Guideline on the management of acute chest syndrome in sickle cell disease

Sickle cell disease (SCD) affects 12 000–15 000 individuals in the UK. Whilst homozygous SCD (sickle cell anaemia — HbSS) is the most common and severe genotype, and is where most of the evidence exists, this guidance should be used for all genotypes of SCD. Acute chest syndrome (ACS) is defined as an acute illness characterized by fever and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on chest X-ray (Charache et al, 1979; Ballas et al, 2010). This definition encompasses cases both where an infective organism is isolated and where no infective cause is identified. It is unique to SCD but in some cases ACS may appear to be similar to bacterial pneumonia in a patient without SCD. ACS may have a severe clinical course and can progress rapidly from mild hypoxia to respiratory failure and death. The presence of hypoxia is not included in the definition, but in clinical practice, hypoxia is a useful predictor of severity and outcome (Vichinsky et al, 1997, 2000). Historically, ACS is one of the most common causes of death in patients with SCD (Platt et al, 1994; Lucas et al, 2008), although mortality is improving with improved medical management (Fitzhugh et al, 2010). ACS can also be associated with significant morbidity, including long-term parenchymal lung damage, pulmonary vascular abnormality and neurological sequelae. Patients may present to hospital acutely unwell with ACS or ACS may develop during a hospital admission following a painful crisis or post-operatively. This guideline will be useful for clinicians working in both high and low prevalence areas and may serve as the foundation for clinical governance measures that can be introduced in individual units with the aim of improving care for patients with SCD. It can be used to inform local pathways and protocols, and we recommend that all acute healthcare organizations should have a protocol for management of this condition (Sickle Cell Society, 2008). In specialist centres such pathways and protocols will be developed locally, but smaller centres should consider linking with a nearby specialist centre and using a shared protocol. Units in acute healthcare organizations in low prevalence areas who may only rarely be confronted with ACS should have clear guidance on: (i) which specialist centre to seek advice from, (ii) criteria for transfer to the specialist centre and (iii) criteria for transfer to a critical care intensive care unit (ICU) (level 3) or high dependency unit (HDU) (level 2). The guideline group was selected by the British Committee for Standards in Haematology (BCSH) to be representative of UK-based medical experts. MEDLINE and EMBASE were searched systematically for publications from 1966 until April 2013 using a variety of key words. The writing group produced the draft guideline, which was subsequently considered by the members of the General Haematology Task Force of the BCSH. The guideline was then reviewed by a sounding board of approximately 50 UK haematologists and members of the BCSH and British Society of Haematology Committee, patient representatives and other interested parties. Comments were incorporated where appropriate. The 'GRADE' system was used to quote levels and grades of evidence, details of which can be found in Appendix I. Criteria used to quote levels and grades of evidence are as outlined in the Procedure for Guidelines Commissioned by the BCSH (Appendix I). Acute chest syndrome refers to a spectrum of disease from a mild pneumonic illness to acute respiratory distress syndrome and multi-organ failure. The initial insult, which may be pulmonary infection, fat embolism and/or pulmonary infarction, causes a fall in alveolar oxygenation tension, which causes HbS polymerization. This, in turn, leads to decreased pulmonary blood flow that exacerbates vaso-occlusion, producing more severe hypoxia such that a vicious cycle of hypoxia, HbS polymerization, vaso-occlusion and altered pulmonary blood flow ensues. There is evidence that VCAM1, which is up-regulated by hypoxia and fat embolism, has a role in the development of ACS as an inducer of red cell adhesion It contributes to increased adherence of red cells to the respiratory endothelium and increased vaso-occlusion within the pulmonary circulation, leading to increased hypoxia (Stuart Dean et al, 2003; Neumayr et al, 2003). The prevalence of both viruses and atypical bacteria as common causes of infection suggest that the clinician must carefully consider the antimicrobial agents prescribed, which should provide coverage against atypical bacteria. The clinical course of ACS is significantly different to that of infectious pneumonia in