajal & Agreda-Perez, 2012) Targeted antibiotics should be started as soon as bone or articular infection is suspected. Incision and drainage should be undertaken in any case with abscess formation, or if a patient does not respond to initial therapy. Bone and soft tissue debridement might also be necessary, especially in cases of infections with MRSA. Whether concurrent bone debridement is performed will depend on the clinical stability of the patient. The ideal choice of antibiotic will be guided by culture results; however empiric antibiotic choices include drugs with good coverage of S. aureus, such as nafcillin, clindamycin, first-generation cephalosporins and vancomycin. In communities with high rates of MRSA, vancomycin should be used. Treatment is typically required for 4–6 weeks.(Harik & Smeltzer, 2010).
Leg ulcers Chronic leg ulcers are a frequent and debilitating complication of SCD. Infection is a complication, rather than a cause, of leg ulcers. Secondary infection of ulcers may occur spontaneously or be a result of trauma. The most commonly isolated bacteria are S. aureus, Pseudomonas, Streptococci, or Bacteroides.(Sehgal & Arunkumar, 1992) Very rarely are these ulcers the source of systemic infections or sepsis. There are no clinical trials of systemic antimicrobials.(Marti-Carvajal et al, 2012). Topical antibiotics are often used. Single institution experiences have suggested improved wound healing when agents like Neomycin, Polymyxin B and Bacitracin are combined with local standard of care compared with standard of care alone but these results cannot be generalized.(Baum et al, 1987).
Meningitis Meningitis from encapsulated bacteria, especially S. pneumoniae, was a major cause of morbidity and mortality in children, but the introduction of vaccination and prophylactic penicillin was associated with a decline in incidence. In a Jamaican cohort study between 1995 and 1999, 23% of 111 patients with pneumococcal infection also met diagnostic criteria for meningitis. Four of these patients (16%) also had SCD, giving a 53% increase in risk.(Trotman et al, 2009) These children were not vaccinated. S. pneumoniae meningitis is extremely rare in adults with SCD, although it remains associated with high mortality. In a series of six patients aged 18–34 years with pneumococcal meningitis, only one of whom was vaccinated, two died. (Olopoenia et al, 1990) In 763
Review the vaccinated patients, the serotype of the infecting organism was not present in the vaccine. Individuals with SCD suspected of having meningitis should have a lumbar puncture and be started on broad spectrum antibiotics. Antibiotics should include a third generation cephalosporin plus vancomycin and ampicillin for patients aged >50 years. The rationale behind this approach is that S. pneumoniae, N. meningitidis and, less often, H. influenzae and group B streptococcus are the most likely causes of community-acquired bacterial meningitis in otherwise healthy adults up to age 60 years, at least in the US.(Schuchat et al, 1997).
Future directions Managing bacterial infection in SCD will most probably never be informed by the results of controlled clinical trials. At best, we can hope for consensus guidelines, but history suggests that their general application will be poorly followed. Because of the geographically diverse phenotypes of disease, varying practices for using antimicrobials, different distributions of infecting organisms and regional variation in antibiotic susceptibility profiles, guidelines are likely to differ considerably worldwide so that universally used treatment approaches cannot be expected. As infectious complications become less common in SCD because of the expanding use of prophylactic measures and perhaps hydroxycarbamide treatment, additional education is needed for primary and subspecialty care providers, patients and their families about
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Author contribution All authors contributed to the design of the review, wrote sections of the manuscript, and approved the final version. AS was supported during the writing of this manuscript by the Harvard Blood Scholars K12 Clinical Hematology Research Career Development Program.
Conflict of interest The authors have no competing interests.
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