Evaluation and management of fever in children and adults with sickle cell disease

INTRODUCTION — Sickle cell disease (SCD) is a potentially immunocompromising state due to variable development of functional asplenia. Most children with sickle cell anemia (Hb SS) and sickle cell beta⁰ thalassemia have decreased to absent splenic function by age one to two years; children with other SCD genotypes lose splenic function later in childhood. Thus, most individuals with SCD are at especially high risk of infection with encapsulated organisms across their lifespan. (See 'Genotype (Hb SS versus SC versus S-beta thalassemia)' below.)

Fever is frequently the first indication of serious and life-threatening bacterial infection. Fever may also indicate other serious SCD-associated conditions such as acute chest syndrome.

The definition of a fever has not been rigorously studied (see 'What constitutes a fever?' below), and a strict cutoff value cannot be used to determine the risk of serious bacterial infection without an evaluation of the individual patient's circumstance. Individuals with SCD and fever at any age should be evaluated and treated promptly to avoid significant morbidity and mortality.

The management of children and adults with SCD and fever is reviewed here. Overviews of other clinical manifestations and their management in individuals with SCD are presented separately. (See "Overview of the clinical manifestations of sickle cell disease" and "Overview of the management and prognosis of sickle cell disease".)

KEY ASPECTS OF MANAGEMENT

Risk of life-threatening infection

Functional asplenia — Individuals with SCD are immunocompromised due to variable lack of splenic function, caused by repeated vaso-occlusive infarctions of the spleen that begin during infancy [1,2]. This hyposplenic or asplenic state, commonly referred to as functional asplenia, places them at risk of life-threatening infections.

The risk of life-threatening infection occurs throughout the lifespan in individuals with SCD. The risk of infection is higher in infants and young children with sickle cell anemia (Hb SS) and sickle cell beta⁰ thalassemia. (See 'Genotype (Hb SS versus SC versus S-beta thalassemia)' below.)

Individuals with functional asplenia are particularly at risk for serious infection with encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae; other organisms are commonly reported. (See "Clinical features, evaluation, and management of fever in patients with impaired splenic function", section on 'Risk of severe infection'.)

Rates of bacteremia and specific organisms — Vaccinations have reduced but not eliminated the risk of serious infection with encapsulated organisms.

●Prior to the availability of H. influenzae type b and pneumococcal vaccines, children <5 years of age with SCD in the United States had high rates of pneumococcal and H. influenzae sepsis, including a 13 percent risk of developing bacterial sepsis (with a 30 percent mortality rate) or meningitis (with a 10 percent mortality rate) [3,4].

●Mortality rates decreased significantly after introduction of a conjugate pneumococcal vaccine in 2000, and, subsequently, with expanded valency pneumococcal conjugate vaccines [5-11]. However, approximately one-fourth of deaths in children during the period from 1999 to 2002 were due to infectious causes, and case series published after the introduction of the newest pneumococcal vaccine indicate a prevalence of bacteremia in febrile patients with SCD of 0.8 to 4 percent [12-15]. However, European data from 2014 to 2019 confirm that even with widespread availability of PCV13, S. pneumoniae remains the leading cause of bacterial infection in children with SCD, and infection results in a 7 percent chance of death and a 17 percent chance of sequelae [16] Further, the evolving pneumococcal conjugate vaccine recommendations make it difficult to know which strains a particular patient has received vaccination against.

●Some strains of S. pneumoniae are not covered by the available vaccines [17]. Other organisms are not covered by immunization, including Salmonella, Escherichia coli, and Staphylococcus aureus [10,13,16,18,19].

In a population-based study from 2021 that included 9503 individuals in the National Health Service of the United Kingdom who were followed over a 10-year period, sepsis requiring hospitalization occurred in 11 percent [20]. Pneumonia, clinically indistinguishable from acute chest syndrome (ACS), was associated with 18 of 29 (62 percent) of respiratory deaths [20].

What constitutes a fever? — The definition of a fever has not been rigorously studied in SCD, and a strict cutoff cannot be used to determine the risk of serious bacterial infection without evaluating the patient. Guidelines from the National Heart Lung and Blood Institute (NHLBI) at the National Institutes of Health (NIH) in the United States suggest using a temperature cutoff of ≥38.5°C (equivalent to approximately ≥101.3°F) to trigger immediate evaluation in the emergency department in all cases [21]. However, many SCD experts use a lower cutoff, such as ≥38°C (≥100.4°F) or ≥38.3°C (≥100.9°F) [21,22]. A reasonable strategy is to use the lower temperature threshold in the subgroup of infants with the highest risk of bacteremia (infants <1 year of age), but no evidence-based recommendations have been established. (See 'Initial evaluation' below.)

Patients and parents/caregivers of an individual with SCD should have clear information about the temperature threshold they should personally use and the importance of in-person evaluation should they develop a temperature at or above that threshold. (See 'Initial evaluation' below.)

The degree of fever in individuals with SCD cannot be considered comparable to individuals without SCD for the following reasons:

●Functional asplenia or hyposplenia – SCD is an immunocompromising state due to ongoing loss of splenic function beginning at an early age. (See 'Risk of life-threatening infection' above and "Overview of the clinical manifestations of sickle cell disease", section on 'Infection'.)

●Other risk factors – Many individuals with SCD have other risk factors for infection including indwelling venous catheters, hypoventilation due to acute chest syndrome or painful events, leg ulcers, and/or other comorbidities.

●Enhanced inflammation – Even viral infections may cause greater morbidity due to intravascular sickling associated with an enhanced inflammatory response.

●Blunted temperature response – Persons with SCD often present having been instructed to take around the clock acetaminophen or a non-steroidal anti-inflammatory medication (NSAID) to manage pain, which may mask the severity of temperature elevation.

●Greater risk for dehydration – SCD causes a urinary concentrating defect that places individuals at greater risk of dehydration.

●Other SCD complications – Common complications of SCD including acute chest syndrome and acute vaso-occlusive painful events cannot be easily distinguished from infectious complications (and commonly coexist with infectious complications). (See 'Evaluation for associated conditions' below and "Evaluation of acute pain in sickle cell disease", section on 'Potentially serious conditions associated with pain'.)

Children, adolescents, adults, and their family members or caregivers should be counseled to seek prompt medical attention for a predetermined elevated temperature. This should occur even if the fever rapidly goes away, with or without antipyretics. (See 'Key aspects of follow-up and prevention' below.)

COVID-19 — The COVID-19 pandemic complicated the evaluation of fever for patients with SCD. Pain is the most common presenting symptom of COVID-19 in adults with SCD [23]. Other common symptoms are cough, fever, and dyspnea [24]. Patients with SCD are not at an increased risk of contracting COVID-19 compared with those without SCD, but they are at higher risk of severe disease.

●A 2022 systemic review of 71 COVID-19 related studies across 15 countries including over 2000 individuals with SCD showed that while adults with SCD typically have a mild to moderate disease course, they also have a twofold to sevenfold increased risk of COVID-19-related hospitalization and a 1.2-fold increased risk of COVID-19-related death relative to adults without SCD; these risks are similar to individuals with similar comorbidities and end-organ damage [25].

When compared specifically with Black individuals without SCD or sickle cell trait, patients with SCD and COVID-19 remained at a higher risk of hospitalization (relative risk [RR] 2.0, 95% CI 1.5-2.7), pneumonia (RR 2.4, 95% CI 1.6-3.4), and pain (RR 3.4, 95% CI 2.5-4.8) [25]. However, the case fatality rates for those with SCD compared with Black persons without SCD or sickle cell trait were not significantly different.