non-sickle individuals, which is probably because of the damaged microvasculature of the lung in individuals with SCD (Ballas et al, 2010). Acute chest syndrome may also be caused by fat embolism. During a painful crisis, vaso-occlusion within the bones leads to bone marrow necrosis and the release of fat emboli. These enter the blood stream and lodge in the pulmonary vasculature causing acute hypoxia. Evidence of fat emboli has been shown on autopsy studies, and fat-laden macrophages have also been found in bronchoalveolar fluid and in induced sputum (Vichinsky et al, 1994). In situ microvascular occlusion and pulmonary infarction can also be associated with ACS and it can be secondary to hypoventilation, causing pulmonary atelectasis, hypoxia and pulmonary intravascular sickling. Microvascular pulmonary infarction must be distinguished from pulmonary embolism, which can present with chest pain and tachypnoea but without a new infiltrate on chest X-ray. Whilst this group of patients have a hypercoagulable state and are at an increased risk of pulmonary embolism, the clinical picture is usually distinct from ACS. Severe bony pain from rib infarcts can lead to splinting and regional hypoventilation in the areas of pain (Rucknagel et al, 1991; Gelfand et al, 1993). Alveolar hypoventilation can also occur secondary to opiate narcosis or in the post-operative period, following a general anaesthetic (Vichinsky et al, 2000). A pre-existing diagnosis of asthma has been shown to be associated with an increased incidence of ACS in children (Boyd et al, 2006). A cohort of 291 infants followed by the Cooperative Study of Sickle Cell Disease for up to 20 years found that 16·8% had asthma and those with asthma has almost twice as many episodes of ACS (0·39 episodes per patient year vs. 0·20 episodes per patient year; P < 0·001) (Boyd et al, 2006). Those with SCD and asthma were younger at their first presentation with ACS with a median age of 2·4 years (Boyd et al, 2006). Bronchospasm and wheeze are common in the context of ACS, and may contribute to local hypoxia. They are most frequently seen in children and commonly have a viral aetiology. Acute chest syndrome is defined as an acute illness characterized by fever and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on chest X-ray. Severe hypoxia is a useful predictor of severity and outcome (1B). Acute chest syndrome has a multifactorial aetiology and an infective cause is common and this should be considered in treatment algorithms (1B). Acute chest syndrome is the second most common reason for hospitalization in SCD and is a leading cause of morbidity and mortality. The clinical features of ACS may not be evident at the time of admission. Nearly half of patients present initially with a painful vaso-occlusive crisis and then develop this complication whilst in hospital. ACS will often develop 24–72 h after the onset of severe pain (Gladwin Henderson et al, 2003). An acute drop in haemoglobin concentration with an associated increase in markers of haemolysis prior to the onset of ACS is common. Reported falls from steady state haemoglobin values have varied from 7 g/l for all genotypes (Vichinsky et al, 1997), to 16–22·5 g/l depending on genotype (Maitre et al, 2000). A greater fall in haemoglobin values has been documented for cases with bilateral lung involvement than for unilateral disease (28·3 g/l vs. 13·3 g/l) (Davies et al, 1984). Acute chest syndrome remains a leading cause of premature mortality in SCD. In a recent national survey in the United Kingdom, ACS was the third most common cause of death reported in adults (Lucas et al, 2008). It is a recognized risk factor for early death in HbSS patients above the age of 20 years (Platt et al, 1994). Respiratory failure is the most common cause of death. Other causes of death in these patients included pulmonary haemorrhage, cor pulmonale, overwhelming sepsis and cerebrovascular events. Mortality rates in ACS will be dependent in part on the appropriateness of medical management. Even with good medical treatment, overall mortality rates of up to 3% are reported, with the overall death rate in adults being four times higher than in children (Vichinsky et al, 1997, 2000). The diagnosis of ACS is typically straightforward when a high level of clinical suspicion is combined with the usual clinical features. In this scenario, the appearance of consolidation on a plain chest X-ray in a sickle cell patient with recent onset hypoxia, tachypnoea, chest signs, fever and chest pain is diagnostic (Vichinsky et al, 2000). However, the diagnosis can be difficult because (i) adult patients are often afebrile (Vichinsky et al, 1997); (ii) clinical features may be few (Davies et al, 