●A 2023 meta-analysis that included over 6000 patients with SCD confirmed to have SARS-CoV-2 infection found an overall case fatality rate of 3 percent [26]. In addition, 10 percent of patients with SCD were admitted to an intensive care unit after complications caused by COVID-19, and 4 percent of them required invasive ventilatory support. However, in-hospital mortality and invasive mechanical ventilation outcomes in SCD are comparable to that in non-SCD patients hospitalized with COVID-19 [27].

Children with SCD are less likely to experience COVID-19-related severe illness and death compared with adults with or without SCD [25].

Pediatric versus adult considerations — Infants, children, adolescents, and adults with SCD are at risk for potentially life-threatening infection. The following age-specific differences may affect decision-making regarding care:

●Infants and young children with SCD may not have received some vaccinations due to their age and the recommended vaccination schedule; these individuals may be unprotected against certain infectious organisms. (See "Overview of the management and prognosis of sickle cell disease", section on 'Immunizations'.)

●Many children under age 5 to 7 years with SCD are receiving regular penicillin prophylaxis. Prophylactic penicillin is not sufficient treatment if fever develops; in fact, it may select for penicillin-resistant pneumococci requiring the use of parenteral agents for treating possible bacteremia. (See "Overview of the management and prognosis of sickle cell disease", section on 'Prophylactic penicillin'.)

●Large population studies are not available to describe the epidemiology of life-threatening bacterial infections in children beyond the penicillin prophylaxis age and/or in adults with SCD. However, risk factors for serious infections persist throughout life, and clinical experience demonstrates that fatal sepsis can occur. In a two-center international study of adults with SCD, 19 percent died from microbiologically-documented infectious organisms [20].

Genotype (Hb SS versus SC versus S-beta thalassemia) — SCD is an umbrella term that includes persons who are homozygous for the S hemoglobin variant (Hb SS, also called sickle cell anemia) as well as various compound syndromes (Hb S in combination with Hb C, beta⁺-thalassemia, or beta⁰-thalassemia). The degree of splenic dysfunction and other markers of disease severity differ depending on the syndrome. (See "Overview of compound sickle cell syndromes".)

●Hb SS and Hb S-beta⁰-thalassemia – Splenic dysfunction begins before one year of age; disease is typically more severe.

●Hb SC and Hb S-beta⁺-thalassemia – Splenic dysfunction is variable and may or may not occur with onset during childhood and adolescence. Disease is typically less severe, but severe complications may occur.

The risks of serious vaso-occlusive complications, bacteremia, and sepsis are generally greater in individuals with Hb SS and Hb S-beta⁰-thalassemia than for Hb SC disease and Hb S-beta⁺-thalassemia [18,28,29]. This is because individuals with Hb SC disease and sickle beta⁺-thalassemia have relatively preserved splenic function during early childhood and perhaps into later life [30].

However, individuals with all forms of SCD must be seen to be at risk for life-threatening infection, and fever may be the first sign that such an infection is present. Individuals with the less severe compound SCD syndromes may also die from bacterial infections [31]. Thus, many centers evaluate children and adults with Hb SC disease and Hb S-beta⁺ thalassemia in a similar fashion as other sickle cell syndromes when fever develops. Criteria for admission to the hospital are also similar for all genotypes. (See 'Criteria for hospital admission' below.)

Input of the primary hematologist — For any individual with SCD and fever, communication with the individual's primary hematologist is critical. The primary hematologist can provide information regarding the individual's baseline hematologic and other laboratory values, prior SCD-related events, vaccinations, and prior episodes of fever and bacteremia. In addition, the hematologist may offer information about medication adherence and care resources in the home.

The primary hematologist can assist with decisions about hospital admission and follow-up of the emergency department visit or admission and should be informed about the clinical course and blood culture results. (See 'Criteria for hospital admission' below.)

INITIAL EVALUATION — A health care provider with the ability to deliver prompt, in-person medical care, including parenteral antibiotics, should evaluate all children and adults with SCD in person within four hours of the onset of the fever, due to the increased relative and absolute risk of life-threatening infection throughout the lifespan. In a cohort of 9503 individuals of all ages with SCD followed for 10 years, sepsis occurred in 11.1 percent [20].

If possible, the assessment should be performed by medical personnel who are knowledgeable about SCD, have information about the particular patient's baseline hematologic values and status, and can provide empiric parenteral antibiotics after at least one blood culture has been drawn (including culture of a central line if present).

The purpose of the evaluation is to:

●Confirm that a fever has occurred and the maximum temperature. If the pre-agreed temperature elevation has occurred, based on patient history or direct measurement (see 'What constitutes a fever?' above), then a history, physical, laboratory evaluation, and administration of a parenteral dose of antibiotic should rapidly occur. Lack of a fever in the emergency department is not a reason to discount a history of fever that occurred at home or elsewhere.

●Identify signs or symptoms that suggest the need for additional testing beyond a complete blood count (CBC) and blood culture, and confirm the choice of empiric parenteral antibiotic(s) required. (See 'Other testing in selected patients' below and 'Empiric antibiotic therapy' below.)

●Determine whether the individual requires admission to the hospital or can be managed as an outpatient. (See 'Criteria for hospital admission' below.)

History — A brief history should be conducted. It is important to assess:

●Symptoms – Assess symptoms suggesting systemic or localized infection, including cough, dyspnea, abdominal pain, diarrhea, bone pain, dysuria, headache, meningeal signs, infectious exposures, and any new symptoms. Viral illness may be present, especially during cold and influenza season, even in individuals with bacteremia.

●Exposures – Determine if the individual has been exposed to others with communicable diseases including influenza, COVID-19, and parvovirus (the cause of aplastic crisis).

●Vaccinations – Vaccination status should be assessed, when possible, in children and adults. Individuals who have not received vaccinations are at greater risk for infection with encapsulated organisms. We follow the Centers for Disease Control and Prevention (CDC) recommendations for vaccinations for children and adults with SCD [32]. (See "Prevention of infection in patients with impaired splenic function", section on 'Vaccinations'.)

●Prior SCD complications and bacteremia – Past history of SCD complications should be reviewed, including prior episodes of bacteremia or sepsis and prior acute chest syndrome (ACS) events. A previous history of pneumococcal bacteremia increases the risk of recurrence and must be considered when deciding on the need for hospitalization [33-35]. (See 'Criteria for hospital admission' below.)

Individuals with prior episodes of ACS are at increased risk for subsequent ACS, which may present as isolated fever without other respiratory symptoms, chest wall pain, or symptoms of a respiratory infection. (See 'Chest imaging and ACS' below.)

●Medications – Current medications may include prophylactic or treatment dose antibiotics or medicines such as acetaminophen or a nonsteroidal anti-inflammatory drug [NSAID] that could blunt temperature response. Concomitant use of hydroxyurea, a common medication prescribed chronically in SCD, may suppress the white blood cell (WBC) count or blunt its rise with stress (including infection), but hydroxyurea has not by itself been shown to increase the risk of febrile bacteremia or sepsis.

●Psychosocial support – Psychosocial considerations and availability of outside support should also be queried. Individuals who are acutely ill, dehydrated, unable to care for themselves, or unable to access medical care should their condition worsen, should be evaluated and treated regardless of the degree of temperature elevation. The individual's primary care clinician and primary hematologist may assist in providing this information. (See 'Input of the primary hematologist' above.)

Examination — A rapid physical examination focused on the following:

•Hemodynamic and cardiopulmonary – Vital signs, pulse oximetry, and cardiopulmonary status are assessed to evaluate for fluid status, hemodynamic instability, or intrapulmonary pathology such as acute chest syndrome (ACS). Upper airway and lungs are examined for signs of upper or lower respiratory tract infection. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)".)

•Venous catheter – Presence or absence of an indwelling central venous or other venous catheter should be noted; cultures should be obtained from the catheter in an individual with SCD and any elevated temperature due to the risk of catheter-related infection. (See "Central venous catheters: Overview of complications and prevention in adults".)

•Abdomen and spleen – Abdominal examination should assess for tenderness and other abnormalities; the spleen should be palpated for enlargement that may signify splenic sequestration. Other potential abdominal complications include gallstone disease, constipation, appendicitis, pelvic inflammatory disease, pregnancy complications, and hepatic sequestration. Comparison of current to baseline examination findings is particularly valuable, especially with reference to spleen or liver enlargement and degree of jaundice. (See 'Evaluation for associated conditions' below and "Overview of the clinical manifestations of sickle cell disease", section on 'Splenic sequestration crisis'.)

•Bone and skin – Bone and skin examination is performed for signs of localized infection or bone ischemia or infarction including erythema, tenderness along any of the long bones or sternum, and presence of skin lesions, including ulcers around the ankles. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Leg ulcers'.)

•Neurologic – A brief neurologic examination is vital to identify evidence of acute stroke and assess the patient's ability to care for themself. Although stroke is not associated with fever, acute stroke is a common enough complication of SCD that it must be considered whenever a patient with SCD presents for medical evaluation and will serve as a baseline for this medical contact. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease", section on 'Differential diagnoses'.)

Vaso-occlusive pain may also be present and requires rapid treatment, concomitant with parenteral antibiotics for fever. (See "Acute vaso-occlusive pain management in sickle cell disease".)

Certain abnormal findings may indicate other complications, as discussed below. (See 'Evaluation for associated conditions' below.)

Diagnostic testing — Rapid empiric parenteral antibiotics are critical to prevent life-threatening sepsis, but diagnostic tests must be obtained to guide therapy and to later narrow the antibiotic spectrum if a specific organism is identified. While it is important to obtain these tests, empiric antibiotics should not be delayed while awaiting the results of testing or to obtain testing that takes excessive additional time.

All patients — The following is appropriate in all patients, with exceptions as listed below [36]:

●CBC – CBC with WBC count, differential, platelet count, and reticulocyte count should be reviewed and compared with the most recent baseline (steady state when well) values [37]. A decrease in hemoglobin of 2 g/dL or more below the individual's baseline may suggest acute chest syndrome (ACS), splenic sequestration, or an aplastic crisis. An elevated WBC count may be normal in a patient with SCD, particularly when stressed, or may suggest an invasive infection. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Anemia'.)

●Blood cultures – At least one blood culture is required, including culture taken from a central venous catheter if present, provided the emergency department personnel are capable of accessing the central line safely. If a central venous catheter is not present or cannot be accessed, a peripheral culture is done.

●Chest radiograph – A chest radiograph should be strongly considered in each case of fever and should be obtained in all patients with fever when lower respiratory findings on auscultation, unexplained decrease in baseline oxygen saturation of at least 3 percent, or chest wall pain are present.

A more challenging clinical decision is whether a radiograph should be obtained in a patient with a fever but no respiratory symptoms. The absence of respiratory findings may provide the false impression that the clinical examination is sufficient to identify ACS or pneumonia, particularly in children with SCD [22,38]. If a patient with SCD has a fever without a source and the clinician elects not to obtain chest imaging, they should be aware that the patient may have undiagnosed ACS and their disposition should reflect the possibility that if respiratory symptoms occur or other symptoms worsen, the patient may require prompt re-evaluation. (See 'Chest imaging and ACS' below.)

The use of lung ultrasound to evaluate ACS is evolving, and performance is user-dependent. (See 'Chest ultrasound in a child or adult with SCD and fever' below.)

●Nasal swab – Nasopharyngeal swab for detection of influenza virus is sent during influenza season. Consider nasopharyngeal swab for additional viral pathogens if symptoms warrant.

●COVID 19 – During periods of high SARS-CoV-2 transmission, testing should be done with any respiratory symptoms (in patients not recently diagnosed with COVID-19) or if there is not clear cause for the fever. (See 'COVID-19' above.)

●Urine – For patients of any age with urinary symptoms such as dysuria, or those with a prior history of urinary tract infection (UTI), urinalysis and culture are appropriate. As in all febrile children, females and uncircumcised males <2 years, and circumcised males <6 months without another source of fever should have a urinalysis and culture. For infants, a catheterized urine specimen is often required; if a catheterized specimen is acquired, it should also be sent for culture. (See "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis", section on 'Laboratory evaluation and diagnosis'.)

Antibiotics should not be withheld while obtaining urinalysis and culture.

For asymptomatic patients over the age of 2 years, a two-step process can be initiated in the emergency department or outpatient setting for evaluation of a potential UTI in all patients with SCD who have a fever without an explanation [39]. In the first step, the urine specimen should be obtained. If urinalysis of a fresh collection (<1 hour) is suggestive of an infection based on a positive leukocyte esterase and positive nitrite, then a second sterile urine for culture should be obtained and treatment directed at a urinary pathogen administered. If the patient is unable to produce a clean catch specimen, catheterization is done and a culture is sent on the first specimen.

●Diarrhea – Stool culture or a DNA-based (polymerase chain reaction [PCR]-based) panel is sent if diarrhea is present.

●Lumbar puncture (LP) – Meningitis and stroke are both considerations in an individual with SCD and fever. Imaging to evaluate stroke should be performed prior to LP. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease", section on 'Neuroimaging'.)

LP is indicated in any patient with fever and at least one of the following [40]:

•Symptoms of meningitis such as nuchal rigidity (typically only present in children at least 12 months of age)

•Otherwise unexplained irritability in a child

•Altered level of consciousness at all ages

•New onset seizure(s); febrile seizure is a diagnosis of exclusion in a child with SCD and fever, after central nervous system pathology has been excluded by neuroimaging

As with other testing, antibiotics should not be withheld while awaiting LP. Antibiotic coverage is broadened to include vancomycin if meningitis is suspected. (See 'Initial antibiotic therapy' below.)

●Bone pain – If high fever and localized bone pain are present, consider obtaining a bone scan, skeletal films, and early orthopedic consultation to evaluate for osteomyelitis or a septic joint.

●Type and screen – Type and screen/crossmatch with extended red blood cell (RBC) antigen phenotype for RBC transfusion if there is evidence of extreme pallor, severe neurologic symptoms, ACS, or acute splenic sequestration. Details regarding transfusion are presented separately. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".)

Obtaining certain tests such as a chest radiograph, lumbar puncture, or urinalysis and culture should not delay the administration of antibiotics, even though the yield of this testing may be lower after antibiotics have been initiated. (See "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis".)

Other testing in selected patients

Chest imaging and ACS — Chest radiography remains the gold standard for evaluating chest pain and/or fever; these findings often coexist. Chest radiography can identify pneumonia and acute chest syndrome (ACS), which are clinically indistinguishable. ACS is defined by a new pulmonary infiltrate on chest imaging plus one or more findings such as fever, tachypnea, wheezing, hypoxemia relative to baseline, or chest wall pain. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section on 'Diagnostic criteria'.)

The decision to obtain chest imaging in every child or adult with a fever and no respiratory symptoms represents a tradeoff between rarely missing an early presentation of ACS or performing too many unnecessary radiographs in a population that will be evaluated many times with chest imaging [41].

Ultimately, the decision to perform a chest radiograph to identify ACS is dependent on the following:

●Age (children more likely)

●History (prior ACS episode more likely)

●Presenting symptoms (respiratory symptoms, particularly hypoxia and chest or chest wall pain more likely)

●Laboratory values (high WBC more likely)

●Disposition (discharge home with unclear follow-up ability in a clinician's office more likely), with the ability to be monitored closely at home and brought back quickly if the respiratory symptoms increase

The presence of an infiltrate should affect the choice of antibiotics and use of other therapies. Studies have shown that neither symptoms nor physical examination findings uniformly predict the presence of ACS in children and adults [22,38].