1984); (iii) hypoxia is difficult to determine on clinical examination unless severe (Vichinsky et al, 1997) and (iv) the radiological signs often lag behind the physical signs (Charache et al, 1979; Davies et al, 1984; van Agtmael et al, 1994). Standard patient monitoring of patients with SCD admitted with acute pain crisis should include at least 4-hourly SpO2 monitoring (on air), heart rate monitoring and blood pressure monitoring. SpO2 should be measured on room air to enhance the sensitivity and specificity of the test to detect significant hypoxia and this is particularly helpful if the patient is located in a general ward environment. Daily clinical examination is also required, which should be more frequent if there is clinical concern. The investigations required for the diagnosis and management of ACS are standard tests available in acute district general hospitals. It should be stressed that clinical suspicion is vital to early diagnosis. Typical findings on plain chest radiography in ACS are segmental, lobar or multilobar consolidation usually involving the lower lobes, or collapse with or without pleural effusion (Leong Madani et al, 2007). Children are less likely to have pleural effusions, but are more likely to have upper or middle lobe disease (Davies et al, 1984; Vichinsky et al, 1997, 2000; Maitre et al, 2000). Radiological signs are often absent early in the illness (Charache et al, 1979; Davies et al, 1984; van Agtmael et al, 1994), or if present, may underestimate the severity of hypoxia (Bhalla et al, 1993), and treatment must not be delayed because the changes on chest X-ray are unremarkable. If initial chest X-ray is normal, a repeat chest X-ray should be performed if there is ongoing clinical suspicion. In the situation of unexplained hypoxia (no clinical features and no radiological signs on chest X-ray), a computerized tomography (CT) scan of the pulmonary arteries should be considered. This will provide clinical data on the pulmonary vasculature as well as the lung parenchyma. An acute fall in haemoglobin concentration and platelet count are often seen in ACS. These are markers of disease severity. A decreasing platelet count to less than 200 × 109/l is an independent risk factor for neurological complications and the need for mechanical ventilation (Vichinsky et al, 2000; Velasquez et al, 2009). Measurement of reticulocytes will confirm adequate bone marrow function and exclude red cell aplasia (erythrovirus B19 infection). Patients with ACS are at risk of developing multi-organ failure as a result of systemic fat emboli and require monitoring of their renal and liver function. C-reactive protein (CRP) levels, if elevated, may be used to follow the clinical progress of patients with ACS. If there is evidence of co-existent infection, the sensitivity and specificity of CRP levels as a biomarker of vaso-occlusion is reduced, but an increasing CRP is still a useful marker of a worsening clinical condition. Blood must be urgently ABO-, Rh- (C, D and E) and Kell-typed with antibody screening for all sickle cell patients at increased risk of ACS (severe vaso-occlusive crisis, previous ACS), and for those with mild ACS as their clinical condition may suddenly deteriorate and require emergency transfusion. Red cell alloimmunization is a common problem in SCD patients and can pose significant difficulties in their management (Vichinsky, 2001). Blood for transfusion should be fully matched for Rh (C, D and E) and Kell type and should be sickle-negative. If the patient is not known to the hospital, they should be asked if they are carrying an antibody card with details of their latest alloantibody profile and any previous alloantibodies detected. In addition must be to the red cell and latest red cell alloantibody profile from the hospital where their usual care is This is especially important because red cell alloantibodies often become over time in sickle cell patients (Vichinsky, increasing the risk of delayed transfusion if blood is It must be that in the UK red cell units for sickle cell patients will usually have to be in from the National Blood which will increase the time it to the blood available for the transfusion. in blood for emergency it is to with the blood transfusion that the blood is required for a sickle cell patient in addition to details on the This must be performed in all patients with ACS who are although the is low (Vichinsky et al, 1997). Although can be used to provide a of SpO2 in patients with sickle cell anaemia et al, et al, The of patients with ACS was and in large (Vichinsky et al, 2000; et al, and in of patients had a less than (Vichinsky et al, 1997). In the of was in the normal with a of being in of of first ACS