●Features predictive of ACS – A model for predicting ACS in a group of children with SCD found the best predictors included a history of ACS, chest pain, cough, and abnormal physical findings [38].

The Cooperative Study of Sickle Cell Disease (CSSD), which prospectively followed 3751 patients enrolled from birth to adulthood, identified 1722 episodes of ACS episodes in 939 patients (one-fourth) of the group and found [42]:

•Children age 2 to 4 years with ACS often presented with fever and cough and a negative physical examination; they rarely had thoracic or chest wall pain.

•Adults with ACS often presented with shortness of breath, chills, and severe pain; they were often afebrile.

●Most children with ACS have a normal examination – A series involving 356 children with SCD who had 609 emergency department visits reported that 62 percent had a normal lung examination and indicated that the lone finding of fever without additional respiratory symptoms in a child with a past history of ACS may also be indicative of recurrent ACS [38]. A third study found that in 23 patients with SCD and fever who had ACS, emergency department clinicians only identified 9 (39 percent) ACS cases before a radiograph was obtained [22].

●Predictors to minimize need for radiographs – A retrospective chart review of 1837 children and adolescents (ages 3 months to 21 years) who presented to the emergency department with fever reported that 185 (10 percent) met ACS criteria [43]. Obtaining chest imaging only for those with shortness of breath, tachypnea, cough, or rales was able to identify 85 percent of ACS cases and allowed 825 children (45 percent of the cohort) to avoid radiation exposure. Including a WBC count ≥18.8/microL or a history of ACS in the criteria for ordering chest imaging increased the diagnostic yield for ACS to 98 percent and still avoided radiation exposure in 430 children (23 percent of the cohort).

●Presentation with pain – In a series of 71 individuals with SCD who were ≥15 years and presented with pain, chest imaging identified acute pneumonia in eight (11 percent), despite none complaining of fever or respiratory symptoms [44]. In another study of 94 individuals with SCD age ≥18 years who presented with pain, chest imaging diagnosed pneumonia in six (6 percent), all of whom had fever [45]. Other studies have reported similar findings.

If an individual with SCD is pregnant and presents with fever, a radiograph may not be done because of concern for the risk of radiation to the fetus. In such situations, a definition of ACS was developed that did not require chest radiography; the definition included a positive finding on lung/chest examination plus at least two of the following [46]:

●Temperature >38°C (>100.4° F)

●Respiratory rate >20 breaths per minute

●Chest pain or abnormal findings on pulmonary auscultatory findings

●Increased oxygen requirement (SpO₂ drop >3 percent from a documented steady-state value on room air)

●A new radiodensity on chest radiograph, if performed

ACS identified using this definition was used to make management decisions, and participants had improved clinical outcomes compared with historical controls [46].

Chest ultrasound in a child or adult with SCD and fever — While chest radiography is the standard approach for evaluating fever in children and adults with SCD, the use of lung ultrasound as an alternative means of identifying lung pathology is increasing, especially point-of-care lung ultrasound performed in the emergency department [47].

Ultrasound can be performed at the bedside without moving the patient to another part of the facility; test performance is user-dependent. A study that evaluated performance characteristics of point-of-care lung ultrasound found the following positive predictive values (PPV) and negative predictive values (NPV) based on review by a blinded expert or a novice reviewer, using radiography as the reference standard [47]:

●PPV, blinded expert – 72 percent (95% CI 59-82 percent)

●PPV, novice – 63 percent (95% CI 46-84)

●NPV, blinded expert – 97 percent (95% CI 93-99)

●NPV, novice – 96 percent (95% CI 92-100)

Procalcitonin may emerge as a biomarker to differentiate bacterial from viral infection — Procalcitonin, if rapidly available, may help resolve diagnostic uncertainty and determine whether home management is safe or if hospital admission is prudent.

Procalcitonin is a serum biomarker that may help distinguish bacterial infection from other causes of fever but has not been formally evaluated in a prospective multicenter cohort study in SCD. Despite this limitation, emerging data suggest a low procalcitonin level indicates that fever is not due to a bacterial infection (table 1). Case series in individuals with SCD and fever have shown that low procalcitonin (<0.6, <1, or <2 ng/mL, depending on the study) can accurately exclude serious bacterial infections [48-50]. A retrospective study of 145 patients with SCD demonstrated that procalcitonin was useful for differentiating between confirmed bacterial infection and vaso-occlusive pain or viral infection [51]. However, prospective studies are needed to confirm these observations.

The procalcitonin value should be interpreted in the context of other clinical findings. A low procalcitonin value should not be used to justify sending a patient home if there are other indications for admission. (See 'Criteria for hospital admission' below.)

Formal evaluation of procalcitonin in a routine clinical setting is required before assessment will become part of routine care. The low prevalence of bacteremia in the modern era will make it challenging to obtain this information without a large multicenter study.

Evaluation for associated conditions — After the initial evaluation for sources of infection and rapid administration of a parenteral dose of empiric antibiotics, evaluation and management of other associated conditions may be appropriate. The following are frequently seen in children and adults with SCD who present with fever:

●Acute chest syndrome – Chest imaging and evaluation of oxygen saturation by pulse oximetry is appropriate if the patient exhibits any signs suggestive of acute chest syndrome (ACS), as noted above and discussed in more detail separately. (See 'Chest imaging and ACS' above and "Acute chest syndrome (ACS) in sickle cell disease (adults and children)".)

●Aplastic crisis due to parvovirus B19 infection – Common manifestations of aplastic crisis include fever, extreme pallor due to severe anemia, reticulocytopenia, and tachycardia [52,53]. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Aplastic crisis'.)

●Acute vaso-occlusive pain – Vaso-occlusive pain episodes are common in individuals with SCD and require prompt treatment. Pain may be accompanied by fever that is usually <38.1° C (<100.5° F). Pain episodes may accompany infectious complications; when this occurs, both the pain and the infection must be evaluated and treated; treatment of pain should not be delayed while evaluating an infectious complication. (See "Evaluation of acute pain in sickle cell disease".)

●Abdominal complications – Children and adults with abdominal pain and fever should be evaluated based on their age, sex, and presentation. (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Opioid side effects' and "Hepatic manifestations of sickle cell disease", section on 'Disorders associated with the sickling process' and "Hepatic manifestations of sickle cell disease", section on 'Disorders related to coexisting conditions'.)

●In addition to a thorough history, evaluation of symptomatic individuals may include an alanine aminotransferase (ALT), total and direct bilirubin, amylase, lipase, alkaline phosphatase, and pregnancy test (human chorionic gonadotropin [HCG]) in females of childbearing potential. Whether the pregnancy test is performed on serum or urine may be institution- or patient-dependent; serum HCG should be obtained if there is any concern for ectopic pregnancy.

Mild elevations in transaminases are common during vaso-occlusive pain and may transiently worsen during the event [54]. Comparison to baseline transaminase values and physical exam findings is important. Limiting hepatotoxic medications should be considered in those with elevated transaminases.

Abdominal ultrasound should be considered if symptoms are present. Typically, the abdominal ultrasound is obtained if history and laboratory values suggest an intraabdominal cause for the fever and abdominal pain. The abdominal ultrasound may facilitate narrowing a broad differential diagnosis that includes (but is not limited to) acute ascending cholangitis, acute cholecystitis, appendicitis, ectopic pregnancy, acute pancreatitis, or an enlarged spleen or liver suggestive of acute splenic or hepatic sequestration.

EMPIRIC ANTIBIOTIC THERAPY

Indications for antibiotics — Fever may be the first and only indication of a serious bacterial infection in an individual with SCD. After an appropriate evaluation (see 'Initial evaluation' above), empiric parenteral antibiotics are used that are active against common bacterial pathogens, regardless of whether any localized infection is identified.

●The identification of a localized bacterial infection (such as acute otitis media) does not alter the need for empiric parenteral antibiotics because bacteremia with the potential to progress to septicemia may still be present.

●Blood culture (at least one) and empiric parenteral antibiotics are also recommended in persons with SCD even in the presence of a documented viral infection (including rapid test positive for influenza, SARS-CoV-2, respiratory syncytial virus [RSV], or varicella) because of the risk of secondary bacterial infection.

Empiric parenteral antibiotics are promptly administered after the initial blood cultures and CBC are obtained, ideally within 60 minutes of triage [37]. Use of nurse-initiated care pathways in the emergency department or acute care setting can help avoid delays and achieve timeliness of antibiotic delivery.

In an observational study of children with sickle cell anemia (Hb SS), the rapid administration of empiric antibiotic therapy appeared to reduce rates of meningitis and deaths due to pneumococcal infection [55]. One study of nonimmunized children who did not receive prophylactic penicillin reported that 8 of the 23 children with pneumococcal septicemia died and 15 developed meningitis prior to the initiation of a clinical program of rapid administration of empiric antibiotics. In contrast, after establishment of this clinical program, there were no deaths and only two cases of meningitis in the 11 children with pneumococcal septicemia. A study of children admitted to the hospital in equatorial Africa documented that children with SCD had a 26-fold higher risk of being bacteremic than children without SCD [56].

A retrospective cohort study of 35,548 encounters from among 11,181 individuals with SCD <22 years identified bacteremia in 405 encounters (1.1 percent) [15,57]. Bacteremia was associated with a history of bacteremia (odds ratio [OR] 1.36, 95% CI 1.01-1.83), osteomyelitis, stroke, central line-associated bloodstream infection (OR 6.39, 95% CI 3.02-13.52), central venous catheter, and apheresis (OR 1.77, 95% CI 1.22-2.55); in contrast, age, sex, hemoglobin SC genotype, and race and ethnicity did not show an association with bacteremia [15,57].

COVID-19-specific therapy should be strongly considered if testing is positive. (See "COVID-19: Management in children" and "COVID-19: Management in hospitalized adults".)

Antibiotic selection

Initial antibiotic therapy — Antibiotic recommendations are based upon the epidemiology and antimicrobial sensitivity patterns of the organisms most likely to cause infection, especially encapsulated organisms. In the United States, the most common bacteria include S. pneumoniae, Salmonella, E. coli, and S. aureus. (See 'Risk of life-threatening infection' above.)

Studies from equatorial Africa have documented high rates of S. aureus [58-61], Klebsiella [58,60,61], Salmonella [58,62], and S. pneumoniae [56].

Presence of an indwelling central line should be considered when selecting antibiotics, although ceftriaxone is generally adequate. Local pathogen profiles and practice patterns will aid in determining if vancomycin is also needed.

The following antibiotic choices are most commonly used in children and adults with SCD and fever in the United States [63,64]:

●Ceftriaxone – Ceftriaxone is often the treatment of choice because it covers encapsulated organisms and has a long half-life, allowing certain individuals to be sent home with close follow-up. The first dose is 50 to 75 mg/kg intravenously (maximum single dose, 2 g). In regions with a high prevalence of antibiotic-resistant S. pneumoniae, higher doses may be given, such as 75 to 100 mg/kg (maximum single dose 2 g).

A rare but potentially life-threatening complication of repetitive exposure to ceftriaxone is acute hemolysis, leading to severe anemia. Individuals treated with ceftriaxone should be observed for at least one hour prior to discharge for signs of hemolysis such as rapidly increasing jaundice or pallor. And any individual with a history of ceftriaxone-induced hemolysis should receive a different antibiotic instead of ceftriaxone or any cephalosporin. (See 'Hemolysis associated with ceftriaxone' below.)

●Vancomycin – Vancomycin is generally reserved for children or adults with suspected meningitis or those who are too hemodynamically unstable for a lumbar puncture to exclude meningitis. Vancomycin may also be added to selected hemodynamically unstable children and adults.

•For children with normal kidney function, vancomycin is administered at a dose of 15 mg/kg intravenously every 6 to 8 hours (maximum single dose 1000 mg); levels should be monitored. (See "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Empiric antibiotic therapy' and "Bacterial meningitis in children older than one month: Treatment and prognosis", section on 'Empiric therapy'.)

•For adults with normal kidney function, loading dose of 25 to 30 mg/kg, rounded to the nearest 250 mg increment, followed by 15 to 20 mg/kg every 8 to 12 hours (maximum dose 2 grams per dose or 60 mg/kg total daily dose). Dosing is adjusted based upon therapeutic monitoring. Many individuals with SCD have abnormal kidney function and require close monitoring with subtherapeutic or supratherapeutic levels. (See "Sickle cell disease effects on the kidney", section on 'Sickle cell nephropathy' and "Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults", section on 'Special populations'.)

If vancomycin is added, the patient should be admitted to the hospital for observation pending negative cultures. If the cultures are negative, vancomycin should be stopped. If vancomycin is continued (eg, based on culture results), levels should be checked, as individuals with SCD have alterations in kidney function that could influence drug pharmacology. (See "Sickle cell disease effects on the kidney", section on 'Prevention and management (sickle nephropathy)'.)

●Respiratory coverage – Oral erythromycin or azithromycin is added to parenteral ceftriaxone for acute chest syndrome and/or pneumonia.

●Oseltamivir – Oseltamivir may be reasonable during influenza season if rapid testing is positive or not readily available. If used, it is given in addition to empiric parenteral antibiotics.

●COVID-19 therapies – COVID-19 therapies should be given in addition to empiric parenteral antibiotics whenever fever is a symptom since bacterial infections drive mortality in patients with COVID-19 [65].

•Outpatients – The oral antiviral nirmatrelvir and ritonavir (Paxlovid) was approved by the US Food and Drug Administration (FDA) in May 2023 for the treatment of mild-to-moderate COVID-19 in adults who are at high risk for progression to severe COVID-19. (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Nirmatrelvir-ritonavir as preferred therapy'.)

Accumulating data show that patients with SCD are at increased for severe disease progression [26]. Thus, nirmatrelvir and ritonavir should be considered in those ≥18 years with SCD and COVID-19.

•Inpatients – For patients with SCD hospitalized with COVID-19, infectious disease consultation should be considered to advise on the use of other therapies such as remdesivir, dexamethasone (which may have unique risks in SCD) and other emerging treatments [66,67]. (See "COVID-19: Management in hospitalized adults", section on 'COVID-19-specific therapy' and "COVID-19: Management in children".)

•Continuing hydroxyurea – In one analysis, hydroxyurea use appeared to improve respiratory distress in patients with COVID-19, none of whom had SCD [68]. In a study in patients with SCD, hospitalization risk for COVID-19 was decreased by 60 percent for every 1 g/dL increase in hemoglobin on admission [69]. Thus, hydroxyurea should be continued and optimized, provided the white blood cell count is reasonable.

Patients allergic to penicillin or cephalosporins — Drug allergies should be accurately documented in all individuals with SCD, repetitively discussed with the patient, and, if possible, an individualized plan for management of febrile illness should be developed. If a patient is not treated with intravenous ceftriaxone, consideration should be given to admission for continued empiric parenteral antibiotics pending a negative culture. (See 'Criteria for hospital admission' below.)

For individuals who are allergic to penicillin, the cross reactivity between penicillin and cephalosporins is small, and many penicillin-allergic patients tolerate cephalosporins without a problem.

For individuals with a known or suspected cephalosporin allergy, the following options are available:

●Levofloxacin – Levofloxacin has better activity against S. pneumoniae than gatifloxacin and moxifloxacin. For adults, the dose for levofloxacin is 10 mg/kg intravenously once daily (maximum dose 750 mg) if there are no concerns for a central nervous system (CNS) infection. For children 6 months to 5 years, the dose of levofloxacin is 8 to 10 mg/kg intravenously twice daily. For children ≥5 years, the dose of levofloxacin is 10 mg/kg once daily (maximum dose, 750 mg/day). Levofloxacin should not be used in infants <6 months.