events in adults (Vichinsky et al, 1997). However, an high prevalence of was reported in one adult patients with no evidence of (Maitre et al, 2000). suggest that a less than on room air should be as severe hypoxia and a of greater than as Acute and samples for against atypical respiratory including pneumoniae, pneumoniae and should be if and for B19 if by the clinical and features (Vichinsky et al, 2000). Mycoplasma infection may be by red cell on a blood and the presence of in The usual screening test for is by for the for viruses in sputum and nasopharyngeal are performed as a virus for a of This may include for A and RSV but will be by the clinical picture and local of specific infective organisms will to and of Although a of other investigations have been reported in the these are not used in the diagnosis and management of ACS in the UK. In a of children with to severe ACS, computerized tomography performed within h of presentation microvascular occlusion in areas of the that normal on chest with an sensitivity and specificity of and (Bhalla et al, 1993). In to chest the of microvascular occlusion on with the clinical severity and of hypoxia (Bhalla et al, 1993). However, in of the high by the of this for diagnosis of ACS is not The of is also to be because of the of ACS to and also because with SCD frequently require other radiological tests for a of other These should from the of where it is to be appropriate. a should be if there is a clinical suspicion of pulmonary embolism. This usually with normal ventilation et al, 2003; et al, However, the may be with pulmonary emboli or by the presence of other such as pleural The role of lung in the diagnosis of ACS has not been in and therefore it has a role in the of this The complication rate of bronchoscopy in patients with ACS has been reported as The commonest reported complication was a fall on but there was a risk of mechanical ventilation following the (Vichinsky et al, 2000). In practice, bronchoalveolar is only likely to be in patients who have to and These combined with the of of bronchoscopy in most the of bronchoscopy only to specific clinical on the clinical features and first is an that is to release from bone marrow et al, and it was initially shown to be in ACS with the levels of with the severity of ACS. It has been that of levels of this may be useful in diagnosis of ACS, but the test is not available et al, and more recent have shown a of only in ACS et al, of bronchoalveolar samples has been used to pulmonary fat embolism (Vichinsky et al, 2000; Maitre et al, 2000). Although ACS patients with pulmonary fat embolism have a more severe clinical course (Vichinsky et al, 1994), this is not standard as it is not necessary to the of fat embolism in clinical The aim of treatment in ACS is to or acute respiratory failure. in the of patients will occur with of the measures The key to is early of ACS and of treatment without and treatment will potentially the of lung and associated long-term sequelae. These are if acute medical and critical care are provided at an early stage. Acute chest syndrome may present as a medical Sickle cell patients with ACS are often and require close monitoring and management by a within and clinical acute and critical is to the of It is not clear the SpO2 is and a is that should be given to SpO2 or within 3% of the SpO2 should be at least 4-hourly that any by increasing requirement can be detected. If the patient is dependent on a of the clinical should be frequent or monitoring is required when there is clinical concern. Patients with ACS are usually unwell to adequate should be given until the patient is to adequate of should be and be by the fluid and Clinical must be given to fluid and the development of acute pulmonary Daily fluid should be using a fluid of and with a daily for fluid sickle cell crisis the and causes chest splinting and alveolar hypoventilation, which can be by lung There is a high bone infarction and ACS (Rucknagel et al, 1991; Gelfand et al, 1993). pain using the is an important of the management of ACS et al, 2003). However, care must be to alveolar hypoventilation from as this the risk of ACS. have found that the of may increase the likelihood of developing ACS et al, et al, However, a not these findings et al, 2007). et al, therefore monitoring with frequent and of pain and in addition to is with pain to the risk of ACS in children and adults admitted with bone and infarction by chest splinting and et al, Whilst there are no on specific in of ACS in adults or as treatment for ACS it is likely to be an important to other of The of the should be to the as by the but as a 10 h during the and the patient is during the is a et al, may also be useful in the