●Ciprofloxacin or ofloxacin – These quinolones can be used for suspected Mycoplasma pneumoniae or Chlamydia pneumoniae in a child or adult who is unable to take a macrolide [70].The usual dose of ciprofloxacin in an adult with normal kidney function is 400 mg intravenously every 12 hours. The dose of ciprofloxacin in a child with normal kidney function is 10 mg/kg intravenously every 8 to 12 hours (maximum, 400 mg/dose).

●Meropenem – The dose in an adult is 500 mg intravenously every 6 hours or 1 to 2 grams intravenously every 8 hours; in a child, the dose is 20 mg/kg intravenously every 8 hours or, if a CNS infection is suspected or documented, 40 mg/kg intravenously every 8 hours (maximum single dose 2 g). Vancomycin is also administered if a CNS infection is suspected or documented. (See "Staphylococcus aureus in children: Overview of treatment of invasive infections", section on 'Choice of therapy' and "Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults".)

Hemolysis associated with ceftriaxone — Ceftriaxone has a favorable efficacy profile in individuals with SCD and fever and is one of the preferred initial antibiotics. (See 'Initial antibiotic therapy' above.)

However, acute care providers need to be aware of rare reports of serious intravascular hemolysis temporally associated with ceftriaxone [71-74]. Hemolysis is immune-mediated and may be severe enough to cause life-threatening anemia. Acute presentation includes increasing jaundice and pallor, or abdominal pain mimicking acute splenic sequestration [75]. (See "Drug-induced hemolytic anemia", section on 'Typical presentation/when to suspect drug-induced hemolysis'.)

Early diagnosis and proper treatment are essential to improve patient outcomes.

●Assessment – Review the CBC and determine severity of anemia. Distinguish acute hemolysis (increased lactate dehydrogenase and bilirubin, red serum or urine) from acute splenic sequestration (enlarged, tender spleen without an increase in baseline hemolysis). Individuals with SCD have ongoing hemolysis at baseline and comparison with baseline values is helpful if possible. (See "Drug-induced hemolytic anemia", section on 'Commonly used tests'.)

●Treatment – For an acute hemolytic reaction due to ceftriaxone, the following interventions are appropriate:

•Drug discontinuation – The patient should not ever receive additional ceftriaxone. If needed, an alternate antibiotic should be provided.

•Transfusion – Red blood cell transfusion for severe, symptomatic anemia or a decline of more than 2 g/dL below the individual's baseline. (See "Drug-induced hemolytic anemia", section on 'Indications for transfusions' and "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Stabilization and transfusion for severe anemia'.)

•Supportive care – If the patient is dehydrated or significantly hypovolemic, they should be treated promptly to become euvolemic and then be kept at a net zero fluid balance, with careful assessment of intravenous and oral fluids and urine output. Excessive intravenous fluid in individuals with SCD, resulting in a net positive fluid balance, has been associated with serious adverse clinical outcomes such as acute chest syndrome (ACS) [76-79].

•IVIG – In extreme, life-threatening cases, intravenous immune globulin (IVIG) has been used in addition to other therapies in the intensive care unit, but supporting evidence is limited to case reports [80].

ACUTE MANAGEMENT DECISIONS

Criteria for hospital admission — The decision to admit or send home from the emergency department must balance the risk of life-threatening infection in a potentially immunocompromised individual with the risk that patients, families, or caregivers may avoid seeking care knowing that any fever will automatically lead to hospital admission. The decision cannot be based exclusively on a single temperature measurement or other criteria. The decision applies to any individual with SCD and fever, either documented in the emergency department or reported from a home temperature measurement. (See 'What constitutes a fever?' above.)

Decisions about admission require the judgment of the individual evaluating the patient's clinical status with input from the parents, caregivers, and the primary hematologist or primary care physician when possible. (See 'Input of the primary hematologist' above.)

No set of criteria has been firmly established that accurately predicts which patient with SCD and fever will have invasive bacterial infection requiring hospital admission. Reports of risk factors for invasive bacterial infection were primarily published prior to the use of pneumococcal conjugate vaccine but still guide clinical decision making [18,33-35,81-86].

The table (table 2) and the following discussion summarize a general list of features that would cause us to admit a patient with SCD and fever to the hospital for ongoing care. There may be other indications for admission and/or situations in which an individual with one of these features may reasonably be managed at home.

●Age – There is no consensus regarding an age at which all infants or toddlers with SCD and fever should be admitted. The decision is based on many factors, including the ability of parents/caregivers to manage a sick child at home in whom fever may be the first manifestation of SCD-related complications.

Decisions to admit every infant <6 months, <12 months, or <24 months of age with a fever is based on local care standards, family and caregiver resources, and the changing epidemiology of bacteremia in children with SCD.

•In the early 1980s, bacteremia rates were 3 to 5 percent in children with SCD [18]; the case fatality rate in children <3 years from pneumococcal bacteremia was 24 percent [18].

•With penicillin prophylaxis and appropriate vaccinations, the incidence of life-threatening bacterial infections has decreased dramatically. In a total of 1118 febrile episodes of children with SCD, nine blood cultures (0.8 percent) grew bacteria that may be associated with an adverse outcome [14].

●Clinical findings – Strongly consider admission if one or more of the following are present:

•Any clinical signs or suspicion of serious bacterial infection (meningitis, pneumonia), systemic toxicity, or hemodynamic instability.

•Proven or suspected acute chest syndrome (ACS) or unexplained hypoxia.

•Temperature ≥40°C (≥104°F) [14,81-86].

•Indwelling venous catheter (central line, subcutaneous port, or peripherally inserted central catheter [PICC]) [86].

•Persistent tachycardia, hypotension, and/or signs of hypoperfusion.

•Evidence of dehydration that cannot be corrected by oral intake.

•Any other acute complication of SCD such as severe pain, aplastic crisis, splenic sequestration, or stroke/neurologic event [14].

●Laboratory findings that favor need for admission:

•White blood cell (WBC) count >30,000 or <5000/microL in an individual who is not taking hydroxyurea [81-86].

Both types of WBC abnormalities are associated with increased risk of bacteremia in febrile children with SCD [14]. For an individual taking hydroxyurea, the lower threshold for the WBC count is unknown, but fever and an absolute neutrophil count (ANC) <500/microL, and in most cases an ANC <1000/microL (if ill-appearing) should prompt admission.

•Platelet count <100,000/microL or below the individual's baseline (which may be lower on hydroxyurea or with chronic splenomegaly).

•Hemoglobin <5 g/dL or decreased by 2 g/dL or more from the individual's baseline [14,81].

●Historical, epidemiologic, or social features that may also be considered:

•Immunizations not up to date, particularly for S. pneumoniae, H. influenzae type b, or COVID-19.

•Prior history of sepsis or bacteremia, particularly with S. pneumoniae [33-35].

•Treatment with an empiric parenteral antibiotic other than ceftriaxone that would reduce the duration of coverage.

•Concerns about the caregiver's ability to identify changes in a patient's clinical status, adherence to therapy, communication, or follow-up, or possible inability to return to the emergency department should cultures be positive.

Hospital admission may be safely avoided in selected individuals, which may improve their quality of life and avoid exposure to hospital-acquired infections or other complications of hospitalization such as venous thromboembolism (VTE).

For individuals who are not admitted to the hospital, 24-hour follow-up phone-call contact must be available. There may be a need for repeat dosing of ceftriaxone in the emergency department or a next-day clinic visit, which should be clearly communicated to the patient, family, and/or caregivers. (See 'Discharge directly from the emergency department' below.)

Inpatient management

Inpatient monitoring and antibiotic changes — Once admitted, inpatient management of children and adults with SCD and fever includes the following [63]:

●Hemodynamic monitoring – Monitor blood pressure and heart rate. Provide supportive care as needed.

●Oxygenation – Monitor oxygen saturation by pulse oximetry. Use supplemental oxygen to maintain the oxygen saturation at patient's baseline value, generally above 90 percent. Aggressively wean oxygen as soon as possible to avoid prolonged oxygen saturation above 94 percent, as this may suppress red cell production.

●Antibiotics – Continue antibiotic coverage and adjust antibiotics when culture results are available (narrow or switch spectrum to match the organisms identified).

•Blood cultures negative – If culture results are negative, antibiotics should be discontinued when the patient has been afebrile for 24 to 48 hours even if a need for continued hospitalization remains.

•Blood cultures positive – If culture results are positive, the treatment for bacteremia is based upon antibiotic sensitivity and local standards. Several days of parenteral cephalosporin therapy followed by oral antibiotics may be appropriate therapy for documented S. pneumoniae bacteremia. Blood cultures are usually repeated if an initial blood culture is positive and/or if the person remains febrile. Once the repeated blood culture becomes sterile and/or the patient has been afebrile for 24 to 48 hours, antibiotics can be changed from intravenous to oral, as long as there is no obvious persistent focus of infection. While on oral antibiotics, any recurrent fever is re-evaluated with blood culture and parenteral antibiotics while awaiting repeat culture results.

A rare but potentially life-threatening complication of ceftriaxone is severe hemolysis and hemolytic anemia [71,72]. This requires immediate intervention. (See 'Hemolysis associated with ceftriaxone' above.)

●Additional evaluations – Further evaluation is performed if necessary. As an example, in a patient with persistent fever and epigastric or severe abdominal pain, an abdominal ultrasound, liver function tests, or serum amylase and lipase may be performed to assess if the symptoms are related to an underlying abdominal process such as cholelithiasis, cholecystitis, hepatitis, pancreatitis, or splenic infarction.

●Hydration – Adequate but not excessive hydration is maintained with parenteral fluids, which are generally administered at a maintenance rate initially. Increased fluids may be required if the patient is hypovolemic or if insensible losses are increased (such as with persistent fever). Overhydration should be avoided, especially in children and adults with respiratory symptoms, because excessive fluids may precipitate or exacerbate acute chest syndrome (ACS). Normal saline bolus in euvolemic patients is associated with higher pain scores and should also be avoided [87-89].

●Venous thromboembolism (VTE) prophylaxis – Prophylaxis for VTE is usually appropriate for adults with SCD admitted to the hospital for an acute medical illness that increases their risk, including infection. VTE prophylaxis is not routinely used in individuals <21 years unless there is a separate indication. (See "Overview of the management and prognosis of sickle cell disease", section on 'Thromboembolism prophylaxis'.)

●Specific sites of infection

•Lungs – Treatment for ACS, which is indistinguishable from pneumonia in children and adults with SCD, should include coverage for encapsulated organisms and mycoplasma species (S. pneumoniae, H. influenzae type b, M. pneumoniae, and C. pneumoniae) [90]. Empirically, a combination of a cephalosporin, such as ceftriaxone or cefuroxime, and an oral macrolide may be used. (See "Resistance of Streptococcus pneumoniae to the macrolides, azalides, and lincosamides" and "Resistance of Streptococcus pneumoniae to beta-lactam antibiotics" and "Acute chest syndrome (ACS) in sickle cell disease (adults and children)".)

•Brain and urinary tract – Treatment of meningitis and urinary tract infection is not different than in individuals without SCD. (See "Bacterial meningitis in children older than one month: Treatment and prognosis" and "Urinary tract infections in infants older than one month and children less than two years: Acute management, imaging, and prognosis" and "Hematogenous osteomyelitis in children: Management".)

•Bone – Treatment of osteomyelitis is similar to individuals without SCD. However, children and adults with SCD commonly develop sterile bone infarcts (localized painful areas of bone with swelling and/or erythema) that may mimic osteomyelitis. The diagnosis of osteomyelitis can be confirmed by culture of blood or infected bone. Bone scan may also be used, although it is not able to reliably distinguish infection from infarct. This subject is discussed separately. (See "Acute and chronic bone complications of sickle cell disease", section on 'Osteomyelitis and septic arthritis'.)

Criteria for discharge from inpatient setting — Children and adults with SCD may be discharged when they are afebrile, there is no growth in their blood cultures for at least 24 hours, and there is no other active SCD complication that requires inpatient management [63].

Bacteremia is less likely in children and adults with appropriate immunizations, making a 24-hour period of observation reasonable in most cases with negative cultures, provided other criteria for safe discharge are met. In addition to negative culture results, the individual should be afebrile (or they will return to the emergency department with recurrent fever), clinically stable, taking adequate fluids and oral medications, and should have a home caregiver, good phone contact, and a clear plan for immediate recall and readmission should their clinical status deteriorate or should blood cultures obtained during the admission become positive [63].

At the time of discharge, patients may receive a second dose of ceftriaxone (or other antibiotic if appropriate) for an additional 24 hours of coverage.

Discharge instructions are listed below. (See 'Discharge from the hospital' below and 'Key aspects of follow-up and prevention' below.)

The benchmark of 24 hours is further supported by a study of all positive blood cultures in children with SCD in a single institution [91]. From among those with positive cultures, the average time to a positive blood culture was 17.1 hours in the pathogen group and 29.5 hours in the contaminant group (p<0.0001). For the children with bacteremia, 89 percent of cultures become positive within 24 hours and 96 percent become positive by 48 hours [91].

Outpatient management — Children or adults who do not meet the above criteria for admission (see 'Criteria for hospital admission' above) are treated with an initial dose of a parenteral antibiotic. Many institutions use ceftriaxone, which provides antibiotic coverage for 24 hours. However, individuals with SCD can have severe hemolysis and hemolytic anemia as a complication of ceftriaxone and should be observed for a period of time (at least one hour) before discharge from the emergency department to assess for this complication. (See 'Hemolysis associated with ceftriaxone' above.)

At the end of the observation period, children and adults are discharged to home if they meet ALL of the following criteria:

●Clinically stable.

●Have a home caregiver and a specific plan for follow-up the next day. Depending upon the clinical setting, this may be a telephone assessment for continued fever and general clinical status, or an appointment for a repeat clinical visit with a second dose of ceftriaxone.

●Have a working telephone number recorded in the medical record at which they can be reached to return should a positive culture be reported.

●The patient/caregiver must be able to recognize worsening of the patient's condition and have a reliable means of transportation to return should that occur or if recalled for a positive culture.

●There are no other health problems that require inpatient management.

The safety of outpatient management for many persons with SCD has been demonstrated in the following studies:

●A single institution study reviewed all children and adults with SCD and fever over an 18-year period from 1993 to 2010 [14]. All had blood cultures drawn at the initial encounter and received empiric ceftriaxone before discharge. A working telephone number for contact was required should the culture return positive. Children who had received any antibiotics prior to blood cultures (other than prophylactic penicillin) or who met criteria for admission were excluded. Of 1118 febrile episodes, 466 (42 percent) were managed in the outpatient setting [14]. There were nine episodes of bacteremia (0.8 percent), and three in the outpatient group (0.6 percent). These three children had received ceftriaxone at the initial visit, were not ill-appearing when called back for admission, and recovered uneventfully.

●A randomized controlled trial randomly assigned 86 children (age 6 months to 12 years) with SCD and fever to inpatient or outpatient treatment after emergency department evaluation and one dose of ceftriaxone [82]. Outpatients returned 24 hours later for a second dose of ceftriaxone. Those at high risk for sepsis (defined by temperatures >40°C (>104°F), white cell count (WBC) >30,000/microL or <5000/microL, and the presence of pulmonary infiltrates on chest radiography) were excluded. No patient in either study group developed sepsis, compared with 7 of 86 episodes in high-risk patients who were excluded from randomization and admitted [82].

DISCHARGE INSTRUCTIONS

Discharge directly from the emergency department — Individuals who do not have concerning features that would warrant hospital admission can be discharged directly from the emergency department. (See 'Criteria for hospital admission' above.)

Typically, they will have received one empiric dose of a parenteral antibiotic such as ceftriaxone and will have been given clear instructions for follow-up. (See 'Outpatient management' above.)

Direct communication between the emergency department clinicians and the individual's primary hematologist is critical, and receipt of communication should be assured.

Education and follow-up instructions include:

●The name and dose of the antibiotic they received.

●Instructions that the individual may take antipyretics. If they have recurrent fever during the period of coverage, they do not need to return to the hospital unless their temperature is ≥40°C (≥104°F) (see 'Criteria for hospital admission' above), but they do need to communicate with the covering clinician.

•The minimum amount of fluid that the patient should drink in 24 hours equal to maintenance fluids.

•Instructions for management of any other complications noted, including sickle cell pain.

•Instructions that they are to return to the emergency department after 24 hours for repeat evaluation should their temperature again exceed a predetermined elevated value (see 'What constitutes a fever?' above).

●The appropriate means of follow-up (phone call versus in-person visit), the appropriate individual with whom to follow up, and a back-up plan to follow if that individual cannot be reached, such as return to the emergency department. Whom to call with questions (primary hematologist or primary care physician, not the emergency department) and the phone number of all contacts.

●When to resume prophylactic penicillin, if prescribed prior to emergency department evaluation of fever.

●Reasons to return to the emergency department, including clinical worsening, respiratory distress, excessive sleepiness, pain not responsive to medications, severe headache or stroke symptoms, signs of dehydration, or nausea and vomiting that prevents oral intake.

Discharge from the hospital — At discharge, it is important to do the following (see "Overview of the management and prognosis of sickle cell disease", section on 'Infection prevention'):

●Resume prophylactic penicillin if previously prescribed, or if other antibiotics have been prescribed, instruct the family and caregivers when to resume the penicillin

●Update immunizations, including seasonal influenza vaccine and COVID-19 vaccination

●Review the necessity of returning for medical evaluation for recurrent temperature >101.3°F (38.5°C)

Despite the universal and repeated recommendation that individuals with SCD and a fever of 101.5°F should be re-evaluated, a 2015 study found that even in a leading center, only 55 percent of parents "always" follow this recommendation [92]. The major difficulty is that there are no clear prognostic indicators for deciding which person with SCD and fever will have bacteremia with a potentially fatal outcome. Thus, frequent reminders of the need to return should fever reoccur after ≥24 hours are important.

Key aspects of follow-up and prevention — Prevention of infections is a major goal of routine management in individuals with SCD, especially young children. This includes:

●For young children (typically until five years of age), twice daily prophylactic penicillin. (See "Overview of the management and prognosis of sickle cell disease", section on 'Prophylactic penicillin'.)

●At all ages, ensuring vaccinations, including pneumococcal, seasonal influenza, COVID-19, or similar are current and complete. (See "Overview of the management and prognosis of sickle cell disease", section on 'Immunizations'.)

●At all ages, education about signs and symptoms of serious infections.

●The importance of contact with the primary hematologist.

●Clear information about when to present to the emergency department (temperature cutoff, clinical findings) and whom to contact when seeking emergency department care, so that the contacted clinician can speak with the emergency department staff and provide information about the patient's history and risk factors for specific infections.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sickle cell disease and thalassemias".)

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Sickle cell disease".)

SUMMARY AND RECOMMENDATIONS

●Definitions and risks – Children and adults with sickle cell disease (SCD) are immunocompromised due to lack of splenic function and are at risk of life-threatening infections, particularly with encapsulated organisms. They may have enhanced inflammation, a blunted temperature response, a greater risk for dehydration, and/or other SCD complications. SCD experts use a cutoff of ≥38 to 38.5°C (≥100.4 to 101.3°F) for empiric parenteral antibiotics and possible admission. Input from the primary hematologist is important for appropriate evaluation and treatment. (See 'Key aspects of management' above.)

●Evaluation – The history focuses on symptoms, vaccination status, prior infection history, medications, and psychosocial support. The examination assesses hemodynamic and cardiopulmonary status, oxygenation, presence of a venous catheter, abdomen, spleen, bones, skin, and neurologic status. Vaso-occlusive pain and/or other SCD complications may be present and should be rapidly assessed. (See 'History' above and 'Examination' above and 'Evaluation for associated conditions' above.)

●Laboratory tests – Diagnostic tests include complete blood count (CBC), reticulocyte count, blood culture, urinalysis, SARS-CoV-2 testing during times of high transmission, and influenza swab during flu season. Chest radiograph or lung ultrasound should be obtained for lower respiratory symptoms, abnormal lung examination, or history of acute chest syndrome (ACS). Individuals with diarrhea should have stool culture, those with meningeal signs should have cerebrospinal fluid analysis, and those with signs of severe anemia should have a type and crossmatch. (See 'Diagnostic testing' above.)

●Antibiotics – Empiric parenteral antibiotics are required in all children and adults with SCD and fever; they should be administered within 60 minutes of presentation. For most patients, we suggest ceftriaxone over other antibiotics (Grade 2C). The dose is 50 to 100 mg/kg intravenously (maximum 2 g). Vancomycin may be added for hemodynamic instability, suspected meningitis, or an indwelling central line or port. Alternatives for cephalosporin-allergic individuals include levofloxacin, ciprofloxacin, ofloxacin, or meropenem. Ceftriaxone can rarely cause life-threatening hemolytic anemia. COVID-19-specific therapy should be strongly considered if testing is positive. Hydroxyurea should be optimized and continued if neutrophil counts allow. (See 'Empiric antibiotic therapy' above.)

●Hospital admission – There is no consensus regarding that age at which all infants or toddlers with SCD and fever should be admitted; typically, infants <12 months are more likely to be admitted. Criteria for hospital admission include temperature ≥40°C (≥104°F), any signs of serious illness, indwelling catheter, immunizations not current, history of bacteremia, concerns about social support or adherence, and significant changes in hematologic parameters from baseline; these are summarized in the table (table 2). Individuals who do not meet any criteria can be managed as an outpatient after receiving a dose of empiric parenteral antibiotic (eg, ceftriaxone) with a specific plan for follow-up the next day and immediate recall for documented bacteremia. (See 'Criteria for hospital admission' above.)

●Inpatient – Inpatient management includes initiation of continuous hemodynamic and oxygen saturation monitoring, appropriate supportive care, continuation of empiric antibiotics, venous thromboembolism (VTE) prophylaxis (age dependent), and readjustment of antibiotics when culture results are available. For acute chest syndrome (ACS), an oral macrolide is also recommended. Patients may be discharged when they are afebrile, have no growth from blood cultures for at least 24 hours, and have no other active SCD complication that requires inpatient management. (See 'Inpatient management' above and 'Discharge from the hospital' above.)

●Prevention – Preventive measures to reduce infection following discharge include comprehensive immunizations, prophylactic penicillin (if age-appropriate), and instructions to return for medical evaluation if fever recurs. (See 'Discharge instructions' above and "Overview of the management and prognosis of sickle cell disease", section on 'Infection prevention'.)

ACKNOWLEDGMENTS — UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.

The UpToDate editorial staff also acknowledges extensive contributions of Donald H Mahoney, Jr, MD, to earlier versions of this topic review.